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Renal transplantation is considered the treatment of choice for patients with end-stage renal disease, since it offers improved survival and quality-of-life benefits as compared with dialysis and is considerably less costly to payers.1,2,3 Currently, there are more than 74,275 patients with end-stage renal disease in the United States on the deceased-donor waiting list, and more than 30,000 new registrants are added each year. Despite this, there are fewer than 18,000 total kidney transplantations in the United States each year.4

The waiting times for kidney transplants continue to increase, owing to the limited supply. This is especially true for patients for whom matching is difficult (those considered to be highly HLA sensitized).4,5,6,7 Alloantibodies (anti-HLA antibodies) arise through previous transplants, blood transfusions, and pregnancy. Currently, approximately 30% of the patients on the waiting list have evidence of sensitization, and only 6.5% of highly sensitized patients (those with a panel-reactive antibody level above 80%) receive a transplant each year.4 Over the past several years, two regimens have evolved to help improve transplantation rates in highly sensitized patients. These are the high-dose intravenous immune globulin protocol and the plasmapheresis plus low-dose intravenous immune globulin protocol.8,9,10,11,12

Our group previously reported results of the use of the high-dose intravenous immune globulin protocol and examined its efficacy in a randomized, multicenter, placebo-controlled trial in highly HLA-sensitized patients conducted by the National Institutes of Health (NIH) (the NIH IG02 study).9 From the NIH IG02 study, we observed that intravenous immune globulin significantly lowered anti-HLA antibody levels (P=0.04) and improved rates of transplantation (primarily from deceased donors) as compared with placebo (35% vs. 17%, P=0.02). The projected mean waiting time to transplantation was 4.8 years for patients treated with intravenous immune globulin as compared with 10.3 years for those who received placebo (P=0.03). The 3-year allograft survival rate was 80% in the intravenous immune globulin group as compared with 70% in the placebo group (P not significant).9

A protocol for high-dose intravenous immune globulin that was similar to the protocol in the NIH IG02 trial was used at our center from 2000 until 200510 and appears to be effective for some patients. However, the protocol required patients to undergo a 4-month period of treatment (with monthly doses of 2 g per kilogram of body weight, for a total of four doses) and was not always effective. For these reasons, we explored other potential approaches that might be as effective, might reduce the time to desensitization, and might be less costly.

Among such treatments, we considered rituximab, a chimeric anti-CD20 monoclonal antibody that reduces B-cell and antibody levels. The role of rituximab as a desensitizing agent has not been clearly defined. This monoclonal antibody has had demonstrated efficacy in the treatment of autoimmune diseases and is reported to be effective in the treatment of antibody-mediated transplant rejection.13,14,15,16 Other groups have reported that rituximab has synergistic effects with intravenous immune globulin in autoimmune skin diseases.
Survival Rates of Patients and Grafts

The 12-month patient and allograft survival rates among the 16 patients receiving a transplant were 100% and 94%, respectively. All 16 of these patients have had at least a year of follow-up. The single allograft that was lost was from a living donor in a recipient with stable renal function 1 year after transplantation who had a severe rejection episode after her immunosuppressive therapy was reduced at an outside hospital. From an immunologic standpoint, 62% of the patients who underwent desensitization and transplantation had panel-reactive antibody levels that were greater than 50%, 63% had had one or more previous transplants, and 69% of patients had a positive cross-match on flow cytometry at the time of transplantation.

Acute Rejection Episodes

Acute rejection episodes occurred in 50% of patients who received a transplant, and 31% of these episodes were C4d+ antibody–mediated rejections. Most rejection episodes occurred within the first month after transplantation and were reversible with treatment. However, two patients had late antibody-mediated rejection episodes (more than 6 months after transplantation) that were related to subtherapeutic immunosuppressive drug levels. Donor-specific antibody levels were monitored after transplantation in four patients with antibody-mediated rejection. Three of the four had increases in donor-specific antibody levels in association with the antibody-mediated rejection. New donor-specific antibodies were not detected, and antibody levels decreased after treatment.

We believe that the data presented here, reflecting the use of a combination of intravenous immune globulin and rituximab, are encouraging and may support further analysis of this approach. There are potential advantages for the use of intravenous immune globulin and rituximab as compared with currently accepted approaches to desensitization. For example, protocols for plasmapheresis and low-dose intravenous immune globulin are suitable only for recipients of transplants from living donors. High-dose intravenous immune globulin has been shown to be effective as a desensitization agent for patients receiving transplants from either living or deceased donors,9 but it requires monthly infusions over a 4-month period for optimal results.

Although transplantation was not a primary end point in the NIH IG02 study,9 35% of the patients underwent transplantation during a 2-year observation period, as compared with 17% in the placebo group. In our smaller, nonrandomized study, transplantation was accomplished in 80% of the patients, and treatment time was reduced from 16 weeks to 5 weeks. In addition, our patients who received a transplant from a deceased donor had been on a waiting list for a mean of 12 years (range, 5 to 27) but received transplants within 5 to 6 months after treatment with intravenous immune globulin plus rituximab. These observations might have important implications for highly sensitized patients awaiting transplants from deceased donors. Larger and longer trials are needed to assess the safety of this approach.