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可溶性尿激酶受体和急性肾损伤
Soluble Urokinase Receptor and Acute Kidney Injury


Salim S. Hayek ... 其他 • 2020.01.30
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摘要


背景

急性肾损伤常见,且对发病率和医疗资源的利用有重大影响。可溶性尿激酶型纤溶酶原激活物受体(suPAR)是一种信号传导糖蛋白,目前认为其参与了肾脏病的发病机制。我们研究了在多种临床背景下,高水平suPAR是否会导致患者易患急性肾损伤,并且利用实验模型确定了suPAR的作用机制,并将其作为治疗靶点进行了评估。

 

方法

我们在接受冠状动脉造影的患者和接受心脏手术的患者中测定了术前suPAR血浆水平,并在危重患者中测定了送入重症监护病房时的suPAR血浆水平。本试验根据suPAR水平的四分位数评估主要结局和次要结局,主要结局是7日时的急性肾损伤风险,次要结局是90日时的急性肾损伤或死亡风险。在实验性研究中,我们使用尿激酶型纤溶酶原激活物受体(uPAR)的单克隆抗体作为治疗策略来减轻接受造影剂给药的转基因小鼠的急性肾损伤。我们还在暴露于重组suPAR的人肾近端小管(HK-2)细胞内评估了细胞生物能和活性氧生成情况。

 

结果

我们在接受冠状动脉造影的3,827例患者、接受心脏手术的250例患者和692例危重患者中评估了suPAR水平。318例(8%)接受冠状动脉造影的患者发生了急性肾损伤。与最低suPAR四分位数相比,最高suPAR四分位数的急性肾损伤的校正比值比为2.66(95%置信区间[CI],1.77~3.99),90日时急性肾损伤或死亡的校正比值比为2.29(95% CI,1.71~3.06)。手术队列和危重队列的结果相似。与野生型小鼠相比,在被给予造影剂的suPAR过表达小鼠中,急性肾损伤的功能性和组织学证据较多。接受suPAR处理的HK-2细胞的能量需求增加,线粒体过氧化物生成增多。uPAR单克隆抗体预处理减轻了suPAR过表达小鼠的肾损伤,并使HK-2细胞的生物能变化恢复正常。

 

结论

在各种临床和实验背景下,高suPAR水平均与急性肾损伤相关(由美国国立卫生研究院等资助)。





作者信息

Salim S. Hayek, M.D., David E. Leaf, M.D., Ayman Samman Tahhan, M.D., Mohamad Raad, M.D., Shreyak Sharma, M.B., B.S., Sushrut S. Waikar, M.D., M.P.H., Sanja Sever, Ph.D., Alex Camacho, Ph.D., Xuexiang Wang, M.D., Ph.D., Ranadheer R. Dande, M.D., Nasrien E. Ibrahim, M.D., Rebecca M. Baron, M.D., Mehmet M. Altintas, Ph.D., Changli Wei, M.D., Ph.D., David Sheikh-Hamad, M.D., Jenny S.-C. Pan, M.D., Michael W. Holliday, Jr., M.D., Ph.D., James L. Januzzi, M.D., Steven D. Weisbord, M.D., Arshed A. Quyyumi, M.D., and Jochen Reiser, M.D., Ph.D.
From the Division of Cardiology, Department of Medicine, University of Michigan, Ann Arbor (S.S.H.); the Divisions of Renal Medicine (D.E.L., S. Sharma, S.S.W.) and Pulmonary and Critical Care Medicine (R.M.B.), Brigham and Women’s Hospital, the Section of Nephrology, Department of Medicine, Boston University School of Medicine (S.S.W.), and the Divisions of Nephrology (S. Sever) and Cardiology (A.C., N.E.I., J.L.J.), Massachusetts General Hospital — all in Boston; Emory Clinical Cardiovascular Research Institute, Emory University School of Medicine, Atlanta (A.S.T., M.R., A.A.Q.); the Department of Medicine, Rush University Medical Center, Chicago (X.W., R.R.D., M.M.A., C.W., J.R.); the Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston (D.S.-H., J.S.-C.P., M.W.H.); and the Veterans Affairs Pittsburgh Healthcare System and the University of Pittsburgh School of Medicine, Pittsburgh (S.D.W.). Address reprint requests to Dr. Hayek at the University of Michigan–Internal Medicine, Frankel Cardiovascular Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109-1382, or at shayek@med.umich.edu; or to Dr. Reiser at Rush University, 1717 W. Congress Pkwy., Chicago, IL 60612, or at jochen_reiser@rush.edu.

 

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