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      C3 glomerulopathy: consensus report

      meeting-report
      1 , * , 2 , 3 , 4 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 9 , 11 , 12 , 13 , 14 , 15 , 1 , 9 , 16 , 17 , 18 , 19 , 1 , 16 , 5 , 20 , 21 , 22 , 23 , 24 , 25 , 9 , 17 , 26 , 1 , *
      Kidney International
      Nature Publishing Group
      clinical immunology, clinical nephrology, complement, glomerulonephritis, immunology and pathology

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          Abstract

          C3 glomerulopathy is a recently introduced pathological entity whose original definition was glomerular pathology characterized by C3 accumulation with absent or scanty immunoglobulin deposition. In August 2012, an invited group of experts (comprising the authors of this document) in renal pathology, nephrology, complement biology, and complement therapeutics met to discuss C3 glomerulopathy in the first C3 Glomerulopathy Meeting. The objectives were to reach a consensus on: the definition of C3 glomerulopathy, appropriate complement investigations that should be performed in these patients, and how complement therapeutics should be explored in the condition. This meeting report represents the current consensus view of the group.

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          Most cited references24

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          Eculizumab for dense deposit disease and C3 glomerulonephritis.

          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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            C3 glomerulopathy: a new classification.

            Several distinct pathological patterns of glomerular inflammation are associated with abnormal regulation of the complement system, specifically, with dysregulation of the alternative pathway of the complement system. However, these conditions share the pathological finding of complement C3 (C3) deposited within the glomerulus in the absence of substantial immunoglobulin. This finding has alerted us and others to the possible presence of genetic and acquired complement dysregulation in individual patients. This article summarizes our current understanding of the relationship between dysregulation of the complement system and glomerular inflammation. Here, we suggest that glomerular pathologies that are characterized by the isolated deposition of C3 could usefully be classified by the term C3 glomerulopathy. In our view, this classification would alert the pathologist and nephrologist to the importance of screening for acquired and genetic abnormalities in complement regulation. In the future, it could help to identify individuals who might benefit from therapeutic inhibition of the complement system.
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              Membranoproliferative glomerulonephritis type II (dense deposit disease): an update.

              Membranoproliferative glomerulonephritis type II (MPGN II) is a rare disease characterized by the deposition of abnormal electron-dense material within the glomerular basement membrane of the kidney and often within Bruch's membrane in the eye. The diagnosis is made in most patients between the ages of 5 and 15 yr, and within 10 yr, approximately half progress to end-stage renal disease, occasionally with the late comorbidity of visual impairment. The pathophysiologic basis of MPGN II is associated with the uncontrolled systemic activation of the alternative pathway (AP) of the complement cascade. In most patients, loss of complement regulation is caused by C3 nephritic factor, an autoantibody directed against the C3 convertase of the AP, but in some patients, mutations in the factor H gene have been identified. For the latter patients, plasma replacement therapy prevents renal failure, but for the majority of patients, there is no proven effective treatment. The disease recurs in virtually all renal allografts, and a high percentage of these ultimately fail. The development of molecular diagnostic tools and new therapies directed at controlling the AP of the complement cascade either locally in the kidney or at the systemic level may lead to effective treatments for MPGN II.
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                Author and article information

                Journal
                Kidney Int
                Kidney Int
                Kidney International
                Nature Publishing Group
                0085-2538
                1523-1755
                December 2013
                30 October 2013
                : 84
                : 6
                : 1079-1089
                Affiliations
                [1 ]Centre for Complement and Inflammation Research, Imperial College London , London, UK
                [2 ]Division of Renal Pathology, Department of Pathology, Columbia University Medical Center and the New York Presbyterian Hospital , New York, New York, USA
                [3 ]Division of Nephrology, Departments of Internal Medicine and Pediatrics, Carver College of Medicine, University of Iowa , Iowa City, Iowa, USA
                [4 ]Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa , Iowa City, Iowa, USA
                [5 ]Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center , Los Angeles, California, USA
                [6 ]Division of Nephrology, Department of Medicine, Columbia University Medical Center and the New York Presbyterian Hospital , New York, New York, USA
                [7 ]Department of Pathology, University of Washington , Seattle, Washington, USA
                [8 ]Department of Pathology, Leiden University Medical Center , Leiden, The Netherlands
                [9 ]Alexion Pharmaceuticals , Cheshire, Connecticut, USA
                [10 ]Division of Pediatric Nephrology, Baylor College of Medicine and Texas Children's Hospital , Houston, Texas, USA
                [11 ]Nephrology Department, Institut de Transplantation Urologie et Nephrologie, CHU de Nantes , Nantes, France
                [12 ]Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic , Rochester, Minnesota, USA
                [13 ]Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center , Nashville, Tennessee, USA
                [14 ]Service d'Immunologie Biologique, Hôpital George Pompidou, AP-HP , Paris, France
                [15 ]Division of Medicine, Centre for Nephrology, University College London , London, UK
                [16 ]Institute of Infection and Immunity, School of Medicine, Cardiff University , Cardiff, UK
                [17 ]Department of Medicine, University of Colorado School of Medicine , Aurora, Colorado, USA
                [18 ]Department of Paediatric Nephrology, Great North Children's Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust , Newcastle Upon Tyne, UK
                [19 ]Trinity Health Kidney Centre, Tallaght Hospital, Trinity College , Dublin, Ireland
                [20 ]INSERM, Service de Néphrologie et de transplantation, Service d'Anatomie Pathologique, Université René Descartes, Hôpital Necker, AP-HP , Paris, France
                [21 ]Cambridge, UK
                [22 ]Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Enfermedades Raras, Ramiro de Maeztu , Madrid, Spain
                [23 ]Service de Néphrologie et de transplantation, Hôpital Necker-Enfants Malades, AP-HP , Paris, France
                [24 ]Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic , Rochester, Minnesota, USA
                [25 ]Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania, USA
                [26 ]Department of Nephrology, Nicosia General Hospital, University of Cyprus , Nicosia, Cyprus
                Author notes
                [* ]Centre for Complement and Inflammation Research, Imperial College London , London W12 0NN, UK. E-mail: matthew.pickering@ 123456imperial.ac.uk or t.h.cook@ 123456imperial.ac.uk
                Article
                ki2013377
                10.1038/ki.2013.377
                3842953
                24172683
                5f5316cc-fd22-4679-b4c0-3bfd6879f068
                Copyright © 2013 International Society of Nephrology

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                : 20 March 2013
                : 30 May 2013
                : 20 June 2013
                Categories
                Meeting Report

                Nephrology
                clinical immunology,complement,immunology and pathology,clinical nephrology,glomerulonephritis

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