Portal de Periódicos da CAPES

Ten Common Mistakes in the Management of Lupus Nephritis

2013; Elsevier BV; Volume: 63; Issue: 4 Linguagem: Inglês

10.1053/j.ajkd.2013.10.056

1523-6838

Bhadran Bose, Earl D. Silverman, Joanne M. Bargman,

Liver Diseases and Immunity

Management of patients with lupus nephritis can be complex and challenging. We suggest that there are some widely held misconceptions about lupus, and unfortunately, these underpin the treatment of many patients. There is little evidence to support the common assumption that intravenous pulse cyclophosphamide is the best treatment for lupus nephritis. Although there is much focus on which immunosuppressive agent to use, too little attention is paid to the proper dose and duration of corticosteroids and concomitant therapy with antimalarial agents. Many clinicians reflexively perform kidney biopsies when these biopsies may be high risk and not influence therapy. There is little emphasis on or awareness of nonadherence to therapy, which is an underappreciated cause of treatment resistance. Resolution of proteinuria and hematuria can take a long time, and immunotherapy should not be intensified based on urine sediment alone. Furthermore, the intensity of the immunosuppression must be considered in the context of lupus nephritis class and duration of kidney damage. Finally, clinicians are aware of the risks of pregnancy in the face of active lupus, but assume that their patients also are aware of this and forget to discuss this with them. With a combined experience of more than 50 years in managing children and adults with lupus, we offer our impression of recurrent mistakes in the management of lupus in general, with a focus on treatment of lupus nephritis. Management of patients with lupus nephritis can be complex and challenging. We suggest that there are some widely held misconceptions about lupus, and unfortunately, these underpin the treatment of many patients. There is little evidence to support the common assumption that intravenous pulse cyclophosphamide is the best treatment for lupus nephritis. Although there is much focus on which immunosuppressive agent to use, too little attention is paid to the proper dose and duration of corticosteroids and concomitant therapy with antimalarial agents. Many clinicians reflexively perform kidney biopsies when these biopsies may be high risk and not influence therapy. There is little emphasis on or awareness of nonadherence to therapy, which is an underappreciated cause of treatment resistance. Resolution of proteinuria and hematuria can take a long time, and immunotherapy should not be intensified based on urine sediment alone. Furthermore, the intensity of the immunosuppression must be considered in the context of lupus nephritis class and duration of kidney damage. Finally, clinicians are aware of the risks of pregnancy in the face of active lupus, but assume that their patients also are aware of this and forget to discuss this with them. With a combined experience of more than 50 years in managing children and adults with lupus, we offer our impression of recurrent mistakes in the management of lupus in general, with a focus on treatment of lupus nephritis. Joanne M. Bargman, MD, FRCPC, was the Donald W. Seldin Distinguished Award recipient at the 2013 National Kidney Foundation Spring Clinical Meetings. This award was established to recognize excellence in clinical nephrology in the tradition of one of the foremost teachers and researchers in the field, Dr Donald W. Seldin. Joanne M. Bargman, MD, FRCPC, was the Donald W. Seldin Distinguished Award recipient at the 2013 National Kidney Foundation Spring Clinical Meetings. This award was established to recognize excellence in clinical nephrology in the tradition of one of the foremost teachers and researchers in the field, Dr Donald W. Seldin. Kidney involvement in systemic lupus erythematosus (SLE) can range from mild to severe and occurs in 50%-70% of patients with lupus.1Bastian H.M. Roseman J.M. McGwin Jr., G. et al.Systemic lupus erythematosus in three ethnic groups. XII. Risk factors for lupus nephritis after diagnosis.Lupus. 2002; 11: 152-160Google Scholar, 2Petri M. Perez-Gutthann S. Longenecker J.C. Hochberg M. Morbidity of systemic lupus erythematosus: role of race and socioeconomic status.Am J Med. 1991; 91: 345-353Google Scholar, 3Pons-Estel B.A. Catoggio L.J. Cardiel M.H. et al.The GLADEL multinational Latin American prospective inception cohort of 1,214 patients with systemic lupus erythematosus: ethnic and disease heterogeneity among "Hispanics.".Medicine (Baltimore). 2004; 83: 1-17Google Scholar Despite advances in therapy, morbidity and mortality remain high. In some studies, lupus nephritis leads to end-stage renal failure in 17%-25% of patients4Adler M. Chambers S. Edwards C. Neild G. Isenberg D. An assessment of renal failure in an SLE cohort with special reference to ethnicity, over a 25-year period.Rheumatology (Oxford). 2006; 45: 1144-1147Google Scholar, 5Ward M.M. Studenski S. Clinical prognostic factors in lupus nephritis. The importance of hypertension and smoking.Arch Intern Med. 1992; 152: 2082-2088Google Scholar, 6Williams W. Sargeant L.A. Smikle M. Smith R. Edwards H. Shah D. The outcome of lupus nephritis in Jamaican patients.Am J Med Sci. 2007; 334: 426-430Google Scholar and also is associated with increased mortality.7Cervera R. Khamashta M.A. Font J. 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 (Baltimore). 2003; 82: 299-308Google Scholar, 8Zonana-Nacach A. Yanez P. Jimenez-Balderas F.J. Camargo-Coronel A. Disease activity, damage and survival in Mexican patients with acute severe systemic lupus erythematosus.Lupus. 2007; 16: 997-1000Google Scholar There are some common misconceptions that are widely held and may compromise optimal therapy of these patients. If these misconception or myths are addressed, we believe the outcome of these patients might improve. These comments are based on our experience over the past quarter century dealing with a diverse ethnic lupus population in academically based multidisciplinary lupus clinics in Toronto. The following are the 10 most common mistakes we have observed surrounding the management of patients with lupus nephritis (Box 1).Box 1Ten Common Mistakes in the Management of Lupus Nephritis1.Assuming that intravenous cyclophosphamide is the gold-standard induction agent for lupus nephritis2.Improper dosing of corticosteroids3.Not using antimalarial agents routinely4.Using urinary sediment for response criteria5.Not scaling the intensity of immunosuppression to the different classes of lupus nephritis, especially class V membranous lupus6.Missing nonadherence to therapy as a cause of "treatment failure"7.Not reducing or minimizing immunosuppressive exposure in patients with advanced kidney disease8.Forgetting to monitor side effects of immunosuppression and to use prophylaxis9.Performing a biopsy on the kidney, especially in a high-risk patient, when it will not affect therapy10.Neglecting to address pregnancy 1.Assuming that intravenous cyclophosphamide is the gold-standard induction agent for lupus nephritis2.Improper dosing of corticosteroids3.Not using antimalarial agents routinely4.Using urinary sediment for response criteria5.Not scaling the intensity of immunosuppression to the different classes of lupus nephritis, especially class V membranous lupus6.Missing nonadherence to therapy as a cause of "treatment failure"7.Not reducing or minimizing immunosuppressive exposure in patients with advanced kidney disease8.Forgetting to monitor side effects of immunosuppression and to use prophylaxis9.Performing a biopsy on the kidney, especially in a high-risk patient, when it will not affect therapy10.Neglecting to address pregnancy Following the initial publication by Austin et al9Austin III, H.A. Klippel J.H. Balow J.E. et al.Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs.N Engl J Med. 1986; 314: 614-619Google Scholar in 1986, intravenous (IV) cyclophosphamide has been considered the gold standard for treatment of lupus nephritis. Based on this study, the National Institutes of Health (NIH) has promoted high-dose cyclophosphamide as a first-line induction agent for lupus nephritis, and this regimen is used by many rheumatologists and nephrologists. The cyclophosphamide dosage is 0.5-1.0 g/m2 monthly for 6 months, followed by repeat dosing every 3 months for 1 year, followed by an additional 2 doses 6 months apart. However, there are major concerns with this regimen, especially in young patients with lupus, due to the risks of gonadal toxicity and malignancy. In 2002, the Euro-Lupus Nephritis Trial compared low-dose IV cyclophosphamide (500 mg IV biweekly for 6 doses) versus the high-dose NIH regimen in 90 patients.10Houssiau F.A. 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: 2121-2131Google Scholar Renal response and relapse rate were similar between the 2 groups. The long-term efficacy of the Euro-Lupus Nephritis Trial regimen also was shown in a 10-year follow-up study.11Houssiau F.A. 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: 61-64Google Scholar However, there was no statistical difference in adverse events between groups. Limitations of the study are that most patients in the study were white, 78% had preserved kidney function (creatinine < 1.3 mg/dL), and the relatively small number (90) of patients treated. Interestingly, few have commented on the role of azathioprine, to which the low-dose IV cyclophosphamide group was transitioned after 3 months. Rather than being a comparison of high- versus low-dose IV cyclophosphamide, this study compared ongoing IV cyclophosphamide (high-dose group) therapy with low-dose IV cyclophosphamide followed by azathioprine past the 3-month point (low-dose group). Therefore, this study could be considered to be one comparing high-dose cyclophosphamide to azathioprine after the 3-month mark. More recently, mycophenolate mofetil (MMF) has been studied as alternative induction therapy to IV cyclophosphamide and may prove particularly effective in patients of African-Caribbean descent. Initially, MMF was compared to oral cyclophosphamide in 42 patients.12Chan T.M. Li F.K. Tang C.S. 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: 1156-1162Google Scholar, 13Chan T.M. Tse K.C. Tang C.S. Mok M.Y. Li F.K. Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis.J Am Soc Nephrol. 2005; 16: 1076-1084Google Scholar Patients received either 12 months of MMF (2 g/d for 6 months and then 1 g/d for 6 months) or 6 months of oral cyclophosphamide (2.5 mg/kg/d) followed by 6 months of oral azathioprine (1.5 mg/kg/d). Both groups received corticosteroids. Complete remission, partial remission, relapse rates, and rate of chronic kidney disease (CKD) or end-stage renal failure were similar between groups. There was a trend for more infections in the cyclophosphamide group, but it was not statistically significant. This trial was followed by 3 randomized controlled trials comparing MMF versus IV cyclophosphamide.14Appel G.B. Contreras G. Dooley M.A. et al.Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.J Am Soc Nephrol. 2009; 20: 1103-1112Google Scholar, 15Ginzler E.M. Dooley M.A. Aranow C. et al.Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis.N Engl J Med. 2005; 353: 2219-2228Google Scholar, 16Ong L.M. Hooi L.S. Lim T.O. et al.Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis.Nephrology (Carlton). 2005; 10: 504-510Google Scholar One of the trials was an open-label crossover noninferiority trial and at 24 weeks showed significantly improved complete and partial remission rates in the MMF group (goal induction dose of 3 g/d) compared to the cyclophosphamide group.16Ong L.M. Hooi L.S. Lim T.O. et al.Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis.Nephrology (Carlton). 2005; 10: 504-510Google Scholar There was an increased rate of pyogenic infection in the cyclophosphamide group. The ALMS (Aspreva Lupus Management Study) induction therapy study showed similar cumulative remission rates between both groups. The renal and nonrenal outcomes were equivalent at 6 months.14Appel G.B. Contreras G. Dooley M.A. et al.Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.J Am Soc Nephrol. 2009; 20: 1103-1112Google Scholar The 2 large trials comparing MMF versus IV cyclophosphamide are summarized in Table 1.Table 1Two Large Studies Comparing MMF Versus IV Cyclophosphamide for Induction Treatment of Lupus NephritisStudyNTherapy (wk)Age (y)Race (%)Kidney Biopsy Class (%)Baseline SCr (mg/dL)24-h Urine Protein (g/d)Intervention (n)OutcomeGinzler15Ginzler E.M. Dooley M.A. Aranow C. et al.Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis.N Engl J Med. 2005; 353: 2219-2228Google Scholar (2005)1402431.5 ± 9.5White, 17; black, 56.5; Asian, 5.5; Hispanic, 20; other, 1III, 15.5; IV, 54.5; V, 19.5; mixed membranoproliferative, 11.51.07 ± 0.504.25 ± 3.3MMF, mean maximal tolerated dose 2.6 g/d + prednisone (71); IV CYC, cumulative dose per patient 7,302 ± 1,695 mg + prednisone (69)MMF group: CR, 22.5%; PR, 29.6%; IV CYC group: CR, 5.8%; PR, 24.6%Appel14Appel G.B. Contreras G. Dooley M.A. et al.Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.J Am Soc Nephrol. 2009; 20: 1103-1112Google Scholar (2009; ALMS)3702431.9 ± 10.7White, 39.7; Asian, 33.2; other, 27III/III + V, 15.7; IV/IV + V, 68.1; V only, 16.21.13 ± 0.904.1 ± 3.7MMF, median dose 2.6 g/d + prednisone (185); IV CYC, median no. of doses, 6.0; median total dose per infusion, 0.75 g/m2 + prednisone (185)Primary efficacy end point achievedaPrimary efficacy end point: decrease in 24-hour urine protein to <3 in patients with baseline nephrotic-range proteinuria (≥3), or by ≥50% in patients with subnephrotic baseline proteinuria (<3), and stabilization (±25%) or improvement in SCr level at 24 weeks. in 56.2% of MMF group; 53% of IV CYC groupNote: Conversion factor for SCr in mg/dL to μmol/L, ×88.4.Abbreviations and definitions: CR, complete remission defined as return to within 10% of normal serum creatinine levels, proteinuria, and urine sediment; CYC, cyclophosphamide; IV, intravenous; MMF, mycophenolate mofetil; PR, partial remission defined as 50% improvement in all abnormal renal measurements without worsening (within 10%) of any measurement; SCr, serum creatinine.a Primary efficacy end point: decrease in 24-hour urine protein to <3 in patients with baseline nephrotic-range proteinuria (≥3), or by ≥50% in patients with subnephrotic baseline proteinuria ( 5 red blood cells and >5 white blood cells per high-power field and/or cellular casts where none existed previously. However, in reality, the quantity of cells or casts observed can be influenced by the duration of centrifuge time and how vigorously the pellet at the bottom of the centrifuge tube is resuspended in the supernatant. We also know that some more benign processes such as mesangial proliferation (class II nephritis) can be associated with red blood cells and red blood cell casts in urine, and these lesions do not require immunosuppressive agents. Hence, using urinary sediment for response criteria can be misleading and can result in unnecessary use of potentially toxic therapies. In our experience, this is recognized more often by nephrologists than by rheumatologists. However, guideline panels setting criteria for kidney involvement in lupus unfortunately have a dearth of nephrologists.32Bargman J.M. Why are rheumatologists treating lupus nephritis?.Nat Clin Pract Nephrol. 2007; 3: 296-297Google Scholar Membranous lupus nephritis (MLN) accounts for approximately 10%-20% of cases of lupus nephritis.33Lewis EJ, Schwartz MM, Korbet SM, eds. Membranous lupus glomerulonephritis. In: Lewis EJ SM, Korbet SM, eds. Lupus Nephritis. Oxford: Oxford University Press; 1999:219-240.Google Scholar Although the risk of decrease in kidney function is not as great as that with the endocapillary proliferative variants, up to 20% of patients with MLN require dialysis or kidney transplantation within 10 years of diagnosis.34No authors listed. Lupus nephritis: prognostic factors and probability of maintaining life-supporting renal function 10 years after the diagnosis. Gruppo Italiano per lo Studio della Nefrite Lupica (GISNEL).Am J Kidney Dis. 1992; 19: 473-479Google Scholar, 35Appel 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. 1987; 83: 877-885Google Scholar, 36Mercadal L. Montcel S.T. Nochy D. et al.Factors affecting outcome and prognosis in membranous lupus nephropathy.Nephrol Dial Transplant. 2002; 17: 1771-1778Google Scholar Kidney survival is only 50% in patients with MLN at 20 years,36Mercadal L. Montcel S.T. Nochy D. et al.Factors affecting outcome and prognosis in membranous lupus nephropathy.Nephrol Dial Transplant. 2002; 17: 1771-1778Google Scholar but a recent study demonstrated kidney survival > 80% at 15 years.37Moroni G. Quaglini S. Gravellone L. et al.Membranous nephropathy in systemic lupus erythematosus: long-term outcome and prognostic factors of 103 patients.Semin Arthritis Rheum. 2012; 41: 642-651Google Scholar Furthermore, there is a sizable incidence of thromboembolic events in patients with MLN.36Mercadal L. Montcel S.T. Nochy D. et al.Factors affecting outcome and prognosis in membranous lupus nephropathy.Nephrol Dial Transplant. 2002; 17: 1771-1778Google Scholar, 38Pasquali S. Banfi G. Zucchelli A. Moroni G. Ponticelli C. Zucchelli P. Lupus membranous nephropathy: long-term outcome.Clin Nephrol. 1993; 39: 175-182Google Scholar Thrombotic events are associated with antiphospholipid antibodies38Pasquali S. Banfi G. Zucchelli A. Moroni G. Ponticelli C. Zucchelli P. Lupus membranous nephropathy: long-term outcome.Clin Nephrol. 1993; 39: 175-182Google Scholar and nephrotic syndrome.36Mercadal L. Montcel S.T. Nochy D. et al.Factors affecting outcome and prognosis in membranous lupus nephropathy.Nephrol Dial Transplant. 2002; 17: 1771-1778Google Scholar High-dose alternate-day corticosteroid has been used widely as the first-line agent. However, this treatment regimen was derived from studies of idiopathic membranous nephropathy and there is little evidence that it works.39No authors listed. A controlled study of short-term prednisone treatment in adults with membranous nephropathy.N Engl J Med. 1979; 301: 1301-1306Google Scholar Still, that does not mean that daily corticosteroid therapy is not effective. A small (42-patient) randomized controlled trial compared adjunctive immunosuppressive drugs with prednisone alone.40Austin III, H.A. Illei G.G. Braun M.J. Balow J