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      Dense Deposit Disease and C3 Glomerulopathy

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          Summary

          C3 glomerulopathy refers to those renal lesions characterized histologically by predominant C3 accumulation within the glomerulus, and pathogenetically by aberrant regulation of the alternative pathway of complement. Dense deposit disease is distinguished from other forms of C3 glomerulopathy by its characteristic appearance on electron microscopy. The extent to which dense deposit disease also differs from other forms of C3 glomerulopathy in terms of clinical features, natural history, and outcomes of treatment including renal transplantation is less clear. We discuss the pathophysiology of C3 glomerulopathy, with evidence for alternative pathway dysregulation obtained from affected individuals and complement factor H (Cfh)-deficient animal models. Recent linkage studies in familial C3 glomerulopathy have shown genomic rearrangements in the Cfh-related genes, for which the novel pathophysiologic concept of Cfh deregulation has been proposed.

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          Proliferative glomerulonephritis with monoclonal IgG deposits.

          G. Markowitz, D A Valeri, Anjali Satoskar … (2009)
          Dysproteinemias that result in monoclonal glomerular deposits of IgG are relatively uncommon. Here, we report the largest series of proliferative glomerulonephritis with monoclonal IgG deposits, a form of renal involvement by monoclonal gammopathy that mimics immune-complex glomerulonephritis. We retrospectively identified 37 patients, most of whom were white (81%), female (62%), or older than 50 yr (65%). At presentation, 49% had nephrotic syndrome, 68% had renal insufficiency, and 77% had hematuria. In 30% of the patients, we identified a monoclonal serum protein with the same heavy- and light-chain isotypes as the glomerular deposits (mostly IgG1 or IgG2), but only one patient had myeloma. Histologic patterns were predominantly membranoproliferative (57%) or endocapillary proliferative (35%) with membranous features. Electron microscopy revealed granular, nonorganized deposits, and immunofluorescence demonstrated glomerular deposits that stained for a single light-chain isotype and a single heavy-chain subtype, most commonly IgG3kappa (53%). During an average of 30.3 mo of follow-up for 32 patients with available data, 38% had complete or partial recovery, 38% had persistent renal dysfunction, and 22% progressed to ESRD. Correlates of ESRD on univariate analysis were higher creatinine at biopsy, percentage of glomerulosclerosis, and degree of interstitial fibrosis but not immunomodulatory treatment or presence of a monoclonal spike. On multivariate analysis, higher percentage of glomerulosclerosis was the only independent predictor of ESRD. Only one patient lacking a monoclonal spike at presentation subsequently developed a monoclonal spike and no patient with a monoclonal spike at presentation subsequently developed a hematologic malignancy. We conclude that proliferative glomerulonephritis with monoclonal IgG deposits does not seem to be a precursor of myeloma in the vast majority of patients.
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            Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H.

            Joanna Warren, Anne Bygrave, M Walport … (2002)
            The alternative pathway of complement is activated continuously in vivo through the C3 'tick-over' pathway. This pathway is triggered by the hydrolysis of C3, resulting in the formation of C3 convertase. This, in turn, generates C3b, which mediates many of the biological functions of complement. Factor H, the main regulator of this activation, prevents formation and promotes dissociation of the C3 convertase enzyme, and, together with factor I, mediates the proteolytic inactivation of C3b. Factor H deficiency, described in 29 individuals from 12 families and in pigs, allows unhindered activation of fluid-phase C3 and severe depletion of plasma C3 (ref. 11). Membranoproliferative glomerulonephritis (MPGN) occurs in factor H-deficient humans and pigs. Although MPGN has been reported in other conditions in which uncontrolled activation of C3 occurs, the role of C3 dysregulation in the pathogenesis of MPGN is not understood. Here we show that mice deficient in factor H (Cfh(-/-) mice) develop MPGN spontaneously and are hypersensitive to developing renal injury caused by immune complexes. Introducing a second mutation in the gene encoding complement factor B, which prevents C3 turnover in vivo, obviates the phenotype of Cfh(-/-) mice. Thus, uncontrolled C3 activation in vivo is essential for the development of MPGN associated with deficiency of factor H.
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              Dimerization of complement factor H-related proteins modulates complement activation in vivo.

              M Colledge, Elena Goicoechea, Svetlana Hakobyan … (2013)
              The complement system is a key component regulation influences susceptibility to age-related macular degeneration, meningitis, and kidney disease. Variation includes genomic rearrangements within the complement factor H-related (CFHR) locus. Elucidating the mechanism underlying these associations has been hindered by the lack of understanding of the biological role of CFHR proteins. Here we present unique structural data demonstrating that three of the CFHR proteins contain a shared dimerization motif and that this hitherto unrecognized structural property enables formation of both homodimers and heterodimers. Dimerization confers avidity for tissue-bound complement fragments and enables these proteins to efficiently compete with the physiological complement inhibitor, complement factor H (CFH), for ligand binding. Our data demonstrate that these CFHR proteins function as competitive antagonists of CFH to modulate complement activation in vivo and explain why variation in the CFHRs predisposes to disease.
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                Author and article information

                Contributors
                Thomas D. Barbour
                Journal
                Journal ID (nlm-ta): Semin Nephrol
                Journal ID (iso-abbrev): Semin. Nephrol
                Title: Seminars in Nephrology
                Publisher: W.B. Saunders
                ISSN (Print): 0270-9295
                ISSN (Electronic): 1558-4488
                Publication date PMC-release: 1 November 2013
                Publication date (Print): November 2013
                Volume: 33
                Issue: 6
                Pages: 493-507
                Affiliations
                [* ]Kidney Research UK, Centre for Complement and Inflammation Research, Imperial College London, London, United Kingdom
                [† ]Department of Rheumatology, Centre for Complement and Inflammation Research, Imperial College London, London, United Kingdom
                [‡ ]Department of Pathology, Centre for Complement and Inflammation Research, Imperial College London, London, United Kingdom
                Author notes
                [* ]Address reprint requests to Thomas Barbour, MD, Centre for Complement and Inflammation Research, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom t.barbour@ 123456imperial.ac.uk
                Article
                Publisher ID: S0270-9295(13)00130-7
                DOI: 10.1016/j.semnephrol.2013.08.002
                PMC ID: 3820036
                PubMed ID: 24161036
                SO-VID: 15d92849-9675-47fa-b505-530cbd845fa9
                Copyright © © 2013 Elsevier Inc.
                License:

                This document may be redistributed and reused, subject to certain conditions.

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                Subject: Article

                Keywords: c3 glomerulopathy,dense deposit,complement
                Data availability:
                Keywords: c3 glomerulopathy, dense deposit, complement

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