Renal redox dysregulation in AKI: application for oxidative stress marker of AKI

• Published in: American journal of physiology. Renal physiology Vol. 307; no. 12; pp. F1342 - F1351
• Main Authors: Kasuno, Kenji, Shirakawa, Kiichi, Yoshida, Haruyoshi, Mori, Kiyoshi, Kimura, Hideki, Takahashi, Naoki, Nobukawa, Yasunari, Shigemi, Kenji, Tanabe, Sawaka, Yamada, Narihisa, Koshiji, Takaaki, Nogaki, Fumiaki, Kusano, Hitoshi, Ono, Takahiko, Uno, Kazuko, Nakamura, Hajime, Yodoi, Junji, Muso, Eri, Iwano, Masayuki
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 15.12.2014
• Subjects: Acute Kidney Injury - diagnosis; Acute Kidney Injury - urine; Adult; Aged; Aged, 80 and over; Animals; Area Under Curve; Biomarkers - urine; Case-Control Studies; Diagnosis, Differential; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Humans; Injuries; Ischemia; Kidney - metabolism; Kidneys; Male; Mice; Middle Aged; Oxidation-Reduction; Oxidative Stress; Predictive Value of Tests; Proteins; Renal Insufficiency, Chronic - diagnosis; Renal Insufficiency, Chronic - urine; Reperfusion Injury - diagnosis; Reperfusion Injury - urine; ROC Curve; Rodents; Thioredoxins - urine; Time Factors; Up-Regulation; cardiopulmonary bypass; renal ischemia-reperfusion; redox
• ISSN: 1931-857X; 1522-1466; 1522-1466
• DOI: 10.1152/ajprenal.00381.2013

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.