McGowan Institute for Regenerative Medicine faculty member Ron Shapiro, MD (pictured), of the Thomas E. Starzl Transplantation Institute and a Professor of Surgery at the University of Pittsburgh, recently assessed a new therapy developed at Cedars-Sinai Medical Center which may improve transplant rates and outcomes for patients awaiting living- and deceased-donor kidney transplantation. The therapy may provide an option for many patients “sensitized” to transplant antigens (human leukocyte antigens, or HLA) who previously would not have been candidates for transplantation because of their intense immune response to these HLA targets.
Dr. Shapiro comments in the New England Journal of Medicine (Reducing Antibody Levels in Patients Undergoing Transplantation, Editorial by Dr. Ron Shapiro, 359;3, July 17, 2008), “As the authors note, their observations need to be confirmed and validated by other centers and in larger numbers of patients and during longer periods of follow-up. However, their approach may represent a breakthrough in the care of sensitized patients awaiting transplantation and may have the potential to help thousands of patients who are languishing on waiting lists around the world.”
HLA exposure can come through blood transfusions, previous transplantation, or pregnancy. Once exposed, the immune system is sensitized to those antigens and develops antibodies to fight them. If a donor organ with the antigens is later transplanted, the antibodies respond, increasing the risk of rejection and loss of the organ. Antibodies to HLA were previously considered an absolute contraindication to transplantation – the risk was too high for transplantation to be an option.
About 30 percent of the 74,000 patients on the transplant waiting lists for a deceased-donor kidney are sensitized, and those with exceptionally high antibody levels are considered especially poor candidates for transplantation. In fact, each year only 6.5 percent of highly sensitized patients receive a transplant. Most remain on dialysis indefinitely, without hope for a life-saving transplant.
“From a quality-of-life perspective, as well as from the financial standpoint, transplantation is a much better option than years of dialysis,” said Stanley C. Jordan, M.D., director of the Division of Nephrology and medical director of the Renal Transplant Program at Cedars-Sinai. The senior author of the journal article, Jordan developed high-dose intravenous immunoglobulin (IVIG) therapy to “desensitize” highly sensitized patients and increase their chances of successful transplantation. The approach became a Medicare approved therapy in 2004 at the conclusion of a National Institutes of Health-funded multicenter study.
Cedars-Sinai is a national leader in desensitization for the highly HLA sensitized patient, offering therapy for those awaiting both living-donor and deceased-donor transplantation. Dr. Jordan’s article describes a Phase I/II safety and limited efficacy trial of a combination of IVIG and rituximab, a monoclonal antibody – an antibody engineered to bind to a specific protein. The combination of IVIG and rituximab appears to offer superior benefits to IVIG alone, improving transplant rates to 80 percent of treated patients. The 1-year patient and graft survival rates were 100 percent and 94 percent, respectively. Based on these results, the new protocol is less costly than IVIG alone yet appears to be highly effective in reducing antibody levels and improving transplantation rates. Larger, multicenter trials are necessary to confirm these findings. Because nearly one-third of kidney failure patients are highly sensitized and few transplant centers specialize in desensitization therapy, many potential candidates are told that a transplant simply is not possible.
For many patients in a highly sensitized state, especially those awaiting a deceased-donor transplant, the combination of IVIG and rituximab appears to offer an alternative to ongoing dialysis.
Illustration: McGowan Institute for Regenerative Medicine.
Cedars-Sinai Medical Center News Release (07/16/08)