National Kidney and Urologic Diseases
Information Clearinghouse (NKUDIC)

A service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH)

Kidney Disease Research Updates
Spring 2012

Cause of FSGS, Devastating Kidney Disease, Discovered

Photograph of a research scientist in front of a microscope, who wears a medical hairnet, mask, gloves, and lab coat.

Focal segmental glomerulosclerosis (FSGS) is a common cause of kidney failure, affecting both children and adults. FSGS is marked in its early stages by proteinuria and can be found in both native and transplanted kidneys. Treatments for FSGS have been limited as the causes of the disease have not been fully understood. However, a team of researchers supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has made a discovery that might yield new treatments and help assess risk in transplantation.

Jochen Reiser, M.D., and colleagues at the University of Miami Miller School of Medicine published a breakthrough paper in Nature Medicine that sheds light on the pathogenesis of FSGS. Researchers have long known that FSGS recurs in about one third of patients who receive a transplant, a sign that the cause of the disease resides in the blood circulating through the kidney rather than in the kidney itself. With funding from NIDDK, Dr. Reiser and colleagues discovered that about two-thirds of people with FSGS have elevated blood levels of a substance called serum soluble urokinase receptor (suPAR). The elevated levels of this factor are not found in people with other glomerular diseases.
FSGS affects kidney function by attacking the glomeruli, the tiny units within the kidney where blood is filtered. There are approximately 1 million glomeruli in each kidney. Each glomerulus includes blood vessels with specially modified walls which serve as the filter. Podocytes are the cells in the vessel wall that regulate which elements of the blood pass through the membrane into the urine. When the kidneys are healthy, protein remains in the blood while wastes and salts pass through the membrane.
Using mouse models and a bank of patient samples, the research team found that circulating suPAR activates a protein on the surface of the podocytes. This disruption causes protein from the blood to pass through the membrane into the urine. As a result, the kidneys become scarred and an FSGS-like disease develops in the mouse. Dr. Reiser and colleagues speculate that reducing the amount of suPAR in the blood by plasmapheresis— a process that filters the blood—might prevent FSGS from developing in the transplanted kidney. The research team also noted that another treatment strategy might be to interfere with the interaction between the suPAR in the blood and the protein on the surface of the membrane cells.
“This is an exciting discovery,” said Reiser in an online video, “because it allows us to track the levels of suPar in the blood of patients with FSGS. This work shows convincingly and for the first time the existence of a circulating FSGS factor. The discovery allows us to potentially derive new therapies that are aimed at removing this protein from the blood, which will give rise to better therapies very soon. Overall it will help us to better stratify risk in transplantation cases and will also help us to engage in more and better research in the future.”
The National Kidney and Urologic Diseases Information Clearinghouse, part of the NIDDK, offers fact sheets and easy-to-read booklets about the kidneys, kidney disease, and treatments for kidney failure. For more information or to obtain copies, visit www.kidney.niddk.nih.gov.

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