Skip to main content

Advertisement

SpringerLink
Log in

Recent advances in the treatment of lupus nephritis

  • Review Article
  • Published:
Clinical and Experimental Nephrology Aims and scope Submit manuscript

Abstract

Lupus nephritis is a common complication of systemic lupus erythematosus (SLE) which is associated with significant morbidity and mortality. The concept of two phases of therapy for lupus nephritis, such as an induction phase and a maintenance phase, is widely accepted. Since the renal involvement in SLE is heterogeneous, the treatment of lupus nephritis is governed by its pathological type and ranges from nonspecific measures, such as maintenance of adequate blood pressure control and blockade of the renin–angiotensin–aldosterone system, to the use of immunosuppressive agents. Cyclophosphamide (CYC) in combination with prednisone has been the standard method of treatment of the proliferative forms of lupus nephritis. However, the high rates of progression to end-stage renal disease coupled with the adverse effects of CYC and prednisone have led to an intensive search for more effective and less toxic therapies for lupus nephritis. We review the options available for the treatment of proliferative and membranous lupus nephritis and summarize the results of recently published clinical trials that add new perspectives to the management of kidney disease in SLE.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Yokoyama H, Okuyama H, Yamaya H. Clinicopathological insights into lupus glomerulonephritis in Japanese and Asians. Clin Exp Nephrol. 2011;15:321–30.

    Article  PubMed  Google Scholar 

  2. Ortega LM, Schultz DR, Lenz O, Pardo V, Contreras GN. Lupus nephritis: pathologic features, epidemiology and a guide to therapeutic decisions. Lupus. 2010;19:557–74.

    Article  PubMed  CAS  Google Scholar 

  3. Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 2004;65:521–30.

    Article  PubMed  Google Scholar 

  4. Najafi CC, Korbet SM, Lewis EJ, Schwartz MM, Reichlin M, Evans J, et al. Significance of histologic patterns of glomerular injury upon long-term prognosis in severe lupus glomerulonephritis. Kidney Int. 2001;59:2156–63.

    PubMed  CAS  Google Scholar 

  5. Borchers AT, Keen CL, Shoenfeld Y, Gershwin ME. Surviving the butterfly and the wolf: mortality trends in systemic lupus erythematosus. Autoimmun Rev. 2004;3:423–53.

    Article  PubMed  Google Scholar 

  6. Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine. 2003;82:299–308.

    Article  PubMed  Google Scholar 

  7. Dooley MA, Falk RJ. Human clinical trials in lupus nephritis. Semin Nephrol. 2007;27:115–27.

    Article  PubMed  CAS  Google Scholar 

  8. Dube GK, Markowitz GS, Radhakrishnan J, Appel GB, D’Agati VD. Minimal change disease in systemic lupus erythematosus. Clin Nephrol. 2002;57:120–6.

    PubMed  CAS  Google Scholar 

  9. Kidney Disease Outcomes Quality Initiative (K/DOQI). K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004; 43: S1–S290.

    Google Scholar 

  10. Tse KC, Li FK, Tang S, Tang CS, Lai KN, Chan TM. Angiotensin inhibition or blockade for the treatment of patients with quiescent lupus nephritis and persistent proteinuria. Lupus. 2005;14:947–52.

    Article  PubMed  CAS  Google Scholar 

  11. Duran-Barragan S, McGwin G Jr, Via LM, Reveille JD, Alarcon GS. Angiotensin-converting enzyme inhibitors delay the occurrence of renal involvement and are associated with a decreased risk of disease activity in patients with systemic lupus erythematosus-results from LUMINA (LIX): a multiethnic US cohort. Rheumatology. 2008;47:1093–6.

    Article  PubMed  CAS  Google Scholar 

  12. Kitamura N, Matsukawa Y, Takei M, Sawada S. Antiproteinuric effect of angiotensin-converting enzyme inhibitors and an angiotensin II receptor blocker in patients with lupus nephritis. J Int Med Res. 2009;37:892–8.

    PubMed  CAS  Google Scholar 

  13. Teplitsky V, Shoenfeld Y, Tanay A. The renin–angiotensin system in lupus: physiology, genes and practice, in animals and humans. Lupus. 2006;15:319–25.

    Article  PubMed  CAS  Google Scholar 

  14. De Albuquerque DA, Saxena V, Adams DE, Boivin GP, Brunner HI, Witte DP, Singh RR. An ACE inhibitor reduces Th2 cytokines and TGF-beta1 and TGF-beta2 isoforms in murine lupus nephritis. Kidney Int. 2004;65:846–59.

    Article  PubMed  Google Scholar 

  15. Monrad SU, Killen PD, Anderson MR, Bradke A, Kaplan MJ. The role of aldosterone blockade in murine lupus nephritis. Arthritis Res Ther. 2008;10:R5.

    Article  PubMed  Google Scholar 

  16. Houssiau FA. Cyclophosphamide in lupus nephritis. Lupus. 2005;14:53–8.

    Article  PubMed  CAS  Google Scholar 

  17. Gourley MF, Austin HA 3rd, Scott D, Yarboro CH, Vaughan EM, Muir J, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med. 1996;125:549–57.

    PubMed  CAS  Google Scholar 

  18. Illei GG, Austin HA, Crane M, Collins L, Gourley MF, Yarboro CH, et al. Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann Intern Med. 2001;135:248–57.

    PubMed  CAS  Google Scholar 

  19. Houssiau FA, Vasconcelos C, D’Cruz D, Sebastiani GD, Garrido Ed Ede R, Danieli MG, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum. 2002;46:2121–31.

    Article  PubMed  CAS  Google Scholar 

  20. Houssiau FA, Vasconcelos C, D’Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli MG, et al. The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide. Ann Rheum Dis. 2010;69:61–4.

    Article  PubMed  CAS  Google Scholar 

  21. Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med. 2000;343:1156–62.

    Article  PubMed  CAS  Google Scholar 

  22. Chan TM, Tse KC, Tang CS, Mok MY, Li FK. Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. J Am Soc Nephrol. 2005;16:1076–84.

    Article  PubMed  CAS  Google Scholar 

  23. Ginzler EM, Dooley MA, Aranow C, Kim MY, Buyon J, Merrill JT, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med. 2005;353:2219–28.

    Article  PubMed  CAS  Google Scholar 

  24. Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009;20:1103–12.

    Article  PubMed  CAS  Google Scholar 

  25. Isenberg D, Appel GB, Contreras G, Dooley MA, Ginzler EM, Jayne D, et al. Influence of race/ethnicity on response to lupus nephritis treatment: the ALMS study. Rheumatology. 2010;49:128–40.

    Article  PubMed  Google Scholar 

  26. Miyasaka N, Kawai S, Hashimoto H. Efficacy and safety of tacrolimus for lupus nephritis: a placebo-controlled double-blind multicenter study. Mod Rheumatol. 2009;19:606–15.

    Article  PubMed  CAS  Google Scholar 

  27. Szeto CC, Kwan BC, Lai FM, Tam LS, Li EK, Chow KM, et al. Tacrolimus for the treatment of systemic lupus erythematosus with pure class V nephritis. Rheumatology. 2008;47:1678–81.

    Article  PubMed  CAS  Google Scholar 

  28. Mok CC, Tong KH, To CH, Siu YP, Au TC. Tacrolimus for induction therapy of diffuse proliferative lupus nephritis: an open-labeled pilot study. Kidney Int. 2005;68:813–7.

    Article  PubMed  CAS  Google Scholar 

  29. Asamiya Y, Uchida K, Otsubo S, Takei T, Nitta K. Clinical assessment of tacrolimus therapy in lupus nephritis: one-year follow-up study in a single center. Nephron Clin Pract. 2009;113:c330–6.

    Article  PubMed  CAS  Google Scholar 

  30. Uchida K, Asamiya Y, Takei T, Itabashi M, Sugiura H, Tsukada M, et al. Pharmacokinetics of orally administered tacrolimus in lupus nephritis patients. Yakugaku Zasshi. 2010;130:113–8.

    Article  PubMed  CAS  Google Scholar 

  31. Tanaka H, Oki E, Tsuruga K, Yashiro T, Hanada I, Ito E. Management of young patients with lupus nephritis using tacrolimus administered as a single daily dose. Clin Nephrol. 2009;72:430–6.

    PubMed  CAS  Google Scholar 

  32. Uchino A, Tsukamoto H, Nakashima H, Yoshizawa S, Furugo I, Mitoma H, et al. Tacrolimus is effective for lupus nephritis patients with persistent proteinuria. Clin Exp Rhematol. 2010;28:6–12.

    CAS  Google Scholar 

  33. Lee T, Oh KH, Joo KW, Kim YS, Ahn C, Han JS, et al. Tacrolimus is an alternative therapeutic option for the treatment of refractory lupus nephritis. Lupus. 2010;19:974–80.

    Article  PubMed  CAS  Google Scholar 

  34. French Cooperative Group. A randomized trial of plasma exchange in severe acute systemic lupus erythematosus. Plasma Ther Transfus Technol. 1985;6:535–9.

    Google Scholar 

  35. Salant DJ. Intravenous methyprednisolone or plasma exchange for adjunctive therapy of severe renal vasculitis? Nat Clin Pract Nephrol. 2008;4:14–5.

    Article  PubMed  CAS  Google Scholar 

  36. Wei N, Klippel JH, Huston DP, Hall RP, Lawley TJ, Balow JE, et al. Randomised trial of plasma exchange in mild systemic lupus erythematosus. Lancet. 1983;1:17–22.

    Article  PubMed  CAS  Google Scholar 

  37. Lewis EJ, Hunsicker LG, Lan SP, Rohde RD, Lachin JM. A controlled trial of plasmapheresis therapy in severe lupus nephritis. The Lupus Nephritis Collaborative Study Group. N Engl J Med. 1992;326:1373–9.

    Article  PubMed  CAS  Google Scholar 

  38. Euler HH, Schroeder JO. Antibody depletion and cytotoxic drug therapy in severe systemic lupus erythematosus. Transfus Sci. 1992;13:167–84.

    Article  Google Scholar 

  39. Walsh M, Jayne D, Moist L, Tonelli M, Pannu N, Manns B. Practice pattern variation in oral glucocorticoid therapy after the induction of response in proliferative lupus nephritis. Lupus. 2010;19:628–33.

    Article  PubMed  CAS  Google Scholar 

  40. Contreras G, Pardo V, Leclercq B, Lenz O, Tozman E, O’Nan P, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med. 2004;350:971–80.

    Article  PubMed  CAS  Google Scholar 

  41. Houssiau FA, Cruz DD, Sangle S, Remy P, Vasconcelos C, Petrovic R, et al. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann Rheum Dis. 2010;69:2083–9.

    Article  PubMed  CAS  Google Scholar 

  42. Lanata CM, Mahmood T, Fine DM, Petri M. Combination therapy of mycophenolate mofetil and tacrolimus in lupus nephritis. Lupus. 2010;19:935–40.

    Article  PubMed  CAS  Google Scholar 

  43. Yumura W, Suganuma S, Uchida K, Moriyama T, Otsubo S, Takei T, et al. Effects of long-term treatment with mizoribine in patients with proliferative lupus nephritis. Clin Nephrol. 2005;64:28–34.

    PubMed  CAS  Google Scholar 

  44. Tanaka H, Tsugawa K, Suzuki K, Nakahata T, Ito E. Long-term mizoribine intermittent pulse therapy for young patients with flare of lupus nephritis. Pediatr Nephrol. 2006;21:962–6.

    Article  PubMed  Google Scholar 

  45. Nozu K, Iijima K, Kamiola I, Fujita T, Yoshiya K, Tanaka R, et al. High-dose mizoribine treatment for adolescents with systemic lupus erythematosus. Pediatr Int. 2006;48:152–7.

    Article  PubMed  CAS  Google Scholar 

  46. Flanc RS, Roberts MA, Strippoli GF, Chadban SJ, Kerr PG, Atkins RC. Treatment of diffuse proliferative lupus nephritis: a meta-analysis of randomized controlled trials. Am J Kidney Dis. 2004;43:197–208.

    Article  PubMed  CAS  Google Scholar 

  47. Zhu B, Chen N, Lin Y, Ren H, Zhang W, Wang W, et al. Mycophenolate mofetil in induction and maintenance therapy of severe lupus nephritis: a meta-analysis of randomized controlled trials. Nephrol Dial Transplant. 2007;22:1933–42.

    Article  PubMed  CAS  Google Scholar 

  48. Lee Y, Woo JH, Choi S, Ji J, Song G. Induction and maintenance therapy for lupus nephritis: a systematic review and meta-analysis. Lupus. 2010;19:703–10.

    Article  PubMed  CAS  Google Scholar 

  49. Sloan RP, Schwartz MM, Korbet SM, Borok RZ. Long-term outcome in systemic lupus erythematosus membranous glomerulonephritis. Lupus Nephritis Collaborative Study Group. J Am Soc Nephrol. 1996;7:299–305.

    PubMed  CAS  Google Scholar 

  50. Markowitz GS, D’Agati VD. The ISN/RPS 2003 classification of lupus nephritis: an assessment at 3 years. Kidney Int. 2007;71:491–5.

    Article  PubMed  CAS  Google Scholar 

  51. Austin HA III, Illei GG, Braun MJ, Balow JE. Randomized, controlled trial of prednisone, cyclophosphamide, and cyclosporine in lupus membranous nephropathy. J Am Soc Nephrol. 2009;20:901–11.

    Article  PubMed  CAS  Google Scholar 

  52. Cattran DC, Alexopoulos E, Heering P, Hoyer PF, Johnston A, Meyrier A, et al. Cyclosporin in idiopathic glomerular disease associated with the nephritic syndrome: workshop recommendations. Kidney Int. 2007;72:1429–47.

    Article  PubMed  CAS  Google Scholar 

  53. Zavada J, Pesickova S, Rysava R, Olejarova M, Horak P, Hrncir Z, et al. Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: the Cyclofa-Lune study. Lupus. 2010;19:1281–9.

    Article  PubMed  CAS  Google Scholar 

  54. Radhakrishnan J, Moutzouris DA, Ginzler EM, Solomons N, Siempos II, Appel GB. Mycophenolate mofetil and intravenous cyclophosphamide are similar as induction therapy for class V lupus nephritis. Kidney Int. 2010;77:152–60.

    Article  PubMed  CAS  Google Scholar 

  55. El Sato. Methotrexate therapy in systemic lupus erythematosus. Lupus. 2001;10:162–4.

    Article  Google Scholar 

  56. Winzer M, Aringer M. Use of methotrexate in patients with systemic lupus erythematosus and primary Sjogren syndrome. Clin Exp Rheumatol. 2010;28:S156–9.

    PubMed  CAS  Google Scholar 

  57. Catapano F, Chaudhry AN, Jones RD, Smith KG, Jayne DW. Long-term efficacy and safety of rituximab in refractory and relapsing systemic lupus erythematosus. Nephrol Dial Transplant. 2010;25:3586–92.

    Article  PubMed  CAS  Google Scholar 

  58. Terrier B, Amoura Z, Ravaud P, Hachulla E, Jouenne R, Combe B, et al. Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry. Arthritis Rheum. 2010;62:2458–66.

    Article  PubMed  CAS  Google Scholar 

  59. Ramos-Casals M, Soto MJ, Cuadrado MJ, Khamashta MA. Rituximab in systemic lupus erythematosus: a systematic review of off-label use in 188 cases. Lupus. 2009;18:767–76.

    Article  PubMed  CAS  Google Scholar 

  60. Cambridge G, Isenberg DA, Edwards JC, Leandro MJ, Migone TS, Teodorescu M, et al. B cell depletion therapy in systemic lupus erythematosus: relationships among serum B lymphocyte stimulator levels, autoantibody profile and clinical response. Ann Rheum Dis. 2008;67:1011–6.

    Article  PubMed  CAS  Google Scholar 

  61. Goldberg A, Katzap E. Belimumab for the treatment of systemic lupus erythematosus. Int J Clin Rheum. 2010;5:407–13.

    Article  CAS  Google Scholar 

  62. Lateer A, Petri M. Biologicals in treatment of SLE. Curr Opin Rheumatol. 2010;22:504–9.

    Article  Google Scholar 

  63. Davidson A, Diamond B, Wofsy D, Daikh D. Block and tackle: CTLA4Ig takes on lupus. Lupus. 2005;14:197–203.

    Article  PubMed  CAS  Google Scholar 

  64. Schroder JO, Zeuner RA. Biologics as treatment for systemic lupus: great efforts, sobering results, new challenges. Curr Drug Discov Technol. 2009;6:252–5.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Kidney Center, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-866, Japan

    Keiko Uchida & Kosaku Nitta

Authors
  1. Keiko Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kosaku Nitta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kosaku Nitta.

About this article

Cite this article

Uchida, K., Nitta, K. Recent advances in the treatment of lupus nephritis. Clin Exp Nephrol 16, 202–213 (2012). https://doi.org/10.1007/s10157-011-0556-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10157-011-0556-4

Keywords

Search

Navigation