Angiotensin II Type-1 Receptor Antibodies Are Associated With Active Allograft Dysfunction Following Pediatric Liver Transplantation

Abstract

Background. Angiotensin II type-1 receptor (AT1R) antibodies have been associated with rejection and allograft loss in solid organ transplantation and may act synergistically with HLA donor-specific antibodies (DSA). Our aims were to assess the prevalence of AT1R antibodies and determine if they were associated with allograft dysfunction in pediatric liver transplant recipients. Methods. We performed a retrospective, cross-sectional study of HLA DSA and AT1R antibodies in 2 cohorts of pediatric liver transplant recipients: a stable control cohort with normal allograft function (n = 70) who consented to have serum samples collected for research purposes during a routine clinic visit and a cohort with active allograft dysfunction (n = 9) whose serum samples were collected as part of clinical care. Results. AT1R antibodies >17 U/mL were detected in 29% of stable control patients and 89% of patients with active allograft dysfunction (P = 0.001). In stable control patients, AT1R antibodies were associated with younger age at transplant (P = 0.010), younger age at time of sample collection (P < 0.001), shorter interval since transplant (P = 0.090), and presence of HLA DSA (P = 0.003). AT1R antibodies in stable control patients were not associated with rejection or allograft loss. However, AT1R antibodies combined with HLA DSA in patients with active allograft dysfunction were associated with rejection and allograft loss. Conclusions. Our results suggest that AT1R antibodies are more common in patients with active allograft dysfunction and may be a risk factor for worse outcomes. Further research is needed to longitudinally assess the clinical impact of HLA DSA and AT1R antibodies.

Non‐HLA AT1R antibodies are highly prevalent after pediatric intestinal transplantation

“…22,24 Although not statistically significant, the median age at time of transplant in this study was younger in patients with AT1R antibodies compared to those without antibodies, an observation also shown in pediatric liver transplantation. 12 The development of infectious enteritis was also more commonly seen in those with AT1R antibodies here.…”

“…28 The negative effects of AT1R antibodies on heart, lung, kidney, and liver transplants have also been suggested. [9][10][11][12][13] However, the role of AT1R antibodies in ITx is unclear. Since AT1R is not distributed in the intestinal epithelium, the postulated mechanisms of AT1R antibody-mediated injury in ITx are damage to the vascular endothelium within the intestinal vasculature or heightened immune reactivity in response to high circulating antibodies.…”

“…Described first in adult kidney transplants, 8 AT1R antibodies have now been linked to adverse outcomes in a number of other solid organ transplants, including the heart, 9 lung, 10 and liver. [11][12][13][14] More recently, AT1R antibodies have also been implicated in intestinal graft rejection. In a study of 29 adult ITx patients, Gerlach et al screened for AT1R and anti-endothelin type A receptor antibodies and found a trend toward a higher risk of overall graft rejection (T-cell mediated rejection (TCMR) and AMR) in the presence of non-HLA antibodies compared to antibody-negative controls (80% versus 55%).…”

“…For that reason, a cutoff level of >17 U/mL was defined as positive in this study to remain consistent with other published transplant studies on AT1R antibodies. 9,12,22 AT1R antibody level of 40 U/mL was the upper limit, and an AT1R antibody level >40 U/mL was coded as 40 U/mL for analysis purposes. HLA-DSA, which had been measured as part of routine clinical care using a single-antigen bead Luminex test (LABScreen; One Lambda, Canoga Park, CA), were extracted from medical records.…”

“…Next, the IF patients served as the control group in this study, but future research may also compare AT1R antibody prevalence with an isolated liver transplant control group given the high frequency of liver-inclusive ITx in pediatrics. In the few pediatric liver transplantation studies of non-HLA antibodies, AT1R antibody prevalence has ranged from 29% to 68% in stable liver transplant recipients 12,14. Finally, analyses from this study were limited to onlyAT1R antibodies.…”