Dataset Information

Mismatches in Gene Deletions and Kidney-related Proteins as Candidates for Histocompatibility Factors in Kidney Transplantation.

ABSTRACT:

Introduction

The genomic mismatch level between donor and recipient may be associated with the risk of rejection and graft survival. We determined the association of genome-level matching with acute rejection in deceased-donor kidney transplantation.

Methods

The study cohort consists of 1025 recipient-donor pairs transplanted in a single center from 2007 to 2017 in Helsinki. The associations between the sums of whole-genome missense variant mismatches and missense mismatches in transmembrane, secretory, and kidney-related proteins, with acute rejection were estimated using Cox model. In addition, we analyzed 40 deletion-tagging variants using Cox model.

Results

The association analysis between mismatch sums of kidney-related proteins and acute rejection resulted in an unadjusted hazard ratio (HR) of 1.15 (95% confidence interval [CI], 1.01-1.30; P = 0.029) and adjusted HR of 1.13 (95% CI, 0.99-1.28; P = 0.071). In deletion analysis, a mismatch in rs7542235 genotype GG tagging a homozygous deletion at the complement factor H-related (CFHR), proteins locus, predisposed to acute rejection with an unadjusted HR of 3.10 (95% CI, 1.53-6.29; P = 0.002) and adjusted HR of 2.97 (95% CI, 1.46-6.05; P = 0.003).

Conclusion

In conclusion, analyses of genome-level mismatches may be useful tools in prediction of transplantation outcome. The relative importance differs between populations, because we found evidence for CFHR deletion but could not replicate the finding of previously reported LIMS1 deletion.

SUBMITTER: Markkinen S

PROVIDER: S-EPMC9751710 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Publications

Mismatches in Gene Deletions and Kidney-related Proteins as Candidates for Histocompatibility Factors in Kidney Transplantation.

Markkinen Salla S Helanterä Ilkka I Lauronen Jouni J Lempinen Marko M Partanen Jukka J Hyvärinen Kati K

Kidney international reports 20220906 11

<h4>Introduction</h4>The genomic mismatch level between donor and recipient may be associated with the risk of rejection and graft survival. We determined the association of genome-level matching with acute rejection in deceased-donor kidney transplantation.<h4>Methods</h4>The study cohort consists of 1025 recipient-donor pairs transplanted in a single center from 2007 to 2017 in Helsinki. The associations between the sums of whole-genome missense variant mismatches and missense mismatches in tr ...[more]

PMID: 36531875

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Project description:IntroductionAntibody mediated rejection (ABMR) is the most common cause of long-term allograft loss in kidney transplantation (KT). Therefore, a low human leukocyte antigen (HLA) mismatch (MM) load is favorable for KT outcomes. Hitherto, serological or low-resolution molecular HLA typing have been adapted in parallel. Here, we aimed to identify previously missed HLA mismatches and corresponding antibodies by high resolution HLA genotyping in a living-donor KT cohort.Methods103 donor/recipient pairs transplanted at the University of Leipzig Medical Center between 1998 and 2018 were re-typed using next generation sequencing (NGS) of the HLA loci -A, -B, -C, -DRB1, -DRB345, -DQA1, -DQB1, -DPA1, and -DPB1. Based on these data, we compiled HLA MM counts for each pair and comparatively evaluated genomic HLA-typing with pre-transplant obtained serological/low-resolution HLA (=one-field) typing results. NGS HLA typing (=two-field) data was further used for reclassification of de novo HLA antibodies as "donor-specific".ResultsBy two-field HLA re-typing, we were able to identify additional MM in 64.1% (n=66) of cases for HLA loci -A, -B, -C, -DRB1 and -DQB1 that were not observed by one-field HLA typing. In patients with biopsy proven ABMR, two-field calculated MM count was significantly higher than by one-field HLA typing. For additional typed HLA loci -DRB345, -DQA1, -DPA1, and -DPB1 we observed 2, 26, 3, and 23 MM, respectively. In total, 37.3% (69/185) of de novo donor specific antibodies (DSA) formation was directed against these loci (DRB345 ➔ n=33, DQA1 ➔ n=33, DPA1 ➔ n=1, DPB1 ➔ n=10).ConclusionOur results indicate that two-field HLA typing is feasible and provides significantly more sensitive HLA MM recognition in living-donor KT. Furthermore, accurate HLA typing plays an important role in graft management as it can improve discrimination between donor and non-donor HLA directed cellular and humoral alloreactivity in the long range. The inclusion of additional HLA loci against which antibodies can be readily detected, HLA-DRB345, -DQA1, -DQB1, -DPA1, and -DPB1, will allow a more precise virtual crossmatch and better prediction of potential DSA. Furthermore, in living KT, two-field HLA typing could contribute to the selection of the immunologically most suitable donors.

Project description:BackgroundIn the context of an aging end-stage renal disease population with multiple comorbid conditions, transplantation professionals face challenges in evaluating the global health of patients awaiting kidney transplantation. Functional status might be useful for identifying which patients will derive a survival benefit from transplantation versus dialysis.Study designRetrospective cohort study of wait-listed patients using data for functional status from a national dialysis provider linked to United Network for Organ Sharing registry data.Setting & participantsAdult kidney transplantation candidates added to the waiting list between 2000 and 2006.PredictorPhysical Functioning scale of the Medical Outcomes Study 36-Item Short Form Health Survey, analyzed as a time-varying covariate.OutcomesKidney transplantation; survival benefit of transplantation versus remaining wait-listed.MeasurementsWe used multivariable Cox regression to assess the association between physical function with study outcomes. In survival benefit analyses, transplantation status was modeled as a time-varying covariate.ResultsThe cohort comprised 19,242 kidney transplantation candidates (median age, 51 years; 36% black race) receiving maintenance dialysis. Candidates in the lowest baseline Physical Functioning score quartile were more likely to be inactivated (adjusted HR vs highest quartile, 1.30; 95% CI, 1.21-1.39) and less likely to undergo transplantation (adjusted HR vs highest quartile, 0.64; 95% CI, 0.61-0.68). After transplantation, worse Physical Functioning score was associated with shorter 3-year survival (84% vs 92% for the lowest vs highest function quartiles). However, compared to dialysis, transplantation was associated with a statistically significant survival benefit by 9 months for patients in every function quartile.LimitationsFunctional status is self-reported.ConclusionsEven patients with low function appear to live longer with kidney transplantation versus dialysis. For wait-listed patients, global health measures such as functional status may be more useful in counseling patients about the probability of transplantation than in identifying who will derive a survival benefit from it.

Dataset Information

Mismatches in Gene Deletions and Kidney-related Proteins as Candidates for Histocompatibility Factors in Kidney Transplantation.

Introduction

Methods

Results

Conclusion

Publications

Mismatches in Gene Deletions and Kidney-related Proteins as Candidates for Histocompatibility Factors in Kidney Transplantation.

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