Pretransplant Sensitization Against Angiotensin II Type 1 Receptor Is a Risk Factor for Acute Rejection and Graft Loss

Abstract

y Both authors contributed equally.The angiotensin II type 1 receptor (AT 1 R) is an emerging target of functional non-HLA antibodies (Ab). We examined the potential of determining the degree of presensitization against AT 1 R as a risk factor for graft survival and acute rejection (AR). The study included 599 kidney recipients between 1998 and 2007. Serum samples were analyzed in a blinded fashion for anti-AT 1 R antibodies (AT 1 R-Abs) using a quantitative solid-phase assay. A threshold of AT 1 R-Ab levels was statistically determined at 10 U based on the time to graft failure. An extended Cox model determined risk factors for occurrence of graft failure and a first AR episode. AT 1 R-Abs >10 U were detected in 283 patients (47.2%) before transplantation. Patients who had a level of AT 1 R-Abs >10 U had a 2.6-fold higher risk of graft failure from 3 years posttransplantation onwards (p ¼ 0.0005) and a 1.9-fold higher risk of experiencing an AR episode within the first 4 months of transplantation (p ¼ 0.0393). Antibody-mediated rejection (AMR) accounted for 1/3 of AR, whereby 71.4% of them were associated with >10 U of pretransplant AT 1 R-Abs. Pretransplant anti-AT 1 R-Abs are an independent risk factor for long-term graft loss in association with a higher risk of early AR episodes.

Accelerated rejection, thrombosis, and graft failure with angiotensin II type 1 receptor antibodies

“…Our patient had ACR with endarteritis and C4d-negative AMR, which is consistent with previous studies of AT 1 R-Ab-mediated allograft rejection [4][5][6][7]. Unfortunately, he was resistant to robust anti-rejection therapy, suggesting that multiple inflammatory and/or immunological factors are likely mediating severe AT 1 R-Ab-mediated rejection that extend beyond complement-fixation or antibody-dependent cellular cytotoxicity.…”

“…Non-HLA antibodies, such as AT 1 R-Abs, have been implicated in allograft rejection and poor long-term graft outcomes, especially in highly sensitized patients [2,[4][5][6][7]. We report the first case of renal artery thrombosis and accelerated rejection associated with AT 1 R-Ab that was refractory to desensitization and resulted in early allograft failure.…”

“…By contrast, non-HLA antibodies such as MHC class I related chain A antibodies (MICA-Abs), anti-endothelial cell antibodies (AECAs), and angiotensin II type 1 receptor antibodies (AT 1 R-Abs) have all been implicated in transplant rejection and failure [2,[4][5][6][7], but preliminary studies have not been adequate to implement routine testing for these antibodies in clinical practice [2]. Furthermore, the mechanism of allograft damage, patterns of clinical presentation, and response to desensitization of non-HLA antibodies have not been clearly established.…”

Autoantibodies Toward the Angiotensin 2 Type 1 Receptor: A Novel Autoantibody in Alzheimer’s Disease

“…Anti-AT1R antibodies were found in 53% of AD patients and in 35% of matched normal controls. The frequency found in our controls is within the range of previously observed AT1R antibody levels in pre-renal transplant patients (23-45%) [25,26]. Ten percent of both patients and controls presented high anti-AT1R levels.…”

“…Most studies on anti-AT1R have utilized a cardiomyocyte based functional bioassay or in-house ELISAs utilizing a peptide sequence corresponding to the 2nd extracellular loop. We have used a stable and reproducible assay with the fulllength receptor embedded in a membrane that has a higher sensitivity [30]. Thus, results from previous studies on cardiac disease, diabetes or hypertension might not be directly comparable to our findings.…”