The Development of a Juvenile Porcine Augmented Renal Clearance Model Through Continuous Infusion of Lipopolysaccharides: An Exploratory Study
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Published on: December 8, 2023
Laura Dhondt1, Siska Croubels1, Robin Temmerman1
1Department of Pharmacology, Toxicology and Biochemistry, Ghent University, Ghent, Belgium.
Insights
Augmented renal clearance (ARC) in critically ill patients affects drug dosing. This study found fluid administration, not just sepsis, significantly increased renal function in piglets, suggesting a need for further investigation into fluid
Area of Science:
- Pharmacology
- Nephrology
- Critical Care Medicine
Background:
- Augmented renal clearance (ARC) impacts drug pharmacokinetics in critically ill patients, particularly children.
- Sepsis is a known trigger for ARC, but underlying mechanisms remain unclear.
- An animal model is needed to elucidate ARC mechanisms.
Purpose of the Study:
- To induce and investigate augmented renal clearance (ARC) in a piglet model.
- To explore the dose-dependent effects of lipopolysaccharides (LPS) on renal function during induced sepsis.
- To evaluate the impact of fluid administration on renal function in this model.
Main Methods:
- Eight-week-old piglets were infused with varying doses of LPS from Escherichia coli over 36 hours to induce sepsis and ARC.
- Renal function was assessed using boluses of creatinine, iohexol, and para-aminohippuric acid (PAH).
- Clinical parameters, hematology, and specific biomarkers were monitored throughout the study.
Main Results:
- Piglets receiving LPS showed increased body temperature, heart rate, and respiratory rate.
- Total body clearance of iohexol, creatinine, and PAH increased significantly post-infusion.
- This increase in renal clearance was observed in both LPS-treated and sham piglets, irrespective of LPS dose.
Conclusions:
- Fluid administration, in addition to potential sepsis, may play a significant role in augmented renal clearance.
- The current piglet model demonstrated increased renal function, but the specific role of LPS requires further study.
- Further research is needed to clarify the contribution of fluid administration to ARC development.
Abstract:
Augmented renal clearance (ARC) as observed in the critically ill (pediatric) population can have a major impact on the pharmacokinetics and posology of renally excreted drugs. Although sepsis has been described as a major trigger in the development of ARC in human critically ill patients, mechanistic insights on ARC are currently lacking. An appropriate ARC animal model could contribute to reveal these underlying mechanisms. In this exploratory study, a state of ARC was induced in 8-week-old piglets. Conscious piglets were continuously infused over 36 h with lipopolysaccharides (LPS) from Escherichia coli (O111:B4) to induce sepsis and subsequently trigger ARC. To study the dose-dependent effect of LPS on the renal function, three different doses (0.75, 2.0, 5.0 μg/kg/h) were administered (two ♂ piglets/dose, one sham piglet), in combination with fluid administration (0.9% NaCl) at 6 ml/kg/h. Single boluses of renal markers, i.e., creatinine [40 mg/kg body weight (BW)], iohexol (64.7 mg/kg BW), and para-aminohippuric acid (PAH, 10 mg/kg BW) were administered intravenously to evaluate the effect of LPS on the renal function. Clinical parameters were monitored periodically. Blood sampling was performed to determine the effect on hematology, neutrophil gelatinase-associated lipocalin, and prostaglandin E2 plasma levels. All piglets that were continuously infused with LPS displayed an elevated body temperature, heart rhythm, and respiratory rate ~1-3 h after start of the infusion. After infusion, considerably higher total body clearances of iohexol, creatinine, and PAH were observed, independent of the administration of LPS and/or its dose. Since also the sham piglet, receiving no LPS, demonstrated a comparable increase in renal function, the contribution of fluid administration to the development of ARC should be further evaluated.
