Non-human leukocyte antigen autoantibodies-anti-angiotensin II type 1 receptor and endothelin type A receptor antibodies-in the diagnosis of antibody-mediated rejection: Biopsy-based transcript diagnostics perspective.

Some kidney allograft biopsies with microvascular inflammation (MVI)-a hallmark of antibody-mediated rejection (AMR)-lack evidence of antihuman leukocyte antigen (HLA) donor-specific antibodies. In these cases, alternative mechanisms of allograft injury may play a role, such as non-HLA angiotensin II type 1 receptor (AT1R) or endothelin type A receptor (ETAR) autoantibodies. In this single-center study, 196 biopsies were evaluated by histology and biopsy-based transcript diagnostics. Anti-HLA antibodies, AT1R-, and ETAR-Ab serology were determined at the time of biopsy. Of 61 histologic AMR, 29 (48%) were identified as molecular AMR (mAMR); of 24 MVI, donor-specific antibody-negative, C4d-negative biopsies, 11 (46%) biopsies were mAMR. Additionally, 6 (16%) of 37 probable AMR biopsies were mAMR. The AT1R-/ETAR-Ab concentration did not differ among histologic categories or across different levels of molecular scores. However, biopsies with mAMR had higher concentrations of AT1R-Ab (P = .09) and ETAR-Ab (P = .02) compared with biopsies with no molecular rejection. The presence of non-HLA autoantibodies did not affect the outcome. Biopsies with MVI at/above threshold showed a higher hazard (hazard ratio: 2.09, 95% confidence interval: 0.90-4.86, P = .09) of the composite endpoint (allograft failure or estimated glomerular filtration rate <15 mL/min). Non-HLA autoantibodies reflect molecular AMR injury, but their clinical utility is likely limited.