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      Complement-Mediated Glomerular Diseases: A Tale of 3 Pathways

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          Abstract

          A renewed interest in the role of complement in the pathogenesis of glomerular diseases has improved our understanding of their basic, underlying physiology. All 3 complement pathways—classical, lectin, and alternative—have been implicated in glomerular lesions both rare (e.g., dense deposit disease) and common (e.g., IgA nephropathy). Here we review the basic function of these pathways and highlight, with a disease-specific focus, how activation can lead to glomerular injury. We end by exploring the promise of complement-targeted therapies as disease-specific interventions for glomerular diseases.

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          Atypical hemolytic-uremic syndrome.

          Marina Noris, Giuseppe Remuzzi (2009)
          Article 0 comments Cited 337 times – based on 0 reviews     Review now
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            Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies.

            Charles Jennette, Peter Heeringa, Adrian Schreiber … (2006)
            Clinical and experimental data indicate that anti-neutrophil cytoplasmic autoantibodies (ANCAs) cause glomerulonephritis and vasculitis. Here we report the first evidence that complement is an important mediator of ANCA disease. Transfer of anti-myeloperoxidase (MPO) IgG into wild-type mice or anti-MPO splenocytes into immune-deficient mice caused crescentic glomerulonephritis that could be completely blocked by complement depletion. The role of specific complement activation pathways was investigated using mice with knockout of the common pathway component C5, classic and lectin binding pathway component C4, and alternative pathway component factor B. After injection of anti-MPO IgG, C4-/- mice developed disease comparable with wild-type disease; however, C5-/- and factor B-/- mice developed no disease. To substantiate a role for complement in human ANCA disease, IgG was isolated from patients with myeloperoxidase ANCA (MPO-ANCA) or proteinase 3 ANCA (PR3-ANCA) and from controls. Incubation of MPO-ANCA or PR3-ANCA IgG with human neutrophils caused release of factors that activated complement. IgG from healthy controls did not produce this effect. The findings suggest that stimulation of neutrophils by ANCA causes release of factors that activate complement via the alternative pathway, thus initiating an inflammatory amplification loop that mediates the severe necrotizing inflammation of ANCA disease.
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              Eculizumab for dense deposit disease and C3 glomerulonephritis.

              E C Heher, Yuzhou Zhang, M. Stokes … (2012)
              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. In 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. The 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. 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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                Author and article information

                Contributors
                Andrew S. Bomback
                Journal
                Journal ID (nlm-ta): Kidney Int Rep
                Journal ID (iso-abbrev): Kidney Int Rep
                Title: Kidney International Reports
                Publisher: Elsevier
                ISSN (Electronic): 2468-0249
                Publication date PMC-release: 01 July 2016
                Publication date Collection: September 2016
                Publication date (Electronic): 01 July 2016
                Volume: 1
                Issue: 3
                Pages: 148-155
                Affiliations
                [1 ]Department of Medicine, Division of Nephrology, Columbia University College of Physicians and Surgeons, New York, New York, USA
                [2 ]Department of Pathology, Columbia University College of Physicians and Surgeons, New York, New York, USA
                Author notes
                [∗ ] Correspondence: Andrew S. Bomback, MD, MPH, 622 West 168th St., PH 4-124, New York, New York 10032, USA.622 West 168th St., PH 4-124New YorkNew York 10032USA asb68@ 123456columbia.edu
                Article
                Publisher ID: S2468-0249(16)30031-6
                DOI: 10.1016/j.ekir.2016.06.005
                PMC ID: 5678788
                PubMed ID: 29142924
                SO-VID: eb0f2ca0-9047-4618-bc32-fc4fefbaf3fa
                Copyright © © 2016 International Society of Nephrology. Published by Elsevier Inc.
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 18 April 2016
                Date revision received : 11 June 2016
                Date accepted : 25 June 2016
                Categories
                Subject: Review

                Keywords: complement,glomerulonephritis,nephrotic syndrome,membranous nephropathy,lupus,iga nephropathy,c3 glomerulopathy
                Data availability:
                Keywords: complement, glomerulonephritis, nephrotic syndrome, membranous nephropathy, lupus, iga nephropathy, c3 glomerulopathy

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