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      Profile of Indian Patients With Membranous Nephropathy

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          Abstract

          Introduction

          The majority of primary membranous nephropathy (MN) cases are no longer considered idiopathic with the discovery of the podocytic autoantigens: phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain–containing 7A (THSD7A). Limited data on PLA2R-related MN in Indians exist in literature, and THSD7A-related MN remains undocumented in this population. We aimed to characterize the baseline PLA2R and THSD7A profile of adult and pediatric membranous nephropathy (MN) in a large Indian single-institution cohort.

          Methods

          A retrospective analysis of all cases of MN (primary and secondary) between 2014 and 2017 was performed with PLA2R direct immunofluorescence and THSD7A immunohistochemistry on the biopsies and anti-PLA2R enzyme-linked immunosorbent assay (ELISA) on baseline sera.

          Results

          MN constituted 10% of kidney biopsies received in the study period. A total of 216 cases with adequate tissue underwent PLA2R direct immunofluorescence, and 110 of them had available sera for PLA2R ELISA. Combining both testing methods, the prevalence of PLA2R-related primary MN was 72.8%, with moderate concordance between the 2 methods (kappa 0.61). PLA2R was also detected in 16.7% cases of secondary MN, most commonly lupus MN. THSD7A immunohistochemistry performed on 176 cases showed a prevalence of 3.4% in primary MN. One case of lupus MN was also positive for THSD7A. Dual positivity (PLA2R and THSD7A) was noted in 2 cases. The large pediatric cohort tested showed a prevalence of 44% of PLA2R based on tissue testing, whereas 1 case demonstrated THSD7A positivity.

          Conclusion

          This study in a large cohort of Indian patients demonstrates prevalence rates of PLA2R- and THSD7A-related MN similar to world literature, including the substantial cohort of pediatric MN. It also confirms variation in MN in the form of outliers within PLA2R (related to tissue and serum testing), dual positivity for PLA2R and THSD7A, and PLA2R/THSD7A-positive secondary MN.

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          A Proposal for a Serology-Based Approach to Membranous Nephropathy.

          An S De Vriese, Richard Glassock, Karl A. Nath … (2017)
          Primary membranous nephropathy (MN) is an autoimmune disease mainly caused by autoantibodies against the recently discovered podocyte antigens: the M-type phospholipase A2 receptor 1 (PLA2R) and thrombospondin type 1 domain-containing 7A (THSD7A). Assays for quantitative assessment of anti-PLA2R antibodies are commercially available, but a semiquantitative test to detect anti-THSD7A antibodies has been only recently developed. The presence or absence of anti-PLA2R and anti-THSD7A antibodies adds important information to clinical and immunopathologic data in discriminating between primary and secondary MN. Levels of anti-PLA2R antibodies and possibly, anti-THSD7A antibodies tightly correlate with disease activity. Low baseline and decreasing anti-PLA2R antibody levels strongly predict spontaneous remission, thus favoring conservative therapy. Conversely, high baseline or increasing anti-PLA2R antibody levels associate with nephrotic syndrome and progressive loss of kidney function, thereby encouraging prompt initiation of immunosuppressive therapy. Serum anti-PLA2R antibody profiles reliably predict response to therapy, and levels at completion of therapy may forecast long-term outcome. Re-emergence of or increase in antibody titers precedes a clinical relapse. Persistence or reappearance of anti-PLA2R antibodies after kidney transplant predicts development of recurrent disease. We propose that an individualized serology-based approach to MN, used to complement and refine the traditional proteinuria-driven approach, will improve the outcome in this disease.
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            Exostosin 1/Exostosin 2–Associated Membranous Nephropathy

            Sanjeev Sethi, Benjamin Madden, Hanna Debiec … (2019)
            In approximately 70%–80% of cases of primary membranous nephropathy (MN), phospholipase A2 receptor (PLA2R)/Thrombospondin Type-1 Domain–Containing 7A (THSD7A) and anti-PLA2R/THSD7A antibodies form immune complexes along the glomerular basement membrane (GBM) that characterize the condition. In other cases of primary MN and all secondary MN, the target antigen is unknown. Using proteomics and immunohistochemistry, the authors detected two proteins, exostosin 1 (EXT1) and exostosin 2 (EXT2), in the GBM of PLA2R-negative MN. EXT1 and EXT2 were absent in all cases of PLA2R-associated MN and controls. Clinical and biopsy findings showed features of autoimmune disease, including membranous lupus nephritis, in 81% of the 26 EXT1/EXT2-associated MN cases the authors identified. These findings suggest that EXT1/EXT2-associated MN represents a distinct subtype of MN, most commonly associated with autoimmune diseases (secondary MN). In membranous nephropathy (MN), which is characterized by deposition of immune complexes along the glomerular basement membrane (GBM), phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain–containing 7A are target antigens in approximately 70% and 1%–5% of cases of primary MN, respectively. In other cases of primary MN and in secondary MN, the target antigens are unknown. We studied 224 cases of biopsy-proven PLA2R-negative MN and 102 controls (including 47 cases of PLA2R-associated MN) in pilot and discovery cohorts. We also evaluated 48 cases of PLA2R-negative presumed primary MN and lupus MN in a validation cohort. We used laser microdissection and mass spectrometry to identify new antigens, which were localized by immunohistochemistry. Mass spectrometry detected exostosin 1 (EXT1) and exostosin 2 (EXT2) in 21 cases of PLA2R-negative MN, but not in PLA2R-associated MN and control cases. Immunohistochemistry staining revealed bright granular GBM staining for EXT1 and EXT2. Clinical and biopsy findings showed features of autoimmune disease, including lupus, in 80.7% of the 26 EXT1/EXT2-associated MN cases we identified. In the validation cohort, we confirmed that EXT1/EXT2 staining was detected in pure class 5 lupus nephritis (eight of 18 patients) and in presumed primary MN associated with signs of autoimmunity (three of 16 patients); only one of the 14 cases of mixed class 5 and 3/4 lupus nephritis was positive for EXT1/EXT2. Tests in seven patients with EXT1/EXT2-associated MN found no circulating anti-exostosin antibodies. A subset of MN is associated with accumulation of EXT1 and EXT2 in the GBM. Autoimmune disease is common in this group of patients.
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              An Indirect Immunofluorescence Method Facilitates Detection of Thrombospondin Type 1 Domain–Containing 7A–Specific Antibodies in Membranous Nephropathy

              Laurence Beck, Thorsten Wiech, Ulf Panzer … (2017)
              Thrombospondin type 1 domain-containing 7A (THSD7A) is a target antigen identified in adult membranous nephropathy (MN) along with the major antigen phospholipase A2 receptor 1 (PLA2R1). The prevalence of THSD7A-Ab-positive patients is unknown, and it is unclear whether the clinical presentation differs between patients positive for PLA2R1-Ab or THSD7A-Ab. We screened serum samples of 1276 patients with MN from three different cohorts for the presence of THSD7A-Ab by Western blot analysis and a newly developed indirect immunofluorescence test (IFT). Compared with Western blot analysis, the IFT had a 92% sensitivity and a 100% specificity. The prevalence of THSD7A-associated MN in a prospective cohort of 345 patients with MN was 2.6%, and most were women. In this cohort, the percentage of patients with THSD7A-associated MN and malignant disease significantly exceeded that of patients with PLA2R1-associated MN and malignant disease. In all cohorts, we identified 40 patients with THSD7A-associated MN, eight of whom developed a malignancy within a median time of 3 months from diagnosis of MN. In one patient with THSD7A-associated MN and metastases of an endometrial carcinoma, immunohistochemistry showed THSD7A expression on the metastatic cells and within follicular dendritic cells of the metastasis-infiltrated lymph node. We conclude that the IFT allows sensitive and specific measurement of circulating THSD7A-Ab in patients with MN. Patients with THSD7A-associated MN differ in their clinical characteristics from patients with PLA2R1-associated MN, and more intensive screening for the presence of malignancies may be warranted in those with THSD7A-associated MN.
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                Author and article information

                Contributors
                Geetika Singh
                Journal
                Journal ID (nlm-ta): Kidney Int Rep
                Journal ID (iso-abbrev): Kidney Int Rep
                Title: Kidney International Reports
                Publisher: Elsevier
                ISSN (Electronic): 2468-0249
                Publication date PMC-release: 02 July 2020
                Publication date Collection: September 2020
                Publication date (Electronic): 02 July 2020
                Volume: 5
                Issue: 9
                Pages: 1551-1557
                Affiliations
                [1 ]Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
                [2 ]Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India
                [3 ]Division of Pediatric Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
                Author notes
                [∗ ] Correspondence: Geetika Singh, Room no. 1048, First Floor, Teaching Block, Department of Pathology, All India Institute of Medical Sciences, New Delhi, India. ggmed22@ 123456gmail.com
                [4]

                PS and HK contributed equally.

                Article
                Publisher ID: S2468-0249(20)31347-4
                DOI: 10.1016/j.ekir.2020.06.024
                PMC ID: 7486174
                PubMed ID: 32954080
                SO-VID: 579dc4d6-eedd-497c-945c-483874cb70d6
                Copyright © © 2020 International Society of Nephrology. Published by Elsevier Inc.
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 3 May 2020
                Date revision received : 21 June 2020
                Date accepted : 23 June 2020
                Categories
                Subject: Clinical Research

                Keywords: membranous nephropathy,pla2r,thsd7a,thrombospondin,elisa
                Data availability:
                Keywords: membranous nephropathy, pla2r, thsd7a, thrombospondin, elisa

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