Reassessment of the clinical impact of preformed donor-specific anti-HLA-Cw antibodies in kidney transplantation.

Anti-denatured HLA-Cw antibodies are highly prevalent, whereas anti-native HLA-Cw antibodies seem to lead to random flow cytometry crossmatch results. We aimed to reassess crossmatch prediction for anti-HLA-Cw using 2 types of single antigen flow beads (classical beads and beads with diminished expression of denatured HLA), and to compare the pathogenicity of preformed anti-denatured and anti-native HLA-Cw antibodies in kidney transplantation. We performed 135 crossmatches with sera reacting against donor HLA-Cw (classical beads fluorescence ≥500); only 20.6% were positive. Forty-three (31.6%) were anti-denatured HLA antibodies (beads with diminished expression of denatured HLA fluorescence <300); all were crossmatch negative. The correlation between classical beads fluorescence and the crossmatch ratio was low (ρ = 0.178), and slightly higher with beads with diminished expression of denatured HLA (ρ = 0.289). We studied 52 kidney recipients with preformed anti-HLA-Cw donor-specific antibodies. Those with anti-native HLA antibodies experienced more acute and chronic antibody-mediated rejections (P = .006 and .03, respectively), and displayed a lower graft survival (P = .04). Patients with anti-native HLA-Cw antibodies more frequently had previous sensitizing events (P < .000001) or plausibility of their antibody profile according to known anti-native HLA-Cw eplets (P = .0001). Anti-native but not anti-denatured HLA-Cw antibodies are deleterious, which underscores the need for reagents with diminished expression of denatured HLA.

Identification of the novel HLA-DQA1*02:32 allele by next-generation sequencing.

HLA-DQA1*02:32 differs from DQA1*02:01:01 by one nucleotide substitution in codon 210 in exon 4.

Identification of the novel HLA-DRB1*14:253 allele by next-generation sequencing.

HLA-DRB1*14:253 differs from DRB1*14:54:01 by one nucleotide substitution in codon 233 in exon 5.

Identification of the novel HLA-DQB1*03:512 allele by next-generation sequencing.

HLA-DQB1*03:512 differs from DQB1*03:02:01 by one nucleotide substitution in codon 89 in exon 2.

Characterization of the novel HLA-DRB1*11:324 allele by sequencing-based typing.

HLA-DRB1*11:324 differs from HLA-DRB1*11:62:02 by one nucleotide substitution in codon 38 in exon 2.

Characterization of the novel HLA-C*06:176:02 allele by sequencing-based typing.

HLA-C*06:176:02 differs from HLA-C*06:176:01 by two nucleotide substitutions in codons 236 and 237 in exon 4.

Characterization of the novel HLA-DRB1*13:03:13 allele by sequencing-based typing.

HLA-DRB1*13:03:13 differs from HLA-DRB1*13:03:01:01 by one nucleotide substitution in codon 180 in exon 3.

Characterisation of the novel HLA-C*07:02:151 allele by sequencing-based typing.

HLA-C*07:02:151 differs from HLA-C*07:02:01:01 by one nucleotide substitution in codon 166 in exon 3.

Characterisation of the novel HLA-DRB4*01:182 allele by sequencing-based typing.

HLA-DRB4*01:182 differs from HLA-DRB4*01:03:01:01 by one nucleotide substitution in codon 172 in exon 3.

Characterization of the novel HLA-B*14:121 allele by sequencing-based typing.

HLA-B*14:121 differs from HLA-B*14:01:01:01 by one nucleotide substitution in codon 319 in exon 6.

Characterization of the novel HLA-C*05:286 allele by sequencing-based typing.

HLA-C*05:286 differs from HLA-C*05:01:01:02 by one nucleotide substitution in codon 283 in exon 5.

Characterization of the novel HLA-B*51:394Q allele by sequencing-based typing.

HLA-B*51:394Q differs from HLA-B*51:01:01:05 by one nucleotide substitution in codon 339 in exon 7.

Characterization of the novel HLA-C*01:263 allele by sequencing-based typing.

HLA-C*01:263 differs from HLA-C*01:02:01:01 by one nucleotide substitution in codon 98 in exon 3.

Characterisation of the novel HLA-DRB4*01:01:12 allele by sequencing-based typing.

HLA-DRB4*01:01:12 differs from HLA-DRB4*01:01:01:01 by one nucleotide substitution in codon 175 in exon 3.

Characterization of the novel HLA-B*14:122 allele by sequencing-based typing.

HLA-B*14:122 differs from HLA-B*14:02:01:01 by one nucleotide substitution in codon 102 in exon 3.

Characterization of the novel HLA-A*32:177 allele by sequencing-based typing.

HLA-A*32:177 differs from HLA-A*32:01:01:01 by one nucleotide substitution in codon -16 in exon 1.

Characterization of the novel HLA-DPB1*1516:01 allele by sequencing-based typing.

HLA-DPB1*1516:01 differs from HLA-DPB1*1229:01 by seven nucleotide substitutions in exon 3.

Characterization of the novel HLA-DQA1*01:03:11 allele by sequencing-based typing.

HLA-DQA1*01:03:11 differs from HLA-DQA1*01:03:01:02 by one nucleotide substitution in codon 59 in exon 2.

Characterization of the novel HLA-DRB1*04:04:20 allele by sequencing-based typing.

HLA-DRB1*04:04:20 differs from HLA-DRB1*04:04:01:04 by one nucleotide substitution in codon 135 in exon 3.

25-hydroxyvitamin D sufficiency is associated with lower de novo anti-HLA donor specific antibody and better kidney transplant outcomes.

T-cell mediated rejection (TCMR), de novo anti-HLA donor-specific antibodies (dnDSAs) and ensuing antibody-mediated rejection (ABMR) reduce kidney transplantation (KT) survival. The immunomodulatory effects of 25-hydroxyvitamin D [25(OH)D] could be beneficial for KT outcomes. We aimed to evaluating the association between 25(OH)D levels, the development of dnDSAs, clinical TCMR and ABMR, and graft survival. This single center retrospective study included 253 KT recipients (KTRs) transplanted without preformed DSA between 2010 and 2013. We measured 25(OH)D in successive serum samples: at KT (M0) and M12 for the entire cohort, and additionally at M24 and/or M36 when sera were available. We assessed graft outcomes up to 5 years post-KT. The proportion of KTRs having sufficient 25(OH)D at KT (M0) was high (81.4%) and then dropped at M12 (71.1%). KTRs with sufficient 25(OH)D at M0 experienced less clinical TCMR (HR, 0.41; 95% CI, 0.19-0.88 in multivariate analysis). A sufficient 25(OH)D at M12 was independently associated with a longer dnDSA-free survival (HR, 0.34; 95% CI, 0.17-0.69). There was no association between 25(OH)D and clinical AMBR. Studying the KTRs with 25(OH)D measurements at M12, M24 and M36 (n = 203), we showed that 25(OH)D sufficiency over the 3 first-years post-KT was associated with a longer graft survival in multivariate analyses (HR, 0.39; 95% CI, 0.22-0.70). To our knowledge, this study is the first showing an association between 25(OH)D sufficiency post-KT and dnDSA occurrence in KTRs. Moreover, we reinforce previously published data showing an association between 25(OH)D, TCMR and graft survival in KT.