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

Ahlenstiel-Grunow, Thurid; Hachmeister, Svenja; Bange, Franz; Wehling, Cyrill; Kirschfink, Michael; Bergmann, Carsten; Pape, Lars

doi:10.1093/ndt/gfw078

Cited by 21 publications

(22 citation statements)

References 30 publications

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“…This complement activation normalized to control levels in remission, except for C3bBbP in STEC-HUS patients. Our results corroborate previous reports of complement activation in children with STEC-HUS [19–23]. …”

Section: Discussionsupporting

confidence: 93%

“…We were surprised to see that in almost 30 % of STEC-HUS patients, a genetic complement aberration could be identified. Several case reports of STEC-HUS patients with complement mutations have been published [35, 39–42], but so far, only one larger cohort was investigated; in 3/25 (12.0 %) STEC-HUS patients, a mutation was identified [23]. …”

Section: Discussionmentioning

confidence: 99%

“…Anecdotal reports have shown low C3 levels and increased complement activation products in children with STEC-HUS, but usually only a few activation markers were measured and in a small research population [19–23]. To answer the question of whether alterations in the alternative complement pathway are common in patients with all forms of HUS, we prospectively determined genetic and serological complement profiles in serum and plasma of children with STEC-HUS or aHUS in the acute and convalescent phase of the disease.…”

Section: Introductionmentioning

confidence: 99%

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Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome

et al. 2016

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BackgroundThe role of complement in the atypical form of hemolytic uremic syndrome (aHUS) has been investigated extensively in recent years. As the HUS-associated bacteria Shiga-toxin-producing Escherichia coli (STEC) can evade the complement system, we hypothesized that complement dysregulation is also important in infection-induced HUS.MethodsSerological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, αFH) and genetic profiles (CFH, CFI, CD46, CFB, C3) of the alternative complement pathway were prospectively determined in the acute and convalescent phase of disease in children newly diagnosed with STEC-HUS or aHUS. Serological profiles were compared with those of 90 age-matched controls.ResultsThirty-seven patients were studied (26 STEC-HUS, 11 aHUS). In 39 % of them, including 28 % of STEC-HUS patients, we identified a genetic and/or acquired complement abnormality. In all patient groups, the levels of investigated alternative pathway (AP) activation markers were elevated in the acute phase and normalized in remission. The levels were significantly higher in aHUS than in STEC-HUS patients.ConclusionsIn both infection-induced HUS and aHUS patients, complement is activated in the acute phase of the disease but not during remission. The C3d/C3 ratio displayed the best discrepancy between acute and convalescent phase and between STEC-HUS and aHUS and might therefore be used as a biomarker in disease diagnosis and monitoring. The presence of aberrations in the alternative complement pathway in STEC-HUS patients was remarkable, as well.Electronic supplementary materialThe online version of this article (doi:10.1007/s00467-016-3496-0) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome

et al. 2016

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“…Forty years later, the demonstration that atypical hemolytic uremic syndrome (aHUS) was a disease of complement alternative pathway dysregulation (4), and that complement blockade therapy improved aHUS prognosis (5), gave a new impetus to the question of a role of complement activation in Shiga toxin-associated HUS. Indeed, elevated plasma levels of complement activation biomarkers were documented at the acute phase of post diarrheal/typical/Shiga toxin HUS (6)(7)(8)(9)(10)(11). In vitro studies and animal models experiments demonstrated that Shiga toxin generates a cascade of endothelial/podocyte injury, complement activation, expression of chemokines and adhesion molecules, neutrophil activation, and thrombus formation (7,(12)(13)(14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

“…In nine of them, genetic screening was motivated by an unusually severe outcome, relapses, or post-transplant recurrence, suggesting that STEC infection triggers aHUS onset and/or preexisting complement variants amplify Shiga toxin-induced complement activation and endothelial/podocyte damage, and worsen disease severity (20)(21)(22)(23)(24)(25)(26)(27). However, seven reported patients who had complement variants had a favorable outcome (9,10,28), leaving the issue of the role of genetics in Shiga toxinassociated HUS unclear.…”

Section: Introductionmentioning

confidence: 99%

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

Frémeaux‐Bacchi

Sellier‐Leclerc

Vieira-Martins

et al. 2019

CJASN

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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.

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Guidelines on the Use of Therapeutic Apheresis in Clinical Practice – Evidence‐Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue

Schwartz

Winters

Padmanabhan

et al. 2019

J of Clinical Apheresis

1,392

1,195

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The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating and categorizing indications for the evidence‐based use of therapeutic apheresis (TA) in human disease. Since the 2007 JCA Special Issue (Fourth Edition), the committee has incorporated systematic review and evidence‐based approaches in the grading and categorization of apheresis indications. This Eighth Edition of the JCA Special Issue continues to maintain this methodology and rigor in order to make recommendations on the use of apheresis in a wide variety of diseases/conditions. The JCA Eighth Edition, like its predecessor, continues to apply the category and grading system definitions in fact sheets. The general layout and concept of a fact sheet that was introduced in the Fourth Edition, has largely been maintained in this edition. Each fact sheet succinctly summarizes the evidence for the use of TA in a specific disease entity or medical condition. The Eighth Edition comprises 84 fact sheets for relevant diseases and medical conditions, with 157 graded and categorized indications and/or TA modalities. The Eighth Edition of the JCA Special Issue seeks to continue to serve as a key resource that guides the utilization of TA in the treatment of human disease.

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

Abstract: 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.

Cited by 21 publications

References 30 publications

Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome

Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome

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

Guidelines on the Use of Therapeutic Apheresis in Clinical Practice – Evidence‐Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue

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