Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d'Immunologie, Paris, France.
Nat Rev Nephrol. 2021 Aug;17(8):543-553. doi: 10.1038/s41581-021-00424-4. Epub 2021 May 5.
Studies of complement genetics have changed the landscape of thrombotic microangiopathies (TMAs), particularly atypical haemolytic uraemic syndrome (aHUS). Knowledge of complement genetics paved the way for the design of the first specific treatment for aHUS, eculizumab, and is increasingly being used to aid decisions regarding discontinuation of anti-complement treatment in this setting. Complement genetic studies have also been used to investigate the pathogenic mechanisms that underlie other forms of HUS and provided evidence that contributed to the reclassification of pregnancy- and postpartum-associated HUS within the spectrum of complement-mediated aHUS. By contrast, complement genetics has not provided definite evidence of a link between constitutional complement dysregulation and secondary forms of HUS. Therefore, the available data do not support systematic testing of complement genes in patients with typical HUS or secondary HUS. The potential relevance of complement genetics for distinguishing the underlying mechanisms of malignant hypertension-associated TMA should be assessed with caution owing to the overlap between aHUS and other causes of malignant hypertension. In all cases, the interpretation of complement genetics results remains complex, as even complement-mediated aHUS is not a classical monogenic disease. Such interpretation requires the input of trained geneticists and experts who have a comprehensive view of complement biology.
补体遗传学研究改变了血栓性微血管病（TMA）的格局，尤其是非典型溶血尿毒综合征（aHUS）。补体遗传学知识为 aHUS 的首个特异性治疗药物依库珠单抗的设计铺平了道路，并越来越多地用于辅助决定在此情况下停止抗补体治疗。补体遗传学研究还用于研究导致其他类型 HUS 的发病机制，并提供了有助于将妊娠和产后相关 HUS 重新归类为补体介导的 aHUS 范畴的证据。相比之下，补体遗传学并未提供补体调节异常与继发形式的 HUS 之间存在关联的确凿证据。因此，目前的数据不支持对典型 HUS 或继发 HUS 患者进行补体基因的系统检测。由于 aHUS 和其他恶性高血压的原因之间存在重叠，因此在评估恶性高血压相关 TMA 的潜在发病机制时应谨慎评估补体遗传学的相关性。在所有情况下，补体遗传学结果的解释仍然很复杂，因为即使是补体介导的 aHUS 也不是一种经典的单基因疾病。这种解释需要接受过培训的遗传学家和专家的输入，他们对补体生物学有全面的了解。
