Old Drug, New Use

Old Drug, New Use 1024 575 Katie Brind'Amour, PhD, MS, CHES
Nationwide Children's style illustration showing a row of houses with a prescription in front of it

Researchers have discovered an adult diabetes drug may provide a new and better way to treat children  with nephrotic syndrome. 

Nephrotic syndrome is one of the most common kidney diseases seen in children. In most cases the cause is unknown. Nephrotic syndrome involves damage to the filtering units of the kidneys (glomeruli) leading to massive protein loss in the urine (proteinuria). This results in low protein levels in the blood (hypoalbuminemia) and swelling in the body (edema).

For decades, the condition has had one mainstay treatment: glucocorticoids. Unfortunately, about 20% of children don’t respond to glucocorticoids , and follow-up options are limited. Furthermore, steroids cause immunosuppression and have other significant side effects, especially when used repeatedly or over long periods of time — so much so that clinical practice guidelines often recommend limiting steroids to the shortest possible duration.

“I’ve been studying the molecular regulation of injury to podocytes — the key cells in the kidney’s filtration barrier — for more than 30 years, looking for novel treatments for childhood nephrotic syndrome,” says William E. Smoyer, MD, a pediatric nephrologist who is vice president of the Abigail Wexner Research Institute at Nationwide Children’s Hospital and director of its Center for Clinical and Translational Research. “I want to find out how and why glucocorticoids work — and why they sometimes don’t — so that I can find more effective and less toxic ways to treat these children.”

Dr. Smoyer’s research team realized glucocorticoids are taken up by cells’ steroid receptors and used to turn hundreds of genes on or off. They figured there might be other drugs that could do the same — without requiring the drug’s characteristic immunosuppression for a beneficial effect.

As it turns out, an entire class of adult diabetes drugs approved by the U.S. Food and Drug Administration (FDA) get into cells by binding to a similar receptor.

“We wondered if we could use already approved drugs for adults with diabetes to treat children with nephrotic syndrome,” says Dr. Smoyer. “If we could stimulate a similar healing process in podocytes using something other than glucocorticoids, we might be able to treat people without suppressing their immune systems and with less toxicity.”

Dr. Smoyer’s team wasted no time studying these approved drugs in podocyte cell cultures in the lab. When the diabetes drug pioglitazone looked promising, they moved to animal models and found similarly encouraging results.

“To our surprise, pioglitazone could reduce proteinuria almost as well as glucocorticoids,” says Dr. Smoyer. “That’s when we realized we had the real opportunity to repurpose pioglitazone for children with nephrotic syndrome.”

Although there are few technical barriers to use of an approved drug for a different indication, the research to confirm efficacy and develop a new formulation for children with nephrotic syndrome has been hard to finance. The drug wouldn’t be classified as a “new chemical entity” with the same patent protection as a brand-new drug; pioglitazone is now made by generic drug companies only.

Dr. Smoyer’s team, however, understood the potential clinical importance of the research and started publishing and sharing the findings at professional conferences. Undeterred by funding challenges and encouraged by immediate interest on behalf of his nephrology colleagues, a promising case study and even supportive outreach from the FDA, Dr. Smoyer hatched plans for a new company dedicated to the development of pioglitazone as a novel, non-immunosuppressive treatment for childhood nephrotic syndrome.

The Office of Technology Commercialization at Nationwide Children’s helped Dr. Smoyer file the patent. NephCure Kidney International, an organization that supports research to find effective treatments for nephrotic syndrome and other glomerular diseases, and of which Dr. Smoyer is a long-time board member, helped facilitate connections for company leadership. And Dr. Smoyer’s new company, NephKey Therapeutics, Inc., was born.

NephKey Therapeutics intends to protect development of a new formulation of the drug, specifically to treat children, using the FDA’s 505(b)(2) pathway.

“This drug has safety data from hundreds of thousands of people, but in this case, they’re the wrong people!” says Dr. Smoyer. “The FDA is very interested in the idea of repurposing a drug to address a significant unmet medical need for children, and their support is probably the best momentum we have going for us.”

A case series reporting further promising results of the drug’s use in children with nephrotic syndrome is pending publication. The full clinical trial is already under discussion with the FDA, and Dr. Smoyer estimates the first round of clinical trial work can be completed with less than $1M in additional funding.

“It took a long time to get to this point,” says Dr. Smoyer, “but things are finally coming together. I’m first and foremost a clinician, and this has been what I’ve been working toward for my entire career: a new and better treatment option for my patients.”


  1. Agrawal S, Chanley MA, Westbrook D, et al. Pioglitazone Enhances the Beneficial Effects of Glucocorticoids in Experimental Nephrotic Syndrome. Sci Rep. 2016;6:24392. Published 2016 May 4.
  2. Agrawal S, Guess AJ, Benndorf R, Smoyer WE. Comparison of direct action of thiazolidinediones and glucocorticoids on renal podocytes: protection from injury and molecular effects. Mol Pharmacol. 2011 Sep;80(3):389-99.
  3. Waller AP, Agrawal S, Wolfgang KJ, Kino J, Chanley MA, Smoyer WE, Kerlin BA; Pediatric Nephrology Research Consortium (PNRC). Nephrotic syndrome-associated hypercoagulopathy is alleviated by both pioglitazone and glucocorticoid which target two different nuclear receptors. Physiol Rep. 2020 Aug;8(15):e14515.

About the author

Katherine (Katie) Brind’Amour is a freelance medical and health science writer based in Pennsylvania. She has written about nearly every therapeutic area for patients, doctors and the general public. Dr. Brind’Amour specializes in health literacy and patient education. She completed her BS and MS degrees in Biology at Arizona State University and her PhD in Health Services Management and Policy at The Ohio State University. She is a Certified Health Education Specialist and is interested in health promotion via health programs and the communication of medical information.