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Association of non-HLA antibodies against endothelial targets and donor-specific HLA antibodies with antibody-mediated rejection and graft function in pediatric kidney transplant recipients.

ABSTRACT:

Background

Non-HLA antibodies against endothelial targets have been implicated in the pathogenesis of antibody-mediated rejection (ABMR), but data in pediatric patients are scarce.

Methods

We retrospectively analyzed a carefully phenotyped single-center (University Children's Hospital Heidelberg, Germany) cohort of 62 pediatric kidney transplant recipients (mean age at transplantation, 8.6 ± 5.0 years) at increased risk of graft function deterioration. Patients had received their transplant between January 1, 1999, and January 31, 2010. We examined at time of late index biopsies (more than 1-year post-transplant, occurring after January 2004) the association of antibodies against the angiotensin II type 1 receptor (AT₁R), the endothelin type A receptor (ET_AR), the MHC class I chain-like gene A (MICA), and vimentin in conjunction with overall and complement-binding donor-specific HLA antibodies (HLA-DSA) with graft histology and function.

Results

We observed a high prevalence (62.9%) of non-HLA antibody positivity. Seventy-two percent of HLA-DSA positive patients showed additional positivity for at least one non-HLA antibody. Antibodies against AT₁R, ET_AR, and MICA were associated with the histological phenotype of ABMR. The cumulative load of HLA-DSA and non-HLA antibodies in circulation was related to the degree of microinflammation in peritubular capillaries. Non-HLA antibody positivity was an independent non-invasive risk factor for graft function deterioration (adjusted hazard ratio 6.38, 95% CI, 2.11-19.3).

Conclusions

Our data indicate that the combined detection of antibodies to HLA and non-HLA targets may allow a more comprehensive assessment of the patients' immune responses against the kidney allograft and facilitates immunological risk stratification.

SUBMITTER: Fichtner A

PROVIDER: S-EPMC8260519 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCorrelation 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.MethodsWe 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 (ABMRh) with and without HLA-DSA.ResultsOne-hundred eighteen patients with normal histology (n = 19), ABMRh (n = 52) or IFTA (n = 47) were studied. ABMRh patients were HLA-DSApos (n = 38, 73%) or HLA-DSAneg (n = 14, 27%). Pre-transplant HLA-DSA and AT1R-Ab were more frequent in ABMRh compared with IFTA and normal histology cases (p = 0.006 and 0.003), without differences in other non-HLA antibodies. Only three ABMRhDSAneg cases showed non-HLA antibodies. ABMRhDSAneg and ABMRhDSApos cases showed similar biopsy changes and graft-survival. Both total class II and DRB1 HLA-EM were associated with ABMRhDSApos but not with ABMRhDSAneg. 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 ABMRhDSApos.ConclusionsIn conclusion, pre-transplant AT1R-Ab is frequently found in ABMRhDSApos patients. However, AT1R-Ab, MICA-Ab, ETAR-Ab or EC-XM+ are rarely found among ABMRhDSAneg patients. Pre-transplant AT1R-Ab may act synergistically with preformed or de novo HLA-DSA to produce ABMRhDSApos but not ABMRhDSAneg. HLA epitope mismatch associates with ABMRhDSApos compared with ABMRhDSAneg, suggesting factors other than HLA are responsible for the damage.

Project description:Background and objectivesThe current allocation algorithm for deceased donor kidney transplantation takes into consideration HLA mismatches at the ABDR loci but not HLA mismatches at other loci, including HLA-DQ. However, the independent effects of incompatibilities for the closely linked HLA-DQ antigens in the context of HLA-DR antigen matched and mismatched allografts are uncertain. We aimed to determine the effect of HLA-DQ mismatches on renal allograft outcomes.Design, setting, participants, & measurementsUsing data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the association between HLA-DQ mismatches and acute rejections in primary live and deceased donor kidney transplant recipients between 2004 and 2012 using adjusted Cox regression models.ResultsOf the 788 recipients followed for a median of 2.8 years (resulting in 2891 person-years), 321 (40.7%) and 467 (59.3%) received zero and one or two HLA-DQ mismatched kidneys, respectively. Compared with recipients who have received zero HLA-DQ mismatched kidneys, those who have received one or two HLA-DQ mismatched kidneys experienced greater numbers of any rejection (50 of 321 versus 117 of 467; P<0.01), late rejections (occurring >6 months post-transplant; 8 of 321 versus 27 of 467; P=0.03), and antibody-mediated rejections (AMRs; 12 of 321 versus 38 of 467; P=0.01). Compared with recipients of zero HLA-DQ mismatched kidneys, the adjusted hazard ratios for any and late rejections in recipients who had received one or two HLA-DQ mismatched kidneys were 1.54 (95% confidence interval [95% CI], 1.08 to 2.19) and 2.85 (95% CI, 1.05 to 7.75), respectively. HLA-DR was an effect modifier between HLA-DQ mismatches and AMR (P value for interaction =0.02), such that the association between HLA-DQ mismatches and AMR was statistically significant in those who have received one or two HLA-DR mismatched kidneys, with adjusted hazard ratio of 2.50 (95% CI, 1.05 to 5.94).ConclusionsHLA-DQ mismatches are associated with acute rejection, independent of HLA-ABDR mismatches and initial immunosuppression. Clinicians should be aware of the potential importance of HLA-DQ matching in the assessment of immunologic risk in kidney transplant recipients.

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