MMA合并肾脏损害

MMA合并肾脏损害,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损害变位酶缺乏 (尤其是 mut0) 患者发病早, 引起肾脏损害的危险性比辅酶钴胺素缺陷者更大, 多早期死亡。 cblC、cblD、cblF缺陷,引起的肾脏损害, 发病较晚, 但是影响患者预后的重要因素之一。,临床表现,MMA所致的肾脏损害多以肾小管间质性损害为主1,临床表现为肾小管功能异常、慢性肾小管酸中毒或肾性高血压1；肾小管早期损伤指标中乙酰氨基葡萄糖苷酶最灵敏，微球蛋白视黄醇结合蛋白次之;,临床表现,少部分患者也以肾小球的病变为主, 临床表现为蛋白尿及血尿, 肾脏病理可表现为局灶节段性肾小球硬化与膜增殖性肾小球肾炎2；尚有报道以慢性血栓性微血管性肾病为惟一表现的甲基丙二酸尿症3,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。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MMA晚期并发症的主要方面5 ，且病死率很高。,临床表现,以肾脏受累为首发症状的易漏诊，且晚期患者可出现肾衰竭,基因型-表型关系,VitB12无效型更容易发展为慢性肾脏疾病（CKD）（30patients）4在VitB12无效型中，在mut0（61%），cblB（66%）更易发生，mut-（0%），cblA（21%）（82patients） 5,发病机制,慢性肾小管间质性肾炎肾小管酸中毒溶血尿毒综合征（cblC）：微血栓性改变,发病机制（1）,慢性肾小管间质性肾炎进行性肾小管间质性肾炎病理特点：单核细胞渗出等慢性炎症、广泛的间质纤维化、肾小管萎缩6 近端小管巨线粒体形成是Mut基因突变的MMA的主要病理改变特征7,发病机制（1）,MMA等毒性代谢产物累计损害；氧化应激；mtDNA稳态破坏,近端小管巨线粒体形成,细胞色素C氧化酶及NADH氧化酶活性降低（近端小管线粒体直接病理改变）6,发病机制（2）,肾小管酸中毒8、9： 高钾、高氯血症、高尿酸血症、高钙尿症，而肾功能正常,发病机制（3）,溶血尿毒综合征（cblC）10：微血栓性改变 同型半胱氨酸的累积； 下游代谢产物蛋氨酸的缺乏,发病机制（3）,改变血管内皮抗血栓形成的特性11；诱导组织纤维蛋白溶酶原活性12增加内皮促凝血物质的表达13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14,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（3）,蛋氨酸的缺乏在血管内皮损伤中也发挥一定作用15,参考文献,【1】Van Hove JL,Van Damme-Lombaerts R,Grunewald S.Cobalamin disorder CblC presenting with lateonset thrombotic microangiopathy. Am JMed Genet, 2002,111: 195-201；【2】Horster F,Hoffmann GF.Pathophysiology,diagnosis,and treatment Of methylmalonic aciduria recent advances and new challenges.Pediatr Nephrol,2004,19:1071-074；【3】Brune lli SM, Meyers KE, Guttenberg M. Cobalamin C deficiency complicated by an atypicalglomerulopathy.Pediatr Nephrol 2002 ,17: 800-803 ；【4】Cosson MA, Benoist JF, Touati G, Dchaux M, Royer N, GrandinL, Jais JP, Boddaert N, Barbier V, Desguerre I, Campeau PM,Rabier D, Valayannopoulos V, Niaudet P, de Lonlay P (2009) Long-term outcome in methylmalonic aciduria: a series of 30 French patients. Mol Genet Metab 97:172178【5】 Hrster F, Baumgartner MR, Viardot C, Suormala T, Burgard P,Fowler B, Hoffmann GF, Garbade SF, Klker S, Baumgartner ER(2007) Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut-, cblA, cblB). Pediatr Res 62:225230,参考文献,【6】Zsuzsanna K. Berry&Seymour RosenMethylmalonic acidemia: A megamitochondrial disorder affecting the kidney. Pediatr Nephrol (2014) 29:21392146【7】 Chandler RJ, Zerfas PM, Shanske S, Sloan J, Hoffmann V, DiMauro S, Venditti CP (2009) Mitochondrial dysfunction in mut methylmalonic acidemia. FASEB J 23:125261【8】 Dudley J, Allen J, Tizard J, McGraw M (1998) Benign methylmalonic acidemia in a sibship with distal renal tubular acidosis.Pediatr Nephrol 12:564566【9】Wolff JA, Strom C, Griswold W, Sweetman F, Kulovich S, Prodanos C, Nyhan WL (1985) Proximal renal tubular acidosis in methylmalonic acidemia. J Neurogen 2:3139【10】Marina A. Morath& Friederike Hrster& Sven W. Sauer Renal dysfunction in methylmalonic acidurias:review for the pediatric nephrologist. Pediatr Nephrol (2013) 28:227235,参考文献,【11】Stamler JS, Osborne JA, Jaraki O, Rabbani LE, Mullins M, Singel D, Loscalzo J (1993) Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest 91:308318;【12】 Hajjar KA (1993) Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J Clin Invest 91:28732879【13】Rodgers GM, Kane WH (1986) Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest 77:19091916【14】Papatheodorou L, Weiss N (2007) Vascular oxidant stress and inflammation in hyperhomocysteinemia. Antioxid Redox Sign