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Background  Correlation between antibody-mediated rejection (ABMR) and circulating HLA donor-specific antibodies (HLA-DSA) is strong but imperfect in kidney transplant (KT) recipients, raising the possibility of undetected HLA-DSA or non-HLA antibodies contributing to ABMR. Detailed evaluation of the degree of HLA matching together with the identification of non-HLA antibodies in KT may help to decipher the antibody involved.    Methods  We retrospectively assessed patients with transplant biopsies scored following Banff’15 classification. Pre- and post-transplant serum samples were checked for HLA and non-HLA antibodies [MICA-Ab, angiotensin-II type-1-receptor (AT 1 R)-Ab, endothelin-1 type-A-receptor (ETAR)-Ab and crossmatches with primary aortic endothelial cells (EC-XM)]. We also analyzed HLA epitope mismatches (HLA-EM) between donors and recipients to explore their role in ABMR histology (ABMR h ) with and without HLA-DSA.    Results  One-hundred eighteen patients with normal histology (n = 19), ABMR h  (n = 52) or IFTA (n = 47) were studied. ABMR h  patients were HLA-DSA pos  (n = 38, 73%) or HLA-DSA neg  (n = 14, 27%). Pre-transplant HLA-DSA and AT 1 R-Ab were more frequent in ABMR h  compared with IFTA and normal histology cases (p = 0.006 and 0.003), without differences in other non-HLA antibodies. Only three ABMR h DSA neg  cases showed non-HLA antibodies. ABMR h DSA neg  and ABMR h DSA pos  cases showed similar biopsy changes and graft-survival. Both total class II and DRB1 HLA-EM were associated with ABMR h DSA pos  but not with ABMR h DSA neg . Multivariate analysis showed that pre-transplant HLA-DSA (OR: 3.69 [1.31–10.37], p = 0.013) and AT 1 R-Ab (OR: 5.47 [1.78–16.76], p = 0.003) were independent predictors of ABMR h DSA pos .    Conclusions  In conclusion, pre-transplant AT 1 R-Ab is frequently found in ABMR h DSA pos  patients. However, AT 1 R-Ab, MICA-Ab, ETAR-Ab or EC-XM +  are rarely found among ABMR h DSA neg  patients. Pre-transplant AT 1 R-Ab may act synergistically with preformed or  de novo  HLA-DSA to produce ABMR h DSA pos  but not ABMR h DSA neg . HLA epitope mismatch associates with ABMR h DSA pos  compared with ABMR h DSA neg , suggesting factors other than HLA are responsible for the damage.

Non-HLA Antibodies and Epitope Mismatches in Kidney Transplant Recipients With Histological Antibody-Mediated Rejection