Deferoxamine for the Prevention of Acute Kidney Injury

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PROJECT SUMMARY Acute kidney injury (AKI) is a common and often devastating complication of cardiac surgery, critical illness, and other clinical settings. No pharmacologic therapy reliably prevents or treats AKI. Abundant data from both animal models and humans indicates that iron plays a key role in the pathogenesis of AKI, particularly in the setting of cardiac surgery. We propose a phase II, double-blind, randomized controlled trial to test whether administration of the iron chelating agent, deferoxamine (DFO), prevents AKI following cardiac surgery. We will enroll 300 adult patients at high risk of AKI following cardiac surgery at three major academic medical centers in Boston. Patients will be randomly assigned, in a 1:1 fashion (n=150/group), to receive DFO (30 mg/kg) or an equal volume of normal saline. DFO (or normal saline) will be administered as a continuous 24-hour intravenous infusion beginning immediately prior to surgery. In Aim 1 we will test the effects of DFO compared to placebo on the incidence of postoperative AKI (primary endpoint). AKI will be defined by changes in serum creatinine and urine output, according to the KDIGO criteria. As secondary endpoints, we will assess longitudinal changes in urinary tubular injury markers, NGAL and KIM-1. We will also test the effects of DFO on the incidence of the following common and biologically plausible extrarenal postoperative endpoints: myocardial infarction, atrial fibrillation, delirium, prolonged mechanical ventilation, and sepsis. In Aim 2 we will tests the effects of DFO compared to placebo on longitudinal measures of circulating iron and oxidative stress, and the inflammatory phenotype of monocytes. Serum iron parameters will include catalytic iron – a toxic, non-physiologic iron species – as well as transferrin saturation and ferritin. Plasma markers of oxidative stress will include F(2)-isoprostane and myeloperoxidase. We will also assess the effect of DFO versus placebo on monocyte (CD14+) expression of IL-6, TNFα, and other markers of inflammation using flow cytometry. In exploratory analyses, we will use next-generation RNA sequencing (RNA-Seq) to assess the effect of DFO on the transcriptome of monocytes, which will facilitate discovery of novel transcripts influenced by DFO. We will also determine the extent to which the effect of DFO on renal and extrarenal acute organ injury (assessed in Aim 1) varies depending on the preoperative expression of key parameters measured in Aim 2. In aggregate, the studies proposed here will test a novel and promising therapeutic strategy for AKI prevention. These studies have strong potential to improve clinical outcomes in patients at risk for AKI. Further, the translational studies proposed here will yield important scientific insights into the role of iron metabolism in the pathophysiology of AKI.