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

Int J Antimicrob Agents. 2018 Feb;51(2):239-243. doi: 10.1016/j.ijantimicag.2017.08.012. Epub 2017 Aug 10.


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. <4 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.

Keywords: Biological markers; Nephrotoxicity; Pharmacokinetics; Pharmacology; Vancomycin.

Publication types

  • Review
  • Systematic Review

MeSH terms

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


  • Anti-Bacterial Agents
  • HAVCR1 protein, human
  • Hepatitis A Virus Cellular Receptor 1
  • Vancomycin