Personalised management of atypical haemolytic uraemic syndrome

溶血性尿毒综合征（HUS）是大肠杆菌O157感染的严重并发症。在约10%的患者中，由于细菌释放的毒素而发生肾衰竭。非典型溶血尿毒综合征是一种罕见的疾病，与这些细菌无关，在许多情况下，这种疾病有遗传倾向。由MRC资助的纽卡斯尔的研究先前发现，补体蛋白基因的异常在大约50%的病例中易患疾病。补体系统通过杀死微生物在保护身体免受感染方面起着重要作用。如果这些补体蛋白质有缺陷，那么身体自身的肾细胞可能会被这些相同的机制损坏。这一关键发现最终导致了一种防止补体激活的药物Eculizumab的引入。这是一种革命性的治疗方法，可以防止患者发生肾衰竭。最近，我们发现了一个对这种药物没有反应的阿胡斯患者亚组。在这些家庭中，我们正在进行遗传分析，以确定根本原因，并确定似乎不参与补体途径的基因。通过识别阿胡斯的这些新的遗传原因，并通过定义简单的血液测试，将快速识别这些患者，我们将防止无效使用补体抑制疗法，避免这种药物的感染性副作用。此外，通过确定导致疾病的新途径，可以开发新的药物来靶向这些途径，从而产生与我们最初发现相同的翻译益处。最终，这项工作将为我们的阿胡斯患者提供个性化治疗。

Haemolytic Uraemic Syndrome (HUS) is a severe complication of infection with the bacteria E.Coli O157. In ~10% of patients kidney failure occurs due to a toxin released by the bacteria. Atypical HUS is a rarer form of the disease which is not associated with these bacteria and in many cases there is a genetic predisposition to the disease. Work in Newcastle funded by the MRC previously identified that abnormalities in genes for complement proteins predispose to disease in around 50% of cases. The complement system plays an important role in protecting the body from infection by killing micro-organisms. If these complement proteins are faulty then the body's own kidney cells can be damaged by these same mechanisms. This key discovery ultimately resulted in the introduction of a drug which prevents complement activation, Eculizumab. This revolutionised treatment for patients with this condition and prevented them from developing kidney failure.More recently we have identified a subgroup of aHUS patients who do not respond to this drug. In these families we are undertaking genetic analysis to identify the underlying cause and are identifying genes that do not appear to be involved in the complement pathway. By identifying these novel genetic causes of aHUS and by defining simple blood tests that will quickly identify these patients we will prevent ineffective use of complement inhibitory therapy, avoiding the infectious side effects of this medication. Additionally, by identifying new pathways responsible for disease, new drugs can be developed to target these pathway resulting in the same translational benefits seen following our original discover. Ultimately this work will allow personalised treatment for our patients with aHUS.