Ketosis as a Therapy for Polycystic Kidney Disease
Abstract
Autosomal-dominant polycystic kidney disease (ADPKD) is a very common, life-threatening genetic disease that leads to kidney failure. Affected patients eventually require lifelong dialysis or kidney transplantation. Many people in military service and the Department of Veterans Affairs (VA) system are affected by PKD because diagnoses are often made at an age after individuals are selected for military service. The high physical demands of military service are not compatible with the later stages of this disease. Only one U.S. Food and Drug Administration (FDA)-approved drug is available to a limited fraction of patients, has only modest efficacy, significantly impacts patients’ quality of life due to side effects and toxicities, and is offered at an extreme cost. An effective, safe, and widely accessible therapy is urgently needed. We have discovered that a highly effective therapy for PKD may be possible without drugs by using dietary interventions and/or a dietary supplement. Successful completion of the proposed work could lead to a disruptive change in ADPKD therapy. We discovered that the metabolic state of ketosis profoundly inhibits PKD progression in mice, rats and cats with PKD. “Ketosis” is the normal response of the body to periods of starvation. During starvation, the carbohydrate stores in the body are rapidly depleted, and the body uses fat reserves instead. Some of the fat is converted to so-called ketones that become a fuel source for cells in the body. The most important ketone is called BHB. We found that ketosis induced by dietary interventions (time-restricted feeding or a ketogenic diet) effectively inhibits the progression of PKD, and even reverses the disease. Remarkably, treatment with BHB in the drinking water alone is almost 100% effective in preventing PKD progression. BHB is FDA-classified as a dietary supplement, is widely available, inexpensive, and has no significant adverse effects. A personal note: In almost 20 years of PKD research experience, I have never seen any drug treatment that is more effective than BHB, neither in our own research nor the literature. Our strong preliminary data lead to compelling hypotheses that will be tested including proposed molecular mechanisms to explain the beneficial effect of ketosis and BHB. The main thrust of this proposal is to generate compelling results to justify clinical trials to investigate the efficacy of dietary interventions and/or BHB supplementation in ADPKD, and to inform the design of such trials. The main significance of this proposal is the enormous potential for clinical translation. Dietary interventions to induce ketosis are well-established. Because dietary interventions frequently fail in clinical practice due to poor patient adherence, our finding that BHB has a dominant beneficial effect could rapidly lead to a highly feasible therapy. To achieve our goals, we will treat mice, rats, and cats with PKD with dietary interventions to induce ketosis (time-restricted feeding or ketogenic diets) or mimic ketosis by supplementation with BHB. We will identify the most effective treatment and investigate the underlying mechanisms. This is a low-risk/high-reward proposal. Our strong preliminary data suggest that most of the experiments will be successful. An emerging effective, safe, and available therapy will have an extremely high impact.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010827
Entities
People
- Thomas Weimbs
Organizations
- United States Army
- University of California, Santa Barbara