Pediatric Surgery: Pediatric Urology 3662435667, 9783662435663

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Prem Puri Editor

Pediatric Surgery Pediatric Urology

Pediatric Surgery

Prem Puri Editor

Pediatric Surgery Pediatric Urology

With 292 Figures and 68 Tables

Editor Prem Puri Newman Clinical Research Professor University College Dublin Dublin, Ireland Consultant Pediatric Surgeon Beacon Hospital Dublin, Ireland

ISBN 978-3-662-43566-3 ISBN 978-3-662-43567-0 (eBook) https://doi.org/10.1007/978-3-662-43567-0 © Springer-Verlag GmbH Germany, part of Springer Nature 2023 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer-Verlag GmbH, DE, part of Springer Nature. The registered company address is: Heidelberger Platz 3, 14197 Berlin, Germany

To my Father-in-law, Dr. Gautam Prakash Seth for inspiration and encouragement

Preface

The last two decades have seen remarkable advances in prenatal diagnosis, imaging, anesthesia, intensive care, and minimally invasive surgery including robotic technology which have radically altered the management of infants and children with congenital and acquired surgical and urological conditions. In recent years, important basic science advances in the fields of regenerative medicine and tissue engineering, pharmacotherapy, genetics, immunology, embryology, and developmental biology offer hope of the translation of basic science discoveries to new clinical therapies for children in the future. Pediatric Surgery provides an authoritative, comprehensive, and up-to-date international reference on the surgical management of both common and rare surgical and urological conditions in infants and children, written by the world’s foremost experts. The authors are leaders in their respective fields and have been chosen in every case for their expertise and experience. The vast amount of information included in Pediatric Surgery is divided into three volumes: Vol. 1: General Principles and Newborn Surgery; Vol. 2: General Pediatric Surgery, Transplantation, Trauma, and Tumors; and Vol. 3: Pediatric Urology. There are three different publication formats of the reference works: (1) printed book, (2) a static e-version on SpringerLink that mirrors the printed book, and (3) a living reference also on SpringerLink that is constantly updateable, allowing the reader to rapidly find up-to-date information on a specific topic. Each chapter is organized in the form of a well-defined and structured review of the topic that allows readers to search and find information easily. Volume 1 of Pediatric Surgery, devoted to General Principles and Newborn Surgery, has 85 chapters and was published in 2020. Volume 2 which has 70 chapters devoted to General Pediatric Surgery, Transplantation, Trauma and Tumors was published in 2021. Volume 3, devoted to Pediatric Urology, has 40 chapters on congenital and acquired urological disorders in infants and children. Each chapter provides a step-by-step detailed practical guide on the management including high-quality color illustrations to clarify and simplify various operative techniques. My hope is that Pediatric Surgery will act as a major reference book for the management of childhood surgical and urological disorders, providing information and guidance to pediatric surgeons, pediatric urologists, neonatologists, pediatricians, and all those seeking more detailed information on surgical and urological conditions in infants and children. vii

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Preface

I wish to thank most sincerely all the contributors from around the world for their outstanding work in the preparation of this innovative international reference book on the management of surgical and urological conditions in infants and children. I also wish to express my gratitude to Dr. Anne Marie O’Donnell for her help in the preparation of this book. I wish to thank the editorial staff of Springer, particularly Ms. Audrey Wong-Hillmann, Ms. Shameem Aysha, and Ms. Divya Rajakumar for all their help during the preparation, production, and publication of this important reference book. Dublin, Ireland 2023

Prem Puri

Contents

Part I

General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1

1

Embryology of the Urinary Tract . . . . . . . . . . . . . . . . . . . . . . K. L. M. Pfistermüller and Peter Cuckow

3

2

Antenatal Hydronephrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . Luis H. Braga and CD Anthony Herndon

17

3

Evaluation and Management of Urinary Tract Infections in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Linda C. Lee, Frank J. Penna, and Martin A. Koyle

35

4

Imaging of the Urinary Tract . . . . . . . . . . . . . . . . . . . . . . . . . Melanie P. Hiorns and Lorenzo Biassoni

49

5

Magnetic Resonance Imaging of the Urinary Tract . . . . . . . Kristin M. Broderick, J. Damien Grattan-Smith, and Andrew J. Kirsch

81

6

Urodynamic Studies of the Urinary Tract . . . . . . . . . . . . . . . Beth A. Drzewiecki and Stuart B. Bauer

95

7

Principles of Minimally Invasive Surgery . . . . . . . . . . . . . . . 109 Joseph J. Pariser, Blake B. Anderson, and Mohan S. Gundeti

8

Chronic Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Tej K. Mattoo, Sweety A. Srivastava, and Melissa Gregory

9

Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143 Dieter Haffner and Christian Lerch

10

Renal Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 Jens Goebel, Jaimie D. Nathan, William Robert DeFoor Jr, and Curtis A. Sheldon

Part II 11

Kidney

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189

Congenital Renal Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . 191 Salvatore Cascio and Piotr Hajduk

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Contents

12

Multicystic Dysplastic Kidney Disease . . . . . . . . . . . . . . . . . . 209 Imran Mushtaq, Maria Asimakidou, and Vasilis Stavrinides

13

Renal Calculus Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 Larisa G. Kovacevic and Yegappan Lakshmanan

Part III Upper Urinary Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 14

Ureteropelvic Junction Obstruction . . . . . . . . . . . . . . . . . . . . 233 Boris Chertin, Galiya Raisin, and Prem Puri

15

Ureterovesical Junction Obstruction . . . . . . . . . . . . . . . . . . . 249 Massimo Garriboli, Alfredo Berrettini, and Irene Paraboschi

Part IV

Vesicoureteral Reflux and Ureteral Duplication . . . . . . . 263

16

Anatomical and Functional Basis of Vesicoureteral Reflux . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 J. Christopher Austin and Steven J. Skoog

17

The Diagnosis and Medical Management of Vesicoureteral Reflux: An Update and Current Controversies . . . . . . . . . . . 277 Saul P. Greenfield

18

Endoscopic Treatment of Vesicoureteral Reflux . . . . . . . . . . 299 Florian Friedmacher and Prem Puri

19

Surgical Treatment of Vesicoureteric Reflux . . . . . . . . . . . . . 309 Mohamed Sameh Shalaby and Laura Jackson

20

Ureteral Duplication and Duplex Systems . . . . . . . . . . . . . . . 327 Ramnath Subramaniam and Alexander Springer

21

Ureteroceles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339 Kristin M. Broderick and Andrew J. Kirsch

Part V

Bladder

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353

22

Nocturnal Enuresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355 Tryggve Nevéus

23

Daytime Urinary Incontinence . . . . . . . . . . . . . . . . . . . . . . . . 375 Tryggve Nevéus

24

Injectable Bulking Agents in the Treatment of Pediatric Urinary Incontinence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391 Julian Wan and Kate H. Kraft

25

Bladder Exstrophy, Epispadias, and Cloacal Exstrophy Peter Cuckow and May Bisharat

26

Bladder Diverticula, Urachal Anomalies, and Other Unusual Conditions of the Bladder . . . . . . . . . . . . . . . . . . . . 421 Kyle O. Rove and Duncan T. Wilcox

. . . 401

Contents

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27

Posterior Urethral Valves . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429 Abhishek Seth, Chester J. Koh, Aylin N. Bilgutay, and David A. Diamond

28

Prune-Belly Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437 Francisco T. Dénes and Anthony A. Caldamone

29

Neurogenic Bladder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461 Salvatore Cascio, Stuart O’Toole, and Malcolm A. Lewis

30

Continent Urinary Diversion . . . . . . . . . . . . . . . . . . . . . . . . . 489 Alison Keenan, Ben Whittam, and Mark P. Cain

31

Augmentation Cystoplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . 507 Boris Chertin, Stanislav Koucherov, and Ofer Z. Shenfeld

Part VI

Genital

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525

32

Hypospadias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527 Pierre Mouriquand, Daniela Brindusa Gorduza, and Pierre-Yves Mure

33

Male Epispadias, Genitourinary Implications . . . . . . . . . . . . 555 Patricia S. Cho and Marc Cendron

34

Phimosis and Buried Penis . . . . . . . . . . . . . . . . . . . . . . . . . . . 575 Navroop Johal and Peter Cuckow

35

Cryptorchidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585 John M. Hutson and Sam Pennell

36

Varicocele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603 Jason P. van Batavia and Kenneth I. Glassberg

37

Testicular Torsion Salvatore Cascio

38

Cloaca and Urogenital Sinus with Normal Rectum . . . . . . . . 639 Alberto Peña and Andrea Bischoff

39

Different Sexual Development . . . . . . . . . . . . . . . . . . . . . . . . 659 Maria Marcela Bailez, Mariana Costanzo, and Javier Ruiz

40

Pediatric and Adolescent Gynecology . . . . . . . . . . . . . . . . . . 685 Stefanie Cardamone and Sarah Creighton

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695

About the Editor

Prem Puri MBBS, LRCP, LRCS(Ed), DCH, MS, FRCS, FRCS(Ed), FACS, FCS Paed Surg (SA)(Hon), FAAP(Hon), DSc(Hon) He is the Newman Clinical Research Professor at the University College Dublin School of Medicine and Medical Science and Consultant Pediatric Surgeon and Director of Surgical Research at the Beacon Hospital. He is currently the Secretary of the International Board of Pediatric Surgical Research. He is past President of the World Federation of Associations of Pediatric Surgeons (WOFAPS), past President of the European Pediatric Surgeons Association (EUPSA), and past President of the World Federation of Associations of Pediatric Surgeons (WOFAPS) Foundation. He was the Editor-in-Chief of Pediatric Surgery International (2001–2021), and on the Editorial Board of several other journals. He was the Director of Research (1989–2009) and President (2009–2016) of the National Children’s Research Centre, Our Lady’s Children’s Hospital in Dublin, the single largest pediatric research institution in Ireland. Professor Puri is known internationally for his research into underlying mechanisms causing birth defects, and innovative treatments, which have benefited millions of children all over the world. His research on vesicoureteral reflux (VUR), the most common urological disorder in children, has had a major worldwide impact on patient treatment, through the development of a 15-min day care endoscopic procedure to replace a major open surgical procedure. As a direct result of his research, this endoscopic treatment has radically altered the management of xiii

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About the Editor

vesicoureteral reflux throughout the world. His research work on Hirschsprung disease and allied disorders, congenital diaphragmatic hernia, and foregut anomalies has provided insights into the pathogenesis and treatment of these congenital conditions. Professor Puri is one of the most cited pediatric surgical researchers in the world. His research work has been cited over 24,500 times in peerreviewed articles with h-index of 77 and i10-index of 502. He has published 11 books and monographs, 147 chapters in textbooks, and over 750 articles in peer-reviewed journals, including many in high impact factor journals, such as New Eng. J. Med, Lancet, British Medical Journal, and Nature Genetics. He is the Editor of Newborn Surgery (4th edition), which is regarded as the authoritative book in the field, and also of the widely acclaimed Pediatric Surgery (Springer Surgery Atlas Series), which had its 2nd edition published in 2019, the 4th edition of Hirschsprung Disease was published in 2019, the Vol. 1 of Major Reference Book on Pediatric Surgery was published in 2020 and the Vol. 2 in 2021, the Vol. 3 (Pediatric Urology) and the 2nd edition of Pediatric Surgery: Diagnosis and Management will be published in 2023. Between 1985 and 2019, Professor Puri trained 80 research fellows in basic science research at the National Children’s Research Centre in Dublin. All these research fellows were young pediatric surgeons/pediatric urologists from 16 countries, who spent 2–4 years in the laboratory. Many of them are now professors and heads of departments of pediatric surgery/pediatric urology in various parts of the world and active academically. He has been awarded many Honorary Fellowships, including the American Surgical Association (ASA), American Academy of Pediatrics, American Pediatric Surgical Association, Canadian Association of Pediatric Surgeons, Japanese Society of Pediatric Surgeons, and Argentinean, Austrian, Canadian, Czech, Croatian, Cuban, Indian, and South African pediatric surgical associations. Professor Puri is a multi-award-winning researcher whose previous awards include People of the Year Award (Ireland), the prestigious Denis

About the Editor

xv

Browne Gold Medal by the British Association of Paediatric Surgeons, Rehbein Medal by the European Paediatric Surgeons’ Association, and Colles Medal by the Royal College of Surgeons in Ireland, for outstanding contribution to pediatric surgery. He has been a visiting professor to many leading universities all over the world and invited speaker at over 250 international scientific meetings.

Contributors

Blake B. Anderson Comer Children’s Hospital, The University of Chicago Medicine, Chicago, IL, USA Maria Asimakidou Department of Pediatric Urology, Great Ormond Street Hospital, London, UK J. Christopher Austin Department of Urology, Division of Pediatric Urology, Oregon Health and Science University, Doernbecher Children’s Hospital, Portland, OR, USA Maria Marcela Bailez Department of Pediatric Surgery, Hospital de Pediatría “Prof. Dr. J.P. Garrahan”, Buenos Aires, Argentina Stuart B. Bauer Department of Urology, Boston Children’s Hospital, Boston, MA, USA Alfredo Berrettini Department of Pediatric Urology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy Lorenzo Biassoni Radiology Department, Great Ormond Street Hospital for Children, London, UK Aylin N. Bilgutay Hackensack Meridian Health, Jersey Shore University Medical Center, Hackensack, USA Andrea Bischoff International Center for Colorectal and Urogenital Care. Children’s Hospital Colorado, University of Colorado, Aurora, CO, USA May Bisharat Consultant Paediatric Urologist, Addenbrooke’s Hospital, Cambridge, UK Luis H. Braga Pediatric Urology, Division of Urology, Department of Surgery, McMaster Children’s Hospital, McMaster University Medical Center (MUMC), Hamilton, ON, Canada Kristin M. Broderick Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA Mark P. Cain Seattle Children’s Hospital, Seattle, WA, USA University of Washington School of Medicine, Seattle, WA, USA

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Anthony A. Caldamone Section of Pediatric Urology, Hasbro Children’s Hospital, Warren Alpert School of Medicine of Brown University, Providence, RI, USA Stefanie Cardamone University College London Hospital, London, UK Salvatore Cascio UCD School of Medicine, University College Dublin and Children’s Health Ireland, Children’s University Hospital, Dublin, Ireland Marc Cendron The Department of Urology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Boris Chertin Department of Urology and Pediatric Urology, Shaare Zedek Medical Center, Faculty of Medical Science, Hebrew University, Jerusalem, Israel Patricia S. Cho The Department of Urology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Mariana Costanzo Department of Endocrinology, Hospital de Pediatría “Prof. Dr. J.P. Garrahan”, Buenos Aires, Argentina Sarah Creighton University College London Hospital, London, UK Peter Cuckow Urologist, the Portland Hospital for Women and Children, London, UK Department of Paediatric Urology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK William Robert DeFoor Jr Clinical Research, Division of Pediatric Urology, Cincinnati Children’s Hospital, Cincinnati, OH, USA Francisco T. Dénes Pediatric Urology Unit, Division of Urology, Hospital das Clínicas, University of São Paulo, São Paulo, SP, Brazil David A. Diamond University of Rochester, Rochester, NY, USA Beth A. Drzewiecki Department of Urology, Pediatric Division, Children’s Hospital of Montefiore, Bronx, NY, USA Florian Friedmacher Department of Pediatric Surgery and Pediatric Urology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany Massimo Garriboli Evelina London Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, UK Kenneth I. Glassberg Department of Urology, Columbia University Medical Center, New York, NY, USA Jens Goebel Section of Pediatric Nephrology, Helen Devos Children’s Hospital, Grand Rapids, MI, USA Daniela Brindusa Gorduza Mère-Enfant – Groupe Hospitalier Est – Service d’Urologie Pédiatrique, Hospices Civils de Lyon, Bron, France

Contributors

Contributors

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J. Damien Grattan-Smith Department of Pediatric Radiology, Children’s Healthcare of Atlanta, Atlanta, GA, USA Saul P. Greenfield Cohen’s Children’s Hospital, Hofstra School of Medicine, Clinical Professor of Urology, New Hyde Park, NY, USA Melissa Gregory Pediatric Nephrology and Hypertension Children’s Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI, USA Mohan S. Gundeti Comer Children’s Hospital, The University of Chicago Medicine, Chicago, IL, USA Dieter Haffner Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany Piotr Hajduk Consultant Pediatric Surgeon and Urologist, Children’s University Hospital, Dublin, Ireland CD Anthony Herndon Pediatric Urology, Division of Urology, Department of Surgery, Children’s Hospital of Richmond, Virginia Commonwealth University School of Medicine, VCU Medical Center, Richmond, VA, USA Melanie P. Hiorns Radiology Department, Great Ormond Street Hospital for Children, London, UK John M. Hutson Department of Paediatrics, University of Melbourne, Urology Department, The Royal Children’s Hospital, Surgical Research Unit, Murdoch Childrens Research Unit, Parkville, VIC, Australia Laura Jackson Department of Paediatric Surgery and Urology, Bristol Royal Hospital for Children, Bristol, UK Navroop Johal Department of Paediatric Urology, Great Ormond Street Hospital for Children, London, UK Alison Keenan Riley Hospital for Children at IU Health, Indianapolis, IN, USA Andrew J. Kirsch Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA Chester J. Koh Texas Children’s Hospital and Baylor College of Medicine, Houston, TX, USA Stanislav Koucherov Department of Pediatric Urology, Shaare Zedek Medical Center, Faculty of Medical Science, Hebrew University, Jerusalem, Israel Larisa G. Kovacevic Department of Pediatric Urology, Children’s Hospital of Michigan, Detroit, MI, USA Martin A. Koyle Department of Surgery (Emeritus), Temerty Faculty of Medicine and Institute of Health Policy Management and Evaluation, Toronto, Ontario, Canada

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Kate H. Kraft Department of Urology, Division of Pediatric Urology, University of Michigan, Ann Arbor, MI, USA Yegappan Lakshmanan Department of Pediatric Urology, Children’s Hospital of Michigan, Detroit, MI, USA Linda C. Lee Department of Surgery, University of British Columbia and Vancouver Island Health Authority, Victoria, BC, Canada Christian Lerch Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany Malcolm A. Lewis Royal Hospital for Children, Glasgow, Scotland University of Port Harcourt Teaching Hospital, Port Harcourt, Nigeria Mbarara University of Science and Technology, Mbarara, Uganda Tej K. Mattoo Pediatrics (Nephrology) and Urology, Wayne State University School of Medicine, Detroit, MI, USA Pierre Mouriquand Université Claude-Bernard – Lyon 1, Villeurbanne, France Mère-Enfant – Groupe Hospitalier Est – Service d’Urologie Pédiatrique, Hospices Civils de Lyon, Bron, France Pierre-Yves Mure Université Claude-Bernard – Lyon 1, Villeurbanne, France Mère-Enfant – Groupe Hospitalier Est – Service d’Urologie Pédiatrique, Hospices Civils de Lyon, Bron, France Imran Mushtaq Department of Pediatric Urology, Great Ormond Street Hospital, London, UK Jaimie D. Nathan Department of Abdominal Transplantation and Hepatopancreatobiliary Surgery, Nationwide Foundation Endowed Chair in Pediatric Transplantation, Columbus, OH, USA The Ohio State University College of Medicine, Nationwide Children’s Hospital, Columbus, OH, USA Tryggve Nevéus Pediatric Nephrology Unit, Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden Stuart O’Toole Royal Hospital for Children, Glasgow, Scotland University of Glasgow, Glasgow, Scotland Irene Paraboschi Department of Pediatric Urology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy Joseph J. Pariser Comer Children’s Hospital, The University of Chicago Medicine, Chicago, IL, USA

Contributors

Contributors

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Alberto Peña International Center for Colorectal and Urogenital Care Children’s Hospital Colorado, Emeritus Professor of Surgery, University of Colorado, Aurora, CO, USA Frank J. Penna Department of Surgery, University of South Carolina and Prisma Health, Columbia, SC, USA Sam Pennell Department of Surgery, Austin Hospital, Heidelberg, VIC, Australia K. L. M. Pfistermüller Great Ormond St Hospital for Children NHS Foundation Trust, London, UK Prem Puri Newman Clinical Research Professor, University College Dublin, Dublin, Ireland Consultant Pediatric Surgeon, Beacon Hospital, Dublin, Ireland Galiya Raisin Department of Urology, Shaare Zedek Medical Center, Jerusalem, Israel Kyle O. Rove Department of Surgery, Division of Urology, University of Colorado, Aurora, CO, USA Javier Ruiz Department of Pediatric Urology, Hospital de Pediatría “Prof. Dr. J.P. Garrahan”, Buenos Aires, Argentina Abhishek Seth Nemours Children’s Health, Orlando, USA Mohamed Sameh Shalaby Department of Paediatric Surgery and Urology, Bristol Royal Hospital for Children, Bristol, UK Curtis A. Sheldon Urogenital Center, Division of Pediatric Urology, Cincinnati Children’s Hospital, Cincinnati, OH, USA Ofer Z. Shenfeld Department of Urology, Shaare Zedek Medical Center, Faculty of Medical Science, Hebrew University, Jerusalem, Israel Steven J. Skoog Department of Urology, Division of Pediatric Urology, Oregon Health and Science University, Doernbecher Children’s Hospital, Portland, OR, USA Alexander Springer Department of Pediatric Surgery, Medical University Vienna, Vienna, Austria Sweety A. Srivastava Pediatric Nephrology and Hypertension Children’s Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI, USA Vasilis Stavrinides Department of Pediatric Urology, Great Ormond Street Hospital, London, UK Ramnath Subramaniam Department of Paediatric Urology, Leeds Teaching Hospitals, Leeds General Infirmary, Leeds, UK

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Jason P. van Batavia Division of Pediatric Urology, Children’s Hospital of Philadelphia, Philadelphia, USA Julian Wan Department of Urology, Division of Pediatric Urology, University of Michigan, Ann Arbor, MI, USA Ben Whittam Riley Hospital for Children at IU Health, Indianapolis, IN, USA Duncan T. Wilcox Department of Pediatric Urology, Children’s Hospital Colorado, Aurora, CO, USA

Contributors

Part I General

1

Embryology of the Urinary Tract K. L. M. Pfistermu¨ller and Peter Cuckow

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

4

Early Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4

Renal Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anomalies of Ureteric Bud Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5 7

Bladder, Trigone, and Lower Ureteric Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Anomalies of the Urogenital Membrane and Cloacal Partitioning . . . . . . . . . . . . . . . . . . . . . . 10 Anomalies of the Trigone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Genital and Reproductive Tract Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Development of the Male Internal Genitalia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Development of the Female Internal Genitalia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Development of the External Genitalia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Development of the Male External Genitalia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Development of the Female External Genitalia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abnormalities of the External Genitalia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10 11 13 14 14 15 15

Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Abstract

Embryology provides the basis for the understanding of human anatomy – as a field, it has expanded exponentially following advances in molecular and experimental techniques. An

K. L. M. Pfistermüller (*) Great Ormond St Hospital for Children NHS Foundation Trust, London, UK

understanding of embryogenesis and the subsequent congenital anomalies is a necessity for the pediatric urologist, giving a foundation for the appropriate clinical management of such conditions. This chapter will focus on key events in the development of the urogenital tract – two entirely different components intimately interwoven embryologically and anatomically.

P. Cuckow Department of Paediatric Urology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK e-mail: [email protected] © Springer-Verlag GmbH Germany, part of Springer Nature 2023 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43567-0_163

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K. L. M. Pfistermu¨ller and P. Cuckow

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Introduction Congenital anomalies of the kidney and urinary tract (CAKUT) are embryonic disorders that arise during development and result in a spectrum of defects in the kidneys and outflow tracts, which include the ureters, the bladder, and the urethra. It has been estimated that CAKUT are responsible for 30% to 50% of all children with chronic renal disease worldwide and that some anomalies can predispose to adult-onset diseases, such as hypertension (dos Santos Junior et al. 2014). Embryology provides the basis for the understanding of human anatomy – as a field, it has expanded exponentially following advances in molecular and experimental techniques. An understanding of embryogenesis and the subsequent congenital anomalies is a necessity for the pediatric urologist, giving a foundation for the appropriate clinical management of such conditions. This chapter will focus on key events in the development of the urogenital tract – two entirely different components intimately interwoven embryologically and anatomically.

Early Events Human gestation starts with fertilization, the fusion of the nuclear material of the haploid spermatozoon and oocyte to form a zygote. The zygote undergoes a series of mitotic divisions while travelling down the fallopian tube to the uterus, resulting in an increase in cell number and, by days 3 to 4, has formed a 16-cell morula (mulberry). The morula consists of an inner cell mass, which forms the true embryo, and the outer cell mass that develops into the trophoblast, a part of the placenta. On entry into the uterine cavity at days 5 to 6, fluid penetrates the glycoprotein shell, zona pellucida, into the intercellular spaces. These spaces coalesce forming a single cavity around the cell mass, and the zygote is now known as a blastocyst, with the inner cell mass called the embryoblast, and is positioned at one pole, while the outer cell mass or trophoblast forms the epithelial wall. The zona pellucida has disappeared, and implantation now begins at the end of the first week.

Following implantation from days 7 to 12, cells of the embryoblast differentiate into two layers, a hypoblast (endoderm) and an epiblast (ectoderm) layer, forming a flat bilaminar disc. At the same time, a small cavity appears adjacent to the epiblast layer that later develops into the amniotic cavity, and the same happens on the hypoblast side of the disc, with this cavity eventually developing into the yolk sac. During the third week, gastrulation occurs – the process that establishes all three germ cell layers of the embryo. Essentially, the process begins with formation of the midline primitive streak on the surface of the epiblast from which cells pour in between the ectoderm and endoderm layers forming a new layer of mesoderm. Around day 17, the mesoderm is further subdivided into three parallel areas assigned laterally from the primitive streak as the paraxial mesoderm (a thickened plate of tissue close to the midline), the visceral or lateral plate mesoderm (continuous with the mesoderm covering the yolk sac), and the intermediate mesoderm in between connecting the paraxial and lateral plate mesoderm. The mesoderm is absent at the head and tail ends of the embryo leaving the endoderm and ectoderm opposed at these regions. At the head end, this region is termed the buccopharyngeal membrane and at the tail end, the cloacal membrane (Fig. 1). Buccopharyngeal membrane

Amniotic cavity

Ectoderm

Mesoderm

Endoderm Yolk sac Cloacal membrane

Fig. 1 Around day 17 the mesoderm is further subdivided into three parallel areas assigned laterally from the primitive streak as the paraxial mesoderm, the visceral or lateral plate mesoderm, and the intermediate mesoderm in between connecting the paraxial and lateral plate mesoderm. The mesoderm is absent at the head and tail ends of the embryo leaving the endoderm and ectoderm opposed in these regions. At the head end, this region is termed the buccopharyngeal membrane, and at the tail end, the cloacal membrane

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Embryology of the Urinary Tract

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The two regions where the endoderm and ectoderm remain opposed are termed the buccopharyngeal membrane at the head end and the cloacal membrane at the tail end. Continued rapid growth of the embryo causes the dorsal surface to bulge into the amniotic cavity, and the head and tail ends bend toward the midline forming the respective head and tail folds. This cephalocaudal folding causes the endoderm lining of the yolk sac to be included within the two folds and along with the lateral folding leads to formation of a tube-like gut; hence, the endoderm is the precursor of the foregut and hindgut (Fig. 2). Once the cloacal membrane appears, the posterior wall of the yolk sac forms a small diverticulum extending into the connecting stalk. This diverticulum is known as the allantois. It may be involved in abnormalities of bladder development. Continued folding moves the connecting stalk and allantois onto the front surface of the embryo along with the cloacal membrane that sits below the allantois. The allantois becomes continuous with the developing hindgut, and this defines the cloaca as the portion of hindgut distal to the confluence of the allantois and hindgut. Either side of this are two elevations, the urogenital folds, which coalesce at their superior ends into the genital tubercle. Formation of the anterior abdominal wall above the cloacal membrane coupled with regression of the tail fold displaces the cloacal membrane inferiorly to leave it facing downward (Fig. 3–5).

Head

Tail fold Yolk sac Allantois Cloacal membrane

Fig. 2 Continued rapid growth of the embryo causes the dorsal surface to bulge into the amniotic cavity, and the head and tail ends bend toward the midline forming the respective head and tail folds. This cephalocaudal folding causes the endoderm lining of the yolk sac to be included within the two folds and along with the lateral folding leads to formation of a tube-like gut; hence, the endoderm is the precursor of the foregut and hindgut

A priority of the embryo is future reproductive potential. To this end, early in development, primordial germ cells are set aside on the wall of the yolk sac. Later in development, they migrate to partake in gonadal differentiation and formation of the genital tract.

Renal Development Human kidney development begins in the first trimester. There are three stages of mammalian kidney development: the pronephros, mesonephros, and metanephros (Rosenblum et al. 2017). The pronephros and mesonephros form and then essentially involute. The metanephros develops into the final functional mammalian kidney. The pronephros consists of simple tubules and forms at three weeks of gestation. Just caudal to the pronephros, the mesonephros forms at four weeks. The development of the mesonephros is heralded by the formation of the mesonephric or Wolffian ducts from the thoracic and lumbar segments. These ducts drain the mesonephroi into the lateral wall of the cloaca. The mesonephros is a primitive renal unit and begins functioning at six to ten weeks. At approximately ten weeks of gestation, the caudal tubules degenerate, leaving the upper nephrons to become part of the genital tract (Fig. 4). At the beginning of the 5th week, a diverticulum develops on the posteromedial aspect of the lower portion of the mesonephric ducts, close to its entrance into the cloaca. This ureteric bud grows backward and interacts with the sacral portion of the intermediate mesoderm known as the metanephric blastema. This interaction stimulates nephron production – a process known as reciprocal induction as described by Mackie and Stevens (1975). The bud dilates to form the renal pelvis and subsequently splits into the major calyces and further into the minor calyces. Further branching forms the definitive collecting duct system, and around the tip of each collecting duct, blastema cells congregate forming a Bowman’s capsule, proximal convoluted tubule, loop of Henle, and distal convoluted tubule, i.e., the nephron. This serial branching process of the ureteric bud is complete by 14 weeks, but synthesis of new

K. L. M. Pfistermu¨ller and P. Cuckow

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Allantois

Gonad Gonad

Mesonephros Mesonephric duct Paramesonephric duct Blastema

Genital tubercle U.G. sinus Tail fold Cloacal membrane

Ureteric bud

U.G. sinus

Ureteric bud

Septum

Cloaca

Müllerian tubercle

Fig. 3 Once the cloacal membrane appears, the posterior wall of the yolk sac forms a small diverticulum extending into the connecting stalk. This diverticulum is known as the allantois. It may be involved in abnormalities of bladder development. Continued folding moves the connecting stalk and allantois onto the front surface of the embryo along with the cloacal membrane that sits below the

allantois. The allantois becomes continuous with the developing hindgut and this defines the cloaca as the portion of hindgut distal to the confluence of the allantois and hindgut. On either side of this are two elevations, the urogenital folds, which coalesce at their superior ends into the genital tubercle

Gonad

Allantois Mesonephros Mesonephric duct

Genital tubercle Cloacal membrane

Metanephros

U.G. sinus

Septum Rectum

Fig. 4 There are three stages of mammalian kidney development: the pronephros, mesonephros, and metanephros (Rosenblum et al. 2017). The pronephros and mesonephros

form and then essentially involute. The metanephros develops into the final functional mammalian kidney

nephrons continues within the parenchyma throughout gestation. The embryonic kidney has a lobulated external appearance. Ascent from its pelvic position occurs between weeks six and ten, and during this relocation, it rotates 90 degrees medially to sit with the hilum facing anteromedially in the renal fossa. Migration to its abdominal position necessitates degeneration of the lower vascular branches and acquisition of new vessels from the aorta until it finally reaches its lumbar position and the definitive renal artery supply is established.

Fetal urine production commences at week ten, but since tubular function only commences from week 14, the initial urine is only a minimal modification of the plasma filtrate. The kidneys in fetal life are not responsible for excretion of waste as this function is performed by the placenta; however, they provide over 90% of the amniotic fluid in the latter part of gestation which is essential to allow the fetus to move as well as for skeletal and lung development. Several lines of evidence indicate that CAKUT is often caused by recessive or dominant

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Gonad Allantois Kidney

Urogenital membrane Anal membrane

Trigone

Fig. 5 The pronephros consists of simple tubules and forms at 3 weeks of gestation. Just caudal to the pronephros, the mesonephros forms at 4 weeks. The development of the mesonephros is heralded by the formation of the mesonephric or Wolffian ducts from the thoracic and lumbar segments. These ducts drain the mesonephroi into the

lateral wall of the cloaca. The mesonephros is a primitive renal unit and begins functioning at 6–10 weeks. At approximately 10 weeks gestation, the caudal tubules degenerate, leaving the upper nephrons to become part of the genital tract

mutations in single (monogenic) genes. To date, approximately 40 monogenic genes are known to cause CAKUT if mutated, explaining 5% to 20% of patients (van der Ven et al. 2018). However, hundreds of different monogenic CAKUT genes probably exist. Whole-exome sequencing (WES) has facilitated discovery of these genes (Murugapoopathy and Gupta 2020). Given the significant advances in prenatal diagnosis and application of genomics over the last decade, many centers now provide genetic counseling for prenatally diagnosed CAKUT disorders (Talati et al. 2019; Westland et al. 2020). Establishing a molecular genetic diagnosis in patients with monogenic CAKUT helps affected families to understand the etiology of their child’s medical condition (Kohl et al. 2021). The following genes play a key role in renal development:

Anomalies of Ureteric Bud Development

WT-1: Role in the formation of the ureteric bud. Pax-2: Acts as a control gene playing a role in the formation of the Wolffian and Mullerian ducts, ureteric bud, and metanephric blastema. GDNF: Expressed in the metanephric blastema. It is a ligand for the RET receptor on the ureteric bud and hence is important for the interaction between the ureteric bud and the metanephric blastema.

Renal Agenesis and Dysplasia Unilateral failure of development of the ureteric bud is found in 0.1% of the population and results in renal agenesis. Alternatively, dysplasia results when there is misplacement of the ureteric bud on the mesonephric duct. This prevents the bud contacting the metanephric blastema in the normal way, and instead, abnormal nephrogenesis ensues (Fig. 6). A low origin of the ureteric bud on the mesonephric duct will cause the bud to reach the urogenital sinus earlier in gestation and so migrate to a more lateral position giving rise to a lateral ectopic ureteric orifice with a shorter tunnel through the bladder wall and give rise to an orifice more prone to reflux. This demonstrates the association between reflux and renal dysplasia. Conversely, a high origin of the ureteric bud will arrive at the urogenital sinus later in gestation and has less time to migrate from the mesonephric duct opening. This may lead to a medial ectopic ureteric orifice either located on the trigone or in one of the mesonephric duct derivatives. It is important to remember that kidneys drained by ectopic ureters are usually dysplastic.

K. L. M. Pfistermu¨ller and P. Cuckow

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2o 1o 3B

3o 2B

1B

Fig. 6 Embryological basis of Weigert- Meyer law complete duplex kidney. 1B insertion at 1 – normal. 3 insertion of ureter from the upper renal moiety (3B) is inferior and medial to the lower renal moiety ureteric insertion (2B to 2). The ureter from the upper renal moiety (3B) is often associated with a ureterocoele at 3 and the ureter draining the lower renal moiety is often associated with vesicoureteric reflux due to its superior and lateral insertion point

Duplex Kidney A duplex kidney arises when two ureteric buds occur on the same side and induce formation of upper and lower renal moieties. If a single bud divides close to its origin, an incomplete duplex system results, drained by a common distal ureter. This anomaly has an incidence of 1:100. If two separate buds form, the result is a complete duplex system with the kidney being drained by two separate ureters. This anomaly is less common with an incidence of 1:1000. The ureteric drainage of a complete duplex system is explained by the Weigert–Meyer law – as the lower ureter reaches the urogenital sinus, it migrates laterally and crosses the upper ureter. This means the lower ureter is prone to reflux, and the upper ureter, arriving later on the urogenital sinus and maintaining a close association with the mesonephric duct opening, is prone to ectopia (Fig. 7). Anomalies of Renal Position, Rotation, and Fusion In order for the kidneys to ascend from the pelvis to their lumbar position, they must pass through the gap between the paired umbilical arteries. Failure to do so leads to a pelvic kidney that lies

close to the common iliac vessels. A pelvic kidney is usually malrotated and will have an anomalous blood supply. If the two pelvic kidneys come together during their ascent, they may fuse resulting in a horseshoe kidney. This occurs in 1 in 500 members of the population with 95% of these cases demonstrating fusion at the lower pole and 5% at the upper pole. Depending on the timing of fusion, the final position of the kidney may be orthotopic, pelvic, or lumbar. When ascent is prevented by the root of the Inferior Mesenteric Artery, a lumbar position results. Horseshoe kidneys demonstrate abnormal rotation and ureteric anatomy with the ureters draining anteriorly over the isthmus. Twenty percent of horseshoe kidneys demonstrates obstructed drainage at the pelviureteric junction.

Bladder, Trigone, and Lower Ureteric Development At four weeks, the urogenital septum, an ingrowth of mesoderm from the point of confluence of the allantois and hindgut, coupled with lateral ingrowth of the Rathke folds divides the cloaca into the anorectal canal and urogenital sinus (see Figs. 3 and 4). This process is complete by six weeks, leaving the cloaca divided into anterior urogenital and posterior anal membranes with the mesonephric ducts draining into the anterior division. The urogenital membrane breaks down during the seventh week allowing continuity between the developing urinary tract and the amniotic cavity (Fig. 5). The upper portion of the primitive urogenital sinus (between the allantois and entry of the mesonephric ducts) is termed the vesicourethral canal and will become the definitive bladder. This primitive bladder increases in size with the growth of the anterior abdominal wall. The allantois, connecting the apex of the bladder to the umbilical root, loses its patency becoming the median umbilical ligament or urachal remnant. Weeks thirteen to sixteen demonstrate initial development of the trigone with circular and

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Embryology of the Urinary Tract

Fig. 7 A duplex kidney arises when two ureteric buds occur on the same side and induce formation of upper and lower renal moieties. If a single bud divides close to its origin an incomplete duplex system results, drained by a common distal ureter. This anomaly has an incidence of 1:100. If two separate buds form, the result is a complete duplex system with the kidney being drained by two separate ureters. This anomaly is less common with an incidence of 1:1000

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Mesonephric duct Ureteric bud Urogenital sinus Metanephric blastema

Kidney

Urogenital sinus

Vas

longitudinal smooth muscle strands developing into discrete inner and outer longitudinal layers and an intervening circular layer – with this musculature in place, continence may be possible. By week 21, definitive urothelium is visible. During cloacal division, the mesonephric ducts distal to the origins of the ureteric buds are incorporated into the wall of the primitive urogenital sinus coupled with widening of the posterior wall of the sinus (Figs. 3 and 4). The ureteric orifices become separated from the mesonephric duct orifices and migrate superolaterally relative to the mesonephric duct openings which remain in a midline position where the epithelium of both ducts fuses forming the posterior urethra (Fig. 5). The triangular area between the two ureteric orifices and the fused mesonephric duct epithelium defines the trigone. Ascent of the kidneys from the pelvis necessitates accompanying elongation of the ureters. The

ureters are initially solid structures with canalization mediated by interaction between angiotensin and the angiotensin 2 receptor. This process of canalization commences cranially and caudally from the midpoint leaving only a membrane (Chwalla membrane) between the lower ureter and urogenital canal by early in the eighth week which disappears by the end of that week. Development of the ureteric musculature most likely accompanies drainage of the first secreted urine at around nine weeks, and by 18 weeks, discernable narrowings are evident at the pelviureteric and vesicoureteric junctions. The distal primitive urogenital sinus becomes the true urogenital sinus forming the entire urethra and vaginal vestibule in the female and the posterior urethra in the male (with the anterior urethra being formed from closure of the urethral folds).

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Anomalies of the Urogenital Membrane and Cloacal Partitioning Exstrophy/Epispadias The exact embryological origin of bladder exstrophy is unclear. It is thought to be due to failure of growth of the lower abdominal wall between the allantois and the urogenital membrane alongside breakdown of the urogenital membrane. Clinically, this manifests as a small open bladder plate, a low set umbilical root and diastasis of the pubic bones. In these patients, the genital tubercle is placed lower; therefore, the cloacal membrance ruptures above it leading to an epispadiac penis with an open dorsal surface that is continuous with the bladder plate. This is a rare anomaly with an incidence of 1:30,000 live births and showing a 3:1 male to female preponderance. It is associated with vesicoureteric reflux and inguinal hernia. Only 50% of bladder exstrophy is diagnosed on antenatal ultrasound. Primary epispadias is even more uncommon with an incidence of 1:120,000 live births and again demonstrating a male dominance at 5:1. The urethra opens on the dorsal aspect of the penis and in the male may be glanular, penile, or penopubic. There is a less severe pubic diastasis than in bladder exstrophy, and there are associated deficiencies of the underlying bladder neck, proximal urethra, and sphincter. The more proximal the meatal opening, the lower the chance of continence in the male leading to an incontinence rate of 70% with primary male epispadias prior to operative intervention. In the female, the clitoris is bifid and the urethra patulous. All female patients with primary epispadias are incontinence at presentation. Cloacal Exstrophy If the septum and lateral Rathke folds also fail to partition the cloaca, the bladder plate is separated into two halves by a central hindgut plate. This is the most severe exstrophy variant, and the phallus is often divided into two widely separated halves. Cloacal exstrophy is more commonly diagnosed antenatally than bladder exstrophy due to the associated renal, sacral, spinal, orthopedic, bowel, and cardiac anomalies.

K. L. M. Pfistermu¨ller and P. Cuckow

Cloacal Anomalies Incomplete septation of the cloaca leads to a communication between the rectum and urogenital sinus. The urethra, vagina, and rectum all open via a common distal channel manifesting clinically as a perineum with a single anterior opening and an imperforate anus.

Anomalies of the Trigone Renal Agenesis If the ureteric bud fails to develop on one side, the ipsilateral trigone also fails to develop. Compensatory unilateral renal hypertrophy occurs in utero. This anomaly is not usually associated with incontinence. Bilateral Single Ectopic Ureters If both ureters maintain their link with the mesonephric duct, the trigone fails to develop. The bladder outlet is incompetent, and the bladder capacity is poor. Even after surgical reconstruction, there is poor urethral continence.

Genital and Reproductive Tract Development The sex of the embryo is decided genetically at fertilization, but it is not until the sixth/seventh week that the gonads acquire discernable male or female characteristics. Early in development, primordial germ cells appear in the wall of the yolk sac, migrating to the genital ridges (which arise during the fifth week of gestation and lie anteromedial to the mesonephros) in the sixth week of development (Fig. 3). The germ cells interact with the surrounding tissue forming primitive sex cords within the developing gonad, divided into an outer cortex and inner medulla. In conjunction with this, the paramesonephric or Müllerian ducts appear lateral to the mesonephric ducts and run parallel to the mesonephric ducts in their upper course. The paramesonephric ducts

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fuse as they approach the urogenital sinus to form the Müllerian tubercle on the posterior wall (Fig. 3). From the sixth week, the primitive gonads begin to develop divergently in a male or female direction. The ovaries develop from the cortex of the indifferent gonad, and their duct system is from the Müllerian (paramesonephric) ducts, while the Wolffian (mesonephric) ducts degenerate. The testes develop from the medulla of the indifferent gonad and maintain the Wolffian (mesonephric) duct system while the Müllerian (paramesonephric) ducts degenerate. It is the presence of the SRY gene on the short arm of the Y chromosome that produces testisdetermining factor which drives development of the male gonad. Lack of the Y chromosome causes development of the female gonad (Fig. 8).

Development of the Male Internal Genitalia As stated above, testis-determining factor is key to this process and causes: • Medullary sex cord development which differentiate into the seminiferous tubules and rete testis. • Regression of the cortical cords. • Development of the tunica albuginea, a dense layer of connective tissue separating the testis from the epithelium. In the seventh week, the developing Sertoli cells of the embryonic testis produce Müllerian inhibiting substance which leads to: • Regression of the Müllerian duct system which forms the vestigial structures in the male of the appendix testis proximally and prostatic utricle distally. • Production of testosterone from the Leydig cells at the eighth week of gestation. • The first stage of testicular descent at 8th to 25th weeks.

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Testosterone acts on the Wolffian (mesonephric) duct system causing development of the male genital ducts. The proximal portion develops into the epididymis, appendix epididymis, and ductuli efferentes. Distal to that point, the duct acquires a smooth muscle wall and becomes the vas deferens. At the terminal portion, a diverticulum develops laterally forming the seminal vesicle and joins the urethra via the ejaculatory ducts. In the prostatic urethra, testosterone initiates development of five pairs of epithelial buds which reach out into the surrounding tissue at around 10 to 16 weeks of gestation. The upper pairs of buds are from mesoderm and eventually form the transitional and periurethral zones of the prostate. It is these regions in the older male that enlarge giving the histological diagnosis of benign prostatic hyperplasia. The lower pairs of buds develop from endoderm and form the peripheral zone. The peripheral zone is the site of 70% of adult prostatic adenocarcinomas. Key to prostatic development is the interaction between testosterone and the mesenchymal androgen receptor; hence, when the androgen receptor is lacking, there is no development of the prostate gland. The bulbourethral glands develop in a similar manner, growing outward from the anterior urethra. Regression of the mesonephros means the testis is left floating freely in the peritoneal cavity on its mesentery. It is attached to the gubernaculum or navigator, by a mesodermal band extending from the lower pole of the testis, along the posterior abdominal wall to the inguinal region where it traverses the abdominal wall musculature (the future inguinal canal). The length of the gubernaculum is static throughout embryonic and fetal growth causing the testis to be drawn into the pelvis. In the sixth month of gestation, a pouch of peritoneum called the processus vaginalis extends through the inguinal canal into the scrotum in front of the gubernaculum. Testicular descent occurs along the posterior wall of the processus vaginalis and is complete by the eighth month. The proximal processus is obliterated by birth leaving the distal part around the testis as the tunica vaginalis. Where obliteration fails, a

K. L. M. Pfistermu¨ller and P. Cuckow

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Paramesonephric duct Mesonephros Gubernaculum

Ureteric bud UG sinus Appendix Appendix of testis of epididymis

Female

Testis

Male

Paraoophoron Ovary Oophoron

Vas deferens

Uterine tube

Ureter

Gubernaculum

Seminal vesicle Utriculus

Uterus Ureter Urethra

Upper vagina

Uterus

Vas

Tube Utriculus

Ovary

Urethra

Broad ligament

Fig. 8 Development of the male and female genital and reproductive tracts

spectrum of anomalies can occur. Where the lumen is significant, abdominal contents can extrude into it forming a hernia. Where the lumen is too small to admit the bowel but a

communication remains, peritoneal fluid can collect forming a hydrocele. Occasionally, cystic remnants can occur along the cord (Fig. 9).

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Embryology of the Urinary Tract

Fig. 9 Development of the male internal genitalia

a

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b

Testis

Processus vaginalis

Muscle

Gubernaculum

Scrotum

c

d

Hernia

Testicular descent occurs in two phases. The first phase is under the control of Müllerian inhibiting substance and insulin-like hormone 3. This takes place at eighth to 25th weeks of gestation where the testis descends along the gubernaculum to the inguinal ligament. The second phase is controlled by testosterone and calcitonin gene-related peptide, occurring at 25 to 30 weeks, and is the final descent of the testis into the scrotum.

Hydrocele

• •

•

Development of the Female Internal Genitalia As stated above, the default pathway for genital development is female. Absence of the SRY gene causes: • Development of the cortical cords. These hold the primordial germ cells which form into

•

Cyst of the cord

primary oocytes, undergoing the first meiotic division and then arresting until puberty. Regression of the medullary cords. Development of the Müllerian (paramesonephric) ducts proximally into the fimbriae and fallopian tubes and distally merging to form the fundus and body of the uterus, cervix, and upper 2/3 of the vagina. Down growth of solid tissue from the Müllerian tubercle within the urorectal septum, called the vaginal plate. This develops a lumen by the 20th week; hence, the upper 2/3 of the vagina develops from the Müllerian system with the lower 1/3 forming from the urogenital sinus. The hymen separates the vaginal lumen from the vestibule. Regression of the Wolffian ducts leaving the vestigial structures of the epoöpheron and paraoöpheron located in the ovarian mesentery and the Gartner’s cyst in the vaginal wall.

K. L. M. Pfistermu¨ller and P. Cuckow

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As already described for the male, the gubernaculum is responsible for migration of the ovary to the pelvis, extending from the lower pole of the ovary, crossing the inguinal canal, and terminating in the labium majorum. During ovarian descent, the gubernaculum becomes folded in the broad ligament of the uterus attaching at its midpoint at the junction between the fallopian tube and body of the uterus. Proximal to this midpoint attachment, the gubernaculum becomes known as the ovarian ligament. Distally, it is the round ligament of the uterus. Incomplete fusion of the Müllerian (paramesonephric) ducts gives rise to a variety of uterine and vaginal anomalies. At the extreme, uterus didelphys results giving an entire duplication of the uterus with each draining by a separate vagina. More common is uterus bicornis in which there are two uterine horns drained by a common vagina. Therefore, depending on the level of incomplete fusion, the uterus may be duplicated and have a complete or partial septum, with a single or duplicated vagina. Occasionally, one of the uterine horns is absent or rudimentary.

Development of the External Genitalia As for internal genital development, the external genitalia is indifferent up to the third month of

gestation. Early development begins with formation of the urogenital folds on either side of the cloacal membrane which fuse anteriorly forming the genital tubercle. Larger swellings, labioscrotal folds, develop laterally fusing in the posterior midline between the urogenital and anal membranes as these membranes separate (Fig. 10).

Development of the Male External Genitalia This process is dependent on the conversion of testosterone to dihydrotestosterone and its subsequent action via the tissue receptors. The genital tubercle enlarges forming the phallus, and at the same time, cells grow into the inferior surface to form the urethral plate. Subsequent involution results in a deep groove on the under surface of the phallus. The tip expands to form the glans. The penile urethra forms from fusion of the genital folds across the groove proximally, whereas the prostatic and membranous urethra are formed from the urogenital sinus. Canalization of the urethra occurs from the tip of the glans and is complete by the 20th week. The labioscrotal folds enlarge into the scrotum, fusing in the midline raphe. The foreskin develops from the base of the glans with growth

clitoris labia minora urethra vagina hymen labia majora

6th week Early 7th week

genital tubercle urethral folds cloacal membrane genital folds

Female

anus

20th week Male raphe scrotum

Fig. 10 Development of male and female external genitalia

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Embryology of the Urinary Tract

initially being more developed on the dorsal aspect of the penis. The foreskin advances distally, now growing on the ventral surface, until it covers the glans and fuses with the midline raphe.

Development of the Female External Genitalia Controlling factors in development of the female external genitalia are not clear, but estrogens play a role. The clitoris is formed from enlargement and folding of the genital tubercle. There is no midline fusion of structures across the perineum. The urogenital folds persist as the labia minora and the labioscrotal folds as the labia majora, meeting posteriorly at the fourchette. The opening of the urethra sits anterior to the vaginal opening which itself is obscured by the hymen until late in gestation.

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Congenital Adrenal Hyperplasia (CAH) Congenital adrenal hyperplasia is the most common of the disorders of sexual differentiation comprising 85% of all ambiguous genitalia in infants. These children have normal female internal genitalia, being genetically 46XX, but secondary to intrauterine androgen exposure, they are virilized with ambiguous genitalia and impalpable gonads. There are three known enzyme defects in the steroid biosynthesis pathway causing CAH, the most common of which is 21α hydroxylase deficiency with an incidence of 1:15,000 live births. Inheritance is autosomal recessive with the defect being carried on chromosome 6. The diagnostic feature is elevated plasma levels of 17α hydroxyprogesterone, the precursor for the reaction driven by 21α hydroxylase. This enzyme deficiency prevents further synthesis down the aldosterone and cortisol pathway, and therefore, an excess is driven down the pathway of testosterone synthesis. This excess of androgens in the female causes phallic enlargement, a closed introitus, and a single channel joining the urethra and vagina onto the perineum.

Abnormalities of the External Genitalia Hypospadias The male anomaly of hypospadias is characterized by failure of development of the urethra to the tip of the penis. It is a common congenital anomaly with an incidence of 1:300. In the most minor form, the urethra opens distally and probably represents a failure of glanular canalization. More severe forms result from failure of fusion of the genital folds resulting in midshaft or proximal openings. In the most severe type, there is complete failure of midline fusion, and the meatal opening sits in between two halves of a bifid scrotum. The endocrine and genetic basis of hypospadias is poorly understood. As outlined above, androgens play a vital role in penile development. Estrogen receptors have been shown to be decreased or absent in hypospadias, and evidence from in vitro fertilization has shown that babies born via this technique of assisted conception have an increased incidence of hypospadias, suggesting a possible causal link with elevated progesterone levels.

Conclusion and Future Directions This chapter has provided a detailed explanation of the embryological development of the urogenital tract with a focus on key events in normal development and a thorough explanation of anomalies that can occur along with their clinical manifestations. In the future, alongside advances in genetics, it is hoped that we may have a better understanding of the aetiology of more inherited genitourinary anomalies.

References dos Santos Junior AC, de Miranda DM, Simões e Silva AC. Congenital anomalies of the kidney and urinary tract: an embryogenetic review. Birth Defects Res C Embryo Today. 2014;102(4):374–81. Kohl S, Habbig S, Weber LT, Liebau MC. Molecular causes of congenital anomalies of the kidney and urinary tract (CAKUT). Mol Cell Pediatr. 2021;8(1):2. Murugapoopathy V, Gupta IR. A Primer on Congenital Anomalies of the Kidneys and Urinary Tracts

16 (CAKUT). Clin J Am Soc Nephrol. 2020;15(5): 723–31. Rosenblum S, Pal A, Reidy K. Renal development in the fetus and premature infant. Semin Fetal Neonatal Med. 2017;22(2):58–66. Talati AN, Webster CM, Vora NL. Prenatal genetic considerations of congenital anomalies of the kidney and urinary tract (CAKUT). Prenat Diagn. 2019;39(9):679–92.

K. L. M. Pfistermu¨ller and P. Cuckow van der Ven AT, Vivante A, Hildebrandt F. Novel Insights into the Pathogenesis of Monogenic Congenital Anomalies of the Kidney and Urinary Tract. J Am Soc Nephrol. 2018;29(1):36–50. Westland R, Renkema KY, Knoers NVAM. Clinical Integration of Genome Diagnostics for Congenital Anomalies of the Kidney and Urinary Tract. Clin J Am Soc Nephrol. 2020;16(1):128–37.

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Antenatal Hydronephrosis Luis H. Braga and CD Anthony Herndon

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Prenatal Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Classification: Grading Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anterior Posterior Renal Pelvic Diameter (APD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Society for Fetal Urology Grading System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Urinary Tract Dilation Grading System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prenatal Intervention for Lower Urinary Tract Obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vesicoamniotic Shunt Placement Versus Fetal Cystoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19 19 20 20 21 22

Postnatal Evaluation of AHN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Renal Ultrasound/Resolution of Urinary Tract Dilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Voiding Cystourethrogram (VCUG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Renal Scintigraphy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Magnetic Resonance Urography (MRU) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

22 22 23 23 24

Postnatal Management of AHN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . P1 UTD (Low Risk) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . P2 UTD (Intermediate Risk) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . P3 (High Risk) UTD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Considerations for Severe Bilateral Hydroureteronephrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Urinary Tract Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antibiotic Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

24 24 24 25 25 25 25

L. H. Braga (*) Pediatric Urology, Division of Urology, Department of Surgery, McMaster Children’s Hospital, McMaster University Medical Center (MUMC), Hamilton, ON, Canada e-mail: [email protected] C. A. Herndon Pediatric Urology, Division of Urology, Department of Surgery, Children’s Hospital of Richmond, Virginia Commonwealth University School of Medicine, VCU Medical Center, Richmond, VA, USA e-mail: [email protected] © Springer-Verlag GmbH Germany, part of Springer Nature 2023 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43567-0_164

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L. H. Braga and C. A. Herndon Etiology of Antenatal Hydronephrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transient or Physiologic Hydronephrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ureteropelvic Junction Obstruction (UPJO-Like HN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vesicoureteral Reflux (VUR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Primary Megaureter/UVJ Obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . LUTO (PUV, PBS, Urethral Stenosis/Atresia) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Posterior Urethral Valves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prune Belly Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Urethral Atresia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Congenital Megacystis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Multicystic Dysplastic Kidney (MCDK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Duplication Anomalies Ureterocele/Ectopic Ureter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26 26 26 27 28 29 29 29 30 30 30 31

Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Abstract

Antenatal hydronephrosis (AHN), also called urinary tract dilation, has been increasingly recognized with the widespread use of fetal ultrasound. Pediatricians, neonatologists, pediatric surgeons, and/or pediatric urologists are often faced with newborns and/or infants with asymptomatic hydronephrosis (HN) detected in utero and are expected to make management decisions regarding their ultrasonographic findings. In most instances, mild to moderate HN carries no clinical relevance as it resolves spontaneously after birth. However, there is a group of infants with urinary tract dilation who merit investigation and should be managed accordingly in order to avoid complications such as urinary tract infections and/or loss of renal function. In this chapter, we will discuss the main urological malformations associated with AHN, as well as their postnatal evaluation and management. Keywords

Antenatal diagnosis · Congenital urological anomalies · Antenatal hydronephrosis · Vesicoureteral reflux · Parental counseling · Fetal intervention Abbreviations

AHN AP

Antenatal hydronephrosis Antibiotic prophylaxis

APD DMSA fUTI GA HN MAG3 MCDK MRU SFU UPJOlike UTD UTI VCUG VUR

Anteroposterior diameter TcDimercaptosuccinic acid Febrile urinary tract infection Gestational age Hydronephrosis TcMercaptoacetyltriglycine Multicystic dysplastic kidney Magnetic resonance urography Society for fetal urology Ureteropelvic junction obstructionlike Urinary tract dilation Urinary tract infection Voiding cystourethrogram Vesicoureteral reflux

Introduction Antenatal hydronephrosis (AHN) represents the second most common anomaly detected during prenatal screening after cardiac defects and occurs with a frequency of 1–3% (Nguyen et al. 2010). The majority of AHN cases are detected in the second trimester, which affords the opportunity for parental counseling before delivery. Discussions may include recommendations for postnatal evaluation and management or referral to tertiary centers when conditions such as posterior urethral valves are suspected. While most conditions such as transient dilation, ureteropelvic junction obstruction (UPJO)-like hydronephrosis and vesicoureteral reflux (VUR) will not lead to surgical intervention, a subset of patients is at

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increased risk of febrile urinary tract infection (fUTI) and may need antibiotic prophylaxis (AP), voiding cystourethrogram (VCUG), and TcMercaptoacetyltriglycine (MAG3). The aim of this chapter will be to review the postnatal management of children with AHN including the role for prenatal intervention, indications for diagnostic tests, and differential diagnosis of the most common conditions with their expected outcomes.

of providers use the anterior-posterior renal pelvic diameter (APD) system prenatally in comparison to postnatally where the SFU or subjective (mild, moderate, severe) systems were more commonly employed (Zanetta et al. 2012). Hydronephrosis grading systems rely on objective and subjective findings. The three most common classifications used are the APD, Society for Fetal Urology (SFU), and the urinary tract dilation (UTD) grading systems.

Prenatal Imaging

Anterior Posterior Renal Pelvic Diameter (APD)

Although fetal metanephric kidney begins at the 28th day of gestation, urine production begins around 14 weeks gestation and can be detected on prenatal ultrasound. The ability of prenatal ultrasound to accurately determine the postnatal diagnosis or etiology of HN varies. Lee et al. demonstrated a linear relationship between increasing severities of prenatal urinary tract dilation and postnatal UPJO-like hydronephrosis. A similar relationship was not observed with other conditions such as VUR or duplex anomalies (Lee et al. 2006). The main benefit of prenatal detection of urological malformations is to allow for an early discussion concerning the main differential diagnosis of AHN and their outcomes. The use of fetal MRI is limited for the evaluation of AHN. The main indication for this modality is the need for specific anatomic detail in the setting of bladder outlet obstruction, such as in cases of cloacal anomaly, urogenital sinus, cloacal/bladder exstrophy, and duplication anomalies. Fetal MRI offers superiority over ultrasound imaging, as ultrasound may be affected by amniotic fluid volume, maternal body habitus, fetal position, or pelvic bony structures.

Classification: Grading Systems Even though AHN is a common condition, consensus regarding its grading is lacking. Zanetta et al. identified this discrepancy in a multispecialty survey, demonstrating that the majority

The most common system used prenatally is the APD system. This strictly objective system is simple and is obtained by measuring the diameter of the renal pelvis in the transverse plane at the level of the hilum. The main disadvantage of this system is that it is operator dependent, which may lead to inaccurate measurements. For example, a common error occurs when the APD measurement is taken from a sagittal kidney view as opposed to the transverse plane. Normative values are described for APD indexed with gestational age. An APD < 4 mm less than 28 weeks and 40% differential renal function. A total of 75 patients were prospectively randomized to surgical intervention versus observation. In the surgery arm, 38/39 maintained renal function and showed improvement of the HN. For the observation arm, 17/36 patients improved, 12 remained stable, and 7 required intervention due to decreased function when the APD ranged from 20 mm to 40 mm (Dhillon 1998).

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L. H. Braga and C. A. Herndon

In general, it is difficult to set an exact value on an APD threshold. Setting a low APD cutoff will increase the sensitivity of detection UPJO-like HN, but it may result in significant over testing. Likewise, raising the APD cutoff will result in better specificity, at the expense of under diagnosing urologic pathology.

Society for Fetal Urology Grading System The Society for Fetal Urology (SFU) is a subjective 5-point grading system that relies on a combination of renal pelvis/calyceal dilation and the integrity of the renal parenchyma (Fernbach et al. 1993) (Table 1). The system is simple but does demonstrate variability with intra-rater and interrater variability, especially with grades II and III hydronephrosis (Rickard et al. 2017). Interestingly, computer-enhanced visual learning appears to be an effective means of teaching the grading system to health care providers. The Chicago group demonstrated effectively through pre- and post-testing that interactive computer module learning improved reliability of grading kidney dilation with the SFU system (Liu et al. 2015). The SFU has been demonstrated to be predictive of both renal function and the need for surgical intervention in patients with AHN. In a retrospective review of 125 patients with AHN, Table 1 SFU grading of hydronephrosis

Grade of hydronephrosis 0 1 2

3

4

Renal image on ultrasound Renal Central renal parenchymal complex thickness Intact Normal Slight splitting Normal Evident splitting, Normal complex confined within renal border Wide splitting pelvis Normal dilated outside renal border; calyces uniformly dilated Further dilatation of Thin pelvis and calyces (calyces may appear convex)

Ross et al. found the SFU system to be predictive of the timing and the need for surgical intervention. Three groups consisting of early surgical intervention, delayed surgical intervention, and continued observation were analyzed with respect to distribution of SFU grade. For early surgical intervention, most (89%) patients demonstrated SFU grade 4 HN. For continued observation, most (78%) patients demonstrated SFU grade 3 HN. For those that underwent delayed surgical intervention, 62% had SFU grade 4 HN (Ross et al. 2011). The SFU classification is a simple system that can easily be learned and demonstrates the ability to predict renal function and the need for surgical intervention. However, it has been fully adopted by other specialties. Furthermore, it does not take into account the entire collecting system including assessment of the urinary bladder or ureter, which may impact postnatal decision-making (Nguyen et al. 2014).

Urinary Tract Dilation Grading System In 2014, to address the lack of consistency in nomenclature, the urinary tract dilation (UTD) grading system was developed by a multidisciplinary team. Terms such as hydronephrosis, caliectasis, pelviectasis, and pelvicaliectasis were discouraged when reporting ultrasound findings. Great effort was made to develop a standardized technique for ultrasound imaging and principles for data reporting. Prenatally, it was felt that the measurement of the APD should be obtained with the spine of the fetus in the 6 or 12 0’clock position. Postnatally, the APD should be obtained at the midpoint of the kidney in the transverse plane, which corresponds to the area of the hilar vessels. The maximal diameter of the renal pelvis should be obtained within the confines of the renal cortex. The UTD grading system consists of a 6-point template that combines two of the most common classifications (APD and SFU) used. An APD cutoff of less than 10 mm was selected in the absence of calyceal or ureteral dilation and felt to represent non-pathologic renal pelvis dilation (Nguyen et al. 2014).

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The intent of this reclassification was to create a more pragmatic approach to the postnatal evaluation of AHN. Parents should be advised that AHN represents a spectrum of disease, and significant pathologic conditions such as VUR may exist in the absence of hydronephrosis (Herndon et al. 1999). Nonetheless, a paradigm shift has occurred regarding the recommendation of VCUG that is no longer based solely on the probability of diagnosing VUR. The six-point evaluation described with the UTD system is used to assign two levels of risk prenatally (A1-low risk and A2/A3-increased risk). A1 (low risk) was defined as 4–7 mm APD at 16–27 weeks or 7–10 mm APD at
28 weeks. Aside from central calyceal dilation (or dilation of the major calyx/infundibulum), all other parameters were normal. A2/A3 (increased risk) was defined as APD >7 mm at 16–27 weeks or > 10 mm at
28 weeks, and/or positive values for one of the other five parameters. Recommendations based on the risk assessment dictate subsequent follow-up within the prenatal period. For A1 UTD detected prior to 28 weeks, a second ultrasound should be performed after 32 weeks of age. For A2/A3, the recommendation was to obtain an ultrasound every 4 weeks until delivery. An ultrasound after 48 h of birth is recommended in both groups (Nguyen et al. 2014).

Prenatal Intervention for Lower Urinary Tract Obstruction The male fetus who presents with severe bilateral hydroureteronephrosis, bladder distension, and decreased amniotic fluid should be considered to have lower urinary tract obstruction (LUTO) until proven otherwise. This condition is a spectrum and thus each case should have an individualized approach. The discussion with the family should be framed around the potential benefit of fetal intervention compared to implicit risks to both the fetus and the mother. The constituents of amniotic fluid shift from the placenta to fetal urine during the 16th week of gestation. Ideally, restoration of amniotic fluid will facilitate pulmonary development and

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potentially facilitate renal development as well. Oligohydramnios that presents after 27 weeks appeared to lend a favorable outcome regarding pulmonary development (Peters et al. 1992). Thus, fetal intervention should be reserved for those that develop this condition very early in the second trimester. The overall need for intervention is rare and estimated to be about 1:60,000. Several large systematic reviews have concluded that although feasible, there does not appear to be sufficient evidence to endorse its use to reliably impact long-term renal function. However, it is clear that postnatal survival is improved in part because those that do not have amniotic fluid restored will suffer fetal and/or neonatal demise (McLorie et al. 2001). Fetal intervention consists of early delivery, fetal shunting, or fetal surgery. Interestingly, practice pattern variation exists between non-US and US physicians who would recommend early delivery in situations of early third trimester identification of bladder outlet obstruction, confirmed lung maturity, and decreasing amniotic fluid. When invasive fetal intervention is considered in the form of vesicoamniotic shunting (VAS) or fetal cystoscopy, a serial assessment of fetal urine should be performed to serve as a basis for renal function (Clayton and Brock 2018). Fetal intervention carries significant risk to the pregnancy and thus all procedures are performed in the controlled environment of the operating room with epidural anesthesia. The fetal anesthesia consists of injection of narcotics and/or paralytics into the umbilical vein with the aid of ultrasound. Percutaneous assess is obtained with both VAS placement or fetal cystoscopy. The clear advantage of fetal cystoscopy is the ability to directly visualize the posterior urethra and establish the diagnosis allowing for directed intervention. Fetal urine biochemistry includes urinary sodium, calcium, osmolarity, total protein, and β-2-microglobulin (Table 2). Serial bladder aspirations have proven more effective at determining renal function. In 2007, a systematic review of 23 studies revealed that urinary calcium and sodium were the strongest predictors of poor renal function while beta-2-microglobulin was

22 Table 2 Fetal urinary markers of obstructive uropathy Fetal urinary markers of obstructive uropathy Urinary marker Abnormal range Na >100 mg/dL Ca >8 mg/dL Beta2-microglobulin >4 mg/dL Osmolality >210 mOsm/L

less predictive. Clinical predictors of poor renal function include oligohydramnios, renal parenchymal cysts, or increased echogenicity (Morris et al. 2007). However, fetal ultrasound urinary tract findings do not correlate with fetal urine biomarkers in their ability to predict renal function. A multicenter prospective randomized trial, Percutaneous shunting in Lower Urinary Tract Obstruction (PLUTO), was designed to assess efficacy of fetal intervention. The population included those with evidence of bladder outlet obstruction in which the benefit of intervention was unclear. However, the study was prematurely terminated due to poor enrollment. A total of 31 patients were randomized, with 16 undergoing successful VAS placement and 15 observed. Perinatal death as expected was higher in the observed cohort, 33% vs. 66%. Equally, no meaningful impact on renal function was demonstrated although two patients demonstrated normal renal function. Complications occurred in 7/16 (44%), 3 PROM and 4 nonfunctional shunts (Morris et al. 2013).

Vesicoamniotic Shunt Placement Versus Fetal Cystoscopy To assess the efficacy of VAS and fetal cystoscopy, a multicenter retrospective review of 111 consecutive patients with LUTO was performed. The strict inclusion criteria were as follows: diagnosis between 16 and 26 weeks, severe LUTO on fetal US, absence of other anatomic abnormalities including cardiac echocardiogram, favorable urine electrolytes, and normal male karyotype. A total of 50 patients who underwent fetal intervention (34 cystoscopy with laser ablation, 16 VAS) were compared to

L. H. Braga and C. A. Herndon

61 patients treated expectantly. Both VAS and FCA demonstrated a clear survival advantage when compared to observation alone in all LUTO cases. Interestingly, for those born with PUV, VAS and FCA demonstrated a 6-month survival advantage compared to the observation arm, but only FCA demonstrated an improvement in renal function (Ruano and Sananes 2015). A severity of disease classification system was developed to better identify patients that could benefit from fetal intervention (Ruano et al. 2016). Specifically, a combination of fetal parameters that include amniotic fluid volume, echogenicity of fetal kidney, renal cortical cysts, renal dysplasia, favorable urinary biomarkers, and the presence of fetal intervention were used to stage patients. The rate of fetal intervention (either fetal cystoscopy or vesicoamniotic shunt), death within 24 h, overall mortality, and the need for renal replacement therapy were all more prevalent in Stage III (worse) patients.

Postnatal Evaluation of AHN Over the last decade, the postnatal evaluation and management recommendations for AHN have become more evidence-based (Capolicchio et al. 2018). A paradigm shift has occurred with recommendations for postnatal imaging and use of antibiotic prophylaxis (AP) tailored to a risk assessment, which includes the likelihood of developing a UTI, renal deterioration, or the need for surgical intervention. Previously, the evaluation was based on the probability of detecting diseases such as VUR, which was found to occur in up to 24% of patients (Herndon et al. 1999).

Imaging Renal Ultrasound/Resolution of Urinary Tract Dilation The initial postnatal US, as previously mentioned, should be obtained after 48 h to account for intravascular volume depletion that occurs after

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Table 3 Postnatal UTD grading system UTD P1 Low risk APD 10–15 mm Central calyceal dilation Parenchymal thickness and appearance normal Ureters normal Bladder normal

UTD P2 Intermediate risk APD
15 mm Peripheral calyceal dilatation Parenchymal thickness and appearance normal Ureters abnormal Bladder normal

delivery. It is important to note that this represents a form of third spacing that is mobilized over the first 24–48 h of life. Three levels of risk (P1, P2, and P3) were developed based on the degree of APD and positive values for the remaining five data points: P1 UTD (low risk) includes APD 10 to 10 mm, who do not show evidence of VUR, should undergo diuretic renography. The renogram should be performed between 6 and 8 weeks of age, to allow at least a degree of maturation of the renal parenchyma. The definition of obstruction is controversial. The majority of asymptomatic children with pelvic-ureteric junction (PUJ) anomalies and slow drainage will improve spontaneously. Only

4

Imaging of the Urinary Tract

a relatively small percentage (around 30%, the numbers vary in different series) require surgery to prevent the onset of complications (pain, UTI, and kidney damage). These are the children who presented to medical attention before ultrasound screening was introduced. PUJ anomaly causes a partial obstruction. Renal dilatation has been interpreted as having a beneficial effect, in absorbing the pressure that results from resistance to urinary outflow before it directs toward the renal parenchyma. At present, the only accepted definition of obstruction to urinary outflow in an asymptomatic child is “impaired drainage which, left untreated, will cause a deterioration of renal function” (Koff 2003). Unfortunately, this is a retrospective definition. Therefore, it is difficult to predict which kidneys will deteriorate if left untreated, and which ones will remain stable and eventually improve. It is crucial to be aware that slow drainage on a renogram does not necessarily mean obstruction: it could represent urinary stasis in a very dilated dysplastic renal pelvis, with no resistance to urinary outflow (a “lazy” pelvis that takes longer to drain) (Amarante et al. 2003). Or it could represent stasis in a dilated renal pelvis caused by a degree of PUJ stenosis, which in turn generates a resistance to urinary outflow and an intrapelvic pressure not high enough to cause a decrease in renal function. Recent retrospective reports have suggested that an impaired cortical transit of tracer on the renogram, defined as the passage from the outer cortex to the inner structures (medulla and collecting system), might be predictive for a significant improvement of function after pyeloplasty, or on the contrary might be associated with a high risk of renal deterioration in cases treated conservatively. A large prospective study is needed to confirm that cortical transit is the best predictor of which children should be operated upon.

Assessment of Vesico-Ureteric Junction Anomaly The renogram is widely used in the assessment of patients with vesico-ureteric junction (VUJ) anomalies. The renogram provides important information on the status of the renal parenchyma

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(focal defects and stretching), the DRF, and the drainage. It is essential that the child be well hydrated, so that the tracer can be seen flowing from the renal pelvis down the ureter. If the child is known to have a neurogenic bladder, placement of a bladder catheter to facilitate bladder drainage (either before the start of the renogram or upon inspection of the postmicturition view, if there is still significant activity in the bladder) will be important to be able to see the distal end of the ureter. Typically, in the case of a megaureter with a VUJ anomaly, the renogram will show urinary stasis within the ureter, more marked at the distal end, which persists on the postmicturition view. If the child has a large renal pelvis in addition to a dilated ureter, it can be difficult to decide whether the features are due to a VUJ anomaly only or a VUJ with an associated PUJ anomaly (Fig. 17). Correlation with US and sometimes a retrograde contrast study will help. In the presence of a dilated renal pelvis and ureter on US, the renogram may show significant urinary stasis in the renal pelvis with little or no stasis within the ureter, suggesting a PUJ anomaly rather than a VUJ. In this case, it is important to be cautious as the features on the renogram could be due to suboptimal hydration and reservoir effect of the renal pelvis. Little or no significant stasis at the distal end of the ureter in the presence of a significant stasis in the renal pelvis cannot exclude the presence of a VUJ anomaly. Correlation with US is essential.

Congenital Renal Anomalies In an infant with a history of posterior urethral valves (PUV), the renogram is usually performed within 3–4 months after valve ablation, to obtain baseline information on the degree of split renal function, the status of the renal parenchyma, and the drainage. In children with a duplex collecting system, the renogram provides essential functional information on the status of the renal parenchyma (Fig. 10). The upper moiety of a duplex typically obstructs via an ectopically implanted ureter with a ureterocele and shows reduced or possibly absent function on a functional isotope study. The result of the functional study directs further

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Fig. 17 Right pelviureteric junction obstruction with synchronous vesicoureteric junction obstruction. (a) Longitudinal ultrasound showing gross hydronephrosis of the right renal pelvis (but no calyceal dilatation), and a very stretched and thinned parenchyma (defined by markers), (b) Transverse ultrasound through the bladder showing a very dilated right ureter (marked). A tiny left ureter can

also be seen, (c) MAG3 study at (i) 2 min showing normal uptake in the unaffected left kidney (posterior view) and relative photopenia of the very dilated right renal pelvis with only a thin rim of functioning parenchyma and then (ii) at 17 min with isotope accumulating in the dilated and obstructed right renal pelvis

management, with heminephrectomy being considered if there is poor upper moiety function. The lower moiety of a duplex can show VUR. This can be elegantly demonstrated during a diuretic renogram if the child is too young to have an isotope

indirect cystogram. The lower moiety of a duplex can show reduced function and scarring on functional imaging. Horseshoe kidneys can show hydronephrosis and urinary stasis at the level of the PUJ. The

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Fig. 18 Horseshoe kidney with a duplex configuration in the left moiety. (a) Ultrasound (transverse) through the mid-abdomen showing the isthmus of renal tissue across the midline (HS), the right moiety (RM), left lower moiety

(LLM), left upper moiety which is dilated (LUM), and the left upper moiety ureter (LU M UR) curving around the left lower moiety, (b) MAG 3 study confirms the presence of functioning tissue across the midline

renogram is very useful in providing information on parenchymal status, on the function of each moiety and on drainage (Fig. 18). Complex renal anomalies may have complex drainage patters and MAG3 studies can help delineate both the configuration of the functioning tissue but also its drainage (Fig. 13).

study in boys under 18 months who have had a radiological MCUG to exclude PUV and in whom the question is ruling out VUR. Nowadays, as the radiological MCUG can be performed with very low radiation dose, provided a good technique is used, the direct isotope cystogram (DIC) is becoming partly obsolete.

Radionuclide Cystography Isotope cystograms are very low-dose studies to identify the ureters and bladder-specific abnormalities. However, the drawback is the poor anatomical detail.

Direct Isotope Cystogram This study requires the use of a bladder catheter. The baby is placed supine on the gamma camera, the bladder is catheterized, the tracer (Tc-99 mpertechnetate, usually 20 MBq) is instilled in the bladder, and a saline infusion is run until the baby feels the urgency of voiding. The image acquisition begins when the tracer is administered and ends when the bladder is empty or when VUR has been demonstrated. The test is performed in girls, usually under 2 years of age, or as a follow-up

Indirect Radionuclide Cystogram This test is performed at the end of the renogram in children who can void on request, usually 3 years of age or older. It has the great advantage of being an entirely physiological nontraumatic test and it makes full use of the radiation already administered with the renogram, with no added radiation. This test requires a lot of patience and significant gamma camera time, as the test is done when the child wants to void and more than one attempt at bladder emptying may be necessary if there is still significant activity within the renal collecting system and bladder after the first void. The IRC has been shown to be less sensitive than the radiological MCUG in detecting VUR. Because of the anatomy of the VUJ, some children never reflux, some children always reflux, and some children sometimes reflux and some other times do not. The IRC will pick out the

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children who always reflux, and will be negative in the ones who never reflux. With regard to the third group, the IRC shows fewer episodes of VUR in comparison to the MCUG. However, if the child does not empty the bladder completely after the first micturition, another cystogram can be acquired minutes later, and so on until the bladder is empty, thus increasing the chances of detecting VUR. The test can give some insight into bladder function. If the bladder never empties on all attempts, this finding raises the suspicion of bladder dysfunction and further evaluation with urodynamics may be helpful. If the voided volume of urine is significantly higher than what is considered physiological for the child’s age, the possibility of a distended bladder has to also be considered. The IRC can be useful in the context of recurrent UTIs, when information on renal cortical integrity and scarring, DRF (often in comparison with previous functional studies), drainage, bladder emptying, and the possible presence of VUR

Fig. 19 (a) MAG3 and IRC in a patient with right-sided reflux, showing the reduction of isotope in the right kidney indicating renal damage (seen on the right side of the image on this standard posterior view), (b) The IRC on the same

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is required. The renogram associated with an IRC in a toilet-trained child can give all these pieces of information in a one-stop shop (Fig. 19). Pitfalls of an IRC include significant urinary stasis in the renal collecting system at the end of the renogram (which makes it difficult to identify VUR), and early bladder emptying, before the acquisition has started, thus missing a significant part of the micturition phase (especially if the child is not really toilet-trained).

Tumor Imaging Bone scanning is currently indicated in patients with metastatic Wilms’ tumors and in rhabdomyosarcomas with unfavorable prognosis. Bone scanning in pediatric oncology requires a very accurate scanning technique to make sure that the sufficient number of counts are acquired, the child is completely still during the acquisition (sedation or general anesthesia are often required

patient shows the reflux occurring in the right kidney with increasing counts from isotope refluxing back to the right kidney from the kidney over time

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in children younger than 4–5 years of age and in uncooperative older children), and the position of the child on the gamma camera couch is perfectly straight, so that the physiological tracer uptake in the epiphyseal growth plates is symmetric and cannot be misinterpreted as metastatic disease. Accurate staging and response assessment is vital in the management of childhood malignancies. Fluorine-18 fluorodeoxyglucose positron emission tomography/CT (FDG PET-CT) provides complimentary anatomical and functional information (Chambers et al. 2019). Fluorodeoxyglucose (FDG) PET CT is in its early phase of evaluation in pediatric uro-oncology. Some recent reports suggest that FDG PET CT provides additional value in detecting regional or distant disease in comparison to standard diagnostic procedures; in particular, bone scanning could be replaced by FDG PET CT as PET can assess the presence of disease in several organs simultaneously and not just in the skeleton (Völker et al. 2007). The standardized uptake value (SUV) of FDG uptake correlates with the grade of tumor differentiation and prognosis, thus helping in directing biopsy in the primary tumor. Also, FDG PET can be used to assess the efficacy of induction chemotherapy, with a small decrease in SUV after chemotherapy being correlated with higher risk of systemic recurrence (Hawkins et al. 2005; Schuetze et al. 2005). These initial reports are encouraging and suggest that a proper evaluation of PET CT in pediatric urogenital tumors is justified (Portwine et al. 2010).

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relevant VUR. Functional magnetic resonance urography provides comprehensive functional information with improved anatomical information in comparison to nuclear medicine renograms. 3Dprinted models are increasingly used for surgical planning. High-quality research studies that can answer important clinical questions are needed. Longterm appropriately powered cohort studies need to fully inform on the clinical significance of different degrees of renal scarring in children with UTIs and the associated risk of hypertension, chronic kidney disease, and, in females, complications in pregnancy. In the context of an antenatally diagnosed hydronephrosis, only a fraction of patients are at risk of losing renal function if left untreated; in the others, the renal pelvic dilatation undergoes spontaneous resolution with time. Currently, we still struggle to reliably identify the hydronephrotic kidney at risk. It is essential to further evaluate in large pediatric studies promising parameters, such as the cortical tracer transit time, for the identification of the kidney at risk.

Cross-References ▶ Antenatal Hydronephrosis ▶ Congenital Renal Anomalies ▶ Evaluation and Management of Urinary Tract Infections in Children

References Conclusion and Future Directions The ultimate goal of renal imaging in children is to fully characterize CAKUT with great accuracy and at the same time providing non-invasive prognostic information in patients at risk of developing CKD. Hence, it is important to develop tools capable to detect the progression of renal disease. The renal US scan should always be the first imaging examination in children. Contrastenhanced US is a new promising modality to evaluate focal renal disease. Contrast-enhanced voiding urosonography has advantages over MCUG, with higher sensitivity for the detection of clinically

Amarante J, Anderson PJ, Gordon I. Impaired drainage on diuretic renography using half-time or pelvic excretion efficiency is not a sign of obstruction in children with a prenatal diagnosis of unilateral renal pelvic dilatation. J Urol. 2003;169(5):1828–31. Awais M, Rehman A, Zaman MU, Nadeem N. Recurrent urinary tract infections in young children: role of DMSA scintigraphy in detecting vesicoureteric reflux. Pediatr Radiol. 2015;45(1):62–8. Brenner D, Elliston C, Hall E, Berdon W. Estimated risks of radiation-induced fatal cancer from pediatric CT. AJR Am J Roentgenol. 2001;176(2):289–96. Chambers G, Frood R, Patel C, Scarsbrook A. 18F-FDG PET-CT in paediatric oncology: established and emerging applications. Br J Radiol. 2019;92(1094): 20180584. https://doi.org/10.1259/bjr.20180584.

80 Conway JJ, Maizels M. The “well tempered” diuretic renogram: a standard method to examine the asymptomatic neonate with hydronephrosis or hydroureteronephrosis. A report from combined meetings of The Society for Fetal Urology and members of The Pediatric Nuclear Medicine Council – The Society of Nuclear Medicine. J Nucl Med. 1992;33(11):2047–51. Grattan-Smith JD, Jones RA. MR urography in children. Pediatr Radiol. 2006;36(11):1119–32; quiz 1228–1119 Hansson S, Dhamey M, Sigstrom O, Sixt R, Stokland E, Wennerstrom M, Jodal U. Dimercapto-succinic acid scintigraphy instead of voiding cystourethrography for infants with urinary tract infection. J Urol. 2004;172(3):1071–3; discussion 1073–1074 Hawkins DS, Schuetze SM, Butrynski JE, Rajendran JG, Vernon CB, Conrad EU 3rd, Eary JF. [18F]Fluorodeoxyglucose positron emission tomography predicts outcome for Ewing sarcoma family of tumors. J Clin Oncol. 2005;23(34):8828–34. Higgins JJ, Urbine JA, Malik A. Beyond reflux: the spectrum of voiding cystourethrogram findings in the pediatric population. Pediatr Radiol. 2022;52(1):134–43. Hiorns MP. Imaging of the urinary tract: the role of CT and MRI. Pediatr Nephrol. 2011;26(1):59–68. Kanal E, Barkovich AJ, Bell C, Borgstede JP, Bradley WG Jr, Froelich JW, Gilk T, Gimbel JR, Gosbee J, KuhniKaminski E, Lester JW Jr, Nyenhuis J, Parag Y, Schaefer DJ, Sebek-Scoumis EA, Weinreb J, Zaremba LA, Wilcox P, Lucey L, Sass N, Safety ACRBRP o M. ACR guidance document for safe MR practices: 2007. AJR Am J Roentgenol. 2007;188(6):1447–74. Koff SA. The beneficial and protective effects of hydronephrosis. APMIS. 2003;Suppl(109):7–12. Lassmann M, Treves ST, E. S. P. D. H. W. Group. Paediatric radiopharmaceutical administration: harmonization of the 2007 EANM paediatric dosage card (version 1.5.2008) and the 2010 North American consensus guidelines. Eur J Nucl Med Mol Imaging. 2014;41(5):1036–41. Lee YJ, Oh SN, Rha SE, Byun JY. Renal trauma. Radiol Clin N Am. 2007;45(3):581–92, ix Levtchenko EN, Ham HR, Levy J, Piepsz A. Attitude of Belgian pediatricians toward strategy in acute pyelonephritis. Pediatr Nephrol. 2001;16(2):113–5. Mendichovszky I, Solar BT, Smeulders N, Easty M, Biassoni L. Nuclear medicine in pediatric nephrourology: an overview. Semin Nucl Med. 2017;47(3): 204–28. Nguyen HT, Benson CB, Bromley B, Campbell JB, Chow J, Coleman B, Cooper C, Crino J, Darge K,

M. P. Hiorns and L. Biassoni Herndon CD, Odibo AO, Somers MJ, Stein DR. Multidisciplinary consensus on the classification of prenatal and postnatal urinary tract dilation (UTD classification system). J Pediatr Urol. 2014;10(6):982– 98. O'Reilly PH. Diuresis renography 8 years later: an update. J Urol. 1986;136(5):993–9. Pelliccia P, Sferrazza Papa S, Cavallo F, Tagi VM, Di Serafino M, Esposito F, Persico A, Vezzali N, Vallone G. Prenatal and postnatal urinary tract dilation: advantages of a standardized ultrasound definition and classification. J Ultrasound. 2019;22(1):5–12. Piepsz A. Antenatally detected hydronephrosis. Semin Nucl Med. 2007;37(4):249–60. Piepsz A. Antenatal detection of pelviureteric junction stenosis: main controversies. Semin Nucl Med. 2011;41(1):11–9. Piepsz A, Ham HR. Pediatric applications of renal nuclear medicine. Semin Nucl Med. 2006;36(1):16–35. Portwine C, Marriott C, Barr RD. PET imaging for pediatric oncology: an assessment of the evidence. Pediatr Blood Cancer. 2010;55(6):1048–61. Prigent A, Cosgriff P, Gates GF, Granerus G, Fine EJ, Itoh K, Peters M, Piepsz A, Rehling M, Rutland M, Taylor A Jr. Consensus report on quality control of quantitative measurements of renal function obtained from the renogram: International Consensus Committee from the Scientific Committee of Radionuclides in Nephrourology. Semin Nucl Med. 1999;29(2):146–59. Schuetze SM, Rubin BP, Vernon C, Hawkins DS, Bruckner JD, Conrad EU 3rd, Eary JF. Use of positron emission tomography in localized extremity soft tissue sarcoma treated with neoadjuvant chemotherapy. Cancer. 2005;103(2):339–48. Vincent K, Murphy HJ, Twombley KE. Urinary tract dilation in the fetus and neonate. NeoReviews. 2022;23(3): e159–74. Viteri B, Calle-Toro JS, Furth S, Darge K, Hartung EA, Otero H. State-of-the-art renal imaging in children. Pediatrics. 2020;145(2):e20190829. Völker T, Denecke T, Steffen I, Misch D, Schönberger S, Plotkin M, Ruf J, Furth C, Stöver B, Hautzel H, Henze G, Amthauer H. Positron emission tomography for staging of pediatric sarcoma patients: results of a prospective multicenter trial. J Clin Oncol 2007;25(34):5435–41. https://doi.org/10.1200/JCO.2007.12.2473 Zhang H, Zhang L, Guo N. Validation of “urinary tract dilation” classification system: correlation between fetal hydronephrosis and postnatal urological abnormalities. Medicine (Baltimore). 2020;99(2):e18707.

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Magnetic Resonance Imaging of the Urinary Tract Kristin M. Broderick, J. Damien Grattan-Smith, and Andrew J. Kirsch

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 Magnetic Resonance Urography Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 Determination of Differential Renal Function and Renal Drainage . . . . . . . . . . . . . . . . 83 Clinical Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 Congenital Renal Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 Evaluation of Ureteral Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 Evaluation of Hydronephrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Evaluation of UPJ Obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 Assessment of Vascular Malformations and Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 Vesicoureteral Reflux . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 Pyelonephritis and Renal Scarring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 Renal Masses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 Current Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

Abstract

K. M. Broderick (*) · A. J. Kirsch Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA J. D. Grattan-Smith Department of Pediatric Radiology, Children’s Healthcare of Atlanta, Atlanta, GA, USA e-mail: [email protected]

Magnetic resonance imaging (MRI) is evolving as an imaging modality for the urinary tract that offers not only superior anatomic but also functional assessment, without the use of ionizing radiation. This comprehensive evaluation of the urinary tract allows for diagnosis of numerous urologic anomalies including ureteropelvic junction obstruction, duplication

© Springer-Verlag GmbH Germany, part of Springer Nature 2023 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43567-0_167

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anomalies, ectopic ureters, and megaureters. Parameters obtained during magnetic resonance urography such as differential renal function, calyceal, and renal transit time help aid in decision making regarding surgical and medical management of these various urologic conditions. This chapter will discuss the technique of magnetic resonance urography (MRU), as well as clinical applications. While MRU is currently more commonly used in cases where conventional imaging modalities fail to fully define complex urologic anatomy and function, it has the potential to become the preferred first-line radiologic study. Keywords

Pediatric Urology · Imaging · Magnetic Resonance Urography · Ectopic Ureter · Ureteropelvic Junction Obstruction · Differential Renal Function · Duplicated System · Hydronephrosis · Urinary obstruction

Introduction Magnetic resonance imaging (MRI) is a powerful tool for identifying anomalies of the genitourinary tract. Despite their widespread use, ultrasound, nuclear renal scintigraphy, computed tomography (CT), and intravenous urography (IVU) all have inherent limitations. While ultrasound can be accurate and cost-effective for diagnosing urinary tract dilation, it is operator-dependent and does not provide information regarding kidney function. Renal scintigraphy provides renal functional assessment, but is unable to provide substantial information regarding anatomy. CT and IVU can provide both anatomic and some qualitative functional assessment; however, along with renal scintigraphy, they both rely on ionizing radiation. Furthermore, CT and IVU expose pediatric patients to nephrotoxic contrast agents. Magnetic resonance urography (MRU) is evolving as the primary tool for comprehensive evaluation of urinary tract anomalies as it provides superb anatomic and functional imaging in a single test that

does not use ionizing radiation (Kirsch et al. 2006; Kirsch and Grattan-Smith 2010; Campo et al. 2022). Importantly, the use of intravenous contrast agents such as gadolinium-DTPA (Gd-DTPA) enables one to assess the concentrating and excretory functions of the kidney (Jones et al. 2011). Image quality is independent of renal function, allowing its use in cases of impaired renal function, bilateral renal involvement, and in solitary kidneys (Wille et al. 2003).

Magnetic Resonance Urography Technique A standardized protocol is essential to ensure consistency and reproducibility across studies and institutions. Meticulous attention to patient preparation and scanning technique is important if high quality images are to be reliably obtained. The key factors in the success of the examination are appropriate hydration and sedation, as well as consistent dosage and timing of contrast and diuretic administration. Hydration: All children are hydrated prior to the study with an intravenous infusion of lactated ringer’s solution since a fluid challenge is integral to a high quality study. For sedated children, the volume infused is calculated to replace the NPO deficit. The following formula is typically used: 4 cc/kg/h for first 10 kg of patient’s weight, plus 2 cc/kg/h for next 10 kg of patient’s weight, plus 4 cc/kg/h for each kg above 20 kg of the patient’s weight. If the child is not sedated, they are hydrated with lactated ringers at a dose of 10 cc/kg given intravenously over 30–40 min (Jones et al. 2011). Sedation: All infants and almost all children up to the age of 7 years will require sedation for MRU. Ideally, a dedicated sedation team of physicians who are able to titrate the depth of sedation for the individual or general anesthesia is used. However, general anesthesia is not required at institutions where sedation protocols are readily available. Older children who are not sedated are asked to either breathe quietly during the study, or if they are able to cooperate, breath-hold imaging is performed. MRU for functional evaluation in neonates before the age of about 3 months is not

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reliable because the kidneys have not yet reached their full functional maturity (Darge et al. 2011). Bladder Catheterization: A bladder catheter is typically placed in children undergoing sedation so that the full bladder does not wake them from sedation. If there is a question of a bladder abnormality, such as a ureterocele, the catheter can be clamped and images of the distended urinary bladder obtained (Jones et al. 2011). Technique: All MRI studies are composed of T1- and T2-weighted images. T1 images are generally of higher quality but cannot delineate fluidfilled structures without the use of Gd-DTPA. Contrast-enhanced T1 images allow visualization of the vascular anatomy and renal parenchymal enhancement, as well as functional evaluation of renal transit time (RTT) and differential renal function (DRF). Image quality of T1 images is affected by poor renal function and diminished contrast excretion in the presence of severe ureteral obstruction. T2 images are independent of renal function and prove to be of greatest value in delineating the anatomy of the collecting system of a poor or nonfunctioning kidney or renal moiety (Cerwinka and Kirsch 2010; Renjen et al. 2012). The MRU protocol begins with precontrast T1 and T2 images through the kidneys, ureters, and bladder. T1 images are acquired by gradient sequences, which allow shorter imaging times. Furosemide dosed at 1 mg/kg, up to a maximum dose of 20 mg, is given at the beginning of the study to enhance the dilation of the urinary tract and to aid in the distribution and dilution of the contrast. Gd-DTPA dosed at 1 mmol/kg is then slowly administered at a rate of 0.1–0.2 mL/s 15 min later and dynamic contrast-enhanced TI imaging of the entire urinary tract is performed. By administering the gadolinium-based contrast agent (GBCA) after the fluid challenge and during the time of maximal diuresis, pathophysiological changes in the kidney that occur in response to this fluid challenge can be visualized. This dose provides excellent enhancement of the kidneys and allows evaluation of the MR nephrogram by differentiating the enhancing parenchyma from the background (Jones et al. 2011). With this, uptake, excretion, and drainage of contrast can be visualized sequentially. Once completed, high resolution volumetric sequences

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are performed to allow mixing of the excreted contrast into the dilated collecting system. Gd-DTPA and technetium DTPA (Tc-DTPA), which is used in renal scintigraphy, share the same carrier molecule and are handled by the kidney in similar fashion. As a result, Gd-DTPA-enhanced MRU measurements of renal perfusion, uptake, and excretion correlate well with those obtained by Tc-DTPA nuclear scintigraphy (Grattan-Smith et al. 2003; Perez-Brayfield et al. 2003). Even at very low concentrations, Gd-DTPA provides high signal intensity allowing for adequate resolution of ureters and renal pelvis even in poorly functioning kidneys. Delayed three dimension maximum intensity projection (MIP) images are then obtained, which provide excellent anatomical resolution revealing anatomy similar to an excretory urogram (Cerwinka and Kirsch 2010; Grattan-Smith et al. 2003). If the ureter is not visualized at the end of the postcontrast portion of the study, the patient may need to be repositioned in the prone position. This is especially important in cases of pelvicalyceal dilation where the contrast may remain in the dependent portion of the pelvis and not reach the ureter until the patient is prone (Darge et al. 2011). The parenchymal phases are typically divided into cortical, medullary, and excretory phases. The cortical phase reflects both renal perfusion and glomerular filtration. The medullary phase typically occurs 45–90 s later and reflects perfusion of the renal medulla and concentration of the contrast agent in the loop of Henle. In the normal kidney, the signal intensity in the renal medulla is always greater than the cortex in this phase. After 30–60 more s, contrast medium is excreted into the pelvicalyceal system and ureter in normal kidneys. The total study time for patients with non-obstructed urinary tracts is typically 45 min, and for poorly draining kidneys the imaging time is typically 1 h.

Determination of Differential Renal Function and Renal Drainage The most crucial time for the functional calculation is the first 3 min after contrast administration. The calyceal transit time (CTT) is the time it takes

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for the contrast material to appear in the calyces. Measurements start when the contrast material first appears in the aorta. Causes of delay in CTT include ipsilateral renal artery stenosis, renal parenchymal disease, marked pelvicalyceal obstruction, and contralateral hyperfiltration. The CTT is most useful when the contralateral kidney is normal. CTT is classified as symmetric, delayed, or rapid in a hydronephrotic system. A symmetric CTT indicates the system remains compensated during the furosemide challenge. A rapid CTT can be seen in cases of intermittent UPJ obstruction and may be seen after successful pyeloplasty (Grattan-Smith et al. 2008). Renal transit time (RTT) is the time it takes for the contrast material to appear in the proximal ureter at the level of the lower pole of the kidney (site of ureteropelvic junction). Similarly, as with CTT, RTT measurements begin when contrast material is first seen in the aorta. Significant pelvicalyceal dilation and/or obstruction at the ureteropelvic junction (UPJ) or obstruction secondary to megaureter are causes of delay in the RTT. All causes of delayed CTT can also lead to delayed RTT. If the RTT is less than 245 s (about 4 min), the system is considered nonobstructed. If the RTT is greater than 490 s (about 8 min), the system is considered to be obstructed. RTT times between 245 s and 490 s are equivocal and usually managed conservatively with close follow-up. Calculating the RTT from the images is relatively straightforward as each individual volume acquisition is time-stamped (Grattan-Smith et al. 2008). The differential renal function (DRF) on renal scintigraphy is one of the key determinants in surgical decision making. With MRU, the DRF is calculated on the basis of the volumetric DRF (vDRF), which is based on the volume of enhancing renal parenchyma, and the Patlak number (pDRF), which is an index of the individual kidney glomerular filtration rate (GFR). The vDRF is calculated by measuring the volume of enhancing renal parenchyma at the time point of homogeneous renal enhancement before contrast excretion is seen in the calyces during the dynamic series. The vDRF tends to underestimate the function of very poorly functioning kidneys as it does not distinguish between normal and

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dysplastic renal tissue. The pDRF is calculated using the Patlak model (Jones et al. 2011; Patlak et al. 1983; Peters 1994). After injection of the Gd-DTPA, sequential intensity values of the aorta and renal parenchyma are measured and entered into the Patlak equation, which generates a plot and numbers. The slope of the graph between the time points following uniform distribution of contrast into the vasculature and prior to excretion of contrast into the collecting system is equal to the GFR. The pDRF changes with acute changes in GFR. The pDRF gives functional information per unit of renal tissue without taking the total volume of the kidney into consideration. In compensated hydronephrotic systems, there is a close correlation between pDRF and vDRF. In decompensated systems, there is a difference in the vDRF and pDRF typically greater than 4% (Darge et al. 2011, 2013; Grattan-Smith et al. 2008; Renjen et al. 2012).

Clinical Applications MRU is most commonly used in cases where conventional imaging modalities fail to fully define complex anatomy and function. The wide range of pediatric urologic anomalies has traditionally required several complementary studies to obtain adequate visualization and definition of the urinary tract and its function, often using ionizing radiation. Since MRU provides a threedimensional anatomic evaluation of the urinary tract, and an assessment of renal function, it has become increasingly popular as the sole imaging modality for urologic pathology.

Congenital Renal Malformations Anomalies of renal position and rotation are well demonstrated by the high-resolution anatomic images. Horseshoe and ectopic kidneys can easily be separated from the background and overlying tissues (Fig. 1) (Mostafavi et al. 1998). Ectopic kidneys with UPJ obstruction can readily be evaluated. Hypoplastic kidneys with associated ureteral ectopia, as well as supernumerary kidneys,

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Fig. 1 (a) Horseshoe kidney with hydronephrosis of the right renal moiety. (b) Coronal view of a horseshoe kidney in a different patient Fig. 2 (a, b) Right ectopic, hypoplastic kidney

can usually be demonstrated, even if there is minimal renal function (Fig. 2). MRU can also be useful in the confirmation of polycystic kidney disease and the evaluation of potential hepatic involvement (Kern et al. 2000). The standard diagnosis of a suspected dysplastic kidney comprises ultrasound, VCUG, and DMSA renal scan. MRU as a single study has proven to be superior in detecting dysplastic renal tissue as well as the site of distal ureteral insertion/obstruction in the case of ureteral ectopia (Riccabona et al. 2004a, b). The various forms of renal dysplasia, including multicystic dysplastic kidney (MCDK), solid renal dysplasia, hypoplasia, loss of corticomedullary differentiation without

parenchymal loss and dysmorphic caliceal system, have characteristic findings on MRU (Fig. 3) (McMann et al. 2006). MRU is excellent at demonstrating anomalies of the upper and lower urinary tract such as ureteroceles and seminal vesicle cysts associated with cystic and dysplastic kidneys (Fig. 4). Anomalous calyceal development is better defined on MRU than on other imaging studies (Figs. 5 and 6). A highly sensitive and radiation-free imaging modality, MRU can provide detailed morphological and functional information that can facilitate conservative and/or surgical management of children with renal fusion anomalies (Chan et al. 2017).

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Fig. 3 (a, b) Left upper pole segmental multicystic dysplastic kidney. (c) No enhancing renal parenchyma seen in the left upper pole

Evaluation of Ureteral Anomalies

Fig. 4 T2-weighted MRU showing a dilated right upper pole and upper pole ureter associated with a ureterocele

Evaluation of ureteral anomalies, with or without duplicated systems, often requires multiple imaging modalities. Ultrasound is often used as a screening tool, and while it can depict the duplicated collecting system, it is rarely able to demonstrate the entire course of the ureters. Renal scan, VCUG, IVP, and retrograde pyelogram with cystoscopy are complementary diagnostic tools, but have the disadvantages of ionizing radiation as well as invasiveness compared to MRU. MRU can accurately image the collecting system from the pelvicalices to the ureterovesical junction. With MRU, dilated and non-dilated, functioning and nonfunctioning renal units are all easily

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diagnose mid-ureteric stricture. The combination of transition in ureteric caliber and delayed excretion are the key features in diagnosis (Fig. 8). Since ureteric anatomy cannot accurately be evaluated by ultrasound or renal scintigraphy, cystoscopy and retrograde ureteropyelography is required to make the diagnosis. As a result, this condition has likely been underdiagnosed. MRU should be considered in children with suspicion for ureteral stricture and in those with equivocal findings on ultrasound and renal scan. Data from MRU is not only helpful in making an accurate diagnosis, but also provides useful information in order to determine optimal management (Arlen et al. 2014).

depicted and can differentiate between ectopic intravesical and ectopic extravesical ureteral insertion. While MRU does not necessarily need to be utilized in cases of routine duplex systems identified on ultrasound, it should be considered the gold standard in cases of complicated duplex systems with suspected ureteral ectopia, which cannot be demonstrated on routine imaging (Staatz et al. 2001) (Fig. 7). Even in cases of diminished or absent functional parenchyma, the location and course of an ectopic ureter can be located by the presence of static fluid (Epelman et al. 2004). In incontinent girls, MRU should be the method of choice for depicting or ruling out ectopic ureter (Figueroa et al. 2014). The ability to delineate the ureteric anatomy on MRU has resulted in our ability to confidently

Evaluation of Hydronephrosis

Fig. 5 Polycalycosis on the left side associated with decompensated UPJ obstruction

Due to its comprehensiveness, MRU has the potential to replace the currently used combination of other imaging modalities in the investigation of hydronephrosis in children. Since the introduction of prenatal ultrasound screening, increasing numbers of children are diagnosed with prenatal hydronephrosis prompting further postnatal imaging. Typically, this includes postnatal ultrasonography, VCUG, as well as nuclear renal scintigraphy. Currently, the most common indication for MRU is the evaluation of hydronephrosis, which is usually a result of obstruction typically related to UPJ obstruction or obstructive megaureter. Moderate to severe hydronephrosis should raise concern regarding the diagnosis of

Fig. 6 (a, b, c) Right-sided calyceal diverticulum, which can be mistaken for a cyst or hydronephrosis on ultrasound

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Fig. 7 (a, b) Duplex right kidney with dysplastic right perineum or distal vagina, identified with white arrow. upper pole moiety and (c) ectopic ureteric insertion into the There is delayed excretion and a delayed dense nephrogram suggesting obstruction to the upper pole moiety

Fig. 8 Moderate dilation of the proximal right ureter with an abrupt transition in caliber at the mid-ureter consistent with mid-ureteric stricture

obstruction. A sensitive test to detect early renal functional deterioration, in order to preserve renal function is the ultimate goal of management. Utilizing the combination of RTT, differential renal function, and various characteristics of the timeintensity curves, MRU is able to demonstrate the classification of obstructed, equivocal, and non-obstructed renal units. The superior anatomic resolution also allows us to visualize characteristics associated with obstruction like marked hydronephrosis, medullary atrophy, fluid levels, and swirling or non-progression of contrast into the ureter (Kirsch et al. 2006; Kirsch and GrattanSmith 2010).

Fig. 9 Numerous fetal folds seen in right ureter as indicated by white arrow

Typically, the diagnosis of fetal folds had been made intraoperatively using retrograde pyelography. MRU is able to provide such a detailed anatomic assessment of the ureter and is able to diagnose fetal folds nonoperatively (Fig. 9). Fetal folds may be associated with hydronephrosis, but on MRU there is no impaired renal function or delay in RTT.

Evaluation of UPJ Obstruction Radiographic evaluation of renal obstruction has evolved from excretory urography and antegrade pressure flow studies (Whitaker test) to ultrasound, diuretic renal scintigraphy, as well as

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Fig. 10 (a, b) MRU demonstrating delayed calyceal transit time on the right, with no contrast visualized in the right ureter on exam, consistent with right UPJ obstruction

Fig. 11 (a, b) Physiologically significant obstruction at the right UPJ related to crossing vessel, demonstrated with white arrow. (c) Post-pyeloplasty MRU showing decrease in right hydronephrosis and improved excretion and

drainage. Presence of right lower pole parenchymal scarring, likely secondary to thrombosis of accessory renal artery in seen

MRU. MRU provides functional information and superior anatomic detail (Viteri et al. 2021; Sizonov et al. 2021). Despite this, there is still no gold standard for evaluating renal obstruction. On MRU, UPJ obstruction presents with renal pelvic dilation with ureteral narrowing with atrophy of the renal pyramids and medulla (Fig. 10). Preoperative crossing vessels may also be seen, which can aid in surgical planning (Fig. 11). MRU can also be used to guide management and assess outcome after pyeloplasty in children with UPJ obstruction. Following correction of UPJ obstruction, DRF, RTT, and Patlak scores have been

shown to improve significantly (Kirsch et al. 2006). Damage to a crossing vessel during pyeloplasty and resultant parenchymal loss can also be demonstrated on postoperative MRU (Fig. 11c).

Assessment of Vascular Malformations and Anomalies The early vascular phase of the MRU provides a detailed evaluation of the vascular system. Vascular anomalies like multiple renal arteries or veins,

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Fig. 12 (a, b) Multiple accessory renal arteries are present on the left with moderate left hydronephrosis with abrupt change in caliber at UPJ

and crossing vessels are easily identified on MRU. One study showed MRI to have 100% sensitivity and specificity for identifying crossing vessels in cases of UPJ obstruction when compared to laparoscopy (Mitterberger et al. 2008). While imaging may not be necessary to look for anomalous vasculature prior to treatment, MRU can be a helpful modality to delineate the vascular anatomy, while also demonstrating the UPJ obstruction (Fig. 12).

Vesicoureteral Reflux Previously, MRU was not able to evaluate vesicoureteral reflux; it was only able to use indirect signs such as ureteral retrograde filling with contrast urine, or increasing or gross ureteral dilation with increasing bladder filling as a hint at the presence of VUR. The current standard of care for evaluation of VUR is the VCUG, which can be an unpleasant experience for children and also exposes them to ionizing radiation in the region of the reproductive organs (Riccabona et al. 2004). Often children with VUR will undergo yearly VCUG as they await spontaneous resolution or a decision for surgical correction. Given the need for serial imaging with ionizing radiation, MR voiding cystography (MRVC) was introduced in 1992. Despite its introduction in the

1990s, it had not become a potential alternative to VCUG until the advent of continuous real-time MR fluoroscopy. MRVC is composed of coronal T1-weighted images of the entire urinary tract obtained prior to transurethral administration of Gd-DTPA, in addition to images obtained during and following voiding. The sensitivity of MRI in grading reflux compared to VCUG is reported at 76–88%, with a specificity of 90%. MRI has the advantages of providing a more comprehensive evaluation of renal damage and reflux nephropathy when compared to VCUG, with a lack of ionizing radiation. Limitations may include incomplete voiding of some infants and young children due to sedation, which could lead to false negative results in children who reflux with voiding. Also a long scan time of MRVC may lead to false negative results as well. Although technically feasible, it seems unlikely that MRVC will gain widespread acceptance for the diagnosis of VUR (Lee et al. 2005; Vasanawala et al. 2009).

Pyelonephritis and Renal Scarring The diagnosis of acute pyelonephritis is primarily a clinical diagnosis with the classic triad of fever, flank pain, and urinary tract infection. However,

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in younger patients the diagnosis may be difficult to make based on history and physical alone, which makes the patient susceptible to parenchymal loss and scarring if not treated appropriately. Dimercapto-succinic acid nuclear scintigraphy (DMSA) has been the gold standard for detection of acute pyelonephritis associated with renal scarring. DMSA has the disadvantages of ionizing radiation, limited spatial resolution and difficulty in delineating acute pyelonephritis from chronic scar. MRU provides the best visualization of anatomic detail and corticomedullary differentiation (Koçyiğit et al. 2014). On MRU, acute pyelonephritis is seen as increased signal intensity on inversion recovery sequences, while wellperfused areas appear dark because gadolinium decreases signal intensity on inversion-recovery images and thus serves as a negative contrast agent. Chronic post-pyelonephritis scars appear as areas of cortical thinning or loss of parenchyma without a change in signal intensity (Fig. 13) (Lonergan et al. 1998). Previous animal studies have shown 91% sensitivity and 93% specificity in MRI diagnosis of acute pyelonephritis compared to pathological examination of the kidney (Weiser et al. 2003). Studies have shown that MRI appears to be as sensitive as DMSA scan in identifying renal scars while also providing exact anatomic localization of the scars, information that is not provided by DMSA (Rodriguez et al. 2001). Fig. 13 (a, b) MRU demonstrating duplicated system with left upper pole renal scarring after several episodes of pyelonephritis

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While DMSA scan and MRU are similar in their ability to diagnose renal parenchymal defects, studies have shown MRU to be superior to DMSA when reviewed by radiologists in classifying the severity of the renal parenchymal defects. Inter-observer agreement is also much greater with MRU than DMSA scan in side-by-side analysis. This is likely due to the superior spatial and contrast resolution compared to DMSA, as well as the lack of background signal (Cerwinka et al. 2014). Studies have also shown MRI to be costeffective when compared with DMSA (Weiser et al. 2003). While imaging in a child with suspected pyelonephritis may not be necessary and depends on the clinical scenario, imaging can be helpful in patients with fever of unknown origin or inconclusive evidence of urinary tract infection or in patients with chronic bacteriuria. In these cases, gadolinium-enhanced MRU is a useful modality to diagnose acute pyelonephritis.

Renal Masses Noninvasive diagnosis of benign from malignant renal masses is essential in avoiding unnecessary potential morbidity associated with biopsy or surgical resection. MRI is an important study in renal lesion characterization due to its superior imaging

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Fig. 14 Large left Wilm’s tumor diagnosed using MRI

capability (Fig. 14). MRI is also helpful for staging in cases of malignancy. MR imaging is capable of detecting extracapsular involvement, vascular invasion, as well as metastatic disease (Gee et al. 2013). However, currently MRI is not the primary diagnostic tool used in tumor detection as cost and availability of CT make it the existing standard for initial tumor imaging.

Current Limitations The frequency of adverse reactions to gadolinium-based contrast is much less than that of iodinated contrast media. Mild reactions, such as headaches, nausea, or mild rash, can occur in up to 8% of patients but can usually be managed with observation or diphenhydramine (Hunt et al. 2009). Although rare, anaphylactoid reactions can occur. Although patients with asthma, allergies, or known drug sensitivities are at higher risk, allergy to iodine-based contrast agents is not a contraindication for use of Gd-DTPA (Murphy et al. 1996; Runge 2001). Nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dematopathy is a scleroderma-like disease that occurs in a subset of patients with renal insufficiency. The incidence of NSF in patients with risk factors is 3% and overall less than 0.1% (Altun et al. 2009). NSF typically presents over a period of days or weeks and appears as skin discoloration and thickening, joint contracture, muscle weakness, and generalized pain. NSF

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is progressive and can be fatal. It has been shown to develop in patients with moderate to end-stage renal disease who have been exposed to high doses of any of the gadolinium-based contrast agents. It is recommended to choose alternative imaging modalities for patients with end-stage renal disease and to dialyze as soon as possible after the imaging study is completed (High et al. 2007). Alternatively, other contrast agents can be used. Prohance should be considered if the GFR is below 60 mL/min, rather than Magnevist (Jones et al. 2011). A disadvantage of MRI in pediatric patients is the need for sedation or anesthesia in infants and small children. Sedation is necessary in order to eliminate motion artifacts as well as the potential psychologic impact of claustrophobia, which can even be a limitation in adults (Cerwinka et al. 2008; Payabvash et al. 2008). Implants such as pacemakers, cochlear implants, drug-delivery systems, and orthopedic hardware are rare in pediatric patients; however, when present, may cause severe device malfunction, injury, and imaging artifact. Ventriculoperitoneal shunt valves, often found in myelomeningocele patients, are compatible with MR but can generate artifact and may require reprogramming after exposure to the magnetic field (Lavinio et al. 2008). Artificial urinary sphincters and contemporary Harrington rods, made of titanium alloys, are compatible with MRI (Cerwinka and Kirsch 2010). Although MRI is currently more costly than ultrasound or nuclear renal scintigraphy, the comprehensive information obtained from just one study may justify its use. By reducing the delay in diagnosis and thus treatment of a disease, as well as limiting the exposure to ionizing radiation in children, the use of MRI has the potential to decrease overall healthcare expenditures in a selected patient population.

Conclusion and Future Directions MRU provides an unprecedented level of anatomic information combined with a variety of functional data while avoiding ionizing radiation.

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While MRU was previously obtained as a second line study in cases where other imaging modalities could not fully define complex anatomy, it is now being used as a first-line study in the diagnosis of many urologic problems. MRU is likely to emerge as the modality of choice for children with complex genitourinary pathology, and the growing application will improve availability and cost in the future.

Cross-References ▶ Congenital Renal Anomalies ▶ Imaging of the Urinary Tract ▶ Multicystic Dysplastic Kidney Disease ▶ The Diagnosis and Medical Management of Vesicoureteral Reflux: An Update and Current Controversies ▶ Ureteropelvic Junction Obstruction ▶ Ureterovesical Junction Obstruction

References Altun E, Martin DR, Wertman R, Lugo-Somolinos A, Fuller ER, Semelka RC. Nephrogenic systemic fibrosis: change in incidence following a switch in gadolinium agents and adoption of a gadolinium policy – report from two U.S. universities. Radiology. 2009;253(3):689–96. Arlen AM, Kirsch AJ, Cuda SP, Little SB, Jones RA, Grattan-Smith JD, Cerwinka WH. Magnetic resonance urography for diagnosis of pediatric ureteral stricture. J Pediatr Urol. 2014; article in press. Campo I, Sertorio F, Wong M, Anfigeno L, Bertolotto M, Mattioli G, Damasio MB. Magnetic resonance urography of congenital abnormalities – what the radiologist needs to know. Pediatr Radiol. 2022;52(5): 985–97. Cerwinka WH, Kirsch AJ. Magnetic resonance urography in pediatric urology. Curr Opin Urol. 2010;20:323–9. Cerwinka WH, Grattan-Smith JD, Kirsch AJ. Magnetic resonance urography in pediatric urology. J Pediatr Urol. 2008;4:74–83. Cerwinka WH, Grattan-Smith JD, Jones RA, Haber M, Little SB, Blews DE, Williams JP, Kirsch AJ. Comparison of magnetic resonance urography to dimercaptosuccinic acid scan for the identification of renal parenchyma defects in children with vesicoureteral reflux. J Pediatr Urol. 2014;10:344–51. Chan SS, Ntoulia A, Khrichenko D, Back SJ, Tasian GE, Dillman JR, Darge K. Role of magnetic resonance

93 urography in pediatric renal fusion anomalies. Pediatr Radiol. 2017;47(13):1707–20. Darge K, Anupindi SA, Jaramillo D. MR imaging of the abdomen and pelvis in infants, children, and adolescents. Radiology. 2011;261:12–29. Darge K, Higgins M, Hwang TJ, Delgado J, Shukla A, Bellah R. Magnetic resonance and computed tomography in pediatric urology: an imaging overview for current and future daily practice. Radiol Clin N Am. 2013;51:583–98. Epelman M, Daneman A, Donnelly LF, Averill LW, Chauvin NA. Neonatal imaging evaluation of common prenatally diagnosed genitourinary abnormalities. Semin Ultrasound CT MR. 2004;35(6):528–54. Figueroa VH, Chavhan GB, Oudjhane K, Farhat W. Utility of MR urography in children suspected of having ectopic ureter. Pediatr Radiol. 2014;44:956–62. Gee MS, Bittman M, Epelman M, Vargas SO, Lee EY. Magnetic resonance imaging of the pediatric kidney: benign and malignant masses. Magn Reson Imaging Clin N Am. 2013;21:697–715. Grattan-Smith JD, Perez-Brayfield MR, Jones RA, Little S, Broecker B, Smith EA, Scherz HC, Kirsch AJ. MR imaging of kidneys: functional evaluation using F-15 perfusion imaging. Pediatr Radiol. 2003;33:293–304. Grattan-Smith JD, Little SB, Jones RA. MR urography in children: how we do it. Pediatr Radiol. 2008a;38:3–17. Grattan-Smith JD, Little SB, Jones RA. MR urography evaluation of obstructive uropathy. Pediatr Radiol. 2008b;38:49–69. High WA, Ayers RA, Chandler J, Zito G, Cowper SE. Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol. 2007;56:21–6. Hunt CH, Harman RP, Hesley GK. Frequency and severity of adverse effects of iodinated and gadolinium contrast materials: retrospective review of 456930 doses. AJR Am J Roentgenol. 2009;193:1124–7. Jones RA, Grattan-Smith JD, Little S. Pediatric magnetic resonance urography. J Magn Reson Imaging. 2011;33: 510–26. Kern S, Zimmerhackl LB, Hildebrandt F, Ermisch-Omran B, Uhl M. Appearance of autosomal recessive polycystic kidney disease in magnetic resonance imaging and RARE-MR-urography. Pediatr Radiol. 2000;30:156–60. Kirsch AJ, Grattan-Smith JD. Magnetic resonance imaging of the pediatric urinary tract. In: Gearhart JP, Rink RC, Mouriquand PDE, editors. Pediatric urology. 2nd ed. WB Saunders; 2010. p. 162–71. Kirsch AJ, Grattan-Smith JD, Molitierno JA. The role of magnetic resonance imaging in pediatric urology. Curr Opin Urol. 2006a;16:283–90. Kirsch AJ, McMann LP, Jones RA, Smith EA, Scherz HC, Grattan-Smith JD. Magnetic resonance urography for evaluating outcomes after pediatric pyeloplasty. J Urol. 2006b;176:1755–61. Koçyiğit A, Yüksel S, Bayram R, Yılmaz İ, Karabulut N. Efficacy of magnetic resonance urography in

94 detecting renal scars in children with vesicoureteral reflux. Pediatr Nephrol. 2014;29(7):1215–20. Lavinio A, Harding S, Van Der Boogaard F, Czosnyka M, Smielewski P, Richards HK, Pickard JD, Czosnyka Z. Magnetic field interactions in adjustable hydrocephalus shunts. J Neurosurg Pediatr. 2008;2:222–8. Lee SK, Chang Y, Park NH, Kim YH, Wood S. Magnetic resonance voiding cystography in the diagnosis of vesicoureteral reflux: comparative study with voiding cystourethrography. J Magn Reson Imaging. 2005;21: 406–14. Lonergan GJ, Pennington DJ, Morrison JC, Haws RM, Grimley MS, Kao TC. Childhood pyelonephritis: comparison of gadolinium-enhanced MR imaging and renal cortical scintigraphy for diagnosis. Radiology. 1998;207:377–84. McMann LP, Kirsch AJ, Scherz HC, Smith EA, Jones RA, Shehata BM, Kozielski R, Grattan-Smith JD. Magnetic resonance urography in the evaluation of prenatally diagnosed hydronephrosis and renal dysgenesis. J Urol. 2006;176:1786–92. Mitterberger M, Pinggera GM, Neururer R, Peschel R, Colleselli D, Aigner F, Gradl J, Bartsch G, Strasser H, Pallwein L, Frauscher F. Comparison of contrastenhanced color doppler imaging (CDI), computed tomography (CT), and magnetic resonance imaging (MRI) for the detection of crossing vessels in patients with ureteropelvic junction obstruction (UPJO). Eur Urol. 2008;53:1254–62. Mostafavi MR, Prasad PV, Saltzman B. Magnetic resonance urography and angiography in the evaluation of a horseshoe kidney with ureteropelvic junction obstruction. Urology. 1998;51(3):484–6. Murphy KJ, Brunberg JA, Cohan RH. Adverse reactions to gadolinium contrast media: a review of 36 cases. Am J Roentgenol. 1996;167:847–9. Patlak CS, Blasberg RG, Fenstermacher JD. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab. 1983;3:1–7. Payabvash S, Kajbafzadeh AM, Saeedi P, Sadeghi Z, Elmi A, Mehdizadeh M. Application of magnetic resonance urography in diagnosis of congenital urogenital anomalies in children. Pediatr Surg Int. 2008;24: 979–86. Perez-Brayfield MR, Kirsch AJ, Jones RA, Grattan-Smith JD. A prospective study comparing ultrasound, nuclear scintigraphy and dynamic contrast enhanced magnetic

K. M. Broderick et al. resonance imaging in the evaluation of hydronephrosis. J Urol. 2003;170:1330–4. Peters AM. Graphical analysis of dynamic data: the PatlakRutland plot. Nucl Med Commun. 1994;15:669–72. Renjen P, Bellah R, Hellinger JC, Darge K. Advances in uroradiologic imaging in children. Radiol Clin N Am. 2012;50:207–18. Riccabona M, Riccabona M, Koen M, Beckers G, Schindler M, Heinisch M, Maier C, Lansteger W, Lusuardi L. Magnetic resonance urography: a new gold standard for the evaluation of solitary kidneys and renal buds? J Urol. 2004a;171:1642–6. Riccabona M, Ruppert-Kohlmayr A, Ekkehard R, Maier C, Lusuardi L, Riccabona M. Potential impact of pediatric MR urography on the imaging algorithm in patients with a functional single kidney. Am J Roentgenol. 2004b;183:795–800. Rodriguez LV, Spielman D, Herfkens RJ, Shortliffe LD. Magnetic resonance imaging for the evaluation of hydronephrosis, reflux and renal scarring in children. J Urol. 2001;166:1023–7. Runge VM. Safety of magnetic resonance contrast media. Top Magn Reson Imaging. 2001;12:309–14. Sizonov VV, Kogan MI, Shidaev AK, Redkin VA, Orlov VM, Piskunov KP. Comparison of functional magnetic resonance urography and dynamic renal scintigraphy in the functional assessment of ureteropelvic junction obstruction in children. Urologiia. 2021;1:90–4. Staatz G, Rohrmann D, Nolte-Ernsting CCA, Stollbrink C, Haage P, Schmidt T, Gunther RW. Magnetic resonance urography in children: evaluation of suspected ureteral ectopia in duplex systems. J Urol. 2001;166:2346–50. Vasanawala SS, Kenedy WA, Ganguly A, Fahrig R, Rieke V, Daniel B, Barth RA. MR voiding cystography for evaluation of vesicoureteral reflux. Am J Roentgenol. 2009;192(5):206–11. Viteri B, Calle-Toro JS, Ballester L, Darge K, Furth S, Khrichenko D, Van Batavia J, Otero H. Potential benefits of functional magnetic resonance urography (fMRU) over MAG3 renal scan in children with obstructive uropathy. J Pediatr Urol. 2021;17(5):659.e1–7. Weiser AC, Amukele SA, Leonidas JC, Palmer LS. The role of gadolinium enhanced magnetic resonance imaging for children with suspected acute pyelonephritis. J Urol. 2003;169:2308–11. Wille S, von Knobloch R, Klose KJ, Heidenreich A, Hofmann R. Magnetic resonance urography in pediatric urology. Scan J Urol Nephrol. 2003;37:16–21.

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Urodynamic Studies of the Urinary Tract Beth A. Drzewiecki and Stuart B. Bauer

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

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Evaluation Prior to Urodynamic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Urodynamicist Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Noninvasive UDS Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Four-Hour Voiding Observation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Uroflowmetry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uroflowmetry Patterns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Invasive Urodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Performing the UDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 Cystometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Assessment of Storage Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bladder Sensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Detrusor Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bladder Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bladder Capacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

103 103 104 104 105

Urethral Function During Filling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 Assessment of Voiding Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pressure Flow Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bladder Function During Voiding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uroflowmetry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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B. A. Drzewiecki (*) Department of Urology, Pediatric Division, Children’s Hospital of Montefiore, Bronx, NY, USA e-mail: [email protected] S. B. Bauer Department of Urology, Boston Children’s Hospital, Boston, MA, USA e-mail: [email protected] © Springer-Verlag GmbH Germany, part of Springer Nature 2023 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43567-0_168

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B. A. Drzewiecki and S. B. Bauer Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

Abstract

This chapter provides a thorough explanation on how to approach a child who presents with lower urinary tract dysfunction, whether it be of neurogenic, anatomic, or functional origin. Formation of a urodynamic question after a comprehensive history and physical examination is paramount in selecting the urodynamic study(ies) that will be most appropriate for each child. Considerate application of each test in a stepwise manner, while including the parent and child throughout the process, will provide the most accurate and reproducible results. Recommendations on how to execute each of the components of a urodynamic study, as well as interpretation, are included in this chapter. Keywords

Urodynamic studies · Neurogenic bladder dysfunction · Non-neurogenic bladder dysfunction · Lower urinary tract symptoms · Incontinence · Cystometry · Uroflowmetry · Dysfunctional voiding

Introduction Children who present with both neurogenic and non-neurogenic bladder dysfunction require careful evaluation of their lower urinary tract and bowel function prior to initiation of treatment. Over the last several decades, urodynamic studies (UDS) have been adapted specifically for infants and children, providing accurate, reproducible, and detailed results, thus enabling tailored treatment to the specific needs of each patient. UDS include all aspects of investigations looking into the function, and dysfunction, of the urinary tract (de Jong and Klijn 2009). These studies may range from voiding diaries and uroflowmetry, to more invasive components

such as cystometry, videourodynamics, and pressure-flow studies. The extent of the workup required is determined by the clinical picture of each child. The goal of UDS is to recreate the child’s natural response while obtaining careful and precise measurements that give insight into the underlying pathophysiological process. Such insight is helpful for both the provider and the patient/caregiver team. In children with neurogenic bladder (NGB) dysfunction, UDS are often utilized prior to treatment to obtain a baseline evaluation, which can be later referenced regarding changes after treatment interventions or growth.

Evaluation Prior to Urodynamic Studies Children referred for overt NGB or persistent lower urinary tract (LUT) symptoms require proper examination prior to forming a “urodynamic question.” A comprehensive history and physical examination with additional radiologic and laboratory information are warranted at the initial visit (Table 1). The development of validated questionnaires has improved objective collection of information pertaining to daily bladder and bowel habits, giving further insight into underlying dysfunction (Bower et al. 2006; Farhat et al. 2000; Sureshkumar et al. 2001). Children and their parents should fill out a frequency/volume chart (FVC), also known as a “voiding diary,” that records daily fluid intake as well as urine output over a 24-h period of time (Fig. 1). FVCs encompassing at least 3 consecutive days are most useful in providing an adequate picture of the child’s daily habits. This detailed account provides objective information to the clinician and family that includes the number of voids, timing and distribution of the voids, timing and quantification of incontinent episodes, and symptoms associated with incontinence, i.e.,

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Table 1 Evaluation prior to UDS History

Physical examination

Voiding diary

Defecation diary

Laboratory Radiology

Information to be obtained Prenatal history Perinatal complications Family history Spinal abnormalities Lower extremity reflexes, muscle mass, strength, gait, sensation Handedness, fine/gross motor coordination Characterization of incontinence: continuous, intermittent, day and/or night Fluid volume in Frequency of catheterizations with/without incontinence between catheterization Frequency of voids Voided volumes Number of bowel movements per day Character of stool: hard, soft, diarrhea Presence of painful defecation Incontinence of stool episodes Urinalysis and urine culture Spinal sonogram if indicated 2 s (Austin et al. 2014) Note pattern shape >50% expected bladder capacity for age If elevated, should repeat study

2–6 s normal Quiet or active during voiding

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volumes 10% bladder capacity can be regarded as elevated. In children >7 years, repetitive PVR >10 mL or 6% bladder capacity can be regarded as elevated (Chang et al. 2013). In some situations, combination uroflowmetry with perineal EMG patches provides greater detailed information regarding behavior of the pelvic floor and external urethral sphincter muscles during micturition. This helps differentiate between functional and anatomic obstruction, and often confirms the underlying cause of an abnormal uroflowmetry pattern before advancing to invasive UDS.

Uroflowmetry Patterns In children, the uroflowmetry pattern is more significant than the actual Qmax due to the ability of the detrusor to generate a strong contraction to overcome any increase in urethral resistance (Drzewiecki and Bauer 2011). The shape of the flow curve provides the most information about an underlying abnormality during the voiding phase (Table 3 and Fig. 2). The normal pattern of urinary flow in a healthy child is arc or bell shaped, regardless of age or gender (de Jong and Klijn 2009; Nevéus et al. 2006). However, about 1% of school-aged children void abnormally with either a flattened or interrupted pattern (Mattson and Spangberg 1994). A tower shaped pattern, with an immediate peak at the onset of flow with high amplitude of short

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Table 3 Uroflowmetry patterns Name Normal Tower Staccato

Interrupted Plateau

Description Bell-shaped curve Sudden, high velocity void for a short period Irregular and undulates without cessation of flow. Fluctuations must be larger than square root of maximum flow Isolated peaks and troughs with discontinuation of flow between voids Flattened, low amplitude, and prolonged void

duration typically represents an overactive bladder contraction (Austin et al. 2014; Nevéus et al. 2006). A plateau or flattened uroflowmetry pattern suggests a fixed obstruction, where the flow is continuous, but all the parameters are lower than would be expected, with Qmax approaching Qave along with an extended voiding time. Staccato voiding, with multiple peaks and troughs throughout voiding, indicates a dynamic obstruction of either the internal or external sphincter, as seen in dysfunctional voiding, or attempts at straining by the child to completely empty the bladder. Interrupted voiding patterns also have peaks and troughs, but the flow must come down to zero. This may be indicative of an underactive or acontractile detrusor with valsalva voiding or an extreme form of dysfunctional voiding. This can only be differentiated with concomitant pelvic floor EMG recording using patch electrodes. Although the shape of a free uroflowmetry may suggest a specific type of abnormality, detailed information about the cause for abnormal voiding cannot be derived from a flow curve alone. When uroflowmetry is combined with intravesical and abdominal pressure recordings, it becomes possible, from the pressure-flow relationship, to analyze the separate contributions of detrusor contractility and bladder outlet function to the overall voiding pattern.

Invasive Urodynamics Invasive UDS are indicated in children who (1) have apparent or suspected neurogenic bladder dysfunction and need baseline studies, (2) are not

Suggested underlying pathology None Overactive detrusor with powerful contraction Inappropriate coordination of sphincter and bladder or sphincter overactivity during voiding (dysfunctional voiding) Underactive bladder with voiding via gravity or increase abdominal pressure or straining Outlet obstruction via anatomic obstruction or functional obstruction from persistent sphincter contraction

improving on treatment regimens, and/or (3) noninvasive studies have not provided adequate diagnostic information. The majority of children with non-neurogenic bladder dysfunction will not require invasive UDS; however, it can have a high yield in children whose initial treatment failed (Kaufman et al. 2006). Ultimately, invasive UDS should be reserved for individuals in whom outcome is likely to affect treatment. In children with NGB, the International Children’s Continence Society has set a standard protocol when an initial baseline and subsequent studies should be performed (Bauer et al. 2012). The initial or baseline study is undertaken at about 3 months of age or as soon as the child is diagnosed, if not at birth. In children with open myelomeningocele, confirmation that the child can empty their bladder via catheterization or sonography should be obtained prior to discharge from the hospital. Studies are repeated 2–3 months after a change in treatment, if not successful, or when there is an increase in hydronephrosis, ureteral dilation, worsening renal function, or changes in lower extremity function or other signs of neurologic deterioration. For myelomeningocele children, UDS should be performed yearly until the toddler stage, and if stable, can be monitored with yearly or biennial RBUS and UDS whenever signs of urinary tract changes appear or new alterations in ambulation or lower extremity function occur. The components of invasive UDS include evaluation of the filling and voiding phase with cystometry and pressure flow studies. A cystometrogram measures the bladder’s capacity, compliance, contractility, emptying ability, and

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Fig. 2 Representative uroflowmetry curves. (a) Normal bell shaped curve. (b) Tower shape curve with sharp increase of short duration. (c) Interrupted curve with

multiple cessations of flow. (d) Plateau curve with prolonged, low amplitude. (e) Staccato curve with irregularity and fluctuations of flow

degree of continence (Austin et al. 2014; Nevéus et al. 2006). This is achieved with continuous pressure recordings from a urethral (intravesical) and a rectal or vaginal catheter (intra-abdominal), where the abdominal pressure (pAbd) is subtracted from the intravesical pressure (pVes) to obtain true detrusor pressure (pDet). Monitoring these parameters account for changes that might

occur during laughing, coughing, crying, movement, or straining throughout the study. In children who are toilet trained, the voiding phase is best evaluated in the sitting position. This will reduce the risk of losing the catheters or urine during repositioning. Only the storage phase can be adequately measured in newborns, which is measured in the supine or semi-recumbant

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position during the study. However, the voiding phase can be observed in newborns by the urodynamicist and should be noted during the study. In facilities that have the capability, combining fluoroscopy with cystometry can add significant information to the study. This is referred to as videourodynamics. It allows real-time evaluation of the bladder shape during the storage and emptying phases, timing of VUR if present, and the configuration of the bladder neck and urethra during voiding.

Performing the UDS Despite one’s best efforts, the test surroundings do not mimic the natural environment and most children have varying levels of apprehension that may influence study results (Finkelstein et al. 2020). Both the child and the parent should be adequately prepared prior to the day of the procedure. One of the most important keys to success is having dedicated and knowledgeable staff. Many children who present for UDS have already had prior invasive studies and thus may be quite anxious. Involving both parent and child throughout the study can increase the likelihood of a more reliable outcome. Age-appropriate distractions such as feeding with a bottle, watching television, or playing a video game can also be helpful to keep the child calm and quiet. Child life specialists, when available, play an extremely useful role to ease the child’s anxiety and keep them focused and relaxed throughout the procedure. When age appropriate, talking the child through the study with visual aids, such as photos or a catheterizable doll, may decrease anxiety as the study progresses (de Jong and Klijn 2009; Drzewiecki and Bauer 2011; Gray 2012). If toilet trained, the child should void into the uroflowmeter prior to insertion of the catheters. A latex-free environment should be maintained; most products now are in compliance (Gray 2012). Application of a topical 1% or 2% lidocaine jelly prior to insertion of the catheters helps alleviate discomfort. A 6 or 7F double lumen catheter is inserted into the bladder under sterile

B. A. Drzewiecki and S. B. Bauer

technique and secured in place. This is done very soon after the child voids so as to obtain an accurate PVR. Sometimes in children with NGB it is neccessary to aspirate the bladder once the catheter is in place to obtain a residual urine volume. Additionally, in these children and those who have a history of poor compliance, obtaining an opening pressure at the time of insertion prior to emptying the bladder provides insight into the pressure of the bladder under “natural fill” circumstances (Drzewiecki and Bauer 2011; Kaefer et al. 1997). Some children with prior urethral surgery, developmental disorders, or extreme levels of anxiety may not permit placement of the catheter in the urodynamic facility, thus requiring catheter placement under sedation, with or without cystoscopy. If done early in the day, this allows for recovery prior to the UDS. Some centers have also utilized a sedation team for placement of catheters in the UDS suite directly (Sweeney et al. 2008). Another alternative to urethral catheterization is natural fill or ambulatory UDS. This utilizes the body’s natural diuresis to fill the bladder but it requires placement of a suprapubic catheter under sedation about 6–24 h prior to the study. The child is permitted to be mobile, thus mimicking a more natural experience. Many centers find this too time consuming or do not have appropriate equipment to perform the technique. Difference in results of natural fill UDS compared to standard UDS has been described; lower voided volumes, higher voiding pressures, a dampened increase in the pressure rise during filling, and increased sensitivity for detecting detrusor overactivity are seen during natural fill studies (Jorgenson et al. 2009). Abdominal pressure is recorded using a 7-10F balloon pressure catheter positioned in either the rectum or vagina. The catheter is generally well tolerated. In order to avoid artifacts from having a rectal ampulla full of stool, the family is instructed to give their child a mild laxative the day before the study. If stool is still palpable in the rectal vault, manual disimpaction may be required to prevent dislodging of the catheter during the examination due to passage of stool or artifacts due to spontaneous contractions from the distended rectum.

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EMG of the striated component of the external sphincter and pelvic floor musculature is an additional important component of UDS; most centers utilize a patch EMG electrode with a capacity of at least 1000 Hz. Patch EMG electrodes are placed on the perineum in the 3 and 9 o’clock positions. In order to ensure the electrodes have good adherence to the skin producing accurate results, it is helpful to degrease the area with an alcohol wipe and exfoliate with gauze prior to patch placement. If the patch gets wet or dislodges during the study, it can be disruptive and lead to confusing results. EMG needle electrodes employed during cystometry provide the most accurate information on individual motor units at rest, in response to sacral reflexes, and during bladder filling and emptying in children with suspected or known neurologic conditions and in whom perineal sensation is diminished or absent. A 24-gauge needle electrode is positioned perineally in boys or paraurethrally in girls to view the electrical signal on an EMG amplifier (Drzewiecki and Bauer 2011).

Cystometry Filling cystometry is the core content of a pediatric urodynamic study and can be used in children including newborn to evaluate lower urinary tract dysfunction (Wen et al., 2018). Retrograde filling of the bladder should be performed at a rate of 5–10% of the expected bladder capacity (and no more than 10 mL/min) with either 0.9% normal saline or contrast medium at a temperature of 25–37
C. Rate of filling may have an effect on capacity, intravesical pressure, or compliance (de Jong and Klijn 2009). The bladder capacity can be estimated based on the child’s MVV or the highest volume of urine obtained on catheterization for those performing CIC. Standard values of expected bladder capacity by age is calculated using the Hjalmas equation (expected capacity in mL ¼ 30 þ (age in years  30)) or in infants (weight in kg  7 ¼ capacity in mL). For children with myelodysplasia, the equation of 24.5  age in years þ 62 ¼ capacity in mL, was shown to more accurately approximate bladder capacity (Palmer et al. 1997).

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A filling cycle should be considered complete once the child has a strong desire to void, a bladder contraction results in micturition, the pDet is greater than 40 cm H2O, or volume infused reaches 150% of MVV. In children without sensation and a neuropathic condition, one filling cycle may suffice. However, in other children, a minimum of two or three cycles is recommended, as the first filling cycle is often artificial and not accurate (Ergun et al. 2022). If utilizing video UDS, images are obtained at intervals of 30–50 mL of infused contrast, during increases in pDet, when VUR is detected, at capacity and during voiding. X-ray memory features help limit exposure time; the average exposure time for a complete study is 0.45 min, making the total amount of radiation less than that of a plain radiograph of the abdomen.

Assessment of Storage Phase During filling, the pAbd, pVes, and pDet are measured continuously, where pDet ¼ pVes-pAbd. Parameters that should be measured during filling are bladder sensation, detrusor activity, bladder compliance, and bladder capacity (Table 4 and Fig. 3).

Bladder Sensation Bladder sensation is difficult to assess for both sensate and insensate children. First sensation of a full bladder, first desire to void, a strong desire to void, or an inability to hold urine should all be recorded during the filling cycle, and correlated with pDet tracings. The filling and voiding phase in children is done in continuity, as the transition from one phase to the other is less marked than in adults. In children who are old enough to articulate their bladder sensations, they should be asked to describe what they are feeling throughout the study. In children who are too young for this, other physical signs such as curling of the toes, tightening of abdominal muscles, or sudden restlessness can indicate that voiding is imminent, and should be noted on the UDS tracing. Sensation can be

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Table 4 Assessment of bladder storage Terminology Bladder sensation

Detrusor function

Bladder Compliance Bladder capacity

Definitions First sensation First desire Strong desire Unable to hold Diminished/absent Normal Overactive Underactive High Low Less than expected Expected More than expected

UDS parameters Correlate each with whether or not a detrusor contraction was present or not Unaware of bladder sensation during filling or detrusor contractions

Quiet during filling Involuntary increased activity during filling No activity at >150% MVV Little change in pressure during filling Increase in pressure as volume increases 150%

normal, increased, or decreased (absent). Decreased or absent sensation is determined when the child has no sensation to void and filling has reached 150% of MVV.

contractility during voiding and the child empties entirely by straining. This presents later in life in association with a chronically obstructed bladder and/or when the child has polyuric kidneys and does not void often enough to meet the demands imposed by excessive urine production.

Detrusor Function Detrusor function during filling is normal, overactive, or underactive (Austin et al. 2014; Nevéus et al. 2006). During filling, the bladder should remain quiet with little to no increase in pressure until it is time for a bladder contraction. Any increase in baseline pDet of 15 cm H2O or more, spontaneous or provoked, is considered an overactive detrusor contraction and is pathological in children (Austin et al. 2014; Nevéus et al. 2006). In neurologically intact children, overactivity may either go unnoticed or be associated with a sense of urgency and a concomitant contraction of the pelvic floor muscles to overcome the sensation (guarding reflex). The first filling cycle may exhibit detrusor overactivity that is not present on subsequent cycles (de Jong and Klijn 2009). Underactive detrusor function has not been well described during the filling cycle, as the bladder is expected to be quiet during this phase. If the child has no sensation of feeling the need to void and filling has surpassed 150% of MVV, no further filling should occur. An underactive bladder is observed when there is no detrusor

Bladder Compliance The bladder is designed to be a highly compliant vessel, allowing for a significant increase in volume without a matching increase in pressure, thus calculated as ΔV/ΔP. Compliance is best measured in a linear fashion; however, pDet tracings on UDS may not permit for such measurements, and therefore multiple measurements at sequenced intervals need to be recorded throughout the study. For standardization purposes, the most linear part of the UDS tracing should be marked off and used to determine compliance. An accepted value for normal compliance is a pDet of 10 cm H2O at expected bladder capacity (de Jong and Klijn 2009; Nevéus et al. 2006) or 5% of the cystometric bladder capacity in children with NGB. In pediatrics, the numeric value of compliance is less important than the shape of the tracing and at the designated places that compliance measurements are taken. A slow, steady rise in pDet throughout filling is more suggestive of a poorly compliant bladder than one that has a

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Fig. 3 Representative cystometrograms. (a) Normal cystometrogram in an infant without evidence of detrusor overactivity during filling, normal bladder capacity and normal compliance with a well generated and sustained bladder contraction. (b) Cystometrogram with multiple

overactive detrusor contractions during filling at low volumes. (c) Cystometrogram in 14 yo F with myelodysplasia who was unable to tolerate anticholinergics. She has a small capacity bladder with an elevated leak point pressure of 45 cm H2O exhibiting a poorly (low) compliant bladder

sharp increase very near capacity. Compliance values also change as the children grow because bladder capacity increases with age.

considered less than expected capacity, and if >150%, then it is considered as greater than expected capacity (Austin et al. 2014; Nevéus et al. 2006).

Bladder Capacity

Urethral Function During Filling Bladder capacity is labelled as less than, normal, or more than expected based on equations previously discussed. Both MVV on the FVC and cystometric capacity should be considered as they may differ, and comparison to calculated values should be expressed in percentages. If the capacity is 1.5–2 cm are not usually amenable to SWL and will require other surgical techniques including percutaneous nephrolithotomy and laparoscopic or robotic pyelolithotomy (Ghani et al. 2014). Staghorn type of stones may occasionally demand an open surgical approach. Nephrectomy may also be a consideration if renal function is markedly decreased, in association with a large stone burden and recurrent UTIs.

Preventive Therapy Fluid and dietary modification are the essential preventive measures in all children with renal stones (Table 6). Increased water intake and restricted salt and increased potassium consumption should be recommended in all (Copelovitch 2012). Pharmacotherapy is required in those with cystinuria and primary hyperoxaluria and in children in whom fluid and dietary modification are insufficient to prevent stone recurrence (Table 6) (Cameron et al. 2005; McKay 2010; Tasian and Copelovitch 2014).

L. G. Kovacevic and Y. Lakshmanan

Surveillance Repeat renal ultrasound and metabolic assessment are needed to diagnose stone recurrence or increasing size of previous stones. The frequency of these tests depends on the presence and severity of the metabolic abnormality, the number of stones, and recurrence rate. A child with a single stone and no evidence of an underlying metabolic abnormality will require less frequent monitoring than a child with multiple stones and a significant metabolic problem known to be at greater risk for recurrent nephrolithiasis (primary hyperoxaluria or cystinuria). Compliance with high fluid intake should be monitored by measuring the urine-specific gravity. In an asymptomatic child, a repeat ultrasonography is usually done 6 months after the initial episode. If it shows no stone recurrence or change in residual stone size, the study can be performed yearly. Metabolic work-up is repeated at four to six weeks after therapy has initiated. If the metabolic abnormality was corrected, repeat studies should be done at six months and then yearly. Re-evaluation is needed if metabolic abnormalities persist. A multidisciplinary approach through a combined “Stone Clinic” including Nephrology, Urology and Dietary services serves these children well for long-term management.

Outcomes The risk of recurrent renal stones in children is between 15% and 20% within 3–13 years, with those who have an identifiable metabolic abnormality being at five-fold higher risk compared to those without (Pietrow et al. 2002). The rate of recurrence is also higher with a family history of stones in first-degree relatives. Few case series have studied the impact of pediatric urolithiasis on the long-term renal function. An increased risk of developing chronic renal insufficiency (CRI) and failure (CRF) was found especially in children with severe metabolic disorders, such as primary hyperoxaluria, cystinuria, and Dent’s disease. Renal tubular damage indicated by increased urinary excretion of beta-

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Table 6 Dietary and pharmacologic intervention in pediatric urolithiasis Condition Hypercalciuria

Hypocitraturia

Hyperoxaluria

Hyperuricosuria

Cystinuria

Dietary High fluid intakea Restricted sodiumb High potassium diet RDA for calcium Moderate animal protein High fluid intake Moderate animal protein High lemon intake Very high fluid intake (PH) Moderate oxalate restriction High magnesium and potassium supplements Low-fat diet Avoid excessive vitamin C RDA for calcium High fluid intake Moderate animal protein Restricted sodium Very high fluid intake (day and night)

Pharmacologic Hydrochlorothiazide (1–2 mg/kg per day, older children 25–100 mg/day)

Potassium citrate (2–4 mEq/kg/day, older children 30–90 mEq/day) Potassium citrate (2–4 mEq/kg/day, older children 30–90 mEq/day) Pyridoxine (8–10 mg/kg per day) for primary hyperoxaluria

Potassium citrate (2–4 mEq/kg/day, older children 30–90 mEq/day) Allopurinol (4–10 mg/kg/day, older children 300 mg per day)c Potassium citrate (2–4 mEq/kg/day, older children 30–90 mEq/day)d Tiopronin (starting dose of 100 mg BID) D-penicillamine (30 mg/kg/day divided in 4 doses) Captopril (0.5–1.5 mg/kg/day divided in 4 doses)

Fluid goal is targeted to maintain an age-related daily urinary volume: Infants 750 mL, small children below five years of age  1000 mL, children between 5 and 10 years of age  1500 mL, children greater than 10 years of age  2000 mL b Less than 2–3 mEq/kg/day c Reserved for children with a known disorder of uric acid metabolism d Dose targeted to achieve a urine pH equal to or above 7.0 a

microalbumin and N-acetyl-beta-glucosaminidase has been reported in children with urolithiasis and/or hypercalciuria.

Future Directions Pediatric urolithiasis has become a significant health problem. Most approaches have been extrapolated from adult studies, but the obvious differences between children and adult urolithiasis indicate the need to revisit established management principles. Despite recent advances, several questions remain. An important one is whether nephrolithiasis is a harbinger of a generalized vascular disease. If this is true, it may change the treatment approach and new prevention strategies may be possible. Markers to predict the risk of stone recurrence and early renal damage are needed, to determine the need for more aggressive therapy.

Prospective multicentric randomized clinical trials are needed to establish the efficacy of dietary and pharmacologic intervention and to formulate alternative therapies. The optimal dosing for thiazides and the efficacy and safety of combined therapy with potassium citrate in children needs to be established. Potential dietary and environmental factors that may contribute to renal stone formation need to be identified.

References Assael BM, Castellani C, Ocampo MB, Iansa P, Callegaro A, Valsecchi MG. Epidemiology and survival analysis of cystic fibrosis in an area of intense neonatal screening over 30 years. Am J Epidemiol. 2002;156(5):397–401. Bagga HS, Chi T, Miller J, Stoller ML. New insights into the pathogenesis of renal calculi. Urol Clin North Am. 2013;40(1):1–12.

228 Bergsland KJ, Coe FL, White MD, Erhard MJ, DeFoor WR, Mahan JD, Schwaderer AL, Asplin JR. Urine risk factors in children with calcium kidney stones and their siblings. Kidney Int. 2012;81(11):1140–8. Bowman RM, McLone DG, Grant JA, Tomita T, Ito JA. Spina bifida outcome: a 25-year prospective. Pediatr Neurosurg. 2001;34(3):114–20. Bush NC, Xu L, Brown BJ, Holzer MS, Gingrich A, Schuler B, Tong L, Baker LA. Hospitalizations for pediatric stone disease in United States, 2002–2007. J Urol. 2010;183:1151–6. Cameron MA, Sakhaee K, Moe OW. Nephrolithiasis in children. Pediatr Nephrol. 2005;20(11):1587–92. Copelovitch L. Urolithiasis in children: medical approach. Pediatr Clin N Am. 2012;59(4):881–96. D'Addessi A, Bongiovanni L, Sasso F, Gulino G, Falabella R, Bassi P. Extracorporeal shockwave lithotripsy in pediatrics. J Endourol. 2008;22(1):1–12. Dogan HS, Tekgul S. Management of pediatric stone disease. Curr Urol Rep. 2007;8(2):163–73. Dursun I, Poyrazoglu HM, Dusunsel R, Gunduz Z, Gurgoze MK, Demirci D, Kucukaydin M. Pedriatric urolithiasis: an 8-year experience of single centre. Int Urol Nephrol. 2008;40(1):3–9. Edvardsson V, Elidottir H, Indridasson OS, Palsson R. High incidence of kidney stones in Icelandic children. Pediatr Nephrol. 2005;20(7):940–4. Evan AP, Lingeman JE, Coe FL, Parks JH, Bledsoe SB, Shao Y, Sommer AJ, Paterson RF, Kuo RL, Grynpas M. Randall’s plaque of patients with nephrolithiasis begins in basement membranes of thin loops of Henle. J Clin Invest. 2003;111(5):607–16. Finlayson B, Reid F. The expectation of free and fixed particles in urinary stone disease. Investig Urol. 1978;15(6):442–8. Ghani KR, Trinh QD, Jeong W, Friedman A, Lakshmanan Y, Menon M, Elder JS. Robotic nephrolithotomy and pyelolithotomy with utilization of the robotic ultrasound probe. Int Braz J Urol. 2014;40(1):125–6. Gurgoze MK, Sari MY. Results of medical treatment and metabolic risk factors in children with urolithiasis. Pediatr Nephrol. 2011;26(6):933–7. Karunakaran P, Pathak A, Shandilya G, Puneeth Kumar KM, Anand M, Yadav P, Srivastava A, Ansari MS. Safety and efficacy of retrograde intrarenal surgery in primary and residual renalcalculi in children. J Pediatr Urol. 2022;18(3):312.e1–5. Kok DJ, Khan SR. Calcium oxalate nephrolithiasis, a free or fixed particle disease. Kidney Int. 1994;46(3):847–54. Kovacevic L, Wolfe-Christensen C, Edwards L, Sadaps M, Lakshmanan Y. From hypercalciuria to hypocitraturia An evolving trend in pediatric urolithiasis? J Urol. 2012;188(4 suppl):1623–7. Kovacevic L, Lu H, Caruso JA, Kovacevic N, Lakshmanan Y. Urinary proteomics reveals association between pediatric nephrolithiasis and cardiovascular disease. Int Urol Nephrol. 2018;50(11):1949–54.

L. G. Kovacevic and Y. Lakshmanan Kovacevic L, Caruso JA, Lu H, Kovacevic N, Lakshmanan Y, Carruthers NJ, Goldfarb DS. Urine proteomic profiling in patients with nephrolithiasis and cystinuria. Int Urol Nephrol. 2019;51(4):593–9. Kwon MS, Lim SW, Kwon HM. Hypertonic stress in the kidney: a necessary evil. Physiology (Bethesda). 2009;24:186–91. McKay CP. Renal stone disease. Pediatr Rev. 2010;31(5): 179–88. Milliner DS. Calcium oxalate in biological systems: Epidemiology of calcium oxalate urolithiasis in man. Boca Raton: CRC Press; 1995. Milliner DS, Murphy MF. Urolithiasis in pediatric patients. Mayo Clin Proc. 1993;68(3):241–8. Miyake O, Kakimoto K, Tsujihata M, Yoshimura K, Takahara S, Okuyama A. Strong inhibition of crystalcell attachment by pediatric urinary macromolecules: a close relationship with high urinary citrate secretion. Urology. 2001;58(3):493–7. Novak TE, Lakshmanan Y, Trock BJ, Gearhart JP, Matlaga BR. Sex Prevalence of pediatric kidney stone disease in the United States: an epidemiologic investigation. Urology. 2009;74(1):104–7. O’Connor PM. Renal oxygen delivery: matching delivery to metabolic demand. Clin Exp Pharmacol Physiol. 2006;33(10):961–7. Perrone HC, dos Santos DR, Santos MV, Pinheiro ME, Toporovski J, Ramos OL, Schor N. Urolithiasis in childhood: metabolic evaluation. Pediatr Nephrol. 1992;6(1):54–6. Pickard R, Starr K, MacLennan G, Lam T, Thomas R, Burr J, McPherson G, McDonald A, Anson K, N'Dow J, Burgess N, Clark T, Kilonzo M, Gillies K, Shearer K, Boachie C, Cameron S, Norrie J, McClinton S. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomized, placebo-controlled trial. Lancet. 2015;386(9991):341–9. Pietrow PK, Pope JC IV, Adams MC, Shyr Y, Brock JW 3rd. Clinical outcome of pediatric stone disease. J Urol. 2002;167(2 Pt 1):670–3. Randall A. The origin and growth of renal calculi. Ann Surg. 1937;105(6):1009–27. Routh JC, Graham DA, Nelson CP. Epidemiological trends in pediatric urolithiasis at United States freestanding pediatric hospitals. J Urol. 2010;184(3):1100–4. Sarkissian A, Babloyan A, Arikyants N, Hesse A, Blau N, Leumann E. Pediatric urolithiasis in Armenia: a study of 198 patients observed from 1991 to 1999. Pediatr Nephrol. 2001;16(9):728–32. Sas DJ. An update on the changing epidemiology and metabolic risk factors in pediatric kidney stone disease. Clin J Am Soc Nephrol. 2011;6(8):2062–8. Sas DJ. Dietary risk factors for urinary stones in children. Curr Opin Pediatr. 2020;32(2):284–7. Sas DJ, Hulsey TC, Shatat IF, Orak JK. Increasing incidence of kidney stones in children evaluated in the emergency department. J Pediatr. 2010;157(1):132–7.

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Schissel BL, Johnson BK. Renal stones: evolving epidemiology and management. Pediatr Emerg Care. 2011;27(7):676–81. Schlomer BJ. Urologic treatment of nephrolithiasis. Curr Opin Pediatr. 2020;32(2):288–94. Seitz C, Liatsikos E, Porpiglia F, Tiselius HG, Zwergel U. Medical therapy to facilitate the passage of stones: what is the evidence? Eur Urol. 2009;56(3):455–71. Shekarriz B, Lu HF, Stoller ML. Correlation of unilateral urolithiasis with sleep posture. J Urol. 2001;165: 1085–7. Singh P, Harris PC, Sas DJ, Lieske JC. The genetics of kidney stone disease and nephrocalcinosis. Nat Rev Nephrol. 2022 Apr;18(4):224–40. Smaldone MC, Docimo SG, Ost MC. Contemporary surgical management of pediatric urolithiasis. Urol Clin North Am. 2010;37(2):253–67. Smith SL, Somers JM, Broderick N, Halliday K. The role of the plain radiograph and renal tract ultrasound in the management of children with renal tract calculi. Clin Radiol. 2000;55(99):708–10.

229 Spivacow FR, Del Valle EE, Boailchuk JA, Sandoval Díaz G, Rodríguez Ugarte V, Arreaga ÁZ. Metabolic risk factors in children with kidney stone disease: an update. Pediatr Nephrol. 2020 Nov;35(11):2107–12. Stapleton FB. Clinical approach to children with urolithiasis. Semin Nephrol. 1996;16(5):389–97. Tasian GE, Copelovitch L. Evaluation and medical management of kidney stones in children. J Urol. 2014;192(5):1329–36. Velázquez N, Zapata D, Wang HH, Wiener JS, Lipkin ME, Routh JC. Medical expulsive therapy for pediatric urolithiasis: systematic review and meta-analysis. J Pediatr Urol. 2015;11(6):321–7. Vrtiska TJ, Hattery RR, King BF, Charboneau JW, Smith LH, Williamson B Jr, Brakke DM. Role of ultrasound in medical management of patients with renal stone disease. Urol Radiol. 1992;14(3):131–8. Yasui T, Iguchi M, Suzuki S, Kohri K. Prevalence and epidemiological characteristics of urolithiasis in Japan: National trends between 1965 and 2005. Urology. 2008;71(2):209–13.

Part III Upper Urinary Tract

Ureteropelvic Junction Obstruction

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Boris Chertin, Galiya Raisin, and Prem Puri

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 Ureteropelvic Junction Obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 Surgical Correction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 Dismembered Pyeloplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 Non-dismembered Pyeloplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 Endoscopic Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246

Abstract

With the wide spread of maternal ultrasound, the incidence of hydronephrosis has increased significantly, altering the practice of urology. Management of antenatal hydronephrosis after birth remains controversial. The decision on surgical intervention has become more

B. Chertin (*) Departments of Urology & Pediatric Urolog, Shaare Zedek Medical Center, Jerusalem, Israel e-mail: [email protected] G. Raisin Department of urology, Shaare Zedek Medical Center, Jerusalem, Israel e-mail: [email protected] P. Puri Newman Clinical Research Professor, University College Dublin, Dublin, Ireland Consultant Pediatric Surgeon, Beacon Hospital, Dublin, Ireland e-mail: [email protected]

complex as a spontaneous resolution of antenatal and even neonatal upper urinary tract dilatation is being increasingly recognized. On the other hand, relief of obstruction is important to prevent irreversible damage to the developing kidneys. Ureteropelvic junction obstruction (UPJO) is the most common pathology of antenatally detected hydronephrosis. Careful follow-up and utilization of the right imaging studies can aid the urologist in tailoring the treatment to each patient individually, thus maximizing renal preservation while avoiding unnecessary interventions.

Introduction With the widespread use of prenatal ultrasound, the incidence of antenatal hydronephrosis (ANH) has increased significantly, altering the practice of

© Springer-Verlag GmbH Germany, part of Springer Nature 2023 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43567-0_175

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urology. A recent review of the trends in prenatal sonography use and subsequent urological diagnoses in the United States, demonstrated a significant increase in overall ultrasound use in the last two decades. Moreover, the mean number of ultrasounds per pregnancy also increased significantly from 2.7 in 1998 to 4.5 by 2005 (Hsieh et al. 2009). ANH is identified in 1–5% of pregnancies and accounts for more than 50% of prenatally detected isolated renal malformations (Clayton and Brock 2011). The condition is bilateral in 17–54% of cases and is occasionally associated with additional abnormalities. The outcome of ANH depends on the underlying etiology (Table 1). Although ANH resolves by birth or during infancy in 41–88% of the patients, urological abnormalities requiring intervention are identified in 4.1–15.4%. Ureteropelvic junction obstruction (UPJO) is the most common cause of pathological ANH (Nguyen et al. 2010), accounting for up to 30% of all ANH cases (Clayton and Brock 2011). Management of these patients after birth remains controversial. On one hand, the recognition and relief of significant obstruction is important to prevent irreversible damage to the kidneys (Chertin et al. 2006), while on the other hand, with the increasing recognition of spontaneous resolution of antenatal and neonatal upper urinary tract dilatations (Nguyen et al. 2010; Ransley et al. 1990; Koff and Campbell 1994), differentiating urinary tract dilatations that are significantly obstructive and require surgery from those that represent mere anatomical Table 1 The etiology of ANH Etiology Transient hydronephrosis UPJ obstruction VUR UVJ obstruction/megaureters Multicystic dysplastic kidney PUV/urethral atresia Ureterocele/ectopic ureter/duplex system Others: prune belly syndrome, cystic kidneydisease, congenital ureteric strictures andmegalourethra

Incidence 41–88% 10–30% 10–20% 5–10% 4–6% 1–2% 5–7% Uncommon

AHN antenatal hydronephrosis, UPJ ureteropelvic junction, VUR vesicoureteral reflux, UVJ ureterovesicular junction, PUV posterior urethral valve

variants with no implications for renal function is not a simple task, especially in newborns.

Ureteropelvic Junction Obstruction Epidemiology The overall incidence of UPJO is approximately 1 in 1500 births. The ratio of males to females is 2:1 in the neonatal period, with leftsided lesions occurring in 60% of cases. In the newborn period, a unilateral process is most common, but bilateral UPJO was found in 10–49% of neonates in some reported series (Chertin et al. 2006). Etiology UPJO is classified as intrinsic, extrinsic, or secondary. Intrinsic obstruction is caused by a failure in transmission of the peristaltic waves across the ureteropelvic junction (UPJ), resulting in a failure of urine propulsion from the renal pelvis into the ureter. This causes multiple ineffective peristaltic waves that eventually lead to hydronephrosis by incompletely emptying the pelvic contents (Peters 2010). Previous studies have suggested various neurogenic and myogenic causes of the peristalsis defect, including: UPJ smooth muscle hypotrophy with accumulation of excessive collagen fibres (Pinter et al. 1997; Solari et al. 2003), reduced innervation within the muscular layer (Murakumo et al. 1997), and a combined mechanism, suggested by Murakuma et al., who concluded that in intrinsic obstruction, nerve fibers were depleted in the muscle layers in the ureteral walls, resulting in dysfunction and atrophy of the muscle fibers and an increase in collagen fibers in the muscle layers with abnormal accumulation of intercellular and interstitial collagen (Murakumo et al. 1997). Altered expression of interstitial cells of Cajal (Solari et al. 2003), platelet-derived growth factor receptor alpha-positive cells (Hunziker et al. 2017), anoctamin-1, and tyrosine phosphorylation (Hunziker et al. 2020) has been suggested to result in failure of transmission of peristaltic waves in UPJO. A recent study showed significantly higher urinary concentration of extracellular matrix proteins in children with UPJO, and particularly, the uTIMP-2 levels

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correlated to the severity of obstruction (Mello et al. 2021). Extrinsic mechanical factors include aberrant renal vessels, bands, adventitial tissues, and adhesions that cause angulation, kinking, or compression of the UPJ. Extrinsic obstruction may occur alone but usually coexists with intrinsic UPJ pathology. Secondary UPJO may develop as a consequence of severe vesicoureteral reflux (VUR) in which a tortuous ureter may kink proximately (Kim et al. 2001). Previous reports have described VUR in 9–15% of children who have UPJO, although the fraction that is secondary to reflux is difficult to determine (Kim et al. 2001). Genetics Phenotypes similar to UPJO have been noted in numerous transgenic mouse models. Many of the suggested genes are involved in ureteric smooth muscle proliferation and differentiation, thus supporting a primary myogenic aetiology (Jackson et al. 2018). Mutation in TBX18, a transcription factor necessary for normal smooth muscle cell proliferation, differentiation, and localization around the developing urothelial stalk, has been described across four generations of a family with congenital anomalies of the kidney and urinary tract (CAKUT), and predominantly UPJO (Jackson et al. 2018). Hereditary UPJO, as an autosomal dominant trait with variable penetrance, was suggested and Izquierdo et al. proposed one of the loci to the short arm of chromosome 6 as responsible for the development of UPJO (Izquierdo et al. 1992). Few studies have found an A–G transition in intron 1 of the AGTR2 gene, a part of the renin– angiotensin system, to be more frequent in patients with UPJO than in the general population (Hahn et al. 2005). In most patients, however, UPJO is a polygenic disorder without an obviously inherited genetic component (Jackson et al. 2018). Prenatal Diagnosis The bladder is visualized by 14 weeks of gestation. The presence of a full bladder provides evidence of renal function. The ureters are usually not seen in the absence of distal obstruction or reflux. The fetal kidneys may be visualized at the same time as the bladder. If not, they are always visualized by the 16th week of

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gestation. However, it is not until 20–24 weeks of gestation, when the fetal kidneys are surrounded by fat, that the internal renal structures appear distinct and renal growth can then be assessed easily. Beyond 20 weeks, fetal urine production is the main source of amniotic fluid. Therefore, major abnormalities of the urinary tract may result in oligohydramnios. Because of the distinct urine tissue interface, hydronephrosis can be detected as early as 16 weeks of gestation. An obstructive anomaly is recognized by demonstrating dilated renal calyces and pelvis. The purpose of AHN assessment is to distinguish children who require follow-up and intervention from those who do not. A multitude of measurement and different gestational age cut-off points have been recommended in the assessment of fetal obstructive uropathy (Shokeir and Nijman 2000; Avni et al. 2007). Routine estimation of anteroposterior diameter (APD) of the renal pelvis in a fetus with hydronephrosis is considered as a useful marker for classification of renal dilatation and possible obstruction. APD renal pelvis threshold values vary in different studies; in a review by Langer B. of 10 large studies involving more than 46,000 screened patients, positive predictive values for pathological dilatation confirmed in the neonate ranged between 2.3% and > 40% for AP renal measurements of 2–3 mm and 10 mm, respectively. This study concluded that only fetuses exhibiting third-trimester AP renal pelvis dilatations >10 mm would merit postnatal assessment (Langer 2000). In a different study, an APD third trimester threshold of 10 mm missed 25% cases of UPJO (Sinha et al. 2013). Table 2 presents APD thresholds for which the best available evidence provides prognostic information. In order to standardize postnatal evaluation of prenatal hydronephrosis, a grading system of Table 2 Definition of ANH by APD Degree of ANH Mild Moderate severe

Second trimester 4 to < 7 mm 7 to  10 mm > 10 mm

Third trimester 7 to < 9 mm 9 to  15 mm > 15mm

ANH Antenatal hydronephrosis, APD Anterior posterior diameter

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postnatal hydronephrosis was implemented in 1993 by the Society for Fetal Urology (SFU) (Fernbach et al. 1993). In the SFU system, the status of calices is paramount while the size of the pelvis is less important. This classification system incorporates collecting system dilation with renal parenchymal findings on a grading spectrum, with grade 1 demonstrating normal parenchymal thickness and only renal pelvis splitting and grade 4 revealing distention of the renal pelvis and calyces in addition to parenchymal thinning (Yamaçake and Nguyen 2013) (Table 3). The SFU grade correlates with the potential for postnatal resolution of the hydronephrosis. SFU grade 1 hydronephrosis resolves in approximately 50% of patients, whereas grades 2, 3, and 4 hydronephrosis resolve in 36%, 16%, and 3% of cases, respectively (Yamaçake and Nguyen 2013). Often, this classification is also applied on prenatal hydronephrosis, though a study by Chertin et al., which followed the natural history of hydronephrosis during the postnatal period (Chertin et al. 2006), found that the SFU grade of prenatal hydronephrosis is not a significant predictive factor for surgery in unilateral hydronephrosis. Due to the various methods in use, in an effort to create a common language between antenatal and postnatal findings, a new classification method was introduced in 2014 – the urinary tract dilatation (UDT) classification. The UTD classification unifies the terminology for urinary tract dilation in the fetus and infant. The System uses six US findings to describe the antenatal and postnatal urinary tract: (Alamo et al. 2010) anterior-posterior renal pelvic diameter (APRPD), (Avni et al. 2007) calyceal dilation with distinction between central and peripheral calyces postnatally, (Bassiouny 1992) renal parenchymal thickness, (Boysen and Gundeti 2017) renal parenchymal appearance, (Carr and El-Ghoneimi 2007) bladder abnormalities, and (Chalmers et al. 2016) ureteral abnormalities. In the fetus, the quantity of amniotic fluid is also evaluated (Chow et al. 2017) (Tables 4 and 5). A management algorithm based on the antenatal and postnatal classifications was also proposed (Tables 6 and 7). The new UDT classification

B. Chertin et al. Table 3 Ultrasound grading scale for hydronephrosis Grade 0 1 2 3

4

Central renal complex Intact Slight splitting Evident splitting confined within renal border Wide splitting pelvis outside renal border. Calices uniformly dilated Further dilation of renal pelvis and calices

Renal parenchyma Normal Normal Normal Normal

Thin

Table 4 Prenatal urinary tract dilation (UTD) classifications for UTD A1 and UTD A2–3 APRPD 16–27 weeks APRPD 28 weeks Calyceal dilation Parenchymal thickness Parenchymal appearance Ureters Bladder Oligohydramnios

UTD A1 4-7 mm 7-10 mm Central or none Normal

UTD A2-3 7 mm 10 mm Peripheral

Normal

Abnormal

Normal Normal None

Abnormal Abnormal Unexplained

Abnormal

APRPD Anterior posterior renal pelvic diameter

has yet to be proven superior to the previous methods described, and further research is required (Rickard et al. 2017). The role of magnetic resonance imaging (MRI) for detection and management of fetal uropathies has gained interest in the last two decades. Most studies have been focused on the additional information the MRI test can provide in cases of inconclusive US findings. These studies have repeatedly concluded that a MRU may help to better characterize urinary tract anomalies when the US findings are inconclusive or not diagnostic, especially in cases of oligohydramnios (Alamo et al. 2010; Yamaçake and Nguyen 2013). Prenatal Intervention Currently, fetal intervention is primarily for those with documented lower urinary tract obstruction (Yamaçake and Nguyen 2013). In the case of AHN, intrauterine intervention is rarely indicated and should only be

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Table 5 Postnatal urinary tract dilation (UTD) classificationa for UTD P1, UTD P2 and UTD P3 Normal 48 h to 1 month 2. 1–6 months later Aneuploidy risk modification if indicated

UDT A2-3 (increased risk) Initial US exam in 4–6 weeks US exam at >48 h to 1 month Specialist consultation, e.g., nephrology, urology

Table 7 Management schema based on urinary tract dilation (UTD) classification system risk stratification of UTD P1, UTD P2 and UTD P3 Follow-up US VCUG Antibiotics Functional scan

UDT P1 (low risk) 1-6 months Discretion of clinician Discretion of clinician Not recommended

UDT P2 (intermediate risk) 1-3 months Discretion of clinician Discretion of clinician Discretion of clinician

UDT P3 1 month Recommended Recommended Discretion of clinician

VCUG Voiding cystourethrogram

performed in well-experienced centers (Tekgül et al. 2015). In the case of severe prenatal bilateral hydronephrosis, severe hydroureteronephrosis, or severe impairment of the solitary kidney, fetal bladder aspiration for urinary proteins and electrolytes may be used in order to predict the renal injury secondary to obstructive uropathy. A fetal urinary sodium level of less than 100 mMol/L, chloride level of less than 90 mMol/L, and an osmolality of less than 210 mOsm/kg are considered as positive prognostic factors for good renal function (Elder 1997). Clinical Presentation The clinical presentation of UPJO has dramatically changed since the advent of maternal ultrasonographic screening (Chertin et al. 2006; Ransley et al. 1990; Koff and Campbell 1994). Before the routine fetal ultrasonography, the commonest presentation

was with abdominal flank mass. Fifty percent of abdominal masses in newborns are of renal origin with 40% being secondary to UPJO. Some patients present with a urinary tract infection, other presentations include irritability, vomiting, and failure to thrive. 10–35% of UPJO are bilateral, and associated abnormalities of the urinary tract are seen in about 30% of patients (Fernbach et al. 1993). UPJ problems are often associated with other congenital anomalies, including imperforated anus, contralateral dysplastic kidney, congenital heart disease, VATER syndrome, and esophageal atresia. In patients with such an established diagnosis, a renal ultrasound examination should be performed (Woolf 2000). Diagnosis With the increasing number of antenatally diagnosed hydronephrosis, it is difficult to interpret the underlying pathology and its

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significance. Severe obstructive uropathies are detrimental to renal function. However, on the other hand, hydronephrosis without ureteral or lower tract anomaly is common. The important aspect of postnatal investigations is to identify the group of patients who will benefit from early intervention to those who need to be carefully followed up. Ultrasound Follow-up ultrasound examination is necessary in the postnatal period in antenatally detected hydronephrosis. If the bilateral hydronephrosis is diagnosed in utero in a male infant, postnatal evaluation should be carried out within 24 hours, primarily because of the possibility of posterior urethral valves. If the ultrasound scan is negative in the first 24–48 hours in any patient with unilateral or bilateral hydronephrosis, a repeat scan should be performed after 5–10 days, recognizing that neonatal physiological dehydration may mask a moderately obstructive lesion. If hydronephrosis is confirmed on the postnatal scan, a further careful scan of the kidney, ureter, bladder, and in boys, the posterior urethra is essential. Ultrasonography depicts the dilated calyces as multiple intercommunicating cystic spaces of fairly uniform size that lead into a larger cystic structure at the hilum, representing the dilated renal pelvis (Fig. 1a). Peripheral to the dilated calyces, the renal parenchyma is usually thinned with normal or increased echogenicity. In order to standardize postnatal evolution of prenatal hydronephrosis, a formerly mentioned SFU grading system of postnatal hydronephrosis is utilized. Typically, the ureter is of normal caliber and not seen (Avni et al. 2007), but if it is dilated, the size of the ureter is also assessed ultrasonographically and graded 1–3 according to ureteral width < 7 mm, 7–10 mm, > 10 mm, respectively. A single ultrasound in the first week of life might not detect all abnormalities of the kidneys or urinary tract, due to low urine flow secondary to dehydration and low glomerular filtration rate. Thus, all newborns with a normal ultrasound in the first week require a repeat study at 4–6 weeks (Sinha et al. 2013). The presence of two normal postnatal renal ultrasounds excludes the presence of significant renal disease.

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Radionuclide Scans Diuretic renograms, using 99mTc DTPA augmented with furosemide, were useful in the diagnosis of urinary tract obstructions for a long time (O’Reilly 1992; Piepsz et al. 1999). DTPA is completely filtered by the kidneys with a maximum concentration of 5% being reached in 5 min, falling to 2% at 15 min. However, in the last decade, it has been reported that the use of tracers that rely on tubular extraction such as 123 I-Hippuran and 99Tc MAG3 (Fig. 1b) may improve the diagnostic accuracy (Upsdell et al. 1992; Nauta et al. 1991; Koff et al. 1988). The kidney of the young infant is immature; renal clearance, even when corrected for body surface, progressively increases until approximately 2 years of age. Therefore, the renal uptake of tracer is particularly low in infants, and there is high background activity. Thus, the traces, such as 123 I-Hippuran and 99Tc MAG3, with a high extraction rate provide reasonable images enabling estimation of the differential kidney function during the first few weeks of life. It is also helpful in assessing the size, shape, location, and function of the kidney. Diuretic augmented renogram is a provocative test and is intended to demonstrate or exclude obstructive hydronephrosis by stressing an upper urinary tract with a high urine flow. Obstruction usually is defined as a failure of tracer washout after diuretic stimulation. If unequivocal, it eliminates the need for further investigations. In equivocal cases, F15 in which furosemide is given 15 min after injection of the radionuclide trace provides a better assessment of the drainage of the upper urinary tract. Forced hydration prior to the scan increases the predictive value of a non-obstructed pattern up to 94% (Nauta et al. 1991). Since glomerular filtration and glomerular blood flow are still low in the newborn, the handling of the isotype is unpredictable and can be misleading. Koff et al. therefore feel that the risk of making a misdiagnosis of obstruction in this age group far outweigh the potential damage to renal function that might result from delaying surgery for a few weeks until the diagnosis can be made more accurately (Koff et al. 1988). Therefore, the timing of the performance of radionuclide studies is of crucial importance. In those cases where DTPA is used as an isotype, radionuclide study should be postponed until 6–8 weeks after birth, allowing the

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Fig. 1 (a) A coronal plane scan through the obstructed left kidney confirms obstruction at the level of the ureteropelvic junction. (b) 99Tc MAG3 scan in the above patient. Clearance curve for left kidney confirming the high-grade obstruction on this side. (c) A 20-minute fulllength film from an IVU series showing left-sided high-

grade ureteropelvic junction obstruction in the same patient. (d) MRU showing ureteropelvic junction obstruction in the same patient (Lt arrow shows UPJ obstruction on the left side; Rt arrow shows normal urinary bladder with balloon of the Foley catheter)

kidney to multiply the number of the functioning glomeruli. When 99Tc MAG3 is utilized in the diagnosis of the obstruction, the radionuclide study may be performed as early as 2 weeks of age in those cases where prompt diagnosis is required.

Magnetic Resonance Imaging Magnetic resonance urography (MRU) is becoming popular in the diagnosis of upper tract obstructions. Some MRI techniques, such as functional MRU, allow for both anatomical and functional assessment of the patient with UPJO; anatomically, crossing vessels and other obstructive pathology are more clearly identified to aid surgical planning. The uptake and excretion times of contrast material within the kidney have been shown to delineate those children with obstruction causing impaired renal function and those without (Chua et al.

Intravenous Urography Diagnosis of UPJO can be made by intravenous urography. This investigation is often not helpful as the concentration of the contrast is unreliable and has no place in the diagnostic armamentarium nowadays (Fig. 1c).

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2016). Currently, the use of MRI for the evaluations of UPJO is only supplementary to the traditional evaluation with US and scintigraphy. However, as this modality requires no radiation exposure, enables detailed anatomical information and its technology is constantly evolving to allow for a better functional evaluation, it might one day become the only examination needed for UPJO diagnosis and assessment (Fig. 1d). Pressure-Flow Study In the equivocal cases and in the presence of impaired function, the pressure flow study (Whitaker Test) and antegrade pyelography may be necessary to confirm or exclude obstruction (Whitaker 1973). The Whitaker test is based on the hypothesis that if the dilated upper urinary tract can transport 10ml/min without an inordinate increase in pressure, the hydrostatic pressure under physiological conditions should not cause impairment of renal function and the degree of obstruction if present is insignificant. However, it is an invasive test and is seldom required. Antegrade pyelography may be performed with ultrasound guidance in patients where diagnosis is difficult. Retrograde pyelography is seldom required to determine the status of ureters. The disadvantages include difficulty in ureteral catheterization in neonates, trauma, and edema which may change a partial obstruction to a complete one. In patients where diagnosis is equivocal, serial examinations may be necessary. Voiding Cystourethrogram (VCUG) The incidence of UPJO and concomitant VUR have been reported to be as high as 18% (Hubertus et al. 2013). On one hand, the presence of VUR might increase the risk of renal scarring and thereby renal function deterioration, thus changing the management of these children with the addition of an oral antibiotic therapy, or a need for VUR correction. On the other hand, VCUG is an invasive procedure associated with radiation exposure and even if reflux is detected, it may have absolutely no clinical impact. Therefore, some guidelines recommend a VCUG to identify cases of VUR in infants with UPJO, while others restrict this test for several risk groups, such as patients with recurrent febrile

B. Chertin et al.

UTIs, dilated ureter, and potentially prior to surgical intervention (Weitz and Schmidt 2017). Treatment A considerable controversy exists regarding the management of newborn urinary tract obstructions. Some authors advocate early surgical intervention to prevent damage to maturing nephrons, while others feel that early surgery carries no specific benefit (Chertin et al. 2006; Ransley et al. 1990; Koff and Campbell 1994). During late prenatal and early postnatal life, there is a progressive increase in the glomerular filtration rate (Koff and Campbell 1994). Additionally, this transition is associated with an abrupt decline in urine output from what appears to be a quite high in utero output to a rather low early neonatal level of urine production. These physiological observations may explain the common observation of hydronephrosis detected antenatally, which on postnatal follow-up reverts to an unobstructed pattern (Hsieh et al. 2009; Koff and Campbell 1994). In 1990 in a pioneer manuscript, Ransley et al. reported the results of nonoperative treatment in newborns with nonrefluxing hydronephrosis and differential renal function >40% (Ransley et al. 1990) at the 6-year follow-up, only 23% needed surgical correction. The most common indication for surgery in this group of children was the deterioration of renal function. In another study, Chertin et al. reported that out of 343 children with postnatal diagnosis of UPJO who were followed conservatively, 52.2% required surgical correction. Gender, side of hydronephrosis, and SFU grade of prenatal hydronephrosis were not significant predictive factors for surgery. However, SFU grade 3–4 of postnatal hydronephrosis and relative renal function (RRF) less than 40% were significant independent risk factors which led to surgical correction (Chertin et al. 2006). Current guidelines divide the patient population into symptomatic and asymptomatic: Symptomatic patients, which include children with recurrent flank pain and urinary tract infections, require surgical correction. For asymptomatic patients, conservative follow-up is the recommended treatment, with serial examinations to observe anatomical and functional improvement. Indications for surgical

14

Ureteropelvic Junction Obstruction

intervention include impaired split renal function (15 mm, respectively, in the third trimester (Nguyen et al. 2014). For the prenatal assessment of the urinary tract, standardized measures have been reported not only for the renal pelvis but also for the ureters. According to the British Association of Pediatric Urologists (BAPU), a retrovesical ureteral diameter greater or equal to 7 mm from 30 weeks’ gestation onwards should be considered abnormal and should be referred for appropriate investigations after birth (Farrugia et al. 2014).

Postnatal Ultrasound The initial approach in case of a prenatal suspect of urological problems is represented by a postnatal ultrasound scan of the urinary tract. It is important to remember that the study should be performed following the initial transitory postnatal oliguria that leads to a physiological neonatal dehydration during the first 48 h after

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birth (European Society for Paediatric Urology). However, in the most severe cases (such as in cases of bilateral hydronephrosis, congenital solitary kidney, or oligohydramnios), an early postnatal scan could still be useful. During the ultrasonographic evaluation, the anteroposterior diameter of each renal pelvis is measured, together with the size of the calyces, the position and the shape of the kidneys, corticomedullary differentiation, thickness and cortical echogenicity of the renal parenchyma. Dilated ureters can be traced and measured from the renal pelvis to their entry into the bladder (European Society for Paediatric Urology) (Fig. 4).

Voiding Cystourethrogram Potential causes of dilatation of kidney and ureter include vesicoureteral reflux and posterior urethral valves. A conventional voiding cystourethrogram should, therefore, be performed to exclude them and discriminate between refluxing and non-refluxing megaureters (European Society for Paediatric Urology).

Diuretic Renography Diuretic renography is the most used diagnostic tool to assess the functional significance and the

Fig. 4 Postnatal USS showing bladder and dilated ureter, coronal (a) and sagittal (b) views

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severity of the urinary flow obstruction, and is recommended particularly in case of hydroureteronephrosis or isolated ureteric dilatation bigger than 10 mm (Farrugia et al. 2014). Technetium-99 m (99mTc) mercaptoacetyltriglycine (MAG3) is the radionuclide of choice. In order to allow full renal maturation, the scintigraphy should be performed after the first 4th to 6th weeks of life, ideally from 3 months of age, and under standardized conditions of hydration and bladder emptiness. According to EAU guidelines, oral fluid intake should be given prior to the examination, while, 15 min before the injection of the radionuclide, a normal saline intravenous infusion is administered at a rate of 15 mL/kg over 30 min, with a subsequent maintenance rate of 4 mL/kg/h for the entire investigation. Furosemide (1 mg/kg: infants 200% predicted capacity and postvoid residual greater than 25% of bladder capacity) and profound overactive bladder (Five or more overactive contractions with maximum pressure greater than 30 cmH2O). Only 10% had isolated profound overactive bladder with a normal capacity. The majority had dilated bladder dysfunction with a small subset having both patterns present. Predictors of bladder dysfunction at presentation during

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infancy were an elevated postvoid residual and grade V VUR (Sillen et al. 1999). There were similar findings reported from Swedish Reflux Trial (randomized study in children ages 1–2 years with Gr III and IV VUR). Patients were evaluated prospectively for voiding problems at entry and 2 years. At entry, 20% of patients had lower urinary tract dysfunction characterized by increased bladder capacity and elevated postvoid residual urine. At 2 years, there was an increase to 34%. In children that were toilet trained, symptoms of overactive bladder (frequency, urgency, urge incontinence) were present in nearly all with bladder dysfunction. Voiding phase problems were defined at dysfunctional voiding (interrupted voiding pattern, straining, or hesitancy), dysfunctional elimination (bowel dysfunction with dysfunctional voiding), and dilated bladder dysfunction (VCUG capacity >200% age predicted volume or maximum voided volume > 150% age predicted volume). Lower urinary tract dysfunction was more common in grade IV VUR than grade III (Sillen et al. 2010). An additional series of patients with dilated bladder dysfunction has been treated with intermittent catheterization to facilitate emptying, but this failed to improve the resolution of VUR in these patients (Sillen et al. 2007). The etiology of this bladder dysfunction is unknown, and given that it is more prevalent in high-grade reflux, there remains the possibility that the VUR is the primary cause of the dysfunction. Furthermore, the presence of abnormal bladder function is a negative predictor for VUR resolution (Yeung et al. 2006; Sjostrom et al. 2010). Early studies in children with VUR were able to document that VUR usually occurs as a low-pressure phenomenon (Hinman et al. 2002; Weiss and Biancani 1983). Additionally, lower pressure at onset of VUR had been shown be a negative predictor for reflux resolution over time that is independent of grade of reflux (Van Arondonk et al. 2007). One of the main hallmarks of bladder dysfunction in older child is elevated bladder pressures which are thought to overpower the ureterovesical junction to drive VUR. Urodynamic patterns found in these children include most commonly detrusor overactivity,

J. C. Austin and S. J. Skoog

followed by dysfunctional voiding (incomplete or intermittent pelvic floor relaxation), and primary bladder neck dysfunction was the least common (Hong et al. 2011; Karami et al. 2012; Kajbafzadeh et al. 2010; Van Batavia et al. 2013). Dysfunctional elimination syndrome in patients with VUR has been a long-recognized risk factor for urinary tract infection and renal scarring (Koff et al. 1998). Recognition and treatment of bladder dysfunction in this group of patients (with biofeedback to treat pelvic floor dysfunction, anticholinergics to treat overactive bladder, or alpha-blockers for primary bladder neck dysfunction) have been shown to be effective with increased rates of VUR resolution and decreased need for surgical repair (Herndon et al. 2001; Homsy et al. 1985; Kajbafzadeh et al. 2010). These findings are strong indicators that the bladder dysfunction in older patients after toilet training plays a significant role in the VUR. Indeed, it has been stressed that identification and management of bladder and bowel dysfunction are an important factors in treating patients with VUR. Bladder and bowel dysfunction is associated with increased risk of urinary tract infection and has been associated with lower success rates in treated VUR using endoscopic injection (Peters et al. 2010; Elder et al. 2006).

Cross-References ▶ Embryology of the Urinary Tract ▶ Surgical Treatment of Vesicoureteric Reflux ▶ The Diagnosis and Medical Management of Vesicoureteral Reflux: An Update and Current Controversies ▶ Ureteral Duplication and Duplex Systems ▶ Urodynamic Studies of the Urinary Tract

References Cerwinka W, Scherz H, Kirsch A. Dynamic hydrodistention classification of the ureter and the double hit method to correct vesicoureteral reflux. Arch Esp Urol. 2008;61(8):882–7. Dikshit M, Acharya V, Shikare S, Merchant S, Pardanani D. Comparison of direct radionuclide cystography with

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Anatomical and Functional Basis of Vesicoureteral Reflux

micturating cystourethrography for the diagnosis of vesicoureteral reflux, and its correlation with cystoscopic appearances of the ureteric orifices. Nephrol Dial Transplant. 1993;8:600–2. Dixon J, Jen P, Yeung C, Chow L, Mathews R, Gearhart J, Gosling J. The structure and automomic innervation of the vesico-ureteral junction in cases of primary reflux. Br J Urol. 1998;81(1):146–51. Elder J, Diaz M, Caldemone A, Cendron M, Greenfield S, Hurwitz R, Kirsch A, Koyle M, Pope J, Shapiro E. Endoscopic therapy for vesicoureteral reflux: a meta-analysis. I. Reflux resolution and urinary tract infection. J Urol. 2006;10(6):716–22. Herndon C, DeCambre M, McKenna P. Changing concepts concerning the management of vesicoureteral reflux. J Urol. 2001;166(4):1439–43. Hinman F, Miller E, Hutch J, Gainey M, Cox C, Goodfriend R, Marshall S. Low pressure reflux: relation of vesicoureteral reflux to intravesical pressure. J Urol. 2002;167:1063–8. Homsy Y, Nsouli I, Hamburger B, Laberge I, Schick E. Effects of oxybutynin on vesicoureteral reflux in children. J Urol. 1985;134(6):1168–71. Hong Y, Altobelli E, Borer J, Bauer S, Nguyen H. Urodynamic abnormalities in toilet trained children with primary vesicoureteral reflux. J Urol. 2011;185(5): 1863–8. Hutch J. Vesic-ureteral reflux in the paraplegic: cause and correction. J Urol. 2002;167:1410–4. Ichikawa I, Kuwayama F, Pope J, Stephens F, Miyazaki Y. Paradigm shift from classic anatomic theories to contemporary cell biological views of CAKUT. Kidney Int. 2002;61(3):889–98. Jannson U, Hanson M, Hanson E, Hellstrom A, Sillen U. Voiding pattern in healthy children 0-3 years old: a longitudinal study. J Urol. 2000;164(6):2050–4. Juskiewenski S, Vaysse P, Moscovici J, de Graeve P, Guitard J. The ureterovesical junction. Anat Clin. 1984;5:251–9. Kajbafzadeh A, Baradaran N, Sedeghi Z, Tourchi A, Saeedi P, Madani A, Ataei N, Taghavinejad A, Mohsseni M. Vesicoureteral reflux and primary bladder neck dysfunction in children: urodynamic evaluation and randomized, double blind, clinical trial on the effect of alpha-blocker therapy. J Urol. 2010;184:2128–33. Karami H, Razi A, Mazloomfard M, Javanmard B. Is there a role for urodynamic study in children with high-grade vesicoureteral reflux. Urology. 2012;79(4):888–91. Koff S, Wagner T, Jayanthi R. The relationship among dysfunctional elimination syndromes, primary vesicoureteral reflux and urinary tract infections in children. J Urol. 1998;160(3 pt 2):1019–22. Leissner J, Allhoff E, Wolff W, Feja C, Hochel M, Black P, Hohenfellner R. The pelvic plexus and antireflux surgery: topographical findings and clinical consequences. J Urol. 2001;165:2652–5. Lyon R, Marshall S, Tanagho E. The ureteral orifice: its configuration and competency. J Urol. 1969;102: 504–9.

275

Mackie G, Awang H, Stephens F. The ureteric orifice: the embryologic key to radiologic status of duplex kidneys. J Pediatric Surg. 1975;10(4):473–81. Martinez Portillo F, Seif C, Braun P, Bohler G, Osmonov D, Leissner J, Hohenfeller R, Aleken P, Juenemann K. Risk of detrusor denervation in antireflux surgery demonstrated in a neurophysiological animal model. J Urol. 2003;170:570–4. NICE (National Institute for Clinical Excellence) Guidelines (CG54). Urinary tract infection in under 16s: diagnosis and management. www.nice.org.uk 2007. Oswald J, Brenner E, Schwentner C, Deibl M, Bartsch G, Fritsch H, Radmayr C. The intravesical ureter in children with vesicoureteral reflux: a morphological and immunohistochemical characterization. J Urol. 2003;170:2423–7. Oswald J, Schwentner C, Lunacek A, Fritsch H, Longato S, Sergi C, Bartsch G, Radmayr C. Reevaluation of the fetal muscle development of the vesical trigone. J Urol. 2006;176:1166–70. Paquin A. Ureterovesical anastomosis: description and evaluation of a technique. J Urol. 1959;82(5):573–83. Peters C, Skoog S, Arant B, Copp H, Elder J, Hudson R, Khoury A, Lorenzo A, Pohl H, Shapiro E, Snodgrass W, Diaz M. Summary of the AUA guideline on management of primary vesicoureteral reflux in children. J Urol. 2010;184(3):1134–44. Pirker M, Rolle U, Shinkai T, Shinkai M, Puri P. Prenatal and postnatal neuromuscular development of the ureterovesical junction. J Urol. 2007;177:1546–51. Roberts K, Downs S, Finnell S, Hellerstein S, Shortliffe L, Wald E, Zerin J, Davidson C. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2-14 months. Pediatrics. 2011;128(3):595–610. Rusu MC, Pop F, Petre N, Dobra MA. The sheath of Waldeyer is not a specific anatomical trait of the ureterovesicaljunction. Morphologie. 2018;102(336): 6–11. Schwentner C, Oswald J, Lunacek A, Fritsch H, Deibl M, Bartsch G, Radmayr C. Loss of interstitial cells of Cajal and gap junction protein connexin 43 at the vesicoureteral junction in children with vesicoureteral reflux. J Urol. 2005;174:1981–6. Schwentner C, Oswald J, Lunacek A, Schlenck B, Berger A, Deibl M, Fritsch H, Bartsch G, Radmayr C. Structural changes of the intravesical ureter in children with vesicoureteral reflux- does ischemia have a role? J Urol. 2006;176:2212–8. Sillen U, Hellstrom A, Hermanson G, Abrahmson K. Comparison of urodynamic and free voiding patter in infants with dilating reflux. J Urol. 1999;161: 1928–33. Sillen U, Holmdahl G, Hellstrom A, Sjostrom S, Solsnes E. Treatment of bladder dysfunction and high grade vesicoureteral reflux does not influence the spontaneous resolution rate. J Urol. 2007;177:325–30. Sillen U, Brandstrom P, Jodal U, Holmdahl G, Sandin A, Sjoberg I, Hansson S. The Swedish reflux trial in

276 children: V. bladder dysfunction. J Urol. 2010;184: 298–304. Sjostrom S, Bacherlard M, Sixt R, Sillen U. Change in urodynamic patterns in infants with dilating vesicoureteral reflux: 3-year followup. J Urol. 2009;182:2446–54. Sjostrom S, Sillen U, Jodal U, Sameby L, Sixt R, Stokland E. Predictive factors for resolution of congenital high grade vesicoureteral reflux in infants: results of univariant and multivariate analysis. J Urol. 2010;183:1177–84. Stephens F, Lenaghan D. The anatomical basis and dynamics of vesicoureteral reflux. J Urol. 1962;87(5):669–80. Tanagho E, Pugh R. The anatomy and function of the ureterovesical junction. Br J Urol. 1963;35:151–65. Tanagho E, Meyers F, Smith D. The trigone: anatomical and physiological considerations in relation to the ureterovesical junction. J Urol. 1968;100:623–32. Thomson A, Dabhoiwala N, Verbeek F, Lamers W. The functional anatomy of the ureterovesical junction. Br J Urol. 1994;73(3):284–91. Tokhmafshan F, Brophy PD, Gbadegesin RA, Gupta IR. Vesicoureteral reflux and the extracellular matrix connection. Pediatr Nephrol. 2017;32(4):565–76. Van Arondonk K, Austin J, Hawtrey C, Graham M, Cooper C. Nuclear cystometrogram-determined bladder

J. C. Austin and S. J. Skoog pressure at the onset of vesicoureteral reflux predicts spontaneous resolution. Urology. 2007;69(4):862–5. Van Batavia J, Ahn J, Fast A, Combs A, Glassberg K. Prevalence of urinary tract infection and vesicoureteral reflux in children with lower urinary tract dysfunction. J Urol. 2013;190:1495–500. Weiss R, Biancani P. Charecteristics of normal and refluxing uretervesical junctions. J Urol. 1983;129: 858–61. Woodburne R. The ureter, ureterovesical junction, and vesical trigone. Anat Rec. 1965;151:243–50. Yeung C, Godley M, Duffy P, Ransley P. Natural filling cystometery in infants and children. Br J Urol. 1995;75(4):531–7. Yeung C, Godley M, Dhillon H, Duffy P, Ransley P. Urodynamic patterns in infancts with normal lower urinary tracts or primary vesico-ureteric reflux. Br J Urol. 1998;81(3):461–7. Yeung C, Sreedhar B, Sihoe J, Sit F. Renal and bladder functional status at diagnosis as predictive factors for the outcome of primary vesicoureteral reflux in children. J Urol. 2006;176:1152–7. Yulcek S, Baskin L. Neuroanatomy of the ureterovesical junction: clinical implications. J Urol. 2003;170: 945–8.

The Diagnosis and Medical Management of Vesicoureteral Reflux: An Update and Current Controversies

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Saul P. Greenfield

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 Methods of Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 Ureteral Diameter Ratio (UDR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 Contrast Voiding Cystourethrogram (VCUG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 Radionuclide Cystography (RnVCUG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 Voiding Urosonography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 CeVUS (Contrast Enhanced Voiding Urosonography) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 Noninvasive Cystography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 Renal and Bladder Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 The “Top Down” Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 Urinary and Serum Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 Who Should Be Evaluated . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 Children with a History of UTI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 The American Academy of Pediatrics Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 The National Institute for Clinical Excellence (NICE) Guidelines . . . . . . . . . . . . . . . . . 286 Infants with Prenatally Detected Hydronephrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 Siblings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 Medical Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 Rates of Resolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 Bowel and Bladder Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289

S. P. Greenfield (*) Cohen’s Children’s Hospital, Hofstra School of Medicine, Clinical Professor of Urology, New Hyde Park, NY, USA e-mail: spgreenfi[email protected] © Springer-Verlag GmbH Germany, part of Springer Nature 2023 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43567-0_178

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S. P. Greenfield Antibiotic Prophylaxis-Current Controversies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 Discontinuing Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 The RIVUR Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 Cross-reference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

Abstract

Primary vesicoureteral reflux (VUR) is most often diagnosed in children after a urinary tract infection (UTI), in infants with a prenatal ultrasound showing hydronephrosis, or in asymptomatic siblings of probands with VUR. While other diagnostic modalities have been advocated, the voiding cystourethrogram (VCUG) remains the most accurate. In particular, renal ultrasound (USG) will miss many children with all grades of reflux. Renal scarring, either due to renal dysplasia at birth or after pyelonephritis, is the most consequential of the sequelae of undiagnosed and untreated VUR. Recurrent urinary infection without pyelonephritic scarring, while of less significance, also contributes to VUR-related morbidity. Long-term, continuous low-dose antibiotic prophylaxis has been the mainstay of medical management. The majority of those with low-grade VUR (grades I, II, and III) outgrow their reflux with somatic growth, and they constitute 90% of all children identified with VUR. Continuous prophylaxis has been shown to prevent recurrent UTIs during the years of observation. More recently, the rationale for continuous prophylaxis has been challenged. Conflicting studies have produced contradictory outcomes, arguing for and against the benefit of prophylaxis. These studies and their shortcomings are discussed at length. Most recently, the results of the NIH-sponsored RIVUR (Randomized Intervention for children with Vesicoureteral Reflux) Trial were published, showing that continuous prophylaxis halved the number of UTIs over a 2-year observation period.

Renal scarring was not decreased, however. The presence of bowel and bladder dysfunction (BBD) was a significant contributing factor to recurrent UTI. While it is known that many children might not require medical management, it is not possible to segregate those at risk for recurrent UTI, with or without renal involvement. The identification of those at greatest risk who would benefit from treatment remains a challenge for future research. Keywords

Vesicoureteral reflux (VUR) · Urinary tract infection (UTI) · Renal scarring · Pyelonephritis · Voiding cystourethrogram (VCUG) · DMSA renal scanning · Renal ultrasound (USG) · Antibiotic prophylaxis · Hydronephrosis · Siblings

Introduction Vesicoureteral reflux is one the most common problems encountered in pediatric urology and has been the subject of intense investigation for over 60 years. The need for diagnosis and management remains controversial and contentious. This chapter will endeavor to put the current controversies into perspective and provide some practical guidelines for clinicians confronted with these children. Ultimately, however, clinical decisions will have to be individualized as there are no sets of easily followed algorithms. In addition, it should be understood that appropriate decisions may differ from child to child and venue to venue, due to cultural, geographic, and social contexts that are not uniform and which present unique circumstances.

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The Diagnosis and Medical Management of Vesicoureteral Reflux: An. . .

Diagnosis Vesicoureteral reflux (VUR) is the retrograde flow of urine from the bladder to the kidney. “Primary” reflux is congenital and is due to deficient formation of the valvular mechanism in the bladder. “Secondary” reflux refers to reflux, which occurs as a result of elevated bladder pressures overcoming and deforming a normal valve. This can be due to physical obstruction of the bladder outlet or neurogenic bladder dysfunction. Except when indicated, this chapter will deal mainly with primary, congenital VUR.

Methods of Imaging Ureteral Diameter Ratio (UDR) The use of distal ureteral diameter ratio (UDR) has been promoted to grade VUR and eliminate the subjectivity of the IRSG system (Cooper et al. 2015). In this proposed schema, the pelvic ureteral width is measured at its greatest diameter and compared with the spinal distance between the bottom of L1 and the top of L3. The UDR has been shown to have better interobserver reliability, and appears to be a better predictor of outcome. Preliminary data have shown children with a lower UDR had fewer breakthrough infections over time, independent of the grade of VUR or the presence of bowel and bladder dysfunction (BBD), and UDR more accurately predicted surgical intervention, and spontaneous resolution of VUR with growth correlated well with the calculated UDR (Cooper et al. 2013; Arlen et al. 2017). However, further research is needed to validate these findings before this system is adopted to either replace or complement the grading system currently in use.

Contrast Voiding Cystourethrogram (VCUG) The mainstay of imaging is the contrast voiding cystourethrogram (VCUG). This requires catheterization and instillation of iodinated contrast in

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an awake child. Static cystograms performed under anesthesia are not satisfactory and will miss reflux in children which might only appear during voiding. Contrast cystograms allow for the grading of reflux, using the now widely accepted International Scale (TamminenMobius et al. 1992). In addition, morphology of the bladder wall and urethra is visualized, as well as ureteral anomalies, such as duplications, ectopic ureter, and periureteral diverticuli. Postvoid residual urine volumes can be estimated. Vaginal voiding in girls can be seen. These observations all have prognostic and management implications. The VCUG, however, is invasive and uncomfortable and entails the use of ionizing radiation. Newer equipment and use of spot fluoroscopy have reduced the radiation exposure. Pretest counseling and child-life intervention have also modified some of the anxiety experienced by both parents and children (Sandy et al. 2011; Giramonti et al. 2012). Some centers give oral Midazolam prior to the study to reduce anxiety (Elder and Longnecker 1995). This practice is not widespread, as it may require special sedation personnel and post-test observation facilities. These may be available in a hospital setting, but not at many outpatient radiology centers. Criteria for performing the VCUG have been called for, in an attempt to standardize such aspects as the height of the contrast agent container, the volume of contrast introduced, number of filling and voiding cycles, and angle of exposure (Palmer et al. 2011). To improve patient safety and to standardize the data obtained when a VCUG is performed, Frimberger and Mercado-Deane (2016) established a standard protocol on how to perform and interpret this test. The International Reflux Study grading system, based upon the contrast VCUG, was first introduced several decades ago, grading reflux from grades I to V (Fig. 1). It has been used to help predict resolution of reflux with somatic growth and to guide both medical and surgical therapy (see below). Unfortunately, the grading system is subjective, and there is not perfect concordance among different readers. This is especially true when deciding between the

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Fig. 1 The International Reflux Study grading system: Grade I – reflux into the ureter only; Grade II – reflux into the renal collecting system without dilatation of the ureter or calyces; Grade III – reflux into the collecting system with mild dilatation of the calyces and ureter; Grade IV – reflux into the collecting system with moderate

dilatation of the calyces and some ureteral tortuosity; Grade V – reflux into the collecting system with extreme dilatation of the calyces and marked ureteral tortuosity. Grades I to III are highlighted, as they represent approximately 90% of the reflux discovered after a UTI in the United States

intermediate grades of II and III. There can be up to 25% disagreement between pediatric radiologists when categorizing reflux in these two grades (Greenfield et al. 2012, Metcalf et al. 2012). The term “dilating reflux” is often used to describe grades III to V, and some have proposed more aggressive clinical approaches to this subset of children. However, the ambiguity between grades II and III may undermine the credibility of these recommendations. Reflux resolution is most reliably determined after there are two negative cystograms approximately one year apart (Greenfield et al. 1997a, b). Up to 27% of children with an initial negative cystogram see reflux on a subsequent study. Therefore, if children are taken off prophylaxis after one normal VCUG, parents and physicians should be alert to any subsequent infections that might require reimaging. Intrarenal reflux (IRR) is seen only on contrast VCUGs and is the progression of visible contrast

up the collecting tubules of the renal papillae (Fig. 2). More renal scars are seen in association with IRR, confirming the hypothesis that reflux enables the entrance of bacteria into the renal parenchyma. However, the presence of IRR does not predict more breakthrough infections in the future, while on prophylaxis, the development of more renal scarring mitigates against the likelihood of reflux resolution (Boubnova et al. 2010). Therefore, its detection should not be used to alter treatment strategies – for example, medical management versus surgical intervention. Positional instillation cystography (PIC) was introduced in an attempt to discover “occult” reflux and remains controversial (Rubenstein et al. 2003; Matsumoto et al. 2011) (Fig. 3). PIC can be used to predict the development of contralateral reflux after unilateral surgical correction. In addition, children who are candidates for PIC will have recurrent episodes of febrile

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Grade I reflux can be missed if the column of radionuclide does not rise above the bladder. Anatomic details of the bladder wall, urethra in boys, and ureter will not be discerned at all. Many will use this method to follow children over the years after an initial contrast VCUG defines the grade and other anatomic details.

Voiding Urosonography CeVUS (Contrast Enhanced Voiding Urosonography)

Fig. 2 Intrarenal reflux: VCUG showing contrast into the parenchyma of the upper pole of the left kidney

pyelonephritis and documented new renal involvement on DMSA renal scanning. Standard voiding cystograms are negative. PIC requires cystoscopy under anesthesia, and a cystoscope with iodonated contrast as an irrigant is aimed directly at the ureteral orifice in question under fluoroscopy. If contrast is seen going up the ureter, reflux is deemed present. Surgical correction, either with open surgery or Deflux injection, has been shown to eliminate these recurrent episodes of pyelonephritis.

Radionuclide Cystography (RnVCUG) The radionuclide voiding cystourethrogram was introduced as a means of avoiding radiation exposure. It was also said to be more accurate, since the child’s abdomen is imaged continuously by a gamma camera during instillation and voiding, not on a spot or intermittent basis. Agents such as Tc99-DTPA are used. However, this still requires catheterization in an awake child. Reflux cannot be graded using the International Scale.

Contrast-enhanced voiding urosonography is a relatively new technique employing an ultrasonographic contrast agent to image the lower urinary tract and detect VUR (Kis et al. 2010; Duran et al. 2012; Papadopoulou et al. 2009). Although catheterization is still necessary, this technique avoids radiation. It may be more sensitive in detecting some low-grade reflux, and it can be used to image the urethra in males. Further study of this modality is needed to determine whether there is a role for this imaging technique in detecting VUR. In addition, it would not be possible to assess the ureteral diameter ratio (UDR) with this technique.

Noninvasive Cystography Much of the controversy surrounding the diagnosis of VUR is due to the invasiveness of the VCUG, which requires catheterization. There have been numerous attempts with different agents and modalities to avoid catheterization. These include the use of radionuclide, MRI, and external bladder warming. MRI with catheterization has also been attempted (Vasanawala et al. 2009; Arthurs et al. 2011). Most MRI techniques, however, require complete sedation for infants and young children. So-called “indirect cystography” involves the intravenous injection of an agent and then imaging both bladder and kidneys in an attempt to discern the retrograde flow of urine. This has been attempted with both MRI and nuclear medicine modalities (Keir et al. 2013). Experiments with external bladder heating have been performed,

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Fig. 3 Positional Instillation Cystography (PIC): Images from a patient who had recurrent right-sided pyelonephritis and a normal VCUG. The DMSA renal scan reveals right upper pole scarring. The lower left image shows contrast

seen up the ureter during a PIC cystogram. The ureteral orifices are shown before and after Deflux injection. The episodes of right-sided pyelonephritis ceased after correction of the “occult” reflux

using sensors that detect increases in temperature of renal collecting system urine, thereby diagnosing reflux (Snow 2011). None of these methods is as accurate as the contrast cystogram and remains investigational.

atrophy, lobar nephronia, or renal abscess would indicate reflux, especially in association with urinary infection. Several studies, however, have shown that both high- and low-grade refluxes are often missed with renal ultrasound imaging (Hoberman et al. 2013, Bayrum et al. 2014, Massanyi et al. 2014, Nelson et al. 2014, Hoberman et al. 2014). Other techniques involving catheterization have been investigated, by instilling agents that are seen by sonography. Ultrasound incorporating Doppler to assess the direction of renal flow has also been attempted with limited success (Fallah et al. 2012; D’Souza et al. 2013). Since catheterization is still required using contrast agents which are seen on ultrasound, the invasiveness remains (Papadopoulou et al. 2009; Kis

Renal and Bladder Ultrasound Renal ultrasound alone has been promoted as a noninvasive, nonradiation means of diagnosing “significant” reflux, and this notion has been incorporated in recent guidelines for diagnosing and treating children (see below) (National Institute for Health and Clinical Excellence 2007; Finnell et al. 2011, Cheng et al. 2011). The renal ultrasound findings of hydronephrosis, severe renal

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The Diagnosis and Medical Management of Vesicoureteral Reflux: An. . .

et al. 2010; Duran et al. 2012). With the exception of one series, all of these methods do not perfectly correlate with the contrast VCUG and reflux would be missed (Kis et al. 2010).

The “Top Down” Approach The “top down” approach is an attempt to limit the need for cystograms to those who may have reflux that is clinically more significant, as DMSA (99m-technitium dimercaptosuccinic acid) scans will identify those who have pyelonephritis or renal scarring (Zeissman and Majd 2009; Abdelhalim and Khoury 2017). Renal ultrasound is a poor modality for detecting renal scarring, unless there is gross atrophy (Fig. 4a, b). This presumes that recurrent cystitis without pyelonephritis is not “significant” morbidity. It also presumes that reflux initially identified after an episode of cystitis will not recur in the future with renal involvement – an unsubstantiated assumption. It is also somewhat “invasive” in that an injection is required and some institutions sedate these children. Ideally, the DMSA scan must be performed either during an acute infection or at most a week or two later, since the photopenia seen during acute pyelonephritis may entirely resolve and not result in a permanent scar (Rushton et al. 1992). This poses a challenge, since many children will undergo treatment of an acute infection in a variety of outpatient settings

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and not be referred for evaluation until much later. Studies that correlate the acute DMSA findings with reflux seen on a VCUG have yielded mixed results, with individual studies showing senstivities ranging from 34% to 96% for grades III to IV reflux (Quirino et al. 2011, Shaikh et al. 2012, Zhang et al. 2012). It is poor at identifying grade I and II reflux. Meta-analyses of pooled data have showed a sensitivity ranging from 65% to 79% (Mantadakis et al. 2010). Some authors have attempted to increase the sensitivity by combining DMSA scanning with renal ultrasound, reporting negative predictive values as high as 97% for grade III to V reflux (Quirino et al. 2011; Tsai et al. 2012).

Urinary and Serum Markers Numerous urinary and serum markers have been investigated in an attempt to diagnose reflux without any imaging studies. Most, but all, need to be obtained during an episode of acute infection. They all have relatively poor sensitivity and specificity and have not been widely adopted or replaced the VCUG as the major diagnostic tool. These include serum calcitonin, urinary mRNA, serum C-Reactive protein, urinary proteomes, urinary metalloproteinases, and serum Interleukin 6 and 8 (Gokce et al. 2010; Leroy et al. 2011; Yilmaz et al. 2012; Drube et al. 2012; Sun et al. 2013; Yildiz et al. 2013; Bulut et al. 2014).

Fig. 4 (a). DMSA images of right upper pole renal scar. (b). Renal ultrasound of same right kidney, read as not having any scarring

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There have been reported increases in accuracy by combining serum procalcitonin levels with renal ultrasound or DMSA renal scan (Leroy et al. 2011; Sun et al. 2013) and by combining C-reactive protein levels with DMSA renal scans (Shaikh et al. 2012). These remain investigational and are not as sensitive as the VCUG.

Who Should Be Evaluated There are three main categories of patients who might have reflux: (1) Children who have had urinary tract infections (UTI), febrile or nonfebrile; (2) Children identified with hydronephrosis prenatally; and (3) Siblings of probands with reflux. Exactly which individuals in each category should be evaluated remains unsettled and contentious.

Children with a History of UTI The etiology of pyelonephritis in individuals with reflux is assumed to be the easy access of bacteria to renal parenchyma from the bladder via an incompetent valve. Pyelonephritis is actually more common in children without reflux, but the organisms are different. In children without reflux, the bacteria are often more virulent, with p-fimbria allowing for retrograde travel from the bladder to the kidney even though the valve is competent. The organisms which cause pyelonephritis in children with reflux are less virulent and often lack p-fimbria (Rushton et al. 1992). In addition, recurrent cystitis without ascending infection occurs, since voiding is not complete and the small numbers of organisms along with urine that is refluxing are not eliminated with each void. Uncircumcised boys and girls are more susceptible to bladder infection, since their distal urethras can be colonized. The shorter urethra in girls also contributes to bladder urine colonization (Cascio et al. 2000). Reflux has been found in 30% to 50% of all children with a documented urinary tract infection. While this prevalence is undeniable, recently controversies have arisen over the need to evaluate every child with a UTI, because

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it is felt that not all reflux is significant. In large series including children of all ages, approximately 90% of children identified with reflux after a UTI have grade I–III reflux (Greenfield et al. 1997a, b, Skoog et al. 1987). Renal scarring is the worst outcome of unrecognized reflux and is present initially in about 20% of those with grade I and II reflux but can be present in as many as 60% of those with grade III and higher. Renal scarring in the worst cases can lead to renal insufficiency and hypertension. Apart from the desire to avoid catheterization, some argue that unless there is a chance of renal scarring, reflux can be left undiagnosed. This ignores the fact, however, that bouts of recurrent cystitis have morbidity—discomfort, visits to physicians, time out of work for families and caregivers. In the United Kingdom in 2007 (National Institute for Health and Clinical Excellence or NICE) and in the United States (American Academy of Pediatrics or AAP) in 2011, guidelines were promulgated reducing the need for evaluating infants and children after a first urinary infection (National Institute for Health and Clinical Excellence 2007, Finnell et al. 2011). As noted above, these guidelines rely upon renal ultrasound to discern significant from nonsignificant reflux. Renal ultrasound, however, has been shown to be an unreliable means of diagnosing both low- and high-grade reflux. In addition, the UK recommendations take into consideration cost to the National Health Service, but ignore future costs to the NHS and to families. The Urology Section of the American Academy of Pediatrics has objected to these guideline recommendations and in a position paper continues to stress the need for a VCUG after a first UTI (Wan et al. 2012).

The American Academy of Pediatrics Guidelines These guidelines were published in 2011 and were specifically limited to the diagnosis and treatment of infants between the ages of 2 and 24 months of age who present with a first febrile UTI (Finnell

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et al. 2011). They were developed by meta-analysis of a number of recent studies of antibiotic prophylaxis in children with reflux, which will be discussed below under Treatment (Garin et al. 2006, Roussey-Kesler et al. 2008, Montini et al. 2008, Pennesi et al. 2008, Craig et al. 2009, Brandstrom et al. 2010, Brandstom et al. 2010). The guidelines committee also contacted the authors of these papers to get raw data, which had not been previously published or submitted to peer review, to bolster their conclusions. Among the recommendations in these guidelines relevant to this discussion are: (1) bagged urine specimens are inaccurate, with a specificity ranging from 14% to 84%, so infants must be catheterized if a UTI is suspected; (2) the risk of finding vesicoureteral reflux that is high grade (grades III to V) is low enough to avoid performing a VCUG unless the renal ultrasound is abnormal; (3) the Fig. 5 Action Statement 5: The AAP recommends against the use of DMSA initially, which would contradict the “Top-Down” approach advocated by some. Renal sonography is considered adequate for imaging and can be delayed if recovery is rapid. The level of evidence is C, which is not the highest (Finnell et al. 2011)

Fig. 6 Action Statement 6: A VCUG is not considered necessary, unless the ultrasound is abnormal. Note that even some would not consider the need for a VCUG if the infection recurred, although the level of evidence (“X”) is low (Finnell et al. 2011)

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finding of reflux after a first infection is not as consequential as thought in the past because the literature does not support the benefit of long-term antibiotic prophylaxis; and (4) renal ultrasound alone is sufficient to identify either high-grade reflux or other underlying anatomic abnormalities. These guidelines relating to imaging have stirred great controversy (Figs. 5 and 6). They ignore the fact that the studies they cite most often used bagged specimens to diagnose reflux (which they criticize as inaccurate), often only used renal ultrasound to assess for scarring under treatment instead of DMSA scanning, did not assess for medication adherence, relied upon diverse local radiologic interpretations of reflux grade, were not all blinded, placebo-controlled or randomized and included large numbers of uncircumcised males from countries where neonatal circumcision is not prevalent. Finally, two of these studies they cited showed a

Action Statement 5 Febrile infants should undergo renal and bladder sonography Sonography should be performed within the first 2 days of treatment, unless clinical improvement is rapid Normal pre-natal sonography does not exclude an abnormality Acute DMSA renal scanning is not recommended Evidence Quality: C: Recommendation

Action Statement 6 VCUG should not be performed after 1st febrile UTI, unless: -sonogram shows hydronephrosis or scarring Evidence Quality: B; Recommendation VCUG should be obtained if febrile UTI recurs Evidence Quality: X; Recommendation

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clear advantage to antibiotic prophylaxis. In a randomized and placebo-controlled study, Craig demonstrated that 19% of children got UTIs on placebo versus 13% on trimethoprim-sulfamethoxazole (Craig et al. 2009). The Swedish Reflux Trial was a study of children with grade III and IV reflux randomized to surveillance, prophylaxis, and endoscopic treatment (Brandstrom et al. 2010, Brandstom et al. 2010). Fifty-seven percent of those on surveillance had recurrent infection versus 19% on prophylaxis. In addition, no children on prophylaxis developed new renal scars seen on renal scan versus eight girls on surveillance.

The National Institute for Clinical Excellence (NICE) Guidelines NICE published its guidelines for the evaluation of children with UTIs in 2007 (National Institute for Health and Clinical Excellence 2007). They categorize UTIs into three subsets: typical, atypical, and recurrent. A typical UTI resolves with treatment in 48 hours. An atypical UTI does not resolve in 48 hours and might have a history of recurrent fevers of unknown origin, abdominal mass, history of prenatal hydronephrosis, palpable abdominal mass or bladder, failure to thrive,

spinal abnormality, and voiding dysfunction. For infants under 6 months of age, they would only perform a VCUG for a typical UTI if the ultrasound was abnormal. Infants with atypical or recurrent infections would be fully evaluated with a VCUG, renal USG and DMSA renal scan. For children 6 months to 3 years of age, those with typical infections would not be evaluated at all, while those with atypical or recurrent infections would undergo renal USG and DMSA renal scan. A VCUG might be performed if the infection was a non-E. Col. bacteria, or the ultrasound was abnormal, or there was a family history of reflux, or there was poor urine flow. For children older than 3 years, those with typical infections would not be evaluated at all, while those with an atypical infection would only have a renal USG performed. In an older child with recurrent infection, a renal USG and DMSA would be performed. They recommend against performing an initial VCUG for anyone older than 3 years for any category of infection (Figs. 7, 8, and 9). NICE guidelines rely heavily upon the renal ultrasound to discover “significant” reflux. As shown above, renal USG misses many children with both high- and low-grade reflux. In addition, since publication of the guidelines, a number of

Imaging for Infants < 6 Months (I: Typical--Responds by 48 hrs, II: Atypical, III: Recurrent)

Typical:

Renal USG alone, VCUG if USG is abnormal

Atypical:

Renal USG, DMSA scan, VCUG

Recurrent:

Renal USG, DMSA scan, VCUG

Fig. 7 Summary of the NICE recommendations, categorized by age and type of infection. Type I – typical (resolves in 48 hours), Type II – atypical (does not resolve in 48 hours, has a history of fevers of unknown origin, or an

abdominal mass, or history of prenatal hydronephrosis, or a palpable abdominal mass, or bladder, or has failure to thrive, a spinal abnormality or bowel and bladder dysfunction), Type III – recurrent (NICE 2007)

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The Diagnosis and Medical Management of Vesicoureteral Reflux: An. . .

Fig. 8 Summary of the NICE recommendations, categorized by age and type of infection. Type I – typical (resolves in 48 hours), Type II – atypical (does not resolve in 48 hours, has a history of fevers of unknown origin, or an abdominal mass, or history of prenatal hydronephrosis, or a palpable abdominal mass, or bladder, or has failure to thrive, a spinal abnormality or bowel and bladder dysfunction), Type III – recurrent (NICE 2007)

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Imaging for Ages 6 mos to 3 yrs (I: Typical--Responds by 48 hrs, II: Atypical, III: Recurrent)

Typical:

None

Atypical:

USG during infection

VCUG only if non-e coli UTI, Fam. Hx of VUR, abnormal USG, poor urine flow DMSA scan Recurrent:

Same as Atypical, but USG can be delayed

Imaging for Children > 3 yrs (I: Typical--Responds by 48 hrs, II: Atypical, III: Recurrent)

Typical:

None

Atypical:

USG during infection

Recurrent:

USG at any time, DMSA scan

VCUG never initially recommended in this age group

Fig. 9 Summary of the NICE recommendations, categorized by age and type of infection. Type I – typical (resolves in 48 hours), Type II – atypical (does not resolve in 48 hours, has a history of fevers of unknown origin, or an

centers have shown that following the guidelines would miss many children with reflux and scarred kidneys (Tse et al. 2009, Lytzen et al. 2011). Finally, both the NICE and AAP guidelines put a greater burden on families and caregivers to accurately identify the first infection – infants and young children in particular have febrile episodes for a variety of reasons, and the first infection diagnosed might not actually be the first. They are not able to communicate their symptoms. The same can be said for the obligation to identify a second or recurrent infection.

abdominal mass, or history of prenatal hydronephrosis, or a palpable abdominal mass, or bladder, or has failure to thrive, a spinal abnormality or bowel and bladder dysfunction), Type III – recurrent (NICE 2007)

Infants with Prenatally Detected Hydronephrosis The widespread use of prenatal ultrasound has resulted in the identification of many newborns with hydronephrosis. This hydronephrosis can be due to many congenital anomalies, including ureteropelvic obstruction, ureterovesical obstruction, posterior urethral valves in boys, duplex collecting systems with ectopic ureters, or ureteroceles and reflux. By far, however, the

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majority of infants with mild degrees renal pelvic dilatation have no significant abnormality at all (Skoog et al. 2010). Follow-up postnatal ultrasounds should be performed at least one week after birth, since the relative dehydration in newborns might result in normal kidney appearance that is grossly hydronephrotic a few weeks later. What constitutes significant renal pelvic dilatation remains unsettled. Some authors advocate evaluating all infants whose renal pelvic diameter is greater than 7 to 10 mm (Grazioli et al. 2010). The American Urologic Association (AUA) published a metaanalysis of screening studies of infants with prenatally detected hydronephrosis (Skoog et al. 2010). The incidence of reflux ranges from 9% in low-grade hydronephrosis to 25% in high-grade hydronephrosis (Skoog et al. 2010; Szymanski et al. 2012). Furthermore, up to 17% of infants with prenatal hydronephrosis, which is not seen at all after birth, will have reflux (Skoog et al. 2010). Renal scarring seen in a neonate who never had an infection is actually renal dysplasia and has been found in a mean of 6% of infants with grade I–III reflux and a mean of 48% in infants with grades IV and V. The sex distribution of prenatally identified reflux differs from that of older children, in that there are many more boys (Oliviera et al. 1998). Much of the published data were of poor quality and retrospective, and so, the AUA conclusions were relatively soft. They recommended performing a VCUG in all infants with higher grades of hydronephrosis (Society for Fetal Urology (SFU) Grades 3–4) either soon after birth or if a UTI develops on observation. They did, however, consider it a reasonable option to perform VCUGs on all infants with lower grades of reflux with or without a UTI. It was also an option to observe these infants and then perform a VCUG if a UTI occurs.

Siblings Reflux is known to have a genetic basis, which has been characterized in the past as autosomal dominant with variable penetrance. Certain gene loci have been associated with the prevalence of reflux (Kelly et al. 2009, Zu et al. 2009, Naseri et al. 2010, Marchini et al. 2011, Zhou et al. 2012; Darlow

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et al. 2017; Verbitsky et al. 2021). In addition, gene loci have been associated with increased susceptibility to breakthrough infection and scarring (Onal et al. 2012). There are numerous sibling studies showing an incidence ranging from 20% to 50% (Wan et al. 1996). Twins also have a high chance of having reflux, especially if the proband’s reflux is high grade (Giannotti et al. 2011). Renal scarring, documented with DMSA renal scans, can be found in screened asymptomatic siblings at rates ranging from 15% to 24% (Wan et al. 1996, Hunziker et al. 2012, Hunzker et al. 2014), without a history of infection. The incidence of sibling reflux declines with age, however, and it is assumed that a number of affected siblings will outgrow their undetected reflux without consequences (Menezes and Puri 2009). Many, therefore, do not suggest evaluating asymptomatic siblings who are older than 3 to 5 years. Rates of scarring are higher, up to 27%, in siblings greater than 1 year and up to 10 years (Wan et al. 1996, Menezes and Puri 2009), suggesting that early recognition may have prevented renal damage in these older siblings. Again, given the quality of the published data, the AUA guidelines panel was not able to make firm recommendations regarding sibling screening (Skoog et al. 2010). They more strongly suggested screening in a sibling who may have had a UTI or who has a smaller kidney on renal ultrasound. It was considered a reasonable option to observe siblings and not evaluate until there was a documented UTI or, conversely, to evaluate all siblings. It was optional to screen older toilet-trained children as well.

Medical Management In the earlier years of investigation, several principles were well established, and these include: sterile reflux is harmless to kidneys, reflux can be outgrown – especially the lower grades (I–III), continuous antibiotic prophylaxis over years of observation until reflux resolves is a safe and successful strategy, and antireflux surgery is not needed as long as infection is eliminated and families are compliant with a multiyear medical regimen. Goldraich and Goldraich followed children

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on long-term prophylaxis, and there was a 3% rate of new scar formation, which only occurred in association with breakthrough infection (Goldraich and Goldraich 1992). They also observed that new scars rarely occurred over the age of 4 years. Skoog followed 545 children on low-dose prophylaxis for 6 months to 10 years (Skoog et al. 1987). Thirteen percent underwent surgery for breakthrough infection, development of infection after antibiotics were stopped, and high-grade reflux persisted into early adolescence, renal insufficiency, or poor compliance. Only 3 of 545 patients developed a new scar as seen on DMSA renal scan, and 2 of those 3 had a breakthrough UTI. Additional studies in the 1980s and 1990s established that continuous prophylaxis was the equivalent of antireflux surgery in preventing infection with renal consequences. Wheeler and colleagues published a meta-analysis of studies that compared open antireflux surgery with long-term prophylaxis, and both appeared to equally diminish the risk of febrile and nonfebrile urinary infection after 5 years of follow-up (Wheeler et al. 2004).

Rates of Resolution Initial reflux grade appears to be the best guide to reflux resolution, although it is imperfect. Longterm resolution rates reported by grade are: I: 83%–92%, II: 56%–80%, III: 46%–62%, IV: 9%–33%, V: 0% (Skoog et al. 1987, Greenfield et al. 1997a, b). More recently, attempts have been made to include age at presentation, improvement seen on the first follow-up cystogram, bowel, and bladder dysfunction, elevated postvoid residuals, and gender and laterality as predictors of resolution (Greenfield et al. 1997a, b, Cannon et al. 2010, Sjostrom et al. 2010). None is precise enough to be definitive with parents, however. As an example, low-grade (I–III) reflux could resolve equally as often in older preadolescent children as in infants (Greenfield et al. 1997a, b). Families should anticipate, therefore, that if they elect long-term prophylaxis with observation, reflux may not resolve until adolescence, when somatic growth stops. Conversely, if reflux persists at that time, it is not going to spontaneously resolve. Newborns and the youngest infants with grade IV–V reflux are an

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exception, in that they have a reasonable chance of resolving their reflux, as opposed to older children – up to 45% by 2 years of age. Abnormal urodynamic patterns have been observed in infants with highgrade reflux (Sjostrom et al. 2009; Sjostrom et al. 2010). High-pressure voiding has been shown to change and resolve, perhaps explaining the higher resolution rates observed for grades IV and V in this age group. Since some studies have shown that infection and renal scarring is less common in older children, many will discontinue prophylaxis after toilet training is complete and observe for recurrent infection expectantly (Goldraich and Goldraich 1992, Herndon et al. 2001).

Bowel and Bladder Dysfunction It is now known that bowel and bladder dysfunction (BBD) can coexist in older toilet-trained children with reflux who are otherwise neurologically normal (Fig. 10). This syndrome consists in mainly of both urinary and fecal holding patterns that appear learned during toilet training. These children are constipated, have larger than normal postvoid residual urines, and void infrequently. They have been shown to have inappropriate sphincteric relaxation during voiding. It is assumed that reflux, if present, is congenital. It has been speculated, however, that since these children present when older with recurrent urinary infection that the reflux, which is mostly low grade, is secondary to this learned behavior. A normal valve might be overcome by higher than normal pressures of voiding. This remains unknown. Many children have BBD and do not reflux. BBD is much more common in girls than boys. Children with untreated BBD have higher rates of breakthrough infection while on prophylaxis, lower rates of reflux resolution, higher rates of surgical failure, and higher rates of renal scarring. Reliably assessing for BBD has been made more accurate by using validated scoring systems based upon questionnaire (DVSS) (Farhat et al. 2000). In addition, flow/EMG (electromyogram) studies in combination with postvoid residual measurement can aid in diagnosis. Evaluation of all older children with reflux by the use of diaries, the DVSS, and noninvasive urodynamics has been advocated (Karami et al. 2012).

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PATIENTS WITH CONGENITAL VUR

PATIENTS WITH BOTH

PATIENTS WITH VOIDING DYSFUNCTION

Voiding Dysfunction: Cause or Effect?

Fig. 10 Illustration of populations of children with BBD and reflux

Children with DVSS scores suggesting BBD as well as abnormal flow studies are candidates for biofeedback therapy. Biofeedback therapy, using computerized games, has been shown to hasten the reflux resolution and lower surgical correction rates. Patch electrodes are placed near the external sphincter, and children can learn to relax the sphincter during voiding with the aid of computer animation. This tends to be more successful in lower grades of reflux (I–III). Biofeedback therapy, however, is only applicable in older children who can cooperate with the therapist. Up to 3 years of therapy has been needed (Fast et al. 2013).

Antibiotic Prophylaxis-Current Controversies Discontinuing Prophylaxis As should be obvious from the previous discussion, the need for diagnosis and treatment of vesicoureteral reflux is not a settled issue. Since scarring rates are relatively low in children with

the lower grades – especially grades I and II – and some studies demonstrated that older children were less susceptible to recurrent infection with or without pyelonephritis, some suggest that treatment can be stopped at some point. The data are conflicting, and all studies are problematic. Although less common, breakthrough infection can occur in children older than 7 years (Greenfield et al. 1997a, b). A recent meta-analysis suggested that antibiotic prophylaxis offered no clear clinical benefit, calling into question the need for even diagnosing and treatment of all children with reflux in a uniform manner (Williams et al. 2009). Issues with the literature include retrospective nature, lack of placebo control, lack of randomization or blinding, failure to measure compliance with medicine taking, accepting bagged specimens from nontoilettrained infants, using renal ultrasound to assess for scarring and not radionuclide scans, relying on local radiographic interpretation of reflux grade without secondary confirmation, and sometimes failure to evaluate all entrants into a study with voiding cystograms. Subpopulations and

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methodologies vary significantly in published series of children with vesicoureteral reflux on antibiotic prophylaxis (Greenfield et al. 2016). Data from different geographic regions may also not be applicable to populations everywhere. In particular, the large numbers of uncircumcised boys in European studies result in different outcomes than the United States or other countries, where neonatal circumcision is prevalent. This is because febrile infections are more common in uncircumcised boys, whether or not they have reflux or are on or off prophylaxis. Girls far outnumber boys in all published series from the United States. Colonization of the distal urethra in uncircumcised boys leads to the diagnosis of more infections in that group as well as a higher incidence of breakthrough infection (see above). The RIVUR trial (Randomized Intervention for children with Vesicoureteral Reflux) was an attempt to overcome some of the inadequacies of the literature and will be discussed below (Carpenter et al. 2013, Hoberman et al. 2014). The problem remains that while it is known that a large number of children with reflux will not necessarily have recurrent infections or renal scarring, it is not possible to perfectly sort out the low- from high-risk populations. Thompson discontinued prophylaxis in children at an average age of 6 years. Not all children had follow-up renal scanning, but new scars were seen on scans in seven children with grade II and III reflux while off of prophylaxis (Thompson et al. 2001). Georgaki-Angelaki stopped prophylaxis in 54 children at an average age of 6 years, greater than 90% had grade III or less, and they were then followed for 4 years (Georgaki-Andelaki et al. 2005). Prior to stopping prophylaxis, none in the group had breakthrough infections for 2 years. They had urine cultures performed every month or after any fever or symptom suggesting infection and no new renal scars were seen, although there were eight infections diagnosed. Kitchens reported a retrospective series of 185 patients with reflux – 160 girls and 25 boys – in whom antibiotic prophylaxis was stopped at an average age of 6 years (Kitchens et al. 2010). The average grade of reflux was 2.4. Children were observed for an average of 2 years, but some were off of medication for 8 years. Fifty girls (31%) and five boys (20%)

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developed infection, and most were febrile. Scarring was not assessed, as DMSA scans were not performed. Most recently, a series of papers appeared in an attempt to measure the consequences of not initiating prophylaxis at all. Garin compared two groups on or off medication after initial diagnosis of grade I–III reflux after a febrile UTI in patients 3 months to 18 years of age from four centers (Garin et al. 2006). All had positive DMSA renal scans initially and were followed for one year. The numbers of patients with recurrent infection were the same in both groups, and slightly more individuals had new renal scarring in the prophylaxis group. They concluded that prophylaxis offered no advantage. Medication compliance was not assessed. The types of organisms and their sensitivities were not disclosed. The sex in those with recurrences was also not disclosed in this largely uncircumcised population, most of whom were from Spain or South America. Older teenagers were included, and they are known to have fewer infections. Nonvoiding infants were catheterized, however. Montini reported on a multicenter one-year trial from Italy, comparing prophylaxis to observation in children 2 months to 7 years of age (Montini et al. 2008). Twelve percent of children on prophylaxis had a recurrent infection versus 20% on no medication. No difference in new scars was seen using DMSA renal scanning. Bagged urine specimens were obtained from nontoilet-trained children. The study was not blinded. There were a large number of boys in this largely uncircumcised cohort – approximately 30%. The gender of those with recurrent UTIs was not disclosed. Bagged specimens are especially inaccurate in uncircumcised infants. One would also expect more breakthrough infections in this group (Cascio et al. 2000). Pennesi reported on another trial in Italian children who presented after a first pyelonephritis episode comparing antibiotics to observation for 2 years in children with grade II to IV reflux (Pennesi et al. 2008). They concluded that continuous prophylaxis was ineffective in reducing the rate of pyelonephritis recurrence. While randomized, this was not blinded. Approximately 50% were boys, and the mean age was about 9 months. DMSA scans were

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obtained. There was no difference in recurrent rates of new scar rates in either group. New scars were only seen in Grade IV patients of unknown gender and occurred more often in the treatment group. Means of urine collection were not described. Roussey-Kesler reported on a French 18-month trial of observation versus prophylaxis in children 1 month to 3 years with grade I–III reflux (Roussey-Kesler et al. 2008). Renal ultrasounds were performed to assess for scarring, not radionuclide scans. Bagged urine collections were performed from nontoilet-trained children. Approximately 30% were boys, and most were not circumcised. Recurrent infections were seen in 17% of the prophylaxis group and 26% of those on observation alone. Almost a third of the prophylaxis group with recurrence had organisms sensitive to cotrimoxazole, suggesting that they were not compliant with medication. In any case, medication adherence was not assessed. They did find, however, that boys with grade III reflux had a significant reduction in recurrent UTI. As detailed above, both the Craig study and the Swedish Reflux Trial appeared to show a significant reduction in recurrent infections and in the Swedish Trial, scarring, in a group on antibiotic prophylaxis (Craig et al. 2009; Brandstrom et al. 2010; Brandstom et al. 2010).

The RIVUR Trial The RIVUR (Randomized Intervention for children with VesicoUreteral Reflux) was an NIH-funded attempt to address some of the limitations of the previously described studies, which have been the basis of the aforementioned guidelines (Carpenter et al. 2013; Hoberman et al. 2014). Specifically, it was designed to have sufficient power to detect differences in UTI recurrence, be randomized, blinded, and placebo controlled, evaluate bowel and bladder dysfunction, rigidly define UTI, only accept catheterized urine specimens from nontoilet-trained infants, and assess the organisms of breakthrough infection and the effect of prophylaxis on stool flora. Children aged 2 to 71 months were enrolled after one or two documented febrile or nonfebrile

S. P. Greenfield

infections. The primary endpoint of the study was recurrent urinary infection. Renal scarring was a secondary endpoint, but given the low grade of reflux in the majority of subjects, the trial was not powered to answer that question. Only individuals with primary reflux were enrolled. Screening and enrollment took place from 2007 to 2011, and participants were observed to 2 years. Toilet-trained children were administered a questionnaire based upon the DVSS (Farhat et al. 2000). Constipation was also evaluated based upon the Paris Consensus on Childhood Constipation Terminology Group (Benninga et al. 2005). The index and all subsequent UTIs had to meet stringent criteria which included a urinalysis that showed pyuria, symptoms, or fever within 24 hours of urine collection and single organism. A renal ultrasound was performed at enrollment, along with a contrast VCUG and DMSA renal scans. The DMSA scans were standardized across centers and were obtained no more than 112 days after the index infection (Zeissman and Majd 2009). A DMSA renal scan was performed at 12 months and at exit at 24 months, unless there was a defined treatment failure, in which case the scan was performed earlier. A VCUG was repeated at 24 months. All renal scans, ultrasounds, and VCUGs were blindly read by two readers whose interpretations were sent to a central data center. Differences were then adjudicated for a final reading. Nineteen clinical sites enrolled 607 children (558 girls and 49 boys), 18 (63%) of whom were not circumcised. This reflects the population that commonly presents with reflux after a urinary infection in the United States and is the largest study of its kind. Median age was 12 months. The index UTI was febrile in 85% of cases. Renal scarring and pyelonephritis were found in 89 (15%). Ninety-two percent of children had grade III or less. Fiftysix of toilet-trained children had BBD, and all but two were girls. Families were contacted every 2 months to assure medication adherence, and medicine bottles were weighed. Children were randomly and blindly assigned to placebo or ™P/SMZ (trimethoprim/sulfamethoxazole). Rectal swabs were obtained for culture. The placebo was manufactured to taste and look like study

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The Diagnosis and Medical Management of Vesicoureteral Reflux: An. . .

medication. Treatment failure was defined as two febrile UTIs, one febrile and three symptomatic UTIs, four nonfebrile symptomatic recurrent UTIs, or new renal scarring seen on the 12-month DMSA renal scan. The results of the RIVUR trial were published recently (Hoberman et al. 2014). Seventy-seven percent took study medication at least 75% of the time, and there was no difference to adherence in both groups. A total of 111 children (18%) had 171 recurrences. Compared to placebo, children on ™P/SMZ had half the number of recurrent infections, and this difference widened over time (Fig. 11). If children with breakthrough infection on ™P/SMZ who had breakthrough UTIs but organisms sensitive to medication – who then presumably were not adherent and on medicine at the time – were added to the placebo group, 3 times as many infections occurred in the placebo

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group. The first recurrent infection occurred one year after enrollment in the medication group, compared to 100 days in the placebo group. This analysis also held true for those under 2 years of age during enrollment and observation, which was the age group targeted by AAP guidelines (Fig. 12). Treatment failures were twice as common in the placebo group. Children with grade III or VI reflux had more recurrences, and hazard ratios were more pronounced for those who had BBD as baseline or whose index UTI was febrile. Hazard ratios consistently favored those on prophylaxis regardless of age at entry, gender, degree of presenting reflux, resistance of index UTI pathogen, or whether or not at 2 years the reflux improved, resolved, or stayed the same. Stool colonization with resistant E. coli was greater in the treatment group, but the difference was not significant. Isolates of those on study medication

Fig. 11 Graph showing that those on placebo had more UTIs than those on TMP/SMZ, and the difference increased over the 2 years of the study (From Hoberman, Greenfield et al., NEJM 2014; DOI: 10.1056/NEJMoa1401811)

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S. P. Greenfield

Fig. 12 Graph showing the increase of recurrent UTIs in those on placebo versus TMP/SMZ in children under age 2 years at diagnosis. The differences increased over the

2 years of the study and were even greater for low-grade (I and II) reflux (From Hoberman, Greenfield et al., NEJM 2014; DOI: 10.1056/NEJMoa1401811)

with breakthrough UTI had more resistance (63% vs. 19%) to ™P/SMZ, and this was to be expected. There was no difference in overall scarring, severe renal scarring, or new renal scarring between both groups. Possible reasons for this include the fact that the vast majority had low-grade reflux, children were enrolled after their first or second UTI, parents and study coordinators were instructed to be vigilant and sought early medical attention for infection, and a 2-year follow-up is relatively short. In addition, as mentioned above, given rates of scarring known to exist in the grades of the majority of patients in RIVUR, the trial was not sufficiently powered to show significant differences. The data from the RIVUR study suggest that in the cohort recruited, long-term prophylaxis is beneficial in significantly reducing recurrent infections in children with reflux. It also suggests that

the diagnosis of reflux is warranted after a first or second infection. Subgroup analysis was not possible, given the small numbers of boys and the relatively small number in each grade with or without BBD. The RIVUR study, therefore, does not allow for a more exact assignment of risk, which might enable clinicians to target therapy to the subset who are at risk for UTI recurrence with or without renal scarring. It is hoped that additional research with genetic and serum markers might prove helpful in that regard.

Conclusion and Future Directions Depending upon one’s vantage point, the recognition and treatment of vesicoureteral reflux have been a major success story or a tale of overdiagnosis and overtreatment. In the United States, the

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The Diagnosis and Medical Management of Vesicoureteral Reflux: An. . .

numbers of children with reflux-related renal insufficiency or hypertension are a smaller number than in past (Vallee et al. 1999). As often happens, the medical community begins to question the validity of more aggressive diagnosis and treatment, when it appears that not all might benefit. At this juncture, however, it is not entirely possible to predict those at risk of recurrent infection, especially those with low- and intermediategrade reflux (I–III) who are the vast majority. Certainly, most are not at risk, but who are they? There is no one correct answer, but it is clear that philosophies of treatment and the cultural ethos of different societies in widely disparate geographic locations inform and influence the answer to these questions. The RIVUR trial confirms that prophylaxis is effective in reducing infections and their associated morbidities. This reduction in frequency should theoretically diminish the possibility of renal damage over the long term in certain individuals. That data may not be uniformly interpreted, however, leaving diagnosis and treatment up to both the physician and family.

Cross-reference ▶ Evaluation and Management of Urinary Tract Infections in Children

References Abdelhalim A, Khoury AE. Critical appraisal of the top-down approach for vesicoureteral reflux. Investig Clin Urol. 2017;58(Suppl 1):S14–22. Arlen AM, Kirsch AJ, Leong T, Cooper CS. Validation of the ureteral diameter ratio for predicting early spontaneous resolution of primary vesicoureteral reflux. J Pediatr Urol 2017;13:383.e1. Arthurs OJ, Edwards AD, et al. Intractive magnetic resonance voiding cystourethrography (iMRVC) for vesicoureteric reflux (VUR) in unsedated infants: a feasibility study. Eur Radiol. 2011;21:1874–81. Bayrum MT, Kavukcu S, et al. Place of ultrasonography in predicting vesicoureteral reflux in patients with mild renal scarring. Urol. 2014;83:904–8. Benninga M, Candy DC, et al. The Paris consensus on childhood constipation terminology (PACCT) group. J Pediatr Gastroeneterol Nutr. 2005;40:273–5.

295

Boubnova J, Sergent-Alaoui A, et al. Evolution and prognosis value of intrarenal reflux. J Ped Urol. 2010;7:638–43. Brandstom P, Neveus T, et al. The Swedish reflux trial in childreh: IV. Renal Damage. J Urol. 2010;184:292–7. Brandstrom P, Esbjorner E, et al. The Swedish reflux trial in children: III. Urinary tract infection pattern. J Urol. 2010;184:286–91. Bulut IK, Mir S, et al. The predictive value of urinary UPIb mRNA levels in VUR and recurrent urinary tract infections. Clin Nephrol. 2014;81:152–8. Cannon GM, Arahna AA, et al. Improvement in vesicoureteral reflux grade on serial imaging predicts resolution. J Urol. 2010;183:709–13. Carpenter MA, Hoberman A, et al. The RIVUR trial: profile and baseline clinical associations of children with vesicoureteral reflux. Pediatrics. 2013;132:e34–45. Cascio S, Colhoun E, Puri P. Bacterial colonization of the prepuce in boys with vesicoureteral reflux who receive antibiotic prophylaxis. J Peds. 2000;139:160–2. Cheng CH, Hang JF, et al. Nephromegaly is a significant risk factor for renal scarring in children with first febrile urinary tract infections. J Urol. 2011;186:2353–5849. Cooper CS, Birusingh KK, Austin JC, et al. Distal ureteral diameter measurement objectively predicts vesicoureteral reflux outcome. J Pediatr Urol 2013;9:99. Cooper CS, Alexander SE, Kieran K, Storm DW. Utility of the distal ureteral diameter on VCUG for grading VUR. J Pediatr Urol 2015;11:183.e1. Craig J, Simpson JM, et al. Antibiotic prophylaxis and recurrent urinary tract infection. NEJM. 2009;361: 1748–59. D’Souza MK, Verma NS, et al. Detecting reflux: does ureteric jet doppler waveform have a role? Pediatr Nephro. 2013;28:1821–6. Darlow JM, Darlay R, Dobson MG, Stewart A, Charoen P, Southgate J, Baker SC, Xu Y, Hunziker M, Lambert HJ, Green AJ, Santibanez-Koref M, Sayer JA, Goodship THJ, Puri P, Woolf AS, Kenda RB, Barton DE, Cordell H. Genome-wide linkage and association study implicates the 10q26 region as a major genetic contributor to primary nonsyndromic vesicoureteric reflux. J Sci Rep. 2017;7(1):14595. Drube J, Schiffer E, et al. Urinary proteome analysis to exclude severe vesicoureteral reflux. Pediatrics. 2012;129:e356–63. Duran C, del Riego J, Riera L, et al. Voiding urosonography including urethrosonography: high-quality examinations with an optimised procedure using a second-generation US contrast agent. Pediatr Radiol. 2012;42:660–7. Elder JS, Longnecker R. Premedication with oral midazolam for voiding cystourethrogram in children: safety and efficacy. Am J Rad. 1995;164:1229–32. Fallah MM, Falahati M, et al. Comparative study of color doppler voiding urosonagraphy without contrast enhancement and direct radionuclide voiding cystography for diagnosis of vesicoureteric reflux in children. J Ultrasound Med. 2012;31:55–61.

296 Farhat W, Bagli DJ, et al. The dysfunctional voiding scoring system: quantitative standardization of dysfunctional voiding symptoms in children. J Urol. 2000;164:1011–5. Fast AM, Nees SN, et al. Outcomes of targeted treatment for vesicoureteral reflux in children with nonneurogenic lower urinary tract dysfunction. J Urol. 2013;190:1028–33. Finnell SME, Carroll AE, et al. Diagnosis and management of an initial UTI in febrile infants and young children. Pediatrics. 2011;128. www.pediatrics.org/cgi/doi/10. 1542/peds.2011-1332 Frimberger D, Mercado-Deane MG. Establishing a Standard Protocol for the Voiding Cystourethrography. Pediatrics. 2016;138(5):e20162590. Garin EH, Olavarria F, et al. Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study. Pediatrics. 2006;117: 626–32. Georgaki-Andelaki H, Kostaridou S, et al. Long-term follow-up of children with vesicoureteral reflux with and without antibiotic prophylaxis. Scan J Inf Dis. 2005;37:842–5. Giannotti G, Menezes M, et al. Sibling vesicoureteral reflux in twins. Pediatr Surg Int. 2011;27:513–5. Giramonti KM, Fox JK, et al. Is parental anxiety and coping associated with girls’ distress during a VCUG? Preliminary findings. J Ped Urol. 2012;8:405–9. Gokce I, Alpay H, et al. Urinary levels of inteleukin-6 and interleukin-8 in patients with vesicoureteral reflux and renal parenchymal scar. Pediatr Nephrol. 2010;25: 905–12. Goldraich NP, Goldraich IH. Follow up of conservatively treated children with high and low grade reflux: a prosepctive study. J Urol. 1992;148:1688. Grazioli S, Parvex P, et al. Antenatal and postnatal ultrasound in the evaluation of the risk of vesicoureteral reflux. Pediatr Nephrol. 2010;25:1687–92. Greenfield SP, Ng M, Wan J. Resolution rates of low grade vesicoureteral reflux stratified by patient age at presentation. J Urol. 1997a;157:1410. Greenfield SP, Ng M, Wan J. Experience with vesicoureteral reflux in children: clinical charactertistics. J Urol. 1997b;158:574. Greenfield SP, Carpenter MA, et al. The RIVUR voiding cystourethrogram pilot study: experience with radiologic reading concordance. J Urol. 2012;188: 1608–128. Greenfield SP, Cheng E, DeFoor W, Kropp B, Rushton HG, Skoog S, Carpenter M. Vesicoureteral Reflux and Antibiotic Prophylaxis: Why Cohorts and Methodologies Matter. J Urol. 2016;196(4):1238–43. Herndon CDA, Ferrer F, McKenna P. Survey results on medical and surgical follow up of patients with vesicoureteral reflux from American Association of Pediatrics, Section on Urology members. J Urol. 2001;165:559.

S. P. Greenfield Hoberman A, Charron M, et al. Imaging studies after a first febrile urinary tract infection in young children. NEJM. 2013;348:195–202. Hoberman A, Greenfield SP, et al. Antimicrobial prophylaxis for children with vesicoureteral reflux. NEJM. 2014;370 https://doi.org/10.1056/NEJMoal401811. Hunziker M, Puri P, et al. Familial vesicoureteral reflux and reflux related morbidity in relatives of index patients with high grade vesicorureteral reflux. J Urol. 2012;188:1463–6. Hunzker M, Colhoun E, et al. Renal cortical abnormalities in siblings of index patients with vesicorureteral reflux. Pediatrics. 2014;133:e933–7. Karami H, Razi A, et al. Is there a role for urodynamic study in children with high grade vesicoureteral reflux? Urology. 2012;79:888–91. Keir MJ, Lambert HJ, Coultard MG. Maximizing the sensitivity of the indirect radionuclide cystogram: a retrospective audit. Pediatr Nephrol. 2013;28:2137–41. Kelly H, Barton D, et al. Linkage analysis of candidate genes in families with vesicoureteral reflux. J Urol. 2009;182:1669–72. Kis E, Nyitrai A, Várkonyi I, et al. Voiding urosonography with second-generation contrast agent versus voiding cystourethrography. Pediatr Nephrol. 2010;25: 2289–93. Kitchens DM, Herndon A, Joseph DB. Outcome after discontinuing prophylactic antibiotics in children with persistent vesicoureteral reflux. J Urol. 2010;184: 1594–7. Leroy S, Boiussou F, et al. Prediction of high grade vesicoureteral reflux after pediatric urinary tract infection: external validation study of procalcitonin-based decision rule. PLoS One. 2011;6:e29556. Lytzen R, Thorup J, Cortes D. Experience with the NICE guidelines for imaging studies in children with first pyelonnephritis. Eur J Pediatr Surg. 2011;21:283–6. Mantadakis E, Vouloumanou EK, et al. Acute Tc-99m DMSA scan for identifying dilating vesicoureteral reflux in children: a meta-analysis. Pediatrics. 2010;128:e169–79. Marchini GS, Onal B, et al. Genome gender diversity in affected sib-pairs with familial vesico-ureteric reflux identified by single nucleotide polymorphism linkage analysis. BJU Inter. 2011;109:1709–14. Massanyi EZ, Preece J, et al. Utility of screening ultrasound after first febrile UTI among patients with clinically significant vesicoureteral reflux. Urol. 2014;82: 905–9. Matsumoto F, Shimada K, et al. Positioning the instillation of contrast at the ureteral orifice cystography can be useful to predict postoperative contralateral reflux in children with unilateral reflux. Int J Urol. 2011;18:80–2. Menezes M, Puri P. Familial vesicoureteral reflux--is screening beneficial? J Urol 2009; 182:1673–1677. Metcalf CB, MacNeilly AE, et al. Reliability assessment of international grading system for vesicoureteral reflux. J Urol. 2012;188:1490–2.

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The Diagnosis and Medical Management of Vesicoureteral Reflux: An. . .

Montini G, Rigon L, et al. Prophylaxis after first febrile urinary tract infection in children? A multicenter, randomized controlled, noninferiority trial. Pediatrics. 2008;122:1064–71. Naseri M, Ghiggeri GM, et al. Five cases of severe vesicoureteric reflux in a family with an X-linked compatible trait. Pediatr Nephrol. 2010;25:349–52. National Institute for health and clinical excellence: urinary tract infection in children. NICE 2007.; http://guidance. nice.org.uk/CG054 Nelson CP, Johnson EK, et al. Ultrasound as a screening test for genitourinary anomalies with UTI. Pediatrics. 2014;133:394–403. Oliviera EA, Diniz JSS, et al. Features of primary vesicoureteric reflux detected by investigation of foetal hydronephrosis. Int Urol Nephrol. 1998;30:535. Onal B, Miao X, et al. Protective locus against renal scarring on chromosome 11 in affected sib pairs with familial vesicoureteral reflux identified by single nucleotide polymorphism linkage analysis. J Urol. 2012;188:1467–73. Palmer BW, Faridali GR et al., Voiding cystourethrograms-are our protocols the same? J Urol 2011; 186: 1668–1671. Papadopoulou F, Anthopoulou A, Siomou E, et al. Harmonic voiding urosonography with a second-generation contrast agent for the diagnosis of vesicoureteral reflux. Pediatr Radiol. 2009;39:239–44. Pennesi M, Travan L, et al. Is antibiotic prophylaxis in children with vesicoureteral reflux effective in preventing pyelonephritis and renal scars? A randomized, controlled trial. Pediatrics. 2008;121:e1489–94. Quirino IG, Silva MP, et al. Combined use of late phase dimercaptosuccinic acid renal scintigraphy and ultrasound as first line screening after a urinary tract infection in children. J Urol. 2011;185:258–63. Roussey-Kesler G, Gadjos V, et al. Antibiotic prophylaxis for prevention of recurrent urinary tract infection in children with low grade vesicoureteral reflux: results from a prospective randomized study. J Urol. 2008;179:674–9. Rubenstein JN, Maizels M, et al. The PIC cystogram: a novel approach to identify “occult” vesicoureteral reflux in children with febrile urinary tract infections. J Urol. 2003;169:2339–43. Rushton HG, Majd M, et al. Renal scarring following reflux and non-reflux pyelonephritis in children: evaluation with technetium-dimercaptosuccinic acid scintigraphy. J Urol. 1992;147:1327. Sandy NS, Nguyen HT, et al. Assessment of parental satisfaction in children undergoing voiding cystourethrography without sedation. J Urol. 2011;185:658–62. Shaikh N, Hoberman A, et al. Identifying children with vesicoureteral reflux: a comparison of 2 approaches. J Urol. 2012;188:1895–9. Sjostrom S, Bachelard M, et al. Change of urodynamic patterns in infants with dilating vesicoureteral reflux: 3-year followup. J Urol. 2009;182:2446–54. Sjostrom S, Sillen U, et al. Predictive factors for resolution of congenital high grade vesicoureteral reflux in

297

infants: results of univariate and multivariate analyses. J Urol. 2010;183:1177–84. Skoog SJ, Belman AB, Majd M. A non-surgical approach to the management of primary vesicoureteral reflux. J Urol. 1987;138:941. Skoog SJ, Peters CA, et al. Pediatric vesicoureteral reflux guidelines panel summary report: clinical practice guidelines for screening siblings of children with vesicoureteral reflux and neonates/infants with prenatal hydronephrosis. J Urol. 2010;184:1145–51. Snow BW. New non-invasive methods to diagnose vesicoureteral reflux. Curr Op in Urol. 2011;21: 339–42. Sun HL, Wu KH, et al. Role of procalcitonin in predicting dilating vesicoureteral reflux in young children hospitalized with a first febrile urinary infection. Ped Inf Dis J. 2013;32:e 348-54. Szymanski KM, Al-Said AN, et al. Do infants with mild prenatal hydronephrosis benefit from screening for vesicoureteral reflux? J Urol. 2012;188:576–81. Tamminen-Mobius BE, et al. Cessation of vesicoreteral reflux for 5 years in infants and children allocated to medical treatment. The international reflux study in children. J Urol. 1992;148(1662) Thompson RH, Chen JJ, et al. Cessation of prophylactic antibiotics in older children with vesicoureteral reflux. J Urol. 2001;166:1465. Tsai JD, Huang CT, et al. Screening high grade vesicoureteral reflux in young infants with a febrile urinary tract infection. Pediatr Nephrol. 2012;27: 955–63. Tse NK, Yuen SL, et al. Imaging studies for the first urinary tract infection in infants less than 6 months old: can they be more selective? Pediatr Nephrol. 2009;24: 1699–703. Vallee JP, Vallee MP, et al. Contemporary incidence of mobidity related to vesicoureteral reflux. Urology. 1999;53:812. Vasanawala SS, Kennedy WA, et al. MR voiding cystography for evaluation of vesicoureteral reflux. Am J Rad. 2009;192:W206–11. Verbitsky M, Krithivasan P, Batourina E, et al. Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux. Am Soc Nephrol. 2021;32(4): 805–20. Wan J, Greenfield SP, et al. Sibling reflux: a dual center retrospective study. J Urol. 1996;156:677. Wan J, Skoog S, et al. On behalf of the Executive Committee, Section on Urology, American Academy of Pediatrics: Section on Urology response to new guidelines for diagnosis and management of UTI. Pediatrics. 2012;129:e1051–3. URL: www.pediatrics.org/ cgi/doi/10.1542/peds. 2011-3615 Wheeler D, Vimalachandra D, et al. Interventions for primary vesicoureteral reflux. Cochrane Database Syst Rev. 2004;3:CD001532. Williams G, Wei L, et al. Long term antibiotics for preventing recurrent urinary tract infection in children

298 (review) the Cochrane collaboration in the Cochrane library. Norfolk: John Wiley & Sons, Ltd; 2009. p. 1–28. Yildiz B, Poyraz N, et al. High sensitive C-reactive protein: a new marker for urinary tract infection, VUR and renal scar. Eur Rev Med Pharmacol Sci. 2013:2598–604. Yilmaz A, Bilge I, et al. Matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in vesicoureteral reflux. Pediatr Nephrol. 2012;27:435–41. Zeissman HA, Majd M. Importance of methodology on 99m-technetium dimercaptosuccinic acid image quality: imaging pilot study for RIVUR (randomized

S. P. Greenfield intervention for children with vesicoureteral reflux) multicenter investigation. J Urol. 2009;182:272–9. Zhang X, Xu H, et al. Accuracy of early DMSA scan for VUR in young children with febrile UTI. Pediatrics. 2012;133:e30–8. Zhou TB, Lin N, et al. Association of ACE I/D gene polymorphism with vesicoureteral reflux susceptibility in children: a meta-analysis. J Ren Angio Aldo Syst. 2012;13:273–81. Zu S, Bartik Z, et al. Mutations in the ROBO2 and SLIT2 genes are rare causes of familial vesico-ureteral reflux. Pediatr Nephrol. 2009;24:1501–8.

Endoscopic Treatment of Vesicoureteral Reflux

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Florian Friedmacher and Prem Puri

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 Instruments, Equipment, and Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 Operative Setup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 Injection Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 STING Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 Ureteric Hydrodistention and Intraluminal Submucosal Injection . . . . . . . . . . . . . . . . . . . . . 302 Postoperative Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 Complications and Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 Persistent or Recurrent Reflux . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304 Obstruction of the Ureterovesical Junction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305

Abstract

Vesicoureteral reflux (VUR) is one of the most common urological abnormalities, affecting 1–2% of the pediatric population and 25–40%

F. Friedmacher Department of Pediatric Surgery and Pediatric Urology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany P. Puri (*) Beacon Hospital, University College Dublin, Dublin, Ireland

of children presenting with urinary tract infection (UTI). The association of VUR, UTI, and renal parenchymal damage is widely recognized. Therefore, timely intervention is essential to prevent recurrent urinary tract infections and reduce the risk of permanent renal parenchymal damage and to minimize sequelae of reflux nephropathy. Since its first clinical application in the early 1980s and the approval of dextranomer/hyaluronic acid (Deflux®) by the US Food and Drug Administration (FDA) in 2001 as an acceptable tissue augmenting substance for subureteral injection, endoscopic

© Springer-Verlag GmbH Germany, part of Springer Nature 2023 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43567-0_179

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treatment of VUR has gained worldwide popularity and is currently the first-line therapy for many infants and children with primary reflux. Over the years, multiple studies have demonstrated safety and long-term efficacy of this minimally invasive outpatient procedure, which has success rates of 77–83% after the first injection and can easily be repeated in cases of failure, with a high rate of subsequent resolution. Ureterovesical junction obstruction after endoscopic correction of VUR has been reported in less than 1% of treated cases and appears to be independent of the tissue augmenting substance, volume, and injection technique. Keywords

Vesicoureteral reflux · Urinary tract infections · Reflux nephropathy · Ureter · Cystography · Endoscopic treatment · Dextranomerhyaluronic acid copolymer · Vantris

Introduction Vesicoureteral reflux (VUR), the retrograde flow of urine from the bladder into the ureter and collecting system of the kidney, is one of the most common urinary tract abnormalities, affecting approximately 1–2% of the pediatric population, 25–40% of children presenting with urinary tract infection (UTI), and over 40% of neonates with prenatally detected hydronephrosis or other renal anomalies (Sargent 2000; Williams et al. 2008; Zerin et al. 1993). The hereditary and familial nature of VUR is well recognized with an estimated prevalence of 27.4% in screened siblings and 35.7% in offspring of index patients (Puri et al. 2011; Hunziker and Puri 2012; Skoog et al. 2010). The association of VUR, UTI, and renal parenchymal damage is also well established (Brandström et al. 2010a; Peters and Rushton 2010). In fact, up to 89% of patients with high-grade reflux are at risk of renal scarring after the first UTI, which can lead to substantial morbidity (Swerkersson et al. 2007). Despite early diagnosis and prompt treatment of VUR,

F. Friedmacher and P. Puri

reflux nephropathy remains a major cause of childhood hypertension, growth impairment, and end-stage renal disease (Diamond and Mattoo 2012). Therefore, timely intervention is essential in infants and children with VUR in order to reduce the risk of permanent renal injury and to minimize sequelae of reflux nephropathy. A number of prospective studies have shown that spontaneous resolution of reflux is much less likely in patients with high-grade reflux, presence of renal scarring, or bladder dysfunction, irrespective of observation length (Knudson et al. 2007; Sjöström et al. 2010). Furthermore, the success of antibacterial treatment for VUR is largely dependent on patient compliance and involves the risk of antibiotic-resistant uropathogens, accompanied by potential breakthrough UTIs (Cara-Fuentes et al. 2015). A meta-analysis including 17,972 children with primary reflux has demonstrated a lack of efficacy for continuous antibiotic prophylaxis (CAP) in terms of decreasing the incidence of UTIs and renal parenchymal damage (Peters et al. 2010). Various anti-reflux procedures have been described for the surgical correction of VUR. Ureteral reimplantation (i.e., open, laparoscopic, or robotic-assisted operations) has a high success rate (Hayn et al. 2008; Peters et al. 2010; Tekgül et al. 2012), but these remain invasive procedures that usually require 2–3 days inpatient hospitalization and temporary urinary catheter drainage. The introduction of endoscopic treatment of vesicoureteral reflux was a radical departure from the standard surgical intervention and observational management of VUR (Puri and O'Donnell 1984; O'Donnell and Puri 1984; Puri 1990). Since the US Food and Drug Administration (FDA) approval of dextranomer/hyaluronic acid (Deflux ®) as a biocompatible tissue augmenting substance for submucosal injection into the refluxing ureteric orifice in 2001, endoscopic treatment of VUR has gained worldwide popularity and is today an integral part of the American Urological Association guidelines (Peters et al. 2010) and also the European Association of Urology guidelines (Tekgül et al. 2012) for the management of primary reflux in children.

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Indications and Contraindications

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The indications for endoscopic treatment of VUR are the same as for open, laparoscopic, or roboticassisted anti-reflux surgery. These include highgrade VUR, breakthrough UTIs on CAP, noncompliance with CAP, and new renal scarring. In addition to primary reflux, endoscopic injection therapy has been used successfully to treat VUR in duplex renal systems, VUR secondary to neuropathic bladder or posterior urethral valves, VUR in failed reimplanted ureters, and VUR in refluxing ureteral stumps.

injection (STORZ) is a 4F catheter onto which is swaged a 21-gauge needle that protrudes approximately 1 cm from the catheter (Fig. 1). Alternatively, a semirigid, metal needle can be used. Since the first description of endoscopic treatment of VUR in the early 1980s, various tissue augmenting substances have been tested (Table 1), but currently only Deflux® is approved by the FDA. Copolymer Deflux®, the most commonly used bulking agent today, is a viscous gel consisting of 80–250 μm dextranomer microspheres (50 mg/mL) in a stabilized hyaluronic acid carrier solution of nonanimal origin (15 mg/mL), which is available in 1-mL prefilled syringes that can be attached to any type of injection catheter.

Contraindications

Operative Setup

The only accepted contraindications for endoscopic correction of VUR are obstructive refluxing megaureters and bladder diverticula greater than 10–15 mm.

Endoscopic correction of VUR is performed under general anesthesia with the patient placed in lithotomy position toward the end of the operating table. After insertion into the urethra, the cystoscope is slowly advanced to allow detailed inspection of bladder wall, trigone, bladder neck, and both ureteric orifices. The bladder should be almost empty before proceeding with the injection, since this helps to keep the refluxing orifice flat rather than away in a lateral part of the field. The injection should not begin until the operator has a clear view all around the affected orifice.

Indications

Instruments, Equipment, and Materials All common pediatric cystoscopes, straight or angled working channel, can be used for this procedure. The disposable Puri flexible catheter for

Fig. 1 Cystoscopy is performed with standard pediatric cystoscopes with a straight or angled working channel. Note the disposable Puri catheter introduced through the cystoscope and ready for the endoscopic subureteral injection

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Table 1 Bulking agents that have been used for endoscopic treatment of VUR in infants and children Bulking agent Autologous chondrocytes, fat or heparinized blood Bovine-based collagen, cross-linked with glutaraldehyde (Contigen ®, Zyplast ®) Calcium hydroxylapatite (Coaptite ®) Dextranomer/hyaluronic acid (Deflux ®) Polyacrylamide hydrogel (Bulkamid ®) Polyacrylate-polyalcohol copolymer (Vantris ®) Polydimethylsiloxane elastomer (Macroplastique ®) Polytetrafluoroethylene (Teflon ®) Pyrolytic carbon-coated zirconium oxide beads (Durasphere ®)

Injection Techniques Over the years, several injection techniques have been described for the endoscopic treatment of VUR including subureteric transurethral injection (STING) (O'Donnell and Puri 1984; Puri 1990 ), intraureteric hydrodistention implantation technique (HIT) (Kirsch et al. 2004), combined HIT/STING, and double HIT (i.e., proximal and distal intraluminal submucosal injections) (Kirsch and Arlen 2014):

Manufacturer C. R. Bard, Inc. (Murray Hill, USA), Collagen Corporation (Palo Alto, USA) Merz Aesthetics, Inc. (Franksville, USA) Q-Med AB (Uppsala, Sweden) Contura, Inc. (Soeborg, Denmark) Promedon (Córdoba, Argentina) Uroplasty, Inc. (Geleen, the Netherlands) DuPont (Wilmington, USA) Carbon Medical Technologies, Inc. (St. Paul, USA)

administration to minimize extrusion of the injected product. Depending on the bulking agent, most refluxing ureters require not more than 0.4–1.0 mL to correct VUR with this technique. In general, a correctly placed injection creates the appearance of a nipple, on top of which sits a slitlike or inverted crescentic orifice (Fig. 2d). If the bulge appears in an incorrect place, e.g., at the side of the ureter or proximal to it, the needle should not be withdrawn. Instead, it should be moved so that the point is in a more favorable position. The non-injected ureteric roof usually retains its compliance while preventing reflux.

STING Procedure The needle is introduced 2–3 mm below the refluxing orifice at the 6 o’clock position into the bladder mucosa and advanced for approximately 4–5 mm into the submucosal portion of the distal ureter (Fig. 2a). However, in children with grade IV and V reflux with a wide ureteric orifice, the needle should be inserted directly into the affected orifice to increase the length of the intravesical ureter. It is important to introduce the needle with pinpoint accuracy before starting the injection as any perforation of the mucosa or the ureter may allow the injected material to escape, which may result in failure. As the tissue augmenting substance is administrated, a bulge slowly starts to appear at the floor of the submucosal ureter (Fig. 2b). While the injection is in progress, the needle is gradually withdrawn until a “volcanic” bulge of implant is seen (Fig. 2c). It is recommended that the needle is kept in position for 30 seconds after

Ureteric Hydrodistention and Intraluminal Submucosal Injection For the HIT, the bladder is semi-filled to allow for good visualization of the affected orifice and to avoid tension within the submucosal layer of the ureter secondary to overdistension. Hydrodistention of the refluxing orifice is initiated to define the injection site within the ureteric tunnel. The needle is inserted approximately 4 mm into the submucosa of the intramural ureter at the 6 o’clock position. At this point, irrigation should be stopped while the tissue augmenting substance is injected. Again, only a small volume of 0.5–1.0 mL is needed to create a sufficient bolus, and the ureteric tunnel should coapt with the injection. The cystoscope is then pulled back toward the bladder neck to visualize the full implantation. After the injection, the needle should also be kept in position for 15–30 seconds to avoid extrusion of the implant. At end of

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Fig. 2 (a) Endoscopic appearance of a refluxing orifice with grade V VUR, with the needle introduced 2–3 mm below the refluxing orifice at the 6 o’clock position into the bladder mucosa. (b) As the tissue augmenting substance is administrated, a bulge slowly starts to appear at the floor of the submucosal ureter. (c) During the administration, the needle is slowly withdrawn until a “volcanic” bulge of implant is seen. (d) A correctly placed injection creates the appearance of a nipple, on top of which sits a slit-like or inverted crescentic orifice

the procedure, the affected orifice should no longer hydrodistend, indicating complete coaptation of both the ureteric tunnel and orifice. If the latter does not completely coapt with a single intraureteric injection, a second more proximal injection (i.e., double HIT) may be contemplated, or a subureteric implantation (i.e., combined HIT/STING) can be performed. Although multivariate analyses have failed to demonstrate a significant difference in outcomes between the STING procedure and HIT (Routh et al. 2007; Watters et al. 2013; Yucel et al. 2007), a more recent meta-analysis showed that the overall resolution of VUR with the STING technique was 71.4%, whereas it was 82.5% with the HIT (Yap et al. 2016). However, a large series from Russia including 4.898 ureters identified a significantly higher incidence of postoperative obstruction of the ureterovesical junction when comparing HIT (1.6%) to STING procedure (0.5%) (Baybikov et al. 2015).

prophylaxis should be continued until voiding cystourethrogram (VCUG), and renal ultrasonography is performed 3 months after the procedure. Antibiotics can be stopped if the VCUG demonstrated resolution of reflux (Fig. 3). Nevertheless, a patient should be considered for further endoscopic treatment if VUR has not resolved. In general, it is recommended that following successful endoscopic correction of VUR, renal and bladder ultrasound is repeated at 1 year and thereafter in 2-year intervals to monitor the appearance of the urinary tract as well as the site and size of the injected implant. Traditionally, postoperative VCUG following endoscopic injection for VUR was recommended (Puri et al. 2012; Friedmacher and Puri 2019). Currently, many centers, due to the concern of high ionizing radiation and traumatic experience for the child during VCUG, recommend an ultrasound 2–3 months after endoscopic correction of VUR and stop antibiotic prophylaxis. The VCUG is performed only in high-risk patients or after recurrent febrile UTIs.

Postoperative Care Complications and Outcomes Postoperative urinary catheterization is not necessary, and patients are usually able to void without any problems after recovery from general anesthesia. The vast majority of infants and children with VUR can be treated as day cases. Antibiotic

If performed correctly, endoscopic treatment of VUR is a safe procedure, and postoperative complications are rare (Hsieh et al. 2010a; Läckgren et al. 2001; Puri et al. 2012; Friedmacher and Puri 2019).

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Fig. 3 (a) VCUG showing bilateral grade V reflux before endoscopic treatment of VUR. (b) VCUG in the same child demonstrating eradication of reflux 3 months after the procedure

Persistent or Recurrent Reflux The only significant problem with endoscopic correction of VUR has been failure in some patients and who needed a repeat injection.. A meta-analysis including 5,527 patients with VUR calculated resolution rates of 78.5% for grades I and II, 72% for grade III, 63% for grade IV, and 51% for grade V after endoscopic therapy with an aggregate success rate of 85% following one or more injections (Elder et al. 2006). Another review of 47 articles reported similar results (Routh et al. 2010a). Furthermore, the Swedish reflux trial revealed that outcomes following endoscopic treatment were significantly better than the spontaneous resolution rate or downgrading in the prophylaxis and surveillance groups, but recurrent VUR was seen in 20% after 2 years (Holmdahl et al. 2010). More recently, a single-center study of 1,551 children with intermediate and high-grade reflux that underwent endoscopic Deflux ® injection demonstrated that VUR persisted in less than 13% of cases and was subsequently eradicated following a second or third injection (Puri et al. 2012). These

findings suggest that results can be improved by simply repeating the procedure, thus being as effective as ureteral reimplantation as shown by a randomized clinical trial (García-Aparicio et al. 2013a). However, a higher incidence of recurrent febrile UTIs has frequently been noted in girls than in boys after successful reflux correction (Brandström et al. 2010b). Hunziker et al. (2012) conducted a long-term follow-up of incidence of febrile urinary tract infections in 1271 children after successful endoscopic correction of VUR. The authors found that 5.7% of children developed febrile UTIs after correction of VUR and predominantly were girls, the majority of whom had bladder bowel dysfunction. The success rate of endoscopic treatment is significantly lower for complete duplicated ureters (68%) (Hunziker et al. 2013) and for neuropathic bladder (62%) (Elder et al. 2006). The results depend on the grade of VUR, with lower efficiency in grade V and bilateral VUR cases (Elder et al. 2006; Routh et al. 2007). Recently, Friedmacher and Puri (2019) reported results of endoscopic treatment in grade IV and V reflux. VUR resolution rate after the first endoscopic

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injection was 70% for grade IV and 62% for grade V cases.

Obstruction of the Ureterovesical Junction Ureteral obstruction (UO) is a well-known but rarely reported complication after endoscopic treatment of VUR. Incidence rates of postoperative UO are normally less than 1% of treated patients, which appears to be independent of bulking agent, volume, and injection technique (Friedmacher and Puri 2019). UO can develop immediately following the procedure or as far on as 63 months (GarcíaAparicio et al. 2013b; Rubenwolf et al. 2013), emphasizing the need for long-term follow-up as asymptomatic or delayed cases may cause deterioration of renal function. Acute UO may occur due to increased resistance at the ureterovesical junction caused by the implant itself or injection in the wrong tissue plane (Ben-Meir et al. 2012; Ben-Meir et al. 2017). Additionally, there is a concerning trend of delayed UO, which may either lead to obstructive symptoms or more frequently to asymptomatic hydroureteronephrosis found on routine follow-up. Several potential mechanisms, which could explain the occurrence of late-onset or progressive UO, have been suggested: gradual increase of resistance at the ureterovesical junction, ineffective ureteral peristalsis, and coaptation or chronic inflammation (Ben-Meir et al. 2017). Moreover, mound calcifications of various tissue augmenting substances at the injection site have been described (Gargollo et al. 2009; Noe 2008; Nepple et al. 2007; Palagiri and Dangle 2011), which may also predispose to UO.

Conclusion and Future Directions With the advent of Deflux®, endoscopic treatment of VUR has become the first-line therapy for many infants and children with reflux. In contrast to CAP, this procedure offers immediate cure with resolution rates ranging from 77 to 83% (Peters et al. 2010; Routh et al. 2010a, 2010b) and is independent of patient or parent compliance. It is

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an efficient and safe long-term option for grade IV and V VUR with success rates of 70% after the first injection, which can be easily repeated in cases of failure with a high subsequent resolution rate (Friedmacher et al. 2018; Stenbäck et al. 2020). Endoscopic treatment is also safe and highly effective in eradicating high-grade VUR in infants, a vulnerable group to develop renal parenchymal damage (Puri et al. 2007; Fuentes et al. 2017; Al Hindi et al. 2022). Compared to open, laparoscopic, or robotic-assisted ureteral reimplantation, this minimally invasive outpatient procedure is associated with decreased patient morbidity and possibly lower costs (Benoit et al. 2006; Kobelt et al. 2003). Furthermore, parental preferences play a major role in the selection of endoscopic intervention over the traditional methods of CAP or ureteral reimplantation (Ogan et al. 2001). A survey of 100 fully counseled parents of children with VUR revealed that 80% opted for endoscopic injection therapy rather than surveillance with CAP or open anti-reflux surgery when given the choice (Capozza et al. 2003). In general, both the opinion of the pediatric urologist/ pediatric surgeon and the individual hospital at which the patient seeks treatment influenced the decision (Hsieh et al. 2010b; Routh et al. 2010b). Further studies with standardized outcome reporting and follow-up are needed to evaluate predictors, technical factors, and long-term durability affecting the success of endoscopic VUR correction.

References Al Hindi S, Mubarak M, Al AH. High-grade vesicoureteral reflux in infants: Our experience with endoscopicsubureteric injections. Urologia. 2022;89(1):120–5. Baybikov R, Sizonov V, Bondarenko S, Dolgov B, Dubrov V, Kagantsov I, et al. Do the type of bulking agents and injection method have any influence on the incidence of ureteral obstruction by endoscopic treatment of reflux? J Pediatr Urol. 2015;11(Suppl 4) Ben-Meir D, Morgenstern S, Sivan B, Efrat R, Livne PM. Histology proved malpositioning of dextranomer/ hyaluronic acid in submucosal ureter in patients after failed endoscopic treatment of vesicoureteral reflux. J Urol. 2012;188(1):258–61. Ben-Meir D, Bahouth Z, Halachmi S. Late-onset Ureterovesical Junction Obstruction Following Endoscopic

306 Injection of Bulking Material for the Treatment of Vesico-ureteral Reflux. Urology. 2017;101:60–2. Benoit RM, Peele PB, Docimo SG. The cost-effectiveness of dextranomer/hyaluronic acid copolymer for the management of vesicoureteral reflux. 1: substitution for surgical management. J Urol. 2006;176(4 Pt 1): 1588–92. Brandström P, Nevéus T, Sixt R, Stokland E, Jodal U, Hansson S. The Swedish reflux trial in children: IV. Renal damage. J Urol. 2010a;184(1):292–7. Brandström P, Esbjörner E, Herthelius M, Swerkersson S, Jodal U, Hansson S. The Swedish reflux trial in children: III. Urinary tract infection pattern. J Urol. 2010b;184(1):286–91. Capozza N, Lais A, Matarazzo E, Nappo S, Patricolo M, Caione P. Treatment of vesico-ureteric reflux: a new algorithm based on parental preference. BJU Int. 2003;92(3):285–8. Cara-Fuentes G, Gupta N, Garin EH. The RIVUR study: a review of its findings. Pediatr Nephrol. 2015;30(5): 703–6. Diamond DA, Mattoo TK. Endoscopic treatment of primary vesicoureteral reflux. N Engl J Med. 2012;366(13):1218–26. Elder JS, Diaz M, Caldamone AA, Cendron M, Greenfield S, Hurwitz R, et al. Endoscopic therapy for vesicoureteral reflux: a meta-analysis. I. Reflux resolution and urinary tract infection. J Urol. 2006;175(2): 716–22. Friedmacher F, Puri P. Ureteral Obstruction After Endoscopic Treatment of Vesicoureteral Reflux: Does the Type of Injected Bulking Agent Matter? Curr Urol Rep. 2019;20(9):49. Friedmacher F, Colhoun E, Puri P. Endoscopic Injection of Dextranomer/Hyaluronic Acid as First Line Treatment in 851 Consecutive Children with High Grade Vesicoureteral Reflux: Efficacy and Long-Term Results. J Urol. 2018;200(3):650–5. Fuentes S, Gómez-Fraile A, Carrillo-Arroyo I, TordableOjeda C, Cabezalí-Barbancho D. Endoscopic Treatment of Vesicoureteral Reflux in Infants. Can We Do It and Should We Do It? Urology. 2017;110:196–200. García-Aparicio L, Rovira J, Blazquez-Gomez E, GarcíaGarcía L, Giménez-Llort A, Rodo J, et al. Randomized clinical trial comparing endoscopic treatment with dextranomer hyaluronic acid copolymer and Cohen's ureteral reimplantation for vesicoureteral reflux: longterm results. J Pediatr Urol. 2013a;9(4):483–7. García-Aparicio L, Rodo J, Palazon P, Martín O, Blázquez-Gómez E, Manzanares A, et al. Acute and delayed vesicoureteral obstruction after endoscopic treatment of primary vesicoureteral reflux with dextranomer/hyaluronic acid copolymer: why and how to manage. J Pediatr Urol. 2013b;9(4):493–7. Gargollo PC, Paltiel HJ, Rosoklija I, Diamond DA. Mound calcification after endoscopic treatment of vesicoureteral reflux with autologous chondrocytes--a normal variant of mound appearance? J Urol. 2009;181(6):2702–7.

F. Friedmacher and P. Puri Hayn MH, Smaldone MC, Ost MC, Docimo SG. Minimally invasive treatment of vesicoureteral reflux. Urol Clin North Am. 2008;35(3):477–88. Holmdahl G, Brandström P, Läckgren G, Sillén U, Stokland E, Jodal U, et al. The Swedish reflux trial in children: II. Vesicoureteral reflux outcome. J Urol. 2010;184(1):280–5. Hsieh MH, Madden-Fuentes RJ, Lindsay NE, Roth DR. Treatment of pediatric vesicoureteral reflux using endoscopic injection of hyaluronic acid/ dextranomer gel: intermediate-term experience by a single surgeon. Urology. 2010a;76(1):199–203. Hsieh MH, Madden-Fuentes RJ, Bayne A, Munch E, Wildenfels P, Alexander SJ, et al. Cross-sectional evaluation of parental decision making factors for vesicoureteral reflux management in children. J Urol. 2010b;184(4 Suppl):1589–93. Hunziker M, Puri P. Familial vesicoureteral reflux and reflux related morbidity in relatives of index patients with high grade vesicoureteral reflux. J Urol. 2012;188 (4 Suppl):1463–6. Hunziker M, Mohanan N, D'Asta F, Puri P. Incidence of febrile urinary tract infections in children after successful endoscopic treatment of vesicoureteral reflux: a long-term follow-up. J Pediatr. 2012;160(6):1015–20. Hunziker M, Mohanan N, Puri P. Dextranomer/hyaluronic acid endoscopic injection is effective in the treatment of intermediate and high grade vesicoureteral reflux in patients with complete duplex systems. J Urol. 2013;189(5):1876–81. Kirsch AJ, Arlen AM. Evaluation of new Deflux administration techniques: intraureteric HIT and Double HIT for the endoscopic correction of vesicoureteral reflux. Expert Rev Med Devices. 2014;11(5):439–46. Kirsch AJ, Perez-Brayfield M, Smith EA, Scherz HC. The modified sting procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. J Urol. 2004;171(6 Pt 1): 2413–6. Knudson MJ, Austin JC, McMillan ZM, Hawtrey CE, Cooper CS. Predictive factors of early spontaneous resolution in children with primary vesicoureteral reflux. J Urol. 2007;178(4 Pt 2):1684–8. Kobelt G, Canning DA, Hensle TW, Läckgren G. The cost-effectiveness of endoscopic injection of dextranomer/hyaluronic acid copolymer for vesicoureteral reflux. J Urol. 2003;169(4):1480–4. Läckgren G, Wåhlin N, Sköldenberg E, Stenberg A. Longterm followup of children treated with dextranomer/ hyaluronic acid copolymer for vesicoureteral reflux. J Urol. 2001;166(5):1887–92. Nepple KG, Knudson MJ, Cooper CS, Austin JC. Symptomatic calcification of subureteral collagen ten years after injection. Urology. 2007;69(5):982. e1–2. Noe HN. Calcification in a Deflux bleb thought to be a ureteral calculus in a child. J Pediatr Urol. 2008;4(1): 88–9.

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O'Donnell B, Puri P. Treatment of vesicoureteric reflux by endoscopic injection of Teflon. Br Med J (Clin Res Ed). 1984;289(6436):7–9. Ogan K, Pohl HG, Carlson D, Belman AB, Rushton HG. Parental preferences in the management of vesicoureteral reflux. J Urol. 2001;166(1):240–3. Palagiri AV, Dangle PP. Distal ureteral calcification secondary to deflux injection: a reality or myth? Urology. 2011;77(5):1217–9. Peters C, Rushton HG. Vesicoureteral reflux associated renal damage: congenital reflux nephropathy and acquired renal scarring. J Urol. 2010;184(1):265–73. Peters CA, Skoog SJ, Arant BS Jr, Copp HL, Elder JS, Hudson RG, et al. Summary of the AUA guideline on management of primary vesicoureteral reflux in children. J Urol. 2010;184(3):1134–44. Puri P. Endoscopic correction of primary vesicoureteric reflux by subureteric injection of polytetrafluoroethylene. Lancet. 1990;335:1320–2. Puri P, O'Donnell B. Correction of experimentally produced vesicoureteric reflux in the piglet by intravesical injection of Teflon. Br Med J (Clin Res Ed). 1984;289: 5–7. Puri P, Mohanan N, Menezes M, Colhoun E. Endoscopic treatment of moderate and high grade vesicoureteral reflux in infants using dextranomer/hyaluronic acid. J Urol. 2007;178(4 Pt 2):1714–6. discussion 1717 Puri P, Gosemann JH, Darlow J, Barton DE. Genetics of vesicoureteral reflux. Nat Rev Urol. 2011;8(10):539–52. Puri P, Kutasy B, Colhoun E, Hunziker M. Single center experience with endoscopic subureteral dextranomer/ hyaluronic acid injection as first line treatment in 1,551 children with intermediate and high grade vesicoureteral reflux. J Urol. 2012;188(4 Suppl):1485–9. Routh JC, Reinberg Y, Ashley RA, Inman BA, Wolpert JJ, Vandersteen DR, et al. Multivariate comparison of the efficacy of intraureteral versus subtrigonal techniques of dextranomer/hyaluronic acid injection. J Urol. 2007;178(4 Pt 2):1702–5. Routh JC, Inman BA, Reinberg Y. Dextranomer/ hyaluronic acid for pediatric vesicoureteral reflux: systematic review. Pediatrics. 2010a;125(5):1010–9. Routh JC, Nelson CP, Graham DA, Lieu TA. Variation in surgical management of vesicoureteral reflux: influence of hospital and patient factors. Pediatrics. 2010b;125(3):e446–51. Rubenwolf PC, Ebert AK, Ruemmele P, Rösch WH. Delayed-onset ureteral obstruction after endoscopic

307 dextranomer/hyaluronic acid copolymer (Deflux) injection for treatment of vesicoureteral reflux in children: a case series. Urology. 2013;81(3):659–62. Sargent MA. What is the normal prevalence of vesicoureteral reflux? Pediatr Radiol. 2000;30(9): 587–93. Sjöström S, Sillén U, Jodal U, Sameby L, Sixt R, Stokland E. Predictive factors for resolution of congenital high grade vesicoureteral reflux in infants: results of univariate and multivariate analyses. J Urol. 2010;183(3):1177–84. Skoog SJ, Peters CA, Arant BS Jr, Copp HL, Elder JS, Hudson RG, et al. Pediatric Vesicoureteral Reflux Guidelines Panel Summary Report: Clinical Practice Guidelines for Screening Siblings of Children With Vesicoureteral Reflux and Neonates/Infants With Prenatal Hydronephrosis. J Urol. 2010;184(3):1145–51. Stenbäck A, Olafsdottir T, Sköldenberg E, Barker G, Stenberg A, Läckgren G. Proprietary non-animal stabilized hyaluronic acid/dextranomer gel (NASHA/Dx) for endoscopic treatment of grade IV vesicoureteral reflux: Long-term observational study. J Pediatr Urol. 2020;16(3):328.e1–9. Swerkersson S, Jodal U, Sixt R, Stokland E, Hansson S. Relationship among vesicoureteral reflux, urinary tract infection and renal damage in children. J Urol. 2007;178(2):647–51. Tekgül S, Riedmiller H, Hoebeke P, Kočvara R, Nijman RJ, Radmayr C, et al. EAU guidelines on vesicoureteral reflux in children. Eur Urol. 2012;62(3):534–42. Watters ST, Sung J, Skoog SJ. Endoscopic treatment for vesicoureteral reflux: how important is technique? J Pediatr Urol. 2013;9(6 Pt B):1192–7. Williams G, Fletcher JT, Alexander SI, Craig JC. Vesicoureteral reflux. J Am Soc Nephrol. 2008;19(5):847–62. Yap TL, Chen Y, Nah SA, Ong CC, Jacobsen A, Low Y. STING versus HIT technique of endoscopic treatment for vesicoureteral reflux: A systematic review and meta-analysis. J Pediatr Surg. 2016;51(12):2015–20. Yucel S, Gupta A, Snodgrass W. Multivariate analysis of factors predicting success with dextranomer/hyaluronic acid injection for vesicoureteral reflux. J Urol. 2007;177(4):1505–9. Zerin JM, Ritchey ML, Chang AC. Incidental vesicoureteral reflux in neonates with antenatally detected hydronephrosis and other renal abnormalities. Radiology. 1993;187(1):157–60.

Surgical Treatment of Vesicoureteric Reflux

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Mohamed Sameh Shalaby and Laura Jackson

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310 General Principles of Surgical Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310 Open Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intravesical Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Glenn-Anderson Technique (Fig. 2a–c for Open and 7a–k for Vesicoscopic) . . . . . . . . . Extravesical Procedures as Lich-Gregoir Technique (Fig. 4a–c) . . . . . . . . . . . . . . . . . . . . . . . Additional Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Psoas Hitch (Fig. 6) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Minimally Invasive Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

311 311 313 315 316 316 316

Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intravesical Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Extravesical Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Outcome of Minimally Invasive Versus Open Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

321 322 322 322

Factors Affecting Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prior Endoscopic Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Grade of VUR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bilateral RALUR-EV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bladder and Bowel Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

323 323 323 323 323 323

Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Persistent Ipsilateral VUR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contralateral VUR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ipsilateral Ureteric Obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Urinary Leak . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bowel Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

323 323 324 324 324 325

Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325

M. S. Shalaby (*) · L. Jackson Department of Paediatric Surgery and Urology, Bristol Royal Hospital for Children, Bristol, UK e-mail: [email protected]; [email protected]

Abstract

Vesicoureteral reflux (VUR) describes the retrograde flow of urine from the bladder into the ureters and upper urinary tract. VUR may lead

© Springer-Verlag GmbH Germany, part of Springer Nature 2023 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43567-0_180

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to pyelonephritis, reflux nephropathy, hypertension and, ultimately, chronic renal disease. Ureteric re-implantation is indicated when conservative management (prophylactic antibiotics, treatment of lower urinary tract dysfunction and surveillance) and/or endoscopic treatment has failed to prevent febrile urinary tract infections or other complications of VUR. Currently, the vast majority of ureteric re-implantations are undertaken by the open approach using an intravesical (Cohen, Glenn-Anderson, Politano-Leadbetter) or extravesical (Lich-Gregoir) technique. Open surgery, by any of these techniques, leads to successful correction of VUR in >95% of cases with a low complication rate. Minimally invasive techniques to correct VUR are described, with laparoscopy or robotic-assisted laparoscopy utilized to recreate the intravesical (vesicoscopic) and extravesical procedures described in open surgery. Increased complications have been reported following minimally invasive repair and, inevitably, operative time is longer than for open surgery. Vesicoscopic surgery is technically challenging due to problems in creating and maintaining pneumovesicum, and the inherently small working space within the bladder. Consequently, the most favored minimally invasive technique currently is the roboticassisted laparoscopic extravesical ureteric re-implantation (RALUR-EV) based on the Lich-Gregoir technique. Nerve-sparing techniques have been implemented to reduce the incidence of urinary retention noted following bilateral laparoscopic (including roboticassisted) extravesical ureteric re-implantation. Following a significant learning curve, recent studies show the results of minimally invasive surgery are approaching those of open techniques. Keywords

Vesico-ureteric reflux · Ureteric re-implantation · RALUR · Cohen · PolitanoLeadbetter · Glenn-Anderson · Lich-Gregoir

M. S. Shalaby and L. Jackson

Abbreviations

RALUR RALUREV UTI VUJ VUR

Robotic-Assisted Laparoscopic Ureteric Reimplantation Robotic-Assisted Laparoscopic Ureteric Reimplantation–Extravesical Urinary tract infection Vesicoureteric junction Vesicoureteric reflux

Introduction Vesicoureteric reflux (VUR) may be classified as primary, related to a congenitally short submucosal ureter or secondary, resulting from high intravesical pressure as seen in children with posterior urethral valves or neuropathic bladder. Initial management of primary VUR is conservative, in the form of prophylactic antibiotics, treatment of lower urinary tract dysfunction and surveillance. The main indication for surgical intervention is breakthrough febrile UTIs while on antibiotic prophylaxis. Surgical approaches are either endoscopic “covered in a separate chapter,” open, laparoscopic, vesicoscopic, or robotic with laparoscopic assistance.

General Principles of Surgical Treatment • Exclude and treat secondary causes of VUR • Optical magnification during open surgery with loupes • Careful dissection of the ureter to maintain its blood supply and protect surrounding structures such as the vas deferens in boys and the extravesical nerve plexi • Ensure sufficient ureteric mobilization to enable a tension free anastomosis • A submucosal tunnel length of around 3–4 times the ureteric diameter is usually adequate. A length to diameter ratio of 5:1 has been traditionally recommended (Paquin Jr. 1959) but is often difficult to achieve in a small bladder and can risk obstructing the ureter. The ureteric orifice configuration plays a significant role in the

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competence of the new ureteric orifice. A 2 mm protruding volcano-shaped orifice significantly increases ureteric orifice competence regardless of tunnel length (Villanueva et al. 2018). Ureteric refashioning (tapering/plication) of the distal ureter should be undertaken if significant ureteric dilatation precludes achieving the required length to diameter ratio Ureteric stenting is not routinely required but is recommended if ureteric refashioning is undertaken, for re-operative cases, for VUR in single kidney and if significant detrusor hypertrophy is present (as seen in posterior urethral valves, neuropathic bladder). Ureteric stenting of at least one ureter in bilateral re-implantation may be considered to avoid the potential complication of anuria secondary to bilateral obstruction from early postoperative edema. A common sheath ureteric re-implantation may be undertaken for a duplicated system whereby both ureters are re-implanted together in the same submucosal tunnel Continuous bladder drainage via a urethral or suprapubic catheter is required postoperatively, particularly when the bladder has been opened during intravesical procedures. This is usually required for 5–7 days.

Open Surgery Currently, open surgery remains the most common approach used for ureteric reimplantation. Broad spectrum intravenous antibiotics are administered at induction of general anesthesia. The child is laid supine. The abdomen, genitalia, and perineum are prepared while ensuring access for sterile intraoperative urethral catheterization if necessary. Different surgical approaches can be used, and the choice is primarily influenced by surgeon experience/preference but also the degree of ureteric dilatation and whether the VUR is unilateral or bilateral.

Intravesical Procedures A Pfannenstiel incision is performed 2 cm above the symphysis pubis extending to the lateral border of the rectus muscles. The anterior rectus

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sheath is opened transversely in line with the skin incision and released superiorly and inferiorly from the underlying rectus muscles using needle point cautery to the level of the symphysis pubis inferiorly and almost up to the umbilicus superiorly. The rectus muscles are split longitudinally in the midline and the linea alba incised. The perivesical space is then entered, the bladder is mobilized with blunt dissection and the peritoneum carefully cleared off the dome of the bladder. If the bladder is empty, it should be partially filled with saline via a Foley urethral catheter to aid identification and dissection. A Denis Brown wound retractor is used, with two blades holding the rectus muscles apart. A pediatric size Balfour retractor may be necessary for the larger, older child. The bladder is opened vertically in the midline between stay sutures extending to within 2 cm of the bladder neck using cautery. An interrupted suture is placed and tied at the inferior limit of the bladder incision to prevent inadvertent tearing of the bladder neck. The Denis Brown ring retractor is then moved within the bladder. The dome of the bladder is packed with saline soaked gauze and a narrow blade over the gauze enables retraction superiorly. Two lateral wider blades hold the sides of the bladder open or alternatively the lateral bladder walls may be held open with stay sutures. Another retractor blade is placed inferiorly. The ureteric orifices are identified and cannulated with an infant feeding tube, usually a 5 or 6F. The tube is passed up to the kidney and secured to the ureteric orifice with a 4/0 absorbable suture. A hemostat clamp is then applied to both suture and ureter for gentle traction to aid ureteric mobilization. Fine needle point cautery is used to circumscribe the urothelium of the ureteric orifice 1–2 mm from its edge. The ureteric orifice is lifted superiorly, and dissection commenced inferiorly and medially dividing the superficial muscle attachments in order to develop a plane outside the ureteric adventitia (Fig. 1a). Careful dissection is continued around the ureter using bipolar diathermy and tenotomy scissors to mobilize the ureter. It is essential to dissect the correct plane outside of the ureteric adventitia to prevent devascularization and subsequent ureteric

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Fig. 1 (a–e) Politano-Leadbetter Technique. (a) The ureteric orifice is dissected. (b) A new hiatus superomedial to the original hiatus is dissected. (c) The ureter is routed up to the new hiatus. (d) The detrusor at the site of the original hiatus is closed. The ureter is passed through the tunnel bringing the distal ureter through from the new hiatus

inferiorly. (e) The end of the distal ureter is trimmed to length and spatulated if necessary. The anastomosis of ureter to bladder urothelium is completed. The urothelium at the site of the new hiatus is closed vertically over the ureter

ischemia. Finally, the peritoneum is identified and is carefully swept away with a pledget ensuring that the ureter is fully mobilized into the bladder with enough length to permit a tension free anastomosis and allow distal trimming of the ureter. Care must be taken in boys to avoid injury to the vas deferens during ureteric dissection. Further steps will depend on the technique of re-implantation to be used. Three commonly used techniques which provide excellent rates of VUR correction are described below: The Cohen cross-trigonal re-implantation is a commonly utilized intravesical procedure. It is

often favored because it is a relatively straightforward and versatile procedure with a low rate of post-operative ureteric obstruction. The disadvantage is that it can be difficult to access the ureteric orifice endoscopically subsequently if necessary. Various techniques are described to ameliorate this problem including retrograde access via cystoscopy and use of curved tip access catheters (Wallis et al. 2003), percutaneous retrograde ureteric catheterization (De Castro et al. 2011), and flexible ureteroscopy (Emiliani et al. 2017). The Politano-Leadbetter re-implantation allows subsequent endoscopic ureteric access but

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is technically more demanding and has a higher risk of inadvertent kinking and obstruction of the ureter. Due to the longer length of submucosal tunnel that is achievable, it is better suited than the Cohen when re-implanting massively dilated ureters, particularly when combined with a psoas hitch to prevent angulation of the ureter as it enters the bladder. In the Glenn-Anderson advancement, the submucosal tunnel is directed infra-hiatally toward the bladder neck, its applicability is hence limited by the length of submucosal tunnel that can be created.

Politano-Leadbetter Technique (Fig. 1a–e) This technique creates a long supra-hiatal submucosal tunnel which runs vertically from a new superomedial hiatus down to the original hiatus (Politano and Leadbetter 1958). Following full mobilization of the ureter into the bladder as described above, a retrovesical pathway to re-route the distal ureter up to a new hiatus needs to be created. The site for the new hiatus superomedial to the original hiatus is selected ensuring the length: diameter ratio is sufficient. The ureter is routed up to the new hiatus by grasping the ureteric stay suture and passing it up through the retrovesical tunnel and through the new hiatus. It is important to check that the ureter has not been kinked or twisted at this point. The detrusor at the site of the original hiatus is closed with interrupted 4/0 absorbable sutures. A submucosal tunnel between the new hiatus and the original hiatus is created using tenotomy scissors to carefully cut and spread in the submucosal plane from one hiatus to the other. Once an adequately sized tunnel has been created the ureteric stay suture is passed through the tunnel bringing the distal ureter through from the new hiatus inferiorly. The end of the distal ureter is trimmed to length and spatulated if necessary on its medial aspect. The ureteric tip is secured at its 5 and 7 o’clock positions with two deep interrupted 4/0 or 5/0 absorbable sutures to the detrusor and urothelium of the bladder. 5/0 absorbable sutures are used to complete the circumferential anastomosis of ureter to bladder urothelium. The urothelium at the site of the new hiatus is closed vertically over the ureter with 5/0

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absorbable interrupted sutures. A 5F feeding tube is passed up the ureter to ensure it passes easily and there are no kinks (Fig. 1a–e). This tube may be left in situ as a stent if required, in which case it should be fixed to the bladder after exiting the ureteral orifice with a 5/0 vicryl rapide suture and then brought out through the bladder closure. The bladder is closed in 2 layers with a 4/0 absorbable continuous suture to the urothelium and then the detrusor around a 12F Foley balloon catheter. A Redivac drain is sited perivesically and the wound is closed. Post-operatively, treatment dose antibiotics are continued orally until the suprapubic catheter and ureteral stents (if present) are removed 1 week post-operatively. Prophylactic dose antibiotics are then continued until clinic review 2–3 months post-operatively with a renal ultrasound scan. Antibiotics can be discontinued at this point if the ultrasound scan is satisfactory, and the child has remained infection free.

Glenn-Anderson Technique (Fig. 2a–c for Open and 7a–k for Vesicoscopic) This technique involves creating an infra-hiatal tunnel down onto the trigone to avoid any blind retrovesical dissection. It allows easy subsequent endoscopic ureteral access if required but is limited by the shorter length of tunnel that can be achieved. Following full mobilization of the ureter into the bladder as previously described, a submucosal tunnel extending inferomedial onto the trigone from the original hiatus is created. The full thickness of the bladder wall superior to the original hiatus is then incised in order to transpose the hiatus cranially. Lift the ureter into the superior aspect of this incision and close the detrusor inferiorly with interrupted 4/0 absorbable sutures ensuring it is not closed too tightly around the ureter. Pass the ureter through the submucosal tunnel by grasping the attached stay suture with a right-angle clip. The distal ureter is trimmed to length and spatulated, if necessary, on its medial aspect. The ureter tip is secured at its 5 and 7 o’clock positions with two deep interrupted

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4/0 or 5/0 absorbable sutures to the detrusor and urothelium of the bladder. 5/0 absorbable sutures are used to complete the circumferential anastomosis of ureter to bladder urothelium. The urothelium at the site of the original hiatus is closed vertically over the ureter with 5/0 absorbable interrupted sutures. Ureteric stenting, insertion of suprapubic catheter then bladder and wound closure are undertaken in the same manner as for the Politano-Leadbetter procedure.

Cohen Cross-Trigonal Technique (Fig. 3a–c) This technique involves creating transverse submucosal tunnels which cross the trigone. It is useful for thick-walled bladders as the trigone is

M. S. Shalaby and L. Jackson

usually less affected than the remainder of the bladder. To create the trans-trigonal submucosal tunnel, a vertical incision is made in the urothelium superolateral to the contralateral ureteric orifice, the exact position depending upon the size of the trigone. Tenotomy scissors are used in a cutting and spreading motion to develop the submucosal tunnel of adequate length and width between the incision and the original hiatus. The ureteric feeding tube is removed from the ureter and the ureter is brought through the submucosal tunnel by passing a right-angle clip retrogradely via the tunnel and grasping the attached stay suture in order to draw it though. The ureter is trimmed to length and spatulated as necessary. The tip of the ureter is secured to the detrusor

Fig. 2 (a–c) Glenn-Anderson Technique. (a) The ureter is mobilized into the bladder. (b) A submucosal tunnel extending inferomedial onto the trigone from the original hiatus is created. (c) Appearance at the end

Fig. 3 (a–c) Cohen Cross-Trigonal Technique. (a) Unilateral Cohen. Creating transverse submucosal tunnel which crosses the trigone. (b) Unilateral Cohen. New ureteric orifice lies superior to the contralateral ureteric

orifice. (c) Bilateral Cohen. The ureter whose original hiatus is more superolateral is tunneled superior to the contralateral orifice. The second ureter is then tunneled inferior to the original hiatus of the first ureter

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and overlying urothelium. A further interrupted suture is used to fix the ureter at the other end of the tunnel to the detrusor. 5/0 absorbable sutures are used to complete the circumferential anastomosis of ureter to bladder urothelium and also to close the urothelium at the original hiatus. When bilateral re-implantation is undertaken the ureter whose original hiatus is more superolateral is tunneled superior to the contralateral orifice. The second ureter is then tunneled inferior to the original hiatus of the first ureter in the same manner as described above. Suprapubic catheter insertion, ureteric stent insertion then bladder and wound closure is undertaken in the same way as for the Politano-Leadbetter procedure.

Extravesical Procedures as Lich-Gregoir Technique (Fig. 4a–c) This technique avoids opening the bladder and is therefore associated with fewer post-operative symptoms such as hematuria and bladder spasms (Aydin et al. 1992). There is also a lower postoperative risk of contralateral VUR (95% (Aydin et al., Aydin et al. 1992; Barrieras et al. 2000; Elder 2019; Silay et al. 2018). Following re-implantation, the incidence of new postoperative renal scarring is 2% (Webster et al. 2000); however, febrile UTIs continue to be seen in 5–10% of patients over the subsequent 10 years post-operatively despite successful VUR correction (Elder 2019; Valla et al. 2009). The minimally invasive approaches are technically challenging, involve a significant learning curve and require specialist equipment and training for the robotic approach. The minimally invasive approach is, however, gaining momentum and starting to generate results closer to that of the open technique. Success rates of minimally invasive intravesical

Outcome Currently, open ureteric re-implantation is the most commonly utilized approach, with estimates from the USA that it outnumbers minimally invasive

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and extravesical procedures ranges from 83–95% and 91–99%, respectively. Due to the significant technical challenge of vescicoscopic surgery, the most favored minimally invasive technique currently is the robotic-assisted laparoscopic extravesical ureteric re-implantation based on the LichGregoir technique.

Intravesical Approach The success rate of laparoscopic intravesical cross-trigonal ureteric re-implantation ranges from 84%–96%. Conversion is required in 0–6% of cases with the majority (75% in one series) of conversions occurring in children less than 2 years old. Complications are noted in up to 15%, again with the majority reported in children with small bladders (Canon et al. 2007; Chung et al. 2018; Jayanthi 2018; Kutikov et al. 2006; Valla et al. 2009; Yeung et al. 2005). A minimum bladder volume of 130 ml is recommended for vesicoscopic repair due to difficulties encountered otherwise with port insertion, maintenance of pneumovesicum, and a small working space for intracorporeal knot tying (Valla et al. 2009).

Extravesical Approach Extravesical ureteric re-implantation is undertaken both laparosocopically and robotically-assisted; however, the robotic approach seems to have become the predominant modality currently. Laparoscopic extravesical ureteric re-implantation undertaken in unilateral and bilateral VUR is reported to have a clinical success rate of 98.3% (Soulier et al. 2017), a cystographic success rate of 95.2% of ureters (Bayne et al. 2012) and a complication rate of approximately 4%. Additionally transient urinary retention is reported in 0.8%–6.5% of patients after bilateral repair (Bayne et al. 2012; Soulier et al. 2017). A systematic review of robotic-assisted laparoscopic extravesical ureteric re-implantations in 1362 children, demonstrated success rate of 72–100%, mean post-operative complication rate

M. S. Shalaby and L. Jackson

of 10.7%, and a mean re-operation rate of 3.9% (Esposito et al. 2021). Complications included ileus, incisional, or port-site hernias, perinephric fluid collections, febrile UTIs, and urinary retention as well as ureteric injury resulting in leakage and obstruction (Akhavan et al. 2014; Boysen et al. 2018; Esposito et al. 2021; Herz et al. 2016). Similar to the vesicoscopic technique, age younger than 3 years is an independent risk factor for complications, and in bilateral procedures is also a risk factor for surgical failure and re-operation (Herz et al. 2016). When compared to each other, children undergoing laparoscopic or robotic-assisted ureteric re-implantations have similar post-operative analgesic requirements, length of stay, and postoperative complication rates (Esposito et al. 2021).

Outcome of Minimally Invasive Versus Open Approach National population level data from the USA comparing short-term outcomes of ureteric reimplantation in children 18 years (total 76,756 admissions) with VUR demonstrates that minimally invasive surgery is associated with a significantly shorter length of stay (almost half of open approach) but higher costs (nearly 1.5 times) and a three times higher rate of urinary complications than open surgery. Children undergoing minimally invasive surgery are significantly older than those undergoing open procedures (Wang et al. 2016). Vesicoscopic re-implantation for children with VUR has a lower success rate (91% vs. 97%), higher complications rate (5% vs. zero), and a significantly longer mean operative time (199 vs. 92 min) compared to open surgery. Analgesic requirements are significantly lower in the vesicoscopic group, with no reported difference in length of stay (Canon et al. 2007). In a systematic review and meta-analysis of 6 retrospective studies on a total of 7122 children with primary VUR, the robotic-assisted laparoscopic technique (RALUR) had significantly shorter hospital stay (mean difference 17.8 h) and less post-operative time with a foley catheter (mean difference 0.32 days), compared to open

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Surgical Treatment of Vesicoureteric Reflux

surgery; however, it is more costly, and has a significantly longer operative time (mean difference 66.69 min). There was no observable difference in success rate, post-operative analgesia requirements, and overall complications. However, short-term 90-day complications appear to be significantly higher following RALUR (Deng et al. 2018). Overall, the data for minimally invasive techniques shows significant variability and it is likely that patient selection and other confounding factors, as well as the surgical learning curve, play a role in this variability.

Factors Affecting Outcome Prior Endoscopic Management Ureteric re-implantation is sometimes undertaken following prior endoscopic injection of bulking agent such as Deflux ®. Fortunately, prior endoscopic injection to the ureteric orifice does not have an impact on the success rate, complication rate, mean operative time, or length of hospital stay for open surgery (Friedlander et al. 2018; Lee et al. 2016; Silay et al. 2018).

Grade of VUR • In general, higher grade VUR is associated with a lower success rate following open re-implantation with a pooled success rate of 99% for grades I–IV and 81% for grade V (Tejwani and Routh 2021). • When considering extravesical re-implantation, at 1 year post-operatively, the success rate is significantly higher in children with grade I–III reflux (99%) versus grade IV–V reflux (94%) (Barrieras et al. 2000). • Similarly, following the Politano-Leadbetter technique, successful correction of VUR is related to the pre-operative grade of VUR, with a success rate of 99% for grades I–II, 95% for grades III–IV and 80% for grade V (Heidenreich et al. 2004). • The same applies to the minimally invasive approach, where grade IV and V VUR is an independent risk factor for surgical failure and

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the need for re-operation following RALUREV (Herz et al. 2016).

Bilateral RALUR-EV Bilateral robotic-assisted laparoscopic extravesical ureteric re-implantation (RALUR-EV) has been associated with lower success rates (72.2% vs. 91.7%), higher complication rates, higher re-operation rates (22.2% vs. 2.7%), more post-operative UTIs, and increased non-surgical readmissions compared with unilateral robotic re-implantations (Herz et al. 2016). Others, however, have not shown any greater morbidity than unilateral ureteric re-implantation (Boysen et al. 2018; Srinivasan et al. 2017).

Age There is no correlation between age and the success of VUR correction following open ureteric re-implantation (Barrieras et al. 2000). However, age younger than 3 years is an independent risk factor for surgical complications following RALUR-EV and is an independent risk factor for surgical failure, complications, and re-operation following bilateral RALUR-EV (Herz et al. 2016).

Bladder and Bowel Dysfunction Dysfunctional voiding affects 1/3 of children with VUR. Pre-operative bladder and bowel dysfunction should be managed aggressively before embarking on surgical correction of VUR as it can negatively impact the outcome, increasing the risk of surgical failure and complications (Herz et al. 2016).

Complications Persistent Ipsilateral VUR • VUR noted in the early post-operative period on VCUG “voiding cystourethrogram” often resolves spontaneously by 1 year postoperatively.

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• Following extravesical ureteric re-implantation, success on VCUG was noted in 93.2% of ureters (91.3% patients) at 3 months, which increased to 97.9% of ureters (95.4% patients) at 12 months. This may be related to bladder dysfunction secondary to bladder irritation in the early post-operative period which subsequently resolves. • Post-operative VUR is more likely to persist in children who had high-grade VUR pre-operatively (Barrieras et al. 2000). • Another cause for persistence reflux is ureterovesical fistula which has been reported following vesicoscopic (Jayanthi 2018) and laparoscopic extra-vesical ureteric re-implantation (Bayne et al. 2012) due to inadvertent ureterotomy/ureteric injury.

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Contralateral VUR • Up to 20% of children will develop contralateral VUR after unilateral open re-implantation. The majority will resolve spontaneously within 2 years. The risk is greater if there was severe VUR or a duplex system on the initial side, or if the contralateral orifice previously refluxed and then resolved pre-operatively (Elder 2019; Hubert et al. 2014; Heidenreich et al. 2004). • Younger age (6 years) and small bladder capacity (