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Molecular Assessment of Microcirculation Injury in Formalin‐Fixed Human Cardiac Allograft Biopsies With Antibody‐Mediated Rejection
Author(s) -
Afzali B.,
Chapman E.,
Racapé M.,
Adam B.,
Bruneval P.,
Gil F.,
Kim D.,
Hidalgo L.,
Campbell P.,
Sis B.,
Duong Van Huyen J. P.,
Mengel M.
Publication year - 2017
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.13956
Subject(s) - medicine , microcirculation , antibody , pathology , immunology
Precise diagnosis of antibody‐mediated rejection ( AMR ) in cardiac allograft endomyocardial biopsies ( EMBs ) remains challenging. This study assessed molecular diagnostics in human EMBs with AMR . A set of 34 endothelial, natural killer cell and inflammatory genes was quantified in 106 formalin‐fixed, paraffin‐embedded EMBs classified according to 2013 International Society for Heart and Lung Transplantation ( ISHLT ) criteria. The gene set expression was compared between ISHLT diagnoses and correlated with donor‐specific antibody ( DSA ), endothelial injury by electron microscopy ( EM ) and prognosis. Findings were validated in an independent set of 57 EMBs . In the training set (n = 106), AMR cases (n = 70) showed higher gene set expression than acute cellular rejection ( ACR ; n = 21, p < 0.001) and controls (n = 15, p < 0.0001). Anti‐ HLA DSA positivity was associated with higher gene set expression (p = 0.01). Endothelial injury by electron microscopy strongly correlated with gene set expression, specifically in AMR cases (r = 0.62, p = 0.002). Receiver operating characteristic curve analysis for diagnosing AMR showed greater accuracy with gene set expression (area under the curve [ AUC ] = 79.88) than with DSA ( AUC = 70.47) and C4d ( AUC = 70.71). In AMR patients (n = 17) with sequential biopsies, increasing gene set expression was associated with inferior prognosis (p = 0.034). These findings were confirmed in the validation set. In conclusion, biopsy‐based molecular assessment of antibody‐mediated microcirculation injury has the potential to improve diagnosis of AMR in human cardiac transplants.