Discovery of urinary metabolomic biomarkers for early detection of acute kidney injury

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.