Urinary C3dg and C5b-9 indicate active immune disease in human membranous nephropathy

Brenchley, Paul; Coupes, Beatrice; Short, Colin D.; O’Donoghue, Dónal; Ballardie, F. W.; Mallick, N. P.

doi:10.1038/ki.1992.143

Cited by 75 publications

(38 citation statements)

References 14 publications

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“…These associations of abnormal factor H molecules with glomerular disease support the commonly held belief that activation of the complement cascade contributes to immunologically mediated glomerular diseases (15,16). Additional circumstantial evidence for this is the presence of complement activation products in glomeruli and in urine (17)(18)(19). The use of animal models has strengthened the case for a role of complement activation in many glomerular diseases.…”

mentioning

confidence: 61%

Complement Factor H Limits Immune Complex Deposition and Prevents Inflammation and Scarring in Glomeruli of Mice with Chronic Serum Sickness

Alexander

Pickering

Haas

et al. 2005

Journal of the American Society of Nephrology

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Factor H is the major complement regulator in plasma. Abnormalities in factor H have been implicated in membranoproliferative glomerulonephritis in both humans and experimental animals. It has been shown that factor H on rodent platelets functions analogously to human erythrocyte complement receptor 1 in its role to traffic immune complexes to the mononuclear phagocyte system. C57BL/6 factor H-deficient mice (Cfh ؊/؊ ) and wild-type (wt) controls were immunized daily for 5 wk with heterologous apoferritin to study the chronic serum sickness GN model. Immunizations were started in 6-to 8-wk-old mice, which was before the development of spontaneous membranoproliferative glomerulonephritis in some Cfh ؊/؊ animals. These data show a role for platelet-associated factor H to process immune complexes and limit their accumulation in glomeruli. Once deposited in glomeruli, excessive complement activation can lead to glomerular inflammation and the rapid development of a scarring phenotype. Glomerular deposition of IgG immune complexes in glomeruli was qualitatively and quantitatively increased in Cfh

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mentioning

confidence: 61%

Complement Factor H Limits Immune Complex Deposition and Prevents Inflammation and Scarring in Glomeruli of Mice with Chronic Serum Sickness

Alexander

Pickering

Haas

et al. 2005

Journal of the American Society of Nephrology

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“…Since IgG4 is incapable of activating the CP and the deposits of MBL and C4b have been found in glomeruli of PMN patients, the LP is considered to play an essential role in the disease pathogenesis. However, the most recent studies show the prevalence of Bb deposits along with C3c and MAC, as well as increased urinary excretion of C3dg and MAC suggesting the AP activation [131,141,[143][144][145]. In fact, a patient with PMN and complete C4 deficiency has been reported, implicating that the disease may develop without the LP activation [146].…”

Section: Primary Membranous Nephropathymentioning

confidence: 99%

The role of the alternative pathway of complement activation in glomerular diseases

2018

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The complement system (CS) has recently been recognized as a bridge between innate and adaptive immunity that constitutes a very complex mechanism controlling the clearance of pathogens, cellular debris, and immune complexes. Out of three known pathways of complement activation, the alternative pathway (AP) plays a critical role in host defense by amplifying the complement response, independently of initiation pathway and continuously maintaining low-level activity in a process called 'thick-over.' A key molecule of the CS is C3, in which the AP is constantly activated. To prevent host cell destruction, a group of the AP regulators tightly controls this pathway of the CS activation. Acquired and genetic abnormalities of the CS may alter the delicate balance between enhancing and inhibiting the AP cascade. These can lead to the uncontrolled CS activation, inflammatory response, and subsequent tissue damage. Since complement components are locally produced and activated in the kidney, the abnormalities targeting the AP may cause glomerular injury. C3 glomerulopathy is a new entity, in which the AP dysregulation has been well established. However, recent studies indicate that the AP may also contribute to a wide range of kidney pathologies, including immune-complex-mediated glomerulonephritis (GN), pauci-immune GN, and primary membranous nephropathy (PMN). This article provides insight into current knowledge on the role of the AP in the pathogenesis of glomerular diseases, focusing mainly on various types of primary and secondary GN and PMN.

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“…C activation fragments may be useful for predicting disease flares in patients with lupus, particularly if the level of intact C3 is confounded by pregnancy or other clinical conditions (30). Urinary C3d and C5b-9 are biomarkers of immunologic glomerular injury in patients with membranous nephropathy (31). Given that the drug eculizumab blocks the cleavage of C5, it is logical that detection of sC5b-9 would be a useful guide to eculizumab therapy, but local C activation may not always cause detectable increases in the systemic levels of sC5b-9 (32).…”

Section: Clinical Biomarkers Of C Activationmentioning

confidence: 99%

All Things Complement

Thurman

Nester

2016

CJASN

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The complement (C) cascade is an ancient system of proteins whose primary role is to initiate and modulate immune responses. During C activation, circulating proteins are cleaved and nascent cleavage fragments participate in a broad range of downstream innate and adaptive immune functions. Although the majority of these functions are either homeostatic or protective, a large body of experimental and clinical evidence also highlights a central role for the C system in the pathogenesis of many types of glomerular disease. From classic pathway activation in lupus nephritis to alternative pathway dysregulation in C3 glomerulopathy, our understanding of the spectrum of C involvement in kidney disease has expanded greatly in recent years. However, the characteristics that make the glomerulus so uniquely susceptible to C-mediated injury are not fully understood, and this remains an area of ongoing investigation. Several C inhibitors have been approved for clinical use, and additional C inhibitory drugs are in development. The use of these drugs in patients with kidney disease will expand our understanding of the benefits and limitations of C inhibition.

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Urinary C3dg and C5b-9 indicate active immune disease in human membranous nephropathy

Cited by 75 publications

References 14 publications

Complement Factor H Limits Immune Complex Deposition and Prevents Inflammation and Scarring in Glomeruli of Mice with Chronic Serum Sickness

Complement Factor H Limits Immune Complex Deposition and Prevents Inflammation and Scarring in Glomeruli of Mice with Chronic Serum Sickness

The role of the alternative pathway of complement activation in glomerular diseases

All Things Complement

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