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  • Review Article
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Treatment of membranous nephropathy: time for a paradigm shift

Nature Reviews Nephrology volume 13, pages 563–579 (2017)Cite this article

Subjects

Key Points

  • Steroids and alkylating agents increase the rate of remission in patients with membranous nephropathy but can cause diabetes mellitus, myelotoxicity, infections, cancer, and other adverse events

  • Calcineurin inhibitors can reduce proteinuria in patients with membranous nephropathy but are nephrotoxic, and these agents should be avoided in patients with abnormal kidney function

  • The discovery of nephritogenic autoantibodies provided a clear rationale for interventions specifically aimed at preventing formation of antigen–antibody immunocomplexes with secondary complement activation, podocyte damage, and proteinuria

  • B cell-targeted therapy with rituximab is at least as effective as steroids and alkylating agents in achieving remission in membranous nephropathy, and available evidence suggests that it is safer and better tolerated

  • In patients with anti-PLA2R-related membranous nephropathy and overt nephrotic syndrome, evaluation of serum autoantibody titre and albumin levels, as well as assessment of proteinuria could guide tailored therapy

  • Traditional immunosuppressive regimens will be replaced by specific, nontoxic agents such as B cell-targeting monoclonal antibodies; modulation of B-cell immunity could lead to a novel therapeutic paradigm in membranous nephropathy

Abstract

In patients with membranous nephropathy, alkylating agents (cyclophosphamide or chlorambucil) alone or in combination with steroids achieve remission of nephrotic syndrome more effectively than conservative treatment or steroids alone, but can cause myelotoxicity, infections, and cancer. Calcineurin inhibitors can improve proteinuria, but are nephrotoxic. Most patients relapse after treatment withdrawal and can become treatment dependent, which increases the risk of nephrotoxicity. The discovery of nephritogenic autoantibodies against podocyte M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain- containing protein 7A (THSD7A) antigens provides a clear pathophysiological rationale for interventions that specifically target B-cell lineages to prevent antibody production and subepithelial deposition. The anti-CD20 monoclonal antibody rituximab is safe and achieves remission of proteinuria in approximately two-thirds of patients with membranous nephropathy. In those with PLA2R-related disease, remission can be predicted by anti-PLA2R antibody depletion and relapse by antibody re-emergence into the circulation. Thus, integrated evaluation of serology and proteinuria could guide identification of affected patients and treatment with individually tailored protocols. Nonspecific and toxic immunosuppressive regimens will fall out of use. B-cell modulation by rituximab and second-generation anti-CD20 antibodies (or plasma cell-targeted therapy in anti-CD20 resistant forms of disease) will lead to a novel therapeutic paradigm for patients with membranous nephropathy.

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Figure 1: Targets for monoclonal antibodies in B-cell lineages.
Figure 2: Prevention of antigen–antibody immunocomplex deposition on the glomerular basement membrane.
Figure 3: Key findings from the GEMRITUX trial38.
Figure 4: The molecular configuration of the CD20 molecule.
Figure 5: Comparison of outcomes with belimumab or rituximab therapy.

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Acknowledgements

Luca Perico, Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy, helped to revise the paragraph on PLA2R epitope spreading and Fig. 2.

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Authors and Affiliations

  1. IRCCS – Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, Bergamo, 24126, Italy

    Piero Ruggenenti & Giuseppe Remuzzi

  2. Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Piazza OMS 1, Bergamo, 24128, Italy

    Piero Ruggenenti & Giuseppe Remuzzi

  3. Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, USA

    Fernando C. Fervenza

  4. Department of Biomedical and Clinical Sciences, University of Milan, Via Festa del Perdono 7, Milan, 20122, Italy

    Giuseppe Remuzzi

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P.R. and F.C.F. researched data for the article. All authors contributed to discussion of the article's content, writing and review/editing the manuscript before submission.

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Correspondence to Giuseppe Remuzzi.

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Competing interests

F.C.F. has received unrestricted research grants from Genentech/Roche, the maker of rituximab. The other authors declare no competing interests.

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Ruggenenti, P., Fervenza, F. & Remuzzi, G. Treatment of membranous nephropathy: time for a paradigm shift. Nat Rev Nephrol 13, 563–579 (2017). https://doi.org/10.1038/nrneph.2017.92

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