Intravenous Immunoglobulin and Rituximab for Desensitization (2010)

We welcome this opportunity to clarify some points raised by Rehman et al. First, our article (1) was thoroughly vetted by the editorial staff of Transplantation and by respected colleagues with extensive experience in desensitization. The authors contend that we are “promoting worldwide use of this protocol with no results to justify the expense.” We disagree with this contention. This is a report of our single-center experience that follows a phase I/II clinical trial (1, 2). We make no statements in either published reports promoting worldwide use of this protocol but state that “the results are encouraging and should be verified further in a randomized-controlled trial.” We have now obtained funding for such a trial. Regarding the validity of defining “highly sensitized” patients by flow panel reactive antibody (PRA), we assert the following: for simplicity of presentation, the flow screening PRA of class I or II is indicated in Figure 1 in our article (1). All sera were tested by multiple antibody methods including complement-dependent cytotoxicity, quantified single-antigen bead Luminex platform assay, or flow cytometry single-antigen beads. Both complement-dependent cytotoxicity and flow cytometry crossmatches (CMXs) were performed. Thus, multiple methods were used to detect and define the antibody status of these patients. All sera contained defined human leukocyte antigen-specific antibodies; no sera were negative for human leukocyte antigen-specific antibodies. The CMX results presented are for flow cytometry T-cell CMXs only. B-cell CMX results were not presented because of interference by rituximab. Certainly, some patients with lower T-cell CMX results had high B-cell CMX results and strong anti-HLA class II antibodies to the same donor. The statement that some patients had low CMX results because of weaker donor-specific antibodies (DSAs) to their donors by chance refers to recipients of deceased donors (DD). There is no way to anticipate whether a patient on the DD list will have weaker DSAs to a given donor. Nonetheless, these patients were transplanted across a positive CMX and would not have been transplanted without the therapy. The authors suggest that these patients were “obviously not highly sensitized against their donors” and would have been transplanted without desensitization. This is inaccurate and represents a misinterpretation of our data. First, patients awaiting DD transplantation were on the waitlist for 95±46 months before treatment and received transplants 4.2±4.5 months after treatment. Seventy-five percent of patients treated had PRAs more than 80%, and all were DSA positive. Patients who underwent desensitization therapy but did not achieve an acceptable level to their living donor(s) were placed on the DD list and given the opportunity to enter a paired kidney donor exchange program. We have previously reported that approximately 80% of patients treated are transplanted (2), and we found that 85% of patients treated during the period covered by this report were transplanted. We consider patients with a positive CMX and DSA positivity to be at unacceptably high risk for antibody-mediated rejection (AMR) without this therapy. Indeed, others (3) have shown high rates of AMR and poor outcomes in patients with negative CMX results but with low level of DSA. This was compared with a group treated with antithymocyte globulin/intravenous immunoglobulin (IVIG) where AMR rates were significantly lower (11% vs. 46%, P=0.0002). In addition, 7.5% of grafts in the control group were lost to AMR versus 0% in the antithymocyte globulin/IVIG group. This also reflects our experience as stated in the text. Thus, our patients are not transplanted unless they have received the immunomodulatory therapy and have CMXs and DSAs at acceptable levels (4). The authors contend that the use of rituximab has not been established as an agent for desensitization. We agree but would contend that there are no agents approved by the Food and Drug Administration for desensitization or treatment of AMR. However, these problems do exist and need our best efforts as we develop clinical trials to evaluate different approaches. The authors' summary comment “It has to be made clear that this protocol does not represent a solution for highly sensitized patients.” We do not agree. Our work (1, 2, 4) and that of others (5–8) suggest that the combination of IVIG/rituximab can modify DSA levels and improve transplant rates and outcomes in this difficult to transplant group. This has been the most effective therapy for improving transplant rates in sensitized DD recipients, and we believe that having a functioning allograft is superior to outcomes seen with chronic dialysis. We understand that this protocol has imperfections. We are always willing to modify or develop alternative approaches if they prove more efficacious. The authors dismiss this approach without offering reasonable alternatives. Stanley C. Jordan1 Nancy L. Reinsmoen2 Ashley A. Vo1 1 Kidney Transplant Program Transplant Immunotherapy Program Comprehensive Transplant Center Los Angeles, CA 2 HLA Laboratory Department of Medicine, Division of Nephrology Cedars-Sinai Medical Center Los Angeles, CA