Complement Inhibitors And Glomerulonephritis

Couser, William G.

doi:10.1097/01.asn.0000057502.76239.7d

Cited by 17 publications

(11 citation statements)

References 26 publications

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“…8 C5a is postulated as a key link between inflammatory and thrombotic pathways 9 and has potent proinflammatory effects. 10 In addition, sublytic C5b-9 levels are associated with platelet, leukocyte, and endothelial activation and damage, 11,12 all of which can further increase AP activation via a positive feedback loop. 11,13,14 The kidney is particularly vulnerable to complement-mediated inflammatory injury occurring from deposition of circulating active complement fragments in the glomeruli and local (renal) complement production and activation.…”

Section: Introductionmentioning

confidence: 99%

Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS

Cofiell

Kukreja

Bedard

et al. 2015

Blood

163

137

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• This exploratory study describes the effect of eculizumab on multiple physiologic pathways affected by complement dysregulation in aHUS.• The results highlight the importance of sustained terminal complement blockade, even in patients with improved clinical laboratory values.Atypical hemolytic uremic syndrome (aHUS) is a genetic, life-threatening disease characterized by uncontrolled complement activation, systemic thrombotic microangiopathy (TMA), and vital organ damage. We evaluated the effect of terminal complement blockade with the anti-C5 monoclonal antibody eculizumab on biomarkers of cellular processes involved in TMA in patients with aHUS longitudinally, during up to 1 year of treatment, compared with in healthy volunteers. Biomarker levels were elevated at baseline in most patients, regardless of mutational status, plasma exchange/infusion use, platelet count, or lactate dehydrogenase or haptoglobin levels. Eculizumab reduced terminal complement activation (C5a and sC5b-9) and renal injury markers (clusterin, cystatin-C, b2-microglobulin, and liver fatty acid binding protein-1) to healthy volunteer levels and reduced inflammation (soluble tumor necrosis factor receptor-1), coagulation (prothrombin fragment F112 and D-dimer), and endothelial damage (thrombomodulin) markers to near-normal levels. Alternative pathway activation (Ba) and endothelial activation markers (soluble vascular cell adhesion molecule-1) decreased but remained elevated, reflecting ongoing complement activation in aHUS despite complete terminal complement blockade. These results highlight links between terminal complement activation and inflammation, endothelial damage, thrombosis, and renal injury and underscore ongoing risk for systemic TMA and progression to organ damage. Further research regarding underlying complement dysregulation is warranted. This trial was registered at www.clinicaltrials.gov as #NCT01194973. (Blood. 2015;125(21):3253-3262)

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Section: Introductionmentioning

confidence: 99%

Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS

Cofiell

Kukreja

Bedard

et al. 2015

Blood

163

137

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“…[7][8][9]. The best therapeutically characterized inhibitors of complement are soluble CR1 (sCR1) and an anti-C5 mAb that inhibits the generation of C5a and the MAC.…”

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confidence: 99%

Complement Inhibitors Targeted to the Proximal Tubule Prevent Injury in Experimental Nephrotic Syndrome and Demonstrate a Key Role for C5b-9

Imai

Song

et al. 2005

The Journal of Immunology

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In glomerular diseases of diverse etiologies, dysfunction of the glomerular barrier to protein passage results in proteinuria, and proteinuria is considered an independent risk factor that plays a direct role in inflammation, interstitial fibrosis, and renal failure. The mechanism by which proteinuria leads to nephrotoxic injury is unclear, but a role for complement in mediating interstitial damage appears likely. We describe a strategy for Ag-specific targeting of complement inhibitors using a single chain Ab fragment and show that complement inhibitors targeted to the tubular epithelium protect against tubulointerstitial injury and renal dysfunction in a rat model of puromycin-induced nephrosis. The targeting of systemically administered complement inhibitors markedly enhanced their efficacy and obviated the need to systemically inhibit complement, thus reducing the risk of compromising host defense and immune homeostasis. Targeted inhibition of complement activation by Crry, and of membrane attack complex (MAC) formation by CD59 was equally therapeutic, demonstrating that the MAC plays a key role in proteinuria-induced tubulointerstitial injury. CD59 activity was dependent on its being targeted to the site of complement activation, and this is the first report of specific inhibition of the MAC in vivo after systemic administration of inhibitor. The data establish the MAC is a valid target for pharmaceutical intervention in proteinuric disorders and provide an approach to investigate the role of the MAC in complement-dependent disease under clinically relevant conditions.

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“…The activation of complement is tightly regulated by several endogenous circulating and cell bound proteins that protect the host from unchecked inflammatory stimuli. Circulating inhibitors that have been identified to date include C1 inhibitor, C4 binding protein, factor H, and clusterin [43,44], which generally converge to stabilize C3 and abrogate activation of the later components of the complement cascade. There has been little study of these in renal disease in general and in MPGN in particular.…”

Section: Complement Activationmentioning

confidence: 99%

“…There has been little study of these in renal disease in general and in MPGN in particular. Membrane-bound regulators include decay-accelerating factor, membrane co-factor protein, complement receptor 1, and CD59 [43,44], all of which also stabilize the complement cascade at points prior to activation of the membrane attack complex.…”

Section: Complement Activationmentioning

confidence: 99%

“…Based on recent studies like those cited above that demonstrate the efficacy of Crry overexpression in inhibition of glomerulonephritis in animal models, there has been considerable enthusiasm amongst investigators to test complement inhibition, in general, and increased Crry activity, in particular, as effective strategies for treating human glomerulonephritis, including MPGN [43]. However, in the one study that directly tested its efficacy, Crry overexpression was ineffective in ameliorating MPGN in TSLP transgenic mice despite elevated circulating and tissue levels of Crry [47].…”

Section: Complement Inhibitionmentioning

confidence: 99%

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Pathogenic mechanisms in membranoproliferative glomerulonephritis

Smith

Alpers

2005

Current Opinion in Nephrology &Amp; Hypertension

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Understanding the contribution of complement activation and innate immunity to the evolution of membranoproliferative glomerulonephritis promises to provide new therapeutic targets for this disease. Inhibitors of the complement cascade are already being tested in clinical trials as therapeutic interventions for some human glomerular diseases. Successful tests of this approach in membranoproliferative glomerulonephritis are still awaited. Our understanding of how the innate immune system modulates glomerulonephritis is still in an early stage, and future studies should be directed at identifying targets and specific interventions that may also benefit patients with this disease.

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Complement Inhibitors And Glomerulonephritis

Cited by 17 publications

References 26 publications

Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS

Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS

Complement Inhibitors Targeted to the Proximal Tubule Prevent Injury in Experimental Nephrotic Syndrome and Demonstrate a Key Role for C5b-9

Pathogenic mechanisms in membranoproliferative glomerulonephritis

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