Antibody testing for cardiac antibody-Mediated rejection: Which panel correlates best with cardiovascular death?
Recent efforts are being undertaken to update and refine current diagnostic criteria for antibody-mediated rejection (AMR) in heart transplantation. We believe that the appropriate reactants are those that best predict the adverse consequences of AMR and therefore tested various models using different reactants to find the best predictors of cardiovascular mortality in pathologically defined AMR.
The study group included only patients in whom all immunofluorescence antibodies of interest had been tested on biopsy specimens obtained after 2002 when C4d was routinely added. We analyzed our data using 3 Cox proportional hazard models with time-varying covariates using an end point of cardiovascular mortality, as previously defined.
In 3,712 biopsy specimens from 422 patients, the 2-antibody model achieved a value of R(2) = 0.930 using C3d and C4d antibodies alone. A model that used 4 antibodies--C3d, C4d, human leukocyte antigen-D related (HLA-DR) and fibrin--was superior (R(2) = 0.988). The model that best predicted cardiovascular mortality included all 6 antibodies: HLA-DR, immunoglobulin (Ig) G, IgM, C3d, C4d, and fibrin (R(2) = 0.989). The models using 4 or 6 antibodies were significantly superior to the model using only C3d and C4d (for each interaction, p < 0.0001).
The combination of complement components, HLA-DR and fibrin, is valuable in defining AMR in patients at risk for allograft loss from cardiovascular causes. Fibrin is particularly important for detecting the presence of severe AMR, with a high likelihood of poor long-term patient outcome.
Available from: Dawn Jaroszewski
- "The role of antibody-mediated rejection in acute and chronic cardiac allograft dysfunction is now firmly established   . However, the topic has been steeped in controversy in heart transplantation stemming from an inability for many years to come to a consensus on the clinical and pathologic diagnosis and on the appropriate treatment   . In part, the difficulty in defining this process arises from the still emerging understanding of the cellular and molecular mechanisms involved . "
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ABSTRACT: Antibody-mediated rejection (AMR) (humoral rejection) of cardiac allografts remains difficult to diagnose and treat. Interest in AMR of cardiac allografts has increased over the last decade as it has become apparent that untreated humoral rejection threatens graft and patient survival. An international and multidisciplinary consensus group has formulated guidelines for the diagnosis and treatment of AMR and established that identification of circulating or donor-specific antibodies is not required and that asymptomatic AMR, that is, biopsy-proven AMR without cardiac dysfunction is a real entity with worsened prognosis. Strict criteria for the diagnosis of cardiac AMR have not been firmly established, although the diagnosis relies heavily on tissue pathological findings. Therapy remains largely empirical. We review an unfortunate experience with one of our patients and summarize recommended criteria for the diagnosis of AMR and potential treatment schemes with a focus on current limitations and the need for future research and innovation.
Available from: Mandeep Mehra
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ABSTRACT: Considerable progress has been made in achieving consensus amongst pathologists and in refining the ISHLT 2005 working formulation criteria for the pathologic diagnosis of AMR (Boxes 1 and 2). Several technical and interpretative issues have been raised. Although some were resolved and a new grading system proposed, further work is required to standardize and validate the consistency and reproducibility of a proposed scoring system for capillary C4d deposition in EMB specimens. Further additional inquiry is needed to address a number of unresolved and essential issues, such as the early histopathologic features of AMR. This can be achieved by establishing a central ISHLT-supported database for collection of digitized images and data of AMR cases to evaluate and clarify areas of uncertainty both in diagnosis and reproducibility. © 2011 International Society for Heart and Lung Transplantation. All rights reserved.
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