Genetics & Other Research
May Unravel FSGS Mysteries

Is it possible that a researcher in a laboratory in Massachusetts or Michigan of Maryland can help you or your loved one in the battle against focal segmental glomerulosclerosis (FSGS)?

If you can be persuaded to give up a little blood and urine for genetic testing, the answer may be yes.  That’s because researchers are finding that some variations of FSGS are caused by gene mutations, and knowing if you such a mutation can be useful to you and your doctor.

At a recent scientific workshop, scientists discussed research showing that FSGS patients with certain genetic mutations are unlikely to respond to steroid therapy. Steroids (and their often troublesome side effects) have been the standard therapy for patients first diagnosed with Nephrotic Syndrome. That condition, in which kidney filters malfunction and leak protein into the urine, can be a precursor to FSGS.

On the other hand, patients with certain mutations will have a reduced risk for a recurrence of FSGS if they need a kidney transplant, it was reported.

Scientists leave it up to nephrologists if and how genetic test results may be used to determine medical decisions.  And researchers take pains to point out that genetic indicators come from anecdotal research with not nearly enough numbers to draw conclusions that can be applied to patient populations. More study (and patient specimens), they say, are needed.

In his presentation to the workshop in Bethesda, MD, researcher Friedhelm Hildebrandt, M.D., of the University of Michigan, reported that the seeds of FSGS seem to be centered in the glomerular slit membrane of each of the one million filters in each kidney.

The slit membrane is shaped in large part by the podocyte, a strange-looking cell with numerous “feet” that fan out like tentacles over the main filtering unit (the glomerulus). The many slits formed by the sprawling mass are where filtration takes place and where some researchers have discovered proteins that interact, talk to each other and affect the shape and integrity of the podocyte.

Another speaker at the workshop, Thomas Benzing, M.D., a researcher from Freiburg Germany, said the “slit diaphragm is where it happens.” In that small space, he said, “proteins build barriers that not only construct the filtration barrier but send signals to the podocyte in a way that lets the podoctye retain the necessary shape.

“When something goes askew, the barrier fails and the podoyte loses shape and the whole system malfunctions,” he said.

Dr. Hildebrandt said that positional cloning, identifying genes based on their location on a chromosome, has helped identify several mutations and is likely to identify many more.

A member of the NephCure Foundation Scientific Advisory Board (SAB), Dr. Hildebrandt has for several years provided genetic testing of the blood of FSGS patients at no charge as part of his ongoing research. More details can be found at www.renalgenes.org.

Another NephCure SAB member, Martin R. Pollak, M.D., Harvard Medical School, Brigham and Women’s Hospital, is a co-author of a pioneering paper reporting on one of the podocyte mutations.  He too has been offering free genetic analysis of patient blood.  More information is available at www.fsgs.bwh.harvard.edu.

Dr. Jeffrey of the National Institute of Diabetes and Digestive and Disease of the Kidney (NIDDK) also offers genetic testing for FSGS at no charge.  More information is available on the website for Dr. Kopp's laboratory, www.intramural.niddk.nih.gov.

The workshop also heard from researcher Roger Wiggins, M.D., University of Michigan, another NephCure SAB member, who has been studying the relationship between podocyte loss and kidney failure.  There are a limited number of podocytes in the kidney, and they may be lost from injury, from an infection or a drug, for example, he said.