Study 2: evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the National Institutes of Health IG02 trial

Abstract

I ntravenous immunoglobulin (IVIG) has potential prophylactic applications in solid organ transplantation. To determine its ability to reduce anti– human leukocyte antigen (HLA) antibody levels and improve transplant potential for patients with endstage renal disease (ESRD), we evaluated IVIG versus placebo in a randomized, double-blinded, placebo-controlled clinical trial. Between 1997 and 2000, 12 US transplant centers entered 101 adult ESRD patients who were highly sensitized to HLA antigens (panel reactive antibody [PRA] levels 50% monthly 3) into the National Institutes of Health IG02 trial. Patients were randomized 1:1 (49 IVIG; 52 placebo) to receive IVIG (Gamimune N 10% SD; Bayer Corp, Clayton, NC; or placebo 0.1% albumin, Bayer Corp). Subjects received IVIG 2 g/kg (maximum dose 180 g) monthly 4 or an equivalent volume of placebo with additional infusions at 12 and 24 months after entry if they did not undergo transplantation. If transplantation was performed, additional infusions were given monthly 4. The primary objective of the study was to determine whether IVIG reduced the number of months on dialysis by improving transplantation rates in highly sensitized patients. Baseline PRA levels were similar in both groups (IVIG 81.2% 2.1% vs 83.8% 1.9%). However, IVIG significantly reduced PRA levels in study subjects over the 2-year study period compared with placebo (P .005). Eighteen (37%) IVIG and 9 (17%) placebo patients underwent transplantation (P .03). More frequent transplants were observed in the IVIG group regardless of transplant history (P .02; prior transplant, 34% vs 10%; no prior transplant, 43% vs 26%). The maximum likelihood estimate of annual transplant rate is 24% for the IVIG group and 12% for the placebo group. There was a significant difference in the penalized time on dialysis (P .04). Of the transplants, 22 of 27 were cadaver transplants (16 IVIG, 6 placebo). Thirteen rejection episodes were reported (12 IVIG vs 1 placebo) in 8 of 18 IVIG subjects and 1 of 9 placebo subjects. Seven graft failures occurred over the study period (3 IVIG, 4 placebo). The remaining patients with viable transplants had a mean serum creatinine level of 1.7 1.1 mg/dL (IVIG) at an average of 529 days after transplantation versus 1.3 0.4 mg/dL for placebo at an average of 607.4 days after transplantation. Adverse events were similar in both groups (23 IVIG, 24 placebo). Headache was the most common infusion-associated adverse event (P .005, IVIG 43% vs placebo 17%). Conclusion: We can conclude that IVIG is superior to placebo in reducing anti-HLA antibody levels and improving transplantation rates in highly sensitized ESRD patients. Although more acute rejection episodes were seen in the IVIG treatment group, the 2-year allograft survival and mean serum creatinine levels were similar. Thus, IVIG treatment offers significant benefits to highly sensitized ESRD patients awaiting transplantation. Immunomodulatory reduction of anti-HLA antibodies can be achieved without immunosuppression and the attendant risks of infection seen with other therapies. From Kidney Transplantation & Transplant Immunology, Cedars-Sinai Medical Center, Los Angeles, CA; and EMMES Corp., Rockville, MD. © 2003 Elsevier Inc. All rights reserved. 0955-470X/03/1704-0000$30.00/0 doi:10.1016/j.trre.2003.10.003