Controversies of the classification of TMA and the terminology of aHUS.
Controversies of the classification of TMA and the terminology of aHUS.
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TMA分类和aHUS术语的争议。
DOI：
10.1007/s10157-017-1524-4
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Kagami S.
中科院分区：
文献类型：
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作者：
Kato H;Nangaku M;Okada H;Kagami S.
血栓性微血管病(TMA)由多种疾病组成。TMA的分类和非典型溶血性尿毒症综合征(AHUS)的定义目前存在争议。在日本肾脏学会和日本儿科学会联合委员会(JSN/JPS)于2014年发布的日本aHUS诊断标准中，除产志贺毒素的大肠杆菌(STEC-HUS)和血栓性血小板减少性紫癜(TTP)外，TMA疾病被广泛定义为aHUS，包括许多TMA并存疾病(继发性TMA)。其中，补体调节因子介导的TMA被称为补体介导的HUS(AHUS)[1]。然而，虽然目前在日本，eculizumab的官方适应症是补体介导的HUS，但有时会被误解为eculizumab适用于所有名为“aHUS”的TMA。此外，我们还承担并在全国范围内对aHUS患者进行诊断，有时所有名称为“aHUS”的TMA都被医生认为与基因有关。在JSN/JPS于2016年修订的日本aHUS临床指南中，将aHUS定义为排除STEC-HUS、TTP和继发性TMA之后的补体介导的HUS，我们详细介绍了鉴别诊断并鼓励医生评估继发性TMA[2]。此外，我们警告医生要注意补体介导的HUS患者在继发性TMA中已有报道，包括HELLP综合征[3]、加速或恶性高血压和肾移植[2]。我们描述了“未来的研究应该调查补体激活异常在继发性TMA病因中的参与程度，继发性TMA人群中补体基因突变患者的比例，以及eculizumab治疗继发性TMA的有效性”。此外，已有新的基因被报道导致TMA，如THBD、DGKE、PLG和INF2。这些基因变异对补体活性的影响尚不清楚，因此eculizumab的有效性仍存在争议。最近KDIGO争议会议公布了TMA的诊断流程图，所有次级TMA都被重新命名为aHUS[4]。然而，名称为aHUS的TMA并不一定意味着所有这些疾病都是先天性或获得性补体介导的HUS。图1描述了TMA的分类和aHUS术语的比较。aHUS的诊断通常需要很长时间，aHUS患者和一些继发性TMA患者受益于补体抑制剂的经验性治疗。然而，TMA由多种病理生理病因组成，补体异常在TMA发生发展中的作用在每种继发性TMA疾病中是不同的。在未来，首先需要评估补体相关的aHUS患者的比例以及补体抑制剂对个别继发性TMA疾病的效果。其次，补体抑制剂作为经验性治疗的适应证应该针对个体继发性TMA疾病进行讨论和决定，而不应该由aHUS的术语来决定。
Thrombotic microangiopathy (TMA) consists of numerous diseases. The classification of TMA and the definition of atypical hemolytic uremic syndrome (aHUS) are currently controversial. In Japanese diagnostic criteria of aHUS published by the Joint Committee of the Japanese Society of Nephrology and the Japan Pediatric Society (JSN/JPS) in 2014, TMA diseases other than Shiga toxin–producing Escherichia coli (STEC)-HUS and thrombotic thrombocytopenic purpura (TTP) were broadly defined as aHUS and included many TMAs with coexisting diseases (secondary TMAs). Among those aHUS, TMA mediated by complement regulatory factors was named complement-mediated HUS (aHUS)[1]. However, while official indication of eculizumab is currently for complement-mediated HUS in Japan, it was sometimes misunderstood that eculizumab has indication for all TMAs with the name of “aHUS”. Furthermore, we undertake and perform nationwide diagnosis for aHUS patients and sometimes all TMAs with the name of “aHUS” were considered as genetic involvement by physicians. In the revision of Japanese clinical guide of aHUS published by JSN/JPS in 2016, aHUS was defined as complement-mediated HUS after the exclusion of STEC-HUS, TTP and secondary TMAs, and we detailed the differential diagnosis and encouraged physicians to evaluate secondary TMAs [2]. Also, we warned physicians to pay attention that complement-mediated HUS patients have been reported among secondary TMAs including HELLP syndrome [3], accelerated or malignant hypertension and kidney transplantation [2]. We described “Future research should investigate the extent of the involvement of abnormal complement activation in the etiology of secondary TMA, the proportion of patients with complement gene mutations among the population with secondary TMA, and the effectiveness of eculizumab for treating secondary TMA”. Also, new genes have been reported to cause TMA such as THBD, DGKE, PLG, and INF2. The involvement of complement activity by these variants of genes is still unknown and thus effectiveness of eculizumab is still controversial. Recent KDIGO Controversies Conference published the diagnostic flow chart of TMA and all secondary TMAs were again named aHUS [4]. However, TMAs with the name of aHUS does not necessarily mean all these diseases are congenital or acquired complement-mediated HUS. Figure 1 depicts the comparison of the classification of TMA and terminology of aHUS.The diagnosis of aHUS usually takes long time, and patients of aHUS and some patients of with secondary TMA benefit from empirical therapy of complement inhibitors. However, TMA consists of the numerous pathophysiological etiologies and the contribution of complement abnormality for the development of TMA is variable among each secondary TMA diseases. In the future, first the proportion of complement-associated aHUS patients and the effect of complement inhibitors for individual secondary TMA diseases need to be evaluated. Secondary, the indications of the complement inhibitors as empiric therapy should be discussed and decided for individual secondary TMA diseases and should not be decided by the terminology of aHUS.