Sandilands Euan A, Cameron Sharon, Paterson Frances, Donaldson Sam, Briody Lesley, Crowe Jane, Donnelly Julie, Thompson Adrian, Johnston Neil R, Mackenzie Ivor, Uren Neal, Goddard Jane, Webb David J, Megson Ian L, Bateman Nicholas, Eddleston Michael
National Poisons Information Service (Edinburgh), Royal Infirmary of Edinburgh, Edinburgh, UK.
BMC Clin Pharmacol. 2012 Feb 3;12:3. doi: 10.1186/1472-6904-12-3.
Contrast-induced nephropathy is a common complication of contrast administration in patients with chronic kidney disease and diabetes. Its pathophysiology is not well understood; similarly the role of intravenous or oral acetylcysteine is unclear. Randomized controlled trials to date have been conducted without detailed knowledge of the effect of acetylcysteine on renal function. We are conducting a detailed mechanistic study of acetylcysteine on normal and impaired kidneys, both with and without contrast. This information would guide the choice of dose, route, and appropriate outcome measure for future clinical trials in patients with chronic kidney disease.
METHODS/DESIGN: We designed a 4-part study. We have set up randomised controlled cross-over studies to assess the effect of intravenous (50 mg/kg/hr for 2 hrs before contrast exposure, then 20 mg/kg/hr for 5 hrs) or oral acetylcysteine (1200 mg twice daily for 2 days, starting the day before contrast exposure) on renal function in normal and diseased kidneys, and normal kidneys exposed to contrast. We have also set up a parallel-group randomized controlled trial to assess the effect of intravenous or oral acetylcysteine on patients with chronic kidney disease stage III undergoing elective coronary angiography. The primary outcome is change in renal blood flow; secondary outcomes include change in glomerular filtration rate, tubular function, urinary proteins, and oxidative balance.
Contrast-induced nephropathy represents a significant source of hospital morbidity and mortality. Over the last ten years, acetylcysteine has been administered prior to contrast to reduce the risk of contrast-induced nephropathy. Randomized controlled trials, however, have not reliably demonstrated renoprotection; a recent large randomized controlled trial assessing a dose of oral acetylcysteine selected without mechanistic insight did not reduce the incidence of contrast-induced nephropathy. Our study should reveal the mechanism of effect of acetylcysteine on renal function and identify an appropriate route for future dose response studies and in time randomized controlled trials.
Clinical Trials.gov: NCT00558142; EudraCT: 2006-003509-18.
对比剂肾病是慢性肾脏病和糖尿病患者使用对比剂时常见的并发症。其病理生理学尚未完全明确；同样，静脉或口服乙酰半胱氨酸的作用也不清楚。迄今为止进行的随机对照试验在对乙酰半胱氨酸对肾功能影响缺乏详细了解的情况下开展。我们正在进行一项关于乙酰半胱氨酸对正常和受损肾脏（无论有无对比剂）作用机制的详细研究。这些信息将为未来慢性肾脏病患者临床试验的剂量选择、给药途径及合适的结局指标提供指导。
方法/设计：我们设计了一项分为4部分的研究。我们开展了随机对照交叉研究，以评估静脉注射（在对比剂暴露前2小时以50毫克/千克/小时的速度注射，然后在接下来的5小时以20毫克/千克/小时的速度注射）或口服乙酰半胱氨酸（在对比剂暴露前一天开始，每天两次，每次1200毫克，共2天）对正常和患病肾脏以及暴露于对比剂的正常肾脏肾功能的影响。我们还开展了一项平行组随机对照试验，以评估静脉或口服乙酰半胱氨酸对接受择期冠状动脉造影的慢性肾脏病Ⅲ期患者的影响。主要结局是肾血流量的变化；次要结局包括肾小球滤过率、肾小管功能、尿蛋白及氧化平衡的变化。
对比剂肾病是医院发病和死亡的一个重要原因。在过去十年中，在使用对比剂前给予乙酰半胱氨酸以降低对比剂肾病的风险。然而，随机对照试验并未可靠地证明其肾脏保护作用；最近一项在缺乏机制性认识的情况下选择口服乙酰半胱氨酸剂量进行的大型随机对照试验并未降低对比剂肾病的发生率。我们的研究应揭示乙酰半胱氨酸对肾功能的作用机制，并为未来的剂量反应研究及适时的随机对照试验确定合适的给药途径。
ClinicalTrials.gov：NCT00558142；EudraCT：2006 - 003509 - 18。
