Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Membranous nephropathy in systemic lupus erythematosus: a therapeutic enigma

Abstract

Renal disease is a major cause of mortality and morbidity in systemic lupus erythematosus. Among the histological classes of lupus nephritis, membranous nephropathy comprises only one-fifth of all cases. Reported survival and rates of end-stage renal disease in membranous lupus nephropathy (MLN) vary considerably, because of substantial heterogeneity among the published studies. The risk of progression from MLN to renal failure is generally reduced in the absence of proliferative lesions, but patients are, nevertheless, at risk of thromboembolic complications. The optimal therapy for MLN remains elusive because of a lack of controlled trials; however, cardiovascular protection and blockade of the renin–angiotensin system should be instituted early in all patients. Mixed membranous and proliferative lupus nephritis should be treated in the same way as pure proliferative lupus nephritis. If MLN is not accompanied by proliferative lesions but is associated with clinically relevant proteinuria, renal insufficiency or failure to respond to supportive therapies, immunosuppressive treatment is indicated. Treatment options include glucocorticoids combined with azathioprine, calcineurin inhibitors or alkylating agents. The efficacy of mycophenolate mofetil in MLN remains to be confirmed. Controlled trials to compare existing immunosuppressive agents and experimental modalities such as sirolimus, rituximab and infliximab should be undertaken in the future.

Key Points

  • Membranous nephropathy is an uncommon subtype of glomerulonephritis in systemic lupus erythematosus

  • The optimal therapy for membranous lupus nephropathy (MLN) is unclear

  • Blockade of the renin–angiotensin system and cardiovascular protection should be instituted early in all patients with MLN

  • Pure MLN with renal insufficiency, substantial proteinuria or failure to respond to supportive therapies is an indication for immunosuppressive treatment

  • Immunosuppressive options include glucocorticoids combined with azathioprine, mycophenolate mofetil, calcineurin inhibitors or alkylating agents

  • Repeat renal biopsy should be considered in patients with refractory MLN to detect any change in histological class, especially when lupus serology is persistently active

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Histological findings of pure membranous lupus nephropathy.
Figure 2: A treatment algorithm for membranous lupus nephropathy.

Similar content being viewed by others

References

  1. Mok, C. C. et al. Long-term outcome of diffuse proliferative lupus glomerulonephritis treated with cyclophosphamide. Am. J. Med. 119, 355 e25–e33 (2006).

    Article  PubMed  Google Scholar 

  2. Vu, T. V. & Escalante, A. A comparison of the quality of life of patients with systemic lupus erythematosus with and without endstage renal disease. J. Rheumatol. 26, 2595–2601 (1999).

    CAS  PubMed  Google Scholar 

  3. Mok, C. C., Tang, S. S., To, C. H. & Petri, M. Incidence and risk factors of thromboembolism in systemic lupus erythematosus: a comparison of three ethnic groups. Arthritis Rheum. 52, 2774–2782 (2005).

    Article  PubMed  Google Scholar 

  4. Bastian, H. M. et al. LUMINA Study Group. LUpus in MInority populations: NAture vs nurture. Systemic lupus erythematosus in three ethnic groups. XII. Risk factors for lupus nephritis after diagnosis. Lupus 11, 152–160 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Wadee, S., Tikly, M. & Hopley, M. Causes and predictors of death in South Africans with systemic lupus erythematosus. Rheumatology (Oxford) 46, 1487–1491 (2007).

    Article  CAS  Google Scholar 

  6. Mok, C. C. & Tang, S. S. Incidence and predictors of renal disease in Chinese patients with systemic lupus erythematosus. Am. J. Med. 117, 791–795 (2004).

    Article  PubMed  Google Scholar 

  7. Gonzalez-Crespo, M. R., Lopez-Fernandez, J. I., Usera, G., Poveda, M. J. & Gomez-Reino, J. J. Outcome of silent lupus nephritis. Semin. Arthritis Rheum. 26, 468–476 (1996).

    Article  CAS  PubMed  Google Scholar 

  8. Christopher-Stine, L. et al. Renal biopsy in lupus patients with low levels of proteinuria. J. Rheumatol. 34, 332–335 (2007).

    PubMed  Google Scholar 

  9. Appel, G. B. et al. Renal involvement in systemic lupus erythematosus (SLE): a study of 56 patients emphasizing histologic classification. Medicine (Baltimore) 57, 371–410 (1978).

    Article  CAS  Google Scholar 

  10. Churg, J. & Sobin, L. H. Renal Disease: Classification and Atlas of Glomerular Disease. (Igaku-Shoin, Tokyo, 1982).

    Google Scholar 

  11. Churg, J., Bernstein, J. & Glassock, R. J. Renal Disease: Classification and Atlas of Glomerular Diseases 2nd edn (Igaku-Shoin, New York, 1995).

    Google Scholar 

  12. Mok, C. C., Wong, R. W. & Lau, C. S. Lupus nephritis in southern Chinese patients: clinicopathologic findings and long-term outcome. Am. J. Kidney Dis. 34, 315–323 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Huong, D. L. et al. Renal involvement in systemic lupus erythematosus. A study of 180 patients from a single center. Medicine (Baltimore) 78, 148–166 (1999).

    Article  CAS  Google Scholar 

  14. Donadio, J. V. Jr, Hart, G. M., Bergstralh, E. J. & Holley, K. E. Prognostic determinants in lupus nephritis: a long-term clinicopathologic study. Lupus 4, 109–115 (1995).

    Article  PubMed  Google Scholar 

  15. Yang, L. Y., Chen, W. P. & Lin, C. Y. Lupus nephritis in children–a review of 167 patients. Pediatrics 94, 335–340 (1994).

    CAS  PubMed  Google Scholar 

  16. Neumann, K. et al. Lupus in the 1980s: III. Influence of clinical variables, biopsy, and treatment on the outcome in 150 patients with lupus nephritis seen at a single center. Semin. Arthritis Rheum. 25, 47–55 (1995).

    Article  CAS  PubMed  Google Scholar 

  17. Adler, S. G., Johnson, K., Louie, J. S., Liebling, M. R. & Cohen, A. H. Lupus membranous glomerulonephritis: different prognostic subgroups obscured by imprecise histologic classifications. Mod. Pathol. 3, 186–191 (1990).

    CAS  PubMed  Google Scholar 

  18. Schwartz, M. M., Kawala, K., Roberts, J. L., Humes, C. & Lewis, E. J. Clinical and pathological features of membranous glomerulonephritis of systemic lupus erythematosus. Am. J. Nephrol. 4, 301–311 (1984).

    Article  CAS  PubMed  Google Scholar 

  19. Sloan, R. P., Schwartz, M. M., Korbet, S. M. & Borok, R. Z. Long-term outcome in systemic lupus erythematosus membranous glomerulonephritis. Lupus Nephritis Collaborative Study Group. J. Am. Soc. Nephrol. 7, 299–305 (1996).

    CAS  PubMed  Google Scholar 

  20. Weening, J. J. et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J. Am. Soc. Nephrol. 15, 241–250 (2004).

    Article  PubMed  Google Scholar 

  21. Leaker, B., Fairley, K. F., Dowling, J. & Kincaid-Smith, P. Lupus nephritis: clinical and pathological correlation. Q. J. Med. 62, 163–179 (1987).

    CAS  PubMed  Google Scholar 

  22. Pasquali, S. et al. Lupus membranous nephropathy: long-term outcome. Clin. Nephrol. 39, 175–182 (1993).

    CAS  PubMed  Google Scholar 

  23. Moroni, G., Maccario, M., Banfi, G., Quaglini, S. & Ponticelli, C. Treatment of membranous lupus nephritis. Am. J. Kidney Dis. 31, 681–686 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Chan, T. M. et al. Treatment of membranous lupus nephritis with nephrotic syndrome by sequential immunosuppression. Lupus 8, 545–551 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Mercadal, L. et al. Factors affecting outcome and prognosis in membranous lupus nephropathy. Nephrol. Dial. Transplant. 17, 1771–1778 (2002).

    Article  PubMed  Google Scholar 

  26. Mok, C. C. et al. Treatment of pure membranous lupus nephropathy with prednisone and azathioprine: an open-label trial. Am. J. Kidney Dis. 43, 269–276 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Cramer, C. H. Jr et al. Clinical presentation and outcome in a cohort of paediatric patients with membranous lupus nephritis. Nephrol. Dial. Transplant. 22, 3495–3500 (2007).

    Article  PubMed  Google Scholar 

  28. Sun, H. O. et al. Long-term outcome of Chinese patients with membranous lupus nephropathy. Lupus 17, 56–61 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Kasitanon, N., Petri, M., Haas, M., Magder, L. S. & Fine, D. M. Mycophenolate mofetil as the primary treatment of membranous lupus nephritis with and without concurrent proliferative disease: a retrospective study of 29 cases. Lupus 17, 40–45 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Gruppo Italiano per lo Studio della Nefrite Lupica (GISNEL). Lupus nephritis: prognostic factors and probability of maintaining life-supporting renal function 10 years after the diagnosis. Am. J. Kidney Dis. 19, 473–479 (1992).

  31. Bono, L., Cameron, J. S. & Hicks, J. A. The very long-term prognosis and complications of lupus nephritis and its treatment. Q. J. Med. 92, 211–218 (1999).

    Article  CAS  Google Scholar 

  32. Appel, G. B., Cohen, D. J., Pirani, C. L., Meltzer, J. I. & Estes, D. Long-term follow-up of patients with lupus nephritis. A study based on the classification of the World Health Organization. Am. J. Med. 83, 877–885 (1987).

    Article  CAS  PubMed  Google Scholar 

  33. Dooley, M. A., Hogan, S., Jennette, C. & Falk, R. Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans. Glomerular Disease Collaborative Network. Kidney Int. 51, 1188–1195 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Mok, C. C. et al. Risk and predictors of arterial thrombosis in lupus and non-lupus primary glomerulonephritis: a comparative study. Medicine (Baltimore) 86, 203–209 (2007).

    Article  Google Scholar 

  35. Lai, K. N. Membranous nephropathy: when and how to treat. Kidney Int. 71, 841–843 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Asanuma, Y. et al. Premature coronary-artery atherosclerosis in systemic lupus erythematosus. N. Engl. J. Med. 349, 2407–2415 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Schieppati, A., Ruggenenti, P., Perna, A. & Remuzzi, G. Nonimmunosuppressive therapy of membranous nephropathy. Semin. Nephrol. 23, 333–339 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Lee, T. M., Su, S. F. & Tsai, C. H. Effect of pravastatin on proteinuria in patients with well-controlled hypertension. Hypertension 40, 67–73 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Donadio, J. V. Jr, Burgess, J. H. & Holley, K. E. Membranous lupus nephropathy: a clinicopathologic study. Medicine (Baltimore) 56, 527–536 (1977).

    Article  Google Scholar 

  40. Gonzalez-Dettoni, H. & Tron, F. Membranous glomerulopathy in systemic lupus erythematosus. Adv. Nephrol. 14, 347–364 (1985).

    CAS  Google Scholar 

  41. Mok, C. C., Lau, C. S. & Wong, R. W. S. Risk factors for ovarian failure in patients with systemic lupus erythematosus receiving cyclophosphamide therapy. Arthritis Rheum. 41, 831–837 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. Wang, A. Y. et al. Severe bone marrow failure associated with the use of alternating steroid with chlorambucil in lupus membranous nephropathy in Chinese. Lupus 10, 295–298 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Austin, H. A., Vaughan, E. M. & Balow, J. E. Lupus membranous nephropathy: randomized controlled trial of prednisone, cyclosporine and cyclophosphamide [Abstract]. J. Am. Soc. Nephrol. 11, 81A (2000).

    Google Scholar 

  44. Radhakrishnan, J., Kunis, C. L., D'Agati, V. & Appel, G. B. Cyclosporine treatment of lupus membranous nephropathy. Clin. Nephrol. 42, 147–154 (1994).

    CAS  PubMed  Google Scholar 

  45. Hallegua, D., Wallace, D. J., Metzger, A. L., Rinaldi, R. Z. & Klinenberg, J. R. Cyclosporine for lupus membranous nephritis: experience with ten patients and review of the literature. Lupus 9, 241–251 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Hu, W. et al. Cyclosporine A in treatment of membranous lupus nephropathy. Chin. Med. J. (Engl.) 116, 1827–1830 (2003).

    CAS  Google Scholar 

  47. Mok, C. C., Tong, K. H., To, C. H., Siu, Y. P. & Au, T. C. Tacrolimus for induction therapy of diffuse proliferative lupus nephritis: an open-labeled pilot study. Kidney Int. 68, 813–817 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Praga, M., Barrio, V., Juárez, G. F. & Luño, J. Grupo Español de Estudio de la Nefropatía Membranosa. Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial. Kidney Int. 71, 924–930 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Maruyama, M. et al. Good response of membranous lupus nephritis to tacrolimus. Clin. Nephrol. 65, 276–279 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Tse, K. C., Lam, M. F., Tang, S. C., Tang, C. S. & Chan, T. M. A pilot study on tacrolimus treatment in membranous or quiescent lupus nephritis with proteinuria resistant to angiotensin inhibition or blockade. Lupus 16, 46–51 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Ginzler, E. M. et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N. Engl. J. Med. 353, 2219–2228 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Contreras, G. et al. Sequential therapies for proliferative lupus nephritis. N. Engl. J. Med. 350, 971–980 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Kapitsinou, P. P., Boletis, J. N., Skopouli, F. N., Boki, K. A. & Moutsopoulos, H. M. Lupus nephritis: treatment with mycophenolate mofetil. Rheumatology (Oxford) 43, 377–380 (2004).

    Article  CAS  Google Scholar 

  54. Spetie, D. N. et al. Mycophenolate therapy of SLE membranous nephropathy. Kidney Int. 66, 2411–2415 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Karim, M. Y. et al. Reduction of proteinuria with mycophenolate mofetil in predominantly membranous lupus nephropathy. Rheumatology (Oxford) 44, 1317–1321 (2005).

    Article  CAS  Google Scholar 

  56. Mok, C. C. & Lai, K. N. Mycophenolate mofetil in lupus glomerulonephritis. Am. J. Kidney Dis. 40, 447–457 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Mok, C. C. Mycophenolate mofetil for non-renal manifestations of systemic lupus erythematosus: a systematic review. Scand. J. Rheumatol. 36, 329–337 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Sinclair, A. et al. Mycophenolate mofetil as induction and maintenance therapy for lupus nephritis: rationale and protocol for the randomized, controlled Aspreva Lupus Management Study (ALMS). Lupus 16, 972–980 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Houssiau, F. A. & Ginzler, E. M. Current treatment of lupus nephritis. Lupus 17, 426–430 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Mok, C. C. et al. Predictors and outcome of renal flares after successful cyclophosphamide treatment for diffuse proliferative lupus glomerulonephritis. Arthritis Rheum. 50, 2559–2568 (2004).

    Article  PubMed  Google Scholar 

  61. Moroni, G. et al. Withdrawal of therapy in patients with proliferative lupus nephritis: long-term follow-up. Nephrol. Dial. Transplant. 21, 1541–1548 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Lui, S. L. et al. Rapamycin attenuates the severity of established nephritis in lupus-prone NZB/W F1 mice. Nephrol. Dial. Transplant. 23, 2768–2776 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Ramos-Barrón, A. et al. Prevention of murine lupus disease in (NZB x NZW)F1 mice by sirolimus treatment. Lupus 16, 775–781 (2007).

    Article  PubMed  Google Scholar 

  64. Medina, F., Fuentes, J., Carranza, I., Fraga, A. & Moreno, J. Sirolimus: a potential treatment for diffuse proliferative lupus nephritis [Abstract]. Ann. Rheum. Dis. 65 (Suppl. 2), S351 (2006).

    Google Scholar 

  65. Leandro, M. J., Cambridge, G., Edwards, J. C., Ehrenstein, M. R. & Isenberg, D. A. B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients. Rheumatology (Oxford) 44, 1542–1545 (2005).

    Article  CAS  Google Scholar 

  66. Gunnarsson, I. et al. Histopathologic and clinical outcome of rituximab treatment in patients with cyclophosphamide-resistant proliferative lupus nephritis. Arthritis Rheum. 56, 1263–1272 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Boumpas, D. T. et al. A pilot study of low-dose fludarabine in membranous nephropathy refractory to therapy. Clin. Nephrol. 52, 67–75 (1999).

    CAS  PubMed  Google Scholar 

  68. Aringer, M., Graninger, W. B., Steiner, G. & Smolen, J. S. Safety and efficacy of tumor necrosis factor α-blockade in systemic lupus erythematosus: an open-label study. Arthritis Rheum. 50, 3161–3169 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mok, C. Membranous nephropathy in systemic lupus erythematosus: a therapeutic enigma. Nat Rev Nephrol 5, 212–220 (2009). https://doi.org/10.1038/nrneph.2009.14

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2009.14

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing