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.

PROJECT NARRATIVE 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. Sepsis is the most frequent cause of AKI, affecting 48 million people worldwide every year, and accounting for approximately 11 million of annual global deaths. Despite these figures, there are no known therapies to prevent or reverse septic AKI; hence this study aims to establish the safety and feasibility of the implementation of metformin in the treatment of AKI in patients with sepsis.