Donor-Derived Cell-Free DNA in Antibody-Mediated Rejection

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BACKGROUND: Donor-derived cell-free DNA (dd-cfDNA) has emerged as a biomarker for antibody-mediated rejection (AMR), but its performance characteristics have not been evaluated in a large contemporary heart transplant population. OBJECTIVES: The study aimed to characterize the incidence and timing of biopsy-proven AMR and evaluate the performance characteristics of dd-cfDNA for AMR. METHODS: The authors included 2,240 subjects from the SHORE (Surveillance HeartCare Outcomes Registry) registry transplanted between 2017 and 2022 with verified biopsy, dd-cfDNA, echocardiographic, and donor-specific antibody (DSA) data. They evaluated the performance characteristics of dd-cfDNA for AMR and the incidence of AMR in different clinical contexts. RESULTS: AMR was present in 2.6% of biopsies with significant variability depending on the clinical context: AMR occurred in 1.1% of biopsies with normal graft function and no DSAs vs 20.4% of biopsies with known DSA and graft dysfunction. In patients with neither DSA nor graft dysfunction, the incidence of AMR was 0.7% for dd-cfDNA levels <0.20%, 1.2% for levels between 0.20% and 0.49%, and 6.7% for dd-cfDNA levels ≥0.50%. In patients with known DSA but no graft dysfunction, the incidence of AMR was 1.4% for dd-cfDNA levels <0.20%, 4.8% for levels between 0.20% and 0.49%, and 15.5% for dd-cfDNA levels ≥0.50%. CONCLUSIONS: The authors document significant context dependent variability of AMR incidence and the utility of dd-cfDNA in predicting biopsy yield. These data complement prior studies on the interpretation of peripheral gene expression profiling and dd-cfDNA for rejection monitoring and should further obviate the need for surveillance biopsies. (Surveillance HeartCare Outcomes Registry [SHORE]; NCT03695601).

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