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Author Notes:

Ruth Sapir-Pichhadze, Centre for Outcomes Research & Evaluation, Research Institute of the McGill University Health Centre, 5252 boul de Maisonneuve, Office 3E.13, Montréal, QC H4A 3S5, Canada. Email: ruth.sapir-pichhadze@mcgill.ca

Study conception and design: HM, KO, RSP Acquisition of data: RSP, BF Analysis and interpretation of data: HM, KO, WZ, WK, AB, JL, YY, RSP Drafting of manuscript: HM, RSP Critical revision: HM, KO, WZ, WK, AB, JL, YY, BF, PK, HMG, FC, RSP

Analyses reported in this article were made possible thanks to Compute Canada Resources for Research Groups 2020: 3021 (RS-P, cna-921–02). We are grateful to Rene Duquesnoy and Marilyn Marrari for their support with HLAMatchmaker and the HLA Epitope Registry. We are grateful to Gilbert J. Burckart, Pharm.D, members of the Genome Canada Transplant Consortium. This work was supported by Genome Canada Large Scale Applied Research Program Award “Precision Medicine CanPREVENT AMR” (273AMR) funded by Genome Quebec, Canada; Genome British Columbia, Canada; Genome Alberta, Canada; and Canadian Institutes of Health Research (CIHR), Canada. RS-P is also supported by a Fonds de recherche du Quebec—Santé chercheur boursier clinician award (grant no. 254386).

All the authors declared no competing interests.

Subjects:

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Urology & Nephrology
  • epitope
  • eplet
  • graft failure
  • human leukocyte antigens
  • immunogenicity
  • kidney transplantation
  • ANTIBODY-MEDIATED REJECTION
  • HLA-DR
  • DQ
  • REGRESSION
  • SELECTION
  • STRATEGY
  • WEBSITE

On Path to Informing Hierarchy of Eplet Mismatches as Determinants of Kidney Transplant Loss

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Journal Title:

KIDNEY INTERNATIONAL REPORTS

Volume:

Volume 6, Number 6

Publisher:

, Pages 1567-1579

Type of Work:

Article | Final Publisher PDF

Abstract:

Introduction: To mitigate risks related to human leukocyte antigen (HLA) incompatibility, we assessed whether certain structurally defined HLA targets present in donors but absent from recipients, known as eplet mismatches (EMM), are associated with death-censored graft failure (DCGF). Methods: We studied a cohort of 118,313 American 0% panel reactive antibodies (PRA) first kidney transplant recipients (2000 to 2015) from the Scientific Registry of Transplant Recipients. Imputed allele-level donor and recipient HLA-A, -B, -C, -DRB1, and -DQB1 genotypes were converted to the repertoire of EMM. We fit survival models for each EMM with significance thresholds corrected for false discovery rate and validated those in an independent PRA > 0% cohort. We conducted network-based analyses to model relationships among EMM and developed models to select the subset of EMM most predictive of DCGF. Results: Of 412 EMM observed, 119 class I and 118 class II EMM were associated with DCGF. Network analysis showed that although 210 eplets formed profiles of 2 to 12 simultaneously occurring EMMs, 202 were singleton EMMs that were not involved in any profile. A variable selection procedure identified 55 single HLA class I and II EMMs in 70% of the dataset; of those, 15 EMMs (9 singleton and 6 involved in profiles) were predictive of DCGF in the remaining dataset. Conclusion: Our analysis distinguished increasingly smaller subsets of EMMs associated with increased risk of DCGF. Validation of these EMMs as important predictors of transplant outcomes (in contrast to acceptable EMMs) in datasets with measured allele-level genotypes will support their role as immunodominant EMMs worthy of consideration in organ allocation schemes.

Copyright information:

© 2021 International Society of Nephrology. Published by Elsevier Inc.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/rdf).
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