De Novo Complement-Binding Anti-HLA Antibodies in Heart Transplanted Patients Is Associated with Severe Cardiac Allograft Vasculopathy and Poor Long-Term Survival

Introduction: De novo anti-HLA donor specific antibodies (DSA) have been inconsistently associated with cardiac allograft vasculopathy (CAV) and long-term mortality. We tested whether C3d-binding de novo DSA were associated with CAV or long-term-survival. Methods: We included 282 consecutive patients without preformed DSA on coronary angiography between 2010 and 2012. Angiographies were classified according to CAV ISHLT grading. The primary outcome was a composite criterion of severe CAV or mortality. As the impact of de novo antibodies should be assessed only after appearance, we used a Cox regression with time-dependent covariables. Results: Of the 282 patients, 51(18%) developed de novo DSA during follow-up, 29 patients had DSA with C3d-binding ability (DSA+C3d+), and 22 were without C3d-binding ability (DSA+C3d-). Compared with patients without DSA, DSA+C3d+ patients had an increased risk for the primary outcome of severe CAV or mortality (adjusted HR = 4.31 (2.40-7.74) p < 0.001) and long-term mortality (adjusted HR = 3.48 (1.97-6.15) p < 0.001) whereas DSA+C3d- did not (adjusted HR = 1.04 (0.43-2.47) p = 0.937 for primary outcome and HR = 1.08 (0.45-2.61) p = 0.866 for mortality). Conclusion: According to this large monocentric study in heart transplant patients, donor specific antibodies were associated with worse clinical outcome when binding complement. DSA and their complement-binding ability should thus be screened for to optimize heart transplant patient follow-up.