Association between Pretransplant Antibody against Angiotensin II Type 1 Receptor and Posttransplant Allograft Injury

Abstract

In heart transplantation (HT), antibodies directed against Angiotensin II type 1 receptor (AT1RAb) have been associated with antibody-mediated rejection (AMR), acute cellular rejection (ACR), and microvasculopathy. The effect of AT1RAb detected pre-HT on immediate post-HT allograft injury remains poorly defined. In this study, we leverage a validated and sensitive blood based biomarker for allograft injury, donor-derived cell-free DNA (ddcfDNA), to examine the association of pre-HT AT1RAb to post-HT allograft injury. AT1RAb testing was performed on pretransplant plasma from HT recipients in the Genomic Research Alliance for Transplantation (GRAfT) multicenter, prospective cohort study, using a quantitative ELISA (One Lambda, ThermoFisher). After HT, serial plasma samples were collected and used to quantitate %ddcfDNA by shotgun sequencing. AT1RAb concentration (units/ml) was used to categorize patients as AT1RAb<30 (n=32) or AT1RA>30 (n=17). A mixed linear model was used to examine post-HT %ddcfDNA trajectories across AT1RAb groups. Histopathology slides were read by a consensus of pathologists to define AMR using ISHLT criteria. Age, gender and clinical features were similar between AT1RAb<30 and AT1RA>30 groups. AT1RAb>30 had a greater proportion of White recipients compared to AT1RAb<30 (59% versus 38%; p = 0.003). While %ddcfDNA on posttransplant Day 1 were similar between AT1RAb<30 vs AT1RAb>30 (p=0.6), in the first year post-HT, ddcfDNA declined by 87% (95% CI 79%-92%) among patients with AT1RAb<30 vs 67% (CI=34%-84%) among patients with AT1RAb>30 (p = 0.04) (Figure). AMR in the first year post-HT was more common among AT1RAb>30 than AT1RAb<30 patients (18% vs 3%, p=0.07); CMR was comparable in each group (41% vs 24%, p=0.2). Preliminary analysis of this heart transplant cohort suggest that high pre-HT AT1RAb is associated with increased early post-HT allograft injury.