Complement and diseases: Defective alternative pathway control results in kidney and eye diseases

Zipfel, Peter F.; Heinen, Stefan; Józsi, Mihály; Skerka, Christine

doi:10.1016/j.molimm.2005.06.015

Cited by 197 publications

(166 citation statements)

References 43 publications

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“…15 Second, recent studies suggest that CKD and AMD share several common genetic susceptibility loci, in particular, those related to key complement pathway proteins. [12][13][14][15][16][17][18]20,21 Genetic variants in complement factor H are associated with some forms of kidney disease, such as atypical hemolytic uremic syndrome, 12,14 whereas C3 variants are associated with IgA nephropathy. 16 Both complement factor H and C3 deficiency are associated with type II membranoproliferative glomerulonephritis, 14,20,21 a disease characterized by kidney failure and early onset retinal drusen, which are structurally and compositionally identical to those that occur in AMD.…”

Section: Discussionmentioning

confidence: 99%

“…8,9 Systemic in-flammatory processes may accelerate the course of CKD 10 and contribute to the development of AMD. 11 More recent evidence suggests that the two conditions have common susceptibility genes, such as complement factor H (CFH), [12][13][14] complement C3, 15,16 and apolipoprotein E (APOE). 17,18 Finally, there are a number of rare inherited syndromes that involve both renal and ocular abnormalities.…”

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confidence: 99%

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CKD Increases the Risk of Age-Related Macular Degeneration

Liew

Mitchell

Wong³

et al. 2008

Journal of the American Society of Nephrology

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Age-related macular degeneration is the leading cause of irreversible blindness in the United States and often coexists with chronic kidney disease. Both conditions share common genetic and environmental risk factors. A total of 1183 participants aged 54ϩ were examined in the population-based, prospective cohort Blue Mountains Eye Study (Australia) to determine if chronic kidney disease increases the risk of age-related macular degeneration. Moderate chronic kidney disease (estimated glomerular filtration rate Ͻ 60 ml/min per 1.73 m 2 based on the Cockcroft-Gault equation) was present in 24% of the population (286 of 1183). The 5-yr incidence of early age-related macular degeneration was 3.9% in participants with no/mild chronic kidney disease (35 of 897) and 17.5% in those with moderate chronic kidney disease (50 of 286). After adjusting for age, sex, cigarette smoking, hypertension, complement factor H polymorphism, and other risk factors, persons with moderate chronic kidney disease were 3 times more likely to develop early age-related macular degeneration than persons with no/mild chronic kidney disease (odds ratio ϭ 3.2; 95% confidence interval, 1.8 to 5.7, P Ͻ 0.0001). Each SD (14.8 ml/min per 1.73 m 2 ) decrease in Cockcroft-Gault estimated glomerular filtration rate was associated with a doubling of the adjusted risk for early age-related macular degeneration (odds ratio ϭ 2.0; 95% confidence interval, 1.5 to 2.8, P Ͻ 0.0001). In conclusion, persons with chronic kidney disease have a higher risk of early age-related macular degeneration, suggesting the possibility of shared pathophysiologic mechanisms between the two conditions. 19: 806 -811, 200819: 806 -811, . doi: 10.1681 Chronic kidney disease (CKD) is a relatively common condition whose prevalence rises rapidly with age. CKD is estimated to affect over 50% of older persons in the United States 1 and has important extrarenal systemic consequences, such as cardiovascular, metabolic, and hematologic abnormalities. However, the effects of CKD on the sensory organs, such as the eye, are not well understood. J Am Soc NephrolAge-related macular degeneration (AMD) is another relatively common condition in older persons and is the leading cause of blindness and low vision in the United States. 2 CKD and AMD may share common risk factors and pathophysiologic mechanisms. 3 For example, vascular risk factors, such as hypertension and cigarette smoking, may increase risk of both conditions. 4 -7 CKD is known to accelerate the progression of atherosclerosis and increase propensity to oxidative stress, 6 both of which are implicated in AMD pathogenesis. 8,9 Systemic in-

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

CKD Increases the Risk of Age-Related Macular Degeneration

Liew

Mitchell

Wong³

et al. 2008

Journal of the American Society of Nephrology

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“…Decreased levels of C3 and factor B as well as increased levels of C3 activation fragments have been described, whereas C4 levels are unaffected (Noris et al, 1999;Stuhlinger et al, 1974;Zipfel et al, 2006). C3, but not C4, is deposited in the glomerulus and arterioles of aHUS patients (Hammar et al, 1978).…”

Section: Discussionmentioning

confidence: 99%

“…Deficiency of complement regulators is a major risk factor for development of aHUS (DragonDurey and Fremeaux-Bacchi, 2005;Esparza-Gordillo et al, 2005;Goodship et al, 2004;Noris and Remuzzi, 2005;Zipfel et al, 2006). More than 50% of patients with aHUS have mutations in one of three complement control proteins: factor H (fH), membrane cofactor protein (MCP; CD46) or factor I (fI) Esparza-Gordillo et al, 2005;Goodship et al, 2004 ;Zipfel et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…More than 50% of patients with aHUS have mutations in one of three complement control proteins: factor H (fH), membrane cofactor protein (MCP; CD46) or factor I (fI) Esparza-Gordillo et al, 2005;Goodship et al, 2004 ;Zipfel et al, 2006). Additionally, factor H auto-antibodies have been reported as a mechanism for the development of sporadic aHUS .…”

Section: Introductionmentioning

confidence: 99%

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Modeling how CD46 deficiency predisposes to atypical hemolytic uremic syndrome

Liszewski

Leung

Schraml

et al. 2007

Molecular Immunology

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Mutations in complement regulatory proteins predispose to the development of aHUS. Approximately 50% of patients bear a mutation in one of three complement control proteins, factor H, factor I, or membrane cofactor protein (MCP; CD46). Another membrane regulator that is closely related to MCP, decay accelerating factor (DAF; CD55) thus far has shown no association with aHUS and continues to be investigated. The goal of this study was to compare the regulatory profile of MCP and DAF and to assess how alterations in MCP predispose to complement dysregulation. We employed a model system of complement activation on Chinese hamster ovary (CHO) cell transfectants. The four regularly expressed isoforms of MCP and DAF inhibited C3b deposition by the alternative pathway. DAF, but not MCP, inhibited the classical pathway. Most patients with MCPaHUS are heterozygous and express only 25-50 % of the wild-type protein. We, therefore, analyzed the effect of reduced levels of wild-type MCP and found that cells with lowered expression levels were less efficient in inhibiting alternative pathway activation. Further, a dysfunctional MCP mutant, expressed at normal levels and identified in five patients with aHUS (S206P), failed to protect against C3b amplification on CHO cells, even if expression levels were increased 10-fold. Our results add new information relative to the necessity for appropriate expression levels of MCP and further implicate the alternative pathway in disease processes such as aHUS.

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Clinical Evaluation of 3 Families With Basal Laminar Drusen Caused by Novel Mutations in the Complement Factor H Gene

Ven¹,

Boon²,

Fauser³

et al. 2012

Arch Ophthalmol

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Elucidation of the clinical BLD phenotype will facilitate identification of individuals predisposed to developing disease-related comorbidity, such as membranoproliferative glomerulonephritis type II. Moreover, with upcoming treatment modalities targeting specific components of the complement system, early identification of patients with BLD and detection of the genetic defect become increasingly important.

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Complement and diseases: Defective alternative pathway control results in kidney and eye diseases

Cited by 197 publications

References 43 publications

CKD Increases the Risk of Age-Related Macular Degeneration

CKD Increases the Risk of Age-Related Macular Degeneration

Modeling how CD46 deficiency predisposes to atypical hemolytic uremic syndrome

Clinical Evaluation of 3 Families With Basal Laminar Drusen Caused by Novel Mutations in the Complement Factor H Gene

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