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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要美国每年有 500,000 名患者接受心脏手术和急性肾损伤 (AKI) 使 25% 的患者康复变得复杂。 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 天时死亡人数会增加 5 倍。尽管取得了进步在手术技术和围手术期患者管理中，心脏手术相关 AKI (CSA-AKI) 仍然存在这是一个主要问题，并且没有任何治疗方法可以改善临床结果。虽然原因有很多之前确定和验证 AKI 新治疗靶点的努力并不成功，一个关键特点是发现工作主要不是由人类数据驱动的。利用 BioVU（范德比尔特大学的大型规模 DNA 生物库），我们根据 ICD 计费代码进行了全表型关联研究 (PheWAS) 约 36,000 名患者的疾病不可知队列中的基因型数据，并确定了新的基因型-表型编码目标蛋白的基因中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 FDA 批准其拮抗剂用于治疗哮喘和过敏性鼻炎，而炎症是 AKI 的机制之一。在其他初步研究中，孟鲁司特可减少临床前模型中的肾损伤，尿浓度白三烯在心脏手术期间显着增加，在发生 AKI 的患者和患者中更是如此与不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%。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 后续举措，我们将首先进行 II 期试验，以衡量孟鲁司特对 CSA-AKI 的影响，以及评估任何安全事件。为了正确设计和执行这一二期试验，我们组建了一个多学科团队由具有相关专业知识和经验的医师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 模拟研究队列来确定研究队列的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 白三烯亚型在之前的研究中； (3) 优化研究设计，以最有效地招募患者并检验假设；和（4）完成所有学习启动任务。该项目的成功完成将使我们能够开始临床立即审判。证明一种安全、负担得起的仿制药可用于预防 CSA-AKI 是当务之急。此外，证明已发布且公开可用的计算 PheWAS 算法是一种药物再利用的有效工具将带来额外的治疗。