Urinary Exosomes Identify Inflammatory Pathways in Vancomycin Associated Acute Kidney Injury.
Urinary Exosomes Identify Inflammatory Pathways in Vancomycin Associated Acute Kidney Injury.
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DOI：
10.3390/ijms22062784
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发表时间：
2021-03-10
影响因子：
5.6
通讯作者：
On Behalf Of The Direct Investigators
中科院分区：
文献类型：
--
作者：
Awdishu L;Le A;Amato J;Jani V;Bal S;Mills RH;Carrillo-Terrazas M;Gonzalez DJ;Tolwani A;Acharya A;Cerda J;Joy MS;Nicoletti P;Macedo E;Vaingankar S;Mehta R;RamachandraRao SP;On Behalf Of The Direct Investigators
背景：万古霉素通常用作耐甲氧西林金黄色葡萄球菌等革兰氏阳性微生物的一线治疗。在高达43%的患者中报告了万古霉素诱导的急性肾损伤（V-AKI），特别是在那些具有较高目标谷浓度的患者中。人类损伤的确切机制仍然难以捉摸，最近的证据指向近端小管细胞凋亡。在这项研究中，我们研究了V-AKI患者尿外泌体的蛋白含量，以进一步阐明损伤机制和潜在反应的生物标志物。研究方法：来自入组DIRECT研究的V-AKI患者和来自UAB-UCSD奥布莱恩中心生物储存库的匹配健康对照的尿样被纳入分析。使用溶剂排阻原理和聚乙二醇诱导沉淀提取外泌体。通过无标记液相色谱质谱法（LC/MS）测定蛋白质鉴别和定量。平均峰值血清肌酐为3.7 ± 1.4 mg/dL，至肾损伤的时间为4.0 ± 3.0天。出院时，90%的患者表现出部分恢复; 33%的患者在第28天完全恢复。对5个V-AKI和7个对照样品的蛋白质组学分析揭示了所有样品中的2009个蛋白质和251个与V-AKI显著相关的蛋白质（Pi评分> 1）。最主要的鉴别蛋白是补体C3、补体C4、半乳糖凝集素-3-结合蛋白、纤维蛋白原、α-2巨球蛋白、免疫球蛋白重链恒定μ和血清转铁蛋白。结论：尿exosomes显示V-AKI肾毒性损伤后炎性蛋白表达上调。进一步的研究是必要的，在一个大的患者样本，以确认这些发现的病理生理机制的阐明和潜在的损伤生物标志物的验证。
Background: Vancomycin is commonly used as a first line therapy for gram positive organisms such as methicillin resistant Staphylococcus aureus. Vancomycin-induced acute kidney injury (V-AKI) has been reported in up to 43% of patients, especially in those with higher targeted trough concentrations. The precise mechanism of injury in humans remains elusive, with recent evidence directed towards proximal tubule cell apoptosis. In this study, we investigated the protein contents of urinary exosomes in patients with V-AKI to further elucidate biomarkers of mechanisms of injury and potential responses. Methods: Urine samples from patients with V-AKI who were enrolled in the DIRECT study and matched healthy controls from the UAB-UCSD O’Brien Center Biorepository were included in the analysis. Exosomes were extracted using solvent exclusion principle and polyethylene glycol induced precipitation. Protein identity and quantification was determined by label-free liquid chromatography mass spectrometry (LC/MS). The mean peak serum creatinine was 3.7 ± 1.4 mg/dL and time to kidney injury was 4.0 ± 3.0 days. At discharge, 90% of patients demonstrated partial recovery; 33% experienced full recovery by day 28. Proteomic analyses on five V-AKI and 7 control samples revealed 2009 proteins in all samples and 251 proteins significantly associated with V-AKI (Pi-score > 1). The top discriminatory proteins were complement C3, complement C4, galectin-3-binding protein, fibrinogen, alpha-2 macroglobulin, immunoglobulin heavy constant mu and serotransferrin. Conclusion: Urinary exosomes reveal up-regulation of inflammatory proteins after nephrotoxic injury in V-AKI. Further studies are necessary in a large patient sample to confirm these findings for elucidation of pathophysiologic mechanisms and validation of potential injury biomarkers.
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