Systemic complement activation and complement gene analysis in enterohaemorrhagic Escherichia coli-associated paediatric haemolytic uraemic syndrome
Systemic complement activation and complement gene analysis in enterohaemorrhagic Escherichia coli-associated paediatric haemolytic uraemic syndrome
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DOI：
10.1093/ndt/gfw078
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发表时间：
2016-07-01
影响因子：
6.1
通讯作者：
Pape, Lars
中科院分区：
文献类型：
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作者：
Ahlenstiel-Grunow, Thurid;Hachmeister, Svenja;Pape, Lars
与非典型溶血性尿毒综合征（阿胡斯）相反，关于小儿肠出血性大肠杆菌诱导的HUS中补体系统的全身激活和补体基因突变，仅发表了单个病例报告和有限的数据（EHEC-HUS）.补体激活在初步诊断为HUS后的4个时间点（第1周、第2周、第3个月和第6个月）分析25例EHEC HUS患儿的CH 50、APH 50、C3 d、sC 5 b-9。7名患者接受了补体C5抑制剂依库珠单抗。对所有患者进行了涉及补体调节和凝血止血的共89个基因的靶向下一代测序，除了接受依库珠单抗治疗的患者外，在整个观察时间内，经典（CH 50）和替代（APH 50）补体途径的活性均正常或甚至升高。相反，可溶性末端补体复合物（sC 5 b-9）的平均浓度在第一个时间点显著升高（平均498 ng/mL），2周后降至正常值。最初升高（42 mU/L）的中位C3 d浓度从第2周起达到正常水平。诊断HUS时sC 5 b-9水平> 320 ng/mL与动脉高血压、水肿和血小板计数降低相关，但与透析持续时间无关。基因分析揭示了各种变化，可能有一个修改的临床course.Complement激活在急性期EHEC-HUS的影响，增加水平的sC 5 b-9，预示着一个穷人的结果。补体改变似乎比以前认为的在EHEC-HUS患者中更频繁，并且被怀疑在疾病的严重程度中起作用。
In contrast to atypical haemolytic uraemic syndrome (aHUS), only single case reports and limited data have been published on systemic activation of the complement system and mutations in complement genes in paediatric enterohaemorrhagic Escherichia coli-induced HUS (EHEC-HUS).Complement activation (CH50, APH50, C3d, sC5b-9) was analysed at four timepoints (Week 1, Week 2, Month 3 and Month 6 after primary diagnosis of HUS) in 25 children with EHEC-HUS. Seven patients received the complement C5 inhibitor eculizumab. Targeted next generation sequencing for a total of 89 genes involved in complement regulation and coagulation and haemostasis was performed in all patients.Activity of classical (CH50) and alternative (APH50) complement pathways was normal or even elevated throughout the observation time, except for patients under eculizumab treatment. In contrast, the mean concentration of the soluble terminal complement complex (sC5b-9) was significantly elevated at the first timepoint (mean 498 ng/mL), dropping to normal values after 2 weeks. Initially elevated (42 mU/L) median C3d concentration reached normal levels from Week 2. Levels of sC5b-9 > 320 ng/mL at the time of HUS diagnosis were associated with arterial hypertension, oedema and lower platelet counts, but not with the duration of dialysis. Genetic analysis revealed various changes that may have had a modifying impact on the clinical course.Complement activation at the acute phase of EHEC-HUS, indicated by increased levels of sC5b-9, predicts a poor outcome. Complement alterations appear to be more frequent in patients with EHEC-HUS than previously thought and are suspected to have a role in the severity of the disease.