Management of the Highly HLA‐ Sensitized Patient. A Novel Role for Intravenous Gammaglobulin

Kidney transplantation has emerged as the desired treatment of choice for patients with end-stage renal disease (ESRD). Data from UNOS (United Network for Organ Sharing) show that patients who are highly sensitized to HLA antigens have limited access to kidney transplantation. Approximately 90% of kidney transplants performed in the USA each year are in patients who have no sensitization. The rate of transplantation of highly sensitized patients has decreased 50% from 1988. Our experience has indicated that patients who develop anti-HLA antibodies are predominantly female, and gain their sensitized state through pregnancy, blood transfusions or from previous transplants that have been rejected. These patients often wait > 5 years for an offer of kidney transplantation because they require a near perfect match to achieve transplantation. Prior to the development of protocols using intravenous gammaglobulin (IVIG), no other effective protocols were available to enhance the ability of these patients to acquire a kidney transplant. Intravenous gammaglobulin preparations are known to have potent immunoregulatory properties in human disease (1). Among these is the ability to reduce or eliminate phlogistic autoantibodies and improve autoimmune diseases. These observations led to the initial investigations by Glotz and our group into the ability of IVIG to regulate alloantibodies in highly sensitized ESRD patients. Our work and that of others 2-10) has shown that IVIG contains anti-idiotypic antibodies that inhibit anti-HLA specific antibodies in vitro and in vivo. Specifically, we and others have shown that highly HLA-sensitized end-stage renal disease patients (ESRD) can experience long-lasting reductions in anti-HLA antibody levels post-IVIG infusions and that successful transplantation can be accomplished with a crossmatch negative histo-incompatible organ 3-8). We and others have also shown that IVIG therapy alone is effective in reversing severe antibody-mediated rejection episodes that are refractory to amelioration by OKT3 or other antilymphocyte preparations (11, 12). IVIG may also be useful for ongoing acute rejection (AR) episodes unresponsive to standard therapies. In our hands, IVIG has been very useful in reversing antibody mediated allograft rejection in cardiac allograft recipients as well. Often, it is easier to document responses, since allograft biopsies are done routinely. The use of IVIG in cardiac allograft recipients for desensitization and treatment of AR episodes needs to be more clearly defined. In this issue of the American Journal of Transplantation, Glotz et al. present data on 15 highly sensitized ESRD patients awaiting transplantation, treated with intravenous gammaglobulin (IVIG) alone in attempts to reduce or eliminate the highly sensitized state. Thirteen were successfully transplanted after IVIG desensitization therapy reduced their anti-HLA antibody levels. These observations come at a critical time as the number of patients coming to the transplant list is increasing, along with an increase in the number of sensitized patients. According to UNOS data, approximately 20% of patients on the current transplant list are sensitized [panel reactive antibody (PRA) > 20%]. In France, more than 50% of patients have reactive PRAs. In addition, ∼ 30% of new patients coming to the transplant list are sensitized. Thus, these patients tend to spend longer times on dialysis before ever being offered a kidney transplant. When transplanted, highly sensitized patients tend to have greater risks for allograft loss through more frequent and intense rejection episodes. Our studies led to an NIH Controlled Clinical Trial of IVIG vs. Placebo which entered 101 patients in a randomized, multicenter trial in the USA. Data from this trial will be available later this year. We have also continued to use IVIG outside the clinical trial format and have found results similar to those reported by Glotz in this issue of AJT. Considering the enormity of the problem, this paper represents an excellent contribution to our understanding, especially when other emerging protocols using plasma exchange with IVIG are also being used (10). Glotz's data suggest that repeated IVIG administrations can desensitize patients and allow for successful transplantation in most patients. Another important observation is the low rate of allograft rejection observed after transplantation. This has not been the case with protocols employing plasma exchange + IVIG (10). Taken together, this paper is an important first contribution to our understanding of the effectiveness of IVIG in highly sensitized patients. Further investigations into the relevant mechanism(s) of action of IVIG in allo-sensitized patients and larger controlled clinical trials of the various therapeutic approaches will be necessary for development of strategies that can predict patients likely to respond to specific therapies. In addition, studies will need to be carried out to examine the relative efficacy of plasma exchange (+) IVIG, anti-CD20 (Rituximab) therapy with/without IVIG and other B-cell-directed agents in managing highly sensitized patients. However, it is important that after so many years of ‘waiting for a perfectly matched kidney’ we can now offer patients an active process to help reduce their anti-HLA antibodies and allow them access to transplantation that they were previously denied.