Anesthesia and Intensive Care Unit, San Raffaele Scientific Institute, University Vita Salute San Raffaele, Milan, Italy.
Crit Care Med. 2013 Mar;41(3):744-55. doi: 10.1097/CCM.0b013e3182741599.
Acute kidney injury is a frequent complication of cardiac surgery and increases morbidity and mortality. As preoperative biomarkers predicting the development of acute kidney injury are not available, we have tested the hypothesis that preoperative plasma levels of endogenous ouabain may function as this type of biomarker.
Endogenous ouabain is an adrenal stress hormone associated with adverse cardiovascular outcomes. Its involvement in acute kidney injury is unknown. With studies in patients and animal settings, including isolated podocytes, we tested the above mentioned hypothesis.
Preoperative endogenous ouabain was measured in 407 patients admitted for elective cardiac surgery and in a validation population of 219 other patients. We also studied the effect of prolonged elevations of circulating exogenous ouabain on renal parameters in rats and the influence of ouabain on podocyte proteins both "in vivo" and "in vitro."
In the first group of patients, acute kidney injury (2.8%, 8.3%, 20.3%, p < 0.001) and ICU stay (1.4±0.38, 1.7±0.41, 2.4±0.59 days, p = 0.014) increased with each incremental preoperative endogenous ouabain tertile. In a linear regression analysis, the circulating endogenous ouabain value before surgery was the strongest predictor of acute kidney injury. In the validation cohort, acute kidney injury (0%, 5.9%, 8.2%, p < 0.0001) and ICU stay (1.2±0.09, 1.4±0.23, 2.2±0.77 days, p = 0.003) increased with the preoperative endogenous ouabain tertile. Values for preoperative endogenous ouabain significantly improved (area under curve: 0.85) risk prediction over the clinical score alone as measured by integrate discrimination improvement and net reclassification improvement. Finally, in the rat model, elevated circulating ouabain reduced creatinine clearance (-18%, p < 0.05), increased urinary protein excretion (+ 54%, p < 0.05), and reduced expression of podocyte nephrin (-29%, p < 0.01). This last finding was replicated ex vivo by incubating podocyte primary cell cultures with low-dose ouabain.
Preoperative plasma endogenous ouabain levels are powerful biomarkers of acute kidney injury and postoperative complications and may be a direct cause of podocyte damage.
急性肾损伤是心脏手术的常见并发症，增加发病率和死亡率。由于目前尚无预测急性肾损伤发生的术前生物标志物，因此我们假设术前血浆内源性哇巴因水平可能具有这种生物标志物的功能。
内源性哇巴因是一种与不良心血管结局相关的肾上腺应激激素。其在急性肾损伤中的作用尚不清楚。通过对患者和动物模型（包括分离的足细胞）进行研究，我们检验了上述假设。
407 名择期心脏手术患者和 219 名其他患者的术前内源性哇巴因水平进行了测量。我们还研究了延长循环外源性哇巴因升高对大鼠肾功能参数的影响，以及哇巴因对足细胞蛋白的“体内”和“体外”影响。
在第一组患者中，急性肾损伤（2.8%、8.3%、20.3%，p < 0.001）和 ICU 住院时间（1.4±0.38、1.7±0.41、2.4±0.59 天，p = 0.014）随着术前内源性哇巴因三分位递增而增加。在线性回归分析中，术前循环内源性哇巴因值是急性肾损伤的最强预测因子。在验证队列中，急性肾损伤（0%、5.9%、8.2%，p < 0.0001）和 ICU 住院时间（1.2±0.09、1.4±0.23、2.2±0.77 天，p = 0.003）随着术前内源性哇巴因三分位递增而增加。术前内源性哇巴因的测定值显著提高（曲线下面积：0.85），优于临床评分单独预测的风险（通过整合鉴别改善和净重新分类改善来衡量）。最后，在大鼠模型中，升高的循环哇巴因降低了肌酐清除率（-18%，p < 0.05），增加了尿蛋白排泄（+54%，p < 0.05），并降低了足细胞nephrin 的表达（-29%，p < 0.01）。通过用低剂量哇巴因孵育足细胞原代培养物，在体外复制了最后一个发现。
术前血浆内源性哇巴因水平是急性肾损伤和术后并发症的有力生物标志物，可能是足细胞损伤的直接原因。
