By William Couser, M.D.
Prior to the 1960’s kidney disease was almost uniformly fatal and resulted in the death of about 20,000 Americans annually, making it the fourth leading cause of death among young adults. During the past two decades dramatic progress has been made in both treatment and prevention of kidney failure. At the present time about 72,000 patients are alive on kidney dialysis. Over 6,800 patients annually receive kidney transplants with steadily improving success rates. Countless other patients are prevented from developing kidney failure as a result of early diagnosis and effective therapy for several forms of progressive kidney disease. Despite these advances, kidney disease kills 12,000 Americans annually and results in a morbidity of about 4 million days, work loss of 765,000 days, loss of earning power of more than $15 million and medical bills that now exceed $2 billion per year to pay for dialysis and transplantation treatments alone.
Benefits of Research in Laboratory Animals to Patients with Kidney Disease
Virtually all of the recent improvements in the care of patients with kidney disease have resulted from the basic research involving the use of laboratory animals. Examples include:
- The materials used to construct the first successful shunt, which allowed patients with kidney failure to be connected to dialysis machines for long-term treatment, were perfected through tests in sheep with kidney failure as were the surgical techniques for implanting these shunts. Development of the arteriovenous shunt allowed the first use of hemodialysis for the long-term treatment of patients with kidney disease.
- Understanding the immune basis for how the body rejects transplanted tissue emerged from studies in mice and guinea pigs. Drugs that could effectively suppress these rejection reactions were then developed and determined to be effective in laboratory animals. The potential to suppress the immune response to allow successful kidney transplants between non-identical individuals was then established in dogs leading directly to successful kidney transplants in man.
- The mechanisms that cause high blood pressure have been defined through studies of high blood pressure in several animal models. Clarification of these mechanisms permitted development of drugs to effectively block them and restore blood pressure to normal. Effective drug therapy for high blood pressure has reduced the incidence of hypertensive kidney disease as well as strokes and heart attacks and has improved the survival of patients with kidney disease.
- Discovery of the immunosuppressive properties of the new drug cyclosporine resulted from studies carried out in mice. Development of this drug for human use has had a dramatic effect on the success rate of kidney transplants and permitted successful transplantation of other organs such as hearts and livers.
- Development of lithotripsy, a new method for removing kidney stones which does not require surgery, derived from studies initially carried out in dogs.
Future Potential of Kidney Disease Research Involving Laboratory Animals
The list of contributions of animal research to improve care of patients with kidney disease is, of course, much longer. However, of more importance is that major advances in the basic sciences of molecular biology and immunology as well as a better understanding of the physiologic reasons for development of progressive renal disease now promise even greater improvements in the care of patients with kidney disease in the near future. All of these advances require additional animal research before they can be fully utilized to treat human diseases. For example:
- Animal research contributed to development of recombinant DNA technology, or “genetic engineering”, techniques that permit very precise identification of the location of defects in the genetic material of cells that cause certain hereditary disorders. Identification of these defects at a molecular level makes realistic the possibility of replacing defective genetic material to correct these defects before they cause disease. Examples of such disease include polycystic kidney disease and hereditary nephritis, diseases that account for up to 25% of all cases of renal failure.
- Research in animal models of kidney failure led to recognition that the normal kidney produces a hormone called erythropoietin. Erythropoietin controls the production of red blood cells. Deficiency in production of erythropoietin in patients with kidney failure results in a chronic anemia and requirement for multiple blood transfusions. Using genetic engineering techniques derived from animal research, erythropoietin has now been successfully produced in large quantities in the laboratory and will be available for treatment of patients with kidney disease. This product is now being tested and holds great promise for reversing one of the major consequences of kidney failure. Further applications of this technology to other problems related to kidney disease require intensive studies in appropriate animal models.
- The development of monoclonal antibodies, highly specific molecules that can react with and identify very subtle differences in kidney structures and in cells that cause kidney structures and in cells that cause kidney structures and in cells that cause kidney disease, was derived from experiments in mice, which led to the Nobel Prize in Medicine in 1984. These antibodies have revolutionized our understanding of immune mechanisms that lead to kidney disease and kidney transplant rejection. They are now being used successfully to reverse certain types of transplant rejection in man. Development of more and better antibodies is likely to improve both organ matching techniques and treatment for transplant rejection. However, these studies require continued animal research.
- Studies carried out in a unique strain of rats in which the glomeruli, or filtering units of the kidney, are present on the kidney surface and therefore are accessible for study, have led to new insights into the mechanisms of progressive kidney disease. Application of sophisticated physiologic techniques to studies in this unique rat strain have demonstrated that increased pressure is responsible for causing additional kidney damage, which creates a vicious cycle leading to progressive loss of kidney function and kidney failure. Outgrowth of this research have included recognition that restriction that restriction of dietary protein intake may reverse this process, resulting in long-term preservation of kidney function in diseased kidneys. Early results of human studies suggest that protein restriction and other forms of therapy directed at this mechanism may significantly slow or even halt the progression of kidney disease in man as it does in animal models. The potential benefits to patients with kidney disease from such therapy could exceed those resulting from the development of dialysis and transplantation. However, continued animal research is required to fully develop and successfully apply this information to human kidney disease.
In recognition of the importance of basic animal research to future progress in preventing and treating kidney disease, the National Kidney Foundation spends about $700,000 annually, the largest single item in the Foundation budget, to support the training of new investigators qualified to conduct the high quality basic research required for continued progress to be made in the fight against kidney disease.
Ironically, at a time when the benefits of basic research to patients with kidney disease are so apparent, and when the potential for continued progress is more exciting than ever before, the conduct of this research is coming under increasing attack from a variety of groups devoted to the cause of animal rights. The animal rights movement seeks to severely restrict, or halt entirely, research involving any laboratory animals. The efforts of animal rights groups to halt the kind of research which has led to major progress in treating kidney disease has taken several forms. Political pressures have resulted in legislative proposals in the United States Congress and in 22 states to increasingly restrict or even eliminate the use of laboratory animals in research.
Prominent personalities in the entertainment industry have been recruited to this cause and have been successful in focusing substantial media attention on animal rights issues, usually without an accurate or informed presentation of the benefits that derive from such research. Personal attacks have been made directly on the integrity and motivation of researchers carrying out studies in laboratory animals, including investigators studying kidney disease. In extreme cases, animal rights activists have engaged in illegal break-ins of laboratories and animal care facilities and have destroyed important research data and stolen animals involved in such studies. The animal rights movement is growing in size, visibility and effectiveness and commands an estimated $200 to $400 million annually in support of their ultimate goal of preventing all research utilizing laboratory animals. Achievement of these objectives would have precluded the development of such treatments as dialysis and transplantation and would prevent the ultimate application to man of some of the exciting new advances that are being made in the study of kidney disease.
In recognition of the complicated ethical and legal considerations involved in laboratory animal research, as well as the essential nature of this work for future progress in treating kidney disease, the Scientific Advisory Board of the National Kidney Foundation has appointed an Animal Research Committee to examine these issues and to outline the policy of the National Kidney Foundation on animal research. The Committee includes adult and pediatric nephrologists involved in kidney disease research as well as lay volunteers including a transplant patient, lawyer, businessman and clergyman. At its first meeting in New York on September 21, 1985, the Committee was unanimous in endorsing the need for continued responsible animal research in kidney disease and in emphasizing the necessity for the National Kidney Foundation to educate all members and Affiliates regarding the importance of this issue to patients with kidney disease.
The Committee will continue to meet quarterly and will issue a complete report on this subject. It also plans to generate educational material outlining the benefits of both past and future animal research to patients with kidney disease as well as information on what types of research are supported by the National Kidney Foundation, why animals are essential to this research, and how such research supported by the National Kidney Foundation is conducted and regulated. Volunteers and Affiliates who wish to become better informed about this important issue are encouraged to contact: National Kidney Foundation, 30 East 33rd Street, New York, NY 10016.
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