Glomerular function and urinary biomarker changes between vancomycin and vancomycin plus piperacillin-tazobactam in a translational rat model

Abstract

AbstractClinical studies have reported additive nephrotoxicity associated with the combination of vancomycin (VAN) and piperacillin-tazobactam (TZP). This study assessed differences in glomerular filtration rate (GFR) and urinary biomarkers between rats receiving VAN and those receiving VAN+TZP. Male Sprague-Dawley rats (n=26) were randomized to receive 96 hours of intravenous VAN at 150mg/kg/day, intraperitoneal TZP at 1400 mg/kg/day, or VAN+TZP. Kidney function was evaluated using fluorescein-isothiocyanate sinistrin and a transdermal sensor to estimate real-time glomerular filtration rate (GFR). Kidney injury was evaluated via urinary biomarkers including kidney injury molecule-1 (KIM-1), clusterin, and osteopontin. Compared to a saline control, only rats in the VAN group showed significant declines in GFR by day 4 (−0.39 mL/min/100 g body weight, 95% CI: -0.68 to -0.10, p=0.008). When the VAN+TZP and VAN alone treatment groups were compared, significantly higher urinary KIM-1 was observed in the VAN alone group on day 1 (18.4 ng, 95% CI: 1.4 to 35.3, p=0.03), day 2 (27.4 ng, 95% CI: 10.4 to 44.3, p=0.002), day 3 (18.8 ng, 95% CI: 1.9 to 35.8, p=0.03), and day 4 (23.2 ng, 95% CI: 6.3 to 40.2, p=0.007). KIM-1 was the urinary biomarker that most correlated with decreasing GFR on day 3 (Spearman’s rho: -0.45, p = 0.022) and day 4 (Spearman’s rho: - 0.41, p = 0.036). Kidney function decline and increased KIM-1 were observed among rats that received VAN only, but not TZP or VAN+TZP. Addition of TZP to VAN does not worsen kidney function or injury in a validated translational rat model.