Therapy of 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
- 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
The optimal treatment of lupus nephritis (LN) varies with the type of renal histology that is present in renal biopsy specimens. Immunosuppressive therapy is indicated in patients with diffuse or focal proliferative LN (class III or IV LN) [1-3]. Immunosuppressive therapy is usually not indicated for minimal mesangial and mesangial proliferative LN. Treatment of patients with lupus membranous nephropathy (class V LN) is presented elsewhere. (See "Diagnosis and classification of renal disease in systemic lupus erythematosus", section on 'Classification' and "Clinical features and therapy of lupus membranous nephropathy".)
Induction and maintenance immunosuppressive therapy of proliferative LN, as well as nonimmunosuppressive therapies, will be reviewed here. The treatment of resistant or relapsing proliferative LN and issues related to end-stage LN are presented separately. (See "Therapy of resistant or relapsing diffuse or focal proliferative lupus nephritis" and "End-stage renal disease due to lupus nephritis".)
RISK FACTORS FOR PROGRESSION
Even with aggressive therapy, some patients with proliferative lupus nephritis (LN) will have a progressive decline in renal function leading to end-stage renal disease (ESRD). Clinical risk factors for progression, evident at the time of initial presentation, include an elevated serum creatinine, hypertension, nephrotic range proteinuria, anemia with a hematocrit below 26 percent, and black and Hispanic race and ethnicity [4-7]. (See 'Race and ethnicity' below.)
The severity of acute and chronic tubulointerstitial disease and interstitial inflammation as well as the presence of cellular crescents also correlate with long-term prognosis in LN, as they do in many other chronic progressive glomerular diseases [5,6,8,9]. (See "Secondary factors and progression of chronic kidney disease", section on 'Tubulointerstitial fibrosis'.)
Risk factors for progression that become evident after initial presentation and during therapy are the frequency and severity of relapses (renal flares) and the degree to which the abnormal features of renal involvement are controlled (complete or partial response of proteinuria, hematuria, and the severity of azotemia) (see 'Failure to achieve a clinical response' below). A complete renal response based upon these clinical criteria may or may not correspond to a histologic complete remission.
- Chapter 10: Immunoglobulin A nephropathy. Kidney Int Suppl (2011) 2012; 2:209.
- Hahn BH, McMahon MA, Wilkinson A, et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken) 2012; 64:797.
- 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.
- Appel GB, Cohen DJ, Pirani CL, et al. Long-term follow-up of patients with lupus nephritis. A study based on the classification of the World Health Organization. Am J Med 1987; 83:877.
- Austin HA 3rd, Boumpas DT, Vaughan EM, Balow JE. Predicting renal outcomes in severe lupus nephritis: contributions of clinical and histologic data. Kidney Int 1994; 45:544.
- Contreras G, Pardo V, Cely C, et al. Factors associated with poor outcomes in patients with lupus nephritis. Lupus 2005; 14:890.
- Sisó A, Ramos-Casals M, Bové A, et al. Outcomes in biopsy-proven lupus nephritis: evaluation of 190 white patients from a single center. Medicine (Baltimore) 2010; 89:300.
- Schwartz MM, Lan SP, Bernstein J, et al. Role of pathology indices in the management of severe lupus glomerulonephritis. Lupus Nephritis Collaborative Study Group. Kidney Int 1992; 42:743.
- Hsieh C, Chang A, Brandt D, et al. Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring. Arthritis Care Res (Hoboken) 2011; 63:865.
- Esdaile JM, Joseph L, MacKenzie T, et al. The benefit of early treatment with immunosuppressive agents in lupus nephritis. J Rheumatol 1994; 21:2046.
- Faurschou M, Starklint H, Halberg P, Jacobsen S. Prognostic factors in lupus nephritis: diagnostic and therapeutic delay increases the risk of terminal renal failure. J Rheumatol 2006; 33:1563.
- Chagnac A, Kiberd BA, Fariñas MC, et al. Outcome of the acute glomerular injury in proliferative lupus nephritis. J Clin Invest 1989; 84:922.
- Korbet SM, Lewis EJ, Schwartz MM, et al. Factors predictive of outcome in severe lupus nephritis. Lupus Nephritis Collaborative Study Group. Am J Kidney Dis 2000; 35:904.
- Chen YE, Korbet SM, Katz RS, et al. Value of a complete or partial remission in severe lupus nephritis. Clin J Am Soc Nephrol 2008; 3:46.
- Chan TM, Tse KC, Tang CS, et al. Long-term outcome of patients with diffuse proliferative lupus nephritis treated with prednisolone and oral cyclophosphamide followed by azathioprine. Lupus 2005; 14:265.
- Korbet SM, Schwartz MM, Evans J, et al. Severe lupus nephritis: racial differences in presentation and outcome. J Am Soc Nephrol 2007; 18:244.
- Barber CE, Geldenhuys L, Hanly JG. Sustained remission of lupus nephritis. Lupus 2006; 15:94.
- 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.
- 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.
- Parikh SV, Nagaraja HN, Hebert L, Rovin BH. Renal flare as a predictor of incident and progressive CKD in patients with lupus nephritis. Clin J Am Soc Nephrol 2014; 9:279.
- Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004; 15:241.
- Austin HA 3rd, Muenz LR, Joyce KM, et al. Diffuse proliferative lupus nephritis: identification of specific pathologic features affecting renal outcome. Kidney Int 1984; 25:689.
- Schwartz MM, Lan SP, Bernstein J, et al. Irreproducibility of the activity and chronicity indices limits their utility in the management of lupus nephritis. Lupus Nephritis Collaborative Study Group. Am J Kidney Dis 1993; 21:374.
- Yokoyama H, Wada T, Hara A, et al. The outcome and a new ISN/RPS 2003 classification of lupus nephritis in Japanese. Kidney Int 2004; 66:2382.
- Mittal B, Hurwitz S, Rennke H, Singh AK. New subcategories of class IV lupus nephritis: are there clinical, histologic, and outcome differences? Am J Kidney Dis 2004; 44:1050.
- Hill GS, Delahousse M, Nochy D, Bariéty J. Class IV-S versus class IV-G lupus nephritis: clinical and morphologic differences suggesting different pathogenesis. Kidney Int 2005; 68:2288.
- Markowitz GS, D'Agati VD. The ISN/RPS 2003 classification of lupus nephritis: an assessment at 3 years. Kidney Int 2007; 71:491.
- Glassock RJ. Reclassification of lupus glomerulonephritis: back to the future. J Am Soc Nephrol 2004; 15:501.
- Dooley MA, Hogan S, Jennette C, Falk R. Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans. Glomerular Disease Collaborative Network. Kidney Int 1997; 51:1188.
- Alarcón GS, McGwin G Jr, Bastian HM, et al. Systemic lupus erythematosus in three ethnic groups. VII [correction of VIII]. Predictors of early mortality in the LUMINA cohort. LUMINA Study Group. Arthritis Rheum 2001; 45:191.
- Barr RG, Seliger S, Appel GB, et al. Prognosis in proliferative lupus nephritis: the role of socio-economic status and race/ethnicity. Nephrol Dial Transplant 2003; 18:2039.
- Contreras G, Lenz O, Pardo V, et al. Outcomes in African Americans and Hispanics with lupus nephritis. Kidney Int 2006; 69:1846.
- Lau KK, Jones DP, Hastings MC, et al. Short-term outcomes of severe lupus nephritis in a cohort of predominantly African-American children. Pediatr Nephrol 2006; 21:655.
- Adler M, Chambers S, Edwards C, et al. An assessment of renal failure in an SLE cohort with special reference to ethnicity, over a 25-year period. Rheumatology (Oxford) 2006; 45:1144.
- Ward MM. Medical insurance, socioeconomic status, and age of onset of endstage renal disease in patients with lupus nephritis. J Rheumatol 2007; 34:2024.
- Lin CP, Adrianto I, Lessard CJ, et al. Role of MYH9 and APOL1 in African and non-African populations with lupus nephritis. Genes Immun 2012; 13:232.
- Valeri A, Radhakrishnan J, Estes D, et al. Intravenous pulse cyclophosphamide treatment of severe lupus nephritis: a prospective five-year study. Clin Nephrol 1994; 42:71.
- 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.
- 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.
- ACCESS Trial Group. Treatment of lupus nephritis with abatacept: the Abatacept and Cyclophosphamide Combination Efficacy and Safety Study. Arthritis Rheumatol 2014; 66:3096.
- Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 2012; 64:1215.
- 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.
- Chan TM, Li FK, Tang CS, 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.
- Contreras G, Pardo V, Leclercq B, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004; 350:971.
- Hall CL, Fothergill NJ, Blackwell MM, et al. The natural course of gold nephropathy: long term study of 21 patients. Br Med J (Clin Res Ed) 1987; 295:745.
- Hall CL, Jawad S, Harrison PR, et al. Natural course of penicillamine nephropathy: a long term study of 33 patients. Br Med J (Clin Res Ed) 1988; 296:1083.
- Potter EV, Lipschultz SA, Abidh S, et al. Twelve to seventeen-year follow-up of patients with poststreptococcal acute glomerulonephritis in Trinidad. N Engl J Med 1982; 307:725.
- Steinberg AD. The treatment of lupus nephritis. Kidney Int 1986; 30:769.
- Gourley MF, Austin HA 3rd, Scott D, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med 1996; 125:549.
- Flanc RS, Roberts MA, Strippoli GF, et al. Treatment for lupus nephritis. Cochrane Database Syst Rev 2004; :CD002922.
- Illei GG, Austin HA, Crane M, 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.
- Yee CS, Gordon C, Dostal C, et al. EULAR randomised controlled trial of pulse cyclophosphamide and methylprednisolone versus continuous cyclophosphamide and prednisolone followed by azathioprine and prednisolone in lupus nephritis. Ann Rheum Dis 2004; 63:525.
- Levey AS, Lan SP, Corwin HL, et al. Progression and remission of renal disease in the Lupus Nephritis Collaborative Study. Results of treatment with prednisone and short-term oral cyclophosphamide. Ann Intern Med 1992; 116:114.
- Houssiau FA, Vasconcelos C, D'Cruz D, 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.
- Houssiau FA, Vasconcelos C, D'Cruz D, et al. Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: lessons from long-term followup of patients in the Euro-Lupus Nephritis Trial. Arthritis Rheum 2004; 50:3934.
- Moroni G, Doria A, Mosca M, et al. A randomized pilot trial comparing cyclosporine and azathioprine for maintenance therapy in diffuse lupus nephritis over four years. Clin J Am Soc Nephrol 2006; 1:925.
- Isenberg D, Appel GB, Contreras G, et al. Influence of race/ethnicity on response to lupus nephritis treatment: the ALMS study. Rheumatology (Oxford) 2010; 49:128.
- McKinley A, Park E, Spetie D, et al. Oral cyclophosphamide for lupus glomerulonephritis: an underused therapeutic option. Clin J Am Soc Nephrol 2009; 4:1754.
- Henderson LK, Masson P, Craig JC, et al. Induction and maintenance treatment of proliferative lupus nephritis: a meta-analysis of randomized controlled trials. Am J Kidney Dis 2013; 61:74.
- Henderson L, Masson P, Craig JC, et al. Treatment for lupus nephritis. Cochrane Database Syst Rev 2012; 12:CD002922.
- Contreras G, Sosnov J. Role of mycophenolate mofetil in the treatment of lupus nephritis. Clin J Am Soc Nephrol 2007; 2:879.
- Walsh M, James M, Jayne D, et al. Mycophenolate mofetil for induction therapy of lupus nephritis: a systematic review and meta-analysis. Clin J Am Soc Nephrol 2007; 2:968.
- Liu Z, Zhang H, Liu Z, et al. Multitarget therapy for induction treatment of lupus nephritis: a randomized trial. Ann Intern Med 2015; 162:18.
- Chen W, Tang X, Liu Q, et al. Short-term outcomes of induction therapy with tacrolimus versus cyclophosphamide for active lupus nephritis: A multicenter randomized clinical trial. Am J Kidney Dis 2011; 57:235.
- Li X, Ren H, Zhang Q, et al. Mycophenolate mofetil or tacrolimus compared with intravenous cyclophosphamide in the induction treatment for active lupus nephritis. Nephrol Dial Transplant 2012; 27:1467.
- Furie R, Nicholls K, Cheng TT, et al. Efficacy and safety of abatacept in lupus nephritis: a twelve-month, randomized, double-blind study. Arthritis Rheumatol 2014; 66:379.
- 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.
- 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.
- 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.
- 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.
- Grootscholten C, Berden JH. Discontinuation of immunosuppression in proliferative lupus nephritis: is it possible? Nephrol Dial Transplant 2006; 21:1465.
- Houssiau FA, D'Cruz D, Sangle S, 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.
- Fischer-Betz R, Specker C, Brinks R, et al. Low risk of renal flares and negative outcomes in women with lupus nephritis conceiving after switching from mycophenolate mofetil to azathioprine. Rheumatology (Oxford) 2013; 52:1070.
- Wofsy D, Appel GB, Dooley MA. Aspreva Lupus Management Study maintenance results. Lupus 2010; 19 (Suppl):CS12.5.
- Stoenoiu MS, Aydin S, Tektonidou M, et al. Repeat kidney biopsies fail to detect differences between azathioprine and mycophenolate mofetil maintenance therapy for lupus nephritis: data from the MAINTAIN Nephritis Trial. Nephrol Dial Transplant 2012; 27:1924.
- Tamirou F, D'Cruz D, Sangle S, et al. Long-term follow-up of the MAINTAIN Nephritis Trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis. Ann Rheum Dis 2016; 75:526.
- Dooley MA, Jayne D, Ginzler EM, et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med 2011; 365:1886.
- RISK FACTORS FOR PROGRESSION
- Delayed therapy
- Failure to achieve a clinical response
- - Relapses
- Class of lupus nephritis
- Race and ethnicity
- NONIMMUNOSUPPRESSIVE THERAPY
- PRINCIPLES OF IMMUNOSUPPRESSIVE THERAPY
- Goal of immunosuppressive therapy
- - Complete response versus complete remission
- Pregnant patients
- INITIAL (INDUCTION) THERAPY
- Approach to initial (induction) therapy
- Preferred therapy: Glucocorticoids plus either cyclophosphamide or mycophenolate mofetil
- - Glucocorticoids
- Dosing of glucocorticoids
- - Choosing between cyclophosphamide and mycophenolate mofetil
- - Efficacy of cyclophosphamide
- - Dosing of cyclophosphamide
- Mycophenolate mofetil
- - Efficacy of mycophenolate mofetil
- - Dosing of mycophenolate mofetil
- - Monitoring patients during initial (induction) therapy
- - Preventing toxicity
- Patients who are resistant to initial therapy
- Less preferred therapies
- - Tacrolimus
- - Rituximab
- - Costimulatory blockade with CTLA4-Ig
- Patients with both diffuse proliferative LN and lupus membranous nephropathy
- EXTENDED (MAINTENANCE) THERAPY
- Choice of agent for extended (maintenance) therapy
- - Preference for mycophenolate mofetil
- Approach to extended (maintenance) therapy
- Dosing and duration of extended (maintenance) therapy
- Glucocorticoid therapy during extended (maintenance) therapy
- Monitoring patients during extended (maintenance) therapy
- SOCIETY GUIDELINE LINKS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS