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Quantifying renal injury among the most commonly used clinical antibiotic combinations

Award Number: R21AI149026
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: 01/16/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2022

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Quantifying renal injury among the most commonly used clinical antibiotic combinations - Project Abstract: There is a fundamental need to improve pre-clinical models used to predict Acute Kidney Injury (AKI) in the setting of polypharmacy (such as with nephrotoxic antibiotics). Until a translational model is developed, risks can only be predicted individually and semi-quantitatively for groups. The long term goal is to improve the kidney safety profile for critically necessary antibiotic therapies. Vancomycin (V) and piperacillin- tazobactam (PT) are exemplars for study as they are the most commonly used antibiotics in the hospital setting and have been widely suggested in clinical literature to synergistically cause AKI. Despite the clinical data, bio- logic plausibility has not been established; it is unclear if elevated serum creatinine (SCr) is a real or a false positive finding for AKI. SCr is neither highly sensitive nor specific for AKI, PT shares transporters with creatinine that could affect clearance independent of AKI, and preliminary data from experimental models strongly suggests that PT does not worsen V induced AKI (and may be protective). The overall objective is to leverage rat models to quantify individual contributions of multiple drugs on AKI. The central hypothesis of this research is that SCr from clinical studies misclassifies AKI, and alternate models more appropriately define AKI. Rigor of prior re- search with urinary biomarkers suggests that non-creatinine biomarkers can improve predictions of AKI in the setting of polypharmacy. Thus, we will create a novel framework to assess AKI in a pre-clinical manner that has distinct advantages over the status quo by pursuing the following AIMs: 1. Define glomerular filtration rates (GFR) for V, PT, and V+PT in rats as calculated by A) serum creatinine clearance (GFRCRCL) and B) inulin (GFRinulin). 2. Create a Physiologic-Based Pharmacokinetic (PBPK) model that describes mass transit and clearance of V, PT, and V+PT between blood, kidneys, and urine AND quantify real-time PK/Toxicodynamic (TD) relationships for A) serum creatinine, B) urinary biomarkers, and C) terminal histopathology. 3. Develop a hu- manized-rat, PK/TD model for simultaneous administration of two nephrotoxins. The proposed studies will ac- complish 3 major goals. First, defining actual GFR in V, PT, and V+PT will provide mechanistic insight on the role of SCr in V+PT therapy. Second, the PBPK model further informs mechanism by understanding the indi- vidual components that increase SCr in V+PT. Finally, this project is innovative because there is not currently a humanized animal model that can separate the AKI contribution from each drug in the setting of polypharmacy. This model has potential benefits compared to allometrically scaled animal models (which result in high peak concentrations for animals) or cellular models (which use static and supraphysiological concentrations). This contribution will be significant because A) results from AIM 1 and 2 will clarify the toxicity profile for the two most commonly used antibiotics and B) successful development of our novel humanized model can vertically advance the field’s understanding of individual drug contribution to AKI in the setting of polypharmacy. This proposal directly addresses the NIH mission to create ‘innovative research strategies’ for ‘improving health.’


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: 2024 ( Subtotal = $0 )
2024	2021	MIDWESTERN UNIVERSITY	555 31ST ST	DOWNERS GROVE	IL	60515	DUPAGE	USA	Allergy and Infectious Diseases Research	000	2	11/15/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $150,000 )
2021	2021	MIDWESTERN UNIVERSITY	555 31ST ST	DOWNERS GROVE	IL	60515	DUPAGE	USA	Allergy and Infectious Diseases Research	000	2	12/28/2020	NON-COMPETING CONTINUATION	$150,000
														Subtotal = $150,000

Issue Date FY: 2020 ( Subtotal = $262,500 )
2020	2020	MIDWESTERN UNIVERSITY	555 31ST ST	DOWNERS GROVE	IL	60515	DUPAGE	USA	Allergy and Infectious Diseases Research	000	1	1/16/2020	NEW	$262,500
														Subtotal = $262,500

Grand Total All Awards = $412,500

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Quantifying renal injury among the most commonly used clinical antibiotic combinations

Award Number: R21AI149026

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: 01/16/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2022

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