Idiopathic membranous glomerulonephritis
2001; Elsevier BV; Volume: 59; Issue: 5 Linguagem: Inglês
10.1046/j.1523-1755.2001.0590051983.x
ISSN1523-1755
Autores Tópico(s)Chronic Kidney Disease and Diabetes
ResumoA 49-year-old Portuguese man presented five years ago with a two-day history of shortness of breath. Over the previous two to three months, he had noticed increasing swelling of his ankles, especially after prolonged standing and, for four to five days prior to admission, moderate central abdominal bloating. When directly questioned, he also reported that he had noticed increased frothiness on urination for the previous three months. He denied paroxysmal nocturnal dyspnea and orthopnea. There was no history of fever, skin rash, or arthralgias. His medical history included mild hypertension for five years, controlled by lisinopril, 10 mg/day. He had a 25 pack-year smoking history. He had no known allergies and no family history of renal disease or diabetes. He had been a construction worker until six months prior to admission, but he had had no exposure to chemicals or hydrocarbons. The patient was divorced and had no children. Physical examination revealed a slightly overweight man whose blood pressure was 160/85 mm Hg and whose heart rate was 76 beats/min and regular. His jugular venous pressure was difficult to detect. His chest was clear. Abdominal examination revealed shifting dullness; he had severe edema of both legs and the sacrum. Urinalysis showed 4+ protein and 3+ blood; microscopic analysis disclosed 8 to 10 red blood cells and 3 to 5 granular casts per high-power field. Laboratory examination showed normal hematology, electrolytes, and liver function tests. The serum creatinine was 1.4 mg/dL; corrected creatinine clearance, 70 mL/min; proteinuria, 13.7 g/day; and serum albumin, 1.9 g/dL. All laboratory screenings for secondary causes were negative or normal including complement profile, antinuclear antibody, antineutrophilic cytoplasmic antibodies, hepatitis B and C serology, HIV serology, and serum immunoglobulins. A Doppler ultrasound examination showed normal renal size with patent veins and no other abnormality. A chest radiograph was normal and examination of the stools for occult blood was negative × 3. Serum cholesterol was 425 mg/dL; LDL, 232 mg/dL; and serum triglycerides, 180 mg/dL. Renal biopsy revealed 27 glomeruli; of these, 2 were globally sclerosed and the rest showed diffuse moderate thickening of the glomerular basement membrane (GBM) with minimal mesangial matrix increase and focal mild patchy interstitial edema and tubular atrophy, but no cellular proliferation. Immunofluorescence microscopy revealed 3+ staining for both IgG and C3 in a diffuse granular pattern along the GBM. Results were negative for all other immunoglobulins. Electron microscopy revealed diffuse epithelial cell foot process effacement and numerous, uniformly sized, electron-dense deposits along the GBM in a subepithelial location with projections of the GBM between the deposits. There were no mesangial deposits. The patient initially was treated by his local nephrologist with corticosteroids (prednisone, 2 mg/kg) on alternate days for eight weeks. The proteinuria remained> 10 g/day and the patient remained edematous; he developed cushingoid facies and gastrointestinal distress. The prednisone was tapered and the patient was managed conservatively. After six months of continued angiotensin-converting-enzyme (ACE) inhibitor therapy and dietary protein restriction (0.8 g/kg/day), the patient remained severely nephrotic and symptomatic. He was referred for a second opinion, and three options were explained to him with their inherent risks and benefits: continued conservative treatment, a six-month course of alternating a cytotoxic agent with corticosteroids, or cyclosporine. The patient was concerned about additional steroid effects and about infertility, and he opted for the course of cyclosporine. Cyclosporine was begun at 3 mg/kg/day, with the trough level by monoclonal assay targeted between 150 and 225 ng/mL. The proteinuria gradually declined and his renal function remained stable. After eight months, his proteinuria was <0.2 g/day and his serum creatinine was 1.2 mg/dL; the corrected creatinine clearance was 90 mL/min. The cyclosporine was discontinued after 10 months. His cholesterol profile normalized but his hypertension persisted. The ACE inhibitor continued to provide good blood pressure control, and at his most recent follow-up visit two months ago, the serum creatinine was 1.2 mg/dL; creatinine clearance, 88 mL/min; and urine protein excretion, 0.12 g/day. DR. DANIEL CATTRAN (Associate Director of Nephrology, University Health Network, Professor of Medicine, University of Toronto, Toronto, Ontario, Canada): Membranous glomerulonephropathy (MGN) remains the most common cause of adult-onset nephrotic syndrome in the world1.Haas M. 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 (368) Google Scholar. Its high incidence, despite its overall good prognosis, still makes MGN the second or third most common primary glomerulonephritis in world registries to progress to end-stage renal disease2.US RENAL DATA SYSTEM USRDS 1999 Annual Data Report. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease. Bethesda, 1999Google Scholar,3.Maisonneuve P. Agodoa L. Gellert R. et al.Distribution of primary renal diseases leading to end-stage renal failure in the United States, Europe and Australia/New Zealand: Results from an international comparative study.Am J Kidney Dis. 2000; 35: 157-165Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar. Although in the industrialized countries the most common variant is idiopathic MGN, infectious agents such as malaria in Africa4.Rabenantoandro R. Rakotondrajao R. Rakotondranaivo S. Rasamindrakotroka A.J. Renal glomerular lesions and Plasmodium falciparum infection.Am J Kidney Dis. 1987; 10: 52-55Abstract Full Text PDF Scopus (3) Google Scholar,5.Goldman M. Lambert P.H. Glomerulopathies associated with parasitoses.Nephrologie. 1985; 6: 49-51PubMed Google Scholar and hepatitis B in parts of Asia are more frequent causes6.Kar N.L. Lai F.M. Chan K.W. et al.The clinical pathological features of hepatitis B virus associated glomerulonephritis.Q J Med. 1987; 63: 323-333PubMed Google Scholar. Etiology also varies with age. In Europe and North America, a variety of malignant tumors have been associated with MGN, with increased frequency beyond the fifth decade7.Burstein D.M. Korbet S.M. Schwartz M.M. Membranous glomerulonephritis and malignancy.Am J Kidney Dis. 1993; 22: 5-10Abstract Full Text PDF PubMed Scopus (142) Google Scholar. This patient's ethnicity, site of residence, age, and the negative screening tests for secondary causes strongly support an idiopathic etiology, and I will focus on that variant of MGN in this Forum. The Heymann model of experimental membranous nephropathy in rats, which closely mimics the human disease, suggests that the highly specialized and terminally differentiated glomerular epithelial cell or podocyte is the target of injury8.Kerjaschki D. Neale T.J. Molecular mechanisms of glomerular injury in rat experimental membranous nephropathy (Heymann nephritis).Am J Kidney Dis. 1996; 7: 2518-2525Google Scholar. Research in the experimental model has focused on the identification of the responsible antigen(s) and the subsequent immune response, the role of complement, and the delineation of the injury process following the activation of complement9.Shankland S.J. New insights into pathogenesis of membranous nephropathy.Kidney Int. 2000; 57: 1204-1205Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar. The antigenic targets of the antibody response in the experimental model have been localized to the membrane of the glomerular epithelial cell and are specifically a 515 kD glycoprotein called megalin, a polyspecific receptor related to the low-density lipoprotein receptor family, and an associated 44 kD protein, known as the receptor-associated protein or RAP8.Kerjaschki D. Neale T.J. Molecular mechanisms of glomerular injury in rat experimental membranous nephropathy (Heymann nephritis).Am J Kidney Dis. 1996; 7: 2518-2525Google Scholar. A primary role for the T-cell is clear in this model. A CD4+ T-cell-dependent, humoral response results in glomerular immunoglobulin deposition and complement activation. The CD4+ help for antibody response is a function of the Th2 cell, which produces interleukin (IL) -4, -5, -6, -10, and -13. Early in the course of the disease, both glomerular and interstitial T-cells as well as macrophage infiltrates are found. A role for cell-mediated injury is supported by the observations that depletion of the cytotoxic CD8+ T-cell reduces the injury and that monoclonal anti-CD4 and anti-CD8 treatment modifies the disease10.Penny M.J. Boyd R.A. Hall B.M. Mycophenolate mofetil prevents the induction of active Heymann nephritis: Association with Th2 cytokine inhibition.J Am Soc Nephrol. 1998; 9: 2272-2282PubMed Google Scholar. Complement activation also is important in producing the glomerular injury. The finding of the C5b-9 membrane attack complex (MAC) within the immune deposits and the recognition that depletion of complement by cobra venom serum prevents the subsequent proteinuria confirm the role of complement in the pathogenesis. The podocyte normally retrieves the MAC from the immune deposits by endocytosis, transports them across the cell, and discharges them by exocytosis into the urinary space11.Couser W.G. Schultz M. Pruchno C.J. Role of C5b-9 in experimental membranous nephropathy.Nephrol Dial Transplant. 1992; 1: 25-31Google Scholar. This process might account for the appearance of these fragments in the urine of patients with membranous nephropathy12.Kon S.P. Coupes B. Short C.D. et al.Urinary C5b-9 excretion and clinical course in idiopathic human membranous nephropathy.Kidney Int. 1995; 48: 1953-1958Abstract Full Text PDF PubMed Scopus (46) Google Scholar. How this sublytic injury from the complex produces proteinuria is unclear. The MAC can activate the formation of radical oxygen species in the rat model, and treatment with anti-oxidants significantly reduces the proteinuria without preventing formation of the deposit8.Kerjaschki D. Neale T.J. Molecular mechanisms of glomerular injury in rat experimental membranous nephropathy (Heymann nephritis).Am J Kidney Dis. 1996; 7: 2518-2525Google Scholar. The MAC also can induce production of specific proteinases, such as gelatinase and metalloproteinase-9, and these proteinases might lead to collagen degradation in the glomerular basement membrane (GBM) and subsequently to increased protein permeability. The podocyte response to injury is not a proliferative one, but rather hypertrophy and increased matrix production. Specific isoforms of transforming growth factor beta and their receptors are up-regulated in the model, and this up-regulation might mediate accumulation of the excess matrix in experimental and human disease13.Shankland S.J. Pippin J. Pichler R.H. et al.Differential expression of transforming growth factor-β isoforms and receptors in experimental membranous nephropathy.Kidney Int. 1996; 50: 116-124Abstract Full Text PDF PubMed Scopus (84) Google Scholar. The cellular response to complement attack, rather than a proliferative reaction, occurs through alteration in the expression of specific cell-cycle proteins and results in podocyte hypertrophy, excess matrix formation, and glomerulosclerosis, according to studies by Shankland et al14.Shankland S.J. Floege J. Thomas S.E. et al.Cyclin kinase inhibitors are increased during experimental membranous nephropathy: Potential role in limiting glomerular epithelial cell proliferation in vivo.Kidney Int. 1997; 52: 404-413Abstract Full Text PDF PubMed Scopus (108) Google Scholar. Other authors have suggested that the cell's response to injury is due to activation of specific signal pathways. Cybulsky et al recently have shown that cytoplasmic phospholipase A2 was increased by C5b-9 in glomeruli of rats with Heymann nephritis15.Cybulsky A.V. Takano T. Papillon J. McTavish A.J. Complement-induced phospholipase A2 activation in experimental membranous nephropathy.Kidney Int. 2000; 57: 1052-1062Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar. This increase in turn released more arachidonic acid precursors, which are important in the synthesis of eicosanoids, such as prostaglandins, thromboxanes, and leukotrienes, all substances that have been implicated in GBM injury. Interruption of the phospholipase activation could lead to a new approach to the treatment of the human disease. The molecular pathogenesis of human membranous nephropathy, however, remains largely unknown. Despite the similarities in the pathology and the elegant dissection of the molecular basis of the injury in the experimental model, parallel findings in the human disease remain elusive. Neither the antigenic equivalent to megalin nor the beneficial effects of the various experimental therapeutic agents have been duplicated in humans. The difficulty in extrapolating information from the experimental model to human disease suggests that certain variables in the human host are important. The exploration of genetic factors that influence susceptibility and/or progression are preliminary, but studies have shown a higher-than-expected association with the HLA-DR2 allele in the Japanese population16.Hiki Y. Kobayashi Y. Itoh I. Kashiwagi N. Strong association of HLA-DR2 and MT1 with idiopathic membranous nephropathy in Japan.Kidney Int. 1984; 25: 953-967Abstract Full Text PDF PubMed Scopus (37) Google Scholar and the literature contains descriptions of a few cases in identical twins17.Guella A. Akhtar M. Ronco P. Idiopathic membranous nephropathy in identical twins.Am J Kidney Dis. 1997; 29: 115-118Abstract Full Text PDF PubMed Scopus (10) Google Scholar. A recent study using molecular techniques in a cohort of patients with idiopathic MGN from England and Greece extended an earlier HLA serologic association with DR318.Vaughan R.W. Tighe M.R. Boki K. et al.An analysis of HLA class II gene polymorphism in British and Greek idiopathic membranous nephropathy patients.Eur J Immunogenet. 1995; 22: 179-186Crossref PubMed Scopus (20) Google Scholar. A particular variation in the gene polymorphism of the DR locus, DRB1*0301, was associated with the disease. No relationship was apparent amongst any of the tested genotypes with severity or progression of the process, but the numbers of patients were small and the observation period limited. The relationship of genetic factors to human idiopathic MGN is still preliminary, but given the variability in its natural history, it is highly likely that susceptibility factors and factors associated with progression will be found. The natural history of idiopathic MGN has been documented in several studies and must be integrated into any management plan. Although a wide variation in outcome has been reported, a review of 11 reports of the natural history of the disease demonstrated a 10-year renal survival within the relatively tight band of 70% to 90%19.Cattran D.C. Pei Y. Greenwood C. Predicting progression in membranous glomerulonephritis.Nephrol Dial Transplant. 1992; 7: 48-52PubMed Google Scholar. A more current pooled analysis of 32 studies estimated survival between 65% and 75% at 10 years and 60% at 15 years Figure 120.Hogan S.L. Muller K.E. Jennette J.C. Falk R.J. A review of therapeutic studies of idiopathic membranous glomerulopathy.Am J Kidney Dis. 1995; 25: 862-875Abstract Full Text PDF PubMed Scopus (156) Google Scholar. Some of even this small scatter is probably the result of variations in diagnostic criteria, choices of end point, baseline characteristics, and statistical techniques21.Marx B.E. Marx M. Prognosis of idiopathic membranous nephropathy: A methodologic meta-analysis.Kidney Int. 1997; 51: 873-879Abstract Full Text PDF PubMed Scopus (35) Google Scholar. This relatively good prognosis is likely an underestimate of today's outcome, given the introduction within the last decade of more potent antihypertensive medications and lowered ideal levels for both systolic and diastolic blood pressure. Gender seems to influence progression. Support for this can be gleaned by looking at gender ratio at presentation versus at end stage. In France the incidence of idiopathic MGN is between 1.2 and 1.7 per 100,000 population, with an age peak between 60 and 79 years. In all age groups, the gender ratio was almost equal22.Simon P. Ramee M.P. Autuly V. et al.Epidemiology of primary glomerular diseases in a French region: Variations according to period and age.Kidney Int. 1994; 46: 1192-1198Abstract Full Text PDF PubMed Scopus (157) Google Scholar. In Japan and elsewhere, a similar gender distribution exists at the start of the process23.Abe S. Amagasaki S.Y. Kato E. et al.Idiopathic membranous glomerulonephritis: Aspects of geographical differences.J Clin Pathol. 1986; 39: 1193-1198Crossref PubMed Scopus (48) Google Scholar,24.Harrison D.J. Thomson D. Macdonald M.K. Membranous glomerulonephritis.J Clin Pathol. 1986; 39: 167-171Crossref PubMed Scopus (34) Google Scholar. However, studies have consistently found that the ratio at end-stage renal disease has shifted to 2 to 3:1 male:female2.US RENAL DATA SYSTEM USRDS 1999 Annual Data Report. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease. Bethesda, 1999Google Scholar,3.Maisonneuve P. Agodoa L. Gellert R. et al.Distribution of primary renal diseases leading to end-stage renal failure in the United States, Europe and Australia/New Zealand: Results from an international comparative study.Am J Kidney Dis. 2000; 35: 157-165Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar. These data indicate that gender strongly influences the severity of the disease. Moreover, the only two factors associated with spontaneous remission are persistent low-grade (subnephrotic) proteinuria and female gender25.Laluck Jr, B.J. Cattran D.C. Prognosis after a complete remission in adult patients with idiopathic membranous nephropathy.Am J Kidney Dis. 1999; 33: 1026-1032Abstract Full Text Full Text PDF PubMed Google Scholar. The relapse rate from complete remission is also high, varying between 30% and 50%, but prognosis for these patients remains excellent, with urinary protein excretion in the great majority remaining subnephrotic and only 5% progressing to chronic renal insufficiency25.Laluck Jr, B.J. Cattran D.C. Prognosis after a complete remission in adult patients with idiopathic membranous nephropathy.Am J Kidney Dis. 1999; 33: 1026-1032Abstract Full Text Full Text PDF PubMed Google Scholar,26.Ponticelli C. Passerini P. Altieri P. et al.Remissions and relapses in idiopathic membranous nephropathy.Nephrol Dial Transplant. 1992; 7: 85-90PubMed Google Scholar. Overall, approximately 30% of patients undergo spontaneous remission (vide supra); about 30% progress to renal failure, 30% have variable degrees of proteinuria but stable function for many years, and about 10% die of nonrenal causes27.Honkanen E. Tornroth T. Gronhagen-Riska C. Natural history, clinical course and morphological evolution of membranous nephropathy.Nephrol Dial Transplant. 1992; 7: 35-41PubMed Google Scholar,28.Donadio Jr, J.V. Torres V.E. Velosa J.A. et al.Idiopathic membranous nephropathy: The natural history of untreated patients.Kidney Int. 1988; 33: 708-715Abstract Full Text PDF PubMed Scopus (215) Google Scholar. Other factors at presentation that have been associated with a poor prognosis include male gender, older age, high levels of proteinuria, and abnormal renal function; histologic factors include tubular interstitial changes and degree of glomerulosclerosis29.Tu W.H. Petitti D.B. Biava C.G. et al.Membranous nephropathy: Predictors of terminal renal failure.Nephron. 1984; 36: 118-124Crossref PubMed Scopus (65) Google Scholar, 30.Davison A.M. Cameron J.S. Kerr D.N. et al.The natural history of renal function in untreated idiopathic membranous glomerulonephritis in adults.Clin Nephrol. 1984; 22: 61-67PubMed Google Scholar, 31.Zucchelli P. Ponticelli C. Cagnoli L. Passerini P. Long-term outcome of idiopathic membranous nephropathy with nephrotic syndrome.Nephrol Dial Transplant. 1987; 2: 73-78PubMed Google Scholar, 32.Murphy B.F. Fairley K.F. Kincaid-Smith P.S. Idiopathic membranous glomerulonephritis: Long-term follow-up in 139 cases.Clin Nephrol. 1988; 30: 175-181PubMed Google Scholar, 33.Schieppati 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 (319) Google Scholar, 34.Magil A.B. Tubulointerstitial lesions in human membranous glomerulonephritis: Relationship to proteinuria.Am J Kidney Dis. 1995; 25: 375-379Abstract Full Text PDF PubMed Scopus (41) Google Scholar. The problem in associating these factors with prognosis, however, is their qualitative nature and poor specificity. An alternate approach based on dynamic changes in renal function does produce a semiquantitative risk of progression35.Pei Y. Cattran D. Greenwood C. Predicting chronic renal insufficiency in idiopathic membranous glomerulonephritis.Kidney Int. 1992; 42: 960-966Abstract Full Text PDF PubMed Scopus (152) Google Scholar,36.Cattran D.C. Pei Y. Greenwood C.M. et al.Validation of a predictive model of idiopathic membranous nephropathy: Its clinical and research implications.Kidney Int. 1997; 51: 901-907Abstract Full Text PDF PubMed Scopus (183) Google Scholar. It uses the clinical parameters of proteinuria and creatinine clearance estimates over fixed periods of time. In its simplest form, this approach demonstrated that the overall accuracy of predicting progression to chronic renal failure when proteinuria values over a 6-month period were persistently greater than 4 g/day was 71%, ≥6 g/day was 79%, and ≥8 g/day was 84% Table 1. If the patient's renal function was impaired at the beginning of these time frames and/or significantly deteriorated over the 6 months of observation, accuracy was even higher and sensitivity was substantially greater, as demonstrated by the percentage value under the R value in Table 1. The advantages of the algorithm are its reliance on very few factors, all of which are standard laboratory measurements of renal function, and its dynamic nature, which allows recalculating the risk of progression over the course of the patient's disease. Age, gender, degree of sclerosis on biopsy, and presence of hypertension are important factors in univariate analyses but are not independent of the factors in the model and hence do not add to the predictive value of the algorithm.Table 1Test characteristics (%) of predicting chronic renal insufficiency in Canadian patientsSix-month minimum persistent proteinuriaProteinuria ≥3.5 g/day at time of biopsy4 g/day6 g/day8 g/dayFull model (R≥0.3)Sensitivity9381645883Specificity3867859386Positive predictive value3446597567Negative predictive value9491878794Accuracy5271798485Data from Reference 36. Open table in a new tab Data from Reference 36. The effects of idiopathic MGN on nonrenal- and renal-related morbidity and mortality are more difficult to determine from the literature. Reviews from Finland and the United States show that a similar high proportion of deaths, between 30% and 60%, are nonrenal-related25.Laluck Jr, B.J. Cattran D.C. Prognosis after a complete remission in adult patients with idiopathic membranous nephropathy.Am J Kidney Dis. 1999; 33: 1026-1032Abstract Full Text Full Text PDF PubMed Google Scholar,28.Donadio Jr, J.V. Torres V.E. Velosa J.A. et al.Idiopathic membranous nephropathy: The natural history of untreated patients.Kidney Int. 1988; 33: 708-715Abstract Full Text PDF PubMed Scopus (215) Google Scholar. Whether their cause is due to comorbid conditions, the effects of the disease, or the treatment is difficult to discern. But details from the reports reveal that most of the deaths are premature (mean age 51) and due either to cardiovascular disease or to cancer37.Honkanen E. Survival in idiopathic membranous glomerulonephritis.Clin Nephrol. 1986; 25: 122-128PubMed Google Scholar. I think it will be useful if we consider therapeutics in four categories. The first, specific immunosuppressive therapy, is aimed at modulating the immune component of the disease. The second, nonspecific therapy, focuses on reducing proteinuria and secondarily slowing disease progression. The third comprises treatment of the secondary effects of the disease, and the fourth is treatment aimed at reducing the complications of the immune-modulating drugs. The observations on the natural history of idiopathic MGN and our ability to predict outcome should perhaps be the background upon which current immunosuppressive protocols are assessed. One approach would be to first establish risk of progression using the results of our algorithm. We could examine the six-month period around the entry point of the major studies, segregate the patients into risk categories, and then discuss the trial results in the context of prognostic grouping. Although somewhat imprecise given the lack of details provided in the reports, this approach would allow us to assess specific therapies from the point of view of risk as well as benefit, the overriding concern both of patients and physicians when considering treatment options. Let us define the categories for risk of progression. Low-risk patients have normal serum creatinine and creatinine clearance values and a peak proteinuria <4 g/day over 6 months of observation. Medium-risk patients have normal or nearly normal serum creatinine and creatinine clearance values and proteinuria ≥4 g/day but <8 g/day over 6 months of observation. Finally, high-risk patients have either abnormal or deteriorating serum creatinine and creatinine clearance values and/or persistent proteinuria ≥8 g/day over 6 months of observation. The long-term prognosis for low-risk patients is excellent. Our validation study examined more than 300 patients from three distinct geographic regions who were followed for more than 5 years. We found that only 5% of patients with these criteria went on to develop chronic renal insufficiency36.Cattran D.C. Pei Y. Greenwood C.M. et al.Validation of a predictive model of idiopathic membranous nephropathy: Its clinical and research implications.Kidney Int. 1997; 51: 901-907Abstract Full Text PDF PubMed Scopus (183) Google Scholar. Blood pressure control and strategies for reduction of urinary protein excretion should be implemented through the use of agents such as the angiotensin-converting-enzyme inhibitors. Immunosuppressive drugs are not recommended and, in the majority of cases, treatment of the secondary effects of the disease is not necessary. Because a small percentage of patients do progress, monitoring of their renal function, proteinuria, and blood pressure should be continued and assessment of their risk of progression periodically recalculated. As one would expect, the individuals classified as medium-risk patients did not fare as well as did the low-risk patients. The entry criteria for patients in the two randomized trials that studied the effects of corticosteroid therapy alone in idiopathic MGN would place these patients in the medium risk category38.A controlled study of short-term prednisone treatment in adults with membranous nephropathy Collaborative Study of the Adult Idiopathic Nephrotic Syndrome.N Engl J Med. 1979; 301: 1301-1306Crossref PubMed Scopus (228) Google Scholar,39.Cattran D.C. Delmore T. Roscoe J. et al.A randomized controlled trial of prednisone in patients with idiopathic membranous nephropathy.N Engl J Med. 1989; 320: 210-215Crossref PubMed Scopus (202) Google Scholar. Prednisone alone was ineffective in inducing and sustaining a reduction in proteinuria in these trials. The follow-up periods were less than four years, and the dose and duration varied, but the evidence does not support the use of corticosteroids as a single agent in the management of MGN patients in this risk category. Ponticelli and coworkers in Italy have found benefit when corticosteroids are combined with a cytotoxic agent. They observed a significant increase both in remissions in proteinuria and renal survival40.Ponticelli C. Zucchelli P. Imbasciati E. et al.Controlled trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy.N Engl J Med. 1984; 310: 946-950Crossref PubMed Scopus (193) Google Scholar,41.Ponticelli C. Zucchelli 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: 1600-1604Abstract Full Text PDF PubMed Scopus (313) Google Scholar. Therapy given for six months consisted of 1 g of intravenous methylprednisolone on the first 3 days of months 1, 3, and 5, followed by 27 days of oral methylprednisolone (0.5 mg/kg/day) alternating in months 2, 4, and 6 with chlorambucil (0.2 mg/kg/day). After 10 years of follow-up, 8% of treated patients versus 40% of untreated patients had reached end-stage renal disease (P = 0.004). Of the treated group, 43% of the time versus 78% of the placebo group's time was spent in a nephrotic state (P = 0.0001). In a second trial, these authors used the same 6-month routine but substituted cyclophosphamide for chlorambucil and found a benefit similar to that in their first trial42.Ponticelli C. Altieri P. Scolari F. et al.A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy.J Am Soc Nephrol. 1998; 9: 444-450PubMed Google Schola
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