3.3 Early plasma biomarkers of cisplatin-induced acute kidney injury
The majority of plasma metabolites (130/181, 71.8%) were decreased by cisplatin treatment in C57BL/6 mice (Figure 3A ). Plasma creatine, L-acetylcarnitine, p-cresol sulfate, phenylalanine, taurine, sulfolithocholylglycine, taurocholate, and tryptophan were among identified plasma metabolites that were increased by cisplatin treatment (Figure 4 , S5 ). In C57BL/6 mice, L-acetylcarnitine and taurine were significantly increased as early as day 1 and day 2, respectively, and remained elevated throughout day 3 and 4 (Figure 4C, 4H ). Although L-acetylcarnitine and taurine were also elevated with cisplatin treatment in FVB/N mice, these changes were only significant on days 3 and 4 (Figure S5C, S5H ). Amino acids phenylalanine and tryptophan exhibited early increases in both strains, though C57BL/6 mice showed significant changes earlier than FVB/N mice. Phenylalanine and tryptophan were significantly elevated on day 1 after cisplatin treatment in C57BL/6 mice (Figure 4F, 4J ), whereas significant increases in both amino acids were observed two days following cisplatin treatment in FVB/N mice (Figure S5F, S5J).Bile acids sulfolithocholylglycine and taurocholic acid showed a similar pattern for both strains of mice, where a transient but significant elevation was observed on day 2 for C57BL/6 mice (Figure 4G, 4I ) and days 2 and 3 for FVB/N mice (Figure S5G, S5I ). Creatine and p-cresol sulfate were significantly elevated in cisplatin-treated FVB/N mice from days 2-4 (Figure S5A, S5E ), and although they showed the same pattern of elevation in C57BL/6 mice, the changes were not statistically significant (Figure 4A, 4E ).
2,3-dihydroxybenzoic acid, equol 4-sulfate, and LysoPC(20:3) were among plasma metabolites decreased by cisplatin treatment (Figure 4, S5 ). In C57BL/6 mice, 2,3-dihydroxybenzoic acid decreased in the early timepoints, but did not show significant early alterations in the plasma of FVB/N mice. Plasma LysoPC(20:3) was consistently decreased for all timepoints for C57BL/6 mice but was not significantly changed in FVB/N mice until day 3. Lastly, plasma levels of equol 4-sulfate were significantly lower in FVB/N mice from days 2-4, but no significant changes were observed in C57BL/6 plasma until day 4 (Figure S5 ).