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      PLA2R antibody, PLA2R rs4664308 polymorphism and PLA2R mRNA levels in Tunisian patients with primary membranous nephritis

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          Abstract

          Background

          Primary membranous nephritis (PMN) is an autoimmune disease induced by the deposit of antibodies (Ab) to the phospholipase receptor A2 receptor (PLA2R) on podocytes. In this context, we aimed to assess the relationships between anti-PLA2R Ab, PLA2R rs4664308 SNP, PLA2R mRNA levels and PMN susceptibility and outcome.

          Methods

          Sixty-eight PMN patients, 30 systemic lupus erythematosus (SLE) patients with secondary MN and 30 healthy control subjects served for anti-PLA2R Ab measurement by ELISA and PLA2R rs4664308 SNP genotyping by a commercial real-time PCR. Twenty patients with tubulo-interstitial nephritis (TIN) were used as controls for renal PLA2R mRNA quantification in PMN patients from kidney biopsies. PLA2R mRNA quantification was carried-out by real-time PCR after RNA extraction.

          Results

          Forty-three (63.2%) PMN patients received initial therapy consisting of alternating monthly cycles of corticosteroids and cyclophosphamide. Twelve (17.6%) patients had resistant PMN to initial therapy and were consecutively treated by cyclosporine or tacrolimus.

          Anti-PLA2R Ab were positive in 54 (79.4%) PMN patients, while all SLE patients and controls were negative, p<0.0001. Moreover, anti-PLA2R Ab levels were significantly higher in PMN patients (134.85 [41.25–256.97] RU/ml) than in SLE patients (3.35 [2.3–4.35] RU/ml) and controls (2 [2–2.3]), p<0.0001. Consequently, a ROC curve showed for 100% specificity a sensitivity of 94.1% at a threshold of 2.6 RU/ml. Besides, Anti-PLA2R antibodies levels were significantly associated to non-remission; p = 0.002.

          The rs4664308*A wild-type allele was significantly more frequent in PMN patients (0.809) than in controls (0.633) and SLE patients (0.65); p = 0.008, OR [95% CI] = 2.44 [1.24–4.82] and p = 0.016, OR [95% CI] = 2.27 [1.15–4.5], respectively.

          Renal PLA2R mRNA levels were significantly higher in PMN patients (218.29 [66.05–486.07]) than in TIN patients (22.09 [13.62–43.34]), p<0.0001. Moreover, PLA2R mRNA levels were significantly higher in non-remission patients (fold-factor vs. partial remission = 2.46 and fold-factor vs. complete remission = 12.25); p = 1.56 10E-8. In addition, PLA2R mRNA and anti-PLA2R Ab levels were significantly correlated, Spearman Rho = 0.958, p<0.0001.

          Conclusion

          Anti-PLA2R Ab and renal PLA2R mRNA could be useful markers for PMN outcome predicting. The PLA2R rs6446308 SNP is associated with PMN susceptibility in Tunisians.

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          Most cited references30

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          The classification of glomerulonephritis in systemic lupus erythematosus revisited.

          The currently used classification reflects our understanding of the pathogenesis of the various forms of lupus nephritis, but clinicopathologic studies have revealed the need for improved categorization and terminology. Based on the 1982 classification published under the auspices of the World Health Organization (WHO) and subsequent clinicopathologic data, we propose that class I and II be used for purely mesangial involvement (I, mesangial immune deposits without mesangial hypercellularity; II, mesangial immune deposits with mesangial hypercellularity); class III for focal glomerulonephritis (involving or =50% of total number of glomeruli) either with segmental (class IV-S) or global (class IV-G) involvement, and also with subdivisions for active and sclerotic lesions; class V for membranous lupus nephritis; and class VI for advanced sclerosing lesions. Combinations of membranous and proliferative glomerulonephritis (i.e., class III and V or class IV and V) should be reported individually in the diagnostic line. The diagnosis should also include entries for any concomitant vascular or tubulointerstitial lesions. One of the main advantages of the current revised classification is that it provides a clear and unequivocal description of the various lesions and classes of lupus nephritis, allowing a better standardization and lending a basis for further clinicopathologic studies. We hope that this revision, which evolved under the auspices of the International Society of Nephrology and the Renal Pathology Society, will contribute to further advancement of the WHO classification.
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            Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy.

            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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              The anti-PLA2R antibody in membranous nephropathy: What we know and what remains a decade after its discovery

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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Investigation
                Role: ConceptualizationRole: Data curation
                Role: ConceptualizationRole: Data curation
                Role: Data curationRole: Formal analysisRole: Investigation
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ValidationRole: Visualization
                Role: ConceptualizationRole: Data curation
                Role: ConceptualizationRole: Data curation
                Role: Conceptualization
                Role: ConceptualizationRole: InvestigationRole: Project administrationRole: SupervisionRole: ValidationRole: Visualization
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                1 October 2020
                2020
                : 15
                : 10
                : e0240025
                Affiliations
                [1 ] Research Laboratory in Immunology of Renal Transplantation and Immunopathology (LR03SP01), Charles Nicolle Hospital, Tunis El Manar University, Tunis, Tunisia
                [2 ] Department of Nephrology and Internal Medicine, Charles Nicolle Hospital, Tunis, Tunisia
                [3 ] Research Laboratory of Kidney Diseases (LR00SP01), Charles Nicolle Hospital, Tunis, Tunisia
                Istituto Di Ricerche Farmacologiche Mario Negri, ITALY
                Author notes

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

                Author information
                http://orcid.org/0000-0002-6376-0950
                Article
                PONE-D-20-17580
                10.1371/journal.pone.0240025
                7529277
                33002091
                8c060989-9758-423d-b7bb-f7a29c8b46c3
                © 2020 Dhaouadi 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
                : 9 June 2020
                : 17 September 2020
                Page count
                Figures: 5, Tables: 4, Pages: 17
                Funding
                Funded by: This study was granted and supported by the Research Laboratory in Immunology of Renal Transplantation and Immunopathology (LR03SP01), and the Research Laboratory of Kidney Diseases (LR00SP01), Charles Nicolle Hospital, Tunis El Manar University, Tunisia.
                This study was supported by the Research Laboratory in Immunology of Renal Transplantation and Immunopathology (LR03SP01), and the Research Laboratory of Kidney Diseases (LR00SP01), Charles Nicolle Hospital, Tunis El Manar University, Tunisia.
                Categories
                Research Article
                Medicine and Health Sciences
                Clinical Medicine
                Clinical Immunology
                Autoimmune Diseases
                Lupus Erythematosus
                Systemic Lupus Erythematosus
                Biology and Life Sciences
                Immunology
                Clinical Immunology
                Autoimmune Diseases
                Lupus Erythematosus
                Systemic Lupus Erythematosus
                Medicine and Health Sciences
                Immunology
                Clinical Immunology
                Autoimmune Diseases
                Lupus Erythematosus
                Systemic Lupus Erythematosus
                Medicine and Health Sciences
                Rheumatology
                Systemic Lupus Erythematosus
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Clinical Medicine
                Signs and Symptoms
                Proteinuria
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Biopsy
                Biology and Life Sciences
                Biochemistry
                Biomarkers
                Creatinine
                Medicine and Health Sciences
                Nephrology
                Nephritis
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Steroid Therapy
                Corticosteroid Therapy
                Biology and Life Sciences
                Genetics
                Single Nucleotide Polymorphisms
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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