血清标志物组合对于药源性不同类型肾损伤模型的评价研究

Combination of serum biomarkers in the evaluation of drug-induced different kidney injury models

目的探讨半胱氨酸蛋白酶抑制蛋白C(CysC)和中性粒细胞明胶酶相关脂质运载蛋白(NGAL)在阿霉素和庆大霉素诱导的大鼠肾损伤中的变化特征,及相关血清标志物组合在药源性肾损伤检测中的意义。方法将66只Wistar大鼠随机分为阿霉素组、庆大霉素组和对照组,分别建立肾小球和肾小管损伤模型。各组于不同时间点采集血样,采用生化分析仪检测血清尿素氮(BUN)、肌酐(Scr)含量,酶联免疫吸附法(ELISA)检测血清CysC和NGAL浓度,光镜下观察肾脏病理组织形态学改变。以肾脏病理组织学检查结果作为药源性肾损伤的阳性诊断标准,采用受试者工作特征曲线(ROC)和Logistic回归分析,评估上述血清标志物及组合对肾小球/肾小管损伤的诊断价值。结果 1阿霉素、庆大霉素所致的两种类型的肾损伤大鼠,其CysC和NGAL出现显著性变化的时间均早于形态学和BUN、Scr改变。2ROC分析结果显示,CysC和NGAL在阿霉素模型中的AUC分别为0.866和0.691,在庆大霉素模型中的AUC分别为0.632和0.698,均大于BUN和Scr;CysC、NGAL分别与BUN和Scr组合,对肾小球和肾小管损伤均表现出较高的检验效能;CysC和NGAL组合对两种类型的肾损伤均有一定的检测价值,AUC、敏感性和特异性均大于0.7。结论 CysC和NGAL在药源性肾损伤模型中出现显著性变化的时间均早于形态学改变和传统的血清标志物,在一定程度上可预测肾损伤的发生部位和发展变化;二者分别与BUN、Scr组合,对肾小球和肾小管损伤均表现出较高的检验效能,其中CysC+NGAL组合可用于评价不同类型的肾损伤。

Objective To explore the change characteristics of serum kidney biomarker cystatin C （CysC） and neutrophil gelatinase-associated lipocalcin（NGAL） in adriamyein（ADR） and gentamicin（GM） -induced kidney injury in rats and the significance of the combined detection. Methods Wistar rats were randomly divided into the drug and the control group, and the kidney injury models of glomerular and renal tubular type were established respectively. The contents of serum blood urea nitrogen（BUN） and creatinine（Scr） were detected by means of biochemical analyzer. The concentrations of serum CysC and NGAL were measured by enzyme-linked immunosorbent assay（ELISA）. The morphological changes of renal pathology were observed by light microscopy. The curve areas of various serum biomarkers and the combinations were compared by receiver operating characteristic curve（ ROC curve） and logistic regression analysis based on renal pathology as positive diagnosis criteria. Results ①The significant changes of CysC and NGAL in both types of injury were earlier than the changes of morphology and BUN and Scr. ②ROC analysis showed that the area under curve（AUC） of CysC and NGAL were 0. 866,0. 691 in ADR model and 0. 632,0. 698 in GM model respectively, which higher than that of BUN or Scr. BUN ＋ Scr combined with CysC or NGAL showed higher efficiency for glomerular and renal tubular injury, respectively. The combination of CysC and NGAL had certain value for two types of renal injury,which AUC, sensitivity and specificity were all more than 0.7. Conclusion The significant changes of CysC and NGAL were earlier than morphological changes and traditional serum markers, which can predict the occurrence and development of renal injury in a certain degree. BUN ＋ Set combined with CysC or NGAL had higher efficiency for glomerular and renal tubular injury, respectively. Combination CysC ＋ NGAL can be used to evaluate different types of drug-induced renal injury.