Abstract

Objective: To assess the usefulness of donor-derived cell-free DNA as a biomarker in the era of heart transplantation for myocardial injury and rejection. Methods: Serial plasma donor-derived cell-free DNA from hearttransplant recipients under surveillance were quantified by single-nucleotidepolymorphism next-generation DNA sequencing along with a contemporaneous endomyocardial biopsy scored for acute cellular and antibody-mediated rejection. Evaluated the utility of donor derived cell free DNA for the diagnosis of acute rejection by comparison to total cell free DNA, troponin, and area under a receiver operating curve analysis, and correlated the cell free DNA with the biopsy grade and with the course of treated acute rejection episodes. Results: Of 182 recipients with paired samples of 916, rejection was found in 9%. Cell-free DNA from donors was higher according to the rejection grade: 0.08% without rejection, 0.15% with cellular rejection and 0.28% with antibody-mediated rejection. It discriminated for all rejection means an area under the curve of 0.82 whereas for antibody-mediated rejection was 0.92, which was greater than both mean antibody level and mean troponin. The negative predictive value for the 0.2% level was 94%. Treated episodes had peaks of donor derived cell free DNA at diagnosis and below threshold after treatment. Conclusion: Donor-derived cfDNA increased in step with myocardial injury and Antibody-Mediated Rejection (AMR) in particular after heart transplantation discriminated and fell with successful therapy outcome with high negative predictive value. The findings suggest it could be used as a noninvasive tool to accompany surveillance biopsy, to rule out rejection.

Keywords: Heart transplantation, Donor-derived cell-free DNA, Allograft rejection, Liquid biopsy, Endomyocardial biopsy, Non-invasive monitoring