Discovering novel injury features in kidney transplant biopsies associated with TCMR and donor aging

The INTERCOMEX investigators

Research output: Contribution to journalArticlepeer-review

Abstract

We previously characterized the molecular changes in acute kidney injury (AKI) and chronic kidney disease (CKD) in kidney transplant biopsies, but parenchymal changes selective for specific types of injury could be missed by such analyses. The present study searched for injury changes beyond AKI and CKD related to specific scenarios, including correlations with donor age. We defined injury using previously defined gene sets and classifiers and used principal component analysis to discover new injury dimensions. As expected, Dimension 1 distinguished normal vs. injury, and Dimension 2 separated early AKI from late CKD, correlating with time posttransplant. However, Dimension 3 was novel, distinguishing a set of genes related to epithelial polarity (e.g., PARD3) that were increased in early AKI and decreased in T cell–mediated rejection (TCMR) but not in antibody-mediated rejection. Dimension 3 was increased in kidneys from older donors and was particularly important in survival of early kidneys. Thus high Dimension 3 scores emerge as a previously unknown element in the kidney response-to-injury that affects epithelial polarity genes and is increased in AKI but depressed in TCMR, indicating that in addition to general injury elements, certain injury elements are selective for specific pathologic mechanisms. (ClinicalTrials.gov NCT01299168).

Original languageEnglish (US)
Pages (from-to)1725-1739
Number of pages15
JournalAmerican Journal of Transplantation
Volume21
Issue number5
DOIs
StatePublished - Nov 30 2020

Bibliographical note

Funding Information:
This research has been principally supported by grants from Genome Canada, Canada Foundation for Innovation, the University of Alberta Hospital Foundation, the Alberta Ministry of Advanced Education and Technology, the Mendez National Institute of Transplantation Foundation, and Industrial Research Assistance Program. Partial support was also provided by funding from a licensing agreement with the One Lambda division of Thermo Fisher. Dr. Halloran held a Canada Research Chair in Transplant Immunology until 2008 and currently holds the Muttart Chair in Clinical Immunology. We thank our valued clinicians in the INTERCOMEX study group who partnered with us for this study by contributing biopsies and feedback (Michael Picton, Timm Heinbokel, Harold Yang, Seth Narins, Carmen Lefaucheur, Alexandre Loupy, Marek Myslak, Bertram Kasiske, Arthur Matas, and Arjang Djamali).

Funding Information:
This research has been principally supported by grants from Genome Canada, Canada Foundation for Innovation, the University of Alberta Hospital Foundation, the Alberta Ministry of Advanced Education and Technology, the Mendez National Institute of Transplantation Foundation, and Industrial Research Assistance Program. Partial support was also provided by funding from a licensing agreement with the One Lambda division of Thermo Fisher. Dr. Halloran held a Canada Research Chair in Transplant Immunology until 2008 and currently holds the Muttart Chair in Clinical Immunology. We thank our valued clinicians in the INTERCOMEX study group who partnered with us for this study by contributing biopsies and feedback (Michael Picton, Timm Heinbokel, Harold Yang, Seth Narins, Carmen Lefaucheur, Alexandre Loupy, Marek Myslak, Bertram Kasiske, Arthur Matas, and Arjang Djamali).

Publisher Copyright:
© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons

Keywords

  • basic (laboratory) research/science
  • biopsy
  • kidney transplantation / nephrology
  • microarray/gene array
  • rejection
  • rejection: T cell mediated (TCMR)
  • rejection: antibody-mediated (ABMR)

PubMed: MeSH publication types

  • Clinical Study
  • Journal Article

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