Donor-Derived Cell-Free DNA Predicts De Novo DSA after Heart Transplantation

Abstract

PurposeDevelopment of de novo donor-specific HLA antibodies (dnDSA) may contribute to allograft injury and dysfunction, antibody-mediated rejection (ABMR), and potential development of cardiac allograft vasculopathy (CAV). Elevated plasma donor-derived cell-free DNA (dd-cfDNA) levels have been demonstrated during acute cellular rejection (ACR) and ABMR events after heart transplant (HT). The purpose of this study is to investigate the relationship between dd-cfDNA and subsequent DSA development.MethodsFrom the 916 HT patients enrolled in the Surveillance Heart Care Outcome Registry (SHORE), we reviewed 2136 samples of dd-cfDNA surveillance monitoring. Patients with ACR or ABMR on biopsy were excluded from analysis. The dnDSAs included HLA Class I and/or Class II epitopes and were analyzed to development of first dnDSA or last negative test, with censoring at 365 days. There were 613 DSA samples paired with dd-cfDNA levels that were obtained within 30 days of the DSA draw, with prior negative endomyocardial biopsy. Cox proportional hazards model fitting was utilized with dd-cfDNA as a covariate (p<0.05).ResultsFrom analysis of 613 paired samples, 127 (20.7%) demonstrated dnDSA with an associated median dd-cfDNA of 1.20% (IQR: 0.100 - 3.10%). 71 (11.6%) were associated with dnDSA Class I and 93 (15.2%) with Class II. When dichotomized for dd-cfDNA > 0.15%, [FIGURE] the positive likelihood ratio for development of Class I and/or Class II dnDSA (+LR) was 4.47 (p=0.03). When analyzed without censoring at 365 days, using dd-cfDNA at this cutoff, the +LR was 5.68 (p=0.02).ConclusionIn the prospective SHORE cohort, elevated dd-cfDNA levels > 0.15% were associated with increased likelihood for the subsequent development of dnDSA within the first year after heart transplantation. Development of de novo donor-specific HLA antibodies (dnDSA) may contribute to allograft injury and dysfunction, antibody-mediated rejection (ABMR), and potential development of cardiac allograft vasculopathy (CAV). Elevated plasma donor-derived cell-free DNA (dd-cfDNA) levels have been demonstrated during acute cellular rejection (ACR) and ABMR events after heart transplant (HT). The purpose of this study is to investigate the relationship between dd-cfDNA and subsequent DSA development. From the 916 HT patients enrolled in the Surveillance Heart Care Outcome Registry (SHORE), we reviewed 2136 samples of dd-cfDNA surveillance monitoring. Patients with ACR or ABMR on biopsy were excluded from analysis. The dnDSAs included HLA Class I and/or Class II epitopes and were analyzed to development of first dnDSA or last negative test, with censoring at 365 days. There were 613 DSA samples paired with dd-cfDNA levels that were obtained within 30 days of the DSA draw, with prior negative endomyocardial biopsy. Cox proportional hazards model fitting was utilized with dd-cfDNA as a covariate (p<0.05). From analysis of 613 paired samples, 127 (20.7%) demonstrated dnDSA with an associated median dd-cfDNA of 1.20% (IQR: 0.100 - 3.10%). 71 (11.6%) were associated with dnDSA Class I and 93 (15.2%) with Class II. When dichotomized for dd-cfDNA > 0.15%, [FIGURE] the positive likelihood ratio for development of Class I and/or Class II dnDSA (+LR) was 4.47 (p=0.03). When analyzed without censoring at 365 days, using dd-cfDNA at this cutoff, the +LR was 5.68 (p=0.02). In the prospective SHORE cohort, elevated dd-cfDNA levels > 0.15% were associated with increased likelihood for the subsequent development of dnDSA within the first year after heart transplantation.