Kidney Week

Abstract: FR-OR130

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

Session Information

• Transplantation: Basic Research
  November 08, 2019 | Location: 150, Walter E. Washington Convention Center
  Abstract Time: 06:18 PM - 06:30 PM

Category: Transplantation

• 1901 Transplantation: Basic

Authors

• Hartung, Erum A., Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

Erum A. Hartung, MD, MS



Erum Aftab Hartung, MD, MTR, is a pediatric nephrologist at the Children's Hospital of Philadelphia and Assistant Professor of Pediatrics at the Perelman School of Medicine of the University of Pennsylvania. Dr. Hartung’s clinical and research focus is in genetic kidney diseases, particularly polycystic kidney disease. She is the Co-Director of the Combined Kidney/Liver Program for patients with autosomal recessive polycystic kidney disease (ARPKD) and other genetic diseases. Her research interests include developing new imaging biomarkers for ARPKD and other hepatorenal diseases.

• Beier, Ulf H., Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

Ulf H. Beier,

• Concors, Seth, University of Pennsylvania Health System, Philadelphia, Pennsylvania, United States

Seth Concors,

• Hernandez, Paul T., Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, United States

Paul T. Hernandez,

• Wang, Zhonglin, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Zhonglin Wang,

• Denburg, Michelle, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

Michelle Denburg,

• Gade, Terence P., University of Pennsylvania, Philadelphia, Pennsylvania, United States

Terence P. Gade,

• Levine, Matthew H., University of Pennsylvania, Philadelphia, Pennsylvania, United States

Matthew H. Levine,

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