Significance of Glomerular Deposition of C3c and C3d in IgA Nephropathy

Nakagawa, Hiroko; Haneda, Masakazu; Gejyo, Fumitake; Kikkawa, Ryuichi

doi:10.1159/000013568

Cited by 29 publications

(29 citation statements)

References 24 publications

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“…It is known that this local complement system in the glomeruli is activated via the alternative or mannose-binding lectin pathway in IgA nephropathy. 24,25 Complement by IgG antibodies proceeds through the classic pathway, as demonstrated by C1 binding. 26 In other words, IgG forms the classic pathway convertase C4bC2a through C1 fixation and subsequently cleaves C3 into C3a and C3b.…”

Section: Discussionmentioning

confidence: 99%

Glomerular IgG deposition predicts renal outcome in patients with IgA nephropathy

et al. 2016

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Glomerular IgG deposition is frequently observed in patients with IgA nephropathy. However, the association between glomerular IgG deposition and progression of IgA nephropathy is uncertain. Six hundred and twentyseven patients with biopsy-proven IgA nephropathy were recruited. Histological variables of the Oxford classification (Oxford-MEST) and the presence of glomerular IgG deposits were assessed. Renal progression defined as end-stage renal disease or 50% reduction in estimated glomerular filtration rate was analyzed using Kaplan-Meier methods and Cox regression analysis. Of the study population, 200 patients (31.9%) had glomerular IgG deposition on immunofluorescence staining. During a mean follow-up of 56.8 ± 37.5 months, the rate of renal progression was significantly higher in the IgA nephropathy patients with glomerular IgG deposition compared with the IgA nephropathy patients without glomerular IgG deposition (39.8 vs 12.3 per 1000 patientyears; Po 0.001). Of patients with IgG deposition, 178 (28.3%), 20 (3.2%), and 2 (0.3%) patients had mild, moderate, and marked glomerular IgG deposits, receptively. Kaplan-Meier analysis revealed that cumulative renal survival was significantly lower in IgA nephropathy patients with the higher intensity of glomerular IgG deposits (Po 0.001). In addition, Cox regression analysis revealed that moderate and marked glomerular IgG deposits significantly predicted renal outcome independent of Oxford-MEST and clinical variables (HR, 2.97; 95% CI, 1.01-8.77; P = 0.04). This study showed that that glomerular IgG deposition was independently associated with poor renal outcome in patient with IgA nephropathy.

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Section: Discussionmentioning

confidence: 99%

Glomerular IgG deposition predicts renal outcome in patients with IgA nephropathy

et al. 2016

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“…15,16 The deposition of C3d, a covalently bound long-lived breakdown product of C3b, thus suggests more prolonged inflammation and complement accumulation. 33,34 The presence of C4b/iC4b in the same areas with C3b/iC3b and C3d may indicate that classical pathway activation is involved in the initiation of alternative pathway amplification in the IA wall.…”

Section: Role Of Oxldl and Crp In Complement Activation In The Ia Wallmentioning

confidence: 99%

Complement system becomes activated by the classical pathway in intracranial aneurysm walls

Tulamo

Frösén

Junnikkala

et al. 2010

Laboratory Investigation

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Inflammation and activation of the complement system in the intracranial aneurysm (IA) wall predispose to IA rupture. We have previously shown that increased C5b-9 accumulation correlates with IA rupture and wall degeneration. To elucidate the underlying mechanisms, we investigated initiators and the pathway of complement activation in unruptured and ruptured IAs. Unruptured and ruptured IA wall samples were studied in parallel sections by immunohistochemical and immunofluorescence stainings for the location and relations of classical and alternative pathway complement components (C1q, C3b/iC3b, C3d, C4b/iC4b; n ¼ 35 and properdin, n ¼ 10), putative complement activators IgG (n ¼ 90), IgM, CRP and OxLDL (n ¼ 10), and complement activation endproduct C5b-9. Classical pathway components were seen in all IAs, and they were located mostly in the extracellular matrix. The early pathway complement components colocalized with each other, but were present in larger areas than C5b-9. The areas positive for complement component accumulation were significantly broader in ruptured than in unruptured IAs. The potential complement activators IgG, IgM, CRP and OxLDL were found mostly in the extracellular matrix and in partial overlap with C5b-9. Lipids were seen in Oil-Red-O staining in colocalization with C5b-9. Complement becomes activated by the classical pathway in the IA wall. The activation appears to be induced by multiple factors, which, in addition to the traditional activators (immunoglobulins, CRP, OxLDL), could involve vascular pressure-induced tissue damage. Despite wide early pathway activation, the terminal pathway is focused on a distinct lipid-rich layer. The profile of the complement components and the association of C5b-9 with lipids in the extracellular matrix indicate a long-term chronic inflammatory process rather than an acute targeted inflammatory reaction. The observed pattern of complement activation may be the consequence of local stress-induced insufficiency of complement regulation in IA walls. KEYWORDS: aneurysm; complement; CRP; immunoglobulin; inflammation; oxidized LDL Saccular intracranial artery aneurysm (IA) rupture causes subarachnoidal hemorrhage (SAH), with up to 50% mortality. 1 However, the mechanisms behind IA development, structural weakening and rupture are poorly understood. In a meta-analysis, 2.3% (range 0.4-6.0%) of various populations were found to harbor IA. 2 Known risk factors for IA rupture and SAH include smoking, hypertension, previous rupture, female gender, excessive alcohol abuse and family history, but these explain only part of the IA disease. 3,4 Inflammation and its key component complement activation precede IA rupture. Inflammatory cell infiltration and deposits of the activation products of the terminal complement pathway can be found in unruptured IAs. 5-9 Immunoglobulins and pro-inflammatory cytokines (eg, TNF-a) have also been detected in human IAs. 8,10 The IA wall undergoes a remodeling process. This is indicated by the expression of vascular growth factor r...

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“…Immunologic markers of effect include changes in several components of the immune system, such as shifts in the distribution of lymphocyte subpopulations and changes in other tissues caused by immune-mediated dysfunction, for example, signs of kidney failure caused by autoimmune kidney disease (21). Consequently, the use of markers with a high correlation to a particular immunotoxic end point is valuable in the identification of the presence of these health effects.…”

Section: Immunologic Markers Of Effectmentioning

confidence: 99%

Approaches to Detecting Immunotoxic Effects of Environmental Contaminants in Humans

Tryphonas¹

2001

Environmental Health Perspectives

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Significance of Glomerular Deposition of C3c and C3d in IgA Nephropathy

Cited by 29 publications

References 24 publications

Glomerular IgG deposition predicts renal outcome in patients with IgA nephropathy

Glomerular IgG deposition predicts renal outcome in patients with IgA nephropathy

Complement system becomes activated by the classical pathway in intracranial aneurysm walls

Approaches to Detecting Immunotoxic Effects of Environmental Contaminants in Humans

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