Causes of Alternative Pathway Dysregulation in Dense Deposit Disease

Zhang, Yuzhou; Meyer, Nicole C.; Wang, Kai; Nishimura, Carla; Frees, Kathy; Jones, Michael B.; Katz, Louis M.; Sethi, Sanjeev; Smith, Richard J.H.

doi:10.2215/cjn.07900811

Cited by 168 publications

(178 citation statements)

References 36 publications

(37 reference statements)

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“…Blood and urine samples were collected immediately before eculizumab infusions. Baseline screening for mutations in several complement genes (e.g., CFH, CFI, CFHR5, and MCP) as well as autoantibodies associated with dysregulation of the alternative pathway (e.g., C3 nephritic factors and factor H autoantibodies) was performed at the University of Iowa as described previously (7,8); in addition, serum and plasma were sent every 4 weeks during the treatment period to the University of Iowa for functional testing of the alternative complement pathway as described previously (7)(8)(9). Fundoscopic examination for presence of drusen was performed during the first month of treatment, with repeat examinations after 1 year of therapy in subjects with detectable drusen.…”

Section: Treatment Regimen and Evaluationsmentioning

confidence: 99%

Eculizumab for Dense Deposit Disease and C3 Glomerulonephritis

Bomback

Smith

Barile

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives The principle defect in dense deposit disease and C3 glomerulonephritis is hyperactivity of the alternative complement pathway. Eculizumab, a monoclonal antibody that binds to C5 to prevent formation of the membrane attack complex, may prove beneficial. Design, setting, participants, & measurementsIn this open-label, proof of concept efficacy and safety study, six subjects with dense deposit disease or C3 glomerulonephritis were treated with eculizumab every other week for 1 year. All had proteinuria .1 g/d and/or AKI at enrollment. Subjects underwent biopsy before enrollment and repeat biopsy at the 1-year mark. ResultsThe subjects included three patients with dense deposit disease (including one patient with recurrent dense deposit disease in allograft) and three patients with C3 glomerulonephritis (including two patients with recurrent C3 glomerulonephritis in allograft). Genetic and complement function testing revealed a mutation in CFH and MCP in one subject each, C3 nephritic factor in three subjects, and elevated levels of serum membrane attack complex in three subjects. After 12 months, two subjects showed significantly reduced serum creatinine, one subject achieved marked reduction in proteinuria, and one subject had stable laboratory parameters but histopathologic improvements. Elevated serum membrane attack complex levels normalized on therapy and paralleled improvements in creatinine and proteinuria.Conclusions Clinical and histopathologic data suggest a response to eculizumab in some but not all subjects with dense deposit disease and C3 glomerulonephritis. Elevation of serum membrane attack complex before treatment may predict response. Additional research is needed to define the subgroup of dense deposit disease/C3 glomerulonephritis patients in whom eculizumab therapy can be considered.

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Section: Treatment Regimen and Evaluationsmentioning

confidence: 99%

Eculizumab for Dense Deposit Disease and C3 Glomerulonephritis

Bomback

Smith

Barile

et al. 2012

Clinical Journal of the American Society of Nephrology

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305

258

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“…For example, fH would be ineffective in C3G patients carrying C3 mutations that render C3 convertase fH resistant or in the presence of autoantibodies to C3 convertase that block regulation by fH. 13,14 Among the non-fH proteins that regulate C3 convertase is soluble CR1. CR1 is a cell-surface glycoprotein expressed on erythrocytes, monocytes, neutrophils, B cells, some T cells, follicular dendritic cells, and podocytes, and modulates the complement cascade at multiple levels (Supplemental Figures 1 and 2).…”

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confidence: 99%

Soluble CR1 Therapy Improves Complement Regulation in C3 Glomerulopathy

Zhang

Nester

Holanda

et al. 2013

Journal of the American Society of Nephrology

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Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are widely recognized subtypes of C3 glomerulopathy. These ultra-rare renal diseases are characterized by fluid-phase dysregulation of the alternative complement pathway that leads to deposition of complement proteins in the renal glomerulus. Disease triggers are unknown and because targeted treatments are lacking, progress to end stage renal failure is a common final outcome. We studied soluble CR1, a potent regulator of complement activity, to test whether it restores complement regulation in C3 glomerulopathy. In vitro studies using sera from patients with DDD showed that soluble CR1 prevents dysregulation of the alternative pathway C3 convertase, even in the presence of C3 nephritic factors. In mice deficient in complement factor H and transgenic for human CR1, soluble CR1 therapy stopped alternative pathway activation, resulting in normalization of serum C3 levels and clearance of iC3b from glomerular basement membranes. Shortterm use of soluble CR1 in a pediatric patient with end stage renal failure demonstrated its safety and ability to normalize activity of the terminal complement pathway. Overall, these data indicate that soluble CR1 re-establishes regulation of the alternative complement pathway and provide support for a limited trial to evaluate soluble CR1 as a treatment for DDD and C3GN. Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are two widely recognized subtypes of C3 glomerulopathy (C3G). 1,2 These ultra-rare renal diseases are caused by fluid-phase dysregulation of the C3 convertase of the alternative pathway (AP) of complement, with variable concomitant dysregulation of the C5 convertase. Consistent with complement-mediated disease acting through the AP, C3G is strongly positive for C3 and notably negative for Igs by immunofluorescence microscopy. 2 Electron microscopy distinguishes DDD from C3GN, with the former characterized by pathognomonic electron-dense transformation of the lamina densa of the glomerular basement membrane (GBM). 3 In C3GN, the electron microscopy deposits are lighter in color, and are more often mesangial and/or subendothelial, intramembranous, and subepithelial in location. 4 In both diseases, mass spectroscopy of laser dissected glomeruli is highly enriched for proteins of the AP and terminal complement cascade. 4,5

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“…A large number of different molecular abnormalities are associated with C dysregulation within the glomerulus (44)(45)(46). Rare variants in the genes for factor H, C3, factor B, factor I, membrane cofactor protein (MCP, or CD46), and thrombomodulin have been identified in patients with aHUS (46,47).…”

Section: Molecular Studiesmentioning

confidence: 99%

“…A number of genetic impairments in AP regulation have also been identified in patients with this disease, including variants in the genes for factor H, factor B, C3, and the CFHRs (27,44,45,55). Experimental analyses of the disease-associated CFHR variants suggest that they impair the ability of factor H to control AP activation on tissue surfaces (18,56).…”

Section: Molecular Studiesmentioning

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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Causes of Alternative Pathway Dysregulation in Dense Deposit Disease

Cited by 168 publications

References 36 publications

Eculizumab for Dense Deposit Disease and C3 Glomerulonephritis

Eculizumab for Dense Deposit Disease and C3 Glomerulonephritis

Soluble CR1 Therapy Improves Complement Regulation in C3 Glomerulopathy

All Things Complement

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