Molecular HLA mismatching for prediction of primary humoral alloimmunity and graft function deterioration in paediatric kidney transplantation

Abstract

IntroductionRejection remains the main cause of allograft failure in paediatric kidney transplantation and is driven by donor-recipient HLA mismatching. Modern computational algorithms enable assessment of HLA mismatch immunogenicity at the molecular level (molecular-mismatch, molMM). Whilst molMM has been shown to correlate with alloimmune outcomes, evidence demonstrating improved prediction performance against traditional antigen mismatching (antMM) is lacking.MethodsWe analysed 177 patients from the CERTAIN registry (median follow-up 4.5 years). molMM scores included Amino-Acid-Mismatch-Score (AAMS), Electrostatic-Mismatch-Score (EMS3D) and netMHCIIpan (netMHC1k: peptide binding affinity ≤1000 nM; netMHC: binding affinity ≤500 nM plus rank <2%). We stratified patients into high/low-risk groups based on risk models of DSA development.ResultsDonor-specific HLA antibodies (DSA) predominantly targeted the highest scoring molMM donor antigen within each HLA locus. MolMM scores offered superior discrimination versus antMM in predicting de novo DSA for all HLA loci; the EMS3D algorithm had particularly consistent performance (area under the receiver operating characteristic curve (AUC) >0.7 for all HLA loci vs. 0.52-0.70 for antMM). ABMR (but not TCMR) was associated with HLA-DQ molMM scores (AAMS, EMS3D and netMHC). Patients with high-risk HLA-DQ molMM had increased risk of graft function deterioration (50% reduction in baseline eGFR (eGFR50), adjusted HR: 3.5, 95% CI 1.6-8.2 high vs. low EMS3D). Multivariable modelling of the eGFR50 outcome using EMS3D HLA-DQ stratification showed better discrimination (AUC EMS3D vs. antMM at 2 years: 0.81 vs. 0.77, at 4.5 years: 0.72 vs. 0.64) and stratified more patients into the low-risk group, compared to traditional antMM.ConclusionMolecular mismatching was superior to antigen mismatching in predicting humoral alloimmunity. Molecular HLA-DQ mismatching appears to be a significant prognostic factor for graft function deterioration in paediatric kidney transplantation.

HLA (emphasis on DQ) compatibility for longer allograft survival in pediatric transplantation: Modern evidence and challenges

“…For example, while Kim et al also demonstrated an association of higher molecular mismatch load (EMS3D, specifically at HLA-DQ locus) and dnDSA and ABMR, no association was found with T-cell-mediated rejection (TCMR). 41 Similarly, Philogene 40 did not confirm an association with any rejection. An association with risk of premature graft loss was shown by Sypek et al but only when analyzed using univariate analysis.…”

“…38 Accordingly, the past few years showed a flurry of studies exploring association between eplet mismatch load, indirectly presented peptides (netMHCIIpan), amino acid mismatches, and electrostatic mismatches and risk of developing locus-specific dnDSA in pediatric patients. [39][40][41][42][43] While many studies confirmed the results published by the Manitoba group, that was not always the case. For example, while Kim et al also demonstrated an association of higher molecular mismatch load (EMS3D, specifically at HLA-DQ locus) and dnDSA and ABMR, no association was found with T-cell-mediated rejection (TCMR).…”

“…While many studies confirmed the results published by the Manitoba group, that was not always the case. For example, while Kim et al also demonstrated an association of higher molecular mismatch load (EMS3D, specifically at HLA‐DQ locus) and dnDSA and ABMR, no association was found with T‐cell‐mediated rejection (TCMR) 41 . Similarly, Philogene 40 did not confirm an association with any rejection.…”

“…In fact, according to OPTN data, there is a higher proportion of highly sensitized pediatric patients listed for re‐transplantation compared with adult patients awaiting re‐transplant 38 . Accordingly, the past few years showed a flurry of studies exploring association between eplet mismatch load, indirectly presented peptides (netMHCIIpan), amino acid mismatches, and electrostatic mismatches and risk of developing locus‐specific dnDSA in pediatric patients 39–43 . While many studies confirmed the results published by the Manitoba group, that was not always the case.…”

“…49,50 Specific for pediatric kidney transplant cohorts, similar associations were reported in different retrospective studies. For example, 39,41,[51][52][53] reported that HLA-DQ dnDSA were more frequent than any other HLA loci. HLA Class II dnDSA (most frequently directed at HLA-DQ) also showed higher association with graft function impairment, suggesting specific pathogenic effect.…”