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Third Edition

Clinical PediatricTMephrology

http://www.taylorandfrancis.com

CRC Press is an imprint of theTaylor & Francis Group, an informa business

Boca Raton London New York

V i c e C h a i r D e p a r t m e n t o f P e d i a t r i c sN o r t h w e s t e r n U n i v e r s i t yF e i n b e rg S ch o o l o f M e d i c i n ea n d A n n & R o b e r t H . L u r i e C h i l d re n ’s H o s p i t a l o f C h i c a g oC h i c a g o , I L , U S A

D i v i s i o n D i r e c t o r o f P e d i a t r i c N e p h r o l o g yM a rc u s P r o f e s s o r o f P e d i a t r i c sE m o r y U n i v e r s i t y S ch o o l o f M e d i c i n ea n d C h i l d re n ’s H e a l t h c a re o f A t l a n t aA t l a n t a , G A , U S

C h a i r m a n , D e p a r t m e n t o f N e p h r o l o g y P h o e n i x C h i l d re n ’s H o s p i t a lP h o e n i x , A Z , U S A a n d E m e r i t u s P r o f e s s o r o f P e d i a t r i c s G e o rg e Wa s h i n g t o n U n i v e r s i t y S ch o o l o f M e d i c i n eWa s h i n g t o n , D C , U S A

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Third Edition

Clinical PediatricINephrology

CRC PressTaylor & Francis Group

Edited By

Karrwal K. Kher

H. William Schnaper

Larry A. Greenbaum

£9

CRC PressTaylor & Francis Group6000 Broken Sound Parkway NW, Suite 300Boca Raton, FL 33487-2742

© 2017 by Taylor & Francis Group, LLCCRC Press is an imprint of Taylor & Francis Group, an Informa business

No claim to original U.S. Government works

Printed on acid-free paperVersion Date: 20160808

International Standard Book Number-13: 978-1-4822-1462-8 (Pack - Book and Ebook)

This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. The publishers wish to make clear that any views or opinions expressed in this book by individual editors, authors or contributors are personal to them and do not necessarily reflect the views/opinions of the publishers. The information or guidance contained in this book is intended for use by medical, scientific or health-care professionals and is provided strictly as a supplement to the medical or other professional’s own judgement, their knowledge of the patient’s medical history, relevant manufacturer’s instructions and the appropriate best practice guidelines. Because of the rapid advances in medi-cal science, any information or advice on dosages, procedures or diagnoses should be independently verified. The reader is strongly urged to consult the relevant national drug formulary and the drug companies’ and device or material manufacturers’ printed instructions, and their websites, before administering or utilizing any of the drugs, devices or materials mentioned in this book. This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole responsibility of the medical professional to make his or her own professional judgements, so as to advise and treat patients appropriately. The authors and publishers have also attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint.

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v

Contents

Preface ix

Contributors xi

PART A KIDNEY ANATOMY AND DEVELOPMENT

1 Anatomy and embryology of the urinary tract 3Kurt E. Johnson

2 Molecular basis of developmental renal disease 17Norman D. Rosenblum

PART B DIAGNOSTIC EVALUATION OF KIDNEY DISEASES

3 Urinalysis 31George J. Schwartz

4 Clinical assessment of renal function 45George J. Schwartz

5 Normal and abnormal kidney function in neonates 73Dave T. Selewski and David J. Askenazi

6 Diagnostic imaging of the urinary tract 87Eglal Shalaby-Rana, Bruce Markle, and Dorothy Bulas

7 Radionuclide renal imaging 105Eglal Shalaby-Rana, Mary Andrich, and Massoud Majd

8 Renal biopsy 115Natalie S. Uy, Mihail M. Subtirelu, and Frederick J. Kaskel

9 Hematuria and proteinuria 127Kanwal Kher and Marva Moxey-Mims

PART C DISORDERS OF HOMEOSTASIS

10 Physiology of glomerular filtration 153H. William Schnaper

11 Sodium and volume homeostasis 165Michel Baum

12 Potassium homeostasis 183Caroline Gluck and Lisa M. Satlin

13 Disorders of mineral metabolism 205Farah N. Ali and Craig B. Langman

14 Acid-base homeostasis 235Raymond Quigley

15 Water homeostasis 255Melissa A. Cadnapaphornchai

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vi Contents

PART D GLOMERULAR AND TUBULAR DISEASES

16 Nephrotic syndrome 285Michelle N. Rheault

17 Primary podocytopathies 305Raed Bou Matar, Rudolph P. Valentini, and William E. Smoyer

18 Nephrotic syndrome in the first year of life 353Christer Holmberg and Hannu Jalanko

19 Membranoproliferative glomerulonephritis 367Carla M. Nester and Danniele G. Holanda

20 Membranous nephropathy 385Georges Deschênes

21 Acute glomerulonephritis 401Diego H. Aviles and V. Matti Vehaskari

22 Rapidly progressive glomerulonephritis and vasculitis 419Franca Iorember and V. Matti Vehaskari

23 Immunoglobulin A nephropathy and Henoch-Schönlein purpura nephritis 435M. Colleen Hastings and Robert J. Wyatt

24 Thrombotic microangiopathies 451John D. Mahan and Stephen Cha

25 Tubulointerstitial nephritis 479Rossana Baracco, Gaurav Kapur, and Tej K. Mattoo

PART E KIDNEY IN SYSTEMIC DISEASES

26 Lupus nephritis 499Carla M. Nester, David B. Thomas, and Debbie S. Gipson

27 Kidney disease in sickle cell disease 519Ibrahim F. Shatat and Sherron M. Jackson

28 Kidney disease associated with diabetes mellitus and metabolic syndrome 533Kanwal Kher and Michele Mietus-Snyder

29 Kidney in viral infections 553Jeffrey B. Kopp

PART F KIDNEY FAILURE

30 Acute kidney injury 571Prasad Devarajan and Stuart L. Goldstein

31 Chronic kidney disease 601Kirtida Mistry

32 Anemia in chronic kidney disease 627Meredith Atkinson

33 Chronic kidney disease bone and mineral disorder 639Katherine Wesseling-Perry and Isidro B. Salusky

34 Nutrition in chronic kidney disease 665Sun-Young Ahn and Robert Mak

PART G RENAL REPLACEMENT THERAPIES

35 Continuous renal replacement therapy 679Akash Deep and Timothy E. Bunchman

36 Hemodialysis 703Raj Munshi and Jordan M. Symons

37 Peritoneal dialysis 723Bradley A. Warady

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Contents vii

38 Renal transplantation 743Asha Moudgil and Stanley C. Jordan

PART H HYPERTENSION

39 Hypertension in children and adolescents 777Karen McNiece Redwine

40 Management of hypertension 803Joseph T. Flynn

PART I INHERITED RENAL DISORDERS

41 Tubulopathies 819Detlef Bockenhauer

42 Renal tubular acidosis 839John W. Foreman

43 Cystic kidney disease 863Lisa M. Guay-Woodford

44 Ciliopathies and nephronophthisis 889John Sayer, Shreya Raman, and Shalabh Srivastava

45 Alport syndrome and thin basement membrane nephropathy 899Michelle N. Rheault and Clifford E. Kashtan

46 Renal disease in syndromic disorders 911Patrick Niaudet

PART J UROLOGIC DISORDERS

47 Hydronephrosis and obstructive uropathies 931Ihor V. Yosypiv

48 Vesicoureteral reflux 953Tej K. Mattoo

49 Urinary tract infection 967Brittany Goldberg and Barbara Jantausch

50 Pediatric renal tumors 993Eugene Minevich, Armando J. Lorenzo, W. Robert DeFoor and Martin A. Koyle

51 Urolithiasis in children 1005Uri S. Alon and Tarak Srivastava

52 Voiding disorders 1025Hans G. Pohl

PART K RESEARCH TOOLS

53 Applied clinical biostatistics 1049Shamir Tuchman

Index 1061

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ix

Preface

�is third edition of Clinical Pediatric Nephrology contin-ues to have as its main goal providing a primer of pediat-ric nephrology. Its intended audience includes committed medical students and general trainees, as well as pediatric nephrology fellows and pediatric nephrologists. Our focus remains on the clinical diagnosis and management of pedi-atric renal disorders.

�e book has been thoroughly updated, and each chapter has been rewritten. �e number of chapters has expanded from 37 to 53. In part, this represents a degree of special-ization, with several chapters divided to focus on speci�c disorders as their pathogenesis has been clari�ed. �e organization of the book has also been changed with an additional emphasis on the physiology of kidney diseases. Sections now cover kidney anatomy and development, diagnostic evaluation, disorders of homeostasis, glomeru-lar and tubular diseases, systemic diseases and the kidney, acute and chronic kidney disease, renal replacement thera-pies, hypertension, inherited disorders, urologic disorders, and research tools. We believe that this reorganization and the expansion in the number of chapters better re�ects the status of pediatric nephrology today. Each chapter includes “Key Points” boxes to emphasize issues that the authors and editors believe are important take-aways in the section, a set of review questions for the reader, and where appropri-ate a clinical vignette describing how the information in the chapter could be clinically applied in real life.

An important change has been an evolution in the edi-torship. Dr. Larry Greenbaum has joined the editorial team. He brings immense experience as an academic nephrolo-gist, clinician and a researcher to the editorial team. His role in shaping the content of the third edition is evident in all sections of the book. We also wish to express our sincerest gratitude and thanks to Dr. Sudesh Makker, who guided the editorial work in the �rst two editions of this book.

We wish to thank all the contributors who worked dili-gently with us, under tight time-lines, through several revi-sions of their texts, and who willingly provided elements

for the chapters that are unique to this publication. �e outstanding editorial, production, and marketing teams at Taylor and Francis have provided support that has been essential to our reaching fruition. We are especially grateful to Our sincerest thanks to Henry Spilberg, who has man-aged the publication of the second edition and guided us in the concept design of the third edition of this book at Taylor and Francis. Miranda Bromage, who has taken over the reigns, has been an inspiration to work with. She provided her extraordinary skills in guiding the production of the book. Henry and Miranda were instrumental in advocating for an “all-color” book, which has enhanced its content and visual appeal. We thank both of them from the bottom of our hearts. Amy Blalock and Linda Van Pelt provided their superb expertise in copy editing and composing the galleys. Kyle Meyer, at the Boca Raton o�ce of CRC Press-Taylor and Francis worked patiently with us in the editing of gal-leys of all chapters. Without his help, publication of this book would not have materialized. Figures in this edition were drawn by a very talented pool of artists. �ey are the unsung heroes of this work. We wish to thank each one of them for their contributions.

We owe a major debt of gratitude to two groups. Our students, residents, nephrology fellows and colleagues have provided inspiration and frequently challenged us on com-munication of scienti�c and educational content, as well as the format of this work. Most importantly, our families, who tolerate our busy and o�en distracting schedules have provided consistent support and a sense of perspective as we undertook this task. �ey provide an essential foundation for our lives. It is only with their individual commitments that we have succeeded in completing this task. We owe our heartfelt gratitude and appreciation to each one of them.

Kanwal K. KherLarry A. GreenbaumH. William Schnaper

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xi

Contributors

Sun-Young Ahn, MDMedical director, nephrology inpatient servicesChildren’s National Health System,The George Washington UniversityWashington DC, USA

Farah N. Ali, MD, MSAssistant Professor of PediatricsAnn and Robert H. Lurie Children’s Hospital of ChicagoChicago, Illinois

Uri S. Alon, MDProfessor of PediatricsUniversity of Missouri, Kansas City School of MedicineandSection of Pediatric NephrologyThe Children’s Mercy HospitalKansas City, Missouri

Mary Andrich, MDClinical Associate Professor of Radiology The George Washington University School of MedicineWashington, DC

David Askenszi MD, MSPHAssociate Professor of PediatricsMedical Director - Pediatric and Infant Center for Acute

NephrologyUniversity of Alabama at BirminghamBirmingham Alabama , USA

Meredith Atkinson, MD, MHSAssociate Professor of PediatricsDivision of Pediatric NephrologyJohns Hopkins University School of MedicineBaltimore, Maryland, USA

Diego H. Aviles, MDDivision Chief, Pediatric NephrologyChildren’s Hospital of New OrleansProfessor of Clinical PediatricsLouisiana State University Health Sciences Center

New OrleansNew Orleans, Louisiana

Rossana Baracco, MDAssistant Professor of PediatricsChildren’s Hospital of MichiganWayne State UniversityDetroit, Michigan, USA

Michel Baum, MDSara M. and Charles E. Seay Chair in Pediatric ResearchProfessor of Pediatrics and Internal MedicineDepartment of PediatricsUniversity of Texas Southwestern Medical CenterDallas, Texas

Detlef Bockenhauer, PhDProfessor of Paediatric NephrologyUCL Institute of Child Health and Great Ormond Street

Hospital for ChildrenNHS Foundation TrustLondon, United Kingdom

Raed Bou Matar, MDAssistant Professor of PediatricsCleveland Clinic Lerner College of Medicine of Case

Western Reserve UniversityCenter for Pediatric NephrologyCleveland, Ohio

Dorothy Bulas, MDProfessor of Pediatrics and RadiologyThe George Washington University School of MedicineChildren’s National Health SystemWashington, DC

Timothy E. Bunchman, MDDirector Pediatric NephrologyChildren’s Hospital of RichmondandProfessor of PediatricsVirginia Commonwealth University School of MedicineRichmond, Virginia

Melissa A. Cadnapaphornchai, MDAssociate Professor of Pediatrics and MedicineUniversity of Colorado Anschutz Medical CampusThe Kidney CenterChildren’s Hospital ColoradoAurora, Colorado

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xii Contributors

Stephen Cha, MDClinical Assistant Professor of PediatricsNortheast Ohio Medical UniversityNephrology & Pediatric Hypertension CenterAkron Children’s HospitalAkron , Ohio

Akash Deep MD, FRCPCHHonorary Lecturer, King’s CollegeDirector, Pediatric Intensive Care UnitKing’s College Hospital, London, UK

W. Robert DeFoor, MD, MPHAssociate Professor of SurgeryUniversity of CincinnatiandDirector Clinical ResearchDivision of Pediatric UrologyCincinnati Children’s Hospital Medical CenterCincinnati, Ohio

Georges Deschênes, MD, PhDHead of Pediatric NephrologyAPHP Robert-Debré, Université Sorbonne-Paris-CitéParis, France

Prasad Devarajan, MDLouise M. Williams Endowed ChairProfessor of Pediatrics and Developmental BiologyDirector of Nephrology and HypertensionCincinnati Children’s Hospital Medical CenterUniversity of Cincinnati School of MedicineCincinnati, Ohio

Joseph T. Flynn, MD, MSChief, Division of NephrologySeattle Children’s HospitalProfessor of PediatricsUniversity of Washington School of MedicineSeattle, Washington

John W. Foreman, MDChief, Pediatric NephrologyDepartment of PediatricsDuke University Medical CenterDurham, North Carolina

Debbie S. Gipson, MD, MSProfessor of PediatricsUniversity of Michigan School of MedicineAnn Arbor, Michigan , USA

Caroline Gluck, MDPediatric Nephrology FellowChildren’s Hospital of PhiladelphiaPhiladelphia, Pennsylvania, USA

Brittany Goldberg MD, MSAdjunct Assistant Professor of PediatricsGeorge Washington University School of MedicineDivision of Infectious DiseasesChildren’s National Health SystemWashington, DC

Stuart L. Goldstein, MD, FAAP, FNKFDirector, Center for Acute Care NephrologyDivision of Nephrology and HypertensionThe Heart Institute CincinnatiChildren’s Hospital Medical CenterCincinnati, Ohio, United States of America

Larry Greenbaum, MD, PhD, FAAPMarcus Professor of Pediatric NephrologyChief, Division of NephrologyEmory University School of MedicineandChildren’s Healthcare of AtlantaAtlanta, Georgia USA

Lisa M. Guay-Woodford, MDHudson Professor of PediatricsGeorge Washington UniversityandDirector, Center for Translational ScienceandDirector, Clinical and Translational Institute at

Children’s NationalChildren’s National Health SystemWashington, DC

M. Colleen Hastings, MD, MSAssociate Professor, Pediatrics and MedicineUniversity of Tennessee Health Science CenterandLe Bonheur Children’s HospitalandChildren’s Foundation Research InstituteMemphis, Tennessee

Danniele Gomes Holanda, MDClinical Assistant ProfessorDirector, Electron Microscopy LaboratoryDepartment of PathologyUniversity of Iowa Hospitals and ClinicsIowa City, Iowa, USA

Christer Holmberg, MD, PhDProfessor of pediatricsPediatric Nephrology and TransplantationChildren’s HospitalUniversity of HelsinkiHelsinkiFinland

Franca Iorember, MD, MPHAssociate Professor of PediatricsClinical Division of NephrologyChildren’s Hospital of New OrleansandDepartment of PediatricsLouisiana State University Health Sciences Center

New OrleansNew Orleans, Louisiana

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Contributors xiii

Sherron M. Jackson, MDAssociate Professor, Pediatric

Hematology-OncologyDirector of Pediatric Sickle Cell ClinicMedical University of South CarolinaCharleston, South Carolina USA

Hannu Jalanko, MDProfessor, Head of the Department Pediatric Nephrology and TransplantationChildren’s Hospital, University of HelsinkiHelsinki University Central HospitalHelsinki, Finland

Barbara Jantausch, MDProfessor of PediatricsGeorge Washington University School of MedicineandDivision of Infectious DiseasesChildren’s National Medical CenterWashington, DC

Kurt E. Johnson, PhDProfessor of Anatomy and Regenerative BiologyProfessor of Obstetrics and Gynecology (Research)George Washington University School of Medicine and

Health SciencesWashington, DC

Stanley C. Jordan, MDDirector, NephrologyDirector, HLA and Transplant Immunology LaboratoryComprehensive Transplant CenterMedical Director, Kidney Transplant ProgramCedars-Sinai Medical Center, Los Angeles, California

Gaurav Kapur, MDAssociate Professor, PediatricsDirector, Pediatric DialysisWayne State University School of MedicineChildren’s Hospital of MichiganDetroit, Michigan, USA

Clifford E. Kashtan, MDProfessor of PediatricsChief, Division of Pediatric NephrologyUniversity of Minnesota Amplatz

Children’s HospitalMinneapolis, Minnesota

Frederick J. Kaskel, MD, PhDProfessor and Vice Chair of PediatricsDirector, Life Course Research ProgramBlock Institute for Clinical & Translational

ResearchAlbert Einstein College of MedicineandChildren’s Hospital at MontefioreBronx, NY

Kanwal K. Kher, MDProfessor Emeritus of PediatricsGeorge Washington University School of MedicineWashington, DCand Division Chief, Nephrology and HypertensionPhoenix Children’s HospitalPhoenix, AZ

Jeffrey B. Kopp, MDKidney Disease SectionNational Institute of Diabetes and Digestive and

KidneyBethesda, Maryland

Martin A. Koyle, MDProfessor Department of Surgery University of Toronto Department Head, UrologyThe Hospital for Sick Children Toronto, Canada

Craig B. Langman, MDThe Isaac A Abt MD Professor of Kidney DiseasesFeinberg School of Medicine, Northwestern UniversityHead, Kidney DiseasesThe Ann and Robert H Lurie Children’s Hospital of

ChicagoChicago, Illinois USA

Armando J. Lorenzo, MDAssociate ProfessorDepartment of SurgeryUniversity of Toronto andDepartment of Urology. The Hospital for Sick Children, Toronto, Canada

John D. Mahan, MDProfessor, Department of PediatricsPediatric NephrologyThe Ohio State University College of MedicineandNationwide Children’s HospitalColumbus Ohio

Massoud MajdProfessor of Pediatrics and RadiologyThe George Washington University School of

MedicineandChildren’s National Health SystemWashington, DC

Robert Mak, MD, PhDPediatric NephrologyUniversity of California San DiegoLa Jolla, California

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xiv Contributors

Bruce Markle, MDAssociate Professor of Pediatrics and RadiologyThe George Washington University School of MedicineChildren’s National Health SystemWashington, DC

Tej K. Mattoo, MD, DCH, FRCP (UK)Professor of PediatricsWayne State University School of MedicineChief, Pediatric Nephrology and HypertensionChildren’s Hospital of MichiganDetroit, Michigan

Karen McNiece Redwine, MD, MPHAssociate Professor of PediatricsPediatric NephrologyUniversity of Arkansas for Medical Sciences/Arkansas

Children’s HospitalLittle Rock, Arkansas

Michele Mietus-Snyder, MDAssociate Professor of PediatricsThe George Washington University School of MedicineandChildren’s National Health SystemWashington, DC

Eugene Minevich, MDProfessor of SurgeryDivision of Pediatric UrologyCincinnati Children’s Hospital Medical CenterCincinnati, Ohio

Kirtida Mistry, MBBCh, DCH, MRCPCHAssistant Professor of PediatricsDivision of Pediatric NephrologyThe George Washington University School of MedicineandMedical Director, Dialysis ServicesChildren’s National Medical CenterWashington, DC

Asha Moudgil, MDProfessor of PediatricsGeorge Washington University School of MedicineActing Chief Division of NephrologyandMedical Director, Renal TransplantationChildren’s National Medical CenterWashington, DC

Marva Moxey-Mims, MDKUH Deputy Director for Clinical ResearchDirector, Pediatric Nephrology and Renal Centers

Programs NIH, NIDDK, DKUH Bethesda, Maryland

Raj Munshi, MDSeattle Children’s HospitalSeattle, Washington

Carla M. Nester, MD, MSAAssistant ProfessorDepartments of Internal Medicine and PediatricsDivision of NephrologyUniversity of Iowa Hospital and ClinicsIowa City, Iowa

Patrick Niaudet, MDPediatric NephrologyHôpital Necker-Enfants MaladesUniversité Paris-DescartesParis, France

Hans G. Pohl, MD, FAAPAssociate ProfessorUrology and PediatricsGeorge Washington UniversityandAssociate Chief, Department of UrologyChildren’s National Medical CenterWashington, DC

Raymond Quigley MDDivision of Pediatric NephrologyUniversity of Texas Southwestern Medical CenterDallas, Texas

Shreya Raman, MBBS, MRCP, MSc, FRCPathSpecialist Registrar in HistopathologyRoyal Victoria InfirmaryNewcastle upon Tyne Hospitals NHS Foundation TrustNewcastle upon Tyne, United Kingdom

Michelle N. Rheault, MDAssistant Professor of PediatricsandMedical Director of DialysisDivision of Pediatric NephrologyUniversity of Minnesota Amplatz Children’s HospitalMinneapolis, Minnesota

Norman D. Rosenblum MD, FRCPCPaediatric NephrologistHospital for Sick ChildrenProfessor of Paediatrics, Physiology, and Laboratory

Medicine and PathobiologyCanada Research Chair in Developmental NephrologyUniversity of TorontoPeter Gilgan Centre for Research and LearningHospital for Sick ChildrenToronto, Canada

Isidro B. Salusky, MDDistinguished Professor of PediatricsChief. Division of Pediatric NephrologyDirector, Clinical and Translational Research CenterAssociate Dean for Clinical ResearchDavid Geffen School of Medicine at UCLALos Angeles, California, USA

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Contributors xv

Lisa M. Satlin, MDHerbert H. Lehman Professor and ChairJack and Lucy Clark Department of PediatricsMount Sinai Medical CenterPediatrician-in-ChiefKravis Children’s Hospital at Mount SinaiIcahn School of Medicine at Mount SinaiNew York, New York

John Sayer, MBChB, PhD, FRCPSenior Clinical Lecturer in NephrologyInstitute of Genetic MedicineInternational Centre for LifeNewcastle UniversityNewcastle Upon Tyne, United Kingdom

H. William Schnaper, MDIrene Heinz Given and John Laporte Given Professorship

in Pediatric ResearchVice Chair, Department of PediatricsNorthwestern University Feinberg School of MedicineandAnn & Robert Lurie Children’s Hospital of ChicagoChicago, Illinois

George J. Schwartz, MDProfessor of Pediatrics and MedicineChief, Division of Pediatric NephrologyDepartment of PediatricsUniversity of Rochester School of MedicineRochester, New York

Dave Selewski, MD, MSAssistant ProfessorPediatric NephrologyUniversity of MichiganAnn Arbor, Michigan

Eglal Shalaby-Rana, MDAssistant Professor of Radiology and PediatricsGeorge Washington University School of MedicineandChildren’s National Medical CenterWashington, DC

Ibrahim F. Shatat, MD, MSAssociate Professor of PediatricsDivision of Nephrology and HypertensionMUSC Children’s HospitalCharleston, South Carolina

William E. Smoyer, MDC. Robert Kidder Endowed ChairVice President Clinical and Translational ResearchDirector, Center for Clinical and Translational ResearchThe Research Institute at Nationwide Children’s HospitalProfessor of PediatricsColumbus, Ohio USA

Shalabh Srivastava, MBBS, MRCPSpecialist Registrar in NephrologyInstitute of Genetic MedicineNewcastle UniversityNewcastle upon Tyne, United Kingdom

Tarak Srivastava, MDAssociate Professor of PediatricsUniversity of Missouri, Kansas City School of MedicineandDirector, Nephrology Research LaboratoryChildren’s Mercy HospitalKansas City, Missouri

Mihail M. Subtirelu, MDAdjunct Associate ProfessorUniversity of Missouri, Kansas City Division of Pediatric NephrologyandChildren’s Mercy HospitalKansas City, Missouri

Jordan M. Symons, MDProfessor of PediatricsUniversity of Washington School of MedicineAttending NephrologistSeattle Children’s HospitalSeattle, Washington, USA

David B. Thomas, MDProfessor of PathologyUniversity of Miami Miller School of MedicineUniversity of Miami HospitalMiami, Florida

Shamir Tuchman, MD, MPHAssistant Professor of PediatricsGeorge Washington University School of MedicineandDivision of Pediatric NephrologyChildren’s National Medical CenterWashington, DC

Natalie S. Uy, MDAssistant Professor of PediatricsPediatric NephrologyColumbia University Medical CenterNew York, NY

Rudolph P. Valentini, MDChief Medical OfficerPediatric NephrologyChildren’s Hospital of MichiganClinical Professor of PediatricsWayne State University School of MedicineDetroit, Michigan

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Vesa Matti Vehaskari, MD, PhDProfessor of PediatricsLSU Health Sciences CenterChildren’s Hospital of New OrleansNew Orleans, Louisiana

Bradley A. Warady, MDProfessor of PediatricsUniversity of Missouri, Kansas City School of MedicineandSenior Associate Chairman, Department of PediatricsDirector, Division of Pediatric NephrologyChildren’s Mercy HospitalKansas City, Missouri

Katherine Wesseling-Perry, MDAssociate Professor of PediatricsDivision of Pediatric NephrologyDavid Geffen School of Medicine at UCLAUniversity of California, Los AngelesLos Angeles, California

Robert J. Wyatt, MD, MSProfessor of Pediatrics University of Tennessee Health Science CenterandLe Bonheur Children’s HospitalMemphis, Tennessee

Ihor V. Yosypiv, MDAssociate ProfessorDepartment of PediatricsTulane University Health Sciences CenterNew Orleans, Louisiana

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PART A

Kidney anatomy and development

1 Anatomy and embryology of the urinary tract 3Kurt E. Johnson

2 Molecular basis of developmental renal disease 17Norman D. Rosenblum

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3

1Anatomy and embryology of the urinary tract

KURT E. JOHNSON

Kidneys serve as an important metabolic organ that elimi-nates nitrogenous waste products, maintains �uid and electrolyte balance, and performs important hormonal functions, such as synthesis of 1-25-dihydroxy vitamin D and erythropoietin. Being paired organs, kidneys have also been used in living organ donation for renal replacement therapy in patients with end-stage renal disease (ESRD). Developmental aspects of kidney have received consider-able attention recently and much has now been deciphered about the control of renal and ureteric development. It is also becoming increasingly clear that nephron endowment at birth is an important fetal factor that may determine the development of hypertension and chronic kidney disease (CKD) in adults. �is chapter discusses the clinically rel-evant anatomy and embryogenesis of the kidneys and the urinary tract.

GROSS STRUCTURE AND RELATIONS

In adults, each kidney is reddish-brown, approximately 11 cm long, 5 cm wide, and 3 cm thick, and weighs approxi-mately 130 g. By renal ultrasound measurement, renal length in healthy newborns has been reported to be 4.21 ± 0.45 cm for the right kidney and 4.32 ± 0.46 cm for the le� kidney.1 Kidneys grow with age and achieve adult length by approximately 18 years of age.2,3 Interestingly, renal length is greater in obese children, possibly re�ecting hypertrophy resulting from hyper�ltration.4 Both kidneys are more or less similar in shape, with a convex lateral surface and a deep recess at the hilum of the kidney on the medial sur-face that is called the renal sinus. �e renal artery and vein

and some adipose tissue occupy the renal sinus, along with a funnel-shaped expansion of the ureter known as the renal pelvis. Within the kidney, the renal pelvis is divided into two elongated major calyces and several shorter branches called the minor calyces.

�e two kidneys lie on the posterior abdominal wall along either side of the vertebral column in the retroperito-neal space, but at slightly di�erent levels. �e le� kidney has its superior pole at approximately the level of the middle of T11 vertebral body and its inferior pole at approximately the level of the bottom of L2. In contrast, the right kidney lies slightly lower, with its superior pole at the top of T12 and its inferior pole at the top of L3. �e superior poles of each kidney are in contact with the diaphragm, and their poste-rior surfaces are covered by skeletal muscles (from medial to lateral): psoas major, quadratus lumborum, and transversus abdominis.

In a longitudinally cut section, the kidney has a darker cortex, whereas the inner medulla is lighter in color. Each kidney has a collection of triangular renal pyramids, or lobes, with a base bordering the cortex and an apex project-ing as renal papillae into the minor calyces (Figure 1.1). Each renal pyramid consists of medullary tissue associated with the corresponding cap of cortical tissue. �e distinction

Gross structure and relations 3Microscopic anatomy 4Renal blood supply 5The renal corpuscle 5

Renal embryology 8References 13Review questions 15Answer key 16

KEY POINT

Newborn kidneys are approximately 4.5 cm long as measured by ultrasound.

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4 Anatomy and embryology of the urinary tract

between cortex and medulla in the kidneys is made di�cult by the projection of medullary tissue into the cortex as med-ullary rays and by the cortical tissue bundled between the renal pyramids, known as the renal columns of Bertin.

�e ureters are 25 cm long in an adult but are of variable length in children. �e ureter has a thick, �bromuscular wall and a small lumen. Along its descent from the abdomi-nal cavity (upper half) into the lesser pelvis (lower half), the ureter is located retroperitoneally and is closely adherent to the overlying peritoneal lining. Ureters enter the urinary bladder posteriorly. �e urinary bladder is a hollow muscu-lar organ located posterior to the symphysis pubis, and its superior surface is covered by a re�ection of the peritoneal lining. It is innervated by nerves from the vesical plexus, which has �bers from two distinct sources: (1) sympathetic lumbar nerves through the hypogastric plexus and (2) para-sympathetic pelvic splanchnic nerves.

MICROSCOPIC ANATOMY

�e renal parenchyma consists of functional units called uriniferous tubules, each with two distinct components: (1) the nephron and (2) the collecting tubules. �e neph-ron consists of the Bowman capsule, proximal convoluted tubules (PCTs), loop of Henle, and distal convoluted tubules (DCTs). Nephrons have highly variable lengths. In general, the super�cial (cortical) nephrons are shorter and the deep (juxtamedullary) nephrons are longer, mostly because of the longer loop of Henle. �ese long nephrons are important

in the urinary concentrating mechanism (Figure  1.2). Uriniferous units converge to form the apex of the renal pyramids as they enter the minor calyces. Starting at the bases of the renal pyramids, adjacent to the corticomedul-lary junction, bundles of tubules and associated blood ves-sels may project toward the surface of the kidney as radially arranged medullary rays.

�e most proximal structure of the nephron is the Bowman capsule, a thin-walled, spherical dilation, which is deeply invaginated into a two layered, cup-like structure, with a visceral layer and a parietal layer. �e space between these two layers, which is continuous with the lumen of the PCTs, is called the urinary (or Bowman) space. �e concave depression in the Bowman capsule is occupied by a network of capillaries known as the glomerulus. �e glomerulus and Bowman capsule together constitute a renal corpuscle and comprise the functional �ltering units in the kidney.

�e PCT receives the glomerular �ltrate from the uri-nary space of Bowman capsule. It is lined by a simple columnar epithelium. Its cells have an abundance of mito-chondria that make the cytoplasm intensely acidophilic. Epithelial cells of the PCT have an elaborate apical micro-villous brush border, which �lls much of the lumen of the PCT, and deep invaginations of the basilar surface mem-brane. �e lateral borders of individual cells are extensively interdigitated, thus giving the individual cells the appear-ance of a tree stump with elaborate buttressing. �ese microscopic features play an important role in the reab-sorption of tubular water, electrolytes, bicarbonate, phos-phate, and amino acids. Proximal tubules also reabsorb and metabolize �ltered albumin in proteinuric states and return the amino acids and dipeptides to body’s nutrition pool. �e PCT leads into a proximal straight tubule, and from there the glomerular �ltrate passes into the descend-ing thin limb, the ascending thin limb, and the ascending thick limb of the loop of Henle.

Once the glomerular �ltrate has ascended the loop of Henle, it passes into the DCT. A portion of the DCT con-tacts the vascular pole of the renal corpuscle, where it forms the macula densa of the juxtaglomerular apparatus (JGA). �e DCT is lined by simple cuboidal epithelium, although it has a wider lumen than the PCT. �ere are only scattered apical microvilli in the DCT. �e cells in the thin limbs of the loop of Henle are generally �attened and are o�en frankly

KEY POINTS

● Nephrons with glomeruli close to the corticomed-ullary junction have long loops of Henle. �ese nephrons participate in the urinary concentration mechanism.

● Super�cial or cortical nephrons have shorter loops of Henle.

Renal

papilla

RenalcortexRenal

medulla

Renalpapilla

Column ofBerti

nPeri-pelvicfat

Figure 1.1 Cut surface of normal kidney of a child with anatomic landmarks shown. (Photograph provided by Ronald Przygodzki, MD.)

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The renal corpuscle 5

squamous. �e collecting tubules, the last component of the nephron, have squamous epithelium, whereas the collecting ducts have taller epithelial cells, starting as cuboidal cells in the cortex but growing taller along the route of descent to the renal papilla, eventually to form tall columnar cells in the walls of the papillary ducts (of Bellini), just before they penetrate the area cribrosa to enter the minor calyx.

RENAL BLOOD SUPPLY

Blood �ow through the kidneys is surprisingly exten-sive (approximately 25% of cardiac output), with approxi-mately 90% �owing through the cortex and the rest �owing through the medulla. �is immense blood supply ensures rapid removal of nitrogenous wastes from the blood by the kidneys. �e renal artery enters the renal sinus and divides

into anterior and posterior branches, which then form seg-mental arteries. Segmental arteries branch into lobar arter-ies for each renal pyramid (lobe), which then branch again, passing in the renal columns, between the renal pyramids as interlobar arteries. Once the interlobar arteries have pen-etrated to the corticomedullary junction, they branch into arcuate arteries, which run parallel to the surface of the kid-ney. At regular intervals along the arcuate arteries, inter-lobular arteries project radially toward the most super�cial parts of the cortex. As the interlobular arteries pass from the deep cortex to the super�cial cortex, they send out branches called a�erent arterioles that supply blood to the glomeruli. A�er leaving the glomerulus, blood enters the e�erent arte-riole. From here, the blood follows di�erent pathways for cortical nephrons and juxtamedullary nephrons. In cortical nephrons, with short loops of Henle, blood passes through a complex network of capillaries, some surrounding the PCTs and DCTs (as a cortical peritubular capillary network). In contrast, in juxtamedullary nephrons, with long loops of Henle, the e�erent arterioles (vasa recta), follow the loop of Henle to its tip. �ese blood vessels then drain into inter-lobular veins, arcuate veins, interlobar veins, and eventually the renal vein.

�e spaces between the renal tubules are �lled with con-nective tissue, known as the renal interstitium. It is relatively sparse in the cortex but more abundant in the medulla. �e renal interstitium also connects to a distinct connective tis-sue capsule around the entire kidney, with an inner layer of potentially contractile myo�broblasts and an outer layer of �broblasts.

THE RENAL CORPUSCLE

�e renal corpuscle is a prominent feature of the renal cor-tex. It consists of three main structures: (1) the glomerulus, a network of capillaries supplied by the a�erent arteriole and drained by the e�erent arteriole; (2) the Bowman cap-sule, an invaginated, balloon-like expansion of the PCT; and, (3) mesangial cells (Figure 1.3). Glomerular capillary endothelial cells have numerous 70- to 100-nm fenestrae

KEY POINTS

● E�erent arterioles of juxtamedullary nephrons develop anatomically distinct, long vascular channels that dip deep into the medulla along the side of their own nephrons and are called vasa recta.

● Vasa recta are low-�ow arteries and are prone to desaturation-induced sickling of red blood cells in patients with sickle cell anemia or sickle cell trait.

Collectingduct

Descendinglimb of loop

of Henle

Distalconvoluted

tubule

Corticalnephron

Juxtamedullarynephron

Juxta-glomerularapparatus

Ascending limbof loop of Henle

Proximalconvoluted

tubule

Figure 1.2 Diagrammatic representation of nephrons arranged in the kidney. Juxtaglomerular nephrons have long loops of Henle that dip deep into medulla and are important in the countercurrent urine concentrat-ing mechanism. Cortical nephrons have relatively short loops of Henle. (Figure in the public domain; artwork by Holly Fischer. Reproduced under Creative Commons Attribution 3.0.)

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6 Anatomy and embryology of the urinary tract

(transcellular pores) without diaphragms, and they rest on a basement membrane (Figure 1.4A). �e glomerular base-ment membrane (GBM) is a multilayered structure with a lamina rara interna (adjacent to capillary endothelium), a lamina densa, and a lamina rara externa (adjacent to the podocytes). �e laminae rarae are rich in polyanions such as heparan sulfate. �ese negatively charged macromolecules presumably repel anions that would otherwise cross from the capillary lumen into the urinary space (and vice versa). In addition, the laminae rarae have an abundance of �bro-nectin, a cell adhesion glycoprotein. Mesangial cells form a

supportive complex between the capillary endothelial cells. �ey can proliferate and produce a basement membrane–like material and appear to have contractile, secretory, and phagocytic activity.

GBM is one of the thickest and most functionally impor-tant basement membranes in the body. �e GBM is a com-plex extracellular matrix that is formed by both capillary endothelial cells and podocytes. It contains type IV colla-gen, laminin, �bronectin, entactin, and proteoglycan com-plex with polyanionic glycosaminoglycans such as heparan sulfate. �e thickness of the GBM varies with age; it is a mean of 373 nm in men and 326 nm in women.5 In children, however, GBM is thinner at birth, rapidly increases in size by the second year of life, and reaches adult proportions by 9 to 11 years of age.6,7 Before 1 year, the thickness of GBM has been reported to be 132 to 208 nm, and it reached 244 to 307 nm by 11 years in one study.6 �inned GBM is usually seen in Alport syndrome, thin basement membrane nephropa-thy (TBMN), and occasionally in immunoglobulin A (IgA) nephropathy.

By electron microscopy, the GBM has a thick, central, electron-dense lamina densa (see Figure  1.4A), with less electron-dense layers adjacent to the capillary endothelial cells (lamina rara interna), and podocytes (lamina rara externa). �e collagen is thought to function as a sca�old for the attachment of other glycoproteins and proteogly-cans that constitute the rest of the GBM. Type IV collagen consists of three intertwined α-chain monomers, each with three distinct domains: the 7S N-terminus, a middle heli-cal collagenous domain, and a C-terminus noncollagenous (NC1) domain.8 �e GBM also allows attachment of epithe-lial cells (through cell surface integrin receptors for extra-cellular matrix molecules such as collagen, laminin, and �bronectin) to itself and one another, and it serves as a part

VC

PC

EMC

Arteriole

DT

MD

MC

Figure 1.3 Light microscopy showing a glomerulus with the juxtaglomerular apparatus. DT, distal tubule; EMC, extraglomerular mesangial cells MC, mesangial cell with mesangial matrix; MD, macula densa; PC, parietal epithe-lial cell; and VC, visceral epithelial cells.

EndC

EpC

(a) (b)

LRELD

LRI

PCPCPC

PC

PCSD

Figure 1.4 (a) Electron micrograph of the basement glomerular capillary. Capillary cross section showing an endothelial cell (EndC), the lamina rara interna (LRT), the lamina rara externa (LRE), the lamina densa (LD), the podocyte foot pro-cesses (PC), the epithelial cell cytoplasm (EpC), and the slit diaphragm (SD). (b) Electron micrograph showing extensive interdigitation of the podocyte foot processes around the basement membrane on the external or urinary side.

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The renal corpuscle / The juxtaglomerular apparatus 7

of the selective �ltration barrier between the lumen of the glomerular capillary (the vascular space) and the lumen of the Bowman capsule (the urinary space).

PODOCYTES

�e visceral layer of the Bowman capsule is formed by a sheet of stellate epithelial cells called podocytes, which have a large central cell body containing a nucleus and numerous primary, secondary, and tertiary branches projecting from the cell body. Podocytes have foot processes, which inter-digitate extensively and attach the podocytes to the lamina rara externa of the GBM (Figure 1.4B).

�e gaps between the adjacent foot processes, known as �ltration slits, are covered by a zipper-like slit diaphragm (SD), which forms the second barrier to macromolecular transport a�er glomerular endothelial and GBM barri-ers.8 �e structure and function of SDs have been the sub-ject of intense study. Discoveries in this area have provided important insights into the role played by the podocytes in glomerular function. �e zipper-like structure of SD is made up of protein molecules from the two adjacent foot-processes that overlie each other in the midline to form the �ltration barrier.9 Of these molecules, nephrin was the �rst to be identi�ed. Nephrin, which forms the bulk of SD �ltra-tion barrier, is a transmembrane protein that is anchored to the cytoplasmic membrane by podocin.10,11 Neph 1, Neph 2, and Neph3 are other important podocyte-SD proteins that are structurally similar to nephrin and are believed to react with both nephrin and podocin to maintain the cytoskel-etal structure and sca�oldings within podocytes.12–15 �e podocyte foot processes are anchored to the GBM by α3β1 integrin.

Mutations in podocytes foot process–associated pro-teins cause proteinuria and nephrotic syndrome. Nephrin (NPHS1 gene) mutation in humans result in the Finnish type of congenital nephrotic syndrome, whereas podocin (NPHS2 gene) mutation also gives rise to steroid-resistant nephrotic syndrome.15–17 In experimental animals, Neph1-lacking mice develop severe proteinuria that resembles the nephrin mutation in humans.

THE JUXTAGLOMERULAR APPARATUS

�e DCT returns to its parent glomerulus and rests close to the vascular pole, in proximity to the a�erent arteriole (see Figure 1.3). �is specialized structure is the JGA. �e JGA consists of three identi�able microscopic structures: (1) specialized cells of the DCT known as the macula densa, (2) juxtaglomerular (JG) cells in the a�erent arteriole, and (3) extraglomerular mesangial (EGM) cells. �e JGA is a sen-sor for sodium delivery to the distal nephron and alters the a�erent and e�erent arterial tone and blood �ow through the locally generated renin-angiotensin system (RAS).

Macula densa

�e macula densa is the collection of columnar epithelial cells in the wall of the DCT in intimate contact with the vascular pole of the Bowman capsule and the JG cells. Here, the nuclei of the tubular epithelial cells are more crowded together than in the rest of the DCT. �e apical surfaces of cells in the macula densa have numerous microvilli and a single cilium.

Juxtaglomerular cells

JG cells are modi�ed smooth muscle like cells in the wall of the a�erent arteriole. �ey are also sometimes found in smaller numbers in the wall of the e�erent arteriole. �ey contain electron-dense granules of renin. As systemic blood pressure falls, the JG cells release their renin granules into the systemic circulation. Renin then cleaves angiotensino-gen into the decapeptide angiotensin I. Angiotensin I is con-verted in pulmonary circulation into angiotensin II by the angiotensin-converting enzyme (ACE) in endothelial cells of alveolar capillaries. Angiotensin II, a potent vasocon-strictor, helps restore blood pressure to the normal range.

Extraglomerular mesangial cells

EGM cells look like �broblasts. �ey provide a communi-cating connection between the macula densa and the JG cells. Ultrastructural studies reveal that EGM cells have long, thin processes that contact both other elements of the JGA. In addition, there are gap junctions at the tips of these processes where the EGM cells contact other cells, probably thus allowing communication among the three cell types of the JGA.

KEY POINTS

● Epithelial cells and their foot processes are now recognized as among the most functionally rel-evant cell types in the glomeruli.

● Alterations in podocytes resulting from gene mutations have been linked to the pathogenesis of several types of nephrotic syndrome in children.

● With aging, podocytes are normally shed in urine. ● Injured podocytes do not regenerate.

KEY POINTS

● �e JGA is a specialized structure that is essential for renin-angiotensin hormone generation.

● �e JGA controls intraglomerular pressure by regulating the relative diameter of the a�erent and e�erent arterioles.

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8 Anatomy and embryology of the urinary tract

RENAL EMBRYOLOGY

Kidney and ureters develop from the intermediate meso-derm, a bulbous ridge of tissue that lies in the intraembryonic mesoderm between the somites and the lateral plate meso-derm. In contrast, bladder and the urethra develop from the urogenital sinus. Renal development occurs in three phases in a cranial to caudal sequence, starting in the fourth week. �e �rst two stages, pronephros and mesonephros, are tran-sitional renal structures, whereas the third stage, the meta-nephros, forms the de�nitive kidney (Figure 1.5).

�e pronephros is the �rst renal structure, which arises as few solid or vesicular tissue segments in the cervical region at the beginning of the fourth week. It degenerates by the end of the fourth week and leaves no adult remnants. �e mesonephric kidney and its associated mesonephric duct form in the urogenital ridge of the intermediate mesoderm from the upper thoracic to the upper lumbar segments. �e mesonephric kidney forms rudimentary nephrons and probably functions in humans to produce some dilute urine. Most of the mesonephros degenerates by the end of the eighth week. �e mesonephric duct persists in boys and men as the epididymis, the vas deferens, and the seminal vesicle, structures that drain the testis. In girls and women, the mesonephric duct forms vestigial structures such as the epoöphoron and Gartner cysts.

�e metanephric kidney is the de�nitive kidney and the last to develop. It begins to form in the ��h week and is

located in the caudal portion of the urogenital ridge. An evagination of the mesonephric duct, called the ureteric bud, grows into the surrounding mesenchyme of the uro-genital ridge, called the metanephric blastema. By a recipro-cal inductive interaction, the metanephric blastema triggers branching of the ureteric bud, thus ultimately forming the renal pelvis, major calyces, minor calyces, and collecting tubules. Meanwhile, the ureteric bud stimulates formation of blood vessels and nephrons in the metanephric blastema. Transformation of the metanephric blastema into a neph-ron undergoes the developmental stages of renal vesicle, comma-shaped body, and S-shaped body (Figure 1.6). �e proximal portion of the S-shaped body invaginates to form the Bowman capsule with a cup-like recess for the develop-ment of glomerular capillaries. �e distal potion connects to the branching ureteric bud to form the collecting duct.

ASCENT OF THE METANEPHROS

�e metanephric kidneys originate in the pelvis (S1 to S2 level), but following decurvature of the body axis and lumbar and sacral body growth, the de�nitive kidneys ascend to the lumbar area (T12 to L3). �e metanephric kidney ascends between 6 and 9 weeks of gestation. When the caudal poles

Cloaca

Mesonephros

Pronephros

Metanephros

Ureteric bud

Figure 1.5 A diagrammatic view showing various phases of renal development in the embryo. The pronephros and mesonephros degenerate, whereas the metanephros formed at 5 weeks of gestation gives rise to the definitive kidney.

S-shapedbody

Early nephron

Metanephricblastema cap

Pretubularaggregate

Renalvesicle

Comma shape

Endothelial cellinvasion

Figure 1.6 Developmental stages of the kidney in the fetus. After the ureteric bud branching, the mesenchymal cells aggregate around the tip of the ureteric bud to form cap-mesenchyme. Next, these cells evolve through the stages of renal vesicle, comma-shaped body, and then S-shaped body. The end of S-shaped body that is clos-est to the ureteric bud fuses with it and becomes part of the distal nephron, whereas the opposite end invaginates to give rise to the glomerular structure. Endothelial cells invade the glomerulus to form glomerular capillaries.

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Renal embryology / Nephron endowment and future health risks 9

of the metanephroi fuse, the ascent of a horseshoe kidney is halted by the inferior mesenteric artery, a branch from the aorta that supplies hindgut derivatives. Initially, the meta-nephroi are supplied by sacral branches of the aorta, but as they ascend cranially, they take new branches from the dorsal aorta that eventually develop into the renal arteries. �e cau-dal branches usually degenerate, but supernumerary renal arteries sometimes persist, o�en caudal to the main renal artery. During ascent, the fetal kidneys also rotate medially by 90 degrees, so that the renal hilum, with the ureter and renal vessels, faces medially. In arrested ascent, metanephric kidneys may be formed in the pelvis, either unilaterally or bilaterally, resulting in ectopic or pelvic kidneys.

CLOACA AND FORMATION OF THE UROGENITAL SINUS

�e most caudal portion of the early hindgut is the cloaca. �e hindgut precursor and cloaca have a diverticulum, called the allantois, which projects far into the umbili-cal cord. By the ��h week, the proximal part of the cloaca becomes slightly expanded into a precursor of the urinary bladder. During the ��h week and onward, the urorectal septum divides the cloaca into a posterior anal canal and an anterior urogenital sinus. �e urogenital sinus eventually gives rise to major portion of urinary bladder, and the pelvic part that becomes the membranous and prostatic urethra, and phallus. Each ureter enters the urinary bladder more lateral to the midline of the bladder, to form a roughly tri-angular structure called the trigone of the bladder, which is de�ned by the two ureteric inlets superiorly and the urethral outlet inferiorly. �e proximal ends of the ureters become incorporated into the wall of the urinary bladder, so that it is lined transiently by mesodermally derived epithelium in the trigone. Later, the trigone is overgrown by endodermally derived epithelium from the rest of the bladder.

�e distal portion of the allantois eventually degenerates, but the proximal portion persists as a urachal diverticulum that still projects into the umbilical cord. Eventually, the proximal urachal diverticulum forms the median umbili-cal ligament. Rarely, however, persistent urachus can lead to urachal �stula, wherein urine leaks from the bladder into the umbilicus or urachal cysts in the median umbilical ligament.

INTRAUTERINE RENAL FUNCTION

In humans, the pronephros is a rudimentary structure. It does not form functional nephrons and involutes in a short time. �e human mesonephric kidney forms rudimentary renal corpuscles with a Bowman capsule and glomerulus and associated tubules, but there is little substantiation of its function. Mesonephric nephrons have short loops of Henle, a structure suggesting that the small volume of urine produced in the mesonephros is likely to be dilute. By the 16th week of gestation, the mesonephric kidney loses

its functional capacity, and the metanephric kidney devel-ops into a urine-producing structure, with renal corpuscles and well-di�erentiated PCTs with microvillous brush bor-ders at the lumen. However, because the loops of Henle are not fully developed, fetal urine is hypotonic with respect to plasma and is slightly acidic. At term, the human fetus voids approximately 450 mL/day into the amniotic �uid. �e ure-thra is patent in the fetus at approximately 8 weeks.

NEPHRON ENDOWMENT AND FUTURE HEALTH RISKS

Each normal adult kidney has approximately 1 mil-lion nephrons, but this estimate is quite variable. Using mature adult kidneys obtained at autopsy, Nyengaard and Bendtsen18 noted the mean nephron number to be 617,000. A more recent US-Australian, multiethnic autopsy study19 in adults revealed a signi�cant variation in nephron num-ber, ranging from 210,332 to 1,825,380 in each kidney, with a mean of 870,582 ± 31,062.

Nephron number in human fetuses increases through-out gestation, from a mean of 15,000 at 15 weeks to 740,000 in each kidney by 40 weeks.20 �is number appears to pla-teau at approximately 36 weeks.20 Nephrogenesis in full-term fetuses concludes by approximately 34 to 36 weeks of gestation, and new nephrons are not formed a�er birth.20,21 Premature infants, conversely, have fewer nephrons, and nephronogenesis may continue a�er birth for as long as 3 months.22,23 �e clinical impact of low endowed nephron number in premature infants is likely to last a lifetime and is referred to as fetal programming. Indeed, renal length and volume by ultrasonography are known to be signi�cantly lower in young adults who were born prematurely (at less than 32 weeks), a �nding suggesting long term adverse renal consequences and risks in these persons.24 An increased risk for hypertension and CKD associated with prematu-rity, low birth weight, and intrauterine growth retardation was suggested by Brenner et al.,25–27 starting in the 1980s. In an Australian study,28 18-year-old survivors of extreme prematurity (gestational age less than 28 weeks) had higher

KEY POINT

�e urethra is patent by the eighth week of gestation, and urine begins to form a part of amniotic �uid at around that time.

KEY POINT

Poor nephron endowment at birth (fetal program-ming) a�ects blood pressure, development of micro-albuminuria, and can lead to ESRD in adults.

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10 Anatomy and embryology of the urinary tract

ambulatory blood pressure readings, thus lending weight to the hypotheses proposed by Brenner and others. A meta-analysis of studies relating prematurity and blood pressure also demonstrated a higher blood pressure in persons who were born prematurely (range, 28.8 to 34.1 weeks).29

�e link between poor nephron endowment and CKD is plausible, but less well established. Microalbuminuria noted in otherwise healthy nondiabetic adults (46 to 54 years old) has been correlated with low birth weight as a risk factor.30 Increased prevalence of ESRD in adults born with a birth weight of less than 2.5 kg was noted in one study in the United States, and the odds ratio for ESRD was 1.4 (95% con�dence interval [CI], 1.1 to 1.8), as compared with a birth weight of 3 to 3.5 kg.31 Carmody and Charlton32 suggested that apart from low nephron endowment in premature infants, other factors that may enhance the risk for CKD include neona-tal acute kidney injury, use of nephrotoxic antibiotics, poor nutrition, and hypoxia in early life.

CONGENITAL ABNORMALITIES OF THE KIDNEY AND URINARY TRACT

�e term congenital abnormalities of the kidney and urinary tract (CAKUT) denotes developmental urologic and renal abnormalities encountered in children.32,33 CAKUT, as a term, also emphasizes the shared developmental destiny of the kidney and the urinary tract (Figure 1.7). �e CAKUT spectrum encompasses diverse clinical disorders, such as unilateral or bilateral renal agenesis, renal hypodysplasia, multicystic dysplastic kidney (MCDK), ureteropelvic junc-tion obstruction, posterior urethral valves, vesicoureteral re�ux (VUR), duplex renal collecting system, ectopic ure-ters, and megaureter.

CAKUT occurs in approximately 1 in 500 live births, but severe abnormalities resulting in neonatal death occur less frequently, in approximately 1 in 2000 births.33,34 By using prenatal ultrasound as the screening method in 709,030 live births, stillbirths, and induced abortions, 1130 infants

and fetuses were diagnosed with at least one renal or uro-logic abnormality, amounting to an incidence of 1.6 in 1000 pregnancies.35 CAKUT is o�en encountered as an isolated or sporadic anomaly, but it can also be a clinical feature of numerous syndromes. Additionally, an increased risk of urinary tract anomalies has been reported in the close family members of these patients.36,37 Some of the common CAKUT malformations are discussed here, as well as in Chapter 2. VUR is discussed in Chapter 48.

Renal agenesis

Bilateral renal agenesis is an uncommon disorder. Potter described 20 cases of bilateral renal agenesis in 5000 autop-sies performed in children and estimated the incidence to be 1 in 3000 to 1 in 4000 births.38,39 Approximately 25% to 40% of fetuses with bilateral renal agenesis are stillborn. Bilateral renal agenesis can result in the clinical features of Potter sequence as a result of prolonged lack of intrauterine urine and oligohydramnios.40–42 Potter sequence (or Potter syndrome) is characterized by: bilateral renal agenesis (or severe fetal renal disease), oligohydramnios, pulmonary

KEY POINTS

Renal risks in premature infants are compounded by: ● Acute kidney injury ● Hypoxia ● Use of nephrotoxic drugs ● Poor nutrition

KEY POINT

CAKUT, as a concept, re�ects a common origin of renal and urologic anomalies in utero.

KEY POINTS

Potter sequence includes: ● Renal agenesis or severe dysplasia ● Oligohydramnios ● Pulmonary hypoplasia ● Low-set ears ● Clubfeet ● Pointed nose

• Renal hypoplasia• Renal dysplasia• Hydronephrosis

• Vesicoureteric re�ux

Abnormalgene products

• Urinary obstruction• Dilated ureters

• Ureteric atresia• Megaureter

Ureteric budanomalies

Abnormal uretericdevelopment

Metanephricgrowth failure

Figure 1.7 Pathogenesis of congenital abnormalities of the kidney and urinary tract. This unifying hypothesis breaks from previously believed concepts that develop-mental renal defects arise from urinary obstruction. It is now believed that genetic defects disrupt critical signal-ing processes between the ureteric bud and nephrogenic mesenchyme, eventually leading to uronephrologic developmental disorders. (Based on Ichikawa I, Kuwayama F, Pope JC, 4th, et al. Paradigm shift from classic anatomic theories to contemporary cell biological views of CAKUT. Kidney Int. 2002 61:889–98.)

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Renal embryology / Congenital abnormalities of the kidney and urinary tract 11

hypoplasia, clubfeet, micrognathia, a pointed nose, and low-set malformed ears.40 Potter facies refers to the typical facial features seen in Potter sequence. Potter sequence can result from any fetal disorder that leads to prolonged oli-gohydramnios. �ere has been an ongoing speculation that bilateral renal agenesis may be an inherited disorder, pri-marily because of a signi�cantly higher incidence of occult renal defects in close relatives of index cases.43 Recessive mutations in the integrin α8-encoding gene ITGA8 have been described in families with fetal loss secondary to bilat-eral renal agenesis.44 Such �ndings are likely to stimulate investigative pathways to genetic pathogenesis of bilateral renal agenesis.

Accurate information of the incidence of unilateral renal agenesis is di�cult to obtain because many of these cases go undetected as a result of compensatory hypertrophy of the contralateral kidney, as well as normal intrauterine and postnatal renal function. Using renal ultrasound screening in healthy school-age children (6 to 15 years), Sheih et al.45 reported the occurrence of unilateral renal agenesis to be 1 in 290 in the general population of children. European data also suggest the incidence of unilateral renal agenesis to be 1 in 2000 births.46

Unilateral renal agenesis is o�en associated with ipsi-lateral defects in other genital duct derivatives such as the ductus deferens in boys and the uterine tubes and uterus in girls. VUR is common (approximately 25%) in these patients, and extrarenal malformations a�ecting the gastro-intestinal, cardiac, and musculoskeletal systems are seen in approximately 30% of patients.46 An increased incidence of renal anomalies in the children and siblings of patients with unilateral renal agenesis has been noted in some studies.36

Pelvic and horseshoe kidneys

Pelvic kidney and horseshoe kidney are related renal mal-formations that result from failed ascent of the kidneys. In horseshoe kidney, the caudal poles of the metanephric kid-ney are fused. Horseshoe kidney is one of the most common congenital anomalies of the kidney. On the basis of abdomi-nal CT scan data in 15,320 patients, the incidence of horse-shoe kidney was noted to be 1 in 666.47 Approximately half of the patients diagnosed with horseshoe kidney are asymp-tomatic; the remainder present for renal stones and ascend-ing urinary tract infections.48 �e Rovsing sign, consisting of nausea, vomiting, and abdominal pain that is accentu-ated on hyperextension, is seen in a minority of patients with horseshoe kidney.48 Horseshoe kidney can occur as an isolated congenital birth defect but is more frequent in patients with Turner syndrome and trisomy 18 (Edwards syndrome).48,49

Multicystic dysplastic kidneys

MCDKs are developmental, nonfunctional cystic masses caused by abnormalities in metanephric di�erentia-tion. �ese kidneys are characterized by abnormal and

noncommunicating dilated cysts of variable size, with little identi�able renal structure or stroma (Figures 1.8 and 1.9). Renal arterial �ow and excretory functions, as demonstrable by mercaptoacetyltriglycine (MAG3) renal scan, are absent.

MCDK is commonly identi�ed by the presence of a unilateral cystic kidney in the fetus during prenatal ultra-sound evaluation. Cystic kidneys may involute during ges-tation in some cases, and the infant is born with a solitary kidney. Other modes of presentation include an abdominal mass noted by the parents or during a clinical examination within few months of birth. In a study of 97 infants with the diagnosis of MCDK, 85% of the cases were detected by pre-natal ultrasound evaluation, 4% by the presence of a mass postnatally, and 11% by a postnatal ultrasound examination

T

(b)

T

(a)

Figure 1.8 (a) Cut section of a kidney from a neonate shows cystic dysplasia. Renal architecture is poorly defined, numerous cysts are present, and the cortico-medullary differentiation is absent. (b) Microscopic sec-tion of a kidney with renal dysplasia. Arrows shows the presence of cartilage. Tubulointerstitial tissue is poorly organized, and a large dilated renal tubule (T) is shown. (Photomicrograph courtesy of Arthur Cohen, MD.)

Figure 1.9 Renal ultrasound scan showing multiple large cysts in an infant with multicystic dysplastic kidney dis-ease. Nuclear scan demonstrated no blood flow or excre-tory function in this kidney.

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12 Anatomy and embryology of the urinary tract

performed for an unrelated diagnosis.50 MCDK is slightly more common on the le� side in some studies, whereas other investigators have noted a right-sided predominance; these �ndings suggest that both sides can be equally involved.38,39 Contralateral kidneys show abnormalities in approximately 40% of cases that include renal agenesis, renal dysplasia or hypoplasia, VUR, hydroureter or pyelectasis, duplex col-lecting system, and ectopic ureters.39 In a meta-analysis of the abnormalities in the contralateral system, Schreuder et al.51 reported VUR in approximately 20% cases: 15% in the contralateral system, ipsilateral VUR in 3.3%, and bilateral VUR in 2.4% cases. Ureteropelvic junction obstruction was the next most common anomaly in the contralateral renal system, accounting for 4.8% cases in this meta-analysis.

Involution of the cystic mass occurs usually occurs over several years, but the rate of involution is variable. Some patients have complete involution of the MCDK in utero and are thus born with a solitary kidney and unilateral agenesis. Complete involution of the MCDK was noted in 34% at 2 years (165 patients), 47% at 5 years (117 patients), and 59% at 10 years (43 patients) in a study from the United Kingdom.52 �e contralateral normal kidney usually under-goes compensatory hypertrophy.

Hypertension has been well documented in patients with MCDK and is believed to be mediated by the RAS.53 More recent studies, however, point out that the risk of hyperten-sion in MCDK is low. In a review of 29 studies, Narchi et al.54 reported hypertension to be present in only 6 of the 1115 cases, a �nding suggesting the mean probability of devel-oping hypertension in MCDK to be 5.4 in 1000 cases (esti-mated 95% CI, 1.9 to 11.7 per 1000).

A high risk for Wilms tumor and renal cell carcinoma in the MCDK was suggested in older studies. However, the risk of tumors was very low in several more recent, com-prehensive, well-conducted studies.55,56 Surgical resection of the MCDK, which was o�en practiced until the late 1980s for the prevention of hypertension and to protect against development of malignant disease, appears to be di�cult to justify with the evidence-based results.54–57

WAGR syndrome

Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation (WAGR) was �rst reported as a distinct clinical disorder by Miller et al.58 in 1964 (Online Mendelian Inheritance in Man [OMIM] number 194072). It is now well established that the disorder results from deletion in dis-tal band of 11p13 in such a way that WT1 and PAX6 genes, which are adjacent to each other, are a�ected by the dele-tion.59 �e WT1 gene deletion results in renal malforma-tions and risk for Wilms tumor; whereas the PAX6 gene deletion results in aniridia and brain malformations.

�e WT1 gene encodes for Wilms tumor suppressor protein (WT1), a transcription factor containing a DNA binding domain, with four zinc �ngers. WT1 transcrip-tion factor is essential for the development of the neph-ron, as well as the gonads, and is thought to be involved in

mesenchymal-epithelial transition in the renal and germ cell lines.60 With mutations in the WT1 gene, the develop-ment of glomeruli and of the proximal and distal tubules is adversely a�ected, leading to renal malformations. A pro-pensity for Wilms tumor in WAGR and other syndromes with the WT1 gene mutation, such as Denys-Drash syn-drome, results from the presence of undi�erentiated or poorly di�erentiated mesenchymal cells in the kidneys.60,61

�e genital malformations seen in WAGR syndrome include cryptorchidism, ambiguous genitalia, hypospadias, streaked ovaries, and hypoplastic uterus. Renal and urinary tract anomalies encountered in WGAR syndrome include hypoplastic kidneys, unilateral renal agenesis, duplicated ureters,, development of focal segmental glomerulosclerosis, nephrogenic rests, nephroblastomatosis, and renal cysts.62 Aniridia can be partial or complete and results in severe visual impairment. Apart from risk of CKD and ESRD imposed by the development of Wilms tumor, patients with WAGR syndrome are inherently at an increased risk for development of ESRD. �e National Wilms Tumor Study Group reports the incidence of ESRD to be 53% in patients with WAGR syndrome.63,64 Monitoring of kidneys by ultra-sound every 3 months until 6 years of age has been recom-mended in some studies for Wilms tumor surveillance in patients with WAGR syndrome.62

Bladder exstrophy

Bladder exstrophy is an uncommon developmental anom-aly seen in newborn infants. It is caused by a ventral body wall, an anterior bladder wall defect, and eversion of the bladder wall mucosa. �e term exstrophy, which is derived from the Greek word ekstriphein, means “turned inside out.” In the newborn infant, the exposed bladder mucosa is bright red and has a raw appearance. �e exposed mucosa sometimes undergoes metaplasia, forming colonic epithe-lium rather than transitional epithelium. Bladder exstrophy is also associated with other congenital abnormalities of the external genitalia such as bi�d penis, epispadias, and abnor-mal scrotal development

Using the Healthcare Cost and Utilization Project Nationwide Inpatient Sample database, Nelson et al.65 estimated the incidence of bladder exstrophy to be 2.15 in 100,000 live births (or approximately 1 in 40,000 births). �e male-to-female ratio was equal in this study, and the congenital malformation appeared to be more common in whites than in nonwhites. Some genetic analyses have dem-onstrated a higher prevalence of duplication of 22q11.21 in patients with bladder exstrophy.66

Surgical repair of bladder exstrophy has evolved since the 1990s. Both early closure and delayed closure of the defect are acceptable surgical options and are generally dictated by technical preference of the surgical team.67 Postrepair atten-tion to incontinence, recurrent urinary tract infections sec-ondary to associated VUR, and correction of epispadias are common concerns to be addressed during childhood. Many patients require continent urinary diversion procedures,

K21764.indb 12 02/09/16 6:02 pm

Renal embryology / Congenital abnormalities of the kidney and urinary tract 13

as well as bladder augmentation by cystoplasty. However, lower urinary tract symptoms persist in 80% of patients with exstrophy as they grow into adulthood.68 Sexual dysfunction is also a concern in adulthood.69 In addition, adenocarci-nomas occur with higher frequency in the exposed bladder mucosa. Surgical intervention and repair can extend the patient’s life and ensure normal renal function.

Angiotensin-converting enzyme fetopathy

Experimental observations indicate that RAS exerts its in�uence on renal development by promoting the ureteric bud branching process and therefore plays a key role in nephrogenesis.70,71 �e RAS may a�ect ureteric bud branch-ing and nephrogenesis through its in�uence on GDNF, the WT1 gene, and the PAX2 gene. Disruption of the RAS dur-ing nephrogenesis by ACE inhibitors (ACEIs) is well known to cause fetopathy.70,72 ACEI fetopathy risk is low if the drug is consumed in the �rst trimester.72–74 Clinical character-istics of ACEI fetopathy are: oligohydramnios, renal tubu-lar dysgenesis, neonatal anuria, skull defects, intrauterine growth retardation, and patent ductus arteriosus.

REFERENCES

1. Scott JE, Hunter EW, Lee RE, et al. Ultrasound mea-surement of renal size in newborn infants. Arch Dis Child. 1990;65:361–4.

2. Pantoja Zuzuárregui JR1, Mallios R, Murphy J. The effect of obesity on kidney length in a healthy pediatric population. Pediatr Nephrol. 2009;24:2023–7.

3. Alev Kadioglu. Renal measurements, including length, parenchymal thickness, and medullary pyramid thickness, in healthy children: What are the normative ultrasound values? AJR Am J Roentgenol. 2010;194:509–15.

4. Rosenbaum DM, Korngold E, Teele RL. Sonographic assessment of renal length in normal children. AJR Am J Roentgenol. 1984;142:467–9.

5. Steffes MW, Barbosa J, Basgen JM, et al. Quantitative glomerular morphology of the normal human kidney. Lab Invest. 1983;49:82–6.

6. Vogler C, McAdams AJ, Homan SM. Glomerular basement membrane and lamina densa in infants and children: An ultrastructural evaluation. Pediatr Pathol. 1987;7:527–34.

7. Morita M, White RH, Raafat F, et al. Glomerular basement membrane thickness in children: A mor-phometric study. Pediatr Nephrol. 1988;2:190–5.

8. Miner JH. Glomerular basement membrane com-position and the filtration barrier. Pediatr Nephrol. 2011;26:1413–7.

9. Rodewald R, Karnovsky MJ. Porous substructure of the glomerular slit diaphragm in the rat and mouse. J Cell Biol. 1974;60:423–33.

10. Kestilä M1, Lenkkeri U, Männikkö M, et al. Positionally cloned gene for a novel glomerular pro-tein—nephrin—is mutated in congenital nephrotic syndrome. Mol Cell. 1998;1:575–82.

11. Wartiovaara J, Ofverstedt LG, Khoshnoodi J, et al. Nephrin strands contribute to a porous slit dia-phragm scaffold as revealed by electron tomogra-phy. J Clin Invest. 2004;114:1475–83.

12. Sellin L, Huber TB, Gerke P, et al. NEPH1 defines a novel family of podocin interacting proteins. FASEB J. 2003;17:115–7.

13. Liu G, Kaw B, Kurfis J, et al. Neph1 and nephrin inter-action in the slit diaphragm is an important deter-minant of glomerular permeability. J Clin Invest. 2003;112:209–21.

14. Garg P, Verma R, Nihalani D, et al. Neph1 cooperates with nephrin to transduce a signal that induces actin polymerization. Mol Cell Biol. 2007;27:8698–712.

15. Grahammer F, Schell C, Huber TB. The podocyte slit diaphragm: From a thin grey line to a complex signalling hub. Nat Rev Nephrol. 2013;9:587–98.

16. Heeringa SF, Vlangos CN, Chernin G, et al. Thirteen novel NPHS1 mutations in a large cohort of children with congenital nephrotic syndrome. Nephrol Dial Transplant. 2008;23:3527–33.

17. Machuca E, Benoit G, Nevo F, Tête MJ, et al. Genotype-phenotype correlations in non-Finnish congenital nephrotic syndrome. J Am Soc Nephrol. 2010;21:1209–17.

KEY POINTS

● �e RAS plays a crucial role in nephrogenesis. ● Maternal ACEI use a�er the �rst trimester is

associated with fetopathy that includes renal dysgenesis.

SUMMARY

A signi�cant advance in our understanding of the signal pathways involved during development of the kidneys and the urinary tract in fetal life has occurred since the 1990s. What has also become obvious is that the renal development is supported by the development of the rest of the urinary tract, especially the ureteric bud. A disruption in any of these developmental processes can lead to abnor-malities of renal development and CAKUT. Nephron endowment at birth is beginning to be recognized as an important predictor of CKD and hypertension in adults. Attention to prenatal health and prevention of poor nephron endowment may be ways that kidney disease and hypertension can be prevented in adults.

K21764.indb 13 02/09/16 6:02 pm

14 Anatomy and embryology of the urinary tract

18. Nyengaard JR, Bendtsen TF. Glomerular number and size in relation to age, kidney weight, and body surface in normal man. Anat Rec. 1992;232,194–201.

19. Hoy WE, Douglas-Denton RN, Hughson MD, et al. A stereological study of glomerular number and volume: Preliminary findings in a multiracial study of kidneys at autopsy. Kidney Int Suppl. 2003;63, S31–7.

20. Hinchliffe SA, Sargent PH, Howard CV, et al. Human intrauterine renal growth expressed in absolute number of glomeruli assessed by the dissec-tor method and Cavalieri principle. Lab Invest. 1991;64:777–84.

21. Moritz KM, Caruana G, Wintour EM. Development of kidneys and urinary tract. In Rodeck CH, Whittle MF, editors. Fetal Medicine: Basic Science and Clinical Practice, 2nd ed. Philadelphia: Churchill Livingstone; 2009. p. 147.

22. Hinchliffe SA, Lynch MR, Sargent PH, et al. The effect of intrauterine growth retardation on the development of renal nephrons. Br J Obstet Gynaecol. 1992;99:296–301.

23. Mañalich R1, Reyes L, Herrera M, et al. Relationship between weight at birth and the number and size of renal glomeruli in humans: A histomorphometric study. Kidney Int. 2000;58:770–3.

24. Keijzer-Veen MG1, Devos AS, Meradji M, et al. Reduced renal length and volume 20 years after very preterm birth. Pediatr Nephrol. 2010;25:499–507.

25. Brenner BM, Garcia DL, Anderson S. Glomeruli and blood pressure: Less of one, more of the other? Am J Hypertens. 1988;1:335–47.

26. Brenner BM, Mackenzie HS. Nephron mass as a risk factor for progression of renal disease. Kidney Int Suppl. 1997;63 S124–7.

27. Luyckx VA, Bertram JF, Brenner BM, et al. Effect of fetal and child health on kidney development and long-term risk of hypertension and kidney disease. Lancet. 2013 20;382:273–83.

28. Roberts G1, Lee KJ, Cheong JL, et al. Higher ambu-latory blood pressure at 18 years in adolescents born less than 28 weeks’ gestation in the 1990s compared with term controls. J Hypertens. 2014;32:620–6.

29. de Jong F, Monuteaux MC, van Elburg RM, et al. Systematic review and metaanalysis of preterm birth and later systolic blood pressure. Hypertension. 2012;59:226–34.

30. Yudkin JS, Phillips DI, Stanner S. Proteinuria and progressive renal disease: Birth weight and micro-albuminuria. Nephrol Dial Transplant. 1997;12(Suppl 2):10–3.

31. Lackland DT, Bendall HE, Osmond C, et al. Low birth weights contribute to high rates of early-onset chronic renal failure in the Southeastern United States. Arch Intern Med. 2000;160:1472–6.

32. Carmody JB, Charlton JR. Short-term gestation, long-term risk: Prematurity and chronic kidney dis-ease. Pediatrics. 2013;131:1168–79.

33. Ichikawa I, Kuwayama F, Pope JC, 4th, et al. Paradigm shift from classic anatomic theories to con-temporary cell biological views of CAKUT. Kidney Int. 2002;61:889–98.

34. Pope JC 4th, Brock JW, 3rd, Adams MC, et al. How they begin and how they end: Classic and new theories for the development and deterioration of congenital anomalies of the kidney and urinary tract, CAKUT. J Am Soc Nephrol. 1999;10:2018–28.

35. Wiesel A, Queisser-Luft A, Clementi M, et al. Prenatal detection of congenital renal malformations by fetal ultrasonographic examination: An analysis of 709,030 births in 12 European countries. Eur J Med Genet. 2005;48:131–44.

36. McPherson E. Renal anomalies in families of indi-viduals with congenital solitary kidney. Genet Med. 2007;9:298–302.

37. Bulum B, Ozçakar ZB, Ustüner E, et al. High fre-quency of kidney and urinary tract anomalies in asymptomatic first-degree relatives of patients with CAKUT. Pediatr Nephrol. 2013;28:2143–7.

38. Mansoor O, Chandar J, Rodriguez MM, et al. Long-term risk of chronic kidney disease in unilateral multicystic dysplastic kidney. Pediatr Nephrol. 2011;26:597–603.

39. Damen-Elias HA, Stoutenbeek PH, Visser GH, et al. Concomitant anomalies in 100 children with unilat-eral multicystic kidney. Ultrasound Obstet Gynecol. 2005;25:384–8.

40. Potter EL. Bilateral renal agenesis. J Pediatr. 1946;29:68–76.

41. Potter EL. Normal and Abnormal Development of the Kidney. Chicago: Year Book Medical Publishers; 1972. p. 1–305.

42. Wilson RD, Baird PA. Renal agenesis in British Columbia. Am J Med Genet. 1985;21:153–69.

43. Roodhooft AM, Birnholz JC, Holmes LB. Familial nature of congenital absence and severe dysgene-sis of both kidneys. N Engl J Med. 1984;310:1341–5.

44. Humbert C, Silbermann F, Morar B, et al. Integrin alpha 8 recessive mutations are responsible for bilateral renal agenesis in humans. Am J Hum Genet. 2014;94:288–94.

45. Sheih CP, Liu MB, Hung CS, et al. Renal abnormali-ties in schoolchildren. Pediatrics. 1989;84:1086–90.

46. Westland R, Schreuder MF, Ket JC, et al. Unilateral renal agenesis: A systematic review on associated anomalies and renal injury. Nephrol Dial Transplant. 2013;28:1844–55.

47. Weizer AZ, Silverstein AD, Auge BK, et al. Determining the incidence of horseshoe kidney from radiographic data at a single institution. J Urol. 2003;170:1722–6.

48. Glenn JF. Analysis of 51 patients with horseshoe kidney. N Engl J Med. 1959;261:684–7.

49. Bilge I, Kayserili H, Emre S, et al. Frequency of renal malformations in Turner syndrome: Analysis of 82 Turkish children. Pediatr Nephrol. 2000;14:1111–4.

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Review questions / Congenital abnormalities of the kidney and urinary tract 15

50. Kuwertz-Broeking E, Brinkmann OA, Von Lengerke HJ, et al. Unilateral multicystic dysplastic kidney: Experience in children. BJU Int. 2004;93:388–92.

51. Schreuder MF, Westland R, van Wijk JA. Unilateral multicystic dysplastic kidney: A metaanalysis of observational studies on the incidence, associated urinary tract malformations and the contralateral kidney. Nephrol Dial Transplant. 2009;24:1810–8.

52. Aslam M, Watson AR, Trent, and Anglia MCDK Study Group. Unilateral multicystic dysplastic kidney: Long term outcomes. Arch Dis Child. 2006;91:820–3.

53. Snodgrass WT. Hypertension associated with multicystic dysplastic kidney in children. J Urol. 2000;164:472–3.

54. Narchi H. Risk of hypertension with multicystic kidney disease: A systematic review. Arch Dis Child. 2005;90:921–4.

55. Narchi H. Risk of Wilms’ tumour with multicystic kidney disease: A systematic review. Arch Dis Child. 2005;90:147–9.

56. Eickmeyer AB, Casanova NF, He C, et al. The natural history of the multicystic dysplastic kidney: Is limited follow-up warranted? J Pediatr Urol. 2014;10:655–61.

57. Tilemis S, Savanelli A, Baltogiannis D, et al. Is the risk of hypertension an indication for prophylac-tic nephrectomy in patients with unilateral mul-ticystic dysplastic kidney? Scand J Urol Nephrol. 2003;37:429–32.

58. Miller RW, Fraumeni JF Jr, Manning MD. Association of Wilms’ tumor with aniridia, hemihypertophy and other congenital malformations. N Engl J Med. 1964;270:922–7.

59. Francke U, Holmes LB, Atkins L, Riccardi VM. Aniridia-Wilms’ tumor associations: Evidence for specific deletion of 11p13. Cytogenet Cell Genet. 1979;24:185–92.

60. Rauscher FJ. The WT1 Wilms tumor gene product: A developmentally regulated transcription factor in the kidney that functions as a tumor suppressor. FASEB J. 1993;7:896–903.

61. Morrison AA, Viney RL, Saleem MA, et al. New insights into the function of the Wilms tumor sup-pressor gene WT1 in podocytes. Am J Physiol Renal Physiol. 2008;295:F12–7.

62. Fischbach BV, Trout KL, Lewis J, et al. WAGR syndrome: A clinical review of 54 cases. Pediatrics. 2005;116:984–8.

63. Breslow NE, Norris R, Norkool P, et al. Characteristics and outcomes of children with the Wilms’ tumor-aniridia syndrome: A report from the National Wilms’ Tumor Study Group. J Clin Oncol. 2003;24:4579–85.

64. Breslow NE, Collins AJ, Ritchey ML, et al. End stage renal disease in patients with Wilms tumor: Results from the National Wilms Tumor Study Group and the United States Renal Data System. J Urol. 2005;174:1972–5.

65. Nelson CP, Dunn RL, Wei JT. Contemporary epide-miology of bladder exstrophy in the United States. J Urol. 2005;173:1728–31.

66. Draaken M, Baudisch F, Timmermann B, et al. Classic bladder exstrophy: Frequent 22q11.21 duplications and definition of a 414 kb phenocritical region. Birth Defects Res A Clin Mol Teratol. 2014;100:512–7.

67. Dickson AP. The management of bladder exstro-phy: The Manchester experience. J Pediatr Surg. 2014;49:244–50.

68. Taskinen S, Suominen JS. Lower urinary tract symptoms (LUTS) in patients in adulthood with bladder exstrophy and epispadias. BJU Int. 2013;111:1124–9.

69. Gupta AD, Goel SK, Woodhouse CR, et al. Examining long-term outcomes of bladder exstro-phy: A 20-year follow-up. BJU Int. 2014;113:137–41.

70. Yosypiv IV. Renin-angiotensin system in ureteric bud branching morphogenesis: Insights into the mecha-nisms. Pediatr Nephrol. 2011;26:1499–512.

71. Song R, Spera M, Garrett C, et al. Angiotensin II AT2 receptor regulates ureteric bud morphogenesis. Am J Physiol Renal Physiol. 2010;298:F807–17.

72. Pryde PG, Sedman AB, Nugent CE, Barr M. Angiotensin-converting enzyme inhibitor fetopathy. J Am Soc Nephrol. 1993;3:1575–82.

73. Buttar HS. An overview of the influence of ACE inhibitors on fetal-placental circulation and perinatal development. Mol Cell Biochem. 1997;176:61–71.

74. Anonymous. Post marketing surveillance for angio-tensin-converting enzyme inhibitor use during the first trimester of pregnancy: United States, Canada, and Israel, 1987–1995. MMWR Morb Mortal Wkly Rep. 1997;46:240–2.

REVIEW QUESTIONS

1. �e juxtamedullary nephrons have long loops of Henle that participate in:

a. Sodium reabsorption b. Chloride transport c. Urine concentrating mechanism d. None of the above

2. Nephrin constitutes a structural component of: a. Endothelial cytoskeleton b. Podocyte cytoskeleton c. Slit diaphragm d. Bowman capsule

3. Which of the following combinations are transitional embryonic kidneys?

a. Metanephros and mesonephros b. Mesonephros and pronephros c. Pronephros and metanephros d. None of the above

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16 Anatomy and embryology of the urinary tract

4. In a premature infant, nephrogenesis can continue up to 3 months a�er birth:

a. True b. False

5. Characteristic �nding on MAG3 renal scan in a patient with multicystic dysplastic kidney (MCDK) is:

a. Photopenic areas in the a�ected kidney suggesting cysts

b. Arterial �ow from the surrounding tissue c. Adequate blood �ow but no excretory function d. No demonstrable renal blood �ow and no excre-

tory function 6. Vesicoureteral re�ux on the same side or contralateral

side of MCDK occurs in: a. Fewer than 5% cases b. 20% cases c. 50% cases d. Almost always in all patients

7. Wilms tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) is caused by:

a. Mutation in WT1 gene b. Mutation in PAX6 gene c. Mutation in PAX6 and WT1 d. Mutation in WT1 and GDNF

8. ACEI-induced fetapathy is more common if the drug exposure occurs in:

a. First 2 weeks of pregnancy b. Six to 12 weeks of pregnancy c. Last week of pregnancy d. A�er �rst trimester of pregnancy

9. Horseshoe kidneys are common in: a. Down syndrome b. Turner syndrome c. WAGR syndrome d. Renal coloboma syndrome

10. Low nephron number at birth is associated with: a. Future risk of diabetes mellitus b. Future risk of cardiac disease c. Future risk of hypertension d. No associated risk of disease

ANSWER KEY

1. c 2. c 3. c 4. a 5. d 6. b 7. c 8. d 9. b 10. c

K21764.indb 16 02/09/16 6:02 pm

References

1 Anatomy and embryology of the urinarytract

1. Scott JE, Hunter EW, Lee RE, et al. Ultrasoundmeasurement of renal size in newborn infants. Arch DisChild. 1990;65:361–4. 2. Pantoja Zuzuárregui JR1, MalliosR, Murphy J. The effect of obesity on kidney length in ahealthy pediatric population. Pediatr Nephrol.2009;24:2023–7. 3. Ale v Kadioglu. Renal measurements,including length, parenchymal thickness, and medullarypyramid thickness, in healthy children: What are thenormative ultrasound values? AJR Am J Roentgenol.2010;194:509–15. 4. Rosenbaum DM, Korngold E, Teele RL.Sonographic assessment of renal length in normal children.AJR Am J Roentgenol. 1984;142:467–9. 5. Steffes MW,Barbosa J, Basgen JM, et al. Quantitative glomerularmorphology of the normal human kidney. Lab Invest.1983;49:82–6. 6. Vog ler C, McAdams AJ, Homan SM.Glomerular basement membrane and lamina densa in infantsand children: An ultrastructural evaluation. PediatrPathol. 1987;7:527–34. 7. Morita M, White RH, Raafat F, etal. Glomerular basement membrane thickness in children: Amorphometric study. Pediatr Nephrol. 1988;2:190–5. 8.Miner JH. Glomerular basement membrane composition and thefiltration barrier. Pediatr Nephrol. 2011;26:1413–7. 9.Rodewald R, Karnovsky MJ. Porous substructure of theglomerular slit diaphragm in the rat and mouse. J CellBiol. 1974;60:423–33. 10. Kestilä M1, Lenkkeri U, MännikköM, et al. Positionally cloned gene for a novel glomerularprotein—nephrin—is mutated in congenital nephroticsyndrome. Mol Cell. 1998;1:575–82. 11. Wartiovaara J,Ofverstedt LG, Khoshnoodi J, et al. Nephrin strandscontribute to a porous slit diaphragm scaffold as revealedby electron tomography. J Clin Invest. 2004;114:1475–83.12. Sellin L, Huber TB, Gerke P, et al. NEPH1 defines anovel family of podocin interacting proteins. FASEB J.2003;17:115–7. 13. Liu G, Kaw B, Kurfis J, et al. Neph1and nephrin interaction in the slit diaphragm is animportant determinant of glomerular permeability. J ClinInvest. 2003;112:209–21. 14. Garg P, Verma R, Nihalani D,et al. Neph1 cooperates with nephrin to transduce a signalthat induces actin polymerization. Mol Cell Biol.2007;27:8698–712. 15. Grahammer F, Schell C, Huber TB. Thepodocyte slit diaphragm: From a thin grey line to acomplex signalling hub. Nat Rev Nephrol. 2013;9:587–98.16. Heeringa SF, Vlangos CN, Chernin G, et al. Thirteennovel NPHS1 mutations in a large cohort of children withcongenital nephrotic syndrome. Nephrol Dial Transplant.

2008;23:3527–33. 17. Machuca E, Benoit G, Nevo F, Tête MJ,et al. Genotype-phenotype correlations in non-Finnishcongenital nephrotic syndrome. J Am Soc Nephrol.2010;21:1209–17. KEY POINTS ● �e RAS plays a crucial rolein nephrogenesis. ● Maternal ACEI use a�er the �rsttrimester is associated with fetopathy that includes renaldysgenesis. SUMMARY

A signi�cant advance in our understanding of the

signal pathways involved during development of

the kidneys and the urinary tract in fetal life has

occurred since the 1990s. What has also become

obvious is that the renal development is supported

by the development of the rest of the urinary tract,

especially the ureteric bud. A disruption in any of

these developmental processes can lead to abnor

malities of renal development and CAKUT. Nephron

endowment at birth is beginning to be recognized as

an important predictor of CKD and hypertension in

adults. Attention to prenatal health and prevention of

poor nephron endowment may be ways that kidney

disease and hypertension can be prevented in adults.

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20. Hinchliffe SA, Sargent PH, Howard CV, et al. Humanintrauterine renal growth expressed in absolute number ofglomeruli assessed by the dissector method and Cavalieriprinciple. Lab Invest. 1991;64:777–84.

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22. Hinchliffe SA, Lynch MR, Sargent PH, et al. The effectof intrauterine growth retardation on the development ofrenal nephrons. Br J Obstet Gynaecol. 1992;99:296–301.

23. Mañ alich R1, Reyes L, Herrera M, et al. Relationshipbetween weight at birth and the number and size of renalglomeruli in humans: A histomorphometric study. KidneyInt. 2000;58:770–3.

24. Kei jzer-Veen MG1, Devos AS, Meradji M, et al. Reducedrenal length and volume 20 years after very preterm birth.Pediatr Nephrol. 2010;25:499–507.

25. Bre nner BM, Garcia DL, Anderson S. Glomeruli andblood pressure: Less of one, more of the other? Am JHypertens. 1988;1:335–47.

26. Bre nner BM, Mackenzie HS. Nephron mass as a riskfactor for progression of renal disease. Kidney Int Suppl.1997;63 S124–7.

27. Luyckx VA, Bertram JF, Brenner BM, et al. Effect offetal and child health on kidney development and long-termrisk of hypertension and kidney disease. Lancet. 201320;382:273–83.

28. Roberts G1, Lee KJ, Cheong JL, et al. Higher ambulatoryblood pressure at 18 years in adolescents born less than28 weeks’ gestation in the 1990s compared with termcontrols. J Hypertens. 2014;32:620–6.

29. de Jo ng F, Monuteaux MC, van Elburg RM, et al.Systematic review and metaanalysis of preterm birth andlater systolic blood pressure. Hypertension.2012;59:226–34.

30. Yudkin JS, Phillips DI, Stanner S. Proteinuria andprogressive renal disease: Birth weight andmicroalbuminuria. Nephrol Dial Transplant. 1997;12(Suppl2):10–3.

31. Lac kland DT, Bendall HE, Osmond C, et al. Low birthweights contribute to high rates of early-onset chronicrenal failure in the Southeastern United States. Arch

Intern Med. 2000;160:1472–6.

32. Car mody JB, Charlton JR. Short-term gestation,long-term risk: Prematurity and chronic kidney disease.Pediatrics. 2013;131:1168–79. 33. Ichikawa I, Kuwayama F,Pope JC, 4th, et al. Paradigm shift from classic anatomictheories to contemporary cell biological views of CAKUT.Kidney Int. 2002;61:889–98. 34. Pop e JC 4th, Brock JW,3rd, Adams MC, et al. How they begin and how they end:Classic and new theories for the development anddeterioration of congenital anomalies of the kidney andurinary tract, CAKUT. J Am Soc Nephrol. 1999;10:2018–28.35. Wiesel A, Queisser-Luft A, Clementi M, et al. Prenataldetection of congenital renal malformations by fetalultrasonographic examination: An analysis of 709,030births in 12 European countries. Eur J Med Genet.2005;48:131–44. 36. McPherson E. Renal anomalies infamilies of individuals with congenital solitary kidney.Genet Med. 2007;9:298–302. 37. Bul um B, Ozçakar ZB,Ustüner E, et al. High frequency of kidney and urinarytract anomalies in asymptomatic first-degree relatives ofpatients with CAKUT. Pediatr Nephrol. 2013;28:2143–7. 38.Mansoor O, Chandar J, Rodriguez MM, et al. Long-term riskof chronic kidney disease in unilateral multicysticdysplastic kidney. Pediatr Nephrol. 2011;26:597–603. 39.Damen-Elias HA, Stoutenbeek PH, Visser GH, et al.Concomitant anomalies in 100 children with unilateralmulticystic kidney. Ultrasound Obstet Gynecol.2005;25:384–8. 40. Potter EL. Bilateral renal agenesis. JPediatr. 1946;29:68–76. 41. Pot ter EL. Normal andAbnormal Development of the Kidney. Chicago: Year BookMedical Publishers; 1972. p. 1–305. 42. Wil son RD, BairdPA. Renal agenesis in British Columbia. Am J Med Genet.1985;21:153–69. 43. Roodhooft AM, Birnholz JC, Holmes LB.Familial nature of congenital absence and severedysgenesis of both kidneys. N Engl J Med. 1984;310:1341–5.44. Humbert C, Silbermann F, Morar B, et al. Integrinalpha 8 recessive mutations are responsible for bilateralrenal agenesis in humans. Am J Hum Genet. 2014;94:288–94.45. Sheih CP, Liu MB, Hung CS, et al. Renal abnormalitiesin schoolchildren. Pediatrics. 1989;84:1086–90. 46.Westland R, Schreuder MF, Ket JC, et al. Unilateral renalagenesis: A systematic review on associated anomalies andrenal injury. Nephrol Dial Transplant. 2013;28:1844–55.47. Weizer AZ, Silverstein AD, Auge BK, et al. Determiningthe incidence of horseshoe kidney from radiographic dataat a single institution. J Urol. 2003;170:1722–6. 48.Glenn JF. Analysis of 51 patients with horseshoe kidney. NEngl J Med. 1959;261:684–7. 49. Bilge I, Kayserili H, EmreS, et al. Frequency of renal malformations in Turner

syndrome: Analysis of 82 Turkish children. PediatrNephrol. 2000;14:1111–4.

50. Kuwertz-Broeking E, Brinkmann OA, Von Lengerke HJ, etal. Unilateral multicystic dysplastic kidney: Experiencein children. BJU Int. 2004;93:388–92.

51. Sch reuder MF, Westland R, van Wijk JA. Unilateralmulticystic dysplastic kidney: A metaanalysis ofobservational studies on the incidence, associated urinarytract malformations and the contralateral kidney. NephrolDial Transplant. 2009;24:1810–8.

52. Aslam M, Watson AR, Trent, and Anglia MCDK StudyGroup. Unilateral multicystic dysplastic kidney: Long termoutcomes. Arch Dis Child. 2006;91:820–3.

53. Snodgrass WT. Hypertension associated with multicysticdysplastic kidney in children. J Urol. 2000;164:472–3.

54. Narchi H. Risk of hypertension with multicystic kidneydisease: A systematic review. Arch Dis Child.2005;90:921–4.

55. Narchi H. Risk of Wilms’ tumour with multicystickidney disease: A systematic review. Arch Dis Child.2005;90:147–9.

56. Eic kmeyer AB, Casanova NF, He C, et al. The naturalhistory of the multicystic dysplastic kidney: Is limitedfollow-up warranted? J Pediatr Urol. 2014;10:655–61.

57. Til emis S, Savanelli A, Baltogiannis D, et al. Is therisk of hypertension an indication for prophylacticnephrectomy in patients with unilateral multicysticdysplastic kidney? Scand J Urol Nephrol. 2003;37:429–32.

58. Mil ler RW, Fraumeni JF Jr, Manning MD. Association ofWilms’ tumor with aniridia, hemihypertophy and othercongenital malformations. N Engl J Med. 1964;270:922–7.

59. Francke U, Holmes LB, Atkins L, Riccardi VM.Aniridia-Wilms’ tumor associations: Evidence for specificdeletion of 11p13. Cytogenet Cell Genet. 1979;24:185–92.

60. Rauscher FJ. The WT1 Wilms tumor gene product: Adevelopmentally regulated transcription factor in thekidney that functions as a tumor suppressor. FASEB J.1993;7:896–903.

61. Morrison AA, Viney RL, Saleem MA, et al. New insightsinto the function of the Wilms tumor suppressor gene WT1 inpodocytes. Am J Physiol Renal Physiol. 2008;295:F12–7.

62. Fischbach BV, Trout KL, Lewis J, et al. WAGR syndrome:A clinical review of 54 cases. Pediatrics. 2005;116:984–8.

63. Breslow NE, Norris R, Norkool P, et al.Characteristics and outcomes of children with the Wilms’tumor-aniridia syndrome: A report from the National Wilms’Tumor Study Group. J Clin Oncol. 2003;24:4579–85.

64. Breslow NE, Collins AJ, Ritchey ML, et al. End stagerenal disease in patients with Wilms tumor: Results fromthe National Wilms Tumor Study Group and the United StatesRenal Data System. J Urol. 2005;174:1972–5. 65. NelsonCP, Dunn RL, Wei JT. Contemporary epidemiology of bladderexstrophy in the United States. J Urol. 2005;173:1728–31.66. Dra aken M, Baudisch F, Timmermann B, et al. Classicbladder exstrophy: Frequent 22q11.21 duplications anddefinition of a 414 kb phenocritical region. Birth DefectsRes A Clin Mol Teratol. 2014;100:512–7. 67. Dickson AP.The management of bladder exstrophy: The Manchesterexperience. J Pediatr Surg. 2014;49:244–50. 68. Tas kinenS, Suominen JS. Lower urinary tract symptoms (LUTS) inpatients in adulthood with bladder exstrophy andepispadias. BJU Int. 2013;111:1124–9. 69. Gupta AD, GoelSK, Woodhouse CR, et al. Examining long-term outcomes ofbladder exstrophy: A 20-year follow-up. BJU Int.2014;113:137–41. 70. Yosypiv IV. Renin-angiotensin systemin ureteric bud branching morphogenesis: Insights into themechanisms. Pediatr Nephrol. 2011;26:1499–512. 71. Son gR, Spera M, Garrett C, et al. Angiotensin II AT2 receptorregulates ureteric bud morphogenesis. Am J Physiol RenalPhysiol. 2010;298:F807–17. 72. Pryd e PG, Sedman AB,Nugent CE, Barr M. Angiotensin-converting enzyme inhibitorfetopathy. J Am Soc Nephrol. 1993;3:1575–82. 73. ButtarHS. An overview of the influence of ACE inhibitors onfetal-placental circulation and perinatal development. MolCell Biochem. 1997;176:61–71. 74. Ano nymous. Postmarketing surveillance for angiotensin-converting enzymeinhibitor use during the first trimester of pregnancy:United States, Canada, and Israel, 1987–1995. MMWR MorbMortal Wkly Rep. 1997;46:240–2. REVIEW QUESTIONS 1. �ejuxtamedullary nephrons have long loops of Henle thatparticipate in: a. Sodium reabsorption b. Chloridetransport c. Urine concentrating mechanism d. None of theabove 2. Nephrin constitutes a structural component of:a. Endothelial cytoskeleton b. Podocyte cytoskeleton c.Slit diaphragm d. Bow man capsule 3. Whi ch of the

following combinations are transitional embryonic kidneys?a. Met anephros and mesonephros b. Mes onephros andpronephros c. Pro nephros and metanephros d. None of theabove

4. In a premature infant, nephrogenesis can continue up to3 months a�er birth:

a. True

b. False

5. Characteristic �nding on MAG3 renal scan in a patientwith multicystic dysplastic kidney (MCDK) is:

a. Photopenic areas in the a�ected kidney suggesting cysts

b. Arterial �ow from the surrounding tissue

c. Adequate blood �ow but no excretory function

d. No demonstrable renal blood �ow and no excretory function

6. Vesicoureteral re�ux on the same side or contralateralside of MCDK occurs in:

a. Fewer than 5% cases

b. 20% cases

c. 50% cases

d. Almost always in all patients

7. Wilms tumor, aniridia, genitourinary anomalies, andmental retardation (WAGR) is caused by:

a. Mutation in WT1 gene

b. Mutation in PAX6 gene

c. Mutation in PAX6 and WT1

d. Mutation in WT1 and GDNF

8. ACEI-induced fetapathy is more common if the drugexposure occurs in:

a. First 2 weeks of pregnancy

b. Six to 12 weeks of pregnancy

c. Last week of pregnancy

d. A�er �rst trimester of pregnancy 9. Horseshoe kidneysare common in: a. Down syndrome b. Turner syndrome c.WAGR syndrome d. Renal coloboma syndrome 10. Low nephronnumber at birth is associated with: a. Future risk ofdiabetes mellitus b. Future risk of cardiac disease c.Future risk of hypertension d. No associated risk ofdisease ANSWER KEY 1. c 2. c 3. c 4. a 5. d 6. b 7.c 8. d 9. b 10. c

2 Molecular basis of developmental renaldisease

(a)

Figure 2.4 Renal dysplasia. (a) A cut section of dysplastic

kidney with malformed collecting system, lack of well-pat

terned renal parenchyma, and absence of corticomedul

lary differentiation. (b) Microscopic section of the kidney

from the patient demonstrating malformed tubules. Some

tubules are widely dilated (T). Arrows show cartilage

within the renal parenchyma. (Figure courtesy of Arthur

Cohen, MD.)

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REVIEW QUESTIONS

1. Metanephric induction begins at:

a. Week 7 of gestation

b. Week 10 of gestation

c. Week 5 of gestation

d. Week 20 of gestation

2. Renal dysplasia is characterized by a decreased numberof nephrons, the presence of collecting ducts surroundedby muscular rings, and elements of aberrant development,such as cartilage, or even calci�ed tissue. a. True b.False 3. Branchio-oto-renal (BOR) syndrome results frommutation of: a. PAX2 b. PEX1 c. SOX9 d. EYA1 4. �emost common urinary tract abnormality associated withmulticystic dysplastic kidney (MCDK) is: a. Duplication ofthe collecting system b. Vesicoureteric re�ux c.Posterior urethral valves d. Wilms tumor 5. During renaldevelopment, the WTI gene is important in: a.Glomerulogenesis b. Tubulogenesis c. Formation of therenal pelvis d. Renal ascent 6. BMP4, expressed in themesenchymal cells surrounding the wol�an duct, exerts apositive control in directing the site from which uretericbud would emerge. a. True b. False 7. Patterning of therenal collecting system (renal pelvis and calyces) iscontrolled by: a. Sonic hedgehog (SHH) and BMP gene familyb. Renin, angiotensinogen genes c. JAGGED1 gene d. SIX1and SIX2 genes 8. �e characteristic renal phenotype inAlagille syndrome consists of: a. Renal dysplasia b.Renal aplasia c. Multicystic dysplastic kidney d.Hypoplasia ANSWER KEY 1. c 2. b 3. d 4. b 5. a 6. b7. a 8. a

3 Urinalysis

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2. Addis T. A clinical classification of Bright’s diseases.JAMA. 1925;85:163–7.

3. The European Confederation of Laboratory Medicine(ECLM). European urinalysis guidelines: Summary. Scand JClin Lab Invest. 2000;60:1–96.

4. Fogazzi GB, Verdesca S, Garigali G. Urinalysis: Corecurriculum 2008. Am J Kidney Dis. 2008;51:1052–67.

5. Edelmann CM Jr, Barnett HL, Stark H, et al. Astandardized test of renal concentrating capacity inchildren. Am J Dis Child. 1967;114:639–44. 6. Iorember FM,Vehaskari VM. Uromodulin: Old friend with new roles inhealth and disease. Pediatr Nephrol. 2014;29:1151–8. 7.International Study of Kidney Disease in Children.Nephrotic syndrome in children: Prediction ofhistopathology from clinical and laboratorycharacteristics at time of diagnosis. Kidney Int.1978;13:159–65. 8. National Kidney Foundation. KDOQIclinical practice guidelines for chronic kidney disease:Evaluation, classification and stratification. Am J KidneyDis. 2002;39(Suppl 1):S1–266. 9. Ginsberg JM, Chang BS,Matarese RA, et al. Use of single voided urine samples toestimate quantitative proteinuria. N Engl J Med.1983;309:1543–6. 10. Hou ser M. Assessment of proteinuriausing random urine samples. J Pediatr. 1984;104:845–8.11. Abi tbol C, Zilleruelo G, Freundlich M, et al.Quantitation of proteinuria with urinary protein/creatinineratios and random testing with dipsticks in nephroticchildren. J Pediatr. 1990;116:243–7. 12. Bangstad H-J,Dahl-Jorgensen K, Kjaersgaard P, et al. Urinary albuminexcretion rate and puberty in non-diabetic children andadolescents. Acta Paediatr. 1993;82:857–62, 1993. 13.Morgenstern BZ, Butani L, Wollan P, et al. Validity ofprotein-osmolality versus protein-creatinine ratios in theestimation of quantitative proteinuria from random samplesof urine in children. Am J Kidney Dis. 2003;41:760–66.14. Hogg RJ, Furth S, Lemley KV, et al. National KidneyFoundation’s kidney disease outcomes quality initiativeclinical practice guidelines for chronic kidney disease inchildren and adolescents: Evaluation, classification, andstratification. Pediatrics. 2003;111:1416–21. 15. AssadiFK. Quantitation of microalbuminuria using random urine

samples. Pediatr Nephrol. 2002;17:107–10. 16. Santer R,Calado J. Familial renal glucosuria and SGLT2: From amendelian trait to a therapeutic target. Clin J Am SocNephrol. 2010;5:133–41. 17. Nys S, van Merode T, BarteldsAI, et al. Urinary tract infections in general practicepatients: Diagnostic tests versus bacteriological culture.J Antimicrob Chemother. 2006;57:955–8. 18. Williams GJ,Macaskill P, Chan SF, et al. Absolute and relativeaccuracy of rapid urine tests for urinary tract infectionin children: A meta-analysis. Lancet Infect Dis.2010;10:240–50. 19. Rabinovitch A, Sarewitz SJ, WoodcockSM et al. Urinalysis and Collection, Transportation, andPreservation of Urine Specimens. Approved Guideline, 2 ed.Clinical and Laboratory Standards document GP16-A2. Wayne,PA: National Committee for Clinical Laboratory Standards;2001. SUMMARY Urinalysis provides an important insight intorenal physiology and also can provide diagnostic cluesinto many pathologic states. It is o�en the �rstinvestigation in the evaluation of patients with renaldisease. �e technology of urinalysis has been evolvingover the years, especially with the development ofchemical analysis using dipsticks. Screening forproteinuria, hematuria, and UTI in the emergencydepartment and physician o�ces has been particularlyfacilitated by these developments. Microscopic analysis ofthe urine sediment requires knowledge and the experienceof having viewed the sediment in physiologic as well asdisease states. Use of stock images for determining theformed urinary sediment components is evolving but is animperfect technique at this stage.

20. Fairley KF, Birch DF. Hematuria: A simple method foridentifying glomerular bleeding. Kidney Int.1984;21:105–8.

21. Sta pleton FB, Roy SI, Noe HN, et al. Hypercalciuriain children with hematuria. N Engl J Med. 1984;310:1345–8.

22. Andres A, Praga M, Bello I, et al. Hematuria due tohypercalciuria and hyperuricosuria in adult patients.Kidney Int. 1989;36:96–9.

23. Fog azzi GB, Edefonti A, Garigali G, et al. Urineerythrocyte morphology in patients with microscopichaematuria caused by a glomerulopathy. Pediatr Nephrol.2008;23:1093–100.

24. Nolan CR, Kelleher SP. Eosinophiluria. Clin Lab Med.1988;8:555–65.

25. Jen kins RD, Fenn JP, Matsen JM. Review of urinemicroscopy for bacteriuria. JAMA 1986;255:3397–403.

26. Graff L. A Handbook of Routine Urinalysis. St. Louis:JB Lippincott; 1983.

27. Fog azzi GB. Crystalluria: A neglected aspect ofurinary sediment analysis. Nephrol Dial Transplant.1996;11:379–87.

28. Hes s B. Drug-induced urolithiasis. Curr Opin Urol.1998;8:331–4.

29. Sal tel E, Angel JB, Futter NG, et al. Increasedprevalence and analysis of risk factors for indinavirnephrolithiasis. J Urol. 2000;164:1895–7.

30. Cho pra N, Fine PL, Price B, Atlas I. Bilateralhydronephrosis from ciprofloxacin induced crystalluria andstone formation. J Urol. 2000;164:438.

31. Lyon A W, Mansoor A, Trotter MJ. Urinary gems:Acyclovir crystalluria. Arch Pathol Lab Med.2002;126:753–4.

32. Fogazzi GB, Cantù M, Saglimbeni L, et al. Amoxicillin:A rare but possible cause of crystalluria. Nephrol DialTransplant. 2003;18:212–4.

33. Nasr SH, Milliner DS, Wooldridge TD, et al.Triamterene crystalline nephropathy. Am J Kidney Dis.2014;63:148–52.

34. Hufnagle KG, Khan SN, Penn D, et al. Renalcalcifications: A complication of long-term furosemidetherapy in preterm infants. Pediatrics. 1982;70:360–3.

REVIEW QUESTIONS

1. Urine was collected on your 3-year-old febrile patientat home and was stored at room temperature for 18 hours.Urinalysis showed speci�c gravity 1.015, pH 6.5, proteinnegative, blood negative, nitrite positive, and leukocyteesterase negative. Your recommendation is: a. Pat ient hasa UTI, obtain a urine culture and start on antibiotics.b. Patient does not have a UTI, but a culture should beobtained. c. Patient does not have a UTI, and nothing moreneeds to be done. d. Pat ient does not have a UTI, and aurine culture does need to be obtained. Obtain aurinalysis in freshly obtained urine in the clinic. 2.

You need to evaluate urinary sediment in a patient withsuspected glomerulonephritis who has had visible hematuriafor 1 week but is improving, with only faintly pink urine.You are unable to evaluate the urinary sediment for thenext 4 hours. Your laboratory technician labeled the urinesample and froze it at –20° C, with the hope of preservingthe casts and cellular elements for you to evaluate later.When you evaluated the urine sediment later in the daya�er thawing it, you found unclear cell types and noclearly identi�able casts were present. Choose the bestinterpretation of these �ndings. a. Patient does not haveglomerulonephritis. b. Patient’s cellular elements andcasts were likely disrupted by freezing. c. Patient hasglomerulonephritis, but there is no evidence of it in theurinary sediment. d. Patient’s urine sample may have beenlabeled incorrectly. 3. A 3+ positive test for heme ondipstick is diagnostic for the presence of: a. Blood inurine b. Myoglobin in urine c. Hemoglobinuria secondaryto intravascular hemolysis d. All of the above 4. Ameta-analysis of pediatric studies has indicated thaturine nitrite test for UTI: a. Correlates best with arandomly obtained urine. b. Has low speci�city and highsensitivity. c. Has high speci�city and low sensitivity.d. Correlates poorly with UTI. 5. Drug-inducedcrystalluria can result in: a. Acute kidney injury b.Renal stone formation c. Nephrocalcinosis d. All of above6. Which of the following correlates highly with signi�cantbacteria in the urine of a patient with UTI? a. 1bacterium/HPF seen in uncentrifuged urine under 40×magni�cation b. 1 bacterium/oil immersion �eld seen incentrifuged urine stained with Gram stain c. 1bacterium/HPF seen in centrifuged urine stained with Gramstain d. 1 bacterium/oil immersion �eld seen incentrifuged urine stained with Sedi-Stain

7. Urine obtained for urinalysis needs to be collected in aclean container that does not have to be sterile. a. Trueb. False

8. A 10-year-old male patient in septic shock is noted tohave a serum creatinine level of 2.0 mg/dL. Although thepatient has good urine output, the intensive fellow wants anephrology consult. Urinalysis shows speci�c gravity1.010, pH 6.5, blood 3+, protein 2+. Microscopic analysisshows TNTC RBCs, a few granular casts, an occasional muddybrown cast, and many renal tubular epithelial cells. Yourinterpretation of the patient’s urinalysis, given theclinical picture is: a. Patient has prerenal azotemia. b.Patient has acute kidney injury. c. Patient hasglomerulonephritis. d. Patient has acute interstitial

nephritis.

9. Dipstick detection for detection of proteinuria is: a.Speci�c for tubular proteinuria b. Nonspeci�c and detectsall types of urinary proteins c. Able to detectmicroalbuminuria d. Speci�c for albuminuria 10. UTIcaused by Proteus, Pseudomonas, Klebsiella,Staphylococcus, and Mycoplasma that produce theurea-splitting enzyme urease can result in crystalluriaand renal stones. a. True b. False ANSWER KEY 1. d 2. b3. d 4. c 5. d 6. b 7. a 8. b 9. b 10. a

4 Clinical assessment of renal function

1. Kanwar YS, Venkatachalam MA. Ultrastructure ofglomerulus and juxtaglomerular apparatus. In: WindhagerEE, editor. Handbook of Physiology, Section 8: Physiology.New York: Oxford University Press; 1992. p. 3–40.

2. Kanwar YS. Biophysiology of glomerular filtration andproteinuria. Lab Invest. 1984;51:7–21.

3. Rose BD, Post TW. Renal circulation and glomerularfiltration rate. In: Wonsiewicz M, McCullough K, Davis K,editors. Clinical Physiology of Acid-Base and ElectrolyteDisorders. New York: McGraw-Hill; 2001. p. 21–70.

4. Brenner BM, Humes HD. Mechanics of glomerularultrafiltration. N Engl J Med. 1977;297:148–54.

5. Deen WM, Lazzara MJ, Myers BB. Structural determinantsof glomerular permeability. Am J Physiol Renal Physiol.2001;281:F579–96.

6. Brenner BM, Hostetter TH, Humes HD. Molecular basis ofproteinuria of glomerular origin. N Engl J Med.1978;298:826–33.

7. Latta H. An approach to the structure and function ofthe glomerular mesangium. J Am Soc Nephrol. 1992;2:S65–73.

8. Abrahamson DR. Structure and development of theglomerular capillary wall and basement membrane. Am JPhysiol Renal Physiol. 1987;253:F783–94. 9. Schwartz GJ.Does kL/P Cr estimate GFR, or does GFR determine k?Pediatr Nephrol. 1992;6:512–5. 10. Ara nt BS, Jr.,Edelmann CM, Jr., Spitzer A. The congruence of creatinineand inulin clearances in children: Use of the TechniconAutoAnalyzer. J Pediatr. 1972;81:559–61. 11. Dalton RN,Haycock GB. Laboratory investigation. In: Barratt TM,Avner ED, Harmon WE, editors. Pediatric Nephrology, 4thed. Baltimore: Lippincott Williams & Wilkins; 1999. p.343–64. 12. US Re nal Data System, USRDS 2002 Annual DataReport: Atlas of End-Stage Renal Disease in the UnitedStates. Bethesda, MD: National Institutes of Health,National Institute of Diabetes and Digestive and KidneyDiseases; 2002. 13. Col e BR, Giangiacomo J, IngelfingerJR, Robson AM. Measurement of renal function without urinecollection. N Engl J Med. 1972;287:1109–14. 14. SchwartzGJ, Feld LG, Langford DJ. A simple estimate of glomerularfiltration rate in full-term infants during the first yearof life. J Pediatr. 1984;104:849–54. 15. Sch wartz GJ,

Gauthier B. A simple estimate of glomerular filtration ratein adolescent boys. J Pediatr. 1985;106:522–6. 16. Talbot NB. Measurement of obesity by the creatininecoefficient. Am J Dis Child. 2005;55:42–50. 17. GreenblattDJ, Ransil BJ, Harmatz JS, et al. Variability of 24-hoururinary creatinine excretion by normal subjects. J ClinPharmacol. 1976;16:321–8. 18. Ric hardson JA, Philbin PE.The one-hour creatinine clearance rate in healthy men.JAMA. 1971;216:987–90. 19. Hellerstein S, Berenbom M,Alon US, Warady BA. Creatinine clearance followingcimetidine for estimation of glomerular filtration rate.Pediatr Nephrol. 1998;12:49–54. 20. Doolan PD, Alpen EL,Theil GB. A clinical appraisal of the plasma concentrationand endogenous clearance of creatinine. Am J Med.1962;32:65–79. 21. Schwartz GJ, Brion LP, Spitzer A. Theuse of plasma creatinine concentration for estimatingglomerular filtration rate in infants, children, andadolescents. Pediatr Clin North Am. 1987;34:571–90. 22.Schwartz GJ, Haycock GB, Chir B, Spitzer A. Plasmacreatinine and urea concentration in children: Normalvalues for age and sex. J Pediatr. 1976;88:828–30. 23. vanAcker BAC, Koomen GCM, Koopman MG, et al. Creatinineclearance during cimetidine administration for measurementof glomerular filtration rate. Lancet. 1992;340:1326–9.24. Sch utte JE, Longhurst JC, Gaffney FA, et al. Totalplasma creatinine: an accurate measure of total striatedmuscle mass. J Appl Physiol. 1981;51:762–6. 25. Jon es JD,Burnett PC. Implication of creatinine and gut flora in theuremic syndrome: induction of “creatininase” in coloncontents of the rat by dietary creatinine. Clin Chem.1972;18:280–4. SUMMARY Clinical care of children with acuteand chronic kidney diseases requires an assessment of renalfunction from both diagnostic and follow-up perspectives.GFR is long established as the best indicator of overallhuman renal function. Estimation of GFR by clearancemethodology, using exogenously administered and endogenousmarkers, has been the mainstay of evaluations over thepast several decades. An estimation of GFR from endogenousbiomarkers by various mathematical equations has beenattempted since the 1980s, and many of these methods areavailable for clinical use. Because of a lack of steadystate for Cr as well as Cys-C in AKI, application of theGFR equations cannot be advocated. Indeed, to predict earlyrenal injury in AKI, especially when surgical interventionsare necessary or nephrotoxic treatments are planned,several novel markers of renal function are beingevaluated. So far, no gold standard markers have beenestablished, and it is likely that a panel of such markersmay be clinically relevant. For the near future, to obtainan accurate appraisal of renal function, GFR may require

direct measurement by plasma or renal clearancetechniques.

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28. Schwartz GJ, Muñoz A, Schneider MF, et al. Newequations to estimate GFR in children with CKD. J Am SocNephrol. 2009;20:629–37.

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al. Urinary citrate excretion in the diagnosis of distalrenal tubular acidosis. J Pediatr. 1978;92:394–400. 148.Endre ZH, Pickering JW, Walker RJ. Clearance and beyond:the complementary roles of GFR measurement and injurybiomarkers in acute kidney injury (AKI). Am J PhysiolRenal Physiol. 2011;301:F697–707. 149. Briguori C,Visconti G, Rivera N, et al. Cystatin C andcontrast-induced acute kidney injury. Circulation.2010;121:2117. 150. Vaidya VS, Ferguson MA, Bonventre JV.Biomarkers of acute kidney injury. Annu Rev Pharmacol.2008;48:463–93. REVIEW QUESTIONS 1. A 5-year-old boy wasadmitted with the diagnosis of acute lymphoblasticleukemia. A�er induction chemotherapy he was noted to behyponatremic, with a serum sodium concentration of 131mmol. Normal saline was given as maintenance solution.Five days later he developed generalized tonic-clonicseizures. His serum electrolytes were as follows: glucose,107 mg/dL; sodium, 122 mmol/L; chloride, 82 mmol/L;potassium, 3.5 mmol/L; and bicarbonate, 22 mmol/L. BUN was16 mg/dL, and creatinine was 0.6 mg/dL. A diagnosis ofSIADH was entertained. �e calculated serum osmolality ofthis patient is: a. 244 b. 122 c. 256 d. 287

2. In a 10-year-old girl who had her right leg amputated atthe hip 6 months ago for osteosarcoma, the Schwartz formulaand modi�ed Schwartz formula do not predict GFRaccurately, and loss of limb needs to be accounted for. a.True b. False

3. Accuracy of predicting GFR by formulas based on serumcystatin C and serum creatinine is: a. No better than eachone alone b. Less accurate than each one alone c. Betterthan each one alone d. Cystatin C alone is always better.

4. Cystatin C is an ideal marker for determining GFR.However, classic clearance methodology for clearance, byusing a timed collection of urine and serum concentration,cannot be used with cystatin C because: a. It is notproduced at a constant rate. b. It is freely �ltered byglomeruli but is entirely reabsorbed in the loop of Henle.c. It is freely �ltered by glomeruli but is entirelymetabolized in the proximal renal tubule. d. It is notfreely �ltered by the glomeruli. e. It cannot be assayedin urine.

5. �e modi�ed Schwartz eGFR formula mandates usingenzymatic serum creatinine measurement that is calibratedto reference standards by isotope dilution massspectroscopy (IDMS), but not to “Ja�e” (alkaline picrate)methods. a. True b. False

6. Urea splitting organisms, such as Proteus, Pseudomonas,Klebsiella, Staphylococcus, and Mycoplasma hydrolyze ureato ammonium and lead to the following changes: a.Decreased urine pH b. No change in urine pH c. Raisedurine and blood pH d. Raised urine pH only

7. Evaluate this statement: “When C H2O is a positivenumber, it indicates increased free water clearance and adiuretic state.” a. True b. False

8. Novel biomarkers of renal function are useful for: a.Early detection of AKI b. Indicating the onset of AKI a�ercardiovascular surgery or contrast use c. Providinginformation on the potential site of tubular injury in AKId. All of the above

9. A 2½ year old white boy presented with a large rightabdominal mass of 2 weeks’ duration. He also had decreasedappetite. Laboratory studies on presentation were asfollows (in mmol/L): serum sodium, 130; potassium, 3.9;chloride, 92; and bicarbonate, 21. BUN and creatinine were10 mg/dL and 0.4 mg/dL, respectively. �e patient weighed13.7 kg and was 92.5 cm tall. He underwent an open biopsyof the abdominal mass that documented the diagnosis ofrhabdoid tumor of the right kidney. Regional lymph nodesand lungs had metastases. Right nephrectomy was followedby chemotherapy. He also underwent right �ank and wholelung radiation. DTPA nuclear GFR was 48 mL/min/1.73 m 2at 6 months. Serum creatinine was 0.6 mg/dL at 6 months,and the serum cystatin C level was 1.03 mg/L. His heightand weight at 6 months postoperatively (2.5 years of age)were 13.6 kg and 95.7 cm, respectively. Calculated GFR byvarious formulas at 6 months was as follows: 104.5mL/min/1.73 m 2 (original Schwartz), 65 mL/min/1.73 m 2(IDMS-traceable Schwartz GFR formula), and 65.8mL/min/1.73 m 2 (CKiD). �e patient’s estimated GFR isbest re�ected by all, except: a. CKiD formula b. Schwartzoriginal eGFR c. DTPA nuclear GFR d. IDMS-traceablecreatinine based Schwartz GFR 10. In the case given inquestion 9, a poor correlation of DTPA nuclear GFR andserum creatinine–based eGFR is best explained by: a.Patient’s receiving radiation therapy b. Fluid volumeretention c. Chemotherapy causing renal toxicities d.Loss of muscle mass resulting from poor nutrition 11. A30-kg male patient has a 2-day history of gross hematuriaand le� �ank pain. He is treated with intravenous �uids,analgesics, and a blocker agents in the emergencydepartment. He passes a stone in the urine. A 24-h urinestudy shows the following: volume, 1200 mL; citrate, 400

mg/g creatinine; oxalate, 0.05 mg/mg creatinine; and Ca/ Crratio, 0.45. �e stone passed is most likely to be: a. Uricacid b. Calcium phosphate c. Calcium oxalate d. StruviteANSWER KEY 1. c 2. a 3. c 4. c 5. a 6. d 7. a 8. d9. b 10. d 11. c

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85. Li S, K rawczeski CD, Zappitelli M, et al. Incidence,risk factors, and outcomes of acute kidney injury afterpediatric cardiac surgery: A prospective multicenter study.Crit Care Med. 2011;39:1493–9. 86. Bagga A, Bakkaloglu A,Devarajan P, et al. Improving outcomes from acute kidneyinjury: Report of an initiative. Pediatr Nephrol (Berl).2007;22:1655–8. 87. Akcan-Arikan A, Zappitelli M, LoftisLL, et al. Modified RIFLE criteria in critically illchildren with acute kidney injury. Kidney Int.2007;71:1028–35. 88. Zappitelli M, Parikh CR, Akcan-ArikanA, et al. Ascertainment and epidemiology of acute kidney

injury varies with definition interpretation. Clin J AmSoc Nephrol. 2008;3:948–54. 89. Ricci Z, Cruz D, Ronco C.The RIFLE criteria and mortality in acute kidney injury: Asystematic review. Kidney Int. 2008;73:538–46. 90.Cuhaci B. More data on epidemiology and outcome of acutekidney injury with AKIN criteria: Benefits of standardizeddefinitions, AKIN and RIFLE classifications. Crit CareMed. 2009;37:2659–61. 91. Uchino S. Outcome prediction forpatients with acute kidney injury. Nephron Clin Pract.2008;109:c217–23. 92. Macedo E, Castro I, Yu L, et al.Impact of mild acute kidney injury (AKI) on outcome afteropen repair of aortic aneurysms. Ren Fail. 2008;30:287–96.93. Bagshaw SM, George C, Bellomo R. Changes in theincidence and outcome for early acute kidney injury in acohort of Australian intensive care units. Crit Care.2007;11:R68. 94. Mehta RL, Kellum JA, Shah SV, et al.Acute Kidney Injury Network: Report of an initiative toimprove outcomes in acute kidney injury. Crit Care2007;11:R31. 95. Koralkar R, Ambalavanan N, Levitan EB,et al. Acute kidney injury reduces survival in very lowbirth weight infant. Pediatr Res. 2011;69:354–8. 96.Viswanathan S, Manyam B, Azhibekov T, Mhanna MJ. Riskfactors associated with acute kidney injury in extremelylow birth weight (ELBW) infants. Pediatr Nephrol (Berl).2012;27:303–11. 97. Ask enazi DJ, Koralkar R, Hundley HE,et al. Fluid overload and mortality are associated withacute kidney injury in sick near-term/term neonate.Pediatr Nephrol (Berl). 2013;28:661–6. 98. Sel ewski DT,Jordan BK, Askenazi DJ, et al. Acute kidney injury inasphyxiated newborns treated with therapeutic hypothermia.J Pediatr. 2013;162:725–9. 99. Ask enazi DJ, Griffin R,McGwin G, et al. Acute kidney injury is independentlyassociated with mortality in very low birthweight infants:A matched case-control analysis. Pediatr Nephrol (Berl).2009;24:991–7. 100. Gadepalli SK, Selewski DT, DrongowskiRA, Mychaliska GB. Acute kidney injury in congenitaldiaphragmatic hernia requiring extracorporeal lifesupport: An insidious problem. J Pediatr Surg2011;46:630–5. 101. Shuhaiber J, Thiagarajan RR, LaussenPC, et al. Survival of children requiring repeatextracorporeal membrane oxygenation after congenital heartsurgery. Ann Thorac Surg. 2011;91:1949–55.

102. Blinder JJ, Goldstein SL, Lee VV, et al. Congenitalheart surgery in infants: Effects of acute kidney injuryon outcomes. J Thorac Cardiovasc Surg. 2012;143:368–74.

103. Kra wczeski CD, Woo JG, Wang Y, et al. Neutrophilgelatinase-associated lipocalin concentrations predictdevelopment of acute kidney injury in neonates and

children after cardiopulmonary bypass. J Pediatr2011;158:1009–15.

104. Alabbas A, Campbell A, Skippen P, et al. Epidemiologyof cardiac surgery-associated acute kidney injury inneonates: A retrospective study. Pediatr Nephrol (Berl).2013;28:1127–34.

105. White SL, Perkovic V, Cass A, et al. Is low birthweight an antecedent of CKD in later life? A systematicreview of observational studies. Am J Kidney Dis.2009;54:248–61.

106. Greenbaum LA, Munoz A, Schneider MF, et al. Theassociation between abnormal birth history and growth inchildren with CKD. Clin J Am Soc Nephrol. 2011;6:14–21.

107. Bas ile DP. The endothelial cell in ischemic acutekidney injury: Implications for acute and chronic function.Kidney Int. 2007;72:151–6.

108. Ask enazi DJ, Feig DI, Graham NM, et al. 3-5 yearlongitudinal follow-up of pediatric patients after acuterenal failure. Kidney Int. 2006;69:184–9.

109. Mammen C, Al Abbas A, Skippen P, et al. Long-termrisk of CKD in children surviving episodes of acute kidneyinjury in the intensive care unit: A prospective cohortstudy. Am J Kidney Dis. 2012;59:523–30.

110. Coc a SG, Singanamala S, Parikh CR. Chronic kidneydisease after acute kidney injury: A systematic review andmeta-analysis. Kidney Int. 2012;81:442–8.

111. Bas ile DP. Rarefaction of peritubular capillariesfollowing ischemic acute renal failure: A potential factorpredisposing to progressive nephropathy. Curr Opin NephrolHypertens. 2004;13:1–7.

112. Guignard JP, Torrado A, Da Cunha O, Gautier E.Glomerular filtration rate in the first three weeks oflife. J Pediatr. 1975;87:268–72.

113. Barnett HL, Hare K, McNamara H, Hare R. Measurementof glomerular filtration rate in premature infants. J ClinInvest. 1948;27:691–9.

114. Vanpee M, Blennow M, Linne T, et al. Renal function invery low birth weight infants: Normal maturity reachedduring early childhood. J Pediatr. 1992;121:784–8.

REVIEW QUESTIONS

1. Which of the following factors is the most important

contributor to the increase in renal blood �ow following

birth?

a. Increased cardiac output

b. Increased renal vascular resistance c. Decreased renalvascular resistance d. Increased circulating plasma volumee. Cha nges in systemic resistance 2. Whi ch of thefollowing statements about the reninangiotensin system isnot true? a. Fetal renin levels are higher than adultlevels. b. Neonatal angiotensin-converting enzyme levelsare higher than adult levels. c. �ere i s a shi� from apredominance of angiotensin receptor type 2 to angiotensinreceptor type 1 following birth. d. Disruptions of theangiotensin type 1 or type 2 receptors are capable ofcausing congenital malformations of the kidney. e. AT-2receptors are coupled to G-proteins. 3. Fetal urine outputbegins at what week during gestation? a. 5th week b. 8thweek c. 12th week d. 20th week e. 36th week 4.Nephrogenesis is completed at: a. 28 we ek s of gestationb. 36 weeks of gestation c. 40 weeks of gestation d. 2weeks following birth e. 2 years of age 5. Which of thefollowing statements about neonatal sodium homeostasis isnot true? a. �ere is an increase in activity of the Na +-H + exchanger in the proximal tubules a�er birth. b. �ereis an initial natriuresis that a�ects term and pretermneonates equally. c. �ere is a shi� toward sodiumconservation at day 4 of life. d. �e loop of Henle has20% of the adult capacity to transport sodium. e. �ereare maturational changes in the distal tubule handling ofsodium a�er birth. 6. When compared to older infants,neonates can be expected to have a lower level of which ofthe following? a. Serum potassium b. Serum phosphorus c.Serum bicarbonate d. Urine glucose e. Urine amino acids7. Which is true of the de�nition of neonatal acute kidneyinjury? a. Oliguria should be the only criterion becauseall neonates with AKI are oliguric. b. An absolute serumcreatinine greater than 1.5 mg/ dL is the best approach.c. �ere are currently no large prospective studies thathave tested di�erent de�nitions against hard clinicaloutcomes. d. Because SCr is stable over the �rst week oflife, looking at an absolute rise in SCr from baselineprovides the best de�nition of neonatal AKI.

e. �e need for dialysis should serve as the de�nition ofAKI.

8. Acute kidney injury has been shown to be associated

with adverse outcomes in which neonatal populations?

a. Infants with very low birth weight

b. Near term/term infants

c. Newborns with perinatal asphyxia treated withtherapeutic hypothermia

d. Newborns undergoing extracorporeal membrane oxygenation

e. Newborns following cardiopulmonary bypass

f. All of the above 9. Compared to the adult kidney,fetal renal blood �ow is typi�ed by which of thefollowing? a. Low renal vascular resistance b. Greaterow to the renal cortex c. Greater �ow to the renal medullad. A larger percentage of the cardiac output ANSWER KEY 1.c 2. e 3. c 4. b 5. b 6. c 7. c 8. f 9. c

6 Diagnostic imaging of the urinary tract

1. Herd D. Anxiety in children undergoing VCUG: Sedationor no sedation? [Review article.] Adv Urol. 2008;498614.

2. Leb owitz RL, Olbing H, Parkkulainen KV, et al.International system of radiographic grading ofvesicoureteric reflux. International Reflux Study inChildren. Pediatr Radiol. 1985;15:105–9.

3. Rosenbaum DM, Korngold E, Teele RL. Sonographicassessment of renal length in normal children. AJR Am JRoentgenol. 1984;142:467–9.

4. Han BK, Babcock DS. Sonographic measurements andappearance of normal kidneys in children. Am J Roentgenol.1985;145:611–16.

5. Moore KI, Persaud TVE. The urogenital system. In: MooreKI, editor. The Developing Human: Clinically OrientedEmbryology, 6th ed. Philadelphia: WB Saunders; 1998. p.303.

6. Thoman DFM. Prenatally detected uropathies:Epidemiological considerations Br J Urol Int.1998;81:8–12.

7. Ngu yen HT, Herndon CD, Cooper C, et al. The Societyfor Fetal Urology consensus statement on the evaluationand management of antenatal hydronephrosis. J Pediatr Urol.2010; 6:212–31.

8. Bas sanese G, Travan L, D’Ottavio G, et al. Prenatalanteroposterior pelvic diameter cutoffs for postnatalreferral for isolated pyelectasis and hydronephrosis: Moreis not always better. J Urol. 2013;190:1858–63.

9. St. A ubin M, Willihnganz-Lawson K, et al. Society forFetal Urology recommendations for postnatal evaluation ofprenatal hydronephrosis: Will fewer voidingcystourethrograms lead to more urinary tract infections? JUrol. 2013;190:1456–61.

10. Laing FC, Burke VD, Wing VW, et al. Postpartumevaluation of fetal hydronephrosis: Optimal timing forfollow up sonography. Radiology. 1984;153:423–4.

11. Eickmeyer AB, Casanova NF, He C, et al. The naturalhistory of the multicystic dysplastic kidney: Is limitedfollow-up warranted? J Pediatr Urol. 2014;10:655–61.

12. Strife JL, Souza AS, Kirks DR, et al. Multicysticdysplastic kidney in children: US follow up. Radiology.1993;186:785–8.

13. England RJ, Haider N, Vujanic GM, et al. Mesoblasticnephroma: A report of the United Kingdom Children’s Cancerand Leukaemia Group (CCLG). Pediatr Blood Cancer.2011;56:744–8

14. Bie ster M, Kolditz D, Kalender WA. Iterativereconstruction methods in X-Ray CT. Phys Med.2012;28:94–108.

15. Mig lioretti DL, Johnson E, Williams A, et al. The useof computed tomography in pediatrics and the associatedradiation exposure and estimated cancer risk. JAMAPediatr. 2013;167:700–7. 16. Boone JM, Hendee WR,Mcnitt-Gray MF, et al. Seltzer SE. Radiation exposure fromCT scans: How to close our knowledge gaps, monitor andsafeguard exposure—Proceedings and recommendations of theRadiation Dose Summit, sponsored by NIBIB, February 24–25,2011. Radiology. 2012;265:544–54. 17. Aspelin P, LaskeyWK, Hermiller JB, et al. Nephrotoxic effects in high riskpatients undergoing angiography. N Engl J Med.2003;348:491–9. 18. Asif A, Epstein M. Prevention ofradiocontrast-induced nephropathy. Am J Kidney Dis.2004;44:12–24. 19. Emch TM, Haller NA. A randomized trialof prophylactic acetylcysteine and theophylline comparedwith placebo for the prevention of renal tubularvacuolization in rats after iohexol administration. ActaRadiol. 2003;10:514–9. 20. Gro bner T. Gadolinium: Aspecific trigger for the development of nephrogenicfibrosing dermopathy and nephrogenic systemic fibrosis?Nephrol Dial Transplant. 2006;21:1104–08. 21. Grobner T,Prischl FC. Gadolinium and nephrogenic systemic fibrosis.Kidney Int. 2007;72:260–4. 22. Mar kova A, Lester J, WangJ, et al. Diagnosis of common dermopathies in dialysispatients: A review and update. Semin Dial. 2012;25:408–18.23. Cow per SE, Robin HS, Steinberg SM, et al.Scleromyxoedema-like cutaneous diseases in renaldialysispatients. Lancet. 2000;356:1000–1. 24. Nar done B,Saddleton E, Laumann AE, et al. Pediatric nephrogenicsystemic fibrosis is rarely reported: A RADAR report.Pediatr Radiol. 2014;4:173–80. 25. Deo A , Fogel M,Cowper SE. Nephrogenic systemic fibrosis: A populationstudy examining the relationship of disease development togadolinium exposure. Clin J Am Soc Nephrol 2007;2:264–7.26. Boyd AS, Zic JA, Abraham JL. Gadolinium deposition innephrogenic fibrosing dermopathy. J Am Acad Dermatol

2007;56:27–30. 27. MacNeil S, Bains S, Johnson C, et al.Gadolinium contrast agent associated stimulation of humanfibroblast collagen production. Invest Radiol. 2011;46:711–7. 28. Vallee JP, Lazeyras F, Khan HG, et al. Absoluterenal blood flow quantification by dynamic MRI andGd-DTPA. Eur Radiol. 2000;10:1245–52. 29. Huang AJ, LeeVS, Rusinek H. Functional renal MR imaging. Magn ResonImaging Clin N Am. 2004;12:469–86. 30. Grenier N,Cornelis F, Le Bras Y, et al. Perfusion imaging in renaldiseases. Diagn Interv Imaging. 2013;94:1313–22. 31. Jones RA, Perez-Brayfield MR, Kirsch AJ, et al. Renal transittime with MR urography in children. Radiology.2004;233:41–50.

32. Zhang H, Prince MR. Renal MR angiography. Magn ResonImaging Clin N Am. 2004;12:487–503.

33. Ley endecker JR, Barnes CE, Zagoria, RJ. MR urography:Techniques and clinical applications. Radiographics.2008;28:23–48.

34. Grattan-Smith JD, Jones RA. MR urography in children.Pediatr Radiol. 2006;36:1119–32.

35. Majd M, Nussbaum Blask AR, et al. Acute pyelonephritis:Comparison of diagnosis with 99mTc-DMSA, SPECT, spiral CT,MR imaging, and power Doppler US in an experimental pigmodel. Radiology. 2001;218:101–8.

36. Lonergan GJ, Pennington DJ, Morrison JC, et al.Childhood pyelonephritis: Comparison of gadolinium-enhancedMR imaging and renal cortical scintigraphy for diagnosis.Radiology. 1998;207:377–84.

37. Goske MJ, Mitchell C, Reslan WA. Imaging of patientswith Wilms’ tumor. Semin Urol Oncol. 1999;17:11–20.

38. Glylys-Morin V, Hoffer FA, Kozakewich, et al. Wilmstumor and nephroblastomatosis: Imaging characteristics atgadolinium-enhanced MR Imaging. Radiology.1999;188:517–21.

39. Hen nigar RA, O’Shea PA, Grattan-Smith JD.Clinicopathologic features of nephrogenic rests andnephroblastomatosis. Adv Anat Pathol 2001;8:276–89.

40. ElMerhi FM, Bae, KT. Cystic renal disease. Magn ResonImaging Clin N Am. 2004;12:449–67.

41. Str and WR, Rushton HG, Markle BM, et al. Autosomal

dominant polycystic kidney disease in infants: Asymmetricdisease mimicking a unilateral renal mass. J Urol.1989;141:1151–3.

42. Bra ncatelli G, Federle MP, Vilgrain V, et al.Fibropolycystic Liver disease: CT and MR imaging findings.Radiographics. 2006;26:659–70.

REVIEW QUESTIONS

1. All of the following are indications for a VCUG except:a. Urinary tract infection b. Hydronephrosis/hydroureterc. To determine kidney function d. Preoperative renaltransplantation

2. Regarding vesicoureteral re�ux, which of the followingis false? a. �ere are �ve grades of re�ux. b. Grade Ire�ux indicates contrast material in the calyces. c. Intrarenal re�ux may be seen with higher grades of re�ux. d.e ur eter is o�en dilated in grades IV and V re�ux. 3.Reg arding the procedure of the VCUG, all statements aretrue, except: a. �e bladder needs to be catheterized. b.Oral sedation with midazolam is available in cases ofextreme anxiety. c. Inf ection is not a complication ofperforming VCUG. d. Parents and child-life specialist mayhelp facilitate the study. 4. Reg arding interpretationof the contrast VCUG, the International Re�ux Studyclassi�es VUR into: a. 4 grades of re�ux b. 5 grades ofre�ux c. Mild, moderate, and severe grades of VUR d. Grade I, Grade II, Grade III 5. Ultrasound is the bestmodality to evaluate for severity of renal obstruction.a. True b. False 6. Echogenic kidneys with loss ofcorticomedullary di�erentiation are speci�c �ndings forglomerulonephritis. a. True b. False 7. At 20 weeks ofgestation, routine ultrasound demonstrates mildpelviectasis (4 to 7 mm) in the fetus. What is thelikelihood of pyelectasis persisting a�er birth in thebaby? a. 20% b. 40% c. 60% d. 80% 8. A good-qualityCT scan of the kidneys should include which of thefollowing? a. Intravenous contrast material administrationb. A three-phase study including delayed excretion imagesc. Multiplanar reconstructions of source images d.Catheter drainage of the bladder e. Hydration and diureticadministration 9. All the following may contribute topotential radiographic contrast material nephrotoxicityexcept: a. Acidosis b. Dehydration c. N-acetyl cysteinetherapy d. Diabetes mellitus e. Prior contrast materialadministration 10. Which of the following is trueregarding nephrogenic systemic �brosis (NSF)? a. It isnot a risk for pediatric-age patients who are not

dehydrated. b. �e serum creatinine is a satisfactoryscreen for administration of gadolinium-based MRI contrastagents (GBCAs). c. A history of dialysis is the onlydetermining factor. d. �ere are a few GBCA agents that areconsidered safe for patients with renal failure (GFR lessthan 30). e. Dissociation of free gadolinium ion from thecontrast agent ligand plays a role.

11. Which imaging modality is best for screening forrecessive polycystic kidney disease? a. x-ray of theabdomen b. Radionuclide renal cortical scan c. CT scan ofabdomen d. Ultrasonography e. Noncontrast MRI ANSWER KEY1. c 2. b 3. c 4. b 5. b 6. b 7. a 8. c 9. c 10. e11. d

7 Radionuclide renal imaging

1. Gelfand MJ, Parisi MT, Treves ST. Pediatric NuclearMedicine Dose Reduction Workgroup. Pediatricradiopharmaceutical administered doses: 2010 NorthAmerican consensus guidelines. J Nucl Med. 2011;52:318–22.

2. Majd M, Rushton HG, Jantausch B, et al. Relationshipamong vesicoureteral reflux, p-fimbriated E. coli andacute pyelonephritis in children with febrile urinarytract infection. J Pediatr. 1991;119:578–85.

3. Rushton HG, Majd M, Chandra R, et al. Evaluation of99m-technetium-dimercaptosuccinic acid renal scans inexperimental acute pyelonephritis in piglets. J Urol.1988;140:1169–74. 4. Par khouse HF, Godley ML, Cooper, Jet al. Renal imaging with 99m Tc-labelled DMSA in thedetection of acute pyelonephritis: An experimental study inthe pig. Nucl Med Commun. 1989;10:63–70. 5. Majd M, BlaskARN, Markle BM, et al. Acute pyelonephritis: Comparison ofdiagnosis with 99m Tc-DMSA SPECT, spiral CT, MR imaging,and power Doppler US in an experimental pig model.Radiology. 2001;218:101–8. 6. Arnold AJ, Brownless SM,Carty HM, et al. Detection of renal scarring by DMSAscanning: An experimental study. J Pediatr Surg.1990;25:391–3. 7. Rushton HG, Majd M, Jantausch B, et al.Renal scarring following reflux and nonrefluxpyelonephritis in children: Evaluation with99mTechnetiumdimercaptosuccinic acid scintigraphy. J Urol.1992;147:1327–32, 8. Patteras JG, Rushton HG, Majd M. Therole of 99mTechnetum dimercapto-succinic acid renal scansin the evaluation of occult ectopic ureters in girls withparadoxical incontinence. J Urol. 199;162:821–5. 9.Gharagozloo AM, Leibowitz RL. Detection of a poorlyfunctioning malpositioned kidney with single ectopicureter in girls with urinary dribbling: Imaging evaluationin 5 patients. Am J Radiol. 1995;164:957–61. 10. Societyof Fetal Urology, Pediatric Nuclear Medicine Council,Society of Nuclear Medicine. The “well-tempered” diureticrenogram: A standard method to examine the asymptomaticneonate with hydronephrosis or hydroureteronephrosis.Report from combined meetings. J Nucl Med.1992;33:2047–51. 11. Ade yoju AAB, Burke D, Atkinson C, etal. The choice of timing for diuresis renography: The F+0method. BJU Int. 2001;88:1–5. 12. Wong DC, Rossleigh MA,Farnsworth RH. Diuretic renography with the addition ofquantitative gravityassisted drainage in infants andchildren. J Nucl Med. 2000;41:1030–6. 13. Ozcan Z,Anderson PJ, Gordon I. Prenatally diagnosed unilateralrenal pelvic dilatation: A dynamic condition on ultrasound

and diuretic renography. J Urol. 2004;172:1456–9. 14.Majd M, Potter BM, Guzzetta PC, et al. Effect of captoprilon the efficacy of renal scintigraphy in the detection ofrenal artery stenosis [Abstract]. J Nucl Med.1983;24:23–8. 15. Lagomarsino E, Orellanna P, Munoz J, etal. Captopril scintigraphy in the study of arterialhypertension in pediatrics. Pediatr Nephrol.2004;19:66–70. 16. Tayl or A. Renovascular hypertension:Nuclear medicine techniques. Q J Nucl Med. 2002;46:268–82.KEY POINTS ● Radionuclide cystography, because of its highsensitivity for VUR and its low radiation burden, isrecommended when serial follow-up studies are required. ●Radionuclide cystography is not adequate for providinginformation on urinary tract anatomy, such as posteriorurethral valve. SUMMARY

Nuclear imaging techniques are a useful adjunct to

other diagnostic imaging modalities in the manage

ment of pediatric nephrology patients. Diuresis renog

raphy provides critical information about conditions

such as obstructive uropathy. Renal cortical scanning

demonstrates the extent of parenchymal involvement in

pyelonephritis and scarring. Radionuclide studies o�er

an opportunity to view the results from a functional

perspective. Together with anatomic imaging, they

assist the pediatric nephrologist in the care of patients

17. Ludwig V, Martin WH, Delbeke D. Calcium channelblockers: A potential cause of false-positive captoprilrenography. Clin Nucl Med. 2003;28:108–12.

18. Sha rfuddin A. Imaging evaluation of kidney transplantrecipients. Semin Nephrol. 2011;31:259–71.

19. Heaf JG, Iversen J. Uses and limitations of renalscintigraphy in renal transplantation monitoring. Eur JNucl Med. 2000;27:871–9.

20. Dubovsky EV, Russell C. Quantitation of renal functionwith glomerular and tubular agents. Semin Nucl Med.1982;12:308–29.

21. Mulligan JS, Blue PW, Hasbargen JA. Methods ofmeasuring GFR with 99mTc-DTPA: An analysis of severalcommon methods. J Nucl Med. 1990;31:1211–9.

22. Coh en ML. Radionuclide clearance techniques. SeminNucl Med. 1974;4:23–8.

23. Piepsz A, Pintelon H, Ham HR. Estimation of normalchromium-51 ethylene diamine tetra-acetic clearance inchildren. Eur J Nucl Med. 1994; 21:12–6.

24. Her d D. Anxiety in children undergoing VCUG: Sedationor no sedation? Adv Urol. 2008:498614.

25. Majd M, Belman AB. Nuclear cystography in infants andchildren. Urol Clin North Am. 1979;6:395–407.

26. Con way JJ, King LR, Belman AB, et al. Detection ofvesicoureteral reflux with radionuclide cystography: Acomparison study with roentgenographic cystography. Am JRoentgenol Radium Ther Nucl Med. 1972;115:720–7.

27. Maj d M. Radionuclide imaging in clinical pediatrics.Pediatr Ann. 1976;15:396–402.

REVIEW QUESTIONS

1. A six-month-old female infant is hospitalized with afebrile urinary tract infection. �e radiopharmaceutical tobe used for assessment for acute pyelonephritis imagingis:

a. 99m Tc-MAG3

b. 99m Tc-pertechnetate

c. 99m Tc-DMSA

d. 99m Tc-DTPA

2. For the patient in question 1, renal cortical imagingdemonstrates multiple areas of photopenia, without loss ofvolume, involving both the upper and lower poles of theright kidney. �e diagnosis is:

a. Renal scarring

b. Multifocal acute pyelonephritis

c. Normal study

3. Clinical indications for DMSA renal corticalscintigraphy include:

a. Urinary tract infection

b. Search for a small ectopic kidney

c. Follow-up in renal trauma

d. All of the above. 4. A 2-month-old male infant wasdiagnosed to have prenatal hydronephrosis in one kidney.Le�-side hydronephrosis was con�rmed by a postnatalultrasound recently. �ere was no evidence of VUR on theVCUG. You should schedule this baby for a: a. DMSA renalscan b. Captopril renal scan c. Radionuclide cystogramd. Diuretic renogram 5. �e in itial imaging on the patientin question 4 demonstrates prompt and symmetric renalfunction with pooling of activity in the dilated le� renalcollecting system and prolonged washout half-time.Drainage on the right side is normal. Renal function isnormal bilaterally. Which of the following would be thebest investigative recommendation? a. MRI of the abdomenb. Repeat diuretic renography in 6 months c. Radionuclidecystogram in 6 months d. DMSA renal scan 6. All of thestatements regarding captopril-enhanced MAG-3 renal scanare true except: a. �e primary use is in the diagnosis ofobstructive uropathy. b. �e primary use is in thediagnosis of renal artery stenosis. c. Calciumchannel–blocking medication should be discontinued for atleast 2 days before the study. d. Either captopril orenalaprilat may be used for ACE blockade. 7. To assessthe function of the transplanted kidney, the best choiceof radionuclide investigation is: a. 99m Tc-DTPA b. 99mTc-pertechnetate c. 99m Tc-DMSA d. 99m Tc-MAG3 8. �emain indication for obtaining a 99m Tc-DTPA renal scanis: a. Evaluate for obstructive uropathy b. Evaluate forvesicoureteral re�ux c. Determine the glomerular �ltrationrate d. �ere are no current indications for obtaining a99m Tc-DTPA renal scan 9. �e following are correctregarding radionuclide cystography except: a. Oralmidazolam may be used for anxiolysis as necessary. b. �eradiotracer used is 99m Tc-pertechnetate. c. It isindicated in the evaluation of vesicoureteral re�ux. d.e bladder does not need to be catheterized. 10. Which oneof the following statements best compares and contraststhe VCUG and the radionuclide cystogram (RNC)? a. �e VCUGhas higher resolution allowing delineation of anatomy andmore accurate grading of re�ux compared to the RNC, which

has higher sensitivity for detecting re�ux and o�ers lessradiation burden.

b. �e RNC has higher resolution allowing delineation ofanatomy and more accurate grading of re�ux compared to theVCUG which has higher sensitivity for detecting re�ux ando�ers less radiation burden.

c. �e RNC and VCUG are very similar to each other, onesimply a radionuclide study and the other a �uoroscopicstudy.

d. None of the above. ANSWER KEY 1. c 2. b 3. d 4. d5. b 6. a 7. d 8. c 9. d 10. a

8 Renal biopsy

1. Pirani CL. Renal biopsy. An historical perspective. In:Silva FG, D’Agati VD, Nadasdy T, editors. Renal BiopsyInterpretation, Churchill Livingstone: New York; 1996:1–19. 2. Iversen P, Brun C. Aspiration biopsy of thekidney. Am J Med. 1951;11:324–30. 3. Korbet SM.Percutaneous renal biopsy. Semin Nephrol. 2002;22:254–67.4. Ric hards NT, Darby S, Howie AJ, et al. Knowledge ofrenal histology alters patient management in over 40% ofcases. Nephrol Dial Transplant. 1994;9:1255–9. 5. Hog gRJ, Portman RJ, Milliner D, et al. Evaluation andmanagement of proteinuria and nephrotic syndrome inchildren: Recommendations from a pediatric nephrology panelestablished at the National Kidney Foundation conferenceon proteinuria, albuminuria, risk, assessment, detection,and elimination (PARADE). Pediatrics. 2000;105:1242–49. 6.Fogo AB. Renal pathology. In: Avner ED, Niaudet P, HarmonWE, editors. Pediatric Nephrology, 5th ed. Philadelphia:Lippincott Williams & Wilkins, 2003; p. 475. 7. Filler G,Young E, Geier P, et al. Is there really an increase innon-minimal change nephrotic syndrome in children? Am JKidney Dis. 2003;42:1107–13. 8. Birk PE, Stannard KM,Konrad HB, et al. Surveillance biopsies are superior tofunctional studies for the diagnosis of acute and chronicrenal allograft pathology in children. Pediatr Transplant.2004;8:29–38. 9. Birnholz JC, Kasinath BS, Corwin HL. Animproved technique for ultrasound guided percutaneousrenal biopsy. Kidney Int. 1985;27:80–2. 10. Wiseman DA,Hawkins R, Numerow LM, Taub KJ. Percutaneous renal biopsyutilizing real time, ultrasonic guidance and asemiautomated biopsy device. Kidney Int. 1990;38:347–9.11. Donovan KL, Thomas DM, Wheeler DC, et al. Experiencewith a new method for percutaneous renal biopsy. NephrolDial Transplant. 1991;6:731–3. 12. Kar k RM, Muehrcke RC.Biopsy of the kidney in the prone position. Lancet1954;1:1047–49. 13. Muehrcke RC, Kark RM, Pirani CL.Technique of percutaneous renal biopsy in the proneposition. J Urol. 1955;74:267–77. 14. Kark RM, MuehrckeRC, Pollak VE, et al. An analysis of 500 percutaneousrenal biopsies. Arch Intern Med. 1958;101:439–351. 15.Komaiko MS, Jordan SC, Querfeld et al. A new percutaneousrenal biopsy device for pediatric patients. PediatrNephrol. 1989;3:191–3. 16. Bur stein DM, Korbet SM,Schwartz MM. The use of the automatic core biopsy systemin percutaneous renal biopsies: A comparative study. Am JKidney Dis. 1993;22:545–52. 17. Feneberg R, Schaefer F,Zieger B, et al. Percutaneous renal biopsy in children: A27-year experience. Nephron. 1998;79:438–46.

SUMMARY

e technical advances in imaging and instruments

have made the percutaneous renal biopsy a safe diag

nostic procedure. Use of real-time ultrasound guid

ance and advanced instruments are the standard of

care in our days. In spite of all the advancements,

there are still a group of well-de�ned contraindica

tions for a percutaneous renal biopsy that the clini

cian must consider carefully. Finally, the success and

safety of the percutaneous renal biopsy in children

require a knowledgeable and experienced pediatric

nephrologist familiar with the technique.

Figure 8.11 Color Doppler evaluation of the kidney dem

onstrating an arteriovenous fistula following a renal biopsy

procedure. The fistula is marked by the area showing the

admixture of blue and red blood flow pattern (arrow).

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renal biopsies: Comparison of inpatient and day careprocedures. Pediatr Nephrol. 2003;18:53–6.

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29. Sweet M, Brouhard BH, Ramirez-Seijas F, et al.Percutaneous renal biopsy in infants and young children.Clin Nephrol. 1986;26:192–94.

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31. al Ra sheed SA, al Mugeiren MM, Abdurrahman MB,Elidrissy AT. The outcome of percutaneous renal biopsy inchildren: An analysis of 120 consecutive cases. PediatrNephrol. 1990;4:600–3.

32. Bohlin AB, Edstrom S, Almgren B. Renal biopsy inchildren: Indications, technique and efficacy in 119consecutive cases. Pediatr Nephrol. 1995;9:201–3.

33. Pel legrini C, Cecconi M, Pieroni G, et al.Percutaneous renal biopsy in children: Use of a fineneedle. Minerva Urol Nefrol. 1996;48:97–101.

34. Ben field MR, Herrin J, Feld L. Safety of kidneybiopsy in pediatric transplantation: A report of theControlled Clinical Trials in Pediatric Transplantation

Trial of Induction Therapy Study Group. Transplantation1999;67: 544–7. 35. Kamitsuji H, Yoshioka K, Ito H.Percutaneous renal biopsy in children: Survey of pediatricnephrologists in Japan. Pediatr Nephrol. 1999;13:693–6.36. Sumboonnanonda A, Srajai K, Vongjirad A, et al.Percutaneous renal biopsy in children. J Med Assoc Thai.2002;85:(Suppl 2)755–61. 37. Proesmans W, Marchal G,Snoeck L, Snoeys R. Ultrasonography for assessment ofbleeding after percutaneous renal biopsy in children. ClinNephrol. 1982;18:257–62. 38. Stegmayr B, Orsten PA. Lysisof obstructive renal pelvic clots with retrogradeinstillation of streptokinase: A case report. Scand J UrolNephrol. 1984;18:347–50. 39. Horowitz MD, Russell E,Abitbol C, et al. Massive hematuria following percutaneousbiopsy of renal allograft: Successful control by selectiveembolization. Arch Surg. 1984;119:1430–3. 40. Fruhwald F,Harmuth P, Kovarik J, et al. Bladder obstruction: A rarecomplication after percutaneous renal biopsy. Eur JRadiol. 1984;4:225–6. 41. Rao K V. Urologicalcomplications associated with a kidney transplant biopsy:Report of 3 cases and review of the literature. J Urol.1986;135:768–70. 42. Sch waighofer B, Fruhwald F, KovarikJ. Sonographically demonstrable changes followingpercutaneous kidney biopsy. Ultraschall Med. 1986;7:44–7.43. Bergman SM, Frentz GD, Wallin JD. Ureteral obstructiondue to blood clot following percutaneous renal biopsy:Resolution with intraureteral streptokinase. J Urol.1990;143:113–5. 44. McDonald MW, Sosnowski JT, Mahin EJ,et al. Automatic spring-loaded biopsy gun with ultrasoniccontrol for renal transplant biopsy. Urology.1993;42:580–2. 45. Mah oney MC, Racadio JM, Merhar GL,First MR. Safety and efficacy of kidney transplant biopsy:TruCut needle vs sonographically guided Biopty gun. AJR AmJ Roentgenol. 1993;160:325–6. 46. Dia z-Buxo JA, DonadioJV Jr. Complications of percutaneous renal biopsy: Ananalysis of 1,000 consecutive biopsies. Clin Nephrol.1975;4:223–7. 47. Bennett AR, Wiener SN. Intrarenalarteriovenous fistula and aneurysm: A complication ofpercutaneous renal biopsy. Am J Roentgenol Radium TherNucl Med. 1965;95:372–82. 48. Eke lund L, Lindholm T.Arteriovenous fistulae following percutaneous renal biopsy.Acta Radiol Diagn (Stockh). 1971;11:38–48. 49. Jor stadS, Borander U, Berg KJ, Wideroe TE. Evaluation ofcomplications due to percutaneous renal biopsy: A clinicaland angiographic study. Am J Kidney Dis. 1984;4:162–5.50. Rollino C, Garofalo G, Roccatello D, et al. ColourcodedDoppler sonography in monitoring native kidney biopsies.Nephrol Dial Transplant. 1994;9:1260–63.

51. Gainza FJ, Minguela I, Lopez-Vidaur I. Evaluation of

complications due to percutaneous renal biopsy inallografts and native kidneys with color-coded Dopplersonography. Clin Nephrol. 1995;43:303–8.

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53. Riccabona M, Schwinger W, Ring E. Arteriovenousfistula after renal biopsy in children. J Ultrasound Med.1998;17:505–8.

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REVIEW QUESTIONS

1. Which of the following is not considered an absolute

contraindication for a percutaneous renal biopsy?

a. Uncooperative patient

b. Chronic glomerulonephritis

c. Uncontrolled severe hypertension

d. Acute pyelonephritis

2. Which of the following statements regarding complica

tions of a renal biopsy is false? a. Mic roscopichematuria is the most common complication. b. �eincidence of perinephric hematoma following renal biopsydepends on the modality of evaluation. c. Mos tarteriovenous �stulas require surgical intervention. d.Macroscopic hematuria usually resolves spontaneously within24 to 48 hours. e. Intravenous hydration is su�cient inmost patients to prevent the formation of large clots. 3.e op timal biopsy site for a native kidney is the: a.Upper pole of the right kidney b. Lower pole of the rightkidney c. Upper pole of the le� kidney d. Lower pole ofthe le� kidney 4. Whi ch of the following is not anindication for renal biopsy in children? a. Rapidlyprogressive glomerulonephritis b. Steroid-resistantnephrotic syndrome c. Renal allogra� dysfunction d. Persistent glomerular hematuria e. Steroid responsivenephrotic syndrome 5. Prebiopsy evaluation should include:a. Complete blood count b. Basic metabolic panel c.Ultrasonographic evaluation of the kidneys d. Coagulationpro�le e. All of the above 6. A 10-year-old girlunderwent a percutaneous renal biopsy and was dischargedfrom the outpatient surgical unit a�er 6 hours ofobservation. Next morning the patient complained of le�side abdominal pain, which was noted to be 8 on a 10-pointscale, and was persistent. Her parent gave heracetaminophen 325 mg orally, but there was no resolutionof pain. She is now seen in the emergency room. Patient

has been urinating well and the urine color is clearyellow. She was afebrile, and abdominal examination showedtenderness in the le� upper quadrant and along the le�ank. �e biopsy site was very tender to touch. No guardingor rebound tenderness was noted. Your most likely initialdiagnostic consideration is: a. Urinary tract infectionb. Perforation of the abdominal viscera c. Perinephrichematoma d. Muscular pain at the biopsy site e.Previously undiagnosed renal stone 7. Initial managementof the patient should include all except: a. Renalultrasound b. Obtain a complete blood count c. Prescribeintravenous morphine d. Prescribe oral codeine anddischarge her home 8. You decided to admit the patient andnoted that her hematocrit had decreased from prebiopsyvalue of 39% to 24% in the emergency room (hemoglobin 13g/dL to 8 g/dL). Patient received morphine intravenouslyand

was relieved of pain. She had mild tachycardia, pulse 99/

min, and BP 105/59 mm Hg. Renal ultrasound demon

strated a large perinephric hematoma. Management of

the patient will include all except:

a. Observe the patient and continue on IV morphine.

b. Ask for invasive radiology team to evacuate perinephrichematoma.

c. May give 5% albumin intravenously.

d. Arrange for a blood transfusion.

e. Repeat CBC in 2 to 4 hours.

9. Hypertension is a presenting manifestation of the post–

renal biopsy arteriovenous �stulas.

a. True

b. False ANSWER KEY 1. b 2. c 3. d 4. e 5. e 6. c 7.d 8. b 9. a

9 Hematuria and proteinuria

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86. Bou wman A, Verbeke J, Brand M, et al. Renal medullaryhyperechogenicity in a neonate with oliguria. Clin KidneyJ. 2010;3:176–8. 87. Diabetes and Chronic Kidney DiseaseWork Group. KDOQI clinical practice guidelines andclinical practice recommendations for diabetes and chronickidney disease. Am J Kidney Dis. 2007;49(Suppl 2):S1–180.88. Mahfoud F, Ukena C, Pöss J, et al. Microalbuminuriaindependently correlates to cardiovascular comorbidityburden in patients with hypertension. Clin Res Cardiol.2012;101:761–6. 89. Wit te EC, Heerspink HJL, de Zeeuw,D,et al. First morning voids are more reliable than spoturine samples to assess microalbuminuria. J Am Soc Nephrol.2009;20:436–43. 90. Hogg RJ, Portman RJ, Dawn Milliner D,et al. Evaluation and management of proteinuria andnephrotic syndrome in children: Recommendations from apediatric nephrology panel established at the NationalKidney Foundation Conference on Proteinuria, Albuminuria,Risk, Assessment, Detection, and Elimination (PARADE).Pediatrics. 2000;105:1242–9. 91. Bra ndt JR, Jacobs A,Raissy HH, et al. Orthostatic proteinuria and the spectrumof diurnal variability of urinary protein excretion inhealthy children. Pediatr Nephrol. 2010;25:1131–7. 92.Cho B S, Choi YM, Kang HH, et al.: Diagnosis of nutcrackerphenomenon using renal Doppler ultrasound in orthostaticproteinuria. Nephrol Dial Transplant. 2001;16:1620–5. 93.Lee SJ, You ES, Lee JE, et al. Left renal vein entrapmentsyndrome in two girls with orthostatic proteinuria. PediatrNephrol. 1997;11:218–20. 94. Devarajan P. Mechanisms oforthostatic proteinuria: Lessons from a transplant donor.J Am Soc Nephrol. 1993;4:36–9. 95. Mar ta BM, Mazzoni,ML, Simonetti GD, et al. Renal vein obstruction andorthostatic proteinuria: A review. Nephrol DialTransplant. 2011;26:562–5. 96. Rob inson RR, Glover SN,Phillip PJ, et al. Fixed and reproducible orthostaticproteinuria: Light microscopic studies of the kidney. Am JPathol. 1961;39:405–17. 97. von Bonsdorff M, Tornroth T,Pasternack A. Renal biopsy findings in orthostaticproteinuria. Acta Pathol Microbiol Immunol Scand.1982;90:11–8. 98. Rytand DA, Spreiter S. Prognosis inpostural (orthostatic) proteinuria: Forty to fifty-yearfollow-up of six patients after diagnosis by Thomas Addis.N Engl J Med. 1981;305:618–21. 99. Thompson AL, DurrettRR, Robinson RR. Fixed and reproducible orthostaticproteinuria. VI. Results of a 10-year follow-upevaluation. Ann Intern Med. 1970;73:235–44. 100. Springberg PD, Garrett LE, Jr., Thompson AL, et al. Fixed andreproducible orthostatic proteinuria: Results of a 20-yearfollow-up study. Ann Intern Med. 1982;97:516–9.

101. Committee on Practice and Ambulatory Medicine and

Bright Futures Steering Committee: Recommendations forpreventive pediatric health care. Pediatrics.2007;120:1376.

102. American Academy of Pediatrics. AAP publicationsreaffirmed and retired. Pediatrics. 2011;127:e857.

103. Sekhar DL, Wang L, Hollenbeak CS, et al. Acosteffectiveness analysis of screening urine dipsticks inwell-child care. Pediatrics. 2010;125;660–3.

104. Yap H K, Quek CM, Shen Q, et al. Role of urinaryscreening programs in children in the prevention ofchronic kidney disease. Ann Acad Med Singapore.2005;34:3–7.

105. Murakami M, Hayakawa M, Yanagihara T, et al.Proteinuria screening for children. Kidney Int Suppl.2005;94:S23–7.

106. Boulware LE, Jaar BG, Tarver-Carr ME, et al.Screening for proteinuria in US adults: Acost-effectiveness analysis. JAMA. 2003;290:3101–14.

107. Qaseem A, Hopkins RH, Jr., Sweet DE, et al.Screening, monitoring, and treatment of stage 1 to 3chronic kidney disease: A clinical practice guideline fromthe American College of Physicians. Ann Intern Med.2013;159:835–7.

REVIEW QUESTIONS

1. Mass screening of children for proteinuria andhematuria is a useful strategy for detection of chronickidney disease in children. a. True b. False

2. In a 2-week-old male newborn, parents report that thediaper is occasionally stained red-brown. �ey are concernedthat he has blood in his urine. You reassure the parentswith the suggestion that he probably has uric acidcrystals in the urine and increasing �uid intake would behelpful. Six weeks later, the patients return, with thesymptom that the infant was irritable and that thered-brown staining of the diapers has persisted.Urinalysis of a bagged urine specimen shows no protein orblood. Centrifugation 10 mL of urine shows a large amountof brownish red sediment. Microscopic analysis shows uricacid crystals in the sediment. You would obtain thefollowing investigations: a. Urine for spot uric acid b.Urine for spot uric acid, spot creatinine c.

Catheterization of the patient and determining an accurate24-h urine uric acid d. Rena l ultrasound, spot urine uricacid, and creatinine

3. Pod ocyturia and podocytopenia are known to occur in:a. Dia betic nephropathy b. Foc al segmentalglomerulosclerosis (FSGS) c. Mem branous nephropathy d.HIV nephropathy e. All of the above 4. An 11-year-oldwhite boy developed pink-brown urine following an upperrespiratory tract infection. Results of cystoscopyperformed in the community hospital were completelynormal. His symptoms resolved in about 1 week. Six monthslater, he again developed fever, nasal stu�ness, and asore throat, and visible hematuria ensued 2 days later. Hewas seen in the local emergency department. Urinalysisshowed 3+ proteinuria, large (4+) blood, and numerous redblood cell casts in the microscopic examination of thesediment. Serum creatinine, 1.5 mg/dL; BUN, 39 mg/ dL;normal electrolytes; ASO titer, normal; C3, 122 mg/dL; C4,32 mg/dL; ANA, negative. �e least likely diagnosis is: a.Poststreptococcal glomerulonephritis b. IgA nephropathyc. �in basement membrane nephropathy d. Alport syndrome5. Proteinuria, by itself, has been proposed to result intubulointerstitial disease by which of the followingmechanisms: a. Complement activation b. Induction ofpro-in�ammatory cytokines c. Epithelial-mesenchymaltransformation d. All of the above 6. Mature podocytescan avidly reproduce in case of detachment or loss fromthe glomerular basement membrane. a. True. b. False. 7.Terminal hematuria is indicative of: a. Urinary tractinfection b. Balanitis c. Posterior urethral or bulbararea lesions d. Bladder trauma 8. In the kidneys, cubilinand megalin are involved in: a. Proximal tubularphosphate reabsorption b. Urinary calcium reabsorption c.Reabsorption of urinary albumin and lowmolecular-weightproteins d. Synthesis of Tamm-Horsfall protein 9. Tubularproteinuria is characterized by: a. Failure to reabsorbthe low-molecular-weight proteins by the proximal tubularcells b. Absence of albumin in the urine proteinelectrophoresis c. Possible assay by determining themicroalbumin/creatinine ratio d. Detection by a positivedipstick test for urine protein

10. Chloride channel-5 (ClC-5) is required in thereabsorption of tubular albumin at which of the followinglevels? a. Acidi�cation of the endocytosis vesicles anddissociation albumin from the cubilin-megalin receptorscomplex b. Attaching tubular albumin to thecubilin-megalin complex c. Transporting of amino acidsand dipeptides on the basolateral surface d. Transporting

the cubilin-megalin complex to the tubular cell surfaceANSWER KEY 1. b 2. d 3. e 4. a 5. d 6. b 7. c 8. c9. a 10. a

10 Physiology of glomerular filtration

1. Bellomo G. A short history of “glomerulus.” Clin KidneyJ. 2013;6:250–1.

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3. Reitsma S, Slaaf DW, Vink H, et al. The endothelialglycocalyx: Composition, functions, and visualization.Pflugers Arch.2007;454:345–59.

4. Bal lermann BJ, Stan RV. Resolved: Capillary endotheliumis a major contributor to the glomerular filtrationbarrier. J Am Soc Nephrol. 2007;18:2432–8.

5. Salmon AH, Ferguson JK, Burford JL, et al. Loss of theendothelial glycocalyx links albuminuria and vasculardysfunction. J Am Soc Nephrol. 2012;23:1339–50.

6. Daniels BS, Hauser EB, Deen WM, Hostetter TH.Glomerular basement membrane: In vitro studies of waterand protein permeability. Am J Physiol. 1992;262:F919–26.

7. St John PL, Abrahamson DR. Glomerular endothelial cellsand podocytes jointly synthesize laminin-1 and -11 chains.Kidney Int. 2001;60:1037–46.

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10. Kar asawa R, Nishi S, Suzuki Y, et al. Early increaseof chondroitin sulfate glycosaminoglycan in the glomerularbasement membrane of rats with diabetic glomerulopathy.Nephron. 1997;76:62–71.

11. Kho shnoodi J, Sigmundsson K, Ofverstedt LG, et al.Nephrin promotes cell-cell adhesion through homophilicinteractions. Am J Pathol. 2003;163:2337–46.

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the rat and mouse. J Cell Biol. 1974;60:423–33. 28.Gagliardini E, Conti S, Benigni A, et al. Imaging of theporous ultrastructure of the glomerular epithelialfiltration slit. J Am Soc Nephrol. 2010;21:2081–9. 29.Bohrer MP, Deen WM, Robertson CR, et al. Influence ofmolecular configuration on the passage of macromoleculesacross the glomerular capillary wall. J Gen Physiol.1979;74:583–93. 30. Latta H, Johnston WH, Stanley TM.Sialoglycoproteins and filtration barriers in theglomerular capillary wall. J Ultrastruct Res. 1975;51:354.31. Hausmann R, Kuppe C, Egger H, et al. Electrical forcesdetermine glomerular permeability. J Am Soc Nephrol.2010;21:2053–8. 32. Peti-Peterdi J, Sipos A. Ahigh-powered view of the filtration barrier. J Am SocNephrol 2010;21:1835–41. 33. Her tig A, Rondeau E. Roleof the coagulation/fibrinolysis system in fibrin-associatedglomerular injury. J Am Soc Nephrol. 2004;15:844–53.

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35. Goldwich A, Burkard M, Olke M, et al. Podocytes arenonhematopoietic professional antigen-presenting cells. JAm Soc Nephrol. 2013;24:906–16.

36. Kriz W. The pathogenesis of ‘classic’ focal segmentalglomerulosclerosis-lessons from rat models. Nephrol DialTransplant. 2003;18(Suppl 6):vi39–44.

37. Hac kl MJ, Burford JL, Villanueva K, et al. Trackingthe fate of glomerular epithelial cells in vivo usingserial multiphoton imaging in new mouse models withfluorescent lineage tags. Nat Med. 2013;19:1661–6.

38. Ven katareddy M, Cook L, Abuarquob K, et al. Nephrinregulates lamellipodia formation by assembling a proteincomplex that includes Ship2, filamin and lamellipodin.PLoS One. 2011;6:e28710.

39. Bohlin AB. Clinical course and renal function inminimal change nephrotic syndrome. Acta Paediatr Scand.1984;73:631.

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41. Kau r H, Chien A, Jialal I. Hyperglycemia induces Toll

like receptor 4 expression and activity in mouse mesangialcells: Relevance to diabetic nephropathy. Am J PhysiolRenal Physiol. 2012;303:F1145–50.

42. Mer kle M, Ribeiro A, Koppel S, et al. TLR3dependentimmune regulatory functions of human mesangial cells. CellMol Immunol. 2012;9:334–40.

43. Suwanichkul A, Wenderfer SE. Differential expression offunctional Fc-receptors and additional immune complexreceptors on mouse kidney cells. Mol Immunol.2013;56:369–79.

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45. Ballermann BJ. Contribution of the endothelium to theglomerular permselectivity barrier in health and disease.Nephron Physiol. 2007;106:19–25.

46. Sis on K, Eremina V, Baelde H, et al. Glomerularstructure and function require paracrine, not autocrine,VEGF-VEGFR-2 signaling. J Am Soc Nephrol.2010;21:1691–701.

47. Lefkowith JB, Schreiner G. Essential fatty aciddeficiency depletes rat glomeruli of resident macrophagesand inhibits angiotensin II–induced eicosanoid synthesis. JClin Invest. 1987;80:947–56. 48. Strutz F, Zeisberg M.Renal fibroblasts and myofibroblasts in chronic kidneydisease. J Am Soc Nephrol. 2006;17:2992–8. 49. Rom agnaniP. Parietal epithelial cells: Their role in health anddisease. Contrib Nephrol. 2011;169:23–36. REVIEW QUESTIONS1. During glomerular �ltration, the passage of largermolecules is restricted by a. �e glycocalyx b. �eglomerular basement membrane c. �e epithelial slitdiaphragm d. All of the above 2. �e podocyte is adi�erentiated cell that provides a static barrier toltration. a. True b. False 3. Inc rease in which of thefollowing does not increase glomerular �ltration? a.E�eren t arteriolar resistance b. Glom erular capillaryhydrostatic pressure c. Glom erular capillary oncoticpressure d. Glo merular capillary blood �ow e. K f 4.Which of the following does not increase macromolecularclearance by the glomerulus? a. Fever b. Shock c.Flexible molecules d. Hypertrophy 5. Fenestration of theglomerular endothelium is maintained in part by productionof a. VEGF b. TGF-β c. COX-2 d. Endothelin e.Glycosaminoglycans ANSWER KEY 1. d 2. b 3. c 4. b 5. a

11 Sodium and volume homeostasis

15. Ares GR, Caceres PS, Ortiz PA. Molecular regulation ofNKCC2 in the thick ascending limb. Am J Physiol RenalPhysiol. 2011;301:F1143–59.

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26. Sch wartz GH, Evan AP. Development of solute transportin rabbit proximal tubule. III. Na-K-ATPase activity. Am JPhysiol. 1984;246:F845–52.

27. Johnson V, Spitzer A. Renal reabsorption of phosphateduring development: Whole-kidney events. Am J Physiol.1986;251:F251–6.

28. Kaskel FJ, Kumar AM, Feld LG, Spitzer A. Renalreabsorption of phosphate during development: Tubularevents. Pediatr Nephrol. 1988;2:129-34.

29. Nei berger RE, Barac-Nieto M, Spitzer A. Renalreabsorption of phosphate during development: Transportkinetics in BBMV. Am J Physiol. 1989;257:F268–74.

30. Seg awa H, Kaneko I, Takahashi A, et al. Growthrelatedrenal type II Na/Pi cotransporter. J Biol Chem.2002;277:19665–72. 31. Shah M, Gupta N, Dwarakanath V, etal. Ontogeny of Na+/H+ antiporter activity in rat proximalconvoluted tubules. Pediatr Res 2000;48:206–10. 32.Twombley K, Gattineni J, Bobulescu IA, et al. Effect ofmetabolic acidosis on neonatal proximal tubuleacidification. Am J Physiol Regul Integr Comp Physiol.2010;299:R1360–8. 33. Becker AM, Zhang J, Goyal S, et al.Ontogeny of NHE8 in the rat proximal tubule. Am J PhysiolRenal Physiol. 2007;293:F255–61. 34. Baum M, DwarakanathV, Alpern RJ, et al. Effects of thyroid hormone on theneonatal renal cortical Na+/ H+ antiporter. Kidney Int.1998;53:1254–8. 35. Gattineni J, Sas D, Dagan A, et al.Effect of thyroid hormone on the postnatal renal expressionof NHE8. Am J Physiol Renal Physiol. 2008;294:F198–204.36. Bau m M, Quigley R. Prenatal glucocorticoids stimulateneonatal juxtamedullary proximal convoluted tubuleacidification. Am J Physiol. 1991;261:F746–52. 37. Bau mM, Biemesderfer D, Gentry D, et al. Ontogeny of rabbitrenal cortical NHE3 and NHE1: Effect of glucocorticoids.Am J Physiol. 1995;268:F815–20. 38. She u JN, Baum M,Bajaj G, et al. Maturation of rabbit proximal convolutedtubule chloride permeability. Pediatr Res. 1996;39:308–12.39. Qui gley R, Baum M. Developmental changes in rabbitproximal straight tubule paracellular permeability. Am JPhysiol Renal Physiol. 2002;283:F525–31. 40. Qui gley R,Harkins EW, Thomas PJ, et al. Maturational changes inrabbit renal brush border membrane vesicle osmotic waterpermeability. J Membr Biol. 1998;164:177–85. 41. Hor sterM. Loop of Henle functional differentiation: In vitroperfusion of the isolated thick ascending segment.

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64. Maa ck T, Atlas SA, Camargo MJ, et al. Renalhemodynamic and natriuretic effects of atrial natriureticfactor. Fed Proc. 1986;45:2128–32. 65. Cogan MG. Atrialnatriuretic factor can increase renal solute excretionprimarily by raising glomerular filtration. Am J Physiol.1986;250:F710–4. 66. Gar vin JL. ANF inhibitsnorepinephrine-stimulated fluid absorption in rat proximalstraight tubules. Am J Physiol. 1992;263:F581–5. 67.Harris PJ, Thomas D, Morgan TO. Atrial natriuretic peptideinhibits angiotensin-stimulated proximal tubular sodiumand water reabsorption. Nature. 1987;326:697–8. 68. Nonoguchi H, Sands JM, Knepper MA. Atrial natriuretic factorinhibits vasopressin-stimulated osmotic water permeabilityin rat inner medullary collecting duct. J Clin Invest.1988;82:1383–90. 69. Knepper MA, Lankford SP, Terada Y.

Renal tubular actions of ANF. Can J Physiol Pharmacol.1991;69:1537–45. 70. Nonoguchi H, Sands JM, Knepper MA.ANF inhibits NaCl and fluid absorption in corticalcollecting duct of rat kidney. Am J Physiol. 1989;256(1 Pt2):F179–86. 71. Adr ogue HJ, Madias NE. Hyponatremia. NEngl J Med. 2000;342:1581–9. 72. Jovanovich A, Berl T.Mortality and serum sodium in CKD-yet another U-shapedcurve. Nat Rev Nephrol. 2012;8:261–3. 73. Ber l T,Quittnat-Pelletier F, Verbalis JG, et al. Oral tolvaptanis safe and effective in chronic hyponatremia. J Am SocNephrol. 2010;21:705–12. 74. Sch rier RW, Gross P,Gheorghiade M, et al. Tolvaptan, a selective oralvasopressin V-2-receptor antagonist, for hyponatremia. NEngl J Med 2006;355:2099–112. 75. Verbalis JG, Adler S,Schrier RW, et al. Efficacy and safety of oral tolvaptantherapy in patients with the syndrome of inappropriateantidiuretic hormone secretion. Eur J Endocrinol.2011;164:725–32. 76. Adrogue HJ, Madias NE. Hypernatremia.N Engl J Med. 2000;342:1493–9. REVIEW QUESTIONS 1. Whichnephron segment reabsorbs salt but not water? a. �ickascending limb b. Proximal tubule c. Cortical collectingduct d. �ick descending limb e. None of the above 2. Apatient with congestive heart failure has intractablehyponatremia. Which drug should be considered in themanagement? a. A nonsteroidal anti-in�ammatory agent b.Morphine c. Tolvaptan d. Vasopressin e. Dexamethasone

3. In comparison to the adult kidney, the neonatal kidneyis characterized by:

a. Fewer glomeruli

b. Fewer tubules

c. Inability to dilute urine

d. Inability to concentrate urine

e. None of the above

4. A neonatal patient presents with a serum sodium of 154mEq/L. You suspect diabetes insipidus. Your initialevaluation should include all of the following except:

a. A family history

b. Determination of how the child is fed

c. A water deprivation test

d. A urine osmolality

e. An assessment of volume status of the child 5. Whichstatement about the collecting tubule is incorrect? a. Itis responsive to aldosterone. b. It is responsive tovasopressin. c. It reabsorbs 1% to 3% of the �lteredsodium. d. It has a lumen positive potential di�erence.e. It has an apical epithelial sodium channel. ANSWER KEY1. a 2. c 3. e 4. c 5. d

12 Potassium homeostasis

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REVIEW QUESTIONS

1. A 16-year-old girl is noted to have a plasma K + concen

tration of 7.0 mEq/L with peaked T waves on ECG. �e

first step of management should be:

a. Administration of IV insulin with glucose

b. Administration of IV sodium bicarbonate c. Administration of nebulized albuterol d. Administration of IVcalcium gluconate e. Administration of IV furosemide 2.Severe hypokalemia may be associated with: a. Hyp otensionb. Rena l concentrating defect c. Skeletal muscle weaknessd. ST depression and appearance of U wave on ECG e. All ofthe above 3. K + is freely �ltered in the glomerulus. �emajority of �ltered K + is reabsorbed in the ________,and the net urinary K + secretion, and thus excretion,occurs in the ____________. a. TALH; distal nephron(distal convoluted tubule and collecting duct) b.Proximal tubule; distal nephron (distal convoluted tubuleand collecting duct) c. Distal nephron (distal convolutedtubule and collecting duct); TALH d. Proximal tubule; TALHe. Distal nephron (distal convoluted tubule and collectingduct); proximal tubule 4. A 10-year-old patient withhistory of acute lymphoblastic anemia is noted to be inseptic shock and disseminated intravascular coagulation.She is paralyzed with succinylcholine for intubation andplaced on pressors for hypotension. Her sedation ismaintained with propofol, and the patient requires multipleunits of pRBCs for severe anemia. Arterial blood gas (ABG)reveals that she is acidotic, with an elevated lactate.Her ABG also reveals a K + of 7.5 mEq/L. �e team sends o�a sample to verify the K + result. You are concerned thatthe value is real because: a. Succinylcholine can promoteK + release from muscle cells. b. �e patient may havesustained acute kidney injury secondary to herhypotension. c. �e patient received a large K + load viaboth intravascular hemolysis and pRBC transfusion. d. Allof the above. 5. An 8-year-old boy with obstructiveuropathy is noted to have chronic hypokalemia and non-gapmetabolic acidosis. Despite his acidosis, his urine pHremains 6.0. His urine is negative for glucose and

protein. Given his underlying uropathy, the patient mostlikely has: a. Type 1 RTA involving the inability of theproximal tubule to reabsorb HCO 3 – b. Type 1 RTAinvolving the inability of the distal nephron to secrete H+ c. Type 2 RTA involving the inability of the proximaltubule to reabsorb HCO 3 – d. Type 2 RTA involving theinability of the distal nephron to secrete H + 6. A2-week-old girl is brought to the emergency department forvomiting and lethargy. She is noted to have thready pulsesand poor capillary re�ll. She has not yet regained birthweight. Samples for CBC, chemistry,

VBG, blood culture, urine culture, and CSF culture are

sent to the laboratory, and the patient is started on IV

antibiotics. Results are signi�cant for acidosis, severe

hyponatremia and hyperkalemia. Based on the patient’s

presumed diagnosis, you expect urine electrolytes to

show:

a. FeNa <1%, TTKG > 8

b. FeNa <1%, TTKG > 8

c. FeNa <1%, TTKG < 4

d. FeNa >10%, TTKG < 4

e. FeNa >10%, TTKG > 8

FeNa = fractional excretion of sodium; TTKG = transtubularpotassium gradient.

7. Patients with nephrotic syndrome are predisposed to

developing hypokalemia because of:

a. Treatment with loop diuretics

b. Impaired reabsorption of �ltered K +

c. Secondary hyperaldosteronism

d. Increased K + �ltration by the glomerulus

e. Choices a and c

8. Bartter syndrome is characterized by the following

derangements:

a. Hypernatremia, hypochloremia, hyperkalemia,hyperprostaglandinemia, metabolic alkalosis

b. Hyponatremia, hyperchloremia, hypokalemia,hypoprostaglandinemia metabolic acidosis c. Hyponatremia,hypochloremia, hypokalemia, hyperprostaglandinemia,metabolic alkalosis d. Hypernatremia, hyperchloremia,hyperkalemia, hyperprostaglandinemia, metabolic acidosisANSWER KEY 1. d 2. e 3. b 4. d 5. b 6. d 7. e 8. c

13 Disorders of mineral metabolism

Figure 13.13 A suggested algorithm for evaluation ofhyperphosphatemia in children.

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REVIEW QUESTIONS

1. All of the following hormones have a net e�ect of reduc

ing serum phosphorus values except:

a. Parathyroid hormone

b. Calcitonin

c. Calcitriol

d. FGF-23

2. Which of the following conditions leads to

hypocalcemia?

a. Pseudohypoparathyroidism

b. Jansen syndrome

c. Vitamin A intoxication

d. �yrotoxicosis

3. When conducting an evaluation of hypocalcemia,

which of the following blood levels WILL NOT be

a�ected by recent administration of intravenous cal

cium therapy?

a. Parathyroid hormone

b. 25(OH) vitamin D

c. Ionized calcium

d. 1,25(OH) 2 vitamin D

4. Hypophosphatemia in Fanconi syndrome leads to

which of the following hormonal changes?

a. Elevated blood FGF-23 levels

b. Elevated blood cortisol levels

c. Lowered blood levels of calcitriol

d. No distinct pattern in calciotropic hormones

e. Elevated blood levels of calcitonin

5. Which of the following segments of the kidney handle

the majority of magnesium homeostasis

A. Proximal tubule

B. �ick ascending limb

C. �in ascending limb

D. Distal convoluted tubule

E. Collecting ducts

a. D and E

b. B and D

c. A and C

d. A and B

e. All of the above

6. Which of the following is not associated with

hypophosphatemia?

a. Tumoral calcinosis

b. Refeeding syndrome

c. XLH

d. Calcitonin therapy

7. Ionized calcium is the biologically active component of

total body calcium and comprises: a. 50% of the total bodycalcium b. 1% of the serum calcium c. 1% of the totalbody calcium d. 50% of the serum calcium 8. �e vastmajority of phosphorus handling occurs in this part of thenephron: a. Proximal tubule b. Loop of Henle c. Distaltubule d. Collecting duct 9. Which of the following isnot associated with hypomagnesemia? a. Chronic diarrheab. Addison disease c. Gitelman syndrome d. Loop diuretics10. When calculating the fractional excretion of magnesium,

the plasma magnesium must be multiplied by 0.7 because:a. �e majority of magnesium is albumin bound. b. �emajority of magnesium is not ultra�ltrable. c. �at is theultra�ltrable percentage of magnesium d. �at is thepercentage of magnesium that is reabsorbed distally. ANSWERKEY 1. c 2. a 3. b 4. d 5. d 6. d 7. d 8. a 9. b10. c

14 Acid-base homeostasis

As discussed previously, the acid-base homeostasis

is determined by respiratory function and metabolic

function. �e challenge has always been to determine

how much of a disturbance is due to the respiratory

or the metabolic components. �e fundamentals of

acid-base physiology were developed during the early

to mid-20th century. Much of this information is

reviewed by Davenport. 2 Henderson had expressed theionization reaction

for a general acid using the principle of mass action

that had been developed in the late 19th century.

Hasselbalch then converted the Henderson equation

into the familiar logarithmic form that is well known

as the Henderson–Hasselbalch equation. As tech

niques improved for the measurement of the com

ponents of the blood gases (i.e. pH and pCO 2 ) e�orts

to determine the two components, respiratory versus

metabolic, began to develop. �e �rst was the stan

dard base. �is was measured by taking the sample of

blood and allowing it to equilibrate with gas to yield

a pCO 2 of 40 mm Hg. �us, a sample with a low stan

dard bicarbonate would indicate a metabolic acidosis. �econcept of base excess was then developed. It is

de�ned as the amount of acid or base needed to titrate the

bicarbonate concentration to 24 mEq/L while keeping the

pCO 2 at 40 mm Hg. �e advantage to this approach was

that it would also take into account the other bu�ers pres

ent in the blood sample, including hemoglobin. During

this time, the approach taken by investigators in Boston

was directed at estimating the predicted values of the

blood gas determinants to understand the patient’s acid

base disturbance, while the approach in Copenhagen was

based on the measured base excess. �is resulted in the

“Great Trans-Atlantic Acid-Base Debate.” 69 Currently,

most physicians use the base excess approach. Morerecently, Stewart reintroduced the concept of

the “strong ion di�erence.” 70 �is is a more physico

chemical approach to the understanding of acid-base

physiology. �e merits of this approach continue to

be debated. 71–74 Even the more practical tools that are

used in the assessment of the patient with acid-base

disorders have evolved. �e acid-base nomogram (see

Figure 14.5) used to be complicated and di�cult to

use, but mobile platform adoption and computing

so�ware are making its clinical applications easier. 75 �ecauses of increased anion gap acidosis have

shi�ed over time. �e occurrence of paraldehyde

overdose is rare, but the �nding of 5-oxoproline over

dose has been reported several times. �us, the mne

monic for increased anion gap acidosis, MUDPILES,

becomes less relevant. A new mnemonic for the 21st

century designated GOLD MARK (see Table 14.2)

has been proposed by Mehta and colleagues. 76

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51. Fenves AZ, Kirkpatrick HM, 3rd, Patel VV, et al.Increased anion gap metabolic acidosis as a result of5-oxoproline (pyroglutamic acid): A role foracetaminophen. Clin J Am Soc Nephrol. 2006;1:441–7.

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61. Kennedy JD, Dinwiddie R, Daman-Willems C, et al.Pseudo-Bartter’s syndrome in cystic fibrosis. Arch DisChild. 1990;65:786–7.

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65. Luk e RG, Galla JH. It is chloride depletion alkalosis,not contraction alkalosis. J Am Soc Nephrol.2012;23:204–7. 66. Shaer AJ. Inherited primary renaltubular hypokalemic alkalosis: A review of Gitelman andBartter syndromes. Am J Med Sci 2001;322:316–32. 67. Javaheri S, Kazemi H. Metabolic alkalosis and hypoventilationin humans. Am Rev Respir Dis. 1987;136:1011–6. 68.Javaheri S, Shore NS, Rose B, Kazemi H. Compensatoryhypoventilation in metabolic alkalosis. Chest.1982;81:296–301. 69. Seve ringhaus JW. Siggaard-Andersenand the “Great Trans-Atlantic Acid-Base Debate.” Scand JClin Lab Invest Suppl. 1993;214:99–104. 70. Morgan TJ. The

Stewart approach: One clinician’s perspective. ClinBiochem Rev. 2009;30:41–54. 71. Kurtz I, Kraut J,Ornekian V, Nguyen MK. Acidbase analysis: A critique of theStewart and bicarbonate-centered approaches. Am J PhysiolRenal Physiol. 2008;294:F1009–31. 72. Kellum JA.Clinical review: Reunification of acidbase physiology. CritCare. 2005;9:500–7. 73. Sig gaard-Andersen O,Fogh-Andersen N. Base excess or buffer base (strong iondifference) as measure of a non-respiratory acid-basedisturbance. Acta Anaesthesiol Scand Suppl.1995;107:123–8. 74. Seve ringhaus JW. Blood gascalculator. J Appl Physiol. 1966;21:1108-16. 75. Pronicka E, Piekutowska-Abramczuk DH, Popowska E, et al.Compulsory hyperventilation and hypocapnia of patientswith Leigh syndrome associated with SURF1 gene mutationsas a cause of low serum bicarbonates. J Inherit Metab Dis.2001;24:707–14. 76. Meh ta AN, Emmett JB, Emmett M. GOLDMARK: An anion gap mnemonic for the 21st century. Lancet.2008; 372:892. REVIEW QUESTIONS 1. A 3-year-old boypresents with a 3-week history of progressive eyeswelling. He also has some swelling in his legs, and hismom reports his abdomen to be more distended. Onexamination, his blood pressure is 110/50 mm Hg and heartrate is 85 beats/min. He is afebrile. He has 2+periorbital edema and 2+ pitting edema of his legs. Hiscardiac and lung examinations were normal. His urinalysisshowed 4+ protein and is negative for blood. His serumchemistries are creatinine, 0.3 mg/dL; sodium, 132 mEq/L;potassium, 4.5 mEq/L; chloride 107 mEq/L; and bicarbonate,25 mEq/L. �is yields an anion gap of zero. Which of thefollowing is the most likely cause of the low anion gap?a. �e laboratory made an error. b. �e serum calcium mustbe elevated.

c. His gamma-globulin fraction must be elevated.

d. His serum albumin is very low.

e. He has bromide intoxication.

2. A 1-year-old infant was admitted with a 3-day history ofdiarrhea. �e laboratory analysis on the day of admissionrevealed sodium, 135 mEq/L; chloride, 115 mEq/L; andbicarbonate 15 mEq/L. A�er 2 days, the diarrhea hasstopped and the patient has been volume expanded with 0.9%saline, the electrolytes were measured again and found tobe sodium 138 mEq/L; chloride, 115 mEq/L; and bicarbonateof 17 mEq/L. �e urinary electrolytes were found to besodium of 35 mEq/L; potassium 75 mEq/L; and chloride of105 mEq/L. �e urine pH was 7.0. �e most likely explanation

for these �ndings is:

a. �e patient has distal RTA.

b. �e patient has cystinosis.

c. �e 0.9% saline has caused dilutional alkalosis.

d. �e ability to increase ammoniagenesis is impairedbecause of the patient’s age.

3. A 15-year-old male patient has reportedly attemptedsuicide by drinking antifreeze containing ethylene glycol.His electrolytes were found to be sodium, 142 mEq/L;chloride, 111 mEq/L; and bicarbonate, 21 mEq/L. Otherlaboratory �ndings were glucose, 72 mg/dL, BUN, 28 mg/dL;and serum osmolality, 345 mOsm/kg water. �e best evidencethat he actually drank the ethylene glycol is:

a. �e history of drinking antifreeze

b. �e elevated anion gap

c. �e high osmolar gap

d. No evidence for ethylene glycol ingestion

4. A 14-year-old female presents with a 3-week history ofpolyuria and polydipsia. �e family also reports that shehas lost 6 lb during this period. On examination, her bloodpressure is 110/59 mm Hg, heart rate is 140 beats/min, andrespiratory rate is 26 breaths/min. Serum chemistriesdemonstrated sodium, 132 mEq/L; potassium, 5.8 mEq/L;chloride, 98 mEq/L; and bicarbonate, 8 mEq/L (anion gap,26). Her serum glucose was 820 mg/dL. Her urinalysisreveals no protein or blood, but had 4+ glucose. Her aniongap is most likely elevated because of:

a. Decreased serum albumin

b. Increased serum acetoacetate

c. Increased serum acetone

d. Increased serum calcium

e. Increased serum lactate

5. �e primary source of acid in our diet is:

a. Fatty acids

b. Citric acid

c. Phosphate

d. Ascorbic acid

e. Sulfur-containing amino acids

6. A 10-kg patient generates 10 mEq of H + /day that needto be excreted in her urine. If the patient’s urine had nobu�ers and he made 1 L of urine, what would be the �nal pHof the urine? a. 1 b. 2 c. 5 d. 6 e. Cannot calculatewith the given information 7. A 6-week-old male infant hashad nonbilious emesis for the past 2 days and appearsvolume depleted. �e electrolyte values were sodium, 132mEq/L; potassium, 2.8 mEq/L; chloride, 88 mEq/L; andbicarbonate 36 mEq/L. �e most likely source for the lossof his potassium is: a. Emesis b. Stool c. Urine d. Hehas not lost any potassium, but it has shi�ed into theintracellular compartment e. Sweat 8. A 2-year-old,ex–29-week preterm infant with bronchopulmonary dysplasiais being seen for diarrhea. He has lost 0.6 kg in the past2 days and now weighs 9.5 kg. His blood pressure is 98/45mm Hg, and his heart rate is 112 bpm. His respiratory rateis 32 breaths/ min, and his lungs have coarse bronchithroughout. His skin turgor is decreased, with positivetenting. Laboratory studies revealed sodium, 136 mEq/L;potassium, 3.6 mEq/L; chloride, 90 mEq/L; and bicarbonate,24 mEq/L. An arterial blood gas sample showed the pH to be7.22 and pCO 2 to be 60 mm Hg. Serum creatinine is 0.5mg/dL. �e most likely explanation for these �ndings is: a.e laboratory made an error in the ABG result. b. �epatient has acute respiratory acidosis that isuncompensated. c. �e patient has chronic respiratoryacidosis with acute metabolic acidosis. d. �e patientmust have had some vomiting. 9. A 3-year-old infant isbeing evaluated for stridor and hyperventilation. Duringthe workup, serum electrolyte examination results revealedsodium, 138 mEq/L; potassium, 4.3 mEq/L; chloride, 108mEq/L; and bicarbonate, 15 mEq/L. To assess the concernregarding the low bicarbonate, the most appropriate nextstep would be: a. Perform a cortisone stimulation test.b. Obtain arterial blood gas sample to assess pH and pCO 2. c. Collect urine for anion gap. d. Perform bicarbonateloading to determine transport maximum for bicarbonate.10. A 13-year-old female presents for the evaluation ofhypertension. Her blood pressure is 165/112 mm Hg. Herfamily history is positive for many individuals with

hypertension, including her mother and two uncles. Herphysical examination is otherwise normal. Laboratoryvalues showed sodium, 145 mEq/L; potassium, 2.8 mEq/L;chloride, 99 mEq/L; and bicarbonate 36 mEq/L. An arterialblood gas has a pH of 7.5 and pCO 2 50 mm Hg. Her urinaryelectrolytes were sodium, 78 mEq/L; potassium 56 mEq/L;and chloride, 148 mEq/L. �ese laboratory values wouldindicate:

a. She is wasting chloride and should be given extrachloride.

b. She most likely has renal tubular acidosis.

c. She needs to be examined for chronic lung disease.

d. She has chloride-unresponsive alkalosis. ANSWER KEY 1.d 2. d 3. c 4. b 5. e 6. b 7. c 8. c 9. b 10. d

15 Water homeostasis

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Improving the clinical management of hypernatremicdehydration: Observations from a study of 67 infants withthis disorder. Clin Pediatr (Phila). 1977;16:411–7. REVIEWQUESTIONS 1. A 3-month-old male infant presents withseizures. He is euvolemic on examination. Initiallaboratory studies include serum sodium of 118 mEq/L withserum osmolality 240 mOsm/kg H 2 O and urine osmolality85 mOsm/kg H 2 O. Further investigation should be directedtoward: a. Family history of diabetes insipidus b. Homepreparation of infant formula c. Central nervous systeminfection as a cause of SIADH d. History of sustainedfever with increased insensible losses 2. A teenage malepatient presents with altered mental status and is foundto have a cerebrospinal �uid specimen positive for herpessimplex virus by polymerase chain reaction. He is mildlyvolume depleted and hypernatremic on admission. What isthe most likely cause of his hypernatremia? a. Table saltingestion b. Poor �uid intake related to altered mentalstatus c. Nephrogenic diabetes insipidus d. Surreptitiousdiuretic use 3. A�er a few days the patient described inquestion 2 returns to his usual diet. He then developshyponatremia with serum sodium of 125 mEq/L, SOsm 258mOsm/kg H 2 O, and UOsm 300 mOsm/kg H 2 O. He isclinically euvolemic. He most likely has: a. Primarypolydipsia related to increased thirst from hypothalamicdysfunction b. Pseudohyponatremia c. Central diabetesinsipidus d. SIADH

4. A 4-week old male infant is admitted with hypovolemia,failure to thrive, and chronic irritability. He ishypernatremic (serum sodium of 159 mEq/L) with UOsm 50mOsm/kg H 2 O. �e most likely cause of his hypernatremiais: a. Child abuse with chronic �uid deprivation b.Chronic diarrhea c. Nephrogenic diabetes insipidus d.Chronic vomiting

5. A 6-month-old male infant with known congenitalX-linked nephrogenic diabetes insipidus has been vomitingeverything he eats or drinks for the past 36 hours. Onpresentation, his weight is decreased 1 kg from baseline.His is afebrile with heart rate 165 bpm and capillaryre�ll 4 seconds. Which of the following parenteral �uidtherapies is most appropriate at this time? a. Fluidbolus with normal saline b. Fluid bolus with D5W c. D50.5 NS at maintenance rate d. D5 0.2 NS at maintenancerate

6. A 16-year-old female patient presents to the adolescentmedicine clinic with fatigue and recent-onset headache. Sheis mildly volume depleted with weight stable from 1 month

ago at 37 kg. Laboratory tests reveal serum sodium of 122mEq/L, SOsm 250 mOsm/kg H 2 O, urine chloride 47 mEq/L,and UNa 55 mEq/L. �e most likely cause of her hyponatremiais: a. Surreptitious diuretic use b. Chronic laxativeabuse c. Bulimia with chronic vomiting d. Primarypolydipsia as a means to reduce hunger

7. A 3-year-old girl undergoes a water deprivation test forpolyuria and polydipsia. Over the course of a 6-hour test,serum sodium increases from 139 to 142 mEq/L, and UOsmchanges from 250 mOsm/kg H 2 O to 850 mOsm/kg H 2 O. �emost likely cause of the polyuria is: a. Primarypolydipsia b. Nephrogenic diabetes insipidus c. Partialnephrogenic diabetes insipidus d. Central diabetesinsipidus 8. A 3-year-old boy undergoes a waterdeprivation test for polyuria and polydipsia. Over thecourse of a 6-hour test, serum sodium increases from 142to 148 mEq/L, whereas UOsm remains lower than 100 mOsm/kgH 2 O. dDAVP is administered and UOsm increases to 850mOsm/kg H 2 O. �e most likely cause of the polyuria is: a.Primary polydipsia b. Nephrogenic diabetes insipidus c.Partial nephrogenic diabetes insipidus d. Central diabetesinsipidus 9. A 12-month-old boy presents with hyponatremicseizures. He is euvolemic. �e following treatment shouldbe provided now: a. Hypertonic saline b. Fluidrestriction c. Conivaptan d. Normal saline bolus 10. A12-month-old boy presents with hypernatremic dehydrationwith associated seizures. Serum sodium is 162 mEq/L.Following �uid resuscitation, his �uid management planshould include: a. Administer normal saline because thishas a lower concentration than the current serum sodium.b. Provide maintenance parenteral �uid support. c.Calculate and correct the free water de�cit whileproviding additional support for maintenance and ongoinglosses. d. Administer D5 0.2 NS at maintenance. ANSWER KEY1. b 2. b 3. d 4. c 5. a 6. a 7. a 8. d 9. a 10.c

16 Nephrotic syndrome

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174. Rei ser J, Gupta V, Kistler AD. Toward the developmentof podocyte-specific drugs. Kidney Int. 2010;77:662–8.REVIEW QUESTIONS 1. �e most likely �nding on kidneyhistopathologic examination for a 2-year-old child withsteroid-sensitive nephrotic syndrome is: a. Minimal changenephrotic syndrome b. Focal segmental glomerulosclerosisc. Membranous nephropathy d. Membranoproliferative

glomerulonephritis e. Mesangial proliferativeglomerulonephritis 2. Sequence variants in the followinggene account for a large fraction of observed FSGS risk inAfrican Americans: a. NPHS2 b. WT1 c. MYH9 d. APOL1e. COQ6 3. Which of the following is not a component ofthe “under�ll hypothesis” of edema formation in nephroticsyndrome? a. Decreased plasma oncotic pressure withleakage of �uid into the interstitial space b.Hypovolemia with renal hypoperfusion c. Activation of therenin-angiotensin-aldosterone system d. Vasopressinrelease e. Increased sodium reabsorption through ENaC 4.Children with an initial presentation of nephroticsyndrome should have all of the following performed,except: a. Complement C3 level b. Genetic testing forNPHS2 mutations c. Serum albumin d. PPD e. Cholesterollevel 5. �e following factors cause increased risk forthrombosis in nephrotic syndrome, except: a. Increasedproduction of protein S by the liver b. Loss of ATIII inthe urine c. Platelet hyperaggregability d. Diminishedbrinolytic activity e. Hyperlipidemia 6. Complications offurosemide therapy for treatment of edema in nephroticsyndrome can include all of the following except: a.Hypokalemia b. Acute kidney injury c. Nephrocalcinosisd. Metabolic acidosis e. �rombosis 7. Live vaccines(varicella, MMR) can be given to which population ofchildren with nephrotic syndrome? a. Children receivingcyclophosphamide b. Children receiving 2 mg/kg/day ofprednisone

c. Children who have been o� high-dose steroids for 1 month

d. Children who have been o� high-dose steroids for 1 week

e. Children receiving 2 mg/kg/day of prednisone andexposed to varicella

8. Complications of 25% albumin infusions in nephroticpatients can include all of the following, except:

a. Pseudotumor cerebri

b. Respiratory distress

c. Congestive heart failure

d. Acute hypertension

e. Pulmonary edema

9. Which of the following is most suggestive of a cause of

nephrotic syndrome other than MCNS?

a. Age 2 years

b. No hematuria

c. Anasarca

d. Stage II hypertension

e. Normal complement 3

10. A�er receiving intravenous furosemide, a 2-year-oldgirl with SSNS develops gross hematuria and hypertension.What study should be performed �rst to evaluate for thecause of the hematuria?

a. Urine calcium-to-creatinine ratio

b. Urine protein-to-creatinine ratio c. Lasix renogram d.Renal ultrasound with Doppler e. Voiding cystourethrogramANSWER KEY 1. a 2. d 3. e 4. b 5. a 6. d 7. c 8. a9. d 10. d

17 Primary podocytopathies

SUMMARY

Nephrotic syndrome is one of the most commonly

encountered kidney diseases in children. Advances in

genetic testing and molecular diagnostics have allowed

for better classi�cation of the disease. Moreover, ani

mal and human research studies have contributed

to an improved understanding of the underlying

pathophysiology. However, many questions remain

unanswered in terms of the pathogenesis behind the

primary glomerular injury, as well as the mechanisms

of edema and dyslipidemia. Furthermore, the path

ways by which the most commonly used medications,

such as corticosteroids, exert their e�ect have not been

fully elucidated. Despite the monumental improve

ments in the mortality and morbidity of children with

this disease, many children with refractory SRNS,

particularly those with underlying genetic mutations,

may not fully respond to the currently available thera

peutic options. Unfortunately, such children continue

to face signi�cant challenges in regard to their quality

of life, and they remain at increased risk for treatment

related toxicities as well as infectious, thrombotic, and

cardiovascular complications. Additional research is

needed to promote a deeper understanding of the

underlying pathogenesis and to provide a wider spec

trum of safe and e�ective treatments.

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442. Fakhouri F, Bocquet N, Taupin P, et al.Steroidsensitive nephrotic syndrome: From childhood toadulthood. Am J Kidney Dis 2003;41:550–7. REVIEW QUESTIONS1. A 3-year-old boy presents with bilateral periorbitalswelling and abdominal distention. Blood pressure is104/66 mm Hg. Urine dipstick revealed 4+ proteinuria andmoderate blood. You discuss the likelihood of response tosteroid therapy with the family. Children who are leastlikely to respond to corticosteroids include: a. Asiansb. African Americans c. Hispanics d. Native Americans e.Whites 2. A 16-year-old female patient with morbid obesityis being referred by her primary physician for evaluationof persistent proteinuria. Physical examination issigni�cant for morbid obesity and acanthosis nigricans.Urinalysis showed 2+ proteinuria but no otherabnormalities. She is normotensive. A spot urineprotein-tocreatinine ratio on a �rst morning urine specimenwas 1.6 mg/mg. You anticipate that her renal biopsy willmost likely show: a. Glomeruli of large diameter b.Subepithelial and subendothelial dense deposits c. Di�usefoot process e�acement d. Splitting and proliferation ofthe glomerular basement membrane e. Increased number anddensity of podocytes 3. Acceptable options for thetreatment of children with steroid-resistant nephroticsyndrome include all of the following except: a. Oralcyclophosphamide b. Mycophenolate mofetil c. Tacrolimusd. Cyclosporine e. Use of angiotensin-converting enzymeinhibitors for refractory proteinuria 4. A 6-year-oldgirl presents with progressive generalized swelling of 2weeks’ duration. She has no reported changes in her urinecolor. Blood pressure measurements in the o�ce are normal.Laboratory workup reveals high-grade proteinuria andsevere hypoalbuminemia. Serum complement levels are normal.You suspect minimal change disease, and you inform parentsthat her prognosis is most closely linked to the followingparameter: a. Presence or absence of systemic hypertensionon presentation b. Age at onset less than 10 years c.Grade of peripheral edema on initial presentation d.Clinical response to oral prednisolone e. Detection anddegree of microscopic hematuria on initial urine dipstick

5. A 12-year-old boy with history of steroid-resistant

nephrotic syndrome presents for follow-up. He has

been treated with cyclosporine, prednisone, lisinopril,

and amlodipine for the last 5 months. His cyclospo

rine levels have been monitored periodically and have

been consistently in the therapeutic range. Laboratory

workup obtained this morning again showed therapeu

tic cyclosporine level, persistent high-grade proteinuria,

and hypoalbuminemia. His serum creatinine is elevated

at 1.5 mg/dL. You also note that his most recent previ

ous creatinine level obtained 8 weeks ago was 0.8 mg/

dL. �e most appropriate next step in the management

of this patient is to:

a. Admit to the hospital for albumin and Lasix infusions.

b. Discontinue lisinopril.

c. Stop cyclosporine therapy and replace with tacrolimus.

d. Encourage oral hydration and repeat kidney functiontests in 1 week.

e. Arrange for a repeat renal biopsy. 6. A 17-year-oldAfrican-American male patient is recently diagnosed withprimary focal segmental glomerulosclerosis (FSGS). A highlikelihood of steroid response has been associated withthe following histologic variant: a. Tip lesion b.Collapsing glomerulopathy c. Perihilar variant d.Cellular variant e. Classic variant ANSWER KEY 1. b 2. a3. a 4. d 5. b 6. a

18 Nephrotic syndrome in the first yearof life

KEY POINT

Transplanting an a dult kidney into an infant requires

excessive �uids (2500 mL/m 2 /day) to provide ade

quate perfusion of the gra�. SUMMARY NS in the �rst year oflife is a rare, usually severe disease that in most casescan be treated only with RTx a�er nephrectomy of thediseased native kidneys. However, the long-term outcomefor these children critically depends on early diagnosisand early institution of supportive treatment withsubsequent PD and RTx.

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al. Nephrosis in two siblings with infantile sialic acidstorage disease. Eur J Pediatr. 1990;149:477–82. 59.Besbas N, Bayrakci US, Kale G, et al.Cytomegalovirusrelated congenital nephrotic syndrome withdiffuse mesangial sclerosis. Pediatr Nephrol.2006;21:740–2. 60. Sha hin B, Papadopoulou ZL, Jenis EH.Congenital nephrotic syndrome associated with congenitaltoxoplasmosis. J Pediatr. 1974;85:366–70. 61. Esterley JR,Oppenheimer EH. Pathological lesions due to congenitalrubella. Arch Pathol. 1969;87:380–88. 62. Ross MJ, KlotmanPE. Recent progress in HIVassociated nephropathy. J Am SocNephrol. 2002;13:2997–3004. 63. Bas ker M, Agrawal I,Bendon KS. Congenital nephrotic syndrome: A treatablecause. Ann Trop Paediatr. 2007;27:87–90. 64. Dud ley J,Fenton T, Unsworth J, et al. Systemic lupus erythematosuspresenting as congenital nephrotic syndrome. PediatrNephrol. 1996;10:752–5. 65. Debiec H, Guigonis V, MougenotB, et al. Antenatal membranous glomerulonephritis due toantineutral endopeptidase antibodies. N Engl J Med.2002;346:2053–60. 66. Hol mberg C, Antikainen M, RönnholmK, et al. Management of congenital nephrotic syndrome ofthe Finnish type. Pediatr Nephrol. 1995;9:87–93. 67. Laakkonen H, Hölttä T, Lönnqvist T, et al. Peritonealdialysis in children under two years of age. Nephrol DialTransplant. 2008;23:1747–53. 68. Laakkonen H, Happonen JM,Marttinen E, et al. Normal growth and intravascular volumestatus with good metabolic control during peritonealdialysis in infancy. Pediatr Nephrol. 2010;25:1529–38.69. Ljungberg P, Holmberg C, Jalanko H. Infections ininfants with congenital nephrosis of the Finnish type.Pediatr Nephrol. 1997;11:148–52. 70. Gellerman J, EhrichJH, Querfeld U. Sequential maintenance therapy withcyclosporine A and mycophenolate mofetil for sustainedremission of childhood steroid-resistant nephroticsyndrome. Nephrol Dial Transplant. 2012;27:1970–8. 71.Stefanidis C, Querfeld U. The podocyte as a target:Cyclosporin A in the management of the nephrotic syndromecaused by WT1 mutations. Eur J Pediatr. 2011;170:1377–82.72. Buescher A, Weber S. The podocytopathies. Eur JPediatr. 2012;171:1151–60. 73. Boyer O, Benoit G,Gribouval O, et al. Mutational analysis of the PLCE1 genein steroid resistant nephrotic syndrome. J Med Genet.2010;47:445–52.

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Q10 supplementation in primary coenzyme Q10 deficiency. NewEngl J Med. 2008;358:2849–50.

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88. van S trahlen KJ, Borzych-Duzalka D, Hataya H, et al.Survival and clinical outcomes of children starting renalreplacement therapy in the neonatal period. Kidney Int.2014;86:168–74. REVIEW QUESTIONS 1. Congenital nephroticsyndrome is best defined as: a. Nephrotic syndrome duringthe �rst year of life b. Nephrotic syndrome during therst 6 years of life c. Nephrotic syndrome during the �rst3 months of life d. End-stage renal disease andproteinuria in infancy e. Proteinuria and hematuria withuremia at birth 2. �e most common causes of congenitalnephrotic syndrome are: a. WT1 mutations b. WT1 and PLCε1mutations c. Neonatal infections d. Galloway-Mowatsyndrome e. NPHS1 and NPHS2 mutations 3. Which of thefollowing is most important in regulating glomerularprotein �ltration? a. �e capillary endothelium b.Mesangial cell function c. �e basement membrane d. �eslit diaphragm e. �e podocyte cell bodies 4. Congenitalnephrotic syndrome secondary to NPHS1 mutation: a. Ismost commonly seen in Turkish children b. Is caused by amutation in the podocin gene c. Usually manifests a�er therst 3 months of life d. Is caused by a nephrin genemutation e. Reacts to cyclosporin A medication 5.Congenital nephrotic syndrome secondary to NPHS2 mutation:a. Presents during the �rst month of life b. Ischaracterized by severe NS and ocular malformations c. Iscaused by a mutation in the podocin gene d. Shows DMS inrenal biopsy e. Reacts to ACE inhibitors and indomethacin6. �e most typical symptoms of congenital nephroticsyndrome is (are): a. Severe nephrosis during the �rst 3months of life b. Malformations and end-stage renalfailure c. Hematuria, high fever, and a typical rash d.Proteinuria and gastrointestinal malformations e. Edema,high creatinine level, and high blood pressure during therst months of life 7. Congenital nephrotic syndrome ismost effectively treated by: a. Dialysis and early renaltransplantation b. ACE inhibitors and indomethacin withcyclosporin A c. �e patients recover spontaneously d.Penicillin e. High-dose immunosuppression

8. Which of the following best represents the long-term

outcome of congenital nephrotic syndrome?

a. Remains poor, with death during the �rst years of life

b. Has improved, because most patients respond to the

medication

c. Is poor regardless of intervention, because the diseasemostly reappears in the gra

d. Is good with early support, dialysis, and renaltransplantation

e. Is poor because gra� survival is still only 50% at 5years ANSWER KEY 1. c 2. e 3. d 4. d 5. c 6. a 7. a8. d

19 Membranoproliferativeglomerulonephritis

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REVIEW QUESTIONS

1. What is the major distinguishing pathologic feature ofthe MPGN kidney biopsy?

a. Immunoglobulin deposition on immuno�uorescence

b. Mes angial interposition into the glomerular basementmembrane

c. Mes angial cell proliferation

d. Pod ocyte e�acement

2. Why w as the name MPGN II changed to dense depositdisease?

a. Only 25 % of patients actually had MPGN.

b. MPG N II is the only MPGN with intramembranous deposits.

c. Dens e deposits were the sole disease-de�ningcharacteristic.

3. Whi ch is the classic laboratory �nding in MPGNpatients?

a. Low platelet count

b. Hyp ocomplementemia

c. Gen etic abnormality

d. Pos itive bacterial cultures

4. Which of the following is not a known cause of secondaryMPGN?

a. Systemic lupus erythematosus

b. Viral infection

c. Licorice intoxication

d. Immunoglobulin de�ciency

5. Name the required immune deposit location for densedeposit disease.

a. Subendothelial deposits

b. Intramembranous deposits

c. Subepithelial deposits

d. Mesangial deposits.

6. What is the ratio of MPGN presentation in childrencompared to that in adults?

a. ¼:1

b. ½:1

c. ¾:1

d. 1:1 7. �e most likely pathologic cause of dense depositdisease is: a. A genetic mutation b. An autoantibody c.A protein inhibitor d. An exposure 8. What is the riskfor end-stage renal disease for a patient with MPGN? a.25% b. 50% c. 75% d. 100% 9. Of the MPGN diseases,which is the most likely to result in end-stage renaldisease? a. DDD b. MPGN I c. MPGN III d. C3GN 10. Whatis the risk for recurrence a�er transplant for MPGN? a.25% b. 50% c. 75% d. 100% 11. Which treatment for MPGNis supported by a randomized controlled trial? a. Steroidtherapy b. None c. Mycophenolate mofetil d. Rituximab12. What is the presentation biomarker that is associatedwith the greatest likelihood of advancing to end-stagerenal disease? a. Proteinuria greater than 2 g b. Degreeof interstitial �brosis on presentation biopsy c. Degreeof creatinine elevation at time of kidney biopsy d.Unknown ANSWER KEY 1. b 2. a 3. b 4. c 5. b 6. a 7.b 8. b 9. a 10. b 11. a 12. d

20 Membranous nephropathy

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REVIEW QUESTIONS

1. Membranous nephropathy is:

a. �e leading cause of nephrotic syndrome in adults

b. �e leading cause of nephrotic syndrome in children c.Idiopathic in most cases, whatever the patient age d.Mainly associated with lupus nephropathy 2. �e diagnosisof membranous nephropathy relies on: a. Nephrotic-rangeproteinuria b. �e age at onset of nephrotic syndrome c.Renal biopsy �ndings of thickened glomerular capillarywall, immunopathology, and electron microscopy showingsubepithelial deposits d. Low circulating C3 and C4 in theplasma 3. �e treatment of idiopathic membranousnephropathy includes all except: a. Prednisone +calcineurin antagonists b. Prednisone + alkylating agentsc. Immunosuppression and ACE inhibitors d.Immunosuppression and ARBs e. Complement blockade byeculizumab 4. Circulating anti-PLA2R antibodies are seenin patients with: a. Membranous nephropathy associated

with systemic lupus erythematosus b. Membranousnephropathy associated with drugs and toxins c. Primaryor idiopathic membranous nephropathy d. Membranousnephropathy associated with hepatitis B 5.Corticosteroids, as a monotherapy, can producelong-lasting remission in patients with membranousnephropathy. a. True b. False ANSWER KEY 1. a 2. c 3.e 4. c 5. b

21 Acute glomerulonephritis

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REVIEW QUESTIONS

1. �e typical “deposits” in acute poststreptococcal

glomerulonephritis seen by electron microscopy are in

which of the following locations?

a. Mesangial

b. Subendothelial

c. Subepithelial

d. Intramembranous

2. Typical glomerular anti-IgG immuno�uorescence in

acute poststreptococcal glomerulonephritis shows

which of the following patterns?

a. Linear along capillary loops

b. Gran ular along capillary loops

c. Gran ular in mesangium

d. No i mmuno�uorescence 3. Acu te postinfectious

glomerulonephritis most commonly follows infection bywhich of the following organisms? a. Group A β-hemolyticstreptococcus b. Group B β-hemolytic streptococcus c.Group C β-hemolytic streptococcus d. Gro up Cstreptococcus 4. Which of the following is true regardingscabies-associated acute postinfectiousglomerulonephritis? a. �e latent period is longer than intonsillitisassociated disease. b. It is usually not causedby group A β-hemolytic streptococcus. c. Complement C3 istypically not decreased. d. An antigen from Sarcoptesscabiei is present in the glomeruli. 5. Which of thefollowing statements is true regarding the epidemiology ofacute poststreptococcal glomerulonephritis? a. It is morecommon in a�uent societies. b. During epidemics,subclinical disease is more common than symptomaticdisease. c. Epidemics are usually caused by non–group Astreptococci. d. Antibiotic prophylaxis is not e�ective.6. A 9-year-old boy presents with symptomless grosshematuria. He has had a sore throat for 2 days. His basicmetabolic panel is normal. Which of the following is themost helpful diagnostic test? a. Complement C3 level b.Complement C4 level c. �roat culture d. ASO titer 7. A6-year-old girl has painless gross hematuria and pu�yeyes. She denies any recent illness. Her BP is 139/76;BUN, 34 mg/dL; creatinine, 1.3 mg/dL; serum albumin, 2.9g/dL; and complement, C3 23 mg/dL. Urine is positive forblood and protein. Which of the following is the mostappropriate treatment? a. Amoxicillin b. Intravenoussteroids c. Chlorothiazide or furosemide d. Observationonly 8. A 9-year-old boy presents with pu�y eyes andheadache. He remembers having a recent sore throat. His BPis 150/90 mm Hg, and he has mild periorbital and pretibialedema. Blood urea nitrogen (BUN) is 30 mg/dL; creatinine,1.3 mg/ dL; and complement C3, 20 mg/dL. Intravenousnicardipine and furosemide are started to control hishypertension. �e next day his metabolic panel showssodium, 132 mmol/L; potassium, 4.8 mmol/L; chloride, 100mmol/L; carbon dioxide, 20

mmol/L; BUN, 60 mg/dL; and creatinine, 3.2 mg/

dL. Which of the following is the most appropriate

next step?

a. Hemodialysis

b. Continuous venovenous hemo�ltration

c. Renal biopsy

d. Intravenous steroid treatment

9. Hypertension in acute postinfectious glomerulonephri

tis is mainly due to which of the following?

a. Activated sympathomimetic nervous system

b. Decreased glomerular �ltration rate

c. Elevated plasma renin level secondary to nephritis

d. Increased �uid volume expansion resulting fromincreased tubular sodium absorption ANSWER KEY 1. c 2. b3. a 4. a 5. b 6. a 7. c 8. c 9. d

22 Rapidly progressive glomerulonephritisand vasculitis

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2. A 13-year-old girl has hemoptysis and is found to haveserum creatinine of 8.5 mg/dL. Which of the following testresults is most likely to be abnormal? a. ANA b. Anti-GBMantibody c. Complement C3 d. ANCA

3. A 15-year-old girl is found to have proteinuria andserum creatinine of 1.8 mg/dL. A week later her s-Cr is4.8 mg/dL. Her hepatitis C titer is positive. Her renalbiopsy shows crescents in 12 of 18 glomeruli.Immuno�uorescence is most likely to show which of thefollowing capillary loop patterns? a. Linear staining foranti-IgG, negative for C3 b. Granular staining for IgG andC3 c. Granular staining for C3, negative for IgG d.Granular staining for IgG, negative for C3

4. Which of the following statements is true regardingRPGN in children? a. It is less common than in adults. b.e most common cause is anti-GBM antibodies. c. It is afrequent complication of APSGN. d. It is ANCA positive inmost cases.

5. A 17-year-old patient has chronic sinusitis, cough, andoral ulcers. Chest x-ray study shows nodular lungdensities. Laboratory evaluation reveals positive cANCA.Which of the following is the most likely diagnosis? a.Granulomatosis with polyangiitis b. Systemic lupuserythematosus c. Dense deposit disease d. Microscopicpolyangiitis

6. Which if the following is true of PAN? a. Itpredominantly involves small vessels. b. It predominantlyinvolves medium-size vessels. c. It is a common cause ofcrescentic glomerulonephritis. d. Renal histology isindistinguishable from RPGN. 7. Which of the following isthe currently recommended regimen for initiation therapyof severe RPGN? a. Cyclophosphamide and high-dose steroidsonly b. Cyclophosphamide, high-dose steroids and

plasmapheresis c. High-dose steroids and plasmapheresisonly d. Cyclophosphamide and plasmapheresis 8. RPGNcaused by which of the following primary diseases is leastlikely to result in ESRD? a. Goodpasture disease b.Granulomatosis with polyangiitis c. IgA nephropathy d.Eosinophilic granulomatosis with polyangiitis 9. Which ofthe following is true of ANCA? a. It is present in allpatients with pauci-immune RPGN. b. It activatesneutrophils by binding to surface antigens. c. pANCA ispredominantly seen with GPA. d. It is produced in responseto known antigenic stimuli. 10. An 11-year-old girl has a6-week history of malaise and weight loss. Serum BUN andcreatinine are 75 mg/dL and 6.4 mg/dL, respectively.Electrolytes are unremarkable. She is suspected to haveRPGN; additional laboratory evaluation is pending. �e mostappropriate next step is: a. Start intravenous �uids andmonitor kidney function. b. Arrange an immediate renalbiopsy. c. Start cyclophosphamide and high-dose steroids.d. Start intermittent hemodialysis. ANSWER KEY 1. c 2. b3. b 4. a 5. a 6. b 7. b 8. c 9. b 10. b

23 Immunoglobulin A nephropathy andHenoch-Schönlein purpura nephritis

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REVIEW QUESTIONS

1. Which of the following histopathologic features is notincluded as a part of the Oxford classi�cation? a.Mesangial hypercellularity b. Endocapillaryhypercellularity c. Segmental glomerulosclerosis d.Tubular atrophy/interstitial �brosis e. Crescent formation

2. �e increased incidence of IgA nephropathy in Asiancountries such as Japan may be due to all of the following,except: a. True racial or ethnic di�erences in incidenceb. Increased detection through school screening programsc. An aggressive approach by pediatric nephrologists inthese countries for performing renal biopsies in childrenwith isolated microscopic hematuria or low levels ofproteinuria d. Increased serum levels of immunoglobulin Ain these populations

3. On renal biopsy, IgA nephropathy is characterized bywhich of the following: a. Dominant or codominantdeposition of immunoglobulin A, mainly in the glomerularmesangium b. Subepithelial humps c. Patchy foot processe�acement d. Prominent subendothelial deposits e.Apple-green birefringence under polarized light

4. A multi-hit hypothesis may explain the pathogenesis ofIgA nephropathy. �e �rst hit is thought to be due to: a.e presence in the serum of galactose-de�cient (orunderglycosylated) IgA1 in which in some carbohydrate sidechains (O-glycans) of the hinge region terminate inN-acetylgalactosamine (GalNAc) or sialylated GalNac ratherthan galactose b. �e generation of antiglycan antibodiesrecognizing this terminal GalNac c. �e formation ofnephritogenic circulating immune complexes containinggalactose-de�cient IgA1 and antiglycan antibody d.Secretion of extracellular matrix components, induction ofnitric oxide synthase, and the release various mediatorsof renal injury such as angiotensin II, proin�ammatory andpro�brotic cytokines, and growth factors

5. Which of the following statements is false? a. Serumgalactose-de�cient IgA1 level is elevated in approximately75% patients with IgA nephropathy; this is a heritabletrait. b. �e majority of �rst-degree relatives withelevated serum galactose-de�cient IgA1 levels do notdevelop clinical manifestations of IgA nephropathy of HSPnephritis. c. A locus at 6q22-23 named IgAN1 is associatedwith the production of galactose-de�cient immunoglobulinA. d. Susceptibility loci for IgA nephropathy have beenfound on chromosome 6p21 in the major histocompatibilitycomplex and on chromosome 1q32 in the complement factor H(CFH) gene cluster. 6. In the United States, thepercentage of children who have gross hematuria at thetime of presentation with IgA nephropathy isapproximately: a. 10% b. 25% c. 50% d. 75% e. 90% 7.e peak incidence of Henoch-Schönlein purpura is betweenages: a. 1 to 3 years b. 2 to 4 years c. 4 to 6 yearsd. 6 to 8 ye ars e. 10 to 1 2 years 8. �e percentage ofchildren with IgA nephropathy who present with overtnephrotic syndrome is: a. Less than 10% b. 10% to 25% c.25% to 5 0% d. 50% to 75% e. Grea ter than 75% 9. �e diagnosis of IgA nephropathy is dependent on: a. Serumgalactose-de�cient IgA1 and antiglycan antibody levels b.Serum immunoglobulin A levels c. Low C 3 levels d. Genetic testing for IgAN1 e. Examination of cortical renaltissue obtained via kidney biopsy 10. A normal urinalysismay eventually be seen in what percentage of pediatricpatients diagnosed with IgA nephropathy? a. 10% b. 20%c. 33% d. 70% e. 90% 11 . All o f the followingfeatures may predict loss of renal function in childrenand adults with IgA nephropathy, except: a. Serialmeasurements of urinary protein excretion averaged over 6month intervals a�er renal biopsy b. Sev ere histologicfeatures on kidney biopsy c. Hyp ertension d. Rena lfunction at time of presentation e. Pers istent hematuria

12. �e mainstay of treatment for persistent proteinuria inthe setting of IgA nephropathy is: a. High-doseintravenous corticosteroids b. Low-dose oralcorticosteroids c. Angiotensin-converting enzymeinhibitors or angiotensin receptor blockers d.Tonsillectomy e. Cyclophosphamide

ANSWER KEY

1. e

2. d 3. a 4. a 5. c 6. d 7. b 8. a 9. e 10. c 11.e 12. c

24 Thrombotic microangiopathies

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trial. JAMA. 2003;290:1337–44. 140. Perez N, Spizzirri F,Rahman R, et al. Ster oids in the hemolytic uremicsyndrome. Pediatr Nephrol. 1998;12:101–4. 141. Reill, A.Prevention and control of enterohaem orrhagic Escherichiacoli (EHEC) infections: Memorandum from a WHO meeting.World Health Or ganization consultation on prevention andcontrol of enterohaemorrhagic Escherichia coli (EHEC)infections. Bull World Health Organ. 1998;76:245–55. 142.Legendre CM, Licht C, Muus P, et al. T erminal complementinhibitor eculizumab in atypical hemolytic uremicsyndrome. N Engl J Med. 2013;368:2169–81. 143. KavanaghD, Goodship TH, Richards A. Atypical hemolytic uremicsyndrome. Semin Nephrol. 2013;33:508–30. 144. U.S. Foodand Drug Administration. Highlights of PrescribingInformation: Soliris [online], 2011. Available at:http://www .accessdata.fda.gov/drugsatfda_docs/label/2011/125166s172lbl.pdf. AccessedApril 14, 2014. 145. Carr R, Cataland SR. Relapse of aHUSafter discontinuation of therapy with eculizumab in apatient with aHUS and factor H mutation. AnnHematol. 2013;92:845–6. 146. Bresin E, Daina E, Noris M,et al. Outcome of renal transplantation in patients withnon-Shiga toxin-associated hemolytic uremic syndrome:Prognostic significance of genetic background. Clin J AmSoc Nephrol. 2006;1:88–99. 147. Saland JM, RuggenentiP, Remuzzi G; Consensus Study Group. Liver-kidneytransplantation to cure atypical hemolytic uremicsyndrome. J Am Soc Nephrol. 2009;20:940–9. 148. Saland J.Liver-kidney transplantation to cure atypi cal HUS: Stillan option post-eculizumab? Pediatr Nephrol. 2014;29:329–32.

149. Nester C, Stewart Z, Myers D, et al. Pre-emptiveeculizumab and plasmapheresis for renal transplant inatypical hemolytic uremic syndrome. Clin J Am Soc Nephrol.2011;6:1488–94.

150. George JN. Thrombotic thrombocytopenic pur pura. NEngl J Med. 2006;354:1927–35.

151. von Baeyer H. Plasmapheresis in thromboticmicroangiopathy-associated syndromes: Review of outcomedata derived from clinical trials and open studies. TherApher. 2002;6:320–8

152. Rock GA, Shumak KH, Buskard NA, et al. Comparison ofplasma exchange with plasma infusion in the treatment ofthrombotic thrombocytopenic purpura. N Engl J Med.1991;325:393–7.

153. Forzley BR, Sontrop JM, Macnab JJ, et al.: TreatingTTP/HUS with plasma exchange: A single centre’s 25-yearexperience. Br J Haematol. 2008;143:100–6.

154. George JN. Congenital thrombotic thrombocyto penicpurpura: Lessons for recognition and management of raresyndromes. Pediatr Blood Cancer. 2008;50:947–8.

155. Mise K, Ubara Y, Matsumoto M, et al. Long term followup of congenital thrombotic thr ombocy topenic purpura(Upshaw-Schulman syndrome) on hemodialysis for 19 years: Acase report. BMC Nephrol. 2013;14:156.

156. Scully M1, McDonald V, Cavenagh J, et al. A phase 2study of the safety and efficacy of ritux imab with plasmaexchange in acute acquir ed thr ombotic thrombocytopenicpurpura. Blood. 2011;118:1746–53

157. Westwood JP, W ebster H, McGuckin S, et al. Rituximabfor thrombotic thrombocytopenic purpura: Benefit of earlyadministration during acute episodes and use ofprophylaxis to prevent relapse. J Thromb Haemost.2013;11:481–90.

158. Distenfeld A, Oppenheim E. The treatment of acutethrombotic thr ombocytopenic purpura with corticosteroidsand splenectomy: Report of three cases. Ann Intern Med.1966;65:245–51.

159. Cataland SR, Jin M, Ferketich AK, et al. An evaluation of cyclosporin and corticosteroids individually asadjuncts to plasma exchange in the treatment of thromboticthr ombocytopenic purpura. Br J Haematol. 2007;136:146–9.

160. Oakes RS, Siegler RL, McReynolds MA, et al.Predictors of fatality in postdiarrheal hemolytic uremicsyndrome. Pediatrics. 2006;117:1656–62.

161. Matsell DG, White CT. An outbreak ofdiarrheaassociated childhood hemolytic uremic syndrome:The Walkerton epidemic. Kidney Int Suppl. 2009;112:S35–7.

162. Oakes RS, Kirkham JK, Nelson RD, et al. Duration ofoliguria and anuria as predictors of chronic renalrelatedsequelae in post-diarrheal hemolytic uremic syndrome.Pediatr Nephrol. 2008;23:1303–8. 163. Caprioli J, NorisM, Brioschi S, et al. Genetics of HUS: The impact of MCP,CFH, and IF mutations on clinical presentation, responseto treatment, and outcome. Blood. 2006;108:1267–79. 164.Amorosi EL, Ultmann JE. Thrombotic throm bocytopenic

purpura: Report of 16 cases and review of the literature.Medicine (Baltimore). 1966;45:139–59. REVIEW QUESTIONS 1.Which of the following molecules is involved in thepathogenesis of pneumococcal HUS? a. Factor H b.Globotriosyl ceramide (Gb3) c. Membrane cofactor protein(CD46) d. Neuraminic acid e. von W illebrand factorcleaving protease ADAMTS13 2. Whi ch of the followinglaboratory �ndings is associated with pneumococcal HUS butnot seen in atypical HUS? a. Hyp ocomplementemia b. Microangiopathic hemolytic anemia c. Nor mal or slightlyelevated prothrombin time d. Pos itive result of a Coombstest e. Pos itive result of a peanut lectin activity test3. Whi ch of the following is associated with a pooroutcome in pneumococcal HUS? a. Fam ily history of aHUSb. His tory of recurrent pneumococcal infections c. Meningitis d. Sero type of S. pneumoniae e. Sev erity ofthrombocytopenia 4. In the treatment of a patient withpneumococcal HUS, which of the following approaches shouldbe avoided? a. Calcium channel blockers b. Continuousvenovenous hemo�ltration c. Hemodialysis d. Peritonealdialysis e. Transfusion of unwashed packed red blood cells5. In the comparison of children with pneumococcal HUS andSTEC-HUS, which of the following is true? a. Children withpneumococcal HUS are not more likely to require acutedialysis. b. �ere is no gender predisposition in STEC-HUS.c. Children with pneumococcal HUS are more likely to beyounger at presentation. d. Children with pneumococcal HUSare less likely to develop chronic kidney disease. e.Children with STEC-HUS are more likely to require redblood cell and platelet transfusions.

6. In children with STEC-HUS, which of the following E.coli serotypes is most commonly identi�ed? a. O157 b.O104 c. O97 d. O144 e. Nontypable

7. What is the most accurate statement about the Shigaliketoxin that results in diarrhea-associated HUS? a. Itbinds to ceramide receptors on susceptible cells. b. Itbinds only to endothelial cells. c. It binds to the Tantigen on RBCs. d. It inhibits ADAMTS-13. e. It isonly toxic in cows.

8. TMA has been associated with which of the followingmedications? a. Calcineurin inhibitors b.Cyclophosphamide c. Eculizumab d. Erythropoietin e.Rituximab

9. Which of the following is the most common long-termsequela of STEC-HUS? a. CKD stage 3 to 5 b. ESRD c. GImalabsorption d. Proteinuria e. Seizures 10. What is

the most commonly de�ned genetic abnormality in individualswith aHUS? a. C3 b. Factor H c. Factor I d. Factor 2e. �rombomodulin ANSWER KEY 1. d 2. d 3. c 4. e 5. c6. a 7. a 8. a 9. d 10. b

25 Tubulointerstitial nephritis

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REVIEW QUESTIONS

1. Which of the following is true regarding drug-inducedATIN? a. ATIN secondary to NSAIDs can present asnephrotic syndrome. b. �e triad of fever, rash, andarthralgia is present in the majority of patients withdrug-induced ATIN. c. Eosinophiluria is pathognomonic forATIN. d. Renal injury always develops soon a�er startingthe o�ending drug. e. Drug-induced ATIN is dose-dependent.

2. �e typical features on light microscopy of a kidneybiopsy in a patient with ATIN are: a. Tubular atrophy andinterstitial �brosis with minimal interstitial in�ammatorycell in�ltration b. Di�use endocapillary proliferationwith crescents and necrosis c. Di�use thickening of theglomerular basement membrane d. Di�use mesangialproliferation e. Interstitial mononuclear cell in�ltrationwith variable degrees of tubular necrosis and regeneration

3. A 15-year-old boy with a history of obstructiveuropathy who received a kidney transplant 8 years ago hasan elevated creatinine level. Renal biopsy showsinterstitial stripe �brosis and tubular atrophy. �esendings are characteristic of: a. Interstitial nephritissecondary to BK virus b. Acute cellular rejection c.Calcineurin inhibitor chronic interstitial damage d.Interstitial nephritis secondary to NSAIDs use e. Chronictransplant nephropathy

4. A 5-year-old girl presents with fever, fatigue, andabdominal pain and is admitted to the hospital because ofAKI with a creatinine value of 1.3. According to historyobtained, she had been taking amoxicillin for 4 days forstrep throat. Her physical examination is normal; herurinalysis reveals a speci�c gravity of 1.009, negativendings for blood and protein, 10 to 20 white blood cells,and no casts. You suspect ATIN secondary to amoxicillin.Which of the following is the next best step in hermanagement? a. Schedule her for a renal biopsy. b.Discontinue amoxicillin and follow creatinine trend. c.Administer pulse corticosteroids followed by oralprednisone. d. Check eosinophils in the urine, ifnegative, continue workup looking for other causes of AKI.e. Change amoxicillin to a cephalosporin. 5. Which of thefollowing urinary biomarkers has been associated with theacute changes seen in ATIN? a.N-acetyl-β-D-glucosaminidase (NAG) b. Kidney injury

molecule-1 (KIM-1) c. Neutrophil gelatinase-associatedlipocalin (NGAL) d. Monocyte chemotactic peptide-1 (MCP-1)e. β 2 -Microglobulin 6. A 10-year-old boy presents withnonoliguric AKI. He has a renal biopsy performed thatshows severe interstitial in�ammation with predominantmononuclear cell in�ltrate and no granulomas;immuno�uorescence is negative. �ere is no history ofmedication use or evidence of any viral or bacterialinfection. �e patient receives corticosteroids and hisrenal function returns to normal. Regarding furtherevaluation and follow-up, which of the following is themost accurate statement? a. He will need follow-up with anephrologist for at least 1 year. b. He can follow upwith his primary care physician for yearly checkups onlyand does not need specialty care. c. He needs anophthalmology evaluation now and every 3 months for thenext year in addition to follow-up with a nephrologist.d. He needs follow-up with a rheumatologist because of thepossibility of underlying autoimmune disease. 7. A12-year-old girl, previously healthy, presents with nauseaand vomiting. She has been taking ibuprofen for a kneeinjury for the last 7 days. She has mild pitting edema onboth lower extremities. Her laboratory results revealsigni�cant proteinuria with a ratio of urine protein tocreatinine of 5.9, elevated serum creatinine of 3.5 mg/dL,normal electrolytes, and a low serum albumin of 2.0 g/dL.You suspect ATIN secondary to NSAIDs and stop themedication. Over the next 2 days her creatinine continuesto rise and you decide to perform a renal biopsy. Which ofthe following would be the most appropriate step in hermanagement while you wait for the results of her biopsy?a. Administer albumin followed by furosemide b. Administerintravenous �uids c. Check complements and serologicndings and test for viral and bacterial infections d.Start intravenous methylprednisolone 10 mg/kg e. Startmycophenolate mofetil 8. Which of the following conditioncan cause secondary tubulointerstitial nephritis? a.Membranous nephropathy b. In�ammatory bowel disease c.Systemic lupus erythematosus d. IgA nephropathy e. All ofthe above

9. Regarding CTIN, which of the following statements istrue? a. In children, the most common cause of CTIN islupus nephritis. b. NSAIDs are the most common causes ofdrugrelated CTIN in children. c. CTIN progresses rapidlyto end-stage renal disease. d. Polyuria, polydipsia, andnocturnal enuresis may be the only manifesting symptoms inchildren with CTIN. e. Corticosteroids are e�ective inthe treatment of CTIN.

10. Regarding prognosis of ATIN in children, which of thefollowing statements is true? a. �e recovery of renalfunction depends on the severity of disease atpresentation. b. Prognosis is independent from thepresence of tubular atrophy. c. Prognosis is worse inpatients with underlying renal disease and when there isprolonged oliguria (more than 3 weeks). d. Most childrenwith ATIN progress slowly to CTIN. e. All of the above.ANSWER KEY 1. a 2. e 3. c 4. b 5. a 6. c 7. d 8. e9. d 10. c

26 Lupus nephritis

Figure 26.9 Renal biopsy findings in the patient. The

glomerulus on the right has endocapillary hypercellularity

in the 5 to 10 o’clock position. In contrast, othercapillary

loops are open, with luminal red blood cells present.

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REVIEW QUESTIONS

1. Renal biopsy was performed in a 15-year-oldAfricanAmerican girl with known SLE for 3 months and arecently noted abnormal serum creatinine of 1.5 mg/ dL for2 weeks. �e light microscopy �ndings of the renal biopsywere compatible with class IV (ISN/RPS 2003) changes.Recommendation for treatment of SLE nephritis in this caseshould be: a. Intravenous steroids and intravenouscyclophosphamide b. Intravenous steroids and rituximab c.Intravenous steroids and mycophenolate mofetil d. Option aor option c e. Option b or option c

2. SLE is more severe and more common in AfricanAmericans. a. True b. False

3. Indicator(s) of poor renal prognosis in lupus nephritisis (are): a. Nephrotic range proteinuria b. Increasedserum creatinine at presentation c. Class III or IV renalpathologic features in renal biopsy d. All of the abovee. None of the above

4. Glomerular mesangial and capillary wall immune depositsof IgA can be seen in: a. SLE nephritis b. IgA nephritisc. HSP nephritis d. All of the above e. Only b and c

5. Renal prognosis of class V lupus nephritis at 10 yearsis: a. ESRD in more than 50% patients b. ESRD in 10% to25% patients c. ESRD in fewer than 5% patients

6. SLE is associated with: a. No genetic predispositionb. Familial aggregation c. Autosomal recessive inheritanced. Autosomal dominant inheritance 7. Steroids alone aree�ective in treatment of class III and class IV lupusnephritis. a. True b. False 8. �e most common cause ofdeath in lupus nephritis is: a. End-stage renal diseaseb. Associated cerebritis c. Overwhelming sepsis d.romboembolic complications 9. Morbidity associated withclass V (membranous) lupus nephritis is caused by: a.Proteinuria and edema b. �romboembolic events c.

Infective events d. All of the above 10. Patients withclass V (membranous) lupus nephritis should receiveinduction therapy with pulse IV steroids and IV Cytoxanprotocol. a. True b. False 11. In treatment ofproliferative lupus nephritis (class III and IV),mycophenolate mofetil (MMF) induction therapy is: a. Lesse�ective than NIH regimen of IV Cytoxan b. More e�ectivethan NIH regimen of IV Cytoxan c. At least as e�ective asNIH regimen of IV Cytoxan d. �ere are no convincingcomparative data available. ANSWER KEY 1. d 2 a 3. d4. d 5. b 6. b 7. b 8. c 9. d 10. b 11. c

27 Kidney disease in sickle cell disease

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SUMMARY

SCD is a multiorgan disorder that can a�ect the

kidney and lead to CKD and ESRD. Renal injury or

SCN starts early in childhood. E�orts to prevent sick

ling, examine potential renoprotective agents, and

develop biomarkers to identify early kidney injury

and patients at risk of disease progression are among

the most important avenues in understanding and

preventing the renal consequences of SCD.

Kidney transplantation o�ers better survival option

for patients with ESRD. With advances in the trans

plant �eld, bone marrow coupled with kidney trans

plantation is becoming a more promising option for

patients with SCD and ESRD.

More emphasis is needed on well-structured transi

tion care programs from childhood to adulthood.

Children with SCD have lower clinic or o�ce BP

than their healthy counterparts. �e signi�cance of

having normal BP for age, sex, and height (relative

hypertension) in children with SCD is unknown.

Abnormalities in ABP measurements and patterns

in children with SCD are prevalent and require more

attention from health care providers. ABP monitor

ing is a valuable tool in identifying masked hyperten

sion and abnormalities in circadian BP.

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REVIEW QUESTIONS

1. Hematuria is more often reported with:

a. HbSS

b. HbSC

c. HbS/β thal

d. Hb AS

e. Hb AA

2. �e most common manifestation of tubular abnormality

in SCD is:

a. Urine concentration defect

b. Urine acidi�cation defect

c. Edema

d. Urine dilution defect

e. a and d

3. In patients with sickle cell disease, the most common

glomerular pathologic �nding on renal biopsy is:

a. Minimal change disease

b. FSGS

c. MPGN

d. IgA nephropathy

e. Membranous nephropathy

4. All the following statements about sickle cell nephropa

thy are correct except:

a. Treatment of hematuria in SCD involves bed rest and

maintenance of a high urinary �ow.

b. Patients with sickle cell disease are at a lower risk ofdeveloping hyperkalemia when treated with ACEIs and βblockers.

c. �e reported prevalence of microalbuminuria andproteinuria in patients with sickle cell disease rangesfrom 16% to 40%.

d. Renal medullary carcinoma is present almost exclusivelyin young black patients with sickle cell trait.

e. Children with sickle cell disease have lower clinic BPmeasurements than their age-, sex-, heightmatchedcounterparts.

5. All of the following statements regarding tubular

function in patients with sickle cell disease are correct

except:

a. Sodium reabsorption is increased.

b. Phosphate reabsorption is increased. c. Potassiumreabsorption is increased. d. Urate secretion isincreased. e. Creatinine secretion is increased. 6. �eearliest manifestation of kidney injury in childhood is:a. Acidosis b. Enuresis c. Hyposthenuria d. Hypertensione. Proteinuria 7. Mechanisms of renal injury include allof the following except: a. Immune complex deposits inthe basement membrane b. Hypoxia in the vasa recta c.Polymerization of sickle hemoglobin d. Hyper�ltration inthe glomerulus e. Medullary �brosis 8. All of thefollowing factors are strong predictors of chronic kidneydisease except: a. Proteinuria b. Hematuria c. CARhaplotype d. Nephrotoxic medications e. Nephroticsyndrome 9. All of the following are known correlates ofmicroalbuminuria and proteinuria except: a. Degree ofhemolysis b. Increasing age c. Elevated blood pressured. Pulmonary hypertension e. Higher hemoglobin levelsANSWER KEY 1. d 2. a 3. b 4. b 5. c 6. c 7. a 8. d9. e

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REVIEW QUESTIONS

1. In the pediatric age group (up to 19 years), diabetesmellitus accounts for ESRD in: a. 10% to 15% b. 20% to50% c. >1% d. >10%

2. Advanced glycation products result from nonenzymaticreaction of glucose with proteins, lipids, and nucleicacids. a. True b. False

3. Podocyes lack insulin receptors. a. True b. False

4. Renin-angiotensin induces glomerular injury in diabeticnephropathy by: a. Systemic hypertension b. Glomerularhypertension c. Increasing podocyte apoptosis d.Increasing tubular sodium concentration and inducingtubuloglomerular feedback

5. The classic pathologic lesion in diabetic nephropathyis: a. Kimmelstiel-Wilson lesion b. Large glomeruli(glomerulomegaly) c. Focal segmental glomerulosclerosisd. Wire loop lesion

6. The la tent phase of diabetic nephropathy in diabetesmellitus type 1 lasts: a. <5 yea rs b. 5 to 10 y ears c.10 to 1 5 years d. 30 to 4 0 years 7. Microalbuminuria ina diabetic 17-year-old girl is best tested in a: a.Random sample obtained in any time b. Random sampleobtained late in the afternoon c. First morning urinesample d. Random sample obtained after ambulating for 4hours 8. Microalbuminuria in a patient with diabetesmellitus type 1 indicates: a. Early diabetic nephropathyb. No clinical significance c. Onset of ESRD d.Development of Kimmelstiel-Wilson lesion 9. A 25-year-oldman with onset of diabetes mellitus at 3 years of age hadbeen lost to follow-up in nephrology for 3 years. He hadsporadic visits with his internist and endocrinologist.Upon his return to the nephrology clinic, his estimatedGFR was 100 mL/min/1.73 m 2 , and he now haswell-documented microalbuminuria and his hemoglobin A1cwas 11.5%. His previous known GFR, obtained 3 years ago,was 135 mL/min/1.73 m 2 . Which of the following bestreflects diabetic nephropathy in this patient? a. Hisdisease has not progressed, because he has a normal GFR.b. He is now cured of diabetic nephropathy, because he

does not have hyperfiltration c. Microalbuminuria inpresence of normal GFR has no clinical significance. d.His renal disease has progressed, because he now hasalbuminuria and his GFR has should be considered to havedeclined from a state of hyperfiltration to “normal.” 10.Which of the following statements best characterizes theuse of angiotensin-converting enzyme inhibitors indiabetic nephropathy? a. ACEIs are ideally started at thetime of the diagnosis of diabetes mellitus to preventdevelopment of microalbuminuria. b. Evidence to suggestthat ACEIs prevent development of microalbuminuria islacking. c. ACEIs improve diabetes control. d. ACEIsprevent progression of microalbuminuria. 11. The centralfindings of metabolic syndrome are: a. Insulin resistanceand hyperglycemia b. Hypertension c. Obesity withincreased waist circumference d. Dyslipidemia e.Microabluminuria f. All of the above g. Only a, b, and e12. Obesity and metabolic syndrome are characterized bymolecular markers of systemic inflammation. a. True. b.False.

13. Renal pathologic findings in obesity and metabolicsyndrome characteristically demonstrate: a.Glomerulomegaly (large glomeruli) b. FSGS with lesspronounced morphologic changes c. Basement membranethickening d. Lesser degree of foot-process fusion e. Allof the above f. Only a, b, and d

ANSWER KEY

1. d

2. a 3. b 4. b 5. a 6. c 7. c 8. a 9. d 10. d 11.f 12. a 13. e

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Kidney Dis. 2012;59:523–30. REVIEW QUESTIONS 1. You havejust initiated peritoneal dialysis for a 5-yearold boy withacute kidney injury (AKI) resulting from hemolytic-uremicsyndrome following infection with Shiga toxin–producing E.coli. �e family is inquiring about the chances of renalfunction recovery. Of the following, the most appropriatestatement regarding the natural history of AKI is: a.Complete renal recovery is the rule. b. Kidneytransplantation is the only hope for renal recovery. c.Progression to chronic kidney disease occurs in 25% ofchildren with dialysis requiring HUS. d. Renal recovery isaided by the use of diuretics. e. Renal recovery isunusual in children with dialysisrequiring AKI. 2. A4-week-old infant with cyanotic heart disease, renaldysplasia, and a baseline serum creatinine of 1.2 mg/dLundergoes a diagnostic cardiac catheterization withcontrast. Five days later, in preparation for cardiacsurgery, the anesthesiologist checks a renal panel andnotes that the serum creatinine is now 2.2 mg/dL. �e urineoutput is normal, and the urinalysis shows a trace amountof protein. Of the following options, the most likelyexplanation for the increase in serum creatinine is: a.Contrast nephropathy b. Laboratory error c. Prerenalazotemia d. Worsening cardiac function e. Wor seningchronic kidney disease 3. A 3-d ay-old infant was born at36 weeks of gestation by emergency cesarean section forfetal distress and placental abruption. Apgar scores were2 and 3 at 1 and 5 minutes, respectively. He was placed onmechanical ventilation and given intravenous hydration. Healso received a single dose of ampicillin and gentamicin,

which was not continued because the result of admis

sion blood culture was negative. Today, the serum cre

atinine is 2.5 mg/dL. Of the following, the most likely

cause of the acute kidney injury is:

a. Nephrotoxicity

b. Perinatal asphyxia

c. Prematurity

d. Respiratory distress syndrome

e. Sepsis

4. You have initiated therapy with enalapril for essential

hypertension in a 14-year-old boy. At follow-up 2 weeks

later, his blood pressure has normalized. However, the

serum potassium level is 5.5 mEq/L in a nonhemolyzed

sample (increased from a baseline of 4.2 mEq/L). Of the

following, the most likely explanation for the hyperkale

mia is:

a. Decreased glomerular �ltration rate

b. Decreased renal blood �ow

c. Excessive dietary intake of potassium

d. Increased distal tubular reabsorption of potassium

e. Increased proximal tubular reabsorption of potassium

5. You are seeing a 10-day-old male infant born at 38

weeks of gestation. �e delivery was complicated by

placental abruption and a tight nuchal cord, with

Apgar scores of 2 and 3 at 1 and 5 minutes, respec

tively, requiring initiation of mechanical ventilation.

For the past 2 days, his serum creatinine concentra

tion has been 1.6 mg/dL, increased from 1.2 mg/dL at

1 day of age. �e serum electrolytes are normal, and

the infant does not have oliguria, edema, or hyperten

sion. Of the following, the most appropriate statement

regarding the current serum creatinine measurement

is that it:

A. Is normal for his age

B. Is not re�ective of kidney dysfunction because the

urine output is normal

C. Re�ects acute kidney injury

D. Re�ects maternal renal function

E. Re�ects physiologic maturation

6. You are seeing a 3-year-old girl who was admitted 5

days ago with oliguric acute kidney injury secondary

to fever, vomiting, and dehydration. Her oral intake

has remained poor, and she has been on an intrave

nous regimen of D5 0.25% NaCl to replace insensible

water losses. Today, the serum sodium is 148 mEq/L,

her weight is down by 5%, and her parents report many

wet diapers last night. Of the following, the most likely

cause of the hypernatremia in this patient is:

a. Excessive glucose intake

b. Excessive sodium administration

c. Laboratory error

d. Recovering acute kidney injury

e. Worsening acute kidney injury 7. You are consulted on a2-year-old boy with tetralogy of Fallot who is scheduledto undergo a de�nitive intracardiac repair procedure.During infancy, he underwent a palliative Blalock-Taussigshunt placement and developed moderate postoperative acutekidney injury that resolved spontaneously. Of thefollowing, the most appropriate intervention to reduce therisk of developing acute kidney injury following hisupcoming intracardiac repair is the preoperativeadministration of: a. Fluids to optimize perioperativehemodynamics b. Furosemide to induce diuresis c. Mannitolto scavenge free radicals d. N-acetylcysteine to providean antioxidant e. Renal-dose dopamine to induce renalvasodilation 8. You are consulting on a 5-year-old girlwho was admitted to the ICU 2 days ago for the managementof sepsis. Laboratory testing today shows a bicarbonate

level of 14 mmol/L, BUN 50 mg/dL, and serum creatinine 2.0mg/ dL. �e ICU team is contemplating bicarbonate therapyfor the metabolic acidosis. Of the following, the mostlikely consequence of bicarbonate therapy in this situationis: a. Hyperchloremia b. Hyperkalemia c.Hyperphosphatemia d. Hypocalcemia e. Hyponatremia 9. Youare seeing a 6-yearold boy who was admitted to thecritical care unit 3 days ago with septic shock. He hasrequired multiple boluses of crystalloids and colloids forhypotension and multiple blood products for disseminatedintravascular coagulation. His urine output has beendecreasing for the past 24 h, and he has been anuric forthe past 12 h. He has developed generalized edema, and hisweight is now 26 kg (up from an admission weight of 20kg). He has received two doses of intravenous furosemide(3 mg/kg) during the past 12 h, with no diuretic response.Of the following, the most appropriate next step in hismanagement is: a. Continue furosemide every 6 h. b.Initiate mannitol diuresis. c. Start fenoldopam. d.Initiate a trial of IV normal saline bolus. e. Prepare forrenal replacement therapy. 10. You are seeing a 5-year-oldboy who initially presented to the emergency departmentabout 24 h ago with a 3-day history of fever, vomiting,poor oral intake, and 1 day of no urine output. Initialassessment in the emergency department found tachycardia,hypotension, lethargy, and di�use abdominal tenderness. Hewas given �uid resuscitation, started on intravenousvancomycin (10 mg/kg/dose every 6 h) and gentamicin (2.5mg/kg/ dose every 8 h), and admitted for close observation.He continues to have anuria. �e serum creatinineconcentration today is 1.6 mg/dL (increased from 0.8 mg/dLat

initial presentation). Of the following, the most appro

priate next step in the management of this patient’s

intravenous antibiotic regimen is:

a. Adjust the antibiotics for a glomerular �ltration rate(GFR) of 75 mL/min.

b. Adjust the antibiotics for a GFR of 50 mL/min.

c. Adjust the antibiotics for a GFR of 10 mL/min.

d. Continue the current regimen of antibiotics.

e. Stop all antibiotics. ANSWER KEY 1. c 2. a 3. b 4. a5. c 6. d 7. a 8. d 9. e 10. c

31 Chronic kidney disease

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198. Vat s AN, Donaldson L, Fine RN, Chavers BM.Pretransplant dialysis status and outcome of renaltransplantation in North American children: A NAPRTCSStudy. North American Pediatric Renal TransplantCooperative Study. Transplantation. 2000;69:1414–9. 199.Mitch WE, Walser M, Buffington GA, et al. A simple methodof estimating progression of chronic renal failure.Lancet. 1976;2:1326–8. 200. Ham ilton BE, Hoyert DL,Martin JA, et al. Annual summary of vital statistics:2010-2011. Pediatrics. 2013;131:548–58. 201. McDonald SP,Craig JC. Long-term survival of children with end-stagerenal disease. N Engl J Med. 2004;350:2654–62. REVIEWQUESTIONS 1. �e most common cause of CKD in children is:a. Focal segmental glomerulosclerosis b. Polycystic kidneydisease c. Congenital anomalies of the kidneys and urinarytract (CAKUT) d. Imm une-mediated glomerulonephritis e.Hemo lytic-uremic syndrome 2. �e in cidence of ESRD inchildren: a. Dec reases with increasing age b. Rema insthe same throughout childhood and adolescence c. Is highest in children younger than 4 years d. Inc reases withadvancing age 3. In th e United States, FSGS is thepredominant cause of CKD in: a. Afr ican Americans b.His panics c. Whit es d. Nati ve Americans e. Asi anAmericans 4. Mor tality of children with ESRD is highestin which age group? a. 0 to 4 years b. 5 to 14 years c.15 to 19 years 5. Angiotensin II plays a role inprogression of CKD by: a. Causing predominant a�erent overe�erent arteriolar vasoconstriction b. Decreasingsingle-nephron GFR c. Increasing proin�ammatory cytokines,chemokines, and cell adhesion molecules d. Stimulatingaldosterone, which itself is injurious to the kidney e.a, b, and d f. c and d 6. What is the most commoncomplication of CKD in children? a. Anemia b.Hypertension c. Fluid and electrolyte abnormalities d.Growth failure e. Mineral and bone disorder

7. �e prevalence of LVH in pediatric dialysis patients is:a. 10% b. 20% c. 30% d. Up to 50% e. Up to 75%

8. In children the fastest rate of growth occurs: a.During infancy b. Age 1 to 4 years c. Age 4 to 10 yearsd. During puberty

9. All of the following contribute to growth impairment inchildren with CKD, except: a. Malnutrition b. Anemia c.GH de�ciency d. Altered post–receptor signaling of JAK2and STAT proteins e. Reduced bioavailability of IGF-1

10. All of the following central and neurocognitive de�citsoccur in children with CKD except: a. Cerebral atrophy b.Speech and language delay c. Lower educational attainmentd. Lower IQ scores e. Macrocephaly and hydrocephalus 11.In children with CKD, all but one of the followingtherapeutic interventions slow progression. a.ACE-inhibitors or angiotensin receptor blockers b. Bloodpressure control c. Minimizing proteinuria d.Cholesterol-lowering therapy ANSWER KEY 1. c 2. d 3. a4. a 5. f 6. b 7. e 8. a 9. c 10. e 11. d

32 Anemia in chronic kidney disease

Adjustment of ESA dosing should be controlled to

minimize large �uctuations in Hb level. KEY POINTS ●Hyporesponsiveness to ESA therapy is common. ● �e risksand bene�ts of escalation of ESA dose versus red bloodcell transfusion must be balanced for individual patients.SUMMARY Anemia is prevalent and is associated with adverseoutcomes in children with CKD. Although various factorscontribute to anemia risk, EPO insu�ciency and ironde�ciency are the major underlying etiologic factors, andthey are the mechanisms most commonly targeted by currenttherapies. Ongoing therapeutic challenges includehepcidin-mediated iron-restricted erythropoiesis andconcerns about the safety and e�cacy of escalating ESAdoses for refractory anemia. Most recommendations regardingESA use and dosing are based on data from adult trials;there have been no interventional studies examining thee�ects of ESA administration on clinical outcomes inchildren. Nevertheless, ESAs continue to be importantcomponents of CKD care in children; use of ESAs shouldbalance the risks and bene�ts.

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6. Jackson RT. Separate hemoglobin standards for blacksand whites: A critical review of the case for separate andunequal hemoglobin standards. Med Hypotheses.1990;32:181–9.

7. Atkinson MA, Pierce CB, Zack RM, et al. Hemoglobindifferences by race in children with CKD. Am J Kidney Dis.2010;55:1009–17.

8. Filler G, Mylrea K, Feber J, et al. How to define anemiain children with chronic kidney disease? Pediatr Nephrol.2007;22:702–7.

9. Greenbaum LA. Anemia in children with chronic kidneydisease. Adv Chronic Kidney Dis. 2005;12:385–96.

10. Atkinson MA, Martz K, Warady BA, et al. Risk foranemia in pediatric chronic kidney disease patients: Areport of NAPRTCS. Pediatr Nephrol. 2010;25:1699–706.

11. Sta ples AO, Wong CS, Smith JM, et al. Anemia and riskof hospitalization in pediatric chronic kidney disease.Clin J Am Soc Nephrol. 2009;4:48–56.

12. Fadrowski JJ, Pierce CB, Cole SR, et al. Hemoglobindecline in children with chronic kidney disease: Baselineresults from the chronic kidney disease in childrenprospective cohort study. Clin J Am Soc Nephrol.2008;3:457–62.

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40. Raimann JG, Levin NW, Craig RG, et al. Is vitamin Cintake too low in dialysis patients? Semin Dial.2013;26:1–5.

41. Kru se A, Uehlinger DE, Gotch F, et al. Red blood celllifespan, erythropoiesis and hemoglobin control. ContribNephrol. 2008;161:247–54.

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45. Ben nett CL, Starko KM, Thomsen HS, et al. Linkingdrugs to obscure illnesses: Lessons from pure red cellaplasia, nephrogenic systemic fibrosis, and Reye’ssyndrome. A report from the Southern Network on AdverseReactions (SONAR). J Gen Intern Med. 2012;27:1697–703.

46. Aga rwal R. Iron, oxidative stress, and clinicaloutcomes. Pediatr Nephrol. 2008;23:1195–9.

47. Fis hbane S. Upper limit of serum ferritin:Misinterpretation of the 2006 KDOQI anemia guidelines.Semin Dial. 2008;21:217–20.

48. Atkinson MA, Pierce CB, Fadrowski JJ, et al.Association between common iron store markers andhemoglobin in children with chronic kidney disease.Pediatr Nephrol. 2012;27:2275–83.

49. Wish JB. Assessing iron status: Beyond serum ferritinand transferrin saturation. Clin J Am Soc Nephrol.2006;1(Suppl 1):S4–8.

50. Kal antar-Zadeh K, Lee GH. The fascinating butdeceptive ferritin: To measure it or not to measure it inchronic kidney disease? Clin J Am Soc Nephrol.2006;1(Suppl 1):S9–18.

51. Looker AC, Dallman PR, Carroll MD, et al. Prevalenceof iron deficiency in the United States. JAMA.1997;277:973–6.

52. Gan z T, Nemeth E. Iron sequestration and anemia ofinflammation. Semin Hematol. 2009;46:387–93.

53. Kal antar-Zadeh K, McAllister CJ, Lehn RS, et al. Alow serum iron level is a predictor of poor outcome inhemodialysis patients. Am J Kidney Dis. 2004;43:671–84.

54. Mor gan HE, Gautam M, Geary DF. Maintenanceintravenous iron therapy in pediatric hemodialysispatients. Pediatr Nephrol. 2001;16:779–83. 55. Warady BA,Kausz A, Lerner G, et al. Iron therapy in the pediatrichemodialysis population. Pediatr Nephrol. 2004;19:655–61.56. Morgan HE, Holt RC, Jones CA, et al. Intravenous irontreatment in paediatric chronic kidney disease patientsnot on erythropoietin. Pediatr Nephrol. 2007;22:1963–5.57. Shander A, Sazama K. Clinical consequences of ironoverload from chronic red blood cell transfusions, itsdiagnosis, and its management by chelation therapy.Transfusion. 2010;50:1144–55. 58. Bes arab A, Bolton WK,Browne JK, et al. The effects of normal as compared withlow hematocrit values in patients with cardiac disease whoare receiving hemodialysis and epoetin. N Engl J Med.1998;339:584–90. 59. Singh AK, Szczech L, Tang KL, et al.Correction of anemia with epoetin alfa in chronic kidneydisease. N Engl J Med. 2006;355:2085–98. 60. Pfe ffer MA,Burdmann EA, Chen CY, et al. A trial of darbepoetin alfain type 2 diabetes and chronic kidney disease. N Engl JMed. 2009;361:2019–32. 61. Bad ve SV, Hawley CM, JohnsonDW. Is the problem with the vehicle or the destination?Does high-dose ESA or high haemoglobin contribute to pooroutcomes in CKD? Nephrology (Carlton). 2011;16:144–53. 62.Goo dkin DA, Fuller DS, Robinson BM, et al. Naturallyoccurring higher hemoglobin concentration does notincrease mortality among hemodialysis patients. J Am SocNephrol. 2011;22:358–65. 63. Ung er EF, Thompson AM, BlankMJ, et al. Erythropoiesis-stimulating agents: Time for areevaluation. N Engl J Med. 2010;362:189–92. 64. Kli gerAS, Foley RN, Goldfarb DS, et al. KDOQI US commentary onthe 2012 KDIGO clinical practice guideline for anemia inCKD. Am J Kidney Dis. 2013;62:849–59. 65. Lestz RM,Fivush BA, Atkinson MA. Association of highererythropoiesis stimulating agent dose and mortality inchildren on dialysis. Pediatr Nephrol. 2014;29: 2021–8.66. Covic A, Cannata-Andia J, Cancarini G, et al.Biosimilars and biopharmaceuticals: What the nephrologistsneed to know—A position paper by the ERAEDTA council.Nephrol Dial Transplant. 2008;23:3731–7. 67. Horl WH.Differentiating factors between erythropoiesis-stimulatingagents: An update to selection for anaemia of chronickidney disease. Drugs. 2013;73:117–30. 68. KDO QIclinical practice guidelines and clinical practicerecommendations for anemia in chronic kidney disease. Am J

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REVIEW QUESTIONS

1. �e initial laboratory evaluation for anemia in a childwith CKD should include which of the following?

a. Complete blood count

b. Reticulocyte count

c. Ferritin

d. Transferrin saturation

e. All of the above

2. Which of the following is not associated with the anemiaof CKD in children?

a. Increased risk for hospitalization

b. Increased fracture risk

c. Decreased quality of life

d. Increased risk for mortality

e. Increased risk for le� ventricular hypertrophy 3. �eprimary site of endogenous erythropoietin production inchildren is: a. Hepa tocytes b. Renal tubular epithelialcells c. Erythroid progenitor cells in bone marrow d.Peritubular �broblasts in the renal cortex e.Juxtaglomerular apparatus 4. Whi ch is the primaryphysiologic stimulus for increased EPO gene expression?a. Hypoxia b. Anemia c. Increased distal tubular sodiumreabsorption d. Urem ia e. Decrease in blood pressure 5.Iron-restricted erythropoiesis can include: a. Absoluteiron de�ciency b. Depletion of accessible iron stores byESAstimulated bone marrow c. In�ammation-associatedimpairment in iron tra�cking d. a and b only e. a, b,and c 6. Children receiving ESA therapy should receiveiron supplementation as indicated to maintain: a.Ferritin greater than 50 ng/mL and transferrin saturationgreater than 20% b. Ferritin greater than 100 ng/mL andtransferrin saturation greater than 10% c. Ferritingreater than 100 ng/mL and transferrin saturation greater

than 20% d. Ferritin greater than 500 ng/mL andtransferrin saturation greater than 30% e. Ferritingreater than 100 ng/mL and transferrin saturation greaterthan 30% 7. All of the following are possible indicationsfor IV iron administration except: a. Poor enteral ironabsorption b. Poor adherence to oral iron supplementationregimen c. Long-term hemodialysis status d. Activesystemic infection e. ESA hyporesponsiveness 8.Short-acting recombinant human erythropoietin formulationshave longer half-lives and are more e�ective whenadministered: a. Subcutaneously b. Intravenously c.Enterally d. Peritoneally e. With hemodialysis 9.Potential advantages of darbepoetin alfa compared withshort-acting recombinant human erythropoietin include: a.Longer interval between doses b. Improved adherence c.Decreased pain with administration d. a and b only e. a,b, and c

10. �e goal rate of hemoglobin increase a�er initiation ofan ESA is:

a. 1 to 2 g/dL per week

b. 1 to 2 g/dL per month

c. 1 to 2 g/dL over 3 months

d. Increase to goal hemoglobin of 11 g/dL over 1 month

e. Increase to goal hemoglobin of 12 g/dL over 3 monthsANSWER KEY 1. e 2. b 3. d 4. a 5. e 6. c 7. d 8. a9. d 10. b

33 Chronic kidney disease bone andmineral disorder

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177. Sla topolsky E, Liapis H, Finch J. Progressiveaccumulation of lanthanum in the liver of normal and uremicrats. Kidney Int. 2005;68:2809–13. 178. Ross C A, TaylorCL, Yaktine AL, Del Valle HB. Dietary Reference Intakesfor Calcium and Vitamin D. Washington, DC: NationalAcademies Press; 2011. 179. Salusky IB, Goodman WG, SahneyS, et al. Sevelamer controls parathyroid hormone-inducedbone disease as efficiently as calcium carbonate withoutincreasing serum calcium levels during therapy with activevitamin D sterols. J Am Soc Nephrol. 2005;16:2501–8. 180.Salusky IB, Kuizon BD, Belin TR, et al. Intermittentcalcitriol therapy in secondary hyperparathyroidism: Acomparison between oral and intraperitonealadministration. Kidney Int. 1998;54:907–14. 181. Nat ionalKidney Foundation. K/DOQI clinical practice guidelines forbone metabolism and disease in chronic kidney disease. Am JKidney Dis. 2003;42:S1–201. 182. Fukagawa M, Okazaki R,Takano K, et al. Regression of parathyroid hyperplasia bycalcitriol-pulse therapy in patients on long-termdialysis. N Engl J Med. 1990;323:421–2. 183. Pie ridesAM, Ellis HA, Simpson W, et al Variable response tolong-term 1alpha-hydroxycholecalciferol in haemodialysisosteodystrophy. Lancet. 1976;1:1092–5. 184. Dobrez DG,Mathes A, Amdahl M, et al. Paricalcitoltreated patientsexperience improved hospitalization outcomes compared withcalcitriol-treated patients in real-world clinicalsettings. Nephrol Dial Transplant. 2004;19:117–81. 185.Sjo den G, Smith C, Lindgren U, DeLuca HF. 1alpha-Hydroxyvitamin D 2 is less toxic than 1alphahydroxyvitamin D 3 in the rat. Proc Soc Exp Biol Med.1985;178:432–6. 186. And ress DL, Norris KC, Coburn JW, etal. Intravenous calcitriol in the treatment of refractoryosteitis fibrosa of chronic renal failure. N Engl J Med.1989;321:274–9. 187. Tha dhani R, Appelbaum E, PritchettY, et al. Vitamin D therapy and cardiac structure andfunction in patients with chronic kidney disease: ThePRIMO randomized controlled trial. JAMA. 2012;307:674–84.188. Schwarz U, Amann K, Orth SR, et al. Effect of 1,25(OH)2 vitamin D 3 on glomerulosclerosis in subtotallynephrectomized rats. Kidney Int. 1998;53:1696–705. 189.Agarwal R, Acharya M, Tian J, et al. Antiproteinuriceffect of oral paricalcitol in chronic kidney disease.Kidney Int. 2005;68:2823–8. 190. Nakane M, Ma J, Ruan X,et al. Mechanistic analysis of VDR-mediated renin

suppression. Nephron Physiol. 2007;107:35–44. 191. WadaM, Nagano N. Control of parathyroid cell growth bycalcimimetics. Nephrol Dial Transplant. 2003;18(Suppl3):iii13-7. 192. Arnold A, Brown MF, Urena P, et al.Monoclonality of parathyroid tumors in chronic renalfailure and in primary parathyroid hyperplasia. J ClinInvest. 1995;95:2047–53.

193. Quarles LD, Yohay DA, Carroll BA, et al. Prospectivetrial of pulse oral versus intravenous calcitriol treatmentof hyperparathyroidism in ESRD. Kidney Int.1994;45:1710–21.

194. Froment DP, Molitoris BA, Buddington B, et al. Siteand mechanism of enhanced gastrointestinal absorption ofaluminum by citrate. Kidney Int. 1989;36:978-84.

195. Jorna FH, Tobe TJ, Huisman RM, et al. Earlyidentification of risk factors for refractory secondaryhyperparathyroidism in patients with long-term renalreplacement therapy. Nephrol Dial Transplant.2004;19:1168–73.

196. Andress DL, Ott SM, Maloney NA, Sherrard DJ. Effectof parathyroidectomy on bone aluminum accumulation inchronic renal failure. N Engl J Med. 1985;312:468–73.

197. de Barros Gueiros JE, Chammas MC, Gerhard R, et al.Percutaneous ethanol (PEIT) and calcitriol (PCIT)injection therapy are ineffective in treating severesecondary hyperparathyroidism. Nephrol Dial Transplant.2004;19:657–63.

198. Diethelm AG, Edwards RP, Whelchel JD. The naturalhistory and surgical treatment of hypercalcemia before andafter renal transplantation. Surg Gynecol Obstet.1982;154:481–90.

199. D’Alessandro AM, Melzer JS, Pirsch JD, et al. Tertiaryhyperparathyroidism after renal transplantation: Operativeindications. Surgery. 1989;106:1049–55.

200. Ber gua C, Torregrosa JV, Fuster D, et al. Effect ofcinacalcet on hypercalcemia and bone mineral density inrenal transplanted patients with secondaryhyperparathyroidism. Transplantation. 2008;86:413–7.

201. Borchhardt K, Sulzbacher I, Benesch T, et al.Lowturnover bone disease in hypercalcemichyperparathyroidism after kidney transplantation. Am J

Transplant. 2007;7:2515–21.

202. Bhan I, Shah A, Holmes J, et al. Post-transplanthypophosphatemia: Tertiary ‘hyper-phosphatoninism’? KidneyInt. 2006;70:1486–94.

203. Even epoel P, Naesens M, Claes K, et al. Tertiary‘hyperphosphatoninism’ accentuates hypophosphatemia andsuppresses calcitriol levels in renal transplantrecipients. Am J Transplant. 2007;7:1193–200.

204. Bonomini V, Feletti C, Di FA, Buscaroli A. Boneremodelling after renal transplantation (RT). Adv Exp MedBiol. 1984;178:207–16.

205. Nie lsen HE, Melsen F, Christensen MS. Asepticnecrosis of bone following renal transplantation: Clinicaland biochemical aspects and bone morphometry. Acta MedScand. 1977;202:2–32.

206. Grotz WH, Mundinger FA, Gugel B, et al. Bone mineraldensity after kidney transplantation: A cross-sectionalstudy in 190 graft recipients up to 20 years aftertransplantation. Transplantation. 1995;59:982–6. 207.Julian BA, Laskow DA, Dubovsky J, et al. Rapid loss ofvertebral mineral density after renal transplantation. NEngl J Med. 1991;325:544–50. 208. Slatopolsky E, Martin K.Glucocorticoids and renal transplant osteonecrosis. AdvExp Med Biol. 1984;171:353–9. 209. Parfrey PS, Farge D,Parfrey NA, et al. The decreased incidence of asepticnecrosis in renal transplant recipients: A case controlstudy. Transplantation. 1986;41:182–7. 210. Isono SS,Woolson ST, Schurman DJ. Total joint arthroplasty forsteroid-induced osteonecrosis in cardiac transplantpatients. Clin Orthop Relat Res. 1987:201–8. 211. EnrightH, Haake R, Weisdorf D. Avascular necrosis of bone: Acommon serious complication of allogeneic bone marrowtransplantation. Am J Med. 1990;89:733–8. 212. Velasquez-Forero F, Mondragon A, Herrero B, Pena JC. Adynamicbone lesion in renal transplant recipients with normalrenal function. Nephrol Dial Transplant. 1996;11(Suppl3):58–64. 213. San chez CP, Salusky IB, Kuizon BD, et al.Bone disease in children and adolescents undergoingsuccessful renal transplantation. Kidney Int.1998;53:1358–64. 214. Lin dberg JS, Culleton B, Wong G, etal. Cinacalcet HCl, an oral calcimimetic agent for thetreatment of secondary hyperparathyroidism in hemodialysisand peritoneal dialysis: A randomized, doubleblind,multicenter study. J Am Soc Nephrol. 2005;16:800–7. 215.All en DB, Goldberg BD. Stimulation of collagen synthesis

and linear growth by growth hormone inglucocorticoid-treated children. Pediatrics.1992;89:416–21. 216. Roo t AW, Bongiovanni AM, EberleinWR. Studies of the secretion and metabolic effects ofhuman growth hormone in children withglucocorticoid-induced growth retardation. J Pediatr.1969;75:826–32. 217. Wehrenberg WB, Bergman PJ, Stagg L,et al. Glucocorticoid inhibition of growth in rats:Partial reversal with somatostatin antibodies.Endocrinology. 1990;127:2705–8. 218. Aubia J, Serrano S,Marinoso L, et al. Osteodystrophy of diabetics in chronicdialysis: A histomorphometric study. Calcif Tissue Int.1988;42:297–301. 219. Movs owitz C, Epstein S, Fallon M,et al. Cyclosporin-A in vivo produces severe osteopeniain the rat: Effect of dose and duration of administration.Endocrinology. 1988;123:2571–7. 220. Bryer HP, Isserow JA,Armstrong EC, et al. Azathioprine alone is bone sparingand does not alter cyclosporin A-induced osteopenia in therat. J Bone Miner Res. 1995;10:132–8.

221. Hokken-Koelega AC, van Zaal MA, van BW, et al. Finalheight and its predictive factors after renaltransplantation in childhood. Pediatr Res. 1994;36:323–8.

222. Fin e RN, Yadin O, Nelson PA, et al. Recombinanthuman growth hormone treatment of children following renaltransplantation. Pediatr Nephrol. 1991;5:147–51.

223. Mitsnefes MM, Kimball TR, Border WL, et al. Abnormalcardiac function in children after renal transplantation.Am J Kidney Dis. 2004;43:721–6.

224. Ish itani MB, Milliner DS, Kim DY, et al. Earlysubclinical coronary artery calcification in young adultswho were pediatric kidney transplant recipients. Am JTransplant. 2005;5:1689–93.

225. Wolf M, Molnar MZ, Amaral AP, et al. Elevatedfibroblast growth factor 23 is a risk factor for kidneytransplant loss and mortality. J Am Soc Nephrol.2011;22:956–66.

226. Wesseling-Perry K, Tsai EW, Ettenger RB, et al.Mineral abnormalities and long-term graft function inpediatric renal transplant recipients: A role for FGF-23?Nephrol Dial Transplant. 2011;26:3779–84.

REVIEW QUESTIONS

A 12-year-old boy has come to a pediatrician’s o�ce for a

school physical. He wakes up several times at night to uri

nate. On examination, he is found to be a pale boy with a

height and a weight that are both below the 3rd percentile.He

has Tanner 1 pubertal development and normal blood pres

sure. Serum electrolytes are sodium, 136 mmol/L; potassium,

3.8 mmol/L; chloride, 108 mmol/; total carbon dioxide, 18

mmol/L; blood urea nitrogen, 40 mg/dL; creatinine, 1.8 mg/

dL (stage 3 CKD); phosphorus, 4 mg/dL; calcium, 9.9 mg/dL;

parathyroid hormone, 170 pg/mL, and hematocrit, 28%.

1. An appropriate serum PTH level for this child with this

degree of renal insu�ciency is:

a. 10 to 65 pg/mL

b. 65 to 110 pg/mL

c. 200 to 300 pg/mL

d. >400 pg/mL

2. Growth hormone therapy should be initiated:

a. Immediately, to maximize �nal height potential

b. A�er correction of acidosis, anemia, and secondaryhyperparathyroidism c. A�er the initiation of dialysis d.A�er successful renal transplantation e. Growth hormonetherapy is contraindicated in this child 3. An 8-year-oldgirl presents with re�ux nephropathy and growth failureand has the following serum biochemical determinations:Serum creatinine, 2.5 mg/dL (CKD stage 4); calcium, 8.9mg/dL; phosphorus, 6 mg/dL; and PTH, 140 pg/mL. �e �rststep in serum phosphorus management is: a. Initiation ofa non–calcium-containing phosphate binder b. Nutritionalassessment and phosphate restriction c. Vitamin D steroltherapy d. Growth hormone therapy 4. A 14-year-old boywith obstructive uropathy and stage 3 CKD has been treatedwith growth hormone therapy for the past 2 years. His

growth velocity has been decreasing over the past 6 months.An indication to stop therapy would be: a. Serum PTH of150 pg/mL b. Height at percentile corresponding to themean parental height c. Tanner 2 pubertal development d.Increasing alkaline phosphatase activity 5. A 10-year-oldboy receiving maintenance hemodialysis is treated withcalcium carbonate and thrice weekly calcitriol to controlhis renal osteodystrophy. His serum PTH level is 700pg/mL; phosphorus, 5 mg/dL; and calcium, 11.5 mg/dL. Toameliorate his hypercalcemia, the next step in his therapyshould include: a. Dietary calcium restriction b. Bonebiopsy c. Switching to a non–calcium-containing phosphatebinder d. Increasing the calcitriol therapy ANSWER KEY 1.a 2. b 3. b 4. b 5. c

34 Nutrition in chronic kidney disease

1. Kidney Disease Outcomes Quality Initiative, NationalKidney Foundation. Clinical practice guidelines fornutrition in chronic renal failure. Am J Kidney Dis.2000;35:S1–140.

2. Furth SL, Stablein D, Fine RN, et al. Adverse clinicaloutcomes associated with short stature at dialysisinitiation: A report of the North American Pediatric RenalTransplant Cooperative Study. Pediatrics. 2002;109:909–13.3. Wong CS, Gipson DS, Gillen DL, et al. Anthropometricmeasures and risk of death in children with end-stagerenal disease. Am J Kidney Dis. 2000;36:811–9. 4. Fos terBJ, McCauley L, Mak RH. Nutrition in infants and veryyoung children with chronic kidney disease. PediatrNephrol. 2012;27:1427–39. 5. Kar lberg J, Schaefer F,Hennicke M, et al. Early age-dependent growth impairmentin chronic renal failure. European Study Group forNutritional Treatment of Chronic Renal Failure inChildhood. Pediatr Nephrol. 1996;10:283–7. 6. KidneyDisease Outcomes Quality Initiative, Clinical PracticeGuideline for Nutrition in Children with CKD: 2008 update.Executive summary. Am J Kidney Dis. 2009;53:S11–104. 7.Zivicnjak M, Franke D, Filler G, et al. Growth impairmentshows an age-dependent pattern in boys with chronic kidneydisease. Pediatr Nephrol. 2007;22:420–9. 8. Schaefer F,Wuhl E, Feneberg R, et al. Assessment of body compositionin children with chronic renal failure. Pediatr Nephrol.2000;14:673–8. 9. Rees L, Shaw V. Nutrition in childrenwith CRF and on dialysis. Pediatr Nephrol.2007;22:1689–702. 10. Van D yck M, Proesmans W. Headcircumference in chronic renal failure from birth. ClinNephrol. 2001;56:S13–6. 11. Warady BA, Belden B, KohautE. Neurodevelopmental outcome of children initiatingperitoneal dialysis in early infancy. Pediatr Nephrol.1999;13:759–65. 12. Borah MF, Schoenfeld PY, Gotch FA, etal. Nitrogen balance during intermittent dialysis therapyof uremia. Kidney Int. 1978;14:491–500. 13.Juarez-Congelosi M, Orellana P, Goldstein SL. Normalizedprotein catabolic rate versus serum albumin as a nutritionstatus marker in pediatric patients receiving hemodialysis.J Ren Nutr. 2007;17:269–74. 14. Kopple JD, Jones MR,Keshaviah PR, et al. A proposed glossary for dialysiskinetics. Am J Kidney Dis. 1995;26:963–81. 15. EdefontiA, Picca M, Damiani B, et al. Models to assess nitrogenlosses in pediatric patients on chronic peritonealdialysis. Pediatr Nephrol. 2000;15:25–30. 16. Leavey SF,Strawderman RL, Jones CA, et al. Simple nutritionalindicators as independent predictors of mortality in

hemodialysis patients. Am J Kidney Dis. 1998;31:997–1006.17. Stenvinkel P, Barany P, Chung SH, et al. A comparativeanalysis of nutritional parameters as predictors of outcomein male and female ESRD patients. Nephrol Dial Transplant.2002;17:1266–74. 18. Wong CS, Hingorani S, Gillen DL, etal. Hypoalbuminemia and risk of death in pediatricpatients with end-stage renal disease. Kidney Int.2002;61:630–7.

SUMMARY

e association between mortality and extremes of

BMI in children with CKD heightens the impor

tance of careful nutritional management in this

patient population. Close assessment, monitoring,

and management of nutritional status in CKD may

have a critical impact on growth and neurodevelop

ment, especially in younger children. 4 �erefore, the

active involvement of a registered dietitian, health

care professionals, and caregivers is essential for pro

viding proper nutritional care to children with CKD.

Moreover, further clinical trials are needed to estab

lish evidence-based guidelines for nutritional assess

ment and management in pediatric CKD.

Table 34.4 Recommended target ranges for serum

parathyroid hormone

Chr onic kidney

disease stage Serum PTH level (pg/mL) 2 35–70 3 35–70 470–110 5 200–300

Source: National Kidney Foundation: K/DOQI clinicalpractice guidelines for bone metabolism and disease inchildren with chronic kidney disease. Am J Kidney Dis2005; 46: S1-121. Reprinted with permission

Abbreviation: PTH, parathyroid hormone.

19. Quan A, Baum M. Protein losses in children oncontinuous cycle peritoneal dialysis. Pediatr Nephrol.1996;10:728–31.

20. Ras hid R, Neill E, Smith W, et al. Body compositionand nutritional intake in children with chronic kidneydisease. Pediatr Nephrol. 2006;21:1730–8.

21. Tsampalieros A, Kalkwarf HJ, Wetzsteon RJ, et al.Changes in bone structure and the muscle-bone unit inchildren with chronic kidney disease. Kidney Int.2013;83:495–502.

22. Mak R H, Cheung WW, Zhan JY, et al. Cachexia andprotein-energy wasting in children with chronic kidneydisease. Pediatr Nephrol. 2012;27:173–81.

23. Gunta SS, Mak RH. Ghrelin and leptin pathophysiology inchronic kidney disease. Pediatr Nephrol. 2013;28:611–6.

24. Gunta SS, Thadhani RI, Mak RH. The effect of vitamin Dstatus on risk factors for cardiovascular disease. Nat RevNephrol. 2013;9:337–47.

25. Ledermann SE, Shaw V, Trompeter RS. Longterm enteralnutrition in infants and young children with chronic renalfailure. Pediatr Nephrol. 1999;13:870–5.

26. Mar ques de Aquino T, Avesani CM, Brasileiro RS, deAbreu Carvalhaes JT. Resting energy expenditure ofchildren and adolescents undergoing hemodialysis. J RenNutr. 2008;18:312–9.

27. Pol lock C, Voss D, Hodson E, Crompton C. The CARIguidelines: Nutrition and growth in kidney disease.Nephrology (Carlton) 2005;10(Suppl 5):S177–230.

28. Ede fonti A, Picca M, Damiani B, et al. Dietaryprescription based on estimated nitrogen balance duringperitoneal dialysis. Pediatr Nephrol. 1999;13:253–8.

29. Salusky IB, Fine RN, Nelson P, et al. Nutritionalstatus of children undergoing continuous ambulatoryperitoneal dialysis. Am J Clin Nutr. 1983;38:599–611.

30. Coleman JE, Watson AR, Rance CH, Moore E. Gastrostomybuttons for nutritional support on chronic dialysis.

Nephrol Dial Transplant. 1998;13:2041–6.

31. Ree d EE, Roy LP, Gaskin KJ, Knight JF. Nutritionalintervention and growth in children with chronic renalfailure. J Ren Nutr. 1998;8:122–6.

32. Van Dyck M, Bilem N, Proesmans W. Conservativetreatment for chronic renal failure from birth: A 3-yearfollow-up study. Pediatr Nephrol. 1999;13:865–9.

33. Bon thuis M, van Stralen KJ, Verrina E, et al.Underweight, overweight and obesity in paediatric dialysisand renal transplant patients. Nephrol Dial Transplant.2013;28(Suppl 4):iv195–iv204.

34. Sec ker D, Mak R. Nutritional challenges in pediatricchronic kidney disease. In: Geary DF, Schaefer F, editors.Comprehensive Pediatric Nephrology, 1st ed. Philadelphia:Mosby; 2008. pp. 743–59. 35. Dello Strologo L, PrincipatoF, Sinibaldi D, et al. Feeding dysfunction in infants withsevere chronic renal failure after long-term nasogastrictube feeding. Pediatr Nephrol. 1997;11:84–6. 36. Col emanJE, Watson AR. Growth posttransplantation in childrenpreviously treated with chronic dialysis and gastrostomyfeeding. Adv Perit Dial. 1998;14:269–73. 37. Pugh P,Watson AR. Transition from gastrostomy to oral feedingfollowing renal transplantation. Adv Perit Dial.2006;22:153–7. 38. Gol dstein SL, Baronette S, GambrellTV, et al. nPCR assessment and IDPN treatment ofmalnutrition in pediatric hemodialysis patients. PediatrNephrol. 2002;17:531–4. 39. Krause I, Shamir R,Davidovits M, et al. Intradialytic parenteral nutrition inmalnourished children treated with hemodialysis. J RenNutr. 2002;12:55–9. 40. Ore llana P, Juarez-Congelosi M,Goldstein SL. Intradialytic parenteral nutrition treatmentand biochemical marker assessment for malnutrition inadolescent maintenance hemodialysis patients. J Ren Nutr.2005;15:312–7. 41. Kop ple JD, Levey AS, Greene T, et al.Effect of dietary protein restriction on nutritionalstatus in the Modification of Diet in Renal Disease Study.Kidney Int. 1997;52:778–91. 42. Menon V, Kopple JD, WangX, et al. Effect of a very low-protein diet on outcomes:Long-term follow-up of the Modification of Diet in RenalDisease (MDRD) Study. Am J Kidney Dis. 2009;53:208–17.43. Cha turvedi S, Jones C. Protein restriction forchildren with chronic renal failure. Cochrane DatabaseSyst Rev. 2007:(17)006863. 44. Win gen AM, Fabian-Bach C,Schaefer F, Mehls O. Randomised multicentre study of alow-protein diet on the progression of chronic renalfailure in children. European Study Group of Nutritional

Treatment of Chronic Renal Failure in Childhood. Lancet.1997;349:1117–23. 45. Boaz M, Smetana S. Regressionequation predicts dietary phosphorus intake from estimateof dietary protein intake. J Am Diet Assoc.1996;96:1268–70. 46. Uri barri J. Phosphorus homeostasisin normal health and in chronic kidney disease patientswith special emphasis on dietary phosphorus intake. SeminDial. 2007;20:295–301. 47. Van Horn L. Fiber, lipids, andcoronary heart disease: A statement for healthcareprofessionals from the Nutrition Committee, American HeartAssociation. Circulation. 1997;95:2701–4. 48. Keane WF,Tomassini JE, Neff DR. Lipid abnormalities in patients withchronic kidney disease. Contrib Nephrol. 2011;171:135–42.49. Saland JM, Pierce CB, Mitsnefes MM, et al.Dyslipidemia in children with chronic kidney disease.Kidney Int. 2010;78:1154–63.

50. Querfeld U, Salusky IB, Nelson P, et al.Hyperlipidemia in pediatric patients undergoing peritonealdialysis. Pediatr Nephrol 1988;2:447–52.

51. Kavey R E, Allada V, Daniels SR, et al. Cardiovascularrisk reduction in high-risk pediatric patients: Ascientific statement from the American Heart AssociationExpert Panel on Population and Prevention Science; theCouncils on Cardiovascular Disease in the Young,Epidemiology and Prevention, Nutrition, Physical Activityand Metabolism, High Blood Pressure Research,Cardiovascular Nursing, and the Kidney in Heart Disease;and the Interdisciplinary Working Group on Quality of Careand Outcomes Research: Endorsed by the American Academy ofPediatrics. Circulation. 2006;114:2710–38.

52. Sch aefer B, Wuhl E. Progression in chronic kidneydisease and prevention strategies [educational paper]. EurJ Pediatr. 2012;171:1579–88.

53. Kidney Disease Outcomes Quality Initiative. Clinicalpractice guidelines for cardiovascular disease in dialysispatients. Am J Kidney Dis. 2005;45:S1–153.

54. American Academy of Pediatrics. National CholesterolEducation Program: Report of the Expert Panel on BloodCholesterol Levels in Children and Adolescents.Pediatrics. 1992;89:525–84.

55. Gidding SS, Dennison BA, Birch LL, et al. Dietaryrecommendations for children and adolescents: A guide forpractitioners. Consensus statement from the American HeartAssociation. Circulation. 2005;112:2061–75.

56. Nii nikoski H, Lapinleimu H, Viikari J, et al. Growthuntil 3 years of age in a prospective, randomized trial ofa diet with reduced saturated fat and cholesterol.Pediatrics. 1997;99:687–94.

57. Cabo J, Alonso R, Mata P. Omega-3 fatty acids andblood pressure. Br J Nutr. 2012;107(Suppl 2): S195–200.

58. Rangel-Huerta OD, Aguilera CM, Mesa MD, Gil A. Omega-3long-chain polyunsaturated fatty acids supplementation oninflammatory biomarkers: A systematic review of randomisedclinical trials. Br J Nutr. 2012;107(Suppl 2):S159–70.

59. Vedtofte MS, Jakobsen MU, Lauritzen L, Heitmann BL.The role of essential fatty acids in the control ofcoronary heart disease. Curr Opin Clin Nutr Metab Care.2012;15:592–6.

60. Calder PC, Yaqoob P. Marine omega-3 fatty acids andcoronary heart disease. Curr Opin Cardiol. 2012;27:412–9.

61. Gor en A, Stankiewicz H, Goldstein R, Drukker A. Fishoil treatment of hyperlipidemia in children andadolescents receiving renal replacement therapy.Pediatrics. 1991;88:265–8.

62. Per eira AM, Hamani N, Nogueira PC, Carvalhaes JT.Oral vitamin intake in children receiving long-termdialysis. J Ren Nutr. 2000;10:24–9. 63. Dibas BI, WaradyBA. Vitamin D status of children receiving chronicdialysis. Pediatr Nephrol. 2012;27:1967–73. 64. Kri leyM, Warady BA. Vitamin status of pediatric patientsreceiving long-term peritoneal dialysis. Am J Clin Nutr.1991;53:1476–9. 65. Warady BA, Kriley M, Alon U,Hellerstein S. Vitamin status of infants receivinglong-term peritoneal dialysis. Pediatr Nephrol.1994;8:354–6. 66. Goo dman WG, Coburn JW. The use of1,25-dihydroxyvitamin D3 in early renal failure. Annu RevMed. 1992;43:227–37. 67. Kidney Disease Outcomes QualityInitiative, National Kidney Foundation. Clinical practiceguidelines for bone metabolism and disease in childrenwith chronic kidney disease. Am J Kidney Dis.2005;46:S1–121. 68. Wang M, Hercz G, Sherrard DJ, et al.Relationship between intact 1-84 parathyroid hormone andbone histomorphometric parameters in dialysis patientswithout aluminum toxicity. Am J Kidney Dis.1995;26:836–44. 69. Rees L. What parathyroid hormonelevels should we aim for in children with stage 5 chronickidney disease: What is the evidence? Pediatr Nephrol.

2008;23:179–84. REVIEW QUESTIONS 1. Which one of thefollowing statements is true? a. No association has beenfound between low body mass index and increased risk formortality in children. b. Growth failure in infants withCKD is mainly due to malnutrition. c. Rates of lineargrowth and neurodevelopment are highest during the seconddecade of life. d. �e nutritional status of children withCKD should be evaluated with the same frequency as insameaged healthy children. 2. Which one of the followingparameters is not included in the typical nutritionalassessment for a child with CKD? a. Headcircumference-for-age percentile for children younger than3 years of age b. Height-for-age percentile c.Weight-for-age percentile d. Triceps skinfold thickness3. Whi ch one of the following statements most accuratelydescribes the factors contributing to cachexia in CKD? a.Ghr elin is an orexigenic hormone that may play a role inthe pathogenesis of cachexia in CKD. b. �e fo urcirculating gene products of ghrelin include acyl ghrelin,des-acyl-ghrelin, obestatin, and melatonin.

c. Leptin is an anorexigenic hormone secreted fromleukocytes.

d. Vitamin supplementation has been shown to have littlee�ect on cachexia in experimental CKD.

4. Which one of the following statements is false?

a. �e energy requirements of children with CKD are higherthan those of healthy children.

b. �e caloric intake for children with CKD should bedetermined from national recommendations of the estimatedenergy requirements based on chronologic age and gender.

c. Children on chronic dialysis who receive nutritionalsupport through gastrostomy tube feedings show improvementin weight and height SDS.

d. �e energy intake from dialysate glucose is approximately8 to 12 kcal/kg/day.

5. For children older than 3 years of age, which of thefollowing distributions of calories from carbohydrates,fat, and protein is recommended?

a. Carbohydrates 25% to 35%, fat 45% to 65%, protein 10%to 30%

b. Carbohydrates 10% to 30%, fat 45% to 65%, protein 25%to 35%

c. Carbohydrates 25% to 35%, fat 10% to 30%, protein 45%to 65%

d. Carbohydrates 45% to 65%, fat 25% to 35%, protein 10%to 30%

6. Which of the following macronutrients is lost throughthe peritoneal dialysate ultra�ltrate?

a. Protein

b. Carbohydrates

c. Lipids

d. None of the above

7. Which of the following statements is true?

a. Dyslipidemia is rare in patients with CKD.

b. Children on PD have low prevalence rates (30% to 40%)of hypertriglyceridemia. c. Dyslipidemia potentiallyaccelerates the progression of CKD. d. Restricting dietaryfat to 30% of the total caloric intake has adverse e�ectson growth. 8. Which one of the following vitaminsupplements is recommended in children on dialysis? a.Vitamin A b. Vitamin E c. Vitamin B d. Vitamin K 9.Which one of the following vitamins inhibits PTH secretionand at large doses causes adynamic bone disease? a.Vitamin A b. Vitamin E c. Vitamin C d. Vitamin D 10.Which of the following medications inhibits PTH secretionby increasing the sensitivity of calcium-sensing receptorsto extracellular calcium? a. Calcitriol b. Paricalcitolc. Cinacalcet hydrochloride d. Doxercalciferol ANSWER KEY1. b 2. d 3. a 4. a 5. d 6. a 7. c 8. c 9. d 10. c

35 Continuous renal replacement therapy

1. Haq NU, Nolph KD. Past, present, and future ofquantified peritoneal dialysis. Semin Dial. 2001;14:263-7.

2. Van S tone JC. Dialysis equipment and dialysate, past,present and the future. Semin Nephrol. 1997;17:214-7.

3. Merrill JP. The use of the artificial kidney in thetreatment of uremia. J Urban Health. 1998;75:911-18.

4. Kramer P, Schrader J, Bohnsack W, et al. Continuousarteriovenous haemofiltration: A new kidney replacementtherapy. Proc Eur Dial Transplant Assoc. 1981;18:743–9.

5. Maxvold NJ, Bunchman TE. Renal failure and replacementtherapy. Crit Care Clin. 2003;19:563-75.

6. Kramer P, Wigger W, Rieger J, et al. Arteriovenoushaemofiltration: A new and simple method for treatment ofover-hydrated patients resistant to diuretics. KlinWochenschr .1977;55:1121-2.

7. Bellomo R, Ronco C. An introduction to continuous renalreplacement therapy. In: Bellomo R, Baldwin I, Ronco C,Golper T, editors. Atlas of Hemofiltration. Philadelphia:Saunders; 2001. p. 1–9.

8. Forni LG, Hilton PJ. Continuous hemofiltration in thetreatment of acute renal failure. N Engl J Med.1997;336:1303-9.

9. Lebedo I. Principles and practice of hemofiltration andhemodiafiltration. Artif Organs. 1998;22:20-5.

10. Par akininkas D, Greenberg LA. Comparison of soluteclearance in three modes of continuous renal replacementtherapy. Pediatr Crit Care Med. 2004;5:269-74. 11.Jenkins R, Harrison H, Chen B, et al. Accuracy ofintravenous infusion pumps in continuous renal replacementtherapies. ASAIO J. 1992;38:808-10. 12. Flores FX, BrophyPD, Symons JM, et al. CRRT after stem celltransplantation: A report from the Prospective PediatricCRRT Registry Group. Pediatr Nephrol. 2008;23:625–63. 13.Hackbarth R, Bunchman TW, Chua AN, et al. The effect ofvascular access location and size on circuit survival inpediatric continuous renal replacement therapy: A reportfrom the PPCRRT registry. Int J Artif Organs.2007;12:1116–21. 14. Davenport A, Aulton K, Payne PB, etal. Hyperlactatemia and increasing metabolic acidosis due

to the use of lactate based fluid during haemofiltration.Intensive Care Med. 1989;15:546-7. 15. Davenport A, WillEJ, Davison AM. The effect of lactate-buffered solutionson the acid-base status of patients with renal failure.Nephrol Dial Transplant. 1989;4:800-4. 16. Davenport A,Aulton K, Payne RB, et al. Hyperlactatemia and increasingmetabolic acidosis in hepatorenal failure treated byhemofiltration. Ren Fail. 1990;12:99-101. 17. DavenportA, Will EJ, Davison AM. Hyperlactataemia and metabolicacidosis during haemofiltration using lactate-bufferedfluids. Nephron. 1991;59:461-5. 18. Thomas AN, Guy JM,Kishen R, et al. Comparison of lactate and bicarbonatebuffered haemofiltation fluids: Use in critically illpatients. Nephrol Dial Transplant. 1997;12:1212-7. 19.Zim merman D, Cotman P, Ting R, et al. Continuousveno-venous haemodialysis with a novel bicarbonatedialysis solution: Prospective cross-over comparison with alactate buffered solution. Nephrol Dial Transplant.1999;14:2387-91. 20. Maxvold NJ, Flynn JT, Smoyer WE, etal. Prospective, crossover comparison of bicarbonate vslactate-based dialysate for pediatric CVVHD. Blood Purif.1999;17:27 (abstract). 21. Barenbrock M, Hausberg M,Matzkies F, et al. Effects of bicarbonate- andlactate-buffered replacement fluids on cardiovascularoutcome in CVVH patients. Kidney Int. 2000;58:1751-7. 22.McLean AG, Davenport A, Cox D, et al. Effects oflactate-buffered and lactate-free dialysate in CAVHDpatients with and without liver dysfunction. Kidney Int.2000;58:1765-72. 23. Bunchman TE, Maxvold NJ, Barnett J,et al. Pediatric hemofiltration: Normocarb® dialysatesolution with citrate anticoagulation. Pediatr Nephrol.2002;17:150-4. 24. Bunchman TE, Maxvold NJ, Brophy PD.Pediatric convective hemofiltration (CVVH): Normocarbreplacement fluid and citrate anticoagulation. Am J KidneyDis. 2003;42:1248-52.

SUMMARY

CRRT has evolved since the 1980s as an e�cient

and safe treatment for AKI in both adult and pedi

atric patients. Newer dialysate and replacement �uid

solutions are available, and now one can safely use

bicarbonate as the bu�er to minimize cardiovascular

instability, as well as to minimize the possibility of con

founding the serum lactic acid levels. Anticoagulation

for maintenance of the CRRT circuit is critical to pro

viding adequate �uid and electrolyte therapy in the

pediatric patient with AKI, and citrate anticoagulation

appears to have multiple bene�ts over heparin anti

coagulation. Prostacyclin is an emerging anticoagu

lant with great promise. Vascular access is critical for

proper functioning of a CRRT circuit, and ideally it

should use the largest catheter possible. Finally, CRRT

may be a useful therapy in other clinical conditions,

such as hyperosmolality, intoxications, hematopoietic

cell transplantation, tumor lysis syndrome prevention,

extracorporeal hepatic support, and plasmapheresis.

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following: sodium, 140 mmol/L; potassium, 6.9 mmol/L;chloride, 105 mmol/L; bicarbonate, 14 mmol/L; BUN, 100mg/dL; and lactate, 4.5 mmol/L. A recent ABG showed: pH,7.23; pAO 2 of 90; and pCO 2 of 43. �e child isreceiving norepinephrine for maintaining hemodynamicstability. Current blood pressure is 90/60 mm Hg. �e childis to be placed on CRRT. 1. Optimal size and site ofplacement of the vascular access is: a. 11-Fr dual-lumencatheter in subclavian vein. b. 8- or 9-Fr dual-lumencatheter in right internal jugular vein

c. 8- or 9-Fr dual-lumen catheter in femoral vein

d. 11-Fr dual-lumen catheter in femoral vein

2. Use of AN 69 membrane based hemo�lter in this patient

may be associated with the risk of:

a. Hemo�lter clotting more frequently

b. Poor clearance, if used in convective mode

c. Anaphylaxis

d. AN69 membrane has less clinical risk than polysulfonemembrane

3. If AN69 membrane hemo�lter is used in CRRT, blood

prime should be avoided in this patient due to presence

of metabolic acidosis and enhanced risk of anaphylaxis.

a. True

b. False

4. To allow optimal functioning of CRRT, the ideal arterial

and venous pressures (as noted on the CRRT monitors)

should be:

a. Greater than 50 mm and less than 400 mm

b. Greater than −50 mm and less than −400 mm

c. Greater than −150 mm and less than 200 mm

d. Greater than −150 mm and less than −200 mm

5. In this septic patient, the best modality of CRRT is:

a. Di�usive method (CVVHD)

b. Convective method (CVVH)

c. Slow continuous ultra�ltration (SCUF)

d. Both convestive and di�usive methods (CVVHDF)

6. Small molecular solutes are removed equally well by

convection and di�usion.

a. True

b. False

7. To optimize solute clearance, the optimal total volume of

dialysate and replacement �uid (if using CVVHDF) is:

a. 2000 mL/h/1.73 m 2

b. 35 mL/kg/h

c. Either a or b

d. Neither a nor b

8. Target net �uid ultra�ltration rate to be ordered should

be:

a. 10 mL/h

b. 1 to 2 mL/kg/h

c. 10 mL/kg/h

d. 25 mL/kg/h

CASE 2

A 14-year-old female patient is admitted with new-onset

AKI, oliguria, hyperkalemia, IDDM, dehydration. Her

laboratory tests show: serum sodium, 175 mmol/L (uncor

rected); glucose, 1300 mg/dL; and BUN, 90 mg/dL.

1. What is this patient’s calculated serum osmolality

(mOsm/L)?

a. 280

b. 380

c. 480

d. 542 2. Osmolality (mOsm/L) of the peritoneal dialysate(PD), 1.5% dextrose, low-calcium solution is: a. 280 b.300 c. 320 d. 344 3. Osmolality (mOsm/L) of hemodialysisdialysate is: a. 280 b. 300 c. 320 d. 340 4.Osmolality (mOsm/L) of dialysate used in CRRT is: a. 280b. 300 c. 320 d. 340 CASE 3 A 16-year-old male patient isadmitted to the intensive care unit with multimedicationoverdose. He has AKI and oliguria. He is unresponsive andbut is hemodynamically stable. No seizures have beennoted. If started on CRRT, 1. �e most important factor(s)in determining drug clearance is(are): a. Protein bindingb. Molecular weight c. Volume of distribution d. All ofthe above 2. �e preferred form of renal replacementtherapy (RRT) in this case is: a. PD b. CRRT convectivec. CRRT di�usive d. CRRT convective and di�usive e. HDstandard f. HD sigh �ux CASE 4 A 3-day-old male newborninfant is admitted to the intensive care unit withsomnolence, refusal to feed for 2 days, and twitching ofthe face today. �e child weighs 2.9 kg (240 mLintravascular blood volume). Serum electrolytes show:sodium, 140 mmol/L; potassium, 5 mmol/L;, CO 2, 14mmol/L; and arterial blood pH, 7.02. Ammonia level was1500 μmol/L. 1. �e best type of renal replacement therapy(RRT) that will lower ammonia most rapidly is: a. PD b.CRRT c. Hemodialysis, standard d. Hemodialysis, high �ux

ANSWER KEY

CASE 1

1. b

2. c

3. a

4. c

5. b

6. a

7. c

8. b CASE 2 1. c 2. d 3. a 4. a CASE 3 1. d 2. f CASE4 1. c

36 Hemodialysis

Figure 36.7 Incident and point prevalent patients withend-stage renal disease, 0 to 19 years old, by treatmentmodality

in the United States. HD, hemodialysis; Inc, incidence; PD,peritoneal dialysis; Prev, prevalence; Tx, transplantation.(From

US Renal Data System. USRDS 2013 Annual Data Report: Atlasof Chronic Kidney Disease and End-Stage Renal Disease in

the United States. Bethesda, MD: National Institutes ofHealth, National Institute of Diabetes and Digestive andKidney

Diseases; 2013.)

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guidelines released at the NKF 2006 spring clinicalmeetings. Nephrol News Issues. 2006;20:40, 42. 29. Daugirdas JT. Simplified equations for monitoring kt/V, PCRn,eKt/V and ePCRn. Adv Ren Replace Ther. 1995;2:295–304.30. Got ch FA. The current place of urea kinetic modelingwith respect to different dialysis modalities. NephrolDial Transplant. 1998;13:10–14. 31. Ley poltd JK, JaberBL, Zimmerman DL. Predicting treatment dose for noveltherapies using urea standard kt/V. Semin Dial.2004;17:142–5. 32. Sur i RS, Garg AX, Chertow GM, et al.Frequent Hemodialysis Network (FHN) randomized trials:Study design. Kidney Int. 2007;71:349–59. 33. Lin dsay RM,Nesrallah G, Suri R, et al. Is more frequent hemodialysisbeneficial and what is the evidence? Curr Opin NephrolHypertens. 2004;13:631–5. 34. Rai mann JG, Thijssen S,Ramos R, Levin NW. More frequent hemodialysis: What do weknow? Where do we stand? Contrib Nephrol. 2011;171:10–6.35. Tom A, McCauley L, Bell L, et al. Growth duringmaintenance hemodialysis: Impact of enhanced nutrition andclearance. J Pediatr. 1999;134:464–71. 36. I. NKF-K/DOQIclinical practice guidelines for hemodialysis adequacy:Update 2000. Am J Kidney Dis. 2001;37(Suppl 1):S7–64. 37.Sarkar SR, Kaitwatcharachai C, Levin NW. Complicationsduring hemodialysis. In: Nissenson AR, Fine RN, editors.Clinical Dialysis. 4th ed. New York: McGraw-Hill; 2005. p.237. 38. Mandal AK, Abernathy T, Nelluri SN, Stitzel V. Isquinine effective and safe in leg cramps? J ClinPharmacol. 1995;35:588–93. 39. Daugirdas JT, Ing TS.First-use reactions during hemodialysis: A definition ofsubtypes. Kidney Int Suppl. 1988;24:S37–43. 40. SchulmanG, Hakim R, Arias R, et al. Bradykinin generation bydialysis membranes: Possible role in anaphylactic reaction.J Am Soc Nephrol. 1993;3:1563–9. 41. Muth CM, Shank ES.Gas embolism. N Engl J Med. 2000;342:476–82.

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REVIEW QUESTIONS

1. A 16-year-old boy with a history of end-stage renaldisease from focal segmental glomerulosclerosis has afailing renal allogra� and will need to return to dialysiswithin the next 6 months. He and his family choosehemodialysis as their preferred modality. He is highlysensitized, and although he will be listed for renaltransplant again, you anticipate that his waiting timewill be at least 1 to 2 years. Of the following, the mostappropriate recommendation for hemodialysis vascularaccess is: a. Art eriovenous �stula b. Art eriovenousgra� c. Femo ral venous catheter d. Int ernal jugularvenous catheter e. Sub clavian venous catheter

2. You a re determining the appropriate hemodialysisprescription for a new patient in your hemodialysis unit.When choosing a dialyzer, you obtain the manufacturer’sspeci�cations regarding the K uf . Of the following, themost accurate statement about K uf is that it de�nes: a.e maximum theoretical limit for ultra�ltration at in�nitetransmembrane pressure b. �e maximum theoretical limit forurea clearance at in�nite blood and dialysate �ow rate c.e minimum required transmembrane pressure necessary toprevent back-�ltration d. �e volume of blood cleared ofurea in 1 min at a given blood �ow rate e. �e volume ofuid that will cross the membrane in 1 h at a giventransmembrane pressure

3. A 12-year-old patient presenting to the emergencydepartment with several weeks of fatigue, malaise, andweight loss is found to have renal failure with BUN 110mg/dL and Cr 11.7 mg/dL. Renal ultrasound demonstratessmall, echogenic kidneys bilaterally. You believe that thepatient likely has had undiagnosed renal dysplasia and nowhas end-stage renal disease. �e patient is tired and thinbut alert without signs of volume overload. You makearrangements to initiate hemodialysis. Of the following,the most appropriate consideration in the initialhemodialysis prescriptions would be: a. Ensure vascularaccess that can provide blood �ow of at least 300 mL/min.b. Avo id heparin anticoagulation for the �rst week. c.Preferentially choose a polysulfone dialyzer membrane. d.Target urea clearance of no more than 30%. e. Use adialyzer with a high KoA. 4. During the dialysis process,several factors are responsible for molecular transport.Of the following, the most accurate statement regardingthe physical principles of molecular transport that areactive in hemodialysis is: a. Adsorption favors movementof smaller molecules over larger molecules. b. Convection

favors movement of smaller molecules over largermolecules. c. Di�usion favors movement of smallermolecules over larger molecules. d. Ultra�ltration favorsmovement of smaller molecules over larger molecules. e.Under most circumstances in hemodialysis, small and largemolecules transport equally. 5. �e hemodialysis apparatusis complex and has multiple components designed to providesafe and e�ective therapy to the patient. Of thefollowing, the option that best describes the two maincomponents of the dialysis apparatus is: a. �e bloodcircuit and the dialysate circuit b. �e hemodialyzer andthe vascular access c. �e arterial segment and the venoussegment d. �e proportioning system and the ultra�ltrationcontroller e. �e “A” concentrate and the “B” concentrate6. An 11-year-old girl is admitted to the intensive careunit with meningococcemia and renal failure as a secondarye�ect of her multiorgan dysfunction syndrome. Herpotassium level has risen to 7.2 mEq/L, with changes onher electrocardiogram suggesting evidence for cardiace�ects. You are preparing to perform emergency hemodialysisto correct the hyperkalemia. Of the following, the mostappropriate option for vascular access would be: a.Arteriovenous �stula b. Arteriovenous gra� c. Bilateralsingle-lumen cephalic vein catheters d. Femoraldouble-lumen venous catheter e. Subclavian double-lumenvenous catheter 7. A 19-year-old male patient has beenreceiving hemodialysis for acute kidney injury for 8 weeksbecause of complications following liver transplantation.He has tolerated his sessions well, but he remainsintubated in the intensive care unit. Over the last week,his platelet count has dropped, and the intensive careunit team is concerned that he may have heparin-inducedthrombocytopenia. �ey ask whether there are options toperform his hemodialysis sessions but limit his heparinexposure. Of the following, the method most likely toensure e�ective hemodialysis sessions and also address theconcern for heparin-induced thrombocytopenia would be to:a. Change unfractionated heparin to low-molecularweightheparin. b. Eliminate heparin and use citrate-containingdialysate. c. Give a heparin bolus at the start ofhemodialysis but avoid use of continuous infusion. d.Perform hemodialysis without anticoagulation. e. Use halfthe previous dose of unfractionated heparin.

8. A 10-month-old boy with end-stage renal disease fromposterior urethral valves who is maintained on peritonealdialysis develops fungal peritonitis and must make atemporary transition to hemodialysis. He weighs 7.7 kg andis polyuric. Of the following, the most accurate statementabout plans for hemodialysis is that: a. Extended session

length is likely required to achieve ultra�ltration goals.b. Heparin cannot be used as the anticoagulant. c. Highmetabolic needs will obligate use of a dialyzer with ahigh KoA. d. Outcome data indicate that the single-poolKt/V target for this age group is 1.6. e. �e patient willlikely need blood prime of the hemodialysis circuit.

9. You are preparing the prescription for a 10-year-oldgirl with end-stage renal disease from renal dysplasia whowill initiate hemodialysis. �e patient has a newright-sided 10-French internal jugular catheter that youanticipate will deliver a blood �ow rate of 150 mL/ min.You have chosen a hemodialyzer with K D for urea of 120mL/min at that blood �ow rate. �e patient weighs 35 kg;she does not appear volume overloaded. You would like totarget a urea clearance of approximately 30% for this �rstsession. Of the following, the dialysis time that willmost likely give a urea clearance closest to the target of30% is: a. 30 min b. 60 min c. 90 min d. 120 min e.180 min 10. You are reviewing the dialysis adequacystudies for your unit and notice that a patient has Kt/Vthis month of 1.1. �e patient has been doing well onhemodialysis, growing, thriving and participating inschool. Results of blood testing have been stable.Previous values for Kt/V over the last 6 months have been1.4 to 1.6. His current prescription is as follows:Dialyzer: KoA 1100 mL/min Vascular access: 12-Frenchright-sided internal jugular catheter Blood �ow rate: 250mL/min Session length: 3 h Schedule: Tuesday, �ursday,Saturday Of the following, the most appropriate next stepto address the low Kt/V for this patient would be to: a.Adjust the dialysis schedule to Monday, Tuesday, �ursday,and Saturday. b. Change to a larger dialyzer with KoA 1400mL/ min. c. Increase dialysis time to 4 h/session. d.Refer the patient for urgent placement of an arteriovenousstula. e. Review session characteristics and repeat Kt/Vmeasurement. ANSWER KEY 1. a 2. e 3. d 4. c 5. a 6. d7. b 8. e 9. b 10. e

37 Peritoneal dialysis

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109. Ara nda RA, Romao Junior JE, Kakehashi E, et al.Intraperitoneal pressure and hernias in children onperitoneal dialysis. Pediatr Nephrol. 2000;14:22–4. 110.Bakkaloglu A. Non-infectious compolications of peritonealdialysis in children. In: Warady BA, Schaefer F, AlexanderS, editors. Pediatric Dialysis, 2nd ed. New York:Springer; 2012. p. 257–71. 111. Levin NW, Zasuwa G.Relationship between dialyser type and signs and symptoms.Nephrol Dial Transplant. 1993;8(Suppl 2):30–9. 112. Rockel A, Klinke B, Hertel J, et al. Allergy to dialysismaterials. Nephrol Dial Transplant. 1989;4:646–52. 113.Purello D’Ambrosio F, Savica V, Gangemi S, et al. Ethyleneoxide allergy in dialysis patients. Nephrol DialTransplant. 1997;12:1461–3. 114. Hothi D, Harvey E. Commoncomplications of haemodialysis. In: Warady B, Schaefer F,Alexander S, editors. Pediatric Dialysis, 2nd ed. NewYork: Springer; 2012:345–74. 115. Boeschoten EW, KredietRT, Roos CM, et al. Leakage of dialysate across thediaphragm: An important complication of continuousambulatory peritoneal dialysis. Neth J Med. 1986;29:242–6.116. Cop po R, Amore A, Cirina P, et al. Bradykinin andnitric oxide generation by dialysis membranes can beblunted by alkaline rinsing solutions. Kidney Int.2000;58:881–8. 117. Hak im RM, Schafer AI.Hemodialysis-associated platelet activation andthrombocytopenia. Am J Med. 1985;78:575–80. 118. SilverSM, DeSimone JA, Jr, Smith DA, et al. Dialysisdisequilibrium syndrome (DDS) in the rat: Role of the“reverse urea effect.” Kidney Int. 1992;42:161–6. 119.Fischbach M, Warady BA. Peritoneal dialysis prescription inchildren: Bedside principles for optimal practice. PediatrNephrol. 2009;24:1633–42; quiz 40, 42. 120. War ady BA,Watkins SL, Fivush BA, et al. Validation of PD Adequest2.0 for pediatric dialysis patients. Pediatr Nephrol.2001;16:205–11. 121. Ver rina E, Amici G, Perfumo F, etal. The use of the PD Adequest mathematical model inpediatric patients on chronic peritoneal dialysis. PeritDial Int. 1998;18:322–8. 122. Morgenstern BZ, Wuhl E, NairKS, et al. Anthropometric prediction of total body waterin children who are on pediatric peritoneal dialysis. JAm Soc Nephrol. 2006;17:285–93. 123. Verrina E, Perri K.Technical aspects and prescription of peritoneal dialysis

in children. In: Warady BA Schaefer F, Alexander S,editors. Pediatric Dialysis, 2nd ed. New York: Springer;2012. p. 169–203. 124. Bakkaloglu SA, Borzych D, Soo Ha I,et al. Cardiac geometry in children receiving chronicperitoneal dialysis: Findings from the InternationalPediatric Peritoneal Dialysis Network (IPPN) registry.Clin J Am Soc Nephrol. 2011;6:1926–33. 125. Gerson A,Hwang W, Fiorenza J, et al. Anemia and health-relatedquality of life in adolescents with chronic kidneydisease. Am J Kidney Dis. 2004;44:1017–23.

126. Goldstein SL, Graham N, Burwinkle T, et al.Healthrelated quality of life in pediatric patients withESRD. Pediatr Nephrol. 2006;21:846–50.

127. Mit snefes MM, Laskin BL, Dahhou M, et al. Mortalityrisk among children initially treated with dialysis forend-stage kidney disease, 1990-2010. JAMA.2013;309:1921–9.

REVIEW QUESTIONS

1. �e greatest percentage of prevalent pediatric patientsreceives which of the following renal replacementmodalities? a. Peritoneal dialysis b. Hemodialysis c.Kidney transplant

2. Which of the following peritoneal membrane porescomprise 90% to total pore area? a. Aquaporins b. Sma llpores c. Lar ge pores

3. Con vective mass transfer is responsible for only asmall portion of large solute removal. a. Tru e b. Fals e

4. �e PE T test should be performed with which one of thefollowing solutions for all older children and adolescentsundergoing PD? a. Icodex trin b. �e re gular clinical �llvolume for that patient c. 110 0 mL/m 2 of a mixture of2.5% and 4.25% PD solution d. 1100 mL/m 2 of 2.5% PDsolution

5. Which one of the following is not an absolutecontraindication to long-term PD? a. Gastroschisis b.Ventriculoperitoneal shunt c. Omphalocele d. Obliteratedperitoneal cavity

6. Which of the following measures has not led to adecreased rate of peritonitis in children and adults?(Choose one) a. Topical application of antibiotic atcatheter exit site b. Flush before �ll technique c.

Disconnect systems d. Use of Tenckho� catheter with curledintraperitoneal portion 7. Which of the following is nottrue about hernias that develop in pediatric patientsundergoing PD? (Choose one) a. �e incidence is directlyproportional to the patient’s age. b. More than 75%require surgical repair. c. Raised IPP is a risk factorfor hernia development. d. Surgical repair should befollowed by no/low-volume dialysis. 8. �e achievement ofPD adequacy should take all but which one of the followingfactors into consideration? a. Peritoneal membrane solutetransport capacity b. Frequency of peritonitis c.Patient’s body surface area d. Residual renal function 9.e term “V” in Kt/V is equivalent to which one of thefollowing? a. Volume of the peritoneal dialysis solutionb. Total blood volume c. Total body water d. Volume ofultra�ltrate 10. An important cause of mortality inpediatric patients undergoing PD includes which one of thefollowing? a. Cardiovascular disease b. Inadequate Kt/Vc. Poor catheter function d. Loss of residual kidneyfunction ANSWER KEY 1. c 2. b 3. b 4. d 5. b 6. d 7.a 8. b 9. c 10. a

38 Renal transplantation

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4. Lubrano R, Perez B, Elli M. Methylmalonic acidemia andkidney transplantation. Pediatr Nephrol. 2013;28:2067–8.

5. McGuire PJ, Lim-Melia E, Diaz GA, et al. Combinedliver-kidney transplant for the man agement ofmethylmalonic aciduria: A case rep ort and review of theliterature. Mol Genet Metab. 2008;93:22–9.

6. Rumsby G, Cochat P. Primary hyperoxaluria. N Engl JMed. 2013;369:2163.

7. El Sayegh S, Keller MJ, Huprikar S, Murphy B. Solidorgan transplantation in HIV-infected recipients. PediatrTransplant. 2004;8:214–21.

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26. Halloran PF. Immunosuppressive drugs for kidneytransplantation. N Engl J Med. 2004;351:2715–29.

27. Mou dgil A, Puliyanda D. Induction therapy in pediatricrenal transplant recipients: An overview. Paediatr Drugs.2007;9:323–41.

28. Jordan SC, Toyoda M, Kahwaji J, Vo AA. Clinicalaspects of intravenous immunoglobulin use in solid organtransplant recipients. Am J Transplant. 2011;11:196–202.

29. Zub er J, Le Quintrec M, Krid S, et al. Eculizumab foratypical hemolytic uremic syndrome recurrence in renaltransplantation. Am J Transplant. 2012;12:3337–54.

30. Matasic R, Dietz AB, Vuk-Pavlovic S. Dexamethasoneinhibits dendritic cell maturation by redirectingdifferentiation of a subset of cells. J Leukocy Biol.1999;66:909–14.

31. Vincenti F. Are calcineurin inhibitors-free regimens

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32. Kin near G, Jones ND, Wood KJ. Costimulation blockade:Current perspectives and implications for therapy.Transplantation. 2013;95:527–35.

33. Phas e II Pharmacokinetics, efficacy, and safety ofbelatacept in pediatric renal transplant recipients: 2013.Available at http://clinicaltrials.gov/ct2/show/NCT01791491. Accessed September 4, 2015.

34. Abu ali MM, Arnon R, Posada R. An update onimmunizations before and after transplantation in thepediatric solid organ transplant recipient. PediatrTransplant. 2011;15:770–7.

35. Kas iske BL, Bia MJ. The evaluation and selection ofliving kidney donors. Am J Kidney Dis. 1995;26:387–98.

36. Piros L, Langer RM. Laparoscopic donor nephrectomytechniques. Curr Opin Organ Transplant. 2012;17:401–5.

37. Shapiro M, Sarwal MM. Pediatric kidney transplantation.Pediatr Clin North Am. 2010;57:393–400.

38. Sarwal MM, Ettenger RB, Dharnidharka V, et al.Complete steroid avoidance is effective and safe inchildren with renal transplants: A multicenter randomizedtrial with three-year follow-up. Am J Transplant.2012;12:2719–29.

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Transplant. 2011;11:2279–96. 45. Troppmann C, McBride MA,Baker TJ, Perez RV. Laparoscopic live donor nephrectomy: Arisk factor for delayed function and rejection inpediatric kidney recipients? A UNOS analysis. Am JTransplant. 2005;5:175–82. 46. Crave di P, Ruggenenti P,Remuzzi G. Sirolimus for calcineurin inhibitors in organtransplantation: Contra. Kidney Int. 2010;78:1068–74. 47.Salvatierra O Jr, Millan M, Concepcion W. Pediatric renaltransplantation with considerations for successfuloutcomes. Semin Pediatr Surg. 2006;15:208–17. 48. Cop polaA, Tufano A, Cerbone AM, Di Minno G. Inheritedthrombophilia: Implications for prevention and treatmentof venous thromboembolism. Semin Thromb Hemost.2009;35:683–94. 49. Kfo ury E, Taher A, Saghieh S, et al.The impact of inherited thrombophilia on surgery: A factorto consider before transplantation? Mol Biol Rep.2009;36:1041–51. 50. Wil son CH, Rix DA, Manas DM. Routineintraoperative ureteric stenting for kidney transplantrecipients. Cochrane Database Syst Rev. 2013;(6)004925.51. Coelho T, Tr edger M, Dhawan A. Current status ofimmunosuppressive agents for solid organ transplantation inchildren. Pediatr Transplant. 2012;16:106–22. 52. Sol ezK, Colvin RB, Racusen LC, et al. Banff 07 classification ofrenal allograft pathology: Updates and future directions.Am J Transplant. 2008;8:753–60. 53. Sis B, Jhangri GS,Riopel J, et al. A new diagnostic algorithm forantibody-mediated microcirculation inflammation in kidneytransplants. Am J Transplant. 2012;12:1168–79. 54.Upadhyay K, Midgley L, Moudgil A. Safety and efficacy ofalemtuzumab in the treatment of late acute renal allograftrejection. Pediatr Transplant. 2012;16:286–93. 55. van den Hoogen MW, Hesselink DA, van Son WJ, et al. Treatmentof steroid-resistant acute renal allograft rejection withalemtuzumab. Am J Transplant. 2013;13:192–6. 56. RobertsDM, Jiang SH, Chadban SJ. The treatment of acuteantibody-mediated rejection in kidney transplantrecipients-a systematic review. Transplantation.2012;94:775–83. 57. Eid L, Tuchman S, Moudgil A. Lateacute rejection: Incidence, risk factors, and effect ongraft survival and function. Pediatr Transplant.2014;18:155–62. 58. Husain S, Sis B. Advances in theunderstanding of transplant glomerulopathy. Am J Kid Dis2013;62:352–63.

59. Wheeler DC, Becker GJ. Summary of KDIGO guideline.What do we really know about management of blood pressurein patients with chronic kidney disease? Kidney Int.2013;83:377–83.

60. Hocker B, Tonshoff B. Treatment strategies to minimize

or prevent chronic allograft dysfunction in pediatricrenal transplant recipients: An overview. Paediatr Drugs.2009;11:381–96.

61. Touma J, Costanzo A, Boura B, et al. Endovascularmanagement of transplant renal artery stenosis. J VascSurg. 2014;59:1058–65

62. Marinella MA. Hematologic abnormalities followingrenal transplantation. Int Urol Neph. 2010;42:151–64.

63. Kahwaji J, Barker E, Pepkowitz S, et al. Acutehemolysis after high-dose intravenous immunoglobulintherapy in highly HLA sensitized patients. CJASN.2009;4:1993–7.

64. Wu Y, Cheng W, Yang XD, et al. Growth hormone improvesgrowth in pediatric renal transplant recipients: Asystemic review and meta-analysis of randomized controlledtrials. Pediatr Nephrol. 2013;28:129–33.

65. Fine RN, Stablein D, Cohen AH, et al. Recombinanthuman growth hormone post-renal transplantation inchildren: A randomized controlled study of the NAPRTCS.Kidney Int. 2002;62:688–96.

66. Ponticelli C, Glassock RJ. Posttransplant recurrence ofprimary glomerulonephritis. CJASN. 2010;5:2363–72.

67. Vin ai M, Waber P, Seikaly MG. Recurrence of focalsegmental glomerulosclerosis in renal allograft: Anin-depth review. Pediatr Transplant. 2010;14:314–25.

68. Sgambat K, Banks M, Moudgil A. Effect of galactose onglomerular permeability and proteinuria insteroid-resistant nephrotic syndrome. Pediatr Nephrol.2013;28:2131–5.

69. Yu CC, Fornoni A, Weins A, et al. Abatacept inB7-1-positive proteinuric kidney disease. N Engl J Med.2013;369:2416-–23.

70. Caires RA, Marques ID, Repizo LP, et al. De novothrombotic microangiopathy after kidney transplantation:Clinical features, treatment, and long-term patient andgraft survival. Transplantation Proc. 2012;44:2388–90.

71. Ponticelli C, Glassock RJ. De novo membranousnephropathy (MN) in kidney allografts: A peculiar form ofalloimmune disease? Transpl Int. 2012;25:1205–10.

72. Swaminathan S, Lager DJ, Qian X, et al. Collapsingand non-collapsing focal segmental glomerulosclerosis inkidney transplants. Nephrol Dial Transplant.2006;21:2607–14.

73. Kas htan CE. Renal transplantation in patients withAlport syndrome. Pediatr Transplant. 2006;10:651–7.

74. Ben oit G, Machuca E, Antignac C. Hereditary nephroticsyndrome: A systematic approach for genetic testing and areview of associated podocyte gene mutations. PediatrNephrol. 2010;25:1621–32. 75. Kidney Disease ImprovingGlobal Outcomes. Clinical practice guideline for thediagnosis, evaluation, prevention, and treatment ofchronic kidney disease-mineral and bone disorder (CKDMBD).Kidney Int. 2009;76(Suppl 113):S3–S121. 76.Kalantar-Zadeh K, Molnar MZ, Kovesdy CP, et al. Managementof mineral and bone disorder after kidney transplantation.Curr Opin Nephrol Hypertens. 2012;21:389–403. 77. Wan nerC, Tonelli M, for Improving Global Outcomes LipidGuideline Development Work Group. KDIGO clinical practiceguideline for lipid management in CKD: Summary of recommendation statements and clinical approach to the patient. Kidney Int. 2014;85:1303–9. 78. Fos ter BJ, MartzK, Gowrishankar M, et al. Weight and height changes andfactors associ ated with greater weight and height gainsafter ped iatric renal transplantation: A NAPRTCS study.Transplantation. 2010;89:1103–12. 79. Pascual J,Perez-Saez MJ, Mir M, et al. Chronic renal allograftinjury: Early detection, accurate diagnosis andmanagement. Transplant Rev (Orlando). 2012;26:280–90. 80.Dha rnidharka VR, Lamb KE, Gregg JA, et al. Associationsbetween EBV serostatus and organ transplant type in PTLDrisk: An analysis of the SRTR National Registry Data inthe United States. Am J Transplant. 2012;12:976–83. 81.Green M, Michaels MG. Epstein-Barr virus infec tion andposttransplant lymphoproliferative dis order. Am JTransplant. 2013;13:41–54 82. Pre ndergast MB, Gaston RS.Optimizing medication adherence: An ongoing opportunityto improve outcomes after kidney transplanta tion. CJASN.2010;5:1305–11. 83. Shellmer DA, Dabbs AD, Dew MA. Medicaladherence in pediatric organ transplantation: What are thenext steps? Curr Opin Organ Transplant. 2011;16:509–14.84. Watson AR, Harden PN, Ferris ME, et al. Transitionfrom pediatric to adult renal services: A consensusstatement by the International Society of Nephrology (ISN)and the International Pediatric Nephrology Association(IPNA). Kidney Int. 2011;80:704–7. 85. Moudgil A,Dharnidharka VR, Lamb KE, et al. Best allograft survival

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REVIEW QUESTIONS

1. A 5-year-old previously healthy child developed acutekidney injury as a result of septic shock. He receivedcontinuous renal replacement therapy for 1 month and thentransitioned to peritoneal dialysis as his kidneys failedto recover. He received a number of blood transfusionsduring his stay in the ICU. His parents ask about theoption of kidney transplant. He has otherwise completelyrecovered and weighs 15 kg. He is CMV IgG positive and EBVIgG negative. �e most important challenge posed for kidneytransplant in this child is:

a. Size of 15 kg

b. Potential for sensitization because of number of bloodtransfusions

c. EBV negative status

d. CMV positive status

2. A 10-year-old with ESRD secondary to FSGS underwentliving kidney transplant from a family friend. �e kidneyworked immediately with good urine output and decrease increatinine. At 36 hours later, he developed severeoliguria and creatinine started to increase. �e next stepin workup of gra� dysfunction includes which of thefollowing?

a. Uri nalysis and urine for ratio of protein to creatinine

b. Rena l ultrasound with Doppler

c. MAG -3 renal scan

d. VCUG

3. A 15year-old girl under went kidney transplant 4 yearsago for ESRD secondary to renal dysplasia with stable serumcreatinine level of 0.6 mg/ dL. For the past year, she o�enmissed clinic appointments, and her tacrolimus trough

levels are quite variable, including some undetectablelevels. She has come to the clinic a�er 8 months and a�errepeated reminders. On questioning, she denies missing anymedications. During clinic visit, she is asymptomatic buther serum creatinine level is 1.1 mg/dL and her tacrolimuslevel is therapeutic. You plan for renal biopsy. �e mostlikely �nding on biopsy would be:

a. Acute rejection

b. Tacrolimus toxicity

c. BKV nephropathy

d. Urinary tract infection

4. A 9-year-old with ESRD secondary to PUV presents forkidney transplant. He has daytime increased frequency andnighttime incontinence. VCUG shows a small-capacitytrabeculated bladder. �e next step in preparation of thischild for transplant includes:

a. Ult rasound and urinalysis and urine culture

b. Uro dynamic studies, bladder augmentation, and use of aMitrofano� procedure for catheterization before transplantc. Blad der augmentation and use of a Mitrofano� procedurefor catheterization a�er transplant d. No specialpreparation needed, because bladder would enlarge a�ertransplant 5. A 6-y ear-old girl with blood group A+ withESRD secondary to renal dysplasia, CPRA of 40% is beingworked up for living-related transplant. She has fourpotential donors. Which one is the best donor for thischild? a. A 30year-old mom with blood group O+, �owcross-match is negative, and there are no donor speci�cantibodies. b. A 32-year-old dad with blood group A+,child has moderately strong donor-speci�c antibody toDR53, �ow B-cell cross-match is positive, and CDCcross-match is negative. c. A 22-y ear-old unrelatedsix-antigen mismatched donor with blood group O+, �owcross-match negative, and there are no donor-speci�cantibodies. d. A 3-y ear-old brother with �ve-antigenmismatch, blood group O+, �ow cross-match is negative, andthere are no donor-speci�c antibodies. 6. A 16-year-oldgirl who received a kidney renal transplant approximately4 months ago was doing well, with a baseline creatininelevel of 0.7 mg/dL. She was on tacrolimus 1 mg capsule (4mg PO BID) and mycophenolate mofetil (CellCept) 500 mg POBID. You receive a call from her mother stating that shehas been accidentally taking 4 (5 mg) capsules of

tacrolimus for the past 2 days. When seen in the emergencyroom, you expect to see: a. Hypertension, tremors, andheadache b. Increase in creatinine, high serum potassium,low CO 2 and magnesium, and high tacrolimus level inblood c. A and B d. Stable creatinine, normal serum K andCO 2 , and high magnesium and tacrolimus level 7. A12-year-old kidney transplant recipient presents to theclinic with unexplained weight loss and intermittent vagueabdominal pain for the past 2 to 3 months. He had ESRDsecondary to nephronophthisis and received a kidneytransplant 8 years ago from a deceased donor. He has beenstable until recently and has not had any acuterejections. He has no fever and denies any other symptoms.His physical examination is normal, except for weightloss of 6 kg. His BP is normal and his creatinine is atits baseline of 0.6 mg/dL and urinalysis is normal. Youwould like to start the workup of his weight loss, and thetests that would be most useful are: a. CMV and BKV viralloads b. Interferon-γ release assay for tuberculosis c.LDH, uric acid, EBV viral load

d. CT scan of abdomen, chest, and pelvis

e. Hemoglobin A 1c

8. A 9-year-old child transplanted with his father’skidney 9 days ago is seen for post-transplant followup inthe clinic. You notice that he has a swelling near theallogra� and in the suprapubic area, which is mildlytender to touch. He had ESRD secondary to renal dysplasia,his Foley catheter was removed on postoperative day 5, andhe was discharged home on postoperative day 6 with a serumcreatinine of 0.7 mg/dL. His serum creatinine today is 1.3mg/dL. Renal ultrasound with Doppler shows good perfusionand normal renal transplant morphology and resistiveindex. An anechoic �uid collection is present next to histransplant and in the pelvis, which was not present 4 daysago. Which tests would help in determining the cause ofacute renal dysfunction in this child?

a. Renal biopsy

b. Pharmacokinetics of tacrolimus

c. MAG-3 renal scan and VCUG

d. Needle aspiration of �uid and measurement of creatininein this �uid

e. c and d

9. A 4-year-old child who received a CMV mismatched kidneytransplant comes to clinic 3 months a�er transplant with ahistory of low-grade fever for 2 days. He had receivedinduction with �ymoglobulin for 4 days and is on steroidwithdrawal protocol. His CBC shows a white cell count of1.5 K and a platelet count of 120 K, decreased from 4.2 Kand 240 K, respectively, 1 week ago. His creatinine hasincreased by 0.2 mg/dL from the baseline. You make adiagnosis of CMV infection based on elevated CMV viralload. �e next best step in management of this child is:a. Decrease MMF and continue the remainder of managementbecause he is already receiving valganciclovir. b. Admitfor intravenous ganciclovir and monitor renal function andCMV viral load. c. Perform renal biopsy to rule out acuterejection before starting any therapy. d. Suspectresistant CMV infection and discontinue allimmunosuppression. 10. �e impact of delayed gra� functionon the outcome of kidney transplants is: a. It wouldincrease the risk for acute rejection. b. It has anegative impact on long-term gra� survival. c. You needto increase the intensity of immunosuppression. d. a, b,and c e. It does not increase acute rejection or have animpact on gra� survival. ANSWER KEY 1. b 2. a 3. a 4.b 5. a 6. c 7. d 8. e 9. b 10. d

39 Hypertension in children andadolescents

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REVIEW QUESTIONS

1. According to current guidelines, the initial evaluationof all children with con�rmed hypertension should includeall of the following except:

a. Renal ultrasound

b. Electrocardiogram

c. Urinalysis

d. Complete history and physical

e. Echocardiogram

2. All of the following low-renin hypertensive disordersare associated with hypokalemia except:

a. Liddle syndrome

b. Adrenal hyperplasia

c. Apparent mineralocorticoid excess

d. Glucocorticoid-remediable aldosteronism

e. Gordon syndrome

3. Renin secretion is increased by all of the followingexcept:

a. Decreased intravascular volume

b. Activation of the sympathetic nervous system

c. Increased aldosterone secretion

d. Hypotension

e. Renal artery stenosis

4. Oscillometric blood pressure monitors directly measure:

a. Pulse pressure

b. Systolic blood pressure

c. Diastolic blood pressure

d. Mean arterial pressure

e. Diurnal blood pressure variation

5. A previously healthy 14-year-old male patient is seenfor a routine school physical examination. His bloodpressure at this visit is 132/70 (95th percentile: 130/83).He is asymptomatic, and the rest of his physicalexamination is normal. �e next step in his evaluation andmanagement should be:

a. Urinalysis

b. Renal ultrasound.

c. Repeat blood pressure in 1 to 2 weeks.

d. Reassurance that his blood pressure is normal

e. Initiation of antihypertensive medication

6. All of the following are associated with a higher riskfor hypertension in the neonatal period except:

a. Umbilical artery catheterization

b. Large for gestational age

c. Bronchopulmonary dysplasia

d. Patent ductus arteriosus

e. Maternal drug use 7. CT imaging of a child withhypertensive encephalopathy will most commonly show changesin the: a. Parieto-occipital white matter b. Hypothalamusc. Pituitary gland d. Prefrontal cortex e. Optic nerve8. All of the following may raise the blood pressure of achild with chronic hypertension who is being treated foran acute asthma exacerbation and allergy symptoms except:a. Prednisone b. Albuterol c. Phenylephrine d. Ibuprofene. Cetirizine 9. Normal blood pressure levels in childrenare based on the child’s: a. Age b. Gender c. Body massindex d. Height e. a, b, and d 10. Children whose BP isgreater than the 90th percentile (or greater than 120/80mm Hg) but less than the 95th percentile should beclassi�ed as prehypertensive. However, these childrenshould be treated as if they were hypertensive if theyhave any of the following conditions except: a. Le�ventricular hypertrophy b. Diabetes mellitus c. Renaldysplasia d. Short stature e. Retinopathy ANSWER KEY 1.

b 2. e 3. c 4. d 5. c 6. b 7. a 8. e 9. e 10. d

40 Management of hypertension

KEY POINT

In patients with renovascular hypertension, anti

hypertensive medications are used frequently—in

the initial management until anatomic correction is

achieved and long term when there is residual hyper

tension or vascular lesions that cannot be corrected.SUMMARY �e management of pediatric hypertension begins bystaging the hypertension based on standard tables,evaluating the patient for the presence of symptoms ortarget organ damage, and determining if there is anunderlying medical condition that warrants more aggressivetreatment. Most patients are initially treated withnonpharmacologic intervention initially, although severe,symptomatic hypertension may warrant intravenousmedications in an intensive care unit. �ere are increasingdata on the safety and e�cacy of antihypertensivemedications in children, but few comparative or long-termdata are available to guide use of a speci�c agent.However, in some instances a speci�c agent is indicated.

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REVIEW QUESTIONS

1. A 16-year-old obese boy with hypertension and type 2diabetes has been referred to you for evaluation. His o�ceblood pressure is 145/82 mm Hg. He has LVH on anechocardiogram and a mildly elevated urinarymicroalbumin-to-creatinine ratio. �e referring physicianprescribed hydrochlorothiazide 50 mg daily. Yourrecommendation should be:

a. Order ambulatory blood pressure monitoring to assesshis blood pressure control.

b. Add metoprolol 100 mg daily to further reduce his bloodpressure.

c. Start regular aerobic exercise and a low-sodium diet.

d. Stop the hydrochlorothiazide and start lisinopril 10 mgdaily.

2. An 8-year-old girl has been found to have con�rmed o�cehypertension. Her weight and BMI are both at the 97thpercentile for age, and her height is at the 40thpercentile. Which of the following changes should be madeto her daily routine?

a. Restriction of caloric intake to 1500 calories/day

b. Supplementation with potassium chloride

c. 30 minutes of brisk walking around the block with hermother a�er school

d. Scheduling for an assessment of obesity in a pediatricendocrinology clinic

3. A 12 year-old girl treated with quinapril for primaryhypertension needs the following issues addressed at herquarterly follow-up appointments:

a. Use of contraception

b. CBC monitoring

c. Edema assessment

d. a and b

e. a, b, and c

4. When deciding whether to start an antihypertensivemedication, the following is the most importantconsideration:

a. �e age of the child

b. �e presence of obesity

c. �e presence of le� ventricular hypertrophy

d. �e success of lifestyle modi�cation

5. A 12-year-old girl with pheochromocytoma has beenreferred to you by the oncology service for assistancewith blood pressure management until surgery, which isscheduled to take place in 2.5 weeks. Which of thefollowing strategies should be employed to control her BP?

a. Sodium restriction and bedrest

b. Start treatment with oral labetalol

c. Start treatment with oral propranolol

d. Sodium restriction and start phenoxybenzamine

e. Start treatment with doxazosin 6. An 8-year-old boypresents to the emergency department a�er having twotonic-clonic seizures. Blood pressures obtained byambulance personnel were 150 to 168/95 to 118 mm Hg.Ativan has been given and seizures have stopped. Which ofthe following measures would not be appropriate? a.Reduction of blood pressure with sublingual nifedipine to110/70 mm Hg b. Insertion of an arterial monitoring linec. Obtain a comprehensive medical history d. Ordernicardipine from the pharmacy 7. A 12-year-old boy isreferred from the urology department with new-onset bloodpressure elevation in the setting of known re�uxnephropathy. In the clinic, his blood pressuremeasurements ful�ll criteria for stage 2 hypertension.Initial evaluations are notable for an estimated GFR of 65mL/min/1.73 m 2 and 3+ proteinuria by dipstick. Which ofthe following drug classes would be considered mostappropriate in this setting? a. Nondihydropyridinecalcium channel blockers b. Loop diuretics c. Angiotensinreceptor antagonists d. Direct-acting vasodilators e.β-Adrenergic blockers 8. Which of the following medicationclasses should be avoided as primary therapy in the

hypertensive female athlete? a. Angiotensin-convertingenzyme inhibitors b. Diuretics c. β-blockers d. Calciumchannel blockers e. a and b 9. Recommendations forstaging hypertension in children and adolescents provideguidance for clinicians in evaluating and managingpatients with elevated blood pressure. �e new stagingsystem recommends immediate institution ofantihypertensive medications for patients with bloodpressure in which of the following stages? a. Stage 2hypertension b. Normal blood pressure c. Stage 1hypertension d. Pre-hypertension e. a and c 10. Youreceive a phone call from a neonatologist in a neighboringcommunity. She has been caring for a now 6-week-old,former 28 weeks of gestation premature infant. She isconcerned about some high blood pressure readings andwants your recommendations regarding treatment. Whatadditional information do you need to make the bestrecommendation? a. �e infant’s current weight and lengthb. �e infant’s medication list c. Details about how theinfant’s blood pressure is being measured

d. a and b

d. b and c

11. An otherwise healthy 16-year-old boy presents witho�ce blood pressure readings of 160/100 mm Hg in bothupper extremities. He is not obese, but there is a strongfamily history of cardiovascular disease. He initiallydenies any symptoms, but at the end of the visit, hismother tells you that he occasionally complains of his legsaching during soccer, and that he sometimes has abdominalpain a�er eating. What medication should you prescribewhile you are waiting for test results to come back?

a. Lisinopril

b. Felodipine

c. Valsartan

d. Metoprolol ANSWERS 1. d 2. c 3. d 4. c 5. e 6. a7. c 8. e 9. a 10. e 11. b

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109. Garcia Nieto V, Cantabrana A, Muller D, ClaverieMartinF. Chondrocalcinosis and hypomagnesaemia in a patient witha new mutation in the gene of the thiazide-sensitive Na-Clcotransporter. Nefrologia. 2003;23:504–9 [in Spanish].

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117. Boyden LM, Choi M, Choate KA, et al. Mutations inkelch-like 3 and cullin 3 cause hypertension and

electrolyte abnormalities. Nature. 2012;482:98–102.

118. Ros er M, Eibl N, Eisenhaber B, et al. Gitelmansyndrome. Hypertension. 2009;53:893–7.

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associated in the newborn period in which of the followingtypes of Bartter syndrome? a. Type 1 b. Type 2 c. Type 3d. Type 4

2. Which type of Bartter syndrome is associated withhearing loss? a. Type 1 b. Type 2 c. Type 3 d. Type 4

3. Barter syndrome is associated with: a. Normocalciuriab. Hypercalciuria c. Hypocalciuria d. a or b e. a or c

4. Gitelman syndrome is characterized by: a. Hypocalciuriab. Hypercalciuria c. Normocalciuria d. None of the above

5. Hypomagnesemia is a feature of: a. Bartter syndrome b.Gitelman syndrome c. Both Bartter syndrome and Gitelmansyndrome d. Neither Bartter syndrome nor Gitelman syndrome

6. Gordon syndrome or pseudohypoaldosteronism-2 is amirror image of Gitelman syndrome. Both these defectsresult from a malfunction or disregulation in which of thefollowing transport channels? a. CLCNKB b. ENaC c. ROMKd. NCC

7. Pseudohypoaldosteronism 1 (PHA1) results fromlossof-function mutations in: a. �e mineralocorticoidreceptor or ENaC b. CLCNKB c. NKCC2 d. CLCN5 8. Liddlesyndrome results from: a. Loss-of-function mutation ofENaC b. Gain-of-function mutation of HSD11B2 c.Gain-of-function mutation of ENaC d. Loss-of-functionmutation of TRPM6 9. Transport of low-molecular-weightprotein from the tubular lumen in the proximal tubules isfacilitated by binding to apical receptors megalin andcubilin. a. True b. False 10. Which of the following arefeatures of renal Fanconi syndrome? a. Hypercalciuria b.Glucosuria c. Low-molecular-weight proteinuria d.Albuminuria e. All of the above ANSWER KEY 1. b 2. d 3.d 4. a 5. b 6. d 7. a 8. c 9. a 10. e

42 Renal tubular acidosis

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REVIEW QUESTIONS

1. �e normal acid production of children is:

a. <1 mEq/kg/day

b. 1 to 3 mEq/kg/day

c. 4 to 6 mEq/kg/day

d. >6 mEq/kg/day

2. �e most important way of excreting acid duringincreased acid production is:

a. Increased ammonium excretion

b. Increased phosphate excretion

c. Increased urea excretion

d. Decreased bicarbonate excretion

3. Pro ximal tubule bicarbonate reabsorption occursbecause of which of the following?

a. Amm onia generation from glutamine

b. Hyd rogen ion excretion by the K + /H + ATPase

c. AE1 in the basolateral membrane

d. Carbonic anhydrase on the brush border membrane

4. For adequate distal tubule acid excretion, there mustbe adequate:

a. Sodium reabsorption

b. Potassium absorption

c. Ammonium absorption

d. Sodium excretion

5. Ammoniagenesis occurs in the:

a. �ick ascending limb

b. Cortical collecting tubule

c. Medullary collecting tubule

d. Proximal tubule

6. Fanconi syndrome involves RTA type:

a. Type I

b. Type II

c. Type III

d. Type IV

7 In RTA, the urine anion gap is:

a. Positive

b. Negative

c. Neutral

8. Type 1 is associated with a mutation in the gene codingfor:

a. NBC1

b. 2Cl /Na/K

c. AE1

d. CA

9. An ab normal β 1 subunit of H + -ATPase is associatedwith:

a. Skeletal dysplasia

b. Early onset deafness c. Cardiac defect d. Mentalretardation 10. �e main abnormality of RTA type 4 is: a.Hyperkalemia causing decreased ammoniagenesis b.Hypokalemia causing decreased ammoniagenesis c.

Hyperkalemia causing increased ammoniagenesis d.Hypokalemia causing increased ammoniagenesis 11.Nephrocalcinosis is associated with: a. Type I RTA b.Type II RTA c. Type IV RTA d. None of above 12. �eanticonvulsant medication, topiramate, is associated with:a. Type I RTA b. Type II RTA c. Type III RTA d. Type IVRTA 13. �e type of RTA requiring the largest dose ofsupplemental alkali to correct the acidosis is: a. Type Ib. Type II c. Type IV 14. �e major urinary bu�er oftitratable acid is: a. Citrate b. Phosphate c. Urate d.Creatinine 15. A simple way of testing the distalnephron’s ability to acidify the urine is to administerorally: a. Phosphate b. Citrate c. Furosemide d.Hydrochlorothiazide ANSWER KEY 1. b 2. a 3. d 4. a 5.d 6. b 7. a 8. c 9. b 10. a 11. a 12. b 13. b 14.b 15. c

43 Cystic kidney disease

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52. Suwabe T, Ubara Y, Sumida K, et al. Clinical featuresof cyst infection and hemorrhage in ADPKD: New diagnosticcriteria. Clin Exp Nephrol. 2012;16:892–902.

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58. Salomon R, Saunier S, Niaudet P. Nephronophthisis.Pediatr Nephrol. 2009;24:2333–44.

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62. Cha ki M, Hoefele J, Allen SJ, et al. Genotypephenotypecorrelation in 440 patients with NPHPrelated ciliopathies.Kidney Int. 2011;80:1239–45.

63. Sang L, Miller JJ, Corbit KC, et al. Mapping theNPHP-JBTS-MKS protein network reveals ciliopathy diseasegenes and pathways. Cell. 2011;145:513–28.

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93. Chapman AB, Guay-Woodford LM, Grantham JJ, et al.Renal structure in early autosomal-dominant polycystickidney disease (ADPKD): The Consortium for Radiologic

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94. Gra ntham JJ, Chapman AB, Torres VE. Volumeprogression in autosomal dominant polycystic kidneydisease: The major factor determining clinical outcomes.Clin J Am Soc Nephrol. 2006;1:148–57.

95. Serra AL, Poster D, Kistler AD, et al. Sirolimus andkidney growth in autosomal dominant polycystic kidneydisease. N Engl J Med. 2010;363:820–9.

96. Walz G, Budde K, Mannaa M, et al. Everolimus inpatients with autosomal dominant polycystic kidneydisease. N Engl J Med. 2010;363:830–40.

97. Tor res VE, Chapman AB, Devuyst O, et al. Tolvaptan inpatients with autosomal dominant polycystic kidney disease.N Engl J Med. 2012;367:2407–18.

98. Anonymous. Summary Minutes of the Drug Safety and RiskManagement Advisory Committee. Available athttp://www.fda. gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM373520.pdf. Accessed October 1, 2015.

99. Mei jer E, Gansevoort RT, de Jong PE, et al.Therapeutic potential of vasopressin V2 receptor antagonistin a mouse model for autosomal dominant polycystic kidneydisease: Optimal timing and dosing of the drug. NephrolDial Transplant. 2011;26:2445–53. REVIEW QUESTIONS 1.Extrarenal complications of ARPKD can include: a.Congenital hepatic �brosis b. Caroli syndrome c. Growthretardation d. Intracranial aneurysms e. All of the above2. All of the conditions below are included inhepatocellular �brocystic disorders, except: a. ARPKD b.ADPKD c. Multicystic dysplastic kidney (MCDK) d.Nephronophthisis (NPHP) e. Joubert syndrome (JBTS) 3. Inwhich of the pediatric age groups can ADPKD manifest? a.Fetus b. Infant c. Child d. Adolescent e. All of theabove 4. Small, contracted kidneys are characteristicallyseen in seen in which of the following cystic disease(s)?a. HNF1B-related disease b. ARPKD c. Nephronophthisis d.Medullary sponge kidney e. None of the above 5. A causalrelationship between hypertension and renal cystic diseasehas been proposed in each of the following disordersexcept: a. ARPKD b. ADPKD c. NPHP d. MCKD e. Simplecysts 6. Gene-based testing is a clinically informativetool for which disorder? a. ARPKD b. ADPKD c. NPHP d.

MCKD e. All of the above 7. Medullary sponge kidney is asingle-gene disorder in a subset of patients. a. True b.False 8. Which disorder is the most common cause ofhyperechoic kidneys in a fetus? a. ARPKD b. ADPKD c.NPHP d. HNF1B-related disease e. Glomerulocystic kidneydisease

9. Glomerular cysts can be observed in which disorders? a.ADPKD b. MCKD2 c. HNF1B-related disease d. Trisomy 18e. All of the above

10. Simple cysts can lead to clinical symptoms inchildhood. a. True b. False ANSWER KEY 1 e 2. c 3. e4. c 5. d 6. e 7. a 8. a 9. e 10. a

44 Ciliopathies and nephronophthisis

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4. A molecular genetic diagnosis can be made in whatpercentage of cases of NPHP?

a. 25%

b. 40%

c. 60%

d. 10%

5. �e histologic features of nephronophthisis may include:

a. Glomerular basement membrane thinning

b. Interstitial �brosis

c. Karyomegaly d. Cortical microcysts e. b and d f. aand c ANSWER KEY 1. d 2. e 3. a 4. c 5. e

45 Alport syndrome and thin basementmembrane nephropathy

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REVIEW QUESTIONS

1. In a patient with persistent microscopic hematuria,which of the following �ndings is suggestive of a diagnosisof Alport syndrome rather than thin basement membranenephropathy?

a. Male gender

b. Family history of hematuria

c. Failed newborn hearing screen

d. Anterior lenticonus

e. Elevated cholesterol

2. X-linked Alport syndrome is caused by mutations inwhich gene?

a. COL4A3

b. COL4A4

c. COL4A5

d. MYH9

e. PAX2

3. Het erozygous females with COL4A5 mutations are at risk

for:

a. Micr oscopic hematuria

b. Pro teinuria

c. End -stage renal disease d. Deafness e. All of theabove 4. ACEIs are NOT indicated for treatment of whichpatient? a. Male with XLAS and proteinuria b. Male withXLAS and microalbuminuria with family history of ESRD atage 20 c. Male with XLAS and microalbuminuria with familyhistory of ESRD at age 50 d. Female with XLAS andproteinuria e. Female with ARAS and proteinuria 5. �istype of mutation in COL4A5 is associated with a milderAlport phenotype: a. Missense mutation b. Large deletionc. Splice site mutation d. Nonsense mutation e. Largerearrangement 6. �e following ophthalmologic �ndings arefrequently observed in patients with Alport syndrome,except: a. Anterior lenticonus b. Myopia c. Cornealerosion d. Maculopathy e. Posterior polymorphousdystrophy 7. α5(IV) may be absent from the GBM and presentin the Bowman capsule in which disorder? a. Males withXLAS b. Females with XLAS c. TBMN d. ARAS e. ARAS andADAS 8. TBMN can be caused by mutations in: a. COL4A3 b.COL4A4 c. COL4A5 d. Both a and b e. Both a and c ANSWERS1. d 2. c 3. e 4. c 5. a 6. b 7. e 8. d

46 Renal disease in syndromic disorders

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syndrome. Am J Med. Genet. C Semin Med Genet.2013;163C:131–40. SUMMARY Genetic and syndromic disorderscan be associated renal malformations, the presence ofrenal cysts, hypercalciuria, nephrocalcinosis, andproteinuria. Progressive loss of renal function, chronickidney disease, and ESRD can also result from some ofthese disorders. Recognition of syndromes that areassociated with renal disease requires the input of agenetics team in addition to the nephrologist. Complexsurgical management in disorders such as VATER or VACTERLassociation requires the involvement of urologic and othersurgical expertise. Genetic diagnosis of many syndromicdisorders is possible now, and the array of availablediagnostic tests for clinical use is ever increasing. �ischapter provides an overview of the common syndromes andgenetic diseases associated with renal manifestations. �ereader is referred to the broader literature on thesubject for a deeper understanding, if needed.

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92. Mor ello R, Zhou G, Dreyer SD, et al. Regulation ofglomerular basement membrane collagen expression by LMX1Bcontributes to renal disease in nail patella syndrome. NatGenet. 2001;27:205–8.

93. Min er JH, Morello R, Andrews KL, et al.Transcriptional induction of slit diaphragm genes by Lmx1bis required in podocyte differentiation. J Clin Invest.2002;109:1065–72.

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REVIEW QUESTIONS

1. Children a�ected with one of the following syndromesare at higher risk of developing Wilms tumor.

a. Bran chio-oto-renal syndrome

b. Ren al-coloboma syndrome

c. Tow nes-Brocks syndrome

d. Bec kwith-Wiedemann syndrome

e. Coc kayne syndrome

2. Whi ch of the following anomalies is not observed inpatients with HNF1B-mutation?

a. Ch olestasis

b. Hypo magnesemia

c. Mul ticystic kidney disease

d. Ver tebral malformations

e. Dia betes mellitus

3. Chi ldren a�ected with one of the following syndromesmay develop proteinuria and a nephrotic syndrome.

a. CHA RGE syndrome

b. Nai l-patella syndrome

c. Ochoa syndrome

d. Fraser syndrome

e. Simpson-Golabi-Behmel syndrome 4. Concerningmitochondrial disorders, which of the following assertionsis not applicable? a. �ey are secondary to defects ofoxidative phosdphorylation. b. Mitochondrial DNA isinherited from the father. c. �e most frequent renalmanifestation is proximal tubulopathy. d. Patients maypresent with hyperlactatemia. e. Patients may develop anephrotic syndrome. 5. All of the following are seen inpatients with Alagille syndrome, except: a. Chroniccholestasis b. Pulmonary artery stenosis c. Posteriorembryotoxon d. Hearing loss e. Vascular abnormalities 6.Which of the following does not apply to nail-patellasyndrome? a. It is an autosomal dominant disease. b.Iliac horns are a pathognomonic radiologic feature of thedisease. c. Urinary tract malformations are frequentlyobserved in nail-patella syndrome. d. Nail-patellasyndrome is caused by mutations of the LMX1B gene. e.End-stage renal disease develops in 10% to 15% of cases.ANSWER KEY 1. d 2. d 3. b 4. b 5. d 6. c

47 Hydronephrosis and obstructiveuropathies

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107. Furness PD, III, Maizels M, Han SW, et al. Elevatedbladder urine concentration of transforming growthfactor-b1 correlates with upper urinary tract obstructionin children. J Urol. 1999;162:1033–38.

108. Trn ka P, Ivanova L, Hiatt MJ, et al. Urinarybiomarkers in obstructive nephropathy. Clin J Am SocNephrol. 2012;7:1567–75. 109. Grandaliano G, Gesualdo L,Bartoli F, et al. MCP-1 and EGF renal expression and urineexcretion in human congenital obstructive nephropathy.Kidney Int. 2000;58:182–8. 110. Li Z, Zhao Z, Liu X, etal. Prediction of the outcome of antenatal hydronephrosis:Significance of urinary EGF. Pediatr Nephrol.2012;27:2251–9. 111. Wasilewska A, Taranta-Janusz K, DębekW, et al. KIM-1 and NGAL: New markers of obstructivenephropathy. Pediatr Nephrol. 2011;26:579–86. REVIEWQUESTIONS 1. �e most common cause of antenatal obstructiveuropathy is: a. Posterior urethral valves b.Vesicoureteric re�ux c. Ureterovesicular junctionobstruction d. Uret eropelvic junction obstruction 2. Routine antenatal ultrasound detects most cases of antenatalhydronephrosis. a. Fals e b. Tru e 3. In pr enatallydetected hydronephrosis, no evidence of urinary tractobstruction is seen in: a. 10% b. 90% c. 50% d. 30% 4.A pren atal ultrasound in a male fetus demonstratebilateral hydronephrosis and a thickened bladder wall. Adiagnosis of posterior urethral valves is beingentertained. �e most important clinical concern in theneonatal period in this patient will be: a. Reducednephron mass b. Urinary tract infection c. Pulmonaryhypoplasia d. Diaphragmatic hernia 5. Risk for CKD andESRD risk in patients with posterior urethral valves isdetermined by: a. Severity of hydronephrosis b. Severityof renal dysplasia c. Frequency of urinary tractinfections d. Amniotic �uid sodium concentration 6. Amale baby at the age of 37 weeks of gestation is born viacesarean section delivery and requires mechanicalventilation a�er resuscitation. His mother had poorprenatal follow-up, and there is no record of her havinghad any prenatal ultrasound evaluations. �e patientdeveloped right-sided pneumothorax on day 2. He did noturinate for 12 hours, urinary bladder catheterization wasdone, and an indwelling catheter was le� in place. Renalultrasound showed bilateral hydronephrosis, bilateralhydroureters and a distended urinary bladder withthickened wall. �e most important next investigative stepin this patient should be:

a. Monitor renal ultrasound for worsening of hydronephrosis

b. Monitor serum creatinine for renal function

c. A DMSA renal scan

d. A nuclear cystogram

e. A contrast vesicocystourethrogram

7. Following are the features of lower urinary tractobstruction in neonates, except:

a. Hematuria following birth

b. Bilateral antenatal hydronephrosis

c. Hypospadias

d. Fetal or neonatal urinary ascites

8. Urinary incontinence is a clinical manifestation oflower urinary tract obstruction:

a. True

b. False

9. Of prenatally detected cases ofpyelectasis/hydronephrosis, 50% to 70% are due to:

a. Ureteropelvic junction obstruction

b. Vesicoureteric re�ux

c. Transient or physiologic neonatal changes

d. Potter syndrome

10. Which of the following disorders can mimichydronephrosis in an antenatal sonogram?

a. Multicystic dysplastic kidney

b. Megaureter

c. Large renal cysts

d. All of the above

11. A 6-year-boy complains of right-side abdominal painevery time he goes out with his parents for dinner or when

parents give him a small carton of juice to drink. He wasseen today in the emergency room with severe right �ankpain. Because of concern about a renal colic, the sta�started him on ½ normal saline an intravenous infusion at1.5 times maintenance. Within a half-hour a�er infusionbeing started, his �ank pain worsened, requiring morphinefor adequate pain control. His urinalysis showed: pH 6.5,speci�c gravity 1.015, no protein, no blood, nitratenegative, and leukocytes negative. Renal ultrasound showsa severe right-side hydronephrosis. �e child has which ofthe following? a. Acute appendicitis b. Renal colic c.Dietl crisis d. Recurrent colonic volvulus 12. Diagnosisof posterior urethral valves in a male a�er 1 year of ageis associated with: a. Better overall prognosis for renalfunction and ESRD compared to neonatal diagnosis b. Worseoverall prognosis for renal function and ESRD compared toneonatal diagnosis ANSWERS 1. d 2. b 3. c 4. c 5. b6. e 7. c 8. a 9. c 10. d 11. c 12. a

48 Vesicoureteral reflux

(a)

(b)

Figure 48.8 The Cohen procedure is the most widely

used technique for surgical correction of vesicoureteral

reflux. (a) The ureters (the procedure is often bilateral)

are mobilized intravesically. (b) Two separate submuco

sal tunnels are created so that each ureter opens on the

opposite side from its hiatus. (Reproduced with permis

sion from: Capozza N, Caione P. Vesicoureteral reflux:

surgical and endoscopic treatment. Pediatr Nephrol.

2007;22:1261–5.)

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82. el-Khatib M, Packham DK, Becker GJ, KincaidSmith P.Pregnancy-related complications in women with refluxnephropathy. Clin Nephrol. 1994;41:50–5.

83. Jun gers P, Houillier P, Chauveau D, et al. Pregnancyin women with reflux nephropathy. Kidney Int.1996;50:593–9.

84. Hollowell JG. Outcome of pregnancy in women with ahistory of vesico-ureteric reflux. BJU Int.

2008;102:780–4.

85. Gru neberg RN, Leakey A, Bendall MJ, Smellie JM. Bowelflora in urinary tract infection: Effect of chemotherapywith special refer ence to cotrimoxazole. Kidney Int Suppl.1 975 ;4:S122–9.

86. Sme llie JM, Tamminen-Mobius T, Olbing H, et al.Five-year study of medical or surgical treat ment inchildren with severe reflux: Radiological rena l findings.The International Reflux Study in Children. PediatrNephrol. 1992;6:223–30.

87. Jodal U, Smellie JM, Lax H, Hoyer PF. Ten-year resultsof randomized treatment of children with severevesicoureteral reflux: Final report of the InternationalReflux Study in Children. Pediatr Nephrol. 2006;21:785–92.

88. Brandstrom P, Esbjorner E, Herthelius M, et al. TheSwedish reflux trial in children. III. Urinary tractinfection pattern. J Urol. 2010;184:286–91.

89. Brandstrom P, Neveus T, Sixt R, et al. The Swedishreflux trial in children. IV. Renal dam age. J Urol.2010;184:292–7. 90. Shakil A, Reed L, Wilder L, Strand WR.Clinical inquiries: Do antibiotics prevent recurrent UTIin children with anatomic abnormalities? J Fam Pract.2004;53:498–500. 91. Cooper CS, Chung BI, Kirsch AJ, etal. The outcome of stopping prophylactic antibiotics inold er children with vesicoureteral reflux. J Urol.2000;163:269–72; discussion 72–3. 92. Tam minen-Mobius T,Brunier E, Ebel KD, et al. Cessation of vesicoureteralreflux for 5 years in infants and children allocated tomedical treatment. The International Reflux Study inChildren. J Urol. 1992;148:1662–6. 93. Allen UD, MacDonaldN, Fuite L, et al. Risk factors for resistance to“first-line” anti microbials among urinary tract isolatesof Esc herichia coli in children. Can Med Assoc J.1999;160:1436–40. 94. Kar pman E, Kurzrock EA. Adversereactions of nitrofurantoin, trimethoprim and sulfamethoxazole in children. J Urol. 2004;172:448–53. 95. Uhari M,Nuutinen M, Turtinen J. Adverse reactions in childrenduring long-term anti microbial therapy. Pediatr Infect DisJ. 199 6;15:404–8. 96. Bol lgren I. Antibacterialprophylaxis in chil dren with urinary tract infection. ActaPaediatr Suppl. 1999;88:48–52. 97. Wil liams G, Lee A,Craig J. Antibiotics for the prevention of urinary tractinfection in children: A systematic review of randomizedcontrolled trials. J Pediatr. 2001;138:868–74. 98. Wheeler D, Vimalachandra D, Hodson EM, et al. Antibiotics and

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114. Lakshmanan Y, Fung LC. Laparoscopic extravesicular ureteral reimplantation for vesicoureteral reflux: Recenttechnical advances. J Endourol. 2000;14:589– 93; discussion593–4.

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2001;166:1893–8. 122. Upadhyay J, Bolduc S, Bagli DJ, etal. Use of the dysfunctional voiding symptom score topredict resolution of vesicoureteral reflux in childrenwith voiding dysfunction. J Urol. 2003;169:1842–6;discussion 6; author reply 6. 123. Schulman SL, Quinn CK,Plachter N, Kodman-Jones C. Comprehensive management ofdysfunctional voiding. Pediatrics. 1999;103:E31. 124.Praga M, Hernandez E, Montoyo C, et al. Long-termbeneficial effects of angiotensin-converting enzymeinhibition in patients with nephrotic proteinuria. Am JKidney Dis. 1992;20:240–8. 125. Ohtomo Y, Nagaoka R,Kaneko K, et al. Angiotensin converting enzyme genepolymorphism in primary vesicoureteral reflux. PediatrNephrol. 2001;16:648–52. 126. Risdon RA. The smallscarred kidney in childhood. Pediatr Nephrol.1993;7:361–4. REVIEW QUESTIONS 1. Which of the followingis associated with a higher incidence of primaryvesicoureteral re�ux diagnosed a�er urinary tractinfection? a. Older age b. Male gender c. AfricanAmerican race d. Family history of vesicoureteral re�ux inparent or sibling 2. Which of the following is a riskfactor for renal scarring a�er a UTI? a. African Americanrace b. High grade vesicoureteral re�ux c. Absence ofvesicoureteral re�ux d. Diarrhea e. Pyuria 3. Hypertension is most directly associated with which of thefollowing? a. His tory of urinary tract infections b. Vesicoureteral re�ux c. Use o f De�ux d. Rena l scarring

4. Which of the following is a risk factor for unsuccessfulendoscopic repair of vesicoureteral re�ux?

a. Neurogenic bladder

b. Congenital re�ux

c. History of UTI

d. Caucasian race

e. Grade I or II re�ux

5. �e success rate of open surgical repair ofvesicoureteral re�ux is approximately:

a. 65%

b. 75%

c. 85%

d. 90%

e. 98% 6. Which of the following is the preferred agentfor treating hypertension in a patient with re�uxnephropathy? a. Calcium channel blocker b. Beta blockerc. ACE inhibitor d. �iazide diuretic ANSWER KEY 1. d 2.b 3. d 4. a 5. e 6. c

49 Urinary tract infection

SUMMARY

Infections of the urinary tract are a common child

hood disorder that can lead to signi�cant morbid

ity and hospitalizations. Our understanding of the

structural and molecular predispositions to UTI

makes it possible to develop a uni�ed diagnostic and

therapeutic approach that can be practiced in ter

tiary care centers and in the community. Such a uni

ed management approach may result in a lowered

long-term risk for renal damage. Recent data suggest

that the renal scarring resulting from UTI may be

determined by host in�ammatory response, pres

ence of urinary tract abnormalities, and the bacte

rial virulence. UTI and chronic pyelonephritis is, by

itself, an uncommon cause of CKD and ESRD.

5. Winberg J, Anderson HJ, Bergstrom T, et al.Epidemiology of symptomatic urinary tract infection inchildhood. Acta Paediatr Scand. 1974;252:1–20.

6. Hellstrom A, Hanson E, Hansson S, et al. Associationbetween urinary symptoms at 7 years old and previousurinary tract infection. Arch Dis Child. 1991;66:232–4.

7. Marild S, Jodal U. Incidence rate of first-time symptomatic urinary tract infection in children under 6 y ears of age. Acta Paediatr. 1998;87:549–52.

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171. Benador D, Benador N, Slosman D, et al. Are youngerchildren at risk of renal sequelae after pyelonephritis?Lancet. 1997;349:17–9.

172. Fernández-Menández JM, Malaga S, Matesanz JL, et al.:Risk factors in the development of early technetium-99mdimercaptosuccinic acid renal scintigraphy lesions duringfirst uri nary tract infection in children. Acta Paediatr.2003;92:21–6.

173. Wennerström, M, Hansson, S, Jodal, U, et al. Primaryand acquired renal scarring in boys and girls with urinarytract Infection. J Pediatr. 2000;136:30–4. 174. Shaikh N,Ewing AL, Bhatnagar S, et al. Risk of renal scarring inchildren with a first urinary tract infection: Asystematic review. Pediatrics. 2010;126:1084–91. 175.Cotton SA, Gbadegesin RA, Williams S, et al. Role ofTGF-beta1 in renal parenchymal scarring follow ingchildhood urinary tract infection. Kidney Int.2002;61:61–7. 176. Hus sein A, Askar E, Elsaeid M, et al.Functional polymorphisms in transforming growthfactorbeta-1 (TGFbeta-1) and vascular endothelial growthfactor (VEGF) genes modify risk of renal paren chymalscarring following childhood urinary tract inf ection.Nephrol Dial Transplant. 2010;25:779–85. 177. Zaf fanelloM, Tardivo S, Cataldi L, et al. Genetic susceptibility torenal scar formation after uri nary tract infection: Asystematic review and meta -analysis of candidate genepolymorphisms. Pediatr Nephrol. 2011;26:1017–29. 178. Poulsen EU, Johannesen NL, Nielsen JB, et al.:Vesico-ureteral reflux. II. The long term outcome ofkidney function in non-surgical treatment. Scand J UrolNephrol Suppl. 1989;125:29–34. 179. Soylu A, Demir BK,Türkmen M, et al. Predictors of renal scar in childrenwith urinary infec tion and vesicoureteral reflux. PediatrNephrol. 2008;23:2227–32. 180. Jod al U. The naturalhistory of bacteriuria in child hood. Infect Dis Clin NorthAm. 1987;1:713–29. 181. Yiee JH, DiSandro M, Wang MH, etal. Does severity of renal scarring on DMSA scan predictabnormalities in creatinine clearance? Urology.2010;76:204–8. 182. Wennerström M, Hansson S, Jodal U, etal. renal function 16 to 26 years after the first urinarytract infection in childhood. Arch Pediatr Adolesc Med.2000;154:339–45. 183. Hir aoka M, HashimotoG, Tsuchida S,et al.: Early treatment of urinary infection preventsrenal damage on cortical scintigraphy. Pediatr Nephrol.2003;18:115–8. 184. Dog anis D, Siafas K, Mavrikou M, etal. Does early treatment of urinary tract infectionprevent renal damage? Pediatrics. 2007;120:e922–8. 185.

Toffolo A, Ammenti A, Montini G. Long-term clinicalconsequences of urinary tract infec tions during childhood:A review. Acta Paediatr. 2012;101:1018–31. 186. Elder JS,Peters CA, Arant BS, Jr, et al. Pediatric vesicoureteralreflux guidelines panel summary report on the managementof pri mary vesicoureteral reflux in children. J Urol. 199 7;157:1846–51. 187. Wennerström M, Hansson S, Hedner T,et al.: Ambulatory blood pressure 16-26 years after thefirst urinary tract infection in childhood. J Hyperten.2000;18:485–91.

188. Beetz R, Schulte-Wissermann H, Troger J, et al.:Long-term follow-up of children with surgically treatedvesicorenal reflux: Postoperative inci dence of urinarytract infections, renal scars and arterial hypertension.Eur Urol. 1989;16:366–71.

189. Jacobson SH, Eklof O, Eriksson CG, et al.:Development of hypertension and uraemia afterpyelonephritis in childhood: 27 year fol low up. B Med J.1989;299:703–6.

190. Sreenarasimhaiah S, Hellerstein S. Urinary tractinfections per se do not cause end-stage kidney disease.Pediatr Nephrol. 1998;12:210–3.

191. Sme llie JM, Prescod NP, Shaw PJ, et al.: Childhoodreflux and urinary infection: A follow-up of 10-41 yearsin 226 adults. Pediatr Nephrol. 1998;12:727–36.

192. U.S. Renal Data System. USRDS 2013 Annual datareport: Atlas of chronic kidney disease and end-stagerenal disease in the United States. Bethesda, MD: NationalInstitutes of Health, National Institute of Diabetes andDigestive and Kidney Diseases; 2 013. pp. 295–306.

193. North American Pediatric Renal Transplant CooperativeStudy. 2011 annual report: Dialysis.https://web.emmes.com/study/ped/annlrept/annualrept2011.pdf . Accessed September 9, 2014.

194. Salo J, Ikäheimo R, Tapiainen T, et al. Childhoodurinary tract infections as a cause of chronic kid neydisease. Pediatrics. 2011;128:840–7.

195. Bryant K, Maxfield C, Rabalais G, et al. Renalcandidiasis in neonates with candiduria. Pediatr InfectDis J. 1999;18:959–63.

196. Phillips JR, Karlowicz MG. Prevalence of Candida

species in hospital-acquired urinary tract infections in aneonatal intensive care unit. Pediatr Infect Dis J.1997;16:190–4.

197. Karlowicz MG. Candidal renal and urinary tractinfection in neonates. Semin Perinatol. 2003;27:393–400.

198. Robins JL, Davies HD, Barton M, et al.Characteristics and outcome of infants with candiduria inneonatal intensive care: A Paediatric InvestigatorsCollaborative Network on Infections in Canada study BMCInfect D 2009;9:183.

199. Rowen JL, Tate JM; Neonatal Candidiasis Study Group.Management of neonatal candidiasis. Pediatr Infect Dis J.1998;17:1007–11.

200. Pappas PG, Kauffman CA, Andes D, et al. Clinicalpractice guidelines for the management of candidiasis:2009 Update by the Infectious Diseases Society of America.Clin Infect Dis. 2009;48:503–35.

201. Drew RH, Arthur RR, Perfect JR. Is it time to abandonthe use of amphotericin B bladder irrigation? Clin InfectDis. 2005;40:1465–70. 202. Azzi A, Fanci R, Bosi A, et al.Monitoring of polyomavirus BK viruria in bone marrowtransplantation patients by DNA hybridization assay and bypolymerase chain reaction: An approach to assess therelationship between BK viruria and hemorrhagic cystitis.Bone Marrow Transplant. 1994;14:235–40. 203. Erard V,Storer B, Corey L, et al. BK virus infec tion inhematopoietic stem cell transplant r ec ipients:Frequency, risk factors, and association withpostengraftment hemorrhagic c ys titis. Clin Infect Dis.2004;39:1861–5. 204. Kim Y J, Kim DW, Lee DG, et al. Humanherpes virus-6 as a possible cause of encephalitis andhemorrhagic cystitis after allogeneic hematopoietic stemcell transplantation. Leukemia. 2 00 2;16:958–9. 205. Comar M, D’Agaro P, Andolina M, et al. Hemorrhagic cystitisin children undergo ing bone marrow transplantation: Aputative role for simian virus 40. Transplantation. 2 004;78:544–8. 206. Lee H -J, Pyo J-W, Choi E-H, et al.Isolation of adenovirus type 7 from the urine of childrenwith acute hemorrhagic cystitis. Pediatr Infect Dis J.1996;15:633–4. 207. Gor czynska E, Turkiewicz D, Rybka K,et al. Incidence, clinical outcome, and management ofvirus-induced hemorrhagic cystitis in chil dren andadolescents after allogeneic hematopoietic celltransplantation. Biol Blood Marrow Tra nsplant.2005;11:797–804. 208. Pad uch DA, Viral lower urinary

tract infections. Curr Urol Rep. 2007;8:324–35. 209.Nagafuji K, Aoki K, Henzan H, et al.: Cidofovir fortreating adenoviral hemorrhagic cystitis in hematopoieticstem cell trans plant recipients. Bone Marrow Transplant.200 4;34:909–14. 210. Ces aro S, Hirsch HH, Faraci M, etal.; European Group for Blood and Marrow Transplantation.Cidofovir for BK virus-associated hemorrhagic cystitis: Aretrospective study. Clin Infect Dis. 200949:233–40. 211.Yusuf U, Hale GA, Carr J, et al. Cidofovir for thetreatment of adenoviral infection in pediat richematopoietic stem cell transplant patients.Transplantation. 2006;81:1398–404. 212. NewcastleAsymptomatic Bacteriuria Group. Asymptomatic bacteriuriain schoolchildren in Newcastle upon Tyne. Arch Dis Child.1975;50:90–102. 213. Newcastle Covert Bacteriuria ResearchGroup. Covert bacteriuria in schoolgirls in Newcastleupon Tyne: 5-year follow-up. Arch Dis Child.1981;56:585–92.

214. Mabbett AN, Ulett GC, Watts RE, et al. Virulenceproperties of asymptomatic bacteriuria Escherichia coli. Int J M ed Microbiol. 2009;299:53–63.

215. Sava ge DCL, Howie G, Adler K, et al.: Controlledtrial of therapy in covert bacteriuria of childhood.Lancet. 1978;1:358–61.

216. Lindberg U, Claesson I, Hanson LÅ, et al.:Asymptomatic bacteriuria in schoolgirls. VIII. Clinicalcourse during a 3-year follow-up. J Pediatr.1978;92:194–9.

217. Cardiff-Oxford Bacteriuria Study Group. Sequelae ofcovert bacteriuria in schoolgirls. Lancet. 1978;1:889–93.

REVIEW QUESTIONS

1. Which bacteria are responsible for most UTIs inchildren?

a. E. co li

b. S. aur eus

c. Kleb siella species

d. Gro up B streptococci

e. Staph ylococcus saprophyticus

2. �e 20 12 AAP Task Force on Circumcision states that allmale infants should undergo circumcision.

a. Tru e

b. Fals e

3. Whi ch symptoms or laboratory test results di�erentiatecystitis from acute pyelonephritis?

a. Abd ominal pain

b. Exc essive crying

c. Hem aturia

d. Feve r

e. Dysu ria

4. According to the 2011 AAP UTI Practice Guideline, whatis the minimum colony count diagnostic of urinary tractinfection?

a. 100,000 CFU/mL

b. 50,000 CFU/mL

c. 20,000 CFU/mL

d. 10,000 CFU/mL

5. All children under 2 years of age should have a renalultrasound a�er diagnosis of UTI.

a. True

b. False

6. A 6-year-old girl with a history of spina bi�darequiring routine urinary catheterization has a history ofmultiple episodes of UTI. She has been on multiple coursesof antibiotics and was recently admitted a�er failingoutpatient therapy on ce�xime. You are suspicious she mayhave developed an ESBL infection. What is the best choiceof empiric therapy for this child? a. Ce�riaxone b.Ce�azidime c. Meropenem d. Ampicillin-sulbactam 7. Amale infant is born at 25 weeks’ gestation and developscandiduria at two weeks of age while in the neonatalintensive care unit. Which antimicrobial agent should be

empirically started? a. Fluconazole b. Micafungin c.Itraconazole d. Amphotericin 8. Which of the followingviruses may cause cystitis in an immunocompromisedpatient? a. Adenovirus b. BK virus c. HHV-6 d. CMV e.All of the above 9. Which of the following therapies isindicated in a 16-year-old girl with Proteus mirabilisbacteriuria found during a routine health screen? a.Ce�xime b. Trimethoprim-sulfamethoxazole c. Cipro�oxacind. Amoxicillin e. No therapy. 10. E. coli associated withasymptomatic bacteriuria have fewer virulence factors thanpathogenic E. coli. a. True b. False ANSWER KEY 1. a 2.b 3. d 4. b 5. a 6. c 7. d 8. e 9. e 10. b

50 Pediatric renal tumors

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5. Knu dson AG, Jr., Strong C. Mutation and cancer: Amodel for Wilms’ tumor of the kidney. J Natl Cancer Inst.1972;48:313–24. 6. Koufos A, Hansen MF, Lampkin BC, et al.Loss of alleles at loci on human chromosome 11 duringgenesis of Wilms’ tumour. Nature. 1984;309:170–2. 7. TonCC, Hirvonen H, Miwa H, et al. Positional cloning andcharacterization of a paired box- and homeobox-containinggene from the aniridia region. Cell. 1991;67:1059–74. 8.Call KM, Glaser T, Ito CY, et al. Isolation andcharacterization of a zinc finger polypeptide gene at thehuman chromosome 11 Wilms’ tumor locus. Cell.1990;60:509–20. 9. Coppes MJ, Haber DA, Grundy PE. Geneticevents in the development of Wilms’ tumor. N Engl J Med.1994;331:586–90. 10. Gessler M, Konig A, Arden K, et al.Infrequent mutation of the WT1 gene in 77 Wilms’ tumors.Hum Mutat. 1994;3:212–22. 11. Diller L, Ghahremani M,Morgan J, et al. Constitutional WT1 mutations in Wilms’tumor patients. J Clin Oncol. 1998;16:3634–40. 12. Mannens M, Slater RM, Heyting C, et al. Molecular nature ofgenetic changes resulting in loss of heterozygosity ofchromosome 11 in Wilms’ tumours. Hum Genet. 1988;81:41–8.13. DeB aun MR, Tucker MA. Risk of cancer during the firstfour years of life in children from the Beckwith-WiedemannSyndrome Registry. J Pediatr. 1998;132:398–400. 14.Bardeesy N, Falkoff D, Petruzzi MJ, et al. AnaplasticWilms’ tumour, a subtype displaying poor prognosis,harbours p53 gene mutations. Nat Genet. 1994;7:91–7. 15.Beckwith JB, Kiviat NB, Bonadio JF. Nephrogenic rests,nephroblastomatosis, and the pathogenesis of Wilms’ tumor.Pediatr Pathol. 1990;10:1–36. 16. Bove KE, McAdams AJ. Thenephroblastomatosis complex and its relationship to Wilms’tumor: A clinicopathologic treatise. Perspect PediatrPathol. 1976;3:185–223. 17. Beckwith JB. Precursor

lesions of Wilms tumor: Clinical and biologicalimplications. Med Pediatr Oncol. 1993;21:158–68. 18.Ganguly A, Gribble J, Tune B, et al. Renin-secretingWilms’ tumor with severe hypertension: Report of a caseand brief review of renin-secreting tumors. Ann InternMed. 1973;79:835–7. 19. Suresh I, Suresh S, Arumugam R, etal. Antenatal diagnosis of Wilms tumor. J Ultrasound Med.1997;16:69–72. 20. Romão RL, Pippi SJL, Shuman C, et al.Nephron sparing surgery for unilateral Wilms tumor inchildren with predisposing syndromes: Single centerexperience over 10 years. J Urol. 2012;188(Suppl4):1493–8. 21. Gunther P, Schenk JP, Wunsch R, et al.Abdominal tumours in children: 3-D visualisation andsurgical planning. Eur J Pediatr Surg. 2004;14:316–21.

SUMMARY

Renal tumors in children are rare. Advances in man

agement have been the result of cooperative stud

ies enrolling patients from di�erent centers. �is

strategy is bound to be the basis for future improve

ments in diagnosis and therapy. �e introduction of

nephron-sparing procedures and minimally invasive

surgery is expected to change current surgical man

agement. Long-term complications from surgery,

chemotherapy, and radiation need to be addressed as

survivors grow into adulthood.

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25. Pow is M, Messahel B, Hobson R, et al. Surgical

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follow-up of testicular function following radiationtherapy for early-stage Hodgkin’s disease. J Clin Oncol1989;7:718–24.

52. Stillman RJ, Schinfeld JS, Schiff I, et al. Ovarianfailure in long-term survivors of childhood malignancy. AmJ Obstet Gynecol. 1981;139:62–6.

53. Bre slow NE, Takashima JR, Whitton JA, et al. Secondmalignant neoplasms following treatment for Wilm’s tumor:A report from the National Wilms’ Tumor Study Group. JClin Oncol. 1995;13:1851–9.

54. Schmidt D, Beckwith JB. Histopathology of childhoodrenal tumors. Hematol Oncol Clin North Am.1995;9:1179–200.

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56. Argani P, Perlman EJ, Breslow NE, et al. Clear cellsarcoma of the kidney: A review of 351 cases from theNational Wilms Tumor Study Group Pathology Center. Am JSurg Pathol. 2000;24:4–18.

57. Tomlinson GE, Breslow NE, Dome J, et al. Rhabdoidtumor of the kidney in the National Wilms’ Tumor Study:Age at diagnosis as a prognostic factor. J Clin Oncol.2005;23:7641–5.

58. Wee ks DA, Beckwith JB, Mierau GW, et al. Rhabdoidtumor of kidney: A report of 111 cases from the NationalWilms’ Tumor Study Pathology Center. Am J Surg Pathol.1989;13:439–58.

59. Mal ik R. Rhabdoid tumor of the kidney. Med PediatrOncol. 1988;16:203–5.

60. Eck schlager T, Kodet R. Renal cell carcinoma inchildren: A single institution’s experience. Med PediatrOncol. 1994;23:36–9.

61. Ren shaw AA, Granter SR, Fletcher JA, et al. Renal cellcarcinomas in children and young adults: Increasedincidence of papillary architecture and unique subtypes. AmJ Surg Pathol. 1999;23:795–802.

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67. Vujanic GM, Delemarre JF, Moeslichan S, et al.Mesoblastic nephroma metastatic to the lungs and heart:Another face of this peculiar lesion—Case report andreview of the literature. Pediatr Pathol. 1993;13:143–53.68. Cook HT, Taylor GM, Malone P, et al. Renin inmesoblastic nephroma: An immunohistochemical study. HumPathol. 1988;19:1347–51. 69. O’H agan AR, Ellsworth R,Secic M, et al. Renal manifestations of tuberous sclerosiscomplex. Clin Pediatr (Phila). 1996;35:483–9. 70.Fittschen A, Wendlik I, Oeztuerk S, et al. Prevalence ofsporadic renal angiomyolipoma: A retrospective analysis of61,389 in- and out-patients. Abdom Imaging.2014;39:1009–13. 71. Dic kinson M, Ruckle H, Beaghler M,et al. Renal angiomyolipoma: Optimal treatment based onsize and symptoms. Clin Nephrol. 1998;49:281–6. REVIEWQUESTIONS CASE 1 A 2-day-old boy is found to have a hard,palpable abdominal mass on routine newborn examination. �epregnancy and delivery were unremarkable. �ere is norelevant family history. Both parents and an older7-year-old sibling are healthy. No other abnormalities areencountered on physical examination. �e baby appears well.He underwent an abdominal ultrasound and, subsequently, aCT scan of the abdomen, shown. 1. Based on thepresentation and �ndings on imaging studies, the �ndingson the le� kidney are most likely to represent: a. Wilmstumor b. Congenital mesoblastic nephroma c. Clear cellsarcoma d. Renal cell carcinoma e. Multilocular cysticnephroma

2. �e best next step in management is:

a. Percutaneous biopsy

b. Open biopsy

c. Chemotherapy (Wilms tumor protocol) and repeat imagingin 6 weeks

d. Partial nephrectomy

e. Radical nephrectomy

CASE 2

A 3-year-old boy presents with rapid increase in abdomi

nal girth. He has been healthy and has no signi�cant medi

cal or surgical history. His family history is unremarkable.

Physical examination demonstrated a normal blood pres

sure for age, no dismorphic features, and a palpable abdom

inal mass. CT evaluation is shown below.

3. Based on these �ndings, all of the following are indi

cated except:

a. Chest CT scan

b. Doppler ultrasound of the renal vein and vena cava

c. Port placement for chemotherapy

d. Bilateral nephrectomies

e. Screen for predisposition syndromes

4. Which of the following are associated with a predisposi

tion to Wilms tumor?

a. Macroglossia

b. Aniridia

c. Hemihypertrophy

d. Cryptorchidism

e. All of the above

5. Which of the following surgical principles regarding

the management of renal masses consistent with Wilms

tumor is true: a. Ipsilateral adrenalectomy is alwaysindicated. b. Removal almost always includes radicalresection of adjacent structures, such as spleen, tail ofpancreas, bowel segment, and liver segment. c. Earlyintraoperative tumor rupture demands aborting the procedureand proceeding with chemotherapy and radiation. d.Ipsilateral lymph node sampling always should be done. e.Nephron-sparing surgical procedures should not be o�ered.CASE 3 A 14-year-old patient with tuberous sclerosis hasthe following �ndings on a routine CAT scan imaging study.6. Which one of the following is an accepted step inmanagement for the lesion highlighted with an arrow? a.Serial imaging with ultrasound b. Reimage every 3 monthswith CT scan c. Open biopsy d. Radical nephrectomy e.Partial nephrectomy and lymph node dissection ANSWER KEY1. b 2. e 3. d 4. e 5. d 6. a

51 Urolithiasis in children

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5. Bet ter OS, Shabtai M, Kedar S, et al. Increasedincidence of nephrolithiasis in lifeguards in Israel. AdvExp Med Biol. 1980;128:467–72.

6. Lattimer JK, Hubbard M. Pediatric urologic admissions. JUrol. 1951:66:289–93.

7. Bass HN, Emanuel B. Nephrolithiasis in childhood. JUrol. 1966;95:749–53.

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c. Severe diarrhea

d. Rendering the urine too alkaline

5. When employing thiazide diuretics:

a. Sodium intake should be liberalized

b. K-citrate should not be used concomitantly

c. �e addition of amiloride is bene�cial

d. Osteopenia may worsen

6. Numerical goals in managing children withhypercalciuria-to-hypocitraturia include:

a. Urine calcium/citrate ratio < 0.20 and Na/K ratio < 2.5

b. Urine calcium/citrate ratio < 0.33 and Na/K ratio < 2.5

c. Urine calcium/citrate ratio < 0.20 and Na/K ratio < 3.5

d. Urine calcium/citrate ratio < 0.33 and Na/K ratio < 3.5

7. Gastrointestinal issues causing hypocitraturia areusually associated with:

a. Severe constipation

b. Fat malabsorption

c. Gastroesophageal re�ux

d. Chronic diarrhea

8. Mild absorptive hyperoxaluria is best treated by:

a. Dietary oxalate restriction

b. Administration of Oxalobacter formigenes

c. Dietary calcium supplementation

d. Avoidance of food high in fat 9. High incidence of uricacid stones in obese population is due to: a. Diet richin purines b. Diet rich in salt c. Decreased ammoniaproduction d. Insu�cient �uid intake 10. To protectagainst stone formation in children on ketogenic diets, itis advisable to give: a. Potassium citrate b. �iazidediuretics c. Allopurinol d. Magnesium oxide ANSWER KEY1. b 2. c 3. a 4. d 5. c 6. b 7. d 8. c 9. c 10. a

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135. Smith EM, Elder JS. Double antimicrobial prophylaxisin girls with breakthrough UTI. Urology. 1994 ;43:708-–12.136. Pohl HG, Bauer SB, Borer JG, et al. The outcome ofvoiding dysfunction managed with clean intermittentcatheterization in neurologically and anatomically normalchildren. BJU Int. 2002;89:923–7. 137. Tanagho EA, MillerER, Lyon RP, Fisher R. Spastic striated external sphincterand urinary tract infection in girls. Br J Urol.1971;43:69–82. 138. Steinhardt GF, Naseer S, Cruz OA.Botulinum toxin: Novel treatment for dramatic urethraldilatation associated with dysfunctional voiding. J Urol.1997;158:190–1. REVIEW QUESTIONS 1. A 2-year-old girl isexpected to begin toilet training in which of thefollowing sequences: a. Daytime bowel, daytime bladder,nocturnal bladder, nocturnal bowel b. Noc turnal bowel,daytime bowel, daytime bladder, nocturnal bladder c. Daytime bladder, nocturnal bladder, nocturnal bowel, daytimebowel d. Nocturnal bladder, nocturnal bowel, daytimebowel, daytime bladder 2. A 6-year-old boy is referredshortly a�er the beginning of second grade with new-onseturinary frequency occurring every 15 minutes. He does nothave nocturnal enuresis and has not had daytime wetting. Hehas never had a urinary tract infection and was completelyasymptomatic before the school year began. His physicalexamination is normal. Your treatment recommendationsinclude: a. Reassurance b. Renal bladder sonography withprevoid and postvoid views of the bladder to investigatewhether he is retaining urine c. An MRI of the sacralspine d. Anticholinergic medication 3. A 7-year-old obesegirl presents with daytime incontinence lasting over ayear. She has been evaluated with multiple urine culturesand only mixed bacterial growth found. She denies urgencyto void, voids approximately �ve times daily, and neverwets the bed. Her mother states that her underpants aresporadically wet, with wetting occurring shortly a�er thegirl voids. Her physical examination is normal. Yourtreatment recommendations include: a. Renal bladdersonography with prevoid and postvoid views of the bladder

to investigate whether she is retaining urine b. An MR Iof the sacral spine c. Ant icholinergic medication d. Reassurance and encouragement to void with her legs widelyspaced

4. An 8-year-old girl presents with incontinence occurringwhen she laughs hard. Her physical examination,urinalysis, and remainder of her history are normal. Youdiagnose giggle incontinence and o�er a prescription for:a. Amitriptyline b. Oxybutynin c. Vasopressin d.Methylphenidate

5. A 9-year-old boy presents with nighttime wetting. Hehas never been completely dry at night and wets the bedapproximately three nights of the week. His father had thesame problem until the age of 13 years. A review of theboy’s voiding patterns shows that he is dry during theday, denies urgency, and has normal bowel movements. He isinterested in becoming dry soon because he is planning tojoin the Boy Scouts. Your treatment recommendationsinclude: a. Nothing, because he will grow out of it around13 years of age, just like his father b. Oxybutynin and abowel program c. Vasopressin d. Amitriptyline

6. A 9-year-old boy presents with nighttime wetting. Hehas never been completely dry at night and wets the bedapproximately three nights out of the week. His fathersu�ered from the same problem until the age of 13 years. Areview of the boy’s voiding patterns shows that heoccasionally has episodes of mild incontinence during theday preceded by the need to void and has bowel movementsevery several days. He is interested in becoming dry soonbecause he is planning to join the Boy Scouts. Yourtreatment recommendations include: a. Nothing as he willgrow out of it around 13 years of age, just like hisfather. b. Oxybutynin and a bowel program c. Vasopressind. Amitriptyline

7. A 6-year-old girl has never been completely dry.Despite that she has no symptoms other than persistentlydamp underpants, her pediatrician has evaluated her forsuspected UTIs. Each urine culture has demonstrated eitherno growth or fewer than 10,000 CFU/mL of mixed growth. Shewas toilet trained at 23 months of age. She voids �vetimes during the day, with normal sensation to void beforeand no evidence of urgency. Her panties are always wet,day and night. She does not wake up to urinate in themiddle of the night. Your initial recommendation includes:a. Timed voiding to make certain that she is not inover�ow incontinence b. A renal-bladder sonogram c. A KUB

examination d. Renal scan e. A VCUG 8. A 6-year-old girlpresents with a history of �ve culture-proved urinarytract infections. She has never had fever with them.Instead, the cultures are obtained because of her chronicurinary incontinence. She wets most every day, generallybeginning around midday and into the a�ernoons. Herincontinence is never preceded by a sense of urgency. Shewill generally stay dry throughout the night, wakes around7 am, but doesn’t void until around lunchtime. She mightvoid once more before bedtime. Which condition is shelikely to have? a. Paradoxical incontinence b. Sensoryde�cient bladder c. Detrusor overactivity d. Primarynocturnal enuresis 9. A 4-year-old girl presents with ahistory of three culture-proved febrile urinary tractinfections. Her only medications include MiraLAX forchronic constipation, though she takes it rarely andcomplains of abdominal pain. She is frequently wet duringthe day, and her incontinence is preceded by urgency. Yourinitial recommendations include: a. Timed voiding andbetter adherence to her bowel program b. Oxybutynin and abowel program c. Trimethoprim-sulfamethoxazole nightly d.Renal bladder sonogram with prevoid and postvoid views anda contrast voiding cystourethrogram, andtrimethoprim-sulfamethoxazole, nightly 10. A 5-year-oldgirl is diagnosed with dysfunctional voiding syndrome a�eran evaluation for wetting, constipation, and recurrentfebrile UTIs. A VCUG was negative. Your treatmentrecommendation includes: a. Timed voiding b. Timedvoiding, bladder program c. Timed voiding, bladderprogram, anticholinergics d. Timed voiding, bladderprogram, antibiotic prophylaxis 11. Identify theincorrect statement regarding voiding abnormalities. a.Hinman syndrome, which is a discoordination between thedetrusor contraction and sphincter relaxation, isinitially managed by injecting Botox (botulinum toxin)into the sphincter. b. Bladder dysfunction from posteriorurethral valve is not static. Whereas detrusoroveractivity predominates in childhood, myogenic failure isseen in adolescence. c. Most infants with neurogenicbladder have complete paralysis of detrusor function. d.Children with cerebral palsy are incontinent only as aresult of their physical limitation, because they cannotreach the toilet in time.

ANSWER KEY

1. b

2. a

3. d

4. d 5. c 6. b 7. d 8. b 9. d 10. d 11. b

53 Applied clinical biostatistics

Figure 53.3 Receiver operating characteristic plot com

paring tests (a) and (b). AUC, area under the curve; Test

x, theoretically perfect discriminatory test; Test c, test

without discriminatory ability. model. All covariates weremeasured only once at the entry into the study. Gender wascoded as 1 for male and 2 for female. U p/c is the urineprotein-to-creatinine ratio on a �rst morning specimen.

Covariate β-Coef�cient P Value 95% Con�dence interval

Age (yr) 6.625 0.024 0.762, 14.012

Gender –6.761 0.003 –8.682, –4.839

Systolic BP 2.322 0.041 0.157, 4.487

Diastolic BP 5.208 0.109 –1.638, 12.054

U p/c 8.312 0.0001 7.926, 8.698

Constant(α ) 3.224 0.000 1.471, 4.977

Answer:

is regression analysis reveals that age, gender, systolic

blood pressure, and a �rst morning urine protein-to-cre

atinine ratio are all signi�cant determinants of the change

(e.g., decline) in eGFR. Based on a nonsigni�cant P value,

diastolic blood pressure was not found to be a determinant

of change in eGFR in the multivariate models despite being

signi�cant in univariate analyses. �ere may be two poten

tial reasons for this. �e �rst is that diastolic blood pres

sure is intimately related to systolic blood pressure.Because

they o�en run together (e.g., co-linear), placing both inthe

model may make one insigni�cant when adjusted for the

other. �e additional possibility is that there was not suf

cient power in the study to detect a signi�cant e�ect of

diastolic blood pressure on eGFR. Although not provided,

if there were insu�cient numbers of patients in the study

to perform a regression with �ve covariates, the diastolic

blood pressure may have been a�ected by this. In looking

at the remaining determinants, age, systolic blood pressure,

and the �rst morning urine protein-to-creatinine ratio,

all had positive and statistically signi�cant β-coe�cients

in the regression. �ese data suggest that there is a direct

relationship with these variables and eGFR in that older

children with higher systolic blood pressures and higher

urine protein-to-creatinine ratios had a higher absolute

change in the eGFR over the year of the study. Conversely,

gender had a negative association with eGFR, implying that

females have a lesser change in eGFR (e.g., protectivee�ect).

Furthermore, looking at the P values and con�dence inter

vals associated with the regression show that the strength

of the association is strongest between the �rst morning

urine protein-to-creatinine ratio and the eGFR. �is can be

inferred because of the narrow con�dence interval and very

low associated P values.

2. Given the results of the multivariate regression inQuestion 1, write the regression equation associated with

this study. Answer: �e variability in eGFR = 3.224 +6.625*(age) + (–6.761)* (gender) + 2.322*(systolic BP) +5.208*(diastolic BP) + 8.312*(U p/c) 3. You wish toevaluate two di�erent diagnostic laboratory tests in termsof their ability to reliably identify disease in yourpopulation of patients. In attempting to do so, youadminister the two diagnostic tests (a) and (b) to a studypopulation of 100 subjects in which the presence orabsence of disease has been con�rmed using a goldstandardmethodology. A�er performing both tests in yourpopulation, you are able to construct the following 2 × 2tables. Test (a): Disease status Test (a) results PresentAbsent Total Positive 22 7 29 Negative 3 68 71 25 75 100Test (b): Disease Status Test (b) Results Present AbsentTotal *Positive 18 2 20 Negative 7 73 80 25 75 100Calculate the sensitivity, speci�city, positive predictivevalues, and negative predictive values for each test. Test(a): Sensitivity = TP/(TP + FN) = 22/22 + 3 = 0.88 × 100 =88% Speci�city = TN/(TN + FP) = 68/68 + 7 = 0.91 × 100 =91% Positive predictive value (PPV) = TP/(TP + FP) = 22/22+ 7 = 0.76 × 100 = 76% Negative predictive value (NPV) =TN/(TN + FN) = 68/68 + 3 = 0.96 × 100 = 96% Test (b):Sensitivity = TP/(TP + FN) = 18/18 + 7 = 0.72 × 100 = 72%Speci�city = TN/(TN + FP) = 73/73 + 2 = 0.97 × 100 = 97%Positive predictive value (PPV) = TP/(TP + FP) = 18/18 + 2= 0.90 × 100 = 90%

Negative predictive value (NPV) = TN/(TN + FN) = 73/73 + 7= 0.91 × 100 = 91%

4. Compare the two diagnostic tests in question 3 in termsof their performance at both ruling in and ruling outdisease in the population.

Answer:

One way to compare the performance of these two tests in

this population is to calculate the likelihood ratios foreach

test.

For test (a): Likelihood ratio (a) =sensitivity/(1-speci�city) = 0.88/(1 – 0.91) = 9.8

For test (b): Likelihood ratio (a) =sensitivity/(1-speci�city) = 0.72/(1 – 0.97) = 24 In thisscenario, test (b) has a higher likelihood ratio

mostly because of its high speci�city. However, the choiceof

which test is most favorable in this example hinges primar

ily on the characteristics of the disease under study.Should

the disease in this example be serious and potentially fatal

if undetected and/or curable on detection, test (a) may be

preferable because of its higher sensitivity. �is is due tothe

lower rate of false-negative results associated with test(a).

A false-negative result in this scenario would have serious

consequences for the health of this population because of

disease severity. However, in a situation in which a disease

is relatively mild and not associated with signi�cant mor

bidity and mortality and/or further testing associated with

a positive test result is both expensive and associated with

its own risks, then test (b) may be preferable. �is isbecause

of its lower rate of false-positive test results (e.g.,higher

speci�city). 5. You have conducted a case-control studyexamining whether maternal exposure to drug x duringpregnancy is associated with the development ofhypertension in children younger than 10 years of age. Inperforming this study, you retrospectively collect data ona group of children diagnosed with hypertension with age-and gender-matched controls sampled from the same generalpopulation. You retrospectively collect exposure data fromthe mothers of these children to drug x during pregnancy.From your data, you are able to construct the following 2 ×2 table: Hypertension status Exposure history HypertensiveNormotensive Total Exposed 20 25 45 Unexposed 5 50 55 25 75100 Calculate the odds of developing hypertension withexposure relative to not being exposed. How does this

metric relate to the calculation of a relative risk?Answer: �is question is asking for a calculation of theodds ratio from this case-control study. �e odds ratio(OR) is calculated from the number of those with diseasedivided by those without disease for each exposure group.In this question this becomes: OR = ad/b c = 20 × 50/5 ×25 = 1000/125 = 8. In the situation in which a case-controlstudy is examining a relatively rare disease, the oddsratio can be a good approximation of the relative risk.However, in this scenario in which hypertension ishypothetically present in 25% of the population, therelative risk for disease associated with exposure x isdi�cult to estimate.