1335. A Translational Nephrotoxicity Model to Probe Acute Kidney Injury with Vancomycin and Piperacillin–Tazobactam

Abstract

BackgroundVancomycin and piperacillin–tazobactam (VAN+TZP) are two of the most commonly utilized antibiotics in the hospital setting and are reported in clinical studies to increase acute kidney injury (AKI). However, no clinical study has demonstrated that synergistic AKI occurs, only that serum creatinine increases with VAN+TZP. Previous preclinical work demonstrated that novel urinary biomarkers and histopathologic scores were not increased in the VAN+TZP group compared with VAN alone. The purpose of this study was to assess changes in urinary output and plasma creatinine between VAN, TZP, and VAN+TZP treatments.MethodsMale Sprague–Dawley rats (n = 32) received either saline, VAN 150 mg/kg/day intravenously, TZP 1,400 mg/kg/day intraperitoneally, or VAN+TZP for 3 days. Animals were placed in metabolic cages pre-study and on drug dosing days 1–3. Urinary output, plasma creatinine, urinary biomarkers were compared daily and kidney histopathology was compared at the end of therapy between the groups. Mixed-effects, repeated-measures models were employed to assess differences between the groups.ResultsIn the VAN-treated rats, urinary output was increased on days 1, 2 and 3 compared with baseline and saline (P < 0.01 for all), whereas it increased later for VAN+TZP (i.e., day 2 and 3 compared with saline, P < 0.001). No changes in urinary output were observed with saline and TZP alone. Plasma creatinine rose for VAN on days 1, 2, and 3 from baseline and VAN+TZP on day 3 (P < 0.02 for all), but no treatment group was different from saline. In the VAN-treated rats, urinary KIM-1 and clusterin were increased on days 1, 2, and 3 compared with controls (P < 0.001). Elevations were seen only after 3 days of treatment with VAN+TZP (P < 0.001 KIM-1, P < 0.05 clusterin). No changes in urinary biomarkers output were observed with saline and TZP alone. Histopathology was only elevated in the VAN group compared with saline (P < 0.002). No histopathology changes were noted with VAN+TZP.ConclusionAll groups with VAN demonstrated kidney injury; however, VAN+TZP did not cause more kidney injury than VAN alone in a rat model of VIKI when using plasma creatinine, urinary output, or urinary biomarkers as outcomes. Histopathology data suggest that adding TZP did not worsen VAN-induced AKI and may even be protective.DisclosuresKevin J. Downes, MD, Merck: Grant/Research Support, Research Grant; Pfizer: Grant/Research Support.