Early and Sensitive Detection of Cisplatin-Induced Kidney Injury Using Novel Biomarkers

Figures

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  Figure 1. Box-and-whisker plots of urinary biomarkers percent change from baseline in treated and non-treated cancer control groups. The box-and-whisker plots depict the 25th and 75th interquartile ranges, median, and total observed ranges. Statistical significance between groups is indicated by P-values obtained from the Kruskal-Wallis test. Symbols represent significance levels: ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001, ∗∗∗∗P < 0.0001. There was a significant change from baseline in all urinary biomarkers compared to non-treated cancer control patients. (a) Alpha glutathione S transferase, (b) clusterin, (c) cystatin C, (d) kidney injury molecule-1 (KIM-1), (e) neutrophil gelatinase-associated lipocalin (NGAL), (f) osteopontin, (g) albumin, and (h) total protein. CFB, change from baseline.

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  Figure 2. The median time to peak change from baseline for each of the measured urine and serum biomarkers in the cisplatin treated group. Each point represents the median biomarker concentration on the day of sample collection (indexed to urine creatinine to correct for variability of urinary tonicity). The shaded areas represent the upper and lower concentration ranges. Samples were collected pre-dose, 12 hours post cisplatin dose, and on day 1, 2, 4, 7, 14, and 21. Serum biomarkers include: (a) serum cystatin C, (b) blood urea nitrogen, (c) serum creatinine, and (d) estimated glomerular filtration rate. Urinary biomarkers include: (e) alpha glutathione S transferase, (f) kidney injury molecule-1 (KIM-1), (g) neutrophil gelatinase-associated lipocalin (NGAL), (h) osteopontin, (i) clusterin, (j) cystatin C, (k) total protein, and (l) albumin.

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  Figure 3. Percent change from baseline in each urinary biomarker corrected for urinary creatinine levels for the stage 1 adjudicated drug-induced kidney injury (DIKI), no-DIKI, healthy, and non-treated groups. The box-and-whisker plots depict the 25th and 75th interquartile ranges, median, and total observed ranges. Lines between groups indicate comparisons made using Dunn's post hoc test following a significant Kruskal-Wallis test. Adjustment for the multiple comparisons was performed using the Bonferroni method. Symbols represent significance levels: ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001, ∗∗∗∗P < 0.0001. There were no differences between DIKI and no-DIKI groups, except cystatin C and neutrophil gelatinase-associated lipocalin. Both DIKI and no-DIKI groups showed significantly greater increases from baseline in all biomarkers compared to healthy and non-treated controls. (a) Alpha glutathione S transferase, (b) clusterin, (c) cystatin C, (d) kidney injury molecule-1 (KIM-1), (e) neutrophil gelatinase-associated lipocalin (NGAL), (f) osteopontin, (g) albumin, and (h) total protein. CFB, change from baseline.

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  Figure 4. The percent change from baseline in each urinary biomarker corrected for urinary creatinine levels for the stage 2 adjudicated multiple biomarker drug-induced kidney injury (MB-DIKI), no-MB-DIKI, healthy, and non-treated groups. The box-and-whisker plots depict the 25th and 75th interquartile ranges, median, and total observed ranges. Lines between groups indicate comparisons made using Dunn's post hoc test following a significant Kruskal-Wallis test. Adjustment for the multiple comparisons was performed using the Bonferroni method. Symbols represent significance levels: ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001, ∗∗∗∗P < 0.0001. There was a significant difference in change from baseline in all urinary biomarkers between MB-DIKI non-treated and healthy. There was a significant difference in change from baseline in cystatin C, albumin, and total protein in MB-DIKI group compared to no-MB-DIKI group. (a) Alpha glutathione S transferase, (b) CLUSTERIN, (c) cystatin C, (d) kidney injury molecule-1 (KIM-1), (e) neutrophil gelatinase-associated lipocalin (NGAL), (f) osteopontin, (g) albumin, and (h) total protein. CFB, change from baseline.

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  Figure 5. Nephron and the locations at which biomarkers signify injury. Majority of biomarkers are urinary biomarkers, except serum cystatin C. A rise in the biomarkers after nephrotoxin exposure can help localize site of injury and provide information on the pathophysiological process leading to kidney injury. α-GST, alpha-glutathione-S-transferase; KIM-1, kidney injury molecule-1; NGAL, urinary neutrophil gelatinase-associated lipocalin.