QUESTIONS SUBMITTED BY THE SUBCOMMITTEE JUVENILE DIABETES Question. I understand that Type 1, or juvenile diabetes, is the result of the immune system destroying cells in the pancreas. The Committee has been told in the past that of the two types of diabetes this type is most likely to result in a cure. Last year the Committee provided an additional $2 million to pursue promising research to find better treatments and a cure for Type 1 diabetes. Could you update the Committee on the progress in this area? Answer. It is now well accepted that insulin dependent diabetes mellitus (IDDM or Type 1) is the result of the inappropriate destruction of the insulin secreting beta cells of the pancreas by the immune system. Therefore, a major site of emphasis for research on this "auto-immune" disease is explaining why the immune system makes this mistake and how the mistake might be prevented or corrected. In the last year or two we have seen several examples of how this enhanced exploration of immune functions has suggested potential clinical approaches to IDDM. When someone becomes ill with IDDM this signifies the culmination of a destructive immune process which has gone on silently for years within that patient. By the time they become sick it is generally too late to prevent or reverse the damage. Therefore, it is important to find markers for the process at an earlier stage. Recently, researchers have discovered the identity of one such marker. This blood-bourne antibody directed at beta cells had been called the "64k antibody" because it attacks a poorly understood constituent of beta cells called the "64k antigen." We now know that this antigen is an enzyme in the beta cell called by its initials, GAD (glutamic acid decarboxylase). With this knowledge, we may be able to develop more sensitive tests for the impending development of IDDM in individuals. In addition, the specific role of GAD in possibly instigating or enhancing the auto-immune process needs now to be elucidated. The ability to identify individuals at high risk for IDDM by various tests (including anti-GAD antibodies and other immunologic or metabolic measures) will give us the opportunity to try immunologic interventions designed to inhibit or arrest the process. The NIDDK, with collaboration from our sister institutes, NIAID and NICHD, sponsored a workshop on Clinical Trials of Immunosuppression for the Prevention of IDDM in April, 1990. Participants for the meeting were drawn from the diabetes and immunology research communities. A consensus was reached that some high-risk individuals could be identified now and that clinical studies to explore the ability of immunomodulation to alter the occurance of IDDM in these individuals was timely and warranted. This group also pointed out that there was still much to be learned about identifying the majority of those at high risk and the best interventions to be tried. The NIDDK, NIAID and NICHD have released two Program Annoucements to encourage the submission of investigator-initiated research proposals in this area. For those already with IDDM, the replacement of destroyed beta cells with transplants of islets has been a long term goal of the diabetes research community and the NIDDK. A major barrier to success continues to be the need for generalized immunosuppressive drugs by the transplant recipient which are frought with major untoward side-effects. A recent immunologic finding by a NIDDK supported investigator has raised a fascinating new approach to preventing transplant rejection. In experimental animals, the placement of a small piece of the transplanted islet tissue in the thymus gland (a gland that is known to play an important role in regulating the immune system) obviates the rejection of transplanted islet tissue placed anywhere else in the animal without continuous powerful immunosuppressive drugs. If this finding is confirmed and extended to man, then the possibilities for islet transplantation as a cure for IDDM will be markedly enhanced. KIDNEY CLINICAL TRIAL Question. I understand the NIDDK has underway a clinical trial which is attempting to determine the effect of low protein diets on slowing, or forestalling kidney failure. This clinical trial still has two more years to go and will require a final year of analysis before the results are known. Are there any preliminary results from the first two years of clinical trials on this diet study? Answer. The clinical trial, Modification of Diet in Renal Disease (MDRD) Study, will determine the effects of low protein and phosphorus diets and control of blood pressure, on loss of kidney function. The study has completed recruiting 800 men and women with mild to moderate loss of kidney function in the fifteen medical centers located throughout the U.S. The response from private physicians to patient recruitment in this clinical trial has been outstanding. Over one-half of the MDRD participants were referred to the study by community physicians. Early results of the dietary intervention are encouraging in that protein intake decreased by 30 percent to 60 percent in the two low protein groups. In addition, control of high blood pressure has been very good. Follow-up of study participants will be completed by December 1992. The final results of the study will become available during the summer of 1993. INTERSTITIAL CYSTITIS Question. IC, or interstitial cystitis, is a very painful bladder disease that afflicts primarily women. Last year the Committee provided additional funding for research in this area and requested that a National Registry be established. What progress has the Institute made in following up on the suggestions made by the Committee? Answer. NIDDK has issued two Requests for Applications in the field of Interstitial Cystitis. The first calls for investigatorinitiated research proposals. The second calls for the development of an Interstitial Cystitis database. The database is a scientific approach to a registry, and was developed in concert with the Interstitial Cystitis Association. Both Requests for Applications are scheduled for funding during FY 1991. END STAGE RENAL DISEASE IN BLACKS Question. End-stage renal disease due to hypertension is a major health problem among Black Americans. In fact, I understand that the incidence rate of End-stage renal disease with a diagnosis or cause of hypertension was 6.5 times greater in blacks than whites. What is known about the prospects for reducing End-stage renal disease by controlling hypertension? Answer. Studies at a George M. O'Brien Kidney and Urology Research Center have shown that Blacks are twice as likely as Whites to demonstrate progression towards renal failure, despite good blood pressure control. The findings strongly point to the need for early detection of hypertension and more creative ways to treat it. This is especially important for individuals who are at high risk, and are thus susceptible to hypertension and renal damage. Studies are in progress which may further the understanding of the consequences of hypertension. These include interactions between angiotensin II and norepinephrine, and hormonal interaction in control of sodium chloride reabsorption. Both studies involve the use of special animal models, and are expected to yield new insights into the causes and possible outcomes of hypertensive renal disease. OSTEOPOROSIS DRUG Question. During the past year there has been considerable media coverage of a two year industry supported study of more than four hundred post-menopausal women that showed that administration of the drug "etidronate" for fourteen days followed by calcium for 76 days reversed bone loss. Has your Institute evaluated this treatment? What is your research agenda in the area of Osteoporosis? Answer. NIDDK provides major support for biomedical research on osteoporosis. Hormones are major factors in the regulation of bone formation and bone loss. As the institute with lead responsibility for endocrine (hormone) research, the NIDDK plays a pivotal role in supporting studies of bone-active hormones and growth factors. The NIDDK also supports a large body of research into calcium absorption and bioavailability as well as research aimed at understanding how vitamin D affects bone. Although NIDDK has not evaluated etidronate therapy, previous research supported by the Institute on the effects of the closely related pyrophosphate was instrumental in the development of bisphosphonates such as etidronate. Similarly, NIDDK anticipates other novel therapies will arise from its ongoing basic research on hormones and growth factors which regulate bone formation. For example, NIDDK is supporting a new clinical trial evaluating parathyroid hormone in the treatment strategy for osteoporosis. The NIDDK recently sponsored a Consensus Development Conference on the "Diagnosis and Management of Asymptomatic Primary Hyperparathyroidism." The conference established guidelines for detection and prevention of silent organ damage, particularly progressive bone loss, in this disorder which affects 100,000 new patients each year in the United States. The NIDDK is among those NIH institutes supporting the Postmenopausal Estrogen/Progestin Intervention clinical trial, which will provide important data on the risks and benefits of the most effective measure to prevent osteoporosis. NIDDK has joined with NIAMS in issuing two new RFAs soliciting basic and clinical research on osteoporosis and expects to expand what already constitutes a major portfolio of research in this area. GENETICS OF KIDNEY DISEASE Question. Doctor, this past year, we heard about the identification of the gene that is responsible for causing Alport Syndrome. What can you tell us about this finding, and what are its implications? Answer. NIDDK investigators at the University of Utah School of Medicine have identified the gene and mutations responsible for the glomerular basement membrane defect which causes the Alport syndrome, to the chromosomal region Xq22. This represents the first cloning of a gene for any kidney disease, as well as the first example of a genetic glomerular basement membrane defect resulting in kidney disease. Until now, the lack of satisfactory markers for Alport syndrome has greatly hampered diagnosis and may have resulted in substantial underdiagnosis. Therefore, the true incidence and prevalence of Alport syndrome may only be known when systematic searches using reliable diagnostic markers are performed. In addition to improving diagnostic efforts, both in Alport syndrome as well as in other kidney diseases, the gene isolation and determination of specific mutations has implications for future treatment and/or prevention of the disease. addition, knowledge of the identity of the defective gene opens the possibility for gene therapy in which the effect of a defective gene could be directly masked. Research can focus into the design of appropriate therapeutic strategies, since it may now be possible to devise forms of effective treatment, or even gene replacement therapy, for the serious forms of Alport syndrome. POLYCYSTIC KIDNEY DISEASE In Question. Over a half million Americans have polycystic kidney disease. What is your Institute doing to help combat this serious disease? Answer. The NIDDK has been working closely with the lay and scientific community interest in Polycystic Kidney Disease (PKD) to promote research and to increase the basic knowledge on all aspects of the disease. It is an inherited disorder which affects 500,000 Americans, and 7,000 new patients are recognized each year. It ranks first among the inherited and congenital conditions leading to end-stage renal disease and ranks fourth (behind kidney disease of diabetes mellitus, hypertension and glomerulonephritis) as a primary cause of end-stage renal disease and as a basic diagnosis among newly identified end-stage renal disease patients. Males and females are affected equally, and its worldwide distribution appears to demonstrate that it affects all races. To address these issues a Request for Research Grant Applications was issued earlier this year, inviting investigations directed at defining and further characterizing the etiology and pathogenesis of PKD. The deadline for receipt of applications is April 25, 1991. It is anticipated that given the sophisticated research technology currently available, coupled with possible applications of emerging new knowledge, major progress can be attained in this area in the near future. KIDNEY DISEASE AND HYPERTENSION IN BLACKS Question. We understand from your opening statement that NIDDK has a plan for a pilot study on kidney disease and hypertension in blacks. Can you tell us more about it? Answer. A Request for Applications for a pilot study on "Kidney Disease and Hypertension in Blacks" will be shortly released by NIDDK. The purpose of this pilot study is to test the feasibility of conducting a full-scale randomized clinical trial on the best approach to therapy for lowering high blood pressure in persons with chronic renal failure due to hypertension. Since endstage renal disease in hypertension is 6 1/2 times more common among blacks than whites, at least seventy percent of the participants in the study will be black. The pilot study will begin in the Spring of 1992 and continue for nearly three years. Upon completion of the pilot study, a decision will be made as to whether a full-scale study will be undertaken. The full-scale study would take an additional seven years to complete. KIDNEY DISEASE OF DIABETES MELLITUS Question. Can you tell us what research progress is being made on kidney disease of diabetes? Answer. In 1987, the Institute began a major new initiative in "Kidney Disease of Diabetes Mellitus." As a result of this initiative, NIDDK funding in this area has increased about sixfold, from about $1.7 million in 1986 to approximately $10.6 million in 1990. In 1990, the Institute again increased funding for this area to sustain an initiative begun in 1987. New awards have been made, including one focused on kidney disease of diabetes mellitus (KDDM) in Native Americans. In addition, a new initiative on KDDM in Blacks with adult onset diabetes mellitus is being planned. Researchers have found that a reduction in blood pressure within the kidney may be one means to arrest kidney disease in diabetics. A new method for assessing kidney function has been developed by NIDDK-sponsored investigators. The method, measuring renal clearance using any one of three radioisotope markers is now being used to assess renal function in all current clinical trials and in the study of kidney disease in the Pima Indians. Institutesponsored animal studies have also shown that the progressive kidney damage often found in diabetics results from high blood pressure levels in the glomerulus. This research revealed that angiotensin-converting enzyme inhibitors, drugs that dramatically reduce glomerular blood pressure, can completely prevent glomerular disease and stabilize kidney disease once it has appeared. This finding, together with recent evidence supporting the value of a low-protein diet in lowering glomerular blood pressure, may represent a breakthrough in treating diabetics with kidney disease. Another group of NIDDK-supported scientists conducted a series of animal studies to learn more about the efficacy of antihypertensive therapy in reducing the progression of KDDM. They |