New Targets for Nephrotic Syndrome Treatment?

Columbus, OH — September 2017

Nephrotic syndrome (NS) is a leading cause of kidney failure despite current therapies.  One of the most serious complications of NS is blood clotting, which is regulated in part by the enzyme thrombin.

A recent study published in the Journal of the American Society of Nephrology has found the mechanisms by which thrombin induces damage of podocytes, the primary target cell of injury in NS, contributing to the progression of disease. Furthermore, the study showed that thrombin-specific inhibition reduced podocyte damage, and reduced the loss of key proteins into the urine from the blood.

“The one organ system the kidney is the most intimately in contact with, all the time, is blood,” says Bryce A. Kerlin, MD, a hematologist and principal investigator in the Center for Clinical and Translational Research at Nationwide Children’s Hospital as well as senior author of the study. “So why should we think it only cleans the blood, and the blood doesn’t do anything to it?”

During NS, thrombin cleaves protease-activated receptors (PARs) 3 and 4 in humans, leading to a cascade of signaling events that ultimately damages podocytes. Better understanding the mechanism by which thrombin damages the kidney could allow manipulation of this mechanism to reduce injury and enhance recovery.

Now that the proper receptors have been identified, this body of research may open up the possibility of using existing thrombin-inhibiting medications to treat the underlying disease, while simultaneously decreasing the risk of life-threatening blood clots.

The study brought together specialists in hematology, nephrology, and other fields to address a condition historically considered to be nephrology-specific. The collaboration allows for the expertise of hematologists like Dr. Kerlin to illuminate complications and nephrologists like contributing author William E. Smoyer, MD, director of the Center for Clinical and Translational Research, to develop innovative new treatments and improve understanding of the disease pathogenesis.

“Where we’ve found very fertile ground to advance our knowledge is in the intersection between the hematology community and the nephrology community,” says Dr. Smoyer. “Dr. Kerlin is talking about using blood thinners instead of steroids, which is what I would normally use, to treat the primary disease. That’s unheard of.”

“There is a lot of power not in the “subspecialty boxes” that medicine draws around how we train doctors, but instead at the intersection between medical subspecialties,” adds Dr. Smoyer. “Some of the best innovation happens there. I wasn’t trained in this and neither was Dr. Kerlin. It’s only a collaboration like this that enables us to do this type of work.”

Sharma R, Waller AP, Agrawal S, Wolfgang KJ, Luu H, Shahzad K, Isermann B, Smoyer WE, Nieman MT, Kerlin BA. Thrombin-induced podocyte injury is protease-activated receptor dependentJournal of the American Society of Nephrology. 2017 Apr 19.  [Epub ahead of print].