title: Discovery of urinary metabolomic biomarkers for early detection of acute kidney injury.
abstract: 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.
authors.affiliation: College of Pharmacy, Pusan National University, Busan, 609-735, Republic of Korea.
authors.forename: A Jin
authors.initials: AJ
authors.lastname: Won
authors.affiliation: Department of Chemistry and Chemistry Institute for Functional Materials, Pusan National University, Busan, 609-735, Republic of Korea.
authors.forename: Siwon
authors.initials: S
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Dankook University, 119, Dandae-ro, Dongnam-gu, Cheonan-si, Chungnam 330-714, Republic of Korea.
authors.forename: Yoon Gyoon
authors.initials: YG
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Dankook University, 119, Dandae-ro, Dongnam-gu, Cheonan-si, Chungnam 330-714, Republic of Korea.
authors.forename: Kyu-Bong
authors.initials: KB
authors.lastname: Kim
authors.affiliation: School of Medicine, Konkuk University, Chungju 380-701, Republic of Korea.
authors.forename: Wahn Soo
authors.initials: WS
authors.lastname: Choi
authors.affiliation: McLaughlin Centre for Population Health Risk Assessment, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Sam
authors.initials: S
authors.lastname: Kacew
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Republic of Korea. hkims@skku.edu.
authors.forename: Kyeong Seok
authors.initials: KS
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Pusan National University, Busan, 609-735, Republic of Korea.
authors.forename: Jee H
authors.initials: JH
authors.lastname: Jung
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Republic of Korea. hkims@skku.edu.
authors.forename: Byung Mu
authors.initials: BM
authors.lastname: Lee
authors.affiliation: Department of Chemistry and Chemistry Institute for Functional Materials, Pusan National University, Busan, 609-735, Republic of Korea.
authors.forename: Suhkmann
authors.initials: S
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Republic of Korea. hkims@skku.edu.
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
mesh_terms: D058186:Acute Kidney Injury / Q000175:diagnosis* / Q000209:etiology / Q000652:urine*; D000818:Animals; D015415:Biomarkers; D001706:Biopsy; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D066244:Proton Magnetic Resonance Spectroscopy; D012372:ROC Curve; D051381:Rats
chemical_list: D015415:Biomarkers