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      Autoantibodies against Phospholipase A 2 Receptor in Korean Patients with Membranous Nephropathy

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          Abstract

          The data were presented in abstract form at the 45 th meeting of the American Society of Nephrology, October 30-November 04 2012, San Diego, CA, USA. Circulating autoantibodies against M-type phospholipase A 2 receptor (PLA 2R) are important pathogenic antibodies of idiopathic membranous nephropathy (MN) in adults. However, previous studies on the clinical impact of anti-PLA 2R antibodies demonstrated several limitations, including insufficient numbers of study subjects and different time points and methods for anti-PLA 2R antibody measurement. To verify the clinical significance of anti-PLA 2R antibodies in Korean patients with MN, we measured autoantibodies in serum samples obtained at the time of biopsy from a total of 100 patients with idiopathic MN who had not yet received immunosuppressive treatment. We detected anti-PLA 2R antibody in 69 patients, and we observed that autoantibody reactivity reflected the severity of disease activity. Proteinuria and hypoalbuminemia were more severe in patients with anti-PLA 2R than in those without the autoantibodies (2.95 g/g vs. 6.85 g/g, P = 0.003; 3.1 g/dL vs. 2.5 g/dL, P = 0.004, respectively). Additionally, the clinical severities worsened proportionally as the levels of anti-PLA 2R antibodies increased ( P = 0.015 and P for trend <0.001 for proteinuria and hypoalbuminemia, respectively). However, neither the levels nor the presence or absence of anti-PLA 2R antibody showed a significant correlation with clinical outcomes, such as remission rate and time to remission. In conclusion, we observed that anti-PLA 2R antibodies are highly prevalent in Korean patients with idiopathic MN and that they reflect the clinical disease activity before the administration of immunosuppressive treatment. However, the levels of anti-PLA 2R antibody at the time of kidney biopsy may not predict the clinical outcomes in current clinical practice.

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          Most cited references 18

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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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            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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              Cyclosporine in patients with steroid-resistant membranous nephropathy: a randomized trial.

              A clinical trial of cyclosporine in patients with steroid-resistant membranous nephropathy (MGN) was conducted. Although MGN remains the most common cause of adult-onset nephrotic syndrome, its management is still controversial. Cyclosporine has been shown to be effective in cases of progressive MGN, but it has not been used in controlled studies at an early stage of the disease. We conducted a randomized trial in 51 biopsy-proven idiopathic MGN patients with nephrotic-range proteinuria comparing 26 weeks of cyclosporine treatment plus low-dose prednisone to placebo plus prednisone. All patients were followed for an average of 78 weeks, and the short- and long-term effects on renal function were assessed. Seventy-five percent of the treatment group versus 22% of the control group (P < 0.001) had a partial or complete remission of their proteinuria by 26 weeks. Relapse occurred in 43% (N = 9) of the cyclosporine remission group and 40% (N = 2) of the placebo group by week 52. The fraction of the total population in remission then remained almost unchanged and significant different between the groups until the end of the study (cyclosporine 39%, placebo 13%, P = 0.007). Renal function was unchanged and equal in the two groups over the test medication period. In the subsequent follow-up, renal insufficiency, defined as doubling of baseline creatinine, was seen in two patients in each group, but remained equal and stable in all of the other patients. This study suggests that cyclosporine is an effective therapeutic agent in the treatment of steroid-resistant cases of MGN. Although a high relapse does occur, 39% of the treated patients remained in remission and were subnephrotic for at least one-year post-treatment, with no adverse effect on filtration function.
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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, USA )
                1932-6203
                2013
                26 April 2013
                : 8
                : 4
                Affiliations
                [1 ]Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
                [2 ]Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
                [3 ]Seoul National University Kidney Research Institute, Seoul, Korea
                [4 ]Severance Biomedical Science Institute, Brain Korea 21, Yonsei University, Seoul, Korea
                Centro di Riferimento Oncologico, IRCCS National Cancer Institute, Italy
                Author notes

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

                Conceived and designed the experiments: YJO SHY SWK YSK. Performed the experiments: YJO SHY. Analyzed the data: YJO SHY DKK. Contributed reagents/materials/analysis tools: SHY DKK. Wrote the paper: YJO SWK YSK.

                Article
                PONE-D-12-39613
                10.1371/journal.pone.0062151
                3637390
                23637987

                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
                Pages: 8
                Funding
                This work was supported by a grant from the Korean Healthcare Technology R&D Project, Ministry of Health, Welfare and Family Affairs, Republic of Korea (A110717). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
                Categories
                Research Article
                Biology
                Immunology
                Autoimmunity
                Medicine
                Clinical Immunology
                Clinical Research Design
                Diagnostic Medicine
                Pathology
                General Pathology
                Biomarkers
                Nephrology
                Chronic Kidney Disease

                Uncategorized

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