Correlation between microvascular inflammation in endomyocardial biopsies and rejection transcripts, donor-specific antibodies and graft dysfunction in antibody-mediated rejection

Abstract

The pathology-based diagnosis of antibody-mediated rejection (AMR) following heart transplantation relies on the 2013 Working Formulation in which microvascular inflammation (MVI) is considered as present or absent regardless of its extent. This work assessed the biological and clinical value of a semiquantitative evaluation of the extent of MVI in endomyocardial biopsies (EMB). We retrospectively graded the extent of MVI in 291 EMB from 291 patients according to a 4-point scale where MVI scores of 0, 1, 2 and 3 represented 0%, 1–10%, 11–50% and > 50% of the myocardial area, respectively. We analyzed the association between the MVI score and tissue rejection molecular activity assessed by micro-arrays or reverse transcriptase multiplex ligation-dependent probe amplification, current pathology classification (pAMR), circulating anti-HLA donor-specific antibodies (DSA) and graft dysfunction. Overall, 172 (59.1%), 33 (11.4%), 42 (14.4%) and 44 (15.1%) EMB were given MVI scores of 0, 1, 2 and 3, respectively. pAMR1(H+) and pAMR2/3 categories were found to be heterogenous in terms of MVI score. Acute cellular rejection grades did not influence the MVI score. In both molecular approaches, we observed a stepwise increase in the expression of AMR-related transcripts with increasing MVI scores, independently of the C4d or CD68 status ( Fig. 1 , P < 0.001). Both the frequency and mean fluorescence intensity of DSA gradually increased with the MVI score ( P < 0.001). Acute graft dysfunction was more frequent in MVI score 3 ( P < 0.001). The intensity of MVI in EMB, based on a semiquantitative evaluation of its extent, has biological and clinical importance.