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Soluble Urokinase Receptor and Acute Kidney Injury.
The New England Journal of Medicine ( IF 96.2 ) Pub Date : 2020-01-30 , DOI: 10.1056/nejmoa1911481
Salim S Hayek 1 , David E Leaf 1 , Ayman Samman Tahhan 1 , Mohamad Raad 1 , Shreyak Sharma 1 , Sushrut S Waikar 1 , Sanja Sever 1 , Alex Camacho 1 , Xuexiang Wang 1 , Ranadheer R Dande 1 , Nasrien E Ibrahim 1 , Rebecca M Baron 1 , Mehmet M Altintas 1 , Changli Wei 1 , David Sheikh-Hamad 1 , Jenny S-C Pan 1 , Michael W Holliday 1 , James L Januzzi 1 , Steven D Weisbord 1 , Arshed A Quyyumi 1 , Jochen Reiser 1
Affiliation  

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.).

中文翻译:

可溶性尿激酶受体和急性肾损伤。

背景技术急性肾损伤很常见,对发病率和医疗保健利用有重大影响。可溶性尿激酶纤溶酶原激活物受体 (suPAR) 是一种信号传导糖蛋白,被认为与肾脏疾病的发病机制有关。我们调查了高水平的 suPAR 是否会使患者在多种临床情况下易患急性肾损伤,并且我们使用实验模型来确定 suPAR 的作用机制并将其作为治疗靶点进行评估。方法 我们在术前测量了接受冠状动脉造影术的患者和接受心脏手术的患者以及重症患者进入重症监护病房时的 suPAR 血浆水平。根据 suPAR 水平的四分位数,我们评估了 7 天时急性肾损伤的风险作为主要结局,90 天时急性肾损伤或死亡的风险作为次要结局。在实验研究中,我们使用抗尿激酶纤溶酶原激活物受体 (uPAR) 的单克隆抗体作为治疗策略,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) 细胞的细胞生物能学和活性氧的产生。结果 在 3827 名接受冠状动脉造影的患者、250 名接受心脏手术的患者和 692 名危重患者中评估了 suPAR 水平。接受冠状动脉造影的 318 名患者 (8%) 出现急性肾损伤。最高 suPAR 四分位数(对比 最低)在 90 天时急性肾损伤的调整比值比为 2.66(95% 置信区间 [CI],1.77 至 3.99),急性肾损伤或死亡的比值比为 2.29(95% CI,1.71 至 3.06)。手术组和重症组的结果相似。给予造影剂的 suPAR 过表达小鼠比野生型小鼠具有更多的急性肾损伤功能和组织学证据。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的产生。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正常化。结论 在各种临床和实验环境中,高 suPAR 水平与急性肾损伤相关。(由美国国立卫生研究院和其他机构资助。)。
更新日期:2020-01-29
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