Editorial Commentary

Our understanding of the importance of anti-human leukocyte antigen (HLA) antibodies to the outcome of solid organ transplantation (SOT) has grown steadily since the early observations of Morris et al. (1, 2) and of Patel and Terasaki (3) almost a half century ago. The Editors of Transplantation are pleased to provide this supplement or colloquium, Antibody-Mediated Rejection: Analyzing the Risk, Proposing Solutions, which provides an update on the current trends in the field based on the proceedings of a symposium held in Madrid, Spain, in February 2013 endorsed by the Spanish Society of Transplantation and the Spanish Society of Immunology with sponsorship and support provided by Astellas. In his introduction (section I), guest editor Manuel Arias notes that despite steady improvements in patient and graft survival after kidney transplantation, graft failure after the first year caused by immunologic and nonimmunologic factors persists at the rate of 3.6% per year. Antibody-mediated rejection (AMR) has increased substantially primarily because of increased HLA-incompatible transplantation and retransplantation and the improved ability to identify even very low titers of anti-HLA antibodies (anti-HLA abs) and donor-specific antibodies (DSAs) before and after transplantation using new solid-phase assays (SPAs). These data permit evaluation of immunologic risk in specific donor-recipient combinations, rational implementation and evaluation of desensitization protocols, diagnosis of suspected AMR, and a metric for evaluating modified and new immunosuppressive protocols. In section II, David N. Rush, Chris Wiebe, Ian W. Gibson, Tom D. Blydt-Hansen, and Peter W. Nickerson of the University of Manitoba discuss de novo DSA as a cause of graft loss. Acute AMR occurs in the presence of pretransplantation DSA or as the more insidious process of chronic AMR in patients who develop DSA after transplantation. C4d staining is a marker of AMR, and the microcirculation endothelium (glomeruli and peritubular capillaries of the transplanted kidney) is the target of antibody-mediated inflammation. Crossmatch-negative recipients with posttransplantation AMR frequently are often found to have previously undetected DSA by SPA in the pretransplantation sera. In addition, the development of posttransplantation DSA in recipients negative for pretransplantation DSA is the strongest predictor for late graft loss. A significant association between poor outcomes and the development of anti-HLA class II DSA has been identified. Human leukocyte antigen mismatching (especially class II) and inadequate immunosuppression (IS) from patient nonadherence or physician-directed IS reduction also increase the risk for DSA formation. The authors emphasize that because therapies for chronic AMR are generally unsatisfactory, prevention strategies to minimize the known risk factors should be pursued. Joana Sellarés analyzes the causes of late kidney transplant failure in section III. She maintains that most graft failures can be attributed to specific causes if appropriate information (adequate histology, antibody studies, or other relevant clinical data) is made available. She identifies four major causes of late graft failure: AMR, glomerulonephritis, polyoma virus nephropathy, and failure in the context of an intercurrent illness. Nonadherence often presents as late rejection eventually leading to graft failure from AMR. She thinks that chronic calcineurin-inhibitor toxicity is not a major cause of graft failure per se, maintaining that it induces fibrosis over time but rarely is the only explanation for failure. Marcos López Hoyos, David San Segundo, and Manuel Arias (section IV) examine the impact of new SPAs on the epidemiology of anti-HLA abs in SOT. SPAs offer sensitive, accurate detection and quantification of pretransplantation and posttransplantation anti-HLA and DSA that can occur in relation to any SOT. Anti-HLA abs after heart, lung, and intestinal transplantations are associated with worse graft survival in all three organs. They assert that liver posttransplantation DSA (especially to class II) can be detrimental to late graft survival. They emphasize the importance of standardization and execution of SPAs and enumerate the specific types of data to be identified. They affirm the need for monitoring DSA in various clinical situations, that is, during desensitization protocols, while monitoring patients with pretransplantation DSA and negative complement-dependent cytotoxicity test results, during actual or suspected bouts of humoral rejection, and while evaluating or implementing changes in IS therapy. In section V, María G. Crespo-Leiro, Raquel Marzoa-Rivas, Eduardo Barge-Caballero, and María J. Paniagua-Martín trace the evolution of the definition and diagnosis of AMR in heart transplantation (HT). A turning point in diagnosis and management was reached at a consensus conference in 2010 (4), which established that AMR should be diagnosed purely on the evaluation of electron microscopic biopsy specimens and that clinical and serologic data should be used as aids in management but not as diagnostic criteria. The conference did prescribe an intensive immunologic monitoring, that is, immunologic staining was to be performed 2 weeks and 1, 3, 6, and 12 months after HT; whenever AMR was suspected on clinical grounds; and at regular intervals thereafter, and on all endomyocardial biopsies after a diagnosis of AMR until they test negative. The conference also recommended serologic tests for DSA (class I and II) 2 weeks and 1, 3, 6, and 12 months after HT and at annual intervals thereafter. It was hoped that uniform diagnostic criteria and data collection would facilitate progress in the research and treatment of AMR after HT. Antibody-mediated rejection in lung transplantation is discussed by Antonio Román in section VI. A humoral response in lung transplant rejection has been implicated because of the identification of pretransplantation anti-HLA abs by SPA, which could contribute to hyperacute or acute rejection. The development of posttransplantation anti-HLA abs also was recognized as a risk factor for chronic, long-term allograft dysfunction and the bronchiolitis obliterans syndrome. Donor-specific antibody development is common after lung transplantation and is associated with worse prognosis for graft and patient survival. The diagnosis of AMR is based on clinical manifestations, the presence of class I and II anti-HLA abs and DSAs, and evidence of complement activation (C4d staining) on biopsy specimens. He emphasizes that C4d staining is a critical finding for humoral rejection that can precede other histologic findings of chronic rejection, thereby underscoring the importance of serial protocol biopsies for optimal management. Daniel Serón analyzes the dynamic relationship of early inflammation, fibrosis, and chronic kidney rejection in section VII. Tubular-interstitial inflammation is common early after renal transplantation and tends to decrease thereafter. Early inflammation alone is not associated with reduced survival, but early progression to fibrosis in stable patients is associated with worse graft survival. Similarly, subclinical inflammation (SCI) leading to fibrosis is associated with lower graft survival. He cites evidence suggesting that early treatment (steroids) of SCI (diagnosed by protocol biopsies) has a beneficial effect on medium- to long-term graft outcome. He states further that the type of IS used can modulate the incidence of SCI and that adequate IS can prevent SCI and fibrosis. Furthermore, he asserts that the presence of SCI is a risk factor for acute rejection in association with IS withdrawal or minimization, although the evidence for a detrimental effect of steroid withdrawal in these circumstances is equivocal. He provides summaries of several major clinical studies confirming that SCI is a risk factor for fibrosis and chronic rejection, both resulting in reduced graft survival, and some suggestive evidence that tacrolimus-based IS regimens including mycophenolate mofetil or sirolimus have lower SCI rates and reduced progression to chronic lesions. Elisabeth Schwaiger and Georg A. Böhmig review new strategies to prevent AMR in section VIII. Antihumoral rejection is based on two complimentary approaches: the removal of harmful antibodies through plasmapharesis or immunoadsorption and the modulation or inhibition of various components of the specific or innate immune system by therapies including intravenous immunoglobulin treatment, C20 antibody rituximab, antithymocyteglobulin, the proteasome inhibitor bortezomib, anti-C5a antibody eculizumab, or even splenectomy. They maintain that extensive serologic analysis for pretransplantation risk of AMR is critical to determine the best transplantation strategy and treatment choices for any given donor-recipient combination. Apheresis combined with one or more other strategies is the most widely used prevention or treatment program. Early diagnosis of AMR based on morphologic, immunohistochemical, and serologic data is critical to implement effective treatment. Unfortunately, many data concerning new therapies are anecdotal, thereby underscoring the need for prospective, controlled clinical trials to define effective treatment(s). The Editors of Transplantation are gratified to publish this supplement or colloquium as a single monograph, which we think contains information of great interest to members of the global transplant community. The Editors acknowledge that the material presented is the record of meeting presentations involving literature reviews combined with author analyses of personal clinical experience including unchallenged opinions and impressions. The Editors state that every effort has been made to identify and delete any bias error or misinformation. The Editors also aver that the individual section articles were not sent out for standard peer review by the Editorial Review Board but were reviewed by the Special Features Editors. Finally, although we are enthusiastic to present this compiled material for our readers’ information and evaluation, we affirm that the opinions and assertions of the authors are theirs alone and no agreement or endorsement on the part of the Editors or publishers of Transplantation should be assumed or implied.

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