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    Recent clinical trials investigating antibodies against CD20 for the treatment of primary membranous nephropathy

  • 1.

    Rojas-Rivera JE, et al. Treatment of idiopathic membranous nephropathy in adults: KDIGO 2012, cyclophosphamide and cyclosporine A are out, rituximab is the new normal. Clin Kidney J 2019; 12:629638. doi: 10.1093/ckj/sfz127

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    • Search Google Scholar
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  • 2.

    Singh L, et al. Understanding podocytopathy and its relevance to clinical nephrology. Indian J Nephrol 2015; 25:17. doi: 10.4103/0971-4065.134531

  • 3.

    Ferreira F, Nunes AT. New treatments in membranous glomerulopathy—from the pitfalls of rituximab to a new era of biological treatments. Port J Nephrol Amp Hypertens 2020; 34:160164. http://doi.org/10.32932/pjnh.2020.10.087

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  • 4.

    Waldman M, Austin HA 3rd. Treatment of idiopathic membranous nephropathy. J Am Soc Nephrol 2012; 23:16171630. doi: 10.1681/ASN.2012010058

  • 5.

    Salvadori M, Tsalouchos A. Editor’s pick: New aspects of pathogenesis and treatment of membranous glomerulopathy after the MENTOR study. EMJ Nephrol 2020; 8:4653. https://www.emjreviews.com/nephrology/article/editors-pick-new-aspects-of-pathogenesis-and-treatment-of-membranous-glomerulopathy-after-the-mentor-study/

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  • 6.

    Fervenza FC, et al. Rituximab or cyclosporine in the treatment of membranous nephropathy. N Engl J Med 2019; 381:3646. doi: 10.1056/NEJMoa1814427

  • 7.

    Delbarba E, et al. Rituximab vs. cyclophosphamide in the treatment of membranous nephropathy: The RI-CYCLO trial. American Society of Nephrology, Kidney Week. October 22, 2020; PO2638. Accessed December 21, 2020. https://www.asn-online.org/education/kidneyweek/2020/program-abstract.aspx?controlId=3470922

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    • Export Citation
  • 8.

    Fernández-Juárez G, et al. The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy. Kidney Int [Published online ahead of print November 7, 2020]. doi: 10.1016/j.kint.2020.10.014; https://www.kidney-international.org/article/S0085-2538(20)31251-5/fulltext

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  • 9.

    National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Rituximab plus cyclosporine in idiopathic membranous nephropathy. ClinicalTrials.gov: NCT00977977. Accessed December 20, 2020. https://clinicaltrials.gov/ct2/show/NCT00977977

    • Search Google Scholar
    • Export Citation
  • 10.

    Klomjit N, et al. Successful treatment of patients with refractory PLA2R-associated membranous nephropathy with obinutuzumab: A report of 3 cases. Am J Kidney Dis 2020; 76:883888. doi: 10.1053/j.ajkd.2020.02.444

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Sethi S, et al. Obinutuzumab is effective for the treatment of refractory membranous nephropathy. Kidney Int Rep 2020; 5:15151518. doi: 10.1016/j.ekir.2020.06.030

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Marcus R, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 2017; 377:13311344. doi: 10.1056/NEJMoa1614598

  • 13.

    Hoffmann-La Roche. A phase III randomized, open-label active comparator-controlled multicenter study to evaluate efficacy and safety of obinutuzumab in patients with primary membranous nephropathy. ClinicalTrials.gov: NCT04629248. Accessed December 29, 2020. https://clinicaltrials.gov/ct2/show/NCT04629248

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Rituximab and Obinutuzumab for Membranous Nephropathy

  • 1 Sahar Semnani, MD, MBA, is a nephrology fellow at the Keck School of Medicine of the University of Southern California, Los Angeles, CA. Eugene Lin, MD, MS, FASN, is an Assistant Professor of Medicine and of Health Policy & Management at the Keck School of Medicine of the University of Southern California, Los Angeles, CA.
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The last two years have brought several promising trials with novel therapies for the treatment of membranous nephropathy, the most common etiology of nephrotic syndrome in adults (1, 2).

Currently, the mainstay of treatment is steroids in combination with alkylating agents (modified Ponticelli regimen) or calcineurin inhibitors (3). With the identification of auto-antibodies against the phospholipase-2 receptor (PLA2R) comes the potential for new therapies (4, 5), including monoclonal antibodies against CD20 on B-lymphocytes: rituximab and obinutuzumab (4).

In 2019, the MENTOR randomized controlled trial showed that rituximab was non-inferior to cyclosporine in inducing complete or partial remission of proteinuria and was superior in maintaining remission after 24 months (6). The RI-CYCLO trial, a smaller pilot study (unpublished) that was presented as an abstract at Kidney Week 2020 Reimagined, suggested similar efficacy between rituximab and cyclophosphamide in complete or partial remission of proteinuria (7). The STARMEN trial, on the other hand, was less favorable for the combination of rituximab and tacrolimus when randomized against the modified Ponticelli regimen (8). The ongoing clinical trial NCT00977977 will shed light on the safety and efficacy of combining rituximab with cyclosporine in patients with membranous nephropathy (9).

Because up to 40% of patients do not respond to rituximab (6), obinutuzumab has garnered interest as an alternative therapy for refractory membranous nephropathy and has demonstrated promise in small studies (10, 11). Although larger trials have not been conducted, obinutuzumab has shown excellent B-cell cytotoxic profiles in treating B-cell malignancies (12). An upcoming trial comparing obinutuzumab to tacrolimus will begin recruiting early this year (11, 13).

These ongoing investigations and trials should generate optimism so that we may soon have alternatives to the Ponticelli regimen for membranous nephropathy, which has been the mainstay of first-line therapy for over 30 years (4). Given the toxicity of alkylating agents and difficulty of administration in many, such a development would be very welcome.

fig1

Recent clinical trials investigating antibodies against CD20 for the treatment of primary membranous nephropathy

Citation: Kidney News 13, 2

The authors report no conflict of interest.

References

  • 1.

    Rojas-Rivera JE, et al. Treatment of idiopathic membranous nephropathy in adults: KDIGO 2012, cyclophosphamide and cyclosporine A are out, rituximab is the new normal. Clin Kidney J 2019; 12:629638. doi: 10.1093/ckj/sfz127

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Singh L, et al. Understanding podocytopathy and its relevance to clinical nephrology. Indian J Nephrol 2015; 25:17. doi: 10.4103/0971-4065.134531

  • 3.

    Ferreira F, Nunes AT. New treatments in membranous glomerulopathy—from the pitfalls of rituximab to a new era of biological treatments. Port J Nephrol Amp Hypertens 2020; 34:160164. http://doi.org/10.32932/pjnh.2020.10.087

    • Search Google Scholar
    • Export Citation
  • 4.

    Waldman M, Austin HA 3rd. Treatment of idiopathic membranous nephropathy. J Am Soc Nephrol 2012; 23:16171630. doi: 10.1681/ASN.2012010058

  • 5.

    Salvadori M, Tsalouchos A. Editor’s pick: New aspects of pathogenesis and treatment of membranous glomerulopathy after the MENTOR study. EMJ Nephrol 2020; 8:4653. https://www.emjreviews.com/nephrology/article/editors-pick-new-aspects-of-pathogenesis-and-treatment-of-membranous-glomerulopathy-after-the-mentor-study/

    • Search Google Scholar
    • Export Citation
  • 6.

    Fervenza FC, et al. Rituximab or cyclosporine in the treatment of membranous nephropathy. N Engl J Med 2019; 381:3646. doi: 10.1056/NEJMoa1814427

  • 7.

    Delbarba E, et al. Rituximab vs. cyclophosphamide in the treatment of membranous nephropathy: The RI-CYCLO trial. American Society of Nephrology, Kidney Week. October 22, 2020; PO2638. Accessed December 21, 2020. https://www.asn-online.org/education/kidneyweek/2020/program-abstract.aspx?controlId=3470922

    • Search Google Scholar
    • Export Citation
  • 8.

    Fernández-Juárez G, et al. The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy. Kidney Int [Published online ahead of print November 7, 2020]. doi: 10.1016/j.kint.2020.10.014; https://www.kidney-international.org/article/S0085-2538(20)31251-5/fulltext

    • Search Google Scholar
    • Export Citation
  • 9.

    National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Rituximab plus cyclosporine in idiopathic membranous nephropathy. ClinicalTrials.gov: NCT00977977. Accessed December 20, 2020. https://clinicaltrials.gov/ct2/show/NCT00977977

    • Search Google Scholar
    • Export Citation
  • 10.

    Klomjit N, et al. Successful treatment of patients with refractory PLA2R-associated membranous nephropathy with obinutuzumab: A report of 3 cases. Am J Kidney Dis 2020; 76:883888. doi: 10.1053/j.ajkd.2020.02.444

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Sethi S, et al. Obinutuzumab is effective for the treatment of refractory membranous nephropathy. Kidney Int Rep 2020; 5:15151518. doi: 10.1016/j.ekir.2020.06.030

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Marcus R, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 2017; 377:13311344. doi: 10.1056/NEJMoa1614598

  • 13.

    Hoffmann-La Roche. A phase III randomized, open-label active comparator-controlled multicenter study to evaluate efficacy and safety of obinutuzumab in patients with primary membranous nephropathy. ClinicalTrials.gov: NCT04629248. Accessed December 29, 2020. https://clinicaltrials.gov/ct2/show/NCT04629248

    • Search Google Scholar
    • Export Citation
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