Elucidating the temporal mechanism of vancomycin kidney toxicity as a means to prevent injury

项目摘要：有一个基本的需要了解Vancomy机制的暂时性- 急性肾损伤(VAN AKI)是因为机械知识到目前为止还没有带来更安全的护理。然而， 这样做需要一系列的活组织检查，在传统的啮齿动物实验中被认为是不可能的。 人类体内的卡路里。我们的插管、镇静和麻痹的猪模型提供了生理学和情景 与人类危重疾病相似，并进一步允许连续活组织检查和中等容量的静脉切割术。定义 煽动机制将为AKI预防研究铺平道路，这些研究将准确地针对：a)避免 细胞聚集，例如通过细胞摄取近端小管细胞对万古霉素和许多 其他肾毒素，例如，megalin介导的摄取或B)将尿毒症可能性降至最低的肾小管情况。 调节蛋白复合体的形成，例如渗透梯度管理。这项研究计划的长期目标是 是改善极其必要的抗生素治疗的肾脏安全性。万古霉素(VAN)是一个前- Emplar研究药物，因为它是医院里开得最多的抗生素，会导致肾脏损伤 导致过高的发病率和死亡率。本申请的目标是：1)定义 VAN AKI的暂时性，以便以后可以重点关注预防策略和2)确定代谢途径- 凡·阿基之前的血液中的象形签名。该提案的中心假设是：1) 先前定义的van AKI机制的暂时性是至关重要的，第一个事件启动了 导致毒性的连锁反应。确定这一引爆点将使预防策略能够准确地 有针对性的，以及2)表征血液代谢组将识别SU-SU之前的病原体特征- 并将比现状监测方法有很大的改进，例如 血清肌酐或尿液生物标志物易受稀释变化的影响。先前研究的严谨性 结果表明：1)VAN可引起肾组织病理损害和肾小球滤过率的改变。2) 我们在三头猪身上的非常小的试点数据展示了识别代谢组特征的希望，这些特征之前 放弃AKI。在这项建议中，我们的目的是：1)确定万古霉素AKI的激发机制和时效性 并对猪肾小球功能的相应变化进行分类和其他金标准和2) 描述发生AKI和不发生AKI的猪的血液代谢组。该项目具有创新性。 由于之前没有任何方法能够回答机械性的时间性，并且识别血液代谢- 基因组签名可能会改善及时检测肾损伤的现状。早期In-In的识别- 陪审团特别具有翻译性，因为它将从生理和情景模拟的模型中确定- 与人类的危重疾病状况相似。这些贡献将是重要的，因为凡肾损伤 与当前的方法是相同的，所提出的方法与理解其他药物相关 (例如，多粘菌素b和顺铂)导致AKI。这项提案的结果将导致直接的临床试验。

Project Abstract: There is a fundamental need to understand the temporality of the mechanism for Vancomy- cin Acute Kidney Injury (VAN AKI) because mechanistic knowledge to date has not led to safer care. However, doing so requires serial biopsy and has been deemed impossible in traditional rodent experiments and unethi- cal in humans. Our swine model of intubated, sedated, and paralyzed pigs offers physiologic and situational similarity to human critical illness and further allows serial biopsy and moderate volume phlebotomy. Defining the inciting mechanism will pave the way for AKI prevention studies that will precisely target: A) avoidance of cellular accumulation such as through cellular uptake at the proximal tubule cell for vancomycin and many other nephrotoxins, e.g., megalin mediated uptake or B) tubular conditions that minimize the likelihood of uro- modulin complex formation, e.g., osmotic gradient management. The long-term goal of this research program is to improve the kidney safety profile for critically necessary antibiotic therapies. Vancomycin (VAN) is an ex- emplar study drug, as it is the most prescribed antibiotic in the hospital setting and causes kidney damage that leads to excess morbidity and mortality. The objectives of this application are to: 1) define the mechanistic temporality of VAN AKI so that prevention strategies can be focused later and 2) identify the metabolomic path- ognomonic signature in blood that precedes VAN AKI. The central hypotheses in this proposal are that: 1) temporality of the previously defined VAN AKI mechanisms is critically important, with the first event initiating a chain reaction leading to toxicity. Identifying this ignition point will allow prevention strategies to be precisely targeted, and 2) characterizing the blood metabolome will identify pathognomonic signatures that precede sus- tained injury and will represent substantial improvements over the status quo monitoring approaches such as serum creatinine or urinary biomarkers that are subject to variability from dilution. The rigor of prior research demonstrates that: 1) VAN causes histopathologic kidney damage and changes to glomerular filtration rate. 2) Our very small pilot data with three swine demonstrate promise for identifying metabolomic signatures that pre- cede AKI. In this proposal, we AIM to 1) Determine the inciting mechanism and temporality of vancomycin AKI in swine and classify the corresponding the changes in glomerular function and other gold standards and 2) Characterize the blood metabolome of swine that develop and do not develop AKI. This project is innovative as no previous approaches have been able to answer mechanistic temporality, and identifying blood metabo- lomic signatures is likely to advance the status quo for timely kidney injury detection. Identification of early in- jury is especially translational since it will be identified from a model that is physiologically and situationally sim- ilar to the human condition of critical illness. These contributions will be significant because VAN kidney injury is common with current approaches, and proposed methodologies are relevant to understanding other drugs (e.g., polymyxin b and cisplatin) that cause AKI. Results from this proposal will lead to directed clinical trials.