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      Treating C3 glomerulopathy with eculizumab

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          Abstract

          Background

          C3 glomerulopathy (C3G) is a rare, but severe glomerular disease with grim prognosis. The complex pathogenesis is just unfolding, and involves acquired as well as inherited dysregulation of the alternative pathway of the complement cascade. Currently, there is no established therapy. Treatment with the C5 complement inhibitor eculizumab may be a therapeutic option. However, due to rarity of the disease, parameters predicting treatment response remain largely unknown.

          Methods

          Seven patients with C3G (five with C3 glomerulonephritis and two with dense deposit disease) were treated with eculizumab. Subjects underwent biopsy before enrollment. The histopathology, clinical data, and response to eculizumab treatment were analyzed. The key parameters to determine outcome were changes of serum creatinine and urinary protein over time.

          Results

          After treatment with eculizumab, four subjects showed significantly improved or stable renal function and urinary protein. A positive response occurred between 2 weeks and 6 months after therapy initiation. One subject (with allograft recurrent C3 glomerulonephritis) initially showed a positive response, but relapsed when eculizumab was discontinued, and did not respond after re-initiation of treatment. Two subjects showed impaired renal function and increasing urinary protein despite therapy with eculizumab.

          Conclusions

          Eculizumab may be a therapeutic option for a subset of C3G patients. The response to eculizumab is heterogeneous, and early as well as continuous treatment may be necessary to prevent disease progression. These findings emphasize the need for studies identifying genetic and functional complement abnormalities that may help to guide eculizumab treatment and predict response.

          Electronic supplementary material

          The online version of this article (10.1186/s12882-017-0802-4) contains supplementary material, which is available to authorized users.

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          Most cited references42

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          Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference.

          In both atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) complement plays a primary role in disease pathogenesis. Herein we report the outcome of a 2015 Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference where key issues in the management of these 2 diseases were considered by a global panel of experts. Areas addressed included renal pathology, clinical phenotype and assessment, genetic drivers of disease, acquired drivers of disease, and treatment strategies. In order to help guide clinicians who are caring for such patients, recommendations for best treatment strategies were discussed at length, providing the evidence base underpinning current treatment options. Knowledge gaps were identified and a prioritized research agenda was proposed to resolve outstanding controversial issues.
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            C3 glomerulopathy: consensus report

            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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              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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                Author and article information

                Contributors
                thomas.welte@uniklinik-freiburg.de
                frederic.arnold@uniklinik-freiburg.de
                julia.kappes@uniklinik-freiburg.de
                maximilian.seidl@uniklinik-freiburg.de
                karsten.haeffner@uniklinik-freiburg.de
                carsten.bergmann@bioscientia.de
                gerd.walz@uniklinik-freiburg.de
                +49 761 270 35590 , elke.neumann-haefelin@uniklinik-freiburg.de
                Journal
                BMC Nephrol
                BMC Nephrol
                BMC Nephrology
                BioMed Central (London )
                1471-2369
                12 January 2018
                12 January 2018
                2018
                : 19
                : 7
                Affiliations
                [1 ]ISNI 0000 0000 9428 7911, GRID grid.7708.8, Department of Nephrology, , Medical Center–University of Freiburg, Germany, ; Hugstetter Strasse 55, 79106 Freiburg, Germany
                [2 ]ISNI 0000 0000 9428 7911, GRID grid.7708.8, Department of Pneumology, , Medical Center–University of Freiburg, Germany, ; Killianstrasse 4, 79106 Freiburg, Germany
                [3 ]ISNI 0000 0000 9428 7911, GRID grid.7708.8, Department of Pathology, , Medical Center–University of Freiburg, Germany, ; Breisacher Strasse 115A, 79106 Freiburg, Germany
                [4 ]ISNI 0000 0000 9428 7911, GRID grid.7708.8, Department of Pediatrics and Adolescent Medicine, , Medical Center–University of Freiburg, Germany, ; Heiliggeiststrasse 1, 79106 Freiburg, Germany
                [5 ]Center for Human Genetics, Bioscientia, Ingelheim, Germany, Konrad-Adenauer-Strasse 17, 55218 Ingelheim, Germany
                Author information
                http://orcid.org/0000-0001-5893-4293
                Article
                802
                10.1186/s12882-017-0802-4
                5767001
                29329521
                99d3dfe4-7ab6-4936-bfd3-728b5f12d6c5
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 31 May 2017
                : 18 December 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2018

                Nephrology
                c3 glomerulopathy,c3 glomerulonephritis,dense deposit disease,complement,eculizumab
                Nephrology
                c3 glomerulopathy, c3 glomerulonephritis, dense deposit disease, complement, eculizumab

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