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      Prognostic value of PLA2R autoimmunity detected by measurement of anti-PLA2R antibodies combined with detection of PLA2R antigen in membranous nephropathy: A single-centre study over 14 years

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          Abstract

          Introduction

          Clinical course of membranous nephropathy (MN) is difficult to predict. Measurement of circulating anti-PLA2R autoantibodies (PLA2R-Ab) and detection in immune deposits of PLA2R antigen (PLA2R-Ag) are major advances in disease understanding. We evaluated the clinical significance of these biomarkers.

          Methods

          In this 14-year retrospective study, we collected data from 108 MN patients and assessed the relationship between clinical course, PLA2R-Ab and PLA2R-Ag. We also assessed THSD7A status.

          Results

          Eighty-five patients suffered from primary MN (PMN) and 23 patients from a secondary form. The median follow-up was 30.4 months [interquartile range, 17.7;56.7]. Among the 77 patients with PMN and available serum and/or biopsy, 69 (89.6%) had PLA2R-related disease as shown by anti-PLA2R-Ab and/or PLA2R-Ag, while 8 patients (8/77, 10.4%) were negative for both. There was no significant difference between these two groups in age at diagnosis and outcome assessed by proteinuria, serum albumin level and eGFR. Two of the 8 negative patients were positive for THSD7A. In patients with PLA2R related PMN, younger age, lower proteinuria, higher eGFR, and lower PLA2R-Ab level at baseline and after 6 months were associated with remission of proteinuria. Initial PLA2R-Ab titer ≤ 97.6 RU/mL and complete depletion of PLA2R-Ab within 6-months were significantly associated with spontaneous remission at the end of follow-up. In rituximab treated patients, lower PLA2R-Ab titer at initiation of treatment, and absence of PLA2R-Ab and higher serum albumin level at 3 months were significantly associated with remission. Noticeably, 81.8% of the patients who achieved remission completely cleared PLA2R-Ab. Depletion of PLA2R-Ab and increase of serum albumin level preceded the decrease of proteinuria.

          Conclusion

          Assessment of PLA2R autoimmunity is essential for patient management. Combination of PLA2R-Ab and PLA2R-Ag increases diagnosis sensitivity. PLA2R-Ab titer is a biomarker of disease severity at initial assessment, and the kinetics of the antibody are significantly correlated to disease evolution.

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          Most cited references19

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          The KDIGO practice guideline on glomerulonephritis: reading between the (guide)lines--application to the individual patient.

          The KDIGO guideline for glomerulonephritis is designed to assist health-care providers in treating patients with glomerular diseases. A guideline is not a set of rules but is intended to allow the practitioner to make an informed decision based on the available evidence. Due to its general nature and the variability of strength of the available studies, it is often difficult to directly apply a guideline to the care of an individual patient. This commonly relates to the limited generalizability of the evidence, i.e., does not cover every clinical scenario. To underscore this point, we have introduced within the context of the glomerulonephritis guideline cases with specific features to illustrate the constant need for clinical judgment. These vignettes are intended to demonstrate how the best treatment plans should be individualized and take into account patient preference and clinical acumen, as well as the best available evidence.
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            Anti-Phospholipase A2 Receptor Antibody Titer Predicts Post-Rituximab Outcome of Membranous Nephropathy.

            Rituximab induces nephrotic syndrome (NS) remission in two-thirds of patients with primary membranous nephropathy (MN), even after other treatments have failed. To assess the relationships among treatment effect, circulating nephritogenic anti-phospholipase A2 receptor (anti-PLA2R) autoantibodies and genetic polymorphisms predisposing to antibody production we serially monitored 24-hour proteinuria and antibody titer in patients with primary MN and long-lasting NS consenting to rituximab (375 mg/m(2)) therapy and genetic analyses. Over a median (range) follow-up of 30.8 (6.0-145.4) months, 84 of 132 rituximab-treated patients achieved complete or partial NS remission (primary end point), and 25 relapsed after remission. Outcomes of patients with or without detectable anti-PLA2R antibodies at baseline were similar. Among the 81 patients with antibodies, lower anti-PLA2R antibody titer at baseline (P=0.001) and full antibody depletion 6 months post-rituximab (hazard ratio [HR], 7.90; 95% confidence interval [95% CI], 2.54 to 24.60; P<0.001) strongly predicted remission. All 25 complete remissions were preceded by complete anti-PLA2R antibody depletion. On average, 50% anti-PLA2R titer reduction preceded equivalent proteinuria reduction by 10 months. Re-emergence of circulating antibodies predicted disease relapse (HR, 6.54; 95% CI, 1.57 to 27.40; P=0.01), whereas initial complete remission protected from the event (HR, 6.63; 95% CI, 2.37 to 18.53; P<0.001). Eighteen patients achieved persistent antibody depletion and complete remission and never relapsed. Outcome was independent of PLA2R1 and HLA-DQA1 polymorphisms and of previous immunosuppressive treatment. Therefore, assessing circulating anti-PLA2R autoantibodies and proteinuria may help in monitoring disease activity and guiding personalized rituximab therapy in nephrotic patients with primary MN.
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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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                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
                3 March 2017
                2017
                : 12
                : 3
                : e0173201
                Affiliations
                [1 ]Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Department of Nephrology and Transplantation, Créteil, France
                [2 ]Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Department of Nephrology and Dialysis, Paris, France
                [3 ]Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine, Department of Clinical Pharmacology and Unité de Recherche Clinique, Paris, France
                [4 ]Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Department of Pathology, Paris, France
                [5 ]Sorbonne Universités, Université Pierre et Marie Curie Univ Paris, Paris, France
                [6 ]Institut National de la Santé Et la Recheche Médicale, Unit, Paris, France
                University of Washington, UNITED STATES
                Author notes

                Competing Interests: Rituximab was provided by Hoffmann-LaRoche. The authors confirm that they are not paid employees or consultants of Hoffmann-LaRoche, that no patents or products are in development in association with this study, and that no other perceivable competing interests exist between the authors and this company. This does not alter our adherence to PLOS ONE policies on sharing data and materials. None of the funding sources played a role in the writing of the manuscript or the decision to submit it for publication.

                • Conceptualization: KD PR HD.

                • Data curation: MC.

                • Formal analysis: MC KD FP HD.

                • Funding acquisition: PR.

                • Investigation: FP KD FM IB HD.

                • Methodology: KD PR FM.

                • Project administration: PR.

                • Resources: KD PR FM.

                • Software: MC FP.

                • Supervision: KD HD PR.

                • Validation: MC FP KD.

                • Visualization: MC KD PR.

                • Writing – original draft: KD FP.

                • Writing – review & editing: PR KD.

                Article
                PONE-D-16-30371
                10.1371/journal.pone.0173201
                5336294
                28257452
                4daea2d7-199e-4358-bdcb-405a80d3e61c
                © 2017 Pourcine et al

                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
                : 3 August 2016
                : 16 February 2017
                Page count
                Figures: 1, Tables: 7, Pages: 18
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100000781, European Research Council;
                Award ID: ERC-2012-ADG_20120314
                Award Recipient :
                Funded by: 7th Framework Programme of the European Community
                Award ID: Contract 2012-305608
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100007013, F. Hoffmann-La Roche;
                Award Recipient :
                This study was funded by grants from the European Research Council ERC-2012-ADG_20120314 (Grant Agreement 322947) and from 7th Framework Programme of the European Community Contract 2012-305608 (European Consortium for High-Throughput Research in Rare Kidney Diseases). Rituximab was provided by Hoffmann–La Roche. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Proteinuria
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Proteinuria
                Biology and Life Sciences
                Biochemistry
                Proteins
                Albumins
                Serum Albumin
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Biopsy
                Research and Analysis Methods
                Immunologic Techniques
                Immunoassays
                Enzyme-Linked Immunoassays
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Serology
                Biology and Life Sciences
                Immunology
                Autoimmunity
                Medicine and Health Sciences
                Immunology
                Autoimmunity
                Medicine and Health Sciences
                Nephrology
                Chronic Kidney Disease
                Biology and Life Sciences
                Anatomy
                Renal System
                Medicine and Health Sciences
                Anatomy
                Renal System
                Custom metadata
                All relevant data are within the paper and its Supporting Information files (2 Excel files).

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