Nephrologists at the Miller School have solved a decades-long search for the cause of a significant form of chronic kidney disease – focal segmental glomerulosclerosis (FSGS).
Working with mouse models and a bank of patient FSGS. The finding, a fundamental principle of the origin of kidney disease, is published in the July 31 edition of the journal Nature Medicine., scientists have discovered the first circulating known to start the process leading to
Jochen Reiser, M.D., Ph.D., professor and vice chair for research in the Department of Medicine and chief of the Division of Nephrology and Hypertension, and Changli Wei, M.D., Ph.D., assistant professor of medicine in the Division of Nephrology and Hypertension, led a team of international researchers and physicians in discovering that a soluble form of the urokinase plasminogen activator receptor (suPAR) is a factor in triggering glomerular kidney disease.
“This is truly monumental and a great team effort that paid off,” Reiser said, “because we can measure the amount of suPAR, and develop targetedfor that factor or prevent what it does to the kidney.”
Each kidney is made up of approximately one million glomeruli, specialized capillary beds that filter the blood. The glomeruli are composed of endothelial cells, a FSGS occurs due to a breakdown of podocytes, fusing them together, and allowing protein to infiltrate the urine leading to scarring of the kidney.and podocytes. The podocytes have cellular foot processes that are bridged by a slit diaphragm and that wrap around the glomerular blood vessels. Podocytes work as goalkeepers in the kidney, preventing protein from leaking into the urine.
Focal segmental glomerulosclerosis is a common type of chronic kidney disease, with more than 5,000 new cases diagnosed each year. It often leads to end-stage renal disease, which affects approximately 20,000 people in the U.S. While podocyte gene defects are one cause, most cases have no known cause. FSGS shares similarities with nephropathy, which is often termed secondary FSGS and is the reason for end-stage renal disease. Reiser’s finding now explains possibly two-thirds of FSGS.
“This discovery is going to change the future of treating chronic kidney disease,” said Pascal J. Goldschmidt, M.D., Senior Vice President for Medical Affairs and Dean of the Miller School, and CEOof UHealth-University of Miami Health System. “By the first circulating factor that triggers the switch for glomerular disease, Jochen and his team have ended a 40-year search by pinpointing how the kidney filtration system breaks down. Scientists around the world can now focus on developing targeted therapies to minimize that factor.”
In 2008, Reiser and Wei published another study in Nature Medicine demonstrating that urokinase receptor (uPAR) can bein the podocyte, activating the β3-integrin switch, a protein involved in cell signaling. Left in an active state, this switch begins to set the podocyte foot processes in motion, leading to the degradation of the filter barrier (proteinuria), eventually turning the glomeruli into scar tissue, leading to glomerular disease.
Clinical reports from nearly 40 years ago revealed that FSGS can recur within minutes of kidneytransplantation, leading physicians to theorize that there were factors in the blood that were degrading the kidney. The hunt for the FSGS factor was on, in an effort to discover one of nephrology’s biggest secrets and to help high-risk patients including children, whose recurrence ofFSGS after transplantation can be as high as 86 percent.
“There is a clear need to discern what’s causing this disease to recur so quickly in so many patients,” Wei said. “Finding the factor will not only improve post-transplant FSGS but will also teach us the reason for pre-transplant FSGS as current therapies are limited, unspecific and minimally effective.”
Over the past decade, Reiser discovered that podocytes were motile cells, and thus the filter barrier in the kidney was a dynamic rather than a static. Following this hypothesis, he began looking for activators of podocyte motility. He and his colleagues used and molecular tools to discover, in a series of high impact publications including this paper’s finding, that blood suPAR or podocyte uPAR are what’s activating the β3-integrin switch in the podocyte. Too much suPAR in the blood and the switch remains active, degrading the podocyte and the kidney filter.
The findings were validated in kidney transplant patient samples. Reiser, director of the Peggy and Harold Katz Family Drug Discovery Center, points out theof this discovery to patients: “This could potentially explain fundamental pathologic issues that occur in chronic kidney diseases.” Those with native kidney disease can now be tested for suPAR levels and provided therapies that will aim to reduce that level. Similarly, transplant patients would have elevated suPAR levels reduced before surgery, ensuring a lower risk for recurrent disease. Reiser says identifying suPAR and the β3-integrin switch opens the door to general principles for other glomerular diseases such asdiabetic nephropathy.
Wei is hopeful their five-year-long study will lead to new treatments. “Patients with FSGS and other glomerular diseases will benefit from our finding very
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