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Abstract: PO2388

Kidney-Intrinsic TLR/MyD88 Signaling Regulates the Susceptibility of Delayed Graft Function Following Kidney Transplantation

Session Information

Category: Transplantation

  • 1901 Transplantation: Basic

Authors

  • Lai, Xingqiang, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, United States
  • Qiu, Longhui, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Wang, Jiao-Jing, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Zhang, Zheng Jenny, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

Delayed graft function (DGF) due to transplant ischemia/reperfusion injury (IRI) adversely affects up to 50% of deceased-donor kidney transplant (KTx) recipients. However, key factors contributing to the severity of IRI remain unclear. We hypothesize that kidney-intrinsic MyD88/Trif pathways could be a key determinant of DGF.

Methods

Kidneys from MyD88 knockout (KO) or MyD88 and Trif double knockout (DKO) mice were harvested and stored in a cold preservation solution (UW) for 4 hours, and then transplanted into bi-nephrectomized syngeneic or allogeneic recipients. Graft survival, renal function, histology change, phenotype analysis, and expression of involved genes, were observed and/or determined. Primary RTECs isolated from B6 and BALB/c mouse kidneys were stimulated by lipopolysaccharide (LPS) and cytokines in supernatant were measured.

Results

C57BL/6 (B6) kidneys were more susceptible to IRI following syngeneic transplant compared to BALB/c kidneys. Genetic ablation of MyD88 in B6 donors, but not BALB/c donors significantly reduced creatinine levels at post operation day (POD) 1-2, compared with wild-type (WT) kidneys. Moreover, compared with recipients of WT kidneys at POD 1-2, recipients of MyD88/Trif DKO kidney allografts showed improved graft function that was consistent with improved tissue integrity. Strikingly, MyD88/Trif DKO in the donor induced indefinite renal allograft survival and preserved intact renal allograft architecture at POD 100. In vitro study showed that levels of cytokines were increased by both B6 and BALB/c RTECs upon LPS (TLR4 agonist) stimulation, but BALB/c RTECs produced significantly higher levels of cytokines (including TNFα, IL-6, and IL-10) in a dose-dependent manner. Expression of KIM-1, a known biomarker for renal cell injury, were significantly increased by B6 RTECs as compared with that in BALB/c RTECs. These results suggest that kidney-intrinsic innate immunity, especially the TLR/Myd88 pathway, plays a critical role in the susceptibility to transplant IRI and DGF.

Conclusion

Kidney-intrinsic TLR/Myd88 signaling regulates the susceptibility of delayed graft function following kidney transplantation.

Funding

  • NIDDK Support