Molecular Assessment of Microcirculation Injury in Formalin-Fixed Human Cardiac Allograft Biopsies With Antibody-Mediated Rejection.
B AfzaliE ChapmanM RacapéBenjamin A AdamP BrunevalF GilD KimL HidalgoP CampbellB SisJ P Duong Van HuyenM MengelPublished in: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (2016)
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.
Keyphrases
- poor prognosis
- endothelial cells
- genome wide
- copy number
- genome wide identification
- binding protein
- left ventricular
- heart failure
- long non coding rna
- gene expression
- end stage renal disease
- ultrasound guided
- risk assessment
- stem cells
- dna methylation
- intensive care unit
- single cell
- chronic kidney disease
- transcription factor
- cell therapy
- newly diagnosed
- extracorporeal membrane oxygenation
- prognostic factors
- hepatitis b virus
- pluripotent stem cells
- climate change
- patient reported outcomes