Donor-Derived Cell-Free DNA at Diagnosis of Cardiac Allograft Rejection Stratifies Risk of Mortality and Graft...

Cardiac acute rejection (AR) is a risk factor for poor outcomes; however, there are limited risk prediction models to stratify these patients for death or prolonged left ventricular (LV) dysfunction. We assessed the prognostic utility of percent donor-derived cell-free DNA (%dd-cfDNA) measured at AR diagnosis for predicting adverse outcomes.

The prospective multicenter GRAfT study (Genomic Research Alliance for Transplantation) enrolled heart transplant recipients and collected serial plasma samples to quantitate %dd-cfDNA. AR was defined as acute cellular rejection, antibody-mediated rejection, as well as biopsy-negative antibody-mediated rejection (donor-specific antibody positivity with LV dysfunction). In the primary analyses, AR was stratified by %dd-cfDNA at diagnosis using a data-driven threshold of 0.15%. Cox regression models assessed the associations between the time-dependent covariates of AR and %dd-cfDNA levels at the AR diagnosis and the outcome of prolonged LV ejection fraction decline (≤50% for ≥90 days) and death.

The study included 277 patients and 3218 %dd-cfDNA measurements. Over a median follow-up of 4.9 years (interquartile range, 2.5-5.0), 53 patients experienced the composite outcome of death or prolonged LV dysfunction, and 75 (27%) patients developed AR, including 43 (15%) patients with acute cellular rejection, 18 (7%) with pathological antibody-mediated rejection, and 14 (5%) with donor-specific antibody+/LV dysfunction. AR was associated with an increased risk of the primary composite outcome (hazard ratio, 4.47 [95% CI, 2.42-8.26]; P<0.001). When AR was stratified by %dd-cfDNA at diagnosis, patients with %dd-cfDNA ≥0.15% had higher risks of prolonged LV dysfunction, death, and the composite outcome compared with patients who had not developed AR at the same follow-up time (hazard ratio, 6.28 [95% CI, 3.04-13.0]; P<0.001 for the composite outcome). In contrast, the risks of death and prolonged LV ejection fraction reduction were not statistically significantly increased among patients who developed AR with %dd-cfDNA <0.15% at diagnosis.

AR with elevated %dd-cfDNA levels at diagnosis is associated with an increased risk of adverse outcomes after heart transplant, offering novel prognostic utility.