Beyond histology: lowering human leukocyte antigen antibody to improve renal allograft survival in acute rejection.
ABSTRACT The common endpoint in the treatment of antibody-mediated rejection (AMR) is functional reversal (creatinine levels). Reduction of human leukocyte antigen (HLA) antibody strength is not commonly considered as an essential endpoint for AMR resolution. The purpose of this study was to determine whether reduction in HLA antibody intensity in patients with histologic AMR reversal influences long-term renal allograft survival.
Renal allograft recipients were included if he or she had a biopsy diagnosis of AMR (between August 2000 and October 2008) and serial evaluation for HLA antibodies prebiopsy and postbiopsy. Antibody reduction was defined as mean fluorescence intensity decrease more than 50% in highest intensity antibody after AMR therapy and the absence of new antibody formation. Patients were treated with plasmapheresis, thymoglobulin/OKT3, and corticosteroids. Survival analysis was performed using STATA/MP v10 (College Station, TX).
Twenty-eight patients were analyzed. Antibody reduction failed to occur in 22 of 28 cases. Baseline characteristics were similar between groups. Antibody nonresponders had significantly shorter allograft survival time (61.4 months) compared with antibody responders (no failures) (P=0.04, log-rank test).
In conclusion, failure to significantly reduce antibody levels and prevent new formation was strongly predictive of allograft loss. This observation suggests that the therapeutic intervention that reduces antibody production may prolong graft survival in transplantation.
Article: Humoral theory of transplantation.[show abstract] [hide abstract]
ABSTRACT: According to the humoral theory of transplantation, antibodies cause allograft rejection. Publications are cited showing that antibodies: (1). cause hyperacute kidney rejection, (2). lead to C4d deposits associated with early kidney graft failures, (3). are a good indicator of presensitization leading to early acute rejections, (4). were present in 96% of 826 patients who rejected a kidney graft, (5). are associated with chronic rejection in 33 studies of kidney, heart, lung and liver grafts, and (6). in three studies, appeared in the circulation BEFORE evidence of bronchiolitis obliterans in lung transplants, and BEFORE kidney rejection. In addition, a prospective cooperative study of 1629 patients in 24 centers demonstrated that antibodies foretold subsequent failures after a follow-up period of 6 months (p = 0.05). The specificity of antibodies detected in the serum of rejecting patients were often not donor specific, presumably because they were absorbed by the rejecting organ. If the humoral theory is accepted, even provisionally, transplanted patients who have antibodies could be treated with immunosuppression until the antibodies disappear to determine whether chronic rejection can be blocked. If successful, in patients who do not have antibodies, immunosuppression could be reduced until antibodies appear.American Journal of Transplantation 07/2003; 3(6):665-73. · 6.19 Impact Factor
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ABSTRACT: Antibody-mediated rejection (AbAR) is increasingly recognized in the renal allograft population, and successful therapeutic regimens have been developed to prevent and treat AbAR, enabling excellent outcomes even in patients highly sensitized to the donor prior to transplant. It has become critical to develop standardized criteria for the pathological diagnosis of AbAR. This article presents international consensus criteria for and classification of AbAR developed based on discussions held at the Sixth Banff Conference on Allograft Pathology in 2001. This classification represents a working formulation, to be revisited as additional data accumulate in this important area of renal transplantation.American Journal of Transplantation 07/2003; 3(6):708-14. · 6.19 Impact Factor
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ABSTRACT: We discuss the potential mechanisms of antibody-induced primary endothelium injury, which includes complement-dependent pathway (membrane attack complex formation, recruitment of inflammatory cells, and complement-complement receptor-mediated phagocytosis) and complement independent pathway antibody-dependent cell cytotoxicity. Secondary to endothelium injury, the following pathological reactions are found to be responsible for progressive tissue injury and final graft function loss: platelet activation and thrombosis, pathological smooth muscle and endothelial cell proliferation, and humoral and/or cellular infiltrate-mediated parenchyma damage after endothelium injury. We also introduce three categories of therapeutic strategy in the prevention and treatment of antibody-mediated rejection: (1) inhibition and depletion of antibody producing cells (immunosuppressants, antilymphocyte antibodies, splenectomy); (2) removal or blockage of preexisting or newly developed antibodies (immunoadsorption, plasmapheresis/plasma exchange, intravenous immunoglobulin); and (3) impediment or postponement of antibody-mediated primary and secondary tissue injury (anticoagulation, glucosteroids). In conclusion, because alloantibodies have destructive effect on allografts, alloantibody monitoring becomes extremely important. It will help clinicians to determine a patient's humoral responses against allograft and will therefore direct clinicians to optimize and/or minimize immunosuppressive drug therapy.Human Immunology 05/2005; 66(4):334-42. · 2.30 Impact Factor