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

Abstract

Urinary biomarkers are superior to serum creatinine for defining onset and extent of kidney injury. This study classifies the temporal predictive ability of biomarkers for vancomycin-induced kidney injury (VIKI) as defined by histopathologic damage. Male Sprague-Dawley rats (n = 125) were randomized to receive 150 to 400 mg/kg of body weight/day vancomycin via once or twice daily intraperitoneal injection over 1, 3, or 6 days. Urine was collected once during the 24 h prior to euthanasia or twice for rats treated for 6 days. Receiver operating characteristic (ROC) curves were employed to assess the urinary biomarker performances of kidney injury molecule 1 (KIM-1), clusterin, osteopontin (OPN), cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) to predict histopathologically defined VIKI (using a national standard pathological assessment scheme from hematoxylin and eosin stained kidneys). Urinary KIM-1, clusterin, and OPN outperformed cystatin C and NGAL with regard to sensitivity and specificity. For the earliest injury, urinary KIM-1 (area under the receiver operating characteristic curve [AUC], 0.662; P < 0.001) and clusterin (AUC, 0.706; P < 0.001) were the most sensitive for predicting even low-level histopathologic damage at 24 h compared to NGAL. KIM-1 and clusterin are the earliest and most sensitive predictors of VIKI. As injury progresses, KIM-1, clusterin, and OPN best define the extent of damage.

Keywords: KIM-1; PK/PD; PK/TD; biomarker; histopathology; injury; kidney; toxicity; urinary; vancomycin.

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.

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).

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.

FIG 4

Schematic of the nephron (51) and urinary biomarker colocalization with injury (21). Bolded biomarker will aid in discretizing injury location.