Antibody-Mediated Rejection: Analyzing the Risk, Proposing Solutions

The beneficial effects of HLA matching in renal transplantation have been known for decades, and an allocation system that emphasizes Class II matching has been proposed. Recent data have demonstrated that the development of dnDSA, particularly against Class II HLA antigens, is a major cause of renal transplant loss. The histopathology of chronic antibody-mediated rejection is characterized by immune injury to the endothelium of the glomeruli and peritubular capillaries. The early phases of injury occur subclinically, many months before graft dysfunction, providing the opportunity for the optimization of current therapies and the evaluation of new treatment strategies. Risk factors for dnDSA development include Class II HLA mismatching, patient nonadherence to IS medications, and prior cellular rejection. Because the current treatment of chronic antibody-mediated rejection is largely unsatisfactory, prevention strategies that attempt to minimize the known risk factors should be adopted. The effects of HLA matching on renal allograft outcomes have been reported in Transplant Registries over the last 20 years (6Y8). Data from the UCLA Tissue Typing Laboratory demonstrated that an increase in the number of A, B, and DR mismatches in renal transplantation patients was associated with a higher incidence of both acute rejection and graft loss, and with impaired renal function at various time points after surgery (6). Conversely, Opelz reported a beneficial effect of HLA matching on graft survival in the recipients of living unrelated kidney donors (7), and Opelz Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. and Döhler subsequently demonstrated that patient and graft survival were better, and rates of rejection in the first year were lower in proportion to the number of matched A and B, and DR antigens in over 135,000 recipients of deceased donor kidneys studied over two decades (8). A beneficial effect of HLA matching (particularly for HLA Class II) has also been reported recently for the recipients of kidneys from heart beating donors in the United Kingdom (9). The idea of kidney allocation that emphasizes DR compatibility has in fact been previously put forward by Doxiadis et al (10). The use of HLA matching as a means of allocating kidneys and improving renal transplantation outcomes has not always received universal support. For example, Su et al (11) reported on over 33,000 renal transplant recipients from the United States Renal Data System (USRDS) database and concluded that the improvement in graft survival attributable to HLA matching had decreased over time and that allocation algorithms that emphasize HLA matching needed to be reconsidered. Furthermore, Matas et al (12) reported that failure of poorly matched grafts did not result in increased rates of sensitization, which questions once more the need of emphasizing HLA matching before transplantation. However, recent data on the development of de novo antibodies against donor HLA antigens (particularly Class II) as a major cause of renal allograft dysfunction and loss (vide infra) will undoubtedly shift the focus back to better HLA matching of donor and recipient pairs in an attempt to improve long-term graft outcomes. ANTIBODIES AND THE HUMORAL THEORY OF TRANSPLANTATION The significance of DSA, as evidenced by the direct consequences of a positive cytotoxic crossmatch at the time of transplantation, was greatly demonstrated in the seminal paper of Patel and Terasaki in 1969 (13). Furthermore, the deleterious effect of ‘‘lymphocytotoxic antibodies’’ detected in the posttransplantation period was clearly established by Martin et al (14) in 1987. An insightful, early review of humoral hyperacute, acute and chronic antibody-mediated rejection was published by Terasaki in 2003 (15). Notwithstanding the abovementioned reports, the modern era in the study of DSA and their effects on allograft outcome has resulted from the development of sensitive solid-phase assays for antibody detection that have exquisite antigen specificity. Additional key observations to support the injurious role of DSA in transplanted organs have been the discovery of tissue C4d staining as a marker of antibody-mediated injury by Feucht et al (16), and the recognition of the microcirculation (glomeruli and peritubular capillaries in the transplanted kidney) as the target for antibody-mediated inflammation in the Banff schema (17). With the combined use of these diagnostic assays, it has become clear that there are two different case scenarios that relate to antibody-mediated allograft injury. The first relates to acute AMR that occurs in patients who have preformed DSA at the time of transplantation. The second relates to the more insidious process of CAMR that occurs in patients who develop dnDSA sometime after transplantation. PREFORMED DSA In renal transplantation patients, early onset AMR has been reported in studies in which preformed DSA were missed in cases where the initial crossmatch was obtained using cytotoxicity and other methods but were detected retrospectively by retesting the pretransplantation sera with solid-phase assays (18, 19). For example, Lefaucheur et al (18) reported on 2,079 patients with a negative cytotoxicity assay against donor T and B lymphocyte pretransplantation, of whom 15% (305) had an acute rejection episode at a median of 3.1 months posttransplantation. Almost half of these patients (n=147) had AMR, which was caused by anti-Class I DSA in one third of the patients and by anti-Class II DSA in the remaining two thirds, after the sera were retested with single-antigen flow bead assays. The authors observed that patients with AMR who had received therapy directed only to T-cells, that is, steroids plus or minus monoclonal or polyclonal anti-T cell therapy, had worse long-term outcomes than patients who received treatment directed against the antibody, that is, steroids or intravenous immunoglobulin (IVIG) or plasmapheresis (PP) plus rituximab. Similarly, in an earlier study from the Mayo Clinic in Rochester, Gloor et al (19) reported on 189 recipients of living donor kidneys who were either crossmatch negative (n=70) or positive (n=119) against their donor. In the latter patients, the crossmatch was performed either by cytotoxicity or by flow cytometry at two levels of mean channel shift (G300 and 9300), before patient desensitization. The sera from these patients were also retrospectively analyzed for DSA by solid-phase assay and were reported as mean fluorescence intensity (MFI) of the sum of the MFI values for Class I and Class II HLA antibody. The patient outcomes reported were early AMR (G90 days), transplantation glomerulopathy, and graft loss. In general, there was a good inverse correlation between the sensitivity of the method for antibody detection and the observed outcomes. In particular, early AMR (G90 days) occurred more commonly with antibodies detected by cytotoxicity, with antibodies causing a greater mean channel shift by flow cytometry, and with antibodies with a higher MFI sum.