Dhondt Laura, Croubels Siska, Temmerman Robin, De Cock Pieter, Meyer Evelyne, Van Den Broeck Wim, De Paepe Peter, Devreese Mathias
Department of Pharmacology, Toxicology and Biochemistry, Ghent University, Ghent, Belgium.
Department of Pharmacy, Ghent University Hospital, Ghent, Belgium.
Front Vet Sci. 2021 Apr 29;8:639771. doi: 10.3389/fvets.2021.639771. eCollection 2021.
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 (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 E 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.
在危重症（儿科）人群中观察到的肾脏清除率增加（ARC）可能对经肾脏排泄药物的药代动力学和剂量学产生重大影响。尽管脓毒症已被描述为人类危重症患者发生ARC的主要触发因素，但目前缺乏对ARC的机制性认识。合适的ARC动物模型可能有助于揭示这些潜在机制。在这项探索性研究中，在8周龄仔猪中诱导出ARC状态。对清醒的仔猪连续36小时输注来自大肠杆菌（O111:B4）的脂多糖（LPS）以诱导脓毒症并随后触发ARC。为了研究LPS对肾功能的剂量依赖性影响，给予三种不同剂量（0.75、2.0、5.0μg/kg/h）（每剂量两只雄性仔猪，一只假手术仔猪），并以6ml/kg/h的速度给予液体（0.9%氯化钠）。静脉注射单次剂量的肾脏标志物，即肌酐[40mg/kg体重（BW）]、碘海醇（64.7mg/kg BW）和对氨基马尿酸（PAH，10mg/kg BW），以评估LPS对肾功能的影响。定期监测临床参数。进行血液采样以确定对血液学、中性粒细胞明胶酶相关脂质运载蛋白和前列腺素E血浆水平的影响。所有持续输注LPS的仔猪在输注开始后约1 - 3小时体温、心律和呼吸频率升高。输注后，观察到碘海醇、肌酐和PAH的全身清除率显著更高，与LPS的给药及其剂量无关。由于未接受LPS的假手术仔猪也表现出类似的肾功能增加，因此应进一步评估液体给药对ARC发生发展的作用。
