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Continuing the paradigm shift in the treatment of idiopathic membranous nephropathy

Nature Reviews Nephrology volume 13, page 720 (2017)Cite this article

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I read with interest the recent Review by P. Ruggenenti et al. (Treatment of membranous nephropathy: time for a paradigm shift. Nat. Rev. Nephrol. 13, 563–579; 2017)1. The observed inconsistency in therapeutic responses with conventional therapies directed at T cells and B cells2, as well as the superior complete remission rates (53%) achieved with rituximab in patients with recurrent membranous nephropathy post-transplantation3 compared to rates in those with native kidneys (13.6–19%)4,5, highlight the important role of T cells in autoimmune kidney diseases6 and the likely added value of T cell-targeted therapies in addition to anti-CD20 monoclonal antibody therapy in increasing remission rates. These observations imply the existence of different immunopathogenic signatures — primarily B cell-mediated pathways with a component of T cell help6,7 — in addition to distinct mechanisms of autoantibody and alloantibody secretion by different B cell lineages, for example, by CD20+ activated B cells in spleen and lymph nodes, CD19+CD20− plasmablasts and short-lived plasma cells in blood, and CD19−CD20−CD38+CD138+ long-lived memory plasma cells located in the bone marrow and ectopically in the inflamed kidney8. These non-proliferating long-lived memory plasma cells produce considerable amounts of IgG autoantibodies and alloantibodies, and provide the basis for humoral memory and refractory autoimmune diseases7,8,9,10.

As pointed out by Ruggenenti et al., the lack of CD19 and CD20 expression by long-lived memory plasma cells renders these cells resistant to depletion by anti-CD20 monoclonal antibodies1,5,9. This resistance might explain the limited rate of sustained complete remission and recovery achieved by rituximab in patients with idiopathic membranous nephropathy, despite successful depletion of circulating B cells4,5,10,11,12. I agree that use of plasma-cell-depleting therapies, such as the newly introduced anti-CD38 monoclonal antibodies and the less specific proteasome inhibitors with anti-B cell and anti-T cell activities13, might offer novel therapeutic alternatives for patients with idiopathic membranous nephropathy, at least in those who are refractory or only partially respond to combined conservative treatment plus rituximab therapy12. Whether new second and third generation anti-CD20 monoclonal antibodies can achieve higher rates of sustained complete remission than rituximab1 remains to be determined, but such agents do not target long-lived memory plasma cells8,14. Surprisingly, another anti-CD20 monoclonal antibody, ofatumumab, failed to demonstrate superiority over rituximab as salvage chemotherapy in patients with relapsed or refractory diffuse large B cell lymphoma15. New immunologic biomarkers are needed to help to identify patients who are likely to respond to T cell3, B cell7,8, or combination therapy12,14. In addition to measuring CD19 and CD20 (Refs 1,4,5,9,11), assessment of patients with membranous nephropathy should include measurement of the long-lived memory plasma cell markers, CD38 and CD138, particularly in patients with relapsing or rituximab-resistant disease7,8,9,10,12,14.

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References

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  1. Renal Transplant Unit, Rafik Hariri University Hospital, Bir Hassan, Beirut, Lebanon

    Antoine Barbari

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Barbari, A. Continuing the paradigm shift in the treatment of idiopathic membranous nephropathy. Nat Rev Nephrol 13, 720 (2017). https://doi.org/10.1038/nrneph.2017.134

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