Genetic and Functional Analyses of Membrane Cofactor Protein (CD46) Mutations in Atypical Hemolytic Uremic Syndrome

Frémeaux‐Bacchi, Véronique; Moulton, Elizabeth A; Kavanagh, David; Dragon-Durey, Marie-Agnès; Blouin, Jacques; Caudy, Amy A.; Arzouk, Nadia; Cleper, Roxanna; François, Maud; Guest, G.; Pourrat, Jacques; Seligman, Roland; Fridman, Wolf‐Herman; Loirat, Chantal; Atkinson, John P.

doi:10.1681/asn.2005101051

Cited by 215 publications

(202 citation statements)

References 34 publications

(53 reference statements)

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“…All exons of the complement regulatory genes were sequenced as described previously (7,(27)(28)(29). The primer sequences for CFH, CFI, MCP, CFB, C3, and C4BP gene screening are available from the authors on request.…”

Section: Genetic Analysesmentioning

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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Section: Genetic Analysesmentioning

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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“…Among the reported cases, approximately 50% had mutations of the complement regulatory proteins factor H (CFH) (7)(8)(9)(10)(11)(12), membrane cofactor protein (13)(14)(15), or factor I (16)(17)(18); mutations occurred less frequently in factor B (19), C3 (20), and thrombomodulin (21).…”

Section: Introductionmentioning

confidence: 99%

Complement Factor H–Related Protein 1 Deficiency and Factor H Antibodies in Pediatric Patients with Atypical Hemolytic Uremic Syndrome

Hofer¹,

Janecke

Zimmerhackl³

et al. 2013

Clinical Journal of the American Society of Nephrology

122

108

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SummaryBackground and objectives This study evaluated the relevance of complement factor H (CFH)-related protein (CFHR) 1 deficiency in pediatric patients with atypical hemolytic uremic syndrome (aHUS) by evaluating both the frequency of deletions in CFHR1 and the presence of complement factor H (CFH) antibodies.Design, setting, participants, & measurements A total of 116 patients (mainly from central Europe) and 118 healthy blood donors were included from 2001 to 2012. The presence of CFHR1 gene deletions was determined in 90 pediatric patients with aHUS and 118 controls by an easy, fast, and cheap PCR assay; 100 patients with aHUS and 42 controls were tested for CFH antibodies by ELISA. Questionnaires were administered to evaluate the clinical and laboratory data.Results Homozygous deletion in CFHR1 was detected in 32% of the patients with aHUS tested, compared with 2.5% of controls (P,0.001). CFH antibodies were present in 25% of the patients and none of the controls. CFH antibodies were detected in 82% of patients with homozygous CFHR1 gene deletion and in 6% of patients without. CFH antibody-positive patients with aHUS showed a significantly lower platelet nadir at disease onset and significantly less frequent involvement of the central nervous system than did antibody-negative patients. Antibody-positive patients also received plasma therapy more often.Conclusion Homozygous deletion in CFHR1 is strongly associated with occurrence of CFH antibodies in pediatric patients with aHUS. However, despite this apparent genetic disease predisposition, it cannot be considered an exclusive cause for aHUS. Initial presentation of Shiga toxin-negative HUS with severe thrombocytopenia and no central nervous system complications in pediatric patients is especially suspicious for CFH antibody aHUS.

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“…[55][56][57][58] Complement system mutations can be implicated in up to 52% of patients who have aHUS. 59 Many different variants in complement genes have been reported to predispose to aHUS, 60-63 such as complement factor H (CFH), 64,65 factor I (CFI), 66,67 C3, 68 thrombomodulin (THBD), 60 membrane cofactor protein (MCP or CD46) 69,70 and factor B (CFB). 71 It was shown that patients who have a mutation in MCP carry the best prognosis, as compared with other genetic abnormalities, and almost all of the above genetic mutations are heterozygous.…”

Section: Role Of Genetic Mutations In Post-bmt Tmamentioning

confidence: 99%

Post-bone marrow transplant thrombotic microangiopathy

Obut

Kasinath

Abdi

2016

Bone Marrow Transplant

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Thrombotic microangiopathy (TMA) is a systemic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and organ failure. Post-bone marrow transplant TMA (post-BMT TMA) is a life-threatening condition that has been reported to afflict between 0.5 and 63.6% of BMT patients. The incidence of post-BMT TMA is affected by evolving therapies such as conditioning regimens. The etiology of post-BMT TMA is thought to be multifactorial, including the effects of immunosuppressive agents, viral infections, TBI and GvHD. A growing body of evidence highlights the importance of complement system activation and endothelial damage in post-BMT TMA. Although plasmapheresis has commonly been used, its therapeutic rationale for the majority of post-BMT TMA cases is unclear in the absence of circulatory inhibitors. It has become possible to target complement activation with eculizumab, a drug that blocks the terminal complement pathway. Early studies have highlighted the importance of anticomplement therapies in treating post-BMT TMA. Moreover, finding complement gene mutations may identify patients at risk, but whether such patients benefit from prophylactic anti-complement therapies before BMT remains to be studied. This review focuses on diagnostic criteria, pathophysiology, treatment and renal outcomes of post-BMT TMA.

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Genetic and Functional Analyses of Membrane Cofactor Protein (CD46) Mutations in Atypical Hemolytic Uremic Syndrome

Cited by 215 publications

References 34 publications

Complement Inhibitor Eculizumab in Atypical Hemolytic Uremic Syndrome

Complement Inhibitor Eculizumab in Atypical Hemolytic Uremic Syndrome

Complement Factor H–Related Protein 1 Deficiency and Factor H Antibodies in Pediatric Patients with Atypical Hemolytic Uremic Syndrome

Post-bone marrow transplant thrombotic microangiopathy

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