Repurposing Montelukast for Cardiac Surgery-Associated Acute Kidney Injury

项目摘要/摘要 在美国，每年有50万患者接受心脏手术和急性肾损伤(AKI) 在25%的患者中使康复变得复杂。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天内死亡人数增加5倍。尽管取得了进步 在外科技术和围手术期患者管理方面，心脏手术相关AKI(CSA-AKI)仍然存在 这是一个主要的问题，而且没有任何治疗方法被证明可以改善临床结果。虽然有很多原因 之前确定和验证AKI新治疗靶点的努力都没有成功，这是一个关键 特点是，发现工作主要不是由人类数据驱动的。利用BioVU(Vanderbilt的大型- Scale DNA Biobbank)，我们基于ICD计费代码进行了一项表现组范围关联研究(Phewas 在一个约36,000名患者的疾病不可知队列中的基因和基因数据，并确定了新的基因-表型 编码蛋白靶标基因的单核苷酸多态之间的关联 孟鲁司特(CystLR1)和AKI表型。孟鲁司特是一种抗炎白三烯受体 FDA批准用于治疗哮喘和过敏性鼻炎的拮抗剂，炎症是AKI的一个机制。 在其他的初步研究中，孟鲁司特可减少临床前模型中的肾损伤，尿药浓度 白三烯在心脏手术期间显著增加，在发生AKI的患者和患者中更是如此 服用孟鲁司特的患者与不服用孟鲁司特的患者相比，随着时间的推移，AKI减少了38%。 确定孟鲁司特是否可以改变用途以预防CsA-AKI和潜在的其他形式的AKI 随后，我们将首先进行第二阶段试验，以衡量孟鲁司特对CsA-AKI和 评估任何安全事件。为了恰当地设计和执行这项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内科医生、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的模拟研究队列来确定研究队列可用性和基线特征 (2)确定孟鲁司特的最佳给药方案，完善试验的机理研究 检测AKI患者尿液中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；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 立即开庭审理。证明一种安全、负担得起的仿制药可以用于预防CsA-AKI是一个主要的优先事项。 此外，还证明了公开发布的计算Phewas算法是一种 有效的药物再利用工具将带来额外的医疗治疗。

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.