Candidate Biomarkers for Sepsis-Associated Acute Kidney Injury Mechanistic Studies.
Candidate Biomarkers for Sepsis-Associated Acute Kidney Injury Mechanistic Studies.
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DOI：
10.1097/shk.0000000000001916
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发表时间：
2022-05-01
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脓毒症相关急性肾损伤（SA-AKI）是脓毒症常见的并发症，但其病理生理机制尚不完全清楚。PERSEVERE是一种经临床验证的血清生物标志物，在预测脓毒症死亡率方面具有高灵敏度，最近的证据表明，它还可以预测脓毒症儿童住院第3天的严重持续性SA-AKI。我们开发了一种PERSEVERE（mPERSEVERE）小鼠模型，以使用mPERSEVERE中的候选生物标志物进一步研究SA-AKI的脓毒症相关生物学基础。八周龄的C57 BL/6雄性小鼠通过盲肠结扎和穿孔（CLP）诱导脓毒症。在CLP后8小时收集mPERSEVERE生物标志物，并在CLP后24小时收获肾脏。使用分类和回归树分析（CART）来生成SA-AKI预测模型。使用真实的实时聚合酶链反应定量候选生物标志物的肾脏基因表达水平。35只小鼠接受CLP。在mPERSEVERE确定为高死亡风险的小鼠中，70%在24小时内发生SA-AKI，而低风险小鼠为22%。CART分析确定了两种mPERSEVERE生物标志物- C-C基序趋化因子配体3（CCL 3）和角质形成细胞衍生趋化因子（KC）-最能预测SA-AKI，受试者工作曲线下面积为0.90。在发生SA-AKI的小鼠中，与没有SA-AKI的小鼠相比，KC的肾表达显著增加（p=0.013），而在患有SA-AKI的小鼠与没有SA-AKI的小鼠中，没有观察到CCL 3的肾表达的差异。KC和CCL 3定位于肾小管上皮细胞，而不是浸润免疫细胞的免疫组织化学。血浆CCL 3 +KC的组合可以预测CLP后24小时小鼠中SA-AKI的发展。在这两种生物标志物中，在患有SA-AKI的小鼠中，仅KC的肾表达增加。需要进一步研究以确定KC是否直接促成SA-AKI的潜在病理生物学。
Sepsis-associated acute kidney injury (SA-AKI) is a frequent complication of sepsis, yet the pathophysiologic mechanisms of SA-AKI are incompletely understood. PERSEVERE is a clinically validated serum biomarker panel with high sensitivity in predicting mortality from sepsis, and recent evidence suggests it can also predict severe, persistent SA-AKI at day 3 of hospitalization among septic children. We developed a murine model of PERSEVERE (mPERSEVERE) to further interrogate the sepsis-related biological underpinnings of SA-AKI using candidate biomarkers within mPERSEVERE. Eight-week-old C57BL/6 male mice underwent induction of sepsis by cecal ligation and puncture (CLP). mPERSEVERE biomarkers were collected at 8-hours and kidneys were harvested at 24-hours post-CLP. Classification and regression tree analysis (CART) was used to generate a SA-AKI predictive model. Kidney gene expression levels of candidate biomarkers were quantified using real time polymerase chain reaction. Thirty-five mice underwent CLP. Among mice identified by mPERSEVERE as high-risk for mortality, 70% developed SA-AKI at 24-hours compared to 22% of low-risk mice. CART analysis identified two mPERSEVERE biomarkers - C-C motif chemokine ligand 3 (CCL3) and keratinocyte-derived chemokine (KC) – as most predictive for SA-AKI with an area under the receiver operating curve of 0.90. In mice that developed SA-AKI, renal expression of KC was significantly increased compared to mice without SA-AKI (p=0.013), whereas no difference was seen in renal expression of CCL3 in mice with SA-AKI vs no SA-AKI. KC and CCL3 localized to renal tubule epithelial cells as opposed to infiltrating immune cells by immunohistochemistry. The combination of plasma CCL3+KC can predict SA-AKI development in mice at 24-hours following CLP. Of these two biomarkers, only renal expression of KC is increased in mice with SA-AKI. Further studies are required to determine if KC directly contributes to the underlying pathobiology of SA-AKI.