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（阿基）是一个独立的死亡风险因素，影响10-15%的住院患者 超过50%的重症监护室患者。阿基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， 脓毒症中携带的阿基可能是可逆的，因为从阿基中恢复的脓毒症患者具有相似的1-和 3-年死亡率与无阿基的患者相同。这些数据与表明阿基的发展 会带来深远的后果，如远程器官功能障碍和感染易感性增加。 这些数据表明，阿基可能是败血症死亡的因果途径， 可以提高脓毒症患者的生存率。然而，没有具体的治疗方法来逆转或预防 脓毒症期间阿基的发展。我们最近证明AMP激活的蛋白激酶 AMPK是一种普遍存在的细胞代谢和能量平衡的主要调节因子，对保护肾脏至关重要 在实验性脓毒症期间免受损伤并提高存活率。我们和其他人已经证明， AMPK的活化保护免于阿基并提高存活率，而抑制则增加肾损伤和死亡。 有趣的是，二甲双胍，推荐用于治疗2型糖尿病的一线药物， 已知AMPK激活剂。基于此，我们已经证明二甲双胍治疗可以降低死亡率- 实验性脓毒症时的症状多项观察性人类研究也支持这一观点。两个最近的Meta- 分析得出结论，二甲双胍暴露与死亡风险降低相关。我们骗- 进行了迄今为止最大的倾向评分匹配回顾性研究，并证明二甲双胍是 与90天时中重度阿基和死亡的几率降低相关， 从阿基中恢复的可能性增加。尽管有这一证据，但仍存在一些知识空白。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，不知道是否有可用的结果， 研究可推广到非糖尿病患者。第三，尽管有60多年的使用记录， 在感染性休克患者中的安全性尚未确定。这项建议旨在进行一项 随机、安慰剂对照、可行性研究，以确定使用口服二甲双胍的安全性和可行性， 以防止脓毒症诱导的阿基的发展，并为未来的全面疗效试验提供信息。我们的- 假设二甲双胍治疗脓毒症安全有效， SIS诱导的阿基生物标志物升高。我们将确定使用二甲双胍治疗成人 脓毒症患者，我们将确定口服二甲双胍的药代动力学特征（目的1）， 实施该治疗（目的2），并估计二甲双胍对以下指标影响的异质性 肾损伤/应激和循环血小板线粒体功能（目的3）。这项研究是关键的第一步 为未来的全面疗效RCT设计提供信息。

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.