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Immunoglobulin G–Degrading Enzyme of Streptococcus pyogenes (IdeS), Desensitization, and the Kidney Allocation System

2018; Lippincott Williams & Wilkins; Volume: 13; Issue: 5 Linguagem: Inglês

10.2215/cjn.12031017

1555-905X

Edmund Huang, Stanley C. Jordan,

Pediatric Urology and Nephrology Studies

In a recent Perspectives article in the Clinical Journal of the American Society of Nephrology, Formica and Kulkarni (1) contextualize the use of the IgG-degrading enzyme of Streptococcus pyogenes (IgG endopeptidase) for desensitization to the era of the new kidney allocation system (KAS). Since the KAS, more highly sensitized kidney candidates have received transplants than before. Therefore, it was suggested that the allocation priority for highly sensitized candidates in the new KAS diminishes the need for desensitization and that waiting for a suitably matched donor is preferable to undergoing an incompatible transplant. As previously reported, the median waiting time for patients with calculated panel reactive antibodies 98%–100% has fallen from >19 years pre-KAS to 3.2 years post-KAS (2). Therefore, it was stated that, if a sensitized patient can receive a compatible transplant quickly, there is "no clinical justification for desensitization" (1). Although it is true that more patients with calculated panel reactive antibodies of 98%–100% were transplanted since the KAS, not all highly sensitized patients benefited to the same degree. Patients with calculated panel reactive antibodies ≥99.95% accounted for 34.0% of candidates with calculated panel reactive antibodies ≥99% (approximately 2700 candidates in the United States) but received only 8% of the transplants for those with calculated panel reactive antibodies ≥99% in the first year after the KAS was implemented (3). For any given calculated panel reactive antibodies percentage, the probability of finding an acceptable match can be estimated with the following formula: 1− (calculated panel reactive antibodies percentage)n, where n is the number of potential donors (4). Using this formula, candidates with calculated panel reactive antibodies of 99.95% would need approximately 6000 match runs to have a 95% probability of an acceptable crossmatch. This estimate increases exponentially and approaches 300,000 match runs as the calculated panel reactive antibodies percentage increases from 99.95% to 100%. In practice, there may be variability in this estimate, because it is derived from HLA frequencies calculated from a limited pool of approximately 12,000 donors; however, clearly, a significant number of highly sensitized candidates will not benefit from the KAS and are unlikely to receive a transplant without desensitization. Although highly sensitized candidates have received transplants more frequently after the KAS, it is unknown how many received transplants with a negative crossmatch. One cannot assume that the increased number of transplants was performed with a negative crossmatch and without donor-specific antibodies. Houp et al. (5) reported that 58% of transplants performed among candidates with calculated panel reactive antibodies of 99%–100% at Johns Hopkins after the KAS was implemented were in the presence of donor-specific antibodies (18 of 30 in 2015 and eight of 15 in 2016), and they noted that 40%–47% of their highly HLA–sensitized list could not be transplanted under the KAS and required desensitization. Here, the authors noted that, before KAS implementation, patients with calculated panel reactive antibodies of 50% determined by cytotoxicity assays could be "converted" to calculated panel reactive antibodies of 100% by using more sensitive Luminex assays and listing mean fluorescence intensities at or below the threshold of detection, thus increasing their chances for early transplantation in the KAS. These patients are not as immunologically challenging as the highly and broadly sensitized patients who have calculated panel reactive antibodies of 100% and are less likely to need desensitization. The Perspectives article cautioned against the use of desensitization, because HLA-incompatible transplants have lower graft survival compared with compatible transplants. This may not be a valid comparison. As discussed above, a large number of patients are so broadly sensitized that their chances of finding a compatible donor are remote. Additionally, it was argued that, as waiting time for a highly sensitized recipient approximates that of a patient with low or zero calculated panel reactive antibodies, "the risk benefit decision shifts to the risks of the procedure compared with the incremental increase in the amount of time spent on dialysis" (1). This argument overly simplifies the challenges of performing transplants in highly sensitized patients. These patients are not only immunologically high risk but are often medically challenging due to the comorbidities incurred from living through years of ESKD. In this high-risk population, forgoing a potential donor in the hope of finding a more suitable offer may not be in the patient's best interest. Sensitized patients are inherently at higher risk for rejection, and even those without donor-specific antibodies at transplant are at elevated risk for both acute and chronic antibody-mediated rejection (6). Therefore, it cannot be assumed that there will be lower rates of antibody-mediated rejection in the new KAS. The rate of antibody-mediated rejection in the United States is unknown, because the Organ Procurement and Transplantation Network does not record information on rejection type or presence of donor-specific antibodies. Longer-term data indicating that the KAS implementation has led to development of fewer de novo donor-specific antibodies or better patient and graft survival is not available, and in the absence of data, one cannot conclude that the KAS has obviated the role of desensitization. Our long-term antibody-mediated rejection rate for sensitized recipients is approximately 25%; in our experience, there was no difference in graft or patient survival up to 5 years post-transplant between 372 desensitized and 538 nondesensitized patients (7). The paper published in the New England Journal of Medicine describing the use of IgG endopeptidase for desensitization in kidney transplantation by Jordan et al. (8) reported results from two separate phase 1–2 studies conducted in the United States and Sweden. The primary objective was to examine safety, and secondarily, it examined efficacy of IgG endopeptidase. The study did not intend to compare IgG endopeptidase desensitization with the KAS; its intent was to help develop more definitive studies that will lead to Food and Drug Administration (FDA) approval. A subsequent multicenter, multinational, phase 2 trial of IgG endopeptidase for desensitization is currently ongoing (NCT02790437). The immediate effect of IgG endopeptidase on donor-specific antibodies in the preliminary study was profound, with near or complete reduction of HLA antibodies at 6 hours. Suppression of HLA antibodies was durable among patients treated with intravenous immunoglobulin and rituximab in the United States. It was questioned in the Perspectives article whether delayed administration of T lymphocyte–depleting therapy, rituximab, and intravenous immunoglobulin after IgG endopeptidase might lead to rejection and compromise long-term graft outcome. This is a theoretical concern that will need to be tested in larger-scale studies, but it was generally not observed in the IgG endopeptidase study. Cell-mediated rejection was infrequent (three of 24 patients). There were seven patients in the United States study with microvascular inflammation; only two of which had donor-specific antibodies and met Banff 2013 criteria for antibody-mediated rejection. Each of the five patients not meeting Banff 2013 antibody-mediated rejection criteria were identified on protocol biopsy. There was only one patient with clinical antibody-mediated rejection detected at 2 months; the other was subclinical antibody-mediated rejection detected on protocol biopsy. There was another patient with hyperacute rejection in the absence of detectable donor-specific antibodies (thus not meeting Banff 2013 antibody-mediated rejection criteria), and this was felt to be related to a non-HLA IgM antibody. The mean creatinine level of study participants was 1.27 mg/dl, which is in contradiction to 2 mg/dl as cited in the Perspectives article. A more recent analysis of 17 patients entered into the United States IgG endopeptidase study shows that, at a mean of 18.6 months post-transplant, patient and graft survival is 94%, with mean serum creatinine of 1.35±0.92 mg/dl. Four patients developed donor-specific antibodies post-transplant that were all ≤2500 mean fluorescence intensity. Biopsies were performed in 15 of 17 patients, with only two meeting Banff 2013 criteria for antibody-mediated rejection (S. Jordan, unpublished observations). It is important to consider the effect of the Perspectives article on future drug development in transplantation. Regardless of one's views on the value of desensitization, we must be cognizant that only one drug (belatacept) has been developed in transplantation in the last decade. We do not see the KAS and desensitization as mutually exclusive therapies but as complementary approaches that allow the life-extending benefits of transplantation for more patients. The statement that outcomes are "poor" for patients receiving transplants after desensitization is not supported by peer-reviewed reports. Data from our center have consistently shown that outcomes are similar to those in nonsensitized patients (7,9); furthermore, a report from 22 United States centers performing desensitization showed the survival benefit of HLA-incompatible transplantation compared with waiting on dialysis (10). We feel that IgG endopeptidase is a first step in improving the process of desensitization. We also feel that IgG endopeptidase will find applicability in desensitizing sensitized patients for heart, lung, and bone marrow transplants. Trials of IgG endopeptidase are also being developed for treatment of antibody-mediated rejection and ABO-incompatible transplantation. Given the mechanism of IgG endopeptidase, it will likely find benefit in treating numerous antibody-mediated autoimmune diseases. Studies are now underway in antiglomerular basement membrane disease (NCT03157037). The Perspectives article concludes that "…with the success of the KAS and kidney paired donation in transplanting all but the most highly sensitized patients in a timely manner with a compatible kidney, the demonstrated risks and subpar outcomes of desensitization no longer have a place in routine clinical kidney transplantation" (1). In the absence of comparative data pre- and post-KAS on de novo/rebound donor-specific antibodies, crossmatch results, antibody-mediated rejection rates, and long-term patient and graft survival, there is no evidence to support this conclusion. This statement has the potential to harm research efforts and will likely deter interest from industry and the FDA in development of novel therapies to address the immunologic barriers to transplantation. In addition, insurers are likely to use this statement to refuse payment for desensitization that will deprive patients of an opportunity for life-saving transplantation. We feel that this is short sighted and that it is not in the best interest of our societies, research efforts, and most of all, our patients. Disclosures S.C.J. received grant support from Hansa Medical and is a consultant for Hansa Medical. E.H. has no disclosures to report.