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      Clinicopathological analysis of proliferative glomerulonephritis with monoclonal IgG deposits in 5 renal allografts

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          Abstract

          Background

          We present a case series of 5 patients with proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) of renal allografts to better define its natural history, presenting characteristics, pathological features and treatment outcome.

          Results

          These 5 patients presented 5 to 19 months post-kidney transplantation for complaints of serum creatinine (Scr) elevation, proteinuria or hematuria. Membranoproliferative glomerulonephritis (MPGN) pattern was the most frequently observed histological manifestation. Immunofluorescence showed monoclonal IgG3κin 3 patients and IgG3λ in the other 2 cases. Immunofluorescence staining helped to establish PGNMID in the absence of conspicuous microscopic changes in one case. Rituximab and bortezomib were effective in alleviating proteinuria in all 4 treated patients and decreasing Scr in 2 cases. Plasmapheresis treatment in another patient was not effective in preventing Scr elevation. At last-follow-up, 2 patients were in dialysis and 2 had improved kidney function with almost normal Scr and no proteinuria. The remaining one patient died of pulmonary infections.

          Conclusions

          We conclude that PGNMID occurs early after kidney transplant. PGNMID should be included in the differential diagnoses of recurrent MPGN in renal allografts. Rituximab and bortezomib are helpful to decrease proteinuria and Scr in a subset of patients. Larger studies are needed to conclusively establish best treatment strategies for PGNMID in renal allografts.

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          Proliferative glomerulonephritis with monoclonal IgG deposits.

          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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            Proliferative glomerulonephritis with monoclonal IgG deposits: a distinct entity mimicking immune-complex glomerulonephritis.

            Renal disease related to the deposition of monoclonal immunoglobulins containing both heavy and light chains can occur in type 1 cryoglobulinemia, Randall type light and heavy chain deposition disease (LHCDD), and immunotactoid glomerulonephritis. We report a novel phenotype of glomerular injury that does not conform to any of the previously described patterns of glomerular involvement by monoclonal gammopathy. Ten cases of unclassifiable proliferative glomerulonephritis manifesting glomerular monoclonal immunoglobulin G (IgG) deposits were identified retrospectively from the archives of the Renal Pathology Laboratory of Columbia University over the past 3 years (biopsy incidence 0.21%). The monoclonal immunoglobulins formed granular electron dense deposits in mesangial, subendothelial, and subepithelial sites, mimicking ordinary immune complex-mediated glomerulonephritis and producing a diffuse endocapillary proliferative or membranoproliferative glomerulonephritis. However, by immunofluorescence, the deposits were monoclonal, staining for a single light chain isotype and a single gamma subclass (including two IgG1kappa, one IgG1lambda, one IgG2lambda, four IgG3kappa, and one IgG3lambda). All cases stained for the three constant domains of the gamma heavy chain (CH1, CH2, and CH3), suggesting deposition of a nondeleted immunoglobulin molecule. Tissue fixation of complement was observed in 90% of cases, and 40% of patients had hypocomplementemia. Clinical presentations included renal insufficiency in 80% (mean serum creatinine 2.8 mg/dL, range 0.9 to 8.0), proteinuria in 100% (mean urine protein 5.8 g/day; range 1.9 to 13.0), nephrotic syndrome in 44%, and microhematuria in 60%. A monoclonal serum protein with the same heavy and light chain isotype as that of the glomerular deposits was identified in 50% of cases (including three IgGkappa and two IgGlambda); however, no patient had clinical or laboratory features of type 1 cryoglobulinemia. No patient had overt myeloma or lymphoma at presentation or over the course of follow-up (mean 12 months). Glomerular deposition of monoclonal IgG can produce a proliferative glomerulonephritis that mimics immune-complex glomerulonephritis by light and electron microscopy. Proper recognition of this entity requires confirmation of monoclonality by staining for the gamma heavy chain subclasses.
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              Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification.

              Membranoproliferative glomerulonephritis (MPGN) is a pattern of injury that results from subendothelial and mesangial deposition of Igs caused by persistent antigenemia and/or circulating immune complexes. The common causes of Ig-mediated MPGN include chronic infections, autoimmune diseases, and monoclonal gammopathy/dysproteinemias. On the other hand, MPGN also can result from subendothelial and mesangial deposition of complement owing to dysregulation of the alternative pathway (AP) of complement. Complement-mediated MPGN includes dense deposit disease and proliferative glomerulonephritis with C3 deposits. Dysregulation of the AP of complement can result from genetic mutations or development of autoantibodies to complement regulating proteins with ensuing dense deposit disease or glomerulonephritis with C3 deposits. We propose a new histologic classification of MPGN and classify MPGN into 2 major groups: Ig-mediated and complement-mediated. MPGN that is Ig-mediated should lead to work-up for infections, autoimmune diseases, and monoclonal gammopathy. On the other hand, complement-mediated MPGN should lead to work-up of the AP of complement. Initial AP screening tests should include serum membrane attack complex levels, an AP functional assay, and a hemolytic assay, followed by tests for mutations and autoantibodies to complement-regulating proteins. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                +86 13851767588 , wjqdoctor@163.com , wjqkidney@hotmail.com
                wjqdoctor@163.com
                wjqdoctor@163.com
                wjqdoctor@163.com
                wjqdoctor@163.com
                wjqdoctor@163.com
                wjqdoctor@163.com
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                wjqdoctor@163.com
                Journal
                BMC Nephrol
                BMC Nephrol
                BMC Nephrology
                BioMed Central (London )
                1471-2369
                11 July 2018
                11 July 2018
                2018
                : 19
                : 173
                Affiliations
                [1 ]ISNI 0000 0001 0115 7868, GRID grid.440259.e, National Clinical Research Center of Kidney Diseases, , Jinling Hospital, Nanjing University Jinling School of Medicine, ; Nanjing, 210000 China
                [2 ]National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing Medical University, Nanjing, 210000 China
                Article
                969
                10.1186/s12882-018-0969-3
                6042340
                29996809
                662730b4-652f-4d90-9264-94709e2dbf59
                © 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
                : 25 October 2017
                : 26 June 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81570681
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2018

                Nephrology
                bortezomib,monoclonality,kidney transplantation,pgnmid,rituximab
                Nephrology
                bortezomib, monoclonality, kidney transplantation, pgnmid, rituximab

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