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Membranous nephropathy: new pathogenic mechanisms and their clinical implications

Abstract

Membranous nephropathy (MN) is characterized histomorphologically by the presence of immune deposits in the subepithelial space of the glomerular filtration barrier; its clinical hallmarks are nephrotic range proteinuria with oedema. In patients with primary MN, autoimmunity is driven by circulating autoantibodies that bind to one or more antigens on the surface of glomerular podocytes. Compared with other autoimmune kidney diseases, the understanding of the pathogenesis of MN has substantially improved in the past decade, thanks to the discovery of pathogenic circulating autoantibodies against phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type 1 domain-containing protein 7A (THSD7A). The subsequent identification of more proteins associated with MN, some of which are also endogenous podocyte antigens, might further advance the clinical characterization of MN, including its diagnosis, treatment and prognosis. Insights from studies in patients with MN, combined with the development of novel in vivo and in vitro experimental models, have potential to improve the management of patients with MN. Characterizing the interaction between autoimmunity and local glomerular lesions provides an opportunity to develop more specific, pathogenesis-based treatments.

Key points

  • The exact pathomechanisms underlying the development of membranous nephropathy (MN) are still not fully defined, but loss of immune tolerance, genetic factors, environmental factors, complement activation, glomerular inflammation and cellular adaptive processes in the glomeruli have major roles.

  • In primary MN, circulating autoantibodies, mostly of the IgG4 subclass, bind to one or more antigens that are endogenously expressed on the surface of podocytes in glomeruli.

  • The identification of target antigens in MN allows a specific, molecular diagnosis based on staining of the target antigens in the glomeruli and detection of autoantibodies in blood.

  • Animal models have confirmed that human phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type 1 domain-containing protein 7A (THSD7A) autoantibodies are pathogenic and induce disease after binding to their respective antigens.

  • MN is driven by autoimmune processes, which are the main target of immunosuppressive treatments. Measurement of anti-PLA2R1 antibodies enables assessment of immunological disease activity and informs the use of immunosuppressive treatments.

  • Potential targets for novel antigen-specific treatment options in MN include autoantibody production, antibody–antigen binding, immune-mediated podocyte injury and cell-specific glomerular pathomechanisms.

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Fig. 1: Pathogenesis of primary membranous nephropathy.
Fig. 2: Autoantibody binding to PLA2R1 and THSD7A domains.
Fig. 3: Known antigens in membranous nephropathy.
Fig. 4: B cell development stages and expression of cell-surface markers.

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Acknowledgements

This work is supported by grants from the Deutsche Forschungsgemeinschaft to E.H. (Heisenberg Programme and project B1 and C1 of the SFB 1192) and R.A.K.S. (project B1 of the SFB 1192).

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All authors researched data for the article, made substantial contributions to discussions of the content, and wrote, reviewed and edited the manuscript before submission.

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Correspondence to Rolf A. K. Stahl.

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E.H. has received fees from Morphosys, Planegg, Germany, and Novartis, Basel, Switzerland, for advisory board activities. R.A.K.S. has received fees from Morphosys, Planegg, Germany, for advisory board activities. L.R. declares no competing interests.

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Epitope spreading

Spreading of the specificity of an immune response from an epitope to another located in the same molecule (intramolecular spreading), or in a different molecule (intermolecular spreading).

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Hoxha, E., Reinhard, L. & Stahl, R.A.K. Membranous nephropathy: new pathogenic mechanisms and their clinical implications. Nat Rev Nephrol 18, 466–478 (2022). https://doi.org/10.1038/s41581-022-00564-1

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