A Randomized Clinical Trial of the Safety and FeasibiLity of Metformin as a Treatment for sepsis induced AKI (LiMiT AKI)

摘要 急性肾损伤(AKI)是影响10%-15%住院患者的独立死亡危险因素 超过50%的患者住进了重症监护室。AKI最常见的原因是败血症， 每年影响全球4800万人。重要的是，死亡风险增加了6-8倍 AKI携带者败血症可能是可逆的，因为从AKI康复的脓毒症患者有类似的1-和 3年死亡率与未发生AKI者相同。这些数据与证据表明，AKI的发展 带来深远的后果，如远程器官功能障碍和对感染的易感性增加。 这些数据表明，AKI可能处于导致脓毒症死亡的原因途径中，而逆转AKI的努力 可提高脓毒症患者的存活率。然而，没有特定的治疗方法可以逆转或预防 脓毒症时AKI的发展。我们最近证明了AMP激活的蛋白激酶 AMPK是一种无处不在的细胞代谢和能量平衡的主调节器，对保护肾脏至关重要 避免损伤，提高实验性脓毒症期间的存活率。我们和其他人已经证明了药理学 激活AMPK可以预防AKI并提高存活率，而抑制AMPK则会增加肾脏损伤和死亡。 有趣的是，推荐用于治疗2型糖尿病的一线药物二甲双胍是一种 已知的AMPK激活剂。在此基础上，我们已经证明了二甲双胍治疗可以降低死亡率。 在实验性脓毒症期间。多项观察性人体研究也支持这一观点。最近的两个Meta- 分析得出的结论是，接触二甲双胍与死亡风险降低有关。我们可以- 引出了迄今为止最大的倾向-分数匹配的回顾研究，并证明二甲双胍是 与中-重度急性肾损伤和90天死亡几率的降低以及- 从AKI中恢复的可能性增加。尽管有这些证据，但在知识方面仍然存在几个差距。首先，它是不- 明确二甲双胍的保护作用是否由混杂因素引起。其次，目前尚不清楚是否有可用的结果 这项研究可以推广到非糖尿病患者。第三，尽管DIA有60多年的使用记录- 对于Btic患者，感染性休克患者的安全性尚未建立。这项提案旨在进行一项 随机、安慰剂对照的可行性研究，以确定口服美多芬的安全性和可行性。 MIN用于预防败血症诱导的AKI的发展，并为未来的全面疗效试验提供信息。我们结束了- ARCHING假说认为，在脓毒症患者的治疗中，二甲双胍是安全有效的。 SIS诱导的AKI生物标志物的升高。我们将确定使用二甲双胍治疗成人的安全性 脓毒症患者，我们将测定口服二甲双胍的药代动力学(目标1)的可行性 实施这一疗法(目标2)，并评估二甲双胍对标记物影响的异质性。 肾脏损伤/应激和循环血小板线粒体功能(目标3)。这项研究是关键的第一步 为设计一种未来的、全面有效的随机对照试验奠定基础。

ABSTRACT Acute kidney injury (AKI) is an independent risk factor for death that affects 10-15% of hospitalized patients and more than 50% of patients admitted to the intensive care unit. The most frequent cause of AKI is sepsis, which affects 48 million people worldwide every year. Importantly, the 6-8-fold increase in the risk of death that AKI carries in sepsis may be reversible because patients with sepsis who recover from AKI have similar 1- and 3-year mortality as those without AKI. These data agree with evidence showing that the development of AKI carries far-reaching consequences like remote organ dysfunction and an increased susceptibility to infection. These data suggest that AKI may be in the causal pathway to death from sepsis and that efforts to reverse AKI may improve the survival in patients with sepsis. However, there are no specific therapies to reverse or prevent the development of AKI during sepsis. We have recently demonstrated that AMP-activated protein kinase (AMPK), a ubiquitous master regulator of cell metabolism and energy balance, is critical to protect the kidney from injury and enhance survival during experimental sepsis. We and others have shown that pharmacologic activation of AMPK protects from AKI and improves survival, while inhibition increases kidney injury and death. Interestingly, metformin, the recommended first-line agent for the treatment of type 2 diabetes mellitus is a known AMPK activator. Based on this, we have demonstrated that treatment with metformin decreases mortal- ity during experimental sepsis. Multiple observational human studies also support this idea. Two recent meta- analyses concluded that exposure to metformin was associated with a decreased risk of mortality. We con- ducted the largest propensity-score matched retrospective study to date and demonstrated that metformin is associated with a decrease in the odds of moderate-severe AKI and death at 90-days, as well as with an in- creased odds of recovery from AKI. Despite this evidence, several gaps in knowledge remain. First, it is un- clear if the protective effect of metformin is due to confounders. Second, it is unknown if the results of available studies are generalizable to non-diabetic patients. Third, despite a track record of over 60 years of use in dia- betic patients, safety has not been established in patients with septic shock. This proposal aims to conduct a randomized, placebo-controlled, feasibility study to establish the safety and feasibility of the use of oral metfor- min to prevent the development of sepsis-induced AKI, and to inform a future full-scale efficacy trial. Our over- arching hypothesis is that, in treatment of patients with sepsis, metformin is safe and effective in reducing sep- sis-induced elevations in AKI biomarkers. We will determine the safety of the use of metformin to treat adult patients with sepsis, and we will determine the pharmacokinetic profile of oral metformin (Aim 1), the feasibility of implementing this therapy (Aim 2), and estimate the heterogeneity of the effect of metformin on markers of kidney injury/stress and on circulating platelet mitochondrial function (Aim 3). This study is the first critical step to inform the design of a future, full-scale efficacy RCT.