Idiopathic Membranous Nephropathy: Outline and Rationale of a Treatment Strategy
2005; Elsevier BV; Volume: 46; Issue: 6 Linguagem: Inglês
10.1053/j.ajkd.2005.08.020
ISSN1523-6838
AutoresPeggy W G du Buf-Vereijken, A. J. W. Branten, Jack F.M. Wetzels,
Tópico(s)Pregnancy and Medication Impact
ResumoIdiopathic membranous nephropathy is a common cause of nephrotic syndrome. The treatment of patients with idiopathic membranous nephropathy is heavily debated. Based on literature data and our own experience, we propose a rational treatment strategy. Patients with renal insufficiency (serum creatinine level > 1.5 mg/dL [>135 μmol/L]) are at greatest risk for the development of end-stage renal disease and should receive immunosuppressive therapy. In patients with normal renal function (serum creatinine level < 1.5 mg/dL [ 1.5 mg/dL [>135 μmol/L]) are at greatest risk for the development of end-stage renal disease and should receive immunosuppressive therapy. In patients with normal renal function (serum creatinine level < 1.5 mg/dL [<135 μmol/L]), risk for developing end-stage renal disease can be estimated by measuring urinary excretion of β2-microglobulin or α1-microglobulin and immunoglobulin G. For low-risk patients, a wait-and-see policy is advised. High-risk patients likely benefit from immunosuppressive therapy. Currently, combinations of steroids with chlorambucil or cyclophosphamide are the best studied. We prefer cyclophosphamide in view of its fewer side effects. Cyclosporine may be an alternative option in patients with well-preserved renal function, although long-term data are lacking. Other immunosuppressive agents, such as mycophenolate mofetil or rituximab, currently are under study; however, data are insufficient to support their routine use. IDIOPATHIC MEMBRANOUS nephropathy (IMN) is one of the most common causes of nephrotic syndrome in adult patients.1Haas M. Meehan S.M. Karrison T.G. Spargo B.H. Changing etiologies of unexplained adult nephrotic syndrome A comparison of renal biopsy findings from 1976-1979 and 1995-1997.Am J Kidney Dis. 1997; 30: 621-631Abstract Full Text PDF PubMed Scopus (412) Google Scholar The natural history varies from a spontaneous complete remission of proteinuria to rapid progression to end-stage renal disease (ESRD). The treatment of patients with IMN has been a regular theme for debate. Opinions of various investigators are as diverse as reported data on the natural history. Some emphasize the high rate of spontaneous remissions and argue against the use of immunosuppressive drugs,2Schieppati A. Mosconi L. Perna A. et al.Prognosis of untreated patients with idiopathic membranous nephropathy.N Engl J Med. 1993; 329: 85-89Crossref PubMed Scopus (362) Google Scholar whereas others point to the high rate of ESRD and favor immunosuppressive therapy.3Ponticelli C. Zuchelli P. Passerini P. et al.A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy.Kidney Int. 1995; 48: 1600-1604Crossref PubMed Scopus (351) Google Scholar The titles of editorial reviews written during the past 25 years clearly reflect the uncertainty in this field, from Cameron’s4Cameron J.S. Membranous nephropathy The treatment dilemma.Am J Kidney Dis. 1982; 1: 371-375Abstract Full Text PDF PubMed Scopus (18) Google Scholar “Membranous Nephropathy: The Treatment Dilemma” in 1982 and “Membranous Nephropathy—Still a Treatment Dilemma”5Cameron J.S. Membranous nephropathy—Still a treatment dilemma.N Engl J Med. 1992; 327: 638-639Crossref PubMed Scopus (31) Google Scholar in 1992 to Glassock’s6Glassock R.J. The treatment of idiopathic membranous nephropathy A dilemma or a conundrum?.Am J Kidney Dis. 2004; 44: 562-566PubMed Scopus (52) Google Scholar “The Treatment of Idiopathic Membranous Nephropathy: A Dilemma or a Conundrum” in 2004. In the current era of evidence-based medicine, some might argue that the discussion can end with the publication of a recent meta-analysis on immunosuppressive therapy for patients with IMN.7Perna A. Schieppati A. Zamora J. Giuliano G.A. Braun N. Remuzzi G. Immunosuppressive treatment for idiopathic membranous nephropathy A systematic review.Am J Kidney Dis. 2004; 44: 385-401PubMed Scopus (113) Google Scholar Based on data derived from 18 randomized controlled trials (RCTs) including more than 1,000 patients, the investigators concluded that immunosuppressive treatment had no benefit in terms of patient and/or renal survival. There was weak evidence in favor of regimens containing alkylating agents in inducing complete remission of proteinuria; however, only when considering patients with relatively well-preserved renal function. Because the use of immunosuppressive therapy in especially this latter group of patients is most questionable, this finding also seems to argue against the use of immunosuppressive therapy. However, conclusions of the meta-analysis are debatable and must not lead to therapeutic nihilism. Specifically, the meta-analysis included RCTs of limited size and quality. Conclusions based on a systematic review, which includes many trials of limited quality, are not necessarily better than conclusions based on results of 1 large, carefully conducted RCT. Furthermore, in view of the limited number of large high-quality RCTs, we must not neglect important and relevant information that can be obtained from carefully conducted observational studies.8du Buf-Vereijken P.W.G. Branten A.J.W. Wetzels J.F.M. Membranous Nephropathy Study GroupCytotoxic therapy for membranous nephropathy and renal insufficiency; Improved renal survival but high relapse rate.Nephrol Dial Transplant. 2004; 19: 1142-1148Crossref PubMed Scopus (85) Google Scholar, 9Torres A. Dominguez-Gil B. Carreno A. et al.Conservative versus immunosuppressive treatment of patients with idiopathic membranous nephropathy.Kidney Int. 2002; 61: 219-227Crossref PubMed Scopus (87) Google Scholar During the past 2 decades, we have systematically studied patients with IMN; our database now includes 279 patients.8du Buf-Vereijken P.W.G. Branten A.J.W. Wetzels J.F.M. Membranous Nephropathy Study GroupCytotoxic therapy for membranous nephropathy and renal insufficiency; Improved renal survival but high relapse rate.Nephrol Dial Transplant. 2004; 19: 1142-1148Crossref PubMed Scopus (85) Google Scholar, 10Reichert L.J.M. Huysmans F. ThM. Assmann K. Koene R.A.P. Wetzels J.F.M. Preserving renal function in patients with membranous nephropathy Daily oral chlorambucil compared with intermittent monthly pulses of cyclophosphamide.Ann Intern Med. 1994; 121: 328-333Crossref PubMed Scopus (71) Google Scholar, 11Reichert L.J.M. Koene R.A.P. Wetzels J.F.M. Urinary excretion of β2-microglobulin predicts renal outcome in patients with idiopathic membranous nephropathy.J Am Soc Nephrol. 1995; 6: 1666-1669PubMed Google Scholar, 12Reichert L.J.M. Koene R.A.P. Wetzels J.F.M. Urinary IgG excretion as a prognostic factor in idiopathic membranous nephropathy.Clin Nephrol. 1997; 48: 79-84PubMed Google Scholar, 13Wetzels J.F.M. Reichert L.J.M. Efficacy of immunosuppressive treatment in patients with membranous nephropathy and renal insufficiency.Kidney Int Suppl. 1997; 61: S63-S66PubMed Google Scholar, 14Branten A.J.W. Reichert L.J.M. Koene R.A.P. Wetzels J.F.M. Oral cyclophosphamide versus chlorambucil in the treatment of patients with idiopathic membranous nephropathy and renal insufficiency.Q J Med. 1998; 91: 359-366Crossref Scopus (85) Google Scholar, 15Branten A.J.W. Wetzels J.F.M. Short- and long-term efficacy of oral cyclophosphamide and steroids in patients with membranous nephropathy and renal insufficiency.Clin Nephrol. 2001; 56: 1-8PubMed Google Scholar, 16du Buf-Vereijken P.W.G. Feith G.W. Hollander D. et al.Restrictive use of immunosuppressive treatment in patients with idiopathic membranous nephropathy High renal survival in a large patient cohort.Q J Med. 2004; 97: 353-360Crossref Scopus (28) Google Scholar, 17du Buf-Vereijken P.W.G. Wetzels J.F.M. Efficacy of a second course of immunosuppressive therapy in patients with membranous nephropathy and persistent or relapsing disease activity.Nephrol Dial Transplant. 2004; 19: 2036-2043Crossref PubMed Scopus (16) Google Scholar, 18Branten A.J.W. du Buf-Vereijken P.W.G. Klasen I.S. et al.Urinary excretion of β2-microglobulin and IgG predict prognosis in idiopathic membranous nephropathy A validation study.J Am Soc Nephrol. 2005; 16: 169-174Crossref PubMed Scopus (123) Google Scholar These studies have enabled us to define risk factors and develop a treatment strategy tailored to the individual patient. Our treatment strategy is shown in Fig 1. In this review, we discuss treatment modalities for patients with IMN and provide arguments based on the literature data and our experience in favor of our strategy. We specifically address the following questions: (1) Has the natural history of IMN changed during the past decades? (2) Is immunosuppressive therapy of proven benefit in patients with IMN when considering hard end points? (3) Should all patients with IMN and nephrotic syndrome be treated with immunosuppressive therapy? (4) Are all immunosuppressive agents equally effective? (5) Which parameters can be used to identify patients at risk for progressive renal insufficiency? A detailed discussion of supportive (nonimmunosuppressive) treatment of patients with membranous nephropathy is beyond the scope of this review. However, it is evident that proteinuric patients should be administered antihypertensive drugs, aiming at target blood pressures of 125/75 mm Hg. Because of their additional antiproteinuric effects, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor antagonists (ARBs) are the preferred agents, although there is no evidence that these agents have changed the natural history of IMN (vide infra). A sodium-restricted diet and diuretics are needed to limit edema formation and enhance the antiproteinuric effects of ACE inhibitors. Hypercholesterolemia is often present in patients with nephrotic syndrome and should be treated according to established guidelines. There is debate over the use of prophylactic anticoagulation. Patients with IMN and nephrotic syndrome are at increased risk for thromboembolic complications. Using a decision-analysis model, Sarasin and Schifferli19Sarasin F.P. Schifferli J.A. Prophylactic oral anticoagulation in nephrotic patients with idiopathic membranous nephropathy.Kidney Int. 1994; 45: 578-585Crossref PubMed Scopus (97) Google Scholar showed that prophylactic anticoagulation increased quality-adjusted life expectancy. We advise oral anticoagulant drugs in patients with a serum albumin level less than 2 g/dL (<20 g/L) or patients who are immobilized. Notably, we are unaware of studies that documented beneficial effects of anticoagulant treatment on the long-term course of renal function in patients with IMN. It is important to define the natural history of IMN. Most probably agree that the overall prognosis determines whether one would ever consider the (early) use of aggressive therapy. In this respect, descriptions of the natural history of IMN are divergent and thus have laid the ground for heavy disputes on the use of immunosuppressive therapy. Schieppati et al2Schieppati A. Mosconi L. Perna A. et al.Prognosis of untreated patients with idiopathic membranous nephropathy.N Engl J Med. 1993; 329: 85-89Crossref PubMed Scopus (362) Google Scholar pointed to the relatively benign course of IMN in untreated patients; 65% of patients followed up for more than 5 years developed spontaneous remission of proteinuria and had an estimated renal survival rate of 88% at 5 years. Conversely, Ponticelli et al3Ponticelli C. Zuchelli P. Passerini P. et al.A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy.Kidney Int. 1995; 48: 1600-1604Crossref PubMed Scopus (351) Google Scholar stressed the poor outcome, observing permanent remission in only 33% of untreated patients followed up for more than 10 years and a renal survival rate of 60% at 10 years. It is no surprise that the first investigators claim that symptomatic treatment is still the best option for patients with IMN, whereas the latter argue that all patients with IMN and nephrotic syndrome should receive immunosuppressive therapy. The short-term outcome ( 1.3Not available73354Not availableNot available3114Cameron et al35Cameron J.S. Healy M.J.R. Adu D. The Medical Research Council trial of short-term high-dose alternate day prednisolone in idiopathic membranous nephropathy with nephrotic syndrome in adults.Q J Med. 1990; 74: 133-156PubMed Google Scholar19905143/81.3 ± 0.4910.4 ± 5.310004.3145229Durin et al36Durin S. Barbanel C. Landais P. Noel L.H. Grunfeld J.P. Long term course of idiopathic extramembranous glomerulonephritis. Study of predictive factors of terminal renal insufficiency in 82 untreated patients.Nephrologie. 1990; 11: 67-71PubMed Google Scholar19908248/349/82 >1.5Not available6808.5393820Schieppati et al2Schieppati A. Mosconi L. Perna A. et al.Prognosis of untreated patients with idiopathic membranous nephropathy.N Engl J Med. 1993; 329: 85-89Crossref PubMed Scopus (362) Google Scholar199310068/321.1 ± 0.55.1 ± 3.66303.322443214Ponticelli et al3Ponticelli C. Zuchelli P. Passerini P. et al.A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy.Kidney Int. 1995; 48: 1600-1604Crossref PubMed Scopus (351) Google Scholar19953929/101.05 ± 0.295.3 ± 2.81000>105284725NOTE. To convert serum creatinine in mg/dL to μmol/L, multiply by 88.4. Durin et al36Durin S. Barbanel C. Landais P. Noel L.H. Grunfeld J.P. Long term course of idiopathic extramembranous glomerulonephritis. Study of predictive factors of terminal renal insufficiency in 82 untreated patients.Nephrologie. 1990; 11: 67-71PubMed Google Scholar provided long-term outcome of a patient cohort originally described by Noel et al37Noel L.H. Zanetti M. Droz D. Long-term prognosis of idiopathic membranous glomerulonephritis.Am J Med. 1979; 66: 82-90Abstract Full Text PDF PubMed Scopus (201) Google Scholar in 1979. Remission at 3 years of follow-up. Open table in a new tab Table 2Calculated Outcomes in Patients With IMN and Nephrotic SyndromeReferencePublication YearNo. of PatientsNephrotic (%)Treated (%)Follow-Up (y)Corrected Renal Function Deterioration (%)Corrected Renal Survival (%/y)Davison et al29Davison A.M. Cameron J.S. Kerr D.N. Ogg C.S. Wilkinson R.W. The natural history of renal function in untreated idiopathic membranous glomerulonephritis in adults.Clin Nephrol. 1984; 22: 61-67PubMed Google Scholar198464810762Not availableMacTier et al30MacTier R. Boulton Jones J.M. Payton C.D. McLay A. The natural history of membranous nephropathy in the west of Scotland.Q J Med. 1986; 60: 793-802PubMed Google Scholar1986379305.34446Zuchelli et al31Zuchelli P. Ponticelli C. Gagnoli P. Passerini P. Long-term outcome of idiopathic membranous nephropathy with nephrotic syndrome.Nephrol Dial Transplant. 1987; 2: 73-78PubMed Google Scholar19874910009.54552/10Donadio et al32Donadio J.J.V. Torres V.E. Velosa J.A. et al.Idiopathic membranous nephropathy The natural history of untreated patients.Kidney Int. 1988; 33: 708-715Crossref PubMed Scopus (226) Google Scholar1988898306.13949/10Cattran et al33Cattran D.C. Delmore T. Roscoe J. et al.Toronto Glomerulonephritis Study GroupA randomized controlled trial of prednisone in patients with idiopathic membranous nephropathy.N Engl J Med. 1989; 320: 210-215Crossref PubMed Scopus (222) Google Scholar19897773043488/8⁎The projected 8-year renal survival is not reliable because 22% of patients were lost to follow-up and median follow-up was only 4 years.Wehrmann et al34Wehrmann M. Bohle A. Bogenschutz O. et al.Long-term prognosis of chronic idiopathic membranous glomerulonephritis. An analysis of 334 cases with particular regard to tubulo-interstitial changes.Clin Nephrol. 1989; 31: 67-76PubMed Google Scholar1989334733544259/4Cameron et al35Cameron J.S. Healy M.J.R. Adu D. The Medical Research Council trial of short-term high-dose alternate day prednisolone in idiopathic membranous nephropathy with nephrotic syndrome in adults.Q J Med. 1990; 74: 133-156PubMed Google Scholar19905110004.352Not availableDurin et al36Durin S. Barbanel C. Landais P. Noel L.H. Grunfeld J.P. Long term course of idiopathic extramembranous glomerulonephritis. Study of predictive factors of terminal renal insufficiency in 82 untreated patients.Nephrologie. 1990; 11: 67-71PubMed Google Scholar19908268085663/10Schieppati et al2Schieppati A. Mosconi L. Perna A. et al.Prognosis of untreated patients with idiopathic membranous nephropathy.N Engl J Med. 1993; 329: 85-89Crossref PubMed Scopus (362) Google Scholar19931006303.35157/8Ponticelli et al3Ponticelli C. Zuchelli P. Passerini P. et al.A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy.Kidney Int. 1995; 48: 1600-1604Crossref PubMed Scopus (351) Google Scholar1995391000>104760/10NOTE. We calculated percentage of renal function deterioration and renal survival after correction for percentage of patients without nephrotic syndrome, assuming 100% survival in nonnephrotic patients. Correction factor = 100/(% nephrotic patients). For this analysis, we excluded studies with a follow-up less than 3 years.28Collaborative Study of the Adult Idiopathic Nephrotic SyndromeA controlled study of short-term prednisone treatment in adults with membranous nephropathy.N Engl J Med. 1979; 301: 1301-1306Crossref PubMed Scopus (250) Google Scholar The projected 8-year renal survival is not reliable because 22% of patients were lost to follow-up and median follow-up was only 4 years. Open table in a new tab NOTE. To convert serum creatinine in mg/dL to μmol/L, multiply by 88.4. Durin et al36Durin S. Barbanel C. Landais P. Noel L.H. Grunfeld J.P. Long term course of idiopathic extramembranous glomerulonephritis. Study of predictive factors of terminal renal insufficiency in 82 untreated patients.Nephrologie. 1990; 11: 67-71PubMed Google Scholar provided long-term outcome of a patient cohort originally described by Noel et al37Noel L.H. Zanetti M. Droz D. Long-term prognosis of idiopathic membranous glomerulonephritis.Am J Med. 1979; 66: 82-90Abstract Full Text PDF PubMed Scopus (201) Google Scholar in 1979. NOTE. We calculated percentage of renal function deterioration and renal survival after correction for percentage of patients without nephrotic syndrome, assuming 100% survival in nonnephrotic patients. Correction factor = 100/(% nephrotic patients). For this analysis, we excluded studies with a follow-up less than 3 years.28Collaborative Study of the Adult Idiopathic Nephrotic SyndromeA controlled study of short-term prednisone treatment in adults with membranous nephropathy.N Engl J Med. 1979; 301: 1301-1306Crossref PubMed Scopus (250) Google Scholar Obviously, conservative treatment of patients with proteinuria has changed dramatically in the past decade. Nowadays, all patients with proteinuria are treated with ACE inhibitors or ARBs. These agents decrease proteinuria and attenuate the deterioration in renal function in patients with diabetic and nondiabetic proteinuric renal diseases.41Lewi
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