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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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          Most cited references 14

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

          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.

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              An immunofluorescence test for phospholipase-A₂-receptor antibodies and its clinical usefulness in patients with membranous glomerulonephritis.

              The recent finding that phospholipase-A(2)-receptor antibodies (PLA(2)R-AB) may play a role in the development of primary membranous glomerulonephritis (MGN) offers the opportunity to measure a marker to help diagnose, classify and eventually monitor the course of patients with MGN. We developed an immunofluorescence test, which allows the easy and specific analysis of the presence of PLA(2)R-AB in serum. The usefulness of this test was studied in 153 healthy blood donors, 90 patients with non-membranous glomerular injuries, 17 patients with a secondary form of MGN and 100 patients with biopsy-proven primary MGN. In addition, in five patients with biopsy-proven MGN, PLA(2)R-AB levels were monitored prospectively for up to 18 months following a single dose of rituximab (RTX) (375 mg/m(2) body surface). PLA(2)R-AB were not found in healthy controls or patients with glomerular lesions other than biopsy-proven primary MGN. Fifty-two patients with primary MGN (52%) were positive for PLA(2)R-AB. The levels ranged from 1:10 to 1:3200. In patients who had MGN and were treated with RTX the fall in PLA(2)R-AB levels was followed by a decrease in proteinuria, whereas an increase in PLA(2)R-AB levels was associated with an increase in proteinuria. These studies show that the new test allows the monitoring of PLA(2)R-AB levels in patients with MGN and may help in making therapeutic decisions for these patients.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                22 September 2015
                2015
                : 10
                : 9
                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
                PONE-D-15-27775
                10.1371/journal.pone.0138841
                4578926
                26393352

                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

                Page count
                Figures: 2, Tables: 3, Pages: 10
                Product
                Funding
                The authors have no support or funding to report.
                Categories
                Research Article
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                All relevant data are within the paper.

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