肾损伤生物标志物在评估钙调磷酸酶抑制剂相关肾损伤中的价值

Value of Biomarkers for Kidney Injury in Evaluating Calcineurin Inhibitors-Associated Kidney Injury

目的:探讨肾损伤生物标志物在评估钙调磷酸酶抑制剂(CNI)相关肾损伤中的价值。方法:构建阿霉素肾病综合征大鼠模型,随机分为4组:空白对照组、激素对照组、激素+环孢素(CsA)组和激素+他克莫司(FK506)组,统计分析4组大鼠在不同治疗时间点(7、14、21 d)血液及尿液中肾损伤生物标志物[中性粒细胞明胶酶相关脂质运载蛋白(NGAL)、肾损伤分子-1(KIM-1)、白细胞介素-18(IL-18)、肿瘤坏死因子-α(TNF-α)、转化生长因子-β(TGF-β)]水平以及肾组织病理变化情况。结果:CNI治疗早期肾脏并未出现明显病理损伤,CNI治疗中期开始出现肾损伤,并且随着治疗时间延长肾损伤逐渐加重,激素+CsA组损伤比激素+FK506组更严重,差异有统计学意义(P<0.05);CNI治疗早中期NGAL、TNF-α和IL-18出现变化,CNI治疗后期TGF-β出现变化,与激素对照组比较差异均有统计学意义(P<0.05);激素+CsA组的NGAL水平与肾小管间质损伤病理评分呈正相关(P<0.05)。结论:NGAL、TNF-α和IL-18是评估CNI治疗早中期相关肾损伤的敏感指标,TGF-β对于CNI治疗后期相关肾损伤具有更好的预警价值;NGAL水平与CsA相关肾损伤病理评分具有更好的相关性。

Objective:To probe into the value of biomarkers for kidney injury in evaluating calcineurin inhibitors(CNI)-associated kidney injury.Methods:The rat model of adriamycin nephrotic syndrome was constructed and randomly divided into the blank control group,hormone control group,hormone+cyclosporin(CsA)group and hormone+tacrolimus(FK506)group.The levels of biomarkers for kidney injury such as neutrophil gelatinase-associated lipid transport protein(NGAL),kidney injury molecule-1(KIM-1),interleukin-18(IL-18),tumor necrosis factor-α(TNF-α)and transforming growth factor-β(TGF-β),and kidney histopathologic changes were statistically analyzed in the blood and urine of the four groups of rats at different time points(7,14,and 21 d).Results:There was no obvious injury in kidney pathology in the early stage.Kidney injury was fund in the middle stage of CNI treatment,which worsened with the prolongation of treatment,and the injury was more severe in the hormone+CsA group than that in the hormone+FK506 group,the difference was statistically significant(P<0.05).There were changes in NGAL,TNF-αand IL-18 in the early and middle stages of CNI treatment,and changes in TGF-βin the late stage of CNI treatment,the differences were statistically significant compared with hormone control group(P<0.05).The levels of NGAL in hormone+CsA group was positively correlated with pathological score of kidney tubulointerstitial injury(P<0.05).Conclusion:NGAL,TNF-αand IL-18 are sensitive indicators for evaluating early and middle CNI-related kidney injury,and TGF-βhas better early warning value for late CNI-related kidney injury.The level of NGAL has a better correlation with the pathological score of CsA-related kidney injury.