Liu Linqiong, Liu Yuxi, Xin Yu, Liu Yanqi, Gao Yan, Yu Kaijiang, Wang Changsong
Departments of Critical Care Medicine, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China.
Departments of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China.
Intensive Care Med Exp. 2024 Oct 1;12(1):88. doi: 10.1186/s40635-024-00667-y.
Polymyxins have been revived as a last-line therapeutic option for multi-drug resistant bacteria and continue to account for a significant proportion of global antibiotic usage. However, kidney injury is often a treatment limiting event with kidney failure rates ranging from 5 to 13%. The mechanisms underlying polymyxin-induced nephrotoxicity are currently unclear. Researches of polymyxin-associated acute kidney injury (AKI) models need to be more standardized, which is crucial for obtaining consistent and robust mechanistic results.
In this study, male C57BL/6 mice received different doses of polymyxin B (PB) and polymyxin E (PE, also known as colistin) by different routes once daily (QD), twice daily (BID), and thrice daily (TID) for 3 days. We continuously monitored the glomerular filtration rate (GFR) and the AKI biomarkers, including serum creatinine (Scr), blood urea nitrogen (BUN), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1). We also performed histopathological examinations to assess the extent of kidney injury.
Mice receiving PB (35 mg/kg/day subcutaneously) once daily exhibited a significant decrease in GFR and a notable increase in KIM-1 two hours after the first dose. Changes in GFR and KIM-1 at 24, 48 and 72 h were consistent and demonstrated the occurrence of kidney injury. Histopathological assessments showed a positive correlation between the severity of kidney injury and the changes in GFR and KIM-1 (Spearman's rho = 0.3167, P = 0.0264). The other groups of mice injected with PB and PE did not show significant changes in GFR and AKI biomarkers compared to the control group.
The group receiving PB (35 mg/kg/day subcutaneously) once daily consistently developed AKI at 2 h after the first dose. Establishing an early and stable AKI model facilitates researches into the mechanisms of early-stage kidney injury. In addition, our results indicated that PE had less toxicity than PB and mice receiving the same dose of PB in the QD group exhibited more severe kidney injury than the BID and TID groups.
多粘菌素已重新成为治疗多重耐药菌的最后一线选择，并且在全球抗生素使用中仍占很大比例。然而，肾损伤往往是限制治疗的因素，肾衰竭发生率在5%至13%之间。目前尚不清楚多粘菌素诱导肾毒性的潜在机制。多粘菌素相关急性肾损伤（AKI）模型的研究需要更加标准化，这对于获得一致且可靠的机制性结果至关重要。
在本研究中，雄性C57BL/6小鼠通过不同途径每天接受一次（QD）、每天两次（BID）和每天三次（TID）不同剂量的多粘菌素B（PB）和多粘菌素E（PE，也称为黏菌素），持续3天。我们持续监测肾小球滤过率（GFR）和AKI生物标志物，包括血清肌酐（Scr）、血尿素氮（BUN）、中性粒细胞明胶酶相关脂质运载蛋白（NGAL）和肾损伤分子-1（KIM-1）。我们还进行了组织病理学检查以评估肾损伤程度。
每天皮下注射一次PB（35mg/kg/天）的小鼠在首次给药后两小时GFR显著降低，KIM-1显著升高。24、48和72小时时GFR和KIM-1的变化是一致的，并表明发生了肾损伤。组织病理学评估显示肾损伤严重程度与GFR和KIM-1的变化之间存在正相关（Spearman相关系数ρ = 0.3167，P = 0.0264）。与对照组相比，其他注射PB和PE的小鼠组GFR和AKI生物标志物未显示出显著变化。
每天皮下注射一次PB（35mg/kg/天）的组在首次给药后2小时持续发生AKI。建立早期稳定的AKI模型有助于对早期肾损伤机制的研究。此外，我们的结果表明PE的毒性低于PB，并且在QD组中接受相同剂量PB的小鼠比BID和TID组表现出更严重的肾损伤。
