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UofL researchers help identify key protein in chronic kidney disease

July 2nd, 2009

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Left to right: Jon Klein, David Powell and Tim Cummins

Three researchers at the University of Louisville are part of an international team that for the first time has identified a key protein at the center of a debilitating kidney disease. The discovery opens the door to new diagnostic tools and potential treatments for membranous nephropathy, a chronic condition in which the body’s own immune system attacks the kidneys.

The findings, which experts described as “a breakthrough,” appear in the July 2, 2009 edition of the New England Journal of Medicine.

Jon Klein, M.D., Ph.D., director of UofL’s Clinical Proteomics Center and one of the study’s co-authors, and his UofL colleagues, David Powell, Ph.D., and Tim Cummins, played a central role in the study by providing expertise available at just a handful of labs around the world.

Approximately 60,000 Americans suffer from membranous nephropathy, said Klein, who holds the James Graham Brown Endowed Chair in Proteomics at the UofL School of Medicine. Two-thirds of those people eventually require regular dialysis to purify their blood, and many eventually must undergo kidney transplants followed by a lifetime of immunosuppressive drug therapy.

The new study builds on more than 25 years of research conducted by David Salant, M.D., a professor of medicine at Boston University. Salant, the lead author of Thursday’s report, had long known that membranous nephropathy was an autoimmune disorder, but scientists around the world were unable to determine the molecular mechanisms behind the disease. Working with Laurence Beck, M.D., a colleague at Boston University, Salant set out to identify the autoimmune mechanisms that cause antibodies to bind to and damage the kidney in patients with membranous nephropathy.

“One of the keys to understanding, diagnosing and treating the disease has always been knowing what proteins in the kidney are being attacked by the body’s immune system,” Klein said. “Until now, we didn’t know. Now we think we do. That’s a pretty big step forward, and it wouldn’t have been possible without the unique work done by Dave Powell and Tim Cummins in the UofL Clinical Proteomics Center.”

Salant and his team of researchers, who include scientists based in Nice, France, first sought Klein’s help about three years ago because they needed a lab that could analyze the thousands of proteins in the kidney and isolate which ones might be involved in membranous nephropathy.

This kind of analysis — known as proteomics — requires specialized knowledge and equipment, both of which were available at UofL in the form of its Core Proteomics Laboratory and Clinical Proteomics Center. The lab was, in fact, one of the first in the nation and one of only a handful in the world to specialize in the proteomic analysis of kidney tissue — a fact Klein attributes to investments made by UofL and the Commonwealth of Kentucky over the past decade to attract top scientists and provide them with state-of-the art facilities through a program called “Bucks for Brains.”

Salant’s group sent affected kidney samples to UofL, where Powell and Cummins examined them with a mass spectrometer to determine which of the proteins had become “bound to” — or attacked by — the antibodies produced in the immune system of a person with membranous nephropathy.

From a list of more than 1,000 possible proteins, Powell was able to identify just 20 likely candidates. Salant’s group then eliminated another 10 using various analytical models and tested the remaining group in laboratory experiments for more than a year. One protein eventually emerged as a key factor in the development and progression of membranous nephropathy.

“I don’t want to overstate our contributions here, because Dr. Salant’s team was the group that ultimately figured out which protein was involved,” Klein said. “But it was our application of proteomic tools that facilitated this breakthrough.”

The UofL and Boston teams now are working together to capitalize on the discovery with the goal of developing a blood or urine test for early detection, supplanting current diagnostic tools like biopsies that are painful and carry a small risk of death.

As for potential treatments, further study will be required. But Klein noted that the protein is a candidate for new approaches that could stop the disease process of membranous nephropathy in its tracks.

“This opens the possibility that we could develop therapies that block the antibodies from binding to this specific protein,” he said. “For example, we could create designer proteins that mimic the target protein, and those designer proteins would then bind with the antibodies, leaving the original protein targets unaffected by the disease process.”

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