• 1.

    Farquhar MG, et al.. The Heymann nephritis antigenic complex: Megalin (gp330) and RAP. J Am Soc Nephrol 1995; 6:3547. https://www.researchgate.net/publication/15620187_The_Heymann_Nephritis_Antigenic_Complex_Megalin_gp330_and_RAP1

    • Search Google Scholar
    • Export Citation
  • 2.

    Beck LH Jr, et al.. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009; 361:1121. doi: 10.1056/NEJMoa0810457

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Tomas NM, et al.. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med 2014; 371:22772287. doi: 10.1056/NEJMoa1409354

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Sethi S. New ‘antigens’ in membranous nephropathy. J Am Soc Nephrol 2021; 32:268278. doi: 10.1681/ASN.2020071082

  • 5.

    A controlled study of short-term prednisone treatment in adults with membranous nephropathy. Collaborative study of the adult idiopathic nephrotic syndrome. N Engl J Med 1979; 301:13011306. doi: 10.1056/NEJM197912133012401

    • Search Google Scholar
    • Export Citation
  • 6.

    Ponticelli C, et al.. Controlled trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Engl J Med 1984; 310:946950. doi: 10.1056/NEJM198404123101503

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Ponticelli C, et al.. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. J Am Soc Nephrol 1998; 9:444450. https://loyolamedicine.org/sites/default/files/gme/nephrology/pdfs/jasn_1998_treatment_of_mn.pdf

    • Search Google Scholar
    • Export Citation
  • 8.

    Qin H-Z, et al.. Evaluating tacrolimus treatment in idiopathic membranous nephropathy in a cohort of 408 patients. BMC Nephrol 2017; 18:2. doi: 10.1186/s12882-016-0427-z

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Rostoker G, et al.. Long-term cyclosporin A therapy for severe idiopathic membranous nephropathy. Nephron 1993; 63:335341. doi: 10.1159/000187219

  • 10.

    Praga M, et al.. Tacrolimus monotherapy in membranous nephropathy: A randomized controlled trial. Kidney Int 2007; 71:924930. doi: 10.1038/sj.ki.5002215

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

    Ramachandran R, et al.. Two-year follow-up study of membranous nephropathy treated with tacrolimus and corticosteroids versus cyclical corticosteroids and cyclophosphamide. Kidney Int Rep 2017; 2:610616. doi: 10.1016/j.ekir.2017.02.004

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

    Dahan K, et al.. Rituximab for severe membranous nephropathy: A 6-month trial with extended follow-up. J Am Soc Nephrol 2017; 28:348358. doi: 10.1681/ASN.2016040449

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

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

  • 14.

    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.sciencedirect.com/science/article/pii/S0085253820312515

    • Search Google Scholar
    • Export Citation
  • 15.

    Scolari F, et al.. Rituximab or cyclophosphamide in the treatment of membranous nephropathy: The RI-CYCLO randomized trial. J Am Soc Nephrol [published online ahead of print March 2021]. doi: https://doi.org/10.1681/ASN.2020071091; https://jasn.asnjournals.org/content/early/2021/02/27/ASN.2020071091

    • Search Google Scholar
    • Export Citation
  • 16.

    KDIGO Clinical Practice Guideline on Glomerular Diseases (Kidney Disease, Improving Global Outcomes [KDIGO]). June 2020. Accessed February 25, 2020. https://kdigo.org/wp-content/uploads/2017/02/KDIGO-GN-GL-Public-Review-Draft_1-June-2020.pdf

    • Search Google Scholar
    • Export Citation
  • 17.

    van de Logt A-E, et al.. Synthetic ACTH in high risk patients with idiopathic membranous nephropathy: A prospective, open label cohort study. PLoS One 2015; 10:e0142033. doi: 10.1371/journal.pone.0142033

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Barrett C, et al.. Effect of belimumab on proteinuria and anti-phospholipase A2 receptor autoantibody in primary membranous nephropathy. Nephrol Dial Transplant 2020; 35:599606. doi: 10.1093/ndt/gfz086

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Podestà MA, et al.. Accelerating the depletion of circulating anti-phospholipase A2 receptor antibodies in patients with severe membranous nephropathy: Preliminary findings with double filtration plasmapheresis and ofatumumab. Nephron 2020; 144:3035. doi: 10.1159/000501858

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Bontscho J, et al.. Myeloperoxidase-specific plasma cell depletion by bortezomib protects from anti-neutrophil cytoplasmic autoantibodies-induced glomerulonephritis. J Am Soc Nephrol 2011; 22:336348. doi: 10.1681/ASN.2010010034

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Appel G, et al.. Eculizumab (C5 complement inhibitor) in the treatment of idiopathic membranous nephropathy. J Am Soc Nephrol 2002; 13:668A. https://www.researchgate.net/publication/312463048_Eculizumab_C5_complement_inhibitor_in_the_treatment_of_idiopathic_membranous_nephropathy

    • Search Google Scholar
    • Export Citation

Treatment Changes in Membranous Nephropathy

  • 1 Mayuri Trivedi, DM, is assistant professor in the Department of Nephrology, Lokmanya Tilak Municipal Medical College and Hospital, Mumbai, India. Zaheer Virani, MD, DNB, is a consultant nephrologist with Prince Aly Khan Hospital, Mumbai, India.
Full access

Membranous nephropathy (MN) is a common cause of adult nephrotic syndrome, which may present as a sub-nephrotic or nephrotic range proteinuria with hypoalbuminemia, hyperlipidemia, and edema. It is an immune-mediated glomerular disease that is pathologically characterized by glomerular intra-membranous and sub-epithelial immune complex deposits (immunoglobulin G4 [IgG4] and complement 3 [C3]) causing membrane thickening.

The pathophysiology of MN was first described by the Heymann nephritis rat model in 1959 (1). Although the target antigen described in that model was “megalin,” which does not play a major role in humans, it set the path for subsequent discoveries of many other target antigens. In 2009, Beck et al. (2) revolutionized the diagnosis and monitoring of this disease by discovering the M-type phospholipase A2 receptor 1 (PLA2R1) as the target antigen in 70% of cases, followed by the discovery of THSD7A (thrombospondin type 1 domain-containing 7a) in 2014 (3). This year, we saw the advent of four new target antigens, including EXT1 (exotosin 1) and EXT2 (exotosin 2), NELL1 (neural epidermal growth factor-like 1 protein), Sema3B (semaphorin 3b), and PCDH7 (protocadherin 7) (4). These discoveries have helped elucidate the pathophysiology of MN and may help in designing more specific antigen-targeted therapy in the future.

In 1979, a study showed that the use of steroids was significantly better for remission of proteinuria and to slow down the decline of kidney function as compared to placebo (5). However, in 1984, Ponticelli et al. (6) showed that the use of cyclic steroids and chlorambucil over a 6-month period was superior in achieving remission with improved kidney function. Following this trial, the use of only steroids in primary MN lost favor. In 1998, once again, Ponticelli et al. (7) went ahead and compared cyclic steroids and chlorambucil with cyclic steroids and cyclophosphamide (the modified Ponticelli regimen) and showed a comparable remission rate and preservation of glomerular filtration rate (GFR) along with the side-effect profile. There has been limited literature for the use of calcineurin inhibitors alone (tacrolimus monotherapy) or with steroids (cyclosporine with steroids) (8−10). These agents tend to show a higher rate of relapse after discontinuation, as compared to alkylating agents (11), and may be used as an alternative if contraindications for alkylating agent use exist. The use of mycophenolate mofetil in MN still lacks the backing of good quality evidence and continues to be used in instances where alkylating agents are not well tolerated.

The new kid on the block for the treatment of MN is rituximab, an anti-CD20 monoclonal antibody. Two recently published trials, Evaluate Rituximab Treatment for Idiopathic Membranous Nephropathy (GEMRITUX; 2017), which compared rituximab to anti-proteinuric therapy (12), and Membranous Nephropathy Trial of Rituximab (MENTOR; 2019), which compared rituximab to cyclosporine with superiority at a 24-month follow-up (13), garnered a lot of attention and have made rituximab the first-line therapy for many cases of MN. The recent Sequential Treatment with Tacrolimus and Rituximab Versus Alternating Corticosteroids and Cyclophosphamide in [Primary Membranous Nephropathy] PMN (STARMEN; 2020) showed that the time-tested cyclic steroid and cyclophosphamide therapy showed significantly greater remission of the disease as compared to tacrolimus with rituximab, albeit with more side effects (14). The hot-off-the-press trial, Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO), finds no significant benefit, or less harm, of rituximab over the modified Ponticelli regimen in the treatment of MN too (15). We wait patiently to see if the newly introduced obinutuzumab, a CD20-directed cytolytic monoclonal antibody, or adrenocorticotropic hormone (ACTH; synthetic corticotropin) does bring in better results for the treatment of MN with a better side-effect profile. Table 1 summarizes the broad treatment guidelines from the 2020 KDIGO glomerular diseases update (16).

t1

Given the fact that the modified Ponticelli regimen has withstood the test of time over 30 years for the treatment of MN and with the advent of some newly described target antigens of MN, we hope to welcome new targeted therapies (Table 2). Until that happens, old is gold!

t2

The authors report no conflicts of interest.

References

  • 1.

    Farquhar MG, et al.. The Heymann nephritis antigenic complex: Megalin (gp330) and RAP. J Am Soc Nephrol 1995; 6:3547. https://www.researchgate.net/publication/15620187_The_Heymann_Nephritis_Antigenic_Complex_Megalin_gp330_and_RAP1

    • Search Google Scholar
    • Export Citation
  • 2.

    Beck LH Jr, et al.. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009; 361:1121. doi: 10.1056/NEJMoa0810457

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Tomas NM, et al.. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med 2014; 371:22772287. doi: 10.1056/NEJMoa1409354

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Sethi S. New ‘antigens’ in membranous nephropathy. J Am Soc Nephrol 2021; 32:268278. doi: 10.1681/ASN.2020071082

  • 5.

    A controlled study of short-term prednisone treatment in adults with membranous nephropathy. Collaborative study of the adult idiopathic nephrotic syndrome. N Engl J Med 1979; 301:13011306. doi: 10.1056/NEJM197912133012401

    • Search Google Scholar
    • Export Citation
  • 6.

    Ponticelli C, et al.. Controlled trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Engl J Med 1984; 310:946950. doi: 10.1056/NEJM198404123101503

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Ponticelli C, et al.. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. J Am Soc Nephrol 1998; 9:444450. https://loyolamedicine.org/sites/default/files/gme/nephrology/pdfs/jasn_1998_treatment_of_mn.pdf

    • Search Google Scholar
    • Export Citation
  • 8.

    Qin H-Z, et al.. Evaluating tacrolimus treatment in idiopathic membranous nephropathy in a cohort of 408 patients. BMC Nephrol 2017; 18:2. doi: 10.1186/s12882-016-0427-z

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Rostoker G, et al.. Long-term cyclosporin A therapy for severe idiopathic membranous nephropathy. Nephron 1993; 63:335341. doi: 10.1159/000187219

  • 10.

    Praga M, et al.. Tacrolimus monotherapy in membranous nephropathy: A randomized controlled trial. Kidney Int 2007; 71:924930. doi: 10.1038/sj.ki.5002215

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

    Ramachandran R, et al.. Two-year follow-up study of membranous nephropathy treated with tacrolimus and corticosteroids versus cyclical corticosteroids and cyclophosphamide. Kidney Int Rep 2017; 2:610616. doi: 10.1016/j.ekir.2017.02.004

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

    Dahan K, et al.. Rituximab for severe membranous nephropathy: A 6-month trial with extended follow-up. J Am Soc Nephrol 2017; 28:348358. doi: 10.1681/ASN.2016040449

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

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

  • 14.

    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.sciencedirect.com/science/article/pii/S0085253820312515

    • Search Google Scholar
    • Export Citation
  • 15.

    Scolari F, et al.. Rituximab or cyclophosphamide in the treatment of membranous nephropathy: The RI-CYCLO randomized trial. J Am Soc Nephrol [published online ahead of print March 2021]. doi: https://doi.org/10.1681/ASN.2020071091; https://jasn.asnjournals.org/content/early/2021/02/27/ASN.2020071091

    • Search Google Scholar
    • Export Citation
  • 16.

    KDIGO Clinical Practice Guideline on Glomerular Diseases (Kidney Disease, Improving Global Outcomes [KDIGO]). June 2020. Accessed February 25, 2020. https://kdigo.org/wp-content/uploads/2017/02/KDIGO-GN-GL-Public-Review-Draft_1-June-2020.pdf

    • Search Google Scholar
    • Export Citation
  • 17.

    van de Logt A-E, et al.. Synthetic ACTH in high risk patients with idiopathic membranous nephropathy: A prospective, open label cohort study. PLoS One 2015; 10:e0142033. doi: 10.1371/journal.pone.0142033

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Barrett C, et al.. Effect of belimumab on proteinuria and anti-phospholipase A2 receptor autoantibody in primary membranous nephropathy. Nephrol Dial Transplant 2020; 35:599606. doi: 10.1093/ndt/gfz086

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Podestà MA, et al.. Accelerating the depletion of circulating anti-phospholipase A2 receptor antibodies in patients with severe membranous nephropathy: Preliminary findings with double filtration plasmapheresis and ofatumumab. Nephron 2020; 144:3035. doi: 10.1159/000501858

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Bontscho J, et al.. Myeloperoxidase-specific plasma cell depletion by bortezomib protects from anti-neutrophil cytoplasmic autoantibodies-induced glomerulonephritis. J Am Soc Nephrol 2011; 22:336348. doi: 10.1681/ASN.2010010034

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Appel G, et al.. Eculizumab (C5 complement inhibitor) in the treatment of idiopathic membranous nephropathy. J Am Soc Nephrol 2002; 13:668A. https://www.researchgate.net/publication/312463048_Eculizumab_C5_complement_inhibitor_in_the_treatment_of_idiopathic_membranous_nephropathy

    • Search Google Scholar
    • Export Citation
Save