肾小管损伤标志物在局灶节段性肾小球硬化患者中的变化及意义

New urinary biomarkers of tubular injury in patients with focal segmental glomerulosclerosis

目的:探讨局灶节段性肾小球硬化(FSGS)患者肾小管功能指标的表达变化特点,寻找更为敏感特异的生物学标志物,早期发现肾小管间质损伤。方法:经肾活检确诊的特发性FSGS组60例,对照为特发性膜性肾病组(IMN)36例、微小病变组(MCD)30例。比较三组患者肾损伤分子1(kidney injury molecule-1,KIM-1)、白介素18(IL-18)、中性粒细胞明胶酶相关载脂蛋白(neutrophil-gelatinase-associated lipocalin,NGAL)与临床病情的变化情况,分析FSGS患者不同病理亚型及不同性质小管间质病变时KIM-1、IL-18、NGAL的表达特点。结果:(1)蛋白尿水平相当的情况下,FSGS患者肾小管功能损伤明显,尿KIM-1、NGAL、NAG、RBP水平均高于IMN、MCD患者(P<0.05)。(2)尿KIM-1升高的患者较正常者血胱抑素C(CysC)增高(P<0.05);尿NGAL升高的患者较正常者蛋白尿、血BUN、尿C3、尿α2-MG均增高,血清总蛋白及白蛋白明显降低(P<0.05)。(3)FSGS患者中,存在急性或慢性合并急性肾小管间质病变者与仅有慢性肾小管间质病变者相比,尿KIM-1、NGAL明显增高(P<0.01),而血清白蛋白降低(P<0.05)。(4)NAG、RBP尚在正常范围的患者KIM-1、NGAL、IL-18已经增高,病理亦证实其肾小管间质存在不同程度的急性病变。尿KIM-1、NGAL、NAG诊断肾小管间质急性病变其ROC曲线下面积大于尿IL-18、RBP、CysC。结论:FSGS患者较IMN、MCD患者存在更为显著的小管间质损伤,其原因独立于蛋白尿严重程度之外。尿KIM-1、NGAL、NAG是诊断肾小管间质急性病变敏感性和特异性较高的生物学标志物。

Objective：We explored the relevance of the markers with tubular interstitial lesion and glomerular function in patients with focal segmental glomerulosclerosis （FSGS） in order to find the specific and sensitive biomarkers. Methodology： Sixty patients with biopsy-proved idiopathic FSGS were recruited in this study. Thirty-six idiopathic menbranuous nephropathy （MN） and 30 minimal change diseases （MCD） were regarded as the control groups. The changes of urinary kideny injury molecule-1 （KIM-1）, IL-18, neutrophil-gelatinase-assoeiated lipoealin （NGAL）, proteinuria, N-acetyl-β-glucosaminidase （NAGase）, retinal-binding protein （RBP） , Cystatin C （CysC）, C3, α2-MG and renal biochemistry were observed in each group and compared. The effects of urinary data, blood biochemistry as well as histological manifestations on the changes of KIM-1, IL-18, NGAL in FSGS patients were evaluated. Results ： （ 1 ） Under the same proteinuria level, urinary KIM-1, IL-18, NGAL, NAG, RBP, C3,α2-MG were increased in patients with FSGS compared with MN and MCD （ P 〈 0. 05 ）. （ 2 ） In FSGS patients, urinary KIM-1 was increased along with serum CysC （P 〈 0. 05 ）, and the patients with higher urinary NGAL showed proteinuria, BUN, urinary C3 and α2-MG increased （ P 〈 0. 05 ）, but serum total protein and albumin decreased （ P 〈 0. 05 ）. （ 3 ） FSGS patients with acute tubular interstitial injury showed KIM-1 and NGAL increased compared with that have only chronic tubular interstitial lesions （P 〈 0. 05）. （4）In 21 patients with normal NAG and RBP, their urinary KIM-1, IL-18, NGAL was also increased, and the acutetubular interstitial lesions were found in histological examinations. Regard to diagnosis acute tubular and interstitial injury, the area under ROC curve of KIM-1, NGAL and NAG were greater than that of IL-18, RBP and CysC. Conclusion：Our study demonstrated the patients with FSGS had serious tubular interstitial damages compared with MN and MCD, and the reason was independent of the quantity of proteinuria. KIM-1, NGAL, NAG are more specific and sensitive novel biomakers than IL-18, RBP and CysC to estimate the acute tubular and interstitial function. Key words focal segmental glomerulosclerosis kideny injury molecule-1 IL-18 neutrophil-gelatinaseassociated lipocalin