Angiotensin II Type 1 Receptor Antibody Mediated Rejection Following Orthotopic Heart Transplant: A Single Center Experience

Abstract

Antibody mediated rejection (AMR) following heart transplant (OTHx) causes significant morbidity and mortality. In particular, diagnosis and management of non-HLA AMR remains challenging. Antibodies to the angiotensin II type 1 receptor (AT1R) causing rejection after kidney transplant have been described, but there is limited data on AT1R-Ab mediated rejection following OHTx. Here, we present our single center experience. We retrospectively reviewed all OHTx cases from the past 2 years with clinically suspected AMR without evidence of canonical donor-specific AMR who had a positive AT1R-Ab titer. Clinical and pathological features were documented. We identified 7 patients, the majority were female (71%), African American (71%), and had prior LVAD support (71%). All patients had NICM pretransplant. Patients presented both early (∼2 weeks) and late (∼7 years) with heart failure; 3 patients presented within 1 year post OHTx. Echocardiography showed progressive graft dysfunction, primarily decreased EF, ventricular wall thickening, and diastolic dysfunction. The average AT1R-Ab titer was 22U/mL at 1:100 dilution (range: 3 to >40 U/mL). Biopsies showed reactive endothelium and increased interstitial macrophages, without pathologic AMR features (negative C4d and <10% intravascular macrophages by CD68). Five patients were empirically treated with plasmapheresis, IVIG and rituximab. One patient did not tolerate plasmapheresis, and treatment was deferred on one patient given low titers and clinical improvement with standard heart failure treatment. All patients were started on an angiotensin receptor blocker (ARB). There were no deaths, and the majority of patients had clinically significant improvement in symptoms and graft function following treatment with an ARB at an average 6 months of follow-up. AT1R-Ab mediated rejection is an underdiagnosed and emerging entity following OHTx that remains ill-defined; it requires a high index of suspicion and should be considered for all OHTx recipients with evidence of graft dysfunction or decompensation. Empiric AMR treatment followed by oral ARB therapy anecdotally improves patient outcomes; however, future studies are needed to better define the pathophysiology, long-term clinical sequelae, and optimal treatment modalities of this disease.