Atypical Haemolytic Uraemic Syndrome Associated with a Hybrid Complement Gene

Venables, Julian P.; Strain, Lisa; Routledge, Danny; Bourn, David; Powell, Helen; Warwicker, Paul; Diaz-Torres, Martha; Sampson, Anne; Mead, Paul; Webb, Michelle; Pirson, Yves; Jackson, Michael S.; Hughes, Anne E.; Wood, Katrina; Goodship, Judith A.; Goodship, Timothy H.J.

doi:10.1371/journal.pmed.0030431

Cited by 188 publications

(171 citation statements)

References 22 publications

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“…Two cousins with disease onset at the ages of 6 months and 20 years (the former also carried the CFI mutation) 3 and two patients with sporadic aHUS (onset: 1 and 22 years) had a previously described heterozygous CFH/CFHR1 hybrid gene including exons 1-21 of CFH and exons 5 and 6 of CFHR1. 13 In a sporadic patient (onset at 5 months), we found another previously reported hybrid CFH/CFHR1 14 including exons 1-22 of CFH and exon 6 of CFHR1. Four of five carriers of CFH/CFHR1 hybrid genes developed ESRD early after disease onset.…”

Section: Genomic Cfh-cfhrs Rearrangementsmentioning

confidence: 56%

“…CFH/CFHR rearrangements were associated with poor clinical prognosis and high risk of post-transplant recurrence. 13,15,16 Of relevance, in a family where two individuals have been affected by aHUS, we found a novel duplication in the CFH-CFHR genomic area. The duplication results in an additional copy of CFHR3 and the formation of an extra hybrid copy of CFHR1 derived from the fusion of the first five exons of CFHR1 and the last exon 23 of CFH.…”

Section: Discussionmentioning

confidence: 75%

“…16 In summary, we describe a new CFHR1/CFH hybrid gene that adds to previously reported genomic rearrangements in the CFH-CFHR region. [13][14][15][16] Such rearrangements are associated with post-transplant recurrence, which however, can be prevented by eculizumab prophylaxis. 16,28 Because of the unaffordable economic burden of such an expensive drug, identification of patients who are the most likely to benefit from eculizumab is mandatory.…”

Section: Discussionmentioning

confidence: 99%

“…The most frequently observed NAHR is the deletion of CFHR3-CFHR1 that is strongly associated with anti-FH autoantibodies and aHUS. 7,[10][11][12] Several hybrid genes deriving from NAHR in the CFH-CFHR region have been also identified in aHUS, [13][14][15] including hybrid CFH/CFHR1 and CFH/CFHR3 genes. Recently, a hybrid CFHR1/CFH gene that encodes a fusion protein with the first three short consensus repeats (SCRs) of FHR1 and the last two SCRs of FH has been reported in a sporadic case of aHUS.…”

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confidence: 99%

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A Novel Atypical Hemolytic Uremic Syndrome–Associated Hybrid CFHR1/CFH Gene Encoding a Fusion Protein That Antagonizes Factor H–Dependent Complement Regulation

Valoti

Alberti

Tortajada

et al. 2015

Journal of the American Society of Nephrology

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Genomic aberrations affecting the genes encoding factor H (FH) and the five FH-related proteins (FHRs) have been described in patients with atypical hemolytic uremic syndrome (aHUS), a rare condition characterized by microangiopathic hemolytic anemia, thrombocytopenia, and ARF. These genomic rearrangements occur through nonallelic homologous recombinations caused by the presence of repeated homologous sequences in CFH and CFHR1-R5 genes. In this study, we found heterozygous genomic rearrangements among CFH and CFHR genes in 4.5% of patients with aHUS. CFH/CFHR rearrangements were associated with poor clinical prognosis and high risk of post-transplant recurrence. Five patients carried known CFH/CFHR1 genes, but we found a duplication leading to a novel CFHR1/CFH hybrid gene in a family with two affected subjects. The resulting fusion protein contains the first four short consensus repeats of FHR1 and the terminal short consensus repeat 20 of FH. In an FH-dependent hemolysis assay, we showed that the hybrid protein causes sheep erythrocyte lysis. Functional analysis of the FHR1 fraction purified from serum of heterozygous carriers of the CFHR1/ CFH hybrid gene indicated that the FHR1/FH hybrid protein acts as a competitive antagonist of FH. Furthermore, sera from carriers of the hybrid CFHR1/CFH gene induced more C5b-9 deposition on endothelial cells than control serum. These results suggest that this novel genomic hybrid mediates disease pathogenesis through dysregulation of complement at the endothelial cell surface. We recommend that genetic screening of aHUS includes analysis of CFH and CFHR rearrangements, particularly before a kidney transplant.

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Section: Genomic Cfh-cfhrs Rearrangementsmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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A Novel Atypical Hemolytic Uremic Syndrome–Associated Hybrid CFHR1/CFH Gene Encoding a Fusion Protein That Antagonizes Factor H–Dependent Complement Regulation

Valoti

Alberti

Tortajada

et al. 2015

Journal of the American Society of Nephrology

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“…Approximately 50% of patients with aHUS have mutations in one of the complement regulatory proteins: Factor H (CFH), factor I (CFI), or membrane co-factor protein (MCP) (3)(4)(5). More recently, mutations in factor B (CFB) and C3 have been associated with aHUS (6,7).…”

Section: H Emolytic Uremic Syndrome (Hus) Is a Clinical Triad Ofmentioning

confidence: 99%

Complement Inhibitor Eculizumab in Atypical Hemolytic Uremic Syndrome

Mache

Acham-Roschitz

Frémeaux‐Bacchi

et al. 2009

Clinical Journal of the American Society of Nephrology

144

103

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Background and objectives: Atypical hemolytic uremic syndrome (aHUS) is associated with a congenital or acquired dysregulation of the complement alternative pathway that leads to continuous complement activation on host cells causing inflammation and damage. Eculizumab, a humanized mAb against complement protein C5, inhibits activation of the terminal complement pathway.Design, setting, participants, & measurements: We report an adolescent with relapsing unclassified aHUS. On admission, a high plasma creatinine level indicated a poor prognosis, and hemodialysis had to be started. Plasma exchanges were initially effective against the microangiopathic hemolytic activity and allowed a temporary improvement of renal function with termination of hemodialysis after 7 wk. Subsequently, plasma exchanges (three times per week) failed to prevent ongoing aHUS activity and progressive renal failure. After 12 wk, aHUS treatment was switched to eculizumab.Results: Eculizumab was effective in terminating the microangiopathic hemolytic process in two aHUS relapses; however, after normalization of complement activity, aHUS recurred and ultimately led to anuric end-stage renal failure.Conclusions: In this patient, complement inhibition by eculizumab temporarily terminated the microangiopathic hemolytic activity. Nevertheless, renal damage as a result of preceding and subsequent aHUS activity resulted in end-stage renal failure; therefore, therapeutic success may depend on early administration of eculizumab. The optimal duration of treatment may be variable and remains to be determined.

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Eculizumab Dosing Regimen in Atypical HUS: Possibilities for Individualized Treatment

Volokhina

Wijnsma

Molen

et al. 2017

Clin Pharma and Therapeutics

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Recent studies indicate that eculizumab is often given in excess to atypical hemolytic uremic syndrome (aHUS) patients. Individualization of treatment is thus highly requested; however, data on the pharmacokinetics and pharmacodynamics of eculizumab remain limited. We analyzed 11 patients during induction (weekly), maintenance (2-weekly), and tapering (every 3-8 weeks) phases of treatment. The trough eculizumab levels increased with each additional dose during the induction phase (depending on body weight). During maintenance, high eculizumab concentrations of up to 772 μg/mL were observed. The levels decreased with each following dose during tapering (3- and 4-week intervals); however, three patients maintained target eculizumab levels over long time periods (30-48 weeks). At intervals of 6-8 weeks, target eculizumab levels were no longer attained. Serum samples with eculizumab concentrations ≥50 μg/mL showed adequate complement blockade. Our data provide essential insight for optimization of eculizumab dosing schemes and lessening of therapy burden for the patients and cost of the treatment.

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Atypical Haemolytic Uraemic Syndrome Associated with a Hybrid Complement Gene

Cited by 188 publications

References 22 publications

A Novel Atypical Hemolytic Uremic Syndrome–Associated Hybrid CFHR1/CFH Gene Encoding a Fusion Protein That Antagonizes Factor H–Dependent Complement Regulation

A Novel Atypical Hemolytic Uremic Syndrome–Associated Hybrid CFHR1/CFH Gene Encoding a Fusion Protein That Antagonizes Factor H–Dependent Complement Regulation

Complement Inhibitor Eculizumab in Atypical Hemolytic Uremic Syndrome

Eculizumab Dosing Regimen in Atypical HUS: Possibilities for Individualized Treatment

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