title: Renal redox dysregulation in AKI: application for oxidative stress marker of AKI.
abstract: Oxidative stress is a major determinant of acute kidney injury (AKI); however, the effects of an AKI on renal redox system are unclear, and few existing AKI markers are suitable for evaluating oxidative stress. We measured urinary levels of the redox-regulatory protein thioredoxin 1 (TRX1) in patients with various kinds of kidney disease and in mice with renal ischemia-reperfusion injury. Urinary TRX1 levels were markedly higher in patients with AKI than in those with chronic kidney disease or in healthy subjects. In a receiver operating characteristic curve analysis to differentiate between AKI and other renal diseases, the area under the curve for urinary TRX1 was 0.94 (95% confidence interval, 0.90-0.98), and the sensitivity and specificity were 0.88 and 0.88, respectively, at the optimal cutoff value of 43.0 μg/g creatinine. Immunostaining revealed TRX1 to be diffusely distributed in the tubules of normal kidneys, but to be shifted to the brush borders or urinary lumen in injured tubules in both mice and humans with AKI. Urinary TRX1 in AKI was predominantly in the oxidized form. In cultured human proximal tubular epithelial cells, hydrogen peroxide specifically and dose dependently increased TRX1 levels in the culture supernatant, while reducing intracellular levels. These findings suggest that urinary TRX1 is an oxidative stress-specific biomarker useful for distinguishing AKI from chronic kidney disease and healthy kidneys.
authors.affiliation: Division of Nephrology, Department of General Medicine, School of Medicine, University of Fukui, Fukui, Japan; kasuno@u-fukui.ac.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kasuno
authors.affiliation: Department of Nephrology and Dialysis, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan;
authors.forename: Kiichi
authors.initials: K
authors.lastname: Shirakawa
authors.affiliation: Division of Nephrology, Department of General Medicine, School of Medicine, University of Fukui, Fukui, Japan;
authors.forename: Haruyoshi
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan;
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mori
authors.affiliation: Division of Nephrology, Department of General Medicine, School of Medicine, University of Fukui, Fukui, Japan;
authors.forename: Hideki
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Division of Nephrology, Department of General Medicine, School of Medicine, University of Fukui, Fukui, Japan;
authors.forename: Naoki
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Intensive Care Unit, Fukui University Hospital, Fukui, Japan;
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Nobukawa
authors.affiliation: Intensive Care Unit, Fukui University Hospital, Fukui, Japan;
authors.forename: Kenji
authors.initials: K
authors.lastname: Shigemi
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, School of Medicine, University of Fukui, Fukui, Japan;
authors.forename: Sawaka
authors.initials: S
authors.lastname: Tanabe
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, School of Medicine, University of Fukui, Fukui, Japan;
authors.forename: Narihisa
authors.initials: N
authors.lastname: Yamada
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, School of Medicine, University of Fukui, Fukui, Japan;
authors.forename: Takaaki
authors.initials: T
authors.lastname: Koshiji
authors.affiliation: Department of Nephrology, Shimada Municipal Hospital, Shizuoka, Japan;
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Nogaki
authors.affiliation: Department of Nephrology and Dialysis, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan;
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kusano
authors.affiliation: Department of Nephrology, Atami Hospital, International University of Health and Welfare, Shizuoka, Japan;
authors.forename: Takahiko
authors.initials: T
authors.lastname: Ono
authors.affiliation: Louis Pasteur Center for Medical Research, Kyoto, Japan;
authors.forename: Kazuko
authors.initials: K
authors.lastname: Uno
authors.affiliation: Department of Preventive Medicine, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan;
authors.forename: Hajime
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Department of Biological Responses, Institute for Virus Research, Graduate School of Medicine, Kyoto University, Kyoto, Japan; and Department of Bioinspired Science, Ewha Womans University, Seoul, Korea.
authors.forename: Junji
authors.initials: J
authors.lastname: Yodoi
authors.affiliation: Department of Nephrology and Dialysis, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan;
authors.forename: Eri
authors.initials: E
authors.lastname: Muso
authors.affiliation: Division of Nephrology, Department of General Medicine, School of Medicine, University of Fukui, Fukui, Japan;
authors.forename: Masayuki
authors.initials: M
authors.lastname: Iwano
mesh_terms: D058186:Acute Kidney Injury / Q000175:diagnosis / Q000652:urine*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D019540:Area Under Curve; D015415:Biomarkers / Q000652:urine; D016022:Case-Control Studies; D003937:Diagnosis, Differential; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011237:Predictive Value of Tests; D012372:ROC Curve; D051436:Renal Insufficiency, Chronic / Q000175:diagnosis / Q000652:urine; D015427:Reperfusion Injury / Q000175:diagnosis / Q000652:urine*; D013879:Thioredoxins / Q000652:urine*; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C491203:TXN protein, human; C515559:Txn1 protein, mouse; D013879:Thioredoxins
keywords: cardiopulmonary bypass; redox; renal ischemia-reperfusion