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Abstract: FR-OR130

Distinct Metabolic Signatures of Murine Kidney Allograft Rejection and Ischemia-Reperfusion Injury (IRI)

Session Information

Category: Transplantation

  • 1901 Transplantation: Basic

Authors

  • Hartung, Erum A., Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • Beier, Ulf H., Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • Concors, Seth, University of Pennsylvania Health System, Philadelphia, Pennsylvania, United States
  • Hernandez, Paul T., Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Wang, Zhonglin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Denburg, Michelle, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • Gade, Terence P., University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Levine, Matthew H., University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background

Acute rejection is an important complication of kidney transplant, and must be distinguished from other causes of allograft dysfunction such as IRI. We hypothesized that tissue metabolomic profiling could identify biomarkers of rejection and IRI in murine models.

Methods

Mismatched kidney transplants were performed using C57BL/6 donors into BALB/c recipients (n=10). Allografts were harvested after 14d when rejection is prominent (TK), with BALB/c recipient kidneys as controls (NK). Separately, unilateral warm IRI was induced in C57BL/6 mice by clamping the renal pedicle for 28 mins. IRI and contralateral control (Ctrl) kidneys were harvested at 24 h, during peak IRI (n=10 each). Kidneys were snap frozen and stored at -80°C prior to mass spectrometry-based non-targeted metabolomic profiling of 879 biochemicals (Metabolon, Inc.). FDR-adjusted t-tests were used to test differences between TK vs. NK, IRI vs. Ctrl, and TK vs. IRI.

Results

Rejecting kidneys had significantly higher levels of metabolites related to the glutathione antioxidant response (GSSG; ophthalmate), tryptophan derivatives (kynurenine, quinolinate), and the TCA cycle derivative itaconate. IRI kidneys had significantly higher levels of saccharopine, 2-aminoadipate (lysine metabolism), fructose, β-citrylglutamate (mitochondrial iron carrier), and (3'-5')-adenylyladenosine (Fig.1). Key metabolites characterizing rejection and IRI, respectively, were itaconate, an immunometabolite released by activated macrophages, and saccharopine, a lysine catabolite reported to cause mitochondrial injury that is potentially relevant to IRI mitochondrial dysfunction.

Conclusion

Acute rejection and IRI have distinct tissue metabolomic signatures. These findings may help in the future development of non-invasive biomarkers to detect rejection and IRI in kidney transplant patients.

Funding

  • NIDDK Support