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Title: Translational Assessment of Drug-Induced Proximal Tubule Injury Using a Kidney Microphysiological System.

Authors: Maass, Christian; Sorensen, Nathan B; Himmelfarb, Jonathan; Kelly, Edward J; Stokes, Cynthia L; Cirit, Murat

Published In CPT Pharmacometrics Syst Pharmacol, (2019 May)

Abstract: Drug-induced kidney injury, a major cause of acute kidney injury, results in progressive kidney disease and is linked to increased mortality in hospitalized patients. Primary injury sites of drug-induced kidney injury are proximal tubules. Clinically, kidney injury molecule-1, an established tubule-specific biomarker, is monitored to assess the presence and progression of injury. The ability to accurately predict drug-related nephrotoxicity preclinically would reduce patient burden and drug attrition rates, yet state-of-the-art in vitro and animal models fail to do so. In this study, we demonstrate the use of kidney injury molecule-1 measurement in the kidney microphysiological system as a preclinical model for drug toxicity assessment. To show clinical relevance, we use quantitative systems pharmacology computational models for in vitro-in vivo translation of the experimental results and to identify favorable dosing regimens for one of the tested drugs.

PubMed ID: 30869201 Exiting the NIEHS site

MeSH Terms: Biomarkers/metabolism; Cell Line; Cisplatin/adverse effects*; Cisplatin/pharmacokinetics; Gentamicins/adverse effects*; Hepatitis A Virus Cellular Receptor 1/metabolism*; Humans; Kidney Tubular Necrosis, Acute/chemically induced*; Kidney Tubular Necrosis, Acute/metabolism; Kidney Tubules, Proximal/cytology; Kidney Tubules, Proximal/drug effects; Kidney Tubules, Proximal/metabolism; Models, Theoretical; Rifampin/adverse effects*; Rifampin/pharmacokinetics; Translational Research, Biomedical

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