Kidney-Intrinsic Innate Immunity and Endoplasmic Reticulum Stress Pathways are Key Determinants of Severity of Ischemia-Reperfusion Injury Following Transplantation

L. Qiu¹, J. Wang¹, X. Yeap¹, C. Lin¹, Y. S. Kanwar², D. Fang², M. M. Abecassis¹, Z. J. Zhang¹

¹Comprehensive Transplant Center, Department of Surgery, Northwestern University, Chicago, IL, ²Department of Pathology, Northwestern University, Chicago, IL

Meeting: 2019 American Transplant Congress

Abstract number: A102

Keywords: Mice, Outcome, Renal function, Renal injury

Session Information

Session Name: Poster Session A: Ischemia Reperfusion & Organ Rehabilition

Session Type: Poster Session

Date: Saturday, June 1, 2019

Session Time: 5:30pm-7:30pm

Presentation Time: 5:30pm-7:30pm

Location: Hall C & D

*Purpose: Ischemia-reperfusion injury (IRI) following kidney transplantation (KTx) frequently leads to delayed graft function and is detrimental to graft longevity. Causes and susceptibilities of KTx IRI are multifactorial, yet key determinants remain elusive, which hinders development of effective interventions. In this study, we aim to identify key factors of IRI susceptibility and to explore the underlying mechanisms.

*Methods: Clinically-relevant mouse models of KTx were used. Kidney grafts from B6 or BALB/c donors were subjected to 4hr cold ischemic time prior to being transplanting into syngeneic or allogeneic bi-nephrectomized recipients. Myd88^-/-Trif^-/- B6 mice were used to study the role of graft-intrinsic innate immunity in KTx IRI. Immediate graft function, as indicated by blood creatinine and BUN levels, were tested at day 1 post-KTx. PAS and TUNEL staining were performed for histological evaluation.

*Results: Regardless of recipient strains or donor-recipient MHC mismatch, kidney grafts from B6 donors exhibited significantly more severe histological and functional impairment compared to that from BALB/c donors, suggesting the predominant role of kidney-intrinsic factors involving genetic background in KTx IRI. Further, upregulation of IL-6, NGAL and endoplasmic reticulum (ER) stress genes including GRP78, IRE1a, XBP1s, and CHOP, were associated with augmented IRI seen in B6 allografts versus BALB/c allografts. Moreover, the augmented activation of inflammatory and stress genes in B6 kidneys was concomitant with increased influx of host neutrophils and endogenous memory CD8 T cells that linked to the inferior renal allograft survival in the acute phase. Lack of Myd88 and Trif signaling in kidney donors significantly downregulated gene expression of XBP1s and IL-6 and diminished host neutrophil influx, along with improved immediate graft function and prolonged allograft survival.

*Conclusions: Our findings highlight the critical role of kidney-intrinsic factors involving genetic characteristics, innate immunity, and ER stress signaling in the susceptibility of KTx IRI. Further studies on the interactions of these factors and interventions designed to focus on these properties may help to prevent KTx IRI.

To cite this abstract in AMA style:

Qiu L, Wang J, Yeap X, Lin C, Kanwar YS, Fang D, Abecassis MM, Zhang ZJ. Kidney-Intrinsic Innate Immunity and Endoplasmic Reticulum Stress Pathways are Key Determinants of Severity of Ischemia-Reperfusion Injury Following Transplantation [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/kidney-intrinsic-innate-immunity-and-endoplasmic-reticulum-stress-pathways-are-key-determinants-of-severity-of-ischemia-reperfusion-injury-following-transplantation/. Accessed May 9, 2025.

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