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      Outcomes of primary membranous nephropathy based on serum anti-phospholipase A2 receptor antibodies and glomerular phospholipase A2 receptor antigen status: a retrospective cohort study

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          Abstract

          Introduction

          Primary membranous nephropathy (PMN) is associated with the anti-phospholipase A2 receptor (anti-PLA2R) antibody in 70% of cases. Some anti-PLA2R-negative patients have the PLA2R antigen in renal tissue. This study examined the prognosis of patients with PMN according to their serum anti-PLA2R antibody (SAb) and glomerular PLA2R antigen (GAg) status.

          Methods

          Patients diagnosed with PMN were included retrospectively. Patients were grouped according to their PLA2R status into the SAb−/GAg−, SAb−/GAg+, and SAb+/GAg + groups. Baseline data, renal biopsy results, treatment, and clinical data were compared among the groups. Cox univariable and multivariable analyses examined the factors related to complete remission (CR).

          Results

          A total of 114 patients were enrolled; 10 (9%) in the SAb−/GAg−, 23 (20%) in the SAb−/GAg+, and 81 (71%) in the SAb+/GAg+ groups. Cumulative CR rate showed a significant difference between the SAb−/GAg − and SAb+/GAg+ groups (log-rank p = 0.003). The multivariable Cox proportional hazard analysis showed that age (HR = 0.968; 95%CI = 0.946–0.990; p = 0.005), SAb+/GAg+ versus SAb−/GAg− (HR = 0.387; 95%CI = 0.190–0.788; p = 0.009), SAb−/GAg+ versus SAb−/GAg− (HR = 0.398; 95%CI = 0.169, 0.939; p = 0.035), total renal chronicity score ≥2 (HR = 0.461, 95%CI: 0.277–0.766, p = 0.003), and IgA deposition (HR = 2.596; 95%CI = 1.227–5.492; p = 0.013) were all independently related ( p < 0.05) to CR.

          Conclusions

          The SAb and GAg status was an indicator of PMN prognosis. The patients with SAb−/GAg − had an increased likelihood of achieving CR than those with SAb−/GAg+ and SAb+/GAg+.

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          Most cited references26

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          Primary Membranous Nephropathy.

          Membranous nephropathy (MN) is a unique glomerular lesion that is the most common cause of idiopathic nephrotic syndrome in nondiabetic white adults. About 80% of cases are renal limited (primary MN, PMN) and 20% are associated with other systemic diseases or exposures (secondary MN). This review focuses only on PMN. Most cases of PMN have circulating IgG4 autoantibody to the podocyte membrane antigen PLA2R (70%), biopsy evidence PLA2R staining indicating recent immunologic disease activity despite negative serum antibody levels (15%), or serum anti-THSD7A (3%-5%). The remaining 10% without demonstrable anti-PLA2R/THSd7A antibody or antigen likely have PMN probably secondary to a different, still unidentified, anti-podocyte antibody. Considerable clinical and experimental data now suggests these antibodies are pathogenic. Clinically, 80% of patients with PMN present with nephrotic syndrome and 20% with non-nephrotic proteinuria. Untreated, about one third undergo spontaneous remission, especially those with absent or low anti-PLA2R levels, one-third progress to ESRD over 10 years, and the remainder develop nonprogressive CKD. Proteinuria can persist for months after circulating anti-PLA2R/THSD7A antibody is no longer detectable (immunologic remission). All patients with PMN should be treated with supportive care from the time of diagnosis to minimize protein excretion. Patients with elevated anti-PLA2R/THSD7A levels and proteinuria >3.5 g/d at diagnosis, and those who fail to reduce proteinuria to <3.5 g after 6 months of supportive care or have complications of nephrotic syndrome, should be considered for immunosuppressive therapy. Accepted regimens include steroids/cyclophosphamide, calcineurin inhibitors, and B cell depletion. With proper management, only 10% or less will develop ESRD over the subsequent 10 years.
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            A Proposal for a Serology-Based Approach to Membranous Nephropathy.

            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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              Autoantibodies against thrombospondin type 1 domain-containing 7A induce membranous nephropathy.

              Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults, and one-third of patients develop end-stage renal disease (ESRD). Circulating autoantibodies against the podocyte surface antigens phospholipase A2 receptor 1 (PLA2R1) and the recently identified thrombospondin type 1 domain-containing 7A (THSD7A) are assumed to cause the disease in the majority of patients. The pathogenicity of these antibodies, however, has not been directly proven. Here, we have reported the analysis and characterization of a male patient with THSD7A-associated MN who progressed to ESRD and subsequently underwent renal transplantation. MN rapidly recurred after transplantation. Enhanced staining for THSD7A was observed in the kidney allograft, and detectable anti-THSD7A antibodies were present in the serum before and after transplantation, suggesting that these antibodies induced a recurrence of MN in the renal transplant. In contrast to PLA2R1, THSD7A was expressed on both human and murine podocytes, enabling the evaluation of whether anti-THSD7A antibodies cause MN in mice. We demonstrated that human anti-THSD7A antibodies specifically bind to murine THSD7A on podocyte foot processes, induce proteinuria, and initiate a histopathological pattern that is typical of MN. Furthermore, anti-THSD7A antibodies induced marked cytoskeletal rearrangement in primary murine glomerular epithelial cells as well as in human embryonic kidney 293 cells. Our findings support a causative role of anti-THSD7A antibodies in the development of MN.
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                Author and article information

                Journal
                Ren Fail
                Ren Fail
                Renal Failure
                Taylor & Francis
                0886-022X
                1525-6049
                17 July 2020
                2020
                : 42
                : 1
                : 675-683
                Affiliations
                [a ]Department of Nephrology, Zhongshan City People’s Hospital , Zhongshan, Guangdong, China
                [b ]Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou, Guangdong, China
                Author notes
                [*]

                These authors contributed equally to this work.

                Supplemental data for this article can be accessed here .

                CONTACT Fengxian Huang hfxyl@ 123456163.net Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University , 58th Zhongshan Road II, Guangzhou510080, Guangdong, China;
                Qing Ye yeqing2318@ 123456aliyun.com Department of Nephrology, Zhongshan City People’s Hospital , Zhongshan, China
                Article
                1792315
                10.1080/0886022X.2020.1792315
                7470143
                32674643
                a6922358-4d32-47d9-b061-72747240c23c
                © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Page count
                Figures: 1, Tables: 3, Pages: 9, Words: 5439
                Categories
                Research Article
                Clinical Study

                Nephrology
                outcome,p,rimary membranous nephropathy,phospholipase a2 receptor,remission
                Nephrology
                outcome, p, rimary membranous nephropathy, phospholipase a2 receptor, remission

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