title: Klotho and S100A8/A9 as Discriminative Markers between Pre-Renal and Intrinsic Acute Kidney Injury.
abstract: Early detection and accurate differentiation of the cause of AKI may improve the prognosis of the patient. However, to date, there are few reliable biomarkers that can discriminate between pre-renal and intrinsic AKI. In this study, we determined whether AKI is associated with altered serum and urinary levels of Klotho, S100A8/A9 (an endogenous ligand of toll-like receptor 4), and neutrophil gelatinase-associated lipocalin (NGAL), which may allow differentiation between pre-renal and intrinsic AKI. A volume-depleted pre-renal AKI model was induced in male Sprague Dawley rats fed a low-salt diet (0.03%) without water 96 h before two intraperitoneal (IP) injections of furosemide (20 mg/kg) at a 24 h interval. In contrast, in the cisplatin-induced intrinsic AKI model, animals were given a single IP injection of cisplatin (5 mg/kg). All of the animals were euthanized 72 h after the first IP injection. Serum and urinary levels of Klotho, S100A8/A9, and NGAL were measured using an enzyme-linked immunosorbent assay. We also performed a proof-of-concept cross-sectional study to measure serum and urinary biomarkers in 61 hospitalized patients with established AKI. Compared to the intrinsic AKI group, the pre-renal AKI group showed a marked depression in urinary Klotho levels (13.21 ± 17.32 vs. 72.97 ± 17.96 pg/mL; P = 0.002). In addition, the intrinsic AKI group showed marked elevation of S100A8/A9 levels compared to the pre-renal AKI group (2629.97 ± 598.05 ng/mL vs. 685.09 ± 111.65 ng/mL; P = 0.002 in serum; 3361.11 ± 250.86 ng/mL vs. 741.72 ± 101.96 ng/mL; P = 0.003 in urine). There was no difference in serum and urinary NGAL levels between the pre-renal and intrinsic AKI groups. The proof-of-concept study with the hospitalized AKI patients also demonstrated decreased urinary Klotho in pre-renal AKI patients and increased urinary S100A8/A9 concentrations in intrinsic AKI patients. The attenuation of urinary Klotho and increase in urinary S100A8/A9 may allow differentiation between pre-renal and intrinsic AKI.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University School of Medicine, Incheon, Korea.|Gachon Medical Research Institute, Gachon University Gil Medical Center, Incheon, Korea.
authors.forename: Ae Jin
authors.initials: AJ
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University School of Medicine, Incheon, Korea.|Gachon Medical Research Institute, Gachon University Gil Medical Center, Incheon, Korea.
authors.forename: Han
authors.initials: H
authors.lastname: Ro
authors.affiliation: Gachon Medical Research Institute, Gachon University Gil Medical Center, Incheon, Korea.
authors.forename: Hyunsook
authors.initials: H
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University School of Medicine, Incheon, Korea.|Gachon Medical Research Institute, Gachon University Gil Medical Center, Incheon, Korea.
authors.forename: Jae Hyun
authors.initials: JH
authors.lastname: Chang
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University School of Medicine, Incheon, Korea.|Gachon Medical Research Institute, Gachon University Gil Medical Center, Incheon, Korea.
authors.forename: Hyun Hee
authors.initials: HH
authors.lastname: Lee
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University School of Medicine, Incheon, Korea.|Gachon Medical Research Institute, Gachon University Gil Medical Center, Incheon, Korea.
authors.forename: Wookyung
authors.initials: W
authors.lastname: Chung
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University School of Medicine, Incheon, Korea.|Gachon Medical Research Institute, Gachon University Gil Medical Center, Incheon, Korea.
authors.forename: Ji Yong
authors.initials: JY
authors.lastname: Jung
mesh_terms: D058186:Acute Kidney Injury / Q000175:diagnosis*; D000209:Acute-Phase Proteins / Q000652:urine; D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D040501:Calgranulin A / Q000097:blood*; D040502:Calgranulin B / Q000097:blood* / Q000652:urine*; D003430:Cross-Sectional Studies; D004195:Disease Models, Animal; D042241:Early Diagnosis; D005260:Female; D005966:Glucuronidase / Q000097:blood* / Q000652:urine*; D006801:Humans; D007668:Kidney / Q000473:pathology; D000090265:Klotho Proteins; D000071068:Lipocalin-2; D054834:Lipocalins / Q000097:blood / Q000652:urine; D008297:Male; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000097:blood / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000209:Acute-Phase Proteins; D015415:Biomarkers; D040501:Calgranulin A; D040502:Calgranulin B; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D005966:Glucuronidase; D000090265:Klotho Proteins