Therapy of resistant or relapsing diffuse or focal proliferative lupus nephritis
- Ronald J Falk, MD
Ronald J Falk, MD
- Nan and Hugh Cullman Eminent Professor of Nephrology
- Chair, Department of Medicine
- Director, UNC Kidney Center
- University of North Carolina-Chapel Hill
- Maria Dall'Era, MD
Maria Dall'Era, MD
- Associate Professor of Medicine
- University of California, San Francisco
- Gerald B Appel, MD
Gerald B Appel, MD
- Section Editor — Glomerular Diseases
- Professor of Medicine
- Columbia University College of Physicians and Surgeons
- Section Editors
- Richard J Glassock, MD, MACP
Richard J Glassock, MD, MACP
- Editor-in-Chief — Nephrology
- Section Editor — Glomerular Diseases
- Emeritus Professor
- The David Geffen School of Medicine at UCLA
- Brad H Rovin, MD
Brad H Rovin, MD
- Section Editor — Glomerular Diseases
- Professor of Medicine and Pathology
- The Ohio State University College of Medicine
Treatment of lupus nephritis (LN) varies with the type of disease (morphologic class) that is present. However, no single regimen is regarded as optimal for all patients with LN, and treatment must be individualized. Combined immunosuppressive therapy is typically indicated in patients with diffuse and focal proliferative LN and in many patients with lupus membranous nephropathy. (See "Diagnosis and classification of renal disease in systemic lupus erythematosus" and "Clinical features and therapy of lupus membranous nephropathy".)
Some patients are truly resistant to initial immunosuppressive treatments despite full compliance with the prescribed regimen. By contrast, a greater number of patients are perceived to have resistant LN.
Relapsing LN is substantially more common than resistant disease. Nearly one-half of patients with proliferative LN who initially achieve a complete response on immunosuppressive therapy will have a relapse (also called renal flare) following reduction in or cessation of immunosuppression.
The treatment of resistant and relapsing LN will be reviewed here. The treatment of proliferative LN and lupus membranous nephropathy, as well as issues related to end-stage LN, are presented separately. (See "Therapy of diffuse or focal proliferative lupus nephritis" and "Clinical features and therapy of lupus membranous nephropathy" and "End-stage renal disease due to lupus nephritis".)
DISEASE RESISTANT TO INITIAL IMMUNOSUPPRESSIVE THERAPY
Patients who fail to achieve a response to initial immunosuppressive therapy are defined as having resistant disease. As noted above, true resistant disease is uncommon. Perceived resistance, which is more common, is often due to incomplete compliance or noncompliance with the prescribed immunosuppressive regimen or to inadequacy of the prescribed regimen.
- KDIGO. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int Suppl 2012; 2:209. http://www.kdigo.org/clinical_practice_guidelines/pdf/KDIGO-GN-Guideline.pdf (Accessed on December 23, 2013).
- Bertsias GK, Tektonidou M, Amoura Z, et al. 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 2012; 71:1771.
- Karim MY, Pisoni CN, Ferro L, et al. Reduction of proteinuria with mycophenolate mofetil in predominantly membranous lupus nephropathy. Rheumatology (Oxford) 2005; 44:1317.
- Dooley MA, Cosio FG, Nachman PH, et al. Mycophenolate mofetil therapy in lupus nephritis: clinical observations. J Am Soc Nephrol 1999; 10:833.
- Glicklich D, Acharya A. Mycophenolate mofetil therapy for lupus nephritis refractory to intravenous cyclophosphamide. Am J Kidney Dis 1998; 32:318.
- Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol 2009; 20:1103.
- Weidenbusch M, Römmele C, Schröttle A, Anders HJ. Beyond the LUNAR trial. Efficacy of rituximab in refractory lupus nephritis. Nephrol Dial Transplant 2013; 28:106.
- Vigna-Perez M, Hernández-Castro B, Paredes-Saharopulos O, et al. Clinical and immunological effects of Rituximab in patients with lupus nephritis refractory to conventional therapy: a pilot study. Arthritis Res Ther 2006; 8:R83.
- Melander C, Sallée M, Trolliet P, et al. Rituximab in severe lupus nephritis: early B-cell depletion affects long-term renal outcome. Clin J Am Soc Nephrol 2009; 4:579.
- Fra GP, Avanzi GC, Bartoli E. Remission of refractory lupus nephritis with a protocol including rituximab. Lupus 2003; 12:783.
- Thatayatikom A, White AJ. Rituximab: a promising therapy in systemic lupus erythematosus. Autoimmun Rev 2006; 5:18.
- Camous L, Melander C, Vallet M, et al. Complete remission of lupus nephritis with rituximab and steroids for induction and rituximab alone for maintenance therapy. Am J Kidney Dis 2008; 52:346.
- Davies RJ, Sangle SR, Jordan NP, et al. Rituximab in the treatment of resistant lupus nephritis: therapy failure in rapidly progressive crescentic lupus nephritis. Lupus 2013; 22:574.
- Cortés-Hernández J, Torres-Salido MT, Medrano AS, et al. Long-term outcomes--mycophenolate mofetil treatment for lupus nephritis with addition of tacrolimus for resistant cases. Nephrol Dial Transplant 2010; 25:3939.
- Lanata CM, Mahmood T, Fine DM, Petri M. Combination therapy of mycophenolate mofetil and tacrolimus in lupus nephritis. Lupus 2010; 19:935.
- Grootscholten C, Berden JH. Discontinuation of immunosuppression in proliferative lupus nephritis: is it possible? Nephrol Dial Transplant 2006; 21:1465.
- Sidiropoulos PI, Kritikos HD, Boumpas DT. Lupus nephritis flares. Lupus 2005; 14:49.
- Houssiau FA, Vasconcelos C, D'Cruz D, 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.
- Ioannidis JP, Boki KA, Katsorida ME, et al. Remission, relapse, and re-remission of proliferative lupus nephritis treated with cyclophosphamide. Kidney Int 2000; 57:258.
- Mosca M, Bencivelli W, Neri R, et al. Renal flares in 91 SLE patients with diffuse proliferative glomerulonephritis. Kidney Int 2002; 61:1502.
- Chan TM, Tse KC, Tang CS, et al. Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. J Am Soc Nephrol 2005; 16:1076.
- Moroni G, Gallelli B, Quaglini S, et al. Withdrawal of therapy in patients with proliferative lupus nephritis: long-term follow-up. Nephrol Dial Transplant 2006; 21:1541.
- Swaak AJ, van den Brink HG, Smeenk RJ, et al. Systemic lupus erythematosus. Disease outcome in patients with a disease duration of at least 10 years: second evaluation. Lupus 2001; 10:51.
- Mok CC, Ying KY, Tang S, et al. Predictors and outcome of renal flares after successful cyclophosphamide treatment for diffuse proliferative lupus glomerulonephritis. Arthritis Rheum 2004; 50:2559.
- Illei GG, Takada K, Parkin D, et al. Renal flares are common in patients with severe proliferative lupus nephritis treated with pulse immunosuppressive therapy: long-term followup of a cohort of 145 patients participating in randomized controlled studies. Arthritis Rheum 2002; 46:995.
- Sprangers B, Monahan M, Appel GB. Diagnosis and treatment of lupus nephritis flares--an update. Nat Rev Nephrol 2012; 8:709.
- Contreras G, Pardo V, Leclercq B, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004; 350:971.
- Dooley MA, Jayne D, Ginzler EM, et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med 2011; 365:1886.
- Moroni G, Quaglini S, Maccario M, et al. "Nephritic flares" are predictors of bad long-term renal outcome in lupus nephritis. Kidney Int 1996; 50:2047.
- Hebert LA, Dillon JJ, Middendorf DF, et al. Relationship between appearance of urinary red blood cell/white blood cell casts and the onset of renal relapse in systemic lupus erythematosus. Am J Kidney Dis 1995; 26:432.
- Chagnac A, Kiberd BA, Fariñas MC, et al. Outcome of the acute glomerular injury in proliferative lupus nephritis. J Clin Invest 1989; 84:922.
- Cheigh JS, Kim H, Stenzel KH, et al. Systemic lupus erythematosus in patients with end-stage renal disease: long-term follow-up on the prognosis of patients and the evolution of lupus activity. Am J Kidney Dis 1990; 16:189.
- Birmingham DJ, Rovin BH, Shidham G, et al. Spot urine protein/creatinine ratios are unreliable estimates of 24 h proteinuria in most systemic lupus erythematosus nephritis flares. Kidney Int 2007; 72:865.
- ter Borg EJ, Horst G, Hummel EJ, et al. Measurement of increases in anti-double-stranded DNA antibody levels as a predictor of disease exacerbation in systemic lupus erythematosus. A long-term, prospective study. Arthritis Rheum 1990; 33:634.
- West CD. Relative value of serum C3 and C4 levels in predicting relapse in systemic lupus erythematosus. Am J Kidney Dis 1991; 18:686.
- Najafi CC, Korbet SM, Lewis EJ, et al. Significance of histologic patterns of glomerular injury upon long-term prognosis in severe lupus glomerulonephritis. Kidney Int 2001; 59:2156.
- DISEASE RESISTANT TO INITIAL IMMUNOSUPPRESSIVE THERAPY
- Definition of complete response
- Treatment of resistant disease
- - Cyclophosphamide resistance
- - MMF resistance
- - Rituximab for cyclophosphamide and MMF resistance
- - MMF plus tacrolimus
- - Belimumab
- RELAPSING DISEASE
- Definition and clinical recognition
- - Monitoring
- Treatment of relapsing disease
- - Mild relapse
- - Moderate to severe relapse
- DIFFUSE PROLIFERATIVE LN PLUS LUPUS MEMBRANOUS NEPHROPATHY
- SOCIETY GUIDELINE LINKS
- SUMMARY AND RECOMMENDATIONS
- Resistant disease
- Relapsing disease