Véronique Frémeaux-Bacchi1,2, Anne-Laure Sellier-Leclerc3, Paula Vieira-Martins4, Sophie Limou5, Theresa Kwon6, Annie Lahoche7, Robert Novo7, Brigitte Llanas8, François Nobili9, Gwenaëlle Roussey10, Mathilde Cailliez11, Tim Ulinski12, Georges Deschênes6, Corinne Alberti13, François-Xavier Weill14, Patricia Mariani15, Chantal Loirat6. 1. Service d'Immunologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France; veronique.fremeaux-bacchi@aphp.fr. 2. Team "Complement and Disease," Centre de recherche des Cordeliers, Sorbonne Université, INSERM, Paris, France. 3. Pediatric Nephrology Department, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France. 4. Service d'Immunologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France. 5. Institute for Transplantation in Urology and Nephrology, Centre Hospitalo-Universitaire de Nantes, Centre de Recherche en Transplantation et Immunologie, Institut National de la Santé et de la Recherche Médicale U1064, Université de Nantes, Ecole Centrale de Nantes, Nantes, France. 6. Pediatric Nephrology Department. 7. Pediatric Nephrology Department, Hôpital Jeanne de Flandre, Centre Hospitalo-Universitaire de Lille, Lille, France. 8. Pediatric Nephrology Department, Centre Hospitalo-Universitaire de Bordeaux, Bordeaux, France. 9. Pediatric Nephrology Department, Centre Hospitalo-Universitaire de Besançon, Besançon, France. 10. Pediatric Nephrology Department, Centre Hospitalo-Universitaire de Nantes, Nantes, France. 11. Pediatric Nephrology Department, Centre Hospitalo-Universitaire de Marseille, Marseille, France. 12. Pediatric Nephrology Department, Hôpital Trousseau, University Pierre and Marie Curie, Assistance Publique-Hôpitaux de Paris, Paris, France; and. 13. Unit of Clinical Epidemiology, Institut National de la Santé et de la Recherche Médicale U1123 and Centre d'Investigation Clinique-Epidémiologie Clinique 1426, and. 14. Institut Pasteur, Unité des Bactéries Pathogènes Entériques, Centre National de Référence des Escherichia coli, Shigella et Salmonella, Paris, France. 15. Laboratory of Microbiology, Escherichia coli Associated National Reference Center, Hôpital Robert Debré, University Paris Diderot, Assistance Publique-Hôpitaux de Paris, Paris, France.
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 next-generation 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 toxin-negative 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.
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 next-generation 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 toxin-negative 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.
Authors: J R Ferraris; V Ferraris; A B Acquier; P B Sorroche; M S Saez; A Ginaca; C F Mendez Journal: Clin Exp Immunol Date: 2015-05-05 Impact factor: 4.330
Authors: Rachel C Challis; Geisilaine S R Araujo; Edwin K S Wong; Holly E Anderson; Atif Awan; Anthony M Dorman; Mary Waldron; Valerie Wilson; Vicky Brocklebank; Lisa Strain; B Paul Morgan; Claire L Harris; Kevin J Marchbank; Timothy H J Goodship; David Kavanagh Journal: J Am Soc Nephrol Date: 2015-10-21 Impact factor: 10.121
Authors: Sjoerd A M E G Timmermans; Jan G M C Damoiseaux; Alexis Werion; Chris P Reutelingsperger; Johann Morelle; Pieter van Paassen Journal: Kidney Int Rep Date: 2021-02-03