Dose,duration, and animal sex predict vancomycin-associated acute kidney injury in preclinical studies |
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Authors: | J Nicholas ODonnell Nathaniel J Rhodes Cristina M Miglis Lejla Catovic Jiajun Liu Cameron Cluff Gwendolyn Pais Sean Avedissian Medha D Joshi Brooke Griffin Walter Prozialeck Anil Gulati Thomas P Lodise Marc H Scheetz |
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Institution: | J. Nicholas O'Donnell,Nathaniel J. Rhodes,Cristina M. Miglis,Lejla Catovic,Jiajun Liu,Cameron Cluff,Gwendolyn Pais,Sean Avedissian,Medha D. Joshi,Brooke Griffin,Walter Prozialeck,Anil Gulati,Thomas P. Lodise,Marc H. Scheetz |
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Abstract: | BackgroundAlthough the exposure-dependent efficacy thresholds of vancomycin have been probed, less is known about acute kidney injury (AKI) thresholds for this drug. Sensitive urinary biomarkers, such as kidney injury molecule 1 (KIM-1), have shown high sensitivity and specificity for vancomycin-associated AKI. The aims of the study were to determine if there were dose–response curves with urinary KIM-1, and to evaluate the impact of therapy duration and sex on observed relationships.MethodsA systematic review was conducted via PubMed/MEDLINE. Data were compiled from preclinical studies that reported individual subject data for urinary KIM-1 concentrations, vancomycin dose (mg/kg), duration of treatment, and sex. Sigmoidal Hill-type models were fit to the individual dose-response data.ResultsA total of 15 studies were identified, 6 of which reported vancomycin dose and KIM-1 data. Of these, three included individual animal-level data suitable for analysis. For all pooled rats, increasing total daily vancomycin doses displayed a dose-response curve with urinary KIM-1 concentrations (50% maximal toxic response=130.4?mg/kg/day). Dose-response curves were shifted left for females vs. males (P?=?0.05) and for long (i.e. ≥7 days) vs. short (i.e. <4 days) duration of vancomycin therapy (P=0.02).ConclusionsThe collective findings demonstrate a clear dose–response relationship between vancomycin dose and AKI. As these analyses focused exclusively on dose-response relationships, additional preclinical data are needed to more clearly define vancomycin exposures that predict the onset of AKI. |
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Keywords: | Vancomycin Biological markers Nephrotoxicity Pharmacokinetics Pharmacology |
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