Angiotensin II type I receptor agonistic autoantibodies are associated with poor allograft survival in liver retransplantation

Abstract

Angiotensin II type I receptor (AT1R) agonistic autoantibodies (AT1R-AA) are detrimental to kidney transplantation. Early studies suggested a similar negative effect in primary liver transplantation. Here, we studied AT1R-AA in a retrospective cohort of 94 patients who received a second liver transplant to determine their prevalence and effects. The concentrations of preformed AT1R-AA before transplantation were higher (p=0.019) in the 48 patients who lost their liver grafts than in the 46 patients whose grafts survived. About half (48/94, 51.1%) of the patients were positive for AT1R-AA>17U/ml before the second liver transplantation. In 22 (23.4%) patients, strong positive AT1R-AA (defined as >40U/ml) were detected, of whom 16 (72.7%) patients lost their grafts. Based on Kaplan-Meier analysis, patients with strong positive AT1R-AA had significantly worse graft survival than those with Accepted Article This article is protected by copyright. All rights reserved. AT1R-AA<40U/ml (p=0.035). In multivariate Cox models that included confounders such as sex and age, either AT1R-AA>40U/ml [HR=1.999 (1.085-3.682), p=0.026] or increased concentrations of AT1R-AA [HR=1.003 (1.001-1.006) per incremental U/ml, p=0.019] were significantly associated with elevated risk for graft loss. In conclusion, our data indicate that there is a high prevalence of AT1R-AA in candidates for second liver transplantation and that their presence is associated with inferior long-term outcomes of the second graft.

Autoantibodies to LG3 are associated with poor long‐term survival after liver retransplantation

“…In a previous study of 94 patients who underwent a second LT, we found that preformed Angiotensin II Type I Receptor agonistic autoantibodies (AT1R-AA) were associated with reduced allograft survival. 25 Specifically, 16/22 (72.7%) patients with strong AT1R-AA (>40 U/ml) had lost their second allografts. However, only one-third (16/48) of patients who lost their second liver allograft had strong AT1R-AA.…”

“…Therefore, the primary aim of this study was to determine if there were other preformed autoantibodies that could explain the difference in graft survival observed in our previous study. 25 To do that, we retrospectively tested a multiplex panel of 33 autoantibodies in pre-operative sera of the same cohort of patients who underwent a second LT.…”

Impact and production of Non‐HLA‐specific antibodies in solid organ transplantation

“…The presence of AT 1 R antibodies is also associated with higher rates of AMR in intestinal and multivisceral transplantation (Gerlach et al., 2017). Recently, in redo liver transplantation, high levels of AT 1 R antibodies have been associated with increased risk of graft loss (Xu et al., 2019). Furthermore, in paediatric liver transplantation, higher levels of AT 1 R antibodies were found in patients with advanced fibrosis (Ohe et al., 2014).…”

Rejection in the setting of non-HLA antibody: New tools for navigating bench to bedside

“…It is important to note that it is the altered pro‐inflammatory content of exosomes (cytokines, chemokines, and costimulatory molecules) released from injured and activated tissues that appears to potentiate HLA and non‐HLA antibody development. Therefore, it will be important to determine how the context of events associated with vascular insults such as ventricular assist device surgery vs liver rejection potentiate non‐HLA antibodies with noninjurious vs injurious potential, respectively 6,7 …”

“…Therefore, it will be important to determine how the context of events associated with vascular insults such as ventricular assist device surgery vs liver rejection potentiate non-HLA antibodies with noninjurious vs injurious potential, respectively. 6,7 New tools in the laboratory hold great promise for understand- New tools for recognizing different phenotypes of non-HLA antibody-mediated injury, particularly subclinical injury, will be complicated given the functional heterogeneity of ECs across vascular beds and the nonimmune factors that contribute to EC dysfunction.…”