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

Award Number: R21AI178328
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/26/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	MIDWESTERN UNIVERSITY	555 31ST ST	DOWNERS GROVE	IL	60515	DUPAGE	USA	Allergy and Infectious Diseases Research	000	2	4/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $119,475 )
2024	2024	MIDWESTERN UNIVERSITY	555 31ST ST	DOWNERS GROVE	IL	60515	DUPAGE	USA	Allergy and Infectious Diseases Research	000	2	5/24/2024	NON-COMPETING CONTINUATION	$119,475
														Subtotal = $119,475

Issue Date FY: 2023 ( Subtotal = $237,401 )
2023	2023	MIDWESTERN UNIVERSITY	555 31ST ST	DOWNERS GROVE	IL	60515	DUPAGE	USA	Allergy and Infectious Diseases Research	000	1	6/26/2023	NEW	$237,401
														Subtotal = $237,401

Grand Total All Awards = $356,876

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

Award Number: R21AI178328

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/26/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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