药物相关肾小管间质性肾炎患者几种尿标志物与肾脏病理的相关性

Correlation between urinary biomarkers and pathological lesions in drug-induced tubulointerstitial nephritis

目的 通过对药物相关肾小管间质性肾炎（DTIN）患者尿标志物与临床病理相关性的研究,发现对DTIN病理改变有相关意义的尿标志物.方法 共40例肾活检确诊的DTIN患者和24例对照入选,取肾活检当日的尿标本,用双抗体夹心ELISA法检测转化生长因子β（TGFβ）;放射性酶联免疫法检测IL-6;酶-底物直接显色法检测N-乙酰-β-氨基葡萄糖苷酶（NAG）;免疫透射比浊法检测α1微球蛋白（α1-MG）.同时对患者组的病理进行半定量评分,并构建受试者工作曲线（ROC）,分析各尿液指标与病理损伤指标之间的相关性.结果 尿α1-MG与DTIN患者肾间质水肿、炎症细胞浸润和肾小管萎缩呈正相关,而尿IL-6与上述指标呈负相关;尿NAG与肾间质炎症细胞浸润和肾小管萎缩呈正相关;尿TGFβ与肾小管萎缩呈正相关;各尿标志物与肾间质纤维化均无相关性.ROC曲线分析结果显示：尿α1-MG鉴别肾间质炎性细胞浸润的ROC曲线下面积（AUC）大于NAG（0.797比0.734,P值＜0.05）,联合检测尿α1-MG和尿NAG能提高诊断的敏感性;而各标志物鉴别肾间质水肿和肾小管萎缩的AUC只有尿α1-MG有统计学意义（AUC=0.723,P=0.027;AUC=0.774,P=0.008）.结论 尿α1-MG和NAG水平能反映肾间质炎症浸润的严重程度,二者联合检测能提高诊断的敏感性.尿α1-MG水平尚能反映肾间质水肿和肾小管萎缩程度.

Objective To find some urinary biomarkers for differential diagnosis in drug-induced tubulointerstitial nephritis （DTIN） by accessing the relationship between their changes and the pathological processes of DTIN.Methods Forty patients biopsy-proven DTIN and 24 healthy controls were enrolled in this study.The urine samples of DTIN patients were collected on the day of biopsy and were measured for the following biomarkers： urinary TGF-β with enzyme-linked immunosorbent assay （ELISA）;urinary IL-6 with radio-immunoassay;N-acetyl-β-D-glucosaminidase （NAG） with enzyme-substrate colorimetric assay;α1-microglobulin （α1-MG） with immune transmission turbidity method.Meanwhile, the pathological changes on renal biopsy were analyzed semi-quantitatively and scored.The relationship between these pathological changes and the urinary biomarkers were analyzed and receiver operating characteristic curve （ ROC curve） of those biomarkers in distinguishing different pathological lesions were constructed.Results Urinary α1- MG levels were positively correlated to interstitial edema, inflammatory cell infiltration and tubular atrophy, while urinary IL-6 were negatively correlated to the above parameters.Urinary NAG had positive relationship with inflammatory cell infiltration and tubular atrophy, while urinary TGF-β had positive relationship with tubular atrophy.ROC analysis results indicated that the area under curve （AUC） of α1-MG was larger than that of NAG （0.797 vs 0.734, P 〈 0.05 ）.Combined measurement of α1-MG and NAG could enhance the sensitivity of detecting interstitial inflammatory cell infiltration.For detecting interstitial edema and tubular atrophy, only α1-MG had statistical significance （ AUC = 0.723, P = 0.027;AUC = 0.774, P = 0.008,respectively）.Conclusions Urinary α1-MG and NAG levels can reflect the severity of interstitial inflammatory infiltration, combined measurement of both can enhance sensitivity.Urinary α1-MG level can also reflect the degree of interstitial edema and tubular atrophy.