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NDT Advance Access originally published online on September 12, 2006
Nephrology Dialysis Transplantation 2006 21(11):3127-3132; doi:10.1093/ndt/gfl360
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Induction and long-term treatment with cyclosporine in membranous nephropathy with the nephrotic syndrome

Efstathios Alexopoulos1, Aikaterini Papagianni1, Mzia Tsamelashvili1, Maria Leontsini2 and Dimitrios Memmos1

1Department of Nephrology and 2Department of Pathology, Hippokration General Hospital, Thessaloniki, Greece

Correspondence and offprint requests to: E. Alexopoulos, MD, Department of Nephrology, Hippokration General Hospital, 49, Konstantinoupoleos str., 54642 Thessaloniki, Greece. Email: nephrol{at}med.auth.gr



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Cyclosporine A (CyA) has been shown to be effective in membranous nephropathy (MN). However, the optimal dose and the duration of treatment remain controversial issues. We evaluated the efficacy of low-dose CyA alone or combined with corticosteroids as induction and long-term treatment for nephrotic patients with MN.

Methods. In the first part of the study, 51 nephrotic patients with MN were treated either with CyA and prednisolone (n = 31) or CyA alone (n = 20) for 12 months. Patients who responded with complete remission (CR) or partial remission (PR) were placed on long-term treatment with lower doses of CyA and prednisolone or CyA alone. The mean follow-up of the second part of the study was 26 ± 16 months and 18 ± 7 months, respectively.

Results. After 12 months of treatment, 26 patients in the combination group and 17 patients in the monotherapy group had a CR or PR of proteinuria (P = NS). Renal function was unchanged in the two groups. During long-term treatment relapses were more frequent in the monotherapy group (47 vs 15%, P < 0.05). Daily CyA dose was higher in non-relapsers in both groups (combination 1.4 ± 0.5 vs 1.0 ± 0.3 mg/kg, P < 0.001, monotherapy 1.5 ± 0.4 vs 1.1 ± 0.2 mg/kg, P < 0.003). Relapsers in both groups had lower CyA trough levels (72 ± 48 ng/ml) compared with non-relapsers (194 ± 80 ng/ml) (P < 0.03). Renal function and proteinuria remained stable during the follow-up.

Conclusion. This study suggests that 12-month therapy with CyA (±prednisolone) is effective in inducing remission in most nephrotic patients with MN and well-preserved renal function. Longer treatment with lower doses is a useful approach to maintain remission. Relapses occur more frequently in the monotherapy group and usually are associated with CyA trough levels <100 ng/ml.

Keywords: cyclosporine; membranous nephropathy; nephrotic syndrome; relapse; remission; trough levels of cyclosporine



   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Membranous nephropathy (MN) is the most common cause of idiopathic nephrotic syndrome (NS) in adults. The pathology and natural history of the disorder have been clearly defined since its initial description, but specific treatment tested in randomized controlled trials has been limited. Corticosteroid therapy alone has been tried in two recent controlled trials with no significant benefit [1, 2]. There is accumulating evidence that immunosuppressive agents (chlorambucil, cyclophosphamide) can reduce proteinuria and may significantly improve long-term kidney survival rates [3, 4]. In other studies, however, the results have been inconsistent [5, 6]. We also found similar response rates of proteinuria using either corticosteroids alone or in combination with cyclophosphamide [7]. In addition, serious drug toxicities remain a potential problem [8], although recent studies may allay this fear [4].

Cyclosporine A (CyA) has been used in the treatment of MN and particularly in patients at risk for progressive renal failure or in steroid-resistant cases [9, 10]. The results were encouraging with respect to both remission of nephrotic syndrome and preservation of renal function. However, the treatment period was relatively short, given the natural history of the disease, and there was a high relapse rate after discontinuation of treatment.

The purpose of this study was to evaluate (i) the effectiveness of a 12-month regimen with CyA in nephrotic patients with idiopathic MN (IMN) and (ii) the effectiveness of a long-term treatment with a very low dose of CyA in the maintenance of the remission and prevention of relapses.



   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Patients of either sex with a biopsy-proven MN and NS were considered for the study. NS was defined as proteinuria exceeding 3 g/24 h and plasma albumin concentrations of <3 g/dl. The criteria for exclusion were a positive serum test for anti-DNA antibodies, hepatitis B antigen or hepatitis C antibodies, a positive Venereal Disease Research Laboratories (VDRL) test and low serum concentrations of C3 or C4. A clinical diagnosis of diabetes mellitus, malignancy, systemic lupus erythematosus, infections or exposure to drugs that could induce MN were also criteria for exclusion. Exclusion criteria also included a serum creatinine (Scr) >2 mg/dl (177 µmol/l) at presentation and comorbid conditions with an expected survival of <2 years. No immunosuppressive agents, plasma exchange therapy, corticosteroids or CyA were allowed in the 6 months prior to the entry in to the study. A blood pressure of ≤140/90 mmHg was considered normal.

Renal histology
Adequate specimens for light microscopy and immunofluorescence were obtained from all patients. All specimens were examined by one pathologist (M.L.) and were evaluated without the knowledge of the patient's clinical diagnosis or clinical characteristics. Glomerular stages were classified according to the system of Ehrenreich and Churg [11]. No follow-up biopsies were performed.

Study design
A full history and physical evaluation as well as laboratory tests including Scr, 24 h urine-collection estimates for protein, serum albumin, haematocrit and a lipid profile including cholesterol and triglyceride estimation were done at the time of diagnosis. Patients were examined every month during the first 6 months, every 2 months until the end of the first year. At each visit, Scr and 24 h urinary protein excretion rates were measured.

Initial treatment
Immediately after diagnosis patients received prednisolone and CyA (combination group) or CyA alone (monotherapy group). The criteria for monotherapy were a history of gastrointestinal bleeding (n = 4) or peptic ulcer (n = 3), significant osteoporosis (n = 3), mild or borderline hyperglycaemia (n = 4), cataract (n = 2), gastric intolerance (n = 2) and reluctance of the patients to receive corticosteroids (n = 2). We preferred to start early, without a run-in period since, in our previous experience [7], none of the patients selected with the same criteria had a spontaneous remission of the NS within 6 months. Prednisolone was given at a starting dose of 0.6 mg/kg/day. The dose of prednisolone was gradually reduced to 10–15 mg at 6 months and remained unchanged until the 12th month of the treatment.

Treatment with CyA was started at a dose of 2–3 mg/kg/day in both groups. The daily quantity was divided and given in two equal doses at 12 h intervals. Adjustments in the dose were made to achieve a whole blood 12 h trough level measured by monoclonal radioimmunoassay between 100 and 200 ng/ml. CyA trough levels were obtained at every visit. The dose was reduced when the confirmed CyA level was in excess of 250 ng/ml, Scr level was >0.3 mg/dl (26 µmol/l) above baseline, serum transaminases increased or total bilirubin level was >2 mg/dl (>34.2 µmol/l). The duration of the initial treatment was 12 months.

Long-term treatment
All patients who responded either with complete remission (CR) or partial remission (PR) to the 12-month therapy, were considered suitable for the long-term study. As in the first part of the study, patients continued either on combination therapy or on CyA alone at doses which are described in the following text. The dose of CyA was tapered in both groups to a maintenance daily dose of about 1–1.5 mg/kg over a period of 2 months. In the combination group, the dose of prednisolone was reduced to about 0.1 mg/kg/day. Visits were then scheduled at 2-month intervals. The patient's clinical status was recorded and complete blood and urine tests including 24 h urine excretion of protein were carried out. The mean follow-up for the combination group was 26 ± 16 months (range 3–45 months) and for the monotherapy group 19 ± 8 months (range 8–40 months). For the treatment of hypertension all classes of antihypertensive agents were allowed including angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists.

Outcome measures
CR was defined as a reduction in proteinuria to ≤0.3 g/24 h for 2 weeks. PR was defined as a reduction in proteinuria of at least 50% and <3 g/24 h for 2 weeks plus stable renal function [12]. End-stage renal disease (ESRD) was defined by the need for permanent dialysis support or when Scr exceeded 6 mg/dl (530 µmol/l) for more than 1 month and in the absence of other causes of renal dysfunction. Early stop points included a ≥30% rise in baseline Scr that was not improved by a 50% reduction in the dose of CyA over a 4-week period. Other premature stop points included the failure to control hypertension with optimal dosages of three antihypertensive agents and the presence of intolerable side effects. Relapse was defined by an increase of 50% or more in baseline proteinuria or the reappearance of the NS for at least 2 weeks, in patients who had a CR or PR.

Statistical analysis
Results were analysed by chi-square test for proportions and by Wilcoxon rank sum test for the comparisons of parametric data between the groups. The calculations were performed using Statview v. 4.5 statistical software (Abacus Concept Inc., Berkeley CA, USA). A two-tailed P-value <0.05 was considered to be statistically significant.



   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Initial treatment
Of the total of 72 patients with idiopathic MN who were diagnosed since 1993 in our department, 12 patients had no NS as defined previously and received no specific treatment. Of the remaining 60 patients, nine were excluded from the analysis because they did not comply strictly to the prescribed treatment (n = 4) or they did not present at the scheduled visits to the clinic (n = 2) or they were lost to follow-up (n = 3). Fifty-one nephrotic patients who fullfiled the inclusion criteria and had a complete follow-up were included in the analysis. Of these, 31 patients received a combination of prednisolone and CyA (combination group) and 20 CyA alone (monotherapy group). There were no significant differences in any of the demographic or laboratory features at baseline between the two groups (Table 1). The severity of tubulointerstitial lesions did not differ between the groups. Mild interstitial fibrosis was diagnosed in 11 patients in the combination group (35%) and in six patients (30%) in the monotherapy group (P = NS). In addition focal tubular atrophy was found in nine patients (29%) of the combination group and in five patients (25%) of the monotherapy group (P = NS). Effects of treatments on remission rates at 6 and 12 months are illustrated in Figure 1. After 6 months of treatment, CR occurred in six patients (19%) of the combination group and in only one (5%) of the monotherapy group (P = NS). PR occurred in 64 and 80% of the patients, respectively. After 12 months of treatment, the rate of CR increased in both groups but remained higher in the combination group (35 vs 20%) although the difference was not significant. At the same time PRs were observed in 15 patients of the combination group (48%) and in 13 patients of the monotherapy group (65%) (P = NS). Taken together after 12 months of therapy 26 patients of the combination group (83%) and 17 patients of the monotherapy group (85%) were either in CR or PR. In eight patients [five in the combination group (17%) and three in the monotherapy group (15%)] who did not respond after 6 months of treatment, CyA was discontinued.


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  		Table 1. Baseline characteristics of the two groups of patients

 

Figure 1
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  		Fig. 1. Remission rates of proteinuria in the two groups at 6 and 12 months.

 
During the study period, the mean CyA trough levels in the combination group were 211 ± 41 ng/ml (range 153–267 ng/ml) and in the monotherapy group 195 ± 180 ng/ml (range 127–305 ng/ml) (P = NS). The mean total dose of prednisolone per patient given during the initial period of treatment (12 months) was 93 mg/kg (range 68–137 mg/kg). All patients completed 12 months of treatment except eight patients who did not respond after 6 months at therapy (mentioned earlier in the article). An increase in baseline creatinine of 30% or more occurred in 13 patients (eight in the combination group and five in the monotherapy group). In all cases, renal function returned to baseline with dose reduction.

At study entry, 10 patients in the combination group (32%) and six in the monotherapy group (29%) were hypertensive. During the period of treatment, six additional patients (five in the combination group and one in the monotherapy group) required antihypertensive medication. In addition, an increase in the dose of the antihypertensive drugs was required in six patients (three in each group). Other signs or symptoms of toxicity were mild hirsutism in 25 patients [15 (48%) in the combination group and 10 (50%) in the monotherapy group], as well as cushingoid and mild hyperglycaemia in 10 (32%) and one (3%) patients, respectively, in the combination group.

After 12 months of treatment, proteinuria decreased and serum albumin increased significantly in both groups, while Scr remained stable (Table 2).


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  		Table 2. Comparative outcome of the two groups after 12 months of treatment

 
Long-term treatment
The long-term treatment included 43 patients who had responded with a complete or partial remission to the 12-month course. The combination group consisted of 26 patients (11 with CR and 15 with PR) and the monotherapy group of 17 patients (four with CR and 13 with PR).

Proteinuria did not differ between the two groups at the time of entry to the long-term protocol (Table 3). Mean Scr was slightly higher in the combination group, but the difference was not significant. The average daily dose of CyA was 1.3 ± 0.4 mg/kg in the combination group and 1.4 ± 0.5 mg/kg in the monotherapy group (P = NS). The mean daily total dose of CyA was 105 ± 25 mg in the combination group and 111 ± 40 mg in the monotherapy group (P = NS). The period of follow-up was 26 ± 16 months in the combination group and 18 ± 7 months in the monotherapy group. During this period, the mean total dose of prednisolone per patient in the combination group was 64 mg/kg (range 49–85 mg/kg).


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  		Table 3. Long-term treatment with CyA. Clinical data of the patients at the beginning of follow-up and cyclosporine dosage throughout the study

 
Relapses and outcome
During this period, four patients relapsed in the combination group (15%) and eight (47%) in the monotherapy group (P < 0.05). The mean time to relapse was 10 ± 2 months in the combination group and 6 ± 4 months in the monotherapy group (P = NS). At the time of relapse the mean dose of CyA was significantly lower in the relapsers in both groups compared with the dose of patients who did not relapse (combination group 1.0 ± 0.3 vs 1.4 ± 0.5 mg/kg/day, P < 0.001 and monotherapy group 1.1 ± 0.2 vs 1.5 ± 0.4 mg/kg/day, P < 0.003). The mean CyA levels in relapsers in both groups were 72 ± 48 ng/ml (range 35–153 ng/ml) and in non-relapsers 194 ± 80 ng/ml (range 100–285 ng/ml) (P < 0.03). The mean trough CyA levels that seemed closely tied to relapse were 69 ± 22 ng/ml (range 40–95 ng/ml) in the combination group and 73 ± 48 ng/ml (range 35–153 ng/ml) in the monotherapy group (P = NS). The mean time to relapse after last measurment of low CyA trough levels was longer in the combination group (11 ± 3.4 months, range 7–15 months) compared with the monotherapy group (5.7 ± 1.8 months, range 3–8 months) although this difference was not significant (P = NS). During relapse, proteinuria increased from 0.6 ± 0.9 to 2.5 ± 0.7 g/24 h in the combination group (P < 0.001) and from 0.9 ± 0.7 to 2.6 ± 0.8 g/24 h in the monotherapy group (P < 0.005). No significant changes in Scr or serum albumin during relapse were seen in either groups (Table 4). All relapses were treated with a temporary increase in the dose of CyA. In two patients of the combination group a temporary increase in the dose of prednisolone was also used for the treatment of the relapse. All patients except one responded to this regimen in a way similar to their initial response. Only one patient, in the combination group who relapsed after the initial CR, remained in PR after treatment of the relapse (Table 5). Scr and daily proteinuria remained stable in both groups during follow-up (Table 5). With regard to side effects, mild tremor was diagnosed in five patients of the combination group (19%) and three of the monotherapy group (17%).


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  		Table 4. Characteristics of patients in both groups before and during relapse

 

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  		Table 5. Comparative clinical data of the two groups after long-term treatment with cyclosporine

 


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
CyA has been used in an uncontrolled fashion [13, 14] and in a few controlled trials in patients with IMN [9, 10]. These studies have shown promising results with respect to both remission of NS and preservation of renal function, together with freedom from serious CyA nephrotoxicity. However, the relapse rate was significant at 33% at 1 year post-CyA treatment, a percentage similar to the one seen with cytotoxics [10, 15]. The usual dose of CyA used in these studies has been 4–6 mg/kg. Also almost all of these studies used CyA in combination with corticosteroids. There are no data with regard to the efficacy of CyA as monotherapy for the treatment of IMN. Also, there are no data regarding the efficacy and safety of lower doses of CyA either in the induction of remission of the NS or in the maintenance of the remission with long-term low-dose treatment.

In this study, after 6 months of therapy, more patients in the combination group were in complete remission (19%) compared with the monotherapy group (5%), although the difference was not significant. At the same time a significant number of patients in both groups were in partial remission (64 vs 80%). The number of patients who failed to respond to therapy was equal in both groups (17 vs 15%). Our results are similar in many respects with those reported by Cattran et al. [10]. After 26 weeks of therapy, total remissions occurred in 75% of their patients which is not much different from the rate recorded in our combination (83%) and monotherapy groups (85%). However, they found a lower rate of complete remissions at 6 months (19 vs 7%), which was almost identical to that obtained in our monotherapy group (5 vs 7%) although they used relatively higher doses of CyA (3.5 vs 2–3 g/kg). The reason for this is not clear, and direct comparisons between different studies are not easy to be made. However, there may be some explanations. Proteinuria at entry was higher in Cattran et al.'s patients (9.7 g/day) which is an indicator of more severe disease but the daily dose of prednisolone was higher in our group (0.6 vs 0.15 mg/kg). These findings may suggest that a combination of prednisolone at a dose used in our study with lower doses of CyA may be more effective in achieving CR in the initial treatment of MN associated with NS of moderate severity and preserved renal function.

It is interesting that on prolonging treatment beyond 6 months, more patients in both groups went into CR. At the end of the 12-month treatment, 35% in the combination group and 20% of patients in the monotherapy group were in CR. The remaining patients were in PR. No relapses were seen during this period of treatment. Similar total remission rates (73%) have been reported by Rostoker et al. [16] who treated nephrotic patients with MN with higher doses of CyA for a median period of 15 months. Moreover, the results of the 12-months treatment in this study are superior to those reported by Cattran et al. [10] who used a shorter protocol. At week 52 of follow-up, only 7.1% of their patients were in CR and 39% were in PR. Thus, prolongation of treatment with lower doses of CyA (±prednisolone) at 12 months, enables a significant proportion of patients to enter into CR, and this policy has become our routine practice for treatment of nephrotic patients with MN.

Hypertension and reversible nephrotoxicity were the major side effects seen in our patients. All patients with suspected nephrotoxicity responded to a decrease in the CyA dose with return to baseline function. None of the patients discontinued treatment. Renal function remained unchanged and serum albumin increased in both groups after 12 months of treatment.

The second aim of our study was to investigate whether a prolonged treatment beyond 12 months with an even lower dose of CyA (±prednisolone) would have increased the response rate or maintained the remission in the responders. Such data are missing in the literature.

Proteinuria and a Scr were comparable in both groups at the beginning of the long-term treatment. The mean daily dose of CyA was comparable in both groups. During the period of follow-up, relapses were more frequently seen in the monotherapy group. The mean time to relapse was shorter in the monotherapy group compared with the combination group. Interestingly, the mean daily dose of CyA at the time of relapse was significantly lower in the relapsers in both groups (around 1.0–1.1 mg/kg) compared with non-relapsers (1.4–1.5 mg/kg). In addition, the mean CyA levels at the time of relapse were significantly lower (<100 ng/ml) in the majority of the patients in both groups, compared with those who did not relapse. Our results indicate that the combination of very low dose of CyA with prednisolone is a better approach to maintain remission of the nephrotic syndrome in MN than monotherapy with CyA. The findings of this study also suggest that a daily CyA dose of 1.4–1.5 mg/kg may be sufficient for maintenance of remission. In contrast, a daily dose of about 1.0–1.1 mg/kg, particularly when associated with CyA trough levels of <100 ng/ml, may increase the likelihood for relapse. In these cases, small doses of corticosteroids may decrease the probability of relapses but the exact mechanism of this favourable effect is not clear. Certainly, our results should be confirmed by further controlled trials and the optimal dose of trough levels of CyA should be tested in larger studies.

There was no evidence that this therapy induced remission but rather, it maintained it. At the time of latest analysis of the results, the remission status remained almost unchanged in both groups. Only one patient in the combination group who relapsed after the initial CR, went finally into PR. This therapy was also associated with stable Scr in both groups. None of the patients who completed the long-term part of the treatment developed chronic renal insufficiency. Our current policy is to maintain this low dose of the drug provided that there are no signs of significant toxic effects. Whether the use of such low dose of CyA for prolonged periods can still be associated with renal toxicity, needs further investigation.

In conclusion, low-doses of CyA combined or not with prednisolone for 12 months are equally effective in inducing remission in most nephrotic patients with MN of moderate severity. The combination of the two drugs increases the chances for CR. Prolonged treatment may be useful in maintaining the remission provided that the daily dose of CyA should be in the range of 1.4–1.5 mg/kg. Relapses occur more frequently in the monotherapy group, when the daily dose of CyA is lower (1.0–1.1 mg/kg) or the CyA trough levels are below 100 ng/ml. A low dose of corticosteroids, however, may help in reducing the frequency of relapses. These results suggest that this treatment is rational and an important option in the management of patients with MN either as initial therapy or as long-term treatment.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Cattran DC, Delmore T, Roscoe J, et al. (1989) A randomized controlled trial of prednisone in patients with idiopathic membranous neprhopathy. N Engl J Med 320:210–215.[Abstract]
  2. Cameron JS, Healy MJ, Adu D. (1990) The Medical Research Council trial of short-term high-dose alternate day prednisolone in idiopathic membranous nephropathy with nephrotic syndrome in adults: the MRC Glomerulonephritis Working Party. Q J Med 74:133–156.[Web of Science][Medline]
  3. Ponticelli C, Zucchelli P, Passerini P, et al. (1995) A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int 48:1600–1604.[Web of Science][Medline]
  4. Ponticelli C, Altieri P, Scolari F, et al. (1998) A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. J Am Soc Nephrol 9:444–450.[Abstract]
  5. Donadio JV, Holley KE, Anderson CF, Taylor WF. (1974) Controlled trial of cyclophosphamide in idiopathic membranous nephropathy. Kidney Int 6:431–439.[Web of Science][Medline]
  6. Shearman JD, Zhou GY, Aarons I, et al. (1988) The effect of treatment with prednisolone or cyclophosphamide, warfarin and dipyridamole combination on the outcome of patients with membranous nephropathy. Clin Nephrol 30:320–329.[Web of Science][Medline]
  7. Alexopoulos E, Sakellariou G, Memmos D, Karamitsos K, Leontsini M, Papadimitriou M. (1993) Cyclophosphamide provides no additional benefit to steroid therapy in the treatment of idiopathic membranous nephropathy. Am J Kidney Dis 21:497–503.[Web of Science][Medline]
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  11. Ehrenreich T and Churg J. (1986) Pathology of membranous nephropathy. In Sommers SC (Ed.). Pathology Annual(New York, Appleton-Century-Crofts) pp. 145–186.
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  15. Ponticelli C and Villa M. (1999) Does cyclosporine have a role in the treatment of membranous nephropathy? Nephrol Dial Transplant 14:23–25.[Web of Science]
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Received for publication: 6. 6.05
Accepted in revised form: 23. 5.06


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