Systemic complement activation and complement gene analysis in enterohaemorrhagic Escherichia coli-associated paediatric haemolytic uraemic syndrome

Nephrol Dial Transplant. 2016 Jul;31(7):1114-21. doi: 10.1093/ndt/gfw078. Epub 2016 May 4.


Background: 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).

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: complement; complement inhibition; haemolytic uraemic syndrome; mutations.

MeSH terms

  • Adolescent
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Biomarkers / blood
  • Child
  • Child, Preschool
  • Complement Activation*
  • Complement Inactivating Agents / therapeutic use
  • Complement System Proteins / genetics*
  • Complement System Proteins / metabolism
  • Enterohemorrhagic Escherichia coli / immunology*
  • Female
  • Hemolytic-Uremic Syndrome / blood
  • Hemolytic-Uremic Syndrome / drug therapy
  • Hemolytic-Uremic Syndrome / immunology*
  • Humans
  • Male
  • Transcriptome / immunology


  • Antibodies, Monoclonal, Humanized
  • Biomarkers
  • Complement Inactivating Agents
  • Complement System Proteins
  • eculizumab