Complement Gene Variants and Shiga Toxin–Producing Escherichia coli–Associated Hemolytic Uremic Syndrome

Abstract

Background and objectives Inherited complement hyperactivation is critical for the pathogenesis of atypical hemolytic uremic syndrome (HUS) but undetermined in postdiarrheal HUS. Our aim was to investigate complement activation and variants of complement genes, and their association with disease severity in children with Shiga toxin-associated HUS. Design, setting, participants, & measurements Determination of complement biomarkers levels and nextgeneration sequencing for the six susceptibility genes for atypical HUS were performed in 108 children with a clinical diagnosis of post-diarrheal HUS (75 Shiga toxin-positive, and 33 Shiga toxin-negative) and 80 French controls. As an independent control cohort, we analyzed the genotypes in 503 European individuals from the 1000 Genomes Project. Results During the acute phase of HUS, plasma levels of C3 and sC5b-9 were increased, and half of patients had decreased membrane cofactor protein expression, which normalized after 2 weeks. Variants with minor allele frequency ,1% were identified in 12 Shiga toxin-positive patients with HUS (12 out of 75, 16%), including pathogenic variants in four (four out of 75, 5%), with no significant differences compared with Shiga toxinnegative patients with HUS and controls. Pathogenic variants with minor allele frequency ,0.1% were found in three Shiga toxin-positive patients with HUS (three out of 75, 4%) versus only four European controls (four out of 503, 0.8%) (odds ratio, 5.2; 95% confidence interval, 1.1 to 24; P=0.03). The genetic background did not significantly affect dialysis requirement, neurologic manifestations, and sC5b-9 level during the acute phase, and incident CKD during follow-up. However, the only patient who progressed to ESKD within 3 years carried a factor H pathogenic variant. Conclusions Rare variants and complement activation biomarkers were not associated with severity of Shiga toxin-associated HUS. Only pathogenic variants with minor allele frequency ,0.1% are more frequent in Shiga toxin-positive patients with HUS than in controls.

Complement activation in sickle cell disease: Dependence on cell density, hemolysis and modulation by hydroxyurea therapy

“…Elevated plasma sC5b‐9 is a hallmark of ongoing complement activation and is measured in clinical practice. The concentration of sC5b‐9 in SCD found here was similar to diseases where the contribution of complement is clearly established, such as C3 glomerulopathies and anti‐neutrophil cytoplasmic antibody‐associated vasculitis . Over 60% of the untreated patients presented with elevated sC5b‐9.…”

Low C3 Serum Levels Predict Severe Forms of STEC-HUS With Neurologic Involvement

“…Moreover, the conclusions of many pediatric studies linking complement activation and disease evolution are conflicting. While some studies showed a relationship between increased activity of complement alternative pathway and poor prognosis, other reports denied such association or just observed trends toward more severe disease, which did not reach statistically significant differences probably due to the small sample size analyzed (20)(21)(22)(23)(24)(25)(26).…”

“…Despite all these relevant findings, only a few clinical studies have correlated the complement system activation with the clinical course. Furthermore, they presented conflicting results and most of them reported small series of patients, or even included patients without microbiological diagnosis (20)(21)(22)(23)(24)(25)(26).…”

Epidemiology of Shiga Toxin-Producing Escherichia coli Infections in Southern Italy after Implementation of Symptom-Based Surveillance of Bloody Diarrhea in the Pediatric Population

“…The risk of developing HUS could be associated with genetic factors [34]. This aspect could be hypothesized in the two female twins with STEC O26 infection but, unfortunately, this issue was not investigated.…”