FIGURE LEGENDS
Figure 1. Assessment of renal injury in untreated (black),
saline-treated (blue), and cisplatin-treated (red) C57BL/6 mice
(A, B ), and FVB/N mice (C, D ). Plasma creatinine
concentrations (A, C ) were normalized to creatinine-d3 standard
before quantification. (B, D ) H&E-stained kidney sections were
scored from 0-5 based on severity of renal injury by a pathologist
blinded to treatment conditions. n=5-9 (exact sample sizes can be found
in Table S1 ), error bars represent mean ± SD. Statistical
analysis was performed using two-way ANOVA, *p < 0.05 compared
to saline control.
Figure 2. Orthogonal partial least squares discriminant
analysis scores plots comparing plasma (A-D ), urine
(E-H ), and kidney (I-L ) samples from saline-treated
(black) and cisplatin-treated (red) C57BL/6 mice at each timepoint: day
1 (A, E, I ), day 2 (B, F, J ), day 3 (C, G,
K ), day 4 (D, H, L ). Model statistics for OPLS-DA were as
follows: (A ) R2Y = 0.989,
Q2Y = 0.369 (B ) R2Y =
0.980, Q2Y = 0.542 (C ) R2Y
= 0.989, Q2Y = 0.467 (D )
R2Y = 0.985, Q2Y = 0.580
(E ) R2Y = 0.627, Q2Y =
0.033 (F ) R2Y = 0.989, Q2Y
= 0.649 (G ) R2Y = 0.989,
Q2Y = 0.295 (H ) R2Y =
0.946, Q2Y = 0.581 (I ) R2Y
= 0.914, Q2Y = 0.101 (J )
R2Y = 0.979, Q2Y = 0.611
(K ) R2Y = 0.944, Q2Y =
0.426 (L ) R2Y = 0.973, Q2Y
= 0.569. n=5-10, exact sample sizes can be found in Table S1 .
Figure 3. Time course cluster analysis of (A) plasma, (B)
urine, and (C) kidney features that were significantly altered by
cisplatin treatment in C57BL/6 mice. The lighter, thinner lines
represent change over time for each individual feature within each
cluster, and the darker, thicker line represents the mean z-score for
all features in each cluster. Boxes represent the median and
interquartile range (IQR), and the whiskers represent 1.5x IQR.
Figure 4. Log transformed relative intensity of
features significantly affected by cisplatin treatment in plasma samples
from C57BL/6 mice. Data are presented as box and whisker plots, where
boxes represent the median and interquartile range (IQR), and whiskers
represent 1.5x IQR. Statistical analysis was performed using two-way
ANOVA, *p<0.05 compared to saline control at each timepoint.
n=5-9, exact sample sizes can be found in Table S1 .
Figure 5. Log transformed relative intensity of features
significantly affected by cisplatin treatment in urine samples from
C57BL/6 mice. Data are presented as box and whisker plots, where boxes
represent the median and interquartile range (IQR), and whiskers
represent 1.5x IQR. Statistical analysis was performed using two-way
ANOVA, *p<0.05 compared to saline control at each timepoint.
n=6-9, exact sample sizes can be found in Table S1 .
Figure 6. Log transformed relative intensity of features
significantly affected by cisplatin treatment in kidney samples from
C57BL/6 mice. Data are presented as box and whisker plots, where boxes
represent the median and interquartile range (IQR), and whiskers
represent 1.5x IQR. Statistical analysis was performed using two-way
ANOVA, *p<0.05 compared to saline control at each timepoint.
n=7-10, exact sample sizes can be found in Table S1 .
Figure 7. Receiver operating characteristic (ROC) analysis of
early plasma biomarkers. (A ) Summary of area under the ROC
curve values calculated for each plasma metabolite at all timepoints.
(B, C ) Multivariate ROC curves generated at (B ) day 1
and (C ) day 2 using a variable number of metabolites. ROC
curves were generated using a sequential combination of the top two to
top ten ranked metabolites, where each metabolite was ranked using the
calculated univariate AUROC at each respective timepoint.
Figure 8. Receiver operating characteristic (ROC) analysis of
early urine biomarkers in C57BL/6 mice. (A ) Summary of area
under the ROC curve values calculated for each urine metabolite at all
timepoints. (B, C ) Multivariate ROC curves generated at
(B ) day 1 and (C ) day 2 using a variable number of
metabolites. ROC curves were generated using a sequential combination of
the top two to top 15 ranked metabolites, where each metabolite was
ranked using the calculated univariate AUROC at each respective
timepoint.