Abstract: TH-PO252

Characterization of the Metabolome and Renal Tubular Cisplatin Disposition in Cisplatin Induced AKI

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Lim, Yong Jin (James), University of Western Ontario, London, Ontario, Canada
  • Hartjes, Emily D., University of Western Ontario, London, Ontario, Canada
  • Urquhart, Brad, University of Western Ontario, London, Ontario, Canada
Background

Cisplatin induces acute kidney injury (AKI) in approximately 1/3 of patients. It is currently unknown why some patients develop AKI and others do not. Cisplatin AKI is diagnosed by increases in serum creatinine (SCr), but nephrotoxicity develops before rises in SCr can be detected. Novel diagnostic/predictive markers of AKI may help explain why some cisplatin patients get AKI while others are resistant. FVB mice have greater susceptibility to cisplatin AKI than C57BL/6 mice. These two mouse strains were used to model the variability of cisplatin response observed in humans. We aim to: 1) Determine the effects of AKI on expression of renal transporters and enzymes involved in cisplatin disposition; 2) Investigate metabolic differences between FVB and C57BL/6 mice using metabolomics, with the goal of biomarker discovery.

Methods

FVB and C57BL/6 strains were treated with 15 mg/kg cisplatin or saline by intraperitoneal injection. Mice were sacrificed 1 and 3 days following treatment, and blood, urine and kidneys were collected. Gene expression was assessed using RT-PCR. Liquid chromatography-mass spectrometry was used for untargeted metabolomics.

Results

In FVB mice, expression of renal uptake transporter Oct2 and metabolizing enzyme Ggt1 were 51% and 66% lower 3 days following cisplatin treatment compared to saline (p<0.05, p<0.01 respectively). Oct1 trended towards lower expression in day 3 cisplatin-treated FVB mice. Principle component analysis (PCA) of untreated FVB and C57BL/6 plasma samples showed clustering based on mouse strain. PCA of day 3 plasma samples clearly separated cisplatin and saline groups for both mouse strains. Multivariate analysis revealed indoxyl sulfate and p-cresyl sulfate to be two metabolites associated with cisplatin AKI.

Conclusion

mRNA expression results suggest that cisplatin alters expression of drug disposition genes in FVB, but not C57BL/6 mice. PCA clustering of baseline mice indicates metabolic differences between the strains, while separation by treatment groups suggests that cisplatin administration alters the metabolic profile of the mice. Our preliminary data suggests possible mechanisms why FVB mice show increased susceptibility to cisplatin AKI compared to the C57BL/6 mice. Further work will to be done to identify additional metabolic changes associated with cisplatin AKI.