Kidney-intrinsic factors determine the severity of ischemia/reperfusion injury in a mouse model of delayed graft function

Longhui Qiu, Xingqiang Lai, Jiao jing Wang, Xin Yi Yeap, Shulin Han, Feibo Zheng, Charlie Lin, Zhuoli Zhang, Daniele Procissi, Deyu Fang, Lin Li, Edward B. Thorp, Michael M. Abecassis, Yashpal S. Kanwar, Zheng J. Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Delayed graft function due to transplant ischemia/reperfusion injury adversely affects up to 50% of deceased-donor kidney transplant recipients. However, key factors contributing to the severity of ischemia/reperfusion injury remain unclear. Here, using a clinically relevant mouse model of delayed graft function, we demonstrated that donor genetic background and kidney-intrinsic MyD88/Trif-dependent innate immunity were key determinants of delayed graft function. Functional deterioration of kidney grafts directly corresponded with the duration of cold ischemia time. The graft dysfunction became irreversible after cold ischemia time exceeded six hours. When cold ischemia time reached four hours, kidney grafts displayed histological features reflective of delayed graft function seen in clinical kidney transplantation. Notably, kidneys of B6 mice exhibited significantly more severe histological and functional impairment than kidneys of C3H or BALB/c mice, regardless of recipient strains or alloreactivities. Furthermore, allografts of B6 mice also showed an upregulation of IL-6, neutrophil gelatinase-associated lipocalin, and endoplasmic reticulum stress genes, as well as an increased influx of host neutrophils and memory CD8 T-cells. In contrast, donor MyD88/Trif deficiency inhibited neutrophil influx and decreased the expression of IL-6 and endoplasmic reticulum stress genes, along with improved graft function and prolonged allograft survival. Thus, kidney-intrinsic factors involving genetic characteristics and innate immunity serve as critical determinants of the severity of delayed graft function. This preclinical murine model allows for further investigations of the mechanisms underlying delayed graft function.

Original languageEnglish (US)
Pages (from-to)1489-1501
Number of pages13
JournalKidney international
Volume98
Issue number6
DOIs
StatePublished - Dec 2020

Keywords

  • delayed graft function
  • donor factors
  • innate immunity
  • ischemia/reperfusion injury
  • kidney transplantation
  • mouse model

ASJC Scopus subject areas

  • Nephrology

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