The discovery of new
biomarkers for early detection of drug-induced
acute kidney injury (AKI) is clinically important. In this study, sensitive metabolomic
biomarkers identified in the urine of rats were used to detect
cisplatin-induced AKI.
Cisplatin (10 mg kg(-1), i.p.) was administered to Sprague-Dawley rats, which were subsequently euthanized after 1, 3 or 5 days. In
cisplatin-treated rats, mild histopathological alterations were noted at day 1, and these changes were severe at days 3 and 5. Blood
urea nitrogen (BUN) and serum
creatinine (SCr) levels were significantly increased at days 3 and 5. The levels of new urinary
protein-based
biomarkers, including kidney injury molecule-1 (KIM-1),
glutathione S-transferase-α (GST-α),
tissue inhibitor of metalloproteinase-1 (TIMP-1),
vascular endothelial growth factor (
VEGF),
calbindin,
clusterin, neutrophil,
neutrophil gelatinase-associated lipocalin (NGAL), and
osteopontin, were significantly elevated at days 3 and 5. Among urinary metabolites,
trigonelline and 3-indoxylsulfate (3-IS) levels were significantly decreased in urine collected from
cisplatin-treated rats prior to histological kidney damage. However,
carbon tetrachloride (CCl4), a hepatotoxicant, did not affect these urinary
biomarkers.
Trigonelline is closely associated with GSH depletion and results in insufficient
antioxidant capacity against
cisplatin-induced AKI. The predominant
cisplatin-induced AKI marker appeared to be reduced in urinary 3-IS levels. Because 3-IS is predominantly excreted via active secretion in proximal tubules, a decrease is indicative of tubular damage. Further, urinary excretion of 3-IS levels was markedly reduced in patients with AKI compared to normal subjects. The area under the curve receiver operating characteristics (AUC-ROC) for 3-IS was higher than for SCr, BUN,
lactate dehydrogenase (LDH), total
protein, and
glucose. Therefore, low urinary or high serum 3-IS levels may be more useful for early detection of AKI than conventional
biomarkers.