Favorable Long-Term Outcome after Liver-Kidney Transplant for Recurrent Hemolytic Uremic Syndrome Associated with a Factor H Mutation

Saland, Jeffrey M.; Emre, Sükrü; Shneider, Benjamin L.; Benchimol, Corinne; Ames, Scott; Bromberg, Jonathan S.; Remuzzi, Giuseppe; Strain, Lisa; Goodship, Timothy H.J.

doi:10.1111/j.1600-6143.2006.01375.x

Cited by 110 publications

(83 citation statements)

References 30 publications

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“…Because CFH, CFI, and C3 are plasma proteins synthesized predominantly by the liver, kidney transplantation alone does not correct the defect. As reported previously, simultaneous liver-kidney transplantation prevented recurrences in patients with CFH mutations but had a high mortality rate (23,24,39,40).…”

Section: Discussionmentioning

confidence: 65%

Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype

Noris¹,

Caprioli²,

Bresin³

et al. 2010

Clinical Journal of the American Society of Nephrology

931

1,194

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Background and objectives: Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Most childhood cases are caused by Shiga toxin-producing bacteria. The other form, atypical HUS (aHUS), accounts for 10% of cases and has a poor prognosis. Genetic complement abnormalities have been found in aHUS.Design, setting, participants, and measurements: We screened 273 consecutive patients with aHUS for complement abnormalities and studied their role in predicting clinical phenotype and response to treatment. We compared mutation frequencies and localization and clinical outcome in familial (82) and sporadic (191) cases.Results: In >70% of sporadic and familial cases, gene mutations, disease-associated factor H (CFH) polymorphisms, or anti-CFH autoantibodies were found. Either mutations or CFH polymorphisms were also found in the majority of patients with secondary aHUS, suggesting a genetic predisposition. Familial cases showed a higher prevalence of mutations in SCR20 of CFH and more severe disease than sporadic cases. Patients with CFH or THBD (thrombomodulin) mutations had the earliest onset and highest mortality. Membrane-cofactor protein (MCP) mutations were associated with the best prognosis. Plasma therapy induced remission in 55 to 80% of episodes in patients with CFH, C3, or THBD mutations or autoantibodies, whereas patients with CFI (factor I) mutations were poor responders. aHUS recurred frequently after kidney transplantation except for patients with MCP mutations.Conclusions: Results underline the need of genetic screening for all susceptibility factors as part of clinical management of aHUS and for identification of patients who could safely benefit from kidney transplant.

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Section: Discussionmentioning

confidence: 65%

Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype

Noris¹,

Caprioli²,

Bresin³

et al. 2010

Clinical Journal of the American Society of Nephrology

931

1,194

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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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“…Recent studies suggest that this was due to heavy complement activation during the operation [32]. In 2006, a successful CLKT was performed on a 5-year old boy with complement factor H (CFH) mutations [33]. Before the operation, extensive plasma exchange (PE) was performed to remove the defective CFH.…”

Section: Clkt In Different Indicationsmentioning

confidence: 99%

Combined liver and kidney transplantation in children

Jalanko

Pakarinen

2013

Pediatr Nephrol

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Simultaneous combined liver-kidney transplantation (CLKT) is a rare operation in pediatric patients so that annually only 10-30 operations are performed worldwide. The main indications for CLKT are primary hyperoxaluria type 1 and autosomal recessive polycystic kidney disease. In addition, CLKT is indicated in individual patients with metabolic or cirrhotic liver diseases and end-stage kidney disease. The surgery and immediate post-operative management of CLKT remain challenging in infants and small children. The patients should be operated on before they become severely ill or develop major systemic manifestations of their metabolic disorder. The liver allograft is immunologically protective of the kidney graft in simultaneous CLKT, often resulting in well-preserved kidney function. The long-term outcome after CLKT is nowadays comparable to that of isolated liver and kidney transplantations.

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Favorable Long-Term Outcome after Liver-Kidney Transplant for Recurrent Hemolytic Uremic Syndrome Associated with a Factor H Mutation

Cited by 110 publications

References 30 publications

Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype

Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype

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

Combined liver and kidney transplantation in children

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