Original Article
Prognosis of Untreated Patients with Idiopathic Membranous Nephropathy
N Engl J Med 1993; 329:85-89July 8, 1993
- Abstract
Background
Defining the most appropriate treatment for patients with idiopathic membranous nephropathy is a matter of controversy. The course of the disorder is often benign, and the immunosuppressive regimens used in some patients have uncertain benefits and substantial risks. We studied the natural history of idiopathic membranous nephropathy in patients who received only symptomatic therapy.
Methods
We prospectively studied 100 consecutive patients (68 men and 32 women; mean [±SD] age, 51 ±17 years) with biopsy-proved idiopathic membranous nephropathy. The patients received diuretic or antihypertensive drugs as needed, but no glucocorticoid or immunosuppressive drugs. We examined the patients and measured their urinary protein excretion and serum creatinine concentrations every 6 months for a mean of 52 months.
Results
Twenty-four (65 percent) of the 37 patients followed for at least five years had complete or partial remission of proteinuria; in 6 others (16 percent), end-stage renal disease developed, and they required dialysis. As calculated by the Kaplan-Meier method, the estimated probability (±the standard error of the estimate) of retaining adequate kidney function was 88 ±5 percent after five years and 73 ±7 percent after eight years. The prognosis was poorer in men and in patients over 50 years of age, but not in patients with the nephrotic syndrome, hypertension, or hypercholesterolemia.
Conclusions
Most untreated patients with idiopathic membranous nephropathy maintain renal function for prolonged periods and are likely to have spontaneous remission. These results do not support the use of glucocorticoids and immunosuppressive drugs in patients with idiopathic membranous nephropathy.
Media in This Article
Figure 1
Mean (+SD) Changes in the Reciprocal of the Serum Creatinine Concentration and in 24-Hour Urinary Protein Excretion in Untreated Patients with Idiopathic Membranous Nephropathy Followed for Five Years.Figure 2
Mean (+SD) Changes in the Reciprocal of the Serum Creatinine Concentration and in 24-Hour Urinary Protein Excretion in Untreated Patients with Idiopathic Membranous Nephropathy Who Maintained Renal Function Throughout the Follow-up Period.Article Activity
- Article
Defining the appropriate treatment for idiopathic membranous nephropathy -- the most common cause of the nephrotic syndrome in adults -- is controversial1-15. The course of the disorder is often benign, but it can result in renal failure. Several regimens of glucocorticoids, immunosuppressive drugs, or both have been used,1-11 but the results are contradictory. Of the 10 controlled trials that have been conducted, only 5 produced results favoring therapy. Furthermore, prolonged therapy with these agents may not be justified,16,17 given the risks of Cushing's syndrome, myelotoxicity, skin cancer, lymphoma, and leukemia18-20. On the other hand, data on the natural history of membranous nephropathy are sparse, since most patients have received some glucocorticoid or immunosuppressive treatment for at least a short time.
In 1974 we began a prospective study of patients with biopsy-proved idiopathic membranous nephropathy who received only symptomatic therapy, consisting of diuretic and antihypertensive drugs and dietary restrictions, as required. When the results of a trial of methylprednisolone and chlorambucil became available,7 we formally compared our results with those in the treated patients in that trial21. The results did not convince us that the proposed protocol was superior to no glucocorticoid or immunosuppressive treatment. We therefore continued our no-treatment policy. We report here the long-term results in the first 100 patients who received only symptomatic treatment.
Methods
Patients
We studied 107 consecutive patients with newly diagnosed, biopsy-proved idiopathic membranous nephropathy who presented from 1974 to 1992 to the division of nephrology because of proteinuria or edema. Our analysis included the results for 100 patients (Table 1Table 1
Base-Line Clinical and Laboratory Data for 100 Patients with Idiopathic Membranous Nephropathy.); the remaining 7 were excluded because their data were incomplete. The minimal follow-up was six months.The pathological criteria for the diagnosis were those of Ehrenreich and Churg: stage I, subepithelial dense deposits; stage II, presence of basement-membrane spikes (silver-staining segments of basement membrane between dense deposits); stage III, incorporation of the dense deposits in the basement membrane; and stage IV, markedly thickened basement membrane22.
None of the patients had any systemic illness, and none received any form of immunosuppression, including glucocorticoids, at any time. Hypertension was treated with a variety of antihypertensive drugs (beta-adrenergic antagonists, calcium-channel antagonists, and angiotensin-converting-enzyme inhibitors), and diuretic drugs (most often furosemide and chlorothiazide) were used to control edema. After 1980, patients who had normal renal function were advised to eat a diet containing 1 g of high-biologic-value protein per kilogram of body weight per day, and those with impaired renal function (serum creatinine concentration, >2 mg per deciliter [177 μmol per liter]) were advised to eat a diet containing 0.6 to 0.8 g of protein per kilogram per day. Patients with edema were advised to restrict their sodium intake to 30 to 50 mmol per day. Physical activity was not restricted.
The patients were evaluated every six months, or more often if needed, during follow-up. At these visits, a physical examination was performed, weight and blood pressure were measured, and serum creatinine, albumin, and cholesterol concentrations and 24-hour urinary protein excretion were determined by standard laboratory methods.
Outcome Measures
The outcome measures were arbitrarily defined as follows. The nephrotic syndrome was considered to be present if urinary protein excretion was ≥ 3.5 g per 24 hours, the serum albumin concentration was <2.5 g per deciliter, and the patient had variable edema. Sustained proteinuria was defined as urinary protein excretion >2.0 but <3.5 g per 24 hours. Partial remission was defined as urinary protein excretion between 0.2 and 2.0 g per 24 hours and a serum albumin concentration ≥ 2.5 g per deciliter, and complete remission as urinary protein excretion ≤ 0.2 g per 24 hours. Kidney failure was defined as the development of end-stage renal disease, as evidenced by a glomerular filtration rate of <10 ml per minute or the need for regular dialysis. Hypertension was defined as systolic blood pressure ≥ 160 mm Hg, diastolic blood pressure ≥ 95 mm Hg, or both.
Statistical Analysis
The retention of adequate renal function was estimated by survival analysis with the method of Kaplan and Meier23. The relation of covariates to the retention of adequate renal function was assessed by univariable analysis with the log-rank test24 and by multivariable analysis with a proportional-hazards model25. The time of renal biopsy was fixed as the starting point for the calculation of the survival curves. Patients were followed until they died or began regular dialysis treatment. Data on patients whose condition had not progressed to end-stage renal disease were excluded from analysis at the time of the last visit.
Results
The base-line clinical and laboratory data for the 100 patients with membranous nephropathy at the time of renal biopsy whom we have followed since 1974 are shown in Table 1. There were 68 men and 32 women. The mean duration of follow-up was 52 months (range, 6 to 208; median, 39). The mean (±SD) urinary protein excretion was 5.1 ±3.6 g per 24 hours (range, 0.58 to 16.8). The majority of the patients excreted between 2 and 10 g of protein per 24 hours; only 10 percent excreted 10 g or more. Fifty-five percent of the patients had hypertension. According to the staging system of Ehrenreich and Churg,22 24 patients had stage I glomerular changes, 51 stage II, 20 stage III, and 5 stage IV.
During follow-up, end-stage renal disease requiring regular dialysis developed in 14 patients, after a mean interval of 71 ±32 months (range, 33 to 136). Among the other 86 patients, at the last visit 68 had renal function that was normal to slightly impaired (serum creatinine concentration, ≤ 1.5 mg per deciliter [132 μmol per liter]), 15 had moderate renal insufficiency (serum creatinine concentration, >1.5 to ≤ 3.0 mg per deciliter [265 μmol per liter]), and 3 had severe renal insufficiency (serum creatinine concentration, >3.0 mg per deciliter). Six patients died, four after the initiation of regular dialysis and two while they still retained some renal function. The causes of death were cardiovascular disease in four patients, infection in one, and massive pulmonary embolism in one.
The changes in renal function in all the patients, expressed as the reciprocal of the serum creatinine concentrations over a five-year period, are shown in Figure 1Figure 1
Mean (+SD) Changes in the Reciprocal of the Serum Creatinine Concentration and in 24-Hour Urinary Protein Excretion in Untreated Patients with Idiopathic Membranous Nephropathy Followed for Five Years.. Renal function deteriorated slightly during the first 36 months of follow-up, then stabilized. Among the 37 patients followed for at least five years, the mean serum creatinine concentration in the 31 who did not have end-stage renal failure was 1.4 ±1.2 mg per deciliter (123 ±104 μmol per liter). The changes in urinary protein excretion during follow-up also are shown in Figure 1. The mean daily protein excretion decreased below 3.5 g per 24 hours in the majority of patients. The results in the patients who maintained renal function throughout the follow-up period were similar (Figure 2Figure 2Mean (+SD) Changes in the Reciprocal of the Serum Creatinine Concentration and in 24-Hour Urinary Protein Excretion in Untreated Patients with Idiopathic Membranous Nephropathy Who Maintained Renal Function Throughout the Follow-up Period.).The overall prognosis of the patients, assessed as the probability of maintaining life-supporting renal function, was estimated by the product-limit method. The end point of the analysis was the development of end-stage renal disease. The probability of retaining adequate renal function was 88 ±5 percent at five years and 73 ±7 percent at eight years (Figure 3Figure 3
Probability of Adequate Renal Function in Untreated Patients with Idiopathic Membranous Nephropathy.).The proportion of patients who had partial or complete remissions increased as a function of time (Figure 4Figure 4
Changes in the Clinical Status of Patients with Idiopathic Membranous Nephropathy.). Thirteen (35 percent) of the 37 patients followed for five years continued to have the nephrotic syndrome or sustained proteinuria. Among these patients, six had the nephrotic syndrome throughout the follow-up period, and seven relapsed after a partial remission. Of the 13 patients who had urinary protein excretion >2.0 but <3.5 g per 24 hours at base line, 7 had partial remissions; their protein excretion decreased from 2.4 ±0.3 to 1.2 ±0.5 g per day. The remaining six patients had sustained proteinuria or the nephrotic syndrome at the end of the follow-up period. Of the 24 patients followed for at least five years who had complete or partial remissions, 20 had serum creatinine concentrations ≤ 1.5 mg per deciliter. Of the 13 patients who still had 24-hour urinary protein excretion >2.0 g after five years, 6 had serum creatinine concentrations ≤ 1.5 mg per deciliter.The probability of kidney survival was assessed according to different explanatory variables by univariable and multivariable analysis. The presence of the nephrotic syndrome, hypertension, elevated urinary protein excretion, or elevated serum cholesterol concentration at base line was not predictive of kidney survival (Table 2Table 2
Probability of Retention of Adequate Renal Function at Eight Years in Patients with Idiopathic Membranous Nephropathy, According to the Presence or Absence of Variables at Base Line.). Among the patients with normal serum creatinine concentrations the presence of the nephrotic syndrome was not predictive of kidney survival. Patients under 50 years of age had a better prognosis. Because women also had a better prognosis, we further analyzed the data with respect to the rate of complete or partial remission of proteinuria during follow-up. Sixty-two percent of the women and 59 percent of the men were in complete or partial remission at four years (P>0.05).The five-year rates of kidney survival for subgroups classified according to urinary protein excretion at base line indicated that the level of initial proteinuria was not predictive of the retention of renal function (Table 3Table 3
Probability of Five-Year Kidney Survival According to the Degree of Proteinuria at Base Line.). The apparently poorer rate of kidney survival among patients with urinary protein excretion ≥ 10 g per 24 hours was not statistically significant, owing to the small number of patients and the large standard error of the estimate.Discussion
The results of this study demonstrate that patients with idiopathic membranous nephropathy who receive only symptomatic treatment have a relatively benign course. The probability that end-stage renal disease would not develop was 88 percent after five years of follow-up and 73 percent after eight years. The results of this study and the few other published reports that allow the calculation of survival curves in untreated patients indicate that the probability of maintaining renal function five years after the onset of the disease ranges from 70 to 92 percent12-14,26-28.
One factor that had a major impact on renal survival in our patients was the frequency of complete or partial remission of proteinuria. Convincing evidence has accumulated in the past few years that patients who have a remission of proteinuria, whether spontaneous or associated with some form of immunosuppressive therapy, have a favorable long-term prognosis17. Any reduction in proteinuria would also be of benefit to the patient in terms of reducing elevated serum lipid concentrations, a risk factor for cardiovascular complications associated with the nephrotic syndrome29,30.
A major finding of this study was that the percentage of patients undergoing spontaneous remission increased with time. This finding supports the suggestion16 that prolonged follow-up may be needed before one can conclude that an individual patient will not have a spontaneous remission. Data from most studies indicate that spontaneous remissions occur in 40 to 67 percent of patients within three to eight years12,13,16. The differences probably reflect differences in prognostic variables such as race, sex, hypertension, base-line urinary protein excretion, and serum creatinine concentration.
In one previously reported series,9 proteinuria remitted in five years in 40 percent of the untreated patients, a frequency lower than that in our series. The explanation for the difference is not known. The patients were presumably comparable with respect to prognostic variables and were from the same part of Italy.
In another study26 60 percent of the untreated patients had spontaneous remission of proteinuria within three years, as compared with 58 percent of the group treated with glucocorticoids.
The age at diagnosis is a major prognostic factor in patients with idiopathic membranous nephropathy. For instance, young patients, particularly those younger than 16 years, have a benign course, with stable renal function and a tendency toward spontaneous remission31. We found that an age of 50 years or more was associated with a significantly reduced probability of renal survival. Even if one accepts the assumption that immunosuppressive treatment can prevent progressive renal insufficiency in patients with an unfavorable prognosis,17 our analysis and other results32 pose another difficult problem: older patients, in whom treatment may be warranted, are those most likely to have unacceptable side effects from immunosuppressive drugs32.
We suggest that until new data or new drugs become available, symptomatic treatment is still the best option for patients with idiopathic membranous nephropathy.
Source Information
From the Mario Negri Institute for Pharmacological Research (A.S., L.M., A.P., T.B., S.G., G.R.) and the Division of Nephrology and Dialysis, Ospedali Riuniti di Bergamo (A.S., G.M., T.B., G.R.), both in Bergamo, Italy.
Address reprint requests to Dr. Schieppati at the Mario Negri Institute for Pharmacological Research, Centro di Ricerche Cliniche per le Malattie Rare, Villa Camozzi, 24020 Ranica, Italy.
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