Evaluation of Fetal and Maternal Vancomycin-Induced Kidney Injury during Pregnancy in a Rat Model

Abstract

Previous literature suggests that maternal vancomycin crosses the placental barrier to the fetus. Further, early animal studies indicated that kidney injury was not observed in the progeny. These studies were conducted prior to the availability of sensitive biomarkers for kidney injury. Therefore, a previous finding of no renal damage to the infant may be misleading. Vancomycin was administered intravenously to pregnant rats at a dose of 250 mg/kg of body weight/day (N = 6 per trimester) on three consecutive gestational days (GD) during trimesters 1, 2, and 3 (T1, T2, and T3, respectively) in three independent cohorts. The dams carried to term and delivered vaginally on GD 21. Kidneys were harvested from dams and pups and homogenized. Samples were prepared by protein precipitation and injected in a liquid chromatography tandem mass spectrometer, and vancomycin was quantified. The kidney tissue homogenate from dams and pups were analyzed for kidney injury molecule-1 (KIM-1). As trimesters progressed, the quantity of vancomycin increased linearly in the kidneys of both rat dams and pups (P < 0.0001 for T1 and T3, P < 0.0001 for T2 and T3, and P < 0.0001 for T3 and T3 control for both rat dams and pups). KIM-1 concentrations in pup kidneys were significantly higher when dams were administered vancomycin in trimesters 1 (P = 0.0001) and 2 (P = 0.0024) than in controls in trimester 3. Data demonstrate persistence of vancomycin in maternal and rat pup kidneys in all three trimesters of pregnancy with associated damage to the kidney, as indicated by expression of KIM-1.

Vancomycin‐Induced Kidney Injury: Animal Models of Toxicodynamics, Mechanisms of Injury, Human Translation, and Potential Strategies for Prevention

“…No adverse effects were noted on fetal viability, weight, or morphology that included external anatomical and internal visceral anomalies and skeletal examination, at vancomycin doses up to 200 mg/kg; though, this dose was nephrotoxic to dams. A more recent study 51 assessing KIM‐1, a sensitive biomarker for VIKI, 39 demonstrated that pups from dams dosed during the first trimester had higher concentration of KIM‐1 in the fetal kidneys compared to the second and third trimesters. This suggests an inverse relationship between trimester of exposure and kidney damage, which warrants further examination 51 …”

In Vitro Nephrotoxicity and Permeation of Vancomycin Hydrochloride Loaded Liposomes

“…Because of the common use and importance of VHCL for life-threatening infections to the mother, it serves as a model drug for our investigation here. Although VHCL was previously FDA-classified as pregnancy category B, emerging data from our previous studies [14] suggest kidney damage in adults. Previously, transplacental crossing of VHCL was observed in women with amnionitis when administered over several days [15,16] and in-term pregnant women [17].…”

“…In rats and rabbits, VHCL was found to be toxic to maternal kidneys at higher doses [18]. Furthermore, data suggest that VHCL crosses the placental barrier [14], although early toxicity studies have not employed the more sensitive assessments of kidney function necessary to classify damage; thus, less is known about VHCL's toxicity to the fetus. Our team has quantified the relationship between fetal VHCL exposure and kidney injury in rat pups at a dose of 250 mg/kg in a small sample (n = 6) [14].…”

“…Furthermore, data suggest that VHCL crosses the placental barrier [14], although early toxicity studies have not employed the more sensitive assessments of kidney function necessary to classify damage; thus, less is known about VHCL's toxicity to the fetus. Our team has quantified the relationship between fetal VHCL exposure and kidney injury in rat pups at a dose of 250 mg/kg in a small sample (n = 6) [14]. VHCL was administered on Gestational Days (GD) 5, 6 and 7 (group I; Trimester 1); on GDs 12, 13 and 14 (group II; Trimester 2); and on GDs 18, 19 and 20 (group III; Trimester 3) [14].…”

“…Our team has quantified the relationship between fetal VHCL exposure and kidney injury in rat pups at a dose of 250 mg/kg in a small sample (n = 6) [14]. VHCL was administered on Gestational Days (GD) 5, 6 and 7 (group I; Trimester 1); on GDs 12, 13 and 14 (group II; Trimester 2); and on GDs 18, 19 and 20 (group III; Trimester 3) [14]. The dams carried to term and delivered vaginally on GD 21.…”