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

阐明万古霉素肾毒性的时间机制作为预防损伤的手段

• 批准号: 10727172
• 负责人: Marc Howard Scheetz
• 金额: $ 23.74万
• 依托单位: MIDWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-26 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727172
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Aminoglycosides; Animal Experiments; Antibiotic Therapy; Antibiotics; Biological Markers; Biopsy; Blood; Blood specimen; Caring; Cells; Cessation of life; Cisplatin; Classification; Clinical; Clinical Trials; Collection; Complex; Contralateral; Creatinine; Critical Illness; Data; Detection; Early Intervention; Early identification; Encapsulated; Epithelium; Event; Experimental Designs; Family suidae; Future; Glomerular Filtration Rate; Goals; Gold; Guidelines; Histopathology; Hospitals; Human; Injury; Injury to Kidney; Intubation; Kidney; Kidney Diseases; Knowledge; LDL-Receptor Related Protein 2; Mediating; Methodology; Methods; Modeling; Monitor; Morbidity - disease rate; Necrosis; Obstruction; Osmosis; Outcome; Oxidative Stress; Paralysed; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Physiological; Plasma; Polymyxin B; Polymyxins; Prevention strategy; Preventive measure; Process; Public Health; Reaction; Recommendation; Research; Risk; Rodent; Safety; Sedation procedure; Serum; Standardization; Staphylococcus aureus infection; Time; Toxic effect; Translating; Tubular formation; UMOD gene; Vancomycin; Venous blood sampling; alternative treatment; clinical implementation; design; experimental study; glomerular function; improved; injury prevention; innovation; kidney biopsy; metabolome; metabolomics; methicillin resistant Staphylococcus aureus; mortality; nephrotoxicity; porcine model; pre-clinical; prevent; programs; renal damage; standard of care; treatment strategy; tubular necrosis; unethical; uptake; urinary

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.

项目摘要：了解Vancomy-的机制的时效性是一个基本的需要