Doses, durations, and gender predict vancomycin-induced kidney injury in pre-clinical studies
2017
O'Donnell, J Nicholas | Rhodes, Nathaniel J. | Miglis, Cristina M. | Catovic, Lejla | Liu, Jiajun | Cluff, Cameron | Pais, Gwen | Avedissian, Sean | Joshi, Medha | Griffin, Brooke | Prozialeck, Walter | Gulati, Anil | Lodise, Thomas P. | Scheetz, Marc H.
BackgroundWhile vancomycin's exposure-dependent efficacy thresholds have been probed, less is known regarding acute kidney injury (AKI) thresholds for vancomycin. Sensitive urinary biomarkers such as Kidney injury molecule 1 (KIM-1) have shown high sensitivity and specificity for vancomycin-associated AKI. We sought to determine if dose-response curves existed with urinary KIM-1. Secondarily, we sought to evaluate the impact of therapy duration and gender status on observed relationships.MethodsA systematic review was conducted via PubMed/MEDLINE. Data were compiled from pre-clinical studies that reported individual subject data for urinary KIM-1 concentrations, vancomycin dose (mg/kg), duration of treatment, and gender status. Sigmoidal Hill-type models were fit to the individual dose-response data.ResultsIn total, 15 studies were identified and six 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) 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 pre-clinical data are needed to more clearly define vancomycin exposures that predict the onset of AKI.
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