Abstract and Introduction
Abstract
Reports have associated non-HLA antibodies, specifically those against angiotensin II type-1 receptor (AT1R), with antibody-mediated kidney graft rejection. However, association of anti-AT1R with graft failure had not been demonstrated. We tested anti-AT1R and donor-specific HLA antibodies (DSA) in pre- and posttransplant sera from 351 consecutive kidney recipients: 134 with biopsy-proven rejection and/or lesions (abnormal biopsy group [ABG]) and 217 control group (CG) patients. The ABG's rate of anti-AT1R was significantly higher than the CG's (18% vs. 6%, p < 0.001). Moreover, 79% of ABG patients with anti-AT1R lost their grafts (vs. 0%, CG), anti-AT1R levels in 58% of those failed grafts increasing posttransplant. With anti-AT1R detectable before DSA, time to graft failure was 31 months—but 63 months with DSA detectable before anti-AT1R. Patients with both anti-AT1R and DSA had lower graft survival than those with DSA alone (log-rank p = 0.007). Multivariate analysis showed that de novo anti-AT1R was an independent predictor of graft failure in the ABG, alone (HR: 6.6), and in the entire population (HR: 5.4). In conclusion, this study found significant association of anti-AT1R with graft failure. Further study is needed to establish causality between anti-AT1R and graft failure and, thus, the importance of routine anti-AT1R monitoring and therapeutic targeting.
Introduction
Investigators have long stressed the importance of both non-HLA immunity and HLA immunity in transplantation. Nevertheless, compared with the abundant evidence about HLA antibodies, there is scant evidence for the impact on graft survival of humoral reactions against non-HLA targets, leaving poor understanding of failure mechanisms that HLA antibodies, alone, cannot explain. Recently, though, there has been increasing agreement that antibodies against non-HLA antigens can trigger an immunological response in solid organ transplantation.
Early studies were limited to antibodies against endothelial cells identified in heart transplantation during acute rejection, cardio allograft vasculopathy and coronary heart diseases, and in renal transplant during hyperacute rejection. Recent studies have more pointedly suggested the role of antibodies in immune responses against tissue-restricted antigens including vimentin, cardiac myosin and the angiotensin II type-1 receptor (AT1R). Still—as noted—the impact of these tissue-restricted antibodies on graft function and survival had not yet been demonstrated.
Because AT1R differs from all other non-HLA antigenic targets in the mechanism of humoral reactions—specifically, the binding of antibodies to AT1R induces unique physiological effects that mimic those of receptor ligand (angiotensin II [Ang-II]) in the renin–angiotensin system (RAS) —we decided to explore the association of anti-AT1R with graft failure. AT1R is distributed among various organs, and is principal mediator of Ang-II's effects, causing (inter alia) vasoconstriction in vascular smooth muscle cells, aldosterone secretion by the adrenal cortex, and sodium re-absorption in proximal tubules. Yet disruption of the RAS leads to various pathological events including hypertension, heart failure, kidney disease, atherosclerosis, and cancer development. Induction of vascular injury by exogenous Ang-II has been thoroughly studied in animals. A similar role for anti-AT1R was observed in kidney transplantation with rats that developed hypertension after passive anti-AT1R transfer. In transplantation, anti-AT1R was shown to be associated with antibody-mediated rejection (AMR) in the absence of DSA.
Despite these many observations, the question of how anti-AT1R development affects postrejection graft survival remained. We hypothesized that anti-AT1R, responding to graft injury caused by rejection or posttransplant lesions unrelated to rejection, may impact long-term graft outcome. This study aimed to examine the incidence of anti-AT1R and the impact of anti-AT1R on graft survival with or without histopathologic diagnoses.