Biochemical and Reno-Protective Effects of Remote Ischemic Preconditioning on Contrast-Induced Kidney Disease

摘要 造影剂诱导的急性肾损伤(CI-AKI)是静脉注射、碘化治疗的常见并发症 广泛用于心导管插管和经皮冠状动脉介入治疗的造影剂 冠心病(CAD)患者行冠状动脉介入治疗(PCI)。在美国，CAD仍然是第一位的 男性和女性的死亡原因，尽管在过去十年中患者的护理有所改善。 尽管经皮冠状动脉介入治疗可以恢复心脏的血流，但用于该手术的造影剂可能会导致CI-AKI， 可能由造影剂引起的肾血管收缩和自由基介导 直接肾小管毒性。据估计，CI-AKI患者的发病率在10%到40%之间 急性心肌梗死患者心导管插入率较高。在 美国每年约有140万例心脏插管手术， 这一估计在未来几十年预计将呈指数级增长。随着对比度的使用越来越多 据媒体报道，CI-AKI的患病率预计也将上升。CI-AKI预测心脏病发作的风险增加， 住院时间越长，住院过程越复杂，住院死亡率越高。 不幸的是，目前还没有有效的预防方案来预防CI-AKI。 远程缺血预适应(RIPC)，由应用一个或多个，短暂发作 肢体缺血再灌注是预防或减轻脑梗塞的一种很有前途的治疗方法。考虑到 肾缺血损伤和肾小管毒性是脑梗塞最常见的病理生理学概念。 RIPC可能通过亚硝酸盐诱导的血管扩张和损伤来预防CI-AKI 相关分子蛋白介导的肾细胞保护。我们的初步数据显示，RIPC 提供肾脏保护，并表明RIPC诱导的保护性改变之间存在联系 分子(亚硝酸盐、环鸟苷一磷酸(CGMP)、金属蛋白酶组织抑制因子2 (TIMP-2)和胰岛素样生长因子结合蛋白7(IGFBP7)与器官保护。然而， RIPC对接受心导管术的冠心病患者CI-AKI的影响尚不清楚， 而这种效应的潜在机制仍不清楚。因此，这项研究旨在填补一个 我们对这种新兴疗法--RIPC的肾脏保护机制的理解存在严重空白。我们 提出一项随机对照试验(RCT)以确定RIPC对CI-AKI(主要结果)的影响 以及血管的中介生物标志物(亚硝酸盐、cGMP、活性氧、不对称 二甲基精氨酸)和肾脏(TIMP-2，IGFBP7，中性粒细胞明胶酶相关脂蛋白，肾脏 高危冠心病患者接受心脏手术后的损伤分子功能(二次结局) 导尿术。这项研究的结果将为设计一项更大的(R01)疗效试验提供参考 确定RIPC对肾功能的长期影响，也有助于开发CI-AKI的新疗法。

ABSTRACT Contrast-induced acute kidney injury (CI-AKI) is a common complication of intravenous, iodinated contrast media, that is widely used for cardiac catheterization and percutaneous coronary intervention (PCI) in patients with coronary artery disease (CAD). In the United States, CAD remains the number one cause of death in both men and women, despite improvement in the care of patients over the last decade. Although PCI restores blood flow to the heart, the contrast media used for the procedure can cause CI-AKI, possibly mediated by contrast–induced vasoconstriction of renal blood vessels and free radical–mediated direct renal tubular toxicity. The incidence of CI-AKI is estimated to range between 10 and 40% in patients undergoing cardiac catheterization with higher rates in patients with acute myocardial infarction. In the United States, approximately 1.4 million cardiac catheterization procedures are performed each year, and this estimate is expected to increase exponentially in the next few decades. With increasing use of contrast media, the prevalence of CI-AKI is also expected to rise. CI-AKI predicts elevated risk of heart attack, longer in-hospital stay, more complicated hospitalization course, and higher in-hospital mortality. Unfortunately, there is no effective prophylactic regimen to prevent CI-AKI. Remote ischemic pre-conditioning (RIPC), elicited by application of one or more, brief episodes of ischemia and reperfusion of a limb, is a promising therapy for preventing or attenuating CI-AKI. Given that renal ischemic injury and tubular toxicity are the most common pathophysiological concepts of CI- AKI, it stands to reason that RIPC may prevent CI-AKI via nitrite-induced vasodilation and damage associated molecular protein -mediated renal cell protection. Our preliminary data suggest that RIPC provides renal protection, and indicates a connection between RIPC-induced changes in protective molecules (nitrite, cyclic guanosine monophosphate (cGMP), tissue inhibitor of metalloproteinases 2 (TIMP-2) and insulin-like growth factor–binding protein 7 (IGFBP7) and organ protection. However, the effect of RIPC on CI-AKI in patients with CAD undergoing cardiac catheterization is not well-established, and the underlying mechanism of such effect remains unclear. Therefore, this study is intended to fill a critical void in our understanding of mechanism of renal protection by this emerging therapy, RIPC. We propose a randomized controlled trial (RCT) to determine the effect of RIPC on CI-AKI (primary outcome) and the mediating biomarkers of vascular (nitrite, cGMP, reactive oxygen species, asymmetric dimethylarginine) and renal (TIMP-2, IGFBP7, neutrophil gelatinase–associated lipocalin, kidney injury molecule-1) function (secondary outcomes) in high risk patients with CAD undergoing cardiac catheterization. The findings from this study will inform the design of a larger (R01), efficacy trial to determine the long-term effect of RIPC on kidney function, and also help develop new therapy for CI-AKI.