Where next with atypical hemolytic uremic syndrome?

Jokiranta, T. Sakari; Zipfel, Peter F.; Frémeaux‐Bacchi, Véronique; Taylor, Christopher M.; Goodship, T; Noris, Marina

doi:10.1016/j.molimm.2007.06.003

Cited by 60 publications

(42 citation statements)

References 79 publications

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“…29,30,48 The same occurred in most patients with combined mutations described here, in whom aHUS manifested on triggering conditions (mainly infections), indicating that environmental factors are critical determinants of HUS development.…”

Section: Discussionsupporting

confidence: 64%

Combined Complement Gene Mutations in Atypical Hemolytic Uremic Syndrome Influence Clinical Phenotype

Bresin

Rurali

Caprioli

et al. 2013

Journal of the American Society of Nephrology

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Several abnormalities in complement genes reportedly contribute to atypical hemolytic uremic syndrome (aHUS), but incomplete penetrance suggests that additional factors are necessary for the disease to manifest. Here, we sought to describe genotype-phenotype correlations among patients with combined mutations, defined as mutations in more than one complement gene. We screened 795 patients with aHUS and identified single mutations in 41% and combined mutations in 3%. Only 8%-10% of patients with mutations in CFH, C3, or CFB had combined mutations, whereas approximately 25% of patients with mutations in MCP or CFI had combined mutations. The concomitant presence of CFH and MCP risk haplotypes significantly increased disease penetrance in combined mutated carriers, with 73% penetrance among carriers with two risk haplotypes compared with 36% penetrance among carriers with zero or one risk haplotype. Among patients with CFH or CFI mutations, the presence of mutations in other genes did not modify prognosis; in contrast, 50% of patients with combined MCP mutation developed end stage renal failure within 3 years from onset compared with 19% of patients with an isolated MCP mutation. Patients with combined mutations achieved remission with plasma treatment similar to patients with single mutations. Kidney transplant outcomes were worse, however, for patients with combined MCP mutation compared with an isolated MCP mutation. In summary, these data suggest that genotyping for the risk haplotypes in CFH and MCP may help predict the risk of developing aHUS in unaffected carriers of mutations. Furthermore, screening patients with aHUS for all known disease-associated genes may inform decisions about kidney transplantation.

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Section: Discussionsupporting

confidence: 64%

Combined Complement Gene Mutations in Atypical Hemolytic Uremic Syndrome Influence Clinical Phenotype

Bresin

Rurali

Caprioli

et al. 2013

Journal of the American Society of Nephrology

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322

290

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“…31 As multiple membrane-bound complement regulators bind to or are expressed at endothelial surface, in the absence of inciting events, the endothelium can control complement even when activity of one regulator is reduced by gene mutations. 32 However, due to defective complement regulation, upon endothelial activation via diverse triggers (infections, drugs, pregnancy, or ischemia/reperfusion), complement products settle on endothelial cells and likely initiate the thrombotic microangiopathy process. 2 Thus, remission state is plausibly metastable in patients with complement gene abnormalities, and any of the above triggers may precipitate a relapse.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of complement activation in aHUS and how to monitor eculizumab therapy

Noris

Galbusera

Gastoldi

et al. 2014

Blood

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Key Points• Endothelial-restricted complement activation occurs in aHUS, and clinical remission relies on efficient endothelial complement inhibition.• Ex vivo serum-induced endothelial C5b-9 deposits are a sensitive tool to monitor complement activation and eculizumab effectiveness in aHUS.Atypical hemolytic-uremic syndrome (aHUS) is associated with genetic complement abnormalities/anti-complement factor H antibodies, which paved the way to treatment with eculizumab. We studied 44 aHUS patients and their relatives to (1) test new assays of complement activation, (2) verify whether such abnormality occurs also in unaffected mutation carriers, and (3) search for a tool for eculizumab titration. An abnormal circulating complement profile (low C3, high C5a, or SC5b-9) was found in 47% to 64% of patients, irrespective of disease phase. Acute aHUS serum, but not serum from remission, caused wider C3 and C5b-9 deposits than control serum on unstimulated human microvascular endothelial cells (HMEC-1). In adenosine 59-diphosphate-activated HMEC-1, also sera from 84% and 100% of patients in remission, and from all unaffected mutation carriers, induced excessive C3 and C5b-9 deposits. At variance, in most patients with C3 glomerulopathies/immune complex-associated membranoproliferative glomerulonephritis, serum-induced endothelial C5b-9 deposits were normal. In 8 eculizumab-treated aHUS patients, C3/SC5b-9 circulating levels did not change posteculizumab, whereas serum-induced endothelial C5b-9 deposits normalized after treatment, paralleled or even preceded remission, and guided drug dosing and timing. These results point to efficient complement inhibition on endothelium for aHUS treatment. C5b-9 endothelial deposits might help monitor eculizumab effectiveness, avoid drug overexposure, and save money considering the extremely high cost of the drug. (Blood. 2014;124(11):1715-1726

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Section: Introductionmentioning

confidence: 99%

“…The mutations and polymorphisms in these proteins are mostly found in heterozygous form and can affect both the secretion and function of the proteins, leading to impaired regulation of the alternative pathway of the complement system [2]. Since many of the patients carry several heterozygous mutations or polymorphisms in different genes, it has been suggested that a combination of several simultaneous hits strongly predisposes to aHUS [20].The complement system, which is a part of the innate immune system, can be activated through three different pathways, the classical, lectin and alternative pathways. The classical pathway is initiated through the interaction of C1 with ligands such as immune complexes.…”

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confidence: 99%

Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I

et al. 2009

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The complement system is regulated by inhibitors such as factor I (FI), a serine protease that degrades activated complement factors C4b and C3b in the presence of specific cofactors. Mutations and polymorphisms in FI and its cofactors are associated with atypical hemolytic uremic syndrome (aHUS). All 14 complement factor I mutations associated with aHUS analyzed in this study were heterozygous and generated premature stop codons (six) or amino acid substitutions (eight). Almost all of the mutants were expressed by human embryonic kidney 293 cells but only six mutants were secreted into the medium, three of which were at lower levels than WT. The remaining eight mutants were not secreted but sensitive to deglycosylation with endoglycosidase H, indicating that they were retained early in the secretory pathway. Six secreted mutants were purified and five of them were functionally altered in degradation of C4b/C3b in the fluid-phase in the presence of various cofactors and on endothelial cells. Three mutants cleaved surfacebound C3b less efficiently than WT. The D501N mutant was severely impaired both in solution and on surface irrespective of the cofactor used. In conclusion, mutations in complement factor I affect both secretion and function of FI, which leads to impaired regulation of the complement system in aHUS.Key words: Atypical hemolytic uremic syndrome . Complement . Factor I IntroductionHemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure [1]. The typical form (diarrhea-positive HUS), which affects 90% of the HUS patients, is associated with infection of Shiga toxin-secreting Escherichia coli. Patients, who are mainly children, suffer from bloody diarrhea, recurrences are uncommon and their prognoses are often good [1]. The other form, called atypical hemolytic uremic syndrome (aHUS), occurs at any age, may be sporadic or familial and has a poor prognosis as approximately 50% of the patients progress to end-stage renal disease and 25% die during the acute phase of the disease. The sporadic form of aHUS may be triggered by non-enteric infections, viruses, pregnancy, drugs, malignancies or transplantation [2]. The familial form of aHUS has now been shown to be associated with genetic abnormalities in complement regulators like factor H (FH) [3][4][5][6], factor I (FI) [4,[7][8][9][10], membrane cofactor protein (MCP) Ã These authors contributed equally to this work. 172 [4,[11][12][13][14], C4b-binding protein (C4BP) [15], factor B (FB) [16] and C3 [17] or autoantibodies against FH [18,19]. The mutations and polymorphisms in these proteins are mostly found in heterozygous form and can affect both the secretion and function of the proteins, leading to impaired regulation of the alternative pathway of the complement system [2]. Since many of the patients carry several heterozygous mutations or polymorphisms in different genes, it has been suggested that a combination of several simultaneous hits strongly predisposes to aHUS [20].The c...

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Where next with atypical hemolytic uremic syndrome?

Cited by 60 publications

References 79 publications

Combined Complement Gene Mutations in Atypical Hemolytic Uremic Syndrome Influence Clinical Phenotype

Combined Complement Gene Mutations in Atypical Hemolytic Uremic Syndrome Influence Clinical Phenotype

Dynamics of complement activation in aHUS and how to monitor eculizumab therapy

Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I

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