M. Kamran Mirza
M Kamran Mirza, Savitri Fedson, Aliya N Husain.
Background: In the past decade C4d has emerged as a potential marker for AMR, however, literature regarding its use as a prognostic tool has been controversial. Currently, the ISHLT recommends C4d staining only in the first 90 days post-transplant. Our aim was to prospectively determine the prognostic value of C4d positivity in post-transplant endomyocardial biopsies (EMBs) by correlating with clinical cardiac dysfunction, cellular rejection, HLA status, death, and cardiac allograft vasculopathy (CAV) at autopsy.
Design: All 5862 endomyocardial surveillance biopsies from 241 consectuvie heart transplant recipients (transplant date 1/2002 - 12/2012) were stained prospectively for C4d from 2004. Immunohistochemical stains were performed on paraffin-embedded tissue using an anti-human C4d polyclonal antibody. Only strong diffuse endothelial staining was considered positive. All patients had at least 1 year of follow-up. Cardiac dysfunction at the time of positive biopsy was evaluated by hemodynamics and echocardiography. Cellular rejection was graded per ISHLT 1990 criteria.
Results: Positive C4d staining was present in 64 biopsies from 34 (14%) patients, 9 of whom (26%) had clinically significant cardiac dysfunction. 22/34 (65%) of C4d positive patients died. Autopsy was performed on 19 (8 C4d negative and 11 C4d positive patients) of the 58 deaths. 11/11 C4d positive patients had histologic evidence of CAV. Six of 8 C4d negative patients (75%) had no CAV, while 2 of 8 did. Time to first episode of C4d positivity was 406+383 (7-1302) days. Time to C4d positivity in 12 surviving patients was 224+191 days and in the 22 expired patients was 505 + 427 days.
Conclusions: In this study, C4d positive patients were younger (by a decade), had higher PRAs and higher mortality (65% vs. 17%) as compared to C4d negative patients. Later C4d positivity is not benign; warranting long-term surveillance. All 11 C4d positive autopsies revealed CAV as the cause of death. Even 1 episode of C4d positivity correlated with a poorer outcome. These findings show a positive association of C4d with CAV and death. Our results indicate a prognostic role for C4d in heart transplantation warranting routine detection (including long-term surveillance) of this marker in the pathologic evaluation of cardiac AMR.