Antibody-Mediated Rejection: An Evolving Entity in Heart Transplantation

Antibody-mediated rejection (AMR) is gaining increasing recognition as a major complication after heart transplantation, posing a significant risk for allograft failure, cardiac allograft vasculopathy, and poor survival. AMR results from activation of the humoral immune arm and the production of donor-specific antibodies (DSA) that bind to the cardiac allograft causing myocardial injury predominantly through complement activation. The diagnosis of AMR has evolved from a clinical diagnosis involving allograft dysfunction and the presence of DSA to a primarily pathologic diagnosis based on histopathology and immunopathology. Treatment for AMR is multifaceted, targeting inhibition of the humoral immune system at different levels with emerging agents including proteasome and complement inhibitors showing particular promise. While there have been significant advances in our current understanding of the pathogenesis, diagnosis, and treatment of AMR, further research is required to determine optimal diagnostic tools, therapeutic agents, and timing of treatment

Donor-Specific Antibody Monitoring: Where Is the Beef?

This review paper discusses the impact of de novo donor-specific antibodies (DSA) to donor HLA antigens in kidney transplantation and summarizes the benefits and challenges that exist with DSA monitoring. Post-transplant DSA is associated with worse allograft outcomes and its detection may precede or coincide with clinical, biochemical, and histologic allograft dysfunction. There are no absolute features of DSA testing results that perfectly discriminate between states of disease and health. In a state of antibody-associated graft dysfunction, removal or reduction in DSA may only provide clinical benefit for some. Furthermore, various factors influence test results, and detection of HLA antibodies must be interpreted within the appropriate clinical and laboratory context. The utility of DSA monitoring is further affected by the limited effectiveness of treatment for antibody-mediated rejection. Although DSA monitoring is potentially beneficial in some circumstances, the optimal screening and treatment strategies are still to be defined

Delayed Graft Function and the Risk for Death with a Functioning Graft

Delayed graft function (DGF) associates with an increased risk for graft failure, but its link with death with graft function (DWGF) is unknown. We used the US Renal Data System to assemble a cohort of all first, adult, deceased-donor kidney transplant recipients from January 1, 1998, through December 31, 2004. In total, 11,542 (23%) of 50,246 recipients required at least one dialysis session in the first week after transplantation. Compared with patients without DGF, patients with DGF were significantly more likely to die with a functioning graft (relative hazard 1.83 [95% confidence interval 1.73 to 1.93] and 1.53 [95% CI 1.45 to 1.63] for unadjusted and fully adjusted models, respectively). The risk for DWGF was slightly higher among women with DGF than among men. There was no significant heterogeneity among other subgroups, and the results were robust to sensitivity analyses. Acute rejection within the first year attenuated the DGF–DWGF association. Cardiovascular and infectious deaths were slightly more prevalent in the DGF group, but the relative hazards of cause-specific death were similar between DWGF and deaths during total follow-up. In summary, DGF associates with an increased risk for DWGF; the mechanisms underlying the negative impact of DGF require further study

A systematic review of the role of C4d in the diagnosis of acute antibody-mediated rejection

In this study, we conducted a systematic review of the literature to re-evaluate the role of C4d in the diagnosis of acute antibody-mediated rejection of kidney allografts. Electronic databases were searched until September 2013. Eligible studies allowed derivation of diagnostic tables for the performance of C4d by immunofluorescence or immunohistochemistry with comparison to histopathological features of acute antibody-mediated rejection and/or donor-specific antibody (DSA) assays. Of 3492 unique abstracts, 29 studies encompassing 3485 indication and 868 surveillance biopsies were identified. Assessment of C4d by immunofluorescence and immunohistochemistry exhibited slight to moderate agreement with glomerulitis, peritubular capillaritis, solid-phase DSA assays, DSA with glomerulitis, and DSA with peritubular capillaritis. The sensitivity and specificity of C4d varied as a function of C4d and comparator test thresholds. Prognostically, the presence of C4d was associated with inferior allograft survival compared with DSA or histopathology alone. Thus, our findings support the presence of complement-dependent and -independent phenotypes of acute antibody-mediated rejection. Whether the presence of C4d in combination with histopathology or DSA should be considered for the diagnosis of acute antibody-mediated rejection warrants further study.We thank Dr Prakash Shah for his helpful comments regarding study protocol design and Ms Yanhong Li for her help with figure production. RS-P is funded by the Eliot Phillipson Clinician Scientist Training Program, Department of Medicine, University of Toronto, Toronto, Ontario, Canada. ACT is funded by a Canadian Institutes for Health Research/Drug Safety and Effectiveness Network New Investigator Award in Knowledge Synthesis. AL is the recipient of a Canada Research Chair in Health Policy and Citizen Engagement. The authors did not receive any grant support to carry out this study