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      Prevalence of Enhanced Granular Expression of Thrombospondin Type-1 Domain-Containing 7A in the Glomeruli of Japanese Patients with Idiopathic Membranous Nephropathy

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          Abstract

          Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults. Autoantibodies against M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A), which mainly belong to the IgG4 subclass, were reported as associated antibodies for the development of MN. Although PLA2R is a major target antigen for idiopathic MN, the prevalence of MN patients seropositive for PLA2R in Japan is lower than that in other countries. In this study, we conducted immunohistochemical analysis of the presence of THSD7A and PLA2R in renal specimens of MN patients to estimate the prevalence of THSD7A/PLA2R-related idiopathic MN in Japan. Enhanced granular expression of THSD7A and PLA2R was detected in 9.1% and 52.7%, respectively, of the patients with idiopathic MN. Although none of patients with secondary MN displayed enhanced granular expression of THSD7A, 5.4% of them had enhanced granular expression of PLA2R. In conclusion, the prevalence of enhanced granular expression of THSD7A in the glomeruli of Japanese patients with idiopathic MN was higher than the prevalence of MN patients seropositive for THSD7A in USA and Europe.

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          Antiphospholipase A2 receptor antibody titer and subclass in idiopathic membranous nephropathy.

          Julia M Hofstra, Hanna Debiec, Colin D Short … (2012)
          The phospholipase A(2) receptor (PLA(2)R) is the major target antigen in idiopathic membranous nephropathy. The technique for measuring antibodies against PLA(2)R and the relationship between antibody titer and clinical characteristics are not well established. Here, we measured anti-PLA(2)R (aPLA(2)R) antibody titer and subclass in a well defined cohort of 117 Caucasian patients with idiopathic membranous nephropathy and nephrotic-range proteinuria using both indirect immunofluorescence testing (IIFT) and ELISA. We assessed agreement between tests and correlated antibody titer with clinical baseline parameters and outcome. In this cohort, aPLA(2)R antibodies were positive in 74% and 72% of patients using IIFT and ELISA, respectively. Concordance between both tests was excellent (94% agreement, κ=0.85). Among 82 aPLA(2)R-positive patients, antibody titer significantly correlated with baseline proteinuria (P=0.02). Spontaneous remissions occurred significantly less frequently among patients with high antibody titers (38% versus 4% in the lowest and highest tertiles, respectively; P<0.01). IgG4 was the dominant subclass in the majority of patients. Titers of IgG4, but not IgG1 or IgG3, significantly correlated with the occurrence of spontaneous remission (P=0.03). In summary, these data show high agreement between IIFT and ELISA assessments of aPLA(2)R antibody titer and highlight the pathogenetic role of these antibodies, especially the IgG4 subclass, given the observed relationships between aPLA(2)R titer, baseline proteinuria, and outcome.
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            PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy.

            Pierre Ronco, Hanna Debiec (2011)
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              Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy.

              Elion Hoxha, Ursula Kneißler, Gesa Stege … (2012)
              The M-type phospholipase A2 receptor (PLA2R) is the major target antigen in idiopathic membranous nephropathy with detectable autoantibodies in the serum of up to 70% of patients. In retrospective studies, the PLA2R-autoantibody titer in the serum was sometimes negative indicating their measurement alone may be inconclusive. In order to better differentiate between primary and secondary membranous nephropathy, we conducted a prospective study that included 88 patients with a histologic diagnosis of membranous nephropathy. Immunohistochemical analysis for PLA2R was faintly positive in kidneys from normal individuals and patients with various other glomerular injuries. In 61 of the 88 patients, PLA2R expression was strongly positive in glomeruli, and in 60 of these patients PLA2R autoantibodies were also detected in the serum. The 27 patients negative for serum PLA2R autoantibodies were faintly positive for PLA2R staining in glomeruli and in 15 of these patients a secondary cause was found. The remaining 12 patients have a yet undetected secondary cause of membranous nephropathy or have different glomerular antigens other than PLA2R. Thus, increased staining for PLA2R in glomeruli of renal biopsies tightly correlates with the presence of PLA2R autoantibodies in the serum and this may help discriminate between primary and secondary membranous nephropathy.
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                Author and article information

                Contributors
                Giuseppe Remuzzi: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 22 September 2015
                Publication date Collection: 2015
                Volume: 10
                Issue: 9
                Electronic Location Identifier: e0138841
                Affiliations
                [1 ]Internal Medicine I, Division of Nephrology, Hamamatsu University School of Medicine, Hamamatsu, Japan
                [2 ]Blood Purification Unit, Hamamatsu University School of Medicine, Hamamatsu, Japan
                [3 ]Division of Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
                Mario Negri Institute for Pharmacological Research and Azienda Ospedaliera Ospedali Riuniti di Bergamo, ITALY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: TI. Performed the experiments: TI. Analyzed the data: TI. Contributed reagents/materials/analysis tools: TI. Wrote the paper: TI HY. Reviewed the manuscript: NO AK SB HY. Obtained permission for use of renal tissue: SB.

                Article
                Publisher ID: PONE-D-15-27775
                DOI: 10.1371/journal.pone.0138841
                PMC ID: 4578926
                PubMed ID: 26393352
                SO-VID: 3a5b85f0-f1f1-4b92-b912-866fc187c5a2
                Copyright statement: Copyright @ 2015
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                Date received : 25 June 2015
                Date accepted : 3 September 2015
                Page count
                Figures: 2, Tables: 3, Pages: 10
                Funding
                The authors have no support or funding to report.
                Categories
                Subject: Research Article
                Custom metadata
                Data Availability All relevant data are within the paper.

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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