The Development of Atypical Hemolytic Uremic Syndrome Depends on Complement C5

Jorge, Elena Goicoechea de; Macor, Paolo; Paixão-Cavalcante, Danielle; Rose, Kirsten L.; Tedesco, F.; Cook, H. Terence; Botto, Marina; Pickering, Matthew C.

doi:10.1681/asn.2010050451

Cited by 107 publications

(71 citation statements)

References 38 publications

(46 reference statements)

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“…Like spontaneous aHUS in a murine model of FH-associated aHUS, 9 experimentally triggered aHUS in hepatocyte-Cfh 2/2 animals was C5 dependent, further supporting the key role of C5 in complementmediated glomerular TMA. Our data illustrate the complex relationship between FH insufficiency and complementmediated renal injury and that the therapeutic use of C5 inhibition in this setting depends on the renal phenotype.…”

Section: Discussionmentioning

confidence: 60%

“…3,6 Pigs 7 and mice 8 with complete FH deficiency develop spontaneous C3G but not aHUS. In both species, the deficiency results in uncontrolled AP activation and secondary consumption of C3 3 and C5, 7,9 which results in absence of plasma complement hemolytic activity. In FH-deficient (Cfh 2/2 ) mice, spontaneous C3G depended on AP activation 8 but not on C5 10 and developed in wild-type kidneys transplanted into Cfh 2/2 recipients.…”

mentioning

confidence: 99%

“…6 C5-dependent spontaneous aHUS did occur in Cfh 2/2 mice transgenic for an FH protein (FHD16-20) that lacked surface recognition domains. 9,12 This led to the paradigm that aHUS occurs when there is a combination of defective regulation of complement activation along the glomerular endothelium (e.g., in the presence of FH mutations that impair surface recognition) and sufficient circulating intact C3 and C5 to enable complement-mediated endothelial injury to occur. 9,12 Here, we report the phenotype of hepatocyte-specific FHdeficient (hepatocyte-Cfh 2/2 ) mice and show that this strain has plasma FH levels of approximately 20% of normal.…”

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confidence: 99%

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Partial Complement Factor H Deficiency Associates with C3 Glomerulopathy and Thrombotic Microangiopathy

Vernon

Ruseva

Cook

et al. 2015

JASN

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The complement-mediated renal diseases C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS) strongly associate with inherited and acquired abnormalities in the regulation of the complement alternative pathway (AP). The major negative regulator of the AP is the plasma protein complement factor H (FH). Abnormalities in FH result in uncontrolled activation of C3 through the AP and associate with susceptibility to both C3G and aHUS. Although previously developed FH-deficient animal models have provided important insights into the mechanisms underlying susceptibility to these unique phenotypes, these models do not entirely reproduce the clinical observations. FH is predominantly synthesized in the liver. We generated mice with hepatocyte-specific FH deficiency and showed that these animals have reduced plasma FH levels with secondary reduction in plasma C3. Unlike mice with complete FH deficiency, hepatocyte-specific FH-deficient animals developed neither plasma C5 depletion nor accumulation of C3 along the glomerular basement membrane. In contrast, subtotal FH deficiency associated with mesangial C3 accumulation consistent with C3G. Although there was no evidence of spontaneous thrombotic microangiopathy, the hepatocyte-specific FH-deficient animals developed severe C5-dependent thrombotic microangiopathy after induction of complement activation within the kidney by accelerated serum nephrotoxic nephritis. Taken together, our data indicate that subtotal FH deficiency can give rise to either spontaneous C3G or aHUS after a complement-activating trigger within the kidney and that the latter is C5 dependent.

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Section: Discussionmentioning

confidence: 60%

mentioning

confidence: 99%

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confidence: 99%

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Partial Complement Factor H Deficiency Associates with C3 Glomerulopathy and Thrombotic Microangiopathy

Vernon

Ruseva

Cook

et al. 2015

JASN

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“…Eculizumab binds specifically to the complement protein C5, halting the complement cascade and inhibiting production of cell-killing protein complexes [131] . Eculizumab, licensed initially for the treatment of paroxysmal nocturnal hemoglobinuria [132] , was recently licensed for the treatment of atypical HUS.…”

Section: Eculizumabmentioning

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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“…En el caso de las mutaciones homocigotas, todos los pacientes presentan disminución de todos los niveles de factor H (<1% -normal 70-130%), C3 (<40-170mg/dL -normal 660-1250mg/dL), factor B (17-70mg/L -normal 90-320mg/L), y CH50 (<10-24%-normal 70-130).En pacientes con mutaciones heterocigotas se pueden encontrar niveles bajos o normales, por ejemplofactor H (30-55%), C3 (240 a 834 mg/dL), factor B (55 a 250 mg/L), y CH50 (59 a 124%) 42 .…”

Section: Rol De Las Pruebas Genéticasunclassified

Síndrome hemolítico urémico atípico, revisión de la literatura y documento de consenso. Enfoque diagnóstico y tratamiento

Córdoba¹,

Contreras²,

Larrarte³

et al. 2015

Rev. Colomb. Nefrol.

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ResumenEl Síndrome Hemolítico Urémico atípico (SHUa) es una enfermedad ultra-huérfana; más del 50% de los pacientes muere, necesita terapia de remplazo renal o sufre insuficiencia renal terminal dentro del primer año de diagnóstico. Con el tratamiento de soporte actual (plasmaféresis o infusión deplasma) 9-15% de los pacientes de SHUa mueren dentro del lapso de 1 año, después de una manifestación clínica de hemólisis. Las consecuencias severas de esta enfermedad refuerzan la importancia del diagnóstico y tratamiento temprano. Las manifestaciones clínicas incluyen la triada clásica de anemia microangiopática, trombocitopenia y daño a otros órganos, donde la insuficiencia renal es la manifestación más común, frecuentemente asociada a otras complicaciones tales como neurológicas, cardíacas y gastrointestinales. Las mutaciones en las proteínas reguladoras del sistema del complemento son reconocidas como las causas de este síndrome; sin embargo, no se identifican en todos los pacientes con diagnóstico de SHUa. Existe una alta tasa de pérdida del injerto postrasplante renal, en aproximadamente 60% de los casos.La plasmaféresis, considerada como terapia de primera línea, no ha demostrado resultados satisfactorios a largo plazo. Desde el año 2011 está disponible en Colombia un anticuerpo monoclonal recombinante dirigido contra el complemento a nivel C5 (eculizumab), medicamento único aprobado para el tratamiento del SHUa. Este tratamiento ha demostrado mejorar, de manera significativa, el pronóstico y la progresión de la enfermedad, y es considerado la primera línea de terapia hoy en día.

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The Development of Atypical Hemolytic Uremic Syndrome Depends on Complement C5

Cited by 107 publications

References 38 publications

Partial Complement Factor H Deficiency Associates with C3 Glomerulopathy and Thrombotic Microangiopathy

Partial Complement Factor H Deficiency Associates with C3 Glomerulopathy and Thrombotic Microangiopathy

Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations

Síndrome hemolítico urémico atípico, revisión de la literatura y documento de consenso. Enfoque diagnóstico y tratamiento

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