尿单核细胞趋化因子-1及γ干扰素诱导蛋白对狼疮肾炎活动性病变的评价

Detection of urinary monocyte chemoattr actant protein-1 and interferon-γ-inducible protein-10 to recognize the disease activity of lupus nephritis

目的 探讨LN患者尿中单核细胞趋化因子（MCP-1）、γy干扰素诱导蛋白（IP-10）水平与临床各项活动性指标的关系及临床意义.方法 选取符合1997年ACR LN分类标准,并排除了原发和其他继发性肾脏病,诊断为LN的患者64例,根据2000年SLEDAI将LN患者分为活动组36例（SLEDAI≥10分）与非活动组28例（SLEDAI＜10分）,并设立健康对照组（20名）,2组中共有37例患者同步接受了肾穿刺检查.收集临床资料、肾脏病理并同步留取尿液标本,ELISA法检测尿标本中MCP-1与IP-10水平.采用t检验、秩和检验、x2检验及Spearman相关性分析进行统计分析.结果 ①活动组尿MCP-1及IP-10水平均显著高于非活动组[672.39 （318.05,2 554.23） pg/ml与152.52,（55.61,330.44 pg/ml）,Z=-4.717 P＜0.01; （38±19） pg/ml与（22±16）pg/ml,=3.576,P＜0.01];②患者尿MCP-1水平与镜下血尿、尿蛋白定量（24 h）、SLEDAI积分及BILAG积分呈正相关（r镜下血尿=0.570,P=0.000;r24hpro=0.569,P=0.000;rSLEDAI =0.600,P=0.000;rBILAG=0.606,P=0.000）;与血白蛋白、补体C3水平呈负相关（r白蛋白=-0.587,P＜0.000; rC3=-0.564,P=0.000）.③尿IP-10水平与尿蛋白定量（24h）、SLEDAI积分及BILAG积分呈正相关（r24hpro=0.305,P=0.018;rSLEDAI=0.334,P=0.009; rBILAG=0.496,P=0.000）,与C4水平呈负相关（rC4=-0.301,P=0.016）.④活动组33例肾活检肾病理结果：15例为Ⅳ型（47％）,6例Ⅲ型（19％）,5例Ⅲ＋V型（16％）,3例V型（9％）,2例Ⅳ＋V型（6％）,2例Ⅱ型（6％）,病变以肾小管上皮细胞严重变性为主,其次为肾小球严重的细胞增生.⑤尿MCP-1与“白金耳”样病变呈正相关（r=0.430,P=0.014）、与细胞性新月体呈正相关（r=0.405,P=0.015）,与活动性评分（AI）呈正相关（r=0.352,P=0.003）;尿IP-10与“白金耳”样病变、细胞性新月体及AI无明显相关性（P＞0.05）.⑥根据尿MCP-1对判断LN全身活动性的ROC曲线,其特异性75.0％,敏感性83.3％,阳性似然比3.33,ROC下面积0.85±0.05.根据尿Ip-10对判断LN全身活动性的ROC曲线,特异性50.0％,敏感性97.2％,阳性似然比1.94,ROC下面积0.74±0.06.⑦根据尿MCP-1对判断LN肾脏活动性病变的ROC曲线,敏感性100％,特异性45.5％,约登指数0.455,阳性似然比1.83,曲线下面积0.74±0.80.根据IP-10对判断LN肾脏活动性病变的ROC曲线,敏感性73.3％,特异性36.4％,约登指数0.097,阳性似然比1.15,曲线下面积：0.49±0.10.结论 尿MCP-1水平与LN全身活动性病变及肾组织活动性病变均密切相关,可作为一种较好的反映LN活动性病变的无创性生物标志物;尿IP-10水平与LN全身活动性病变相关,但对肾脏活动性病变的诊断价值不如尿MCP-1.

Objective In this study,we measured the levels of urinary monocyte chemoattractant （MCP）-1 and interferon-γ-inducible protein （IP-10） and further analyzed their associations with clinical and pathological data in lupus nephritis patients in order to find the non-invasive biomarkers which canpredict disease activity.Methods MCP-1,IP-10,VEGF levels were measured in urine samples from 64 lupus nephritis patients and 20 healthy volunteers.Clinical disease activity was determined by SLEDAI and BILAG scores.The lupus nephritis patients were divided into two groups：active disease group （SLEDAI scores ≥ 10points,n=36） and non-active group （SLEDAI score〈10 points,n=28）.Of all patients enrolled,37 patients had a concomitant kidney biopsy performed at the time of urine collection.The predictive performance of uri-nary MCP-1 and IP-10 for renal flare,the Student＆#39;s t test,Mann-Whitney U test,Chi-square test,and re-ceiver operating characteristic （ROC） curves were constructed for analysis.Results The urinary MCP-1 and urinary IP-10 levels of the active group was significantly higher than that of the non-active group [MCP-1672.39（318.05,2 554.23）pg/ml vs 152.52,（55.61,330.44）pg/ml,Z=-4.717,P〈0.01; IP-10 （38±19） pg/ml vs （22±16） pg/ml,t=3.576 P〈0.01].The level of urinary MCP-1 was positively correlated with the levels of hematuria and 24 hours protein quan-tification,as well as the scores of SLEDAI and BILAG （rbemahuria=0.570,P=0.000; r24hpro=0.569,P=0.000; rSLEDAI=0.600,P=0.000; rBILAG=0.606,P=0.000）,and it was also positively correlated with the scores of cellular crescent,wire loop,and AI （rCC=0.405,P=0.015; rwire loop=0.430,P=0.014; rAI=0.352,P=0.003）,while nega-tively correlated with the level of C3 and plasma albumin （rc3=-0.564,P=0.000; ralb=-0.587,P=0.000）.It had no correlation with the scores of wire loop and CI （P〉 0.05）.The level of uIP-10 was positively correlated with the protein quantification in 24 hours and the scores of SLEDAI and BILAG （r24hpro=0.305,P=0.018; rSLEDAI=0.334,P=0.009; rSILAG=0.496,P=0.000）,while negatively correlated with the level of C4 （rC4=-0.301,P=0.016）.The R0C curve of uMCP-1 to predict the activity of SLE showed that its specificity was 75.0%,sensitivity was 83.3%,and the area under the ROC curve was 0.85±0.05.The ROC curve of urinary IP-10 to predict the activity of SLE showed that its specificity was 50.0%,sensitivity was 97.2%,its area under the ROC curve was 0.74±0.06.The ROC curve of urinary MCP-1 to predict renal flare shows that its specificity was 45.5%,its sensitivity was 100%,and the area under the ROC curve was 0.74±0.80.The ROC curve of urinary IP-10 to predict renal flare showed that its specificitywas 36.4%,its sensitivity was 73.3%,and its area under the ROC curve was 0.49 ±0.10.Conclusion Urinary MCP-1 and urinary IP-10 predict renal flare in patients with lupus nephritis.Furthermore,urinary MCP-1 is a more specific and sensitive forecaster of renal flare in patients with a history of lupus nephritis than urinary IP-10.