Rationale: Sepsis is the cause of nearly half of acute kidney injury (AKI) and, unfortunately, AKI in sepsis is associated with unacceptably high rates of mortality. Early detection of AKI would guide the timely intervention and care of sepsis patients. Currently, NephroCheck, based on urinary [TIMP2]*[IGFBP7], is the only FDA approved test for early detection of AKI, which has a relatively low sensitivity for sepsis patients./nMethods: In vitro, BUMPT (Boston University mouse proximal tubular cell line) cells were treated with lipopolysaccharides (LPS). In vivo, sepsis was induced in mice by LPS injection or cecal ligation and puncture (CLP). To validate the biomarker potential of miR-452, serum and urinary samples were collected from 47 sepsis patients with AKI, 50 patients without AKI, and 10 healthy subjects./nResults: miR-452 was induced in renal tubular cells in septic AKI, and the induction was shown to be mediated by NF-κB. Notably, serum and urinary miR-452 increased early in septic mice following LPS or CLP treatment, prior to detectable renal dysfunction or tissue damage. Sepsis patients with AKI had significantly higher levels of serum and urinary miR-452 than the patients without AKI. Spearman's test demonstrated a remarkable positive correlation between urinary miR-452 and serum creatinine in sepsis patients (r=0.8269). The area under the receiver operating characteristic curve (AUC) was 0.8985 for urinary miR-452. Logistic regression analysis showed a striking 72.48-fold increase of AKI risk for every 1-fold increase of urinary miR-452 in sepsis patients. The sensitivity of urinary miR-452 for AKI detection in sepsis patients reached 87.23%, which was notably higher than the 61.54% achieved by urinary [TIMP2]*[IGFBP7], while the specificity of urinary miR-452 (78.00%) was slightly lower than that of [TIMP2]*[IGFBP7] (87.18%)./nConclusions: miR-452 is induced via NF-κB in renal tubular cells in septic AKI. The increase of miR-452, especially that in urine, may be an effective biomarker for early detection of AKI in sepsis patients.

中文翻译：

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发现和验证miR-452作为败血症急性肾损伤的有效生物标志物

理由：败血症是近半数的急性肾损伤（AKI）的病因，不幸的是，败血症中的AKI与死亡率高得令人无法接受。早期发现AKI将指导败血症患者的及时干预和护理。目前，基于尿液[TIMP2] * [IGFBP7]的NephroCheck是唯一获FDA批准的AKI早期检测方法，对败血症患者的敏感性相对较低。/n方法： 体外，BUMPT（波士顿大学小鼠近端用脂多糖（LPS）处理细胞）。体内通过LPS注射或盲肠结扎穿刺（CLP）在小鼠中诱发败血症。为了验证的miR-452的生物标志物的潜力，血清和尿样品从47名败血症AKI患者，50名患者没有AKI，和10个健康subjects./n收集结果：在脓毒症AKI的肾小管细胞中诱导了miR-452，并且该诱导被证明是由NF-κB介导的。值得注意的是，在LPS或CLP治疗后，败血症小鼠的血清和尿液miR-452早期升高，而肾功能不全或组织受损才被发现。患有AKI的败血症患者的血清和尿液miR-452的水平明显高于没有AKI的患者。Spearman检验证明败血症患者尿中miR-452与血清肌酐之间存在显着正相关（r = 0.8269）。对于尿液miR-452，接收器工作特征曲线（AUC）下的面积为0.8985。Logistic回归分析显示，败血症患者尿中miR-452的每增加1倍，AKI风险显着增加72.48倍。脓毒症患者尿中miR-452对AKI检测的敏感性达到87.23％，结论：脓毒症AKI患者肾小管细胞中可通过NF-κB诱导miR-452。miR-452的增加，尤其是尿中的增加，可能是败血症患者早期检测AKI的有效生物标志物。