This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Renal transplantation has emerged as the renal replacement therapy of choice for patients with end stage renal disease, and offers superior life expectancy and quality of life as compared to maintenance on dialysis. In the United States there are over 53,000 patients with end stage renal disease that are waiting for a kidney transplant. Over 200,000 patients in the United States are currently on dialysis. Of these patients, greater than 30% are considered highly sensitized to human leukocyte antigens (HLA), with an anti-HLA panel reactive antibody (PRA) of greater than 30%. Panel reactive antibody is a measurement (between 0-100%) used to determine the percent a potential recipient is sensitized against donor class 1 HLA antigens. Patients with elevated anti-HLA antibodies often wait extended periods of time for a compatible donor. Transplantation of incompatible organs with positive antibody cross-matches usually results in severe rejection and allograft loss. In addition, sensitized patients who receive a transplant from a living donor or deceased donor have a much shorter graft half-life. Recently, strategies to acutely eliminate alloantibodies have been reported, incorporating the use of immunosuppression, antibody depletion by plasmapheresis and intravenous immune globulin to modulate immune responses against alloantigen. The incidence of antibody mediated rejection associated with such protocols is significant, suggesting acute desensitization may not be durable in many patients. An alternative to currently employed desensitization approaches would be the use of immunosuppression to achieve long lasting reductions in anti-HLA antibodies in patients on the kidney transplant waiting list. This would have the advantage of increasing potential for transplantation from both living and deceased donors. Alemtuzumab is a humanized monoclonal antibody against CD52 which depletes T and B cells, monocytes and certain dendritic cells. Because of Alemtuzumab's depletional effect on both T cells, B cells and certain populations of dendritic cells, it may be ideally suited for eliminating certain memory B cell responses, such as in patients who have developed anti-HLA antibodies. We propose to use Alemtuzumab to achieve durable reduction in anti-HLA antibodies in end stage renal disease patients awaiting renal transplantation. Subjects will be infused with four doses of Alemtuzumab on four consecutive days. They will be monitored periodically for three years to assess the durability of the reduction in anti-HLA antibodies. The hypothesis being that persons previously considered untransplantable may become transplantable and have the same chance for a successful and long lasting transplant as in those patients with a PRA 30%.
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