Personalised management of atypical haemolytic uraemic syndrome

溶血性尿毒症(HUS)是感染E.Coli O157细菌后的严重并发症。在大约10%的患者中，肾衰竭是由于细菌释放的毒素造成的。非典型HUS是一种较罕见的疾病，与这些细菌无关，在许多情况下，这种疾病有遗传易感性。在纽卡斯尔，由MRC资助的研究之前发现，补体蛋白基因的异常在大约50%的病例中易患疾病。补体系统在通过杀死微生物来保护身体免受感染方面发挥着重要作用。如果这些补体蛋白有缺陷，那么人体自身的肾脏细胞可能会受到同样的机制的损害。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。这使这种疾病患者的治疗发生了革命性的变化，防止了他们发展为肾衰竭。最近，我们发现了一组对这种药物没有反应的aHUS患者。在这些家族中，我们正在进行基因分析，以确定潜在的原因，并识别似乎与补体途径无关的基因。通过确定这些新的aHUS的遗传原因，并通过定义简单的血液测试来快速识别这些患者，我们将防止无效使用补体抑制治疗，避免这种药物的感染性副作用。此外，通过识别导致疾病的新途径，可以开发针对这些途径的新药，从而产生与我们最初发现相同的翻译益处。最终，这项工作将允许我们的AHUS患者进行个性化治疗。

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.