Early Donor-Derived Cell-Free DNA Predicts Peak Allograft Function in Heart Transplant

Abstract

Donor-derived cell-free DNA (ddcfDNA) is a validated marker of allograft injury in heart transplant, predicting both acute cellular (ACR) and antibody mediated rejection (AMR). In lung transplant, early post-transplant ddcfDNA is as a strong predictor of peak allograft function and survival. The importance of early ddcfDNA in heart transplant recipients (HTR) is unclear. HTR were monitored in a multi-center prospective study conducted by the Genomic Research Alliance for Transplantation (GRAfT). Early plasma samples were assayed for ddcfDNA by shotgun sequencing on post-transplant Days 1, 7, and 28. The relationship of early ddcfDNA levels to peak ejection fraction (EF) anytime during follow-up and the occurrence of AMR were assessed using non-parametric tests. Peak ejection fractions (average of two highest post-transplant values) were grouped as low (<55%), normal (55% ≤EF <65%), and high (EF ≥65%). ddcfDNA levels were also compared for patients who went on to develop AMR (ISHLT ≥ PAMR1) and controls (no AMR; ACR ≤ grade 1R). 129 HTRs were monitored for a median (IQR) 367 (163-625) days after transplantation. 17 AMR episodes were detected at a median (IQR) of 14 (8-93) days. Post-transplant day 1 ddcfDNA levels correlated inversely with peak EF, with progressively higher values in the high, normal, and low EF groups (2.9% vs 3.5% vs 8.1%; p=0.05); levels were 2.5X higher for low versus high peak EF (p=0.02). Higher ddcfDNA levels in the low peak EF group persisted at days 7 (0.45% vs 0.39% vs 0.89%; p=0.23) and 28 (0.33% vs 0.35% vs 0.65%; p=0.36), though these differences were not significant. Day 7 post-transplant ddcfDNA levels were higher for patients who developed AMR than for controls (0.63% vs 0.42%; p=0.03). Early ddcfDNA may have prognostic implications for peak allograft function and future rejection risk in HTR. Patients with low peak EF and those who go on to develop AMR appear to have higher and persistent early post-transplant allograft injury compared to other HTR.