Metformin as a Novel Therapy for Autosomal Dominant Polycystic Kidney Disease
Abstract
Autosomal dominant polycystic kidney disease (ADPKD), the most commonly inherited kidney disease, is characterized by the development of cysts in the kidney that impair function. Of those affected, half will progress to end state kidney disease, requiring dialysis or kidney transplant. To date, no effective and safe therapies exist for this deadly disease. A recent clinical trial evaluating the drug tolvaptan in ADPKD patients found that it had benefit to the kidneys, but tolvaptan caused frequent urination and also injured the liver in a small number of patients. Our goal, therefore, is to develop new strategies to treat ADPKD. The development of cysts in ADPKD patients results from two cellular processes. The first is an increase in the number of kidney cells that make up the outer surface of the cyst, and the second is an increase in fluid secretion into the cyst. We have shown that a single protein, AMP-activated protein kinase (AMPK), can inhibit both of those processes. Moreover, another lab showed that the genetic mutation that causes ADPKD alters the energy metabolism of the cell, which in turn inhibits AMPK activity. Metformin, a generic anti-diabetic drug that has an extensive safety record, activates AMPK. Indeed, we found that metformin slows the cyst formation in animal models of ADPKD, supporting the potential of metformin as a therapy for ADPKD. Metformin, first described in 1922, has been used to treat diabetes for over 50 years. More recently, it has been prescribed to patients with polycystic ovary syndrome. Researchers have also shown that metformin may have activity against cancers, prompting multiple clinical trials in this area. The most common side effect is gastrointestinal distress, but slowly ramping up the dose of metformin can lessen this. A more serious side effect is lactic acidosis, a condition characterized by acid build-up in tissues. Individuals with kidney impairment can develop lactic acidosis when taking metformin. However, this is a very rare occurrence, even more so if the kidney impairment is only mild, such as what occurs in early ADPKD. Based on the literature and our own work, we hypothesize that metformin may serve as a novel therapy for early stage ADPKD by activating AMPK. We will test this using a Phase 2 clinical trial in which 96 individuals with early ADPKD (an estimated glomerular filtration rate of 60 or greater) will be treated with metformin or placebo for 2 years. Patients will be recruited from the University of Maryland Medical Center and Tufts Medical Center, both of which have active PKD clinics. Through follow-up visits, lab work, and questionnaires, we will assess the safety and tolerability of metformin in this patient population. We will also measure the total and cyst volumes of the kidney and liver via magnetic resonance imaging to gauge the effectiveness of this drug. We also predict that proteins and small molecules involved in regulating the energy metabolism of the cell as well as proteins directly involved in AMPK function will be altered in ADPKD patients. Levels of these proteins and small molecules may then subsequently change with metformin therapy. To test this idea, urine samples from patients in the clinical trial will be sent to the University of Pittsburgh, and levels and activity of these specific proteins and small molecules measured. We hope to identify an easily isolated protein or small molecule that can act as a biomarker for disease severity and response to metformin therapy. Successful completion of this study would have a significant impact on this patient population by laying the groundwork for a new treatment strategy as well as by providing a new way to help guide treatment decisions.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510663
Entities
People
- Kyongtae Bae
Organizations
- United States Army
- University of Pittsburgh