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/摘要 在美国，每年有50万患者接受心脏手术，急性肾损伤（AKI） 使25%的患者的恢复复杂化。AKI与随后的术后心律失常、伤口 感染和败血症，并独立预测30天死亡率增加5倍。尽管取得了进步 在外科技术和围手术期患者管理中，心脏手术相关AKI（CSA-AKI）仍然 这是一个主要的问题，而且没有治疗方法可以改善临床结果。虽然有很多原因 以前鉴定和验证AKI新治疗靶点的努力一直不成功，这是一个关键因素， 一个特点是，发现工作主要不是由人类数据驱动的。利用BioVU（范德比尔特的大型- 规模的DNA生物库），我们进行了表型全关联研究（PheWAS）的基础上ICD计费代码 和基因型数据，并确定了新的基因型-表型 编码蛋白质靶点的基因中的单核苷酸多态性之间的关联 孟鲁司特（CYSTLR1）和AKI表型。孟鲁司特是一种抗炎白三烯受体 AKI是FDA批准用于治疗哮喘和过敏性鼻炎的AKI拮抗剂，并且炎症是AKI的机制。 在另外的初步研究中，孟鲁司特在临床前模型中减少肾损伤， 在心脏手术期间，白三烯显著增加，在发生AKI的患者中更是如此， 与未服用孟鲁司特的患者相比，服用孟鲁司特的患者随着时间的推移AKI降低了38%。 为了确定孟鲁司特是否可以重新用于预防CSA-AKI和潜在的其他形式的AKI， 随后的举措，我们将首先进行第二阶段试验，以衡量孟鲁司特对CSA-AKI的影响， 评估任何安全事件。为了正确设计和执行这项II期试验，我们组建了一个多学科的 由具有相关专业知识和经验的医生、科学家和工作人员组成的团队，以实现四个具体目标： (1)通过使用VUMC模拟研究队列，确定研究队列可用性和基线特征 合成衍生物;（2）确定最佳孟鲁司特给药方案并完善试验的机制研究 通过测量发生和未发生AKI的患者尿液中的LTC4、LTD4和LTE4白三烯亚型 （3）优化研究设计，以最有效地招募患者并检验假设;以及（4） 完成所有研究启动任务。该项目的成功完成将使我们能够开始临床 立即审判证明安全、负担得起的仿制药可用于预防CSA-AKI是一个主要优先事项。 此外，证明已发布和公开可用的计算PheWAS算法是一种 药物再利用的有效工具将导致额外的医疗。