Department of Pharmacy Practice, Chicago College of Pharmacy, Midwestern University, Downers Grove, IL, USA; Midwestern University Chicago College of Pharmacy Pharmacometrics Center of Excellence, Downers Grove, IL, USA.
Department of Pharmacy Practice, Chicago College of Pharmacy, Midwestern University, Downers Grove, IL, USA; Midwestern University Chicago College of Pharmacy Pharmacometrics Center of Excellence, Downers Grove, IL, USA; Department of Pharmacology, College of Graduate Studies, Midwestern University, Downers Grove, IL, USA.
Int J Antimicrob Agents. 2022 May;59(5):106583. doi: 10.1016/j.ijantimicag.2022.106583. Epub 2022 Apr 2.
Vancomycin (VAN) causes acute kidney injury as defined by serum creatinine (SCr) increase. Glomerular filtration rate (GFR) is the gold standard for defining kidney function, and SCr is often used as a GFR surrogate; however, SCr changes can lag behind acute functional decline. We sought to define the rate and extent of GFR change for VAN in a translational rat model. Male Sprague Dawley rats received VAN 150 mg/kg/day intravenously (n = 6) or saline (n = 5) once daily followed by an intravenous injection of fluorescein isothiocyanate-sinistrin (FITC-sinistrin) for 3 days. FITC-sinistrin fluorescence was monitored transdermally prior to VAN administration and daily during treatment. GFR was calculated from FITC-sinistrin clearance. A mixed-effects model compared urinary biomarkers and GFRs between treatments and across days of dosing. Urinary biomarkers for injury and GFR were compared between treatment groups and correlated with VAN kidney accumulation. Mean GFR for saline-treated animals was 1.07, 1.20, 1.15 and 1.24 mL/min/100g body weight (b.w.) pre-treatment and at Days 1-3, respectively. VAN-treated rats had lower GFR after treatment (0.457, 0.584 and 0.759 mL/min/100g b.w. on Days 1-3, respectively; P ≤ 0.05). KIM-1 and clusterin were elevated on Day 1 for VAN-treated animals. The relationship between VAN accumulation in the kidney with GFR and biomarkers followed a four-parameter Hill slope (R = 0.6 and R = 0.9, respectively). Rats receiving VAN had a significant decline in GFR immediately following the first dose, which correlated with increasing VAN concentrations in the kidney and urinary biomarkers.
万古霉素（VAN）引起血清肌酐（SCr）升高定义的急性肾损伤。肾小球滤过率（GFR）是定义肾功能的金标准，SCr 常被用作 GFR 替代物；然而，SCr 的变化可能滞后于急性功能下降。我们试图在转化大鼠模型中定义 VAN 的 GFR 变化率和程度。雄性 Sprague Dawley 大鼠每天一次静脉内（n = 6）或生理盐水（n = 5）接受 150mg/kg/天 VAN 治疗，随后连续 3 天静脉内注射荧光素异硫氰酸酯-sinistrin（FITC-sinistrin）。在 VAN 给药前和治疗期间每天通过皮肤监测 FITC-sinistrin 荧光。从 FITC-sinistrin 清除率计算 GFR。混合效应模型比较了两种治疗方法之间和治疗期间不同天数的尿生物标志物和 GFR。比较了治疗组之间的损伤和 GFR 尿生物标志物，并与 VAN 肾脏蓄积相关。生理盐水处理动物的平均 GFR 分别为 1.07、1.20、1.15 和 1.24 mL/min/100g 体重（b.w.），分别为治疗前和第 1-3 天。VAN 治疗大鼠在治疗后 GFR 降低（第 1-3 天分别为 0.457、0.584 和 0.759 mL/min/100g b.w.；P ≤ 0.05）。VAN 治疗动物在第 1 天 KIM-1 和 clusterin 升高。VAN 肾蓄积与 GFR 和生物标志物之间的关系遵循四参数 Hill 斜率（R = 0.6 和 R = 0.9）。接受 VAN 治疗的大鼠在首次给药后 GFR 明显下降，这与肾内 VAN 浓度的增加和尿生物标志物相关。
