On Path to Informing Hierarchy of Eplet Mismatches as Determinants of Kidney Transplant Loss
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 s...
Main Authors: | , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2021-06-01
|
Series: | Kidney International Reports |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S246802492101024X |
id |
doaj-a737c4c2e73244fdb19201d3e24aacfb |
---|---|
record_format |
Article |
spelling |
doaj-a737c4c2e73244fdb19201d3e24aacfb2021-06-09T05:58:47ZengElsevierKidney International Reports2468-02492021-06-016615671579On Path to Informing Hierarchy of Eplet Mismatches as Determinants of Kidney Transplant LossHossein Mohammadhassanzadeh0Karim Oualkacha1Wenmin Zhang2William Klement3Amelie Bourdiec4Jennat Lamsatfi5Yang Yi6Bethany Foster7Paul Keown8Howard M. Gebel9Frans Claas10Ruth Sapir-Pichhadze11Centre for Outcomes Research and Evaluation, Research Institute of McGill University Health Centre, Montreal, Quebec, CanadaDepartment of Mathematics, University of Quebec in Montreal, Montreal, Quebec, CanadaQuantitative Life Sciences, McGill University, Montreal, Quebec, CanadaCentre for Outcomes Research and Evaluation, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada; Canadian Blood Services, Ottawa, Ontario, CanadaCentre for Outcomes Research and Evaluation, Research Institute of McGill University Health Centre, Montreal, Quebec, CanadaDepartment of Mathematics, University of Quebec in Montreal, Montreal, Quebec, CanadaDepartment of Mathematics and Statistics, McGill University, Montreal, Quebec, CanadaCentre for Outcomes Research and Evaluation, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada; Department of Pediatrics, Montreal Children’s Hospital of the McGill University Health Centre, Montreal, Quebec, CanadaUniversity of British Columbia, Vancouver, British Columbia, CanadaPathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USADepartment of Immunology, Leiden University Medical Centre, Leiden, NetherlandsCentre for Outcomes Research and Evaluation, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada; Division of Nephrology and Multi-Organ Transplant Program, Department of Medicine, McGill University, Montreal, Quebec, Canada; Correspondence: 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.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.http://www.sciencedirect.com/science/article/pii/S246802492101024Xepitopeepletgraft failurehuman leukocyte antigensimmunogenicitykidney transplantation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hossein Mohammadhassanzadeh Karim Oualkacha Wenmin Zhang William Klement Amelie Bourdiec Jennat Lamsatfi Yang Yi Bethany Foster Paul Keown Howard M. Gebel Frans Claas Ruth Sapir-Pichhadze |
spellingShingle |
Hossein Mohammadhassanzadeh Karim Oualkacha Wenmin Zhang William Klement Amelie Bourdiec Jennat Lamsatfi Yang Yi Bethany Foster Paul Keown Howard M. Gebel Frans Claas Ruth Sapir-Pichhadze On Path to Informing Hierarchy of Eplet Mismatches as Determinants of Kidney Transplant Loss Kidney International Reports epitope eplet graft failure human leukocyte antigens immunogenicity kidney transplantation |
author_facet |
Hossein Mohammadhassanzadeh Karim Oualkacha Wenmin Zhang William Klement Amelie Bourdiec Jennat Lamsatfi Yang Yi Bethany Foster Paul Keown Howard M. Gebel Frans Claas Ruth Sapir-Pichhadze |
author_sort |
Hossein Mohammadhassanzadeh |
title |
On Path to Informing Hierarchy of Eplet Mismatches as Determinants of Kidney Transplant Loss |
title_short |
On Path to Informing Hierarchy of Eplet Mismatches as Determinants of Kidney Transplant Loss |
title_full |
On Path to Informing Hierarchy of Eplet Mismatches as Determinants of Kidney Transplant Loss |
title_fullStr |
On Path to Informing Hierarchy of Eplet Mismatches as Determinants of Kidney Transplant Loss |
title_full_unstemmed |
On Path to Informing Hierarchy of Eplet Mismatches as Determinants of Kidney Transplant Loss |
title_sort |
on path to informing hierarchy of eplet mismatches as determinants of kidney transplant loss |
publisher |
Elsevier |
series |
Kidney International Reports |
issn |
2468-0249 |
publishDate |
2021-06-01 |
description |
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. |
topic |
epitope eplet graft failure human leukocyte antigens immunogenicity kidney transplantation |
url |
http://www.sciencedirect.com/science/article/pii/S246802492101024X |
work_keys_str_mv |
AT hosseinmohammadhassanzadeh onpathtoinforminghierarchyofepletmismatchesasdeterminantsofkidneytransplantloss AT karimoualkacha onpathtoinforminghierarchyofepletmismatchesasdeterminantsofkidneytransplantloss AT wenminzhang onpathtoinforminghierarchyofepletmismatchesasdeterminantsofkidneytransplantloss AT williamklement onpathtoinforminghierarchyofepletmismatchesasdeterminantsofkidneytransplantloss AT ameliebourdiec onpathtoinforminghierarchyofepletmismatchesasdeterminantsofkidneytransplantloss AT jennatlamsatfi onpathtoinforminghierarchyofepletmismatchesasdeterminantsofkidneytransplantloss AT yangyi onpathtoinforminghierarchyofepletmismatchesasdeterminantsofkidneytransplantloss AT bethanyfoster onpathtoinforminghierarchyofepletmismatchesasdeterminantsofkidneytransplantloss AT paulkeown onpathtoinforminghierarchyofepletmismatchesasdeterminantsofkidneytransplantloss AT howardmgebel onpathtoinforminghierarchyofepletmismatchesasdeterminantsofkidneytransplantloss AT fransclaas onpathtoinforminghierarchyofepletmismatchesasdeterminantsofkidneytransplantloss AT ruthsapirpichhadze onpathtoinforminghierarchyofepletmismatchesasdeterminantsofkidneytransplantloss |
_version_ |
1721388384448937984 |