Strategic Plan for Pediatric Urology

NIDDK – Research Progress Report

Department of Health and Human Services

National Institutes of Health

National Institute of Diabetes & Digestive & Kidney Diseases
Strategic Plan for Pediatric Urology

NIDDK – Research Progress Report

Department of Health and Human Services

National Institutes of Health

National Institute of Diabetes & Digestive & Kidney Diseases

NIH Publication No. 06-5879

February 2006

TABLE OF CONTENTS

Planning Committee................................................................................................................................... 1

Contributors................................................................................................................................................. 1

Executive Summary..................................................................................................................................... 7

I. The Urinary Tract

A. Upper Urinary Tract

1. Urinary Tract Development and Maldevelopment................................................................... 15

2. Nephrolithiasis............................................................................................................................... 21

B. Lower Urinary Tract

3. Lower Urinary Tract Obstruction............................................................................................... 23

4. Vesicoureteral Reflux.................................................................................................................... 25

5. Urinary Tract Infection................................................................................................................ 29

6. Neurogenic Bladder...................................................................................................................... 31

7. Voiding Dysfunction.................................................................................................................... 34

8. Enuresis.......................................................................................................................................... 36

9. Exstrophy-Epispadias Complex and Cloacal Malformation................................................... 37

II. The Genital Tract

10. Development and Maldevelopment of the Genital Tract..................................................... 43

11. Cryptorchidism........................................................................................................................... 47

12. Hypospadias................................................................................................................................ 49

13. Hernia and Hydrocele................................................................................................................ 51

14. Congenital Anomalies Of Sexual Differentiation................................................................... 52
III. Other Pediatric Urinary Conditions

15. Pediatric Genitourinary Tumors............................................................................................... 57

16. Pediatric Genitourinary Trauma............................................................................................... 59

17. Testicular Torsion........................................................................................................................ 61

18. Phimosis and Circumcision Practice........................................................................................ 62

19. Varicocele..................................................................................................................................... 64

IV. Research Methodologies

20. Animal Models............................................................................................................................ 67

22. Biomechanics............................................................................................................................... 68

23. Nanotechnology.......................................................................................................................... 70

24. Stem Cell Biology........................................................................................................................ 73

25. Clinical and Developmental Imaging....................................................................................... 74

26. Systems Biology........................................................................................................................... 76

27. Tissue Engineering..................................................................................................................... 80

28. Clinical Trials and Epidemiology.............................................................................................. 82

29. Therapies and Diagnostics......................................................................................................... 85

V. Training And Manpower

30. M.D. Training.............................................................................................................................. 89

31. Ph.D. Training............................................................................................................................. 91

32. Collaborative Programs............................................................................................................. 92
Planning Committee and Contributors 1

CONTRIBUTORS

Anthony Atala, M.D.

William Boyce Professor and Chair

Department of Urology

Wake Forest University School of Medicine

Winston-Salem, NC

Darius J. Bagli, M.D. C.M.

Associate Professor of Surgery

Department of Surgery

The Hospital For Sick Children, University of 

 Toronto

Toronto, Ontario 

Linda A. Baker, M.D.

Associate Professor

Department of Urology

University of Texas Southwestern Medical Center

 at Dallas

Dallas, TX 

Laurence S. Baskin, M.D.

Chief, Pediatric Urology

Department of Urology

University of California, San Francisco 

 Children’s Medical Center

San Francisco, CA 

Craig Peters, M.D.

Co-Chair

Barry Kogan, M.D.

Co-Chair

Anthony Atala, M.D. 

Linda Baker, M.D. 

Monica Liebert, Ph.D.

Sanjay Nigam, M.D. 

John Park, M.D. 

NIDDK Ex-Officio Members

Josephine Briggs, M.D.

Stuart Howards, M.D.

Marva Moxey-Mims, M.D.

Leroy Nyberg, Ph.D., M.D.

Elizabeth Wilder, Ph.D.

Publication Developer and Editor

Mark Geanacopoulos, Ph.D.

PLANNING COMMITTEE
2 Planning Committee and Contributors

Sheri A. Berenbaum, Ph.D.

Professor

Department of Psychology and Department of 

 Pediatrics

The Pennsylvania State University

University Park, PA 

Joseph G. Borer, M.D.

Assistant Professor of Surgery (Urology) and 

 Assistant in Urology

Department of Urology

Harvard Medical School 

Children’s Hospital Boston

Boston, MA 

Kevin T. Bush, Ph.D.

Assistant Project Scientist

Department of Medicine

University of California, San Diego

La Jolla, CA 

Bartley G. Cilento, Jr., M.D.

Department of Urology

Children’s Hospital Boston

Boston, MA 

Martin J. Cohn, Ph.D.

Associate Professor

Departments of Zoology and Anatomy and Cell 

 Biology

University of Florida

Gainesville, FL 

Richard Czerw, Ph.D.

President

NanoTechLabs Inc.

Winston-Salem, NC 

David A. Diamond, M.D.

Associate Professor of Surgery

Harvard Medical School

Children’s Hospital Boston

Boston, MA 

Jack S. Elder, M.D.

Director of Pediatric Urology

Department of Urology

Case Western Reserve University School of

 Medicine

Cleveland, OH 

Michael Freeman, M.D.

Director

Urological Diseases Research Center

Children’s Hospital Boston

Boston, MA

Kenneth I. Glassberg, M.D.

Professor of Urology

Department of Urology

Morgan Stanley Children’s Hospital of New York-

 Presbyterian

New York, NY 

L. Earl Gray

Research Biologist

Endocrinology Branch

Environmental Protection Agency

Durham, NC

Saul P. Greenfield, M.D.

Director, Pediatric Urology; Associate Professor of

 Clinical Urology

Department of Urology

State University of New York at Buffalo, School 

 of Medicine and Biomedical Sciences

Buffalo, NY 

Shuk-Mei Ho, Ph.D.

Professor of Surgery

Cell Biology and Physiology

Department of Surgery

University of Massachusetts Medical School

Worcester, MA 

Alejandro Hoberman, M.D.

Associate Professor/Division Chief

Department of Pediatrics; General Academic 

 Pediatrics

University of Pittsburgh School of Medicine

Pittsburgh, PA 
Planning Committee and Contributors 3

Barry Kogan, M.D.

Professor, Surgery and Pediatrics

Division of Urology

Albany Medical College

Albany, NY

Bradley P. Kropp, M.D.

Associate Professor, Chief Pediatric Urology

Department of Urology

University of Oklahoma

Oklahoma City, OK 

Peter A. Lee, M.D., Ph.D.

Professor 

Department of Pediatrics

Penn State College of Medicine

Hershey, PA

Robert M. Levin, Ph.D.

Director of Research

Basic and Pharmaceutical Sciences

Albany College of Pharmacy

Albany, NY

Max Maizels, M.D.

Professor of Urology

Department of Urology

Children’s Memorial Hospital

Chicago, IL 

Cathy Mendelsohn, Ph.D.

Assistant Professor

Department of Urology and Pathology

Columbia University

New York, NY 

Dawn S. Milliner, M.D.

Professor of Medicine; Professor of Pediatrics

Department of Internal Medicine; Department 

 of Pediatric & Adolescent Medicine 

Mayo Clinic

Rochester, MN

Sanjay Nigam, M.D.

Professor

Department of Pediatrics, Medicine and 

 Cellular and Molecular Medicine; Division of 

 Nephrology

University of California, San Diego

San Diego, CA 

John M. Park, M.D.

Associate Professor, Director of Pediatric 

 Urology

Department of Urology

University of Michigan Medical School

Ann Arbor, MI

David Penson, M.D., MPH

Associate Professor

Department of Urology and Preventive 

 Medicine

University of Southern California

Los Angeles, CA 

Craig Peters, M.D.

Professor

Department of Urology

University of Virginia School of Medicine

Charlottesville, VA

John C. Pope, M.D.

Assistant Professor

Surgical Oncology

Vanderbilt University

Nashville, TN

Alexandra Quittner, Ph.D. 

Professor 

Psychology Department

University of Miami

Miami, FL

Jonathon Ross, M.D.

Vice Chairman and Head of Pediatric Urology

Glickman Urological Institute

Cleveland, OH 
4 Planning Committee and Contributors

Michael Sacks, Ph.D.

Professor

Department of Bioengineering

University of Pittsburgh

Pittsburgh, PA

David E. Sandberg, Ph.D.

Associate Professor of Psychiatry and Pediatrics

Psychiatry Department

School of Medicine and Biomedical Sciences, 

University at Buffalo

Women and Children’s Hospital of Buffalo

Buffalo, NY 

Ellen Shapiro, M.D.

Professor of Urology

Department of Urology

New York University School of Medicine

New York, NY 

Linda D. Shortliffe, M.D.

Professor and Chair of Urology, Chief of Pediatric 

 Urology

Department of Urology

Stanford University

Stanford, CA 

Shay Soker, Ph.D.

Associate Professor of Surgical Sciences

Institute for Regenerative Medicine

Wake Forest University Health Sciences

Winston-Salem, NC 

T. Scott Stadler, Ph.D.

Assistant Professor

Molecular and Medical Genetics Department

Oregon Health and Sciences University

Portland, OR

Terry T. Turner, Ph.D.

Professor of Urology and Cell Biology

Department of Urology

University of Virginia School of Medicine

Charlottesville, VA 

Margaret Vizzard, Ph.D.

Associate Professor

Department of Neurology and Anatomy and 

 Neurobiology

University of Vermont College of Medicine

Burlington, VT 

Julian Wan, M.D.

Clinical Associate Professor of Urology

Department of Urology

University of Michigan

Ann Arbor, MI 

Valerie L. Ward, M.D.

Staff Radiologist, Instructor in Radiology

Department of Radiology

Harvard Medical School

Children’s Hospital Boston

Boston, MA 

Duncan T. Wilcox, M.D.

Associate Professor Pediatric Urology

Department of Urology

University of Texas, Southwestern Medical 

 Centre at Dallas

Dallas, TX 

Stephen A. Zderic, M.D.

Associate Professor of Urologic Surgery

Division of Pediatric Urology

Children’s Hospital of Philadelphia

Philadelphia, PA

GRAPHIC DESIGN

Scott A. Kyle

The Scientific Consulting Group, Inc.
Strategic Plan for Pediatric Urology 5
6 Strategic Plan for Pediatric Urology

Blank
Executive Summary 7

STRATEGIC PLAN FOR PEDIATRIC UROLOGY

NIDDK — RESEARCH PROGRESS REPORT

Pediatric urology is a well-established area of clinical medicine that deals with the diseases of 

the urinary and genital tracts of children. These include a wide range of conditions that are 

both birth defects and acquired conditions, all having a spectrum of severity that ranges from 

causing early death or renal failure to the social burden of incontinence. Pediatric urology 

remains an underserved field in terms of research funding and activity relative to the health 

impact of pediatric urological conditions. Many of the conditions cared for by the pediatric 

urologist are relatively rare and unfamiliar—for example, posterior urethral valves—yet have 

profound impact on long-term health of the child and adult. Others are extremely common, 

such as urinary tract infection (UTI), yet may have a wide spectrum of severity that conveys 

the impression of relatively mild impact. Some conditions may have both direct health impact 

as well as potentially severe psychosocial impact, such as the intersex conditions and other 

congenital anomalies of the genitalia.

Much of the clinical challenge intrinsic to pediatric urology rests in the need to discriminate 

between children at risk for severe long-term complications and requiring intervention 

and the larger group who are not. The relative infrequency of many conditions necessitates 

development of multicentered clinical studies with the requisite infrastructure of database 

management, registries, and data analysis centers. The complexity and variety of the 

congenital anomalies seen in pediatric urology will require intensive basic science investigation 

to develop a clinically relevant understanding of the pathophysiological mechanisms of disease. 

This will require robust collaborative initiatives between clinicians and basic scientists in order 

to take advantage of modern scientific understanding and current technologies to develop 

such knowledge. Constraints to developing the necessary manpower infrastructure from 

both the basic scientific and clinical arenas are substantial and may represent one of the more 

formidable obstacles to maturation of the field of pediatric urological investigation. These 

obstacles must be overcome in order to elevate pediatric urology and the care given to many 

children by pediatric urologists above the increasingly archaic and reactive patterns of clinical 

care now in practice. Although the wide spectrum of conditions seen in pediatric urology may 

appear as yet another obstacle, the fact that they touch upon nearly every aspect of biology and 

medicine may make pediatric urology an ideal portal into the critical aspects of many disease 

processes and developmental anomalies.

Executive Summary
8 Executive Summary

Major Clinical Needs in Pediatric 

Urology

Key disease groups

Obstruction

Urinary obstruction is the major cause of renal 

failure in children and can be directly associated 

with abnormalities of kidney development 

producing dysplasia, another major cause of kidney 

failure. The wide range and severe impact of 

these conditions is well known, but the molecular 

mechanisms of these effects are unknown. As a 

result, the ability to predict clinical outcomes, select 

patients at risk or modify these effects specifically, is 

extremely limited. Integral to these goals will be a 

more thorough understanding of the developmental 

mechanisms in the kidney and urinary tract, 

since these are all influenced by obstructive 

processes. Understanding the basic mechanisms 

of the response to obstruction should permit 

development of biomarkers for these conditions 

that will facilitate identification and stratification of 

patients by their predicted outcomes. This would 

facilitate more specific therapy. These measures will 

clearly depend upon the development of clinical 

trial systems in obstructive uropathies to permit 

validation of potential diagnostic and therapeutic 

technologies.

Urinary Infection and Reflux

The frequency of urinary tract infections and their 

potential for causing kidney damage and other 

related morbidity make them a major challenge 

for pediatric urology research. The complex 

mechanisms by which bacteria infect the urinary 

tract and, in cases of pyelonephritis, cause renal 

injury, should be topics of investigation. Treatments 

to interfere with uropathogenetic colonization 

without prolonged antibiotic use and to prevent 

the complication of permanent renal damage are 

needed. Clinical management would benefit greatly 

from new methods that would permit immediate 

identification of infectious bacteria in patients 

as well as better technologies for imaging after a 

UTI, as well as identifying inflammation and renal 

scarring.

Vesicoureteral reflux (VUR) is a developmental 

defect in which abnormal insertion of the ureter 

into the bladder causes retrograde flow of urine 

into the ureter and the upper urinary tract. It may 

also be caused by lower urinary tract dysfunction. 

The most important complication of VUR, which 

affects 1 percent of children, is an increased risk 

of upper urinary tract infection leading to renal 

scarring and damage. The severity of the reflux 

and its complications range from cases where renal 

abnormalities are present at birth (these children 

account for most cases of subsequent renal failure) 

to the more prevalent mild and moderate cases 

where kidney damage is not present at birth and 

where the reflux is likely to resolve spontaneously. 

Milder cases are generally treated by antibiotic 

prophylaxis, which is effective in preventing UTI 

and its complications. The long-term individual 

and societal side effects of the antibiotics are 

unknown; indeed, there is increasing concern 

about the resulting emergence of resistant bacterial 

strains. New clinical trials will be needed to 

determine whether withholding of antibiotics until 

an infection is suspected is advisable. Another 

challenge is to determine optimal timing and type 

of therapy for children with VUR, whether this 

is open surgery, laparoscopic surgery, endoscopic 

injection, or observation. These decisions need 

to be based upon rigorous outcomes data based 

upon clinically relevant parameters over sufficiently 

long periods to capture the critical elements of 

reflux outcomes. It will also be essential for any 

clinical trials to be tightly integrated with a more 

complete understanding of the pathophysiology 

of critical events related to reflux, including renal 

growth, scarring, immune responses, and healing 

processes, as well as the genetic bases for these 

processes. Without this information, the ability to 

identify patients at risk, or to enhance therapeutic 

interventions, will be inadequate.
Executive Summary 9

Bladder Dysfunction

Abnormalities of bladder function are wide ranging 

in causes and effects. They may produce quality of 

life challenges such as incontinence or bed-wetting 

(which has an extremely high prevalence), or they 

may produce a significant risk for infection and 

kidney injury when neurological abnormalities are 

the cause. The bladder’s complexity is only now 

being recognized and presently knowledge of its 

normal, and abnormal, development and functional 

maturation is limited. Improved understanding is 

absolutely critical to our ability to identify patients 

at risk as well as to intervene for both quality of life 

and health issues. Research in this area will require 

indepth knowledge of developmental biology, 

neurobiology, and smooth muscle and epithelial cell 

biology.

Hypospadias and Genital Anomalies

Hypospadias is the second most common birth 

defect, and its incidence is increasing, according 

to the Centers for Disease Control and Prevention. 

Although there is increasing evidence that 

environmental factors such as maternal exposure 

to endocrine disruptors during pregnancy might 

explain the increased incidence, the etiology of 

hypospadias remains unknown in the majority of 

cases. A program of developmental genetic research 

leading to a better understanding of urethral 

development will provide insights into the causes 

of this congenital disorder and explanations for its 

increased incidence.

Congenital anomalies of the sex organs confront 

clinicians with urgent needs to assign sex and 

perform appropriate surgical reconstruction. Sex 

assignment decisions in which optimal gender was 

based on factors such as the potential for sexual 

function and reproductive potential have been 

highly contested; though studies are very limited, 

reports of affected individuals have indicated 

dissatisfaction with not only the gender assigned, 

but also resentment of the processes of decisionmaking and information sharing. Prospective 

studies of gender identity and reproductive function 

and quality of life are needed in this group of 

patients to guide clinicians and families in making 

decisions about gender assignment and surgical 

reconstruction. The relative infrequency of these 

conditions emphasizes the need for multicentered 

clinical studies with the requisite infrastructure of 

database management, registries, and data analysis 

centers.

Developmental Andrology

Cryptorchidism requiring surgery occurs in 

approximately 1 percent of male births. While 

surgical therapy is highly successful, it does not 

always prevent impaired reproductive function. 

Given the very high incidence of these conditions, 

the research challenge is to determine the genetic 

and endocrinological basis of cryptorchidism 

and to develop strategies to prevent the loss of 

fertility. Varicocele is another condition associated 

with impaired fertility that develops in the early 

adolescent years. The underlying mechanisms of 

development and its effect on testicular function 

remain unclear, despite its occurrence in up to 15 

percent of young men.

Key research themes

Molecular and Genetic Basis of 

Developmental Anomalies

Understanding the cellular and molecular basis 

of urinary tract development is a prerequisite 

for advancing the diagnosis and treatment of 

genitourinary tract disease in the post-genomic 

era. Exceedingly complex—and understudied—

this area of developmental biology has important 

implications for congenital kidney and urinary tract 

disease, as well as the potential to provide critical 

insights into a variety of other developmental 

systems. The complexity of the urogenital system 

and the frequency of congenital abnormalities 
10 Executive Summary

suggest that an improved understanding of these 

processes will yield a broader understanding 

of other systems as well. This will be critical 

in both clinical diagnostics and therapeutics 

with a wide variety of methodologies, including 

tissue engineering, stem cells, gene therapy, and 

nanotechnology. 

Formation of the genitalia is a complex 

developmental process involving genetic 

programming, cell differentiation, hormonal 

signaling, enzyme activity, and tissue remodeling. 

Understanding the molecular mechanisms of 

normal development is critical if we are to be 

successful in elucidating the causes of abnormalities 

of both the internal and external genitalia. Basic 

research in this area will be vital for prevention 

and treatment of diseases such as hypospadias, 

epispadias, undescended testes, and uterine 

abnormalities. Specific priorities should include:

• Characterize the programs of gene expression 

that mediate the formation, function, and 

injury response of individual genitourinary 

tract structures using genetic models of 

mice, cell culture, biomechanical studies, and 

bioinformatics in a multidisciplinary manner.

• Establish the data-sharing platforms that 

will allow the productive integration of gene 

expression and proteomic data sets with threedimensional morphometric data, as well as 

existing human and mouse genetic databases.

• Explore how in vitro developmental biology—

including organ and cell culture, as well as 

stem cell technology—can be exploited for 

tissue engineering of genitourinary (GU) tract 

structures.

• Apply the insights into urinary tract 

development obtained from investigations in 

model systems to human malformations—such 

as renal dysplasia, renal ectopia, congenital 

hydronephrosis, reflux, and posterior urethral 

valves.

• Improve the description, diagnosis, and 

treatment of conditions of maldevelopment, 

with classification and diagnostic systems 

based upon multi-dimensional parameters.

• Develop systems to permit sharing of 

biological specimens and knowledge, linked 

with clinical registries using institutional 

arrangements that foster multidisciplinary 

investigation, as in Centers of Excellence for 

Pediatric Urology.

• Provide incentives and opportunities for 

investigators in developmental biology to enter 

into understudied aspects of genitourinary 

tract development, including (but not limited 

to) ureter and bladder formation

• Develop better treatments to prevent or correct 

conditions of maldevelopment: improve 

surgical success, both open and minimally 

invasive (endoscopic, laser, laparoscopic, 

and robotic), and develop potential drugs for 

treating the diseases without surgery.

Outcomes Assessments: Health

and QOL

Throughout all aspects of pediatric urology, there 

is a significant need for enhanced tools to facilitate 

clinical research that can directly impact patient 

care. These limitations have hindered clinical 

progress to date and will limit the ability to apply 

novel technologies in a specific way. Without 

adequate systems to assess, compare, and monitor 

clinically relevant outcomes, new and promising 

technologies may not be able to be appropriately 

validated in pediatric urologic conditions. Steps 

critical to enhancing clinical research include:

• Establish standard definitions of pediatric 

urologic conditions for use in clinical practice 

and research. 

• Develop a set of standardized objective 

and patient-centered outcomes for use in 

clinical research of various pediatric urologic 

conditions.

• Establish clinical research networks to 

undertake randomized clinical trials.
Executive Summary 11

• Create pediatric urology disease registries for 

use in clinical research and improvement of 

quality of care.

• Develop systems to permit adequate training 

of clinical researchers with interest and 

experience in pediatric urology.

New Technologies in Research and 

Clinical Practice

Powerful new tools have become available to the 

researcher and the clinician during the last decade 

and with them an as yet unrealized capacity to 

improve our understanding of many more disease 

processes and ameliorate them in children. 

Pediatric urology is currently limited in its ability 

to tap into the new methodologies because of a 

variety of infrastructural, attitudinal, and financial 

limitations. To advance the care of children with 

Pediatric Urological diseases, these limitations must 

be overcome in the near future. The principle areas 

where important new knowledge and insight may 

be gained include:

• Systems Biology

• Bioinformatics

• Gene Chip Arrays

• Proteomics

• Genomics

• Metabolomics

• Nanotechnology

• Stem Cells and Tissue Engineering

• Biomechanics

• Bio-imaging Technology 

In the clinical arena, novel technologies are 

emerging to enhance therapeutic interventions, and 

with increasing basic understanding of diseases, 

new technologies are certain to emerge. These 

include:

• Minimally Invasive Surgery and Robotics

• Tissue Engineering

• Imaging Technologies

• Technology Assessment

Each of these novel technologies is highlighted in 

this report, and all share similar needs to permit 

needed integration of their capabilities with 

pediatric urological needs and patients. Therefore, 

it is strongly recommended that efforts and funding 

be committed to:

• Arrange joint mentoring of researchers by 

mentors with extensive experience in pediatric 

urology and novel technologies.

• Fund new investigators taking a 

multidisciplinary approach to pediatric 

urology and aspects of novel technologies.

• Encourage multidisciplinary research efforts 

between scientists and clinicians experienced 

in these technologies, urologists, and industry.

• Establish regional resource centers for novel 

technologies and pediatric urology to assist 

with development and application of these 

technologies.

• Develop educational programs to acquaint 

the next generation of pediatric urological 

researchers with emerging technologies.

• Convene workshops to foster interaction 

between clinicians and scientists experienced 

in these new technologies and pediatric 

urological researchers.

Training and Manpower Infrastructure

A variety of institutional pressures make life 

exceedingly difficult for pediatric urologists 

contemplating a research career. We recommend 

new training mechanisms that would allow those 

with a strong commitment to immerse themselves 

in research under the mentorship of scientific 

leaders in the field.
12 Executive Summary

The participation of Ph.D. investigators in 

research with direct applications to pediatric 

urology is inadequate. We discuss some cultural 

barriers to this participation and advocate 

training programs to support graduate students 

studying research problems centered on urologic 

disease, with urologists participating as advisors. 

Postdoctoral programs in urology research also are 

recommended.

We underscore the importance of collaboration 

between basic scientists and clinicians in pediatric 

urology research. If the number of collaborative 

projects is to grow, novel funding mechanisms 

may be needed to address the unique demands 

of the clinician scientist struggling to fulfill dual 

roles, as well as those of the basic scientist, as she 

or he attempts to maintain funding within, or in 

collaboration with, a clinical department.
Strategic Plan for Pediatric Urology 13
14 Strategic Plan for Pediatric Urology
Strategic Plan for Pediatric Urology 15

I. Th e Urinary Tract

The urinary tract can be divided into upper and 

lower tracts: the upper tract refers to the kidneys and the ureters (production and transport 

of urine); the lower tract comprises the bladder 

and urethra (storage and emptying of urine). The 

kidneys continually fi lter the blood to maintain 

water and electrolyte balance, remove wastes and 

foreign chemicals, and perform a variety of hormonal functions, including the regulation of blood 

pressure. The ureters pump the urine produced 

by the kidneys into the bladder at low pressure 

without causing the holdup, or stasis, that might 

permit infections. The renal pelvis and the ureter 

pump urine in a similar manner, with an automatic pacemaker that controls the rate and force of 

contraction. The urine then passes into the bladder through the ureterovesical junction, which is 

confi gured in such a way as to prevent backwash, 

or refl ux, of urine from the bladder into the ureter 

and kidney.

A. Upper Urinary Tract

1. Urinary Tract Development and Maldevelopment

Understanding the cellular and molecular basis 

of urinary tract development is a prerequisite for 

advancing the diagnosis and treatment of genitourinary tract disease in the post-genomic era. 

Exceedingly complex—and understudied—this 

area of developmental biology has important 

implications not only for congenital kidney and 

urinary tract disease, but also for devising new 

approaches to tissue engineering and organ 

repair and regeneration. What is required to 

advance the fi eld is a multifaceted strategy that 

utilizes genetic investigation, organ culture, and 

cell culture, combined with multidisciplinary 

approaches. Th e collaborative eff orts of cell 

and developmental biologists, clinicians, computational scientists, and tissue engineers will 

enable investigators to examine molecular and 

Summary 

cellular mechanisms underlying the formation of 

individual genitourinary tract structures, their 

patterning, the fates of diff erent cells in the genitourinary tract, and the way in which epithelial and 

mesenchymal cells interact in normal and disease 

states. Th e impact of such a research program on 

pediatric diseases such as obstructive and refl ux 

uropathies, as well as end-stage kidney disease, 

could be profound.

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16 Strategic Plan for Pediatric Urology

Health Impact

Abnormal development of the urinary tract occurs 

in as many as 1.0 percent of all pregnancies and 

leads to a large and varied group of malformations, 

including those associated with obstruction and 

voiding dysfunction. As the use of fetal sonography 

provides earlier detailed anatomical information 

to parents, the challenge to the pediatric urologist 

is to reliably differentiate patients who have 

aberrant anatomy, but in whom these constitute 

incidental findings of no long-term significance, 

from those in whom a detailed workup and 

therapy are warranted. It should be noted that 

several urogenital tract abnormalities—of which 

renal dysplasia and hydronephrosis are the most 

important—can lead to end-stage renal disease 

(ESRD), thereby constituting a significant fraction 

of children and young adults requiring renal 

dialysis or transplantation. A clear understanding 

of the normal development of the urinary tract is a 

fundamental prerequisite to developing therapeutic 

or interventional treatments that prevent ESRD.

A Brief Description of Normal Urinary 

Tract Development

Kidney, renal pelvis, and ureter

Urinary tract formation depends on reciprocal 

interactions between epithelial and mesenchymal 

cell types. Development is initiated by the 

formation of the ureteric bud, an epithelial 

outgrowth of the Wolffian duct. The tip of the 

ureteric bud induces the kidney primordium to 

mature and begin to undergo successive branching 

to form the renal collecting system, which in 

humans consists of roughly 1 million collecting 

ducts. Meanwhile, the ureteric bud induces the 

formation of the nephrons. The mature kidney 

will be composed of a roughly 1 million nephrons, 

each consisting of a filtration unit (the glomerulus), 

a proximal tubule, the loop of Henle, and a 

distal tubule that connects with the collecting 

duct. Nephron function—maintaining the fluid 

composition of the body through the production 

of urine— is crucial for life; it depends upon the 

architecture of the kidney, in large part determined 

by the branching pattern of the ureteric bud.

Connecting the upper and lower urinary tract

The distal portion of the ureteric bud (i.e., that 

portion of the ureteric bud that lies outside 

the metanephric mesenchyme) will eventually 

differentiate into the ureter, a water-tight epithelial 

tube enclosed in a smooth muscle coat that propels 

urine to the bladder via rhythmic contractions of 

the smooth muscle (peristalsis). Defects in the 

development of the supravesical portions of the 

urinary tract include renal dysplasia, as well as 

malformations of the urinary tract distal to the 

kidney (e.g., megaureter, ureteropelvic junction 

obstruction, vesicoureteral reflux, ectopic/

duplicated ureters, and posterior urethral valves). 

See “Renal Dysplasia” and “Ureteral Anomalies” 

below.

Bladder, trigone, and urethra

The bladder and urethra are thought to be formed 

from the urogenital sinus. The bladder trigone, 

the portion of the urogenital sinus between the 

bladder body and urethra, appears to derive from 

the intermediate mesoderm as the distal ureter 

inserts into the urogenital sinus. As development 

progresses, the bladder differentiates into a 

muscular structure lined by urothelium and 

begins to function in the collection, storage, and 

elimination of urine. Storage and emptying of the 

bladder requires coordination between the bladder 

and the urethra. Relatively little is known about 

the innervation of the urinary bladder that occurs 

during embryogenesis.

Common problems that affect the bladder and 

urethra include spinal cord defects (spina bifida), 

congenital bladder outlet obstruction (posterior 

urethral valves, ectopic ureterocele), acquired 

bladder obstruction (voiding dysfunction), and 
Strategic Plan for Pediatric Urology 17

congenital anatomic anomalies (bladder exstrophy, 

imperforate anus, prune belly syndrome, and 

ureteral ectopia). A significant number of children 

born with these defects will have morbidity directly 

related to their bladder dysfunction. Disorders of 

the urethra are discussed in a later section.

Major Disorders of Upper Urinary 

Tract Development 

Renal dysplasia

While dysplasia is the leading cause of renal failure 

in children, it still has no universal definition. 

The term refers to a histologic diagnosis in which 

part or all of the kidney did not develop properly, 

causing a decline in kidney function. Associated 

conditions include obstruction (posterior urethral 

valves, ureteropelvic or ureterovesical junction 

obstruction), ureteral bud abnormalities (ectopic 

ureters, ureteroceles, and vesicoureteral reflux) 

and defects in genes and genetic pathways involved 

in normal kidney development and apoptosis. 

Renal dysplasia also is associated with certain 

developmental syndromes where multiple defects 

in other organs are found. The manifestation of 

dysplasia can range from small poorly functioning 

kidneys to large non-functioning, cystic ones 

(multicystic dysplastic kidney [MCDK]); it is likely 

that there are unique mechanistic pathways leading 

to each of the various forms of the condition. A 

classification and grading system for dysplastic 

kidneys, based upon histological, molecular, and 

biochemical criteria, would facilitate research in 

his area. 

Upper urinary tract obstruction

Obstruction of the kidney is a major cause 

of kidney failure and other complications in 

children. Urinary tract blockage can occur at any 

level from the kidney to the urethral meatus; in 

congenital cases, the most common locations of 

obstruction include the ureteropelvic junction 

(between the kidney and ureter), the ureterovesical 

junction (between ureter and bladder), and the 

bladder outlet (here, in males, obstruction is 

often secondary to posterior urethral valves). 

The blockage causes urinary tract “ballooning” 

(dilatation) above the blockage — hydronephrosis 

refers to this dilation in the kidney, and is the cause 

of kidney failure in 16 percent of children who 

undergo transplantation. Urinary dilation, found in 

up to 2 percent of pregnancies, is the most common 

abnormality noted prenatally. Current imaging 

methods (ultrasonography, radionuclide imaging, 

and pyelography), do not allow for differentiation 

of patients at risk for renal deterioration and those 

with little risk. New, non-invasive, accurate imaging 

methods for assessing and prognosticating renal 

function need to be developed. 

Hydronephrosis is usually accompanied by 

increased pressure in the kidney, and when severe 

and prolonged, can lead to kidney damage or 

destruction. In prenatal cases, cysts, kidney tissue 

malformation, and dysplasia can develop, replacing 

the normal kidney tissue. Growth of the kidney 

can be both augmented and impaired, and several 

growth factors have been implicated in dysplasia 

resulting from obstruction. (In a neonatal rat 

model, exogenous epidermal growth factor partially 

rescues changes induced by urinary tract blockage.) 

If hydronephrosis develops postnatally, the kidneys, 

especially in the presence of infection, may become 

scarred and damaged without associated dysplasia.

A hallmark of obstruction is the development of 

interstitial renal fibrosis, a phenomenon that has 

been extensively examined in non-obstructive 

models, yielding insights with potential relevance 

to obstruction. Molecular mediators of fibrosis 

include the renin-angiotensin system (already 

implicated in obstructive changes), cytokines 

such as TGFß1, as well as direct regulators 

of extracellular matrix homeostasis, MMPs 

(metalloproteinases) and TIMP (tissue inhibitors 

of metalloproteinases). It should be noted that 

the highly specialized functions of the various 
18 Strategic Plan for Pediatric Urology

kinds of renal cells can be affected by obstruction 

beyond obvious growth and injury responses. 

Functional consequences of obstruction can include 

impairment of glomerular and tubular function, 

with clinical implications such as azotemia (renal 

failure), diabetes insipidus, and renal tubular 

acidosis.

Hydronephrosis is a condition that can significantly 

impair the developing kidney. One focus of research 

should be intercellular signaling within the tubules 

and between the epithelia and mesenchymal 

compartments of the developing kidney; altered 

epithelium-mesenchyme transitions, which are a 

critical part of normal kidney development, are very 

likely to play a key role in obstructive nephropathy. 

The signal transduction mechanisms underlying 

these processes are being elucidated, and they need 

to be understood in the context of obstruction. The 

complex integrative functions of the kidney cannot 

be neglected, particularly the impact of obstruction 

on renal innervation and humoral regulation, as well 

as angiogenesis and the development and regulation 

of the renal vasculature. Obstruction also has been 

demonstrated to affect apoptosis through wellcharacterized molecular mediators of this process. 

The regulation and role of apoptosis in the developing 

kidney, and its involvement in the kidney damage 

accompanying hydronephrosis, need to be further 

investigated. 

Other ureteral anomalies

Many anomalies of the ureter—including 

vesicoureteral reflux and abnormal entry of 

the ureters into the bladder (ectopic ureter or 

ureterocele)—result from abnormal ureteral 

budding. Abnormal ureter locations can lead 

to ureteral blockage, and in rare cases, ureteral 

communication with other structures such as the 

seminal vesicle, vas deferens, and vagina. 

The best described ureteral anomaly, megaureter, 

can be classified in three general categories: 

(1) obstructed megaureter, (2) refluxing megaureter, 

and (3) non-obstructed, non-refluxing megaureter. 

All are presumed to be caused by an abnormality 

at the junction of the ureter and the bladder. In 

obstructed megaureter, the junction appears to be 

thickened and narrowed so that the normal flow of 

urine from ureter to bladder is impeded; this causes 

the ureter to distend and become quite enlarged. In 

refluxing megaureter, the ureters join the bladder 

in such a way that extensive vesicoureteral reflux 

occurs causing the ureter to become very enlarged. 

Prune belly syndrome (PBS) is a complex congenital 

anomaly characterized by abnormal abdominal 

muscles, undescended testes, infertility, and massive 

urinary tract dilation. Bilateral massive megaureters 

are typically present. While there is no evidence 

of obstruction, these ureters typically drain very 

poorly, and this can result in urinary tract infections 

and kidney failure. Very little is known about the 

cause of this disease or why the urinary tract is so 

abnormal. 

The diagnosis of renal dysplasia and ureteral 

anomalies is typically performed by ultrasound 

to detect ureter and kidney dilation; voiding 

cystography can detect vesicoureteral reflux, and 

nuclear renography is used to determine kidney 

function and establish whether there is a blockage 

present in the system. Newer modalities such as 

magnetic resonance imaging (MRI) have recently 

been reported to enhance both anatomic and 

functional detail. MRI may permit the clinician 

to obtain an accurate anatomical picture of the 

entire urinary tract and determine the obstructive 

nature of megaureter in a single test. Radiation is 

avoided, and the contrast reagent does not harm the 

kidney, while the imaging quality is excellent. The 

disadvantages are high costs and the possible need 

for anesthesia in younger children.
Strategic Plan for Pediatric Urology 19

Priorities for Basic Research

1. Clarify the mechanisms by which the normal 

GU tract development is regulated—to include 

the glomerulus, proximal and distal tubules, 

collecting ducts, renal pelvis, ureter, bladder, 

and urethra.

• Characterize the program of gene expression 

that mediates formation of individual GU tract 

structures.

• Determine how collecting ducts, renal pelvis, 

and ureter derive from the Wolffian duct and 

ureteric bud. 

• Identify the reciprocal epithelial-mesenchymal

signals required for patterning of GU tract 

tissues. 

• Generate the mouse strains that will permit 

the conditional and tissue specific expression

of molecular markers of cell origin that can 

define cell lineage in development of the upper 

urinary tract. Elucidate the origin of cells 

comprising the epithelial and mesenchymal 

structures of the GU tract (e.g., formation of 

the bladder trigone). 

• Encourage multidisciplinary approaches,

bringing together those who investigate 

the development of the GU tract through 

organ culture, murine genetic models, cell 

culture systems, biochemical approaches, and 

bioinformatics.

• Establish the data sharing platforms that

will allow the productive integration of gene 

expression and proteomic data sets with three 

dimensional morphometric data as well as 

existing human and mouse genetic databases.

2. Clarify the molecular and cellular mechanisms

of urine transport in the upper GU tract and the 

voiding reflexes in the lower GU tract. 

• Identify and characterize the molecular and 

cellular mediators that regulate pyeloureteral 

peristalsis. 

• Identify cell populations that form the 

pacemaker cells and sympathetic nerves that 

control muscle contraction in the renal pelvis 

and ureter.

• Understand formation and function of neurons 

that control the voiding reflexes. 

• Identify the developmental switching 

mechanism(s) that convert the voiding reflexes 

from the neonatal to the adult pattern. 

• Define the relationship of ureteral muscle 

function (contractility) to the microscopic 

findings.

Priorities for Translational and Clinical 

Research

1. Determine how knowledge of the 

developmental biology of the GU tract can be 

applied to tissue engineering purposes.

• Explore how in vitro developmental biology 

(including work in organ and cell culture) can 

be exploited for tissue engineering of GU tract 

structures.

• Combine stem cell approaches with in vitro

developmental systems to devise new strategies 

for engineering GU tract structures.

2. Apply the insights into urinary tract 

development obtained from investigations in 

model systems to human malformations such 

as renal dysplasia, renal ectopia, congenital 

hydronephrosis, reflux, and posterior urethral 

valves.

• Identify candidate genes for GU tract 

malformations through transcriptional 

profiling of developing urinary structures 

and subsequent analysis using sophisticated 

informatics approaches. 

• Establish national human tissue banks and 

repositories of human specimens to more 

effectively investigate whether results in 
20 Strategic Plan for Pediatric Urology

mutant mice or in vitro developmental systems 

are applicable to diseases seen in humans. 

• Develop appropriate murine models for 

renal dysplasia, hydronephrosis, and 

ureteral anomalies and other diseases of 

maldevelopment. 

• Evaluate genetic pathways implicated in 

human disease and murine models of disease 

in animals amenable to detailed physiological 

studies and, where applicable, in organ culture 

systems.

3. Characterize the developmental determinants of 

renal dysplastic syndromes and chronic bladder

dysfunction.

• Investigate the role of epithelial-mesenchymal 

interactions in development—in injury, 

fibrosis, dysplastic syndromes, and childhood 

malignancy.

• Elucidate the developmental origins of bladder 

disease in children and adults (e.g., interstitial 

cystitis, voiding dysfunction in childhood, and 

reemergence of primitive reflexes after spinal 

cord injury).

4. Improve the description, diagnosis, and 

treatment of conditions of maldevelopment.

• Improve the diagnosis, classification, and 

histopathological description of dysplasia and 

other developmental disorders. 

• Conduct trials to establish the true natural 

history of the varying degrees and causes of 

renal obstruction. 

• Develop tests using novel technologies 

(from bioengineering, proteomics, etc.) for 

the purposes of determining the severity of 

disease and identifying which patients would 

benefit from surgery or drug treatments. New 

imaging methods or biomarkers to identify 

those at risk for renal deterioration among 

patients with obstruction and other conditions 

are critically are critically needed. needed.

• Develop better treatments to prevent or correct 

conditions of maldevelopment: improve 

surgical success, both open and minimally 

invasive (endoscopic, laser, laparoscopic, 

and robotic), and develop potential drugs for 

treating the diseases without surgery.

Infrastructural Needs

• Unimpeded sharing of mouse strains relevant 

to urological disease; central human tissue 

banks and repositories; clinical registries

• Institutional arrangements that encourage 

multidisciplinary approaches, including 

Centers of Excellence for Pediatric Urology

• Incentives and opportunities for investigators 

in developmental biology to enter into 

understudied aspects of GU tract development, 

including (but not limited to) ureter and 

bladder formation
Strategic Plan for Pediatric Urology 21

Kidney stones in children are increasing in 

prevalence and often require a lifetime of dietary 

changes, medication, and hospitalizations. 

The condition is often painful and frequently 

requires surgery. It should be noted that the rare 

inherited diseases like primary oxaluria that 

cause kidney stones are life threatening because 

of the risk of kidney failure, and these inherited 

diseases cannot be adequately addressed with 

current therapies. Multi-center trials are needed 

to compare the effectiveness of extracorporeal 

shock wave lithotripsy and percutaneous 

nephrolithotripsy for stone removal and 

to evaluate the use of medications to aid 

spontaneous passage. Critical goals for basic 

research include a detailed understanding of the 

metabolic basis of the stone diseases, identifying 

the genetic determinants of susceptibility, 

and understanding the mechanism of crystal 

attachment and stone formation in the 

urinary tract.

Summary 

2. Nephrolithiasis

Health Impact

Stones of the kidneys and urinary system 

(urolithiasis) are a growing problem in pediatric 

urology and now account for one in 7,600 to 10,000 

hospital admissions. In developing countries where 

diet is poor and dehydration common, pediatric 

urolithiasis is endemic. In the United States, 

hospitalizations, surgery, parental time away from 

work to care for the affected child, and chronic 

medications all add to the economic burden. 

Children with stone disease may be faced with a 

lifetime of medical issues, as many will become 

adult stone formers. Dietary restrictions and 

vigorous fluid intake are typically needed to prevent 

recurrence. Kidney stones are often extremely 

painful to pass and may be accompanied by 

urinary infection. Hospitalizations and surgery are 

frequently required. Children whose kidney stones 

are symptomatic of rare diseases due to inherited 

defects in metabolism—distal RTA, cystinuria, 

and primary hyperoxaluria—may suffer kidney 

damage or failure and require dialysis and/or organ 

transplantation. 

Clinical Presentation and Treatment

Formation of stones in a child is a manifestation 

of abnormal metabolism in the majority of cases, 

although sometimes it is related to abnormal 

structure of the urinary tract. In approximately 

one-half of pediatric cases, urinary stone disease 

is familial. Typically, specialized blood and urine 

testing is performed to identify the root cause of the 

stone production. In 80 percent of cases, stones are 

composed predominantly of calcium compounds 

with calcium oxalate stones being the most 

common subtype. Infection stones, uric acid stones, 

and cystine stones can also affect children. 

Once a stone is identified, it can be monitored 

for spontaneous passage if no complicating issues 

arise. However, stones greater than 5 mm rarely 

pass unaided. Three main avenues of surgical 

treatment exist—extracorporeal shock wave 

lithotripsy (ESWL), ureteroscopic lithotripsy, and 

percutaneous nephrolithotripsy (PCNL). Open 

surgery is rarely required. 

ESWL is typically the first choice of therapy for 

fragmenting a urinary stone and is about 80 percent 

successful, but sometimes the stone is too hard to 

break or the fragments do not pass out in the urine. 

Short-term studies suggest there are no lasting effects 

of the shock waves on the growing pediatric kidney, 

but long-term studies to verify this are lacking.

Ureteroscopy is a surgical procedure in which 

tiny long telescopes (ureteroscopes) are passed 

into the urinary system through the urethra, 

into the bladder and up the ureter to the stone. 

Specialized devices (including lasers) are then 
22 Strategic Plan for Pediatric Urology

passed through the ureteroscope to fragment 

the stone. Subsequently, some or all of the stone 

fragments can be removed from the body with the 

ureteroscope. Performed under anesthesia, this 

technically challenging procedure is generally safe 

but somewhat riskier than ESWL, and 90 percent 

effective at stone removal in children.

In percutaneous nephrolithotripsy, a special hollow 

tube is passed through the skin of the back directly 

into the affected kidney. Under anesthesia, special 

telescopes (endoscopes) are passed to fragment 

and remove the stones. This procedure is typically 

performed for larger or hard-to-break kidney stones 

or in other special situations. In rare cases, blood 

transfusion is required. The stones are eliminated 

in 90 percent of cases. Open stone surgery is rarely 

needed and now is used only for the most complex 

cases with large stone burden.

Priorities for Basic Science Research

• Obtain a thorough understanding of the 

metabolic basis—in the kidney, intestines, and 

bone—of stone formation in children. 

• Characterize the genetic determinants of 

increased susceptibility to stone formation 

in certain individuals. Conduct additional 

familial studies to identify the genetic basis of 

inherited diseases that cause stone formation.

• Determine how crystals and stones attach to 

the surfaces of cells in the urinary tract. 

Priorities for Translational and Clinical 

Research

• Study the long-term effect of excess urine 

calcium in childhood, including the risks of 

recurring stone formation and osteoporosis.

• Validate pediatric standard reference ranges 

(stratified for age and sex) for lithogenic and 

stone-inhibiting urine solutes and metabolites.

• Use proteomics methodologies to identify 

factors that promote and prevent stone 

formation.

• Perform multicenter outcomes analyses of 

ESWL versus PCNL for large stone burden 

in children. Evaluate the long-term effects of 

ESWL on the pediatric kidney.

• Perform a prospective, double-blind, 

randomized clinical trial investigating the 

usefulness of medications to help spontaneous 

passage of symptomatic distal ureteral stones 

in children. Possible medications could 

include alpha-blockers, steroids, and calciumchannel blockers.

• Develop stone-imaging techniques that 

minimize X-ray exposure. 

• Develop improved miniaturized 

instrumentation for pediatric lithotripsy.
Strategic Plan for Pediatric Urology 23

impairment of urine flow. Anatomic obstruction 

is more frequent in males; the most common 

cause is PUV, a developmental anomaly resulting 

in membranous folds in the posterior urethra 

that occurs in approximately 10 percent of 

prenatally diagnosed uropathies. Acquired voiding 

dysfunction and neurological disease are also causes 

of outlet obstruction. 

Neonates with PUV may exhibit underdevelopment 

of the lung caused by oligohydramnios, and 

morbidity and mortality associated with pulmonary 

hypoplasia are significant. Renal impairment—that 

resulting from primary renal dysplasia and that 

which is secondary to bladder dysfunction—

occurs in 20 to 65 percent of boys with PUV and 

often leads to kidney failure. Persistent urinary 

incontinence is present in as many as 50 percent of 

patients. Urodynamic studies indicate that bladder 

function deteriorates with time: in early life, the 

bladders are hypercontractile—characterized by 

small capacity, high-pressure detrusor contractions, 

and high voiding pressures. Subsequently, the 

patterns change with PUV patients developing 

abnormally large capacity bladders and 

experiencing emptying difficulties, indicating an 

evolving bladder decompensation. The degree of 

bladder dysfunction in patients is correlated with 

loss of renal function.

Numerous approaches have been tried to improve 

postnatal outcomes in PUV patients. The possible 

B. Lower Urinary Tract

3. Lower Urinary Tract Obstruction

Mechanical lower urinary tract obstruction (i.e., 

of the bladder outlet) occurs predominantly in 

male children and the most common cause is 

posterior urethral valves. Prenatal prognosis is 

poor, and while the condition can be addressed 

surgically in neonates, these children are at 

long-term risk for renal failure and urinary 

incontinence. Improved methods for both 

prenatal diagnosis and predicting risk for later 

complications are needed. Clinical trials will 

be required to assess the value of therapeutic 

approaches such as upper urinary tract 

diversion, intermittent catheterization, and 

pharmacologic interventions. More research is 

needed to understand how pressure and ischemia 

attributed to obstruction cause long-term decline 

in neuromuscular control of the bladder.

Summary 

Health Impact 

Prenatal diagnosis of bladder outlet obstruction 

confers a poor prognosis with a large number of 

fetuses succumbing before birth. Among the one in 

5,000 to 8,000 males born with the most common 

cause of bladder outlet obstruction in children—

posterior urethral valves (PUV)—25 percent will 

experience renal failure. Many more will have 

the burden of significant long-term lower urinary 

tract dysfunction requiring costly treatments, 

including intermittent catheterization and surgical 

augmentation of bladder function. 

Clinical Presentation and Treatment

Bladder outlet obstruction is defined as obstruction 

at the bladder neck or urethra resulting in 

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24 Strategic Plan for Pediatric Urology

benefit of early delivery to improve renal outcome 

needs to be weighed against the risk of pulmonary 

immaturity, and to date, there have been no studies 

documenting the actual benefit of early delivery. 

Vesico-amniotic shunts have been placed for 

many years with little positive impact on kidney 

function, although the disappointing results might 

reflect overly stringent patient selection. Overall, 

fetal intervention is plagued by the lack of both an 

accurate diagnosis of bladder outlet obstruction and a 

reliable indicator of postnatal renal function.

Postnatal treatments consist of immediate bladder 

drainage, followed by endoscopic valve ablation. 

These children often still have a poor prognosis 

for both renal function and urinary continence. 

Consequently, a more proactive management is 

now being advocated. Some clinicians suggest 

upper urinary tract diversion when early bladder 

drainage does not improve renal parameters, while 

others advocate the early use of clean intermittent 

catheterization or overnight drainage, similar to 

that used with neuropathic bladder. Pharmacologic 

intervention to relax the bladder outlet or bladder 

muscle have been helpful in some cases; why only 

some patients respond to this approach is not known.

Pathophysiology of Bladder 

Obstruction

Proper urine storage and evacuation by the bladder 

depends on: (1) appropriate tissue viscoelasticity, 

(2) reflex peripheral-spinal neuromuscular control, 

and (3) central nervous system modulation of 

neuromuscular reflexes to coordinate bladder and 

sphincter function. These three elements undergo 

progressive integration during development and 

postnatal maturation, and by late development in 

utero, the bladder is already filling and emptying. 

At birth, reflex voiding is occurring between 

one and two dozen times per day. Maintaining a 

normal frequency and volume of bladder filling and 

emptying may be important to long-term bladder 

function.

Obstruction leads to complex changes in the 

dynamic properties of the bladder, including 

increased voiding pressures, and a decrease in the 

volume required to trigger the voiding reflex, or an 

uninhibited voiding reflex. Later changes may lead 

to bladder decompensation. Sensory nerve changes 

that occur with obstruction may cause urinary 

frequency or urgency, and decreased appreciation of 

bladder filling. The variability in observed bladder 

pathology suggests that the obstructive process—

and perhaps the possibility of its reversal—may 

be quite different in the developing bladder as 

contrasted with the mature bladder. The cellular 

mechanisms by which obstruction leads to changes 

in bladder function are largely unknown, but results 

from some initial investigations have suggested 

several promising lines of research. The stretched 

bladder urothelium secretes signaling molecules 

that could mediate broad effects on surrounding 

tissues, including proliferative effects on bladder 

muscle. Obstruction damages peripheral nerves, 

thereby altering peripheral and CNS pathways 

mediating bladder function. The contractility 

of smooth muscle bundles is greatly reduced 

following obstruction. Other important topics for 

investigation include the role of extracellular matrix 

in the bladder’s response to obstruction and the 

consequences of damage to the vasculature perfusing 

the bladder.

Priorities for Basic Research

• Determine how the urothelium functions as 

a pressure sensor; characterize the relevant 

cellular signal transduction mechanisms.

• Investigate how and to what extent obstruction 

causes peripheral and central nervous system 

damage, and how it affects the vasculature.

• Elucidate cholinergic and adrenergic function 

in obstructed bladder muscle.

• Characterize the dynamic composition and 

structure of the bladder extracellular matrix. 

Define the role of the ECM in pathogenesis 

caused by caused by obstruction. obstruction. 
Strategic Plan for Pediatric Urology 25

• Define the role of angiogenesis as a response 

to, or as a mediator of, fibroproliferative 

change and ECM remodeling. 

• Determine the impact of ischemia on the 

smooth muscle cells of the bladder.

Priorities for Translational Clinical and 

Research

• Determine how developmental timing of 

obstruction determines pathology.

• Develop obstruction models that are more 

appropriate to human disease in terms 

of severity, duration, and location of the 

obstruction. Use existing transgenic animals 

to study the role of specific genes in bladder 

obstruction.

• Develop methods for more accurate diagnosis 

of prenatal PUV and prediction of long-term 

renal function. 

• Conduct randomized, controlled trials to assess 

fetal interventions.

• Define the relationship between the 

development of oligohydramnios and postnatal 

pulmonary function and how a finding of 

oligohydramnios should guide prenatal 

intervention.

• Conduct trials to evaluate new methods of 

managing the obstructed bladder to improve 

bladder and renal function.

• Assess the quality of life in PUV patients and 

families.

Infrastructural Needs

• Unimpeded sharing of mouse strains relevant 

to urinary tract obstruction 

• A clinical registry of PUV patients and banking 

of PUV patient tissue samples

4. Vesicoureteral Refl ux

Vesicoureteral refl ux (VUR) aff ects 1 percent 

of children and is a developmental defect in 

which an abnormal attachment of the ureter 

to the bladder causes retrograde fl ow of 

urine into the ureter and kidney. Th e most 

important complication of VUR is an increased 

risk of a urinary tract infection leading to 

renal damage or scarring. Th e severity of the 

refl ux and its complications varies from cases 

where renal scarring is present at birth (these 

children account for most cases of subsequent 

renal failure) to the more prevalent mild and 

moderate cases where kidney damage is not 

present at birth and where the refl ux is likely 

to resolve spontaneously. Milder cases are 

generally treated by antibiotic prophylaxis, 

which is eff ective in preventing UTI and its 

complications. Th e long-term side eff ects of 

the antibiotics are unknown; there is also 

concern about the resulting emergence of 

resistant bacterial strains. New clinical trials 

will be needed to determine if withholding of 

antibiotics until an infection is suspected is 

advisable. Another challenge is to determine 

in which cases a surgical procedure (e.g., open 

surgery to recreate the valve between the 

ureter or bladder or cystoscopic treatment by 

subureteral injection of a bulking agent) is 

recommended instead of medical therapy. 

Summary 

Health Impact

It is estimated that 1 percent of children have VUR 

and approximately 50,000 new cases are diagnosed 

annually, making it the most common inherited 

anomaly of the urinary tract. VUR may predispose 

an individual to kidney infection, which can cause 

kidney damage or scarring and significant related 

morbidity, including reduced renal function, 
26 Strategic Plan for Pediatric Urology

kidney failure. Unfortunately, the etiology of 

prenatal kidney damage is unknown. Children 

born with VUR without renal complications are at 

significant risk for subsequent kidney damage as 

a result of UTI. The mechanism of scar formation 

is incompletely understood, and predicting which 

children with VUR are most likely to develop kidney 

scarring is not possible at present. Factors such 

as age, gender, reflux grade, ethnicity, voiding 

dysfunction, and genetic determinants may play a 

role. Other than antibiotic treatment, methods to 

minimize the severity of kidney damage following 

UTI are unknown. 

Detection and Evaluation

Currently, the diagnosis of VUR can be made only 

by voiding cystography (voiding cystourethrogram 

or radionuclide cystogram) in which a catheter is 

inserted through the urethra into the bladder, and 

images of the bladder are obtained during filling 

and voiding. The severity of VUR is graded on 

a scale of I (least severe) to V (most severe). The 

procedures produce discomfort, and for some 

children they are traumatic; in some centers, mild 

sedation or conscious sedation has been utilized 

to reduce the trauma of the catheterization. 

Cystography exposes the ovaries or testicles to 

radiation. Typically, many children with VUR will 

undergo serial cystography to monitor the status of 

the reflux condition. 

Kidney imaging includes an ultrasound to assess 

hydronephrosis and kidney size, and some children 

undergo an intravenous pyelogram or radionuclide 

kidney scan to determine whether there is kidney 

damage. In complex cases in which there are 

questions regarding urinary tract anatomy, CT or 

MR scans are used. Abnormal kidney imaging does 

not predict the presence or absence of VUR. 

Screening

Reflux is usually diagnosed in children after a UTI 

and in their siblings and offspring. Although the 

genetic basis of the condition is not known, 40 

In relatively severe type IV vescioureteral 

reflux, urine refluxes all the way up the 

ureter, with marked dilation of the ureter 

and calyces. (© Fairman Studios LLC 

2003)

hypertension, and impaired growth. In the past, 

kidney failure in children was attributed to VUR 

in as many as 20 percent of cases. Currently, only 

3 to 5 percent of children with kidney failure have 

VUR, with the decreased incidence attributed to 

improved diagnosis and treatment of both VUR 

and UTI. However, the long-term effects VUR in 

terms of reflux-related kidney damage are not well 

documented, as national renal transplantation 

registries do not accurately identify reflux as the 

underlying cause of renal failure. While antibiotic 

prophylaxis has been shown to be effective 

in preventing UTI and its complications, the 

treatments are costly and may require many years 

of observation, including surveillance of urinary 

cultures and periodic cystography. There is concern 

about the possible adverse side effects of long-term 

antibiotic usage and the accompanying emergence of 

resistant bacterial strains.

Clinical Presentation and Treatment 

Pathogenesis of Renal Scarring

Kidney damage associated with VUR can be present 

at birth or it may occur after a UTI. Children 

with the most severely affected kidneys at birth 

account for the majority of individuals who develop 
Strategic Plan for Pediatric Urology 27

to 50 percent of siblings will have asymptomatic 

VUR. Diagnosis of VUR in asymptomatic children 

can prevent its infection-related complications, 

however, the advantage of preventive management 

is unproven. VUR also is found in infants with 

dilatation of the kidneys in utero and is the most 

common treatable cause of prenatal dilation of the 

kidney. In these cases, it is more likely to be severe 

and involve both kidneys. 

Medical Therapy

The primary goals of therapy in children with VUR 

are to prevent UTI and kidney damage. Many, 

although not all of those with mild or moderate 

VUR, have spontaneous resolution in later 

childhood. Factors such as gender, age, voiding 

dysfunction, reflux grade, and circumcision status 

may determine the risk of VUR-related morbidity. 

In prospective randomized trials, continuous 

low-dose antibiotic prophylaxis has been shown 

to be generally effective in the prevention of both 

urinary infection and the development of new renal 

scars. Consequently, most children with VUR are 

managed initially with daily antibiotic prophylaxis. 

However, the medical regimen is costly and may 

require many years of observation, surveillance 

of urinary cultures several times per year, and 

periodic cystography. Recent studies have implied 

that some children with VUR, particularly those 

with less severe VUR, may not need daily antibiotic 

prophylaxis. However, the general validity of these 

studies has been questioned, and discontinuing 

prophylaxis has not become common practice in 

the United States.

Voiding Dysfunction

There is an association between lower urinary 

tract (bladder and sphincter) dysfunction and 

congenital VUR. In utero voiding dysfunction 

may account for the high grade of neonatal 

reflux seen predominantly in male infants. In 

older children, voiding dysfunction as well as 

abnormal bowel habits may develop during the 

toilet training years, and the untreated condition 

has been associated with increased rates of 

breakthrough UTI, kidney scarring, and surgical 

failure. Evaluation and management of voiding 

function should be an integral part of the treatment 

of every child with VUR, but currently no standard 

definitions or validated symptom scores for it exist. 

The appropriate role of invasive bladder testing in 

VUR patients with voiding dysfunction is unclear, 

and the benefits of medications for bladder function, 

biofeedback, and bladder training are unknown. 

Surgical Therapy

Surgical therapy—to eliminate VUR and thereby 

minimize the risks of kidney infection and 

damage—is often recommended for individuals 

who have breakthrough infection or have persistent 

high-grade reflux. The procedure recreates the 

valve between the ureter and bladder and has a 

success rate of more than 95 percent. In recent 

years, improvements in perioperative management 

have reduced hospital stays to 1 or 2 days in many 

centers. Laparoscopic ureteral reimplantation has 

been studied at a few pediatric urology centers. A 

new outpatient approach not requiring an incision 

is cystoscopic treatment by subureteral injection 

wherein a bulking agent with the consistency 

of toothpaste is slowly injected into the ureteral 

opening, changing its shape and providing 

improved backing to the ureter. The success rate 

is up to 85 percent, although some children need 

two or three injections. There are ongoing concerns 

regarding the durability of bulking agents. Children 

treated with FDA-approved Deflux (dextranomer/

hyaluronic) have a 10 percent VUR recurrence rate at 

3 years, and its safety and efficacy beyond 5 years are 

unknown. 

Clinical Trials/Outcomes

The optimal management of children with reflux 

must be determined based on a variety of projected 

health outcomes subsequent to different treatments. 
28 Strategic Plan for Pediatric Urology

These outcomes include UTI, hypertension, 

somatic growth, complications during subsequent 

pregnancy, the need for further medical testing, 

VUR resolution, complications from medical and 

surgical therapy, and renal outcomes like scarring, 

growth, and function. 

To date, only three prospective randomized trials 

comparing medical management (daily antibiotic 

prophylaxis for 2 to 5 years) to open surgical 

treatment in children with VUR and UTI have been 

performed. Most of the children in these trials 

had moderate or severe reflux, often with kidney 

scarring at the outset. Although the incidence 

of new renal scarring between the surgical and 

medical arms was similar, children who had 

undergone surgery and discontinued antibiotic 

prophylaxis were significantly less likely to develop 

kidney infection than those who still had reflux and 

were receiving daily antibiotic therapy. In addition, 

at the end of 5 years, the majority of children in the 

antibiotic treatment arm still had VUR. Currently, 

however, many cases of VUR detected through 

screening, are low grade.

The role of endoscopic therapy remains unclear. 

A recent meta-analysis of more than 100 reports 

of children undergoing subureteral implantation 

has shown that the VUR resolution rate is high, 

but other outcomes were not reported in most 

series. However, the incidence of UTI following 

endoscopic therapy appears to be significantly lower 

than following open surgical correction. 

Other considerations relevant to VUR clinical 

practice are ongoing concerns in the medical 

community regarding the emergence of resistant 

strains of infectious organisms caused by 

widespread antibiotic usage, as well as questions 

as to the long-term safety of daily antibiotic 

prophylaxis. Although daily antibiotics are 

considered standard therapy in children with 

VUR diagnosed following a UTI, there are no 

contemporary trials evaluating the relative 

effectiveness of close clinical monitoring in which 

antibiotics are withheld until a UTI is suspected 

(“observation therapy”).

Priorities for Basic Science Research

• Investigate the genetic basis of kidney 

development and the genetic/developmental 

aberrations that lead to VUR.

• Create genetically engineered animal models of 

VUR relevant to human disease.

• Develop noninvasive radiologic or biological 

methods for detecting and monitoring VUR.

• Elucidate the molecular basis of renal scarring 

after UTI.

• Identify genetic or other biomarkers that 

predict reflux or kidney scarring and failure. 

Priorities for Translational and Clinical 

Research

High Priority

• Determine the safety of observation therapy 

in children with VUR and UTI compared to 

conventional medical therapy (daily antibiotic 

prophylaxis), as well as selection criteria for 

patients suitable for this approach.

• Evaluate the patterns of bacterial resistance in 

children receiving antibiotic prophylaxis.

• Assess the psychological impact of cystography 

on children with VUR using contemporary 

quality of life instruments.

• Apply contemporary outcomes instruments 

to assess quality of life and health care costs in 

children with VUR who have been treated in 

different ways.

• Evaluate the long-term safety and efficacy of 

currently available injectable materials. 

• Determine the effectiveness of immediate 

endoscopic therapy compared to conventional 

medical therapy.
Strategic Plan for Pediatric Urology 29

Medium Priority

• Determine the role of voiding dysfunction in 

the development of VUR in newborns and 

older children and its role as a risk factor for 

complications of reflux.

• Revise national registry mechanisms to 

ensure the accurate prospective collection of 

data. Establish, using registry data, the true 

incidence of reflux-related renal insufficiency.

• Determine whether VUR should be corrected 

before adolescence.

• Assess the risk of hypertension in adolescents 

and young adults with lesser amounts of renal 

scarring.

• Develop new materials for endoscopic therapy 

that are safer and more durable.

• Determine if circumcision can eliminate the 

need for prophylaxis in boys with VUR.

• Determine whether VUR increases the risk of 

lower urinary tract infection.

Low Priority

• Assess the benefit of sedation or hypnosis 

during cystography, as well as the benefit 

of having support personnel present for the 

procedure.

• Determine if bladder pressure during VUR has 

prognostic value for predicting spontaneous 

resolution. 

• Develop criteria for reflux screening in 

newborns on whom a dilated kidney was 

discovered prenatally.

• Determine which family members of children 

with reflux should undergo screening and 

treatment.

• Determine if non-surgical alternatives to 

prophylactic antibiotics are feasible.

• Devise better methods of diagnosing and 

treating voiding dysfunction in children with 

VUR.

• Develop improved techniques of laparoscopic 

anti-reflux surgery

• Determine risk factors for the most severe 

complications of reflux occurring during 

pregnancy.

• Conduct prospective studies of young 

adults with both corrected and uncorrected 

reflux to assess clinical risk factors for late 

complications of reflux.

5. Urinary Tract Infection

Th e frequency of urinary tract infections and 

their potential for causing kidney damage and 

other related morbidity make them a major 

challenge for pediatric urology research. Th e 

complex mechanisms by which bacteria infect 

the urinary tract and, in cases of pyelonephritis, 

cause renal scarring should be topics of 

investigation. Treatments to interfere with 

uropathogenetic colonization without prolonged 

antibiotic use and to prevent renal scarring are 

needed. Clinical management would benefi t 

greatly from new methods that would permit 

immediate identifi cation of infectious bacteria 

in patients, as well as improved technologies for 

post UTI. 

Summary 

Health Impact

Urinary tract infections (UTIs) are frequent in 

children of all ages (3 percent of prepubertal girls 

and 1 percent of prepubertal boys are diagnosed 

annually), and they cause significant morbidity that 

can lead to renal failure. Although they are not 

reportable diseases, and accurate incidence data are 

not readily available, UTIs have been estimated to 
30 Strategic Plan for Pediatric Urology

African Americans. Among infants with UTI, 

18 percent will develop recurrences. 

Treatment is generally based on age and severity 

of clinical presentation. In general, neonates are 

admitted for intravenous antimicrobials. Children 

appearing very sick, toxic, or unable to take fluids 

may require hospitalization as well. In most 

cases, broad spectrum antibiotics (amoxicillin, 

cephalosporins, aminoglycosides, sulfonamides 

and fluoroquinolones) are used for 7 to 14 days. 

The emergence of bacteria resistant to frequently 

used antibiotics limits the efficacy of these drugs in 

treating UTIs. 

Children with an initial UTI are generally evaluated 

with imaging studies for possible upper (kidney) 

or lower tract (bladder) abnormalities. These 

studies may include kidney and bladder ultrasound 

and a voiding cystourethrogram. The necessity for 

performing renal ultrasounds following an initial 

episode of UTI when a prenatal ultrasound was 

performed close to birth is questionable. The role of 

kidney scans in the management of young children 

with UTI has not been evaluated systematically. 

During urinary tract infection, 

quiescent reservoirs of bacteria form in 

the bladder mucosa, helping to explain 

the limited effectiveness of antibiotics. 

Rod-shaped E. coli are labeled with 

green fluorescent protein (Courtesy 

of Dr. Scott Hultgren, Washington 

University School of Medicine).

account for 40,000 hospitalizations each year at a 

cost of $180 million. The impact is much greater 

when one takes into account that UTIs are generally 

treated on an outpatient basis; they account for 

1.1 million visits to pediatrician’s offices and 

94,000 visits to emergency departments annually. 

No evidence is available regarding the cost of 

medications, hospitalizations, office visits, tests, or 

the burden posed by long-term care for UTI and 

complications such as hypertension, complications 

during pregnancy, and renal scarring. 

Clinical Description and Treatment 

UTIs in children can be classified according to 

probable site of disease. Cystitis or infection of the 

bladder, is the most prevalent; pyelonephritis refers 

to infection of the kidney. On the basis of clinical 

symptoms, it may be difficult to determine the site 

of infection, and furthermore, symptoms of UTI 

(dysuria, frequency, urgency, fever, and back and 

abdominal pain) may be non-specific. Routine 

urinalysis results, although quickly available, are 

usually unreliable. The diagnosis of UTI is made 

with a urine culture, the results of which are not 

available for at least 24 hours. 

Bacteria enter the urinary tract from the rectum, 

and infection depends on attachment to the urinary 

tract wall by specialized surface structures called 

pili. Ascent of the bacteria to the kidneys can occur 

through either the ureter or through spread from 

lymph or blood flow. Pyelonephritis is the most 

frequently occurring serious bacterial illness in 

febrile infants and children, and it results in kidney 

scars in approximately 20 percent of cases. The 

reasons why some children develop scars while 

others do not is currently unknown. At particularly 

high risk for UTI are neonates, uncircumcised 

infant boys, girls older than 3 months, children 

with urinary tract anomalies or voiding problems, 

children with neurologic abnormalities affecting 

the bladder, and hospitalized children (UTIs are the 

most frequent nosocomial infection in children). 

Evidence suggests a lower incidence of UTI in 
Strategic Plan for Pediatric Urology 31

Priorities for Basic Research 

• Develop a better understanding of the 

genetic and molecular basis of bacterial 

uropathogenicity. 

• Establish procedures to prevent uropathogenic 

microbial shift (resistance). 

• Identify host factors that determine the 

risk, severity, and recurrence of bacterial 

colonization and infection.

• Elucidate the role of the immune response in 

the course of UTI.

• Characterize the mechanism of renal scarring 

as a complication of UTI.

• Identify biomarkers predictive of the 

complications of UTI.

Priorities for Translational and Clinical 

Research

• Determine the prevalence of UTI in various 

ethnic and racial groups.

• Determine the correlation of UTI signs 

and symptoms with the level of infection in 

children older than 24 months.

• Describe the natural history of asymptomatic 

bacteriuria.

• Improve methods to characterize the 

pathogenicity of clean voided specimens in 

toilet-trained children (3 to 13 years). 

• Develop new technologies for immediate 

identification of bacteria and sensitivities.

• Optimize methods for post-UTI imaging.

• Determine the utility of prenatal 

ultrasonography in UTI evaluation.

• Develop improved methods for imaging of 

inflammation and scarring.

• Develop approaches for prevention of 

uropathogenic colonization.

• Explore non-antimicrobial interventions and 

treatments.

• Evaluate existing antibiotics more thoroughly, 

and develop new antibiotics.

• Develop means of preventing renal scarring 

using adjunctive therapy.

• Determine the efficacy of antibiotic 

prophylaxis in preventing recurrences and 

renal scarring following acute pyelonephritis. 

6. Neurogenic Bladder

Abnormal bladder function can have profound 

consequences for a child’s health such as 

constant urinary leakage and, ultimately, 

deterioration of kidney function. An improved 

understanding of lower urinary tract 

dysfunction and its management is critical to 

the physical, social, and psychological wellbeing of children with neural abnormalities 

aff ecting bladder function. Th e following major 

recommendations are made for future research: 

• Investigate, using tools and approaches 

from developmental genetics, molecular 

and cell biology, neurophysiology, and 

biomechanics, the progression of the 

neurogenic bladder in order to develop 

novel therapies.

• Conduct multicenter prospective studies of 

the value of early, aggressive treatment for 

children with neurogenic bladder.

• Conduct longitudinal studies of the 

long-term outcomes for children with 

neurogenic bladder, including assessments 

of cancer risk, renal function, continence, 

growth, and quality of life issues.

Summary 
32 Strategic Plan for Pediatric Urology

bladder dysfunction can lead to upper urinary tract 

dilatation (hydronephrosis), vesicoureteral reflux, 

urinary tract infection, urinary tract stones, urinary 

incontinence, renal deterioration and, ultimately, 

renal failure requiring dialysis. In addition to 

causing a dramatic alteration in the quality of life 

of the child, these clinical problems translate into 

millions of dollars in annual health care costs for 

hospitalization, surgery, and imaging evaluation. 

Additional long-term health care expenditures 

are associated with followup visits, surgery, 

urodynamic measurement, chronic medication, 

diapers, caretakers, lost work for parents, and 

multidisciplinary health care teams. 

Clinical Description and Treatment 

Most children with neurogenic bladder present 

at birth suffer from a recognized neurological 

disorder. They have long-term problems with 

bladder control and need clean, intermittent 

catheterization several times a day in combination 

with anticholinergic drugs. This regimen is 

inadequate for many children, who ultimately 

require multiple surgical interventions to allow 

adequate urinary storage. Although studies now 

suggest that early intervention improves ultimate 

bladder compliance and results in fewer surgical 

interventions, there is a treatment burden to families 

in instituting these programs. Neuromodulation 

and bladder stimulation have also been shown to 

improve bladder function in a few patients. 

Surgical intervention may include bladder 

augmentation or replacement with portions of 

intestine and bladder neck procedures to improve 

continence. Since none of these treatments is 

ideal, many children suffer from the consequences 

of inadequate and improper urinary storage, 

including complications such as bacteriuria, stones, 

continual leakage, and, in the most severe cases, 

deterioration of renal function related to persistent 

high bladder pressures. Even those successfully 

treated with bladder augmentation may suffer longThe initial stages of bladder function begin in the 

older fetus as it develops reflex emptying. The 

complex development of neuronal control of the 

bladder continues after birth and throughout the 

next few years of normal child development. The 

bladder/urethra complex is responsible for the safe 

storage and efficient expulsion of urine, and when 

the neural input to this complex is abnormal due to 

maldevelopment, trauma, or disease, a “neurogenic 

bladder” results. Neurogenic bladders may exhibit 

problems with safe, low-pressure storage of urine 

and/or complete low-pressure expulsion of urine.

Viewed very broadly, the condition has diverse 

origins. The most common is spina bifida, or 

myelomeningocele. Other causes include tethered 

cord, spinal cord injuries, and tumors. Several 

conditions produce patterns similar to that of 

a neurogenic bladder and may have similar 

pathophysiology, including congenital bladder 

outlet obstruction (i.e., posterior urethral valves), 

abnormalities of bladder development (exstrophy, 

ureterocele, ureteral ectopia, and prune belly 

syndrome), and dysfunctional voiding. Spina 

bifida, a congenital defect in which part of the 

spinal column is imperfectly closed, is the most 

common underlying cause of the “neurogenic 

bladder,” and it affects 3,000 newborns in the 

United States each year. Ninety-five percent of 

patients with spina bifida have some degree of 

bladder dysfunction, with major economic and 

social impact on the child’s well-being. Spina 

bifida is linked to dietary deficiencies, particularly 

insufficient folic acid, but regional differences in 

its incidence not explicable by diet suggest other 

factors, including genetic predisposition, in certain 

individuals. Prenatal spine closure has decreased 

the incidence of hydrocephalus, but not the severity 

of neurological bladder impairment.

Health Impact 

Bladder dysfunction resulting from neurological 

abnormalities is a common and challenging 

problem seen by pediatric urologists. Neurogenic 
Strategic Plan for Pediatric Urology 33

term complications of the operation, including 

urinary tract infection, stone disease, metabolic 

derangements leading to bone and growth problems, 

spontaneous bladder perforation, and an increased 

long-term risk of bladder cancer.

Priorities for Basic Research

• Investigate the development of the normal 

and neurogenic bladder; one focus should be 

the role of growth factors and integrin/ECM 

interactions in the complex signaling networks 

that mediate normal and abnormal bladder 

development and innervation.

• Define the intrinsic changes in smooth 

muscle associated with neurogenic bladder, 

including the mechanisms that lead to aberrant 

deposition of connective tissue within muscle 

bundles and the development of fibrosis. 

• Elucidate the roles of various modulators 

of bladder tone and contractility, including 

prostaglandins, angiotensin, nitric oxide, and 

others.

Priorities for Clinical and Translational 

Research

• Improve surgery and other fetal interventions 

for neurogenic bladder.

• Identify the basis of regional differences in the 

incidence of spina bifida. 

• Develop minimally invasive urodynamics 

methodologies for measuring bladder 

pressure, with one goal being improved patient 

stratification prior to therapy.

• Conduct clinical trials that establish the 

usefulness of early aggressive management of 

neurogenic bladders.

• Evaluate alternative therapies for neurogenic 

bladder, including neuromodulation and 

bladder stimulation.

• Continue research in tissue engineering of 

bladders. Investigate whether tissue from 

neurogenic bladder patients can be used to 

regrow normally functioning bladder tissue. 

• Conduct long-term studies to define the risk 

of long-term complications related to bladder 

augmentation, including metabolic effects and 

tumor formation.

• Perform long-term quality of life evaluations of 

children with neurogenic bladder.

Infrastructural Needs

Clinical and translational research in the study 

of children with neurogenic bladder is hampered 

by the lack of well-trained, well-funded physician 

scientists with interest in this area. Training of 

academic urologists capable of undertaking large 

prospective clinical trials and translational research 

is essential.

• Make available training awards for 

undergraduate and medical student 

mentorships in established laboratories 

studying neurogenic bladder, as well as awards 

for physician scientists with an interest in the 

field. 

• Establish a neurogenic bladder patient registry 

and national tissue bank. 

• Provide funding for multidisciplinary and 

multicenter collaborative studies relevant to 

neurogenic bladder disease. 
34 Strategic Plan for Pediatric Urology

Infants void frequently—as many as 20 voids per 

day are normal—largely without being aware of 

it. By the age of 1 or 2, a child has developed an 

awareness of bladder fullness and the ability to start 

and stop voiding. As they grow older, children 

develop better control, store more urine, and void 

less frequently. The mean age for achieving toilet 

training in the daytime is about 2 years old. With 

continued maturation and growth, this process of 

increasing bladder capacity and decreasing voiding 

frequency continues, until by puberty, an adult 

pattern is achieved: four voids while awake and 

a bladder capacity of approximately 12 ounces. 

Development is such that children first achieve 

bowel control, then daytime urine control, and 

finally night-time urine control. 

As the bladder stores urine, it gradually expands 

to maintain low pressure. Voiding involves 

coordinating muscles to relax the bladder neck 

and sphincter and to contract the bladder (lack of 

coordination in this process is termed dyssynergy). 

Voiding dysfunction, the disturbance of normal 

bladder storage and emptying, has a spectrum of 

7. Voiding Dysfunction

Voiding dysfunction is a general term 

encompassing several syndromes in which 

the child fails to empty the bladder normally, 

has abnormal urgency and/or frequency, or 

incontinence. Although several clinical forms 

have been identifi ed, a universal classifi cation 

system for urologic practice is lacking and 

should be a major priority. Epidemiological 

research that could help establish causes and 

long-term consequences is called for. Improved 

urodynamic techniques, selective therapeutics, 

and the identifi cation of a valid biomarker 

for various syndromes could lead to more 

eff ective treatment of this common and complex 

condition. 

Summary 

clinical presentations ranging from minor urgency 

and frequency to severe syndromes that damage 

bladder and kidney function.

The causes of voiding dysfunction are not clear. 

Adverse psychosocial support for toileting, 

inadequate cognitive development, and genetic 

factors have been suggested. Several clinical forms 

are recognized: the Hinman syndrome is typified 

by children whose urinary tracts are severely 

damaged by dyssynergy. The bladder and sphincter 

muscles working against each other markedly raise 

bladder storage pressures, resulting in vesicoureteral 

reflux, hydronephrosis, UTIs, and even renal failure. 

Infrequent voiding or “Lazy Bladder” syndrome 

presents with children who delay voiding habitually 

by maneuvers such as sitting on the heel of their 

foot. Constipation, often indicated by encopresis 

(fecal soiling), is frequently associated with and 

aggravates many forms of voiding dysfunction. 

Other forms include the overactive or unstable 

bladder with urgency and frequency, giggle 

incontinence, and post-void wetting. Voiding 

dysfunction significantly affects children with 

vesicoureteral reflux, nearly half of whom will show 

some of its symptoms and experience an increased 

incidence of breakthrough urine infection and 

ureter reimplantation.

There are reports of familial voiding dysfunction 

associated with Down’s syndrome and the Ochoa 

syndrome, the gene for which has been tentatively 

mapped to chromosome 10q23-q24.

Health Impact

The prevalence of voiding dysfunction in children is 

estimated to be around 20 percent, with girls more 

frequently affected than boys. However, it should 

be noted that urinary incontinence encompasses a 

heterogeneous family of disorders and the economic 

burden of voiding dysfunction in children is 

difficult to assess. An estimate of $15 to $20 million

in annual costs from voiding dysfunction of all 

etiologies, primarily stemming from outpatient 

visits, has been made.
Strategic Plan for Pediatric Urology 35

Clinical Description and Treatment 

Children with voiding dysfunction may present 

with wetting, UTI, constipation, urgency, frequency, 

and painful voiding. They appear normal, with 

no neurologic deficits or urinary anomalies. It 

is important to elicit an accurate history of toilet 

habits; a questionnaire of elimination habits 

is helpful and can quantify severity. Urine is 

examined to evaluate for infection. Ultrasound can 

be useful but is not always needed. Plain abdominal 

films are helpful in assessing constipation and the 

appearance of the bony spine, and MRI can show 

spinal cord abnormalities. Urodynamic studies may 

be done to demonstrate dyssynergy and bladder 

instability. Cystoscopy is usually not necessary.

Treatment is multimodal and directed by the child’s 

age, symptoms, and needs. Behavioral therapy 

with biofeedback can correct aberrant toileting, 

and computer games have been used to conduct 

and reinforce biofeedback training. However, 

biofeedback is often not covered by insurance 

carriers because of a lack of evidence validating 

its efficacy. “Lazy” bladders can be treated by a 

scheduled voiding program. Bowel regimens can 

correct the fecal soiling and constipation, which 

may be contributing factors. Anticholinergic drugs 

can dampen bladder spasms, and alpha-blockers are 

useful to help relax the bladder neck and sphincter. 

More severe cases may require intravesical 

instillation or injection of drugs such as botulinum 

toxin, although these are short-term solutions. Very 

poor bladder emptying can be managed by clean 

intermittent catheterization.

Priorities for Basic Research

• Conduct epidemiological research on possible 

causes of aberrant toilet training, including 

adverse psychosocial support for toileting, 

inadequate cognitive development, and genetic 

factors.

• Investigate potential molecular mechanisms 

underlying voiding dysfunction and relating 

to the development of neural control of the 

bladder. 

Priorities for Clinical and Translational 

Research

• Develop a classification system for voiding 

dysfunction, including a validated symptom 

score scale to assess individual cases 

objectively.

• Develop more sensitive urodynamic testing 

methods appropriate for children; investigate 

the use of telemetry technology to permit 

continuous or “at home” monitoring in a more 

natural environment.

• Define the effectiveness of biofeedback 

training and research cost-effective 

biofeedback programs; promote development 

of interactive biofeedback computer programs; 

determine if biofeedback training can reduce 

the incidence of UTI and severity of VUR in 

patients with voiding dysfunction.

• Determine the long-term effects of voiding 

dysfunction, including its association with 

UTI, hypertension, kidney scarring, renal 

failure, effects on sexuality and social 

development, and possible psychological 

consequences. 

• Assess the long-term impact of performing 

intermittent catheterization on acquisition 

of urethra stricture, UTI, and psychological 

health.

• Identify a biomarker for voiding dysfunction 

among families with multiple affected 

members. 

• Develop more selective agents (e.g., anticholinergics, alpha blockers, calcium channel 

blockers, botulinum toxin) that act specifically 

on the bladder. Investigate alternative delivery 

methods such as intravesical instillation of 

drugs.

• Encourage development of 

multidisciplinary programs involving 

pediatricians, psychologists, psychiatrists, 

gastroenterologists, neurologists, and 

neurosurgeons to better treat the condition. 
36 Strategic Plan for Pediatric Urology

Nocturnal enuresis (NE) results when the bladder 

contracts during sleep without the child’s control. 

While wetting the bed at night is considered normal 

in infants, society expects night dryness by age 5 

years. However, NE affects about 15 percent of 

5-year-old children; from that age, prevalence tends 

to diminish steadily so that the rate is only 3 percent 

in adolescents. NE is a heterogeneous disorder 

that may be caused by overlapping problems in 

the kidneys, bladder, and central nervous system. 

In 50 percent of bedwetters, there is a deficiency 

of antidiuretic hormone (ADH), and the normal 

nightly decrease in urine production does not occur. 

Another renal deficiency that may cause enuresis is 

a lack of aquaporin, a protein that transports water 

out of the urinary tract. Some children with NE 

show a sleep disorder characterized by a reduced 

perception of bladder filling and the inability to 

8. Enuresis

Th e physical basis of many cases of nocturnal 

enuresis is still diffi cult to determine. Renal 

defi ciencies, hormonal abnormalities, small 

bladder, and psychological and social factors 

have been identifi ed as playing a role in its 

etiology, but continued research to clarify its 

neurophysiological basis is needed. Clinical 

trials can validate and optimize current 

pharmacological and behavioral treatment 

modalities. 

Summary 

• Improve awareness and understanding of 

voiding dysfunction among primary care 

doctors, allied health workers, families, and 

patients.

• Assess the therapeutic role of complementary 

medical methods, such as acupuncture for 

dysfunctional voiding.

inhibit urination; bedwetting in children with deep 

sleep is worsened by a small bladder. Children with 

NE have a greater tendency to be diagnosed with 

attention deficit hyperactivity disorder (ADHD), 

which may need to be addressed as part of the 

treatment plan.

Health Impact

Nocturnal enuresis affects about 500,000 children 

in America and is responsible for about one-third 

of outpatient visits for wetting; the annual rate of 

outpatient visits has doubled during a 7-year period, 

to 200 per 100,000 children. In America, the yearly 

medical cost of NE is estimated at $20 million. In 

Europe, the cost of not treating enuresis was more 

than treating it. 

Clinical Treatment 

Nocturnal enuresis has been viewed as an 

untreatable condition by the public. In fact, it is 

a legitimate condition that can be treated with 

pharmacological and behavioral interventions. 

Imipramine addresses both the bladder and central 

nervous system abnormalities. Initial response rates 

approximate 50 percent; however, the long-term 

cure rate is only 25 percent. A serious drawback 

is that imipramine can be lethal. Oxybutnin helps 

manage NE associated with bladder overactivity in 

20 percent of children. Combination therapy with 

imipramine and oxybutnin is sometimes prescribed, 

but it does not provide a lasting cure. DDAVP, 

an antidiuretic hormone analog, improves the 

kidney’s concentrating ability in about 50 percent 

of children, but unfortunately about 30 percent 

of those showing improvement relapse after the 

medicine is stopped. A small bladder size may 

reduce the success rate of drug treatment. 

The moisture alarm, which is a conditioning device, 

is the most effective treatment for NE, with up to 90 

percent of children who initially respond being cured, 

and this course of treatment is associated with an 
Strategic Plan for Pediatric Urology 37

increase in bladder capacity. Many parents resist 

this approach because it is very labor intensive.

Priorities for Basic Research

• Research should be directed to improved 

understanding of the physiological basis of 

nocturnal enuresis, including such topics 

as water transport by the kidney, control 

of bladder function by the central nervous 

system, and bladder control during sleep. 

• Identify genetic factors associated with this 

disorder.

Priorities for Translational and Clinical 

Research

• Conduct clinical trials to determine the most 

cost-effective and expedient treatments. 

• Improve awareness of NE as a disease entity.

9. Exstrophy-Epispadias Complex 

and Cloacal Malformation

Th e exstrophy-epispadias complex is a set 

of developmental anomalies involving the 

urinary, genital, and intestinal tracts, as well 

as the musculoskeletal system. Cloaca is a 

malformation in the female wherein the urinary, 

genital, and gastrointestinal tracts exit the 

body as a single opening. Th ese rare conditions 

require extensive surgical intervention to 

achieve urinary tract function. To properly 

evaluate treatments, long-term clinical trials 

assessing outcomes such as bladder and 

kidney function and quality of life are needed. 

Establishment of a patient registry is a vital 

prerequisite for adequate clinical trials. 

Summary 

Exstrophy-epispadias complex is an all-encompassing 

term for a spectrum of congenital anomalies of the 

bladder and urethra. As an example, in bladder 

exstrophy the bladder, bladder outlet, and urethra 

are exposed as an “open book” on the lower 

abdominal wall. The cause of exstrophy is not 

clearly understood, and few surgically created 

animal models and no natural models of this 

condition exist. Major goals in the management 

of exstrophy are preservation of normal kidney 

function, development of adequate bladder 

function, including urinary continence, and 

provision of acceptable cosmesis, and function 

of the genitalia. To achieve these goals, multiple 

complex surgeries, lengthy hospitalizations, and 

intense followup are typically required. Cloaca is 

a rare and complex malformation in the female 

wherein the urinary, genital and gastrointestinal 

tracts exit the body as a single opening (common 

channel), having serious consequences for bladder 

and kidney function. Spinal cord abnormalities are 

present in approximately one-third of these patients

Health Impact

Exstrophy occurs in one in 30,000 live births 

while epispadias is seen in one in 400,000. Cloaca 

occurs in approximately one in 50,000 live female 

births. Although they are rare, the impact of these 

conditions is enormous. Patients face multiple and 

often life-long challenges: urinary tract infections 

that can be complicated by vesicoureteral reflux 

(backflow of urine from bladder to kidney), urinary 

incontinence, sexual dysfunction, and problems 

with fertility. Of grave concern is that some of 

these patients develop kidney failure. Multiple, 

complex surgical procedures are typically required, 

and lifelong evaluation and a dedicated caregiver 

are requisites. The economic costs to family and 

society are significant, and the impact of these 

conditions on childhood and family life is profound. 

Clinical Issues

We highlight here some current issues in the clinical 

treatment of these disorders and the research 

initiatives needed to resolve them.
38 Strategic Plan for Pediatric Urology

skeletal and soft tissue, are abnormal in exstrophy—

have implications for the necessity and timing 

of osteotomy, and significantly impact outcome. 

Anatomical study via autopsy and radiologic imaging 

in the normal and exstrophic newborn would shed 

light on current surgical approaches and stimulate 

development of more appropriate and effective 

techniques for management.

Long-term Outcome/Quality of Life: Long-term 

data on outcome in this group of patients is limited. 

Basic questions remain unanswered: What is the 

chance of a newborn being dry and voiding? What 

is the chance of normal fertility? Can an affected 

female carry a pregnancy? What is the risk of 

bladder malignancy? Consequently, long-term 

outcome studies including documentation of “Quality 

of Life” issues are vital. Sexual function in both 

males and females has been described in small 

series, but a more detailed understanding of the 

sexual and fertility issues in these patients is needed.

Gender: In some children born with cloacal 

exstrophy and a 46XY male genotype, the choice 

of the optimal gender of rearing is still a fiercely 

debated issue. A thorough, well-constructed and 

multidisciplinary retrospective evaluation of these 

patients (whether or not “gender reassigned”) is 

needed. 

Cloaca

Epidemiology/Pathophysiology: Currently, there 

are a number of genetically created animal models 

with cloaca. This has led to ongoing human genetic 

studies. Banking of DNA in these patients and their 

families would improve the chances of identifying 

genetic components to this problem.

Diagnosis and Management: Prenatal diagnosis has 

been reported, but the sensitivity and specificity has 

not been documented. As many families opt for 

termination once the diagnosis is made, an accurate 

evaluation of prenatal diagnosis is important. 

Recently, the role of total urogenital mobilization 

(TUM) for the management of these girls has been 

Exstrophy

Fetal Diagnosis and Intervention: Prenatal 

diagnosis of exstrophy has been described. 

However, evaluation of the sensitivity and specificity 

of prenatal diagnosis is critical for counseling. Since 

there is no available treatment for the fetus, fetal 

intervention, potentially in the form of coverage or 

closure of the exstrophy defect, should be explored.

Initial Surgical Management: Currently, there are 

two popular methods used to treat exstrophy: the 

multistage and the single-stage complete primary 

repair of exstrophy (CPRE) techniques. The only 

valid way to answer which of these treatment 

options, if either, provides superior outcome is to 

form multicenter groups committed to collaborative 

prospective studies. Similarly, the use of adjunctive 

surgical procedures such as osteotomy (partial 

incision of the pelvic bones to facilitate closure) 

in the newborn with exstrophy is sporadic among 

institutions and without consensus regarding 

indications.

Kidney Function: The majority of exstrophy 

patients begin life with normal kidney number 

and function. Unfortunately, approximately 20 

percent develop renal damage and some kidney 

failure. The pinnacle of our priorities of care 

should be maintaining normal kidney function. 

A prospective evaluation of renal function alone, 

and with comparison to continence, may identify 

relationship(s) between these two important 

outcomes, as well as predictors of loss of renal 

functional loss.

Bladder Function/Urinary Continence: Following 

repair, reports of urinary continence rates vary 

from the 20 percent to 70 percent. There is no 

standard definition of continence for this group of 

patients and standardization of nomenclature is 

warranted. As continence is highly dependent upon 

bladder function, prospective evaluation of bladder 

function following either CPRE or the multistage 

repair with standardized urodynamic study would 

be informative in determining and comparing 

outcomes. Pelvic anatomical relationships—both
Strategic Plan for Pediatric Urology 39

described. This technique is now widely used, and 

there is no common alternative method to compare 

for short common channels. For longer common 

channels, separation of the vagina and urethra, and 

tubularization of the channel is still performed. 

Standardized terminology (short versus long channel) 

for appropriate surgical care and valid comparison is 

needed.

Kidney function: Kidney function is impaired 

in a significant number of these children and 

is associated with congenital kidney anomalies 

and late renal failure. Early, more aggressive 

management of the bladder has been described, 

but the impact of this on the kidneys has not been 

studied.

Bladder Function/Urinary Continence: Urinary 

and fecal incontinence is common, occurring in 

up to 60 percent of patients. The current effect of 

TUM on both short and long common channels 

has been described, yet needs further evaluation. 

Detailed outcome of bladder function with 

urodynamic study is needed in these patients.

Long-term outcome: Complete long-term

outcomes of urinary tract, gastrointestinal tract, 

kidney, and sexual function are important, as are 

gynecological outcome and fertility rate. A cohort 

study is vital to understanding the impact of this 

condition on patients. “Quality of life” studies would 

add greatly to the current literature. 

Priorities for Research

Our knowledge of basic, fundamental cause and 

effect relationships in exstrophy and cloaca are 

extremely limited. Therefore, studies that evaluate 

both environmental and genetic risk factors are 

needed. In addition, the development of animal 

models that clarify our understanding of the 

defect and its impact on bladder development 

and function at the basic level and provide 

further insight into optimal management would 

be valuable. The genetic construction of animal 

models with cloaca has led to ongoing genetic 

studies in humans. The rarity of exstrophy and 

cloaca makes scientifically valid clinical studies 

difficult as most centers see few patients.

• Continue to develop relevant animal models to 

further fundamental understanding. 

Exstrophy

• Conduct a collaborative, prospective 

evaluation of kidney and bladder function 

for single and multistage approaches to 

management.

• Investigate long-term quality of life issues 

including sexual function and fertility.

• Fetal intervention, potentially in the form of 

coverage or closure of the exstrophy defect, 

should be explored.

• Conduct a prospective evaluation of renal 

function and continence in exstrophy patients 

and clarify the relationship between these 

two outcomes, as well as predictors of renal 

functional loss.

• Perform detailed anatomical characterization 

via autopsy and radiologic imaging in the 

normal and exstrophic newborn to shed light 

on current surgical approaches, and stimulate 

development of more appropriate and effective 

techniques for management. 

• Investigate the developmental consequences of 

exstrophy on the bladder and pelvic floor on a 

molecular basis to enhance ultimate function 

potential.

Cloaca

• Document the sensitivity and specificity of 

prenatal diagnosis.

• Develop a standardized terminology (short 

versus long channel) for appropriate surgical 

care and valid comparisons. 

• Perform detailed outcome studies with 

urodynamic measurements to assess bladder

function in patients after reconstruction.
40 Strategic Plan for Pediatric Urology

• Conduct a cohort study to assess quality of 

life and long-term outcomes such as kidney 

function, sexual function, fertility, and other 

relevant parameters.

Infrastructural Needs 

Develop a national or international registry that 

would facilitate communication and collaboration 

between centers, and potentiate the prospective, 

randomized trials that are an absolute necessity 

if new treatments for patients with these rare 

conditions are to be developed.
Strategic Plan for Pediatric Urology 41
42 Strategic Plan for Pediatric Urology
Strategic Plan for Pediatric Urology 43

II. Genital Tract

10. Development and Maldevelopment of the Genital Tract

Formation of the genitalia is a complex 

developmental process involving genetic 

programming, cell diff erentiation, hormonal 

signaling, enzyme activity, and tissue 

remodeling. Understanding the molecular 

mechanisms of normal development is critical 

if we are to be successful in elucidating the 

causes of abnormalities of both the internal 

and external genitalia. Basic research in this 

area will be vital for prevention and alleviation 

of diseases such as hypospadias, epispadias, 

undescended testes, and uterine abnormalities.

Summary 

Sexual Differentiation and 

Development in the Early Embryo

The early embryo is sexually “indifferent”—

structurally the same in genetic males and females 

and bipotential; subsequent development into 

male and female genital tracts is determined by 

a complex set of interactions based on genetic, 

molecular, and ultimately, physiological processes. 

Much of the development of the genital tract 

is determined by gonadal development. The 

sexually undifferentiated gonad is first observed 

histologically at 5 to 6 weeks post-conception 

as a thickening in the urogenital ridge, with 

differentiation into an ovary or testis beginning 

around the 7th week. Ovarian development was 

thought to be constitutive (i.e., in the absence of 

a specific genetic signal, an ovary will develop). 

Recently, however, genes that may induce ovarian 

development have been identified. The critical gene 

for testicular development is the SRY gene, found 

on the Y chromosome. Although numerous other 

genes are involved, the presence of SRY will, in 

nearly all cases, induce testicular development.

Alongside the indifferent gonads are two closely 

related ductal systems, the Wolffian and the 

Müllerian ducts. The Wolffian duct is originally the 

nephric duct and only later develops into a genital 

duct in the male fetus. Indeed, the Wolffian duct 

very early in development joins the cloaca, and the 

lower end of this duct gives rise to the ureteral bud, 

a critical element in the formation of the kidney. 

The Müllerian duct, in contrast, is purely a genital 

duct, developing somewhat later and not reaching 

the urogenital sinus until about the 9th week.

Without the SRY gene, the gonad develops into 

an ovary; the Müllerian duct system develops 

into the fallopian tubes, and as it meets and fuses 

with its contralateral mate, the uterus and most 

of the vagina are formed. The Wolffian ducts 

remain rudimentary once their contribution to 

the developing kidney is completed. In males, the 

endocrine contributions of the cells within the 

developing testis have a strong influence on male 

ductal development. Local testosterone, produced 

by developing Leydig cells under the influence 

of maternal human chorionic gonadotrophin, is 

thought to be the primary element in the growth 

and development of the Wolffian ducts into the 

collecting ducts for the testis, including the rete 

testis, epididymis, vas deferens, seminal vesicles 

and ejaculatory ducts, as well as the developing 

prostate. Equally important, the Sertoli cells in 

the developing testis secrete Müllerian inhibitory 

factor, a hormone that prevents development of the 
44 Strategic Plan for Pediatric Urology

Müllerian ducts and leads to their degeneration by 

apoptotic mechanisms.

The external genitalia are also indifferent and 

bipotential early in development—not until 

about 3 months post-conception can male/

female differences be determined. Again, female 

development is constitutive, with the clitoris, 

urethra, vaginal vestibule and labia developing 

unless other factors intervene. In the male, 

under the influence of androgens— primarily dihydrotestosterone, derived locally from systemic 

testosterone—the genital tubercle grows much 

larger and forms the penis. The urethral folds fuse 

to form the male urethra and the genital swellings 

form the scrotum as opposed to the labia.

Although most research has focused on the effects 

of hormonal stimulation on the development of the 

genital tracts, it is now recognized that the genetic 

factors and hormonal effects that influence genital 

development may play roles in the development of 

other systems. SRY is expressed in the brain, and 

testosterone has been shown to affect many other 

organs including the testis, prostate and brain. 

Hence, the development of the genital tract appears 

Schematic of normal process of sexual differentation. The anatomy of the internal 

reproductive structures and external genitalia of genetic males and females are 

initially bipotential (“We all start out the same”). Differentation is the consequence 

of a cascade of events from determination of the gonad, to secretions of the 

fetal testis, to differentiation of reproductive structures. (From Kobayashi, A. 

and Behringer, R. Developmental genetics of the female reproductive tract in 

mammals. Nature Reviews Genetics 4 2003 969-9800)
Strategic Plan for Pediatric Urology 45

to have wide-ranging effects on other systems and 

clearly may affect behavior independently of any 

psychological effects of abnormal external genitalia.

Research Challenges 

Clearly, a better understanding of the development 

of the genital tract from the perspectives of 

anatomy, embryology, physiology, and genetics 

must inform treatment of patients with congenital 

anomalies in this area. In spite of the fact that the 

GU tract has one of the highest rates of congenital 

malformation (upwards of 2 percent), surprisingly 

little is known in genetic terms; a survey of the 

literature indicates that fewer than 20 articles 

examining gene function during GU development 

have been published between 2002-2004. In the few 

instances when a developmental approach has been 

adopted, important insights into the mechanisms 

underlying specific defects of the genitourinary 

tract have been achieved.

Initially, the major determinants of gender-specific 

development were thought to be genes whose 

products are required for androgen signaling. 

However, recent investigations of developmental 

genes suggest there are equally important 

factors controlling the formation of these tissues 

independently of androgen signals. To explain how 

sexual differentiation is ultimately regulated, it will 

be necessary to elucidate how hormonal and nonhormonal determinants are integrated, particularly at 

the level of transcription. 

Because transcription factors interact with DNA 

in a tissue-specific context, investigations focused 

on discerning the tissue-specific DNA binding 

sites will provide a mechanistic link between the 

transcription factors, their target genes, and tissues 

affected by loss of transcription factors or target 

gene expression. The identification of the DNA 

sequence elements bound by GU transcription 

factors also will permit translational collaborations 

between clinicians and basic scientists, because 

patient DNA samples can be re-evaluated for

mutations in the cis-regulatory sequences necessary

for normal gene expression.

Genetically engineered mice, bearing loss of 

function mutations (knockouts, conditional 

knockouts, and gene fusions permitting 

fluorescence-based localization) will permit 

investigators to correlate gene function with 

specific congenital defects. While the mouse is 

the essential genetic model, it is important to note 

that significant morphological and physiological 

differences exist between the human and mouse 

GU tract. Other model sytems (including zebrafish, 

chicken, frog, and some yet to be identified) may 

be needed to address particular developmental 

questions. 

Development of the External Genitalia: 

Penis, Clitoris, Testes

Development of mammalian external genitalia 

requires tight coordination of proximodistal 

outgrowth, three-dimensional patterning, and 

tubular morphogenesis. The developmental 

program can be divided operationally into two 

distinct phases. The first involves initial outgrowth 

and patterning of a bud of cells known as the 

genital tubercle, which is the embryonic precursor 

to the penis and clitoris. The second phase is 

hormonally controlled and involves either (a) continued growth and differentiation of the penis, 

or (b) arrest of outgrowth and differentiation of 

the clitoris. During the first phase, there are no 

discernable morphological differences between 

male and female external genitalia. In the embryo, 

external genital development is initiated when 

paired cellular outgrowths emerge on either side of 

the cloaca and then merge medially to form a single 

genital tubercle. An extension of (epithelial) tissue 

from the lining of the cloaca moves between these 

swellings to form the urethral plate, a two-layered 

sheet of cells that later cavitates to form the urethral 

tube. The urethral plate extends to the distal tip of 

the genital tubercle where, in the clitoris, it persists 

as an epithelial cord; or, in the penis, it canalizes to 

form a urethral tube.

Surprisingly, even at the tissue and cellular levels, 

the embryology of external genital structures remains 
46 Strategic Plan for Pediatric Urology

unclear. For example, most medical embryology 

texts indicate that the opening of the penile urethra 

forms by in-growth of cells at the distal tip of the 

penis, although recent experimental work has failed 

to find evidence for this process. Therefore, we 

still do not know which cells give rise to the distal 

urethra, the region most frequently affected in 

hypospadias.

While malformations of the external genital system 

occur at a frequency second only to that of cardiac 

defects, the molecular mechanisms that regulate 

early development of the external genitalia, and 

which are presumably deregulated in congenital 

abnormalities, remain largely unknown. 

To date, fewer than 10 genes have been identified 

with roles in external genital development, most 

playing roles in development of other organs 

systems. Given the high number of children that 

present with isolated malformations of the external 

genitalia, it seems unlikely that mutations in such 

developmental control genes are a major causal 

factor. Instead, localized genitourinary defects may 

result from altered regulation of gene expression in 

the genitalia, either by exposure to environmental 

factors that influence gene activity, or by mutation 

of DNA sequences are critical to transcriptional 

control. 

Interactions between the genetic pathways that act 

during phase one and the hormonal cues that act in 

phase two remain to be explored. Local and systemic 

signals must be integrated for normal genital 

development to occur, yet how these signaling 

pathways intersect and influence one another is 

largely unknown. This question is particularly 

germane to understanding how environmental 

factors contribute to abnormal genital development. 

Development of the Internal Genitals: 

Ovary, Uterus, Fallopian Tube, and 

Testes

Formation of normal internal genitalia is a complex 

process that remains incompletely understood. By 

the 8th week, a testis will develop male hormoneproducing cells, while an ovary will develop female 

hormone producing cells. Hormone production by 

the fetal testis is active, while the ovaries are nearly 

silent. Several key testicular male hormones act to 

masculinize the two sets of embryonic paired tubes 

and induce testicular descent into the scrotum. 

These male hormones are not made by the ovary, 

so the two sets of embryonic paired tubes feminize. 

Adjacent to the developing gonads, the Müllerian 

ducts and the Wolffian ducts develop extending 

from the midback to the external genitals. In 

males, testosterone causes the Wolffian ducts to 

differentiate into the several parts of the male 

reproductive tract—the tubing needed to carry the 

sperm from the testis to the penis. Other testis 

hormones cause the Müllerian ducts to regress 

and the testes to descend into the scrotum. In 

females, the absence of male hormones causes the 

Wolffian ducts to regress, while the Müllerian ducts 

differentiate into the female reproductive tract. 

Approximately one in 2,000 women in the United 

States are affected by an abnormally formed uterus 

or vagina, which can lead to infertility and repeat 

miscarriage.

Formation of normal internal genitalia is a complex 

process that remains incompletely understood. We 

are beginning to identify the key genes and proteins 

that are crucial for this development as well as the 

important timing of their appearance. Clearly, 

research needs to continue to understand how these 

molecular processes work together and how their 

alteration results in birth defects.
Strategic Plan for Pediatric Urology 47

11. Cryptorchidism

Cryptorchidism requiring surgery occurs in 

approximately 1 percent of male births. Th e 

research challenge is to determine the genetic 

and endocrinological basis of this anomaly 

and to develop strategies to prevent the loss of 

fertility associated with the bilateral condition.

Summary 

Priorities for Research 

• Identify the genes and signaling pathways 

necessary for the development of the genitalia. 

Which genes are under hormonal control; 

what are the patterns of tissue-specific gene 

regulation, and how are they determined?

• Elucidate the cell lineage of the genitalia.

• Define the molecular mechanisms by 

which environmental factors disrupt genital 

development.

• Produce, characterize, and validate animal 

models for normal and abnormal genital 

development. Mouse knockout strains, 

conditional knockouts and GFP strains 

should be freely available within the research 

community. 

• Develop novel molecular tools to treat and 

prevent genital abnormalities and improve 

reproductive potential. 

• Investigate the effect of sexual differentiation 

and genital development on other organs 

systems, including the brain.

Cryptorchidism, the absence of a testicle from the 

scrotum, is the most common anomaly of male 

sexual differentiation, affecting 1 percent of 1-yearold boys.

Health Impact

The economic impact of surgical care for this 

disease is significant. In 2002, 4.022 million 

births occurred in the United States. Given that 

cryptorchidism requires surgery in 0.8-1 percent 

of all male births, a conservative estimate of 

the annual cost of its surgical care in the United 

States is $189 million. The bilateral form of the 

condition impacts fertility, and crytorchidism also 

is associated with an increased risk of testicular 

malignancy.

Clinical Presentation and Treatment

When a testis is not found in the scrotum, the testis 

may be undescended (halted in the normal path 

of descent) or ectopic (strayed off of the normal 

path of descent). In other cases, cryptorchid 

males will have either no testis or a shriveled 

remnant of a testicle (“testicular nubbin”), likely 

representing the end result of testicular torsion. In 

one-third of cases, cryptorchidism is associated 

with abnormal development of the male ductal 

system (epididymis), and this can contribute to 

maldescent and infertility. Cryptorchidism also can 

be associated with ambiguous genitalia and intersex 

conditions.

The mainstay of treatment is early orchiopexy, 

surgical placement of the testicle into the scrotum. 

Currently, this procedure is recommended between 

6 and 12 months after birth, since after that point 

spontaneous descent is unlikely to occur. In 

testes remaining cryptorchid beyond 12 months, 

histological deterioration of the germ cells has been 

observed. Alternative therapy may include drugs to 

stimulate testosterone production, but unfortunately 

these rarely cause testicular descent.

Fertility

Recent reports indicate that only 65 percent of 

men who had bilateral cryptorchidism achieve 

paternity, compared with 93 percent of controls. 

The endocrine profiles, which may be normal or 
48 Strategic Plan for Pediatric Urology

Abdominal cryptorchidism, the path of 

normal descent is shown in green 

(Image provided courtesy of Dr. Sam 

Gambhir).

abnormal, are not necessarily predictive of fertility. 

Fertility in unilateral cryptorchidism was not 

appreciably different from controls in recent studies.

To combat infertility, some centers are investigating 

the use of medications such as gonadotropinreleasing hormone agonists to preserve the germ 

cells of the testis (future sperm) in prepubertal 

children. However, the value of this therapy 

remains to be determined.

Cancer

It is recognized that there is an increased incidence 

of testicular tumors, particularly seminomas within 

cryptorchid or formerly cryptorchid testes. This 

incidence may be greater than previously thought 

and may be different among different populations. 

It is unclear what factors cause carcinoma in situ 

cells in the immature testis to become malignant. 

The general consensus has been that correcting the 

location of the cryptorchid testis does not alter the 

risk of malignancy. 

Priorities for Research

• Characterize the genetic basis of familial 

cryptorchidism.

• Identify and characterize the endocrinopathy 

of cryptorchidism, in infancy and prior to or 

after treatment, and assess its role in fertility.

• Define the predisposing factors for infertility 

(genetic factors, environmental factors, and 

any potential biomarkers) in the bilateral 

cryptorchid population. 

• Identify novel medical strategies to treat 

maldescent, the loss of germ cells, or associated 

infertility and associated risks. (Gonadotropin 

releasing hormone GnRH research strategies 

should focus upon identifying patient groups 

at greatest risk for infertility and upon 

treatments to enhance fertility.)

• Assess whether subgroups are susceptible 

to malignancy and identify risk factors for 

intervention.

• Perform studies to assess whether endocrine 

disruptors induce human cryptorchidism.

• Investigate the frequency and endocrinopathy 

of testicular ascent, and perform a longitudinal 

study to assess the long-term outcomes.

• Determine the incidence of epididymal 

anomalies in cryptorchidism and their 

significance. 
Strategic Plan for Pediatric Urology 49

12. Hypospadias

Hypospadias is the second most common 

birth defect, and its incidence is increasing 

according to the Centers for Disease Control 

and Prevention. Although there is increasing 

evidence that environmental factors such as 

maternal exposure during pregnancy may 

explain the increased incidence, the etiology of 

hypospadias remains unknown in the majority 

of cases. A program of developmental genetic 

research leading to a better understanding of 

urethral development will provide insights 

into the causes of this congenital disorder and 

explanations for its increased incidence. 

Summary 

Hypospadias can be defined as an arrest in normal 

development of the urethra, foreskin, and ventral 

aspect of the penis. This results in a wide range 

of abnormalities with the urethral opening being 

anywhere along the bottom of the shaft of the penis, 

within the scrotum, or even in the perineum. The 

more severe forms of hypospadias are associated 

with penile curvature. Left uncorrected, patients 

with severe hypospadias may need to sit down to 

void and tend to shun intimate relationships due to 

anxiety related to abnormal sexuality. Babies born 

with severe hypospadias and penile curvature may 

have “ambiguous genitalia” in the newborn period.

Health Impact

Hypospadias is one of the most common congenital 

anomalies in the United States, occurring in 

approximately one in 250 newborns or roughly 

one in 125 live male births. There is significant 

morbidity associated with some surgical procedures 

to correct severe forms of hypospadias, as well as 

potential psychosocial consequences of having 

an abnormal penis. In addition to the difficulty 

of surgery, the emotional and physical stress for 

the parents of patients with abnormal appearing 

genitalia must be considered.

Development of the Male External 

Urogenital System 

Formation of the external male genitalia is a 

complex developmental process involving genetic 

programming, cell differentiation, hormonal 

signaling, enzyme activity, and tissue remodeling. 

Up until 7 weeks gestation, the male and female 

genitalia are essentially indistinguishable. Then, 

under the influence of testosterone in response to 

a surge of luteinizing hormone from the pituitary, 

masculinization of the external genitalia gland 

occurs. The penile urethra forms as a result of 

fusion of the medial edges of the endodermal 

urethral folds, and ectodermal edges of the urethral 

groove fuse to form the median raphe. By 12 weeks, 

the coronal sulcus separates the glans from the shaft 

of the penis, and the urethral folds have completely 

fused in the midline on the ventrum of the penile 

shaft. During the 16th week of gestation, the 

glanular urethral appears; evidence suggests two 

possible means by which it could form: endodermal 

cellular differentiation or primary intrusion of the 

Two theories of urethral development. 

Ectodermal intrusion theory is older, and 

endodermal differentiation is more recent 

(from LS Baskin, Hypospadias and urethral 

development, Journal Of Urology 163 (3): 

951-956 © 2000).
50 Strategic Plan for Pediatric Urology

causation. Environmental factors under 

consideration as causative agents for hypospadias 

include parental occupation, obesity, exposure to 

chemicals, including endocrine disruptors 

(e.g., gestational exposure to progestins and 

estrogen-like compounds), and smoking.

The case for chemical exposure as a causative 

factor is supported by animal models, which 

demonstrate that in utero exposure to a variety of 

environmental chemicals—pesticides, plasticizers, 

and pharmaceuticals—can cause hypospadias. 

Some of these have been shown to act as 

estrogens, antiandrogens, and inhibitors of fetal 

testis. Furthermore, some researchers have noted 

that a variety of other endpoints related to male 

reproductive health and dependent on hormonal 

action—testicular cancer, cryptorchidism, and 

impaired semen quality—may have increased 

in parallel with levels of these environmental 

pollutants.

Attempts to determine risk for hypospadias have 

yielded a number of maternal and paternal factors. 

In traditional studies of maternal risk factors for 

congenital anomalies, maternal age and primiparity 

were found to be significantly associated with 

hypospadias, although some studies have contested 

the maternal age effect. Paternal risk factors include 

abnormalities of the father’s scrotum or testes, low 

sperm motility, and abnormal sperm morphology. 

(It has been suggested that the recent increase in 

hypospadias reflects the improvement in fertility 

treatment, contributing to more sub-fertile men 

fathering children.) There is strong consensus in 

the literature that boys with hypospadias have lower 

birth weight, and it has been reported that they also 

have a lower placental weight than controls.

While these risk factors do not reveal direct 

information about the causes of hypospadias, they 

provide additional information that may reveal a 

common developmental pathway and can inform 

future research. For example, there is growing 

evidence that androgens play a central role in 

the lower birth weight of girls compared to boys. 

ectodermal tissue from the glans. Recent studies 

support a theory of endodermal differentiation 

indicating that the epithelium of the entire urethra 

is of urogenital sinus origin.

Etiology of Hypospadias

Reports of increasing incidences of hypospadias 

have raised questions concerning etiology, 

treatment, and prevention. To date, there is no 

sound understanding of the etiology of hypospadias 

that can inform primary prevention efforts and 

improve therapeutics. 

Genetic Impairment

Adequate virilization of the urogenital sinus 

and external genitalia during embryogenesis is 

dependent on the conversion of testosterone to 

DHT by 5α-reductase, and it has been demonstrated 

that defects in the androgen receptor gene are 

associated with isolated hypospadias. However, the 

frequency of these genetic defects accounts for an 

extremely small subset of cases. Furthermore, no 

significant differences in the androgen precursors 

as measured by defects in three major enzymes 

in the biosynthetic pathway of testosterone—3βhydroxysteroid dehydrogenase, 17α-hydroxylase, 

and 17,20-lyase—were found between the controls 

and the individuals with hypospadias. Increasingly, 

researchers are examining the role of cellular 

signals other than testosterone and DHT in the 

morphogenesis of the phallus and the etiology 

of hypospadias. Normal embryogenesis of the 

urogenital system depends on cell-cell signaling, 

and it has been hypothesized that aberrant signaling 

between cell layers (epithelium and mesenchyme) 

could lead to hypospadias.

Environmental Factors

The reported increase in cases of hypospadias 

during the last 30 years and the fact that known 

genetic defects explain only a small percentage of 

cases has raised concerns about environmental 
Strategic Plan for Pediatric Urology 51

Androgens are also crucial to the development 

of the male reproductive tract. Perhaps exposure 

to an agent that compromises the weight-gaining 

advantage of androgen during gestation could play a 

role in the development of hypospadias and lowered 

birth weight.

Clinical Treatment

The only treatment for hypospadias is surgical 

repair of the anatomical defect. Reconstruction, if 

performed by an experienced pediatric urologist, 

generally involves a single outpatient procedure. 

Occasionally, however, more extensive surgery is 

required, or patients may face multiple surgeries to 

improve results. 

Research Priorities 

The origin of most hypospadias is unknown, 

and real insight will depend on a more 

fundamental understanding of the process of 

normal genital development. The incidence of 

hypospadias appears to have increased in the last 

generation. The hypothesis that this is explained 

by environmental pollutants is supported by 

experiments in animal models of hyposapdias and 

should be investigated further.

Basic Research

• Identify the genes that regulate normal 

urethral development and establish the cell 

lineage of the developing genitals.

• Elucidate at the molecular level cell-cell 

interactions and intercellular signaling critical 

to external genital development.

• Determine, at a molecular level, etiologies of 

hypospadias.

 Translational Research

• Characterize the impact of environmental 

factors on genital development and their 

mechanism of action, and develop guidelines 

to limit harmful exposure.

• Develop reliable outcome measures, and 

perform outcome studies with respect 

to quality of life, sexual function, and 

psychosocial well-being for the surgical repair 

of hypospadias.

13. Hernia and Hydrocele 

Occurring in approximately 1 percent of 

males, inguinal hernia and hydrocele can be 

successfully treated surgically. A key priority 

for clinical research is to validate non-invasive 

methods of detecting silent hernias, thereby 

eliminating unnecessary surgery.

Summary 

The processus vaginalis develops during the 3rd 

month of gestation as a natural pocket of the lining 

of the abdominal cavity. It extends through the 

muscle layers of the groin (inguinal canal) to reach 

the scrotum during the 7th month. This pocket 

usually seals itself off prior to birth, but remains 

open in some children, and is termed a patent 

processus vaginalis (PPV). The precise timing and 

the factors controlling closure of the processus are 

unknown, although new research has implicated 

insulin-3, a testis hormone. When the PPV 

produces a groin swelling accentuated by crying 

or grunting, it is termed an inguinal hernia (IH). 

When fluid collects in the PPV beside the testicle, it 

is called a hydrocele.
52 Strategic Plan for Pediatric Urology

Health Impact

Approximately 1 to 5 percent of children are 

affected by IH, with a significant male and rightsided predominance. IH is highest in the first 

year of life, and premature infants have a higher 

incidence (16 to 25 percent). A variety of other 

disorders, including undescended testis, exstrophy, 

intersex, ascites, ventriculo-peritoneal shunts 

incidence, peritoneal dialysis, and cystic fibrosis, are 

associated with higher incidence. Although the costs 

of surgical repair of the bulging PPV are justified, 

surgery for the silent hernia is controversial and adds 

unnecessary hospital and anesthesia costs for all the 

negative explorations.

Clinical Treatment

An IH will not resolve spontaneously and should 

be repaired within several weeks of diagnosis. In 

fact, if intestines travel into the PPV and become 

trapped, the intestines can become gangrenous 

and emergency surgery is needed. Surgical 

complications are fortunately uncommon. Most 

hydroceles resolve by 24 months of age without 

surgery. In children with a one-sided hernia, a 

silent hernia without symptoms may be present 

on the other side. This silent hernia will become 

symptomatic in 10 to 15 percent of patients. 

Controversy exists in its management—although 

many surgeons perform exploration on the side with 

the possible silent hernia, it is usually unnecessary 

since no hernia is found in 80 to 90 percent of cases. 

Some studies have suggested that ultrasound detects 

silent hernia with up to 92 to 95 percent accuracy, 

but it is not used routinely. Inguinal laparoscopy is 

used to detect the presence of a contralateral PPV, 

yet controversy exists as to its overall clinical value.

Priorities for Research

• Investigate molecular and hormonal factors 

that may predispose to the development of 

hernias and hydroceles.

14. Congenital Anomalies of 

Sexual Diff erentiation

Congenital anomalies of the sex organs 

can confront clinicians with the need to 

assign sex and perform appropriate surgical 

reconstruction. Sex assignment decisions in 

which optimal gender was based on factors 

like potential for sexual functioning and 

reproductive potential have been highly 

contested; aff ected individuals may object to 

the gender assigned, and they may resent the 

eff ects of genital surgery and feel a sense of 

stigmatization. Prospective studies of gender 

identity and reproductive function and quality 

of life are needed in this group of patients 

to guide clinicians and families in making 

decisions about gender assignment and surgical 

reconstruction. 

Summary 

Patients with congenital anomalies of the sex 

organs present major challenges to the clinician. 

These conditions include anomalies of the gonads, 

internal reproductive ducts, and external genitalia, 

including malformations like cloacal exstrophy and 

penile agenesis. The primary focus here is on that 

subset of conditions in which there are issues of 

sex assignment and surgical reconstruction of the 

genitalia to match assigned sex.

• Identify and validate novel, noninvasive, or 

minimally invasive perioperative methods to 

detect silent hernias. 

• Improve awareness of hydrocele and hernia 

in children of the parents of at-risk groups to 

decrease time elapsed until diagnosis.
Strategic Plan for Pediatric Urology 53

Health Impact

The use of screening procedures, prenatally and 

in newborns, has increased the early diagnosis 

of many anomalies of sexual differentiation. 

State-mandated screening for congenital adrenal 

hyperplasia indicates that its incidence is in the 

range of one in 10,000 to one in 15,000 live births. 

Abnormalities of sexual differentiation force many 

families and clinicians to make difficult decisions 

regarding sex assignment with insufficient outcome 

data. Individuals who are unhappy with their 

sex assignment may have profound psychological 

disturbance.

Clinical Management and Treatment

There is currently a crisis in clinical management of 

children with disorders of sexual differentiation, and 

it has received considerable public attention. It stems 

from two issues. First, for some of these disorders, 

there are insufficient data to guide the clinician 

and family in sex assignment. Second, the optimal 

application of surgery and its timing remain unclear.

Sex assignment

Until the mid-1950s, medical management of 

individuals with disorders of sexual differentiation 

was guided by the belief that an individual’s 

‘‘true sex’’ could be determined by examination 

of internal anatomy. Then, based on reports 

suggesting that this assumption was incorrect, 

guidelines were changed; sex assignment decisions 

were based on the principle of ‘‘optimal gender,’’ 

which considered multiple aspects of outcome, 

most prominently, the potential for complete sexual 

functioning, with particular emphasis on phallic 

size and reproductive potential. This approach, 

largely uncontested until recently, is predicated on 

two assumptions: (1) ‘‘gender identity’’ (i.e., identification of self as either girl/woman or boy/man) 

is not firmly established at birth, but rather is the 

outcome of the sex of rearing; (2) stable gender 

identity and positive psychological adaptation 

require that genital appearance match assigned sex, 

which often calls for reconstructive genital surgery. 

Clinical outcomes have demonstrated that there is a 

window of time until the second year of life, during 

which gender identity is malleable. Therefore, this 

clinical management strategy suggests that early 

surgical correction of genitalia is critical.

This clinical approach to disorders of sexual 

differentiation has recently been criticized from 

several perspectives. First, the notion of gender 

‘‘neutrality’’ at birth has been challenged by several 

highly publicized cases of unsuccessful gender 

reassignment in which the patient ultimately 

initiated a return to their original gender. Some 

have interpreted these outcomes in terms of the 

effect of genes and/or androgens on the brain, and 

this is supported further by increasing experimental 

evidence.

A second challenge to the ‘‘optimal gender’’ policy 

comes from affected individuals who are angry 

about their treatment. They object to the fact that 

they were either not informed or were misinformed 

about their condition and had difficulty obtaining 

accurate information about their condition and 

treatment. They feel stigmatized and shamed 

by the secrecy surrounding their condition and 

its management. Many also attribute poor adult 

sexual function to damaging genital surgery and 

repeated and insensitive genital examinations, both 

performed without their consent.

As a result of these concerns, there exist no clear 

guidelines to direct the current practice of gender 

assignment. Indeed, there is evidence that clinicians 

have altered their management strategies with limited 

outcome data to support these changes. In conditions 

in which psychosocial factors are paramount, there 

are few mental health specialists with the specific 

expertise to participate in interdisciplinary care and 

clinical research for these conditions.
54 Strategic Plan for Pediatric Urology

Surgical Intervention

The “optimal gender” policy mandated early 

surgical reconstruction to normalize the appearance 

of the genitalia in accordance with the assigned 

gender. Although this approach was thought to be 

successful in most cases, only limited long-term 

outcome data are available. Because of concerns 

regarding irreversibility and possible sensory 

damage to the genitalia after early surgery, this 

policy has been questioned, and some have gone so 

far as to suggest a total moratorium on surgery of 

the genitalia in children. 

Although current techniques used by skilled 

surgeons may produce better cosmetic and 

functional outcomes than in the past, confirming 

evidence is essential. Unfortunately, systematic 

outcome data about sexual function in individuals 

with disorders of sexual differentiation and the data 

pertaining to the association of sexual function 

with genital appearance and types of genital 

surgery is lacking. There are either retrospective 

or anecdotal reports with incomplete measures 

and limited comparison groups. These suffer from 

sampling bias and the insensitivity of measures of 

sexual function. Even the best studies show poor 

correspondence between objective and subjective 

indicators, and wide variation in subjects’ responses. 

Indeed it is unclear whether gender identity requires 

gender-consistent genital appearance.

Priorities for Research 

Research on disorders of sexual differentiation 

has been difficult for a number of reasons: (1) the 

relatively low incidence of some of these disorders; 

(2) difficulties in obtaining representative samples—

individuals with poor outcome may be more likely 

to speak out; (3) continuing improvements in 

surgical techniques; (4) the complexity of outcome; 

(5) the likelihood that outcomes are influenced by 

complex psychosocial factors; (6) some important 

outcomes are not readily apparent until adulthood; 

(7) limited measurement tools; and (8) limited 

normative data on relevant outcomes.

• Develop appropriate animal models for gender 

identity and surgical reconstruction.

• Identify intermediate markers/predictors 

of adult endpoints (for example, childhood 

indicators of adult gender identity and sexual 

and reproductive function).

• Determine for these conditions the optimal 

timing and type of genital reconstructive 

surgery with regard to anatomic, reproductive, 

and psychosexual outcomes.

• Examine patient and family adaptation 

following the diagnosis of children with these 

conditions when mental health specialists have 

been integrated into the care of the child.

• Elucidate the process of decisionmaking 

regarding sex assignment and genital surgery 

by physicians and families.

• Conduct long-term prospective and 

retrospective studies of gender identity, sexual 

and reproductive function, and quality of 

life in relation to early medical, surgical, and 

psychosocial factors.

• Determine the importance, for gender identity 

and quality of life, of concordance of the 

genitalia and physical appearance with sex of 

rearing.

• Identify new molecular markers for the rapid 

diagnosis of disorders of sexual differentiation.

Infrastructural Needs

• Workshops that facilitate the skills 

development of qualified mental health 

professionals.

• A patient registry to facilitate recruitment of 

representative samples of patients with rare 

conditions for outcome studies.
Strategic Plan for Pediatric Urology 55
56 Strategic Plan for Pediatric Urology
Strategic Plan for Pediatric Urology 57

III. Other Pediatric Urinary Conditions

15. Pediatric Genitourinary Tumors

Treatment of renal, bladder/prostate, and 

testicular tumors in children may entail 

signifi cant short- and long-term morbidity, 

as well as the threat of death from metastatic 

disease or complications of treatment. Th e large 

multicenter groups under the umbrella of the 

Children’s Oncology Group (COG) have defi ned 

the standard management of these tumors 

in the United States, and COG continues to 

develop large prospective studies. We suggest 

research priorities—studies of the cytogenetic 

changes underlying tumorigenesis, the 

evaluation of organ-sparing approaches, and 

longitudinal study of late eff ects of treatment 

on organ function and secondary malignancy 

risk—which are not currently a focus of COG.

Summary 

Current Clinical Management

Kidney

The initial treatment for children with kidney 

cancer (Wilms’ tumor is the most common kidney 

and genitourinary tumor in children) is removal of 

the affected kidney. Based on the type of kidney 

cancer and extent of the disease, children receive 

multiagent chemotherapy with or without radiation 

therapy. The cure rate for most patients following 

these protocols is approximately 90 percent.

Bladder

Current therapy for bladder and prostate 

cancers, which account for 3 percent of pediatric 

genitourinary tumors, emphasizes bladder salvage. 

Most tumors are biopsied and then treated with 

chemotherapy in the hope of gaining enough 

tumor shrinkage to allow for bladder preservation. 

Many children receive pre- and postoperative 

radiotherapy as well. Survival is approximately 85 

percent with this approach, although 40 percent will 

have lost bladder function after 4 years.

Testis

Yolk sac tumor of the testis is highly curable; 

prospective multicenter trials in Europe and the 

United States have shown that a nearly 100 percent 

survival can be achieved for prepubertal children. 

However, this cure rate requires removal of the 

affected testicle and, for patients with metastatic 

disease, multiagent chemotherapy. Adolescents 

with mixed germ cell tumors have been managed 

largely as adults with some combination of removal 

of the testicle, removal of abdominal lymph nodes, 

and chemotherapy depending on the stage and 

histology of the tumor.

Health Impact

Wilms’ tumor, cancer of the bladder and prostate 

(rhabdomyosarcoma), and testicular tumors 

(yolk sac and mixed germ cell tumors) account 

for a significant fra ction of all solid pediatric 

tumors. While the outcome for children with genitourinary cancers has improved in the last century, 

many children still die from these tumors. The 

children who survive are subject to the long-term 

complications of chemotherapy, radiation, and 

surgical removal of some or all of the affected organ.

Research Priorities

Many clinical questions regarding the standard 

management of pediatric genitourinary tumors are 
58 Strategic Plan for Pediatric Urology

being addressed by COG. However, these studies 

are inherently conservative and can answer only a 

limited number of questions with each protocol. 

There are many important questions that need to be 

addressed by additional studies.

Since children treated for genitourinary cancer 

have a known increased risk for other cancers later 

in life, clinical studies are needed to identify the 

specific risk of late secondary malignancies and 

the implications for initial treatment and longterm surveillance. These should take into account 

both treatment effect and genetic predisposition to 

help understand the pathogenesis of the secondary 

tumors. Other functional endpoints must be 

evaluated for a variety of pediatric genitourinary 

tumors: long-term gonadal function in adults 

treated for testicular tumors in childhood, longterm kidney function in those treated for Wilms’ 

tumor with chemotherapy and radiation, and longterm bladder function after radiation treatment of 

rhabdomyosarcoma. 

Organ-sparing approaches for pediatric genitourinary 

tumors need to be assessed in terms of safety and 

effectiveness. For example, in the treatment of 

Wilms’ tumor, partial removal of the kidney has 

proven effective in special cases; investigation of 

the wider use of kidney-sparing surgery could 

significantly reduce the long-term risk to kidney 

function in these children. 

Basic Research

• Elucidate the role of the fetal tissue lesion 

nephrogenic rests in development of cancer in 

Wilms tumor patients. 

• Apply cytogenetic approaches that identify the 

genetic and mechanistic basis of genitourinary 

tumorigenesis as a prelude to intelligent 

stratification of patients for treatment. 

Translational and Clinical Research

• Conduct multicenter studies of organ-sparing 

approaches for pediatric genitourinary cancers, 

particularly partial kidney removal for Wilms’ 

tumor.

• Conduct prospective studies of treatment 

options for adolescents with testicular cancer.

• Evaluate with epidemiologic and outcome 

studies whether the adult protocols for surgery 

and chemotherapy used to treat adolescents 

with testicular cancer including mixed germ 

cell tumors are appropriate.

• Conduct longitudinal studies of long-term 

outcomes including renal, bladder, and 

gonadal function, and the risk of secondary 

malignancies.

• Conduct phase I/II trials needed to develop 

new therapies, particularly for patients with 

high-risk disease.

Infrastructural Needs

• Training of academic urologists capable of 

undertaking large, prospective clinical trials 

assessing the evaluation and management of 

children with pediatric genitourinary cancer.

• Establishment of a pediatric genitourinary 

cancer patient registry.

• Expansion of the COG tissue banks, with 

access to non-COG scientists for appropriate 

studies.

• Administrative mechanisms to encourage 

multidisciplinary and multicenter collaborative 

studies.

• Establishment of research awards for the 

investigation of genitourinary cancers in 

children.
Strategic Plan for Pediatric Urology 59

16. Pediatric Genitourinary 

 Trauma

Th e treatment of pediatric genitourinary 

trauma would greatly benefi t from the reestablishment of a national database to track 

trends in causes and management. Two 

important questions to be addressed would be 

the long-term sequelae of major kidney injuries 

and the value of prompt expert intervention in 

pediatric genitourinary trauma. Continued 

research into the basis of graft survival 

and approaches to combating infection in 

reconstructive surgery is called for if the results 

of reconstructive surgery are to be improved. 

Summary 

While trauma centers have increased survival and 

decreased morbidity, trauma remains the leading 

cause of death and injury for people between the 

ages of 1 and 44 years. Both upper urinary tract and 

genital trauma often occur with other injuries—

sports and recreational injuries comprise the largest 

single reason for primary care office visits outside of 

routine checkups, and pose unique concerns about 

future maturation and fertility. Representing 8 to 10 

percent of all trauma cases, renal trauma is the most 

common urological trauma. Most genital trauma 

is blunt trauma resulting from accidents and falls, 

and infrequently can have profound psychosocial 

consequences including incontinence, loss of sexual 

and reproductive function, and altered body image. 

Except for a few differences, the evaluation and 

treatment of pediatric genital trauma parallels that 

of adults. In general, management is improved by 

prompt expert intervention. Below, we list some 

categories of trauma and make recommendations 

for future research.

Kidney and Ureteral Trauma

Motor vehicle accidents and falls cause most 

pediatric renal and ureteral trauma. Children 

are especially at risk because the rib cage and 

abdominal musculature is less rigid and well 

developed than in adults. Most kidneys can be 

saved, and advances in imaging and resuscitation 

and support make conservative therapy effective in 

85 to 90 percent of cases. 

Bladder and Urethral Trauma

These are usually due to falls and accidents; often 

the pelvis may have been broken. When trauma is 

suspected, careful, thorough imaging is called for. 

Management is usually conservative with diversion 

of the urine and secondary repair after the other 

injuries have been stabilized.

Penile Trauma

Minor penile injuries usually heal well with little 

consequence. More serious injuries result from 

amputation, bites, and surgical mishaps. Bites, 

especially human ones, pose a high risk of infection 

and require aggressive treatment with antibiotics 

and debridement. In circumcision, the glans, if 

not carefully protected, can be cut or amputated. 

Current practice is to preserve as much tissue as 

possible and attempt primary repair. Partial or 

complete amputations can be reattached. When the 

amputated segment is unusable, later reconstruction 

is possible using a penile prosthesis and grafts.

Scrotal and Testicle Trauma

Blunt scrotal and testicle trauma, typically 

presenting with bruising, swelling, and pain, is 

common in boys. Severe testicular injuries are rare, 

comprising fewer than 5 percent of recreation- and 

sports-related pediatric injuries. Most severe are 

testicular rupture and traumatic torsion.

Genital Skin Avulsion

Rapid deceleration injury can result in genital 

avulsion; the loose genital skin can become snagged 

while the rest of the body continues moving rapidly. 
60 Strategic Plan for Pediatric Urology

The scrotum, labia, and penile shaft are well 

vascularized, and unless there is massive infection 

or tissue loss, primary repair can yield good results.

Perineal Laceration

The perineum can become torn apart as the 

result of a crush or rollover injury: the pelvic 

bone splinters, the floor of the pelvis tears, and 

the urethra and genitalia become disrupted. 

Management is complex and requires immediate 

control of bleeding, colostomy to divert the fecal 

stream, and bony fixation.

Burns

Thermal and electrical burns to the genitalia 

in children are managed like those in adults. 

Radiation burns can occur as a side effect of 

radiotherapy. Treatment requires complete excision 

of the affected skin and graft reconstruction.

Sex Abuse

Sexual abuse occurs in both boys and girls. 

It is often underreported because of fear and 

embarrassment by the child, and overlooked by 

health care and child care providers. 

Research

Pediatric trauma occurs sporadically and it is 

difficult to make any significant observations 

without a larger pool of data. Therefore, it needs 

to be tracked nationally. The National Pediatric 

Trauma Registry (NPTR) served this purpose for 

many years. For example, it gave firm evidence on 

the safety of sports participation for boys with only 

one testicle or kidney. Unfortunately, it is no longer 

funded and became inactive in 2003.

Many of the posttraumatic reconstructive surgical 

techniques require mobilization of healthy 

tissues for graft coverage and reconstruction. 

Critical to the improvement of these is a better 

characterization of the fine vascular and 

neurological anatomy of the genitalia, as well as 

improved means of combating infection, which 

remains the primary complication that jeopardizes 

reconstruction efforts. For patients with insufficient 

local skin, research should be directed to better 

understanding of the use of other tissues, such as 

the buccal mucosa, and to developing practical 

engineered tissues grown from donor cells taken 

from the patient’s own genitalia. 

Priorities

• Develop new techniques to prolong graft 

survival and improve functional and cosmetic 

results.

• Develop improved methods of combating 

infection as a complication of reconstructive 

surgery—in ways that deter development of 

antibiotic resistance. 

• Investigate the fine vascular and neurological 

anatomy of the genitalia. 

• Explore the use of other tissues, such as the 

buccal mucosa, in genital reconstructive 

surgery and develop practical engineered 

tissues grown from donor cells taken from the 

patient’s own genitalia. 

• Evaluate the effect of prompt intervention at 

specialty centers.

Infrastructural Needs 

A national patient registry and database should 

be restarted to track trends in the causes and 

management of pediatric urinary genital trauma.
Strategic Plan for Pediatric Urology 61

17. Testicular Torsion

A delay in the diagnosis and treatment of 

testicular torsion (spontaneous rotation of the 

testicle) can result in signifi cant morbidity, 

including loss of the testicle. While early 

diagnosis and rapid surgical detorsion is 

imperative, it is currently diffi cult to distinguish 

testicular torsion from other diseases of the 

scrotum, and new diagnostic approaches are 

needed. If new therapeutic approaches are 

to be developed, investigation, at the cellular 

level, of the consequences of torsion and 

accompanying ischemia will be essential. New 

assays are needed to determine testicular 

viability at the time of surgery.

Summary 

Testicular torsion is the spontaneous rotation of 

the testicle, resulting in its compromise or death 

due to the twisting of the arteries and veins that 

vascularize it. In humans, the long-term effects 

of testicular torsion are not well characterized; in 

animal models, severely reduced testicular blood 

flow for one hour can lead to permanent testicular 

atrophy. The degree of hormonal dysfunction in the 

torsed testis has been variably reported, but there is 

a consensus that the endocrine function of the testis 

is significantly reduced acutely after torsion repair. 

Health Impact

Affecting one in 4,000 males under the age of 

25, testicular torsion is a significant source of 

emergency room and emergency surgery costs. 

Delay of diagnosis can result in significant 

morbidity, including loss of the testicle and medicallegal costs. Fortunately rare, bilateral testicular 

torsion, which typically presents at birth, results 

in loss of the testes, sterility, and the inablility to 

produce testosterone. 

Clinical Presentation and Management

Testicular torsion is the most common cause 

of acute pain with scrotal swelling in children. 

It is primarily seen in the newborn or in the 

peripubertal male, and while it is a sporadic disease, 

several reports of familial torsion, both neonatal 

and peripubertal, exist in the literature, suggesting 

a genetic predisposition in some cases. Abnormal 

attachments between the testis, vas deferens, 

epididymis, vessels and the scrotum, called the 

“bell-clapper deformity,” have been noted in affected 

children (autopsy series found 12 percent of testes 

with this deformity), but currently the molecular 

and developmental basis of these anomalies is 

unknown. Occurrence of torsion on one side is 

associated with increased risk of torsion of the 

opposite testis. Although testis growth during 

puberty and trauma have been suggested to trigger 

the torsion event, this hypothesis has not been 

proven and should be researched further. Some 

families and children affected by testicular torsion 

suffer from worries about future fertility and the 

absence of one testicle, and occasionally they opt for 

the placement of a testicular prosthesis.

Testicular torsion (torsion of the 

spermatic cord) © Todd Buck, 

Illustration Inc.
62 Strategic Plan for Pediatric Urology

Diagnosis

Because of the high morbidity associated with this 

condition, early recognition and rapid surgical 

detorsion are imperative. However, the clinical and 

radiological evaluation can be quite challenging, 

since many other nonsurgical diseases of the 

scrotum can masquerade as testicular torsion. The 

diagnosis is made currently by history, physical 

examination, urinalysis, and ultrasound or nuclear 

scan. None are perfect, and research addressing 

alternative strategies for diagnosis is greatly needed.

Therapy

If the diagnosis can be made within 6 hours of 

the onset of testicular pain, there is a chance 

that the testis can be salvaged if the torsion is 

released. However, testicular torsion is of variable 

severity—dependent upon the duration and degree 

of twist and therefore the duration and degree of 

vascular compromise—and there is variability in 

the severity of symptoms. At the time of surgery, it 

can be an equivocal and rather subjective decision 

as to whether the testis is viable, and methods to 

objectively assess the viability need to be developed. 

If treated rapidly, the testis can be untwisted, and 

permanent immobilizing stitches are then placed in 

both the untorted testis (orchiopexy or septopexy).

Unfortunately, treatment is often delayed and the 

necrotic testis must be removed (orchiectomy). 

The opposite testicle is also at risk of torsion, 

therefore, a simultaneous orchiopexy is performed 

on the opposite testicle. The worst scenario is 

that of bilateral testicular torsion, which typically 

presents at birth. In these fortunately rare cases, 

virtually none of the testes are salvaged, leaving the 

child unable to produce testosterone and without 

reproductive potential.

Priorities for Research

It is important to understand the cellular 

pathophysiology of testicular torsion so that 

new therapies can be developed to deactivate 

the degenerative cascade initiated by the torsion 

event. Animal models of testicular torsion have 

been particularly helpful in understanding the 

mechanism of torsion-induced damage. There 

are experimental data to suggest that anti-sperm 

antibodies might develop after testicular torsion and 

impair fertility. This has not been definitely proven 

in humans and should be studied further.

• Characterize at the molecular and cellular 

level ischemia/reperfusion injury, including 

subsequent germ cell apoptosis in the torsed 

testes. 

• Improve and validate novel, noninvasive 

means to detect torsion, such as biomarkers or 

imaging techniques.

• Identify assays to determine testicular viability 

at the time of surgery. 

• Create medical therapies to diminish ischemiareperfusion damage to the torsed testis.

• Identify risk factors for torsion; improve its 

anatomical characterization.

• Define and validate the diagnosis of 

intermittent torsion by novel biomarkers.

• Assess long-term endocrine function and 

fertility in patients with past torsion.

18. Phimosis and Circumcision 

Practice

Th e benefi ts of routine circumcision remain 

controversial. We suggest that the eff ect of 

neonatal circumcision on UTI frequency be 

evaluated prospectively using cohort-matched 

groups in a statistically sound longitudinal 

study. 

Summary 
Strategic Plan for Pediatric Urology 63

patient is technically uncircumcised. Finally, 

topical corticosteroid cream (0.05-0.1 percent 

betamethasone) applied to the penis can loosen the 

scarring in mild and moderate cases. Circumcision 

rates have changed with time and reflect population 

and socioeconomic shifts; in the United States, there 

are regional differences, with the Northeast and 

Midwest having the highest circumcision rates of 

newborns.

Given the potential benefits of circumcision, some 

researchers call for a change in the official American 

Academy of Pediatrics policy, which currently does 

not go so far as to recommend it as routine practice. 

However, opponents of routine circumcision point 

out that STDs occur in circumcised men and that 

STD prevention depends more on promoting 

safe sex practices. Furthermore, other factors are 

associated with penile cancer besides circumcision, 

and penile cancer incidence in societies with low 

circumcision rates and high levels of hygiene 

is comparable to that in societies with high 

circumcision rates. The UTI risk studies were 

nearly all retrospective and may have been skewed 

by other risk factors such as vesicoureteral reflux. 

Another factor that must be weighed in the balance 

is complications from circumcision; while the 

complication rate is very low, disastrous outcomes 

such as total loss of the penis are possible. Routine 

circumcision in the population would mean that 

thousands of children would be placed at risk to 

prevent just one case of cancer.

Priorities for Research

• Prospectively study the effect of neonatal 

circumcision on UTI frequency using cohort 

matched groups in a statistically sound 

longitudinal study. Two arms of investigation 

could be males with no genitourinary 

anomalies and males at increased risk from 

genitourinary anomalies.

• Investigate the efficacy of surgical alternatives 

to complete circumcision such as the dorsal slit 

and corticosteroid creams. 

The foreskin covers the glans or head of the penis. 

At birth, it is not retractable, but in most children it 

becomes so by age 5. In some children, formation 

of a tight ring of scar (phimosis) due to repeat 

infection, irritation, or tearing prevents retraction; 

this causes spraying of the urine and traps urine 

beneath the foreskin, fostering infection in the urine 

or in the penis. Other health effects of circumcision 

are somewhat controversial. The tougher and easier 

to clean exposed glans may increase resistance to 

STDs, including HIV, and prevents penile cancer as 

this rare malignancy occurs almost exclusively in 

uncircumcised men. Human papilloma, which can 

hide under the foreskin, is associated with cervical 

cancer—women diagnosed with it are more likely to 

have an uncircumcised sexual partner.

Health Impact

Removal of the foreskin which toughens the 

skin of the glans, has been theorized to have 

many additional beneficial effects. In addition 

to possibly preventing the cervical cancer caused 

by sexual contact, it appears to prevent penile 

cancer, a rare malignancy affecting about 1,000 

men in the United States—patients are almost 

exclusively uncircumcised men. Furthermore, 

in uncircumcised infants, UTIs have been shown 

to be more common, perhaps because the moist 

environment under the foreskin can harbor UTI 

bacteria. In those particularly vulnerable 

(e.g., boys with congenital urinary anomalies, such 

as posterior urethral valves, prune belly syndrome, 

vesicoureteral reflux, and hydronephrosis), 

circumcision might be a way to decrease the risk

of UTI.

Current Clinical Practice

Phimosis can be treated in three major ways. First, 

the foreskin can be removed by circumcision. 

Serious complications are rare and may include 

bleeding, infection, or damage to penis. Second, 

the dorsal foreskin can be slit to retract it more 

easily. Some families prefer this because the 
64 Strategic Plan for Pediatric Urology

19. Varicocele

Treating varicocele in adolescents to improve 

prospects for fertility in adulthood remains 

controversial. A prospective clinical trial to 

assess long-term outcomes (semen parameters, 

testicular growth, and fertility) of watchful 

waiting versus surgery is needed to permit 

rational therapy. Such a study could provide 

specimens, including serum and fractionated 

semen for identifi cation of novel biomarkers, to 

predict fertility problems.

Summary 

Varicocele, the abnormal dilation of the veins of the 

testis, occurs in approximately 15 percent of teenage 

and adult males. The major long-term concerns 

are impaired testicular growth and infertility. The 

pathophysiology of varicocele remains unclear. 

Some patients have compression of venous drainage 

associated with absent or poorly functioning valves 

of the testicular veins. This can result in increased 

testicular temperature bilaterally and be associated 

with increased bilateral testicular blood flow, a 

decline in intratesticular testosterone, and a decline 

in spermatogenesis, likely through increased germ 

cell apoptosis.

The future fertility status of the adolescent children 

with varicocele is not known. Thus, there is a 

need to determine which adolescents are at risk 

• Study the effect of education of pediatricians 

and parents on the proper care of the 

uncircumcised penis, with the goal of 

preventing pathological phimosis. 

• Investigate on an epidemiological basis the 

role of cultural influences and U.S. regional 

migration on decision making for or against 

circumcision.

and in need of intervention. Varicocele surgery 

successfully restores fertility in only 40 to 50 percent 

of infertile men who undergo repair. The possible 

advantage of earlier surgery should be investigated.

Health Impact

Affecting as many as 40 percent of infertile adult 

men, varicocele represents the most common 

clinical finding associated with reversible male 

factor infertility. The incidence in adolescents 

approximates that in adults (15 percent), and 

the long-term followup of these children entails 

enormous costs. Furthermore, tens of thousands 

of surgeries in adolescents with varicocele are 

performed annually, despite controversy as to 

whether they prevent infertility.

Clinical Description and Management

Varicocele most commonly occurs on the left 

side, but it can occur bilaterally and affect the 

function of both testes. The condition varies in 

severity, described by grades 1-3. Impaired growth 

of the affected testis can be seen in many boys 

with varicocele and may result in impaired sperm 

production. Fewer than 5 percent of patients 

experience testicular pain, and this can be relieved 

by surgery. Some families and children affected by 

varicocele suffer from worries about future fertility. 

Varicoceles can be managed surgically and 

observationally; there is controversy as to whether 

surgery impacts future fertility. Impaired growth 

of the involved testis has been the most widely 

accepted criterion for surgical intervention. 

While size difference would appear to represent 

an objective and logical sign on which to base a 

surgical management decision, the reality is more 

complicated. After hypotrophy, a commonly 

used criterion for surgical correction has been 

a large varicocele. The adult data correlating 

varicocele size with fertility status would suggest 

that large grade III varicoceles correspond to lower 
Strategic Plan for Pediatric Urology 65

• Identify possible clinical and hormonal 

indicators that allow identification of 

adolescents at risk for infertility. 

• Define clear indications for intervention to 

correct varicocoele.

• Provide specimens, including serum and 

fractionated semen, for identification of novel 

biomarkers. 

• Identify the molecular basis of testicular 

damage in varicocele by assaying for novel 

biomarkers from banked specimens, including 

testicular vein blood and fractionated semen.

• Exploit the use of animal models of varicocele 

to study factors that control testicular growth 

and the mechanisms by which varicocelectomy 

restores fertility.

• Assess the outcomes of testicular arterysparing surgery versus other methods.

• Study the health benefit of educating primary 

caregivers and teens on varicocele to increase 

early detection.

sperm counts and improved response to surgical 

correction of the varicocele.

It is rational to manage most adolescent patients 

with a varicocele by observation and regular 

followup examinations. Those who would clearly 

fall into this category would be boys with equal 

testicular volume and no symptoms, independent of 

varicocele size. In fully developed adolescent males, 

it is desirable to obtain semen analysis data when 

they are willing to comply.

Priorities for Research

Perform well-designed clinical study(s) to assess 

long-term outcomes of watchful waiting versus 

surgery for varicocele. Ideally, the study would:

• Determine whether early repair improves 

semen parameters, testicular growth, and 

fertility.

• Develop reference data of normative semen 

parameters in the fully developed male 

adolescent.
66 Strategic Plan for Pediatric Urology
Strategic Plan for Pediatric Urology 67

IV. Research Methodologies

20. Animal Models

At present, our understanding of cellular 

and molecular mechanisms of normal and 

abnormal development of the genitourinary 

system lags behind that of other organ 

systems. A broad program of research using 

model organisms is essential if this situation 

is to be remedied. While the mouse remains 

indispensable, non-mammalian models such as 

the zebrafi sh hold great promise; rat, chicken, 

frog, and other models will continue to have 

unique applications. Essential to progress will 

be collaborations; between clinician and basic 

researcher, between those working in vivo and 

in vitro, and among those with expertise in 

diff erent animal systems.

Summary 

Deletion of a calcium signaling protein, 

calcineurin, causes defects in pyeloureteral 

peristalsis, obstruction, and nephropathy in the 

developing mouse. Blue bars indicate length 

change in the most proximal segment of the 

ureter (from CP Chang et al. Calcineurin is 

required in urinary tract mesenchyme for the 

development of the pyeloureteral peristaltic 

machinery. Journal Clinical Investigation 113: 

1051-1058 © 2004). 

Basic understanding of development and 

maldevelopment of the GU tract will derive largely 

from work in model organisms. The mouse is the 

most widely used system for a number of good 

reasons: available resources and infrastructure 

include a sequenced genome, cDNA and genomic 

microarrays, tissue- and stage-specific cDNA 

libraries, and a multitude of mutant lines. 

Morphology and physiology is sufficiently similar 

to that of humans so that translational research can 

be accomplished. Among mammals, the mouse 

is uniquely amenable to intensive genetic and 

experimental manipulation. In vitro mammalian 

studies often use cells from rats as well as mice, and 

the rat is the primary model for physiology studies. 

Models for obstruction include sheep as well as rats, 

and bladder dysfunction has been studied mainly in 

cats and sheep.

Non-mammalian models have been underutilized 

but hold great promise for progress in this area. 

Zebrafish and medakafish have the advantage 

of being genetically tractable model systems 

with rapidly expanding genomic and proteomic 

resources and extremely short generation times. 

The power of the frog (Xenopus) system derives 

from the ease with which embryos can be 

manipulated. It is now possible to generate 

transgenic frogs, carry out genetic crosses, 

overexpress genes by electroporation and 

microinjection, and prevent gene function using 

antisense oligonucleotides or morpholinos. The 

Control

Control

Mutant

Mutant
68 Strategic Plan for Pediatric Urology

chick embryo has been a powerful system for 

developmental studies of numerous organs and, 

while not amenable to genetics, it offers a number 

of advantages over the mouse. Chick eggs are 

inexpensive, easy to obtain, and well suited to in

ovo/vivo experimental manipulations, including 

tissue recombinations, surgeries, overexpression 

and knockdown of genes, and analysis of cell 

lineage by microinjection of lineage tracers and 

heterospecific transplantation. We suggest that a 

highly collaborative research effort continue across 

multiple experimental systems, profiting from the 

unique advantages and potentials of each.

Research Priorities

Multifaceted, collaborative approaches need to be 

strongly encouraged.

• Combine in vitro and in vivo/genetic 

approaches within the same animal model.

• Encourage collaborative efforts involving 

two or more investigators with expertise in 

different systems (e.g., in vivo versus in vitro, 

or in different animal models).

• Clinicians and basic researchers should work 

jointly to develop new in vivo and in vitro

systems using model organisms.

• Use multiple animal models for the purpose 

of tissue engineering; this research will require 

interactions between cell and developmental 

biologists, clinicians, and physiologists. 

• Investigate patterns of genitourinary 

malformations and disease in natural animal 

populations exposed to environmental 

contaminants. 

Infrastructural Needs

All mutant mouse strains, particularly those 

produced in large centers, should be included in a 

database and be freely available for use as animal 

models or for in vitro studies of genitourinary 

disease.

21. Biomechanics

While biomechanics is a discipline essential to a 

functional understanding (from the cellular to 

the organ level) of organs of the genitourinary 

tract and to such goals as reengineering of the 

bladder wall, its application to urologic research 

has been limited. We list some important 

research goals in this area and underline the 

need to bring together selected specialists in 

biomechanical science and urologists with 

interests in the role of mechanical properties in 

urological disease. 

Summary 

Overview of Biomechanical Science as 

Related to the Bladder

Biomechanics, the study of mechanical forces in 

living cells and tissues, pertains to the bladder as a 

smooth muscle organ with dynamic prerequisites: 

urine storage at low pressure, and efficient and 

complete evacuation of urine through active muscle 

contraction. A comprehensive biomechanical 

description of the bladder would encompass the 

following topics, among others:

• fluid dynamics in non-rigid conduits including 

the bladder outlet, sphincter mechanisms, and 

urethra 

• the mechanics of the individual cells 

(e.g., the effect of mechanical forces on the 

bladder smooth muscle cells, urothelial cells, 

and other cells in bladder) 

• cell forces that may influence the extracellular 

matrix

• the assembly of connective proteins and 

other molecules that underlie the bladder’s 

viscoelastic properties 

• modification of intrinsic cell biomechanical 

behavior (e.g., muscle cell contractility and 
Strategic Plan for Pediatric Urology 69

blood vessel mechanics) by neurotransmitters 

and hormones 

• the effect of mechanical bladder smooth 

muscle cell (BSMC) properties on 

cell phenotype and the surrounding 

microenvironment

Multiple cellular and molecular effects of 

mechanical stimuli have been described in whole 

animal bladder models, urothelium, BSMC cells 

subjected to strain, stretch, and compression, as well 

as the whole bladder in tissue culture. However, 

no systematic approaches have been established for 

such studies. Therefore, a more robust utilization of 

the principles of biomechanics, which can provide a 

conceptual framework to integrate mechanical force 

information from the molecular to the organ level, 

is clearly needed.

Biomechanics and Clinical Needs

If clinical practice is to be successful in maintaining 

the low-pressure storage and event-free evacuation 

critical to protecting the upper urinary tract, it 

must be informed by an understanding of the 

biomechanical properties of the bladder and its 

cellular and extracellular matrix components. It 

should be noted that biomechanical properties 

may also impact non-storage and emptying 

conditions, such as infection and tumor growth, 

in so far as microorganisms and tumor cells may 

respond to transient or permanent changes in cell 

biomechanics.

Biomechanics is of course fundamental to the 

long-term engineering goal of duplication of native 

bladder wall; here there is a need to establish 

minimal functional prerequisites necessary to 

guide design of functional bladder replacements. 

Also critical to the success of the bioengineering 

enterprise are models of long-term remodeling and 

engineered tissue survival that minimize the need 

for costly animal trials; because of the complexity of 

the remodeling process, in vitro model development 

should be undertaken first to avoid costly in vivo

testing and development. 

Research Obstacles

Our knowledge of bladder structure and 

shape—thought to be closely associated with 

the development and spatial distribution of wall 

tension—is very incomplete. Areas of contact 

with other pelvic structures still need to identified, 

quantified, and mapped out over a reconstructed, 

three-dimensional surface. We also know little or 

nothing about how the bladder layers are connected, 

to say nothing of the mechanical properties of these 

connections or how the bladder can accommodate 

large volume variations. Furthermore, a systematic 

approach to the biomechanical properties of cells 

with respect to their impact on bladder function 

and development is lacking.

Progress in these areas is greatly hindered by 

insufficient communication between clinical 

urologists and urologic investigators on the one 

hand, and biomechanical scientists on the other: 

clinical urologists and urologic investigators often 

possess only ad hoc knowledge of biomechanical knowledge of biomechanical 

science and do not appreciate its complexity; basic 

biomechanical scientists are largely unaware of 

bladder research goals and have not shown interest 

in developing clinically relevant models of bladder 

function.

Research Priorities

• Create new biomechanical models for the 

bladder with potential application to other 

systems (particularly the cardiovascular 

system). These should include organ culture 

models, and mechanical models describing 

tissue and cell behavior. Mechanical models 

of bladder wall function and wall stress should 

take into account the influence of adjoining 

pelvic cavity structures. 
70 Strategic Plan for Pediatric Urology

• Characterize the bladder’s shape; areas of 

contact with other pelvic structures should be 

identified and quantified.

• Investigate the mechanical role of individual 

tissue components.

• Characterize the three-dimensional tissue 

structure of the bladder and other urologic 

organs from the cellular to the tissue level 

(1 – 1,000 μm)1

Infrastructural Needs

• Create a database of transgenic animals to 

collect unappreciated, non-utilized bladder 

tissues from existing existing transgenic animal models. transgenic animal models. 

This issue potentially cuts across all areas of 

bladder research.

• Convene a meeting/roundtable of selected 

specialists in biomechanical science and 

urologists with interest in the role of 

mechanical properties in bladder disease. The 

overall goal should be better communication of 

bladder biomechanical/biological requirements 

and questions to basic physical science, 

engineering, and biomechanics scientists. 

1

 This will require high-throughput approaches to streamline 

integration of diverse imaging data into a three-dimensional 

structure. The structural information should be converted 

into databases suitable for immediate use in bioinformatic and 

computational biomechanics applications.

23. Nanotechnology

Nanotechnology is a new cross-disciplinary 

fi eld emerging from technological advances that 

permit the manipulation of individual atoms 

and molecules. It promises to have manifold 

applications in disease detection, medical 

imaging, construction of complex biomaterials, 

and drug delivery and targeting. We propose 

steps to foster the active collaboration and 

communication between diverse scientifi c, 

engineering, and medical research communities 

necessary to develop the technologies that could 

revolutionize medical practice. 

Summary 

Nanotechnology has the potential to revolutionize 

biology and medicine by offering the ability to 

control and manipulate matter at a resolution that 

is at the molecular and atomic scale, in the 1 to 

100 nanometer range. This means that scientists 

in this field are able work with individual atoms 

and molecules—a nanometer, or a billionth of 

a meter, is, about one eighty-thousandth of the 

diameter of a human hair, and only 10 times the 

diameter of the smallest atom. This technology 

does not derive from a single scientific discipline. 

Rather, it is a multidisciplinary combination of 

physics, chemistry, biomechanics, material science, 

and biology. Broadly speaking, nanotechnology 

incorporates:

• Research and technology in the length scale of 

approximately 1 to 100 nanometers

• Creation and utilization of structures, devices, 

and systems that have novel properties and 

functions because of their small and/or 

intermediate size

• Creation and utilization of materials, devices, 

and systems by building from the level of 

atoms and molecules
Strategic Plan for Pediatric Urology 71

Two approaches to nanotechnology development 

are used: “top-down” and “bottom-up.” In the 

top-down approach, development is driven mainly 

from the traditional disciplines of engineering and 

physics, and it makes use of current technologies 

like lithography used in making computer chips. 

This approach has the advantage of large-scale 

fabrication and more rapid integration of existing 

technologies. The bottom-up approach, starting 

from single atoms and molecules and exploiting the 

novel physical properties of the nanostructures, has 

more in common with chemistry and molecular 

biology. It uses the self-assembly of atoms or 

molecules to form nanometer-sized structures 

and is generally more difficult to control and 

characterize. However, in this field, both these 

approaches are often required concurrently. For 

example, in developing an antigen-specific sensor, 

the supporting circuitry would be fabricated from 

the top-down approach on traditional substrates, 

while the actual sensing element, consisting of 

biological molecules or nanoparticles, would be 

self-assembled.

Nanotechnology promises to allow us to 

communicate chemical information at a cellular and 

subcellular level, to place artificial components and 

The electric properties of derivatized carbon 

nanotubes could make them invaluable as 

biosensors.

assemblies inside cells, and to fabricate materials 

using self-assembly methods. New materials for 

use in pediatric urology could be created to act as 

templates for cell growth, structural components 

in tissue engineering, and antimicrobial surfaces. 

Nanostructured materials will facilitate early 

detection of diseases such as cancer and enable 

unprecedented advances in drug delivery 

technology.

As with any new field, applying breakthroughs in 

basic research in nanoscience to medicine presents 

obstacles to be overcome. Often it is difficult to 

fully characterize the structure or morphology 

of nanomaterials, particularly when they are 

functionalized or encapsulated. Typically, several 

advanced microscopy and analytical techniques 

such as NMR, EPR, and optical spectroscopy are 

required. Nanoparticles easily form aggregates, 

reducing their effectiveness as therapeutic agents, 

and toxicity studies have not kept pace with 

development and will lag for some time due to the 

proliferation of new nanomaterials.

Research Goals and Opportunities

It is difficult to encapsulate the research program of 

this new and diverse field in terms of priorities; we 

highlight some general directions for research that 

are likely to impact pediatric urology.

• Develop biocompatible exogenous 

nanomaterials to control infection and 

mitigate biofilm formation on the surface of 

long-term indwelling catheters, dressings, and 

engineered urological implants. Nanoparticles 

have been shown to be effective antimicrobials 

against bacteria and have shown the ability to 

penetrate biofilms.

• Incorporate nanomaterials in tissue 

engineering. Prosthetic bladders and urethra 

may benefit by the use of nanomaterials in the 

scaffolding to promote cell growth, quantify 

remodeling rates, and allow localized drug 

delivery. Nanomaterials might also be used 
72 Strategic Plan for Pediatric Urology

as templates for neuron growth when treating 

urologic diseases caused by spinal cord 

injuries.

• Develop nanotechnology to improve 

drug targeting and specificity and allow 

timed, local release of drugs. Tumorrestricted surface antigens may be targeted 

by adding specific nanoreceptors on the 

surface of nanoparticles. Drugs may be 

incorporated into nanoscale particles with 

coatings several nanometers in thickness, 

permitting controlled, local release of a drug 

through biodegradation of the encapsulant or 

stimulated release by radiation.

• Create specific and rapid nanosensors for 

early detection of urological diseases using 

the properties of nanotubes and other 

technology.

• Enhance imaging systems for contrast at the 

cellular level using nanotechnology. Nanoiron, and gadolinium particles can be used 

to enhance contrast in magnetic resonance 

imaging (MRI). Quantum dots allow visible 

and infrared imaging enhancement of tumors 

and cellular processes, and monitoring of 

tissue scaffolds during remodeling. 

Infrastructural Needs

One of the most significant hurdles the new field 

presents is in education. Although the number of 

institutions offering programs in nanotechnology 

is growing, programs are primarily at the 

undergraduate level. Instruction needs to be 

developed for medical graduate and postgraduate 

students in pediatric urology to help them integrate 

the new technology. Since nanotechnology cuts 

across traditional disciplines such as biology, 

chemistry, engineering, physics, and material 

science, a new paradigm will be needed to train 

basic and clinical researchers.

Nanoscientists have materials and technologies in 

need of applications, and clinicians have problems 

in need of materials. A dialogue must be fostered 

between the two groups through seminars and 

workshops. Industrial, as well as academic, 

participation should be encouraged for effective 

cross-fertilization of ideas. 

• Arrange joint mentoring of researchers by 

mentors with extensive experience in pediatric 

urology and nanotechnology.

• Fund new investigators taking a 

multidisciplinary approach to urology and 

nanotechnology.

• Encourage multidisciplinary research efforts 

between nanoscientists, urologists, and 

industry.

• Establish regional technical centers for 

nanotechnology and pediatric urology to assist 

with fabrication of new materials and their 

characterization.

• Develop educational programs to acquaint the 

next generation of urological researchers with 

nanotechnology.

• Convene workshops to foster interaction 

between clinicians and nanoscientists. 
Strategic Plan for Pediatric Urology 73

24. Stem Cell Biology

If the promise of stem cell research is to be 

realized in terms of benefi cial treatments 

for patients, some major hurdles must be 

overcome. Methods for identifying, isolating, 

and enriching human stem cells—including 

those of the GU tract—at diff erent stages of 

diff erentiation will need to be developed, and 

scientists need better means of tracking the 

location and fate of stem cells in the body. 

Much remains to be learned about the 

molecular signaling mechanisms that would 

mediate functional integration into human 

tissue. 

Summary 

Stem cells are undifferentiated, self-renewing 

cells that have the unique potential to produce 

many kinds of cells in the body. Various types of 

these cells are thought to be actively maintained 

in diverse adult tissues, including the intestinal 

lining, the hematopoietic system, and muscle. Their 

normal role in human disease is currently unclear. 

When grown in culture, stem cells can be induced 

to differentiate into many specialized cell types that 

form muscle, nerves, cartilage, blood, and other 

tissue. This property could revolutionize medicine, 

enabling doctors to repair specific tissues or to grow 

organs. A vast research effort has been directed 

to transplantation of these cells into animals with 

damaged or diseased organs—some improved 

function has been reported, but how enhanced 

function occurs and whether it derives from the 

function of differentiated stem cells remain unclear.

Major Research Obstacles

Significant challenges have to be overcome 

before any type of stem cell can be harnessed 

and translated to meaningful treatments for 

patients. These include identifying the optimal 

type of stem cell for specific assays and therapies 

for individual disorders, harvesting and growing 

sufficient quantities of the appropriate cell type, 

deciding the best therapeutic strategy for each 

condition to be treated, and assessing the potential 

side effects that may arise when such pluripotent 

cells are introduced into a patient. While methods 

exist to follow how some stem cells differentiate 

in animal models, there are no well-defined, noninvasive methods with which to study the survival, 

migration, fate, and function of stem cells in the 

living animal or human, and there are currently 

few markers, antibodies, or probes with which to 

distinguish specific classes of stem cell. Currently, 

little is known about the host environments that 

facilitate regeneration of tissue or the molecular 

signals that are responsible for tissue organization. 

Research Priorities

• Isolate and characterize in molecular terms the 

stem cells from the GU tract.

• Investigate the effect of urological diseases on 

the fate of stem cells from the GU tract.

• Define in vitro culture conditions for 

maintenance and differentiation of GU tract 

stem cells.

• Use existing in vitro systems for complex 

morphogenesis to study cell biology, 

differentiation, and morphogenetic behavior of 

stem cells in three-dimensional environments.

• Utilize stem cells for drug discovery studies.

• Develop methods for identifying, isolating, 

and enriching human stem cell populations at 

different stages of differentiation.

• Develop reliable protocols for expansion, 

maintenance, verification, preservation, 

storage, and shipment of stem cells.

• Develop non-invasive methods and agents 

with which to visualize or track stem cells in 

the body.

• Develop therapies based on stem cells to treat 

urological diseases.
74 Strategic Plan for Pediatric Urology

Infrastructural Needs

Advancing stem cell research will require 

dissemination of technical knowledge and skills 

in cell culture techniques across a variety of 

disciplines and disease research areas. There are 

few investigators who have sufficient experience 

with this research tool.

• Educational courses focused on the cell culture 

techniques for human embryonic stem cells; 

designated workshops for the dissemination 

of technical knowledge pertaining to isolation, 

characterization, maintenance, in vitro

assessment, and in vivo application of stem 

cells.

• Standardized laboratory practices for use of 

human stem cells including proper exposure 

precautions, safe methods of disposal, and 

recordkeeping.

• Centers that will bring together basic stem cell 

biologists, researchers skilled in novel modes 

of cell delivery, urologists with disease-specific 

expertise, and investigators experienced in 

developing and assessing animal models of 

human diseases to create new research teams.

• A national stem cell repository and stem cell 

technology and bioinformatics core. This 

clearinghouse could receive, process, store, and 

distribute information on stem cells.

Imaging technology is central to both basic 

and clinical research in pediatric urology. 

In the area of basic research, understanding 

the genetic basis of genitourinary tract 

development depends on precise images of the 

developing urinary tract as researchers assess 

the consequences of a specifi c mutation or use 

gene fusions to localize specifi c proteins. On 

the clinical side, the key impact of imaging 

technologies is to provide a noninvasive 

means for researching the onset and extent 

of pediatric urology disorders, as well as to 

provide the means to evaluate eff ectiveness of 

treatment. Th e use of imaging technologies, 

such as prenatal MRI to examine genitourinary 

tract development in real-time, will provide, 

for the fi rst time, the capability to assess the 

cellular and molecular processes aff ected during 

urologic malformation. Th is will facilitate the 

accurate diagnosis and treatment of common 

pediatric urologic disorders. 

Summary 

Research Priorities

Imaging innovations have progressed rapidly, but a 

rigorous and systematic assessment of the emergent 

technologies has not been performed. Formal 

assessments are required to determine whether they 

will actually result in improvements in GU-specific 

health outcomes and be cost effective.

• Develop non-invasive imaging technologies:

• to target GU abnormalities

• to facilitate the analysis of prenatal GU 

tissues and improve the understanding of 

how congenital urologic malformations 

occur 

25. Clinical and Developmental

Imaging
Strategic Plan for Pediatric Urology 75

• to eliminate or reduce the radiation 

exposure to children during the diagnosis 

and management of common pediatric 

urologic disorders

• Develop imaging technologies to examine 

newly identified GU genes for their specific 

patterns of expression and function in tissues 

commonly affected by urologic malformations.

• Support the production of novel mouse lines 

bearing gene fusions and other constructs to 

facilitate the imaging analysis of gene function 

during prenatal GU development.

• Develop non-invasive imaging technologies 

for large animal models to identify processes 

and mechanisms involved in the diagnosis and 

therapy of pediatric urologic disorders.

• Examine whether the fusion of functional and 

anatomic images can replace invasive imaging 

procedures.

• Expand the use of low-radiation dose 

fluoroscopy and nuclear medicine technologies 

to facilitate the analysis of urologic disorders.

Infrastructural Needs

Pediatric urology requires a focused funding 

initiative to help insure that both the clinical and 

developmental imaging sciences are integral to 

the training and practice of pediatric urologists. 

Programs that provide enhanced research 

opportunities for pediatric urologists to understand 

imaging technology assessment and gene function 

in a developmental context will augment their 

clinical pediatric urology training and their 

effectiveness as caregivers. 

• Establish programs in which education in 

imaging science is integral to the training of 

urologists.

• A platform for the sharing of imaging 

information on the developing urinary tract by 

clinicians and researchers

A mouse strain expressing a Hoxb7-Gfp transgene which is localized in the ureter and Wolffian ducts 

has been-stained with E-cadherin, a general epithelial marker that also labels the urogenital sinus, 

the primordium of the bladder, and urethra. The ureter and the Wolffian duct (both in green) are 

initially fused (left panel). During days 13-14 the ureter separates from the Wolffian duct, inserts in 

the urogenital sinus and is transposed to a new position at the base of the developing bladder (right 

panel). Disruption of this process underlies a number of developmental anomalies in humans including 

VUR, thought to affect 1 to 2 percent of the population (courtesy of Dr. Catherine Mendelsohn, 

Columbia University).
76 Strategic Plan for Pediatric Urology

26. Systems Biology

Technological advances in the separation and 

characterization of biomolecules, coupled 

with the emerging fi eld of bioinformatics, have 

allowed for the acquisition and organization 

of enormous amounts of data describing 

an organism in terms of gene and protein 

expression, metabolism, DNA modifi cation, 

and other parameters. Th e possibilities for 

identifying relevant biomarkers to assist the 

clinician in the diagnosis and treatment of 

specifi c diseases are enormous. We propose 

some specifi c steps to ensure that clinical 

investigators in urology can take advantage of 

this new fi eld. 

Summary 

“Systems Biology” is a new term for the discipline 

forming in response to the assembly of enormous 

data sets of biological information, data sets 

made possible by advances in biotechnology—

automated DNA sequencers, chip-based methods 

of transcriptome and genome scanning, mass 

spectrometry-based methods for sequencing 

proteins, and many others. These data sets are quite 

diverse; they might include the sequences of entire 

genomes of related organisms, tables specifying the 

relative expression of all the genes in an organism 

in a particular tissue under specific conditions, or 

the relative amounts of all different proteins in a 

particular cell.

The organization and analysis of the data to address 

meaningful questions in biology and medicine 

depend on powerful computational tools and the 

emerging discipline of bioinformatics. The transfer 

of data between laboratories, across technical 

platforms, and between investigators with divergent 

expertise presents complex problems whose 

solutions are now in their infancy, and are a focus of 

active research.

The categories below give some idea of the breadth 

of investigations in systems biology:

Genomics

The systematic study of the genetic information 

of an organism (genome) offers researchers the 

prospect of developing new insights into the 

genetic basis of disease. Based on assays for single 

nucleotide polymorphisms (SNPs) in populations, 

scientists can identify individuals who are at genetic 

risk for particular diseases or particular adverse 

outcomes in the clinic. Studies often extend beyond 

one generation and require tracking of ancestral 

groups and migration/immigration patterns, and 

the number of specimens and the genetic loci to be 

analyzed in these studies is enormous. Additional 

challenges occur at the level of computation and 

data analysis. Several high-throughput platforms 

are becoming available for rapidly assessing SNPs, 

permitting us to envision a genetics-based urologic 

practice.

Transcriptomics

With the advent of high-density oligonucleotide 

or cDNA arrays, the transcription of thousands 

of genes in a particular biological sample can be 

studied simultaneously. After a decade of efforts 

toward standardization of array platforms, attaining 

accurate annotation of thousands of genes, and 

development of data-mining software, global gene 

profiling has becoming a common experimental 

tool. If its application in pediatric urology is still 

limited, the conceptual and technical foundations 

now exist for: (1) comprehensive description 

of transcriptomes (the set of all RNAs in an 

organism) and deeper insight into the program 

of transcriptional regulation; (2) identification of 

novel molecular pathways for the discernment of 

new disease mechanisms; (3) discovery of gene 

clusters whose expression are altered in a predisease state (biomarkers) or are associated with 

subsets of patients (patient-stratification tools), 

and; (4) identification of molecular targets of 
Strategic Plan for Pediatric Urology 77

value to intervention and classification of patients’ 

responses. When combined with appropriate 

animal models or well-designed clinical trials, this 

technology may become one of the most powerful 

tools for pediatric urologic investigations.

Epigenomics

Epigenetic mechanisms mediate heritable changes 

in gene expression that do not involve a change 

in DNA sequence per se. They can involve either 

chemical modifications of the DNA itself or 

modifications of proteins that are closely associated 

with DNA. Epigenetic regulation controls 

important biological processes such as imprinting, 

X chromosome inactivation, and transcriptional 

control of gene expression; its disruption 

contributes significantly to the etiology of many 

human diseases. In the past decade, “epigenomics,” 

or the study of whole-genome epigenetic changes, 

has gained momentum with the advent of 

modern investigative tools: methylation-sensitive 

fingerprinting, restriction landmark genome 

scanning, and methylation-specific oligonucleotide 

arrays that allow identification of aberrant hypo- or 

hyper-methylation sequences and simultaneous 

assessment of methylation status of multiple CpG 

islands. Like the SNP- based approaches for the 

systematic analysis of sequence, determining 

the methylation patterns of a large enough 

number of genes has the potential to yield highly 

discriminating signatures for specific diseases.

Proteomics

The field of proteomics began with efforts to 

determine the structure, expression, localization, 

activity, and cellular roles of the ensemble 

of proteins (proteome) in the body. Great 

progress has been made in this field of research 

owing to novel instrumentation, experimental 

strategies, and bioinformatics methods. A more 

contemporary goal of proteomics research is to 

obtain a comprehensive, quantitative description 

of expression of hundreds, if not thousands, 

of proteins/peptides, and changes in their 

interrelationship under the influence of biological 

perturbations such as disease or drug treatment. 

The complex information that proteomics provides 

has the same potential for providing biomarkers 

and other predictive information as the genebased approaches outlined above. Current stateof-the-art methodologies of proteomics permit 

(1) pattern recognition (without identification of 

specific proteins/peptides) via protein profiling by 

sophisticated separation methods; (2) identification 

of proteins/peptides using a multidimensional 

protein identification technology (MudPIT); 

(3) relative and absolute protein quantification 

using techniques such as isotope-coded affinity tag 

(ICAT) labeling, iTRAQ, and metabolic labelingTwo methodologies that permit a systems 

biology approach. In gene expression 

arrays (top), the immobilization of defined 

DNA sequences at particular points in a 

grid allows for simultaneous measurement 

of the abundance (reflected by pixel color) 

of all RNAs in a biological sample. In the 

lower panel, the electrophoretic separation 

of a complex mixture of proteins allows 

the amount of each protein component 

to be quantified. In both approaches, 

sophisticated methods of data acquistion 

and analysis allow clinicians to identify 

patterns of abundance that are markers for 

diseases.
78 Strategic Plan for Pediatric Urology

MS; and (4) construction of two-dimensional ion 

density maps of proteins directly from the surface of 

tissue sections using MALDI imaging.

Metabolomics

Metabolomics is the systematic study of the 

metabolites of a cell or organism. Traditionally, 

characterization of abnormal metabolites in blood, 

urine, or tissue biopsies has been used to detect 

diseases such as inborn errors of metabolism. 

However, the concept of parallel analyses of all 

the metabolites in a biological sample has been 

made possible only because of because of rapid advances rapid advances

in technologies such as gas chromatography 

mass spectroscopy. With these technologies, all 

the metabolites in the sample set are taken into 

statistical consideration to derive the algorithms 

permitting disease or disease-stage identification 

and prediction of patient response.

A major goal of systems biologists is the creation of 

“networks” of various kinds. These include signal 

transduction, protein-protein, DNA-protein, and 

three-dimensional mapping types of networks. For 

example, one extension of traditional proteomic 

approaches would be to characterize, using yeast 

two-hybrid methods, the set of protein-protein 

interactions that characterize the state of a 

living cell.

Relation to Clinical Needs

The value of the systematic approaches briefly 

described above might be illustrated by recalling 

traditional approaches. Urinary markers of VUR, 

for example, have been identified using educated 

guesses as to what markers might be important, 

and testing them with relatively crude detection 

technologies such as Western blotting. In the 

systemic approach, all of the proteins that appeared 

in the urine during the course of VUR (and during 

its spontaneous resolution, and in uninfected 

patients) can be systematically identified and, using 

computer-based analytical techniques, patterns that 

are specific to VUR can be ascertained. With the 

advent of proteomics, genomics, and epigenomics, 

we are able to identify many more potential 

biomarkers or highly discriminative markerclusters that may serve as diagnostic, prognostic, 

and therapeutic tools. Significant challenges 

remain in identifying sufficient numbers of these 

markers or marker-signatures, testing them through 

case-control studies and prospective trials, and 

developing the statistical and computational tools 

necessary to analyze and model complex data sets.

Research Opportunities

Most major teaching centers include facilities 

and expertise for genomics research. Proteomics 

capabilities also are becoming more common, 

and within a few years will be ubiquitous at major 

centers. The proximity of these technologies and 

specialists trained in their use means that it will be 

possible for clinical and basic scientists conducting 

urologic disease research to use these approaches 

in their own studies. Some specific research 

opportunities are:

• Establishment of databases of gene and protein 

expression patterns in the genitourinary tract, 

at various stages of development in health and 

disease. 

• Application of urine proteomic information 

to developing biomarkers of diagnostic and 

predictive value, including markers that predict 

response to certain clinical interventions.

• Identification of at-risk populations based on 

systems biology approaches.

• Identification of markers for cell types destined 

to become components of the upper or lower 

collecting system.

• Creation of cross-platform approaches that 

incorporate relevant animal models.

• Use of pharmacogenomics to discover new 

drugs and treatment protocols.
Strategic Plan for Pediatric Urology 79

• Identification of maternal factors that 

contribute to pediatric disease.

• Decoding gene function and complex 

biological pathways that govern diseases 

through the identification of unique 

transcriptomes and their master switches.

Infrastructural Needs

There is a significant technical, cultural, and 

conceptual chasm between most clinical and basic 

researchers in urology and those doing genomics, 

proteomics, and other systems biology studies. 

Most systems biology experts have little familiarity 

with urology as a discipline, and often little or 

no familiarity with medical fields in general. A 

common misconception of basic researchers 

in “leading edge” fields is that urology-focused 

questions are either trivial, derivative, or otherwise 

uninteresting. Because it is more likely that longterm interest in an area will be spawned when 

one “grows up” in it, pediatric urology needs new 

mechanisms for attracting gifted and promising 

graduate students and junior scientists with an 

interest in basic research. Research training 

programs specifically focused on pediatric urology, 

and in urologic disease in general, need to be 

developed and implemented.

Systems biology is a technology-driven area. 

Consequently, infrastructure needs are great and 

require an extremely large amount of financial 

capital and other resources. Leaders of urology 

research programs need to be positioned within 

their own institutions in a manner that will allow 

them to maximize their colleagues’ access to and 

participation in the newly forming infrastructure 

elements (e.g., genomics programs and proteomics 

core facilities) that are relevant to systems biology 

studies.

• New NIH pre- and postdoctoral training 

programs integrating systems biology with 

urological disease research.

• Better participation of national medical 

organizations (the American Urological 

Association in particular) in maintenance and 

development of academic training programs 

that promote state-of-the-art research 

involving clinicians.

• Systems biology requires high levels of 

dedication and willingness to acquire new 

expertise. Integration of systems biology 

research with urology will require clinicians 

to focus less on high-volume patient care and 

make more of a commitment to research.

• Development of financial instruments 

within academic urology practices that will 

allow research-oriented urologists to pursue 

academic research careers without being 

overwhelmed with clinical demands.

• Establishment of accessible tissue banks linked 

to comprehensive clinical databases.
80 Strategic Plan for Pediatric Urology

27. Tissue Engineering

Millions of American children suff er from 

congenital and acquired urologic diseases. 

Dysfunctional organs from these diseases 

interfere with the normal development of the 

child and have a large economic impact on 

our health care system. In the future, tissue 

engineering will play an important role in 

the treatment of pediatric urologic disease. 

Recommendations for future research on tissue 

engineering include:

• Conduct tissue engineering research of the 

bladder, urethra, kidney, and pelvic floor 

with the following goals:

• Increased understanding of normal 

and abnormal cells and developmental 

biology

• Development of cell therapy

• Development of tissue and organ 

replacement

• Enhance training and education of 

physician/scientists in tissue engineering.

• Enhance interdisciplinary collaboration 

and education.

• Establish appropriate infrastructure, 

training, and core facilities for research.

Summary 

Diseased pediatric urologic tissues have 

traditionally been replaced or repaired with 

autologous tissues harvested from other sites of the 

body or by heterologous transplantation. However, 

these approaches rarely replace the entire function 

of the original tissue. For example, many congenital 

and acquired pediatric urologic conditions render 

the child’s bladder dysfunctional. When these 

dysfunctional bladders require reconstruction, a 

surgical procedure called bladder augmentation 

is required. This complicated surgical procedure, 

which uses tissue from the patient’s own 

gastrointestinal tract, is associated with significant 

complications, including infection, intestinal 

obstruction, mucus production, electrolyte 

abnormalities, perforation, and cancer. Other 

pediatric urologic disease states—hypospadias, 

exstrophy, and epispadias, posterior urethral 

valves, prune belly syndrome, intersex, urinary 

incontinence vesicoureteral reflux, renal failure, and 

hormone-deficient states—require replacement of 

organs or organ systems, and the need for advances 

in tissue engineering to meet this need is critical. 

Tissue regeneration may or may not require cells. If 

cells are needed, several sources might be available, 

including mature stem progenitor stem cells and 

Engineered Bladder Prior to Implantation. 

A small piece of tissue is obtained from the 

bladder in need of replacement or repair. 

The progenitor muscle and urothelial cells 

are expanded and seeded separately on 

each side of a three dimensional bladder 

shaped scaffold. The construct is placed 

in a bioreactor where the tissue is allowed 

to grow. One week later, the engineered 

bladder is ready for implantation (courtesy 

of Dr. Anthony Atala, Wake Forest 

University).
Strategic Plan for Pediatric Urology 81

other cell types occurring naturally in a person’s 

body (autologous) or derived from another source 

(heterologous). Stem cell populations associated 

with the urinary tract recently have been identified, 

although their characterization is incomplete.

Current tissue engineering techniques using cellscaffold composite grafts to induce regeneration 

have utilized cultured cells from the normal animal animal 

organs. However, future clinical application of this 

technology in patients with abnormal organs will 

involve the use of cells derived from the pathologic 

abnormal organs. For normal organ regeneration 

process to occur successfully in humans, cultured 

cells from the abnormal abnormal organs must not be organs must not be 

terminally differentiated and must possess normal 

proliferative and functional characteristics, and 

differentiate normally. Unfortunately, little 

knowledge exists as to whether cells from an 

abnormal organ retain normal growth patterns 

and functional characteristics in an in vitro culture 

environment.

Priorities for Basic Research

During the past 2 decades, it has been established 

that the bladder, urethra, penis, vagina, ureter, 

pelvic floor, and kidney have the potential to 

regenerate. From this work, it is now clear 

that interactions between the epithelium and 

mesenchyme are essential for the formation of 

normal tissues and organs. These discoveries may 

be exploited soon to generate sizable quantities 

of tissue suitable for study and transplantation, 

provided that strategies can be developed to 

isolate, expand, and differentiate native, autologous 

cells in vitro and in vivo. This will require that 

cellular signaling or growth factors that mediate 

the development of normal functional tissues be 

identified.

• Elucidate the cell signaling that occurs between 

the epithelium and smooth muscle of pediatric 

urologic organs and the role of extrinsic 

growth factors and their receptors.

• Define further the immunobiology of 

biomaterials used for tissue engineering.

• Define the effects of biomaterials on 

surrounding normal tissue.

• Determine how the mechanism of tissue 

regeneration differs from normal wound 

healing.

Priorities for Translational Research

It is a reasonable prospect that advances in cell 

biology and cell research may enable scientists 

to grow tissues and organs in the laboratory—a 

small population of cells given the appropriate 

molecular cues would proliferate and differentiate 

into functional organs. This would eliminate many 

of the current obstacles to organ replacement, such 

as donor-recipient mismatches and limited organ 

availability. 

• Develop models of long-term remodeling and 

engineered tissue survival to minimize costly 

animal trials. 

• Explore the effect of the pediatric urologic 

organ biomechanical properties on early 

regeneration.

• Develop methods to manipulate the local 

environment (through the scaffold material, 

extracellular matrix, or appropriate growth 

factors) to induce the controlled regeneration 

of tissues or organs starting from these cells.

• Define and standardize biomaterials in terms 

of such properties as elasticity, induction of 

cellular proliferations, and stability.

• Explore the use of biomaterials with bioactive 

functional groups to increase revascularization 

and other processes critical to normal 

regeneration.

• Establish biomaterial preparation and scaffold 

production and standardization laboratories.

• Develop cell production capabilities and 

cellular function tools.
82 Strategic Plan for Pediatric Urology

Infrastructural Needs

The development of tissue engineering technologies 

is currently hampered by a lack of appropriately 

trained investigators. The new technologies that 

would most likely yield the greatest impact are not 

taught well, and few training programs provide 

students with in-depth skills to perform tissue 

engineering research.

• Institute training awards that allow 

outstanding health scientists to develop 

expertise in tissue engineering and materials 

science under the guidance of outstanding 

investigators in this field.

• Establish Centers of Excellence dedicated to 

tissue engineering. 

• Establish a kidney, bladder, urethral, and pelvic 

floor primary and stem cell bank that would 

include a depository and central distribution 

center for sharing cells, reagents, and model 

systems.

• Establish a patient registry to assist in 

obtaining needed samples from a large 

population.

Public interest and educational efforts

As the sciences of tissue engineering continue to be 

developed, scientists should not overlook particular 

experimental therapies that could raise ethical 

concerns among some members of the public. 

Forums that discuss the ethical, legal, and social 

issues in biomedical research should guide policy 

decisions in these areas. These forums include the 

NIH Office of Biotechnology Activities, the NIH 

Office of Human Research Protections, and the 

President’s National Bioethics Advisory Committee

Ongoing communication among scientists, 

physicians, educators, ethicists, theologians, elected 

officials and the public is essential to guide the 

future of this research, and to ensure that America 

continues to invest judiciously and responsibly in 

biomedical research.

28. Clinical Trials and Epidemiology

Pediatric urologic practice should be guided by 

the kinds of objective criteria that can be only 

obtained through sound clinical trials and valid 

and comprehensive epidemiological studies. 

Top priorities are:

• Establishment of standard definitions of 

pediatric urologic conditions for use in 

clinical practice and research 

• Development of a set of standardized 

objective and patient-centered outcomes 

for use in clinical research of various 

pediatric urologic conditions

• Organization of clinical research networks 

to undertake randomized clinical trials

• Creation of pediatric urology disease 

registries for use in clinical research and 

improvement of quality of care

Summary 

Pediatric urology is a focused subspecialty 

of general urology that deals with relatively 

uncommon congenital disorders. Consequently, 

clinical research is hampered by difficulty in 

assembling adequate samples from which to draw 

meaningful conclusions. The research enterprise also 

is hindered by a lack of a standard nomenclature 

and validated outcomes for various conditions, and 

the absence of a centralized support structure and 

inadequate funding.

Current Needs in Clinical Research in 

Pediatric Urology

Standard definitions 

There are no established standard classification 

systems or nomenclature for many pediatric urologic 

conditions (e.g., hydronephrosis, hypospadias). This 

is a significant hindrance to clinical research, as 

existing studies often focus on disparate populations 
Strategic Plan for Pediatric Urology 83

conditions, and there are significant differences in 

the information technology platforms of existing 

databases that prevent data sharing. Shared 

databases with common data elements should be 

developed, with the software for these databases 

available to all investigators. Software should be 

constructed in such a manner that participating 

centers have the option of uploading data (stripped 

of personally identifying information) to the World 

Wide Web for analysis in the aggregate. As new 

data platforms are developed, they should be vetted 

by NIDDK staff, representatives of the various 

professional societies, and patient advocacy groups 

to ensure both the clinical utility and research 

applicability of the software. If feasible, a standing 

board should be created to facilitate this process.

Clinical Research Networks

There are no established clinical research networks 

in pediatric urology and few adequately sized 

randomized clinical trials have been completed. 

Collaborative networks will be needed for the 

conduct of large, randomized clinical trials. These 

networks should include a mix of academic and 

community medical centers, and they should utilize 

an interdisciplinary approach.

Disease registries

Patient registries, essentially databases containing 

information about clinical characteristics 

(e.g., gender, classification of condition, description 

of treatment), treatment interventions, and 

outcomes of a patient population with a particular 

condition, are vital tools in clinical research. 

Particularly useful in conditions that are relatively 

rare, registries can merge a geographically diverse 

patient population and thereby aid the development 

of randomized clinical trials and observational 

studies. There are few adequate disease registries 

available to address scientific questions in pediatric 

urology. Those that do exist tend to be from single 

institutions and are either not generalizable or of 

inadequate size. We propose the funding of patient 

registries in pediatric urology that share the following 

of affected children with the same condition, 

limiting the generalizability and validity of the 

results. A series of NIH-sponsored multidisciplinary 

workshops should be convened with the explicit goal 

of developing these definitions and classification 

systems. Each workshop would address a specific 

pediatric urologic condition. Patient advocacy 

groups and professional societies would be included 

in the planning process and the workshop itself.

Training in clinical research methodologies

There are few investigators in pediatric urology 

formally trained in clinical research methodologies 

such as clinical trial design, epidemiology, or 

health services research. Targeted NIH funding 

for new clinical researchers in pediatric urology is 

recommended. Included in this initiative should be 

health care professionals from other disciplines—

behavioral specialists, social scientists, and 

others—to promote an interdisciplinary model of 

care for patients with urological conditions and an 

associated research agenda. Workshops on topics 

ranging from study design to grant writing should 

be held to encourage the development of advanced 

research skills and promote new collaborations 

among investigators.

A central coordinating center

Pediatric urology clinical researchers do not have 

adequate support services to generate pilot data 

with which to support initial grant applications. We 

suggest the establishment of a central clinical research 

and epidemiology coordinating center with expertise 

in biostatistics and study design to support novel 

studies in the field. This shared resource would 

then be available to support new investigators 

and assist in generating pilot data for future grant 

applications.

Widely accessible, standardized databases to 

support clinical research

Currently, there is no agreement on the required 

data elements for databases of pediatric urologic 
84 Strategic Plan for Pediatric Urology

features: (1) standardized collection of patient 

demographic information (including socioeconomic 

status, race/ethnicity and other sociodemographic 

factors); (2) standardized nomenclature of disease 

and descriptions of treatments, procedures, and 

outcomes; (3) inclusion of health-related quality of 

life (HRQOL) measures; (4) methods to ensure the 

generalizability of the collected data; and 

(5) collection of serum and tissue for deposit into 

existing NIDDK repositories. 

Standardized objective and patient-centered 

outcomes 

There is great debate regarding which objective 

endpoints should be used to define a successful 

outcome after treatment for many conditions in 

pediatric urology and, at the same time, there are 

few patient-centered tools for assessing outcomes 

in these diseases. We suggest that standardized 

objective outcomes (short- and long-term) must be 

developed for use in clinical research in pediatric 

urology. Included in these should be functional 

status and patient-reported symptom severity 

and HRQOL. The opinions of patient advocacy 

groups should be solicited in the development 

of these measures. Disease-specific HRQOL 

instruments should capture the distinct perspectives 

of the patient, his/her parents, and the health 

care provider. New instruments should provide a 

unique and much-needed perspective on patients’ 

physical and psychosocial outcomes that are less 

focused on “pathology” (e.g., clinical depression) 

and more focused on adjustment to daily living. 

Finally, these instruments should be culturally 

sensitive and should be validated in Spanish and 

well as English, in an effort to capture the unique 

impact of pediatric urologic disease in minority and 

underserved populations.

Inclusion of minority and underserved 

populations 

Many clinical studies do not enroll adequate 

numbers of minority or underserved subjects, 

limiting the generalizability of the results. Recent 

evidence suggests that careful preparation and 

planning of clinical studies can significantly 

increase minority and underserved subject 

recruitment and retention. Two models have 

been developed to guide the investigator: the 

Interactional Model for Recruiting Ethnically 

Diverse Research Participants and the Recruitment 

Triangle. These models essentially tailor the study 

personnel and recruitment strategies to the target 

populations, identifying key barriers to recruitment 

of minority and underserved individuals, and 

developing successful strategies based on incentives, 

outreach to parents and health care providers, 

improved communication, and other elements. 

They should be used in pediatric urology clinical 

research.

Identification of risk factors 

Few genetic, environmental, and behavioral 

risk factors for the development of pediatric 

urologic conditions have been identified. 

Standard epidemiologic research methodologies, 

such as case-control and observational cohort 

designs, should be employed to identify genetic, 

environmental, and behavioral risk factors for 

pediatric urologic disease. Birth certificate 

registries, like the one in the State of Washington, 

should be utilized to help identify cohorts as well 

as in utero exposures that put children at risk for 

development of pediatric urologic disease.

Top Priorties

• Establish standard definitions of pediatric 

urologic conditions for use in clinical practice 

and research. 

• Develop a set of standardized objective 

and patient-centered outcomes for use in 

clinical research of various pediatric urologic 

conditions.

• Establish clinical research networks to 

undertake randomized clinical trials.

• Create pediatric urology disease registries for 
Strategic Plan for Pediatric Urology 85

use in clinical research and improvement of 

quality of care.

Additional Priorities

• Foster the development of clinical research 

within pediatric urology by establishing a 

central clinical research and epidemiology 

coordinating center to support novel studies in 

the field.

• Increase the number of pediatric urology 

investigators formally trained in clinical 

research methodologies.

• Develop bioinformatic software for use in 

pediatric urology and make it available in 

the public domain for use by all interested 

investigators.

• Encourage the enrollment of minority and 

underserved populations into pediatric 

urologic studies.

• Identify risk factors for the development of 

and/or severity of pediatric urologic diseases.

29. Th erapies and Diagnostics

Research that seeks to rigorously assess the 

usefulness of new technologies in pediatric 

urology, with the ultimate emphasis on child 

health outcomes, as well as cost-eff ectiveness, 

is strongly encouraged. Collaboration between 

industry and academia is essential for the 

development of new diagnostic and therapeutic 

technologies; professional societies can play 

a vital role in developing evidence-based 

guidelines for their use, and modern methods 

of communication by the National Institutes of 

Health and other organizations can ensure that 

the public and health care professionals have 

the information they need to guide them.

Summary 

Many new technologies (e.g., endoscopic correction 

of vesicoureteral reflux) come into common 

clinical practice before a complete evaluation of 

their societal value or cost-effectiveness has been 

documented. In some instances, the efficacy of 

these new technologies can be questioned based 

on the inadequacy of the original clinical study 

design. However, once these technologies become 

commonplace and widely used, it is difficult to 

re-evaluate their role and change clinical practice 

patterns. This mandates that a more careful 

assessment of new technologies be performed prior to 

widespread implementation.

Assessment, Validation, and Diffusion of New 

Technologies

The critical assessment of a new pediatric urologic 

technology should be based on a well-validated 

conceptual framework. Thornbury and Fryback’s 

“hierarchy of levels of efficacy” guides the logical 

evaluation of a new technology from the laboratory 

to clinical practice. Specifically, the framework 

directs the performance of studies in a defined 

order, and provides data on the technical feasibility 

(level 1), diagnostic accuracy (level 2), impact on 

diagnosis (level 3), changes in clinical management 

(level 4), improvement in child health outcomes 

(level 5), and societal value/cost-effectiveness (level 

6). Special emphasis, especially in those diseases 

having long-term ramifications, should be placed on 

the last two levels, which are generally neglected in 

childhood diseases. Without long-term assessment 

with perpetual databases and ongoing statistical 

efficacy and cost analysis, the cost-benefit analysis 

that should be the basis of health care policy cannot 

be performed.

Workshops and forums to discuss ethical, legal, and 

social issues related to the new technology, and best 

practice adoption through evidence-based guideline 

formation by professional organizations, also are 

needed. Modern information and communication 

technologies are effective tools to help in the 
86 Strategic Plan for Pediatric Urology

collection, processing, and targeted distribution 

of information from which clinicians, researchers, 

administrators, policymakers in health, and the 

public can benefit.

Corporations have the financial resources and the 

incentives to develop new technologies; academic 

medical centers provide the medical expertise and 

the infrastructure to evaluate and implement these 

new technologies. In spite of the mutual need, 

complex legal and financial issues have sometimes 

stymied corporate collaboration with academic 

research. This is particularly true in pediatrics, 

where pharmaceuticals and medical devices are not 

often developed or tested and where there are few 

incentives to include children when evaluating new 

technologies.

Priorities

• Support research proposals that incorporate 

rigorous technology assessment with emphasis 

on health outcomes and cost-effectiveness.

• Encourage development and testing of new 

technologies in children. 

• Establish grants targeted at collaborative 

research in pediatric urology between industry 

and academic medical centers.

• Disseminate evidence-based information to the 

lay public and health care professionals.

• Partner with professional organizations to 

develop evidence-based guidelines.

• Encourage forums to examine ethical, legal, 

social issues related to new technology in children.


Strategic Plan for Pediatric Urology 89

V. Training And Manpower

30. M.D. Training

A variety of institutional pressures make life 

exceedingly diffi cult for pediatric urologists 

contemplating a research career. We 

recommend new training mechanisms that 

would allow those with a strong commitment 

to immerse themselves in research under the 

mentorship of scientifi c leaders in the fi eld.

Summary 

A Scarcity of Research Opportunities

During the last decade, funds for supporting 

urology training have progressively dwindled—

while reimbursements to hospitals have been greatly 

decreased and managed care has reduced clinical 

revenues to academic departments, departmental 

administrative costs to support residency and 

fellowship training programs have greatly increased. 

Historically, many urology training programs 

offered 1 year of basic research training during 

residency training. This often was funded by 

the hospital or, in rare cases, endowments within 

urology departments. However, during the last 

decade, the overwhelming majority of urology 

training programs have been transformed from 

6- to 5-year training programs in which the 

maximum amount of time that can be allocated to 

basic research is only 6 months. As a result, many 

program directors, considering a 6-month exposure 

to the laboratory too short, even as it limits needed 

clinical experience, have decided to abandon a 

research experience altogether. While most would 

agree that a research experience is important for 

trainees, it might not represent the optimal resource 

allocation in the present environment, where the 

overwhelming majority of urology trainees seek 

private practice opportunities and may not be 

motivated to take full advantage of the research 

experience. 

Medical School Research Training

Since the overwhelming majority of individuals 

who ultimately pursue academic careers are from 

the minority who complete subspecialty training, 

the focus of a program to foster research should 

be on this group, beginning at the medical school 

level. Pediatric urologists at academic institutions 

need to actively seek out students interested in a 

summer research experience or an additional year 

in a pediatric urology laboratory that would provide 

a sound foundation and exposure to their field. 

Funds that would facilitate this research training 

would be well justified, as a superb mentoring 

experience with scientific leaders in pediatric 

urology will attract individuals with a true interest 

in basic research to enter the field. It is envisaged 

that these individuals then will seek urology 

programs with a research year, further enhancing 

their interest in basic science. 

Fellowship Training

At present, the entire burden for supporting 

fellowship trainees falls on the department ellowship trainees falls on the department 

or fellowship program. While the return on 

investment in clinical training is readily apparent, 

there are no revenues derived from a research 

experience to defray costs. Further complicating 

matters is the fact that, with their pressing clinical 

responsibilities, pediatric urology fellows are 

at a decided disadvantage in competing for the 

funds to support a research program. Although a 

small subset of urology fellows does successfully 

compete for AFUD scholarships, the number of 
90 Strategic Plan for Pediatric Urology

these awards is inadequate1. Currently, the NIH 

does fund pediatric urology fellows with 2- or 3-

year training grants, but only a limited number of 

pediatric urology programs currently have these. 

(The new NIH guidelines that reduce to 50 percent 

the required time commitment for the K08 and R21 

grants will be very helpful.)

Incentives

During the past decade, manpower in pediatric 

urology has changed in response to the everchanging health care environment. There has been 

an increase in pediatric urologic positions, but at 

the same time, a decrease in some years in those 

seeking pediatric urology fellowships. The decline 

is related in part to the emergence of new lucrative 

subspecialties attracting the best and the brightest 

trainees. We suggest that program directors 

or affiliate hospitals might consider financial 

incentives for individuals entering pediatric urology, 

especially since, in the academic setting, these 

individuals often serve the underprivileged and the 

poorly insured, while at the same time trying to 

build clinical practices and establish themselves as 

basic science investigators. 

Recommendations

• Pediatric urologists at academic institutions 

should focus on attracting medical students 

interested in a summer research experience 

or an additional year in a pediatric urology 

laboratory committed to providing a sound 

foundation in research, while exposing 

students to the field. Allocated funds for these 

medical students could be provided.

• One- or 2-year research funding should be 

widely offered for pediatric urology fellowship 

training programs. This should be a mentored 

experience with the goal of providing a strong 

foundation in the scientific method and 

exposure to competitive, high-level research. 

• The timetable for grant applications should 

be synchronized with the match for pediatric 

urology fellowships.

• To ensure a pool of high-quality individuals 

to meet the needs of pediatric urology, new 

strategies are needed to attract individuals 

in medical school as residents to pediatric 

urology. 

1

 One of the reasons fellows do not apply for the AFUD 

scholarship is that the notification of some of the matching 

fellowship training program is after deadline for submission of 

an AFUD grant—the timetable for grant applications needs to 

be adjusted to meet the match for pediatric urology fellowships.
Strategic Plan for Pediatric Urology 91

31. Ph.D. Training

Th e participation of Ph.D. investigators in 

research with direct applications to pediatric 

urology is inadequate. We discuss some 

cultural barriers to this participation and 

advocate training programs to support graduate 

students studying research problems centered 

on urologic disease with urologists participating 

as advisors. Postdoctoral programs in urology 

research also are recommended. 

Summary 

The Ph.D. degrees relevant to biomedical research 

usually are obtained after the successful completion 

of an undergraduate science major, followed by 

course work and extensive independent research in 

a specialized area as a graduate student. Following 

the defense of a thesis before a panel of senior 

faculty, graduates typically go on to postdoctoral 

positions of varied intellectual independence prior 

to obtaining positions as scientists in academia or 

industry. Postdoctoral training is a critical element 

of the Ph.D. career path. The most promising Ph.D. 

graduates typically seek out postgraduate training 

in leading laboratories, ones that routinely publish 

papers in high-impact journals such as Cell, Nature, 

and Science. With their technical knowledge, 

and scientific training, Ph.D.s are an essential 

component of any biomedical research program 

that aspires to national competitiveness and 

research productivity. Without their participation 

at the postdoctoral, staff scientist, and faculty levels, 

it is unlikely that most urologists would be able 

to assemble research teams of sufficient quality to 

conduct research at the highest level. Partly because 

of the emergence of industry as an attractive career 

option for young Ph.D.s, the percentage of Ph.D.s 

with faculty career potential willing to commit to a 

career path in academics may be declining. 

Opportunities and Obstacles in 

Pediatric Urology

Although historically underfunded, pediatric 

urology presents some very favorable opportunities 

to those in research: urological diseases are rich 

with unexplored territory and clinical urology 

programs at major teaching centers reside within 

a “scientist-rich” environment; programs in large 

cities are generally located near some of the finest 

laboratories in the world. Furthermore, NIH 

is actively seeking meritorious applications in 

areas in urology where it has recognized specific 

needs. This might offer major advantages to those 

contemplating urology research compared to 

those in fields such as cardiovascular research and 

neuroscience, where competition for grants can be 

fierce and award decisions arbitrary.

Training and Recruitment

Unfortunately, for cultural reasons, urology is at 

present poorly positioned to compete for the best 

scientists. Senior academic leaders in urology 

frequently have little understanding of the modern 

research process or the unique aspects of the Ph.D. 

career path in comparison to that of the academic 

surgeon. In marked contrast to the situation in 

medicine, the field does not reward urologists 

who concentrate on research. Research-focused 

urologists frequently are criticized by their peers for 

not generating “their share” of clinical dollars. The 

field does not host a single basic science journal of 

sufficient impact factor to attract quality, cuttingedge research papers. For these reasons, Ph.D. 

scientists who encounter an academic urologist 

with whom they might consider collaborating on 

scientific grounds, might be put off or otherwise 

conclude that such a collaboration would not be a 

productive or enlightening endeavor. 

Most Ph.D. training programs do not produce 

scientists who are prepared for research in urology. 

Their expertise generally is highly focused to 

certain model systems and methods of analysis. 

Their ability or tendency to read outside of their 
92 Strategic Plan for Pediatric Urology

own discipline may also be limited. Most are not 

familiar with problems inherent to clinical research.

Infrastructural Recommendations

To retain excellent scientists in urology at o retain excellent scientists in urology at all levels, 

urology research needs to be structured along 

the lines of mature research programs in areas 

with historically strong research (e.g., neurology, 

endocrinology, and pathology). Although the 

questions addressed in a urology department’s 

research labs should be restricted to those with 

some relevance to important questions in the field, 

this should be approached with a broad-minded 

view of what is in fact topical. The “culture” of the 

research lab in urology needs to be one of openness, 

fun, egalitarianism, and a willingness to try out 

new ideas. The laboratory should not be organized 

according to a hierarchical or dogmatic structure; 

this has no resemblance to the environment 

in which most Ph.D.s were trained. It is in an 

atmosphere where new approaches and research 

questions are encouraged, and ideas flow freely 

that conceptual breakthroughs are likely to occur. 

Familiarity and intimacy with one or more research 

areas, combined with appropriate mentoring and 

attention to career path from superiors, will foster 

professional commitment and will grow the field.

• Active participation of urologists in Ph.D. 

training programs, either as collaborators 

on projects or as “clinical-partner” mentors, 

would increase the familiarity of young 

scientists with urological problems and make 

them aware of potential research opportunities 

in urology. 

• We propose training programs for graduate 

students studying basic research problems 

centered on urologic disease. Urologists could 

participate in these programs and could help in 

the recruitment of students.

• NIH should sponsor training programs for 

M.D.s to do urology-focused research before 

or during their urology residency (preferably

for 2-year duration).

• Urologists and urology researchers should 

be poised to attract Ph.D.s fresh out of their 

graduate training into their research programs. 

• Postdoctoral programs in urology research 

are needed. These might entail a mechanism 

to recruit graduate students prior to their 

completion of their Ph.D. 

32. Collaborative Programs

We underscore the importance of collaboration 

between basic scientists and clinicians in 

pediatric urology research. If the number of 

collaborative projects is to grow, novel funding 

mechanisms may be needed to address the 

unique demands of the clinician scientist 

struggling to fulfi ll dual roles as well as those 

of the basic scientist as she or he attempts to 

maintain funding within, or in collaboration 

with, a clinical department. 

Summary 

The nature of modern productive research is such 

that there is little role for the individual scientist. 

While this may be unfortunate, it is obvious that 

real progress in understanding diseases relevant 

to pediatric urology, and in developing novel 

diagnostic and therapeutic methods, will come from 

the concerted application of conceptual frameworks 

and methodologies from molecular biology, 

genetics, and cellular physiology, coupled with 

clinical insight. Collaboration by those with diverse 

expertise is essential; each team member brings 

a unique and critically important perspective, 

and intellectual insights beyond the initial grasp 

of any one individual may be attained. The role 

of the clinician in this collaboration is becoming 

increasingly strained: as basic science advances, 

it requires specialized knowledge and training, 

making it more difficult for clinicians to participate, 
Strategic Plan for Pediatric Urology 93

even as their participation becomes essential as 

translational possibilities emerge.

Support of Collaborative Research 

Involving the Clinician and Basic 

Scientist

Training

A basic exposure to research experience and 

methods should remain an essential part of 

urological training, and this can be extended 

into the fellowship years of pediatric urology. 

Conversely, exposure of basic researchers to 

those who have clinical training and interests is 

also vital. Research support from NIH should 

therefore encourage and foster the development 

of collaborative efforts in pediatric urology related 

research through support of both Ph.D. as well as 

M.D. training tracks, with situationally appropriate 

mechanisms. The duration and constraints of the 

support should recognize the different needs, time 

demands, and roles of members of the team.

Establishing and maintaining laboratories

In relatively young fields of research such as 

pediatric urology, there is a strong need to support 

the initiation of viable research programs at more 

institutions than currently include them in their 

portfolios. The development of new laboratories 

should be in the context of a collaborative effort, 

perhaps as off-shoots of established laboratories. 

NIH-sponsored initiatives that support the early 

work of a young clinician scientist or basic scientist 

in pediatric urology departments with mentorship 

from an established investigator might foster these 

new programs. Novel mechanisms of funding 

that encourage developing collaborative projects 

between basic scientists and clinician scientists 

would serve to assist in such new programs, as well 

as fostering the maintenance of such laboratories. 

An ongoing challenge to pediatric urological 

research has been how to perpetuate productive 

research efforts as both clinician scientists and 

basic scientists strive to ensure grant funding in an 

environment of shrinking clinical support. NIH 

should consider as a priority the need to develop 

funding mechanisms that recognize the unique 

demands of the clinician scientist as she or he 

struggles to fulfill dual roles as well as those of the 

basic scientist as she or he attempts to maintain 

funding within, or in collaboration with, a clinical 

department. Funding mechanisms that permit 

less commitment of research time to participate 

in collaborative research should be considered. 

Mechanisms that permit research training of 

physicians also are advised. Recognition of the 

value of basic scientists in translational fields is 

equally important.

Priorities

The development of collaborative efforts in 

pediatric urology-related research should be 

fostered through support of Ph.D. and M.D. 

training tracks with situationally appropriate 

mechanisms.

• Novel mechanisms of funding that encourage 

collaborative projects between basic scientists 

should be considered: the clinicianscientist should be supported in such ways 

as to facilitate protecting time from clinical 

demands without placing unrealistic financial 

demands on the clinician or the clinical 

department.

• The basic scientist collaborating in pediatric 

urology research should have funding to 

support development of his or her laboratory, 

particularly through graduate and postdoctoral 

students, collaboration with other basic 

scientists, and involvement with the basic 

science community.
Department of Health and Human Services

National Institutes of Health

National Institute of Diabetes & Digestive & Kidney Diseases

NIH Publication No. 06-5879

February 2006