Conventional Pig as Animal Model for Human Renal Drug Excretion Processes: Unravelling the Porcine Renal Function by Use of a Cocktail of Exogenous Markers

Dhondt, Laura; Croubels, Siska; Paepe, Peter De; Wallis, Steven C.; Pandey, Saurabh; Roberts, Jason A.; Lipman, Jeffrey; Cock, Pieter De; Devreese, Mathias

doi:10.3389/fphar.2020.00883

Cited by 18 publications

(11 citation statements)

References 51 publications

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“…Throughout all the test scenarios, the computer script managed a simulated urine output fixed at 5 mL/min when the MAP was 50 mmHg or higher, mimicking a basal urine rate, and zero when the MAP dropped below this threshold. While the urine rate selected is above the upper limit of physiological urinary flow rates observed in swine of 2.03 +/− 1 mL/kg/h [ 26 ], the scenarios and testing setup can be adjusted to meet the needs of end users. The higher rate was selected due to peristaltic pump hardware limitations with slower flow rates.…”

Section: Methodsmentioning

confidence: 99%

An Automated Hardware-in-Loop Testbed for Evaluating Hemorrhagic Shock Resuscitation Controllers

et al. 2022

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Hemorrhage remains a leading cause of death, with early goal-directed fluid resuscitation being a pillar of mortality prevention. While closed-loop resuscitation can potentially benefit this effort, development of these systems is resource-intensive, making it a challenge to compare infusion controllers and respective hardware within a range of physiologically relevant hemorrhage scenarios. Here, we present a hardware-in-loop automated testbed for resuscitation controllers (HATRC) that provides a simple yet robust methodology to evaluate controllers. HATRC is a flow-loop benchtop system comprised of multiple PhysioVessels which mimic pressure-volume responsiveness for different resuscitation infusates. Subject variability and infusate switching were integrated for more complex testing. Further, HATRC can modulate fluidic resistance to mimic arterial resistance changes after vasopressor administration. Finally, all outflow rates are computer-controlled, with rules to dictate hemorrhage, clotting, and urine rates. Using HATRC, we evaluated a decision-table controller at two sampling rates with different hemorrhage scenarios. HATRC allows quantification of twelve performance metrics for each controller configuration and scenario, producing heterogeneous results and highlighting the need for controller evaluation with multiple hemorrhage scenarios. In conclusion, HATRC can be used to evaluate closed-loop controllers through user-defined hemorrhage scenarios while rating their performance. Extensive controller troubleshooting using HATRC can accelerate product development and subsequent translation.

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Section: Methodsmentioning

confidence: 99%

An Automated Hardware-in-Loop Testbed for Evaluating Hemorrhagic Shock Resuscitation Controllers

et al. 2022

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“…Since the mechanism of ARC is not yet clear, there are only limited animal studies on ARC have been reported. In these studies, iohexol and p -aminohippuric acid (PAH) were detected in blood as potential markers to evaluate the GFR, effective renal plasma flow and tubular secretion ( Dhondt et al, 2020 ; Stroobant et al, 2020 ). Dhondt et al used lipopolysaccharides (LPS) by continuous infusion to induce a sepsis piglets model, and elevated clearances of GFR marker iohexol and exogenously creatinine and effective renal plasma flow (ERPF) marker PAH were observed ( Dhondt et al, 2021b ).…”

Section: What We Will Domentioning

confidence: 99%

Augmented Renal Clearance: What Have We Known and What Will We Do?

Luo

Wang

et al. 2021

Front. Pharmacol.

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Augmented renal clearance (ARC) is a phenomenon of increased renal function in patients with risk factors. Sub-therapeutic drug concentrations and antibacterial exposure in ARC patients are the main reasons for clinical treatment failure. Decades of increased research have focused on these phenomena, but there are still some existing disputes and unresolved issues. This article reviews information on some important aspects of what we have known and provides suggestion on what we will do regarding ARC. In this article, we review the current research progress and its limitations, including clinical identification, special patients, risk factors, metabolism, animal models and clinical treatments, and provide some promising directions for further research in this area.

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“…In the renal superficial veins, humans, cats, and dogs are reported to have ‘stellate veins’, whereas rats have only spur like veins [ 211 ]. The porcine renal function analytes such as creatinine, blood urea nitrogen (BUN) and anion secretion [ 22 , 23 , 212 ] are comparable to human’s. The size of pigs as well as other LAM allow for the serial collection of blood analysis for biomarkers.…”

Section: Interventions Of Aki Tested In the Porcine Modelsmentioning

confidence: 99%

Large animal models for translational research in acute kidney injury

et al. 2020

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While extensive research using animal models has improved the understanding of acute kidney injury (AKI), this knowledge has not been translated into effective treatments. Many promising interventions for AKI identified in mice and rats have not been validated in subsequent clinical trials. As a result, the mortality rate of AKI patients remains high. Inflammation plays a fundamental role in the pathogenesis of AKI, and one reason for the failure to translate promising therapeutics may lie in the profound difference between the immune systems of rodents and humans. The immune systems of large animals such as swine, nonhuman primates, sheep, dogs and cats, more closely resemble the human immune system. Therefore, in the absence of a basic understanding of the pathophysiology of human AKI, large animals are attractive models to test novel interventions. However, there is a lack of reviews on large animal models for AKI in the literature. In this review, we will first highlight differences in innate and adaptive immunities among rodents, large animals, and humans in relation to AKI. After illustrating the potential merits of large animals in testing therapies for AKI, we will summarize the current state of the evidence in terms of what therapeutics have been tested in large animal models. The aim of this review is not to suggest that murine models are not valid to study AKI. Instead, our objective is to demonstrate that large animal models can serve as valuable and complementary tools in translating potential therapeutics into clinical practice.

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Conventional Pig as Animal Model for Human Renal Drug Excretion Processes: Unravelling the Porcine Renal Function by Use of a Cocktail of Exogenous Markers

Cited by 18 publications

References 51 publications

An Automated Hardware-in-Loop Testbed for Evaluating Hemorrhagic Shock Resuscitation Controllers

An Automated Hardware-in-Loop Testbed for Evaluating Hemorrhagic Shock Resuscitation Controllers

Augmented Renal Clearance: What Have We Known and What Will We Do?

Large animal models for translational research in acute kidney injury

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