A collaboration of Miller School physicians, surgeons and scientists has unlocked the mechanism of a drug used to prevent recurrent kidney disease. The finding, which has implications for the diagnosis and treatment of many other diseases, involves the action of rituximab, a B-cell lymphoma therapy, in treating recurrent focal segmental glomerulosclerosis (FSGS) in children and young adults.
Alessia Fornoni, M.D., Ph.D., assistant professor of medicine in the Division of Nephrology and Hypertension, is the lead author of the study which not only shows that rituximab is a valid treatment strategy in preventing recurrent FSGS in kidney transplant patients, but also for the first time uncovers a previously unknown mechanism of action of rituximab. The finding is published in the June 1 edition of the journal Science Translational Medicine.
Focal segmental glomerulosclerosis often leads to end-stage renal disease in pediatric and adult patients. While kidney transplantation can improve the mortality rate, as many as 80 percent of patients suffer a recurrence of the kidney disease and lose the transplanted organ. Therefore, there is a great need to find effective, long-lasting therapies.
Co-corresponding authors George W. Burke III, M.D., professor of surgery and director of the Division of Kidney and Pancreas Transplantation, and 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, have been collaborating on how to change the rate of recurrence of FSGS in their young patients following transplantation. Reiser says they began "an ideal collaboration" working with Fornoni, merging the disciplines of nephrology and surgery with science in an effort to find a solution.
Burke says this study started with the patients, working in a "bedside to bench and back to bedside process." The team knew of a case in which rituximab had been given to two lymphoma patients and proved effective against their kidney disease as well.
Using the biopsy tissue and serum collected from Burke's transplant patients, what Fornoni describes as a "gold mine of information," the team of scientists took a closer look at how the cancer drug worked in more than 40 patients.
Rituximab is a monoclonal antibody that targets the CD20 molecule on the surface of B cell lymphocytes. Podocytes, or kidney cells, express certain properties similar to B cells, leading Fornoni, Reiser and Burke to theorize that rituximab was working via podocytes, not B cells.
In cases of recurrent FSGS, they observed that patients express a decrease in the amount of a protein (SMPDL-3b) regulating lipids at the plasma membrane (outer layer of a cell). Working between the patient samples and the laboratory, Fornoni, Burke and Reiser discovered that rituximab preserves SMPDL-3b and directly binds and protects kidney cells by modulating the composition and function of lipids at the plasma membrane. Of the patients given rituximab, the recurrence rate went from 64 percent down to 26 percent.
Reiser, director of the Peggy and Harold Katz Family Drug Discovery Center, says, "This will open doors to analyze other very important aspects of kidney diseases in general." Fornoni says the finding is also unique as it uncovers an assay that can be used before transplant to identify patients at risk for recurrent disease and to guide therapeutic decisions, allowing for a personalized medicine approach. The discovery, Fornoni says, "will likely unveil new clinical indications for rituximab beyond its original function and lead to new pathways involved in regulating cell function."
Burke points out that the observed benefit was accomplished with a single dose of rituximab given to patients within 24 hours of receiving a kidney transplant. They expect to expand the application of rituximab to adult FSGS patients receiving transplants.
The team also worked with Camillo Ricordi, M.D., scientific director of the Diabetes Research Institute, which provided support through its cell transplant center.
The team says the study results have implications far beyond kidney disease. The findings support reexamining diseases such as diabetes and atherosclerosis, which are characterized by an alteration of lipids at the plasma membrane level. "This is really a huge leap in terms of how we look at these diseases," says Reiser. "How we diagnose them, treat them and how we can derive new treatments. It's really a very powerful collaboration."
Source:
University of Miami Miller School of Medicine
