Summary of the National Institutes of Arthritis, Diabetes, Digestive and Kidney Diseases Conference on Urolithiasis: State of the Art and Future Research Needs

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Vol. 153,4-9,January 1995 Printed in V.S.A.

JOURNAL OF UROLOGY

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State of the Art Article -

SUMMARY OF THE NATIONAL INSTITUTES OF ARTHRITIS7DLABETES, DIGESTIVE AND KIDNEY DISEASES CONFERENCE ON UROLITHIASIS: STATE OF THE ART AND FUTURE RESEARCH NEEDS MARTIN I. RESNICK*

AND

LESTER PERSKY

From the Department of Urology, Case Western Reserve University School of Medicine, Cleveland, Ohio

KEY WORDS:urinary calculi; kidney calculi; consensus development conferences, NIH; National Institutes of Health

Many facts and statistics regarding urolithiasis are well known. Approximately two-thirds of patients with urolithiasis have calcium oxalatekalcium phosphate stones, and these calculi occur more commonly in men and white patients. The lifetime chance of an individual having a stone is approximately 10 to 15% and if that individual is untreated the chance of recurrence is nearly 60% within approximately 10 years. Many treatment programs include the use of various medications that have been effective in either eliminating or decreasing the incidence of stone recurrence. Recent treatment developments in percutaneous techniques and extracorporeal shock wave lithotripsy (ESWLP) have lessened the morbidity associated with open stone surgery and represent a major advance in management of this common problem. We also know that many stone patients exhibit low urinary volumes and/or hypercalciuria. Other metabolic disorders are also well recognized, including hyperuricosuria, hyperoxaluria and hypocitraturia. Identification of these disorders is relatively easy and treatment programs, including dietary modification in addition to pharmacological agents, have been shown to be effective. Prevention is recognized as being preferable to treatment (for example ESWL) and recurrence. With this background, why was another conference on urolithiasis needed? A National Institutes of Health (NIH) sponsored consensus conference on prevention and treatment of kidney stones was held March 28 to 30,1988 and many of these points were emphasized. Additionally, stone disease is not fatal, most patients eventually do well, incapacitation is usually short-lived and most return to their normal lifestyles. Although most individuals with kidney calculi pass the stone, often hospitalization is required. For individuals requiring intervention various procedures are performed, most in the operating room and most requiring anesthesia with use of ancillary medical personnel. Although patients as a group do well, there is significant expense associated with this treatment, time lost from work, need for recuperation and attendant morbidity. Additionally, after appropriate treatment most of these patients are not evaluated and resume their previous life-style, and many may have a recurrent stone. Another problem in the clinical arena relates to medical management itself. Although various pharmacological agents are available and many have been proved to be efficacious, treatment failures occur. Long-term followup is required to determine that preexisting stones do not grow and that new stones do not form. Efforts are needed to assess medical therapy better and also to develop new agents that can be used either alone or in combination to prevent stone formation more effectively in those so predisposed. Many investigations in the past have attempted to identify * Re uests for reprints: De artment of Urology, University Hospitals of%leveland, 11100 Eucld Ave., Cleveland, Ohio 44106. fDornier Medical Systems, Inc., Marietta, Georgia.

causes of stone formation. However, it is most evident that the processes involved remain unknown. Remarks to this point have addressed inadequacies in what is already known but it must be noted that much remains unknown. Various biochemical and metabolic studies have attempted to differentiate the stone former from the nonstone former and, although trends exist, no clear or distinct differentiation of the 2 groups can be made consistently. For example, there are patients who have no abnormalities but multiple stones form as well as those who have many abnormalities that should but do not predispose them to stone formation. Significant efforts are required in answering the basic question as to why individuals have stones or, in another way, why they do not. A natural extension of these studies would be to identify those characteristics that would allow the identification of one predisposed to stone formation before the actual event. Ideally this would result in the appropriate use of prophylactic or preventive measures in select populations, which could help t o alleviate this debilitating disorder. Many areas of investigation have entered the realm of molecular biology with identification of specific genes and gene products that are associated with specific diseases. Investigative efforts in stone disease in this realm are in their infancy but major efforts will be required because it is likely that the answer to stone disease will be found by investigations of this type. The purpose of this current conference was not only to outline the state of the art but also to identify clearly the directions in which we want opportunities for research efforts. Respected investigators with laboratory and clinical experience expressed their views as to what is unknown (see Appendix). They also expressed their views as to what is needed to answer these questions. Past experiences were reviewed and it is hoped that we can learn from them so that future efforts will be enhanced. T H E SPECIAL CENTERS FOR ORIENTED RESEARCH (SCOR) PROGRAM

Dr. Lynwood Smith (Mayo Clinic, Rochester, Minnesota) reviewed the SCOR program on urolithiasis, which was developed following the in-depth study of research needs in nephrology and urology funded by the NIH under the leadership of Drs. Carl Gottschalk and William Lassiter. The study began in 1974 with a final report being presented in 1976. The committee on urolithiasis included Doctor Smith (Chair), and Drs. William Boyce, Birdwell Finlayson (deceased), John Meyer and Charles Y. C. Pak. In addition, Drs. Claude Arnaud, Frank Knox, Robert Pitts and Hibbard Williams served as consultants to the group and Drs. Jay Gillenwater, Thomas Stamey and Lassiter were representatives from the supervising committee to the group. During that in-depth review, needs for research in urolithiasis were identified and the development of SCOR in Urolithiasis by 4

UROLITHIASIS

the NIH resulted. Through the peer review process, 5 SCOR were established: Chicago, Illinois (Dr. F. C. Coe), Dallas, Texas (Doctor Pak), Gainesville, Florida (Doctor Finlayson), New Haven, Connecticut (Dr. Howard Rasmussen) and Rochester, Minnesota (Doctor Smith). The funding for these programs was for 5 years (1977through 1982). For this review, it was not possible to obtain a list of all publications that were produced by each of the centers, although it was clear that all were productive through the 5-year period. The center at Mayo Clinic published 47 peer reviewed articles, and 46 symposia contributions and chapters during this period. They had 7 articles in collaboration with 3 other SCOR and did studies with all 4 SCOR. Productivity of the other 4 SCOR was also high with the development of multiple programs involving various disciplines. The SCOR were successful in addressing needs but also in identifymg new areas of activity. New investigators in various disciplines were recruited to assist in clinical and basic stone research. Currently, 3 of the original SCOR continue to have active NIH funding in urolithiasis through program projects (University of Florida, University of Texas Southwestern and University of Chicago). 1988 CONSENSUS CONFERENCE

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tance has a role in these conditions. In some cases the specific inherited defect is identified and much is known but in others knowledge is limited beyond the fact that the condition appears to be inherited. For instance, in the conditions of cystinuria and renal tubular acidosis the defects are identified but little or no studies have been conducted regarding the genetics. This also is true in the diseases related to purine metabolism, including the Lesch-Nyhan syndrome, xanthinuria and 2,8-dihydroxyadeninuria.In the syndrome of primary hyperoxaluria the specific enzymatic defects are defined, and in some patients with type 1 primary hyperoxaluria it has been shown that the primary defect is one of mistargeting, with the enzyme located in the mitochondria instead of the peroxisome. In the syndrome of idiopathic calcium oxalate urolithiasis, inheritance appears to be autosomal dominant and with at least 4 abnormalities, including idiopathic hypercalciuria, absorptive hypercalciuria, hyperoxaluria and renal tubular defects, there is strong evidence that the associated abnormalities leading to stone formation are familial. For instance, 46 of 86 patients (60.5%) with idiopathic calcium oxalate urolithiasis have a family history of urolithiasis, and this was present in first degree relatives in more than 50% of the patients. To date, little work has been done to define the underlying abnormalities with intestinal and renal transport, and metabolism that lead to stone formation. Significant efforts must be directed into this most common syndrome in terms of defining the pathophysiology and, more specifically,the genetics of the conditions that fall within this heterogeneous syndrome.

Doctor Coe reviewed the NIH Consensus Development Conference on treatment of kidney stones held in Bethesda, Maryland from March 28 to 30, 1988. The Consensus Conference emphasized ESWL and stone pathogenesis with emphasis on basic and clinical research. The main issues for basic research were inhibitors, genetics of idiopathic hypercalciuria, cell crystal interactions with their regulation and effects, creation of new agents for oxalate reduction, and PATIENT CARE inhibition of parathormone and calcitriol actions. Clinical Problems related to patient care were addressed by Drs. research on stones concerned pathogenesis of human idiopathic hypercalciuria, bone disease in idiopathic hypercalci- Joseph Segura (Mayo Clinic, Rochester, Minnesota) and uria, identification of patients at risk before the initial stone Jacob Lemann, Jr. (Medical College of Wisconsin, Milwauand optimal duration of treatment, that is can it be safely kee, Wisconsin). The treatment of surgical stones remains technically based and focused on shock wave instrumentastopped with time. Genetic factors mainly concerned idiotion. The only factors that might change with time are ecopathic hypercalciuria, and metabolic studies addressed nomic. Currently, ESWL remains the more expensive option. idiopathic hypercalciuria and associated bone disease. InhibVarious technological innovations will continue to be develitors and promoters, including Tamm-Horsfall protein, oped for intracorporeal lithotripsy but these are unlikely to nephrocalcin and uropontin, were considered excellent areas change the thrust of the management of surgical stones. for research efforts, and discussions included nutritional and Research into the bioeffects of ESWL is important and should epidemiological factors. continue, particularly into what long-term effects may occur. For ESWL the Consensus Conference emphasized the im- This need was emphasized at the 1988 Consensus Conferportance of long-term injury, effects of ultrasound on renal ence but unfortunately progress has been slow and funding tissue, development of the ideal test for kidney function after for research efforts has been limited. The development of ESWL, creation of an animal model of stones to use in eval- ESWL and percutaneous lithotripsy led to the erroneous uating ESWL and whether ESWL decreased or worsened belief that the stone problem had been solved. Lithotripsy subsequent stone formation. does not stop recurrence and it is obviously not the final answer. EPIDEMIOLOGY OF UROLITHIASIS Information is currently lacking with respect to a number of other important clinical issues. For instance the proportion Doctor Smith addressed epidemiology of urolithiasisprevalence of the disease, how it has changed and benefits of of patients in the total stone-forming population who have therapy. In the United States 60 to 70% of stones from the only a single stone episode during the lifetime, as well as the urinary tract contain calcium oxalate as the principal crystal, characteristics of patients destined to have recurrent stones often mixed with small amounts of calcium phosphate (apa- and factors that predict the frequency of recurrence remain tite). Other crystalline components include magnesium am- unknown. Further studies are needed to define the genetic, monium phosphate (9to lo%), calcium phosphate or apatite metabolic and nutritional factors that predict stone recur(9%), uric acid (10%) and cystine (less than 1%). Based rence. With respect to calcium containing stones, information on multiple population studies, 5 to 15% of our population is needed to determine if there are differences among pawill have symptomatic stone disease by the age of 70 years, tients with pure calcium oxalate stones compared to those with the problem being twice as common in men compared with with mixed calcium oxalatdapatite, pure apatite or pure women. Worldwide, the prevalence of urolithiasis in men by brushite stones. Knowledge is required to determine the minthe age of 70 years varies from approximately 4% in England imum set of laboratory studies that should be obtained for to 20% in Saudi Arabia. Medical conditions that can be com- patients with the first stone. Additional collaborative treatment trials are needed in plicated by the formation of a stone within the urinary tract include cystinuria, renal tubular acidosis, some forms of uric carefully defined subsets of patients characterized with reacid lithiasis, primary hyperoxaluria and the syndrome of spect to stone composition, clinical characteristics (including idiopathic calcium urolithiasis. It is probable that inheri- family history of stones), dietary habits, and urine and blood

6

UROLITHIASIS

composition.Studies are also needed to determine the benefit epithelial cells from stone-forming kidneys produce defective of treatment following ESWL when there are residual stone or abnormal crystallization inhibitors, or promote crystallifragments in an effort to prevent regrowth as well as the zation and crystal retention? What are the reasons for these formation of new calculi. With respect to struvite (infection) differences? Do the membranes of epithelial cells lining the stones, the development of effective new and nontoxic urease gut and/or renal tubules have abnormal oxalate transport? inhibitors is needed together with the continuing develop- What are the reasons for such abnormal transport? Crystal-tissue interaction. What are the molecular events ment of antibacterial drugs. Collaborative treatment trials of new sulfhydryl exchange drugs are required to improve the at crystal tissue interface? What are the mechanisms intreatment of cystinurina and cystine stones, and further volved in crystal retention? Can crystal retention be averted? studies should be conducted to determine the most effective What is the speclscity of crystal-molecular interactions? What is the structure and role in crystal formation and retention? treatments to prevent recurrent uric acid calculi. Does renal injury of nephrolithiasis result in the production of abnormal crystallization modulators? BASIC RESEARCH ESWL. What are the long-term effects of repetitive ESWL Drs. Neil Mandel (Medical College of Wisconsin, Milwau- on renal mass, structure and function? What is the associakee, Wisconsin) and Saeed Khan (University of Florida, tion between injury caused by ESWL, and the formation and Gainesville, Florida) addressed the state of the art of basic retention of crystals in kidneys? What are the possible effects research. The 1988 Consensus Conference on the prevention of endothelium protective agents on ESWL induced injury to and treatment of urolithiasis defined specific areas for future the kidney? What are the mechanisms involved in stone basic research in urolithiasis. These directives focused on fragmentation and tissue injury? Is there an association becrystal formation and retention, and the role of the renal cell; tween ESWL of the kidneys and stone recurrence? Can preinhibitors and promoters of crystal formation and growth; treatment with free radical scavengers and vasodilators deoxalate synthesis, absorption and transport; molecular bio- crease the injury caused by the shock waves? Does ESWL chemistry and regulation of ion transporters; enzyme and affect the urinary crystallization inhibitory potential? receptor regulation of 1,25-dihydroxy-vitaminD synthesis; Macromolecules and inhibitors. Will more proteins be isocell and tissue injury, and the physics of ESWL using animal lated from urine or kidney cells that show calcium oxalate models, and probes and therapeutic protocols in genetic id- crystal growth or aggregation inhibition? Is there a sequence iopathic nephrolithiasis. or structural homology related to that inhibition? Although Review of stone research literature from 1983 to 1993 molecular weights, sequencing and structural information indicates that these directives continue to be the most focal are available on known macromolecular inhibitors, how do issues in kidney stone research. Major advances in stone the macromolecular inhibitors interact with crystals at the research since the 1988 Consensus Conference appear t o molecular level? How and why are the macromolecular inhave been in several areas, including crystal retention and hibitors expressed, and how is the process regulated? Are the role of the renal cell in stone maturation, the identifica- macromolecular inhibitors always present in human urine tion and characterization of new crystal and stone growth and are they structurally or compositionally modified in inhibitor macromolecules, a better understanding of how stone formers? Are the structural and compositional variasome urinary macromolecules possess crystal growth inhibi- tions of macromolecules under genetic control and can they tor and promoter activities, the identification of specific ge- be regulated? netically based liver enzyme defects that are correlated with Renal tubular function and regulation. Which enzymes are primary hyperoxaluria, an increased level of understanding involved in the synthesis and regulation of 1,25-dihydroxyof the production and regulation of 1,25-dihydroxyy-vitamin vitamin D and parathormone? How do the receptors for 1,25D3, the-use of animal models in defining the pathophysiology dihydrow-vitamin D and parathormone function. What are of cell injury following ESWL, and a better definition of the the-identity, character and molecular function of the vitamin correlation among cell injury, shock voltage and number of D dependent calcium binding protein in the intestine and the shocks. vitamin D independent calcium binding protein? What is the There must be an increased emphasis on the molecular molecular basis of renal tubular transport of calcium? What aspects of urolithiasis, especially in the areas of stone growth is the structure and action of calcium transport protein? Are and the role of the renal cell, expression and action of inhibthere mild defects in the enzymes that metabolize glyoxylate itory urinary macromolecules, and synthesis, as well as that might contribute to endogenous oxalate and mild hypertransport and regulation of oxalate, phosphate, citrate and oxaluria? Are they potential sites for drug or gene therapy? Is salient cations. Recent observations on the genetic basis of it possible to define better the calcium and oxalate intraluprimary hyperoxaluria with defined enzyme defects high- minal concentrations in normal subjects and stone formers? light the importance of defining any genetic basis for idioCan we define the calcium and oxalate transport mechapathic nephrolithiasis. Finally, many of the ongoing and pronisms? Is there a cellular oxalate transport abnormality in posed studies on urolithiasis might benefit from an expanded calcium oxalate stone formers? Is it an inheritable defect? use of molecular biological techniques as research issues Using new and more accurate oxalate determinations, are become more molecularly and genetically oriented. Further there abnormalities in renal oxalate clearance rates in studies are required on crystal-cell interaction. In vitro studstone formers? What cells are involved and how are they ies have demonstrated that cellular membranes and their different? What is the importance of molecular events on lipid components are capable of nucleating crystals of cal- expression of oncogenes, such as c-fos, c-myc or c-jun? What cium oxalate and calcium phosphate. Crystal retention is the importance of inflammation and lipid peroxidation within the nephron is essential for the establishment of the in response to the presence of crystals? What is the imporstone nidus, and there is mounting evidence that crystal tance of crystal endocytosis and stimulation of deoxyriboretention is accomplished by an increase in crystal mass nucleic acid synthesis? through aggregation and by crystal attachment to the injured epithelium. FUTURE BASIC RESEARCH NEEDS

STATE OF THE ART CLINICAL RESEARCH (MEDICAL AND SURGICAL)

The role of renal tubular cells in nephrolithiasis. What are the differences in epithelial cellular structure and function between patients who do and do not have stones? Do the

Doctor Pak reviewed clinical research activities. Overall, meaningful progress has been made in clinical research but some areas of investigation with promising leads require

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further investigation, and certain areas of neglect must be explored. Much support is required for clinically oriented studies directed at characterizing stone patients and assessing treatment programs. Areas of active investigation or progress include improved understanding of idiopathic hypercalciuria (early studies suggest abnormality in the 3'-region of the vitamin D receptor gene for vitamin D dependent form), calcium sparing action of potassium salts, ability of new diphosphonates to correct immobilization hypercalciuria, stone-forming risk of calcium supplementation (the finding that the risk is attentuated by intestinal adaptation in normal subjects), oxalylcoenzyme A decarboxylase gene (it has been cloned, sequenced and expressed in experimental animals), bucillamine in cystinuria (bioavailability studies suggest improved hypocystinuric action over tiopronin), nephrocalcin (an assay for this important inhibitor has been established), pathogenesis of hypocitraturia (primary intestinal hypocitraturia does not exist but the possibility of renal hypocitraturia is being explored by attempted cloning of the sodium citrate co-transporter gene), a randomized trial with potassium citrate (efficacy in stone disease has now been established and a randomized trial with potassium magnesium citrate is ongoing), the role of medical treatment lithotripsy (a retrospective study suggests a major role for medical treatment) and shock wave induced renal injury. Areas needing continuing and expanding investigation include further delineation of the molecular defect in absorptive hypercalciuria, clinical application of oxalyl-coenzyme A decarboxylase gene, initiation of randomized trial with bucillamine, continued molecular biology of sodium citrate cotransporter gene, completion of randomized trial with potassium magnesium citrate, stone forming risk of calcium supplements in patients with absorptive hypercalciuria, randomized trial with medical treatment after lithotripsy (to document findings from a retrospective study) and further needs in ESWL (prospective randomized trial on renal damage, attempted medical amelioration of steinstrasse and residual stones). Areas of neglect requiring attention include clinical application of macromolecular inhibitors, renal handling of oxalate, vitamin D antagonists, safe urease inhibitors, inhibitors of oxalate synthesis, chemolytic agents for stone removal, safer analogues of thiazide, subclinical bone disease in hypercalciuria and molecular biology of cystinuria and renal tubular acidosis. ECONOMICS

The economic impact of urolithiasis was addressed by Dr. Ian Thompson (BrookeArmy Medical Center, Fort San Houston, San Antonio, Texas). Estimates of the incidence of stone disease in the United States population varied from 0.36 to 10/1,000 hospital admissions and from 6.87 to 20.8/10,000 person-years. It has been estimated that approximately 5%of United States women and 12% of United States men will have at least 1 episode during their lifetimes. The rates of hospital discharge for stone disease have been estimated as 140/100,000 of the population but as many as 70% of the patients will not require hospitalization. The peak incidence occurs in the 15 to 44-year age group and the hospital stay increases with age. Recurrence rates increase with followup, with 1, 5 and 10-year recurrence rates being 13.7%,34.8% and 52%, respectively. The Agency for Health Care Policy and Research in the Hospital Cost and Utilization Project polled 1,005 hospitals encompassing 715,386 discharges. Stone disease accounted for 1.9% of hospital discharges and the cost for the average stay of 3 days ranged from $2,582 for ureteral stones to $3,738 for renal stones. A cost calculation for annual cost of stone disease in the United States was performed. The United States population of 1992 was estimated as

252,688,000. To correct for cost increases since 1984, a 9% inflation factor was used (a somewhat conservative estimate). The median income for a single consumer of $22,838 per year was used. For 140 urolithiasis admissions per 100,000 population the total number of admissions for urolithiasis was 353,780 and the nonhospitalized stone episodes totaled 873,694. The cost of evaluation, including excretory urogram, urinalysis, urine culture and serum electrolytes, was $440 (estimate). Therefore, the total cost was $155,663,200. Hospital charges (from Agency for Health Care Policy and Research data for an average stay of 3 days with an average daily charge of $800) was $848,072,000. The cost of professional services obtained from the CHAMPUS data base is shown in table 1. Indirect costs must also be considered. If it is assumed that approximately 300,000 patients between 15 and 64 years old are hospitalized for 3 days, the lost wages during hospitalization would be $84,500,000 and during a 2-day recovery this figure would be $56,300,000. If another 70% of patients are not hospitalized and there is a 2-day loss of wages for care and evaluation, the total cost would be $358,025,000 (evaluation) and $128,500,000 (wages). The final costs for the care of patients with urolithiasis in the United States for 1993 are shown in table 2. These preliminary investigations emphasize several points but also demonstrate how little is known regarding the epidemiology and cost of urolithiasis in the United States. It is well known that stone disease will affect a significant number of patients in this country, and the expense of treatment includes evaluation, treatment, lost wages and other costs. Methods of decreasing the expense of the disease include prevention of stone disease and a more cost-effective use of existing therapeutic modalities. The cost-effectiveness of these methods remains to be evaluated and further investigations are needed. FUNDING

Dr. Glenn Preminger (Duke University, Durham, North Carolina) presented a review of funding for urolithiasis research-medical and urological. Current problems in funding of urological research efforts include low funding by the NIH, perceived inadequate peer review and lack of congressional support. Funding sources for investigative efforts include competitive grants, contract awards, pharmaceuticaVequipment manufacturer support, clinical laboratory funds and clinically generated funds. Competitive grants and contract awards are primarily through NIH, and funding levels have been low in recent years. The results of a questionnaire to urologyhephrology program directors indicated that nephrology programs derive 46% of the research funding from competitive and contractual grants in contrast to 13% for urology programs. Clinically generated funds support only 8% of nephrology programs and 68% of urology programs. Manufacturer grants support 18% and 14% of nephrology and urology programs respectively. The funding survey also indicated that 52% of

TABLE1. Cost of professional services Pmcedure

ESWL Open lithotomy Staghorn Percutaneous: Less than 2 cm. More than 2 em. Ureteroscopv: With biketing With lithotripsy

Total cost

9h All Procedures

Total Cost

66 1

0.1

$605.2 18,521 $ 2,430,469 $ 522,179

5 1

$ 31,574,865 $ 7,701,790

19 8

$ 79,989,658 $ 35,038,371

100

$762,475,853

__

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UROLITHIASIS TABLE2. Final costs costs Inpatient: Evaluation Hospitalization Professional services Wages (when in hospital) Wages (recovery) Outpatient care: Evaluation Wages

5 155 million $848 million 5 762 million $ 84 million 5 56 million

5 358 million $ 128 million

Total costs $2.39 billion These data were computed with the assistance of Dr. Scott Optenberg, Chief Statistician, United States Army Clinical Investigation Activity, Health Services Command.

nephrology program grants were funded in contrast to only 22% of urology grants. It is generally believed that funding problems are related partly to the NIH review process. Urolithiasis grants are mostly reviewed by General Medicine B and Surgery, Anesthesiology and Trauma study sections, which often lack representative basic science and clinical expertise in urolithiasis. These problems are further compounded by only the occasional use of special or ad hoc reviewers to assist study section reviews. Experience indicates that award rates tend to be higher for similar grants for special study section reviews compared to standard reviews. Other identified problems are that urology research proposals are often reviewed by different study sections. Most study sections (agencies) do not maintain data on nonfunded grants and there is a lack of a centralized registry to track urolithiasis funding. Additionally, urolithiasis is not a "popular" disease in that patients do not die of the problem and only a small number of patients suffer significant long-term morbidity. No patient or advocate group represents this disease to present their case to Congress. Funding solutions are vaned and include enhancing public education to the morbidity, cost and associated problems (for example bone disease) with urolithiasis. Additionally, a n increased awareness by Congress of urolithiasis may lead to the establishment of directed funds to study this disease. It would be beneficial if a request for application for basic and clinical research was established for urolithiasis and a centralized registry of stone disease (including information on funding) was developed. RESEARCH GRANTS

I have reviewed urolithiasis research grants. The extramural urolithiasis program of the National Institute of Diabetes, Digestive and Kidney Diseases urges and supports research and training in urolithiasis. Other areas of directed interest include studies of the prostate, bladder, urinary tract infection, male sexual function and dysfunction, and pediatric urology. Distribution of these funds in fiscal year 1992 indicates the expenditures of $9,514,296 for bladder related research, $8,614,180 for prostate related research, $4,134,225 for urolithiasis research, $1,955,305 for urinary tract infection research, $1,101,933 for male sexual function and dysfunction, and $1,345,061 for other research projects. The urolithiasis research program encompasses basic and clinical research on factors affecting urinary tract stone formation, including genetic factors in urolithiasis, intrinsic urolithiasis inhibitors and promoters, nutrition and urolithiasis, environmental factors and prevention of urolithiasis. Programs are also directed toward basic and clinical research in the treatment of urolithiasis. As noted by Doctor Preminger, 6 study sections review urolithiasis grant applications. There were 19 urolithiasis grant applications in fiscal year 1992 and only 2 were funded.

Currently, there are 16 active grants: R01-(9), R29-(1), R37(l),R44-(1), R55-(2) and P0142). Total direct cost of all urolithiasis research grants is $2,913,337 with total cost being $4,134,225. It is believed that funding problems for urolithiasis research relates not only to the need for more applications but also the recruitment of new investigators in the field. The review process must be assessed so that expertise on study section review is available. Finally, committed funds for urolithiasis research would help to generate interest in this area and subsequently enhance funding levels.

TRAINING PROGRAMS

Drs. Leroy Nyberg and Gary Striker (NIH) reviewed training programs in urolithiasis (medical and doctorate degrees). Multiple awards are available t o assist in investigative efforts. The National Research Service Awards are given to individuals and institutions but currently none is directed toward urolithiasis efforts. Another avenue includes the Research Career Development Award, the KO8 in clinical science and the K11 in physical science. A new program includes the joint effort of the American Foundation of Urologic Disease (AFUD)and the National Institute of Arthritis, Diabetes and Digestive and Kidney Disease. The purpose of this award is to increase the number of basic research trainees in urology and applies to the medical and doctorate levels. The purpose of the program is to integrate research training with residency training and provide adequate financial support for the trainee. Half of the trainees are doctorates. For those in residency programs it is planned that the research experience will be undertaken 2 or 3 years into the residency program and after investigative training is completed the chief residency year will be fulfilled. Clinical investigator applications will then be initiated and funding will be derived from AFUD and NIH. Individuals completing the program will likely serve on full-time faculties of medical schools and enhance the research efforts of urology departments. Currently, funding of this program has been awarded to the University of Pennsylvania and Northwestern University. It is also important to recognize that various groups can be influential in developing funding efforts. The Interagency Coordinating Committee includes representatives of NIH, the Veterans Administration, Food and Drug Administration and other federal agencies. Research efforts can be directed from these groups to specific areas of activity. The National Kidney and Urological Diseases Advisory Board (NKUDAB) is one of several advisory boards that report to Congress. It was established in June 1986 by the Secretary of Health and Human Services, and includes 18 members appointed by the Secretary and 19 ex oficio members. The NKUDAB has many responsibilities, including review and evaluate the implementation of kidney and urological diseases plan, update the plan, advise Congress, the Secretary, the Assistant Secretary of Health and the directors of federal agencies, and act as a liaison with other agencies. Active areas related to urolithiasis research include the convening of a workshop on long-term consequences of lithotripsy held on February 3 to 4, 1992. In March an ad hoc committee was developed to formulate clinical trials and in May a protocol was discussed by the Research Subcommittee of the NKUDAB. In September the protocol was accepted by the NKUDAB. Other recommendations of the NKUDAB related to urolithiasis research include examine the need for medical versus surgical therapy of minimally symptomatic stones, identify the optimal management of lower pole stones and the role of ESWL or ureteroscopy for ureteral stones and

UROLITHIASIS

maintain a registry of ESWL patients. These recommendations were included in the annual report for fiscal year 1993 to Congress. General recommendations to enhance funding for urolithiasis research as related to existing programs include the expansion of training grants in urolithiasis and increasing activity in other training grants activities, such as physiology and endocrinology. There is a need for increased clinical investigation and there is also a need for increasing directed funds through Congress. A request for application for stone disease would be most helpful in furthering these goals.

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evidence to indicate that there has been a decrease in incidence. The problems have been well described but a clear understanding of the fundamental cause of the problem has not been realized. General recommendations to enhance urolithiasis research include recruitment of new investigators in various disciplines to urolithiasis research, expansion of training grants in urolithiasis, obtain support of organized groups for urolithiasis research (for example American Society of Nephrology, American Urological Association, National Kidney Foundation, AFUD and so forth), improve the NIH review process of urolithiasis research proposals and develop a request for GENERAL DISCUSSION application for urolithiasis. Areas of investigation to emphaAfter all presentations were completed a general discus- size include genetic and metabolic factors in urolithiasis; sion followed in an effort to identify future needs and develop intrinsic urolithiasis inhibitors and promoters; nutritional, recommendations. I t must be emphasized that the general environmental and epidemiological factors; prevention and perception is that there has been unsatisfactory progress treatment (medical and surgical including ESWL) of urolisince the 1988 Consensus Conference. Although it is recog- thiasis; cell surfacekell transport-crystal interaction, and nized that much has been learned, more needs to be known no exclusion of other areas of pertinent investigation. on how to treat stone disease better. Stone disease is a significant clinical problem affecting a large percentage of APPENDIX the population, resulting in significant morbidity and costs. The organizing committee consisted of Dr. Martin I. Experience indicates that recurrence can be lessened only by approximately 50% based on current knowledge and greater Resnick (Cleveland, Ohio), Dr. Ralph Bain (Bethesda, efforts are required to decrease this number. Most prospec- Maryland), Dr. Raymond L. Hackett (Gainesville, Florida), tive trials do not prevent the disease and efforts are needed Drs. Jack Lemann and Neil Mandel (Milwaukee, Wisconsin), to know why stone formation occurs. Although there have Dr. Charles Y. C. Pak (Dallas, Texas) and Dr. Joseph Segura been increased efforts in treating the disease there is no (Rochester, Minnesota).