Efficacy of a second course of immunosuppressive therapy in patients with membranous nephropathy and persistent or relapsing disease activity

Peggy W. G. du Buf-Vereijken1,2 and Jack F. M. Wetzels1

1 Department of Nephrology, University Medical Center St Radboud, Nijmegen and 2 Department of Internal Medicine, Amphia Hospital, Breda, the Netherlands

Correspondence and offprint requests to: Peggy W.G. du Buf-Vereijken, UMC St Radboud, Department of Nephrology, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands. Email P.duBuf{at}nier.umcn.nl



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. A single course of immunosuppressive treatment improves renal survival in patients with idiopathic membranous nephropathy (iMN) and renal insufficiency. However, not all patients respond and relapses occur within 5 years in 30% of patients. It is unknown if a second course of immunosuppressive therapy is effective in such patients.

Methods. We have prospectively studied and evaluated the clinical course in 15 patients (14 male, one female; age: 52±12 years) with iMN who have received a repeated course of immunosuppressive therapy because of deteriorating renal function associated with relapsing or persistent nephrotic syndrome.

Results. The first course of immunosuppression was started 8 months (range: 0–143 months) after renal biopsy and consisted of chlorambucil (n = 8) or cyclophosphamide (n = 7); the second course consisted of cyclophosphamide in all patients. The interval between the first and second course was 40 months (range: 7–112 months). Total follow-up was 110 months (range: 46–289 months). Renal function and proteinuria improved at least temporarily in all patients after the second course. During follow-up, an additional course of therapy was given in four patients. Status at the end of follow-up was complete remission (n = 2), partial remission (n = 8), persistent proteinuria (n = 3), end-stage renal disease (n = 1) and death (n = 1, due to cardiovascular disease while nephrotic). Renal survival was 86% at 5 and 10 years of follow-up. The repeated courses of immunosuppression have resulted in a gain of dialysis-free survival time of ≥93 months (range: 43–192 months).

Conclusions. Our results indicate that patients with iMN who do not respond well or relapse after a first course of immunosuppressive therapy and have renal insufficiency should be offered a second course of immunosuppression. Such a strategy maintains renal function in the majority of patients.

Keywords: chlorambucil; cyclophosphamide; immunosuppressive therapy; membranous nephropathy; relapse; renal survival



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Idiopathic membranous nephropathy is the most common cause of nephrotic syndrome in adults [1]. Studies on the natural history of the disease show that ≤50% of untreated patients will progress to end-stage renal disease (ESRD) [2]. A randomized controlled study has provided evidence that a 6 month course of alternating prednisone and chlorambucil improves renal survival in patients with idiopathic membranous nephropathy, a nephrotic syndrome, and normal renal function at the start of therapy [3]. In view of the toxicity of immunosuppressive therapy, most nephrologists have argued that treatment should be restricted to patients with evidence of renal insufficiency or long-standing, severe nephrotic syndrome [4]. Observational studies have, indeed, suggested that immunosuppressive therapy is effective when started in patients with renal insufficiency [5–8]. Most treatment regimens consisted of a combination of prednisone and an alkylating agent, notably chlorambucil or cyclophosphamide, administered for a period of 6–12 months.

Since 1986 we have also used a restrictive treatment policy in patients with idiopathic membranous nephropathy.

We have initially used the so-called Ponticelli regimen, a 6 month course of alternating cycles of prednisone and chlorambucil [3]. From 1991 onwards, we have regularly used a cyclophosphamide-based regimen. Although a single course of immunosuppressive therapy was effective in most patients, some did not respond [8,9]. Furthermore, in ≤30% of patients the disease relapsed with recurrent proteinuria [8,10–12]. It is uncertain if a repeated course of immunosuppression is effective in patients with idiopathic membranous nephropathy and persistent or relapsing nephrotic syndrome. We have regularly offered a second course of immunosuppressive therapy to such patients if there was evidence of deteriorating renal function. For the present study we have analysed the outcome in 15 prospectively followed patients who have received a second course of immunosuppressive therapy. Our data indicate that retreatment is effective and attenuates progressive renal failure.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
From 1986 onwards we have used immunosuppressive therapy in adult patients with membranous nephropathy. Treatment was restricted to patients with renal insufficiency (defined as a serum creatinine >135 µmol/l, a calculated endogenous creatinine clearance <70 ml/min or a rise in serum creatinine of >50%) and a proteinuria of ≥2.0 g/10 mmol creatinine or to patients with a severe, intolerable nephrotic syndrome. Eligible patients were treated in our University Hospital or by nephrologists in referring hospitals. Details of our treatment protocols and of the outcome in treated patients have been described previously [5,8,9]. In brief, during the period 1986–1991, our immunosuppressive therapy consisted of a 6 month course of alternating cycles of prednisone (1 g methylprednisolone intravenously (i.v.) on three consecutive days, followed by oral prednisone 0.5 mg/kg/day at months 1, 3 and 5) and chlorambucil (0.15 mg/kg/day at months 2, 4 and 6). Thereafter, a regimen containing cyclophosphamide became our therapy of choice. This regimen consisted of corticosteroids (1 g methylprednisolone i.v. on three consecutive days at months 1, 3 and 5, followed by oral prednisone 0.5 mg/kg on alternate days for 6 months) and oral cyclophosphamide in a dose of 1.5–2.0 mg/kg/day for 12 months. All treated patients have been followed prospectively and were regularly seen in the outpatient clinic. For the present study, we have selected all patients who have received a second course of immunosuppressive therapy because of relapsing or persistent nephrotic syndrome and deterioration of renal function.

Calculations and statistics
For this study, the time of follow-up started at the time of biopsy. Follow-up ended with the last clinical visit or at the occurrence of ESRD or death. The interval between consecutive courses of immunosuppression was calculated from the beginning of the first course to the beginning of the second course. Mean arterial pressure (MAP) was calculated as diastolic blood pressure plus one-third of the pulse pressure (systolic blood pressure – diastolic blood pressure). Proteinuria was expressed as g/10 mmol creatinine (protein–creatinine index). A complete remission of proteinuria (CR), partial remission (PR), persistent proteinuria and nephrotic range proteinuria were defined as a protein–creatinine index of ≤0.2, 0.21–2.0, 2.1–3.4 and ≥3.5 g/10 mmol creatinine, respectively, where in case of remission, renal function should have improved or at least stabilized compared with the value at the start of the immunosuppressive therapy. Relapses of proteinuria were defined as nephrotic range proteinuria after a PR or CR of the proteinuria or a rise in proteinuria of >50% in patients in whom proteinuria had improved initially by >50%, without reaching values ≤2.0 g/10 mmol creatinine.

For each individual we have estimated dialysis-free survival time gained by therapy. To this end we have plotted the course of 1000/serum creatinine (= glomerular filtration rate (GFR)) vs time for each individual patient. The decrease of GFR in the period before the start of immunosuppression was defined by the trend line and the estimated time of onset of ESRD was derived by extrapolation. A value of 1000/serum creatinine of 1 was used as the ESRD reference value. Next, we estimated the expected time of onset of ESRD after treatment by extrapolating a trend line drawn through the point of the last observation in parallel with the first line. The procedure is illustrated for one patient in Figure 1. It is evident that this procedure provides a minimum estimate of the gained dialysis-free survival time, since in most patients there is no apparent decrease of GFR at the moment of last observation.



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Fig. 1. Estimate of dialysis-free survival time gained by therapy. To estimate the gain of dialysis-free survival time, we have plotted 1000/serum creatinine (1000/Screat; Screat in µmol/l) vs time. A trend line was drawn to estimate the decline in renal function before the start of the first immunosuppressive therapy. The expected date of onset of ESRD (without therapy) was derived by extrapolating the trend line. A value of 1000/Screat of 1 was used as a marker of ESRD. The date of onset of ESRD after therapy was estimated from a parallel line, drawn through the point of last observation. The figure represents data from patient no. 3; in this patient the onset of ESRD was delayed by ≥164 months.

 
When considering concomitant drug treatment, special attention was given to the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (AIIA), because of their favourable effects on blood pressure and protein excretion.

Renal survival, defined as being alive without dialysis, was calculated from the time of renal biopsy. The cumulative probabilities of a clinical event (death or ESRD) were estimated according to Kaplan and Meier. Unless otherwise stated, values are given as medians with the range. The Wilcoxon signed rank test was used for comparisons of clinical data within the total group of treated patients at different time points. A P-value of <0.05 was considered significant. All statistical procedures were done using SPSS software (SPSS version 10.0; Chicago, IL, USA).



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Fifteen patients (14 male, one female) were eligible for the study. Mean age at biopsy was 51 years (range: 24–68 years). An overview of patient characteristics, laboratory values at biopsy, time intervals to first immunosuppressive course and between first and second course, and total time of follow-up are given in Table 1.


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Table 1. Overview of demographic parameters, laboratory values at biopsy, time intervals to first immunosuppressive course and between first and second courses, and total time of follow-up

 
In Table 2 we have provided detailed information for each patient on the given courses of immunosuppression, side effects, necessary dose reductions, concomitant use of ACEI and/or AIIA, cumulative dosage of cyclophosphamide and estimated gained dialysis-free survival time. Four patients had received prednisone monotherapy in the early disease period. The first course of effective immunosuppression was started at a median of 8 months (range: 0–143 months) after renal biopsy and consisted of chlorambucil in eight patients and of cyclophosphamide in seven patients. The interval between the first and second course was 40 months (range: 7–112 months). All patients received cyclophosphamide as the second course.


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Table 2. Overview of given immunosuppression with side effects, use of ACEI and/or AIIA, cumulative dosage of cyclophosphamide and gained time to ESRD

 
In three patients (all treated with chlorambucil), retreatment started within 6 months after the end of the first course. In all other patients, retreatment started >2 years after the end of the first course. Total follow-up was 110 months (range: 46–289 months). One patient was lost to follow-up due to non-compliance.

In Table 3 an overview is given of the course of serum creatinine and proteinuria during the two consecutive immunosuppressive courses. We have depicted serum creatinine and urinary protein excretion at the start of the first and second courses of therapy, the lowest value after the start of each course of therapy and the value at the end of follow-up.


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Table 3. Efficacy of immunosuppressive courses and status at the end of follow-up

 
Efficacy of the first course of immunosuppression
Data are presented in Table 3. Renal function improved in all but one patient, who showed stabilization of serum creatinine. Proteinuria improved in all patients, but CR (one) or PR (seven) were achieved in only eight patients.

Nine out of the 15 patients used an ACEI and/or AIIA at the start of the first course of immunosuppression. Mean arterial blood pressure amounted to 103 mmHg (range: 97–123 mmHg) at the start of the first immunosuppressive course and 101 mmHg (range: 87–121 mmHg) at 12 months (NS).

Efficacy of the second course of immunosuppression
Data are presented in Table 3. At the start of the second course of immunosuppression, renal function was worse in 11 patients in comparison with renal function at the start of the first course and was, by definition, worse in all cases in comparison with the best renal function achieved after the first course. Renal function and proteinuria improved in all patients during the second course of immunosuppression. Ten patients achieved CR (one) or PR (nine). The efficacy of the repeated courses of immunosuppression is visualized in Figures 2 and 3, depicting the time course of the change in 1000/serum creatinine and proteinuria in relation to the start of the second course of therapy. Eleven patients used an ACEI and/or AIIA at the start of the second course of immunosuppression. Despite this, all but one patient had a nephrotic syndrome at this time point. Mean arterial blood pressure was 108 mmHg (range: 78–130 mmHg) at the start of the second immunosuppressive course and 95 mmHg (range: 80–110 mmHg) at 12 months (NS).



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Fig. 2. Efficacy of the second course of immunosuppressive therapy on change in renal function. The start of the second immunosuppressive course is indicated by t = 0. Follow-up is shown from 6 months before to 60 months after the second course. The figure plots the change in 1000/serum creatinine value (µmol/l) compared with the value at the start of therapy, which was set at 0.

 


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Fig. 3. Efficacy of the second course of immunosuppressive therapy on proteinuria. The start of the second immunosuppressive course is indicated by t = 0. Follow-up is shown from 6 months before to 60 months after the second course. Proteinuria is expressed as g/10 mmol creatinine. The reference line reflects a proteinuria of 2 g/10 mmol creatinine, the threshold for defining a partial remission.

 
Follow-up after the second course
Thus far, four patients have received a third (four) or even fourth (one) course of immunosuppression, because of new relapse (Table 2). At the end of follow-up, two patients were in CR, eight were in PR, three had persistent proteinuria, one had developed ESRD and one had died due to cardiovascular disease while nephrotic (Table 2). Renal survival (alive without dialysis) from the time of biopsy was 86% at 5 and 10 years. The repeated courses of immunosuppression have resulted in an estimated dialysis-free survival time gained by therapy of ≥93 months (range: 43–192 months). This estimate is a minimum and underestimates the real gain, since in seven patients renal function was stable or even improving at the end of follow-up.

Immunosuppressive therapy-related complications
The side effects of immunosuppressive treatment are detailed per patient in Table 2. Side effects were frequent and often necessitated dose reduction. The second course of immunosuppression was not more frequently associated with side effects.

The cumulative dosage of cyclophosphamide was 48 g (range: 17–146 g) (Table 2). In only one patient did the dosage exceed 100 g. This particular patient received a high dose because of his body weight (>100 kg) and the absence of side effects. The cumulative dose is lower than expected, even in patients who received two courses of cyclophosphamide. This is explained by the fact that, in most patients, dose reduction was necessary because of haematological side effects. Furthermore, if the cumulative dose of cyclophosphamide tended to reach the 100 g threshold, we have favoured to replace cyclophosphamide by azathioprine or cyclosporin (third courses; Table 2).



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Our study indicates that a second course of immunosuppressive therapy is effective in patients with membranous nephropathy and deteriorating renal function who have not responded well or who have relapsed after a first course of immunosuppressive therapy. In the short-term, renal function improved and proteinuria decreased in all patients during the second course. Also, at the end of follow-up, renal function was maintained in the majority of patients. Admittedly, one-quarter of patients have needed an additional course of treatment. The overall good outcome is reflected in the renal survival rate of 86% at 5 and 10 years from renal biopsy.

Most patients with membranous nephropathy and renal insufficiency will progress to ESRD if left untreated [7,8,13]. Historical control studies have shown renal survival rates of only 20–32% after 7 years [7,8,13]. We and others have provided evidence that a single course of 6–12 months of immunosuppressive therapy is effective and improves renal survival [7,8,13].

However, with prolonged follow-up it has become evident that many patients will relapse, with a relapse rate of 28% at 5 years of follow-up [8]. It is evident that relapses still can occur after a second course of immunosuppressive therapy (in our present study, four out of 15 patients have needed a third course of immunosuppression).

Our study, thus, provides arguments for an active treatment policy in patients with membranous nephropathy, relapsing proteinuria and deterioration of renal function. Although our study cohort is relatively small, to date there are few data on this particular group of patients available in the literature [13,14]. Most data on repeated courses of immunosuppressive therapy relate to patients with relapsing nephrotic syndrome without renal insufficiency [3,10,14,15]. Ponticelli et al. [10] reported on 169 patients with a variable degree of proteinuria and normal renal function, half of whom were treated with immunosuppression. Of 111 patients entering a PR or CR, 42 relapsed to nephrotic range proteinuria. Relapses occurred more frequently after a PR. Half of the relapsing patients entered a spontaneous remission again. Fifteen patients were treated again; nine of 11 patients treated with chlorambucil had a persistent remission on retreatment. Repeated cytotoxic therapy clearly increased the chance of a stable remission. Renal function deterioration occurred in a minority of patients (six out of 42), mainly in patients with persistent proteinuria [10]. Positive responses to retreatment in low-risk populations have been reported by others as well [14,15]. However, relapses after retreatment occur even in this low-risk population [3,10,15].

Blood pressure control in the early years of the study was not optimal when considering current guidelines. Treatment of blood pressure has become more aggressive in the recent decade. This is reflected by the fact that MAP was 103 mmHg at the start of the first course and 95 mmHg at 12 months after the second course of immunosuppressive therapy. The target MAP of 92 mmHg is difficult to achieve in patients with renal failure and older age. However, most patients were using ACEI or AIIA and it is unlikely that a more aggressive antihypertensive strategy could have prevented the observed deterioration of renal function, thus, obviating the need for repeated immunosuppressive therapy. It is well established that renal function may deteriorate in many patients with membranous nephropathy despite well-controlled blood pressures and the use of ACEI or AIIA [8].

Two important questions must be addressed with respect to our treatment strategy. First, is it allowed to delay the start of immunosuppressive therapy until renal dysfunction is apparent? There is no support for this strategy from randomized trials. However, a recent analysis of our data has provided arguments that a restrictive treatment policy is justified. We have studied the outcome of a restrictive treatment strategy in a large cohort of adult patients with membranous nephropathy. Details of this study will be published elsewhere [16]. Thus far, nearly half of the patients have received immunosuppressive therapy, mainly because of renal insufficiency. At the end of follow-up, 67% of patients were in CR or PR. Renal survival was 94% at 5 years and 88% at 7 years. From these data we concluded that restricted therapy is justified in view of the good overall outcome, whilst preventing immunosuppressive therapy in more than half of the patients.

The second question is whether the advantages of a second (or even third or fourth) course of immunosuppressive therapy outweigh the short- and long-term side effects, particularly in patients with established moderate to severe renal insufficiency. To be able to balance the benefits and risks, we have estimated the dialysis-free survival time gained by therapy. It is evident that treatment-attributable survival time greatly exceeds the duration of the treatment courses. Furthermore, in the discussion of the side effects of treatment, it is important to realize that most patients who develop ESRD will receive a kidney transplant, thus, necessitating life-long immunosuppression with the related side effects. Our data indicate that the use of a second course of immunosuppressive therapy is not associated with more frequent or more severe side effects in the short-term. Of course, it is important to consider the long-term side effects, the most important one being the potential of cyclophosphamide to induce (bladder) malignancies [17,18]. For this reason, we have often replaced cyclophosphamide by azathioprine or cyclosporin whenever a third or fourth course of immunosuppressive therapy was needed. The risk of cyclophosphamide-related bladder cancer increases with the duration (especially >2.7 years) and the cumulative dosage (mainly >100 g) of cyclophosphamide treatment [17]. The cumulative duration of cyclophosphamide therapy and the administered dosage of cyclophosphamide are well below these values in most of our patients.

It is evident that not all patients respond well to treatment and it is likely that non responsive patients may develop ESRD with longer follow-up. One could consider taking a renal biopsy to aid in treatment decisions, particularly to prevent that treatment is instituted in patients with chronic sclerotic lesions.

It might be questioned whether it is possible to reduce the dose of cyclophosphamide. Ponticelli et al. [11] have used cyclophosphamide in an alternating schedule, limiting the duration of cyclophosphamide therapy to 3 months. However, this short regimen has been studied extensively only in patients with normal renal function. We previously have reported a comparison of the Ponticelli regimen (with chlorambucil) and our 12 month cyclophosphamide regimen [5]. We found the cyclophosphamide regimen more effective and less toxic than chlorambucil. It remains to be proved if these differences are related to the difference in duration of treatment or the type of agent. Future studies are needed to settle this issue; meanwhile, we favour the 12 month regimen in patients with renal insufficiency.

Another strategy would be to use other immunosuppressive agents, such as mycophenolate mofetil or cyclosporin. To date, information on the efficacy of mycophenolate mofetil in patients with idiopathic membranous nephropathy and renal insufficiency is limited and inconclusive. Cyclosporin has been evaluated in a small randomized study, demonstrating an improvement in creatinine clearance and a decrease in proteinuria [19]. Relapses occur, however, in about one-third of patients after cyclosporin withdrawal, thus, necessitating long-term administration of the drug [20,21]. Furthermore, transient renal dysfunction and hypertension can occur in cyclosporin-treated patients [19–21].

In conclusion, a repeated course of immunosuppressive therapy with cyclophosphamide and prednisone improves renal function and retards the progression of renal insufficiency in patients with idiopathic membranous nephropathy, relapsing proteinuria and deteriorating renal function. The advantage of a renewed course of immunosuppressive treatment (i.e. a delay of onset of ESRD) must be weighed against the side effects. We would like to argue in favour of a strategy of repeated immunosuppression, in particular in patients who would otherwise progress to ESRD, necessitating renal transplantation with its associated life-long immunosuppression.



   Acknowledgments
 
P.W.G. du Buf-Vereijken is supported by a grant from the Dutch Kidney Foundation (NSN: PC152).

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 15. 3.04
Accepted in revised form: 19. 4.04