MMA合并肾脏损害

1、MMAMMA合并肾脏损害合并肾脏损害临床表现临床表现以变位酶或其辅酶钴胺素缺陷的患者均可引起肾脏以变位酶或其辅酶钴胺素缺陷的患者均可引起肾脏损害损害变位酶变位酶缺乏缺乏 ( (尤其尤其是是 mut0) mut0) 患者发病早患者发病早, , 引起肾脏损引起肾脏损害的危险性比辅酶钴胺素缺陷者害的危险性比辅酶钴胺素缺陷者更大更大, , 多多早期死亡早期死亡。 cblCcblC、cblDcblD、cblFcblF缺陷缺陷, ,引起引起的肾脏的肾脏损害损害, , 发病较晚发病较晚, , 但是影响患者预后的重要但是影响患者预后的重要因素之一。因素之一。临床表现临床表现MMAMMA所所致的肾脏损害多以肾小

2、管间质性致的肾脏损害多以肾小管间质性损害为主损害为主11 , ,临床临床表现为肾小管功能异常表现为肾小管功能异常、慢性、慢性肾小管肾小管酸中毒酸中毒或或肾性高血肾性高血压压11；肾小管早期损伤指标中乙酰氨基葡萄糖苷酶最灵肾小管早期损伤指标中乙酰氨基葡萄糖苷酶最灵敏敏，微球蛋白视黄醇结合蛋白次之微球蛋白视黄醇结合蛋白次之; ;临床表现临床表现少部分患者少部分患者也以肾小球的病变为主也以肾小球的病变为主, , 临床表现为蛋临床表现为蛋白尿及白尿及血尿血尿, , 肾脏病理可表现为局灶节段性肾小球肾脏病理可表现为局灶节段性肾小球硬化与硬化与膜增殖膜增殖性性肾小球肾炎肾小球肾炎22；尚有报道尚有报道以慢

3、性以慢性血栓血栓性性微血管微血管性性肾病肾病为惟一表现的为惟一表现的甲基丙二酸尿症甲基丙二酸尿症33临床表现临床表现慢性肾小管间质性肾炎早期一般无明显临床表现，慢性肾小管间质性肾炎早期一般无明显临床表现，直至晚期。直至晚期。肾小管功能障碍导致进行性的慢性肾小管间质肾炎肾小管功能障碍导致进行性的慢性肾小管间质肾炎及终末期肾病，是及终末期肾病，是MMAMMA晚期并发症的主要方面晚期并发症的主要方面55 ，且病死率很高。且病死率很高。临床表现临床表现以以肾脏受累为首发肾脏受累为首发症状症状的易漏的易漏诊，且诊，且晚期患者可晚期患者可出现出现肾衰竭肾衰竭基因型基因型- -表型关系表型关系VitB12V

4、itB12无效型更容易发展为慢性肾脏疾病（无效型更容易发展为慢性肾脏疾病（CKDCKD）（30patients30patients）44在在VitB12VitB12无效型中，在无效型中，在mut0mut0（61%61%），），cblBcblB（66%66%）更）更易发生，易发生，mutmut- -（0%0%），），cblAcblA（21%21%）（）（82patients82patients） 55发病机制发病机制慢性肾小管慢性肾小管间质性肾炎间质性肾炎肾小管酸中毒肾小管酸中毒溶血尿毒综合征（溶血尿毒综合征（cblCcblC）：）：微血栓性改微血栓性改变变发病机制（发病机制（1 1）慢性肾小管

5、间质性肾炎慢性肾小管间质性肾炎进行进行性肾小管间质性肾炎病理性肾小管间质性肾炎病理特点：单核细胞渗出特点：单核细胞渗出等慢性炎症、广泛的间质纤维化、肾小管等慢性炎症、广泛的间质纤维化、肾小管萎缩萎缩66 近端小管近端小管巨线粒体形成是巨线粒体形成是MutMut基因突变的基因突变的MMAMMA的主要的主要病理改变病理改变特征特征77发病机制（发病机制（1 1）MMAMMA等毒性代谢产物累计等毒性代谢产物累计损害；损害；氧氧化化应激；应激；mtDNAmtDNA稳态稳态破坏破坏 近端小管巨线粒体形成近端小管巨线粒体形成细胞色素细胞色素C C氧化酶及氧化酶及NADHNADH氧化酶活性降低氧化酶活性降低

6、（近端小管线粒体直接病理改变（近端小管线粒体直接病理改变）66发病机制（发病机制（2 2）肾小管酸中毒肾小管酸中毒88、99： 高钾、高氯血症、高尿酸血症、高钙尿症，而肾功能正高钾、高氯血症、高尿酸血症、高钙尿症，而肾功能正常常发病机制（发病机制（3 3）溶血尿毒综合征（溶血尿毒综合征（cblCcblC）1010：微血栓性改变微血栓性改变 同型半胱氨酸的累积；同型半胱氨酸的累积； 下游代谢产物蛋氨酸的缺乏下游代谢产物蛋氨酸的缺乏发病机制（发病机制（3 3）改变血管内皮抗血栓形成的特性改变血管内皮抗血栓形成的特性1111；诱导组织纤维蛋白溶酶原活性诱导组织纤维蛋白溶酶原活性1212增加内皮促凝血

7、物质的表达增加内皮促凝血物质的表达1313刺激促炎通路及脂质过氧化反应刺激促炎通路及脂质过氧化反应引起细胞内自由基的积聚引起细胞内自由基的积聚1414 高同型半胱氨酸通过以下几方面损害肾小球内皮细胞高同型半胱氨酸通过以下几方面损害肾小球内皮细胞发病机制（发病机制（3 3）蛋氨酸的缺乏在血管内皮损伤中也发挥一定作蛋氨酸的缺乏在血管内皮损伤中也发挥一定作用用1515参考文献参考文献【1 1】Van Hove JL,Van DammeVan Hove JL,Van Damme- -Lombaerts R,Grunewald S.Cobalamin disorder CblC presenting L

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