Successful Liver-Kidney Transplantation in Two Children With aHUS Caused by a Mutation in Complement Factor H

Jalanko, Hannu; Peltonen, Seija; Koskinen, Aino; Puntila, Juha; Isoniemi, Helena; Holmberg, C; Pinomäki, Anne; Armstrong, Elina; Koivusalo, Anna-Maria; Tukiainen, Eija; Mäkisalo, Heikki; Saland, Jeffrey M.; Remuzzi, Giuseppe; Córdoba, Sarai; Lassila, R.; Meri, Seppo; Jokiranta, T. Sakari

doi:10.1111/j.1600-6143.2007.02029.x

Cited by 90 publications

(64 citation statements)

References 22 publications

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“…However, patients with CFI or complement factor H (CFH) mutations have much worse prognoses since the FI and FH proteins are mainly produced in the liver. There have been some successful combined renal and liver transplantations where the patients with a CFH mutation received extensive plasma therapy before, during and after the operation and as a consequence do not show any evidence of disease in the renal graft [36,37]. It is important to assess the functional impact of mutations/polymorphisms identified in aHUS patients as this knowledge can affect the mode of treatment.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…In anti-CFH autoantibody-positive patients, add-on immunosuppression may be reasonable (11). In CFH mutation carriers, liver-kidney transplantations have occasionally been performed (17). aHUS is characterized by an impaired complement regulation.…”

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

143

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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“…The initial outcomes in patients with CFH mutations were disappointing [128] . Nevertheless, favorable outcomes have recently been reported in patients treated with intensive plasma therapy before and during surgery [129,130] .…”

Section: Combined Liver-kidney Transplantationmentioning

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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Successful Liver-Kidney Transplantation in Two Children With aHUS Caused by a Mutation in Complement Factor H

Cited by 90 publications

References 22 publications

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

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

Complement Inhibitor Eculizumab in Atypical Hemolytic Uremic Syndrome

Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations

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