Deleterious effect of anti-angiotensin II type 1 receptor antibodies detected pretransplant on kidney graft outcomes is both proper and synergistic with donor-specific anti-HLA antibodies.

Abstract

Both donor-specific antibodies (DSA) and anti-angiotensin II type 1 receptor antibodies (AT1R-abs) have been associated with poor graft outcomes after kidney transplantation (KT). We aimed to understand the impact of pretransplant AT1R-abs with or without concomitant DSA on KT outcomes. Seventy-six patients transplanted in 2009 were studied. DSA (MFI > 1000) and/or AT1R-abs (>10UI) were detected by solid-phase assays in pre-KT sera. Multivariable Cox regression models were used to determine independent predictors of outcomes: acute rejection (AR) and graft failure. At transplant, 48 patients were AT1R-abs (-)/DSA (-), 12 AT1R-abs (+)/DSA (-), 9 AT1R-abs (-)/DSA (+) and 7 AT1R-abs (+)/DSA (+). Incidence of acute rejection at 1-year increased from 6% in AT1R-abs (-)/DSA (-), to 35% in AT1R-abs (+)/DSA (-), 47% in AT1R-abs (-)/DSA (+) and 43% in AT1R-abs (+)/DSA (+) (P < 0.001). No difference in DSA strength and C1q-binding ability was observed between AT1R-abs (-) /DSA (+) and AT1R-abs (+)/DSA (+) patients. Graft survival at 6-years was the lowest in AT1R-abs (+)/DSA (+) (57%), followed by AT1R-abs (+)/DSA (-) (67%), and higher in AT1R-abs (-)/DSA (-) (94%) and AT1R-abs (-)/DSA (+) (89%) patients (P = 0.012). AT1R-abs (+)/DSA (-) (HR = 6.41, 95% CI: 1.43-28.68; P = 0.015) and AT1R-abs (+)/DSA (+) (HR = 7.75, 95% CI: 1.56-38.46; P = 0.012) were independent predictors of graft failure. Acute rejection incidence and graft failure were associated with both DSA and AT1R-abs. These results demonstrate a proper negative effect of AT1R-abs on graft outcomes, besides a synergistic one with DSA. Pretransplant AT1R-abs should be acknowledged to better stratify patients' immunological risk.