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

远程缺血预处理对造影剂诱发的肾脏疾病的生化和肾脏保护作用

• 批准号: 9456061
• 负责人: Oladipupo Olafiranye
• 金额: $ 19.46万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9456061
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Acute myocardial infarction; Ambulances; Attenuated; Biochemical; Biological Markers; Blood Pressure; Blood Vessels; Blood flow; Cardiac Catheterization Procedures; Cardiac Surgery procedures; Cause of Death; Cessation of life; Clinical; Complication; Contrast Media; Coronary Arteriosclerosis; Cyclic GMP; Cytoprotection; Data; Diagnostic; Double-Blind Method; Free Radicals; Generations; Guanosine Monophosphate; Healthcare; Heart; Heart failure; Hospital Mortality; Hospitalization; Incidence; Injury; Intervention; Intravenous; Ischemia; Ischemic Preconditioning; Kidney; Kidney Diseases; LCN2 gene; Length of Stay; Limb structure; Long-Term Effects; Mediating; Mediator of activation protein; Molecular; Morbidity - disease rate; Myocardial Infarction; N,N-dimethylarginine; Nitric Oxide; Nitrites; Organ; Oxides; Participant; Patient Care; Patient risk; Patients; Periodicity; Plasma; Prevalence; Prevention strategy; Procedures; Process; Proteins; Randomized; Randomized Controlled Trials; Reactive Oxygen Species; Regimen; Renal Tissue; Renal function; Reperfusion Therapy; Research Personnel; Research Project Grants; Resources; Risk; TIMP2 gene; Testing; Time; Tissue Inhibitor of Metalloproteinases; Toxic effect; Tubular formation; United States; Vasodilation; Woman; cost; design; efficacy trial; healthy volunteer; high risk; inhibitor/antagonist; insulin-like growth factor binding protein-related protein 1; kidney cell; kidney vascular structure; men; mortality; novel therapeutics; percutaneous coronary intervention; pressure; prevent; primary outcome; prophylactic; protective effect; rat KIM-1 protein; response; secondary outcome; urinary; vasoconstriction

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.

摘要 造影剂诱导的急性肾损伤（CI-AKI）是静脉内碘化造影剂的常见并发症， 造影剂，广泛用于心导管插入术和经皮冠状动脉介入治疗 (PCI)冠状动脉疾病（CAD）患者。在美国，CAD仍然是第一 尽管在过去十年中，对病人的护理有所改善，但男女死亡的原因仍然存在。 尽管PCI恢复了心脏的血流，但用于该手术的造影剂可能导致CI-AKI， 可能由造影剂诱导的肾血管收缩和自由基介导的 直接肾小管毒性。CI-AKI的发生率估计在10%至40%的患者中 急性心肌梗死患者接受心导管插入术的比率更高。在 在美国，每年进行大约140万次心导管插入术， 预计这一估计数在今后几十年内将呈指数级增长。随着对比度使用的增加 媒体，CI-AKI的患病率预计也会上升。CI-AKI预测心脏病发作的风险增加， 住院时间长，住院过程复杂，住院死亡率高。 不幸的是，没有有效的预防方案来预防CI-AKI。 远程缺血预处理（RIPC），通过应用一个或多个短暂的缺血性脑损伤事件引起。 肢体缺血和再灌注是预防或减轻CI-AKI的有前景的疗法。鉴于 肾缺血性损伤和肾小管毒性是CI最常见的病理生理学概念， 因此，RIPC可以通过亚硝酸盐诱导的血管舒张和损伤来预防CI-AKI。 相关分子蛋白介导的肾细胞保护。我们的初步数据表明，RIPC 提供肾保护，并表明RIPC诱导的保护性变化之间的联系， 分子（亚硝酸盐、环磷酸鸟苷（cGMP）、金属蛋白酶组织抑制剂2 （TIMP-2）和胰岛素样生长因子结合蛋白7（IGFBP 7）和器官保护。但 RIPC对接受心导管插入术的CAD患者的CI-AKI的影响尚未明确， 其作用机制尚不清楚。因此，本研究旨在填补 在我们理解这种新兴疗法（RIPC）的肾脏保护机制方面存在严重空白。我们 提出一项随机对照试验（RCT），以确定RIPC对CI-AKI的影响（主要结局） 以及血管的介导生物标志物（亚硝酸盐、cGMP、活性氧、不对称性 二甲基精氨酸）和肾（TIMP-2，IGFBP 7，中性粒细胞明胶酶相关脂质运载蛋白，肾 接受心脏手术的高危CAD患者的损伤分子-1）功能（次要结局） 漂浮导管本研究的结果将为更大规模（R 01）的疗效试验的设计提供信息， 确定RIPC对肾功能的长期影响，并帮助开发CI-AKI的新疗法。