UCLA

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 (AT₁R)-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 AT₁R-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_hDSA_neg cases showed non-HLA antibodies. ABMR_hDSA_neg and ABMR_hDSA_pos cases showed similar biopsy changes and graft-survival. Both total class II and DRB1 HLA-EM were associated with ABMR_hDSA_pos but not with ABMR_hDSA_neg. Multivariate analysis showed that pre-transplant HLA-DSA (OR: 3.69 [1.31-10.37], p = 0.013) and AT₁R-Ab (OR: 5.47 [1.78-16.76], p = 0.003) were independent predictors of ABMR_hDSA_pos.

Conclusions

In conclusion, pre-transplant AT₁R-Ab is frequently found in ABMR_hDSA_pos patients. However, AT₁R-Ab, MICA-Ab, ETAR-Ab or EC-XM⁺ are rarely found among ABMR_hDSA_neg patients. Pre-transplant AT₁R-Ab may act synergistically with preformed or de novo HLA-DSA to produce ABMR_hDSA_pos but not ABMR_hDSA_neg. HLA epitope mismatch associates with ABMR_hDSA_pos compared with ABMR_hDSA_neg, suggesting factors other than HLA are responsible for the damage.