Nephrology 7E 2016 PDF - PDFCOFFEE.COM (2024)

ellis d. avner william e. harmon patrick niaudet norishige yoshikawa francesco emma stuart l. goldstein Editors

Pediatric Nephrology Seventh Edition

OFFICIALLY ENDORSED BY

1 3Reference

Pediatric Nephrology

Ellis D. Avner • William E. Harmon Patrick Niaudet • Norishige Yoshikawa Francesco Emma • Stuart L. Goldstein Editors

Pediatric Nephrology Seventh Edition

With 506 Figures and 310 Tables

Editors Ellis D. Avner Department of Pediatrics Medical College of Wisconsin Children’s Research Institute Children’s Hospital Health System of Wisconsin Milwaukee, WI, USA

William E. Harmon Boston Children’s Hospital Harvard Medical School Boston, MA, USA

Patrick Niaudet Service de Néphrologie Pédiatrique Hôpital Necker-Enfants Malades Université Paris-Descartes Paris, France

Norishige Yoshikawa Department of Pediatrics Wakayama Medical University Wakayama City, Japan

Francesco Emma Division of Nephrology Bambino Gesù Children’s Hospital – IRCCS Rome, Italy

Stuart L. Goldstein Division of Nephrology and Hypertension The Heart Institute Cincinnati Children’s Hospital Medical Center, College of Medicine Cincinnati, OH, USA

ISBN 978-3-662-43595-3 ISBN 978-3-662-43596-0 (eBook) ISBN 978-3-662-43597-7 (print and electronic bundle) DOI 10.1007/978-3-662-43596-0 Library of Congress Control Number: 2015954467 Springer Heidelberg New York Dordrecht London # Springer-Verlag Berlin Heidelberg 2009, 2016 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper Springer-Verlag GmbH Berlin Heidelberg is part of Springer Science+Business Media (www. springer.com)

Preface

Through its past six editions, Pediatric Nephrology has become the standard medical reference for health care professionals treating children with kidney disease. This new edition, published 6 years since the previous version, reflects the tremendous increase in critical information required to translate molecular and cellular pathophysiology into the prevention, diagnosis, and therapy of childhood renal disorders. This text is particularly targeted to pediatricians, pediatric nephrologists, pediatric urologists, and physicians in training. It is also targeted to the increased number of health care professionals comprising the multidisciplinary teams required to provide comprehensive care for children with kidney disease and their families: geneticists, genetic counselors, nurse specialists, dialysis personnel, nutritionists, social workers, and mental health professionals. Finally, this reference is designed to serve the needs of primary care physicians (internists and family practitioners) as well as internist nephrologists who are increasingly involved in the initial evaluation and/or the longitudinal care of children with renal disease under different health care delivery systems evolving throughout the world. To keep pace with the dramatic changes in pediatric renal medicine since the publication of the previous edition, the content of the seventh edition of Pediatric Nephrology has been completely revised, updated, and enlarged. The seventh edition contains 83 chapters in 3 volumes, which are organized into 12 main sections. The text begins with an overview of the basic developmental anatomy, biology, and physiology of the kidney, which provides the basic information necessary to understand the developmental nature of pediatric renal diseases. This is followed by a comprehensive coverage of the evaluation, diagnosis, and therapy of specific childhood kidney diseases, including the extensive use of clinical algorithms. Of special note is a section focused on rapidly evolving research methodologies, which are being translated into new clinical approaches and therapies for many childhood renal diseases. The final sections focus on comprehensive, state-of-the-art reviews of acute and chronic renal failure in childhood. Many chapters of the seventh edition have been completely rewritten by new authors, all recognized as global authorities in their respective areas. The remainder of the text has been totally revised, with junior authors often joining senior authors from the previous edition. The number of contributors has increased by 20 %. In addition to the new section on Global Pediatric Nephrology, which focuses on unique aspects of pediatric nephrology practice v

and the epidemiology of pediatric renal disease in different regions of the world, all of the chapters reflect a global perspective. This has been achieved through a dynamic, evolving relationship between the Editors and the International Pediatric Nephrology Association (IPNA). This has led to the continued endorsement of Pediatric Nephrology as the standard global reference text in the field of childhood kidney disease. We are proud that the IPNA logo adorns the cover of Pediatric Nephrology in recognition of this endorsement. The Editors look forward to this dynamic interaction with IPNA to take advantage of future opportunities that such collaboration may provide in the areas of education and outreach. Other major changes are also evidenced by the new publication of the seventh edition of Pediatric Nephrology as a basic reference handbook in the SpringerReference series. Representing advances in state-of-the-art electronic publishing, there are regularly updated online versions of each chapter of this text at SpringerLink.com. The new publishing format has led to a welcome expansion of the published text to three volumes and the increased utilization of high-resolution, color figures. Further, two new Editors, Professor Francesco Emma of Ospedale Pediatrico Bambino Gesu in Rome, Italy, and Professor Stuart L. Goldstein of the University of Cincinnati, USA, have joined the Editorial Team. The addition of new Editors continues to provide a dynamic mixture of continuity, new ideas, new perspectives, and globalism, which has distinguished each new edition of the text. Professors Emma and Goldstein join the four Editors from the sixth edition: Senior Editor and Emeritus Professor Ellis D. Avner, from the Medical College of Wisconsin, USA, and Professors William E. Harmon M.D. of Harvard University, USA, Patrick Niaudet, from the Hôpital Necker-Enfants Malades in Paris, France; and Norishige Yoshikawa from Wakayama, Japan. The current Editors are internationally recognized leaders in complementary areas of pediatric nephrology and along with the more than 150 contributors reflect the global nature of the text and the subspecialty it serves. The Editors wish to thank a number of individuals whose efforts were critical in the success of this project. The book would never have reached this seventh edition without the dedication of our professional colleagues at Springer, Gabriele Schroder, Sandra Lesny, Gregory Sutorius, and particularly Mr. Andrew Spencer, Senior Editor of Major Reference Works, who served as our “guide for the perplexed” in all aspects of project management. We thank our families, and particularly our wives (Jane, Diane, Claire, Hiro, and Elizabeth) for their support and understanding. In particular, the Senior Editor wishes to recognize his lifetime partner in all endeavors, Jane A. Avner, Ph.D., for her extraordinary editorial assistance. And finally, we thank our mentors, our students, and most importantly, our patients and their families. Without them, our work would lack purpose.

Preface

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Finally, the Editors wish to dedicate this seventh edition of Pediatric Nephrology to three former Editors who passed away in 2014. Professors Martin Barratt, Malcolm A. “Mac” Holiday, and Robert Vernier were extraordinary physicianscientists who served as mentors to a generation of pediatric nephrologists. This text would not exist without their efforts, commitment, and selﬂess contributions. Ellis D. Avner William E. Harmon Patrick Niaudet Norishige Yoshikawa Francesco Emma Stuart L. Goldstein

Contents

Volume 1 Part I

Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Embryonic Development of the Kidney . . . . . . . . . . . . . . . . . Carlton Bates, Jacqueline Ho, and Sunder Sims-Lucas

Development of Glomerular Circulation and Function Alda Tufro and Ashima Gulati

....

Renal Tubular Development . . . . . . . . . . . . . . . . . . . . . . . . . . Michel Baum

Clinical Perinatal Urology . . . . . . . . . . . . . . . . . . . . . . . . . . . . David A. Diamond and Richard S. Lee

Renal Dysplasia/Hypoplasia . . . . . . . . . . . . . . . . . . . . . . . . . . 115 Paul Goodyer and Indra R. Gupta

Developmental Syndromes and Malformations of the Urinary Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 Chanin Limwongse

Part II

Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

179

Physiology of the Developing Kidney: Sodium and Water Homeostasis and Its Disorders . . . . . . . . . . . . . . . . . . . . . . . . 181 Nigel Madden and Howard Trachtman

Physiology of the Developing Kidney: Potassium Homeostasis and Its Disorder . . . . . . . . . . . . . . . . . . . . . . . . . 219 Lisa M. Satlin and Detlef Bockenhauer

Physiology of the Developing Kidney: Acid-Base Homeostasis and Its Disorders . . . . . . . . . . . . . . . . . . . . . . . . 247 Peter D. Yorgin, Elizabeth G. Ingulli, and Robert H. Mak

Bone Developmental Physiology . . . . . . . . . . . . . . . . . . . . . . . 279 MH Lafage-Proust ix

Contents

Physiology of the Developing Kidney: Disorders and Therapy of Calcium and Phosphorous Homeostasis . . . . . . . 291 Amita Sharma, Rajesh V. Thakker, and Harald J€uppner

Nutrition Management in Childhood Kidney Disease: An Integrative and Lifecourse Approach . . . . . . . . . . . . . . . . 341 Lauren Graf, Kimberly Reidy, and Frederick J. Kaskel

Physiology of the Developing Kidney: Fluid and Electrolyte Homeostasis and Therapy of Basic Disorders (Na/H2O/K/Acid Base) . . . . . . . . . . . . . . . . . . . . . . 361 Isa F. Ashoor and Michael J. G. Somers

Part III Translational Research Methods

....................

423

Translational Research Methods: Basics of Renal Molecular Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425 Gian Marco Ghiggeri, Maurizio Bruschi, and Simone Sanna-Cherchi

Translational Research Methods: The Value of Animal Models in Renal Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447 Jordan Kreidberg

Basics of Clinical Investigation . . . . . . . . . . . . . . . . . . . . . . . . 473 Susan L. Furth and Jeffrey J. Fadrowski

Genomic Methods in the Diagnosis and Treatment of Pediatric Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499 Karen Maresso and Ulrich Broeckel

Translational Research Methods: Renal Stem Cells . . . . . . . 525 Kenji Osafune

Translational Research Methods: Tissue Engineering of the Kidney and Urinary Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . 571 Austin G. Hester and Anthony Atala

Part IV Clinical Approach to the Child with Suspected Renal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

593

Clinical Evaluation of the Child with Suspected Renal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595 Mohan A. Shenoy and Nicholas J. A. Webb

Laboratory Investigation of the Child with Suspected Renal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613 George van der Watt, Fierdoz Omar, Anita Brink, and Mignon McCulloch

Contents

Growth and Development of the Child with Renal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637 Bethany Foster

Diagnostic Imaging of the Child with Suspected Renal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667 Jonathan Loewen and Larry A. Greenbaum

Pediatric Renal Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705 Agnes B. Fogo

Part V

Glomerular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

751

Congenital Nephrotic Syndrome . . . . . . . . . . . . . . . . . . . . . . . 753 Hannu Jalanko and Christer Holmberg

Inherited Glomerular Diseases . . . . . . . . . . . . . . . . . . . . . . . . 777 Michelle N. Rheault and Clifford E. Kashtan

Idiopathic Nephrotic Syndrome in Children: Genetic Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805 Olivia Boyer, Kálmán Tory, Eduardo Machuca, and Corinne Antignac

Idiopathic Nephrotic Syndrome in Children: Clinical Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839 Patrick Niaudet and Olivia Boyer

Immune-Mediated Glomerular Injury in Children . . . . . . . . 883 Michio Nagata

Complement-Mediated Glomerular Injury in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927 Zoltán Prohászka, Marina Vivarelli, and George S. Reusz

Acute Postinfectious Glomerulonephritis in Children . . . . . . 959 Bernardo Rodríguez-Iturbe, Behzad Najaﬁan, Alfonso Silva, and Charles E. Alpers

Immunoglobulin A Nephropathies in Children (Includes HSP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 983 Koichi Nakanishi and Norishige Yoshikawa

Membranoproliferative and C3-Mediated GN in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1035 Christoph Licht, Magdalena Riedl, Matthew C. Pickering, and Michael Braun

Membranous Nephropathy in Children . . . . . . . . . . . . . . . . . 1055 Rudolph P. Valentini

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Contents

Volume 2 Part VI

Tubular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1077

Nephronophthisis and Medullary Cystic Kidney Disease in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1079 Friedhelm Hildebrandt

Childhood Polycystic Kidney Disease . . . . . . . . . . . . . . . . . . . 1103 William E. Sweeney Jr., Meral Gunay-Aygun, Ameya Patil, and Ellis D. Avner

Aminoaciduria and Glycosuria in Children . . . . . . . . . . . . . . 1155 Israel Zelikovic

Renal Tubular Disorders of Electrolyte Regulation in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201 Olivier Devuyst, Hendrica Belge, Martin Konrad, Xavier Jeunemaitre, and Maria-Christina Zennaro

Renal Tubular Acidosis in Children . . . . . . . . . . . . . . . . . . . . 1273 Raymond Quigley and Matthias T. F. Wolf

Nephrogenic Diabetes Insipidus in Children . . . . . . . . . . . . . 1307 Nine V. A. M. Knoers and Elena N. Levtchenko

Cystinosis and Its Renal Complications in Children . . . . . . . 1329 William A. Gahl and Galina Nesterova

Pediatric Fanconi Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 1355 Takashi Igarashi

Primary Hyperoaxaluria in Children . . . . . . . . . . . . . . . . . . . 1389 Pierre Cochat, Neville Jamieson, and Cecile Acquaviva-Bourdain

Pediatric Tubulointerstitial Nephritis . . . . . . . . . . . . . . . . . . . 1407 Uri S. Alon

Part VII

Kidney Involvement in Systemic Diseases . . . . . . . . . . . 1429

Renal Involvement in Children with Vasculitis . . . . . . . . . . . 1431 Seza Ozen and Diclehan Orhan

Renal Involvement in Children with Systemic Lupus Erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1449 Patrick Niaudet, Brigitte Bader-Meunier, and Rémi Salomon

Renal Involvement in Children with HUS . . . . . . . . . . . . . . . 1489 Carla M. Nester and Sharon P. Andreoli

Contents

xiii

Sickle Cell Nephropathy in Children . . . . . . . . . . . . . . . . . . . 1523 Connie Piccone and Katherine MacRae Dell

Diabetic Nephropathy in Children . . . . . . . . . . . . . . . . . . . . . 1545 M. Loredana Marcovecchio and Francesco Chiarelli

Renal Manifestations of Metabolic Disorders in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1569 Francesco Emma, William G. van’t Hoff, and Carlo Dionisi Vici

Infectious Diseases and the Kidney in Children . . . . . . . . . . 1609 Jennifer Stevens, Jethro A. Herberg, and Michael Levin

Nephrotoxins and Pediatric Kidney Injury . . . . . . . . . . . . . . 1655 Takashi Sekine

Part VIII

Urinary Tract Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1693

Urinary Tract Infections in Children . . . . . . . . . . . . . . . . . . . 1695 Elisabeth M. Hodson and Jonathan C. Craig

Vesicoureteral Reﬂux and Renal Scarring in Children . . . . . 1715 Tej K. Mattoo, Ranjiv Mathews, and Indra R. Gupta

Pediatric Obstructive Uropathy . . . . . . . . . . . . . . . . . . . . . . . 1749 Bärbel Lange-Sperandio

Pediatric Bladder Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 1779 Etienne Berard

Urolithiasis in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1821 Vidar Edvardsson

Pediatric Renal Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1869 Elizabeth Mullen, Jordan Kreidberg, and Christopher B. Weldon

Volume 3 Part IX

Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1905

Epidemiology of Hypertension in Children . . . . . . . . . . . . . . 1907 Midori Awazu

Pathophysiology of Pediatric Hypertension . . . . . . . . . . . . . . 1951 Ikuyo Yamaguchi and Joseph T. Flynn

Evaluation of Hypertension in Childhood Diseases . . . . . . . . 1997 Eileen D. Brewer and Sarah J. Swartz

xiv

Contents

Management of the Hypertensive Child . . . . . . . . . . . . . . . . . 2023 Demetrius Ellis and Yosuke Miyashita

Part X

Acute Renal Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2099

Pathogenesis of Acute Kidney Injury . . . . . . . . . . . . . . . . . . . 2101 David P. Basile, Rajasree Sreedharan, and Scott K. Van Why

Evaluation and Management of Acute Kidney Injury in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2139 Stuart L. Goldstein and Michael Zappitelli

Part XI

Chronic Renal Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2169

Pathophysiology of Progressive Renal Disease in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2171 H. William Schnaper

Management of Chronic Kidney Disease in Children . . . . . . 2207 Rene G. VanDeVoorde, Craig S. Wong, and Bradley A. Warady

Handling of Drugs in Children with Abnormal Renal Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2267 Guido Filler, Amrit Kirpalani, and Bradley L. Urquhart

Endocrine and Growth Abnormalities in Chronic Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2295 Franz Schaefer

Mineral and Bone Disorders in Children with Chronic Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2349 Katherine Wesseling-Perry and Isidro B. Salusky

Peritoneal Dialysis in Children . . . . . . . . . . . . . . . . . . . . . . . . 2381 Enrico Verrina and Claus Peter Schmitt

Hemodialysis in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2433 Lesley Rees

Immunology of Pediatric Renal Transplantation . . . . . . . . . 2457 Elizabeth G. Ingulli, Stephen I. Alexander, and David M. Briscoe

Pediatric Renal Transplantation . . . . . . . . . . . . . . . . . . . . . . . 2501 Nancy M. Rodig, Khashayar Vakili, and William E. Harmon

Immunosuppression for Pediatric Renal Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2553 Jodi M. Smith, Thomas L. Nemeth, and Ruth A. McDonald

Complications of Pediatric Renal Transplantation . . . . . . . . 2573 Vikas R. Dharnidharka and Carlos E. Araya

Contents

Part XII

IPNA: Global Pediatric Nephrology . . . . . . . . . . . . . . . . . 2605

IPNA: Global Pediatric Nephrology, Introduction and Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2607 Pierre Cochat and Isidro B. Salusky

AFPNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2613 Mignon McCulloch, Hesham Safouh, Amal Bourquia, and Priya Gajjar

ALANEPE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2631 Vera Koch, Nelson Orta, and Ramon Exeni

AsPNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2639 Hui-Kim Yap, Man-Chun Chiu, Arvind Bagga, and Hesham Safouh

Pediatric Nephrology in North America Victoria F. Norwood and Maury Pinsk

ANZPNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2673 Deborah Lewis

ESPN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2681 Rosanna Coppo

JSPN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2687 Kazumoto Iijima

. . . . . . . . . . . . . . . . 2665

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2697

Contributors

Cecile Acquaviva-Bourdain Centre de référence des maladies rénales rares Néphrogones, Hôpital Femme Mère Enfant, Hospices Civils de Lyon & Université de Lyon, Lyon, France Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Lyon, France Stephen I. Alexander Discipline of Paediatrics and Child Health, The University of Sydney, Sydney, New South Wales, Australia Division of Nephrology, Children’s Hospital at Westmead, Sydney, New South Wales, Australia Uri S. Alon Section of Pediatric Nephrology, The Children’s Mercy Hospital and Clinics, University of Missouri at Kansas City, School of Medicine, Kansas City, MO, USA Charles E. Alpers Department of Pathology, University of Washington, Seattle, WA, USA Sharon P. Andreoli Division of Nephrology, Indianapolis, IN, USA Corinne Antignac Laboratory of Hereditary Kidney Diseases, Inserm UMR 1163, Paris, France Paris Descartes, Sorbonne Paris Cité University, Imagine Institute, Paris, France Department of Genetics, MARHEA reference center, Necker – Enfants Malades Hospital, Paris, France Carlos E. Araya University of Central Florida and Nemours Children’s Hospital, Orlando, FL, USA Isa F. Ashoor Division of Nephrology, Children’s Hospital, New Orleans, LA, USA Anthony Atala School of Medicine, Department of Urology, Wake Forest Institute for Regenerative Medicine, Wake Forest University, Winston Salem, NC, USA

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xviii

Contributors

Ellis D. Avner Department of Pediatrics, Medical College of Wisconsin, Children’s Research Institute, Children’s Hospital Health System of Wisconsin, Milwaukee, WI, USA Midori Awazu Department of Pediatrics, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan Brigitte Bader-Meunier Service d’Immunologie et Pédiatrique, Hôpital Necker-Enfants Malades, Paris, France

Rhumatologie

Arvind Bagga Division of Nephrology, All India Institute of Medical Sciences, New Delhi, India David P. Basile Indiana University School of Medicine, Indianapolis, IN, USA Carlton Bates Department of Pediatrics, Division of Pediatric Nephrology, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Michel Baum Departments of Pediatrics and Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA Hendrica Belge Zurich Institute for Human Physiology, University of Zurich, Institute of Physiology, Zurich Center for Integrative Human Physiology (ZIHP), Z€ urich, Switzerland Etienne Berard Pediatric Nephrology Unit, Universitary Hospital of Nice (France), Nice, France Detlef Bockenhauer Great Ormond Street Hospital, Institute of Child Health, University College London, London, UK Amal Bourquia Paediatric Nephology, Red Cross War Memorial Children’s Hospital, Dept. of Paediatric Medicine, University of Cape Town, Western Cape, South Africa Olivia Boyer Service de Néphrologie Pédiatrique, Hôpital Necker-Enfants Malades, Université Paris-Descartes, Paris, France Michael Braun Renal Section, Department of Pediatrics, Texas Children’s Hospital, Balyor College of Medicine, Houston, TX, USA Eileen D. Brewer Department of Pediatrics Renal Section, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA Anita Brink Department of Pediatrics and Child Health (Nuclear Medicine), University of Cape Town, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa David M. Briscoe Department of Pediatrics, Harvard Medical School, Boston, MA, USA Division of Nephrology, Transplant Research Program, Boston Children’s Hospital, Boston, MA, USA

Contributors

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Ulrich Broeckel Department of Pediatrics, Medical College of Wisconsin and Children’s Hospital of Wisconsin, Milwaukee, WI, USA Maurizio Bruschi Laboratory of Physiopathology of Uremia, Division of Nephrology, Dialysis and Transplantation, Istituto Giannina Gaslini, Genoa, Italy Francesco Chiarelli University of Chieti, Chieti, Italy Man-Chun Chiu Department of Pediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong University, Kowloon, Hong Kong Pierre Cochat Centre de référence des maladies rénales rares Néphrogones, Hôpital Femme Mère Enfant, Hospices Civils de Lyon & Université de Lyon, Lyon, France IBCP-UMR 5305 CNRS, Université Claude-Bernard Lyon 1, Lyon, France Rosanna Coppo Nephrology Dialysis and Transplantation Unit, Azienda Ospedaliera-Universitaria Città della Salute e della Scienza di Torino, Regina Margherita Children’s University Hospital, Turin, Italy Jonathan C. Craig Centre for Kidney Research, The Children’s Hospital at Westmead, Westmead, Sydney, NSW, Australia Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia Katherine MacRae Dell Center for Pediatric Nephrology, Department of Pediatrics, Cleveland Clinic Children’s and Case Western Reserve University, Cleveland, OH, USA Olivier Devuyst Zurich Institute for Human Physiology, University of Zurich, Institute of Physiology, Zurich Center for Integrative Human Physiology (ZIHP), Z€urich, Switzerland Vikas R. Dharnidharka Pediatric Nephrology, Washington University School of Medicine and St. Louis Children’s Hospital, St. Louis, MO, USA David A. Diamond Department of Urology, Harvard Medical School, Boston Children’s Hospital, Boston, MA, USA Carlo Dionisi Vici Division of Metabolic Diseases, Bambino Gesù Children’s Hospital – IRCCS, Rome, Italy Vidar Edvardsson Landspitali – The National University Hospital of Iceland, Reykjavik, Iceland and Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland Demetrius Ellis Department of Pediatrics, Division of Pediatric Nephrology, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Francesco Emma Division of Nephrology, Bambino Gesù Children’s Hospital – IRCCS, Rome, Italy

Ramon Exeni Department of Nephrology, Children’s Hospital “San Justo”, Buenos Aires, Argentina Jeffrey J. Fadrowski Department of Pediatrics, John Hopkins University School of Medicine, Baltimore, MD, USA Guido Filler Departments of Pediatrics, Medicine, and Pathology Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada Children’s Hospital of Western Ontario, Children’s Health Research Institute (CHRI), London, ON, Canada Joseph T. Flynn Division of Nephrology, Seattle Children’s Hospital; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA Agnes B. Fogo Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA Bethany Foster The Research Institute of the McGill University Health Centre, Montreal, QC, Canada Susan L. Furth Departments of Pediatrics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA William A. Gahl Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA Priya Gajjar Paediatric Nephology, Red Cross War Memorial Children’s Hospital, Dept. of Paediatric Medicine, University of Cape Town, Western Cape, South Africa Gian Marco Ghiggeri Laboratory of Physiopathology of Uremia, Division of Nephrology, Dialysis and Transplantation, Istituto Giannina Gaslini, Genoa, Italy Stuart L. Goldstein Division of Nephrology and Hypertension, The Heart Institute, Cincinnati Children’s Hospital Medical Center, College of Medicine, Cincinnati, OH, USA Paul Goodyer Division of Pediatric Nephrology, Montreal Children’s Hospital, McGill University, Montreal, QC, Canada Lauren Graf Children’s Hospital at Monteﬁore, Albert Einstein College of Medicine, Bronx, NY, USA Larry A. Greenbaum Department of Pediatric Radiology, Emory University School of Medicine, Atlanta, GA, USA Ashima Gulati Department of Pediatrics, Nephrology Section, Yale School of Medicine, New Haven, CT, USA

Contributors

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Meral Gunay-Aygun Medical Genetics Branch, The Intramural Program of the Ofﬁce of Rare Diseases, National Human Genome Research Institute, Bethesda, MD, USA Department of Pediatrics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA Indra R. Gupta Department of Pediatrics and Department of Human Genetics, Division of Pediatric Nephrology, Montreal Children’s Hospital, McGill University, Montréal, QC, Canada William E. Harmon Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Jethro A. Herberg Imperial College London, London, UK Austin G. Hester School of Medicine, Department of Urology, Wake Forest Institute for Regenerative Medicine, Wake Forest University, Winston Salem, NC, USA Friedhelm Hildebrandt Harvard Medical School, Boston, MA, USA Jacqueline Ho Department of Pediatrics, Division of Pediatric Nephrology, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Elisabeth M. Hodson Centre for Kidney Research, The Children’s Hospital at Westmead, Westmead, Sydney, NSW, Australia Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia Christer Holmberg Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland Takashi Igarashi National Center for Child Health and Development (NCCHD), Tokyo, Japan Kazumoto Iijima Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan Elizabeth G. Ingulli Department of Pediatrics, University of California, San Diego, CA, USA Division of Nephrology, Rady Children’s Hospital San Diego, San Diego, CA, USA Kidney Transplant Program, Rady Children’s Hospital, San Diego, CA, USA Hannu Jalanko Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland Neville Jamieson Department of Surgery, Addenbrookes Hospital, Cambridge University Teaching Hospitals, Cambridge, UK Xavier Jeunemaitre Department of Molecular Genetics, Hôpital Européen George Pompidou, Paris, France

xxii

Harald J€ uppner Departments of Medicine and Pediatrics, Endocrine Unit and Pediatric Nephrology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Clifford E. Kashtan Department of Pediatrics, Division of Pediatric Nephrology, University of Minnesota Masonic Children’s Hospital, Minneapolis, MN, USA Frederick J. Kaskel Division of Pediatric Nephrology, Children’s Hospital at Monteﬁore, Albert Einstein College of Medicine, Bronx, NY, USA Amrit Kirpalani Departments of Pediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada Nine V. A. M. Knoers Departments of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands Vera Koch Instituto da Criança- Pediatric Nephrology Unit, Department of Pediatrics, University of Sao Paulo Medical School, Sao Paulo, Brazil Martin Konrad Department of General Pediatrics, Pediatric Nephrology, University Hospital, M€unster, Germany Jordan Kreidberg Children’s Hospital Boston, Boston, MA, USA MH Lafage-Proust INSERM U 1059, Université de Lyon, Saint-Etienne, France Bärbel Lange-Sperandio Dr. v. Hauner Children’s Hospital, Department of Pediatric Nephrology, LMU, Munich, Germany Richard S. Lee Department of Urology, Harvard Medical School, Boston Children’s Hospital, Boston, MA, USA Michael Levin Department of Medicine, Imperial College London, London, UK Elena N. Levtchenko Department of Pediatric Nephrology, Department of Growth and Regeneration, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium Deborah Lewis Sydney, NSW, Australia Christoph Licht Division of Nephrology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada Research Institute, Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada Department of Paediatrics, University of Toronto, Toronto, ON, Canada Chanin Limwongse Department of Medicine, Division of Medical Genetics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkoknoi, Bangkok, Thailand Jonathan Loewen Department of Pediatric Radiology, Emory University School of Medicine, Atlanta, GA, USA

Contributors

xxiii

Eduardo Machuca Department of Nephrology, Medical School, Pontiﬁcia Universidad Católica de Chile, Santiago, Chile Nigel Madden NYU Langone Medical Center and NYU School of Medicine, New York, NY, USA Robert H. Mak Pediatric Nephrology, University of California, San Diego, CA, USA Pediatric Nephrology Division, Rady Children’s Hospital, San Diego, CA, USA M. Loredana Marcovecchio University of Chieti, Chieti, Italy Karen Maresso Section of Genomic Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA Ranjiv Mathews The Nevada School of Medicine, The Johns Hopkins School of Medicine, Las Vegas, NV, USA Tej K. Mattoo Pediatric Nephrology and Hypertension, Wayne State University School of Medicine, Children’s Hospital of Michigan, Detroit, MI, USA Mignon McCulloch Department of Paediatric Intensive Care/Nephrology, University of Cape Town, Red Cross War Memorial Children’s Hospital, Cape Town, Western Cape, South Africa Ruth A. McDonald Division of Nephrology, Seattle Children’s, University of Washington, Seattle, WA, USA Yosuke Miyashita Department of Pediatrics, Division of Pediatric Nephrology, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Elizabeth Mullen Hematology Oncology, Dana-Farber/Boston Children’s Blood Disorders and Cancer Center, Boston, MA, USA Michio Nagata Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan Behzad Najaﬁan Department of Pathology, University of Washington, Seattle, WA, USA Koichi Nakanishi Department of Pediatrics, Wakayama Medical University, Wakayama City, Japan Thomas L. Nemeth Department of Pharmacy, Seattle Children’s, University of Washington, Seattle, WA, USA Carla M. Nester Stead Family Department of Pediatrics, Department of Internal Medicine, Divisions of Nephrology, University of Iowa Children’s Hospital, Carver College of Medicine, Iowa City, IA, USA Galina Nesterova Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

xxiv

Patrick Niaudet Service de Néphrologie Pédiatrique, Hôpital NeckerEnfants Malades, Université Paris-Descartes, Paris, France Victoria F. Norwood University of Virginia, Charlottesville, VA, USA Fierdoz Omar Chemical Pathology, University of Cape Town and National Health Laboratory Service, Red Cross Children’s Hospital and Groote Schuur Hospital, Cape Town, South Africa Diclehan Orhan Department of Pediatric Pathology, Hacettepe University, Sihhiye, Ankara, Turkey Nelson Orta Service of Pediatric Nephrology, Children’s Hospital “Jorge Lizarraga”, University of Carabobo, Valencia, Venezuela Kenji Osafune Center for iPS Cell Research and Application (CiRA), Kyoto University, Sakyo-ku, Kyoto, Japan Seza Ozen Department of Pediatrics, Faculty of Medicine, Hacettepe University, Sihhiye, Ankara, Turkey Ameya Patil Department of Pediatrics, Medical College of Wisconsin, Children’s Research Institute, Children’s Hospital Health System of Wisconsin, Milwaukee, WI, USA Connie Piccone Rainbow Babies and Children’s Hospital, Cleveland, OH, USA Matthew C. Pickering Centre for Complement and Inﬂammation Research, Imperial College, London, UK Maury Pinsk University of Alberta, Edmonton, AB, Canada Zoltán Prohászka 3rd Department of Medicine, Faculty of Medicine, Semmelweis University, Budapest, Hungary Raymond Quigley Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA Lesley Rees Department of Nephrology, Great Ormond Street Hospital for Children NHS Trust, London, UK Kimberly Reidy Division of Pediatric Nephrology, Children’s Hospital at Monteﬁore, Albert Einstein College of Medicine, Bronx, NY, USA George S. Reusz 1st Department of Pediatrics, Faculty of Medicine, Semmelweis University, Budapest, Hungary Michelle N. Rheault Department of Pediatrics, Division of Pediatric Nephrology, University of Minnesota Masonic Children’s Hospital, Minneapolis, MN, USA Magdalena Riedl Research Institute, Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada Department of Paediatrics, Innsbruck Medical University, Innsbruck, Tyrol, Austria

Contributors

xxv

Nancy M. Rodig Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Bernardo Rodríguez-Iturbe Nephrology Service, Hospital Universitario, Maracaibo, Estado Zulia, Venezuela Hesham Safouh Faculty of Medicine, Center for Pediatric Nephrology and Transplantation (CPNT), Cairo University, Orman, Giza, Egypt Rémi Salomon Service de Néphrologie Pédiatrique, Hôpital Necker-Enfants Malades, Université Paris-Descartes, Paris, France Isidro B. Salusky Division of Pediatric Nephrology, Clinical Translational Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Simone Sanna-Cherchi Division of Nephrology, Columbia University, College of Physicians and Surgeons, New York, NY, USA Lisa M. Satlin Department of Pediatrics, Division of Pediatric Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Franz Schaefer Division of Pediatric Nephrology, University Children’s Hospital, Heidelberg, Germany Claus Peter Schmitt Centre for Pediatric and Adolescent Medicine, Heidelberg, Germany H. William Schnaper Division of Kidney Diseases, Ann and Robert H. Lurie Children’s Hospital of Chicago, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Takashi Sekine Department of Pediatrics, Toho University Faculty of Medicine, Meguro-ku, Tokyo, Japan Amita Sharma Department of Pediatrics, Pediatric Nephrology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Mohan A. Shenoy Department of Pediatric Nephrology, Royal Manchester Children’s Hospital, Manchester, UK Alfonso Silva Nephrology Service, Hospital Universitario, Maracaibo, Estado Zulia, Venezuela Sunder Sims-Lucas Department of Pediatrics, Division of Pediatric Nephrology, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Jodi M. Smith Division of Nephrology, Seattle Children’s, University of Washington, Seattle, WA, USA Michael J. G. Somers Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Rajasree Sreedharan Medical College of Wisconsin, Milwaukee, WI, USA Jennifer Stevens University Hospital Wales, Cardiff, S. Wales, UK

xxvi

Sarah J. Swartz Department of Pediatrics Renal Section, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA William E. Sweeney Jr. Department of Pediatrics, Medical College of Wisconsin, Children’s Research Institute, Children’s Hospital Health System of Wisconsin, Milwaukee, WI, USA Rajesh V. Thakker Radcliffe Department of Medicine, Academic Endocrine Unit, University of Oxford, OCDEM (Oxford Centre for Diabetes, Endocrinology and Metabolism), The Churchill Hospital Headington, Oxford, UK Kálmán Tory Laboratory of Hereditary Kidney Diseases, Inserm UMR 1163, Paris, France Department of Pediatrics, Semmelweis University, Budapest, Hungary Howard Trachtman NYU Langone Medical Center and NYU School of Medicine, New York, NY, USA Alda Tufro Department of Pediatrics, Nephrology Section, Yale School of Medicine, New Haven, CT, USA Bradley L. Urquhart Departments of Pediatrics, Department of Medicine, Physiology and Pharmacology, Western University, London, ON, Canada Children’s Health Research Institute (CHRI), London, ON, Canada Khashayar Vakili Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Rudolph P. Valentini Pediatric Nephrology, Children’s Hospital of Michigan, Detroit, MI, USA Wayne State University School of Medicine, Detroit, MI, USA George van der Watt Chemical Pathology, University of Cape Town and National Health Laboratory Service, Red Cross Children’s Hospital and Groote Schuur Hospital, Cape Town, South Africa Scott K. Van Why Medical College of Wisconsin, Milwaukee, WI, USA William G. van’t Hoff Great Ormond Street Hospital, London, UK Rene G. VanDeVoorde Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Enrico Verrina Nephrology, Dialysis and Transplantation Unit, Giannina Gaslini Childrens Hospital, Genoa, Italy Marina Vivarelli Division of Nephrology and Dialysis, Children’s Hospital Bambino Gesù-IRCCS, Rome, Italy Bradley A. Warady Pediatric Nephrology, Children’s Mercy Hospital, Kansas City, MO, USA Nicholas J. A. Webb Department of Pediatric Nephrology, Royal Manchester Children’s Hospital, Manchester, UK

Contributors

xxvii

Christopher B. Weldon Department of Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA Katherine Wesseling-Perry Division of Pediatric Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Matthias T. F. Wolf Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA Craig S. Wong Pediatric Nephrology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA Ikuyo Yamaguchi Division of Pediatric Nephrology, University of Texas School of Medicine at San Antonio, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA Hui-Kim Yap Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore Peter D. Yorgin Pediatric Nephrology, University of California, San Diego, CA, USA Pediatric Nephrology Division, Rady Children’s Hospital, San Diego, CA, USA Norishige Yoshikawa Department of Pediatrics, Wakayama Medical University, Wakayama City, Japan Michael Zappitelli Pediatrics, Division of Nephrology, Montreal Children’s Hospital, McGill University Health Center, Montreal, QC, Canada Israel Zelikovic Department of Physiology and Biophysics, Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel Division of Pediatric Nephrology, Rambam Medical Center, Haifa, Israel Maria-Christina Zennaro Inserm U970, Paris Cardiovascular Research Center, Paris, France

Part I Development

Embryonic Development of the Kidney Carlton Bates, Jacqueline Ho, and Sunder Sims-Lucas

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Studying the Kidney and Urinary Tract Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Development of the Metanephros . . . . . . . . . . . . . . . . . .

Nephron Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Speciﬁcation of Nephron Progenitors/Cap Mesenchyme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nephron Induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nephron Segmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Glomerulogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular Control of Podocyte Terminal Differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular Control of Glomerular Capillary Tuft Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8 10 11 12 12 13 13

Renal Stroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Vascular Development of the Kidney . . . . . . . . . . . . . . Angiogenesis Versus Vasculogenesis . . . . . . . . . . . . . . . . . Origins of the Peritubular Capillary Endothelia . . . . . . Molecular Control of Renal Vascular Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Collecting System Development . . . . . . . . . . . . . . . . . . . . Ureteric Bud Induction and Outgrowth . . . . . . . . . . . . . . . Renal Branching Morphogenesis . . . . . . . . . . . . . . . . . . . . . Patterning of the Medullary and Cortical Collecting Ducts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lower Urinary Tract Development . . . . . . . . . . . . . . . . Anatomic and Functional Development . . . . . . . . . . . . . . Molecular Control of Ureter and Bladder Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bladder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ureter–Bladder Anastomosis . . . . . . . . . . . . . . . . . . . . . . . . .

14 15 16 17 17 17 19 20 21 21 23 25 25

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

C. Bates (*) • J. Ho • S. Sims-Lucas Department of Pediatrics, Division of Pediatric Nephrology, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA e-mail: [emailprotected]; [emailprotected]; [emailprotected] # Springer-Verlag Berlin Heidelberg 2016 E.D. Avner et al. (eds.), Pediatric Nephrology, DOI 10.1007/978-3-662-43596-0_1

Introduction The mammalian kidney functions as a key regulator of water balance, acid–base homeostasis, maintenance of electrolytes, and waste excretion. The performance of these activities depends on the development of specific cell types in a precise temporal and spatial pattern, to produce a sufficient number of nephrons. Over the past several decades, considerable advances have been made in understanding the molecular basis for this developmental program. Defects in this program result in congenital anomalies of the kidney and urinary tract, which are the leading causes of chronic kidney disease and renal failure in children. These developmental disorders range from renal malformations, such as renal aplasia (absence of the kidney), dysplasia (failure of normal renal differentiation), and hypoplasia (smaller kidneys), to urinary tract abnormalities such as vesicoureteral reflux and duplicated collecting systems. This chapter describes the embryology of the kidney and urinary tract, as a means to understand the developmental origins of these disorders. Human kidney development starts in the fifth week of gestation, and new nephrons are formed until approximately 32–34 weeks gestation [1–3]. Remarkably, nephron endowment is quite variable ranging from 200,000 to 1.8 million nephrons per person [4]. While the human kidney continues to grow after 34 weeks gestation, this occurs due to the growth and maturation of existing nephrons, rather than the formation of new nephrons. The mature mammalian kidney cannot compensate for nephron loss due to renal injury by the de novo generation of nephrons [2, 5]. Therefore, the number of nephrons present at birth in an individual is an important determinant of long-term kidney health. Therefore, reduced nephron number is associated with hypertension and chronic kidney disease [6, 7]. Critical determinants of nephron endowment are structural development and three-dimensional nephron patterning. The formation of kidneys in utero involves the coordinated regulation of critical developmental processes: differentiation,

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morphogenesis, and regulation of cell number. Differentiation is the process by which precursor cells or tissues mature into more specialized cells. During kidney development, renal mesenchymal cells have the potential to differentiate into nephron epithelia or stromal cells and interstitial fibroblasts. Morphogenesis describes the process whereby cells and tissues acquire threedimensional patterns. This is particularly important in the kidney, as the three-dimensional relationship between the nephrons, the vasculature, and the collecting system is critical for normal kidney structural function. Finally, the regulation of cell number at different stages of development is crucial. Such regulation maintains a balance between cellular proliferation and programmed cell death or apoptosis. All of these processes are integrated tightly and regulated both spatially and temporally in normal renal development. The molecular control of these developmental processes has been the subject of several recent comprehensive reviews [8–14]. Genetic, epigenetic, and environmental factors all regulate differentiation, morphogenesis, and cell number within the developing kidney. Mutational analyses in animal models have provided significant insights into the genetic control of renal development. Genes critical for kidney development in animal models include transcription factors that act as master regulators of other genes, growth factors that signal to other cells, and adhesion molecules that regulate how cells interact with each other and with the extracellular matrix. Increasingly, analyses of humans with congenital renal malformations (such as renal aplasia or duplex kidneys) have identified gene mutations originally described in animal models [15]. Recent studies have also implicated epigenetic mechanisms (defined as heritable changes in gene activity that are not caused by changes in DNA sequence) in regulating nephron formation. Two major classes of epigenetic molecules that appear to regulate renal development include chromatin remodeling proteins and regulatory RNAs such as miRNAs [16–22]. Finally, environmental influences that may interact with genetic and

Embryonic Development of the Kidney

epigenetic factors are also important in determining nephron number and patterning. For example, vitamin A deﬁciency leads to decreased nephron number in rodents and has been implicated in decreased renal size in humans [23, 24].

Studying the Kidney and Urinary Tract Development The methods for studying the molecular and genetic control of kidney development have continued to evolve over the past several decades. Visualization of tissue morphology and expression of individual genes and proteins in the developing kidney have traditionally been performed on tissue sections by general staining (e.g., hematoxylin and eosin), detecting messenger RNA (mRNA) via in situ hybridization or protein via immunohistochemistry (Fig. 1a–c). The advent of high-throughput technologies to detect gene expression with microarrays and more recently by high-throughput RNA sequencing has resulted in the ability to assay the transcriptome of the developing kidney and/or different kidney tissue compartments in an unbiased fashion. These techniques have led to large public databases that describe the gene expression of the developing kidney, including the GenitoUrinary Development Molecular Anatomy Project (URL: www. gudmap.org) and Eurexpress (URL: www. eurexpress.org) [25–27]. A classical technique to analyze kidney development is to culture rodent embryonic kidneys in vitro as explants. Studies using these methods were the first to show that reciprocal interactions between the metanephric mesenchyme and the ureteric bud are critical to induce the formation of new nephrons and ureteric branching (Fig. 1d) [28]. Moreover, kidney explants still allow one to modulate the expression and function of specific genes and proteins using reagents such as antisense oligonucleotides or blocking antibodies [29, 30]. While these experiments have been illuminating, the growth of embryonic kidney explants differs from kidney development in vivo in several key ways: lack of blood flow,

growth limitations from diffusion of the culture media across the air–media interface, and distortions in the three-dimensional kidney architecture as explants flatten in culture. Recently, several methods to generate more physiological and quantifiable three-dimensional reconstructions of developing kidneys and urinary tracts have been developed. One method utilizes exhaustive serial sectioning through developing kidneys, histological staining, projection of each serial image onto a monitor to identify each tissue lineage, and rendering of the serial images into a three-dimensional image (Fig. 1e) [31, 32]. This technique allows for the quantification of both developing nephron structures and the branching ureteric tree. Another method uses optical projection tomography to image through the full thickness of a developing kidney that has been whole mount stained for a specific tissue and also permits the quantification of these elements [33]. Physical, chemical, and genetic strategies can be used to manipulate developing kidneys in vivo. For example, ureteric obstruction in utero in sheep and monkeys results in hydronephrotic kidneys with renal dysplasia [34, 35]. In addition, dietary manipulations including high doses of vitamin A or dietary protein restriction result in kidney and urinary tract defects [36, 37]. Transgenic approaches have also been used to drive gene expression in specific spatiotemporal patterns, usually in the mouse. In these experiments, a transgenic construct consisting of a tissue-specific promoter and the gene of interest is randomly inserted into the genome, leading to expression of that gene in a tissue-specific pattern. The limitations of this approach include: (1) that the random insertion can result in unintended changes in gene expression (due to other nearby promoters/enhancers near the site of integration), (2) that the insertion of the transgene into the genome may lead to loss of function of an endogenous gene, and that (3) epigenetic factors may silence the construct. The increased utilization of bacterial artificial chromosome (BAC) constructs, which contain more of endogenous promoter elements than are found in traditional plasmid constructs, has led to more faithful and reliable transgene expression.

Fig. 1 Experimental methods utilized to study kidney development. (a) Hematoxylin and eosin (H&E)-stained tissue section of a control postnatal day 0 mouse kidney. The ureteric bud is outlined in yellow, and the arrow points to the cap metanephric mesenchyme. (b) In situ hybridization in a control mouse embryonic day 16.5 tissue section for the transcription factor, Wt1, which stains the metanephric mesenchyme and developing glomeruli. (c) Immunoﬂuorescent staining in a control embryonic day 14.5 mouse tissue section for the transcription factor, Wt1 (red), and lotus tetragonolobus lectin (LTL, green), which stains the proximal tubule. (d) Embryonic culture of a transgenic embryonic day 11.5 HoxB7GFP mouse kidney,

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demonstrating branching ureteric structures (green) after 5 days of growth. (e) 3D reconstruction of an embryonic day 13.5 mouse kidney with the ureteric epithelium depicted in pink and developing nephron types including renal vesicles (blue), comma-shaped bodies (red), S-shaped bodies (purple), and glomeruli (green) (Reproduced with kind permission from Springer Science +Business Media: Sims-Lucas S. Kidney Development: Methods and Protocols, Methods in Molecular Biology, vol. 886, 2012, pp 81, Figure 3F) (f) H&E-stained tissue section of a postnatal day 0 mouse kidney lacking microRNAs in the ureteric lineage using a conditional knockout approach (HoxB7Cre; Dicerﬂx/ﬂx)

Embryonic Development of the Kidney

As opposed to transgenic approaches, homologous recombination is the method whereby a gene is “knocked-out of” or “knocked-into” the mouse genome. Using these methods, a gene of interest is deleted so that it becomes nonfunctional, or a gene (such as a green fluorescent reporter) is added to the genome at a specific locus. A limitation to traditional knockout techniques is that global loss of function of the gene may result in extrarenal effects (such as early embryonic lethality), which can impact or severely limit the study of the gene’s function in the kidney. Given these limitations, it has become more common to perform conditional gene targeting (e.g., with the Cre–loxP system) (Fig. 1f) and/or inducible gene targeting (e.g., with tamoxifen), allowing for kidney- and/or urinary tract-specific gene deletion (using a kidney zebrafish specific Cre-) and/or at a particular time (driving induction of gene targeting with a drug). While most investigators using genetically modified animals utilize mice, a growing number of scientists study kidney development in other model systems, such as avians, zebrafish, and Xenopus. These simple systems are obviously limited by their inability to recapitulate the complex regulation of development previously described in three-dimensional mammalian kidney formation. However, their simplicity has advantages in isolating possible molecular pathways involved in specific renal developmental processes. These systems produce larger number of embryos in a shorter period of time than in mammals. Many of these models, such as zebrafish and Xenopus, have only a one-dimensional pronephric tubule as a kidney. However, many of the genes which pattern such simple structures have important roles in mammalian metanephric kidney development. Increasingly, investigators using have utilized more sophisticated techniques such as transgenic fish to examine the roles of genes or drugs in modifying nephron progenitor populations [38]. Finally, the advent of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPRassociated protein (Cas) techniques should eventually allow relatively quick and easy genetic modifications of any animal model desired [39].

Development of the Metanephros The mesoderm forms as one of the three embryonic germ layers during gastrulation. The mammalian kidney develops from the intermediate mesoderm, lying between the somites and lateral plate mesoderm, on the posterior abdominal wall of the developing embryo. In mammals, three pairs of embryonic kidneys develop from the intermediate mesoderm: the pronephros, the mesonephros, and the metanephros (Fig. 2). At their maximal development, the pronephros and mesonephros extend from the cervical to the lumbar levels of the developing embryo. The pronephric and mesonephric nephrons are induced to differentiate by signals from the adjacent pronephric/mesonephric ducts, paired epithelial tubules running in a longitudinal course along the embryo on either side of the midline. The mesonephric duct (also known as the Wolfﬁan duct) continues to grow caudally in the embryos to eventually fuse with the cloaca, which eventually gives rise to the bladder. The pronephros is not functional in mammals, but is the functional kidney in larval ﬁsh [40] and frogs [41]. The mesonephros becomes the mature kidney in these lower species and is functional in mammals during embryogenesis. Ultimately, the pronephros and mesonephros largely degenerate in mammals. Portions of the mesonephros and mesonephric duct persist in mammals as the rete testis, efferent ducts, epididymis, vas deferens, seminal vesicle, and prostate in males [42]. In mammalian females, remnants of the mesonephric tubules persist as the epoophroron and paroophoron. The mature mammalian kidney, the metanephros, is derived from two tissues, the ureteric bud and metanephric mesenchyme (see a recent review in Ref. [13]). Starting at approximately embryonic day 10.5 in the mouse and the 5th week of gestation in humans, reciprocal inductive signals cause the ureteric bud to grow out from the caudal portion of the mesonephric duct and the metanephric mesenchyme to condense around the ureteric bud to form nephron progenitors. The ureteric bud ultimately gives rise to the collecting system, including the collecting ducts, renal calyces, renal pelvis, and ureters [2, 43]. In turn, the nephrogenic metanephric mesenchyme

Fig. 2 Schematic overview of kidney development. Mammalian kidney development begins with the formation of the nephric duct, which is divided into three segments: pronephros, mesonephros, and metanephros. The pronephros degenerates in mammals, whereas the mesonephros forms the male reproductive organs (rete testis, efferent ducts, epididymis, vas deferens, seminal vesicles, and prostate). The metanephros becomes the mature mammalian kidney and is derived from inductive interactions between the metanephric mesenchyme and the ureteric bud (Reproduced with kind permission from Springer Science +Business Media: Moritz K, et al. Factors Inﬂuencing Mammalian Kidney Development: Implications for Health in Adult Life, Morphological Development of the Kidney, Advances in Anatomy and Cell Biology, volume 196, 2008, pp 9–16, ﬁgure number 1)

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limbs of the loops of Henle, and the distal convoluted tubule [2, 43]. Just after the condensation of nephrogenic mesenchyme around the ureteric bud, stromal metanephric mesenchyme (or renal stroma) develops adjacent to the nephrogenic mesenchyme. The renal stroma develops into perivascular cells, vascular smooth muscle, ﬁbroblasts, mesangial cells, renin-producing cells, and even some peritubular endothelial cells (see below). The transcription factor, Odd-skipped related 1 (Osr1), is one of the several key molecules necessary to specify portions of the posterior intermediate mesoderm to become the mesonephric duct, ureteric bud, and metanephric mesenchyme (nephrogenic and stromal) [44]. Osr1-expressing cells in the intermediate mesoderm have been shown to give rise to most of the cellular components of the metanephric kidney, including the nephron, vascular cells, interstitial cells, and the mesonephric duct (including its derivatives, viz., the ureteric bud/collecting system) [45]. Other molecules critical for speciﬁcation and development of the mesonephric duct include the transcription factors Paired box 2 (Pax2) [46], Pax8 [47], Lim homeobox 1 (Lhx1) [48], Gata binding protein 3 (Gata3) [49], and the receptor tyrosine kinase, Ret [50]. Many key signaling pathways have been shown to drive reciprocal interactions between the ureteric epithelium, the renal mesenchymal lineages, and the renal vasculature. Ureteric bud outgrowth depends on inductive signals from nephron progenitors [51–53], stromal cells [54–58], and angioblasts [59, 60], as well as from itself [61]. The nephrogenic mesenchyme relies in part on signaling from the ureteric bud and renal stroma for self-renewal and for initiation of nephron formation [8, 11, 62–64]. Subsequent nephrogenesis (i.e., patterning and differentiation of nephron epithelia) is highly dependent on factors from both ureteric epithelial and stromal cells [57, 65, 66].

Nephron Formation differentiates into the epithelial cells that comprise the mature nephron, including the parietal cells and podocytes of the glomerulus, the proximal convoluted tubule, the ascending and descending

The metanephric mesenchyme gives rise to nephrogenic mesenchyme or nephron progenitors, which self-renew and have the capacity to

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form the multiple epithelial cell types of the nephron. Much research is geared toward understanding this progenitor cell population, which is critical for determining nephron endowment and thus long-term kidney health. Anatomically, there are several steps that take place in nephron formation. After the ureteric bud has penetrated the metanephric mesenchyme, nephron progenitors condense around the ﬁrst ureteric ampulla, forming “cap mesenchyme.” As the ureteric bud continues to branch and elongate, the nephrogenic mesenchyme continues to form new caps surrounding each ureteric tip. After the initial few ureteric branches, the earliest cap mesenchymal cells receive spatiotemporal cues to begin the differentiation process to form epithelialized renal vesicles [67]. Subsequent growth and differentiation of the renal vesicle results in formation of the comma-shaped body, which then lengthens to form the S-shaped body. The lower limb of the S-shaped body begins to differentiate into glomerular podocytes. During this time, endothelial cells migrate into the cleft of the lower limb of the S-shaped body and will ultimately form the glomerular capillary loops [68, 69]. Simultaneously, nascent mesangial cells, derived from renal stroma (see below), also migrate into this cleft. Thus, the lower limb of the S-shaped body forms the immature glomerulus.

Concurrently, the middle and upper limbs of the S-shaped body elongate and differentiate into nephron tubules including proximal tubules, loops of Henle (including descending and ascending limbs), and distal convoluted tubules. The terminal ends of the distal convoluted tubules eventually connect to ureteric epithelia, which ultimately form the collecting system (collecting ducts, renal pelvis, and ureters) (Fig. 3). Nephrogenesis repeats in a radial fashion with the ﬁrst nephrons forming in the juxtamedullary regions and last in the peripheral cortex, until the full complement of nephrons is reached. During prenatal and/or postnatal life, each nephron increases in size and complexity as it matures. Starting in the ﬁrst month of life, maturing proximal tubules transition from a columnar to cuboidal epithelium, develop microvilli, and increase their tubular dimensions [70, 71]. While the earliest limbs of the Henle loop are located in the renal cortex, subsequent maturation and elongation of these limbs in utero results in the loops pushing through the corticomedullary boundary in term infants [72–74]. Postnatal maturation results in the Henle loops eventually reaching the inner renal medulla in the mature kidney. Thus, the urinary concentrating capacity of newborn infants is limited by a reduced medullary tonicity gradient, due to the relatively shorter

Fig. 3 H&E-stained sections showing the four stages of nephron formation in mice. (a) Image of a renal vesicle, the ﬁrst stage of nephron formation. (b) Image of a commashaped body that has differentiated from a vesicle. (c) Image of an S-shaped body, the third stage of nephron formation. (d) Image of an immature glomerulus that

differentiated from the lower limb of the S-shaped body (Reproduced with kind permission from Springer Science +Business Media: Sims-Lucas S. Analysis of 3D Branching Pattern: Hematoxylin and Eosin Method, Methods in Molecular Biology, volume 886, pp 73–86, 2012, Figure 3, panels A–D)

loops of Henle. Finally, as the distal convoluted tubule matures, a portion of the cells are found in close proximity to the future vascular pole of the developing glomerulus, where they develop into the macula densa [72].

Specification of Nephron Progenitors/ Cap Mesenchyme Differentiation of the intermediate mesoderm and metanephric mesenchyme into nephron progenitors and their derivatives is genetically defined by the sequential upregulation of several transcription factors, cell adhesion molecules, and growth factors. The intermediate mesoderm and early metanephric mesenchyme express the transcription factors Sal-like 1 (Sall1) [75], Sine oculis homeobox homolog 1 (Six1) [76], Eyes absent homolog 1 (Eya1) [77, 78], and the secreted peptide growth factor, Glial-derived neurotrophic factor (Gdnf) [79]. Induction of cap mesenchyme/nephron progenitors by the ureteric bud tips is marked by expression of transcription factors such as Wilms tumor 1 (Wt1) [80]; Cbp/p300interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 1 (Cited1) [81]; and Sine oculis homeobox homolog 2 (Six2) [82], as well as the transmembrane molecules cadherin-11 [83] and α8 integrin [84]. The earliest epithelial derivative of the cap mesenchyme, the renal vesicle, is marked by the transcription factors Pax2 [85] and Lhx1 [86]. The use of tissue-specific gene knockouts generally via conditional transgenic techniques has revealed the importance of several transcription factors (including many mentioned above) in the specification of the cap mesenchyme. Conditional homozygous deletion of Eya1 [78], Six1 [76], Pax2 [87, 88], Wt1 [80], Sall1 [75], Six2 [82], or Lhx1 [86, 89] leads to bilateral renal aplasia or severe renal dysgenesis from defects in cap mesenchyme specification and/or differentiation; these mesenchymal defects are often accompanied by ureteric induction and/or branching abnormalities due in large part to loss of GDNF signaling from the metanephric mesenchyme. Pax2 mutant mice generate a metanephric

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mesenchyme that is unable to differentiate into nephrons and fail to form the mesonephric duct, which is required for ureteric bud induction [88]. In Lhx1 [86, 89] and Sall1 [75] mutants, the metanephric mesenchyme does induce ureteric bud formation, but it fails to elongate and branch, and the mesenchyme is once again unable to differentiate into nephrons. In Wt1 mutants, a defective metanephric mesenchyme is formed, but rapidly undergoes apoptosis [80]. Six2, a specific marker of nephron progenitors, is required for the maintenance of progenitor cells, but not for nephron differentiation; deletion of Six2 in mice results in the formation of ectopic nephron tubules and the rapid depletion of nephron progenitor cells [82]. Similarly, the p53–E3 ubiquitin ligase, murine double minute 2 (Mdm2), appears critical for the maintenance of nephron progenitor cells [91]. Recent studies have identified factors that govern the delicate balance of self-renewal and differentiation of nephron progenitors, including WNT genes. Studies from the mid-1990s showed that lithium chloride, a potent inducer of Wnt signaling, was able to drive tubulogenesis in isolated rodent metanephric mesenchyme cultures [92–94]. More recently Wnt9b, secreted from ureteric bud cells, was shown to be required for the differentiation of nephron progenitor cells. Genetic deletion of Wnt9b resulted in a failure of nephron progenitors to undergo the mesenchymal to epithelial transition that is required to form the renal vesicle [95]. A subsequent study revealed that Wnt9b, along with signals from the renal stroma (see below), plays an essential role in mediating the decision of nephron progenitors to self-renew or differentiate [64, 96]. Another major signaling pathway that has been shown to mediate nephron progenitor survival is the fibroblast growth factor (FGF) signaling pathway. FGF ligands are secreted peptides that bind and signal through their receptor tyrosine kinases, FGF receptors (FGFRs). Isolated nephrogenic zone cell culture studies revealed that addition of FGF1, 2, 9, and 20 ligands drives the expression of nephron progenitor markers and progenitor proliferation [97]. More recently, in vivo mouse studies showed that Fgf9 and Fgf20 are critical for

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maintaining nephron progenitor survival, proliferation, and competence to respond to inductive signals; furthermore, FGF20 mutations in humans were shown to be associated with severe renal dysplasia [98]. Other work in mice has identified that the Fgfrs critical for metanephric mesenchyme development are Fgfr1 and Fgfr2. Conditional deletion of Fgfr1 and Fgfr2 in the metanephric mesenchyme leads to severe renal dysgenesis [99–101]. Several studies have shown that a balance between cell survival and apoptosis is necessary for normal nephron progenitor function. Classic in vitro studies using isolated metanephric mesenchyme have shown that nephron progenitors undergo massive apoptosis when cultured without an inducer [102]. Coculture with isolated ureteric buds or heterologous inducers, such as embryonic spinal cords, dampens apoptosis and drives progenitor survival [43, 52]. Other studies have identified several factors that when added to metanephric mesenchyme or nephrogenic zone cell cultures drive progenitor survival, including transforming growth factor-β2 (TGF-β2), TGFα, leukemia inhibitory factor (LIF), epidermal growth factor (EGF), FGF2, and bone morphogenetic protein 7 (BMP7) [62, 103–105]. Whether some or all of these factors act as endogenous nephron progenitor inducers remains to be determined. Counterbalancing cell survival, apoptosis is required for normal nephron progenitor function. Moreover, suppression of apoptosis via pharmaceutical or genetic means leads to kidney malformations including abnormal ureteric branching and defective nephrogenesis [106, 107]. Relative “overabundance” of nephron progenitors also leads to epithelial and/or stromal cell defects [108, 109]. Recent studies have revealed the importance of epigenetic mechanisms that regulate nephron progenitor specification, survival, and potential for differentiation. Histone deacetylases (HDACs) are enzymes that remove acetyl groups from histones, which then modulate (usually stimulate) gene transcription. Recent work has revealed that Class I HDACs are highly expressed in nephron progenitors and are required for the proper expression of several key developmental genes

including Osr1, Eya1, Pax2, Wt1, and Wnt9b (among others) [16]. MicroRNAs (miRNAs) are small noncoding RNAs that bind to specific mRNA targets to block translation and promote mRNA degradation. Conditional targeting of dicer, an enzyme required for the processing of all miRNAs, in mouse nephron progenitors, led to a loss of the progenitors due to excessive apoptosis, likely from upregulation of the proapoptotic protein, Bim [22]. A more recent study revealed that conditional deletion of a specific miRNA cluster, the miR-17~92 complex, in nephron progenitors led to decreases in progenitor proliferation, fewer numbers of nephrons, proteinuria, and podocyte damage. Moreover, this report was the first to identify a specific miRNA cluster essential for kidney development [110].

Nephron Induction The initial differentiation step of nephron progenitors is to undergo a mesenchymal to epithelial transition to form the renal vesicle. In vitro experiments utilizing isolated rodent metanephric mesenchymal rudiments (similar to and including some of the survival studies noted above) have identiﬁed exogenous factors that stimulate nephron progenitors to undergo tubulo-epithelial differentiation [52]. Some of these growth factors can act alone or in concert with others and include FGF2 [111], LIF [63, 105, 112], TGFβ2 [105, 113], growth/differentiation factor-11 (GDF-11) [105, 114], and WNT1/4 [115, 116]. Sequestration of Wnt ligands in intact rodent kidney explants by addition of secreted frizzled-related proteins (sFrps) leads to decreases in mesenchyme-derived tubulogenesis [117]. More recent mouse genetic experiments have identiﬁed at least some of the critical endogenous pathways and growth factors necessary for the induction of the mesenchymal to epithelial transition. For example, global deletion of Wnt4, normally expressed in renal vesicles, did not perturb cap mesenchyme formation; however, the mutant nephron progenitors were completely unable to form renal vesicles [95]. Conditional deletion of Fgf8 in the metanephric mesenchyme leads to a block of nephrogenesis beyond the renal

vesicle stage. Fgf8 likely normally acts with Wnt4 to drive Lhx1 expression [118, 119]. Interestingly, global deletion of Fgfr-like 1, a membrane-bound Fgf receptor that lacks an intracellular tyrosine kinase domain, also leads to a block in nephrogenesis similar to Fgf8 conditional mutants [120].

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glomeruli and proximal tubules [127]. In vivo, conditional deletion of Notch2 or Rbpsuh in mouse metanephric mesenchyme leads to an absence of proximal tubules and glomerular epithelium [128]. Finally, ectopic Notch expression in nephron progenitor cells results in the premature differentiation of the progenitors into proximal nephron epithelia [130].

Nephron Segmentation Glomerulogenesis Establishment of a proper proximal–distal axis is critical for normal nephron segmentation. Negative reciprocal interactions between Wt1 and Pax2 at early stages of nephron development appear vital to proximal–distal axis patterning [121–123]. In the S-shaped body, Wt1 is localized to the lower limb and inhibits Pax2 expression, which together drives cells toward podocyte fates [124]. Transgenic mice with overexpression of Pax2 throughout the embryo including developing nephrons develop glomerular defects and renal cystic dysplasia [125]. In contrast Pax2 is expressed in the upper limb of the S-shaped body and represses Wt1 expression, stimulating these cells to become proximal and distal tubular nephron segments [118, 126]. Two other transcription factors critical for proximal–distal axis patterning of the nephron include Lhx1 and Brain speciﬁc homeobox 1 (Brn1), both of which are expressed at the renal vesicle stage. Conditional deletion of Lhx1 throughout the metanephric mesenchyme blocks nephrogenesis at the renal vesicle stage and also leads to a loss of Brn1 expression [86]. Conditional targeting of Brn1 in the metanephric mesenchyme does not block proximal nephrogenesis; however, the loop of Henle fails to form, and distal convoluted tubules fail to terminally differentiate [73]. These results suggest that Lhx1 acts earlier in nephron patterning than Brn1, which is a critical distal nephron patterning. Notch receptor signaling, mediated largely by Recombining binding protein suppressor of hairless (Rbpsuh), appears critical for proximal nephron patterning [127–129]. Use of a Notch inhibitor in mouse metanephric kidney explants led to a loss of proximal cell fates, including

Glomerulogenesis is initiated when the commashaped body differentiates into the S-shaped body [2, 131]. During this time, immature podocytes along the lower limb are highly proliferative and have a columnar shape with apical cell attachments and a single-layer basement membrane [131]. Concurrently, endothelial and mesangial cell progenitors are recruited into the lower cleft of the S-shaped body, which will become the vascular pole [132]. While mesangial cells originate from the renal stroma (see below), the developmental origin of the glomerular endothelium is still unclear. Transplantation of avascular rodent embryonic kidney rudiments under neonatal kidney capsule led to the formation of endothelial precursors or angioblasts originating from the graft metanephric mesenchyme [132–134]. However, engraftment of embryonic rat kidney rudiments onto avian chorioallantoic membrane led to vascular ingrowth of avian vessels into the rat glomeruli [135]. As will be expanded on in the Vascular Development section below, it is likely that both processes/sources contribute to the formation of glomerular capillaries. As the S-shaped body matures, the lower cleft transforms into a cup shape conﬁguration. At this time the podocytes lose their proliferative ability [136] and differentiate, forming foot processes and slit diaphragms, specialized intracellular junctions critical for proper glomerular ﬁltration [137, 138]. Concurrently, the composition of the glomerular basement membrane changes from laminin-1 to laminin-11 and from α -1 and α -2 type IV collagen chains to α -3, α -4, and α -5 type IV collagen chains [139]. Several mouse knockout mice models have shown how

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failure in these transitions leads to structural and functional glomerular basement membrane defects [140–142]. At this stage of development, the nascent mesangial cells act as a scaffold for the formation of the glomerular capillary loops and ultimately form the supportive core for the entire glomerulus via the deposition of extracellular matrix [143, 144]. Developing glomerular endothelial cells branch extensively during this time and begin differentiating into fenestrated endothelia [2] (see Vascular section below). By 32–34 weeks gestation, glomerulogenesis/ nephrogenesis ceases in humans, whereas it persists in mice and rats for 7–10 days following full gestation [2]. In newborn humans, the superﬁcial glomeruli are the most immature and are smaller than the deeper juxtamedullary glomeruli [71]. While no new glomeruli are formed after birth, they continue to grow and mature postnatally, reaching their adult size at approximately three and a half years of age [71].

Molecular Control of Podocyte Terminal Differentiation Transcription factors and epigenetic factors, including microRNAs, have been shown to be critical for podocyte differentiation. Examples of essential transcription factors include Wt1, podocyte expressed 1 (Pod1), Lim homeobox 1b (Lmx1b), and Mafb. Several studies utilizing murine genetic knockout models of Wt1 have demonstrated its critical roles in mediating podocyte differentiation [145–148]. In humans, WT1 mutations can lead to diffuse mesangial sclerosis, characterized by podocyte differentiation defects resulting in varied glomerular lesions and proteinuria, and can occur as an isolated disease or in association with Denys–Drash or Frasier syndromes [149–152]. Deletion of Pod1, expressed in stromal cells, leads to nonautonomous podocyte defects at the capillary loop stage in mice [153]. Genetic deletion of Lmx1b or Mafb leads to podocyte differentiation defects past the capillary loop stage [154, 155]. Furthermore, mutations in the LMX1b gene in humans lead to nail–patella syndrome, which is often associated

with glomerular basement membrane thickening and proteinuria that can progress to chronic kidney disease [156, 157]. Three studies recently showed the importance of microRNAs in maintaining differentiated podocytes in the mouse. Targeted ablation of dicer in murine podocytes, resulting in a loss of all miRNAs, led to podocyte injury, severe proteinuria, and tubular damage starting 2 weeks after birth [20, 158, 159].

Molecular Control of Glomerular Capillary Tuft Development There are several signaling cascades that have been implicated in the homing and maturation of the endothelial and mesangial precursors to form the glomerular capillary tuft. Vascular endothelial growth factor (VEGF), which is secreted from the podocytes at the S-shaped body stage, promotes recruitment of endothelial precursors to the vascular cleft [160, 161]. Angiopoietin-1 and -2, growth factors expressed by podocytes and mesangial cells, respectively, are also critical for normal glomerular capillary development [162]. Mesangial cell recruitment into the cleft is largely mediated by the secretion of plateletderived growth factor (PDGF)-B by endothelial cells, which binds PDGF receptor-β (PDGFRβ) on the mesangial cell progenitors [163]. Mice that lack either Pdgfβ or Pdgfrβ fail to form glomerular capillary tufts demonstrating the importance of mesangial cell recruitment [164, 165]. Finally, Notch2 and its ligand Jagged1 are critical for glomerular endothelial and mesangial cell development. Notch2 hypomorphic mice and Notch2/ Jagged1 compound heterozygous mice develop glomerular aneurysms and possess no mesangial cells [166].

Renal Stroma The renal stroma, like the nephrogenic mesenchyme, is derived from Osr1-positive intermediate mesoderm and the metanephric mesenchyme [167, 168]. A hallmark of the initial renal stroma is the expression of the transcription factor,

Foxd1, which is seen as early as E11.5 in the mouse. The renal stroma is initially located at the periphery of the kidney and interdigitates between the developing nephron units and ureteric tips. One function of the early renal stroma is to support framework for the developing vessels, nephron progenitors, and ureteric epithelia. As embryonic kidney development progresses, stromal cells are present in both the peripheral renal cortex and the medulla surrounding developing collecting ducts. At this time, the cortical stroma expresses Foxd1, Aldehyde dehydrogenase 1 family, member A2 (Raldh2), Retinoic acid receptor α (Rarα), and Rarβ2, while the medullary stroma expresses Fgf7, Pod1, and Bmp4. Many of these stromally expressed genes have been shown to be critical for nephrogenesis and ureteric branching morphogenesis by virtue of mouse knockout studies [54, 55, 57, 58, 153, 169]. At birth, many of the developmental stromal cells have undergone apoptosis and are replaced by nephron segments such as loops of Henle [170]. Many stromal derivatives do survive giving rise to ﬁbroblasts, lymphocyte-like cells, glomerular mesangial cells, renin-expressing cells, vascular smooth muscle cells, pericytes, and a subpopulation of peritubular endothelial cells [168, 170, 171]. As noted, signaling from the renal stroma is critical for ureteric morphogenesis. Three genes/ pathways expressed within the stroma, retinoic acid, Foxd1, and Pod1, modulate ureteric branching by regulating expression of Ret, a receptor tyrosine kinase expressed in ureteric tips and required for ureteric development (see below). Vitamin A is converted to its active form, retinoic acid, by the enzyme Raldh2 in the renal stroma. Moreover, blockade of retinoic acid signaling in mice, by deletion of Raldh2 or by combined deletion of the retinoic acid receptors, Rarα and Rarβ2, leads to hypoplastic kidneys with a reduction in the number of ureteric branches; the ureteric branching defects are linked to the downregulation of Ret expression in mutant embryos, which in the case of the retinoic acid receptor mutants can be rescued by forced re-expression of Ret in the ureteric tissues [55, 56, 172]. Foxd1 (expressed in cortical stroma

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and the renal capsule) or Pod1 (found in medullary stroma) appears to appropriately restrict Ret expression to ureteric tips; genetic deletion of either gene leads to mis-expression of Ret throughout the entire ureteric tree and subsequent ureteric branching defects [54, 57, 153, 173]. Cross talk from the stroma is also critical for nephron development. Mouse genetic studies show that Foxd1 and Pod1 are necessary for normal nephron patterning (in addition to ureteric morphogenesis) [54, 153]. Loss of Foxd1 in mice leads to premature differentiation of stromal cells, which inhibits Bmp7-mediated nephron progenitor differentiation [174]. Two recent studies have shown how complete ablation of renal cortical stroma with diphtheria toxin leads to abnormally thickened nephron progenitor caps and a decreased ability of progenitors to differentiate [64, 175]. Mechanistically, it appears that loss of the protocadherin Fat4 in the stroma perturbs the activity of the transcription factors, Yap and Taz, which in turn disrupts Wnt9b signaling and nephron differentiation [64]. Thus, in addition to providing a “framework” for the rest of the developing kidney, the renal stroma actively signals to other renal lineages and differentiates into cells that populate the mature kidney.

Vascular Development of the Kidney The adult kidney receives approximately 25 % of the cardiac output. Furthermore, the adult kidney has a high complex vascular network with different functions and therefore different specialized endothelia depending on location [176]. Speciﬁcally, three major types of endothelial cells are present within the kidney, including fenestrated (in glomerular capillaries), fenestrated with diaphragms (in peritubular capillaries and ascending vasa recta), and continuous capillaries (in descending vasa recta) (Fig. 4). Not surprisingly, these various endothelial cell types have heterogeneous expression proﬁles and often appear to have different developmental origins [21, 177, 178].

Embryonic Development of the Kidney

Fig. 4 Electron microscopy demonstrating the varied renal endothelium. (a, e) Glomerular capillaries contain fenestrated endothelium without diaphragms (e, arrows) and share a basement membrane (*) with podocyte foot processes (large arrowhead) that are separated by slit diaphragms (small arrowhead). (b, f, g) Peritubular capillaries have fenestrated endothelial cells that are covered with diaphragms (f, g, arrows) and have a thick basement membrane (*) separating them from the tubular cells. (c, h, i) Ascending vasa recta (AVR) also have fenestrated

endothelium with diaphragms (c, h, i, arrow). (d, h, i) Descending vasa recta (DVR) possess endothelium that is non-fenestrated, thick, and continuous (d, h, i). RBC red blood cell, EC endothelial cell. Panels (a–d) scanning electron micrographs. Panels (e–i) transmission electron micrographs (Reproduced with kind permission from Springer Science+Business Media: Stolz DB and SimsLucas S. Unwrapping the origins and roles of the renal endothelium, Pediatr Nephrol. 2015;30(6):865–72, Figure 2)

Angiogenesis Versus Vasculogenesis

progenitors (marked by Flk1/Vegfr2) form primitive vascular networks, particularly within the renal stroma, that subsequently join with and are pruned by the angiogenic vessels [182]. The vasculogenic endothelial cell progenitors within the kidney appear to arise from the Osr1-expressing intermediate mesoderm, as is the case with the rest of the metanephric kidney [45]. Finally, speciﬁcation of the endothelium (whether angiogenic or vasculogenic in origin), including arterial, venous, capillary, or lymphatic fates, is driven by growth factor signaling pathways and

Blood vessels can form by angiogenesis, in which new vessels sprout from existing vessels, or by vasculogenesis, in which de novo vessels form from endothelial progenitors (Fig. 5). Extensive linage tracing experiments and transplantation studies have shown that both of likely occur in renal vascular formation [176, 179–181]. The early renal artery and efferent arterioles appear to be primary sites from which new angiogenic vessels sprout within the developing kidney. Simultaneously, renal endothelial

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Fig. 5 Schematic diagram of vascular formation in the developing mouse kidney. Top panels. Angiogenic vessels (red) grow out from the major branches of the renal artery and track with the branching ureteric epithelium (orange). Middle panels. Vasculogenic vessels form from progenitor cells (yellow, middle panel) within the metanephric mesenchyme (blue) and form a primitive vascular plexus (yellow, right panel). Bottom panels. Schematic

diagrams depicting how a combination of angiogenesis and vasculogenesis likely leads to vessel formation in the kidney. E10.5–12.5 = embryonic days 10.5–12.5 (Reproduced with kind permission from Springer Science +Business Media: Stolz DB and Sims-Lucas S. Unwrapping the origins and roles of the renal endothelium, Pediatr Nephrol. 2015;30(6):865–72, Figure 1)

transcription factors, including Vegf, Ephrin, Notch, and Sox [183].

peritubular capillaries has been less well deﬁned. Recent studies, however, have found that peritubular capillaries arise from a combination of resident endothelial progenitors as well as invading angiogenic vessels [182, 184, 185]. One intriguing study found that Foxd1-positive renal cortical stroma cells give rise to a subset of the peritubular endothelia but not the glomerular endothelia [184].

Origins of the Peritubular Capillary Endothelia While the formation of glomerular capillaries has been extensively studied (see above), the origin of

Embryonic Development of the Kidney

Molecular Control of Renal Vascular Development A key signaling pathway mediating renal vascular development is the VEGF pathway. VEGF ligands are expressed early in the metanephric mesenchyme and later in the developing glomerular podocytes, distal tubules, and collecting ducts and at low levels in the proximal tubules [68, 69]. Developing endothelial cells, including those that arise from existing vessels and those forming de novo, express VEGF receptors; thus, VEGF signaling appears to drive both angiogenesis and vasculogenesis within the kidney. Interestingly, Vegfr2 is present on the apical surface of ureteric epithelium, which likely accounts for the stimulatory role of Vegf on ureteric growth [132, 186]. Hypoxia-inducible factors (HIFs), a family of transcriptions factors, are likely master regulators of angiogenesis and vasculogenesis within the developing kidney [187]. These molecules are activated during periods of low oxygenation, as occurs during embryogenesis, and are downregulated postnatally. The HIF genes are largely located in the nephrogenic zone, including podocytes, developing collecting ducts, and developing endothelial cells [187, 188]. HIF proteins induce expression of VEGF ligands, Vegfr1, and Vegfr2 during kidney development by directly binding to hypoxia-responsive elements on those genes [189–192]. Angiopoietin (Ang) growth factors that bind to Tie receptors also appear to have critical roles in renal vascular development and are at least in part regulated by HIF and VEGF signaling [193, 194]. Ang1, which is expressed in the metanephric mesenchyme, maturing nephron tubules, and podocytes, signals through Tie2, which is expressed on endothelial cells [195]. Conditional deletion of Ang1 or Tie2 in mice leads to glomerular capillary defects including endothelial cells that do not attach to the basement membrane [196, 197]. Ang2, expressed in vascular smooth muscle cells and pericytes, binds to Tie1 that is expressed by endothelial cells. Genetic deletion of Ang2 leads to upregulation of Tie2 signaling and significant defects in renal peritubular capillaries [198].

The Notch signaling pathway appears to regulate renal angiogenic vessel outgrowth [199]. Notch receptors induce sprouting by stimulating the expression of Vegfr2 in vascular tip cells. Simultaneously Notch inhibits Vegfr2 signaling in adjacent vascular stalk cells, causing them to remain dormant. Thus Notch regulates the pattern of branching in angiogenic vessels.

Collecting System Development Ureteric bud formation begins in the 5th week of gestation in humans and at embryonic day 10.5 in mice. As noted previously, signals from the metanephric mesenchyme cause the ureteric bud to form from the mesonephric duct and then invade the mesenchyme. Overall, collecting duct system development includes (i) ureteric bud outgrowth, (ii) branching of the ureteric bud, and (iii) patterning of the collecting duct system, all of which is discussed in more detail below.

Ureteric Bud Induction and Outgrowth Failure of ureteric bud outgrowth results in renal aplasia, which can occur unilaterally or bilaterally [200]. The GDNF–RET signaling pathway is crucial for bud outgrowth. The receptor tyrosine kinase RET and its coreceptor GFRα1 are expressed in the mesonephric duct, the initial ureteric bud, and later in the branching ureteric tips, while its ligand, GDNF, is present in the metanephric mesenchyme (Fig. 6) [201–203]. Targeted deletion of Gdnf, Ret, or Gfrα1 in mice generally results in bilateral renal aplasia due to a lack of ureteric bud outgrowth [202, 204–209]. Heterozygous mutations of RET have also been identiﬁed in humans with bilateral renal aplasia, and a rare RET polymorphism has been reported in individuals with nonsyndromic vesicoureteral reﬂux [210, 211]. Moreover, the renal aplastic phenotype is not fully penetrant in a subset of Gdnf / or Ret/ mutant mice [202, 204], suggesting that other molecular pathways play a role in ureteric bud outgrowth. Some examples of other pathways include signaling through integrins such as

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Fig. 6 Schematic diagram of the molecular control of ureteric bud induction. GDNF is secreted from the metanephric mesenchyme and binds to its receptor, Ret (and its coreceptor GFRα1) on the mesonephric duct, to induce ureteric bud formation. Slit2/Robo2 and FoxC1 inhibit the domain of GDNF expression and thus limit ureteric

bud induction to a single site from the mesonephric duct. Sprouty1 (in the mesonephric duct) and Bmp4 (in tailbudderived mesenchyme around the mesonephric duct) repress GDRF–Ret signaling and thus restrict ureteric bud induction to its proper site

α8 integrin [84] and enzymes involved in proteoglycan synthesis such as heparan sulfate 2-sulfotransferase (Hs2st) [212]. Many studies have focused on the molecular mechanisms that regulate GDNF–RET expression and/or signaling. Prior to kidney development, Ret is expressed throughout the mesonephric duct, and Gdnf is present throughout the intermediate mesoderm adjacent to the mesonephric duct [50, 201]. At the time of ureteric bud induction, Gdnf expression becomes restricted to the posterior intermediate mesoderm next to the site of ureteric bud outgrowth; once the ureteric bud has invaded the mesenchyme, Ret expression becomes restricted to ureteric bud tips [50]. In vitro studies with Gdnf-soaked agarose beads show that the entire length of the mesonephric duct is competent to respond to Gdnf by initiating ectopic ureteric bud formation [201, 213]. Moreover, mice that ectopically express Gdnf or Ret in vivo develop renal malformations such as duplex kidney and hydronephrosis [214, 215]. Together, these data show that GDNF–RET signaling is highly spatially regulated for a single ureteric bud to form in the correct location from the mesonephric duct.

At least three genes, Foxc1, Slit2, and Robo2, are thought to be crucial in restricting Gdnf to the posterior intermediate mesoderm (Fig. 6). Homozygous mutant mice for all three genes develop ectopic ureteric buds, multiple ureters, hydroureter, and anterior expansion of Gdnf expression [216, 217]. Foxc1 encodes a transcription factor co-expressed with Gdnf in the metanephric mesenchyme [216]. In the central nervous system, the secreted protein Slit2 functions as a chemorepellent during migration of axons that express its receptor Robo2 [218, 219]. In the developing kidney, Slit2 is expressed in the mesonephric duct, and Robo2 is detected in the metanephric mesenchyme [220]. ROBO2 missense mutations in humans have been identiﬁed in families with vesicoureteral reﬂux and/or duplex kidneys [221]. Two other genes, Sprouty1 (Spry1) and Bmp4, act in a negative feedback loop with GDNF–RET signaling (Fig. 6). Loss of Spry1, which is normally expressed in the mesonephric duct, results in ectopic ureteric bud induction, multiple ureters, multiplex kidneys, and hydroureter [222, 223]. Spry1 mutant embryonic kidneys have increased expression of Gdnf and GDNF–RET

Embryonic Development of the Kidney

target genes and have increased sensitivity to GDNF-induced ureteric induction in organ culture. Bmp4 is expressed in the tailbud-derived mesenchyme (different than renal mesenchyme) immediately next to the mesonephric duct and ureteric bud [169, 224]. Mice heterozygous for Bmp4 have ectopic or duplicated ureteric buds, resulting in hypodysplastic kidneys, hydroureteronephrosis, and ureteral duplications [225, 226]. In vitro, Bmp4 has been shown to block the ability of Gdnf to induce ureteric bud outgrowth from the mesonephric duct [85, 227]. BMP4 mutations have also been described in humans with renal tract malformations [228]. The downstream effects of GDNF–RET signaling, namely, ureteric bud proliferation, survival, and ureteric outgrowth and branching, are mediated by the transcription factors, Etv4 and Etv5. Combined deletion of Etv4 and Etv5 causes bilateral renal aplasia in mice [229]. Etv4 and Etv5 drive expression of several critical genes in the ureteric bud tip, including Wnt11, Cxcr4, Mmp14, Myb, and Met [229]. Furthermore, genetic deletion studies in mice have shown that Wnt11 is necessary for normal Gdnf expression in the metanephric mesenchyme [230].

Renal Branching Morphogenesis After growing into the metanephric mesenchyme, the ureteric bud bifurcates into a T-shaped structure. The ureteric bud then continues to branch, ultimately generating about 15 generations of branches, with the earliest branches remodeling to form the calyces and renal pelvis [231]. The process of ureteric branching includes (1) expansion of the ureteric bud at its leading tip (termed the ampulla), (2) division of the ampulla to form new branches, and (3) elongation of newly formed branches [232, 233]. In humans, during the ﬁrst 9 generations of branching, ureteric bud tips induce formation of new nephrons from the surrounding cap mesenchyme at about a 1:1 ratio [2]. Ureteric bud branching is completed by the 20th–22nd week of human gestation, and subsequent collecting duct maturation occurs by elongation of peripheral (cortical) segments and

remodeling of central (medullary) segments [2]. At this stage, four to seven new nephrons are induced around each tip of a terminal collecting duct branch [2, 43]. Localized cell proliferation contributes to initial ureteric bud outgrowth from the mesonephric duct, formation and growth of ampullae, and elongation of ureteric branches [61, 108, 234, 235]. Cell survival is also critical for normal renal branching morphogenesis; defects in cell survival are associated with renal cystic dysplasia and urinary tract dilatation. Moreover, targeted deletion of bcl2 [236] and AP-2 [237], genes critical for cell survival, results in increased apoptosis and collecting duct cysts in mice. In addition, experimental models of fetal and neonatal urinary tract obstruction lead to apoptosis in dilated collecting ducts [238, 239]. Several signaling pathways are necessary for branching morphogenesis. In addition to its role in ureteric bud induction, GDNF–RET signaling has been shown to be critical for ureteric branching in vivo and in vitro [213, 215]. As noted, Wnt11, expressed in ureteric tips, is necessary for maintaining normal Gdnf expression; conversely, Wnt11 expression is reduced when Gdnf signaling is absent. Furthermore, Wnt11 mutant mice have defective ureteric branching morphogenesis and thus develop renal hypoplasia [230, 240]. Finally, conditional targeting of β-catenin, a key mediator of canonical Wnt signaling, in the ureteric lineage results in aberrant branching, loss of ureteric bud tip gene expression, and premature expression of differentiated collecting duct genes [241, 242]. Fibroblast growth factor signaling is also critical for ureteric branching. In vitro studies have shown that exogenous Fgf ligands differentially modulate ureteric bud growth and proliferation [243]. FGF10 preferentially stimulates proliferation at ureteric bud tips, whereas FGF7 increases cell proliferation throughout the developing collecting ducts [243]. In vivo, global deletion of Fgf7 or Fgf10 in mice results in ureteric branching defects and hypoplastic kidneys [58, 244]. Conditional targeting studies in mice have revealed that Fgfr2 is likely the key Fgf receptor mediating effects on ureteric branching [245–247]. Loss of

Fgfr2 in the ureteric bud results in hypoplastic ureteric ampullae with reduced proliferation and increased apoptosis, ultimately leading to a signiﬁcant reduction in ureteric branching and hypoplastic kidneys. In addition, an interesting study revealed that while combined loss of Sprouty1 and Gdnf in mice largely rescues ureteric defects compared to when either locus is deleted alone, additional loss of Fgf10 in the combined mutants led to complete loss of ureteric branching and renal aplasia [248]; thus, FGF signals appear to be able to largely substitute for GDNF in promoting ureteric morphogenesis in the absence of Sprouty1. Finally, a combination of in vitro and in vivo experiments revealed that Fgf signaling acts in a coordinated fashion with Wnt11 and Gdnf to regulate ureteric morphogenesis, in concert with Sprouty genes [249].

Patterning of the Medullary and Cortical Collecting Ducts From the 22nd–34th week of human gestation [2] and embryonic day 15 birth in mice [43], the cortical (peripheral) and medullary (central) regions of the kidney become established. The relatively compact, circumferential renal cortex comprises approximately 70 % of the mature kidney volume [250]. The renal medulla develops modiﬁed a cone shape and occupies the remainder of the mature kidney volume [250]. The apex of the medullary cone consists of collecting ducts converging in the inner medulla and is termed the papilla. Ultimately, medullary collecting ducts become morphologically distinct from cortical collecting ducts. Medullary collecting ducts become elongated and linear and remain relatively unbranched in a region devoid of glomeruli. In contrast, collecting ducts in the renal cortex remain branched and induce nephrogenic cap mesenchyme to form nephrons throughout nephrogenesis. These morphological differences are likely due in part to distinct axes of growth in the developing renal cortex and medulla. The renal cortex grows circumferentially, which preserves the organization of the peripheral tissues, including

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differentiating glomeruli, nephron tubules, and collecting ducts [250]. In contrast, the developing renal medulla expands longitudinally, perpendicular to the axis of cortical growth, due to elongation of outer medullary collecting ducts [250]. Stromal cells may be a source of stimulatory cues for the medullary growth [250]; studies have shown that mice lacking the stromal transcription factors Foxd1 and Pod1 have abnormal medullary collecting duct patterning [54, 66, 251]. Finally, apoptosis appears to participate in remodeling the branched medullary ureteric tissues into elongated tubules, as programmed cell death normally occurs prominently in developing medullary ureteric epithelia that become the papilla, calyces, and renal pelvis [108]. Multiple genes have been implicated in the differentiation of cortical and medullary collecting ducts, including those that encode for soluble growth factors (Fgf7, Fgf10, Bmp4, Bmp5, and Wnt7b), proteoglycans (Gpc3), cell cycle regulatory proteins (p57KIP2), and components of the renin–angiotensin axis (angiotensin and angiotensin type 1 and 2 receptors). Fgf7 mutant mice have marked papillary underdevelopment, while Fgf10 null kidneys exhibit medullary dysplasia with fewer loops of Henle and medullary collecting ducts, increased medullary stroma, and enlargement of the renal calyx [58, 244]. The ability of FGF ligands to bind properly to their receptors requires interactions with cell surface proteoglycans, including glypicans [252]. Glypican-3 (GPC3) is required for normal medullary patterning in humans and mice [253, 254]. Moreover, the medullary dysplasia observed in Gpc3-deﬁcient mice appears to result from unrestrained proliferation and overgrowth of the ureteric bud and collecting ducts, followed by aberrant apoptosis [253, 254]. The Gpc3/ medullary defects appear to be driven by altered responses of mutant collecting duct cells to growth factors including Fgfs [254–256]. Finally, mice lacking the cell cycle protein p57KIP2 demonstrate medullary dysplasia, with fewer inner medullary collecting ducts [257]. Together, these studies reveal the importance of balanced cell proliferation and apoptosis in medullary collecting duct patterning.

Embryonic Development of the Kidney

Proper elongation and growth of medullary collecting ducts also appears to rely on oriented cell divisions. Studies have shown that canonical Wnt signaling in collecting ducts via Wnt7b leads to proper oriented cell division and survival [258, 259]. Furthermore, α3β1 integrin and the receptor tyrosine kinase c-Met act in concert to regulate Wnt7b expression and signaling in medullary collecting ducts [259]. Finally, angiotensin (Agt) and angiotensin receptors (Agtrs) appear critical for the development of the renal calyces, pelvis, and ureter. Mice lacking Agt or Agtr1 genes demonstrate progressive widening of the calyx and atrophy of the papillae and underlying medulla [260, 261]. These defects appear to be caused by decreased proliferation of the smooth muscle cells that line the renal pelvis. Loss of Agtr2 causes a range of renal anomalies secondary to ureteric mispatterning, including vesicoureteral reflux, duplex kidney, renal ectopia, ureteropelvic Fig. 7 H&E-stained sections from E15.5 and P1 mouse ureters and bladders. E15.5 ureters and bladders have early urothelium (u), an inner layer of mesenchyme (future lamina propria, arrows), and an outer layer of condensing mesenchyme (future muscle, m). P1 ureters and bladders have a more stratified urothelium (u) and well-developed lamina propria (arrows) and outer muscle (m) layers. The adventitial layer of fibroblasts that surrounds the muscle in both tissues is not labeled. Ureters =100 magnification; bladders =40 magnification

or ureterovesical junction stenoses, renal dysplasia or hypoplasia, multicystic dysplastic kidney, and renal aplasia [107].

Lower Urinary Tract Development Anatomic and Functional Development Concurrent with metanephric kidney formation, the embryonic ureter and bladder develop the former functioning to propel urine into the latter which stores urine until an appropriate time to expel it via the urethra. Similar to the kidney, the ureter and bladder undergo maturation largely due to reciprocal interactions between an epithelium (i.e., urothelium) and surrounding mesenchyme that forms the lamina propria, muscle, and adventitia (Fig. 7). For a recent detailed review on anatomic and molecular control of lower urinary tract development, see [262].

Ureter development begins simultaneously with metanephric kidney development around the 5th week of gestation in humans and at E10.5 in the mouse, when the ureteric bud arises from the mesonephric duct [262]. Thus the embryonic origin of the ureteral urothelium is the intermediate mesoderm, the same as the metanephric kidney. By E11.5 in the mouse, the ureteric bud has been segmented into a distal portion that will develop into the ureter and a proximal end that has invaded the metanephric mesenchyme to eventually branch and form the collecting ducts and renal pelvis (see above). The mesenchyme surrounding the early developing ureter consists largely of tailbud-derived mesenchyme that appears to be crucial for directing the distal ureteric bud toward a ureter fate [263]. Between E10.5 and E13.5, the nascent ureter transitions from attaching to the nephric duct to emptying directly into the early bladder (see below). By E13.5, a thin outer ring of ureteral mesenchyme condenses and expresses alpha smooth muscle actin (αSMA) mRNA, the first marker of differentiation toward a smooth muscle fate [264]. αSMA protein expression is not noted until E14.5 in the proximal portion of the ureter (nearest the kidney) and then throughout the entire length of ureter by E16.5; thus, ureter muscle development progresses in a rostral to caudal direction [265]. Concurrent with development of the mesenchymal layers, the ureteral urothelium gradually matures from a simple epithelium to a stratified epithelium consisting of at least three cell types: basal, intermediate, and superficial/ umbrella cells. Each of these cell types has distinct structural features and molecular markers [266]; moreover, recent data strongly suggests that urothelial basal cells, arising from the original ureteric epithelium, serve as the progenitors for other ureteral urothelial cell types [266]. A unique feature of urothelium (compared with other epithelia) is the apical expression of urothelial plaques, consisting of uroplakins, which likely have several functions, including providing a permeability barrier and acting as a binding site for uropathogenic E. coli [266]. An important function of the ureter is to continuously propel urine from the renal pelvis to the

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bladder. The ability of the ureter to undergo peristaltic waves of contraction followed by relaxation appears to be intrinsic and not dependent on urine ﬂow; cultured explants of E13.5 mouse ureters attached to kidneys begin to undergo spontaneous peristaltic contractions within a few days, as do isolated and cultured E15.5 ureters [268]. Elegant studies recently identiﬁed a population of pacemaker cells at the junction of the renal pelvis and the kidney that express hyperpolarization-activated cation-3 (Hcn3) channels (a family of channels that are also present in cardiac pacemakers) [269]. Loss of Hcn3 activity in mice leads to abnormal coordination and frequency of ureter contractions [269]. Following this study, another described a population of secondary pacemakers that are located in the muscle of the mouse proximal ureter (starting at the ureteropelvic junction) and that have morphological and molecular features similar to intestinal pacemakers including expression of c-kit [268]. Thus, like the cardiac conduction system, the ureter has primary and secondary pacemakers that act to drive urinary propulsion in a coordinated fashion. The embryonic bladder initially forms around the 5th gestational week in humans and at E11.5–12.5 in the mouse [262, 270]. Unlike the ureter, bladder urothelium is derived from the endodermal urogenital sinus, formed from the ventral region of the cloaca. At E11.5–12.5, the urogenital sinus further subdivides into an anterior portion, which will become the bladder, and a posterior portion that forms the urethra and portions of the female vagina. The mesenchyme that surrounds the bladder urothelium is largely thought to be from splanchnic mesoderm, although fate-mapping studies reveal that tailbud mesenchyme also contributes to bladder mesenchyme (similar to the ureter) [263]. By E13.5, the bladder is recognized as a distinct structure that is attached directly to the ureters. As is the case with ureters, αSMA mRNA expression in the developing bladder muscle precedes protein expression; mRNA expression appears as early as E11.5 in mice [264], while protein expression begins at E13.5 [270]. Unlike the ureter (and many other organs with smooth muscle such as the intestine)

Embryonic Development of the Kidney

that has a thin ring of mesenchyme that begins to differentiate into muscle, the entire outer half of the bladder mesenchyme condenses simultaneously and strongly expresses αSMA by E15.5 [264, 271]. Similar to the ureter, the bladder urothelium matures from a simple epithelium to a stratiﬁed epithelium, consisting of cell types similar to the ureter, most of which also express uroplakins and urothelial plaques [266]. While bladder urothelial basal cells were originally thought to be the progenitor cell for the other urothelial cell types, recent careful lineage tracing studies revealed the presence of a previously unidentiﬁed transient population of cells, known as “P” cells that serve as the progenitors in embryos [272]; moreover, there are dynamic changes in relative composition of bladder urothelial cell types throughout development (Fig. 8). P-cell

Foxa2+ Upk+ P63+ Shh+ Krt5–

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While the connection of the ureters with the bladder is critical, how this occurs has been the subject of some debate. What is clear is that between E12.5 and E13.5, the common nephric duct (caudal portion of the mesonephric duct between the ureter base and future bladder) moves adjacent to the bladder, allowing for the ureters and rostral nephric ducts (future male gonadal excretory ducts) to separate and empty directly into the bladder. The triangular portion of the bladder demarcated by the entry points of the ureters and the bladder neck (where the remaining embryonic nephric ducts empty) is known as the trigone. Historically the common nephric duct was thought to become incorporated into the bladder to form the trigone. However, elegant fatemapping studies reveal that the common nephric duct undergoes complete apoptosis starting at E12.5 in the mouse and that the urothelium of the trigone originates entirely from the bladder urothelium [273]. Moreover, a separate study showed that the muscle present in the trigone arises mostly from the bladder with only a few ﬁbers emanating from ureteral muscle [274]. Thus, the trigone originates mostly from bladder tissues and not the mesonephric duct.

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Molecular Control of Ureter and Bladder Development

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Fig. 8 Graph demonstrating the proportion of different murine bladder urothelial cell types during development. “P” cells, an early transient progenitor population appear first, followed dynamic changes in the proportion of their derivatives [intermediate (I ), superficial (S), and basal (B) cells] through adulthood. Immunohistochemical markers of each cell type are listed (Foxa2 forkhead box A2, Upk uroplakins, P63 tumor protein P63, Shh sonic hedgehog, Krt5 keratin 5) (Reproduced with kind permission from Elsevier. Gandhi, D, et al. Retinoid signaling in progenitors controls specification and regeneration of the urothelium. Developmental Cell, volume 26, pp 469–482, 2013, adapted from Figure 2)

Ureter The pathways critical for early ureteric bud formation were already covered in the section on kidney development above. Thus, an overview of the molecular control of ureter development will be presented in this section (Fig. 9). Once the ureteric bud has formed, Bmp4 is secreted by tailbud-derived mesenchyme surrounding the distal ureteric bud, driving the epithelium toward a urothelial fate; moreover, ectopic Bmp4 expression around proximal portions of the ureteric bud directs it to become urothelium instead of collecting duct epithelium [263]. The transcription factor Tbx18 is also critical for normal urothelial development and is expressed throughout the mesenchyme investing the distal ureter. The genetic ablation of Tbx18 in mice leads to

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Fig. 9 Genetic pathways regulating ureter development. The cell layers of the developing ureter include the urothelium (green) and mesenchymal lamina propria/stromal cells (pink), smooth muscle (yellow), and adventitia (blue). Tbx18, expressed in mesenchyme, is critical for smooth muscle and urothelial development. Uroplakins (UPKs) are not only markers of urothelium but critical for urothelial morphogenesis. Sonic hedgehog (Shh) is secreted by urothelium, binding to patched (Ptch) receptors to regulate morphogenesis of smooth muscle and Hcn3 and c-Kit expressing pacemakers [via interactions with Smoothened (Smo) and Gli3 repressor (Gli3R)]. Other Shh targets including Bmp4 (acting through Smad

proteins) and Tshz3 regulate smooth muscle morphogenesis. Wnt ligands in urothelium bind to Fzd receptors and stabilize β-catenin to stimulate smooth muscle development and repress adventitial expansion. Angiotensin 2 (AngII) binds to type 1 receptors (Agtr1) that along with calcineurin b1 subunits also pattern smooth muscle. Dlg1 is critical for lamina propria/stromal cell morphogenesis (Reproduced with kind permission from Wiley Periodicals, Inc. Rasouly, HM and Lu W. Lower urinary tract development and disease. Wiley Interdisciplinary Reviews: Systems Biology and Medicine, volume 5, pp 307–342, adapted from Figure 3)

severe mispatterning of the mesenchyme and then secondary defects in urothelial development [277]. Finally, not only are uroplakins markers of urothelial maturation, but they are also critical for normal urothelial morphogenesis. Loss of either uroplakin II or uroplakin IIIa leads to severe urothelial plaque defects, hypoplastic superficial cells, urothelial leakiness, hydronephrosis, and vesicoureteral reflux [276, 277]. Moreover, mutations in UPKIIIa in humans have been associated with severe renal dysplasia and reflux [279], whereas the role of UPKII in humans is still unclear [279].

Signaling from the ureteral urothelium has also been shown to be critical for mesenchymal patterning. The growth factor, Sonic hedgehog (Shh), is secreted by the urothelium and binds to its receptor, Patched 1, in surrounding mesenchyme. Conditional ablation of Shh in developing ureteric epithelium leads to loss of mesenchymal proliferation and smooth muscle differentiation [265]. Furthermore, Shh signaling from urothelium has also been shown to be critical for the formation of Hcn3 and c-kit expressing pacemakers within the ureteral muscle, via the hedgehog signaling mediators Smoothened and Gli13

Embryonic Development of the Kidney

repressor [268]. In addition, downstream targets of Shh signaling have been identified as necessary for ureteral muscle development. One target, Bmp4, is essential for normal ureteral muscle investment around the ureter, particularly at the ureterovesical junction (in addition to having its aforementioned role in urothelial differentiation) [280]. The transcription factor, Teashirt 3 (Tshz3), downstream of both Shh and Bmp4, is critical for proximal ureteral smooth muscle differentiation and for normal ureteral peristaltic function; deletion of Tshz3 in mice leads to severe muscle patterning defects and congenital hydronephrosis [281]. A role for SHH in human urinary tract development was confirmed in patients with Pallister–Hall syndrome, who have mutations in GLI3 and urinary tract anomalies such as hydroureter and hydronephrosis [268, 282]. Finally, Wnt ligands are also secreted by the urothelium, bind to frizzled receptors in the mesenchyme, and signal primarily by stabilization of β-catenin (Ctnnb1). Genetic ablation of Ctnnb1 leads to failure of mesenchymal proliferation and differentiation into smooth muscle cells, with concurrent expansion of the outer adventitial fibroblast layer [283]. Other genes within the ureteral mesenchyme have been shown to be critical for normal mesenchymal development. As alluded to, loss of the transcription factor Tbx18 leads to decreased proliferation and failure of smooth muscle differentiation and ultimately severe hydroureteronephrosis [275]. Similarly, conditional ablation of the calcineurin b1 subunit in developing ureteral mesenchyme leads to reduced smooth muscle proliferation and hydronephrosis [284]. Furthermore, genetic ablation of the angiotensin type 1 receptor (which is expressed in ureteral mesenchyme) leads to smooth muscle hypoplasia, lack of peristalsis, and ultimately hydronephrosis [285]. Finally, discs large homolog 1 (Dlg1) is the only gene identified to date that is necessary for lamina propria/stromal cell development; genetic deletion of Dlg1 in mice led to an absence of the entire ureteral lamina propria layer and disorganized muscle development [286].

Bladder Compared with the ureter, much less is known about the molecular control of bladder development. Some of the pathways critical for formation of the urogenital sinus (future bladder) have been identiﬁed. Bidirectional signaling between ephrin-B2 and EphB2, a ligand and its receptor tyrosine kinase, is critical for septation of the cloaca into the ventral urogenital sinus and the dorsal anorectal canal [287]. Sonic hedgehog signaling is also critical for the formation of the urogenital sinus. In mice, the loss of Shh or compound mutations in the downstream hedgehog mediators, Gli2 and Gli3, leads to failure of cloacal septation [288]. During later stages of bladder formation, urothelial cell stratiﬁcation is dependent on retinoid signaling emanating from the lamina propria surrounding the urothelium; forced expression of a dominant negative retinoic acid receptor in developing mouse urothelium leads to a loss of S cells, I cells, and uroplakins [272]. There are also some limited data on genetic pathways critical for bladder mesenchyme development. As is true in the ureter, several studies have shown that Shh signaling from the bladder urothelium is necessary for bladder mesenchyme morphogenesis; loss of Shh in mice leads to a complete loss of smooth muscle formation [289–292]. Another mouse line, termed the megabladder mouse (mgb/), is a random transgene insertional mutant that lacks outer mesenchymal condensation, has very limited αSMA expression, and ultimately develops a massive bladder with no functional detrusor [271]. While the gene disrupted in mgb/ mice is still unknown, Shh signaling appears perturbed, and the bladders lack expression of myocardin, a transcription factor critical for smooth muscle development [293].

Ureter–Bladder Anastomosis There are some data on genetic pathways necessary for the proper connection between the ureter and bladder, i.e., apoptosis of the common nephric duct starting at E12.5 in mice. Retinoid signaling

from the bladder has been shown to be critical for this process. Genetic ablation of retinaldehyde dehydrogenase-2, an enzyme expressed in the urogenital sinus and necessary for retinoic acid synthesis, led to persistence of the common nephric duct with ureters ending blindly in the mesonephric duct [273]. In addition, Ret has also been shown to be essential for ureter–bladder anastomosis. Mice with a point mutation in tyrosine 1015, the phospholipase Cγ binding site on Ret (RetY1015), have a persistent common nephric duct due to enhanced proliferation and decreased apoptosis [294]. Lower urinary tract defects contribute substantially to chronic kidney disease in children, necessitating a better understanding about the genes regulating lower urinary tract morphogenesis. While our understanding of the molecular control of ureter and bladder development trails that of the kidney, more studies are emerging on how the ureter and bladder form.

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36 270. Price KL, Woolf AS, Long DA. Unraveling the genetic landscape of bladder development in mice. J Urol [Research Support, Non-U.S. Gov’t]. 2009;181(5):2366–74. 271. Singh S, Robinson M, Nahi F, Coley B, Robinson ML, Bates CM, et al. Identification of a unique transgenic mouse line that develops megabladder, obstructive uropathy, and renal dysfunction. J Am Soc Nephrol. 2007;18(2):461–71. 272. Gandhi D, Molotkov A, Batourina E, Schneider K, Dan H, Reiley M, et al. Retinoid signaling in progenitors controls specification and regeneration of the urothelium. Dev Cell [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. 2013;26(5):469–82. 273. Batourina E, Tsai S, Lambert S, Sprenkle P, Viana R, Dutta S, et al. Apoptosis induced by vitamin A signaling is crucial for connecting the ureters to the bladder. Nat Genet. 2005;37(10):1082–9. 274. Viana R, Batourina E, Huang H, Dressler GR, Kobayashi A, Behringer RR, et al. The development of the bladder trigone, the center of the anti-reflux mechanism. Development. 2007;134(20):3763–9. 275. Airik R, Bussen M, Singh MK, Petry M, Kispert A. Tbx18 regulates the development of the ureteral mesenchyme. J Clin Invest. 2006;116(3):663–74. 276. Kong XT, Deng FM, Hu P, Liang FX, Zhou G, Auerbach AB, et al. Roles of uroplakins in plaque formation, umbrella cell enlargement, and urinary tract diseases. J Cell Biol. 2004;167(6):1195–204. 277. Hu P, Deng FM, Liang FX, Hu CM, Auerbach AB, Shapiro E, et al. Ablation of uroplakin III gene results in small urothelial plaques, urothelial leakage, and vesicoureteral reflux. J Cell Biol. 2000;151(5): 961–72. 278. Jenkins D, Bitner-Glindzicz M, Malcolm S, Hu CC, Allison J, Winyard PJ, et al. De novo Uroplakin IIIa heterozygous mutations cause human renal adysplasia leading to severe kidney failure. J Am Soc Nephrol. 2005;16(7):2141–9. 279. Jenkins D, Bitner-Glindzicz M, Malcolm S, Allison J, de Bruyn R, Flanagan S, et al. Mutation analyses of Uroplakin II in children with renal tract malformations. Nephrol Dial Transplant. 2006; 21(12):3415–21. 280. Wang GJ, Brenner-Anantharam A, Vaughan ED, Herzlinger D. Antagonism of BMP4 signaling disrupts smooth muscle investment of the ureter and ureteropelvic junction. J Urol. 2009;181(1): 401–7. 281. Caubit X, Lye CM, Martin E, Core N, Long DA, Vola C, et al. Teashirt 3 is necessary for ureteral smooth muscle differentiation downstream of SHH and BMP4. Development [Research Support, Non-U.S. Gov’t]. 2008;135(19):3301–10. 282. Kang S, Graham Jr JM, Olney AH, Biesecker LG. GLI3 frameshift mutations cause autosomal

C. Bates et al. dominant Pallister-Hall syndrome. Nat Genet. 1997;15(3):266–8. 283. Trowe MO, Airik R, Weiss AC, Farin HF, Foik AB, Bettenhausen E, et al. Canonical Wnt signaling regulates smooth muscle precursor development in the mouse ureter. Development. 2012;139:2009–3108. 284. Chang CP, McDill BW, Neilson JR, Joist HE, Epstein JA, Crabtree GR, et al. Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery. J Clin Invest. 2004;113(7):1051–8. 285. Miyazaki Y, Tsuchida S, Nishimura H, Pope JCt, Harris RC, McKanna JM, et al. Angiotensin induces the urinary peristaltic machinery during the perinatal period. J Clin Invest [Research Support, Non-U.S. Research Support, U.S. Gov’t, Gov’t P.H.S.]. 1998;102(8):1489–97. 286. Mahoney ZX, Sammut B, Xavier RJ, Cunningham J, Go G, Brim KL, et al. Discs-large homolog 1 regulates smooth muscle orientation in the mouse ureter. Proc Natl Acad Sci U S A. 2006;103(52):19872–7. 287. Dravis C, Yokoyama N, Chumley MJ, Cowan CA, Silvany RE, Shay J, et al. Bidirectional signaling mediated by ephrin-B2 and EphB2 controls urorectal development. Dev Biol. 2004;271(2):272–90. 288. Mo R, Kim JH, Zhang J, Chiang C, Hui CC, Kim PC. Anorectal malformations caused by defects in sonic hedgehog signaling. Am J Pathol. 2001; 159(2):765–74. 289. Baskin L, DiSandro M, Li Y, Li W, Hayward S, Cunha G. Mesenchymal-epithelial interactions in bladder smooth muscle development: effects of the local tissue environment. J Urol. 2001;165(4): 1283–8. 290. DiSandro MJ, Li Y, Baskin LS, Hayward S, Cunha G. Mesenchymal-epithelial interactions in bladder smooth muscle development: epithelial speciﬁcity. J Urol. 1998;160(3 Pt 2):1040–6; discussion 79. 291. Cao M, Tasian G, Wang MH, Liu B, Cunha G, Baskin L. Urothelium-derived Sonic hedgehog promotes mesenchymal proliferation and induces bladder smooth muscle differentiation. Differentiation [Research Support, N.I.H., Extramural]. 2010; 79(4–5):244–50. 292. Cheng W, Yeung CK, Ng YK, Zhang JR, Hui CC, Kim PC. Sonic Hedgehog mediator Gli2 regulates bladder mesenchymal patterning. J Urol [Research Support, Non-U.S. Gov’t]. 2008;180(4):1543–50. 293. DeSouza KR, Saha M, Carpenter AR, Scott M, McHugh KM. Analysis of the Sonic Hedgehog signaling pathway in normal and abnormal bladder development. PLoS One [Research Support, N.I.H., Extramural]. 2013;8(1):e53675. 294. Hoshi M, Batourina E, Mendelsohn C, Jain S. Novel mechanisms of early upper and lower urinary tract patterning regulated by RetY1015 docking tyrosine in mice. Development. 2012;139(13):2405–15.

Development of Glomerular Circulation and Function Alda Tufro and Ashima Gulati

Contents

Introduction

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Development of the Kidney Vasculature . . . . . . . . . . . 38 Vasculogenesis and Angiogenesis . . . . . . . . . . . . . . . . . . . . 38 The Glomerular Filtration Barrier . . . . . . . . . . . . . . . . . 41 Components of the GFB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Glomerular Filtration Barrier (GFB) Selective Permeability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Glomerular Hemodynamics and Assessment of Renal Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Renal Blood Flow: Basic Concepts . . . . . . . . . . . . . . . . . . . Perinatal Considerations for Renal Blood Flow and GFR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Concept of Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . .

46 47 47 50

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

A. Tufro (*) • A. Gulati Department of Pediatrics, Nephrology Section, Yale School of Medicine, New Haven, CT, USA e-mail: [emailprotected] # Springer-Verlag Berlin Heidelberg 2016 E.D. Avner et al. (eds.), Pediatric Nephrology, DOI 10.1007/978-3-662-43596-0_2

From the Malpighian corpuscle description and Bowman’s sketch to defining its ultrastructure and molecular function, the ways we look at the kidney glomerulus have evolved tremendously. The first systematic exploration of the body with a microscope led to the identification of “Malpighian corpuscles” as “glands” within the kidney [1]. Two centuries later, a more sophisticated microscope enabled Sir William Bowman to identify glomerular capillary tufts in animal and human kidneys and demonstrate a relationship between the capillary tuft and the renal tubule [2]. Since then, the understanding of the human glomerulus as a specialized structure uniquely adapted for renal filtration at the proximal part of the nephron has considerably advanced. The human definitive kidney is a highly complex organ system with an average number of ~1 million functional units called nephrons. Nephrogenesis involves the development of the glomerulus (glomerulogenesis) and the renal tubule (tubulogenesis) from mesenchymal progenitors residing in the metanephric mesenchyme and ureteric bud. The specification, maintenance, and commitment of nephron progenitors and the regulatory processes that transform nephron progenitors into a functional nephron are detailed elsewhere ([3]; see ▶ Chaps. 1, “Embryonic Development of the Kidney,” and ▶ 18, “Translational Research Methods: Renal Stem Cells” in this text). The current chapter aims to 37

combine established knowledge and new findings pertaining to the structural and functional aspects of glomerular development, describe intricacies of the glomerular filtration barrier at the molecular level, and provide insight into future research areas. Three attributes make the human glomerulus a fascinating focus of research and clinical significance: first is the synchrony among vasculogenesis, angiogenesis, and epithelial and stromal differentiation; second, the glomerular unique ultrastructure provides controlled regulation of filtration while acting as a barrier; and third, the glomerulus is the major controller of renal hemodynamics and provides functional advantages for effective filtration. Each of these attributes and their relevance for clinical use will be discussed in the following sections.

Development of the Kidney Vasculature The kidney vasculature develops in a patterned fashion, allowing structural and functional development of the glomerular circulation that eventually handles 20 % of the cardiac output for the purpose of clearing metabolic waste products and toxins and maintaining fluid and electrolyte balance [4]. The complex architecture of the renal vasculature is essential for the organ function and comprises an arterial tree and three capillary beds. Single renal arteries branch and direct over 90 % of the renal blood flow to glomeruli in the renal cortex. The glomerular capillary bed length amplifies the area for filtration, allowing the highest fluid outflow rate in the body. Glomerular capillaries are flanked by high-resistance afferent and efferent arterioles, which regulate the rate of blood flow through the capillary bed and thereby glomerular filtration. Two postglomerular capillary networks emerge in series from efferent arterioles. Efferent arterioles from superficial glomeruli give rise to cortical peritubular capillaries, while those from the juxtamedullary glomeruli give rise to vasa recta. Close alignment of the postglomerular microvasculature with cortical and medullary renal tubules is critical for oxygen

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delivery to all nephron segments and for fluid and solute reabsorption from them. As a result of fluid removal by glomerular ultrafiltration, oncotic pressure in postglomerular capillaries increases above hydrostatic pressure. Thus, peritubular capillaries are poised for fluid and solute reabsorption.

Vasculogenesis and Angiogenesis The formation of the kidney vasculature comprises in situ differentiation of endothelial cells from hemangioblasts present in the metanephric mesenchyme and capillary assembly, a process called vasculogenesis, and angiogenesis wherein capillary growth occurs by the sprouting and/or splitting of existing capillaries within or surrounding the developing kidney [5–9]. In vivo, vasculogenesis and angiogenesis might occur sequentially or simultaneously [10].

Vasculogenesis and Angiogenesis Contribute to the Kidney Vasculature The origin of kidney endothelial cells and the mechanisms involved in kidney vascularization have been extensively examined in experimental models and debated for quite some time. Genetic fate mapping and the identiﬁcation of molecular guidance cues from angiogenic factors have largely resolved these controversies. The hypothesis of extrarenal angiogenic origin of kidney endothelial cells is supported by elegant interspecies transplantation experiments and by the absence of vascular development in embryonic kidneys cultured ex vivo [11–13]. As shown in other embryonic vascular beds [14], Sariola and colleagues showed evidence of angiogenesis in undifferentiated embryonic mouse kidney rudiments after the transplantation onto avian chorioallantoic membrane [15, 16]. Indeed, grafts were well vascularized, and both the glomerular and the vessel endothelium expressed an avian nuclear marker, suggesting that the glomerular endothelium is derived from extrinsic (avian) vasculature rather than by the differentiation of endothelial cells native to the metanephric mesenchyme [15–17]. Abrahamson et al. demonstrated that

Development of Glomerular Circulation and Function

embryonic kidneys grafted under the renal capsule of newborn mice were vascularized by host endothelium, whereas adult hosts failed to vascularize the grafts [18], suggesting that the angiogenic activity of the host is crucial to this process. The hypothesis of the endogenous, vasculogenic origin of glomerular endothelial cells is supported by the identification of native endothelial precursors in the metanephric mesenchyme, by the exposure of avascular metanephric kidneys to hypoxia or angiogenic factors, and by grafting experiments [18–21]. These findings were facilitated by the landmark discovery of vascular endothelial growth factor (VEGF) receptors Flk1 and Flt1, as indispensable for endothelial differentiation and vascular assembly and thus genetic markers of endothelial precursors [22–24]. Flk1+ and Flt1+ angioblasts were detected within the avascular metanephric mesenchyme [19–21], demonstrating that endothelial progenitors in situ enable vasculogenesis in the developing kidney [25–28]. Flt-1 and Flk-1 are expressed in isolated cells before any morphologic evidence of vascular development in the metanephric blastema [25]. Within 24 h in culture, Flk-1-expressing cells align to form cord-like structures, followed by the acquisition of lumen and typical endothelial cell phenotype in the following 2 days. As renal vascularization proceeds, Flt-1 and Flk-1 are expressed in contiguous endothelial cells [25]. Exposure of avascular kidney rudiments to hypoxia similar to that occurring in embryonic tissues leads Flk1+ angioblasts present within the metanephric blastema to form primitive vascular networks via the upregulation of VEGF [29]. Similarly, exposure to exogenous VEGF enables avascular embryonic kidneys to develop capillaries [25, 30]. Genetically tagged LacZFlk1+ embryonic mouse kidneys grafted into the anterior chamber of the rat eye develop glomeruli vascularized by graft rather than host endothelial cells [31]. Remarkably, the glomerular basement membrane and mesangial matrix were noted to be exclusively of graft origin, implying the selfsufficient capability of the metanephric mesenchyme to form the glomerulus [19]. Furthermore, Tie-1/LacZ metanephros transplanted into the

nephrogenic cortex of wild-type mice develop transgene-expressing glomerular capillary loops [31]. In contrast, glomerular Tie-1/LacZ + vessels do not develop in rudiments placed in organ culture on 20 % O2 [31]. This capability of Flk1+ angioblasts to give rise to a primitive vasculature has subsequently been conﬁrmed in vitro and in vivo explant assays [18, 19, 32, 33]. These observations imply that endothelial progenitors present at the onset of mouse nephrogenesis differentiate and undergo morphogenesis to become glomerular capillaries when experimental conditions resemble those found in the metanephros in vivo, such as moderate hypoxia. Together, a large body of experimental data demonstrates that both vasculogenesis and angiogenesis contribute to the formation of kidney vasculature under the inﬂuence of a variety of growth factors and guidance proteins. Blood vessels are comprised of endothelial cells and associated vascular mural cells including pericytes and vascular smooth muscle cells. While the data outlined above provide evidence for the presence of endothelial progenitors in the metanephric blastema as well as ingrowing endothelial cells, genetic fate mapping experiments demonstrate that Foxd1+ cells present at the periphery of the metanephric blastema give rise to most vascular mural cells, thus contributing to the overall vascular structural development [34].

Angiogenic Factor Signaling Is Critical for Patterning the Kidney Vasculature The kidney endothelium undergoes specification into distinct histological types in arteries, veins, capillaries, and lymphatics, including continuous endothelium or endothelium fenestrated with diaphragms. This specification is adapted to the tissue permeability characteristics and is determined by local microenvironmental cues, irrespectively of the endothelial cell lineage [35]. For example, the grafting of embryonic vessels with fenestrated endothelium into the brain resulted in tight continuous endothelium typical of the blood-brain barrier [36]. Though the progenitor lineage might contribute to endothelial cell heterogeneity within the kidney, endothelium specification by local environmental cues involves dynamic cross

talk between various signaling pathways that communicate by way of growth factors [37]. Soluble angiogenic factors and guidance proteins including VEGF-A, basic ﬁbroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and semaphorin 3A play a key role in kidney vascularization. VEGF-A is a pleiotropic glycoprotein originally described as a vascular permeability and endothelial growth factor [38–40]. VEGF is a direct-acting speciﬁc endothelial cell mitogen that stimulates angiogenesis and regulates embryonic vessel development in a gene dosagedependent manner [41]. VEGF-A is required for endothelial cell differentiation, survival, proliferation, and migration, as well as for vascular assembly, maintenance, and remodeling; thus it is critical for physiological angiogenesis [42, 43]. During kidney development, VEGF-A expressed in the metanephric mesenchyme acts as a chemoattractant for endothelial cells and directs their migration toward developing nephrons [30]. Glomerular development starts when nephrons are at the S-shaped body stage, at which time podocytes differentiate and express VEGF-A, leading endothelial progenitors to migrate into and differentiate in the adjacent “vascular cleft.” Podocytes synthesize three VEGF-A isoforms (VEGF121-165-189) by alternative splicing [44]. VEGF-A isoforms with differences in size, membrane, and extracellular matrix-binding properties (VEGF121 and the most abundant VEGF165 are secreted) enable gradient formation and endothelial cell chemoattraction [30]. The glomerular endothelium forms a single capillary loop initially that later forms the mature glomerular tuft. VEGF-A is indispensable for normal development of glomerular capillaries [45] and to acquire their fenestrated phenotype [46–48]. The principal source of VEGF-A in the renal glomerulus is the podocyte [49]. Continuous expression of VEGF-A in podocytes and tubular cells and of Flk1 on the adjacent endothelia induces and maintains the fenestrated endothelia and also regulates vascular permeability [26, 48, 50, 51]. Podocytes and tubular cells express VEGF-A throughout life, unlike other tissues that cease expressing VEGF-A at the completion of

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development [25, 26]. Moreover, tightly regulated VEGF-A is required to establish and maintain a normal podocyte phenotype, i.e., foot processes linked by slit diaphragms, as revealed by both loss- and gain-of-function mouse models [45, 52–54]. VEGF-A signals in autocrine and paracrine fashion in podocytes, renal tubules, and endothelial cells promoting the survival, proliferation, and migration in vitro and in vivo [44, 45, 55–62]. VEGF-A receptors are most abundant in endothelial cells, but they are expressed by multiple cells, including podocytes and tubular cells [44, 57, 59, 60, 62–64]. Two VEGF-A tyrosine kinase receptors, VEGFR-1 [previously known as fms-like tyrosine kinase-1 (Flt-1)] and VEGFR-2 [formerly murine fetal liver kinase 1 (flk-1)/human kinase insert domain receptor (KDR)], and two co-receptors, neuropilin-1 and neuropilin-2 (NRP1 and NRP2), have been described. VEGF-A signals are transduced through VEGFR2 and NRP1 and NRP2 amplify VEGFR2 signals, while VEGFR1 functions mostly as a decoy [65]. The importance of VEGF-A signaling for embryonic vascular development is illustrated by gene deletion experiments. Both heterozygous and homozygous VEGF-A knockout mice die during embryogenesis due to major vascular defects [66, 67]. Flk-1deficient mice die in utero because of an early defect in the development of hematopoietic cells and endothelial cells [22]. Flt-1-deficient mice die later in utero, due to the disorganization of the early embryonic vasculature [23, 68]. Hypoxia leads to the stabilization of HIF-1α, a transcriptional activator of hypoxia-inducible genes, including VEGF-A, erythropoietin, and other angiogenic factors expressed in the kidney, such as angiopoietin-1, angiopoietin-2, PDGFBB, and FGFβ [10, 69]. Although it is likely that several signaling pathways contribute to the angiogenic response to hypoxia in kidney development resulting in glomerular vascularization, undoubtedly VEGF-A plays a critical role [10]. Accordingly, the deletion of podocyte VEGF-A reduces the glomerular endothelial cells [45]. In contrast, the ablation of semaphorin 3A, a guidance protein that functions as a negative regulator of endothelial cell survival and

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migration, which is also secreted by podocytes [70, 71], results in glomerular capillary hyperplasia [72]. Conversely, excess podocyte semaphorin 3A leads to glomerular endothelial apoptosis and a low number of glomerular endothelial cells [72]. Together, these studies indicate that glomerular capillary development depends on pro- and antiangiogenic signaling pathways shared with other vascular beds, while it is clear that podocytes play a key role controlling glomerulogenesis. Other hypoxia-regulated angiogenic factors control the relationship between endothelial and mesangial cells during glomerular development, as revealed by targeted deletion experiments. The ablation of PDGF B, or its receptor PDGFR beta, expressed by endothelial and mesangial cells, respectively, and involved in vessel maturation, results in glomeruli with aneurysm-like glomerular capillaries and lacking mesangial cells [73, 74]. Similarly, the targeted ablation of CXCL12, its receptor CXCR4 or RBP-J, a transducer of notch signaling, and angiopoietin1 results in single-loop or ballooned glomerular capillaries associated with mesangial cell deﬁcit in some mutants [75–79]. The studies summarized here illustrate the critical role of hypoxiaregulated angiogenic factors and their signaling in the differentiation, proliferation, migration, and mutual regulation among glomerular endothelium, mesangial cells, and podocytes. The development of postglomerular capillary beds is thought to be driven and regulated by a similar array of angiogenic factors secreted by renal tubules and endothelial or mural cell precursors, including VEGF-A, angiopoietins, stromal cell-derived factor-1, erythropoietin, and angiotensin II. These factors are involved in the remarkable alignment of postglomerular capillaries with the renal tubules. The deletion of VEGF-A from developing renal tubules results in a hypoplastic medulla with fewer peritubular capillaries [79, 80]. Angiopoietin-2 regulates peritubular capillary architecture by promoting vascular mural cell differentiation in the presence of VEGF [81]. SDF-1 signaling from vascular mural cell progenitors to its receptor in endothelial cells regulates the size and distribution of

peritubular capillaries [77]. Moreover, vasa recta postnatal development is controlled by angiotensin II and mediated by increased tubular VEGF secretion [82]. Notably, the deletion of Foxd1 progenitors, a transcription factor expressed in the renal stroma, disrupts peritubular capillary development, recruitment of vascular mural cells, and nephron patterning [4]. This suggests that regulators of the local environment, as discussed above in regard to hypoxia, directly or indirectly inﬂuence epithelial-endothelial-mural cell cross talk and ultimately the patterning of the renal vasculature.

The Glomerular Filtration Barrier The renal glomerulus controls the filtration of water and solutes while at the same time acting as a barrier retaining vital molecules such as plasma proteins. The glomerular filter functions as a semipermeable, macromolecular sieve capable of excluding molecules larger than serum albumin (MM 66,400) [83, 84]. The glomerular filtration barrier (GFB) separating the vasculature from the urinary space consists of a three-layered in-series structural arrangement of highly specialized cells that interact with one another (Fig. 1). The components of the GFB include three layers: the fenestrated endothelial cells lined by a glycocalyx, the glomerular basement membrane (GBM), and the slit diaphragm, which links the neighboring podocyte foot processes.

Components of the GFB Table 1 and see also ▶ Chaps. 1, “Embryonic Development of the Kidney,” and ▶ 18, “Translational Research Methods: Renal Stem Cells” of this text.

The Podocyte Podocytes, the glomerular visceral epithelial cells that reside within the Bowman’s space and bathe in the glomerular ﬁltrate, are a specialized and anatomically unique feature of the glomerulus. The podocyte has microtubule-based cellular

A. Tufro and A. Gulati

Fig. 1 Ultrastructure of a typical glomerular capillary loop: podocyte foot processes ( fp), slitdiaphragm (thin arrow), glomerular basement membrane (GBM), capillary (cap) endothelial cell (EC) with fenestrations (thick arrows)

extensions known as primary processes and actin-based interdigitating secondary processes known as foot processes, which rest on the GBM [85, 86]. Mature podocyte foot processes are connected by modiﬁed adherens junctions called slit diaphragms (SD). During glomerulogenesis, columnar podocytes are joined by tight junctions, which migrate toward the basal side and acquire SD features as differentiation proceeds. The major molecular components of the glomerular ﬁltration barrier are described in Table 1. The ultrastructure of the SD has been conventionally studied using transmission electron microscopy (TEM) (Fig. 1), EM tomography, and scanning EM [87–90]. Rodewald and Karnovsky described the SD as “zipper structure arrangement” with regular pores with a mean width of ~40A, which would restrict the passage of most serum proteins [87]. Tryggvason et al. [89] provided new insight into the threedimensional molecular structure of the podocyte slit diaphragm by identifying the extracellular domain of nephrin as the backbone of the SD and irregular pores with similar average width. Recent examination of the slit diaphragm using scanning EM challenges the view of an ordered “zipper-like” SD structure and suggests a heteroporous structure with ellipsoidal pores of ~120 A radius measured by digital morphometry [90]. Tracer studies followed by TEM show that

the filtration of large molecules such as ferritin (MM ~500,000) is hindered at the GBM, whereas smaller proteins such as horseradish peroxidase (MM 40,000) are filtered by the GBM but retained by the SD [91–93]. In addition to its structural function as a filtration barrier and cell-cell junction, the SD is a signaling protein complex that dynamically determines podocyte cell behavior. Extracellular domains of nephrin, neph1, P-cadherin, and FAT1 contribute to the SD protein complex, which includes multiple scaffolding, receptors, and actin-binding proteins, through direct and indirect protein interactions. The list of SD complex members is ever growing, and their roles are documented in gene ablation experiments, as well as human mutations leading to proteinuria and glomerular disease ([94–111], Table 1).

The Glomerular Basement Membrane The GBM is the extracellular gel-like matrix component that lies between podocytes and endothelial cells, composed of four major macromolecules: laminin, type IV collagen, nidogen, and heparan sulfate proteoglycan [112] (see Table 1). In the mature GBM, laminin is a trimer consisting of α5, β2, and γ1 laminin chains (α5β2γ1 or 521), and collagen IV is a trimer consisting of α3, α4, and α5 chains [113]. In contrast, laminin α1β2γ1 and α1 and α2 collagen IV

Development of Glomerular Circulation and Function

Table 1 Known molecular components of the glomerular filtration barrier (Refs. [94–113]) Protein/ localization Slit diaphragm Nephrin

Neph-family proteins (Neph1–3)

Podocin

Gene

Function

Characteristic

References

NPHS1

Finnish form of congenital nephrotic syndrome Infantile nephrotic syndrome Autosomal recessive inheritance Phenotype of the mice lacking Neph1 resembles that of nephrin-deﬁcient mice

Transmembrane protein localized to SD

[94–100, 103, 104]

Neph1–3 are components of the SD

[101, 102]

Transmembrane protein interacts with nephrin and neph1 Multidomain scaffolding protein at the SD

[105, 106]

Component of SD

[110]

Component of SD

[111]

Adhesion molecule, large protocadherin at SD contains a larger extracellular domain than traditional cadherins Present in cytoplasmic component of SD

[195]

Zinc ﬁnger transcription factor and RNA-binding protein

[193]

Neph1 (Kirrel) Neph2 (Kirrel3) Neph3 (Kirrel2) NPHS2

CD2-associated protein

CD2AP

Phospholipase C epsilon 1

PLCE1

Transient receptor potential cation channel subfamily C member 6 FAT

TRPC6

Zonula occludens-1

Podocyte WT-1

Autosomal recessive steroidresistant nephrotic syndrome (infantile and childhood) Autosomal recessive infantile steroid-resistant nephrotic syndrome Autosomal recessive infantile and early childhood steroidresistant nephrotic syndrome; major gene of DMS Autosomal dominant Juvenile and adult onset FSGS

FAT

Component of SD, co-localizes with ZO-1

ZO-1

Most commonly associated with tight junctions, sometimes associated with adherens junctions

WT-1

First identiﬁed as a tumor suppressor gene for Wilms tumor Expression restricted to the podocyte Denys-Drash syndrome – diffuse mesangial sclerosis within the glomeruli Frasier syndrome – glomerulosclerosis

[107–109]

[195]

(continued)

A. Tufro and A. Gulati

Table 1 (continued) Protein/ localization LMX1B

Pod1/epicardin/ capsulin

Gene LMX1B

Pod1

Integrins

Function Regulates podocyte-speciﬁc gene expression; KO mice show reduced expression of foot processes Unique role in renal development and in the patterning of the skeletal system; mutation causes nail-patella syndrome KO mice glomerular development arrests at single capillary loop stage Alpha3beta1 integrin Major integrin expressed by podocytes Important for podocyte differentiation Receptor for some isoforms of laminin Major laminin-binding integrin Alpha1beta1 Alpha2beta 2 are collagen IV receptors Maintains podocyte cell separation Deﬁcient mice are susceptible to hypertension

Podocalyxin

Podxl

GLEPP1

Synaptopodin

Foot process assembly

Alpha-actinin 4

ACTN4

VEGF-A

VEGF

Angiopoietin-1

Familial FSGS has been described Endothelial cell mitogen for endothelial cell differentiation, survival, proliferation, and migration Remodeling and maturation of capillaries

GBM Laminin

LAMB2 (humans)

Juvenile isoforms LM-111 and LM-511 replaced by mature isoform LM-521 in mature glomeruli No known human mutations in LAMA1/B1/C1/A5 Mutations in human LAMB2 gene known (Pierson syndrome)

Characteristic LIM-homeodomain transcription factor

References [193]

Basic helix-loop-helix transcription factor

[193]

Adhesion protein in the GBM

[194]

Sulfated cell surface sialomucin-charged protein Cell surface protein Receptor tyrosine phosphatase Actin-associated cytoskeletal protein Actin-binding protein

[195]

[113]

Glycoprotein

[25, 26]

70 kDa glycoprotein

[31]

Large (~800 kd) heterotrimer of alpha, beta, and gamma glycoprotein chains

[194]

[195]

(continued)

Development of Glomerular Circulation and Function

Table 1 (continued) Protein/ localization Type-IV collagen

Nidogen

Agrin (most abundant) and perlecan

Gene COL4A3, A4, A5

Function Alpha-1,2 in early nephron, shift to 3,4,5 subunits in mature GBM Mutations in human COL4A3, A4 (autosomal recessive), A5 (most common, X-linked) genes – Alport syndrome One of the integral basement membrane protein Function not yet determined Negatively charged GBM components originally thought to contribute to the charge selective barrier (however, current evidence challenges this REF)

are expressed in the developing GBM [114]. Specific basement membrane protein isoforms are crucial for glomerular development, morphology, and function, as mutations in laminin β2 (LAMB2) or collagen IV (Alport) alter the GBM structure and lead to progressive glomerular disease. The mechanisms for transitions from immature to adult-type isoforms of the GBM proteins are not completely understood, but these substitutions are important for the structural and functional integrity of the GFB [113, 115–117]. It has long been accepted that the net negative charge of the GBM is a crucial component of the glomerular capillary wall’s filtration barrier to plasma albumin, which is also negatively charged and should therefore be repelled by the GBM [91]. However, the concept of charge selectivity has recently been called into question. Removal of these negatively charged proteoglycans has no effect on the glomerular filtration barrier permeability to either albumin or to a negatively charged tracer [118]. It has been suggested that GBM charge plays a minor role in imparting the glomerular filter with charge selectivity and argued that the GBM functions as a gel where macromolecules traffic by diffusion depending on their molecular size [119] or their size and anionic charge [120].

Characteristic Triple helical heterotrimer of collagen IV alpha chains

References [194]

Two isoforms A and B, each consisting of a single polypeptide chain

[112, 113]

Heparan sulfate proteoglycans with negatively charged sulfated glycosaminoglycan side chains

[112, 113]

The Glomerular Endothelial Cell Layer and Its Contributions to the Filtration Barrier The endothelium functions as a barrier, regulates vasomotor tone, and controls tissue inflammation and thrombosis. Glomerular endothelial cells form a fenestrated capillary bed and play a role in the filtration function [121]. Endothelial fenestrations are transcellular holes that allow the plasma flowing through the capillaries to reach the GBM, even though fenestrations are plugged by a glycocalyx-like material consisting of sulfated proteoglycans and glycoproteins that impart barrier properties [51, 55–57]. The glomerular endothelial surface layer has a thickness similar to that of the GBM consisting of two elements, the glycocalyx and the cell coat [122]. It has been proposed that the endothelial glycocalyx might contribute significantly to the GFB permselectivity [122–127]. The glycocalyx components are covalently bound to the endothelial cell membrane and are attached to the glycocalyx by charge-charge interactions [128, 129]. Damage to the glycocalyx and endothelial cell coat causes proteinuria in the absence of detectable damage to the GBM or the podocytes, but the evidence remains indirect [130, 131].

As discussed above, the assembly and integrity of endothelial cells are regulated by angiogenic factor signaling. VEGF-A is necessary for the survival of endothelial cells, to establish and maintain the integrity of endothelial fenestrae, as demonstrated by knockdown and loss of function in vivo experiments, and endothelial cell damage leading to TMA in humans treated with VEGF-A receptor blockers [35, 46, 47, 61]. Angiopoietin-1 produced by mural cells supports endothelial cell survival and decreases vascular permeability by inhibiting VEGF-induced eNOS activation [132]. Angiopoietin-2 is stored in Weibel-Palade bodies and secreted by activated endothelial cells. Angiopoietin-2 and angiopoietin-1 compete for signaling via the Tie2 receptor; in the presence of VEGF-A, angiopoietin-2 leads to angiogenesis, whereas in the absence of VEGF-A, it causes endothelial cell apoptosis [133]. Davis et al. showed that podocyte-speciﬁc overexpression of angiopoietin-2 leads to apoptosis of glomerular endothelial cells, without affecting the podocytes [134]. In addition, mesangial cells affect the glomerular endothelial cell properties and promote glomerular endothelial cell survival by inactivating TGFβ [78, 135–138].

Glomerular Filtration Barrier (GFB) Selective Permeability The glomerular filtration barrier has size-selective properties and differentially handles molecules of varying size. Small molecules up to the size of inulin filter freely, whereas large molecules such as plasma proteins are held back. The sieving coefficient for a particular molecule is the ratio of its concentration in the glomerular filtrate relative to the plasma concentration. The GFB pore theory assumes that the capillary wall consists of cylindrical pores of two or various sizes allowing size-selective passage of molecules through them [139–143]. The fiber matrix theory, an extension of the pore theory, posits that the GFB consists of pores filled with a fiber matrix [144]. Various mathematical models have been proposed and applied to the porous substructure of the barrier to predict macromolecular sizes that will be

A. Tufro and A. Gulati

compatible for crossing the barrier. In general, there has been a discrepancy between these calculations and the in vivo descriptions of molecular sieving, suggesting that other mechanisms might be involved [145, 146]. Kedem and Katchalsky have proposed flux equations for defining the physical properties of the GFB and require no specification of its substructure [147]. Charge selectivity has been an age-old phenomenon assumed to operate at the level of the GBM due to the presence of negatively charged proteoglycans, which were thought to repel the anionic proteins. However, present-day emphasis is on the endothelial layer glycocalyx property conferring charge selectivity to the GFB. Smithies proposed that the size selectivity of the glomerulus resides solely in the GBM, which functions as a concentrated gel and macromolecules permeate mostly by diffusion and also by fluid flow (convection). Hence, this gel permeation/ diffusion model suggests that lower filtration rate causing lower water flow and thus a higher concentration of proteins in the proximal tubular fluid and the tubular mechanisms of reabsorption saturate earlier to increase proteinuria [119]. Data from children with nephrotic syndrome fit this hypothesis [148], provided the degree of podocyte effacement is also taken into account, suggesting that the latter influences the size selectivity of the GFB beyond limitations of GFR. Recently, Moeller and colleagues proposed an electrokinetic model, whereby a local electric field “streaming potential” is established across the glomerular filter that prevents plasma proteins from entering or crossing the filter [120]. This hypothesis fits data from several previous models but awaits further experimental confirmation.

Glomerular Hemodynamics and Assessment of Renal Function The molecular basis of glomerular architecture discussed previously argues that the glomerular structure provides functional advantages leading to controlled glomerular ﬁltration. Mammalian glomerular capillary pressure averages 50 mmHg, which is approximately 50 % of the

Development of Glomerular Circulation and Function

mean systemic arterial pressure, with waveform characteristics similar to the central aorta [149]. The glomerular capillaries form a highpressure system with about 4 times the pressure of systemic capillaries and confer a functional advantage due to higher blood ﬂow rates enabling higher clearance as they ﬁlter large volumes of plasma (~180 l/day).

Renal Blood Flow: Basic Concepts Renal blood flow is approximately 1 L/min (20 % of cardiac output) Fig. 2. Renal plasma flow is the portion of the renal blood flow available for ultrafiltration: RPF = (1-Hct)*RBF, thus given a normal Hct of 40 %, RPF is approximately 600 ml/min. Renal blood flow (RBF) is determined systemically by the renal perfusion pressure that depends on the systemic arterial blood pressure (SBP) and locally by the renal vascular resistance (RVR), so RBF/SBP/RVR. The unique architecture of the renal vasculature enables to control the RVR at two sites, the afferent and efferent arterioles, where significant pressure drops occur, leading to relatively high glomerular capillary pressure and low peritubular

Fraction of cardiac output perfusing the kidneys %

Age, days

0 15

Fig. 2 Renal blood ﬂow as a percentage of cardiac output, plotted versus age, in growing rats between 17 and 60 days of age (From Ref. [196])

capillary pressure. Thus changes in arteriolar resistance lead to changes in glomerular plasma flow and glomerular capillary pressure, which can influence GFR. For example, during sympathetic stimulation or increased angiotensin II, both afferent and efferent resistance increase; thus RPF decreases, but GFR remains constant due to the opposite effect of afferent and efferent resistance on GFR. This intrinsic autoregulation occurring via neurohumoral mechanisms is mainly a consequence of local adjustment of RVR secondary to changes in efferent arteriolar tone. The efferent arteriole is normally in a state of only partial constriction, and any increase or decrease in blood flow is accompanied by a reciprocal change in glomerular filtration pressure, with the result that the filtration rate remains relatively unchanged [150–152]. Though the efferent arteriole seems to take precedence over the afferent as a controller of renal hemodynamics, the contributions of pre-and postglomerular vasculature vary owing to specific circumstances. The efferent arteriole seems to be the major regulator of renal blood flow during conditions of stress or after the administration of angiotensin-converting enzyme inhibitors or receptor blockers [150–152]. However, the large increase in RPF to the remnant kidney after a nephrectomy leads to a dramatic decrease in afferent arteriole resistance, driving a rapid increase in GFR. Generally, increased glomerular plasma flow leads to increased GFR. The reduction in hematocrit in euvolemic patients increases RPFs and is a mechanism contributing to hyperfiltration injury in anemic states [153]. Under normal conditions, the glomerular filtrate is a steady fraction of the RPF, the so-called filtration fraction (FF) [149]. FF = GFR/RPF. Because normal GFR is 125 ml/min and RPF 600 ml/min, normal FF is 0.2. FF is higher at low RPF and when efferent arteriole resistance is increased.

Perinatal Considerations for Renal Blood Flow and GFR The fetal human kidney main function from gestation week 16 onwards is to produce urine to

A. Tufro and A. Gulati

maintain normal amniotic fluid volume, as the fetal fluid-electrolyte homeostasis and solute clearance are achieved through the placenta and maternal kidney function. Though nephrogenesis is complete by 34–36 weeks of gestation, the efficiency of the renal excretory system akin to most other organ systems is age dependent even in postnatal life related to structural maturation [154]. It is of utmost importance to the clinician to be aware of the functional capacity of the newborn kidney and the extreme states of vulnerability posed by prematurity and at the same time understand the expected sequence of physiologic adaptations of kidney function that shall occur with time during a successful transition to extrauterine life. The proportion of cardiac output flowing through the kidney increases with gestational and postnatal age; the fetal kidney is receiving only 2–3 % of the cardiac output in animals and humans alike [155–157]. The low fetal renal blood flow, which does not attain adult levels until 2 years of age, forms the basis for reduced capacity for glomerular filtration in the newborn period and early childhood [158] Fig. 3. The normally low GFR in neonates is further decreased in premature infants due to 2 160 GFR, ml/ min/ 1.73m

150

100

Age, months

0 0

Fig. 3 Glomerular ﬁltration rate (GFR) during the ﬁrst year of life (From Ref. [197])

lower renal perfusion, incomplete nephrogenesis, or reduced nephron number associated with prematurity Figs. 4 and 5. The most elaborate quantitative data on postnatal RPF in neonates and small children has been provided from the measurement of renal extraction ratios of PAH. PAH clearance in neonates increases from about 65 % to attain 90 % of adult value by 5 months of age. RPF increased from about 140 ml/min/1.73 m2 at 8 days of age in a full-term infant to 580 ml/min/1.73 m2 at 5 months of age. Comparatively, the RPF in normal adults is 625 ml/min [159]. In preterm neonates, the RPF (PAH clearance) is presumably lower, though not measured. The renal hemodynamic alterations between fetal and adult life are mainly accompanied by a gradual decrease in RVR and consequent increments in RBF [160]. See comment in PubMed Commons below. Inulin clearance of premature and term neonates remains low despite the correction for body size [161]. This has been attributed to factors related to the low permeability of the glomerular filtration barrier, small available surface area for filtration, low systemic arterial pressure, and relatively high resistance of the afferent glomerular arteriole [154]. Measurements of filtration pressure in guinea pigs suggest a 2.5-fold increase within the first 2 postnatal months. This in conjunction with maturational changes in permeability of the filtration barrier and increase in available surface area for filtration could account for a 20-fold increase in GFR [162]. GFR increases during postnatal development and maturation in various animal species [163, 164]. Barnett et al. showed that GFR in preterm infants does not increase postnatally as rapidly as in full-term infants [165]. The overall developmental pattern of postnatal GFR changes in the humans suggests nonlinear increments in GFR that are much more pronounced with postnatal age beyond 34 weeks of gestation, coinciding with the time when nephrogenesis is completed, as compared to much slower GFR increases at lower gestational age (Fig. 6) [166]. However, this has been questioned by recent estimates of GFR [167]. Overall, neonates constitute a high-risk group requiring thoughtful fluid management and choice

Development of Glomerular Circulation and Function

Fig. 4 Creatinine clearance measured within 24–40 h of birth in 30-week premature to 40-week full-term infants (From Ref. [198])

CREATININE CLEARANCE (ml/min/1.73 M2) r = 0.643 p = < .001

50 40

30 20

GESTATION (Weeks)

PLASMA CREATININE (mg/dl)

1.8 1− 30 days n = 52 r = −0.575 p < 0.001

1.6 1.4

31− 94 days n = 29 r = 0.006 PNS

1.2 1.0 0.8 0.6 0.4 0.2

100

AGE (Days)

Fig. 5 Plasma creatinine values during the ﬁrst 3 months of life in low-birth-weight infants (less than 2,000 g). (From Ref. [199])

and dosage of exogenous agents, aiming at primum non nocere.

GFR: Basic Concepts Our understanding of the GFR has followed a distinct timeline with advances in evaluation of

renal hemodynamics and knowledge of glomerular physiology. The classical concept of glomerular filtration stems from Ludwig’s filtration theory that states that water and solutes move across the glomerular filtration barrier due to a hydrostatic pressure difference that favors filtration [168].

A. Tufro and A. Gulati

creatinine clearance (ml / min)

6 5 4 3 2 1

32 34 36 gestational age (wks)

Fig. 6 Increase in creatinine clearance with GA (gestational + postnatal ages). Infants studied at birth were grouped for GA and are represented by mean values 1 SD connected by the solid line (y = 0.170 4.95, r = 0.51, P T/p.Cys603Ser c.1811delT/p.Leu604fs c.1817G>C/p.Cys606Ser c.1834G>T/p.Gly612X c.1897G>A/p.Gly633Arg c.1934G>C/p.Cys645Ser c.1935C>A/p.Cys645X c.1951C>T/p.Arg651X c.1954C>T/p.Arg652X (2 f) c.1977A>C/p.Arg659Ser

c.2020A>T/p.Lys674X c.2145delA/p.Glu716fs c.2270C>G/p.Ser757X c.2275C>T/p.Pro759Ser c.2306_07inv/p.Leu769Pro c.2310C>A/p.Asn770Lys c.2327A>G/p.Gln776Arg c.2413T>C/p.Ser805Pro c.2445C>A/p.Ser815Arg c.2527T>C/p.Ser843Pro c.2630T>C/p.Leu877Pro c.2753G>A/p.Trp918X c.2799+1G>A/Splicing (3 f) c.2936T>C/p.Leu979P

mutations (litterature)

c.402T>C/p.Phe134X c.488C>G/p.Ser163X c.1004delG/p.Ser335,fs c.1131dupT/p.Glu378,fs (2 f) c.1308T>A/p.Cys436X c.1375delT/p.Ser459,fs c.1509insA/p.Tyr503X c.1609C>T/p.Arg537X(2 f)

c.1768C>T/p.Arg590X

c.2017C>T/p.Arg673X c.2024C>G/p.Ser675X c.2125delA/p.Thr709,fs c.2365G>T/.p.Gly789X/Splicing c.2365+3delA/splicing c.2453C>T/p.Ser818L (2 f) c.2460insA/p.His821,fs c.2771T>C/p.Leu924P c.2839C>T/p.Arg947X c.2871dupC/p.Ala958,fs c.2899C>T/p.Gln967X c.2915A>G/p.Glu972G

Fig. 9 NR3C2 mutations in renal pseudohypoaldosteronism type I. The NR3C2 gene is represented with its intron/exon structure (exons are represented by boxes or black lines, introns by spaces in between). Eight exons [2–9] code for the functional domains of the MR protein. NR3C2 mutations identiﬁed in PHA1 are depicted on the

gene. The functional domains of the MR are indicated. DBD, DNA binding domain; LBD, ligand binding domain; (PHA.NET), unpublished mutations identiﬁed in the context of the clinical and research network PHA.NET (PI: M-C. Zennaro, Paris)

α-ENaC mutations on the renin–aldosterone system, growth, and pubertal development of PHA1 patients [482]. Three patients homozygous for nonsense and frameshift mutations in α-ENaC presented short stature, poor growth, and growth hormone tests compatible with the diagnosis of GH deﬁciency. In all patients, there was an

age-dependent normalization in the urinary Na/K ratios accompanied by an exaggerated renin–aldosterone system response probably contributing to age-dependent amelioration. In contrast, one patient compound heterozygous for a missense mutation and for a frameshift mutation of α-ENaC presented normal growth, normal

Renal Tubular Disorders of Electrolyte Regulation in Children

puberty, and decrease of renin–aldosterone axis activity with age. These results demonstrate distinct genotype–phenotype relationships in generalized PHA1 patients that depend on the degree of functional ENaC impairment. If undetected during the ﬁrst week of life, multisystem PHA1 can lead to neonatal death; however, if detected, the patients may lead near normal lives on a lifelong high-salt diet [483]. Extensive genetic investigation of PHA1 patients in recent years has also shown that the disease comprises a continuum of phenotypically and/or biologically distinct entities that may challenge the current genetic classiﬁcation of the disease. Indeed, investigation of heterozygote carriers of a α-ENaC p.Ser562Pro mutation, responsible for generalized PHA1 in homozygous patients, revealed a subclinical salt-losing phenotype with increased sweat sodium and chloride concentrations without additional hormonal or clinical manifestation [484]. Furthermore, recessively inherited ENaC mutations, associated with partial loss of channel function, may result in a mild phenotypic expression of PHA, with a saltlosing disorder in a premature infant, but only a biological phenotype in a sibling born at term [485]. We recently observed a case of recessive PHA1 with an extremely severe phenotype of dehydration and hyperkalemia, but without cutaneous or pulmonary phenotype, caused by MR mutations [486]. These cases broaden the spectrum of clinical phenotypes in renal PHA1 and support corresponding genetic screening for the disease in patients with isolated renal salt-losing syndromes and/or failure to thrive.

Treatment and Prognosis Treatment of PHA1 consists in the replacement of salt loss and rehydration, as well as correction of hyperkalemia and acidosis in the acute phase of the disease. Since the main differential diagnosis is congenital adrenal hyperplasia or isolated deficiency in aldosterone synthase (CMOI and CMOII) [487], replacement therapy with fludrocortisone and hydrocortisone may be undertaken while confirming the diagnosis by hormonal measurements. Early postnatal hyperkalemia may sometimes complicate antenatal Bartter syndrome

1251

(aBS, due to mutation in the potassium channel ROMK) [488]. Its association with hyponatremia and hyperreninemic hyperaldosteronism may erroneously suggest the diagnosis of PHA1. However, hyperkalemia appears usually very early and normalizes by the end of the first postnatal week, whereas PHA1 is characterized by permanent hyperkalemia. Other distinctive features of aBS patients are metabolic alkalosis as well as hypercalciuria and nephrocalcinosis. Also maternal hydramnios, present in aBS, is a rare event in generalized PHA1. After the acute period, treatment consists in salt supplementation. The doses vary depending on the severity of the disease. Neonatal genetic diagnosis on cord blood may allow rapid diagnosis and management of the condition in affected offspring from PHA1 families with identified mutations. In renal and secondary PHA1, 3–20 mEq/kg/day of Na given as NaCl and NaHCO3 are sufficient to compensate for the salt loss and are followed by rapid clinical and biochemical improvement. The expansion of extracellular volume results in increased tubular flow and delivery of sodium to the distal nephron, creating a favorable gradient for potassium secretion. Nevertheless, ion exchange resins are often associated to the treatment to normalize potassium levels. The amount of sodium required depends on the severity of the symptoms and is deduced from the normalization of plasma potassium concentration and plasma renin. Since renal PHA1 improves with age, treatment can be discontinued after a variable period of time in most patients, generally around age 18–24 months. Older children are generally asymptomatic on a normal salt intake and show a normal growth and psychomotor development, although they may evolve on the lower percentiles of the growth curve, despite adequate medical therapy [489]. In contrast to renal PHA1, generalized PHA1 represents a therapeutic challenge. No evidencebased treatment has been described, and therapeutic intervention is patient specific. Generally, high doses of sodium (between 20 and 50 mEq/kg/day) are used, together with ion exchange resins and dietary manipulations to reduce potassium levels. Corticoid treatment is sometimes associated and seems to provide some additional benefit.

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Administration of indomethacin may be useful in occasional patients [490]. Symptomatic treatment is necessary for the respiratory tract illnesses and to correct the skin phenotype. Only few cases of generalized PHA1 followed up for several years or into adulthood have been described: treatment is necessary throughout life, consisting of salt supplementation (8–20 g NaCl/day) and ion exchange resins [460, 491]

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Renal Tubular Acidosis in Children

Raymond Quigley and Matthias T. F. Wolf

Contents

Introduction

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1273 Historical Development of Classiﬁcation of RTA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1273 Physiology of Acid Secretion . . . . . . . . . . . . . . . . . . . . . 1275 Proximal Renal Tubular Acidosis (Type II RTA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fanconi Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Congenital Isolated Proximal RTA . . . . . . . . . . . . . . . . . Congenital Fanconi Syndrome . . . . . . . . . . . . . . . . . . . . . Acquired Isolated Proximal RTA . . . . . . . . . . . . . . . . . . . Acquired Fanconi Syndrome . . . . . . . . . . . . . . . . . . . . . . .

1279 1279 1282 1282 1282 1284 1286 1286

Distal Renal Tubular Acidosis (Type 1 RTA) . . . 1286 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1286 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1288 Type III Renal Tubular Acidosis . . . . . . . . . . . . . . . . . 1290 Type IV Renal Tubular Acidosis . . . . . . . . . . . . . . . . . Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aldosterone Deﬁciency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aldosterone Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acquired . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1291 1291 1291 1291 1292 1292

Diagnosis and Treatment of Renal Tubular Acidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1293 Differentiating Proximal and Distal RTA . . . . . . . . . . 1296 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1296 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1296

R. Quigley (*) • M.T.F. Wolf Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA e-mail: [emailprotected] # Springer-Verlag Berlin Heidelberg 2016 E.D. Avner et al. (eds.), Pediatric Nephrology, DOI 10.1007/978-3-662-43596-0_35

Renal tubular acidosis (RTA) is a condition in which there is a defect in renal excretion of hydrogen ion, or reabsorption of bicarbonate, or both, which occurs in the absence of or out of proportion to an impairment in the glomerular filtration rate [1]. Thus, RTA is distinguished from the renal acidosis that develops as a result of advanced chronic kidney disease [2–4]. Albright originally described the disease as “renal acidosis resulting from tubular insufficiency without glomerular insufficiency” to emphasize this distinction [5]. The term was reduced to “renal tubular acidosis” by Pines and Mudge in their studies published in 1951 [6]. These renal tubular abnormalities can occur as an inherited disease or can result from other disorders or toxins that affect the renal tubules.

Historical Development of Classification of RTA The historical development of renal tubular acidosis parallels the historical development of our understanding of renal physiology. As with many complex diseases, investigations into disease processes improve our understanding of normal physiology, and, in turn, the advances in basic physiologic research shed light on pathophysiology and mechanisms of diseases. This is apparent in the historical development of renal tubular 1273

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acidosis, which began in the early twentieth century and is now extending into the molecular biologic era as medicine has entered the twentyfirst century. In addition, some of the confusion with the classification scheme of RTA stems from its historical development. At the British Paediatric Association meeting in 1935, Lightwood described six infants out of an autopsy series of 850 that had “calcium infarction” of the kidneys [7]. This would later be recognized as the first report of infants with nephrocalcinosis from renal tubular acidosis. Butler et al. described a series of four infants with similar findings in 1936 [8]. In addition to nephrocalcinosis, these infants were also found to have hyperchloremia and acidosis, suggesting that there was a relationship between the biochemical findings and nephrocalcinosis. It was not clear from these first reports if the biochemical findings were the cause of the calcium deposits in the kidneys or were the result of damage to the renal tubules from the calcinosis. The first description of the potential pathophysiologic explanation for these findings was put forward by Albright et al. in 1946 [5]. In this classic description of various forms of osteomalacia, the authors also outlined the treatment of these patients with a solution of citric acid and sodium citrate that was advocated by Dr Shohl. Albright described this form of acidosis as “renal acidosis resulting from tubular insufficiency without glomerular insufficiency” to distinguish this form of acidosis from the acidosis that occurs in renal failure. The entity of “infantile renal acidosis” was then described by Lightwood in 1953 in a series of 35 infants [9]. This was a larger series of infants than his first description, and they had similar clinical histories and biochemical findings as the series by Butler [8]. The first description of an adult with similar findings was made in 1945 by Baines et al. [10]. During the 1940s and 1950s, a number of cases of renal tubular acidosis were described and led to investigations of the renal acidification defect [4, 11]. The primary feature in these patients was the inability to lower their urine pH despite having mild to moderate acidosis. This became the defining characteristic of this disease as reported in a series

R. Quigley and M.T.F. Wolf

of studies by Elkinton [12–14]. In the classic report by Pines and Mudge, the term “renal tubular acidosis” was used to replace the previously more cumbersome term of “renal acidosis resulting from tubular insufficiency without glomerular insufficiency” [6]. This new term was emphasized in an editorial review by Elkinton and has remained the term for this disease ever since [12]. Thus, at the end of the 1950s, renal tubular acidosis was thought to be a disease process that limited the ability of the kidneys to lower the urine pH, despite the fact that the patient had mild to moderate acidosis. Although the concept of glomerular filtration had been well established in the early twentieth century, the measurement of the rate of glomerular filtration in humans had not yet been performed. This was accomplished by the pioneering work of Homer Smith. He was one of the first to conceive of the idea of a renal excretion system in which there was a high glomerular filtration rate which required tubular reabsorption of solutes [15]. The fact that the glomerular filtration rate was very high and was followed by tubular modifications of the urine had profound effects on the ideas of bicarbonate handling and acid secretion. The disorder of renal tubular acidosis was initially thought to be due to the inability of the kidney to maintain the steep pH gradient in the distal nephron segment. The idea that this disorder could arise from the inability of the proximal tubule to recover the filtered bicarbonate was first suggested in 1949 by Stapleton [16]. He reported a patient that had significant amounts of bicarbonate in the urine at low concentrations of serum bicarbonate. This idea was further advanced by Soriano in a report of two patients that demonstrated an abnormally low threshold for bicarbonate excretion [17, 18]. Based on their findings in these patients, Soriano and Edelmann proposed classifying patients with RTA as having either distal or proximal tubule defects. This was the initial description of the need for a classification scheme for this disease, suggesting that there could be multiple causes for this disease process. The dichotomy of proximal and distal RTA was firmly established in the classic review by Rodriguez-Soriano and Edelmann which summarized the understanding of the pathophysiology at

Renal Tubular Acidosis in Children

that time [1]. The nomenclature of type I and type II RTA was established by the end of the 1960s in a review by Morris [19]. In this review, distal RTA was referred to as type I (or classic) and proximal RTA as type II. The author also described a type III RTA as those patients that displayed features consistent with both forms of RTA. In 1972, McSherry et al. described several patients that displayed characteristics of classic type I RTA but in addition had a reduced threshold for bicarbonate reabsorption [20]. These patients seemed to fit the description of type III RTA. Subsequently, the reabsorption of bicarbonate in these patients normalized so that they were thought to have classic type I RTA with a developmental immaturity of the proximal tubule. Since that time, type III RTA has been essentially dropped from the classification scheme of RTA. It is interesting to note that the review by Gennari and Cohen did not mention type III RTA [21]. In the middle of the twentieth century, the discovery of aldosterone revolutionized our understanding of the physiology of sodium and potassium metabolism [22]. Subsequently, it was found that patients with aldosterone deficiency had a form of RTA that resembled that of distal RTA, but the patients had hyperkalemia and not hypokalemia [23, 24]. This form of RTA was then referred to as type IV RTA. More recently, other defects in distal nephron transporters have also been characterized and resemble the findings of type IV RTA. Although they are not true aldosterone-deficient syndromes, they also are described as type IV RTA since these patients also have hyperkalemia. To add to the confusion, a review published in 1986 classified RTAs as type I (distal), type II (proximal), and type III (aldosterone-deficient RTA) [25]. In recent years, there have been suggestions to clarify the classification of RTAs in a scheme that is based more on the pathophysiologic mechanism of the disease [26, 27]. While this might eventually be the preferred nomenclature, most practicing nephrologists continue to use the historical classification. The other schemes will be discussed as part of the pathophysiology of RTA. Over the past century, advances in renal physiology, acid–base chemistry, and molecular

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genetics have greatly improved our understanding of the various forms of renal tubular acidosis. Currently, the diagnosis and classiﬁcation of the various types of renal tubular acidosis continue to rely on biochemical measurements of blood and urine. During the twenty-ﬁrst century, however, the diagnosis of renal tubular acidosis may eventually be made by a molecular genetic approach and not by extensive biochemical testing.

Physiology of Acid Secretion The kidney is the primary organ for long-term acid–base regulation. Thus, an understanding of the normal renal excretion of acid is necessary to understand the defects present in patients with RTA (see also ▶ Chap. 9, “Physiology of the Developing Kidney: Acid-Base Homeostasis and Its Disorders”). The typical Western diet generates approximately 1 mmol of H+/kg of body weight in adults [28]. In addition, children generate acid from the production of hydroxyapatite in growing bone and thus generate a total of approximately 2–3 mmol of H+/kg of body weight [29–31]. The acid generated from the diet and bone growth necessitates the excretion of acid by the kidneys. The amount of acid excreted by the kidneys is referred to as net acid excretion (NAE) and is expressed quantitatively as NAE ¼ UNH4 þ þ UTA UHCO3 V; where V is the urine ﬂow rate, UNH

is the urine

ammonium concentration, UTA is the urine titratable acid concentration, and UHCO3 is the urine bicarbonate concentration. Thus, the components of acid secretion can be thought of as bicarbonate reclamation to prevent bicarbonate loss, ammonium excretion, and titratable acid excretion. The processes for maintaining acid–base balance are quite complex, but the basic concepts will be reviewed so that the pathophysiologic changes in RTA can be described. The kidneys are responsible for the excretion of nitrogenous waste products, principally urea, that are generated from our diet. In mammalian

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R. Quigley and M.T.F. Wolf Blood

Tubular lumen HCO3– NHE3 Na+ H+

Na+

H+

HCO3–

NBC1 Na+

3HCO3–

H + HCO3– CA IV CA II H2O + CO2

H2O + CO2 Glutamine Glutaminase

NHE3 Na+ NH4+

NH4+

NH3

Glutamate Glutamate dehydrogenase α-Ketoglutarate HCO3– Glucose

H+ NH4+

Fig. 1 Model of bicarbonate reabsorption by a proximal tubule cell. The Na–K–ATPase located in the basolateral membrane generates and maintains the low intracellular sodium concentration. Protons are excreted into the tubule lumen by the sodium–proton exchanger (NHE3) where they combine with bicarbonate to form carbonic acid. In the presence of carbonic anhydrase IV (CAIV), the carbonic acid is hydrolyzed to water and carbon dioxide

which enter the cell and recombine to form carbonic acid by the action of intracellular carbonic acid II (CAII). The carbonic acid ionizes into a proton which is then excreted into the lumen and bicarbonate which is transported by the sodium bicarbonate symporter (NBC1) into the bloodstream (Reprinted with permission from Fry and Karet [216])

kidneys, urea is excreted primarily by filtration, which requires having a high filtration rate so this can be accomplished. The average adult will filter about 150–180 l of blood per day. Because bicarbonate is freely filtered in the glomerulus, a large amount of bicarbonate (about 4,000 mEq/day in an adult) must be reabsorbed by the tubules each day to prevent loss of base. The bulk of the filtered bicarbonate is reabsorbed in the proximal tubule by mechanisms that are illustrated in Fig. 1. A number of proteins, both transporters and enzymes, work in concert to reclaim approximately 80 % of the filtered bicarbonate in this tubule segment [32–36]. The initial step in the reabsorption of bicarbonate is the secretion of protons into the tubular

lumen. About two thirds of the proton secretory rate is provided by the sodium–proton antiporter [37–39]. The isoform that is present on the luminal membrane of the proximal tubule has been termed NHE3 (sodium–hydrogen exchanger 3). In addition to the secretion of protons, NHE3 also secretes ammonium ions by acting as a sodium–ammonium exchanger [40–42]. Metabolic acidosis increases both NHE3 expression and ammonia secretion via AT1 receptor activation [43, 44]. The energy for proton and ammonium secretion by the antiporter is derived from the low intracellular sodium concentration that is maintained by the basolaterally located sodium–potassium ATPase. There is evidence that approximately one third of the proton

Renal Tubular Acidosis in Children

BICARBONATE (mMols/100 ml. glomerular filtrate)

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J.L.A. R.F.P W.A.S

3.2 2.8

red

filte

reabsorbed

2.4 2.0 1.6 1.2 0.8

ete

r exc

0.4

PLASMA BICARBONATE (mMols/L)

Fig. 2 Bicarbonate titration curves for normal humans. At low concentrations of serum bicarbonate, all of the ﬁltered load can be reabsorbed. The process of bicarbonate reabsorption is saturable, so once the delivered bicarbonate

rate exceeds the transport maximum, bicarbonate will be excreted in the urine (Reprinted with permission from Pitts et al. [51])

secretory rate is provided by a proton ATPase located in the luminal membrane [39, 45]. This transporter derives its energy directly from ATP. Once the hydrogen ion is in the lumen of the proximal tubule, it combines with bicarbonate to form carbonic acid, which will then form carbon dioxide and water as shown in the following equation:

for secretion into the tubule lumen, while the bicarbonate ion is then transported through the basolateral membrane by the sodium bicarbonate cotransporter, NBC [34, 49, 50]. The overall process for reabsorbing bicarbonate in the proximal tubule is saturable [51]. This is illustrated in Fig. 2. When the serum bicarbonate concentration is within the normal range, the filtered load of bicarbonate can be almost completely reabsorbed. If the serum bicarbonate concentration begins to rise, the filtered load of bicarbonate will then exceed the reabsorption rate of the kidney, and bicarbonate will then be excreted into the urine. This has been studied in humans who were administered bicarbonate to determine the point at which bicarbonate would appear in the urine [51]. The data from these experiments form a titration curve (see Fig. 2). The threshold at which bicarbonate is excreted thus determines the normal serum concentration of bicarbonate. An additional task in maintaining acid–base balance for the proximal tubule is the generation of ammonia to serve as a buffer to efficiently

Hþ þ HCO3 !H2 CO3 þ CO2 :

carbonic anhydrase

! H2 O

The enzyme, carbonic anhydrase, is critical for catalyzing this process [46–48]. One isoform of this enzyme (carbonic anhydrase IV) is located in the brush border membrane of the proximal tubule and serves to catalyze the forward reaction, while another isoform of the enzyme (carbonic anhydrase II) is located inside the tubule cell for catalyzing the reverse reaction [46]. Thus, carbon dioxide and water can move rapidly into the proximal tubule cell and recombine to form carbonic acid which will ionize to form bicarbonate and a hydrogen ion. The hydrogen ion is then available

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excrete the bulk of the acid that is generated from our diet. It has long been recognized that the excretion of ammonium is critical to the overall excretion of acid by the kidneys [52]. This is primarily due to ammonium’s ability to buffer hydrogen ions. To excrete 100 mmol of unbuffered H+ at a pH of 4.0 ([H+] = 104 mol/l) would require a volume of 1,000 l of urine. The reaction of ammonia and H+ to form ammonium has a pKa of approximately 9.0 [53]. Thus, at a pH of 7.0, 99 % of all the ammonia in the urine is in the form of ammonium ion and is excreted as ammonium chloride, limiting the amount of free hydrogen ions in the urine. Thus, the ammonium excretion rate is a quantitatively more important factor for the excretion of acid than the urine pH. This can also create confusion in the assessment of a patient’s ability to excrete acid. The equation that defines net acid excretion (see above) does not include information about the urine pH. Since the pKa of the ammonia–ammonium equilibrium is 9, if the patient is excreting a large amount of protons as ammonium, the pH will tend to rise even though the amount of acid being excreted has increased. The tubular handling of ammonia and ammonium is complex [42, 54–56]. Briefly, ammonia is generated in the proximal tubule by the metabolism of glutamine and is secreted into the tubule lumen by the sodium–proton exchanger, NHE3, as the ammonium ion (see Fig. 1). The diffusion of ammonia gas across the proximal tubule apical membrane accounts for a small fraction of the total excretion of ammonia. The ammonium ions are then reabsorbed into the interstitium by the thick ascending limb of Henle to be secreted again by the collecting ducts [55–57]. The generation of ammonia by the proximal tubule can be upregulated in the presence of acidosis by fiveto tenfold over baseline in adults [52, 58, 59]. The ability of the neonatal kidney to upregulate ammonium excretion is somewhat limited and can prolong the recovery phase of acidosis in infants. The upregulation of ammonium production and secretion serves as the principal means of correcting acidosis that is due to non-renal causes. As will be seen below, the inability of

R. Quigley and M.T.F. Wolf

the kidney to secrete acid as ammonium is a key feature of RTA. The thick ascending limb of Henle is responsible for the continued reabsorption of bicarbonate as well as ammonium [60–62]. The transporters involved include the sodium–hydrogen exchanger (NHE3); the sodium–potassium-2 chloride cotransporter, NKCC2; and the sodium–potassium ATPase [60]. The thick ascending limb of Henle reabsorbs approximately 10 % of the filtered bicarbonate. The distal nephron is responsible for the secretion of protons that are then buffered by ammonia and titratable acid. The cell type in the collecting duct that is responsible for this is the alphaintercalated cell that is depicted in Fig. 3. The luminal membrane has a proton ATPase that utilizes ATP directly to secrete protons into the lumen of the tubule [63–66]. This generates a bicarbonate ion that is then excreted through the basolateral membrane by the anion exchanger AE1 in exchange for a chloride ion [67, 68]. The chloride can then exit the cell by the potassium chloride cotransporter (KCC) or the chloride channel, CLC-Kb [69, 70]. Carbonic anhydrase II is critical for the formation of the carbonic acid in the cell that ionizes into the proton and bicarbonate ion [47]. In beta-intercalated cells the polarity of transporters is reversed with pendrin as the apical Cl/ HCO3 exchanger, thus secreting HCO3 into the tubule lumen and H+ ATPase and H+/K+ ATPase at the basolateral membrane. Beta-intercalating cells convert to alpha-intercalating cells when exposed to acidosis. This conversion is promoted by the protein hensin which if absent induces RTA in mice [71, 72]. The principal cells of the collecting duct are responsible for the reabsorption of sodium and the secretion of potassium and thus do not directly secrete protons into the tubular fluid. However, these processes influence the rate of acid secretion indirectly by affecting the electrical potential difference across the epithelium. Thus, disease processes or drugs that have a primary effect on sodium or potassium transport in the collecting duct can eventually lead to acid–base disturbances.

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Tubular lumen

Blood H+

H+

Cl–

HCO3–

H+–ATPase NH3

H+ 2–

HPO4

H+ + HCO3–

K+ H+/K+–ATPase NH4+ HPO42–

CA II

H2O + CO2

HCO3– AE1 Cl–

K+ KCC4 Cl–

CIC-Kb

Fig. 3 Model of acid excretion in an alpha-intercalated cell in the distal nephrons. Protons are excreted into the tubule lumen by the proton ATPase and are buffered by ammonia or titratable acid (mostly phosphate). Inside the cell, carbonic anhydrase II (CAII) provides the protons and bicarbonate through the hydration of carbon dioxide to

form carbonic acid. Bicarbonate is excreted into the bloodstream by action of the chloride bicarbonate exchanger (AE1) on the basolateral membrane. Chloride homeostasis is maintained by the potassium chloride cotransporter (KCC4) and the chloride channel (ClC-Kb) (Reprinted with permission from Fry and Karet [216])

As discussed above, the proximal tubule generates ammonia that is eventually excreted as ammonium as a mechanism for acid excretion. The other major buffers in the urine are referred to as titratable acids and include phosphate, sulfate, and many other anions. Of the many buffers available, the quantitatively most significant is phosphate. Phosphate exists in the blood as several different ionic species (H3PO4, H2PO41, HPO42, and PO43) with H2PO41 and HPO42 being the most abundant at physiologic pH. The pK for the equilibrium between H2PO41 and HPO42 is 6.8; thus, at a normal blood pH of 7.4, the ratio of H2PO41: HPO42 is approximately 4:1. As the urine passes through the collecting duct where the pH is lower, HPO42 can accept protons and be converted to H2PO41 and will aid in the buffering of excreted acid. In addition to bicarbonate reabsorption and ammonia generation, the proximal tubule reabsorbs almost the entire filtered load of glucose and amino acids as well as approximately 85 % of the filtered load of phosphate. These processes are coupled to the apical membrane sodium

electrochemical gradient and are thus driven by the low intracellular sodium concentration and the negative electrical potential inside the cell. Diseases that affect the ability of the proximal tubule cell to maintain this gradient result in a condition known as the Fanconi syndrome [73]. This is a form of proximal tubule dysfunction that includes proximal RTA, glucosuria, aminoaciduria, and phosphaturia. As will be discussed below, most forms of proximal RTA are associated with the Fanconi syndrome.

Proximal Renal Tubular Acidosis (Type II RTA) Pathophysiology As discussed above, the transport of bicarbonate in the proximal tubule is a saturable process. Thus, the transport of bicarbonate exhibits the typical titration curve which has a threshold for bicarbonate reabsorption as illustrated in Fig. 2 [51]. This threshold for the reabsorption of bicarbonate is the

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R. Quigley and M.T.F. Wolf

BICARBONATE mmoles/100ml GLOMERULAR FILTRATE

4.0 *S.K.

3.6

*W.F.

TE FIL

3.2 2.8 2.4 REABSORBED

2.0 1.6 1.2 0.8

EXCRETED

0.4

18 20 22 24 26 28 30 SERUM BICARBONATE mmoles/liter

Fig. 4 Bicarbonate titration curves for patients with proximal renal tubular acidosis. Patients with proximal RTA have a reduced threshold for bicarbonate reabsorption and will thus excrete signiﬁcant amounts of bicarbonate in their

urine at lower serum bicarbonate concentrations. Thus, their titration curves are shifted to the left (Reprinted with permission from Soriano et al. [18])

main factor determining the serum bicarbonate concentration. If the serum bicarbonate concentration rises above the threshold, the ﬁltered load will exceed the transport maximum for reabsorption and bicarbonate will be excreted. This will bring the serum concentration down until it matches the threshold, and then all of the ﬁltered bicarbonate is again reabsorbed. The hallmark of proximal RTA is a reduced threshold for the reabsorption of bicarbonate as illustrated in Fig. 4, and thus, these patients will have a low serum bicarbonate concentration [18, 74]. When the serum bicarbonate concentration increases and approaches the normal range, patients with proximal RTA will develop bicarbonaturia. Their bicarbonate titration curve is similar to that of normal patients, but it is shifted down (see Fig. 4). It is important to note that the threshold for bicarbonate excretion is

generally in the 14–18 mEq/l range and remains stable [1, 18]. This reduction in the capacity for reabsorption of bicarbonate makes the treatment of patients with proximal RTA difﬁcult. Most patients require well over 6 mEq/kg/day of bicarbonate therapy to make an improvement in their serum bicarbonate concentration [75, 76]. As the patient is treated with bicarbonate and the serum bicarbonate rises, bicarbonate excretion will increase dramatically with little increase in the serum bicarbonate concentration. In addition, the distal delivery of the non-reabsorbable anion will obligate the excretion of sodium and potassium. This leads to volume depletion and an increase in the serum aldosterone concentration [77]. The combination of the increased distal delivery of sodium and the elevated aldosterone concentration leads to a marked excretion of potassium. Thus, many patients with

Renal Tubular Acidosis in Children

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8.5 8.0

URINE pH

7.5 7.0 6.5 6.0 5.5 5.0 4.5

11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 SERUM BICARBONATE mmoles / liter

Fig. 5 Urine pH of patients with proximal RTA. When patients with proximal RTA become acidotic, their serum bicarbonate concentration falls below the threshold for

excretion. Because their distal nephron is intact, they can lower their urinary pH to values less than 6.0 (Reprinted with permission from Rodriguez-Soriano et al. [1])

proximal RTA become hypokalemic during the treatment of the disease. Although the treatment of these patients can be difficult, their overall acid–base balance is generally good. In patients with proximal RTA, when the serum bicarbonate remains at or below the threshold for bicarbonate excretion, the patient can reclaim the filtered load of bicarbonate and will remain in relative acid–base balance [17, 18, 75]. This is due to the fact that the patient’s distal nephron remains intact and is able to excrete the acid generated from their diet and will help prevent the patient from developing a large base deficit. This is reflected in the fact that their urine pH can decrease to less than 5 (Fig. 5) [1]. Thus, while most patients with proximal RTA have a low serum bicarbonate, it will remain constant because the patient remains in acid–base balance. The acid–base balance of patients with pure proximal RTA has been extensively studied [75, 76]. At baseline, the patients were found to be in acid–base balance with normal ammonium and titratable acid excretion and did not develop a base deficit. When challenged with an ammonium chloride load, they were able to increase the excretion of acid in the form of ammonia as well as titratable acid [75].

While the excretion of ammonium increased in this study, it is unclear if patients with proximal RTA have the same capacity to increase ammonia excretion as normal individuals. Because the proximal tubule is the site of ammoniagenesis, there could conceivably be a defect in the ammonia generation rate. When these patients were loaded with ammonium chloride, their excretion of acid was increased; however, the ratio of ammonia excretion to titratable acid excretion remained constant [17, 18, 75]. This brought into question their ability to increase ammonia excretion in the face of an acid load and thus would probably not be able to recover from acidosis as well as a normal patient would. It was also thought that the level of ammonium excretion could be considered low for the chronic acidotic state [75]. A more recent study has indicated that while patients with proximal RTA are in balance at baseline, when their acidosis worsens, they cannot fully compensate [78]. In this study, patients with proximal RTA were loaded with ammonium chloride for 3 days. Previous studies had been performed with an acute ammonium chloride load. The chronic loading demonstrated that the patients with proximal RTA indeed had an inability to increase their ammonium excretion as compared to the normal control subjects [78].

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Interestingly, the patients with proximal RTA were able to lower their urine pH to a value below the control subjects’ urine pH (4.66 vs. 5.00). This was thought to be due to the fact that the normal subjects had higher amounts of ammonium in their urine to buffer the protons. The mechanism for the ability to maintain acid–base balance is due in part to an increase in titratable acid excretion [75]. Because of their intact distal nephrons, these patients can also lower their urine pH to the 4.5–5 range. However, this usually occurs at very low serum pH values and is depicted in Fig. 5 [1]. Calcium excretion rates in patients with proximal RTA were found to be within the normal range, indicating that there was no loss of calcium from their bones [75, 76]. There was also no evidence of rickets or osteomalacia in these patients with isolated proximal RTA [75].

R. Quigley and M.T.F. Wolf

(i.e., rickets), generalized aminoaciduria, and glucosuria [73]. Later, it was found that the tubular reabsorption of bicarbonate was impaired, and the deﬁnition then included proximal RTA [1]. Recent reports indicate that severe osteomalacia can develop in adult patients with the Fanconi syndrome [79, 80]. Hypokalemia also develops in most patients with this disorder [81]. There are numerous diseases that present with the Fanconi syndrome, but they appear to have a ﬁnal common pathway for the proximal tubule dysfunction. A number of studies have indicated that depletion of the intracellular ATP store is responsible for the loss of the transmembrane sodium gradient [82, 83]. This then leads to the inability to secrete protons and reabsorb glucose, phosphate, and amino acids.

Etiology Fanconi Syndrome As discussed above, the proximal tubule is also responsible for the reabsorption of glucose, amino acids, and phosphate by sodium-dependent transport systems (see also ▶ Chaps. 41, “Cystinosis and Its Renal Complications in Children,” ▶ 42, “Pediatric Fanconi Syndrome,” and ▶ 50, “Renal Manifestations of Metabolic Disorders in Children”). Many of the processes that interfere with the reclamation of bicarbonate are due to a defect in maintaining a low intracellular concentration of sodium and will thus affect the reabsorption of all of these solutes. This condition is known as the Fanconi syndrome which can be thought of as a global dysfunction of the proximal tubule [73]. Thus, proximal RTA can be divided into isolated proximal RTA, which is relatively rare, and Fanconi syndrome, which is actually a more common cause of proximal RTA. This will be an important point in the clinical presentation and workup of these patients. In addition to the problems with bicarbonate wasting, patients with the Fanconi syndrome have additional pathophysiologic changes. The original deﬁnition of the Fanconi syndrome consisted of skeletal ﬁndings secondary to hypophosphatemia

As with most clinical disease processes, isolated proximal RTA and the Fanconi syndrome can occur as an inherited defect or as an acquired disease. We will ﬁrst discuss the congenital causes of this syndrome and then review the acquired causes.

Congenital Isolated Proximal RTA As mentioned above, isolated proximal RTA is rare [84]. The initial descriptions of isolated proximal RTA were of infants that had a transient form of the disease [1, 76, 85]. This form was found predominately in males and appeared to improve after several years of life. Patients presented with failure to grow and repeated bouts of vomiting and dehydration. This form follows a sporadic inheritance pattern and has no known cause. There is a well-described kindred of patients from Puerto Rico that have isolated proximal RTA that follows an autosomal dominant pattern of inheritance [75]. To date, there are no reports of a gene defect in this family. Interestingly, the patients are more severely affected as infants, but tend to have less of a problem when they are older. This suggests that either the defect is

Renal Tubular Acidosis in Children

attributable to a developmental transporter or to compensation with age by other transport processes in the more distal nephron segments. Children in these families have moderate acidosis and do not grow at normal rates unless they receive treatment [75]. As discussed above, treatment with alkali therapy does not fully correct their acidosis because of the increased excretion of the administered base, but treatment will allow them to grow at near-normal rates. In recent years, another family with isolated proximal RTA that has an autosomal dominant inheritance pattern has been reported [86]. The clinical features of this family were very similar to the previous report [75]. A candidate gene approach was taken in an attempt to determine the genetic defect in this family. Extensive sequencing was done on many of the genes known to be involved in the proximal tubule reabsorption of bicarbonate; carbonic anhydrase II and IV as well as carbonic anhydrase XIV; NBC1; NHE2, NHE3, and NHE8 as well as the sodium proton exchanger regulatory proteins NEHRF1 and NEHRF2; and the chloride bicarbonate exchanger, SLC26A6. However, no defects were found. The authors concluded that either additional proteins are involved in the regulation of bicarbonate reabsorption or that there might have been defects in transcription factors that could regulate the expression of these genes [86]. A rare cause of isolated proximal RTA is a mutation in the sodium bicarbonate cotransporter, NBC1, which is inherited in an autosomal recessive pattern [87–89]. The initial patients described were two brothers that had proximal RTA as well as eye and dental abnormalities [90]. Since then, only a few other patients have been described with these features [87, 90, 91]. Other patients were found to have developmental delay, short stature, pancreatitis, band keratopathy, cataract, glaucoma, and basal ganglia calciﬁcation [92, 93]. These patients were found to have a mutation in the SLC4A4 gene which encodes the sodium bicarbonate cotransporter, NBC1. NBC1 is a large transmembrane protein formed by 1,035 amino acids and is responsible for transporting bicarbonate out of the proximal tubule cell and

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into the bloodstream [88, 91, 94, 95]. Although SLC4A4 mutations are very rare causes of isolated proximal RTA, they have demonstrated the critical function of NBC1 in the proximal tubule reabsorption of bicarbonate. The sodium bicarbonate cotransporter NBC1 is critical in the membrane transport of bicarbonate [50, 67, 68, 96–98]. This class also includes the chloride bicarbonate exchanger that will be discussed in the section on distal RTA. The sodium-coupled bicarbonate transporter NBC1 is expressed primarily at the basolateral membrane in the proximal tubule and is also found in other tissues such as the eyes as well as the heart [88]. This kidney-speciﬁc isoform is determined by alternate splicing of the gene. Defects in this transporter result in proximal RTA due to the inhibition of bicarbonate transport in the proximal tubule. Because of the distribution of the protein in the eye, patients also develop ocular defects such as band keratopathy, cataracts, and glaucoma [88, 99]. Recently it was found that some SLC4A1 mutations cause a defect in protein trafﬁcking, while other SLC4A4 mutations result in reduced protein activity [92, 100, 101]. Defects in carbonic anhydrase cause dysfunction of the proximal tubule, but because of its distribution in the distal nephron, these defects cause combined proximal and distal RTA [102, 103]. These will be discussed in detail below in the section on Type III RTA. The sodium–hydrogen exchangers have been considered candidate genes for the cause of isolated proximal RTA; however, to date there have been no defects found in these genes. To determine the role of these exchangers in overall acid–base balance, knockout mouse models have been generated. The primary sodium–hydrogen exchanger in the apical membrane of the proximal tubule is NHE3 [37]. Mice that have had NHE3 knocked out have a modest metabolic acidosis [104]. They have an elevated serum aldosterone level as well as upregulation of colonic sodium transporters indicating that these animals have evidence of volume contraction [104]. Perfusion of the proximal tubules in vitro shows a reduced ability to acidify the urine [105]. As discussed above, a recent study in patients with isolated

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proximal RTA failed to detect a defect in any known gene for bicarbonate transport including NHE3 [86]. Another mouse model of proximal RTA was developed recently [106]. The TASK2 K+ channel is located in the proximal tubule and appears to regulate bicarbonate transport. When this channel was knocked out, the animals developed acidosis which was due to renal bicarbonate wasting [106]. TASK2 is a member of the two-pore domain channel family and is sensitive to changes in extracellular pH. Amino acids in the extracellular loop seem to be responsible for pH sensing [107]. TASK2 may contribute to the basolateral membrane potential thus driving Na+-base transport via NBC1 [101].

Congenital Fanconi Syndrome There are a number of genetic defects that result in the Fanconi syndrome. These are listed in Table 1 and will be described brieﬂy. The most common cause of congenital Fanconi syndrome is cystinosis which is an autosomal recessive disorder [108–110]. This disease results from a defect in the gene CTNS which encodes for the lysosomal membrane transporter, cystinosin [109, 111]. Lysosomes are organelles responsible for degradation of proteins within the cell. Cystinosin is responsible for the transport of cystine out of the lysosome so that the organelle can continue to function. In the disease cystinosis, cystine accumulates within the lysosome of the cells throughout the body [110]. It is not clear how this leads to the Fanconi syndrome, but it appears to be related to the depletion of intracellular ATP [82, 83]. The other diseases that result in the Fanconi syndrome are much more rare. One in particular is worth mentioning because it is thought to be the cause of the syndrome ﬁrst described by Fanconi [112–117]. This is a defect in the facilitative glucose transporter GLUT2. This transporter is responsible for transporting glucose out of the proximal tubule cell and into the bloodstream. Thus, a mutation in this protein would lead to accumulation of glucose within the

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proximal tubule. It is unclear how this would cause the Fanconi syndrome, but could be due to the consumption of intracellular phosphate by the accumulated glucose. Hereditary fructose intolerance is of interest because this served as a useful model for the study of the Fanconi syndrome [118, 119]. The cause of the Fanconi syndrome in this disorder is thought to be due to the depletion of intracellular phosphate that occurs when the cell is presented with a load of fructose. Patients with this disorder tend to have normal renal function and no acid–base disturbance when they remain on a fructose-restricted diet. The oculocerebrorenal syndrome of Lowe is due to a mutation in the OCRL1 gene which encodes for the enzyme, phosphatidylinositol 4,5-bisphosphate 5-phosphatase [120]. This causes an accumulation of phosphatidylinositol 4,5-bisphosphate in the cells which presumably leads to the Fanconi syndrome. OCRL1 was shown to have various cellular functions ranging from membrane trafficking, endocytic recycling, phagocytosis, ciliogenesis, cell adhesion, and polarity to actin polymerization [121, 122]. The syndrome is inherited in an X-linked pattern. Mutations in OCRL1 are also identified in approximately 15 % of patients with Dent disease, initially called Dent disease type 2 [123]. Presently, it is not well understood how loss of OCRL1 function leads to the symptoms associated with Lowe syndrome and Dent-2 disease. Dent disease is caused by mutations in the chloride channel encoded by the gene, CLCN5 [124–128]. The original term for this disorder was X-linked hypercalciuric nephrolithiasis. The chloride channel that the gene encodes for is found in intracellular organelles and appears to be critical for maintaining pH gradients. CLCN5 encodes a two chloride (Cl)/proton (H+) exchanger rather than a pure Cl channel. Using a mouse model that uncoupled the proton exchange activity of the molecule, CLCN5 was converted into a pure Cl channel. Compared to CLCN5 knockout mice (ATP)-dependent acidification of renal endosomes was intact in these animals, but endocytosis of the proximal tubule was also impaired thus suggesting that endosomal

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Table 1 Inherited causes of the Fanconi syndrome Disease Cystinosis Tyrosinemia Fanconi–Bickel syndrome Hereditary fructose intolerance Dent’s disease type 1 Dent’s disease type 2 Lowes syndrome Galactosemia Fanconi renotubular syndrome 3 Wilson’s disease

Gene defect Cystinosin (CTNS) Fumarylacetoacetase GLUT 2 Fructose-1-phosphate aldolase (ALDOB)

Inheritance AR AR AR AR

OMIM 219800 276700 138160 229600

CLCN5 OCRL1 Phosphatidylinositol 4,5-bisphosphate 5-phosphatase deﬁciency (OCRL1) Galactose-1-phosphate uridylyltransferase (GALT) EHHADH

X X

300009 300555 309000

AR AD

230400 615605

ATPase, Cu(2+)-transporting, beta polypeptide (ATP7B)

277900

AD autosomal dominant, AR autosomal recessive, X x-linked

chloride concentration, which is raised by CLCN5 in exchange for protons accumulated by the H+ATPase, may play a role in endocytosis [129]. Loss of CLCN5 function also alters receptor-mediated endocytosis and trafﬁcking of megalin and cubilin thus explaining low molecular weight proteinuria. CLNC5 interacts with a kinesin family member 3B (KIF3B), a heterotrimeric motor protein that facilitates fast anterograde translocation of membranous organelles [130]. CLCN5 knockout mice are characterized by reduced surface expression of NHE3 in proximal tubules, and it was shown that CLCN5 may contribute to RTA by interfering with the exocytic trafﬁcking of NHE3 [131]. Interestingly, carbonic anhydrase type III seems to be upregulated in the urine of patients with Dent disease due to CLCN5 mutations and in megalin knockout mice [132]. Overall, it is not well understood how this defect results in the Fanconi syndrome. Other diseases that lead to the Fanconi syndrome include galactosemia and tyrosinemia [133–135]. These disease processes can also be controlled by diet. Rarely, other forms of glycogen storage disease can result in the Fanconi syndrome [136–138]. Mitochondrial defects can also rarely be associated with the Fanconi syndrome [139–142]. Alterations of gene products involved in oxidative phosphorylation as BCS1L, UQCC2,

and FBXL4, which are all expressed in mitochondria, were shown to cause proximal RTA in humans [143–145]. Recently, mutations in the transcription factor HNF1 alpha have been associated with dysfunction of the proximal tubule [146]. In addition, these defects result in maturity-onset diabetes of the young type 3 (MODY3) [147]. This syndrome has been reproduced in a mouse model [148]. Thus, it appears that this transcription factor is a key regulator of glucose metabolism and could impact the function of the proximal tubule. Interestingly, HNF1 alpha was also shown to regulate the expression of CLCN5 in the proximal tubule [149]. Mutations in EHHADH were found to be inherited in an autosomal dominant fashion in a large kindred with renal Fanconi syndrome with prominent rickets, renal bicarbonate loss, and development of RTA [150]. The encoded EHHADH protein is mostly expressed in peroxisomes along the terminal segments of the proximal tubule and is involved in fatty acid oxidation. The mutant protein is mistargeted to mitochondria resulting in impaired mitochondrial oxidative phosphorylation. Interestingly, Ehhadh knockout mice did not have renal Fanconi syndrome indicating that the EHHADH mutation in humans causes the phenotype by a dominant negative effect [150].

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Acquired Isolated Proximal RTA Most diseases and toxins that affect the proximal tubule result in the Fanconi syndrome; thus, it is rare for isolated proximal RTA to be acquired. The primary cause of isolated proximal RTA is the inhibition of carbonic anhydrase (CA) [151–154]. Acetazolamide is given to treat pseudotumor cerebri and some forms of glaucoma. One side effect of this treatment is the development of proximal RTA. Indeed, this is often used as a marker of treatment adequacy. A number of other medicines can also cause CA inhibition, e.g., hydrochlorothiazide and topiramate [151–153, 155, 156].

Acquired Fanconi Syndrome There are many toxins and medications including heavy metals that are now known to affect the proximal tubule and result in the Fanconi syndrome [154, 157–159]. In particular, a number of well-documented cases of Fanconi have been reported with valproic acid [160, 161]. These appear to be reversible processes, but the time of resolution can be signiﬁcant. Chinese herbs containing aristolochic acid have also been associated with the Fanconi syndrome [162, 163]. Other agents that have been associated with the Fanconi syndrome include aminoglycosides, ifosfamide, cisplatin, the antiviral agent tenofovir, and salicylate [164–172]. Disease processes that cause the Fanconi syndrome are either immune-mediated diseases or paraproteinemia syndromes. For example, Sjögren’s disease will typically cause distal RTA but has been reported to cause the Fanconi syndrome [173]. The classic paraproteinemia that results in the Fanconi syndrome is multiple myeloma [174–176]. Other conditions that are associated with the Fanconi syndrome include vitamin D deﬁciency [177, 178]. The mechanism of action for this process is not well understood. In addition, proximal RTA has been reported in pregnancy and with paroxysmal nocturnal hemoglobinuria [179, 180].

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Distal Renal Tubular Acidosis (Type 1 RTA) Pathophysiology The hallmark of distal RTA is the inability to lower the urine pH maximally in the face of moderate to severe systemic acidosis [1]. This is clearly shown in Fig. 6 where the urine pH is graphed against the serum bicarbonate concentration. As can be seen in the normal individuals, the urine pH decreases to a value of approximately 4.5–5.0, but the patients with distal RTA fail to reduce their urine pH below 6.5. While this feature has been known for many years and was the initial defining characteristic of RTA, the causes of this dysfunction have only recently been elucidated. The primary function of the distal nephron in acid–base homeostasis is excretion of the acid generated by the metabolism of our diet. As described earlier, the typical Western diet generates approximately 1 mmol of acid per kilogram of body weight [28]. Children have an additional 1–2 mmol of acid per kilogram body weight that is generated from the formation of hydroxyapatite in the growing bone. Thus, the distal nephron in the growing child has the task of excreting between 1 and 3 mmol of acid per kilogram [29–31]. If the distal nephron is not capable of performing this function, the patient will use the existing buffers in the body to buffer this acid. Most of the pathophysiologic consequences of distal RTA are due to the accumulation of acid. Even though the proximal tubule is functioning normally to reabsorb the filtered load of bicarbonate, the patient will continue to accumulate acid and develop an ever increasing base deficit. After the bicarbonate buffers in the extracellular fluid space are depleted, the bones begin to serve as the buffer source for the accumulated acid. Hydroxyapatite can be dissolved to liberate hydroxyl ions to help in the neutralization of the acid. Studies in patients with distal RTA have shown that they are in negative calcium balance due to the reabsorption of bone [1]. This will lead to nephrocalcinosis and nephrolithiasis.

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8.5 8.0

URINE pH

7.5 7.0 6.5 6.0 5.5 5.0 4.5

11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 SERUM BICARBONATE mmoles /liter

Fig. 6 Urine pH of patients with distal RTA. Because patients with distal RTA cannot excrete hydrogen ions against a gradient in the distal nephron, they are unable to

signiﬁcantly lower their urine pH, even when they become very acidotic (Reprinted with permission from RodriguezSoriano et al. [1])

Fig. 7 Nephrocalcinosis in a patient with distal RTA (Reprinted with permission from Serrano and Batlle [183])

Another contributing factor to the development of nephrocalcinosis is the fact that citrate reabsorption in the proximal tubule will be increased to help provide for base equivalents [181, 182]. The resulting hypocitraturia will contribute to the development of nephrocalcinosis and nephrolithiasis. This can be used to help differentiate distal RTA from proximal RTA as seen in Fig. 7 [183]. In growing bones, the acid–base disturbance will lead to rickets, whereas in the older patient, they will develop osteomalacia. The description of this was provided by Albright in 1946 [5]. Nephrocalcinosis has also been associated with increased production of red cells [184, 185]. It is

not clear what the mechanism is in these patients. Erythrocytosis has been observed in some patients with distal RTA, presumably as a result of the nephrocalcinosis [184, 185]. The proximal tubule provides ammonia that is delivered to the distal nephrons to serve as a buffer. The previous paradigm of a passive, lipid-phase NH3 diffusion and NH4+ trapping has been replaced by a model in which transporter-mediated movement of NH3 and NH4+ occurs. In the proximal tubule NH4+is secreted by NHE3 and different potassium channels [41, 186]. In the thick ascending limb, NH4+ reabsorption involves NKCC2 and NHE4. In the

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collecting duct aquaporins and Rh glycoproteins such as Rhbg and Rhcg participate in NH4+ secretion [42, 187–190]. Recently, it has been appreciated that the rate of ammonium excretion in patients with distal RTA is less than that of normal subjects [26, 27, 191]. This is presumably due to the fact that ammonia that is not converted to ammonium ion by the secretion of protons can then diffuse back into the bloodstream and is subsequently not excreted. There have been a number of reports of patients with distal RTA that have hyperammonemia at the time of presentation when they are extremely acidotic [192–194]. This presentation may be more common than previously thought. In one small cohort of 11 patients with either ATP6V1B1 or ATP6V0A4 mutations, four patients presented with hyperammonemia at disease onset [195]. They do not have liver dysfunction, but they have an inability to excrete the ammonia generated in the proximal tubule. This phenomenon has led some investigators to postulate that the excretion of ammonium be used as a new classification scheme of RTA [191]. While this could result in a more physiologic scheme for the classification of RTA, this is probably not practical at the present time. The measurement of ammonium in the urine is not a routine laboratory test. Methods for estimating ammonium excretion will be discussed in the section on clinical aspects. Another pathophysiologic finding in patients with classical distal RTA is hypokalemia [196, 197]. The exact mechanism for this is not entirely clear but is at least partially due to elevated aldosterone concentrations in these patients [198]. Careful studies have indicated that the aldosterone concentration is routinely elevated in patients with distal RTA. A few patients had aldosterone concentrations in the normal range, but were inappropriately normal for the degree of hypokalemia. It was thought that the patients were mildly volume depleted because of mild proximal tubule dysfunction. The hypokalemia can be severe and cause muscle paralysis [199]. This has occasionally been the presenting sign of RTA [200, 201]. Patients with distal RTA also seem to be at a higher risk for rhabdomyolysis due to hypokalemia. In a report describing

R. Quigley and M.T.F. Wolf

14 patients with hypokalemic rhabdomyolysis, 7 patients carried the diagnosis of distal RTA [202].

Etiology Congenital Distal RTA Congenital forms of distal RTA are divided into autosomal dominant (type Ia) and autosomal recessive with (type Ib) and without (type Ic) hearing loss. The molecular basis for these forms of inherited distal RTA has become clear over the past few years and has greatly improved our understanding of the molecular basis of renal acid–base metabolism. Autosomal dominant distal RTA is caused by mutations in the anion exchanger (AE1) that is located in the basolateral membrane of the alphaintercalated cells of the collecting duct. This exchanger is responsible for the basolateral exit of bicarbonate into the bloodstream. Thus, if the protein is not functioning, acid secretion into the tubule lumen will be limited. The biology of AE1 has proven to be very interesting [67, 203, 204]. The exchanger is also located in the red cell membrane where it was ﬁrst discovered and was termed “band 3 protein” [204]. While it serves to function in the red blood cell as an anion exchanger, it also binds to other membrane proteins and contributes to the stability of the red cell membrane. Tetrameric AE1 forms a macrocomplex with ankyrin and the Rh complex proteins that attaches the macrocomplex to the erythrocyte cytoskeleton through binding of ankyrin [205, 206]. This macrocomplex may be involved in gas exchange. Rh-associated glycoprotein (RhAG) and aquaporin 1(AQP1) are also members of this macrocomplex and also form gas channels for CO2 and in the case of RhAG also for NH3. Interestingly, this multiprotein complex combines with AE1 and Rh complex proteins which are important players for bicarbonate reabsorption and ammonia secretion, not only in the erythrocyte but also in the collecting duct [42]. Mutant AE1 is unable to exchange anions and causes the red blood cell to leak monovalent cations [207]. This cation leak seems to be more

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prominent in the cold and may be less signiﬁcant in warmer, tropical climate [208]. Thus, heterozygous defects in AE1 cause destabilization of the erythrocyte membrane, resulting in mild to moderate hemolytic anemia which is characteristic for hereditary spherocytosis and Southeast Asian ovalocytosis (SAO) [203]. The mutations in AE1 that result in autosomal dominant distal RTA are located in different areas of the molecule than the mutations causing the red cell membrane defects [209, 210]. Different isoforms of AE1 are expressed in red blood cells and the kidney with a truncated renal AE1 version. Most heterozygous mutations causing hereditary spherocytosis and SAO are located in the truncated part which is not expressed in the kidney, and so most patients with these disorders do not have RTA. In temperate countries, dRTA caused by SLC4A1 mutations is rare and is almost invariably autosomal dominant. Red cell morphology is usually unaffected as AE1 is only reduced by 20–30 % [206]. An exception is patients in the tropics and particularly in Southeast Asia where patients more frequently have homozygous or compound heterozygous mutations in the gene SLC4A1, which encodes AE1 [211–214]. These patients develop dRTA and frequent hemolysis, which can become lifethreatening. The mutations in tropical dRTA are different from those found in the nontropical countries and frequently include a deletion of the residues 400–408, which also causes SAO [215]. The clinical symptoms are typically more severe with an earlier age of onset in patients with homozygous or compound SLA4A1 mutations compared to patients with autosomal dominant distal RTA who tend to develop a less severe form of RTA [216, 217]. The higher prevalence of recessive familial dRTA in the tropics is possibly caused by a protective effect of these mutations against malaria, and as pointed out above the cation leak caused by AE1 mutations may not be that prominent in warmer climates [215]. The autosomal recessive distal RTA with hearing loss (type Ib) was found to be due to mutations in a subunit (ATP6V1B1) of the proton pump located on the apical membrane of the alphaintercalated cell of the collecting duct [218].

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This led to the discovery of the proton pump location in the inner ear [219, 220]. The proton pump is a key transporter in the secretion of hydrogen ions [63–66]. It is a complex molecule with multiple subunits that are speciﬁc to the location in the body. Subsequent to the initial discovery, a number of other mutations have been discovered that are responsible for autosomal recessive distal RTA with hearing loss [221, 222]. In 1996, a large family with this form of RTA and hearing loss was reported [223]. The defect has been recently determined to be a truncating mutation of the ATP6V1B1 gene. The altered subunit is impaired from organizing with the rest of the proton pump for complete function [224]. As families were characterized for mutations in the proton pump, it was clear that some of the families did not have hearing loss and did not have defects in the ATP6V1B1 subunit. This led to the designation of autosomal recessive distal RTA without hearing loss (type Ic). Defects in a separate subunit (ATP6V0A4 or also called ATP6N1B) were found to be the cause in the initial families studied [225]. Subsequently, a number of patients developed hearing loss later in life. These patients were found to have a [226] defect in subunits that were found in the inner ear [222]. The human phenotype of ATP6V0A4 mutations was recapitulated in an Atp6v0a4 knockout mouse model characterized by dRTA and hearing loss. In addition these animals had impaired sense of smell [227, 228]. Distal RTA has also been described in patients with medullary sponge kidney (MSK). Interestingly, two patients with mutations in ATP6V1B1 and ATP6V0A4 were reported who in addition to dRTA and late hearing loss also had MSK [229, 230]. Mouse models of distal RTA have also been developed. A mouse model that lacks AE1 (slc4a1) has been produced and found to have many of the same features as the human disease [231]. The importance of the potassium chloride transporter KCC4 for function of the alphaintercalated cells was shown in a knockout model [69]. These mice had features of distal RTA. A mouse that lacked the transcription factor

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Foxi1 was shown to have distal RTA [232]. This transcription factor is evidently important in the development of the alpha-intercalated cells. There are no known human mutations in this factor, but the mouse model raises the possibility of this being another gene to consider in human disease.

Acquired Distal RTA The most common cause of acquired distal RTA is immunologic destruction of the alpha-intercalated cells. This occurs most frequently with Sjögren’s syndrome [233, 234]. Distal RTA in Sjögren’s has been reported to occur in about one third of the patients and after a duration of 10 years [200, 234]. It can also occur in patients with systemic lupus erythematosus and has been reported in a patient with Graves’ disease [235–237]. Distal RTA has also been reported in renal transplant patients; however, it is not clear if this is immune mediated or secondary to the medications [238]. A number of medications have been found to cause distal RTA. The classic example is amphotericin [239]. This model has been used to study the pathogenesis of RTA in the laboratory [240, 241]. The primary defect in acid secretion due to amphotericin appears to be an increase in the permeability of the collecting duct cells to hydrogen ions. This would then prevent the formation of the gradient that is necessary to secrete protons into the urine. While these results helped explain the pathophysiology of the backleak and are important clinically, this probably does not apply to patients with inherited defects that result in distal RTA. Other medications that are known to cause distal RTA include lithium, foscarnet, and melphalan [242–244]. The mechanisms for these effects are not clear. Acquired distal RTA can also result from the treatment of hypophosphatemic rickets [245]. This is probably a result of the nephrocalcinosis that develops from the high dose of vitamin D these patients receive. Examination of patients with idiopathic hypercalciuria also demonstrated some defects in renal acidiﬁcation [246]. An interesting association of distal RTA and ingestion of vanadate has been proposed as a

R. Quigley and M.T.F. Wolf

mechanism for the high endemic rate of RTA in northeastern Thailand [247]. These patients develop severe hypokalemia, and it is thought that this could be due to inhibition of the H–K–ATPase by vanadate. There is a high level of vanadate in the soil in this area, and experiments with rats have shown that administration of vanadate can lead to renal tubular acidosis [248]. Glue sniffing has been listed as a cause of distal RTA; however, careful examination of a patient with acidosis from glue sniffing suggests a different cause of the acidosis [249]. The toluene in the glue is rapidly metabolized to hippuric acid which is promptly excreted by the kidneys. When measurements were made of ammonium excretion rates, they were found to be normal. Thus, the conclusion is that while there might be some renal tubule damage from the glue sniffing, the bulk of the acidosis results from hippuric acid production. The prompt excretion of the hippurate prevents the development of an increase in the anion gap [249].

Type III Renal Tubular Acidosis Type III RTA refers to a form of renal tubular acidosis that has features of both proximal RTA and distal RTA. During the middle of the twentieth century, a number of patients were found to have features of both forms of RTA, and the third type of RTA was suggested. It was subsequently found that these patients had distal RTA with a transient form of proximal RTA. Thus, the term fell out of favor and had not been used. More recently, a form of RTA that occurs with some forms of osteopetrosis has been characterized that seems to meet the criteria for the designation of type III RTA. This association was originally described in 1972 [250]. Subsequently, the defect was found to be a mutation in the gene for carbonic anhydrase II [102]. After the initial finding of the genetic defect, a number of other patients have been described with similar clinical findings [103, 251, 252]. These patients have other extrarenal findings such as cerebral calcifications as well as the bone problems associated with osteopetrosis [103]. It should be pointed out that osteopetrosis can be caused by a defect in a

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number of different genes that affect the osteoclast [253]. Thus, the ﬁnding of osteopetrosis does not imply that the patient will have a defect in carbonic anhydrase II and will develop RTA. The form of osteopetrosis associated with the carbonic anhydrase deﬁciency is the syndrome known as Guibaud–Vainsel syndrome or marble brain disease [253].

Type IV Renal Tubular Acidosis The effects of aldosterone on electrolyte balance have been extensively studied since the discovery of aldosterone in the 1950s [22]. The initial findings demonstrated dramatic effects of aldosterone on sodium reabsorption and potassium secretion. In the latter half of the twentieth century, it became clear that aldosterone also had effects on acid–base balance. With the recent advances in molecular biology, the mechanisms involved in the genetic causes of type IV RTA have been elucidated [254]. Type IV RTA was initially used to describe patients that developed acidosis from aldosterone deficiency. This could occur as an inherited defect, such as congenital adrenal hyperplasia, or could be acquired as in Addison’s disease. The principal feature that distinguished type IV RTA from classic type I RTA was the finding of hyperkalemia. Patients with type IV RTA are hyperkalemic, while many of the patients presenting with classic type I RTA were hypokalemic. This led investigators to believe that the cause of this form of RTA was aldosterone deficiency. Later it became apparent that many of the patients were not aldosterone deficient, but had a decreased responsiveness of the renal tubules to aldosterone and hence developed hyperkalemic RTA. Currently the term type IV RTA is applied to all forms of hyperkalemic RTA, regardless of the serum aldosterone concentration.

Pathophysiology The primary effect of aldosterone on the collecting duct is to stimulate sodium reabsorption and

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potassium secretion in the principal cells [255]. This results in an enhancement of the lumennegative electrical potential that can then help promote proton secretion. Aldosterone also has direct effects on the alpha-intercalated cells to promote proton secretion by upregulating the expression of the proton ATPase as well as carbonic anhydrase [255]. The effect of aldosterone on ammonia excretion is not clear. There is evidence that aldosterone deficiency could directly inhibit the production of ammonia, while other studies indicate that the effect could be secondary to hyperkalemia [256–258]. Ammonia secretion in patients with aldosterone deficiency was low and was shown to increase after administration of mineralocorticoid; however, it was still not clear if the effect could be secondary to changes in potassium concentration. Patients that are aldosterone deficient or resistant to the actions of aldosterone have increased excretion of sodium which leads to volume depletion and potentially a decrease in the glomerular filtration rate [259, 260]. Thus, many of the symptoms of this process are secondary to the volume depletion. The acidosis in most patients with type IV RTA is not as severe as in other forms of RTA [259]. Thus, the main clinical problem with most of these patients is hyperkalemia. Treatment often relies on restricting the intake of potassium but will ultimately depend on the cause of the RTA.

Etiology As discussed above, type IV RTA can result from a deﬁciency of aldosterone or from a resistance of the renal tubules to the actions of aldosterone.

Aldosterone Deficiency Aldosterone deficiency can be the result of a global dysfunction of the adrenal gland, referred to as Addison’s syndrome, or it can be the result of isolated aldosterone or mineralocorticoid deficiency. The most common inherited form of mineralocorticoid deficiency is congenital adrenal hyperplasia (CAH) which is due to

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21-hydroxylase deﬁciency [261, 262]. Other infants can present with isolated aldosterone synthase deﬁciency which is not a severe disease process since the glucocorticoid pathway remains intact [263].

Aldosterone Resistance There are a number of inherited and acquired conditions that result in resistance of the tubules to the action of aldosterone. The pathway for aldosterone action includes the mineralocorticoid receptor and the epithelial sodium channel (ENaC). Defects in both of these components result in type IV RTA. Because of the renal tubular resistance to aldosterone, aldosterone concentrations in the blood are quite elevated. Thus, this is referred to as pseudohypoaldosteronism (PHA). Defects in the mineralocorticoid receptor lead to an autosomal dominant form of PHA [264]. This form is the least severe of the PHAs, and patients tend to improve as they get older. This is presumably due to compensation by other pathways to reabsorb sodium and secrete potassium and hydrogen ions. An autosomal recessive form of PHA is due to defects in ENaC [265]. Patients with this form can be severely affected since the ﬁnal pathway for sodium regulation in the collecting duct involves ENaC. In addition, they have severe pulmonary problems at birth because ENaC is present in the lungs and is a key factor in the reabsorption of ﬂuid from the lung space after birth. Both of these forms of PHA lead to salt loss and volume depletion. Patients tend to be hypotensive and dehydrated. Additionally, plasma concentrations of renin and aldosterone are quite elevated because of the volume depletion. A form of PHA that occurs in patients that are hypertensive was originally thought to be due to a “chloride shunt” in the collecting duct and was referred to as PHA type 2 or Gordon’s syndrome [266]. These patients are characterized by having hyperkalemia and acidosis, but have a low concentration of renin and aldosterone in their plasma. This led investigators to hypothesize that the paracellular pathway in the collecting

R. Quigley and M.T.F. Wolf

duct was allowing chloride to be reabsorbed at a higher rate than was needed [267]. This would cause the electrical potential difference in the tubule to decrease and would thus decrease the excretion of potassium and protons. Recent discoveries have shown that PHA type 2 is due to defects in WNKs (with no lysine kinases) [268]. Speciﬁcally, there are families with the syndrome that have mutations in WNK1 and some with mutations in WNK4. The biology of the WNKs has turned out to be very complicated and is beyond the scope of this chapter. However, they seem to be key players in the regulation of potassium and blood pressure. Other patients with PHA type 2 were found to have mutations in genes for CUL3 and KLHL3, which encode Cullin-3 and Kelch-like-3 proteins [269, 270]. The mutations found in KLHL3 are all in a domain that is important for substrate and Cullin binding. Both proteins are involved in ubiquitination. KLHL3 is expressed in the distal convoluted tubule and collecting duct, whereas CUL3 is strongly expressed in the proximal tubule but also weaker in the distal convoluted tubule and collecting duct. KLHL3 downregulates NCC expression at the cell surface [270]. Both CUL3 and KLHL3 decrease WNK4 levels by ubiquitination and subsequent degradation [271]. In particular, patients with CUL3 mutations seem to present early in infancy with hyperkalemia, hypertension, and metabolic acidosis [269, 272].

Acquired Addison’s disease can be an autoimmune disease or can be the result of damage to the adrenal gland from infection or infarction. Treatment involves replacing the adrenal hormones as needed as well as treating the underlying infection. In adult patients, diabetes is a leading cause of type IV RTA as a result of hyporeninemic hypoaldosteronism [273]. There are other disease processes that also lead to a decrease in production of renin that would then lead to a decrease in aldosterone secretion. If the patient has type IV RTA from acquired hypoaldosteronism, treatment with mineralocorticoids will correct the defect [274].

Renal Tubular Acidosis in Children

Tubular resistance to aldosterone can occur as a result of a number of different processes. Autoimmune diseases can lead to interstitial nephritis that decreases the tubule responsiveness to aldosterone [275]. Patients with systemic lupus erythematosus classically develop type 1 RTA, but have been reported to present with type IV RTA [226]. Infections such as acute pyelonephritis can also cause a resistance to aldosterone action. Probably the most common cause of acquired type IV RTA in the pediatric age range is obstruction of the urinary tract. The mechanism by which obstruction causes resistance of the tubule to aldosterone is not clear, but this is commonly seen in patients with posterior urethral valve or with prune-belly syndrome. Type IV RTA can also been seen in patients with a renal transplant [276]. This could be due to either an immune-mediated mechanism, or it could be related to medications used for the treatment of rejection. In particular, calcineurin inhibitors are known to cause type IV RTA [238, 277]. Other medications that are known to interfere with the action of aldosterone include angiotensinconverting enzyme inhibitors (ACE inhibitors), heparin, prostaglandin inhibitors (NSAIDs), and a number of potassium-sparing diuretics. These would include amiloride and trimethoprim which block the epithelial sodium channel and spironolactone which blocks the mineralocorticoid receptor [254].

Diagnosis and Treatment of Renal Tubular Acidosis The diagnosis of renal tubular acidosis represents a challenge to the clinician for a number of reasons. Depending on the severity of the disease presentation, the patient could present with ﬁndings consistent with proximal and distal RTA. The patients are also many times quite volume depleted at presentation, and it is not clear how much this impacts the serum chemistries. In addition, patients with infections can be septic and in shock. Thus, the complete evaluation of a patient for renal tubular acidosis might have to occur after the acute illness has subsided.

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As with any complex disease, the diagnosis of RTA begins with clinical suspicion. If the disease is not being considered in the differential diagnosis, then a deﬁnitive diagnosis will not be made. There have been a number of recent reviews that outline practical guidelines for the diagnosis and management of RTA [278–281]. This section of the chapter will focus on the reasoning behind the laboratory testing that is recommended for the workup of patients with suspected RTA. The inherited forms of renal tubular acidosis present almost uniformly with failure to grow and repeated episodes of vomiting and dehydration [1, 76]. It should be emphasized that most of these patients are very ill appearing at the time of presentation. The patient with failure to grow that otherwise appears healthy has a much lower probability of having RTA. A recent study examined patients referred for failure to thrive that had serum chemistries indicating the possibility of RTA [282]. Simply performing a venous blood gas analysis in the patients demonstrated the absence of acidosis. The ﬁrst step in the evaluation of patients with an acidosis is to determine the serum anion gap [283–286]. Patients with RTA are characterized by having a normal anion gap. This is also referred to as a hyperchloremic metabolic acidosis. Interpretation of the anion gap can occasionally be misleading. Other factors can affect the anion gap such as serum protein concentrations, calcium, and other anions such as phosphate [284, 287]. Thus, the determination of a normal anion gap acidosis can only be correctly made when these factors are taken into account. Although renal tubular acidosis should be suspected in these patients with metabolic acidosis with a normal anion gap, there are other disorders to consider in the differential diagnosis such as gastrointestinal loss of bicarbonate. The workup of these patients is therefore designed to differentiate whether the acidosis is of renal or extrarenal origin. Thus, it is necessary to examine the response of the kidney to the metabolic acidosis. As discussed above, the normal renal response to metabolic acidosis is to increase ammonium chloride excretion as a way to enhance hydrogen ion excretion to correct the acidosis. Unfortunately,

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R. Quigley and M.T.F. Wolf 200

A Phosphate < 20mM/L. Phosphate 20 -49mM/L. Phosphate > 50mM/L.

Urine Bicarbonate Concentration in mEq/L.

150

100

5.5

6.0

6.5 Urine pH

7.0

7.5

8.0

Fig. 8 Urinary bicarbonate concentration as a function of urinary pH. As can be seen, once the urine pH becomes less than 6.5, the concentration of bicarbonate is less than

10 mEq/l. This might have an impact in determining the urinary anion gap (Reprinted with permission from Kennedy et al. [307])

measuring ammonium in the urine is not a routine function in most hospital laboratories. Over time, several approaches have been taken to estimate the urinary excretion of ammonium to determine if the kidney is responding normally [288–292]. The measurement of the urine pH can be helpful but also can be misleading in the diagnosis of RTA [293]. Where it tends to be helpful is in

determining whether or not there is bicarbonate in the urine (see Fig. 8). The simplest test that was devised is to measure the urine sodium, potassium, and chloride concentrations and calculate the urinary anion gap using the following equation: Urinary anion gap ¼ UNa þ UK UCl ;

Renal Tubular Acidosis in Children

where UNa is the urinary sodium concentration, UK the urinary potassium concentration, and UCl the urinary chloride concentration. This approach is based on the fact that the unmeasured cations and anions are constant and that ammonium would be the primary cation other than sodium and potassium that would be excreted with chloride. The amount of ammonium in the urine when the anion gap is zero turned out to be 80 mmol/l. The other assumptions in this approach are that there is no appreciable bicarbonate in the urine and the patient is not receiving medications that are excreted in the urine in ionic form such as penicillins. If the urine pH is less than 7, the urinary bicarbonate will be less than 10 mmol/l (see Fig. 8). This simple approach has been veriﬁed in normal controls as well as patients with RTA and gastrointestinal causes of acidosis [288, 290]. Modiﬁcations to the urinary anion gap calculation have been made to expand its application to conditions that could yield misleading results. If patients are excreting other anions, ammonium would be excreted with the unmeasured anion instead of chloride. Thus, the urinary anion gap would underestimate the amount of ammonium in the urine. The osmolal gap was developed to take this into account [291]. The osmolal gap is calculated by the following equation: Urine osmolal gap ¼ measured urine osmolality calculated urine osmolality: The calculated osmolality is determined by the following equation: Calculated osmolality ¼ Na þ K þ Cl þ HCO3 urea nitrogen 2:4 glucose : þ 18 þ

This was shown to correctly account for the unmeasured anions in patients with ketoacidosis [291]. An additional modiﬁcation was then developed because of the difﬁculty in measuring the

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urine bicarbonate concentration. This method replaces the urine bicarbonate and chloride measurement by multiplying the sum of the sodium and potassium concentrations by 2 [289]. Urine NH4 þ

urea glucose þ Urineosm 2 ðNa þ K Þ þ 2:8 18 ¼ 2 þ

where the quantity in the brackets is the calculated urine osmolality. The above approaches are designed to estimate the amount of ammonium in the urine. Normal controls have about 80 mmol/l of ammonium in the urine [290]. What makes the test work well in the evaluation of acidosis is the fact that normal individuals will have an increase in their ammonium excretion but the patients with RTA will not. A recent study examined the correlation of these techniques with actual measurement of urinary ammonium [294]. This study concluded that the correlation many times was not good and that direct measurement of the urinary ammonium would be a better method. Another problem with this approach is that neonates were found to have a poor correlation between urinary anion gap and urinary ammonium concentration [295]. Another approach to examine the urine for proton secretory rate is to measure the urine and blood pCO2 during bicarbonate loading [296–298]. The idea is to take advantage of the low level of carbonic anhydrase activity in the distal nephron. When the patient is loaded with bicarbonate, the delivery to the proximal tubule will exceed the transport maximum, and signiﬁcant amounts of bicarbonate will be delivered to the distal nephron. If the patient has a normal proton secretory rate, hydrogen ions will be secreted into the tubule lumen. Although there is CA II in the distal nephron, the rate of reaction is slow enough that the carbon dioxide will be excreted in the urine and not reabsorbed. Under these conditions, normal individuals will have a urinary pCO2 of greater than 70 mmHg or a blood–urine pCO2 of greater than 30 mmHg. Patients with a defect in hydrogen ion secretion will have a urinary pCO2 of less than 70 mmHg or

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a blood–urine pCO2 of less than 30 mmHg. This method has been shown to be useful in neonates as well as adults [298]. Other tests might be indicated if the results of the above remain indeterminate. Traditionally, the patient’s ability to acidify the urine is tested using acute or chronic loading with ammonium chloride [279]. Because of the unpalatable nature of the ammonium loading, urinary acidiﬁcation can be evaluated using a combination of a mineralocorticoid and furosemide [299].

Differentiating Proximal and Distal RTA Once it has been determined that the patient has RTA, it is necessary to determine if it is a proximal or distal defect. Usually this can be determined by the associated ﬁndings in the patient. As outlined above, most patients with proximal RTA have the Fanconi syndrome. Thus, it is very helpful to evaluate the urine for glucosuria and phosphaturia. If these are normal but the patient is suspected of having a proximal tubule defect, it might be necessary to perform a bicarbonate titration to ﬁnd the threshold for bicarbonate excretion [279]. The serum potassium concentration will also help determine if the patient has a type IV RTA. Another useful determination is a renal sonogram or X-ray to determine if the patient has nephrocalcinosis (see Fig. 7). Patients with distal RTA have hypocitraturia and therefore are much more likely to have nephrocalcinosis and form renal stones. Patients with proximal RTA are in relative acid–base balance so that they have normal amounts of citrate in their urine, and they do not excrete large amounts of calcium.

Treatment The treatment of RTA will of course be determined by the type and cause of RTA. The Fanconi syndrome due to cystinosis should be treated with cysteamine [300–303]. This will prevent further damage to the renal tubular cells by preventing the accumulation of cystine. However, these patients continue to have the Fanconi syndrome and

R. Quigley and M.T.F. Wolf

require large amounts of alkali therapy as well as phosphate and vitamin D. The sporadic forms of proximal RTA are also difﬁcult to correct completely, but mild improvements in their acid–base status allow them to grow normally [75]. These patients tend to improve with age and will need less alkali as they grow. The treatment of distal RTA is somewhat more straightforward. The amount of alkali needed to correct the acidosis and maintain normal acid–base balance is much less than that needed in patients with proximal RTA. The dosage of alkali necessary has been recently studied. Using potassium citrate, investigators have found that 3–4 mEq/kg/day was necessary to normalize the urinary citrate excretion [304, 305]. A previous study had also indicated that the dosage of alkali needed to be higher in younger children and decreased to about 3 mEq/kg/day after the age of 6 years [77]. The importance of continued therapy in these children has been a recent concern [306]. It appears that subclinical acidosis could have long-term effects on the bone, resulting in osteoporosis. The loss of calcium from the bones would also lead to nephrocalcinosis and renal stone formation.

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1303 222. Stover EH, Borthwick KJ, Bavalia C, Eady N, Fritz DM, Rungroj N, et al. Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss. J Med Genet. 2002;39(11):796–803. 223. Bajaj G, Quan A. Renal tubular acidosis and deafness: report of a large family. Am J Kidney Dis. 1996;27 (6):880–2. 224. Fuster DG, Zhang J, Xie XS, Moe OW. The vacuolarATPase B1 subunit in distal tubular acidosis: novel mutations and mechanisms for dysfunction. Kidney Int. 2008;73(10):1151–8. 225. Smith AN, Skaug J, Choate KA, Nayir A, Bakkaloglu A, Ozen S, et al. Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing. Nat Genet. 2000;26(1):71–5. 226. Li SL, Liou LB, Fang JT, Tsai WP. Symptomatic renal tubular acidosis (RTA) in patients with systemic lupus erythematosus: an analysis of six cases with new association of type 4 RTA. Rheumatology (Oxford). 2005;44(9):1176–80. 227. Lorente-Canovas B, Ingham N, Norgett EE, Golder ZJ, Karet Frankl FE, Steel KP. Mice deﬁcient in H+ATPase a4 subunit have severe hearing impairment associated with enlarged endolymphatic compartments within the inner ear. Dis Model Mech. 2013;6(2):434–42. 228. Norgett EE, Golder ZJ, Lorente-Canovas B, Ingham N, Steel KP, Karet Frankl FE. Atp6v0a4 knockout mouse is a model of distal renal tubular acidosis with hearing loss, with additional extrarenal phenotype. Proc Natl Acad Sci USA. 2012;109(34): 13775–80. 229. Fabris A, Anglani F, Lupo A, Gambaro G. Medullary sponge kidney: state of the art. Nephrol Dial Transplant. 2013;28(5):1111–9. 230. Carboni I, Andreucci E, Caruso MR, Ciccone R, Zuffardi O, Genuardi M, et al. Medullary sponge kidney associated with primary distal renal tubular acidosis and mutations of the H+ATPase genes. Nephrol Dial Transplant. 2009;24(9):2734–8. 231. Stehberger PA, Shmukler BE, Stuart-Tilley AK, Peters LL, Alper SL, Wagner CA. Distal renal tubular acidosis in mice lacking the AE1 (band3) Cl/HCO3 exchanger (slc4a1). J Am Soc Nephrol. 2007; 18(5):1408–18. 232. Blomqvist SR, Vidarsson H, Fitzgerald S, Johansson BR, Ollerstam A, Brown R, et al. Distal renal tubular acidosis in mice that lack the forkhead transcription factor Foxi1. J Clin Invest. 2004;113(11):1560–70. 233. Cohen EP, Bastani B, Cohen MR, Kolner S, Hemken P, Gluck SL. Absence of H(+)-ATPase in cortical collecting tubules of a patient with Sjogren’s syndrome and distal renal tubular acidosis. J Am Soc Nephrol. 1992;3(2):264–71. 234. Pertovaara M, Korpela M, Kouri T, Pasternack A. The occurrence of renal involvement in primary Sjogren’s

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R. Quigley and M.T.F. Wolf 251. Borthwick KJ, Kandemir N, Topaloglu R, Kornak U, Bakkaloglu A, Yordam N, et al. A phenocopy of CAII deficiency: a novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis. J Med Genet. 2003;40(2):115–21. 252. Nagai R, Kooh SW, Balfe JW, Fenton T, Halperin ML. Renal tubular acidosis and osteopetrosis with carbonic anhydrase II deficiency: pathogenesis of impaired acidification. Pediatr Nephrol. 1997;11 (5):633–6. 253. Del Fattore A, Cappariello A, Teti A. Genetics, pathogenesis and complications of osteopetrosis. Bone. 2008;42(1):19–29. 254. Karet FE. Mechanisms in hyperkalemic renal tubular acidosis. J Am Soc Nephrol. 2009;20(2):251–4. 255. Wagner CA, Geibel JP. Acid–base transport in the collecting duct. J Nephrol. 2002;15 Suppl 5:S112–27. 256. Sartorius OW, Calhoon D, Pitts RF. The capacity of the adrenalectomized rat to secrete hydrogen and ammonium ions. Endocrinology. 1952;51(5):444–50. 257. Sartorius OW, Calhoon D, Pitts RF. Studies on the interrelationships of the adrenal cortex and renal ammonia excretion by the rat. Endocrinology. 1953;52(3):256–65. 258. Welbourne TC, Francoeur D. Influence of aldosterone on renal ammonia production. Am J Physiol. 1977;233(1):E56–60. 259. DuBose Jr TD. Hyperkalemic hyperchloremic metabolic acidosis: pathophysiologic insights. Kidney Int. 1997;51(2):591–602. 260. DuBose Jr TD. Molecular and pathophysiologic mechanisms of hyperkalemic metabolic acidosis. Trans Am Clin Climatol Assoc. 2000;111:122–33; discussion 33–4. 261. White PC, New MI, Dupont B. Congenital adrenal hyperplasia (2). N Engl J Med. 1987;316(25):1580–6. 262. White PC, New MI, Dupont B. Congenital adrenal hyperplasia. (1). N Engl J Med. 1987;316(24): 1519–24. 263. White PC. Steroid 11 beta-hydroxylase deficiency and related disorders. Endocrinol Metab Clin North Am. 2001;30(1):61–79, vi. 264. Geller DS, Rodriguez-Soriano J, Vallo Boado A, Schifter S, Bayer M, Chang SS, et al. Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I. Nat Genet. 1998;19(3):279–81. 265. Chang SS, Grunder S, Hanukoglu A, Rosler A, Mathew PM, Hanukoglu I, et al. Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nat Genet. 1996;12(3): 248–53. 266. Gordon RD. Syndrome of hypertension and hyperkalemia with normal glomerular filtration rate. Hypertension. 1986;8(2):93–102. 267. Schambelan M, Sebastian A, Rector Jr FC. Mineralocorticoid-resistant renal hyperkalemia without salt wasting (type II pseudohypoaldosteronism): role of

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1305 284. Kraut JA, Madias NE. Serum anion gap: its uses and limitations in clinical medicine. Clin J Am Soc Nephrol. 2007;2(1):162–74. 285. Kraut JA, Madias NE. Differential diagnosis of nongap metabolic acidosis: value of a systematic approach. Clin J Am Soc Nephrol. 2012;7(4):671–9. 286. Oh MS, Carroll HJ. The anion gap. N Engl J Med. 1977;297(15):814–7. 287. Kraut JA, Madias NE. Approach to patients with acid–base disorders. Respir Care. 2001;46(4): 392–403. 288. Batlle DC, Hizon M, Cohen E, Gutterman C, Gupta R. The use of the urinary anion gap in the diagnosis of hyperchloremic metabolic acidosis. N Engl J Med. 1988;318(10):594–9. 289. Dyck RF, Asthana S, Kalra J, West ML, Massey KL. A modification of the urine osmolal gap: an improved method for estimating urine ammonium. Am J Nephrol. 1990;10(5):359–62. 290. Goldstein MB, Bear R, Richardson RM, Marsden PA, Halperin ML. The urine anion gap: a clinically useful index of ammonium excretion. Am J Med Sci. 1986;292(4):198–202. 291. Halperin ML, Margolis BL, Robinson LA, Halperin RM, West ML, Bear RA. The urine osmolal gap: a clue to estimate urine ammonium in “hybrid” types of metabolic acidosis. Clin Invest Med. 1988;11 (3):198–202. 292. Kim GH, Han JS, Kim YS, Joo KW, Kim S, Lee JS. Evaluation of urine acidification by urine anion gap and urine osmolal gap in chronic metabolic acidosis. Am J Kidney Dis. 1996;27(1):42–7. 293. Richardson RM, Halperin ML. The urine pH: a potentially misleading diagnostic test in patients with hyperchloremic metabolic acidosis. Am J Kidney Dis. 1987;10(2):140–3. 294. Kirschbaum B, Sica D, Anderson FP. Urine electrolytes and the urine anion and osmolar gaps. J Lab Clin Med. 1999;133(6):597–604. 295. Sulyok E, Guignard JP. Relationship of urinary anion gap to urinary ammonium excretion in the neonate. Biol Neonate. 1990;57(2):98–106. 296. DuBose Jr TD, Caflisch CR. Validation of the difference in urine and blood carbon dioxide tension during bicarbonate loading as an index of distal nephron acidification in experimental models of distal renal tubular acidosis. J Clin Invest. 1985;75(4): 1116–23. 297. Kim S, Lee JW, Park J, Na KY, Joo KW, Ahn C, et al. The urine-blood PCO gradient as a diagnostic index of H(+)-ATPase defect distal renal tubular acidosis. Kidney Int. 2004;66(2):761–7. 298. Lin JY, Lin JS, Tsai CH. Use of the urine-to-blood carbon dioxide tension gradient as a measurement of impaired distal tubular hydrogen ion secretion among neonates. J Pediatr. 1995;126(1):114–7. 299. Walsh SB, Shirley DG, Wrong OM, Unwin RJ. Urinary acidification assessed by simultaneous furosemide and fludrocortisone treatment: an

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Nephrogenic Diabetes Insipidus in Children

Nine V. A. M. Knoers and Elena N. Levtchenko

Contents

History

History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1307 Deﬁnition and Clinical Manifestations . . . . . . . . . . 1307 Diagnostic Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1309 Cellular Physiology of Arginine Vasopressin’s Antidiuretic Action in the Distal Nephron . . . . . . 1309 Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1312 X-Linked Nephrogenic Diabetes Insipidus: Mutations in the AVPR2 Gene . . . . . . . . . . . . . . . . . . . 1312 Genotype-Phenotype Correlations in X-Linked NDI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1314 The Autosomal Recessive and Autosomal Dominant Forms of Nephrogenic Diabetes Insipidus: Mutations in the Aquaporin-2 Water Channel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1314 Differential Diagnosis Between the X-Linked and the Autosomal Forms of NDI . . . . . . . . . . . . . . . . . . 1316 Nephrogenic Diabetes Insipidus in Females . . . . . 1317 Acquired Nephrogenic Diabetes Insipidus . . . . . . 1317 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1318 Conventional Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1318

First familial cases with diabetes insipidus were described by McIlraith in 1892; however, he did not distinguish between renal and neurohormonal forms of the disorder [1]. The renal type of diabetes insipidus was appreciated as a separate entity more than 50 years ago, when it was described independently by two investigators: Forssman [2] in Sweden and Waring et al. [3] in the United States. In 1947, Williams and Henry [4] noticed that injection of antidiuretic hormone (ADH) in doses sufﬁcient to induce systemic side effects could not correct the renal concentrating defect. They coined the term nephrogenic diabetes insipidus. Subsequent studies revealed active hormone in the serum and urine of affected persons and lent further support to the theory of renal unresponsiveness to vasopressin. Nephrogenic diabetes insipidus is synonymous with the terms vasopressin- or ADH-resistant diabetes insipidus and diabetes insipidus renalis.

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1321

Definition and Clinical Manifestations N.V.A.M. Knoers (*) Departments of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands e-mail: [emailprotected] E.N. Levtchenko Department of Pediatric Nephrology, Department of Growth and Regeneration, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium e-mail: [emailprotected] # Springer-Verlag Berlin Heidelberg 2016 E.D. Avner et al. (eds.), Pediatric Nephrology, DOI 10.1007/978-3-662-43596-0_36

Congenital nephrogenic diabetes insipidus (NDI) is a rare inherited disorder, characterized by insensitivity of the distal nephron to the antidiuretic effects of the neurohypophyseal hormone arginine vasopressin (AVP). As a consequence, the kidney loses its ability to concentrate urine, which may lead to severe dehydration and electrolyte 1307

1308

imbalance (hypernatremia and hyperchloremia). Patients with NDI have normal birth weight and pregnancies are not complicated by polyhydramnios. The urine-concentrating defect in NDI is present from birth, and manifestations of the disorder generally emerge within the ﬁrst weeks of life. With breast milk feedings, infants usually thrive and do not develop signs of dehydration. This is because human milk has a low salt and protein content and therefore a low renal osmolar load. With cows’ milk formula feedings, the osmolar load to the kidney increases, resulting in an increased demand for free water. This is usually not provided by oral feeding, and therefore hypernatremic dehydration appears. Irritability, poor feeding, and poor weight gain are usually the initial symptoms [5]. Patients are eager to suck but may vomit during or shortly after the feeding. Dehydration is evidenced by dryness of the skin, loss of normal skin turgor, recessed eyeballs, increased periorbital folding, depression of the anterior fontanel, and a scaphoid abdomen. Intermittent high fever is a common complication of the dehydrated state, predominantly in very young children. Body temperature can be normalized by rehydration. Seizures can occur but are rare and most often seen during therapy, particularly if rehydration proceeds too rapidly. Constipation is a common symptom in children with NDI. Nocturia and nocturnal enuresis are common complaints later in childhood. Untreated, most patients fail to grow normally. In a retrospective study of 30 male NDI patients, most children grew below the 50th percentile, most of them having standard deviation (SD) scores lower than 1 [6]. Some well-treated patients, however, may achieve normal adult height. Catch-up growth occurs at least in some patients after normalization of water and electrolyte balance, especially in those with adherence to treatment. Bone maturation is generally not delayed [7]. Weight-for-height SD scores are initially low, followed by global normalization at school age [6]. Initial feeding problems and the ingestion of large amounts of low-caloric ﬂuid resulting in a decreased appetite may play roles in failure to thrive seen in NDI [8, 9].

N.V.A.M. Knoers and E.N. Levtchenko

Furthermore, it is possible that repeated episodes of dehydration have some as yet undetermined negative effects on growth. Mental retardation has long been considered an important complication of untreated NDI and assumed to be a sequel of recurrent episodes of severe brain dehydration and cerebral edema caused by overzealous attempts at rehydration [10–12]. Additional evidence underscoring the assumption that NDI has adverse effects on the cerebrum is provided by several reports describing intracranial calcifications in NDI patients [13, 14]. Such lesions are generally considered to be the result of hemorrhage or necrosis. Most of the reported patients with cerebral calcifications were mentally retarded. Nowadays mental retardation is rare due to earlier recognition and treatment of NDI. Exact estimates of the current frequency of mental retardation under modern treatment are unknown, but in the largest psychometric study ever reported, only 2 of the 17 male NDI patients (aged 3–30 years) had a total intelligence quotient more than 2 SD below the norm. Fourteen patients had an intelligence score within or above the normal range and one patient had a general index score between 1 and 2 SD [15]. The psychological development of NDI patients is influenced by a persistent desire for drinking and the need for frequent voiding, which compete with playing and learning. Therefore, many NDI patients are characterized by hyperactivity, distractibility, short attention span, and restlessness. In the psychometric study mentioned earlier, the criteria for attention-deficit/ hyperactivity disorder were met in 8 of 17 tested NDI patients [15]. Persistent polyuria can result in the development of megacystis, trabeculated bladder wall, hydroureter, and hydronephrosis [6, 16, 17]. Urinary tract distension may be seen on ultrasound examination even in infants [18] and young children [19]. Potential complications of urinary tract dilatation are rupture of the urinary tract, infection, intractable pain, improper bladder function, and/or kidney failure. These complications may occur as early as the second decade of life. Large-capacity hypotonic bladder

Nephrogenic Diabetes Insipidus in Children

Table 1 Causes of secondary nephrogenic diabetes insipidus Monogenetic diseases associated with secondary NDI Renal Fanconi syndromes Bartter syndrome (type 1 or type 2) Familial hypomagnesemia with hypercalciuria and nephrocalcinosis Distal renal tubular acidosis (dRTA) Apparent mineralocorticoid excess (AME) Ciliopathies (nephronophthisis, Bardet–Biedl syndrome, etc.) Other renal diseases Obstructive uropathy Renal dysplasia Postischemic damage Amyloidosis Sarcoidosis Chronic renal failure Renal impairment in sickle-cell disease or trait Drug induced Lithium Ifosfamide Amphotericin B Tetracyclines Biochemical abnormalities Hypercalcemia, hypercalciuria, and nephrocalcinosis Hypokalemia

dysfunction might require clean intermittent catheterization [17]. Patients should be trained to void regularly in order to assure that maximal urinary bladder capacity remains within normal range. Both patient groups with AVPR2 and AQP2 mutations can develop urinary tract dilatation and bladder dysfunction [16, 20].

Diagnostic Procedures The observation of polyuria in a dehydrated infant, together with the ﬁnding of a high serum sodium concentration and inappropriately diluted urine (Uosm < Posm), provides presumptive evidence for a renal concentrating defect. To conﬁrm the concentrating defect and to distinguish the renal form of diabetes insipidus from the central form, a vasopressin test is performed with 1-desamino-8-D-arginine vasopressin (DDAVP),

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a synthetic analogue of the natural arginine vasopressin that produces a high and prolonged antidiuretic effect. In the test, DDAVP (10 μg for infants 1 year old) is administered intranasally. Urine is collected during the subsequent 5.5 h. The first collected portion of the urine should be discarded. The maximal urine osmolality in any collected aliquot is chosen as a measure of the concentrating capacity [21]. After DDAVP administration, NDI patients are (1) unable to increase urinary osmolality, which remains below 200 mOsm/kg H2O (normal values: 600, between 1 and 2 years old between 600 and 800, >2 years old >800 mOsm/kg H2O), and (2) cannot reduce urine volume or free-water clearance. Plasma vasopressin levels are normal or only slightly increased in affected children. Other laboratory findings have been described, which mainly result from chronic dehydration. Serum sodium concentration is generally elevated and may be above 170 mmol/L. There is also an increase in serum chloride concentration and retention of urea and creatinine. All values are normalized by adequate rehydration. In addition, reduced glomerular filtration rate (GFR) and renal blood flow can return to normal when a normal hydration state has been achieved. The primary congenital form of NDI has to be differentiated from central diabetes insipidus (due to lack of AVP) and from the secondary or acquired forms, which are much more common [22]. In our experience, the urinary osmolality obtained after DDAVP administration in secondary disorders is always higher than in NDI. Several secondary causes, some of which will be discussed later, are listed in Table 1.

Cellular Physiology of Arginine Vasopressin’s Antidiuretic Action in the Distal Nephron The physiologic action of vasopressin on the renal collecting duct has been one of the most intensively studied processes in the kidney. Arginine vasopressin (AVP, ADH) is synthesized on the

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ribosomes of the magnocellular neurons of the supraoptic and paraventricular nuclei of the hypothalamus as a large biologically inactive bound form. Within storage granules, the hormone is cleaved into the biologically active form and transported down the neuronal axons to the posterior pituitary and stored there. Following appropriate stimuli, AVP is secreted from the posterior pituitary into the circulation as biologically active hormone. AVP release is regulated by changes in plasma osmolality (by >2 %) but can also occur in response to nonosmotic stimuli. These nonosmotic stimuli are generally related to changes in either total blood volume or the distribution of extracellular fluid. Patients with depleted effective circulating volume may secrete ADH even in the presence of low plasma osmolality. In addition, physical pain, emotional stress, and certain drugs (e.g., nicotine) influence the release of AVP. In its effector organ, the kidney, AVP binds to vasopressin type-2 (V2) receptors on the basolateral membrane of the principal inner medullary collecting duct cells and of the arcade cells (Fig. 1, review in Ref. [23]). The arcades are long, highly branched renal tubule segments that connect distal convoluted tubules of several deep and midcortical nephrons to the origin of cortical collecting ducts. Upon binding of AVP, the V2 receptor is activated and then stimulates GTP loading of the small GTPase-αGS – subunit of its coupled trimeric G-protein – eventually leading to dissociation of the G-protein from the receptor. GTP-αGS can then bind to the membraneassociated adenylate cyclase (AC), activating it, which results in an increase in intracellular cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). The elevated cAMP levels stimulate protein kinase A (PKA), leading to phosphorylation of AQP2 which in turn initiates a redistribution of aquaporin-2 (AQP2) water channels from intracellular vesicles to the apical plasma membrane, rendering this membrane water permeable. The increase in apical membrane permeability allows water to flow from the tubule lumen to the hypertonic medullary interstitium, via AQP2 in the apical membrane and via AQP3 and AQP4, constitutive water channels in the basolateral membrane. This then leads

N.V.A.M. Knoers and E.N. Levtchenko

to the formation of concentrated urine. Upon fluid intake, AVP release into the blood decreases, AQP2 is redistributed into intracellular vesicles, and water reabsorption is reduced. Katsura et al. have shown that the AVP-regulated recycling of AQP2 can occur at least six times with the same molecules [24]. In recent years, our knowledge of the AQP2 dynamics in the cell has increased significantly (Fig. 1). For further details the reader is also referred to several excellent reviews on this subject (review in Refs. [23, 25–28]). AQP2 is 1 of the 13 members of the aquaporin family of water channels. After transcription AQP2 is folded into its native monomeric conformation in the endoplasmic reticulum, and homotetramerization takes place [29]. The tetramers are forwarded to the Golgi apparatus, where two out of four monomers are complex N-glycosylated. These functional water channels are then stored in endosomal vesicles to be transported to the apical membrane [30]. Phosphorylation of a PKA-consensus site in AQP2, the serine at position 256 in the cytoplasmic carboxy-terminus, is absolutely essential for AQP2 delivery to the apical membrane [31, 32]. In addition, it has been shown that anchoring of PKA to PKA-anchoring proteins (AKAPs), which ensures targeting of PKA to AQP2-bearing vesicles, is another prerequisite for AVP-mediated AQP2 translocation [33]. Studies using oocytes as a model system indicated that for plasma membrane localization three out of four monomers in an AQP2 tetramer need to be phosphorylated [34]. PKA is the main kinase for AQP2 phosphorylation, but other kinases may potentially participate in the regulation of AQP2 trafficking. Besides PKA sites, putative phosphorylation sites for PKG, PKC, and casein kinase II are also present in the AQP2 sequence. The molecular machinery for the docking and fusion of AQP2-containing vesicles with the apical membrane is similar to the process of synaptic vesicle fusion with the presynaptic membrane and involves vesicle (v) SNAREs (soluble NSF attachment protein receptors) and target membrane (t) SNAREs. The apical membrane-specific t-SNARE is syntaxin 4, which interacts

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Fig. 1 Intracellular signal transduction pathway initiated by AVP binding to V2R. Via activation of adenylate cyclase and cAMP-production stimulation, PKA is activated and phosphorylates its target proteins AQP2, Rho-GDI, and CREB-1. The transcription factor CREB1-p stimulates AQP2 transcription, Rho-GDI-p initiates actin reorganization required for AQP2 transport, and AQP2-p homotetramers are transported to the apical membrane. There they render the membrane permeable for water, which is reabsorbed from the passing pro-urine

and transported back into the bloodstream by AQP3 and AQP4. Rab5-mediated AQP2 endocytosis by clathrincoated vesicles is triggered by short-chain ubiquitination and leads to termination of the response. Internalized AQP2 vesicles are transported to early and late endosomes as well as multivesicular bodies (MVBs) for storage. From MVBs they can then either be lysosomally degraded or recycled via the Rab11-dependent slow-recycling pathway (From Ref. [23], with kind permission from Springer Science and Business Media)

speciﬁcally with the v-SNARE protein VAMP2 located on the cytoplasmic side of AQP2containing endosomal vesicles [35–38]. V- and t-SNAREs are recycled by the AAA-type ATPase

NSF. Reorganization of the actin cytoskeleton is another important mechanism required for AQP2 transport and accumulation at the apical membrane [39, 40]. The actin cytoskeleton most likely

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provides a network that anchors the AQP2bearing vesicles in the unstimulated cell. Vasopressin has been shown to depolymerize apical F-actin in rat inner medullary collecting duct, resulting in the fusion of AQP2-carrying vesicles with the apical membrane [41], indicating that reorganization of the apical actin network may be critical in promoting the trafficking of AQP2bearing vesicles. Rho inhibition through PKA-mediated phosphorylation of Rho-GDP dissociation inhibitor (Rho-GDI) is shown to be a key event for actin reorganization inducing AQP2 translocation [39, 40]. Counterbalancing increased expression on the plasma membrane, AQP2 is internalized. During this endocytotic process, AQP2 accumulates in clathrin-coated pits and is internalized via a clathrin-mediated process [42]. Endocytosis is regulated by short-chain ubiquitylation at lysine 270 (K270) in the AQP2 terminal tail [43, 44]. To be available for recycling, AQP2containing endosomes need to be redistributed to the perinuclear region. This process is mediated by dynein-dependent transport along microtubules [45, 46]. Specificity of the endocytotic AQP2 internalization is mediated by Rab5 protein, an effector-binding factor involved in plasma membrane-to-early-endosome transport [47]. From the endosomal system – early/late endosomes and/or multivesicular bodies (MVBs) – AQP2 is either recycled by the Rab11-dependent slow-recycling pathway or marked for lysosomal degradation [48]. Prolonged K270 ubiquitylation induces MVB trafficking and localization to internal vesicles of MVBs followed by lysosomal degradation, while deubiquitylation increases localization to early endosomes and the limiting membrane of MVBs and enables AQP2 recycling [44]. Long-term adaptation to circulating AVP levels, for instance, in a dehydrated state, is accomplished by increasing the expression of AQP2 mRNA and protein. PKA-mediated phosphorylation of a cAMP-responsive element-binding protein 1(CREB-1) stimulates synthesis of AQP2 by binding to the AQP2 gene promotor and activating its transcription, which increases intracellular AQP2 levels [49].

N.V.A.M. Knoers and E.N. Levtchenko

Genetics Three different inheritance patterns of NDI have been recognized. In most cases (about 90 %), NDI is transmitted as an X-linked recessive trait (MIM304800). In these families, female carriers who are usually unaffected transmit the disease to sons, who display the complete clinical picture [2, 4, 50]. In 1988, the major NDI locus was mapped to the distal region of the long arm of the X chromosome (Xq28) [51], and in 1992 mutations in the AVPR2 gene were shown to underlie X-linked NDI [52–54]. In a minority of families (about 10 %), the transmission and phenotypic characteristics of NDI are not compatible with an X-linked trait. In these families, females display the complete clinical picture of NDI and are clinically undistinguishable from affected male family members [55–57]. Family pedigrees suggested the existence of both an autosomal recessive (MIM 222000) and an autosomal dominant form (MIM 125800) of NDI. It was subsequently demonstrated that both autosomal forms of NDI are caused by mutations in the AVP-sensitive aquaporin-2 water channel [58, 59]. The prevalence of NDI is not exactly known, but the disease is assumed to be rare. The estimate of the prevalence of NDI in Quebec, Canada, is 8.8:1,000,000 males [60]. In the Dutch population of about 16 million, at least 50 different families are known.

X-Linked Nephrogenic Diabetes Insipidus: Mutations in the AVPR2 Gene The X-linked form of NDI is caused by inactivating mutations in the AVPR2 gene (MIM 300538) ([52–54], reviews in Refs. [23, 28, 61]). AVPR2 is a relatively small gene, consisting of three exons separated by two short intervening sequences (introns); two isoforms are known that are generated by alternative splicing [62]. AVPR2 is localized on the X chromosome on locus Xq28. The cDNA encodes a receptor protein of 371 amino acids, has a predicted molecular mass of approximately 40 kDa, and shares the general

Nephrogenic Diabetes Insipidus in Children

structure of a G-protein-coupled receptor consisting of seven hydrophobic transmembrane helices, connected by extracellular and intracellular loops. The receptor contains one unique consensus sequence site for N-linked glycosylation in the extracellular amino-terminus [63] and phosphorylation sites for G-protein-coupled receptor kinases (GRK) represented by a serine cluster in the carboxy-terminus [64, 65]. The N-terminal part of the protein including the first transmembrane domain and the positively charged first intracellular loop are important for proper insertion and orientation in the membrane [66]. A conserved glutamate-dileucine motif in the intracellular carboxy-terminal part of the receptor is essential for receptor transport from the endoplasmic reticulum (ER) to the Golgi apparatus [67]. Two conserved adjacent cysteines in the C-terminus are palmitoylated, thereby anchoring the carboxy tail to the plasma membrane and controlling the tertiary structure of this region of the receptor [68]. At this writing, more than 240 distinct disease-causing mutations in AVPR2 have been identified, and the number is constantly increasing ([69, 70] and review in Refs. [23, 28, 61] and www.hgmd.org). The mutations are not clustered in one domain of the V2 receptor but are scattered throughout the protein, except for the part coding for the N- and C-terminal tails of the receptor. More than 50 % of the mutations are missense mutations. Nucleotide deletions and insertions causing frameshifts (26 %), nonsense mutations (13 %), large deletions (7 %), large in-frame insertions/duplications (1 %), splice-site mutations (1 %), and complex rearrangements (2 %) account for the remainder of mutations ([12, 69], and review in Refs. [23, 28, 61, 71]). In addition to these disease-causing mutations, at least 21 AVPR2 variations that do not lead to disease are known. These non-disease-causing variations are most likely polymorphisms that can be found in more than 1 % of the population. The G12E mutation, for example, has also been found in non-affected individuals, suggesting that it belongs to this class of polymorphisms that do not exert a significant effect on proper functioning of the V2 receptor [72]. Several mutations are

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recurrent as evidenced by the fact that these mutations were found on different haplotypes in ancestrally independent families. The most frequent of these recurrent mutations (D85N, R106C, R113W, R137H, S167L, and R337X) occur at potential mutational hot spots. AVPR2 mutations seem to be present in all ethnical groups tested with no preference of one mutation for any ethnic group over others. The molecular mechanism underlying the renal insensitivity for AVP differs between mutants. As upcoming pharmacological treatments for NDI likely depend on the underlying mechanism, GPCR mutations in general and V2 mutations in particular have been divided in different classes according to their cellular fate [73, 74]. Class I comprises all mutations that lead to improperly processed or unstable mRNA, like promoter alterations, exon skipping, or aberrant splicing. This class also holds frameshift and nonsense mutations, which result in truncated proteins like W71X, 458delG (frameshift, 161X), and R337X. Class II mutations are missense or insertions/ deletions of one or more nucleotide triplets, resulting in fully translated proteins. Due to the mutation, however, mutant receptors are misfolded and retained in the endoplasmic reticulum (ER), as the ER is the organelle that has the cellular quality control over proper folding and maturation of synthesized proteins. Misfolded proteins are subsequently mostly targeted for proteasomal degradation [75]. Intracellular entrapment of missense V2R mutants and their rapid degradation likely represents the most important cause of NDI, as more than 50 % of the mutations in V2R are missense mutations and cellular expression revealed that most of these result in ER-retained proteins. The amount of retention and degradation varies within this class, since different mutations affect protein folding to a different extent, sometimes allowing partial transport of at least partially active receptors to the plasma membrane [76]. Class III mutations result in full-length receptors expressed at the cell surface, but interfere with proper interaction with their natural ligands, thereby causing reduced/abolished signaling [77].

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Class III mutations can be subdivided into two minor groups. IIIa mutations interfere with binding of or signal transduction to the coupled trimeric G-protein, leading to a reduced activation of adenylate cyclase and thus formation of cAMP. Mutations in this group are missense mutations and in-frame deletions, mostly located in transmembrane and intracellular domains. Examples are the D85N and P322S mutations [78]. IIIb mutations interfere with, or reduce, AVP binding. These mutations, which are also mostly missense and small in-frame deletions or insertions, especially involve residues thought to be in or close to the AVP-binding pocket, of which delR202 is a clear example [79]. Finally, class IV is assigned to all mutations that neither interfere with protein synthesis of maturation, not with ligand binding, but affect other aspects of protein function. The NDI R137H mutation, located in the well-conserved DRY/H motif of GPCRs, is the best-characterized example of this class. The effect of this mutation is constitutive internalization of V2, leading to reduced expression of the receptor in the plasma membrane and thereby reduced adenylate cyclase-dependent cAMP signaling upon AVP binding [80, 81]. Sometimes, mutants do not exert a full phenotype of a particular class and then often also show features of another class. For example, some V2R missense mutants are partially ER retained (class II), but are also partially expressed in the plasma membrane, where they might show a reduced G-protein coupling (class IIIa) or AVP binding (class IIIb). As such, it provides an explanation for the observed small antidiuretic response to high doses of DDAVP in NDI patients harboring such mutations [82].

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manifestation, not at birth but later in childhood, and without growth retardation. Examples of mutations causing partial NDI are D85N, V88M, G201D, M311V, N317S, P322S, and S329R [83–86]. Functional studies of some of these mutations by in vitro expression systems have conﬁrmed the partial phenotype of the NDI. P322S is the most remarkable of these three mutations, since another mutation substituting proline 322, namely, P322H, is associated with a severe phenotype. By in vitro expression of both P322H and P322S in COS-7 cells, Ala et al. [79] have shown that the P322H mutant had totally lost the ability to stimulate the Gs/adenylate cyclase system, whereas the P322S mutant was able to stimulate adenylate cyclase, albeit less than the wild-type receptor. Thus, the in vitro experiments closely correspond to the clinical phenotype. On the basis of threedimensional modeling of the P322H and P322S mutant receptors, a plausible hypothesis to explain the molecular basis for the mild phenotype of the P322S has been proposed. Based on this modeling, it is suggested that complete loss of function of the P322H receptor could be due, in part, to hydrogen bond formation between the His322 side chain and the carboxyl group of Asp85, which does not occur in the P322S receptor [79]. Intrafamilial variability of the X-linked NDI phenotype has also been described. A nice example is the case described by Kalenga et al., who reported a Belgian family in which the R137H mutation was associated with severe NDI in the proband but with very mild NDI in his affected brother [87]. Genetic and/or environmental modifying factors are likely to account for this intrafamilial phenotype variability.

The Autosomal Recessive and Autosomal Dominant Forms of Nephrogenic Diabetes Insipidus: Mutations in the Almost all mutations in the V2 receptor gene result Aquaporin-2 Water Channel Genotype-Phenotype Correlations in X-Linked NDI

in a uniform clinical NDI phenotype with polyuric manifestations in the ﬁrst weeks of life and poor growth. There are, however, a few exceptions to this rule. Several mutations appear to be associated with a milder form of NDI, characterized by a later

Both the autosomal recessive and the autosomal dominant types of NDI are caused by mutations in the AQP2 water channel gene (MIM 107777; GenBank accession number z29491).

Nephrogenic Diabetes Insipidus in Children

The human AQP2 gene is a small gene consisting of 4 exons, comprising 5 kb genomic DNA. The 1,5 kb mRNA encodes a protein of 271 amino acids which has a predicted molecular weight of 29 kDa [88]. AQP2 belongs to a family of membrane integral proteins, aquaporins, which function as selective water transporters throughout the plant and animal kingdom. In mammals, 13 different aquaporins have been identified to date, 8 of which (aquaporins 1–4, 6–8, and 11) are highly expressed in the kidney. Like other aquaporins, AQP2 is assembled in the membrane as a homotetramer in which each 29 kDa monomer, consisting of six membrane-spanning α-helical domains and intracellular N- and C-termini, is a functional water channel. The six transmembrane domains are connected by five loops (A through E). The mechanism of selectivity for water of aquaporins in general has been revealed in the homologous AQP1 protein [89, 90] and has further been strengthened by molecular dynamics modeling approaches [91, 92] and was recently also confirmed for AQP2 [93]. The water pore is formed between the first and sixth transmembrane domains and is lined by the intracellular B-loop and the extracellular E-loop. AQP2 is exclusively localized in the apical membrane and a subapical compartment of collecting duct cells. It is upregulated by dehydration or AVP, indicating that it is the AVP-regulated water channel. To date, 46 putative disease-causing mutations in AQP2 have been identified in families with autosomal recessive NDI ([69, 70, 94–96], reviews in Refs. [23, 61, 71]). These include 38 missense mutations, 2 nonsense mutations, 3 small deletions, and 3 splice-site mutations. Most mutations are found between the first and last transmembrane domain of AQP2. Expression studies in Xenopus laevis oocytes have revealed that most AQP2 missense mutations that cause recessive NDI are class II mutations. Thus, these mutations lead to misfolding of the mutant protein, retention in the endoplasmic reticulum (ER), and rapid degradation of AQP2 (review in Refs. [23, 78]). In agreement with extensive degradation, AQP2 could not be detected in the urine of patients with recessive NDI [97]. When overexpressed in oocytes and Chinese hamster

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(CHO) cells, six of these AQP2 mutants (A147T, T126M, G64R, L22V, A47V, and T125M) confer water permeability [98, 99]. This indicates that at high expression levels, these AQP2 mutant proteins escape from the ER and are routed to the plasma membrane, where they are functional. In terms of possible treatment strategies, these results are of high importance, since they suggest that functional channels may be stimulated to reach the plasma membrane by restoring mutant trafficking (discussed later in treatment). One AQP2 missense mutation, P262L, located in the AQP2 C-terminal tail, a region until then believed to result in dominant NDI, surprisingly was found to be involved in recessive NDI [100]. In cell biological experiments, it was shown that the P262L mutant is a functional water channel that forms heterooligomers with wt-AQP2. These wt-AQP2/AQP2-P262L heterotetramers are located in the apical membrane, indicating that the apical sorting of wildtype AQP2 is dominant over the missorting signal of AQP2-P262L. This is different from dominant NDI, because in this form mutants retain wt-AQP2 in intracellular locations (see below). The recessive inheritance in the two patients encountered (patients were heterozygous for a R187C or A190T mutation on one allele, combined with a P262L mutation on the other allele) can be explained as follows: AQP2-R187C and AQP2-A190T are retained in the ER and do not interact with AQP2-P262L. AQP2-P262L folds properly and assembles in homotetramers, but will be retained mainly in intracellular vesicles. The consequent lack of sufficient AQP2 proteins in the apical membrane of the patients’ collecting duct cells explains their NDI phenotype. In the parents coding for wt-AQP2 and AQP2-R187C or AQP2-A190T, wt-AQP2 will not interact with either mutant but will form homotetrameric complexes, of which the insertion into the apical membrane will be regulated properly by vasopressin and will give a healthy phenotype. In the parents coding for wt-AQP2 and AQP2-P262L, both proteins likely assemble into heterotetramers. The dominancy of wt-AQP2 sorting on the localization of AQP2-P262L will result in proper AVP-regulated trafficking of the heterotetrameric

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complexes to the apical membrane and will also give a healthy phenotype [100]. At present ten families have been described with autosomal dominant NDI, initially uncovered due to father-to-son transmission of the disease. In these families subsequent sequencing of the AQP2 gene revealed putative disease-causing mutations of one AQP2 allele. The identiﬁed mutations in AQP2 comprise small deletions, insertions, and missense mutations ([69], review in Refs. [23, 101]). All mutations causing dominant NDI are located in the coding region of the C-terminal tail of AQP2, which is not part of the pore-forming segment but contains important sorting signals that govern intracellular transport of the protein [78, 102]. Indeed, all mutants AQP2 proteins found in dominant NDI appeared to be folded functional water channels that were sorted to other subcellular locations in the cell than wt-AQP2, e.g., late endosomes/lysosomes and the basolateral membrane. Because none of these mutants was misfolded, they were, in contrast to AQP2 mutants in recessive NDI, able to interact and form heterotetramers with wt-AQP2. Due to this wt-mutant interaction and the dominancy of the missorting signals in the mutant protein, the wt-mutant complexes are also missorted. Formation of heterotetramers with wt-AQP2 has been shown for most of the dominant AQP2 mutants. For instance, expression studies in polarized cell lines have revealed that the dominant AQP2E258K mutant is routed to the Golgi complex or late endosomes/lysosomes [59]. In co-expression studies with wild-type AQP2, a dominantnegative effect was observed, caused by impaired routing of wild-type AQP2 to the plasma membrane after hetero-oligomerization with the E258K mutant [103]. Mistargeting to the basolateral membrane has been reported for the AQP2-721delG, AQP2-763-772del, AQP2-812818del, and AQP2-779-780insA mutants [102, 104]. The AQP2-727delG mutant was shown to interfere with the routing of wild-type AQP2 to the apical membrane by its mistargeting to the basolateral membrane and late endosomes/lysosomes [104]. The loss of appropriate AQP2 heterotetramer trafﬁcking in dominant NDI is

N.V.A.M. Knoers and E.N. Levtchenko

caused by several mechanisms. The phosphorylation site at Ser256, serving as an introducible apical sorting signal, may be inactivated, overruled by basolateral sorting signals, or reprogrammed to induce basolateral sorting, all causing intracellular misrouting ([105–108] and review in Ref. [23]). Dominant NDI patients have a milder phenotype when compared to milder recessive forms of NDI, suggesting that some wt-homotetramers are formed that are able to reach the apical membrane [103].

Differential Diagnosis Between the X-Linked and the Autosomal Forms of NDI With a few exceptions, no differences in clinical symptoms between X-linked and autosomal recessive forms of NDI can be observed, nor in the time of onset of the disease. Only in a minority of patients with the X-linked form of NDI, namely, those individuals carrying V2R mutations with partial insensitivity to AVP, the disease onset is not directly after birth but later in childhood. In general the initial symptoms in most autosomal dominant cases also appear later in childhood. Male patients with X-linked NDI can be discriminated from patients with autosomal recessive NDI on the basis of their extrarenal reaction to the intravenous administration of the synthetic V2-vasopressin analogue 1-desamino-8-D-arginine vasopressin (DDAVP). Patients with autosomal recessive NDI show a decrease in blood pressure, an accelerated heart rate, and an increase in von Willebrand factor, factor VIII, and tissuetype plasminogen activator levels, whereas in patients with X-linked NDI, these extrarenal responses are absent as a result of an extrarenal mutant V2R [109]. In female patients, the interpretation of this intravenous DDAVP test is more complicated. Although absence of the extrarenal responses to intravenous administration of DDAVP in females clearly points to the presence of a V2R defect, a normal response cannot be interpreted as indicative of a defect beyond the V2R and thus an AQP2 defect. For instance, a

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symptomatic female patient described by Moses et al., who was shown to be heterozygous for a V2R mutation, showed a twofold increase in factor VIII activity after administration of DDAVP [110]. The discrepancy between the renal and extrarenal response to DDAVP in these female V2R mutation carriers might be explained by variability in the pattern of X-inactivation between different tissues.

In conclusion, clinical NDI phenotypes may correlate with the X-inactivation patterns in females with heterozygote V2R mutations. In some female carriers, however, the clinical phenotype cannot be predicted by evaluation of X-inactivation patterns in peripheral blood cells, probably due to the fact that X-inactivation ratios within an individual may vary between different tissues.

Nephrogenic Diabetes Insipidus in Females

Acquired Nephrogenic Diabetes Insipidus

Several families have been described in which females show classical clinical and laboratory features of NDI. After the identiﬁcation of AQP2 mutations as a cause for autosomal recessive NDI, and in some cases for autosomal dominant NDI, a satisfying explanation for the complete manifestation of the disease in some females had been found. However, several families have been reported in which symptomatic females do not have an AQP2 defect but are heterozygous for a V2 receptor defect [111–114]. In some of these women, maximal urinary osmolality after DDAVP administration does not exceed 200 mosmol/L. Of interest, in some of the reported families, asymptomatic female family members shared the same V2 receptor mutation with the manifesting females [111, 115]. The most likely explanation for the existence of different phenotypes in carriers of a V2 receptor mutation, varying from no symptoms to complete manifestation of the disorder, is skewed X-inactivation [116]. This hypothesis was underlined by studies investigating the X-inactivation patterns in peripheral blood leukocytes of female carriers via the detection of a methylated trinucleotide repeat in the human androgen receptor gene [117]. In asymptomatic females random X-inactivation was found, while in most female carriers who showed clinical NDI symptoms, skewed X-inactivation patterns occurring preferentially to normal X alleles were recognized. In a few females with over clinical NDI, however, random X-inactivation was identiﬁed.

Although the hereditary forms of NDI are relatively rare, a wide range of pathologic conditions and drug treatments can lead to acquired NDI (Table 1). In our experience, the urine osmolality obtained after DDAVP administration in these acquired disorders is always higher than in congenital NDI. All these disorders have been shown to coincide with decreased expression of AQP2 or deregulated AQP2 trafficking to the apical membrane [118–123]. For instance, prolonged treatment with lithium, the drug of choice for treating bipolar disorders and prescribed to 1 in 1,000 of the population, leads to the development of NDI in at least 20% if treated individuals [124]. The development of lithium-NDI is believed to occur in two phases. In the first short-time phase, lithium causes a decrease in AQP2 expression ([125], review in Ref. [126]). Lithium enters the cells via epithelial sodium channel (ENaC) and accumulates in principal cells [125, 127]. How lithium downregulates AQP2 is not clear but likely involves glycogen synthase kinase type 3β, which is important in AVP-regulated antidiuresis and is inhibited by lithium [128–130]. Lithium also influences AQP2mediated water reabsorption by increased tubular release of prostaglandin E2 [129]. In the second phase, lithium reduces the percentage of principal cells in the collecting duct to the advantage of intercalated cells, involved in acid-base homeostasis [131]. The exact contribution of this collecting duct remodeling in the lithium-induced resistance to vasopressin remains to be elucidated.

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Treatment Conventional Treatment Symptomatic treatment of NDI is focused on establishing and maintaining normovolemia by replacing urinary water losses and reducing urinary volume. Adequate supply of fluid to prevent dehydration is the most important component of the therapy. For reducing urine output, a low-solute diet is applied to diminish the renal osmolar load and decrease obligatory water excretion [132]. Initially, a diet low in sodium (1 mmol/ kg per day) as well as protein (2 g/kg per day) was recommended. However, severe limitations of dietary protein may introduce serious nutritional deficiencies. Therefore, it is preferable to prescribe dietary restriction of sodium only. Diuretics such as hydrochlorothiazide (2–4 mg/kg per 24 h) were the first class of drugs shown to be effective in lowering the urine volume in NDI [133]. When combined with a reduction of salt intake, hydrochlorothiazide reduces urine volume by 20–50 % of baseline values. However, thiazide-induced hypokalemia may cause further impairment or urineconcentrating ability in patients with NDI. Another possible risk associated with hypokalemia is cardiac arrhythmia. Simultaneous administration of potassium salt is therefore advised in most cases. Very low daily sodium intake in combination with thiazide diuretics should be avoided to prevent the development of hyponatremia. There is ample evidence that the combined administration of hydrochlorothiazide with either a prostaglandin-synthesis inhibitor, such as indomethacin (2 mg/kg per 24 h), or the potassiumsparing diuretic amiloride, is much more effective in reducing urine volume than the thiazide diuretic alone [134–138]. Prolonged use of prostaglandinsynthesis inhibitors, however, is often complicated by gastrointestinal and hematopoietic side effects. Gastrointestinal complaints and complications include anorexia, nausea, vomiting, abdominal pain, ulceration, perforation, and hemorrhage. Hematopoietic reactions include neutropenia, thrombocytopenia, and, rarely, aplastic anemia.

N.V.A.M. Knoers and E.N. Levtchenko

In addition, renal dysfunction has been described during indomethacin therapy, most often consisting of a slight reduction in GFR. In patients, who are not tolerating indomethacin, selective inhibitors of cyclooxygenase-2 (COX-2) might be helpful [139]. Caution in using indomethacin and selective COX-2 inhibitors in NDI is warranted as their administration can potentially lead to the acute deterioration of renal function in dehydrated patients. Amiloride counterbalances the potassium loss from prolonged use of thiazides and thus prevents hypokalemia. Since amiloride appears to have only minor long-term side effects, the combination of hydrochlorothiazide (2–4 mg/kg/24 h) with amiloride (0.3 mg/kg/24 h) is the first choice of treatment. Our personal experience of more than 20 years with the amiloridehydrochlorothiazide combination, however, indicates that amiloride is less well tolerated in young children below the age of 4–6 years because of persistent nausea. Therefore we advise the temporary use of the combination of indomethacinhydrochlorothiazide in these young children. For a long time the following mechanism for the antidiuretic effect of thiazides in NDI has been proposed: thiazides reduce sodium reabsorption in the distal tubule by inhibition of the NaCl cotransporter (NCC). This subsequently results in increased sodium excretion, extracellular volume contraction, decreased glomerular filtration rate, and increased proximal sodium and water reabsorption. Consequently, less water and sodium reach the collecting tubules and less water is excreted [140, 141]. This long-standing hypothesis has been challenged by Magaldi, who reported new insights into the possible mechanism of action, based on microperfusion studies in rat inner medullary collecting duct (IMCD) [142, 143]. In these studies it was shown that in the absence of vasopressin, hydrochlorothiazide, when added to the luminal side, increased osmotic and diffusional water permeabilities, thus, decreasing water excretion. When prostaglandins were added, the effect of thiazides decreased. This finding may offer one explanation why indomethacin potentiates the effect of thiazides

Nephrogenic Diabetes Insipidus in Children

in NDI [143]. Antidiuretic effect of thiazides is associated with an increase in AQP2 expression in collecting duct cells [144]. Long-term side effects of chronic thiazide administration such as hyperuricemia, alterations in serum lipid spectrum, and glucose intolerance should be monitored. Although the drugs mentioned above reduce urine excretion, they are unable to achieve urine volumes produced in healthy individuals. Therefore the general problem remains, although the symptoms are relieved. Consequently, current research focuses on methods to treat NDI on a more causative level than solely try to ﬁght the symptoms (Fig. 2; for detailed reviews [23, 28]).

Therapeutic Strategies for Treatment of X-Linked NDI Because in vitro expression studies reveal that the majority of AVPR2 mutations in X-linked NDI result in normal protein that is retained within the endoplasmic reticulum (ER), agents that restore plasma routing are under investigation as potential treatments. Promising agents are cellpermeable V2R antagonists and agonists that in vitro rescue the intracellular retention of several V2R mutants [145–148]. An important problem with the antagonists is that once the mutant V2R is rescued to the basolateral membrane, the antagonist needs to be displaced by high concentrations of AVP/DDAVP to induce cAMP signaling. Therefore, low-affinity antagonists are believed to have the highest clinical value. However, their efficiency in rescuing is lower than that of highaffinity ligands, and the high concentrations required to be administered for sufficient activity by low-affinity antagonists might lead to severe complications in patients. The use of non-peptide agonists has somewhat circumvented this problem since they do not need displacement to activate V2R. All high-affinity agonists have been shown to induce receptor maturation as well as translocation to the plasma membrane and to elicit a cAMP response [148]. The feasibility of treatment with these so-called pharmacologic “chaperones” has been tested in vivo. In individuals with NDI who have missense AVPR2 mutations, Bernier et al. showed

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that treatment with a non-peptide V1a receptor antagonist had beneﬁcial effects on urine volume and osmolality starting a few hours after administration. However, the long-term effect of this drug could not be tested because the clinical development of this V1a receptor antagonist was interrupted during the course of this study as a result of possible interference with the cytochrome P450 metabolic pathway [147]. Remarkably, certain non-peptide V2R agonists, such as OPC51, VA88, and VA89, were shown to be able to intracellularly stimulate the V2R and increase cAMP production and AQP2 translocation to the apical membrane [149]. In contrast to pharmacochaperone-assisted folding and rescue of the receptors, the localization and maturation state of the V2R did not change upon activation, indicating that these compounds do not act as molecular chaperones. The mode of action by which receptors trapped intracellularly can still activate their coupled G-protein and how this stimulates adenylate cyclase is not yet understood. Future in vivo and clinical testing has to conﬁrm whether the pharmacological chaperones and the intracellularly acting non-peptide agonists have the desired positive effects in patients and meet the safety requirements. In patients with X-linked NDI, bypassing the V2R could be an alternative way to treat the disease. By stimulation of the E-prostanoid receptor EP4, NDI symptoms were greatly reduced in a conditional AVPR2-deletion mouse model [150]. This was due to raised AQP2 levels, most probably as a consequence of cAMP production caused by EP4 stimulation. Recently, a similar effect was seen after stimulation of the EP2 receptor by the agonist butaprost [151]. The EP2 receptor is a more interesting candidate for treatment of NDI than the EP4 receptor since EP2 agonists have already been tested in clinical studies for other diseases and have shown promising results concerning safety issues. However, clinical trials in NDI are necessary to evaluate the effects and safety of EP2 agonists for this disorder. Another potential therapeutic strategy bypassing the V2R could be an activation of the

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Fig. 2 Therapeutic approaches to treat NDI. Approaches 1–4 focus on X-linked NDI, 5–6 are suited for autosomal recessive NDI, and 7 applies to autosomal dominant NDI. (1) Cell-penetrating V2R antagonists induce native folding and rescue V2R to the basolateral membrane. Displacement of the antagonist by high AVP/DDAVP concentrations is required to induce cAMP signaling. (2) Agonists function similarly, but do not need displacement to activate V2R. (3) ER-penetrating agonists can stimulate misfolded V2R without inducing maturation and induce prolonged signaling. (4) Stimulation of EP2 by butaprost activates

N.V.A.M. Knoers and E.N. Levtchenko

cAMP production as well as AQP2 phosphorylation and targets AQP2 to the apical membrane without involvement of V2R. (5) Glycerol acts as pharmacological chaperone in high concentrations, rescuing AQP2 mutants from the ER. (6) Hsp90-inhibitor 17-AAG enables AQP2 mutant escape from the ER. (7) Rolipram inhibits PDE-4 and increases AQP2 concentration in the apical membrane by slowing down dephosphorylation and downregulating re-internalization (From Ref. [23], with kind permission from Springer Science and Business Media)

Nephrogenic Diabetes Insipidus in Children

cGMP-signaling pathway. Several groups have shown that nitric oxide donors and atrial natriuretic factor stimulate the insertion of AQP2 in renal epithelial cells in vitro and in vivo via a cGMP-dependent pathway without increasing the expression of AQP2 [152, 153], and the selective cGMP phosphodiesterase inhibitor sildenafil citrate (Viagra) prevents degradation of cGMP resulting in increased membrane expression in AQP2 in vitro and in vivo [154]. In a small number of NDI patients subjected to clinical trials with sildenafil citrate, no decreases in urine volume or increases in urine osmolality were observed (personal communication in Ref. [28]). Alternative AVP-independent strategies are the use of calcitonin, which has a vasopressin-like effect on AQP2 trafficking and urine-concentrating ability via cAMP-mediated mechanism [155] and of various statins (simvastatin, fluvastatin) that were reported to increase AQP2 expression and water reabsorption in the kidney via an as yet unknown mechanism [156, 157]. Very recently, using a systemic high-throughput chemical screening procedure, Nomura et al. identified AG-490 (an EGF receptor and JAK-2 kinase inhibitor) as a compound that stimulates AQP2 exocytosis, induces AQP2 membrane accumulation, and stimulates urine concentration in an AVP-independent manner [158]. Despite these promising results in in vitro studies and in animal models, none of these compounds has yet been translated into therapy of NDI.

Therapeutic Strategies for Treatment of Autosomal NDI Similarly to V2R mutants, the majority of AQP2 mutants causing autosomal recessive NDI are missense mutations that lead to aberrant folding of AQP2 in the ER. Hence, ﬁnding substances that are able to reestablish natural AQP2 folding holds comparable promises for treatment of recessive NDI as it has been shown for the X-linked form. In CHO and MDCK cells, glycerol has proven the applicability of chemical chaperones to AQP2 by restoring ER export in high concentrations [99]. Yang et al. described partial restoration of cellular AQP2 processing upon treatment of conditional AQP2-T126M knock-in mice with an

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Hsp90 inhibitor, 17-allylamino-demethoxygeldanamycin (17-AAG), eventually resulting in improved urinary concentrating ability [159]. The precise explanation underlying the beneﬁcial effect of this Hsp inhibitor remains to be elucidated. Furthermore, it is not unlikely that Hsp90 inhibition may have severe side effects that outweigh the advantages [160]. Therefore, lengthened studies addressing safety issues of Hsp90 or other chaperone inhibitors have to be conducted in order to elucidate the applicability of these compounds in NDI therapy. Based on the improvement of AVP-dependent cAMP signaling of collecting duct cells in a hypercalcemia-induced NDI mouse model, Sohara et al. also tested the phosphodiesterase-4 inhibitor Rolipram in the knock-in dominant NDI mice [161]. Their data indicated that Rolipram is able to increase cAMP levels leading to increased AQP2 phosphorylation and translocation to the apical membrane. Phosphodiesterase-4 is a common protein that also is involved in immunosuppressive and anti-inﬂammatory pathways, and therefore its inhibition may have severe side effects. Rolipram has been tested in two male patients with X-linked NDI and did not cause any relief of symptoms [162], but the potential for other PDE inhibitors in the treatment of NDI needs to be examined further.

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correction by chemical chaperones. J Clin Invest. 1998;101:2257–67. 100. De Mattia F, Savelkoul PJ, Bichet DG, et al. A novel mechanism in recessive nephrogenic diabetes insipidus: wild-type aquaporin-2 rescues the apical membrane expression of intracellularly retained AQP2-P262L. Hum Mol Genet. 2004;13:3045–56. 101. Loonen AJM, Knoers NVAM, van Os CH, et al. Aquaporin 2 mutations in nephrogenic diabetes insipidus. Semin Nephrol. 2008;28:252–65. 102. Kuwahara M, Iwai K, Ooeda T, et al. Three families with autosomal dominant nephrogenic diabetes insipidus caused by aquaporin-2 mutations in the C-terminus. Am J Hum Genet. 2001;69:738–48. 103. Kamsteeg E-J, Wormhoudt TAM, Rijss JPL, et al. An impaired routing of wild-type aquaporin-2 after tetramerization with an aquaporin-2 mutant explains dominant nephrogenic diabetes insipidus. EMBO J. 1999;18:2394–400. 104. Marr N, Bichet DG, Lonergan M, et al. Heteroligomerization of an aquaporin-2 mutant with wild-type aquaporin-2 and their misrouting to late endosomes/ lysosomes explains dominant nephrogenic diabetes insipidus. Hum Mol Genet. 2002;11:779–89. 105. de Mattia F, Savelkoul PJ, Kamsteeg EJ, et al. Lack of arginine vasopressin-induced phosphorylation of aquaporin-2 mutant AQP2-R254L explains dominant nephrogenic diabetes insipidus. J Am Soc Nephrol. 2005;16:2872–80. 106. Savelkoul PJ, De Mattia F, Li Y, et al. p.R254Q mutation in the aquaporin-2 water channel causing dominant nephrogenic diabetes insipidus is due to a lack of arginine vasopressin-induced phosphorylation. Hum Mutat. 2009;30:E891–903. 107. Kamsteeg EJ, Savelkoul PJ, Hendriks G, et al. Missorting of the aquaporin-2 mutant E258K to multivesicular bodies/lysosomes in dominant NDI is associated with its monoubiquitination and increased phosphorylation by PKC but is due to the loss of E258. Pﬂugers Arch. 2008;455: 1041–54. 108. Kamsteeg EJ, Stoffels M, Tamma G, et al. Repulsion between Lys258 and upstream arginines explains the missorting of the AQP2 mutant p.Glu258Lys in nephrogenic diabetes insipidus. Hum Mutat. 2009;30:1387–96. 109. van Lieburg AF, Knoers NVAM, Mallman R, et al. Normal ﬁbrinolytic responses to 1-desamino-8D-arginine vasopressin in patients with nephrogenic diabetes insipidus caused by mutations in the aquaporin-2 gene. Nephron. 1996;72:544–6. 110. Moses AM, Sangai G, Miller JL. Proposed cause of marker vasopressin resistance in a female with X-linked recessive V2 receptor abnormality. J Clin Endocrinol Metab. 1995;80:1184–6. 111. van Lieburg AF, Verdijk MAJ, Schoute F, et al. Clinical phenotype of nephrogenic diabetes insipidus in females heterozygous for a vasopressin type-2 receptor mutation. Hum Genet. 1995;96:70–8.

1325 112. Sato K, Fukuno H, Taniguchi T, et al. A novel mutation in the vasopressin V2 receptor gene in a woman with congenital nephrogenic diabetes insipidus. Intern Med. 1999;38:808–12. 113. Chan Seem CP, Dossetor JF, Penney MD. Nephrogenic diabetes insipidus due to a new mutation of the arginine vasopressin V2 receptor gene in a girl presenting with non-accidental injury. Ann Clin Biochem. 1999;36:779–82. 114. Faerch M, Corydon TJ, Rittig S, et al. Skewed X-chromosome inactivation causing diagnostic misinterpretation in congenital nephrogenic diabetes insipidus. Scand J Urol Nephrol. 2010;44:324–30. 115. Nomura Y, Onigata K, Nagashima T, et al. Detection of skewed X-inactivation on two female carriers of vasopressin type 2 receptor gene mutation. J Clin Endocrinol Metab. 1997;82:3434–7. 116. Migeon BR. X inactivation, female mosaicism, and sex differences in renal diseases. J Am Soc Nephrol. 2008;19:2052–9. 117. Satoh M, Ogikubo S, Yoshizawa-Ogasawara A. Correlation between clinical phenotypes and X-inactivation patterns in six female carriers with heterozygote vasopressin type 2 receptor mutations. Endocr J. 2008;55:277–84. 118. Marples D, Christensen S, Christensen EI, et al. Lithium-induced down-regulation of aquaporin-2 water channel expression in rat kidney medulla. J Clin Invest. 1995;95:1838–45. 119. Kwon T-H, Laursen UH, Marples D, et al. Altered expression of renal AQPs and Na+ transporters in rats with lithium-induced NDI. Am J Physiol. 2000;279: F552–64. 120. Marples D, Dorup J, Knepper MA, et al. Hypokalemia-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla and cortex. J Am Soc Nephrol. 1996;6:325. 121. Frokiaer J, Marples D, Knepper M, et al. Bilateral ureteral obstruction downregulates expression of the vasopressin-sensitive aquaporin-2 water channel in rat kidney medulla. J Am Soc Nephrol. 1995;6:1012. 122. Teitelbaum I, Strasheim A, McGuinness S. Decreased aquaporin aquaporin-2 content in chronic renal failure. J Am Soc Nephrol. 1996;7:1273. 123. Sands JM, Naruse M, Jacobs JD, et al. Changes in aquaporin-2 protein contribute to the urine concentrating defect in rats fed a low protein diet. J Clin Invest. 1996;97:2807–14. 124. Walker RJ, Weggery S, Bedford JJ, et al. Lithiuminduced reduction in urinary concentration ability and aquaporin-2(AQP2) excretion in healthy volunteers. Kidney Int. 2005;67:291–4. 125. Kortenoeven ML, Li Y, Shaw S, et al. Amiloride blocks lithium entry through the sodium channel thereby attenuating the resultant nephrogenic diabetes insipidus. Kidney Int. 2009;76:44–53. 126. Kishore BK, Ecelbarger CM. Lithium: a versatile tool for understanding renal physiology. Am J Physiol Renal Physiol. 2013;304:F1139–49.

1326 127. Christensen BM, Zuber AM, Lofﬁng J, et al. alphaENaC-mediated lithium absorption promotes nephrogenic diabetes insipidus. J Am Soc Nephrol. 2011;22(2):253–61. 128. Kjaersgaard G, Madsen K, Marcussen N, et al. Tissue injury after lithium treatment in human and rat postnatal kidney involves glycogen synthase kinase-3β-positive epithelium. Am J Physiol Renal Physiol. 2012;302:F455–65. 129. Rao R, Zhang MZ, Zhao M, et al. Lithium treatment inhibits renal GSK-3 activity and promotes cyclooxygenase 2-dependent polyuria. Am J Physiol Renal Physiol. 2005;288:F642–9. 130. Rao R, Patel S, Hao C, et al. GSK3beta mediates renal response to vasopressin by modulating adenylate cyclase activity. J Am Soc Nephrol. 2010;2:428–37. 131. Christensen BM, Marples D, Kim YH, et al. Changes in cellular composition of kidney collecting duct cells in rats with lithium-induced NDI. Am J Physiol Cell Physiol. 2004;286:C952–64. 132. Berl T. Impact of solute intake on urine ﬂow and water excretion. J Am Soc Nephrol. 2008;19:1076–8. 133. Crawford JD, Kennedy GC. Chlorothiazide in diabetes insipidus renalis. Nature. 1959;193:891–2. 134. Monnens L, Jonkman A, Thomas C. Response to indomethacin and hydrochlorothiazide in nephrogenic diabetes insipidus. Clin Sci. 1984;66:709–15. 135. Rasher W, Rosendahl W, Henricho IA, et al. Congenital nephrogenic diabetes insipidus: vasopressin and prostaglandins in response to treatment with hydrochlorothiazide and indomethacin. Pediatr Nephrol. 1987;1:485–90. 136. Jakobsson B, Berg U. Effect of hydrochlorothiazide and indomethacin on renal function in nephrogenic diabetes insipidus. Acta Paediatr. 1994;83:522–5. 137. Alon U, Chan JCM. Hydrochlorothiazide-amiloride in the treatment of congenital nephrogenic diabetes insipidus. Am J Nephrol. 1985;5:9–13. 138. Knoers N, Monnens LAH. Amiloridehydrochlorothiazide in the treatment of congenital nephrogenic diabetes insipidus. J Pediatr. 1990;117:499–502. 139. Pattaragarn A, Alon US. Treatment of congenital nephrogenic diabetes insipidus by hydrochlorothiazide and cyclooxygenase-2 inhibitor. Pediatr Nephrol. 2003;18:1073–6. 140. Early LE, Orloff J. The mechanism of antidiuresis associated with the administration of hydrochlorothiazide to patients with vasopressin-resistant diabetes insipidus. J Clin Invest. 1962;52:2418–27. 141. Shirley DG, Walter SJ, Laycock JF. The antidiuretic effect of chronic hydrochlorothiazide treatment in rats with diabetes insipidus. Clin Sci. 1982;63:533–8. 142. Cesar KR, Magaldi AJ. Thiazide induces water reabsorption in the inner medullary collecting duct of normal and Brattleboro rats. Am J Physiol. 1999;277:F750–6.

N.V.A.M. Knoers and E.N. Levtchenko 143. Magaldi AJ. New insights into the paradoxical effect of thiazides in diabetes insipidus therapy. Nephrol Dial Transplant. 2000;15:1903–5. 144. Kim GH, Lee JW, Oh YK, et al. Antidiuretic effect of hydrochlorothiazide in lithium-induced nephrogenic diabetes insipidus is associated with upregulation of aquaporin-2, Na-Cl co-transporter, and epithelial sodium channel. J Am Soc Nephrol. 2004;15:2836–43. 145. Morello J-P, Salahpour A, Laperriere A, et al. Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J Clin Invest. 2000;105:887–95. 146. Robben JH, Sze M, Knoers NV, et al. Functional rescue of vasopressin V2 receptor mutants in MDCK cells by pharmacochaperones: relevance to therapy of nephrogenic diabetes insipidus. Am J Physiol Renal Physiol. 2007;292:F253–60. 147. Bernier V, Morello JP, Zarruk A, et al. Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus. J Am Soc Nephrol. 2006;17:232–43. 148. Jean-Alphonse F, Perkovska S, Frantz MC, et al. Biased agonist pharmacochaperones of the AVP V2 receptor may treat congenital nephrogenic diabetes insipidus. J Am Soc Nephrol. 2009;20:2190–203. 149. Robben JH, Kortenoeven ML, Sze M, et al. Intracellular activation of vasopressin V2 receptor mutants in nephrogenic diabetes insipidus by nonpeptide agonists. Proc Natl Acad Sci U S A. 2009;106: 12195–200. 150. Li JH, Chou CL, Li B, et al. A selective EP4 PGE2 receptor agonist alleviates disease in a new mouse model of X-linked nephrogenic diabetes insipidus. J Clin Invest. 2009;119:3115–26. 151. Olesen ET, Rutzler MR, Moeller HB, et al. Vasopressin-independent targeting of aquaporin-2 E-prostanoid receptor agonists alleviates nephrogenic diabetes insipidus. Proc Natl Acad Sci U S A. 2011;108:12949–54. 152. Bouley R, Breton S, Sun TX, et al. Nitric oxide and atrial natriuretic factor stimulate cGMP-dependent membrane insertion of aquaporin 2 in renal epithelial cells. J Clin Invest. 2000;106:1115–26. 153. Boone M, Kortenoeven M, Robben JH, et al. Effect of the cGMP pathway on AQP2 expression and translocation: potential implications for nephrogenic diabetes insipidus. Nephrol Dial Transplant. 2010;25:48–54. 154. Bouley R, Pastor Soler N, Cohen O, et al. Stimulation of AQP2 insertion in renal epithelial cells in vitro and in vivo by the cGMP phosphodiesterase inhibitor sildenaﬁl citrate (Viagra). Am J Physiol Renal Physiol. 2005;288:F1103–12. 155. Bouley R, Lu HA, Nunes P, et al. Calcitonin has a vasopressin-like effect on aquaporin-2 trafﬁcking and urinary concentration. J Am Soc Nephrol. 2011;22: 59–72.

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156. Procino G, Barbieri C, Carmosino M, et al. Fluvastatin modulates renal water reabsorption in vivo through increased AQP2 availability at the apical plasma membrane of collecting duct cells. Pflugers Arch. 2011;462:753–66. 157. Li W, Zhang Y, Bouley R, et al. Simvastatin enhances aquaporin-2 surface expression and urinary concentration in vasopressin-deficient Brattleboro rats through modulation of Rho GTPase. Am J Physiol Renal Physiol. 2011;301:F309–18. 158. Nomura N, Nunes P, Bouley R, et al. High-throughput chemical screening identifies AG-490 as a stimulator of aquaporin 2 membrane expression and urine concentration. Am J Physiol Cell Physiol. 2014;307: C597–605.

1327 159. Yang B, Zhao D, Verkman AS. Hsp90 inhibitor partially corrects nephrogenic diabetes insipidus in a conditional knock-in mouse model of aquaporin-2 mutation. FASEB J. 2009;23:503–12. 160. Taiyab A, Sreedhar AS, Rao C. Hsp90 inhibitors, GA and 17AAG, lead to ER stress-induced apoptosis in rat histiocytoma. Biochem Pharmacol. 2009;78:142–52. 161. Sohara E, Rai T, Yang SS, et al. Pathogenesis and treatment of autosomal-dominant nephrogenic diabetes insipidus caused by an aquaporin 2 mutation. Proc Natl Acad Sci U S A. 2006;103:14217–22. 162. Bichet DG, Ruel N, Arthus MF, et al. Rolipram, a phosphodiesterase inhibitor, in the treatment of two male patients with congenital nephrogenic diabetes insipidus. Nephron. 1990;56:449–50.

Cystinosis and Its Renal Complications in Children

William A. Gahl and Galina Nesterova

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1330 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1330 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1330 The Basic Defect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1330 Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1331 Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1332 The CTNS Gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1332 Cystinosis Variants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1333 Early Clinical Manifestations . . . . . . . . . . . . . . . . . . . . Renal Tubular Fanconi Syndrome with Rickets . . . Glomerular Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Growth Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ocular Involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cognition and Psychological Aspects . . . . . . . . . . . . . . Other Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laboratory Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . .

1333 1333 1335 1335 1336 1337 1337 1337 1338

Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Postnatal Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prenatal Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Heterozygote Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1338 1338 1339 1339 1339

Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Replacement of Renal Losses . . . . . . . . . . . . . . . . . . . . . . Other Symptomatic Treatments . . . . . . . . . . . . . . . . . . . . Renal Replacement Therapy . . . . . . . . . . . . . . . . . . . . . . . Oral Cysteamine Therapy . . . . . . . . . . . . . . . . . . . . . . . . . .

1339 1340 1340 1341 1342

Cysteamine Eyedrops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1345 Other Therapeutic Considerations . . . . . . . . . . . . . . . . . . 1345 Cystinosis in Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Growth and Appearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . Myopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pancreatic Involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypogonadism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Central Nervous System Involvement . . . . . . . . . . . . . Ocular Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Occupations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment of Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1346 1346 1346 1347 1347 1347 1348 1348 1348 1348 1348

Cystinosis Advocacy Groups . . . . . . . . . . . . . . . . . . . . . 1349 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1349 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1350

W.A. Gahl (*) • G. Nesterova Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA e-mail: [emailprotected]; [emailprotected] # Springer-Verlag Berlin Heidelberg (outside the USA) 2016 E.D. Avner et al. (eds.), Pediatric Nephrology, DOI 10.1007/978-3-662-43596-0_37

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Introduction Overview Nephropathic cystinosis [1–3] deserves a special place in the annals of clinical medicine as the ﬁrst treatable lysosomal storage disease. The pathophysiology itself, based upon the formation of cystine crystals within the lysosomes of cells, is remarkable. The presence of cystine crystals provides a clue to the basic defect in cystinosis, i.e., failure to transport cystine out of lysosomes [4–6]. This created a new area of biomedical investigation, explained the lysosome’s function in salvaging small molecules for reutilization by the cell, and revealed a new category of lysosomal storage disorders due to transport defects rather than enzyme deﬁciencies [7]. Even more striking, a rational therapy of cystine depletion (i.e., cysteamine) emerged [8–10], transforming nephropathic cystinosis from a universally fatal disease to a treatable chronic disorder with a decent quality of life and increased life span. Today, physicians can even observe the gradual dissolution of cystine crystals by cysteamine eyedrops bathing the corneas of patients’ eyes [11–13].

History Cystinosis was ﬁrst described by Abderhalden in 1903 [14], when understanding of its renal disease remained rudimentary. Fanconi, de Toni, and Dubre recognized the renal tubular defect of cystinosis in the 1930s [4], and this complication retains the appellation Fanconi syndrome today. Generalized aminoaciduria was noted as a concomitant of nephropathic cystinosis in the late 1940s [15], and cystine storage within cellular lysosomes was proven in the late 1960s [16]. By 1982, the basic defect of impaired lysosomal membrane transport of cystine was reported [4–6], and therapy with the cystine-depleting aminothiol cysteamine was shown to be safe and effective by 1987 [9]. Over the past two decades, numerous nonrenal complications of cystinosis

W.A. Gahl and G. Nesterova

have been described, and oral cysteamine therapy has been shown to prevent virtually all of them [17, 18].

The Basic Defect Cystine has a molecular weight of 240 Da and consists of two molecules of cysteine (HS-CH2CH(NH3+)COO) joined by a disulfide bond. The equilibrium between cystine and cysteine depends upon their redox potentials and the pH of the milieu; if a high enough concentration of cystine is present (>2 mM), it may precipitate out of solutions because of its poor solubility [19]. Cysteine, which is very soluble, is produced by the hydrolysis of proteins; this occurs within lysosomes by the action of acidic hydrolases. Cysteine is then oxidized to cystine within lysosomes, where it accumulates if the cell is cystinotic [16, 20]. For decades, scientists investigated the cause of lysosomal cystine accumulation in cystinosis [2]. One possibility was a defective enzyme responsible for the reduction of cystine to cysteine, or for catalyzing disulfide interchange reactions between cystine and other free thiols. This hypothesis was examined, but no deficiency in a cystine-catabolizing enzyme was found [21]. Another possibility was that, in cystinosis, cystine could not exit lysosomes because a transporting system present in normal lysosomal membranes was defective in cystinosis. Indeed, normal polymorphonuclear leukocytes were able to clear themselves (i.e., their lysosomes) of cystine, but cystinotic cells could not [22]. Studies of isolated granular fractions, i.e., lysosomes, gave similar results [5]. In fact, normal, cystine-loaded lysosomes could transport cystine in either direction across their membranes, while cystinotic lysosomes could neither take up nor release cystine [4, 23]. Cystine transport in neutrophil lysosomes was subsequently shown to be ligand specific, stereospecific, and ATP-dependent [5, 6]. It displayed classical saturation kinetics (Fig. 1) and countertransport. Similar findings were observed in cultured lymphoblasts [6]. In composite, these discoveries proved that the process

Cystinosis and Its Renal Complications in Children

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Fig. 1 Lysosomal cystine transport in leukocyte granular fractions (normal lysosomes were loaded with cystine by exposure of whole leukocytes to cystine dimethylester, which is hydrolyzed to cystine within the acidic lysosome. Cystinotic lysosomes contain endogenously produced cystine. The abscissa gives the level of cystine loading per unit of hexosaminidase, i.e., per lysosome. The ordinate gives

the rate of cystine egress in picomoles per minute per unit of hexosaminidase. Normal lysosomal cystine egress exhibits saturation kinetics, while cystinotic lysosomes show virtually no cystine egress. Heterozygotes for cystinosis, with half the number of lysosomal cystine transporters, display half the normal maximal velocity of cystine egress) (Reprinted from SCIENCE [4])

of lysosomal cystine transport is carrier mediated and deﬁcient in cystinosis. Indeed, heterozygotes for cystinosis displayed half the maximum velocity of cystine transport [24], consistent with having half the normal number of cystine carriers (Fig. 1). The later discovery of the cystinosis gene, CTNS, and studies of its gene product, cystinosin, demonstrated that this protein does indeed transport cystine, in a process driven by the hydrogen ion gradient across the lysosomal membrane [25, 26].

cystine storage (to 10–1,000 times normal levels), patients with cystinosis develop microscopic crystals of cystine, apparent within lysosomes on electron microscopy [20]. Subcellular fractionation using sucrose density gradients [16] verified the lysosomal location of cystine. Tissues containing cystine crystals include the cornea, conjunctiva, liver, spleen, kidneys, intestines, rectal mucosa, pancreas, testes, lymph nodes, bone marrow, macrophages, thyroid, muscle, and choroid plexus [2, 9]. Crystals form in macrophages but not in cultured fibroblasts or lymphoblasts. The crystals are generally hexagonal or rectangular and appear birefringent under polarizing light (Fig. 2). To preserve crystals during histological processing, tissues should be fixed in absolute alcohol rather than in aqueous solutions. Tissue damage accompanies the intracellular cystine accumulation of cystinosis, with the

Pathology Patients who have not received long-term cystinedepleting therapy exhibit speciﬁc pathological features. As a consequence of excessive cellular

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transporters and pathways, including redox-based signaling or protein cysteinylation [38]. Finally, cystine crystals have been proposed to activate endogenous inﬂammasomes [39].

Genetics

Fig. 2 Birefringent cystine crystals in cystinosis tissue under light microscopy (note rectangular and needlelike shapes. Some crystals are undergoing dissolution due to the aqueous ﬁxative)

greatest effects in the kidney. Renal tubules show a characteristic narrowing called a swan-neck deformity [27], followed by interstitial nephritis and endothelial glomerular proliferation, necrosis, and hyalinization. Formation of atubular glomeruli and a glomerulotubular disconnect appear to represent a maladaptation to renal injury, contributing to the progression of renal insufficiency [28, 29]. Crystals are occasionally seen within glomeruli. In the eye, the retina exhibits patchy hypopigmentation [30] crystals appear occasionally in the iris and rarely in the retina [31]. In older patients, the thyroid and testes appear fibrotic. Muscle histopathology involves a late vacuolar myopathy with variation in fiber size, atrophy of type I fibers, and ring fibers [32, 33]. In the liver of untreated adults, nodular regenerative hyperplasia can occur [34]. The pathogenesis of tissue damage in cystinosis is thought to involve cellular metabolic mitochondrial oxidative stress [35], cell dysfunction, and death, followed by replacement with fibrous tissue. Crystal enlargement could burst the lysosomes, releasing hydrolytic enzymes that might destroy the cell, but this remains a working hypothesis. There are data supporting a more ordered loss of cells through the process of apoptosis, which is putatively triggered by cystine accumulation [36]. Loss of cystinosin in proximal tubules may disrupt endolysosomal pathways, leading to the loss of urinary ligands [37], or may result in the unregulated activation of other

Cystinosis is an autosomal recessive disorder, and heterozygotes are always entirely normal. The disease occurs with an incidence of approximately one in 100,000–200,000 live births, although there are genetic isolates of cystinosis, including one with a frequency of 1 in 26,000 in Brittany [40] and another among French Canadians. Within the US population, one in 150–200 individuals carries a cystinosis (i.e., CTNS) mutation. This number allows counseling of persons, ascertained to be heterozygotes because a family member was diagnosed, with respect to their risk of having a child with cystinosis by an unrelated mate. Perhaps 600–700 cystinosis patients reside in the United States, approximately half of them having undergone a renal allograft procedure. It is estimated that 20–40 children with cystinosis are born annually in the United States. Our own patients are from all over the world, including Mexico, Brazil, Bolivia, Venezuela, India, Iran, Egypt, Australia, and a variety of European countries. The pan-ethnic distribution of the disease, along with the scarcity of reports of cystinosis in underdeveloped countries, suggests that large numbers of patients around the world are not diagnosed. In general, cystinosis breeds true within families; siblings manifest very similar clinical severities.

The CTNS Gene The cystinosis gene was mapped to chromosome 17p13 in 1995 [41] and identiﬁed in 1998 [25]. It contains 12 exons within 23 kb of genomic DNA and codes for a 367-amino acid protein, cystinosin, with seven transmembrane domains. The function of cystinosin as a cystine transporter

Cystinosis and Its Renal Complications in Children

has been conﬁrmed [26]. Over 200 different CTNS mutations including deletions, insertions, nonsense, missense, and splice site mutations have been reported in Human Gene Mutation Database; they are found in different combinations in individuals with cystinosis [1, 42, 43]. The promoter [44], leader sequence, transmembrane regions, and non-transmembrane regions are affected by different mutations. The most common mutation is a 57,257 deletion removing the ﬁrst 10 exons of CTNS [45, 46]. This deletion arose in Germany ~500 AD and is present in the homozygous or heterozygous state in more than half of the cystinosis patients of European descent [46]. Homozygosity for this deletion is associated with a slightly greater frequency of nonrenal complications of cystinosis in adulthood [18]. Otherwise, there is only a mild correlation of genotype and phenotype within nephropathic cystinosis patients. Two other founder mutations, W138X and G339R, have been reported among French Canadians [47] and Amish Mennonites of southwestern Ontario [48], respectively.

Cystinosis Variants Traditionally, cystinosis has been divided into three subtypes [2]. Infantile nephropathic cystinosis is the classic disease, described below and comprising 95 % of cases. Affected individuals have two severe CTNS mutations. Patients with intermediate (formerly juvenile or adolescent) cystinosis have milder disease, with diagnosis in adolescence or early adulthood; they eventually develop renal failure. Intermediate patients number fewer than 20 reported cases and carry one severe and one mild CTNS mutation [49]. Patients with ocular (formerly adult or benign) cystinosis never exhibit renal failure or retinal hypopigmentation, but have cystine crystals in their bone marrow and corneas [2]. They do have measurable residual cystine-transporting capacity in their polymorphonuclear leukocytes’ lysosomes [50]. The only clinical manifestation of ocular cystinosis is photophobia, and patients are generally diagnosed incidentally on eye

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examination that includes the use of a slit lamp. There exist approximately 20 ocular cystinosis patients, who have either one mild and one severe or two mild CTNS mutations [51]. Several ocular cystinosis patients from different families have at least one allele with a 928 G > A mutation in CTNS. The distinction among the three types of cystinosis is artiﬁcial, since there exists a continuum of disease severity rather than discrete categories. A Ctns/ mouse accumulates cystine in its tissues; the manifestation of renal disease depends upon the murine model’s genetic background [52, 53].

Early Clinical Manifestations As for patients with other lysosomal storage disorders, individuals with cystinosis appear entirely normal at birth. Nevertheless, the disease eventually affects nearly every tissue of the body, with variable times of onset. The signs and symptoms can be described as early and late ﬁndings, demarcated roughly by adolescence. The earliest manifestations of cystinosis involve complications of renal Fanconi syndrome and growth retardation [54].

Renal Tubular Fanconi Syndrome with Rickets Cystinosis, the most common identifiable cause of renal Fanconi syndrome in childhood, is also one of the most treatable causes, so it should be considered first when renal tubular solute wasting is recognized. In cystinosis, Fanconi syndrome is not evident at birth but generally appears at 6–12 months of age, with variable severity. Undoubtedly, some infants die of the dehydration and electrolyte imbalance associated with the Fanconi syndrome, without the benefit of a diagnosis. The Fanconi syndrome of cystinosis (Table 1) is primarily a proximal tubular defect. It includes failure to reabsorb water, bicarbonate (acidosis), electrolytes (hypokalemia and occasional hyponatremia), minerals (phosphaturia,

1334 Table 1 Characteristics of renal tubular Fanconi syndrome in cystinosis Polyuria Polydipsia Dehydration (fever) Proteinuria Glucosuria Aminoaciduria Acidosis Hypokalemia Hyponatremia (salt craving) Hypophosphatemia Hypocalcemia Hypomagnesemia Hypocarnitinemia Increase serum alkaline phosphatase Rickets Tetany Growth failure

hypocalcemia, and hypomagnesemia), amino acids, carnitine, glucose, and small molecular weight proteins (less than 50,000 Da). Capillary electrophoresis mass spectrometry (CE_MS) can detect small proteins (i.e., osteopontin, uromodulin, fragments of collagen alpha-1 chains) that reflect the tubular origin of the proteinuria and can be helpful in diagnosing FS [55]. The clinical manifestations of renal tubular Fanconi syndrome include polyuria (often 2–3 L per day in small children and sometimes up to 5–6 L per day), dehydration (sometimes with consequent fevers), and polydipsia [56]. Urine osmolality can be 200–300 mOsm/L. Large volumes of fluid intake fill the stomach and reduce appetite. Acidosis typically lowers the serum carbon dioxide level to below 20 mEq/L, and chronically untreated children can have levels below 5 mEq/L. Serum potassium concentrations below 2.0 mEq/L are not rare, and values below 3 mEq/L are common. Phosphate and calcium wasting causes rickets, with low serum phosphate and calcium and elevated heat-labile alkaline phosphatase levels (2,000–3,000 U/L in florid cases). In some cases, significant hypocalcemia triggers secondary hyperparathyroidism, exacerbating bone reabsorption. Altered metabolism of

W.A. Gahl and G. Nesterova

1,25D(OH)2 or abnormal cellular resistance to its action deserves further investigation as possible additional factors in the mechanism of rickets. Children may fail to walk because of the bone pain, and they exhibit tender, swollen wrists and ankles due to metaphyseal widening. In severe cases, frontal bossing, a rachitic rosary, and genu valgum/varum develop. Osteoporosis and epiphyseal fraying are visible on radiographs (Fig. 3). The combination of hyperphosphaturia and hypercalciuria often results in medullary nephrocalcinosis [57]. Hypocalcemia can cause painful episodes of tetany or even seizures, especially 20–30 min after a dose of an alkalinizing medication that lowers circulating concentrations of ionized calcium. Magnesium is lost commensurately with calcium, and serum magnesium levels are often low. Little is known about early structural damage in proximal tubules, although the mouse provides a model for studying the pathology. The “swan-neck” deformity follows cell dedifferentiation, defective apical endocytosis, metaplasia of Bowman’s epithelium, thickening of the basement membrane, and increased apoptosis, resulting in atubular glomeruli and renal failure [58]. The poor health of infants and small children with cystinosis makes them irritable and picky eaters. Carnitine is only ~70 % reabsorbed in cystinosis (normal, 97 %), leading to chronically low levels of free carnitine, typically 11 μM (normal, ~40 μM) [59]. Since carnitine is essential for fatty acid transport into mitochondria, carnitine deficiency may contribute to poor muscle development, although this has not been proven. The aminoaciduria of cystinosis can be quantified using the Fanconi Syndrome Index (FSI), a measurement of the daily urinary excretion of 21 specific amino acids, expressed per kg of body weight [60]. For children with cystinosis, the FSI is always above normal (94 45 μmol/kg/day) and is often ~1 mmol/kg/day. Urine organic acids have been reported elevated in children with cystinosis, but without apparent clinical consequences [2]. The Fanconi syndrome of cystinosis can mislead physicians in several ways. The combination of polyuria and glucosuria has led to the incorrect

Cystinosis and Its Renal Complications in Children

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Fig. 3 Rickets in a 16-month-old boy with nephropathic cystinosis (note widening of the metaphysis, fraying of the epiphysis, and osteoporosis)

diagnosis of diabetes mellitus, which can be readily dismissed by the finding of a normal serum glucose. Other patients have carried the diagnosis of diabetes insipidus, hyperaldosteronism, or Bartter’s syndrome for years before being correctly diagnosed as having cystinosis [2, 3]. The tubular proteinuria of cystinosis can reach nephrotic levels; some children excrete 3–4 g of protein per day. This can be taken to reflect glomerular damage, which may be present to a certain extent, but the bulk of the protein is generally of low molecular weight, reflecting tubular dysfunction. Urine protein electrophoresis can distinguish tubular from glomerular proteinuria. Finally, as cystinosis patients approach renal failure, their reduced filtration function creates the expectation that oliguria, hyperkalemia, and hyperphosphatemia will occur. In cystinosis, however, the tubular defect trumps the glomerular damage. Patients with creatinine clearances less than 30 mL/min/1.73 m2 can still have urine volumes of 3 L and, if not supplemented, profound dehydration, hypokalemia, and phosphate wasting.

function slowly but inexorably decreases. By age 10, most children with cystinosis have reached renal failure and require transplantation or dialysis. In a European study of 205 cystinosis children, the mean age for end-stage renal disease was 9.2 years [62]. However, rates of decline are somewhat variable, with milder patients maintaining function until age 12 and severely affected children losing function by age 6. The substantial reserve of human kidneys means that serum creatinine seldom rises above normal until 5 years of age, especially if growth retardation creates a reduced creatinine load on the kidneys. However, measurement of glomerular ﬁltration rate using a 24-h urine collection and calculation of creatinine clearance generally reveals a significant deﬁcit at the time of diagnosis even at a year of age. The uremia of cystinosis resembles that of other renal disorders, except that the growth retardation, osteodystrophy, and anemia may be somewhat exaggerated by comparison. Hypertension can accompany chronic renal failure or arise in the posttransplant period, but cystinosis itself does not predispose to this complication.

Glomerular Damage Growth Impairment Cystinosis accounts for ~5 % of chronic renal failure in children [61]. By the time a typical cystinosis infant is diagnosed at approximately 1 year of age, signiﬁcant renal glomerular damage has already occurred. It has been postulated that rapid progress to renal damage could be explained by inﬂammation caused by cystine crystals [39]. A reasonable estimate would place the creatinine clearance at the time of diagnosis at approximately 70 % of normal, and this level of

Newborns with cystinosis are normal in height, weight, and head circumference. While head circumference is maintained, height and weight percentiles generally fall by 6–12 months of age; failure to thrive is often the ﬁrst indication of the diagnosis. By 1 year of age, the average infant with cystinosis has a height at the third percentile [9]. Without treatment, growth continues at 50–60 % of the normal rate. By age 8, the average

1336 150

140 50 130 3 120

110 Height (cm)

Fig. 4 Natural history of growth in children with cystinosis (mean values for cystinosis children are superimposed upon a normal growth chart. On average, a child with cystinosis falls from normal height to the third percentile at 1 year of age and continues to grow slowly so that the height age is 4 years when the chronological age is 8 years) (Reprinted from the New England Journal of Medicine [9])

W.A. Gahl and G. Nesterova

Cystinosis 100 (5) 90

(19)

(22)

(14)

(2) (9)

(22) 70

(27) (23)

untreated child with cystinosis has the height of a 4-year-old (Fig. 4). In the past, some poorly treated, posttransplant adults achieved less than 4 f. in height. Weight usually follows height, but with greater variability. The normal head circumference, combined with reduced height and weight, gives the impression of macrocephaly, but this is relative, not absolute. In patients not receiving growth hormone therapy, bone age usually lags behind chronological age by 1–3 years. Children with retarded bone ages retain growth potential past the usual age of epiphyseal closure, but height is never gained past age 20, regardless of the bone age. The cause of impaired growth has not been deﬁnitively determined. Growth hormone is normal [63], although patients respond to supraphysiologic doses of growth hormone [64]. Hypophosphatemic rickets, acidosis, poor nutrition, renal insufﬁciency,

4 5 6 Age (yr)

and cystine storage in the bone probably all contribute to the metabolic bone disease and poor growth of cystinosis. However, with adequate nutrition, mineral replacement of renal losses, and cystinedepleting therapy, a normal growth rate can be achieved. (See below.)

Ocular Involvement A patchy retinal depigmentation has been described early in infancy in cystinosis, but the primary ophthalmic manifestation of cystinosis is photophobia. This occurs due to corneal crystals that ﬁrst appear in the anterior third of the cornea. Corneal crystals are always present by 16 months of age on slit lamp examination and are diagnostic for cystinosis [13]. Prior to then, the crystals may not be apparent. The number of crystals increases with age, reaching

Cystinosis and Its Renal Complications in Children

a maximum discernible density by ~8 years of age. An atlas of corneal crystal density at different ages has been published [13]. Crystal density among ocular cystinosis patients appears less than that of patients with classical disease. Children with cystinosis complain of sensitivity to light at variable ages, but usually not until 5–10 years of age. They squint to the point that, without treatment, they can eventually develop blepharospasm refractory to all modes of therapy. Often, patients wear dark glasses outside and turn down the lights inside. Occasionally, a child with cystinosis may experience a corneal ulceration as a crystal breaks through the corneal epithelium. This complication occurs much more frequently in adolescence and adulthood, when haziness of the cornea also appears.

Hypothyroidism In the natural history of cystinosis, approximately half of patients are hypothyroid by age 10 [65] and 90 % by age 30 [66]. Thyroxine and free T4 are low and TSH is high, pointing to primary hypothyroidism, although partial pituitary resistance has also been reported [67]. In cystinosis, the thyroid tissue appears ﬁbrotic with occasional crystals present.

Cognition and Psychological Aspects Children with cystinosis learn normally and have low normal full-scale IQs [68, 69]. However, recent evidence indicates isolated deﬁcits in visual processing [70] and tactile recognition [71]. Short-term visual memory can be impaired [71], and patients may exhibit behavioral and social problems [72, 73]. The latter are related in part to their chronic disease, renal failure, and growth retardation.

Other Clinical Findings Cystinosis children are notoriously poor eaters, with understandable craving for salty foods such

1337

as pickles, ketchup, and potato chips [56]. In addition, many children exhibit a pica for hot foods such as jalapeno peppers and tabasco sauce, without an obvious explanation. Young children and infants exhibit an increased tendency toward vomiting, which is more severe in the morning prior to eating. Some of this may be related to medications, but there appears to be an intrinsic disease-specific element as well. Excessive water intake with increased thirst causes abdominal distention and a sense of fullness, which further contributes to nausea, vomiting, and poor appetite. The nausea and vomiting often decrease with age and generally cease by 7–8 years of age. Rarely, a patient may suffer from gastrointestinal immotility and have projectile vomiting upon eating or drinking slight amounts of food or water. One-third to one-half of cystinosis children 10–18 years of age have mild hepatomegaly on physical examination [65], with no identifiable cause. One 9-year-old boy had hepatic venoocclusive disease and underwent a liver transplantation [74]. Patients from lightly pigmented backgrounds sometimes appear less pigmented than other family members. This may reflect dysfunction of melanosomes, which are lysosome-related organelles, or formation of excessive cysteinyl-dopaquinone, the precursor of pheomelanin, a blond-red pigment. Alternatively, the blond pigmentation characteristic of cystinosis may reflect the high frequency of Germanic and Nordic heritage among cystinosis patients. African American and Hispanic patients have pigmentation indistinguishable from that of their siblings. Most cystinosis patients manifest decreased sweat production, causing flushing, heat avoidance, and occasional hyperthermia [75]. In addition, tear and saliva production is often reduced in cystinosis. Enuresis in children with cystinosis may reflect the large volume of urine produced daily. Patients combat infections in a normal fashion, although gastroenteritis in children with Fanconi syndrome will cause dehydration much more rapidly than in normal individuals. Idiopathic intracranial hypertension, or pseudotumor cerebri due to nonabsorptive hydrocephalus, has been reported in several patients and has been attributed, in part,

1338

to cystinosis itself [76]. Optic nerve compression due to idiopathic intracranial hypertension has caused blindness in at least two children with cystinosis.

Laboratory Abnormalities In addition to laboratory aberrations related to the Fanconi syndrome (▶ Chap. 42, “Pediatric Fanconi Syndrome”), children with cystinosis frequently exhibit mild microscopic hematuria, an elevated sedimentation rate, increased platelet counts, and anemia that is excessive for the degree of renal failure [2]. Cholesterol levels are usually elevated, with each of the lipoprotein fractions proportionally increased. The hypercholesterolemia persists after renal transplantation [17, 18].

Diagnosis Because a safe and efﬁcacious treatment exists for cystinosis, physicians should maintain a high index of suspicion in patients demonstrating any characteristic ﬁndings. Unfortunately, the average age of diagnosis for cystinosis remains just over 1 year [2], and even today several patients escape detection for years, despite manifesting typical signs and symptoms.

Postnatal Diagnosis A family history of cystinosis will naturally point to this disease in a child with suggestive ﬁndings. However, even without a previously affected sibling, evidence of renal tubular Fanconi syndrome (polyuria, polydipsia, proteinuria, glucosuria, acidosis, dehydration, electrolyte imbalance, salt craving, and tetany) should prompt investigation for cystinosis. Other signs include poor growth, failure to walk at an appropriate age, and other evidence of rickets. The presence of typical corneal crystals on slit lamp examination by an experienced ophthalmologist will establish the

W.A. Gahl and G. Nesterova

diagnosis. Such crystals are usually not apparent within the ﬁrst several months of life, but crystals are always present by 16 months of age [13]. Elevated intracellular-free (nonprotein) cystine concentrations also are diagnostic. Cystinosis patients have high concentrations of cystine in a variety of cell types, but polymorphonuclear leukocytes are the preferred cells in which to assay cystine [1–3]. While cystinotic lymphocytes have three- to ﬁvefold elevations above normal cystine concentrations, neutrophils have 50–100 times the normal levels, i.e., 3–23 nmol half-cystine/ mg protein (normal, 12–24 h) can cause cystine to leach out of leukocytes, giving spuriously low values. Relatively little sensitivity is needed to simply make a diagnosis of cystinosis, but high sensitivity is necessary when monitoring therapy with cystine-depleting agents. (See below.) In the past, biopsies of the kidney, bone marrow, rectal mucosa, or conjunctiva were performed to make establish the diagnosis of cystinosis [2]. Such biopsies are no longer indicated.

Cystinosis and Its Renal Complications in Children

CTNS mutation analysis can confirm the diagnosis of nephropathic cystinosis, and a multiplex PCR methodology is available for identification of the common 57,257-bp deletion. A specific mutation panel has been optimized for the French-Canadian population [1, 7, 46]. However, molecular methods play little or no role in postnatal diagnosis of cystinosis. Development of a newborn screening test for cystinosis will potentially allow broader therapeutic success [79]. Two methods have been proposed: (a) tandem mass spectrometry for the determination of derivative seven-carbon (C7) sugars in dried blood spots (DBS), which detects homozygosity for the CTNS 57-kb deletion, and (b) molecular genetic testing for the most common CTNS mutations [80].

Prenatal Diagnosis When one child has been diagnosed with cystinosis, the disorder can be identified in subsequent pregnancies by several methods. At 8–10 weeks of gestation, chorionic villus samples can be directly assayed for cystine, as long as enough tissue (5 mg wet weight) is available [81]. At 14–16 weeks’ gestation, amniotic fluid cells can be cultured for approximately 4 weeks to obtain enough cells to measure the cystine content [82]. Measurement of cystine in a placenta will make the diagnosis at birth [83]. In addition, any of these cell sources can be used for molecular diagnosis, as long as both mutations have been previously identified in the affected sibling.

Heterozygote Detection Carrier (heterozygote) detection based upon leukocyte cystine measurement is problematic. While carrier levels can be as high as 1 nmol half-cystine/mg protein, they can also be within the normal range (80–85 % in normal subjects with normal phosphate levels) and low serum phosphate. Rickets and osteomalacia result from increased urinary wasting of phosphate and impaired 1α-hydroxylation of 25-hydroxy vitamin D3 by proximal tubule cells [29]. The maximal threshold of phosphate (TmP/GFR) is a very sensitive indicator that reﬂects the reabsorption of phosphate in the renal tubules. The Tm/GFR is usually very low in patients with FS (normal values 2.3–4.3 mg/dl). PTH level are normal or elevated in patients with FS. Serum 1,25dihydroxy vitamin D3 is variable [30, 31]. Rickets usually manifest in small children with bowing deformity of the lower limbs, distal femur, ulna, and the radius. Other signs include increased tendency for fractures, skull bossing, delayed fontanelle closure, craniotabes (soft skull), “rachitic rosary,” Harrison’s groove, and wrist widening.

1359

ðUp=PpÞ 100 TRP ð%Þ ¼ 1 ðUcr=Pcr Þ ðp ¼ amino acid, cr ¼ creatinine, U ¼ urine, P ¼ plasmaÞ TmP=GFR ¼ TRP Sp ðGFR ¼ glomerular filtration rate, S ¼ serumÞ

Metabolic Acidosis More than 85 % of filtered load of bicarbonate (HCO3) is reabsorbed by the proximal tubule cells (also see ▶ Chaps. 9, “Physiology of the Developing Kidney: Acid-Base Homeostasis and Its Disorders” and ▶ 39, “Renal Tubular Acidosis in Children”). This is accomplished by the coordinated function of luminal membrane Na+/H+ exchanger, luminal membrane carbonic anhydrase IVand XIV, and basolateral membrane Na+/HCO3 cotransporter [30]. Defective bicarbonate reabsorption in the proximal tubules results in hyperchloremic metabolic acidosis and is a common feature of FS. The anion gap is normal. In overt forms of FS, more than 30 % of the filtered load of HCO3 is not reabsorbed; patients have low plasma HCO3 levels (12–18 mEq L1). Fractional excretion of HCO3 (FEHCO3) under efficient alkali treatment that increases plasma HCO3 within the normal ranges is >15 % in patients with FS. Acidification in the distal tubule is usually normal, but can be sometimes impaired due to chronic hypokalemia or combined proximal-distal disease/toxicity. ð% Þ Fractional excretion of HCO 3 = ð Ucr=Pcr Þ 100 ¼ U HCO =P HCO 3 3 HCO 3 ¼ bicarbonate, cr ¼ creatinine, U ¼ urine, P ¼ plasmaÞ

Sodium and Potassium Losses Sixty to eighty percent of ﬁltered load of Na+ is reabsorbed in the proximal tubules in the normal condition. Renal Na+ reabsorption in the proximal

1360

tubules is decreased in patients with FS. This may cause hypotension and dehydration; some patients develop hyponatremia. Hypokalemia is secondary to increased delivery of Na+ to the distal segments and activation of the renin-angiotensin system by hypovolemia. Potassium wasting may cause lifethreatening severe hypokalemia.

Hypercalciuria Hypercalciuria is commonly observed in FS. In patients with heavy low-molecular-weight proteinuria, such as in Dent disease, different mechanisms may play in opposite directions. Defective endocytosis of parathyroid hormone (PTH) increases its expression on the cell surface of proximal tubular cells, where it stimulates 25-hydroxyvitamin D3 1-hydroxylase to produce more 1,25-dihydroxyvitamin D3, raising serum levels of this vitamin. Conversely, patients lose in their urine the vitamin D3-binding protein, which binds 25-hydroxyvitamin D3 and presents it to the enzyme. The ﬁnal levels of 1,25dihydroxyvitamin D3 depend on the balance of these opposite processes. Often, patients with FS have slightly elevated serum levels of 1,25dihydroxyvitamin D3, which increases intestinal Ca2+ reabsorption and causes hypercalciuria (absorptive hypercalciuria) [31]. Hypercalciuria is rarely associated with nephrolithiasis in patients with FS, possibly because of the polyuria and alkalized urine. Patients with Dent disease, however, can present with hypercalciuria and nephrolithiasis.

Hyperuricosuria (Uricosuria) Uric acid (urate) is the end product of purine metabolism in humans. Because of its small molecular size (MW = 126 D), uric acid is freely filtered from the glomerulus. Approximately 90–95 % of the filtered load of uric acid is eventually reabsorbed in the proximal tubules. A fourcomponent hypothesis has been proposed to explain the renal uric acid transport mechanism; it includes glomerular filtration, presecretory

T. Igarashi

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1386 207. Marshansky V, Ausiello DA, Brown D. Physiological importance of endosomal acidiﬁcation: potential role in proximal tubulopathies. Curr Opin Nephrol Hypertens. 2002;11:527–37. 208. Winter WE, Nakamura M, House DV. Monogenic diabetes mellitus in youth. The MODY syndromes. Endocrinol Metab Clin North Am. 2000;28:765–85. 209. Hamilton AJ, Bingham C, McDonald TJ, et al. The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype. J Med Genet. 2014;51:165–9. 210. Murer H, Forster I, Biber J. The sodium phosphate cotransporter family SLC34. Pﬂugers Arch. 2004;447:763–7. 211. Magen D, Berger L, Coady M, et al. A loss-of-function mutation in NaPi-IIa and renal Fanconi’s syndrome. N Engl J Med. 2010;362:1102–9. 212. Tieder M, Sakarcan A, Neiberger R. Elevated serum 1,25-dihydroxyvitamin D concentrations in siblings with primary Fanconi’s syndrome. N Engl J Med. 1988;319:845–9. 213. Ben-Ishay D, Dreyfuss F, Ylmann TD. Fanconi syndrome with hypouricemia in an adult. Am J Med. 1961;31:793–800. 214. Klootwijk ED, Reichold M, Helip-Wooley A, Tolaymat A, Broeker C, Robinette SL, et al. Mistargeting of peroxisomal EHHADH and inherited renal Fanconi’s syndrome. N Engl J Med. 2014;370:129–38 215. Sheldon W, Luder J, Webb B. A familial tubular absorption defect of glucose and amino acids. Arch Dis Child. 1961;36:90–5. 216. Friedman AL, Trygstad CW, Chesney RW. Autosomal dominant Fanconi syndrome with early renal failure. Am J Med Genet. 1978;2:225–32. 217. Patrick A, Vameron JS, Ogg CS. A family with a dominant form of idiopathic Fanconi syndrome leading to renal failure in adult life. Clin Nephrol. 1981;16:289–92. 218. Wen SF, Friedman AL, Oberley TD. Two case studies from a family with primary Fanconi syndrome. Am J Kidney Dis. 1989;13:240–6. 219. Tolaymat A, Sakarcan A, Neiberger R. Idiopathic Fanconi syndrome in a family. Part I. Clinical aspects. J Am Soc Nephrol. 1992;2:1310–7. 220. Wornell P, Crocker J, Wade A, et al. An Acadian variant of Fanconi syndrome. Pediatr Nephrol. 2007;22:1711–5. 221. Nieman N, Pierson M, Marchal C, et al. Nephropathie familiale glomerulotubulaire avec syndrome de Toni-Debré-Fanconi. Arch Fr Pediatr. 1968;25:43–69. 222. McVicar M, Exeni R, Susin M. Nephrotic syndrome and multiple tubular defects in children: an early sign of focal segmental glomerulosclerosis. J Pediatr. 1980;97:918–22. 223. Ren H, Wang W-M, Chen X-N, et al. Renal involvement and follow up of 130 patients with primary Sjögren syndrome. J Rheumatol. 2008;35:278–84.

T. Igarashi 224. Yang Y-S, Peng C-H, Sia S-K, et al. Acquired hypophosphatemia osteomalacia associated with Fanconi’s syndrome in Sjögren syndrome. Rheumatol Int. 2007;27:593–7. 225. Batuman V. Proximal tubular injury in myeloma. Contrib Nephrol. 2007;153:87–104. 226. Vanmassenhove J, Sallee M, Guilopain P, et al. Fanconi syndrome in lymphoma patients: report of the ﬁrst case series. Nephrol Dial Transplant. 2010;25:2516–20. 227. Parker C. Eculizumab for paroxysmal nocturnal haemoglobinuria. Lancet. 2009;373:759–67. 228. Friedman AL, Chesney R. Fanconi’s syndrome in renal transplantation. Am J Nephrol. 1981;1: 145–7. 229. Dobrin RS, Vernier RL, Fish AJ. Acute eosinophilic interstitial nephritis and renal failure with bone marrow-lymph node granuloma and anterior uveitis. Am J Med. 1975;59:325–33. 230. Igarashi T, Kawato H, Kamoshita S, et al. Acute tubulointersitial nephritis with uveitis syndrome presenting as multiple tubular dysfunction including Fanconi’s syndrome. Pediatr Nephrol. 1992;6:547–9. 231. Wen YK. Tubulointerstitial nephritis and uveitis with Fanconi syndrome in a patient with ankylosing spondylitis. Clin Nephrol. 2009;72:315–8. 232. Tung KS, Black WC. Association of renal glomerular and tubular immune complex disease and autoimmune basement membrane antibody. Lab Invest. 1975;32:696–700. 233. Griswold WR, Krous HF, Reznik V, et al. The syndrome of autoimmune interstitial nephritis and membranous nephropathy. Pediatr Nephrol. 1997;11: 699–702. 234. Makker SP, Widstrom R, Huang J. Membranous nephropathy, interstitial nephritis, and Fanconi syndrome – glomerular antigen. Pediatr Nephrol. 1996;10:7–13. 235. Kinoshita-Katahashi N, Fukasawa H, Ishigaki S, et al. Acquired Fanconi syndrome in patients with Legionella pneumonia. BMC Nephrol. 2013;14:171. 236. Alexandridis G, Liamis G, Elisaf M. Reversible tubular dysfunction that mimicked Fanconi’s syndrome in a patient with anorexia nervosa. Int J Eat Disord. 2001;30:227–30. 237. Watanabe T. Proximal renal tubular dysfunction in primary distal renal tubular acidosis. Pediatr Nephrol. 2005;20:86–8. 238. Hall AM, Bass P, Uniwin R. Drug- induced renal Fanconi syndrome. QJM. 2014;107:261–9. 239. Cleveland WW, Adams WC, Mann JC, et al. Acquired Fanconi syndrome following degraded tetracycline. J Pediatr. 1965;66:333–42. 240. Gainza FJ, Minguela JI, Lampreabe I. Aminoglycoside-associated Fanconi’s syndrome: an underrecognized entity. Nephron. 1997;77:205–11.

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241. Ghiculescu R, Kubler P. Aminoglycoside-associated Fanconi syndrome. Am J Kidney Dis. 2006;48: E89–93. 242. Min HK, Kim EO, Lee SJ, et al. Rifampin-associated tubulointerstitial nephritis and Fanconi syndrome presenting as hypokalemic paralysis. BMC Nephrol. 2013;14:13. 243. Tsimihodiomos V, Psychogios N, Kakaidi V, et al. Salicylate-induced proximal tubular dysfunction. Am J Kidney Dis. 2007;50:463–7. 244. Zaki EL, Springate JE. Renal injury from valproic acid: case report and literature review. Pediatr Neurol. 2002;27:318–9. 245. Bagnis CI, Deray G, Baumelou A, et al. Herbs and the kidney. Am J Kidney Dis. 2004;44:1–11. 246. Hong Y-T, Fu L-S, Chung L-H, et al. Fanconi’s syndrome, interstitial ﬁbrosis and renal failure by aristolochic acid in Chinese herbs. Pediatr Nephrol. 2006;21:577–9. 247. Takamoto K, Kawada M, Usui T, et al. Aminoglycoside antibiotics reduce glucose reabsorption in kidney through down-regulation of SGLT1. Biochem Biophys Res Commun. 2003;308:866–71. 248. Humes HD. Aminoglycoside nephrotoxicity. Kidney Int. 1988;33:900–11. 249. Endo A, Fujita Y, Fuchigami T, et al. Fanconi syndrome caused by valproic acid. Pediatr Nephrol. 2010;42:287–90. 250. Buttemer S, Pai M, Lau KK. Ifosfamide induced Fanconi syndrome. BMJ Case Reports. 2011;2011. 251. Zamialuski-Tucker MJ, Morris ME, Springate JE. Ifosfamide metabolite chloroacetaldehyde causes Fanconi syndrome in the perfused rat kidney. Toxicol Appl Pharmacol. 1994;129:170–5. 252. Yaseen X, Michoudet C, Baverel G, et al. Mechanisms of the ifosfamide-induced inhibition of endocytosis in the rat proximal kidney tubule. Arch Toxicol. 2008;82:607–14. 253. Sayed-Ahmed MM, Hafez MM, Aldelemy ML, et al. Downregulation of oxidative and nitrosative signaling by L-carnitine in ifosfamide-induced Fanconi syndrome rat model. Oxid Med Cell Longev. 2012;2012:696704. 254. Pratt CB, Meyer WH, Jenkins JJ, et al. Ifosfamide, Fanconi’s syndrome, and rickets. J Clin Oncol. 1991;9:1495–9. 255. Hanquinet S, Wouters M, Devalck C, et al. Increased renal parenchymal echogenicity in ifosfamideinduced renal Fanconi syndrome. Med Pediatr Oncol. 1995;24:116–8. 256. Badary OA. Taurine attenuates Fanconi syndrome induced by ifosfamide without compromising its antitumor activity. Oncol Res. 1998;10:355–60. 257. Portill D, Nagothu KK, Megyesi J, et al. Metabolomic study of cisplatin-induced nephrotoxiciy. Kidney Int. 2006;69:2194–204. 258. François H, Coppo P, Hayman J-P, et al. Partial Fanconi syndrome induced by Imanitib therapy: a

1387 novel cause of urinary phosphate loss. Am J Kidney Dis. 2008;51:298–301. 259. Meier P, Dautheville-Gibal S, Ronco PM, et al. Cidofovir-induced end-stage renal failure. Nephrol Dial Transplant. 2002;17:148–9. 260. Ho ES, Lin DC, Mendel DB, et al. Cytotoxicity of antiviral nucleotides adefovir and cidofovir is induced by the expression of human renal organic anion transporter 1. J Am Soc Nephrol. 2000;11: 383–93. 261. Tanji N, Tanji K, Kambham N, et al. Adefovir nephotoxicity: possible role of mitochondrial DNA depletion. Hum Pathol. 2001;32:734–40. 262. Daugas E, Rougier J-P, Hill G. HAART-related nephropathies in HIV-infected patients. Kidney Int. 2005;67:393–403. 263. Law ST, Li KK, Ho YY. Acquired Fanconi syndrome associated with prolonged adefovir dipivoxil therapy in a chronic hepatitis B patient. Am J Ther. 2013;20: e713–6. 264. Verheist D, Monge M, Meynard J-L, et al. Fanconi syndrome and renal failure induced by tenofovir: a ﬁrst case report. Am J Kidney Dis. 2002;40:1331–3. 265. Malik A, Abraham P, Malik N. Acute renal failure and Fanconi syndrome in an AIDS patient on tenofovir treatment-case report and review of literature. J Infect. 2005;51:e61–5. 266. Rafat C, Fakhouri F, Ribeil JA, et al. Fanconi syndrome due to deferasirox. Am J Kidney Dis. 2009;54:931–4. 267. Rheault MN, Bechtel H, Neglia JP, et al. Reversible Fanconi syndrome in a pediatric patient on deferasirox. Pediatr Blood Cancer. 2011;56:674–6. 268. Murphy N, Elramah M, Vats H, et al. A case report of deferasirox-induced kidney injury and Fanconi syndrome. WMJ. 2013;112:177–80. 269. Gil HW, Yang JO, Lee EY, et al. Paraquat-induced Fanconi syndrome. Nephrology (Carlton). 2005;10:430–2. 270. Hruz P, Mayr M, Löw R, et al. Fanconi’s syndrome, acute renal failure, and tonsil ulceration after colloidal bismuth substrate intoxication. Am J Kidney Dis. 2002;39:E18. 271. Otten J, Vis HL. Acute reversible renal tubular dysfunction following intoxication with methyl-3choromone. J Pediatr. 1968;73:422–5. 272. Butler HE, Morgan JM, Smythe CM. Mercaptopurine and acquired tubular dysfunction in adult nephrosis. Arch Intern Med. 1965;116:853–6. 273. Moss AH, Gabow PA, Kaehny WD, et al. Fanconi syndrome and distal renal tubular acidosis after glue snifﬁng. Ann Intern Med. 1980;92:69–70. 274. Barbier O, Jacquillet G, Tau M, et al. Effect of heavy metals on, and handling by, the kidney. Nephron Physiol. 2005;99:105–10. 275. Chisolm JJ, Harrison HC, Eberlein WE, et al. Aminoaciduria, hyperphosphaturia and rickets in lead poisoning. Am J Dis Child. 1955;89:159–68.

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T. Igarashi River basin, based on health examinations in 1967 and 1968. Int J Environ Health Res. 2007;17:231–42. 279. Elizbieta S-J, Roman L. Metabolic bone disease in children: etiology and treatment options. Treat Endocrinol. 2006;5:297–318. 280. Plank C, Konrad M, Dörr HG, et al. Growth failure in a girl with Fanconi syndrome and growth hormone deﬁciency. Nephrol Dial Transplant. 2004;19:1910–2.

Primary Hyperoaxaluria in Children

Pierre Cochat, Neville Jamieson, and Cecile Acquaviva-Bourdain

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1390 Primary Hyperoxaluria Type 1 (PH1) . . . . . . . . . . . Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oxalate Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Supportive Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Urological Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Organ Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future Developments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1390 1390 1392 1393 1394 1394 1396 1396 1396 1399

Primary Hyperoxaluria Type 2 (PH2) . . . . . . . . . . . 1400 Metabolic Derangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1400

Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . .

1400 1400 1401 1401

Primary Hyperoxaluria Type 3 (PH3) . . . . . . . . . . . Metabolic Derangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . .

1401 1401 1401 1401 1402 1402

Diagnostic Approach to Primary Hyperoxaluria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1402 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1402 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1402

P. Cochat (*) Centre de référence des maladies rénales rares Néphrogones, Hôpital Femme Mère Enfant, Hospices Civils de Lyon & Université de Lyon, Lyon, France IBCP-UMR 5305 CNRS, Université Claude-Bernard Lyon 1, Lyon, France e-mail: [emailprotected] N. Jamieson Department of Surgery, Addenbrookes Hospital, Cambridge University Teaching Hospitals, Cambridge, UK e-mail: [emailprotected] C. Acquaviva-Bourdain Centre de référence des maladies rénales rares Néphrogones, Hôpital Femme Mère Enfant, Hospices Civils de Lyon & Université de Lyon, Lyon, France Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Lyon, France e-mail: [emailprotected] # Springer-Verlag Berlin Heidelberg 2016 E.D. Avner et al. (eds.), Pediatric Nephrology, DOI 10.1007/978-3-662-43596-0_39

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Introduction Hyperoxaluria may be either a secondary or a primary disease. Three distinct autosomal recessive inherited enzyme defects of glyoxylate metabolism have been related to type 1, type 2, and type 3 primary hyperoxalurias (PH), i.e., alanine: glyoxylate aminotransferase (AGT), glyoxylate reductase/hydroxypyruvate reductase (GRHPR), and 4-hydroxy-2-oxoglutarate aldolase (HOGA), respectively; in addition, a few other patients with PH have been reported without identification of PH1, PH2, nor PH3 so that other rare metabolic defects are likely to exist. Among all PH patients, type 1 accounts for 73–80 %, type 2 for 5–10 %, type 3 for 8–10 %, and others for 5–11 % [1]. The global survival rate is better for PH3 than PH2 and better for PH2 than PH1. Oxalate, a dicarboxylic acid (HOOC-COOH), is an end product of metabolism in humans. It is soluble when combined with sodium, potassium, or magnesium but highly insoluble in the form of its calcium salt and has a tendency to crystallize in the renal tubules [2]. The primary defect of inherited hyperoxaluria is overproduction of oxalate, primarily by the liver, with resultant increased excretion by the kidney. The earliest symptoms among those affected are related to hyperoxaluria, and a diagnosis of PH must be considered in any child with a first kidney stone [3]. Renal damage is ultimately due to a combination of tubular toxicity from oxalate, nephrocalcinosis with both intratubular and interstitial calcium oxalate (CaOx) deposits, obstruction from stones, and often superimposed infection that progressively lead to renal impairment and subsequent chronic kidney disease (CKD). Inflammation has been recently shown to contribute to CKD progression in animal models of calcium oxalate-induced nephrocalcinosis [4, 5]. A second phase of tissue damage develops when patients reach chronic kidney disease stage 3b (CKD-3b). At this stage, the kidneys become unable to efficiently excrete the oxalate load that they receive; as a consequence, plasma oxalate (Pox) rises and exceeds its saturation threshold, which leads to oxalate deposition in all tissues (systemic oxalosis), particularly in the

P. Cochat et al.

skeleton [6]. In the kidneys as well as in the skeleton, the activities of macrophages and giant cells are stimulated by oxalate crystals, and serum levels of the macrophage/osteoclast-derived tartrateresistant acid phosphatase 5b (TRACP-5b) enzyme have been proposed to represent a reliable marker of the total calcium oxalate burden [7]. Secondary hyperoxaluria may occur in the setting of poisoning with oxalate precursors (ethylene glycol, ascorbic acid, xylitol, etc.) or with enteric hyperoxaluria, particularly after bowel resection, which may lead to sequestration of calcium in the gut, leaving oxalate in its more soluble sodium form, which is then taken up by the colon [8]. Excess dietary intake has also been linked with secondary hyperoxaluria. Secondary hyperoxaluria must be excluded prior to investigating a patient for primary hyperoxaluria.

Primary Hyperoxaluria Type 1 (PH1) PH1 is one of the most challenging conditions for both adult and pediatric nephrologists worldwide. The diagnostic strategy has improved during recent years and can now be based on reasonable recommendations [3]. However, due to its rarity and variable phenotype, therapeutic guidelines cannot be generated entirely from evidencebased information and necessarily include expert opinions and experiences [9].

Pathophysiology PH1 (MIM 259900) is an autosomal recessive disorder (~1:100,000 live births per year in Europe), caused by the functional defect of the liver-speciﬁc peroxisomal, pyridoxal-50 -phosphate-dependent enzyme AGT (MIM 604285) leading to oxalate overproduction [10, 11]. The disease occurs because AGT activity is impaired or because AGT is mistargeted to mitochondria, which likely explains the observed heterogeneity of results obtained with enzymatic activity assays. The median age of the initial symptoms is 5–6 years;

Primary Hyperoaxaluria in Children

A Healthy

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B Stage 1

Plasma

Liver Glyoxylate

Oxalate

Glyoxylate

AGT [B6]

Glycine

Oxalate

Glycolate

Urine

Plasma

Liver

Glycolate

Glycolate Oxalate

C Stage 2

Urine

D Stage 3

Plasma

Liver

Glycolate Oxalate

Plasma

Liver

Glyoxylate

Oxalate

Skeleton Oxalate

AGT [B6]

Skeleton Oxalate

Oxalate

Glyoxylate AGT [B6]

Glycine

GFR < 30-44 mL/min per 1.73 m

Glycolate

Glycine

ESRD/RRT

Glycolate Bone Joints

Urine

Glycolate Oxalate

Fig. 1 Primary hyperoxaluria type 1. Normally, oxalate synthesized in the liver from glyoxylate detoxiﬁcation is secreted into plasma and excreted in urine (Panel A). With a moderate degree of renal insufﬁciency, oxalate is overproduced and excreted by the kidneys (Stage 1, Panel B), but the increased load can cause crystalluria (inset at left, showing monohydrated calcium oxalate crystal in the urine) and the production of oxalate stones in the kidney (inset at right, showing a typical infrared spectrometry analysis, Courtesy of Prof. Jean-François Sabot). In CKD-4, progressive renal damage may include diffuse nephrocalcinosis (Panel C, with the inset at left showing

diffuse nephrocalcinosis on ultrasonography (Courtesy of Prof. Jean-Pierre Pracros) and the inset at right showing oxalate crystals in the proximal renal tubule under polarized light (Courtesy of Dr. Frederique Dijoud)). In patients with CKD-5, the oxalate load cannot be cleared effectively, and oxalate crystals are deposited in all tissues (Panel D, with inset at left showing massive bone and joint involvement (Courtesy of Prof. Jean-Pierre Pracros) and the inset at right showing oxalate crystals in a bone biopsy specimen, May–Gr€ unwald–Giemsa stain (Courtesy of Dr. Georges Boivin))

end-stage renal disease (ESRD) is reached in 50 % of patients between 25 and 40 years of age [10, 12]. Based on registry data, PH1 accounts for 1–2 % of pediatric end-stage renal disease (ESRD) in Europe, USA, and Japan but is more prevalent in countries in which consanguineous marriages are common and exceeds 10 % in some North African and Middle East nations [13–17]. In addition to the progressive decline of GFR due to renal parenchymal damage, continued overproduction of oxalate by the liver combined with reduced oxalate excretion by the kidneys raises Pox above a critical saturation level. As a

result of that, oxalate deposition occurs in many organs, leading to systemic involvement, termed “oxalosis”; bones represent the major compartment where the insoluble oxalate pool is deposited (Figures 1 and 2). Calcium salts of glycolate are soluble and do not appear to cause signiﬁcant disease in humans. The infantile form of PH1 often presents as a life-threatening condition with very fast progression to ESRD due to very high oxalate load combined with immature GFR; approximately half of these infants have ESRD at the time of diagnosis, and 80 % have ESRD by the age of 3 years [18, 19].

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Fig. 2 Primary hyperoxaluria type 1: simpliﬁed global course of the disease

Oxalate production

Systemic involvement Oxalate storage Nephrocalcinosis

Urolithiasis GFR CKD-1 GFR > 90

CKD-2 89 > GFR > 60

Stage 1

Recent reviews on molecular pathophysiology of the disease or therapeutic approaches allow to make management recommendations for PH1 [1, 3, 9].

Diagnosis Because of the rarity of the disease and because many physicians have limited knowledge on inherited forms of urolithiasis, there is on average a 5-year gap between the initial symptoms and the diagnosis of PH1 [10, 12]. The association between renal calculi, nephrocalcinosis, and renal impairment is strongly suggestive of PH1; in addition, family history may add important information [3]. From a clinical standpoint, PH1 is usually diagnosed in patients presenting with one of the following ﬁve clinical pictures [20, 21]: – Infant with early nephrocalcinosis and kidney failure (35 %) – Recurrent urolithiases and progressive renal failure in children or adolescents (25 %) – Occasional stone passage in adulthood (15 %) – Recurrence of the disease after renal transplantation in patients with previously unrecognized PH1 (10 %) – Asymptomatic subjects with a positive family history of PH1 (15 %)

CKD-3 59 > GFR > 30 Stage 2

CKD-4 29 > GFR > 15

CKD-5 GFR < 14

Stage 3

Based on the European pediatric registry data, the median age at first symptoms is 4 years, and the mean age at diagnosis is 7.7 years; 43 % of index PH1 patients already have ESRD at diagnosis [14]. The median age at renal replacement therapy (RRT) has decreased from 9.8 years in 1979–1989 to 1.5 years in 2000–2009, demonstrating major advances in early diagnosis and treatment [14]. Crystalluria, infrared spectroscopy, and morphologic characteristics examination allow identification and quantitative analysis of urinary crystals and stones; these analyses usually show CaOx monohydrate crystals (type Ic whewellite) in excess of 200/mm3 in cases with heavy hyperoxaluria [22]. In patients with normal or significant residual GFR, hyperoxaluria (urine oxalate, Uox >1 mmol/1.73 m2 BSA per day, control 0.5 mmol/ 1.73 m2 per day) are indicative of PH1, but some patients do not present with hyperglycoluria (Table 1) [1]. Pox concentration is not useful for diagnosis when the GFR is >40 mL/min per 1.73 m2 since it is usually normal (5 red blood cells/high-power field, red blood cell casts in the urinary sediment, or =2+ on dipstick; or impaired renal function, measured or calculated glomerular filtration rate (Schwartz formula) 0.5 g/day or red casts 8. Psychosis or seizures 9. Hemolytic anemia or leucopenia (300 mg/24” to emphasize the continuous nature of albuminuria as a risk factor for renal and cardiovascular complications [45].

Pathogenesis of Diabetic Nephropathy DN is the result of an interplay between hemodynamic and metabolic factors in the renal microcirculation [46] and the consequent activation of common intermediate pathways, associated with

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HYPERGLYCEMIA

Hemodynamic factors (Hypertension, Ang II, endothelins, NO)

Increased mitochondrial superoxide production

Metabolic factors

Polyol and Hexosamine pathways

Cytokines

• • • • • •

Growth factors

DAG-PKC

ROS

AGEs

NF-KB

Thickness of glomerular basement membrane Proliferation of mesangial cells Accumulation of matrix proteins Podocytes loss Mesangium and arterial wall hyalinosis Tubulo-interstitial fibrosis & glomerulosclerosis

DIABETIC KIDNEY DISEASE

Fig. 1 Metabolic and hemodynamic factors implicated in the pathogenesis of diabetic nephropathy. NO nitric oxide, Ang II angiotensin II, ROS reactive oxidative species,

DAG-PCK diacylglycerol-protein kinase advanced glycosylated end products

increased synthesis and release of growth factors, cytokines, chemokines, and oxidant species, which are all final mediators of renal damage [6, 46] (Fig. 1). Typical morphological changes in the diabetic kidney are represented by diffuse glomerular basement membrane thickening, mesangial expansion, hyalinosis of the mesangium and arteriolar walls, broadening and effacement of podocyte foot processes, reduction in podocyte number, glomerulosclerosis, and tubulointerstitial fibrosis [47]. These morphological changes in the kidney develop years before the clinical appearance of MA and overt proteinuria, and this is an alarming aspect of DN, given that when the disease is clinically evident, some of the structural damage is already irreversible [19]. Thickening of the basement membrane is a common biopsy finding related to DN; it is associated with loss of glycosaminoglycans and therefore of negative charges, with consequent increased loss of anionic albumin [48, 49].

A subsequent increase in the size of membrane pores leads to the development of nonselective proteinuria. An imbalance between the production and the degradation of mesangial matrix proteins, together with an increase in mesangial cells number, is responsible for mesangial expansion in DN [49]. Hyperglycemia and renal hypertension together with other factors can activate pathways leading to an increased synthesis and deposition of matrix proteins, particularly by stimulating local production of cytokines and growth factors [50]. Furthermore, the same factors can inhibit proteins and enzymes implicated in the degradation of the extracellular matrix, for example, by a nonenzymatic glycation of these components [50]. As in other progressive glomerulopathies, changes in podocyte characteristics are a key feature of DN [51]. Podocytes are highly specialized epithelial cells, interconnected by foot processes, which delimit the slit diaphragm, the main

AGEs

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size-selective barrier in the glomerulus. The diabetic milieu can induce several morphological changes in these epithelial cells, as emerged from both human and experimental studies [48]. The first detectable alteration in podocytes in the context of DN is a broadening and effacement of their foot processes [48]. These progressive podocyte changes lead to a decrease in their density and number and a detachment from the glomerular basement membrane. The last phenomena are directly correlated to levels of ACR and to the decline in GFR [48]. Podocytes can also undergo hypertrophy, apoptosis, and increased synthesis of collagen IV, whereas there is a decreased synthesis of proteins such as nephrin [48]. Another characteristic of DN is the hyalinosis of the afferent and efferent arterioles in the glomerulus, due to the accumulation of complement components, fibrinogen, immunoglobulins, albumin, and other plasma proteins [52]. Hypertrophy and sclerosis of the juxtaglomerular apparatus is another frequent finding in DN [53].

Hemodynamic Factors Hemodynamic factors implicated in the pathogenesis of DN include systemic and intraglomerular pressure and activation of vasoactive mediators [46]. Glomerular hypertension is the results of reduced resistance in both the afferent and efferent arterioles, effect which is predominant in the former. On the basis of several experimental studies, it has been suggested that a subset of patients with diabetes could be predisposed to intraglomerular hypertension, due to defects in the renal mechanisms of ﬂow autoregulation [54]. The lack of the normal vasoconstriction in the afferent arteriole in response to increased systemic hypertension, associated with the constriction of the efferent arteriole, contributes to the increase in intraglomerular blood pressure [50]. A potential mediator of the afferent arteriole dilation is an increased oxidative burden. In fact, reactive oxygen species (ROS) can affect K+ channels in the afferent arteriole with consequent hyperpolarization and increased Ca+ inﬂux and vasodilation. K+ channels have a dominant role in the

M. Marcovecchio and F. Chiarelli

electromechanical function of the afferent arteriole but only a minor effect on the efferent arteriole [55]. Glomerular hypertension can in turn induce the activation of several pathways and molecules, which can mediate renal injury. In particular, it has been shown that it can, for example, activate GLUT-1 in glomerular cells, thereby inducing an intracellular hyperglycemic milieu [50]. Angiotensin II is a key mediator of DN, by exerting both hemodynamic and nonhemodynamic effects [46]. The hemodynamic effects of angiotensin II include both systemic and renal vasoconstriction [56]. In the kidney, angiotensin II also increases glomerular capillary pressure and permeability. Non-hemodynamic effects of angiotensin II include activation of transforming growth factor-beta 1 (TGF-ß1) and other cytokines, activation of ROS production in mesangial cells, stimulation of extracellular matrix and inhibition of its degradation, activation of the intracellular NF-kB, and reduction in podocyte nephrin expression [56, 57]. Other factors that have been implicated in the hemodynamic changes related to DN are vasoactive hormones, which can inﬂuence the intrarenal circulation by acting on the afferent and efferent arterioles. In particular, endothelin and vasopressin are the most relevant vasoconstrictors in this context, whereas nitric oxide, bradykinin, prostaglandins, and atrial natriuretic factor are the main vasodilators [46].

Metabolic Factors Growth Factors Several growth factors have been implicated in the pathogenesis of DN, through complex intrarenal systems [58–60]. GH/IGF, TGF-ß, vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and connective tissue growth factor (CTGF) are among those more known and investigated [58–60]. The implication of the GH-IGF system in the pathogenesis of DN is well established [58, 59]. Diabetes is associated with decreased hepatic production of IGF-1 related to portal insulinopenia, with consequent lack of the

Diabetic Nephropathy in Children

inhibitory feedback of IGF-1 on the anterior pituitary and therefore GH hypersecretion [61, 62]. The integrity of GH receptors in peripheral tissues, other than the liver, can cause a local increased production of IGF-1, which can in turn exert paracrine effects [61, 62]. Antagonist of the GH/IGF-1 system, including somatostatin analogues, GH and IGF-1 receptors antagonists, as well as antagonists of downstream factors activated by GH/IGF-1, such as the ACE and AGE systems, have been found to have beneficial effects on the diabetic kidney in animal models [58]. TGF-ß is considered as a crucial factor in the development of renal kidney disease [58–60]. It appears to be a key point of convergence of both hemodynamic and metabolic pathways activated in DN. In the diabetic milieu, several factors can induce increased expression of this growth factor, such as hyperglycemia, hypertension, mechanical strains, and protein kinase C (PKC). TGF-ß is a pro-fibrotic cytokine, which has a key role in the expansion of extracellular matrix, by stimulating production of several components of the matrix and, in the meantime, by altering extracellular matrix composition [58–60]. VEGF is another relevant growth factor implicated in the pathogenesis of DN, even though its role in this context is not as well defined as for diabetic retinopathy [58–60]. In particular, VEGF is a key angiogenic factor, which influences the proliferation of endothelial cells and exerts a pivotal role in vascular integrity [60]. Anoxia is an important stimulus for its production as well as AGE, angiotensin II, and oxidative stress [60]. VEGF is expressed in different cells in the kidney, including podocytes and tubular cells. Increased VEGF levels have been reported in both T1D and T2D and have been related to DN [63]. In children with T1D and MA, VEGF levels are reduced when compared with diabetic children with normoalbuminuria, and they have an independent predictive value for future development of DN [64]. CTGF is one of the most recent identified growth factors with a role in DN. Increased concentrations of CTGF have been detected in the glomerulus of diabetic patients and animals

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[65–67]. In adult patients with T1D, increased levels of CTGF are strongly correlated with the severity of DN [68, 69] and are an independent predictor of ESRD and mortality [70]. CTGF is considered to be the downstream mediator of TGF-ß in extracellular matrix synthesis. However, there is also evidence of a TGF-ß-independent regulation of CTGF, which is related to a direct activation of its synthesis by hyperglycemia, AGEs, and static pressure [67, 71, 72].

Cytokines DN is considered an inflammatory disease, and several cytokines have been implicated in its pathogenesis: interleukin (IL)-1, IL-6, IL-18, and tumor necrosis factor-alpha (TNF-α) [73]. In the kidney, inflammatory cytokines are synthesized and released by endothelial, mesangial, glomerular, and tubular cells [73]. IL-1 has been implicated in increased vascular permeability, proliferation of extracellular matrix and abnormalities in microcirculation [73]. IL-6 has been also implicated in inducing changes in the extracellular matrix [73]. TNF-α has been shown to have a cytotoxic effect on glomerular, mesangial, and epithelial cells in the kidney [60, 73]. Chemokines and cytokines implicated in monocytes/macrophages recruitment have been related to the development and progression of DN [74]. Monocytes chemoattractant protein-1 (MCP-1) is a chemokine with the highest chemotactic activity towards monocytes. For MCP-1 a causative role in the development of DN has been suggested, through recruitment of monocyte/macrophage in the kidney [75]. Furthermore, in vitro studies have shown that MCP-1, by interacting with its receptor (CCR2) can promote fibronectin deposition in the diabetic glomerulus [76]. Blocking the MCP-1/CCR2 pathway ameliorates glomerulosclerosis, indicating that the MCP-1/CCR2 pathway could play a crucial role in the progression of DN [77]. Increased MCP-1 levels have been reported in subjects with diabetes when compared with controls, and it has been shown that plasma and urine MCP-1 levels can be used to assess renal inflammation in this disease [78].

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Advanced Glycation End Products and Their Receptors Another link between elevated glucose levels and DN resides in a direct effect of nonenzymatic glycosylation of cellular macromolecules, causing alterations of their structural and functional properties [79–82]. AGEs have been implicated in several biologic activities, mostly by binding to the AGE-specific receptors (RAGEs) on many cells. In particular, they can enhance oxidative stress and stimulate the release of cytokines and growth factors, which in turn accelerate chronic inflammation and endothelial dysfunction [80]. Increased serum levels of AGEs have been detected in children and adolescents with T1D, already before the development of clinically evident signs of microvascular complications [83]. Animal studies support the role of AGE in the pathogenesis of DN. In fact, blockage of AGE, with aminoguanidine, significantly reduces renal changes [84]. There is also a large body of evidence for a predictive role of the soluble form of the RAGE (sRAGE) in the development of vascular diabetic complications, including DN [85]. sRAGE can be measured in peripheral blood, and it seems to result from the expression of a RAGE splice gene variant that encodes an amino-terminally truncated form of the receptor and/or from the cleavage of the native membranous receptor [85]. Serum sRAGE levels are significantly higher in patients with diabetes than in healthy subjects and positively associated with the presence of coronary artery disease [86] and also independently related to albumin excretion [85]. A circulating C-truncated form of the RAGE (esRAGE) exists and seems to work as a scavenger for AGEs and in this way could exert a protective for diabetic complications. Reduced circulating levels of esRAGE have been found in patients with T1D and are related to the severity of vascular complications [87, 88]. Oxidative Stress Oxidative stress is one of the most important factors involved in the pathogenesis of DN [50, 82]. Several pathways have been related to an increased production of oxidative stress in the

M. Marcovecchio and F. Chiarelli

context of DN: increased mitochondrial electron transport; the AGEs-RAGE system; an increased activity of cytochrome P-450, xanthine oxidase, cyclooxygenase, and lipoxygenase; increased glucose auto-oxidation; and an impaired activity of endothelial nitric oxide synthase [89]. Many of the pathways activated by hyperglycemia can induce mitochondrial superoxide overproduction, and blockage of this effect can reduce damage related to high glucose levels [90, 91]. This increased mitochondrial production of ROS can in turn stimulate different processes, including protein kinase C activity, synthesis of growth factors and cytokines, and stimulation of NF-kB. Oxidative stress seems to play an important role also in the context of the so-called metabolic memory [92]. In fact, increased mitochondrial superoxide production consequent to hyperglycemia could induce not only immediate effects, such as activation of PKC or other pathways, but it might also damage mitochondrial DNA [92]. This, in turn, could lead to synthesis of altered subunits of the electron transport system, which could produce increased amount of superoxide even in the presence of physiological glucose levels [92].

Intracellular Factors Polyol and Hexosamine Pathways The polyol pathway has been implicated in the pathogenesis of DN, through the action of aldose reductase, the ﬁrst and rate-limiting enzyme in this pathway [92]. Aldose reductase reduces the aldehyde form of glucose to sorbitol in a reaction which consumes NADPH. In physiological situations, sorbitol is then oxidized to fructose by sorbitol dehydrogenase and therefore addressed again into the glycolysis. In the presence of hyperglycemia, the production of sorbitol overcomes the potential of its oxidation by sorbitol dehydrogenase, with accumulation in several cells, including renal tubular and glomerular cells. Several mechanisms have been suggested to link the polyol pathway to the development of diabetic complications. These include a dysregulation of the cellular osmotic status, reduction of

Diabetic Nephropathy in Children

Na+/K+-ATPase activity, and cytosolic increase in NADH/NAD + and decrease in NADPH [92]. The depletion of NADPH appears to be the most important mediator, as it is associated with an impairment of several enzymatic reactions requiring this enzyme, such as nitric oxide synthase, cytochrome P450, and glutathione reductase, thereby altering the intracellular oxidantantioxidant status and inducing vasoconstriction and poor blood supply [92]. The hexosamine pathway converts fructose-6 phosphate in N-acetylglucosamine, which is a substrate for reactions such as proteoglycan synthesis and generation of O-linked glycoprotein [92, 93]. N-acetylglucosamine has been implicated in the activation of the transcriptional factor Sp1, which is associated with increased synthesis of factors, such as TGF-ß1 and PAI-1, which in turn are associated to the development of vascular complications [92, 93]. In addition, the hexosamine pathway is also associated with increased oxidative stress, and the effects of the activation of this pathway can be prevented by overexpression of antioxidants, such as superoxide dismutase [90].

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Emerging Role of MicroRNA in the Pathogenesis of Nephropathy MicroRNAs (miRNAs) are short noncoding RNAs, which regulate gene expression. They are implicated in several biological and pathological processes, including cell proliferation, differentiation, apoptosis, and carcinogenesis. Recent data suggest an important role of miRNA in the kidney, where they regulate renal development, homeostasis, and physiological functions. In addition, miRNAs have also been implicated in the pathogenesis of kidney diseases, including DN [96]. One of the main miRNAs associated with DN is mir-192, which seems to have a key role in regulating ﬁbrosis. Other DN-associated miRNAs are mir-377, mir-200, mir-216a, mir-141, mir-29, and mir-93 [97]. The emerging information on a key role of miRNAs in the pathogenesis of DN suggests that miRNAs might have a great potential to be used, in the future, as novel diagnostic and prognostic biomarkers in the context of this vascular complication of diabetes.

Risk Factors Diacylglycerol-Protein Kinase C Pathway The diacylglycerol (DAG)-PKC system can induce several alterations, which can contribute to DN [92, 94, 95]. These mechanisms include changes in endothelial permeability, vasoconstriction, increased synthesis of extracellular matrix and stimulation of cytokines synthesis, cell growth, angiogenesis, and leukocyte adhesion [92, 94, 95]. Hyperglycemia can stimulate de novo synthesis of DAG, followed by the activation of PKC [92]. PKC modulates the activity of various enzymes, including phospholipase A2, Na+/K+ ATPase as well as the expression of genes related to components of the extracellular matrix [92, 94]. PKC-beta is the major isoform induced in the kidney by hyperglycemia, and ruboxistaurin, a PKC-beta isoform-selective inhibitor, has been shown to have a beneﬁcial effect on microvascular complications, by normalizing endothelial dysfunction and GFR and reducing loss of visual function [84].

Glycemic Control Several observational studies have shown a strong correlation between glycemic control, as assessed by HbA1c, and DN in adults and youth with T1D and T2D [20, 98]. In addition, the probability of reverting from MA to normoalbuminuria is also inﬂuenced by glycemic control [21]. Further evidence for the key role of hyperglycemia in the pathogenesis of DN comes from two landmark interventional studies, the Diabetes Control and Complication Trial (DCCT) [99] and the United Kingdom Prospective Diabetes Study (UKPDS) [100]. The DCCT, a multicenter prospective controlled clinical trial involving 1,441 patients with T1D, undoubtedly proved the beneﬁcial effect of maintaining low levels of HbA1c in reducing the risk of developing MA. The DCCT cohort included a group of 195 adolescents, aged 13–17 years, where intensive insulin treatment reduced the risk and progression of MA by 54 % compared

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to conventional treatment [101]. In addition, the DCCT follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) [102], highlighted the important phenomenon of “metabolic memory.” In fact, even though already after 2 years since the end of the DCCT, HbA1c levels were similar between the previously intensively and conventionally treated groups, those who beneﬁted in the past of a better metabolic control still had an advantage in terms of development of complications [102]. With regard to the adolescent cohort, the EDIC study showed that in the previously intensively treated group, the risk of MA and proteinuria decreased by 48 % and 85 %, respectively [102]. Another interesting ﬁnding of the DCCT and the UKPDS [99, 100] was the lack of a clear threshold for HbA1c below which the risk of complications was annulled; instead there was a continuous reduction in complication risk as glycemic control improved. In contrast, another study showed a threshold effect for the development of MA at an HbA1c value of about 8.1 % [103].

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in youth with T1D, such as an impairment in the nocturnal fall in blood pressure [112] and abnormalities in daytime diastolic blood pressure [113].

Dyslipidemia Dyslipidemia can also contribute to renal disease in the context of diabetes. Based on adult studies, subjects developing MA have higher cholesterol levels than subjects who do not progress [114], and reduction in cholesterol levels predicts regression of MA to normoalbuminuria. Triglyceride levels have also been suggested as a predictor of progression or regression of MA [115, 116]. Lipid abnormalities are also associated with rates of urinary AER and risk of MA during puberty [117, 118]. Total cholesterol and LDL cholesterol levels have been associated with albumin excretion rates and with the development of DN both in cross-sectional and longitudinal studies [118–120].

Puberty Blood Pressure Increased blood pressure in people with diabetes significantly increases the risk of progression towards ESRD [104]. Evidence also exists on a link between increased blood pressure and earlier stages of DN, such as MA [13]. A direct correlation between albumin excretion and increases in blood pressure is present, even when both these parameters are still within the normal range [105, 106]. However, the temporal relationship between MA and rises in blood pressure is not completely clear, given that different studies have often reached opposite conclusions [107–110]. On the one hand, increases in blood pressure have been found to precede MA and therefore to influence its development [108–110]. On the other hand, other studies have not supported this hypothesis and instead suggested that the two phenomena could occur together [107, 111]. The use of ambulatory blood pressure monitoring has allowed the identification of early alterations in blood pressure associated with future risk of MA

In patients with childhood-onset T1D MA often develops during puberty [121]. Puberty is characterized by many physiological changes, involving both hormonal and metabolic processes [122]. These factors together with psychological issues are frequently responsible of a poor metabolic control [122]. However, in addition to poor glycemic control, other changes occurring during puberty can contribute to the risk of developing MA [41]. Changes in sex hormones and in the GH-IGF axis have been shown to play an important role in this context [122]. These changes can interact with the diabetic milieu and the genetic background and contribute to the risk of developing DN and other vascular complications of T1D. The higher testosterone levels and free androgen index found in adolescent girls with MA when compared with matched controls without MA [123] could contribute to renal disease and also to the female predominance of this complication during puberty [20, 41, 123].

Diabetic Nephropathy in Children

Puberty is generally associated with a decrease in insulin sensitivity, which reaches a peak at stages 3 and 4 [124, 125]. Adolescents with T1D are more insulin resistant when compared with healthy controls [122], and this has mainly been attributed to the effect of increased GH. Circulating GH levels are increased in adolescents with T1D, whereas circulating IGF-1 levels are decreased, due to reduced portal insulin and consequent lack of effect of insulin on the expression of GH receptors in the liver [61, 62]. In contrast, as the expression of GH receptors seems to be insulin independent in other peripheral organs and tissues, such as the kidney, an increased local production of IGF-1 with an associated paracrine action could be implicated in renal disease [61, 62]. In cross-sectional studies, these high renal levels of IGF-1 have been associated with the development of DN [126]. Increased urinary GH and IGF-1 levels have been found in adolescents with T1D and correlated with albumin excretion [126]. In addition, increased urinary GH has been related to increased renal size, which in turn is a risk factor for MA [126].

Age at Diagnosis and Duration of Diabetes Duration of diabetes is another major factor associated with risk of complications [127]. In children, the relationship between diabetes duration and risk of MA has been found in some studies [30, 37, 41], but not conﬁrmed in others [28]. The role of prepubertal duration of diabetes has been the object of a wide discussion, generated by discordant results emerged from different studies. Although in some studies [30, 39, 128, 129] the risk of developing MA was higher in children with onset of diabetes at or after puberty, suggesting that prepubertal duration was not a main determinant, other studies have underlined the contribution of prepubertal duration to the risk of developing MA [130–133]. Children with onset of diabetes before the age of 5 years may have a delayed onset of complications, but after puberty there is an acceleration in their

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development [41, 134]. Furthermore, some children with an early prepubertal onset of diabetes can also develop MA before puberty [41].

Genetic Factors Epidemiological and family-based studies support the role of genetic factors in its pathogenesis. The observation that only 30–50 % of subjects with T1D are at risk for DN along with that related to the increasing prevalence of DN during the first 20 years after diagnosis, followed by a plateau [135], suggests that only a subset of patients is really susceptible to this complication. The DCCT and other studies have shown a familial cluster of DN, with a 2.3 increased risk of developing nephropathy for siblings of a proband with DN when compared to siblings of a proband without DN [136]. A family history of hypertension has also been shown to be a risk factor for developing DN [137]. Parents of patients developing DN have higher blood pressure when compared to parents of subjects free of this complication [138–140], and the risk seems to be increased by three- to fourfold. In addition, a family history of dyslipidemia, insulin resistance, type 2 diabetes, or a cluster of these cardiovascular risk factors significantly increases the risk of DN [141, 142], suggesting also a role of cardiovascular genes in predisposing to this complication. DN appears to be a complex genetic traits, with the contribution of different genes and an effect of their interaction with environmental factors [143]. Several genes have been suggested as potential candidates in the pathogenesis of DN, but there is no evidence for a major effect of a single gene so far [143]. DN is the combination of albuminuria and reduced GFR, and it has been shown that both these two components are highly heritable traits and that they have a different genetic basis [143]. However, the results of genetic studies have been often conflicting, due to differences in the populations studied, to the small sample size, and also to differences in the definition of the trait analyzed [144]. Among the most common genes that have been investigated for their potential relationship with

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DN are those encoding for components of the renin-angiotensin system and mainly the angiotensin-converting enzyme (ACE) gene and the angiotensin receptor I gene. In particular, the insertion/deletion polymorphism in the ACE gene has been the object of intense investigations. However, as emerged from a meta-analysis, it appears to have a small effect on the risk for developing DN in European populations [145]. Polymorphisms in the ACE gene have been related also to differences in the response to treatment with ACE inhibitors (ACEI) [146], thus suggesting the importance of future pharmacogenomic approaches in this area. Other candidate genes have been those encoding lipoproteins (in particular apolipoprotein E), aldose reductase, and heparan sulfate [147]. In addition, as it is well known that inflammation, glycation, and oxidation pathways as well as growth factors play an important role in the development of vascular complications, other possible candidate genes might be those encoding for components of these systems [147]. A genome-wide association study (GWAS) in adults with T1D from the Genetics of Kidneys in Diabetes (GoKinD) cohort has identified 11 single nucleotide polymorphisms (SNPs) in 4 chromosomal regional associated with advanced stages of DN [148]. Two of these SNPs, located near the FRMD3 and CARS loci, and which were shown to be expressed in the human kidney, were replicated in the DCCT/EDIC cohort, therefore emerging as likely candidate variants influencing DN susceptibility [148]. A more recent GWAS in adults and youth with T1D has reported some evidence of a potential association between variants in the GLRA3 gene, encoding the α-3 subunit of the neuronal glycine receptor (a ligand-gated chloride channel) and albuminuria [149]. However, further studies are required to replicate these findings in other populations and to clarify the function of these genetic variants.

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study in young individuals with T1D, smoking was associated with 2.8-fold increased risk of MA, whereas smoking cessation caused a significant improvement in AER [152]. The link between smoking and DN can be related to an increased oxidant burden caused by cigarette smoking [153]. In addition, as smokers have also higher blood pressure when compared to nonsmokers [154], this can represent an additional connection between smoking and the risk of developing DN.

Diet A high-protein intake has been suggested as a potential risk factor for the development of DN, with a normalization of GFR associated with a reduction of protein intake [155, 156]. It seems that animal proteins exert a stronger effect than vegetable proteins [157], whereas a high intake of fish proteins has emerged as a factor able to reduce the risk of DN [158]. The exact mechanisms explaining the association between protein intake and DN are not completely clear, although glucagon, prostaglandin, and the renin-angiotensin system have been suggested as potential mediators [157, 159]. Diet can be a source of AGEs, which are key players in the pathogenesis of DN. In the context of diabetes, AGEs are mainly produced endogenously as a result of hyperglycemia [160]; however, specific foods and modes of cooking can contribute to the AGE load [161]. Other factors investigated in relation to DN are fat, minerals, vitamins, and fibers [162–164]. In particular, as DN is associated with an increased oxidant burden, the potential effect of treatment with antioxidants has been investigated, but the results have been inconclusive [165–167].

Other Factors Smoking Smoking is an independent risk factor for the development and progression of DN in adults with diabetes [150, 151]. In a large prospective

Recently, it has been shown that in adolescents with T1D, clinical markers of insulin resistance, such as body mass index, are associated with the development of MA, in addition to glycemic control [168].

Diabetic Nephropathy in Children

Another factor that has been related to MA is low birth weight [169]. Intrauterine growth retardation might lead to reduced nephron number and decreased renal functional reserve, with increased susceptibility to renal disease in response to other environmental factors [169]. This theory might also explain the association between short stature and risk of DN [169, 170] as well as the relationship between impaired growth during puberty and risk of MA [171]. However, no association has been found between birth weight or gestational age and MA in young people with T1D [137].

Screening and Diagnosis Urinary Albumin Excretion Measurement of albumin excretion is the basis for the diagnosis of DN [15] (Table 2). MA is the earliest detectable marker of DN and represents an important risk factor for the development of DN and cardiovascular disease [172]. MA is not only a phenomenon related to renal damage but is associated with a more generalized sieving of albumin from the blood bed, due to a general endothelial dysfunction [173]. Screening for MA can be performed in three ways: (1) 24-h collection, (2) timed collection (e.g., overnight), and (3) albumin-creatinine ratio (ACR) on a spot urinary sample [174]. 24-h or timed urine collections are often difﬁcult to be performed, particularly in children, with lack of accuracy in this age group. Therefore, the easiest way is the assessment of the ACR in a spot urine, Table 2 Screening recommendations based on the International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines Screening recommendation for microalbuminuria Annual assessment of albumin excretion from age 10 or at onset of puberty if this is earlier, after 2 to 5 years’ diabetes duration Method: urinary albumin-creatinine ratio or ﬁrst morning albumin concentration Exclude other causes of increased albumin excretion: Strenuous exercise, orthostatic proteinuria, hypertension, acute febrile illnesses, smoking, urinary infections, nephritis, menstruation

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preferably using the first voided urine in the morning, in order to avoid bias related to the known diurnal variation in albumin excretion. The correct interpretation of albumin excretion requires that other factors and conditions which could influence it are excluded. Exercise, urinary tract infections, acute febrile illness, immunoglobulin A or other forms of nephritis, marked hypertension, and menstrual cycle in female can all cause transient increase in albumin excretion. Given that the intraindividual daily variation in albumin excretion may fluctuate by 40–50 %, multiple measurements of albumin excretion are required [174]. The definition of MA can be (1) albumin excretion rate between 20 and 200 μg/min or 30–300 mg in 24-h urine collection; (2) ACR 2.5–25 mg/mmol in males or 3.5–25 mg/mmol in females, or 30 μg/mg for either gender; and (3) albumin concentration 30–300 mg/l in early morning urine sample [174]. Persistent MA is defined as 2 out of 3 abnormal samples collected over a period of 3–6 months [174]. Values above the upper limit for MA definition are diagnostic of macroalbuminuria or overt nephropathy. Based on the recent International Society for Pediatric and Adolescent Diabetes guidelines, screening should be performed and should start from 10 years of age, or at onset of puberty if this is earlier, with 2–5-year diabetes duration [175].

Prevention and Treatment Intensive Blood Glucose Control The DCCT and the EDIC studies have provided strong evidence for the important role of good glycemic control for the reduction of risk of micro- and macrovascular complications in subjects with T1D, including also adolescents [99, 101, 102]. In the adolescent cohort of the DCCT, the beneﬁcial effects on complications were obtained, even though the mean HbA1c was signiﬁcantly higher, by about 1 %, when compared to the adult cohort [101]. This underlines an important issue in achieving a good metabolic control during puberty. Psychological

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issues, together with the effect of the physiological insulin resistance [124, 125] that occurs during puberty and the numerous changes in the hormonal milieu [122], give rise to several problems in managing adolescents with T1D [122]. Similarly to the DCCT results, other studies have shown the difﬁculties in achieving a good glycemic control and avoiding in the meantime the risk of episodes of hypoglycemia and weight gain [176]. The issue of weight gain is of particular relevance for adolescent girls, who often omit their insulin injection in order to avoid overweight [177]. Therefore, other strategies need to be implemented to improve glycemic control, particularly during adolescence.

Blood Pressure Control In adults with T1D and MA, treatment with ACEI or angiotensin receptor blockers (ARBs) is recommended based on the evidence of a positive effect in reducing the rate of progression and also in promoting regression of MA [13]. A beneficial effect of ACEI has been shown in microalbuminuric normotensive patients, where ACE inhibition can arrest the increase in or even reduce AER [178]. Furthermore, in patients with diabetes but with albumin excretion within the normal range, ACEI have been proven to be effective in reducing the risk of developing MA [105]. This effect appears to be independent of baseline blood pressure, renal function, and type of diabetes [179]. A recent systematic review and meta-analysis has shown that in subjects with diabetes, only ACEI can prevent the doubling of serum creatinine compared to placebo [180]. In addition, in placebo-controlled studies, only ACEI (at the maximum tolerable dose) were found to significantly reduce the risk of all-cause mortality [181]. However, there is no guidance for the use of ACEI or ARBs in the pediatric population in the context of MA. In fact, these drugs have been approved and used for the treatment of hypertension, but there is no indication for MA. Few studies have been performed and confirmed the likely efficacy of ACEI in adolescents with MA, but

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there have been no formal randomized controlled trials (RCT) [182–185]. Overall these studies have shown that ACEI lead to a reduction in albumin excretion. However, it is difficult to draw definitive conclusions from these studies, and the issue of the potential long-term use of ACEI in individual with MA raises also the problem related to potential side effects of these drugs. A key safety issue related to the use of ACEI and ARBs is the potential risk of congenital malformation when used during pregnancy [186]. Therefore, when starting treatment with these drugs in adolescent girls, they need to be aware of this risk, and birth control measure needs to be recommended. The efficacy of ACEI in adolescents with T1D at risk for DN is currently being investigated by the multicenter Adolescent Diabetes Intervention Trial (AdDIT) [187]. The ADA recommends starting treatment with ACEI in the presence of persistent MA [188]. Similarly the recent ISPAD guidelines suggest using ACEI or ARB in the presence of persistent MA in order to prevent progression to proteinuria.

Management of Dyslipidemia Many large-scale interventional trials have demonstrated that treatment with statins, the most effective lipid-lowering drug class, significantly reduces the risk of coronary heart disease events and total mortality. People with diabetes and DN often present dyslipidemia, and statin therapy has been associated with a significant reduction in risk of macrovascular complications [189]. Statins have effects other than the reduction in cholesterol levels [190]. In fact, they have beneficial properties, such as inhibition of arterial smooth muscle cell proliferation, prevention of oxidation of LDL cholesterol, plaque stabilization, effects on macrophages, improvement of endothelial dysfunction, and anti-inflammatory and antithrombotic effects [190]. Abnormal lipid profiles are often detected in adolescents with T1D [117, 191, 192], and they have been associated with endothelial dysfunction and MA [193]. However, there

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is no consensus on the role of statin treatment in this age group mainly because no RCT has been conducted. Management of dyslipidemia in pediatric patients relies on the results of trials conducted in adults [194] and in children with familial hypercholesterolemia [195–197]. The efﬁcacy of statins in adolescents with T1D at risk for DN is currently being investigated by the multicenter trial AdDIT [187].

Diet Intervention and Smoking Cessation A low-protein diet seems to reduce the increase in albumin excretion rate and the decline in GFR in adults with type 1 diabetes. A meta-analysis of studies investigating the effect of protein intake has shown that a diet restriction to 0.5–0.8 g/kg/ day reduces the risk of progression of DN [198]. However, there are no speciﬁc data for children and adolescents, where generally a minimum of protein intake of 1 g/kg is sufﬁcient for normal growth, but it is not clear whether this reduces the risk of DN [199]. As smoking is common among adolescents with T1D [200] and it is related to the development of DN [150], it is important to discourage young people from smoking as early as possible.

New Potential Therapeutic Strategies New potential therapeutic possibilities for the treatment of DN are emerging, and they include drugs targeting speciﬁc pathways implicated in the pathogenesis of DN (inhibitors of advanced glycation, PKC inhibitors, glycosaminoglycans) [84, 201, 202]. However, up to now, there are few experimental data on these new potential treatments and limited information derived from studies in humans. Therefore, future studies are required for a better evaluation of these drugs as well as for the development of new therapies, which could target other speciﬁc metabolic or hemodynamic pathways implicated in the pathogenesis of DN.

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Renal Involvement in Youth with Type 2 Diabetes Microvascular complications, such as nephropathy, can also occur in patients with onset of T2D during adolescence [203]. Although there are fewer studies on T2D-related than T1D-related microvascular complications, it seems that there are some differences between the two forms of diabetes. In particular, vascular complications occur earlier in patients with T2D than in those with T1D, and early signs of complications can be detected already at T2D onset or soon after [11, 12]. The early appearance of complications in the context of T2D is due to the fact that T2D is characterized by a long “silent” period before diagnosis is made [203]. Overt T2D is generally preceded by a phase of insulin resistance/ hyperinsulinemia and impaired glucose tolerance, conditions known to be able to induce endothelial dysfunction and vascular damage [203]. T2D mainly occurs in obese adolescents, and the typical poor glycemic control of adolescence, due to poor adherence to therapy, can also contribute to the high risk of developing vascular complications [204]. In addition, adolescents with T2D have a greater prevalence of risk factors for diabetic complications, such as dyslipidemia, hypertension, and insulin resistance [205, 206]. Several studies have shown that the prevalence of MA is higher in T2D than in T1D youth; its onset is more rapid, and it is often detectable at the time of diagnosis [203]. In addition, whereas, at least among some populations, the incidence of nephropathy among T1D patients has declined during the past decades, this is not the case for T2D [207]. Among Pima Indian youth with T2D, MA was detected in 22 % of the population, already at the time of diagnosis, and this prevalence increased up to 60 % after 10-year diabetes duration. A study performed in American youth found MA in 40 % of the study population after a diabetes duration of 1.5 years [208]. In a more recent study, Eppens et al. reported a prevalence of microalbuminuria of 7 % at the time of diagnosis, and this prevalence rose to 28 % during a follow-up period of 3 years [209]. Recent data

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from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study highlight that youth-onset T2D and its complications may be much more aggressive and treatment resistant than its adult counterpart. In the TODAY study, MA was found in 6.3 % of adolescents with T2D at baseline and rose to 16.6 % by end of study, independently of treatment [12]. A longitudinal study evaluating renal outcomes and overall survival in youth with T2D, with a prevalence of MA of 26.9 % and of macroalbuminuria of 4.7 % [210], reported that they have a fourfold increased risk of renal failure when compared with youth with T1D [210]. In addition, youth-onset T2D appears to be more aggressive than adult-onset T2D, as supported by the ﬁnding that the former group has a ﬁvefold increased risk of ESRD than the latter one [210]. This appears to be related to the longer duration of the disease in the youth-onset T2D. These data are clearly alarming and highlight the need of prompt interventions to prevent the onset of T2D and related complications. Factors which have been associated with the development of nephropathy in youth with T2D are similar to those in youth with T1D and include high HbA1c, duration of the disease, hypertension, and dyslipidemia [11, 12]. Treatment and preventive strategies are also similar to T1D and rely on good glycemic control, treatment of hypertension, dyslipidemia, and other associated comorbidities. One important point is that screening for microalbuminuria should be started already at the time of diagnosis of T2D.

Conclusions DN represents a serious complication of childhood-onset diabetes associated with a significant morbidity due to the progressive loss in renal function and the associated risk for cardiovascular disease. Even though kidney failure and overt nephropathy are not common in children and adolescents, important structural and functional alterations at the renal level occur already during childhood and accelerate during puberty. Several risk factors have been associated with the

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development of DN, but a lot still needs to be clariﬁed in order to develop better preventive and therapeutic strategies, which could reduce the burden associated with DN and therefore improve the prognosis of young people with diabetes.

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M. Marcovecchio and F. Chiarelli 204. Dean HJ, Sellers EA. Comorbidities and microvascular complications of type 2 diabetes in children and adolescents. Pediatr Diabetes. 2007;8 Suppl 9:35–41. 205. Rodriguez BL, Dabelea D, Liese AD, Fujimoto W, Waitzfelder B, Liu L, et al. Prevalence and correlates of elevated blood pressure in youth with diabetes mellitus: the SEARCH for diabetes in youth study. J Pediatr. 2010;157(2):245–51. 206. Kershnar AK, Daniels SR, Imperatore G, Palla SL, Petitti DB, Pettitt DJ, et al. Lipid abnormalities are prevalent in youth with type 1 and type 2 diabetes: the SEARCH for Diabetes in Youth Study. J Pediatr. 2006;149(3):314–9. 207. Yokoyama H, Okudaira M, Otani T, Sato A, Miura J, Takaike H, et al. Higher incidence of diabetic nephropathy in type 2 than in type 1 diabetes in early-onset diabetes in Japan. Kidney Int. 2000;58(1):302–11. 208. Ettinger LM, Freeman K, DiMartino-Nardi JR, Flynn JT. Microalbuminuria and abnormal ambulatory blood pressure in adolescents with type 2 diabetes mellitus. J Pediatr. 2005;147(1):67–73. 209. Eppens MC, Craig ME, Cusumano J, Hing S, Chan AK, Howard NJ, et al. Prevalence of diabetes complications in adolescents with type 2 compared with type 1 diabetes. Diabetes Care. 2006;29(6): 1300–6. 210. Pavkov ME, Bennett PH, Knowler WC, Krakoff J, Sievers ML, Nelson RG. Effect of youth-onset type 2 diabetes mellitus on incidence of end-stage renal disease and mortality in young and middle-aged Pima Indians. JAMA. 2006;296(4):421–6.

Renal Manifestations of Metabolic Disorders in Children

Francesco Emma, William G. van’t Hoff, and Carlo Dionisi Vici

Contents

Hereditary Tyrosinemia Type 1 . . . . . . . . . . . . . . . . . . 1597

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1570

Lecithin Cholesterol Acyltransferase Deﬁciency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1597

Methylmalonic Acidemia . . . . . . . . . . . . . . . . . . . . . . . . . 1585 Renal Tubular and Glomerular Dysfunction . . . . . . . 1585 Management of End-Stage Renal Disease in Methylmalonic Acidemia . . . . . . . . . . . . . . . . . . . . . . . . 1586

Lysinuric Protein Intolerance . . . . . . . . . . . . . . . . . . . . 1598 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1598

Cobalamin Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1587 Glycogen Storage Diseases . . . . . . . . . . . . . . . . . . . . . . . . 1588 Clinical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1588 Glycogen Storage Disease Type I (GSD I) . . . . . . . . . 1588 Fanconi–Bickel Syndrome . . . . . . . . . . . . . . . . . . . . . . . . 1589 Mitochondrial Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 1590 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1590 Renal Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1591 Congenital Disorders of Glycosylation . . . . . . . . . . 1592 Disorders of Uric Acid and Purine Metabolism and Transport . . . . . . . . . . . . . . . . . . . . . . . Disorders of Purine Metabolism . . . . . . . . . . . . . . . . . . . Hyperuricosuria and Hypouricemia . . . . . . . . . . . . . . . . Familial Juvenile Hyperuricemic Nephropathy . . . .

1593 1593 1594 1595

Fabry Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1595

F. Emma (*) Division of Nephrology, Bambino Gesù Children’s Hospital – IRCCS, Rome, Italy e-mail: [emailprotected] W.G. van’t Hoff Great Ormond Street Hospital, London, UK e-mail: [emailprotected] C. Dionisi Vici Division of Metabolic Diseases, Bambino Gesù Children’s Hospital – IRCCS, Rome, Italy e-mail: [emailprotected] # Springer-Verlag Berlin Heidelberg 2016 E.D. Avner et al. (eds.), Pediatric Nephrology, DOI 10.1007/978-3-662-43596-0_46

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1570

Introduction While the majority of children with renal dysfunction have a structural, immunological, or infective disorder, some have a metabolic defect arising from an abnormality in the biochemical pathways of cell metabolism. Moreover, improved survival of patients with metabolic disorders has uncovered in many cases symptoms secondary to chronic renal lesions that were not apparent when these diseases where ﬁrst described (e.g., methylmalonic acidemia). Conversely, extrarenal manifestations have become apparent in other patients with metabolic diseases that during childhood manifest primarily with isolated renal or urological symptoms (e.g., nephropathic cystinosis). Pediatric nephrologists should always remain vigilant to the possibility of a metabolic disorder, especially when children have extrarenal symptoms. In general, the proximal renal tubule, which has a very high energy expenditure, is sensitive to metabolic disorders that interfere with ATP generation (e.g., respiratory chain defects). Tubulopathies of various forms can also be observed in diseases caused by mutations in solute carriers (e.g., Fanconi–Bickel syndrome). In other cases, the metabolic dysfunction manifests with nephrocalcinosis and/or urolithiasis, arising from defective reabsorption of a speciﬁc solute (e.g., cystine in cystinuria) or as a result of the urinary excretion of abnormally elevated plasma constituents (e.g., oxalate in primary hyperoxaluria). Tubular and tubulointerstitial lesions can also result from acute or chronic toxic insults to the tubular epithelium (e.g., myoglobinuria in fatty acid oxidation defects, methylmalonic acid in methylmalonic acidemia). In other cases, the metabolic disorder interferes with normal embryogenesis, resulting in congenital abnormalities of the kidneys and urinary tract (CAKUT) or in polycystic kidney disease (e.g., Zellweger’s syndrome). Finally, metabolic defects can cause glomerular lesions as a consequence of abnormal deposition of storage material (e.g., Fabry disease, glycogen storage diseases), defects in the synthesis of structural glomerular components (e.g.,

F. Emma et al.

congenital disorder of glycosylation type 1), or toxic damage to podocytes or endothelial cells (e.g., nephrotic syndrome in respiratory chain defects, hemolytic uremic syndrome in cobalamin C and MHTFR deficiencies). In many metabolic disorders, substrate accumulation or enzyme deficiency can be documented in the kidney but without evidence of renal dysfunction (e.g., some lysosomal storage disorders). Sometimes, the disease only manifests as changes in urine color (e.g., black in alkaptonuria, green–blue in Harnup disease) or odor (e.g., maple syrup disease, isovaleric acidemia). In other cases, renal involvement is secondary to damage of other organs; for example, renal failure can develop as a result of acute rhabdomyolysis and myoglobinuria in Tarui disease (glycogen storage disease type VII) or in peroxisomal defects. This review concentrates on those disorders in which there is a clear renal functional or structural abnormality. Disorders of the gonads and adrenal glands can produce renal symptoms and urogenital malformations but are covered elsewhere in the textbook. Likewise, renal involvement is a major feature of specific metabolic disorders (e.g., primary hyperoxaluria) that are described in detail in separate sections of the textbook and are only briefly mentioned here. Owing to the complexity of metabolic pathways, a large number of defects have been characterized to date at the molecular level. This has generated the need to develop systematic classifications of metabolic diseases, a task that was undertaken by the Society for the Study of Inborn Errors of Metabolism (SSIEM), among others. The SSIEM taxonomy categorizes diseases based on the principle that defects belonging to the same biological pathway are likely to have similar clinical features and are often treated using similar approaches. In a spirit of consistency, the authors have chosen to use the SSIEM classification in this chapter and to provide the OMIM reference ID for each disease (Table 1). Given the high number of metabolic disorders that can have renal or urological symptoms, many diseases are only presented in tabular form;

OMIM Disease Gene Main features Disorders of amino acid and peptide metabolism Cystinosis 219800 Failure to thrive, vomiting, rickets, often CTNS blond - fair hair, corneal cystine crystals, multisystem involvement Tyrosinaemia type 1 276700 Hepatomegaly, acute/ chronic liver disease, FAH hepatocellular carcinoma, rickets, neurological crises Lysinuric protein intolerance 222700 Failure to thrive, hepatosplenomegaly SLC7A7 vomiting, refusal of protein-rich foods, interstitial pneumopathy/alveolar proteinosis, immune dysfunction, encephalopathy Cystinuria 220100 SLC3A1 SLC7A9 Propionic academia 606054 Vomiting, hypotonia, failure to thrive, PCCA hyperammonemic PCCB coma, encephalopathy, cardiomyopathy

Table 1 Metabolic diseases with renal or urological involvement

Fanconi syndrome chronic renal failure

Tubulopathy chronic renal failure hypertension immune mediated glomerulonephritis tubulo-interstitial nephritis

Chronic renal failure (adult)

Calculi

Tubular

Fanconi syndrome chronic renal failure

Renal features

Glomerular

Tubulointerstitial

Primary renal involvement

Stones NC CAKUT

(continued)

HUS Infarction

50 Renal Manifestations of Metabolic Disorders in Children 1571

Rash, dysmorphism, anemia, splenomegaly, recurrent infections, systemic lupus erythematosus Ochronotic pigmentation of cartilage and collagen, arthritis Ectopia lentis, skeletal abnormalities, Marfanlike features, neuropsychiatric symptoms, thromboembolism Mental retardation ataxia, retinopathy

Main features Vomiting, hypotonia, failure to thrive, hyperammonemic coma, encephalopathy, cardiomyopathy

266130 GSS Disorders of fatty acid and ketone body metabolism Disease OMIM Main features Gene Carnitine palmitoyl transferase 255120 Fasting/illness leading deﬁciency 1 to encephalopathy, CPT1A seizures, hepatomegaly

236200 CBS

Homocystinuria

Oxoprolinuria

203500 HGD

OMIM Gene 251000 MUT 251100 MMAA 251110 MMAB 170100 PEPD

Alkaptonuria

Prolidase deﬁciency

Disease Methylmalonic academia

Table 1 (continued)

Renal tubular acidosis

Renal features

Renal colic, urolithiasis

Renal infarction hypertension

Urine turns black on standing if alkaline calculi (adults)

Lupus nephritis

Renal features Tubulopathy tubulointerstitial changes chronic renal failure

Tubular

Tubular +

Glomer

Glomerular

Tubulointerstitial

Tubulointerstitial +

Primary renal involvement

Stones NC

CAKUT

HUS Infarction

1572 F. Emma et al.

CPT2 201475 VLCAD 609016 HADHA 609015 HADHB

608836

Glycogen storage disease type 1a

232200 G6PC

Disorders of carbohydrate metabolism Galactosemia 230400 GALT

Fatty acid oxidation disorders

Carnitine palmitoyl transferase deﬁciency 2

Vomiting, diarrhea, poor growth, jaundice, liver disease, hypotonia, cataracts Hepatomegaly, hypoglycemia, poor growth, lactic acidosis

Liver disease (steatosis, hypoketotic hypoglycemia, hepatomegaly), acute neonatal illness, cardiomyopathy, myopathy, encephalopathy retinopathy, neuropathy, hypoparathyroidism

Microcephaly, cataract, cardiomyopathy, hepatomegaly, myopathy

Tubular dysfunction, nephrocalcinosis, Fanconi syndrome, hypercalciuria, hyperﬁltration, rarely distal tubular acidosis, renal calculi, proteinuria, focal segmental glomerulosclerosis, chronic renal failure

Fanconi syndrome

Enlarged polycystic kidneys, Dysplastic renal parenchyma Hydronephrosis Lipid accumulation in kidney, especially in proximal convoluted tubules Renal insufﬁciency Renal tubulopathy, Myoglobinuria acute renal failure

(continued)

50 Renal Manifestations of Metabolic Disorders in Children 1573

227810 SLC2A2

229600 ALDOB

223000 LCT

606824 SGLUT1

606003 TALDO

Hereditary fructose intolerance

Congenital lactase deﬁciency

Glucose-galactose malabsorption

Transaldolase deﬁciency

OMIM Gene 232220 SLC37A4

Fanconi Bickel syndrome

Disease Glycogen storage disease type 1b

Table 1 (continued)

Skin laxity, hepatosplenomegaly, Liver failure, cirrhosis. Neonatal multi-system form (hydrops)

Acute onset after fructose ingestion: poor feeding, vomiting, poor growth, hypoglycemia, liver failure, aversion to sweets and fruit Watery diarrhea, metabolic acidosis, poor weight gain Watery diarrhea

Main features Hepatomegaly, hypoglycemia, poor growth, lactic acidosis, neutropenia, inﬂammatory bowel disease Hepatomegaly, rickets, poor growth, hypoglycemia

Nephrocalcinosis, hypercalciuria, hypercalcemia Calculi, nephrocalcinosis, hypercalcemia Undeﬁned tubulopathy Genitourinary malformations Nephrocalcinosis, hypertension

Fanconi syndrome, hyperﬁltration, “diabetic-like” nephropathy Fanconi syndrome, rarely acute renal failure

Renal features Focal segmental glomerulosclerosis, hyperﬁltration

Tubular

Glomerular +

Tubulointerstitial

Primary renal involvement

Stones NC

CAKUT

HUS Infarction

1574 F. Emma et al.

GRHPR 613616 HOGA1 233100 SLC5A2 232600 PYGM

260000

259900 AGXT

530000 Large mtDNA deletion 540000 m.3243A>G m.3271T>C

520000 m.3243A>G m.14709T>C m.8396A>G

Kearns Sayre syndrome

MIDD

MELAS

266150 PC

Pyruvate carboxylase deﬁciency (some forms)

Disorders of energy metabolism GRACILE syndrome 603358 BCS1L

McArdle disease

Renal glycosuria

Primary Hyperoxaluria Types 1,2,3

Stroke-like episodes, encephalopathy, deafness, macular dystrophy, myopathy, diabetes mellitus Maternal inherited diabetes mellitus, deafness

Severe growth retardation, cholestasis, liver hemosiderosis Metabolic acidosis, neurological symptoms, hepatomegaly Ophthalmoplegia, retinal degeneration, heart block, ataxia, hyperparathyroidism

Recurrent rabdomyolisis, muscle cramps, weakness, exercise intolerance,

In severe cases PH1: Optic atrophy Retinopathy Heart block Arterial spasm Pathologic fractures Acrocyanosis Peripheral neuropathy

Focal segmental glomerulosclerosis

Bartter-like syndrome, hypomagnesemia

Tubular acidosis, renal impairment

Fanconi syndrome

Myoglobinuria, oligo/ anuric acute renal failure

Glycosuria

Calculi/ nephrocalcinosis Acute/chronic renal failure

(continued)

50 Renal Manifestations of Metabolic Disorders in Children 1575

220110 Multiple

611719 MRPS22

Combined oxidative phosphorylation deﬁciency 5

557000 Large mtDNA deletion 124000 BCS1L

607426 COQ2 614650 COQ6 614654 COQ9 614652 PDDS2 604712 RRM2B

OMIM Gene 614052 TMEM70

Complex IV deﬁciency

Complex III deﬁciency

Pearson syndrome

Mitochondrial ribonucleotide sub.2

Coenzyme Q10 deﬁciencyPDSS2

Coenzyme Q10 deﬁciencyCoQ9

Coenzyme Q10 deﬁciencyCoQ6

Disease Neonatal mitochondrial encephalopathy, cardiomyopathy Coenzyme Q10 deﬁciencyCoQ2

Table 1 (continued)

Encephalopathy, liver dysfunction, failure to thrive Encephalopathy, Leigh syndrome, epilepsy, cardiomyopathy, liver failure, myopathy, failure to thrive Cardiomyopathy, hypotonia, oedema, ascitis

Dysmyelination, seizures, failure to thrive, ophtalmoplegia, ptosis, myopathy Pancytopenia, pancreatic dysfunction

Leigh syndrome, blindness

Encephalomyopathy, cardiomyopathy

Deafness, seizures

Encephalomyopathy, liver failure, deafness

Main features Hypospadia, criptorchidism

Tubulopathy

Chronic renal failure

Tubulopathy

Proximal renal tubulopathy

Tubulopathy

Steroid resistant nephrotic syndrome

Tubulopathy

Steroid resistant nephrotic syndrome

Renal features Genito-urinary malformations

Tubular

Glomerular

Tubulointerstitial

Primary renal involvement Stones NC CAKUT +

HUS Infarction

1576 F. Emma et al.

162000 UMOD 614723 APRT

Familial hyperuricemic nephropathy

220150 SLC22A12

258900 UMPS

Hereditary renal hypouricemia

Hereditary orotic aciduria

Adenine phosphoribosyltransferase deﬁciency

300322 HPRT1

Lesch Nyhan syndrome Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) deﬁciency

Megaloblastic anemia, immunodeﬁciency, failure to thrive

Lesch Nyhan syndrome (complete deﬁciency): developmental delay, choreo-athetoid movements, self mutilation Partial deﬁciency: gouty arthritis Gout

IUGR, encephalopathy, seizures, deafness, ophtalmoplegia, multiorgan failure mtDNA depletion 8a 612075 Encephalopathy, seizures, impaired RRM2B vision, failure to thrive Disorders in the metabolisms of purines, pyrimidines and nucleotides SCID -adenosine deaminase 102700 Severe combined deﬁciency immunodeﬁciency ADA

612073 SUCLG1

mtDNA depletion 5

Proximal tubulopathy

Calculi 2,8-dihydroxyadenine (2,8-DHA) Acute/ chronic renal failure Urolithiasis (urate/ calcium oxalate), hyperuricemia, hypercalciuria, Uric acid nephropathy/ acute renal failure Obstructive uropathy orotic acid crystalluria, hematuria, urolithiasis

Gout, urolithiasis, chronic renal failure

Transient renal tubular acidosis, proteinuria, mesangial sclerosis Acute/chronic renal failure

Tubulopathy

(continued)

50 Renal Manifestations of Metabolic Disorders in Children 1577

300661 PRPS1

OMIM Gene 278300 607633 XDH 603592 XDH-AO 305920

302960 EBP

308050 NSDHL

Conradi Hunnerman syndrome

CHILD syndrome

Disorders of the metabolism of sterols Smith-Lemli-Opitz syndrome 270400 DHCR7

Phosphoribosylpyrophosphate synthetase superactivity

Glutamyl ribose-5-phosphate glycoproteinosis

Xanthinuria type 2

Disease Xanthinuria type 1

Table 1 (continued)

Hemidysplasia, ichythyosiform erythrodema, limb defects

Facial dysmorphism, hypotonia, cataract, mental retardation, abnormalities of limbs, brain, genitalia Dysmorphic features, skeletal dysplasia, cataract, ichthyosis, mental retardation

Coarse facies, optic atrophy, muscle wasting, failure to thrive, seizures, neurological deterioration Neurological deterioration, deafness, dysmorphic features, gout

Main features Myopathy, arthropathy

Female renal dysgenesis/hypoplasia Male hypospadia criptorchidism Renal dysgenesis/ hypoplasia

Cystic dysplasia, hypoplasia, agenesis, duplication, PUJ obstruction, VUR

Uric acid stones

Proteinuria, chronic renal failure

Renal cysts (rare) Acute renal failure

Renal features Calculi, acute renal failure

Tubular

Glomerular

Tubulointerstitial

Primary renal involvement

Stones NC +

CAKUT

HUS Infarction

1578 F. Emma et al.

607330 SC5DL

201750 POR

Latosterolosis

Antley-Bixler syndrome with genital anomalies

611771 APOE

Congenital disorders of glycosylation Congenital disorder of 212065 glycosylation type 1a PMM2

Lipoprotein glomerulopathy

Disorders of lipid and lipoprotein metabolism Lecithin: cholesterol 245900 acyltransferase deﬁciency LCAT

602398 DHCR24

Desmosterolosis

Ataxia, olivopontocerebellar hypoplasia, peripheral neuropathy, strabismus, inverted nipples, hepatomegaly, ‘Orange peel’ skin, abnormal subcutaneous fat tissue distribution, mental retardation, primary ovarian failure, prolonged prothrombin time

Elevated apolipoprotein E

Corneal lipid deposits Corneal opacities

Dysmorphic features, developmental delay, skeletal dysplasia, Arthrogryposis Osteosclerosis Dysmorphic features, cataract, hepatic cholestasis, hexadactily, mental retardation Dysmorphic features, skeletal dysplasia,

Proteinuria (congenital nephrotic syndrome), microcysts

Proteinuria, hematuria, renal failure Nephrotic syndrome (resistant to treatment), hematuria, hypertension, renal failure. Glomerular lipoprotein thrombi

Hydronephrosis, renal dysgenesis/hypoplasia Ambigous genitalia

Hypospadia

Renal dysgenesis/ hypoplasia Ambigous genitalia

(continued)

50 Renal Manifestations of Metabolic Disorders in Children 1579

261540 B3GALTL

603585 SLC35A1

608779 COG7

Congenital disorder of glycosylation type 1l

B3GALTL – Congenital disorder of glycosylation (Peter-plus syndrome)

Congenital disorder of glycosylation type 2f

Congenital disorder of glycosylation type 2e

301500 GLA

608776 ALG9

Disease Congenital disorder of glycosylation type 1h

Lysosomal disorders Fabry’s disease

OMIM Gene 608104 ALG8

Table 1 (continued)

X-linked disorder, acroparesthesias, angiokeratoma, hypohidrosis, strokelike episodes, corneal, lens opacities, abdominal pain, angina, cardiomyopathy, cramps

Main features Intrauterine growth retardation, neonatal, ascites protein-losing enteropathy, cerebellar hypoplasia, hepatomegaly, cataract Brain atrophy, epilepsy, mental retardation, hepatosplenomegaly Dysmorphic features, developmental delay, short limb dwarﬁsm, cataract, coloboma, skeletal dysplasia Epilepsy, mental retardation, macrothrombocytopenia Microcephaly, epilepsy, developmental delay, hepatomealy, failure to thrive, ventricular septal defect Hyposthenuria, renal tubular acidosis, proteinuria, chronic renal failure Renal sinus parapelvic cysts, hyposthenuria,

Neurogenuc bladder, obstructive uropathy, renal tubulopathy

Proteinuria

Hydronephrosis Hydrourether, kidney/ ureteral duplication

Renal cysts

Renal features Renal cysts, tubulopathy

Tubular +

Glomerular

Tubulointerstitial +

Primary renal involvement Stones NC

CAKUT

HUS Infarction

1580 F. Emma et al.

256540

Galactosialidosis (early infantile form)

607014 IDUA

269920 SLC17A5

230800 GBA

254900 SCARB2/ LIMP2

Mucopolysaccharidosis type I (Hurler syndrome)

Infantile sialic acid storage disease

Gaucher’s disease

Action myoclonus renal failure syndrome

CTSA

250100 ARSA

Metachromatic leucodystrophy

Myoclonus, tremor, ataxia, horizontal saccades, dysphagia, no cognitive deterioration

Neurologic and intellectual regression, spasticity, ataxia, optic atrophy, leukodystrophy, incontinence Hydrops, edema, coarse facies, inguinal hernias, visceromegaly, spinal involvement, corneal and fundal abnormalities, cardiomyopathy, developmental delay, telangiectasias Coarse facies, corneal clouding, visceromergaly, dysostosis multiplex, developmental delay Hydrops, edema, dysmorphism, hepatosplenomegaly, hypotonia, poor growth, developmental delay Hepatosplenomegaly, hypersplenism Proteinuria, hematuria, acute glomerulonephritis, calculi Proteinuria, nephritic syndrome, focal segmental glomerulosclerosis

Proteinuria, nephrotic syndrome

Nephrotic syndrome, hypertension (due to aortic luminal narrowing)

Proteinuria, nephrotic syndrome Chronic renal failure

Renal tubular acidosis, mild aminoaciduria, mild renal impairment +

(continued)

50 Renal Manifestations of Metabolic Disorders in Children 1581

214100 PEX1 214110 PEX5 266510 PEX12

OMIM Gene Main features

Facial dysmorphism, enlarged fontanel, hypotonia, severe developmental delay, brain dyslasia, seizures, cataract, retinopathy, deafness, hepatomegaly, jaundice, hepatomegaly Disorders in the metabolism of vitamins and (non-protein) co-factors Imerslund-Grasbeck syndrome 261100 Malabsorption of vitamin B12, CUBN megaloblastic anemia, AMN peripheral neuropathy Cobalamin deficiencies cblC, 277400 Developmental delaty, cblD, cblF, cblJ (combined hydrocephalus, MMACHC methylmalonic aciduria and microcephaly, visual 277410 homocystinuria) impairment, C2orf25 nistagmous, 277380 dysmorphysms, LMBRD1 megaloblastic anemia, pancytopenia, 614857 cardiomyopathy, ABCD4 pulmonary hypertension, MTHDH deficiency 172460 Megaloblastic anemia, severe combined MTHFD1 immune deficiency

Disease Peroxisomal disorders Peroxisome biogenesis disorders – Zellweger’s spectrum disorders (including NALD, IRD)

Table 1 (continued)

Hemolytic uremic syndrome, glomerulopathy

Hemolytic uremic syndrome

Tubular

Low molecular weight proteinuria

Microcysts/large cortical cysts

Renal features

Glomerular

Tubulointerstitial

Primary renal involvement Stones NC

CAKUT

HUS Infarction

1582 F. Emma et al.

Acute intermittent porphyria

176000 HMBS

Disorders of porphyrin and heme metabolism Doss hepatic porphyria 612740 ALAD

259730 CA2

Carbonic anhydrase II deﬁciency (osteopetrosis with renal tubular acidosis)

Abdominal pain, constipation, vomiting, neurologic features, muscle pain Abdominal pain, constipation, acute episodes of neuropatic/ psychotic symptoms, neuropathy (usually after puberty)

Osteopetrosis, fractures, cerebral calciﬁcation, mental retardation, poor growth, hepatosplenomegaly

Rickets, developmental delay, hypercalcemia, craniosynostosis Disorders in the metabolism of trace elements and metals Wilson’s disease 277900 Liver disease, neurological symptoms, ATP7B Kayser-Fleischer rings, hemolytic anemia, cardiomyopathy Menke’s disease 309400 X-linked disorder, kinky hair, developmental ATP7A delay and regression, seizures, skin laxity and hypopigmentation, herniae, Molibdenum cofactor 252150 Severe developmental deﬁciency delay microcephaly, MOCS1 seizures, spasticity,

241500 ALPL

Hypophosphatasia (infantile form)

Urine may turn red/purple Acute or chronic renal failure, urinary retention, hypertension

Urine may turn red/purple Hypertension

Xanthine stones, Increased urinary xanthine, hypoxanthine, S-sulfocysteine Mixed type of RTA

Fanconi syndrome, proteinuria, rarely acute renal failure, distal RTA, hypercalciuria, calculi Bladder or ureteric diverticulae, stones, urinary infections, chronic renal failure

Hypercalciuria, nephrocalcinosis

(continued)

50 Renal Manifestations of Metabolic Disorders in Children 1583

Other disorders Blue diaper syndrome

Porphyria variegata

Disease Hereditary coproporphyria

Table 1 (continued)

211000

176200 PPOX HFE

OMIM Gene 121300 CPOX

Hypercalcemia

Main features Abdominal pain, constipation, acute episodes of neuropatic/ psychotic symptoms, neuropathy, photosensitivity, hemolytic anemia Abdominal pain, constipation, acute episodes of neuropatic/ psychotic symptoms Hypercalciuria, nephrocalcinosis Indicanuria, blue discoloration of urine

Hypertension

Renal features Hypertension

Tubular

Glomerular

Tubulointerstitial

Primary renal involvement

Stones NC

CAKUT

HUS Infarction

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Renal Manifestations of Metabolic Disorders in Children

extrarenal symptoms, which are present in the vast majority of cases, are also listed but are restricted to the most common features. For each disease, the prominent type of renal or urological manifestation is indicated; the reader should keep in mind, however, that in many disorders, different types of lesions can coexist.

Methylmalonic Acidemia Isolated methylmalonic acidemia (MMA) is an autosomal recessive organic acidemia, resulting from impaired metabolism of methylmalonylcoenzyme A. The disease represents one of the most common inborn errors of organic acid metabolism and is caused by defects in the activity of the enzyme methylmalonyl-coenzyme A mutase (MUT). This enzyme is part of the mitochondrial metabolic pathway allowing carbon skeletons derived from the metabolism of branched amino acids (50 %) and odd-chain fatty acids (30 %) or from the intestinal flora (20 %) to be converted into succinyl-coenzyme A ([1, 2]). Enzyme deficiency can be complete (mut0) or partial (mut-) or may be secondary to decreased synthesis of the MUT cofactor deoxyadenosylcobalamin. These latter forms of the disease are caused by mutations in enzymes involved in the biosynthesis of adenosylcobalamin from cobalamin (MMAA, MMAB) and are more likely to respond to vitamin B12, which is associated with better prognosis [3, 4]. Patients usually present in the neonatal period or early infancy with lethargy, vomiting, poor feeding, failure to thrive, and recurrent metabolic acidosis. Cobalamin-unresponsive patients with neonatal onset of symptoms and complete deficiency of the apoenzyme have a poor prognosis with a mortality of approximately 50 % within the first decade and have a significant incidence of neurological, cardiac, and renal manifestations [2, 4, 5]. Same patients present with severe neonatal hyperammoniemia, due to secondary inhibition of intermediary metabolism pathways by propionyl-coenzyme A and other related compounds [1]. A history of hyperammonemia at diagnosis correlates with poorer cognitive outcome [6].

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Renal Tubular and Glomerular Dysfunction From the renal standpoint, MMA causes a tubulopathy and chronic renal failure. Most patients have evidence of tubular dysfunction during childhood, which often becomes very profound during episodes of metabolic decompensation that are usually triggered by intercurrent infection, causing massive renal salt and bicarbonate losses. In a study of seven cobalamin-unresponsive patients, five had defects in urine concentration, two had impaired urine acidification, three had urine phosphate losses, and several had hyporeninemic hypoaldosteronism [7]. Development of chronic renal impairment has also been documented during childhood in cobalaminunresponsive MMA patients. Walter et al. documented low GFR in 8 of 12 studied children, 5 of whom had a GFR 1,000 higher than the reference values after 2 months. The patient experienced subsequent neurological complications [20]. Most likely, this is due to the very limited transport capacities of the blood–brain barrier for dicarboxylic acids including methylmalonate [21]. Patients who receive combined liver–kidney transplantation may have better metabolic control after the procedure than patients receiving isolated liver transplantation [22]. Preoperative hemodialysis is advocated to decrease methylmalonate levels and the risk of metabolic decompensation during the procedure [22], although recent experiences question the validity of this approach [23]. Overall, liver transplantation in MMA remains a procedure with a significant rate of short-term mortality and morbidity. While there have been successes, worryingly liver transplantation does not seem to protect from further neurological toxicity in the medium and long term [11, 19, 20, 22, 24]. There have also been reports of isolated renal transplant in MMA [25–29]. A 24-year-old patient demonstrated improved clinical and metabolic control after an isolated renal transplant, although she developed diabetes mellitus and suffered marked cyclosporin toxicity [29]. In another report, a 12-year-old boy received isolated kidney transplantation and showed a fourfold to eightfold decrease in serum methylmalonate 6 years after transplantation, allowing to increase his protein intake without further metabolic decompensation episodes [26]; his neurological status remained compromised. A favorable outcome 12 years after transplant with an improvement in urine methylmalonate excretion has been demonstrated in a 17-year-old patient after renal transplantation who subsequently underwent a successful pregnancy [30]. A similar good outcome was also reported in a 14-year-old girl with a 4-year follow-up. Of notice, the first patient had a mutmutation, the second had cblB-type MMA, while the latter two patients had cblA-type MMA, which are often associated with milder phenotypes. Brassier et al. have reported on four patients with mut0 MMA who received a kidney graft at a

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mean age of 7.9 years for repeated metabolic decompensations, three of which had chronic renal failure and one had normal renal function. Renal transplantation improved renal function in all patients with chronic renal failure and metabolic parameters in all four patients, allowing increasing protein intake. Plasma methylmalonate levels decrease on average sixfold but less than what is reported in liver transplantation and remained signiﬁcantly higher than normal levels. However, no acute metabolic decompensation was observed after a mean follow-up of 2.8 years. One patient died after developing hepatoblastoma and neurological complications, and a second patient experienced neurological impairment. Several other cases of renal transplantation in MMA have not been reported in the literature. Taken together, these data suggest that isolated kidney transplantation may provide partial enzyme replacement and could have a safer outcome at least in the short term compared to liver transplantation.

Cobalamin Defects Cobalamin is an essential cofactor in several metabolic pathways. Once entered into the cell, cobalamin is converted into two coenzymes, adenosylcobalamin in the mitochondria that is required for the metabolism of methylmalonate and methylcobalamin in the cytosol that is required for the metabolism of homocysteine. Genetic defects of the cobalamin pathway are autosomal recessive diseases characterized by MMA (impaired synthesis of adenosylcobalamin), homocystinuria (impaired synthesis of methylcobalamin), or both [2, 31]. Combined methylmalonic aciduria and homocystinuria (cblC type) is the most common inborn disorder of cobalamin metabolism. From the renal standpoint, hemolytic uremic syndrome (HUS) has been reported in patients with cobalamin C or with cobalamin G deﬁciencies, which cause defects in the biosynthesis of adenosylcobalamin and methylcobalamin [32–34] or in the activity of methionine synthase [35], respectively. Pulmonary hypertension can be

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observed in infants with cobalamin deficiencies [36]; therefore, defects of the cobalamin pathway should always be suspected when a child with pulmonary hypertension develops thrombotic microangiopathy [33, 35]. Patients with cobalamin C deficiency have defective function of the two enzymes dependent on these cofactors (methylmalonyl CoA mutase and N-methyl tetrahydrofolate: homocysteine methyltransferase). These children have homocystinuria, hypomethioninemia, and cystathioninuria in addition to methylmalonic aciduria. Most present in early infancy with poor feeding, failure to thrive, hypotonia, retinitis, respiratory distress, and cardiomyopathy. Investigation shows a megaloblastic anemia, pancytopenia, and liver dysfunction. Generally, the prognosis has been poor, but cases with milder phenotypes responding to hydroxycobalamin therapy have been reported [37]. Few cases are diagnosed later in older children who developed hypertension, proteinuria, and chronic renal impairment in association with FSGS or an unclassified glomerulopathy [34, 38–40]. A case of eculizumab-resistant HUS in an adult patient has also been described [41]. Patients with cobalamin G deficiency cannot convert homocysteine into methionine. In the absence of methionine synthase, they present with homocystinuria without MMA, low plasma methionine levels, and megaloblastic anemia. These patients usually develop symptoms in early infancy, which include in most cases variable degrees of neuromuscular degeneration. Labrune et al. have described one girl with pulmonary hypertension that developed HUS at the age of 19 months [31, 35]. Mechanisms underlying the development of HUS in these diseases are not well elucidated but are probably related to toxic damage of homocysteine and related compounds (including methylmalonate in cobalamin C defects) to endothelial cells [37, 39]. The genetic background also influences disease expression [24, 39]. A number of patients with defective absorption of the cobalamin–intrinsic factor (IF) complex (Imerslund–Grasbeck syndrome) have persistent proteinuria [42]. The cobalamin–IF complex

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binds to cubilin in the intestinal brush border. Cubulin expression at the cell surface requires the coexpression of amnionless and is not restricted to the intestine but is also present in the renal proximal tubule, where it interacts with megalin [43, 44]. The cubilin–megalin complex is responsible for receptor-mediated endocytosis of ﬁltered albumin and low–molecular weight proteins; thus, patients with Imerslund–Grasbeck syndrome in which the cubilin (CUB) or the amnionless (AMN) genes are defective present with albuminuria and low–molecular weight proteinuria [43]. Other inconstant manifestations include megaloblastic anemia, poor growth, neurological deterioration in adulthood, and premature atherosclerosis [45]. Recurrent urinary tract infections and urinary tract malformations have also been reported [45].

Glycogen Storage Diseases Clinical Glycogen storage diseases (GSD) are genetic disorders of the metabolism and regulation of glycogen. Two forms of GSD have signiﬁcant renal manifestations: GSD type 1 can lead to a tubulopathy and CKD, while Fanconi–Bickel syndrome presents with a characteristic renal disease.

Glycogen Storage Disease Type I (GSD I) Glycogen storage disease type I (GSD I) is transmitted in an autosomal recessive mode and is characterized by defects in the glucose-6-phosphatase complex, which is a key enzyme that converts glucose-6-phosphate into glucose and inorganic phosphate [46]. Most defects involve the catalytic unit, causing GSD Ia (80 %) or von Gierke disease, while defects in the glucose-6phosphate translocase cause GSD-Ib (20 %). Patients with GSD-I accumulate glycogen in the liver, kidney, and intestinal mucosa; they present with poor tolerance to fasting, hypoglycemia,

Renal Manifestations of Metabolic Disorders in Children

lactic acidosis, hypeuricemia, hyperlipidemia, growth retardation, and hepatomegaly; long-term complications include delayed puberty, hepatic adenomata, and renal disease [46]. In a majority of patients, the diagnosis is made after investigating a protruded abdomen caused by severe hepatomegaly. Life expectancy of patients has considerably improved with dietary management that allows achieving better metabolic control [47]. Chen and colleagues were among the first to draw attention to the complication of ESRD in older GSD-I patients [48]. In their 1988 review, a significant number of patients aged 13–47 years had renal dysfunction (proteinuria, hypertension, or chronic renal failure). Subsequent investigators have demonstrated renal tubular and glomerular abnormalities [49–53]. Ultrasonography shows renal enlargement secondary to glycogen deposition [54, 55]. The mechanisms of renal damage are not fully understood although there may be important comparisons with diabetic nephropathy [56]. Both diabetes mellitus and GSD-I involve increased flux through the pentose phosphate pathway, increasing triose phosphates and diacylglycerol and thereby stimulating protein kinase C and the renin–angiotensin system. Yiu demonstrated upregulation of angiotensin and increased oxidative stress in a mouse model of GSD Ia [57, 58]. These effects are directly related to kidney disease and not to systemic effects of liver dysfunction. Selective invalidation of the glucose-6-phosphatase gene in murine kidneys is sufficient to cause nephropathy [59]. These animals develop nephromegaly and renal accumulation of lipids (de novo lipogenesis), activate the renin–angiotensin system, and develop microalbuminuria [59].

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nephrolithiasis [47, 51, 53]. A Gitelman-like syndrome of hypomagnesemia and hypocalciuria has also been described in a patient with glycogen storage disease type II [51].

Glomerular Dysfunction Patients with GSD I develop hyperfiltration and albuminuria [48–50, 56, 60]. Nearly all patients aged more than 25 years have renal disease and microalbuminuria; more than half have proteinuria [52, 59]. In a Dutch study that reviewed data from 39 patients with GSD-I, a biphasic pattern was observed in the time course of GFR and ERPF. On average, GFR rose between 10 and 15 years of age to 180–190 ml/min/1.73 m2, and renal blood flow (RBF) increased to 850–900 ml/ min/1.73 m2. Thereafter, GFR and RBF decreased, while microalbuminuria increased [50]. Patients with better metabolic control had better renal outcome. Treatment with ACE inhibitors decreased GFR, in particular in patients with hyperfiltration [50]. Persistent hyperfiltration leads to focal and global glomerulosclerosis and to a decline in GFR [49, 50]. Other histological abnormalities include glycogen deposition in proximal tubules, glomerular enlargement, and thickening and lamellation of GBM [59, 61, 62]. Management of the metabolic abnormalities including frequent feeds and the use of uncooked cornstarch are the mainstays of treatment of GSD nephropathy [47]. Antiproteinuric and lipidlowering agents may have a role [46]. Liver transplantation has been performed to prevent malignant change in hepatic adenomata, and combined liver–kidney transplantation has also been successful [63, 64].

Fanconi–Bickel Syndrome Renal Tubular Dysfunction Proximal tubular dysfunction occurs as an early feature in GSD I but is generally subclinical, and a frank Fanconi syndrome is rare. Although tubular proteinuria and enzymuria is signiﬁcantly elevated in GSD I patients, plasma electrolytes are less disturbed [46, 47, 51–53, 60, 61]. Distal tubular function is also perturbed. Hypercalciuria and hypocitraturia predispose GSD I patients to

The Fanconi–Bickel syndrome is a very rare autosomal recessive disorder of monosaccharide transport, presenting in the ﬁrst year of life with hepatomegaly (due to glycogen storage), hypoglycemia, and a severe generalized proximal tubulopathy leading to rickets. The extent of the Fanconi syndrome can be equal in magnitude to that of disorders such as cystinosis or tyrosinemia

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but is particularly characterized by heavy glycosuria and galactosuria [65–68]. Milder phenotypes have also been described [69]. Treatment is directed toward frequent feeds (and the use of uncooked cornstarch) together with management of the tubulopathy. The condition arises due to mutations in the GLUT2 facilitative glucose transporter (encoded by the SLC2A2 gene), which is expressed in hepatocytes, in pancreatic beta cells, and in the basolateral membranes of intestinal and renal tubular epithelial cells [70, 71], Decreased monosaccharide uptake by the liver explains the postprandial hyperglycemia and hypergalactosemia, which is exacerbated by inappropriately low insulin secretion due to abnormal glucose sensing by pancreatic beta cells [72, 73]. The inability of the liver to transport glucose together with heavy losses of glucose from the renal tubule contributes to preprandial hypoglycemia [71]. Renal glomerular hyperﬁltration, microalbuminuria, and diffuse mesangial expansion have been reported, and reduced GFR has been observed in some adults [74, 75]. Successful pregnancies have been reported [75, 76].

Mitochondrial Disorders Introduction Mitochondrial disorders are caused by defects in the respiratory chain enzymes, which are located in this organelle. The respiratory chain is responsible for the process of oxidative phosphorylation, in which electrons are transferred to oxygen, generating a proton gradient (complexes I-IV). The ﬂow of protons back through the mitochondrial membrane releases energy, which allows for the formation of ATP (complex V or ATP synthase) [77]. The respiratory chain enzyme complexes are encoded partly by mitochondrial and partly by nuclear DNA. Mitochondrial DNA (mtDNA) is constituted of a single double-stranded loop that, unlike nuclear DNA, is inherited exclusively from the mother and randomly segregates during each cell division. If mutated, the proportion between mutant and wild-type mtDNA can therefore vary from tissue to tissue and can also alter over time,

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explaining the enormous heterogeneity of mitochondrial disorders [77–79]. The classification of mitochondrial disorders is based on clinical, biochemical, and molecular phenotypes. A large number of disease-causing mutations in mtDNA have been reported to date and are collected in online databases, freely accessible (http://www. mitomap.org). Some phenotypes are predominantly associated with mutations of given genes and are therefore classified as syndromes or associations [80]. The clinical features are extremely heterogeneous and often change with time, but virtually all patients have neurological symptoms at some point. The first symptoms develop before 1 month of age in approximately one-third of patients and before 2 years of age in more than 80 % of cases [79]. Frequent manifestations include myopathy, encephalopathy, seizures, developmental delay, ophthalmoplegia, retinal degeneration, cardiomyopathy, endocrinopathy, and liver disease. Exceptionally, patients remain monosymptomatic. Skeletal muscles are frequently affected, in part because somatic mutations occur more frequently in myoblasts [78]. Exercise intolerance is a common complaint, which is often dismissed as psychogenic or mislabeled as chronic fatigue syndrome or rheumatic fibromyalgia. Many patients with mtDNA mutations fall into this group; the frequent lack of a clear maternal inheritance further deflects the physician from considering a mitochondrial cytopathy [78]. Typically, patients develop progressive multisystemic involvement, with symptoms increasing in number and severity overtime as more tissues become affected. Some, such as sensorineural deafness or cardiomyopathy, may remain subclinical and require systematic testing. Specific skin and hair lesions have also been described [81]. Measurement of plasma lactate, which is often the first investigation of a child suspected of mitochondrial dysfunction, may give a normal result in many patients. Conversely the majority of patients have increased urinary excretion of lactate [78]. Careful delineation of other system involvement, tissue biopsies, and detailed biochemical and molecular studies are required to confirm a defect in mitochondrial function.

Renal Manifestations of Metabolic Disorders in Children

Renal Manifestations Tubular disorders represent the most frequently observed form of renal mitochondrial diseases. In a review of 42 patients with mitochondrial disorders, 21 had renal involvement [82]. Of these, only eight patients had overt diseases, suggesting that the prevalence of tubular dysfunction is underestimated. Proximal tubular cells have high metabolic rates and are very rich in mitochondria. Not surprisingly, a majority of mitochondrial tubulopathies involve the proximal tubular segments. Varying degrees of tubular dysfunction may be seen, but the commonest distinct renal phenotype is a Fanconi syndrome, usually occurring in infants with multisystem dysfunction, in which case the prognosis is poor [78, 79, 83–86]. A majority of patients also have low–molecular weight proteinuria. Generalized proximal tubular dysfunction has also been reported in children with specific mitochondrial syndromes, including Kearns–Sayre syndrome, Pearson’s syndrome, Leigh’s encephalopathy, and Coenzyme Q10 deficiency [78, 79, 87–98]. In some children, isolated renal tubular acidosis, isolated hypomagnesemia, hypercalciuria, or a Batter-like phenotype are the prominent tubular manifestations [79, 82, 90, 99–103]. The most frequent biochemical findings are defects in complex III and IV, followed by complex I deficiencies [78]. Primary glomerular diseases have been less frequently reported. These include a number of sporadic cases characterized by steroid-resistant proteinuria secondary to nonimmune forms of glomerulonephritis, mostly focal segmental glomerulosclerosis (FSFG) [78, 79, 94], and two well-defined entities, namely, mutations in the mitochondrial gene encoding for the tRNALEU and mutations in nuclear genes encoding for enzymes required for the de novo synthesis of coenzyme Q10 (CoQ10). The most frequent mtDNA defect is the 3,243 A > G point mutation in the leucine tRNA gene, which was initially described in children with MELAS syndrome (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes syndrome) [104]. Clinical manifestations of the

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3243 A > G mutation, however, are not restricted to full-blown MELAS syndrome but can also express as diabetes, deafness, gastrointestinal disease, neuromuscular symptoms, glomerular disease, or a combination of the above [104, 105]. Most patients with renal involvement present with asymptomatic proteinuria. Personal or familial (maternal branch) history of diabetes or deafness is frequently observed [105–114]. When sensorineural deafness is present, patients can be misleadingly diagnosed with Alport syndrome [106, 110]. In general, female patients seem to be more affected than male patients. The age of diagnosis ranges 15–50 years, although cases presenting in early childhood have been reported [105]. The prevalent renal histology ﬁnding is consistent with FSGS. Cases of chronic tubulointerstitial nephritis and cystic kidney disease have also been described [105, 108]. A peculiar vasculopathy with hyalinosis of small arteries and myocyte necrosis has been noticed in several reports [107, 112, 114]. Nephrotic syndrome develops in approximately one-third of cases. Most patients become hypertensive, and cases of preeclampsia have been described in pregnant subjects [107]. Chronic or end-stage renal failure developed within 10 years in approximately 50 % of cases after diagnosis. A majority of patients has extrarenal symptoms at diagnosis; some, in particular in younger patients, additional symptoms appear during follow-up [105–114]. Deafness has been reported in approximately two-thirds of cases and diabetes mellitus in approximately half. Other ﬁndings include neuromuscular symptoms, retinal dystrophy, and cardiomyopathy. CoQ10 biosynthesis defects deserve a special mention among mitochondrial defects since they represent the only treatable mitochondrial disorder. The link between CoQ10 and renal disease was established in 2000, when three siblings were diagnosed with a complex clinical syndrome characterized by progressive encephalopathy and steroidresistant nephrotic syndrome (SRNS) [115]. Two siblings developed ESRD and required transplantation at ages 8 and 9, respectively; the third sibling had a more severe course and died at 8 years of age after rapid neurological deterioration. The two surviving children were treated with oral CoQ10,

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which resulted in a substantial improvement of their neurological condition over 3 years. Two other siblings with similar clinical features were reported in 2005 [116]. Both developed SRNS at 12 months of age. The first child developed progressive encephalomyopathy and stroke-like episodes at 18 months. Oral CoQ10 therapy was initiated at 22 months of age and was able to stop encephalomyopathy progression. The younger sister was treated immediately after she developed proteinuria and had an excellent clinical response without developing neurological symptoms [117]. Mutations in the COQ2 gene were identified in these two siblings as the first report of a genetic defect associated with primary CoQ10 deficiency [118]. Other COQ2 mutations have been found in five additional patients presenting with congenital or early-onset SRNS [119–121]. Mutations in two other genes involved in CoQ10 biosynthesis have also been identified in patients with similar clinical features, namely, in the PDSS2 gene (one patient) [122] and in the COQ6 gene (11 patients from 5 different kindreds) [123]. Although disease characteristics and progression are variable, most patients developed a glomerulopathy. Symptoms always begin within the first years of life; SRNS was the presenting symptom in a majority of cases. Unless treated, renal disease rapidly progressed to ESRF. Associated clinical features included deafness and encephalomyopathy in COQ6 patients; severe forms with neonatal onset may also present with liver failure and severe lactic acidosis [119, 120]. Defects in genes required for CoQ10 biosynthesis can also present with other phenotypes. One patient with a COQ9 mutation had severe multisystem disorder with renal tubulopathy but no apparent glomerular involvement [88]. The histological picture in CoQ10-related glomerulopathies is generally consistent with FSGS; electron microscopy shows numerous dysmorphic mitochondria in the cytoplasm of podocytes [119]. One of the most important aspects of CoQ10 biosynthesis defects is the clinical response to oral treatment. Empirically, CoQ10 doses of 30–50 mg/kg per day have been given to patients, but there is no practical method to monitor the efficacy of therapy other than observing the clinical response [117, 123].

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Closely related to these disorders, mutations in the ADCK4 gene (aarF domain containing kinase 4) have been identiﬁed in 15 individuals with SRNS from 8 unrelated families [124]. ADCK4 is not directly involved with the biosynthesis of CoQ10 but interacts with enzymes of this pathway. Patients with ADCK4 mutations have reduced CoQ10 levels and mitochondrial respiratory chain activity. One patient showed partial remission following CoQ10 treatment. Compared to other cases of CoQ10 biosynthesis defects, extrarenal involvement appears less frequent, and the age of onset is higher, ranging from infancy to early adulthood [124]. Tubulointerstitial nephritis and cystic kidney diseases have been reported in sporadic cases [78, 79].

Congenital Disorders of Glycosylation Congenital disorders of glycosylation (CDG) are a group of inherited multisystem disorders in which there is defective glycosylation of proteins. The most well-known group comprises defects of N-glycosylation that are frequently disorders affecting multiple pathways [125, 126]. Conversely, defects in O-glycosylation usually result in symptoms that are more organ specific [126]. Other defects involve lipid-linked glycosylation, which resemble more N-glycosylation defects and defects involving the glycosylation of the glycophosphatidylinositol anchor, which resemble more O-glycosylation defects [126]. Since they were first described, a large number of subtypes have been identified, and new classifications have been proposed [127, 128]. The presentation of CDG can be extremely heterogeneous, ranging from fatal multisystem disorders in infancy to multiple exostoses, progeria, or developmental delay in older children [126, 127, 128]. Diagnostically, abnormal isoelectric focusing of serum transferrin is usually the first screening test (although it will not identify all forms) and when abnormal should lead to more detailed enzymatic and genetic testing. In the past, genes responsible for CDGs were identified on biochemical bases; currently, the preferred approach is to use next-generation sequencing

Renal Manifestations of Metabolic Disorders in Children

techniques and/or targeted sequencing after initial biochemical investigations [125]. It is estimated that >2 % of the human genome encodes for proteins involved in the biosynthesis or in the recognition of glycans; CDGs probably represent an underdiagnosed group of diseases that include milder forms that are yet to be recognized [126, 129]. The exact contribution of CDGs to genetic defects of the kidneys and urinary tract remains to be established. Children with the commonest form, phosphomannomutase 2 (PMM2)-CDG, previously termed CDG-Ia, may have dysmorphism, hypotonia, failure to thrive, diarrhea, abnormal fat pads, inverted nipples, abnormal eye movements, hepatomegaly, and cardiomyopathy [126, 127]. Investigations often show hypothyroidism and olivopontocerebellar atrophy [130]. With time, many patients that survive lose their characteristic infantile features; cases with milder phenotypes have also been described [131]. One of the commonest renal manifestations is the presence of microcysts which produce a hyperechoic picture on ultrasonography, most commonly found in children with multisystem variants [128, 132, 133]. Cysts are located predominantly in the cortex and probably arise from tubules [132]. The kidneys may be enlarged, and single cysts have also been reported [132]. Some children present a tubulopathy [132, 134]. Proteinuria has been recorded in several patients with CDG and may contribute to severe edema and ascites that these infants sometimes develop. Some have early-onset nephrotic syndrome (Jaeken and Sinha 2009; [135]); their biopsies usually show diffuse mesangial sclerosis [135, 136].

Disorders of Uric Acid and Purine Metabolism and Transport Children who develop renal calculi, acute renal failure in the neonatal period, or crystal nephropathy require investigation of their purine metabolism. Purines are involved in the synthesis of nucleotides and coenzymes, in signal transduction (e.g., cAMP), and in the generation of ATP. The

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metabolic end product, uric acid, and its immediate precursor, xanthine, are insoluble in urine, so that overexcretion can predispose to the development of crystal formation. Uric acid is primarily generated in the liver by xanthine oxidase, an enzyme that is inhibited by allopurinol. In lower vertebrates, uric acid is converted into allantoin by uricase; the evolutionary advantage of retaining uric acids in humans is unclear and has been hypothetically attributed to its effects on salt retention, cell oxidation, or innate immunity (upon crystallization) [137]. High uric acid levels can result from excessive purine intake, defects of purine metabolism, decreased excretion, or a combination of the above. Urates are freely filtered in the glomerulus and are reabsorbed in the renal tubule by a complex interplay between secretion and reabsorption processes [137]. Numerous proteins have been identified as urate transporters [137]. Of these, the two best-characterized proteins are URAT1 and GLUT9 that mediate the luminal and basolateral uptake of uric acid, respectively [138, 139]. This process is age and sex dependent, with children reabsorbing less of the filtered urate and consequently having lower plasma urate concentrations [140]. In adults, the fractional excretion of uric acids is approximately 10 %, usually higher in females than males; newborns excrete approximately 35 % of their filtered load, while infants younger than 1 year have a fractional excretion of uric acid ranging 13–26 % [141]. As glomerular filtration rate declines, the fractional excretion of urate increases [142].

Disorders of Purine Metabolism Urolithiasis is the commonest renal manifestation of disorders of purine production. Children may or may not have typical features of calculi (pain, hematuria, infection). In some, the diagnosis is made following family studies or during investigation of crystalluria. Very rarely, these disorders present with oliguric or anuric acute renal failure, either due to bilateral obstructive calculi [143] or due to crystal nephropathy, which can sometimes occur within the neonatal period [144, 145].

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Lesch–Nyhan syndrome is inherited in an X-linked recessive manner and nearly always presents in males [146]. However, heterozygous females can manifest severe symptoms [147]. The disease is due to mutations in the hypoxanthine–guanine phosphoribosyl transferase gene HPRT1. Patients are healthy at birth but demonstrate within the first months of life psychomotor delay and symptoms resembling dystonic cerebral palsy. In time, they develop action dystonia, choreoathetosis, ballismus, cognitive and attention deficits, and self-injurious behavior (biting of fingers and lips leading to mutilating loss of tissue) [148]. Most patients have an intelligence quotient (IQ) around 50; seizures are also frequent [146, 148]. The mechanisms leading to neurological symptoms are only partially understood [149]. Overproduction of uric acid is present at birth and has been estimated to be fivefold to tenfold the rate of production of healthy individuals [150]. Attenuated variants of Lesch–Nyhan syndrome have been reported [146, 151]. The so-called KelleySeegmiller syndrome corresponds to a less severe form of HPRT1 mutations; patients develop hyperuricemia and gout with mild to no neurological deficits [152]. The analysis of more than 600 cases of HPRT1 mutations shows a significant genotype–phenotype correlation [153]. The diagnosis is based on clinical and biochemical findings (hyperuricemia and hyperuricosuria) followed by molecular and genetic testing [146, 148]. Treatment includes allopurinol, which should be used carefully to avoid hyperxanthinuria, purine restriction, and high fluid intake. Alkalinization aiming at a urinary pH of 6.0–7.0 helps in preventing stone formation and dissolving existing calculi [148]. Phosphoribosyl pyrophosphate (PRPP) synthetase superactivity is also X-linked and is caused by increased activity of the enzyme that forms PRPP from ribose-5-phosphate and adenosine triphosphate (ATP) [154]. Some affected individuals have neurodevelopmental abnormalities, particularly sensorineural deafness; in these pedigrees, heterozygous female subjects can develop gout and hearing impairment [155]. The disease usually shows in young male patients with

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gouty arthritis and uric acid nephrolithiasis, sometimes leading to ESRD [148]. Patients have high plasma and urine uric acid levels. Increased generation of uric acid is present since the first year of life [148, 154]. The differentiated diagnosis is primarily with partial forms of HGPRT deficiency, which may present with very similar biological and clinical signs. Adenine phosphoribosyl transferase (APRT) deficiency is an autosomal recessive disease, secondary to mutations in the APRT gene. The enzyme catalyzes the formation of AMP from adenine and phosphoribosylpyrophosphate and acts as a salvage system for the recycling of adenine into nucleic acids. Deficiency in APRT results in the accumulation of adenine, which is oxidized by xanthine oxidase into 2,8-dihydroxyadenine, a very insoluble compound [156]. Nearly all Japanese patients carry the same mutation [157], while approximately 30 mutations have been reported in Caucasians [148]. The deficiency can also be partial [157]. Patients may develop nephrolithiasis in early childhood or remain silent for decades [148]. Infrared spectrophotometry of stones and crystals allows to distinguish 2,8-dihydroxyadenine from uric acid. Allopurinol prevents the formation of 2,8-dihydroxyadenine. In addition, dietary purine restriction and high fluid intake are recommended, but alkalinization of urines is not useful since the 2,8-dihydroxyadenine solubility is not pH dependent [148]. Undiagnosed patients may develop chronic renal failure [158]. Defects in xanthine oxidase result in xanthinuria, which is characterized by excretion of large amounts of xanthine in the urine and a tendency to form xanthine stones; uric acid levels are markedly decreased both in serum and urine. Xanthinuria also occurs in molybdenum cofactor deficiency. Hyperuricemia with subsequent hyperuricosuria is also a feature of glycogen storage disease type I (see above).

Hyperuricosuria and Hypouricemia Calculi and renal failure can occur as a result of disorders of urate transport in the renal tubule.

Renal Manifestations of Metabolic Disorders in Children

Hyperuricosuria and hypouricemia can occur as a result of generalized proximal tubular dysfunction (e.g., Fanconi syndrome) but can also occur in hereditary renal hypouricemia secondary to mutations in URAT1 or GLUT9 [138]. URAT1 mutations cause nephrolithiasis and exercise-induced acute renal failure in approximately 10 % of patients and are more common in the Japanese and possibly in non-Ashkenazi Jewish populations [159]. GLUT9 mutations were identiﬁed in subjects with renal hypouricemia after genome-wide association studies had shown that genetic variations in SLC2A9 have strong inﬂuence on serum uric acid concentrations [160–163].

Familial Juvenile Hyperuricemic Nephropathy Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal dominant disorder leading to hyperuricemia, gout, progressive tubulointerstitial damage, impaired urinary concentrating ability, and progressive renal failure [140, 164, 165]. The disease is secondary to mutations in the UMOD gene that encodes for uromodulin (Tamm–Horsfall protein); mutations in the same gene also cause medullary cystic kidney disease type 2 (MCKD2) [165]. Being allelic disorders, FJHN and MCKD2 are collectively referred to as uromodulin-associated kidney disease (UAKD) [166]. Uromodulin genetic variants are also associated with chronic kidney disease (CKD) and hypertension in the general population [167]. Uromodulin is a kidney-speciﬁc protein that is exclusively expressed by epithelial cells lining the thick ascending limb (TAL) of Henle’s loop [168]. It is mainly located at the apical plasma membrane and is secreted in the tubular lumen after several post-translational modiﬁcations that include N-glycosylation, proteolysis, and polymerization of secreted proteins [165, 169]. Uromodulin has been hypothesized to have a role in water and electrolyte balance in the TAL, in protecting against urinary tract infection, in preventing the formation of kidney stones, and in activating innate immunity mechanisms

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in the kidney. Altogether, UAKD is a rare disorder; approximately 100 mutations have been reported so far, and its prevalence is estimated to be 1/100,000 [165]. Reduced fractional excretion of uric acid is present in the majority of patients and is frequently associated with gout in adulthood [166, 170]. Mild impairment of urineconcentrating ability is an almost constant finding, sometimes resulting in polyuria and polydipsia [171]. Chronic renal failure generally occurs between the second and fourth decade of life, although a significant intra- and interfamilial variability has been observed [164, 165, 172]. There is no specific therapy, but hyperuricemia predates renal impairment, and allopurinol may reduce the progression of the nephropathy, suggesting that renal damage could be, at least in part, related to hyperuricemia [164, 165, 173]. Only limited data are available on kidney transplantation, indicating no recurrence after transplantation [174]. Tubulointerstitial nephritis associated with hyperuricemia have been reported in UMODnegative patients that harbor mutations in the transcription factor hepatocyte nuclear factor-1β (TCF2), in particular when autosomal dominant pedigrees include family members with renal malformations [175, 176]. Hypouricosuric hyperuricemia associated with progressive kidney failure, early-onset anemia, hyperkalemia, and low blood pressure have also been reported in autosomal dominant families with specific mutations in the signal sequence of the renin gene (REN). Typically, renal failure develops in mid-adulthood [177].

Fabry Disease Fabry disease is an X-linked disorder in which glycosphingolipids, predominantly globotriaosylceramide (GL-3), accumulate in plasma and tissues as a result of a deﬁciency of α-galactosidase A, which is encoded by the GLA gene [178, 179]. The reported incidence is approximately 1:200,000, which largely underestimates the true prevalence; newborn screenings have shown prevalence as high as 1:3,100 [178, 180]. High incidence of late-onset/mild

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phenotypes, however, raises important ethical issues related to when the screening should be performed. The diagnosis can be made by demonstrating deficient α-galactosidase A activity in plasma or leukocytes [181]. Sequencing of the GLA gene is particularly important in female heterozygous, which may have preserved enzyme activity [182]. Heterozygous females have long been considered asymptomatic carriers. However, many experience symptoms, and some have significant multisystemic involvement that reduces significantly their quality of life [178, 183]. Thus, Fabry disease should be regarded as a condition with a large spectrum of clinical phenotypes; female patients develop symptoms later in life and are less likely to be diagnosed during childhood [184]. Affected males usually present in childhood with recurrent painful crises of the hands and feet that are related to damage of small peripheral nerve fibers. Typically, patients complain of acute episodes of burning pain originating in the extremities and irradiating toward the limbs and of episodes of chronic burning and tingling paresthesias [185]. Other early signs include gastrointestinal symptoms (nausea, vomiting, abdominal pain) that are often underappreciated, absence or decreased sweating (anhidrosis or hypohidrosis), and a characteristic skin rash, termed angiokeratoma corporis. The rash consists in small raised skin lesions clustered around tights, buttocks, groins and, umbilicus [178]. Slit-lamp examination reveals corneal and lenticular opacities. In many patients, these signs are not recognized, and diagnosis is delayed for years. Data from 1,765 patients including 54 % males and 46 % females enrolled in the Fabry Registry show that the median ages at onset of symptoms were 9 and 13 years in males and females, respectively, but that diagnosis was on average delayed by approximately 15 years in both groups [186]. Presenting symptoms in males included neurological pain (62 %), skin signs (31 %), gastroenterological symptoms (19 %), renal signs (17 %), and ophthalmological signs (11 %) [186]. Progressive deposition of GL-3 in the heart, blood vessels, and kidneys leads to the development of valvular and conduction abnormalities,

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angina, cerebrovascular disease, and progressive renal damage, usually in adult life. Patients can develop stroke episodes; Fabry’s disease should always be excluded in young patients with unexplained stroke [187]. Overt kidney disease is rare in children, but renal histological changes can be demonstrated in children even without proteinuria [188]. The natural course of Fabry nephropathy in children has not been fully appreciated yet. Microalbuminuria and proteinuria usually develop in the second or third decade of life [186, 188, 189]. Chronic renal failure is uncommon in childhood but has been reported as early as adolescence [178, 179, 190, 191]. The urine may contain casts and desquamated cells containing lipid globules [192]. Isosthenuria indicates defective tubular function. End-stage renal failure occurs typically around the fourth decade [178, 191] and represents the primary cause of death in untreated patients with Fabry disease [193]. Data from the Fabry disease registry show a 15–20 year reduction in life expectancy in male subjects compared to the general population, which is primarily related to cardiovascular morbidity in patients that had progressed to end-stage renal failure [194]. The renal prognosis may be better in patients with residual α-galactosidase A activity [179]. Nephropathy does not recur in the allograft, and transplanted patients have better outcomes than patients maintained on dialysis [195]. Histological examination of the kidney demonstrates inclusions with a characteristic “onion skin” appearance in tubular epithelia, podocytes, and endothelium [192]. In an adult review of 24 patients (mean age 38 years), 50 % had renal sinus cysts compared to 7 % in healthy matched controls, leading the authors to suggest that multiple renal sinus cysts in a patient with kidney disease should raise suspicion of Fabry’s [196]. Recent studies indicate that approximately 1 % of adult males with undiagnosed causes of ESRF have Fabry disease; this diagnosis should be suspected in all patients with progressive chronic kidney diseases of unknown etiology [195, 197]. Urinary protein excretion is strongly associated with progression of chronic renal failure [198].

Renal Manifestations of Metabolic Disorders in Children

The current causal treatment is enzyme replacement therapy, which appears to be safe and efficient at improving symptoms of pain, gastrointestinal disturbances, hypo- and anhidrosis, left ventricular mass index, glomerular filtration rate, and quality of life [199, 200]. Early treatment is probably essential to impact on renal function since little benefits have been observed in patients treated when they had already developed overt proteinuria [201].

Hereditary Tyrosinemia Type 1 Hereditary tyrosinaemia type 1 (HT1) is caused by deficiencies in fumarylacetoacetate hydrolase, the final enzyme of the tyrosine degradation pathway, which is mainly expressed in the liver and in the kidneys [202]. Lack of enzyme activity causes accumulation of several toxic compounds [e.g., succinylacetone (SA) and fumarylacetoacetate (FAA)], which have important pathogenetic effects such as rendering cells more susceptible to free radicals or promoting mutagenesis. As a result, hepatic and renal cells undergo apoptotic cell death or adaptive changes in gene expression that expose patients to the risk of developing liver malignancies. In the vast majority of patients, symptoms are primarily related to liver disease; variable degrees of renal dysfunction, however, can usually be detected by routine laboratory analyses in most cases. Animal studies suggest that FAA is the main culprit for the observed glomerulosclerosis and interstitial fibrosis [203], whereas SA is primarily responsible for tubular dysfunction [204]. Typically, HT1 patients suffer from proximal tubular disease of variable degree; patients with overt Fanconi syndrome often develop severe hypophosphataemic rickets. In time, nephrocalcinosis and/or glomerulosclerosis develop in some patients, leading to chronic renal failure. Liver involvement is always present. Patients may present at different ages; in general, early onset of symptoms correlates with more severe disease [202]. Three main presentations have been characterized. In the acute-onset form, which is also the most frequent, patients present within the first 6 months of life with hepatic and

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systemic failure. In the subacute form (6–24 months), liver disease is less severe; most patients present with hepatosplenomegaly, coagulopathy, failure to thrive, and rickets. In the chronic form, patients develop symptoms after the age of 2 years and present with subclinical liver and/or renal tubular dysfunction. Treatment with NTBC [(2-(2nitro-4-trifluoromethylbenzoyol)1,3 cyclohexanedione), nitisinone], an inhibitor of 4-hydroxyphenylpyruvate dioxygenase, which fully suppresses SA production, has dramatically changed the outcome of this disease, which was previously a devastating disorder. With NTBC, liver failure resolves, and the risk of developing hepatocellular carcinoma is dramatically decreased. From the renal standpoint, data on NTBC efficiency are limited, with only few long-term studies available. In a large cohort study of 21 patients treated with NTBC for 10 years [205], proteinuria (present in all patients) and phosphaturia (present in half of the patients) resolved in most patients within 1 year of therapy [205]. Another multicenter study collected 45 patients with HT1 that have been treated from diagnosis with NTBC in combination with tyrosineand phenylalanine-restricted diets [206]. Forty-three percent of patients had rickets at onset, and 86 % had evidence of a tubuloptahy. After a mean follow-up of nearly 5 years, only one-third of patients had residual tubular dysfunction without evidence of glomerular disease or chronic renal failure [206]. Other anecdotal reports show rapid normalization of tubular dysfunction within the first weeks of NTBC therapy [207, 208]

Lecithin Cholesterol Acyltransferase Deficiency Lecithin cholesterol acyltransferase (LCAT) is required for the esterification of cholesterol with unsaturated fatty acid derived from lecithin. Patients with LCAT deficiency accumulate unesterified cholesterol and phosphatidylcholine in plasma and tissues [209]. Sequels of tissue accumulation occur within childhood and include grayish corneal opacities, a hemolytic anemia,

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and proteinuria (sometimes in the nephrotic range) leading to progressive renal failure in adulthood [209, 210]. Tendon xanthomata and atherosclerosis have been described in a few cases. Biochemically, LCAT deﬁciency is characterized by a low total cholesterol concentration, variable triglyceride concentration, and abnormalities of lipoprotein structure and composition. The histology of the kidney shows mesangial hypercellularity and expansion with foam lipid deposits, holes and vacuolization in the glomerular basement membrane, arteriolar narrowing due to intimal thickening, and subendothelial lipid deposits [210, 211]. More than 80 different mutations have been described; genotype–phenotype correlations have been reported [211].

Lysinuric Protein Intolerance Lysinuric protein intolerance (LPI) is an autosomal recessive defect of cationic amino acid (lysine, arginine, and ornithine) transport in the basolateral aspects of intestinal and renal tubular cells. The disease is caused by mutations in the SLC7A7 gene, which encodes the y + LAT1 protein. y + LAT1 forms heterodimers with the protein 4F2hc, which is required for the expression of the transporter at the cell surface [212]. A founder effect has been reported, explaining high incidence of the disease in Finland (1/60,000 births) and to a lesser extent in southern Italy and northern Japan. Sporadic cases have been described worldwide. Most but not all symptoms of LPI are related to derangements of the urea cycle. For long, the disease was considered to represent a benign condition if patients were treated with low-protein diet and citrulline. More careful analyses have shown, however, that LPI is a multisystemic disease that in some subjects can cause severe complications even under treatment. There is no overt genotype–phenotype correlation, and disease severity varies signiﬁcantly among patients with the same mutation. Symptoms range from nearly normal features to severe protein intolerance, failure to thrive, osteoporosis, hepatosplenomegaly, respiratory failure, renal disease, and immunological disorders, chieﬂy

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pulmonary alveolar proteinosis, hemopagocytic lymphohystiocitosis, and immune-mediated glomerulonephritis. In the majority of cases, patients have mild proteinuria with or without microscopic hematuria; some may progress to end-stage renal failure. In a review of 39 patients aged 1–62 years, 74 % had proteinuria, 38 % hematuria, 36 % hypertension, 38 % a raised plasma creatinine, and 4 patients required dialysis [213, 214]. Renal biopsies usually show membranous glomerulonephritis or proliferative glomerulonephritis with immune complex deposits [215, 216]. In general, the most severe cases dying from alveolar proteinosis also have chronic renal failure. Cases of renal Fanconi syndrome have been reported [217]. Glomerular disease appears to be primarily related to immunological disturbances and shares similarities with lupus nephrites. High serum levels of inflammatory molecules such as sIL-2RA, sCD8, TNFα, and IL-6 are often observed in LPI patients along with elevated ferritin and LDH levels [218]. The amino acid transport defect explains part of the observed symptoms. Overproduction of nitric oxide secondary to arginine trapping in cells has been reported [219, 220]. Impaired arginine efflux in macrophages compromises their phagocytic functions [218, 221]. Patients self-select a protein-poor diet but as a consequence are nutritionally deficient in many substrates [213, 214]. The aim of treatment is to prevent hyperammonemia and to provide sufficient quantities of proteins and essential amino acids to allow normal growth. Oral supplementation with L-citrulline mitigates postprandial hyperammonemia and ameliorates protein intolerance [212, 220]. Some immune disorders associated with LPI including renal glomerular lesions may be treated with immunosuppressive medications; no systematic studies are available.

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2. Fenton WA, Gravel RA, Rosenblatt DS. Disorders of propionate and methylmalonate metabolism. In: Valle D, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson KM, et al, editors. The online metabolic and molecular bases of inherited disease. New York: McGraw-Hill. 3. Coelho D, Suormala T, Stucki M, Lerner-Ellis JP, Rosenblatt DS, Newbold RF, et al. Gene identiﬁcation for the cblD defect of vitamin B12 metabolism. N Engl J Med. 2008;358(14):1454–64. 4. Horster F, Garbade SF, Zwickler T, Aydin HI, Bodamer OA, Burlina AB, et al. Prediction of outcome in isolated methylmalonic acidurias: combined use of clinical and biochemical parameters. J Inherit Metab Dis. 2009;32(5):630–9. 5. Cosson MA, Benoist JF, Touati G, Dechaux M, Royer N, Grandin L, et al. Long-term outcome in methylmalonic aciduria: a series of 30 French patients. Mol Genet Metab. 2009;97(3):172–8. 6. O’Shea CJ, Sloan JL, Wiggs EA, Pao M, Gropman A, Baker EH, et al. Neurocognitive phenotype of isolated methylmalonic acidemia. Pediatrics. 2012;129(6): e1541–51. 7. D’Angio CT, Dillon MJ, Leonard JV. Renal tubular dysfunction in methylmalonic acidaemia. Eur J Pediatr. 1991;150(4):259–63. 8. Walter JH, Michalski A, Wilson WM, Leonard JV, Barratt TM, Dillon MJ. Chronic renal failure in methylmalonic acidaemia. Eur J Pediatr. 1989;148(4):344–8. 9. Horster F, Baumgartner MR, Viardot C, Suormala T, Burgard P, Fowler B, et al. Long-term outcome in methylmalonic acidurias is inﬂuenced by the underlying defect (mut0, mut-, cblA, cblB). Pediatr Res. 2007;62(2):225–30. 10. Hauser NS, Manoli I, Graf JC, Sloan J, Venditti CP. Variable dietary management of methylmalonic acidemia: metabolic and energetic correlations. Am J Clin Nutr. 2011;93(1):47–56. 11. van’t Hoff W, McKiernan PJ, Surtees RA, Leonard JV. Liver transplantation for methylmalonic acidaemia. Eur J Pediatr. 1999;158 Suppl 2:S70–4. 12. Kruszka PS, Manoli I, Sloan JL, Kopp JB, Venditti CP. Renal growth in isolated methylmalonic acidemia. Genet Med. 2013;15(12):990–6. 13. Chandler RJ, Zerfas PM, Shanske S, Sloan J, Hoffmann V, DiMauro S, et al. Mitochondrial dysfunction in mut methylmalonic acidemia. FASEB J. 2009;23(4):1252–61. 14. Zsengeller ZK, Aljinovic N, Teot LA, Korson M, Rodig N, Sloan JL, et al. Methylmalonic acidemia: a megamitochondrial disorder affecting the kidney. Pediatr Nephrol. 2014;29:2139–46. 15. Manoli I, Sysol JR, Li L, Houillier P, Garone C, Wang C, et al. Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia. Proc Natl Acad Sci U S A. 2013;110(33):13552–7. 16. Morath MA, Okun JG, Muller IB, Sauer SW, Horster F, Hoffmann GF, et al. Neurodegeneration

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renal diseases. Clin J Am Soc Nephrol. 2010;5(6): 1079–90. 177. Zivna M, Hulkova H, Matignon M, Hodanova K, Vylet’al P, Kalbacova M, et al. Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure. Am J Hum Genet. 2009;85(2):204–13. 178. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30. 179. Grunfeld JP, Lidove O, Joly D, Barbey F. Renal disease in Fabry patients. J Inherit Metab Dis. 2001;24 Suppl 2:71–4; discussion 65. 180. Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, et al. High incidence of later-onset Fabry disease revealed by newborn screening. Am J Hum Genet. 2006;79(1):31–40. 181. Mayes JS, Scheerer JB, Sifers RN, Donaldson ML. Differential assay for lysosomal alphagalactosidases in human tissues and its application to Fabry’s disease. Clin Chim Acta. 1981;112(2): 247–51. 182. Linthorst GE, Vedder AC, Aerts JM, Hollak CE. Screening for Fabry disease using whole blood spots fails to identify one-third of female carriers. Clin Chim Acta. 2005;353(1–2):201–3. 183. Wang RY, Lelis A, Mirocha J, Wilcox WR. Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med. 2007;9(1):34–45. 184. Wilcox WR, Oliveira JP, Hopkin RJ, Ortiz A, Banikazemi M, Feldt-Rasmussen U, et al. Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry. Mol Genet Metab. 2008;93(2):112–28. 185. Hopkin RJ, Bissler J, Banikazemi M, Clarke L, Eng CM, Germain DP, et al. Characterization of Fabry disease in 352 pediatric patients in the Fabry Registry. Pediatr Res. 2008;64(5):550–5. 186. Eng CM, Fletcher J, Wilcox WR, Waldek S, Scott CR, Sillence DO, et al. Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis. 2007;30 (2):184–92. 187. Rolfs A, Bottcher T, Zschiesche M, Morris P, Winchester B, Bauer P, et al. Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study. Lancet. 2005;366(9499):1794–6. 188. Tondel C, Bostad L, Hirth A, Svarstad E. Renal biopsy findings in children and adolescents with Fabry disease and minimal albuminuria. Am J Kidney Dis. 2008;51(5):767–76. 189. Gubler MC, Lenoir G, Grunfeld JP, Ulmann A, Droz D, Habib R. Early renal changes in hemizygous and heterozygous patients with Fabry’s disease. Kidney Int. 1978;13(3):223–35. 190. Ramaswami U, Najafian B, Schieppati A, Mauer M, Bichet DG. Assessment of renal pathology and dysfunction in children with Fabry disease. Clin J Am Soc Nephrol. 2010;5(2):365–70.

1606 191. Schiffmann R. Natural history of Fabry disease in males: preliminary observations. J Inherit Metab Dis. 2001;24 Suppl 2:15–7; discussion 1–2. 192. Sessa A, Meroni M, Battini G, Maglio A, Brambilla PL, Bertella M, et al. Renal pathological changes in Fabry disease. J Inherit Metab Dis. 2001;24 Suppl 2:66–70; discussion 65. 193. Schiffmann R, Warnock DG, Banikazemi M, Bultas J, Linthorst GE, Packman S, et al. Fabry disease: progression of nephropathy, and prevalence of cardiac and cerebrovascular events before enzyme replacement therapy. Nephrol Dial Transplant. 2009;24(7): 2102–11. 194. Waldek S, Patel MR, Banikazemi M, Lemay R, Lee P. Life expectancy and cause of death in males and females with Fabry disease: ﬁndings from the Fabry Registry. Genet Med. 2009;11(11):790–6. 195. Mignani R, Feriozzi S, Schaefer RM, Breunig F, Oliveira JP, Ruggenenti P, et al. Dialysis and transplantation in Fabry disease: indications for enzyme replacement therapy. Clin J Am Soc Nephrol. 2010;5(2):379–85. 196. Ries M, Bettis KE, Choyke P, Kopp JB, Austin 3rd HA, Brady RO, et al. Parapelvic kidney cysts: a distinguishing feature with high prevalence in Fabry disease. Kidney Int. 2004;66(3):978–82. 197. Thadhani R, Wolf M, West ML, Tonelli M, Ruthazer R, Pastores GM, et al. Patients with Fabry disease on dialysis in the United States. Kidney Int. 2002;61(1):249–55. 198. Wanner C, Oliveira JP, Ortiz A, Mauer M, Germain DP, Linthorst GE, et al. Prognostic indicators of renal disease progression in adults with Fabry disease: natural history data from the Fabry Registry. Clin J Am Soc Nephrol. 2010;5(12):2220–8. 199. Pisani A, Visciano B, Roux GD, Sabbatini M, Porto C, Parenti G, et al. Enzyme replacement therapy in patients with Fabry disease: state of the art and review of the literature. Mol Genet Metab. 2012;107(3):267–75. 200. Wang RY, Bodamer OA, Watson MS, Wilcox WR, Diseases AWGoDCoLS. Lysosomal storage diseases: diagnostic conﬁrmation and management of presymptomatic individuals. Genet Med. 2011; 13(5):457–84. 201. Warnock DG, Ortiz A, Mauer M, Linthorst GE, Oliveira JP, Serra AL, et al. Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation. Nephrol Dial Transplant. 2012;27(3):1042–9. 202. de Laet C, Dionisi-Vici C, Leonard JV, McKiernan P, Mitchell G, Monti L, et al. Recommendations for the management of tyrosinaemia type 1. Orphanet J Rare Dis. 2013;8:8. 203. Sun MS, Hattori S, Kubo S, Awata H, Matsuda I, Endo F. A mouse model of renal tubular injury of tyrosinemia type 1: development of de Toni Fanconi syndrome and apoptosis of renal tubular cells in

F. Emma et al. Fah/Hpd double mutant mice. J Am Soc Nephrol. 2000;11(2):291–300. 204. Spencer PD, Roth KS. Effects of succinylacetone on amino acid uptake in the rat kidney. Biochem Med Metab Biol. 1987;37(1):101–9. 205. Santra S, Preece MA, Hulton SA, McKiernan PJ. Renal tubular function in children with tyrosinaemia type I treated with nitisinone. J Inherit Metab Dis. 2008;31(3):399–402. 206. Masurel-Paulet A, Poggi-Bach J, Rolland MO, Bernard O, Guffon N, Dobbelaere D, et al. NTBC treatment in tyrosinaemia type I: long-term outcome in French patients. J Inherit Metab Dis. 2008;31(1): 81–7. 207. Larochelle J, Alvarez F, Bussieres JF, Chevalier I, Dallaire L, Dubois J, et al. Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Quebec. Mol Genet Metab. 2012;107(1–2):49–54. 208. Lindstedt S, Holme E, Lock EA, Hjalmarson O, Strandvik B. Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. Lancet. 1992;340(8823):813–7. 209. Gjone E. Familial lecithin: cholesterol acyltransferase deficiency–a clinical survey. Scand J Clin Lab Invest Suppl. 1974;137:73–82. 210. Imbasciati E, Paties C, Scarpioni L, Mihatsch MJ. Renal lesions in familial lecithin-cholesterol acyltransferase deficiency. Ultrastructural heterogeneity of glomerular changes. Am J Nephrol. 1986;6(1):66–70. 211. Hirashio S, Ueno T, Naito T, Masaki T. Characteristic kidney pathology, gene abnormality and treatments in LCAT deficiency. Clin Exp Nephrol. 2014;18(2): 189–93. 212. Sebastio G, Sperandeo MP, Andria G. Lysinuric protein intolerance: reviewing concepts on a multisystem disease. Am J Med Genet C Semin Med Genet. 2011;157C(1):54–62. 213. Tanner LM, Nanto-Salonen K, Niinikoski H, Jahnukainen T, Keskinen P, Saha H, et al. Nephropathy advancing to end-stage renal disease: a novel complication of lysinuric protein intolerance. J Pediatr. 2007;150(6):631–4, 4 e1. 214. Tanner LM, Nanto-Salonen K, Venetoklis J, Kotilainen S, Niinikoski H, Huoponen K, et al. Nutrient intake in lysinuric protein intolerance. J Inherit Metab Dis. 2007;30(5):716–21. 215. DiRocco M, Garibotto G, Rossi GA, Caruso U, Taccone A, Picco P, et al. Role of haematological, pulmonary and renal complications in the long-term prognosis of patients with lysinuric protein intolerance. Eur J Pediatr. 1993;152(5):437–40. 216. Parenti G, Sebastio G, Strisciuglio P, Incerti B, Pecoraro C, Terracciano L, et al. Lysinuric protein intolerance characterized by bone marrow abnormalities and severe clinical course. J Pediatr. 1995;126(2):246–51.

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217. Benninga MA, Lilien M, de Koning TJ, Duran M, Versteegh FG, Goldschmeding R, et al. Renal Fanconi syndrome with ultrastructural defects in lysinuric protein intolerance. J Inherit Metab Dis. 2007;30(3): 402–3. 218. Barilli A, Rotoli BM, Visigalli R, Bussolati O, Gazzola GC, Gatti R, et al. Impaired phagocytosis in macrophages from patients affected by lysinuric protein intolerance. Mol Genet Metab. 2012;105(4): 585–9. 219. Mannucci L, Emma F, Markert M, Bachmann C, Boulat O, Carrozzo R, et al. Increased NO production

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in lysinuric protein intolerance. J Inherit Metab Dis. 2005;28(2):123–9. 220. Ogier de Baulny H, Schiff M, Dionisi-Vici C. Lysinuric protein intolerance (LPI): a multi organ disease by far more complex than a classic urea cycle disorder. Mol Genet Metab. 2012;106(1): 12–7. 221. Barilli A, Rotoli BM, Visigalli R, Bussolati O, Gazzola GC, Kadija Z, et al. In lysinuric protein intolerance system y + L activity is defective in monocytes and in GM-CSF-differentiated macrophages. Orphanet J Rare Dis. 2010;5:32.

Infectious Diseases and the Kidney in Children

Jennifer Stevens, Jethro A. Herberg, and Michael Levin

Contents Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1610 Systemic Sepsis and Septic Shock . . . . . . . . . . . . . . . . . 1610 Speciﬁc Bacterial Infections Causing Renal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Meningococcus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Staphylococcus Aureus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Streptococcus Pyogenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gastrointestinal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . Mycobacterium Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . Treponema Pallidum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mycoplasma Pneumoniae . . . . . . . . . . . . . . . . . . . . . . . . . . Legionnaires’ Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1613 1613 1614 1616 1620 1621 1622 1622 1622

Rickettsial Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1623 Rocky Mountain Spotted Fever . . . . . . . . . . . . . . . . . . . . 1623 Q Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1624 Intravascular and Focal Bacterial Infections . . . 1625 Bacterial Endocarditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1625 Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hepatitis B Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hepatitis C Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Herpes Viruses: Cytomegalovirus . . . . . . . . . . . . . . . . . . Herpes Viruses Varicella-Zoster Virus . . . . . . . . . . . . . Herpes Viruses: Epstein-Barr Virus . . . . . . . . . . . . . . . .

Herpes Viruses: Herpes Simplex Virus . . . . . . . . . . . . Human Immunodeﬁciency Virus . . . . . . . . . . . . . . . . . . . Human Polyomaviruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . Viral Hemorrhagic Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Common Virus Infections . . . . . . . . . . . . . . . . . . . Coronavirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1632 1632 1635 1637 1640 1641

Parasitic Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Schistosomiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Leishmaniasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Filariasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1641 1642 1644 1645 1645

Fungal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1646 Miscellaneous Conditions . . . . . . . . . . . . . . . . . . . . . . . . . Hemorrhagic Shock and Encephalopathy . . . . . . . . . . Kawasaki Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Xanthogranulomatous Pyelonephritis (XGP) . . . . . .

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1647

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J. Stevens (*) University Hospital Wales, Cardiff, S. Wales, UK e-mail: [emailprotected] J.A. Herberg Imperial College London, London, UK e-mail: [emailprotected] M. Levin Department of Medicine, Imperial College London, London, UK e-mail: [emailprotected] # Springer-Verlag Berlin Heidelberg 2016 E.D. Avner et al. (eds.), Pediatric Nephrology, DOI 10.1007/978-3-662-43596-0_47

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The kidney is involved in a wide range of bacterial, viral, fungal, and parasitic diseases. In most systemic infections, renal involvement is a minor component of the illness, but in some, renal failure may be the presenting feature and the major problem in management. Although individual infectious processes may have a predilection to involve the renal vasculature, glomeruli, interstitium, or collecting systems, a purely anatomic approach to the classiﬁcation of infectious diseases affecting the kidney is rarely helpful because most infections may involve several different aspects of renal function. In this chapter, a microbiological classiﬁcation of the organisms affecting the kidney is adopted. Although they are important causes of renal dysfunction in infectious diseases, urinary tract infections and hemolytic uremic syndrome (HUS) are not discussed in detail because they are considered separately in ▶ Chaps. 47, “Renal Involvement in Children with HUS,” and ▶ 53, “Urinary Tract Infections in Children,” respectively. Elucidation of the cause of renal involvement in a child with evidence of infection must be based on a careful consideration of the geographic distribution of infectious diseases in different countries. A history of foreign travel; exposure to animals, insects, or unusual foods or drinks; outdoor activities such as swimming or hiking; and contact with infectious diseases must be sought in every case. The clinical examination should include a careful assessment of the skin and mucous membranes and a search for insect bites, lymphadenopathy, and involvement of other organs. A close collaboration with a pediatric infectious disease specialist and hospital microbiologist will aid the diagnosis and management of the underlying infection. A tantalizing clue to the pathogenesis of glomerular disease is the marked difference in the incidence of nephrosis and nephritis in developed and underdeveloped areas of the world. In several tropical countries, glomerulonephritis (GN) accounts for up to 4 % of pediatric hospital admissions; the incidence in temperate climates is 10- to 100-fold less. This difference might be explained by a complex interaction of several different factors, including nutrition, racial and genetically determined differences in immune responses, and exposure to infectious diseases. A

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growing body of evidence, however, suggests that long-term exposure to infectious agents is a major factor in the increased prevalence of glomerular diseases in developing countries. Renal involvement in infectious diseases may occur by a variety of mechanisms: direct microbial invasion of the renal tissues or collecting system may take place in conditions such as staphylococcal abscess of the kidney occurring as a result of septicemic spread of the organism; ascending infection commonly occurs due to infection in the urinary tract; damage to the kidney may be caused by the systemic release of endotoxin or other toxins and activation of the inﬂammatory cascade during septicemia or due to a focus of infection distant from the kidney; ischemic damage may result from inadequate perfusion induced by septic shock; the kidney may be damaged by activation of the immunologic pathways or by immune complexes resulting from the infectious process. In many conditions, a combination of these mechanisms may be operative. In the assessment of renal complications occurring in infectious diseases, the possibility of druginduced nephrotoxicity caused by antimicrobial therapy should always be considered. The nephrotoxic effects of antibiotics and other antimicrobial agents are not addressed in this chapter but are covered in ▶ Chap. 67, “Handling of Drugs in Children with Abnormal Renal Function”.

Bacterial Infections Bacterial infections associated with renal disease and the likely mechanisms causing renal dysfunction are shown in Table 1.

Systemic Sepsis and Septic Shock Impaired renal function is common in systemic sepsis, and acute kidney injury (AKI) is an independent risk factor for mortality in pediatric sepsis [1]. Depending on the severity of the infection and the organism responsible, the renal involvement may vary from insigniﬁcant proteinuria to AKI requiring dialysis. The organisms causing AKI as

Infectious Diseases and the Kidney in Children

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Table 1 Likely mechanisms causing renal dysfunction in bacterial infections

Organism Neisseria meningitidis

Staphylococcus aureus

Staphylococcus epidermidis Group A Streptococcus

Haemophilus inﬂuenzae Leptospira interrogans Streptococcus pneumoniae

Site/infection Septicemia Chronic meningococcemia Renal abscess

Infection localized to the kidney

Systemic infection; toxin/ inﬂammation ++

Ischemia/ hypoperfusion; vasomotor nephropathy ++

Distant infection; “immunologic/ delayed”

+ ++

Distant abscess/ endocarditis Sepsis Toxic shock Shunt infection

++ ++ ++

Sepsis

Toxic shock APSGN Brazilian purpuric fever Leptospirosis, Weil’s disease Sepsis

++ ++

++ + (HUS) – neuraminidase associated

Pneumonia

Escherichia coli and Shigella Salmonella species Vibrio species Klebsiella Yersinia species Campylobacter jejuni Mycobacterium tuberculosis Treponema pallidum Mycoplasma pneumoniae Legionella Rickettsia rickettsii Coxiella burnetii

Sepsis Diarrhea Colitis Sepsis Diarrhea Cholera Sepsis Enteritis Enteritis Tuberculosis

++ ++ ++ ++ ++ ++

++ (HUS) ++(HUS) + + (HUS)

+ + +

Pneumonia

+ + +

+ (HUS)

Syphilis

Pneumonia Rocky Mountain spotted fever Q fever

Others

+ (HUS) Rhabdomyolysis

+ +

++ frequent complication of infection, + uncommon but recognized complication, APSGN acute poststreptococcal glomerulonephritis, HUS hemolytic uremic syndrome

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part of systemic sepsis vary with age and geographic location and also differ in normal and immunocompromised children. In the neonatal period, group B streptococci, coliforms, Staphylococcus aureus, and Listeria monocytogenes are the organisms usually responsible. In older children, Neisseria meningitidis, Streptococcus pneumoniae, group A Streptococcus, and Staphylococcus aureus account for most of the infections. In people who are immunocompromised, a wide range of bacteria are seen, and, similarly, in tropical countries, other pathogens, including Haemophilus influenzae, Salmonella species, and Pseudomonas pseudomallei, must be considered. Vaccines against N. meningitides, S. pneumoniae, and H. influenzae have reduced the impact of these infections, but their uptake varies in different countries. Systemic sepsis usually presents with nonspecific features: fever, tachypnea, tachycardia, and evidence of skin and organ underperfusion. The pathophysiology of renal involvement in systemic sepsis is multifactorial [2, 3]. Hypovolemia with diminished renal perfusion is the earliest event and is a consequence of the increased vascular permeability and loss of plasma from the intravascular space. Hypovolemia commonly coexists with depressed myocardial function because of the myocardial depressant effects of endotoxin or other toxins. The renal vasoconstrictor response to diminished circulating volume and reduced cardiac output further reduces glomerular filtration, and oliguria is thus a consistent and early event in severe sepsis. A number of vasodilator pathways are activated in sepsis, including nitric oxide and the kinin pathways. This may lead to inappropriate dilatation of vascular beds. Vasodilatation of capillary beds leading to warm shock is common in adults with sepsis due to Gram-negative organisms but is less commonly seen in children, in whom intense vasoconstriction is the usual response to sepsis. If renal underperfusion and vasoconstriction are persistent and severe, the reversible prerenal failure is followed by established renal failure with the characteristic features of vasomotor nephropathy or acute tubular necrosis. Other mechanisms of renal damage in systemic sepsis include direct effects of endotoxin and

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other toxins on the kidney and release of inflammatory mediators such as tumor necrosis factor (TNF) and other cytokines, arachidonic acid metabolites, and proteolytic enzymes. Leukocyte-endothelial interactions result in physical congestion of the medullary vasculature and further decrease regional blood flow. Nitric oxide (NO) is postulated to play a key role in the pathophysiology of renal failure in sepsis. NO is produced from three cell-specific nitric oxide synthase (NOS) isoforms. Within the kidney, endothelial NOS (eNOS) is expressed in endothelial cells and plays a role in vascular relaxation, inhibition of leukocyte adhesion, and platelet aggregation. Endothelial injury in renal ischemia has been reported to impair the production of NO by eNOS. Inducible NOS (iNOS) has been implicated as an important mediator of vasodilatation and is upregulated within the medulla and the glomeruli in sepsis. The alteration of NOS expression and NO production within the systemic circulation and the kidney has supported the extensive testing of NOS inhibitors in sepsis and renal ischemia [4]. Trials of selective NO synthase inhibition did not offer any advantages over saline resuscitation [5]. Activation of coagulation is an important component of the pathophysiology of septic shock and contributes to intraglomerular thrombosis. Tubular injury then leads to cell detachment and intratubular obstruction and tubular backleak. Recovery necessitates the clearance of the necrotic cells and debris as well as the repair of the nonfatally injured cells. Activation of multiple prothrombotic and antifibrinolytic pathways occurs, together with downregulation of antithrombotic mechanisms such as the protein C pathway. Treatment with activated protein C has been shown to improve outcome of adult septic shock, but has not been confirmed to have benefit in pediatric sepsis and may carry a risk of bleeding particularly in infants [6]. The renal findings early in septic shock are oliguria, with high urine/plasma urea and creatinine ratios, low urine sodium concentration, and a high urine/plasma osmolarity ratio. Once established, renal failure supervenes, and the urine is of poor quality with low urine/plasma urea and creatinine ratios, elevated urine sodium

Infectious Diseases and the Kidney in Children

concentration, and low urine osmolarity. Proteinuria is usually present, and the urine sediment may contain red cells and small numbers of white cells.

Management of AKI in Systemic Sepsis The management of AKI in systemic sepsis depends on early diagnosis and administration of appropriate antibiotics to cover the expected pathogens. Reliance on creatinine and urine output to identify AKI (using, e.g., the pediatric RIFLE score [7]) may in the future be improved using alternative biomarkers, such as neutrophil gelatinaseassociated lipocalin (NGAL) [2, 8]. Management is directed at improving renal perfusion and oxygenation. Volume replacement with crystalloid or colloid should be undertaken to optimize preload. Central venous pressure or pulmonary wedge pressure monitoring is essential to guide volume replacement in children in severe shock. The use of low-dose (2–5 pg/kg/min) dopamine to reduce renal vasoconstriction together with administration of inotropic agents such as dobutamine or epinephrine to improve cardiac output may reverse prerenal failure. Early elective ventilation should be undertaken in patients with severe shock. If oliguria persists despite volume replacement and inotropic therapy, dialysis or hemoﬁltration should be instituted early, because septic and catabolic patients may rapidly develop hyperkalemia and severe electrolyte imbalance. In most children who develop AKI as part of systemic sepsis or septic shock, the renal failure is of short duration, and recovery can be expected within a few days of achieving cardiovascular stability and eradication of the underlying infection. Occasionally, renal cortical necrosis or infarction of the kidney may result in prolonged or permanent loss of renal function.

Specific Bacterial Infections Causing Renal Disease Meningococcus Neisseria meningitidis continues to be a major cause of systemic sepsis and meningitis in both developed and underdeveloped parts of the world.

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In developed countries, most cases are caused by group B and Y strains, particularly after introduction of meningococcal C vaccination, whereas epidemics of meningococcal groups A, C, and W135 continue to occur in many underdeveloped regions of the world [9]. In 2013, a meningococcal B vaccine was approved for use in Europe, Canada, and Australia, and it has been used in the United States to help control outbreaks (see www. meningitis.org/menb-vaccine). Peak incidence is in infants for group B disease and teenagers and young adults for groups C. However, the disease can occur at any age. There are two major presentations of meningococcal disease: meningococcal meningitis presents with features indistinguishable from those of other forms of meningitis, including headache, stiff neck, and photophobia. Lumbar puncture is required to identify the causative agent and distinguish this from other forms of meningitis. Despite the acute nature of the illness, the prognosis is good, and most patients with the purely meningitic form of the illness recover without sequelae. The most common sequelae is hearing loss and so all children should have a hearing test after discharge [10]. Meningococcemia with purpuric rash and shock is the second and more devastating form of the illness. Affected patients present with nonspeciﬁc symptoms of fever, vomiting, abdominal pain, and muscle ache. The diagnosis is only obvious once the characteristic petechial or purpuric rash appears. Patients with a rapidly progressive purpuric rash, hypotension, and evidence of skin and organ underperfusion have a poor prognosis, with a mortality of 10–30 %. Adverse prognostic features include hypotension, a low white cell count, absence of meningeal inﬂammation, thrombocytopenia, and disturbed coagulation indices or a combination of these [11]. Renal failure was seldom reported in early series of patients with meningococcemia, perhaps because most patients died rapidly of uncontrolled septic shock. With advances in intensive care, however, more children are surviving the initial period of profound hemodynamic derangement, and renal failure is more often seen as a major management problem. Children with fulminant sepsis,

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particularly with Gram-negative organisms including N. meningitidis, can develop renal failure in association with rhabdomyolysis [12]. The pathophysiology of meningococcal septicemia involves the activation of cytokines and inflammatory cells by endotoxin [13]. Mortality is directly related to both the plasma endotoxin concentration and the intensity of the inflammatory response, as indicated by levels of TNF and other inflammatory markers. Patients with meningococcemia have a profound capillary leak leading to severe hypovolemia. A loss of plasma proteins from the intravascular space is probably the major cause of shock, but myocardial suppression secondary to IL6 production is also important [14]. Intense vasoconstriction further impairs tissue and organ perfusion, and vasculitis with intravascular thrombosis and consumption of platelets and coagulation factors is also present. Oliguria is invariably present in children with meningococcemia during the initial phase of the disorder. This is prerenal in origin and may respond to volume replacement and inotropic support. If cardiac output cannot be improved and renal underperfusion persists, established renal failure supervenes. Occasionally, cortical necrosis or infarction of the kidneys occurs. Children with meningococcemia should be aggressively managed in a pediatric intensive care unit, with early administration of antibiotics (penicillin or a thirdgeneration cephalosporin), volume replacement, hemodynamic monitoring, and the use of inotropic agents and vasodilators. If oliguria persists despite measures to improve cardiac output, elective ventilation and dialysis should be instituted early. Because activation of coagulation pathways occurs, severe acquired protein C deficiency may result and is usually associated with substantial mortality [15]. Protein C is a natural anticoagulant which also has an important anti-inflammatory activity. Despite evidence for impaired function of the activated protein C pathway in meningococcal diseases [15] and adult trials suggesting benefit of activated protein C administration in septic shock (PROWESS trial) [16], pediatric trials of activated protein C showed no clear benefit and were associated with increased risk of intracranial bleeding in very young infants [6].

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The role of aPC therapy in pediatric sepsis remains unclear. Most patients who survive the initial 24–48 h of the illness and regain hemodynamic stability will ultimately recover renal function even if dialysis is required for several weeks. The least common presentation of meningococcal sepsis is chronic meningococcemia. Patients with this form of the illness present insidiously with a vasculitic rash, arthritis, and evidence of multiorgan involvement. The features may overlap those of Henoch-Schonlein purpura or subacute bacterial endocarditis (SBE), and the diagnosis must be considered in patients presenting with fever, arthritis, and vasculitic rash, often accompanied by proteinuria or hematuria. Response to antibiotic treatment is good, but some patients may have persistent symptoms for many days resulting from an immune-complex vasculitis.

Staphylococcus Aureus Staphylococcal infections may affect the kidneys by direct focal invasion during staphylococcal septicemia, forming a renal abscess, by causing staphylococcal bacteremia, or by toxin-mediated mechanisms, as in the staphylococcal toxic shock syndrome. Staphylococcal Abscess. Staphylococcal renal abscess presents with fever, loin pain and tenderness, and abnormal urine sediment, as do abscesses caused by other organisms. The illness often follows either septicemia or pyelonephritis. The diagnosis is usually considered only when a patient with clinical pyelonephritis shows an inadequate response to antibiotic treatment. The diagnosis is conﬁrmed by ultrasonography or computed tomographic scan, which shows swelling of the kidney and intrarenal collections of ﬂuid. Antibiotic therapy alone may result in cure, and empirical therapy should cover both Gram-positive and Gram-negative organisms until microbiological diagnosis has been achieved. Treatment may require percutaneous drainage alongside antibiotic therapy, which may need to persist for 2–4 weeks. Open drainage may be necessary if this approach has failed [17].

Infectious Diseases and the Kidney in Children

Staphylococcal Toxic Shock Syndrome. The staphylococcal toxic shock syndrome is a systemic illness characterized by fever, shock, erythematous rash, diarrhea, confusion, and renal failure. The disorder was ﬁrst described by Todd et al. in 1978 in a series of seven children [18]. During the 1980s, thousands of cases were reported in the United States. Most cases were in menstruating women in association with tampon use. Menstrual and non-menstrual cases are now equally common, including children of both sexes and all ages [19]. The illness usually begins suddenly with high fever, diarrhea, confusion, and hypotension, together with a diffuse erythroderma [20]. Mucous membrane involvement with hyperemia and ulceration of the lips and oral mucosa or vaginal mucosa, strawberry tongue, and conjunctival injection are usually seen. Desquamation of the rash occurs in the convalescent phase of the illness. Confusion is often present in the early stages of the illness and may progress to coma in severe cases. Multiple organ failure with evidence of impaired renal function, elevated levels of hepatic transaminases, thrombocytopenia, elevated CPK, and disseminated intravascular coagulation (DIC) is often seen. According to CDC criteria, the diagnosis is made on the basis of the clinical features of fever, rash, hypotension, and subsequent desquamation along with deranged function of three or more of the following organ systems: the gastrointestinal (GI), mucous membranes, renal, hepatic, hematologic, central nervous system, and muscle. Other disorders causing a similar picture, such as Rocky Mountain spotted fever, leptospirosis, measles, and streptococcal infection, must be excluded. The staphylococcal toxic shock syndrome is caused by infection or colonization with strains of S. aureus that produce one or more protein exotoxins [21]. Most cases in adults are associated with toxic shock toxin I; in children, many of the isolates associated with the syndrome produce other enterotoxins (A to F). The staphylococcal enterotoxins induce disease by acting as superantigens [22], which activate T cells bearing speciﬁc V beta regions of the T-cell receptor; this

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causes proliferation and cytokine release. The systemic illness and toxicity are believed to result largely from an intense inflammatory response induced by the toxin. The site of toxin production is often a trivial focus of infection or simple colonization, and bacteremia is rarely observed. Renal failure in toxic shock syndrome is usually caused by shock and renal hypoperfusion. In the early stages of the illness, oliguria and renal impairment are usually prerenal and respond to treatment of shock and measures to improve perfusion. In severe cases and in patients in whom treatment is delayed, AKI develops as a consequence of prolonged renal underperfusion, and dialysis may be required. In addition to underperfusion, direct effects of the toxin or inflammatory mediators may also contribute to the renal damage. Recovery of renal function usually occurs, but in severe cases with cortical necrosis or intense renal vasculitis, prolonged dialysis may be required. The management of staphylococcal toxic shock syndrome depends on early diagnosis and aggressive cardiovascular support with volume replacement, inotropic support, and, in severe cases, elective ventilation. If oliguria persists despite optimization of intravascular volume and administration of inotropic agents, dialysis should be commenced early [19]. Antistaphylococcal antibiotics should be started as soon as the diagnosis is suspected and the site of infection identified. Current advice in the Red Book (http://aapredbook.aappublications. org) is that initial empiric antimicrobial therapy should include an antistaphylococcal antibiotic effective against beta-lactamase-resistant organisms and a protein synthesis-inhibiting antibiotic such as clindamycin to stop further toxin production [23]. If there is a focus of infection such as a vaginal tampon, surgical wound, or infected sinuses, the site should be drained early to prevent continued toxin release into the circulation. The intravenous administration of immunoglobulins may be considered when infection is refractory to several hours of aggressive therapy, an undrainable focus is present, or persistent oliguria with pulmonary edema occurs. With aggressive intensive care, most affected patients survive, and

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renal recovery is usual, even in patients who have had severe shock and multiorgan failure. Relapses and recurrences of staphylococcal toxic shock syndrome occur in a proportion of affected patients because immune responses to the toxin are ineffective in some individuals. Panton-Valentine Leukocidin (PVL)Producing Staphylococcal Infection. In recent years, there have been increasing reports of severe staphylococcal disease, associated with shock and multiorgan failure, caused by strains of staphylococci producing the PVL toxin. Panton-Valentine leukocidin (PVL) is a phage-encoded toxin, which profoundly impairs the host response due to its toxic effect on leukocytes (see review [24]). PVL-producing strains are associated with tissue necrosis and increased propensity to cause abscesses in lung, bone, joint, and soft tissue infections. Perinephric abscesses have been reported [25]. There are increasing numbers of children and adults admitted with fulminant sepsis and shock due to PVL-producing strains, and renal failure is a signiﬁcant component of the multiorgan failure. In addition to intensive care support, antibiotic treatment of PVL strains should include antibiotics which reduce toxin production, such as clindamycin, linezolid or rifampicin, as well as vancomycin if the strain is resistant to methicillin. Beta-lactam antibiotics should be avoided, as there is some data to suggest that PVL toxin production can be increased by these antibiotics under some conditions [23, 26]. Immunoglobulin infusion may also be of beneﬁt. PVL sepsis is often associated with thrombosis, and prophylactic heparin should be commenced in seriously ill patients. Aggressive surgical drainage of all collections requires close consultation with orthopedic and surgical teams.

Streptococcus Pyogenes The group A streptococci (GAS) are extracellular Gram-positive organisms. They are a major worldwide cause of renal disease, usually as poststreptococcal nephritis. However, in addition to this postinfection immunologically mediated disorder, GAS can cause AKI as part of an

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invasive infection with many features of the staphylococcal toxic shock syndrome. Acute Poststreptococcal Glomerulonephritis. Acute poststreptococcal GN (APSGN) is a delayed complication of pharyngeal infection or impetigo with certain nephritogenic strains of GAS, though many cases of postinfectious GN are unrelated to Streptococcus [27]. Worldwide, the incidence of APSGN is decreasing, although clusters of cases continue to occur [28]. APSGN after pharyngeal infection is associated with different serotypes as compared to pyoderma and skin infections [28]. Different strains can be serotyped according to the antigenic properties of the M protein found in the outer portion of the bacterial wall. The pathology and pathogenesis of the disorder is discussed in detail in ▶ Chap. 31, “Acute Postinfectious Glomerulonephritis in Children”. Detection of GAS in patients with APSGN may be possible by culture from the skin or the throat in some patients. Other evidence of infection with a GAS can be obtained through the antistreptolysinO titer (ASOT), which is increased in 60–80 % of cases. Early antibiotic treatment can reduce the proportion of cases with elevated ASOT to 30 %. Anti-deoxyribonuclease B and anti-hyaluronidase testing has been shown to be of more value than ASOT in confirming group A streptococcal infection in impetigo-associated cases. Decreased C3 and total hemolytic complement levels are found in 90 % of cases during the first 2 weeks of illness and return to normal after 4–6 weeks. Penicillin should be given to eradicate the GAS organisms. Erythromycin, clindamycin, or a firstgeneration cephalosporin can be given to patients allergic to penicillin. Early antibiotic therapy can help to prevent the immune response against the streptococcal antigens and thus the progression to glomerulonephritis and other rheumatic fever sequelae. Treatment failures have been thought to be due to the coexistence of beta-lactamaseproducing bacteria in the tonsillopharynx or due to streptococci that have invaded the epithelial cells and are protected from the antibiotics. In these instances, amoxicillin was given with clavulanate [29]. Close contacts and family members who are culture-positive for GAS should also be given penicillin, although antibiotic treatment

Infectious Diseases and the Kidney in Children

is not always effective in eliminating secondary cases. Recurrent episodes are rare, and immunity to the particular nephritogenic strain that caused the disease is probably lifelong. Antibiotic prophylaxis is therefore unnecessary. Most studies suggest that the prognosis for children with APSGN is good, with more than 90 % making a complete recovery. However, 10 % of cases may have a prolonged and more serious course with long-term chronic renal failure [30]. Other Streptococci. APSGN has also been described after outbreaks of group C streptococcal infection. For example, Streptococcus equi subsp. zooepidemicus has been found responsible for large epidemics in South America [31]. Group C streptococcal infection has occurred after consumption of unpasteurized milk from cattle with mastitis. Patients developed pharyngitis followed by APSGN. Endostreptosin was found in the cytoplasm of these group C strains, and during the course of the illness, patients developed antiendostreptosin antibodies. This antigen has been postulated to be the nephritogenic component of GAS. In addition, strains of group G streptococci have been implicated in occasional cases of APSGN [32]. Isolates possessed the type M12 protein antigen identical to the nephritogenic type M12 antigen of some group A streptococcal strains. Streptococcal Toxic Shock Syndrome and Invasive Group A Streptococcal Infection. Group A Streptococcus causes a severe illness with similarities to the staphylococcal toxic shock syndrome, occurring in both children and adults, associated with invasive group A streptococcal disease [33]. Patients with this syndrome present acutely with high fever, erythematous rash, mucous membrane involvement, hypotension, and multiorgan failure [34, 35]. Unlike staphylococcal toxic shock syndrome, in which the focus of infection is usually trivial and bacteremia is seldom seen, the streptococcal toxic shock syndrome is usually associated with bacteremia or a serious focus of infection such as septic arthritis, myositis, or osteomyelitis. Laboratory ﬁndings of anemia, neutrophil leukocytosis, thrombocytopenia, and DIC are often present, together with

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impaired renal function, hepatic derangement, and acidosis. AKI requiring dialysis occurs in a signiﬁcant proportion of cases. It is not clear why there are increasing numbers of cases with invasive disease caused by GAS, nor why there has been an emergence of streptococcal toxic shock syndrome and indeed a similar syndrome caused by some Pseudomonas and Klebsiella strains. The most common antecedent of invasive GAS disease is varicella infection, with the streptococcal infection developing after the initial vesicular phase of the disease is subsiding. Strains causing toxic shock syndrome and invasive disease appear to differ from common isolates of GAS in producing large amounts of pyrogenic toxins that may have superantigenlike activity. Another important mechanism is the production by invasive GAS of an IL8 protease. IL8 serves as a molecular bridge between receptors on neutrophils and the vascular endothelium. Cleavage of this protein prevents neutrophil attachment to the endothelium and results in uncontrolled spread of the bacteria through the tissues [36]. In severe cases, necrotizing fasciitis occurs with extensive destruction of the subcutaneous tissues and is often associated with multiorgan failure. The pathophysiology of streptococcal toxic shock syndrome and that of invasive disease is similar in that superantigen toxins that induce release of cytokines and other inﬂammatory mediators play a role in both conditions. However, GAS toxic shock is usually more severe, carries a higher mortality, and is more often associated with focal collections or necrotizing fasciitis. Treatment of streptococcal toxic shock syndrome depends on the administration of appropriate antibiotics, aggressive circulatory support, and treatment of any multiorgan failure. Surgical intervention to drain the infective focus in the muscle, bone, joint, or body cavities is often required. Antibiotic therapy with beta-lactams should be supplemented by treatment with a protein synthesis-inhibiting antibiotic, such as clindamycin, and it is suggested that this limits new toxin production [37, 38]. Pooled intravenous immunoglobulins are now in widespread use in the treatment of toxic shock,

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particularly when caused by Streptococcus [39, 40], though not all studies have reported benefit [35]. Prospective observational studies have suggested that the concomitant use of immunoglobulin with clindamycin has a positive synergistic effect on mortality [41, 42]. The role of steroids remains unclear, with their hemodynamic benefit set against the detrimental effects of hyperglycemia secondary to gluconeogenesis [43, 44]. The benefit of insulin therapy to control hyperglycemia is unclear. A study in adults found that intensive insulin therapy increased the risk of serious adverse events [45]. In contrast to adult patients, in children with severe sepsis, the use of activated protein C (drotrecogin) cannot be recommended, as in a multicenter trial, fatality was increased in the treatment group [6]. Recovery of renal function occurs in patients who respond to treatment of shock and the eradication of the infection.

Streptococcus Pneumoniae Infection with S. pneumoniae is one of the most common infections in humans and causes a wide spectrum of disease, including pneumonia, otitis media, sinusitis, septicemia, and meningitis. Despite the prevalence of the organism, a significant renal involvement is relatively rare but is seen in two situations: pneumococcal septicemia in asplenic individuals or in those with other immunodeﬁciencies presents with fulminant septic shock in which renal failure may occur as part of a multisystem derangement. The mortality from pneumococcal sepsis in asplenic patients is high, even with early antibiotic treatment and intensive support. The second nephrologic syndrome associated with S. pneumoniae is a rare form of HUS. It accounts for 5–15 % of all HUS cases in children and typically develops 3–13 days after streptococcal infection. The incidence following streptococcal infection is 0.4–0.6 %. Since the introduction of the 7- and 13-valent vaccines, there have been reports of HUS cases caused by strain not covered in the vaccine [46]. In 1955, Gasser and colleagues described HUS as a clinical entity in children, and they included two infants with pneumonia among the ﬁve patients they described [47].

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HUS associated with pneumococcal infection differs in pathophysiology from that caused by the commoner Vero toxin-producing E. coli. S. pneumoniae (as well as influenza and Clostridia species) produce the enzyme neuraminidase which cleaves sialic acid from the surfaces of exposed cells [48]. Neuraminidase causes desialation of red blood cells, and possibly other blood cells and endothelium, by the removal of terminal neuraminic acid, which leads to unmasking of the Thomsen-Friedenreich antigen (T antigen) which is present on the surface of red blood cells, platelets, and glomerular capillary endothelia. Normal serum contains antibodies to this antigen which cause a widespread agglutination of blood cells and platelets when the antigen is exposed, resulting in intravascular obstruction, hemolysis, thrombocytopenia, and renal failure. The direct Coombs test is positive in 90 % of cases of streptococcal HUS [49], either from bound anti-T IgM or from anti-T antibodies. The diagnosis of Thomsen-Friedenreich antibody-induced HUS should be suspected in patients with AKI, thrombocytopenia, and hemolysis after an episode of pneumonia or bacteremia caused by S. pneumoniae. Fragmented red blood cells will usually be present on blood film. Association of HUS with S. pneumoniae is defined by culture of pneumococci from a normally sterile site within a week before or after onset of signs of HUS. Clues to a pneumococcal cause, in addition to culture results, include severe clinical disease, especially pneumonia, empyema, pleural effusion, or meningitis; hemolytic anemia; positive results on a direct Coombs test; and difficulties in ABO crossmatching or a positive minor crossmatch incompatibility [46]. However, when renal disease is seen in the context of severe pneumococcal infection, it is important to maintain a broad diagnostic perspective, because of the frequency of acute tubular necrosis in septic shock and DIC. Therapy for this syndrome should be with supportive treatment and antibiotics (usually a thirdgeneration cephalosporin); dialysis may be required if renal failure occurs. Because normal serum contains antibodies against the ThomsenFriedenreich antigen, blood transfusion should be

Infectious Diseases and the Kidney in Children

undertaken with washed red blood cells resuspended in albumin rather than plasma [50]. Exchange transfusion and plasmapheresis have been used in some patients, with the rationale that these procedures may improve outcome by eliminating circulating neuraminidase [51]. Intravenous IgG has been used in a patient and was shown to neutralize neuraminidase present in the patient’s serum [52]. In comparison to patients with the more common diarrhea-associated HUS, S. pneumoniaeinduced HUS patients have a more severe renal disease. They are more likely to require dialysis. Their long-term outcome may be affected by the severity of the invasive streptococcal disease itself, and a signiﬁcant proportion of surviving patients (30–70 %) develop end-stage renal failure [53]. A review of UK cases found an eightfold increase in early mortality as compared to diarrhea-induced HUS. Fresh frozen plasma should be avoided unless there is active bleeding as there are concerns that the preformed anti-TF antibodies are present in FFP [51].

Leptospira Leptospirosis is an acute generalized infectious disease caused by spirochetes of the genus Leptospira. It is primarily a disease of wild and domestic animals, and humans are infected only occasionally through contact with animals. Most human cases occur in summer or autumn and are associated with exposure to Leptospira-contaminated water or soil during recreational activities such as swimming or camping. In adolescents and adults, occupational exposure through farming or other contact with animals is the route of infection. The spirochete penetrates intact mucous membranes or abraded skin and disseminates to all parts of the body, including the cerebrospinal ﬂuid (CSF). Although Leptospira do not contain classic endotoxins, the pathophysiology of the disorder has many similarities to that of endotoxemia. In severe cases, jaundice occurs because of hepatocellular dysfunction and cholestasis. Renal functional abnormalities may be profound and out of proportion to the histologic changes in the kidney [54]. Renal involvement is

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predominantly a result of tubular damage, and spirochetes are commonly seen in the tubular lesions. The inflammatory changes in the kidney may result from either a direct toxic effect of the organism or immune-complex nephritis. However, hypovolemia, hypotension, and reduced cardiac output caused by myocarditis may contribute to the development of renal failure. In severe cases, a hemorrhagic disorder caused by widespread vasculitis and capillary injury also occurs [54, 55]. The clinical manifestations of leptospirosis are variable. Of affected patients, 90 % have the milder anicteric form of the disorder, and only 5–10 % have severe leptospirosis with jaundice. The illness may follow a biphasic course. After an incubation period of 7–12 days, a nonspecific flulike illness lasting 4–7 days occurs, associated with septicemic spread of the spirochete. The fever then subsides, only to recur for the second, “immune,” phase of the illness. During this phase, the fever is low grade, and there may be headache and delirium caused by meningeal involvement, as well as intense muscular aching. Nausea and vomiting are common. Examination usually reveals conjunctival suffusion, erythematous rash, lymphadenopathy, and meningism. The severe form of the disease (Weil’s disease) presents with fever, impaired renal and hepatic function, hemorrhage, vascular collapse, and altered consciousness. In one series, the most common organs involved were the liver (71 %) and kidney (63 %). Cardiovascular (31 %), pulmonary (26 %), neurologic (5 %), and hematologic (21 %) involvements were less common [56]. Vasculitis, thrombocytopenia, and uremia are considered important factors in the pathogenesis of hemorrhagic disturbances and the main cause of death in severe leptospirosis [57]. Urinalysis results are abnormal during the leptospiremic phase with proteinuria, hematuria, and casts. Uremia usually appears in the second week, and AKI may develop once cardiovascular collapse and DIC are present [58]. The clinical features of leptospirosis overlap with those of several other acute infectious diseases, including Rocky Mountain spotted fever, toxic shock syndrome, and streptococcal sepsis.

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The diagnosis of leptospirosis should be considered in febrile patients with evidence of renal, hepatic, and mucous membrane changes and rash, particularly if a history of exposure to freshwater is found. Diagnosis can be confirmed by isolation of the spirochetes from blood or CSF in the first 10 days of the illness or from urine in the second week [58]. The organism may be seen in biopsy specimens of the kidney or skin or in the CSF by dark-field microscopy or silver staining. Serologic tests to detect leptospirosis are now sensitive and considerably aid the diagnosis. Immunoglobulin M (IgM) antibody may be detected as early as 6–10 days into the illness, and antibody titers rise progressively over the next 2–4 weeks. Some patients remain seronegative, and negative serologic test results do not completely exclude the diagnosis. In one series, levels of IgM and IgG anticardiolipin concentrations were significantly increased in leptospirosis patients with AKI [57]. Leptospirosis is treated with intravenous penicillin or other beta-lactam antibiotics. The severity of leptospirosis is reduced by antibiotic treatment, even if started late in the course of the illness [55]. Supportive treatment with volume replacement to correct hypovolemia, administration of inotropes, and correction of coagulopathy is essential in severe cases. Dialysis may be required in severe cases and may be needed for prolonged periods until recovery occurs.

Gastrointestinal Infections The diarrheal diseases caused by Escherichia coli, Salmonella, Shigella, Campylobacter, Vibrio spp., and Yersinia remain important and common bacterial infections of humans. Although improvements in hygiene and living conditions have reduced the incidence of bacterial gastroenteritis in developed countries, these infections remain common in underdeveloped areas of the world, and outbreaks and epidemics continue to occur in both developed and underdeveloped countries. Renal involvement in the enteric infections may result from any of four possible mechanisms.

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Severe Diarrhea and Dehydration. Regardless of the causative organism, diarrhea results in hypovolemia, abnormalities of plasma electrolyte composition, and renal underperfusion. If severe dehydration occurs and is persistent, oliguria from prerenal failure is followed by vasomotor nephropathy and established renal failure. Systemic Sepsis and Endotoxemia. E. coli, Shigella, and Salmonella (particularly Salmonella typhi) may invade the bloodstream and induce septicemia or septic shock. AKI is commonly seen in infants with E. coli sepsis but is also reported with Klebsiella, Salmonella, and Shigella infections. Its pathophysiology and treatment were discussed previously. Enteric Pathogen-Associated Nephritis. Enteric infections with E. coli, Yersinia, Campylobacter, and Salmonella have been associated with several different forms of GN, including membranoproliferative GN (MPGN), interstitial nephritis, diffuse proliferative GN, and IgA nephropathy. In typhoid fever, GN ranging from mild asymptomatic proteinuria and hematuria to AKI may occur [59]. Renal biopsy ﬁndings show focal proliferation of mesangial cells, hypertrophy of endothelial cells, and congested capillary lumina. Immunoﬂuorescent studies show IgM, IgG, and C3 deposition in the glomeruli, with Salmonella antigens detected within the granular deposits in the mesangial areas. In the IgA nephropathy after typhoid fever, Salmonella vi antigens have been demonstrated within the glomeruli. Yersinia infection has been reported as a precipitant of GN. Transient proteinuria and hematuria are found in 24 % of patients with acute Yersinia infection and elevated creatinine levels in 10 %. Renal biopsy reveals mild mesangial GN or IgA nephropathy. Yersinia antigens, immunoglobulin, and complement have been detected in the glomeruli. Yersinia pseudotuberculosis is well recognized as one of the causes of acute tubulointerstitial nephritis causing AKI, especially in children; patients have histories of drinking untreated water in endemic areas [60, 61]. The illness begins with the sudden onset of high fever, skin rash, and GI symptoms. Later in the course, periungual desquamation develops, mimicking Kawasaki disease. Elevated erythrocyte sedimentation rate,

Infectious Diseases and the Kidney in Children

C-reactive protein level, and thrombocytosis are noticeable, and mild degrees of proteinuria, glycosuria, and sterile pyuria are common. AKI, which typically develops 1–3 weeks after the onset of fever, follows a benign course with complete recovery. Renal biopsy mainly reveals ﬁndings of acute tubulointerstitial nephritis. Antibiotic therapy, although recommended, does not alter the clinical course, but reduces the fecal excretion of the organism [62]. Enteric Pathogen-Induced Hemolytic Uremic Syndrome. HUS is characterized by three distinct clinical signs: AKI, thrombocytopenia, and microangiopathic hemolytic anemia. It was ﬁrst described in 1955 and was associated with infection by Shiga toxin-producing Shigella dysenteriae. A major breakthrough in the search for the cause of HUS occurred in the 1980s when Karmali et al. reported that 11 of 15 children with diarrhea-associated HUS had evidence of infection with a strain of E. coli that produced a toxin active on Vero cells [63]. In diarrhea-associated HUS in the United States and most of Europe, E. coli 0157:H7 is the most important of these strains. E. coli 0157:H7 occurs naturally in the GI tract of cattle and other animals, and humans become infected through contaminated food products. Most outbreaks have been associated with consumption of undercooked meat, but unpasteurized milk and cider, drinking water, and poorly chlorinated water for recreational use have also been implicated as vehicles for bacterial spread. HUS is discussed in detail in ▶ Chap. 47, “Renal Involvement in Children with HUS”.

Mycobacterium Tuberculosis The global epidemic of Mycobacterium tuberculosis is persisting. Several factors have contributed to this, including the emergence of the human immunodeﬁciency virus (HIV) infection epidemic, large inﬂuxes of immigrants from countries in which tuberculosis (TB) is common, the emergence of multiple-drug-resistant M. tuberculosis, and breakdown of the health services for effective control of TB in various countries. The World Health Organization

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(WHO) estimated that in 2012 there were 8.6 million incident cases of tuberculosis (TB) in the world, a rate of 122 per 100,000 population. Tuberculosis deaths were estimated at 1.3 million. One-third of the world’s population is currently infected with TB, and the estimated lifetime risk of developing disease is 5–10 % (http://www. who.int/mediacentre/factsheets/fs104/en/). Mycobacteria, both M. tuberculosis and atypical mycobacteria, have also emerged as important causes of opportunistic infection in immunocompromised patients undergoing dialysis and in patients undergoing renal transplantation. The possibility of mycobacterial disease must be considered in patients with fever of unknown origin or unexplained disease in the lungs or other organs. Results of the Mantoux test are often negative, and diagnosis depends on maintaining a high index of suspicion and isolating the organism from the infected site. Primary Progressive TB. Although most infected children successfully contain the infection and enter a state of latency, about 10 % develop progressive primary or postprimary infection, with mycobacteria disseminating to many organs of the body during the lymphohematogenous phase of the disease. Tubercle bacilli can be recovered from the urine in many cases of miliary TB. Hematogenously spread tuberculomata develop in the glomeruli, which results in caseating, sloughing lesions that discharge bacilli into the tubules. In most cases, the renal lesions are asymptomatic and manifest as mycobacteria in the urine or as sterile pyuria. Tuberculomata in the cortex may calcify and cavitate or may rupture into the pelvis, discharging infective organisms into the tubules, urethra, and bladder. Dysuria, loin pain, hematuria, and pyuria are the presenting features of this complication, but in many cases, the renal involvement is asymptomatic, even when radiologic and pathologic abnormalities are very extensive. Continuing tuberculous bacilluria may cause cystitis with urinary frequency and, in late cases, a contracted bladder. The intravenous urogram is abnormal in most cases. Early ﬁndings are pyelonephritis with calyceal blunting and calycealinterstitial reﬂux. Later, papillary cavities may be seen, indicating papillary necrosis. Ureteric

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strictures, focal calciﬁcation, hydronephrosis, and cavitation may also be seen. Renal function is usually well preserved, and hypertension is uncommon. In some cases, either the infection itself or reactions to the chemotherapeutic agents may result in renal failure with evidence of an interstitial nephritis [64]. Renal TB. Classic symptomatic renal TB is a late and uncommon complication in children. The average latency period between pulmonary infection with bacillemia and clinical urogenital tuberculosis is 22 years, and renal TB is more commonly seen in adults [65]. Adult studies have shown that 26–75 % of renal TB coexists with active pulmonary TB and 6–10 % of screened sputum-positive pulmonary TB patients have renal involvement. The diagnosis is established by isolation of mycobacteria from the urine or by the presence of the characteristic clinical and radiographic features in a child with current or previous TB. Renal TB is treated with drug regimens similar to those used for other forms of TB, with isoniazid, rifampicin, pyrazinamide, and ethambutol administered initially for 2 months and isoniazid and rifampicin then continued for a further 7–10 months. Late scarring and urinary obstruction may occur in cases with extensive renal involvement, and such patients should be followed by ultrasonography or intravenous urogram. Surgical intervention may be required in the form of stenting, percutaneous nephrostomy, or partial or total nephrectomy [66].

Treponema Pallidum Renal involvement in both congenital and acquired syphilis has an estimated occurrence of 0.3 % in patients with secondary syphilis and between 5 % and 16 % in those with congenital syphilis [67]. The most common manifestation of renal disease in congenital syphilis is the nephrotic syndrome, with proteinuria, hypoalbuminemia, and edema. In some patients, hematuria, uremia, and hypertension may be seen. The renal disease is usually associated with other manifestations of

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congenital syphilis, including hepatosplenomegaly, rash, and mucous membrane findings. Nephritis in congenital syphilis is usually associated with evidence of complement activation, with depressed levels of Clq, C4, C3, and C5. Histologic findings are a diffuse proliferative GN or a membranous nephropathy. The interstitium shows a cellular infiltrate of polymorphonuclear and mononuclear cells [68]. Immunofluorescent microscopy reveals diffuse granular deposits of IgG and C3 along the glomerular basement membrane (GBM). Mesangial deposits may also contain IgM. On electron microscopy, scattered subepithelial electron-dense deposits are seen, with fusion of epithelial cell foot processes [68]. Good evidence exists that renal disease is due to an immunologically mediated reaction to treponemal antigens. Antibodies reactive against treponemal antigens can be eluted from the glomerular deposits, and treponemal antigens are present in the immune deposits. Treatment of both congenital and acquired syphilis with antibiotics results in rapid improvement in the renal manifestations [68].

Mycoplasma Pneumoniae Renal involvement is surprisingly rare in Mycoplasma pneumoniae infection considering the prevalence of this organism and its propensity to trigger immunologically mediated diseases such as erythema multiforme, arthritis, and hemolysis. Acute nephritis associated with Mycoplasma infection may occur 10–40 days after the respiratory tract infection [69]. A few cases of IgA nephropathy have been reported following Mycoplasma infection [70]. Renal histopathologic ﬁndings include type 1 MPGN, proliferative endocapillary GN, and minimal change disease [71]. Antibiotic treatment of the infection does not appear to affect the renal disease, which is self-limited in most cases [69].

Legionnaires’ Disease Since its recognition in 1976, Legionnaires’ disease, caused by Legionella pneumophila, has

Infectious Diseases and the Kidney in Children

emerged as an important cause of pneumonia. The disease most commonly affects the elderly but has been reported in both normal and immunocompromised children. Renal dysfunction occurs in a minority of patients [72]. Those who develop renal failure can present with transient azotemia, hematuria, proteinuria, pyuria, or cylindruria. They are usually severely ill, with bilateral pulmonary inﬁltrates, fever, and leukocytosis. Shock may be present, and the renal impairment has been associated with acute rhabdomyolysis with high levels of creatine phosphokinase and myoglobinuria. Renal histologic examination usually shows a tubulointerstitial nephritis or acute tubular necrosis [72, 73]. The pathogenesis of the renal impairment is uncertain, but the organism has been detected within the kidney on electron microscopy and immunoﬂuorescent studies, which suggests a direct toxic effect. Myoglobinuria and decreased perfusion may also be contributing factors, however. Mortality has been high in reported cases of Legionnaires’ disease complicated by renal failure. Treatment is based on dialysis, intensive care, and antimicrobial therapy with erythromycin [72]. Steroid therapy may be effective for tubulointerstitial nephritis [73].

Rickettsial Diseases The rickettsial diseases are caused by a family of microorganisms that have characteristics common to both bacteria and viruses and that cause acute febrile illnesses associated with widespread vasculitis. With the exception of Q fever, all are associated with erythematous rashes. There are four groups of rickettsial diseases: 1. The typhus group includes louse-borne and murine typhus, spread by lice and ﬂeas, respectively. 2. The spotted fever group includes Rocky Mountain spotted fever, tick typhus, and related Mediterranean spotted fever and rickettsial pox, which are spread by ticks and mites, with rodents as the natural reservoir.

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3. Scrub typhus, which is spread by mites. 4. Q fever, which is spread by inhalation of infected particles from infected animals. Rickettsial diseases have a worldwide distribution and vary widely in severity, from self-limited infections to fulminant and often fatal illnesses. In view of the widespread vasculitis associated with these infections, subclinical renal involvement probably occurs in many of the rickettsial diseases. However, in Rocky Mountain spotted fever, tick typhus, and Q fever, the renal involvement may be an important component of the illness.

Rocky Mountain Spotted Fever Rocky Mountain spotted fever is the most severe of the rickettsial diseases. The incidence has increased over the last decade from less than two cases per million persons in 2000 to over six million in 2010. The mortality has declined to 0.5 % in the same time period. Children under 10 years, those with a compromised immune system and those with a delayed diagnosis are at an increased risk of fatality. Prior to specific antibiotic therapy, the mortality was 25 % (http://www. cdc.gov/rmsf/stats/). The onset occurs 2–8 days after the bite of an infected tick, and the majority of cases occur during the summer months. High fever develops initially, followed by the pathognomonic rash, which occurs between the second and sixth days of the illness. The rash initially consists of small erythematous macules, but later these become maculopapular and petechial, and in untreated patients, confluent hemorrhagic areas may be seen. The rash first appears at the periphery and spreads up the trunk. Involvement of the palms and soles is a characteristic feature. Headache, restlessness, meningism, and confusion may occur together with other neurologic signs. Cardiac involvement with congestive heart failure and arrhythmia are common. Pulmonary involvement occurs in 10–40 % of cases. Infection is associated with an initial leukopenia, followed by neutrophil leukocytosis. Thrombocytopenia occurs in most cases [74].

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Histopathologically, the predominant lesions are in the vascular system. Rickettsiae multiply in the endothelial cells, which results in focal areas of endothelial cell proliferation, perivascular mononuclear cell infiltration, thrombosis, and leakage of red cells into the tissues. The renal lesions involve both blood vessels and interstitium, and acute tubular necrosis may occur. Acute GN with immune-complex deposition has been reported [75], but in most cases the pathology appears to be a direct consequence of the invading organism on the renal vasculature. Renal dysfunction is an important complication of Rocky Mountain spotted fever. Elevation of urea and creatinine levels occurs in a third of children, and acidosis is common. AKI was associated with increased mortality – 20 % in a recent Mexican cohort [76]. Factors at presentation that have been associated with increased risk of developing renal impairment in adults are increasing age, rising bilirubin, thrombocytopenia, and neurological involvement. In one adult case series, factors associated with increased mortality were raised creatinine, raised bilirubin and AST, hypernatremia, thrombocytopenia, increasing age, and neurological involvement [77]. Prerenal renal failure caused by hypovolemia and impaired cardiac function may respond to volume replacement and inotropic support, but AKI may subsequently occur, necessitating dialysis. Rocky Mountain spotted fever is diagnosed by the characteristic clinical picture, the exclusion of disorders with similar manifestations (e.g., measles, meningococcal disease, and leptospirosis), and detection of specific antibodies in convalescence. Culture of Rickettsia rickettsii, immunofluorescent staining, and polymerase chain reaction (PCR) testing of blood and skin biopsy specimens are available only in reference laboratories. Antibiotics should be administered in suspected cases without awaiting confirmation of the diagnosis [74]. Doxycycline is the drug of choice for children of any age. Chloramphenicol is also effective. Intensive support of shock and multiorgan failure may be required in severe cases, and peritoneal dialysis or hemodialysis may be required until renal function returns.

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Q Fever Q fever is caused by Coxiella burnetii and has a worldwide distribution, with the animal reservoir being cattle, sheep, and goats. Human infection follows inhalation of infected particles from the environment. The clinical manifestations range from an acute self-limited febrile illness with atypical pneumonia to involvement of specific organs that causes endocarditis, hepatitis, osteomyelitis, and central nervous system disease [78]. Proliferative GN may be associated with either Q fever endocarditis, rhabdomyolysis, or a chronic infection elsewhere in the body. Tubulointerstitial nephritis (attributed to immune-complex deposition) is usually associated with chronic rather than acute disease. The incidence of renal complications in Q fever is unknown due to the small numbers of case reports, but a recent case series of 54 patients demonstrated that 33 % had renal failure [79]. Renal manifestations range from asymptomatic proteinuria and hematuria to AKI, hypertension, and nephrotic syndrome. Renal histologic findings are those of a diffuse proliferative GN, focal segmental GN, or mesangial GN. Immunofluorescent studies reveal diffuse glomerular deposits of IgM in the mesangial, together with C3 and fibrin. Coxiella burnetii antigen has not been identified within the renal lesions. IgG antibodies to cardiolipin and lupus anticoagulant have been demonstrated in acute-phase serum samples [80]. Treatment of the underlying infection may result in remission of the renal disease, but prolonged treatment may be required for endocarditis. Doxycycline is the first line recommended treatment for adults and children and has not been linked to dental staining as occurs with other tetracyclines and so can be used in children of all ages who are hospitalized with Q fever [81]. Co-trimoxazole has been used as a safe alternative (deemed safe in pregnant women) as has clarithromycin. In the acute setting, treatment should continue until 3 days after the fever has subsided (usual duration is 2–3 weeks). Chronic infection requires a longer treatment, usually 18 months (CDC recommendation).

Infectious Diseases and the Kidney in Children

Intravascular and Focal Bacterial Infections Nephritis has been reported in association with the presence of a wide range of microorganisms that cause chronic or persistent infection (Table 2). It is likely that any infectious agent that releases foreign antigens into the circulation, including those of very low virulence, can cause renal injury either by deposition of foreign antigens in the kidney or by the formation of immune complexes in the circulation, which are then deposited within the kidney. Nephritis is most commonly seen in association with intravascular infections such as SBE or infected ventriculoatrial shunts, but it is also seen after focal extravascular infections; ear, nose, and throat infections; and abscesses.

1625 Table 2 Focal infections causing glomerulonephritis Site of infection Infective endocarditis

Shunt infections

Bacterial Endocarditis Renal involvement is one of the diagnostic features of bacterial endocarditis. Virtually all organisms that cause endocarditis also produce renal involvement (Table 2). Although endocarditis caused by bacteria is the most common and is readily diagnosed by blood culture, unusual but important causes of culture-negative endocarditis include Q fever and Legionella infection. In the immunocompromised individual, opportunistic pathogens such as fungi and mycobacteria are important causes. The usual renal manifestations of SBE are asymptomatic proteinuria, hematuria, and pyuria. Loin pain, hypertension, nephrotic syndrome, and renal failure may occur in more severe cases. The renal lesions occurring in endocarditis are variable, and focal embolic and immunecomplex-mediated features may coexist [82, 83]. Embolic foci may be evident as areas of infarction, intracapillary thrombosis, or hemorrhage. More commonly, there is a focal necrotizing or diffuse proliferative GN. Immunoﬂuorescent studies show glomerular deposits of IgG, IgM, IgA, and C3 along the GBM and within the mesangium. Electron microscopy reveals typical electron-dense deposits along the GBM and within the mesangium [82].

Focal abscess Osteomyelitis Pyelonephritis Pneumonia

Otitis media Gastrointestinal infection

Organism Coagulase-negative staphylococci Staphylococcus aureus Streptococcus pneumoniae Viridans streptococci Enterococci Anaerobic streptococci Diphtheroids Haemophilus inﬂuenzae Coliforms Bacteroides Coxiella burnetii Legionella Candida albicans Coagulase-negative staphylococci Staphylococcus aureus Diphtheroids Gram-negative bacilli Anaerobes Staphylococcus aureus Gram-negative bacilli Staphylococcus aureus Streptococcus pyogenes Coliforms Streptococcus pneumoniae Klebsiella Staphylococcus aureus Mycoplasma Streptococcus pneumoniae Staphylococcus aureus Yersinia Campylobacter Salmonella Shigella

Early reports suggested that the renal lesions were caused by microemboli from infected vegetations depositing in the kidney, a hypothesis supported by the occasional presence of bacteria within the renal lesions. Most subsequent evidence, however, indicates that immunologic mechanisms rather than emboli are involved in the pathogenesis in most cases: bacteria are rarely found within the kidney, and renal involvement occurs with lesions of the right side of the heart,

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which would not be likely to embolize to the kidney. Immune complexes containing bacterial antigens are present in the circulation, and both bacterial antigens and bacteria-speciﬁc antibodies can be demonstrated within the immune deposits in the kidney. Serum C3 level is usually low, and complement can be found within both the circulating and the deposited immune complexes. These features all support an immune-complex-mediated pathogenesis of the renal injury. Treatment of the endocarditis with antibiotics usually results in resolution of the GN and is associated with the disappearance of immune complexes from the circulation and return of C3 levels to normal. The prognosis of the renal lesions in SBE generally depends on the response of the underlying endocarditis to antibiotics or, in cases of antibiotic failure, to surgical removal of the infective vegetations [84].

Shunt Nephritis In patients previously treated by shunting for hydrocephalus, there is a well-documented association of GN with infected ventriculoatrial shunts. The incidence of shunt nephritis has decreased due to the preference of ventriculoperitoneal shunts over ventriculoatrial shunts; however, shunt nephritis has been reported with the former [85]. Coagulase-negative staphylococci are the causative organisms in 75 % of cases. It is an immune-complex disease with chronic hyperantigenemia, hyperglobulinemia, and the deposition of immunoglobulins, complement, and immune complexes on the glomerular basement membrane [86]. The clinical and pathologic ﬁndings are similar to those in SBE. Presenting features are proteinuria, hematuria, and pyuria, and they may progress to renal failure. Immune complexes containing the bacterial antigens and complement are present in the serum, and C3 is depressed. Histologic ﬁndings are those of a diffuse mesangiocapillary GN. The prognosis for the renal lesion is good if the infection is treated early. This usually involves removal of the infected shunt or replacement of a VA with a VP shunt and administration of appropriate

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antibiotics, though possible progression to end-stage renal disease requires frequent renal monitoring of patients with ventriculoatrial shunts [87]. Certain case reports have also seen beneﬁt with the use of steroids as adjunctive therapy [88].

Other Focal Infections GN has been reported after chronic abscesses, osteomyelitis, otitis media, pneumonia, and other focal infections (Table 2). AKI has been the presenting feature of focal infections in various sites, including the lung, pleura, abdominal cavity, sinuses, and pelvis. Many different organisms have been responsible, including S. aureus, Pseudomonas, E. coli, and Proteus species. This is probably another example of immune-complex GN. C3 level is decreased in approximately one-third of reported cases, and immunoﬂuorescent studies reveal diffuse granular deposits of C3 in the glomeruli of all reported instances, with a variable presence of immunoglobulin. The renal lesion is that of MPGN and crescentic nephritis. The renal outcome is reported to be good with successful early treatment of the underlying infection.

Viral Infections The role of viral infections in the causation of renal disease has been less well defined than that of bacterial infections. Clearly defined associations of renal disease have been made with hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, and hantaviruses, but the role of most other viruses in the pathogenesis of renal disease is not clearly defined. Most viruses causing systemic infection may trigger immunologically mediated renal injury. With increasing application of molecular techniques, it may be that a significant proportion of GNs currently considered to be idiopathic will ultimately be shown to be virus induced. In children with immunodeficiency states and those undergoing renal transplantation, viruses such as cytomegalovirus (CMV) and polyomavirus have been recognized to be associated with nephropathy.

Infectious Diseases and the Kidney in Children

Hepatitis B Virus About 2,000 million people alive today have been infected with hepatitis B at some point in their lives, of these 350 million become chronically infected and are carriers of the disease. There are an estimated four million acute cases per year, and per year 25 % of carriers (one million) die from cirrhosis, chronic active hepatitis, or primary hepatocellular carcinoma. The infection is most common in Africa and the Orient, where it is acquired in childhood by vertical transmission from infected mothers or by horizontal transmission from other children or adults. In developed countries, transmission in adults occurs more often by blood product exposure, sexual contact, or intravenous drug use. The epidemiology of HBV infection in children is changing following the widespread use of effective vaccination at birth, in both developed and developing countries. HBV is a complex DNA virus with an outer surface envelope (HBsAg) and an inner nucleocapsid core containing the hepatitis B core antigen (HBcAg), DNA polymerase, protein kinase activity, and viral DNA. Incomplete spherical and ﬁlamentous viral particles consisting solely of HBsAg are the major viral products in the circulation and may be present in concentrations of up to 1,014 particles per milliliter of serum. Hepatitis B e antigen (HBeAg) can be released from HBcAg by proteolytic treatment and may be found in the circulation either free or complexed to albumin or IgG antibodies. The presence of HBeAg correlates with the presence of complete viral particles and the infectivity of the individual. Infection with HBV may result in either a selflimited infectious hepatitis followed by clearance of the virus and complete recovery, or a chronic or persistent infection in which the immune response is ineffective in eliminating the virus. Chronic HBV infection with continued presence of viral antigens in the circulation caused by an ineffective host immune response provides the bestdocumented example of immunologically mediated renal injury caused by persistent infection. The risk of chronic infection varies inversely with age with 90 % of infants infected at birth

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developing chronic infection, compared to 25–50 % of children infected between 1 and 5 years and 1–5 % of people infected as older children and adults. Chronic infection is also common in those with immunodeﬁciency.

Patterns of Hepatitis B Virus Immunologically Mediated Renal Disease Several forms of renal disease secondary to hepatitis B infection have been identified including membranous glomerulonephritis, mesangioproliferative glomerulonephritis, as well as IgA nephropathy and focal segmental glomerulosclerosis (FSGS) [89]. Hepatitis B has also been linked with polyarteritis nodosa (PAN). Prodromal Illness. In the early prodromal phase of HBV hepatitis, before the onset of jaundice, some patients develop fever, maculopapular or urticarial rash, and transient arthralgias or arthritis. Occasionally, proteinuria, hematuria, or sterile pyuria is observed. The syndrome usually lasts 3–10 days and often resolves before the onset of jaundice [90]. There have been no histologic studies of the renal changes during this prodromal period. Hepatitis B Virus-Associated Polyarteritis Nodosa. HBV infection is associated with polyarteritis nodosa, a vasculitis affecting the small- and medium-sized vessels (HBV PAN). Most of these cases have been in adults, but the disorder has also been reported in children, where it is estimated that approximately one-third of PAN cases are caused by HBV [91, 92]. HBV PAN appears to be uncommon in Africa and the Orient, where infection is usually acquired in childhood, and has declined in incidence following the introduction of HBV vaccination [93]. HBV PAN presents weeks to months after a clinically mild hepatitis but may occasionally predate the hepatitis. After a prodromal illness, frank vasculitis affecting virtually any organ appears. Abdominal pain, fever, mononeuritis multiplex, and pulmonary and renal involvement may occur and can be the first clinical presentation of hepatitis B [94]. The renal involvement may appear as hypertension, hematuria, proteinuria, or renal failure. Laboratory investigations reveal a florid

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acute-phase response, leukocytosis, and anemia. Transaminase levels are usually elevated, and HBsAg is present in the circulation. The pathology consists of focal inflammation of small- and medium-sized arteries, with fibrinoid necrosis, leukocyte infiltration, and fibrin deposition. Renal pathology may be limited to the mediumsized arteries or may coexist with GN [95]. Circulating immune complexes containing HBsAg and anti-HBs antibodies are usually present in the circulation. C3, C4, and total hemolytic complement levels are depressed. A positive ANCA excludes HBV PAN [93]. Although most evidence suggests that the pathogenesis involves an immune-complex-mediated vasculitis, autoantibody- or cell-mediated vascular injury may coexist. If the condition is untreated, the mortality is high. Most studies suggest that steroids or immunosuppressants help to suppress the vasculitis but potentially predispose to chronic infection or progressive liver disease. Successful treatment of hepatitis B-associated PAN with nucleoside analogues such as lamivudine or newer antiviral drugs, either alone or in combination with interferon-alpha and conventional immunosuppressive therapy, has been reported [93, 96]. Hepatitis B Virus-Associated Membranous Glomerulonephritis. HBV is now the major cause of membranous GN (MGN) in children worldwide. The proportion of patients with MGN caused by HBV is directly related to the incidence of HBsAg in the population, with 80–100 % of all cases of MGN in some African and Oriental countries being associated with HBV (see ▶ Chap. 34, “Membranous Nephropathy in Children”). HBV MGN usually presents in children aged 2–12. There is a striking male predominance. The virus is usually acquired by vertical transmission from infected mothers or horizontally from infected family members. Unlike adults with HBV MGN, children do not usually have a history of hepatitis or of active liver disease, but liver function test results are generally mildly abnormal. Liver biopsy specimens may show minimal abnormalities, chronic persistent hepatitis, or (occasionally) more severe changes. The renal manifestations are usually of proteinuria, nephrotic syndrome, microscopic hematuria,

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or (rarely) macroscopic hematuria. Hypertension occurs in less than 25 % of cases, and renal insufﬁciency is rare. HBsAg and HBcAg are usually present in the circulation, and HBe antigenemia is seen in a high proportion of cases. Occasionally, HBsAg may be found in the glomeruli but is absent from the circulation. C3 and C4 levels are often low, and circulating immune complexes are found in most cases. Immunohistologic study reveals deposits of IgG and C3 and (less commonly) IgM and IgA in subepithelial, subendothelial, or mesangial tissue. HBV particles may be seen on electron microscopy, and all the major hepatitis B antigens, including HBsAg, HBcAg, and HBeAg, have been localized in the glomerular capillary wall on immunoﬂuorescence. Immunologic deposition of HBV and antibody in the glomerular capillary wall is clearly involved in the glomerular injury, but the underlying immunologic events are incompletely understood [90]. Passive trapping of circulating immune complexes may be involved, but the circulating immune complexes containing HBsAg are usually larger than would be expected to penetrate the basement membrane. HBsAg and HBcAg are anionic and are therefore unlikely to penetrate the glomerular capillary wall. In contrast, HBeAg forms smaller complexes with anti-HBe antibodies and may readily penetrate the GBM. This may explain the observation that HBeAg in the circulation frequently correlates with the severity of the disease [90]. An alternative mechanism for immune-mediated glomerular injury is the trapping of HBV antigens by antibody previously deposited in the kidney. Anti-HBe antibodies are cationic and may readily localize in the glomerulus and subsequently bind circulating antigen and complement. The third possibility is that the depositions of HBV and antibodies are consequences of glomerular injury by cellular mechanisms or autoantibodies. Little evidence supports this view at present [90]. A transgenic mouse model of HBV-associated nephropathy has been developed, in which HBsAg and HBcAg is expressed in the liver and kidney, particularly tubular epithelial cells, without viral replication. In these mice, gene expression analysis revealed

Infectious Diseases and the Kidney in Children

upregulation of acute-phase proteins, particularly C3, although measurable serum C3 levels were reduced. This supports the notion that local persistent expression of HBV viral proteins contributes to HBV-associated nephropathy [97]. Other Hepatitis B Virus Glomerulonephritides. HBV infection has been associated with a variety of other forms of GN in both adults and children [95]. Both MPGN and mesangial proliferative GN may be triggered by HBV. In several countries where HBV is common, the proportion of patients with these forms of nephritides who test positive for HBV greatly exceeds the incidence of positivity in the general population. As with MGN and HBV-associated PAN, circulating immune complexes and localization of HBV antigens in the glomeruli have been reported in both MPGN and mesangial proliferative GN, and it is likely that similar mechanisms are occurring [90]. Several other forms of GN have been associated with HBV, including IgA nephropathy, focal glomerulosclerosis, crescentic nephritis, and systemic lupus erythematosus, but the evidence for these associations is less consistent than for the entities discussed earlier [95].

Treatment of Hepatitis B Virus Glomerulonephritis HBV is normally cleared as a result of cellmediated responses in which cytotoxic T cells and natural killer cells eliminate infected hepatocytes. It is not surprising, therefore, that the administration of steroids and immunosuppressive agents either may have no effect on HBV disease or may increase the risk of progressive disease. Children with HBV MGN have a good prognosis, and two-thirds undergo spontaneous remission within 3 years of diagnosis. Steroid therapy does not appear to provide any additional beneﬁt [90, 98]. Antiviral therapy with pegylated interferon-alpha and lamivudine is used to treat HBV, and in some cases, elimination of the infection with antiviral therapy in both children and adults is associated with improvement or resolution of the coexisting renal disease [99]. There are isolated case reports of pegylated interferon successfully treating IgA nephropathy associated with HBV [100]. There have been some

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promising results with newer antiviral agents such as adefovir and entecavir in treating HBV glomerulonephritis in combination regimens [101].

Hepatitis C Virus HCV is an enveloped, single-stranded RNA virus of approximately 9.4 kilobases in the Flaviviridae family. There are six major HCV genotypes. Hepatitis C is a common disease affecting approximately 400 million people worldwide. In the United States, 4.1 million persons are estimated to be anti-HCV positive, and 3.2 million may be chronically infected [102]. An estimated 240,000 children in the United States have antibody to HCV, and 68,000–100,000 are chronically infected. Children become infected through receipt of contaminated blood products or through vertical transmission. The risk of vertical transmission increases with higher maternal viremia and maternal coinfection with HIV. Acute HCV infection is rarely recognized in children outside of special circumstances such as a known exposure from an HCV-infected mother or after blood transfusion. Most chronically infected children are asymptomatic and have normal or only mildly abnormal alanine aminotransferase levels. Although the natural history of HCV infection during childhood seems benign in the majority of instances, the infection can take an aggressive course in a proportion of children, leading to cirrhosis and end-stage liver disease during childhood. The factors responsible for this more aggressive course are unidentiﬁed [103]. Even in adults, the natural history of HCV infection has a variable course, but a signiﬁcant proportion of patients will develop some degree of liver dysfunction, and 20–30 % will eventually have end-stage liver disease as a result of cirrhosis. The risk of hepatocellular carcinoma is significant for those who have established cirrhosis. Hepatitis C is currently the most common condition leading to liver transplantation in adults in the “Western world.” GN has been described as an important complication of chronic infection with HCV

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in adults [104]. The clinical presentation is usually of nephrotic syndrome or proteinuria, hypertension, or hematuria, with or without azotemia. MPGN, with or without cryoglobulinemia, and MGN are most commonly described [105]. Isolated case reports of other, more unusual patterns of glomerular injury, including IgA nephropathy, focal segmental glomerulosclerosis, crescentic GN, fibrillary GN, and thrombotic microangiopathy, have also been associated with HCV infection [106]. Glomerular deposition of hepatitis antigens and antibodies has been described and is believed to play a role in pathogenesis. Cryoglobulinemia is a common accompaniment of GN that is associated with the depression of serum complement levels [106]. Renal failure may develop in 40–100 % of patients who have MPGN. The presence of viruslike particles as well as viral RNA within the kidney sections of patients with HCV-associated glomerulopathies has been reported [107]. The diagnosis should be suspected if glomerular disease is associated with chronic hepatitis, particularly with the presence of cryoglobulins, but renal biopsy is necessary to establish a definitive diagnosis. HCV infection is relatively common in children with end-stage renal disease and is an important cause of liver disease in this population. HCV-infected renal transplant recipients had higher mortality and hospitalization rates than other transplant recipients [108], and HCV infection has been reported to be associated with de novo immune-mediated GN, especially type 1 MPGN, in renal allografts, resulting in accelerated loss of graft function. The PEDS-C trials, a randomized controlled trial in children and adolescents, have shown that ribavirin and pegylated interferon is superior to pegylated interferon and placebo in treating chronic hepatitis C in this age group, and this combination constitutes the US standard of care [109]. Clinical trials are currently underway investigating the efficacy of a new generation of HCV antiviral drugs, including sofosbuvir, boceprevir, and telaprevir in combination with pegylated interferon and ribavirin. Triple therapy has been associated with a higher sustained virological response in adults [110].

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Hepatitis C may be complicated by systemic mixed cryoglobulinemic (MC) vasculitis and in some cases by a polyarteritis nodosa (PAN)-type non-cryoglobulinemic vasculitis [111]. Treatment with interferon-α (IFN-α) and ribavirin mostly is associated with an improvement of vasculitic symptoms. In some cases, exacerbation and rarely new onset of vasculitis of the peripheral nervous system have been described after this treatment. In fulminant cases, immunosuppressive therapy with steroids, and cyclophosphamide, or rituximab may be needed to control life-threatening vasculitis prior to antiviral treatment [111].

Herpes Viruses: Cytomegalovirus CMV is one of the eight human herpes viruses. Transmission of the virus requires exposure to infected body fluids such as breast milk, saliva, urine, or blood. Individuals initially infected with CMV may be asymptomatic or display nonspecific flulike symptoms. After the initial infection CMV, like all herpes viruses, establishes latency for life but will be periodically excreted by an asymptomatic host. CMV replicates within renal cells, and on biopsy samples from immunocompromised hosts, viral inclusions can be visualized by light microscopy in cells of the convoluted tubules and collecting ducts [112]. Glomerular cells and shed renal tubular cells may have characteristic inclusions, but clinically evident renal disease is rare and is seen virtually only in immunocompromised or congenitally infected children. The clinical manifestations of CMV-induced renal disease in congenitally infected infants are variable and range from asymptomatic proteinuria to nephrotic syndrome and renal impairment. In congenital CMV infection, histologic changes of viral inclusions commonly occur in the tubules. In addition, proliferative GN has been reported, with evidence on electron microscopy of viral immune deposits in glomerular cells [113]. In CMV-infected immunocompromised patients, immune-complex GN has been documented with mesangial deposits of IgG, IgA, C3, and CMV antigens within glomeruli. Eluted glomerular

Infectious Diseases and the Kidney in Children

immunoglobulins have been shown to contain CMV antigens [114]. CMV is the most common viral infection after kidney transplantation. Experience with pediatric kidney transplant recipients suggests a 67 % incidence of CMV infection, with approximately 67 % being negative at the time of transplantation [115]. The direct and indirect effects of CMV infection result in a significant morbidity and mortality among kidney transplant recipients. CMV-negative patients who receive a CMV-positive allograft are at risk for primary infection and graft dysfunction. Patients who are CMV seropositive at the time of transplantation are also at risk of reactivation and superinfection. Tubulointerstitial nephritis is a well-characterized pathologic feature of renal allograft CMV disease, which can be difficult to distinguish from injury caused by rejection. Histologic evidence of endothelial cell injury and mononuclear cell infiltration in the glomeruli has been reported. CMV glomerular vasculopathy in the absence of tubulointerstitial disease, causing renal allograft dysfunction, has also been reported [116]. Beyond the acute allograft nephropathy associated with CMV viremia, CMV is known to cause chronic vascular injury. This may adversely affect the long-term outcome of the allograft and may be the explanation for the observed association with chronic allograft nephropathy. Techniques for rapidly diagnosing CMV infection include shell vial culture, pp65 antigenemia assay, PCR, and the hybrid-capture RNA-DNA hybridization assay for qualitative detection of CMV PCR. Reverse transcriptase PCR (RT PCR) can detect viral mRNA transcripts in peripheral blood but is less sensitive than pp65 or PCR [117]. Immune histocytochemistry is used for diagnosing end-organ disease. Quantitative plasma PCR testing (PCR viral load) is increasingly used for diagnosis and monitoring of CMV viremia in renal transplant recipients [117]. The American Society of Transplantation (AST) recommends monitoring for CMV by quantitative viral load monthly for the first year after transplantation, and the Kidney Disease Improving Global Outcomes (KDIGO) recommends an additional 3 monthly surveillance for the second year.

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Antiviral agents that have been shown to be effective against CMV include ganciclovir, valganciclovir, foscarnet, and cidofovir. Ganciclovir remains the drug of choice for treating established disease. Intravenous ganciclovir therapy is preferred in children because of the erratic absorption of oral ganciclovir. Major limitations of ganciclovir therapy are the induction of renal tubular dysfunction and bone marrow toxicity, principally neutropenia and thrombocytopenia. Dosage adjustments are necessary for recipients with renal dysfunction. Oral valganciclovir is recommended for CMV prophylaxis posttransplant [118]. Duration of chemoprophylaxis is dependent on the serostatus of the donor and recipient [115]. While it is effective in reducing the incidence of symptomatic CMV, prospective viral surveillance studies have shown subclinical infection in 12–22 % of pediatric kidney transplant recipients, hence the importance of viral surveillance [115]. Use of other antiviral agents such as foscarnet and cidofovir is limited because of nephrotoxicity and difﬁculty of administration. The role of high-titer CMV immunoglobulin therapy in reducing severe CMV-associated disease after stem cell transplant remains unclear [119].

Herpes Viruses Varicella-Zoster Virus The association of varicella with nephritis has been known for more than 100 years since Henoch reported on four children with nephritis that occurred after the appearance of varicella vesicles. Varicella, however, is rarely associated with renal complications. In fatal cases with disseminated varicella and in the immunocompromised individual, renal involvement is more common. Histologic ﬁndings in fatal cases include congested hemorrhagic glomeruli, endothelial cell hyperplasia, and tubular necrosis. In mild and nonfatal cases and in nonimmunocompromised individuals, varicella is occasionally associated with a variety of renal manifestations, ranging from mild nephritis to nephrotic syndrome and AKI [120]. Histologic ﬁndings include endocapillary cell proliferation, epithelial and

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endothelial cell hyperplasia, and inﬂammatory cell inﬁltration. Rapidly progressive nephritis has also been reported. Immunohistochemical studies reveal glomerular deposition of IgG, IgM, IgA, and C3. On electron microscopy, granular electron-dense deposits have been found in the paramesangial region, and varicella antigens may be deposited in the glomeruli. The features suggest an immune-complex nephritis. Elevated circulating levels of IgG and IgA immune complexes and depressed C3 and C4 levels support this possibility [121]. Fulminant disseminated varicella and varicella in immunocompromised patients should be treated with intravenous acyclovir.

Herpes Viruses: Epstein-Barr Virus Renal involvement is common during acute infectious mononucleosis, usually manifesting as an abnormal urine sediment, with hematuria in up to 60 % of cases. Hematuria, either microscopic or macroscopic, usually appears within the first week of the illness and lasts for a few weeks to a few months. Proteinuria is usually absent or low grade. More severe renal involvement with proteinuria, nephrotic syndrome, or acute nephritis with renal failure is much less common. AKI may be seen during the course of fulminant infectious mononucleosis with associated hepatic failure, thrombocytopenia, and encephalitis. It is usually caused by interstitial nephritis that is likely the result of immunopathologic injury precipitated by Epstein-Barr virus (EBV) infection. However, the identification of EBV DNA in the kidney raises the possibility that direct infection might play a role [122, 123]. The renal involvement must be distinguished from myoglobinuria caused by rhabdomyolysis, which may occur in infectious mononucleosis, and from bleeding into the renal tract as a result of thrombocytopenia. Renal histologic findings in EBV nephritis are an interstitial nephritis with mononuclear cell infiltration and foci of tubular necrosis. Glomeruli may show varying degrees of mesangial proliferation. On immunohistochemical study, EBV antigens are seen in glomerular and tubular deposits.

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The prognosis for complete recovery of renal function is good. Treatment with corticosteroids may have a role in the management of EBV-induced AKI and may shorten the duration of renal failure [124]. EBV-associated posttransplantation lymphoproliferative disease is a recognized complication in renal transplant recipients. Subclinical infection occurs in 35–40 % of pediatric renal transplant recipients [115]. Latent infection of EBV in renal proximal tubular epithelial cells has been described as causing idiopathic chronic tubulointerstitial nephritis [125].

Herpes Viruses: Herpes Simplex Virus The herpes simplex virus (HSV) causes persistent infection characterized by asymptomatic latent periods interspersed with acute relapses. As with other chronic and persistent infections, immunologically mediated disorders triggered by HSV are well recognized, and it is perhaps surprising that HSV has rarely been linked to nephritis. Acute nephritis and nephrotic syndrome have been associated with herpes simplex encephalitis. Renal histology shows focal segmental GN with mesangial and segmental deposits of IgM, C3, and HSV antigens. As with other herpes viruses, HSV has been suggested as a trigger for IgA nephritis, MPGN, and membranous nephropathy, but no conclusive evidence exists of an etiologic role for HSV.

Human Immunodeficiency Virus The WHO estimate that in 2012 there were 35.3 million people living with HIV worldwide, with 3.3 million being children. Of these 260,000 were new infections (www.unaids.org – UNAIDS Global Report on the global AIDS epidemic 2013). The number of children under 15 years of age receiving antiretroviral therapy (ART) in lowand middle-income countries rose from 566,000 in 2011 to 630,000 in 2012 (www.unaids.org – Global update on HIV treatment 2013). Renal involvement occurs in 2–15 % of HIV-infected children in the United States [126–128]. Since the development of antiretroviral

Infectious Diseases and the Kidney in Children

therapy (ART), however, the incidence of end-stage renal disease in HIV infection in both adults and children in industrialized countries has declined, but it is predicted that the dramatic decline in AIDS-related deaths will lead to an ageing population of HIV-infected individuals who will be at risk of non-HIV-related renal problems, such that the numbers of HIV-positive ESRD patients will increase in the United States [129]. HIV infection is associated with a number of renal pathologies. HIV-associated nephropathy (HIVAN) is a syndrome of glomerular and tubular dysfunction, which can progress to end-stage renal failure. It is discussed more fully below. Glomerular syndromes other than HIVAN include a range of immune-mediated syndromes (HIV immune-complex kidney disease (HIVICK)) including MGN that resembles lupus nephritis and immune-complex GN, with IgA nephropathy and HCV-associated MPGN being the most common forms [126, 127]. There have also been several case reports of amyloid kidney. The kidneys may be affected by various other mechanisms. Opportunistic infections with organisms such as BK virus (BKV) that give rise to nephropathy and hemorrhagic cystitis have been reported in association with HIV infection [130]. Systemic infections accompanied by hypotension can cause prerenal failure leading to acute tubular necrosis. Acute tubular necrosis has also been reported in HIV patients after the use of nephrotoxic drugs such as pentamidine, foscarnet, cidofovir, amphotericin B, and aminoglycosides. Intratubular obstruction with crystal precipitation can occur with the use of sulfonamides and intravenous acyclovir. Indinavir is well recognized to cause nephropathy and renal calculi [131]. MPGN associated with mixed cryoglobulinemia and thrombotic microangiopathy/atypical HUS in association with HIV infections have been reported [132, 133].

HIV-Associated Nephropathy (HIVAN) HIVAN is characterized by both glomerular and tubular dysfunction, the pathogenesis of which is not entirely known. HIVAN is a clinicopathologic

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entity that includes proteinuria, azotemia, focal segmental glomerulosclerosis or mesangial hyperplasia, and tubulointerstitial disease [128]. In adults in the United States, there is a markedly increased risk of nephropathy among African American persons with HIV infection. This appears to be true in children as well, but the data are sparse. The spectrum of HIVAN seems to be coincident with the degree of AIDS symptomatology. It is thought that HIVAN can present at any point in HIV infection, but most patients with HIVAN have CD4 counts of less than 200 106 cells/mL, which suggests that it may be primarily a manifestation of late-stage disease [134]. The microscopic features of HIVAN in children comprise of classical FSGS with or without mesangial hyperplasia combined with microcystic tubular dilatation and interstitial inflammation [135]. Collapsing FSGS is the hallmark of adult disease, and this has been shown in children as well. In the affected glomeruli, visceral epithelial cells are hypertrophied and hyperplastic and contain large cytoplasmic vacuoles and numerous protein resorption droplets. There is microcystic distortion of tubule segments, which contributes to increasing kidney size. Podocyte hyperplasia can become so marked that it causes obliteration of much of the urinary space, forming “pseudocrescents” [136]. Capillary walls are wrinkled and collapsed with obliteration of the capillary lumina. The interstitium is edematous with a variable degree of T-cell infiltration. The Bowman capsule can also be dilated and filled with a precipitate of plasma protein that represents the glomerular ultrafiltrate. One of the most distinctive features of HIVAN, however, is the presence of numerous tubuloreticular inclusions within the cytoplasm of glomerular and peritubular capillary endothelial cells [136]. Immunofluorescence testing is positive for IgM and C3 in capillary walls in a coarsely granular to amorphous pattern in a segmental distribution [137]. The presence of the HIV genome in glomerular and tubular epithelium has been demonstrated using complementary DNA probes and in situ hybridization. Proviral DNA has been detected

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by PCR in the glomeruli, tubules, and interstitium of microdissected kidneys from patients who had pathologic evidence of HIVAN, but it has also been detected in the kidneys of HIV-positive patients with other glomerulopathies and in those with undetectable levels of viral RNA in the peripheral blood [138]. The kidney has been postulated to behave as a separate compartment to the blood with ongoing viral replication in the kidneys despite achieving serological suppression with ART [138, 139]. Transgenic murine models provide some of the strongest evidence for a direct role of HIV-1 in the induction of HIVAN. These mice do not produce infectious virus but express the HIV envelope and regulatory genes at levels sufficient to recreate the HIVAN that is seen in humans. Animal models have shown that the nef and vpr genes contribute to HIVAN through encoding for podocyte dysfunction and apoptosis of renal tubular epithelial cells, respectively [135]. HIV is thought to infect renal tubuloepithelial cells through direct cell-cell transmission which then act as a separate viral compartment and facilitates replication distant from the blood. HIVAN 1 and 2 are the host susceptibility genes identified in animal models for HIVAN. Two variants (g1and G2) in the ApoL1 gene have been identified as the susceptibility alleles that contribute to the increased risk of FSGS in African Americans (previously attributed to MYH9 on chromosome 22) [135]. HIVAN is more likely in patients with a family history of ESRD. HIVAN can manifest as mild proteinuria, nephrotic syndrome, renal tubular acidosis, hematuria, and/or AKI [128]. Nephrotic syndrome and chronic renal insufficiency are late manifestations of HIVAN. Children with HIVAN are likely to develop transient electrolytic disorders, heavy proteinuria, and AKI due to systemic infectious episodes or nephrotoxic drugs. Early stages of HIVAN can be identified by the presence of proteinuria and “urine microcysts” along with renal sonograms showing enlarged echogenic kidneys. Urinary renal tubular epithelial cells are frequently grouped together to form these microcysts, which were found in the urine of children with HIVAN who had renal tubular

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injury [128]. Advanced stages of HIVAN typically present with nephrotic syndrome with edema, heavy proteinuria, hypoalbuminemia, and few red or white blood cells in urinary sediments. Hypertension may be present, but usually blood pressure is within or below the normal range. HIVAN in adults follows a rapidly progressive course, with end-stage renal disease developing within 1–4 months, but in children this rapid progression does not necessarily occur. Deﬁnitive diagnosis of HIVAN should be based on biopsy results, and biopsy should be performed if a signiﬁcant proteinuria is present, because in approximately 50 % of HIV-infected patients with azotemia and/or proteinuria (>1 g/24 h) who undergo renal biopsy, the specimen will have histologic features consistent with other renal diseases [134].

HIV Immune-Complex Kidney Disease (HIVICK) HIVCK is thought to arise by deposition of immune complexes or by in situ formation of immune complexes in the parenchyma [126]. The immune complexes consist of HIV antigens bound to IgG and IgA. IgA nephropathy, membranous and membranoproliferative glomerulonephritis, and a lupus-like glomerulonephritis are included in HIVCK. Like HIVAN, it occurs in Afro-Caribbeans but can also be found in Caucasians [126]. Acute interstitial nephritis (AIN) results mainly from medications used to treat HIV and its complications. Nonsteroidal anti-inﬂammatory drugs, rifampicin, co-trimoxazole, and protease inhibitors (PI) like idinavir and ritonavir have been implicated [140]. All classes of ART can cause renal toxicity except the integrase inhibitors and the CCR5 antagonists. Tenofovir can cause proximal tubular nephropathy and can present as complete or partial Fanconi syndrome [141, 142]. Therefore, it is essential that children on ART have regular urinalysis to check for the emergence of proteinuria and hematuria. HAART should be given to children with symptomatic HIV disease. Speciﬁc treatment of HIVAN remains controversial. Several studies have looked at the role of HAART with or without

Infectious Diseases and the Kidney in Children

angiotensin I-converting enzyme (ACE) inhibitors, and even cyclosporin with somewhat encouraging results. However, as yet, no randomized case-controlled trials have been undertaken [126]. Most of the studies have been small and retrospective, and many have included patients both with and without renal biopsy-proven HIVAN. Cyclosporin has been used to treat HIVAN in children with remission of nephrotic syndrome [143]. Similar responses have been reported to treatment with corticosteroids in various studies; however, steroids are not currently recommended for the routine management of HIVAN. There has been short-term improvement in kidney function in children with lymphoid interstitial pneumonitis, but there is the risk of exacerbation of infection with TB when used in developing countries, and in the absence of HAART, it has not been shown to limit the progression of HIVAN in children [126–128]. The general regimen used to treat patients with HIV, including HAART, should be applied to children with HIVAN. The dosages of some medications must be adjusted to the patients’ glomerular filtration. There are reports of spontaneous regression of HIVAN with supportive management and treatment with HAART, particularly with regimens containing protease inhibitors [144]. The kidneys of transgenic mice have been found to have elevated levels of TGF-β messenger RNA and protein [145]. Furthermore, gene expression analysis on tubular epithelial cells from a patient with HIVAN found upregulation of several inflammatory mediator genes downstream of interleukin 6 and of the transcription factor NFkB [146]. Several therapeutic options have been aimed specifically at the presumed role of TGF-β in the pathogenesis of HIVAN. Treatment directed at its synthesis using gene therapy to block TGF-β gene expression is being explored. Therapy directed at decreasing the activity of TGF-β using anti-TGF-β antibodies or other inhibitory substances is also an area of investigation. To date, these novel therapeutic approaches have not yielded any promising advancement in treatment. In the HAART era, the outlook for HIV patients with ESRD has improved, but these

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patients fare worse than ESRD patients without HIV [147]. Most reports of HIV-infected patients on hemodialysis have shown poor prognosis, with mean patient survival times ranging from 14 to 47 months. Mortality is therefore still close to 50 % within the first year of dialysis. In general, improved survival is associated with younger age at initiation of hemodialysis and with higher CD4 counts. Complications such as infection and thrombosis tend to occur at a higher rate in HIV-infected hemodialysis patients. Cross infection with HIV in dialysis patients is very rare. Peritoneal dialysis is an alternative for HIV-infected patients. The incidence of peritonitis varies across studies, but some studies did report a higher incidence of Pseudomonas and fungal peritonitis in the HIV-positive population [148]. Infections with unusual organisms such as Pasteurella multocida, Trichosporon beigelii, and Mycobacterium avium-intracellulare complex have also been reported. Several studies, however, have suggested that there is no significant difference between the HIV-infected and non-HIV-infected populations. Of note is that virus capable of replication in vitro has been recovered from the peritoneal dialysis effluent, and it can be recoverable for up to 7 days in dialysis bags at room temperature and for up to 48 h in dry exchange tubing [148]. Kidney transplantation in HIV-infected individuals with end-stage renal disease has shown excellent 3–5-year survival rates [149, 150]. These group of patients do experience an increase risk of rejection but not of opportunistic infections. Most issues revolve around immunosuppressive therapy and interactions with ART.

Human Polyomaviruses The human polyomaviruses are members of the papovavirus family and signiﬁcant pathogens in immunocompromised patients. They are non-enveloped viruses ranging in size from 45 to 55 nm, with a circular, double-stranded DNA genome that replicates in the host nucleus. The best-known species in this genus are the BKV, the JC virus (JCV), and the simian virus SV40. BKV

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establishes infection in the kidney and the urinary tract, and its activation causes a number of disorders, including nephropathy and hemorrhagic cystitis. BKV-associated nephropathy is a cause of renal dysfunction in renal transplantation patients [151]. JCV establishes latency mainly in the kidney, and its reactivation can result in the development of progressive multifocal leukoencephalopathy. There are a few reports of nephropathy in association with JCV infection [152, 153], but BKV poses a much bigger problem in this regard.

BK Virus BKV infection is endemic worldwide. Seroprevalence rates as high as 60–80 % have been reported among adults in the United States and Europe. The peak incidence of primary infection (as measured by acquisition of antibody) occurs in children 2–5 years of age. BKV antibody may be detected in as many as 50 % of children by 3 years of age, and in 60–100 % of children by 9 or 10 years of age; antibodies wane thereafter. BKV infection may be particularly important in the pediatric transplantation population, in whom primary infection has a high probability of occurring while the children are immunosuppressed [151]. Primary infection with BKV in healthy children is rarely associated with clinical manifestations. Mild pyrexia, malaise, vomiting, respiratory illness, pericarditis, and transient hepatic dysfunction have been reported with primary infection. Investigators hypothesize that after an initial round of viral replication at the site of entry, viremia follows with dissemination of the virus to distant sites at which latent infection is established. The most frequently recognized secondary sites of latent infection are renal and uroepithelial cells. Reactivation and urinary shedding occurs in 10–60 % of immunocompetent individuals, with higher rates among the immunocompromised [154]. Secondary infection has been reported to cause tubulointerstitial nephritis and ureteral stenosis in renal transplantation patients. It may be that renal impairment in immunocompromised patients and in nonrenal solid organ transplant recipients is found to be frequently associated with BKV infection.

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BK Virus Nephropathy in Patients Undergoing Renal Transplantation The reported prevalence of BKV nephropathy in renal allografts is between 1 % and 8 % [155]. Asymptomatic infection is characterized by viral shedding without any apparent clinical features. Viruria, resulting from either primary or secondary infection, can persist from several weeks to years. Tubulointerstitial nephritis associated with BKV in renal transplant recipients is accompanied by histopathologic changes, with or without functional impairment. “Infection” and “disease” must be differentiated carefully. BKV infection (either primary or reactivated) can progress to BKV disease, but will not always do so [156]. Furthermore, not all cases of BKV disease lead to renal impairment. However, infection can progress to transplant dysfunction and graft loss, although the diagnosis may be complicated by the coexistence of active allograft rejection. BKV nephritis has a bimodal distribution, with 50 % of BKV-related interstitial nephritis cases occurring 4–8 weeks after transplantation and the remainder of patients developing disease months to years after transplantation. Allograft failure is due mainly to extensive viral replication in tubular epithelial cells leading to frank tubular necrosis [153]. Although damage is potentially fully reversible early in the disease, persisting viral damage leads to irreversible interstitial fibrosis. Tubular atrophy and allograft loss has been observed in 45 % of affected patients. In most cases, BKV nephropathy in adult renal transplant recipients represents a secondary infection associated with rejection and its treatment. In children, however, primary BKV infection giving rise to allograft dysfunction may occur [156]. The definitive diagnosis of BKV nephropathy requires renal biopsy. Histopathologic features include severe tubular injury with cellular enlargement, marked nuclear atypia, epithelial necrosis, denudation of tubular basement membranes, focal intratubular neutrophilic infiltration, and mononuclear interstitial infiltration, with or without concurrent tubulins [153]. This constellation of histologic features, particularly severe tubulitis, is often misinterpreted as rejection, even by the experienced pathologist. The

Infectious Diseases and the Kidney in Children

presence of well-demarcated basophilic or amphophilic intranuclear viral inclusions, primarily within the tubular and parietal epithelium of the Bowman capsule, can help distinguish BKV disease from rejection. Additional tests such as immunohistochemistry, PCR analysis, or electron microscopy of biopsied tissue aimed at the identification of BKV may be required. PCR assays of viral load in tubular cells have been reported to be a sensitive marker for diagnosis and monitoring. Other Implications of BK Virus in Renal Transplantation BKV infection may cause ureteral obstruction due to ureteral ulceration and stenosis at the ureteric anastomosis. BKV-associated ureteral stenosis has been reported in 3 % of renal transplant patients and usually occurs between 50 and 300 days after transplantation. Ulceration due to inflammation, proliferation of the transitional epithelial cells, and smooth muscle proliferation may lead to partial or total obstruction. High-level BKV replication is implicated in acute, lateonset, long-duration hemorrhagic cystitis after bone marrow transplantation [157]. There are two case reports in children of renal carcinomas arising in the transplanted kidney in association with BK virus nephropathy. It remains unclear whether BK virus itself has oncogenic potential in the transplant setting, but this is possible given that the big T antigen (T-Ag) expressed by polyomavirus family viruses has been shown to have the ability to disrupt chromosomal integrity [158, 159]. Treatment Whether patients with asymptomatic viremia or viruria need specific therapeutic intervention is not certain. Review of the literature suggests that careful reduction of immune suppression, combined with active surveillance for rejection, will result in clinical improvement. Reduction in immunosuppression may precipitate episodes of acute cellular rejection, which need to be judiciously treated with corticosteroids. The outcome of BKV nephropathy is unpredictable, and stabilization of renal function may occur regardless of whether maintenance immunotherapy is altered or not [160].

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Cyclosporin, mycophenolate, and sirolimus have all been shown to possess in vitro antiviral activity against BK virus, but these findings have not been confirmed by in vivo clinical trials. Several studies have sought to identify a particular immunosuppressant or combination of drugs that increases the risk of BK virus, but results have not favored one particular regimen over another [154]. A systematic review by Johnston et al. in adults found that there was no reduction in graft loss by combining cidofovir or leflunomide with immunosuppression reduction to treat polyomavirus-associated nephropathy [161]. Prospective trials are required to address the impact of various immunosuppressive agents on BK virus replication, and randomized controlled trials are still required to define the optimal treatment of the condition.

Viral Hemorrhagic Fever Viral hemorrhagic fever involves at least 12 distinct RNA viruses that share the propensity to cause severe disease with prominent hemorrhagic manifestations. The viral hemorrhagic fevers, widely distributed throughout both temperate and tropical regions of the world, are important causes of mortality and morbidity in many countries. Most viral hemorrhagic fevers are zoonoses (with the possible exception of dengue virus), in which the virus is endemic in animals and human infection is acquired through the bite of an insect vector. Aerosol and nosocomial transmissions from infected patients are important for Lassa, Junin, Machupo, and Congo-Crimean hemorrhagic fevers and Marburg and Ebola viruses. Viral hemorrhagic fevers have many clinical similarities but also important differences in their severity, major organs affected, prognosis, and response to treatment. In all viral hemorrhagic fevers, severe cases occur in only a minority of those affected; subclinical infection or nonspeciﬁc febrile illness occurs in the majority. Fever, myalgia, headache, conjunctival suffusion, and erythematous rash occur in all the viral hemorrhagic fevers [162]. Hemorrhagic manifestations range from petechiae and bleeding from venipuncture

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sites to severe hemorrhage into the GI tract, kidney, and other organs. A capillary leak syndrome, with evidence of hemoconcentration, pulmonary edema, oliguria, and ultimately shock, occurs in the most severely affected patients. Renal involvement occurs in all the viral hemorrhagic fevers, proteinuria is common, and prerenal failure is seen in all severe cases complicated by shock. However, in Congo-Crimean hemorrhagic fever and hemorrhagic fever with renal syndrome (HFRS), an interstitial nephritis, which may be hemorrhagic, is characteristic, and renal impairment is a major component of the illness.

Dengue Dengue is caused by a flavivirus that is endemic and epidemic in tropical America, Africa, and Asia, where the mosquito vector Aedes aegypti is present [163]. Classic dengue is a self-limited nonfatal disease; dengue hemorrhagic fever and dengue shock syndrome, which occur in a minority of patients, have a high mortality if not aggressively treated with fluids. After an incubation period of 5–8 days, the illness begins with fever, headache, arthralgia, weakness, vomiting, and hyperesthesia. In uncomplicated dengue, the fever usually lasts 5–7 days. Shortly after onset, a maculopapular rash appears, sparing the palms and the soles, and is occasionally followed by desquamation. Fever may reappear at the onset of the rash. In dengue hemorrhagic fever and dengue shock syndrome, the typical febrile illness is complicated by hemorrhagic manifestations, ranging from a positive tourniquet test result or petechiae to purpura, epistaxis, and GI bleeding with thrombocytopenia and evidence of a consumptive coagulopathy. Increased capillary permeability is suggested by hemoconcentration, edema, and pleural effusions [163]. In severe cases, hypotension and shock supervene, largely as a result of hypovolemia. Renal manifestations include oliguria, proteinuria, hematuria, and rising urea and creatinine. AKI occurs in patients with severe shock, primarily as a result of renal underperfusion. However, glomerular inflammatory changes may also occur. Children with dengue hemorrhagic fever show hypertrophy of

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endothelial and mesangial cells, mononuclear cell inﬁltrate, thinning of basement membranes, and deposition of IgG, IgM, and C3. Electron microscopy shows viral particles within glomerular mononuclear cells [164]. The diagnosis of dengue is made by isolation of the virus from blood or by serologic testing. There is no speciﬁc antiviral treatment, and management of patients with dengue shock syndrome or dengue hemorrhagic fever depends on aggressive circulatory support and volume replacement with colloid and crystalloid [165, 166]. With correction of hypovolemia, renal impairment is usually reversible, but dialysis may be required in patients with established AKI.

Yellow Fever Yellow fever is caused by a flavivirus and is transmitted by mosquito bites, typically Aedes species. It remains an important public health problem in Africa and South America. Renal manifestations are common and include albuminuria and oliguria. Over the next few days after first manifestation of infection, shock, delirium, coma, and renal failure develop, and death occurs 7–10 days after onset of symptoms. Laboratory findings include thrombocytopenia and evidence of hemoconcentration, rising urea and creatinine levels, hypernatremia, and deranged liver function test results. Pathologic findings include necrosis of liver lobules, cloudy swelling and fatty degeneration of the proximal renal tubules, and, often, petechiae in other organs. The oliguria appears to be prerenal and is due to hypovolemia; later, acute tubular necrosis supervenes. At present, there is no effective antiviral agent for yellow fever. Congo-Crimean Hemorrhagic Fever (CCHF) Congo-Crimean hemorrhagic fever, first recognized in the Soviet Union, is now an important human disease in Eastern Europe, Asia, and Africa. It is a tick-borne zoonotic viral disease caused by CCHF virus of the genus Nairovirus (family Bunyaviridae) [167]. Severely affected patients become stuporous or comatose 5–7 days into the illness, with evidence of hepatic and renal

Infectious Diseases and the Kidney in Children

failure and shock. Proteinuria and hematuria are often present. The disease is fatal in 15–50 % of cases. The WHO recommends ribavirin as the treatment of choice, but a systematic metaanalysis showed no change in mortality rate in the randomized controlled trials; observational studies showed a reduction in mortality by 44 % but were heavily confounded [167, 168]. Randomized controlled trials are needed in a setting with full supportive care to further address this question. The role of immunoglobulin has also been tried, but no case-control trials have been conducted to support a beneﬁcial effect.

Rift Valley Fever Rift Valley fever is found in many areas of sub-Saharan Africa. In humans, most infections follow mosquito bites or animal exposure. The infection may present as an uncomplicated febrile illness, with muscle aches and headaches. In 10 % of patients, encephalitis or retinal vasculitis occurs as a complication. In a small proportion of cases, a fulminant and often fatal hemorrhagic illness occurs with hematemesis, melena, epistaxis, and evidence of profound DIC. Severe hepatic derangement, renal failure, and encephalopathy are often present. Despite intensive care, mortality is high. Hemorrhagic Fever and Renal Syndrome (Hantavirus) The viruses causing HFRS all belong to the Hantavirus genus in the Bunyaviridae family. The hantaviruses are distributed worldwide and are maintained in nature through chronic infection of rodents and small mammals [169]. Transmission to humans is by aerosolized infectious excreta. Human disease usually occurs in summer among rural populations with exposure to rodent-infested barns or grain stores. Urban transmission can occur, however. At least ﬁve hantaviruses are known to cause HFRS: Hantaan, Seoul, Puumala, Porogia, and Belgrade viruses. HFRS is endemic in a belt from Norway in the west through Sweden, Finland, the Soviet Union, China, and Korea to Japan in the east. The clinical severity of HFRS varies throughout this belt. Clinical entities include Korean hemorrhagic fever, nephropathia

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epidemica in Scandinavia, and epidemic hemorrhagic fever in Japan and China. In general, HFRS due to Hantaan, Porogia, and Belgrade viruses is more severe and has higher mortality than that due to Puumala virus (nephropathia epidemica) or Seoul virus. Hantaan is predominant in the Far East, Porogia and Belgrade in the Balkans, and Puumala in Western Europe; Seoul has a worldwide distribution. The clinical features of the disease vary [170]. The incubation period is 4–42 days. Although HFRS occurs with the same clinical picture in children as in adults, both incidence rates and antibody prevalence rates are very low in children under 10 years of age. Mild cases are indistinguishable from other febrile illnesses. In more severe cases, fever, headache, myalgia, abdominal pain, and dizziness are associated with the development of periorbital edema, proteinuria, and hematuria. There is often conjunctival injection, pharyngeal injection, petechiae, and epistaxis or GI bleeding. The most severely affected patients develop shock and renal failure. The disease usually passes through five phases: febrile, hypotensive, oliguric, diuretic, and convalescent. Laboratory findings include anemia, lymphocytosis, thrombocytopenia, prolonged prothrombin and bleeding times, and elevated levels of fibrin degradation products. Liver enzyme levels are elevated, and urea and creatinine levels are elevated during the oliguric phase. Proteinuria and hematuria are consistent findings. The renal histopathologic findings are those of an interstitial nephritis with prominent hemorrhages in the renal medullary interstitium and renal cortex. Acute tubular necrosis may also be seen. Immunohistochemical analysis reveals deposition of IgG and C3, and the GBM, mesangial, and subendothelial deposits may be seen on electron microscopy [171]. Recovery from Hantavirus-associated disease is generally complete, although chronic renal insufficiency is a rare sequel of HFRS. In mildly affected patients, the disease is self-limiting, and spontaneous recovery occurs. However, in severe cases, with shock, bleeding, and renal failure, dialysis and intensive circulatory support may be required. Mortality rates vary depending on the strain of virus; rates are 5–15 % for hemorrhagic

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fever and renal syndrome in China and signiﬁcantly lower for the milder Finnish form associated with the Puumala virus strain. Ribavirin is active against Hantaan viruses in vitro, and clinical trials indicate that both mortality and morbidity can be reduced by treatment with this antiviral agent if it is administered early in the course of illness. Dosages of 33 mg/kg followed by 16 mg/kg every 6 h for 4 days and then 8 mg/kg every 8 h for 3 days have been used [172].

Lassa Fever Lassa fever is a common infection in West Africa, caused by an arenavirus, and usually manifests as a nonspeciﬁc febrile illness. In 10 % of cases, a fulminant hemorrhagic disease occurs. In severe cases, proteinuria and hematuria are usually present, and renal failure may occur. Ribavirin is effective in decreasing mortality. As in other hemorrhagic fevers, intensive hemodynamic support and correction of the hemostatic derangements are important components of therapy [162]. Argentine and Bolivian Hemorrhagic Fevers Junin and Machupo viruses, the agents of Argentine and Bolivian hemorrhagic fever, respectively, cause hemorrhagic fevers with prominent neurologic features and systemic and hemorrhagic features similar to those of Lassa fever. Oliguria, shock, and renal failure occur in the most severe cases. Marburg Disease and Ebola Virus Disease Marburg and Ebola viruses have been associated with outbreaks of nosocomially transmitted hemorrhagic fever. West Africa has experienced the largest outbreak of Ebola, with several thousand cases in Liberia, Sierra Leone, and Guinea. Mortality in this outbreak has been high with 40–60 % of those affected succumbing. Both viruses cause fulminant hemorrhagic fever. Onset is with high fever, headache, sore throat, myalgia, and profound prostration. An erythematous rash on the trunk is followed by hemorrhagic conjunctivitis, bleeding, impaired renal function, shock, and

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respiratory failure. Renal histopathologic findings in fatal cases are of tubular necrosis, with fibrin deposition in the glomeruli. There is no specific treatment for these disorders.

Other Common Virus Infections There are many ubiquitous viral pathogens that infect large proportions of the population annually and yet are rarely associated with renal disease. The literature contains scattered reports of acute nephritis after infection with many of these viruses. The improvement in molecular diagnostic techniques has led to the recognition of other viruses that play an important role in childhood illness, for example, the human metapneumovirus [213] and Boca virus [214]. The latter only appears to have the greatest clinical impact when present in combination with other viruses. There are no reports of a signiﬁcant direct renal pathology with these viruses. Adenovirus. Adenovirus is a major cause of hemorrhagic cystitis and is commonly implicated as the cause of hemorrhagic cystitis in [173]. Boys are affected more often than girls, and hematuria persists for 3–5 days. Microscopic hematuria, dysuria, and frequency may occur for longer periods. Adenovirus types 11 and 21 are the usual strains isolated. It has been implicated in causing necrotizing granulomatous tubulointerstitial nephritis in transplant recipients, primarily affecting the distal nephron [174, 175]. The prevalence of viremia in adult transplant recipients is estimated at 6.5 %. Case reports in adults have reported treatment with immunosuppressant reduction, intravenous cidofovir, and immunoglobulin to try and prevent rejection [175]. Enterovirus. Picornaviruses, including enteroviruses, have been linked with acute nephritis and AKI associated with rhabdomyolysis. Coxsackie B virus can be isolated in urine. Direct infection of kidney cells is supported by in vitro work demonstrating lytic infection of human podocyte and proximal tubular epithelial cell cultures, although different strains exhibit variable degrees of

Infectious Diseases and the Kidney in Children

nephrotropism. Renal damage in vivo may have both a direct lytic mechanism and an immunecomplex basis [176]. In the newborn, enteroviruses cause fulminant disease with DIC, shock, and liver failure, and AKI may occur. Influenza. Influenza A viruses are important infectious agents that have caused pandemics over the last two decades. The beginning of the last decade saw outbreaks of Avian flu (H5N1and H7N7), and the latter part of the decade dealt with the pandemic of H1N1. Both cause a flulike illness with prominent respiratory and gastrointestinal symptoms. Renal failure can develop as part of the critical illness, in particular renal tubular necrosis. The WHO recommends that a standard regimen of oseltamivir used to treat seasonal flu be used to treat H5N1, but in the severely ill higher doses may be required [177, 178]. Oseltamivirresistant viruses have been reported in Southeast Asia. Peramivir and zanamivir have also been used to treat influenza A virus subtypes. Combinations of antiviral drugs with different modes of action have been explored to improve the outcome of influenza viremia, and studies are still underway in this area [177]. Measles Virus. Renal involvement from measles virus is uncommon, although measles virus can be cultured from the kidney in fatal cases. An acute GN has been reported to follow measles with evidence of immune deposits containing measles virus antigen within the glomeruli. The nephritis is generally self-limiting [179]. Mumps Virus. Mild renal involvement is common during the acute phase of mumps infection. One-third of children with mumps have abnormal urinalysis results, with microscopic hematuria or proteinuria. Mumps virus may be isolated from urine during the first 5 days of the illness, at a time when urinalysis findings are abnormal. Plasma creatinine concentrations usually remain normal, despite the abnormal urine sediment, but more severe cases in unvaccinated children have resulted in fatal interstitial nephritis with interstitial mononuclear cell infiltration, edema, and focal tubular epithelial cell damage [180]. Renal biopsy specimens in adult mumps nephritis demonstrate an MPGN with deposition of IgA,

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IgM, C3, and mumps virus antigen in the glomeruli, which suggests an immune-complex-mediated process [181].

Coronavirus Most coronavirus infections are mild respiratory infections with no renal involvement. Two highly pathogenic species are described, with renal cell tropism, and the renal effects of infection require further elucidation. SARS-CoV. Severe acute respiratory syndrome (SARS) was ﬁrst seen in South China in 2002. It is caused by a SARS coronavirus (SARS-CoV). Predominantly, it causes a viral pneumonia, with diffuse alveolar damage; it has considerable mortality [182]. Renal effects are not generally significant in the pathophysiology of SARS. Acute renal impairment is uncommon in SARS but where present is associated with a high mortality and is a negative prognostic indicator for survival [183]. Case reports have documented rhabdomyolysis in association with SARS and AKI as a cause for AKI. SARS-CoV has been found in the kidney tissue at postmortem [184, 185]. SARS-CoV enters cells via angiotensinconverting enzyme 2 (ACE2) [186], and it is thought that the invasion of the kidney tissue reﬂects the virus’ tropism for ACE2, which is expressed on kidney cells. Middle East Region Coronavirus (MERSCoV). MERS-CoV causes an illness clinically similar to SARS-CoV. It was discovered following an outbreak in the Middle East in 2012, and new cases continue to arise. Mortality is high – up to 40 %. AKI has been noted in a number of case reports. In vitro studies suggest that MERS-CoV has tropism for kidney epithelial cells [187].

Parasitic Infections Chronic exposure to infectious agents is a major factor in the increased prevalence of glomerular diseases in developing countries. Malaria is the best-documented parasitic infection associated

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with glomerular disease, but other parasitic infections including schistosomiasis, ﬁlariasis, leishmaniasis, and possibly helminth infections may also induce nephritis or nephrosis.

Malaria Plasmodium malariae and Quartan Malaria Nephropathy Malaria is estimated to cause up to 500 million clinical cases of illness and more than one million deaths each year. The association of P. malariae (quartan) malaria and nephritis has been well known in both temperate and tropical zones since the end of the nineteenth century. Epidemiologic studies early evidence for a role of Plasmodium malariae in glomerular disease. Chronic renal disease was a major cause of morbidity and mortality in British Guiana in the 1920s. The frequent occurrence of P. malariae in the blood of these patients led to detailed epidemiologic studies that implicated malaria as a cause of the nephrosis. After the eradication of malaria from British Guiana, chronic renal disease ceased to be a major cause of death in that country [188]. The link between malaria and nephrotic syndrome was strengthened by studies in West Africa in the 1950s and 1960s that demonstrated a high prevalence of nephrotic syndrome in the Nigerian population [189]. The pattern of nephrotic syndrome differed from that in temperate climates, with an older peak age, extremely poor prognosis, and unusual histologic features. The incidence of P. malariae parasitemia in patients with the nephrotic syndrome in Nigeria was vastly in excess of that occurring in the general population, whereas the incidence of Plasmodium falciparum parasitemia was similar to that in the general population. The age distribution of nephrotic syndrome also closely paralleled that of P. malariae infection [189]. In some affected patients, circulating immune complexes and immunoglobulin, complement, and antigens were present in the glomeruli that were recognized by P. malariaespeciﬁc antisera.

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Clinical and Histopathologic Features of Quartan Malaria Nephropathy Most patients have poorly selective proteinuria and are unresponsive to treatment with steroids or immunosuppressive agents. The characteristic lesions of quartan nephropathy are capillary wall thickening and segmental glomerular sclerosis, which lead to progressive glomerular changes and secondary tubular atrophy [189]. Cellular proliferation is conspicuously absent. Electron microscopy shows foot-process fusion, thickening of the basement membrane, and increase in subendothelial basement membrane-like material. Immunofluorescent studies show granular deposits of immunoglobulin, complement, and P. malariae antigen in approximately one-third of patients. The prognosis for the nephrotic syndrome in most African studies has been poor, regardless of whether the histologic findings were typical of quartan malaria nephropathy or whether P. malariae parasitemia was implicated. Treatment with steroids and azathioprine is generally ineffective, and a significant proportion of patients progress to renal failure. In addition to the histologic pattern, termed quartan malaria nephropathy, P. malariae infection is associated with a variety of other forms of histologic appearance, including proliferative GN and MGN. Although quartan malaria nephropathy has been clearly linked to P. malariae infection in Nigeria, studies from other regions in Africa have not revealed the typical histopathologic findings described in the Nigerian studies. Furthermore, quartan malaria nephropathy may be seen in children with no evidence of P. malariae infection or deposition of malaria antigens in the kidney. This, together with the fact that antimalarial treatment does not affect the progression of the disorder, raises the possibility that factors other than malaria might be involved in the initiation and perpetuation of the disorder. There is now a view that the patterns of childhood renal disease described in the last century may no longer be representative of the current situation. The variable patterns of renal disease throughout Africa may no longer reflect a dominant role for

Infectious Diseases and the Kidney in Children

“malarial glomerulopathy,” and the relative causative role of tropical infections in nephropathy remains an unanswered question [190]. Most likely, a number of different infectious processes, including malaria, hepatitis B, schistosomiasis, and perhaps other parasitic infections that cause chronic or persistent infections and often occur concurrently in malaria areas, may all result in glomerular injury and a range of overlapping histopathologic features.

Renal Disease Associated with Plasmodium falciparum Infection Plasmodium falciparum appears to be much less likely to cause a signiﬁcant glomerular pathology. Epidemiologic studies have failed to show a clear association between parasitemia and the nephrotic syndrome. Whereas renal failure appears to be a common complication of severe malaria in adults, it seldom occurs in children. Renal biopsy specimens from adult patients with acute P. falciparum infections who have proteinuria or hematuria show evidence of glomerular changes, including hypercellularity, thickening of basement membranes, and hyperplasia and hypertrophy of endothelial cells [191]. Electron microscopy reveals electron-dense deposits in the subendothelial and paramesangial areas. Deposits of IgM, with or without IgG, are localized mainly in the mesangial areas. Plasmodium falciparum antigens can be demonstrated in the mesangial areas and along the capillary wall, which suggests an immune-complex GN. The changes, generally mild and transient, are probably unrelated to the AKI that may complicate severe P. falciparum infection [191]. Heavily parasitized erythrocytes play a central role in the various pathologic factors [192]. Renal failure occurring in severe P. falciparum malaria is usually associated with acidosis, volume depletion, acute intravascular hemolysis, or heavy parasitic infection that leads to acute tubular necrosis. Recent studies have conﬁrmed an important role for volume depletion in children with severe Plasmodium falciparum malaria, who characteristically have evidence of tachycardia, tachypnea, poor perfusion, and in severe cases

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hypotension [193]. Volume expansion with either colloid or crystalloid results in improvement in hemodynamic indices and reduction in acidosis [194]. However, a phase 3 randomized trial of 20–40 ml/kg albumin, saline, or maintenance fluids only showed increased mortality in patients receiving bolus fluids [195]. This surprising finding has been intensively debated, and bolus fluids have been part of standard resuscitation measures for children with critical illness worldwide. A likely explanation for the adverse affects of fluid bolus is that deterioration in pulmonary or neurological condition was associated with fluid administration. As the trial was conducted in African countries where ventilator support was not available, it is not clear that the findings can be extrapolated to settings where ventilator support and modern intensive care are available. However in the light of this trial, routine volume expansion with colloid or crystalloid is currently not recommended for children with severe malaria in settings where intensive care monitoring and support is not available.

Blackwater Fever The term blackwater fever refers to the combination of severe hemolysis, hemoglobinuria, and renal failure. It was more common at the start of the twentieth century in nonimmune individuals receiving intermittent quinine therapy for P. falciparum malaria. Blackwater fever has become rare since 1950, when quinine was replaced by chloroquine. However, the disease reappeared in the 1990s, after the increase in use of quinine because of the development of chloroquine-resistant organisms. Since then, several cases have been described after therapy with halofantrine and meﬂoquine, molecules similar to quinine (amino alcohol family) [196]. Renal failure generally occurred in the context of severe hemolytic anemia, hemoglobinuria, and jaundice. The pathophysiology of the disorder is unclear; however, it appears that a double sensitization of the red blood cells to the P. falciparum and to the amino alcohols is necessary to provoke the hemolysis. Histopathologic ﬁndings include swelling and vacuolization of proximal tubules, necrosis

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and degeneration of more distal tubules, and hemoglobin deposition in the renal tubules. Recent studies indicate a better outcome with earlier initiation of intensive care and dialysis combined with necessary changes in antimalarial medications.

Schistosomiasis Schistosomiasis affects 200 million people living in endemic areas of Asia, Africa, and South America. The infection is usually acquired in childhood, but repeated infections occur throughout life. Schistosoma japonicum is found only in the Orient, whereas Schistosoma haematobium occurs throughout Africa, the Middle East, and areas of Southwest Asia. Schistosoma mansoni is widespread in Africa, South America, and Southwest Asia. Human infection begins when the cercarial forms invade through the skin, develop into schistosomula, and move to the lungs via the lymphatics or blood. They then migrate to the liver and mature in the intrahepatic portal venules, where male/female pairing takes place. The adult worm pairs then migrate to their final resting site – the venules of the mesenteric venous system of the large intestine (S. mansoni) or in the venules of the urinary tract (S. haematobium). The females release large numbers of eggs, which may remain embedded in the tissues, embolize to the liver or lungs, or pass into the feces or urine. Clinical manifestations may occur at any stage of the infection. Cercarial invasion may cause an intense itchy papular rash. Katayama fever is an acute serum sickness-like illness that occurs several weeks after infection, as eggs are being deposited in the tissues. Deposition of the eggs in tissues results in inflammation of the intestines, fibrosis of the liver, and portal hypertension. With S. haematobium, chronic inflammation and fibrosis of the ureters and bladder may lead to obstructive uropathy. Renal manifestations of schistosomiasis occur most commonly in S. mansoni infection [197]. Schistosomal nephropathy usually presents with symptoms including granulomatous inflammation

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in the ureters and bladder, but glomerular disease (probably on an immune-complex basis) may also occur. Renal disease usually occurs in older children or young adults with long-term infection, but serious disease may also occur in young children. There have been isolated case reports of young children presenting with nephrotic syndrome secondary to Schistosoma haematobium infection directly causing membranoproliferative glomerulonephritis [198]. The early renal tract manifestations of schistosomiasis are suprapubic discomfort, frequency, dysuria, and terminal hematuria. In more severe cases, evidence of urinary obstruction appears. Poor urinary stream, straining on micturition, a feeling of incomplete bladder emptying, and a constant urge to urinate may be severely disabling symptoms. The fibrosis and inflammation of ureters, urethra, and bladder may be followed by calcification and may result in hydroureter, hydronephrosis, and bladder neck obstruction. Renal failure may ultimately develop, and there is a suspicion that squamous cell carcinoma of the bladder may be linked to the chronic infective and inflammatory process. Secondary bacterial infection is common within the obstructed and inflamed urinary tract. The hepatosplenic form of S. mansoni infection may be accompanied by a glomerulopathy in 12–15 % of cases, manifested in the majority as nephrotic syndrome. Histopathologic findings include mesangioproliferative GN, focal segmental glomerulosclerosis, mesangiocapillary GN, MGN, and focal segmental hyalinosis. Immune complexes may be detected in the circulation of these patients, and glomerular granular deposition of IgM, C3, and schistosomal antigens are seen on immunofluorescence [197]. Usually schistosomaspecific nephropathy is a progressive disease and is not influenced by antiparasitic or immunosuppressive therapy. The diagnosis is confirmed by the detection of schistosomula eggs in feces, urine, or biopsy specimens. Eggs are shed into the urine with a diurnal rhythm, and urine collected between 11 AM and 1 PM is the most useful. Urinary sediment obtained by centrifugation or filtration through a Nuclepore membrane should be examined. In

Infectious Diseases and the Kidney in Children

cases in which studies of urine and feces yield negative results in patients in whom the diagnosis is suspected, rectal biopsy specimens taken approximately 9 cm from the anus have a high diagnostic yield for both S. mansoni and S. haematobium infection. Biopsy of the liver or bladder may be required to establish the diagnosis. Antibodies indicating previous infection can be detected using enzyme-linked immunosorbent assay or radioimmunoassay. The tests are sensitive but lack specificity and may not differentiate between past exposure and current infection. Praziquantel is the drug of choice for treatment of schistosomiasis. A single oral dose of 40 mg/kg is effective in S. haematobium and S. mansoni infection and is usually well tolerated. The alternative drug for S. mansoni infection is oxamniquine. Complete remission of urinary symptoms may occur in renal disease of short duration, but in late disease with extensive fibrosis, scarring, and calcification, obstructive uropathy and renal failure may persist after the infection has been eradicated.

Leishmaniasis Visceral leishmaniasis is a chronic protozoon infection characterized by fever, hepatosplenomegaly, anemia, leukopenia, and hyperglobulinemia [199]. Proteinuria and/or microscopic hematuria or pyuria has been reported in 50 % of patients with visceral leishmaniasis. AKI in association with interstitial nephritis has also been reported. Renal histologic analysis in patients with visceral leishmaniasis reveals glomerular changes, with features of a mesangial proliferative GN or a focal proliferative GN, or a generalized interstitial nephritis with interstitial edema, mononuclear cell inﬁltration, and focal tubular degeneration. Immunoﬂuorescence reveals deposition of IgG, IgM, and C3 within the glomeruli, as well as electron-dense deposits in the basement membrane and mesangium on electron microscopy [200]. Circulating immune complexes together with immunoglobulin and complement deposition in the glomeruli suggests an immune-

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complex cause. Renal disease in leishmaniasis is usually mild and may resolve after treatment of the infection. Renal dysfunction may be associated with treatment for visceral leishmaniasis with antimony compounds.

Filariasis Proteinuria is more common in filarial hyperendemic regions of West Africa than in nonfilarial areas. Renal histologic analysis has shown a variety of different histopathologic appearances; the most common is diffuse mesangial proliferative GN with C3 deposition in the glomeruli [201]. Renal biopsy specimens also demonstrate large numbers of eosinophils in the glomeruli, and microfilariae may be seen in the lumen of glomerular capillaries. Filarial antigens have been detected within immune deposits within the glomeruli. Lymphatic filariasis is also associated with chyluria [202].

Hydatid Disease Echinococcus granulosus causes chronic cysts within a variety of organs [203]. In addition, nephrotic syndrome in association with hydatid disease has been reported. Membranous nephropathy, minimal change lesions, and mesangiocapillary GN have been described in association with hydatid disease [204]. Immunoﬂuorescence reveals deposits of immunoglobulin, complement, and hydatid antigens within the glomeruli. Remission of nephrotic syndrome has been reported with treatment by antiparasitic agents such as albendazole. Toxoplasmosis Nephrotic syndrome has occasionally been reported as a manifestation of congenital toxoplasmosis. Dissemination of previously latent toxoplasma infection in patients undergoing treatment with immunosuppressive drugs has been increasingly recognized in recent years. Reactivation of toxoplasmosis or progression of recently acquired primary infection should be considered in patients undergoing renal transplantation or

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immunotherapy for renal disease who develop unexplained inﬂammation of any organ.

Fungal Infections Fungal infections of the kidneys and urinary tract occur most commonly as part of systemic fungal infections in patients with underlying immunodeficiency, as focal urinary tract infections in patients with obstructive lesions, or as a result of indwelling catheters [205]. Although candidal infection is the most common fungal infection in both immunocompromised and nonimmunocompromised hosts, virtually all other fungal pathogens may invade the renal tract during severe immunocompromise. Urinary infection with Candida albicans is most commonly a component of systemic candidiasis in patients who are severely immunocompromised. Systemic candidiasis is also seen in premature and term infants with perinatally acquired invasive candidiasis. Presentation is usually with systemic sepsis, fever or hypothermia, hepatosplenomegaly, erythematous rash, and thrombocytopenia. Systemic candidiasis may be seen on ophthalmologic investigation as microemboli in the retina. The first clue to the underlying diagnosis may be the presence of yeasts in the urine. Candidal involvement of the urinary tract may affect all structures including the glomeruli, tubules, collecting system, ureters, and bladder. Microabscesses may form within the renal parenchyma, and large balls of fungi may completely obstruct the urinary tract at any level. AKI caused by systemic candidiasis or obstruction of the renal tracts with fungal hyphae is a well-recognized complication of systemic candidal infection. Indwelling catheters (which form a nidus for persistent infection) should be removed [205]. Successful treatment of nonobstructing bilateral renal fungal balls by fluconazole either alone or in combination with liposomal amphotericin B has been reported [206]. In the presence of obstruction, however, percutaneous nephrostomy to relieve the obstruction with anterograde amphotericin B irrigation, coupled with systemic

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antifungal therapy, is the mainstay of treatment. Amphotericin B is the most effective antifungal agent, but it is not excreted in the urine. Local irrigation via nephrostomy provides good results, however. For treatment of urinary tract candidiasis, it is usually combined with ﬂuconazole or 5-ﬂucytosine, both of which are excreted in high concentrations in the urine. Treatment is required for weeks to months to ensure complete elimination of the fungus, and the ultimate outcome is largely dependent on whether there is a permanent defect in immunity.

Miscellaneous Conditions Hemorrhagic Shock and Encephalopathy In 1983, Levin et al. first described hemorrhagic shock and encephalopathy, which appeared to be distinct from previously recognized pediatric disorders [207]. Other cases have subsequently been reported from several centers in the United Kingdom, Europe, Israel, the United States, and Australia, and the syndrome is now recognized as a distinct severe childhood disorder. Hemorrhagic shock and encephalopathy usually affect infants in the first year of life, with a peak onset at 3–4 months of age. A prodromal illness with fever, irritability, diarrhea, or upper respiratory infection occurs 2–5 days before the onset in two-thirds of cases. Affected infants develop profound shock, coma, convulsions, bleeding and evidence of DIC, diarrhea, and oliguria. Laboratory findings include acidosis, falling hemoglobin and platelet levels, elevated urea and creatinine levels, and elevated levels of hepatic transaminases. Despite vigorous intensive care, the prognosis is poor, and most affected infants die or are left severely neurologically damaged [208]. A small number of patients have been reported to survive without residual sequelae. The renal impairment appears to be largely prerenal in origin, and when aggressive volume replacement and treatment of the shock results in improved renal perfusion, rapid improvement in renal function is usually observed. In patients with

Infectious Diseases and the Kidney in Children

profound shock unresponsive to initial resuscitation, vasomotor nephropathy supervenes and dialysis may be required. Myoglobinuria in association with hemorrhagic shock and encephalopathy has been reported.

Kawasaki Disease Following the description of the mucocutaneous lymph node syndrome by Kawasaki in 1968, Kawasaki disease (KD) has been recognized as a common and serious childhood illness with a worldwide distribution. Although the etiology remains unknown, epidemiologic features clearly suggest an infective cause. The disease occurs in epidemics, and wavelike spread has been demonstrated during outbreaks in Japan (see ▶ Chap. 45, “Renal Involvement in Children with Vasculitis”). The main complication of KD is the development of a vasculitis affecting the small- and mediumsized muscular arteries. Although the coronary arteries are most commonly affected in severe cases, the vasculitis can be widespread and affect axillary, femoral, carotid, renal, and mesenteric arteries [209]. Renal involvement in KD is common, with proteinuria and sterile pyuria being commonly detected during the acute disease [210]. More severe kidney involvement is less common, but there are reports of a broad spectrum of other kidney involvement including acute kidney injury, interstitial nephritis, immune-complex nephritis, nephrotic syndrome, and hemolytic uremic syndrome. The vasculitis of KD involves neutrophil and lymphocytic influx into the vessel wall, with destruction of the intima and media. Involvement of extrarenal or intrarenal vasculature can result in areas of infarction or in hypertension. Reported histological features in KD patients with more severe forms of renal involvement include interstitial infiltration of leukocytes, immune-complex nephritis, swelling of endothelial and mesangial cells, dense deposits, and vasculitis [210]. Treatment of KD is aimed at rapid cessation of the inflammatory process. In patients who do not respond to intravenous immunoglobulin, addition of other anti-inflammatory agents

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including steroids, anti-TNF agents, anakinra, or cyclosporine has been reported to be beneﬁcial.

Xanthogranulomatous Pyelonephritis (XGP) XGP is a chronic inflammatory disorder of the kidney that invades the parenchyma, characterized by granulomatous inflammation with giant cells and foamy histiocytes. Most are unilateral and are caused by urinary tract obstruction, infection, nephrolithiasis, diabetes, and/or immunocompromise. It is rare in children, but when it occurs, it typically affects boys under 8 years of age [211]. A case series by Quinn et al. showed an incidence of 6/1,000 surgically proven chronic pyelonephritis. Case reports have associated it with renal vein thrombi [212]. It presents with anorexia, weight loss, fever, chills, and dull, persistent flank pain. It occurs in 1 % of all renal infections, and E. coli, Proteus, and Pseudomonas infections are implicated. XGP has also been referred to as a pseudotumor as it can be radiologically and clinically indistinguishable from renal carcinoma. The treatment is surgical [211].

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1648 7. Schneider J, Khemani R, Grushkin C, Bart R. Serum creatinine as stratified in the RIFLE score for acute kidney injury is associated with mortality and length of stay for children in the pediatric intensive care unit. Crit Care Med. 2010;38:933–9. 8. Ronco C, Legrand M, Goldstein SL, Hur M, Tran N, Howell EC, Cantaluppi V, Cruz DN, Damman K, Bagshaw SM, et al. Neutrophil gelatinase-associated lipocalin: ready for routine clinical use? An international perspective. Blood Purif. 2014;37:271–85. 9. Harrison LH, Trotter CL, Ramsay ME. Global epidemiology of meningococcal disease. Vaccine. 2009;27 Suppl 2:B51–63. 10. Edmond K, Clark A, Korczak VS, Sanderson C, Griffiths UK, Rudan I. Global and regional risk of disabling sequelae from bacterial meningitis: a systematic review and meta-analysis. Lancet Infect Dis. 2010;10:317–28. 11. Couto-Alves A, Wright VJ, Perumal K, Binder A, Carrol ED, Emonts M, de Groot R, Hazelzet J, Kuijpers T, Nadel S, et al. A new scoring system derived from base excess and platelet count at presentation predicts mortality in paediatric meningococcal sepsis. Crit Care. 2013;17:R68. 12. Kumar AA, Bhaskar E, Palamaner Subash Shantha G, Swaminathan P, Abraham G. Rhabdomyolysis in community acquired bacterial sepsis–a retrospective cohort study. PLoS One. 2009;4:e7182. 13. Brandtzaeg P, van Deuren M. Current concepts in the role of the host response in Neisseria meningitidis septic shock. Curr Opin Infect Dis. 2002;15:247–52. 14. Pathan N, Hemingway CA, Alizadeh AA, Stephens AC, Boldrick JC, Oragui EE, McCabe C, Welch SB, Whitney A, O’Gara P, et al. Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock. Lancet. 2004;363:203–9. 15. Faust SN, Levin M, Harrison OB, Goldin RD, Lockhart MS, Kondaveeti S, Laszik Z, Esmon CT, Heyderman RS. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med. 2001;345:408–16. 16. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699–709. 17. Angel C, Shu T, Green J, Orihuela E, Rodriquez G, Hendrick E. Renal and peri-renal abscesses in children: proposed physio-pathologic mechanisms and treatment algorithm. Pediatr Surg Int. 2003;19:35–9. 18. Todd J, Fishaut M, Kapral F, Welch T. Toxic-shock syndrome associated with phage-group-I staphylococci. Lancet. 1978;312:1116–8. 19. Chuang YY, Huang YC, Lin TY. Toxic shock syndrome in children: epidemiology, pathogenesis, and management. Paediatr Drugs. 2005;7:11–25. 20. Buchdahl R, Levin M, Wilkins B, Gould J, Jaffe P, Matthew DJ, Dillon MJ. Toxic shock syndrome. Arch Dis Child. 1985;60:563–7.

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1653 169. Watson DC, Sargianou M, Papa A, Chra P, Starakis I, Panos G. Epidemiology of Hantavirus infections in humans: a comprehensive, global overview. Crit Rev Microbiol. 2014;40:261–72. 170. Manigold T, Vial P. Human hantavirus infections: epidemiology, clinical features, pathogenesis and immunology. Swiss Med Wkly. 2014;144:w13937. 171. Grcevska L, Polenakovic M, Oncevski A, Zografski D, Gligic A. Different pathohistological presentations of acute renal involvement in Hantaan virus infection: report of two cases. Clin Nephrol. 1990;34:197–201. 172. Rusnak JM, Byrne WR, Chung KN, Gibbs PH, Kim TT, Boudreau EF, Cosgriff T, Pittman P, Kim KY, Erlichman MS, et al. Experience with intravenous ribavirin in the treatment of hemorrhagic fever with renal syndrome in Korea. Antiviral Res. 2009;81:68–76. 173. Allen CW, Alexander SI. Adenovirus associated haematuria. Arch Dis Child. 2005;90:305–6. 174. Storsley L, Gibson IW. Adenovirus interstitial nephritis and rejection in an allograft. J Am Soc Nephrol. 2011;22:1423–7. 175. Parasuraman R, Zhang PL, Samarapungavan D, Rocher L, Koffron A. Severe necrotizing adenovirus tubulointerstitial nephritis in a kidney transplant recipient. Case Rep Transplant. 2013;2013:969186. 176. Pasch A, Frey FJ. Coxsackie B viruses and the kidney–a neglected topic. Nephrol Dial Transplant. 2006;21:1184–7. 177. Beigel J, Bray M. Current and future antiviral therapy of severe seasonal and avian inﬂuenza. Antiviral Res. 2008;78:91–102. 178. Muthuri SG, Venkatesan S, Myles PR, LeonardiBee J, Al Khuwaitir TS, Al Mamun A, Anovadiya AP, Azziz-Baumgartner E, Baez C, Bassetti M, et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with inﬂuenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med. 2014;2:395–404. 179. Lin CY, Hsu HC. Measles and acute glomerulonephritis. Pediatrics. 1983;71:398–401. 180. Kabakus N, Aydinoglu H, Bakkaloglu SA, Yekeler H. Mumps interstitial nephritis: a case report. Pediatr Nephrol. 1999;13:930–1. 181. Lin CY, Chen WP, Chiang H. Mumps associated with nephritis. Child Nephrol Urol. 1990;10:68–71. 182. Lau YL, Peiris JSM. Pathogenesis of severe acute respiratory syndrome. Curr Opin Immunol. 2005;17:404–10. 183. Chu KH, Tsang WK, Tang CS, Lam MF, Lai FM, To KF, Fung KS, Tang HL, Yan WW, Chan HW, et al. Acute renal impairment in coronavirusassociated severe acute respiratory syndrome. Kidney Int. 2005;67:698–705. 184. Farcas GA, Poutanen SM, Mazzulli T, Willey BM, Butany J, Asa SL, Faure P, Akhavan P, Low DE, Kain KC. Fatal severe acute respiratory syndrome is

1654 associated with multiorgan involvement by coronavirus. J Infect Dis. 2005;191:193–7. 185. Ding Y, He L, Zhang Q, Huang Z, Che X, Hou J, Wang H, Shen H, Qiu L, Li Z, et al. Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways. J Pathol. 2004;203:622–30. 186. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426:450–4. 187. Eckerle I, Muller MA, Kallies S, Gotthardt DN, Drosten C. In-vitro renal epithelial cell infection reveals a viral kidney tropism as a potential mechanism for acute renal failure during Middle East Respiratory Syndrome (MERS) coronavirus infection. Virol J. 2013;10:359. 188. Giglioli G. Malaria and renal disease, with special reference to British Guiana. II The effect of malaria eradication on the incidence of renal disease in British Guiana. Ann Trop Med Parasitol. 1962;56:225–41. 189. Hendrickse RG, Gilles HM. The nephrotic syndrome and other renal diseases in children in Western Nigeria. East Afr Med J. 1963;40:186–201. 190. Ehrich JHH, Eke FU. Malaria-induced renal damage: facts and myths. Pediatr Nephrol. 2007;22:626–37. 191. Boonpucknavig V, Sitprija V. Renal disease in acute Plasmodium falciparum infection in man. Kidney Int. 1979;16:44–52. 192. Elsheikha HM, Sheashaa HA. Epidemiology, pathophysiology, management and outcome of renal dysfunction associated with plasmodia infection. Parasitol Res. 2007;101:1183–90. 193. Maitland K, Levin M, English M, Mithwani S, Peshu N, Marsh K, Newton CRJC. Severe P. falciparum malaria in Kenyan children: evidence for hypovolaemia. QJM. 2003;96:427–34. 194. Maitland K, Pamba A, Newton CRJC, Levin M. Response to volume resuscitation in children with severe malaria. Pediatr Crit Care Med. 2003;4:426–31. 195. Maitland K, Kiguli S, Opoka RO, Engoru C, OlupotOlupot P, Akech SO, Nyeko R, Mtove G, Reyburn H, Lang T, et al. Mortality after ﬂuid bolus in African children with severe infection. N Engl J Med. 2011;364:2483–95. 196. Van den Ende J, Coppens G, Verstraeten T, Van Haegenborgh T, Depraetere K, Van Gompel A, Van den Enden E, Clerinx J, Colebunders R, Peetermans WE, et al. Recurrence of blackwater fever: triggering of relapses by different antimalarials. Trop Med Int Health. 1998;3:632–9. 197. Barsoum RS. Schistosomiasis and the kidney. Semin Nephrol. 2003;23:34–41. 198. Seck SM, Sarr ML, Dial MC, Ka EF. Schistosoma haematobium-associated glomerulopathy. Indian J Nephrol. 2011;21:201–3.

J. Stevens et al. 199. van Griensven J, Diro E. Visceral leishmaniasis. Infect Dis Clin North Am. 2012;26:309–22. 200. Caravaca F, Munoz A, Pizarro JL, Saez de Santamaria J, Fernandez-Alonso J. Acute renal failure in visceral leishmaniasis. Am J Nephrol. 1991;11:350–2. 201. Yap HK, Woo KT, Yeo PP, Chiang GS, Singh M, Lim CH. The nephrotic syndrome associated with filariasis. Ann Acad Med Singapore. 1982;11:60–3. 202. Graziani G, Cucchiari D, Verdesca S, Balzarini L, Montanelli A, Ponticelli C. Chyluria associated with nephrotic-range proteinuria: pathophysiology, clinical picture and therapeutic options. Nephron Clin Pract. 2011;119:c248–53; discussion c254. 203. Moro P, Schantz PM. Echinococcosis: a review. Int J Infect Dis. 2009;13:125–33. 204. Gelman R, Brook G, Green J, Ben-Itzhak O, Nakhoul F. Minimal change glomerulonephritis associated with hydatid disease. Clin Nephrol. 2000;53:152–5. 205. Kauffman CA. Diagnosis and management of fungal urinary tract infection. Infect Dis Clin North Am. 2014;28:61–74. 206. Stocker M, Caduff JH, Spalinger J, Berger TM. Successful treatment of bilateral renal fungal balls with liposomal amphotericin B and fluconazole in an extremely low birth weight infant. Eur J Pediatr. 2000;159:676–8. 207. Levin M, Hjelm M, Kay JD, Pincott JR, Gould JD, Dinwiddie R, Matthew DJ. Haemorrhagic shock and encephalopathy: a new syndrome with a high mortality in young children. Lancet. 1983;2:64–7. 208. Levin M, Pincott JR, Hjelm M, Taylor F, Kay J, Holzel H, Dinwiddie R, Matthew DJ. Hemorrhagic shock and encephalopathy: clinical, pathologic, and biochemical features. J Pediatr. 1989;114:194–203. 209. Eleftheriou D, Levin M, Shingadia D, Tulloh R, Klein NJ, Brogan PA. Management of Kawasaki disease. Arch Dis Child. 2014;99:74–83. 210. Watanabe T. Kidney and urinary tract involvement in Kawasaki disease. Int J Pediatr. 2013;2013:831834. 211. Chaudhary R, Singh K, Jain N, Biswas R. Chronic flank pain, fever and an unusual diagnosis. BMJ Case Rep. 2011;2011. published online. doi: 10.1136/ bcr.08.2011.4646. 212. Gupta G, Singh R, Kotasthane DS, Kotasthane VD, Kumar S. Xanthogranulomatous pyelonephritis in a male child with renal vein thrombus extending into the inferior vena cava: a case report. BMC Pediatr. 2010;10:47. 213. Schildgen V, van den Hoogen B, Fouchier R, Tripp RA, Alvarez R, Manoha C, Williams J, Schildgen O. Human Metapneumovirus: lessons learned over the first decade. Clinical Microbiology Reviews. 2011;24(4):734–754. 214. Allander T et al. Cloning of a human parvovirus by molecular screening of respiratory tract samples. PNAS. 2005;102(34):12891–6.

Nephrotoxins and Pediatric Kidney Injury

Takashi Sekine

Contents

Introduction

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1655 Mechanisms Underlying Nephrotoxicity of Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . General Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathways of Accumulation of Substances in Renal Cells (Drug Transporters and Endocytosis Mechanisms) . . . . . . . . . . . . . . . . . . . . . . . . . . Modulation of Renal Blood Flow, Particularly Afferent and Efferent Arterioles . . . . . . . . . . . . . . . . . . . . Nephrotoxic Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antiviral Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antifungal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antineoplastic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Calcineurin Inhibitor (Cyclosporin A) . . . . . . . . . . . . . NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radiocontrast Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Environmental Substances . . . . . . . . . . . . . . . . . . . . . . . . . Natural Toxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Biologic Nephrotoxins . . . . . . . . . . . . . . . . . . . . . . .

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T. Sekine (*) Department of Pediatrics, Toho University Faculty of Medicine, Meguro-ku, Tokyo, Japan e-mail: [emailprotected]; [emailprotected] # Springer-Verlag Berlin Heidelberg 2016 E.D. Avner et al. (eds.), Pediatric Nephrology, DOI 10.1007/978-3-662-43596-0_48

The kidney and liver play central roles in the elimination of xenobiotic substances including drugs, environmental substances, food additives, and their metabolites. All xenobiotic substances are ultimately excreted into the urine via the kidney or into the feces via the liver and bile duct in their original form or as metabolites [1–3]. Considering this essential role of the kidney, it is reasonable to expect it to be susceptible to these xenobiotics. In addition, several speciﬁc functions of the kidney (e.g., tubular transport, metabolism of xenobiotics, and concentration of urine) and changes in hemodynamics in the kidney may cause nephrotoxicity. In clinical practice, it is not uncommon for nephrotoxicity to limit the usage of speciﬁc drugs. For example, vancomycin, a key drug for methicillin-resistant Staphylococcus aureus (MRSA), possesses potential nephrotoxicity [4], and its inappropriate usage often causes severe acute kidney injury (AKI). The same is true for cisplatin, which has been used for solid tumors, such as seminoma, lung cancer, and ovarian tumors. However, cisplatin has very high nephrotoxicity and the total dose must be strictly limited. Thus, the consideration and knowledge of drug nephrotoxicity are essential in medical practice. In this chapter, the basic mechanisms of the development of nephrotoxicity will be explained. Thereafter, each drug possessing potential 1655

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nephrotoxicity both from clinical aspects and the mechanisms underlying drug nephrotoxicity will be reviewed. 4.

Mechanisms Underlying Nephrotoxicity of Substances General Perspectives The reasons why the kidney is vulnerable to many substances are complex, and several characteristics explain this vulnerability. The following are the main causes of the susceptibility of the kidney to xenobiotics. 5. 1. The kidney and liver are the final pathways for the excretion of xenobiotics and their metabolites, and most of the toxic substances ingested are finally excreted from the kidney and liver. In particular, hydrophilic drugs and/or their metabolites are preferentially excreted from the kidney. 2. The kidney, especially the proximal tubular cells, possesses specific secretory pathways for xenobiotics. During the transcellular transport of certain substances from the peritubular capillaries to the tubular lumen, their concentrations in the proximal tubular cells become very high transiently. When these substances possess cytotoxicity, they impair renal epithelial cells. In addition, some substances are taken up from the glomerular filtrate into tubular cells. Over the past decade, many of these pathways have been identified and are presently called “drug transport systems.” In addition, the proximal tubular cells possess endocytosis mechanisms by which various substances including nephrotoxic compounds, such as aminoglycosides, are taken up into the proximal tubular cells. 3. The concentration of urine is one of the most important functions of the kidney. In adult, 180 L of plasma is filtrated from glomeruli in a day, whereas the final urinary output is only 1.0–1.5 L/day. Since more than 99 % of the

10.

fluid is reabsorbed through the nephron segments, the renal tissues are exposed to highly concentrated xenobiotics that are finally excreted into the urine. The kidney consumes a large amount of energy to transport ions, fluid, and organic substances [5]. The energy consumed in the tubular cells is mostly utilized by Na+, K+-ATPase. Alteration of the renal blood flow ultimately leads to ischemia. Ischemia causes ATP depletion in the tubular cells, which attenuates the function of Na+, K+-ATPase. Since Na+, K+-ATPase is essential for cellular function, the decreased activity of Na+, K+-ATPase results in profound cellular damage. As described above, the kidney consumes a large amount of oxygen, so oxidative stress commonly occurs in the kidney. Several nephrotoxic agents, such as cisplatin, markedly induce oxidative stress. Several drugs influence renal hemodynamics and alter the renal plasma flow (RPF) and glomerular filtrate rate (GFR). When these changes are severe and persistent, renal tissues are exposed to ischemic damage and kidney functions deteriorate. Tubular cells possess metabolic enzymes including cytochrome P450 for phase I biotransformation and conjugating enzymes such as glucuronyl transferase for phase II biotransformation. In tubular cells, these enzymes occasionally produce toxic compounds. Several compounds disturb the normal function of the endoplasmic reticulum (ER), called “ER stress.” ER stress in tubular cells may adversely affect cellular functions, which may result in cell injury or death. Some drugs are highly concentrated in the tubular lumen and crystallize under specific urinary conditions, such as low pH. This can result in the obstruction of tubular lumens, leading to obstructive nephropathy. An allergic mechanism should be considered in drug-induced nephrotoxicity. However, this chapter will focus on substances that directly impair the kidney without the involvement of immune mechanisms.

Nephrotoxins and Pediatric Kidney Injury

To facilitate the understanding of these complex nephrotoxic mechanisms, nephrotoxic mechanisms will be divided into the following three categories and each mechanism will be explained in detail: (1) pathways of accumulation of substances in renal cells, (2) the fates of cells exposed to the above mentioned nephrotoxic substances, and (3) modulation of renal hemodynamics by nephrotoxic substances.

Pathways of Accumulation of Substances in Renal Cells (Drug Transporters and Endocytosis Mechanisms) Transepithelial Transport Pathways (Drug Transporters) The kidney has two primary pathways for excreting all substances into the urine, namely, glomerular filtration and tubular secretion. Glomerular filtration is governed by two issues, plasma filtration fraction and the charge and size barriers of the glomerulus. The amount of filtrated plasma is only approximately 20 % of the renal plasma flow so the kidney can excrete up to 20 % of substances into the urine during one renal perfusion. The molecular weight threshold for glomerular filtration is approximately 65 KDa. While drugs can freely pass through glomerular capillaries in their free form, hydrophobic drugs are mostly bound to the albumin in plasma, thereby preventing their elimination via glomerular filtration. Thus, the clearance of each drug by glomerular filtration is determined by the unbound fraction of drugs in the plasma and GFR. Tubular secretory pathways possess high potential for the transfer of drugs and their metabolites from the blood circulation to the urine across the proximal tubules. A remarkable example is p-aminohippurate (PAH), where approximately 90–95 % of PAH is excreted via tubular secretion during one renal perfusion. For this reason, PAH has been used to estimate RPF. In addition, reabsorption from the urine is another important function of the kidney, by which essential nutrients, such as glucose, amino acids, and

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vitamins, are salvaged from the glomerular filtrate. Specific transport systems, comprising membrane transporters, have also been identified to be involved in the reabsorption. Numerous studies conducted over the last 70 years have revealed that proximal tubular cells possess two distinct pathways for the secretion of organic substances, namely, organic anion and cation transport systems. A prominent feature of the classical organic anion transport pathway, i.e., the PAH transport system, is that it interacts with and transports a variety of organic anions with unrelated chemically heterogeneous weak acids with a carbon backbone of a certain size and a net negative charge at physiological pH (pKa 400 and between bacteriological cure and AUC/MIC >850 [65]. There was obviously no significant correlation between the effect of vancomycin and T > MIC, which

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applied to all patients [65]. These data and the lack of correlation between the effect of vancomycin and T > MIC established the guideline of intermittent vancomycin dosing with target trough levels of 15–20 mg/L [61]. Patel suggested the rapidly decreasing probability of attaining the target of AUC/MIC 400 with increasing MIC above 1 mg/L, particularly in patients with wellpreserved kidney function [66]. Information on the renal recovery from vancomycin nephrotoxicity is scarce. A meta-analysis of available studies suggests that the glycopeptide teicoplanin is as effective as vancomycin, particularly in mildly sick patients, while having a lower incidence of nephrotoxicity and infusion-related side effects [67]. Affected Nephron Segments and Vasculature Vancomycin is almost exclusively excreted from the kidney [68] mainly via glomerular ﬁltration and to some extent via active tubular secretion [69]. It has been suggested that the proximal renal tubular cells are the main nephron segment impaired by vancomycin [70]. Vancomycininduced renal damage requires the energydependent transport of vancomycin from the blood to the proximal tubular cells across the basolateral membrane. In the proximal tubular cells, vancomycin presents a pronounced lysosomal tropism [71]. Histopathologically, renal tissues show tubulointerstitial nephritis, sometimes with granulomas in the kidney impaired by vancomycin [72]. Mechanisms Underlying Cytotoxicity Animal studies suggest that oxidative stress might underlie the development of vancomycin-induced toxicity, and genetic expression analyses in mice have suggested the involvement of oxidative stress and mitochondrial damage in vancomycininduced kidney injury [73, 74]. An experiment supports this hypothesis. In rats, curcumin ameliorates the decreases in antioxidant enzyme activity and glutathione peroxidase activity induced by vancomycin and counters vancomycin nephrotoxicity [75]. The protective and antioxidation effects

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of vitamin E, vitamin C, N-acetylcysteine, caffeic acid phenethyl ester, and erythropoietin on vancomycin nephrotoxicity have also been observed in rodent models [76, 77]. Nevertheless, whether antioxidant therapy protects against vancomycin nephrotoxicity has not been studied in humans. In addition, the complement pathway and inﬂammation in vancomycin renal toxicity have also been implicated.

Antiviral Drugs The exact frequency of nephrotoxicity induced by antiviral drugs is difﬁcult to determine [78]. Antiviral drugs cause AKI through a variety of mechanisms. Direct renal tubular toxicity has been described with a number of new medications. These include cidofovir, adefovir dipivoxil, and tenofovir, as well as acyclovir. Crystal deposition in the tubular may promote the development of renal failure. Several different drugs have been described to induce crystal nephropathy, including acyclovir and the protease inhibitor indinavir. Kidney injury associated with antiviral drugs involves diverse processes having effects on the renal transporters, as well as on tubule cells.

Acyclovir Clinical Aspects Acyclovir is an antiviral agent that is commonly used to treat severe viral infections including herpes simplex and varicella zoster, in children [79]. Acyclovir enters in HSV-infected cells and is phosphorylated by thymidine kinase; phosphorylated acyclovir is an active form for HSV. Acyclovir is generally well tolerated; however, in some cases, severe nephrotoxicity has been reported [79]. Acyclovir-induced nephrotoxicity is typically noticed by elevated plasma level of creatinine and abnormal urine sediments [80]. AKI mediated by this compound is characterized a gradual return to baseline kidney function on discontinuation of the drug [81]. A systematic review of the literature reveals a pronounced, transient elevation (up to ninefold in

T. Sekine

some cases) of plasma creatinine levels in children, often without any other clinical evidence of overt nephrotoxicity [82]. As explained by Urakami and colleagues, both organic anion and cation transporting pathways may play a role in the renal tubular transport of creatinine [83]. This fact has been supported by many other studies [82]. Affected Nephron Segments and Vasculature Pathologic examination of the biopsy specimen revealed loss of proximal-tubule brush border and dilated proximal and distal tubules with flattening of lining cells and focal nuclear loss [81]. Organic anion transporters (OAT) and organic cation transporters (OCT) were revealed to be involved in the renal tubular transport of acyclovir [84]. Mechanisms of Cytotoxicity The mechanisms of acyclovir-induced nephrotoxicity had been believed its crystallization in tubular lumen leading obstructive nephropathy [81, 85]. Sawyer reported on four patients with a chronic fatigue syndrome who experienced five episodes of acute renal insufficiency associated with highdose (500 mg/m2) intravenous acyclovir administered intravenously as one-hour infusion [85]. Nephrotoxicity developed despite precautions to avoid volume contraction. Examination of the urinary sediment of three patients by polarizing microscopy showed bi-refringent needleshaped crystals within leukocytes. In the most severely affected patient, a serum creatinine concentration of 8.6 mg/dl developed, and the patient underwent percutaneous renal biopsy that revealed foci of interstitial inflammation without tubular necrosis. Urine, blood, and renal tissue levels of acyclovir were high. They concluded that combined data from these patients support crystalluria and obstructive nephropathy as a mechanism of acyclovir-induced renal failure in humans. They emphasized the importance of maintaining adequate hydration during high-dose acyclovir therapy. Thus, drug crystal formation in collecting tubules resulting in an intraparenchymal form of obstructive nephropathy has been

Nephrotoxins and Pediatric Kidney Injury

suggested as the mechanism for acyclovir nephrotoxicity [81]. However, there are several documented cases of acyclovir-induced nephrotoxicity in the absence of crystalluria [82]. Dos Santos ﬁrst showed that acyclovir induced a nonoliguric ARF, and no tubular obstruction was detected in the animal’s kidneys by light microscopy using rats. His results showed that acyclovir affects renal microcirculation in the absence of crystalluria [86]. Thus, acute tubular necrosis is a part of the spectrum of renal damage due to acyclovir.

Ganciclovir Clinical Aspects Ganciclovir, a homologue of acyclovir, is a guanosine analogue that is believed to inhibit the inclusion of deoxyguanosine triphosphate into viral DNA [87]. It is approved by the Food and Drug Administration for the treatment of cytomegalovirus (CMV) retinitis in patients who are immunocompromised and for the prevention of CMV infection in at-risk transplant recipients. It has also been studied and is recommended for the treatment of congenital, CNS, disseminated, and retinal CMV infection and for the prevention of CMV infection in posttransplantation and human immunodeﬁciency virus (HIV)-exposed or HIV-infected children [87]. However, most of safety research regarding ganciclovir comes from the adult population. In addition to neutropenia, the most common untoward effects linked to ganciclovir are nephrotoxicity, thrombocytopenia, hypocalcemia, hypomagnesemia, and hypokalemia. These occur at rates ranging from 2 % to 6 % [88].

Cidofovir Clinical Aspects Cidofovir is an antiviral drug with activity against a wide array of DNA viruses including poxvirus [89]. Despite its remarkable coverage, cidofovir causes proximal tubular cell injury and AKI in a dose-dependent manner. Treatment

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with cidofovir requires the routine use of prophylactic measures. A correct knowledge of the cellular and molecular mechanisms of cidofovir toxicity may lead to the development of alternative prophylactic strategies. Lalezari performed randomized controlled trial comparing 48 patients with AIDS and previously untreated peripheral CMV retinitis who were randomly assigned to immediate (n = 25) or deferred treatment (n = 23) [90]. The intravenous cidofovir regimen was a dose 5 mg/kg of body weight, once weekly for 2 weeks and then once every other week. To minimize nephrotoxicity, oral probenecid and intravenous hydration with normal saline were administered with each cidofovir infusion. Asymptomatic neutropenia (15 %) and proteinuria (12 %) were the most common serious adverse events observed. Cidofovir treatment was discontinued in 10 of 41 patients (24 %) because of protocol-defined treatment-limiting nephrotoxicity. They also suggested that probenecid and saline hydration appeared to minimize drug-related nephrotoxicity. Affected Nephron Segments and Vasculature and Mechanisms of Cytotoxicity Oritz reported that cidofovir induced apoptosis in primary cultures of human proximal tubular cells in a temporal (peak apoptosis at 7 days) and concentration (10–40 mg/ml) pattern consistent with that of clinical toxicity [89]. Apoptosis was identified by the presence of hypodiploid cells, by the exposure of annexin V binding sites, and by morphological features and was associated with the appearance of active caspase-3 fragments. Cell death was specific as it was also present in a human proximal tubular epithelial cell line (HK-2), but not in a human kidney fibroblast cell line, and was prevented by probenecid. An inhibitor of caspase-3 (DEVD) prevented cidofovir apoptosis. The survival factors present in serum, insulin-like growth factor-1 and hepatocyte growth factor, were also protective. These data suggest that apoptosis induction is a mechanism contributing to cidofovir nephrotoxicity.

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Tenofovir Clinical Aspects Tenofovir was used first in 2001 and remains the only NtRTI approved by the US Food and Drug Administration (FDA) for the treatment of HIV infection [91]. Tenofovir was also approved for treatment of chronic hepatitis B in adults in 2008 [92]. Tenofovir is available in fixed-dose combination with emtricitabine and efavirenz [93]. Tenofovir is eliminated unchanged in the urine by a combination of glomerular filtration and proximal tubular secretion, and 20–30 % of the drug is actively transported into renal proximal-tubule cells by organic anion transporters [94]. Kidney toxicity may lead to acute kidney injury (AKI), chronic kidney disease (CKD), and features of proximal tubular injury, including Fanconi syndrome, isolated hypophosphatemia, and decreased bone mineral density [94]. Two studies have demonstrated tubular dysfunction with tenofovir in 17–22 % of tenofovir-treated patients (versus 6 % and 12 % of highly active antiretroviral therapy (HAART)-treated or HAART-naive HIV patients) [94]. Mechanisms of Cytotoxicity A detailed understanding of the molecular mechanism of tenofovir active tubular secretion will facilitate the assessment of potential renal drug–drug interactions with coadministered agents. Tenofovir is taken up by human organic anion transporters 1 and 3 and efflux into urine by MRP4 in proximal-tubule cells [95]. The major renal biopsy finding is varying degrees of chronic tubulointerstitial scarring with tubular atrophy and interstitial fibrosis [96]. Currently available information suggests that all of the nephrotoxicity due to tenofovir is based on a common pathogenesis and pathology. The proximal tubular cell is the main target of tenofovir toxicity due the existence of drug transporters that favor tenofovir accumulation. The nephrotoxicity mechanism was initially postulated by a structural similarity between tenofovir and the nephrotoxic acyclic nucleotide including analogues adefovir and cidofovir. These two drugs cause a proximal tubulopathy, possibly in part due to decreasing

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mitochondrial DNA (mtDNA) replication through inhibition of mitochondrial DNA polymerase [94]. However, only minimal mtDNA depletion was noted in renal proximal tubular cells cultured with tenofovir [97]. Furthermore, early randomized clinical trials and post-marketing data supported the renal safety of tenofovir in relatively healthy patients with HIV infection [94]. Neither Fanconi syndrome nor drug discontinuation because of renal events was observed in early trials [98]. In contrast, several studies, animal models, and even cell culture data support the notion that tenofovir is nephrotoxic for proximal tubular cells [94]. The mismatched results between clinical trials and case reports may be explained because clinical trials have strict inclusion and exclusion criteria. By contrast in routine clinical practice, patients may have associated conditions, medications, or background that may predispose to tenofovir nephrotoxicity [99]. Current evidence suggests that mitochondria are the target organelles of tenofovir cytotoxicity [94].

Adefovir Clinical Aspects Adefovir is mainly eliminated unchanged via the kidneys by a combination of glomerular filtration and tubular secretion, with secretion contributing about 60 % and 35 % to the renal clearance of adefovir and cidofovir, respectively [100]. A case report by Tanji suggested possible pathophysiological mechanisms and nephron segment impaired due to adefovir [101]. A 38-year-old white homosexual man with HIV infection was treated with adefovir on HAART, including hydroxyurea, stavudine, indinavir, and ritonavir. Histologic examination of the renal biopsy showed severe acute tubular degenerative changes primarily affecting the proximal tubules. Affected Nephron Segments and Vasculature Adefovir has a high affinity for substrates of hOAT1 [102], whereas they were found to be only marginally transported by hOAT3 in some studies. At least with respect to adefovir, this finding might be explained by an affinity for

Nephrotoxins and Pediatric Kidney Injury

hOAT3 about 50-fold lower than for hOAT1 [103]. As described by Tanji, the main site of targeted nephron segment of adefovir appears to be proximal tubular cells [101]. Mechanisms of Nephrotoxicity Adefovir-induced cellular damage has been attributed to mitochondrial injury, impaired ATP synthesis, and/or interference with ATP-dependent cellular mechanisms [104]. Tanji reported that upon ultrastructural examination, proximal tubular mitochondria were extremely enlarged and dysmorphic with loss and disorientation of their cristae. Functional histochemical stains for mitochondrial enzymes revealed focal tubular deﬁciency of cytochrome C oxidase, a respiratory chain enzyme partially encoded by mitochondrial DNA (mtDNA), with preservation of succinate dehydrogenase, a respiratory chain enzyme entirely encoded by nuclear DNA (nDNA). Immunoreactivity for COX subunit I (encoded by mtDNA) was weak to undetectable in most tubular epithelial cells, although immunoreactivities for COX subunit IVand iron sulfur subunit of respiratory complex III (both encoded by nDNA) were well preserved in all renal tubular cells. Single-renal tubule polymerase chain reaction revealed marked reduction of mtDNA in COX-immunodeﬁcient renal tubules. This observation indicates that adefovir-induced nephrotoxicity is mediated by depletion of mtDNA from proximal tubular cells through inhibition of mtDNA replication.

Indinavir Clinical Aspects Indinavir is an antiretroviral from the protease inhibitor class and was among the ﬁrst agents used as part of potent combination antiretroviral therapy (ART). Its efﬁcacy resides in the suppression of HIV replication, which has been well documented in large, randomized, controlled trials [105]. Indinavir is notorious for causing renal and urologic toxicity mediated by tubular crystallization [106]. Asymptomatic indinavir crystalluria is very common, possibly occurring in up to two-thirds of treated individuals [105].

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Several different clinical presentations of indinavir nephrotoxicity are observed. Approximately 4 % of treated patients with indinavir experience acute urolithiasis due to indinavir crystalluria, sometimes complicated by obstructive uropathy and post renal acute renal failure. Because indinavir stones are radiolucent, secondary signs of obstruction on imaging studies in the context of ﬂank pain and dysuria usually suggest the diagnosis [105].

Antifungal Drugs Amphotericin B Clinical Aspects Amphotericin B has been in clinical use for more than 50 years and has remained one of the most effective drugs for the treatment of serious fungal infections. Its usage has increased in recent years as the result of aggressive intensive care support and the increased number of immunocompromised patients [107]. However, amphotericin B use is limited by its dose-dependent nephrotoxicity. The incidence of AKI in adult patients treated with amphotericin B is 49–65 % [107, 108]. However, the data for children are scarce and might show different trends, since the pharmacokinetics of amphotericin B in children differs from that in adults. Amphotericin B elimination half-life appears to be inversely correlated with patient age, so individualized dosing based on drug monitoring has been recommended. Risk factors for amphotericin B-induced AKI include cumulative dose, treatment duration, dosing schedule, concomitant therapy with diuretics or other nephrotoxic drugs, and impaired glomerular ﬁltration at the baseline. A number of RCTs in adults demonstrate that the lipid formulation of amphotericin B (lipid complex, colloidal dispersion, and liposomal form) decreases nephrotoxicity [109]. Three new formulations have been developed with improved efﬁcacy and tolerability: amphotericin B in a lipid complex (ABLC, Abelcet), an amphotericin B colloidal dispersion, and liposomal amphotericin B (AmBisome). Three prospective randomized

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studies have clearly shown that AmBisome is less nephrotoxic than amphotericin B. In a doubleblind randomized trial, signiﬁcantly fewer patients receiving AmBisome had nephrotoxic effects. In addition, fewer patients developed hypokalemia in the group receiving AmBisome. A recent multicenter double-blind study has shown that AmBisome (3 or 5 mg/kg/day) has a better safety proﬁle than Abelcet (5 mg/kg) [110]. Goldman proposed guidelines for preventing amphotericin nephrotoxicity by saline infusion prior to the administration of amphotericin (10–15 ml/kg body weight) and the use of lipid formulations in children with either known side effects to conventional amphotericin B, reduced GFR, or concomitant nephrotoxic medication [111]. Affected Nephron Segments and Vasculature and Mechanisms Underlying Nephrotoxicity The two major pathophysiological mechanisms of the development of amphotericin B-induced AKI are (1) the direct effects of the drug on ergosterol in the epithelial cell membrane and (2) renal vasoconstriction due to increased vascular resistance. As opposed to most nephrotoxic agents which affect proximal tubular cells, amphotericin B induces distal tubulopathy. Amphotericin B forms pores in the epithelial cell membrane, altering permeability, and as a consequence alters tubular and vascular smooth muscle cell function.

Antineoplastic Drugs Cisplatin and Carboplatin Clinical Aspects Cisplatin (cis-diamminedichloroplatinum II, CDDP) is widely used in chemotherapeutic regimens for solid or hematologic tumors. However, its usage is limited by tumor cell resistance and diverse effects such as nephrotoxicity, ototoxicity, neurotoxicity, and high emetic risk [112]. Cisplatin nephrotoxicity is a major limiting factor in 20 % of the patients who receive the drug, triggering injury to renal tubular cells [113]. Cisplatin

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may induce both acute and chronic renal toxicity [114], as a progressive and persistent decrease in GFR may occur in each treatment cycle. Polyuria regularly follows cisplatin administration and occurs in two phases. The ﬁrst is within the ﬁrst 24–48 h after administration; urine osmolality decreases, while GFR remains stable. This stage of early polyuria usually reverses spontaneously. The second phase is 72–96 h after cisplatin administration and is characterized by an increase in urine volume and a persistent decrease in GFR [38]. Treatment protocols may reduce the dosage or omit this medication when GFR is less than 60 mL/min/1.73 m2. Most children receiving cisplatin experience some acute loss of kidney function, with considerable individual variation in severity. Womer demonstrated a mean decrease in GFR of 8 % in patients who received a dose of 100 mg/m2 per body surface area [115]. The extent of the decrease in GFR correlates with the peak serum or urine platinum concentration and cisplatin infusion rate [116]. The long-term recovery or stability of renal function is generally favorable [117]. Among children with decreased GFR at the end of treatment, 92 % showed at least some improvement, with 46 % attaining normal GFR when reassessed at 2 1/2 years [118]. Furthermore, 80 % of those with normal GFR at the end of treatment maintained their normal GFR during the follow-up period. Magnesium-wasting tubulopathy occurred in all patients treated with cisplatin. The level of serum magnesium decreased markedly, and most patients required supplementation and had hypocalcemia and/or hypokalemia. Among the children who developed cisplatin-induced hypomagnesemia, approximately one-third to two-thirds remained hypomagnesemic [118, 119]. The concomitant use of cisplatin with other nephrotoxic agents, particularly ifosfamide, increases the risk of renal injury [120]. Carboplatin is a cisplatin analogue with a similar pharmacological effect to cisplatin. It is less nephrotoxic than cisplatin; however, myelosuppression is its major dose-limiting side effect. Unlike cisplatin, carboplatin is not transformed into toxic metabolites by renal tubule cells [121].

Nephrotoxins and Pediatric Kidney Injury

Clinically significant decreases in GFR and hypomagnesemia following carboplatin administration are rare. Paradoxically, it is possible that the risks of renal insufficiency and tubulopathies are higher for carboplatin/ifosfamide therapy than for cisplatin/ifosfamide combination therapy [122]. To avoid serious nephrotoxicity, several interventions have been carried out. Intravenous administration of mannitol and saline is the clinical intervention most commonly used. In a prospective phase II randomized trial, a dose of 100 mg/m2 IV cisplatin every 3 weeks plus forced hydration with or without mannitol diuresis was tested [123]. A total of 67 patients were evaluated: 33 were not given mannitol and 34 were given mannitol in the arm. Life-threatening renal toxicity was less severe in the patients who received mannitol, and the patients tolerated higher doses of cisplatin. Renal toxicity occurred mostly after the first dose of chemotherapy. Cisplatin should not be given to volume-depleted patients. Another potential aspect is to take the patient’s GFR into account in dosing. Moreover, the concurrent administration of NSAIDs, aminoglycosides, or other nephrotoxic drugs should be avoided. Recently, a liposomal formulation of cisplatin, lipoplatin, was developed to reduce the toxicity of cisplatin. Phase 1 and phase 2 clinical trials showed no nephrotoxicity in adults up to a dose of 125 mg/m2 every 14 days [124]. Data in pediatric oncology are not yet available. Affected Nephron Segments and/or Vasculature Cisplatin enters renal tubular cells by passive diffusion or transporter-mediated facilitated diffusion, leading to disproportionate drug accumulation. A basolateral organic cation transporter (OCT) has been linked to uptake of cisplatin into renal tubular cells and has been found to be a factor determining drug pharmacokinetics and the severity of adverse effects including nephrotoxicity [125]. OCT2, which is mainly expressed in the basolateral membrane of the S2 and S3 segments of proximal tubular cells, is the critical transporter for the uptake of cisplatin from peritubular capillaries [125]. Recent studies have shown that OCT1-/OCT2-deficient mice are protected from cisplatin-induced tubular

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damage [125]. Additionally, the high-afﬁnity copper transporter (CTR1) might be related to cisplatin nephrotoxicity [113]. Mechanisms Underlying Nephrotoxicity The pathophysiological mechanisms underlying cisplatin nephrotoxicity are very complex. The proposed injury pathway is as follows: (1) accumulation of cisplatin mediated by the transport pathway as described above, (2) metabolic conversion of cisplatin into nephrotoxins and accumulation of these toxins in kidney cells, (3) DNA injury, (4) cell transport system alteration, (5) mitochondrial dysfunction, (6) oxidative and nitrosative stress, (7) inﬂammatory response, (8) activation of mitogen-activated protein kinase (MAPK), and (9) activation of apoptotic pathways. After cisplatin is taken up in the proximal tubular cells, it binds to plasma proteins, since platinum complexes have high reactivity with amino acid thiol groups such as cysteine [113]. Approximately 90 % of the platinum in the blood binds to albumin and other plasma proteins, which leads to the inactivation of a large number of cisplatin molecules. Thereafter, chloride ligands in cisplatin are displaced, thus allowing cisplatin hydration to occur. Subsequently, water molecules replace one or two chloride ligands, resulting in the formation of [Pt (H2O) Cl (NH3) 2] + and [Pt (H2O) 2 (NH3) 2] 2 + cations. These cations are the origin of positively charged molecules, which readily react with nuclear DNA to form covalent bonds with purine bases, particularly in the N7 position, resulting in 1,2-intrachain cross-links, which strongly correlates with cisplatin-induced genotoxic effects [126, 127]. Positively charged platinum ions bind to components of DNA, RNA, and proteins and impair the replication and transcription functions, leading to cell cycle arrest and apoptosis [126, 127]. Cisplatin also causes renal proximal tubular cell dysfunction. In particular, it interferes with the transport of water and renal tubular cell nutrient transporters, such as Na+K+-ATPase, Na+K+-2CI– cotransporter, and type III Na+/H+ exchanger, and water-permeable channels including aquaporins

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1, 2, and 3. Several lines of evidence suggest that cisplatin accumulates in the mitochondria of renal cells, disturbing mitochondrial functions, enhancing the generation of reactive oxygen species (ROS), inhibiting the absorption of calcium in the mitochondria, and causing the release of proapoptotic factors, which ultimately lead to renal tubular cell death [128]. Oxidative stress is also implicated in renal injury caused by cisplatin. ROS production, depletion of antioxidant systems, and stimulation of renal accumulation of lipid peroxidation products have been suggested as the main mechanisms associated with cisplatin nephrotoxicity. These mechanisms cause the activation of oxidative metabolism by stimulating the production of ROS by impaired mitochondria. The increased production of reactive oxygen and nitrogen species arising from cisplatin administration results in significant damage to cell structure and function, which finally leads to cell dysfunction and signaling for the activation of both apoptotic and cell survival pathways, causing kidney damage and cell death [129, 130]. Inflammatory mechanisms are also strongly related to cisplatin nephrotoxicity. Cisplatin activates phosphorylation and the subsequent translocation of a transcription factor, nuclear factor Kappa B (NF-κB), to the nucleus. Activation of NF-κB promotes the transcription of specific genes encoding inflammatory mediators, which induces immune, proliferative, antiapoptotic, and inflammatory responses [131]. The mitochondrial or intrinsic pathway has emerged as a key factor causing renal tubular cell death in experimental models of cisplatin nephrotoxicity. The BCL-2 family proapoptotic proteins (BAX and BAK) function as “molecular integrators” to the mitochondrial pathway, and in vivo models have been used to clarify their roles in cisplatin apoptosis [113]. Furthermore, cisplatin induces apoptosis via ER stress. In renal tubular cells treated with cisplatin, caspase12 may act downstream of p53 and upstream of caspase-3. The activation of the extrinsic pathway by the binding of cell death receptors through plasmatic membrane ligands leads to the recruitment and activation of caspase-8 and caspase-10,

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which activate caspase-3 to possibly recruit the mitochondrial pathway. The main ligands of cell death include Fas and TNF and their corresponding receptors (TNFRs 1 and 2) [132, 133].

Ifosfamide Clinical Aspects Ifosfamide predominantly causes chronic tubulopathy, which sometimes begins to become apparent months or years after the completion of chemotherapy. The most common manifestation of ifosfamide nephrotoxicity is proximal tubular dysfunction, namely, Fanconi syndrome, and, less often, decreased GFR [134]. Approximately 60 case reports of ifosfamide nephrotoxicity, predominantly from pediatric populations, have been published [135]. The incidence of Fanconi syndrome ranges between 1.4 % and 5 % of ifosfamide-treated patients, and another 15 % of patients develop severe, but subclinical, tubular dysfunction. Skinner ﬁrst pointed out that in addition to overt renal Fanconi syndrome, most patients treated with a high cumulative dose of ifosfamide develop subclinical renal impairment, primarily located at the proximal tubular cells [136]. Fanconi syndrome is typically observed months or even years following the cessation of chemotherapy. For the majority of patients, Fanconi syndrome does not resolve over time. On the other hand, end stage renal failure in these patients has not yet been observed. The reversibility of renal damage has been demonstrated in only a few patients [135]. There are risk factors predicting the development of chronic ifosfamide nephrotoxicity. The most important one is the cumulative dose of ifosfamide (>60–100 g/m2) [137–139]. Other risk factors include patient age (more than 3–5 years) [138, 139], renal irradiation [140], and unilateral nephrectomy [140]. Combined therapy with cisplatin accelerates nephrotoxicity [141]. Arndt followed renal function in patients (median age, 16 years) for at least 3 months following the completion of a chemotherapy regimen, which included 54 g/m2 ifosfamide,

Nephrotoxins and Pediatric Kidney Injury

360 mg/m2 cisplatin, doxorubicin, and high-dose methotrexate. They found that the mean GFR was 97 ml/min/1.73 m2, and 10 out of 24 patients (42 %) had reduced GFR [142]. During chemotherapy, acute renal tubular dysfunction often resolves prior to the next course; however, permanent and potentially progressive kidney damage may also occur [143]. Approximately 30 % of ifosfamide-treated children develop persistent tubulopathy and 5 % develop Fanconi syndrome [144]. In a rat model of ifosfamide-induced tubular damage, Fanconi syndrome was attenuated by pretreatment with glycine [145]. The protection against this damage is considered to be mediated by membrane stabilization. Schlenzig proposed the use of carnitine for protection again such damage [146]. Affected Nephron Segments and Vasculature and Mechanisms Underlying Nephrotoxicity Ifosfamide is metabolized by the cytochrome P450 system, particularly its isoenzymes IIB and IIIA [147]. These enzymes are also expressed in proximal tubular cells. Ifosfamide mustard alkylated DNA has a higher afﬁnity to proteins and is effective over a long time [148]. Following the local tubular metabolism of ifosfamide, speciﬁc damage to proximal tubular DNA, either nucleic or mitochondrial, could explain the longlasting regenerative inability and failure of the energy-dependent functions of these cells. The ifosfamide–mesna combination induces glutathione depletion in both plasma [149] and renal tubular cells, which makes proximal tubular cells susceptible to oxidative stress.

Methotrexate Clinical Aspects Methotrexate is one of the key drugs used in the treatment of childhood leukemia. High-dose methotrexate administration can cause acute kidney injury. The most commonly accepted mechanism underlying this drug-induced toxic effect is the precipitation of MTX and its metabolites in the distal tubules, leading to obstructive uropathy and tubular necrosis.

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Urinary alkalization and hydration are very effective for protection from MTX-induced renal dysfunction. More recently, carboxypeptidase-G (2) [CPDG(2)] (a recombinant bacterial enzyme that rapidly hydrolyzes MTX to inactive metabolites) has become available for the treatment of MTX-induced renal dysfunction. CPDG(2) administration has been well tolerated and results in consistent and rapid reductions in plasma MTX concentrations by a median of 98.7 %. Early administration of CPDG(2) in combination with leucovorin may be beneficial for patients with MTX-induced renal dysfunction and significantly elevated plasma MTX concentrations [150]. Affected Nephron Segments and Vasculature and Mechanisms Underlying Nephrotoxicity In addition to glomerular filtration, methotrexate is extensively secreted from proximal tubular cells via organic anion transporters. Because methotrexate has very low solubility in acidic fluids, it often precipitates and crystallizes in tubular lumens, which might result in AKI due to obstructive nephropathy. Other than the high-dose regimen, the direct cause of the nephrotoxicity of methotrexate is not known.

Bevacizumab Clinical Aspects Bevacizumab, a VEGF inhibitor, has been used in a variety of malignancies offering substantial clinical beneﬁt when combined with standard chemotherapy [151]. The use of VEGF inhibitors in cancer treatment has been associated with increased incidence of hypertension (3–36 %) and proteinuria (21–63 %) [152, 153]. Thrombotic microangiopathy (TMA) is the most frequently encountered renal pathology [154, 155]. However, the available histopathological data are limited. Cryoglobulinemic glomerulonephritis [156] and immune complexmediated focal proliferative glomerulonephritis [157] have also been described. Combination therapy with bevacizumab with high-dose bisphosphonates has been considered as a risk factor for developing proteinuria [158].

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Stylianou describes a patient with small-cell lung cancer who developed diffuse extracapillary necrotizing crescentic glomerulonephritis, temporarily necessitating hemodialysis, following administration of bevacizumab and zoledronate [151]. Affected Nephron Segments and Vasculature and Mechanisms Underlying Nephrotoxicity VEGF signaling is of pivotal importance for the development of physiological glomerulus and the preservation of glomerular integrity and function. VEGF and its receptors are expressed by podocytes and capillary endothelial cells, respectively [159]. Several mechanisms may underlie VEGF inhibition-related proteinuria [159], yet the precise role of the VEGF pathway remains to be elucidated. There are data suggesting that both increased and diminished VEGF expression may be related to glomerular injury. Disruption of the VEFG pathway is accompanied by endotheliosis similar to preeclampsia [159], downregulation of nephrin expression, and loss of podocytes [160] and may also interfere with the physiological process of renal repair following glomerular injury [151].

Calcineurin Inhibitor (Cyclosporin A) Presently, two types of calcineurin inhibitors (CNI) are available. The prototype of this drug is cyclosporin A. Tacrolimus, the second type of calcineurin inhibitor, appears to possess similar toxicological effects.

Clinical Aspects The introduction of the calcineurin inhibitor cyclosporin A (CyA) in human kidney transplantation in the late 1970s revolutionized transplantation medicine and made transplantation a preferable therapeutic intervention option for end-stage renal disease [161]. In 1984, the potent immunosuppressive properties of another CNI, tacrolimus, were discovered, and tacrolimus was used successfully in human liver, kidney, and heart allograft recipients [162]. In addition, these

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two strong immunosuppressive drugs have been used for various disorders, such as steroiddependent nephrotic syndrome, lupus nephritis, and many immunological disorders. CyA nephrotoxicity shows two clinical manifestations, alteration of renal blood flow and tubular toxicity. The alteration caused by CyA is due to the changes in the vascular resistance of renal vessels. CyA increases the resistance of the afferent alterioles of glomeruli, resulting in a decreased GFR. The tubular toxic effects of CyA include proximal and distal tubular impairment. The alterations in distal tubules include impaired hydrogen and potassium excretion and urinary concentration. CyA induces both AKI and chronic kidney impairment. Acute nephrotoxicity is a hemodynamically mediated phenomenon characterized by the absence of permanent structural changes and reversibility with the decrease in the dose or discontinuation. In 1984, Myers was the first to demonstrate that the long-term use of CyA in heart transplant recipients is associated with not only a reversible decrease in GFR but also irreversible renal functional deterioration as a result of progressive tubulointerstitial injury and glomerulosclerosis [163], which is called “chronic CNI nephrotoxicity.” Thereafter, many clinical studies have confirmed that the long-term use of CyA could induce nephropathy after renal transplantation. The nephrotoxicity of CyA was studied in dogs after 3-week administration of the drug at a high dose (20 mg/kg/day), and renal histopathological analysis showed nonspecific tubular lesions and glomerular modifications. There were lipids in the mesangial cells that appeared foamy [164]. Histopathological and functional studies have shown that CyA has various nephrotoxic effects. These are probably due to its various pharmacological actions, including the receptor-mediated activation of the second messenger and alterations of gene transcription, metabolism, and hemodynamics. CyA also induces apoptosis in various cell types. Thus, distinct from other nephrotoxic agents, the nephrotoxicity of CyA must be considered from several points of view. The main challenge after renal transplantation is to maintain a reasonable balance between the

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Fig. 7 Renal cell apoptotic mechanisms of CyA-induced nephrotoxicity (From Ref. [168] with permission)

efficacy (rejection prevention) and toxicity of the immunosuppressive agents used. CNI dose is adjusted only in cases of apparent side effects as a dose–effect relationship was suggested by Calne in 1979 [165]. In 1981, Keown was the first to establish an association between serum CyA concentrations and immunosuppression capacity in renal allograft recipients [166]. Klintmalm was the first to demonstrate the relationship among CyA dose, plasma CyA level, and renal allograft interstitial fibrosis [167]. Renal histopathological analysis shows several characteristic changes in CyA-induced nephropathy. The first is arteriopathy including constrictive proliferation with mucoid thickening and arterial hyalinosis. The second is the injury of proximal tubular cells. When the high-dose administration of CyA is prolonged, chronic histological changes progress, resulting in functional renal impairment. The typical histological changes induced by CyA include diffuse interstitial fibrosis or striped interstitial fibrosis, tubular atrophy, and arteriolopathy.

Affected Nephron Segments and Vasculature Because CyA is a very lipophilic drug, it distributes and enters into various cell types, particularly fat cells, kidney cells, and liver cells. There are no

speciﬁc pathways or mechanisms by which CyA accumulates in some speciﬁc kidney cells. It distributes in tubular cells and renal vessels including the endothelium. Thus, in many of these renal cells, CyA exerts the pharmacological and toxicological effects described below.

Mechanisms Underlying Nephrotoxicity The mechanisms underlying CyA nephrotoxicity described above are very complex, because CyA affects a variety of cellular functions that affect each other (Fig. 7) [168]. The decrease in GFR due to CyA is caused by intrarenal vasoconstriction. The factors contributing to this vasoconstriction include the aldosterone system, involving endothelin, nitric oxide, prostaglandins, and free radicals, and the sympathetic system, including vasopressin, atrial natriuretic factor(s), and other substances [169]. A number of reports have indicated that apoptosis is one of the causes of CyA nephrotoxicity involving the (1) Fas/Fas ligand pathway, (2) mitochondrial pathway, (3) ER stress, (4) angiotensin II (AngII), (5) hypertonicity pathway, and (6) nitric oxide (NO)-related pathway. The Fas/Fas ligand pathway activated by CyA was investigated in three studies using rats treated with CyA (15 mg/kg/day) for 4 or 6 weeks; the

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results indicate the involvement of apoptosis. In all three studies, renal cell apoptosis was shown [170–172]. Moreover, a decreased level of Bcl-2 was observed in the three studies, an increased Fas/Fas-l level was observed in one study, and an increased caspase-3 level was observed in two studies. Controlled studies on the relationship between the mitochondrial pathway and CyA-induced nephropathy have been reported [171–176]. CyA has been shown to induce ER stress in cultured human and rat proximal tubular cells [177, 178]. Isometric vacuolization of proximal tubular cells is a marker of acute CyA nephrotoxicity [179] and has been shown to be a manifestation of dilated ER and lipid droplet formation [180]. The ER pathway was evaluated in two studies [178, 181]. In both studies, rats were treated for 4 weeks with CyA. CyA significantly induced the mRNA expression of a 78 kDa glucoseregulated protein, protein disulfide isomerase, a C/EBP homologous protein (CHOP), and a homocysteine-induced ER protein in a dose- and time-dependent manner. Short-term (1 week) treatment with CyA activated both the ER stress and proapoptotic responses (upregulation of both caspase-12 and CHOP mRNAs and their proteins). Chung administered rats with CyA (15 mg/kg) for 28 days and demonstrated renal dysfunction, typical pathologic lesions (arteriolopathy, interstitial fibrosis, and inflammatory cell infiltration), and apoptotic cell death [174]. The expression levels of proinflammatory and pro-fibrotic molecules such as AngII, OPN, and TGF-beta1 increased. They also showed that rosiglitazone treatment ameliorated renal injury. Lim evaluated the effects of CyA treatment on urinary concentration ability in rats [182], showing increased urine volume and fractional excretion of sodium and decreased urine osmolality and free-water reabsorption in the treated rats compared with controls. These functional changes were accompanied by decreased expression levels of AQP (1–4) and UT (UT-A2, -A3, and UT-B), although there were no significant changes in the expression levels of AQP2 in the cortex and outer medulla or that of UT-A1 in the inner medulla (IM). Infusion of vasopressin reversed the

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CyA-induced impaired ability to concentrate urine. TUNEL-positive renal tubular cells were observed in both the cortex and medulla. Moreover, the number of TUNEL-positive cells correlated with the AQP2 or UT-A3 expression level within the inner medulla. In conclusion, CyA treatment impairs urine concentration ability by decreasing AQP and UT expression levels. Thomas examined the relationship between TI injury induced by CyA and NO [183], by treating rats with CyA with or without L-NG-nitroarginine methlyester (L-NAME) (to block nitric oxide) or L-arginine (to provide a precursor for nitric oxide formation) for 5 weeks. Animals treated with CyA + L-NAME had a statistically significant increase in the number of apoptotic cells compared with the CyA-treated animals. Treatment with L-arginine and CyA resulted in a decrease in the number of apoptotic tubulointerstitial cells compared to CyA alone. The addition of L-arginine did result in a significant reduction in the number of interstitial fibrotic lesions (P < 0.0001).

NSAIDs Clinical Aspects NSAIDs are very widely used for various diseases owing to their antipyretic, analgesic, and antiinflammatory effects. Ibuprofen, acetylsalicylic acid (ASA), and acetaminophen are the most frequently used agents for fever reduction in children. Over the past 20 years, because of the association between ASA use and Reye’s syndrome, much interest has been directed toward ibuprofen and acetaminophen [184]. In addition to fever, they are also administered for other conditions such as juvenile idiopathic arthritis, patent ductus arteriosus (PDA) closure, and Kawasaki disease. Currently, several cases of severe and sometimes irreversible renal insufficiency have been documented in neonates exposed to indomethacin prenatally or in the first days of their life for PDA treatment [185, 186]. AKI is a well-known adverse effect of these drugs in adults, whereas the incidence of nephrotoxicity due to NSAIDs in children is unknown. Generally, NSAIDs are safely used when clinicians

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Fig. 8 A review of intrarenal vasodilators, with basic mechanisms of action for NO, PGE2, and bradykinin from [37] with permission. Second messengers and receptors mediating vasodilatation in the kidney are shown. Note that another receptor subtype of the same

active agent may cause vasoconstriction, e.g., P2X receptor for ATP. For some agents, as NO, vasodilator inﬂuence may be both direct, via a speciﬁc second messenger, and indirect, by inhibition of a vasoconstrictor (20-HETE)

pay attention to their nephrotoxic risks. However, in serious conditions, particularly dehydration in children, the frequency of adverse reactions increases. Krause showed the presentation and outcome of AKI due to NSAIDs. They reported that seven patients aged 13–17.5 years developed AKI after treatment with various NSAIDs including naproxen, diclofenac, ibuprofen, dipyrone, and paracetamol [187]. Six of the patients used more than one kind of NSAID. The time interval between NSAID administration and the emergence of symptoms ranged from 1 to 4 days. The most common symptoms presented were flank pain (four patients), abdominal pain (three patients), and vomiting (three patients). All patients showed nonoliguric AKI. Microscopic hematuria and proteinuria were found in five patients and leukocyturia in two patients. Kidney biopsy was performed in three patients, which showed findings consistent with mild interstitial inflammation in one patient and normal renal tissue in two patients. All the patients were treated with intravenous fluids, and one patient received corticosteroids. Renal function was completely normalized in all patients within 7–16 days. The COX-2 inhibitor celecoxib has been reported as a frequent cause of adult AKI [188, 189]. The use of the COX-2 inhibitor in children is rare;

however, AKI in three children treated with the COX-2 inhibitor rofecoxib has been recently reported. Evidently, all children were treated without renal replacement therapy. However, a renal biopsy performed on one child showed acute interstitial nephritis [190].

Affected Nephron Segments and Vasculature and Mechanism Underlying Cytotoxicity The pharmacological mechanism of NSAIDs is the inhibition of prostaglandin biosynthesis by the blockade of cyclooxygenase (COX) [191, 192] (Fig. 8). Prostanoids act as modulators and mediators in a large spectrum of physiological and pathophysiological processes within the kidney [192]. On the one hand, the potent vasoconstrictor and platelet-aggregating thromboxane (TX) A2 is involved in the pathophysiology of a variety of glomerular diseases, such as hemolytic uremic syndrome (HUS) and immune-mediated glomerulopathies. Prostaglandin (PG) E2, on the other hand, interferes with tubular electrolyte and water handling. Clinical data support the hypothesis that this member of the prostanoid family contributes to the pathophysiology of Bartter syndrome, hyperprostaglandin E syndrome, idiopathic hypercalciuria, and renal diabetes

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insipidus [192]. The physiological and protective role of renal vasodilator prostanoids (PGI2 and PGE2) has been studied during treatment with nonsteroidal anti-inﬂammatory drugs. Part of the pharmacological effects of furosemide and converting enzyme inhibitors is mediated by PGI2 and PGE2.

Radiocontrast Agents General Aspects AKI associated with contrast media represents the third most common cause of in-hospital renal function deterioration after decreased renal perfusion and postoperative renal insufficiency [193]. Although generally benign, this complication is associated with mortality rates ranging from 3.8 % to 64 %, depending on the increase of creatinine concentration [193]. The incidence of AKI due to triiodinated radiocontrast media has been reported to be in the range between 1 % and 20 % in adults [194]. However, the incidence in children is unknown. The maximum creatinine increase usually occurs 3–5 days after the administration of contrast media. Urine analysis often reveals granular casts, tubular epithelial cells, and minimal proteinuria, but results may be entirely unremarkable in some cases. Barrett reported that patients with preexisting renal impairment, those with congestive heart failure, those with dehydration, and those receiving nephrotoxic drugs are at a higher risk [195]. In most cases, AKI due to contrast media is mild and renal impairment reverses within a week [194]. To facilitate the recovery from AKI, avoidance of further nephrotoxic injury and control of the fluid and electrolyte balance is required. In severe cases, dialysis may be necessary. In an effort to reverse these hemodynamic changes, vasodilators and diuretics have been tested as prophylactic drugs. However, their effectiveness has not been confirmed. Recently, considerable interest in these drugs has resulted from the initial encouraging data obtained regarding the positive effects of the prophylactic administration of

T. Sekine

antioxidant compounds, such as acetylcysteine and ascorbic acid. Briguori divided pharmacological agents on the basis of the efﬁcacy of prophylaxis of AKI due to contrast media in high-risk patients into three types [193]: 1. Promising: N-acetylcysteine, theophylline 2. Contraindication: dopamine, fenoldopam mesylate, atrial natriuretic peptide 3. Further investigation needed: calcium antagonists As mentioned above, the most promising preventive methods to avoid the nephrotoxicity of contrast media include intravenous hydration and administration of acetylcysteine [196, 197]. N-acetylcysteine is a radical scavenger, indicative of the development of contrast-medium-induced nephropathy via ROS, suggesting the nephrotoxicity of contrast media.

Affected Nephron Segments and/or Vasculature and Mechanisms Underlying Nephrotoxicity The pathogenesis of conditions induced by the nephrotoxicity of contrast media is complex and not fully understood (Fig. 9) [195]. At the moment, the pathophysiology of conditions induced by the nephrotoxicity of contrast media is an alteration in renal hemodynamics [193] and direct toxic damage to renal tubular epithelial cells. These effects may be partially mediated by the generation of ROS. There are many lines of evidence showing that contrast media directly exert their toxic effects on tubular cells, particularly proximal tubular cells, because various excreted proteins and enzymes have been detected in patients [195]. However, it is difﬁcult to separate the direct effects of contrast media on tubular cells from the effects of ischemia in vivo. The second mechanism is ischemic injury. It has been repeatedly demonstrated that the injection of contrast media into the renal artery of mammals including humans causes a response in RBF [195]. Alterations in the metabolism of prostaglandin, nitric oxide, endothelin, or adenosine may also play a role [194].

Nephrotoxins and Pediatric Kidney Injury

Fig. 9 Proposed mechanisms associated with contrast media nephrotoxicity (From Ref. [195] with permission)

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CONTRAST MEDIA

PREDISPOSING CONDITIONS e.g. Dm nephropathy

ETA , adenoelne PGI2,NO

Red cell sludging

Vasoconstriction

Renal lachemia

Cytotoxicity

O2radical formation Tubular injury

Enzymurla

Environmental Substances Heavy Metals Heavy metals are a poorly deﬁned group of elements. Some are necessary for the human body, such as iron (Fe), cobalt (Co), copper (Cu), and zinc (Zn). It is unclariﬁed whether other metals such as lead (Pb), cadmium (Cd), and arsenic (As) are necessary for the body. However, these heavy metals show direct adverse effects on the kidney, and they are particularly nephrotoxic, even at “normal” levels. There is no clear evidence of the nephrotoxicity of other metals such as uranium and mercury [198]. Heavy metals are metabolized in the liver, and they bind to lowmolecular-weight proteins (12 years.

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– Search for symptoms of LUT disorders. Even prior to potty training, most parents have observed a voiding stream and are able to characterize it as normal, thick or thin, and continuous or interrupted and to give an estimated voiding frequency. Wetting should be periodic, without leakage between or retention. Usually, parents can describe various signs of incontinence (stress, urgency, dribble, interrupted or insensate) that they have observed in their child. These observations are more accurate if they have another child for comparison. They have to be specifically questioned about these symptoms. In infants with difficult bladder problems, some authors propose a 4-h voiding observation of the freely moving infant with control of bladder volume by frequent ultrasound examinations and measuring of the voided volume (weight of diapers) [48]. After potty training, a dysfunctional voiding symptom score (DVSS) is a help to identify the symptoms and severity of LUTS [43–45]. – In older patients, a pediatric urinary incontinence quality of life score (PIN-Q) quantifies the emotional and psychological impact of the pathology [49]. – Psychological screening: the high rate of comorbid behavioral disorders associated with BBD is best evaluated by the ICCS document on the psychological consequences of enuresis [50], and this scale can be used for other bladder disorders.

Pelvic Ultrasound Ultrasound analysis provides anatomical data, searches for the impact on the upper urinary system, measures the bladder thickness, and measures the post-void residue (PVR). Some authors add the rectum diameter. • Bladder thickness: normal-validated values do not exist (dependent on technique and ultrasound material). An upper limit of the anterior

E. Berard

wall thickness 30 mm correlates with rectal impaction on digital rectal examination [54]. • Frequent ultrasounds during a 4-h ﬁlling observation are validated to evaluate bladder function during infancy and allow the repeated measurement of bladder ﬁlling and residual volume [37].

Urodynamic Examinations We mainly refer in the text to the ICCS [37] and International Continence Society [55] (in adults) recommendations and terminology for the method and interpretation. We refer for indications to a recent review [56] and add some additional remarks according to the literature. Three main examinations can be conducted: uroflowmetry, pelvic electromyography, and cystometric techniques. The first two are noninvasive and can be proposed in all patients (if pertinent: see below), but are not mandatory for diagnosis at the first level. Cystometric techniques are helpful in the case of neurological pathologies and are not routinely carried out in neurologically intact children. The aim of urodynamics is to objective symptoms with precise measurements, to identify pathophysiological processes according to the classification of LUT disorders previously described (see supra). However, we have to keep in mind the lack of a consensus on the precise method of measurement, signal processing, quantification, documentation, reproducibility, and interpretation. 1. Urine flow measurement: Uroflowmetry is noninvasive and inexpensive. It is an indispensable screening test for most patients [56]. Only indicated in toilet-trained children,

Pediatric Bladder Disorders

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Fig. 2 Normal and pathologic uroflows. (a) Normal uroflow: bell shaped. (b) Tower-shaped curve: note the high flow rate, low voiding time, and maximum flow rate >30 ml/s. (c) Staccato curve: note irregular flow rate but over the zero line, normal maximum flow rate, and a

decreased average flow rate. (d) Interrupted-shaped curve: flow rate returns to 0; note that voiding time is 13 s and flow time 10 s (retarded voiding start). (e) Plateau-shaped curve: note low amplitude, prolonged flow curve, long voiding time, retarded voiding start

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E. Berard

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Fig. 3 Schema of a normal urodynamic exam. A bladder catheter allows to fill the bladder and to measure bladder pressure and urethral counter pressure (and the abdominal pressure, not on the graft, remains stable during the cycle). Skin electrodes register EMG. Uroflow is measured during voiding. Perfused filling is obtained until the functional or

estimated (Koff’s formula) bladder volume. Near 100 % of functional bladder volume, intravesical pressure increases, followed by intra-urethral pressure and the child perceives urgency. Voiding occurs when the urethral pressure decreases, pelvic ﬂoor activity decreases (EMG), and the detrusor contracts. After a complete voiding, ﬁlling restarts

uroflowmetry can be performed for the first time without electromyography (EMG) during consultation and is useful to authenticate reported voiding symptoms. It requires the voided volume to be at least 50 % of the EBV for the child’s age. Details about the technique for adults can be found elsewhere [57]. However, for children, there are no clear technical recommendations comparing different uroflowmeters by testing, although the accuracy and precision of the flow rate signals depend on the flow meter.

More attention is given to the design of the curve than to precise values. The registered parameters are: • The maximum ﬂow rate (Q max) is measured at the peak level with a duration 2 s (Fig. 3). The accepted minimal rate is 15 ml/s. • Flow curve shape: – A normal curve is smooth bell shaped. – A tower-shaped curve, often short lasting, with a sudden high amplitude, indicates an uncontrolled detrusor contraction.

Pediatric Bladder Disorders

– A staccato-shaped curve with fluctuating flow, but never returning to zero during voiding, suggests incoordination of the detrusor and sphincters or urethra. – An interrupted-shaped curve is similar to the staccato one but the flow returns to zero during voiding; it indicates more severe forms of incoordination of the detrusor and sphincters or urethra. – A plateau-shaped curve with low amplitude and prolonged flow curve is suggestive of bladder or urethral obstruction, sphincteral or urethral overactivity or an underactive bladder. Additional EMG differentiates anatomical and muscular problems.

In adults, the blind interpretation of the same 25 urine flow measurements (normal and pathologic) by 58 urologists gave a Cohen’s κ of 0.46 in normal patient examinations (qualified as moderate concordance) and 0.30 (low concordance) in pathologic patients [58]. Another study reported on reproducibility on a second lecture of the same graph by the same urologist, 8 weeks after the first lecture and between four urologists. It found a κ among urologists of 0.36–0.54 and between the two interpretations by the same urologist of 0.54. In all cases, these results are insufficient to give a medical decision [59]. A debated topic is the need (or not) for two or three successive uroflowmetric measurements to affirm diagnosis, but the reproducibility in the same patient is poorly documented.

Electromyography (EMG) of the Pelvic Floor EMG, performed with adhesive skin electrodes (less commonly needle electrodes), gives a global analysis of several superposed muscles. It provides information on the adequacy of muscular activities according to the bladder cycle (Fig. 1). During normal ﬁlling, the muscular activity is regular and at a low level, without increases. During voiding, the muscular activity is quite absent. Brutal increases or uncoordinated activity are pathologic, but do not allow the

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identiﬁcation of a particular muscle. This nonaggressive examination can be easily proposed [56] and is easy to interpret in pathologic cases, but its reproducibility and the degree of accordance between experts have not been established.

Cystometric Techniques (For additional technical considerations and definitions of ICCS, see Ref. [37]). Cystometric testing is expensive and invasive for the patient and requires specialized equipment and expertise. Fully trained staffs are required, and with proper patient cooperation, which is often the real limiting factor in children, the physiology of the lower urinary tract can be analyzed. But cystometric studies remain, by their nature, unphysiologic. Merely the fact of introducing a catheter into the bladder (suprapubic or transurethral) is not a physiological situation and can by itself modify the bladder dynamic. Our goal in this part is not for the reader to become an expert in urodynamics, but more to give him some basic knowledge. The detailed recommendations for adults are the basis of the current practice in children [60]. An imminent document by the ICCS will provide precise techniques and criteria for children. Indeed, the diameter of the catheter, speed of filling, amplitude of pressure variations, and normal values remain to be consensually defined, and each of these parameters could influence the results. Cystometric techniques are not routinely used in neurologically intact children, but are used to improve classification and gain a better understanding of pathophysiology [37]. Cystometry analyzes both emptying and voiding phases by pressure measures. A suprapubic catheter or transurethral catheterization is used while the pressure in the abdomen is monitored via a rectal balloon. Natural fill cystometry is more physiologic but time consuming, and thus is rarely performed. Moreover, if the intrarectal and intravesical pressure are a true pressure measure (aeric or hydric), the so-called urethral pressure is not a true pressure. With the oldest material (often still used) using a perfused catheter, it is the counter pressure to impose on a

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perfused liquid (with its own properties) to allow it to flow. It depends on the quality of the epithelium, the viscosity of the liquid used, the catheter diameter, the orifice diameter, and the perfusion speed. In adults, a study demonstrated that between different catheters and according to the orientation and level of the catheter orifice in the urethra, the results are different (as high as 50 cm H2O) [61]. The modern use of a pressure transducer does not avoid such a problem because contact with a compacted stool in the rectum can also induce false measures. The definitions according to ICCS [37] of the main registered parameters are: – Bladder sensation during filling: physical symptoms of discomfort or reduced awareness regardless of the volume (in particular with an underactive detrusor or neurogenic bladder). – Bladder compliance describes the relationship between changes in bladder volume and in detrusor pressure (in ml per cm H2O). – Detrusor function during filling: an increase in bladder pressure for low volumes (low bladder compliance) and detrusor overactivity during filling (due to an overactive detrusor or neurogenic bladder). – Bladder capacity: before spontaneous miction, to compare with the EBV. – The urethral function during filling detects urethral leakage. However, this parameter is still debated and rarely analyzed outside some specialized centers. – Leak point pressures: detrusor leak point pressure is the pressure at which leakage is observed (in the absence of a detrusor or abdominal contraction), and abdominal leak point pressure is the lowest increase in bladder pressure (detrusor or abdominal contraction) that provokes leakage. – Voiding cystometry analyzes the pressure–volume relationship during voiding with the coordination of the pelvic floor and urethral relaxation followed by detrusor contraction. – Detrusor and urethral function during voiding: with normal opening and closing during and after voiding.

E. Berard

The reproducibility of cystometric techniques has been questioned by many authors [62]. Overall, blinded studies indicate that this methodology requires further improvement to develop a standardized methodology that generates consistent results. Measurement of vesical and abdominal pressures, however, provides important information, particularly in neurogenic bladder. Some authors propose the addition of ﬂuoroscopy (video urodynamics) to analyze the aspect of the bladder wall, the presence or absence of VUR, the efﬁciency of emptying, and the appearance of the bladder neck and urethra, but the use of such additional X-ray examination is still debated and reserved for expert centers [63].

Clinical Approach and Management of Incontinences As deﬁned above, children’s incontinences can be divided into three major categories, with some overlapping between pathologies: (1) abnormal LUT anatomy, (2) interrupted innervation (neurogenic or neuropathic bladder), and (3) abnormal voiding in the absence of any anatomical or neurological lesions (also called dysfunctional bladder).

Abnormal LUT Anatomy and Bladder Pathologies The anatomic causes of bladder dysfunction fully illustrate the complex and close relationship between development in the fetal life of anatomic structures of LUT, histological differentiation of tissues, and maturation of the different levels required for neurological control of continence. After surgical correction of the urologic malformation, follow-up should include regular evaluation of the bladder function and search for associated renal dysplasia. Such anatomic malformations may also have a peripheral neurogenic component responsible for further bladder malfunction. Anatomic causes of bladder malfunction include bladder exstrophy/epispadias, urogenital sinus and cloaca malformations, ectopic ureter, ureterocele, etc. We only refer to the major

Pediatric Bladder Disorders

concepts about these pathologies, which are more in the ﬁeld of surgeons, but pediatric nephrologists are often included in the multidisciplinary staff for such patients or concerned in the case of CRI and kidney transplantation [64].

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explain recurrent urinary infections in spite of treatment with antibiotics and/or reimplantation surgery.

Prune-Belly Syndrome Epispadias Undiscovered female epispadias is a classic, but uncommon, cause of leakage after the age of potty training in girls. A stress component is often associated with the leakage. A simple inspection of the perineum demonstrates a biﬁd clitoris and short urethra. Epispadias in boys (except with minimal distal forms of epispadias) is also often associated with incontinence and is easy to diagnose. In both sexes, it should be treated surgically as early as possible to avoid an acquired bladder dysfunction [65].

Bladder Exstrophy Bladder exstrophy results in abnormal development (before and after birth) of the bladder neck and proximal urethra (sphincteric incompetence), causing bladder dysfunction (a small bladder with poor compliance) and low urethral resistance. A surgical correction performed shortly after birth allows reconstruction of the bladder neck and proximal urethra, enabling normalization of the bladder function [2, 66]. Bladder exstrophy may have genetic bases [7].

Ureter Malformations Due to the common embryologic origin of the ureter and trigone, bladder neck, and urethra, the association between ureter malformation and LUT dysfunction is frequent. At the time of urological surgery in the ﬁrst months of life, parents should be made aware of such a possible problem, even later in life. In particular, children with congenital vesicoureteral reﬂux have greater potential for dysfunction of both the bladder neck and the sphincter [2]. Such bladder dysfunction can

Prune-belly syndrome (also called Eagle–Barrett syndrome) includes megacystis, an overlying thin, lax, wrinkled skin, and bilateral cryptorchidism. In nearly half of patients, prune-belly syndrome is associated with malformations of the cardiopulmonary, gastrointestinal, and orthopedic systems. Renal dysplasia is always associated [67]. Different theories have been proposed for pathophysiology, ranging from bladder obstruction during fetal life (and an obstructive uropathy is sometimes reported but not constantly) to a primary defect in the abdominal muscle [68, 69]. Several genes have been identiﬁed in prune-belly syndrome but do not cover all cases [7]. In experimental models, like in prune-belly syndrome, the histological analysis demonstrates a thin disorganized bladder wall [70, 71]. The need for a vesical follow-up after the surgical time is fully recognized [2].

Posterior Urethral Valves (PUV) In the case of PUV, the kidneys, ureters, and bladder develop in an environment of obstruction and overpressure. It affects not only the anatomical and functional properties but also the histological structure. The result is associated renal dysplasia, megaureters, and a loss of compliance and capacity of the bladder. In the case of late surgical repair, urodynamics demonstrate increasing bladder pressure with poor ﬁlling compliance, decreased sensation, poor capacity, a dysfunctional bladder, and sphincteric dysfunction, with frequent severe polyuria (resulting in chronic bladder overdistension), which is termed “valve bladder syndrome” (Fig. 4; [72, 73]). If the patient is surgically treated in the ﬁrst days of life, many of these pathologic functions can be reversed [74]. A systematic follow-up is required [2, 73, 74].

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E. Berard 100 Pves cmH2 O Pabd cmH2 O

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Fig. 4 Boy early operated for posterior urethral valves, 11-year-old: note increased bladder volume, poor compliance of bladder with regular increase of bladder pressure, permanent EMG activity during ﬁlling and voiding

without a true detrusor contraction but only pelvic and urethral sphincter decreased activity. Pves = vesical pressure; Pabd = abdominal pressure; Pdet = detrusor pressure = Pves – Pabd; Vol = infused volume

Ureterocele

Conversely, bilateral single ectopic ureters and the upper tract are often associated with bladder hypoplasia and dysfunction, because of the absence of bladder function before birth. Even after surgical correction, the prognosis of bladder function is poor.

Ureterocele is a malformation frequently associated with a duplex kidney. It results from an embryonic abnormality of the upper end of ureteral bud, but is sometimes associated with dysfunction of the bladder base, neck, and proximal urethra (originating from the caudal end of the ureteral bud) [74, 75]. Large ureteroceles that extend down the urethra (cecoureterocele) are frequently associated with bladder dysfunction.

Ureteral Ectopia The unilateral ectopic ureter (commonly a result of a duplicated renal collecting system) terminates at a different site: in males, usually the urethra (and generally continent), in female the mid-urethra, fourchette, vagina, cervix uterus, uterus, or fallopian tube. It is a frequent cause of permanent incontinence discovered at the age of post-potty training [76]. It is not usually associated with bladder dysfunction per se, but is more on the edge of differential diagnosis of bladder dysfunctions.

Cloaca and Urogenital Sinus Technically, boys do not have classical cloaca or urogenital sinus malformations (however, boys with an imperforate anus, particularly higher forms, are potentially subject to bladder dysfunction as well as girls with a cloaca). In girls, cloaca malformation is an early (third to fourth week of gestation) dysembryonic disorder with a persistent common cavity composed of the lower urinary tract, genital tract, and gastrointestinal tract [77]. A urogenital sinus malformation is (only) the conﬂuence of the urinary and genital tracts. The bladder wall and abdomen are not closed during the fetal life, and the role of closure has been seen in the bladder development.

Pediatric Bladder Disorders

These pathologies may involve the bladder, bladder neck, and urethra, as well as spinal cord development, because the spinal cord develops at the same time as the lower urinary tract [78]; therefore, patients with cloaca or urogenital sinus malformations have significant potential for abnormalities of the spinal cord (tethering of the spinal cord, filum terminale, lipomas, diastematomyelia, and syrinx of the spinal cord). The broad spectrum of these malformations can also be associated with pelvic floor dysmorphism, all kinds of ureteral malformation, renal dysplasia, and disorders of peripheral innervation. The care of such patients is beyond the scope of this text and detailed in surgical textbooks.

Neurogenic Bladders All forms of spinal dysraphisms or myelodysplasia are the most frequent cause of a neurogenic bladder. Spina bifida is a general denomination including different abnormal closures of the spinal canal (between 2 and 5 weeks of gestational age). Deficiency of folic acid is recognized as a major etiology for these pathologies, and the frequency is decreasing in countries where women, before becoming pregnant, ingest 400 μg/day of folic acid (by alimentation or supplementation) [79]. However, other genetic etiologies exist, inside the folate metabolism [80] or in other genes, in particular if associated with other malformations [81]. The broad spectrum of dysraphisms includes some minor understated spine abnormalities (spina bifida occulta, hairy patch, lipome, cutaneous/dermal malformation, post-anal dimple) and various grades of myelomeningoceles at different spinal levels (lumbar, sacral, thoracic, and cervical). It has been reported that neural tissue may be abnormal both above and below the bony defect ([82]; Fig. 5). Thus, the level and importance of dysraphism are poorly predictive of bladder dysfunction. As many as 20–60 % of all cases will suffer from bladder malfunction at different ages during the lifetime and a minor malformation cannot exclude bladder malfunction (40 % in

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Fig. 5 Moderate neonatal closed sacral myelomeningocele in a boy with (at urodynamic exam) severe form of neurogenic bladder. Note ﬂattened buttocks. It illustrates the discrepancy between skin lesion and severity of neurogenic bladder (Image Pr J. Breaud)

spina biﬁda occulta; Fig. 6). Moreover, different growth rates between the vertebral bodies and the elongating spinal cord can introduce a dynamic factor with increasing age during infancy. Fibrosis may surround the cord at the site of meningocele closure, and the cord can become tethered during growth, which can lead to changes in bowel, bladder, and lower extremity function. Other etiologies for a neurogenic bladder include sacral agenesis (close to dysraphism), imperforate anus (higher forms), cerebral palsy, and traumatic spinal cord injuries. In all forms of neurogenic bladder, urodynamic testing is recommended [56, 83].

Principles of Management of Neurogenic Bladders (Outside Neurosurgery) For a long time, neurogenic bladders were left untreated or treated late, with a frequent evolution to end-stage renal disease and even precocious death. A modern approach, in a growing number of cases, allows a relatively good quality of life and avoidance of end-stage renal disease. The medical approach is increasingly preferred in collaboration with a surgical approach [83, 84].

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Fig. 6 Neurogenic bladder in a 15-year-old boy with spina biﬁda: estimated bladder volume = 320 ml; note a very poor bladder compliance, and uninhibited bladder contraction for low volume, desire to void (Urg), and EMG amplitude increases while the child try to void

(Void) demonstrating detrusor/sphincter dyssynergia. Pves = vesical pressure; Pabd = abdominal pressure; Pdet = detrusor pressure = Pves – Pabd; Vol = infused volume

Evaluation and Follow-Up of Neurogenic Bladders

detrusor areflexia. In the case of dyssynergic voiding, an improved bladder function and a protective effect on the renal function have been demonstrated by the use of precocious clean intermittent bladder catheterization (CIC) and anticholinergic medication [84]. Early evaluation and treatment are recommended, as soon as the diagnosis is established. The initial evaluation of the neonate includes the search for urinary infection, renal insufficiency and post-voiding residual measure (spontaneous or after the Credé maneuver), if miction can be obtained. However, clinical and ultrasound examinations are insufficient to evaluate bladder malfunction; urodynamics can be performed by suprapubic or urethral catheterization as soon as possible. While attempting to make a later decision on the management of a neurogenic bladder, urodynamics allows an early decision to be made between continuing CIC and allowing spontaneous miction. In the case of an overactive bladder, anticholinergic medications are started. Repeated urodynamics after a few months evaluates the efficacy of the treatment.

The ICCS recently gave recommendations for the evaluation and follow-up of such pathologies [83]. The main concepts are as follows:

Open Spinal Dysraphism or Myelomeningoceles Neural tube defects are classified by the degree of involvement of spinal elements in the meningocele, myelomeningocele, and lipomeningocele (if fatty tissue develops inside the cord structure). Myelomeningoceles account for 85 % of open spinal dysraphisms, and nerve roots, spinal cord tissue, or both are included in the sac. After the neonatal search for other associated malformations (Arnold–Chiari malformation, herniation of cerebellar tonsils, hydrocephalia, etc.) and before the neurosurgical time (first weeks of life), the first bladder evaluation is required. Nearly two-thirds of such children have bladder contractions, while one-third have

Pediatric Bladder Disorders

If an ultrasound demonstrates anomalies in the upper tract (kidney and ureters) or poor bladder compliance or abnormal thickness, cystography is warranted. VUR is frequently associated with evolution to end-stage renal disease, in particular in those with a high-pressure bladder. VUR is responsible for renal scars on DMSA scanning. High grade reflux necessitates CIC and anticholinergic medications; low-grade reflux can be managed expectantly. A close follow-up is proposed during the first 2 years of life (because of the rapid skeletal growth). In an overactive detrusor, an ultrasound examination every 6 months and urodynamics yearly are recommended. After 2 years of age until adulthood, any changes in ambulation or lower extremity function (by spinal cord tethering), changes in continence, or occurrences of urinary infection need repeated urodynamics. At least a yearly ultrasound controls changes in hydronephrosis, bladder thickness, and residual volume, and any change in these parameters requires urodynamics. The risk of tethering secondary to skeletal growth decreases between 2 years and puberty and re-increases during the pubertal spurt. Particular attention is required during puberty because hormonal changes may impact on the lower urinary tract and 45 % of patients with incontinence become continent after going through puberty. During adulthood, renal bladder ultrasound remains required every 3 years and the follow-up of renal function adapted to the level of renal insufficiency.

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weakness, muscle atrophy, and gait change. The same explorations as for open lesions are required.

Sacral agenesis Sacral agenesis, defined as the absence of two or more lower vertebral bodies, is the etiology of 1 % of bladder malfunction. Diagnosis is difficult to suspect in the neonatal period. Perineal sensation and lower extremity function are usually normal (Fig. 7). It is suspected in patients with flattened buttocks. In older children, the signs are those of all LUT malfunction (urinary infection and incontinence). Diagnosis is confirmed using a lateral film of the lower spine. Only 20 % of patients with sacral agenesis have normal miction; others suffer from various associations of detrusor and sphincter disorders with possible consequences for the upper tract (reflux, hydronephrosis). Sacral agenesis has frequent renal-associated anomalies, in particular unilateral agenesis, with a marked decrease in renal volume, increasing the risk of end-stage renal disease.

Imperforate Anus An imperforate anus is associated in 10–50 % of cases with a neurogenic bladder (with variations according to the level of imperforation and of the rectourethral ﬁstula). Unilateral renal agenesis and intraspinal anomalies are frequently associated.

Spina Bifida Occulta Spinal Cord Injury Any spina biﬁda occulta, suspected by the discovery (in the neonatal period or afterwards) of a gluteal cleft or hairy patch, needs a spinal ultrasound (6 s. Treated with α blockers Under (their own) treatment regimen, uroﬂowmetry normalized in all the subtypes

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(89 patients). They confirmed such results in larger populations [99–101] and demonstrated resolution of VUR if present [100]. They also demonstrated the frequent association of constipation and encopresis with the following frequency according to the subgroups: (1) 49 %; (2) 33 %; (3) 23 %; (4) 19 % [102]. Even though such a classification, based on their own practice for urodynamics and their own criteria and treatments, remains to be discussed, these results seem to be a new track for classification and further studies are required. As we have seen, authors are not in agreement on the method for diagnosis, treatment, and follow-up. In particular, the appropriate place for urodynamics and the good prescription and methodology of such examinations is hardly discussed.

Treatment of LUTD All the authors agree on the need for a first phase of treatment with basic measures, even before classification, to analyze the true voiding problem and not the consequences of factors interfering with the bladder function. This initial step should involve education of the child/family regarding bowel/bladder dysfunction, timed voiding, adequate fluid intake, aggressive management of constipation, and hygiene (changing of wet clothing, containment products, skin care, and correct wiping technique) [94]. The ICCS formulated recommendations for the management of constipation [21]. Similarly, for optimal voiding, the teaching of a relaxed and correct toilet posture: buttock support, foot support, and hip abduction [94]. Behavioral or psychiatric disorders should be treated. These recommendations should be made in all cases of primary or secondary LUTD. According to the ICCS, the next step in primary LUTD is biofeedback sessions and muscular training, but with various methods between centers (which need harmonization), with or without EMG control [37]. With various methods, several teams have recently published efficacy [92, 94, 102, 103, 104]. The recommendations for drug therapy are blurred and consensus does not exist.

Pediatric Bladder Disorders

Pharmacological agents to relax the detrusor would be (in our state of knowledge) bladder relaxants and anticholinergic therapies. However, antimuscarinic therapies are also active in UBC, and these latter are not efficient in underactive bladders, and α-1 adrenergic blockers should be proposed (but off-label) [94]. α-1 blockers could also be used for a hypertonic bladder neck and urethra. Another different proposed approach, at least in some severe cases, is botulinum-A toxin injected into the detrusor or sphincter. It has been proposed safely for focal hypertonia (off-label) [94]. Since neuromodulation was granted US Food and Drug Administration approval, several teams have tried such techniques in different types of incontinence in children. The experimental models are promising. However, in 2011, Barroso et al. [105] undertook a systematic review of the literature. In the 70 articles evaluated, the electrical stimulation methods (sacral transcutaneous, sacral implanted device, posterior tibial, anogenital, intravesical, etc.) and the electrical parameters varied. The populations were scarce and nonhomogeneous. The duration and frequencies of treatment were variable among the studies. Only two were randomized. No proved efficacy can be demonstrated. Another meta-analysis [106] on the efficacy of percutaneous tibial nerve stimulation for an overactive bladder has been made. The definitions of success differed between studies and the results were variable (37–82 %), but not different concerning the effect of antimuscarinic therapies (in two randomized trials). Once more, clinical controlled trials versus sham devices and predictable variables for successful responses are urgently needed. In spite of the hope for a nonaggressive treatment and plausible efficacy (in the light of animal experiments and use in adult pathologies), no conclusion can be drawn in children. As we have seen, there is no classification or consensual protocol for LUTD, and each team has its own attitude. The actual lack of a validated classification is a major obstacle. The first step remains expert consensus, followed by large studies with common classifications and protocols.

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Associated Disorders with Incontinence in Apparently Normal Children In 15–40 % of patients with voiding malfunction (enuresis and LUTD), some non-urologic disorders are associated. Given the imprecise deﬁnitions in older publications, the frequency of associations with MNE or LUTD is difﬁcult to determine. However, their frequency is beyond a single coincidence.

Psychological Disorders Their frequent association keeps in mind a putative common mechanism. Following an abundant literature, the ICCS provides us with a summary [107]. Beyond the effect on self-esteem, quality of life, and psychological distress, already evocated in all urinary incontinence, 20–30 % of patients with MNE, 20–40 % with daytime urinary incontinence, and 50 % with fecal incontinence have psychiatric behavioral and emotional disorders (according to the criteria for ICD-10). This frequency is two to three times higher than in the general population. The rate of such disorders increases in older patients, in males, and in patients with low socioeconomic status. Behavioral disorders can be predominantly externalizing disorders (conduct disorders, aggressivity, attention deficit and hyperactivity disorder (ADHD)) or rarely internalizing disorders (introversive attitude, anxiety, depressive disorder, and emotional symptoms). In primary MNE, the rate does not differ significantly from that of the general population. Conversely, in secondary MNE, the frequency increases to 75 % (and it is an argument to separate these two pathologies). The most frequent condition is ADHD. According to different diagnostic criteria, the frequency varies from 9 % to 28 % of MNE. Conversely, since 1997, in patients consulting for ADHD, according to the old urinary classification, 21 % suffer from MNE and 6.5 % from LUTD [108]. A recent publication (with recent definitions but with few patients) studied the event-related potentials in response to 160 negative, neutral, or positive pictures. Children with MNE showed more intense responses than controls, whereas those with ADHD did not

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differ from the controls. Children with MNE + ADHD elicited the strongest responses [109]. They concluded that children with MNE process emotions differently from children with ADHD and controls. In daytime incontinent patients, ADHD is associated in 25–37 % of cases. Many other psychiatric disorders can coexist with MNE: conduct disorders, aggressiveness, and depressive and anxiety disorders. In LUTD, the associated psychological problems can be oppositional behavior (10 %), conduct problems (12 %), and anxiety (11 %). Children with ADHD + MNE are more resistant to alarm treatment. The positive results at 6 months of treatment in ADHD + MNE versus MNE groups varied from 43 % to 69 % and at 12 months from 19 % to 66 %. Noncompliance was reported in 38 % of ADHD + MNE patients versus 22 % in MNE patients [110]. Similarly, in LUTD associated with ADHD or psychological problems, the treatment outcome and compliance were worse. In such associations, incontinence is harder to care for: whether by a compliance defect or perhaps by a true different nosologic pathway, the question remains open. The same psychological problems can be found, but with lower incidence, in fecal incontinence. Several questionnaires have been proposed to score such psychological problems in clinical assessment (CBCL questionnaire, T scores, SSIPPE, etc.), and if positive, the help of a psychiatric assessment is required. Later language and scholarly acquisitions have been noted by some authors without, in the present literature, a clear relationship with a particular category of incontinence according to the newer terminology [111–114].

Sleeping Disorders Sleep apneas and parasomnias are frequent occurrences in MNE. The parents often signal a deep sleeper [94, 115, 116]. Wolﬁsh et al. studied a group of boys with enuresis compared with controls. While the children were asleep, an ear insert sounded tones of up to 120 dB every 10 min until they awoke, and they registered simultaneous polysomnography. The overall total nighttime frequency of successful

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arousal was 9.3 % for the patients with enuresis and 39.7 % for the normal controls.

Obstruction of Upper Respiratory Airways An obstructed upper airway, especially with apneas, is frequent in MNE [117, 118]. Some cases of MNE disappear after tonsillectomy [119]. Obesity Some authors noted an increased frequency of MNE, with more difﬁcult forms to treat, in obese children [120].

Other Miscellaneous Incontinences Without Urologic or Neurologic Malformations In this paragraph, we included some unclassiﬁable incontinences: Non-neurogenic neurogenic bladder, incontinences after kidney transplantation and in patients with cerebral palsy.

Non-neurogenic Neurogenic Bladder (NNNB), Ochoa’s Syndrome, and Hinman’s (or Hinman–Allen’s) Syndrome The non-neurogenic neurogenic bladder, identiﬁed as early as 1997 [121], is a condition that associates symptoms of a neurogenic bladder without any spinal cord lesion on MRI [122]. Only a few publications report on this rare entity, which needs to be revisited. The literature is confusing, the terminology unrevised, and the criteria puzzling. It seems possible to distinguish three different entities: isolated NNBB, NNBB in Ochoa’s syndrome, and NNNB in Hinman’s syndrome. All patients have been symptomatic since early infancy with a poor stream, chronic urinary retention, and bilateral hydroureteronephrosis. Vesicoureteric reﬂux is often present in the three conditions, which can be complicated by urosepsis and end-stage renal disease. Ochoa’s or urofacial syndrome, observed in both genders, includes a congenital NNNB

Pediatric Bladder Disorders

together with an abnormal grimace upon smiling, laughing, or crying and bilateral weakness in the distribution of the facial nerve and, in the majority of these patients, nocturnal lagophthalmos, which is described as the inability to close the eyelids during sleep [123–125]. The urethral walls contract at the same time as the detrusor. The second condition is Hinman’s syndrome, with a large-capacity bladder with increasing filling pressure, uninhibited detrusor contraction, and ineffective bladder contractions during voiding [126–128]. Associated chronic renal insufficiency is frequent. These children (a majority of girls) commonly have an important familial problem, with one of the parents tending to be domineering, exacting, unyielding, intolerant, and “treating” the child with both mental and physical punishments (more frequently than in other bladder disorders). The association of a particular parental behavior and a bladder disorder in the child suggests a common genetic factor. For a long time, these three conditions have been considered as different forms of a common disorder. The recent discovery of an autosomic recessive inheritance and of genes in Ochoa’s syndrome has led to the differentiation of these pathologies [129–131]. In Ochoa’s syndrome, two genetic mutations have been found. The first encodes heparase 2, which has a key role in peripheral neurologic development. The role of the protein of the second gene (LRIG2) remains unclear, but the common symptomatology is consistent with the hypothesis that LRIG2 codes for proteins, which work in a common pathway. This first demonstration of a genetic factor implicated in a bladder disorder makes possible the discovery of other genetic factors in other bladder dysfunctions, because the familial aggregation of such conditions is frequently noted.

Cerebral Palsy Half of children suffering from cerebral palsy have a spectrum of clinical and urodynamic bladder dysfunction with a high risk of renal damage [132]. Of these children, 77.4 % void spontaneously but are incontinent [92] during the day and

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night or rarely limited to nocturnal leakage. Continent children have a similar pathologic storage proﬁle and differ from children with daytime or nocturnal incontinence in their ability to sense bladder fullness. Urodynamic evaluation is required to propose the best treatment for such patients [133, 134]. The ﬁrst urinary infection in a patient suffering from cerebral palsy imposes the search for such a disorder.

Bladder Dysfunction After Kidney Transplantation Urinary infections are frequent after kidney transplantation, in children as in adults, whereas they are uncommon in other forms of immunosuppression. Herthelius and Oborn evaluated bladder function (with a questionnaire, uroflowmetry, and bladder ultrasound) in 68 child recipients of a renal graft [135]. Among them, only 23 were transplanted for a urological illness (the remaining 45 were for glomerular of ischemic disease). Surprisingly, 49 patients (72 %) had abnormal bladder function (low bladder capacity 26 %, abnormal urinary flow 50 %, post-void residue 32 %), with similar frequencies in the urological group and the others. This result was confirmed by another study in a group of transplanted patients in CRI for a glomerular illness [136] and several studies confirmed these surprising results in adults and in children. Moreover, Herthelius and Oborn demonstrated that before dialysis and kidney transplantation, during CRI (glomerular filtration 3y MNE (primary or secondary) Polyuric Small bladder Sleeping mechanism

Filling disoders: - overactive bladder - urethral instability Voiding disorders - hypertonic urethral sphincter - hypertonic pelvic floor - lazy bladder

Fig. 9 Decision making tree for children’s incontinences. MNE monosymptomatic nocturnal enuresis, NNNB non-neurogenic neurogenic bladder

two-thirds of cases are enuresis and one-third are LUT disorders. Secondary LUT disorders are underestimated and recognized. A decisionmaking tree is proposed in Fig. 9. The ﬁrst goal of the history and examination is to exclude differential diagnosis. The second step is the search for signs of an anatomical disorder (urinary or neurogenic abnormality) by careful

skin examination and detailed neurological examination (including anal tonus). Among the urological anatomical malformations, the only non-evident one is an ectopic ureter and epispadias. For the third step, a single sign of dysfunctional voiding requires the ﬁrst search for interfering factors, in particular constipation. After their

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cure, the diagnosis of primary continence disorder could be assumed with enuresis for symptoms exclusively during sleeping time and LUTD if there is a single sign of voiding dysfunction. A urinary strip could be helpful to exclude urinary infection and diabetes and detect an overconcentration of urine (density >1,020) or when an inversion of the ADH cycle (by comparison of diurnal and nocturnal density) is suspected (even if laboratory urinary measure of osmolarity is more reliable). In enuresis, for the ﬁrst time, no other examinations are required. In LUT disorders, an ultrasound of the kidneys and bladder (with the search for post-voiding residue, vesical wall thickness, dilatation of upper urinary tract, renal dysplasia) is helpful. In LUT dysfunction, if the disorder is not fully characterized (the majority of cases), uroﬂowmetry and EMG can be proposed. Cystometry is mandatory in neurogenic bladders and in other cases individually discussed.

Conclusion The ﬁeld of urinary incontinence represents a broad spectrum of various disorders from benign harmless conditions with effective and easy treatment to complex pathologies involving cellular differentiation, the LUT anatomy, the central and peripheral nervous systems, and psychiatric components. From an underevaluated specialty of emunctories, often devalued among caregivers, the science of bladder disorders becomes a fascinating transversal specialty, mixing together basic cellular knowledge, pathophysiology, and the best clinical practice for history, clinical examination, patient’s medical education, and empathy with the child. Although the simplest disorder only needs a good history and clinical examination, the more severe ones require multidisciplinary staff with technical equipment. Because important parts of pathophysiology remain in the shadows, in some cases, in spite of a full exploration, we are currently unable to propose a satisfactory treatment. However, a better understanding of the bladder physiology will allow us to propose better approaches and treatments in the future, for

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example, electrical stimulation has potential. In such cases, our present therapy should not compromise future treatment. Bladder function often seems to be the last in line, and bladder treatment a “comfort” treatment to envisage after the correction of “noble organs” has been performed. In several models, we illustrated the degradation of bladder function with time if the bladder is left untreated. Having an early worry about bladder function is essential for a patient’s wellness but also to avoid consequences for the renal function. Bladder dysfunctions appear outside urologists’ ofﬁces, and pediatric nephrologists should be aware of medical contexts involving bladder function, the possible (or impossible) precise diagnosis, and proposals for therapy.

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E. Berard 56. Drzewiecki BA, Bauer SB. Urodynamic testing in children: indications, technique, interpretation and significance. J Urol. 2011;186:1190–7. 57. Rowan D, James DE, Kramer AEJL, Sterling AM, Suhel PF. Urodynamic equipment: technical aspects. J Med Eng Tech. 1987;11:57–64. 58. Van de Beek C, Stoevelaar HJ, McDonnell J, Nijs HG, Casparie AF, Janknegt RA. Interpretation of uroflowmetry curves by urologists. J Urol. 1997;157:164–8. 59. Chou TP, Gorton E, Stanton SL, Baessler K, Rienhardt G. Can uroflowmetry patterns in women be reliably interpreted? Int Urogynecol J. 2000;11:142–7. 60. van Waalwijk Van Doorn E, Anders K, Khullar V, Kulseng-Hanssen S, Pesce F, Robertson A, Rosario D, Schäfer W. Standardisation of ambulatory urodynamic monitoring: report of the standardisation sub-committee of the International Continence Society for Ambulatory Urodynamic Studies. Neurourol Urodyn. 2000;19:113–25. 61. Dompeyre P, Hermieu JF, Horpitean V, Seguy E, Delmas V, Boccon-Gibod L. Comparative study of 230 women to determine the maximum closure pressure and functional length of the urethra at 0, 3, 6, and 9 o’clock. Prog Urol. 1999;9:1090–5. 62. Bael A, Verhulst J, Lax H, Hirche H, van Gool JD. Investigator bias in urodynamic studies for functional urinary incontinence. J Urol. 2009;182 (4 Suppl):1949–52. 63. Glassberg KI, Combs AJ, Horowitz M. Nonneurogenic voiding disorders in children and adolescents: clinical and videourodynamic findings in 4 specific conditions. J Urol. 2010;184:2123–7. 64. Riley P, Marks SD, Desai DY, Mushtaq I, Koffman G, Mamode N. Challenges facing renal transplantation in pediatric patients with lower urinary tract dysfunction. Transplantation. 2010;89:1299–307. 65. Eeg KR, Khoury AE. The exstrophy-epispadias complex. Curr Urol Rep. 2008;9:158–64. 66. Inouye BM, Massanyi EZ, Di Carlo H, Shah BB, Gearhart JP. Modern management of bladder exstrophy repair. Curr Urol Rep. 2013;14:359–65. 67. Woolf AS, Thiruchelvam N. Congenital obstructive uropathy: its origin and contribution to end-stage renal disease in children. Adv Ren Replace Ther. 2001;8:157–63. 68. Wheatley JM, Stephens FD, Hutson JM. Prune-belly syndrome: ongoing controversies regarding pathogenesis and management. Semin Pediatr Surg. 1996;5:95–106. 69. Volmar KE, Fritsch MK, Perlman EJ, Hutchins GM, Tonni G, Ida V, Alessandro V, Bonasoni MP. Prunebelly syndrome: case series and review of the literature regarding early prenatal diagnosis, epidemiology, genetic factors, treatment, and prognosis. Fetal Pediatr Pathol. 2013;31:13–24.

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70. Volmar KE, Fritsch MK, Perlman EJ, Hutchins GM. Patterns of congenital lower urinary tract obstructive uropathy: relation to abnormal prostate and bladder development and the prune belly syndrome. Pediatr Dev Pathol. 2001;4:467–72. 71. Thiruchelvam N, Nyirady P, Peebles DM, Fry CH, Cuckow PM, Woolf AS. Urinary outﬂow obstruction increases apoptosis and deregulates Bcl-2 and Bax expression in the fetal ovine bladder. Am J Pathol. 2003;162:1271–82. 72. Glassberg KI. The valve bladder syndrome: 20 years later. J Urol. 2001;166:1406–14. 73. Nasir AA, Ameh EA, Abdur-Rahman LO, Adeniran JO, Abraham MK. Posterior urethral valve. World J Pediatr. 2011;7:205–16. 74. Sherman ND, Stock JA, Hanna MK. Bladder dysfunction after bilateral ectopic ureterocele repair. J Urol. 2003;170:1975–7. 75. Abrahamsson K, Hansson E, Sillén U, Hermansson G, Hjälmås K. Bladder dysfunction: an integral part of the ectopic ureterocele complex. J Urol. 1998;160:1468–70. 76. Hanson GR, Gatti JM, Gittes GK, Murphy JP. Diagnosis of ectopic ureter as a cause of urinary incontinence. J Pediatr Urol. 2007;3:53–7. 77. Warne SA, Hiorns MP, Curry J, Mushtaq I. Understanding cloacal anomalies. Arch Dis Child. 2011;96:1072–6. 78. Borg H, Holmdahl G, Olsson I, Wiklund LM, Sillén U. Impact of spinal cord malformation on bladder function in children with anorectal malformations. J Pediatr Surg. 2009;44:1778–85. 79. Laurence KM, James N, Miller MH, Tennant GB, Campbell H. Double blind randomized controlled trial of folate treatment before conception to prevent recurrent of neural tube defect. BMJ. 1981;282:1509–11. 80. Marini NJ, Hoffmann TJ, Lammer EJ, Hardin J, Lazaruk K, Stein JB, Gilbert DA, Wright C, Lipzen A, Pennacchio LA, Carmichael SL, Witte JS, Shaw GM, Rine J. A genetic signature of spina biﬁda risk from pathway-informed comprehensive genevariant analysis. PLoS One. 2011;6:e28408. 81. Copp AJ, Stanier P, Greene ND. Neural tube defects: recent advances, unsolved questions, and controversies. Lancet Neurol. 2013;12:799–810. 82. Emery JL, Lendon RG. The local cord lesion in neurospinal dysraphism (meningomyelocele). J Pathol. 1973;110:83–96. 83. Bauer SB, Austin PF, Rawashdeh YF, de Jong TP, Franco I, Siggard C, Jorgensen TM. International Children’s Continence Society’s recommendations for initial diagnostic evaluation and follow-up in congenital neuropathic bladder and bowel dysfunction in children. Neurourol Urodyn. 2012;31:610–4. 84. Kaefer M, Pabby A, Kelly M, Darbey M, Bauer SB. Improved bladder function after prophylactic

1817 treatment of the high risk neurogenic bladder in newborns with myelomeningocele. J Urol. 1999;162:1068–71. 85. Van Gool JD, Dik P, de Jong TP. Bladder–sphincter dysfunction in myelomeningocele. Eur J Pediatr. 2001;160:414–20. 86. Rawashdeh YF, Austin P, Siggaard C, Bauer SB, Franco I, de Jong TP, Jorgensen TM, International Children’s Continence Society. International Children’s Continence Society’s recommendations for therapeutic intervention in congenital neuropathic bladder and bowel dysfunction in children. Neurourol Urodyn. 2012;31:615–20. 87. Neveus T, Eggert P, Evans J, Macedo A, Rittig S, Tekg€ ul S, Vande Walle J, Yeung CK, Robson L. Evaluation of and treatment for monosymptomatic enuresis: a standardization document from the International Children’s Continence Society. J Urol. 2010;183:441–7. 88. Franco I, von Gontard A, De Gennaro M, International Children’s Continence Society. Evaluation and treatment of nonmonosymptomatic nocturnal enuresis: a standardization document from the International Children’s Continence Society. J Pediatr Urol. 2013;9:234–43. 89. Vande Walle J, Rittig S, Bauer S, Eggert P, MarschallKehrel D, Tekgul S. Practical consensus guidelines for the management of enuresis. Eur J Pediatr. 2012;171:971–83. 90. De Guchtenaere A, Vande Walle C, Van Sintjan P, Donckerwolcke R, Raes A, Dehoorne J, Van Laecke E, Hoebeke P, Vande WJ. Desmopressin resistant nocturnal polyuria may benefit from furosemide therapy administered in the morning. J Urol. 2007;178:2635–9. 91. Fai-Ngo Ng C, Wong S-N, The Hong Kong Childhood Enuresis Study Group. Comparing alarms, desmopressin and combined treatment in Chinese enuretic children. Pediatr Nephrol. 2005;20:163–9. 92. Nijman RJ. Classification and treatment of functional incontinence in children. BJU Int. 2000;85 Suppl 3:37–42. 93. Franco I. Overactive bladder in children. Part 1: Pathophysiology. J Urol. 2007;178(3 Pt 1):761–8. 94. Van Gool JD, de Jong TP, Winkler-Seinstra P, Tamminen-Möbius T, Lax H, Hirche H, Nijman RJ, Hjälmås K, Jodal U, Bachmann H, Hoebeke P, Walle JV, Misselwitz J, John U, Bael A, European Bladder Dysfunction Study. Multi-center randomized controlled trial of cognitive treatment, placebo, oxybutynin, bladder training, and pelvic floor training in children with functional urinary incontinence. Neurourol Urodyn. 2014;33:482–7. 95. Bael A, Lax H, de Jong TP, Hoebeke P, Nijman RJ, Sixt R, Verhulst J, Hirche H, van Gool JD, European Bladder Dysfunction Study. The relevance of urodynamic studies for urge syndrome and dysfunctional voiding: a multicenter controlled trial in children. J Urol. 2008;180:1486–93.

1818 96. Hoebeke P, Renson C, De Schryver M, De Schrijver L, Leenaerts E, Schoenaers A, Deschepper E, Vande Walle J, Van den Broeck C. Prospective evaluation of clinical voiding reeducation or voiding school for lower urinary tract conditions in children. J Urol. 2011;186:648–54. 97. Combs AJ, Grafstein N, Horowitz M, Glassberg KI. Primary bladder neck dysfunction in children and adolescents I: pelvic floor electromyography lag time – a new noninvasive method to screen for and monitor therapeutic response. J Urol. 2005;173:207–10. 98. Van Batavia JP, Combs AJ, Hyun G, Bayer A, Medina-Kreppein D, Schlussel RN, Glassberg KI. Simplifying the diagnosis of 4 common voiding conditions using uroflow/electromyography, electromyography lag time and voiding history. J Urol. 2011;186(4 Suppl):1721–6. 99. Van Batavia JP, Combs AJ, Glassberg KI. Short pelvic floor EMG lag time II: use in management and followup of children treated for detrusor overactivity. J Pediatr Urol. 2014;10:255–61. 100. Fast AM, Nees SN, Van Batavia JP, Combs AJ, Glassberg KI. Outcomes of targeted treatment for vesicoureteral reflux in children with nonneurogenic lower urinary tract dysfunction. J Urol. 2013;190:1028–32. 101. Van Batavia JP, Combs AJ, Fast AM, Glassberg KI. Use of non-invasive uroflowmetry with simultaneous electromyography to monitor patient response to treatment for lower urinary tract conditions. J Pediatr Urol. 2014;10:532–7. 102. Combs AJ, Van Batavia JP, Chan J, Glassberg KI. Dysfunctional elimination syndromes – how closely linked are constipation and encopresis with specific lower urinary tract conditions? J Urol. 2013;190:1015–20. 103. Desantis DJ, Leonard MP, Preston MA, Barrowman NJ, Guerra LA. Effectiveness of biofeedback for dysfunctional elimination syndrome in pediatrics: a systematic review. J Pediatr Urol. 2011;7:342–8. 104. Kajbafzadeh AM, Sharifi-Rad L, Ghahestani SM, Ahmadi H, Kajbafzadeh M, Mahboubi AH. Animated biofeedback: an ideal treatment for children with dysfunctional elimination syndrome. J Urol. 2011;186:2379–84. 105. Barroso Jr U, Tourinho R, Lordêlo P, Hoebeke P, Chase J. Electrical stimulation for lower urinary tract dysfunction in children: a systematic review of the literature. Neurourol Urodyn. 2011;30:1429–36. 106. Burton C, Sajja A, Latthe PM. Effectiveness of percutaneous posterior tibial nerve stimulation for overactive bladder: a systematic review and metaanalysis. Neurourol Urodyn. 2012;31:1206–16. 107. Von Gontard A, Baeyens D, Van Hoecke E, Warzak WJ, Bachmann C. Psychological and psychiatric issues in urinary and fecal incontinence. J Urol. 2011;185:1432–6.

E. Berard 108. Robson WM, Lane M, Jackson HP, et al. Enuresis in children with attention-deficit hyperactivity disorder. South Med J. 1997;90:503–5. 109. Equit M, Becker A, El Khatib D, Rubly M, Becker N, von Gontard A. Central nervous system processing of emotions in children with nocturnal enuresis and attention-deficit/hyperactivity disorder. Acta Paediatr. 2014. 110. Crimmins CR, Rathburn SR, Husmann DA. Management of urinary incontinence and nocturnal enuresis in attention-deficit hyperactivity disorder. J Urol. 2003;118:1347–51. 111. Hjalmas K, Arnold T, Bower W, et al. Nocturnal enuresis: an international evidence based management strategy. J Urol. 2004;171:2545–6. 112. Chandra M, Saharia R, Hill V, et al. Prevalence of diurnal voiding symptoms and difficult arousal from sleep in children with nocturnal enuresis. J Urol. 2004;172:311–6. 113. Özkan KU, Garipardic M, Toktamis A, et al. Enuresis prevalence and accompanying factors in schoolchildren: a questionnaire study from southeast Anatolia. Urol Int. 2004;73:149–55. 114. Zink S, Freitag CM, Von Gontard A. Behavioral comorbidity differs in subtypes of enuresis and urinary incontinence. J Urol. 2008;179:295–8. 115. Dhondt K, Baert E, Van Herzeele C, Raes A, Groen LA, Hoebeke P, Vande WJ. Sleep fragmentation and increased periodic limb movements are more common in children with nocturnal enuresis. Acta Paediatr. 2014;103:e268–72. 116. Wolfish NM. Sleep/arousal and enuresis subtypes. J Urol. 2001;166:2444–7. 117. Stone J, Malone PSJ, Atwill D, et al. Symptoms of sleep-disordered breathing in children with nocturnal enuresis. J Pediatr Urol. 2008;4:197–202. 118. Alexopoulos EI, Kostadima E, Pagonari I, et al. Association between primary nocturnal enuresis and habitual snoring in children. Urology. 2006;68:406–9. 119. Weider DJ, Satecia MJ, West RP. Nocturnal enuresis in children with upper airway obstruction. Otolaryngol Head Neck Surg. 1991;105:427–32. 120. Guven A, Giramonti K, Kogan BA. The effect of obesity on treatment efficacy in children with nocturnal enuresis and voiding dysfunction. J Urol. 2007;178:1458–62. 121. Allen TD. The non-neurogenic neurogenic bladder. J Urol. 1977;117:232–8. 122. Al Mosawi AJ. Identification of nonneurogenic neurogenic bladder in infants. Urology. 2007;70:355–6. 123. Ochoa B. Can a congenital dysfunctional bladder be diagnosed from a smile? The Ochoa syndrome updated. Pediatr Nephrol. 2004;19:6–12. 124. Aydogdu O, Burgu B, Demirel F, Soygur T, Ozcakar ZB, Yalcinkaya F, Tekgul S. Ochoa syndrome: a spectrum of urofacial syndrome. Eur J Pediatr. 2010;169:431–5.

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125. Mermerkaya M, S€ uer E, Özt€ urk E, G€ ulpınar Ö, Gökçe Mİ, Yalçındağ FN, Soyg€ ur T, Burgu B. Nocturnal lagophthalmos in children with urofacial syndrome (Ochoa): a novel sign. Eur J Pediatr. 2014;173:661–5. 126. Williams DI, Hirst G, Doyle D. The occult neuropathic bladder. J Pediatr Surg. 1975;9:35–8. 127. Allen TD, Bright TC. Urodynamic patterns in children with dysfunctional voiding problems. J Urol. 1978;119:247–51. 128. Allen TD. The non-neurogenic neurogenic bladder. J Urol. 1977;117:719–24. 129. Pang J, Zhang S, Yang P, Hawkins-Lee B, Zhong J, Zhang Y, Ochoa B, Agundez JA, Voelckel MA, Fisher RB, Gu W, Xiong WC, Mei L, She JX, Wang CY. Loss-of-function mutations in HPSE2 cause the autosomal recessive urofacial syndrome. Am J Hum Genet. 2010;86:957–62. 130. Woolf AS, Stuart HM, Roberts NA, McKenzie EA, Hilton EN, Newman WG. Urofacial syndrome: a genetic and congenital disease of aberrant urinary bladder innervation. Pediatr Nephrol. 2014;29:513–8. 131. Roberts NA, Woolf AS, Stuart HM, Thuret R, McKenzie EA, Newman WG, Hilton EN. Heparanase 2, mutated in urofacial syndrome, mediates peripheral neural development in Xenopus. Hum Mol Genet. 2014;25. 132. G€undoğdu G, Köm€ ur M, Avlan D, Sarı FB, Delibaş A, Taşdelen B, Naycı A, Okuyaz C. Relationship of bladder dysfunction with upper urinary tract deterioration in cerebral palsy. J Pediatr Urol. 2013;9:659–64.

1819 133. Richardson I, Palmer LS. Clinical and urodynamic spectrum of bladder function in cerebral palsy. J Urol. 2009;182(4 Suppl):1945–8. 134. Karaman MI, Kaya C, Caskurlu T, Guney S, Ergenekon E. Urodynamic ﬁndings in children with cerebral palsy. Int J Urol. 2005;12:717–20. 135. Herthelius M, Oborn H. Bladder dysfunction in children and adolescents after renal transplantation. Pediatr Nephrol. 2006;21:725–8. 136. Van der Weide MJ, Cornelissen EA, Van Achterberg T, Smits JP, Feitz WF. Dysfunction of lower urinary tract in renal transplant children with nephrologic disease. Urology. 2006;67:1060–5. 137. Oborn H, Herthelius M. Lower urinary tract symptoms in children and adolescents with chronic renal failure. J Urol. 2010;183:312–6. 138. Bergmann M, Corigliano T, Ataia I, Renella R, Simonetti GD, Bianchetti MG, von Vigier RO. Childhood extraordinary daytime urinary frequency – a case series and a systematic literature review. Pediatr Nephrol. 2009;24:789–95. 139. Glazier DB, Ankem MK, Ferlise V, Gazi M, Barone JG. Utility of biofeedback for the daytime syndrome of urinary frequency and urgency of childhood. Urology. 2001;57:791–3. 140. Lottmann H. Traitement de l’énurésie nocturne en France. Presse Med. 2000;29:987–90. 141. Lee SD, Sohn DW, Lee JZ, et al. An epidemiological study of enuresis in Korean children. BJU Int. 2000;85:869–73. 142. Mattsson S. Urinary incontinence and nocturia in healthy school children. Acta Pediatr. 1994;83:950–4.

Urolithiasis in Children

Vidar Edvardsson

Contents

Clinical Features of Urolithiasis . . . . . . . . . . . . . . . . . . 1851

Epidemiology of Urolithiasis in Children and Adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1822

Diagnostic Evaluation of Urolithiasis . . . . . . . . . . . . 1851

Clinical Risk Factors for Urolithiasis . . . . . . . . . . . . Idiopathic Hypercalciuria . . . . . . . . . . . . . . . . . . . . . . . . . . . Hyperoxaluria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypocitraturia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hyperuricosuria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structural Malformations of the Urinary Tract and Urinary Tract Infections . . . . . . . . . . . . . . . . . . . . . . . Drug- and Toxin-Induced Renal Stones . . . . . . . . . . . . Clinical Conditions Associated with Urolithiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1824 1825 1827 1830 1830 1831 1832

Management of Acute Symptomatic Stone Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1853 Kidney Stone Prevention . . . . . . . . . . . . . . . . . . . . . . . . . Prescription of Adequate Fluid Intake . . . . . . . . . . . . . Dietary Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prescription of Pharmacotherapy . . . . . . . . . . . . . . . . . . .

1855 1855 1856 1857

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1858

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Mechanism of Stone Formation . . . . . . . . . . . . . . . . . . 1835 Genetic Aspects of Stone Disease . . . . . . . . . . . . . . . . . Family Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Twin Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genealogy Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Linkage and Candidate Gene Studies . . . . . . . . . . . . . . Genome-Wide Association Studies . . . . . . . . . . . . . . . . Rare Monogenic Causes of Urolithiasis . . . . . . . . . . . . Monogenic Causes of Urolithiasis Associated with Hypercalciuria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Monogenic Causes of Urolithiasis Not Associated with Hypercalciuria . . . . . . . . . . . . . . . . . . . .

1837 1837 1838 1838 1838 1839 1839 1840 1844

V. Edvardsson (*) Landspitali – The National University Hospital of Iceland, Reykjavik, Iceland and Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland e-mail: [emailprotected] # Springer-Verlag Berlin Heidelberg 2016 E.D. Avner et al. (eds.), Pediatric Nephrology, DOI 10.1007/978-3-662-43596-0_53

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1822

Epidemiology of Urolithiasis in Children and Adolescents Urolithiasis is a common health disorder in all parts of the world with an estimated lifetime prevalence of approximately 10–12 % in men and 5–6 % in women [1, 2]. In the 1950s to the 1970s, the estimated incidence of pediatric urolithiasis in the United States was 1–2 % that of adults [3, 4], and other earlier studies found stones to account for 1 in 7,600 to 1 in 1,000 pediatric US hospital admissions [5–7]. A recently published study of patients younger than 18 years hospitalized between 2002 and 2007, based on a validated collection of pediatric hospital data (the Pediatric Health Information System database), found childhood stone disease to account for 1 in 685 pediatric hospitalizations in the United States [8]. Although the epidemiology of urolithiasis in children and adolescents has to date been less well defined than in the adult population, two recent population-based studies [9, 10] have suggested a significant increase in the frequency of childhood kidney stone diagnosis. A study by Sas et al. [9] conducted in the state of South Carolina found an increase in the incidence of symptomatic kidney stones in children and adolescents less than 18 years of age, from 7.9 per 100,000 children in 1996 to 18.5 per 100,000 in 2007. In that study the highest incidence increase was seen in females aged 14–18 years, followed by the age group 9–13 years. The incidence rate, however, did not significantly change in children aged less than 9 years. Another population-based pediatric study, based on the Rochester Epidemiology Project, reported an increase in the incidence of urolithiasis from 7.2 per 100,000 in the years 1984–1990 to 14.5 per 100,000 in the years 2003–2008 [10]. The greatest incidence rise in both of the above studies was observed in teenagers where it reached approximately 35 per 100,000 children while only a limited increase was seen in children under the age of 10 years [9, 10]. In the South Carolina study, the risk of developing clinical stone events was 10 times greater in children aged 14–18 years than for children aged 0–3 years [9]. Male preponderance for kidney stone disease has in multiple studies

V. Edvardsson

been reported for both pediatric [11, 12] and adult [1, 13] stone disease. Interestingly, a number of recent studies clearly show childhood kidney stone disease to be more common in the female gender [8, 9, 14], particularly in the age group 10–17 years [9, 15]. Furthermore, a number of pediatric studies have shown a more rapid incidence rise in girls than boys [9, 15, 16], and in the study by Sas et al. [9], the overall male–female ratio changed from approximately 1:1 in the year 1996 to 1:1.4 in the year 2007. Interestingly, our group [13] and others [17, 18] have shown a decreasing male predominance of kidney stone disease in the adult population, particularly the youngest age groups where the male–female ratio is now close to 1:1. Thus, kidney stone disease is becoming more common in the female gender. Although the incidence of pediatric nephrolithiasis is rising, the reason why this increase has occurred is not known. The most frequently discussed and studied potential causes for the increase in childhood kidney stone disease are obesity, increased intake of sodium and fructose, and decrease in the intake of calcium and water and increasing use of antibiotics [19]. Obesity has in the adult population been shown to be associated with stone disease. A large prospective study of three large adult US cohorts (the Health Professionals Follow-Up Study, the Nurses’ Health Study I, and the Nurses’ Health Study II) including approximately 240,000 subjects found both obesity and weight gain increase the risk of kidney stone formation [20]. In children and adolescents, however, epidemiologic data do not suggest a link between higher BMI percentiles and stone formation [19]. Between 1996 and 2007, a period during which a signiﬁcant increase in pediatric kidney stone disease was observed [9], no signiﬁcant changes occurred in the rates of overweight or obesity in US children [21]. Kieran et al. [22] studied the association between BMI percentiles and stone formation in a US pediatric population. Although a higher proportion of the stone-forming children were obese than the general pediatric population in their state, higher BMI was not associated with earlier stone development, larger stones, or the need for multiple

Urolithiasis in Children

surgical procedures. Surprisingly, lower percentile body weight children had their first clinical stone events significantly earlier than upper percentile or normal body weight peers, and stone size and the need for surgical procedures did not vary with body mass. A recent US study by Bergsland et al. [23] noted no significant differences in age-adjusted body weight between stoneforming children, their non-stone-forming siblings, and healthy children. Similar observations have also been made by Sas et al. [19] who found stone formers to have a slightly lower BMI percentile than their general non-stone-forming population. Studies of the correlation between obesity and urinary metabolic risk factors for stone formation in children have shown conflicting results [24, 25]. Eisner et al. [25] examined the association between body mass index percentiles and 24 h urine chemistry studies in 43 children with a history of kidney stones. In that study high body mass was associated with decreased urine oxalate excretion and increased supersaturation of calcium phosphate while no association was found with any other urinary parameters. Moreover, higher body mass did not correlate with lower urine pH as it does in adults. Further, a Turkish study, which compared urinary stone risk profiles in 44 overweight and 50 normal weight non-stone-forming children, found overweight children to have higher excretion of urinary oxalate and uric acid, higher supersaturation (SS) of calcium oxalate, lower urine volume, and lower citrate and magnesium excretion [24]. Lastly, in a retrospective study of children who had been found to have idiopathic hypercalciuria, overweight children were more likely to develop clinical stone events than their normal weight peers [26]. A causative relationship between kidney stones and increased sodium and fructose intake and reduced intake of calcium has not been clearly demonstrated [19]. Inverse relationship has been described between dietary calcium intake and the risk of symptomatic kidney stones in several prospective observational studies in the adult population [27–29]. Dietary calcium is believed to decrease oxalate absorption from the gut by binding free oxalate, thereby preventing dietary hyperoxaluria and reducing urinary

1823

calcium oxalate crystallization [30]. Indeed, a low-calcium diet has in the adult population been shown to increase the risk of nephrolithiasis and urinary oxalate excretion, while a diet containing normal amounts of calcium and reduced amounts of animal protein and sodium decreased the risk of symptomatic kidney stones as well as urinary oxalate excretion [31]. Ambient temperature increase has in the adult population been associated with increased risk of stone formation, an effect which is much greater in men than women [32]. In addition, there is evidence that reduced water intake increases the risk of kidney stones [29] and US children seem to be drinking less water than before [33]. Low intake of water and increased environmental heat, both of which lead to small urine volume, increase urinary supersaturation and the risk of nephrolithiasis [34, 35]. A sufﬁciently high intake of water and probably other ﬂuids has been shown to effectively prevent kidney stone recurrence [36], and some studies indicate that the type of beverage consumed may affect stone formation [37, 38]. The potential contribution of ambient temperature and less water intake to increasing stone prevalence in childhood has, however, not been systematically studied. Finally, stone formation may be associated with antibiotic use. Oxalobacter formigenes is a unique intestinal organism that relies on oxalate degradation to meet most of its energy and carbon needs [39]. A reduced Oxalobacter formigenes gut colonization leads to increased availability of oxalate for intestinal absorption which is a risk factor for calcium oxalate stone disease. Changes in antibiotic use and prescription rates may, therefore, affect the incidence of childhood stone disease. However, recent epidemiologic US data suggesting a decrease in the use of antibiotics in American children makes the association between kidney stones and antibiotic use less likely [40, 41]. The prevalence of urolithiasis varies between ethnic groups and geographical areas [42], and the probability of having a kidney stone event has been reported in adults to be 1–5 % in Asia, 5–9 % in Europe, 13 % in North America, and 20 % in Saudi Arabia [43]. In Western

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industrialized nations, kidney stones are most common in non-Hispanic Caucasians, followed by Mexican Americans, and the lowest risk is observed in African Americans [1, 42]. Similar differences between ethnic groups have also been observed in a number of recent pediatric studies [8, 9, 44]. A considerable regional variability exists in stone prevalence in North America with the highest reported probability of stone formation in the South and lowest in the West [1, 45]. However, contrasting earlier work, a recent retrospective study of 3,989 pediatric hospital admissions for 3,815 patients with urolithiasis, based on Pediatric Health Information System data from 41 freestanding pediatric US hospitals, found stone hospitalizations to be more common in the North Central region compared to the Southern states which is very interesting considering the fact that the Northern Central region is primarily inhabited by Caucasians of European descent, the ethnic group with the highest rate of stone formation, while the majority of the Southern population is African American [8]. In the study by Sas et al., the incidence of kidney stones was higher in children living in rural compared to urban communities [9]. Similar to that observed in adults, occurrence in late summer months increased the risk of hospitalization due to pediatric stone disease [8]. Children and adolescents in Western countries predominantly form calcium stones. In a recent large US study of pediatric urinary stone composition, 89 % of the stones contained calcium salts and stone composition associated with both age and gender but not geographical region [46]. The study, which is the largest one reported to date, included a total of 5,245 ﬁrst kidney stones submitted for analysis to a reference laboratory from all 50 US states between the years 2000 and 2009 from children aged 1–17 years. Calcium oxalate and magnesium ammonium phosphate (struvite) were signiﬁcantly more often found in stones from females than males (86 % vs. 79 % and 4.8 % vs. 3.8 %, respectively), and conversely, stones containing uric acid were more commonly seen in males than females (1.4 % vs. 0.6 %). Percentage of calcium oxalate containing stones increased with age while stones containing calcium phosphate

V. Edvardsson

were most common in the youngest children. Struvite-containing stones decreased with age as did ammonium acid urate containing stones. Calcium was found in 89.2 % of the stones, 83 % contained calcium oxalate and 61 % calcium phosphate, and 4.4 % included struvite. Other identified stone components were ammonium acid urate (2.8 %), cystine (2.3 %), uric acid (0.9 %), and calcium carbonate (0.4 %). Similarly, in a recent small study of pediatric kidney stones based on the Rochester Epidemiology Project, 71 % of the stones were composed of calcium oxalate and 25 % calcium phosphate, 3 % had infection-related stones, only 2 % had stones composed of uric acid, and none of the 84 incident stone formers had cystine or other stone types [10]. Interestingly, there are indications that the prevalence of the different stone subtypes in ordinary calcium stone formers may be changing. A single-center study of the composition of stones from 179 children found a significantly higher proportion of calcium phosphate stones (60 % vs. 47 %) in pediatric stone formers in the period 2001–2010 when compared to the years 1992–2000 [47]. Finally, stone composition in many of the developing countries such as India, Pakistan, and Southeast Asia and the Middle East, where urolithiasis is endemic, is very different from that in the Western world [48, 49]. Endemic calculi are most frequently confined to the bladder and are predominantly comprised of ammonium acid urate which is associated with the excretion of a high acid load secondary to an acidogenic rice or “single cereal” diet and diarrhea, combined with a low dietary phosphate intake and urinary excretion [50]. The association between stone types and various clinical conditions is presented in Table 1.

Clinical Risk Factors for Urolithiasis Recognized urine risk factors for calcium kidney stone formation in the absence of systemic diseases include familial (idiopathic) hypercalciuria, hyperoxaluria, hypocitraturia, low urine volume, and hyperuricosuria [23, 51, 52]. These stone risk factors have been reported in 40–95 % of ﬁrst time pediatric stone formers [6, 14, 53] and up to 95 %

Urolithiasis in Children

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Table 1 Kidney stone type and associated conditions [87] (Modified with permission from Dawn Milliner, MD, Mayo Clinic, Rochester Minnesota, and Springer Science and Business Media) Stone type Calcium oxalate

Calcium phosphate

Magnesium ammonium phosphate (struvite) Carbonate apatite Uric acid

2,8-Dihydroxyadenine Cystine

Associated conditions Idiopathic stone disease Hypercalciuria, idiopathic or of any cause Dietary hyperoxaluria Enteric hyperoxaluria Primary hyperoxaluria ADPKD Cystic ﬁbrosis Ketogenic diet (mixed calcium stone) Drug-induced metabolic stones Idiopathic stone disease Hypercalciuria, idiopathic or of any cause RTA Dent disease type I Dent disease type II (OCRL mutations) Drug-induced metabolic stones Ketogenic diet Infection-related stones

Hyperuricosuria Metabolic syndrome Ketogenic diet (pure and/or mixed with calcium) HPRT deﬁciency, partial or complete Hereditary renal hypouricemia Tumor lysis syndrome Glycogen storage disease, type 1 ADPKD Wilson’s disease APRT deﬁciency Cystinuria

of adults with recurrent kidney stone disease [54]. Tables 2 and 3 show normal values for urinary solute excretion in children less than 18 years of age, and metabolic abnormalities associated with urolithiasis are listed in Table 4.

Idiopathic Hypercalciuria Idiopathic hypercalciuria is deﬁned as the renal overexcretion of calcium, despite normal serum calcium levels, in the absence of a secondary cause (Tables 2 and 3) [55]. It is the most common underlying risk factor for nephrolithiasis, present in 75–80 % of pediatric kidney stone patients [14, 56] and 40–50 % of adults with recurrent calcium stones [54, 57]. A recent carefully designed study by Bergsland et al. [23] found hypercalciuria to be the principal risk factor for calcium stone formation in children, and the remaining established stone risk factors found in adults, such as hyperoxaluria, hypocitraturia, abnormal urine pH, or low urine volume, did not differ between stone formers and controls. Included in the study were 129 children with calcium stones, 105 non-stone-forming siblings from the same families, and 183 age- and gendermatched healthy children without family history of kidney stones. Siblings of stone formers had higher calcium excretion than healthy normal children, those with 1–2 stones exceeded both the siblings and normals, and children with >2 stones exceeded all the other groups. The mechanisms of idiopathic hypercalciuria include (1) an increased intestinal calcium absorption mediated either by a direct increase in calcium absorption (type 1 absorptive hypercalciuria) or through excess 1,25(OH)2D3-mediated calcium absorption (type II absorptive hypercalciuria), (2) a decreased renal absorption of either calcium (renal hypercalciuria) or phosphorus (type III absorptive hypercalciuria), and/or (3) enhanced bone resorption (resorptive hypercalciuria) [58]. Bone mineral density is reduced in individuals with idiopathic hypercalciuria, and a large cross-sectional study from the Third National Health and Nutrition Examination Survey (NHANES III) showed that men, more than women, with history of kidney stones had lower femoral neck bone mineral density (BMD) and higher fracture risk than did men without kidney stones [59]. Further, urinary calcium excretion has been shown to be the best predictor of bone loss in idiopathic hypercalciuric adult stone formers [60]. Finally, an inverse linear correlation between age and bone mineral content

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V. Edvardsson

Table 2 Random urine solute-to-creatinine ratioa by age [79, 114, 121] (Modified with permission from Wiley-Blackwell)

Urinary solute Calcium

Oxalate

Cystine

Uric acid

Citrate Magnesium

Age 0–1 years 1–2 years 2–3 years 3–5 years 5–7 years 7–10 years 10–17 years 2–5 years 6–12 years >18 years 6 months 2 years

Excretion 2,000 mL/24 h in older children and adolescents, and > 3,000 mL/24 h in older adolescents and adults may be required [79]. Gastric tube placement may be needed to achieve adequate hydration in patients with the most severe stone diseases. In the USA, children above the age of 3 years do not consume the amount of water recommended by the Institute of Medicine [281]. Moreover, the stone risk may be increased by the excessive consumption of sugary drinks which unfortunately is particularly common at the present time in children and young adults [281]. Fructoseand glucose-containing drinks adversely affect stone risk by increasing the urinary excretion of both calcium and oxalate [301]. Sugary drinks should also be avoided as they may increase the risk of stones [281]. Interestingly, children with calcium stone disease may beneﬁt from drinking citrate-rich drinks such as lemonade and orange juice although these drinks tend to contain considerable amounts of sugar [49].

Dietary Considerations Quality studies of dietary interventions in children with stone disease have not been performed to

date [281]. The risk of symptomatic kidney stones has in prospective observational studies been inversely associated with dietary calcium intake [302]. The theory is that dietary calcium may bind intestinal oxalate, thereby reducing its intestinal absorption, renal excretion, and urinary calcium oxalate crystallization [121]. Further, a low-calcium diet appears to be a less effective treatment for calcium stone disease than a normal calcium diet with reduced amounts of animal protein and sodium [31]. Based on the above studies, the advised dietary calcium intake in children with kidney stones is approximately 100 % of recommended daily allowance (RDA), and both excessive calcium consumption and calcium restriction should be avoided [49]. Furthermore, since sodium is known to increase urinary calcium excretion, the limitation of sodium intake to 2–3 mEq/kg/day is also recommended [49, 121]. Protein consumption confers an acid load which promotes skeletal calcium losses, increased urinary calcium excretion, and both urinary acidiﬁcation and hypocitraturia [49]. Additionally, purine intake parallels that of animal protein intake which may increase urinary uric acid excretion that in adults has been shown to be a risk factor for calcium stone disease [281]. Therefore, protein intake of children with urinary stone disease should be approximately 100 % of RDA, to assure physical growth and development, while excessive protein consumption should be avoided [49]. Childhood stone formers with acidic urine or

Urolithiasis in Children

hypocitraturia may beneﬁt from diets rich in fruits and vegetables which deliver both potassium and alkali through citrate which protects against kidney stone formation [82]. Finally, since the contribution of diet to urinary oxalate excretion is more signiﬁcant than previously recognized, dietary oxalate likely contributes more to calcium oxalate stone formation than previously recognized [81]. Therefore, children with calcium oxalate stones and/or documented hyperoxaluria should avoid food items rich in oxalate (beets, chives, chocolate, green tea nuts, okra, parsley, rhubarb, soy beans, spinach, star fruit, sweet potatoes, tofu, and wheat bran) and vitamin C supplements [49, 114, 121].

Prescription of Pharmacotherapy Targeted pharmacotherapy, based on thorough urine stone risk factor evaluation, is indicated in children who have recurrent idiopathic calcium kidney stones and in all subjects with treatable hereditary stone disorders (Table 8) [49, 121]. The goal of drug treatment, and all other treatment modalities applied, is to reduce urinary concentration and supersaturation of the stone-forming ions involved and their salts or minerals. A reduction in urinary supersaturation can be reached by (a) reducing excretion of the stone-forming ion involved, (b) complexation of the ions involved with known inhibitors of stone formation, and (c) manipulation of urine pH. The pharmacologic treatment of patients with calcium stones and hypercalciuria may include thiazide diuretics that reduce renal calcium excretion [121]. Hydrochlorothiazide is the most commonly used preparation, and the recommended dose is 0.5–2 mg/kg/day in children, given twice a day due to its relatively short half-life [49, 121]. The much longer-acting thiazide preparation chlorthalidone can be prescribed once per day and may lead to more satisfactory results. Amiloride can be added to thiazide treatment in patients with hypercalciuria if they develop hypokalemia and hypocitraturia implying potassium depletion and when the calciuric effect of thiazide treatment is suboptimal [114]. The mechanism of

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action includes volume contraction and increased proximal tubular reabsorption of calcium [281]. No pediatric studies have to date assessed the effect of thiazide treatment on stone recurrence while randomized clinical trials in adults have shown between 40 % and 80 % reduction in stone recurrence in treated patients [281]. The safety of combined thiazide and potassium citrate treatment in children is not known. Patients with calcium stones and hypocitraturia should be prescribed oral potassium citrate therapy in the dose of 2–4 mEq/kg/day in children and 30–90 mEq/day in adults [49]. Urinary citrate acts by complexing calcium ions and thereby decreasing urinary supersaturation of calcium oxalate and also by direct inhibition of both crystal growth and aggregation [281, 303]. Since citrate confers a signiﬁcant alkali load, care must be taken to prevent a rise in the urine pH to more than 6.3 or 6.5 as alkaline pH increases the risk of calcium phosphate stone formation [49, 281]. In adults, clinical trials have conﬁrmed a reduction in stone recurrence risk in patients treated with potassium citrate while the evidence is less robust in children [281]. One prospective cohort study observed a reduction in true stone recurrence, as well as regrowth rates after shock wave lithotripsy in 96 stone-forming children prescribed potassium citrate. As eluted at above, citrate-rich drinks may increase urinary citrate excretion. Children with kidney stones and dRTA have chronic acidemia, hypercalciuria, and hypocitraturia and frequently form calcium phosphate stones due to these risk factors and their inability to acidify the urine [281]. The recommended treatment is potassium citrate in the dose of 2–4 mEq/kg per day which has been shown to normalize both urinary calcium and citrate and serum bicarbonate [304]. As always, when prescribing alkali treatment, urine pH should be monitored closely to prevent increasing the already alkaline urine pH to above 6.3, which in turn would increase the probability of calcium phosphate crystal formation [49, 281]. Children with epilepsy treated with a ketogenic diet are at an increased risk of forming kidney stones, and the underlying stone risk factors include chronic acidemia, hypercalciuria,

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hypocitraturia, and reduced oral ﬂuid intake, and in contrast to those with dRTA, these children have low urine pH [87, 281]. Stone composition includes uric acid, calcium phosphate, mixed calcium and uric acid, and ammonium urate [87]. Potassium citrate therapy reduces the incidence of kidney stones in these children, and some authors have advocated the prophylactic use of potassium citrate in this population at high risk for nephrolithiasis [305]. Treatment of the occasional pediatric patient with pure uric acid stones includes alkali treatment aiming for a urine pH elevation to no more than 6.5 to avoid the formation of calcium phosphate stones which form in alkaline urine. Patients with uric acid stones tend to have low urine pH, and the drug of choice is potassium citrate in the dose of 1–2 mEq/kg/day divided twice daily [281]. Oral administration of neutral phosphate and magnesium preparations, which bind urinary calcium and oxalate, respectively, may also reduce stone risk in selected patients. The treatment of hereditary monogenic causes of kidney stones, such as APRT deﬁciency, cystinuria, Dent disease, and PH, is described in the sections of this chapter dealing with these diseases.

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1867 type III. Am J Hum Genet. 2010;87(3):392–9. Epub 2010/08/28. 269. Danpure CJ. Molecular etiology of primary hyperoxaluria type 1: new directions for treatment. Am J Nephrol. 2005;25(3):303–10. Epub 2005/ 06/18. 270. Milliner DS. The primary hyperoxalurias: an algorithm for diagnosis. Am J Nephrol. 2005;25(2): 154–60. Epub 2005/04/28. 271. Monico CG, Rossetti S, Belostotsky R, Cogal AG, Herges RM, Seide BM, et al. Primary hyperoxaluria type III gene HOGA1 (formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis. Clin J Am Soc Nephrol. 2011;6(9):2289–95. 272. Mandrile G, van Woerden CS, Berchialla P, Beck BB, Acquaviva Bourdain C, Hulton SA, et al. Data from a large European study indicate that the outcome of primary hyperoxaluria type 1 correlates with the AGXT mutation type. Kidney Int. 2014;86(6): 1197–204. Epub 2014/07/06. 273. Jacob DE, Grohe B, Gessner M, Beck BB, Hoppe B. Kidney stones in primary hyperoxaluria: new lessons learnt. PLoS One. 2013;8(8):e70617. Epub 2013/08/14. 274. Hoppe B, Langman CB. A United States survey on diagnosis, treatment, and outcome of primary hyperoxaluria. Pediatr Nephrol. 2003;18(10): 986–91. Epub 2003/08/16. 275. Leumann E, Hoppe B, Neuhaus T. Management of primary hyperoxaluria: efficacy of oral citrate administration. Pediatr Nephrol. 1993;7(2):207–11. Epub 1993/04/01. 276. Milliner D. Treatment of the primary hyperoxalurias: a new chapter. Kidney Int. 2006;70(7):1198–200. 277. Monico CG, Rossetti S, Olson JB, Milliner DS. Pyridoxine effect in type I primary hyperoxaluria is associated with the most common mutant allele. Kidney Int. 2005;67(5):1704–9. Epub 2005/04/21. 278. Hoppe B, Groothoff JW, Hulton SA, Cochat P, Niaudet P, Kemper MJ, et al. Efficacy and safety of oxalobacter formigenes to reduce urinary oxalate in primary hyperoxaluria. Nephrol Dial Transplant. 2011;26(11):3609–15. Epub 2011/04/05. 279. Cochat P, Liutkus A, Fargue S, Basmaison O, Ranchin B, Rolland MO. Primary hyperoxaluria type 1: still challenging! Pediatr Nephrol. 2006;21 (8):1075–81. 280. Illies F, Bonzel KE, Wingen AM, Latta K, Hoyer PF. Clearance and removal of oxalate in children on intensified dialysis for primary hyperoxaluria type 1. Kidney Int. 2006;70(9):1642–8. Epub 2006/ 09/07. 281. Tasian GE, Copelovitch L. Evaluation and medical management of kidney stones in children. J Urol. 2014;192(5):1329–36. Epub 2014/06/25. 282. Lande MB, Varade W, Erkan E, Niederbracht Y, Schwartz GJ. Role of urinary supersaturation in the evaluation of children with urolithiasis. Pediatr Nephrol. 2005;20(4):491–4. Epub 2005/02/18.

1868 283. Routh JC, Graham DA, Nelson CP. Trends in imaging and surgical management of pediatric urolithiasis at American pediatric hospitals. J Urol. 2010;184 (4 Suppl):1816–22. Epub 2010/08/24. 284. Johnson EK, Faerber GJ, Roberts WW, Wolf Jr JS, Park JM, Bloom DA, et al. Are stone protocol computed tomography scans mandatory for children with suspected urinary calculi? Urology. 2011;78(3): 662–6. Epub 2011/07/05. 285. Passerotti C, Chow JS, Silva A, Schoettler CL, Rosoklija I, Perez-Rossello J, et al. Ultrasound versus computerized tomography for evaluating urolithiasis. J Urol. 2009;182(4 Suppl):1829–34. Epub 2009/08/21. 286. Karmazyn B, Frush DP, Applegate KE, Maxﬁeld C, Cohen MD, Jones RP. CT with a computer-simulated dose reduction technique for detection of pediatric nephroureterolithiasis: comparison of standard and reduced radiation doses. AJR Am J Roentgenol. 2009;192(1):143–9. Epub 2008/12/23. 287. Oosterlinck W, Philp NH, Charig C, Gillies G, Hetherington JW, Lloyd J. A double-blind single dose comparison of intramuscular ketorolac tromethamine and pethidine in the treatment of renal colic. J Clin Pharmacol. 1990;30(4):336–41. Epub 1990/04/01. 288. Bartﬁeld JM, Kern AM, Raccio-Robak N, Snyder HS, Baevsky RH. Ketorolac tromethamine use in a university-based emergency department. Acad Emerg Med. 1994;1(6):532–8. 289. Sandhu DP, Iacovou JW, Fletcher MS, Kaisary AV, Philip NH, Arkell DG. A comparison of intramuscular ketorolac and pethidine in the alleviation of renal colic. Br J Urol. 1994;74(6):690–3. Epub 1994/12/01. 290. Gonzalez A, Smith DP. Minimizing hospital length of stay in children undergoing ureteroneocystostomy. Urology. 1998;52(3):501–4. Epub 1998/09/08. 291. Eberson CP, Pacicca DM, Ehrlich MG. The role of ketorolac in decreasing length of stay and narcotic complications in the postoperative pediatric orthopaedic patient. J Pediatr Orthop. 1999;19(5):688–92. Epub 1999/09/17. 292. Splinter WM, Reid CW, Roberts DJ, Bass J. Reducing pain after inguinal hernia repair in children: caudal anesthesia versus ketorolac tromethamine. Anesthesiology. 1997;87(3):542–6. Epub 1997/10/08. 293. Purday JP, Reichert CC, Merrick PM. Comparative effects of three doses of intravenous ketorolac or morphine on emesis and analgesia for restorative dental surgery in children. Can J Anaesth. 1996;43(3): 221–5. Epub 1996/03/01.

V. Edvardsson 294. Salerno A, Nappo SG, Matarazzo E, De Dominicis M, Caione P. Treatment of pediatric renal stones in a Western country: a changing pattern. J Pediatr Surg. 2013;48(4):835–9. Epub 2013/04/16. 295. Mee MJ, Egerton-Warburton D, Meek R. Treatment and assessment of emergency department nausea and vomiting in Australasia: a survey of anti-emetic management. Emerg Med Australas. 2011;23(2):162–8. Epub 2011/04/15. 296. Aydogdu O, Burgu B, Gucuk A, Suer E, Soygur T. Effectiveness of doxazosin in treatment of distal ureteral stones in children. J Urol. 2009;182(6): 2880–4. Epub 2009/10/23. 297. Mokhless I, Zahran AR, Youssif M, Fahmy A. Tamsulosin for the management of distal ureteral stones in children: a prospective randomized study. J Pediatr Urol. 2012;8(5):544–8. Epub 2011/11/22. 298. Tasian GE, Cost NG, Granberg CF, Pulido JE, Rivera M, Schwen Z, et al. Tamsulosin and spontaneous passage of ureteral stones in children: a multiinstitutional cohort study. J Urol. 2014;192 (2):506–11. Epub 2014/02/13. 299. Pietrow PK, Pope JCI, Adams MC, Shyr Y, Brock JWI. Clinical outcome of pediatric stone disease. J Urol. 2002;167(2 Pt 1):670–3. 300. Diamond DA, Menon M, Lee PH, Rickwood AM, Johnston JH. Etiological factors in pediatric stone recurrence. J Urol. 1989;142(2 Pt 2):606–8. discussion 19. Epub 1989/08/01. 301. Nguyen NU, Dumoulin G, Henriet MT, Regnard J. Increase in urinary calcium and oxalate after fructose infusion. Horm Metab Res. 1995;27(3):155–8. Epub 1995/03/01. 302. Taylor EN, Curhan GC. Role of nutrition in the formation of calcium-containing kidney stones. Nephron Physiol. 2004;98(2):55–63. 303. Tekin A, Tekgul S, Atsu N, Bakkaloglu M, Kendi S. Oral potassium citrate treatment for idiopathic hypocitruria in children with calcium urolithiasis. J Urol. 2002;168(6):2572–4. 304. Domrongkitchaiporn S, Khositseth S, Stitchantrakul W, Tapaneya-olarn W, Radinahamed P. Dosage of potassium citrate in the correction of urinary abnormalities in pediatric distal renal tubular acidosis patients. Am J Kidney Dis. 2002;39(2): 383–91. Epub 2002/02/13. 305. McNally MA, Pyzik PL, Rubenstein JE, Hamdy RF, Kossoff EH. Empiric use of potassium citrate reduces kidney-stone incidence with the ketogenic diet. Pediatrics. 2009;124(2):e300–4. Epub 2009/07/15.

Pediatric Renal Tumors

Elizabeth Mullen, Jordan Kreidberg, and Christopher B. Weldon

Contents Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1870 Genetics of Wilms’ Tumors and the Two-Hit Hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1871 Syndromes Associated with WTs . . . . . . . . . . . . . . . . . . 1879 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1880 Risk Stratiﬁcation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biological Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1881 1881 1881 1881 1881

Surgical Considerations in Renal Tumors . . . . . . History and Physical Exam . . . . . . . . . . . . . . . . . . . . . . . . . Laboratory Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radiographic Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . Anesthetic Evaluation and Perioperative Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1881 1882 1884 1884

Operative Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . Postoperative Course . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical Questions and Controversies . . . . . . . . . . . . . Gross Hematuria at Presentation . . . . . . . . . . . . . . . . . . . Pulmonary Metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intravascular Extension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bilateral Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Role of Partial Nephrectomy . . . . . . . . . . . . . . . . . . The Role of Laparoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . .

1888 1890 1890 1891 1892 1892 1892 1893 1894

Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1894 Special Circumstance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1894 Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1895 Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1895 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1896

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E. Mullen (*) Hematology Oncology, Dana-Farber/Boston Children’s Blood Disorders and Cancer Center, Boston, MA, USA e-mail: [emailprotected] J. Kreidberg Children’s Hospital Boston, Boston, MA, USA e-mail: [emailprotected] C.B. Weldon Department of Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA e-mail: [emailprotected] # Springer-Verlag Berlin Heidelberg 2016 E.D. Avner et al. (eds.), Pediatric Nephrology, DOI 10.1007/978-3-662-43596-0_80

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Overview Renal tumors in children occur at an incidence of almost 8 per 1,000,000 representing approximately 7 % of all childhood cancers [1]. The vast majority (>90 %) of these are Wilms’ tumors (WTs), but many other histological types of renal tumors also occur in children (Table 1). The incidence of each type of renal tumor is tightly correlated to the age of the patient. WT, most common in children under age 5, is much less often diagnosed in adolescents and young adults. An adolescent over 15 years of age with a renal tumor is more likely to have renal cell carcinoma than WT. Rhabdoid tumor of the kidney (RTK) and congenital mesoblastic nephroma (CMN) are seen almost exclusively in infants less than a year, and clear cell sarcoma almost always occurs

Table 1 Pediatric renal tumors Nephroblastomic tumors

Mesoblastic nephroma Clear cell sarcoma Rhabdoid tumor Renal epithelioid tumors of childhood

Nephroblastoma (Wilms’ tumor) Favorable histology Anaplasia (diffuse, focal) Nephrogenic rests and nephroblastomatosis Cystic nephroma and cystic partially differentiated nephroblastoma Metanephic tumors Metanephic adenoma Metanephic adenoﬁbroma Metanephic stromal tumor Favorable histology Cellular, classic, mixed

Papillary renal cell carcinoma Renal medullary carcinoma Renal tumors associated with Xp11.2 translocations Oncocytic renal neoplasms following neuroblastoma

Angiolipoma Ossisfying renal tumor of infancy A wide variety of histological types of renal tumors occur in children; the overwhelming majority (>90 %) are Wilms’ tumors

in children less than 4 years old. With current multimodality therapy, curative therapy can be provided for the majority of children with a diagnosis of favorable-histology Wilms’ tumor; however, the cure rates for children with relapsed or anaplastic WT and RTK remain unacceptably low. This chapter will touch on several pediatric renal tumors but, given the overwhelming prevalence, will focus largely on WTs. The principles of the diagnostic evaluation, surgical management, and the use of appropriate chemotherapy and radiotherapy used in WT can be generalized to some of the other less common renal tumors. Although preserved specimens of bilateral kidney tumors from a child, later identiﬁed as nephroblastoma, date from the 1700s, the most common renal tumor of childhood became inexorably tied with the name of Max Wilms, a Professor of Surgery, when in 1899, he wrote a detailed monograph describing seven children suffering from renal “mixed tumors” [2, 3]. He provided a meticulous description of the triphasic morphology of this tumor, comprised of three deﬁning components: epithelium, blastema, and stroma (Fig. 1). Also termed as nephroblastoma, the tumor became widely known as “Wilms’” tumor. It has become well recognized that WTs can have great histological diversity. Cell types seen in normal developing kidney can be present, as well as diverse elements such as adipose tissue, cartilage, skeletal muscle, and neuroglial tissue. These elements appear to arise from stromal differentiation. Epithelial differentiation can be seen with the presence of renal tubules, glomeruli, or comma and S-bodies. Tumors can be triphasic, with all three components; monophasic, with epithelial differentiation only; or biphasic, containing exclusively blastemal and stromal cells. Max Wilms also offered the important insight that all of these tumor components developed from a common undifferentiated germ cell. Along with the observation that the morphology of WT correlates with phases of normal renal development, this has helped build an understanding into the link between organogenesis and tumorogenesis in the kidney [4]. Study of this relationship has fostered understanding of the correlation between WT and a variety of renal abnormalities. It has

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Fig. 1 Gross and microscopic images of favorable histology Wilms’ tumor. (a) Gross pathologic specimen, demonstrating typical friability, pink and variegated coloration,

cystic changes, and area of hemorrhage and necrosis. (b) Classic microscopic triphasic histology of Wilms’ tumor, containing blastemal, stromal and epithelial elements

also helped elucidate the connection between the persistence of embryonic renal tissue (termed nephrogenic rests) and risk for the development of WT. The expanding knowledge of the genetics of WT has added both answers and new questions into this link.

stromal (or mixed) and whether there are mutations or altered gene expression of the Wilms’ tumor-1 (WT1), β-catenin, and/or insulin-like growth factor 2 (IGF2) genes. Although most Wilms’ tumors are sporadic and unilateral, there exist a subset that are bilateral [7, 8]. This duality is also a feature of retinoblastoma, a childhood tumor of the eye [9]. Bilateral Wilms’ tumors or retinoblastomas are typically found earlier in life than unilateral tumors. This difference led Knudsen and Strong to suggest that a “two-hit” model may explain the relatively earlier occurrence of bilateral tumors, such that children with bilateral tumors were hypothesized to have a constitutional inherited or germline mutation and an additional mutation or “hit” at the remaining functional allele will produce the tumor [10]. In contrast, the more common sporadic unilateral tumors must result from both alleles being mutated somatically, a sequence that takes longer to occur during fetal or postnatal life. The Knudsen/Strong two-hit theory has been borne out by a long history of genetic and molecular studies [10] and provides the basis for the modern concept of tumor suppressor genes. RB1 was identiﬁed as the tumor suppressor gene for retinoblastoma, and Wilms’ tumor-1 (WT1) gene was similarly identiﬁed for Wilms’ tumor [11, 12]. However, Wilms’ tumor is genetically remarkably more complicated; the WT1 gene is

Genetics of Wilms’ Tumors and the Two-Hit Hypothesis Over 90 % of Wilms’ tumors are unilateral and sporadic. Wilms’ tumors are derived from the nephrogenic mesenchyme, a tissue that is only present in the fetal kidney. As such, Wilms’ tumor presentations are almost always restricted to young children, either at birth or during the first few years of life [5]. Because the nephrogenic mesenchyme is only present in fetal kidneys, the tumor is most likely initiated before birth. “Wilms’ tumor” is in actuality a group of neoplasms that are all derived from the fetal kidney but that display variation in their histology and response to treatment. The classification of Wilms’ tumors has undergone several rounds of revisions. A recent study based on mutational analysis, transcriptional profiling, and histology of over 200 Wilms’ tumors found 4 (and possibly 5) major subtypes [6]. The primary distinguishing criteria for Wilms’ tumors include determination of whether the histology is mainly epithelial or

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lost in a minority (~10–15 %) of Wilms’ tumors [13–15]. This observation has led to a decadeslong search for additional tumor suppressor genes for Wilms’ tumor. Recently, these studies identiﬁed an X chromosome gene, WTX, as a tumor suppressor gene for Wilms’ tumor [16, 17]. Although a long history of cytogenetic and other studies suggest the presence of an additional tumor suppressor gene at the 11p15 locus, a classic tumor suppressor gene has not yet been identiﬁed at this locus [18–20].

The Identification of the Wilms’ Tumor-1 Gene Although most Wilms’ tumors are sporadic and are not accompanied by extrarenal manifestations; the study of syndromic Wilms’ tumor provided an avenue to identifying the WT1 gene. A large number of chromosomal deletions were identiﬁed on chromosome 11 in individuals with the WAGR syndrome (Wilms’ tumor, aniridia, genitourinary malformations, and mental retardation); this eventually led to the delimitation of a locus on chromosome 11p13 harboring a tumor suppressor gene for Wilms’ tumor [19, 21]. Consistent with the “two-hit theory,” constitutional hemizygosity for a tumor suppressor gene at 11p13 would predispose an individual to Wilms’ tumor, and somatic LOH (loss of heterozygosity) at 11p13 in the nephrogenic mesenchyme would result in the initiation of an oncogenic process leading to a Wilms’ tumor. Additionally, LOH at 11p13 was also apparent in individuals with sporadic Wilms’ tumor [22, 23]. These studies identiﬁed a minimal 30 kb region on 11p13 that received the moniker WT1 and as a presumptive tumor suppressor gene [24, 25]. Soon afterward, the WT1 gene was positionally cloned and sequenced independently by two groups by mapping small regions of overlap among chromosomal deletions in germline and sporadic tumors [11, 12]. Additional mutations in WT1 were then found in individuals with sporadic Wilms’ tumor [26]. The Structure of WT1 The mammalian WT1 gene contains 10 exons and encodes a 55-kDa protein, the major structural

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features of which are four zinc fingers (Fig. 1) [27]. These zinc fingers are able to bind both DNA and RNA, and in addition to its well-studied role as a transcription factor, WT1 has also been studied as a protein that may affect RNA splicing [28]. Four major splice forms of WT1 have been characterized, produced by two major alternative splicing events: one that inserts a 15 amino acid exon 5 and the other that inserts three additional amino acids (lysine-threonine-serine; or KTS) at the end of the third zinc finger. Most tissues that express WT1 express all four splice forms though at characteristically distinct ratios [29]. Alternative translational start sites are also thought to contribute to the heterogeneity of WT1 peptides, but the functional importance of alternative start sites is unknown [30, 31]. Moreover, the functional significance of exon 5 remains unclear. Even though exon 5 s conserved among higher vertebrates, there was no apparent phenotype resulting from the derivation of mice in which this exon was deleted [32]. Despite the surprising absence of a phenotype in exon 5 deleted mice, isoforms of WT1 containing exon 5 are over-expressed in Wilms’ tumor and other malignancies [33], and studies in vitro suggest a potential role in the regulation of cell survival and proliferation [34]. However, both the + KTS and –KTS forms of WT1 are required for normal development; mice able to express only the + KTS or –KTS, but not both, exhibit abnormal kidney and gonadal development [35].

Molecular Studies on the Function of WT1 in the Nephrogenic Mesenchyme The WT1 gene has been subject to extensive genetic analysis in humans. Many mutations have been found, including a large number that affect the zinc finger region. The third zinc finger region appears to represent a “hot spot” for mutations that result in significant phneotypes [13]. Mutations in WT1 are associated with two human syndromes. Denys-Drash syndrome (DDS) includes severe glomerular and gonadal dysgenesis and Wilms’ tumor [36]. Frasier syndrome is caused by an inability to splice in the KTS segment [37]; this syndrome also includes gonadal dysgenesis but not Wilms’ tumor.

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It remains a mystery why DDS includes Wilms’ tumor and Frasier syndrome does not. Perhaps this relates to the degree to which the respective causative mutations cause loss of WT1 function in kidney progenitor cells. The zinc fingers of WT1 bear homology to other Kruppel family zinc finger proteins [12], especially one named early growth response-1 (EGR1), that binds GC-rich sequences that are commonly found in the 50 regions of many genes. Therefore, most early studies that identified transcriptional targets of WT1 focused on genes that had these GC-rich elements in their promoter region (reviewed in [38]). These studies variously reported transcriptional activating or repressing functions of WT1, but many of the putative target genes were not expressed in the developing kidney and therefore of questionable relevance to the role of WT1 in the kidney. Recent studies have shed more light on the role of WT1 in kidney progenitor cells and their differentiation into nephrons. These studies may also contribute to our understanding of the role of WT1 in the biogenesis of Wilms’ tumor. A ChIP-Chip microarray approach was used by Hartwig et al. in which WT1-associated chromatin obtained by chromatin immunoprecipitation (ChIP) was used to probe the 50 regions of all genes within the murine genome [39]. Hartwig et al. identified a consensus WT1 binding site and a target gene set that included many genes known to be important for kidney progenitor cells (e.g., Pax2, Bmp7, VegfA). Moreover, components of several of the most important signal transduction pathways in development (BMP, FGF, Notch, Shh, and others) were identified as WT1 target genes, such that WT1 may regulate the output of multiple signaling processes during nephrogenesis. Many novel WT1 target genes were also identified, among them genes involved in the epigenetic regulation of gene expression. A more recent WT1 ChIP-Seq study further identified several FGF genes as WT1 targets. As FGF signaling is well known to be crucial for progenitor cell self-renewal and survival, these studies brought additional understanding to requirement for WT1 in maintaining kidney progenitor cells in the embryonic kidney [40].

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Additional mechanistic insight into the function of WT1 came from Essafi et al., whose work suggested a chromatin–switch model [41]. Wnt4, a gene essential to the mesenchymal-to-epithelial transformation (MET) in kidney development, was identified as a WT1 target gene. CTCF is a chromatin-binding protein that “insulates” or demarcates sections of chromosomes from regulatory influences outside the demarcated domain. WT1 maintained Wnt4 expression in a CTCFdelimited domain. This was demonstrated by WT1-dependent recruitment of the transactivator p300 and WT1-dependent maintenance of histone modifications consistent with transcriptionally active chromatin. In contrast, in the epicardium of the heart, Wnt4 is not expressed, despite the presence of WT1. However, unlike the kidney, in the epicardium WT1 associated with the Basp1 corepressor (instead of p300) at the Wnt4 locus. Thus, it appears that the activator versus repressor function for WT1 is context dependent [41]. It remains unknown what mechanism determines whether WT1 confers transcriptional activation versus repression and associates with p300 versus Basp1 respectively. Whether WT1 can associate with both activating and repressive complexes in the same cells, or whether in any given cell or tissue it associates with one and not the other, is an important question that remains to be answered.

Embryonic Expression of WT1 and Phenotypes of WT1 Mutant Mice WT1 expression begins in the intermediate mesoderm that gives rise to the entire urogenital system [42]. Its expression becomes localized to the mesonephric condensations and then to the metanephric mesenchyme [42–44]. As kidney development proceeds, WT1 expression localizes to the nephron progenitor population and derivative structures, primarily those that become glomerular podocytes. Notably, WT1 is expressed more broadly than Six2, a gene whose expression most clearly deﬁnes the self-renewing and committed progenitor population (see Fig. 2). Rather, WT1 is also expressed in the stroma adjacent to the progenitors though at lower levels than in progenitors. As progenitors are induced to form nephrons, WT1 expression continues in the pretubular

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Fig. 2 WT1 expression in human fetal kidney. WT1 protein is stained brown. Staining is present in the progenitor population (Pr) and adjacent stroma (St) and in pretubular aggregates (PTA) and early podocytes (Pod) (Courtesy of Dr. Valerie Schumacher)

aggregates and the renal vesicle, where its expression becomes restricted to cells that become the glomerulus [45]. WT1 is particularly highly expressed in immature podocytes and in mature podocytes throughout life. In the adult kidney, WT1 expression is entirely restricted to podocytes [44]. Wt1 was among the ﬁrst genes studied by gene targeting or “knockouts” in mice. Embryos unable to express Wt1 exhibited complete kidney and gonadal dysgenesis [46] (see Fig. 3). These mutant embryos also displayed a thin myocardium, probably due to defective or absent epicardium. This latter aspect of the phenotype caused midgestational death and resorption of most homozygous mutant embryos. In Wt1 homozygous mutant embryos the metanephric mesenchyme was transiently present at E11.5, when it ﬁrst appears as a distinct structure, but apoptotic cells were already apparent, and by E12.5, the

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metanephric mesenchyme had entirely disappeared as a distinct structure. Therefore, Wt1 does not appear to be required to specify the metanephric mesenchyme lineage [46]; rather other evidence suggests that this lineage specification involves the Eya1:Six1:Pax2 protein complex [47, 48]. Despite the initial appearance of a histologically distinct metanephric mesenchyme, the ureteric bud fails to grow out from the Wolffian duct in Wt1 homozygous mutant embryos. This is similar to several other gene knockouts that affect the viability of the metanephric mesenchyme. Ureteric bud outgrowth is primarily mediated by glial cell line-derived neurotrophic factor (GDNF). However, GDNF was not identified as a WT1 target gene in aforementioned studies (GDNF is actually regulated by PAX2). As such, the failure of ureteric bud outgrowth is probably caused by insufficient expression of GDNF by apoptotic metanephric mesenchyme [46, 49]. Further studies on the role of WT1 in nephrogenesis made use of transgenic mice derived with YACs (yeast artificial chromosomes) containing the Wt1 gene [50–52]. In the most successful YAC rescues, which were presumably those in which transgenes produced the highest levels of WT1, pretubular aggregates were present in transgenic kidneys, but these failed to undergo a successful MET to form nephrons, representing a partial rescue of nephrogenesis and suggesting that MET required higher levels of WT1 than is required to maintain viability of progenitor cells themselves [50–52]. A related phenotype was observed in conditional mutant mice, in which Wt1 was inactivated in the progenitor (cap mesenchyme) population at E13.5 [53]. In these conditionally mutant embryos, Six2-expressing progenitors persisted, but they also failed to undergo MET. How can the studies discussed above be formulated into a comprehensive model for WT1 function in the kidney progenitors and in MET? First, the identification of Pax2, VegfA, Bmp7, and other members of FGF and BMP/TGFβ

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Fig. 3 Wt1 mutant phenotype (Adapted from Armstrong et al. [42]). (a, b) E14.5 embryos; arrows show embryonic kidney in wild type (a) and missing kidney in Wt1/ (b); (c, d) E11.5 urogenital area showing ureteric bud (U ) and metanephric mesenchyme (M ) in wild type (c) and

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metanephric mesenchyme (M ) without ureteric bud in Wt1/ embryo. (e, f) High-power image of metanephric mesenchyme in wild type (e) and Wt1/ (f) E11.5 embryos. Apoptotic cells (dark fragmented nuclei) are present in Wt1/ (arrow)

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signaling pathways as targets of WT1 may explain the apoptosis of the metanephric mesenchyme in WT1 mutant embryos [39]. Additionally, the identiﬁcation of Wnt4 as an additional target gene is consistent with the observations that YAC rescued embryos and the conditional mutant embryos fail to undergo MET [41]. Nevertheless, the situation is probably more complex, and WT1 is probably orchestrating the expression of many other genes that regulate multiple signal transduction pathways involved in nephrogenesis.

Other Tumor Suppressor Genes for Wilms’ Tumor WTX and β-catenin: The ﬁnding of many mutations in the β-catenin gene (CTNNB1) in Wilms’ tumors has emphasized the role of Wnt/β-catenin signaling in the progression of Wilms’ tumor [54–58]. These mutations in CTNNB1 most typically affect the domain associated with degradation, i.e., these mutations constitutively stabilize β-catenin in the tumor [54, 58, 59]. Moreover, mutations in CTNNB1 and WT1 are often found in the same tumor and sometimes combined with mutations in the other Wilms’ tumor suppressor gene, WTX [16, 17, 58, 59]. The WTX protein antagonizes Wnt/β-catenin signaling by forming an association with a β-catenin degradation complex that promotes the ubiquitination and degradation of β-catenin [16, 60]. WTX mutations can either be found coexistent with WT1 mutations or independently of mutations in WT1 [56, 61]. Regardless, the combination of WT1 and WTX mutations still accounts for less than half of all Wilms’ tumors, suggesting that other genes and/or processes remain to be identiﬁed in the initiation and progression of these tumors [56]. Furthermore, in some Wilms’ tumors where WTX mutations have been found, they are not present in adjacent nephrogenic rests (see below) but only in the tumor, suggesting that mutation of WTX is a relatively late event in tumor formation [56, 61]. Observing both WT1 and CTNNB1 mutations in Wilms’ tumors brings forward questions of whether WT1 and β-catenin act together in normal kidney development and whether the initiation and/or progression of Wilms’ tumor involves the

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same signal transduction that regulates the growth, self-renewal, and differentiation of kidney progenitor cells during normal kidney development. WT1 and β-catenin do not appear to be components of the same transcriptional complex. However, WT1 does appear to regulate expression of CXXC5 (RINF) that in turn regulates Wnt/β-catenin signaling [62]. We may hypothesize that WT1-mediated expression of CXXC5 may modulate Wnt/β-catenin to regulate the numbers of cells undergoing MET to maintain a balance between progenitor self-renewal and nephron differentiation. The role of CXXC5 in Wilms’ tumor is not yet known. Perhaps loss of WT1 leads to decreased expression of CXXC5 that then leads to increased β-catenin transcriptional activity. 11p15: Loss of heterozygosity at 11p15 is a second long-standing observation in Wilms’ tumors, often occurring independently of any changes at 11p13 [19, 63–65]. It is intriguing that in contrast to the early success at ﬁnding a classic tumor suppressor gene at 11p13, similar searches have not been successful at 11p15. However, 11p15 is a highly studied locus as it contains the H19 and IGF2 (insulin-like growth factor 2) genes that undergo reciprocal imprinting via DNA methylation, IGF2 being expressed from the paternal allele and H19 from the maternal allele [66]. Loss of heterozygosity or loss of imprinting (LOI) at the IGF2 locusresulting in biallelic overexpression of IGF2 in the tumor is a common phenotype among Wilms’ tumors [18, 67–69]. Beckwith-Wiedemann syndrome (BWS), a fetal overgrowth syndrome where overgrowth of many organs is observed, is also associated with overexpression of IGF2 [70–72]. Indeed, embryonal-type tumors, most commonly Wilms’ tumors, are commonly observed in BWS. Moreover, although Wilms’like tumors do not develop in mice heterozygous for WT1, a Wilms’ tumor phenotype was obtained in mice by conditional mutation of WT1 and concomitant transgenic overexpression of IGF2 [53].

The Cell of Origin for Wilms’ Tumor WT1 is expressed in both Six2 progenitors and Foxd1-expressing stroma, but lineage-tracing

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studies have demonstrated that the Six2 domain deﬁnes the stem-progenitor cell in the embryonic kidney [73] and thus the Six2 pool is usually assumed to be the cell of origin for Wilms’ tumors. This assumption is challenged by a recent study in which Lin28 is overexpressed in embryonic kidneys of transgenic mice, resulting in a Wilms’ tumor-like phenotype characterized by abundant Six2-expressing cells [74]. Lin28 is expressed in stem cell (and other) populations where it affects the stability of microRNAs, particularly the Let-7 family [75, 76]. Unexpectedly, the Wilms’-like phenotype was obtained only when Lin28 was overexpressed under control of a WT1-Cre knockin. Progenitor overgrowth did not result from either Six2, Foxd1, or ureteric bud-speciﬁc Cre-directed overexpression of Lin28. The Lin28 Wilms’ tumor result suggests either that WT1 may be expressed in a pre-Six2 progenitor outside the Six2 domain that is the real Wilms’ precursor cel, or that Lin28 overexpression must occur in multiple cell types, i.e., a Six2 cell and a non-Six2-expressing cell, both of which express WT1, to obtain the Wilms’-like phenotype. Of great implications for regenerative biology of the kidney, the Wilms’ tumor-like phenotype could be reversed in these mice by terminating expression of Lin28, with subsequent differentiation of this overgrowth of progenitor-like cells, which was presumably mediated by Wnt signals from ureteric bud-like structures that accompanied this progenitor overgrowth.

Other Influences on Kidney Progenitor Cell Expansion Interactions between progenitors and surrounding stroma have come to the forefront in understanding the regulation of progenitor growth and differentiation. This ﬁrst became evident through the knockout of Foxd1, a transcription factor expressed in the stroma surrounding the cap mesenchyme that led to expansion of the Six2expressing progenitor cells [77]. The aforementioned Lin28 result may also be a consequence of Lin28 overexpression in both progenitors and stromal cells [74]. Additionally, a protocadherin Fat4, expressed by the stroma, is also required for maintaining proper boundaries of the progenitor

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domain [78]. Fat4 turns out to regulate the activity of YAP, a component of the Hippo signaling pathway, in the kidney progenitor population. Abnormal expression and activation of YAP has also recently been described in Wilms’ tumors [79]. However, in contrast to Wilms’ tumors, progenitor overgrowth in Foxd1 or Fat4 mutant mice is relatively circumscribed, indicating that loss of whatever constraint the stroma places on progenitor cells is not sufﬁcient by itself to lead to tumor formation.

The Relationship of Wilm’s Tumors to Nephron Progenitor Cells In their most basic characterization, Wilms’ tumors result from unrestrained growth and aberrant differentiation of kidney progenitor cells. In reality, this is a gross oversimplification as there is significant histological complexity to Wilms’ tumors; some tumors show an epithelial predominance and others a blastemal or mesenchymal predominance. Adding to this complexity, different tumor subtypes are known that contain cell types plausibly obtained from kidney progenitor cells but also cell types such as stroma and smooth muscle that would not be expected to derive from kidney progenitors. In addition, two distinct precursor structures are known: perilobar nephrogenic rest (PLNR) and intralobar nephrogenic rest (ILNR) [5]. As suggested by this nomenclature, PLNRs are located in the peripheral tissue of the kidney, and ILNR are located deep within the parenchyma of the kidney. WT1 mutations tend to be associated with ILNR, and LOH at 11p15 is more commonly found in PLNR [58, 68, 80]. Recently, an updated and expanded categorization of Wilms’ tumors was suggested by a study that systematically applied transcriptional profiling and mutational analysis to over 200 Wilms’ tumors [6]. Four (and possibly five) types of Wilms’ tumors were defined, shown as S1–S5 in Fig. 4. S1 was characterized by a strong epithelial component that might be derived from cells emerging after initial induction of the nephron. This class did not have mutations in WT1 (or CTNNB1 or WTX), a finding consistent with the requirement for WT1 for MET, and tumors

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S2 tumors S3 tumors S5 tumors

Wnt activation ↑IGF2 ? ILNR

ILNR ILNR or PLNR WT1 loss ↑IGF2

Intermediate mesodern

S1 tumors

Metanephric mesenchyme Post-induction early nephron

Fig. 4 A schematic of possible origins of different types of Wilms’ tumors (according to Gadd et al. [6]) (Reprinted under permission from Elsevier)

actually showed high expression of WT1. In contrast, WT1 was lost in S2 and S3 tumors that were also characterized by activating mutations in β-catenin in the former or increased expression of IGF2 in the latter. S2 and S3 tumors were associated with ILNR, and their gene expression patterns suggested that they arise from either the intermediate mesoderm or metanephric mesenchyme respectively. S5 tumors, in contrast to S2 and S3, were also suggested to be derived from the metanephric mesenchyme. However, S5 tumors show increased expression of Igf2 but did not show loss of WT1. This group was the only group with PLNR, although ILNR was also present. A smaller and less well-deﬁned S4 group was similar to S2 though with some signiﬁcant differences in patterns of gene expression. Most studies that have characterized WT1 function in kidney development have demonstrated a transcriptional activation function for WT1, with target genes including Fgf’s 8, 16 and 20, Bmp7, VegfA, and Pax2 that are required

to maintain the progenitor population [39, 40] (though in other tissues such as epicardium, WT1 acts in a repressive complex [41]). Therefore, to achieve an understanding of WT1’s role in Wilms’ tumor, we must integrate two seemingly contradictory ﬁndings: (1) WT1 has a positive effect on maintaining kidney progenitor cells, and (2) loss of WT1 leads to Wilms’ tumor, that is in some sense an uncontrolled proliferation of progenitor cells. Furthermore, some Wilms’ tumors retain expression of WT1. One possible explanation takes into account that tumors presumably arise from a single cell that has undergone LOH, but remains in the midst of cells that retain gene function. This is obviously quite distinct from the situation in Wt1 mutant mouse embryos in which all cells are devoid of Wt1 and no kidney progenitors survive. In the case of a single cell undergoing LOH, it is possible that it is “rescued” in a non-cell-autonomous manner until other changes in gene expression or in the tumor microenvironment make the tumor a selfsustaining entity.

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An alternative explanation is suggested by previously mentioned studies on WT1 conditional mutant mice. In this study, an additional signal, overexpression of Igf2, was required to obtain Wilms’-like tumors. Additionally, the role of WT1 in nephron differentiation should be considered. WT1 is not only required to maintain progenitors but also for MET and subsequent steps in nephron differentiation. In the absence of WT1, nephron progenitor cells may persist in a progenitor state, or as poorly differentiated nephrons, while continuing to proliferate and form tumors. This is consistent with the phenotype of the conditional knockout of WT1, where Six2-expressing progenitors are present though they fail to differentiate [53]. Moreover, aforementioned studies using transgenic WT1-expressing YACs demonstrated that lower levels of WT1 could rescue survival of nephron progenitor cells but was not sufﬁcient to allow these cells to progress to pretubular aggregates nor to form nephrons [50, 52].

Conclusion A potential model for the formation of Wilms’ tumors that synthesizes current knowledge would suggest that low expression of WT1 maintains progenitors but does not allow their differentiation into nephrons. In those tumors that have lost expression of WT1, these cells may either represent early blastemal cells similar to those that are brieﬂy present in Wt1 mutant embryos at E10.5 before they undergo apoptosis or, alternatively, that harbor other mutations such as those that increase expression of Igf2 due to loss of imprinting or perhaps increase expression of Lin28, as well as mutations that prevent degradation of β-catenin, that together allow progenitors to maintain their viability independently of WT1.

Syndromes Associated with WTs As previously mentioned in the discussion of the identiﬁcation and cloning of the WT1 gene, ten to ﬁfteen percent of WTs occur in children with recognized malformations, including hemihypertrophy, cryptorchidism, hypospadias, or

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in association with a recognizable genetic syndrome [81].

WAGR Syndrome (WT, Aniridia, Genitourinary Malformation, Mental Retardation Syndrome [21, 82, 83]) WAGR syndrome is caused by a microdeletion at 11p13 that deletes both WT1 and Pax6 [82, 83]. WAGR is associated with aniridia in all cases resulting from hemizygosity for Pax6 [84–86] but is variably associated with WT (50 % risk of WT) [87] and genitourinary malformations due to hemizygosity for WT1. WAGR is also variably associated with mental retardation and congenital heart disease; however, the gene(s) on 11p13 responsible for these defects have not been identified [88]. Denys-Drash, Frasier and BeckwidthWiedeman Syndromes DDS includes the triad of WT (90 % risk of WT development) [36, 89], genitourinary malformations, and nephropathy (mesangial sclerosis), but various combinations of these features have been reported [13, 90, 91]. DDS is caused by intragenic WT1 point mutations that either eliminate or alter the structure of the zinc finger region. The most common mutation is an arginine-to-tryptophan transition in exon 9 (Arg 394) or other missense alterations in the zinc finger domains encoded by exons 8 and 9 [4, 92]. The increased severity of kidney disease associated with DDS, as compared with WAGR, raises the possibility of a dominant-negative effect that is mediated by dimerization of mutant and wild-type proteins through their N terminal domains [93, 94]. Frasier syndrome bears similarity to DDS and is characterized by gonadal dysgenesis, often resulting in XY sex reversal in males [4], progressive glomerular nephropathy (focal segmental glomerulosclerosis) [95], or gonadoblastoma. Interestingly Frasier syndrome (FS) [37, 96] much less commonly (less than 5 %) includes WTs among its features. FS is caused by mutations in intron 9 of WT1 that affect splicing and prevent expression of the + KTS isoforms of WT1 (discussed below) [37, 96]. Beckwith-Wiedemann syndrome (BWS) is the most common WT-associated condition, affecting

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1 in 13, 000 children, and is probably related to a large degree to LOI at 11p15 [64, 97, 98], resulting in hyperexpression of IGF2. BWS is characterized by prenatal overgrowth and increased incidence of embryonal tumors of liver (hepatoblastoma), muscle (rhabdomyosarcoma), and kidney. This syndrome carries a 10 % risk of WT [99]. While the genetics of WT formation in BWS is not completely understood, at least 20 % of BWS patients exhibit paternal uniparental disomy for 11p15 that contains the IGF2 and H19 imprinting locus strongly associated with sporadic WT [64], and these children have a high risk (64 %) of developing embryonal tumors [98]. In addition, familial BWS is linked to chromosome 11p15 [20]. A third, unidentiﬁed tumor suppressor gene on 11p15 has been linked to rhabodomyosarcoma [100], suggesting that at least three genes on 11p15 may predispose to growth abnormalities and WT as well as other embryonal tumors. Other genetic syndromes associated with increased incidence of WT [101, 102] include Simpson-Golabi-Behmel syndrome (linked to Xp26) [103–106], Perlman syndrome [107–110], Sotos syndrome (linked to 5q35) [111, 112], and Bloom’s syndrome (linked to 15q26) [113, 114].

Familial Wilms’ Tumor True familial WT is extremely rare, accounting for only 1–2 % of all cases [10], suggesting that de novo germline mutations rather than familial transmission of a mutant allele underlie the genetic predisposition [4]. In addition, reduced fertility may be associated with germline mutations in genes that regulate urogenital development [99]. The low number of familial cases may reﬂect the historic lethality of this cancer before individuals with tumors reached reproductive age. With the advent of effective therapy in the past few decades, such that most individuals with WTs survive to adulthood, it will be important to observe in the future whether familial cases become more common in the population. Two familial WT genes have been mapped – FWT1 (Familial WT 1 locus; also known as WT4) at 17q12-21 [115] and FWT2 at 19q13.4 [116], but

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neither gene has been identiﬁed. In addition, familial cases unlinked to any previously identiﬁed loci have been reported, indicating that other familial WT genes may exist [117].

Treatment The modern-day treatment of WT is a paradigm of the success of multimodality management, as well as testament to the importance of collaborative national and international studies in pediatric cancer. Clinical trials which led to identiﬁcation of active chemotherapy agents, as well as appreciation of the radiosensitivity of WT, along with advances in surgical techniques and postoperative care, have led to remarkable improvement in the outcomes of children with WT. A universally lethal disease at the turn of the nineteenth century, survival increased to about 25 % with surgery only in the early 1900s; the use of routine postoperative radiation therapy resulted in an almost 50 % survival rate in the 1950s; the discovery of the effectiveness of chemotherapy drugs (initially vincristine and actinomycin) increased survival to the 70–80 % range in the 1970s [118]. Further improvements in both the overall outcome of patients with renal tumors and a decrease in overall toxicity through limiting exposure to unnecessary therapy for low-risk patients have come about through the work of large collaborative groups. Although many groups have made important contributions, the two largest are the International Society of Pediatric Oncology (SIOP) and the National Wilms Tumor Study Group (NWTS.), which was supplanted by the Children’s Oncology Group (COG) in 2002. Although these two groups (SIOP and NWTS/COG) have fundamentally different approaches to the treatment of WT, both have strategies which have resulted in overall survival (OS) rates approaching 90 % [119–121]. SIOP therapies have been based on prenephrectomy chemotherapy, and NWTS/ COG approach has advocated upfront nephrectomy in almost all cases. Although outcome from each approach has been excellent, it is difﬁcult to extrapolate improvements in therapy from

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one group to the other, given the confounding variable of the surgical timing, as the divergence in the approach results in differences in staging and therapeutic stratiﬁcation systems.

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risk (blastemal or diffuse anaplasia), intermediate risk (regressive, stromal, mixed, epithelial, or focal anaplasia), and low risk (completely necrotic or cystic partially differentiated).

Age

Risk Stratification Staging The treatment of WT is stratified according to the risk of relapse of the tumor, with lower-stage and favorable-histology tumors receiving less intensive therapy than higher-stage, unfavorable-histology tumors. Known prognostic factors, such as age of the patient, size of the tumor, stage, histology, and genetic findings, are used to riskstratify the patients. NWTS/COG staging is based on anatomical staging at presentation; SIOP staging is based on postchemotherapy findings. A comparison of the two systems is presented in Table 2.

Histology The most powerful prognostic factor for outcome in WT is the histology of the tumor. NWTS and COG define WT as favorable histology (FH) if anaplasia is not identified (Fig. 5). Anaplasia may be focal or diffuse and is defined by the presence of large mitotic figures, large and bizarre nuclei, and hyperchromasia (Fig. 5). Anaplasia is associated with worse outcome [122, 123] and merits intensification of therapy. Patients with low-stage focal anaplasia do better than those with diffuse anaplasia [124, 125]. Rhabdoid tumor of the kidney (Fig. 6) and clear cell sarcoma were initially believed to be subsets of unfavorable histology of WT but are now understood to be completely distinct tumor types [124, 126]. SIOP bases its histological classification of WT largely on response to therapy. A revised working classification of all renal tumors was developed by SIOP in 2001 [127] (Table 3). WTs are classified into three risk groups: high

Increasing age has been shown to be correlated with decreased prognosis by both cooperative groups [128, 129]. Age is used by COG as a prognostic factor, along with tumor size. A subset of patients less than 2 years of age with tumors less than 550 g have been shown to do well with nephrectomy only [130, 131]. Adult event-free survival rates of WT have been shown to be lower than WT in pediatric patients but may be confounded by greater toxicity of treatment seen in adults [132–134].

Biological Factors As with other tumors, there is much interest in identifying biological factors that correlate with prognosis. Combined LOH of 1p and 16q was found to be a significant adverse prognostic factor in the fifth NWTS trial [135] and was used prospectively to risk-stratify patients on the first generation of COG renal tumor protocols. Patients with LOH of 1p and 16q were treated with intensification of therapy and were found to have improved eventfree survival (EFS) and overall survival (OS) [136]. 1q has also been identified as an adverse prognostic factor in FHWT in a cohort of patients on NWTS 4 [137] and validated to be independent of stage in a cohort from NWTS 5 [138].

Surgical Considerations in Renal Tumors Surgery was the ﬁrst modality used in the treatment of renal tumors, and it continues to be of critical importance today. Regardless of tumor type or multimodality treatment protocol, surgery serves as the mainstay to achieve local control of, histopathologically assess, and anatomically stage children with renal tumors.

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Table 2 Staging systems for pediatric renal tumors Stage I

COG (before chemotherapy) (a) Tumor is limited to the kidney and completely excited (b) The tumor was not ruptured before or during removal (c) The vessels of the renal sinus are not involved beyond 2 mm (d) There is no residual tumor apparent beyond the margins of excision

(a) Tumor extends beyond the kidney but is completely excised (b) No residual tumor is apparent at or beyond the margins of excision (c) Tumor thrombus in vessels outside the kidney is stage II if the thrombus is removed en bloc with the tumor. Although tumor biopsy or local spillage confined to the flank were considered stage II by NWTSG in the past, such events will be considered stage III in COG studies Residual tumor confined to the abdomen (a) Lymph nodes in the renal hilum, the periaortic chains, or beyond are found to contain tumor (b) Diffuse peritoneal contamination by the tumor (c) Implants are found on the peritoneal surfaces (d) Tumor extends beyond the surgical margins either microscopically or grossly (e) Tumor is not completely respectable because of local infiltration into vital structures

III

Presence of hematogenous metastases or metastases to distant lymph nodes

Bilateral renal involvement at the time of initial diagnosis

SIOP (after chemotherapy) (a) The tumor is limited to kidney or surrounded with fibrous pseudocapsule if outside of the normal contours of the kidney. The renal capsule or pseudocapsule may be infiltrated with the tumor but does not reach the outer surface and is completely resected (resection margins “clear”) (b) The tumor may be protruding into the pelvic system and “dipping” into the ureter (but it is not infiltrating their walls) (c) The vessels of the renal sinus are not involved (d) Intrarenal vessel involvement may be present (a) The tumor extends beyond kidney or penetrates through the renal capsule and/or fibrous pseudocapsule into perirenal fat but is completely resected (resection margins “clear”) (b) The tumor infiltrates the renal sinus and/or invades blood and lymphatic vessels outside the renal parenchyma but is completely resected (c) The tumor infiltrates adjacent organs or vena cava but is completely resected (a) Incomplete excision of the tumor which extends beyond resection margins (gross or microscopic tumor remains postoperatively) (b) Any abdominal lymph nodes are involved (c) Tumor rupture before or intraoperatively (irrespective of other criteria for staging) (d) The tumor has penetrated though the peritoneal surface (e) Tumor implants are found on the peritoneal surface (f) Tumor thrombi present at resection margins of vessels or ureter, transected or removed piecemeal by surgeon (g) The tumor has been surgically biopsied (wedge biopsy) prior to preoperative chemotherapy or surgery Hematogenous metastases (lung, liver, bone, brain, etc.) or lymph node metastases outside the abdominal-pelvic region Bilateral renal tumors at diagnosis. Each side should be substaged according to the above criteria

NWTS/COG and SIOP staging systems differ mostly in timing of staging, prior to chemotherapy versus after chemotherapy

History and Physical Exam Children with renal masses frequently present asymptomatically and are often diagnosed either by the caregiver during a routine activity (bathing)

or by the healthcare professional on a well-child visit. Often the child can appear very well, and the diagnosis can be surprising to the parents and healthcare professionals. Patients can also present with symptoms of hematuria or with

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Fig. 5 Anaplasia in Wilms’ tumor. Microscopic-view anaplasia in Wilms’ tumor. (a) There is diffuse nuclear enlargement, at least three times normal size (compare

with tumor cells in top center), with marked pleomorphism. (b) Abnormal, enlarged mitotic ﬁgures reﬂect an increased DNA content

Fig. 6 Rhabdoid Gross and Microscopic Images. (a) Rhabdoid tumor of the superior pole with extrarenal extension extending to Gerota’s fascia. The tumor ruptured the renal capsule and formed a desmoplastic neocapsule seen at the superior portion of the specimen. There was extensive microscopic extension into the renal sinus vein. (b) Microscopic appearance of a rhabdoid tumor. The tumor cells are frequently discohesive with vesicular nuclei and

prominent nucleoli. The nuclei are often indented by an eosinophilic cytoplasmic inclusion composed of whorled aggregates of intermediate ﬁlaments. Rhabdoid tumors are characterized by a loss of chromosome 22q11.2 in an area involving the INI1 gene. The inset is an immunohistochemical stain for INI1 demonstrating retention in normal renal tubular cells (right) and loss in the tumor cells (left)

gastrointestinal complaints, most often constipation. Findings of an abnormal hemogram or urinalysis testing or unexplained hypertension are not uncommon in both symptomatic and asymptomatic patients. Any of these ﬁndings should prompt a thorough abdominal exam and consideration of abdominal imaging.

Surgical consultation is warranted from the time of diagnosis. Once the presence of a mass is conﬁrmed, additional history of associated medical problems that might compromise therapy or predispose the child to risks of peritreatment morbidity should be established. History should include any evidence of developmental delay or

1884 Table 3 Revised S.I.O.P. working classification of pediatric renal tumors A. For pretreated cases I. Low-risk tumors Mesoblastic nephroma Cystic partially differentiated neproblastoma Completely necrotic nephroblastoma II. Intermediate-risk tumors Nephroblastoma – epithelial type Nephroblastoma – stromal type Nephroblastoma – mixed type Nephroblastoma – regressive type Nephroblastoma – focal anaplasia III. High-risk tumors Nephroblastoma – blastemal type Nephroblastoma – diffuse anaplasia Clear cell sarcoma of the kidney Rhabdoid tumor of the kidney B. For primary nephrectomy cases I. Low-risk tumors Mesoblastic nephroma Cystic partially differentiated nephroblastoma II. Intermediate-risk tumors Nonanaplastic nephroblastoma and its variants Nephroblastoma – focal anaplasia III. High-risk tumors Nephroblastoma – diffuse anaplasia Clear cell sarcoma of the kidney Rhabdoid tumor of the kidney

unusual growth patterns that may be consistent with predisposing genetic syndromes, as well as any possible history of bleeding disorders in the patient or the family. The accurate assessment of vital signs cannot be overstated. The degree of hypertension in these children can be signiﬁcant, and this may change the perioperative anesthetic management. The degree of thoracic and abdominal compromise from the mass should also be investigated thoroughly to determine the anesthetic and operative risk for the patient as well. Despite very large masses, most children do not have signiﬁcant respiratory embarrassment at presentation unless there is considerable metastatic pulmonary disease. Documenting the resting respiratory rate, decreased or absent breath sounds, and presence of effusions or consolidative

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processes is important. The abdominal exam should focus on the site of the mass and any evidence for involvement of the contralateral side. The presence of ascites should also be considered. A genitourinary exam is also important to investigate the presence of hernias, hydroceles, or varicolceles that may give indications about the size, location, and vascular structures affected by the mass. Tenderness on exam should also alert the physician to the presence of tumor hemorrhage or rupture with subsequent peritoneal irritation.

Laboratory Evaluation Baseline laboratory studies include urinalysis, complete blood count with differential, chemistry proﬁle, liver function tests, coagulation proﬁle, and blood typing for possible transfusion during surgical intervention. An association of WT and von Willebrand disease is well established and should be investigated preoperatively [139, 140].

Radiographic Evaluation Radiographic studies consist of plain radiography and axial imaging. Abdominal and chest radiograph series are procured to evaluate the presence of disease and associated ﬁndings of ascites, effusions, consolidative processes, or the suggestion of metastatic disease. These studies are followed by either computed tomography (CT) (Fig. 7) or magnetic resonance (MR) (Fig. 8) imaging techniques with axial, coronal, and sagittal formatting to enable three-dimensional reconstruction and hence the adequate documentation of tumor size, location, organ invasion, intravascular involvement, lymphadenopathy, the presence of contralateral disease, the presence of a solitary kidney, horseshoe kidney, or other anatomic variant, the presence of metastatic disease, and the suggestion of tumor spillage or rupture at diagnosis. Furthermore, one must make sure that the tumor in question truly arises from the kidney and not from simply the retroperitoneum or an adjacent organ

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Fig. 7 CT images (axial (a) and coronal (b)) showing left renal mass with renal vein and IVC extension with evidence of pulmonary metastasis (c)

(germ cell tumor, sarcoma, or neuroblastoma). Differentiating this fact can be difﬁcult, especially with neuroblastoma, but with primary renal tumors the parenchyma is splayed out around the mass (“claw sign” (Fig. 9)) as opposed to simply being compressed or indented. Delayed sequences can also be ordered to evaluate for the presence of tumor within the collecting system (MR or CT ureterogram). Ureteral involvement can also be documented on an intravenous pyelogram. One has to consider the risk of radiation-induced malignancy when contemplating which exam to order (CT vs. MR) [141], but accurate preoperative planning must take precedence over the concern for secondary malignancies if there is any question. A comparison of preoperative CT or MRI for patients with WT supported either as a reasonable for preoperative imaging [142]. Both CT and MRI were found to have high speciﬁcity, with relatively low sensitivity for detection of local lymph node metastasis

and capsular penetration. The study concluded that the choice of imaging modality for initial staging of WT should be based on institutional expertise, with the primary consideration of specific clinical information being sought from the study, and in addition, consideration of radiation exposure and need for sedation. The identification of preoperative rupture is clinically important information. A COG study retrospectively evaluated the diagnostic performance of CT in identifying the presence or absence of preoperative Wilms’ tumor rupture, using rupture found at surgery as the standard. The study concluded that CT has moderate specificity but relatively low sensitivity in the detection of preoperative rupture, with ascites beyond the cul-de-sac the most sensitive finding factor predictive of rupture [143]. Adjuvants to CT and MRI include vascular ultrasonography (US) that is probably more sensitive for diagnosing inferior vena cava and renal vein involvement. If renal vein and/or IVC

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Fig. 8 MRI bilateral nephroblastoma. (a) [T1] and (b) [T2] at diagnosis showing bilateral masses. After 2 months of chemo Rx masses have decreased in size (c) [Coronal T2], (d) [Axial T2], and (e) [Axial T1]

involvement is discovered, then further studies may be warranted to document the degree of tumor thrombus progression including the presence of atrial (echocardiogram) or suprahepatic vein IVC involvement (MR or CT venogram). Furthermore, US is also an excellent modality to investigate the kidney parenchyma to better deﬁne the architecture and assist in deﬁning the characteristics of the mass and the contralateral kidney. Nuclear imaging studies do not have a role in

these patients except to possibly document the baseline glomerular ﬁltration rate and renal function contributed by each kidney in anticipation of a nephrectomy. However, these tests are seldom performed preoperatively and often do not change preoperative management of the patient. A bone scan (Fig. 10) may be ordered to document the presence of bony metastasis if the mass is thought to be a clear cell sarcoma of the kidney. Bone scan is not routinely done in WT. A CT of the brain is

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Fig. 9 CT images (a) [axial], (b) [axial], and (c) [coronal] of right renal mass with evidence of a “claw sign” (white arrow) and with extension into the renal pelvis/proximal ureter causing obstruction

Fig. 10 CT images (a) [bone window] and (b) [abdominal window] showing intraspinal extension of tumor and bone metastasis, (c) (axial) and (d) (coronal) display

corresponding o bone scan images, and (e) CT coronal image shows extent of intraspinal spread

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recommended to evaluate for metastasis in renal rhabdoid tumors and clear cell sarcoma and can be considered in renal cell carcinoma but not in other variants as the other tumors are not prone to neural involvement at time of diagnosis. Finally, special attention should be considered for renal masses that do not ﬁt the classical radiological description of known lesions as they may be pseudotumors. An excellent review has recently been published by Malkan and colleagues [144]. Careful multidisciplinary review should be undertaken in these cases to ensure the risks of a renal malignancy are balanced by the need for renal parenchyma preservation.

Anesthetic Evaluation and Perioperative Considerations Once the child has been properly assessed and evaluated, primary resection as opposed to biopsy and neoadjuvant chemotherapy is espoused by most North American centers. This pathway differs from the regimens proposed by SIOP, and this issue will be discussed in greater detail below. Prior to surgery, anesthetic preparation concerning the child’s pulmonary function, renal function, degree of anemia and hypertension, and the extent of the planned resection is performed. Discussions between the surgical team and the anesthesia team are critical to assess the risk of hemorrhage and the probable conduct of the operation. An intra-arterial line is of vast importance for hemodynamic monitoring and arterial blood gas sampling during the operation to ensure optimal respiratory function. A nasogastric tube and transurethral bladder drainage catheter (“foley” catheter) are inserted as well to drain the gut and to monitor urine output. Furthermore, gross hematuria can also be assessed during the operation with the use of a transurethral bladder catheter. Several intravenous lines are also placed in the upper extremities for rapid ﬂuid administration and resuscitation during the operation, and the largest bore intravenous catheters that can be placed are recommended. Furthermore, the lower extremities are avoided as IV sites if possible, so as to ensure resuscitation can proceed in the event

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that the IVC is clamped during the operation. Previously typed blood products should be available in the operating room prior to beginning the operation. Finally, an epidural catheter or other regional analgesic technique (paravertebral catheter) is recommended for intraoperative hemodynamic stability and postoperative pain management. These catheters blunt the body’s physiological response to the operative insult by controlling the sensation of pain from the beginning of the case. The patient’s hemodynamics are generally more stable with fewer swings in the patient’s blood pressure and heart rate. Furthermore, with the incisional pain blunted postoperatively by these techniques, the patient can usually be extubated at the end of the operation assuming that there were no intraoperative complications and hemorrhage was kept to a minimum. These adjuvant analgesic techniques can then be used in the postoperative period for all analgesia needs, and it can remain in until there is return of bowel function and an oral pain regimen can be started (usually within 5–7 days).

Operative Considerations The operation then begins with the child positioned either supine or slightly raised on an ipsilateral flank roll to 15–20 of elevation from the operating room table. These positions afford the greatest exposure to the abdomen – retroperitoneal and intraperitoneal spaces. A report from the NWTSG documented the importance of the type and size of the incision with which to remove the involved kidney without subsequent rupture or intraoperative complications [145]. A generous transverse or bilateral subcostal incision is generally recommended as opposed to flank or paramedian incisions secondary to the higher reported rates of rupture of the tumors [145]. Furthermore, an ipsilateral thoracoabdominal incision centered over the greatest diameter of the mass to ensure adequate exposure to the entire retroperitoneum and adjacent chest cavity can also be employed. This latter approach allows for a wide field of view via the abdominal portion of the incision, and the thoracic extension of the

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incision provides the unique exposure to the retroperitoneum superiorly and posteriorly where the tumor is most likely to be adherent to the diaphragm and surrounding soft tissues. Furthermore, the entire IVC can be exposed (right-sided tumors) for adequate proximal and distal control if a caval or renal vein thrombectomy is needed, or for left-sided tumors the incision can be carried over to the right anterior superior iliac spine to allow for adequate exposure of the IVC from the left side. At the conclusion of the operation, a thoracostomy tube may be required but not always as the pneumothorax can usually be evacuated without issue. Regardless of the type of incision, upon entering the abdomen, a peritoneal survey is conducted to look for evidence of occult metastatic disease. The entire peritoneal surface is palpated, as is the liver and contralateral kidney. Any free fluid is removed and sent for cytology, especially if there is evidence of rupture. Once these maneuvers are performed, the ipsilateral colon is mobilized and brought to the center via the medial visceral rotation technique. Care should be taken to define the tissue planes appropriately so as not to injure the colonic mesentery or to dissect too closely to the renal capsule so as to increase the risk of inadvertent perforation. Early recommendations had advocated dissecting the hilum first to gain vascular control, but this led to increased intraoperative hemorrhage and other morbidities. It is now recommended to defer the renal hilar dissection until the kidney has been fully mobilized and the renal pedicle is easier and safer to manipulate, isolate, and divide. The kidney and tumor should be circumferentially dissected off the retroperitoneal structures. The ipsilateral adrenal gland is often removed as well. Utmost care must be taken so as not to injure the tumor capsule and allow for iatrogenic rupture and tumor spillage. A generous margin of soft tissue should be included with the kidney and mass if needed and possible to decrease the risk of perforation. This may even necessitate removing a portion of the diaphragm. Prior to dividing the renal vein, directly palpate the renal vein and IVC to ensure there is no tumor thrombus. If present, then complete resection of all tumor including a caval thrombectomy is in order so as to not cut across

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the tumor and create iatrogenic intraperitoneal spillage. If the mass on exploration is too extensive as to require adjacent organ resection (colon, spleen, liver, etc.) or intravascular involvement precludes safe tumor thrombectomy, then only a biopsy of the mass should be performed and adjuvant therapy begun prior to formal resection and local control. If the kidney and tumor can be removed, then the ipsilateral lymph nodes should be sampled so as to adequately stage the tumor, regardless of histopathological type. The lymph node areas involved should be hilar, paraaortic, and paracaval. A formal retroperitoneal lymph node dissection is neither warranted nor indicated as earlier studies have confirmed [146]. All renal tumor types necessitate lymph node sampling, though data are only available for nephroblastoma. Studies conducted through NWTSG have shown that gross inspection of the lymph nodes by the operative surgeon is not adequate to define lymph node involvement in nephroblastoma [147]. Inadequate lymph node sampling has led to understaging patients and hence undertreatment with an increased incidence of local recurrence as demonstrated in NWTSG 4 [145]. Finally, the ureter should be transected as close to the bladder as possible without forming a diverticulum or outpouching that can then serve as a source of infection. Generally, the ureter is carefully traced to the pelvic rim and dissected anteriorly to the junction with the bladder and then transected where convenient. Palpation of the ureter should also take place prior to transaction to ensure there is no intraureteral tumor involvement. If the ureter is transected across tumor, then it is considered spillage with subsequent possible upstaging of the tumor and resultant increased therapy. Cystoscopy and ureteroscopy (or retrograde ureterograms) are only advocated for those with preoperative gross hematuria to define the possibility or bladder or ureter involvement [148]. At the conclusion of the operation, and under the same anesthetic, consideration should be given to the placement of an intravenous vascular access device for adjuvant therapy where appropriate. An intraoperative frozen section can be performed on the tumor prior to abdominal

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closure to determine the histopathological subtype. Once known, a discussion between pathologist, oncologist, and surgeon should be held to determine the need for adjuvant chemotherapy. If the tumor type is amenable to chemotherapy, then permanent vascular access should be placed at the same operative setting. If there is any doubt about the diagnosis or if the tumor is not amenable to adjuvant therapy (renal cell carcinoma), then the placement of a vascular access device is deferred. Finally, in those children younger than 2 years of age and with small tumors (10 cm), had extensive IVC involvement (above the hepatic veins and into the right atrium), and required resection of adjacent organs should all undergo biopsy and neoadjuvant chemotherapy prior to resection for local control. These studies also pointed out that resections performed through suboptimal incisions (flank or paramedian laparotomy) and by nonpediatric specialists were also at greater risk of intraoperative perforation and spillage and increased morbidity [145, 157]. A COG study of patients enrolled on the Renal Tumor Biology and Risk Classification Study AREN03B2 determined that intraoperative tumor spill occurs in about one out of every ten cases of primary nephroureterectomies for Wilms’ tumor and that right-sided and larger tumors are at higher risk of intraoperative rupture [158]. Tumors that appear to have perforated with free intraperitoneal spillage at diagnosis may also warrant biopsy to confirm the pathological diagnosis and then neoadjuvant chemotherapy. The technique of biopsy, percutaneous versus open, has also been an area of debate and study [159]. Biopsies performed via a percutaneous core needle technique increase the risk of discordant pathology and seeding of the needle tract. Open biopsy with lymph node sampling at the time of diagnosis is another method that has traditionally been used. Based on results of NWTS studies demonstrating that patients undergoing any type of prechemotherapy biopsy had higher rates of relapse, all patients undergoing initial biopsy will be considered stage III in the COG staging system [160].

Gross Hematuria at Presentation Ureteral extension of nephroblastoma is a rare phenomenon present in only 2 % of cases in a recent NWTSG review [148]. This correlates with the few reports in the literature to date.

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In reviewing the NWTSG reports, the authors found that of the cohort of children with ureteral involvement, 49 % had evidence of gross hematuria. This symptom serves as a significant clue to the presence of tumor extension into and through the collecting system, and hence, due diligence should be undertaken by the treating medical personnel. Preoperative imaging studies may find evidence of ureteral tumor thrombus in almost 63 % of patients, and CT was the most helpful modality. Prior to resection, however, cystoscopy, retrograde ureterograms, and direct palpation of the ureter to determine the presence of tumor thrombus are all warranted so as to define the extent of disease and have a complete resection. If the tumor thrombus is inadvertently missed and transected at surgery, then this would be considered intraoperative tumor spillage with subsequent tumor upstaging.

Pulmonary Metastases Patients with WT and pulmonary metastasis have been shown to do better with intensiﬁed chemotherapy with or without radiation therapy [161–163]. Although centers have recommended primary pulmonary metastasectomy to spare the morbidity of expanded therapy [162, 164], the NWTSG has demonstrated the superior efﬁcacy of chemotherapy and radiotherapy over chemotherapy and surgery, regardless of pathological subtype [165, 166]. Green and colleagues demonstrated that pulmonary metastasectomy did not have an effect on outcome in patients treated on NWTS 1–3 studies. The SIOP approach to patients with pulmonary disease, however, does include possible pulmonary nodule resection. Patients are treated with 6 weeks of upfront therapy, and if the lung nodules respond completely to chemotherapy, or are surgically resected, the patients are treated without lung radiation, with good overall survival [167]. Ehrlich and colleagues demonstrated the importance of pretreatment biopsy of pulmonary lesions not radiographically consistent with metastatic disease as critical to avoiding overtreatment of children who may have other reasons for small pulmonary lesions [168].

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Intravascular Extension A minority of children present with evidence of intravascular involvement with nephroblastoma (4 %) [169]. Diagnosis includes a combination of axial imaging (CT and/or MR) in addition to ultrasonography, including echocardiography to establish atrial involvement if warranted. Surgical extirpation of all disease – including the entire thrombus – is recommended. Furthermore, if all intravascular disease can be resected, there is no change in prognosis [170]. However, recommended timing of the resection has changed. An upfront resection followed by adjuvant therapy was initially recommended, but it has too great a morbidity in comparison to neoadjuvant chemotherapy and subsequent nephrectomy [145, 171]. A recent report from NWTSG documented the success of this approach and the clear ability of neoadjuvant chemotherapy to safely facilitate the subsequent nephrectomy and thrombectomy [169]. Speciﬁcally, the surgical morbidity was reduced by 50 % (26–13 %) with neoadjuvant chemotherapy, and the most severe complications occurred in the upfront surgery cohort.

Bilateral Disease Bilateral renal mass in children has been deﬁned as stage V disease. Diagnosis and staging of these patients is similar to those children who present with unilateral disease save for the overriding mandate to save renal parenchyma. Whereas North American and European centers have differed on the management of unilateral disease (neoadjuvant chemotherapy vs. upfront resection), a common pathway has emerged in the treatment of children with bilateral disease. The goal of treatment in this cohort of children has been renal preservation to avoid the need for permanent renal replacement therapy. The current Children’s Oncology Group protocol mirrored SIOP’s approach and discouraged pretreatment biopsies (open or percutaneous). However, if tumors do not respond to neoadjuvant chemotherapy, then biopsy is recommended to ensure

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concordant histopathological results and adequate chemotherapeutic regimens. Discordant tumors (unfavorable on one side and favorable on the other side) exist, and if missed, this scenario can allow for the undertreatment of the patient. Ideally, after neoadjuvant chemotherapy (threedrug regimen assuming favorable histology), successful partial nephrectomies can be performed. The NWTSG evaluated this cohort of patients in NWTSG-4 [172], and total gross resection of disease was accomplished in 88 % of cases. However, there was a higher percentage of both local recurrence (8 %) and positive margins (16 %) in this cohort. These results were deemed acceptable secondary to a substantial, successful partial nephrectomy rate (72 %) and overall survival (81 % at 4 years). The success of this pathway was also echoed by other authors [173].

The Role of Partial Nephrectomy Nephron-sparing surgery for unilateral nephroblastoma has not been adequately studied using prospective, randomized trials. Data amassed from the cohort of patients with bilateral tumors has shown this surgical extirpative modality to be an effective procedure when married to pretreatment biopsy and neoadjuvant chemotherapy (see prior section on Bilateral Tumors). The dominant philosophy when dealing with the children with bilateral tumors is to preserve renal parenchyma and avoid permanent renal replacement therapy. Pursuant to this goal, several groups [174–176] have attempted to apply parenchymal sparing surgery to unilateral disease recognizing the long-term morbidity of radical nephrectomy for unilateral tumors, including other renal injury (trauma, infection, obstruction), decreased glomerular ﬁltration rate and the onset of renal failure, and metachronous nephroblastoma in the contralateral kidney. Haecker and colleagues evaluated their cohort of patients undergoing partial nephrectomy in nephroblastoma and recommended that it only be used for patients with small, favorable-histology tumors after neoadjuvant chemotherapy [175]. There was a higher local recurrence rate in the partial

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nephrectomy cohort, as well as a lower survival in unfavorable-histology tumors. Hence, the authors concluded that partial nephrectomy is feasible in small lesions, histologically favorable tumors that responded to neoadjuvant chemotherapy. Linni and colleagues published their result in analyzing the role of partial nephrectomy in unilateral nephroblastoma and recommended that this approach is not ready for universal application [176]. However, they did stress that in specific cases it is reasonable to consider partial nephrectomy if the tumor decreases by 50 % or greater in volume after neoadjuvant chemotherapy, if the tumor is easy to resect (unipolar lesion), if preservation of greater than 50 % of the kidney remains after resection, and if there are pathologically negative para-aortic lymph nodes. Results of the UKW-3 trial have been reported by Arul and colleagues, addressing the feasibility of unilateral, partial nephrectomy in a cohort of patients with favorable-histology nephroblastoma [174]. The study attempted to determine the ability of the surgeon to adequately define the resection plane (“marking”) on the nephrectomy specimen ex vivo in light of the following criteria: (1) clear resection margins, (2) no vascular invasion, (3) no pelvic invasion, and (4) >50 % of the kidney preserved. The study was unsuccessful as there were no specimens officially “marked,” but of the specimens identified by the surgeon as being a candidate for partial nephrectomy, 70 % were deemed pathologically not to meet the above criteria to be eligible for a partial nephrectomy. However, whereas intraoperative ultrasound was not available during this study 18 years ago, it may facilitate partial nephrectomy by defining the proper plane of dissection today and is recommended by the author a routine manner of practice (CBW). A COG study of patients enrolled on the Renal Tumor Biology and Risk Stratification Study AREN03B2 identified as Very Low Risk (patients with FHWT, age < 2 years, tumor weigh 110/66 >119/71 104/63 113/67 >115/76 >125/80 108/69 116/74 >120/82 >128/87 115/77 123/82 >127/90 >135/95 121/79 130/83 >132/92 >142/96 126/81 135/85 >139/93 >147/98 131/84 140/89 >144/97 >152/102 No data 140/90 No data >160/100 88/– 101/57 100/56 104/65 107/70 116/77 121/80 124/82 125/82 No data

88/– 107/60 107/60 110/69 113/74 122/80 128/83 131/85 132/86 140/90

>106/– >113/69 >116/78 >119/83 >128/89 >132/92 >136/94 >138/95 No data

>106/– >115/75 >119/72 >122/81 >125/86 >134/93 >140/96 >143/98 >144/98 >160/100

HTN hypertension, Ht height, Hg mercury a Adapted from blood pressure tables in the 2004 Fourth Report on Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents [1] for blood pressure measured by auscultation with a sphygmomanometer on at least three separate occasions; if systolic and diastolic categories differ, categorize by the higher value b Adapted from the Report of the Second Task Force on Blood Pressure Control in Children – 1987 [13] c Adapted from the 2003 Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [9]

Fig. 2 Severe hypertensive retinopathy in a child with long-standing untreated hypertension showing arteriolar narrowing, hemorrhages and exudates, and papilledema

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Screening Evaluation of Hypertension

Rarely, unilateral facial paralysis (Bell’s palsy of the seventh cranial nerve) can be the initial presentation of severe hypertension in a child [32, 33]. Careful auscultation of the abdomen may reveal a bruit suggestive of renovascular disease, but a bruit is audible only about 50 % of the time in these patients [34]. Femoral pulses may be diminished in patients with coarctation of the aorta or middle aortic syndrome. Determination of height, weight, and BMI with comparison to percentiles for age and gender should always be included as part of the screening physical examination. Screening laboratory evaluation should be minimally invasive and cost-effective. Screening for rare endocrine causes of hypertension should not be done initially in every pediatric patient with hypertension. Screening studies for all patients should include complete blood count, urinalysis, and serum electrolytes, creatinine, and BUN [1–5]. In adolescents with suspected primary hypertension and no suspicion for endocrine abnormalities, serum electrolytes may not be that useful. However, a low potassium concentration with metabolic alkalosis may indicate a rare but treatable disorder, like primary or secondary hyperaldosteronism or Liddle syndrome. Elevated serum potassium in conjunction with metabolic acidosis may suggest chronic renal disease, which is conﬁrmed by the presence of an increased serum creatinine concentration. Creatinine clearance can be estimated from serum creatinine (Schwartz formulas) [35] or measured directly with a 24-h urine collection. Since renal disease is the most common cause of hypertension in children and the kidney is also a target organ for damage from untreated hypertension, urinalysis is an important screening test. Hematuria and red cell casts with or without proteinuria suggests glomerular disease. Isolated hematuria also may be associated with dilatation of the urinary tract or trauma. Proteinuria may be seen in nonglomerular conditions such as reﬂux nephropathy, obstructive uropathy, or interstitial nephritis, as well as glomerular diseases like focal segmental glomerulosclerosis or membranoproliferative glomerulonephritis. Proteinuria alone may be a sign of end-organ damage from hypertension, but must be distinguished, especially in adolescents, from

Episodic or sustained, acute or chronic hypertension, whether stage 1 or stage 2, merits further screening and specific detailed evaluation as dictated by the screening. A convenient algorithm for evaluation of pediatric hypertension is shown in Fig. 1. The direction of further detailed laboratory and radiographic or biopsy evaluation of hypertension should become apparent after taking a detailed personal and family history, performing a careful physical examination and ordering a few simple laboratory tests. The personal history should include specific questioning regarding the occurrence of headaches, sleep disturbance, visual symptoms, nosebleeds, palpitations, episodic rapid pulse, pallor or flushing, joint pains, rash, edema, gross hematuria, excessive weight gain or loss, or decreased height growth. Neonatal history of low birth weight or the use of umbilical artery catheters may provide clues to the diagnosis of primary hypertension in an adolescent [26–28] or hypertension from renal artery thrombosis or emboli in an infant, respectively. Detailed dietary history may reveal excessive intake of sodium, fructose, or caffeinated beverages, especially soft drinks or energy drinks [4, 25]. A medication history should include specific questions about over-the-counter drugs like pseudoephedrine or herbal preparations like ephedra, St. John’s wort, ginseng, or licorice [29, 30], as well as prescription drugs. Adolescents should be questioned privately for a history of substance abuse or the possibility of pregnancy. Family history of hypertension, heart attacks, or stroke is particularly important for children with primary hypertension. A large percentage of children with primary hypertension will have a close relative with the same disease [2–5, 13]. Physical examination may reveal specific signs of genetic disease, such as the elfin facies of Williams syndrome, the café-au-lait spots and small skin neurofibromata of neurofibromatosis type I, the physical features of Cushing syndrome, or ambiguous genitalia associated with congenital adrenal hyperplasia or Denys-Drash syndrome. Hypertensive retinopathy may be present in children with severe or long-standing hypertension [31] (Fig. 2).

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orthostatic (postural) proteinuria, which is a benign condition. A renal ultrasound examination is a simple, noninvasive test that is appropriate to perform early in the evaluation of any hypertensive child [1–5]. Although it may not provide much information for the adolescent in whom primary hypertension is strongly suspected, a renal ultrasound helps exclude congenital anomalies that have previously gone undetected. The renal ultrasound provides information about the size and architecture of each kidney and the lower urinary tract. Abnormal kidneys may be small or asymmetric (renovascular disease, vesicoureteral reflux, or dysplasia); hyperechoic, symmetric, and normal or large (renal parenchymal disease like glomerulonephritis); or large with or without cysts (polycystic kidney disease, multicystic dysplastic kidney). Hydronephrosis and/or hydroureters may be associated with congenital obstructive uropathy or vesicoureteral reflux. Color-coded Doppler analysis with B-mode ultrasonography is termed duplex ultrasonography [36] and provides information about the patency and flow within the main renal vessels, including the more distal segments of the main renal artery, to help diagnose renovascular hypertension. During Doppler evaluation, care should be taken to scan the entire artery from origin at the aorta to renal hilum to improve sensitivity and accuracy. Obtaining measurements in two views, both anterior and oblique, improves identification of fibromuscular dysplasia in the middle to distal segments of the main renal artery. The limited amount of body fat in many children and the proximity of renal vessels to the skin surface allow the use of high-frequency transducers to improve the technical quality; obese patients provide a technical challenge. Color Doppler images can demonstrate global perfusion as well as patency of flow through large renal arteries and veins. Turbulence at a stenotic site alters peak systolic and end-diastolic blood flow velocities and creates a characteristic pattern of flow detected by the spectral Doppler waveform (Fig. 3). The sensitivity of the Doppler flow study is limited for detection of stenosis in accessory renal arteries, intrarenal arteries, or mildly

E.D. Brewer and S.J. Swartz

stenotic arteries [37, 38]. A positive Doppler flow study may be helpful in directing further evaluation, but a negative study does not rule out significant renovascular disease, and Doppler flow evaluation is not needed when a renal arteriogram is planned.

Directed Specific Evaluation of Hypertension After Screening Specific evaluation 1: If the screening evaluation is normal or only positive for obesity, sleep problems, or a positive family history for essential hypertension, detailed evaluation should be directed toward the diagnosis of primary hypertension (Fig. 1). Since primary hypertension is largely a diagnosis of exclusion and less common in young children, renovascular disease must always be ruled out, especially if the child is less than 10 years old. Primary hypertension: The specific evaluation of primary hypertension is designed to determine the presence of cardiovascular risk factors, such as hyperlipidemia and insulin resistance, and to assess any end-organ damage to the heart or kidneys [1]. In children elevation of serum uric acid level may help distinguish primary from secondary hypertension. Many decades ago, increased serum uric acid concentrations were noted in children with primary hypertension but largely ignored until recent reports that serum uric acid is significantly higher at presentation in children with primary hypertension compared to children with secondary hypertension [39, 40]. Elevated uric acid may play an early pathogenetic role in childhood hypertensives by activating cellular pathways that lead to increased renovascular tone, fibrosis, and irreversible arteriolosclerosis [39]. ABPM may help distinguish primary from secondary hypertension, the latter of which is more likely to have greater daytime diastolic blood pressure load, greater nocturnal systolic blood pressure load, and blunted nocturnal dipping [18, 19]. End-organ damage may already be evident at presentation of primary hypertension in adolescents.

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Fig. 3 Renal transplant ultrasound with Doppler flow evaluation in a child. Left upper panel: The resistive index is high (0.6) and the flow pattern turbulent, suggesting transplant renal artery stenosis, which was confirmed by digital subtraction angiography (DSA) (arrow)

shown in the right panel. Left lower panel: Normalization of the Doppler ﬂow study with resistive index lower (0.4) and no turbulence after successful balloon angioplasty of the stenosis

An echocardiogram is the best way to screen for left ventricular hypertrophy and will also serve as a baseline study for comparison later in the course of therapy [1]. APBM may also be useful to identify which children may be at greatest risk for developing end-organ damage from hypertension [4, 18, 19]. Renovascular disease: Renovascular disease is the cause of hypertension in about 10 % of the children referred for diagnosis [41, 42]. Children with renovascular hypertension are frequently asymptomatic [42]. Their hypertension is often severe and may be hard to control with medication before proceeding with speciﬁc evaluation [42]. An angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB) may provide the best control but, with prolonged use, can also lead to loss of function in the affected

kidney from reduced arterial ﬂow in an area of severe stenosis (Fig. 4). Patients with bilateral renal artery stenosis are at risk for developing acute renal failure at the onset of ACEI or ARB therapy. A child’s response to an ACEI, such as captopril, during radionuclide imaging, with either diethylenetriaminepentaacetic acid (DTPA), mercaptoacetyltriglycine (MAG3), or dimercaptosuccinic acid (DMSA), has been used in the evaluation for renal artery stenosis and is referred to as a captopril renal scan [42–44]. Although a captopril renal scan may help lead to a diagnosis, the test is invasive and only moderately sensitive (50–70 %) in children, especially if disease is bilateral [42–44]. Since a renal arteriogram is both diagnostic and potentially therapeutic when coupled with balloon angioplasty, a captopril renal scan is not a necessary test for the evaluation of children with a

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Fig. 4 Sequential 99TcDTPA radionuclide renal scans in an infant with unilateral left renal artery stenosis treated medically, because body size was too small to allow transluminal balloon angioplasty. (a) At diagnosis at 1-month-old, 40 % function left kidney, 60 % function right kidney. (b) At 1-year-old after 11 months of oral ACEI therapy for left main renal artery stenosis, 26 % function left kidney, 74 % function right kidney

high likelihood of renal artery stenosis at centers with skilled pediatric interventional radiologists. A renal perfusion scan with DTPA or MAG3 may be useful to identify segmental areas of hypoperfusion or infarction, especially those associated with an embolus from an umbilical artery catheter used in the neonatal period [44–46]. Intravenously administered MAG3 is initially ﬁltered by the glomerulus and then taken up into the kidney primarily by proximal tubular secretion, so MAG3 can be used for estimation of tubular function as well as renal plasma ﬂow. Selective renal arteriography with or without digital subtraction angiography (DSA) enhancement is the gold standard for diagnosis of renal artery stenosis [47–56]. Renal arteriography has the added advantage that therapeutic transluminal balloon angioplasty [48–53] or placement of bridging stents [42, 52, 53] can be performed during the same procedure. Balloon angioplasty may be possible even in small children, using

balloon catheters designed for coronary artery angioplasty [54]. The disadvantage of renal arteriography is that it is invasive, exposes the child to nephrotoxic radiocontrast agents, and usually requires general anesthesia for small or uncooperative children [47, 56]. Deep conscious sedation may be effective for cooperative older children and adolescents. If performed by an experienced interventional radiologist, the renal arteriogram can be done safely as a 1-day outpatient procedure in most children. The incidence of severe complications, such as intimal tear or injury, renal artery thrombosis, or branch embolus, is very low in experienced hands. Patients need to be observed for 4–6 h post-procedure for possible complications. Arterial puncture carries the risk of hematoma formation at the site and vascular compromise to the extremity. Computed tomographic angiography (CTA) and magnetic resonance angiography (MRA) are 80–90 % accurate alternatives to renal arteriogram

Evaluation of Hypertension in Childhood Diseases

Fig. 5 Computer-reconstructed 3D CTA image from a 2.5-year-old boy with failure to thrive and severe hypertension, showing mild narrowing of the distal aorta and stenosis of the right main renal artery and its proximal branches (arrow)

for evaluation of renovascular disease [55–58]. Stenosis of accessory renal arteries or of the more distal portions of renal arteries, as in patients with ﬁbromuscular dysplasia, is more likely to be missed with these techniques. Both modalities allow scans of high resolution during quiet breathing or within a 5–30-sec breath hold [55, 58], so movement artifact is minimized for children, especially with the shorter 5–10-sec breath hold for CTA [58]. CTA requires only a peripheral intravenous approach, can assess nonvascular but surgically correctable occult renal or suprarenal neoplasms, and produces excellent images of the renal vasculature, including 3-dimensional (3D) visualization with appropriate software [55, 58] (Fig. 5). A limited CT scan of the abdomen may be performed before CTA to provide additional information about the anatomy of the kidneys, adrenals, and surrounding structures [36]. CTA is very useful for evaluation of children and adolescents, in whom the need for invasive renal angiography is not clear-cut [58]. The disadvantage of CTA is that it uses ionizing radiation and requires nephrotoxic iodinated radiocontrast

2007

agents [36, 55, 58]. MRA has the advantages of being minimally invasive and avoiding ionizing radiation but requires the use of gadolinium contrast enhancement, which puts patients with chronic renal failure, especially those with less than 30 % renal function, at risk for nephrogenic systemic ﬁbrosis [59–61]. At our center, MRA may be useful for infants and children too small to undergo balloon angioplasty, as well as for neonates [62], but currently we rely mostly on CTA and avoid MRA for any patient with even mild renal failure. Plasma renin activity measured in samples from peripheral veins or especially from selective renal veins may provide additional useful information for evaluation of renovascular disease [42, 63]. Selective sampling of renal vein renins may be done conveniently at the time of renal arteriogram to provide supporting evidence for unilateral or bilateral disease. The inferior vena cava above and below the renal veins should be sampled at the same time as the renal veins. If the selective renal vein renin concentration is at least 1.5 times greater than concentration in the contralateral kidney, the result is diagnostic for renin-mediated hypertension from that kidney [63]. If the contralateral kidney is normal, renal vein renin concentration should actually be decreased due to downregulation of renin production in the normal kidney from increased circulating angiotensin II [64, 65]. If the ratio between renal vein renin from the contralateral kidney and caudal inferior vena cava is 85 % (overweight) [114]. The prevalence of HTN in obese school children in the Houston area (BMI 95th percentile) was 11 % compared to 1–3 % in those with BMI 75th percentile [3]. Another study also from the USA has demonstrated that the prevalence of metabolic syndrome among all adolescents was 4.5 % [115]. Thus, obesity with or without metabolic syndrome predisposes to HTN and other cardiovascular complications.

Mechanisms of Obesity-Related HTN The mechanisms mediating obesity-related HTN are complex and incompletely understood [116–119]. Several interrelated clinical conditions and multiple mechanisms may interact to raise BP [116]. For example, there appears to be an association between obesity, sleep apnea, and HTN. There are over 50 different substances derived from adipose tissue that have been implicated in BP control [120]. The mechanisms can be

2035 Table 3 Mechanisms of obesity-related HTN Sympathetic nervous system activation Renal Mechanisms 1. Shift of pressure natriuresis toward sodium and fluid retention 2. Renal renin-angiotensin-aldosterone system activation 3. Renal tissue compression by perirenal fat resulting in reduced medullary blood flow and increased renin secretion Hormonal abnormalities 1. Insulin resistance/hyperinsulinemia 2. Hyperleptinemia 3. Adipose tissue derived renin-angiotensinaldosterone system activation 4. Increased or decreased adipokines Endothelial dysfunction 1. Activation of proinflammatory pathways to induce atherosclerotic vascular wall changes 2. Reduced vasodilatation due to nitric oxide inactivation and degradation This table depicts a simplified list of mechanisms. Many of these factors likely interact to cause HTN

grouped into sympathetic nervous system (SNS) activation, renal mechanisms, hormonal abnormalities, and endothelial dysfunction as shown in Table 3. Epidemiological and clinical studies implicate SNS activation as playing an important role in obesity-related HTN [121, 122]. Combined α- and β-adrenergic blockade signiﬁcantly reduced BP in obese hypertensive patients compared to lean hypertensive controls, again suggesting that increased sympathetic activity is an important factor in obesity-related HTN [123]. A recent study in obese children found a high correlation between the serum level of the adipose tissue-derived hormone leptin, heart rate, and BP, suggesting that leptin may mediate this effect through the SNS [124, 125]. Infusion of leptin into animals raised pulse rate and BP, and these increases were abolished after combined α- and β-adrenergic blockade [126, 127]. Finally, there are adipocytederived peptides collectively termed adipokines, including adiponectin and resistin, that may modulate BP [120]. Thus, future development of leptinor adipokine-suppressive drugs may be useful in managing obesity-related HTN.

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D. Ellis and Y. Miyashita Increase in arterial pressure

Normal 5x Na/H2O (Excretion = Normal intake of Sodium)

Hypertension 3x

1x 0 50 100 150 200 250 Arterial pressure, mm Hg

Hereditary forms of hypertension • SHR • Dahl S • TGR Secondary forms of hypertension • Goldblatt • RRM + Salt • All • Adrenergic • Aldo + salt • DOCA + salt • Endothelin

Decrease in blood volume

Fig. 1 Etiopathogenesis of salt-sensitive hypertension. Schematic representation of the pressure-natriuresis hypothesis for the long-term control of arterial pressure. In normal animals, any elevation in arterial pressure would be expected to increase sodium and water excretion via pressure natriuresis. Because sodium and water intake is habitually determined and remains relatively ﬁxed, the increase in sodium and water excretion slowly lowers blood volume sufﬁciently until arterial pressure returns exactly to control. The pressure-natriuresis relationship

either exhibits a reduced sensitivity (slope reduction) or is shifted in a parallel manner toward a higher set point, in every experimental model of hypertension studied to date. Thus, sodium and water are retained until arterial pressure is elevated sufﬁciently to restore sodium and water balance. SHR indicates spontaneously hypertensive rats; Dahl S, Dahl salt-sensitive rats; TGR, transgenic renin gene rats; RRM, reduced renal mass; Aldo, long-term administration of aldosterone; DOCA, long-term administration of deoxycorticosterone acetate

Several renal mechanisms have been proposed to mediate obesity-related HTN including impairment of pressure natriuresis, activation of renin-angiotensin-aldosterone system (RAAS), and structural changes in the kidney [116]. As illustrated in Fig. 1, pressure natriuresis is a homeostatic mechanism, whereby excessive salt intake and extracellular ﬂuid retention are excreted in order to reduce venous return and cardiac output until BP normalizes. Conversely, with hypotension, the kidneys retain salt and water to raise BP. With obesity, this feedback mechanism appears to shift toward increased renal tubular sodium reabsorption [125]. Although the exact pathophysiology has not been fully elucidated, insulin resistance and hyperinsulinemia, activation of RAAS, and increased SNS could all play a role in this renal impairment [125]. With obesity, studies have shown paradoxic activation rather than the expected suppression of RAAS in the setting of sodium retention and extracellular ﬂuid expansion [128, 129]. Individuals with central obesity initially had high plasma

levels of peripheral renin activity, aldosterone, and angiotensin-converting enzyme, which improved within 6 months of gastric bypass surgery [128]. There appears to be both renal RAAS activation and adipose tissue synthesis of RAAS hormones. Renal RAAS activation may occur by compression of the kidney by perirenal fat that elevates interstitial fluid hydrostatic pressure leading to reduced medullary blood flow [130]. This results in decreased detection of sodium concentration by the macula densa leading to increased renin secretion and elevation of BP occurring through angiotensin II-induced systemic vasoconstriction, direct sodium and water retention, and increased aldosterone production [116]. There is also a growing recognition that obesity represents a state of chronic, low-grade inflammation leading to various proinflammatory pathways and oxidative stress leading to endothelium-dependent relaxation [131] and nitric oxide inactivation and degradation in the vessel wall leading to reduced vasodilatation [131], both of which can promote development of HTN.

Management of the Hypertensive Child

Weight Stabilization or Weight Reduction Weight loss may lead to reversal of the pathophysiological pathways of obesity-related HTN discussed above. Weight reduction and DASH diet are the most effective lifestyle measures of achieving optimal BP control in adults [132]. If recommendations for weight reduction provided by primary care providers prove ineffective within a 6-month period, referral to weight management services may be of beneﬁt. Such programs are now available at most pediatric centers and provide a comprehensive evaluation of risks, formulate a program of diet and exercise, and monitor the effectiveness of interventions. If conservative measures for weight reduction fail, and the child is severely obese (BMI >40) with fatty liver, type 2 diabetes, hyperlipidemia, or stage II HTN, bariatric surgery may be a reasonable option to reduce appetite and stave off these important lifelong medical complications. Because of theoretical concerns that such radical and permanent procedure may cause an abrupt change in nutrition and thereby impair long-term brain and sexual development, there has been a reluctance to employ bariatric surgery in children and particularly in those under 14 years of age. However, these complications have not occurred even in preschool children undergoing laparoscopic sleeve gastrectomy which is relatively safe, while obesity, diabetes, and HTN could be reversed by the procedure [133, 134]. The optimal BMI conducive to improvement of BP has not been established, but a BMI of 25 kg/m2 is a reasonable goal in older children [135] and 1.5 mg/dL or eGFR 40 % had signiﬁcantly lower eGFR and higher level of proteinuria than controls [319]. It was concluded that children with

Management of the Hypertensive Child

pre-HTN defined at this BPL limit should have renal function and proteinuria measured as an indicator of renal injury related to pre-HTN. Other studies have also shown that even mild elevation in BP in children may result in an increased LVMI and c-IMT [36, 320–322]. Children and adolescents with CKD, proteinuria, and established HTN benefitted by the use of intensified intervention with ACEI to achieve mean arterial pressure near the 50th percentile rather than the usual goal of BP < the 90th percentile [308]. Newer investigations have uncovered multiple biological functions of aldosterone beyond its well-established role in potassium and volume/ BP homeostasis. The unregulated stimulation of aldosterone in many renal disorders has been implicated in progressive tubulointerstitial fibrosis and dysfunctional cardiac remodeling associated with chronic HTN. Aldosterone receptor antagonists are often helpful as add-on secondor third-line drugs in individuals with HTN resistant to other agents [323]. Use of this class of agents may reduce BP by their diuretic action, as well as by non-volume-mediated effects [324–329]. Anti-aldosterone agents may also offset the rebound elevation in plasma aldosterone concentrations (“aldosterone escape”) noted after an initial fall in plasma aldosterone concentrations evident after starting ACEI [324]. Higher serum potassium concentrations particularly in individuals with GFR below 60 mL/min/1.73 m2 managed with ACEI may be partly responsible for stimulating aldosterone biosynthesis in this setting. Hence, in theory, with proper monitoring and prevention of hyperkalemia, the combined use of spironolactone or eplerenone together with ACEI or ARB may afford more optimal nephroprotection in children with HTN and/or proteinuria [328].

Renovascular HTN This category of HTN includes renal microvascular disease, renal artery stenosis due to multiple etiologies, and renal focal ischemia due to renal microthrombi or scarring after pyelonephritis. HTN associated with these disorders is often

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resistant to antihypertensive agents that do not inhibit the RAAS. A “critical” fall in perfusion to a part or to the entire kidney in these disorders stimulates renin release and AT-II and other mechanisms tending to restore renal perfusion, but in the process also raises systemic BP [330–332]. Because angiotensin II plays a pivotal role in renovascular HTN, it is targeted for pharmacologic blockade. An example of this is renal artery stenosis (RAS). There are no comparisons of the complications of revascularization procedures and medical management of RAS in children. While nonmedical approaches have an associated risk for hemorrhage, vessel or renal perforation, and thrombosis leading to loss of renal function, this approach is often preferred in children as it offers the possibility of a permanent cure, particularly in children having stenosis at the ostium or abdominal aorta syndrome. Conversely, ACEI or ARB use is contraindicated in children with severe bilateral RAS and in children with unilateral severe RAS with a solitary functioning kidney. The authors also advise against the use of diuretics or potent direct vasodilators as an acute drop in systemic BP may lead to infarction of kidneys with “critically” reduced blood ﬂow (>50 % drop) evident on ACEI-assisted scan or in those managed with diuretics and salt restriction leading to diminished circulatory volume. Once the location and severity of the stenosis is established by imaging studies, a decision may be made to administer oral ACEI, intravenous enalaprilat, or ARB. As a caveat, the medical management of RAS should take place with great caution so as to avoid rapid lowering of systemic BP. Salt restriction should be moderate, and diuretics should be avoided. For pharmacologic management of renovascular HTN other than bilateral RAS in infants, the authors recommend starting with low-dose captopril and titrating upward as needed. Older children may receive labetalol or carvedilol as the initial agent, and an ACEI or ARB may then be added depending on BP response. Sodium nitroprusside or fenoldopam infusion may be administered in children with hypertensive emergency (e.g., vessel dissection, cerebrovascular accident, seizures,

2064

retinal hemorrhage, or Bell’s palsy) (see section “Hypertensive Emergency and Urgency”). In all instances serum creatinine concentration should be carefully monitored. If it rises by more than 20 % above baseline levels, ACEI or ARB may be stopped, reduced in dosage, or substituted with intravenous nitroprusside or labetalol, until a revascularization procedure is performed.

Oligonephronia (Renal Hypoplasia) This condition implies a reduced nephron number and possibly represents a very important and underappreciated cause of HTN both in children as well as in adults suspected of having primary HTN. The number of nephrons in healthy individuals is quite variable ranging from 0.8 to 1.8 million. Infants with low birth weight or intrauterine growth retardation may be susceptible to HTN during early childhood because of reduced nephron number leading to an impaired ability to excrete salt and water [333–336]. Thus, early detection and management of such HTN may be useful in preventing renal dysfunction and other end-organ injury in early adulthood.

Diabetic Nephropathy Progression of CKD occurs even faster in individuals with diabetes and HTN than in nondiabetics with CKD [337, 338]. The rate of renal functional decline is still higher in diabetics with combined HTN and proteinuria. A minority of children with type I or type II diabetes have the incipient phase of diabetic nephropathy with microalbuminuria and no overt proteinuria. While there is some dispute as to the desired target BP in adults with diabetic nephropathy, recommended goals are 142/92 mmHg during sports preseason screening examination ultimately developed sustained HTN [379].

Unique Aspects of Hypertensive Athletes There are two potential unique phenomena that can lead to isolated systolic HTN in conditioned athletes. The first is the development of “athlete’s heart” with very high resting stroke volume and cardiac output, low peripheral vascular resistance, and low heart rate [380]. These athletes may develop high pulse pressure, and systolic BP is often in the range of prehypertension up to stage I HTN [381]. The second potential source of systolic HTN in athletes is “spurious systolic HTN” as a result of exaggerated pulse pressure amplification in the arm [382]. This is felt to occur as a result of the progressive decrease in arterial diameter from the heart to the arm and the corresponding increase in arterial impedance resulting in brachial SBP being 30–40 mmHg higher than central SBP possibly reflecting greater stroke volume in athletes [382]. This phenomenon is most common in young adult males, and although long-term cardiovascular significance of this is uncertain, it may represent intermediate risk between normotensive and hypertensive individuals [383]. Another potential predictor of eventual development of HTN in athletes is exaggerated BP response to exercise. In a study of athletes

Management of the Hypertensive Child

involved in endurance sports, aged 17–24 years old, those with exaggerated BP response to exercise during their training period had higher 24 h ABPM mean SBP (136 vs. 117, p = 0.02) [384]. Further, athletes with exaggerated BP response to exercise had lower apolipoproteinA1, which is considered to be a cardioprotective factor [384]. In contrast to adults where maximum normal systolic BP response to exercise testing is defined as 220 mmHg, there is no clear definition of upper threshold of normal maximum BP response to exercise in children. Cuff systolic BPs up to 240 mmHg have been recorded in studies of normotensive postpubertal male athletes [385, 386]. When evaluating athletes with elevated BP, particular attention should be paid not only their diet and activity level, but to other potential behavioral contributors including use of alcohol, caffeine (including energy drink consumption), illicit drugs including stimulants, tobacco, nonsteroidal anti-inflammatory drugs, human growth hormone, erythropoietin, anabolic steroids, diet pill, and herbal supplements [382]. In addition, sports and energy drinks are a large and growing beverage industry now marketed to children and adolescents [108]. See sections “Caffeine” and “Sports Drinks” and their potential roles in raising BP. The AAP recommends healthcare providers to screen for sports and energy drink usage in children and adolescents, and it recommends the consumption of sports drinks only during prolonged vigorous physical activity and to prohibit the consumption of energy drinks [108].

Management of HTN in Athletes Epidemiological data in different populations have shown a strong association between higher physical activity with lower BP [387–390]. In addition, activity intervention trials in pediatrics have shown increased activity level leading to weight loss with decreased abdominal fat which were associated with vasodilatory response, diminished arterial stiffness, and reduction in BP [29, 391]. However, not all types of physical activities are felt to be safe or helpful for

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hypertensive athletes. The Council on Sports Medicine and Fitness in the AAP released a policy statement regarding athletic participation by children and adolescents with systemic HTN [392]. This policy statement includes a description of two classes of exercises which may affect BP differently. The ﬁrst is termed dynamic exercise, which involves changes in muscle length and joint movements with rhythmic contractions that develop relatively small intramuscular force. This type of exercise causes a marked increase in oxygen consumption, cardiac output, heart rate, stroke volume, and systolic BP, as well as a moderate increase in mean arterial pressure and a decrease in diastolic BP and total peripheral resistance [393]. The second type is termed static exercise which involves development of relatively large intramuscular force with little or no change in muscle length or joint movement. This type of exercise causes a small increase in oxygen consumption, cardiac output, and heart rate, with no change in stroke volume, a marked increase in systolic and diastolic blood pressure and mean arterial pressure, and no appreciable change in total peripheral resistance [393]. As illustrated in Fig. 4, most physical activities and sports involve both dynamic and static components to varying degrees. The concern with static exercise is the acute increase in diastolic BP and the large muscle mass that may elevate resting BP. Although limited evidence showed no greater risk with highly static exercise, the current expert opinion is to be more cautious with stage II hypertensive athletes who participate in highly static exercise. The AAP recommends no limitation in competitive athletic participation for youths with prehypertension or stage I HTN in the absence of end-organ damage or concomitant heart disease. For athletes with end-organ damage or stage II HTN, the AAP recommends restrictions on highly static sports (classes IIIA and IIIC on Fig. 4) until their BP normalizes after intervention [392]. Lastly, there is no speciﬁc pharmacologic recommendation for antihypertensive drug therapy for competitive hypertensive athletes, but attention must be paid when choosing drug classes. According to the World Anti-Doping Agency,

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D. Ellis and Y. Miyashita

Fig. 4 Classification of sports according to cardiovascular demands (based on combined static and dynamic components). This classification is based on peak static and dynamic components achieved during competition. It should be noted, however, that the higher values may be reached during training. The increasing dynamic component is defined in terms of the estimated percent of maximal oxygen uptake (MaxO2) achieved and results in an increasing cardiac output. The increasing static component is related to the estimated percent of maximal voluntary contraction (MVC) reached and results in an increasing blood pressure load. The lowest total cardiovascular

demands (cardiac output and blood pressure) are shown in Box IA, and the highest are shown in Box IIIC. Boxes IIA, IB, IIIA, IIB, IC, IIIB, and IIC depict low-moderate, moderate, and high-moderate total cardiovascular demands. These categories progress diagonally across the table from lower left to upper right. *Danger of bodily collision. †Increased risk if syncope occurs. ∇Participation not recommended by the American Academy of Pediatrics. + The American Academy of Pediatrics classifies cricket in the IB box (low static, moderate dynamic) (Original figure from Ref. [393] and the legend to this figure from Ref. [392])

all diuretics including thiazides are banned due to their ability to mask the presence of anabolic steroids. In addition, diuretics may impair exercise tolerance due to decreased intravascular volume and may predispose the athlete to

dehydration and electrolyte abnormalities [394, 395]. In precision sports like archery, automobile driving, billiards, golf, shooting, and skiing/snowboarding, β-blockers are banned [396]. Generally β-blockers should be avoided in

Management of the Hypertensive Child

hypertensive athletes because of its potential to cause fatigue and concern of heart block especially in aforementioned athletes with “athlete’s heart.”

Oral Contraceptive (OC) Use An increasing number of adolescents are receiving oral contraceptive agents to manage dysmenorrhea or for birth control purposes. Depending on the estrogen content and interplay of dietary and genetic risk factors, or interaction with other drugs and vasoactive substances, such adolescents may develop symptomatic or asymptomatic HTN. Newer OCs contain less estrogen (25–35 mg estrogen) than older OCs which contained >50 mg estrogen and were often associated with a rise in BP. The pathomechanism of estrogeninduced HTN involves an alteration in the RAAS and ensuing sodium and ﬂuid retention [397].

Pregnancy-Associated HTN In 2012, there were 29.4 births for every 1,000 adolescent females ages 15–19 and 305,388 babies born to females in this age group [398]. New-onset HTN may occur in up to 8 % of pregnancies [399, 400]. Adolescents have a signiﬁcant higher risk for pregnancy-associated HTN and for having small-for-gestational-age offspring who may also be susceptible to HTN. Gestational HTN in adolescents may also be a forerunner for development of sustained maternal HTN 6–9 years after pregnancy. The spectrum of HTN during pregnancy includes the more common disorder, preeclampsia (associated with proteinuria); the much less common conditions of eclampsia (proteinuria and seizures); and gestational HTN (no proteinuria). Collectively these disorders occur in 10 % of all pregnancies and cause considerable maternal and infant morbidity and mortality. The incidence of preeclampsia has risen by 40 % in the past 10–20 years [400, 401]. The condition typically presents with proteinuria, edema, headache, emesis, abdominal pain, and

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visual disturbances after 20 weeks of pregnancy. Risk factors for the disorder include obesity, a large gap between pregnancies, multiparity, and teen pregnancy. Also, preeclampsia occurring during a previous pregnancy increases the subsequent risk from 3.3 % to 20 %. Preexisting HTN and renal disease are important risk factors in 30 % of women who develop preeclampsia. Moreover 20 % of individuals with eclampsia will go on to develop sustained systemic HTN after pregnancy. The pathogenesis of preeclampsia and its more serious form, eclampsia, is partly elucidated. According to the leading hypothesis, a reduction in uteroplacental blood flow related to abnormal arterioles in the cytotrophoblast may initiate placental ischemia. This then leads to synthesis and release of proangiogenic factors and vasoactive substances which favor aberrant local and systemic vasoconstriction rather than the physiologic vasodilation and blood volume expansion observed during normal pregnancy. Elevated plasma concentrations of the vasoconstrictors thromboxane and endothelin 1 and reduction in vasodilatory prostaglandins and nitric oxide have been found in this disorder [401, 402]. Also, there is an increase in proinflammatory cytokines, tumor necrosis factor-α, and interleukins 1 and 6 which stimulate endothelin synthesis but reduce acetylcholine-mediated vasodilation, all of which favor the development of HTN [403–406]. Experimental evidence also implicates prolonged inhibition of nitric oxide synthase in the pathogenesis of eclampsia-associated HTN [407, 408]. This leads to loss of modulation of vasoconstrictor substances resulting in renal and systemic vasoconstriction, proteinuria, and intrauterine growth retardation and high fetal morbidity similar to that encountered in humans with this disorder. Although preeclampsia usually resolves after delivery of the infant and placenta, it is desirable to manage the HTN until at least 32 weeks of gestation so as to limit the complications of prematurity in the fetus. Provided that there is no end-organ damage, as a general rule, a higher threshold for treatment may be used because lower BPs may compromise placental blood flow and affect the growth and overall safety of

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the infant. The consensus recommendation is to manage sustained increases of systolic BP >150 mmHg or diastolic BP >95 mmHg. Most clinicians recommend pharmacologic therapy for BP >140/90 mmHg for gestational HTN or preeclampsia, for preexisting HTN further aggravated by gestation, for asymptomatic individuals with organ damage, or for symptomatic women at any time during pregnancy. Pregnancy is a compelling contraindication for use of ACEI, ARB, and renin inhibitors because of teratogenic events noted as early as the first trimester of pregnancy that was previously thought to be a safe period [409]. Birth defects include cardiovascular and neurologic complications, craniofacial deformities, and renal dysplasia leading to renal insufficiency and oligohydramnios. Drugs that do not affect placental blood flow are recommended [410]. In addition to 81 mg of aspirin per day, drug choices include methyldopa, labetalol, and nifedipine (the only calcium antagonist tested in pregnancy). Intravenous labetalol is the drug of choice for managing preeclampsia. Alpha-methyldopa may be an initial agent; hydralazine is another such agent. In individuals nearing delivery, prophylaxis against seizures (eclampsia) is essential during labor and for 1–2 days after delivery. This consists of intravenous magnesium sulfate starting with a 4-g loading dose (over 15–20 min), followed by 2 g per hour by continuous infusion thereafter. The goal is to maintain BP in the high normal range (95 % on three separate occasions compared to neonates of similar, post conceptional age and body weight [12, 412, 418]. After the neonatal period or 44 weeks of post conceptional age, the norms published previously suffice for determining the presence of HTN [412]. Renovascular causes of HTN predominate in this population [414, 419, 420]. Common etiologies include renal thromboemboli secondary to umbilical vascular access and right-to-left shunts because of ventricular septal defect or patent ductus arteriosus. Other causes include acute cortical necrosis associated with asphyxia, sepsis, or circulatory shock leading to renal venous thrombosis or kidney injury, along with hypercarbia related to bronchopulmonary dysplasia leading to sodium and fluid retention and HTN [415]. Intracranial hemorrhage leading to neurogenic or “central” HTN, polycystic kidney disease, coarctation of the aorta, and iatrogenic causes such as use of glucocorticoids, caffeine, dopamine, and inadequate pain control may be less common causes. Pharmacologic management of neonatal HTN is highly individualized and complicated by the fact that dosages, safety, goal BP, and efficacy of various antihypertensive agents have not been studied prospectively or systematically. Furthermore, the benefit of such agents in preventing

Management of the Hypertensive Child

Table 12 Pharmacologic hypertension

therapy

2075 neonatal

Angiotensin-converting enzyme inhibitors Captopril 0.05–2.0 mg/kg/day PO (divided q6–12 h) Enalaprilat 5–10 μg/kg/dose IV (q8–24 h) Beta-adrenergic antagonists Esmolol 100–500 μ/kg IV load over 1–2 min, then 50–500 μg/kg/min IV continuous infusion Labetalol 1–20 mg/kg/day PO (divided q8–12 h) 0.2–1.0 mg/kg/dose IV bolus or 0.25–3.0 mg/kg/h IV continuous infusion Propranolol 0.5–5.0 mg/kg/day PO (divided q6–12 h) Calcium channel antagonists Amlodipine 0.1–0.6 mg/kg/day PO (divided q12 h) Isradipine 0.05–0.15 mg/kg/dose PO (q6 h) Nifedipine 0.125–0.5 mg/kg/dose PO (divided q6–8 h) (max dose = 3 mg/kg/day) Nicardipine 0.5–3.0 μg/kg/min IV continuous infusion Diuretics Bumetanide ?? Chlorothiazide 20–30 mg/kg/day PO (divided q12 h) Furosemide 0.5–4.0 mg/kg/dose IV/PO (divided q6–8 h) (max dose = 4 mg/kg/day) Hydrochlorothiazide 2–3 mg/kg/day PO (divided q12 h) Vasodilator Hydralazine 0.1–0.6 mg/kg/dose IM/IV q4–6 h OR 0.75–5.0 μg/kg/min IV continuous infusion Sodium 0.5–8.0 μg/kg/min IV nitroprusside continuous infusion

cardiac dysfunction, pulmonary insufﬁciency, and intracranial hemorrhage should be balanced against the risks of developing renal dysfunction or hypoperfusion of the brain and viscera as BP is being lowered. Gradual titration of such medications is particularly important in this population. Table 12 shows the dosages of antihypertensive medications utilized in neonates. Neonates with severe HTN (>99th percentile) with or without symptoms of HTN which may be

unique to this population are best managed with continuous short-acting intravenous agents which can be readily titrated to gradually reduce BP below the 95th percentile. For such purpose, the calcium channel blocker nicardipine has been very useful [421, 422]. Other agents that can be employed in this clinical setting include esmolol [423], labetalol [424], and sodium nitroprusside [425]. Such infants should be in the ICU and have their BP monitored continuously by an intraarterial transducer. In neonates with less severe HTN (95th percentile–99th percentile) and no symptoms who may be unable to absorb oral agents, intermittent administration of intravenous hydralazine or labetalol may be employed. Intravenous ACEI such as enalaprilat, or oral agents such as captopril, although helpful for managing renovascular HTN, should be used with caution [426] [427]. This is because neonates have a physiologically hyperactive RAAS which helps support systemic BP and renal perfusion. This places stressed neonates at high risk for developing acute oliguric kidney injury after ACEI use, particularly when renal artery stenosis is the suspected cause of HTN. In neonates capable of absorbing oral medications, the short-acting calcium channel blocker isradipine given at a dosage of 0.05–0.1 mg/kg/ dose every 6–8 h is a very useful agent particularly in bronchopulmonary dysplasia or steroidinduced HTN [208, 428]. Amlodipine is another agent of this class which, like isradipine, can also be compounded into an oral suspension, but its longer duration of action and delayed onset of action make it less suitable in newborn with acute-onset HTN. In the absence of RAS, captopril at 0.01–0.1 mg/kg/dose given every 8 h is usually effective in newborns suspected of having other forms of renovascular HTN. However, ACEI may impair nephrogenesis, and their use prior to 44 weeks post conceptional age has been questioned [429]. Beta-blockers are generally avoided in sick newborns as these agents tend to adversely affect an already stressed cardiovascular system. Diuretics are generally avoided but may be used with caution in infants with bronchopulmonary dysplasia [430].

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Surgery is reserved for newborn with aortic coarctation, adrenal or renal tumors causing HTN, unilateral renal dysplasia or intractable HTN secondary to nephroblastomatosis, or polycystic renal disease. Correction of RAS should be deferred until the infant is of sufﬁcient size to undergo such delicate procedure with the prospect of successful correction. Many causes of HTN that begin in the newborn period resolve spontaneously by 1 year of age. Thus, “step-down” care should be anticipated. Also, most infants tend to outgrow their medication dosages due to rapid body growth during infancy.

Hypertensive Emergency and Urgency Hypertensive emergency is deﬁned by the presence of acute end-organ injury with implication that immediate reduction in BP is needed. Although a large majority of children who present with hypertensive emergency have BP >99th percentile, it is not strictly deﬁned by numerical values. Hypertensive urgency is a similar level of HTN but without severe symptoms or end-organ damage. This distinction may be arbitrary and relies on the judgment of the treating clinician [431].

Symptoms and Signs Unlike adults in whom hypertensive emergencies usually occur in individuals with known and often severe preexisting HTN, in children the discovery of HTN is typically made at the time of presentation with symptomatic HTN. The severity of manifestations in children with hypertensive emergency often depends on the chronicity of HTN as well as on the magnitude of the BP elevation. Children with cardiac outlet obstruction or cardiomyopathy may become symptomatic despite mild HTN. The most common symptoms of HTN in the majority of older children who present to the emergency department are those of hypertensive encephalopathy manifested by

D. Ellis and Y. Miyashita

headache, nausea, vomiting, mental confusion, blurred vision, agitation, or frank seizures. Other manifestations may include cerebral infarction, intercerebral or retinal hemorrhage, congestive heart failure, acute pulmonary edema (and shortness of breath), acute kidney injury, or microangiopathic hemolytic anemia. Uncommon sequelae of hypertensive emergencies in children include myocardial infarction or aortic dissection. Newborns and infants with severe HTN may present with congestive heart failure, hypertensive retinopathy, respiratory distress, apnea or cyanosis, extreme irritability, hypotonia, convulsions, or coma. Vomiting or diarrhea as well as failure to thrive may be among the global chronic manifestations of HTN in this younger age group. In the absence of renal disorders which often predispose to hypertensive crisis, one must be aware of previously unrecognized cardiac and endocrinologic etiologies of HTN which may inﬂuence the therapeutic strategy.

Pathophysiology Chronic HTN leads to compensatory, functional, and structural changes in arterial vessels which tend to maintain perfusion to the brain and kidneys in particular, while protecting against injury which may otherwise result from organ hyperperfusion due to HTN [432]. When systemic BP surpasses the compensatory limits of autoregulation, arterial injury such as ﬁbrinoid necrosis and organ ischemia may follow [433, 434]. Conversely when BP is suddenly reduced below the new steady-state limits of compensation, ischemic injury may be enhanced particularly in individuals with atherosclerotic or other structural hypertensive arterial changes. Many children with hypertensive emergencies do not have structural vascular lesions and are, therefore, less susceptible to organ ischemia after BP lowering. Conversely, the lack of adaptive responses in children with acute and rapid rise in BP may predispose to symptoms at BP levels which may not be gauged as being sufﬁciently high to produce such symptoms.

Management of the Hypertensive Child

Table 13 Age-specific common etiologies of severe HTN Age range Neonates

Children

Adolescents

Common etiologies Renovascular disease Thrombi in renal artery or vein Renal artery stenosis Coarctation of aorta Autosomal recessive polycystic kidney disease Renal parenchymal disease Caffeine overdose Renal parenchymal disease Acute glomerulonephritis Hemolytic uremic syndrome Reﬂux nephropathy Renovascular disease Coarctation of aorta Neuroendocrine tumors Similar to children, in addition: Substance abuse Cocaine Amphetamines Preeclampsia Drug overdose Pseudoephedrine Phenylpropanolamine Nonsteroidal anti-inﬂammatory drugs

General Principles of Management If hypertensive emergency is suspected, evaluation and therapy should occur concurrently [431, 435, 436]. Targeted history and physical examination should seek the potential etiology of HTN and severity and duration of HTN. This includes assessing for end-organ damage and contraindications to urgent initiation of therapy such as head trauma, stroke, intracranial mass, and pain. In contrast to adults, where severe HTN is most often due to uncontrolled primary HTN, children and adolescents are more likely to have secondary HTN (See Table 13 for age speciﬁc common etiologies of severe HTN). Assuming that the clinical setting permits, a basic investigation of children without a known etiology of HTN may be done prior to administration of antihypertensive agents and should include serum chemistries, BUN, creatinine, PRA, aldosterone, plasma metanephrines, urinalysis, and urine catecholamines.

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When patients are more stable, evaluation should expand to imaging studies such as renal ultrasonography to screen for renal structural and parenchymal disease and echocardiography to evaluate for left ventricular hypertrophy. Because renal ultrasonography with Doppler study is not deﬁnitive to diagnose renal vascular disease [437], it may be further investigated with computed tomography angiography, magnetic resonance angiography, and/or digital subtraction angiography. Dilated ophthalmologic exam should also take place. Brain MRI should be obtained if there is concern for posterior reversible encephalopathy syndrome (PRES).

Antihypertensive Therapy Table 14 lists antihypertensive agents used to treat children and adolescents with acute HTN. As in the case with many pediatric antihypertensive medications, a number of these agents do not have pediatric FDA approval for acute HTN. A review of multiple adult studies failed to produce statistical superiority of any single agent, and the outcome was not uniform between studies [438]. As a general rule, agents with short duration of action are preferred such that when BP reduction is gauged as excessive, the effect can be quickly reversed by stopping the agent and/or administering normal saline. One of the most important goals of hypertensive emergency and urgency therapy is prompt but gradual lowering of BP because the duration of HTN is often difficult to determine upon presentation. The current recommendation is to reduce mean arterial pressure by no more than 25 % within the first 8–12 h and then gradually normalize it in the next 48–72 h [431, 439]. Such approach tends to reduce the risk of organ ischemia including cerebral hypoperfusion and even death [431, 440]. Figure 5 is an algorithm for treating hypertensive crisis including unique considerations for specific secondary HTN. After the initial assessment, the provider must consider factors such as the type and severity of hypertensive symptoms, BP measurement, patient location within the

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Table 14 Antihypertensive agents for acute HTN (from Ref. [438]) Drug Nicardipine

Class CCB

Labetalol

α- and β-adrenergic blocker

Hydralazine

Direct vasodilator

Esmolol

β1 adrenergic blocker ACEI

Enalaprilat Fenoldopam

Route IV bolus or infusion IV bolus or infusion

Dose Bolus: 30 μg/kg up to 2 mg/dose; infusion: 0.5–4 μg/kg/min Bolus: 0.2–1 mg/kg/ dose, up to 40 mg/dose; infusion 0.25–3 mg/kg/h

IV bolus or IM IV infusion IV bolus IV infusion

IV: 0.2–0.6 mg/kg, maximum single dose 20 mg 100–500 μg/kg/min, up to 1,000 μg/kg/min 5–10 μg/kg/dose up to 1.2 mg/dose 0.2–0.8 μg/kg/min

IV infusion

0.5–10 μg/kg/min

IV bolus IV infusion

0.05–0.1 mg/kg/dose, up to 5 mg 0.5–3.5 μg/kg/min (limited pediatric data on dosing) 1–3 mg/kg every 5–15 min

Sodium nitroprusside

Dopamine receptor agonist Direct vasodilator

Phentolamine

α blocker

Clevidipine

CCB

Diazoxide

Direct vasodilator

IV bolus

Isradipine

CCB

Clonidine

Central α agonist

Minoxidil

Direct vasodilator

0.05–0.1 mg/kg/dose up to 5 mg/dose 0.05–0.1 mg/dose, may be repeated up to 0.8 mg total 0.1–0.2 mg/kg/dose up to 10 mg/dose

hospital, and tolerability of oral medication, in order to determine whether IV or oral agents are the optimal initial therapy. With the exception of hypertensive children with intracranial hemorrhage, ischemic or traumatic brain injury, those with hypertensive emergency may be managed by careful administration of an initial IV bolus of labetalol or hydralazine. Subsequently, these children should be transferred to the intensive care unit where continuous infusion of nicardipine or labetalol can be used with an intra-arterial catheter to continuously monitor BP. In hypertensive

Comments May cause reﬂex tachycardia

Contraindicated in asthma, heart failure, and diabetics. May cause hyperkalemia and hypoglycemia. Does not cause reflex tachycardia May cause reflex tachycardia, fluid retention, or headaches. When given as IV bolus, give every 4 h May cause bradycardia. Contraindicated in asthma and heart failure. Very short acting May cause prolonged hypotension, hyperkalemia, and acute renal failure Limited pediatric experience

Associated with cyanide and thiocyanate toxicity. Monitor cyanide levels with prolonged use (>48 h) or in hepatic or renal failure; or co-administer with sodium thiosulfate May cause tachycardia Contraindicated in those with egg and soy allergy as well as lipid disorders Large boluses may result in severe hypotension, no longer available in many countries Stable suspension can be compounded Side effects include dry mouth and sedation

Most potent vasodilator; long acting; longterm effects include ﬂuid retention and hirsutism

urgency, oral agents such as isradipine and clonidine are recommended. If a child cannot tolerate oral medication, the use of IVagents is acceptable. These patients must have follow-up BP monitoring with the oscillometric device programmed to measure BP at short intervals.

IV Agents Recommended ﬁrst-line IV bolus agents are hydralazine and labetalol [441]. Nitroprusside

Management of the Hypertensive Child

Fig. 5 Proposed algorithm for management of acute HTN in children and adolescents. CHF congestive heart failure, IV intravenous, PO oral, GN glomerulonephritis, NE neuroendocrine, BP blood pressure (from Ref. [438])

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Severe acute hypertension

Life-threatening symptoms (seizures, CHF, etc)

Minor symptoms (nausea, headache, vomiting)

Hypertensive emergency

Hypertensive urgency

Bolus dose of IV hydralazine or labetalol followed by nicardipine or labetalol infusion

Unable to tolerate PO medication: IV hydralazine or labetalol

Able to tolerate PO medication: isradipine or clonidine

Consider these a gents in unique secondary hypertension cases GN: Loop diuretics NE tumor: α-blocker followed by β-blocker Drug overdose: Phentolamine and lorazepam Pregnancy: Labetalol or hydralazine Convert to scheduled long acting antihypertensive agents when BP in the range of 90th–95th percentile for age, gender and height

was traditionally used, but has fallen out of favor because of concerns for cyanide toxicity and tachyphylaxis with prolonged use. Recommended ﬁrst-line continuous IV agents are nicardipine and labetalol which have been studied in pediatric patients although not in a randomized controlled fashion [421, 424]. Other less commonly used agents include esmolol [442] and enalaprilat [426]. Enalaprilat is the only available IV ACE inhibitor, and it can induce acute kidney injury, oliguria, and hyperkalemia [426]. Its use in neonates and patients with chronic kidney disease and volume depletion should be avoided. Other agents such as fenoldopam and clevidipine have not been used frequently in pediatrics, but they may be promising based on studies of these agents during surgery [443, 444].

Oral Agents Oral agents should be limited to acute hypertensive patients with minimal or mild symptoms such as nausea and headache. Most commonly used agents in this setting are isradipine and clonidine mainly because of their availability as stable oral suspensions. Isradipine has been studied for acute HTN in hospitalized setting where all age groups between 0.1 and 21.9 years were found to have significant reduction in BP with doses of 0.06–0.11 mg/kg [428]. This study identified a group of patients that experienced significant hypotension with isradipine who were concurrently taking azole antifungals, a known inhibitor of isradipine metabolism. The study also recommended an initial dose of 0.05 mg/kg rather

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than 0.1 mg/kg for children or =55 years of age with systemic hypertension. Am J Cardiol. 2005;95(9):1060–4. Epub 22 Apr 2005.

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2096 405. Baumwell S, Karumanchi SA. Pre-eclampsia: clinical manifestations and molecular mechanisms. Nephron Clin Pract. 2007;106(2):C72–81. 406. Conrad KP, Benyo DF. Placental cytokines and the pathogenesis of preeclampsia. Am J Reprod Immunol. 1997;37(3):240–9. 407. Molnar M, Suto T, Toth T, Hertelendy F. Prolonged blockade of nitric oxide synthesis in gravid rats produces sustained hypertension, proteinuria, thrombocytopenia, and intrauterine growth retardation. Am J Obstet Gynecol. 1994;170(5 Pt 1):1458–66. Epub 01 May 1994. 408. Yallampalli C, Garfield RE. Inhibition of nitric oxide synthesis in rats during pregnancy produces signs similar to those of preeclampsia. Am J Obstet Gynecol. 1993;169(5):1316–20. Epub 01 Nov 1993. 409. Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med. 2006;354(23): 2443–51. Epub 09 June 2006. 410. Wagner SJ, Barac S, Garovic VD. Hypertensive pregnancy disorders: current concepts. J Clin Hypertens (Greenwich). 2007;9(7):560–6. Epub 10 July 2007. 411. Nickavar A, Assadi F. Managing hypertension in the newborn infants. Int J Prevent Med. 2014;5 Suppl 1: S39–43. Epub 03 May 2014. 412. Dionne JM, Abitbol CL, Flynn JT. Hypertension in infancy: diagnosis, management and outcome. Pediatr Nephrol. 2012;27(1):17–32. Epub 25 Jan 2011. 413. Seliem WA, Falk MC, Shadbolt B, Kent AL. Antenatal and postnatal risk factors for neonatal hypertension and infant follow-up. Pediatr Nephrol. 2007;22 (12):2081–7. Epub 18 Sept 2007. 414. Flynn JT. Neonatal hypertension: diagnosis and management. Pediatr Nephrol. 2000;14(4):332–41. Epub 25 Apr 2000. 415. Abman SH, Groothius JR. Pathophysiology and treatment of bronchopulmonary dysplasia. Current issues. Pediatr Clin North Am. 1994;41(2):277–315. Epub 01 Apr 1994. 416. Nwankwo MU, Lorenz JM, Gardiner JC. A standard protocol for blood pressure measurement in the newborn. Pediatrics. 1997;99(6):E10. Epub 01 June 1997. 417. Kent AL, Kecskes Z, Shadbolt B, Falk MC. Normative blood pressure data in the early neonatal period. Pediatr Nephrol. 2007;22(9):1335–41. Epub 18 Apr 2007. 418. Zubrow AB, Hulman S, Kushner H, Falkner B. Determinants of blood pressure in infants admitted to neonatal intensive care units: a prospective multicenter study. Philadelphia Neonatal Blood Pressure Study Group. J Perinatol. 1995;15(6):470–9. Epub 01 Nov 1995. 419. Kilian K. Hypertension in neonates causes and treatments. J Perinat Neonatal Nurs. 2003;17(1):65–74; quiz 5–6. Epub 29 Mar 2003. 420. Buchi KF, Siegler RL. Hypertension in the first month of life. J Hypertens. 1986;4(5):525–8. Epub 01 Oct 1986.

D. Ellis and Y. Miyashita 421. Flynn JT, Mottes TA, Brophy PD, Kershaw DB, Smoyer WE, Bunchman TE. Intravenous nicardipine for treatment of severe hypertension in children. J Pediatr. 2001;139(1):38–43. Epub 11 July 2001. 422. Gouyon JB, Geneste B, Semama DS, Francoise M, Germain JF. Intravenous nicardipine in hypertensive preterm infants. Arch Dis Child Fetal Neonatal Ed. 1997;76(2):F126–7. Epub 01 Mar 1997. 423. Wiest DB, Garner SS, Uber WE, Sade RM. Esmolol for the management of pediatric hypertension after cardiac operations. J Thorac Cardiovasc Surg. 1998;115(4):890–7. Epub 12 May 1998. 424. Thomas CA, Moffett BS, Wagner JL, Mott AR, Feig DI. Safety and efficacy of intravenous labetalol for hypertensive crisis in infants and small children. Pediatr Crit Care Med. 2011;12(1):28–32. Epub 25 May 2010. 425. Benitz WE, Malachowski N, Cohen RS, Stevenson DK, Ariagno RL, Sunshine P. Use of sodiumnitroprusside in neonates – efficacy and safety. J Pediatr. 1985;106(1):102–10. 426. Wells TG, Bunchman TE, Kearns GL. Treatment of neonatal hypertension with enalaprilat. J Pediatr. 1990;117(4):664–7. Epub 01 Oct 1990. 427. Mason T, Polak MJ, Pyles L, Mullett M, Swanke C. Treatment of neonatal renovascular hypertension with intravenous enalapril. Am J Perinatol. 1992;9(4): 254–7. Epub 01 July 1992. 428. Miyashita Y, Peterson D, Rees JM, Flynn JT. Isradipine for treatment of acute hypertension in hospitalized children and adolescents. J Clin Hypertens (Greenwich). 2010;12(11):850–5. Epub 09 Nov 2010. 429. Guron G, Friberg P. An intact renin-angiotensin system is a prerequisite for normal renal development. J Hypertens. 2000;18(2):123–37. Epub 29 Feb 2000. 430. Engelhardt B, Elliott S, Hazinski TA. Short- and longterm effects of furosemide on lung function in infants with bronchopulmonary dysplasia. J Pediatr. 1986;109(6):1034–9. Epub 01 Dec 1986. 431. Flynn JT, Tullus K. Severe hypertension in children and adolescents: pathophysiology and treatment. Pediatr Nephrol. 2009;24(6):1101–12. Epub 08 Oct 2008. 432. Traon AP, Costes-Salon MC, Galinier M, Fourcade J, Larrue V. Dynamics of cerebral blood flow autoregulation in hypertensive patients. J Neurol Sci. 2002;195(2):139–44. Epub 19 Mar 2002. 433. Elliott WJ. Hypertensive emergencies. Crit Care Clin. 2001;17(2):435–51. Epub 14 July 2001. 434. Kase CS. Hypertensive vascular disease and cerebral microcirculation. Neurologia. 1999;14 Suppl 2:22–30. Epub 24 June 1999. Enfermedad vascular hipertensiva y microcirculacion cerebral. 435. Singh D, Akingbola O, Yosypiv I, El-Dahr S. Emergency management of hypertension in children. Int J Nephrol. 2012;2012:420247. Epub 12 May 2012. 436. Patel HP, Mitsnefes M. Advances in the pathogenesis and management of hypertensive crisis. Curr Opin Pediatr. 2005;17(2):210–4. Epub 01 Apr 2005.

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437. Tullus K, Roebuck DJ, McLaren CA, Marks SD. Imaging in the evaluation of renovascular disease. Pediatr Nephrol. 2010;25(6):1049–56. Epub 27 Oct 2009. 438. Cherney D, Straus S. Management of patients with hypertensive urgencies and emergencies: a systematic review of the literature. J Gen Intern Med. 2002;17 (12):937–45. Epub 11 Dec 2002. 439. Suresh S, Mahajan P, Kamat D. Emergency management of pediatric hypertension. Clin Pediatr. 2005;44 (9):739–45. Epub 06 Dec 2005. 440. Marik PE, Rivera R. Hypertensive emergencies: an update. Curr Opin Crit Care. 2011;17(6):569–80. Epub 12 Oct 2011. 441. Webb TN, Shatat IF, Miyashita Y. Therapy of acute hypertension in hospitalized children and adolescents. Curr Hypertens Rep. 2014;16(4):425. Epub 14 Feb 2014. 442. Tabbutt S, Nicolson SC, Adamson PC, Zhang X, Hoffman ML, Wells W, et al. The safety, efﬁcacy, and pharmacokinetics of esmolol for blood pressure control immediately after repair of coarctation of the aorta in infants and children: a multicenter, doubleblind, randomized trial. J Thorac Cardiovasc Surg. 2008;136(2):321–8. Epub 12 Aug 2008. 443. Tobias JD, Schechter WS, Phillips A, Weinstein S, Michler R, Berkenbosch JW, et al. Clevidipine for perioperative blood pressure control in infants and children undergoing cardiac surgery for congenital heart disease. J Pediatr Pharmacol Ther. 2011;16(1): 55–60. Epub 01 Jan 2011. 444. Hammer GB, Verghese ST, Drover DR, Yaster M, Tobin JR. Pharmacokinetics and pharmacodynamics of fenoldopam mesylate for blood pressure control in pediatric patients. BMC Anesthesiol. 2008;8:6. Epub 08 Oct 2008.

2097 445. Thomas CA. Drug treatment of hypertensive crisis in children. Paediatr Drugs. 2011;13(5):281–90. Epub 06 Sept 2011. 446. Kirsten R, Nelson K, Kirsten D, Heintz B. Clinical pharmacokinetics of vasodilators. Part II. Clin Pharmacokinet. 1998;35(1):9–36. Epub 23 July 1998. 447. Constantine E, Linakis J. The assessment and management of hypertensive emergencies and urgencies in children. Pediatr Emerg Care. 2005;21(6):391–6; quiz 7. Epub 09 June 2005. 448. Egger DW, Deming DD, Hamada N, Perkin RM, Sahney S. Evaluation of the safety of short-acting nifedipine in children with hypertension. Pediatr Nephrol. 2002;17(1):35–40. Epub 17 Jan 2002. 449. Sasaki R, Hirota K, Masuda A. Nifedipine-induced transient cerebral ischemia in a child with Cockayne syndrome. Anaesthesia. 1997;52(12):1236. Epub 05 Mar 1998. 450. Castaneda MP, Walsh CA, Woroniecki RP, Del Rio M, Flynn JT. Ventricular arrhythmia following short-acting nifedipine administration. Pediatr Nephrol. 2005;20(7):1000–2. Epub 10 May 2005. 451. MacDonald JL, Johnson CE, Jacobson P. Stability of isradipine in an extemporaneously compounded oral liquid. Am J Hosp Pharm. 1994;51(19):2409–11. Epub 01 Oct 1994. 452. Flynn JT. Nifedipine in the treatment of hypertension in children. J Pediatr. 2002;140(6):787–8. Epub 20 June 2002. 453. Truttmann AC, Zehnder-Schlapbach S, Bianchetti MG. A moratorium should be placed on the use of short-acting nifedipine for hypertensive crises. Pediatr Nephrol. 1998;12(3):259. Epub 18 June 1998. 454. Hollander JE. Cocaine intoxication and hypertension. Ann Emerg Med. 2008;51(3 Suppl):S18–20. Epub 15 Jan 2008.

Part X Acute Renal Injury

Pathogenesis of Acute Kidney Injury

David P. Basile, Rajasree Sreedharan, and Scott K. Van Why

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2102 Phases of Acute Kidney Injury . . . . . . . . . . . . . . . . . . . 2102 Renal Hemodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Renin-Angiotensin System . . . . . . . . . . . . . . . . . . . . . . . . . Arachidonic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adenosine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endothelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nitric Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2104 2105 2105 2106 2106 2107

Repair Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Heat Shock Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Regeneration: Growth Factors . . . . . . . . . . . . . . . . . . . . . Regeneration: Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . Long-Term Sequelae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2120 2120 2121 2122 2123

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2125 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2125

Alterations in Microvasculature . . . . . . . . . . . . . . . . . 2107 Nephronal Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2108 Tubule Segment Susceptibility to Injury . . . . . . . . . . . 2109 Intratubular Obstruction and Backleak . . . . . . . . . . . . . 2109 Cellular and Metabolic Alterations . . . . . . . . . . . . . . Adenine Nucleotide Metabolism . . . . . . . . . . . . . . . . . . . Reactive Oxygen Molecules . . . . . . . . . . . . . . . . . . . . . . . . Intracellular Calcium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phospholipids and Lipases . . . . . . . . . . . . . . . . . . . . . . . . . Disruption of Tubule Cell Architecture . . . . . . . . . . . .

2110 2110 2111 2112 2113 2114

Cell Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2115 Necrosis and Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2115 Autophagy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2117 Inﬂammatory Response . . . . . . . . . . . . . . . . . . . . . . . . . . . 2117 Genetic Susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2118 Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2119

D.P. Basile Indiana University School of Medicine, Indianapolis, IN, USA R. Sreedharan • S.K.Why (*) Medical College of Wisconsin, Milwaukee, WI, USA e-mail: [emailprotected] # Springer-Verlag Berlin Heidelberg 2016 E.D. Avner et al. (eds.), Pediatric Nephrology, DOI 10.1007/978-3-662-43596-0_56

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Introduction The sudden loss of renal function that may result from inadequate renal perfusion, arterial or venous obstruction, renal cell injury, or acute obstruction to urine flow historically has been termed acute renal failure (ARF). Several years ago the term acute kidney injury (AKI) was proposed to replace the term ARF [1]. Usage of “AKI” is now widespread. Unfortunately it is often used imprecisely, defeating the purpose of the change in nomenclature. AKI was not meant simply to be synonymous with the old term ARF, nor the more similar old term acute tubule necrosis (ATN). The change was meant to standardize the definition to reflect the spectrum of the condition and mechanisms that underlie the accompanying renal dysfunction. The modern term was intended to facilitate translation of knowledge gained from basic science studies of AKI and thereby contribute to improved clinical studies of AKI by defining affected patients more precisely. In so doing, evaluation of potential biomarkers as predictive of severity of renal injury and outcomes could be enhanced [2]. In addition, specific welldefined target populations could then be chosen for translational studies of potential treatment modalities, identified in basic science studies of AKI, which had been found to limit injury or enhance recovery of injured renal cells from a specific insult. The operative word in the term AKI is “injury,” and the unifying feature of AKI has been understood to be primarily renal tubule cell injury, although cellular injury in other compartments of the kidney is now being elucidated. The clinical manifestations of AKI can range from a minimal but sustained elevation in serum creatinine (renal insufficiency) to anuric renal failure. Rapidly and fully reversible causes of acute renal functional insufficiency, such as acute and reversible cardiac insufficiency or volume depletion, are specifically excluded from the spectrum of AKI [1]. Thus, the use of the term “prerenal AKI” is both nonsensical and antiquated [3], effectively reverting back to the old imprecise term ARF and accompanying terms such as “prerenal ARF.” More precise and clear, then, is to keep the term AKI separate from potentially rapidly reversible prerenal causes of acute renal insufficiency. As intended, this

D.P. Basile et al.

can facilitate improved patient care and targeted clinical studies of AKI separate from rapidly reversible causes of renal insufficiency. The review of the pathogenesis of AKI in this chapter, then, is restricted to this precise definition. Renal cell injury results from an ischemic, toxic (e.g., myoglobin), or toxicant (e.g., aminoglycoside) insult, which causes acute tubular damage with an accompanying loss of ability to reabsorb filtered solute. The resulting decrease in glomerular filtration rate (GFR), an invariable component of AKI, can therefore be viewed as a successful adaptive response, since continued filtration of plasma across the glomerular basement membrane without reabsorption of the filtrate by injured renal tubules would result in massive losses of salt and water [4]. Thus, the decreased GFR associated with AKI prevents severe depletion of extracellular fluid. Renal ischemia is both the most common isolated cause of AKI and most common contributor to multifactorial AKI, such as in sepsis syndrome with multi-organ dysfunction. For decades, AKI studies have focused on models of ischemic renal cell injury. From these studies it is clear that AKI manifestations can range from mild, sublethal cell injury with disrupted renal cell architecture and function to fulminant necrotic cell death (i.e., ATN). Furthermore, both extremes, along with the full spectrum of intervening cell injury features, can be present simultaneously or sequentially after the insult (Fig. 1). We describe the pathophysiology of AKI, as revealed in experimental models, both in vivo and in vitro, of ischemia-induced AKI. Included are classical concepts of ATN as well as a contemporary understanding of the vascular, cellular, molecular, and metabolic alterations associated with renal cell injury. Mechanisms that lead to cell injury and death will be addressed along with processes that can result in cellular repair and renal recovery.

Phases of Acute Kidney Injury Clinically, AKI can be divided into initiation, extension, maintenance, and recovery phases. These clinical phases directly relate to cellular

Pathogenesis of Acute Kidney Injury

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Fig. 1 Disruption and recovery of renal tubule architecture. Ischemia disrupts normal polar distribution of membrane transport proteins and adhesion molecules, causing loss, respectively, of reabsorptive function and tubule integrity. Sublethally injured cells can recover normal structure and function. More severely injured cells die of

apoptosis or necrosis, resulting in denudation and obstruction of the tubule. Restoration of tubule structure proceeds through dedifferentiation, proliferation, and redifferentiation processes likely mediated by growth factors and stem cells

events that occur during the injury and recovery process (Fig. 2). The initiation phase of AKI occurs when renal blood ﬂow decreases to a level causing severe cellular ATP depletion that in turn leads to acute renal tubule cell injury and dysfunction [5]. Renal ischemia rapidly induces a number of structural and functional alterations in renal proximal tubule cells that are directly related spatially and temporally with disruption of the normal framework of ﬁlamentous actin (F-actin) [6–8] (described later in this chapter). The extent of these alterations depends on the severity and duration of ischemia. Although these alterations may fall short of being lethal to the cell, they disrupt the ability of renal tubules to maintain normal function. In addition, ischemic injury to vascular smooth muscle and endothelial cells during the initiation phase contributes to the structural abnormalities observed in the renal vasculature in ischemic AKI [9–11]. Recent studies show

that “activation” of epithelial and possibly endothelial cells during the early initiation phase induces a variety of chemokines and cytokines [12, 13] that are instrumental in initiating the inflammatory cascade (see below). The cellular localization of these phenomena within the kidney is just beginning to be elucidated [14]. The extension phase, which occurs during reperfusion, is promoted by continued regional hypoxia along with triggering of an inflammatory response (Fig. 2). Both events are more pronounced in the corticomedullary junction (CMJ), or outer medullary region, of the kidney [12, 15]. It is during this phase that renal vascular endothelial cell damage appears to play a central role in the continued ischemia of renal tubules, as well as in the accompanying inflammatory response. Tubule cells continue to undergo injury and death, with both necrosis and apoptosis occurring predominantly in the outer medulla [16].

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Ischemia 100

Repair

Initiation

GFR (%)

Cell Injury

BBM loss Exfoliation Tubular Obstruction

Redifferentiation Repolarization CMJ Hypoxia Microvascular injury with obstruction, Ex te coagulopathy & inflammation n

Dedifferentiation Migration Proliferation

sio

ov ec

ery

Maintenance 00

Days Fig. 2 Relationship of cellular to clinical phases of AKI. Impaired renal blood ﬂow causes the initiation phase with onset of cellular injury, particularly in the proximal tubule (BBM brush border membrane). The extension phase is manifested by microvascular injury triggering inﬂammatory processes and causing ongoing corticomedullary

junction (CMJ) hypoxia. During the maintenance phase, GFR reaches a nadir as cellular repair begins. The recovery phase is marked by progressive cell and organ structural and functional recovery, with concomitant improvement in GFR (From Ref. [76])

In contrast, the proximal tubule cells in the outer cortex, where blood flow has returned to near normal levels, undergo cellular repair during this phase. As cellular injury continues in the CMJ region during the extension phase, the GFR continues to fall. There is continued production and release of chemokines and cytokines that further enhance the inflammatory cascade [17]. Leukocytes infiltrate in as early as 2 h, and inflammatory cell infiltration in the outer medullary region of the kidney is significant by 24 h following ischemia [18–21]. During the maintenance phase of AKI, tubule cells undergo dedifferentiation, repair, migration, and proliferation in an attempt to restore cellular and tubule integrity (Fig. 2). GFR is stable but remains substantially diminished. The cellular repair and reorganization during this phase sets the stage for improvement in global organ function. Blood flow returns toward normal, and cellular homeostasis is restored. During the recovery phase, return of cellular differentiation, epithelial

polarity, and normal cellular and organ function is achieved [8, 18–23]. Thus, renal function is directly linked to the cycle of cell injury and recovery.

Renal Hemodynamics Renal vasoconstriction is intense in experimental and clinical AKI [24]. Because vasoconstriction was considered to be the dominant factor, it was suggested long ago that the term “vasomotor nephropathy” might be more appropriate than acute renal failure to describe this condition [25]. The hypothesis was that an insult to the renal tubular epithelium results in release of vasoactive compounds that increase cortical vascular resistance causing a decrease in renal blood ﬂow (RBF), thus perpetuating injury to the tubule and furthering the cycle. Release of vasoconstrictive compounds may then diminish GFR by constricting afferent and efferent arterioles,

Pathogenesis of Acute Kidney Injury

thereby causing diminished urine output, or oliguria. Candidates for the vasoconstrictive components of AKI include angiotensin, metabolites of arachidonic acid, adenosine, endothelin, and nitric oxide.

Renin-Angiotensin System The renin-angiotensin system (RAS) functions in a manner consistent with the renal vasoconstriction hypothesis [26]. Several pathophysiological factors may enhance RAS activity in the development of AKI. Volume depletion or reduction in renal perfusion pressure will activate the RAS, which initially may be adaptive to preserve GFR. However, prolongation of this hypoperfusion state will result in frank parenchymal tissue damage, heralding the onset of AKI. Proximal tubule damage then results in reduced solute reabsorption and increased distal nephron solute delivery, which can amplify tubular glomerular feedback. Several findings suggest that this system may have a role in the pathogenesis of AKI: (a) hyperplasia of the juxtaglomerular apparatus with increased renin granules is found both in patients and in experimental animals with AKI, (b) plasma renin activity is increased in patients with AKI, and (c) changing intrarenal renin content modifies the degree of renal functional impairment. For example, feeding animals a high-salt diet, which suppresses renin production, prior to a renal injury preserves renal function compared with animals fed a low-salt diet, which stimulates renin production. Furthermore, losartan, an Angiotensin II type 1 (AT1) receptor antagonist, prevents ischemic AKI in rats; however, this effect has largely been attributed to an effect of AT1 receptor activity on inflammatory cells rather than on vascular tone [27]. Other findings suggest that the RAS is not fully responsible for the changes in renal hemodynamics and function in AKI. The degree of renal injury is not changed by immunizing animals against renin-angiotensin, treating with angiotensinconverting enzyme inhibitors, or infusing with a competitive antagonist to Angiotensin II.

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Therefore, the role of the RAS as the modulator of renal injury in AKI is uncertain despite extensive investigation. Nevertheless, recent ﬁndings have renewed interest in this pathway, since it appears that a hormone downstream from renin and angiotensin, aldosterone, may play a central role in ischemiainduced AKI [28]. Prior mineralocorticoid receptor (MR) blockade with spironolactone was found to prevent the typical reductions in RBF and GFR during reperfusion after ischemia and substantially reduced accompanying renal histological damage and tubule apoptosis. The protection conferred by MR blockade correlated with changes in other pathways that have been implicated in AKI. Primarily, it appeared that MR blockade decreased oxidative stress present during reperfusion after renal ischemia.

Arachidonic Acid Arachidonic acid (AA) is released from membrane phospholipids in the renal outer medulla in response to ischemia. AA can then be metabolized by several enzymes to produce various vasoactive compounds. One pathway is through cyclooxygenases to produce prostaglandins, several of which are potent renal vasodilators. While inhibition of prostaglandin production is associated with decreased RBF and can affect the severity of AKI, the precise role of prostaglandins in the induction and maintenance of AKI is not established [6]. Prostaglandin inhibitors, such as nonsteroidal anti-inﬂammatory drugs, increase the risk for development of AKI and may act synergistically with other insults [29]. AA can also be metabolized to 20-hydroxyeicosatetraenoic acid (20-HETE) by cytochrome P450 ω-hydroxylase. In the kidney, 20-HETE modulates vascular tone, RBF, and sodium transport in the tubule. Recent studies have demonstrated a role for 20-HETE in ischemic AKI [30]. Ischemia induces a dramatic increase in 20-HETE in the rat kidney. Inhibition of 20-HETE synthesis worsens AKI. Administration of 20-HETE analog ameliorates ischemic AKI and prevents the typical postischemic

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decrease in renal medullary blood ﬂow in rat kidneys. So, 20-HETE may mitigate AKI by preventing postischemic medullary hypoxia by increasing renal medullary blood ﬂow [30].

Adenosine Adenosine, produced from catabolism of adenine nucleotides, is a potent vasoconstrictor of renal vasculature, whereas it is a vasodilator of peripheral vasculature [31]. The infusion of methylxanthines, which block adenosine receptors, inhibits the tubuloglomerular feedback mechanism and the decrease in GFR that accompanies reduced tubular absorption, suggesting that adenosine may be involved in the modulation of renal vascular resistance in AKI. In some experimental models, infusion of methylxanthines has been associated with diminished functional impairment. The proposal that adenosine is an important vasoactive compound following an acute tubule insult is attractive, because it would link alterations in cell metabolism with hemodynamic changes. However, the evidence that adenosine is a major factor in the vasoconstrictive response is inconclusive because of the following: (a) methylxanthines have a variety of effects in addition to the inhibition of adenosine receptors; (b) although adenosine is produced following the initiation of adenine nucleotide catabolism, it is rapidly catabolized by adenosine deaminase when released into extracellular fluid; (c) intrarenal levels of adenosine diminish very rapidly upon the establishment of reflow to the kidney, while renal vasoconstriction is continued through the early phases of reperfusion following an ischemic injury; and (d) when tissue adenosine levels are increased by inhibition of adenosine deaminase during ischemia, postischemic recovery of renal function is enhanced [32]. A recent study in the A1 adenosine receptor (A1AR) mouse knockout model may help reconcile these apparent discrepant effects of adenosine on renal blood flow and AKI. The increased delivery of sodium chloride to the macula densa due to dysfunction of the ischemic proximal tubule

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would be expected to cause afferent arteriolar constriction (i.e., tubuloglomerular feedback) via A1AR activation and thereby decrease GFR [33]. However, knockout of the A1AR resulted in a paradoxical worsening of ischemic renal injury, and exogenous activation of A1AR was protective [34]. Thus, tubuloglomerular feedback following ischemic injury, contributed to by activation of adenosine receptors, may be an adaptive response that limits delivery of solute to damaged proximal tubules, thereby reducing the demand for ATP-dependent resorptive processes. The effect of exogenous A1AR activation in human AKI is not known.

Endothelin Endothelin, among its various biological activities, is a potent renal vasoconstrictor [35–38]. Endothelin conveys its effects via at least two distinct receptor subtypes: the ET-A and ET-B receptors. Activation of either receptor has the potential to reduce GFR. Raised endothelin levels in plasma and in both the cortex and medulla of the kidney are found in experimental animals after induction of renal ischemia [35]. In a rat model of cold ischemic storage and transplant, pre-pro-endothelin mRNA was upregulated and immunoreactive ET-1 localized in the peritubular capillary endothelial cells following reperfusion injury [39]. The postischemic infusion of anti-endothelin antibody or endothelin receptor antagonists provides protection from ischemic injury in animal models [35–37, 40, 41]. Nonselective and ET-Aspeciﬁc antagonists protect rats from AKI [42–44]. Selective ET-A antagonism inhibits afferent arteriolar constriction, while speciﬁc activation of ET-B resulted in both afferent constriction and efferent vasodilation [45]. In humans, there is evidence that the endothelin system may be activated in the setting of acute kidney injury. Increased endothelin levels are found in patients with AKI due to severe sepsis [46]. However, the effect of ET antagonism in humans is less clear, as it did not afford protection against contrast-induced nephropathy [47].

Pathogenesis of Acute Kidney Injury

Nitric Oxide Nitric oxide (NO) is a potent renal vasodilator, which is widely distributed in the kidney, and is produced by constitutive and inducible synthetases located in endothelial cells and renal tubules [48]. While a specific role for these compounds in cerebral ischemia has been established [49], the effect of either stimulation or inhibition of nitric oxide synthetase (NOS) on ischemic or toxic AKI is confusing and, at times, contradictory. The apparent contradictory effects are likely attributable to the differential distribution and specific effects of each NOS isoform on renal vasculature and tubules. Nonselective NOS inhibition was found to worsen renal function and cause profound renal vasoconstriction [49]. NOS3 (endothelial NOS) is produced at high levels in the renal medulla [50] and may be important to counter renal vasoconstrictors such as Angiotensin II to preserve medullary blood flow [51]. Following renal injury, endothelial NOS function is impaired with accompanying loss of vasodilator responses to acetylcholine and bradykinin [52]. In addition, NOS3 knockout mice manifest more renal damage in response to endotoxin [53]. Increasing renal NO activity by administration of L-arginine, the NO donor molsidomine, or the eNOS cofactor tetrahydrobiopterin can preserve renal vascular perfusion and attenuate AKI induced by ischemia [54–59]. In contrast, the rat kidney was protected from ischemic injury when inducible NOS was targeted with antisense oligonucleotides, suggesting that NO had a direct cytotoxic effect on renal epithelia [60]. A similar cytotoxic effect of NO was found in isolated proximal tubule cells subjected to hypoxia [61]. Therefore, inducible NOS, either by promoting inflammation or oxidative stress, may be deleterious to the kidney. Hence the contradiction: stimulation of NO in the renal vasculature via NOS could modulate vasoconstriction and potentially lessen AKI, but induction of NO via NOS in renal tubules is cytotoxic [48, 49, 60]. So, this complex biological system may indeed play a role in the pathogenesis of AKI, but the specificity of action remains to be

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determined and may depend on whether vascular or tubular effects of NOS predominate in a particular setting. Interestingly, urinary nitrate, a metabolite of NO, was found to be elevated in children with early AKI in a pediatric emergency center suggesting more study of the NO pathway is warranted in the study of AKI [62]. All things considered, persistent renal vasoconstriction is a well-documented event during reperfusion following renal ischemia, but once AKI has been established, the infusion of potent vasodilators such as prostaglandins or dopamine does not lead to sustained improvement in GFR [63, 64]. Confirming the findings of animal studies, several human trials of renal vasodilators such as dopamine have failed to demonstrate improvement in GFR in established AKI despite augmentation of total renal blood flow [65]. Although renal hemodynamic factors play an important role in initiating AKI, alterations in renal vascular resistance and renal perfusion on a macroscopic scale may not be dominant determinants of renal epithelial cell injury. They may, in fact, be an adaptive response to ameliorate further cellular injury during reperfusion. On the other hand, microvascular alterations are now recognized to play a major role, as discussed below.

Alterations in Microvasculature A consistent observation is medullary vascular congestion following experimentally induced ischemic renal injury. Advances in recent years, including application of in vivo microscopy, have given substantial credence to the concept that injury to the vascular endothelium is central to the initiation and extension of AKI. The microvascular endothelium undergoes direct structural alterations after an ischemic insult and is both a source of and a target for inﬂammatory injury [66–70]. Similar to features described years earlier in tubule epithelial cells, an ischemic insult has been found to disrupt the structural integrity of both the actin cytoskeleton within endothelial cells and the junctional complexes between endothelial cells [10, 71]. Consequent endothelial cell

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swelling, bleb formation, and cell death or detachment of viable cells occurs, and circulating endothelial cells have been found in humans with septic shock [72]. Sites of endothelial denudation may be prone to prolonged vasoconstriction. Minimally invasive intravital microscopy in animals has revealed sporadic cessation and even reversal of blood flow in peritubular capillaries of the renal cortex during reperfusion [73, 74]. Nearinfrared laser speckle blood flow imaging shows that AKI in animal models was associated with an increase in the heterogeneity of blood flow, which is independent of total organ perfusion [75]. Such heterogeneity may underlie the focal hypoxia that contributes to the extension of renal injury during reperfusion. Administration of fully differentiated endothelial cells into postischemic rat kidneys ameliorated these early alterations in microvascular flow and the subsequent loss of GFR [74]. Similar but less impressive amelioration of AKI was achieved using surrogate cells expressing endothelial nitric oxide synthase (eNOS). It has been suggested that alterations in microvascular perfusion patterns occur, in part, as a result of microvascular leukocyte adhesion. While the early alterations in renal perfusion may result from physiological factors regulating vascular tone, subsequent alterations in flow due to infiltration of inflammatory cells are associated with progression to the extension phase of AKI (see Fig. 2). The latter mechanism may be the reason for the lack of efficacy in vasodilator therapy once AKI is established [76]. Ischemic AKI increases endothelial expression of a variety of adhesion molecules that promote endothelial-leukocyte interactions. These include intercellular adhesion molecule-1 (ICAM-1), P-selectin, and E-selectin [67, 77]. Ablation of the ICAM-1 gene or pretreatment with ICAM-1 antibody rendered mice resistant to ischemic AKI, raising the promise of the latter approach in humans. However, trials with anti-ICAM-1 monoclonal antibody administered post-ischemia did not prevent AKI manifested as delayed graft function in cadaveric transplant recipients [67]. Similarly, initial studies of animals with

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gene knockouts and treatment with monoclonal antibodies or pharmacologic inhibitor have suggested a role for endothelial E- and P-selectins in the microvascular injury [77–79]. Subsequent studies, though, demonstrated that platelet P-selectin, not endothelial P-selectin, is the key contributor to AKI [80]. Proposed mechanisms include initial adhesion of platelets to the endothelium with subsequent recruitment of leukocytes or adhesion of platelets to neutrophils with consequent intraluminal cell aggregate formation and trapping in narrow peritubular capillaries [77]. Furthermore, derangements in the coagulation cascade, such as alterations in tissue-type plasminogen activator and plasminogen activator inhibitor-1 in the kidney [81], may combine with the alterations in adhesion molecules to cause the ﬁbrin deposits characteristically found in the renal microvasculature following ischemic injury. Despite the lack of apparent beneﬁt from the trial of anti-ICAM-1 in limiting AKI in kidney transplantation, the series of investigations in the past several years that have highlighted the important role that microvascular injury plays in ischemia-induced AKI provide rationale for additional trials of pro-angiogenic agents in AKI. These may include agents that can mobilize or increase the pool of bone marrow-derived pro-angiogenic cells such as erythropoietin, bone morphogenic protein, vascular endothelial growth factor, and statins [70].

Nephronal Factors “Nephronal factors” refers to the unique susceptibility of a speciﬁc nephron segment to injury. The best studied following ischemia is the S3 segment of the proximal tubule and the medullary thick ascending limb (mTAL). There has been controversy over the relative importance of each of these segments in AKI [82]. What is clear, though, is that studies of cellular injury and repair in both segments have provided important insights into the pathophysiology of tubular cell injury.

Pathogenesis of Acute Kidney Injury

Tubule Segment Susceptibility to Injury Medullary Thick Ascending Limb: The mTAL appears to be particularly vulnerable to hypoxia because oxygen tension in the medulla is low and the mTAL segment has high oxygen consumption [83]. This relationship was deﬁned in isolated kidneys that were perfused with cell-free perfusate. Injury to the mTAL is prevented by increased oxygen delivery through addition of red blood cells to the perfusate. Furthermore, the degree of mTAL necrosis depended on the workload imposed on this segment. Decreasing the workload by inhibiting mTAL solute transport diminished the severity of injury; increasing the workload had the opposite effect. The relationship of these observations to the pathogenesis of AKI in man is controversial, since reducing oxygenation in experimental animals does not reproduce the lesions seen in the isolated-perfused kidney model. Nevertheless, studies of the unique vulnerability of this nephron segment to hypoxia have provided insight into the relationship between oxygen supply, workload, and the cellular targets of ischemic, hypoxic, or anoxic injury [82]. Straight Segment of the Proximal Tubule: The straight segment of the proximal tubule (S3 segment) is highly dependent on oxidative phosphorylation to supply the energy necessary for its bulk transport functions. It is particularly susceptible to ischemia and to nephrotoxins that disrupt energy supply or mitochondrial function [26, 84]. The earliest alterations in the S3 segment, after mild or brief ischemia, are found in the brush border and consist of bleb formation and internalization of the luminal membrane. With more prolonged ischemia, these changes progress to a more severe form of sublethal injury characterized by cell swelling, mitochondrial condensation, and broader disruption of cellular morphology. Simultaneous with these changes, other cells in this segment may progress to a lethal injury such that the tubule epithelium is denuded from the basement membrane (see Fig. 1). These changes in the S3 segment result in two important

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pathophysiological events: intratubular obstruction and backleak.

Intratubular Obstruction and Backleak Cell and brush border debris become impacted in the hairpin turn of the loop of Henle causing obstruction and backleak of tubular fluid in some nephron segments. Intratubular obstruction following ischemic injury has been demonstrated by histomorphology and by finding elevated proximal tubular pressure [84–86]. The backleak of tubular fluid resulting from loss of tubular integrity in AKI has been demonstrated in both experimental animals and patients [84–87]. In animals, microinjection of inulin or horseradish peroxidase into normal nephrons results in inulin being collected only from that kidney and staining of horseradish peroxidase only in that tubule lumen. In contrast, after microinjection into an injured nephron, inulin is found to be excreted by the contralateral kidney and horseradish peroxidase is found in both intra- and peritubular loci. In patients with AKI, backleak has been demonstrated by the differential clearance of graded dextrans [87]. Since filtration is preserved and inulin, urea, and creatinine leak back into the circulation, the renal clearances of these solutes no longer represent GFR in patients with AKI. They nevertheless retain clinical utility in the global assessment of renal clearance ability. The cellular and molecular mechanisms of tubule obstruction and backleak have been well defined [88, 89]. Integrins are outer membrane proteins, basolaterally located in epithelial cells that attach the cell to the extracellular matrix. Following ischemia or ATP depletion, integrins become detached from the extracellular matrix, allowing both dying and viable cells to leave the tubule basement membrane and float into the tubule lumen. In addition, integrins become displaced from the basal to the luminal domain, which allows intraluminal sloughed cells to attach to cells that remain in place, contributing to tubule obstruction (Fig. 1). The integrin attachment

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occurs via an arginine-glycine-aspartic acid (RGD) sequence [88]. The infusion of RGD peptide abolished the characteristic increase in proximal tubule pressure and substantially improved renal function following ischemia, thus conﬁrming the central role of integrin disruption to the processes of intratubular obstruction and backleak in AKI [90, 91].

Cellular and Metabolic Alterations Adenine Nucleotide Metabolism Energy depletion and restoration play a pivotal role in renal cell injury [6]. In vivo, renal ischemia causes a profound fall in ATP; in vitro, metabolic inhibition of ATP production is used to induce cellular injury similar to the in vivo ischemia model. Within 5–10 min of inducing ischemia, nearly 90 % of renal ATP has been consumed [32]. With reperfusion, renal ATP levels recover in a bimodal fashion (Fig. 3). In the ﬁrst few minutes of reperfusion, there is rapid but

Fig. 3 Renal ATP depletion and recovery during ischemia and reperfusion. The initial rapid phase of ATP recovery occurs via phosphorylation of residual renal AMP and ADP. Slow phase recovery represents resynthesis and phosphorylation of adenine nucleotides

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incomplete recovery of ATP to 50–70 % of normal levels, depending on the duration of ischemia [92, 93]. ATP recovery during the initial phase correlates highly with the total pool of adenine nucleotides (ATP + ADP + AMP) present in the kidney at the end of the ischemic interval. The total adenine nucleotide pool, mainly AMP, decreases as the duration of ischemia increases. So, ATP recovery during initial reperfusion is accomplished primarily by oxidative phosphorylation of the residual cellular nucleotides (AMP and ADP). A second, slow phase of ATP recovery occurs over hours following the initial rapid phase. ATP recovery rate in the second phase also is a function of the preceding duration of ischemia; longer ischemic intervals result in slower recovery rates. The second phase requires synthesis of ATP from purine nucleotide degradation products and salvage pathways or from precursors provided during reperfusion (Fig. 3). A primary role for ATP depletion in ischemia-induced epithelial cell injury is supported by several ﬁndings: (1) when ATP catabolism is inhibited during

Pathogenesis of Acute Kidney Injury

renal ischemia, the structural and functional manifestations of AKI are signiﬁcantly ameliorated [6, 84, 94]; (2) graded reductions in cellular ATP, either in vivo or in vitro, determine the severity of cellular disruption [95, 96]; and (3) augmentation of ATP recovery during reperfusion substantially enhances recovery of renal structure and function [6]. Restoration of mitochondrial structure and function impacts on the later phase of cellular recovery. Mitochondrial respiratory protein abnormalities persisted for 6 days after the insult in two different animal models of AKI, and markers of mitochondrial biogenesis were elevated in both. So disruption of mitochondrial homeostasis persists even in the presence of mitochondrial recovery signals [97]. Administration of a pharmacological activator of mitochondrial biogenesis, after induction of AKI by ischemia, expedited recovery of mitochondrial proteins and function, along with faster recovery of markers of tubule polarization and differentiation [98]. Therefore, impaired adenine nucleotide metabolism and mitochondrial homeostasis are both a consequence and predictor of renal cell injury and recovery. Furthermore, altered ATP metabolism triggers several pathways that lead to deranged epithelial structure and function: reactive oxygen molecules, increased intracellular calcium, activation of phospholipases, and disruption of tubule cell architecture. Each of these downstream events is discussed below.

Reactive Oxygen Molecules Reactive oxygen molecules (ROM) have been implicated in a variety of kidney diseases, including reperfusion injury after ischemia [99]. The most highly reactive oxygen molecules are free radicals such as hydroxyl radical (OH) or superoxide anion (O2). The high reactivity and brief existence of these molecules result in injury close to the site of free radical generation. Other oxygen species such as hydrogen peroxide (H2O2) and hypochlorous acid (HOCl), not being free radicals, are less reactive. However they have longer half-lives than free radicals and may cross cell

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membranes to cause injury distant from their site of origin. ROM are generated during reperfusion of kidneys [99]. Ischemia induces metabolism of the adenine nucleotides to adenosine, inosine, and hypoxanthine. Ischemia also may cause a conformational change in xanthine dehydrogenase (which uses NAD as an electron receptor) to xanthine oxidase, which uses oxygen [100]. Once perfusion and oxygen delivery is returned, xanthine oxidase can metabolize hypoxanthine to xanthine and uric acid, generating hydrogen peroxide and superoxide anion. Mitochondria produce reactive species though electron transport systems, which when damaged by ischemia may leak the injurious oxygen metabolites. The respiratory burst and myeloperoxidase released from activated PMNs produce superoxide anion, hydrogen peroxide, and hypochlorous acid [99]. Prostaglandin metabolism may also provide reactive molecules. Iron can play a signiﬁcant part by donating electrons to hydrogen peroxide to form the highly damaging hydroxyl radical [101]. In this way, iron release may be responsible for the injury resulting in hemoglobin- or myoglobin-induced AKI [102]. Once generated, ROM damage cellular components and extracellular matrix [6]. Intracellular proteins can be oxidized, resulting in conformational changes with loss of enzymatic activity or compromised integrity of structural proteins. Membrane lipids and lipoproteins undergo peroxidation by free radicals; these propagate and result in progressive membrane damage. Hydroxyl radicals damage DNA and oxidize matrix proteins. Reactive oxygen metabolites may contribute to ischemia by deleterious interactions with nitric oxide synthetases or with NO itself. NO can combine with superoxide to form peroxynitrate, a potent oxidant. Because of these putative actions, much attention was focused on ROM in ischemiareperfusion injury [76, 92, 99]. Animal models show ROM involved in the pathogenesis of AKI, but whether ROM play a signiﬁcant role in human AKI has long been questioned. The effects of enhancing endogenous antioxidants (superoxide dismutase, glutathione, catalase,

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apotransferrin, or neutrophil gelatinase-associated lipocalin, NGAL) or administering exogenous free radical scavengers (N-acetylcysteine, deferoxamine, or edaravone) have been examined [103–106]. Animal studies have shown benefit from treatment with the antioxidants or free radical scavengers, but similar translational studies in humans, so far, have been inconclusive or have shown no benefit. However, a significant increase in oxidative stress has been observed in humans with AKI [107]. In addition, genomic studies identified an association between serum catalase and a specific catalase allele with the severity of AKI in ICU patients [108]. So, despite the large number of studies on this topic, no final conclusion can be made as to the importance of reactive oxygen species in the pathogenesis of AKI, since strong evidence exists both for and against these compounds having a dominant role.

Intracellular Calcium Under normal circumstances, extracellular ﬂuid calcium concentration exceeds that of intracellular free calcium (Cai) by a factor of 104. The remarkably low Cai is maintained by a variety of mechanisms that remove calcium from the cell or sequester it within intracellular compartments. Calcium is extruded from cells by plasma membrane Ca-ATPase and the Na/Ca-exchanger. Intracellular sequestration is mediated by Ca-ATPase in the endoplasmic reticulum and by calcium uptake into mitochondria. A fall in cellular ATP would be expected to reduce the activity not only of Ca-ATPase but also Na/K-ATPase and thereby affect the Na/Ca-transporter. The net effect of cellular ATP depletion on extrusion of Ca from the cell and sequestration in the endoplasmic reticulum, then, would be to decrease calcium transport contributing to a rise in Cai. In addition, it has been suggested that release of Ca from cellular organelles contributes substantially to the rise in cytosolic Ca. The contribution of mitochondrial damage to the observed rise in cytosolic calcium after ischemic or hypoxic injury appears to be minimal,

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because even damaged mitochondria are able to sequester calcium actively [92]. However, the converse effect may be a mechanism in lethal cell injury. That is, the increase in cytosolic Ca that occurs through mechanisms outlined above can lead to unrestricted uptake by mitochondria. A substantial rise in mitochondrial calcium levels, then, occurs after cell injury is lethal. The question whether high Cai levels play a central role in the pathophysiology of cell injury or whether Cai changes are merely secondary to cell death has been controversial. Increased cell and mitochondrial Ca levels are linked to cell death but were thought not to increase until irreversible changes had occurred [109, 110]. Later studies, however, demonstrated a reversible increase in Cai early in the course of cell injury in isolated proximal tubules [111]. In an in vitro model, it was found that graded levels of ATP depletion caused signiﬁcant, early increases in Cai in renal cells but did not cause cell death. Furthermore, the increases in Cai were tightly and inversely correlated to the level of ATP depletion and preceded disruption of membrane protein-cytoskeleton interactions and induction of putative recovery mechanisms through the stress response [96]. Finally, attenuation of ischemia-induced AKI is found in mice deﬁcient in the Na/Ca-exchanger and in animals administered compounds that inhibit this exchanger, both models that would be expected to diminish the secondary rise in Cai mediated via the reverse mode of the Na/Ca-exchanger during and after ischemia [112, 113]. Therefore, alterations in Cai appear not to be merely a terminal manifestation of lethally injured cells but play an important early role in the pathogenesis of ischemia-induced AKI. Increased Cai may play an early role in AKI by mediating several aspects of sublethal injury and a later role in a subsequent transition to lethal injury after a more severe insult. An increase in Cai may activate calpain, contributing to degradation of the cytoskeleton, and could increase activity of other proteases and phospholipases that contribute to either sublethal cell disruption or cell death, and it could inhibit mitochondrial oxidative phosphorylation. The latter effect would lead to a vicious

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cycle of progressive cell energy depletion, further cell injury, and eventual cell death. However, alterations in Cai also could activate recovery mechanisms, such as induction of the stress response [96]. Furthermore, increased cytosolic calcium dramatically induces calcium binding proteins such as annexin A2 and S100A6, which play an important role in cell proliferation during recovery from AKI in animal models [114]. The relative contribution that change in Cai makes to speciﬁc pathophysiological versus recovery mechanisms in AKI is yet to be deﬁned.

Phospholipids and Lipases The striking morphological changes that occur in proximal tubules after ischemia, especially brush border membrane bleb formation, and the release of intracellular enzymes such as lactate dehydrogenase suggest that significant membrane alterations are part of the cellular injury in AKI. Changes in intracellular calcium flux have been shown to activate endogenous phospholipase, and some phospholipase may be activated by decreased cellular ATP. Phospholipase activation causes breakdown of membrane phospholipids into free fatty acids and lysophospholipids, which can disrupt membranes and be precursors of active metabolites that promote inflammation and further activate phospholipases. Moreover, the lack of ATP during ischemia may prevent the synthesis of new phospholipids to replenish membranes. The result, then, is a generalized loss of membrane phospholipids with an accumulation of degradation products that by their detergent activities can further disrupt cell membranes, eventually leading to loss of membrane integrity and cell death (reviewed in detail in Ref. [115]). As discussed earlier, another mechanism that may contribute significantly to progressive membrane deterioration is injury by oxygen free radicals. ROM generated during reperfusion peroxidate lipids, which can propagate through other membrane lipids causing widespread membrane damage. In fact, signs of lipid peroxidation provide significant evidence for free radical generation during reperfusion. It is suggested that

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certain phospholipase isoforms may limit, rather than enhance, membrane injury by hydrolyzing phospholipids oxidized by ROM [115]. Removal of the damaged, oxidized lipids is thereby facilitated, limiting progressive membrane damage from these toxic metabolites. Renal ischemia indeed causes activation of phospholipase (PLA2) and a rapid fall in cortical phospholipid levels [116]. The detrimental effects of PLA2 can be offset by unsaturated free fatty acids [117], suggesting that PLA2 may be cytotoxic by degradation of phospholipids in cell membranes or through accumulation of lysophospholipids [118]. It appears, though, that the role PLA2 plays in renal cell injury depends on both the particular isoform of PLA2 and the insult applied to cause AKI [115]. For example, cytosolic calcium-dependent PLA2 is implicated in mediating oxidant-induced renal cell injury. On the other hand, endoplasmic reticulum Ca-independent PLA2 appears to have a role in phospholipid repair in proximal tubules that varies according to the insult applied [119]. Just as phospholipase activity may vary according to the stimulus and domain, and either contribute to or limit the injury depending on the context, the role of lipid alterations similarly can differ in AKI [120]. While free fatty acid and lysophospholipid accumulation may contribute to membrane damage, cholesterol accumulation appears to stabilize plasma membranes and limit renal cell injury in models of AKI. Acute tubule injury initially lowers, then increases, cholesterol content in renal tubule cells [121]. When renal cells were treated with a variety of agents to reduce cholesterol content, cell susceptibility to injury from ATP depletion was substantially increased, suggesting that cholesterol is a cytoprotectant in the context of ischemic AKI [122]. So, while the understanding of lipid alterations in AKI has become more complex, the story is similar to that of changes in Cai. The role of these alterations may be pathologic or adaptive, depending on the type and severity of the insult, on the location of the intracellular perturbations, and on the particular isoforms active in the affected areas.

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Disruption of Tubule Cell Architecture Renal tubule cells are highly specialized for their primary function of ion and small molecule transport, which depends on their polar structure. The change in proximal tubule cell polarity that occurs during AKI has profound effect on this function (Fig. 4) [123]. The plasma membrane of proximal tubule cells is divided into apical and basolateral domains by tight junctions shared with neighboring cells. The apical membrane, facing the tubule lumen, differs from the basolateral membrane both in lipid and membrane protein composition. The microvilli of the apical domain are rich in sodium-dependent cotransporters and Na/H-antiporters, which effect reabsorption of glucose, amino acids, phosphate, and bicarbonate along

Fig. 4 Disruption of proximal tubule cell polarity. Ischemia causes loss of apical brush border, opening of tight junctions, and loss of cell polarity that impairs

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with sodium. The sodium gradient across the apical membrane, which drives the function of these transporters, is established and maintained by Na/ K-ATPase located on the basolateral membrane. Plasma membrane polarity is maintained by the tight junctions that prevent lateral diffusion of membrane phospholipids and proteins into the opposite domain. In addition, the cortical cytoskeleton anchors membrane proteins, such as Na/K-ATPase, in speciﬁc domains through an intricate sequence of linked proteins. The actinbased cytoskeleton is a dynamic structure that maintains cellular polarity and mediates a number of processes necessary to sustain both structure and function of renal epithelia [124]. Interactions between cytoskeletal proteins and plasma membrane proteins are responsible for functions that

transepithelial solute reabsorption. Recovery of function parallels recovery of cell architecture

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include cell adhesion, endocytosis, signal transduction, and activity of ion channels. The loss of cellular polarity is a fundamental alteration in renal epithelial injury that causes reduced transepithelial sodium reabsorption. Renal ischemia disrupts normal renal cell polarity. Proximal tubule tight junction integrity, a barrier to diffusion of membrane components across domains in healthy tubule cells, is lost. Membrane lipids and proteins that are highly mobile redistribute between apical and basolateral domains. Membrane proteins such as Na/K-ATPase, which normally are anchored to the actin cortical cytoskeleton, can migrate when this attachment is broken (Fig. 4). After as little as 5 min of renal ischemia, there is loss and internalization of brush border membranes, and basolateral Na/K-ATPase migrates to apical membranes [123]. The actin cytoskeleton plays an important role in this process. Renal ischemia alters actin microfilaments and organized polymerization in proximal tubule cells [124, 125]. Actin disruption itself results in opening of tight junctions and loss of the polar distribution of those proteins that anchor Na/K-ATPase to the plasma membrane [93, 126–128]. Ankyrin, which links Na/K-ATPase to fodrin, normally is limited to the basolateral domain. After ischemia, ankyrin migrates with Na/K-ATPase to the apical domain. Fodrin, which normally links actin to ankyrin and Na/K-ATPase, becomes dissociated and solubilized throughout the cytosol [128, 129]. Actin depolymerizing factor (ADF, also known as cofilin) participates in ischemia-induced actin cytoskeletal alterations and determines the rate and extent of these ATP depletion-induced changes in actin [130]. ADF/cofilin is normally maintained in an inactive form by Rho GTPases. ATP depletion inactivates Rho GTPase, causing activation and relocalization of ADF/cofilin to the surface membrane [130, 131]. Concomitantly, ATP depletion dissociates the actin-stabilizing proteins tropomyosin and ezrin, allowing activated ADF/cofilin to bind and cleave actin, leading to microvillus breakdown [132]. Finally, atypical protein kinase (aPKC) signaling, impaired during ATP depletion, participates in tight junction disassembly during cell injury.

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aPKC function is important for tight junction reassembly during recovery, a feature necessary for restoration of cell polarity and tubule integrity [133]. The ischemia-induced alteration of renal tubule cell architecture underlies the reduction in transepithelial sodium reabsorption, which is manifested clinically as increased fractional excretion of sodium and is a hallmark of AKI. Recovery of normal sodium reabsorption occurs after normal renal cell structure and membrane polarity is restored in sublethally injured cells during recovery from AKI.

Cell Death Necrosis and Apoptosis After an ischemic or toxic insult, cells can proceed down one of several pathways: recovery from sublethal injury or death by necrosis or apoptosis. Indeed, individual cells can simultaneously be moving through each of these pathways in AKI (Fig. 5). The hierarchy of injury that results depends on the cell type, location, and on the severity of the insult [96, 134, 135]. Cell death by necrosis tends to follow a severe insult that leads to metabolic collapse of the cell and is more prominent in the outer medulla where the severity

Fig. 5 The spectrum of cellular outcomes in acute kidney injury. The particular outcome of an injured cell depends on the severity, duration, and speciﬁcity of the insult and on the type of cell and location. In acute kidney injury, the entire spectrum of responses can occur in different cells simultaneously (Adapted from Ref. [309])

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of the injury is exacerbated by vasoconstriction and microvascular congestion. Necrosis is massive, rapid, and near synchronous leading to cell lysis with secondary injury to surrounding tissue. Typical features of necrosis include cytoplasmic swelling, loss of membrane integrity, and nuclear and cellular fragmentation. Cell death from apoptosis is a more organized, regulated process that leads to cytoplasmic and nuclear shrinkage, DNA condensation and fragmentation, and eventual cell breakdown into membrane-bound apoptotic bodies. These apoptotic bodies are cleared rapidly in vivo by other cells, thus making the assessment of how much apoptosis occurs following a renal injury difficult. While clinical acute renal failure from ischemic or toxic injury has long been called acute tubular necrosis (ATN), this term has been questioned since biopsy of patients with ARF rarely show necrotic features [136]. However, biopsies of patients typically are late in the course of ARF and may miss earlier signs of necrosis. Animal models of ischemic or toxic injury clearly show at least focal areas of necrosis early during reflow. Nevertheless, the current understanding that a renal insult can lead to simultaneous sublethal and lethal injury, both necrosis and apoptosis, in cells in different areas of the kidney has led to the change in terminology from ARF or ATN to acute kidney injury (AKI, see Introduction) [1]. Measuring apoptotic cell death in vivo has been problematic, leading to controversy over whether this is an important pathway in AKI. This is an important issue since the same type of insult in vivo or in vitro can cause either necrosis or apoptosis [137]. Definitive morphologic criteria have established apoptosis as a pathway to cell death in renal epithelia both in vivo and in vitro [138, 139]. It has been confirmed that apoptosis is an important feature of human AKI [140, 141]. Biochemical assays can be helpful to quantify apoptosis, but are not uniformly reliable measures of apoptosis in vivo or in vitro, unless traditional cell morphology criteria are also applied. For example, neither endonuclease activation nor DNA laddering, previously thought to be features unique to apoptosis, consistently discriminate

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between necrosis and apoptosis in injured renal epithelia [142, 143]. However, the specificity of TUNEL staining for apoptosis in several forms of in vivo renal cell injury was determined using accepted morphological criteria and was found to be 99 % specific for apoptosis in in vivo ischemic renal injury [144]. Studies such as these have shown that apoptosis is an important mechanism of cell death in AKI and have allowed for exploration of apoptotic pathways that might be active after a renal injury. The process of apoptosis has been separated into three sequential phases: initiation, commitment, and execution phases. The initiation phase can be activated by extrinsic factors or intrinsic cell stress [76, 145]. Membrane receptors and the Fas pathway can contribute to the extrinsic initiation phase of apoptosis in ischemia, and interference with this pathway can ameliorate in vivo AKI [146–149]. The series of intracellular derangements in cell architecture, metabolism, and function during ischemia are likely a major trigger to the intrinsic pathway for initiation of apoptosis following ischemia. Central to the commitment phase of apoptosis are several changes in mitochondria. Loss of mitochondrial transmembrane potential is pivotal to the apoptotic cascade; interventions that prevent the mitochondrial permeability transition avert apoptotic nuclear and cell membrane alterations [150–153]. Bax translocation from its cytoplasmic pool to mitochondria contributes to opening of mitochondrial pores and the mitochondrial permeability transition with subsequent release of cytochrome C [154–156]. Bax-mediated apoptosis has been demonstrated in cultured proximal tubule cells following ATP depletion injury [156]. An imbalance between the proapoptotic (Bax, Bid) and antiapoptotic (Bcl-2, Bcl-xL) members of the Bcl-2 family of proteins, as well as the proapoptotic protein p53, is implicated in the commitment phase of apoptosis in both animal [157–159] and human [140, 160, 161] conditions of ischemia-induced AKI. Though cytochrome C release from mitochondria is not specific for apoptosis, it follows the mitochondrial permeability transition that is modulated by the Bcl-2 protein family and indicates commitment to cell death.

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Its release is an essential factor in causing downstream activation of the effector proteins for apoptosis [135, 150, 156]. Caspase 3 is the effector protein that lies at a critical juncture in apoptosis pathways. Activation of Caspase 3 begins the execution phase of apoptosis [162–164]. A series of additional caspases are activated in the execution phase that cleave multiple cellular proteins, including cytoskeletalassociated proteins and endonuclease inhibitors, resulting in the characteristic morphology of apoptosis – cell shrinkage, membrane bleb formation, nuclear condensation, and fragmentation [135].

Autophagy Autophagy is a cell stress response involving bulk degradation of damaged organelles, protein aggregates, and macromolecules in cytoplasm. This cellular mechanism is suggested to be an adaptive response that protects against AKI by limiting cell death. Indeed, studies indicate that blocking autophagy pharmacologically or genetically accelerates apoptosis [165]. As such, autophagy may be a pathway to be manipulated in preventing AKI.

Inflammatory Response Although studies many years ago suggested that the immune system had no role at all in ischemiainduced AKI, a growing body of evidence in the past several years indicates that the inflammatory response plays a major role in AKI. The inflammatory cascade is initiated at the vascular endothelium. Renal injury leads to increase in the expression of leukocyte adhesion molecules ICAM-1 and P and E-selectin on endothelial cells, and interference in these pathways results in less inflammation and injury after renal ischemia [16, 166–168]. Inflammatory cascades initiated by endothelial dysfunction can be augmented by potent mediators generated by the ischemic proximal tubule. Both pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, TGF- β) and chemotactic cytokines (MCP-1, IL-8, RANTES) are

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generated following renal ischemia and can enhance inflammation [66, 67, 169, 170]. Strategies to modulate the inflammatory response by altering cytokine action have been tried in AKI. IL-10 is a potent anti-inflammatory cytokine that provides protection against ischemic AKI by inhibiting maladaptive cytokine production by Th1 cells [171]. Administration of a monoclonal antibody against the pro-inflammatory cytokine IL-6 reduced pro-inflammatory cytokine production, decreased neutrophil infiltration, and ameliorated structural and functional consequences of ischemic AKI [172]. Furthermore, several agents with generalized anti-inflammatory effects are being studied as candidates to prevent or treat acute kidney injury. These include statins and erythropoietin (with anti-inflammatory actions separate from their better known cholesterol lowering and erythropoietic effects, respectively) and alphamelanocyte-stimulating hormone [173–177]. Signaling of Toll-like receptors (TLR) on immune cells from any stimuli causes an inflammatory state, which when uncontrolled can lead to tissue damage [178]. The effect of a specific TLR may depend on the specific injury. Inhibition of TLR-2 by gene knockout or antisense treatment prevents ischemia-induced renal dysfunction and suppresses some cytokines in cultured proximal tubule cells [179, 180]. TLR 9 genetic and pharmacological suppression, but not TLR 2 or 4, protects against sepsis-induced AKI [181, 182]. However, TLR 4-induced IL-22 protects against ischemia-reperfusion injury by accelerating proximal tubule epithelial regeneration [183, 184]. The conflicting findings of these studies indicate not only that the effect may vary according to the particular renal insult but that TLR pathways need to be explored in more detail to define clearly their role in AKI. Leukocyte infiltration into injured kidneys has been documented following ischemia, neutrophils being the first, followed closely by macrophages [67, 185]. The significance of neutrophil infiltration is not clear because neutrophil depletion or blockade of function provides only partial protection and only in some animal models, and neutrophil infiltration appears not to be a prominent

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feature of ischemic renal injury in humans [67]. Selective macrophage depletion and manipulation of macrophage infiltration into the kidney decreases the severity of AKI. Macrophages are dependent on coordinated action of T cells and neutrophils [186, 187]. Although it is the most abundant immune cell in the kidney, the role of the dendritic cell in AKI is not known. The role of T cells has been intensely studied; they have been found in the kidney in both animal and human ischemic AKI [67, 188, 189]. Mice subjected to T-cell depletion and mice with a double knockout of CD4/CD8 are protected against injury from ischemia [190, 191]. Reversal of protection in the latter model occurs with adoptive transfer of wild-type T cells into the knockout mice. Although there are conflicting reports on the role of T and B cells in AKI, recent studies demonstrate that mice deficient in both T and B cells (RAG-1 mice) are protected from ischemic renal injury [192–194]. Complicating the T-cell picture further is the identification of both protective (Th2 phenotype) and deleterious (Th1 phenotype) subtypes of CD4 T cells [195]. IFN-gamma from Th1 CD4 T cells acting early contributes to ischemic renal injury [194]. Recently, T regulatory cells were determined to have a fundamental role in balancing the inflammatory response within the kidney in AKI. Resistance to developing AKI following preconditioning is attributed to T regulatory cells. Along with numerous agents that promote proliferation, function, and trafficking of endogenous T regulatory cells, studies using adoptive transfer of T regulatory cells indicate their protective role in AKI [196]. Compared with wild-type animals, B-cell-deficient mice kidneys, with comparable T-cell and neutrophil infiltration following ischemic renal injury, are partially protected both structurally and functionally [197]. Wild-type serum transfer, but not B-cell transfer, into these B-cell-deficient mice restored susceptibility to ischemic AKI, implicating a soluble serum factor as a mechanism by which B-cell deficiency confers renal protection [197]. Ischemia-reperfusion injury in most organs activates the classical pathway of the complement cascade. However, the alternative pathway, along with the mannose-binding lectin

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pathway of complement activation, appears to predominate in ischemic AKI in animals and humans [198–200]. Studies focused on C5a, a powerful chemoattractant for inflammatory cells, suggest that it contributes to renal injury and impairs recovery [201–204]. Another complement protein, Factor B, may also have an integral role in augmenting the inflammatory response in ischemic AKI [198]. The clear involvement of the immune system in ischemic AKI suggests a mechanism underlying the consistent observation that development of AKI substantially increases overall morbidity and mortality in patients suffering from a variety of diseases, including isolated cardiac disease, sepsis, and multi-organ dysfunction [205–209]. In that context, it has been intriguing to see animal studies documenting distant organ effects and dysfunction in the heart, lungs, and brain after isolated ischemic AKI [210, 211]. It has been suggested that these distant effects of renal ischemia may be mediated by inflammatory signals generated in the injured kidney [212, 213].

Genetic Susceptibility In the clinical realm, it has long been observed that the incidence or severity of AKI varies widely between patients who have apparently been subjected to the same renal insult. While unrecognized environmental factors may certainly play a role, this observation has led clinicians to suspect that individual patients may have an inherent genetic susceptibility or resistance to developing AKI. This has led investigators to explore whether differences in genetic background affect the risk of developing AKI. Speciﬁc human genetic polymorphisms have been linked to either resistance or susceptibility to develop AKI [205]. These human studies have implicated genetic polymorphisms of pro- and anti-inﬂammatory cytokines and heme oxygenase-1 (HO-1) as potential determinants of susceptibility to ischemic renal injury [205]. Genetic polymorphisms of the stress protein Hsp72 were associated with neonatal susceptibility to develop AKI. The Hsp72 (1267) GG

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allele has low inducibility of the Hsp72 protein. Neonates carrying the Hsp72 (1267) GG genetic variation had increased risk of AKI [214, 215]. Furthermore, several maternal and fetal cytokine genetic polymorphisms were linked to the incidence and severity of sepsis, necrotizing enterocolitis, and eventual AKI [215]. The proliferation of such studies led to a systematic review to determine whether any polymorphism could be conclusively associated with AKI. Of 35 individual polymorphisms whose association with AKI had been reported and examined in the review, only one polymorphism, APO E e2/e3/e4 (a regulator of inflammation), had more than one study showing a significant impact on AKI incidence [216]. However, that association was not confirmed in a larger study. The authors concluded that since current association studies do not provide definitive evidence linking specific genetic variations to AKI, a different approach is required. They conclude the need to restrict such studies to a narrow consensus definition of AKI (as discussed in the introduction to this chapter) and a shift from a priori hypothesisdriven to genome-wide association studies [216]. Studies of different rat strains give credence to this approach, along with the concept that genetic background can substantially influence vulnerability to AKI. The inbred Brown-Norway (BN) rat strain is profoundly resistant to developing AKI following ischemia when compared with other inbred and outbred rat strains [217]. The strainspecific protection appears to be on a cellular level since immediate cellular manifestations of ischemic AKI are limited, and the protection is sustained. The specific mechanism providing this protection is yet to be determined, but a relationship to differential gene expression is indicated by the finding of increased constitutive expression of inducible heat shock proteins, putative cytoprotectants, in the protected strain. To define the genetic basis for resistance to AKI further, consomic rats were studied, in which individual chromosomes from the AKI-resistant BN rat were placed into the genetic background of an AKI-sensitive rat strain. Nine chromosomes on consomic strains were found to contain alleles that afford protection against

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developing AKI [218]. So, full protection against ischemic injury in the BN rat likely is from multiple beneficial alleles working in concert. In silico analysis then identified at least 36 candidate genes on the chromosomes found to contain protective alleles, with several candidate genes previously linked to the pathophysiology of AKI [218]. So natural variants of these alleles, or yet to be identified alleles on the chromosomes identified to harbor protective genes, provide protection against AKI in the rat. Since both the rat and human genomes have been fully sequenced, the results from this study could be exploited further to guide future translational clinical studies in humans to identify modulators of AKI in susceptible patient populations. This approach might then allow identification of individuals genetically predisposed to develop AKI in a specific clinical setting, as well as predict the severity of AKI once established.

Biomarkers Advances in functional genomics and cDNA microarray-based technologies have revealed the landscape of the numerous pathways activated by AKI [219–223]. Novel genes with altered expression and new signal transduction pathways have been discovered that may serve as biomarkers of AKI. Kidney injury molecule-1 (KIM-1) protein is upregulated following ischemia on the apical membranes of proximal tubule cells. The ectodomain of KIM-1 is cleaved and released into tubule lumen. This sliced part of KIM-1 is detected early in urine even with mild proximal tubule injury from a variety of causes. Increase in urinary KIM-1 has been shown to be prognostic in several human studies, making it a promising noninvasive urinary biomarker of AKI [224]. Neutrophil gelatinase-associated lipocalin (NGAL) is also rapidly expressed in kidney cells in response to several forms of stress. Antiapoptotic and tubular epithelial proliferative effects of NGAL suggest a protective role in AKI. NGAL ﬁltered in the glomerulus is reabsorbed in the proximal tubule, resulting in only low levels in urine. In AKI, the distal nephron increases NGAL

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expression resulting in increased serum NGAL levels. Decreased proximal tubule absorption of filtered NGAL in AKI, in combination with increased production by tubular epithelial cells, leads also to increased NGAL levels in urine. Tumors, sepsis, and leukocyturia, without any renal injury, can also result in increased NGAL levels, making them important confounders when interpreting NGAL data. Combining two different assays to quantitate monomeric NGAL, the form of NGAL predominately produced by kidney epithelia, may help overcome such other clinical confounders. Further studies should determine the best NGAL assay and specific informative cutoff values for the different clinical situations [225]. Additional urinary biomarkers identified as detecting early kidney injury include Cystatin C, N-acetyl β-D-glucosaminidase (NAG), and Interleukin 18. Any individual biomarker, if accepted as a biomarker of renal injury, can help overcome the shortcomings of serum creatinine as a measure of AKI, which include the inability to differentiate early between established kidney injury and reversible hemodynamic changes resulting in physiologically reduced GFR. Since each biomarker has unique strengths and weaknesses, using a marker panel might be more reliable in determining the type and severity of kidney injury and allow for more precise prognosis models [226]. The clinical utility of individual novel urinary biomarkers is further discussed in Chapter.

Repair Mechanisms Just as multiple pathways to cell injury are activated in AKI, the repair processes necessary to restore kidney structure and function would be expected to be multifaceted. The mechanisms to renal recovery might include (a) endogenous repair of sublethally injured cells, (b) proliferation of surviving renal tubular cells, or (c) replacement of dead cells by stem cells. The rapid initiation of repair in injured tubules supports the theory of endogenous repair of sublethally injured cells, with replacement of denuded segments of tubules with cells of either proximal

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or distal tubule origin [227–229]. A deep understanding of the recovery process could identify interventions that augment cellular repair to restore kidney function more quickly and fully.

Heat Shock Proteins Heat shock proteins (Hsps), also called stress proteins, are elaborated in cells in response to a variety of injurious stimuli. Hsps function as protein chaperones and are essential to basic cell function and survival by providing routine assistance in intracellular protein handling [230]. The two stress protein families most studied in AKI are the Hsp70 and the small Hsp 25/27 class. Heat shock transcription factor-1 (HSF-1) activation, the most proximal component of the stress response, is rapid after onset of renal ischemia, and significant Hsp induction in the kidney soon follows [95, 231, 232]. Renal tubule cells that suffer loss of structural integrity in AKI regain their normal architecture and polarity through remodeling [123]. Recycling of damaged proteins is a primary mechanism of cellular repair following ischemia or ATP depletion [128, 233]. The chaperone capacity of Hsps may be central to the repair process. Hsp72 binds specifically to disrupted Na/K-ATPase, and Hsp25/27 binds specifically to disorganized actin filaments in renal epithelial cells injured by ischemia or ATP depletion [234–236]. Furthermore, both Hsp72 and Hsp25/27 have been shown to be protective against injury from in vitro ischemia in proximal tubule cells [235–237]. Hsp72 and 25/27 appear to work synergistically to preserve renal cell structure [238]. Supporting the in vitro studies, proximal tubule cells isolated from transgenic mice that overexpress human Hsp27 are tolerant to hydrogen peroxide injury. However, these same mice manifest more severe ischemic AKI in vivo [239]. The worse renal outcome in vivo was attributed to increased pro-inflammatory gene expression, along with increased neutrophil and lymphocyte infiltration into the kidney early after ischemia. Selective renal overexpression of Hsp27 protected against ischemic renal injury

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in vivo, which was in direct contrast to the finding in animals with systemic Hsp27 overexpression [240]. With renal-specific Hsp27 overexpression, protection against AKI was attributed to decreased neutrophil infiltration of kidneys and reduced pro-inflammatory gene expression. A more actively primed stress response may contribute to the phenomenon, long recognized by clinicians, that the immature kidney appears to be resistant to insults that produce profound AKI in older patients. The neonatal rat kidney has increased constitutive activity of HSF-1 compared with mature animals, with accompanying increased expression of Hsp72 [241, 242]. Blocking HSF-1 function reduces Hsp72 expression and the tolerance of isolated immature renal tubules to anoxia [241–243]. Stress proteins, then, appear to be central to the resistance of immature kidneys to ischemic or anoxic injury. It was thought, therefore, that the cellular stress response regulated by HSF-1 would also be central to resistance to in vivo AKI in mature animals. It was a surprise when HSF-1 knockout mice, with absent Hsp induction following renal ischemia, were found to be resistant to developing AKI after an ischemic insult [244]. HSF-1 knockout mice had an increased baseline level of immunomodulatory Foxp3+ regulatory T cells resident in the kidney, which appears to prevent development of usual features of AKI. First, the pro-inflammatory environment that develops in wild-type mice kidneys shortly following an ischemic insult did not develop in the HSF-1 knockout. Second, the typical medullary vascular congestion seen in wild-type kidneys after ischemia was nearly absent in the HSF-1 knockout. Thus, Hsps clearly provide protection at the cellular level in renal tubules, but the systemic effect of inducible Hsps may be instead harmful in the setting of an in vivo ischemic insult. Detrimental effects of inducible Hsps, outside of the renal tubule and in the microvasculature, may conflict with their beneficial effects within renal tubule cells subjected to ischemia. The inducible stress response appears to augment an ischemic insult in vivo by facilitating pro-inflammatory mechanisms of renal injury. The most recent studies, then, uniquely connect the rapidly inducible

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cellular stress response, regulated by HSF-1, to pathways of inﬂammation in ischemiainduced AKI.

Regeneration: Growth Factors It has long been suspected that growth factors, produced locally or exogenous to the kidney, contribute to proliferation and redifferentiation of the tubule epithelial cell following AKI (Fig. 1). Many studies have supported this concept. These include epidermal growth factor (EGF), insulinlike growth factor-1 (IGF-1), hepatocyte growth factor (HGF), parathyroid hormone-related peptide (PTHrP), basic ﬁbroblast growth factor, osteopontin, neural cell adhesion molecule, and transforming growth factor-beta 1 (TGF-β) [228, 245–247]. More recently, products of the putative antiaging gene Klotho were found to protect against AKI, probably through growth factor like activities of Klotho [248]. Growth factor function may be intimately linked to processes of apoptosis. In the rat model of AKI, expression of pro- and antiapoptotic members of the Bcl-2 gene family (Bcl-2, Bcl-X (L), Bax) is related to tubule expression of EGF, IGF-1, and TGF-β, all growth factors thought to be reparative in AKI [247]. The study suggested that the distal tubule is resistant to ischemic injury through antiapoptotic effects of Bcl-2 genes, and its survival allows expression of growth factors critical not only to the survival and regeneration of its own cell population (autocrine action) but also to the adjacent ischemia-sensitive proximal tubule cells (paracrine action). AKI in rats increases expression of transcription factors Ets-1 and Wnt-4 that are in pathways involved in cell cycle progression [249]. Nephrogenic proteins including basic ﬁbroblast growth factor (bFGF), vimentin, neural cell adhesion molecules, paired homeobox-2, bone morphogene protein-7, Noggin, Lim-1, Engrailed, Smad, phospho-Smad, hypoxia-inducible factor-1 alpha (HIF-1 alpha), vascular endothelial growth factor (VEGF), and Tie-2 are all induced by renal ischemia in a pattern similar to that seen in normal renal development, and

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administration of bFGF accelerated induction of many of those nephrogenic proteins during recovery [250, 251]. HIF-1 alpha is rapidly activated by renal ischemia, and growth factors VEGF and erythropoietin, both regulated by this transcription factor, appear to have important effects on renal epithelial cells and endothelial cells in the renal microvasculature. Erythropoietin administration prior to renal ischemia protects the kidney against the injury through mechanisms that limit apoptosis [252]. The relative importance of the many growth factors identified to be active in AKI has rarely been addressed. One study, however, directly compared the effect of two of these growth factors in AKI using a transgenic mouse model with targeted overexpression in the proximal tubule of HGF in one strain and PTHrP in another strain. The strain with increased HGF in the proximal tubule had a fourfold increase in tubule cell proliferation and a threefold decrease in apoptotic tubule cell death, along with rapid recovery from ischemic injury, compared with either the mice with targeted proximal tubule overexpression of PTHrP or background strain control mice [253]. This study confirmed the importance of HGF during the recovery process but raised questions about the role of rapid PTHrP induction in the proximal tubule after renal ischemia. By extension, it also raises questions about all of the growth factors identified as being induced by renal ischemia whose functional effects are yet to be defined. Some may be beneficial, whereas some, such as TGF-β, may have detrimental effects in the long term. A delicate balance of these factors may determine whether tissue remodeling following renal injury results in restitution of normal architecture or proceeds to a dead end of irreversible fibrosis.

Regeneration: Stem Cells With the advent of stem cell research, the possibility that some form of stem cell might be integral to kidney repair after AKI rapidly came to the fore. Along with embryonic stem cells, non-embryonic/adult stem cells that can

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differentiate into more than one type of specialized cell come from several sources. The best characterized are hematopoietic stem cells that can differentiate into any of the blood cell lines. Mesenchymal stem cells reside in the bone marrow and can differentiate into a variety of mesenchymal tissues in vitro and in vivo. Tissue-specific progenitor cells may reside in any organ and can differentiate into a range of cells as the need arises. Each of these potential sources of stem cells is actively being studied to determine the contribution to renal repair following acute kidney injury [254]. Both types of bone marrow-derived stem cells (BMDSC), hematopoietic stem cells (HSC) and mesenchymal stem cell/stromal cells (MSC), have been evaluated in AKI. Although some studies have supported the concept of BMDSC homing to injured kidneys and differentiation of non-inflammatory bone marrow-derived cells into renal tubule cells [255–257], recent studies indicate that BMDSC contribute minimally to repopulation of tubular epithelia [258–262]. It now appears clear that repopulation of denuded tubules after AKI comes from proliferation of surviving intrinsic kidney cells, rather than from exogenous or endogenous stem cells [260]. Nevertheless, evidence that BMDSC have a role in the repair process is consistent. The severity of renal injury in mice whose bone marrows were ablated was worse than without ablation and was reversible with infusion of lineage negative bone marrow cells [256]. Although not confirmed that MSCs engraft into renal tubules, MSCs have functional effects in AKI, such as blunting the rise in serum creatinine and altering pro-inflammatory cytokine and growth factor expression [258, 263]. These findings suggest that protection by MSC may be mediated by paracrine or endocrine actions [263, 264]. Furthermore, mobilizing endogenous BMDSCs may be a therapeutic option in AKI using stem cell factor or colonystimulating factors (macrophage-CSF or granulocyte-CSF) [265, 266]. The beneficial effects of these agents might be through ameliorating injury pathways detailed earlier in this chapter, along with affecting recovery pathways. The basic science studies of stem cells in AKI are

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now being translated into clinical studies. Recent Phase 1 clinical trials using allogeneic MSC show that they are safe and protective against AKI in patients undergoing on-pump cardiac surgery [267].

Long-Term Sequelae The focus in the clinical realm, and in experimental models of AKI, typically is on the severity of the acute renal manifestations and the speed and completeness of early recovery. Little attention had been commonly given to long-term sequelae in the kidney following an episode of AKI, since it was thought most patients who survive the triggering event appear to recover renal function completely. Decades ago it was found that many adult patients who suffered from acute renal failure never recovered renal function completely, manifested by decrements in GFR and urinaryconcentrating ability months to years later [268–272]. Prior to 2003 these studies were few, had small sample size, and used varying definitions for both AKI and progression. As a result, considerable speculation on a causative link between AKI and subsequent chronic kidney disease (CKD) persisted. However, in the last decade, there has been a dramatic increase in research on the chronic effects of AKI [76, 273–276]. Recent studies using large databases have found significant correlation between AKI and progression to CKD and end-stage renal disease (ESRD) [277]. Metaanalysis found an 8.8-fold increase risk for CKD and a 3.3-fold increase risk for ESRD in surviving AKI patients after hospital discharge [278]. In addition, the finding of significant and progressive renal insufficiency in adolescence and early adulthood after recovery from AKI as a neonate is of particular interest. Though the neonatal kidney may be more resistant to AKI, it may be more prone to develop late sequelae once AKI has been established [76, 273–276]. The cause of progression to CKD following AKI is not clearly identified. Animal models indicate that there is a lack of fidelity in the repair responses following injury. Renal repair can be

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classified as either adaptive or maladaptive, and both may occur simultaneously. Maladaptive repair is the development of fibrosis in the tubular and interstitial compartments in response to acute kidney injury. Several pathophysiological processes may contribute to maladaptive repair (see Fig. 6). Many nephrons may not be able to regenerate completely after the injury, leading to disconnection of intact glomeruli from residual tubule segments with progressive later decline in overall renal function [279, 280]. Another potential mechanism is that inflammatory mediators of renal injury, initiated by AKI, may persist and cause progressive renal dysfunction [281]. It has been shown both in humans and in animal models that there is a reduction in capillary density in the kidney following acute injury. This response is irreversible and indicative of poor adaptive nature of the vascular cells. The reduction in renal capillary density appears to contribute to chronic local hypoxia, likely a major stimulus driving interstitial fibrosis [282–284]. Following AKI there is an expansion of interstitial fibroblasts and myofibroblasts [285]. The expansion of the interstitial space has been attributed to pericyte activation into a myofibroblastlike state [286], invasion of fibrocytes [287], and endothelial-mesenchymal cell transition (EndoMT) in which endothelial cells are transformed to interstitial fibroblasts [288]. Pro-fibrotic factors such as TGF-β, CTGF, and PDGF-B facilitate the expansion of the interstitium. These factors may be provided by infiltrating macrophages or lymphocytes [285]. Persistent oxidative stress from infiltrating inflammatory cells or injured tubular cells may contribute to progressive injury [289, 290]. Pro-fibrotic growth factors are produced by epithelial cells that fail to redifferentiate fully after acute injury [291] or tubular cells that become growth arrested in the G2 phase of the cell cycle [292]. In response to DNA damage in ischemic AKI, cells activate the DNA damage response signaling pathways [293]. The effect of these signaling pathways is to enhance G2/M arrest; therefore, this mechanism is implicated in fibrosis of the kidney after AKI [292].

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Tubular Injury

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Microvascular/ Endothelial Injury

Relative Decrease in Growth Factors Relative Increase in Angioinhibitors tosis MMP Activation

Apop Pe

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Altered Vascular Tone ↑ Leukocyte Adhesion Altered Coagulation ↑ Permeability

↓ Vascular Trophic Support, Inhibition of Vascular Repair ↑ Profibrotic cytokines

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Reduced Capillary Density Reduced Blood Flow Hypoxia

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↓ Blood Flow, ↑ Inflammation Extension of acute tubular injury

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Continued Stimulation of HIF

Interstitial Fibrosis Progression to CKD

Fig. 6 Potential pathways from AKI through microvascular injury to chronic kidney disease (CKD). Renal microvascular injury in AKI, in addition to extending the acute tubule injury, contributes to development of CKD through several possible mechanisms. Microvascular injury triggers inﬂammation with increase in pro-ﬁbrotic cytokines

and inhibition of vascular repair. Subsequent microvascular dropout can contribute to ongoing local hypoxia. Chronic hypoxia along with endothelial-mesenchymal transition (EndoMT) may then promote interstitial ﬁbrosis (From Ref. [76])

Persistent changes in renal tubular cells after AKI may also contribute to maladaptive repair, such as through epigenetic alterations including histone modifications, DNA methylation, and chromosomal conformational changes that regulate gene expression. Histone deacetylase inhibitors accelerate recovery and decrease post-injury fibrosis after ischemia/reperfusion [294] and aristolochic acid nephrotoxicity [295]. In addition, prolonged mitochondrial dysfunction in injured tubule cells may promote progression to fibrosis. Development of fibrosis in the folic acidinduced AKI model was associated with suppression of mitochondrial biogenesis [296]. Finally, kidneys suffer from long-term rarefaction of capillaries [282, 283] and ongoing oxidative stress [289, 290] after transient ischemia. The thought that chronic renal hypoxia may contribute

to progressive renal dysfunction in patients is suggested by ﬁnding impaired renal oxygenation in kidney transplants affected by chronic allograft dysfunction [297]. Thus, strategies to prevent renal microvascular loss potentially could mitigate progression to CKD. Supplementation of rats with exogenous VEGF-121, early in the course of AKI, preserves renal microvasculature and mitigates progression to CKD in rats [283, 298]. However, the capillaries of the kidney appear to have limited repair potential once rarefaction is established [299]. Blockade of TGF-β, which is highly expressed after AKI, preserves microvascular density [300]. TGF-β may be pivotal in a vicious cycle triggered by AKI, since it can stimulate apoptosis in endothelial cells [301], stimulate endothelial-mesenchymal transition [302], and is itself a ﬁbrinogenic factor that is

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triggered by hypoxia [303]. Blocking TGF-β, then, could intervene on several processes that may contribute to chronic, progressive renal injury after AKI. In the absence of vascular repair, renal vasodilators might reduce intrarenal hypoxia after AKI and thereby prevent progression to CKD. Delayed administration of L-arginine improved renal blood ﬂow and oxygenation and prevented CKD progression without restoring capillary density [283]. Antagonists of endothelin, a potent renal vasoconstrictor, may slow progression of CKD following AKI in mice [304]. Another potential strategy to prevent CKD after AKI is through activating intrinsic defensive mechanisms against hypoxia and oxidative stress. HIF activation prior to induction of AKI lessens the acute injury and prevents the later development of ﬁbrosis [305, 306]. Pharmacological Nrf2 activation induces antioxidative genes and ameliorates AKI in mice [307, 308]. Although it remains to be determined whether Nrf2 activation can prevent the transition of AKI to CKD, it may be a promising approach.

Conclusion The mechanistic study of AKI that leads to clinical acute renal failure continues to advance rapidly. The progressive discovery of the many facets in the pathogenesis of the injury, markers of the injury, and potential recovery mechanisms provides hope that therapy targeted to the kidney injury specifically, along with ongoing advances in supportive therapy, will substantially improve survival and wellness of patients affected by acute kidney injury. Suggested by the many interactive pathways in AKI outlined here, no single intervention alone is likely to alter outcome substantially. An integrated approach may be required to limit injury or facilitate renal recovery. Having a clear understanding of the pathogenesis of acute kidney injury from a particular renal insult should help direct when to intervene with a specific therapy and which intervention would be most likely to benefit the patient.

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Evaluation and Management of Acute Kidney Injury in Children

Stuart L. Goldstein and Michael Zappitelli

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2140 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A Brief History of Child AKI Definition . . . . . . . . . . The KDIGO AKI Definition . . . . . . . . . . . . . . . . . . . . . . . Challenges with AKI Definition . . . . . . . . . . . . . . . . . . . .

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Epidemiology: Incidence, Disease Patterns, and Outcome Associations . . . . . . . . . . . . . . . . . . . . . . . . Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Short-Term Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Long-Term Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Etiology and Approach to Evaluation . . . . . . . . . . . General Concepts and History Taking . . . . . . . . . . . . . Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laboratory Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . Evaluating AKI in Speciﬁc Settings . . . . . . . . . . . . . . . Evaluating Serum Creatinine Rise: Distinguishing Adaptive Renal Response from True Tubular Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Future of AKI Evaluation: Biomarkers . . . . . . . Cystatin C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fluid Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrolyte Management . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Pharmacological Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . Renal Replacement Therapy . . . . . . . . . . . . . . . . . . . . . . . Modality Choice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vascular Access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Machines and Hemoﬁlters . . . . . . . . . . . . . . . . . . . . . . . . . . Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anticoagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drug Dosing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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AKI Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2161 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2161

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S.L. Goldstein (*) Division of Nephrology and Hypertension, The Heart Institute, Cincinnati Children’s Hospital Medical Center, College of Medicine, Cincinnati, OH, USA e-mail: [emailprotected] M. Zappitelli Pediatrics, Division of Nephrology, Montreal Children’s Hospital, McGill University Health Center, Montreal, QC, Canada e-mail: [emailprotected] # Springer-Verlag Berlin Heidelberg 2016 E.D. Avner et al. (eds.), Pediatric Nephrology, DOI 10.1007/978-3-662-43596-0_57

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S.L. Goldstein and M. Zappitelli

Introduction

A Brief History of Child AKI Definition

The field of acute kidney injury (AKI) has undergone a dramatic change over the past decade. Intensive recent research which standardized AKI definitions and improved the clinician’s ability to identify individuals at highest risk of developing AKI reveals the strong association between AKI and negative patient outcomes. An ongoing paradigm shift is occurring with regard to identifying the presence of AKI using kidney tissue injury biomarkers before evidence of kidney dysfunction is present. The lack of current AKI-specific therapy has had the secondary benefit of developing a strong appreciation of the importance of AKI prediction, prevention, and management of its complications early in the course of critical illness. The recent formation of several national and international AKI organizations [1–4] has led to increased AKI awareness, promotion of research, and the development of the first ever AKI clinical practice guideline document [1]. This chapter will review standard clinical evaluation and differential diagnosis of AKI, while considering recent research with respect to AKI definitions, novel diagnostic tests, and prevention strategies, followed by a description of current knowledge on treatment of severe AKI, using renal replacement therapy (RRT).

In 2004, the Acute Dialysis Quality Initiative (an international consensus group of experts) developed the empiric RIFLE (Risk, Injury, Failure, Loss, End-Stage Kidney Disease) criteria to define AKI [2]. The underlying concept was to employ changes in current biomarkers of kidney function (increase in SCr or decrease in urine output) to define and then stratify AKI severity. For example, using SCr criteria, RIFLE R (“risk”) or mild AKI was defined as a 50 % SCr increase (or a 25 % reduction in estimated glomerular filtration rate [eGFR]) from baseline or as urine output 6 h; RIFLE F (“failure”) or severe AKI definition included a tripling of SCr from baseline or urine output 24 h or anuria for >12 h. Ackan-Arikan slightly modified the RIFLE definition to enhance its applicability in children, by specifically assessing change in eGFR, rather than change in SCr, in addition to other small modifications [5]; this definition is referred to as the pediatricmodified RIFLE definition (pRIFLE). In 2007, another international AKI expert consensus group proposed a simpler modified version of the RIFLE criteria, called the Acute Kidney Injury Network (AKIN) definition [4]. While the RIFLE definition allows for evaluation of change in SCr or change in eGFR to define AKI severity, the AKIN definition focuses on using acute SCr change to define three stages of AKI severity, in addition to three severity stages of acute urine output decrease. Though a pediatric-specific AKIN definition has not been proposed, several studies have applied the AKIN definition to describe child AKI epidemiology, particularly if height (required to estimate glomerular filtration rate (GFR) for the pRIFLE definition) was not available. Because of their close similarities, use of the RIFLE or the AKIN definitions leads to very similar descriptions of AKI epidemiology, except that the RIFLE definition appears more sensitive to detect milder AKI [1, 6]. Each of the AKIN, RIFLE, and pRIFLE AKI definitions is shown side by side in Table 1. They served as

Definition One of the most important research advancements in the AKI field has been work performed to derive a standardized, multidimensional AKI definition. Until recently, studies describing AKI epidemiology have used a wide variety of definitions, ranging from mild elevations in serum creatinine (SCr) to the requirement of RRT. The advent of standardized AKI definitions has allowed the pediatric community to evaluate AKI epidemiology across the world and understand its burden of illness.

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Table 1 Comparison of serum creatinine (SCr) criteria in acute kidney injury (AKI) definitions proposed prior to the current Kidney Disease: Improving Global Outcomes (KDIGO) definition (Table 2) Acute Kidney Injury Network (AKIN)a Stage Criteria 1 SCr rise to 1.5 to 3 months failure)

Abbreviations: eGFR estimated glomerular filtration rate The AKIN [4] and RIFLE [2] definitions utilize the same urine output criteria for AKI as described below in Table 2, the KDIGO definition. As in KDIGO, a patient may fulfill criteria for AKI for all three definitions in the table, if they fulfill either the SCr or the urine output criteria. The pRIFLE [5] criteria urine output criteria differed slightly: R: