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Researchers launch human clinical trial to halt progression of polycystic kidney disease

A treatment for a disease that can make kidneys grow as large as footballs before renal failure occurs is the focus of human clinical trials that begin this fall under the guidance of a team of IU researchers and a colleague at the Mayo Clinic.

INDIANAPOLIS -- Under a three-year, $600,000 Food and Drug Administration grant, Bonnie Blazer-Yost (pictured) and Dr. Sharon Moe will serve as co-principal investigators into whether pioglitazone -- also known by its trade name Actos -- is an effective long-term therapy to stop autosomal dominant polycystic kidney disease, or PKD, in its tracks.

Between one in 400 and one in 1,000 people suffer from PKD, according to the National Institute of Diabetes and Digestive and Kidney Diseases. It accounts for 2.2 percent of kidney failures reported in the U.S. annually, according to the U.S. Renal Data System.

While healthy adult kidneys are the size of a fist and weigh less than a pound, polycystic kidneys can weigh as much as 20 to 30 pounds. The fluid-filled cysts initially grow out of nephrons -- tiny filtering units within the kidney -- but eventually separate from the nephrons and continue their growth while the kidney enlarges as well. Other PKD complications can include high blood pressure, liver cysts and blood vessel problems in the brain and heart.

Autosomal dominant PKD is the most commonly inherited kidney disorder. Children of a parent with the gene mutation have a 50 percent chance of inheriting it. Most cases are identified in patients between ages 30 and 50, and more than half experience kidney failure by age 70.

“It does not seem to affect most people until mid-life. But when it does it becomes painful and increasingly debilitating,” Blazer-Yost said. “At present, there are no FDA-approved drugs to treat PKD, and the only therapies are to either aspirate the larger cysts to relieve the pain or perform a transplant once the kidney fails.

“What we hope to demonstrate is the ability to halt or greatly inhibit cystic growth in our trial participants. If this proves successful, it will lead to larger trials with the ultimate goal of having a treatment for PKD that can be used as a lifelong medication.”

Blazer-Yost is a biology professor at Indiana University-Purdue University Indianapolis, while Moe serves as a professor and chief of nephrology at the Indiana University School of Medicine. Dr. Robert Bacallao, an associate professor of medicine and director of the Polycystic Kidney Disease Clinic at the IU School of Medicine, also will serve as a co-investigator. Dr. Vicente Torres, a professor of medicine at the Mayo Clinic’s Division of Nephrology and Hypertension in Rochester, Minn., will consult and provide magnetic resonance imaging interpretation for the study.

Supplementary funding is provided by the Kansas City, Mo.-based PKD Foundation, which will purchase drugs for the trial. The Indiana University Research and Technology Corp. also is working with Blazer-Yost to find commercial partners for additional drug development.

“This trial demonstrates the strength that Indiana University brings to discovering life-changing treatments for patients when scientists and physicians collaborate,” said David Wilhite, IURTC’s assistant director of technology commercialization.  

Blazer-Yost’s work to battle PKD originated in diabetes research. Shortly after arriving at IUPUI in 1993, she worked with GlaxoSmithKline to determine why rosiglitazone, a Type 2 diabetes drug also known as Avandia, caused fluid retention. Her findings revealed that the drug affected a different electrolyte channel -- one involving chloride -- than the drug company expected.

“As it turned out, this was the same chloride channel involved in cyst growth in PKD,” Blazer-Yost said. “In PKD, the chloride channel causes chloride secretion into the cysts, water follows and the cysts enlarge.”

From there, Blazer-Yost and the late Dr. Vincent Gattone, an IU School of Medicine professor of anatomy and cell biology who died of cancer in 2014, used animal models to study how rosiglitazone and the similar compound pioglitazone may be useful in treating PKD. Through studies funded by IUPUI and the IU School of Medicine, it was shown that both drugs not only delayed PKD cyst growth in rats, but did so in concentrations 10 times smaller than doses used to treat diabetes.

“This is exciting because it diminishes any side effect of these already safe compounds,” Blazer-Yost said. “Because of this, we foresee these drugs as being a lifelong medication that will keep the disease from getting worse.”

Because pioglitazone already is used to treat diabetes, research could move quickly into human clinical trials, to be based at the IU School of Medicine, Blazer-Yost said. Patient recruitment begins this month, with 28 subjects envisioned for the study’s first two phases. For information about volunteering for the trial, contact Kristen Ponsler-Sipes at 317-944-7580, or kmponsle@iu.edu.

(Source: Bill W. Hornaday, Innovate Indiana)