A Strategic Plan for Research

A REPORT OF THE BLADDER RESEARCH PROGRESS REVIEW GROUP

National Institute of Diabetes & Digestive & Kidney Diseases

National Institutes of Health

August 2002

OVERCOMING BLADDER DISEASE
A Strategic Plan for Research

A REPORT OF THE BLADDER RESEARCH PROGRESS REVIEW GROUP

National Institute of Diabetes & Digestive & Kidney Diseases

National Institutes of Health

August 2002

OVERCOMING BLADDER DISEASE
1 Letter from the Chair

2 Executive Committee

3 Acknowledgements

5 Executive Summary

Section A: Basic Science of the Lower Urinary Tract

19 Introduction

21 Chapter 1 Urothelium (Epithelium)

28 Patient Profile Urothelial Cancer 

(Bladder Cancer)

31 Chapter 2 Connective Tissue

41 Chapter 3 Muscle

47 Chapter 4 Nerves and Blood Vessels 

58 Patient Profile Neurogenic Bladder

Section B: Common Clinical Conditions

61 Introduction

63 Chapter 5 Problems of the Developing

Genitourinary Tract in Children

80 Patient Profile Cloacal and Bladder Exstrophy

82 Patient Profile Vesicoureteral Reflux

85 Chapter 6 Urologic Disease in

Maturation and Aging

91 Patient Profile Post-Prostatectomy

Incontinence

93 Chapter 7 Bladder Outlet Obstruction

100 Patient Profile Posterior Urethral Valves,

Obstructive Uropathy

103 Chapter 8 Interstitial Cystitis

114 Patient Profile Interstitial Cystitis

117 Chapter 9 Urinary Tract Infections

133 Chapter 10 Urologic Problems in 

Diabetes Mellitus

144 Patient Profile Diabetic Bladder

147 Chapter 11 Urinary Incontinence

158 Patient Profile Pelvic Floor Trauma,

Incontinence

161 Chapter 12 Urothelial Cancer 

(Bladder Cancer)

174 Patient Profile Bladder Cancer

Section C: Methodologies & Technologies for Future Research

177 Introduction

179 Chapter 13 Clinical Trials

183 Chapter 14 Epidemiology

187 Chapter 15 Emerging Technologies 

and Pharmacology

199 Letter Benjamin Franklin to 

His Brother

Appendices

201 Appendix 1 Executive Committee

203 Appendix 2 Work and Focus Groups

207 Appendix 3 Participants

213 Index

TABLE OF CONTENTS
I am pleased to present Overcoming Bladder Disease: 

A Strategic Plan for Bladder Research, developed by the

Bladder Research Progress Review Group (BRPRG), to

the Advisory Committee of the Director of the National

Institute of Diabetes and Digestive and Kidney Diseases

(NIDDK). The BRPRG’s assessment of the Institute’s

progress in bladder research and strategic plan for future

research was undertaken at the request of Dr. Allen

Spiegel, director of the NIDDK. This strategic plan 

recommends future research directions and priorities

and the means of implementing recommendations.

The BRPRG was an independent group of scientists 

and medical professionals who are prominent in 

clinical and basic research and professional and lay

patient organizations related to the bladder. These 

colleagues represent the wide expertise required to

assess the state of bladder research in the United States

and to recommend research actions that could reduce

morbidity and mortality of bladder diseases previously

neglected. Such research has the potential for improving

the quality of life of Americans with problems of the

developing and aging urinary tract and with conditions

such as urinary obstruction, interstitial cystitis, urinary

tract infection, complications of diabetes, urinary 

incontinence, and cancer. 

The BRPRG was composed of an Executive Committee

and 14 subcommittees. In developing this plan, the

Executive Committee had many discussions and held

plenary meetings throughout 2001 with the objective 

of developing a strategic national plan for bladder

research. The BRPRG analyzed and assessed ongoing 

scientific investigation relevant to the lower urinary

tract, defined unmet needs in bladder research, and

developed goals and recommendations for future

research and its implementation. 

This was a difficult task, and the hard work of the 

BRPRG is evident in this report. The report emphasizes

the current deficiencies in research efforts related to

bladder and the intense need for improvement in the

resources designated for bladder research. Advances in

biomedical science and technology have opened the door

for rapid and significant advances in bladder research

that will improve the diagnosis, management, and 

prevention of bladder problems for many Americans. 

My colleagues and I thank the Institute and its leadership for their recognition of the need for assessing 

bladder research. We anticipate following the progress 

of the recommendations made in this report, and we 

will be pleased to discuss our findings with the leadership of the National Institute of Diabetes and Digestive

and Kidney Diseases.

Respectfully submitted,

Linda M. Dairiki Shortliffe, M.D.

Chair, Bladder Research 

Progress Review Group

Letter from the Chair
2 OVERCOMING BLADDER DISEASE

William de Groat. Ph.D.

John O. DeLancey, M.D.

Monica Liebert, Ph.D.

John D. McConnell, M.D.

Vicki Ratner, M.D.

Anthony J. Schaeffer, M.D.

William D. Steers, M.D.

Dana Weaver-Osterholtz, M.D.

We, the undersigned members of the Bladder Research Progress Review Group 

Executive Committee, concur with this report:

Executive Committee
A Strategic Plan for Research 3

Josephine P. Briggs, M.D., Director, Division of Kidney, Urologic, and 

Hematologic Diseases (DKUH), National Institute of Diabetes and Digestive 

and Kidney Diseases (NIDDK), was the Executive Director of the BRPRG. 

Her expertise, advice, and support contributed tremendously to the 

development of the Strategic Research Plan. 

The BRPRG thanks numerous National Institutes of Health representatives who helped provide technical information and organizational 

support. In particular, Leroy M. Nyberg, Ph.D., M.D., Director, 

Urology Program, NIDDK, and Monica Liebert, Ph.D., formerly, 

Associate Director, Urology Research, NIDDK, and currently, Director 

of Research, American Urological Association.

We thank Mary Harris, writer and editor, Office of Communications, 

NIDDK, for her outstanding organizing efforts and Carolyn Benson,

writer and editor, DKUH, for her outstanding scientific writing and 

editing for this report.

The BRPRG also thanks the American Urogynecologic Society, 

American Urological Association, National Bladder Foundation,

and the National Institute on Aging for co-sponsoring with the 

NIH the meeting at Xerox Park University.

ACKNOWLEDGEMENTS
EXECUTIVE SUMMARY AND RECOMMENDATIONS

Introduction

Diseases and conditions affecting the bladder and 

associated structures of the lower urinary tract are a

leading cause of urinary incontinence, pelvic pain, and

kidney failure, and they often contribute to poor quality

of life. It has been estimated that 35 million Americans

suffer from bladder disease and most have chronic conditions. Bladder problems have been reported to cost

Americans more than $16 billion per year in healthrelated expenses, and this estimate does not take 

into account the associated physical and emotional 

disabilities that are considered “unmentionable” 

by many men, women, and children.

Benjamin Franklin documented the poor quality 

of life for people with bladder problems in 1752. 

He invented the first flexible urethral catheter, made 

of silver and covered with gut, to help his brother 

empty his bladder. Franklin’s brother suffered from

bladder outlet obstruction caused by bladder stones.

Years later, Franklin, who suffered from the same 

problem, was forced to catheterize himself intermittently with his own invention.1 (See page 199) Although

technology now provides better instrumentation, 

medical science has not solved many cases of urinary

retention—or other problems related to the bladder—

and intermittent catheterization much as Franklin

described is still used. 

Bladder diseases and problems affect people of all ages,

races, and ethnic groups. Even with access to the best

medical care, many people still suffer bladder pain, 

urinary incontinence, and loss of bladder function that

may damage the kidneys. Strides have been taken to

improve diagnosis, management, and treatment of 

bladder diseases, but many primary questions about

bladder formation, function, and disease remain.

Moreover, although vital organs such as the heart, 

lungs, liver, kidneys, and pancreas have been successfully transplanted, medical science has been unable 

to transplant or totally replace the bladder.

The Bladder Research Progress Review Group (BRPRG)

was formed by the National Institute of Diabetes and

Digestive and Kidney Disease (NIDDK) of the National

Institutes of Health (NIH) to examine the state of 

bladder research in the United States and to develop 

a plan for future research in this area. The members of

the BRPRG are a multidisciplinary group of recognized

experts in bladder research. Their task was a complex

one because many diseases and conditions of the urinary

tract such as incontinence, obstruction, interstitial 

cystitis, and spina bifida affect the bladder’s structure

and function. For instance, some conditions such as

bladder exstrophy are primary and become lifelong

health concerns. Other conditions such as bladder 

dysfunction resulting from diabetes, aging, or spinal

cord injury are secondary and create acute and chronic

medical problems. Still other conditions that primarily

affect the nervous system or vascular systems, for 

example multiple sclerosis and Parkinson’s disease, 

also affect the bladder. Bladder diseases such as bladder

cancer or urinary tract infections affect specific tissues

such as bladder epithelium; thus, research on these 

tissues will contribute directly to overall progress in 

cancer and infectious diseases research and not to

research on bladder alone.

From early 2000 to July 2001, members of the BRPRG

had discussions and intensive meetings to examine 

all areas of bladder-related problems categorized by 

diseases and by organ or tissue in an attempt to develop 

a strategic bladder research plan. This plan is provided

in this document. 

Overwhelmingly, the BRPRG has concluded that bladder

research in the United States is inadequate, fraught with

a number of impediments, and lags behind research 

in other areas that affect the health of Americans to a

similar degree. The extent of health problems associated

with the bladder emphasizes the urgent need to expand

rapidly bladder health-related research not only to 

diagnose, manage, and treat bladder diseases, but also 

1 Kimbrough, HM. Benjamin Franklin (1706-1790). Investig Urology, 1975;12(6):509-10. A Strategic Plan for Research 5
to discover the risk and preventive factors that will 

ultimately improve overall health. Recent discoveries

and technological advances in biomedical science 

have provided a unique opportunity to make rapid 

and important advances in bladder research that might

improve diagnosis, management, and prevention of

bladder problems.

This report outlines future critical research on the 

basic science of the lower urinary tract and clinical 

studies of bladder diseases and conditions. It also 

makes specific recommendations for focused inclusion

of biotechnologies that offer opportunities for bladder

research. In addition, the report describes the kinds 

of programs that will provide a pipeline of new

researchers through training, new collaborations, 

and infrastructure to support this work. The potential

consequences of rapid progress in bladder research

could save many children, women, and men from 

the physical and emotional consequences of bladder 

diseases and conditions. 

The U.S. Investment in Bladder Health 

and Research

The U.S. Government, through the National Institutes 

of Health (NIH) will spend an estimated $67.8 million 

on bladder research in fiscal year 2002. This modest

investment pales in comparison with the health and

societal costs of bladder-associated problems to the 

U.S. economy. People with congenital and acquired

bladder and urethral disease frequently have chronic

problems that require long-term health care and that

could lead to disease in other systems.

To allow bladder research to “catch up” with other

research areas that have made dramatic advances over

the past 20 years, a disproportionate investment must 

be made toward bladder research programs, training,

and infrastructure.

Strategic Research Priorities

The bladder is a unique organ. The transitional 

epithelium that lines its inner surface and other parts 

of the lower urinary tract occurs nowhere else in the

body. Although similar to other types of epithelial tissue,

transitional epithelium has unique properties. 

The bladder also has the unusual capability of allowing

willful storage and emptying—a function that is quite 

different from other hollow organs such as the heart 

or stomach, neither of which is subject to this kind of

voluntary control. As such, the bladder has unusual 

basic functions and properties that still need to be

6 OVERCOMING BLADDER DISEASE

NATIONAL INSTITUTES OF HEALTH URINARY BLADDER RESEARCH

(Dollars in Thousands)

Participating Institutes and Centers FY 2002 Estimate

National Cancer Institute (NCI) $31,300

National Heart, Lung, and Blood Institute (NHLBI) 195

National Institute of Diabetes and 14,300

Digestive and Kidney Diseases (NIDDK) 

National Institute of Neurological Disorders 

and Stroke (NINDS) 1,107

National Institute of Allergy and 

Infectious Diseases (NIAID) 4,737

National Institute of Child Health and 

Human Development (NICHD) 6,200

National Institute of Biomedical Imaging 

and Bioengineering (NIBIB) 1,235

National Institute of Environmental 

Health Sciences (NIEHS) 505

National Institute on Aging (NIA) 3,000

National Institute on Deafness and 

Other Communication Disorders (NIDCD) 60

National Center for Complementary and 

Alternative Medicine (NCCAM) 780

National Institute on Alcohol Abuse 

and Alcoholism (NIAAA) 2,371

National Center for Research Resources (NCRR) 1,194

National Institute of Nursing Research (NINR) 807

TOTAL (NIH) 67,791
A Strategic Plan for Research 7

explored to allow better understanding of the mechanisms involved. The bladder, furthermore, offers a

unique research environment; agents may be delivered

into this hollow organ for measurement, absorption,

adhesion, and potentially treatment.

The BRPRG has outlined the following specific areas 

in which strategic bladder research will make important

contributions to basic scientific knowledge and to

improved management and potential prevention of 

bladder diseases and conditions:

• New technology-driven basic and clinical research

• Focused research for basic systems and disease

• Epidemiology, outcomes evaluations, prevention, 

and bioethics

• Research infrastructure

Tremendous opportunity exists for rapid advances in

bladder research if scientists explore and exploit new

methodologies and technologies already used successfully in other areas. These tools, applied to basic

research on the bladder, will allow new discoveries 

of the function of this unique organ and its tissues 

and will advance our understanding of bladder disease.

Because these methodologies and technologies crosscut

many areas of research, the BRPRG recommends that

they be emphasized in strategies that foster bladder

research development. Furthermore, the BRPRG 

recommends that future bladder research be based 

upon a stable and ongoing mechanism for recruiting,

training, and retaining future investigators in this area. 

New Technology-Driven Basic and Clinical Research

Clinical and basic bladder research could benefit 

from the rapidly emerging biotechnology discoveries in

genomics, proteomics, and molecular and microarray

technology. Rapidly developing pharmacologic discovery

and computer technology open the door for clinical 

trials and database achievements that were not 

previously possible.

Focused Research for Basic Systems and Disease

Focused research plans should target improved management for persons with neurogenic bladder, developmental problems, diabetes, infection, inflammation, 

and obstruction. This report outlines research focused

on (1) identifying and managing specific populations 

at risk for disease and its complications and (2) 

preventing these problems. Equally important is

research to examine normal and abnormal bladder 

function and the contributions of nerves, blood vessels,

muscles, connective tissues, and epithelium to general

problems of the organ.

Epidemiology, Outcomes Evaluations, Prevention, and Bioethics

Clinical research is the cornerstone of health improvement for all Americans. Although basic research in the

area of the bladder will increase our knowledge, this

basic knowledge needs to be translated into active 

clinical research.

Research Infrastructure

Because past efforts in bladder research have been 

meager, the BRPRG recommends extraordinary support

for rapidly increasing research projects, research programs, manpower training, and technology in the area 

of the bladder. In particular, investment in information

technology is essential to make core resources such as

biostatistics, bioinformatics, epidemiology, outcomes

evaluations, and bioethics widely available.
RECOMMENDATIONS FOR STRATEGIC RESEARCH PRIORITIES

* Develop new technology-driven basic and clinical 

research techniques, including

• Animal models (genetic knockout models)

• Stem cell therapy

• Gene therapy

• Tissue engineering

• Functional imaging

• Biomechanical and micro-engineering technology

• Genomics and proteomics

• Cell regulation

* Develop focused research plans for basic systems 

and disease

* Conduct studies that include epidemiology, outcomes 

evaluations, prevention, and bioethics

* Establish a research infrastructure

Basic Science Advances and Opportunities

The BRPRG has outlined basic science areas in which

bladder research can make important contributions 

to all areas of scientific research. Basic science areas

include bladder epithelium, connective tissue, muscle,

and nerves and blood vessels. These research priorities

override disease boundaries. Although difficult to 

categorize, the BRPRG decided to group these research

priorities according to tissue type even though it 

recognizes that many of these initiatives also crosscut

tissue and organ areas.

RECOMMENDATIONS FOR BLADDER EPITHELIUM RESEARCH

* Explore anatomic epithelial and transitional cell 

variation and function in the bladder

* Examine regulation of normal and abnormal bladder 

epithelial cell growth and differentiation, specifically 

with relation to

• Gender

• Age

• Stretch

* Identify epithelial-mesenchymal interactions

* Determine cellular and molecular bases for epithelial 

disease and variation

RECOMMENDATIONS FOR CONNECTIVE TISSUE RESEARCH

* Examine regulation of collagen deposition

* Identify relationships of connective tissue 

to regeneration

* Determine cell-matrix interactions with relation 

to cell-cell regulation, including

• Cell signaling

• Bladder development, function, mechanics, 

injury, and regeneration

* Develop tissue, cell, and molecular imaging techniques

8 OVERCOMING BLADDER DISEASE
A Strategic Plan for Research 9

RECOMMENDATIONS FOR BLADDER MUSCLE RESEARCH

* Determine characteristics of smooth and 

striated muscle physiology

* Explore neuromodulation of bladder muscle

* Examine receptor and effector pharmacology

* Identify bladder muscle (detrusor) biomechanics

RECOMMENDATIONS FOR NERVES AND 

BLOOD VESSELS RESEARCH

* Explore brain imaging and bladder function

* Improve basic knowledge of bladder neurophysiology

—both mechanical motor and sensory function

* Examine mechanisms involved in neural 

communication with the bladder

* Explore mechanisms of nerve and vascular 

protection, preservation, and regeneration during 

aging, injury, and disease

* Improve knowledge of anatomic and physiologic 

changes related to alterations of bladder blood supply

Focused Research Plans for 

Common Clinical Conditions

Many diseases have bladder manifestations, but several

conditions affect large populations. The BRPRG has

focused on a number of high-impact bladder conditions

and has recommended research priorities for them.

High-impact conditions include:

• Problems of the developing genitourinary tract 

in children

• Urologic disease in maturation and aging

• Bladder outlet obstruction

• Interstitial cystitis

• Urinary tract infections

• Urologic effects of diabetes

• Urinary incontinence

• Cancer

Problems of the Developing Genitourinary Tract in Children

Normal bladder function is a critical part of human

development. Abnormal development can have a 

profound impact on bladder and kidney function and 

on psychological and social development. Abnormal

development can cause the inability to control urine,

resulting in intermittent wetness from urinary leakage

and urinary retention; infection; pain; and, at times,

kidney dysfunction and failure. 

Genitourinary tract abnormalities are the most common

birth abnormality. Dilatation of the urinary tract occurs

in most developmental problems, and prenatal ultrasonography may identify this in as many as 1 in 500

pregnancies. Vesicoureteral reflux, one of the most 

common causes of kidney failure in children, occurs 

in an estimated 1 percent to 2 percent of newborns. 

In addition, at 10 years of age, as many as 5 percent of

children still do not have bladder control.
10 OVERCOMING BLADDER DISEASE

With normal development, the bladder is a supple,

expandable organ. Urine is transported from the kidneys

to the bladder via the ureters, and the bladder serves to

store urine. As humans mature, control over the bladder

occurs with development, and the bladder can then be

willfully emptied at socially acceptable times. Injury,

disease during development, or even aging may interrupt

normal development, causing problems of inadequate

storage or emptying so that frequency, urgency, leakage,

vesicoureteral reflux, infections, stones, or kidney 

deterioration may occur. 

Birth defects related to the urinary tract alone or to

abnormal development in other systems of the body 

have lifelong consequences. These defects include 

the following:

• Myelodysplasia (e.g., spina bifida)

• Congenital and acquired bladder outlet obstruction

(e.g., posterior urethral valves, ectopic ureteroceles,

dysfunctional voiding)

• Vesicoureteral reflux

• Congenital anatomic anomalies (e.g., bladder 

exstrophy, neurogenic bladder with imperforate 

anus or cloaca, and prune belly syndrome)

Complications of birth defects cause social and 

psychological maladjustment in addition to lifelong 

high medical expenses.

Research addressing developmental anomalies of the

lower urinary tract is lacking. As of July 2001, only five

studies of the lower urinary tract could be identified as

being supported by the National Institutes of Health.

Although attempts to examine the reason for abnormal

bladder contractility following abnormal development

are ongoing, progress in understanding even normal

fetal and developmental bladder physiology is slow. 

Better understanding of the developmental abnormalities will have to occur before methods to prevent these

problems and their consequences can be identified.

RECOMMENDATIONS FOR GENITOURINARY 

TRACT PROBLEMS IN CHILDREN RESEARCH

* Improve understanding of lower urinary tract 

development and dysfunction

* Determine risk factors for abnormal urinary tract 

development and its consequences

* Identify preventive measures to decrease risk 

* Develop better management and treatment

Urologic Disease in Maturation and Aging; Obstruction

In both sexes, aging appears to cause a decline in bladder

contractility and an increase in involuntary contractions

leading to classic lower urinary tract symptoms including

nighttime voiding (nocturia) and urge incontinence.

Both factors have profound effects on bladder emptying

and storage. After their childbearing years, women

almost universally encounter change in bladder and

urethral function; however, understanding of the aging

process at the cellular and molecular levels remains

rudimentary. Moreover, even though the consequences

of benign prostatic hyperplasia (BPH) cause problems

for many men, limited effort has been directed toward

prevention and treatment options. 

RECOMMENDATIONS FOR MATURATION AND AGING RESEARCH

* Examine the aging urinary tract at the cellular and 

molecular levels to understand the changes causing 

bladder dysfunction

* Investigate and identify the molecular, cellular, 

gender, and potentially genetic factors that lead 

to dysfunction of aging

* Develop preventive, management, and therapeutic 

interventions
RECOMMENDATIONS FOR BLADDER OUTLET 

OBSTRUCTION RESEARCH

* Identify the impact of age on BPH pathophysiology 

and treatment outcomes

* Analyze central and peripheral nervous system 

contributions to voiding dysfunction and identify 

related potential therapies

* Identify new therapeutic targets by determining 

genomic and proteomic urinary tract changes 

caused by obstruction

Interstitial Cystitis

Interstitial cystitis (IC) is a debilitating, chronic bladder

syndrome that causes urinary urgency and frequency

often associated with continual pelvic and bladder pain.

Although exact prevalence is unknown, it is estimated

that 700,000 to one million people have IC in this 

country. The incidence in Americans has been reported

to be three times that in Europe and about the same as

the number of people who have inflammatory bowel 

disease and Parkinson’s disease. 

Although anyone can have IC, 90 percent of sufferers 

are reported to be women in their most productive years.

Fifty percent of IC patients are unable to work full-time.

In 1988, IC was estimated to cost $1.7 billion in medical

expenses and lost wages, costs that would be significantly

higher today considering rising costs and greater numbers of patients. According to a 1990 report, people on

kidney dialysis have a better quality of life than people

who have IC. 

The diagnosis of IC is difficult to make. While theories

abound, there is no known cause. As a result, neither 

a cure nor a consistently effective therapy is available.

Symptoms of IC may be either mistaken for a urinary

tract infection or considered to be nothing more than a

reflection of the patient’s anxiety. This delays diagnosis. 

Lesions of pinpoint bladder bleeding are hallmarks of 

IC, but they are often seen only under general anesthesia

when the bladder is examined with a cystoscope, thus

making diagnosis difficult. Although some ongoing

research has been trying to establish the cause of IC, 

none has been found. However, other avenues of research

are looking to establish conclusive diagnostic markers of

the disease that would improve diagnosis and enhance

further research on management and treatment. 

RECOMMENDATIONS FOR INTERSTITIAL CYSTITIS RESEARCH

* Establish epidemiology and natural history of IC

* Identify disease markers for diagnosis and progression

* Conduct IC management and therapy trials

* Educate the public and health profession

Urinary Tract Infection

Urinary tract infections (UTIs) are common among

women, men, and children. Adult women have about a

50 percent lifetime risk of developing a UTI, and it has

been reported that by age 24, one-third of women have

had one. When they occur in special populations of risk,

including young children and the elderly, UTIs can cause

pain, severe illness, loss of kidney function, and high

blood pressure. In addition, UTIs currently account for

more than a third of the 2 million infections that occur

in hospitals each year. Most of these UTIs are secondary

to an indwelling urethral catheter. Catheter-related UTI

has been estimated to be responsible for 40 percent of

all institution-related infections. The total annual cost

of UTIs in the United States has been estimated to be

greater than $1 billion, and this estimate does not

include hospital costs. 

Children are at special risk for UTIs. Approximately 3

percent of prepubertal girls and 1 percent of prepubertal

boys are diagnosed annually with UTIs. Approximately 18

percent of infants who develop a UTIs during their first

A Strategic Plan for Research 11
12 OVERCOMING BLADDER DISEASE

year of life experience a recurrence during subsequent

months. Recurrent UTIs in infants and children are

associated with significant morbidity, including

impaired kidney function, end-stage renal disease, 

and possible complications of pregnancy. Other people

at risk of developing severe complications from UTI

include people with neurogenic bladders caused by 

diabetes or other diseases that impair the nervous 

system, people with catheters, pregnant women, the 

elderly, and people with kidney transplants. 

Factors that cause or allow bacteria to attach to the 

skin, enter, and then ascend the urinary tract to the 

kidney and, at times, enter the blood stream are not 

well defined. Although a routine UTI often can be easily

treated with antimicrobial drugs, this is not always the

case. Certain bacteria have been identified that have a

particular virulence for the urinary tract. These bacteria

are constantly changing and becoming resistant to the

antimicrobial agents currently available. For people who

are at high risk of complications or who get frequent

recurrent UTIs, some strides have been made to block

UTI with vaccines. These vaccines are being developed

and their long-term efficacy will need to be examined.

RECOMMENDATIONS FOR URINARY TRACT 

INFECTION RESEARCH

* Determine host-pathogen interactions

* Identify bacterial pathogenesis

* Identify host-cell responses

* Determine host susceptibility to infection 

and inflammation

Urologic Consequences of Diabetes Mellitus

At least 25 percent of Americans who have diabetes 

mellitus will develop urinary tract complications of 

diabetes such as urinary incontinence or retention,

infection, or other lower urinary tract symptoms, but 

the true incidence of urinary tract dysfunction associated

with diabetes is unknown. It is unknown because little

attention has been focused in this area. 

What is known, however, is that people with diabetes

suffer from increased complications of urinary tract

infections, such as kidney abscesses, papillary necrosis,

and gas-forming infections of the kidney (emphysematous pyelonephritis) that may be lethal. In the United

States, diabetes is probably the most common condition

associated with kidney papillary necrosis, which is most

likely related to a combination of diabetes and urinary

tract infection. 

People with diabetes also develop voiding difficulties

that manifest as incontinence and urinary retention.

These voiding problems are probably related to a 

common complication of diabetes—sensory neuropathy.

In observational studies, men and women with diabetes

had a 30 percent to 70 percent increased risk of 

urinary incontinence. 

Although general research on diabetes mellitus improves

our understanding of the disease, specific issues related 

to the urinary tract need to be examined. The pathophysiology of urinary tract dysfunction and urinary 

tract infection in people with diabetes is so little known

that no efforts to determine risk or to predict or prevent

these complicating problems have been made. In addition, almost nothing is known about the combined effect

on the bladder of diabetes and prostatic enlargement, 

a problem that occurs in most aging men, or about the

combined effects of diabetes, pregnancy, and childbirth

in women. 
A Strategic Plan for Research 13

RECOMMENDATIONS FOR DIABETIC BLADDER RESEARCH

* Identify and characterize changes in the diabetic 

bladder at the molecular and cellular level

* Identify markers and risk factors that predict 

early urinary tract involvement

* Examine the clinical history of disease progression 

with relation to gender, ethnicity, and race

* Perform clinical trials to identify efficacious 

preventive and therapeutic strategies

Urinary Incontinence

About 13 million Americans, most of them women, 

suffer from urinary incontinence, a problem often 

associated with pregnancy, childbirth, and aging. 

In addition, many diseases and conditions are associated

with incontinence, including spinal cord injury or

abnormalities, Parkinson’s disease, multiple sclerosis,

and diabetes. After pregnancy and childbirth, about 

30 percent of women develop problems with bladder

control, and almost 30 percent of all people over age 

60 have some urinary leakage. In older Americans,

problems with bladder control cause urgent trips to 

the bathroom, thus increasing the risk of falls and 

subsequent fractures by an estimated 20 percent to 

30 percent. 

Although new imaging techniques have improved our

current knowledge of the anatomy of the pelvic area, 

the reasons for different forms of incontinence remain

understudied and elusive. Different kinds of surgical

operations have been developed to improve urinary

incontinence in females, but few of these operations

have been validated by quantitative outcome measures

and few have withstood the test of time. The reasons for

failure of many initially successful operations are not

totally clear; 

however, failure may relate to lack of understanding of

the basic mechanisms of incontinence and the changes

that occur with aging.

To improve the overall quality of life of Americans

affected by urinary incontinence, an investment in

research is needed to enhance our understanding of

continence and incontinence, to identify risk factors 

and quantitative measures of incontinence severity, 

and to develop effective preventive efforts and treatment. This will require multidisciplinary investigations

from basic scientists, bioengineers, and clinicians 

who specialize in the management, measurement, 

and imaging of male and female incontinence. 

RECOMMENDATIONS FOR URINARY INCONTINENCE RESEARCH

* Develop novel techniques to measure neural, muscular, 

and vascular function of the bladder

* Identify risk factors related to childbirth and aging

* Improve understanding of the mechanisms of urinary 

incontinence

* Develop a national registry and tissue bank of patients 

suffering from urinary incontinence

Bladder Cancer

Bladder cancer is the sixth most commonly diagnosed,

non-cutaneous cancer in Americans. Currently,

400,000 Americans have been estimated to have a 

diagnosed case of bladder cancer. These patients undergo continued surveillance examinations that are costly

and invasive. For this reason, the development of new

techniques for detection, prevention, chemoprevention,

and treatment are imperative. Furthermore, the research

community needs to investigate the basic biology of 

cancer in the bladder epithelium (urothelium) and

develop disease models to examine abnormal cellular
14 OVERCOMING BLADDER DISEASE

growth, regulation, cell-cell interaction and signaling,

differentiation and control, field effect versus clonality,

and urothelial alterations with age and gender to understand why this cancer has increased so rampantly and to

discover markers, ways to prevent the disease, and new

treatments. 

Advances in imaging that make use of virtual endoscopy,

contact microscopy, fluorescent cystoscopy, novel ultrasound examinations, magnetic resonance imaging

(MRI), and positron emission tomography (PET) could

lead to more rapid diagnosis, less invasive management,

and more successful outcomes.

RECOMMENDATIONS FOR BLADDER CANCER RESEARCH

* Use the bladder as a model to study and treat cancer

* Develop and test bladder cancer preventive measures

* Identify new bladder cancer markers to replace

current invasive bladder cancer testing

Methodologies & Technologies

Clinical Trials and Epidemiology

Methodologies such as bioinformatics, epidemiology,

and advances in computer technology permit linkage 

of patient and disease data and allow clinical research 

to be performed using databases that surpass previous

capabilities and capacities. These methodologies and 

technologies apply new rigor to clinical trials involving

outcomes evaluations and neural networks. In studies 

of complex conditions, bioinformatics and biostatistics

allow scientists to make inferences and conclusions 

that were previously impossible to make.

RECOMMENDATIONS FOR CLINICAL TRIALS 

AND EPIDEMIOLOGY RESEARCH

* Fund pilot studies with potential for high risk and 

high gain 

* Prioritize clinical studies in which short-term gain and

extramural funding are unlikely. These studies include 

• Alternative therapies

• Prevention studies

• Long-term outcome studies

• Behavioral studies

• Surgical trials

* Develop national clinical trials and a data center 

with core consultation services

• Outcomes analysis

• Biostatistics

• Bioethics

• Epidemiology

* Establish multi-center studies to examine low-incidence,

high-impact bladder problems

* Provide industrial partner grants to examine factors 

that may not be the interests of industry but can be 

performed simultaneously (“piggy-back” grants)

Clinical trials of bladder disease are scarce. Enormous

opportunities for data gathering and for examination 

of best practices and management of bladder disease

exist through clinical bladder trials, yet they have 

been under utilized and under funded in the area 

of bladder research.
A Strategic Plan for Research 15

Emerging Technologies and Pharmacology

Current advances in biotechnology have created progress

in other areas of scientific endeavor at a rapid rate. All

areas of bladder research and all patients with bladderassociated health problems would benefit from

• New biologic (cellular or molecular) and functional

imaging techniques and genomics or proteomics 

techniques to identify persons at risk for bladder 

disease or dysfunction

• Bioengineering technology such as stem cell or gene

therapy or tissue engineering techniques that allow

repair, replacement, or even prevention of abnormal

bladder tissue or function

As rapidly as research has progressed in proteomics 

and genomics, pharmacologic discovery aimed at 

modulating, augmenting, or blocking specific receptors

has also progressed. New drug delivery systems that

allow drug delivery at a specific time and place are 

possible, and the bladder is an ideal organ in which 

to deliver them. 

In addition the development of new technologies for

biomedicine would have a great impact on how studies 

of the bladder, urethra, and pelvic floor are conducted.

Technologies currently in use by many researchers are

usually low throughput technologies, meaning that the

number of tests they can perform in a given period 

of time is low, a limitation that hampers the study of 

biologically heterogeneous disorders in humans.

Another limitation involves research tools currently

available for analyzing nucleic acids and proteins. 

These tools rely on large sample sizes, a problem 

when dealing with both humans and small animal 

models where starting material is limited.

RECOMMENDATIONS FOR EMERGING TECHNOLOGIES AND 

PHARMACOLOGY RESEARCH

* Develop tissue and bladder renewal and replacement techniques using stem cell and tissue engineering technology

* Develop minimally invasive diagnostic techniques for 

the lower urinary tract using micro-engineering and 

biomechanical technology to perform functional bladder 

imaging, urodynamics, and biomechanical assessment

* Establish a research infrastructure focused on the bladder

that includes core facilities to harness genomic (and 

microarray), proteomic, and bioinformatics technology

* Support drug development and delivery systems that 

affect the following:

• Sensory pathways

• Micturition through the nervous system

• Muscular activity

• Blood flow

• Connective tissue

• Gene therapy
16 OVERCOMING BLADDER DISEASE

Resource and Infrastructure Needs

At this time in medicine, clinical research is severely

challenged. Clinical investigators have less time for 

clinical research because of the increasing complexities

involved in performing their day-to-day patient care

activities. Clinical trials are often inadequately funded.

Clinical research is expensive, and human research is

highly regulated requiring high degrees of organization

and support. Many bladder diseases have a long natural 

history, and outcomes trials must be undertaken over

many years, facts that make clinical research even 

more complicated. 

The BRPRG has concluded that current clinical research

on the lower urinary tract lags behind many other 

disease areas because of inadequate prior funding.

Building an effective program in bladder research

requires not only financial support, but also an underlying infrastructure. New requests for applications

(RFAs) are needed to address the listed research 

priorities. Efficient and effective clinical research 

programs are needed that not only allow recruitment 

of high-risk patients, minority patients, and special

groups, but also provide long-term follow up. These 

programs must have a high regard for patient health 

and safety. To achieve this, a stable well-supported

infrastructure of professionals who are knowledgeable 

in research methodology, outcomes evaluations, 

biostatistics, data analyses, and epidemiology is

required. These resources in different forms need to 

be available at targeted local, regional, and national 

sites to assess and perform clinical research.

Because of the paucity of bladder research, the BRPRG

recommends that the number of investigators interested

in bladder research be increased by efforts to attract

established investigators into the field and to train new

investigators. The BRPRG recommends that this be

achieved by prioritizing RFAs of collaborative research

and by establishing a mechanism for program and 

proposal review and evaluation that is specific to 

the lower urinary tract. The BRPRG also recommends 

that establishment of a planning group for implementing these recommendations be considered at 

the national level. 

The future of United States bladder research needs to 

be created today. This can be effectively accomplished 

by creating an infrastructure and by recruiting, training,

and retaining investigators.

RECOMMENDATIONS FOR RESOURCE AND 

INFRASTRUCTURE NEEDS

* Increase the investigator workforce as follows:

• Train new investigators

• Attract established investigators into the field

* Create new bladder multidisciplinary research and 

training programs

* Create national resource centers

* Support data and tissue banks for bladder research

* Provide incentives for NIH-academic-industrial 

research initiatives

* Establish NIH bladder planning and review panels
Conclusion

The BRPRG has reviewed the bladder research effort

funded by the federal government and has found this

portfolio to be deficient both in total and in proportionate funding when compared with other organs and 

major disease areas that affect the human condition 

to a similar degree. 

The United States has a large population that is 

affected by bladder diseases and conditions, and many 

of these problems have been neglected to a large part

because of poor education of the public and health 

professionals and because of the social stigma attached 

to urinary processes. Social stigma has prevented 

many from speaking out about these problems and 

has undoubtedly limited the number of public advocacy

groups that have formed. In addition, some people 

with these conditions—children, the elderly, and 

people with neurological impairments—are unable 

to be advocates. 

The United States has been a leader in biomedical

research, and it can play a major role in the effort 

to improve the lives of people with bladderimpairing conditions.

To implement the recommendations in this report, the

Executive Committee of the BRPRG asks the National

Institute of Diabetes and Digestive and Kidney Diseases

and other institutes and centers of the National

Institutes of Health (NIH) to increase bladder research

funding over a seven-year period. Other institutes 

and programs of the NIH might also contribute to this

effort by recognizing the bladder component of many

diseases that are already being studied. Substantial

increases in funding will allow bladder research levels 

to become commensurate with other important areas 

of human problems.

With the continually increasing life expectancy of the

American public, bladder conditions will have a rising

impact on the United States in social and economic 

proportions. An investment in research funding at this

time has the potential to improve the quality of life of 

the American people and to dramatically decrease the

emotional, psychological, societal, and financial 

burden of bladder diseases. 

A Strategic Plan for Research 17
A Strategic Plan for Research 19

Although it appears to be a simple storage organ, the bladder 

is physiologically more complex than previously thought.

Recent studies have revealed exquisitely timed biochemical

interactions occurring between cells in the bladder’s various

tissue layers and the peripheral and central nervous systems

that synchronize the storing and releasing of urine. These

interactions, when normal, create a seamless chain of events

that is often taken for granted by healthy people. However, a

disturbance in one part of this intricate system can affect other

parts, leading to dysfunction, disease, and poor quality of life.

The lower urinary tract comprises the bladder, the ureters, 

the bladder outlet (vesical neck and urethra), and the 

sphincter muscle. Predominantly a muscular organ, the 

bladder stores and empties urine. 

Urine flows from the kidneys through two ureters, which are

long tubes inserted into the bladder, a balloon-like structure

made of a thin layer of smooth (visceral) muscle. The bladder

stores the urine, stretching as it fills. A sphincter muscle 

located where the bladder opens into the urethra prevents

urine from leaking. This circular, striated (skeletal) muscle 

or sphincter is in a state of contraction until it receives a 

message from the brain to relax. 

The storage capacity of the bladder is about 10 to 20 ounces 

of urine. When the bladder has about half its capacity, nerves

send signals to the brain that the bladder is getting full. During

voiding, the sphincter relaxes, the bladder muscle (detrusor)

contracts, and urine is voluntarily discharged into the urethra,

the canal through which urine is expelled from the body. 

Dramatic changes occur in the lower urinary tract during a

person’s lifetime. In the fetus, the bladder initially serves as 

a conduit that transmits urine from the ureter and dispels it

through the urachus, the fetal urinary canal located between

the bladder and the umbilicus, into the amniotic fluid.

Eventually, the bladder expands and becomes a prototype 

storage organ in the fetus. Later in fetal development and in

the newborn, the bladder develops reflex activity controlled 

by the central nervous system. At first, reflex emptying is 

inefficient, but it becomes more efficient as the nervous system

matures and is able to coordinate the functions of the urethra

and urethral sphincter with those of the bladder.

During reflex voiding, the detrusor muscle and the epithelium 

of the bladder send a message that the bladder is full over

afferent (ingoing) pathways into the spinal cord. The spinal

cord transmits this information to a switching circuit in the

brain stem that automatically turns on and relays the information back through the spinal cord and efferent (outgoing)

nerves to the bladder, which then empties. Eventually the 

cerebral cortex takes control over the brain stem. 

During early childhood, the bladder develops as a sensory

organ. Sensation is a function that must develop in children for

them to realize the bladder is full. When this occurs, voluntary

control of urination or voiding can be achieved. The cerebral

cortex allows voluntary control, that is, the system can be

turned on and off at will. Normal voiding depends on good 

coordination between the brain and the spinal cord.

The bladder is composed of smooth muscle, the type of 

muscle that is found in most organs of the body; epithelium;

connective tissue; nerves; and blood vessels. Complex 

biochemical interactions that are still being discovered 

occur among these structures. Therefore, this finely tuned 

system is not always in a steady state during a person’s 

lifetime, as research and life experiences have revealed.

Diseases and conditions such as multiple sclerosis and stroke,

infection, hereditary factors, diabetes, injury to the peripheral

and central nervous systems, and aging, to name a few, 

can reverse this development process. 

SECTION A BASIC SCIENCE OF THE LOWER URINARY TRACT
CHAPTER 1
A Strategic Plan for Research 21

Basic Science of the Lower Urinary Tract

UROTHELIUM

DID YOU KNOW?

. The urothelium—epithelial 

tissue lining the inner surface 

of the lower urinary tract—

functions as a barrier to microorganisms and toxins and may

also act as a sensory organ.

. Practically every major disease 

of the bladder, including cancer,

interstitial cystitis, and infection,

involves the urothelium.

. The urothelium holds great

potential for research studies

because it is readily accessible.

Summary and Recommendations

The inner surface of the urinary tract is lined with epithelial tissue or 

urothelium, which functions as a barrier to bacteria, environmental carcinogens, toxins, and the highly variable waste products in urine. Practically 

every major disease of the bladder, including cancer, infection, inflammation,

and developmental anomalies, involves the urothelium. 

Studies of the urothelium hold great potential for making an impact on 

the treatment of not only urologic diseases, but also diseases in other areas 

of the body. The Bladder Research Progress Review Group has made the 

following recommendations (in order of priority) for research on lower 

urinary tract urothelium: 

* Determine how normal urothelium develops and performs its unique 

biological functions by investigating the following:

• Synthesis, assembly, and function of urothelial cell differentiation 

products

• Influence of cell-cell interactions and other extracellular signals 

on urothelial biology

• Molecular bases of the urothelium’s permeability barrier function

• Secretion of urinary proteins, including growth factors

• Possible urothelial involvement in the function of nerve cells

• Identification of additional urothelial differentiation markers 

(factors by which a cell or molecule can be recognized and identified)

using cDNA microarray and tissue array technologies
22 OVERCOMING BLADDER DISEASE

* Determine how the urothelium develops pathology in

response to disease-causing stimuli by identifying

• Interactions between uropathogenic bacteria, 

the urothelium, and the mechanisms of 

recurrent UTI

• Altered oncogenes (genes that encode proteins

involved in cell growth and regulation that when

mutated can cause abnormal cell growth) and

other genetic mutation

• Urine components, including carcinogenes 

and tumor-promoting agents, toxins, and 

growth-modulating factors

• Abnormal urothelial gene expression patterns 

by using cDNA microarray and tissue 

array technologies

* Develop shared resources for urothelial research as follows:

• Develop a “urochip,” a cDNA microarray chip 

specific to urologic and bladder genes

• Expand and support new technology, including

proteomics and tissue arrays

• Develop bioinformatics to analyze the high

throughput data (data that can be generated efficiently in a few tests in a relatively short time) 

• Develop multi-institutional tissue banks, tissue

registries, and transgenic repositories

• Increase funding to support training grants and

shared core facilities

* Determine the differences in structure and function of 

urothelial cells from different regions of the urinary tract. 

This will provide critical baseline information for all

future studies on urothelial biology and diseases.

* Identify the mesenchymal signals that direct the differentiation pathways of urothelial cells. The striking plasticity 

of adult urothelium, which can differentiate into

prostate-, colon- and seminal-vesicle-like structures

in response to mesenchymal signals, provides unique

opportunities to better understand mesenchymalurothelial interaction and urothelial differentiation. 

* Identify the roles of urinary markers in the pathogenesis 

of interstitial cystitis (IC). At least six urine markers

have been shown in blinded studies to be significantly different between IC patients and controls.

These differences may provide clues to the pathogenetic mechanism for this poorly understood 

bladder disorder.

* Determine the effects of age and gender on urothelial 

structure and function.

* Delineate the effects of mechanical stretching on urothelial

growth and apical surface area expansion, and determine 

the molecular bases for such regulation.

* Elucidate the structure and function of the urothelial 

glycocalyx, a filamentous coating on the apical surface 

of certain bladder urothelial cells, or glycosoaminoglycan

(GAG), a protein-polysaccharide complex lining the apical

surface of bladder urothelial cells, in normal urothelial 

biology and in interstitial cystitis.

* Develop and characterize additional in vitro (test tube) 

models of urothelial growth and differentiation using both

human and other mammalian urothelial cells for studying

urothelial-mesenchymal interactions and their roles in 

disease processes.

* Develop and characterize additional novel animal models 

for urothelial diseases.
A Strategic Plan for Research 23

Background

The urothelium is the major tissue lining the surface 

of almost the entire urinary tract. Recent research has

indicated that the urothelium functions somewhat like

the nervous system; that is, urothelial cells express

receptors and release transmitters such as nitric oxide

and adenosine triphosphate (ATP). Thus, urothelial cells

appear to play a role in normal bladder sensation. What

is not known, however, is whether the urothelium functions as a sensory organ throughout the different stages

of development. 

The urothelium also functions as a barrier to bacteria,

environmental carcinogens, toxins, and the highly variable waste products in urine. Consequently, practically

every major disease of the bladder involves the urothelium. The following are just a few:

* Urothelial cancer—Ninety-five percent of all bladder

cancer is urothelial cancer, which annually affects

56,000 Americans and is the fifth most commonly

diagnosed non-skin malignancy in this country. 

* Urinary tract infection—Urinary tract infection, or 

UTI as it is commonly referred to, affects both sexes,

but significantly more women than men. Every year

an estimated 7 million cases of uncomplicated UTI 

occur in the United States. Bacteria known as type 

1-fimbriated or piliated Escherichia coli cause more

than 90 percent of the cases. These bacteria attach 

to urothelial cell surface receptors before invading

the urinary tract. Without such initial binding to 

the urothelium, the bacteria would be removed by 

urination and no infection could occur. Invasion 

of type 1-piliated E. coli into the kidney may be

responsible for more than 250,000 cases of kidney

infection (pyelonephritis). The emergence of 

bacteria resistant to antibiotics presents a serious

health problem.

* Interstitial cystitis—Known as the “painful bladder 

syndrome,” interstitial cystitis is an extremely debilitating condition affecting an estimated 700,000 to 

1 million people in the United States, mostly females.

Defects in the urothelium are thought to play a major

role in this problem. 

* Vesicoureteral reflux—A hereditary problem affecting

almost 1 percent to 2 percent of all children, vesicoureteral reflux can cause serious kidney damage 

even before a child is born and is one of the leading

causes of kidney failure in children. 

Studies of the urothelium hold great potential for making

an impact on the treatment of not only urologic diseases,

but also diseases in other areas. Urothelium is both

readily accessible to routine examination and particularly plastic in terms of developmental potential. Thus, it

provides unique opportunities for a better understanding of (1) interactions between the mesenchyme and

urothelium and (2) determination of tissue fate during

embryonic development. 

In addition, the urothelium exhibits intriguing biological

properties, including colonization of the bladder by 

multiple tumors in separate locations (the “field effect”);

this phenomenon occurs despite the entire urothelium

being bathed in and exposed to the same urine environment. Finally, normal and diseased human urothelial

cells are readily available for study. For these reasons,

urothelial research has the potential for revealing basic

biologic principles that are of value to all fields of 

scientific inquiry. 
24 OVERCOMING BLADDER DISEASE

Research Advances and Opportunities

Reducing the morbidity and mortality of widespread

debilitating conditions of the lower urinary tract will

depend on future research projects that focus on 

achieving a better understanding of the following: 

• Differences in the structure of urothelial cells from

different regions of the urinary tract

• Regulation of urothelial growth and differentiation

• Cellular and molecular bases of urothelial diseases

• Differences in the function of urothelial cells

Differences in Structure of Urothelial Cells

Urothelial cells from the renal pelvis, ureter, bladder,

and proximal urethra traditionally have been thought 

to be the same cell types. However, subtle, but potentially important, gender- or age-related urothelial 

differences exist. 

Some recent studies suggest that urothelial cells may 

be more heterogeneous than previously thought.

Urothelial cells from the ureters, kidneys, and trigone

region of the bladder (the area of the bladder that forms

a triangle between the insertion of the two ureters and

the point where the urethra begins) are thought to be

derived from the embryonic mesoderm, while urothelial

cells of the urethra and the bladder wall, excluding the

trigone, are derived from the embryonic endoderm. 

Tissue recombination studies indicate that urothelial

cells from different regions of the lower urinary tract can

give rise to various types of urothelial cells when signaled

by various embryonic mesenchyme. Thus, the endoderm-derived bladder urothelium gives rise to prostate

tissue in response to embryonic urogenital or seminal

vesicle mesenchyme, while the mesoderm-derived

ureter urothelium gives rise to seminal vesicle cells.

Taken together, these data raise the intriguing possibility

that significant cellular, structural, and functional 

differences may exist among the urothelial cells of 

different regions of the urinary tract. This concept has

significant implications in the biology and pathogenesis

of urothelial diseases. 

Urothelial Differentiation Markers and Diseases

Characterization of genes differentially expressed in

urothelial cells is an important step towards a better

understanding of urothelial structure and function.

Recently, a group of uroplakins—integral membrane

proteins—has been identified as the major differentiation (specialization) product of mammalian urothelial

cells. Studies of uroplakins have led to a better understanding of several important bladder diseases and 

conditions, including urinary tract infection, bladder

cancer formation, and vesicoureteral reflux, a 

congenital anomaly. 

For example, uroplakin Ia is a receptor for type1-

piliated Escherichia coli, a bacterium involved in recurrent UTIs and antibiotic resistance. The binding of

type1-piliated E. coli to uroplakin receptors is facilitated

by the bacteria’s filamentous projections called pili or 

fimbriae. Bacterial attachment can result in at least 

two effects, one leading to programmed cell death

(apoptosis) and shedding (exfoliation) of urothelial 

cells, possibly as a way of host self-defense, and the

other leading to bacterial invasion into urothelial cells

and propagation. Understanding bacterial invasion is

important for developing better treatments for antibiotic

resistance and infection relapse. A vaccine that blocks

type 1-piliated E. coli from attaching to urothelial cells 

is being developed and has shown promising results in

animal studies and human trials. 

Studies of the promoter of the uroplakin II gene helped

define the roles of specific oncogenes in bladder cancer.

Oncogenes are genes normally responsible for making

proteins involved in regulating cell growth. However,

when these genes are mutated or abnormally activated,

they can make altered proteins that lead to uncontrolled

cell growth or tumor formation. For example, the 

oncogene, SV40T, when directed by the uroplakin II
A Strategic Plan for Research 25

promoter to express in the bladder urothelium resulted

in the formation of localized bladder cancer and later,

full-blown transitional cell cancer. In contrast, H-RAS,

an oncogene frequently activated in melanoma and 

in cancer of the colon, lung, and pancreas, led to the 

formation of a papillary tumor. This provided strong 

evidence supporting the two-pathway hypothesis of

bladder tumor development. 

Another recent study has established that the TammHorsfall protein, a mucoprotein contained in the 

mucus urothelial cells of the bladder and the most 

abundant protein in human urine, is the major defense

factor for preventing type 1-piliated E. coli from 

adhering to the uroplakin receptors on urothelial 

cells in the bladder. 

Finally, the genetic ablation of the uroplakin III gene 

in mice has resulted in the formation of grossly 

abnormal superficial (umbrella) urothelial cells, which

are functionally deficient because they form an inferior

permeability barrier, a condition that would increase

susceptibility to toxins and possibly uropathogenic

microorganisms. In addition, the mice suffered from

vesicoureteral reflux, the retrograde flow of urine from

the bladder into the ureters and kidneys. This surprising

finding is important because it suggests that genetic

defects causing urothelial abnormalities can result in

reflux, an important pediatric urologic problem that can

have a significant effect on families because 30 percent

of siblings of children with known reflux will have the

disorder as well. 

It has also been suggested that a glycosaminoglycan

(GAG) layer (a protein-polysaccharide complex) lining

the apical surface of bladder urothelial cells inhibits 

bacterial adherence and contributes to the urothelium’s

function as a barrier to microorganisms and toxins. 

The composition and function of GAG has been 

the subject of much discussion and needs to be 

studied further. 

Regulation of Urothelial Cell Growth and Differentiation

Abnormal urothelial cell growth appears to be related 

to several important bladder diseases, including cancer

and interstitial cystitis; therefore, determining the roles

of the factors that stimulate or inhibit cell growth in 

the urothelium is of great importance. 

Recent data indicate that human urothelial cells synthesize many growth factors. Some of these factors are

implicated in the regulation of urothelial cell growth 

and differentiation. Data on these factors may be 

relevant to interstitial cystitis, which features thinning

and sometimes ulceration of the urothelium. 

Studies have recently identified two novel growthmodulating factors that are both synthesized and 

secreted into the urine by the urothelial cells of 

persons with interstitial cystitis. Those growthmodulating factors are

• A small-sized growth-inhibiting factor that may 

have important implications as a diagnostic tool

• A small-sized urine factor that can cause the programmed cell death (apoptosis) of urothelial cells 

Two hours after infection, a type 1 piliated Escherichia coli bacterium (left)

adheres to epithelial cells on the bladder wall of a mouse. The bacterium 

uses pili (right) to bind to uroplakin Ia receptors in the epithelial cells. 

(Photo Credit: Matthew A. Mulvey, Yolanda S. Lopez-Boado, Carole L. Wilson, 

Robyn Roth, William C. Parks, John Heuser, and Scott J. Hultgren. 

Adapted from Science, 282:1494-97. Copyright 1998, the American Association 

for the Advancement of Science.)

=
26 OVERCOMING BLADDER DISEASE

Further studies of these factors, which occur mainly 

in persons with interstitial cystitis, may lead to an

improved understanding of the pathogenesis and novel

treatment of this disease. 

Another interesting recent finding indicates that

mechanical stretch can influence growth factor production by the bladder’s smooth muscle cells. This process

could play a role in both the excessive growth of bladder

muscle (hypertrophy) present in many bladder diseases

and in the regulation of urothelial growth.

Novel Urothelial Cell Functions

Although the urothelium has been traditionally thought

of as a permeability barrier, recent studies indicate that

it is functionally versatile. These studies have discovered

that (1) the urothelium can secrete a variety of proteins

into the urine in addition to certain growth factors and

(2) activation of urothelial cells by mechanical, chemical,

or noxious stimuli results in the release of neurotransmitters such as nitric oxide and adenosine triphosphate

(ATP), which may stimulate adjacent nerves.

• Secretion of proteins and growth factors. The urothelium

can secrete a variety of proteins into the urine in

addition to certain growth factors. This activity has 

a potentially practical application; the promoter of

the uroplakin gene in transgenic mice (mice that 

have had a gene transplant in which new DNA was

introduced into their germ cells by injection into 

the nucleus of the ovum) could be used to drive the

urothelial production and secretion of pharmaceutically important human recombinant proteins such 

as human growth factors.

• Release of neurotransmitters. Activation of urothelial

cells by mechanical, chemical, or noxious stimuli

results in the release of neurotransmitters such as

nitric oxide and adenosine triphosphate (ATP), which

may stimulate adjacent nerves. In addition, urothelial

cells exhibit functional capsaicin receptors, proteins

that are located in nerves that detect certain types 

of pain. These observations raise the possibility 

that urothelial cells may communicate with nerve

receptors that convey stimuli to the central nervous

system via chemical signaling between cells, thereby

participating in normal bladder sensation. Because

abnormal interactions between the urothelium and

nerve cells could play a role in painful bladder 

disorders such as interstitial cystitis, these new 

findings suggest that urothelium can function in 

several new ways, and that defects in these processes

could play a role in certain bladder disorders.

Uroplakin Ia, the urothelial receptor for bacterial adhesin FimH, is

localized on the six inner domains of the 16 nm urothelial plaque particle.

In this atomic force microscopy image, mouse and bovine plaques are

visualized. The averaged images of the luminal (upper left half) and the

cytoplasmic (lower right half) surfaces of bovine and mouse urothelial

plaques, respectively, display propeller-shaped 16 nm AUM particles on the

luminal surface and ~14nm diameter, circular protrusions on the cytoplasmic

surface. (Photo Credit: Guangwei Min, Martin Stolz, Ge Zhou, Fengxia Liang, Peter

Sebbel, Danial Stoffler, Rudi Glockshuber, Tung-Tien Sun, Ueli Aebi, Xiang-Peng Kong.

The Journal of Molecular Biology. 317:967-706. Copyright© 2002, Elsevier Science.)
A Strategic Plan for Research 27

Mechanisms of Urothelial Permeability Barrier Function

Because the composition of urine differs sharply from

that of blood, the urothelium must block the passage of

many molecules that normally pass freely across biological membranes. These molecules include water, urea,

and ammonia. As a result, the urothelium has evolved as

the most effective permeability barrier known to exist in

mammals. This is attributed to both the tight junctions

interconnecting the superficial urothelial cells (umbrella

cells) and the highly specialized urothelial apical 

surface membranes. 

Recent studies have indicated that both membrane 

lipids and proteins contribute to the permeability 

barrier function. The availability of in vitro (test tube)

and in vivo (animal) model systems opens new avenues

for further studies on the roles of specific proteins and

lipids in urothelial barrier function. In vitro systems can

also be useful for studying the effects of antibiotics and

certain proteins secreted by eosinophils—a type of white

blood cell associated with inflammation—on urothelial

barrier function. These proteins may play a role in 

disease states.

Research Requirements 

Workforce

Training grants should be available to prepare 

young investigators for a career in bladder research. 

In addition, special grants designed to attract established investigators to bladder research will be 

highly desirable. 

Infrastructure

Establishment of multi-center programs would aid

research projects that require the recruitment of large

patient populations, such as projects for bladder cancer

or vesicoureteral reflux.

Shared Resources

Resources that can be shared by all investigators would

facilitate and expedite research studies. These resources

are as follows:

• Tissue banks. A major impediment to urothelial

research has been the lack of well-controlled 

clinical specimens. A tissue bank of normal and 

diseased human bladder biopsy and urine specimens

will be tremendously helpful to the urothelial

research community. 

• Bladder-specific microarray chips. Commercial microarray chips usually do not contain some of the genes

of unique interest to bladder research, such as

urothelial-specific genes. The National Institutes 

of Health (NIH) should consider the possibility of

funding the development of such special reagents.

• Depository of transgenic and knockout mouse embryos.

Many transgenic mouse lines, potentially useful 

for bladder research, are lost when they become 

too expensive for individual laboratories to maintain

or to store as frozen embryos. A depository of frozen

embryos, funded by the NIH, will alleviate the waste

of these potentially valuable resources. A website 

at NIH listing the available shared resources such 

as these frozen embryos would be useful.

• Exploratory research technologies. Many currently 

available technologies, such as cDNA microarrays,

subtraction libraries, gene ablation techniques, 

and the genomic project, are mainly exploratory 

in nature (as opposed to hypothesis-driven). 

These technologies have generated extremely useful information and surprising new insights into 

a variety of human diseases. The use of such technologies is grossly under-funded in the urothelial

field, and their use needs to be encouraged by the

National Institute of Diabetes and Digestive and

Kidney Diseases (NIDDK). Requests for Application

(RFAs) in these areas would be highly desirable.
In October 2000, Randy Hunter noticed blood in his urine. 

When it didn’t go away after a few days, he went to his primary

care physician, who thought it might be a bladder infection 

and treated him with a course of antibiotics. The bleeding 

continued, however, and Hunter’s doctor referred him to a 

urologist who performed a cystoscopy, a procedure that uses 

a fiberoptic scope to view the inside of the bladder. During that

procedure, a tumor was discovered, and it was resected along

with a portion of the bladder muscle. A biopsy revealed that

Hunter, age 44, had invasive bladder cancer.

“It surprised both my doctor and me because of my relatively

young age at the time and because I was not a smoker and 

didn’t drink alcohol excessively,” Hunter says. He also notes 

that he had never lived in rural areas where there are wells that

could be contaminated with carcinogens or in areas with known

industrial toxins in the environment. Hunter also puzzles over

the fact that he had no symptoms before the blood appeared,

although in retrospect, he did have a problem sitting through

the duration of his sons’ soccer games. 

A week and a half after cancer was diagnosed, Hunter’s 

bladder, prostate gland, and surrounding lymph nodes were

removed, and a urinary diversion was performed. A urinary

diversion involves connecting the ureters to a portion of the

small intestine, usually the ileum or jejunum, which is looped

off and used as reservoir for urine. While the ureters are 

inserted into one end of the loop, the other end is fashioned

into a stoma and is brought out through the skin. 

In a traditional urinary diversion such as an ileostomy, a plastic

bag is sealed to the skin around the stoma, and urine collects

in the bag. However, Hunter’s surgeon performed a relatively

new procedure called a continent urinary diversion, which

means that Hunter can retain urine in the intestinal reservoir

and use intermittent catheterization to drain it. Patients who

have this procedure do not have to wear a bag. 

In the continent urinary diversion, the surgeon uses a portion 

of the bowel where the small intestine joins the large intestine.

This area has a natural valve that can be incorporated into the

stoma, allowing the stoma to close until a catheter is inserted

and the urine is drained. The stoma is usually located near 

the navel. Patients who have a urinary diversion can remain

continent between catheterizations.

After two weeks in the hospital, “basically getting my strength

back and dealing with the hoses coming out of me,” Hunter 

was discharged with a temporary urinary catheter and two

abdominal drains. “It was a little rough for a while,” he says. 

During his first few weeks at home, Hunter had to learn to

change his bandages and flush the catheter so that it wouldn’t

become clogged from the mucous that is normally manufactured by the intestinal mucosa. 

“The first few times it was a little scary,” says Hunter, who had

visiting nurses helping him, “but once I learned the routine and

learned to recognize when it was becoming clogged, I got used

to it.” The routine became easier after the catheter and drains

were removed in the third week after surgery. 

At first, Hunter catheterized himself intermittently every 

three hours, but gradually moved up to four as his intestinal

pouch stretched. “You think that three hours is not a problem,

but you have to plan your life so that you can be near a 

bathroom,” Hunter explains. “Some public restrooms aren’t 

that convenient or clean.”

28 OVERCOMING BLADDER DISEASE

PATIENT PROFILE

Randy Hunter 

Bladder Cancer, Cystectomy, Urinary Diversion
A Strategic Plan for Research 29

Wherever he goes, Hunter carries with him disposable 

catheters and lubricating gel. Catheterization must be as 

clean as possible to avoid infection. Although he can now 

drain the catheter directly into the toilet, in the first few weeks

of this routine, he had to measure the urine to be sure that 

the reservoir was draining properly. To do this, he had to 

carry a container as well. 

In addition to catheterizing himself periodically, Hunter also 

has to irrigate the reservoir by flushing it with saline solution.

This is to ensure that the reservoir and stoma are not clogged

by mucous. He also drinks a lot of fluid to dilute the urine 

and mucous.

When Hunter returned to his job as an information technology

specialist, he was worried that he wouldn’t remember to

catheterize himself and the reservoir would leak, so he set 

his watch alarm, something that aroused the curiosity of his

co-workers. Now, he is able to sense when his “bladder” is

full. He can even sleep through the night without waking 

up to drain it.

Eighteen months after surgery, Hunter visits his urologist and

oncologist every three to four months for a physical exam and

blood work, and a CT scan is done every other visit. Hunter is

able to play tennis with his twin sons, who are 17, and take 

his 13-year-old daughter to her activities. He has also played

some golf. Last April he and his wife went on a cruise, and 

he went swimming for the first time since his surgery. He has 

also become involved with the American Cancer Society’s

Relay for Life and is serving on the organizing committee 

this year.

Hunter feels fortunate that his cancer had not spread to 

the lymph nodes and that he did not need chemotherapy 

or radiation. He remains puzzled, however, about why he

developed bladder cancer in the first place. He would like

research to find out why. He would also like to educate people

about the signs and symptoms of bladder cancer, how to 

prevent it, and the types of treatment that are available for it.

“Every day I’m reminded of what I went through. I see the 

scar and the stoma in the mirror,” he says. “I want others to 

not have to go through this.”
CHAPTER 2
A Strategic Plan for Research 31

Basic Science of the Lower Urinary Tract

CONNECTIVE TISSUE AND MATRIX

Summary and Recommendations

Despite the biological and medical importance of connective tissue, little is

known about the chemical, physical, and mechanical characterization of this

tissue and how it may become altered during development and disease or as a

result of normal aging, childbirth, hormonal deprivation, and mechanical

deformation or stretch. Little is also known about the potential risk factors 

for disease or protective factors that are related to connective tissue.

After an extensive review of past and current research on connective 

tissue of the bladder, the Bladder Research Progress Review Group 

made the following suggestions:

* Develop better methods to image the bladder, preferably using nonor minimally destructive approaches

* Develop a rapid method to map the complete bladder wall fiber structure 

The major stress bearing fibers of the bladder wall (smooth muscle and 

collagen fibers) can withstand high tensile force but have low torsional 

and flexural stiffness. Thus, identifying the directions in which the tissue 

is able to withstand the greatest tensile stresses will identify the directions 

in which the fibers are oriented. Fiber orientation leads to an understanding and predictability of the mechanical properties of the tissue. Although 

available microscopic techniques can provide quantitative information 

on fiber structure, this information is by definition highly localized, 

making it difficult to quantify larger scale fiber structural features.

* Develop a method of auto identification and segmentation from imaging data 

to streamline the processing of collagen, smooth muscle, cellular material, 

vasculature, and elastin

* Convert structural information into databases suitable for immediate use 

(e.g., bioinformatics and computational biomechanics applications)

DID YOU KNOW?

. Significant alterations in connective tissue of the lower urinary

tract occur in pelvic organ 

prolapse, diabetes, incontinence,

interstitial cystitis, nervous 

system diseases, and obstruction.

. Connective tissue serves as 

a scaffold for cells and as a 

repository for growth factors,

cytokines (proteins that regulate

the intensity and duration of 

the immune response), and

inflammatory factors. 

. Reciprocal cell signaling 

pathways in connective tissue 

are important during development,

wound healing, and disease 

progression, but they are 

incompletely understood. 
32 OVERCOMING BLADDER DISEASE

* Investigate the following: 

• What are the physical limits on the interactions

between epithelium and other layers within the

bladder wall?

• Is communication based upon cell-cell contact,

diffusion of materials between cells or systemic

circulation, or a combination of any of these?

Background

Connective tissue is the material between the cells of the

body that gives various tissues form and strength. This

composite of structural macromolecules or extracellular

matrix is also involved in delivering nutrients to the 

tissues and in the special functioning of certain tissues.

Connective tissue also connects and supports other 

tissues of the body, and, with few exceptions, is highly

vascular. It differs from many other types of tissue

because it contains relatively few cellular elements 

and abundant non-cellular material.

Structure and Function in the Urinary Tract

Connective tissue connects the various layers of tissues

lining the urinary tract. Nerves, blood vessels, and

lymph vessels also lie within its supporting structure. 

In the lower urinary tract, connective tissue connects the

layers of the mucous membrane to each other and to

underlying parts. The mucous membrane of the urinary

tract is continuous with the reproductive system in both

males and females.

Connective tissue is composed of cells separated from

one another by a semi-fluid ground substance composed

of fibrillar proteoglycans and tissue fluid. This extracellular compartment delivers supplies from the blood to

the cells and carries cellular waste products back to the

blood and lymph. The matrix contains an irregular network of collagenous bundles and elastic fibers, the principal structural features of connective tissue. The collagenous bundles are composed of collagen molecules

that are members of a family of structural proteins.

Collagen bundles contain many covalently crosslinked fibers that provide great tensile strength but not

flexibility. In the bladder, collagen fibrils form a sheath

around bundles of muscle fibrils and connect them. 

The elastic fibers of connective tissue contain a protein

called elastin. 

Other cells also lie within the extracellular matrix; these

cells include plasma cells, macrophages, mast cells, and

blood cells. Macrophages and mast cells perform

immune system activities. Macrophages ingest and

digest other cells, such as bacteria and foreign particles,

and are involved in producing antibodies; mast cells

produce heparin, histamine, and other proteolytic

enzymes and are involved in immediate hypersensitivity

reactions to perceived foreign substances. Mast cells may

also play a role in the maintenance of the matrix.

Fibers found in the matrix interact with a variety of 

other proteins. The quantity and arrangement of these

components have an impact on the non-cellular matrix;

therefore, characterization of the matrix could provide

important information about the passive properties of

the bladder wall, ureters, and pelvic floor. 

Of equal importance are the interactions that occur

between the cells residing within connective tissues 

and the structural macromolecules themselves.

Connective tissues can serve as a scaffold for cells and 

as a repository for growth factors, cytokines (hormonelike proteins that regulate the immune response),

inflammatory factors, and factors that support or prevent

the growth of blood vessels. As these materials act on 

the cells residing within connective tissues, the cells 

in turn may express altered phenotypes (forms) whose

secreted products change the composition of connective

tissue. These alterations can compromise the structural

integrity and strength of connective tissue, thereby

altering its physiologic function. 

The dynamic nature of reciprocal cell signaling pathways

is incompletely understood; however, these processes

are important during development, wound healing, 

and disease progression.
A Strategic Plan for Research 33

Bladder Muscle and Connective Tissue

The normal, unstretched bladder has muscle bundles

called fascicles, which are of varying sizes, lengths, and

orientation. The fascicles run as geodesic lines around

the bladder, sometimes leaving discontinuities. 

A collagen sheet surrounds each muscle fascicle, and

wavy collagen bundles connect the muscle fascicles to

each other. Each collagen bundle is in a helical coil 

that lengthens and thins during distention of the 

intact bladder. 

Elastin has been found on the surface of muscle fascicles

as well as within them. Because they are bundled and

surrounded by collagen and elastin layers, the muscle

fascicles can move independently and contract freely. 

In addition, the bundled structure allows for large

stretches to occur in the bladder wall.

Dysfunctional Connective Tissue in the Bladder

The status of connective tissue in the lower urinary 

tract affects its physiologic function. It also affects other

tissues that are structurally associated with connective

tissue. Although connective tissue is passive, that is, 

it does not require metabolic energy for its function,

connective tissue forms the structural and architectural

framework upon which tissue integrity and tensile

strength are based. Diseases and conditions such as

pelvic organ prolapse, diabetes, interstitial cystitis, 

neuropathic bladder, and obstruction of the lower 

urinary tract in men secondary to benign prostatic

hyperplasia (BPH) or prostate cancer are all characterized by significant alterations in connective tissue. 

Despite the biological and medical importance of 

connective tissue, little is known about the chemical,

physical, and mechanical characterization of this tissue

and how it may become altered during development 

and disease, or as a result of normal aging, childbirth, 

hormonal deprivation, and mechanical deformation,

that is, stretch or compression. Little is known about 

the potential risk factors or protective factors that are

related to connective tissue.

Connective tissue diseases or their pathologies are

broadly interpreted to include deterioration of the 

fundamentally passive mechanical and structural 

characteristics of tissues that contain connective tissue.

Weakened connective tissue, whatever the cause, most

likely plays a role in incontinence. An example is the

long-established association of urinary incontinence

with menopause. This association strongly suggests 

that estrogen loss contributes to connective tissue 

deterioration, perhaps by decreasing the total collagen

content in tissues.

Incontinence is a clinical symptom of altered connective

tissue. It is caused by increased laxity of the pelvic floor,

the sphincter muscle of the urethra, and associated

structures and also by altered storage properties of the

bladder. These alterations can occur during vaginal

delivery or because of hysterectomy and subsequent

pelvic organ prolapse. 

Elastic Fiber

Stretch

An illustration of the arrangement of elastic fibers of connective 

tissue at rest and during stretching. (Courtesy of Charles Curry, 

PA-C, University of Florida Physician Assistant Program)
34 OVERCOMING BLADDER DISEASE

Alterations in connective tissue can also affect children.

Obstructive disorders of the lower urinary tract, secondary to either physical obstruction or obstruction caused

by nervous system diseases, can be present and cause

changes in bladder architecture that involve fibrosis, 

the formation of abnormal amounts of collagenous 

fiber bundles in the connective tissue matrix of the 

bladder wall. Fibrosis of the bladder causes loss of 

bladder elasticity, which can interfere with urine 

storage and cause kidney damage. 

Abnormal matrix development in young bladders may

not be clinically evident until later in life. The cause 

of this process is largely unexplored.

Men with BPH experience an increase in the connective

tissue of the bladder wall in response to the mild

obstruction, and men with post-prostatectomy incontinence may have damage to urethral connective tissue.

Mature adults often have age-related changes to the

bladder and urethral tissue, including increased tissue

fragility, decreased elasticity, and alterations in force

generation. Neurologically compromised patients may

also have bladder dysfunction and associated alterations

in connective tissue.

Research Advances and Opportunities

A review of the current active portfolio at the National

Institutes of Health (NIH) identified a total of 16 grants

that partly or fully study connective tissue research;

however, none of these grants involves connective 

tissue of the lower urinary tract. Although several 

recent advances have been made in the understanding 

of connective tissue of the lower urinary tract and the 

role it plays in disorders, much still needs to be done.

Immunohistochemistry and gene expression, regeneration, genomics and proteomics, and cell signaling and

regulation are discoveries that can be built on to further

our understanding of connective tissue function in 

lower urinary tract disorders. 

Immunohistochemistry and Gene Expression

Studies reported in 1996 that bladder dysfunction in

pediatric patients is characterized by excessive deposition of several collagen types within the muscle bundles

of the bladder wall. Immunohistochemistry has demonstrated that this fibrosis consists of two types of collagen,

types I and III. Researchers observed that when collagen

gene expression increased, protein deposition increased.

This correlation suggests that bladder dysfunction alters

gene expression in the cells of the bladder wall. Because

they are accompanied by compromised bladder elasticity, these alterations in connective tissue could adversely

affect the physiologic function of the bladder.

Regeneration

Another 1996 study suggests that the bladder has an

uncanny ability to regenerate. Researchers partially

removed the bladders of rats and sutured a tissue matrix

devoid of all cellular elements to the defect. The exact

composition of this acellular matrix was unknown, but 

it likely contained collagen, elastin, and other non-cellular matrix elements. Within four days, the epithelium

completely covered the acellular matrix, and within two

weeks, native smooth muscle was seen streaming into

the acellular matrix in association with a new epithelium. 

Prostate

Bladder

Urethra Rectum

The enlarged prostate gland in benign prostatic hyperplasia or BPH

squeezes the urethra, causing an increase in bladder pressure that results

in an increase in connective tissue and a subsequent thickening of the

bladder wall. (Photo Credit: The American Foundation for Urologic Disease)
A Strategic Plan for Research 35

It is hypothesized that cellular interactions between the

epithelium, non-cellular matrix, and the embryonic

mesenchyme facilitate new growth of smooth muscle.

The ability to use an acellular matrix to regenerate 

portions of the bladder wall underscores the importance

of connective tissue in promoting the normal architectural regeneration of bladder wall tissues and raises 

the expectation that new therapies will eventually be

developed based on this type of research. 

Genomics and Proteomics

Research opportunities also exist in the areas of

genomics and proteomics. Tissue samples from persons

with disorders of the lower urinary tract can be analyzed

at the genomics level to characterize global gene expression. Similar types of studies of proteins found in 

urine and blood and in lower urinary tract tissues can 

be done in proteomics. Genomics and proteomics may

ultimately help to determine 

• A common genotype or phenotype that exists for

women with stress incontinence

• The genomic and proteomic “fingerprint” of each of

the cell types within the lower urinary tract

• Genomic and proteomic fingerprints that can be used

to define a “normal” cell phenotype

• Genomic and proteomic fingerprints that differ 

in males and females, young and old, people with

neurogenic bladders, people with Parkinson’s 

disease, and other groups

Cell Regulation and Cell Signaling 

The urinary bladder is formed in the embryo from 

(1) epithelial cells derived from the endoderm and 

(2) mesenchymal cells derived from the urogenital sinus

and allantois. Bladder mesenchyme differentiates into

bladder smooth muscle via an unknown signaling mechanism originating from the epithelium. This signaling

between the epithelium and mesenchyme hypothetically

occurs through diffusion of growth factors. 

Supporting this hypothesis is evidence that a number of

known growth factors and their receptors are regulated

as a function of bladder development and are also modulated during experimental bladder outlet obstruction.

Furthermore, growth factors most likely affect degradative proteins in the non-cellular matrix. These proteins

play a role in bladder remodeling during development

and in partial outlet obstruction. An alternative hypothesis is that signaling in embryonic bladder development

occurs via the non-cellular matrix and connective tissue. 

Cell signaling also occurs after the bladder has formed,

for example during bladder injury. KGF, a growth factor

secreted by the bladder’s connective tissue framework, 

is directly responsible for the proliferation of epithelium

during bladder injury. KGF acts directly on the epithelium, which harbors the receptor. In humans, bladder

epithelium turns over once or twice a year and has 

the incredible ability to immediately proliferate when

injured, covering the exposed areas of bladder muscle

and submucosa, the layer of connective tissue 

underneath the mucous epithelium. 

It follows that the ideal cellular lining for the bladder 

is epithelium. However, for patients requiring bladder

enlargement, the bladder is often augmented with 

intestinal or gastric segments. This procedure creates

numerous problems because the tissues that are used 

are structurally and functionally different from bladder

tissue. Studies suggest that cell signaling between the

bladder epithelial cells and the intestinal stroma 

(muscle and non-cellular matrix) leads to changes 

in the epithelium (urothelium). 

This hypothesis was tested by tissue recombination

experiments performed by combining rat and mouse

rectal mesenchyme and stroma with epithelium from

embryonic, newborn, and adult mice or rats, respectively. Both mouse and rat epithelium were changed to a

glandular morphology under the influence of rectal 

mesenchyme. The epithelial transdifferentiation into

glandular epithelium was not a function of epithelial 

age and occurred in the embryonic, newborn, and 

adult epithelium. Likewise, rectal mesenchyme from 
36 OVERCOMING BLADDER DISEASE

embryonic, neonatal, and adult animals induced 

glandular differentiation in bladder epithelium 

(urothelium).

In summary, cell signaling is important in bladder

development, bladder injury, and bladder regeneration.

The components of the bladder—urothelium, extracellular matrix, and muscle, along with nerves and 

blood vessels—are involved in this signaling process.

Elucidating this process is crucial for a better understanding of both normal and abnormal lower urinary

tract development. 

Specific Opportunities for Connective 

Tissue Research

Specific opportunities for connective tissue and matrix

research exist in the following areas, based on recent

research discoveries:

* Immunohistochemistry and Gene Expression 

• Explore how bladder dysfunction alters gene

expression in the cells of the bladder wall

• Determine how alterations in connective 

tissue adversely affect the physiologic function 

of the bladder

* Regeneration

• Explore how the bladder regenerates

• Determine the cellular interactions among the

urothelium, the non-cellular connective tissue

matrix, and the mesenchyme that facilitate new

growth of smooth muscle

• Develop new therapies involving the use of an 

acellular matrix to regenerate portions of the 

bladder wall

* Genomics and Proteomics

• Determine whether a common genotype or phenotype exists for persons with stress incontinence

• Identify the genomic and proteomic “fingerprint”

of each of the cell types within the lower 

urinary tract

• Investigate whether genomic and proteomic 

fingerprints can be used to define a “normal” 

cell phenotype

• Establish whether genomic and proteomic 

fingerprints differ in males and females, young

and old, people with neurogenic bladders, people

with Parkinson’s disease, and other groups

* Cell Regulation and Cell Signaling 

Cell signaling is important in bladder development,

bladder injury, and bladder regeneration. The components of the bladder—epithelium, non-cellular

connective tissue matrix, muscle, nerves, and blood

vessels—are clearly involved in this signaling process.

A better understanding of this process is critical to

understand both normal and abnormal development.

• Explore cell signaling between the epithelium and

mesenchyme that hypothetically occurs through

diffusion of growth factors. (According to research

evidence, a number of known growth factors and

their receptors are regulated as a function of bladder development and are also modulated during

experimental bladder outlet obstruction.) 

• Investigate the growth factors that most likely

affect non-cellular matrix degradative proteins,

which play a role in bladder remodeling during

development and in partial outlet obstruction 

• Explore the alternative hypothesis that signaling 

in bladder development occurs via the noncellular matrix and connective tissue

• Determine the role of the non-cellular connective

tissue matrix scaffold in the cell signaling that

occurs in healing epithelial injury
A Strategic Plan for Research 37

Future Research Areas

Future research areas important for understanding 

connective tissue and matrix of the lower urinary tract

include cell differentiation and matrix elements, matrix

proteins, genomics and proteomics, animal model

development, bladder mechanics, gene expression,

behavioral techniques, and people with special needs.

Cell Differentiation and Matrix Elements 

Future research on the lower urinary tract must define

the elements that maintain the differentiative state 

of cell types within the lower urinary tract and pelvic

floor. Tissue engineers and other researchers who 

study the effects of obstruction, aging, and pathology 

on the bladder would benefit from information about 

matrix elements. Questions for researchers are 

as follows:

• What factors control the phenotypic stability 

of individual cell types in the bladder, urinary 

sphincter, ureter, and pelvic floor?

• Are these factors age-, hormone-, cytokine-, 

or sex-dependent?

• What is the role of the non-cellular connective 

tissue matrix in maintaining cellular phenotype?

Does the matrix change with age?

• Does the matrix sequester cytokines, hormones, 

and other factors that influence cellular type?

• What signals emanating from the matrix influence

the epithelium?

• Do integrins—non-cellular matrix receptors that 

play a role in cell adhesion—alter cell behavior? 

If so, which integrins, and do these types of 

interactions change with pathology, with aging, 

and during development?

• What is the role of the epithelial and smooth 

muscle basement membranes in maintaining 

cellular phenotype? 

• How do cells interact with the matrix?

• Are there specific receptors for domains within 

individual matrix macromolecules? 

• How are such receptors acquired? Do they become

altered in disease?

• What are the basic elements of cell-matrix 

interactions?

• How does the matrix control smooth muscle cell 

differentiation? What molecules are involved?

• Can these events be duplicated using stem cells 

or other forms of undifferentiated cells?

Matrix Proteins

Little is know about the function of protein fragments

derived from matrix proteins. These types of fragments

can be generated by a variety of mechanisms that decompose proteins and might be expected to have profound

biological activities. Questions for research to answer 

are as follows:

• Does degradation of the matrix lead to phenotypic

modulation of cells that interact with degraded matrix

components? 

• What types of materials involved in degradation are

normally present within the normal bladder, the

developing bladder, and the diseased bladder? 

• How are these enzymes modulated?

• Does age alter the normal complement of degradative

enzymes present?

• Does the hormonal environment alter these same

degradative enzymes?

• What types of matrix macromolecules do all cell 

types in the bladder produce? 
38 OVERCOMING BLADDER DISEASE

Genomics and Proteomics 

Genomic and proteomic studies of tissue-specific 

gene and protein expression would provide valuable

information on the specific complement of genes and

proteins that defines bladder, urethral, ureteral, and

pelvic floor tissues.

Animal Model Development

Another potentially valuable area is the development 

of animal models to study interactions between the 

mesenchyme and the epithelium. Questions that

research needs to answer are as follows:

• Are certain types of chemical compounds sequestered

within the matrix?

• What are the causes of urinary incontinence and

pelvic organ prolapse in women?

• What behavioral therapies (e.g., stretching and

strengthening exercises) will help women maintain

normal connective tissue?

• Does diet, including vitamin C, improve post-operative outcome and overall connective tissue strength? 

Bladder Mechanics 

Little is known about the manner in which the bladder

can mechanically accommodate large-volume variations.

Questions for research include:

• How are the mucosal and bladder muscle (detrusor)

layers connected?

• Can these connections be mechanically characterized?

• What is the three-dimensional structure of the 

bladder wall in both health and disease?

• How is tension generated through the interactions 

of the proteins, actin and myosin conveyed across 

the cell membrane to the non-cellular matrix and 

to other tissue layers in the bladder wall?

Gene Expression

The ability to evaluate gene expression at the cell-type,

tissue, and organ level is also lacking in lower urinary

tract research. Some of the problems in this area are

technology-based and concern the inability or difficulty

individual researchers have in accessing appropriate

technology to carry out high throughput (the number 

of tests that can be performed in a given period of time)

experiments at the cellular and molecular levels. For

example, tissue-specific and cell-type-specific marker

proteins for lower urinary tract cells are largely

unknown. With the appropriate characterization of 

individual cell types within the bladder wall, pelvic 

floor, and other structures of the lower urinary tract,

characterization can be accomplished. This characterization will lead to the development of specific reagents 

and cDNA probes to permit further refinement of the

traits of each of the cell types unique to the structures

and tissues being studied. 

The development of these tools will enhance the 

research capabilities of investigators and permit 

them to use genomic and proteomic tools to formulate 

hypothesis–driven research. Such tools are being 

made available to researchers of other organ systems,

and similar efforts should be undertaken to ensure 

that bladder research successfully takes advantage of 

information provided by the Human Genome Project. 

Behavioral Techniques

Questions for future behavioral research are as follows:

• Can behavioral techniques such as biofeedback and

exercise improve urinary function?

• Are there behavioral manifestations of the aging

process that affect urination?

• Does exercise improve the long-term health and

physiologic function of the lower urinary tract? 
A Strategic Plan for Research 39

People with Special Needs 

Connective tissue research directed at groups 

of patients with special needs is also important. 

These groups include

• Children with lower urinary tract disorders 

that may predispose them to kidney damage

• Adults with spinal cord injury or other illnesses 

that compromise lower urinary tract function

• Aging adults who show progressive deterioration 

of urinary function and its associated morbidity

• People with diabetes

• Women with interstitial cystitis

• Women at risk for developing urinary incontinence

and pelvic organ prolapse

In regard to the latter, research on rectal prolapse 

has indicated that joint mobility might be a possible

marker for connective tissue abnormalities of the 

lower urinary tract. 

In addition, there is a great need to understand 

the molecular changes that occur in the connective 

tissue of pregnant women. Connective tissue of the

uterus increases tenfold during pregnancy, then 

disappears within a few weeks after childbirth. With

pregnancy, women often experience the simultaneous

onset of urinary tract infections. Because joint mobility

is well documented during pregnancy and resolves after

childbirth, some bladder injury involving damage to

connective tissue might occur during childbirth. 

Investigations into using the presence of striae, bands 

of connective tissue that appear on the abdomen of some

pregnant women, and joint mobility as indicators or

markers of potential connective tissue damage might

reveal information that would motivate clinicians to

modify the mode of delivery and prevent bladder injury

during childbirth.
CHAPTER 3
A Strategic Plan for Research 41

Basic Science of the Lower Urinary Tract

MUSCLE

DID YOU KNOW?

. Many diseases and conditions

such as diabetes, Parkinson’s

disease, stroke, and multiple

sclerosis have a significant

impact on bladder muscle.

. Failure of bladder muscle to

function properly can lead to

recurrent infection, incontinence,

urine retention, voiding dysfunction, irreversible muscle failure,

and disease in other parts of the

urinary tract such as the kidney.

Summary and Recommendations

Understanding normal muscle structure and function and the changes that lead

to bladder disease is critically important to public health. However, compared

with the current understanding of other muscle types, such as those of the heart

or blood vessels, the understanding of lower urinary tract muscle is woefully

inadequate. Poor funding and lack of research in this area have contributed

substantially to this situation. 

To improve prevention and treatment of lower urinary tract disorders, more

research must be done to elucidate the functions of normal myocytes—the cells

that form muscle—and to understand the impact of age and disease on these

cells. Correction of altered muscle cell function can correct the symptoms of

bladder dysfunction; therefore, the Bladder Research Progress Review Group

recommends that the National Institutes of Health (NIH)

* Conduct more basic studies of the muscle structure and function of the urinary and

reproductive systems, including studies of 

• Biomechanics

• Comparative muscle physiology (i.e., urethral smooth muscle versus 

bladder smooth muscle; urethral sphincter versus rectal sphincter)

• Characteristics of receptor and effector pharmacology and cell signal

transduction in smooth muscle of the urinary and reproductive tracts

• Three-dimensional anatomy and its correlation with function
42 OVERCOMING BLADDER DISEASE

* Conduct more molecular, cellular, and tissue investigations

into lower urinary tract muscle deterioration and failure.

Examples of interesting modulatory factors to be studied

include

• Nerve factors

• Growth factors

• Programmed cell death (apoptosis)

• Progenitor cells (i.e., stem cells)

• Trauma (i.e., vaginal delivery)

• Hormones

• Aging

• Development

* Develop new imaging technologies and apply non-invasive

methods from other fields (e.g., cardiology) to assess 

muscle function in the body

* Conduct studies of the basic disease mechanisms, 

prevention, and treatment of end-stage bladder failure

* Investigate smooth and skeletal muscle stem cells, their

role in normal development, and their use in regeneration

Background

Because the bladder is predominantly a muscular organ,

muscle disorders are common and clinically significant.

Failure of the bladder muscle to function properly can

lead to infection, incontinence, urine retention, voiding

dysfunction, irreversible muscle failure, and disease in

other parts of the urinary tract such as the kidney. 

Muscle tissue, like other tissue, is composed of cells and

non-cellular substance located outside the cells. Muscle

cells or myocytes are elongated and are called fibers.

These fibers are embedded in areolar connective tissue. 

Normal Bladder Muscle

The normal, unstretched bladder has muscle bundles 

or fascicles of varying sizes, lengths, and orientation 

that are surrounded by a collagen sheet. Connecting 

the fascicles to each other are wavy collagen bundles 

that form helical coils, which lengthen and thin during

distention of the intact bladder. Running as geodesic

lines around the bladder, the muscle fascicles cover 

the shortest distance between two points, sometimes

leaving discontinuities. 

Elastin has also been found on the surface of muscle 

fascicles. Bundled and surrounded by collagen and

elastin layers, the muscle fascicles can move independently, which allows them to contract freely. In addition,

this bundled structure allows for large stretches to occur

in the bladder wall. 

Bladder muscle has three layers: an inner longitudinal

layer, a middle circular layer, and an outer longitudinal

layer. Where the bladder opens into the urethra, the 

circular fibers are thick and form a sphincter muscle 

that is normally in a state of contraction. The sphincter

relaxes only when nerves, reacting to the accumulation 

of a quantity of urine, send signals to the brain that it is

necessary to release the urine. Disorders affecting the

muscle of the bladder wall often affect the ureters and

the bladder outlet, and vice versa. 
A Strategic Plan for Research 43

Bladder muscle, like all muscle, has several distinguishing characteristics:

• Irritability (excitability)—muscle cells receive 

stimuli and, like all cells, respond to it

• Contractility—muscle cells can change shape and

become shorter

• Extensibility—muscle cells can stretch

• Elasticity—muscle cells can readily return to their

original form when the stretching force is removed

Because the underlying epithelium, nerves, and bloodborne hormones and modulators, including urine substances under certain conditions, can affect bladder

muscle cells, diverse arrays of cell signaling mechanisms

can affect the physiology of the muscle cell as well. In

addition, more than one receptor-effector system is

likely to be activated at any point in time in any given

muscle cell.

Research on smooth muscle has indicated that regional

hormonal mechanisms may be involved in the stretchevoked release of excitatory substances from smooth

muscle and that these substances may drive smooth

muscle activity. This type of research could have a 

major impact on conditions that involve instability 

of the bladder muscle, which can cause incontinence.

Muscle Dysfunction

The bladder is predominantly a muscular organ.

Disorders of the bladder and urethral sphincter are

common and of significant clinical importance. Bladder

muscle dysfunction can lead to infection, incontinence,

urine retention, voiding dysfunction, and eventually,

irreversible muscle failure or end-stage bladder failure.

Other parts of the urinary tract such as the kidney may

also eventually be affected. 

Common symptoms of bladder muscle dysfunction and

other lower urinary tract muscle disorders are

• Frequency and urgency

• Incontinence and pelvic floor disorders

• Urine retention (i.e., end-stage bladder failure)

• Upper urinary tract diseases, such as hydronephrosis

(blockage) 

• Bladder muscle overactivity

In turn, aging and various disease states affect the 

detrusor muscle of the bladder and its associated lower

urinary tract musculature. Some primary diseases and

conditions are 

• Diabetes mellitus

• Injury from therapies such as radiation and surgery

• Neurologic dysfunction (hypocontractility) resulting

from multiple sclerosis, Parkinsonism, spinal cord

injury, stroke, and developmental anomalies

• Overactive bladder (hypercontractility), detrusor

muscle instability (with or without impaired 

contractility), and pelvic floor disorders

• Interstitial cystitis 

• Obstruction caused by benign enlargement of the

prostate gland (benign prostatic hyperplasia or BPH)

and prostate cancer

• Effects of vaginal delivery

• Vascular injury
44 OVERCOMING BLADDER DISEASE

Research Advances and Opportunities

Advances

Studies have been underway to develop gene therapy for

stress incontinence. The concept behind this potential

therapy is to build up the deficient urethral sphincter

muscle. To achieve this, tissue engineering or cellbased ex vivo gene therapy appears to be more logical

than conventional viral vector gene therapy. According 

to one study, muscle-derived, cell-based tissue 

engineering (autologous cell transplantation) may 

have several advantages over the current treatment 

for urinary incontinence—bovine collagen injection. 

The advantage of autologous cell transplantation is that

the transplanted cells will not cause an immune system

or allergic reaction and, therefore, will survive longer

than injected collagen, which is derived from cows.

Transplanted cells can also serve as a natural bulking

agent when injected into the bladder and urethra, and

they may form muscle fibers that become part of the 

host muscle. Therefore, the transplanted cells serve 

as a blocking agent and are physiologically capable of

improving bladder (detrusor) muscle contractility. 

A study of this technique demonstrated three facts in 

the emerging field of urologic tissue engineering: 

• Injecting skeletal-muscle-derived cells into the 

urethal sphincter is feasible

• Gene transfer to the bladder and urethra is feasible

• Injected human-muscle-derived collagen has greater

persistence than injected bovine collagen 

In the autologous cell transplantation procedure 

currently being developed to construct functionally 

and anatomically normal, tissue-engineered bladders, 

bladder urothelial and muscle cells newly isolated from

an animal attached to biodegradable matrices (scaffolds)

in vitro. When implanted in vivo, these cells reorganized

into multi-layered structures. After implantation, the

supporting cell matrix became vascularized in concert

with expansion of the cell mass, thereby allowing cell

survival by diffusion of nutrients across short distances. 

Gene therapy has also recently achieved several 

important milestones with the development of tissue

engineered for bladder replacement using a small 

intestine scaffold seeded with bladder smooth muscle

and epithelium. In another development, cartilage cells 

were injected for the treatment of stress incontinence

and vesicoureteral reflux. Urge incontinence is another

disorder that would benefit from gene therapy. 

Possible gene therapy strategies for overactive bladders

and urge incontinence may include suppression of 

bladder muscle activity or neural pathways that trigger

the micturition (voiding) reflex.

A bladder engineered in the laboratory. (Photo Credit: Dr. Anthony Atala, 

Children’s Hospital and Harvard Medical School.) 
A Strategic Plan for Research 45

Opportunities

Research on lower urinary tract muscles has provided

numerous opportunities for furthering our understanding of lower urinary tract diseases. Research

opportunities exist in 

• Neuromodulation treatment of hyperactive and

underactive bladder muscle disorders.

• Magnetic resonance imaging (MRI) for detection 

of abnormalities in levator muscles.

• Data on the fine structure underlying overactivity 

and underactivity of bladder muscle in older adults.

• Improved understanding of smooth (visceral) and 

striated (skeletal) muscle physiology and cell biology 

in other organs; this understanding could be applied 

to the lower urinary tract in the future.

• Evidence that the striated muscle within the urethra

deteriorates at twice the rate present in other striated

muscles and is accompanied by the loss of intramuscular nerve axons. Also, a great many variations exist

in the number of viable fibers present among persons

of the same age. 

Understanding normal muscle structure, function, 

and the changes that lead to bladder disease is of 

critical importance to public health. Unfortunately, 

compared with the current understanding of other 

muscle types such as those of the heart or blood 

vessels, the understanding of lower urinary tract 

muscle is woefully inadequate. To improve prevention

and treatment of lower urinary tract disorders, more

research must be done to elucidate the functions of 

normal muscle cells and to understand the impact of 

age and disease on these cells. 
CHAPTER 4
A Strategic Plan for Research 47

Summary and Recommendations

Research on how the nervous system and vascular system influence dysfunctions of the lower urinary tract has many potentially important avenues for

progress. In the past decade, a major emphasis on research in neuroscience 

has advanced (1) knowledge about peripheral nerves and their relationship with

peripheral organs and (2) knowledge about the central nervous system (CNS)

and how it changes. These advances may have specific applications for research

projects that study the lower urinary tract. 

The development of transgenic models may also be necessary. Transgenic 

models are organisms in which new DNA has been introduced into the germ

cells by injection into the nucleus of the ovum (gene transplant). Some 

transgenic animal models already available for different disease states are 

of relevance to the bladder. These models could be used to determine whether 

it is possible to minimize the effect of injury to nerves or to accelerate their 

healing with such things as hormonal substances and nerve growth factors.

Based on a review of the current research portfolio at the National Institutes 

of Health (NIH), the Bladder Research Progress Review Group has made the 

following specific high priority recommendations for increased research 

funding and resources:

* Improve assessment and quantification of neural function of the lower urinary tract. 

* Improve knowledge of nerve cell-target interactions, endothelial factors, and 

epithelial factors

* Improve basic anatomic and physiologic information on gender and aging differences

in neural pathways involved in voiding (micturition)

* Develop strategies to protect nerves during critical life events and investigate 

neurotrophic factors and nerve regeneration in the lower urinary tract

* Improve basic anatomic and physiologic information concerning the impact of 

blood supply on lower urinary tract function

Basic Science of the Lower Urinary Tract

NERVES AND BLOOD VESSELS

DID YOU KNOW?

. Diseases and conditions of the

nervous system such as spinal

cord injury, multiple sclerosis, 

and Parkinson’s are highly 

associated with lower urinary 

tract dysfunction. 

. The specific or separate role of

nerves and blood vessels in the

development of lower urinary 

tract disorders is currently deficient or unknown and requires 

significantly more research.

. Possible gene therapy strategies

for overactive bladders and 

urge incontinence may include

suppression of nerve pathways

that trigger the micturition 

(voiding or urination) reflex. 

. Preliminary studies have also 

been done to determine the 

benefits of gene therapy for 

overflow incontinence caused 

by diabetic neurogenic bladder

dysfunction and interstitial 

cystitis (IC) and for bladder 

pain caused by IC.
48 OVERCOMING BLADDER DISEASE

* Advance genomics and proteomics technologies

* Develop novel therapies, technologies, and gene therapy 

for lower urinary tract disorders

* Define the neurotransmission principles unique to lower 

urinary tract function

Background

Normal functioning of the lower urinary tract depends

on intact and appropriate coordination of nerves in the

central and peripheral nervous systems. Unlike other

organ systems, the lower urinary tract absolutely

requires this coordinated control. The lower urinary

tract must also receive a blood supply that is not only

adequate, but also highly regulated and modulated. 

As a result, the lower urinary tract is affected by a wide

spectrum of circumstances and life events, many of

which have a basis in the nervous and vascular systems,

that interact and are interdependent in the lower urinary

tract. Pertinent examples include, but are not limited

to, degenerative diseases of the nervous system such 

as Alzheimer’s and Parkinson’s, spinal cord injury,

maternal birth trauma, diabetes, multiple sclerosis,

benign prostatic hyperplasia (BPH), post-surgical events

in both males and females, pelvic radiation therapy, 

and urinary incontinence. Spinal cord injury, multiple

sclerosis, and Parkinson’s disease in particular are 

highly associated with lower urinary tract dysfunction.

The specific or separate role of vascular factors in the

development of lower urinary tract disorders is currently

unknown and requires significantly more research. 

Because they play a central role in lower urinary tract

function, the nervous and vascular systems are also

involved in virtually every disorder or problem of the

lower urinary tract. If these problems are to be overcome

and even prevented, the neurovascular influences must

be vigorously investigated. 

Development of Bladder Control

The neurophysiologic mechanism of normal bladder

control involves bladder storage of urine and voluntary

evacuation. This mechanism is controlled by a complex

integration of sympathetic, parasympathetic, and 

somatic innervation that involves the lower urinary 

tract, the sacral spinal cord, the midbrain, and higher

cortical centers of the brain. 

Voiding starts in the fetus and is mainly by reflex at 

frequent intervals. Bladder filling triggers afferent

(inflowing) nerves that, through spinal reflexes, cause

relaxation of the external urinary sphincter. This results

in complete emptying of the bladder. By the time a child

is six months of age, bladder capacity has increased and

the frequency of voiding has decreased. 

Between one and two years of age, conscious sensation

develops, and by two to three years of age, the ability 

to initiate and inhibit voiding from the cerebral cortex

develops. At this time the lower urinary tract is most

susceptible to abnormal, learned input into the cerebral

cortex. This input may be as simple as telling a child 

not to wet his or her pants, no matter what—a command

that may lead to either appropriate socialization or 

a pathologic failure to relax the sphincter when it 

is appropriate. 

Storage and periodic voiding of urine by the bladder

requires coordinated and appropriate input from the

nervous system. The elements of the nervous system

involved in lower urinary tract control include

• Peripheral nerves in the bladder and in the wall

of the urethra

• Autonomic (organ) and voluntary (skeletal) 

sensory and motor nerves and ganglia

• Local (segmental) spinal circuits

• Long-loop connections to the brain stem 

(pons) micturition center, the center that 

controls urination
A Strategic Plan for Research 49

• Reciprocal connections between the cerebral 

cortex, the brain autonomic centers (centers 

that regulate nerve impulses activating smooth

muscles of organs and glands), and the brain 

stem micturition center 

Unfortunately, the current state of knowledge about 

neurovascular influences is extremely deficient. Current

behavioral, pharmacologic, and surgical treatments of

lower urinary tract disorders arising from problems 

in the nervous system are often inadequate, cause complications, and fail to eradicate the underlying condition. 

In addition, drugs used to manage these disorders are

restricted to compounds that affect neurotransmission

only in the peripheral nervous system (e.g., anticholinergics and alpha-adrenergic antagonists). More effective

and innovative approaches are needed.

Nervous system and vascular system contributions to

disorders of the lower urinary tract may be amenable 

to prevention or early intervention efforts. Certain 

conditions such as spinal cord injury are receiving

intense research funding, and collaboration with

researchers in these areas may elucidate information

that will enhance optimal lower urinary tract function 

in afflicted individuals. For example, well-studied 

progressive diseases of the nervous or vascular systems

may provide an opportunity to develop prevention or

early intervention programs that could reduce lower 

urinary tract malfunction. Also, identifying modifiable

obstetric practices may reduce maternal birth injury, 

a cause of urinary incontinence. These are high-yield

areas for research funding with immediate opportunities

for translational research and rapid clinical impact.

Research Advances and Opportunities

In the past decade, a major emphasis on research in

neuroscience has advanced knowledge about the peripheral nervous system and the organs it serves and about

the central nervous system (CNS) and how it changes.

These advances may have specific applications for

research projects that study the lower urinary tract.

Several important avenues for progress have developed

recently, including studies on brain imaging, biochemistry of the nervous system, interactions between 

nerve cells and target organs, nerve protection and

preservation, nerve regeneration, neurotrophic factors,

blood supply, genomics and proteomics technologies,

gene therapy and tissue engineering, and development

of transgenic models.

Brain Imaging

Recently, interest has focused on using new brain 

imaging methods to obtain insight into normal 

voiding, to localize brain abnormalities associated 

with incontinence, or to determine the site of action 

of pharmaceutical agents. 

These new methods rely on changes in the metabolism

or oxygen use of nerve cells in the brain to assess their

function during urination. When active, the nerve cells

use more oxygen and activate metabolic pathways whose

constituents can be monitored. When a person voids or

attempts to hold urine, very specific sites within the

brain and spinal cord are activated. These areas behave

differently as a person ages or if the brain has been

injured from lack of oxygen caused by obstruction of 

its blood supply. 

Studies in humans indicate that voluntary control of

voiding is dependent on (1) connections between the

frontal cortex of the cerebrum and a region of the 

hypothalamus and (2) connections between a small lobe

near the center of the cerebral cortex (the paracentral

lobule) and the brain stem. Lesions in these areas of 

the cerebral cortex appear to increase bladder activity

directly by removing the cortex’s inhibitory control.

Brain imaging studies in human volunteers have 
50 OVERCOMING BLADDER DISEASE

implicated two areas of the cerebrum—the frontal 

cortex and the anterior cingulate gyrus—as the areas 

of the brain that control urination and have indicated

that urination is controlled predominantly by the right 

side of the brain. Gyri are the prominent, rounded 

elevations that form the cerebral hemispheres.

Positron emission tomography (PET) has been used 

on human subjects to determine which brain areas are

involved in human micturition (urination). According 

to one study,

• Urination was associated with increased blood flow 

in four areas of the brain (the right dorsomedial 

pontine tegmentum, the periaqueductal grey, the

hypothalamus, and the right inferior frontal gyrus) 

• Withholding urine was associated with decreased

blood flow in the right anterior cingulate gyrus of 

the cerebrum

• Unsuccessful attempts to urinate were associated 

with increased blood flow in the right ventral pontine

tegmentum of the brain stem, an area that according

to animal studies appears to control the motor 

neurons innervating the pelvic floor, and in the 

right inferior frontal gyrus of the cerebrum. 

These results suggest that the human brain stem 

contains specific nuclei responsible for the control of 

urination, and that the regions for micturition in the

brain stem and the cerebral cortex are predominantly 

on the right side of the brain. 

The results of the PET study were in accordance with 

the results of a clinical study of patients with chronic

paralysis of one side of the body (hemiplegia). In this

study, which dealt with the chronic sequelae of stroke,

frequency and urgency of urination occurred more commonly in patients with lesions of the right hemisphere.

Such studies are extremely useful in delineating normal

and abnormal processes in the brain that are associated

with bladder disorders. With further study, these techniques may be useful for diagnosis or for planning therapy.

Another PET study, conducted in adult female 

volunteers, identified brain structures involved in 

the voluntary motor control of the pelvic floor during

rest, repetitive pelvic floor straining, sustained pelvic

floor straining, and sustained abdominal straining. 

The results revealed that two sections of the cerebrum

are activated during contraction of the abdominal 

muscles: the superomedial precentral gyrus (the most

medial portion of the cerebrum’s motor cortex) and 

the superolateral precentral gyrus, also in the cerebrum.

Significant activations were found in the cerebellum, 

the supplementary motor cortex, and the thalamus as

well. The portion of the cerebrum known as the right

anterior cingulate gyrus was activated during sustained

pelvic floor straining. 

Normal urethral sphincter function appears to be 

present in stroke victims whose lesions are restricted 

to the basal ganglia or thalamus. When these patients

sensed an impending involuntary bladder contraction 

or its onset, they were able to voluntarily contract the

sphincter muscle and stop, or considerably lessen, 

the effect of the abnormal urination reflex. Under the

same circumstances, people with lesions in the cerebral

cortex or internal capsule, the layer of white matter 

that connects the cortex to the brain stem, were unable

to forcefully contract the sphincter muscle. Thus, 

they have a profound abnormality in the cerebral-tocorticospinal circuitry necessary for voluntary control 

of the sphincter muscle. 

.

.

Increased activation of areas in the brain on positron emission 

tomography(PET scan), left, with voiding, right, with attempts 

to hold urine. (Photo Credit: Dr. Bertil Blok, University of Groningen,

Groningen, Netherlands)

PMC

L-region
A Strategic Plan for Research 51

Biochemistry Studies 

A variety of autonomic system disorders and emotional

disorders such as depression and anxiety are associated

with changes within the prefrontal cortex, the area of the

cerebrum responsible for biologic intelligence. Because

many emotional states are associated with overactive

bladder, neurochemical changes within this area of 

the brain may also have an impact on a range of voiding

dysfunctions.

Studies of the biochemical process that activates 

serotonin, a neurotransmitter that stimulates bladder

smooth muscle, have determined that the serotoninactivating system plays a major role in voiding as well 

as in emotional states such as depression, anxiety, and

eating disorders. Differences between men and women

in the operation of the serotonin-activating system 

may explain why certain psychiatric disorders such as

depression, anorexia, and bulimia, and certain disorders

of the lower urinary tract are more common in women. 

Women have substantially lower levels of 5-HT than 

men do. This substance is involved in the production 

of serotonin. In one study using PET scans, areas of the

brain that demonstrated lowered 5-HT function corresponded to areas of the brain that had a decreased blood

supply when subjects were instructed to hold urine. 

Data from several studies circumstantially support a 

role for reduced 5-HT activity or receptor function, 

hormonal influences, and linkage between brain sites 

for depression, hyperactive voiding, and altered 5-HT

activity. Studies such as these may help direct and 

monitor drug development for bladder disorders.

Interactions between Nerve Cells and Target Organs

Recent studies have revealed that communication

between nerves and their target organs is not unidirectional, as previously thought. The nervous system and

target organs have a chemical dialogue that is essential

for the normal functioning of the lower urinary tract, 

as well as for adaptation to pathological conditions. 

This dialogue, if dysfunctional, could contribute to a

variety of urinary tract disorders. 

Various examples of non-traditional, nerve-target 

organ interactions in the urinary bladder have been

identified, including

• Alterations in afferent nerves and efferent nerves

caused by neurotrophic factors (factors involved in

the nutrition and metabolism of nerve cells) that are

released from smooth muscle cells in the enlarged

and thickened bladder wall. 

• Chemical communication between cells of the 

bladder’s epithelium and afferent nerves

• Chemical interactions between afferent nerves 

and mast cells during inflammation

A more detailed understanding of the mechanisms

underlying two-way neuron-target organ communication would provide new insights into the pathophysiologic mechanisms underlying voiding dysfunction and identify new molecules and pathways 

as targets for drug therapy.

Nerve Protection, Preservation, and Regeneration Studies

Research on nerve protection, preservation, and 

regeneration has advanced rapidly in recent years and is

the outcome of allocation of research resources to these

areas, based on the needs of patients affected by stroke,

neurodegenerative diseases, nervous system trauma, 

and pediatric developmental abnormalities, and also on

the recognition that the nervous system is particularly

susceptible to the damaging effects of the ischemiareperfusion cycle. In this cycle, tissue is injured because

obstructed blood flow reduces the supply of oxygen to 

the cells (ischemia) and further damage occurs when 

the blood supply is restored (reperfusion injury). 
52 OVERCOMING BLADDER DISEASE

Very little of this information has been applied directly

to research affecting the lower urinary tract. A notable

exception is the currently supported effort to deliver

neurotrophic genes (i.e., nerve growth factor or NGF)

to the lower urinary tract to treat the effects of diabetes.

NGF has been found to play a significant role in the 

support, maintenance, and phenotype of many bladder

peripheral efferent nerves. NGF also prevents programmed cell death (apoptosis) of nerve cells stressed 

by obstructed blood flow (ischemia) and reperfusion

events as well as by nerve toxins.

Neurotrophic Factors

Knowledge about the relationship between neurotrophic

factor action and apoptotic cell death in the nervous 

system has advanced rapidly in the past few years.

Specific strategies have been developed to ameliorate

and prevent the induction of programmed nerve cell

death caused by a variety of stresses and events. Very 

little is known regarding the impact of specific life

events on nerve cell death and function in the lower 

urinary tract or how this may be altered.

Blood Supply

Normal bladder function depends on the delivery of 

an adequate supply of blood and nutrients to the bladder

mucous tissue, muscle, and nerves. Recent research 

evidence indicates that several dysfunctions of the 

urinary and reproductive tracts are linked to reduced

blood flow and the subsequent decreased oxygen supply

to the cells. Examples include diabetic bladder disorder,

obstructive bladder disease, and bladder muscle 

instability and loss of elasticity. 

Genomics and Proteomics Technologies

A goal of the Human Genome Project is the cataloging 

of all human cDNA sequences. One result of this 

effort has been the evolution of functional genomics, 

a science that will deepen the biologic understanding 

of human physiology and disease through the total 

elucidation of gene function in both normal and 

pathophysiologic states. 

The DNA microarray is the first effective, rapid, and

nearly universally applicable tool of functional genomics

to be used for unraveling mechanisms of cell function

and disease pathogenesis at the whole-genome scale.

The advent of DNA microarray technology has been 

heralded as the beginning of a new epoch in biomedical

research principally because this technology is easily

integrated both operationally and conceptually into

ongoing research projects.

These evolving technologies hold the promise to 

provide insights ranging from predispositions to 

lower urinary tract dysfunctions, to the targeting of 

specific therapies to responsive patient subgroups, 

to the idiosyncratic handling of drugs. Such data may

provide markers (a characteristic or factor by which 

a cell or molecule can be recognized or identified) for

use in early detection and prevention strategies or gene

promoters, which would allow selective targeting to the

lower urinary tract.
A Strategic Plan for Research 53

Gene Therapy and Tissue Engineering

Possible gene therapy strategies for overactive bladders

and urge incontinence may include suppression of 

bladder muscle activity or neural pathways that trigger

the micturition (voiding) reflex. It is also plausible that

gene transfer of inhibitory neurotransmitters into the

bladder and bladder afferent pathways can suppress 

the urination reflex, thereby inhibiting bladder hyperactivity. In addition, because NGF has been implicated 

as a chemical mediator to induce overactive bladders 

in various pathological conditions, such as spinal cord

injury, urethral obstruction, and chronic bladder

inflammation, antibody-based gene therapy to suppress

NGF expression is a potential therapy for the treatment

of urge incontinence.

Preliminary studies have also been done to determine

the benefits of gene therapy for overflow incontinence

caused by diabetic neurogenic bladder dysfunction 

and interstitial cystitis (IC) and for bladder pain 

caused by IC. 

Transgenic Models

Some transgenic animal models, animals in which 

new DNA has been introduced into germ cells by 

injection into the nucleus of the ovum (gene transplant),

are already available for different disease states of 

relevance to the bladder. These models could be used 

in future studies to determine whether it is possible to

minimize the effect of injury to nerves or to accelerate

their healing with such things as hormonal substances 

and nerve growth factors.

Future Research

Assessment and Quantification of Nerve Function 

Despite the preeminent role of nerves in urination and

in maintaining continence, assessing whether nerves are

functioning properly relies on indirect measurements.

Electrodiagnostic tests such as electromyography (EMG)

offer little more than a detailed physical examination. 

An EMG is difficult to perform, lacks sensitivity, and 

is costly. More sensitive and accurate tests are needed 

to ascertain whether difficulties in voiding or in urine 

loss arise from abnormalities in muscles versus nerves. 

Questions that need to be answered in this area are 

as follows:

• What issues, such as chronic pain and trauma, are

specific to the bladder and what clinical situations

need to be addressed?

• Why do some patients, even without a neuropathologic process or diabetes, lose the ability to contract 

the bladder? How can this be prevented or treated

more effectively?

• How can we determine whether a problem is caused

by afferent (inflowing) fibers, efferent (outflowing)

fibers, or the nerve?

• Based on imaging, what are the pain pathways 

outside the bladder? What are the pain pathways

inside the bladder?

• Can imaging be used to explore serotonin transporters and other genes?

• Can specific drugs be used to investigate specific

nerve and neuromuscular pathways?

• Are specific drugs for receptor subtypes useful in

investigating the role of these receptors in bladder

and urethral function?

• What techniques should be used in clinical trials 

to measure neural milieu in patients?

• What imaging technique should be used to clinically

characterize patients? 
54 OVERCOMING BLADDER DISEASE

• How are we to understand or address issues of 

nervous system control? How can these issues 

be studied in humans?

• How can neuroscientists be attracted to study the

lower urinary tract?

• What are appropriate models for nerve research?

• Is the rat bladder model used in a number of 

experiments applicable to humans? 

Neuron-Target-Organ Interactions, Endothelial and 

Epithelial Factors

A more detailed understanding of the mechanisms

underlying two-way neuron-target organ communication is needed to answer the following questions:

• What are the disease-causing physiological 

mechanisms underlying voiding dysfunction?

• Are there new molecules and pathways that can 

be used as targets for drug therapy?

Gender and Aging Differences in Micturition Pathways

In the next few decades, dollars spent in management 

of these bladder problems will significantly increase 

for two reasons:

• The proportion of the aged population in the United

States is increasing each year with the maturation 

of the so-called “baby-boomers.” 

• The prevalence of voiding dysfunction such as urinary

incontinence and overactive bladder increases 

significantly with age. 

Unfortunately, most of the financial resources for 

bladder problems are relegated to hygienic protection

(diapers and pads) and not to research and medical

treatment of this pressing problem. Our understanding

of the basic changes in nerve pathways related to aging 

is embarrassingly inadequate to make significant

improvement in the voiding dysfunction of the aged

population at this juncture in time.

In addition, before age 65, urinary incontinence and

overactive bladder are significantly more prevalent in

females compared with males. It is not well understood

why this is so and whether it is from childbirth or hormonal (estrogen) status. Estrogen can modulate nerve

circuitry; therefore, this hormone possibly affects the

nerve pathways regulating urination and continence.

It follows that one of the priorities for neurovascular

research of the lower urinary tract must be to improve

our understanding of the effect of aging and gender on

nerves as well as on blood vessels in the lower urinary

tract. By understanding these mechanisms, we can

increase the quality of life and also the efficiency of

health care dollars spent. 

Answers to the following critical questions will advance

our understanding in this area:

• How many motor nerve nuclei are in the bladder of 

an adult woman? Of an adult man? Do these nuclei

decrease with time?

• Why are women affected disproportionately by bladder disorders? Is it because of the structure of the

lower urinary tract in women? Is it hormonal? Is it

because of life events such as childbirth? Are there

gender-specific aspects of bladder nerve circuits?

• What are the genetics of nerve degeneration in 

the elderly?

• What happens to bladder nerves with aging?

• How do degenerative diseases of the nervous system

have an impact on bladder function?

• Can preventative measures (medical, pharmacological, and physical) prevent voiding changes that occur

with aging?

• How does sensory perception of bladder fullness

change with age? Is it a function of gender?
A Strategic Plan for Research 55

Funding research issues related to these areas will

increase not only our knowledge, but also the quality 

of life of many people. Health care expenditures will

decrease as a result.

Neurotrophic Factors and Nerve Regeneration

Our understanding of the relationship between the 

neurotrophic factors, action, and apoptotic cell death in

the nervous system has witnessed rapid recent advances.

This advancement includes the development of specific

strategies to ameliorate and prevent the induction of

apoptosis in nerves that is caused by a variety of stresses

and events. Very little is known regarding the impact 

of specific life events on nerve cell death and function 

in the lower urinary tract or how this may be altered.

Questions that research should endeavor to answer 

are as follows:

• What specific damage to the control of nerves in 

the lower urinary tract might be prevented by nerveprotective intervention and in what situations? 

Based on what animal models?

• What other neurotrophic factors are important in 

the lower urinary tract?

• Is it possible to capitalize on biological mechanisms

governing nerve growth and regeneration to ameliorate or reverse damage to the nerve circuits of the

lower urinary tract?

• Do some persons lack mechanisms that support 

post-traumatic or post-surgical nerve recovery? 

Does nerve-supportive therapy improve outcomes?

Impact of Blood Supply

Recent research evidence indicates that several dysfunctions of the urinary and reproductive tracts are linked 

to obstructed blood flow and the resulting decreased

oxygen supply to the cells (ischemia). Urogenital dysfunctions responsible for this include diabetic bladder

disease, obstructive bladder disease, and instability 

and loss of elasticity in bladder muscle (detrusor).

Questions that need to be answered are as follows:

• What is the pathophysiology of ischemia-induced

nervous system disorders of the bladder?

• Is there hard evidence to show that reduced oxygen 

or some element of ischemia actually leads to

nerve damage?

• What is the relation between degree and duration 

of ischemia and neuropathy?

• How does the bladder vasculature adapt to repeated

distension and contraction?

• Are there differences between bladders of men and

women with respect to the susceptibility to ischemia?

• What is the effect of high pressure in, and overdistension of, the bladder on blood flow and 

nerve integrity?

• How does ischemic reperfusion cause bladder 

structural damage and dysfunction?

• Does aging correlate with differential susceptibility 

to atherosclerotic change?

• What is the anatomy and physiology of blood supply

in the human bladder?

• How is blood flow to the bladder regulated?

• What is the role of anoxia (absence of oxygen in blood

and tissues) in inducing bladder wall damage?

• Does atherosclerosis affect certain vascular beds

more than others?

• Are there risk factors that contribute to bladder

ischemia such as smoking, hypertension, and diabetes?
56 OVERCOMING BLADDER DISEASE

• Is blood flow altered during aging or as a result of

other diseases?

• Are there racial differences in susceptibility to

ischemia?

• Can nerve regulation of blood flow affect disorders?

• What is the role of nitric oxide in the regulation of

blood flow under normal and pathological conditions?

• Can pharmacological alteration of peripheral blood

flow be effective in the treatment of specific bladder

pathologies?

• What is the effect of radiation on genitourinary 

blood flow? 

• What is the length of time that the bladder can be

ischemic under different conditions in people with

obstruction?

• Can we develop non-invasive blood flow measurement tools in humans? 

• Are antioxidant therapies effective in the treatment 

of obstructive bladder disease? 

Genomics and Proteomics Technologies

The widespread use of microarray technology has been

hampered by several factors that should be addressed.

These barriers are as follows: 

• The absence of a biotechnology center that produces

cDNA arrays based on bladder libraries. None of 

the biotechnology centers recently funded by the

National Institutes of Health is related to urology. 

• Technical barriers that range from poor experimental

design to lack of equipment and expertise to perform

experiments and analyze data. Investigators of lower

urinary tract dysfunction should be trained in all

aspects of microarray analysis, and a separate 

training module should be devoted to bioinformatics and data analysis. 

• The costs of using microarray technology are 

virtually insurmountable for the average investigator.

Therefore, initial support for development of

Biotechnology Centers in Urology with abilities to

synthesize oligonucleotides and print arrays and 

perform hybridization will ensure that the scientific

community could use this technology at significantly

reduced cost. By providing these services at reduced

cost, the centers will not only provide inexpensive

microarray service to the urologic community, but

also act as a stimulus for commercial vendors to 

lower their price barriers. 

Questions to ask in genomics and proteomics research 

of the lower urinary tract are as follows:

• What is expressed differently in the nerves supplying

the pelvic viscera?

• Is there a genetic predisposition that leads to 

voiding disorders?
Novel Therapies, Technologies, and Gene Therapy 

Novel therapies and technologies include the promotion

of re-innervation, gene delivery, devices for neurocontrol, regulation of the development of new blood vessels

(angiogenesis), and novel drug delivery systems targeted

at nerve transmission that is selective to the urinary tract. 

One example of lower urinary tract gene therapy is 

that which could be used for stress incontinence. The

concept of gene therapy strategies for stress incontinence is to build up the deficient urethral sphincter. 

To achieve this, tissue engineering or cell-based ex 

vivo gene therapy appears to be more logical than 

conventional viral vector gene therapy. 

According to one study, muscle-derived, cell-based 

tissue engineering may have several advantages over the

current treatment for urinary incontinence—collagen

injection. The tissue engineering technique derives cells

from the incontinence patient and then injects those

cells back into the patient (autologous cell transplantation). The advantages of this technique are as follows:

• Transplanted cells will not cause an immune system

or allergic reaction and, therefore, will survive longer

than injected collagen derived from cows

• Transplanted cells can serve as a natural bulking

agent when transplanted into the bladder and urethra

• Transplanted cells form muscle fibers that become

innervated into the host muscle where they serve as 

a blocking agent and are physiologically capable of

improving bladder (detrusor) muscle contractility

This study demonstrated three facts in the emerging

field of urologic tissue engineering: 

• The feasibility of injecting cells derived from skeletal

muscle into the urethal sphincter

• The feasibility of gene transfer to the bladder 

and urethra

• The greater persistence of injected collogen derived

from a patient’s muscle versus injected bovine collagen

Unique Neurotransmission Principles

Neurotransmission principles unique to the lower 

urinary tract are relevant to the development of 

(1) drugs and therapies specifically designed for 

the lower urinary tract (i.e., identification of neurotransmitter pairing) and (2) effective agents that act 

on the central nervous system circuits of the lower 

urinary tract. Although important and likely to reveal

useful therapeutic targets, most commercial activity is

focused on unique neurotransmission principles; 

therefore, this area did not rank as highly as an area 

likely to yield rapid progress. Nonetheless, the 

following basic questions are relevant:

• How do nerves function differently in the bladder

from nerves in other areas?

• How does this affect function—differentially?

Research Requirements 

Research requirements are as follows:

• Loan forgiveness is essential to recruit physician

investigators.

• Stable increased funding targeted to these areas is

needed to attract young and seasoned investigators 

to the field.

• Centralized resources for genomic and proteomic

research efforts will accelerate progress. 

• Increased interaction and co-sponsorship with 

other institutes at NIH (i.e., the National Institute 

of Neurological Disorders and Stroke, the National

Institute on Aging, and the National Heart, Lung, and

Blood Institute) will foster synergy and efficiency.

A Strategic Plan for Research 57
58 OVERCOMING BLADDER DISEASE

PATIENT PROFILE

Patricia Francis is a woman of many interests who has 

had significant success over a long career as a graphic 

artist, photographer, editor, and naval historian. All of these

pursuits have been sharply curtailed or diminished by the

effects of multiple sclerosis (MS), an autoimmune disease 

that destroys the myelin sheath protecting certain nerve fibers.

She cannot use her hands very well and walks with great 

difficulty. She has trouble manipulating her cameras and

equipment. An avid gardener, known throughout her community

as the “Flower Lady” for the bouquets she delivers and the 

plant seeds she shares, Pat has unfortunately had to restrict

this activity as well. 

Once her ability to draw was compromised, Francis began 

work on a history of naval aviators who flew during the Korean

War and in later military conflicts. However, the limited use of

her hands has caused her to have problems with this project 

as well.

“Like Matisse, I’ve had to find different ways of making art,”

she says.

Francis began her own heroic struggle almost 15 years ago, 

at the age of 50, when she noticed that she was experiencing

“increasing fatigue, weakness, and flu-like or lancinating nerve

and muscle pain” that occurred at least three to four days a

week and was associated with periods of physical activity. 

The physical limitations and pain continued undiagnosed 

until eight years ago, when she suffered a head injury from 

an automobile accident. Brain imaging studies taken as a

result of the accident showed some abnormalities that in 

retrospect were indicative of multiple sclerosis.

Three more years passed before physicians could conclusively

tell her she had MS. “As strange as it sounds, I was relieved

and grateful to hear that there was a disease process at work,”

she says. “I knew something was wrong and had been wrong 

for many years, but I thought the diagnosis wouldn’t be 

determined until I was autopsied. Now I could hope to find

somebody who might be able to help me deal with the pain 

and other manifestations of the disease.” By the time she was

diagnosed, the nerve damage to her urinary tract caused by MS

was so extensive that Francis lost significant sensation in her

bladder and could no longer tell when it was becoming full.

In a neurogenic bladder, nerves that carry messages to 

the bladder muscle do not work properly. Francis experiences 

leakage of urine because the bladder muscle has lost tone, 

but she also experiences urinary retention because nerves do

not relay the message that its time to let go. Urine that stays

too long in the bladder can lead to a urinary tract infection, 

Patricia Francis

Neurogenic Bladder, Multiple Sclerosis
A Strategic Plan for Research 59

which could spread to the kidneys. It could also lead to reflux 

of urine into the ureters and kidneys, a condition that can

cause kidney damage. 

“I don’t know when I have to urinate,” Francis says. “When I’m

out in public, this is especially hard. I feel a great sense of

relief when I’ve been able to reach a bathroom without an accident.” The problem is especially difficult because she walks

with the assistance of two leg braces and a cane. 

To lessen the severity of incontinence, Francis does preventive

bladder training. She sees a physical therapist and does 

Kegel exercises to strengthen the muscles of the pelvic floor,

using an electronic device to give her feedback on how well 

she is doing. Kegel exercises involve contracting and raising 

the pelvic floor muscles. 

Francis also schedules when she voids. Before she leaves the

house, she goes to the bathroom, and when she arrives at her

destination, she goes again. “Either my bladder is not holding

much, or it’s unstable and making me go frequently,” she says.

“Because of this, traveling even a moderate distance is no

longer an option. Rest stops are too far apart.”

When Francis’ bladder becomes full or releases urine, she has 

a great deal of cramping pain. The cramping disturbs her

sleep, Francis says, which adds to the problem of nighttime

voiding, a common occurrence in people with a neurogenic

bladder. Sometimes she even dreams she is urinating and

awakens with a start. These problems have placed her in 

a double bind. The urinary symptoms exacerbate the MS 

symptoms by causing her to not get enough rest, which 

would reduce her muscle pain. 

“My body requires restorative sleep, not the kind of sleep that

one gets with sleep medications,” Francis says. “When I tried 

to take them, I felt even more tired and was unable to think

effectively.”

Francis struggles to keep a balance in her life between the

activities she loves and the physical realities of her illnesses.

She limits her fluids at night and when she leaves home. 

She limits the time she spends at the computer and the 

trips she takes beyond the borders of her home. She limits

physical exertion. She has given up most of the artwork and 

the gardening that provided so much pleasure in the past. 

Francis and her husband have also experienced the financial

limitations of a chronic illness. “This is an expensive illness,

and insurance doesn’t pay for a lot of things I need,” Francis

says. “You have to juggle costs and decide what is more important to buy.” 

Although limits have become an integral part of her life, any

conversation with her reveals an important truth. This is a

woman who will not limit her creative ideas. She will make the

adjustments, much as Matisse did, and like Matisse she will

work despite the pain. 

“My choice is to function as if I were a zombie or to be productive, so I deal with the pain by working,” says Francis, explaining that she relegates the pain to the status of background

noise. “I don’t take medications during the day unless I can’t

stand it. When it seems to be getting worse, it’s important to

short circuit pain rather than wait until it’s really bad.” 

When night comes, it’s a different story. Pain medications 

provide welcome relief. “At night, it’s hard to make bladder 

pain and the ‘bee-stinging’ pain of MS background noise,” 

she explains. “By the end of the day, one is tired of coping 

with pain.”
A Strategic Plan for Research 61

SECTION B COMMON CLINICAL CONDITIONS

Bladder disease in its many forms affects the health and well

being of millions of Americans. Some diseases of the bladder—

bladder cancer, posterior urethral valves, and cloacal exstrophy, to name a few—are life-threatening, requiring surgery,

other therapies, and long-term follow-up. Other diseases such

as interstitial cystitis, vesicoureteral reflux, and urinary tract

infections may cause more widespread problems in the upper

urinary tract—the kidneys—or in other body systems. Loss 

of normal organ function and the resulting chronic health 

problems that are debilitating, painful, and costly in terms 

of personal finances, emotional health, and productivity are

frequent outcomes of these complications.

Seemingly less serious, chronic conditions such as urinary

incontinence may also have potentially severe effects.

Incontinence with urinary leakage may appear to those 

without the problem to be a condition of the elderly that 

people, especially women, learn to live with as they grow 

older. In fact, urinary incontinence may affect people of all

ages and creates burdens similar to other chronic health 

problems. These burdens are magnified by the social stigma

attached to the leakage of urine. 

Other bladder conditions are caused by diseases that 

develop first in other systems, such as diabetes, a disease 

of the endocrine system, and multiple sclerosis, a disease 

of the nervous system. While these diseases may only involve

the urinary tract secondarily, in some situations the primary

symptoms may be urinary incontinence or other symptoms 

of bladder or urinary tract dysfunction. 

Although basic scientific research on the lower urinary tract

will increase our knowledge of how the bladder functions, 

this basic knowledge needs to be translated into active 

clinical research that will take what has been learned in 

the laboratory to the patients who suffer from these diseases

and who volunteer for a studies that will eventually benefit

other patients.

The Bladder Research Progress Review Group has selected 

high-impact bladder conditions on which to focus this 

report and has recommended research priorities. The 

high-impact conditions include the following: problems 

of the developing genitourinary tract in children; urologic 

conditions of maturation and aging; bladder outlet 

obstruction; interstitial cystitis; urinary tract infections; 

effects of diabetes; urinary incontinence; and cancer.
CHAPTER 5
Common Clinical Conditions

PROBLEMS OF THE DEVELOPING 

GENITOURINARY TRACT IN CHILDREN

DID YOU KNOW?

. Genitourinary birth defects are 

the most common congenital

abnormalities in newborns.

. Approximately one out of every

5,000 to 8,000 male infants 

are born with posterior urethral

valves, which have immediate 

life-threatening consequences.

. Vesicoureteral reflux affects an

estimated 1 percent to 2 percent 

of children and is the most 

common cause of kidney failure 

in children. 

. About one in 5,000 infants 

are born with spina bifida, the

most common primary cause of

neurogenic bladder dysfunction 

in children. 

A Strategic Plan for Research 63

Summary and Recommendations

Normal bladder function is a critical part of human development. Abnormal

bladder development can have profound consequences such as constant 

urinary leakage and, ultimately, deterioration of kidney function. An improved

understanding of lower urinary tract development will not only facilitate the

treatment of childhood voiding disorders, but also provide insight into adult

disorders. Many bladder pathologies that affect adults—obstruction and loss 

of nerve supply, for example—recapitulate fetal events. 

The Bladder Research Progress Review Group made an extensive and 

comprehensive review of this research area and developed the following 

recommendations for future research:

* Investigate the mechanisms of lower urinary tract development and dysfunction 

at the molecular, genetic, and cellular levels to identify the causes of neurogenic

bladders, voiding problems, and problems causing obstruction to urination

* Develop better treatment for these disorders

* Determine the epidemiology and confounding factors related to bladder diseases 

and develop a means of evaluating prospectively and longitudinally the risk factors

related to problems such as urinary tract infections, vesicoureteral reflux, daytime

wetting, enuresis, and hydronephrosis.

Specific recommendations for each developmental condition are located 

at the end of this chapter.
64 OVERCOMING BLADDER DISEASE

Background

During normal bladder development, dramatic changes

occur that are critical for normal bladder function. In the

fetus, the bladder is initially an extension of the ureters,

and it acts as a conduit for urine, which then flows out 

of the fetus’ body through the urachus and into amniotic

fluid. Only with time does the bladder develop a storage

function. The initial stages of this function begin in the

older fetus as it develops reflex emptying. This process

continues after birth and throughout the next few years

of normal human aging. In time, the child develops 

voluntary sensory control of urination. Thus, normal

voluntary continence with normal bladder storage 

and emptying takes complex coordination between 

the bladder and the urethra. 

In the normal state, the bladder is a supple, distensible

organ. Urine is transported to the bladder from the 

kidneys via the ureters. The bladder’s function is to 

store urine at a constant low pressure, then empty 

completely at socially acceptable intervals. This lowpressure storage concept can be described as bladder

elasticity. Abnormal excessive bladder contractions

caused by disease, may cause the bladder to lose 

elasticity, changing to a stiff-walled, high-pressure 

storage chamber. 

Abnormal development, injury, disease, or the aging

process itself can interrupt or reverse this normal 

bladder developmental path, causing problems of 

inadequate storage or emptying, that is, involuntary

voiding or incontinence, as well as serious consequences

ranging from frequency and urgency to urinary leakage,

vesicoureteral reflux, infections, stones, and, ultimately,

deterioration of kidney function requiring dialysis. 

One example of an anatomic developmental problem 

that occurs in the embryo is bladder exstrophy. 

In infants born with bladder exstrophy, there is a 

gap in the anterior wall of the bladder and the abdominal wall located in front of it exposes the bladder’s 

posterior wall. 

Abnormal embryonic development in other body 

systems such as the nervous system can also cause an

anatomically normal bladder to develop abnormally. 

This occurs, for example, when the spinal cord, especially

the lower part, develops abnormally. Several conditions

can result from this, depending on the extent of the

abnormal development, but these conditions are generally known as myelodysplasia. Later in life, diseases 

that affect the nervous system such as diabetes and

Parkinson’s disease, spinal cord injuries, and aging 

also have an impact on the lower urinary tract. 

Genitourinary birth defects are the most common 

congenital abnormalities in newborns. In children,

abnormal bladder function secondary to abnormal

development occurs frequently. Common problems

include spinal cord defects (spina bifida), congenital 

and acquired bladder outlet obstruction (posterior 

urethral valves, ectopic ureteroceles, dysfunctional 

voiding), and congenital anatomic anomalies (bladder

exstrophy, imperforate anus, prune belly syndrome, 

and ureteral ectopia). A significant number of children

who are born with these defects, which are described

below, will have morbidity directly related to their 

bladder function.

Epidemiology

From a socioeconomic point of view, abnormal 

development of the lower part of the spinal cord or

myelodysplasia constitutes a significant health problem

in the United States. The incidence of spina bifida, a

form of myelodysplasia, is reported to be approximately 

1 per 5,000 live births. Approximately 70 percent of 

people with myelodysplasia have decreased bladder 

elasticity that is clinically significant.

Posterior urethral valves occur only in males. They 

are membranous folds that develop within the posterior

(prostatic) urethra, and it is estimated that they occur 

in one out of every 5,000 to 8,000 births of male infants.

Because these folds or valves obstruct the outflow of

urine, approximately 30 percent of infants with valves

have a clinically significant decrease in bladder 
A Strategic Plan for Research 65

elasticity. Congenital bladder outlet obstruction 

has immediate life-threatening consequences as 

well as long-term consequences on kidney and 

bladder function. There does not appear to be any 

known ethnic or familial predisposition toward 

the development of posterior urethral valves.

Vesicoureteral reflux, the abnormal retrograde flow 

of bladder urine into the upper urinary tract as the result

of an incompetent junction between the ureter and the

bladder, affects approximately 1 percent to 2 percent 

of children. Vesicoureteral reflux can result in severe

infection and kidney failure and is a common cause 

of the latter in children. In children who do not have

urologic symptoms or a history of infection, the incidence of vesicoureteral reflux is estimated to be less 

than 1 percent. In children with a history of symptomatic

urinary tract infection, the incidence of this condition 

is estimated to range from 20 percent to 50 percent. 

Enuresis or bedwetting, another persistent and 

pervasive problem, might reflect abnormal bladder

development as well. More common in boys than in

girls, enuresis affects 5 million to 7 million children

between the ages of 6 and 18. The incidence varies in

different societies, but in five-year-old children in 

the United States, the incidence is about 15 percent 

to 20 percent. About 1 percent to 2 percent of older 

adolescents have nocturnal enuresis. After the age 

of six, childhood bed-wetting or enuresis becomes a 

very important problem for the child and the parents. 

In addition, some evidence indicates that children 

with enuresis might be predisposed to future bladder 

problems as adults. 

Daytime urinary incontinence, nocturnal enuresis, 

and dysfunctional voiding affect an estimated 5 percent

of families with children. Approximately 15 percent to 

20 percent of children are incontinent during the day 

at age 5, 5 percent at age 10, and 1 percent above age 15. 

Developmental Problems 

Developmental problems affecting the bladder in 

fetuses, newborns, children, and adolescents, may 

be grouped into the following categories:

• Abnormal or injured nerve development: 

myelodysplasia, neurogenic bladder

• Associated anatomic abnormality: posterior 

urethral valves, vesicoureteral reflux, ureteroceles,

ectopic ureters

• Unclear causes: nocturnal enuresis; dysfunctional

voiding; non-neurogenic, neurogenic bladder

• Incomplete or abnormal anatomic development:

exstrophy and its variants, prune belly syndrome,

imperforate anus, and cloacal abnormalities

These problems are described in the sections that follow.

Myelodysplasia and neurogenic bladder—Myelodysplasia 

is an abnormality in the development of the spinal cord,

especially the lower part of the cord. Neurogenic bladder

is bladder dysfunction that originates in or is caused 

by the nervous system or nerve impulses. In children,

spina bifida, a type of myelodysplasia, is the most 

common primary cause of neurogenic bladder dysfunction. Second siblings in the same family have a 2 percent

to 5 percent risk of being born with the same disorder. 

Spina bifida arises from a defect in the formation of 

the neural tube. The cause of this defect is uncertain, 

but various teratogens such as alcohol and zinc, as well 

as some medications such as valproic acid, have been

implicated. Recent evidence has suggested that a deficient maternal intake of folic acid is associated with the

development of spina bifida and that supplementation

may reduce the chances of acquiring such birth defects

seven-fold.
66 OVERCOMING BLADDER DISEASE

About 95 percent of children with spina bifida have

abnormal innervation of the bladder. Because of

increased bladder pressure and the potential for 

vesicoureteral reflux, obstruction, and infection, 

children with spina bifida are at risk for kidney 

damage unless nerve and bladder abnormalities 

are recognized early and intervention is prompt. 

Children with spina bifida 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 often require multiple surgical

interventions to allow adequate urinary storage. 

Surgical interventions may include bladder augmentation or replacement with portions of intestine and 

bladder neck procedures to improve continence.

However, none of these treatments is ideal, and many

children suffer from the consequences of inadequate 

and improper urinary storage. Complications may

include bacteriuria, stones, continual leakage, and, 

in the most severe cases, deterioration of renal 

function related to persistent high bladder pressures. 

Major short-term care costs include the costs of surgery,

if it is possible, to close the vertebral arches through

which the spinal cord and meninges protrude, hospitalization, and imaging evaluation. Long-term health care

costs include costs for follow-up visits, surgery, urodynamic measurement, chronic medication, diapers, 

caretakers, lost work for parents, multidisciplinary

health care teams, and ultimately, lost work for the 

person with this problem as he or she becomes an adult.

Vesicoureteral reflux—Vesicoureteral reflux, the abnormal

retrograde flow of urine already in the bladder into the

upper urinary tract, is the result of an incompetent junction between the ureter and the bladder. Vesicoureteral

reflux and its associated recurrent UTIs are the most

common causes of renal scarring in children and may

cause severe renal dysfunction. In children with reflux

nephropathy or renal scarring from vesicoureteral reflux

and infection, hypertension and progressive renal 

dysfunction may occur even if the reflux resolves. 

Reflux is the most common cause of kidney failure in

children. It is often detected in children who have had

recurrent urinary tract infections (UTIs) or an unexplained, recurrent febrile illness. Infections are often

severe and kidney failure frequently results. In children

with a history of symptomatic urinary tract infection, the

incidence has been estimated to range from 20 percent

to 50 percent. In those who do not have urologic symptoms or a history of infection, the incidence is less than 

1 percent. Hydronephrosis, dilation of the kidney pelvis

and calyces, is a secondary outcome of reflux, and it 

can be detected by prenatal ultrasound. However, 

most infants born with vesicoureteral reflux alone 

are asymptomatic at birth.

Risk factors for vesicoureteral reflux are as follows:

• Age — Reflux is most common in very young children

and incidence declines with age.

• Race — Reflux is more common in fair-skinned 

children. It is significantly less prevalent in black

children and in children of Mediterranean origin

when compared with white children. White girls 

have been reported to have 10 times the incidence 

as black girls. 

• Sibling predisposition — Reflux occurs in approximately

40 percent of the siblings of children with known

reflux. Younger siblings are at greatest risk. In many

of these children, there may be no documented 

history of symptomatic infections. For this reason,

most pediatric urologists and nephrologists advocate

routine screening of siblings of children with 

known reflux.

• Sex — Because of the epidemiology of UTI in children,

boys and girls may present with reflux at different

ages. In the neonatal period, UTIs are more common

in uncircumcised boys than in girls; therefore, many

more boys will be diagnosed with reflux. After the

first year of life, the incidence of UTIs becomes 

much higher in girls than in boys; therefore, most

school-age children diagnosed with reflux are girls.
A Strategic Plan for Research 67

An increased understanding of the pathologic mechanisms and the natural history of reflux have led to

improvements in both medical and surgical approaches

to treating this condition. Effective treatment greatly

depends on early detection and the institution of 

antibiotic prophylaxis. The primary goal in both medical

and surgical management is to prevent development of

pyelonephritis, an inflammation and infection of the

kidney, and the formation of scarring. Close follow-up

and periodic reevaluations are necessary for all children

with this problem. When indicated, surgical correction

of reflux has been shown to be safe and effective.

Short-term costs for vesicoureteral reflux include the

costs of evaluation and imaging. Long-term costs are 

for medications, surgery, imaging evaluation, renal

insufficiency, hypertension, and transplantation.

Posterior urethral valves—Posterior urethral valves are 

the most common congenital cause of bladder outlet

obstruction and one of the most common urologic 

emergencies that occur in fetuses and newborns.

Incidence has been estimated to be one per 5,000 to

8,000 male births. The immediate survival of the infant

with posterior valves depends on early recognition and

stabilization of the acute metabolic abnormalities that

result from obstruction. 

Occurring only in male infants, posterior urethral valves

are membranous folds within the posterior (prostatic)

urethra. These folds obstruct the outflow of urine. The

presence of valves becomes evident in a wide spectrum

of clinical symptoms, depending on the degree of

obstruction that developed in the fetus. Urethral valves

may be detected before birth by prenatal ultrasound

examination or after birth. Prenatal diagnosis of 

posterior urethral valves has provided pediatricians 

and pediatric urologists with an opportunity to initiate

treatment immediately after birth.

Signs and symptoms of posterior urethral valves in 

a newborn that has not been diagnosed prenatally are 

as follows:

• Respiratory distress

• Presence of microorganisms in the blood and 

tissues (sepsis)

• Abnormal levels of urea and other nitrogenous 

substances in the blood plasma (azotemia)

• Abdominal distention

• Bladder dysfunction

Congenital bladder outlet obstruction can be life 

threatening, and it has long-term consequences on 

kidney and bladder function. 

Approximately one-third of all children with valves 

will have significant lower urinary tract dysfunction

manifested most commonly by urinary incontinence. 

In a small but significant number of children, bladder

dysfunction may be so severe as to lead to further 

deterioration of renal function. 

Definitive relief of the obstructing valves can be achieved

surgically, using several techniques. Long-term medical

management includes a frequent timed voiding regimen

to reduce urinary residual and stasis, which can lead to

infection; anticholinergic medications to treat those

children who manifest low-capacity, hyper-reflexic

bladders; clean intermittent catheterization for poor

emptying of the bladder; antibiotic prophylaxis for 

persistence of vesicoureteral reflux; and treatment of

renal insufficiency, if needed (some children with 

valves continue to have deterioration of kidney function

resulting in chronic renal insufficiency). 

Renal insufficiency can lead to a variety of metabolic

abnormalities and growth retardation. In cases where

surgical and medical therapies fail, it may be necessary 

to surgically augment the bladder capacity to achieve 

urinary continence and preserve renal function. Bladder

augmentation using gastrointestinal segments produces
68 OVERCOMING BLADDER DISEASE

its own metabolic complications depending on the 

intestinal segment used. Long-term follow up in these

children is necessary because they may also be at 

significant risk of malignancy. 

Health care costs for children with posterior urethral

valves are disproportionately high when compared 

with the number of infants affected with this condition.

Long-term costs are high because children with poor

outcomes such as kidney failure need chronic care. 

Voiding dysfunction and daytime incontinence—The term

voiding dysfunction in childhood means a dysfunction 

of the lower urinary tract that does not have a recognized

organic cause (e.g., neurological disease, injury, or 

congenital malformation). Although the term voiding

dysfunction is more accurate, it is often used interchangeably with the term “bladder dysfunction.” 

In general, voiding dysfunction is a disturbance in 

the coordination between the bladder muscle and the 

external sphincter activity. It can take many forms,

including the inability to voluntarily start or to stop

voiding, poor bladder emptying, incontinence, and 

high pressures in the bladder. 

Normal lower urinary tract function includes storage of

urine at low pressures (made possible by an accommodating, low-pressure bladder and a closed sphincter)

and voluntary emptying (including not only a voluntary

bladder contraction, but also an involuntary sphincteric

relaxation just before bladder contraction). Because

older children can control their external sphincter more

easily than their bladder muscle, they can more easily

stop urination than start it. Contraction of the external

sphincter is subconscious and normal during bladder

filling, but it is pathologic during bladder contraction or

voiding. In the worst of these cases, this can cause lower

(and upper) urinary tract deterioration. 

Daytime urinary incontinence is the involuntary leakage

of urine in a child older than five years of age (the age at

which a normally healthy child in our society should have

acquired daytime continence). This particular age however depends on the culture of the family. For example,

in some Asian families continence is expected between

ages two and three.

Daytime urinary incontinence, nocturnal enuresis, and

dysfunctional voiding affect an estimated 5 percent of

families with children. Approximately 15 percent to 20

percent of children are incontinent during the day at age

5, 5 percent at age 10, and 1 percent above age 15. About

80 percent of all of these children are incontinent only 

at night. 

By the age of four, most children with a normal and

healthy development can manage both the bladder 

maturity and social skills required to stay dry during 

the day. The prevalence of urinary incontinence (UI) 

in children has not been well studied mainly because 

the definition of voiding dysfunction or functional

incontinence is unclear. However, the following 

points are known:

• Of all children with a wetting problem, 10 percent

will only have symptoms by day, 75 percent only by

night, and 15 percent by both day and night.

• About 15 percent of five-year-old children have UI,

mostly at night.

• Studies in children just starting school (six to seven

years of age) have shown that 3.1 percent of the girls

and 2.1 percent of the boys had an episode of daytime

wetting at least once a week. Most of these children

had urinary urgency (82 percent of the girls and 74

percent of the boys).

• For reasons that are not understood, there is also 

a difference in prevalence depending on whether 

the child lives in colder (2.5 percent) or hotter areas

(1 percent). 
A Strategic Plan for Research 69

• The spontaneous cure rate for daytime wetting is

similar to that for nocturnal enuresis (about 14 

percent of children will improve without treatment

each year). 

• A strong association exists between bladder dysfunction and bacteriuria. However, it is not known

whether the bacteria cause the bladder dysfunction

first or vice versa (it is likely that bladder dysfunction

causes an increased rate of bacteriuria). Probably,

both are true, and this often leads to a “vicious cycle.”

• The diagnosis of a urinary tract infection (UTI)

should not be overlooked because in children symptoms are often systemic (e.g., fever and failure to

thrive), rather than localized in the urinary tract.

• Bladder dysfunction is also commonly associated 

with bowel dysfunction. The anal sphincter, the

external urinary sphincter, and the pelvic floor 

muscles constitute an integrated unit. Treatment 

of chronic constipation and encopresis can result 

in complete resolution of bladder symptoms.

• A higher incidence of bed-wetting occurs when 

daytime wetting is present. However, a corollary 

of this is that daytime wetting or frequency without 

concomitant nighttime incontinence or nighttime

voiding (nocturia) is most likely not organic. 

Many studies have noted psychiatric disturbances 

associated with dysfunctional voiding. However, it is 

difficult to differentiate whether psychological factors 

or social pressures are the primary reason for the 

voiding problem, or whether the incontinence has led 

to psychosocial problems. In a condition with severe

social consequences, separating cause from effect is 

difficult. Psychosocial or psychiatric help should only be

the primary focus in unusual cases (e.g., sexual abuse). 

A child with dysfunctional voiding may have a functional

obstruction where the bladder muscle joins the sphincter (detrusor-sphincter dyssynergia) and, therefore,

high pressure within the bladder at voiding. Recognizing

the voiding dysfunction that presents along with 

vesicoureteral reflux is important because surgical 

correction of the reflux will often not change the child’s

voiding habits and, therefore, only part of the problem

will be solved. 

Urinary incontinence in children can be primary or 

secondary. Primary incontinence means that the child

has never been dry. Secondary incontinence means that

the child has been dry for at least six months and then

starts to wet again. A history of secondary incontinence

is of greater concern to clinicians because more consideration must be given to factors that might bring on this

problem (e.g., infection, neurological abnormalities, 

or sexual abuse). 

Many different varieties of voiding dysfunction exist,

and they manifest different symptoms. While some

forms may account for rare episodes of urinary leakage

(giggle incontinence) in children, severe forms may

cause urinary retention or such poor voiding (e.g., nonneurogenic neurogenic bladder or Hinman’ s syndrome)

that bladder and kidney function are impaired. The

causes and reasons for the different symptoms and 

signs are unclear.

Enuresis—Enuresis has been recognized for millennia,

and it affects virtually all cultures. Defined as the 

persistence of inappropriate voiding of urine beyond 

the age of anticipated control, enuresis can occur both

during the day and at night (diurnal) or at night only

(nocturnal). Depending somewhat on the age of the

child, about 15 percent of nocturnal enuretic children

are also wet during the day. In a few, enuresis occurs

only during the day. 

Enuresis is more common in boys than in girls. In 

the United States, enuresis affects 5 million to 7 million

children between the ages of 6 and 18. After the age 

of six, childhood bed-wetting becomes an important 

problem for the child and the parents. 
70 OVERCOMING BLADDER DISEASE

Enuresis can be 

categorized as either

primary or secondary,

depending on the

child’s history.

Primary enuresis 

is designated if the

child has always been

wet, whereas the term

secondary enuresis is

used if the child has

had a dry period of at

least a month before

wetting again. About

20 percent of children

with nocturnal enuresis can be classified as secondary.

Concern about the new onset of enuresis often encourages unnecessary investigation. The causes and 

treatments of enuresis vary considerably.

Nocturnal enuresis is a symptom (as opposed to a 

disease) and, as such, is likely to have many different

causes. Furthermore, these factors are not mutually

exclusive, and children may have a complex interrelationship of explanations. Possible causal factors 

are genetics, maturational delay, sleep disorders, 

psychological factors, urinary tract infection (UTI), 

and nocturnal polyuria.

In many cases, the cause of enuresis remains uncertain

because an extensive evaluation is invasive and not 

generally cost-effective. Therapy in a given child is 

often prescribed without regard to the specific etiology. 

Enuresis has a strong genetic component. The incidence is 77 percent among children whose mother and 

father both had enuresis, 44 percent if one parent had

enuresis, and 15 percent if neither parent had enuresis.

Monozygotic twins (identical twins) have twice the 

concordance than dizygotic twins (fraternal twins). 

Costs of enuresis treatment vary according to the 

therapy and supplies. Therapy includes positive 

reinforcement methods; anticholinergic and 

antidepressant drugs; desmopressin acetate, a synthetic

antidiuretic hormone administered at night via nasal

spray; conditioning techniques using an alarm that 

goes off when urine connects with the circuit; avoidance 

of allergenic foods; and hypnotherapy and psychotherapy, which are not considered appropriate for 

the average child.

Exstrophy-epispadias complex—Exstrophy-epispadias 

complex is an all-encompassing term for a spectrum 

of congenital anomalies of the bladder and urethra that

range from epispadias, a malformation in male infants

in which the urethra opens on the dorsal aspect of 

the penis, to cloacal exstrophy, a complex of severe

abdominal anomalies that can affect both male and

female infants. Exstrophy-epispadias complex occurs in

one infant per 30,000 to 40,000. Within this spectrum

of anomalies, classic bladder exstrophy occurs in 60 

percent, epispadias (all forms) in 30 percent, and complex cloacal exstrophy and other variants in 10 percent.

In the embryo, persistence of the cloacal membrane

after the fourth week of gestation prevents the lateral

mesoderm from migrating medially. Once the membrane disappears by the ninth week, the posterior 

wall of the bladder is exposed to the outside, with 

the umbilicus adjacent to the bladder wall. 

In the most common form of primary epispadias—

penopubic—the urethral opening (meatus) is located

where the base of the penis joins the lower abdominal

wall. Other variations may exist including a very mild

form of dorsal glanular epispadias, where the urethral

meatus is located at the back of the head of the penis. 

The most severe form of epispadias, cloacal exstrophy,

occurs in the early stages of embryonic development. 

In the developing embryo, the urorectal septum normally forms and divides the cloaca, a chamber into which 

the hindgut and allantois empty, into anterior and 

posterior compartments. However, when an abnormally

large cloacal membrane perforates before the cloaca 

is divided, an exstrophied bladder separated by an

Enuresis

Possible Causes 

• Genetics

• Maturational delay

• Sleep disorders

• Psychological factors

• Urinary tract infection

• Nocturnal polyuria
A Strategic Plan for Research 71

exstrophied ileocecal bowel area results. Children born

with this condition usually have two everted bladder

units separated by an everted segment of the intestine,

generally the cecum, which has a blind end. At birth, the

exposed bladder and urethra are obvious malformations.

Exposure of the bladder results in bacterial colonization,

thickening of the bladder, and resultant fibrosis, which

replaces muscle and reduces the bladder’s elasticity. Up

to 66 percent of the children with cloacal exstrophy have

problems in the upper urinary tract as well. 

Once the bladder has been surgically closed, vesicoureteral reflux occurs in most children as a result of

the abnormal placement of the ureters and the lack of

muscular backing by the bladder. Inguinal hernias are

common (both direct and indirect), especially in boys.

The testes are normally descended in most cases. Some

children may have rectal prolapse (10 percent to 20 

percent) because of muscle weakness in the pelvic floor. 

In girls, the clitoris is divided on both sides of the 

urethra; the vagina is tilted anteriorly and may often 

be narrowed. Despite this, girls are potentially fertile. 

In boys, the penis usually is significantly rotated and

shortened. The corporal bodies of the penis are separate

(unlike the normal penis in which the corpora communicate) and diverge to attach to the inferior rami of the

pubis, which are rotated laterally and anteriorly. Thus,

osteotomy, performed on the pubic bone to restore 

normal distance at the symphysis (the cartilaginous 

joint that unites the two sides of the pubis), results 

in further shortening of the already stubby penis.

Significant problems are associated with this anomaly,

including herniation of the abdominal organs into the

umbilical sac (omphalocele) and numerous gastrointestinal anomalies, including malrotation, duplication,

duodenal atresia (absence of a normal opening or

lumen), and Meckel’s diverticulum, (a remnant of 

the embryonic yolk sac that forms a blind pouch in 

the intestine). Significant genitourinary anomalies,

including separate bladder halves and cleft genitalia, 

are also associated with this condition. 

Newborn males are often gender converted to female as 

a result of inadequate genital development and the poor

prognosis for developing a normal male phenotype. 

In the past, children with the most severe and rare form

(incidence of 1:200,000 live births) of the exstrophyepispadias complex were usually left to die. With modern

surgical techniques and a multidisciplinary approach to

their care, children

with this complex 

disorder can achieve

acceptable lifestyles. 

Recently, a staged

approach to closure

has been found to

provide adequate

drainage of kidneys

and to enhance 

the potential for 

continence after

reconstruction. The

three phases of the

staged approach are 

as follows: (1) primary

bladder closure, 

performed during 

the newborn period, (2) epispadias closure, performed

between six months and one year of age, and (3) bladder

neck reconstruction and ureteral re-implantation.

With the current staged approach, continence rates of 

up to 50 percent and 60 percent have been reported,

although this varies among treatment centers and 

surgeons. In most children who remain incontinent 

after the staged procedures, the bladder capacity is to

blame. Surgical bladder augmentation or creation of a

bladder reservoir using bowel can be performed to solve

this problem. In some children, the bladder outlet is

weak, and placement of an artificial urinary sphincter 

or urethral augmentation with collagen or Teflon 

injection may be beneficial. 

Stages of Exstrophy Closure

Stage 1: Primary bladder 

closure, performed during 

the newborn period to 

convert the extrophied 

bladder to an epispadias

Stage 2: Epispadias closure,

performed between six 

months and one year of age

Stage 3: Bladder neck 

reconstruction and 

ureteral re-implantation
72 OVERCOMING BLADDER DISEASE

Renal deterioration is prevented if bladder pressures

remain relatively low and if the child remains on antibacterial prophylaxis because of reflux. In children with

more severe forms of exstrophy who may require urinary

diversion (e.g., connecting the ureters to an abdominal

stoma or opening), upper tract damage can occur, and it

varies according to the type of diversion.

Imperforate anus—Imperforate anus comprises a spectrum of anomalies involving the anus and rectum; these

anomalies range from simple anal fistula to complex

cloacal malformations involving multiple organ systems. 

By the eighth week of gestation, the primitive hindgut in

the embryo becomes separated into the rectum and the

urogenital sinus by the descending urorectal membrane.

Incomplete migration or fusion of the membrane may

result in persistent communication between the rectum

and the urogenital

sinus—a fistula—

as well as malformations of the 

pelvic musculature

(sphincter).

Anorectal anomalies

can be divided into

high, intermediate,

or low defects based

on the level of the

fistula between the

rectum and the 

urinary tract or 

on the degree of

malformation or absence of the rectum. Most children

with high lesions will require a colostomy to temporarily

divert fecal material until a more distal repair can be

accomplished. In lower or more minor lesions, a minor

reconstruction of the posterior portion of the rectum 

and anus may accomplish the job without having to

resort to a colostomy. Until lower urinary tract 

anomalies are ruled out or reconstructed, children are

placed on prophylactic antibiotics to avoid sepsis, the

presence of pathogens in the blood.

Associated anomalies of imperforate anus are seen in 

up to 50 percent of cases and urologic involvement in 

26 percent to 50 percent. Generally, the more severe 

the defect, that is, the higher the connection between 

the rectum and urethra or between the rectum and 

vagina, the higher the incidence of associated anomalies. 

Factors contributing to morbidity in these children 

are related mainly to genitourinary anomalies, spinal

(especially sacral) anomalies, other malformations, 

and the quality of bowel and urinary sphincters. 

Prune belly syndrome—Prune belly syndrome (PBS) 

is sometimes referred to as Eagle-Barrett, triad, or 

mesenchymal dysplasia syndrome. The incidence of

these syndromes ranges from one in 35,000 live births

to one in 50,000 live births, with most cases occurring 

in boys and only 3 percent to 5 percent in girls. Prune

belly syndrome has three major pathologic anomalies,

although other coexisting orthopedic, pulmonary, and

cardiac anomalies have been noted as well: (1) deficient

or absent abdominal wall musculature; (2) various

ureteral, bladder, and urethral abnormalities involving

marked dilatation; and (3) bilateral undescended testes.

The definitive origin of prune belly syndrome remains

controversial, but two theories predominate: 

Obstructive theory—Severe bladder outlet obstruction

existed early in gestation and was subsequently relieved

after irreversible damage had occurred. Obstruction

resulted in bladder distention, ureteral dilation, and

hydronephrosis, as well as atrophy of the abdominal 

wall muscles by the increased pressure and interference

with the blood supply. However, most children with

prune belly syndrome lack anatomic obstruction at 

the time of birth. 

Mesodermal defect theory—A primary defect in mesenchymal development occurred early in gestation. 

Imperforate Anus 

Associated Anomalies

• Spinal malformations

• VACTERRL syndrome

(Vertebral, Anal,

Cardiovascular Tracheal,

Esophageal, Radial,

Renal, and Limb 

abnormalities)

• Genitourinary anomalies
A Strategic Plan for Research 73

Clinical manifestations of prune belly syndrome are 

as follows:

• Kidneys: Kidney abnormalities are the major 

determinants of survival, with a 20 percent chance 

of stillbirth or death in the neonatal period from 

renal dysplasia and the associated pulmonary

hypoplasia. An additional 30 percent of children 

will develop urosepsis or renal failure or both in 

the first two years of life. 

• Ureters: Severely dilated and tortuous, the ureters

are most severely affected at the lower end and appear

to have patchy areas of fibrosis. Vesicoureteral reflux

is present in 75 percent of these children. Although

their radiographic appearance is alarming, drainage

is generally adequate. 

• Bladder: The bladder is generally capacious, smoothwalled, and irregularly thick, without a meshwork of

fibers (trabeculation). Often, a remnant of the urachus (the urinary outlet in the fetus that connects the

bladder to the umbilicus) or a diverticulum (an out

pouching of the intestinal wall) creates an hourglass

configuration. Functionally, children with these

bladders exhibit a diminished sensation of fullness

and have a large capacity with poor contractility,

decreased voiding pressures, and, thus, a poor 

ability to empty.

• Prostate gland and posterior urethra: The prostatic

urethra is elongated and characteristically tapers 

to the membranous region, which gives rise to the

typical radiographic appearance of a triangular 

posterior urethra. 

• Anterior urethra: Although the urethra is most often

normal in this syndrome, both urethral atresia

(absence of a urethral opening or of a patent urethral

lumen) and megalourethra (dilation of the urethra)

can be seen. 

• Testicles:

Cryptorchidism

(failure of both or

one of the testes to

descend) is seen

universally in boys

with prune belly

syndrome, the

gonads characteristically being

found high in 

the abdomen.

Histologically, 

the testes are

markedly 

abnormal, thus

rendering patients infertile. 

• Abdominal musculature: The most characteristic 

manifestation of prune belly syndrome is the 

wrinkled, “prune-like” skin of the abdomen in the 

newborn infant. Skeletal muscle underdevelopment

is seen in all three layers of the abdominal wall 

muscles. Complications are surprisingly minimal.

The inability to sit up directly from the supine 

position may delay the onset of walking, but it 

rarely affects normal physical activity.

• Other associated anomalies: Other anomalies are

found in more than 65 percent of children, the most

common being cardiopulmonary and gastrointestinal, and include orthopedic and developmental 

problems as well. Pulmonary abnormalities range 

in severity, with the most significant arising in 

cases where the mother has an insufficient amount 

of amniotic fluid (oligohydramnios). Children 

who survive the neonatal period usually have no 

associated pulmonary problems.

Prune Belly Syndrome

Major Anomalies 

• Deficiency or absence 

of abdominal wall 

musculature

• Ureteral, bladder, and 

urethral anomalies, 

manifested in most cases

by marked dilation

• Bilateral undescended

testes
74 OVERCOMING BLADDER DISEASE

Prenatal ultrasound is capable of detecting abnormal

urinary tract dilation as early as 14 weeks gestation.

However, differentiating prune belly syndrome from

other causes of urinary tract dilation is difficult. In the

presence of oligohydramnios, prenatal intervention has

been advocated to decompress the dilated bladder and

restore the amniotic fluid volume. Although prenatal

intervention may improve pulmonary function, its 

ability to improve kidney function is uncertain. 

Children with severe forms of prune belly syndrome

usually do not survive the neonatal period; however, 

for the few who do survive, urinary diversion is often

recommended to provide optimal urinary drainage. 

Moderately affected children with PBS usually are 

treated medically unless infection persists despite

antibiotic prophylaxis, renal growth is inadequate, 

or renal function is decreasing. In these cases the 

urinary tract is reconstructed with ureteral tailoring 

and correction of reflux to reduce stasis. Reconstruction

of the abdominal wall and repair of the undescended 

testicle(s) (orchidopexy) are often performed 

simultaneously. 

Mildly affected children have good renal function; 

therefore, surgical intervention is usually not necessary.

However, life-long antimicrobial prophylaxis is often

instituted. Repair of the undescended testicle(s) may be

delayed until such time as any other reconstructive procedures may become necessary or at about six months.

Abnormalities of bladder drainage are the principal

source of problems in childhood, and they may lead to

renal deterioration. Pyelonephritis or renal deterioration may prompt a re-implantation and, perhaps, tailoring of the ureters to improve drainage and prevent

reflux. However, these procedures are complicated

because of poor peristaltic movement of the ureters and

the abnormal bladder into which they are reimplanted.

Because of persistent stasis of urine postoperatively,

nearly all children with this condition are maintained on

lifelong antibacterial prophylaxis. 

Adequate drainage can be obtained with clean intermittent catheterization, but this can be difficult because

children with prune belly syndrome have normal 

urethral sensation and some have urethral anomalies.

For this reason, a continent abdominal stoma, an 

opening to the surface of the body, may be useful. 

Persons who survive infancy with mildly impaired 

kidney function may develop kidney failure as a result 

of chronic pyelonephritis and damage to nerves from

reflux (reflux nephropathy). Clean, intermittent selfcatheterization to alleviate chronic retention should 

be performed. Kidney transplantation can be performed

successfully. Early intra-abdominal repair of testicles 

is warranted in boys with prune belly syndrome because

repair in infancy allows placement of the testicles into

the scrotum without division of the spermatic vessels,

which may not be possible later in life. Although likely 

to be infertile, these children may benefit from advances

in fertility techniques in the future. Major reconstruction of the abdominal wall can be done at the same time

as orchiopexy. 

Ureteroceles—A ureterocele is a cystic dilatation of the

terminal intravesical segment of the ureter. Ureteroceles

are discovered in 1 in 500 autopsy cases. They occur four

to seven times more frequently in females and are more

common in white children. Ureteroceles are bilateral in

10 percent of cases. Eighty percent of cases are associated with the upper pole of a duplex system, and 60 percent have an orifice located ectopically in the urethra. 

Ureteroceles are classified as being either intravesical

(within the bladder) or ectopic (some portion extends

beyond the bladder neck). Other terms commonly

encountered include stenotic (intravesical with a small

orifice), sphincteric (ectopic with the orifice within the

urethral sphincter), sphinctero-stenotic (same as sphincteric with a stenotic orifice), and cecoureterocele (some

part extends beyond the bladder neck, but the orifice is

in the bladder). 
A Strategic Plan for Research 75

In the first few months of life, children with a ureterocele are most commonly diagnosed by a clinician who is

seeing them for symptoms of a urinary tract infection.

Some ureteroceles are detected incidentally on antenatal

ultrasonography. Some children may have a palpable

abdominal mass secondary to an obstructed kidney.

Although urethral obstruction is rare, the most common

cause of urethral obstruction in girls is urethral prolapse

of a ureterocele. 

Diagnostic tests for ureterocele are abdominal ultrasonography; intravenous urography (IVU); voiding 

cystourethrography (VCUG), which is performed in 

all children with this problem; renal scan, which 

will determine the relative function of all the renal 

segments; and cystoscopy. 

The type of treatment of a ureterocele depends on the

type and the mode of presentation. Most children will

require surgery, which ranges from endoscopic incision

to complete open reconstruction. If the child presents

with sepsis, secondary to obstruction, then immediate

drainage of the kidney is necessary. Often, endoscopic

incision of the ureterocele is the first step. 

Ectopic ureters—The ureters normally insert into 

the bladder wall in the trigone region of the bladder. 

When a ureter inserts below this region, it is said to be

ectopic. The ectopic ureteral opening is always along the

pathway of normal development of the mesonephric 

system. Thus, in boys, it may lie in the bladder neck,

prostate (to the level of the ejaculatory duct orifice), 

or even along the course of the male genital system,

including the epididymis. In girls, the orifice may lie 

in the bladder neck, urethra, vagina, or, rarely, in the

cervix and uterus.

Ectopic ureters occur more commonly in girls than in

boys (ratio of 6 to 1). Approximately 70 percent of

ectopic ureters are associated with complete ureteral

duplication. Boys are more likely than girls to have single 

system ectopia.

Associated with

this condition, is a

high incidence of

abnormal tissue

development in

the segment of the

kidney parenchyma that is drained

by the ectopic

ureter. Also, the

incidence of 

contralateral

duplication is as

high as 80 percent. 

In boys, ectopic

ureters are usually discovered during an evaluation 

for urinary tract infections. If the ectopic ureter enters

the genital ducts, epididymoorchitis, a simultaneous

inflammation of the epididymis and testis, is possible.

Boys never present with incontinence because the

ectopic ureter is always inserted above the external 

urethral sphincter.

In infancy, girls usually present at examination with a

urinary tract infection. However, older girls tend to

present with incontinence. This is usually described 

by the parent as the child always being wet even though

she has normal voiding habits, or the child becoming

more wet when sitting on the parent’s lap (urine pooling

in the dilated ureter or vagina). If the ectopic ureter is

located outside the urethra and the kidney has developed

abnormal tissue, some children may have pyonephrosis,

pus in the kidney that distends the pelvis and calyces. 

Diagnostic tests for ectopic ureter are abdominal 

ultrasonography; intravenous urography (IVU); voiding

cystourethrogram (VCUG); dye tests, if the sonogram,

IVU, and VCUG fail to establish the diagnosis; diuretic

renography, an important test to assess upper pole 

renal function before surgery; and cystoscopy, which 

can be helpful in identifying the ureteral orifice within

the urethra. 

Facts about Ectopic Ureters

• More common in girls 

than boys (a ratio of 6:1)

• Usually discovered during 

a doctor’s visit for UTI

• Often associated with

abnormal tissue development in the kidney

• Requires surgery or 

bladder reconstruction 

or replacement.
76 OVERCOMING BLADDER DISEASE

The type of surgical treatment of ectopic ureter depends

on whether or not it presents in a duplex or single system. At times when the bladder is totally dysfunctional,

bladder reconstruction or replacement may be needed.

This is usually done using intestinal segments. Urinary

tract reconstruction may also be required in children

with bladder dysfunction that is secondary to spinal cord

injuries, myelomeningocele (protrusion of the spinal

cord and it membranes through a defect in the vertebral

column), posterior urethral valves, cloacal anomalies,

exstrophy, and other bladder abnormalities. 

The ideal bladder augmentation or bladder substitution

technique has been elusive. Current methods incorporate gastrointestinal segments into the urinary tract and

result in many complications. These complications

include calculi (stones), electrolyte imbalance, mucus

production, bone demineralization, and perforations.

None of the current reconstructive or replacement 

techniques is ideal.

Current Research 

Research on the developmental anomalies of the lower

urinary tract has been woefully lacking. Currently, 

only five studies of lower urinary tract development are

sponsored by the National Institutes of Health (NIH).

Much more needs to be done to determine the causes 

of these devastating conditions, which engender much

suffering and debilitation for children and their families. New research studies are needed to build on the

current state of knowledge determined by previous

research. These studies should focus on 

• Nitric oxide protective mechanism of fetal bladder

function

• Developmental aspects of calcium mediation of 

contraction. Past studies have shown that the fetal

bladder is more dependent on extracellular calcium

for mediating contraction, thus indicating a significant difference between the bladders of fetuses 

and newborns and the bladders of adults in their 

sensitivity to calcium channel blocking agents and

potassium channel openers 

• Coordination between vascularization of the 

developing bladder’s smooth muscle elements 

and the contractile function of the smooth muscle.

(Since ischemia may be a major factor in fetal 

bladder dysfunction, this is an important focus 

area for future research.)

• Genetic characterization of bladder problems

• Bioengineering of bladder tissue

• Pharmacologic manipulation of continence with 

relation to bladder innervation

• Mesenchymal epithelial signaling in development

and disease

• Fetal and developmental bladder physiology

A voiding cystourethrogram of an infant girl with a febrile urinary tract 

infection shows bilateral grade 4 vesicoureteral reflux. On voiding, the urine 

backs up from the bladder (bottom) into the ureter and kidney (upper right). 

(Photo Credit: Digital Urology Journal, Pediatric Uroradiology Rounds, Reflux 

and Intrarenal Reflux, http://www.duj.com. Copyright Digital Urology Journal)
A Strategic Plan for Research 77

• Defining bladder markers (characteristics or factors

by which a cell or molecule can be recognized and

identified) such as uroplakin

• Epithelium-stroma interactions

• Fetal sheep model of bladder development

• Fetal surgery

• Tissue engineering 

Research Opportunities

Research opportunities exist in many areas that have

been virtually ignored by research projects. Research

studies are needed to 

• Characterize and define the epithelium

• Characterize and define the stroma and the smooth

muscle cells

• Determine the epithelial-mesenchymal interactions

in the normal state and during disease

• Identify growth factors

• Explain the process involved in bladder 

wound healing 

• Develop new techniques and materials for 

bladder replacement 

• Determine the abnormal cellular signaling involved

in developmental anomalies

• Determine the genes involved in pediatric 

bladder disease

• Develop in vitro and in vivo models for bladder 

development with biomaterials

• Determine the efficacy and benefit of fetal surgery 

for bladder abnormalities

• Continue to develop fetal models of normal, 

obstructive, and neurologic injury

• Create a bank of human DNA samples 

(tissue samples)

• Apply genomic research to variants using microarrays

to determine polymorphisms related to variants

• Work with human and mouse genome initiatives

• Create animal models

• Understand the pathophysiology of bladder and 

urinary tract muscle developmental response in fetus,

neonate, and growth through adolescence associated

with non-obstructive and obstructive hydronephrosis

• Develop new fetal diagnosis and monitoring 

technologies for bladder and urinary tract 

developmental anomalies

• Explore the potential use of pharmacotherapy in 

the fetus

• Investigate the use of drugs to treat an uncoordinated sphincter 

• Determine the consequences of long-term pediatric

drug use

• Explore gender differences in pharmacological 

sensitivity

• Define the role of estrogen receptors in regulating

lower urinary tract function

• Determine differences in response to pharmacological agents among fetuses and neonates

• Institute preventive measures at childhood 

such as healthy bladder habits and pelvic floor 

muscle programs that can prevent future 

bladder dysfunction
78 OVERCOMING BLADDER DISEASE

Research Requirements

More investigators are needed in the field; therefore,

fellowships should be established in all areas that 

promote studies in bladder function. To advance 

this goal, the Bladder Research Progress Review 

Group (BRPRG) made the following suggestions:

• Provide academic fellowship training support

• Establish awards

• Offer loan forgiveness

• Make the grant award system less cumbersome

• Establish a means of time-sensitive interaction 

with the NIH 

• Recognize the clinical applicability and limitations 

of current models (animal versus human, female 

versus male)

• Establish curriculum on urinary incontinence in

medical schools

• Create tissue banks and urine storage for future 

studies on children with bladder dysfunctions.

• Encourage research that studies the spectrum of

bladder dysfunctions across the lifespan, from 

pediatrics to geriatrics. In this respect, the BRPRG

recommends that the NIH encourage new investigators in this field under the auspices of established

bladder investigators.

Recommendations for Specific Conditions

The BPRG made the following specific research 

recommendations for each developmental condition

described in this chapter and for other related disorders. 

Myelodysplasia, Spina Bifida 

• Explore the means to prevent spina bifida through

diet, fetal treatment, or C-section

• Explore the efficacy of neonatal versus delayed 

treatment of bladder dysfunction

• Address the psychosocial effects of spina bifida 

and bladder dysfunction

• Investigate the long-term outcome of bladder 

dysfunction in persons with spina bifida

• Investigate the effects of early pharmacological 

therapy

• Determine the feasibility of re-innervation of 

the bladder

• Identify the genes that are involved and determine

how reversible they are, either genetically or 

pharmacologically 

Vesicoureteral Reflux 

• Develop non-invasive diagnostic techniques

• Determine the risk of stopping antibiotic prophylaxis

• Determine long-term outcomes and fetal and 

maternal risk

• Establish genetic markers

• Develop endoscopic surgical approaches and

injectable materials
A Strategic Plan for Research 79

Posterior Urethral Valves 

• Develop non-invasive diagnostic techniques

• Develop fetal intervention techniques for renal and

bladder function

• Determine long-term outcomes

• Identify genetic markers

• Develop endoscopic surgical approaches

• Develop new drug therapies

Urinary Incontinence, Dysfunctional Voiding, and Enuresis

• Determine the mechanisms of normal voiding

• Identify genetic markers

• Develop new pharmacologic interventions

• Establish awareness and education programs

Exstrophy-Epispadias Complex, Imperforate Anus, 

Prune Belly Syndrome

• Develop better diagnostic techniques

• Identify genetic markers

• Develop new pharmacologic interventions

• Establish awareness and education programs

• Improve surgical techniques

Ureterocele, Ectopic Ureters

• Develop diagnostic techniques

• Identify genetic markers

• Develop new pharmacologic intervention

• Establish awareness and education programs

• Determine long-term outcomes

• Define obstruction

• Determine who needs treatment

• Identify the need for antibiotic prophylaxis

• Develop new surgical techniques

• Establish embryological studies 
80 OVERCOMING BLADDER DISEASE

PATIENT PROFILE

Colin Golliver and his twin brother, Sean, were born seven and 

a half weeks prematurely with serious problems that even an

ultrasound did not entirely anticipate. Sean had two large 

hernias that caused him a great deal of pain, but Colin had

cloacal and bladder exstrophy, one of the most serious birth

defects a newborn could face.

“When my doctor first saw Colin, he couldn’t tell if he was a 

boy or girl,” says Susan Golliver, the twins’ mother. “He had 

an exposed bladder that seeped urine, his abdominal organs

herniated into the umbilical cord, his penis was in two parts,

and his testicles were inside his body.” In addition, his mother

said, Colin’s large bowel was in two parts and his spinal 

cord was tethered,” that is, strands of it were attached to his

tailbone, a problem that would cause him to develop nerve

damage resulting in numbness or loss of feeling in his legs 

as he grew. 

Cloacal and bladder exstrophy is a rare and complex congenital

malformation that occurs in the embryo during the early weeks

of pregnancy when tissues that form organs are developing. It

requires skilled medical and surgical care for years after birth.

Infants born with this malformation have abdominal organs

located outside the abdomen, an open bladder, a rectum that

communicates with the bladder, absence of the rectum’s normal anal opening, spinal defects, and a pelvic bone separated

in the front. In girls, the vagina is often absent and the clitoris

is split in two; in boys, the penis and scrotum are divided into

two halves. The cause of cloacal exstrophy is unknown, and in

many parts of the world, boys who are born with it are often

surgically converted to girls.

Immediately after birth, Colin was transferred to the pediatric

intensive care unit of Children’s Hospital in Tulsa, Oklahoma,

an hour and a half from his home. Three days later, he had the

first of many surgeries to correct his problems. Because his

upper colon was not connected to the rectum, surgeons 

connected it the surface of his abdomen, where his bowel

movements could now be eliminated into a bag that would 

be glued to the skin surrounding the stoma or abdominalintestinal opening. The surgery went well and in November,

Colin re-entered the hospital for his next surgery–freeing his

spinal cord from his tailbone. This surgery also went well, but

his parents and physicians would not know how this problem

would affect his ability to use his legs until he developed further.

The following December, after receiving two hormone injections

to enlarge the two halves of his penis so that they could be

joined, Colin had his third major surgery, which lasted 14

hours. Surgeons closed the bladder, repaired his hernias, 

surgically constructed an anus, brought his undescended 

testicles to the outside of his body, and joined the two portions

of his penis. Fixator pins were also inserted into the two 

sections of Colin’s pelvis to join the pubic bones. 

Colin’s post-operative period was as complicated as his 

surgery. Because of the fixator pins, he had to lie on his back

for several weeks, making normal things that parents do for

their babies–bathing, feeding, burping, diaper changing, and

cuddling, for example–extremely difficult. In addition, Colin’s

mother also emptied her son’s colostomy bag and provided skin

care for the area around the stoma. “We couldn’t hold Colin, 

but we talked to him a lot,” says Golliver, who expressed her

milk and fed him with a bottle. At times, she even bent over

him and nursed him. By the end of January 2002, six weeks

after surgery, Colin was doing well. His repaired bladder, which

Colin Golliver

Cloacal and Bladder Exstrophy

The Golliver Family (Colin shown on left)
A Strategic Plan for Research 81

surgeons cautioned often doesn’t stay sealed, was functioning

normally, and he was urinating on his own. However, Susan 

had to intermittently catheterize him to be sure his bladder 

was emptying.

In February, after a long winter of providing physical and 

emotional care to her three children, Susan Golliver became

seriously depressed. At this time, surgeons were anticipating

the next surgery–attachment of the two portions of Colin’s

bowel and repair of the stoma. To prepare her son’s colon for

the surgery, Golliver had to gradually dilate the stoma several

times a day with metal rods that increase in diameter. It was 

a procedure that caused Colin to scream in pain and his 

mother to crumble. 

“One day I woke up and thought, ‘What have I gotten myself

into? I just can’t handle this anymore,’” Golliver says. “I had

been strong for months because of the surgeries. I had been

going on adrenaline for so long.” 

Golliver attributes the depression to her disappointment that

she could no longer continue to nurse her sons and to the 

subsequent hormonal changes that were occurring as she

weaned them. Stress, lack of sleep, and the demands of 

her husband’s job, which was threatened by his company’s 

financial difficulties, were also contributing factors.

“My body just couldn’t keep up with the demand,” Golliver

explains. “I had had months of interrupted sleep, where I

couldn’t get more than two to three hours at a time.” She also

rarely left her house. Once she stopped nursing the twins, a

decision she made reluctantly, her husband Tom, who was

working long hours during the day, was able to share the night

shift with her. With more sleep, her depression began to lift.

Relatives were also able to pitch in even more than they 

had previously, including babysitting so that Golliver 

could run errands. 

In early April, Colin had his fourth surgery. The two portions 

of his colon were successfully connected making a colostomy

unnecessary. In May, at the age of nine months, a time when

most children are crawling, as is his brother Sean, Colin was

still having difficulty sitting in his high chair, but he was trying

to move about the floor by rolling, according to his mother. “The

pediatrician is not concerned,” she says, “because he has full

range of motion.” Colin is receiving physical therapy to

strengthen his muscles, and his mother believes that before

long he will be able to follow Sean’s lead.

Surgery to relocate the urethral opening from the backside of

Colin’s penis to the normal position at its tip is scheduled next.

Surgeons are also considering re-implanting a ureter into the

bladder because Colin has had two bladder infections and 

vesicoureteral reflux, a condition in which urine backs up into

the ureter(s) and kidney(s), where it can cause scarring and

impair function. Reflux is a potentially devastating condition 

for all children but particularly for Colin because he has only

one kidney. Constipation may also become a problem, even

though it has not happened so far. If it should become chronic,

his mother says further surgery will be necessary to keep the

bowel patent.

“It’s been a hard journey,” says Golliver, “but Colin is a blessing to our family. He has taught us to face each day with hope,

faith, and empathy for others. Through all of his trials, he has

been such a peaceful baby. God definitely gave him a sweet

disposition to deal with his pain.” Golliver also pays tribute 

to Colin’s surgeons, who she says treat him with respect and

dignity. “They are like an extended family to us, providing 

us with not only their medical expertise, but also great 

emotional support.”

Colin’s sister, Lauren, as well as her parents, are still puzzling

about why Colin developed this problem. “I told [Lauren] that

no one knows, but maybe she will become a doctor when she

grows up and figure it out,” Golliver says. “This type of birth

defect happens between the 8th and 12th weeks of pregnancy,

a time when most people don’t even know they’re pregnant.

Maybe in the future, scientists will find a way to prevent it 

or do something to correct it [before the child is born].”
82 OVERCOMING BLADDER DISEASE

PATIENT PROFILE

At the age of 18, Timothy Hawkins doesn’t remember much

about the pain and discomfort he experienced as a little boy,

when he was frequently sick. His mother, Mary Pat, says he

suppresses that memory because “he went through a lot.” 

What Tim does remember is as follows: Going to the bathroom

and seeing “all these lumps of things in my urine.” Having

high fevers and going in to the doctor’s office and hospital 

for numerous tests—“ultrasounds and a VCUG” or voiding 

cystourethrogram, a diagnostic test that involves threading a

catheter through the urethra, filling the bladder to maximum

capacity with a radiographic dye solution, and following the

flow of urine on x-ray as the child voids. Taking antibiotics

every day between the ages of three and five to prevent kidney

infection and to preserve kidney function. Going into the 

hospital with his parents for surgery when he was five years 

old for the removal of his right kidney. And having bad 

dreams after surgery that he thinks were caused by “the 

pain killers I took.” 

“My right kidney was deteriorating because I had reflux,” 

Tim says. “The urine backed up into both my kidneys, but 

the right one was worse. When I was in kindergarten the 

right kidney had to be removed.” Vesicoureteral reflux is the

abnormal flow of urine from the bladder back into the ureter(s) 

and kidney(s). It is the most common cause of kidney failure 

in children and is usually diagnosed when a urinary tract 

infection or UTI occurs. 

About one-third of children with UTI have reflux, which can

occur from primary or secondary causes. Primary reflux occurs

during fetal development when the tunnel in the bladder wall

where the ureter inserts fails to grow long enough, thereby 

preventing the valve that forms at that juncture from closing

properly. This permits backflow of urine and bacteria into the

ureter(s) and even the kidney(s). Secondary reflux occurs as 

the result of conditions such as posterior urethral valves 

(see profile of Hayden Gantz, Chapter 7), which obstruct the

urethra, or bladder infection that causes swelling.

Tim’s mother has more vivid memories of those years. She

describes Tim’s fevers, which were also caused by ear infections, as “raging” and frequent, and remembers putting him in

a tub of tepid water to bring them down. She remembers her

son telling her at the age of three that “sometimes poop comes

out from where I pee” and the horror she felt when she saw

dark lumps in the bottom of the toilet bowl after he urinated

standing up. She remembers the anger and frustration she felt

toward Tim’s pediatrician when he told her over the phone that

she was probably over-reacting and that she should give her

son cranberry juice. 

“Neither Tim’s pediatrician nor the emergency room physicians

took a urinalysis to see if the problem was caused by a urinary

tract infection, a sign of reflux,” Mary Pat says. “A urinalysis is

now done routinely when a child has a high fever.” 

She also remembers her father, a physician, urging her to ask

Tim’s doctor to perform an ultrasound to visualize Tim’s urinary

tract, and she remembers making an urgent phone call to her

sister-in-law, a radiologist, to ask her to find someone who

would do this when Tim’s physician said it was unnecessary. 

Mary Pat and her husband Jim soon decided that they needed 

to consult a pediatric urologist at a major medical center. 

“She placed Tim on continuous antibiotic therapy to see if 

his kidneys would heal,” Mary Pat explains. Antibiotic therapy

usually corrects secondary reflux caused by infection, and 

it prevents further damage if the cause is primary, that 

is, genetic. 

Timothy Hawkins

Vesicoureteral Reflux
A Strategic Plan for Research 83

Many children also outgrow reflux. During a period of “watchful

waiting” to see if this would occur, Tim was monitored at 

intervals with urinalyses, ultrasounds, and VCUGs. However,

when he was five years old, it became obvious that the right

kidney was not going to heal, and it had to be removed.

By age nine, Tim’s urologist determined that his reflux was 

primary and that it had not improved in the left ureter. 

Re-implantation of the ureter was now necessary because 

his urologist feared that in time it would cause further damage

to his remaining kidney. The surgery involved lengthening 

the canal in the bladder wall where the left ureter inserts 

and then re-implanting the ureter. 

Tim describes his life since his surgery as “fairly normal.” 

He graduated from high school last June and this fall will go 

to Santa Clara University in California. Although he has not

been able to play contact sports since his first surgery because

of the risk of injury to his remaining kidney, he has found other

outlets for his interest in sports. He played Little League 

baseball for a few years, learning to bat left handed so that 

if he were hit by a wild pitch, the side that doesn’t have a 

kidney would absorb the impact. But when the pitches got 

faster, he decided it was time to drop out. In high school, he

took up golf, which he has grown to love, and has played on 

his school team. “I sometime wish I could play football, though,

but that’s not an option,” he adds.

Tim has been monitored with ultrasounds periodically to see 

if his remaining kidney is growing. “It grows larger to make 

up for the kidney that was removed,” he explains. He recently

had an MRI to check on scarring in that kidney. “Everyone has

a little scarring. It can occur when you hold back going to the

bathroom,” he says. “But I’m more susceptible to it because 

of the reflux.”

Recently, one of Tim’s younger cousins was discovered to have

reflux after he developed bladder control problems and side

pain. At the age of 6, the cousin’s ureter was reimplanted.

Because of the familial implications, Tim has begun to think

about what a genetic disease will mean for his children. 

“My doctor says that some reflux is genetic and there’s a good

chance that my kids would have the same problem with reflux,”

he says. “Maybe by doing research, doctors could test my kids

before they develop problems or even before they’re born so 

that they don’t develop scarring and high blood pressure or 

lose a kidney.”

The Hawkins Family (Tim, second from left)
CHAPTER 6
A Strategic Plan for Research 85

Common Clinical Conditions

UROLOGIC DISEASE IN MATURATION AND AGING

DID YOU KNOW?

. During aging, the urethra 

deteriorates in many people, 

and urethral pressure declines 

1 percent per year.

. Aging causes a decline in the

bladder’s ability to contract 

but also a dramatic increase 

in the prevalence of involuntary

contractions.

. Aging causes a decline in 

bladder capacity.

. Prostate enlargement and outlet

obstruction are common and

costly problems in aging men.

. Urinary incontinence caused 

by changes in the urethra and

bladder is a common and costly

problem for aging women.

Summary and Recommendations

For reasons that are not well understood, the incidence and prevalence 

of urologic disease—especially urinary incontinence, benign prostatic 

hyperplasia (BPH), urinary tract infections, prostate cancer, and neurogenic

bladder—increase with age. The aging process itself, even in the absence 

of disease, is likely a major contributor. 

Unfortunately, little is known about the effects of age on the bladder and 

urethra. The dearth of human research in this area and the lack of accepted

experimental models have hindered medical knowledge about the urologic

problems of maturation and aging and limited prevention and treatment

options as well. The little data that are available from clinical studies suggest

that lower urinary tract function changes substantially with age. In women,

urethral length and elasticity, as well as sphincter strength, seem to decline

with age. In men, the prostate enlarges, although it is not known why there 

is variability in the degree of growth and its varied effects to bladder function

on storage and emptying 

After an extensive and comprehensive review of this research area, the

Bladder Research Progress Review Group (BRPRG) has recommended 

that future research do the following:

* Investigate the developmental mechanisms and the disease mechanisms of 

the lower urinary tract at the molecular, genetic, and cellular levels to identify 

the causes of neurogenic bladders, voiding problems, and problems causing

obstruction to urination and to develop better treatment for these disorders.

* Examine the aging urinary tract at the molecular and cellular levels and 

understand the causes of dysfunction.

* Establish clinical research programs that deal with the pathophysiology and 

management of the aging and dysfunctional urinary bladder and sphincter.
86 OVERCOMING BLADDER DISEASE

Specific studies related to each of these areas have 

been recommended by the BRPRG and are listed below:

* Developmental and Disease Mechanisms 

• Genetic mechanisms

• Molecular and cell biology

• Developmental markers 

• Stem cell and cell lineage studies

* Epidemiology and Genetics 

• Longitudinal studies

• Prospective database

• Validated questionnaire

• Psychosocial factors

• Identification of developmental risk factors 

leading to adult lower urinary tract dysfunction

* Epigenetics

• Urinary tract infection

• Aging

• Clinical studies of normal older people coupled

with basic science (molecular and cell biology) 

• Relevant experimental models

Background

Lower urinary tract function changes substantially 

with age, according to some research studies on human

subjects. In women, the length and elasticity of the 

urethra appears to decline with age, and sphincter

strength seems to diminish. In men, the prostate

appears to enlarge, although whether or not this is 

true in all men is unknown. 

An improved understanding of the development of 

the lower urinary tract will provide greater insight into

disorders brought on by maturation and aging and facilitate their prevention and treatment. Many adult bladder

pathologies such as obstruction and loss of nerve supply

recapitulate fetal events. 

The Urethra and Urinary Incontinence 

The urethra is the organ that provides closure of the

lower urinary tract and prevents incontinence. Urinary

incontinence (UI) is a remarkably common condition, 

particularly in women. The medical and work-related

costs of urinary incontinence are estimated to be 

$26 billion dollars per year. 

The two most influential urethral factors in urinary

incontinence are urethral function and urethral 

support. Despite the high prevalence of UI, almost 

nothing is known about the factors involved in the

growth and development of a proper urethra (or its 

support structures); how the urethra deteriorates 

with age; and how good function and support can 

be maintained throughout maturation and aging.

The urethra has a complex layered structure, including

circular striated, longitudinal, and smooth muscle surrounding a specialized sealing core of blood vessels and

mucosa. Once formed, the urethra deteriorates during

the aging process. Urethral pressure declines 1 percent

per year after adulthood. Early exploratory studies 

have indicated that striated muscle cell numbers in 

the urethra decline 2 percent per year; loss of smooth
A Strategic Plan for Research 87

muscle has not been studied. This loss of striated muscle

is twice as great as that found in other parts of the body,

and the cellular and genetic factors for this accelerated

loss are not known. 

Perhaps the greatest human sexual dimorphisms exist 

in the urethra. Gaining insight into the development 

and physiology of the female urethra should lead to

important improvements in understanding urinary

incontinence and its treatment. For example, if the

mechanisms for increased deterioration in the muscle

within the urethra wall were known, preventive strategies might be sought and advice given to women to 

prevent this problem from developing. 

Understanding why some women lose muscle must 

be based on an understanding of the cellular and 

genetic mechanisms that maintain normal muscle 

bulk. The effect of neural connections, growth factors,

vascular supply, proper response to normal stresses, 

and the signals and genetics of these processes in the

urethra deserve research attention equal to that in 

the bladder. 

The signaling mechanisms that result in the proper 

orientation, integration, and maturation of the urethra’s

muscle layers are virtually unstudied. In addition to

forming adequate quantities of smooth and striated

muscle, the urethra must integrate with the abundant

connective tissue in the sphincter to effect closure.

Failure of these critical steps could lead to inadequate

closure of the sphincter in the adult. Identification of 

the processes of urethral function and the genes that

control them may explain the known familial aspect 

of urinary incontinence. 

A second area important to continence concerns the 

levator ani muscle (the muscle that raises the pelvic

floor) and the endopelvic fascia. Contraction of the 

levator ani muscle at the time of increased abdominal

pressure plays an important role in maintaining urethral

closure and integrity of this mechanism. Connective 

tissue supports of the urethra connect the muscles to 

the urethral support apparatus and provide strength 

to the urethra in maintaining continence.

Bladder Dysfunction 

In both sexes, aging appears to cause a decline in the

contractility of the bladder’s detrusor muscle and a 

dramatic increase in the prevalence of involuntary

detrusor contractions. Aging also appears to cause 

a decline in bladder capacity. Furthermore, the 

ultra-structure of the bladder muscle (detrusor) 

may change substantially with age. In the only study 

of this to date, aging was associated with an increase 

in the space between or among cells; a decrease in the 

density of normal smooth muscle junctions (adherens);

and the appearance of junctions called protrusion 

or abutment junctions, which are not seen in 

younger people.

In the protrusion or abutment junctions in older people,

the space between cells is significantly smaller than in

normal smooth muscle junctions. Two other features 

of bladder muscle in younger people are also absent: 

(1) the abutting basement membranes that interpose

central linear density and (2) the dense plaques 

normally present below the sarcolemma that anchor 

the converging ultramicroscopic threads of proteins 

that make up muscle fibrils (myofilaments). Such

changes may reflect de-differentiation and may even 

set the stage for the emergence of involuntary bladder

muscle contractions in the elderly. 

A dramatic decrease also occurs in the number of cell

caveolae, small pockets in cells that extend outside the

cell wall; this phenomenon may mediate the decline 

in muscle contractility. Because these data, like the 

physiological data cited previously, are virtually all

derived from small, cross-sectional studies, it is not

clear how much this decrease in caveolae reflects the

process of aging itself or the influence of cohort and 

secular effects (e.g., the number of pregnancies, the

obstetrical practice). The impact of subclinical neurological disease has not been well addressed in studies,

further limiting the ability to disentangle the effects 

of the aging process from other factors. Moreover, 

the cause of such changes—regardless of underlying

associations—is completely unexplored. 
88 OVERCOMING BLADDER DISEASE

The changes brought on by aging are virtually uninvestigated in other important areas as well. These areas

include epithelial structure and function, bladder

immune function, and changes in neural control 

stemming from changes in the neural axis from the 

cerebral cortex to the nerves that innervate the bladder.

Nighttime voiding or nocturia is another common 

problem faced by elderly men and women, and it is

reported in approximately 80 percent of persons over

age 75. Nocturia causes significant sleep deprivation and

has been reported to be a cause of falls and hip fracture.

Therefore, in addition to morbidity, it has a significant

impact on quality of life and medical costs. 

Besides developing abnormal bladder elasticity, older

people can also develop poor bladder contractility 

secondary to muscle and nerve damage incurred by 

other illnesses associated with aging (e.g., diabetes).

Secondary dysfunction causes significant morbidity.

Damage incurred during surgery and possibly from 

aging of the musculature of the urinary bladder 

sphincter can also lead to significant morbidity 

from urinary incontinence. 

Outlet Obstruction and Post-Prostatectomy Incontinence

As men age, the prostate enlarges. Obstruction of the

bladder outlet is a common outcome that can affect bladder function and have a great economic impact on older

men. Overactive bladder is also increasingly prevalent in

aging men, as a consequence of obstruction, as a function of aging, or both. 

A clinically significant decrease in bladder elasticity

occurs in approximately 20 percent of men with benign

prostatic hyperplasia (BPH). In the United States, about

two in ten men with BPH will have prostate surgery for

relief of obstruction; however, relief does not necessarily

return the bladder to a normal state. 

Prostate cancer starts to have an impact on men in 

their sixth decade of life and beyond. As more and more

younger, healthy men undergo radical extirpation of the

cancerous prostate, the incidence of post-prostatectomy

urinary incontinence increases. These problems are

serious and, although not life-threatening, have a dramatic impact on quality of life and overall medical costs.

The incidence of post-radical prostatectomy incontinence ranges from a low of 5 percent to a high of 60 percent, depending on whether the physician or the patient

is reporting outcomes. Risk factors for this problem have

been identified and include age and pre-existing bladder

and sphincter dysfunction. Recent studies indicate that

outcomes of surgical intervention for prostate cancer

may depend on the specific techniques used to perform 

a radical prostatectomy. 

[Editor’s Note: Problems in the lower urinary tract that are related to aging 

such as obstruction of the bladder outlet and urinary incontinence will also 

be discussed in subsequent chapters with those titles.]

Current Research 

Current research on bladder development includes 

studies on

• Laboratory models of human urothelium

• Amphibian bladder/No glucose transport model 

• HOXA 13 regulation of vascular development 

• Urogenital smooth muscle development

• Bladder remodeling and the role of growth factors

• Elastic microfibrils

The National Institute of Diabetes, Digestive, and 

Kidney Diseases (NIDDK) is currently funding studies 

of prostatitis, medical therapies of prostatic symptoms,

urinary incontinence treatment, and interstitial cystitis

treatment. Few individual grants are directed to the 

non-surgical management of urinary incontinence.

Major areas of recent advances in understanding the

effects of maturation and aging are as follows:

• Genetic characterization of bladder problems

• Bioengineering of bladder tissue
A Strategic Plan for Research 89

• Pharmacologic manipulation of continence with 

relation to bladder innervation

• Mesenchymal epithelial signaling

• Definition of bladder markers (uroplakin)

• Epithelial/stroma interactions

• Fetal sheep model of bladder development

• Tissue engineering 

• Neuromodulation of the sacral reflex arc to manage

bladder dysfunction

Research Opportunities

Future research on the bladder and urethra during 

maturation and aging could focus on the following areas:

* Basic Mechanisms of Development and Aging 

• Characterize and define urothelium, stroma, 

and smooth muscle cells

• Identify eptithelium-mesenchyme interactions 

in normal state and during disease

• Determine the relationship between growth 

factors and adhesion

• Explore the mechanisms of bladder wound healing

• Explore new techniques for bladder replacement 

• Identify abnormal cellular signaling mechanisms

• Develop laboratory and human models for bladder

development with biomaterials 

* Genome Studies

• Identify and analyze genetic risk factors related 

to complications (e.g., renal insufficiency) 

• Create a bank of human DNA samples 

• Apply genomic research to variants using 

microarrays to determine polymorphisms related

to variants 

• Collaborate with human and mouse genome 

initiatives

• Create animal models

• Determine the effect of developmental bladder

anomalies on an aging population (i.e., dysfunctional voiding effects on later incontinence in 

elderly people)

* Pharmacology Studies

• Identify sex differences in pharmacological 

sensitivity

• Determine the role of estrogen receptors in the

regulation of lower urinary tract function

• Identify the differences among adults, including

the elderly, in response to pharmacological agents 

* Studies of Adult Women 

• Gain insight into the development and physiology

of the female urethra that will facilitate treatment

and prevention of urinary incontinence (UI)

• Conduct longitudinal studies to understand 

the natural history of bladder diseases (i.e., the

effect of early bladder disease on later bladder

dysfunction)

• Elucidate opportunities for prevention (obstetric)

of UI

• Explore opportunities for enhanced surveillance

of hormonal effects and their influence on 

continence and incontinence

• Advance the knowledge of familial and genetic

influence on continence mechanisms

• Investigate the relationship between UI and 

pelvic organ prolapse in women. 
90 OVERCOMING BLADDER DISEASE

* Studies of Adult Men

• Determine and understand the risk factors that

influence development of post-prostatectomy

incontinence, incontinence that often develops

after the prostate gland has been removed. 

A prospective study that considers good baseline information regarding continence status 

and other potential risk factors is necessary 

to understand and potentially to prevent the 

occurrence of incontinence after prostatectomy.

* Other Studies

• Create a longitudinal population database focusing

on bladder function from childhood to aging. This

database would pursue the prevalence and incidence of, and the risk factors for, various bladder

dysfunctions (obstructed and irritative symptoms)

and urinary incontinence. More specifically, the

database would support a longitudinal study of

children with specific bladder dysfunctions who

would be monitored through childhood and 

adulthood. Ideally, data collection could include

collection and preservation of tissue as well as

documentation of symptoms and physical and

urodynamic findings. 

• Establish an animal model that could mimic 

the aging human bladder.

• Study the central nervous system’s (CNS)control

of human voiding in people with normal and 

abnormal bladder function. New technology 

such as magnetic resonance imaging (MRI) 

and positron emission tomography (PET) could 

be used to monitor control sites in the CNS

• Conduct studies to clarify the cause of nocturia in

the elderly; this condition has a significant impact

on their quality of life and on medical costs.

• Study childhood preventive measures such 

as healthy bladder habits and pelvic floor 

muscle programs

Research Requirements

Future research would benefit from the following areas:

Workforce

• Provide academic fellowship training support

• Establish awards

• Offer loan forgiveness

• Make the grant award system less cumbersome

Infrastructure

• Establish curriculum on urinary incontinence 

in medical schools

• Create tissue banks and urine storage for future 

studies on people with bladder dysfunctions

Implementation

• Develop a mechanism for time-sensitive 

interaction with NIH

• Recognize the clinical applicability and limitations 

of current models (animal versus human, female 

versus male)

• Encourage research that studies the spectrum 

of bladder dysfunctions across the lifespan, 

from childhood to old age 

• Encourage new investigators in this field under 

the auspices of established bladder investigators
A Strategic Plan for Research 91

PATIENT PROFILE

At the age of 68, after his prostate gland had been surgically

removed because of cancer, Alfred Artzberger became incontinent. At first, surgeons thought the incontinence was the result

of scar tissue forming in the upper urethra, where the surgery

had been performed. Scar tissue interferes with the ability 

of the urinary sphincter, the circular muscle that controls 

the bladder outlet, to stay contracted. To correct the incontinence, surgeons dilated the scar tissue several times and 

then removed it, but Artzberger remained incontinent.

Eventually his physicians concluded that during the delicate

cancer surgery, a small section of the sphincter muscle 

had been excised along with the prostate. Artzberger’s 

incontinence would be permanent.

“I leaked all the time,” Artzberger says, “so I had to wear 

diapers. These were thin children’s diapers—Huggies 5—

which caused little to no discomfort.” He continued to work 

as a sales executive and brought small plastic bags to work

with him so that he could dispose of the diapers in the normal

trash. He also informed his co-workers about his problem.

Eventually, Artzberger began to investigate possible solutions 

to his bladder problem. At the urging of his son, a physician, 

he consulted an expert on incontinence, who suggested a 

surgical implant of an artificial sphincter, a relatively 

new technology. 

An artificial sphincter functions much like the 

biological one—it regulates the bladder’s ability to store 

and empty urine. The implant consists of a cuff that fits around

the bladder neck, a pressure-regulating balloon that is placed

under the abdominal muscles and filled with liquid, and a 

control pump that inflates the cuff so that the urethra will 

close tightly. The control pump mechanism is usually placed 

in the scrotum for men and in the labia for women. The 

artificial sphincter stays contracted while the bladder fills 

up. When Artzberger feels pressure from the full bladder, 

he goes to the bathroom as usual and relaxes the sphincter 

by pressing the valve in his scrotum. 

“The bladder empties as near to normal as you can get,” 

he says. “The only thing that’s different is that after voiding, 

I have to wait about 20 seconds to allow the sphincter to

close.” Not everyone with an artificial sphincter implant 

has such positive results. Some patients experience urethral

erosion—the eating away or inflammation of the surface 

layer of the urethra—or mechanical failure of the artificial

sphincter, which must then be removed surgically. Infection 

is also an issue. “I’ve had tremendous success with the 

artificial sphincter,” Artzberger says, “and I’m back to a 

normal life.”

Five years after the implant, he continues to have good 

results and has had no adverse reactions. As a retiree 

at the age of 74, he plays tennis, enjoys golfing, does 

woodworking, and goes on vacations.

Alfred Arzberger

Post-Prostatectomy Incontinence
CHAPTER 7
A Strategic Plan for Research 93

Common Clinical Conditions

BLADDER OUTLET OBSTRUCTION

DID YOU KNOW?

. Congenital bladder obstruction

can cause irreversible bladder

changes and life-threatening

kidney problems.

. Functional bladder obstruction

— the loss of coordination

between the bladder and its 

outlet—is a major problem 

for people with neurological 

disorders such as multiple 

sclerosis.

. In most men, the prostate

enlarges as they age, causing

urinary frequency, urgency, 

nighttime voiding, and slow

stream that can be not 

only annoying, but also 

life threatening.

Summary and Recommendations

Bladder outlet obstruction is a common condition, particularly in 

aging men, most of whom develop enlargement of the prostate gland 

or benign prostatic hyperplasia (BPH). Obstruction of the lower urinary 

tract may have several devastating consequences, including upper 

urinary tract deterioration with hydronephrosis (dilation of the pelvis 

and calices of one or both kidneys) and kidney failure. In children born 

with developmental bladder obstruction such as posterior urethral 

valves (see Chapter 5, Problems of the Developmenting Genitourinary 

Tract in Children), obstruction causes not only irreversible bladder 

changes, but also life-threatening kidney changes. 

For men with BPH, the more common and bothersome symptoms are 

those that have to do with voiding because they affect quality of life. 

BPH causes urinary frequency, urgency, slow stream, and nighttime 

voiding (nocturia), and it may also cause the bladder to empty incompletely. Incomplete bladder emptying is a predisposing factor for urinary

tract infection (UTI), and total urinary retention follows in many cases. 

Severe functional bladder obstruction also occurs in children with 

spina bifida, who can develop both severe urinary incontinence and 

kidney changes. People with neurological disorders such as spinal cord

injury, multiple sclerosis, and myelomeningocele (protrusion of the spinal

cord and its membranes through a defect in the vertebral column) often

develop voiding dysfunction as well. Voiding dysfunction results from 

the loss of coordination between the bladder and its outlet and is 

characterized by functional bladder obstruction. 
94 OVERCOMING BLADDER DISEASE

The Bladder Research Progress Review Group (BRPRG)

made the following recommendations for future

research efforts in bladder obstruction:

* Analyze the central and peripheral nervous system changes

that contribute to voiding dysfunction in people with outlet

obstruction, and thereby identify therapeutic interventions

* Determine the genomic and proteomic changes that 

underlie the alterations in the lower urinary tract that 

are produced by outlet obstruction, and thereby identify

therapeutic targets

* Determine the impact of age on pathophysiology and 

treatment outcomes for obstruction

Background

Epidemiology

The prevalence of histological BPH increases steadily as

a men age. Few men below age 30 have enlarged prostate

glands, but 50 percent of men between the ages of 60

and 69 and 90 percent of men between ages 70 and 89

have BPH. Similarly, the prevalence of bladder outlet

obstruction symptoms increases with advancing age.

Moderate to severe symptoms are present in 18 percent

of men ages 40 to 49 and in 56 percent of men ages 70 to

79. These symptoms increasingly interfere with quality

of life as men age, causing them to seek treatments. The

bladder’s response to obstruction is the primary determinant of symptoms after BPH develops; therefore,

emphasis on research in this area is crucial. 

Although the highest incidence of bladder outlet

obstruction is in the older male population, congenital

bladder obstruction is far and away the more devastating

problem because it results in life-threatening kidney

changes in addition to irreversible bladder changes. 

The incidence of children born with urethral valves has

been reported to be one out of every 5,000 to 8,000 male

births. Of those children, up to 25 percent will go into

end-stage kidney

failure, requiring

kidney dialysis and

transplantation.

According to the

2001 U.S. Renal

Data System

(USRDS) Report,

obstructive uropathy

accounts for 9 

percent of all endstage renal disease

in children.

Renal insufficiency

in childhood results

in many years of

therapy. The USRDS

reported in 2001

that the average cost of a year on kidney dialysis is

$50,000. Numerous other persons with urethral valve

obstruction suffer from mild to moderate renal insufficiency and have problems with urinary incontinence.

Most require pharmacological and behavioral therapy.

Up to 5 percent of boys with posterior urethral valves will

have voiding dysfunction that results in functional outlet

obstruction. The consequences of this include recurrent

UTI, vesicoureteral reflux (reflux of urine from the bladder into the ureters), and hydronephrosis (dilatation of

one or both kidneys). 

Severe functional bladder obstruction also occurs in

children with spina bifida, who can develop both severe

urinary incontinence and kidney changes. In addition,

neurological disorders such as spinal cord injury, multiple sclerosis, and myelomeningocele often lead to voiding dysfunction characterized by functional bladder

obstruction as a result of loss of coordination between

the bladder and its outlet.

Groups at Risk

• Aging men, who commonly

develop benign prostatic

hyperplasia (BPH)

• Children with developmental or congenital 

bladder obstruction 

(e.g., urethral valves)

• Adults and children with

neurological disorders 

(e.g., spinal cord injury,

multiple sclerosis, and

myelomeningocele)
A Strategic Plan for Research 95

Current Research 

During the past decade, a substantial number of basic

research grants from the National Institutes of Health

(NIH) have been awarded for research that focused 

on bladder obstruction. This work has been highly productive, and knowledge gained from it has led to many

more questions regarding the role of nerves, muscle,

epithelium, matrix, and blood vessels in the development of lower urinary tract dysfunction and symptoms.

Many of these issues are being investigated further in

basic science research projects focused on these areas.

Funding for NIH Research 

In fiscal year 2000, NIH-funded basic research on 

the effect of obstruction on bladder function was more

limited than in previous years. A review of the portfolio

identified a total of 10 individual NIH-funded grants.

Although some overlap clearly exists between these

grants in regard to research topics, the major topics

included obstruction-induced changes in collagen

expression, growth factors, contractile mechanisms, 

and metabolism. Only one grant focused on the effect 

of obstruction during development; the remainder 

dealt with obstruction in adults.

Major research topics that were not included in the 

portfolio included the effects of obstruction on the

urothelium (epithelium), blood vessels, and nervous

system, and the contribution of the nervous system 

to bladder symptoms induced by obstruction. 

In addition, the relevance of animal research to 

human research on bladder obstruction remains 

to be determined.

It is clear that only a small group of moderately 

experienced investigators is currently funded to study

the effect of outlet obstruction on bladder function. 

The focus of these studies is relatively narrow in scope 

in comparison to the large number of important topics 

in this field. NIH currently funds two ongoing clinical

studies of bladder obstruction. One is studying the 

effect of saw palmetto, an herbal product commonly 

used in alternative or complementary medicine to 

treat symptoms of BPH. The other is the multi-center

study, Medical Therapy of Prostatic Symptoms (MTOPS), 

which is looking at the effect of the drug, Proscar, 

on prostatic obstruction, and comparing it with the

effects of alpha-adrenergic blocking agents. 

An x-ray of a boy with posterior urethral valves (PUV) and associated

severe vesicoureteral reflux secondary to the PUV. Below the bladder

(center), on the left, is the posterior urethra, which has become dilated 

as the result of obstruction by valves. Above the bladder and to the 

right and left are ureters, which are dilated from the abnormal reflux 

of urine on voiding. 
96 OVERCOMING BLADDER DISEASE

Recent Advances 

Recent research has made several advances in the

understanding of the mechanisms of obstruction and in

the methods of treatment. These breakthroughs include

improved understanding of the following:

• Alterations in the afferent (inflowing) and efferent

(outflowing) nerves of the lower urinary tract after

obstruction occurs

• Roles of physiological and biochemical factors related

to, or dependent on, nutrition

• Roles of early response genes after outlet obstruction

occurs

• Role of the ischemia-reperfusion cycle in bladder

dysfunction after outlet obstruction occurs.

(Obstruction causes a decrease in local blood 

flow [ischemia], and when blood flow is restored 

[reperfusion], tissue is often injured by the 

release of certain chemicals)

• Role of aging in the development of symptoms associated with bladder outlet obstruction, as is evident

from the findings that elderly men and women have

similar sensory symptoms

• Alternative therapies that may be effective in the

treatment of obstructed bladder disorder

• Alterations in the extracellular matrix of the bladder

that may be caused by outlet obstruction

• Treatment of BPH, which according to the results 

of the MTOPS study is effectively treated with two

families of medications: one that decreases the size 

of the prostate and the other that alters bladder

response to obstruction, either locally or centrally 

Research Opportunities 

Opportunities for research in bladder obstruction 

exist in the topic areas of genomics, cell regulation 

and signaling, technology, behavioral therapy, 

health services and outcomes, and groups with 

special needs.

Genomics

Identifying the genes in each bladder cell type that 

is modulated by obstruction is critical. Based on 

this information, it would be valuable to develop

• Gene arrays to allow for more detailed studies 

of cell and tissue changes that occur after 

obstruction develops

• Genetic therapies that respond to these genetic 

alterations

• Pharmacological interventions that target the 

protein consequences of these genetic changes

• Genetic markers associated with a high risk of 

bladder damage and failure from obstruction

• Genetic markers that predict reversibility and 

irreversibility of bladder decompensation
A Strategic Plan for Research 97

Cell Regulation and Signaling

Future research projects in cell regulation and 

signaling should

• Classify bladder obstruction based on the cellular and

molecular changes that take place after obstruction

• Determine the time course of bladder obstruction

based on the cellular and molecular changes that 

take place after obstruction

• Assess the differences in cell-cell interactions in 

the obstructed bladder compared with the normal

bladder (compensated bladder compared with

decompensated bladder)

• Target pharmacological therapy based on cell 

regulation and signaling

• Target pharmacological therapy based on the 

heterogeneity of bladder afferent nerves

Technology

Non-invasive technologies for the evaluation of bladder

obstruction and its consequences are greatly needed. 

In particular, there is a need for non-invasive 

technologies for

• Diagnosis of obstruction (especially in children)

• Monitoring of the progression of obstruction from

mild, compensated forms to severe, decompensated

bladders

• Evaluation of the quality of bladder muscle, mucosa,

and connective tissue 

• Measurement of bladder oxygenation

• Functional metabolic imaging of the bladder

• Functional brain imaging to analyze changes 

in central neural pathways following bladder 

obstruction

Other technology needs include new and innovative

techniques for

• Bladder replacement for treatment of end-stage

bladder failure following obstruction

• Reduction of bladder outlet resistance

Behavioral Therapy

These investigations should include

• Trials of various forms of biofeedback on voiding 

dysfunction, particularly in children with urinary

tract infections, reflux, and hydronephrosis

• Clinical studies of the effects of alternative therapies

(e.g., acupuncture, herbal medications, phytotherapies, and magnet therapy) on bladder dysfunction

related to obstruction 

Health Services and Outcomes

Research studies of health services and outcomes 

should include

• Randomized prospective long-term studies 

comparing different methods of treating the lower

urinary tract symptoms associated with obstruction

• Long-term outcome studies of the effect of urinary

diversion and prophylactic therapy in children 

with bladder obstruction or neuropathic bladder

• Natural history of obstruction following antiincontinence procedures
98 OVERCOMING BLADDER DISEASE

• Long-term outcome studies of pharmacologic 

therapy for prostatic obstruction

• Economic impact of sequential treatments of 

prostatic obstruction

• Natural history of sex differences in neonatal voiding

• Clinical trials based on cellular pathophysiology 

(e.g., free radical scavengers and growth factor 

agonists and antagonists)

Groups with Special Needs

Several groups have special needs that are critically

important to study. Future research projects should

focus on

• Differences in the response of the bladder to

obstruction during growth and development

• Differences in the response of the bladder to

obstruction during aging

Alterations of the bladder vasculature in response to

obstruction

• Consequences of vascular disease on the response 

of the bladder to obstruction

• Reversibility of bladder dysfunction after release 

of obstruction

• Effects of male and female hormonal milieus on 

the effects of bladder obstruction

• Effects of the following on the response of the 

bladder to obstruction: systemic hormones

(endocrine), hormones produced in and restricted 

to the local environment (paracrine), and cells 

that self-stimulate by producing a factor and also 

a receptor for that factor (autocrine) 

Research Requirements 

Manpower and infrastructure needs and the need 

for tissue banks must be addressed if research in 

bladder obstruction is to be successful.

Workforce

Incentives are critically needed for research in 

bladder obstruction. Few researchers have been 

interested in this area, and the number of grants 

is insufficient to encourage scientists to work in 

it. Training and development programs are needed 

as well as tuition and loan forgiveness. Incentives 

are needed to attract and retain residents, postresidents, and mid-level investigators.

Infrastructure

Because single institutions are unlikely to have 

the individual scientists needed to develop a 

critical mass, establishing multi-center research 

centers would allow interested researchers to 

collaborate productively. 
A Strategic Plan for Research 99

Tissue and Specimen Banks

A critical deficiency in research today is the lack of

human studies of bladder obstruction. A fundamental

problem with carrying out meaningful research in

human beings is the lack of suitably characterized 

tissue and specimen samples. One solution to this 

problem is tissue and specimen banking. Currently,

three tissue repositories specifically study 

bladder tissue:

• The Interstitial Cystitis Multi-Center Study Group,

which houses approximately 75 specimens and is

funded by NIH

• The Cancer Center Tissue Core at the University 

of California, San Francisco, which is an interdisciplinary group that consists of clinical and

research scientists. Their tissue core collects fresh,

frozen, and formalin-fixed, paraffin-embedded tissue from a variety of organs, including the bladder

• The Cell and Tissue Bank for Marker Studies of

Diseases of the Bladder, Prostate, Kidney, Lung, 

and Breast, which is located in the Oklahoma City

Veterans Medical Center. Bladder tissue and bladder

washings are stored along with source characterization and profiling

None of these tissue banks specifically collects tissue

from obstructed human bladders or from suitable 

controls. The development of a tissue bank to study

human bladder tissue is important. Urine and blood

samples would also be useful because they may reflect

bladder activity. 

Other Needs 

• Pharmaceutical and biotechnology interactions

should be encouraged—especially for alternative

therapies

• Public interest and educational efforts

• Ongoing review and advisory groups
100 OVERCOMING BLADDER DISEASE

PATIENT PROFILE

Hayden Gantz’s mother, Carolyn, first noticed that his urine

appeared cloudy when she began toilet training him at the 

age of 3. She took a urine sample to the laboratory at the 

children’s hospital where she works as a nursing assistant, 

and had it examined. “It had all kinds of things in it that

shouldn’t be there,” Gantz says. The presence of protein in

urine makes it appear cloudy and is a sign of kidney disease. 

Gantz immediately took her son to a physician who specializes

in children’s urologic problems. During the examination, the

physician noticed “pus” in Hayden’s diaper and admitted him

to the hospital. Urinary tract infection, which is uncommon 

in boys at any age, is a sign of posterior urethral valves or PUV.

Laboratory tests and radiography confirmed that Hayden had

PUV, membranous folds in the posterior urethra that form 

during embryonic development and obstruct urine flow. In 

addition, one of Hayden’s kidneys was so severely damaged

from reflux of urine that it was not functioning. The other 

kidney was also damaged.

Posterior urethral valves are a life-threatening condition that

occurs in approximately one in 8,000 newborn males. By the 

time many male infants with obstructive valves are born, 

they already have severe damage to their bladders and kidneys

because as fetuses, they were unable to eliminate urine 

effectively. The high pressure produced by the blockage causes

the bladder wall to thicken as the result of collagen deposition.

Muscle tone declines and urine eventually refluxes back into the

ureters and ultimately the kidneys, where the high pressure

causes more damage and impairs kidney function. Once kidney

damage occurs, secondary effects to other organ systems such

as the lungs soon follow. Approximately one-third of children

with posterior urethral valves progress to end-stage kidney 

disease and need kidney transplants.

Today, diagnosis of urethral valves is often made by ultrasound

during pregnancy. However, 12 years ago when Gantz was 

pregnant with Hayden, ultrasounds during pregnancy were rare,

and even today, they are not routinely used. Also, according to

some estimates, ultrasounds detect only 45 percent of children

with valves. Children with mild cases can go undetected and

are often not diagnosed until they are much older, when kidney 

damage has occurred.

Three days after being admitted to Children’s Hospital, 

surgeons operated on Hayden to ablate the valves in his 

urethra and remove his non-functioning kidney and its ureter. 

They also tried to re-implant the other ureter into his bladder 

to correct the reflux and improve the function of the other 

kidney, but according to Gantz, they decided that this would 

not correct the problem. 

Hayden Gantz

Posterior Urethral Valves, Obstructive Uropathy,

Kidney Transplant
A Strategic Plan for Research 101

“Hayden’s bladder muscle was so stretched from the blockage 

that the bladder couldn’t hold urine well,” Gantz explains. “It

leaked constantly.” Instead, surgeons performed a ureterostomy, 

a surgical procedure that connects the ureter to a portion of the

small intestine from which surgeons create an abdominal stoma 

or opening to the surface of the abdomen. Because the bladder

is bypassed, urine flows through the stoma, located under the

navel, into a bag that is glued to the skin. 

Although the ureterostomy worked well during the seven years

that Hayden grew from a toddler to a pre-teen, it also caused 

him many social problems that resulted in embarrassment and

tears. Children who didn’t understand Hayden’s problem—

and some who did—accused him of wetting his pants.

“Kids can be cruel,” Ganz says. “His teachers worked with his

classmates to explain some of the problems without going into

too much detail, but many times Hayden came home in tears. 

At other times, he’d just shrug it off.” Although Hayden wore

baggy clothes to hide the pouch, it was more visible in summer

because of lighter fabric. It also came off more frequently when

he perspired or swam in the public pool. During one of these

episodes, an inquisitive child asked Gantz if Hayden had 

been shot. 

When Hayden was 10 years old, physicians who had been monitoring the deteriorating function of his remaining kidney decided

that it was time to perform a transplant. Hayden was developing

uremia, a build-up of urea and other nitrogenous wastes in the

blood. But before the transplant could be done, Hayden had to

undergo bladder dilatation in preparation for connecting his new

kidney to the lower urinary tract. For three weeks, Gantz, who is a

single parent, had to inject increasing amounts of sterile saline

into her son’s bladder up to 10 times a day, a process that was

extremely painful in the beginning. Because Hayden’s bladder

was inactive for seven years, she explained, it could only hold 

30 cc, a small amount. At the end of three weeks, his bladder

was able to hold 500 cc, a normal amount.

“Pain is nothing new to Hayden,” his mother sadly explains. 

“He’s had a lot of painful things done to him over the years, 

but he’s a real trooper.” 

In June 2001, after school had finished for the year, Hayden 

had a kidney transplant. The ureterostomy was repaired and 

the ureters from the new kidney were connected to his bladder.

“The greatest words I’ve ever heard from my son were, ‘Mom, 

I have to pee,’” says Gantz. 

During the postoperative period, Hayden’s new kidney functioned

well, but his bladder and urethra were still a problem. His 

urethra had scar tissue where the valves were removed and this

made urinating quite painful. In addition, the bladder muscle’s

tone was so poor it went into spasms, causing more pain, leakage, and frequent voiding. Hayden was reluctant to leave home

for fear of being incontinent or having other children see him in 

pain, but bladder function eventually improved over the ensuing

months and the urethral irritation subsided.

In the fall, Hayden had a temporary setback. He developed

mononucleosis that required hospitalization because he is 

taking drugs to suppress his immune system. The drugs prevent

rejection of his new kidney and he will be on them his entire life.

Today, “Hayden can do anything he wants except contact 

sports,” his mother says. “In the beginning he had a few 

accidents and came home from school in tears, but now during

the day, you would never know he has a bladder problem.”

Asleep, it’s another problem. “He doesn’t have a strong enough

sensation during sleep to know that his bladder is full,” Gantz

explains. But she is used to this. “A lot of things have gotten 

wet over the years.” It is another hurdle that she hopes Hayden

will be able to surmount.
CHAPTER 8
Common Clinical Conditions

INTERSTITIAL CYSTITIS

DID YOU KNOW?

. Although precise prevalence is

unknown, interstitial cystitis 

(IC) has been estimated to affect

700,000 to 1 million people, 90

percent of whom are women.

. The median age of onset is 40,

but 25 percent of people who

have IC are under 30 years old.

. Some men diagnosed with 

non-bacterial prostatitis may 

in fact have IC.

. People on kidney dialysis have

been reported to have a better

quality of life than people 

with IC. 

. Fifty percent of people with IC 

are unable to work full time.

. IC is estimated to cost 1.7 billion

dollars in medical expenses and

lost wages annually.

A Strategic Plan for Research 103

Summary and Recommendations

Interstitial cystitis (IC) is a debilitating, chronic bladder syndrome that

causes urinary urgency, frequency, and pain in the bladder and pelvic

region. Some people with IC find that even a small amount of urine in the

bladder causes discomfort, pressure, tenderness, or intense pain in that

organ and in the surrounding pelvic region—symptoms that might resemble

a urinary tract infection. However, analysis of a urine culture indicates 

no detectable infection, and symptoms of IC do not respond to antimicrobial therapies. 

Although it affects mostly women, IC can occur in people of any age, sex, 

or race. The cause is unknown and the diagnosis is difficult. With neither 

a cure nor a consistently effective therapy available to treat it, IC has a 

negative impact on all aspects of a person’s life. The pain of IC is often

severe and can necessitate trips to the bathroom as often as every 15 

minutes, both day and night. Severe symptoms leave many people homebound and unable to socialize, sleep, work, or travel—deprivations that 

lead to depression and poor quality of life. 

Although precise prevalence is unknown, as many as 700,000 to 1 million

Americans may have IC, roughly equivalent to the number of people who

have inflammatory bowel disease and Parkinson’s disease. More people 

may have this condition, but have not yet been diagnosed. 

After a comprehensive review of the current research on interstitial cystitis

and the research opportunities available, the Bladder Research Progress

Review Group (BRPRG) made the following high priority recommendations:

* Investigate the cause and development of IC through studies that will also

• Identify urinary, epithelial, inflammatory, vascular, and 

neurologic abnormalities

• Identify specific markers associated with pathogenesis, risk, 

disease activity, prognosis, response to therapy, and remission

• Classify subgroups of people based on abnormalities and markers
104 OVERCOMING BLADDER DISEASE

* Conduct epidemiologic research, including population 

and case-control studies of incidence, prevalence, and 

natural history

* Conduct clinical trials of novel therapies

* Increase awareness of IC among the public and among

health professionals 

Background

Interstitial cystitis (IC) is one of the most challenging

and frustrating problems facing people who have this

disease, primary care providers, and urologists. At first

glance, IC may be mistaken for a common, treatable

bladder infection, thereby delaying accurate diagnosis.

However, persistence of symptoms despite treatment

with antibiotics and despite a urine culture that is 

negative for microorganisms may indicate IC rather 

than an uncomplicated urinary tract infection. People

with IC face an illness that has potentially devastating

physical, emotional, psychological, and socioeconomic

consequences, an illness that is difficult to diagnose 

and has no uniformly effective treatment.

No blood or urine test is currently available to make

diagnosis easy. Providers often consider IC only after

ruling out other problems such as infections, bladder

cancer, and bladder stones. Peering into the bladder

using a cystoscope (a thin telescope), the urologist 

distends the bladder with fluid (hydrodistention) and

sees an irritated, inflamed bladder, which also may be

stiff and have scars, glomerulations, and Hunner’s

ulcers. Glomerulations are superficial areas of pinpoint

bleeding caused by inflammation. Hunner’s ulcers are

stellate in form and are generally solitary and involve

deeper layers of the bladder. Cystoscopy to visualize

these changes is performed only when the person is

under general or regional anesthesia.

The type and intensity of IC symptoms vary from person

to person. Even in the same person, symptoms may

range from annoying to incapacitating. People with IC

feel an urgent or frequent need to urinate. Some find

that even a small amount of urine in the bladder causes

discomfort, pressure, tenderness, or intense pain, 

which can be felt not only in the bladder, but also in the

surrounding pelvic region. Symptoms may change in

intensity as the bladder fills with urine or as it empties,

but frequency is not always related to bladder size; many

people with severe frequency have normal bladder

capacity. Sexual intercourse can also be painful for 

both men and women with IC, and intimacy is often

impossible because of the severity of the pain. In

women, symptoms of IC typically worsen around the

time of menstruation. Severe symptoms leave many

people homebound and unable to socialize, sleep, 

work, or travel—deprivations that lead to depression 

and a poor quality of life. 

Etiology

Several theories about the cause of IC have arisen

because of particular features of this condition. 

As a result, some experts have speculated that IC may 

actually include several sub-classes or separate diseases.

One theory currently being investigated is that IC may 

be caused by a defect in the protective lining of the 

bladder, allowing substances in the urine to cause 

irritation. Another theory being investigated is that 

IC is an immunogenic or autoimmune condition.

Neurogenic inflammation has also been posed as a 

contributing or causal factor in the development of IC. 

Researchers are beginning to explore the possibility 

that heredity may play a part in IC. Recent genetic 

studies reveal an inherited susceptibility to IC among

first-degree relatives and among some families with 

IC in multiple generations. To date, no gene has been

implicated as a cause. 

Research has recently shown that IC involves increased

bladder permeability, mast cell activation, neurogenic

inflammation, and various growth factors.
A Strategic Plan for Research 105

* Increased bladder permeability. IC may be caused 

by a defect in the protective lining of the bladder, 

thereby allowing irritating substances in the urine 

to penetrate the bladder. This could result in 

symptoms of pain, urinary frequency, and urgency.

* Elevated number of mast cells. Interstitial cystitis is

associated with elevated mast cell counts in the 

bladder tissue. Mast cells produce many irritating

substances, including histamine, eosinophilic

chemotactic factor, and leukotrienes—substances 

that can contribute to inflammation and pain.

Research evidence for mast cell involvement 

comes from a mouse model in which mast-celldeficient mice exhibit a reduced sensitivity to the

inflammatory mediator, lipopolysaccharide (LPS).

Together, these findings suggest a pro-inflammatory

model whereby substance P nerves of the bladder

activate the mast cells, which in turn release potent

inflammatory mediators and histamine, substances

that can further antagonize nerves. A critical question

in this model is, “What factor or factors initiate the

loop?” This is an area of intense investigation.

* Neurogenic inflammation. Pain is a common symptom 

of interstitial cystitis. It often persists even after 

the bladder has been removed, suggesting a strong

central nervous system component. However, events

originating in the nervous system that affect the 

bladder are also likely contributors to the pain of

interstitial cystitis. Data point to a strong role for

nerve pathways in interstitial cystitis pain, and continued efforts to identify the pain receptor pathways

of the bladder are central to our understanding of

this condition. Estrogen may enhance nerve growth

factor expression in the bladder and contribute to

inflammation of nerves, suggesting a basis for interstitial cystitis afflicting primarily females. 

* Growth factors. Heparin-binding epidermal-growthfactor-like growth factor (HB-EGF) has been found

to be decreased in the urine of people with IC. This

might inhibit the repair of the injured bladder lining,

thereby contributing to the symptoms of IC. Also,

research indicates that nerve growth factor (NGF)

plays a role in IC.

Epidemiology

People of any age, race, or sex can have IC; however,

approximately 90 percent of those with IC are women.

Once thought to be a rare, post-menopausal disease, 

IC is now estimated to affect 700,000 to 1 million men,

women, and children in the United States, a number 

that is roughly equivalent to the number of people who

have inflammatory bowel disease and Parkinson’s 

disease. Many more people are likely to have IC, but 

they have not yet been diagnosed or are misdiagnosed.

On average, it takes five to seven years to obtain a 

diagnosis of IC. 

According to data from the Nurses Health Studies I and

II and from prior epidemiological studies, IC is more

common among younger women. This debunks the myth

that IC is exclusive to women who are post- menopausal.

Symptoms of IC typically occur around age 40, but at

least 25 percent of people with IC are younger than age

30. Studies also suggest that some men who have been

diagnosed with non-bacterial prostatitis may actually

have IC. 

People with IC are also disproportionately diagnosed

with diseases such as vulvodynia (burning and irritation

in the vulva), allergies, irritable bowel syndrome, 

systemic lupus erythematosus (an autoimmune disease

that results in episodes of inflammation of the joints,

tendons, and other connective tissues and organs),

inflammatory bowel disease (Crohn’s disease and 

colitis), fibromyalgia (chronic widespread musculoskeletal pain and fatigue disorder of uncertain cause),

and asthma. Some people have a genetic predisposition

to these diseases, and this may be a factor for people 

with IC as well. The prevalence of IC among first-degree
106 OVERCOMING BLADDER DISEASE

relatives is several times higher than the prevalence of 

IC in the general population. Preliminary data reveal 

that approximately 4 percent of people with IC have at

least one family member with the condition. Additional

studies into the genetics of IC, including linkage analysis, are now underway. 

Cost and Impact

The economic impact of IC is significant. Symptoms are

so severe that only about half of the estimated 700,000

to 1 million people with this disease are able to work full

time. In 1988, that meant that IC accounted for an estimated $1.7 billion in medical expenses and lost wages,

costs that would be significantly higher today considering rising costs and greater numbers of people with IC. 

In addition to the financial considerations, the human

toll can be devastating. According to one study, people

with IC have a poorer quality of life than people who are

on kidney dialysis because many become housebound,

unemployed, and unable to enjoy hobbies, a restaurant

meal, a movie, travel, physical intimacy, or other simple

pleasures that contribute to living a good life. 

Current Research

The IC research program began at the National Institute

of Diabetes and Digestive and Kidney Diseases (NIDDK)

in 1987 with two clinical grants and five basic research

grants totaling $1.1 million. Thanks to strong congressional support, the program has grown dramatically and

in fiscal year 2000 included a record 46 grants totaling

$11.2 million, including basic research on underlying

bladder dysfunction and clinical research. The investment has led to a better understanding of the problem.

NIDDK’s IC database was the first systematic, multicenter, observational, longitudinal effort to collect

demographic, dietary, diagnostic, symptom, treatment,

and other information from a large number of people

with the condition. The database also laid the groundwork for NIDDK’s IC Clinical Trials Group (ICCTG), 

a consortium to test potential treatments.

The ICCTG is also gathering information that

researchers hope will provide better methods for diagnosing IC. The October 2000 meeting, “Interstitial

Cystitis and Bladder Research: Progress and Future

Directions,” encouraged scientists to share research

ideas and results. The Interstitial Cystitis Association, 

an advocacy group for people with IC, and the NIDDK

both co-sponsored the meeting.

Men with non-bacterial prostatitis (NBP) may also 

benefit from clinical research on IC, since non-bacterial

prostatitis is a similar condition. Some experts suggest

that NBP may be the male equivalent of IC. However,

preliminary data reveal that antiproliferative factor

(APF), a marker unique to people with IC, is rarely 

found in men with benign prostatic hyperplasia (BPH), 

a condition that often causes inflammation of the

prostate. Some of the same researchers are studying 

both conditions, increasing opportunities for the 

cross-fertilization of ideas relevant to both conditions. 

NIDDK hopes to extend the breadth and depth of the IC

research program to understudied areas of high priority

by supporting projects that will increase understanding

of the fundamental needs for normal bladder function

and the errors that lead to dysfunction by attracting 

talented investigators from other fields and by 

collecting and analyzing more and better data on IC.

Based on expert recommendations, NIDDK is planning 

a two-pronged approach to epidemiological studies. 

In the first approach, the Urology in America Database

will be mined for physician and hospital costs and the 

frequency of bladder and other urinary tract disorders.

In the second approach, reliable data will be obtained to

more accurately estimate the number of men and women

who have chronic painful bladder syndromes such as IC

and to identify the degree of disability caused by these

conditions. This latter initiative began in FY 2001, with

projects funded under the request for application (RFA),

“Epidemiology of Chronic Pelvic Pain of the Bladder and

Interstitial Cystitis.”
A Strategic Plan for Research 107

Highlights of Currently Funded NIDDK Research 

NIDDK’s Interstitial Cystitis Clinical Trials Group

(ICCTG), a consortium of nine clinical centers across 

the country, is evaluating the safety and efficacy of various treatments for IC. Currently, ICCTG is studying an

innovative intravesical treatment involving a bacterium

known as bacillus Calmette-Guerin (BCG). BCG is

thought to work by stimulating the immune system. 

The NIDDK has also investigated or continues to 

investigate the following areas: 

• Role of nitric oxide 

• Sensory and sympathetic nervous system effects 

• Afferent mechanisms underlying bladder pain

• Urine and bladder diagnostic markers

• Pain sensitivity and menstrual cycle effects

• Urine anti-proliferative peptides

• Chronic pelvic pain of the bladder and IC 

(epidemiology RFA to be funded)

• Neurogenic inflammation

• Stress-induced neuroinflammatory changes

• Quantitative study of urinary bladder 

sensory processing

• Immune mediators

• Nitric oxide transduction mechanisms in UTI and IC

• Studies of pain in people with IC

• Afferent plasticity underlying urethral and 

pelvic pain

Two specific areas of investigation include diagnostic

markers and tests and new treatments.

Diagnostic Markers and Tests

Efforts are underway to find less painful, less invasive,

and more accurate diagnostic tests for IC. At present,

clinical findings of urinary urgency, frequency, and pain

in the absence of other urologic conditions, along with

the presence of glomerulations or Hunner’s ulcers on

cystoscopy, are considered to be the gold standard for

the diagnosis of IC. However, urinary markers hold 

great promise for potential development into a clinical

test and may provide clues into the cause and treatment

of IC. Markers are unique factors found in a particular

disorder that can be recognized and identified.

Conclusive diagnosis of IC using a marker would

enhance both epidemiologic and biologic studies of 

its pathophysiology. 

Researchers have identified the following factors that

may explain the changes in the bladder that occur 

with IC:

• Heparin-binding-epidermal-growth-factor-like

growth factor (HB-EGF)—HB-EGF is important 

for epithelial cell proliferation and wound healing. 

In one study, urine and blood samples were obtained

from three groups: people who were asymptomatic,

people with IC, and people with urologic conditions

other than IC, including those with urinary tract

infections. HB-EGF levels were significantly

decreased only in the urine and serum of people 

with IC. These findings suggest that the lack of HBEGF may be responsible for the bladder’s inability 

to repair damaged epithelium. The presence of

decreased levels of HB-EGF in the serum of people

with IC suggests that IC may be a systemic disease.

• Anti-proliferative factor (APF) — Anti-proliferative

factor is found only in the urine of people with 

IC. This protein inhibits HB-EGF production 

and may prevent the growth of new, healthy 

bladder epithelium. 
108 OVERCOMING BLADDER DISEASE

Both HB-EGF and APF were confirmed as markers for 

IC in a recent blinded study. These research findings

could lead to a diagnostic test and the identification of

agents to suppress production of APF, block its actions,

or enhance production of the epithelial growth factor,

allowing the growth of healthy bladder cells lining 

the bladder. 

Additional urinary markers that might be useful as 

diagnostic markers or objective measures of treatment

response were recently confirmed in another study.

Interleukin-6 (IL-6) was found to be increased in some

people with IC and may be produced by inflammatory 

or bladder epithelial cells. Studies have also shown that

cyclic GMP (guanosine monophosphate), a factor necessary for the synthesis of DNA and RNA, is also decreased

in people with IC. Epidermal growth factor (EGF) has

been confirmed to be significantly elevated in the urine

of people with IC, as well.

A lactulose-rhamnose test, similar to the test used to

diagnose gastrointestinal permeability, is also being

investigated. This test for bladder permeability involves

instilling a sugar solution into the bladder and subsequently checking for levels of this sugar molecule in 

the serum. Far less invasive to the patient when compared to cystoscopy and hydrodistention under general

anesthesia, this new permeability test may distinguish

intact bladders from permeable bladders. 

These new tests and markers currently under investigation will undoubtedly help to make the diagnosis 

and treatment of IC more accurate and less painful 

in the future.

Potential Treatments

The NIDDK’s ICCTG is evaluating the safety and efficacy

of potential treatments. The first trial by this consortium

tested oral medications, pentosan polysulfate sodium

(Elmiron®

) and hydroxyzine hydrochloride (Atarax ®).

Earlier studies suggested that each drug targets different

aspects of IC. Elmiron,® the first oral medication

approved for IC, reinforces the bladder lining, which

usually acts as a barrier to the toxicity of urine, whereas

Atarax,® an antihistamine, reduces the activity of mast

cells, which may cause bladder inflammation and pain.

The two drugs may also work synergistically, leading to

quicker, more potent symptom relief. 

The second ICCTG clinical trial is testing whether the

bacterium, bacillus Calmette-Guérin (BCG), will relieve

the pelvic pain and frequent urination that are hallmarks

of IC. Earlier studies in people with IC suggest that BCG

stimulates a protective immune response (the production of type 1 T helper cells) and downplays a harmful

immune response (production of type 2 T helper cells) 

in the bladders of people with IC. Results of both clinical

trials will be announced on NIDDK’s website

(www.niddk.nih.gov) when they become available.

Other new treatments being tested by pharmaceutical

companies include Resiniferatoxin‚ (RTX), sacral nerve

stimulation devices, hyaluronic acid (Cystistat‚), and 

SI-7201 (sodium hyaluronate). 

Cystoscopic images showing (left) glomerulations–tiny hemorrhages 

that are a telltale sign of interstitial cystitis–and (right) a healthy 

bladder. (Photo Credit: Healthcommunities.com, Inc., interstitial cystitis on 

urologychannel,® http://www.urologychannel.com/interstitialcystitis. 

Copyright© 2002, Healthcommunities.com, Inc.)
A Strategic Plan for Research 109

Critical Research Areas

The usefulness of the NIDDK criteria for IC research

needs to be re-established, and a consensus conference

on the definition and diagnosis of IC is urgently needed

to assist the practicing clinician as well as to establish

guidelines for future research. 

The following areas have been defined by the BRPRG 

as being critical to IC research, and resources should 

be directed towards them: 

• Etiology and pathogenesis

• Epidemiology

• Disease markers

• Molecular biology

• Genetics

• Neurological aspects

Etiology and Pathogenesis

Arguably, this is the most important research area in IC.

Well-designed studies of clinical patients and material

should be directed at understanding the primary defect

and the subsequent disease development sequence

(pathogenesis) in IC. These studies conceivably could

include one or more of the following areas: urine,

epithelium, blood vessels, inflammatory response, 

neurologic activity, or pelvic floor dysfunction.

Specific urinary markers that may indicate a mechanism

of pathogenesis should also be studied further. One such

marker, anti-proliferative factor (APF), has been shown

to alter the production of at least three growth factors

and one growth-factor-binding protein by bladder

epithelial cells in vitro. Additional studies on the acute

and chronic effects of APF on epithelial function and

mechanisms of growth factor regulation (e.g., release 

of signaling molecules and formation of tight junctions)

are warranted. Studies on the role of other markers in IC

(including interleukin-6 and cyclic GMP) should also 

be pursued. 

Collaborative research on the cause and pathogenesis 

of IC and associated disorders—vulvodynia, allergies,

irritable bowel syndrome, lupus, fibromyalgia, asthma,

Crohn’s disease, colitis, and Sjögren’s Syndrome—

should be studied .

Epidemiology

Population-based studies would give the most accurate

data on incidence, prevalence, and potential risk factors

and identify a cohort of incident cases, which is critical

to understanding the etiology and natural history of 

this disease.

The identification of IC cases compared to appropriately

matched controls is the most cost-effective method of

identifying risk factors, demographic features, familial

aggregation, and non-urinary clinical syndromes associated with IC. Enrichment of such case control studies 

by new onset cases will allow important investigations of

recent antecedent events and of early urine, serum, and

histopathologic factors that might provide clues to the

development of the disease.

Large cohorts of persons who do not have IC, along with

baseline data and specimens, would allow identification

of incident cases with not only the advantages attendant

to study of new onset cases as above, but also the availability of pre-IC urine and blood specimens allowing a

search for causative factors. Identification of new cases

and banking of such specimens could be incorporated

into ongoing large cohort studies such as the Nurses’

Health Study I and II.

Finally, longitudinal studies of people with IC would be

appropriate to define natural history, including prognosis, prognostic factors, and incidence of complications

and aggravating events. Identifying cohorts of persons

with IC that were established sometime in the past (such

as those in the IC Database or those who participated in

earlier therapeutic trials) could minimize the expense 

of this type of study. These people could be re-enrolled

with appropriate collection of data and then prospectively followed.
110 OVERCOMING BLADDER DISEASE

Disease Markers

The identification of a diagnostic marker that has 

excellent sensitivity, specificity, positive predictive

value, and negative predictive value and that does not

require an expensive or invasive technique (e.g., cystoscopy with hydrodistention under general anesthesia)

is critical. A number of markers have been reported by

numerous investigators and are being compared in the

same patient group. The most promising diagnostic

markers identified in recent blinded studies include

anti-proliferative factor (APF), heparin-bindingepidermal-growth factor-like growth factor (HB-EGF),

and epidermal growth factor (EGF). The markers should

be studied further, and one or two markers should be

included in all subsequent clinical and epidemiologic

studies to confirm diagnostic capability and to 

determine usefulness in predicting prognosis or 

in monitoring natural history or therapy. 

At this point in time, IC is a field driven almost 

exclusively by clinical observations. It would seem 

that this field is ideally suited to translational research;

however, given the lack of knowledge of the cause and

natural history of IC, a reverse approach would be 

appropriate. This approach would look at the clinical

course of persons with IC and identify responders to

treatment, non-responders, and those in spontaneous

remission. Serum, urine, and tissue specimens could 

be collected from people with IC and from control

groups to identify abnormal gene expression patterns 

in people with IC using proteomics and cDNA microarray technology. This approach might identify 

additional disease markers and lead to greater 

understanding of the mechanisms involved in the 

development of IC.

Molecular Biology

An understanding of the cellular gene expression of

bladder tissues that differ between persons with IC and

persons who are “normal” could lead to an understanding of the pathogenesis of IC. Development of certain

tools, including microarrays for human bladder epithelial cells would be useful for these studies. It is possible

that different molecular targets will be identified in 

different subgroups of people with IC. Identifying 

subgroups could lead to targeted treatments. 

The application of new technology developed in the field

of cancer could dramatically advance current research 

in IC. These advances allow the isolation of pure populations of individual cell types in sufficient cell numbers to

analyze their gene and protein expression. Laser capture

microdissection (LCM) will allow the isolation of pure

populations of lymphoid cells and epithelium from 

people with IC and from normal controls for gene and

protein profiling. For example, proteomics technologies

such as mass-spectroscopy can isolate, characterize, and

define proteins in the urine. Using these methodologies,

new tests to diagnose and monitor IC could be developed, and persons with IC could be classified into 

subgroups based on protein expression. These technologies are valuable because they do not involve an

invasive procedure and could also be used after 

treatment to define changes at the protein level. 

Genetics

Preliminary published reports indicate a higher-thanexpected prevalence of IC among first-degree relatives 

of index IC cases, concordance among monozygotic

(identical) twins for IC, and several families with IC in

multiple generations. These findings are consistent with

an inherited susceptibility to IC. Linkage analysis and

positional cloning can be used to identify location of

susceptibility gene(s) to IC. The rapid progress being

made in sequencing the human genome will facilitate

identification of such genes. 
A Strategic Plan for Research 111

Neurologic Aspects 

The nerve-cell-like properties of epithelial cells 

should be examined to identify how these properties 

are changed in people with IC. These properties include

the release of transmitters (i.e., nitric oxide and adenosine triphosphate [ATP]), the expression of transmitter

receptors (i.e., cholinergic, adrenergic, serotonergic,

and capsaicin receptors), response to transmitters, 

communication with afferent (inflowing) nerve cells,

communication with efferent (outflowing) nerve cells,

and intracellular signaling mechanisms that mediate

transmitter actions.

The properties of bladder afferent nerve cells should 

be studied in more detail, particularly those involved 

in triggering painful sensations. Topics for research

should include 

• Mechanisms that underlie acute and chronic 

sensitization of afferent receptors

• Identification of molecular targets for the 

pharmacologic modulation of afferent excitability

• Changes in the expression of ion channels and 

receptors in chronic pathological conditions

• Cross-talk between afferent and efferent nerves 

or between epithelial cells and afferent nerves

• Mechanisms involved in the central processing 

of afferent input from the bladder, including 

neurotransmitters, plasticity induced by chronic

pathological conditions, and targets for pharmacotherapy of bladder pain 

Early Diagnosis and Treatment

Early diagnosis could be helpful in avoiding the dramatic

physical, psychological, and socioeconomic impact of 

IC and in facilitating a higher likelihood of response to

treatment. Physician education and public awareness are

imperative. Treatment of this devastating condition has

not been fundamentally improved over many years, and

investigators cannot wait for the aforementioned goals 

to come to fruition before focusing on new treatment

modalities for this group of people. Good clinical trials

are imperative. Clinical studies should be combined with

basic science (i.e., markers and genomic and proteomic

studies). Promising therapies should be studied in a

controlled multi-center manner as is currently being

done by the NIDDK IC Clinical Trials Group. 

Additional Opportunities for Research

Research areas such as animal models, the pathophysiology of symptom production, the IC Database, 

and normal bladder structure and function would also 

be extremely valuable.

Animal Models 

Progress in understanding the pathogenesis of IC 

comes with the development of faithful model systems.

Currently, few model systems exist for the study of IC. 

A feline model exhibits many similarities to human 

IC, but the prevalence of IC among cats is not high. 

In addition, this model is not easily amenable to 

experimental manipulation or genetic analysis. 

An acute rat model of neurogenic cystitis based on 

infection with neurotrophic pseudo-rabies virus 

(PRV) shows promise for experimental manipulation,

but the systemic effects of PRV limit the use of this

model for characterizing chronic aspects of IC. 
112 OVERCOMING BLADDER DISEASE

Valid in vitro IC models that mimic the important 

cell-to-cell interactions in the bladder are also needed

because such a system could be easily manipulated.

Thus, the development of better in vitro and in vivo

models for the study of interstitial cystitis is 

clearly needed. 

Two types of animal experiments would be useful in

understanding IC:

• Animal experiments using agents that result in

urgency, frequency, and pain in the animal model 

• Subsequent studies to look at the mechanism of 

this effect, to identify markers and molecular targets

associated with the above symptoms, and to investigate possible therapeutic interventions 

Studies should be performed to test cause-and-effect

hypotheses through the use of precise physiologic

defects engineered by drugs or genetic knockout 

animals. Additional studies on Feline Urologic

Syndrome, a naturally occurring bladder disorder 

in cats that mimics certain features of human IC, 

are also warranted. 

Pathophysiology of Symptom Production

Whether an etiology for IC is known or not, an understanding of the means by which the symptoms of IC are

produced may lead to new and effective interventions.

Interstitial Cystitis Data Base (ICDB)

Much data have been collected by the Interstitial Cystitis

Data Base (ICDB) and should be analyzed to increase our

understanding of IC. For instance, the database could

provide answers to the following questions:

• What pathologic features are associated with what

symptoms of IC?

• Is hydrodistention necessary for diagnosis in people

with appropriate symptoms, negative urine culture,

and negative pre-hydrodistention cystoscopy? 

• Is a biopsy necessary for diagnosis? 

• Are urodynamics studies necessary for diagnosis? 

Answers to these and certain other questions may be

within the ICDB. Newer additional data should be

included in order to gain a better understanding of 

the pathophysiology of IC. This data would provide a

newer perspective, since the definition, diagnosis, 

and treatment of IC have substantially evolved since

1991, when the ICDB was started. 

Normal Bladder Structure and Function

Not enough is known about the normal bladder. Studies

including, but not limited to, epithelial differentiation,

proliferation and migration, hormonal response and

receptors, and epithelial antigen presentation would

ultimately have effects upon our understanding of IC.

Studies to identify specific physiologic interactions

between and among different bladder wall components

would be useful. Finally, development of in vitro, multilayered, differentiated human bladder epithelium would

allow studies to better determine regulation of normal

bladder epithelial cell proliferation and differentiation.

Hunner’s ulcers in a patient with interstitial cystitis. The image on the 

right clearly shows the common stellate pattern of the ulcer. As is typical, 

the center of the lesion has a large amount of granulation tissue present,

probably as a result of small tears and bleeding that may occur with 

bladder filling. (Photo Credit: Dr. Robert Moldwin, Albert Einstein College 

of Medicine, Bronx, NY)
A Strategic Plan for Research 113

Outside Sources for Research

The Interstitial Cystitis Association’s Pilot Research

Program and the Fishbein Family Interstitial Cystitis

Research Foundation both provide funding for pilot

projects specifically on interstitial cystitis. These pilot

research grants have enabled researchers to study new

ideas and obtain preliminary data. They have also

attracted new researchers to this growing field. Many

recipients of these pilot grants have gone on to receive

NIH funding. Much of the pilot research funded over 

the past decade has resulted in important advances in

the field of IC research, including urinary markers and

the genetics of IC. 

Research Requirements and Impediments

Requirements

* Workforce. Encouraging career development in urology, urogynecology, and urologic research is essential.

The growing fields of women’s urology and urogynecology appear to be merging. This provides potential

opportunities for an academic career for residents

and fellows, but only if funding is provided to them

early on. For example, the American Foundation for

Urologic Disease (AFUD) administers a successful

research scholars program that fosters careers in

urologic research by providing young researchers

with grant opportunities during their urologic fellowships. Additional programs are imperative to attract

bright talented researchers, especially in today’s

challenging medical climate, where the costs of 

medical education are high.

* Tissue banks. A large quantity of material—serum,

urine, and biopsy specimens—is available from the

NIDDK IC Data Base (ICBD). Urine specimens from

the current NIDDK IC Clinical Trials Group are also

being banked. 

* Pharmaceutical and biotechnology efforts. The pharmaceutical industry has shown significant interest 

in developing therapies for urinary urgency and 

frequency and for evaluating these therapies once

FDA approval has been obtained. These therapies

include bacillus Calmette-Guerin (BCG), resiniferatoxin (RTX‚), hyaluronic acid (Cystistat‚), sodium

hyaluronate (SI-7201), and sacral nerve stimulation devices. 

Impediments

• Delay in diagnosis and treatment

• Lack of a clinically available specific test for IC

• Lack of awareness within the medical community

• Lack of public awareness

• Lack of epidemiologic data

• Poor understanding of etiology and pathogenesis

• Lack of adequate treatments and pain management
114 OVERCOMING BLADDER DISEASE

PATIENT PROFILE

In 1994, when she was barely 20 years old and a student at the

University of Pennsylvania, Kara Fishbein Goldman was diagnosed with interstitial cystitis or IC. She did not have too many

symptoms of IC at that time, she says, but she had vulvodynia,

chronic pain in the vulva, a symptom often associated with IC. 

While Goldman was under anesthesia for treatment of the vulvodynia, her doctor dilated the bladder with sterile saline solution and used a cystoscope to visualize the bladder wall. 

He found areas of inflammation and pinpoint bleeding called

glomerulations, which are characteristic of IC. Eventually,

Goldman developed other symptoms of the disease—

urinary frequency, urgency, and a burning sensation in the

bladder—symptoms that she has experienced constantly 

for the past eight years.

Goldman describes her pain as feeling as though she has a 

bad bladder infection—a burning type pain that gets worse 

as her bladder becomes full—but “antibiotics don’t cure it 

and other medications provide little relief,” she says. “I feel 

like I have to [urinate] all the time, and it gets worse when the

bladder is full. The pain is constant, but the severity varies.” 

Symptoms of IC vary from patient to patient, but they generally

cluster around an urgent need to urinate; frequent urination

both day and night; reduced bladder capacity; and feelings 

of pressure, tenderness, and pain around the bladder, pelvis, 

and genital area that may increase as the bladder fills. 

“With IC, everybody is different. The pain presents in different

ways in different people,” Goldman explains. “Some have sharp

pain, some have a burning sensation all the time where the

inside of your body feels like it’s on fire.” She believes IC is

more like a syndrome, a collection of symptoms. “Some people

have some symptoms from the syndrome. Some people have

other symptoms from the syndrome.” In fact, Goldman’s 

identical twin, Beth Fishbein, who developed IC a year after 

she did, has had milder symptoms. Currently in medical school,

Fishbein is stabilized on a low dose of medication.

In some ways, Goldman and her sister were lucky. Their IC 

was diagnosed in the early stages, obviating the need to search

for a diagnosis, a frustrating journey most people with IC are

forced to undertake because many physicians are unfamiliar

with the condition or because symptoms are often confused

with other illnesses such as urinary tract infections. Even 

after IC has been diagnosed, many patients still have to 

search for new or different treatments that may help with 

their particular symptoms.

In the year after her diagnosis, Goldman instilled a weekly 

“cocktail” of medications prescribed by her physician into her

bladder through self-catheterization. The bladder instillation

included a local anesthetic, an antibiotic, and a steroid to 

reduce inflammation. This regimen kept her symptoms under 

control for about a year, but then the “cocktail” ceased to be

Kara Fishbein Goldman

Interstitial Cystitis

From left, Kara and Beth Fisbein
A Strategic Plan for Research 115

effective, Goldman says, so she stopped it. Her pain gradually 

got worse, and became difficult to manage in the year before her

wedding. She tried numerous oral medications, including tricyclic

antidepressants, drugs that relax the bladder muscle, block

pain, and have some effect on the body’s allergic response,

which appears to be involved in IC. Other drugs prescribed 

for her condition include a drug to relieve nerve pain; a drug 

that appears to augment the bladder lining; several pain 

medications; and drugs to relieve the bladder spasms that 

often accompany and worsen urinary urgency, frequency, and 

pain. All of the medications helped for only a little while,

Goldman says, and a neurostimulation device implanted in 

the epidural space of her sacrum did not provide any relief.

Interstitial cystitis has no cure and no universal treatment; 

therefore, physicians must try several treatments to relieve 

symptoms. People with IC have responded to various therapies, 

but even so, a particular treatment may work only temporarily.

Flare-ups and remissions also occur. 

“The [pain medicine] doesn’t ever make my pain go away,” 

she says, “It just makes me tired and sleepy and less aware of

myself.” This creates a dilemma. She either works in pain or

takes off and sleeps. During the workday, Goldman forgoes the

pain medicine, but when the pain is severe, she takes off from

work, takes the medicine, and sleeps. She says she’s lucky

because some people wake up from the pain; she does not. 

“There’s nothing much I can do to make myself feel better,” 

she says. “I’m either working or sleeping. I don’t want to sleep 

the rest of my life.”

Goldman has tried to explain her illness to her students, coworkers, and friends to help them understand why she cannot

function as well as she would like. She has had varying degrees 

of success. “People don’t understand chronic pain,” she says. 

“I look absolutely fine, and people can’t see that I’m in pain. I’m

not limping and I don’t look particularly bad.” Last October and

this spring, Goldman’s pain was so severe she had to take quite 

a number of days off from her teaching job. “This year was really

bad. I missed a lot of days of school, and I’m taking a leave of

absence [next school term]. This illness has affected my life in 

a big way,” Goldman says, adding that she and her husband,

Steve, had hoped to have children by now, but can’t because of

all the medications she’s on. 

Goldman says she feels fortunate to have an extremely supportive and caring spouse and parents, who have been very helpful

in her often frustrating search for therapy that will ease her

symptoms. In 1997, after realizing that scientists knew very 

little about IC, Goldman’s parents, Bob and Laurie Fishbein,

established the Fishbein Family Interstitial Cystitis Research

Foundation, which endows pilot studies of IC. Goldman also

acknowledges great support from the Interstitial Cystitis

Association, which has provided her with information about 

IC and treatment options and has put her in touch with other

people with IC. 

So far, Goldman’s search for effective treatment and pain relief 

has taken her to six gynecologists, three urologists, and two pain

specialists in two states. She hopes that her yearlong leave from

teaching will lead to better health and perhaps to the fulfillment 

of a long-delayed goal. “I want to be free to go wherever I need 

to go in the country to see consultants,” she says. “I’ll take it 

easy and try to feel better. Maybe if I can get off the drugs, 

I’ll try to get pregnant.... I’ll revise as I go. I’ll keep trying 

different things.”
CHAPTER 9
A Strategic Plan for Research 117

Common Clinical Conditions

URINARY TRACT INFECTIONS

DID YOU KNOW?

. Urinary tract infections 

(UTIs) are responsible for an 

estimated seven million visits 

to doctors’ offices.

. UTIs cause approximately one

million visits to emergency

departments each year.

. Adult women have about a 

50 percent lifetime risk of 

developing a UTI.

. Globally, direct costs of 

UTI are estimated to be 

$6 billion annually. 

. Catheter-related UTIs account 

for 40 percent of all hospitalacquired infections. 

Summary and Recommendations

Urinary tract infections (UTIs) are common problems in men and women 

of all ages. However, certain groups have a greater risk of developing them.

In particular, females are far more likely than males to develop a UTI, 

except in the first few months of life. In the United States, an estimated

seven million cases of uncomplicated UTI occur annually in women, and

approximately a third of the women who have an initial infection will 

develop a recurrence. Although few studies have been done on postmenopausal women, about 10 percent to 15 percent of this population 

experience recurrent UTIs. 

Other groups at increased risk for developing UTIs are infants; pregnant

women; the elderly; and persons with spinal cord injuries, catheters, 

diabetes, multiple sclerosis, and urologic abnormalities. UTIs in children

cause significant morbidity and may lead to end-stage kidney disease. 

UTIs also cause significant morbidity and mortality in elderly men 

and women.

Better studies of the incidence of UTIs research are needed. It has been

estimated that fewer than 70 investigators work in UTI research throughout

the world and that only $20 million is spent on UTI research per annum.

Currently, determinations of incidence are largely based on analyses of

poorly documented, small, non-representative databases. Prospective, 

population-based studies are also critically needed. The Bladder Research

Progress Review Group (BRPRG) has conducted a comprehensive study 

of current research on urinary tract infections and inflammation and 

recommends that the research community do the following:

* Increase basic and clinical research to study the processes of infection of 

the bladder. Areas of interest and goals for future research include

• Bacterial pathogenesis 

• Host tissue and innate immune responses

• Host adaptive immune responses
118 OVERCOMING BLADDER DISEASE

• Host susceptibility to infection and inflammation

• Comprehensive epidemiological studies of UTI

• Prevention and treatment of UTIs in normal and

special hosts

* Create new regional centers equipped with advanced technologies for genetic, proteomic, and functional bacterial

and cellular arrays. The regional centers should also 

be equipped with related technologies necessary for

contemporary research in infection of the bladder.

Ongoing support for the operation of these centers

and technologies should also be provided. 

Background

Urinary tract infections (UTIs) are frequently encountered in clinical practice. Classifications of the various

clinical forms of UTI have been devised to account for

differences in pathogenic mechanisms, sites of disease,

and other host factors such as comorbidities (concomitant but unrelated disease processes). For example, 

UTIs are often classified as either uncomplicated 

or complicated. 

• Uncomplicated UTIs occur in persons, primarily

women, whose urinary tracts are normal in anatomy

and function. 

• Complicated UTIs occur in children and in persons

who have underlying medical conditions that 

render infections more difficult to diagnose and

treat. People with complicated UTIs require greater

medical vigilance both before and after treatment.

Serious forms of UTI require hospitalization or

extended hospital stays that are very costly.

Urinary tract infections in adults may also be classified

into other clinical categories, including acute or recurrent UTI, acute kidney infection, catheter-associated

UTI, and urosepsis, invasion of surrounding tissues and

the blood stream by pathogens that originally infected

the urinary tract. 

Incidence and Prevalence

Urinary tract infections are not reportable diseases in

the United States; therefore, accurate incidence data 

are lacking. Estimates often differ depending on the

diagnostic criteria (e.g., clinical presentation, urinalysis, 

and culture) and the situation in which the criteria were

used (e.g., office visit, hospital discharge, self-report 

or physician diagnosis, and population screening).

According to the most recent epidemiologic data from

the 1997 National Ambulatory Medical Care Survey and

the 1997 National Hospital Ambulatory Medical Care

Survey, UTIs are the reason for nearly seven million

office visits each year and another one million emergency department visits, resulting in approximately

100,000 hospitalizations. 

UTIs are more common in females than in males, except

in the first few months of life. Adult women have about 

a 50 percent lifetime risk of developing a UTI. One study

of first-time, symptomatic UTI in children younger than

age six estimated that girls have three times the risk of

boys for developing a UTI. Symptomatic UTI is also 

common among young, sexually active, adult women,

ages 18 to 29. 

The overall prevalence of bacteria in the urine (bacteriuria) that do not produce symptoms (asymptomatic 

bacteriuria) has been estimated at 5 percent in young,

ambulatory women, and prevalence generally increases

with age in both women and men. Asymptomatic bacteriuria is particularly serious in pregnant women,

although only a small percentage of them are diagnosed

with it. This condition is associated with adverse effects

on the newborn and an abnormal course of pregnancy.

The incidence increases with age, the number of times 

a woman has given birth (parity), diabetes, and history 

of UTI. 

Both asymptomatic bacteriuria and symptomatic 

UTI have been reported to be more prevalent among

women with diabetes than among men with the disease.

Women also reportedly have three times as many 

hospitalizations for an acute kidney infection than 

their male counterparts.
A Strategic Plan for Research 119

Among people older

than age 70 who 

are living independently, the incidence

of asymptomatic

bacteriuria has 

been estimated 

to be three times

greater for women

(16 percent to 18

percent) than for

men (6 percent).

However, studies

that categorize 

prostatitis (inflammation or infection

of the prostate 

gland) with UTI 

have found nearly comparable rates among older 

men and women. 

In addition to pregnant women, infants, and the 

elderly, other populations are also at increased risk;

these include persons with spinal cord injuries,

catheters, diabetes, urologic abnormalities, and multiple

sclerosis (MS). People with MS appear to be at significant increased risk of UTI. In one study of urinary tract 

dysfunction in people with MS, nearly 90 percent had

urinary tract infections, with bacteriuria affecting up to

74 percent. A UTI frequently precedes relapse of MS

symptoms, and recurrent UTIs have been associated with

acute exacerbation and neurologic progression of MS.

HIV status appears to be another risk factor for UTI.

Studies have reported that the incidence of UTI among

women and men who are HIV positive is greater than the

incidence among women and men who are HIV negative. 

In addition, UTIs currently account for more than a third

of the two million infections that occur in hospitals each

year. Most of these UTIs are secondary to an indwelling

urethral catheter. Catheter-related UTI has been 

estimated to be responsible for 40 percent of all 

institution-related infections. Although a decrease has

occurred in catheter-related UTI rates among patients in

intensive care units during the past decade, the rates

remain high. 

Cost and Impact

Even if it is uncomplicated, a urinary tract infection

reportedly causes adults six days of frequent and painful

urinations, including two days of reduced activity and 

at least one day of missed work. When a UTI occurs in a

young child, these costs frequently involve hospitalization and loss of work for the parents. The financial and

medical implications are enormous, in part because 

UTI is such a common disease. Direct costs of UTI

include medical charges for doctor visits and drugs 

and non-medical costs associated with travel, sick 

days, and morbidity. Indirect costs associated with 

lost output must also be considered. 

The total annual cost of UTIs in the United States has

been estimated to be greater than $1 billion, and this

estimate does not include hospital costs. Annual direct

costs of UTI in women have been reported to be $659

million and indirect costs, $936 million. Moreover,

annual costs of hospital-related UTIs have been 

estimated to range between $424 million and $451 

million. Catheter-related UTIs, which are responsible

for well over a third of all hospital-related infections, 

significantly increase the cost and impact of UTIs.

Conditions that 

Complicate a UTI

• Extremes of age (children 

or elderly adults) 

• Anatomic abnormalities 

of the urinary tract 

• Metabolic and hormonal

abnormalities 

(e.g., diabetes)

• Impaired host defenses 

• Medical conditions affecting urinary tract function

• Catheterization
120 OVERCOMING BLADDER DISEASE

Groups at Risk

Infants and Children

Approximately 18 percent of infants who develop a 

UTI during their first year of life experience a recurrence

during the subsequent months. Recurrent urinary tract

infections in infants and children are associated with

significantly greater morbidity, including impaired 

kidney function, end-stage kidney disease, and possible

complications of pregnancy. 

Approximately 

3 percent of prepubertal girls and 

1 percent of prepubertal boys are 

diagnosed annually 

with UTIs. The 

clinical course 

and sequelae of 

UTI in children is 

different from that 

of adults. Guidelines

developed by the

American Academy 

of Pediatrics recommend that children

ages two months to

two years who have 

an unexplained fever

should be evaluated for a UTI because of its serious

potential consequences. Children with a confirmed 

diagnosis of UTI are candidates for further imaging

studies of the upper and lower urinary tract, including

renal ultrasonography and voiding cystourethrography. 

Recent research has demonstrated the significant 

health benefits of early identification and management

of childhood urinary tract infections. Accurate and early

diagnosis, combined with close medical supervision and

improved health care, can minimize the long-term consequences of childhood UTI. Many effective and appropriate antimicrobial agents are available for treatment.

Children with a history of UTI may require long-term,

low-dose antibiotic treatment until a full evaluation for

anatomic abnormalities has been completed. If significant anatomic abnormalities are found, long-term, lowdose antibiotic therapy may be recommended for years. 

Recurrent UTIs in children have been associated with

scarring in the kidney, which may place children at

greater risk of developing progressive kidney disease.

Children with scarring in both kidneys have a more 

serious prognosis than those with scarring in one.

Current investigations are exploring possible genetic

predispositions for childhood UTI and scarred kidneys. 

People with Urinary Catheters

Catheter-associated UTI is the most common institution-acquired infection, accounting for an estimated 

one million cases or more annually in U.S. hospitals and

nursing homes. The medical and financial ramifications

of this condition are significant: hospital-acquired UTI

leads to one extra hospital day per patient, or nearly one

million extra hospital days per year. Each episode of

symptomatic UTI has been estimated to add $676 to the

hospital bill, with catheter-related bacteremia, the presence of viable bacteria in the blood, estimated to cost

nearly $2,900.

The duration of catheterization has been directly associated with the risk of UTI. Most catheterization is generally of short duration (less than 30 days) and is associated with hospitalizations for surgery or an acute illness.

In contrast, long-term catheterization (more than 30

days) is often needed for persons who are in rehabilitation or long-term care facilities. Catheters enable small

numbers of microorganisms that infect the urinary tract

(uropathogens) to persist and multiply in the bladder in

a short time period, resulting in an incidence of bacteriuria among people with catheters of 8 percent overall. 

Virtually all people with long-term catheters experience

bacteriuria, which is predominantly caused by as many

as eight different species of microorganisms. Although

Escherischia coli is still the predominant organism, these

people are more commonly infected with uropathogens

that are more likely to be resistant to common antimiWho’s at Risk for UTI?

• Infants and children 

• People with catheters, 

spina bifida, spinal cord

injuries, and diabetes 

• Pregnant women

• The elderly

• People with renal 

transplants

• People in certain racial 

and ethnic groups
A Strategic Plan for Research 121

crobials and more difficult to eradicate. These

uropathogens include Candida, Enterococcus,

Pseudomonas aeruginosa, Klebsiella, Enterobacter, 

and Staphylococcus aureus. Proteus spp. is associated 

with catheter obstruction in the bladder or kidney, 

renal stones, and chronic pyelonephritis. 

Clinical ramifications of long-term catheterization

include fevers, bacteremia, acute and chronic kidney

infection, kidney stones, catheter obstruction, and

death. Prevention of catheter-associated UTI depends 

on meticulous maintenance of the closed catheter system.

Minimizing the duration of catheterization or using

intermittent catheterization has been shown to significantly reduce the risk of institution-acquired infection. 

People with Spinal Cord Injuries

UTIs are common among people with spinal cord injuries,

most of whom are young men. UTIs in this population

are often complicated and associated with significant

morbidity and mortality. It has been estimated that

nearly half of them will die of kidney-related problems. 

People with spinal cord injuries have unique concerns

that have an impact on the risk and management of UTI.

Spinal cord injury can have anatomical and physiological 

consequences, including

bladder over-distention, 

vesicoureteral reflux

(reflux of urine from 

the bladder into the

ureters during voiding),

urinary stones, bacterial

colonization of the 

perineum (the region

between the anus 

and the vagina or 

scrotum), and highpressure voiding. 

The 1992 National

Institute on Disability

and Rehabilitation

Research Consensus

Conference examined

the problems associated with UTI in 

persons with spinal

cord injuries. 

The Consensus

Conference report

stated that indwelling

catheters most likely

lead to persistent 

bacteriuria, and, as 

a result, intermittent

catheterization—although expensive and difficult to

manage—is preferred. Intermittent catheterization has

been shown to decrease lower urinary tract complications by reducing the incidence of stones, by maintaining low pressure within the bladder, and by eliminating

the complications associated with an indwelling catheter. 

The UTI Consensus Conference determined that asymptomatic bacteriuria does not require treatment unless

the upper urinary tract is at risk. Persons with spinal

cord injuries who retain use of their hands, that is, people with lower level injuries or incomplete lesions, are

more likely to be able to use intermittent catheterization,

thereby reducing their risk of UTI.

At any time, approximately a third of people with spinal

cord injuries have bacteriuria. Escherichia coli remains 

a common uropathogen, in addition to Enterococcus,

Pseudomonas, and Proteus mirabilis. The presenting

symptoms of UTI (particularly lower tract) in this population are atypical, and clinicians often find it difficult 

to determine when treatment is required. Clinicians 

with limited experience in managing persons with 

spinal cord injuries particularly tend to over-treat 

UTIs, thus increasing the risk of promoting multidrug resistant bacteria. 

Pregnancy

Risk Factors for UTI

• A history of UTIs 

• Lower socioeconomic 

status

• Sickle-cell trait 

and anemia

• Minimal medical care

• Older age or increased 

number of births

Spinal Cord Injury

Risk Factors for UTI

• Reflux

• Bladder overdistension

• Urinary obstruction 

• Impaired voiding 

• Urinary stones
122 OVERCOMING BLADDER DISEASE

Research is needed to provide further information 

about the transition from asymptomatic bacteriuria to

symptomatic UTI and how to prevent this from occurring

(i.e., method of catheterization, technique of catheter

cleaning and changing, use of preventative medications,

and bladder muscle pressure reduction). In addition,

research should also explore why certain people are

more susceptible to clinical UTI. 

Pregnant Women

UTIs are the most common bacterial infections during

pregnancy. From 4 percent to 10 percent of pregnant

women will have bacteria present in the urine but 

will not have symptoms of infection (asymptomatic 

bacteriuria), and 1 percent to 4 percent will develop an

acute UTI. Kidney infection or pyelonephritis develops

in approximately one-third of pregnant women who 

have untreated bacteriuria, whereas bacteriuria rarely

progresses to kidney infection in a woman who is not

pregnant. Kidney infection is the most common, severe

bacterial infection of pregnant women, and it frequently

requires hospitalization. 

Untreated, asymptomatic bacteriuria during pregnancy

has significant consequences, including kidney infection, low-birth weight infants, anemia, and pregnancyinduced hypertension. Although some subsequent 

studies have disputed the earlier findings, untreated

asymptomatic bacteriuria is clearly associated with 

acute kidney infection and low-birth weight infants.

Research has highlighted the importance of screening

for asymptomatic bacteriuria early in pregnancy. It has

been recommended that pregnant women be screened

during the first prenatal visit. 

Elderly People

In the past decade, research has revealed important 

differences in UTIs between older and younger populations and within geriatric populations, depending on

whether they live in the community or in institutions. 

A study of elderly people older than 65 years who were

not institutionalized found genitourinary infections to

be the second most

common form of infection, accounting for

nearly a quarter of all

identified infections. 

Symptomatic UTI is

found among older

men and older women

and is generally 

considered to be 

complicated. Viable

bacteria may be 

present in the blood

(bacteremia), even

without a demonstrable kidney infection. Functional and

anatomic predispositions are common.

Changes in the function of the prostate, 

for example, may 

predispose older men

to UTI and obstructive disease. Neurologic and other

diseases that cause incontinence and debility can

increase the risk of UTI, and certain drugs such as

antibiotics, anticholinergics (drugs antagonistic to

parasympathetic nerve fibers), and psychotropics 

(drugs used to treat mental disorders) can have an

impact on bladder function, creating conditions 

apparently favorable to UTI. Asymptomatic bacteriuria 

is a common and often benign disorder among elderly

people, affecting approximately half of women and a

third of men. Treatment of this condition appears to

have minimal benefit in this population. 

UTI symptoms are often atypical in older people and 

may mimic medical conditions such as pneumonia, heart

attack, or dehydration. Older people are also infected

with a broader spectrum of pathogenic organisms than

younger people, and up to a third are infected with several organisms at a time. Antimicrobial resistance rates

are greater among elderly people, particularly among

those who reside in long-term care facilities. This has

Aging

Facts about UTI

• As people age, symptomatic UTI becomes 

more common in men 

as well as in women

• Bacteria in the bladder 

can spread to the blood 

stream even before causing 

a kidney infection

• Symptoms of UTI are 

atypical; therefore, 

diagnosis is often made 

only after ruling out 

heart attack, pneumonia, 

or dehydration

• Resistance to antibiotics 

is increased
A Strategic Plan for Research 123

been attributed to selection pressures in people who

have been frequently treated with antibiotics or exposed

to people who have been. Management approaches

include longer courses of therapy (greater than seven

days), preferably with fluoroquinolones or trimethoprim-sulfamethoxazole (TMP/SMX) when organisms

responsive to treatment with TMP/SMX are isolated. 

In men, if the prostate is involved, longer courses of

therapy may be indicated to reduce the risk of recurrence. 

Estrogen deficiency in postmenopausal women has been

associated with anatomic, mucosal, and smooth muscle

changes, as well as with changes in vaginal flora. Older

women may have anatomic changes that have resulted

from childbearing or surgery of the reproductive organs.

Topical estrogen has been shown to reduce the frequency

of UTI by more than half. A recent randomized trial of

women with heart disease showed no decrease in risk 

of UTI from one commonly used regimen of systemic

estrogen. Because this trial was not population-based

and other current regimens have not been tested, more

data are needed before formulating recommendations

for or against the use of systemic estrogens for prevention of UTI.

People with Diabetes

In general, people with diabetes appear to have up to

four times the risk for bacteriuria than people who do

not have diabetes. Bacteriuria and UTI are more common among women with diabetes than among men with

the disease. In addition, persons with diabetes are more

likely to develop UTI as a result of unusual pathogens

that infect the urinary tract or to have severe complications such as emphysematous cystitis (an inflammation

and infection of the bladder wall caused by gas-forming

bacteria), and emphysematous pyelonephritis, which is

the same type of infection but located within the kidney.

Both diseases are diagnosed almost exclusively in people

with diabetes. 

The pathogenesis of UTI in persons with diabetes

remains controversial. Underlying bladder dysfunction

is a known risk factor for a subset of this population.

Other risk factors include anatomical and functional

abnormalities, poor blood sugar control, impaired

leukocyte (white blood cell) function, vascular complications, and urinary tract problems caused by disorders 

of the nervous system. The microorganisms that cause

UTI in people with diabetes are generally comparable to

those that cause UTI

in people without 

diabetes: E. coli

appears to predominate, although

research suggests 

an increasing role 

of Klebsiella and 

fungal pathogens 

in both hospitalacquired and community-acquired UTI. 

People with diabetes,

even though they 

may be ambulatory,

are considered to

have complicated

infections; therefore,

accurate diagnostic

testing, including

urine cultures before and after therapy, is important.

People with diabetes are at risk for upper urinary tract

involvement, obstruction, and severe or unusual 

complications, and they need to be carefully monitored.

Imaging studies should be considered for those who

require hospitalization. 

Management of UTI in people with diabetes often

requires a broad-spectrum agent and longer treatment

durations (more than seven days for lower tract infection) because infections are more difficult to eradicate.

Those who have kidney infections are often hospitalized. 

Diabetes

Facts about UTI

• Diabetes significantly 

increases the risk for a UTI, 

and women are at even 

greater risk than men

• Infections with unusual

pathogens are more likely

• Risk for severe and unusual

complications of UTI, such 

as infection of the bladder 

and kidney by gas-forming 

bacteria, is increased

• UTI is often the cause 

of hospitalizations
124 OVERCOMING BLADDER DISEASE

People with Kidney Transplants

UTI is the most frequent infectious complication of a

kidney transplant. UTI is also the most common cause 

of the spread of microorganisms and their toxins into 

the circulating blood (septicemia) after transplantation.

Hospitalization is frequently required for kidney transplant recipients who contract septicemia because it 

is associated with substantially decreased survival.

Factors that may put the kidney transplant recipient 

at increased risk for serious UTIs include bladder

catheterization, immunosuppression, glucose 

intolerance, and short ureters.

Ethnic Populations

Few data exist on whether or not risks of UTI are 

higher in specific racial and ethnic minorities.

Unpublished preliminary data suggest an increased 

risk of kidney infections in African American women.

Current Research 

Recent research has made many gains in elucidating 

the mechanisms involved in the development of 

bacterial disease, the host response in inflammation 

and infection, and the innate response to infection.

Bacterial Pathogenesis

Attachment of bacteria to host tissues is a key aspect 

of the pathogenesis of UTIs. This attachment may be

mediated by pili or fimbriae, by non-fimbrial virulence

factors, and by other phenomena described below. 

* Pili (Fimbriae)—Most pathogenic strains of the 

bacteria, E. coli, have filamentous projections on 

the surface called interchangeably “pili” or 

“fimbriae.” The pili or fimbriae bind to specific

receptors on epithelial cell membranes. As mediators of host-pathogen interactions, pili have 

long been regarded as important virulence factors 

in the pathogenesis of UTIs. 

Type 1 pili and P fimbriae are most commonly 

associated with virulence in the urinary tract. 

Type 1 pili constitute a major virulence factor

expressed by approximately 80 percent of common uropathogenic E. coli isolates. Type 1 pili 

bind to mannose groups on host cell glycoproteins. 

Although type 1-piliated uropathogenic E. coli bind 

to a variety of epithelial cells, including human 

vaginal cells, the specific receptors for type 1 pili 

on many tissues of the human urinary tract remain 

to be identified. In contrast to type 1 pili, P fimbriae

bind to sequences in cell surface glycosphingolipids. 

* Non-pilus virulence determinants—In addition to 

producing pili (fimbriae), uropathogenic E. coli

produce virulence factors such as the secreted 

protein, hemolysin. This protein forms holes in 

cell membranes and induces changes in calcium 

levels within the host cells, possibly influencing 

cell signaling. Other examples of non-pilus virulence

factors include cytotoxic necrotizing factor (CNF),

which can alter cell shape, and Sat, a virulence 

factor associated with cytotoxic activity. 

A high resolution micrograph

of a type 1 E. coli pilus. The red

arrow points to the FimH

adhesin, which plays a role 

in the formation of biofilms.

Biofilms cover bacterial 

populations, rendering them

resistant to antimicrobials

and antibiotics.

(Photo Credit: Matthew A.

Mulvey, Joel D. Schilling, 

Juan J. Martinez, and 

Scott J. Hultgren. Proceedings 

of the National Academy of

Sciences 97;16:8829-35.

Copyright 2000, National

Academy of Sciences, U.S.A.) 

=
A Strategic Plan for Research 125

Often virulence determinants in bacteria are located 

on contiguous regions of DNA called “pathogenicity

islands.” Certain pathogenicity islands are correlated

with virulence in the urinary tract. Since the pathogenicity islands are likely to encode other virulence factors,

sequencing these pathogenicity islands, identifying

novel virulence determinants, and understanding the

functions of encoded proteins are key targets for future

basic research on UTI. Subsequently, findings of basic

studies may be translated into therapeutic advances. 

* Internalization—Laboratory studies have shown that

epithelial cells in culture internalize isolates of

uropathogenic E. coli. Studies in mice have identified

a similar phenomenon in bladder tissue. These 

findings indicate that E. coli can establish a potential

reservoir that permits intracellular proliferation of

uropathogenic E. coli within bladder epithelial cells,

and this may be the mechanism for recurrent UTIs.

These observations generate many important 

questions, including, 

• What is the nature of the intracellular 

compartment(s) or reservoirs exploited by 

uropathogenic E. coli in vivo (during infection 

in intact humans)?

• What are the mechanisms of establishment 

of these reservoirs?

• Are novel bacterial genes involved in 

intracellular proliferation?

• How do bacteria proliferate in such reservoirs?

• Are intracellular uropathogenic E. coli resistant 

to known anti-microbial therapies?

* Microbial dynamics—Colonization of the vaginal

mucosa by uropathogenic E. coli strains is a key event

that precedes an ascending urinary tract infection.

Yet in some women, the vaginal mucosa can become

colonized without development of a urinary tract

infection, or the UTI may develop weeks or months

after colonization. The factors that promote the 

initiation of ascending infection from a colonization

event are not yet clear, although bacterial responses

to environmental conditions are likely mediators.

For example, recent data indicate that a bacterial

stress response pathway called Cpx regulates the

expression of P fimbriae; therefore, virulence 

factor expression most likely can respond to 

cellular signals. 

The expression of type 1 pili also is coordinately 

regulated by the expression of other virulence 

factors, and the adhesin of type 1 pili known as 

FimH plays a role in the formation of biofilms—

collections of proteinaceous material (slime) that

cover the bacterial populations and often render 

them resistant to sterilization and antimicrobial

treatments. Thus, an important question is, how 

do uropathogenic E. coli modulate gene expression 

in the body during colonization and ascending 

infection? Quorum sensing is a mechanism by 

which many bacteria monitor their own population

dynamics and modulate activity accordingly, and it 

is likely that uropathogenic E. coli employ a similar

mechanism as well.

* Antimicrobial resistance—One recent study showed 

that a significant percentage of microoganisms 

isolated in kidney infection were resistant to the

drug, trimethoprim-sulfamethoxazole (TMP/SMX), 

resulting in a 50 percent failure rate for treatment of 

kidney infection caused by these resistant organisms.

Similar, unpublished data from Israel on the treatment of uncomplicated UTI show equally high failure

rates for treatment of TMP/SMX-resistant E. coli.

These and other data demonstrate that resistance is 

a global trend. Thus, understanding the mechanisms

of resistance will likely lead to the development of

novel antimicrobial agents and extend the use of 

current therapies. 

* Bacterial genomics—Genomics is an increasingly

important tool for the characterization of uropathogenic E. coli isolates. Related non-uropathogenic

strains of E. coli have been sequenced in their entirety. A preliminary draft of the sequence for another

strain is available.
126 OVERCOMING BLADDER DISEASE

Host Response: Inflammation and Inflammatory Response

The host immune response to infection involves discrimination between self and non-self, or between

pathogen versus commensal organism, an organism that

is harmless and actually benefits the species in which it

lives. Immune responses are broadly classified as innate

(natural) immunity or as adaptive (acquired) responses. 

In innate immunity, host pattern recognition receptors

recognize molecules expressed by the pathogen that are

unique to it, highly conserved, and essential for its survival, such as lipopolysaccharide (LPS). In adaptive

immune responses, lymphocytes recognize pathogens

via specific antigen receptors, and memory for responses

occurs. Innate responses are thus less specific, broader

in spectrum, and present from birth without a known

capacity for memory. Activation of the innate immune

system may result in immediate killing of the pathogen

and recruitment of adaptive responses, including elaboration of cytokines, proteins that regulate the intensity

and duration of the immune response, and other 

inflammatory mediators. 

The connections between these two arms of the immune

system are complex and the subject of intense research

efforts. Although less research has been focused on the

immune response as compared with other infection,

some interesting recent discoveries have been made 

that suggest exciting avenues for further research. 

They are as follows:

* Host response to type 1 pili—The simple pilus-mediated interaction of uropathogenic E. coli with target

epithelial cells can induce significant responses from

the host. Type 1 pili induce rapid cell death (apoptotic

response) that leads to the exfoliation (sloughing off)

of superficial epithelial cells. This loss of superficial

cells can be thought of as a host defense, since many

of the invading uropathogenic E. coli are purged with

the urine as the bladder lining is shed. However, the

invading pathogens may also exploit the apoptotic

(programmed cell death) response to establish 

reservoirs. Uropathogenic E. coli appear to actively

enhance the programmed cell death response. 

Type 1 pili assist with the internalization of uropathogenic E. coli in a response that involves activation of

signaling cascades and cytoskeletal rearrangements.

How other virulence factors such as CNF1 interact

with pilus-induced events is an important area 

of investigation.

* Host response to P fimbriae—P fimbriae also induce

epithelial responses. In animal models and human

studies, P fimbriae enhance urinary tract colonization, trigger the local host response, and lower the

threshold for significant bacteriuria. P-fimbriated 

E. coli appear to activate the ceramide pathway via 

the release of ceramide from membrane receptor

glycosphingolipids, rather than from sphingomyelin.

Thus, while P fimbriae and type 1 pili share the ability to activate cellular response, they do so through

different signaling pathways. 

Type 1 piliated Escherichia coli attach to epithelial cells on the bladder 

wall. (Photo Credit: Matthew A. Mulvey, Joel D. Schilling, Juan J. Martinez,

and Scott J. Hultgren. Proceedings of the National Academy of Sciences, 2000;

97(16):8829-35. Copyright 2000, National Academy of Sciences, U.S.A.)
A Strategic Plan for Research 127

* Cytokine production—Uropathogenic E. coli induce 

the release of cytokines from the urinary tract.

Cytokines are hormone-like proteins that (1) 

regulate the intensity and duration of the immune

response and (2) mediate cell-to-cell communication. Two cytokines, interleukin-6 and interleukin8, are secreted into the urine at high concentrations.

Epithelial cells locally secrete interleukin-8, a

response that is important for the recruitment 

of neutrophils, a type of white blood cell, to the

infection site. Uropathogenic E. coli elicit these

cytokine responses when their surface molecules,

such as lipopolysaccarhides (LPS) and flagella, 

stimulate toll-like receptors on host epithelial 

cells. Interaction with toll-like receptors results in

induction of transcription, which is mediated by 

NF kappa B, an activator of the interleukin-8 gene

and a key regulator of inflammation. Uropathogenic

E. coli can also suppress the activity of NF kappa B,

thus potentially modifying host cytokine production.

Other pathogenic bacteria alter the host immune

response in this manner via specific virulence 

determinants. Investigating the means by which

uropathogenic E. coli may suppress or augment 

host immune responses in this manner is an 

exciting new area of inquiry. 

* Innate immune response—The innate immune

response to UTIs is thought to involve neutrophils

and mast cells. Drawn to the infected bladder by the

release of epithelial interleukin-8, neutrophils can

act as phagocytes that ingest and digest uropathogenic E. coli. Mast cells, immune cells involved in

allergic responses, are present in all layers of the

bladder and are activated by interactions between

type 1 pili and the CD48 glycolipid. This interaction

results in both internalization of uropathogenic E. coli

and activation of mast cells, which release histamine

and other pro-inflammatory mediators. Although the

potential role for mast cells in bacterial clearance from

the bladder is not yet known, factors released by mast

cell activation are consistent with the symptoms of

bladder inflammation (cystitis), including pain. 

Research Opportunities 

Opportunities for research into the cause, treatment,

and prevention of urinary tract infection are numerous.

Implementation of the latest tools offered by genomics

and proteomics will likely contribute to major advances

in our understanding of the pathogenesis of UTIs as well

as identify novel therapeutic targets. Studies in molecular epidemiology, materials engineering (e.g., catheters),

and vaccine development will help to identify susceptible

people and prevent the occurrence of UTIs. Together,

research into each of the areas described below will ultimately enhance our ability to prevent and treat UTIs and

reduce this significant burden on our health care system.

A six-step model of the pathogenic cascade of type 1-piliated uropathogenic Escherichia coli. Step 1: bacteria bind to superficial bladder 

epithelial cells through the use of the FimH adhesin on the tip of the

pili. Step 2: bacteria invade the epithelium. Step 3: bacteria replicate

within bladder epithelial cells. Step 4: bladder epithelial cells exfoliate

and flux into urine. Step 5: bacteria form colonies and reservoirs in

deeper layers of epithelium. Step 6: bacterial infection recurs. 

(Photo Credit: Dr. Scott Hultgren, Department of Molecular Microbiology,

Washington University in St. Louis, School of Medicine.)

Step 1 Binding

Step 6 Recurrence

Step 5 Reservoir Formation

Step 4 Fluxing/Epithelial Cell Exfoliation

Step 2 Invasion

Step 3 

Intracellular Replication
128 OVERCOMING BLADDER DISEASE

Bacterial Attachment

Genomic techniques have begun to reveal intriguing,

previously unknown, virulence determinants of E. coli.

Emerging evidence shows that bacteria use multiple 

virulence factors to infect the bladder and that cross 

talk occurs between bacteria and host cells. In addition,

bacterial resistance is rapidly emerging worldwide and

has far greater clinical consequence in the urinary tract

and beyond than previously understood. Key recent

findings and intriguing leads in the areas of bacterial

pathogenesis and host response to antimicrobials 

are summarized below.

* Virulence determinants—Bacterial attachment is thought

to enhance virulence by promoting colonization of

the urinary tract and by initiating effects upon the

tissue, such as inducing the production of cytokines.

Uropathogenic E. coli express several classes of

adhesins that bind to specific receptors on epithelial

cell membranes. The uropathogenic E. coli strain 

differs from most E. coli strains isolated from the

feces of healthy people. Numerous epidemiologic

studies have suggested that factors such as type 1 pili,

afimbrial adhesins, hemolysin, aerobactin, capsule

factor, and cytotoxic necrotizing factor (CNF) have a

role in the pathogenesis of urinary tract infections.

Many of these factors have not been proven to be

involved in disease, but it is suspected that they contribute to the disease process. Furthermore, temporal

control of type 1 pili expression may be required for

successful colonization of the urinary tract. 

Uropathogenic E. coli and other pathogenic E. coli

harbor pathogenicity islands, large blocks of genes

that do not appear in the E. coli normally found in

feces. The pathogenicity islands possess genomes

that are 20 percent larger than E. coli K-12 and other

nonpathogenic fecal strains, suggesting the presence

of many pathogenesis genes that have yet to be 

discovered. Genomic techniques are beginning to 

be used to discover genes present in a very potent

uropathogenic E. coli strain but absent from an

E. coli laboratory strain. 

* Type 1 pili—Pili (fimbriae) present in most uropathogenic E. coli strains mediate the attachment of these

microorganisms to bladder cells. Although type 

1-piliated organisms induce the host to respond

through programmed cell death (apoptosis) and the

shedding of bladder epithelial cells, uropathogenic 

E. coli can resist the innate host inflammatory

response by invading into deeper tissue. 

The ability of type 1-piliated uropathogenic E. coli

to invade the cells of the bladder epithelium and 

persist without being present in urine, may provide

an explanation for some recurrent UTIs. One study

showed that many recurrent UTIs are caused by 

the same bacterial strain isolated from the original

infection. Research that proves uropathogenic E. coli

is not strictly a pathogen that exists outside cells but

one that could emerge from within a cell reservoir to

cause recurrent UTIs would have a direct impact on

the methods for detecting and treating UTIs. Studies 

that are currently underway to address these issues

will eventually lead to new and better approaches 

for treating UTIs. 

* P fimbriae—In animal models and human studies, 

P fimbriae (pili) enhance urinary tract colonization,

trigger the local host response, and lower the threshold for significant bacteriuria. There is evidence for

direct cell activation by specific P fimbrial binding

glycosphingolipids (GSLs) and through disruption 

of GSL integrity and ceramide release. The exact

mechanism of this process requires further study,

but these data show that GSLs are important in 

cell-cell interactions and are involved in translating

cell-activating signals. Additional studies show 

that P fimbriae recruit toll-like receptor 4 as a 

co-receptor in cell signaling, suggesting that the

ceramide response is only one of several determinants of P fimbriae-mediated cell activation. 

Further elucidation of the effects of P fimbriae on

cell signaling in the urinary tract will provide basic

information about the function of this system, as well

as a better understanding of a means of treating UTIs. 
A Strategic Plan for Research 129

Host-Pathogen Interactions and Bacterial Pathogenesis

As compared with other pathogens such as Salmonella

(typhoid-causing bacteria) and Yersinia (plague-causing

bacteria), relatively little is known about how uropathogenic bacteria interact with urinary tract tissues to

induce inflammation. New data suggest that uropathogenic E. coli cause changes in the bladder epithelial cells

and cross talk occurs between them. Further investigations of these findings, as well as applying knowledge

learned in other systems such as Salmonella and Yersinia

pathogenesis, are among the key goals of future research

investigations. These future investigations should 

• Elucidate further the mechanisms of inducing

inflammation and infection by known virulence

determinants of uropathogenic E. coli, such as 

type 1 piliated and P fimbriated E. coli, hemolysin,

cytotoxic necrotizing factor 1 (CNF-1), and others

• Coordinate regulation of virulence factor expression

and pathogenic effects, including environmental

sensing, host-pathogen cross-talk, and opportunities

for non-antibiotic intervention

• Investigate pathogenicity islands and other 

undiscovered virulence-associated traits

• Conduct clinically based and animal model studies

linked to basic science investigations in microbiology

• Identify other new pathogenic organisms of the 

urinary tract, possibly non-bacterial or fastidious

Genomics and Proteomics Technologies

To accelerate the discovery process in bladder infection

and inflammation, infrastructures and initiatives in

biotechnology supported by the National Institutes 

of Health (NIH) are essential to develop and employ 

state-of-the-art technologies, broadly including

• Microarray analysis for measuring gene activation

• Proteomics to determine levels of proteins

• Functional arrays to measure specific biochemical

responses of epithelial cells and bacterial pathogens 

Investigators would then exploit the high-throughput

(the number of tests that can be performed in a given

period of time) capabilities of these new technologies to

rapidly analyze multitudes of clinical specimens as well

as to completely characterize important experimental

models of bladder diseases. These complimentary

approaches would lead to an enhanced understanding 

of the pathogenesis of UTIs as well the identification 

of novel therapeutic targets for clinical intervention. 

Molecular Epidemiology 

New genetic fingerprinting techniques are under development and should be applied to expanded strain collections from populations of interest. Through the application of new and existing molecular epidemiology techniques, several key areas of research should be explored,

including, 

• Elucidation of the lineages of uropathogenic E. coli

and other uropathogens 

• Identification of the environmental reservoirs of

these organisms (e.g., food, water, and animals) 

and the host

• Determine the means of acquisition and spread 

of uropathogens 

• Characterize the development of mutations resulting

in antimicrobial resistance

• Apply these findings to vulnerable groups, such as

persons with spinal cord injuries

Knowledge derived from these studies can be 

correlated with findings from basic science and 

health outcomes studies. This will allow development 

of principles for controlling the spread of resistant 

and virulent organisms. 
130 OVERCOMING BLADDER DISEASE

Host Susceptibility and Response

Research is needed on the following:

• Genetic predisposition and polymorphisms

• Existence of subtle defects and differences

• Innate and adaptive immunity in the urinary tract

• Chemokines, cytokines and their receptors, and

antimicrobial peptides in the bladder and urogenital epithelium

• Individual variations in response

• Relationships of the host response with underlying

diseases and comorbidities

• Response of the urinary epithelium to lipopolysaccharide (LPS) and other inflammatory mediators

Modeling

Small animal models have been useful in studies of

knockout mice and specialized host response traits.

Primate models might be more useful in studies of 

concepts that are specific to host and pathogen where

primate host responses could be defined and compared

with human host responses.

Vaccines for UTI

Two vaccines for urinary tract infections caused by

E. coli are currently under development. The first 

vaccine targets the FimH adhesin molecule on type 1 

pili of uropathogenic E. coli. FimH and type 1 pili are

necessary for bladder colonization, and the vaccination

that targets FimH on type 1 pili has produced protection

against bacteriuria and cystitis in mice and monkeys.

This vaccine also may protect against subsequent 

ascension of the bacterial infection to the kidney, 

since early studies have shown that the anti-FimH 

antibody prevents more than 90 percent of random 

E. coli UTI isolates from attaching to epithelial cells.

The second vaccine comprises multiple, heat-killed 

bacterial strains of E. coli, Proteus, Klebsiella, and

Enterococcus faecalis. Currently undergoing Phase II

investigations, this vaccine is administered as a vaginal

suppository. Women initially receive one suppository 

per week for three weeks, followed by one suppository

monthly. However, continuous boosters may be necessary, as UTI recurrences occur soon after treatment 

is stopped.

More research is needed to investigate 

• Vaccines that protect against other organisms 

besides E. coli

• Vaccines that are not adhesin-based

Probiotics and Other Measures

Interest in alternative therapies has led to investigations

of probiotics for the prevention of UTI. Probiotics are

defined as living microorganisms that are administered

to promote the health of the host by (1) treating or preventing infections caused by strains of pathogens or 

by (2) conferring upon the host other health benefits

such as lowered cholesterol, reduced risk of cancer, 

and improved tolerance to lactose. Most probiotics 

are administered as food or dietary supplements, and

benefits are assumed to be limited to the intestine.

Research has demonstrated that uropathogens replace

the normal lactobacilli-dominant vaginal flora in healthy

women who have UTI. In addition, a one-week course 

of the antibiotic, amoxicillin, was shown to disrupt the

lactobacilli that normally inhabit the vagina. This disruption lasted up to six weeks. As a result, one proposed

goal of therapeutic trials with probiotics has been to

replenish the vaginal flora in people who have had 

UTIs and antibiotic therapy. This would be accomplished

by the intravaginal application of exogenous lactobacilli.

This avenue of prevention is currently under further

investigation.

Another area of probiotics research is investigating the

effectiveness of cranberry juice and other potential 

competitive inhibitors of adherence and colonization.
A Strategic Plan for Research 131

Future studies in this area will require the proper

assessment of relevant outcomes, which are needed 

to better define the active ingredients in cranberry 

and other potentially inhibitory preparations.

Special Catheter Materials and Biofilms

Research should focus on developing special catheters

resistant to biofilm formation that will reduce the 

incidence of infections in people who have indwelling

catheters. Bioengineering collaborations to develop

infection-resistant or antibiotic-impregnated catheters

should be examined. 

Health Surveillance and Outcomes

Current management of acute uncomplicated UTI is

often empiric, without the use of a urine culture or of

susceptibility testing to guide therapy. The rationale for

this approach is based on the narrow and predictable

spectrum of agents causing acute uncomplicated UTI 

and the susceptibility patterns of anticipated pathogens.

However, as is true for other infections among people

who are not in facilities such as hospitals or nursing

homes, antimicrobial resistance among pathogens that

cause community-acquired UTIs is increasing. 

As the problem of antimicrobial resistance becomes

more widespread, the use of narrow-spectrum, inexpensive antimicrobial agents becomes less feasible, affecting

both the cost of, and the access to, health care. Preliminary data suggest that the increase in trimethoprimsulfamethoxasole (TMP/SMX) resistance is associated

with poorer bacteriologic and clinical outcomes when

TMP/SMX is used for therapy. 

Further research is needed to determine which factors

best predict resistance and at what level resistance

developed in the laboratory truly has clinical implications. In addition, surveillance data that combine 

susceptibility test results in the lab with epidemiologic

and clinical patient characteristics are needed for a more

accurate estimate of resistance rates among women 

with uncomplicated infection. Treatment of UTI may

contribute to global development of antibiotic resistance. 

Research Requirements 

Workforce and Infrastructure

Multi centers and program research centers are needed.

The National Institutes of Health (NIH) should also create new mechanisms and significantly modify ongoing

programs in infection, inflammation, and interstitial

cystitis to maximize recruitment, training, and career

development of investigators in other disciplines.

Possible mechanisms for achieving this include multidisciplinary training grants in inflammation, infection,

and host-pathogen interactions and center grants or

Centers of Excellence.

An NIH-Industry-Academia Task Force should also be

established to foster interactive research with pharmaceutical and biotechnology companies in the investigation of UTI.

Tissue and Specimen Banks

The NIH should expand the support of programs that

procure human tissues and bank them. In addition, 

bacterial and fungal isolates should be characterized so

that they may serve cutting-edge research in infection,

inflammation, and interstitial cystitis. The availability 

of a range of bacterial and fungal isolates and human 

tissues to establish DNA and RNA libraries should be

ensured as well. 

Advisory and Review Groups

The NIH should create ongoing review and advisory

groups and public interest and educational efforts in 

collaboration with the National Bladder Foundation, the

Bladder Health Council, and the American Foundation

for Urologic Disease.
CHAPTER 10
A Strategic Plan for Research 133

Common Clinical Conditions

UROLOGIC COMPLICATIONS OF DIABETES MELLITUS

DID YOU KNOW?

. Urinary tract infections are 

common in people who have 

diabetes.

. Healthy post-menopausal women

with type 2 diabetes have twice

the risk of urinary tract infections

than other women have.

. Diabetes increases the severity 

of urinary tract infections and

unusual consequences such as

upper urinary tract diseases.

. Peripheral neuropathy, a 

disorder of peripheral nerves 

and a complication of diabetes,

can lead to increased amounts 

of urine left in the bladder after

voiding—an environment that

promotes bacterial growth.

Summary and Recommendations

Diabetes mellitus is a major health concern, and diseases of the lower 

urinary tract are common among men and women with both type 1 and 

type 2 diabetes. Because diabetes significantly alters the urinary tract, 

more than 25 percent of people who have this disease will develop costly 

and debilitating urologic complications. These complications include

incontinence, infections, loss of sensation, and retention of urine.

Unfortunately, the mechanisms involved are poorly understood. 

Moreover, little is known about the prevalence, natural history of 

progression, and risk factors of these complications. The paucity of 

knowledge has been a barrier to developing the best methods of 

prevention and treatment of urologic complications. 

Clinical and basic science research projects on bladder and urethral 

dysfunction in persons with diabetes have received insufficient funding 

to make an impact on these problems. Only five basic projects and two 

clinical projects are currently funded at the National Institutes of Health

(NIH). The National Institute of Diabetes and Digestive and Kidney 

Diseases (NIDDK) supports a number of ongoing clinical trials studying

people with type 1 and type 2 diabetes and one population-based cohort

study that includes adults with and without diabetes. These clinical trials

analyze measures of lower urinary tract dysfunction, and they provide 

some beneficial information on urologic complications. However, 

ancillary studies such as these are often limited to self-reporting 

questionnaires, which provide information on the impact of disease 

on quality of life and activities of daily living; in-person interviews; 

and voiding diaries. These measures can only provide an initial, broad 

view of urologic issues.

The Bladder Research Progress Review Group has concluded that 

new research initiatives are needed to improve knowledge of the 

basic disease mechanisms involved in urologic dysfunctions caused 

by diabetes. Research studies are needed to
134 OVERCOMING BLADDER DISEASE

* Improve methodologies for measuring bladder dysfunction.

Research must develop

• Urine, blood, or cell markers—characteristics or

factors by which a cell or molecule can be recognized and identified—that are generic for early

bladder dysfunction and useful in both clinical

and animal settings 

• Markers that are specific for diabetic bladder 

dysfunction and useful in both clinical and 

animal settings

• Neurophysiologic methods to assess diabetic 

sensory threshold and function

* Assess changes in the bladder and urethra that are 

secondary to diabetes. To assess changes that occur 

in nerves, blood vessels, muscles, and epithelium, it

will be necessary to

• Establish a formal link with Mouse Models 

of Diabetic Complications (MMDC) and other 

on-going studies to determine diabetic urologic

pathology in mice, including urinary tract 

infection

• Study the effect of diabetes on female and male

(i.e., prostate) urethral function 

* Establish large multi-centered, randomized controlled 

trials of treatment outcomes in older persons with type 2

diabetes. These trials will determine whether or not 

overactive bladder treatments, both behavioral and 

pharmacological, are efficacious in older men and

women with type 2 diabetes. Clinical trials linked 

to other primary treatment studies should establish

relationships between treatment and control of 

the primary diabetes signs and symptoms and 

incidence and progression of associated bladder 

and urethral changes.

Goals of Research

The BRPRG defined and described the following

research goals:

* Clarify the basic disease mechanisms for bladder and 

urethral dysfunction in diabetes. Conduct extensive 

further study of bladder and urethral dysfunction 

in diabetes to

• Identify and characterize the effects of diabetes

mellitus on the nerves and muscles that contribute

to urethral function, both during the filling and

voiding phases of urination. Both in vivo and 

in vitro techniques should be considered to 

elucidate the mechanisms of action of diabetes 

on urethral function

• Perform biomechanical characterizations of both

the normal and diabetic urethra

• Correlate changes in passive biomechanical 

properties and active urethral responses

• Evaluate the use of gene therapy to treat diabetesinduced urethral pathophysiology and, in so

doing, develop new methods to treat diabetic 

urinary tract dysfunctions

* Identify the specific genetic determininants of diabetes and

its complications. Both type 1 and type 2 diabetes and

their complications have strong genetic determinants. Defining the specific genes involved and 

characterizing the specific bladder and urethral 

manifestations of the genetic subtypes is essential to

understanding the urologic complications of persons

with diabetes. Examining these subtypes may allow

preventive and management therapies to be tailored

specifically to them. 

Defining the genes for diabetes and its complications

may isolate genetically determined environmental

and pharmacologic response variations. Thus, a

major goal for the coming decade must be to identify

these predisposing genes. Collaboration with the

National Consortium for the Study of the Genetics 
A Strategic Plan for Research 135

of Diabetes is necessary to create a strong, coordinated effort for analysis of the role of genetics in 

urologic complications of diabetes. Research should

be enhanced in animal studies and clinical trials 

to discover the biochemical mechanisms by which

diabetes genes function to create susceptibility to

urologic complications 

* Discover the disturbances in cell signaling and cell 

regulation that cause diabetes and its complications.

Disturbances in cell signaling and cell regulation 

are central to disturbances in insulin secretion and

action, which lead to diabetes and to complications 

in both small and large blood vessels. Basic research

in this area is essential not only to understand 

diabetes, but also to understand many diabetesrelated complications. Most importantly, this type 

of “discovery” research can identify important 

targets for new treatments. The NIH should 

• Increase research in the fundamental science 

of cellular signaling as it relates to urologic 

complications in diabetes 

• Expand support of interdisciplinary research to

identify the mechanisms of these complications

* Develop a program to assess the effect of obesity on lower

genitourinary tract function. Obesity is a major risk 

factor for the development of type 2 diabetes and

insulin resistance, as well as a major cause of morbidity and mortality in the United States. Obesity 

disproportionately affects minorities. More than 60

percent of African American, Mexican American, 

and American Indian women meet the criteria of

being overweight, and between 33 percent and 37

percent are obese. Moreover, obesity in children and

adolescents is increasing at alarming rates, leading 

to the occurrence of type 2 diabetes in these groups.

Obesity, including type 2 diabetes, has been causally

related to certain urogenital diseases, including 

urinary incontinence and pelvic organ prolapse.

Moreover, obesity and diabetes are described as 

factors that increase complications in those people

undergoing surgery. One mechanism to achieve this

goal is to look at obesity as a concomitant but unrelated disease process in ongoing NIH-sponsored

clinical trials such as those conducted by the Urinary

Incontinence Treatment Network, Pelvic Floor

Dysfunction Network, and Prostatitis and Interstitial

Cystitis Treatment Network. 

* Expand research into the complications of diabetes in small

and large blood vessels. The different types of diabetes

and the array of complications they present offer a

wide range of specific research needs that are unique

to each. The microvascular and macrovascular complications of diabetes are responsible for most of 

the morbidity and mortality in both type 1 and 

type 2 diabetes. Understanding and combating the

complications of diabetes will require significantly

expanded research on the mechanisms involved in

the development of complications. Specifically, the

NIH should

• Expand support of research to identify the mechanisms of the diabetes complications in small and

large blood vessels that may relate to the lower

urinary tract

• Recruit scientists from outside the field to enrich

research on diabetic urologic complications 

• Significantly increase the investment in fundamental research to determine the mechanisms 

of the nerve damage in diabetes, to expand

research on nerve regeneration and rescue, 

and to evaluate methods to enhance peripheral

and autonomic function 

• Increase research to determine the mechanisms

responsible for the loss of the vascular-protective

effect in premenopausal diabetic women 
136 OVERCOMING BLADDER DISEASE

* Support research on the impact of diabetes in women, 

children, and the elderly. Diabetes presents additional

problems to women because of its impact on reproductive health and its causal relationship with 

vascular complications. Children and the elderly

present special problems in the management of 

diabetes and may have additional physiological 

variables that must be addressed. To address 

these problems, the NIH should

• Increase basic and clinical research to identify 

the mechanisms by which the intrauterine environment, including the diabetic environment,

affects both the immediate and long-term health

outcomes for children and their risks of diabetes

and obesity

• Support research to determine the impact of type 1

and type 2 diabetes on women, including the

impact on their reproductive health

• Increase studies on age-related changes in the

development of type 2 diabetes and its relationship to urologic diseases such as aging and pelvic

organ prolapse 

* Increase research into the prevalence and impact 

of diabetes complications in minority populations. 

Under-represented populations, including African

Americans, Hispanics, American Indians, and

Asians, have the highest incidence of diabetes and

the highest rates of complications. These groups are

rapidly growing segments of the population, and 

specific research must address the reasons for the

disproportionate impact of diabetes that they bear.

The NIH should

• Increase efforts in accurate identification 

of urologic complications of diabetes in 

minority populations 

• Support research to identify risk factors, 

comorbidities, and primary and secondary 

prevention strategies for urologic complications 

of diabetes in minority populations 

* Explore the potential of genetic engineering for treating

diabetes-related urologic dysfunction. The ability 

to modify the function of cells through genetic 

engineering opens up tremendous opportunities 

for new therapeutic approaches to diabetes and 

its complications. The NIH should

• Increase research to explore the potential use 

of genetic engineering 

• Bolster research to explore unique applications 

of gene therapy for tissue-specific approaches 

to urologic complications 

* Establish a comprehensive clinical research program. 

This can be achieved through the following actions:

• Increase funding of meritorious clinical trials 

of emerging new therapies for urologic 

complications of diabetes

• Develop effective partnerships among the NIH,

academia, and industry for collaboration and 

co-funding of clinical trials in diabetic urologic

dysfunction 

• Initiate clinical studies of promising new 

therapies for diabetic urologic diseases, such 

as gene therapy or tissue-specific approaches 

• Initiate studies to determine the reasons that

women and some minority populations with 

diabetes have higher risks for diabetic urologic

complications 

• Increase opportunities for, and support of, 

clinical research training 

* Create an infrastructure and develop resources that will

enhance research into urologic dysfunctions related to 

diabetes. An effective program of diabetes research

can exist only if there is a supportive infrastructure.

New and expanded initiatives are required to address

issues such as human resources, clinical research,

animal research, special needs, high-cost technology, and other components of infrastructure. 
A Strategic Plan for Research 137

* Establish mechanisms for the ongoing review, evaluation,

and advice regarding implementation of the recommendations set forth by the Bladder Research Progress Review

Group. To accomplish this goal, the NIH should

• Create new mechanisms and significantly modify

existing programs to maximize recruitment,

research training, and research career development

of diabetes investigators, including special initiatives to attract investigators from other disciplines 

• Advocate and provide incentives for urologic 

input to the Comprehensive Diabetes Research

Centers to provide enhanced infrastructure 

support and to enhance the effectiveness of 

existing Diabetes Centers 

• Create a National Diabetes Technology Task Force

with urologic representation 

• Provide funding for assessing bladder and urethral

function in collaboration with the Centers for

Animal Models of Diabetes and Related Disorders 

• Support mechanisms to develop and characterize

larger animal models of type 1 and type 2 diabetes

and their urologic complications 

• Expand support of programs for procurement of

human tissues and organs to serve cutting-edge

diabetes research, to obtain appropriate tissues for

the study of urologic complications of diabetes and

genetic research, and to ensure the availability of a

range of human tissues required to establish DNA

and RNA libraries 

• Establish an NIH-Industry-Academia Task Force,

with urologic representation, to foster interactive

research initiatives 

• Establish a urologic advisory panel to review and

make recommendations concerning intramural

NIH diabetic urologic research efforts

• Advocate for urologic representation on Strategic

Planning in Diabetes Research that would report

biennially to Congress and to directors of the NIH

and the NIDDK 

Background

Although diabetes is known to significantly alter the 

urinary tract, the pathophysiologic mechanisms involved

in this process are poorly understood. The best methods

of prevention and treatment of these complications are

also unknown. 

Bladder and Urethral Dysfunction in Diabetes

Coordination of the smooth and striated urethral

sphincteric mechanisms with bladder activity during

urination is essential for efficient voiding. Diabetic

bladder disease is well established, but little is known 

of the effects of diabetes mellitus on the urethra.

Diabetes may interfere with both smooth and striated

muscle relaxation at the level of the muscle layers 

themselves or at the level of the nerves controlling them.

Indeed, diabetes has been reported to impair urethral

relaxation in rabbits. This, together with anecdotal 

clinical evidence that men with both benign prostatic

hyperplasia (BPH) and diabetes mellitus are especially 

at risk for urinary retention, suggests that diabetes may

result in a disruption of vital bladder-urethral interaction leading to an increase in outlet resistance. The

result is a worsening of the over-distension caused 

by the bladder muscle’s weakened reflexes and its

inability to contract sufficiently . 

Sensory neuropathy is one of the most common 

complications of diabetes. The abnormal function of the

bladder afferent nerve pathway (the pathway that sends

nerve impulses to the central nervous system) is a key

clinical manifestation in cellular disorders of the lower

urinary tract that frequently occur in people who suffer

from diabetes (diabetic cystopathy). Interestingly, recent

research evidence has demonstrated that afferent pathways in the urethra normally play a role in the control 

of bladder function. This thereby leads to the possibility

that positive feedback from the urethra’s afferent nerves

may also be compromised by diabetic neuropathy, the 
138 OVERCOMING BLADDER DISEASE

condition that results from the damaging effects of high

blood sugar (hyperglycemia) on nerves. Such a situation

would be expected to contribute to the weakened bladder

reflexes associated with diabetes. Findings of urogenital

afferent dysfunction in humans with diabetes support

this hypothesis.

Epidemiology

More than 25 percent of people who have diabetes 

will develop urinary tract complications. Unfortunately,

knowledge of the prevalence, natural history of progression, and risk factors of these urologic dysfunctions is

inadequate. The annual costs of diabetes have been 

estimated at more than $98 billion. Approximately 

16 million Americans, including more than 12 percent 

of adults older than age 40, have diabetes. In recent

years, diabetes has become more prevalent in the U.S.

population, and it is increasing as the population ages.

According to National Diabetes Group Data 1995, 

type 2 diabetes accounts for approximately 90 percent 

of all cases of diabetes mellitus, and this subtype 

causes most complications. 

As a result, in the next decade, a large percentage of 

the U.S. population will most likely have symptoms 

of lower urinary tract disorders. According to recent

studies, diabetes appears to have the following effects 

on the bladder: 

• Diminished sensibility

• Poor contractility

• Increased residual urine

Urologic dysfunctions such as urinary incontinence, 

urinary tract infections, lower urinary tract symptoms,

sensory neuropathy, and urinary retention are common

and costly complications of this disease. The epidemiology of urologic complications is not well known. In three

large observational studies performed in 1990, 1995, 

and 1996, diabetes was reported to be associated with 

a 30 percent to 70 percent increased risk of urinary

incontinence in women and men. Research on the type

of incontinence associated with diabetes has been limited, but a study in 1997 suggests that the risk for urge

incontinence increases about 50 percent, while risk for

stress incontinence does not increase. Epidemiologic

data are lacking on the prevalence of incontinence 

in men with diabetes and the relationship with 

prostatic hyperplasia.

Risk factors for urologic complications among adults

with diabetes have not been well established. No clinical

trials have been performed of interventions to reduce

the risk of urologic diseases. And no prospective studies

of early diabetic disease have included urologic diseases

as an outcome.

Risk Factors for Urologic Diseases

Studies suggest that long duration, severe disease, poor

glycemic control, and presence of peripheral neuropathy

increase the risk of urologic diseases among adults with

diabetes. One likely cause of urologic complications is

microvascular disease (disease of small blood vessels),

which causes damage to the small blood vessels and

nerves of the urethral sphincter and bladder. 

The metabolic consequence of intraneural hyperglycemia (high blood glucose within nerves) in people

with poorly controlled or uncontrolled diabetes mellitus

is glycosylation of nerve proteins, which leads to altered

and impaired blood flow, oxidative stress, autoimmunity, 

and deprivation of nerve growth factors. Glycosylation

may be involved in the pathogenesis of microvascular

disease. Specifically, in diabetic rats, alteration in 

nerve regulation and dysfunction of the nerves of the

autonomic nervous system result in bladder dysfunction. 
A Strategic Plan for Research 139

The length of time a person has had diabetes, the baseline blood sugar (glucose) level, and the degree of control they have over blood glucose levels have an influence

on new development and progression of other small

blood vessel complications in persons with type 1 and

type 2 diabetes. If microvascular complications also

damage the blood vessels and nerves of the urethral

sphincter and bladder, risk factors for microvascular

disease may also be risk factors for urologic diseases

among diabetics. 

According to a 1998 study, certain racial and ethnic

groups are at greater risk of developing diabetes than

whites of a similar age; these groups include African

Americans (1.6-fold), Mexican Americans (1.9-fold),

other Hispanic/Latino Americans (2-fold), and

American Indians and Alaskan Natives (2.8-fold).

African American women, however, are at a threeto four-fold decreased risk of stress incontinence 

despite their having a higher risk of diabetes and 

obesity, which are risk factors for incontinence. 

No large studies have been conducted of prevalence 

for, or risk factors associated with, incontinence 

in different racial groups with diabetes.

Risk for Urinary Tract Infections

Although diabetes mellitus is commonly believed to 

confer an increased risk for many infections, especially

urinary tract infections, data to support this are limited.

However, in the past 30 years, several studies have

reported that both bacteriuria (the presence of bacteria

in the urine) and urinary tract infections (UTIs) are

more common in persons with diabetes than in other

people. Recently, healthy postmenopausal women with

type 2 diabetes were found to have a nearly two-fold

increased risk of UTIs. Most studies indicate that UTIs

are more common among women who have diabetes 

than among men with the disease. 

Studies have also shown that having diabetes increases

the severity of UTIs and unusual manifestations such as

upper urinary tract disease. Serious complications such

as abscesses of the kidney or of the connective tissue 

and fat surrounding the kidney and decay of the kidney

papillae are more frequently reported for persons 

with diabetes. 

A number of factors have been postulated to increase 

the risk of UTIs in persons with diabetes. These factors

include the possible effects of 

• Glucose in the urine (glycosuria) and a high level 

of glucose in the circulating blood (hyperglycemia)

on bacterial growth and immune function

• Peripheral neuropathy, a disorder of the nerves 

leading to the bladder that can cause an increase 

in residual urine volume, which can allow increased

bacterial growth. 

Few well-designed epidemiological studies correlating

improved glycemic control with risk of UTIs and of

upper tract disease have been reported.

Prevention and Treatment of Bladder Dysfunction

Control of blood glucose has been shown to reduce 

the risk of diabetic complications. Intensive glycemic

control delays the onset and the progression of

microvascular complications of diabetes, including 

non-inflammatory disease of the retina (retinopathy),

kidney disease (nephropathy), and nervous system 

disorders (neuropathy) in both type 1 and type 2 diabetes. Reduced risk of large blood vessel complications

such as atherosclerotic cardiovascular disease has 

not been clearly demonstrated. If small blood vessel

complications are important in the etiology of urinary

incontinence, intensive glycemic control may prevent 

or improve severity of urinary incontinence. 
140 OVERCOMING BLADDER DISEASE

Weight reduction in women with impaired glucose 

tolerance decreases the risk of developing diabetes.

Weight reduction in moderately obese women also 

significantly improves urinary incontinence. This

improvement in incontinence in moderately obese

women may motivate them to lose weight, which 

reduces the risk of developing diabetes, improves

glycemic control, and reduces the incidence of small

blood vessel complications. The long-term effects of

weight loss on the incidence and severity of incontinence

in women with diabetes has not been evaluated. Also,

evidence regarding the effectiveness of weight loss to

prevent or decrease diabetes or incontinence severity 

in different racial groups with diabetes is limited.

Direction of Epidemiological Research

Although urologic diseases are common health problems

in men and women with diabetes, risk factors, pathophysiologic mechanisms, and possible interventions 

are not well understood. It is important to determine 

the following:

• Prevalence and incidence of urologic diseases 

for adults with type 1 and type 2 diabetes who live 

at home 

• Risk factors associated with urologic diseases, 

especially aspects of diabetes severity (duration;

treatment; glycemic control; and presence of

microvascular complications, including retinopathy,

nephropathy, and neuropathy) that are associated

with greater risk or severity of urologic diseases 

• Effectiveness of interventions, including glycemic

control and weight reduction, in preventing or

reducing severity of urologic diseases among 

adults with diabetes

Current Research 

A review of the active research portfolio at the NIH has

revealed that current research on urologic dysfunction

caused by diabetes is limited. Although a few funded

studies examine the mechanisms of bladder dysfunction

in diabetes and the relationship to nitric oxide, insulinlike growth factors, and nerve growth factor, these

mechanisms are not yet detailed. They have been 

conducted using diabetic rat models. 

The NIDDK has a few prospective cohort studies among

adults with impaired glucose tolerance, type 1 diabetes,

and type 2 diabetes, and one population-based cohort

study that includes adults with and without diabetes.

Although analyzing measures of urologic dysfunction

provides a highly efficient means of evaluating urinary

incontinence prevalence, incidence, and risk factors

among persons with diabetes, this area needs much

more exploration. 

The fields of urology and urogynecology have taken 

little notice of urologic dysfunctions in diabetes, 

and the work that has been done is mainly on clinical 

reports of urinary tract infections. More recently, 

there has been interest in erectile dysfunction in 

diabetes, with both clinical and basic animal model

studies being performed. Reports are minimal on 

how diabetes affects urethral and prostate function.
A Strategic Plan for Research 141

Future Research 

Objectives

The BRPRG recommends that scientific objectives of

future research on the effects of diabetes on the lower

urinary tract should be as follows:

• Identify and characterize the cellular and molecular changes that occur in diabetic lower urinary 

tract dysfunction and compare them with the 

normal bladder

• Develop short-term, clinical pilot studies to 

further characterize lower urinary tract dysfunction in persons with diabetes, and test novel 

treatment strategies

• Identify and characterize genetic markers that may

predict early urinary tract involvement in diabetes

• Identify preventive strategies for diabetic complications in the lower urinary tract

• Determine the prevalence and natural history of 

urologic complications in longitudinal studies of 

men and women with diabetes

• Identify preventable or modifiable risk factors that

will direct the design of trials to determine whether

risk reduction results in lower incidence or severity

of urinary incontinence, lower urinary tract 

symptoms, urinary tract infections, or diabetic 

bladder dysfunction 

• Identify racial and ethnic differences in urologic

complications

• Increase the diversity of scientific expertise 

applied to clinical and basic research studies of 

the urinary tract

• Integrate multidisciplinary groups of investigators 

to study urologic complications in diabetes

• Involve new investigators in research studies and

training related to the urinary tract

Scope

The urinary bladder and urethra are complex organs 

with many interacting molecular, cellular, and tissue

elements. The scope of the research strategy recommended in this paper is meant to encompass all the

molecular and cellular components and interactions 

that occur both in the normal organ and tissue and in 

the diabetic tissue. Broad areas for investigation include,

but are not limited to, the following:

• Pathogenic mechanisms

• Genetic mechanisms

• Therapeutic strategies

• Markers of early dysfunction

Stem Cells

Stem cells are multipotential progenitors capable of 

self-renewal and multi-lineage differentiation. They 

are, therefore, of great medical interest because of 

their potential therapeutic use for organ renewal and

replacement. The BRPRG recommends that NIH launch

a prospective study to identify and isolate multipotent

stem cells or progenitor cells from the pancreas and 

to determine whether pancreatic stem cell therapy to

cure diabetes can reverse the urologic complications 

of diabetes. 

Research into urinary tract stem cell therapy should 

also be a priority because of potential implications 

for bladder renewal. Studies should be established to

determine whether stem cell injection to the lower 

urinary tract can improve or reverse the complications 

of diabetes. Specific examples would be muscle-derived

stem cells injected into the diabetic neuropathic bladder

to improve contractility and stem-cell-aided ex vivo

gene therapy to restore neurotrophic factors in 

diabetic neuropathy.
142 OVERCOMING BLADDER DISEASE

Research Requirements and Impediments

The BRPRG has defined needs in several areas that 

will be critical to advancing knowledge of urologic 

dysfunction in diabetes research initiatives. Manpower

needs, infrastructure requirements, and the need for

tissue and specimen banks must be addressed if this

effort is to succeed.

Workforce

Only a few well-trained clinical researchers are investigating urologic dysfunctions in diabetes. A complete

funding program is necessary to develop a cadre of welltrained clinical investigators and physician scientists.

This program should include funding for fellows, young

faculty, and mid-level faculty. At the young faculty level,

funding for four to five years after fellowship (modeled

after a K23 award) is necessary to allow for professional

development. At the mid-career level, funding for four

to five years (K24 funding) is needed for faculty to 

mentor fellows and young faculty. In addition, the 

program should give priority to the recruitment of 

quality scientists who have doctorates and expertise 

in diabetes and who would study the effects of diabetes

on the lower urinary tract. 

Infrastructure

Translation of basic research into human therapies

depends on an active and vigorous clinical research 

program. However, several prevailing forces have 

significantly hampered clinical research and clinical 

trials in diabetes. Investigator-initiated clinical 

research is declining as a result of the 

• Decreasing numbers of clinical investigators

• Limitations on funding of clinical research

• High cost of clinical research

• Complexity of clinical challenges 

A major factor hampering clinical trials is the lack 

of infrastructure to organize and support them. A comprehensive program for tackling a significant public

health problem such as diabetes requires a major 

investment of funds, not only in basic research, but also

in clinical research and clinical trials. The latter are 

particularly needed to document the safety and efficacy

of various therapeutic strategies and to generate the

knowledge base for “evidence-based medicine” that 

will lead to better treatment of diseases. To achieve 

these goals, the NIH must

• Create an infrastructure to facilitate clinical trials—

both to improve efficiency and to lower costs. This

need is especially apparent in diabetes, where the

path from clinical trials to “hard endpoints” 

may take many years and even decades.

• Commit to using clinical trials as a mechanism 

to develop the proper base of knowledge and to

assure steady improvement in the care of people 

with diabetes.

• Establish collaborative research programs that 

would link bladder research with ongoing diabetes

research programs.
A Strategic Plan for Research 143

Tissue and Specimen Banks

Tissue and specimen banking can serve the researcher

by allowing single samples to be used in multiple 

projects and by allowing longitudinal collections 

with thorough source profiling. Tissue and specimen 

collections vary considerably from formal repositories 

to informal collections that reside in the laboratory

freezers of individual researchers. 

Urine and blood samples that may represent a reflection

of bladder activity and offer potential for evaluation 

are part of a number of large, longitudinal studies. 

Of particular interest are studies that may allow the 

clinician to predict early diabetic urologic dysfunction. 

The following are either important longitudinal studies

or NIDDK-sponsored studies with banks of tissues 

and specimens that relate to diabetes:

• Family Investigation of Nephropathy and Diabetes:

serum, plasma, urine, DNA, and transformed cells

• Genome Scan for NIDDM Susceptibility Genes

among Samoans: DNA

• Metabolic Epidemiology of Diabetes in Japanese

Americans: white blood cells and DNA

• Diabetes and Cardiovascular Disease in Three Ethnic

Groups: blood

• Epidemiology of Diabetes Interventions and

Complications Study: blood, urine, serum, and DNA

• Cohort Registry of Type 1 Diabetes in Wisconsin:

plasma

• Diabetes Prevention Program: serum and DNA

• Diabetes Prevention Trial for Type 1 Diabetes: 

serum, plasma, and DNA
144 OVERCOMING BLADDER DISEASE

PATIENT PROFILE

Roger Parrish first learned that he had diabetes in 1994 when

he was 55 years old. He was feeling extremely tired all the 

time and had developed bladder problems that caused urinary

frequency and urgency. As Parrish tells it, “I was going to 

the bathroom to urinate about every half hour, even at night. 

I went that often whether I drank anything or not.” 

Parrish’s physician gave him a complete physical and did a

fasting blood sugar test—his blood glucose level was

720mg./dL, miles above the current threshold, 125 mg./dL, for

identifying people with diabetes. With a diagnosis of type 2

diabetes, Parrish was placed on oral medications to lower his

blood sugar and was given a diet to follow. After a few weeks

on this regimen, he began to feel better, but the urinary frequency and urgency continued, although not as severe. He got

up to void at least three to four times a night. 

The elevated blood sugar in diabetes can cause autonomic 

diabetic neuropathy, a condition in which the autonomic 

nerves that help control the body’s involuntary functions such

as digestion and urination become damaged. Autonomic diabetic neuropathy (or cystopathy as it is called when it refers 

to the bladder alone) creates difficulty in knowing when the

bladder is full, difficulty in emptying the bladder completely,

and frequent bladder infections. In the latter, nerve damage

prevents the bladder from emptying properly, and the urine 

that remains becomes a medium for bacterial growth.

Parrish’s first urinary tract infection occurred not long after his

diabetes was diagnosed, when he had a bout with gastroenteritis. “I felt like I was straining when I went to the bathroom,” 

he says. “It was very painful.” Urinary tract infections are rare

in men but common in all persons with diabetes, as are other

infections. “One of the biggest things that happen to you when

you get diabetes is that you can suffer from more sickness,” 

Parrish says. “Your system is more vulnerable and you get 

more bugs, more flu, more colds. I never had colds much 

before I got diabetes.”

When blood glucose levels are maintained at a lower level, 

neuropathic symptoms lessen and may even prevent or delay

the onset of other problems. Parrish maintained his glucose

levels with diet and oral medications until this year when his

blood sugar started to climb, and he developed other neuromuscular problems associated with diabetes. 

In spring 2002, when he had surgery for a problem related to

diabetes, Parrish developed a second urinary tract infection,

which he says was precipitated by a drug reaction that

occurred in hospital. 

“It was very painful. I hurt more when I passed water than

when I didn’t, and it hurt worse at the end of passing water,”

he explains. “I thought back pain or a headache was pain 

but they didn’t come close. It was terrible.” Parrish says the

infection had an effect on his blood sugar, which went up to

420 mg./dL. “I was lucky to have not suffered a stroke, which

can happen when blood sugar is that high.” 

Roger Parrish

Diabetic Bladder

Roger and Frances Parrish
A Strategic Plan for Research 145

Parrish’s urologist performed cystoscopic tests to determine the

source of his bladder problems. A cystoscope allows the urologist

to visualize the interior of the bladder and to perform tests that

measure bladder capacity, elasticity, and contractility. “He filled

up my bladder with a dye solution and it felt like I was going to

explode,” Parrish says. “It was very uncomfortable, but it was

over quickly. I took pyridium [a medication that soothes the 

bladder lining] and antibiotics for months [for the bladder 

infection], and I’ve been feeling weak and drained. It drains 

you when you get an infection like that.”

Parrish’s physician recently placed him on insulin, and his blood

glucose levels now range between 90 mg./dL and 146 mg./dL.

The urinary frequency and urgency he had been experiencing

have diminished considerably in the short time that he has been

on insulin. He now goes to the bathroom every two hours and

“once a night or sometimes twice.” However, since the urgency

diminished, he was able to hold his urine so well that he was

putting off voiding when he was busy, something his physician

discourages. “She told me that holding back too long could 

damage the bladder,” he says. “It makes the bladder work 

harder and then it gets weaker.” 

Because of the severity of the urinary tract infection that

occurred after surgery, Parrish has had to take extended sick

leave from his job as supervisor of parking and transport at the

University of Virginia where he handles special functions such as

football games and conferences, and also from a part-time job

as a certified nursing assistant at Martha Jefferson Home Health

Care, where he specializes in the care of the elderly, a job that

gives him great satisfaction. “I love being with older folks.

There’s a lot of wisdom and knowledge there,” Parrish says. 

Parrish might also be described as a person who possesses a

great deal of wisdom and knowledge. Since developing diabetes,

he has been particularly careful about his diet and lifestyle.

Lifestyle factors such as smoking and alcohol can contribute to

nerve damage in diabetics. A nonsmoker who also does not drink

alcohol, Parrish believes this may have limited the severity of 

his problems. “ My biggest problem had been eating and not

getting enough rest. If I changed my diet 10 years before I was

diagnosed with diabetes, I would have been better off,” he says. 

Knowing that diabetes was prevalent in his family might have

helped as well. Although diabetes has affected almost every

member of his father’s family, Parrish never knew they had the

disease until after he developed it himself. “Then everyone started talking about their problems, including bladder problems.” 

Parrish would like the medical community to see if there is a 

better way to educate people about the effects of diabetes and

about how to prevent it. He also wonders whether research could

develop a way to detect it earlier or prevent it and the neuropathy

it causes. “Maybe some of the problems I had like the bladder

infections could have been avoided,” he says. 

Parrish is trying to change the course of the disease in his own

family by educating his children, ages 27 to 44, about diabetes

and its consequences. Although he’s had varying degrees of 

success with them, he says his wife has improved her diet 

considerably since his diabetes was diagnosed, and she stopped

smoking a few years ago. The couple has enjoyed a long and

happy marriage, during which they have taken memorable trips

to various states and Canada and romantic interludes to the

Caribbean Islands. They plan to stay healthy so that they can

have more of the same, he says. 

“I know I won’t live forever, but I don’t want to die for something

I could have prevented,” says Parrish, who measures his blood

sugar three and sometimes four times a day, administers insulin

accordingly, follows a prescribed diet, and sees his physician

every three months. 
CHAPTER 11
A Strategic Plan for Research 147

Common Clinical Conditions

URINARY INCONTINENCE

DID YOU KNOW?

. Approximately 13 million

Americans—many of them

women—suffer from urinary

incontinence, a condition that 

is not normal at any age.

. Nearly half of those affected 

are too ashamed to discuss 

this problem—even with 

health care professionals. 

. As many as 30 percent of new

mothers develop bladder control

problems after giving birth.

. An estimated 28 percent of

adults over age 60 have some

form of urinary incontinence.

Summary and Recommendations

For the 13 million people in the United States who live with urinary incontinence (UI), the condition is a daily embarrassment. Nearly half of these

Americans are too ashamed to even discuss this problem with their health

care professionals. Instead, they suffer silently, without help, becoming

dependent on toilet paper, pads, or diapers. According to research studies,

people who are incontinent seek help when their condition becomes severe,

but many years of suffering have occurred before that time. Early treatment

would be beneficial.

Most people afflicted with this condition are women. Despite the high

prevalence and impact of UI, research has lagged significantly behind

research into other conditions. In the current bladder research portfolio of

the National Institutes of Health (NIH), UI research is under represented

and under funded. It is a fertile area for development of high-yield

research, with the likelihood of rapid translation to clinical care of millions

of Americans. 

New research initiatives must be launched to

• Improve understanding of the mechanisms of UI 

• Develop more effective treatments

• Identify risk factors for incontinence and develop measures to eliminate

or reduce them

• To achieve these goals, the Bladder Research Progress Review Group

made the following recommendations:

* Increase the size, scope, number, and funding for NIH-sponsored multidisciplinary urinary incontinence research centers 

* Encourage industry-NIH relationships in incontinence-related research
* Recruit established scientists from other relevant areas

(e.g., cardiac or gastrointestinal physiology, cell signaling,

biomechanical engineering, genomics, and proteomics) to

apply their work to the urinary tract and incontinence by

encouraging collaborative efforts between basic and clinical scientists 

* Encourage special interest groups for conditions such as

Parkinson’s disease, multiple sclerosis, spinal cord injury,

and diabetes to be advocates for urinary incontinence

through better information for people with incontinence 

* Increase research funding for studies that use cellular and

molecular techniques to examine the basic mechanisms 

of bladder and urethral interactions that create urinary

continence and incontinence 

* Support research to develop appropriate animal models of

urinary incontinence

* Develop novel techniques (both invasive and noninvasive)

for measuring neural, muscular (striated and smooth), and

vascular function relating to continence and incontinence 

* Identify risk factors for urinary incontinence related to

childbirth and aging so that prevention measures and

improved disease-specific treatment can be developed

* Initiate research to develop preventive and therapeutic

approaches to urinary incontinence that are sensitive 

to gender, race, and culture, and develop the means

of measuring outcomes for treatments in these 

varied settings

* Develop a national data registry and tissue bank of 

people suffering from incontinence to meet the needs 

of researchers for well-characterized tissue samples 

* Explore with the Centers for Disease Control and 

Prevention the possibility of establishing a national 

registry for surgical treatment of urinary incontinence,

especially procedures using new technology

Background

Basic Mechanisms of Incontinence

The urinary bladder is a complex organ that is poorly

understood at this time. It has a simple purpose—to hold

and empty urine on demand. The bladder’s function can

be thought of as an equation of holding=emptying, with

movement from holding to emptying routinely based on

intentional neural and cerebral control. Incontinence

therefore should be thought of as an imbalance—a 

tipping of the equation by one or more variables or by

interaction of variables. There are many contributing

components to each side of the equation—some more

understood than others—but, undoubtedly, many 

variables are not appreciated at the present time.

Some variables have functions on both sides of the 

equation. Historically, the most studied variable in 

UI—pelvic attachments—is a static one and pertains 

to stress incontinence, that is, hypermobility of the 

urethra. In fact, the most reproducibly successful 

solution for hypermobility is surgical reattachment. 

This success is predicated on an understanding of 

the underlying mechanism. 

HOLDING EMPTYING

Bladder small muscle Urethra small and striated muscle

Urethra small and striated muscle Bladder small and striated muscle

Epithelium Epithelium columnar and squamous

Hydrophobic interphase

Nerves Nerves

Neural transmitters Neural transmitters

Growth factors Growth factors

Collagen Collagen

Vascularity Vascularity

Hormones Hormones

Pelvic attachments

148 OVERCOMING BLADDER DISEASE
A Strategic Plan for Research 149

Our understanding of the basic mechanisms of incontinence needs to be expanded to include the complex 

biochemical and rapidly changing variables such as

urothelial products—growth factors, collagen production,

and angiogenesis, the development of new blood vessels,

to name a few. Once this mechanism is understood,

treatment development with translation to clinical 

care will follow.

Another example of a tip in the equation is the loss of

estrogen in a postmenopausal woman. The bladder and

the urethra are both affected by the estrogen deficiency,

but the urethra’s diminished vascularity and tone is

more critical, resulting in incontinence and loss of 

control. Fortunately, once estrogen deficiency is 

diagnosed, treatment is inexpensive and effective.

The cause of a person’s incontinence is often elusive.

Currently, the medical community uses a small series of

tests, including a physical exam, blood work, cystoscopy,

urodynamics, and radiologic imaging, to evaluate a person who is incontinent. Each test gives reliable, meaningful, but limited, data. Estrogen deficiency will be

determined by a combination of rather mild physical

changes, nonspecific symptoms, and a blood test, which

has only moderate sensitivity and specificity. More likely

than not, a patient will receive an empiric trial. This is

the state for many variables for the bladder equation

detailed above. Many variables have no defined test with

which to determine its level of effect on the bladder.

Improved testing with yet-to-be-developed biomarker

and imaging technologies is a major clinical need.

To successfully treat incontinence, the medical community needs to acquire a broad and in-depth understanding of the variables of the bladder equation along with

their complex interactions. Studies of the mechanism 

of UI lay the groundwork for treatment development 

and rapid translation to the clinical care of millions 

of Americans.

Prevalence

Because it is a highly personal and often embarrassing

issue, UI is far more prevalent than reported. According

to some estimates, more than 13 million Americans 

suffer from UI, including 28 percent of adults above age

60 and 15 percent below. Every study that included both

men and women in the study population has reported 

a higher prevalence of incontinence in women, with

female to male ratios approximately 4:1 below age 60 

and 2:1 for age 60 and above. 

Established risk factors for both men and women

include family history, impairment of mobility and 

cognition, lower urinary tract symptoms, and age. 

Some of the strongest epidemiologic risk factors in

women include obesity, childbirth, and certain surgeries. In men, bladder outlet obstruction and prostate 

surgery are important risks factors. The frail elderly

deserve special consideration because of the balance

between co-existing conditions and bladder function.

Certain life events or health conditions increase the risk

of UI. Urge incontinence is more common in women

after they reach age 60, and stress incontinence more

common in younger women. In women who have given

birth vaginally, as many as 30 percent develop bladder

control problems. 

Some epidemiologic studies suggest that Caucasian

women are more susceptible to UI than African

American women (18 percent and 15 percent, respectively), and that Caucasian women have a higher 

prevalence of genuine stress incontinence compared

with African American women. 

Obesity is a significant independent risk factor for

incontinence in older women. Some evidence suggests

that obesity is an independent risk factor for certain

sub-types of UI. Family history may play a role; firstdegree relatives of elderly people with UI have been

reported to have an increased prevalence of nocturnal

enuresis. A similar familial predisposition has been

reported for childhood enuresis.
150 OVERCOMING BLADDER DISEASE

In older Americans, UI has been associated with a 20

percent to 30 percent increased risk of falls and fractures and a three-fold increased risk of nursing home

admissions. Although it does not necessarily lead to

death, UI has a profound effect on the health, activities

of daily living, and quality of life of older people. 

Cost and Impact 

The most recent estimate of the annual direct costs of 

UI in persons of all ages is $16 billion (1995 dollars). 

Of that amount, $11 billion were spent in the community

and $5 billion in nursing homes. Previous estimates 

of UI costs were $6.6 billion (1984 dollars) and $10.3

billion (1987 dollars). This cost increase is greater than

can be accounted for by medical inflation. Although costs

of routine care, complications, diagnosis, and treatment

are included, these comprehensive estimates most likely

underestimate the societal cost of urinary incontinence

because conservative assumptions about prevalence 

and cost were used. 

The annual direct cost of incontinence is similar to 

the annual direct costs of other debilitating and some

life-threatening diseases, including osteoporosis,

Alzheimer’s disease and other dementias, arthritis, 

and HIV/AIDS infections. While these illnesses vary 

in prevalence and in their effects on quality of life 

and daily functioning, this is a striking example of 

the large cost of illness of UI as compared with 

other common medical conditions.

More than 75 percent of UI costs are for the care of

women. Costs for women over age 65 are almost two

times the costs for women under age 65 (approximately

$8 billion and $4 billion, respectively). 

Risk Factors in Adult Women

Adult women bear a disproportionate burden of UI

because UI occurs earlier in life and persists longer.

Stress incontinence is the predominant type of UI 

in women younger than age 60; urge and mixed 

incontinence become more common after that age. 

Childbirth is a known risk factor, and, according to most

studies, the first birth appears to be associated with the

greatest increase in risk. Vaginal delivery and hysterectomy are established risk factors for both transient postpartum UI and UI in later life. This association appears

to be strongest for stress incontinence. According to

some research studies, damage often occurs to nerves

and muscles of the pelvic floor during these events. 

Further studies are needed to identify modifiable risk

factors of childbirth. Although risk of UI is not likely 

to have an impact on a woman’s decision to bear 

children, and would not be considered an indication 

for a Caesarean section, specific events of childbirth

need further investigation; these events include

• Use of forceps

• Type of anesthesia

• Administration of oxytocin (a hormone used to

induce labor)

• Performance of elective episiotomy (surgical incision

of the vulva to prevent laceration)

• Management of the second stage of childbirth

The complex interrelationship between events of childbirth, other reproductive factors, and the development

of UI has been largely unexamined and is an important

area for research. Gender-specific research is essential

for advances in clinical care of persons with gender

dimorphic conditions such as urinary incontinence. 

In some studies, hysterectomy has been associated with

increased risk of UI in women. Although the relationship

may be seen because hysterectomy is a major life event

for women, there is evidence that some subtle neurologic

damage associated with hysterectomy may contribute to

the development of UI. Continence surgery is not completely effective and researchers are diligently seeking

better ways to select specific procedures for specific

incontinent women.

Menopause traditionally has defined lower urinary tract

changes caused by estrogen deficiency; however, data
A Strategic Plan for Research 151

regarding the association between menopause and UI 

are conflicting. Several studies have even reported a

higher prevalence of UI in older women taking hormone

replacement therapy. 

Obesity has been defined as an independent risk factor

for UI in women according to one study. In theory,

increased body weight increases abdominal pressure

during exertion, thus increasing the amount of pressure

on the bladder during such activities. It has been suggested that obesity is an independent risk factor for

stress and mixed incontinence but not for urge incontinence. In one study, morbidly obese women who lost

weight after barometric surgery improved their UI 

significantly. Research is needed to determine whether

simple weight reduction in moderately obese women can

achieve similar improvements in urinary incontinence.

According to some studies, family history of UI in a 

first-degree relative may increase the risk of UI three 

to six fold in women.

Risk Factors in Adult Men

Beginning in the sixth to seventh decades of life, 

the prevalence of urinary incontinence (UI) in men

approaches that of women. Physiologic changes caused

by increasing age (see Risk Factors with Advancing 

Age, below) contribute to this as does comorbid disease.

Moreover, UI is the most devastating adverse outcome

after treatment for both benign prostatic hypertrophy

and prostate cancer. Both of these conditions are 

common diseases in this age group, with UI occurring 

in 1 percent to 5 percent depending on the type of 

operation. All types of prostatectomies ablate the 

proximal sphincter mechanism, which consists of the

smooth muscle of the bladder neck and the proximal

prostatic urethra, as well as the non-muscular elements

of the walls of these structures. Although prostatectomy

ideally leaves enough of the distal sphincteric mechanism intact to allow continence in the absence of 

bladder hyperactivity and sensory urgency, radical

prostatectomy has great potential for significant distal

sphincteric mechanism destruction. Transurethral

prostatectomy is less likely to disturb this mechanism. 

Overflow incontinence represents another form of bladder-related incontinence that seems to be more common in men than in women, although it occurs in both.

Overflow incontinence results from obstruction of the

bladder outlet or from inactivity of the detrusor muscle

that is either neurologic or pharmacologic in origin.

Overflow incontinence also results from inadvertent

overdistention of the bladder. The primary pathophysiology of overflow incontinence is actually a failure of the

bladder to empty. This leads to urinary retention with

“overflow” incontinence caused by either continuous 

or episodic elevation of pressure within the bladder as

opposed to the pressure in the urethra. 

Risk Factors with Advancing Age 

For a variety of reasons, UI becomes more prevalent 

with age. Even in the absence of disease, aging affects 

the lower urinary tract. People older than age 65 will 

suffer from UI—15 percent to 30 percent while living at

home, 33 percent while living in an acute care setting,

and 50 percent while living in a nursing home. Although

providers and older people alike will dismiss UI as a

normal part of aging, it is abnormal at any age. 

Many physiologic changes occur to the bladder during

aging, but these changes predispose people to UI—they

do not cause it. These changes include a decline both in

bladder contractility and in its capacity and ability to

postpone voiding. In women, the urethral length and

maximum urethral closing pressure also decline, while

in men, the prostate enlarges causing obstruction. In

addition, elderly people excrete most of their fluid intake

at night; therefore, two trips to the bathroom at night 

are the norm. This predisposition and the increased

likelihood that an older person will develop a comorbid

disease (physiologic, pathologic, or pharmacologic)

explain why elderly people are so likely to develop UI. 

The role of impaired renal concentrating abilities, shifts

in the pattern of fluid excretion to later in the day and

night, slowed central nervous system processing and

reaction time, and decreased vision and mobility and

their interactions remain unclear. What is clear is that

the complexity of urinary incontinence in elderly people
152 OVERCOMING BLADDER DISEASE

warrants a unique approach as that which has been

described in several medical journal review articles in

recent years. 

Unfortunately, even state-of-the-art approaches leave

most older adults only partially treated. Moreover, 

criteria for the best use of diagnostic procedures in the

elderly are lacking. Comparison of outcomes for different patient groups would be helpful, but outcome measures designed for younger people do not always weigh

outcomes in a manner appropriate for elderly people.

Further complicating the situation, older adults are more

likely than younger adults to suffer adverse effects of

both the UI and its treatment, and such effects often 

differ for younger patients (e.g., falling and fractures).

All of these difficulties are magnified in the nearly two

million Americans who are institutionalized, nearly 

two-thirds of whom are incontinent. Not surprisingly,

the cost and burden of disease for elderly people living

with UI are disproportionately high.

Risk Factors for Pediatric Incontinence

Although we are all born “incontinent,” we readily learn

to control when and where urine is passed during cultural “potty training.” Some loss of urine control with urge

is seen during bladder training, but enuresis or bedwetting is the main bladder control problem in children.

Enuresis is prevalent in an estimated 15 percent to 20

percent of five-year-old children, and the spontaneous

remission rate is approximately 15 percent annually

between the ages of five and nineteen. The embarrassment and social stigma attached to enuresis is appreciable for these children.

Family history is an established risk factor. Other risk

factors include behavioral disturbances, constipation,

frequent nighttime voiding (nocturnal polyuria), depth

of sleep, urinary tract infection, and spina bifida occulta

and other neurologic conditions. The evaluation of

enuresis distinguishes monosymptomatic nocturnal

enuresis from enuresis associated with attention deficit

disorder and hyperactivity disorder. Dysfunctional voiding and neuropathic bladder and sphincter dysfunction

are the main indications for urodynamic studies. There

are urgent research priorities in the epidemiology of

enureseis (properly classified), effectiveness of treatment modalities, and the prospective implications of

childhood enuresis on adult UI.

Loss of urine in children other than enuresis should be

termed urinary incontinence. However, less is known

about the prevalence of this except in structural abnormalities such as epispadias and bladder exstrophy or

neurologic conditions (e.g., myelomeningocele) that 

are associated with an open bladder neck. Many of 

these conditions are recognized and treated surgically.

Otherwise, urge syndrome and urge incontinence in

children may be treated with bladder retraining and

biofeedback and the occasional use of medications.

Risk Factors for Neuropathic Incontinence 

Because controlled bladder storage and emptying

depend on an intact cerebospinal axis, nearly any 

neurologic injury or disease can lead to voiding 

dysfunction related to inadequate storage and uncoordinated emptying, and consequently to UI. Although 

normal bladder storage and emptying is based on 

low-pressure storage, neurologic damage may create

high-pressure bladder storage, which may lead to 

subsequent damage to the upper urinary tract. Bladder

and urethral dysfunction are commonly caused by

stroke, Parkinson’s disease, spinal cord injury, 

multiple sclerosis, diabetes, and disk disease.

* Stroke. Bladder symptoms are present during the

acute phase in approximately 70 percent of stroke

victims, and about one-third have persistent 

symptoms, usually bladder overactivity, urgency, 

and urge incontinence. 

* Parkinson’s disease. Voiding dysfunction is particularly

troublesome in people who are afflicted with

Parkinson’s disease. Symptoms generally consist of

urgency, frequency, nocturia, and urge incontinence.

The most common urodynamic correlate is instability

of the bladder muscle (detrusor hyperreflexia).

Parkinson’s disease complicates any consideration 

of treatment for prostatic enlargement, particularly
A Strategic Plan for Research 153

whether prostatectomy will be beneficial or harmful.

Men with Parkinson’s disease and other degenerative disorders such as Shy-Drager syndrome often

respond unpredictably to routine treatments. 

* Spinal cord injury. Controlled and coordinated bladder

emptying depends on an intact neural axis. Loss of

nerve input above the level of the sacrum (the level 

of the spinal cord responsible for control of the 

bladder) often results in lack of voluntary bladder

storage and coordinated urethral relaxation and

bladder emptying. This voiding dysfunction is often

managed with intermittent urethral and bladder

catheterization to empty the bladder, but loss of the

low-pressure bladder storage capability between

intermittent catheterizations often causes incontinence. Even with the best current management,

which requires high maintenance and intense 

medical follow-up, people with spinal cord injuries

are at risk for persistent incontinence and damage 

to their kidneys and bladder. 

* Multiple sclerosis. More than half of the people who

have this disease complain of voiding symptoms at

some time. In approximately 10 percent of people

with MS, bladder involvement is part of the presenting symptom complex and constitutes the sole initial

complaint, either in the form of acute urinary retention of an unknown cause or in the acute onset of

involuntary bladder contractions with urgency and

frequency. This instability of the bladder muscle that

occurs with urge incontinence is the most commonly

detected abnormality. 

* Diabetes mellitus. Peripheral and autonomic neuropathies are common in diabetes. Diabetic neuropathy has been attributed to loss of the myelin

sheath that surrounds nerve fibers (segmental

demyelinization) and impairment of nerve conduction. Middle-aged and elderly people with longstanding or poorly controlled diabetes tend to 

develop neuropathy, which affects the bladder 

as well as other parts of the body. An early manifestation of diabetic neuropathy may be instability of

the bladder muscle. The insidious onset of impaired

bladder sensation can be the first manifestation of

bladder muscle involvement. Surprisingly, few large, 

well-documented studies of voiding dysfunction 

in persons with diabetes have been published. 

The incidence of diabetic bladder involvement is

uncertain, because people who are diabetic may 

not seek care for bladder symptoms. However, if

specifically questioned by their clinicians, many

report symptoms of voiding dysfunction. 

* Disk disease. Most disk protrusions compress the

spinal roots in the disk interspaces of the lower 

lumbar and upper sacral areas of the vertebral column (i.e., L4 to L5 or L5 to S1). Voiding dysfunction

caused by a prolapsed or herniated disk correlates

with the usual clinical manifestations of low back

pain radiating in a girdle-like fashion along the

involved spinal root areas. The most consistent 

urodynamic finding is failure of the bladder muscle

to have a reflex reaction even when full (detrusor

areflexia) and retention. However, a herniated 

disk may initially irritate nerve roots and causes

exaggerated reflexes (detrusor hyperreflexia) and

urge incontinence. Surgical correction may not

improve bladder function, and it may be difficult 

to separate changes in bladder function that are 

the result of the disk sequelae from changes that 

are secondary to the surgery. A prospective study

assessing the bladder function of 20 elderly people

after lumbar decompressive laminectomy for disk or

spinal stenosis reported improved bladder function

in 60 percent by one year. 

Current Research

Research in UI is impeded by the lack of knowledge

about the basic mechanisms of continence. Urinary

incontinence is the least studied of all bladder conditions, and significant areas of study are absent or minimal in the current research portfolio at the. A review of

the National Institutes of Health (NIH) portfolio found 
154 OVERCOMING BLADDER DISEASE

• Little research on the urethra, even though experts

have recommended that both the bladder and the

urethra, which together form the lower urinary tract,

be studied as a functional and anatomical unit

• Lack of age-, race-, and gender-specific urinary

incontinence research. Anatomic, physiologic, and

etiologic considerations clearly differ by age and sex 

• UI research funding, moreover, fails to reflect the

disproportionate majority of incontinence problems

found in women and the need for preventing and

managing these problems 

Current epidemiologic research has focused on several

life-events in women that appear to increase the risk for

developing urinary incontinence. These unique life

events include childbearing (especially vaginal delivery),

hysterectomy, and menopause. New mothers who

become incontinent are affected with urinary incontinence earlier in life and suffer longer. New mothers 

who have a single vaginal delivery have been estimated 

to have a two- to eleven-fold increase in the risk of 

urinary incontinence.

The NIH recently embarked on a major study that will

investigate the nature of the disease mechanisms of UI.

The Urinary Incontinence Treatment Network (UITN)

comprises three clinical centers that will address a number of issues in the area of urinary incontinence, beginning with the effectiveness of current surgical therapies. 

Research Opportunities

Scientific knowledge of the physiology of urinary incontinence (UI) lags far behind that of other conditions.

Current understanding of UI may be compared to the

state of knowledge about atherosclerotic heart disease 

in the 1950s. For progress to occur, future research must

do the following:

• Clarify the mechanisms of incontinence so that 

better diagnostic tools can be made 

• Identify risk factors that contribute to incontinence

so that preventive measures and disease-specific

treatments can be developed

• Define treatment outcomes 

• Improve treatment

Basic Mechanisms of Incontinence 

Research in UI has multiple potential pitfalls. Similar to

cardiovascular health, a study of the system in its entirety

(the lower urinary tract and its adjacent genital and

intestinal systems) is essential for a sound scientific

understanding of the development and decline in continence. The latter is currently dichotomized into bladder

or urethral dysfunction, whereas most experts suspect

that another mechanism might include neuromuscular

dysfunction, anatomic displacement, or other defects. 

Because our basic understanding of UI is inadequate, 

no good clinical tests exist to stratify and distinguish

between types of UI. For example, one woman has urge

incontinence because of a weak sphincter, another

because of operant conditioning, another because 

of neurological damage, and yet another because of

abnormal reflex activity or abnormal muscle reactivity.

At this time, there are only a limited number of tests 

to distinguish between these types of UI.

Consequently, effective preventive strategies await a

more adequate understanding of the causal factors. For

example, the role of the maldevelopment of the urethra

and pelvic floor, damage to the urethra and its nerve

supply during vaginal delivery, and deterioration with

age have not been studied. Studying the urethral sphincter, for example, in a woman who has stress incontinence because of the loss of urethral support reveals

normal findings, while evaluating the urethral sphincter

of a woman with normal support reveals important

insights into the cause of the problem. Once this level of

knowledge is reached, then studying the cellular mechanisms involved in sphincter dysfunction can proceed.
A Strategic Plan for Research 155

Risk Factors for Incontinence 

We do not need additional prevalence studies. Current

epidemiologic research has directed focus to several 

life events that appear to increase risk for development

of UI. These unique life events are especially apparent 

in women. They include vaginal delivery, hysterectomy,

and menopause. New mothers who become incontinent

are affected with UI earlier in life and suffer for more

years. Study of these vulnerable periods of life may

improve understanding of these risk factors and 

potential interventions.

Prevention of UI and improved disease-specific 

treatment will depend on research that examines

• Development and maturation of bladder control 

in children and factors that alter this development

• Effect and impact of aging on the physiology 

of urinary continence and the interaction of 

age-related diseases, drug therapy, and lifestyle 

patterns such as habits 

• Effect of risk factors such as vaginal delivery, 

occupational hazards (e.g., heavy lifting and 

restricted access to bathrooms), hysterectomy,

menopause, obesity, race, prostatectomy, and 

benign prostatic hyperplasia

Clinical Assessment and Treatment

To improve clinical assessment and treatment of UI,

research needs to 

• Develop methodology to screen for UI in the primary

care setting and quantify the severity of the problem

• Examine pelvic floor anatomy and physiology through

advanced imaging techniques that will improve

understanding and diagnosis of incontinence 

• Devise testing that will differentiate between 

the different types of UI and improve or validate 

urodynamic testing

• Develop outcomes analysis to measure treatment

efficacy related to continence, patient satisfaction,

complications, and cost

• Develop and evaluate new surgical and pharmacologic

treatments using these outcomes analyses

Research Requirements and Impediments

Requirements

The Bladder Research Progress Review Group has

defined needs in several areas that will be critical to 

urinary incontinence research initiatives. Workforce

needs, infrastructure requirements, implementation

issues, and the need for other resources such as data

analysis, tissue and specimen banks, and a system 

for reporting data must be addressed if this effort is 

to succeed.

* Workforce. The lack of clinical and basic science

research in UI is a major concern. The state of

knowledge for UI seriously lags behind the state 

of knowledge of other conditions. Yet such research

has the potential to yield significant results, because

so little is currently known. Poor funding, lack of 

scientific investigation, and stigma may have hindered the entry of researchers into this area in the

past. Scientists with expertise in muscle physiology,

smooth muscle pharmacology, anatomy, cell signaling, and neurophysiology are urgently needed to 

help elucidate the causes of UI. Attracting such 

scientists may require special funding initiatives 

in the basic science of this condition and education

of investigators about the importance and prevalence

of UI problems. 

Workforce needs also exist in the clinical evaluation

and treatment of UI. Primary care providers are the

initial step in the evaluation and management of 

urinary incontinence in the community. Yet, many 

of these providers have had little or no training in UI,

a barrier to effective treatment. Given the magnitude

of the problem, emphasis should be placed on
156 OVERCOMING BLADDER DISEASE

increasing UI education for medical students and

primary care residents. Urologists and gynecologists

are the clinicians principally involved in the specialized evaluation and management of UI, although

some nurses, rehabilitation specialists, neurologists,

geriatricians, family practitioners, and internists

have a special emphasis and clinical interest in

incontinence. A three-year joint fellowship in

FlexiPlus Pelvic Muscle Rehabilitation System

(FPMRS) is available to urologists and gynecologists

through the joint efforts of the American Board 

of Obstetrics and Gynecology and the American

Board of Urology. 

* Infrastructure. UI research may be especially appropriate for programs in multi-center networks and

program research centers to conduct because UI is

included in general pelvic floor disorders such as

pelvic organ prolapse, fecal incontinence, and pelvic

pain. The bladder cannot be considered an isolated

organ in this system, and a multidisciplinary

approach using urologists, gynecologists, coloproctologists, physical therapists, and pain specialists 

will best address these complex conditions. Program

centers would be tremendously helpful in fostering

such multidisciplinary interactions, especially centers with fellowship training. Multi-center approaches to research into the treatment of incontinence 

may solve some of the problems of research in this

area. Multi-center networks in both non-surgical

and surgical areas may overcome the problem of

patient enrollment. 

During the past few years, pharmaceutical and 

medical device companies have sponsored research

in urinary incontinence because of the large 

populations affected by UI and the dirth of current

treatment options. However, because outcomes

analyses of UI are poorly developed, the measures 

of treatment efficacy related to continence, patient

satisfaction, complications, and cost have often 

been incomplete. Through the development of better

outcomes analyses and collaborative efforts, research

of UI may be furthered more rapidly.

* Implementation. The NIH should provide strategically

targeted requests for applications (RFAs) to initiate

much-needed UI research that is consistent with 

the recommendations of the Bladder Research

Progress Review Group. In addition, the NIH should

investigate and facilitate study section infrastructure

to facilitate proper grant review. Within the NIH,

regular inter-institutional interaction and 

collaboration on UI research is also in order. 

Furthermore, a program should be launched to 

educate legislators about the need for increased

funding of UI research, which has been seriously

under funded in the past. This discrepancy 

discriminates against new mothers, children

(Chapter 5), and elderly citizens (Chapter 6) who 

disproportionately bear the burden of this condition. 

The enduring problem of incontinence. A 17th century drawing of a

man with urinary incontinence. Around his waist is a belt with a bottle

attached. In: Fabricius Hildamus G, Opera. Frankfurt: Dufour. 1682
A Strategic Plan for Research 157

* Other resource needs. Improving and expanding 

UI research will require the NIH to take the 

following measures:

• Adopt the Consolidated Standards for

Supporting Trials (CONSORT) system for 

comparing clinical trials—The CONSORT 

system (http://www.consort-statement.org/ ) 

has facilitated the comparison between clinical

trials in many areas and should be required in 

all NIH-sponsored clinical trials. 

• Establish tissue and specimen banks—As in

many areas of bladder research, there is a critical

need for basic scientists to have adequate access 

to tissues and specimens for research. Genetic

research can be advanced through the banking 

of blood specimens from well-characterized 

individuals in clinical trials. Once genetic determinants of UI are identified, these specimens 

can be used to amplify the knowledge obtained 

in small genetic studies. 

• Analyze cost, outcomes, and preference data—

Cost-effectiveness analyses incorporate data 

on both health care outcomes and costs. These

analyses comprehensively describe the relative

value of alternative interventions for a specific

medical condition. For UI, cost-effectiveness

analyses have focused on strategies for nursing

home management and on comparison of surgical

techniques for stress incontinence. Few data are

available on the costs or cost-effectiveness of

behavioral or surgical treatments. No data are

available on patient preference (utility) for

treatment and health outcomes in UI. 

Impediments

Several impediments to research exist as well, which

must be corrected if research outcomes are to be favorable. Those impediments include limited UI experience

in review groups, the presence of concomitant but unrelated disease processes (comorbidities), and a social

stigma that precludes the formation of an effective 

lobbying group for people who suffer from UI.

* Limited UI expertise in grant review groups. As the NIH 

is currently structured, multiple study sections

review requests for funding of UI research; expertise

in UI is not required for membership in these study

sections. There is a need for inter-institution NIH

synergies and for RFAs in UI to be reviewed by ad hoc

study sections with experts in urinary incontinence. 

* Comorbidities. Concomitant but unrelated pathologic

or disease processes (comorbidities) complicate 

UI research. Comorbidities in the pelvis that need 

to be considered include disease of the prostate, 

aging, pelvic organ prolapse, pelvic pain, fecal 

incontinence, and rectal prolapse. Comorbidities

outside the urinary tract must be considered as 

well; they include systemic disease, diabetes, and

neurologic disorders. 

* Social stigma and lack of an active lobbying group.

Another important impediment to UI research is 

the stigma attached to the condition. Although 

millions of Americans suffer from UI, they are too

embarrassed to come forward to publicly discuss

their problem. This stigma has been a significant

barrier to research funding and participation in 

clinical trials because people with UI have not 

formed active lobbying or advocacy groups. As a

result, even experienced legislators are not aware 

of the scope of UI and the suffering it causes.

Research funding is also often enhanced when a 

public figure discusses the personal effects of a 

condition. To date, no public figure has been willing

to discuss his or her personal struggles with UI.
158 OVERCOMING BLADDER DISEASE

PATIENT PROFILE

Melissa Lavender got out of bed the morning after her first

child was born and realized that she had “no bladder control 

at all.” Until then, she had led an active life with no medical

problems to speak of. She watched her diet. She jogged 12

miles a week. She exercised to keep her muscles toned. 

Lavender who was 40 when her son was born had had the

choice during labor of having a Cesarean section or a vaginal

delivery with the assistance of forceps. She chose the latter,

but now believes that her bladder problems were the result 

of that choice. In fact, childbirth in any form is a known risk

factor, and, according to most studies, the first birth appears 

to be associated with the greatest increase in risk. Trauma 

to the muscles and nerves of the pelvic floor during childbirth—such as that which can occur during prolonged 

pushing—can result in incontinence during the postpartum

period, and it places a woman at a greater risk for 

incontinence later in life.

During the weeks that followed childbirth, Lavender struggled

to balance her new role as a mother with the challenges 

presented by her physical condition. She felt that in time, 

the incontinence would improve, but it continued to be severe.

At her six-week exam, Lavender sought the advice of her 

obstetrician/gynecologist, who told her to wait six months

because research studies indicate that if the problem is 

minor, it goes away in that time. The physician also 

prescribed Kegel exercises to strengthen the pelvic floor 

muscles. Lavender performed them regularly, but at the 

end of three months, her condition had not improved. 

Lavender then decided to consult a physician who specializes 

in the urologic as well as the gynecologic problems of women.

“She was very empathic,” Lavender says. “She told me that 

my pelvic floor muscles were, in effect, in shock and not 

functioning properly due to the traumatic procedure.” 

The physician gave her a pessary, an appliance that supports

the uterus and corrects displacement, and an electronic device

that stimulates muscles to improve tone. Lavender used both,

and the stimulator did improve muscle tone in the pelvic 

floor, but the improvement lasted only as long as she used 

the device. Lavender longed to return to her normal life. She

wanted to run again, she wanted to return to the satisfying 

sexual relationship she had had with her husband, and she

wanted another child.

Melissa Lavender

Pelvic Floor Trauma, Incontinence
A Strategic Plan for Research 159

“Incontinence wreaks havoc on your life,” she says. “I felt 

unattractive and unappealing. It stressed my sexual relationship

with my husband even though he reassured me that everything

was fine. I was depressed and always felt that I could smell

urine. I wore pads all the time, and they got thicker. Any bearing

down motion like bending over to pick something up from the

floor caused leakage. Eventually, I got good enough so I could

manage a run, but I had to plan it so that there was a bathroom

midway. Women who suffer incontinence are always aware 

of where the bathroom is.”

Lavender decided to consult a physical therapist specializing 

in pelvic floor dysfunction. She learned to plan her trips to the

bathroom rather than urinating on demand; she learned the

proper way to perform Kegel exercises and was given an exercise

program. “Proper pelvic floor exercises and bladder training 

are very hard to do,” Lavender says. “But I got to the point 

of dealing with the incontinence as many people do.” 

The incontinence eventually improved, but when Lavender

became pregnant again, her bladder problems returned, and 

they were worse. In April 2001, she gave birth to her second

child, a daughter, and the delivery went well, but she 

continued to be incontinent. She used more absorbent pads 

and did bladder training again, but did not sufficiently improve.

Eight months later, Lavender had a hysterectomy, surgical 

reconstruction of the vagina, and a procedure to “tack up” 

the urethra and bladder. After surgery, she followed a 12-week

protocol—no lifting (not even the baby)—which necessitated

household help 24 hours a day, seven days a week—and no 

sexual relations. Nine weeks later, she says she was 75 

percent better. 

“I’ve come to realize that there is no happy pill. If this is as 

good as it gets, at least I’m better,” Lavender says. “I’m trying 

to go to the bathroom every one and a half hours. It’s still 

challenging to make it to the toilet when I have to go. I’m 

also doing a structured set of Kegel exercises, and probably

eventually will use a muscle stimulator again. I watch my 

diet, and constipation is forbidden.... I’m aware of my 

condition all the time.”

Lavender has become an advocate for women’s health, 

particularly for women who suffer from urinary incontinence. 

She is especially concerned about the stigma attached to 

incontinence. “Thirteen to twenty million women are incontinent,

but no one talks about it,” she says. “People talk about sex all

the time on television, but incontinence—no one goes there. 

No one wants to wear a little yellow ribbon. This isn’t something

we should carry about in our own little world.”

For the time being, she has confined her initiatives to the

Chicago area. She is starting support groups for women with

incontinence who are postpartum, menopausal, and elderly 

and is working on monthly education forums at local hospitals.

She has also launched a publicity campaign to encourage 

people who have incontinence to talk about how it has affected

the quality of their lives. 

“It’s tragic that we don’t even know how many people have 

this problem because people aren’t talking about it,” she says. 

“If we don’t talk about it, nothing will be done.”
CHAPTER 12
A Strategic Plan for Research 161

Common Clinical Conditions

URETHELIAL CANCER (BLADDER CANCER)

DID YOU KNOW?

. Bladder cancer is the fifth most

commonly diagnosed, non-skin

malignancy in Americans.

. Bladder cancer is closely 

associated with environmental toxins.

. Approximately 400,000 people 

had bladder cancer in 1999.

. Men have four times the rate 

of bladder cancer of women.

. Women and African Americans 

of both genders have a 35 

percent to 100 percent greater

likelihood of dying from bladder

cancer if they develop it than

Caucasian men do.

Summary and Recommendations

As people age, incidence and mortality from bladder cancer increase. Both

incidence and disease-specific mortality are roughly twice as great for men

and women after age 80 than they are for men and women ages 65 to 69.

People with bladder cancer require numerous treatments that are highly

morbid, expensive, and time-intensive (even for monitoring indolent disease), and family members or society must often assume these expenses,

particularly for home care and transportation. 

The impact of bladder cancer is greatest in middle-aged and elderly

Caucasian men. It is the seventh leading cause of cancer death in men and

the fifth most commonly diagnosed, non-cutaneous malignancy in the

United States. Approximately 12,000 Americans die each year from bladder

cancer according to the National Cancer Institute. Based strictly on these

factors alone, both the financial and societal costs of bladder cancer are

considerable. 

The Bladder Research Progress Review Group divided research priorities for

urothelial cancer into two levels. 

Level I Priorities

* Develop early detection, prevention, and chemoprevention techniques

* Develop models (including animal models) of prevention, abnormal growth 

regulation, differentiation, and control to assess field effect versus clonality 

and to define urothelial alterations that are associated with age and gender

* Investigate the basic biology of urothelial cancer, including growth factors, 

cell signaling, development of new blood vessels (angiogenesis), wound healing,

programmed cell death (apoptosis), and cell-cell interactions

* Study and implement strategies to reverse the dramatic gender, race, and age

disparities that currently exist
162 OVERCOMING BLADDER DISEASE

* Create a research infrastructure by establishing 

• Tissue banks 

• Specimen arrays

• cDNA microarrays

• Proteomics with demographic, clinical, and 

outcome correlation

• Matched and unmatched normal specimens

• Informatics and mathematical systems to analyze

data, model applications, and future studies

* Create a research infrastructure by instituting 

multidisciplinary collaborative grants and training 

opportunities to enhance team building and attract 

new investigators to the field

Level II Priorities

* Improve and develop imaging techniques such as 

• Virtual endoscopy

• Contact microscopy

• Fluorescent cystoscopy

• Novel ultrasound examinations

• Magnetic resonance imaging (MRI)

• Positron emissions tomography (PET)

* Develop and improve gene delivery to the urothelium 

Background

About 400,000 Americans have been estimated to 

have epithelial cancer of the bladder (urothelial cancer).

Because urothelial cancer is almost never found incidentally at autopsy, and because the means of diagnosis—

endoscopic inspection and biopsy—have not changed 

for many decades, this increased incidence cannot be

attributed to improvements in diagnostic methods 

such as technological innovations or changes in health

practice (e.g., organized or ad lib screening).

Epidemiology

Several characteristics of urothelial cancer make it 

particularly suitable for epidemiological investigations.

Of all the urologic malignancies, urothelial cancer is

most closely associated with environmental carcinogens.

Several putative carcinogenic exposures have been 

identified in humans, including 

• Cigarette smoke 

• A variety of industrial and workplace exposures

• Arsenic and other chemicals in artesian well water 

in endemic regions of blackfoot disease in Taiwan,

Chile, and Argentina

• Chinese weight reduction herbs contaminated 

by A. franghi 

• Acetaminophen and other analgesics

• Chronic, continual urinary tract infections—

particularly infections of S. hematobium or 

infections occurring in patients with bladders that

have been damaged because of events originating 

in the nervous system (neurogenic bladders) and

indwelling catheters 

The demographic profile of urothelial cancer is well

characterized, being most common in middle-aged and

elderly Caucasian men in the United States. Men have

four times the rate of women. Women and African

Americans of both genders have roughly one-third to
A Strategic Plan for Research 163

one-half the incidence of this cancer than Caucasian

men, but these two groups have a 35 percent to 100 

percent greater likelihood of dying from bladder cancer

than white men do if they develop it. Understanding

these differences quite likely will at least “level the 

playing field” by normalizing mortality rates to those 

of middle-aged Caucasian men.

As people age, incidence of and mortality from bladder

cancer increase. Incidence for both men and women

roughly doubles between ages 65 and 69 and after age

80. Moreover, if bladder cancer develops after age 

80, the chance of dying from it also doubles. These 

differences are unquestionably caused by many 

factors, which include 

• Specific characteristics of tumor biology and 

host defenses 

• Personal, societal, and group values that influence

habits, lifestyles, and patterns of behavior

• Availability of health care

• Concomitant but unrelated disease processes

(comorbidities) that influence diagnostic evaluations, management recommendations, and 

treatments selected, as well as other factors

A comprehensive investigation of these issues has 

not been carried out. 

According to biological and clinical trial evidence, 

early detection may be beneficial in reducing mortality

and morbidity from this disease, although a prospective

randomized screening study with unscreened controls

has never been carried out. Of great relevance to the

screening issue is that urothelial cancer is almost never

found incidentally at autopsy, implying that early detection in asymptomatic people is not likely to be harmful.

Additionally, this means that the repetitions of testing

must be relatively frequent because the pre-clinical

prevalence of bladder cancer is quite brief.

Finally, although the methods of genetic fingerprinting

are improving and more information is being obtained

about genetic influences that control inactivation and

activation of several putative carcinogenic agents in 

the environment, compelling data to demonstrate the 

existence of a major inherited susceptibility for this 

disease are lacking. Indeed, the little data that do exist

indicate that, except for extremely rare cases associated

with an obvious familial predisposition, strong inherited

tendencies are not seen. These data highlight the need

for further understanding of the multitudinous events

taking part in the development of bladder cancer.

Cost of Bladder Cancer

The therapies used to treat aggressive, localized, and

metastatic disease include surgical removal of the 

bladder and urinary diversion, high-dose pelvic 

radiotherapy, and multi-drug chemotherapy. These

therapies are highly morbid and expensive. Urothelial

cancer is the second most prevalent malignancy in 

middle-aged and elderly men, who must undergo 

continued surveillance examinations that are costly 

and somewhat morbid. Precise economic assessments 

of these exams are needed.

Based on at least preliminary analyses, screening for

bladder cancer would be cost-effective when compared

with other diseases where early detection has been 

recognized as beneficial (e.g., mammography for breast

cancer and blood pressure checks for hypertension).

Because our understanding of bladder cancer biology 

is limited and the treatments for aggressive local,

regional, and metastatic disease are still not very 

effective and are associated with significant morbidities,

the potentially positive impact of early intervention on

reducing mortality at a seemingly acceptable economic

cost would be important to investigate.

Because bladder cancer is primarily a disease of the 

elderly, with the median age at diagnosis for both men

and women being well beyond the usual age of retirement, cancer of the bladder and its treatment may at 

first seem to have relatively little impact on economic

productivity. However, people with this disease require

numerous treatments that are time-intensive (even for

monitoring indolent disease), and family members or
164 OVERCOMING BLADDER DISEASE

society must often assume these expenses, particularly

for home care and transportation. Thus, sophisticated

economic analyses are needed to remotely understand

not only the direct health care costs of this disease, but

also the societal costs.

Impact of Bladder Cancer

When urothelial cancer invades bladder muscle, the

standard treatment for locally invasive cancer remains

surgical removal of the bladder (cystectomy) and some

form of urinary diversion. Although in healthy people, 

a high proportion of men and a significant proportion 

of women can undergo orthotopic bladder substitution

(substitution in the normal position of the bladder), 

this situation is not the same as having one’s own 

bladder. Under the best of circumstances, urinations 

are not normal; roughly 80 percent of those who have

had substitution wake up at night to urinate (nocturia) 

or experience nocturnal incontinence, 5 percent or 

more experience daytime stress incontinence, and 20

percent to 30 percent of women have urinary retention

that requires intermittent self-catheterization. 

Additionally, the instances of urinary tract infections

and upper urinary tract compromise are certainly greater

than when a normal bladder is in place. Depending on

the patient’s desires, the comorbidities involved, the

extent of the tumor, and the technical considerations,

approximately 25 percent to 50 percent of men and 50

percent to 75 percent of women who undergo cystectomy

cannot undergo bladder substitution. Although both

continent, catheterizable reservoirs and conduit systems

to handle diverted urine are technically quite successful,

their psychological and physical impact may be negative

because a small abdominal opening called a stoma is

necessary. Abdominal stomas are also associated with 

a high incidence of urinary tract infections and upper

urinary tract deterioration. 

Short-term voiding function complications caused by

pelvic radiotherapy tend to be less than those caused by 

a cystectomy. However, at least 5 percent to 10 percent 

of patients experience significant long-term bladder or

rectal toxicities, which can range from being manageable 

annoyances to lifethreatening matters.

Surgical treatments 

for the latter often 

have extremely serious

consequences. Thus, 

a comprehensive

assessment is needed of

the consequences of

urothelial cancer treatment, particularly its

effects on the bladder’s

function(s) over time. 

Significant sexual

problems also result from bladder cancer therapies. 

The vagina of women treated by either cystectomy or

radiation therapy often becomes nearly functionless

because its size is compromised, lubrication is inadequate, and the formation of fibrous tissue (fibrosis) 

has occurred (particularly after radiation), making it

inelastic. In certain women, this is a major issue. 

Men, despite the employment of nerve-sparing 

surgical techniques, experience at least a 30 percent 

to 40 percent chance of serious erectile dysfunction,

depending on their age, comorbidities, and smoking

exposure. If anything but a thorough attempt is made 

to spare nerves controlling erections or if a total removal

of the urethra (urethrectomy) is needed, the likelihood

of developing this complication is even greater. These

are significant problems, and at times, they force 

people to choose therapies that may be less than 

optimal (e.g., partial, rather than total, cystectomy) 

for their disease management.

The above problems are amplified in the rare, but 

tragic, instances of bladder malignancies occurring in

children. Tumors are primarily sarcomas and are usually

treated with multi-modality therapies—often with organ

preservation in mind. Again, information about the 

outcomes of such treatments is poorly documented, 

particularly in relation to continued growth, body 

image, sexual functioning, reproductive capacities, 

and development of subsequent malignancies. Because

of the relative rarity of these tumors, access to a national

database is necessary.

Orthotopic

Bladder Substitution: 

Complications

• Bedwetting

• Night-time voiding

• Stress incontinence

• Urinary retention

• Urinary tract infection
A Strategic Plan for Research 165

Special At-Risk Groups

Research is needed to explain (1) the lower incidence,

yet higher mortality, of bladder cancer in women and 

in African Americans than in white men and (2) the

increasing incidence and mortality of bladder cancer

with advancing age in both sexes and in all races. With

regard to race and ethnicity, Hispanic Americans, who

have an incidence of bladder cancer closer to African

Americans (i.e., roughly half that of Caucasians), have 

a mortality rate even lower than that of Caucasians 

(i.e., roughly half that of African Americans of each sex).

The reasons for this are not well understood, but it raises

a serious question about whether economics, access 

to care, and other social factors alone can explain the 

higher mortalities seen in women, elderly people, and

African Americans. Information about other ethnic

groups (e.g., Asian Americans and American Indians) 

is not readily available and is also needed.

Three other groups worth considering for research

include 

• People with spinal cord injuries, particularly those

with long-term indwelling catheters, which place

them at higher risk for developing both squamous

and transitional cell cancers of the bladder 

• Former smokers, who after smoking cessation have 

a far more rapid decline in their risk for developing

lung or esophageal cancer than they do in their risk

for developing bladder cancer 

• People exposed to industrial and other purported

environmental carcinogens

The term urothelial bladder cancer represents a 

continuum from indolent to aggressive disease. It is 

of interest to note that although suspected carcinogens

predispose for a greater incidence of bladder cancer

(except in the young), they do not predispose preferentially for indolent or aggressive cancers—indicating 

that there is probably a common molecular pathway(s) 

in the process of urothelial carcinogenesis 

(cancer development).

Current Research 

The Bladder Research Progress Review Group reviewed

the bladder research portfolio of the National Institutes

of Health (NIH) for February 2001. The review identified

a total of 42 individual grants investigating bladder cancer, many of which were components of larger projects.

Significantly, only three applications investigate the

basic biology of bladder cancer, including such broad

areas as tumor invasion, metastases, cell signaling,

growth factors and cytokines (hormone-like proteins

that regulate the intensity and duration of the immune

response), immune system surveillance and detection,

angiogenesis, and interactions between the stroma and

the urothelium. 

Even more important is that none of the grants directly

investigate the two most fundamental questions “unique”

to bladder cancer: (1) the clonal effect versus the field

effect explanation for urothelial cancer’s multichronotropic behavior (behavior that affects the rate 

of rhythmic movements in the body) and (2) the degree

to which low-grade and high-grade urothelial cancers

share common molecular origins and are molecularly

separate diseases. Similarly, only two applications 

investigate one of the most promising and important

aspects of bladder cancer research—prevention. None

investigated standard or novel epidemiological issues

(except as were associated with mechanisms of chemical

carcinogenesis), and none could be classified as health

services or outcomes research despite overwhelming

data indicating the urgent need for these approaches. 

Therapeutics is seriously underrepresented also, with

only four grants dealing with new approaches, although

admittedly the research portfolio provided may have

omitted some translational treatment grants. 
166 OVERCOMING BLADDER DISEASE

Research Opportunities

Clearly, research efforts must be refocused in urothelial

cancer of the bladder. Most NIH-sponsored research is

investigating chemical carcinogenesis, genetics/molecular genetics, and molecular diagnosis. There is a dearth

of research on cell signaling, cell regulation, and tumor

biology; a great paucity of research on health services;

virtually no research on outcomes or on the problems 

of special groups; virtually no research on behavior and

quality-of-life, which is clearly needed; very limited

effort on prevention of disease or improving treatment

for invasive and metastatic disease; and very little 

work on developing new ways to image (e.g., virtual

endoscopy), diagnose (e.g., contact microscopy), and

treat (e.g., genetic therapies) urothelial cancer with

methods that may or may not be directly adaptable 

to other solid tumor sites.

Investigations into the use of technology have only

recently begun, and this area is promising because 

based on the large quantities of tissues and body fluids

available and on the predictable nature of this malignancy’s behavior, urothelial bladder cancer is a particularly

suitable cancer for certain technological approaches such

as genomics and proteomics. Much of these research

efforts, including participation in clinical trials, would

be greatly advanced by developing a suitable infrastructure consisting of multiple centers that would carry out

clinical trials and facilitate the obtaining and storing 

of tissue and fluid samples, along with relevant clinical

information and long follow up.

New Technologies 

New technologies for facilitating research on urothelial

cancer of the bladder include gene therapy, proteomics

tools such as immunowalking, and better animal models,

including hemizygous, transgenic, and knockout mice. 

Gene therapy. Gene 

therapy is a new and

somewhat experimental

technology that

replaces an absent 

or faulty gene with a

normal, working gene

so that the body can

manufacture the correct protein or enzyme

necessary for cell

metabolism and function. Vectors such as

viruses are used to

carry the normal gene

to body cells. The

unique accessibility 

of urothelial tumors,

the confined space in

which they grow, and, to a large degree, the impermeability of the bladder provide significant opportunities 

in the area of gene therapy and other targeted therapies. 

The ability to deliver vectors locally to the bladder 

coupled with the ability to repeatedly biopsy the 

epithelium over time provide a unique platform for

assessing these limitations. In addition, the intravesical

administration of vectors directly into the bladder where

they have direct exposure to target cells, should minimize the vector’s exposure to immune system clearance,

which is a problem with systemic delivery. 

In summary, if these delivery methods are ineffective 

in the bladder, it is difficult to imagine how they will 

be successful on the relatively inaccessible sites in 

which the four more common malignancies (cancer of

the prostate, breast, lung, and colon) arise. Similarly, 

the availability of tissues and fluids, and the current

knowledge about bladder cancer’s epidemiology, 

indicate that genomic and proteomic approaches offer

great opportunities to define genetic and epigenetic 

(gene activity rather than in gene structure) alterations 

in urothelial cells associated with age, gender, race, 

Gene Therapy

Current Limiting Factors

• Inability to deliver 

constructs to target 

cells and organs

• Inability to assess 

both targeting and

therapeutic gene

expression over time

• Limitations imposed 

on the above by 

development of

immune responses 

to vectors (carriers)
A Strategic Plan for Research 167

carcinogen exposure, and exposure avoidance (e.g.,

smoking and smoking cessation). These studies are 

likely to provide critical insights into the puzzling 

epidemiologic and demographic observations discussed previously. This information will ultimately 

result in improved disease detection, prevention, 

and possibly treatment. 

Immunowalking and proteomics. Immunowalking is a 

variant of proteomics, the study of protein expression 

by the genes. Immunowalking has enormous potential

for facilitating research on the processes of malignant

urothelial transformation and progression. The approach

makes use of proteomic technologies to reveal and 

identify proteins that are differentially expressed in

fresh tumors and normal epithelium. Thereafter, 

specific antibodies against the differentially expressed

proteins are used (immunowalking) to stain serial 

cryostat sections of specimens obtained from tumorbearing patients who have undergone removal of 

malignant bladder tissue. The urothelium of these

patients is expected to exhibit a spectrum of abnormalities, ranging from early stages of transformation 

to invasive disease. 

Better animal models. Classical animal models for bladder

cancer studies include carcinogen-induced models in

rats, dogs, and mice. Cancer is induced in these animals

after intravesical or oral administration of carcinogens.

A limitation of these models is that the types of cancers

that develop frequently include significant amounts of

squamous cell carcinoma rather than transitional cell

carcinoma, which is the far more common bladder 

cancer histology in humans. 

Furthermore, these classical animal models do not 

typically result in metastatic disease because the animals’ lives are limited by obstruction of the ureters and

kidney failure. Although this may be the normal course

of untreated human bladder cancer, the models do 

not address the major cause of bladder cancer death 

in humans today—uncontrollable metastatic disease.

Even with the above-mentioned drawbacks, these 

classical models have contributed significantly to our

understanding of bladder carcinogenesis and the 

development of immunotherapy involving the intravesical administration of bacillus Calmette-Guerin

(BCG), a bacterium used as what is thought to be a nonspecific immune system stimulant. BCG is dissolved in

normal saline solution and administered into the bladder, where it binds to the bladder tissue and stimulates

an immune response that interferes with the growth 

of local tumors. Classical animal models have also contributed to the development of new chemoprevention

agents, currently under phase III testing. 

A more recent study of p53 hemizygous mice that had a

normal lifespan and had not developed cancer may be

very useful for chemoprevention studies. P53, a protein

that normally suppresses tumors, actually causes them

when it is mutated. In the hemizygous mouse, only one

normal p53 allele is inherited from parents, the other

allele is missing. By feeding a mutagenic substance

excreted in urine, urothelial cells are exposed to this

chemical, and mutation of the remaining p53 allele

results in a defective gene product. Thus, it is not surprising that bladder cancers can be induced in the mice

by feeding them with p-cresidine, an azo dye analogue

that is carcinogenic. The p53 hemizygous mice developed

cancers within four to six months with this regimen,

while wild-type littermates required nine to twelve

months to develop cancer (because the mutagen had 

to mutate both copies of p53 in the same target cell).

Xenograft mouse models of bladder cancer have also

been useful in research. A xenograft is a graft transferred

from an animal of one species to an animal of another

species. These mice receive human bladder tumor cells

that are injected either intravenously or intraperitoneally into organs other than the bladder. Tumors often

“take” because the host mouse is immunodeficient, 

so it does not reject the cells from a foreign species as 

an immunologically intact animal would. Importantly, 

as one study showed, the organ environment provides

important and specific signals in tumor development. 

In another study, a xenograft model with bladder cancer 
168 OVERCOMING BLADDER DISEASE

was developed to study metastasis and therapies. More

recently, tumor cells were generated that express green

fluorescent proteins that emit light when stimulated.

Tumors developing from such cells in the bladder can be

monitored for metastasis and measured non-invasively

using a specific light source. 

Transgenics is a relatively new technique that uses

genetically modified mice to drive bladder cancer 

development. The uroplakin-II gene’s promoter, which

is only expressed in urothelium, has been used to drive

the expression of a viral protein, “large T antigen,” that

results in both superficial and invasive bladder cancers.

More recently, the uroplakin promoter has been used to

drive urothelial over-expression of the RAS oncogene,

resulting in mice with only superficial papillary cancers.

Another study found that the FABP gene’s promoter can

also drive tissue-specific gene expression in epithelium.

In addition, these promoters potentially could be used 

to develop other transgenic bladder cancer models.

Because genetically modified animals are a powerful

resource in studying the role of putative oncogenes

(genes that may foster malignancies if mutated or 

activated) and suppressor genes in the carcinogenic

process, additional transgenic and knockout animals

should be derived. Transgenic animals have had new

DNA introduced into their germ cells through injection

into an ovum. Knockout animals are genetically engineered animals whose genome has been altered by

recombination so that a gene is deleted. These animals

would also be important for studies of growth factors,

cellular interactions, and, possibly, immunity in both

normal and pathologic processes.

Several promoters, such as those of various keratins, 

frequently have been used to drive gene expression in

urothelial tissues such as the skin. The urothelium

expresses these keratins as well, although at lower levels.

Thus, such transgenics may also have bladder abnormalities. This phenomenon is not well appreciated, and the

bladder is often not even examined for phenotypic

changes when keratin-specific transgenic and knockout

mice are studied. Other transgenic animals may also

show unexpected bladder phenotypes that are not identified or explored because the bladder is frequently not

included in the tissues evaluated. 

Finally, because some genes are essential for development, some knockout mice do not reach adulthood.

Similarly, because bladder cancer is associated with

aging, altered gene expression may not be a lifelong phenomenon. Therefore, it has been recommended that

inducible systems should have a number of applications

for examining gene function at selected times in postnatal life, under selected physiologic or pathophysiologic

conditions.

Providing investigators with readily accessible information about these models is as important as developing

them. A Genetically Altered Animal Models Database of

Bladder Cancer, similar to one developed by the National

Heart, Lung, and Blood Institute

(http://www.nhlbi.nih.gov/resources/medres/transgen.htm), would provide information on useful animal

models and prevent wasteful duplication of effort. This is

another example of the infrastructural support that is

needed to promote bladder cancer research.

Bladder Cancer as a Model System for Research 

The bladder is an ideal model organ system. In that

capacity, bladder cancer could be used as a model 

to study

• New technological developments relevant to other

tumor sites that are less accessible for study—The

delivery of chemicals directly into the bladder has

been done for years in the form of intravesical therapy. However, the delivery of new agents (e.g., vectors

for genetic manipulations, vaccines, labeled agents

for photodynamic diagnostic tests, and new treatments) is already being explored, but far less so than

would be expected considering this disease’s

anatomic location. 
A Strategic Plan for Research 169

• Tumor-host (immune) interaction—The natural

history and current therapy of human bladder cancer

provide outstanding opportunities for dissecting

immune mechanisms in the bladder, including 

those related to tumors. Malignant tissue is readily

and repeatedly accessible, and tumor-associated

immune populations and cytokines (proteins that

regulate the intensity and duration of the immune

response and mediate cell-cell communication)

could be sampled via routinely scheduled cystoscopy

and biopsy (standard of care), bladder washings, or

the collection of fluids or cells and molecules normally shed in urine. With these specimens, the

tumor-host interaction could be examined over time.

In addition, the routine use of intravesical BCG for

the treatment of superficial bladder cancer could

provide a surrogate antigen (target) that would allow

investigators to study the induction and effector 

arms of the immune response and to investigate 

the tumor’s effects on immune function.

New Prevention Strategies

Clearly, the best way to reduce bladder cancer mortality

is to prevent its development. Proposed strategies

include avoidance of putative carcinogen exposure 

(e.g., smoking) and reduction of carcinogen exposure

(e.g., increased fluid ingestion to dilute carcinogens).

These strategies appear attractive, although their success

has not been tested in a prospective fashion. In the 

case of rare specific exposures, including exposure to 

A. franghi in Chinese weight-loss herbs and to arsenicrelated substances in contaminated well water, regulatory measures have proven quite effective in lowering

urothelial cancer incidence, although effects on 

disease-specific mortality have yet to be reported.

A complementary approach to avoidance has been the

use of chemopreventive agents. Several agents have 

prevented carcinogen-induced bladder tumors in 

preclinical animal studies. In clinical prevention trials,

some of these agents appear promising in other human

tumor sites. Currently in phase III testing in the United

States are the oral polyamine synthesis inhibitor, 

DFMO; the cyclooxygenase 2 (COX 2) inhibitor, 

celocoxib; and the vitamin A analog, 4HPR. Results 

of these trials are not yet available. In prior phase III 

trials, other retinoids—vitamin B6 and alpha tocopherol

(a vitamin E analog)—have had mixed or negative 

results, and some retinoids have been quite toxic. 

Most of these agents have been, or are being, tested in

secondary preventive settings on patients whose superficial tumors were completely resected but who are at risk

for developing recurrences. Although this represents an

attractive and large population to study, depending on

trial design, this may be testing both prevention of new

tumors and treatment of existing ones. However, without

success at the secondary level, it would be hard to justify

a primary preventative trial specifically for bladder cancer because of the much greater sample sizes required. 

A presumed assumption in the design of some of the

secondary trials is that preventing low-grade tumors 

may also be helpful in preventing high-grade ones.

Although data exist to the contrary, most of the clinical,

epidemiological, and molecular evidence appears to 

support this hypothesis.

Promising natural products include plant estrogens

(phytoestrogens) such as genestine, which can inhibit

growth factor tyrosine kinases, should also be tested.

However, significant further effort must be placed 

in this area. Along with new candidate agents, perhaps 

the greatest need in prevention studies is that of characterizing intermediate molecular marker endpoints of

premalignancy, the reversal of which correlate with a

successful outcome. Finally, a combination of agents,

including a combination with existing intravesical 

therapies, is beginning to be pursued and is 

theoretically attractive.
170 OVERCOMING BLADDER DISEASE

New Molecular Markers 

Compared with many other tumor sites, much progress

has been made in the molecular diagnosis of urothelial

cancers. Several molecular epigenetic and genetic markers have the capacity to diagnose 80 percent to 95 percent of Grade 3 tumors and 40 percent to 80 percent of

low-grade ones. These tests have generated considerable

financial interest, with an eye on ultimately replacing

more invasive means of diagnosis and monitoring, 

particularly cystoscopy. 

To date, no commercially available test has the sensitivity, particularly for low-grade tumors, to be useful by

itself in establishing an initial diagnosis or in monitoring patients. However, several markers in various 

stages of testing and commercial development have 

this potential. 

The most promising new molecular markers include

Immunocyt, a combination of three monoclonal antibodies to bladder-cancer-associated antigens and 

cytology; hyaluronidase and hyaluronic acid; BLCA-4, a

nuclear matrix protein; Survivan, a protein that inhibits

programmed cell death (apoptosis); telomerase activity

and protein; several tests of genetic instability in DNA 

in urine using a panel of marker DNA microsatellites

(compared with genomic DNA); and fluorescence in 

situ hybridization (FISH) analysis of a combination 

of chromosomal markers.

Although aggressive attempts to define a market for

these products continue, it is possible that some 

combination of markers could be scored in such a way

that would make them have sufficient sensitivity and

acceptable specificity to be able to replace cystoscopy 

in diagnosis and monitoring. Eventually these markers

could be used for screening demographically defined, 

at-risk populations (e.g., middle-aged and elderly male

smokers and former smokers) in a non-invasive or 

minimally invasive fashion. 

Such combination studies are desperately needed, 

but industry has a limited interest in these trials because 

a commercial competitor may benefit more than the 

sponsoring company. This problem also occurs with 

innovative use of 

combinations of agents

in preventive and 

therapeutic strategies.

Additionally, detection

and particularly

screening endeavors

are ideally suited for

mathematical modeling

to optimize and

streamline study

designs and strategies

before extensive clinical testing occurs. 

For example, repetitive

reagent strip testing 

for blood in the urine

(hematuria) has been

shown to have sufficient sensitivity for

screening purposes;

however, the specificity

of this reagent strip

could be improved with a second tier of marker tests that

would determine which person with hematuria should

proceed to cystoscopy. This strategy would be more

attractive to potential screening subjects, but it awaits the

combination marker analysis and appropriate modeling. 

Once a combination of markers is available, a phase 

III, randomized, prospective, controlled trial of bladder

cancer screening is clearly warranted by the

• High incidence of the disease

• Great success in treating superficial tumors with a

relatively non-morbid means

• Serious deficiencies in treating more locally

advanced and metastatic cancers with means that 

are highly morbid

• Compelling clinical evidence that virtually all people

who die of urothelial cancer (those with metastases)

have malignancies that invade the bladder muscle 

at the time that metastases occur or before

Promising

Molecular Markers

• Immunocyt

• Hyaluronidase and

hyaluronic acid

• BLCA-4 

• Survivan

• Telomerase activity 

and protein 

• Fluorescence in situ

hybridization (FISH)

analysis

• Tests of genetic instability in DNA in urine

using a panel of marker

DNA microsatellites
A Strategic Plan for Research 171

Because between 70 percent and 90 percent of all people

with muscle-invading bladder cancer currently have 

that level of invasion at the time of their initial bladder

cancer diagnosis (i.e., they do not come from the enormous pool of people with previously treated superficial

tumors), the need for earlier detection as a major means

of reducing bladder cancer mortality is obvious.

Requirements for Bladder Cancer Research

Although it could be argued that important initiatives

and funding mechanisms for novel approaches to 

bladder cancer are lacking, only 50 percent of all 

NIH-funded research in bladder cancer is occurring

through traditional, investigator-initiated (i.e., RO1,

R21/29, and PO1 grants that are entirely on bladder 

cancer) mechanisms. This indicates that more creative

requests for applications (RFAs) and other funding

mechanisms are not necessarily the only answer.

Alternatively, prostate cancer and breast cancer have

recruited major investigators from other fields because

of the funds available, and this lesson could well be

applied to bladder cancer, which, although it is the fifth

most common non-cutaneous malignancy in the United

States, lags well behind these diseases in overall funding. 

If even a small but proportionate increase is made 

for bladder cancer research (a justified increase based 

on the disease’s incidence), it is likely that huge strides

could be made, if in no other area than in equalizing

mortalities in women, elderly people, and African

Americans to the mortalities of middle-aged Caucasian

men. This alone would cut bladder mortality by 

20 percent. 

If the economical use of public funds to address health

care concerns is truly the highest priority, the magnitude

of support going to bladder cancer research seems 

disproportionately low when compared with support 

for research on other malignancies and diseases. This 

is particularly true because so much is known about

bladder cancer and because it is likely that relatively

simple interventions such as earlier detection, smoking

cessation (with a particular emphasis on people at risk

for, or who already have, bladder cancer), and education

(directed particularly at demographic groups with 

disproportionately high morbidity and mortality) 

might have a major beneficial impact in reducing 

mortality and morbidity. 

Tissue and Specimen Banks 

Some of the most exciting and novel scientific 

approaches such as informatics, proteomics, genomics,

and novel imaging—approaches that are particularly 

suitable for bladder cancer applications—have significantly lagged behind efforts in other tumor sites.

Admittedly, in creating useful tissue banks and arrays,

technical challenges arise in harvesting, dissecting, 

and orienting bladder tumor tissue. However, with care,

these and other technical problems can be surmounted

to obtain appropriate specimens for array preparation

and banking. This often requires an interested team 

of investigators and infrastructural support. 

A cystoscopic image of a superficial papillary tumor of the bladder. 

(Photo Credit: Healthcommunities.com, Inc., Bladder Cancer on 

urologychannel.® All rights reserved. http://www.urologychannel.com. 

Copyright 2002, Healthcommunities.com, Inc.)
172 OVERCOMING BLADDER DISEASE

Advances in cancer are tightly linked to the availability 

of tissue specimens for study. Tissue is a snapshot picture of a tumor, but a complete biology is linked to that

tissue becoming malignant. Molecular changes that

would be reflected in outcome are already present in the

tumor tissue when it is resected. Adequate access to

tumor and normal tissue is a chronic problem for

research in cancer. In the bladder, the cancer process 

is a continuum from normal cells to abnormal tissue

development (dysplasia) to localized tumors to invasive

and metastatic disease, with both flat and papillary 

(exophytic and endophytic) pre-malignant and preinvasive stages. To facilitate research in bladder cancer,

the development of an extensive network of tissue banks,

both institution-based and cooperative, is essential. 

Tissue and specimen banks will require significant 

support for storage, registration, and dissemination 

of the tissue. Tissue banks will need to include frozen

specimens (in liquid nitrogen) as well as paraffinembedded tissue. Ideally, tissue and specimen banks

should contain simultaneously obtained, ostensibly 

normal, epithelium from the same patient’s bladder.

Moreover, these specimen samples must be tied to 

complete clinical, epidemiologic, demographic, genetic,

and other information, with accurate and long-term 

follow up.

Tumor Registry Systems 

Tissue and specimen banks are also integral parts of

tumor registry systems that record outcomes. These 

registries will be of great importance in the development

of better prognostic markers, which requires sufficient

tissue correlated with known outcomes. 

Currently, the number, size, and quality of such banks 

of malignant and normal tissues and exfoliated cells

(with good clinical correlation and follow-up) are 

inadequate for the needs of modern molecular research

in bladder cancer, and there is no access to samples 

(and clinical information) for worthy investigators 

outside laboratories where such banks reside. Establishment of these banks, with a ready distribution of highquality specimens, would greatly facilitate research.

High Throughput Methodologies

High throughput technologies are capable of performing a

large number of tests in a short period of time. A number

of new high throughput technologies have been recently

developed that will dramatically alter bladder cancer

research. Laser capture microdissection (LCM) allows 

the collection of small, pure populations of cells. The 

current emphasis of research in the post-genome era 

is the profiling of cDNA expression (using DNA chips)

and its correlation with protein expression (using both

immunologic and mass-spectroscopic identification of

proteins). Now tissue arrays with samples of hundreds 

of tumors are available. 

This high throughput technology moves the study of 

cancer from in-depth observations on a few specimens

to the study and verification of observations on a sufficient number of cancers, reaching statistically valid 

conclusions in very brief periods of time. Some of 

these techniques are applicable to urine specimens 

(both soluble and cellular components) as well. High

throughput methodologies offer the opportunity to

define proteins that would be useful in making diagnoses, formulating prognoses, and monitoring patients.

Bioinformatics Systems

A far bigger hurdle to overcome, and one that is by 

no means unique to bladder cancer research, is the

enormous barrier to developing tissue and specimen

banks with critically important clinical, correlative, 

and follow-up information that is placed by institutional

review boards. These constraints are based on concerns

about patient confidentiality, informed consent, 

potential financial profit, patient reimbursement, 

and other ethical issues. A national policy, spearheaded

by the National Institutes of Health and the National

Academy of Sciences, but accepted by the public and

other constituencies, is needed immediately to 

overcome these hurdles.
A Strategic Plan for Research 173

Both the development of strong inter-institutional 

tissue banks with correlative clinical information and 

the use of high throughput methodologies for the analysis of tumors require the development of bioinformatics

systems. Such systems will benefit all disciplines that 

use tissue and that are engaged in high throughput

methodologies. The funding needs for such resources

exceed what has traditionally been available through

normal granting mechanisms. Additional financial 

support will be required to make sure that data are 

collected and disseminated. 

Review Groups with Knowledge of Urothelial Cancer

Clearly, bladder cancer research is relatively underfunded, but it might also be under applied for. Data 

were not available to the authors of this report on the

number of research applications accepted or rejected 

for urothelial cancer as opposed to other cancers.

However, review groups with a particular interest in, 

and knowledge of, this disease might greatly improve 

the prospects for funding—particularly of R01 and 

R29 grants. 

Grants are often sent to more general study sections 

(no data were provided on this) where reviewers 

unfamiliar with the nuances of bladder cancer may 

not be able to fairly appraise the specific merits of 

an application in terms of this unique disease site. 

In such review groups, lack of appreciation of models 

and approaches that have specific relevance to bladder

cancer (e.g., carcinogenic models and use of endoscopic

evaluations) but are not directly applicable to tumors

with which the reviewers may be more familiar mitigates

against the success of a bladder cancer application in 

the peer-review process.

Epidemiology and Basic Scientific Mechanisms 

of Disease Research

More research on epidemiology and basic biological

mechanisms of urothelial cancer is clearly needed. 

Multi-Center Programs and Networks

Mechanisms for funding multi-center programs with

sufficient infrastructure support to promote novel 

investigations (and indeed an emphasis on this) and

recruitment of new investigators may be productive 

ways to sponsor further research. Recently, a Bladder

Cancer Special Program of Research Excellence (SPORE)

was awarded to MD Anderson Tumor Institute in

Houston, Texas; this may indicate that there is an 

awareness of this problem. 

Public Interest and Educational Efforts

These efforts are clearly important, and they have 

been enormously effective for prostate cancer and 

breast cancer research. Patient advocacy groups also do

not exist for cancer of the bladder as they do for many

other malignant and non-malignant diseases. Such

groups not only improve research and educational

efforts, but also permit clinical researchers to be 

more aware of the needs and priorities of patients.
174 OVERCOMING BLADDER DISEASE

PATIENT PROFILE

In 1967, Hubert Humphrey, Vice President of the United 

States and a presidential candidate, discovered blood in 

his urine—often the first sign of urinary tract disease. 

The vice president immediately consulted his doctors, who

examined his bladder with a cystoscope, but found nothing 

that appeared abnormal. His physicians also sent samples 

of his urine and bladder tissue to pathologists who performed

tests for abnormal cells, but none of the samples positively

established that cancer was present. A tissue sample from 

a tiny spot in Humphrey’s bladder did show irregularities in

some cells; however pathologists were unable to agree on 

a diagnosis.

Although it was somewhat controversial, Humphrey’s physicians

decided on a period of watchful waiting. The vice president

continued his campaign for the presidency, but lost the election

to Richard Nixon, who ironically declared a “War on Cancer” in

1972. Six years later, Humphrey lost his personal war on cancer. 

Vice President Humphrey’s medical history reveals much 

about the difficulty of diagnosing bladder cancer. Technology

available at the time was unable to detect cancer cells until

1969, two years after his symptoms first appeared. Biopsies

taken of tumors at that time revealed “in situ cancer,” that 

is, localized malignant tumors in the epithelium, the mucous

tissue lining the inner surface of the bladder. By 1973, a 

biopsy report noted “pre-invasive malignancy,” cancer that 

was about to invade underlying tissue and muscle. Although

Humphrey received radiation therapy and localized chemotherapy for the disease, by 1976 the cancer had become 

invasive, necessitating removal of the bladder. Lymph nodes

removed during surgery indicated that the cancer had spread 

to other parts of his body. Hubert Humphrey died of cancer 

in January 1978 at the age of 66.

Bladder cancer is frequently undetected in its early stages,

even today. It usually does not cause symptoms such as 

blood in the urine or frequent urinations until large tumors 

are present. Even when symptoms do appear in early stages,

finding cancerous cells among thousands of normal cells 

in urine or in biopsied bladder tissue is difficult and often

impossible. Clearly, development of markers that point to 

early disease could reduce the high morbidity and mortality

associated with bladder cancer. 

Hubert Humphrey

Bladder Cancer

(Photo Credit: U.S. Senate Historical Office)
A Strategic Plan for Research 175

Better tests appear to be on the horizon. In the past decade,

advances in biotechnologies and the science of genomics and

proteomics have laid the groundwork for early diagnosis. New

technologies allow for replication of DNA samples from scarce

genes, and new types of DNA analysis are now capable of 

detecting cells with genetic mutations. 

One preliminary screening tool for bladder cancer in its early

stages was tested in 1994 by a team of researchers at Johns

Hopkins University School of Medicine, using Humphrey’s urine

and tissue samples. The team obtained permission from

Humphrey’s widow to use a urine sample collected in 1967 and a

tumor sample collected several years later. Armed with new

knowledge about mutations in genes and a new technique, the

polymerase chain reaction (PCR), which allows scientists to

make multiple copies of DNA from scarce genes, the researchers

set out to see if cells sloughed off into Humphrey’s urine would

show signs of disease. 

In studying the cells of the tumor sample (collected in 1973

when cancer was visible in Humphrey’s bladder), researchers

discovered that the cells had mutations in the p53 gene. Certain

mutations in this gene are now recognized as the cause of 60

percent of very aggressive bladder cancers. In Humphrey’s case,

one DNA building block, adenine, had replaced another, thymine,

in the sequence. The mutation was not present in the noncancerous tissues of Humphrey’s bladder. 

In a separate, but similar procedure, researchers took the urine

sample collected when Humphrey was first examined in 1967

and again used PCR. They discovered that even when physicians

could not determine whether cancer was present, cells in

Humphrey’s urine had markers of the type of mutation that

caused his cancer.

Although researchers have demonstrated how a marker for 

incipient disease could lead to early diagnosis and treatment,

developing a test that has the sensitivity to detect all types of

bladder cancer is not so simple. Microsatellite analysis has 

been available for approximately 10 years, but it is still not a

standard tool or test. Mutations in p53 are not present in all

bladder cancers, and in fact, many different mutations in this

gene can cause the disease, which is strongly associated with

environmental toxins and smoking.

According to the American Cancer Society, the incidence of 

bladder cancer in the United States increased 30 percent

between 1985 and 2000. Currently, between 250,000 and

500,000 people have this disease. Many are elderly men and

women who face years of treatment that includes surgical

removal of the bladder, urinary diversion, high-dose pelvic 

radiotherapy, and multi-drug chemotherapy, treatments that 

are not only expensive, but also highly morbid. With better 

preventive strategies and more sensitive molecular screening

tools that take advantage of the great strides made in 

genomics and proteomics, the pain and suffering caused 

by bladder cancer could be reduced.
A Strategic Plan for Research 177

SECTION C METHODOLOGIES & TECHNOLOGIES 

FOR FUTURE RESEARCH

Bladder research would benefit from recent advances in

biotechnology that have created rapid progress in other 

areas of scientific endeavor. All areas of bladder research 

and all patients with bladder-associated health problems 

would specifically benefit from the following advances:

• New biologic (cellular or molecular) and functional 

imaging techniques and genomics and proteomics 

techniques to identify persons at risk for bladder 

disease or dysfunction

• Bioengineering technology such as stem cells, gene 

therapy, and tissue engineering techniques that allow 

repair, replacement, or even prevention of abnormal 

bladder tissue or function

As rapidly as research has progressed in proteomics and

genomics, pharmacologic discovery aimed at modulating, 

augmenting, or blocking specific receptors has also 

progressed. New drug delivery systems allowing drug 

delivery at a specific time and place are possible, and 

the bladder is an ideal organ in which to deliver them.

Methodologies such as bioinformatics and epidemiology 

and advances in computer technology permit linkage of 

patient and disease data and allow clinical research to 

be performed using databases that surpass previous 

capabilities and capacities. The methodologies and 

technologies apply new rigor to clinical trials involving 

outcomes evaluations and neural networks. In studies of 

complex conditions, bioinformatics and biostatistics allow 

scientists to make inferences and conclusions that were 

previously impossible to make.

At this time in medicine, clinical research is severely 

challenged. Clinical investigators have less time for clinical

research because of the increasing complexities involved 

in performing their day-to-day patient care activities. 

Clinical trials are poorly funded. Clinical research is 

expensive, and human research is highly regulated requiring

high degrees of organization and support. Many bladder 

diseases have a long natural history, and outcomes trials 

must be undertaken over many years, facts that make 

clinical research even more complicated. 
CHAPTER 13
A Strategic Plan for Research 179

Methodologies & Technologies 

for Future Research

CLINICAL TRIALS IN LOWER URINARY TRACT RESEARCH

DID YOU KNOW?

. Few clinical studies have 

been conducted on disease 

of the lower urinary tract.

. Enormous opportunities are 

currently available for data 

gathering and examining 

best practices in bladder 

disease management.

Summary and Recommendations

Clinical trials related to bladder disease are scarce. Currently, the National

Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the

National Institutes of Health (NIH) is conducting clinical trials or programs

in only four areas of bladder disease—bladder cancer, interstitial cystitis,

incontinence, and obstruction. 

Enormous opportunities for data gathering and for examination of best

practices and management of bladder disease exist through clinical trials,

yet they have been under utilized and under funded in the area of bladder

research. Examination of issues that have been impediments might provide

an incentive to programs applying for future clinical trials in bladder

research. 

The Bladder Research Progress Review Group prioritized the research

opportunities and implementation recommendations for clinical trials

activities. Their recommendations are as follows:

First Priority

* Fund pilot studies with high-risk, high-gain potential

* Prioritize clinical studies lacking short-term gain in which funding from other

sources is unlikely, such as

• Alternative therapies (e.g., saw palmetto)

• Prevention studies (e.g., childbirth injuries)

• Long-term outcome studies

• Behavioral studies 

• Long-term management and surgical trials
180 OVERCOMING BLADDER DISEASE

* Develop a core clinical trial resource center (NIDDK) 

with core consultation services in

• Biostatistics

• Epidemiology

• Outcomes evaluation

• Ethics

Second Priority

* Encourage establishment of multi-center studies 

to examine low-incidence and high-impact bladder 

diseases or problems 

* Provide industrial partnering grants to piggyback 

basic or epidemiologic research (e.g., examination of

potential molecular markers for detection, monitoring, 

and screening)

Current Research and Opportunities 

for Research

A number of initiatives would benefit many investigators

and offer advances in understanding diseases that have

few treatment options. These initiatives would

• Standardize tissue and specimen banking issues,

particularly relating to prioritization of studies and

ethical issues

• Provide infrastructure expertise and support perhaps

at regional or national centers for biostatistical, epidemiologic, ethical, and outcomes clinical research

• Provide specific support for pilot clinical trials that

lack corporate interest or support, such as high-risk

but high-gain treatment of specific complex or severe

bladder problems.

Some areas in which clinical trials may offer advances

include diabetes, development, cancer, incontinence,

infection, inflammation, and obstruction. 

Diabetes

Although the NIH has an organized infrastructure of

research programs in diabetes, none of these programs

appears to be currently conducting research related to

the lower urinary tract. Better communication among

ongoing studies in the diabetes program may allow 

identification of studies related to diabetic bladder and

its risk factors. An examination of the epidemiology 

and risk factors for bladder involvement in diabetes 

is needed, and this could be done within the existing

infrastructure as listed below:

• Mouse Models of Diabetic Complications Consortium

• Therapeutic Approaches to Diabetes 

Mellitus Program

• Type 1 Diabetes Clinical Trials Program

• Type 2 Diabetes Clinical Trials Program

• Diabetes Prevention Program

• Endocrine Pancreas Program

• Complications Genetics Program

• Type 1 Diabetes Epidemiology Research Program

• Type 2 Diabetes Epidemiology Research Program

• National Diabetes Data Group

• Diabetes Mellitus Interagency 

Coordinating Committee

• National Diabetes Education Program

• Diabetes Centers Program
A Strategic Plan for Research 181

Development

The NIH should conduct longitudinal behavioral studies

of voiding patterns and of subjects’ elimination history

to track the natural history of voiding problems from

childhood to adult. (e.g., 30-year studies)

Cancer

The NIH should conduct the following research studies

on cancer of the lower urinary tract:

• Advanced cancer and outcomes

• Assessment of patient populations for risk

• Use of the bladder as a biologic model for 

development and delivery of various therapeutic

interventions such as gene therapy

• Potential of supplemental studies related to cancer

biology to be added to cancer trials

Incontinence

The NIH should provide support for

• Small Business Innovation Research (SBIR) 

grants and joint venture research with the 

pharmaceutical companies

• Biofeedback and Kegel exercises for 

voiding dysfunction

Infection and Inflammation

The NIH should conduct studies that examine 

and evaluate

• Longitudinal follow-up of the natural history 

of interstitial cystitis

• Treatments and emergence of antimicrobial 

resistance

• Significance of bacteriuria in the neurogenic 

and catheterized bladder

• Natural history of bladder function in persons 

with recurrent urinary tract infections

• Risk for bacterial and fungal urinary tract infection

Obstruction

The NIH should investigate the following:

• Treatment of benign prostatic hyperplasia (BPH)

using alternative therapies such as antioxidants

• Bladder and ureteral obstruction and their effects 

on muscle, upper urinary tract, and kidney function,

with examination for markers of renal failure 

(longitudinal study)
CHAPTER 14
A Strategic Plan for Research 183

Methodologies & Technologies 

for Future Research

EPIDEMIOLOGY OF BLADDER DISORDERS

DID YOU KNOW?

. Lack of data on risk factors 

in urethral and bladder 

dysfunction limits therapeutic 

and preventive efforts.

. Lack of information on 

prevalence and incidence of 

lower urinary tract dysfunction

prevents accurate estimates 

of health care costs and 

resource planning.

Summary and Recommendations

Prevalence, incidence, natural history of, and risk factors for urethral 

and bladder dysfunction are essential core research areas. However, the

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

has traditionally funded few epidemiologic research projects. In 2001, for

example, the NIDDK Epidemiologic Research Portfolio was only funded at

$5.3 million. This is in sharp contrast to funding for basic science ($41.7

million), clinical trials ($8.3 million), and applied and developmental

research ($8.8 million).

Data on the prevalence and incidence of disease are important because 

they are used to assess the burden of disease. This information is vitally

important to estimate health care costs and to direct resource planning.

Identification of risk factors provides the foundation for determining 

what causes a disease and how to prevent it. Our current paucity of information on established risk factors in urethral and bladder dysfunction 

limits preventive efforts and highlights the need for increased epidemiologic research funding.

The Bladder Research Progress Review Group made the following 

recommendations for future research efforts:

* Increase markedly the number and funding of epidemiology research— particularly longitudinal studies—to estimate incidence and to determine the natural

history of the disease. These studies should

• Use validated and standardized questionnaires in epidemiological

studies. (Most epidemiologic studies in the past ascertained outcomes

by patient self-report. Ideally, self-report measures should be validated and standardized.) 

• Obtain representative samples of target populations and wellconducted data collections for epidemiologic studies. 
184 OVERCOMING BLADDER DISEASE

• Use cross-sectional studies as efficient and 

reasonable methods to determine prevalence 

and to identify potential risk factors. 

• Provide careful measurement of a wide 

variety of potential risk factors and a very 

large sample to allow for statistical adjustment 

for multiple potential-confounding variables 

and careful follow-up over several years 

(longitudinal studies).

• Study risk factors to define causality.

• Append ancillary studies of urethra and bladder 

dysfunction to large ongoing longitudinal studies 

for an efficient means to evaluate incidence and 

natural history of disease.

* Conduct economic analyses to assist with more 

rational, effective, and economically sound medical 

decision-making.

Background

During the past three decades, rapidly increasing health

care costs have outpaced inflation and consumed more

than 13 percent of the United States gross domestic

product according to the Economic Report of the

President. Cost-effectiveness analyses incorporate data

on both health outcomes and costs and comprehensively

describe the relative value of alternative interventions

for a specific medical condition. Few data exist on the

cost-of-illness or cost-effectiveness of treatments for

urethral and bladder dysfunction. In addition, no data

are available on patient preference (utility) for treatment

and health outcomes. For economic analyses in each area

of urethral and bladder disease, measurement of direct

and indirect costs, patient preferences (utilities) and

economic evaluation, preferably cost-effectiveness

analysis, are needed in future studies. 

Research Requirements and Impediments

Requirements

The Bladder Research Progress Review Group has identified critical needs for epidemiologic research in the

areas of workforce issues, infrastructure, tissue and

specimen banks, and interactions with biotechnology

and pharmaceutical companies.

Workforce. The area of bladder dysfunction research has

few well-trained clinical researchers. A complete funding program for development of a cadre of well-trained

clinical investigators would include funding for fellows,

young faculty, and mid-level faculty.

Support for two- to three-year fellowship training 

programs in clinical research methods is essential. 

To be successful, fellows require focused didactic 

training, expert mentoring, and a clear research plan.

Because urology and urogynecology are surgical 

specialties, a 20 percent to 25 percent clinical activities

restriction should be reconsidered. A possible reasonable clinical activity level would be limited to 25 percent

for the first year, 50 percent for the second year, and 

50 percent for the third year.

At the early investigator level, four- to five-year funding 

after fellowship (similar to the Women’s Reproductive

Health Research Career Development Award of the

National Institute of Child and Human Development,

which is modeled after a K23 award) is necessary to 

allow for professional development. At the midcareer level, funding (K24 award) for four to five 

years is needed for mid-level faculty to mentor 

fellows and junior faculty.
A Strategic Plan for Research 185

Infrastructure. Currently, the basic mechanisms of 

urethral and bladder dysfunction remain largely 

speculative; data on prevalence, incidence, and 

associated risk factors are limited; major gaps exist 

in our knowledge of therapeutic efficacy; and information about the economic impact of urethral and bladder

dysfunction is scarce. Multi-disciplinary, multi-center

research programs with representation from departments of obstetrics, gynecology, and reproductive 

sciences, urology, epidemiology, and biostatistics, 

geriatrics, and medicine are necessary to foster and

facilitate research in clinical and basic science of 

the lower urinary tract. 

Funding mechanisms are needed to establish the 

infrastructure necessary to support the model of a

“bench-to-bedside” collaborative research paradigm

and to allow direct translation of scientific data to

improved patient care. In collaboration with basic 

scientists, clinical epidemiologists can answer 

interesting and novel scientific questions. 

Tissue and specimen banks. Tissue, blood, or urine 

samples could be collected and banked in wellcharacterized cohorts. 

Interactions with pharmaceutical and biotechnological 

companies. Industry-sponsored research is an engine 

of progress and opportunities. Most clinical trials of 

new drugs and devices are sponsored by industry. These 

clinical trials are an important part of the foundation 

of clinical practice and public health, and they can be

a source of important advances in medical science.

Industry sponsorship generates pressures to produce

research results and reports that may be favorable to the

marketing of drugs and devices. Academic investigators

can increase the objectivity and quality of this research

by assuming leadership roles in study design and by 

conducting research and disseminating results. This

engagement can lead not only to more appropriate use 

of treatments and tests, but also opportunities for 

generating and testing new scientific ideas. 

Impediments

Historically, the vast majority of research supported 

by the NIDDK has been in basic science. Most reviewers

and consultants are senior basic science investigators

who are not trained in clinical research methodology 

and design. Study sections and planning meetings 

for future research agendas should consider including 

senior epidemiologists from other fields who are 

familiar with the importance and quality of epidemiologic research.

Research Opportunities 

Effective prevention requires an understanding of the

causes and natural history of diseases of the urethra 

and bladder. The BRPRG recommends that research

* Markedly increase the number and funding of epidemiology

research and specifically longitudinal studies that will:

• Determine the prevalence and incidence of, and 

risk factors associated with, urethral and bladder

dysfunction, especially those that are preventable 

or modifiable

• Establish the burden of these dysfunctions in 

economic, health, and quality of life terms

• Test the effectiveness of risk factor modification 

to prevent or decrease severity of disease 

* Support training of fellows, junior faculty, and mentors 

in epidemiologic research

* Establish review and funding mechanisms that will support 

the infrastructure to build multi-disciplinary clinical and 

basic science research
CHAPTER 15
A Strategic Plan for Research 187

DID YOU KNOW?

. Current bladder reconstruction

techniques use tissue from 

a person’s GI tract that can 

cause significant complications,

including infection and cancer.

. Bulking agents used in current

procedures to relieve both 

severe urinary incontinence 

and urinary reflux are not 

entirely biocompatible. 

. Stem cell populations 

associated with the urinary 

tract have been identified.

. Development and applications 

of tissue bioengineering techniques could enable people to

“self-donate” an organ such 

as a bladder.

An estimated 35 million Americans suffer from bladder disease, and most 

of them have problems that are chronic. Dysfunction of the lower urinary tract 

can be the result of congenital problems, inflammation, infection, or various

lesions of the nervous system. These diseases and conditions interfere with 

the bladder’s ability to function as a low-pressure storage and emptying 

vehicle. The outcome is both reduced bladder elasticity and urinary incontinence, with subsequent deterioration of the upper urinary tract. Bladder 

disease often involves or results in the loss of tissue structure or function, 

problems that lead to increased morbidity and poor quality of life. 

In the future, emerging technologies such as tissue engineering, stem cells, 

and genomics will play an important role in the diagnosis and treatment 

of bladder disease. After an extensive review of past and current research 

on the lower urinary tract, the Bladder Research Progress Review Group

(BRPRG) made the following recommendations for future research on 

these technologies:

* Conduct stem cell therapy and tissue engineering research of the bladder, 

urethra, and pelvic floor, with the goals of

• Increased understanding of cell and developmental biology

• Development of cell therapy

• Development of tissue and organ replacement 

* Develop instrumentation for minimally invasive diagnosis of lower urinary tract 

disorders. Instrumentation should include

• Functional imaging

• Urodynamics

• Biomechanical assessment

Methodologies & Technologies 

for Future Research

EMERGING TECHNOLOGIES AND PHARMACOLOGY
188 OVERCOMING BLADDER DISEASE

* Establish the appropriate infrastructure, training, and core

facilities for research, including 

• Genomics and proteomics

• Bioinformatics

Background

Better alternatives for repair of the bladder, urethra, and

pelvic floor will involve tissue-engineering techniques

that attempt to recapitulate normal organ function.

Diseased bladder, urethral, and pelvic floor tissues have

traditionally been replaced or repaired with tissues harvested from other sites of the body or transplanted from

another body. However, these approaches rarely replace

the entire function of the original tissue. For example,

current bladder reconstructive procedures use tissue

from the patient's own gastrointestinal tract. This is a

complicated surgical procedure associated with significant complications, including infection, intestinal

obstruction, mucus production, electrolyte abnormalities, perforation, and cancer. When reconstructed reservoirs become dysfunctional, a surgical procedure called

bladder augmentation is required. These potential side

effects have impelled researchers to develop new technologies in the field of tissue engineering.

In other disease states, such as urinary incontinence 

or vesicoureteral reflux, artificial agents (e.g., Teflon

paste and silicone micro-particles) have been used as

bulking substances; however, these substances are not

entirely biocompatible. 

Engineered tissues are critically needed to replace 

or repair lost and functionally deficient genitourinary

organs. Cells may or may not be needed for tissue 

regeneration. If cells are needed, then several sources

may be available, including

• Autologous cells—cells that occur naturally in a 

person’s body

• Heterologous cells—cells derived from another

source

• Mature stem cells

• Progenitor stem cells

Stem cell populations associated with the urinary 

tract have been recently identified, although their 

characterization is incomplete. Stem cells have been

classically defined as a subpopulation of cells that are

present in self-renewing tissues and responsible for 

the long-term maintenance and acute repair of the

organ. The main criteria used to identify such cells 

are as follows:

• Slow-cycling

• High in vivo and in vitro proliferative potential

• Cytological and ultra-structural features

• Expression of certain “stem cell markers”

• Well-protected location and specialized “stem 

cell niche”

• Associations with predominant sites of 

tumor initiation 
Recent findings have shown that stem cells are also 

present in some tissues that have not been traditionally

regarded as self-renewing, such as tissues of the liver,

brain, and heart. Moreover, unexpected flexibility in

some stem cell populations has been demonstrated,

including the ability of hematopoietic and mesenchymal

stem cells to be directed to the formation of other cell

types, such as smooth muscle cells. Stem cells can also 

be derived from embryos and from nuclear transfer

using somatic cells. 

Stem cells are classified according to the types of cells

they are capable of producing. Unipotent stem cells 

produce a single fixed type of daughter cell; multipotent

stem cells produce several fixed types of daughter cells;

and pluripotent stem cells do not have a fixed potential

for development. Pluripotent stem cells are capable of

generating different cell types of single or multiple

organs or tissues. 

The completion of several large-scale sequencing 

projects has provided the genomic sequences for

humans and several other species. This is an extraordinary opportunity to discover and characterize genes and

gene groups that play important roles in regulatory pathways and biological processes such as the development 

of the bladder and its response to injury and disease.

Elucidating the genetic program changes that are associated with normal maturation or pathologic alterations

within the bladder will lead to hypotheses that can be

tested using genetic, biochemical, and pharmacological

analyses. This, in turn, will catalyze and form the basis 

of future advances at all levels of bladder, urethral, and

pelvic floor research.

Cost and Impact

The financial costs associated with loss of tissue function

in the bladder, urethra, and pelvic floor are estimated to

amount to tens of billions of dollars. The societal costs

are enormous. People with congenital and acquired

bladder and urethral disease frequently have chronic

abnormalities that require long-term health care 

and that could lead to disease in other organ systems.

Diagnostic techniques and tissue engineering techniques for treatments that use either autologous cells or

stem cells could provide better long-term solutions for

people suffering from bladder and urethral disease.

Congenital and acquired defects of the lower urinary

tract result in the bladder’s inability to function as a 

low-pressure storage and emptying vehicle. This results

in reduced bladder elasticity and urinary incontinence

with subsequent deterioration of the upper urinary tract.

More than 50,000 people are diagnosed with bladder

cancer each year according to the American Cancer

Society, and a subset of them requires surgical removal

of the bladder (cystectomy). More than 15,000 people

per year may benefit from research that develops

improved techniques for bladder replacement. 

New tissue engineering, stem cell, and genomic technologies could have a great impact on the health care 

of more than 13 million Americans who have urinary

incontinence and the subset of that population that has

disorders of the urethra and pelvic floor, problems that

lead to increased morbidity and poor quality of life. 

A Strategic Plan for Research 189

A bladder engineered in the laboratory. (Photo Credit: Dr. Anthony Atala, 

Children’s Hopital and Harvard Medical School.) 
190 OVERCOMING BLADDER DISEASE

The application of gene expression profiling technologies to normal and genetically or experimentally 

modified bladders would allow

• Insight into coordinate regulation and would 

coordinate function among groups of molecules

• Characterization of novel genes and proteins

involved in carrying out specific biologic processes

• Improved understanding of regulatory cascades and

the biologic processes themselves

• Ability to profile the effects of an individual gene, 

a drug, an injury, or a hormone on the bladder 

The development of new technologies for biomedicine

would have a great impact on how studies of the bladder,

urethra, and pelvic floor are conducted. Current technologies have the primary limitation of low throughput,

which means that the number of tests that can be performed in a given period of time is low. This especially

hampers the study of biologically heterogeneous 

disorders in humans. Additionally, current research

tools for analyzing nucleic acids and proteins rely on

large sample sizes. This limits the application of 

these tools in both humans and small animal models

where starting material is limited. 

What the polymerase chain reaction (PCR) has done 

for research over the last 10 years will be equaled by the

development of new high throughput technologies that

allow the analysis of large numbers of specimens with

minimal volume and the ability to analyze increasingly

smaller populations of pure cells. These technologies

could lead to great advancements in the understanding 

of congenital and acquired disorders of the bladder 

and play a role in the development of new drugs 

and therapies.

The engineering of bladder, urethral, and pelvic floor

tissues and structures, either for complete replacement

or for augmentation of organ function, would be advantageous for a large number of disease states. The engineering of tissues could be performed with biomaterials

or cells alone for smaller defects or with biomaterials

with cells for larger deficiencies. The cells could be

autologous, heterologous, or from stem cell sources.

Bioengineering technologies could provide an available

repository of tissues for revitalization of the lower 

urinary tract. 

Identification of urologic stem cells is of major 

importance because

• Urologic stem cells may be the targets of chemical

and viral oncogenesis (development and growth 

of neoplasms—abnormal tissue that proliferates 

rapidly) and could therefore be a predominant source

of malignancy that may lead to neoplastic conditions

such as bladder and prostate cancer

• A deficiency of urologic stem cells may lead to a 

variety of tissue abnormalities, including acquired

abnormalities such as hypercontractile bladders 

and developmental abnormalities involving the

ureteric bud, urogenital sinus, and müllerian 

and wolffian structures

• Urologic stem cells may be ideal targets for 

gene therapy

A Tetrad PCR Machine used for setting up polymerase chain reactions (PCR). 

The machine makes multiple copies of DNA from scarce genes. 

(Photo Credit: Harvard Medical School/Partners Healthcare System for 

Genetics and Genomics and Biopolymers Facility Sequencing Core.) 
A Strategic Plan for Research 191

• Urologic stem cells may play a major role in wound

repair secondary to injury or in acquired inflammatory conditions such as interstitial cystitis

• Urologic stem cells may be needed for the construction of artificial tissues and organs

Development and applications of tissue bioengineering

techniques using stem cells could enable people to “selfdonate” an organ such as a bladder. Non-diseased cells

could be harvested from the patient and grown into a full

or partial organ in the laboratory, which would then be

transplanted into the donor. All people with bladder 

disease could benefit from advances in the areas of

genomics, tissue engineering, and stem cells. 

Current Research and Opportunities

Current extramural and intramural research on bladder

genomics, tissue engineering, and stem cells funded by

the National Institutes of Health (NIH) includes studies

on the bioengineering of bladder tissue, novel scaffolds

for bladder replacement, muscle-cell-mediated gene

therapy for incontinence, gene-environment interactions (Odyssey cohort), comparison of in vivo and in vitro

tissue engineering, and genetic susceptibility 

to bladder cancer. Research opportunities exist in

genomics, stem cells, cell signaling and regulation, 

tissue engineering, biomechanics, bioinformatics, 

gene therapy, and genetic engineering.

Genomics

The completion of several large-scale sequencing projects has provided the genomic sequences for a number of

species, including humans. This affords an extraordinary

opportunity to discover and characterize genes and gene

groups that play important roles in regulatory pathways

and biological processes such as the development of the

bladder and its response to injury and disease. Applying

expression-profiling strategies to the various cellular

compartments (e.g., epithelium, smooth muscle, and

stromal tissue) within the bladder and urethra could be

especially informative. Technologies to accomplish this

are emerging and include laser capture microdissection

(LCM) and fluorescence-activated cell sorting (FACS).

However, because of the current amounts of RNA 

needed for expression profiling using microarrays, 

these approaches, especially LCM, may be limited to 

the use of PCR-based approaches designed to examine

selected gene products or to look for mutations or polymorphisms in candidate genes. In addition, FACS

requires the availability of specific cell surface markers

or fluorescently labeled cells. Attention should be given 

to genes with known significance in development, 

proliferation, and differentiation and maintenance 

of smooth muscle cells or of bladder epithelium. This

includes growth factors, cell-signaling components,

oncogenes (genes that normally encode proteins

involved in cell growth or regulation), and transcription

factors (factors involved in transferring genetic code

information from one kind of nucleic acid to another).

Genomics and proteomics may also help characterize the

sequence of events that occur during bladder regeneration. For example, genomic analysis of tissue samples

ABI 3700 Capillary Electrophoresis Units Sequencing Instruments used to 

determine the sequence of amino acids in DNA. (Photo Credit: Harvard 

Medical School/Partners Healthcare System for Genetics and Genomics 

and Biopolymers Facility Sequencing Core.) 
192 OVERCOMING BLADDER DISEASE

from regenerated tissue at different points in time could

characterize global gene expression. Similar studies of

proteins found in the tissue as well as in the urine could

be used for proteomics. Additionally, the gene-expression profile and proteomic “fingerprint” of each cell type

that regenerates could be obtained. These fingerprints

could then be compared to “normal” cells as well as to

the “abnormal” cells from which they were obtained. 

Genomics and proteomics will play a large role in defining what happens to all types of bladder cells once they

are placed in culture. Future research should

• Identify changes in gene expression profiles in a

normal setting versus a pathological setting and in

developmentally recapitulated tissue using tissueengineering techniques. Knowledge gained may 

lead to future studies of transgenic- or virus-based

approaches that target relevant growth or differentiation modulators to selected bladder compartments.

• Design a therapeutic strategy to alter interactions

between epithelial cells and connective tissue cells

within the bladder microenvironment. For example,

reducing or preventing tumor progression by altering

the expression of a gene involved in epithelial cell

proliferation may be possible.

• Identify the underlying genetic program(s) involved

in the initiation and progression of many pathological conditions, particularly if animal models 

can be developed. 

• Study the progression of bladder disease from 

normal to end-stage disease—a critical study that

requires establishing reproducible and acceptable

animal models.

• Conduct clinical studies to acquire epidemiological

data regarding familial patterns of occurrence of

bladder, urethral, and pelvic floor disease. These

families could then be analyzed to seek out the 

genetic bases of these disorders.

• Identify persons with a predisposition for disease 

to assure early intervention.

• Develop genomic and proteomic databases that

specifically address cells of the lower urinary tract,

including epithelium; bladder smooth muscle;

fibroblasts (cells capable of producing collagen) in

the lamina propria (the layer of connective tissue

underlying the epithelium of a mucous membrane),

the pelvic floor, and the perimysium, (the fibrous

sheath surrounding smooth muscles); myofibroblasts

(cells that have some properties of smooth muscle

such as contractility and are thought to be involved in

the contracture of wounds); and urethral sphincter

cells. Once these data sets are developed, cell-typespecific chip arrays can be prepared and used to profile these subsets of genes in normal and diseased

bladders. 

• Apply state-of-the-art genomic approaches such as

laser capture microscopy, tissue arrays, and mass

spectroscopy to the study of the complex mixed tissue

types of the lower urinary tract. Information obtained

using these tools will enhance the ability to design

therapies. For example, drug treatments could be

designed based on the receptor content and signaling

pathways discovered in this way.

A Packard Monotrack Robot, designed for high throughoutput screening of 

randomly selected compounds for a defined assay, for example, testing the 

function of specific proteins, drugs, and antibodies. (Photo Credit: Harvard 

Medical School/Partners Healthcare System for Genetics and Genomics and 

Biopolymers Facility Sequencing Core.) 
A Strategic Plan for Research 193

Stem Cells, Cell Regulation, and Cell Signaling 

During the past 20 years, remarkable progress has been

made in elucidating the tissue interactions and molecules that regulate the formation of the bladder, urethra,

and pelvic floor. 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 seminal discoveries may soon be exploited

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 and stem cells in vitro and in vivo.

Cell signaling occurs during normal and abnormal 

bladder development. The cellular signaling or growth

factors required to regenerate normal functional bladder

tissue are not known. Research on cell signaling in the

bladder should

• Focus on understanding the mechanism of bladder

regeneration.

• Elucidate further the cell signaling that occurs

between the epithelium and smooth muscle of the

bladder and the role of extrinsic growth factors and

their receptors. This knowledge will direct future

biomaterial development.

• Define further the immunobiology of biomaterials

used for tissue engineering.

• Define the effects of biomaterials on the 

surrounding normal tissue.

• Determine the role of hormones, growth factors, and

cytokines (hormone-like proteins that regulate the

duration and intensity of the immune response and

mediate cell-to-cell communication) present in the

biomaterials used for tissue regeneration. 

• Determine how the mechanism of tissue regeneration differs from normal wound healing.

Understanding the cell signaling mechanisms occurring

during tissue regeneration is crucial if engineering 

technology is to develop a viable alternative for bladder,

urethra, and pelvic floor repair. Furthermore, the stem

cell biology of the bladder, urethra, and pelvic floor is

largely unknown. Research should

• Define the features and location of these stem cells.

• Establish reproducible conditions and protocols for

identifying, retrieving, and maintaining stem cells.

• Use several approaches to identify and isolate 

bladder, urethral, and pelvic floor stem cells, 

including the use of cell-specific markers to sort

putative stem cells from tissues; the evaluation 

of in vitro and in vivo growth and differentiation 

capabilities; and the use of morphologic, molecular,

and clonigenic (the ability of a stem cell population 

to be derived from a single cell) assays. 

• Establish the lineage relationship between disparate

cell types.

• Identify signaling molecules that direct decisions

concerning stem cell fate.

• Generate monoclonal antibodies and complementary

DNA (cDNA) probes that discriminate between

pluripotent stem cells and developmental intermediary epithelial, vascular, and mesenchymal progenitor

cell types. 

• Develop novel approaches to characterization, such

as using microarray methods to determine the profile

of expressed genes. 

• Define the developmental potential of bladder, 

urethral, and pelvic floor stem cells, and the 

properties of immediate committed daughter cells.

For example, which stem cells are present in adult

tissues? When and how do stem cells generate

epithelial, mesenchymal, and vascular progenitors?

What is the normal function of these stem cells in

urologic organs? What is the role of these stem cells

in maintaining homeostasis in self-renewing cell

populations? 
194 OVERCOMING BLADDER DISEASE

• Employ current fate-mapping techniques (i.e., retroviral-mediated gene transfer approaches) to address

the above questions. 

• Determine functional genomics, including gene

expression profiling and surface markers.

A variety of adult organs have been identified as containing stem cells that may be sufficiently pluripotent to

generate cells in organs other than the ones from which

they were derived. For instance, bone marrow stem cells

could be induced to differentiate into smooth muscle

cells. These findings need to be documented further and

to be applied rigorously to the identification of bladder,

urethral, and pelvic floor stem cells. Research needs to

• Define the genes controlling stem cell division

(asymmetric and symmetric) and the commitment 

of progeny to a particular fate. 

• Determine the interaction of these cells with the

microenvironment that helps define its stem origin.

Once stem cells have been identified, they can be injected into normal and dysfunctional tissue. These cells

could be genetically modified to provide or enhance

expression of a depleted growth factor. Furthermore,

these cells could accelerate recovery processes and

enhance repair of the bladder, urethra, or pelvic floor.

The role of tissue engineering and stem cells in bladder,

urethral, and pelvic floor disease needs to be defined.

The engineered tissues or stem cells could be therapeutic

targets for gene therapy, and their activity could be modulated for therapeutic benefit, in combination with

radiotherapy and chemotherapy, for a variety of bladder

conditions, including neoplasia (rapid, abnormal cell

growth) and inflammatory disease.

Tissue Engineering

Advances in cell biology and cell research will enable

scientists to grow tissues and organs in the laboratory

starting from only a few cells. For example, under the

appropriate conditions, cells could theoretically be

“instructed” to develop into a bladder. This would 

eliminate many of the current obstacles to organ

replacement, such as donor-recipient mismatches 

and limited organ availability. Future research studies

should attempt to

• Define the conditions required for the formation 

of bladder, urethral, and pelvic floor tissues and

organs. Tissue formation has been established as

being dependent on the presence of organ-specific

cells and biocompatible matrices; however, the full

extent of tissue-inducing parameters remains to 

be identified.

• Determine the precise role of the cells in the 

formation of tissues and organs.

• Determine the possible role of blood vessel 

and nerve elements in regulating tissue and 

organ formation.

• Develop minimal functional parameters necessary 

to produce functional tissue replacements.

• Develop models of long-term remodeling and 

engineered tissue survival to minimize costly 

animal trials. 

• Develop an in vitro (test tube) model to minimize 

the costly in vivo (animal) testing and development

that is involved in the complex remodeling process. 

• Develop instrumentation for minimally invasive

diagnosis of lower urinary tract disorders involving

biomechanical assessment, functional imaging, 

and urodynamics.
A Strategic Plan for Research 195

Novel technologies capable of capturing the developmental potential of the cells need to be explored. 

Future research should

• 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.

• Explore further the effect of the bladder biomechanical properties on early regeneration.

• Determine cell production capabilities and cellular

function tools.

• Define and standardize biomaterials and their 

desirable material properties (e.g., elasticity and

intrinsic growth factors) with the appropriate 

degradation profile.

• Explore the use of material chemistry or its micro

and macro structure to increase re-vascularization

and to promote normal regeneration. The addition 

of bioactive groups or other functional groups to

allow improved interactions with peptides or proteins to enable tuning of the tissue scaffolds may 

be needed to achieve a specific cellular response.

• Establish biomaterial preparation and scaffold 

production and standardization laboratories.

• Explore novel technologies capable of capturing 

the developmental potential of the cells.

• Define methods of manipulating 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.

• Develop cell production capabilities and cellular

function tools.

• Integrate desirable material properties (e.g., elasticity) with the appropriate degradation profile. 

Bioinformatics

The subject of emerging technologies brings special

issues to the bladder, urethra, and pelvic floor. The 

past 10 years have seen dramatic advances in the development of instrumentation for the study of molecular

biology. Completion of the human genome brings about

new challenges for applying this wealth of data. As a part

of this effort, there has been a resurgence of interest in

the application of technologies for the study of proteins.

LCM and the development of cDNA microarray analysis

of gene expression offer the ability to define the gene

expression patterns of individual tissue types. These

technologies all focus on using smaller samples of 

material for discovery research. The development of

newer techniques that may define individual small 

cell populations would be a significant advance in the

dissection of bladder, urethra, and pelvic floor tissues

into functional elements. 

Current challenges include (1) determining the progression to disease and (2) collecting tissue specimens 

that would define this spectrum. To accomplish this,

adequate animal model systems of the bladder, urethra,

and pelvic floor need to be developed. The bladder and

urethra consist of an innervated, complex, muscular

layer lined with epithelium. Most model systems poorly

replicate this system, failing to correctly mimic the

extrinsic processes present within these organ systems.

Cell populations that need to be addressed include

epithelium, fibroblasts, myoblasts (primitive muscle

cells with the potential for developing into a muscle

fiber), and contractile cells of the bladder, urethra, and

pelvic floor, as well as the non-cellular components of

these organs.

Future research projects should endeavor to

• Define the changes that occur in the progression 

to disease rather than in end-stage disease states.

• Develop resources around cell types in the bladder,

urethra, and pelvic floor, including cDNA and 

protein profiles of these cell types.
196 OVERCOMING BLADDER DISEASE

• Make available and refine technologies that will 

isolate and study as individual components the 

functionally separate cell populations of the 

bladder, urethra, and pelvic floor.

• Define the mechanisms by which extrinsic processes

affect the cell populations of these organ systems. 

• Define the factors that predispose people to disease.

Bioinformatics is expected to play a major role in 

bladder and urethral genomics, tissue engineering, 

stem cell research, and clinical application. Selfrenewing stem cells usually originate from a rare 

multipotent cell population. During the engineering 

of tissue structures, genome-wide gene expression

analyses should be performed to define regulatory 

pathways in bladder cells and their global genetic 

programs. Subtracted cDNA libraries from native 

bladder and stem cell populations should be analyzed

with bioinformatic and array hybridization strategies. 

A large percentage of the several thousand gene products

that would be characterized are expected to correspond

to previously undescribed molecules, some involved in

regulatory functions. As the research in the area of tissue

engineering and stem cells proceeds, the ability to 

rapidly access previously observed cell behavior would

prove valuable. This behavior will be a function of the

cell's environmental context, and it should be tracked 

at the levels of molecular expression and whole-cell

responses. In this way, data can be aggregated to predict

cell responses and, thereby, to control cell roles in 

tissue regeneration. 

These sets of complete data should be made available 

in biologic process-oriented databases, representing 

the molecular phenotype of specific cell populations.

Training and equipment in the area of bioinformatics

will be needed to accomplish the above. In addition,

access to deposited searchable databases generated from

bladder-associated microarray and proteomic studies

must be made available to the scientific community.

These efforts should be coordinated with current NIH

committees working on functional genomic and bioinformatics initiatives.

A considerable infrastructure is required to support 

the genomic approaches listed above. This includes a

bioinformatics unit to assist with database mining, gene

discovery, sequence analysis, and expression analysis.

Access to computer systems, database infrastructure,

and direct-user support for the identification and 

characterization of genes under study is important as

well. Advanced commercial high-throughput technologies are available and include commercial microarray

systems and subtraction cDNA methods. 

Gene Therapy and Genetic Engineering

Technologies such as gene therapy and genetic engineering are also essential for the eventual use of tissue engineering and stem cell technologies in treating the spectrum of diseases affecting the bladder, urethra, and

pelvic floor. An appropriate focus is expected in these

areas of research. 

Research Requirements

Workforce

The development of emerging technologies is currently

hampered by the lack of appropriately trained investigators. Currently, 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 this research. In addition, few students

are interested in acquiring these skills. Cooperation 

and coordination with other NIH initiatives must 

be fostered. 

Several training awards should be directed to the fields

of bladder and urethral genomics, tissue engineering,

and stem cell research. These awards may be given to

• Train newly independent scientists who can demonstrate the need for a period of intensive research

focus as a means of enhancing their research 

directives in the areas of bladder, urethral, and 

pelvic floor genomics, tissue engineering, or stem

cell research
A Strategic Plan for Research 197

• Train research scientists who have identified a 

mentor with extensive experience in bladder, 

urethral, and pelvic floor genomics, tissue 

engineering, or stem cell research

• Train health scientists who have the opportunity 

to receive research training in the areas of bladder,

urethral, and pelvic floor genomics, tissue engineering, or stem cell research

• Train or provide supplemental funding to outstanding scientists who have demonstrated a sustained

level of productivity and whose expertise, research

accomplishments, and contributions to the field 

have been, and will continue to be, critical to the

mission outlined in this report

Infrastructure

Successful applications of bladder, urethral, and pelvic

floor genomics, tissue engineering, or stem cell research

should be pursued through NIH-solicited and investigator-initiated research programs, training, and scientist

awards. Multi-centered and program research centers

should be established. The use of genomic-based 

technologies is of major importance. Furthermore,

understanding the basic processes that control stem 

cell progeny will facilitate new approaches to wound

repair and the creation of tissues and organs for 

transplantation. 

In addition, clinical applications for tissue engineering

and stem cells will improve preventive and therapeutic

approaches, including gene transfer, for a wide range of

bladder, urethral, and pelvic floor diseases. Examples

include cancer, functional disorders, end-stage organ

disease, and congenital abnormalities. Thus, findings

generated from this research will be highly relevant to

many NIH components.

Tissue and Specimen Banks

The development of appropriate tissue and specimen

banks containing paraffin-embedded and frozen tissues

is essential for the application of these technologies.

Because they are aimed at high-throughput, statistically

relevant conclusions, many technological approaches 

are dependent on samples from large populations. 

Some technologies will be able to use both the cellular

components and the free proteins for analysis, a freely

available benefit that will require the development 

of registries and core storage facilities to identify 

appropriate people for study. 

With highest priority, a bladder, urethral, and pelvic

floor primary and stem cell bank should be established

that would include a depository and central distribution

center for sharing cells, reagents, and model systems. 

An academic center with access to human and animal

urologic tissue sources would be preferable as a selected

site. The primary and stem cell and reagent bank would

operate under the auspices of the National Institute of

Diabetes and Digestive and Kidney Diseases (NIDDK) 

of the NIH. 

Interactions with Pharmaceutical/Biotechnology Companies

Interactions with the biotechnology and large pharmaceutical industries should be encouraged. These 

industries have the research and development budgets 

to support the extensive equipment and specialized 

personnel cost incumbent with this research. They 

also have dedicated resources that they seek to use.

Additionally, pharmaceutical and biotechnology 

companies are well motivated to study these processes

because they are primarily chronic and affect an aging

population. Technology development is expected to 

drive biological discovery for the next decade. 
198 OVERCOMING BLADDER DISEASE

Public Interest and Educational Efforts

As the sciences of bladder, urethral, and pelvic floor

genomics, tissue engineering, and stem cells continue 

to be developed, scientists should not overlook 

particular experimental therapies that could raise 

ethical concerns among some members of the public.

Although the scientific rationale for a particular type 

of research may be quite clear to researchers, it could 

be quite controversial to the public as a whole. 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 for Protection from Research Risks

• 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.

Ongoing Review and Advisory Groups

The NIDDK should hold workshops to discuss scientific

issues relevant to bladder, urethral, and pelvic floor

genomics, tissue engineering, and stem cell research.

These workshops should also include discussions

regarding inter-institutional collaborations that would

further advance research in these areas.

A mechanism should be established within the NIDDK 

to coordinate all endeavors in bladder, urethral, and

pelvic floor genomics, tissue engineering, and stem 

cell research and to ensure proper development, 

oversight, and evaluation of established guidelines.

PHARMACOLOGY

Recommendations

The Bladder Research Progress Review Group made the

following recommendations for future research in pharmacology of the lower urinary tract, in order of priority: 

* Develop drugs that can modulate bladder sensory pathways

in the peripheral and central nervous systems, including

drugs that mediate visceral pain.

* Develop specific drugs that can modulate the micturition

(voiding) threshold in the central nervous system.

* Develop orally administered smooth-muscle-specific 

agents for treatment of lower urinary tract smooth-muscle

disease, including overactive bladder (myogenic origin) 

and contractile failure.

* Develop drugs that protect peripheral post-ganglionic

nerves from degeneration (neuroprotective drugs) and

drugs that can stimulate nerve growth and regeneration.

(These drugs would be useful in the treatment of diseases

such as diabetes, bladder obstruction, and degenerative

diseases of the nervous system such as multiple sclerosis)

* Develop drugs that can affect the properties of urinary

tract epithelium, including drugs that can alter the 

arachidonic acid cascade involved in the inflammatory

process, causing symptoms of urinary urgency, 

frequency, and pain. 

* Develop drugs to improve blood flow to the bladder, 

possibly by stimulating angiogenesis (development 

of blood vessels).

* Develop novel chronic drug delivery systems, 

including administration of drugs directly into 

the bladder (intravesical administration).

* Develop drugs to regulate connective tissue matrix 

synthesis and degradation.
A Strategic Plan for Research 199

From The Writings of Benjamin Franklin, Volume II: Philadelphia, 1726 - 1757

Benjamin Franklin to John Franklin The Flexible Catheter 

Philadelphia, December 8, 1752

Dear Brother,

Reflecting yesterday on your Desire to have a flexible Catheter, a Thought struck into my Mind 

how one might possibly be made: And lest you should not readily conceive it by any Description 

of mine, I went immediately to the Silversmith’s, and gave Directions for making one, (sitting 

by ‘till it was finish’d), that it might be ready for this Post. But now it is done I have some Apprehensions that it may be too large to be easy: if so, a Silversmith can easily make it less, by twisting 

it on a smaller Wire, and putting a smaller Pipe to the End, if the Pipe be really necessary. This

Machine may either be cover’d with a small fine Gut first clean’d and soak’d a Night in a Solution 

of Alum and Salt in Water, then rubb’d dry which will preserve it longer from Putrefaction: then wet

again, and drawn on, and ty’d to the Pipes at each End where little Hollows are made for the Thread

to bind in and the Surface greas’d: Or perhaps it may be used without the Gut, having only a little

Tallow rubb’d over it, to smooth it and fill the Joints. I think it is as flexible as could be expected in 

a thing of the kind, and I imagine will readily comply with the Turns of the Passage, yet has Stiffness

enough to be protruded; if not, the enclos’d Wire may be us’d to stiffen the hinder Part of the Pipe

while the fore Part is push’d forward; and as it proceeds the Wire may be gradually withdrawn. 

The Tube is of such a Nature, that when you have Occasion to withdraw it its Diameter will lessen,

whereby it will move more easily. It is also a kind of Scrue, and may be both withdrawn and introduc’d by turning. Experience is necessary for the right using of all new Tools or Instruments, 

and that will perhaps suggest some Improvements to this Instrument as well as better direct the

Manner of Using it. 

I have read Whytt on Lime Water. You desire my Thoughts on what he says. But what can I say? He

relates Facts and Experiments; and they must be allow’d good, if not contradicted by other Facts 

and Experiments. May not one guess by holding Lime Water some time in one’s Mouth, whether 

it is likely to injure the Bladder? 

I know not what to advise, either as to the Injection, or the Operation. I can only pray God to 

direct you for the best, and to grant Success. 

I am, my dear Brother Yours most affectionately 

I find Whytt’s Experiments are approv’d and recommended by Dr. Mead.
A Strategic Plan for Research 201

CHAIR: Linda Dairiki Shortliffe, M.D.

Chair, Department of Urology

Stanford University School of Medicine

Stanford, California 

William C. de Groat, Ph.D.

Department of Pharmacology

University of Pittsburgh School of Medicine

Pittsburgh, Pennsylvania 

John O. DeLancey, M.D.

Department of Obstetrics and Gynecology

University of Michigan

Ann Arbor, Michigan 

Monica Liebert, Ph.D.

Director of Research

American Urological Association, Inc.

Baltimore, Maryland 

John D. McConnell, M.D.

Chairman, Department of Urology

University of Texas Southwestern Medical Center

Dallas, Texas 

Vicki Ratner, M.D.

NIDDK Advisory Council Member

President, Interstitial Cystitis Association

Rockville, Maryland 

Anthony J. Schaeffer, M.D.

Chairman, Department of Urology

Northwestern University Medical School

Chicago, Illinois 

William D. Steers, M.D.

Chair, Department of Urology

University of Virginia 

Health Sciences Center

Charlottesville, Virginia 

Dana Weaver-Osterholtz, M.D.

Clinical Associate Professor

University of Missouri

Columbia, Missouri 

EXECUTIVE COMMITTEE
A Strategic Plan for Research 203

Group 1:

Diabetes, Cancer, Development

Diabetes

Chairs: Michael Chancellor, Robert Weiss

Jeanette Brown

George Christ

William de Groat

Susan Keay

Edward Macarak

Anthony Schaeffer

Michael Siroky

Ann Stapleton

Jeremy Tuttle

Dana Weaver-Osterholtz

Ursula Wesselman

Cancer

Chair: Edward Messing

Harris Foster

Stephen Hewitt

Edmund Lattime

Monica Liebert

Vicki Ratner

Ricardo Saban

Michael Sacks

Tung-Tien Sun

Development

Chairs: Larry Baskin, Ananias Diokno

James Ashton-Miller

Anthony Atala

Linda Brubaker

Toby Chai

John DeLancey

Philip Hanno

Anna Herzog

Barry Kogan

Bradley Kropp

James Lessard

Robert Levin

Peggy Norton

Neil Resnick

Brenda Russell

Linda Shortliffe

William Steers

WORK AND FOCUS GROUPS
204 OVERCOMING BLADDER DISEASE

Group 2:

Incontinence, Technologies, 

Inflammation/Infection/Interstitial Cystitis, Obstruction

Incontinence

Chairs: Linda Brubaker, Peggy Norton

James Ashton-Miller

Larry Baskin

Toby Chai

George Christ

John DeLancey

Anna Herzog

Neil Resnick

William Steers

Jeremy Tuttle

Emerging Technologies

Chairs: Anthony Atala, Bradley Kropp

Michael Chancellor

Stephen Hewitt

James Lessard

Monica Liebert

Edward Macarak

Brenda Russell

Michael Sacks

Tung-Tien Sun

Inflammation/Infection/Interstitial Cystitis

Chairs: Philip Hanno, Anthony Schaeffer, 

Ann Stapleton

Jeanette Brown

Ananias Diokno

Harris Foster

Susan Keay

Edmund Lattime

Edward Messing

Vicki Ratner

Ricardo Saban

Michael Siroky

Ursula Wesselman

Obstruction

Chair: Barry Kogan

William de Groat

Robert Levin

Linda Shortliffe

William Steers

Dana Weaver-Osterholtz

Robert Weiss
A Strategic Plan for Research 205

Group 3: 

Epithelium, Muscle, Nerve/Vascular, 

Connective tissue/Matrix

Epithelium

Chairs: Susan Keay, Tung-Tien Sun 

Anthony Atala

Philip Hanno

Stephen Hewitt

Edmund Lattime

Edward Messing

Vicki Ratner

Anthony Schaeffer

Ann Stapleton

Robert Weiss

Muscle

Chairs: George Christ, Harris Foster

James Ashton-Miller

John DeLancey

Ananias Diokno

Anna Herzog

Barry Kogan

James Lessard

Neil Resnick

Brenda Russell

Linda Shortliffe

Nerve/Vascular

Chairs: Toby Chai, Jeremy Tuttle

Michael Chancellor

William de Groat

Robert Levin

Ricardo Saban

Michael Siroky

William Steers

Ursula Wesselman

Connective Tissue/Matrix

Chair: Edward Macarak

Larry Baskin

Linda Brubaker

Jeanette Brown

Bradley Kropp

Monica Liebert

Peggy Norton

Michael Sacks

Dana Weaver-Osterholtz
206 OVERCOMING BLADDER DISEASE

Focus Groups:

Clinical Trials, Epidemiology, Pharmacology

Clinical Trials

Chairs: Linda Shortliffe, William Steers

James Ashton-Miller

Anthony Atala

Larry Baskin

Ananias Diokno

Harris Foster

Barry Kogan

Bradley Kropp

Edmund Lattime

Edward Messing

Peggy Norton

Vicki Ratner

Michael Sacks

Anthony Schaeffer

Linda Shortliffe

Michael Siroky

William Steers

Dana Weaver-Osterholtz

Robert Weiss

Epidemiology

Chairs: Jeanette Brown, Anna Herzog

John DeLancey

Philip Hanno

Susan Keay

Monica Liebert

Neil Resnick

Ann Stapleton 

Pharmacology

Chair: Robert Levin

Linda Brubaker

Toby Chai

Michael Chancellor

George Christ

William de Groat

Stephen Hewitt

James Lessard

Edward Macarak

Brenda Russell

Ricardo Saban

Tung-Tien Sun

Jeremy Tuttle

Ursula Wesselman
A Strategic Plan for Research 207

James Ashton-Miller, Ph.D.

Distinguished Research Scientist

Biomechanics Research Laboratory

University of Michigan

Ann Arbor, MI

Anthony Atala, M.D.

Associate Professor of Surgery

Division of Urology

Harvard/Children’s Hospital

Boston, MA

Larry Baskin, M.D.

Chief, Pediatric Urology

University of California-San Francisco

San Francisco, CA 

Lisa Begg, Dr.PH

Director of Research Programs

Office of Research on Women’s Health

National Institutes of Health

Bethesda, MD 

Frank Bellino, Ph.D.

Program Administrator

Endocrinology Branch

National Institute on Aging

National Institutes of Health

Bethesda, MD 

Carolyn Vogel Benson

Writer-Editor

Division of Kidney, Urologic, 

and Hematologic Diseases

National Institute of Diabetes and 

Digestive and Kidney Diseases

National Institutes of Health

Bethesda, MD 

Josephine P. Briggs, M.D.

Director

Division of Kidney, Urologic, 

and Hematologic Diseases

National Institute of Diabetes and 

Digestive and Kidney Diseases

National Institutes of Health

Bethesda, MD 

Jeanette S. Brown, M.D.

Professor

Department of Obstetrics, Gynecology, 

and Reproductive Sciences

Epidemiology and Biostatistics

Director, Women’s Continence Center

University of California, San Francisco

San Francisco, CA 

Linda Brubaker, M.D.

Professor and Fellowship Director

Department of Obstetrics and Gynecology

Loyola University Medical Center

Maywood, IL 

Toby Chai, M.D.

Assistant Professor

Division of Urology

University of Maryland

Baltimore, MD 

PARTICIPANTS
208 OVERCOMING BLADDER DISEASE

Jodi Chappell

American Urogynecologic Society

Manager, Congressional and Regulatory Affairs

Smith, Bucklin, and Associates, 

Health Care Practice Group

Washington, DC 

Michael B. Chancellor, M.D.

Professor

University of Pittsburgh 

Pittsburgh, PA 

George Christ, Ph.D.

Professor

Albert Einstein College of Medicine

Bronx, NY 

William C. de Groat, Ph.D.

Professor of Pharmacology

Department of Pharmacology

University of Pittsburgh School of Medicine

Pittsburgh, PA 

John O. DeLancey, M.D.

Norman F. Miller Professor

Department of Obstetrics and Gynecology

University of Michigan Medical Center

Ann Arbor, MI 

Ananias Diokno, M.D.

Chief, Department of Urology

William Beaumont Hospital

Royal Oak, MI 

Richard Farishian, Ph.D.

Deputy Director

Office of Scientific Program and Policy Analysis

National Institute of Diabetes and 

Digestive and Kidney Diseases

National Institutes of Health

Bethesda, MD 

Harris E. Foster, M.D.

Associate Professor of Surgery

Section of Urology

Yale University School of Medicine

New Haven, CT 

Cheryl Gartley

President and Founder

The Simon Foundation for Continence

Wilmette, DE 

Philip M. Hanno, M.D.

Division of Urology

University of Pennsylvania

Philadelphia, PA 

Mary M. Harris

Writer-Editor

Office of Communications and Public Liaison

National Institute of Diabetes and 

Digestive and Kidney Diseases

National Institutes of Health

Bethesda, MD 

Anna R. Herzog, Ph.D.

Senior Research Scientist

Institute for Social Research

University of Michigan

Ann Arbor, MI 

Stephen Hewitt, M.D., Ph.D.

Clinical Investigator

Laboratory of Pathology

National Cancer Institute

National Institutes of Health

Bethesda, MD 
A Strategic Plan for Research 209

Stephen P. Heyse, M.D., M.P.H.

Medical Officer

National Institute of Allergy and Infectious Diseases

National Institutes of Health

Bethesda, MD 

Susan Keay, M.D., Ph.D.

Associate Professor of Medicine

Department of Medicine

Division of Infectious Diseases

University of Maryland School of Medicine

Baltimore, MD 

Barry Kogan, M.D.

Chief, Division of Urology

Albany Medical College

Albany, NY 

Bradley Kropp, M.D.

Associate Professor of Urology

Department of Urology

University of Oklahoma Health Sciences Center

Oklahoma City, OK 

John W. Kusek, Ph.D.

Director, Urologic and Renal Clinical Trials Program

National Institute of Diabetes and 

Digestive and Kidney Diseases

National Institutes of Health

Bethesda, MD 

Edmund C. Lattime, Ph.D.

Associate Director

Cancer Institute of New Jersey

Professor of Surgery, Molecular Genetics, 

and Microbiology

UMDNJ-Robert Wood Johnson Medical School

New Brunswick, NJ 

James Lessard, Ph.D.

Professor

Division of Developmental Biology

Children’s Hospital Medical Center

Cincinnati, OH 

Robert M. Levin, Ph.D.

Director of Research

Office of Research Administration

Albany College of Medicine

Albany, NY 

Monica Liebert, Ph.D.

Director, Office of Research

American Urological Association, Inc.

Baltimore, MD 

Edward Macarak, Ph.D.

Professor

University of Pennsylvania

Philadelphia, PA 

John D. McConnell, M.D.

Professor and Chairman

Department of Urology

University of Texas Southwestern Medical Center

Dallas, TX 

Edward Messing, M.D.

Professor and Chairman

Department of Urology

University of Rochester Medical Center

Rochester, NY 
210 OVERCOMING BLADDER DISEASE

Peggy Norton, M.D.

Associate Professor

Department of Obstetrics and Gynecology

University of Utah School of Medicine

Salt Lake City, UT 

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

Director, Urology Program

Division of Kidney, Urologic, and Hematologic Diseases

National Institute of Diabetes and 

Digestive and Kidney Diseases

National Institutes of Health

Bethesda, MD 

Vicki Ratner, M.D.

President, Interstitial Cystitis Association

Rockville, MD 

Neil M. Resnick, M.D.

Professor and Chief

Division of Geriatric Medicine

Department of Medicine

University of Pittsburgh School of Medicine

Pittsburgh, PA 

Brenda Russell, Ph.D.

Professor

Department of Physiology and Biophysics

University of Illinois at Chicago

Chicago, IL 

Ricardo Saban, D.V.M., Ph.D.

Associate Professor

Department of Physiology

College of Medicine

University of Oklahoma

Oklahoma City, OK 

Michael Sacks, Ph.D.

Assistant Professor

Department of Bioengineering

University of Pittsburgh

Pittsburgh, PA 

Anthony J. Schaeffer, M.D.

Professor and Chair

Department of Urology

Northwestern University Medical School

Chicago, IL 

Linda Dairiki Shortliffe, M.D.

Chair, Department of Urology

Stanford University School of Medicine

Stanford, CA 

Michael B. Siroky, M.D.

Chief, Urology

Boston VA Medical Center

Boston, MA 

Debra Slade, M.A.

President

National Bladder Foundation

Ridgefield, CT 

Ann Stapleton, M.D.

Associate Professor of Medicine

University of Washington

Seattle, WA 

William D. Steers, M.D.

Chair, Department of Urology

University of Virginia

Charlottesville, VA 
A Strategic Plan for Research 211

Tung-Tien Sun, Ph.D.

Director

Department of Dermatology

New York University School of Medicine

New York, NY 

Jeremy B. Tuttle, Ph.D.

Professor

Department of Neuroscience

University of Virginia

Charlottesville, VA 

Dana Weaver-Osterholtz, M.D.

Clinical Associate Professor

University of Missouri

Columbia, MO 

Anne Weber, M.D.

Project Officer

National Institute on Deafness and Other

Communication Disorders

National Institutes of Health

Bethesda, MD 

Robert Weiss, M.D.

Professor and Chief

Section of Urology

Yale University School of Medicine

New Haven, CT 

Ursula Wesselman, M.D.

Associate Professor

Department of Neurology/Neurosurgery

Johns Hopkins University School of Medicine

Baltimore, MD 
A Strategic Plan for Research 213

INDEX

adhesin, 26, 124-125, 127, 130

aging (see also elderly), 1, 3, 5-6, 9-10, 12-13, 19, 31, 33, 37-39, 42-43, 47,

54-57, 61, 64, 85-90, 93-94, 96, 98, 122, 136, 148,

151, 155, 157, 168, 197, 207

Alaskan Natives, 139

American Indian(s), 135-136, 139, 165

animal models, 8, 15, 22, 38, 47, 53, 55, 77, 89, 111, 

126, 128, 130, 137, 148, 161, 166-168, 

190, 192

anoxia, 55

antibiotic(s), 23-24, 27-28, 67, 72, 74, 78-79, 82, 104, 114, 120, 

122-124, 130-131, 145

antibiotic resistance (see also resistance), 24, 131

antimicrobial resistance (see also resistance), 122, 125, 129, 131, 181

antiproliferative factor (APF), 106-110

apoptosis (see also cell death)

areflexia, 153

arrays (see also microarrays), 22, 43, 56, 96, 118, 129, 162, 

171-172, 192

Asian(s), Asian Americans, 68, 136, 165

attachment, 24, 124, 128

augmentation, 66-67, 71, 76, 188, 190

autoimmune, 58, 104-105

autologous cell transplantation, 44, 57

bacillus Calmette-Guerin (BCG), 107-108, 113, 167, 169

bacteremia, 120-122

bacterial invasion (see also invasion), 24

bacteriuria, 66, 69, 118-123, 126, 128, 130, 139, 181

bedwetting (see also enuresis), 65, 152, 164

benign prostatic hyperplasia (BPH), 10-11, 33-34, 43, 48, 85, 88, 

93-96, 106, 137, 155, 181

bioengineering, 6, 15, 76, 88, 131, 177, 187, 190-191, 210-211

biofilm(s), 124-125, 131

bioinformatics, 7, 14-15, 22, 31, 56, 172, 177, 188, 

191, 195-196

biomechanics, 9, 31, 41, 191, 207

biotechnology, 7, 15, 56, 99, 113, 129, 131, 177, 184, 

197-198

birth (see childbirth)

bladder dysfunction, 5, 10, 34, 36, 41, 47, 53, 63, 65, 67-69, 

76-78, 87, 89, 96-98, 106, 123, 134, 

138-141, 183-185

blood sugar (see also hyperglycemia), 123, 138-139, 144-145

blood supply, 9, 47-49, 51-52, 55, 72

blood vessels, 1, 7-9, 19, 32, 36, 41, 45, 47, 54, 57, 86, 95, 109, 

134-135, 138-139, 149, 161, 198

blood in urine (see also hematuria), 28, 174

bovine collagen, 44, 57

brain imaging, 9, 49, 58, 97

cancer, 1, 5-6, 9, 13-14, 21, 23-25, 27-29, 33, 43, 61, 85, 88, 91, 

99, 104, 110, 130, 151, 161-175, 179-181, 187-191, 197, 

203, 208-209

carcinogen(s), 21, 23, 28, 162, 165, 167, 169, 

carcinogenesis, 165-167

catheter(s), 5, 11-12, 28-29, 82, 117, 119-122, 131, 162, 165, 199

catheterization, 5, 28-29, 66-67, 74, 119-122, 124, 153

Caucasian(s), 149, 161-163, 165, 171

cell-cell interactions, 21, 97, 128, 161

cell death, 24-25, 42, 52, 55, 126, 128, 161, 170

cell growth, 8, 22, 24-25, 191, 194

cell signaling, 8, 31-32, 34-36, 43, 124, 128, 135, 148, 155, 161, 

165-166, 191, 193

ceramide pathway, 126

childbirth (see also vaginal delivery, pelvic floor, pelvic floor trauma),

12-13, 31, 33, 39, 54, 148-150, 158, 179

b

c

a
214 OVERCOMING BLADDER DISEASE

children, 9-12, 17, 19, 23, 25, 34, 39, 44, 61, 63-76, 78, 80-83, 90-91, 

93-94, 97, 100-101, 105, 115, 117-120, 135-136, 145, 150, 

152, 155-156, 164, 189, 207, 209

colonization, 23, 71, 121, 125-126, 128, 130

congenital, 6, 10, 24, 63-65, 67-68, 70, 80, 93-94, 187, 189-190, 197

collagen, 8, 31-34, 42, 44, 57, 71, 95, 100, 148-149, 192

connective tissue, 1, 8, 15, 19, 31-39, 42, 87, 97, 139, 192, 198, 205

cystectomy, 28, 164, 189

cystopathy, 137, 144

cystoscopy, 14, 28, 75, 104, 107-108, 110, 112, 149, 162, 169-170

cytokines, 31-32, 37, 126-128, 130, 165, 169, 193

cytotoxic necrotizing factor (CNF), 124, 128-129

diabetes, 1, 3, 5-7, 9, 12-13, 17, 19, 27, 31, 33, 39, 41, 43, 48, 

52-53, 55, 61, 64, 88, 106, 117-120, 123, 133-145, 148, 

152-153, 157, 179-180, 183, 197-198, 201, 203, 207-209

diabetic bladder, 1, 13, 52, 55, 134, 137, 141, 153, 180

differentiation, 8, 14, 21-22, 24-25, 36-37, 112, 141, 161, 191-193

dysfunctional voiding (see also voiding dysfunction), 10, 64-65, 68-69, 

79, 89, 152

ectopic ureters, 65, 75, 79

Escherichia coli, E. coli, 23-25, 121, 123-130

effector, 9, 41, 169

elastin, 31-34, 42

elderly (see also aging), 11-12, 17, 54, 61, 87-90, 96, 117, 119-120, 122,

136, 145, 149, 151-153, 156, 159, 161-163, 165,

170-171, 175

endoderm, 24, 35

end-stage bladder failure, 42-43, 97

enuresis (see also bedwetting), 63, 65, 68-70, 79, 149, 152

enzymes, 32, 37

eosinophils, 27

epidemiology, 1, 5-8, 13, 21-27, 32, 34-38, 43-44, 51, 77, 88-89, 95, 107,

109-110, 112, 127-128, 130, 134, 148, 162, 166-168, 172,

174, 191-193, 195, 198, 205

epigenetics, 86

epispadias, 70-71, 152

epithelium (urothelium), 1, 5-8, 13, 19, 32, 34-38, 43-44, 51, 77, 95, 107,

109-110, 112, 127-128, 130, 134, 148, 166-168,

172, 174, 191-193, 195, 198, 205

estrogen, 33, 54, 77, 89, 105, 123, 149-150

exfoliation, 24, 126-127

exstrophy, 1, 5, 10, 61, 64-65, 70-72, 76, 80, 152

female(s) (see also women), 13, 23, 32, 35-36, 48, 50, 54, 70-71, 74, 78,

87, 89-90, 98, 105, 117-118, 134, 149

fiber, 31, 33-34, 195

field effect, 14, 23, 161, 165

fibrosis, 34, 71, 73, 164

fimbria, fimbriae (see also pili), 24, 124-126, 128

FimH, 26, 124-125, 127, 130

Franklin, Benjamin, 1, 5, 199

frequency (see also urinary frequency), 10-11, 43, 48, 50, 64, 69, 93, 

103-107, 112-115, 123, 144-145, 152-153, 198

gene expression, 22, 34-38, 110, 125, 166, 168, 190, 192, 194-196

gene therapy, 8, 15, 44, 47-49, 53, 57, 134, 136, 141, 166, 177, 181, 

190-191, 194, 196

genomics, 7-8, 15, 34-38, 48-49, 52, 56, 96, 125, 127, 129, 148, 

166, 171, 175, 177, 187-188, 190-192, 194, 196-198

glomerulations, 104, 107, 114

glucose, 88, 124, 138-140, 144-145

glycocalyx, 22

glycosoaminoglycans (GAG), 22, 25

glycososphingolipids (GSL), 128

glycosuria, 139

glycosylation, 138

growth factor(s), 21, 25-26, 31-32, 35-36, 42, 47, 53, 77, 87-89, 95, 

98, 104-105, 107-110, 138, 140, 148-149, 161, 165, 

168-169, 191, 193, 194-195

growth-factor-binding protein, 109

growth-modulating factors, 22

d

e

f

g
A Strategic Plan for Research 215

hematuria (see also blood in urine), 170

hemolysin, 124, 128-129

high throughput, 22, 38, 172, 190

Hispanic, 136, 139, 165

Hispanic/Latino Americans, 139

hormone, hormonal, 31, 33, 37, 42-43, 51, 53-54, 70, 80-81, 89 98, 

112, 119, 148, 150-151, 190, 193

host self-defense, 24

host response, 124, 126, 128, 130

Hunner’s ulcers, 104, 107, 112

hydronephrosis, 43, 63, 66, 72, 77, 93-94, 97

hyperglycemia, 138-139

hyperreflexia, 152-153

hypertension, 55, 66-67, 122, 163

immune response(s), 31-32, 108, 117, 126-127, 165-167, 169, 193

immunohistochemistry, 34, 36

immunowalking, 166-167

imperforate anus, 10, 64-65, 72, 79

incontinence (see also urinary incontinence), 1, 5, 9-10, 12-13, 31, 33-36,

38-39, 41-44, 47-49, 53-54, 57, 59, 61, 64-65, 67-69, 75, 

78-79, 85-91, 93-94, 122, 133, 135, 138-141, 147-159, 

164, 179-181, 187-189, 191, 204

infection (see also urinary tract infection), 1, 7, 9, 11-12, 19, 21, 

23-25, 28-29, 41-43, 58, 65-67, 69-70, 74-76, 82, 86, 91, 93,

100, 103-104, 111, 114, 117-131, 134, 144-145, 152, 164, 

180-181, 187-188, 204

inflammation, 7, 12, 21, 27, 51, 53, 67, 75, 91, 104-108, 114, 117-119,

123-124, 126-127, 129, 131, 180-181, 187, 204

inflammatory response, 109, 126, 128

infrastructure, 6-8, 15-16, 27, 90, 98, 131, 136-137, 142, 155-156, 162,

166, 173, 180, 184-185, 188, 196-197

internalization, 125-127

interstitial cystitis (IC), 1, 5, 9, 11, 21-23, 25-26, 31, 33, 39, 43, 47, 

53, 61, 88, 99, 103-115, 131, 135, 179, 181, 

191, 201, 204, 209

invasion, 23-24, 118, 127, 165, 171

ischemia, 51-52, 55-56, 76, 96

Kegel exercises, 59, 158-159, 181

kidney, 0-1, 3, 5-6, 9-12, 17, 23, 27, 34, 39, 41-43, 59, 63-69, 73-76, 

81-83, 88, 93-94, 99-101, 103, 106, 117-118, 120-125, 130, 

133, 139, 167, 179, 181, 183, 197, 201, 207-209

kidney infection (see also pyelonephritis), 23, 82, 118, 121-122, 125

kidney transplant (see also transplant), 100-101, 124

laser capture microdissection (LCM), 110, 172, 191, 195

male (see also men), 13, 63-64, 67, 70-71, 75, 78, 90, 94, 98, 100, 

106, 118, 134, 149, 170

markers, 11, 13-14, 21-22, 24, 39, 52, 77-79, 86, 89, 96, 103, 107-113,

134, 141, 170, 172, 174-175, 180-181, 188, 191, 193-194

mast cells, 32, 51, 105, 108, 127

matrix, 31-32, 34-38, 44, 95-96, 170, 195, 198, 205

men (see also male), 5-6, 10-12, 23, 33-34, 51, 55, 85-86, 88, 90-91, 

93-94, 96, 103-106, 117-119, 121-123, 133-134, 

137-141, 144, 149, 151, 153, 161-165, 171, 175

menopause, 33, 150-151, 154-155

mesenchymal signals, 22

mesenchyme, 23-24, 35-36, 38, 193

Mexican American(s), 135, 139

microarray(s) (see also arrays), 7, 15, 21-22, 27, 52, 56, 77, 89, 110, 

129, 162, 191, 193, 195-196

microbial dynamics, 125

microvascular disease, 138-139

micturition, 15, 44, 47-50, 53-54, 198

models, modeling, 8, 13, 15, 22, 38, 47, 49, 53-55, 77-78, 85-86, 88-90,

111-112, 126, 128-130, 134, 137, 140, 148, 161, 

166-168, 170, 173, 180, 190, 192, 194

multiple sclerosis, 5, 13, 19, 41, 43, 47-48, 58, 61, 93-94, 117, 119, 

148, 152-153, 198

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216 OVERCOMING BLADDER DISEASE

muscle, 1, 8-9, 19, 26, 28, 31-38, 41-45, 50-53, 55, 57-59, 68-69, 71, 

73, 76-77, 86-91, 95, 97, 100-101, 115, 122-123, 134, 137, 

148, 151-155, 158-159, 164, 170, 174, 181, 189, 191-195, 205

muscle dysfunction, 43

muscle failure, 41-43

myelodysplasia (see also spina bifida), 10, 64-65, 78

myelomeningocele, 76, 93-94, 152

nephropathy, 66, 74, 139-140, 143

nerve(s), 1, 7-9, 9, 21, 26, 32, 36, 42-43, 45, 47-49, 51-58, 63, 65-66, 74,

80, 86, 88, 105, 108, 111, 113, 115, 122, 133-134, 135, 137-139,

140, 144-145, 148, 153-154, 158, 164, 194, 198, 205

neurogenic, neurogenic bladder, 1, 7, 10, 12, 35-36, 47, 53, 58-59, 63, 65,

69, 85, 104-105, 107, 111, 162, 181

neuromodulation, 9, 45, 89

neuropathic, neuropathic bladder, 33, 97, 141, 144, 152

neuropathy, 12, 55, 133, 137-141, 144-145, 153

neurostimulation, 115

neurotransmitters, 26, 53, 111

neurotrophic, 47, 49, 51-52, 55, 111, 141

nitric oxide, 23, 26, 56, 76, 107, 111, 140

nighttime voiding (see also nocturia), 10, 59, 69, 88, 93, 152

nocturia (see also nighttime voiding), 10, 59, 69, 88, 90, 93, 152, 164

obesity, 135-136, 139, 149, 151, 155

obstruction, 1, 5, 7, 9-11, 31, 33-37, 43, 49, 53, 56, 61, 63-67, 69, 72, 75,

79, 85-86, 88, 93-99, 121, 123, 149, 151, 167, 179-181, 188,

198, 204

oncogenes, 22, 24, 168, 191

Parkinson’s disease, 5, 11, 13, 35-36, 41, 48, 64, 103, 105, 148, 152-153

Parkinsonism, 43

pathogenicity islands, 125, 128-129

pelvic floor, 1, 15, 32-33, 37-38, 43, 50, 59, 69, 71, 77, 87, 90, 109, 135,

150, 154-156, 158-159, 187-190, 192-198

pelvic organ prolapse, 31, 33, 38-39, 89, 135-136, 156-157

permeability, 21, 25-27, 104-105, 108

P fimbriae, 124, 126, 128

pharmacology, 1, 9, 15, 41, 89, 155, 187, 198, 201, 206, 208

pili, 23-25, 124-128, 130

polymerase chain reaction (PCR), 175, 190

posterior urethral valves (PUV), 1, 10, 61, 63-65, 67-68, 76, 79, 

82, 93-95, 100

post-prostatectomy incontinence, 1, 34, 88, 90-91

pregnancy, 12-13, 39, 80-81, 100, 118, 120-122

probiotics, 130

prostate, 22, 24, 28, 33-34, 43, 73, 75, 85-86, 88, 90-91, 93-94, 96, 99,

106, 119, 122-123, 134, 140, 149, 151, 157, 166, 171, 173, 190

prostate cancer, 33, 43, 85, 88, 151, 171, 173, 190

prostatectomy, 88, 90, 151, 153, 155

prostatitis, 88, 103, 105-106, 119, 135

proteomics, 7-8, 15, 22, 34-38, 48-49, 52, 56, 110, 127, 129, 148, 162,

166-167, 171, 175, 177, 188, 191-192

prune belly syndrome, 10, 64-65, 72-74, 79

pyelonephritis (see also kidney infection), 12, 23, 67, 74, 121-123

P53, 167, 175

quorum sensing, 125

receptors, 15, 23-26, 35-37, 53, 77, 89, 111-112, 124, 126-128, 

130, 177, 193

reflux (see also vesicoureteral reflux), 1, 9-10, 23-25, 27, 44, 59, 61, 

63-67, 69, 71-74, 76, 78, 81-83, 94, 97, 100, 121, 187-188

regeneration, 8-9, 34-36, 42, 47, 49, 51, 55, 135, 188, 191, 193, 

195-196, 198

renal scarring (see also hypertension), 66-67, 83

reperfusion, 51-52, 55, 96

repositories, 22, 99, 143

resistance (see also antibiotic and antimicrobial), 24, 97, 122, 125, 

128-129, 131, 135, 137, 181

reservoirs, 125-127, 129, 164, 188

retention (see also urinary retention), 5, 9, 12, 41-43, 58, 69, 74, 93, 133,

137-138, 151, 153, 164

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A Strategic Plan for Research 217

serotonin, 51, 53

smoking, 55, 145, 164-165, 167, 169, 171, 175

specimen banks, 99, 131, 142, 155, 157, 171-172, 184-185, 197

sphincter, 19, 33, 37, 41-44, 48, 50, 57, 68-69, 71-72, 74-75, 77, 85-88,

91, 138-139, 151-152, 154, 192

spina bifida (see also myelodysplasia), 5, 10, 63-66, 78, 93-94, 120, 152

spinal cord injury, 5, 13, 39, 43, 47-49, 53, 93-94, 121, 148, 152-153

stem cells, 37, 42, 141, 177, 187-191, 193-194, 196-198

stress incontinence, 35-36, 44, 57, 138-139, 148-150, 154, 157, 164

stress response, 125

stroke, 6, 19, 41, 43, 50-51, 57, 144, 152

Tamm-Horsfall, 25

tissue banks, 16, 22, 27, 78, 90, 98-99, 113, 143, 162, 171-172

tissue engineering, 8, 15, 44, 49, 53, 57, 77, 89, 177, 187-189, 

191, 193-194, 196-198

tissue recombination, 24, 35

toxins, 21-23, 25, 28, 52, 124, 161, 175

transduction, 41, 107

transgenic(s), 22, 26-27, 47, 49, 53, 166, 168

transplant (see also kidney transplant), 5, 26, 47, 53, 100-101, 124

trigone, 24, 75

tumor-host interaction, 169

type 1-fimbriated (piliated), 23-25, 124, 127-128

ureterocele, 74-75, 79

ureterostomy, 101

urethra, 15, 19, 24, 33-34, 42, 44-45, 48, 57, 64, 67, 70-75, 82, 85-87, 

89, 91, 95, 100-101, 134, 137, 141, 148-149, 151, 154, 159, 

164, 184-185, 187-191, 193-196

urge incontinence, 10, 44, 47, 53, 138, 149, 151-154

urgency, 10-11, 43, 50, 64, 68, 93, 103, 105, 107, 112-115, 144-145, 

151-153, 198

urinary diversion, 28, 72, 74, 97, 163-164, 175

urinary frequency (see also frequency), 93, 105, 114, 144-145

urinary incontinence (see also incontinence), 1, 5, 9, 12-13, 33, 38-39, 44, 

48-49, 54, 57, 61, 65, 67-69, 78-79, 85-90, 93-94,

135, 138-141, 147-148, 150-157, 159, 187-189

urinary retention (see also retention), 5, 9, 12, 58, 69, 93, 137-138, 151, 

153, 164

urinary tract infection (UTI) (see also infection), 1, 11-12, 23-24, 58, 65-66,

69-70, 75-76, 82, 86, 93, 100, 103-104, 119,

125, 127, 134, 144-145, 152, 164, 181

urinary urgency (see also urgency), 11, 68, 103, 107, 113, 115, 198

uropathogens, uropathogenic, 22, 25, 120-121, 124-130

uroplakin(s), 24-26, 77, 89, 168

urothelium (see also epithelium), 1, 13, 21-27, 35-36, 88-89, 95, 162, 

165, 167-168

vaccine(s), 12, 24, 127, 130, 168

vaginal delivery (see also childbirth), 33, 42-43, 150, 154-155, 158

valves (see also vesicoureteral valves), 1, 10, 61, 63-65, 67-68, 76, 79, 82,

93-95, 100-101

vesicoureteral reflux (see also reflux), 1, 9-10, 23-25, 27, 44, 61, 63-67, 69,

71, 73, 76, 78, 81-82, 94, 121, 188

virulence factors, 124-126, 128

voiding dysfunction (see also dysfunctional voiding), 11, 41-43, 51, 54, 

68-69, 93-94, 97, 152-153, 181

vulvodynia, 105, 109, 114

women (see also female), 5-6, 10-13, 23, 35, 38-39, 51, 54-55, 61, 

85-89, 91, 96, 103-106, 113, 117-120, 122-125,

130-131, 133-136, 138-141, 147, 149-151, 

154-155, 158-159, 161-165, 171, 175, 184, 207

workforce, 16, 27, 90, 98, 113, 131, 142, 155, 184, 196

xenograft, 167

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Front Cover: Drawings by Leonardo daVinci (Photo Credit: Investigative Urology, 1965, Vol. 3: 99-109.)