Pediatric Nephrology

, Volume 28, Issue 11, pp 2069–2078 | Cite as

The treatment of systemic lupus proliferative nephritis



Lupus nephritis is one of the most common and serious complications of systemic lupus erythematosus (SLE) in childhood affecting more than 80 % of patients. Treatment of this complication has undergone significant evolution in recent years. A series of randomized controlled trials has clarified the role of a variety of immunomodulating regimens including some novel biologic medications. This review touches on the major trials that have influenced practice and shaped current thinking about the treatment of proliferative lupus glomerulonephritis.


Lupus Nephritis Systemic lupus erythematosus Pediatric lupus Mycophenolate mofetil 


  1. 1.
    Austin HA 3rd, Klippel JH, Balow JE, le Riche NG, Steinberg AD, Plotz PH, Decker JL (1986) Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med 314:614–619PubMedCrossRefGoogle Scholar
  2. 2.
    Boumpas DT, Austin HA 3rd, Vaughn EM, Klippel JH, Steinberg AD, Yarboro CH, Balow JE (1992) Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 340:741–745PubMedCrossRefGoogle Scholar
  3. 3.
    Gourley MF, Austin HA 3rd, Scott D, Yarboro CH, Vaughan EM, Muir J, Boumpas DT, Klippel JH, Balow JE, Steinberg AD (1996) Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med 125:549–557PubMedCrossRefGoogle Scholar
  4. 4.
    Illei GG, Austin HA, Crane M, Collins L, Gourley MF, Yarboro CH, Vaughan EM, Kuroiwa T, Danning CL, Steinberg AD, Klippel JH, Balow JE, Boumpas DT (2001) Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann Intern Med 135:248–257PubMedCrossRefGoogle Scholar
  5. 5.
    Austin HA 3rd, Boumpas DT, Vaughan EM, Balow JE (1995) High-risk features of lupus nephritis: importance of race and clinical and histological factors in 166 patients. Nephrol Dial Transplant 10:1620–1628PubMedGoogle Scholar
  6. 6.
    Dooley MA, Hogan S, Jennette C, Falk R (1997) Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans. Glomerular disease collaborative network. Kidney Int 51:1188–1195PubMedCrossRefGoogle Scholar
  7. 7.
    Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, Garrido Ed Ede R, Danieli MG, Abramovicz D, Blockmans D, Mathieu A, Direskeneli H, Galeazzi M, Gul A, Levy Y, Petera P, Popovic R, Petrovic R, Sinico RA, Cattaneo R, Font J, Depresseux G, Cosyns JP, Cervera R (2002) Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 46:2121–2131PubMedCrossRefGoogle Scholar
  8. 8.
    Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, de Ramon GE, Danieli MG, Abramovicz D, Blockmans D, Cauli A, Direskeneli H, Galeazzi M, Gul A, Levy Y, Petera P, Popovic R, Petrovic R, Sinico RA, Cattaneo R, Font J, Depresseux G, Cosyns JP, Cervera R (2010) The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide. Ann Rheum Dis 69:61–64PubMedCrossRefGoogle Scholar
  9. 9.
    Grootscholten C, Ligtenberg G, Hagen EC, van den Wall Bake AW, de Glas-Vos JW, Bijl M, Assmann KJ, Bruijn JA, Weening JJ, van Houwelingen HC, Derksen RH, Berden JH (2006) Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus nephritis. A randomized controlled trial. Kidney Int 70:732–742PubMedCrossRefGoogle Scholar
  10. 10.
    Grootscholten C, Bajema IM, Florquin S, Steenbergen EJ, Peutz-Kootstra CJ, Goldschmeding R, Bijl M, Hagen EC, Van Houwelingen HC, Derksen RH, Berden JH (2007) Treatment with cyclophosphamide delays the progression of chronic lesions more effectively than does treatment with azathioprine plus methylprednisolone in patients with proliferative lupus nephritis. Arthritis Rheum 56:924–937PubMedCrossRefGoogle Scholar
  11. 11.
    Arends S, Grootscholten C, Derksen RH, Berger SP, de Sevaux RG, Voskuyl AE, Bijl M, Berden JH (2012) Long-term follow-up of a randomised controlled trial of azathioprine/methylprednisolone versus cyclophosphamide in patients with proliferative lupus nephritis. Ann Rheum Dis 71:966–973PubMedCrossRefGoogle Scholar
  12. 12.
    Lewis EJ, Hunsicker LG, Lan SP, Rohde RD, Lachin JM (1992) A controlled trial of plasmapheresis therapy in severe lupus nephritis. The Lupus Nephritis Collaborative Study Group. N Engl J Med 326:1373–1379PubMedCrossRefGoogle Scholar
  13. 13.
    Wallace DJ (1999) Apheresis for lupus erythematosus. Lupus 8:174–180PubMedCrossRefGoogle Scholar
  14. 14.
    Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, Lau CS, Wong AK, Tong MK, Chan KW, Lai KN (2000) Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med 343:1156–1162PubMedCrossRefGoogle Scholar
  15. 15.
    Chan TM, Tse KC, Tang CS, Mok MY, Li FK (2005) Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. J Am Soc Nephrol 16:1076–1084PubMedCrossRefGoogle Scholar
  16. 16.
    Ginzler EM, Dooley MA, Aranow C, Kim MY, Buyon J, Merrill JT, Petri M, Gilkeson GS, Wallace DJ, Weisman MH, Appel GB (2005) Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 353:2219–2228PubMedCrossRefGoogle Scholar
  17. 17.
    Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, Li LS, Mysler E, Sanchez-Guerrero J, Solomons N, Wofsy D (2009) Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol 20:1103–1112PubMedCrossRefGoogle Scholar
  18. 18.
    Touma Z, Gladman DD, Urowitz MB, Beyene J, Uleryk EM, Shah PS (2011) Mycophenolate mofetil for induction treatment of lupus nephritis: a systematic review and metaanalysis. J Rheumatol 38:69–78PubMedCrossRefGoogle Scholar
  19. 19.
    Contreras G, Pardo V, Leclercq B, Lenz O, Tozman E, O'Nan P, Roth D (2004) Sequential therapies for proliferative lupus nephritis. N Engl J Med 350:971–980PubMedCrossRefGoogle Scholar
  20. 20.
    Houssiau FA, D'Cruz D, Sangle S, Remy P, Vasconcelos C, Petrovic R, Fiehn C, de Ramon GE, Gilboe IM, Tektonidou M, Blockmans D, Ravelingien I, le Guern V, Depresseux G, Guillevin L, Cervera R (2010) Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann Rheum Dis 69:2083–2089PubMedCrossRefGoogle Scholar
  21. 21.
    Dooley MA, Jayne D, Ginzler EM, Isenberg D, Olsen NJ, Wofsy D, Eitner F, Appel GB, Contreras G, Lisk L, Solomons N (2011) Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med 365:1886–1895PubMedCrossRefGoogle Scholar
  22. 22.
    Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, Utset TO, Gordon C, Isenberg DA, Hsieh HJ, Zhang D, Brunetta PG (2010) Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 62:222–233PubMedCrossRefGoogle Scholar
  23. 23.
    Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, Maciuca R, Zhang D, Garg JP, Brunetta P, Appel G (2012) Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 64:1215–1226PubMedCrossRefGoogle Scholar
  24. 24.
    Lightstone L (2012) The landscape after LUNAR: rituximab's crater-filled path. Arthritis Rheum 64:962–965PubMedCrossRefGoogle Scholar
  25. 25.
    Alarcon-Segovia D, Tumlin JA, Furie RA, McKay JD, Cardiel MH, Strand V, Bagin RG, Linnik MD, Hepburn B (2003) LJP 394 for the prevention of renal flare in patients with systemic lupus erythematosus: results from a randomized, double-blind, placebo-controlled study. Arthritis Rheum 48:442–454PubMedCrossRefGoogle Scholar
  26. 26.
    Furie R (2006) Abetimus sodium (riquent) for the prevention of nephritic flares in patients with systemic lupus erythematosus. Rheum Dis Clin North Am 32:149–156, x.Google Scholar
  27. 27.
    Navarra SV, Guzman RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, Li EK, Thomas M, Kim HY, Leon MG, Tanasescu C, Nasonov E, Lan JL, Pineda L, Zhong ZJ, Freimuth W, Petri MA (2011) Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 377:721–731PubMedCrossRefGoogle Scholar
  28. 28.
    Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D, Sanchez-Guerrero J, Schwarting A, Merrill JT, Chatham WW, Stohl W, Ginzler EM, Hough DR, Zhong ZJ, Freimuth W, van Vollenhoven RF (2011) A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 63:3918–3930PubMedCrossRefGoogle Scholar
  29. 29.
    Chiche L, Jourde N, Thomas G, Bardin N, Bornet C, Darque A, Mancini J (2012) New treatment options for lupus - a focus on belimumab. Ther Clin Risk Manag 8:33–43PubMedCrossRefGoogle Scholar
  30. 30.
    Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA (2010) Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis 69:20–28PubMedCrossRefGoogle Scholar
  31. 31.
    Schmajuk G, Yazdany J, Trupin L, Yelin E (2010) Hydroxychloroquine treatment in a community-based cohort of patients with systemic lupus erythematosus. Arthritis Care Res (Hoboken) 62:386–392CrossRefGoogle Scholar
  32. 32.
    Zonana-Nacach A, Barr SG, Magder LS, Petri M (2000) Damage in systemic lupus erythematosus and its association with corticosteroids. Arthritis Rheum 43:1801–1808PubMedCrossRefGoogle Scholar
  33. 33.
    Mosca M, Tani C, Carli L, Bombardieri S (2011) Glucocorticoids in systemic lupus erythematosus. Clin Exp Rheumatol 29:S126–S129PubMedGoogle Scholar
  34. 34.
    Watson L, Leone V, Pilkington C, Tullus K, Rangaraj S, McDonagh JE, Gardner-Medwin J, Wilkinson N, Riley P, Tizard J, Armon K, Sinha MD, Ioannou Y, Archer N, Bailey K, Davidson J, Baildam EM, Cleary G, McCann LJ, Beresford MW (2012) Disease activity, severity, and damage in the UK Juvenile-Onset Systemic Lupus Erythematosus Cohort. Arthritis Rheum 64:2356–2365PubMedCrossRefGoogle Scholar
  35. 35.
    Gladman DD, Urowitz MB, Rahman P, Ibanez D, Tam LS (2003) Accrual of organ damage over time in patients with systemic lupus erythematosus. J Rheumatol 30:1955–1959PubMedGoogle Scholar
  36. 36.
    Brunner HI, Silverman ED, To T, Bombardier C, Feldman BM (2002) Risk factors for damage in childhood-onset systemic lupus erythematosus: cumulative disease activity and medication use predict disease damage. Arthritis Rheum 46:436–444PubMedCrossRefGoogle Scholar
  37. 37.
    Walsh M, Jayne D, Moist L, Tonelli M, Pannu N, Manns B (2010) Practice pattern variation in oral glucocorticoid therapy after the induction of response in proliferative lupus nephritis. Lupus 19:628–633PubMedCrossRefGoogle Scholar
  38. 38.
    Mina R, von Scheven E, Ardoin SP, Eberhard BA, Punaro M, Ilowite N, Hsu J, Klein-Gitelman M, Moorthy LN, Muscal E, Radhakrishna SM, Wagner-Weiner L, Adams M, Blier P, Buckley L, Chalom E, Chedeville G, Eichenfield A, Fish N, Henrickson M, Hersh AO, Hollister R, Jones O, Jung L, Levy D, Lopez-Benitez J, McCurdy D, Miettunen PM, Quintero-del Rio AI, Rothman D, Rullo O, Ruth N, Schanberg LE, Silverman E, Singer NG, Soep J, Syed R, Vogler LB, Yalcindag A, Yildirim-Toruner C, Wallace CA, Brunner HI (2012) Consensus treatment plans for induction therapy of newly diagnosed proliferative lupus nephritis in juvenile systemic lupus erythematosus. Arthritis Care Res (Hoboken) 64:375–383CrossRefGoogle Scholar
  39. 39.
    Cimaz R (2012) Pediatric rheumatic disease: Treating lupus nephritis in children–is there a gold standard? Nat Rev Rheumatol 8:192–193PubMedCrossRefGoogle Scholar
  40. 40.
    Guiducci C, Gong M, Xu Z, Gill M, Chaussabel D, Meeker T, Chan JH, Wright T, Punaro M, Bolland S, Soumelis V, Banchereau J, Coffman RL, Pascual V, Barrat FJ (2010) TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature 465:937–941PubMedCrossRefGoogle Scholar
  41. 41.
    Chan TM (2012) Recent progress in the treatment of proliferative lupus nephritis. Am J Med 125:642–648PubMedCrossRefGoogle Scholar
  42. 42.
    van Tellingen A, Voskuyl AE, Vervloet MG, Bijl M, de Sevaux RG, Berger SP, Derksen RH, Berden JH (2012) Dutch guidelines for diagnosis and therapy of proliferative lupus nephritis. Neth J Med 70:199–207PubMedGoogle Scholar
  43. 43.
    Hahn BH, McMahon MA, Wilkinson A, Wallace WD, Daikh DI, Fitzgerald JD, Karpouzas GA, Merrill JT, Wallace DJ, Yazdany J, Ramsey-Goldman R, Singh K, Khalighi M, Choi SI, Gogia M, Kafaja S, Kamgar M, Lau C, Martin WJ, Parikh S, Peng J, Rastogi A, Chen W, Grossman JM (2012) American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken) 64:797–808CrossRefGoogle Scholar
  44. 44.
    Bertsias GK, Tektonidou M, Amoura Z, Aringer M, Bajema I, Berden JH, Boletis J, Cervera R, Dorner T, Doria A, Ferrario F, Floege J, Houssiau FA, Ioannidis JP, Isenberg DA, Kallenberg CG, Lightstone L, Marks SD, Martini A, Moroni G, Neumann I, Praga M, Schneider M, Starra A, Tesar V, Vasconcelos C, van Vollenhoven RF, Zakharova H, Haubitz M, Gordon C, Jayne D, Boumpas DT (2012) Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 71:1771–1782Google Scholar
  45. 45.
    Podolskaya A, Stadermann M, Pilkington C, Marks SD, Tullus K (2008) B cell depletion therapy for 19 patients with refractory systemic lupus erythematosus. Arch Dis Child 93:401–406PubMedCrossRefGoogle Scholar
  46. 46.
    Fei Y, Wu Q, Zhang W, Chen H, Hou Y, Xu D, Li M, Zhang X, Zhao Y, Zeng X, Zhang F (2012) Low-dose tacrolimus in treating lupus nephritis refractory to cyclophosphamide: a prospective cohort study. Clin Exp RheumatolGoogle Scholar
  47. 47.
    Harada T, Ozono Y, Miyazaki M, Sasaki O, Miyazaki K, Abe K, Nagashima J, Tukazaki S, Shioshita T, Ichinose H, Shimamine R, Nishikawa Y, Nishikido M, Yamaguchi K, Kohno S, Taguchi T (1997) Plasmapheresis in the treatment of rapidly progressive glomerulonephritis. Ther Apher 1:366–369PubMedCrossRefGoogle Scholar
  48. 48.
    Stummvoll GH, Schmaldienst S, Smolen JS, Derfler K, Biesenbach P (2012) Lupus nephritis: prolonged immunoadsorption (IAS) reduces proteinuria and stabilizes global disease activity. Nephrol Dial Transplant 27:618–626PubMedCrossRefGoogle Scholar
  49. 49.
    Zheng T, Chunlei L, Zhen W, Ping L, Haitao Z, Weixin H, Caihong Z, Huiping C, Zhihong L, Leishi L (2009) Clinical-pathological features and prognosis of thrombotic thrombocytopenic purpura in patients with lupus nephritis. Am J Med Sci 338:343–347PubMedCrossRefGoogle Scholar
  50. 50.
    Hirai Y, Iyoda M, Shibata T, Ashikaga E, Hosaka N, Suzuki H, Nagai H, Mukai M, Honda H, Kuroki A, Kitazawa K, Akizawa T (2008) Lupus nephritis associated with positive MPO-ANCA in a patient with underlying autoimmune hemolytic anemia. Clin Exp Nephrol 12:393–397PubMedCrossRefGoogle Scholar
  51. 51.
    Mina R, Brunner HI (2010) Pediatric lupus–are there differences in presentation, genetics, response to therapy, and damage accrual compared with adult lupus? Rheum Dis Clin North Am 36:53–80PubMedCrossRefGoogle Scholar

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© IPNA 2012

Authors and Affiliations

  1. 1.UT Southwestern Medical CenterDallasUSA

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