Evaluation of Vancomycin Exposures Associated with Elevations in Novel Urinary Biomarkers of Acute Kidney Injury in Vancomycin-Treated Rats

Abstract

ABSTRACTVancomycin has been associated with acute kidney injury (AKI). However, the pharmacokinetic/toxicodynamic relationship for AKI is not well defined. Allometrically scaled vancomycin exposures were used to assess the relationship between vancomycin exposure and AKI. Male Sprague-Dawley rats received clinical-grade vancomycin in normal saline (NS) as intraperitoneal (i.p.) injections for 24- to 72-h durations with doses ranging 0 to 200 mg/kg of body weight divided once or twice daily. Urine was collected over the protocol's final 24 h. Renal histopathology was qualitatively scored. Urinary biomarkers (e.g., cystatin C, clusterin, kidney injury molecule 1 [KIM-1], osteopontin, lipocalin 2/neutrophil gelatinase-associated lipocalin 2) were assayed using a Luminex xMAP system. Plasma vancomycin concentrations were assayed by high-performance liquid chromatography with UV detection. A three-compartment vancomycin pharmacokinetic model was fit to the data with the Pmetrics package for R. The exposure-response in the first 24 h was evaluated using Spearman's nonparametric correlation coefficient (rs) values for the area under the concentration-time curve during the first 24 h (AUC0–24), the maximum concentration in plasma during the first 24 h (Cmax0–24), and the lowest (minimum) concentration in plasma after the dose closest to 24 h (Cmin0–24). A total of 52 rats received vancomycin (n= 42) or NS (n= 10). The strongest exposure-response correlations were observed between AUC0–24and Cmax0–24and urinary AKI biomarkers. Exposure-response correlations (rsvalues) for AUC0–24, Cmax0–24, and Cmin0–24were 0.37, 0.39, and 0.22, respectively, for clusterin; 0.42, 0.45, and 0.26, respectively, for KIM-1; and 0.52, 0.55, and 0.42, respectively, for osteopontin. However, no differences in histopathological scores were observed. Optimal sampling times after administration of the i.p. dose were 0.25, 0.75, 2.75, and 8 h for the once-daily dosing schemes and 0.25, 1.25, 14.5, and 17.25 h for the twice-daily dosing schemes. Our observations suggest that AUC0–24or Cmax0–24correlates with increases in urinary AKI biomarkers.