Bonnie L. Blazer-Yost - US grants

There is a critical need for safe, inexpensive treatments that can delay the progression of cyst enlargement and the accompanying destruction of the renal parenchyma that leads to renal failure in the majority of autosomal polycystic kidney disease (ADPKD) patients. In ADPKD, the earlier the onset of treatment, the greater the potential benefit to the patient, therefore, drugs for this disease should be considered life-long therapy. Our overall goal is to develop efficacious drugs that can be safely used from the time of diagnosis in ADPKD patients. The objective in the proposed studies is to conduct a preliminary evaluation of drug therapy using a low dose of an insulin sensitizing agent, the PPAR? agonist, pioglitazone, in the treatment of ADPKD. Our previous cell culture studies showed that low doses of PPAR? agonists, including pioglitazone, inhibit the synthesis of the CFTR (cystic fibrosis transmembrane conductance regulator) Cl- channel in the cell type that lines the renal cysts. CFTR is the major ion channel postulated to be involved in transepithelial Cl- and, secondarily, water flux into the cyst lumen resulting in cyst expansion. Our in vivo animal studies have shown that the two FDA approved PPAR? agonists, pioglitazone or rosiglitazone, inhibited cyst growth in the PCK rat model of PKD. In addition to inhibiting cyst growth, PPAR? agonist therapy is expected to have beneficial effects on other parameters of PKD such as dyslipidemia, hypertension and endothelial function. Based on these data, we hypothesize that treatment with low dose pioglitazone will slow cyst expansion in human ADPKD patients and delay the progression of disease. The proposed study is a double-blind, placebo controlled, cross-over trial of pioglitazone (15 mg/day) versus placebo therapy for the treatment of ADPKD. The study is a pilot study to test the safety and efficacy of pioglitazone to slow progression of PKD assessed by percent change in kidney volume by MRI compared to one year of placebo. 28 subjects will be enrolled. A one year cross-over design provides the best opportunity to obtain meaningful safety and efficacy data in a short term protocol by allowing each patient to serve as his/her own control. This will facilitate the design of a future multi center randomized trial. Based on data from large scale studies in normal volunteers and diabetic patients, low dose pioglitazone is relatively safe for long term treatment. Thus, this drug may provide a safe option for treatment of ADPKD patients and an increase in length and quality of life.

? DESCRIPTION (provided by applicant): Living organisms necessitate the uptake of energy and of building blocks, and the elimination of waste. Therefore, the barrier that separates them from the environment cannot be completely tight to the movement of water, ions, and small organic molecules. As a consequence, cells from their beginning created basic mechanisms to maintain and regulate their water content and volume. When disrupted, these basic functions can have severe consequences for an organism, and diseases of salt and water transport are involved in both acute and chronic conditions that impact over 50% of the population, and have been documented to cost the health care system billions of dollars annually. The goal of the proposed symposium Cell Biology of Volume Regulation and Fluid Homeostasis, an 11th International Symposium on Cell Volume Regulation is to cover both the basic mechanisms of cell volume regulation and their implications in several major diseases including hypertension, brain disorders and lung and kidney diseases. Specifically, we propose 10 scientific sessions: The first part of the conference Cell Biology of Volume Regulation and Fluid Homeostasis, is divided into 5 sessions: I.1 Molecular Mechanisms of Cell Volume Regulation: Transporters and Ion Channels; I.2 Salt-sensitive Mechanisms in Regulation of Apoptosis and Autophagy; I.3 Cell Volume Regulation in Cell Proliferation and Migration; I.4 Lipid Regulation of Osmotic- and Mechano-sensitive Ion Transport Mechanisms; and I.5 Hydration and water transport through the membrane. The second part of the conference Diseases of Volume Regulation and Fluid Homeostasis, is divided into 4 sessions: II.1 Role of Salt Transport in Hypertension; II.2 Fluid-Electrolyte Contributions to Disease Progression in Polycystic Kidney Disease; II.3 Osmoregulation and Hydration in Cystic Fibrosis; and II.4 Osmoregulation in Neurological and Brain Disorders. A 10th scientific session will be dedicated to Young Investigators. In addition, we propose a new educational outreach initiative that will include high school and community college students. This will be achieved via a Lunch and Learn with a Professor sessions that will focus on salt and water in the diet and on small groups discussions about science and scientists personal experiences. It is the first time in the last decade that an International Symposium on Cell Volume Regulation is organized in the United States, which we believe is critically important to facilitate the interaction of the American scientists to the international community and foster international collaborations in this area. Narrative: The major goal of this international scientific meeting on Cell Volume Regulation and Fluid Homeostasis is to cover both the basic mechanisms of cell volume regulation and the roles of these mechanisms in several major diseases including hypertension, brain disorders and lung and kidney diseases. In addition, the meeting will include an educational outreach program that will include high school students and community college students to foster the interest of the students to science.

There is a critical need for safe, inexpensive treatments that can delay the progression of cyst enlargement and the accompanying destruction of the renal parenchyma that leads to renal failure in the majority of autosomal polycystic kidney disease (ADPKD) patients. In ADPKD, the earlier the onset of treatment, the greater the potential benefit to the patient, therefore, drugs for this disease should be considered life-long therapy. Our overall goal is to develop efficacious drugs that can be safely used from the time of diagnosis in ADPKD patients. The objective in the proposed studies is to conduct a preliminary evaluation of drug therapy using a low dose of an insulin sensitizing agent, the PPAR? agonist, pioglitazone, in the treatment of ADPKD. Our previous cell culture studies showed that low doses of PPAR? agonists, including pioglitazone, inhibit the synthesis of the CFTR (cystic fibrosis transmembrane conductance regulator) Cl- channel in the cell type that lines the renal cysts. CFTR is the major ion channel postulated to be involved in transepithelial Cl- and, secondarily, water flux into the cyst lumen resulting in cyst expansion. Our in vivo animal studies have shown that the two FDA approved PPAR? agonists, pioglitazone or rosiglitazone, inhibited cyst growth in the PCK rat model of PKD. In addition to inhibiting cyst growth, PPAR? agonist therapy is expected to have beneficial effects on other parameters of PKD such as dyslipidemia, hypertension and endothelial function. Based on these data, we hypothesize that treatment with low dose pioglitazone will slow cyst expansion in human ADPKD patients and delay the progression of disease. The proposed study is a double-blind, placebo controlled, cross-over trial of pioglitazone (15 mg/day) versus placebo therapy for the treatment of ADPKD. The study is a pilot study to test the safety and efficacy of pioglitazone to slow progression of PKD assessed by percent change in kidney volume by MRI compared to one year of placebo. 28 subjects will be enrolled. A one year cross-over design provides the best opportunity to obtain meaningful safety and efficacy data in a short term protocol by allowing each patient to serve as his/her own control. This will facilitate the design of a future multi center randomized trial. Based on data from large scale studies in normal volunteers and diabetic patients, low dose pioglitazone is relatively safe for long term treatment. Thus, this drug may provide a safe option for treatment of ADPKD patients and an increase in length and quality of life.