It is with great interest that we read the recent article by Stegall et al. (1) (A comparison of plasmapheresis vs. high-dose IVIG desensitization in renal allograft recipients with high levels of donor-specific alloantibody, Am J Transplant 2006; 6:346–351) that compared a single high-dose (HD) IVIG (2g/kg) to two intense plasmapheresis protocols (PP). The authors conclude that both protocols are effective in improving transplant rates in T-AHG CMX (+) patients. However, the IVIG protocol was less effective (38% vs. 84% vs. 88%) (p < 0.01) than the two intensive PP protocols. The single HD IVIG protocol was associated with very high antibody-mediated rejection (AMR) rates (80% vs. 37% vs. 29%) (p < 0.05) when compared with the two PP protocols. For the entire group, the actuarial graft survival at 1 year was 82%. An additional finding of interest was the lack of response to any therapy in patients who demonstrated anti-T-AHG CMX titers > 1:32.
Our group has more than 16 years experience in the use of IVIG for desensitization purposes (2). The data presented in this paper contrast with our clinical experience and data generated from a prospective, double-blinded, placebo-controlled, multicenter study of IVIG versus placebo in highly sensitized patients (3). Data from the NIH-IG02 study (2) showed that IVIG was effective in reducing panel reactive antibodies (PRAs) and improving transplant rates in very highly sensitized patients (PRAs > 80%). Unfortunately, we do not know the titers of antibody in this study. All patients received at least four doses of IVIG 2g/kg (maximum dose 180 g/month). The study was carried out during 1997–2002, with most patients receiving deceased donor transplants. Fifty percent of patients in the IVIG group experienced rejection episodes, but the mean serum creatinine levels at 3 years (1.6 mg/dL IVIG vs. 1.4 mg/dL placebo) and graft survival (80% IVIG vs. 70% placebo) were not statistically different. The mean projected time to transplant was 10.4 years for the placebo group and 4.8 years (p < 0.03) for the IVIG group. Our own subsequent experience with more than 100 patients using a similar multiple-dose protocol has allowed us to transplant ∼90% of patients successfully. Currently, we have an AMR rate of ∼20% and graft survival at 5 years of 87%.
Why such a contrast with the data presented by Stegall et al.? After careful review of the paper, we feel there are three potential reasons for the poor rates of transplantation and high rates of AMR in the single HD IVIG protocol. First, we believe that the multiple-dose IVIG approach results in prolonged modulation of donor-specific antibody (DSA) in patients who eventually can be transplanted. This was demonstrated in the IG02 study (3) where transplant rates did not differ until 1–2 years into the study. We have subsequently shown that even though the PRAs returned to baseline at 12–18 months, the HLA class 1 and class 2 antibody levels were significantly suppressed (>2 years) in those who received transplants in the IVIG group (4). This contrasts to the data presented by Stegall et al. who showed no long-term effect on antibody by any of the protocols employed.
Second, our policy is not to transplant patients until the CDC CMX is negative and the T-cell flow cytometry CMX is ∼200 channel shifts (CS) (normal: <50 CS). Stegall et al. transplanted some patients with positive T-AHG CMXs who showed a decrement in titer (1:8). These patients tended to do poorly regardless of the desensitization protocol used.
Third and possibly most important of all, Stegall et al. demonstrated that the titer of antibody was critical to the success of all therapies. Our experience with IVIG is based on first testing the patient's sera with IVIG in vitro. If inhibition is seen, then the drug is used. This is very successful in our hands (2,5). However, the success of this approach may reflect a selection bias for patients with lower titers of anti-HLA antibody and defer nonresponders to more intense therapies (i.e. PP). The ability to assess levels of sensitization is also encumbered by the number and variety of tests available for anti-HLA antibody detection. In addition, there are considerable obstacles presented by the use of HD IVIG and Thymoglobulin®. Both can give false positive results in the T-AHG CMX and standard CDC CMX assays. In the past, we were concerned with the broadness of specificities and less with the depth of sensitization. For some patients their sensitization is ‘a mile wide but only an inch deep’ while others have high titers of antibodies that are recalcitrant to current treatments. This observation is an important contribution of Stegall et al.
Unfortunately, there is currently no standard approach to assess the highly sensitized patient. The centers involved most with desensitization use techniques they are familiar with and, in their hands, predict responses to various therapies that determine the best time for transplantation. It is an important objective to develop reproducible techniques that give a reliable assessment of antibody specificity and titer that can also be used to assess the efficacy of selected desensitization protocols without being susceptible to interference by drugs used in the treatment. More importantly, it is critical to establish antibody levels that allow patients to be transplanted without a high risk of allograft rejection or loss.
We would agree with Stegall et al.'s conclusion that no protocol is perfect for desensitization and prevention of AMR. However, we feel the HD IVIG protocol is as effective as PP when given in multiple doses.
The critical issues for the future of desensitization lie not in comparing PP to IVIG but in development of better tools that assess the depth and breadth of sensitization without susceptibility to interference from treating drugs, and development of safe trigger points for transplantation. Resolution of these issues through prospective multicenter trials should lead to a consensus approach that would improve access and outcomes in this difficult-to-transplant population.