The utility of circulating donor specific antibody to predict biopsy-proven antibody-mediated rejection and to provide prognostic value after heart transplantation in children

Abstract

Aim Heart transplantation (HT) is a life-saving option for children with end-stage heart failure. Antibody-mediated rejection (AMR) is a significant cause of morbidity and mortality in HT. The current diagnostic criteria for AMR are based on endomyocardial biopsy (EMB) showing evidence of C4d and C3d deposition, and capillary endothelial changes, including neutrophil and macrophage infiltration, and interstitial edema. Although the presence of donor specific antibody (DSA) is a risk factor for the development of AMR after HT, it is currently not required for diagnosis of AMR. In this study, we aimed to investigate the sensitivity, specificity, predictive values and prognostic implications of circulating DSA using EMB as the gold standard for AMR diagnosis in a cohort of pediatric HT recipients. Methods Retrospective study in pediatric HT patients that had follow-up care between 2009–2013 and had at least one EMB paired with DSA testing within 3 days of the biopsy. Positive DSA was defined at a mean fluorescent intensity (MFI) ⩾ 2000 using single antigen bead testing. Results Of the 66 patients included, 26 (39%) had at least 1 HLA DSA positive test. Of the 26 patients with positive DSA, 18 (69%) had at least one antibody against HLA-DQ. In 7 (27%) of the 26 patients with positive DSA, the only antibody detected was against HLA-DQ. Of 236 DSA EMB pairs analyzed, 132 (56%) pairs were negative for DSA, 23 (10%) pairs had HLA DSA Class I only, 59 (25%) pairs had HLA DSA Class II only, and 22 (9%) pairs had both HLA class I and II DSA. HLA DSA testing had a sensitivity = 92.6%, specificity = 62.2%, PPV = 24.0%, and NPV = 98.5% for biopsy-proven AMR. Kaplan–Meier analysis showed that patients with positive HLA DSA results and biopsy-proven AMR trended toward a higher incidence of cardiovascular mortality, and coronary artery vasculopathy after 3 years compared to patients without circulating DSA and a negative biopsy. Conclusions The results of HLA-DSA testing in this cohort, showing excellent sensitivity and NPV for biopsy-proven AMR suggest for the first time, that DSA testing could be used for non-invasive prediction of AMR absence in heart transplantation, and avoid unnecessary biopsies. The value of DSA testing for biopsy-proven AMR and outcome prognosis in HT is important to study in future multi-center prospective studies.