Vancomycin has been associated with acute kidney injury (AKI).A cute kidney injury (AKI) is a major contributor to patient morbidity and mortality in the hospital setting (1, 2). While the etiology of AKI is multifactorial, many cases among hospital patients are related to medication exposure (2). Not surprisingly, the risk of drug-induced AKI is highest among critically ill, hospitalized patients (3), who carry multiple risk factors for the development and progression of AKI. Vancomycin, the antibiotic most frequently administered in the hospital setting (4), has been implicated as a cause of AKI in a number of clinical (5-7) and animal (8-10) studies. Among the clinical studies, the incidence of vancomycin-induced AKI has been associated with higher doses of vancomycin (11, 12), increasing numbers of vancomycin doses (12), and elevated trough concentrations (7, 13).While a number of clinical studies have shown that more intensive vancomycin dosing regimens are associated with an increased risk of AKI, these studies could only suggest an association with kidney injury. As these studies were largely observational in nature, it is difficult to discern if the association was reflective of a true effect or was biased due to confounders. For example, patient confounder factors, such as severity of illness, residence in an intensive care unit, and concurrent receipt of nephrotoxins, may influence the vancomycin exposure-response profile that best predicts clinical AKI.Animal systems are ideally suited to define exposure-response relationships, as they provide flexibility to titrate dosing groups and minimize the influence of external covariates on the observed results. To date, animal models of AKI have confirmed that vancomycin is a nephrotoxin. Dose-ranging studies have revealed that an increase in the vancomycin dose and an increase in the duration of treatment in rats are associated with increases in histopathological damage and elevations in novel urinary biomarkers of AKI (8-10). However, a prospectively derived ex-
Vancomycin has been associated with acute kidney injury in preclinical and clinical settings; however, the precise exposure profiles associated with vancomycin-induced acute kidney injury have not been defined. We sought to determine pharmacokinetic/pharmacodynamics indices associated with the development of acute kidney injury using sensitive urinary biomarkers. Male Sprague-Dawley rats received clinical-grade vancomycin or normal saline as an intraperitoneal injection. Total daily doses between 0 and 400 mg/kg of body weight were administered as a single dose or 2 divided doses over a 24-h period. At least five rats were utilized for each dosing protocol. A maximum of 8 plasma samples per rat were obtained, and urine was collected over the 24-h period. Kidney injury molecule-1 (KIM-1), clusterin, osteopontin, cystatin C, and neutrophil gelatinase-associated lipocalin levels were determined using Milliplex multianalyte profiling rat kidney panels. Vancomycin plasma concentrations were determined via a validated high-performance liquid chromatography methodology. Pharmacokinetic analyses were conducted using the Pmetrics package for R. Bayesian maximal concentrations were generated and utilized to calculate the 24-h area under the concentration-time curve (AUC), the maximum concentration (), and the minimum concentration. Spearman's rank correlation coefficient ( ) was used to assess the correlations between exposure parameters, biomarkers, and histopathological damage. Forty-seven rats contributed pharmacokinetic and toxicodynamic data. KIM-1 was the only urinary biomarker that correlated with both composite histopathological damage ( = 0.348, = 0.017) and proximal tubule damage ( = 0.342, = 0.019). The vancomycin AUC and were most predictive of increases in KIM-1 levels ( = 0.438 and = 0.002 for AUC and = 0.451 and = 0.002 for). Novel urinary biomarkers demonstrate that kidney injury can occur within 24 h of vancomycin exposure as a function of either AUC or .
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.