C4d: A Marker for Cardiac Allograft Vasculopathy
Muhammad K Mirza, Savitri Fedson, Yiqing Chi, Susana R Marino, Aliya N Husain. University of Chicago Medical Center, Chicago, IL; Munster Community Hospital, Munster, IN
Background: In the past decade C4d has emerged as a potential marker for antibody-mediated rejection (AMR); however, evidence on its use as a prognostic tool has been controversial. To date, there is no consensus of the value of C4d in the pathologic assessment of AMR. Here, we present a correlation of our prospective study of C4d immunoreactivity in endomyocardial biopsies with clinical cardiac dysfunction, cellular rejection, HLA status, death, and cardiac allograft vasculopathy (CAV) at autopsy.
Design: 3758 endomyocardial surveillance biopsies from 200 heart transplant recipients (1/2004 - 9/2010) were stained prospectively for C4d. Immunohistochemical stains were performed on paraffin-embedded tissue using an anti-human C4d polyclonal antibody. 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 echocardiography. Cellular rejection was graded per ISHLT 1990 criteria.
Results: Positive C4d staining was present in 43 biopsies from 25 patients (12%). 9/25 patients (36%) had clinically significant cardiac dysfunction at the time of positive biopsy. In C4d positive patients, the mean PRA was 33%. At first C4d positivity, concomitant cellular rejection was as follows: 15/25 (60%) grade 0, 3/25 (12%) grade 1A, 6/25 (24%) grade 1B, 1/25 (4%) grade 2 and 1/25 (4%) had grade 3B rejection. 24/200 patients (12%) died, 16 of whom (67%) were C4d positive. Autopsy was performed on 18 of the 24 deaths (8 C4d negative and 10 C4d positive patients). At autopsy 10/10 C4d positive patients had histologic evidence of cardiac allograft vasculopathy (CAV). Six of 8 C4d negative patients (75%) had no CAV, while 2/8 had CAV. Six C4d positive deaths did not have autopsy. Nine of 25 (36%) C4d positive patients are alive 1-3 years post-transplant.
Conclusions: C4d positive patients contributed to 67% of the overall mortality. All 10 autopsies (100%) on C4d positive patients revealed CAV as the cause of death. In the C4d negative group, 75% of all deaths were due to non-cardiac causes. 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 of this marker in the pathologic evaluation of cardiac AMR.
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 6, Monday Morning