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，以了解暂时性的机制，为Vancomy- 急性肾损伤（货车），因为迄今为止的机械知识还没有导致更安全的护理。然而，在这方面， 这样做需要连续的活组织检查，在传统的啮齿动物实验中被认为是不可能的， 人体内的cal我们的插管、镇静和麻痹猪模型提供了生理和情境 类似于人类危重疾病，并且还允许连续活检和中等体积的静脉切开术。限定 煽动机制将为阿基预防研究铺平道路，这些研究将精确地针对：A）避免 细胞蓄积，例如通过万古霉素在近端小管细胞的细胞摄取， 其它肾毒素，例如，巨蛋白介导的摄取或B）使尿- 调节蛋白复合物的形成，例如，渗透梯度管理这项研究计划的长期目标是 是为了改善肾脏的安全性，以便进行非常必要的抗生素治疗。万古霉素（货车）是一种前- emplar研究药物，因为它是医院环境中最常用的抗生素，并导致肾损伤， 导致发病率和死亡率过高。本申请的目的是：1）定义机械的 货车的暂时性，以便以后可以集中预防策略，2）确定代谢组学路径- 血液中的无名氏特征本提案的核心假设是：1） 先前定义的货车机制的暂时性至关重要，第一个事件引发了一个 连锁反应导致中毒。确定这一点火点将使预防战略能够准确地 靶向的，和2）表征血液代谢组将识别在sus之前的特征性特征， 持续性伤害，并将代表对现状监测方法的实质性改进，例如 血清肌酸酐或尿生物标志物受稀释变化的影响。先前研究的严谨性 结果表明：1）货车可引起肾组织病理学损害和肾小球滤过率改变。（二） 我们用三头猪进行的非常小的试验数据表明，有希望确定代谢组学特征， 放弃阿基。在本提案中，我们的目的是1）确定万古霉素阿基的激发机制和时间性 在猪和分类相应的肾小球功能的变化和其他金标准和2） 表征发生和未发生阿基的猪的血液代谢组。这个项目是创新的 由于以前没有任何方法能够回答机械的时间性，并且识别血液代谢物， lomic签名可能会促进及时检测肾损伤的现状。早期识别- 陪审团是特别翻译，因为它将被确定从一个模型，是生理和情境模拟， 与人类的危重病情况相似。这些贡献将是显著的，因为货车肾损伤 与当前的方法是共同的，并且所提出的方法与理解其他药物有关。 (e.g.,多粘菌素B和顺铂）。该提案的结果将导致定向临床试验。

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.