Comparative Performance of Urinary Biomarkers for Vancomycin-Induced Kidney Injury According to Timeline of Injury

Gwendolyn M. Pais; Sean N. Avedissian; J. Nicholas O’Donnell; Nathaniel J. Rhodes; Thomas P. Lodise; Walter C. Prozialeck; Peter C. Lamar; Cameron Cluff; Anil Gulati; Julie C. Fitzgerald; Kevin J. Downes; Athena F. Zuppa; Marc H. Scheetz

doi:10.1128/AAC.00079-19

DOI: 10.1128/AAC.00079-19

Article Figures & Data

Figures

Tables
Additional Files

Open in new tab
Download powerpoint
FIG 1
(a) Flow chart for animal dosing. TDD, total daily dose; q12h, every 12 h; *, missed second dose on day 6. (b) Timeline of the experiments.
Open in new tab
Download powerpoint
FIG 2
Representative photomicrographs of hematoxylin and eosin (H&E) stained rat kidney sections. (a and d) Normal histology of kidney tissue in control rats administered normal saline intraperitoneally once daily for 24 h (×40) and 72 h (×200), respectively. (b) Classic wedge-shaped region of infarct (asterisk, ×20) with (c) necrosis of tubular epithelium and portions of glomeruli (arrowheads, ×100) in cortex of rats treated with vancomycin 200 mg/kg once daily for 24 h. (e) Multiple tubules containing sloughed cells (arrowheads) in cortex of rats treated with vancomycin 400 mg/kg once daily for 72 h (×100).
Open in new tab
Download powerpoint
FIG 3
ROC analysis for vancomycin studies. (a to d) ROC curves demonstrating sensitivity and specificity of urinary KIM-1, clusterin, OPN, cystatin C, and NGAL with respect to a histopathology grade of ≥1 on day 1 (a) and on day 3 (b) and a histopathology grade of ≥2 on day 1 (c) and on day 3 (d). Animal numbers, n; histopath = 0, n = 32; histopath ≥ 1, n = 93; histopath ≥ 2, n = 37.
Open in new tab
Download powerpoint
FIG 4
Schematic of the nephron (51) and urinary biomarker colocalization with injury (21). Bolded biomarker will aid in discretizing injury location.

TABLE 1

Comparative analysis of diagnostic performance characteristics of urinary biomarkers with different severity grades of histopathology using area under the receiver operating characteristic curves^a

Subgroup	Biomarker (ng/ml)	Day 1 biomarkers predicting 24 h histopath (AUC [95% CI])	Day 3 biomarkers predicting 72 h histopath (AUC [95% CI])	Day 2 biomarkers predicting 144 h histopath (AUC [95% CI])	Day 6 biomarkers predicting 144 h histopath (AUC [95% CI])
Histopath of ≥1	NGAL	0.320 (0.14–0.50)	0.758 (0.61–0.91)	0.649 (0.39–0.91)	0.760 (0.56–0.96)
	KIM-1	0.661 (0.50–0.82)	0.923 (0.85–1.00)	0.752 (0.59–0.91)	0.918 (0.82–1.00)
	Clusterin	0.706 (0.55–0.86)	0.892 (0.80–0.99)	0.754 (0.59–0.92)	0.889 (0.78–1.00)
	OPN	0.590 (0.41–0.77)	0.952 (0.90–1.00)	0.615 (0.41–0.82)	0.757 (0.58–0.94)
	Cystatin C	0.483 (0.29–0.68)	0.688 (0.49–0.89)	0.692 (0.47–0.91)	0.538 (0.29–0.78)
Histopath of ≥2	NGAL	0.381 (0.16–0.60)	0.555 (0.36–0.75)	0.668 (0.44–0.90)	0.71 (0.53–0.89)
	KIM-1	0.762 (0.46–1.00)	0.822 (0.70–0.95)	0.913 (0.79–1.00)	0.90 (0.80–1.00)
	Clusterin	0.762 (0.52–1.00)	0.801 (0.67–0.93)	0.861 (0.74–1.00)	0.82 (0.68–0.96)
	OPN	0.714 (0.46–0.97)	0.695 (0.53–0.86)	0.828 (0.68–0.98)	0.85 (0.72–0.99)
	Cystatin C	0.394 (0.14–0.65)	0.549 (0.37–0.72)	0.695 (0.49–0.90)	0.55 (0.34–0.76)
Histopath of ≥3	NGAL	Outcome does not vary	0.571 (0.37–0.77)	0.931 (0.84–1.00)	0.58 (0.40–0.76)
	KIM-1	Outcome does not vary	0.476 (0.21–0.74)	0.986 (0.95–1.00)	0.83 (0.68–0.99)
	Clusterin	Outcome does not vary	0.381 (0.23–0.53)	0.793 (0.63–0.96)	0.72 (0.53–0.92)
	OPN	Outcome does not vary	0.511 (0.18–0.84)	0.755 (0.60–0.91)	0.69 (0.52–0.86)
	Cystatin C	Outcome does not vary	0.488 (0.00–1.00)	0.813 (0.48–1.00)	0.37 (0.16–0.57)

↵a AUC, area under the receiver operating characteristic curve; CI, confidence interval; NGAL, neutrophil gelatinase-associated lipocalin; KIM-1, kidney injury molecule-1; OPN, osteopontin.