Correlation of Donor-Specific Antibodies, Complement and Its Regulators with Graft Dysfunction in Cardiac Antibody-Mediated Rejection

Antibody-mediated rejection (AMR) is an immunopathologic process in which activation of complement often results in allograft injury. This study correlates C4d and C3d with HLA serology and graft function as diagnostic criteria for AMR. Immunofluorescence staining for C4d and C3d was performed on 1511 biopsies from 330 patients as part of routine diagnostic work-up of rejection. Donor-specific antibodies were detected in 95% of those with C4d+C3d+ biopsies versus 35% in the C4d+C3d- group (p = 0.002). Allograft dysfunction was present in 84% in the C4d+ C3d+ group versus 5% in the C4d+C3d- group (p < 0.0001). Combined C4d and C3d positivity had a sensitivity of 100% and specificity of 99% for the pathologic diagnosis of AMR and a mortality of 37%. Since activation of complement does not always result in allograft dysfunction, we correlated the expression pattern of the complement regulators CD55 and CD59 in patients with and without complement deposition. The proportion of patients with CD55 and/or CD59 staining was highest in C4d+C3d- patients without allograft dysfunction (p = 0.03). We conclude that a panel of C4d and C3d is diagnostically more useful than C4d alone in the evaluation of AMR. CD55 and CD59 may play a protective role in patients with evidence of complement activation.