IgA肾病合并肾小球基底膜弥漫性变薄的临床特点及COL4A3/COL4A4的基因连锁分析

目的 对IgA肾病合并肾小球基底膜弥漫性变薄(TGBM-IgAN)患者的临床病理情况进行系统研究；并在TGBM-IgAN患者的家系中，初步探讨同薄基底膜肾病(TGBMD)相关基因COL4A3/COL4A4的关系。方法 根据透射电镜下GBM的厚度，以GBM的平均厚度小于250 nm及GBM变薄的范围至少达到50%为诊断GBM变薄的标准，明确GBM弥漫性变薄在散发性IgA肾病患者及肾脏病家族史阳性的患者中所占的比例。将234例IgA肾病患者分成合并GBM弥漫性变薄组(n=30)及正常GBM厚度组(n=204)，比较两组患者的临床和病理特点。应用2号染色体长臂分别与COL4A3/COL4A4基因连锁的微卫星体PAX3及HaeⅢ-酶切限制性多态性片段(RFLP)位点作为多态性遗传标记，对其中3个TGBM-IgAN的家系进行COL4A3/COL4A4基因连锁分析。结果 本研究中IgA肾病GBM正常厚度为(352.43±32.11) nm，TGBM-IgAN的GBM厚度为(205.56±23.48) nm。(1)在家族性IgA肾病患者中，TGBM-IgAN患者所占比例为31.8%(21/66)，明显高于其在散发性IgA肾病中所占比例11%(24/219)；(2)30例TGBM-IgAN患者临床特点:女性为主(20/30)，合并肾脏病家族史比例高，均有血尿，尿蛋白量少，预后较好；(3)3个TGBM-IgAN家系中，2个家系与COL4A3/COL4A4的连锁分析提示与COL4A3/COL4A4基因连锁，LOD值为1.53(θ=0)。结论 家族性TGBM-IgAN明显高于散发性患者，合并GBM弥漫变薄的呈家族聚集性发病的IgA肾病患者家系可能为薄基底膜肾病家系，建议在家族性IgA肾病的定义中应强调电镜下GBM形态和厚度的观察。

Clinical characteristics of IgA nephropathy patients with TGBM and the linkage analysis of COL4A3/COL4A4 gene

Objective To investigate the clinical and pathological characteristics and prognosis of IgA nephropathy (IgAN) patients with uniformly thin glomerular basement membrane (TGBM)， as well as the relationship between IgAN with TGBM and thin glomerular basement membrane disease (TGBMD). Methods According to systematic measurement of GBM thickness by electron microscope (EM)， the IgAN patients were divided into two subgroups: IgAN with normal-GBM， and IgAN with TGBM. Based on the clinicopathological data， the clinical and pathological analysis and the linkage analysis with COL4A3/COL4A4 gene in three IgAN with TGBM pedigrees were performed. Microsatellites PAX3 and HaeⅢ-RFLP， closely linked to the COL4A3 and COL4A4 loci at 2q35-37， were used as genetic linkage markers. Family genetic linkage analysis was performed with the Population and Pedigree Analysis Programs. Results The normal thickness of GBM was (352.43±32.11) nm， and the TGBM(205.56±23.48) nm in IgAN patients. (1) 31.4% (21/66) patients were accompanied with TGBM in the familial IgAN (FIgAN)， while only 11% (24/219) in the sporadic IgAN. (2) The clinical manifestations of 30 IgAN patients with TGBM were generalized as following: predominant in the affected female， persistent haematuria， the high incidence of familial history with renal disease， the less quantity of urinary protein and benign clinical courses. (3) Linkage analysis in three IgAN with TGBM pedigrees indicated that two of them were linked with PAX3， HaeⅢ-RFLP makers of COL4A3/COL4A4 gene respectively， and the LOD score was 1.53 (θ=0.00). Conclusions The clinical features of IgAN patients with TGBM are different from those with normal GBM. Some families of IgAN with TGBM may converge with the families of TGBMD， so the electron microscopy examination is necessary for familiar IgAN.