Soluble Urokinase Receptor and Acute Kidney Injury
Soluble Urokinase Receptor and Acute Kidney Injury
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DOI：
10.1056/nejmoa1911481
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发表时间：
2020-01-30
影响因子：
158.5
通讯作者：
Reiser, Jochen
中科院分区：
文献类型：
--
作者：
Hayek, Salim S.;Leaf, David E.;Reiser, Jochen
背景
急性肾损伤较为常见，对发病率和医疗资源利用有重大影响。可溶性尿激酶型纤溶酶原激活物受体（suPAR）是一种信号糖蛋白，被认为与肾脏疾病的发病机制有关。我们研究了在多种临床情况下，高水平的suPAR是否会使患者易患急性肾损伤，并且我们利用实验模型来确定suPAR的作用机制以及评估其作为治疗靶点的可能性。
方法
我们对接受冠状动脉造影的患者、接受心脏手术的患者在术前以及重症患者进入重症监护病房时测量血浆suPAR水平。我们根据suPAR水平的四分位数，将7天内发生急性肾损伤作为主要结局，将90天内发生急性肾损伤或死亡作为次要结局来评估风险。在实验研究中，我们使用一种针对尿激酶型纤溶酶原激活物受体（uPAR）的单克隆抗体作为一种治疗策略，以减轻接受造影剂的转基因小鼠的急性肾损伤。我们还评估了暴露于重组suPAR的人肾近端小管（HK - 2）细胞的细胞生物能量学和活性氧生成情况。
结果
对3827名接受冠状动脉造影的患者、250名接受心脏手术的患者以及692名重症患者的suPAR水平进行了评估。318名（8%）接受冠状动脉造影的患者发生了急性肾损伤。最高suPAR四分位数（相较于最低四分位数）发生急性肾损伤的校正优势比为2.66（95%置信区间[CI]，1.77 - 3.99），90天内发生急性肾损伤或死亡的校正优势比为2.29（95%CI，1.71 - 3.06）。在手术组和重症患者组中也有类似发现。给予造影剂的suPAR过表达小鼠比野生型小鼠有更明显的急性肾损伤的功能和组织学证据。经suPAR处理的HK - 2细胞显示出更高的能量需求和线粒体超氧化物生成。用uPAR单克隆抗体预处理可减轻suPAR过表达小鼠的肾损伤，并使HK - 2细胞的生物能量变化恢复正常。
结论
在各种临床和实验情况下，高suPAR水平与急性肾损伤相关。（由美国国立卫生研究院及其他机构资助。）在三个有急性肾损伤风险的患者队列中测量了可溶性尿激酶型纤溶酶原激活物受体。利用实验模型评估suPAR作为治疗靶点。在临床和实验环境中，高suPAR水平均与急性肾损伤相关。
Background Acute kidney injury is common, with a major effect on morbidity and health care utilization. Soluble urokinase plasminogen activator receptor (suPAR) is a signaling glycoprotein thought to be involved in the pathogenesis of kidney disease. We investigated whether a high level of suPAR predisposed patients to acute kidney injury in multiple clinical contexts, and we used experimental models to identify mechanisms by which suPAR acts and to assess it as a therapeutic target. Methods We measured plasma levels of suPAR preprocedurally in patients who underwent coronary angiography and patients who underwent cardiac surgery and at the time of admission to the intensive care unit in critically ill patients. We assessed the risk of acute kidney injury at 7 days as the primary outcome and acute kidney injury or death at 90 days as a secondary outcome, according to quartile of suPAR level. In experimental studies, we used a monoclonal antibody to urokinase plasminogen activator receptor (uPAR) as a therapeutic strategy to attenuate acute kidney injury in transgenic mice receiving contrast material. We also assessed cellular bioenergetics and generation of reactive oxygen species in human kidney proximal tubular (HK-2) cells that were exposed to recombinant suPAR. Results The suPAR level was assessed in 3827 patients who were undergoing coronary angiography, 250 who were undergoing cardiac surgery, and 692 who were critically ill. Acute kidney injury developed in 318 patients (8%) who had undergone coronary angiography. The highest suPAR quartile (vs. the lowest) had an adjusted odds ratio of 2.66 (95% confidence interval [CI], 1.77 to 3.99) for acute kidney injury and 2.29 (95% CI, 1.71 to 3.06) for acute kidney injury or death at 90 days. Findings were similar in the surgical and critically ill cohorts. The suPAR-overexpressing mice that were given contrast material had greater functional and histologic evidence of acute kidney injury than wild-type mice. The suPAR-treated HK-2 cells showed heightened energetic demand and mitochondrial superoxide generation. Pretreatment with a uPAR monoclonal antibody attenuated kidney injury in suPAR-overexpressing mice and normalized bioenergetic changes in HK-2 cells. Conclusions High suPAR levels were associated with acute kidney injury in various clinical and experimental contexts. (Funded by the National Institutes of Health and others.)Soluble urokinase plasminogen activator receptor was measured in three patient cohorts at risk for acute kidney injury. Experimental models were used to assess suPAR as a therapeutic target. High suPAR levels were associated with acute kidney injury in both clinical and experimental settings.