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Dialysis Discussion => Dialysis: News Articles => Topic started by: okarol on August 03, 2011, 11:04:56 PM
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Nephrologists Discover Cause of Common Kidney Disease
08.04.2011
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 samples, scientists have discovered the first circulating factor known to start the process leading to FSGS. The finding, a fundamental principle of the origin of kidney disease, is published in the July 31 edition of the journal Nature Medicine.
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 targeted treatments for 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 membrane 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. FSGS occurs due to a breakdown of podocytes, fusing them together, and allowing protein to infiltrate the urine leading to scarring of the kidney.
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 diabetic nephropathy, which is often termed secondary FSGS and is the most common 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 CEO of UHealth-University of Miami Health System. “By identifying 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 be produced in 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 kidney transplantation, 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 of FSGS 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 structure. Following this hypothesis, he began looking for activators of podocyte motility. He and his colleagues used genetic 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 the benefit of 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 as diabetic 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 soon.”
http://med.miami.edu/news/nephrologists-discover-first-ever-blood-circulating-factor-that-causes-well
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The cause of fsgs really has been a mystery, and now we have substantive clues!! This is fantastic! Maybe those newly diagnosed can have the disease process stopped. What do you think they'd use...plasmapheresis or some such procedure? How would they get rid of those circulating elements they've found cause fsgs? Well, it's probably too late for me, but if I am ever lucky enough to get a transplant, maybe by then, they will be able to do so much more to make sure the risk of fsgs recurrence is greatly decreased. There's still hope!!!
Oh my God, can you imagine...this could lead to a cure for fsgs!! It's wonderful news!!
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It's pretty exciting to think there's some progress in understanding what causes this and maybe down the track some forms of treatment. Always good news to see articles like this!
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If they can make this work out into a cure, and continue with their efforts to cure juvenile diabetes, just think how much shorter the wait list could be in the future! :bandance;
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Exactly. There needs to be a lot more work done on trying to keep people off dialysis in the first place, too.
This news of the cause of FSGS is so marvellous. I was diagnosed 20 years ago, right after my son was born, but once it became apparent that he was having developmental difficulties, I didn't think much about my kidneys for at least a decade. But once I moved back to the US and saw a neph here, I clearly remember my first visit with him, and he was not optimistic about my chances to stave off dialysis for much longer. He DID, however, tell me that there was so much research going on in nephrology that I shouldn't lose hope. As pessimistic as I am in general, I HAVE been optimistic that soon there would be some breakthroughs, and this is a good one.
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This is Awesome News!!! Now Im not real familar with FSGS, but if they find a cure, then would there be a possibility the kidneys can start to function again?
lmunchkin :flower;
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I have FSGS and this is definitely good news.
The Wikipedia article on FSGS should be updated to include this new information.
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This is Awesome News!!! Now Im not real familar with FSGS, but if they find a cure, then would there be a possibility the kidneys can start to function again?
lmunchkin :flower;
I could be wrong, but I doubt it. I don't think a "cure" would revitalize scarred tissue and make it function normally again. I'm thinking that the scarring you have is permanent. But if they could devise a way of removing from the blood this suPAR stuff, then maybe it would stop the sclerotic process, so if you are diagnosed with fsgs but still have a reasonable amount of function left, perhaps you could avoid that slide down into the abyss.
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So most likely the final Prognosis is No to the cure, but these findings may help to bring about a prevention in the future! I wonder if these studies are done on animals or do they have human volunteers that bring them to this conclusion. IDK, but its a sign in the right direction!
lmunchkin :flower; :bandance; :bandance; :bandance;