Redefining Cardiac Antibody-Mediated Rejection With Donor-Specific Antibodies and Graft Dysfunction
Jason F. Goldberg, Xin Tian, Ann Bon, Yifei Xu, Eleanor F. Gerhard, Ruth Brower, Moon Kyoo Jang, Hyesik Kong, T. Andargie, Woojin Park, Samer S. Najjar, Inna Tchoukina, Keyur B. Shah, Steven Hsu, M.E. Rodrigo, Charles C. Marboe, Gerald J. Berry, Hannah A. Valantine, Palak Shah, Sean Agbor-Enoh
Abstract
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.