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.
Highlights
Acute kidney injury (AKI) is a serious problem associated with high morbidity and mortality [1]
We showed that decreased urinary Klotho and increased urinary S100A8/A9 levels may be helpful in differentiating between pre-renal and intrinsic AKI
The urinary Klotho/creatinine ratio was decreased in a VD-induced AKI animal model and pre-renal AKI patients
Summary
Acute kidney injury (AKI) is a serious problem associated with high morbidity and mortality [1]. Despite remarkable progress in medical care, the incidence of AKI in hospitalized patients remains high [2]. It has been considered reliable to use serum creatinine for the diagnosis of AKI, but it is a somewhat inadequate gold standard for many reasons. Serum creatinine has poor specificity, because it is affected by age, gender, muscle mass, dietary intake, and medications, all of which may lead to changes in serum creatinine without actual kidney injury [4]. The use of serum creatinine may cause delays in diagnosis and treatment because serum creatinine tends to increase slowly after injury [6]. There has been recent interest in identifying novel AKI biomarkers for early diagnosis and risk stratification
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