Repurposing Montelukast for Cardiac Surgery-Associated Acute Kidney Injury

重新利用孟鲁司特治疗心脏手术相关的急性肾损伤

• 批准号: 10043764
• 负责人: Frederic Tremaine Billings
• 金额: $ 38.91万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10043764
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adult; Affect; Algorithms; Allergic rhinitis; Animal Model; Anti-Inflammatory Agents; Arachidonic Acids; Arrhythmia; Asthma; Binding; Budgets; Cardiac Surgery procedures; Caring; Case Report Form; Cessation of life; Characteristics; Chronic Kidney Failure; Clinical; Clinical Protocols; Clinical Trials; Clinical trial protocol document; Code; Cohort Studies; Communities; Complication; Consent Forms; Contracts; DNA; Data; Deterioration; Development; Diagnosis; Dialysis procedure; Disease; Dose; Electronic Health Record; Eligibility Determination; End stage renal failure; Enrollment; Event; Exclusion Criteria; FDA approved; Functional disorder; Generic Drugs; Genes; Genotype; Goals; Inflammation; Inflammatory; Informed Consent; Infrastructure; Injury to Kidney; Intensive Care Units; Kidney Diseases; Language; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotriene Receptor; Leukotrienes; Measures; Medical; Methods; Monitor; Nephritis; Operative Surgical Procedures; Outcome; Patient Outcomes Assessments; Patient Recruitments; Patient Representative; Patients; Perioperative; Pharmaceutical Preparations; Pharmacology; Phenotype; Physicians; Postoperative Period; Pre-Clinical Model; Prevalence; Prevention; Procedures; Proteins; Publishing; Recovery; Regimen; Renal function; Research Design; Risk; Risk Factors; Safety; Sample Size; Scientist; Secure; Sepsis; Single Nucleotide Polymorphism; Site; Societies; Specimen; Statistical Data Interpretation; System; Techniques; Testing; Time; Treatment Efficacy; United States; Urine; Wound Infection; base; biobank; cohort; design; disease phenotype; experience; human data; improved; montelukast; mortality; multidisciplinary; new therapeutic target; novel; novel therapeutics; patient population; phase II trial; phenome; prevent; primary endpoint; programs; recruit; secondary endpoint; shared database; tool; urinary

PROJECT SUMMARY/ABSTRACT Each year 500,000 patients undergo cardiac surgery in the United States, and acute kidney injury (AKI) complicates recovery in 25% of patients. AKI is associated with subsequent postoperative arrhythmias, wound infections, and sepsis, and independently predicts a 5-fold increase in death at 30 days. Despite advancements in surgical technique and perioperative patient management, cardiac surgery-associated AKI (CSA-AKI) remains a major problem and no therapies have been shown to improve clinical outcomes. While there are many reasons that previous efforts to identify and validate new therapeutic targets for AKI have been unsuccessful, a key feature is that discovery efforts were not primarily driven by human data. Leveraging BioVU (Vanderbilt's large- scale DNA biobank), we performed a Phenome-Wide Association Study (PheWAS) based on ICD billing code and genotype data in a disease-agnostic cohort of ~36,000 patients and identified novel genotype-phenotype associations between single nucleotide polymorphisms in the gene that encodes the protein target of montelukast (CYSTLR1) and AKI phenotypes. Montelukast is an anti-inflammatory leukotriene receptor antagonist that is FDA approved to treat asthma and allergic rhinitis, and inflammation is a mechanism of AKI. In additional preliminary studies montelukast reduces renal injury in preclinical models, urinary concentrations of leukotrienes increase significantly during cardiac surgery and more so in patients who develop AKI, and patients taking montelukast have a 38% reduction in AKI over time compared to patients not taking montelukast. To determine if montelukast can be repurposed to prevent CSA-AKI and potentially other forms of AKI in subsequent initiatives, we will first perform a phase II trial to measure the effect of montelukast on CSA-AKI and assess any safety events. To properly design and execute this phase II trial we assembled a multidisciplinary team of physician scientists and staff with the relevant expertise and experience to accomplish four specific aims: (1) Determine study cohort availability and baseline characteristics by simulating study cohorts using VUMC's Synthetic Derivative; (2) Determine optimal montelukast dosing regimen and refine the trial's mechanistic studies by measuring LTC4, LTD4, and LTE4 leukotriene subtypes in urine of patients who did and did not develop AKI in a previous study; (3) Optimize study design to most efficiently recruit patients and test the hypothesis; and (4) Complete all study startup tasks. The successful completion of this project will allow us to commence the clinical trial immediately. Proving that a safe, affordable, generic drug can be used to prevent CSA-AKI is a major priority. In addition, demonstration that the published and publicly available computational PheWAS algorithm is an effective tool for drug repurposing will lead to additional medical treatments.

项目总结/文摘