Redefining Cardiac Antibody-Mediated Rejection With Donor-Specific Antibodies and Graft Dysfunction

BACKGROUND: Heart transplant recipients with donor-specific antibodies (DSAs) have an increased risk for antibody-mediated rejection. However, many patients with graft dysfunction and DSA do not have evidence of antibody-mediated rejection by endomyocardial biopsy (EMB). METHODS: Participants from this prospective, multicenter study underwent serial EMB, echocardiogram, DSA, and donor-derived cell-free DNA evaluations. Outcomes were defined as pAMR+ (pAMR≥1) or DSA+/left ventricle (LV) dysfunction (DSA presence+LVEF drop ≥10% to an LVEF≤50%). Cox regression evaluated the association between antibody-mediated rejection categories and death or sustained (for 3 months) reduction of LVEF to <50%. RESULTS: Two hundred sixteen patients (29% women, 39% Black race, median age 55 [interquartile range, 47–62] years) had 1488 EMB, 2792 DSA, 1821 echocardiograms, and 1190 donor-derived cell-free DNA evaluations. DSAs were present in 86 patients (40%). Fourteen patients had isolated pAMR+ episodes and 8 patients had isolated DSA+/LV dysfunction episodes; 2 patients had pAMR+ and then subsequently DSA+/LV dysfunction with pAMR+. Median %dd-cfDNA was significantly higher at diagnosis of pAMR+ (0.63% [interquartile range, 0.23–2.0]; P =0.0002), or DSA+/LV dysfunction (0.40% [interquartile range, 0.36–1.24]; P <0.0001), compared with patients without these outcomes (0.01% [interquartile range, 0.0001–0.10]). Both pAMR+ and DSA+/LV dysfunction were associated with long-term clinical outcome of death (n=18) or prolonged LV dysfunction (n=10): pAMR+ (hazard ratio, 2.8 [95% CI, 1.03–7.4]; P =0.043); DSA+/LV dysfunction (hazard ratio, 26.2 [95% CI, 9.6–71.3]; P <0.001); composite of both definitions (hazard ratio, 6.5 [95% CI, 2.9–14.3]; P <0.001). Patients who developed pAMR+ or DSA+/LV dysfunction within the first 6 months of transplant were more likely to die within 3 years posttransplant (hazard ratio, 3.9 [95% CI, 1.03–14.6]; P =0.031). CONCLUSIONS: Expanding the characterization of antibody-mediated rejection to include patients with DSA and concurrent allograft dysfunction identified DSA+ patients at risk for death and prolonged LV dysfunction.