(五)GBM变薄的发生机制
1.基因突变：家系调查表明，TBMN约80%～100%有阳性血尿家族史，后代中约50%发病，男女比例接近，显示其遗传方式为常染色体显性遗传［2，11］。此点与AS主要以XD方式遗传不同，加上免疫组化检查所见TBMN之GBM存在GP抗原而XD-AS缺如，说明二者有本质的区别。GBM主要由胶原Ⅳ组成，其分子由三条α肽链缠绕而成。已知α链(Ⅳ)亚单位有6种，即α1～α6链。相应的编码基因为COL4A1～COL4A6。α1(Ⅳ)、α2(Ⅳ)链广泛分布于多种基膜，而α3～α5(Ⅳ)链则主要分部于肾脏、耳、眼。已证实XD-AS发病系因COL4A5/COL4A6(位于X染色体)突变所致，常染色体隐性遗传的AS与COL4A3、COL4A4(位于2号染色体)突变有关。TBMN患者GBM极度变薄提示有胶原Ⅳ缺陷［11］。有人推测，胶原Ⅳ基因突变产生了TBMN。从遗传方式看，COL4A5、COL4A6在TBMN中的致病性可除外，有学者也排除了COLA1、COL4A2突变与TBMN有关的可能性［11］。最近有学者报告在一个良性家族血尿的家系中(先证者为TBMN)，发现编码α4(Ⅳ)链胶原区域的COL4A4发生了错义突变(missense mutation)［12］；但另一项研究则未发现TBMN家族存在有COL4A3、COL4A4突变，同时也排除了GBM另外二种组分——纤粘连蛋白(fibronectin)和层粘连蛋白B2(laminin B2)的编码基因突变与TBMN发病有关，说明TBMN基因存在异质性(heterog neity)［13］，其确切定位有待进一步研究。
2.获得性GBM变薄：多种获得性肾小球疾病可有GBM变薄，但有学者认为这不能除外是原发病和TBMN并存［10］。Coleman等［5］曾测定了8例微小病变型肾病的GBM厚度，发现6例(6/8)肾组织含有GBM显著变薄的肾小球，其中4例平均GBM厚度亦变薄，这些病例均无肾脏病家族史。对一例局灶性球性硬化者连续3次肾活检显示，其GBM厚度由正常而进行性变薄。他们还注意到即使已变薄的GBM，亦可随原发病好转而增厚至正常，即GBM厚度呈可逆性改变［14］。有学者报告了对类风湿性关节炎伴尿异常患者GBM厚度的测量结果，发现接受金制剂治疗者，其GBM厚度显著薄于未接受者，在肾小球脏层上皮细胞内含有金颗粒者几乎均发生了GBM变薄［15］。可见，GBM变薄可为继发性或获得性病变。已知脏层上皮细胞是GBM合成的主要细胞，其功能损害可导致Ⅳ型胶原合成和分布失衡而使得GBM厚度异常。
作者单位：467000 平顶山，济南军区第一五二中心医院儿科(王志敏)；武汉，同济医科大学附属同济医院儿科(王韵琴)
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