Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome

Bienaimé, Frank; Dragon-Durey, Marie-Agnès; Regnier, Catherine H.; Nilsson, Sara C.; Kwan, W. H.; Blouin, Jacques; Jablonski, Mathieu; Renault, Nicolas; Rameix‐Welti, Marie‐Anne; Loirat, Chantal; Sautès-Fridman, Catheriné; Villoutreix, Bruno O.; Blom, Anna M.; Frémeaux‐Bacchi, Véronique

doi:10.1038/ki.2009.472

Cited by 166 publications

(165 citation statements)

References 44 publications

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“…Heterozygous mutations in the THBD gene were recently documented in Italy [47,54] . Cells with anomalous THBD are less efficient at inactivating C3b.…”

Section: Thbd Mutationsmentioning

confidence: 99%

“…In Europe, five national and continental registries report more than 1000 patients with complement abnormalities with an incidence of approximately 1.5-1.8 per million inhabitants [46,47] . Overall, aHUS accounts for 5% of all HUS cases.…”

Section: Epidemiologymentioning

confidence: 99%

“…Cells with anomalous THBD are less efficient at inactivating C3b. THBD mutations account for 3%-5% of patients with aHUS, according to registries from United States [77] and Italy [47] . In addition, mutations related to the genes encoding proteins that activate and potentiate the complement pathway may occur.…”

Section: Thbd Mutationsmentioning

confidence: 99%

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Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations

Salvadori

Bertoni²

2013

WJN

114

111

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Hemolytic uremic syndrome (HUS) is a rare disease. In this work the authors review the recent findings on HUS, considering the different etiologic and pathogenetic classifications. New findings in genetics and, in particular, mutations of genes that encode the complement-regulatory proteins have improved our understanding of atypical HUS. Similarly, the complement proteins are clearly involved in all types of thrombotic microangiopathy: typical HUS, atypical HUS and thrombotic thrombocytopenic purpura (TTP). Furthermore, several secondary HUS appear to be related to abnormalities in complement genes in predisposed patients. The authors highlight the therapeutic aspects of this rare disease, examining both "traditional therapy" (including plasma therapy, kidney and kidneyliver transplantation) and "new therapies". The latter include anti-Shiga-toxin antibodies and anti-C5 monoclonal antibody "eculizumab". Eculizumab has been recently launched for the treatment of the atypical HUS, but it appears to be effective in the treatment of typical HUS and in TTP. Future therapies are in phases Ⅰ and Ⅱ. They include anti-C5 antibodies, which are more purified, less immunogenic and absorbed orally and, anti-C3 antibodies, which are more powerful, but potentially less safe. Additionally, infusions of recombinant complement-regulatory proteins are a potential future therapy.

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“…Heterozygous mutations in the THBD gene were recently documented in Italy [47,54] . Cells with anomalous THBD are less efficient at inactivating C3b.…”

Section: Thbd Mutationsmentioning

confidence: 99%

Section: Epidemiologymentioning

confidence: 99%

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Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations

Salvadori

Bertoni²

2013

WJN

114

111

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“…In reality, the incidence of complement-aHUS is not known precisely. However, more than 1000 aHUS patients investigated for complement abnormalities have been reported from five European registries or series [17,18,[20][21][22][26][27][28] and one from the USA [23].…”

Section: Epidemiologymentioning

confidence: 99%

Atypical Hemolytic Uremic Syndrome

Loirat¹,

Frémeaux‐Bacchi²

2016

Pediatric Kidney Disease

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Hemolytic uremic syndrome (HUS) is defined by the triad of mechanical hemolytic anemia, thrombocytopenia and renal impairment. Atypical HUS (aHUS) defines non Shiga-toxin-HUS and even if some authors include secondary aHUS due to Streptococcus pneumoniae or other causes, aHUS designates a primary disease due to a disorder in complement alternative pathway regulation. Atypical HUS represents 5 -10% of HUS in children, but the majority of HUS in adults. The incidence of complement-aHUS is not known precisely. However, more than 1000 aHUS patients investigated for complement abnormalities have been reported. Onset is from the neonatal period to the adult age. Most patients present with hemolytic anemia, thrombocytopenia and renal failure and 20% have extra renal manifestations. Two to 10% die and one third progress to end-stage renal failure at first episode. Half of patients have relapses. Mutations in the genes encoding complement regulatory proteins factor H, membrane cofactor protein (MCP), factor I or thrombomodulin have been demonstrated in 20-30%, 5-15%, 4-10% and 3-5% of patients respectively, and mutations in the genes of C3 convertase proteins, C3 and factor B, in 2-10% and 1-4%. In addition, 6-10% of patients have anti-factor H antibodies. Diagnosis of aHUS relies on 1) No associated disease 2) No criteria for Shigatoxin-HUS (stool culture and PCR for Shiga-toxins; serology for anti-lipopolysaccharides antibodies) 3) No criteria for thrombotic thrombocytopenic purpura (serum ADAMTS 13 activity > 10%). Investigation of the complement system is required (C3, C4, factor H and factor I plasma concentration, MCP expression on leukocytes and anti-factor H antibodies; genetic screening to identify risk factors). The disease is familial in approximately 20% of pedigrees, with an autosomal recessive or dominant mode of transmission. As penetrance of the disease is 50%, genetic counseling is difficult. Plasmatherapy has been first line treatment until presently, without unquestionable demonstration of efficiency. There is a high risk of post-transplant recurrence, except in MCP-HUS. Case reports and two phase II trials show an impressive efficacy of the complement C5 blocker eculizumab, suggesting it will be the next standard of care. Except for patients treated by intensive plasmatherapy or eculizumab, the worst prognosis is in factor H-HUS, as mortality can reach 20% and 50% of survivors do not recover renal function. Half of factor I-HUS progress to end-stage renal failure. Conversely, most patients with MCP-HUS have preserved renal function. Anti-factor H antibodies-HUS has favourable outcome if treated early.

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“…Complete FI deficiency is associated with recurrent infections and in some cases also with glomerulonephritis and autoimmune diseases such as systemic lupus erythematosus (Nilsson et al, 2007;Vyse et al, 1996). Heterozygous deficiency of FI predisposes to atypical haemolytic uremic syndrome (Bienaime et al, 2010;Nilsson et al, 2010a;Richards et al, 2001). In the current study we characterize the molecular defects of FI in two patients with complete FI deficiency carrying novel mutations in the CFI gene.…”

Section: Introductionmentioning

confidence: 99%