Dr. Grantham is Professor of Medicine at the University of Kansas Medical Center, Kansas City, Kansas, USA, and a member of the Nephrology and Hypertension Division of Internal Medicine. He has served in this position for 27 years. He also serves as Editor of The Journal of the American Society of Nephrology, headquartered at the University of Kansas Medical Center. Additionally, Dr. Grantham is Chairman of the Polycystic Kidney Research (PKR) Foundation, Kansas City, Missouri. His clinical and research training took place at the University of Kansas Medical Center, at The National Heart Institute, NIH (National Institutes of Health), Bethesda, Maryland, and at the Physiologic Laboratory, Cambridge, England. Dr. Grantham is widely regarded as one of the nation's leading authorities on polycystic kidney disease.
I was able to reach Dr. Grantham thanks to Tanja Dunbar, Vice President of The PKR Foundation. I had a few definite questions I wanted to ask him on behalf of readers who either have polycystic kidney disease themselves, or who have friends or family members who do. My questions and Dr. Grantham's thoughtful responses follow.
Cooper: What, if anything, can be done to halt the progression of polycystic kidney disease to renal failure, dialysis, and end- stage renal failure? In other words, what can patients do preventively to slow or perhaps even reverse the progression of the disease? Anything?
Dr. Grantham: At the moment there is no specific treatment for polycystic kidney disease to prevent progression to renal failure, dialysis, and end- stage renal failure. On the other hand, there are complicating factors that can accelerate the rate of disease progression and we can do something about these problems.
Hypertension
Over 50 percent of patients with polycystic kidney disease have high blood pressure. This often begins in teenagers and young adults, and continues throughout the patient's lifetime. It is well known that long- standing hypertension can accelerate the progression of many types of renal disease, and it is not unreasonable to suppose that polycystic kidney disease progression would be accelerated by hypertension as well. At the moment, no compelling study has been done showing improvement in the rate of progression in patients who have been treated for high blood pressure, but studies are currently under way. Until those studies are completed, it makes good sense to follow a prescription that brings the blood pressure well into the normal range and keeps it there. This may require dietary restriction of sodium chloride and supplementation with vasodilator drugs that decrease blood pressure.
Infection
Polycystic kidneys seem to be unusually susceptible to bacterial invasion and infection. This inflammation can accelerate the rate of disease progression. In polycystic kidney disease patients, urinary tract infections should be recognized and treated promptly. There are several excellent antibiotics that can be used to treat the acute infections.
General measures
The maintenance of a high quality lifestyle also makes good sense. This includes keeping the body weight within the range of normal values for age and height, ingestion of a diet containing the proper balance of carbohydrate, protein and fat, moderate exercise on a regular basis, avoidance of tobacco products, and judicious use of alcohol. It is also wise to avoid use of over- the- counter and prescription drugs that may be potentially injurious to kidneys, including non- steroidal anti- inflammatory drugs (aspirin- like compounds) and nephrotoxic antibiotics.
Cooper: What new or experimental treatments are on the horizon for patients with this disease? How soon, in your opinion, will these treatments become available? What are the current challenges/obstacles to making such treatments a reality?
Dr. Grantham: Several treatments have been attempted in experimental animals with polycystic kidney disease, with varying levels of success. Taxol, a drug used to treat cancer, has been shown to slow the progress of a rapidly progressive form of polycystic disease in mice. Experiments are currently under way to determine the effects of Taxol on experimental animals with the more slowly progressive form of polycystic kidney disease that is similar to that seen in adult humans.
Methylprednisolone, a drug used to treat inflammatory diseases and transplant rejection, has been shown to slow the progression of polycystic kidney disease and improve kidney function in rats and mice.
Lovastatin, a drug that lowers the cholesterol level of blood, has been shown to slow the progression of polycystic kidney disease in rats, and the ingestion of alkali slows progression. Diets low in potassium content accelerate the rate of polycystic kidney disease in rats. Diets containing excessive amounts of protein accelerate progression of disease in polycystic mice and rats, whereas low protein diets have been shown to slow the progression of polycystic kidney disease in rats and mice with the disease.
From the foregoing, it is fair to state that there are many interesting new findings in research, but it is much too premature to consider those treatments that slow PKD progression in rodents to be appropriate therapy for humans. There are other interesting compounds in the "pipe- line," so to speak, but the preliminary studies on these have not been released. Any drug or diet treatment will have to be carefully studied in experimental animals and in careful clinical trials before a recommendation for widespread use in humans can be made. My personal goal is to see an effective treatment for polycystic kidney disease before the turn of the century.
Cooper: What, in your opinion, are some of the most promising therapies or treatments that will, in the future, make a significant difference in the lives of those with polycystic kidney disease?
Dr. Grantham: We have learned a great deal about how cysts form in the kidney and the molecular mechanisms underlying cyst formation and cyst expansion. We also know that the cysts are not structures that simply crowd out the normal tissue. They probably cause the production of other substances that have injurious effects on the normal tissue within the polycystic kidney.
This general theory has led to a number of ideas for potential therapy of polycystic kidney disease. One theory supposes that the disease can be diminished by decreasing the rate at which the gene is expressed in the abnormal kidney cells. In order to accomplish this goal, it will be necessary to direct molecules to the cells of the kidney where the cysts are being formed that will paralyze the abnormal gene product and prevent it from forming the cysts in the first place. This is not "gene therapy" in the usual sense, but it is a form of therapy that depends on knowing the types of molecules that are being generated by the abnormal gene in the kidney cells.
We also know a great deal about some of the pathways that control the growth of cells in polycystic kidneys. There are a number of interesting chemicals that are being tested in cancer treatment centers that may prove useful in slowing the growth of cells in polycystic kidneys. The fluid that accumulates within the cysts is what makes them grow so large. There is reason to think that chemicals can be designed that will slow the pumping of fluid into the cysts and thereby markedly reduce the size to which polycystic kidneys expand.
Finally, the cysts cause inflammation to occur in the kidney and this inflammation may very well be the factor that leads to scarring and ultimate destruction of the kidney function. Drugs that interfere with the inflammatory reaction may prove to have an important place in the treatment of polycystic kidney disease.
Cooper: Thank you, Dr. Grantham, for an informative and enlightening interview.
Dr. Grantham: You're welcome, Joel. And thank you for giving me this opportunity to communicate with the individuals who visit your World Wide Web site.
Dr. Grantham may be reached through the PKR Foundation. For more information about polycystic kidney disease, I highly recommend a book published by the PKR Foundation entitled, "Q&A on PKD: PKRF's scientific advisors answer patient questions about dealing with polycystic kidney disease today." For information on how to obtain a copy of the book as well as other literature on PKD, contact:
PKR Foundation for research in polycystic kidney disease
4901 Main Street, Suite 320
Kansas City, Missouri 64112Phone: (816) 931-2600,
FAX: (816) 931-8655,
1-800-PKD-CURE (753-2873)e-mail: 75713.2275@compuserve.com