Treatment of idiopathic membranous nephropathy UpToDate

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Treatment of idiopathic membranous nephropathy
Author: Daniel C Cattran, MD
Section Editors: Richard J Glassock, MD, MACP, Fernando C Fervenza, MD, PhD
Deputy Editor: Albert Q Lam, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2017. | This topic last updated: Nov 09, 2016.
INTRODUCTION — Membranous nephropathy (MN) is among the most common causes of the nephrotic
syndrome in nondiabetic adults, accounting for up to one-third of biopsy diagnoses. (See "Overview of heavy
proteinuria and the nephrotic syndrome", section on 'Etiology'.)
MN in adults is most often idiopathic (approximately 75 percent of cases) but can be caused by a variety of
drugs, infections, and underlying diseases. These include gold, penicillamine, systemic lupus erythematosus,
malignancy, and hepatitis B and C virus infection (table 1).
It is often not possible to distinguish idiopathic from secondary MN on clinical grounds alone, even though
serologic studies (eg, antinuclear antibodies, hepatitis B serology) and a history of drug exposure or cancer may
be revealing of a potential cause. However, there are certain findings on electron microscopy and
immunofluorescence that suggest secondary disease. In patients with secondary MN, cessation of the offending
drug or effective treatment of the underlying disease is usually associated with improvement in the nephrotic
syndrome. (See "Causes and diagnosis of membranous nephropathy".)
The treatment of idiopathic MN, beginning with a review of the natural history and risk factors for progressive
disease, will be presented here. The clinical trials supporting the efficacy of initial immunosuppressive regimens
and the effectiveness of alternative agents in unresponsive patients are discussed in detail separately. (See
"Alternative agents in the treatment of idiopathic membranous nephropathy".)
NATURAL HISTORY — In view of the potential toxicity of the drugs used to treat idiopathic membranous
nephropathy (MN), with or without the nephrotic syndrome, the decision to initiate therapy is based, in part, upon
an understanding of the natural history of untreated patients, with and without features of the nephrotic syndrome
at presentation [1-4]:
The relatively benign short-term course in many patients with idiopathic MN was illustrated in a report of 100
consecutive patients who received no immunosuppressive therapy [2]. The incidence of spontaneous remission
increased over time. Of the 37 patients followed for at least five years, 65 percent were in complete or partial
remission, and 16 percent had progressed to end-stage renal disease (figure 1).
Most of the patients in this study had only mild to moderate disease. At baseline, the mean serum creatinine was
1.1 mg/dL (97 micromol/L), only 41 percent had edema, 37 percent were nonnephrotic (protein excretion less
than 3.5 g/day), and 56 percent excreted less than 5 g of protein per day.
Risk factors for progressive idiopathic MN — In view of the often benign clinical course, immunosuppressive
®
®
Spontaneous complete remission of proteinuria occurs in 5 to 30 percent at five years [2-4]●
Spontaneous partial remission (≤2 g of proteinuria per day) occurs in 25 to 40 percent at five years [2-4]●
The occurrence of end-stage renal disease in untreated patients is approximately 14 percent at five years,
35 percent at 10 years, and 41 percent at 15 years [1,4]
●
agents should be considered only in those with idiopathic MN who are most at risk for progressive disease or
who have severe symptomatic nephrotic syndrome. Both histologic and clinical findings may be important in risk
assessment.
Clinical findings — Clinical findings associated with a higher risk of developing end-stage renal disease
include older age at onset (particularly greater than 50 years), male sex, nephrotic-range proteinuria (particularly
if protein excretion exceeds 8 to 10 g/day), and an increased serum creatinine at presentation [2,5-10].
In contrast to these adverse risk factors, women, children, and young adults, nonnephrotic-range proteinuria, a
progressive decline in protein excretion, and presentation with normal renal function have been associated with a
relatively benign course [1,3,11-13]. In addition, patients of Asian ancestry seem to have a better long-term
prognosis than other ancestries [5].
The following studies illustrate the prognostic importance of certain clinical features [5,8-10,12-14]:
A review of the literature analyzed the evidence concerning the clinical significance of the above risk factors for
progressive deterioration of renal function among patients with idiopathic MN [11]. The following conclusions
were drawn:
In a series of 184 patients with idiopathic MN from Toronto, Canada the overall likelihood of progressing to a
creatinine clearance ≤60 mL/min per 1.73 m was 26 percent at a mean follow-up of 5.8 years [8]. In
contrast, the risk was 66 percent in patients with proteinuria exceeding 8 g/day for more than six months.
●
2
Among 949 nephrotic patients from Japan with idiopathic MN, the overall rates of renal survival (defined as
serum creatinine less than 3.0 mg/dL [265 micromol/L]) were 96, 90, 81, and 61 percent at 5, 10, 15, and 20
years after diagnosis, respectively [5]. On multivariate analysis, significant predictors at presentation of
progression to end-stage renal disease were male gender, age greater than 60 years, serum creatinine
concentration ≥1.5 mg/dL (≥133 micromol/L), and tubulointerstitial lesions ≥20 percent of the renal biopsy
area.
●
Among 108 patients from Toronto who presented with subnephrotic proteinuria (defined as less than 3.5
g/day, mean 2.2 g/day), 40 percent remained subnephrotic and 60 percent developed nephrotic-range
proteinuria. The median follow-up time was 55 months in the former group and 82 months in the latter [13].
The patients who did develop nephrotic-range proteinuria had a modestly but statistically significant higher
rate of proteinuria at baseline (2.4 versus 2.0 g/day) and a significantly higher rate of loss of estimated
glomerular filtration rate (following development of nephrotic-range proteinuria) during follow-up (3.5 versus
0.9 mL/min per year).
Approximately 70 percent of patients who developed nephrotic-range proteinuria did so within the first year.
This probably explains why the rate of loss of renal function in these patients was similar to that in 287
patients who had nephrotic-range proteinuria at presentation.
●
In one study, among 328 patients with nephrotic-range proteinuria, a greater than 50 percent reduction in
protein excretion at one year predicted eventual spontaneous remission [12].
●
Patients with persistent normal renal function at three years have a favorable prognosis and are unlikely to
benefit from therapy. However, it is unclear if treatment should be withheld until patients display evidence of
deteriorating renal function.
●
A good prognosis is also associated with female sex, younger age at onset, the absence of glomerular
scarring (segmental sclerosis) and tubulointerstitial disease on renal biopsy, and nonnephrotic-range
proteinuria.
●
An extended duration (eg, six months) of heavy proteinuria has a poor prognosis. (See 'Probability of
progression' below.)
●
Histologic findings — Histologic findings are frequently regarded as important predictors of outcome, as the
risk of progression is increased in patients with glomerular scarring (segmental sclerosis) and correlates more
closely with the severity of the tubulointerstitial disease than with the degree of glomerular injury [5,15,16]. This
observation is typical of most glomerular diseases. (See "Secondary factors and progressionof chronic kidney
disease", section on 'Tubulointerstitial fibrosis'.)
More marked tubulointerstitial disease is often associated with older age, higher mean arterial pressure, and
lower creatinine clearance at presentation [10]. Thus, although tubulointerstitial disease severity is associated
with reduced renal survival, it may not predict this outcome independent of baseline clinical variables [10].
Importance of attaining remission — Attainment of a complete remission (whether spontaneous or not) is
associated with good long-term outcomes. In contrast, little is known about the prognosis in patients with a partial
remission.
The prognostic importance of attaining remission was best evaluated in a study cohort of 348 patients with
nephrotic syndrome due to idiopathic MN from Toronto: 39 percent received no immunosuppressive therapy, 45
percent received one immunosuppressive drug, and 16 percent received combined immunosuppressive therapy
[17].
A complete remission was defined as protein excretion below 0.3 g/day, while a partial remission was defined as
protein excretion below 3.5 g/day plus a 50 percent or greater reduction in protein excretion from the peak value
(for example, a patient with a peak value of 8.0 g/day who experiences a decline to a value of 4.0 g/day has not
experienced a remission). Renal failure was defined as a creatinine clearance ≤15 mL/min, initiation of dialysis,
or renal transplantation. Five patients had renal failure at initial assessment and were excluded from the analysis.
Over the five-year mean observation period, a complete, partial, or no remission was realized in 102, 136, and
110 patients (29, 39, and 32 percent), respectively. The mean time to complete remission was 30 months, and
the mean time to partial remission was 23 months.
At a median follow-up of five years, the following findings were associated with a better renal survival on
multivariate analysis that took into account clinical and laboratory data:
Given the heterogeneity of regimens and the high frequency of spontaneous remission, conclusions could not be
reached regarding specific treatment groups.
Probability of progression — Based upon a study of 184 patients identified through the Toronto
Glomerulonephritis Registry, a semiquantitative algorithm has been developed to predict the probability of
progression to chronic kidney disease, which was defined as a creatinine clearance ≤60 mL/min per 1.73 m [8].
The probability of progression was assessed for those with 4, 6, and 8 g/day of proteinuria that persisted for 6, 9,
12, or 24 months.
Multiple additional variables (including age, sex, serum creatinine, and creatinine clearance on presentation,
serum albumin, presence of hypertension, rate of change of creatinine clearance, and therapy) were also tested
to determine whether the predictive value provided by proteinuria could be improved. Of these variables, the
initial creatinine clearance and the rate of change of clearance were the most useful predictors.
Based upon this approach, the best fitting logistic model utilized the following clinical characteristics:
Higher initial creatinine clearance and lower proteinuria at presentation.●
Lower mean arterial blood pressure over the observation period.●
Attainment of complete or partial remission in proteinuria. None of the 32 patients who attained complete
remission developed renal failure during follow-up, while a partial remission was independently associated
with a slower decrease in renal function over time (-0.17 versus -0.86 mL/min per month with no remission)
and a lower incidence of renal failure (9 versus 29 percent, adjusted hazard ratio [HR] 0.17).
●
2
The addition of renal pathology as a variable had no effect on the performance of the model.
This model was tested in two additional populations of patients identified through the Italian Idiopathic
Membranous Nephropathy Study group (110 patients) and a database obtained from Helsinki University (84
patients) [9]. The accuracy in predicting the development of chronic renal insufficiency was 85, 87, and 79
percent in populations from Toronto, Finland, and Italy, respectively. This was higher than the predictive value of
proteinuria >3.5 g/day at the time of biopsy, which was only 52, 43, and 34 percent, respectively, in the same
populations.
Based upon the best fitting logistic model, the following are examples of the risk of progression to a creatinine
clearance ≤60 mL/min per 1.73 m for patients with specific clinical characteristics over a follow-up period of
more than five years:
Based upon this model, we define low-, moderate-, and high-risk patient subsets with varying degrees of risk for
progression to more advanced kidney insufficiency (defined as a creatinine clearance ≤60 mL/min per 1.73 m )
over five years:
This risk stratification applies only to the likelihood of progressive renal failure. It does not take into account the
risks that may be associated with other complications of the nephrotic syndrome, such as worsening
atherosclerosis due to hypercholesterolemia and thromboemboli due to the associated hypercoagulable state.
Thus, in addition to preservation of renal function, immunosuppressive therapy may be beneficial by shortening
the overall exposure to the nephrotic state, thereby minimizing the risk of other complications. (See 'Lipid
lowering' below and 'Anticoagulation' below.)
Acute decline in renal function — Progressive MN typically occurs gradually. Some patients develop an acute
decline in renal function and at least three disorders should be excluded in this setting:
Persistent proteinuria for over six months●
Creatinine clearance upon presentation●
Slope of the decline in creatinine clearance over the assessed proteinuria period●
2
The risk is only 6 percent for the patient with proteinuria <3.5 g/day and stable normal renal function over six
months
●
The risk increases to 72 percent in the patient with proteinuria of 12 g/day, and a creatinine clearance on
presentation of 96 mL/min, which declines to 78 mL/min by six months
●
2
Low risk – Proteinuria remains less than 4 g/day and creatinine clearance remains normal for a six-month
follow-up period. Such patients have a less than 8 percent risk of developing chronic renal insufficiency over
five years.
●
Moderate risk – Proteinuria is between 4 and 8 g/day and persists for more than six months. Creatinine
clearance is normal or near normal and remains stable over six months of observation. Chronic renal
insufficiency develops over five years in approximately 50 percent of these patients.
●
High risk – Proteinuria is greater than 8 g/day and persists for three months and/or renal function that is
either below normal (and considered due to MN) or decreases during the observation period. Approximately
75 percent of such patients are at risk of progression to chronic renal insufficiency over five years.
●
Acute bilateral renal vein thrombosis which may be associated with flank pain. (See "Renal vein thrombosis
and hypercoagulable state in nephrotic syndrome".)
●
Drug-induced acute interstitial nephritis, in which white cell, white cell casts, and possibly eosinophils are
typically seen in the urine sediment. (See "Clinical manifestations and diagnosis of acute interstitial
nephritis".)
●
Secondary MN — In patients with secondary MN, cessation of the offending drug (eg, penicillamine, gold, or
nonsteroidal anti-inflammatory drug) or effective treatment of the underlying disease is usually associated with
improvement in the nephrotic syndrome. With penicillamine- or gold-associated disease, protein excretion may
continue to rise for the first 1 to 12 months (mean 2 months) after the offending drug has been discontinued
[18,19]. The mean time to resolution of proteinuria is 9 to 12 months, although two to three yearsis required in
some cases. These issues are discussed in detail elsewhere. (See "Causes and diagnosis of membranous
nephropathy".)
NONIMMUNOSUPPRESSIVE THERAPIES — Given the high rate of gradual spontaneous improvement in
patients with idiopathic membranous nephropathy (MN) (figure 1) [1,2], only selected patients with more severe
or progressive disease should receive immunosuppressive therapy. (See 'Immunosuppressive therapy' below.)
In contrast, almost all patients are candidates for more general therapies for nephrotic syndrome, such as
angiotensin inhibition, lipid lowering, and, in selected patients, anticoagulation. Other aspects of therapy include
diuretics to control edema and maintenance of adequate nutrition. (See "Overview of the management of chronic
kidney disease in adults" and "Pathophysiology and treatment of edema in patients with the nephrotic
syndrome".)
Angiotensin inhibition — Administration of an ACE inhibitor or an angiotensin II receptor blocker (ARB) is
recommended in virtually all patients with proteinuric chronic kidney disease since such therapy may significantly
reduce the rate of disease progression, acting at least in part by lowering the intraglomerular pressure. (See
"Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
The evidence for a renal protective effect with an ACE inhibitor or an ARB is relatively weak among patients with
MN. Possible benefits with use of an ACE inhibitor or ARB were noted in a study from the Spanish Group for the
Study of Glomerular Disease (GLOSEN), which retrospectively examined the outcomes of 328 patients with MN
and nephrotic-range proteinuria (>3.5 g/day) [12]. Although none were treated with immunosuppressive
medication, 67 percent of patients received either an ACE inhibitor or ARB, and 32 percent developed complete
or partial remission, defined as reduction of protein excretion to <0.3 g/day in at least three consecutive visits, or
to <3.5 g/day with normal serum albumin, respectively. The mean time to achieve partial or complete remission
was approximately 15 and 39 months. However, because this was not a randomized controlled trial, it is not
possible to draw definitive conclusions about the benefit of ACE inhibitors or ARBs on the frequency of
spontaneous remission [20]. Furthermore there was a significant rise in the serum creatinine among patients who
did not remit in this study, suggesting that there is a significant hazard associated with withholding
immunosuppressive therapy in all patients while waiting for spontaneous remission.
Other observations from this study were as follows:
In addition, limited data from other trials in small numbers of patients with idiopathic MN suggest that the
antiproteinuric response and slowing of disease progression is less in MN than in other glomerular diseases
Superimposed crescentic glomerulonephritis, in which red cells and cellular casts are found in the urine
sediment. (See "Causes and diagnosis of membranous nephropathy".)
●
Remission was more frequent with lower baseline proteinuria: 37, 26, and 22 percent among those with
baseline protein excretion <8, 8 to 12, and >12 g/day, respectively.
●
The chances of achieving remission were higher among patients treated with ACE inhibitor or an ARB
compared to those who were not: 22, 33 and 36 percent compared to 11, 14, and 19 percent at 1, 2, and 3
years, respectively. These differences were only significant among patients who had protein excretion <8
g/day, but were not observed among those with more severe proteinuria.
●
Independent predictors for remission included baseline serum creatinine, baseline protein excretion, and
>50 percent reduction in protein excretion at one year.
●
[17,21,22].
Proteinuria goal — The optimal proteinuria goal in patients with chronic kidney disease is less than 1000
mg/day. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section
on 'Proteinuria goal'.)
However, this goal is often not attainable in patients with idiopathic MN. As noted above, the renal prognosis in
idiopathic MN is markedly improved in patients who attain at least partial remission of proteinuria, defined as
protein excretion below 3.5 g/day plus a 50 percent or greater reduction in protein excretion from the peak value
[17]. Partial remission was independently associated with a slower decrease in renal function over time (-0.17
versus -0.86 mL/min per month with no remission) and a lower incidence of renal failure (9 versus 29 percent,
adjusted hazard ratio [HR] 0.17). (See 'Importance of attaining remission' above.)
Attainment of partial remission can result from one or more of the following: angiotensin inhibition,
immunosuppressive therapy, and spontaneous remission, which is not uncommon in idiopathic MN (figure 1).
(See 'Natural history' above.)
Goal blood pressure — The goal blood pressure in patients with MN is the same as it is in other patients with
proteinuric chronic kidney disease. Attainment of this goal can slow the progression of proteinuric chronic kidney
disease and can provide cardiovascular protection since chronic kidney disease is associated with a marked
increase in cardiovascular risk. The data supporting these recommendations are presented separately. (See
"Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Blood
pressure goal' and "Chronic kidney disease and coronary heart disease", section on 'Blood pressure control'.)
Attainment of the blood pressure goal in patients with MN usually requires more than angiotensin inhibition alone.
Correction of volume overload is of particular importance and usually requires loop diuretics. Diuretics should be
pushed until the blood pressure goal is reached or the patient has attained "dry weight" which, in the presence of
persistent hypertension, is defined as the weight at which further fluid removal leads to symptoms (fatigue,
orthostatic hypotension) or to decreased tissue perfusion as evidenced by an otherwise unexplained elevation in
the blood urea nitrogen and/or serum creatinine concentration. (See "Overview of hypertension in acute and
chronic kidney disease", section on 'Choice of antihypertensive therapy'.)
A low-salt diet is an important component of antihypertensive therapy (especially when using angiotensin
inhibitors) and edema control in patients with MN. In addition, a high-salt diet can increase proteinuria, and in
some individuals, a high-salt diet rather than increased immunologic activity should be considered as an
underlying cause of worsening proteinuria. (See 'Exclusion of high salt intake' below and "Antihypertensive
therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Importance of salt intake'.)
Lipid lowering — Hyperlipidemia, with often dramatic elevations in the serum cholesterol concentration, is
commonly present in patients with nephrotic syndrome. The mainstay of therapy for such hypercholesterolemia is
statins. This issue is discussed in detail elsewhere. (See "Lipid abnormalities in nephrotic syndrome" and "Statins
and chronic kidney disease".)
Anticoagulation — Patients with nephrotic syndrome, particularly those with MN, are at increased risk for
thrombotic events, such as deep vein and renal vein thrombosis or pulmonary embolism. (See "Renal vein
thrombosis and hypercoagulable state in nephrotic syndrome".)
The risk in MN was illustrated in a series of 898 patients in the Glomerular Disease Collaborative Network and
the Toronto Glomerulonephritis Registry [23]. Clinically evident and radiologically confirmed venous
thromboembolic events occurred in 7.2 percent of patients. The median time to the first thromboembolic event
was 3.8 months; 74 percent occurred within the first two years of diagnosis and 86 percent occurredwithin three
years. A low serum albumin concentration at the time of diagnosis, but not the degree of proteinuria,
independently predicted a venous thromboembolic event. Compared with patients who had a serum albumin
concentration greater than 2.8 g/dL, the risk of an event was 2.5-fold greater in patients with a serum albumin
concentration below 2.8 g/dL.
All patients who have a thromboembolic event should be treated initially with low molecular weight or
unfractionated heparin, followed by oral anticoagulation (eg, warfarin), the same regimen used for patients
without nephrotic syndrome who have deep vein thrombosis or a pulmonary embolism. (See "Renal vein
thrombosis and hypercoagulable state in nephrotic syndrome" and "Overview of the treatment of lower extremity
deep vein thrombosis (DVT)", section on 'Summary and recommendations'.)
A separate issue is the possible role of prophylactic anticoagulation in patients at high risk for thromboembolism.
This issue, including the definition of high risk, is discussed elsewhere. (See "Renal vein thrombosis and
hypercoagulable state in nephrotic syndrome", section on 'Prophylactic anticoagulation'.)
IMMUNOSUPPRESSIVE THERAPY
Indications for and choice of therapy — Since many patients with mild to moderate disease undergo
spontaneous remission (figure 1) and immunosuppressive agents have appreciable toxicity, the decision to treat
must be based upon the probability that the patient will have progressive disease (defined as an otherwise
unexplained elevation in serum creatinine or persistent high-grade or increasing proteinuria in patients at
moderate to high risk for progression) [24].
We tailor our treatment regimen based upon the risk of progressive disease, using the algorithm described above
[8,9,25]. (See 'Probability of progression' above.) First-line immunosuppressive therapy consists of cytotoxic
drugs (usually cyclophosphamide) plus glucocorticoids or a calcineurin inhibitor with low-dose or no
glucocorticoids (a regimen based upon cytotoxic drugs is preferred in some high-risk patients with declining
glomerular filtration rate due to MN and an estimated glomerular filtration rate above 30 mL/min/1.73 m ).
Patients who do not respond to one regimen are usually treated with the other, and those with resistant disease
may be treated with rituximab. These recommendations are broadly similar to those made by the Kidney
Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for glomerulonephritis [26].
The evidence supporting the efficacy of this approach will be presented below. Alternative immunosuppressive
for which there is less evidence of benefit, such as mycophenolate mofetil, are discussed separately. (See
"Alternative agents in the treatment of idiopathic membranous nephropathy".)
Measurement of protein excretion — As noted in the following sections, risk stratification into low, moderate,
and high risk for progression is based upon the degree of proteinuria obtained on a 24-hour collection and on the
glomerular filtration rate as estimated from the creatinine clearance [8,9]. A random urine protein-to-creatinine
ratio should not be used for initial risk stratification since the relationship between the ratio and 24-hour protein
excretion varies widely among patients (figure 2). (See "Assessment of urinary protein excretion and evaluation
of isolated non-nephrotic proteinuria in adults".)
In contrast, the urine protein-to-creatinine ratio may be performed serially to detect changes in protein excretion
(either spontaneously or after therapy) over time. We determine the ratio from an overnight collection, not a
random specimen. However, when therapeutic decisions will be made from the degree of proteinuria, we perform
a 24-hour collection for protein excretion and creatinine clearance since the criteria to treat or not to treat are
based upon studies using 24-hour collections.
Low risk for progression — There is a low risk for progressive disease among asymptomatic patients with
normal renal function and protein excretion that remains less than 4.0 g/day on a 24-hour urine collection for a
six-month observation period. Such patients should not be treated with immunosuppressive therapy as long they
have subnephrotic proteinuria since they have an excellent long-term prognosis and often undergo spontaneous
partial or complete remission [2-4,13,27]. (See 'Probability of progression' above.)
Such patients should be treated with appropriate nonimmunosuppressive therapy (as described above) and
monitored periodically for disease progression. We suggest clinical assessment and measurement of urinary
2
protein excretion and serum creatinine every three months for two years and twice yearly thereafter since the risk
of developing progressive disease falls significantly after two years. The rationale for prolonged monitoring for
disease progression was provided by a review of 395 patients with membranous nephropathy (MN), 108 of
whom (27 percent) presented with subnephrotic proteinuria [13]. Among these patients, 66 (61 percent)
progressed to nephrotic syndrome; of these, 46 patients (70 percent) progressed within the first year, 11 (18
percent) progressed between years 1 to 4, and 9 patients (13 percent) progressed after year 4 (19 percent).
Moderate risk for progression — Patients at moderate risk for progression have the following clinical features
that persist for over six months: protein excretion between 4.0 and 8.0 g/day on a 24-hour urine collection,
normal or near normal renal function (defined as creatinine clearance ≥80 mL/min), and asymptomatic disease or
edema controlled by diuretics.
As previously mentioned, up to 45 percent of such patients undergo spontaneous complete or partial remission
over a period of three to six years (figure 1) [1-4]. Spontaneous remission is most likely in women, children, those
with lesser amounts of proteinuria, and adults under age 50 years with a normal serum creatinine concentration
and benign histologic features [1-3,8]. Although unproven, the rate of partial remission may be higher with the
use of ACE inhibitors or ARBs. (See 'Angiotensin inhibition' above.)
Several trials have assessed the effect of immunosuppressive agents in patients with idiopathic MN. The efficacy
of combination regimens using glucocorticoids plus either cytotoxic therapy (cyclophosphamide or chlorambucil)
or a calcineurin inhibitor therapy is summarized below. In contrast, glucocorticoids alone are not effective, with
the possible exception of Japanese patients [5].
A number of other drugs have been tried in the treatment of patients at moderate risk of progression but are not
considered first-line agents. These include mycophenolate mofetil, intravenous immune globulin, and synthetic
adrenocorticotropic hormone (ACTH). Rituximab may be of benefit in patients with resistant MN. (See 'Resistant
disease' below and "Alternative agents in the treatment of idiopathic membranous nephropathy".)
Cytotoxic therapy plus glucocorticoids — Three randomized prospective trials that primarily enrolled
patients who would be categorized as having moderate risk for progression found that cyclophosphamide and
chlorambucil, both given with glucocorticoids, are effective in inducing remission of proteinuria and preventing
progression to end-stage renal disease [3,4,28].
Two of the trials, mostly of patients with moderate disease (mean protein excretion 6 g/day in one), reported 10-
year follow-up [3,4]. The patients receiving immunosuppressive therapy had significantly higher rates of complete
or partial remission (88 versus 47 percent and 72 versus 34 percent with symptomatic therapy alone) and a
higher rate of surviving without end-stage renal disease (92 versus 60 percent and 89 versus 65 percent). Partial
remission was defined as a normal serum creatinineplus protein excretion less than 2 g/day or, in one trial, more
than 50 percent less than baseline, whichever was lower. In one of the trials, 15 of the 46 patients assigned to
supportive therapy alone chose to have immunosuppressive therapy at 2 to 4.5 years after initial randomization;
seven of these patients attained complete or partial remission [4]. Thus, the true rate of remission with
symptomatic therapy alone was 20 percent, not 34 percent.
Cyclophosphamide and chlorambucil-based regimens are equally effective, as noted in a randomized head-to-
head comparative trial that primarily enrolled moderate-risk patients (mean protein excretion 7 to 8 g/day and
mean serum creatinine 1.05 mg/dL [93 micromol/L]) [28]. However, since chlorambucil has more side effects, we
prefer administering the cyclophosphamide-based regimen. Most studies evaluating cytotoxic therapy have
included prednisone, and it is the clinical impression of many clinicians that cyclophosphamide alone is likely to
be less beneficial [3,25,29]. (See "General toxicity of cyclophosphamide in rheumatic diseases".)
Given the lower rate of toxicity with cyclophosphamide, the preferred regimen is oral prednisone (0.5 mg/kg per
day) or methylprednisolone (0.4 mg/kg per day) given for months 1, 3, and 5 plus oral cyclophosphamide (2.0 to
2.5 mg/kg per day) given for months 2, 4, and 6 [4,28]. The glucocorticoid months begin with pulse
methylprednisolone, 1 g intravenously daily for three days, without oral prednisone.
Calcineurin inhibitors — Both cyclosporine and tacrolimus have proven efficacy in patients with idiopathic
MN. Cyclosporine plus low-dose prednisone (maximum of 10 mg/day) is effective in inducing remission of
proteinuria and in preventing progression to end-stage renal disease [30-32]. The best data are from a
randomized trial of 51 patients (mean protein excretion 9.3 g/day and mean serum creatinine 1.2 mg/dL [106
micromol/L]) who were unresponsive to at least an eight-week course of daily glucocorticoid therapy [30]. The
patients were assigned to prednisone (0.15 mg/kg up to a maximum dose of 15 mg/day) plus either placebo or
cyclosporine (dose adjusted to maintain a trough blood level of 125 to 225 mcg/L) for 26 weeks.
The cyclosporine-treated group had a significantly higher rate of complete (≤300 mg/day) or partial remission of
proteinuria, which was defined as less than 3.5 g/day plus at least a 50 percent reduction from baseline (75
versus 22 percent with placebo). Renal function was the same in both groups. One year after the cessation of
therapy, relapse of proteinuria was common, but 39 percent of treated patients were still in remission, compared
to 13 percent with placebo. (See 'Relapsing disease' below.)
Tacrolimus is an alternative to cyclosporine since outcomes appear to be similar. Tacrolimus is less commonly
associated with some of the side effects observed with cyclosporine, such as hirsutism or gingival hypertrophy.
On the other hand, there is more clinical experience with cyclosporine. (See "Pharmacology of cyclosporine and
tacrolimus".)
The efficacy of tacrolimus (without glucocorticoids) was demonstrated in a randomized trial of 48 patients with
MN who were treated with tacrolimus (0.05 mg/kg per day for 12 months with a six-month taper) or placebo [33].
The rate of complete or partial remission was significantly higher with tacrolimus at both 12 months (82 versus 24
percent) and 18 months (94 versus 35 percent).
Rituximab — Rituximab has been used in patients with idiopathic membranous nephropathy who have failed
previous treatment with other immunosuppressive regimens. (See 'Resistant disease' below.)
Rituximab may have benefit among patients with a moderate risk of progression who have not previously
received immunosuppressive therapy. In one unblinded trial, 75 patients with persistent proteinuria greater than
3.5 g/day after six months of treatment with angiotensin inhibition, diuretics, and a statin (nonimmunosuppressive
therapy) were randomly assigned to rituximab (two infusions of 375 mg/m administered one week apart; 37
patients) or no rituximab (38 patients) [34]. Nonimmunosuppressive therapy was continued in all patients. At six
months, there was no significant difference in the primary composite endpoint of complete (<500 mg/day) or
partial (<3.5 g/day with ≥50 percent reduction compared to baseline) remission of proteinuria between patients
treated with or without rituximab (35 versus 21 percent, respectively). Proteinuria, serum creatinine, and
estimated glomerular filtration rate (eGFR) at six months were also similar between the two groups, but serum
albumin levels were higher in those treated with rituximab (3.0 versus 2.4 g/dL). Anti-PLA2R antibodies, which
were present in 73 percent of patients at baseline, disappeared in a greater proportion of patients receiving
rituximab (50 versus 12 percent). Serious adverse events were similar between the two groups.
The lack of benefit from rituximab at six months may be attributed in part to the short duration of the trial. In a
post-trial observational phase that followed patients for an additional 12 months, the rate of complete or partial
remission was higher among patients treated with rituximab (65 versus 34 percent) [34]. In addition, patients
treated with rituximab had less proteinuria (2195 versus 4701 mg/g) and higher serum albumin levels (3.2 versus
2.7 g/dL). These findings are consistent with observational studies that demonstrate a maximal reduction in
proteinuria at 18 to 24 months after treatment with rituximab [35,36].
Summary of moderate risk — Patients at moderate risk for progression have protein excretion between 4.0
and 8.0 g/day obtained on a 24-hour collection, which persists for six months, normal or near normal renal
function (defined as creatinine clearance ≥80 mL/min), and asymptomatic disease or edema controlled by
diuretics.
As mentioned above, up to 45 percent of such patients will undergo spontaneous partial or complete remission
over three to four years (figure 1) [1-3]. Since immunosuppressive therapy has potentially serious side effects
2
and is associated with an appreciable relapse rate, we suggest close monitoring without the administration of
immunosuppressive medications for six months in patients at moderate risk for progression, providing renal
function remains stable and edema is controlled with diuretics. Subsequent therapy varies with the course of the
disease:
However, other experts would continue to withhold immunosuppressive therapy beyond six months in patients
who continue to show a progressive reduction in proteinuria, even though protein excretion remains above 4
g/day. This strategy is based upon the observation that an appreciable number of these patients eventually
undergo spontaneous remission (figure 1) and will therefore avoid the potential adverse effects of
immunosuppressive therapy.
Cyclophosphamide-glucocorticoid and calcineurin inhibitor-glucocorticoid regimens appear to have similar
efficacy, although relapses seem to be more common with calcineurin inhibitors. (See 'Relapsing disease' below.)
The choice between these regimens can depend upon a variety of factors, including patient preference. As an
example, a woman of child-bearing age may want to avoid cyclophosphamide because of its fertility risk, while an
older patient with hypertension may prefer to avoid the vascular side effects of cyclosporine or tacrolimus. (See
"General toxicity of cyclophosphamide in rheumatic diseases", section on 'Female gonadal toxicity' and
"Pharmacology of cyclosporine and tacrolimus".)
We do not initiate immunosuppressive therapy if protein excretion spontaneously or as a consequence of
angiotensin inhibition falls to less than 4 g/day
●
Among patients who do not have a decline in24-hour protein excretion to less than 4 g by six months, we
suggest continuation of nonimmunosuppressive therapies and initiation of cyclophosphamide plus
glucocorticoids, or either cyclosporine or tacrolimus plus glucocorticoids
●
If cytotoxic therapy is chosen, there is a lower rate of toxicity with cyclophosphamide than chlorambucil. The
preferred regimen is oral prednisone (0.5 mg/kg per day) or methylprednisolone (0.4 mg/kg per day) given
for months 1, 3, and 5 plus oral cyclophosphamide (2.0 to 2.5 mg/kg per day) given for months 2, 4, and 6
[4,28]. The glucocorticoid months begin with pulse methylprednisolone, 1 g intravenously daily for three
days, without oral prednisone.
●
Either cyclosporine or tacrolimus are options if a calcineurin inhibitor-based approach is chosen. The
preferred regimen for cyclosporine is treatment for at least six months at a dose of 3 to 5 mg/kg per day in
two divided doses to maintain whole blood trough levels of 120 to 200 mcg/L; some investigators would also
initiate therapy with prednisone given every other day (maximum 10 mg every other day). More prolonged
cyclosporine use may be associated with nephrotoxicity [37].
Subsequent therapy is based upon the initial response:
●
Among those with a complete remission (protein excretion ≤300 mg/day), we gradually taper the
cyclosporine dose with therapy being discontinued after at least two to four months.
•
Among those with a partial remission (protein excretion less than 3.5 g/day plus at least a 50 percent
reduction from baseline), we start to reduce the cyclosporine dose to the minimally nephrotoxic range of
1.5 to 2.5 mg/kg per day, which is given for at least one to two years. The duration of therapy is based
upon an ongoing assessment of the benefits and risks. Relapse of proteinuria can occur after
cyclosporine is discontinued. (See 'Relapsing disease' below.)
•
If a tacrolimus-based approach is chosen for initial therapy, the preferred regimen is 0.05 mg/kg per day in
two divided doses to maintain whole blood trough levels between 3 and 5 mcg/L. The dose may be
increased to achieve a higher trough level between 5 and 8 mcg/L if there is no reduction in proteinuria by
two months, providing the renal function has not worsened.
●
Cyclosporine or tacrolimus should be discontinued if no response occurs by four to six months. In addition,
patients who do not respond to one of these drugs are unlikely to respond to the other.
Patients treated with either a cyclophosphamide or a calcineurin inhibitor-based regimen are considered
unresponsive if a substantial reduction in proteinuria (30 to 50 percent from peak levels) is not observed after six
months of therapy. In such patients, we consider the other regimen, such as cyclophosphamide and
glucocorticoids in those initially treated with a calcineurin inhibitor. There are no published studies that have
assessed the effectiveness of this strategy, although it appears to be successful in our personal experience.
Among patients who do not respond to initial cyclophosphamide plus glucocorticoid therapy, we usually wait
three to six months after the cessation of cytotoxic therapy before initiating a calcineurin inhibitor, unless the
patient has severe symptoms or a rise in serum creatinine.
Some patients fail treatment with both cyclophosphamide and calcineurin inhibitor-based regimens. The
treatment of such patients is discussed below. (See 'Resistant patients' below.)
High risk for progression — High-risk patients with idiopathic MN are defined as those with protein excretion
exceeding 8 g/day that persists for more than three months and/or renal function that is either below normal (and
considered due to MN) or decreases during the observation period, despite maximum nonimmunosuppressive
therapy. These patients are also likely to have prominent nephrotic symptoms or signs, such as marked
hypoalbuminemia and edema. Approximately 75 percent of such patients progress to worsened renal
insufficiency over five years.
One problem with estimating the glomerular filtration rate by creatinine clearance or an estimation equation is
that creatinine secretion is often markedly increased in patients with nephrotic syndrome compared with normal
controls [38]. As a result, the serum creatinine will be lower than expected from the glomerular filtration rate in a
given patient, and the creatinine clearance will overestimate the glomerular filtration rate by a greater degree
than in nonnephrotic subjects. In one study, the overestimate was 36 mL/min per 1.73 m in nephrotic patients
with a serum albumin level less than 2.6 g/dL, compared with 11 mL/min per 1.73 m in normal controls [38].
(See "Assessment of kidney function".)
Choice of therapy — High-risk patients are usually treated with immunosuppressive therapy, as described
below. (See 'Summary of high risk' below.)
Our treatment preferences for high-risk patients differ according to the course of renal function during the
observation period:
The preference of cytotoxic therapy in those patients who are high risk because of deterioration of GFR due to
idiopathic MN is based upon the United Kingdom (UK) Membranous Trial, an open-label randomized trial of 108
patients [39]. Smaller trials and observational studies have also suggested that therapy combining
glucocorticoids with a cytotoxic drug may be beneficial in such patients [28,29,40-44].
The UK Membranous Trial only enrolled patients who had a progressive decline in estimated glomerular filtration
Among patients who attain a complete or partial remission, tacrolimus should be continued for 12 months
and then tapered over 6 months (reducing the dose by 25 percent every 2 months to zero). Monitoring is the
same as with cyclosporine therapy.
2
2
For patients who are classified as high risk because of deterioration of glomerular filtration rate (GFR) due to
membranous nephropathy, combination therapy with glucocorticoids and a cytotoxic drug (ie,
cyclophosphamide or chlorambucil, preferably cyclophosphamide) appears to provide the best protection
against progressive renal disease.
●
For all other patients who are classified as high risk, including those with protein excretion exceeding 8
g/day that persists for more than three months, combination therapy consisting of either glucocorticoids plus
a cytotoxic drug or glucocorticoids plus cyclosporine are equally acceptable treatment options.
●
rate (eGFR, calculated using the Cockcroft-Gault equation) of at least 20 percent during the preceding two years
and a baseline serum creatinine less than 3.4 mg/dL (300 micromol/L); enrolled patients had a mean eGFR of 50
mL/min per 1.73 m and a mean protein excretion of 8.5 g/day. In addition, no patient was receiving anti-
inflammatory or immunosuppressive therapy at baseline.
Patients were randomly assigned to one of the following three therapies:
The primary endpoint (an additional decline in eGFR of at least 20 percent) occurred significantly less frequently
with glucocorticoids and chlorambucil as compared with supportive treatment alone (58 [19/33] versus 84 [31/37]
percent). However, cyclosporine therapy did not reduce the incidence of renal function loss as compared with
supportive treatment (81 [29/36] versus 84 percent). In addition, fewer patients who received glucocorticoids and
chlorambucil developed end-stage renal disease (1 patient compared with 4 patients receiving supportive
treatment and 6 patients receiving cyclosporine).
There was no difference in mortality among the three groups. Nearly all patients received angiotensin-converting
enzyme (ACE) inhibitors. The frequency of adverse events were similar in the glucocorticoid/chlorambucil and
cyclosporine groups, although patients receiving glucocorticoids and chlorambucil had significantly moreserious
adverse events than those receiving supportive treatment only (primarily hematological events such as
leukopenia and anemia).
Limitations of the UK Membranous Trial include the following:
Although the UK Membranous Trial used chlorambucil, a cyclophosphamide-based regimen is thought to be
equally effective, as noted in a randomized head-to-head comparative trial that primarily enrolled moderate-risk
patients (mean protein excretion 7 to 8 g/day and mean serum creatinine 1.05 mg/dL [93 micromol/L]) [28]. In
addition, observational data showed greater benefit with daily oral cyclophosphamide (1.5 to 2.0 mg/kg per day)
for one year compared with daily oral chlorambucil in months 2, 4, and 6; both groups received the same
glucocorticoid regimen [40]. Chlorambucil also has more side effects; therefore, we prefer administering a
cyclophosphamide-based regimen. (See "General toxicity of cyclophosphamide in rheumatic diseases".)
The results of the UK Membranous Trial (which found no benefit from cyclosporine) contrast with two smaller
randomized trials that showed benefit from cyclosporine in patients defined as high risk based upon, respectively,
reduced GFR and high-grade persistent proteinuria:
2
Supportive treatment plus glucocorticoids and cytotoxic therapy for six months – During months 1, 3, and 5,
patients received intravenous methylprednisone (1 g/day for three days), followed by oral prednisolone (0.5
mg/kg/day for 28 days); during months 2, 4, and 6, patients received oral chlorambucil (0.15 mg/kg/day
throughout the month).
●
Supportive treatment plus cyclosporine for twelve months – The initial dose of cyclosporine was 5
mg/kg/day, and the dose was adjusted to achieve a plasma concentration of 100 to 200 mcg/L.
●
Supportive treatment alone.●
Patients with declining GFR due to MN comprise a small fraction of all patients with idiopathic MN [17]. It is
not known whether the results of this trial apply to other patients with MN.
●
In addition, the cyclosporine dose escalation in this trial was faster than common practice. Since calcineurin
inhibitors such as cyclosporine can produce an acute reversible reduction in GFR, it is possible that this
could have produced some of the adverse renal events. (See "Cyclosporine and tacrolimus nephrotoxicity".)
●
The majority of patients were followed for less than one year.●
One trial randomly assigned 17 patients with progressive disease (baseline creatinine clearance about 50
mL/min per 1.73 m ) to placebo or cyclosporine monotherapy (3.5 mg/kg per day, with dose adjustment to
maintain a 12-hour trough cyclosporine concentration of 110 to 170 mcg/L) for 12 months [45]. Cyclosporine
●
2
Summary of high risk — High-risk patients with idiopathic MN are defined as those with 24-hour protein
excretion exceeding 8 g/day that persists for more than three months and/or renal function (estimated from the
serum creatinine) that is either below normal or decreases during the observation period, despite maximum
conservative therapy. These patients have an approximately 75 percent chance of progression to end-stage renal
disease without effective therapy [8,32]. Patients who present with severe symptoms, marked hypoalbuminemia
(<2.0 g/dL), or an elevated serum creatinine that does not represent preexisting disease may be treated with
immunosuppressive therapy without delay. Patients with advanced and chronic renal impairment (estimated
glomerular filtration rate less than 30 mL/min/1.73 m for >3 months) are a possible exception since it is not clear
that immunosuppressive therapy is beneficial in this subgroup.
The decision to treat high-risk patients with more than 8 g/day of proteinuria and/or progressive disease must be
individualized. Many of these patients respond to therapy, particularly those with normal or near normal renal
function [28,30]. The likelihood of benefit probably decreases with more advanced disease, but it is not possible
to predict in advance which patients will have a clinically significant response.
Patients considered to be at high risk because of deteriorating renal function should be carefully assessed for
other causes that may be additional to or independent of MN. As an example, older patients or those with long-
standing hypertension may have a reduced glomerular filtration rate independent of MN [10]. Patients who have
no other apparent reasons for reduced renal function or who have progressive deterioration while under
observation should be treated without delay.
In general, our approach is as follows:
produced a greater decline in proteinuria and a slowing of renal function decline as compared with placebo.
A second trial randomly assigned 51 patients with heavy proteinuria (mean 9.3 g/day) but intact renal
function to combination therapy with cyclosporine (dose adjusted to maintain a trough blood level of 125 to
225 mcg/L) plus prednisone (0.15 mg/kg up to a maximum dose of 15 mg/day) or to prednisone alone and
followed them for 26 weeks [30]. The cyclosporine-treated group had a significantly higher rate of complete
or partial remission of proteinuria (75 versus 22 percent with placebo).
●
2
In patients classified as high risk because of deteriorating renal function due to idiopathic MN and for whom
immunosuppressive therapy is felt appropriate, we suggest combination therapy with glucocorticoids and a
cytotoxic agent (cyclophosphamide or chlorambucil). For reasons presented above, we prefer
cyclophosphamide rather than chlorambucil. (See 'Choice of therapy' above.)
●
In patients selected for cytotoxic therapy, we suggest daily oral therapy rather than pulse intravenous
therapy with the cytotoxic agent. This preference is based upon a randomized trial of 18 patients
assigned to either oral chlorambucil or intravenous cyclophosphamide; both groups received
glucocorticoids [41]. The patients assigned to daily oral chlorambucil had a significant reduction of
serum creatinine at six months from 2.9 to 2.1 mg/dL (260 to 186 micromol/L). In contrast, the patients
treated with monthly intravenous cyclophosphamide pulses had an increase in serum creatinine from
2.5 to 3.4 mg/dL (218 to 297 micromol/L). Both groups had a similar reduction in proteinuria.
•
If cytotoxic therapy is chosen, an acceptable regimen is the one used in the UK Membranous Trial,
substituting cyclophosphamide for chlorambucil: during months 1, 3, and 5, treat with intravenous
methylprednisone (1 g/day for three days), followed by oral prednisone (0.5 mg/kg/day for 28 days);
during months 2, 4, and 6, treat with oral cyclophosphamide (1.5 to 2.0 mg/kg per day).
•
In high-risk patients who decline or who cannot receive cytotoxic therapy, we suggest treatment with
cyclosporine in combination with glucocorticoids. As an example, a woman of child-bearing age may
want to avoid cyclophosphamide therapy because of its fertility risk. (See "General toxicity of
cyclophosphamide in rheumatic diseases", section on 'Female gonadal toxicity'.)
•
Once therapy is discontinued, there is an appreciable relapse rate (25 to 30 percent) that may require a second
course with attendant side effects. The relapse rate may be somewhat lower and more delayed with cytotoxic as
compared with cyclosporine therapy. (See 'Relapsing disease' below.)
Relapsing disease — Relapse to nephrotic-range proteinuria, after an initial response to immunosuppressive
therapy, may require repeat treatment. The approach to retreatment is partially dependent upon the initial
regimen. However, before immunosuppressive therapy is considered, a change in diet to a high salt and/or high
protein intake should be excluded as a cause of the increasing proteinuria. Salt restriction is also important for
control of both blood pressure and edema. (See 'Goal blood pressure' above.)Exclusion of high salt intake — In patients with proteinuric chronic kidney disease, the antiproteinuric effect
of angiotensin inhibitors and non-dihydropyridine calcium channel blockers is enhanced with salt restriction and
impaired by a high salt intake even when blood pressure control is appropriate [46,47]. Presumed mechanisms
are that high salt intakes increase intraglomerular pressure and flow [46,47]. (See "Antihypertensive therapy and
progression of nondiabetic chronic kidney disease in adults", section on 'Importance of salt intake'.)
The potential importance of a high salt intake as a cause of relapsing proteinuria in idiopathic MN was illustrated
in a series of seven patients who underwent repeat renal biopsy [48]. Four patients had recurrent active disease
and were treated with immunosuppressive therapy. The other three patients did not have active MN as evidenced
by the absence of subepithelial immune deposits on electron microscopy, although there were chronic changes
such as thickening and vacuolization of the glomerular basement membrane. These patients, compared with
those with active disease, had on 24-hour urine collection much higher rates of excretion of both sodium (353
versus 141 meq/day) and urea nitrogen (15.7 versus 9.6 g/day). Furthermore, lowering sodium intake in two of
these patients from approximately 300 to less than 100 to 200 mg/day was associated with marked reductions in
the 24-hour urine protein-to-creatinine ratio from 4.5 to less than 1.5 g/day and from 2.4 to approximately 1.0
g/day. The effect of dietary protein restriction was not evaluated.
Cytotoxic therapy — Among patients treated with cyclophosphamide-based therapy, relapse of proteinuria
has been described in 25 to 30 percent [4,28,42,49,50]. Such patients may be treated with a calcineurin inhibitor
or with a second course of cytotoxic therapy using the same regimen [28,42,50]. We do not give more than two
courses of cytotoxic therapy in patients who repeatedly relapse.
The apparent benefits of cytotoxic therapy in this setting must be weighed against the adverse effects of a
second course, as treatment-related complications (primarily bone marrow depression and infection) are
common, occurring in as many as two-thirds of high-risk patients treated with daily oral cytotoxic therapy [42]. In
addition, the risk of gonadal toxicity is high in patients who receive more than one course of cyclophosphamide.
Thus, for patients in whom gonadal toxicity is a factor, we suggest treatment with calcineurin inhibitors rather
than cyclophosphamide.
Calcineurin inhibitors — Among patients treated with calcineurin inhibitor-based therapy, a higher rate of
relapse has been reported than with cytotoxic therapy [30,31,33,37]. Similar findings have been noted in patients
with lupus membranous nephropathy. (See "Clinical features and therapy of lupus membranous nephropathy".)
In a trial cited above, relapse occurred in 9 of the 21 (43 percent) cyclosporine-treated patients who attained
remission at 52 weeks [30]. No further relapses occurred in the ensuing 26 weeks, which was the end of follow-
In all other patients classified as high risk (eg, those with protein excretion exceeding 8 g/day that persists
for more than three months but with normal eGFR), we suggest either combination therapy with
glucocorticoids and a cytotoxic agent or combination therapy with glucocorticoids and cyclosporine. If
cyclosporine therapy is chosen, an acceptable regimen is 3.5 mg/kg per day for 12 months, starting at a
lower dose and gradually increasing to achieve a 12-hour trough cyclosporine concentration of 110 to 170
mcg/L [45]. Given the risk of nephrotoxicity with cyclosporine, we attempt to maintain trough concentrations
at the lower end of the target range and monitor the serum creatinine concentration. (See "Cyclosporine and
tacrolimus nephrotoxicity".)
●
up. Relapses may occur more frequently when lower doses of cyclosporine (1.0 to 1.1 mg/kg per day) are used,
when the trough levels are less than 100 mcg/L, or perhaps when cyclosporine is given without glucocorticoids,
which we do not recommend [31].
Relapses can occur during tapering or after cessation of cyclosporine therapy. In either case, we treat with
cyclosporine at a dose of 3 to 5 mg/kg and continue to monitor renal function and whole blood trough levels. An
alternative, particularly in patients who did not tolerate the initial cyclosporine regimen, is cyclophosphamide-
based therapy.
Limited data suggest similar results with tacrolimus. In one trial, relapse occurred in 9 of 19 (47 percent) patients
who attained complete or partial remission [33]. All of the relapses occurred at a mean of 4.2 months after the
cessation of tacrolimus therapy.
Resistant disease — The optimal approach to moderate- or high-risk patients with stable renal function who fail
treatment with both cyclophosphamide and calcineurin inhibitor-based regimens is not known. We prefer a trial of
rituximab in such patients, although limited data are available suggesting efficacy.
Several observational (nonrandomized) studies in patients with idiopathic resistant MN have reported outcomes
following the administration of rituximab:
In a large single-center study, 100 patients with idiopathic MN and persistent proteinuria greater than 3.5
g/day despite six months of angiotensin inhibition were treated with one to four weekly infusions of rituximab
(375 mg/m ) [35]. At baseline, 32 patients had previously failed immunosuppressive therapy with other
agents; the mean age was 52 years, mean serum creatinine was 1.2 mg/dL (106 micromol/L), and mean
proteinuria was 9.1 g/day. Patients were followed for a minimum of six months (mean follow-up, 29 months).
Complete remission, defined as a reduction in proteinuria to below 0.3 g/day, was achieved in 27 patients;
partial remission, defined as a reduction in proteinuria by more than 50 percent to a level below 3 g/day, was
achieved in 38 patients. The remaining 35 patients did not achieve remission. The proportion of patients
having a complete or partial remission did not differ according to prior therapy with other immunosuppressive
agents. Rituximab therapy was generally well tolerated: 28 patients had infusion reactions that were
considered minor, and 11 patients had serious adverse events, none of which were considered related to
therapy.
●
2
A follow-up to this study reported outcomes with rituximab therapy according to anti-phospholipase A2
receptor (anti-PLA2R) autoantibody titers [51]. Complete remission was attained by 33 percent of patients,
and partial remission was attained by 31 percent. Although the rate of complete or partial remission was
similar among patients with and without detectable anti-PLA2R antibodies, autoantibody-positive patients
with lower titers had significantly greater remission rates compared with patients who had higher titers.
Specifically, complete or partial remission occurred in 82 percent of patients with titers <87 RU/mL, 59
percent of patients with titers 87 to 204 RU/mL, and in only 37 percent of patients with titers >204 RU/mL.
In another study, rituximab (1 g given two weeks apart) was given to 15 severely nephrotic patients (6.1 to
23 g/day) with MN; seven had failed previous immunosuppressive therapy and eight had a creatinine
clearance below 80 mL/min per 1.73 m [52]. At 12 months, two and six patients had achieved complete or
partial remission, respectively; seven of these eight patients had a baseline creatinine clearance above 80
mL/min per 1.73 m . In contrast, five of the six patients who did not attain remission at 12 months had a
baseline creatinine clearance below 75 mL/min per 1.73 m . The likelihood of remission was not related to
previous treatment. Adverse effects were minor and primarily consisted of infusion reactions.
●
2
2
2
The same groupreported a second observational study in which 20 patients with MN, protein excretion
greater than 5.0 g/day, and creatinine clearance greater than 30 mL/min per 1.73, were treated with a
different rituximab regimen: four weekly doses of rituximab 375 mg/m with retreatment at six months
independent of the initial response [36]. Eleven patients (55 percent) had failed prior immunosuppressive
therapy. At 12 months, complete or partial remission had occurred in 10 patients, and, at 24 months, among
●
2
We suggest therefore the somewhat simpler and cheaper regimen of a dose of 1 g given intravenously and
repeated in two weeks. Patients who continue to have significant proteinuria may have this dose repeated at six
months.
A decline in anti-phospholipase A2 receptor (PLA2R) antibodies may predict the clinical response to rituximab
treatment [53]. PLA2R is a transmembrane receptor that is highly expressed in glomerular podocytes and has
been identified as a major antigen in human idiopathic MN [54]. (See "Causes and diagnosis of membranous
nephropathy", section on 'Phospholipase A2 receptor'.)
Anti-PLA2R antibodies were measured in serum samples from 35 patients with MN who were treated with
rituximab as part of the two studies cited above [53]. Serum samples were collected prior to treatment with
rituximab and at 1, 3, 6, 9, and 12 months after treatment. Twenty-five patients (71 percent) had PLA2R
antibodies at baseline. Of these, PLA2R antibodies declined or disappeared in 17 (68 percent) weeks or months
prior to any observed change in proteinuria. Patients who had a decline in anti-PLA2R were more likely to
achieve remission compared with those in whom the level of anti-PLA2 antibodies did not change (59 versus 0
percent, respectively at 12 months and 88 versus 33 percent, respectively at 24 months). One patient who
relapsed had a return of anti-PLA2R antibodies prior to the onset of proteinuria. The lag-time between
disappearance of circulating anti-PLA2R antibodies and a remission of proteinuria may help to explain why only
about 75 to 80 percent of patients with idiopathic MN are positive for anti-PLA2R antibody in cross-sectional
studies [55-57]. The anti-PLA2R autoantibody-negative patients may be in the midst of a spontaneous or
treatment-induced remission. (See "Causes and diagnosis of membranous nephropathy", section on
'Phospholipase A2 receptor'.)
Although this study needs to be validated in prospective clinical trials, it suggests that monitoring serum anti-
PLA2R antibodies may allow a more accurate assessment of the immunological response to rituximab (and
possibly other therapies) than is provided by measurement of proteinuria alone [58].
Immunosuppressive agents in older patients — Patients above age 65 years appear to progress at the same
rate as younger subjects [59]. However, most of the above randomized trials had few, if any, patients over age 65
years [3,4,28,30,45].
Two retrospective studies of 115 patients older than 60 to 65 years found little evidence of benefit from
glucocorticoids alone with a higher incidence of side effects, such as infection, peptic ulcer disease, and
gastrointestinal disturbances [60,61]. However, there may be a response to cytotoxic or to cyclosporine therapy,
as discussed above. This was illustrated in a retrospective study of 41 patients over age 65 years who were
treated with steroids, steroids plus chlorambucil, or supportive therapy [61]. At a mean follow-up of 92 months, a
greater percentage of patients who received chlorambucil were in remission compared to patients who did not.
In older patients, immunosuppressive therapy should be considered only for those who are at high risk for
progression and after maximum conservative therapy has failed [60,61]. A careful examination to rule out an
underlying malignancy is mandatory before considering immunosuppressive therapy in older patients with
apparently idiopathic MN.
PROGNOSIS — Patients who undergo spontaneous or drug-induced remission generally have a good long-term
prognosis. Thirty to 40 percent of patients who receive cytotoxic therapy plus glucocorticoids undergo complete
remission of proteinuria, 30 to 50 percent undergo partial remission, and the incidence of progressive renal
insufficiency is only about 10 percent [3,4,27,28]. Relapse of proteinuria occurs in up to 20 to 30 percent of
cases, and such patients should be considered for retreatment [4,28,42,49].
18 patients who completed the study, 16 achieved either a complete (4) or partial (12) remission. These data
suggest that rituximab may provide benefit to patients who failed prior immunosuppressive therapy,
especially those with relatively preserved renal function. In the two studies cited above, four weekly doses of
rituximab (375 mg/m ) appear to have the same effect on proteinuria reduction as a regimen of 1 g every
two weeks.
2
The prognosis after complete remission (whether treatment-associated or spontaneous) was reported in 82
adults with biopsy-confirmed idiopathic membranous nephropathy (MN) [49]. The mean total observation time
was 101 months, 69 months of which was in the post-remission period. Three distinct groups of patients were
identified:
No patient subsequently developed end-stage renal disease. Multivariate analysis revealed that female sex and
persistently low levels of proteinuria were associated with a durable remission. These parameters are also
associated with a better long-term prognosis [62].
By comparison, progressive disease is characterized by persistent heavy proteinuria and a gradual elevation in
the serum creatinine concentration over a period of years. As noted above, however, effective therapy can
improve outcomes in such patients. (See 'Summary of high risk' above.)
Patients who attain partial remission have a much better outcome than those with stable or progressive disease.
This was illustrated in an observational study that included 136 patients with idiopathic MN who had partial
remission and 110 who had no remission [17]. At a median follow-up of five years, partial remission was
independently associated with a slower decrease in renal function over time (-0.17 versus -0.86 mL/min per
month with no remission) and a lower incidence of renal failure (9 versus 29 percent, adjusted hazard ratio [HR]
0.17). (See 'Importance of attaining remission' above.)
The durability of remission (spontaneous or treatment-associated) is associated with improved renal survival.
One prospective study examined this relationship among 376 patients with idiopathic MN who achieved complete
or partial remission after a period of nephrotic-range proteinuria [63]. Persistent remission at 3, 6, 12, and 24
months after remission onset, compared with disease relapse at each of these time points, was associated with a
significantly lower risk of the primary endpoint (end-stage renal disease or 50 percent reduction in estimated
glomerular filtration rate [eGFR], HRs 0.48, 0.35, 0.37, and 0.40, respectively).
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries
and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in
adults".)
SUMMARY AND RECOMMENDATIONS — Membranous nephropathy (MN) is among the most common causes
of the nephrotic syndrome in nondiabetic adults. MN is often idiopathic but may also be caused by drugs and
underlying diseases. (See 'Introduction' above.)
Prognosis — The most important predictors of risk for a progressive decline in renal function are persistent
severe proteinuria for at least three months, a reduced creatinine clearance at presentation, and a decline in
creatinine clearance over the assessed proteinuria period. (See 'Risk factors for progressive idiopathic MN'
above.)
The following categoriesof risk for progression, which are used for therapeutic decisions, are based upon the
degree of proteinuria and the creatinine clearance as measured in a 24-hour collection. A random urine protein-
to-creatinine ratio should not be used for risk stratification, but can be used for serial monitoring. (See
'Measurement of protein excretion' above.)
Those who remained in remission (67 percent)●
Those with a remitting, relapsing course but without renal insufficiency (20 percent)●
Those who developed renal insufficiency (13 percent)●
Low risk of progression – Protein excretion remains less than 4 g/day and creatinine clearance remains
normal for a six-month follow-up period.
●
Moderate risk of progression – Protein excretion is between 4 and 8 g/day and persists for more than six
months, and creatinine clearance is normal or near normal and remains stable over 6 to 12 months of
observation.
●
Other significant adverse risk factors include age greater than 50 years and male gender. (See 'Clinical findings'
above.)
Nonimmunosuppressive therapy — Nonimmunosuppressive therapy is given to almost all patients with
idiopathic MN, even those who require treatment with immunosuppressive drugs.
Immunosuppressive therapy
Low risk
Moderate risk
High risk of progression – Protein excretion is greater than 8 g/day and persists for three months and/or
creatinine clearance is reduced (and considered due to MN) or declines over three months of observation.
(See 'Probability of progression' above.)
●
For patients with persistent proteinuria, we recommend angiotensin inhibition with an ACE inhibitor or an
ARB (Grade 1B). (See 'Angiotensin inhibition' above.)
●
The proteinuria goal is less than 1000 mg/day. For the many patients who cannot attain this goal, we
suggest a goal of at least partial remission, which has been defined as protein excretion below 3.5 g/day
plus a 50 percent or greater reduction in protein excretion from the peak value (Grade 2B). In addition to
angiotensin inhibition, other factors that can contribute to these goals are spontaneous remission and
immunosuppressive therapy. (See 'Proteinuria goal' above and 'Importance of attaining remission' above.)
●
The goal blood pressure in patients with MN is the same as it is in other patients with proteinuric chronic
kidney disease. This is discussed separately. (See 'Goal blood pressure' above and "Antihypertensive
therapy and progression of nondiabetic chronic kidney disease in adults".)
●
The management of dyslipidemia and hypercoagulability in patients with the nephrotic syndrome are
discussed separately. (See "Lipid abnormalities in nephrotic syndrome" and "Renal vein thrombosis and
hypercoagulable state in nephrotic syndrome".)
●
For patients who remain at low risk of progression over a six-month period, we recommend continued
observation rather than administering immunosuppressive therapy (Grade 1B). Such patients should be
periodically monitored every three months for two years and twice yearly thereafter to assess for disease
progression that might warrant therapy. (See 'Low risk for progression' above.)
●
For patients who remain at moderate risk for progression and do not continue to show a progressive decline
in proteinuria at six months, we recommend the initiation of immunosuppressive therapy rather than
continued observation (Grade 1B).
●
For moderate-risk patients with a progressive decline in protein excretion over this period that remains
above 4 g/day, we suggest immunosuppressive therapy rather than continued observation (Grade 2C).
However, some clinicians would continue to withhold immunosuppressive therapy beyond six months in
such patients who are doing well and are at high risk of having an adverse event with immunosuppressive
therapy.
●
If immunosuppressive therapy is administered, we recommend either a cytotoxic-based or calcineurin
inhibitor-based regimen, each combined with glucocorticoids, rather than other therapies or glucocorticoid
monotherapy (Grade 1B). The choice between a cytotoxic-based or calcineurin inhibitor-based regimen
depends primarily upon clinician and patient preference, after a thorough discussion of the potential benefits
and risks. As an example, calcineurin inhibitor-based therapy may be preferred among those who elect to
avoid toxicity of cytotoxic agents, such as the risk of decreased fertility. (See 'Summary of moderate risk'
above.)
●
High risk
Relapsing patients — Relapse of proteinuria occurs in 25 to 30 percent of patients treated with
cyclophosphamide and a higher percentage of those treated with a calcineurin inhibitor. The choice of therapy
varies with the initial regimen that was used and with concerns about toxicity. (See 'Relapsing disease' above.)
Resistant patients — Resistant patients are defined as those with moderate or high risk disease who fail an
adequate trial of treatment with both cyclophosphamide-based and calcineurin inhibitor-based regimens. (See
'Resistant disease' above.)
If a cytotoxic-based therapy is chosen, we recommend a cyclophosphamide-based regimen rather than
chlorambucil because of a lower rate of side effects (Grade 1B). Our preferred regimen is presented above.
(See 'Summary of moderate risk' above.)
●
If a calcineurin-based therapy is chosen, the administration of either cyclosporine or tacrolimus is largely
based upon patient preference. As an example, tacrolimus may be preferred among those who wish to avoid
some of the side effects commonly observed with cyclosporine, such as hirsutism or gingival hypertrophy.
Our preferred cyclosporine and tacrolimus-based regimens are presented above. (See 'Summary of
moderate risk' above.)
●
Patients treated with either a cyclophosphamide or a calcineurin inhibitor-based regimen are considered
unresponsive if a substantial reduction in proteinuria (30 to 50 percent from peak levels) is not observed
after four to six months of therapy.
●
Among those who do not respond to initial treatment with a cyclophosphamide or a calcineurin inhibitor-
based regimen, we suggest treatment with the other regimen (Grade 2C). The dosing regimens are the
same as those described for initial therapy, as tolerated. For patients initially treated with cytotoxic therapy,
we usually wait three to six months after the cessation of cytotoxic therapy before initiating a calcineurin
inhibitor, unless the patient has severe symptoms or a rise in serum creatinine secondary to active MN. (See
'Summary of moderate risk' above.)
●
For patients who are at high risk of progression, we recommend the initiation of immunosuppressive therapy
rather than continued observation (Grade 1B). (See 'High risk for progression' above and 'Summary of high
risk' above.)
●
In patients classified as high risk because of declining renal function, we suggest combination therapy with
glucocorticoids and a daily oral cytotoxic agent (cyclophosphamide or chlorambucil) rather than cyclosporine
or other therapies (Grade 2B). For reasons presented above, we prefer cyclophosphamide rather than
chlorambucil. An acceptable dosing strategy is discussed above. Patients who wish to avoid cytotoxic
therapy (eg, a woman of child-bearing age) can reasonably choose treatment with cyclosporine and
glucocorticoids. (See 'Summary of high risk' above and 'Choice of therapy' above.)
●
In other high-risk patients selected for immunosuppressive therapy (based on persistent high-grade
proteinuria but preserved renal function), we recommend either a cytotoxic-based or a calcineurin inhibitor-
based regimen, each in combination with glucocorticoids, rather than other therapies (Grade 1B). An
acceptable calcineurin-based dosing strategy is presented above. (See 'Summary of high risk' above and
'Choice of therapy' above.)
●
Among patients initially treated with a calcineurin