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

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.