Subclinical Antibody-Mediated Rejection

Manuel Arias The role of anti-HLA antibodies and, thus, the importance of the humoral response have been relegated for decades in the pathogenesis of transplant rejection and graft loss due to the predominance of the cell theory (T-Centric). However, in recent years, epidemiological and clinical evidence has proven otherwise. In addition, neither the academy nor the industry has deepened in the investigation of new drugs directed to control antibody-mediated allogeneic response. Therefore, the immune management of organ transplant recipients is clearly unsatisfactory, especially in the long term. Beyond general dosing guidelines for immunosuppressive agents and clinical diagnostic tests for rejection, which are focused on organ function but not on immunological markers, there are few objective tools to determine the aggregate status of a patient's alloimmune response. Recent studies indicate that antibody-mediated rejection (ABMR) is among the most important barriers to improving long-term outcomes. In recent years, understanding the roles of acute and chronic ABMR has improved because of major progress in the technical ability to detect and quantify recipient anti-HLA antibody production. Additionally, new knowledge of the immunobiology of B cells and plasma cells that pertains to allograft rejection and tolerance has emerged. Still, questions regarding the classification of ABMR, the accuracy of diagnostic approaches, and the efficacy of various strategies for managing affected patients abound.1 These and other lesser known reasons contribute to the disappointing attrition of grafts on a slowly progressive downward slope observed with impotence by the shortage of effective drugs. Noninvasive biomarkers that could serve as predictive tools or surrogate end points for rejection might help clinicians to individualize immunosuppression (IS) and allow for early intervention, ideally before clinically evident organ dysfunction. Although the growing understanding of organ rejection has provided numerous candidate biomarkers, none has been confirmed in robust validation studies as sufficiently useful to guide clinical practice out of the boundaries of the traditional clinical methods. The development of ABMR caused by donor-specific antibodies (DSA) is considered a risk factor for low graft survival after kidney transplantation. Although less studied, the deleterious consequence of ABMR is being increasingly seen in other solid organ transplantations, such as heart and lung.2 Recent reports have shown that the occurrence of DSA in the liver, classically considered a relatively resistant organ to DSA-mediated injury, can result in lower graft and patient survival.3-8 The diagnosis of ABMR after transplantation has been defined using a combination of clinical, histological, and immunological criteria. Recently, a subclinical variety of ABMR which may also progress into chronic ABMR has been described.9 In these cases, and considering the lack of clinical evidence, the availability of more sensitive diagnostic tests allowing the early detection of low titers of DSA3 and the routine use of protocol biopsies10 could facilitate the early start of an appropriate immunosuppressive treatment.3 This review addresses the spectrum of ABMR after organ transplantation, including some aspects of its pathogenesis, risk factors, and outcomes. In this document, relevant professionals review and update different topics. In the first chapter, Dr Serón reviews the influence of IS in surveillance biopsies and subclinical kidney rejection. In his chapter, early inflammation and its relation with fibrosis and the development of de novo DSA (dnDSA) is assessed, stressing the importance of its prevention. In his chapter, a critical analysis of the role of DSA in liver graft loss is presented by Dr Herrero. Despite that liver transplantation has been considered poorly affected by humoral rejection, recent evidence shows a relationship between acute and chronic rejection and the presence of preformed and dnDSA. Considering the increased risk of graft fibrosis, graft loss, and lower patient survival, DSA should considered in liver transplantation. 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