Kim Ae Jin, Ro Han, Kim Hyunsook, Chang Jae Hyun, Lee Hyun Hee, Chung Wookyung, Jung Ji Yong
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.
PLoS One. 2016 Jan 22;11(1):e0147255. doi: 10.1371/journal.pone.0147255. eCollection 2016.
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.
急性肾损伤（AKI）病因的早期检测和准确鉴别可能改善患者的预后。然而，迄今为止，几乎没有可靠的生物标志物能够区分肾前性和内在性AKI。在本研究中，我们测定了AKI是否与血清和尿液中α-klotho、S100A8/A9（Toll样受体4的内源性配体）及中性粒细胞明胶酶相关脂质运载蛋白（NGAL）水平的改变相关，这可能有助于区分肾前性和内在性AKI。在间隔24小时腹腔注射两次呋塞米（20mg/kg）之前96小时，给雄性Sprague Dawley大鼠喂食低盐饮食（0.03%）且不供水，诱导容量耗竭性肾前性AKI模型。相反，在顺铂诱导的内在性AKI模型中，给动物单次腹腔注射顺铂（5mg/kg）。在首次腹腔注射后72小时对所有动物实施安乐死。使用酶联免疫吸附测定法测量血清和尿液中α-klotho、S100A8/A9及NGAL的水平。我们还进行了一项概念验证性横断面研究，以测量61例已确诊AKI的住院患者的血清和尿液生物标志物。与内在性AKI组相比，肾前性AKI组尿液中α-klotho水平显著降低（13.21±17.32 vs. 72.97±17.96 pg/mL；P = 0.002）。此外，与肾前性AKI组相比，内在性AKI组S100A8/A9水平显著升高（血清中：2629.97±598.05 ng/mL vs. 685.09±111.65 ng/mL；P = 0.002；尿液中：3361.11±250.86 ng/mL vs. 741.72±101.96 ng/mL；P = 0.003）。肾前性和内在性AKI组之间血清和尿液NGAL水平无差异。对住院AKI患者的概念验证性研究也表明，肾前性AKI患者尿液中α-klotho降低，内在性AKI患者尿液中S100A8/A9浓度升高。尿液中α-klotho的降低和尿液中S100A8/A9的升高可能有助于区分肾前性和内在性AKI。
