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NCF-Funded Researcher Finds Cancer Drug Helps Post-Transplant

Dr. Alessia Fornoni, an assistant professor of medicine in the Division of Nephrology and Hypertension at the University of Miami’s Miller School of Medicine, and her team discovered an interesting finding when studying young patients with Focal Segmental Glomerulosclerosis (FSGS) undergoing a kidney transplant.

FSGS is a disease that affects the kidney’s filtration system allowing valuable proteins needed for good health to escape from circulating blood into the urine.  FSGS is one the major primary kidney diseases causing end stage renal disease requiring dialysis and/or kidney transplant.  A major problem of patients with FSGS receiving a kidney transplant is a very high risk for recurrence of FSGS leading to loss of the transplanted organ. Fornoni identified that the drug rituximab, used primarily for cancer treatment, can help reduce the post-transplant recurrence of FSGS.

Fornoni’s research showed that post-transplant patients who received rituximab had a 26 percent chance of recurrence, compared to a 64 percent recurrence rate for patients who didn’t take the drug. Fornoni’s research also suggests that a test for the prediction of recurrent FSGS could be developed in the pre-transplant setting and help guide patient-specific therapeutic decisions.

Now, with a new grant from The NephCure Foundation, Fornoni will work with kidney biopsies and blood from patients with FSGS to characterize new mechanisms responsible for the recurrence of FSGS after transplantation and to define the molecular mechanisms by which rituximab may protect kidney function. 

“Our study may lead to a novel clinical indication for rituximab; it may also unveil new targets for drug development, and may lead to an assay to identify which patients are at risk for recurrent FSGS disease after a kidney transplant”, says Fornoni. “NephCure’s families and their children provide motivation for me to work very hard in search for a cure. I am grateful for NephCure’s support to help me continue with this line of research.”

FSGS is the second-leading cause of kidney failure in children and there are 5,400 new cases diagnosed each year among children and adults. Supporting research also proves that the disease is five times more prevalent among African Americans. Additionally, the FSGS disease group accounts for approximately 12 percent of prevalent end stage renal disease (ESRD) cases at an annual cost in the United States of more than $4 billion.

Although the mortality rate associated with ESRD can be partially improved by kidney transplantation, many patients with FSGS tend to loose the transplanted organ due to the recurrence of the disease. In fact, recurrence rates as high as 80 percent have been reported, and there is limited capability to predict recurrent FSGS in post-transplant patients.

The NephCure Foundation has committed over $7 million for research to find a cure for FSGS and Nephrotic Syndrome.

MORE ABOUT THE STUDY

Fornoni and her colleagues used as a starting point the knowledge of two cases in which a monoclonal antibody called rituximab was used in the treatment of the patients’ lymphoma (a cancer in the lymphatic cells of the immune system) but it also seemed to improve the patients’ kidney disease. Fornoni and her colleagues then followed 27 high-risk patients with primary FSGS who received kidney transplants to determine how rituximab exerts a therapeutic effect.

Although the mechanisms of FSGS disease are still unclear, research indicates that injury to podocytes (a specialized kidney cell) plays a pivotal role in the disease. There is evidence that factors in the blood of patients with recurrent FSGS enhance the permeability of small blood vessels leading to large amounts of protein leaking into the urine (a condition called proteinuria). Fornoni’s laboratory research identified that rituximab binds to SMPDL-3b, a protein that regulates lipids at the outer layer of the podocyte, and reverses the negative effect of the FSGS blood factor(s) on podocyte structure that can lead to cell death. The research of Dr. Fornoni’s team is highly innovative because it identifies a new mechanisms by which rituximab may directly protect podocyte function, thus offering a strong rational for the utilization of rituximab for the prevention of FSGS recurrence and probably for many other diseases characterized by proteinuria. Furthermore, Dr. Fornoni has established and validated an assay that allows for the identification of patients at risk for recurrent FSGS. This assay is based on the utilization of sera from patients with FSGS collected prior to kidney transplant, which is much less invasive than obtaining kidney biopsies. When the sera is placed in contact with normal human podocytes, the behavior of podocytes can tell us how that patient will “accept” the kidney transplant and which medications are likely to be protective for that particular individual.