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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2000  |  Volume : 11  |  Issue : 3  |  Page : 345-352
Treatment of Membranous Nephropathy


Division of Nephrology and Dialysis, IRCCS, Ospedale Maggiore, Milano, Italy

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Keywords: Membranous nephropathy, Nephrotic syndrome, Steroids, Cytotoxic agents, Cyclosporine A.

How to cite this article:
Passerini P, Ponticelli C. Treatment of Membranous Nephropathy . Saudi J Kidney Dis Transpl 2000;11:345-52

How to cite this URL:
Passerini P, Ponticelli C. Treatment of Membranous Nephropathy . Saudi J Kidney Dis Transpl [serial online] 2000 [cited 2019 May 21];11:345-52. Available from: http://www.sjkdt.org/text.asp?2000/11/3/345/36656

   Introduction Top


Idiopathic membranous nephropathy (IMN) is a glomerular disease, which occurs worldwide and usually develops in the adult age. In 70% of patients, IMN is associated with the nephrotic syndrome (NS). Those patients who maintain non-nephrotic proteinuria usually have an excellent prognosis even in the long-term. The natural outcome of nephrotic patients may be variable, with some patients maintaining a normal renal function and also achieving spontaneous remission of proteinuria, while others progress to terminal renal failure or die from complications related to the NS. The proportions of these different outcomes are difficult to estimate. As a matter of fact, there are probably racial and geographical differences and also the criteria of selection of patients in the studies devoted to IMN have been variable. By limiting our analysis to a selected group of adult patients with IMN and NS who never received any specific treatment, we found that 50% of patients either died or progressed to end貞tage renal failure within 6-14 years from clinical onset. [1]

Apart from renal function deterioration, IMN may expose nephrotic patients to the clinical consequences of the NS. It has been estimated that in American adults with prolonged NS from whatever cause, the risk of death and coronary heart disease is increased respectively 11 and 4.3 times in comparison to age and sex matched controls. [2] Moreover, patients with IMN are particularly exposed to thrombotic events. MacTier et al [3] found 14 arterial occlusive complications and 11 episodes of venous thrombosis in 37 untreated patients with IMN followed for a mean period of 64 months. Bellomo and Atkins [4] calculated an overall incidence of 29% renal vein thrombosis, 17% pulmonary embolism and 11% deep venous thrombosis in nephrotic patients with IMN. Therefore, although some patients may have a spontaneous favorable course, IMN cannot be considered as a benign disease.

Therapy of membranous nephropathy

The possibility that any form of specific therapy can alter the natural course of IMN is still debated among nephrologists. Glucocorticoids and immunosuppressive agents have been largely used in IMN with different results. More recently cyclosporine has also been tried, but the experience with this agent is still preliminary.

Assessing the results of a therapy from uncontrolled studies is very difficult in a disease with a variable outcome such as IMN. Moreover, the criteria for treatment, the types and the duration of treatment, and the characteristics of patients considered were extremely variable in the different studies. Thus, the possible role for any therapeutic trial should be mainly evaluated on the basis of the results of controlled trials. In this paper we will review the main therapeutic approaches tried in IMN, focusing mainly on the results of the controlled trials.

Corticosteroids

Four prospective controlled trials with corticosteroids have been published. In these studies prednisone was administered according to two different therapeutical schedules (a) low-dose prednisone for six months, (b) high-dose prednisone for eight weeks.

a) In a study of Black et al, [5] 19 patients with IMN and NS were randomly assigned either to symptomatic therapy or to prednisone, at a mean dose of 20-30 mg per day for at least six months, gradually tapered to 14 mg per day at one year. After two years, 20% of the controls and 40% of the treated patients had a daily proteinuria lower than one gram; the difference was insignificant. Side effects were frequent and there were more cardiovascular deaths in the treated group. Clearly, the study did not have any statistical validity, because of the insufficient number of patients enrolled. A similar therapeutical protocol was evaluated in a Canadian study [6] in which 158 patients with or without NS were assigned to receive symptomatic therapy or prednisone at a dose of 45 mg/m2 on alternate days for six months. No differences could be seen between the two groups at any time point either in the mean urinary protein excretion or in the mean creatinine clearance up to four years of follow-up. Therapy was usually well tolerated. The size of the study was adequate, but the untreated controls had such a benign course to find any significant difference even if treatment would have been effective. This favorable outcome was largely influenced by the inclusion of non-nephrotic patients, who usually have an excellent natural course. b) The second schedule was evaluated by two controlled trials. In a multicenter study conducted in USA, 72 nephrotic patients with IMN were randomly allocated to symptomatic therapy or high-dose alternate-day prednisone (mean dose 125 mg) for at least two months. [7] Steroid負reated patients showed significantly higher probabilities of achieving complete or partial remission of proteinuria than controls. However, in many cases NS relapsed so that at the end of a mean follow-up of 23 months there was no difference between the two groups. The mean creatinine clearance declined steeper in controls (10 per cent per year) than in treated patients (2% per year). Treatment was well tolerated with major side effects occurring only in two patients. The study was criticized because the control group had a course more severe than usually seen. The same therapeutic protocol was assessed in a multicenter trial organized by the medical research council. [8] In this double苑lind study, 107 adult nephrotic patients with IMN were randomly allocated to prednisone, 125 mg every other day for eight weeks, or to placebo. All patients had a potential follow-up of at least three years. Although a few treated patients had an early reduction of proteinuria, no difference in the mean levels of proteinuria or in serum creatinine could be seen between the two groups at one, two or three years.

In summary, the available controlled trials do not show a clear benefit of gluco苞orticoids over symptomatic therapy. This has been confirmed by a recent meta苔nalysis which did not find any difference either in the odds ratio of remission or in the 5-year renal survival between treated and untreated patients. [9] However, the limitation of the available studies was represented by a potentially inappropriate use of corticosteroids, which were given either for too short periods or at too low doses. One cannot exclude a better efficacy of corticosteroids when given more aggressively. As a matter of fact, the use of methylprednisolone pulses plus alternate苓ay prednisone for six months [10] had better chances of obtaining remission of the NS (55% vs. 33%) than symptomatic treatment in nephrotic patients, selected with the same criteria. [11] Although the cumulative doses of corticosteroids were relatively high (11.5 g), the incidence of side effects was low; only one patient had to stop therapy because of a renal vein thrombosis. Thus, a more aggressive treatment with corticosteroids given with intravenous high苓ose pulses and moderate alternate-day oral prednisone could increase the probability of response without severe toxicity.

Immunosuppressive Agents

Several randomized trials have pros計ectively evaluated the role of immuno貞uppressive agents in IMN. In an English study, nine patients with membranous nephropathy were assigned to supportive therapy and five to azathioprine (2.5 mg/Kg per day) plus low-dose prednisone (20 mg per day) for eight weeks. [12] The mean creatinine clearance decreased from 105 to 76 ml/min in controls, while increased from 66 to 86 ml/min in treated patients. Proteinuria did not change in controls (from 9.8 to 9.9 g/day) but decreased from 6.4 to 5.2 g/day in treated patients, after a follow up of six months. Clearly, no conclusion can be drawn from such a trial without any statistical power.

Two small controlled studies explored the role of alkylating agents. Donadio et al [13] randomly assigned 22 patients with IMN to non-specific therapy or to cyclophos計hamide for one year, at a mean dose of 1.8 mg/Kg per day. After a follow-up of one year, there was a trend to a greater decline of proteinuria in treated patients (mean reduction 4.7 g per day vs. 2.6 g per day) but the difference was not significant. The small size of the groups and the short follow-up cannot allow reaching any firm conclusion.

In a trial including several forms of primary glomerulonephritis, Lagrue et al [14] randomly allocated 41 nephrotic patients with IMN either to be given chlorambucil (0.2 mg/Kg/day for 6 months then 0.1 mg/Kg/day for further 6 months) or azathioprine (3 mg/Kg/day for 6 months then 2 mg/Kg/day for a further 6 months) or placebo. After a mean follow-up of two years there were nine complete and four partial remission among 16 patients treated with chlorambucil. There was only one partial remission among the 11 patients receiving azathioprine and there were two complete and one partial remission among the 14 patients who were given placebo. Unfortunately the prolonged use of chlorambucil exposed the patients to severe complications. Out of 37 patients with various types of glomerulonephritis treated with chlorambucil for at least one year three developed malignancy (skin cancer, gastric cancer and acute leukemia respectively).

Two Australian studies investigated the role of cyclophosphamide in association with an anticoagulant and an antiplatelet agent. In the first trial, [15] 54 patients were assigned to symptomatic therapy or to cyclophosphamide plus warfarin plus dipyridamole for three years. Therapy had to be discontinued in several patients because of the side effects. Those who could complete the 3-year-treatment showed significantly lower levels of proteinuria and higher levels of serum albumin when compared with untreated controls. The mean levels of creatinine clearance did not differ in the two groups. A possible criticism to this study is that the administration of cyclophosphamide and anticoagulants for three years was disproportionately rich in side effects in comparison with the beneficial influence on proteinuria.

More recently, Murphy et al [16] randomized 40 patients either to symptomatic therapy alone or to cyclophosphamide for six months plus dipyridamole and warfarin for two years. Treated patients showed a significantly greater reduction of proteinuria and a larger number of complete and partial remissions when compared with controls.

Looking at these controlled trials it seems that azathioprine is ineffective while alkylating agents can significantly reduce proteinuria or improve the chances of remission. This beneficial effect has been confirmed in a recent study of meta苔nalysis, [17] which showed that in patients given alkylating therapy the probability of attaining a complete remission was 4.6 times higher than in untreated controls. No conclusion could be drawn regarding the effects of treatment on renal function, as the follow-up was too short in three out of the five studies analyzed.

Alternating Glucocorticoids and Cytotoxic Drugs

An Italian multicenter study assessed the efficacy of a different approach consisting of a 6-month treatment with three cycles of a 2-month therapy. Each cycle began with one gram pulse of intravenous methyl計rednisolone repeated for three consecutive days followed by oral methylprednisolone (0.4 mg/Kg per day) for one month; then steroid was stopped and chlorambucil (0.2 mg/Kg per day) was given for one month. Eighty-one adult patients with IMN and NS were randomized to receive either symp負omatic treatment or the combined therapy. The two groups were homogeneous at randomization. After a median follow-up of five years, 23 of 32 treated patients were without nephrotic syndrome (12 complete and 11 partial remission), while out of 30 controls only two were in complete remission (proteinuria less than 0.2 g per day) and seven in partial (proteinuria less than two grams per day). One patient in the treated group died of lung cancer a few months after randomization and two in the control group died respectively of cardiac infarct and of hepato-renal failure. Four patients had to stop treatment respectively because of peptic ulcer (2 cases), gastric intolerance, and pneumonia. [11]

The results of this trial have been updated at 10 years of follow-up. [18] The probability of having a remission of the nephrotic syndrome (complete plus partial) was significantly higher in treated patients (83 per cent versus 38 per cent) (p=0.0000). At the last visit 40% of treated patients versus only 5% of untreated controls were in complete remission. The slope of the reciprocal of plasma creatinine with time decreased after 10 years from 1.0 to 0.84 in treated patients and from 1.0 to 0.51 in controls. The probability of surviving without dialysis at 10 years was 92% in patients treated with methylprednisolone and chlorambucil versus 60% in untreated controls (p=0.0038). In the long-term, one treated patient became obese and another one developed diabetes.

In another Italian multicenter trial [10] the effects of the combined treatment with methylprednisolone and chlorambucil were compared with those of methylprednisolone alone given at the same cumulative dosage than in the other arm (3 pulses at month 1, 3, 5 plus oral methylprednisolone 0.4 mg/Kg every other day for 6 months). The number of remissions, complete plus partial, was significantly higher at one year (58 per cent vs. 26 per cent), two years (54 per cent vs. 32 per cent) and three years (66% vs. 40%) for patients assigned to combined therapy. At four years still there was a 20% difference of remission in favor of the combined treatment (62% vs. 42%) but, due to the smaller number of patients at risk, the difference was not significant. At any rate, at the end of a mean follow-up of 54 months, 64 per cent of patients given combined therapy vs. 38% of patients given steroids alone were without nephrotic syndrome, the difference being significant. The chances of remission were associated with the absence of mesangial sclerosis at initial biopsy, with the use of combined treatment and with a plasma creatinine lower than 88 pmol/l (one mg/dl). There was a trend towards a lesser slope of the reciprocal of plasma creatinine in patients treated with combined therapy but the difference was not significant. One patient per group died. Four patients in the group treated with steroids and chlorambucil had severe side effects, which completely reversed after treatment was stopped (infections in two cases, liver dysfunction and gastric intolerance to chlorambucil). One patient treated with steroids alone stopped therapy because of renal vein thrombosis.

In a third controlled trial [19] patients were randomized to be given methylprednisolone (one g intravenously for three consecutive days followed by oral prednisone, 0.5 mg/Kg/day for 27 days) alternated every other month either with chlorambucil (0.2 mg/Kg/day for 1 month) or with cyclo計hosphamide (2.5 mg/Kg/day for 1 month). Among 87 patients followed for at least 1 year, 36 of 44 (82%) assigned to methyl計rednisolone plus chlorambucil entered complete or partial remission of the NS, versus 40 of 43 (93%) assigned to methylprednisolone plus cyclophosphamide (p=0.116). The reciprocal of plasma creatinine improved in the cohort groups followed for one year for both treatment groups (p<0.01) and remained unchanged when compared with basal values in the cohort groups followed for two and three years.

A decision analysis was made by Piccoli et al [20] on the results of the two first Italian trials respectively comparing methylpred要isolone and chlorambucil with no treatment [17] and with methylprednisolone alone. [10] Assuming triple probabilities and costs for methylprednisolone plus chloram苑ucil compared to methylprednisolone alone, with no risk for supportive therapy, the decision analysis showed that the improvement in expected quality-adjusted life expectancy for a 40-year old man with IMN and nephrotic syndrome would be of 7.2 years if combined treatment is compared to supportive therapy and of 2.6 years if compared to steroids alone. In other words, the combined therapy may recover 64% of life expectancy of which 64% can also be obtained with methylprednisolone alone. To offset the 36% advantage in expected survival with combined therapy versus methylpred要isolone alone, we have to assume that all patients treated with combined therapy undergo either fatal (5% vs. 0.3% with methylprednisolone alone) or non-fatal complications (95% vs. 15% with methylprednisolone alone), clearly an absurd rate of complications. To offset the longer survival of methylprednisolone and chlorambucil compared with supportive therapy, the number of fatal and non-fatal complications caused by the combined therapy should be abysmal.

Cyclosporine (CsA)

Several non-controlled trials have been conducted in IMN. Taking the results together, it appears that CsA may be effective in inducing partial or complete remission of the NS in 50 to 60% of patients. [21] How long should CsA be given before considering it ineffective is unclear. A recent German multicenter study [22] showed that 34% of patients treated with CsA reached complete remission after a median treatment duration of 225 days; in the majority of patients the remission occurred after six months, so that a prolonged administration of CsA may be needed in IMN before considering the disease as refractory to treatment in a particular patient.

CsA was also used in patients with impaired renal function. Cattran et al [23] assigned 17 patients with severe proteinuria and/or renal dysfunction to receive placebo or CsA for 1 year. Proteinuria significantly decreased in the treated group; moreover the decline in creatinine clearance was more rapid in placebo than in CsA-treated group.


   Conclusions Top


There is general agreement that non要ephrotic patients do not require specific treatment since their risks of renal failure or other complications are minimal.

It is still controversial whether and when nephrotic patients with IMN should be treated. Some investigators are in favor of an early treatment to improve the probabilities of remission of NS and to prevent long-term renal insufficiency. Others prefer to wait for treatment until renal insufficiency develops, since they feel that some 40-50 per cent of patients would receive an unnecessary treatment. The decision is not easy since we have good markers of a bad prognosis (unfortunately when it is often too late to intervene) such as renal failure [24],[25] and diffuse interstitial fibrosis, [26] but we lack of markers which can guarantee of a benign outcome in the long負erm. A possible predictor of a favorable outcome in the long-term is represented by complete remission of proteinuria. [27] This event occurs, however, in only 15% of patients and may take several years. [1] Thus, a therapeutic decision is more based on a clinical ground than on scientific basis.

At present a six-month course alternating methylprednisolone and chlorambucil or cyclophosphamide every other month, has the highest therapeutic index among the various regimens suggested. This treatment not only favors remission of the NS, but can also protect renal function in the long-term, and is usually well tolerated. In the case of poor response or contraindications to this treatment a trial with cyclosporine may be done. The main problem with cyclosporine is that in most responders' proteinuria increases when the drug is stopped. However, if the drug is given for a prolonged period and is tapered off gradually (0.5 mg/Kg every month) the risk of relapse may be reduced. [28] Since cyclosporine is nephrotoxic and may lead to progressive renal dysfunction it should not be used in patients with renal insufficiency, severe hypertension and/or tubulointerstitial lesions. The initial doses should not exceed 5 mg/Kg/day or 4 mg/Kg/day with the new micro-emulsion form of the drug.

 
   References Top

1.Ponticelli C, Passerini P. Membranous nephropathy. In: Ponticelli C, Glassock RJ, eds. Treatment of primary glomeruloneph訃itis. Oxford University Press 1997:146-85.  Back to cited text no. 1    
2.Ordonez JD, Hiatt RA, Killebrew EJ, Fireman BH. The increased risk of coronary heart disease associated with nephrotic syndrome. Kidney Int 1993;44:638-42.  Back to cited text no. 2    
3.MacTier R, Boulton-Jones JM, Payton CD, Mclay A. The natural history of membranous nephropathy in the West of Scotland. Q J Med 1986;60:793-802.  Back to cited text no. 3    
4.Bellomo R, Atkins RC. Membranous nephropathy and thromboembolism: is prophylactic anticoagulation warranted? Nephron 1993;63:249-54.  Back to cited text no. 4    
5.Black DA, Rose G, Brewer DB. Controlled trial of prednisone in adult patients with the nephrotic syndrome. Br Med J 1970;3:421-6.  Back to cited text no. 5    
6.Cattran DC, Delmore T, Roscoe J, et al. A randomized controlled trial of prednisone in patients with idiopathic membranous nephropathy. N Engl J Med 1989;320: 210-5.  Back to cited text no. 6    
7.Collaborative Study of the Adult Idiopathic Nephrotic Syndrome. A controlled study of short-term prednisone treatment in adults with membranous nephropathy. N Engl J Med 1979;301: 1301-6.  Back to cited text no. 7    
8.Cameron JS, Healy MJ, 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;74:133-56.  Back to cited text no. 8    
9.Hogan SL, Muller KE, Jennette JC, Falk RG. A review of therapeutic studies of idiopathic membranous glomerulopathy. Am J Kidney Dis 1995;25:862-75.  Back to cited text no. 9    
10.Ponticelli C, Zucchelli P, Passerini P, Cesana B. The Italian Idiopathic Memb訃anous Nephropathy Treatment Study Group. Methylprednisolone plus chloram苑ucil as compared with methylpred要isolone alone for the treatment of idiopathic membranous nephropathy. N Engl J Med 1992;327:599-603.  Back to cited text no. 10    
11.Ponticelli C, Zucchelli P, Passerini P, et al. A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Engl J Med 1989; 320:8-13.  Back to cited text no. 11    
12.Medical Research Council Working Party. Controlled trial of azathioprine and prednisone in chronic renal disease. Br Med J 1971;2:239-41.  Back to cited text no. 12    
13.Donadio JV Jr, Holley KE, Anderson CF, Taylor WF. Controlled trial of cyclophos計hamide in idiopathic membranous nephropathy. Kidney Int 1974;6:431-9.  Back to cited text no. 13    
14.Lagrue G, Bernard D, Bariety J, Druet P, Guenel J. Traitement par le chlorambucil et l' azathioprine dans les glomerulo要ephrites primitives: resultats d'une etude controlee. J D'Urol Nephrol 1979;81:655-72.  Back to cited text no. 14    
15.Tiller DJ. A prospective randomized trial in the use of cyclophosphamide, dipyridamole and warfarin in membranous and mesangiocapillary glomerulonephritis. In: Zurukzoglu W, Papadimitriou M, Pyrpasopoulos M, Sion M, Zamboulis C (ed). Proceedings of the 8th International Congress of Nephrology. University Studio and Karger. Tessaloniki and Basel 1981;345-54.  Back to cited text no. 15    
16.Murphy BF, McDonald I, Fairley KF, Kincaid-Smith PS. Randomized controlled trial of cyclophosphamide, warfarin and dipyridamole in idiopathic membranous glomerulonephritis. Clin Nephrol 1992;37: 229-34.  Back to cited text no. 16    
17.Imperiale TF, Goldfarb S, Berns JS. Are cytotoxic agents beneficial in idiopathic membranous nephropathy? A meta苔nalysis of the controlled trials. J Am Soc Nephrol 1995;5:1553-8.  Back to cited text no. 17    
18.Ponticelli C, Zucchelli P, Passerini P, et al. A 10-year follow-up of a randomized study with methylprednisolone and chlo訃ambucil in membranous nephropathy. Kidney Int 1995;48:1600-4.  Back to cited text no. 18    
19.Ponticelli C, Altieri P, Scolari F, et al. A randomized study comparing methylpred要isolone plus chlorambucil versus methyl計rednisolone plus cyclophosphamide in idiopathic membranous nephropathy. J Am Soc Nephrol 1998;9:444-50.  Back to cited text no. 19    
20.Piccoli A, Pillon L, Passerini P, Ponticelli C. Therapy for idiopathic membranous nephropathy: tailoring the choice by decision analysis. Kidney Int 1994;45: 1193-202.  Back to cited text no. 20    
21.Ponticelli C, Passerini P. The place of cyclosporin in the management of primary nephrotic syndrome. Bio Drugs 1999; 12(5):327-41.  Back to cited text no. 21    
22.Fritsche L, Budde K, Farber L, et al. Treatment of membranous glomerulopathy with cyclosporin A: how much patience is required? Nephrol Dial Transplant 1999; 14:1036-7.  Back to cited text no. 22    
23.Cattran DC, Greenwood C, Ritchie S, et al. A controlled trial of cyclosporin in patients with progressive membranous nephropathy. Canadian Glomerulonephritis Study Group. Kidney Int 1995;47:1130-5.  Back to cited text no. 23    
24.Donadio JV Jr, Torres VE, Velosa JA, et al. Idiopathic membranous nephropathy: the natural history of untreated patients. Kidney Int 1988;33:708-15.  Back to cited text no. 24    
25.Pei Y, Cattran D, Greenwood C. Predicting chronic renal insufficiency in idiopathic membranous glomerulo-nephritis. Kidney Int 1992;42:960-6.  Back to cited text no. 25    
26.Wehrmann M, Bohle A, Bogenschutz O, et al. Long-term prognosis of chronic idiopathic membranous glomerulo要ephritis. An analysis of 334 cases with particular regard to tubulo-interstitial changes. Clin Nephrol 1989;31:67-76.  Back to cited text no. 26    
27.Passerini P, Pasquali S, Cesana B, Zucchelli P, Ponticelli C. Long-term outcome of patients with membranous nephropathy after complete remission of proteinuria. Nephrol Dial Transplant 1989;4:525-9.  Back to cited text no. 27    
28.Meyrier A, Noel LH, Auriche P, Callard P. Long-term renal tolerance of cyclosporin A treatment in adult idiopathic nephrotic syndrome. Collaborative Group of the Societe de Nephrologie. Kidney Int 1994;45:1446-56.  Back to cited text no. 28    

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Correspondence Address:
Patrizia Passerini
Divisione di Nefrologia e Dialisi, Instituto di Ricovero e Cura a Carattere Scientifico Ospedale Maggiore di Milano, Via Commenda, 15-20122, Milano
Italy
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