A 10-year follow-up of idiopathic membranous nephropathy patients on steroids and cyclophosphamide: a case series

Abstract

The studies of idiopathic membranous nephropathy (IMN) require sufficiently long duration of follow-up to understand the effect of treatment on the development of end-stage renal disease (ESRD) in IMN. The aim was to assess the remission rates with steroids and cyclophosphamide regimen for IMN at the end of 10 years of follow-up. A prospective, open-label study performed in Nephrology department of a state run tertiary care centre in a southern state of India. Adult (age >18 years) patients with biopsy-proven IMN of at least 6-month duration were included in the study. Patients received a 6-month course of alternate months of steroid and cyclophosphamide. The patients were followed for 10 years. Study end points were doubling of serum creatinine, development of ESRD, or death. A total of 58 IMN patients were recruited from 1997 to 2001. Out of 58 patients included, only 48 patients could complete the treatment schedule in six months. The remission rate at the end of 10 years was 58.6% (34 in 58 patients). The probability of dialysis-free survival in our study was 89.6% at the end of 10 years follow-up. The regimen of steroids and cyclophosphamide in IMN had a remission rates not as high as reported before. It was associated with high relapse rates and more infections.

• Idiopathic membranous nephropathy
• steroids
• cyclophosphamide
• follow-up
• remission

Introduction

Idiopathic membranous nephropathy (IMN) is the most common cause of nephrotic syndrome in adults.1 A universal consensus of modality of therapy is lacking. The regimen proposed by Ponticelli et al.2^,3 has shown both short-and long-term benefits. Most untreated patients with IMN have maintained renal functions for prolonged periods, and hence no treatment was suggested by Schieppati et al.4 Emergence of several new modalities of treatment like mycophenolate mofetil, immunoglobulins and rituximab is exciting, but has not substituted for treatment with steroids and cyclophosphamide.5 The studies require sufficiently long duration of follow-up to understand the effect of treatment on the development of end stage renal disease (ESRD) in IMN. A substantial proportion (about 40–50%) of IMN eventually progress to ESRD at the end of 15 years and some succumb to complications of the nephrotic state.6 In a systematic review which included all studies reported up to 1994, Hogan et al.7 found renal survival averaged about 50% at 14 years. There were only two studies3^,5 in the past with 10-year follow-up of IMN patients. The objective of this study was to assess the remission rates with steroids and cyclophosphamide regimen for IMN at the end of 10 years of follow-up.

Materials and methods

Study design

A prospective study was conducted with the regimen of steroids and cyclophosphamide in adult (age >18 years) patients with biopsy-proven IMN of at least 6 months duration. The study was done in the Nephrology department of a state run tertiary care centre in a southern state of India. It was done as an academic study with no funding from any source. Institute Ethics Committee approval was taken before the start of the study. The number of patients of IMN screened between 1997 and 2001 were 182. Out of which, sixty-seven patients dropped out or were irregular in visits to OPD after initial few consultations. This was mainly due to lack finances. The inability for repeated visits to OPD and admission for injection methyl prednisolone was cited as the reason by 40 patients. At our institute renal biopsy is done free; subsequent treatment is charged. The consent was not given by 17 patients for cyclophosphamide therapy. New patients were not considered to the study after December 2001, though the treatment protocol of idiopathic membranous nephropathy at our Institute continued to be the same. The last dose of cyclophosphamide was given in March 2001. A parallel group of patients receiving either calcineurin inhibitors or mycophenolate mofetil was not considered as in our unit, these drugs are usually recommended for the patients who relapsed after the regimen of steroids and cyclophosphamide.

Nephrotic syndrome was defined8 as proteinuria 40 mg/m²/hour along with serum albumin <3.0 g/dL, edema and hyperlipidemia. Complete remission (CR) was defined as when the proteinuria declined to <300 mg/d on at least three occasions checked once a week for three weeks, along with serum albumin >3.0 g/dL and disappearance of edema. Partial remission (PR) was defined 50% reduction in proteinuria from its peak value.9 Relapse of nephrotic syndrome was defined as proteinuria 40 mg/m²/hour along with serum albumin <3.0 g/dL, edema and hyperlipidemia. End stage renal disease was defined as requirement of dialysis. Hypertension was defined as supine BP >140/90 mmHg. Kidney biopsy was evaluated by light microscopy and immunofluorescence. Patients with normal serum creatinine with proteinuria between 4 and 8 g/day were included in the study. No patient with proteinuria less than 4 g/day was included. Patients with systemic illness, malignancy, diabetes mellitus, and hepatitis B surface antigen positivity, or renal vein thrombosis and those who had received steroids or immunosuppressive drugs for two months at any time in the course of illness were excluded from the study.

Treatment

Patients received a 6-month course of alternate months of steroids and cyclophosphamide. The treatment regimen consisted of intravenous methylprednisolone (Solu-Medrol; Pfizer, New Delhi, India) 1 g/d for 3 consecutive days followed by oral prednisolone (prednisolone; Wysolone; Wyeth Limited, Mumbai, India) 0.5 mg/kg per day for 27 days in the first, third, and fifth months and oral cyclophosphamide (Endoxan; Baxter India Pvt Ltd, New Delhi, India) at 2 mg/kg per day in the second, fourth, and sixth months. Patients also received angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blockers, statins and dietary sodium restriction, diuretics, and antihypertensive agents. All medications except the steroids and cyclophosphamide were continued for the 10-year period.

Follow-up

During treatment with steroids and cyclophosphamide, the patients were seen once a month. After that the follow-up visits were scheduled for every two months for six months, and thereafter every six months or more frequently when required for a total period of 10 years. Parameters monitored included 24-h urinary protein, serum creatinine, blood urea, serum sodium, serum potassium, serum protein, serum albumin, serum cholesterol, hemogram and complete urine examination at each visit. Treatment was halted when a patient exhibited any evidence of active ulcer disease, neoplasm, diabetes, and/or life-threatening infections. Pregnant women were also withdrawn from the study. Study end points were doubling of serum creatinine, development of ESRD, or patient death.

Results

A total of 58 IMN patients were recruited from 1997 to 2001. Out of 58 patients included, only 48 patients could complete the treatment schedule in six months. There were complications of treatment in six patients during the treatment phase and four more patients could not complete treatment in six months owing to financial constraints. These 10 patients took 9.7 ± 2.1 months. The entire group could complete the treatment phase in 6.6 ± 1.3 months. The complications developed in six patients were, one patient each of pulmonary tuberculosis (completed treatment in 14 months), psychosis (completed treatment in 11 months), bone marrow suppression (completed treatment in 12 months), acute pancreatitis, myocardial infarction and gastric intolerance to steroids. The characteristics of patients are shown in Table 1. The outcomes of the patients are shown in Table 2.

Table 1. Baseline characteristics of the patients.

Characteristic	Result
Number of patients	58
Age (mean) (years)	38.1
Age: range (years)	22 to 63
Male: female	40: 18
Duration of symptoms of nephrotic  symptoms prior to presentation (months)	10.7 ± 1.0*
Hypertension	6 (10.34%)
Serum creatinine in µmol/L (mg/dL)	108.7 ± 18.5 (1.2 ± 0.2)
Blood urea nitrogen in mmol/L (mg/dL)	17.8 ± 4.6 (6.3 ± 2.7)
Hemoglobin in g/L (g/dL)	129 ± 15 (12.9 ± 1.5)
Total serum proteins in g/L (g/dL)	48 ± 8 (4.8 ± 0.8)
Serum albumin in g/L (g/dL)	24 ± 3 (2.4 ± 0.3)
Serum cholesterol mmol/L (mg/dL)	8.5 ± 2.8 (329.1 ± 111.5)
24-hour urine protein (g/day)	6.1 ± 0.0.9
Mean number of glomeruli on renal biopsy	14.8 ± 7.9
Percentage of patients with 30% of glomeruli  sclerosed on renal biopsy	12.0
Percentage of patients with interstitial fibrosis  and tubular atrophy on renal biopsy	15.5
eGFR (mL/min/1.73 m^2)**	59.4 ± 21.8

Notes: *Based on history.

**Calculated using 6-variable MDRD formula.

Table 2. Progression in patients.

Number of patients (%)	9 Months	18 Months	36 Months	60 Months	96 Months	120 Months
Remission (CR + PR)	45 (77.5%)	43 (74.1%)	45 (77.5%)	42 (72.4%)	38 (65.5%)	34 (58.6%)
Complete remission	18 (31.0%)	18 (31.0%)	18 (31.0%)	16 (27.5%)	16 (27.5%)	16 (27.5%)
Partial remission	27 (46.5%)	25 (43.1%)	27 (46.5%)	24 (41.3%)	22 (37.9%)	18 (31.0%)
Persistent nephrotic syndrome or relapse*	13 (22.4%)	14 (24.1%)	10 (17.2%)	12 (20.6%)	14 (24.1%)	11 (18.9%)
Doubling of serum creatinine*	–	1 (1.7%)	3 (5.1%)	4 (6.8%)	5 (8.6%)	7 (12.0%)
ESRD	–	–	–	–	1 (1.7%)	6 (10.3%)
Death	–	–	–	–	–	–

Note: *Patients whose serum creatinine had doubled were not considered in the category of persistent nephrotic syndrome.

The median doses of enalapril and ramipril during follow-up were 12.5 mg/d in two divided doses. The median dose of losartan during follow-up was 62.5 mg/d in two divided doses. The other anti hypertensives used were: amlodipine, metoprolol and prazosin. The median blood pressure was 125/80 mm Hg. Atorvastatin was also given in a median dose of 10 mg/d.

There were 11 (out of 58; 18. 9%) who had persistent or relapsed nephrotic syndrome at the end of 120 months. The mean proteinuria was 4.82 ± 0.68 g/day. They were treated with ACEi and angiotensin receptor blockers. No immunosuppression was given to them.

Discussion

There are two different extremes of approach to patients of IMN with nephrotic syndrome. While some clinicians favor an early treatment at the time of presentation, others prefer to treat the patient after a six-month observation period with regular follow-up. Waiting for six months may be too late, since even a moderate increase of serum creatinine may reflect an underlying development of irreversible histological lesions that markedly reduce the chances of a beneficial response to treatment. Moreover, an early treatment can prevent the potential complications of nephrotic syndrome. Those who argue against early treatment point that some 40–50% of patients would receive an unnecessary treatment since they will not develop ESRD. Unfortunately, it is not easy to recognize at the time of initial presentation which patient will have an uncomplicated, favorable evolution and which patient is destined to develop renal failure.10

In our study, at presentation a thorough history was taken to ascertain the time of onset of first symptom before the presentation and also whether there was reduction in swelling of feet or disappearance of frothy urine. The patients in the present study had presented several months (10.7 ± 1.0 months) after the onset of symptoms (Table 3). During this period, none of them had reduction in swelling of feet or disappearance of frothy urine. In addition, all patients were in medium risk of progression category.11 It was possible that during this period the patients might not have received any treatment or might have received a diuretic. In the medium risk of progression category conservative management was for six months only.

Table 3. Complications of therapy.

Complications
Psychosis	One patient each
Gastric intolerance to- cyclophosphamide
Acute pancreatitis
Myocardial infarction
Herpes zoster	2 Each
Bone marrow suppression
Pulmonary tuberculosis	9
Impaired glucose tolerance	5
Drug reaction	3
Total	25/58 (43.10%)

Considering these conditions and others like illiteracy, ignorance, poverty and malnutrition in our country, it was therefore decided that the waiting further for spontaneous remission was not prudent.

As the patients presented several months after the onset of symptoms, there was no method to ascertain that the patients had a spontaneous remission and presented to us in a relapse. In a previous Indian study, spontaneous remission was documented in 35% of patients in supportive treatment group.5

Though Schieppati et al.4 reported high rates (65% at 5 years) of spontaneous remission, other Italian study done during the same period reported only 5% of untreated patients with IMN and nephrotic syndrome in complete remission after 10 years of follow-up3.

The strength of the study was the 10-year follows up of the patients of IMN treated with a combination of steroids and cyclophosphamide. The combination of steroids and cytotoxic therapy had favorably affected the long-term natural history of IMN. The remission rates of the two previous prospective studies with a 10-year follow-up are given in Table 4.

Table 4. Previous studies.

Reference	Number of patients	Initial remission rates	At 10-year follow-up
2, 3	42	30 (71.4%) at 2 years	92% Without developing ESRD
5	47	34 (72.3%) at 1 year	89% Dialysis free survival

In our study the remission rate at the end of 18 months was 43 (74.1 %) of 58 patients. At the end of 120 months, 34 (58.6%) of 58 patients were in remission. The probability of dialysis-free survival in our study was 89.6% at the end of 10 years follow-up. The reason for low remission rates at 120 months could be difficult in completing scheduled six months of treatment in time. The two features – presentation after several months of onset of symptoms and difficulty in completing treatment, are common for the majority in a developing country. The previous Indian study5 on the treatment of idiopathic membranous nephropathy was silent on these difficulties.

The side effects of the steroids and cyclophosphamide were 43.1%, higher than the two previous studies of 10-year follow-up. Ponticelli et al.2 reported side effects in 29% of patients treated with chlorambucil, most commonly gastrointestinal problems, including peptic ulcers. Ten percent of treated patients had to stop therapy because of side effects, and all patients recovered after adequate therapeutic measures. In the other Indian study,5 infections were dominant, but there was no difference between the steroids and cyclophosphamide and supportive treatment groups in the incidence of infections.

The relapse rates in the previous studies were 26%3 and 24%.5 In the present study at 120 months there were 11 out of 58 (18.9%) who had persistent or relapsed nephrotic syndrome. They were treated with ACEi and angiotensin receptor blockers. No immunosuppression was given.

The probability of dialysis free survival in our study was 89.6% at the end of 10 years follow-up. Pooled data from several studies show that approximately 50% of patients with nephrotic range proteinuria exhibit deterioration in renal function, and the corrected 10-year renal survival varied between 49 and 63%.12 Notwithstanding, the complication of pulmonary tuberculosis and persistent or relapsed nephrotic syndrome patients, the two features that should have been the arguments against the therapy, the 10-year dialysis-free survival achieved in this study was an encouraging feature.

The eGFR, using the 6-variable Modification of Diet in Renal Disease had suggested the presence of renal impairment at the onset of study. It highlights that the patients in the present study also had similar renal impairment and had shown favorable results with steroids and cyclophosphamide therapy. Other investigators have regularly used serum creatinine values to define renal function. It is now realized that the often used threshold value of 1.5 mg/dL (135 µmol/L) in reality already indicated the presence of renal impairment. The use of serum creatinine level as a marker of glomerular filtration rate was problematic in patients with nephrotic syndrome, as it was observed that the creatinine secretion was increased in patients with nephrotic syndrome, thus leading to marked overestimation of GFR.13 It was hence recommended that even slight increase in serum creatinine level indicated renal impairment and was used to calculate eGFR using 6-variable Modification of Diet in Renal Disease formula, which gives credence to serum albumin also.12

In our patients the mean GFR was less than 60 mL/min/1.73 m2. It suggested that our patients were in chronic kidney disease stage 2.

Patients in the present study, therefore, represented a group who progressed to renal impairment before they received a definitive treatment. The use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in IMN was not effective,12 and use of ACEi was not found to be an independent predictor of outcome in a cohort of IMN.14

The long-term value of renin angiotensin system blockade in the management of IMN has been assessed largely by observational studies.15 Hence, failure to use these two classes of drugs before presenting to us should not be strictly taken as a risk factor for progression of patients in our patients.

Including this study, the three studies with a 10-year follow-up revealed more than 50% remission (CR + PR) rates. But the Cochrane meta-analysis12 concluded that there was only weak evidence in favor of alkylating agents in inducing remission of proteinuria, especially in those with preserved renal function; but the renal failure, ESRD, and death were not favorably influenced by cytotoxic agents. But it was later learnt that the meta-analysis was dominated by three studies, out of which, two had 12 and 24 months follow-up16^,17 and third one had retrospectively studied control patients.18

The limitations of this study were: (1) only 31.8% (58 out of 182) of IMN patients were included in the study. (2) Risk stratification of patients could not be done. It was not done because patients were in medium risk of progression. The standard deviations in the Table 1 depict the lack of dispersion of the 24 hour urine protein values in patients. (3) Ten patients required 9.7 ± 2.1 months to complete therapy. These patients might have influenced the outcome negatively.

The present study was not an ideal trial, but in a real life practice in a developing country conditions induce delayed presentation, irregular follow-up and drop out. The main messages of the study were: long-term follow-up studies were required to understand the effect of treatment of IMN. The remission rates after 10 years of steroids and cyclophosphamide was lower than initial remission rates. A future research opportunity is a study of patients of IMN with renal impairment according to eGFR, using the 6-variable Modification of Diet in Renal Disease.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.