Epidemiological Approach to Identifying Genetic Predispositions for Atypical Hemolytic Uremic Syndrome

Sullivan, Maren; Erlic, Zoran; Hoffmann, Michael M.; Arbeiter, Klaus; Patzer, Ludwig; Budde, Klemens; Höppe, Bernd; Zeier, Martin; Lhotta, Karl; Rybicki, Lisa; Böck, Andreas; Berisha, Gani; Neumann, Hartmut P. H.

doi:10.1111/j.1469-1809.2009.00554.x

Cited by 66 publications

(61 citation statements)

References 37 publications

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“…In practice, some publications on (D-) HUS/aHUS in children include S pneumoniae -HUS, a frequent category in children [19]. Also, some publications on complement-HUS include some secondary aHUS [18,20], while others exclude the various causes indicated above (except pregnancy and contraceptive pill) [17,[21][22][23]. This may explain differences in results.…”

Section: Disease Name and Synonymsmentioning

confidence: 61%

“…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%

“…Gender and age at onset aHUS is equally frequent in boys and girls when onset occurs during childhood [17], while there is a female preponderance in adults [20]. aHUS occurs at any age, from the neonatal period to the adult age (extremes: 1 day to 83 years [17,18].…”

Section: Clinical Descriptionmentioning

confidence: 99%

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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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Section: Disease Name and Synonymsmentioning

confidence: 61%

Section: Epidemiologymentioning

confidence: 99%

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Atypical Hemolytic Uremic Syndrome

Loirat¹,

Frémeaux‐Bacchi²

2016

Pediatric Kidney Disease

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“…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%

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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“…Patients with aHUS present at any time of year, and may have had a family member with aHUS with or without a similar age of onset (36)(37)(38)(39). They rarely have bloody diarrhea, often have an insidious onset, and tend to have severe arterial hypertension and a relapsing course.…”

Section: Inborn Errors Of Metabolismmentioning

confidence: 99%