Dose, duration, and animal sex predict vancomycin-associated acute kidney injury in preclinical studies

O’Donnell, J. N. and Rhodes, N. J. and Miglis, C. M. and Catovic, L. and Liu, J. and Cluff, C. and Pais, G. and Avedissian, S. and Joshi, M. D. and Griffin, B. and Prozialeck, W. and Gulati, A. and Lodise, T. P. and Scheetz, M. H.

Int J Antimicrob Agents (2018) 51: 239–243

DOI: 10.1016/j.ijantimicag.2017.08.012

Abstract

BACKGROUND: Although 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. METHODS: A 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. RESULTS: A 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. \textless4 days) duration of vancomycin therapy (P=0.02). CONCLUSIONS: The 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.

Citation

O’Donnell, J. N., Rhodes, N. J., Miglis, C. M., Catovic, L., Liu, J., Cluff, C., Pais, G., Avedissian, S., Joshi, M. D., Griffin, B., Prozialeck, W., Gulati, A., Lodise, T. P., & Scheetz, M. H. (2018). Dose, duration, and animal sex predict vancomycin-associated acute kidney injury in preclinical studies. Int J Antimicrob Agents, 51(2), 239–243. https://doi.org/10.1016/j.ijantimicag.2017.08.012 Animals, Male, Rats, Female, Humans, Dose-Response Relationship, Drug, Nephrotoxicity, Pharmacokinetics, Anti-Bacterial Agents/*toxicity, Pharmacology, Acute Kidney Injury/*chemically induced, Biological markers, Hepatitis A Virus Cellular Receptor 1/*metabolism, Vancomycin, Vancomycin/*toxicity

Keywords

• Animals
• Male
• Rats
• Female
• Humans
• Dose-Response Relationship
• Drug
• Nephrotoxicity
• Pharmacokinetics
• Anti-Bacterial Agents/*toxicity
• Pharmacology
• Acute Kidney Injury/*chemically induced
• Biological markers
• Hepatitis A Virus Cellular Receptor 1/*metabolism
• Vancomycin
• Vancomycin/*toxicity