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
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Membranous nephropathy is an uncommon subtype of glomerulonephritis in systemic lupus erythematosus
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The optimal therapy for membranous lupus nephropathy (MLN) is unclear
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Blockade of the renin–angiotensin system and cardiovascular protection should be instituted early in all patients with MLN
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Pure MLN with renal insufficiency, substantial proteinuria or failure to respond to supportive therapies is an indication for immunosuppressive treatment
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Immunosuppressive options include glucocorticoids combined with azathioprine, mycophenolate mofetil, calcineurin inhibitors or alkylating agents
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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
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References
Mok, C. C. et al. Long-term outcome of diffuse proliferative lupus glomerulonephritis treated with cyclophosphamide. Am. J. Med. 119, 355 e25–e33 (2006).
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).
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).
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).
Wadee, S., Tikly, M. & Hopley, M. Causes and predictors of death in South Africans with systemic lupus erythematosus. Rheumatology (Oxford) 46, 1487–1491 (2007).
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).
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).
Christopher-Stine, L. et al. Renal biopsy in lupus patients with low levels of proteinuria. J. Rheumatol. 34, 332–335 (2007).
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).
Churg, J. & Sobin, L. H. Renal Disease: Classification and Atlas of Glomerular Disease. (Igaku-Shoin, Tokyo, 1982).
Churg, J., Bernstein, J. & Glassock, R. J. Renal Disease: Classification and Atlas of Glomerular Diseases 2nd edn (Igaku-Shoin, New York, 1995).
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).
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).
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).
Yang, L. Y., Chen, W. P. & Lin, C. Y. Lupus nephritis in children–a review of 167 patients. Pediatrics 94, 335–340 (1994).
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).
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).
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).
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).
Weening, J. J. et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J. Am. Soc. Nephrol. 15, 241–250 (2004).
Leaker, B., Fairley, K. F., Dowling, J. & Kincaid-Smith, P. Lupus nephritis: clinical and pathological correlation. Q. J. Med. 62, 163–179 (1987).
Pasquali, S. et al. Lupus membranous nephropathy: long-term outcome. Clin. Nephrol. 39, 175–182 (1993).
Moroni, G., Maccario, M., Banfi, G., Quaglini, S. & Ponticelli, C. Treatment of membranous lupus nephritis. Am. J. Kidney Dis. 31, 681–686 (1998).
Chan, T. M. et al. Treatment of membranous lupus nephritis with nephrotic syndrome by sequential immunosuppression. Lupus 8, 545–551 (1999).
Mercadal, L. et al. Factors affecting outcome and prognosis in membranous lupus nephropathy. Nephrol. Dial. Transplant. 17, 1771–1778 (2002).
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).
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).
Sun, H. O. et al. Long-term outcome of Chinese patients with membranous lupus nephropathy. Lupus 17, 56–61 (2008).
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).
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).
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).
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).
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).
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).
Lai, K. N. Membranous nephropathy: when and how to treat. Kidney Int. 71, 841–843 (2007).
Asanuma, Y. et al. Premature coronary-artery atherosclerosis in systemic lupus erythematosus. N. Engl. J. Med. 349, 2407–2415 (2003).
Schieppati, A., Ruggenenti, P., Perna, A. & Remuzzi, G. Nonimmunosuppressive therapy of membranous nephropathy. Semin. Nephrol. 23, 333–339 (2003).
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).
Donadio, J. V. Jr, Burgess, J. H. & Holley, K. E. Membranous lupus nephropathy: a clinicopathologic study. Medicine (Baltimore) 56, 527–536 (1977).
Gonzalez-Dettoni, H. & Tron, F. Membranous glomerulopathy in systemic lupus erythematosus. Adv. Nephrol. 14, 347–364 (1985).
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).
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).
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).
Radhakrishnan, J., Kunis, C. L., D'Agati, V. & Appel, G. B. Cyclosporine treatment of lupus membranous nephropathy. Clin. Nephrol. 42, 147–154 (1994).
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).
Hu, W. et al. Cyclosporine A in treatment of membranous lupus nephropathy. Chin. Med. J. (Engl.) 116, 1827–1830 (2003).
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).
Praga, M., Barrio, V., Juárez, G. F. & Luño, J. Grupo Español de Estudio de la NefropatĂa Membranosa. Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial. Kidney Int. 71, 924–930 (2007).
Maruyama, M. et al. Good response of membranous lupus nephritis to tacrolimus. Clin. Nephrol. 65, 276–279 (2006).
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).
Ginzler, E. M. et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N. Engl. J. Med. 353, 2219–2228 (2005).
Contreras, G. et al. Sequential therapies for proliferative lupus nephritis. N. Engl. J. Med. 350, 971–980 (2004).
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).
Spetie, D. N. et al. Mycophenolate therapy of SLE membranous nephropathy. Kidney Int. 66, 2411–2415 (2004).
Karim, M. Y. et al. Reduction of proteinuria with mycophenolate mofetil in predominantly membranous lupus nephropathy. Rheumatology (Oxford) 44, 1317–1321 (2005).
Mok, C. C. & Lai, K. N. Mycophenolate mofetil in lupus glomerulonephritis. Am. J. Kidney Dis. 40, 447–457 (2002).
Mok, C. C. Mycophenolate mofetil for non-renal manifestations of systemic lupus erythematosus: a systematic review. Scand. J. Rheumatol. 36, 329–337 (2007).
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).
Houssiau, F. A. & Ginzler, E. M. Current treatment of lupus nephritis. Lupus 17, 426–430 (2008).
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).
Moroni, G. et al. Withdrawal of therapy in patients with proliferative lupus nephritis: long-term follow-up. Nephrol. Dial. Transplant. 21, 1541–1548 (2006).
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).
Ramos-Barrón, A. et al. Prevention of murine lupus disease in (NZB x NZW)F1 mice by sirolimus treatment. Lupus 16, 775–781 (2007).
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).
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).
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).
Boumpas, D. T. et al. A pilot study of low-dose fludarabine in membranous nephropathy refractory to therapy. Clin. Nephrol. 52, 67–75 (1999).
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).
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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
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DOI: https://doi.org/10.1038/nrneph.2009.14
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