【作者】 邱强；

【导师】 陈香美；

【作者基本信息】 中国人民解放军军医进修学院 ， 内科学， 2005， 博士

【摘要】 背景及目的 IgA肾病是世界范围内最常见的原发性肾小球疾病,是终末期肾病(ESRD)的主要病因,因此,对IgA肾病预后的准确判断及进展机制的研究具有重要意义。在本研究中,我们对IgA肾病肾功能状态与病理分级之间的关系进行了探讨,并对微血管病变在IgA肾病进展中的作用及纤溶酶原激活物系统在微病变中的作用进行了研究。 方法 ① 通过对大样本861例IgA肾病患者临床病理资料的等级相关和有序Logistic多因素分析,寻找与IgA肾病肾功能状态确切相关的病理指标。根据与IgA肾病肾功能状态确切相关的病理指标进行病理分级,通过ROC曲线比较该病理分级方法与传统Lee氏分级反映IgA肾病患者肾功能下降的敏感性和特异性。② 利用激光微切割方法分别分离24例IgA肾病患者肾组织切片(8μm)中的肾小球(20个/例)和肾小管及其周围间质(200个/例),应用TaqMan实时定量PCR检测肾小球及肾小管间质内纤溶酶原激活物(PA)及纤溶酶原激活物抑制剂-1(PAI-1)的mRNA表达。采用计算机图像分析系统定量分析毛细血管密度及PAI-1、组织型纤溶酶原激活物(tPA)及尿激酶型纤溶酶原激活物(uPA)的蛋白表达。应用线性回归统计学方法,分析PA/PAI-1mRNA与毛细血管密度之间的关系。 结果 ① 肾小球全球硬化、肾小管萎缩、间质纤维化、血管病变与IgA肾病肾功能分期呈等级相关,根据上述4项病理指标积分进行的分级(GTIV,为四项病理指标的英文单词第一个大写字母缩写)与Lee氏分级相比反映IgA肾病肾功能分期的敏感性和特异性更高(P值均小于0.001)。② 随着病变的加重,IgA肾病毛细血管密度均随之减小。IgA肾病患者的肾小球毛细血管袢密度及肾小管周围毛细血管密度均与血清肌酐值成负相关,R~2分别为0.6946和0.6271(P值均<0.05)。肾小球tPA mRNA/PAI-1mRNA比值与肾小球毛细血管袢密度呈正相关(R~2=0.7094,P<0.001);肾小管间质uPA mRNA/PAI-1更多还原

【Abstract】 Background and Object IgA nephropathy is the most common primary glomerulonephritis worldwide and a major cause of end stage renal disease (ESRD).Therefore, it is important to exactly estimate the prognosis and to study the progressive mechanism of IgA nephropathy. In this study, we explored the relationship between renal function and histological indexes, and studied the role of microvascular lesions in IgA nephropathy progression and its association to plasminogen activator system.Methods (1) By rank-order correlation and ordinal logistic regression analysis of 861 IgA nephropathy patients’ clinicopathological data, the histological indexes exactly associated with glomerular filtration rate (GFR) stage were selected. Based on total score’s distribution by GFR stage of the selected histology lesions a new histological grading system was set up, whose sensitivity and specificity for IgA nephropathy GFR stage were compared with traditional Lee’s grading system using the ROC curve method. (2) 20 renal glomeruli or 200 renal tubules and peritubular interstitial per patient were captured by Laser Microdissection System from IgA nephropathy renal biopsy slides (8μm). Plasminogen activator (PA) mRNA and plasminogen activator inhibitor-1 (PA1-1) mRNA levels in glomerulus and tubulointerstitial area were measured by Taqman quantitative real-time PCR. Capillaries densities and PA/PAI-1 protein expressions in glomerulus and tubulointerstitial area were measured using immunohistological staining method and computer image analyses system. The associations between PA/PAI mRNA and capillaries densities were analyzed using linear regression analysis.Results (1) Glomerular global sclerosis, tubular atrophy, interstitial fibrosis and vascular lesions were correlated with IgA nephropathy GFR stages at multivariate and univariate analysis. The histological grading system based on the total score of glomerular global sclerosis, tubular atrophy, interstitial fibrosis and vascular更多还原