Clinical implication of urinary midkine as a sensitive biomarker of acute kidney injury

虽然急性肾损伤（AKI）是ICU治疗患者预后最重要的预测指标，但在血清肌酐升高之前，还没有敏感的生物标志物来诊断AKI。近年来，一些尿液生物标志物如NGAL、IL-18、KIM-1、NHE3、KC和L-FABP被报道为AKI新的候选敏感生物标志物。我们报道了肝素结合生长因子midkine（MK）在病变肾脏中被诱导，并促进缺血性肾再灌注损伤动物模型中白细胞的趋化性（Sato W., et. al., J Immunol 2001; 167: 3463-3469）。缺血损伤后，MK的表达主要在近端小管中增强。在这里，我们评估了人类MK是否从肾小管上皮细胞进入尿液，并可能作为人类急性肾损伤的一种有效的尿液生物标志物。Western blot分析显示，缺氧处理的人小管上皮细胞（HK2）中MK的表达增加，而20 μM BSA处理的HK2细胞中MK的表达没有增加。细胞裂解液中MK的表达无差异。尿液MK测量共纳入583例患者，包括对照组（n=33）、不同形式急性肾小管坏死（ATN）患者（n=33）和其他慢性肾脏疾病患者（n= 517）。采用酶联免疫分析法测定尿MK水平。与其他慢性肾脏疾病患者或对照组相比，ATN患者尿MK水平显著升高。对于尿中MK浓度，受试者工作特征（ROC）曲线分析诊断ATN的敏感性为97.0%，特异性为91.1%，临界值为70.0 pg/ml。我们已经证实尿MK水平是ATN的敏感生物标志物，有助于疾病的早期诊断。我们获得了“AKI早期诊断的临床检查：尿MK测量”的专利（2008-048954,Ref: K20070222）。少

Although acute kidney injury (AKI) is the most important predictor of the prognosis of the patients treated in the field of ICU, there have been no sensitive biomarkers to diagnose AKI before the rising of serum creatinine. Recently, several urinary biomarkers such as NGAL, IL-18, KIM-1, NHE3, KC, and L-FABP are reported as a candidate of new sensitive biomarker of AKI.We reported that midkine(MK), a heparin-binding growth factor, was induced in the diseased kidneys and promoted chemotaxis of leukocytes in the animal models of an ischemic renal reperfusion injury(Sato W., et. al., J Immunol 2001 ; 167 : 3463-3469). The enhanced expression of MK was detected mainly in the proximal tubules after ischemic injuries. Here, we evaluated whether human MK is shed into urine from the tubular epithelial cells, and may serve as a potent urinary biomarker of acute kidney injuries in human.Western blot analysis showed that the increased expression of MK was detected in the culture media from cultur … More ed human tubular epithelial(HK2)cells treated with hypoxia, but not from HK2 cells treated with 20 μM BSA. There were no differences in the MK expression in the cell lysates.For the measurement of urinary MK, 583 patients, including controls (n=33), patients with different forms of acute tubular necrosis (ATN) (n=33), and patients with other chronic renal diseases(n= 517), were studied. Urinary MK level was determined by enzyme-linked immunoassay.The urinary MK levels were significantly higher in patients with ATN compared to levels in patients with other chronic renal diseases or controls. For concentration in urine of MK, the receiver-operating characteristic(ROC)curve analysis for diagnosis of ATN showed that sensitivity was 97.0 %, and specificity was 91.1 % for a cut-off value of 70.0 pg/ml.We have confirmed that urinary MK level serves as a sensitive biomarker of ATN facilitating the early diagnosis of the disease. We obtained the patent(2008-048954, Ref : K20070222)for "Clinical examination for the early diagnosis of AKI : Urinary MK measurement". Less