INTRODUCTION
This chapter makes treatment recommendations for patients with biopsy-proven membranous
nephropathy (MN) believed to be of unknown cause (IMN). The treatment of secondary
forms of MN will not be covered in this chapter, except for MN associated with hepatitis
B and C. The cost implications for global application of this guideline are addressed
in Chapter 2.
7.1:
Evaluation of MN
7.1.1: Perform appropriate investigations to exclude secondary causes in all cases
of biopsy-proven MN. (Not Graded)
BACKGROUND
The diagnosis of MN is made on kidney biopsy. Diagnostic features include capillary
wall thickening, normal cellularity, IgG and C3 along capillary walls on immunofluorescence,
and subepithelial deposits on electron microscopy. MN is often seen in association
with an underlying disorder (secondary MN).
191, 192, 193
Secondary MN is more common in children (75%) than adults (25%) (Table 12). The diagnosis
of IMN is made by exclusion of secondary causes, using history, physical exam, and
apppropriate laboratory tests (e.g., serology, imaging) and by careful examination
of the kidney biopsy by light, immunofluorescence, and electron microscopy. In IMN,
deposition of the IgG4 subclass of IgG is dominant, whereas other IgG subclasses dominate
in secondary forms of MN.
194, 195
Distinguishing secondary MN from IMN is very important, since the therapy in the former
must be directed at the underlying cause and some of the treatments for IMN are potentially
toxic both to the patient and the kidney.
RATIONALE
MN is due to a clinically recognizable underlying disorder in a variable percentage
of cases, depending on age and geography.
191, 192, 193, 196, 197, 199, 200, 201, 202
The recognition of the underlying disorder responsible for MN has important implications
for prognosis and therapy.
MN is typically a disease of adults (fewer than 3% of cases are found in children).
The frequency and etiology of secondary causes varies in different geographic areas
191, 192, 193, 196, 197, 199, 200, 201, 202, 203
(Table 12). IMN is often a “diagnosis of exclusion”. A recent study
200
has shown that about 70–80% of IMN patients exhibit circulating antibodies of IgG4
subtype against a conformation-dependent epitope in the M-type phospholipase A2 receptor.
Such autoantibodies appear to be absent or very uncommon in patients with secondary
MN. If the absence of autoantibodies to phospholipase A2 receptor in secondary MN
is validated and a sensitive and specific assay for autoantibodies becomes available,
it could become a valuable marker to positively identify (“rule in”) IMN. The IgG4
subclass dominates in the deposits of IMN, while IgG1, IgG2, and/or IgG3 dominate
in secondary forms of MN.
194, 195
The most important secondary causes include systemic lupus (in younger women), chronic
hepatitis B infection (especially in East Asia
196
), drugs (such as nonsteroidal anti-inflammatory agents, gold and mercury compounds)
and malignancy (especially in patients presenting over the age of 65 years). Specific
evaluations should exclude secondary causes of MN before specific immunosuppressive
therapy is considered. Detailed morphological studies show mesangial deposits by electron
microscopy and prominent IgG1, 2, or 3 subclass deposits by immunofluorescence in
secondary MN. These features can be helpful in suspecting a secondary form of MN (see
also Table 13 for a detailed listing of causes of MN).
RESEARCH RECOMMENDATIONS
Studies are needed to validate the utility of antibody against M-type phospholipase
A2 receptor in terms of its accuracy in separating primary from secondary MN.
Studies are needed to determine the most cost-effective panel of investigations for
screening an underlying (covert) malignancy in the older patient with MN.
7.2:
Selection of adult patients with IMN to be considered for treatment with immunosuppressive
agents (see 7.8 for recommendations for children with IMN)
7.2.1: We recommend that initial therapy be started only in patients with nephrotic
syndrome AND when at least one of the following conditions is met:
urinary protein excretion persistently exceeds 4 g/d AND remains at over 50% of the
baseline value, AND does not show progressive decline, during antihypertensive and
antiproteinuric therapy (see Chapter 1) during an observation period of at least 6
months; (1B)
the presence of severe, disabling, or life-threatening symptoms related to the nephrotic
syndrome; (1C)
SCr has risen by 30% or more within 6 to 12 months from the time of diagnosis but
the eGFR is not less than 25–30 ml/min per 1.73 m2
AND this change is not explained by superimposed complications. (2C)
7.2.2: Do not use immunosuppressive therapy in patients with a SCr persistently >3.5 mg/dl
(>309 μmol/l) (or an eGFR <30 ml/min per 1.73 m2) AND reduction of kidney size on
ultrasound (e.g., <8 cm in length) OR those with concomitant severe or potentially
life-threatening infections. (Not Graded)
BACKGROUND
The commonest presentation of IMN is nephrotic syndrome with preserved kidney function.
About 50% of patients with persistent high-grade proteinuria eventually progress to
ESRD, often after many years of observation. Complete remission of nephrotic syndrome
predicts excellent long-term kidney and patient survival. A partial remission also
significantly reduces the risk of progression to ESRD (see Table 14 for definitions
of complete and partial remission used in this chapter). The primary aims of treatment,
therefore, are to induce a lasting reduction in proteinuria. All currently used treatment
modalities have significant toxicity; therefore, selecting patients at high risk of
progression is important so that exposure to treatment-related adverse events is minimized.
The degree and persistence of proteinuria during a period of observation helps in
selecting patients for this therapy. There is no agreed definition of the “point of
no return” in the evolution of IMN after which the risks of immunosuppressive drugs
become unacceptable and futile. However, the presence of severe tubular interstitial
fibrosis, tubular atrophy, and glomerular obsolescence on biopsy, accompanied by persistent
elevation of SCr >3.5 mg/dl (>309 μmol/l) (or eGFR <30 ml/min per 1.73 m2), and reduction
in kidney size on ultrasound may be such indicators.
RATIONALE
There is low- to moderate-quality evidence to support a recommendation that patients
with time-averaged proteinuria <4.0 g/d or those who achieve a complete or partial
remission have an excellent long-term prognosis.
Observational studies of the natural history of IMN have shown that male gender, persistent
heavy proteinuria, and elevated SCr at diagnosis predict the risk of later progressive
decline in kidney function, although these factors may not all be independent risks.
About 30–35% of patients with IMN eventually undergo spontaneous remission of nephrotic
syndrome; therefore, it is reasonable to delay specific therapy for at least 6 months
utilizing supportive therapy, including RAS blockade (see Chapter 1 for details) unless
the patient has unexplained rapid deterioration in kidney function or there are complications
related to uncontrolled nephrotic syndrome. However, the frequency of spontaneous
remissions is lower with higher grades of proteinuria at presentation.
It may be difficult to define precisely the time of onset of a partial remission,
since some patients experience a slow reduction in proteinuria, even in the absence
of specific treatment, to non-nephrotic levels over several years.
There is support for the use of predictive models for determining risk of progression
in IMN (i.e., persistent proteinuria >4 g/d and/or decline in kidney function over
a 6-month period of observation).
There is low-quality evidence to support a recommendation that the period of observation
may be extended in patients who exhibit a consistent progressive decline in proteinuria
during observation, have stable kidney function, and no complications related to the
nephrotic state.
About 80% of adults with IMN have nephrotic syndrome at presentation
206
and the remainder have subnephrotic proteinuria (see definitions in Chapter 1). The
disease course may be punctuated with spontaneous remissions and relapses.
197, 207, 208, 209, 210, 211, 212, 213, 214
In about 20% of patients, there is spontaneous complete remission of the nephrotic
syndrome, and another 15–20% undergo partial remission. Remission may be delayed for
as long as 18–24 months. In a recent study, the mean time to remission was 14.7±11.4
months following presentation.
215
About 15–30% suffer one or more relapses, leaving about 50% of the patients with persistent
nephrotic syndrome. Data from natural history studies and placebo arms of intervention
studies show that about 30–40% of the patients with persistent nephrotic syndrome
progress to ESRD over 10 years.
208, 216
Those with a persistent nephrotic syndrome are also exposed to the related complications,
including infections, thromboembolic events, and accelerated atherosclerotic cardiovascular
disease.
The likelihood of spontaneous remission and progression is dependent upon the age,
gender, degree of proteinuria, and kidney function at presentation.
216, 217
The risk of progression is highest in those with proteinuria >8 g/d, persistent for
6 months. A validated algorithm allowed creation of a model based on time-averaged
proteinuria over 6 months, CrCl at diagnosis, and the slope of CrCl over 6 months
that correctly identified patients at risk of progression with 85–90% accuracy.
218
Based on this model, patients at low risk for progression present with a normal CrCl,
proteinuria consistently <4 g/d, and have stable kidney function over a 6-month observation
period. Patients at medium risk for progression (∼50–55% probability of developing
progressive CKD over 10 years) have normal kidney function that remains unchanged
during 6 months of observation, but continue to have proteinuria between 4 and 8 g/d.
Those classified as high risk for progression (65–80% probability of progression to
advanced CKD within 10 years from diagnosis) have persistent proteinuria >8 g/d, independent
of the degree of kidney dysfunction.
219, 220
Treatment-induced remissions are associated with an improved prognosis.
221, 222
The 10-year survival free of kidney failure is about 100% in complete remission, 90%
in partial remission, and 50% with no remission. Patients with complete or partial
remission have a similar rate of decline in CrCl: −1.5 ml/min/y for complete remission,
and −2 ml/min/y for partial remission. Although spontaneous remissions are less common
in those with higher baseline proteinuria, they are not unknown; a recent report
215
showed spontaneous remission in 26% among those with baseline proteinuria 8–12 g/d
and 22% among those with proteinuria >12 g/d. Treatment with RAS blockade, and a 50%
decline of proteinuria from baseline during the first year of follow-up, were significant
independent predictors for remission. Most reported natural history studies were performed
in an era before drugs that act on the RAS became available. The long-term value of
RAS blockade in management of IMN has been assessed largely by observational studies
and has been observed only in those patients with proteinuria (<10 g/d) at baseline.
A recent small RCT (n=27) compared an ACE-I (lisinopril, up to 10 mg/d) to an ARB
(losartan, up to 100 mg/d) in patients with IMN and variable-range proteinuria (2.5–7 g/d).
Both agents were of comparable efficacy, reducing proteinuria on average by 2.5 g/d
by 12 months. The absence of a placebo control and the failure to include patents
with higher-grade proteinuria (>8–10 g/d) weaken the impact of the study.
223
There is only low-quality evidence to support the value of other predictors, such
as hypertension, histologic evidence of interstitial fibrosis and tubular atrophy,
persistently elevated urinary C5b-9, and excretion of increased quantities of low-
or high-molecular-weight proteins (β2-microglobulin and IgG) in urine.
224, 225
Staging of MN by histologic criteria has limited utility for prediction of outcomes
or response to therapy in IMN.
7.3:
Initial therapy of IMN
7.3.1: We recommend that initial therapy consist of a 6-month course of alternating
monthly cycles of oral and i.v. corticosteroids, and oral alkylating agents (see Table
15). (1B)
7.3.2: We suggest using cyclophosphamide rather than chlorambucil for initial therapy.
(2B)
7.3.3: We recommend patients be managed conservatively for at least 6 months following
the completion of this regimen before being considered a treatment failure if there
is no remission, unless kidney function is deteriorating or severe, disabling, or
potentially life-threatening symptoms related to the nephrotic syndrome are present
(see also Recommendation 7.2.1). (1C)
7.3.4: Perform a repeat kidney biopsy only if the patient has rapidly deteriorating
kidney function (doubling of SCr over 1–2 month of observation), in the absence of
massive proteinuria (>15 g/d). (Not Graded)
7.3.5: Adjust the dose of cyclophosphamide or chlorambucil according to the age of
the patient and eGFR. (Not Graded)
7.3.6: We suggest that continuous daily (noncyclical) use of oral alkylating agents
may also be effective, but can be associated with greater risk of toxicity, particularly
when administered for >6 months. (2C)
BACKGROUND
Three RCTs have shown that monotherapy with oral corticosteroids is not superior to
symptomatic therapy alone in IMN. Orally administered akylating agents (cyclophosphamide
or chlorambucil), most commonly in conjunction with steroids, are effective in inducing
remission and preventing ESRD (Online Suppl Tables 22–25). The toxicity profile suggests
that cyclophosphamide might be preferred to chlorambucil.
RATIONALE
There is moderate-quality evidence to recommend a 6-month cyclical regimen of alternating
alkylating agents (cyclophosphamide or chlorambucil) plus i.v. pulse and oral corticosteroids
(see Table 15 for description of regimen) for initial therapy of IMN meeting the criteria
in Recommendation 7.2.1 above. This evidence indicates this treatment is superior
to supportive therapy alone in inducing remissions and preventing long-term decline
of kidney function, including the need for dialysis, in patients with IMN and persisting
nephrotic syndrome. The risks and adverse events associated with the use of cyclophosphamide
in IMN are summarized in Table 16.
Other combined regimens of cyclophosphamide and corticosteroids have also been used.
Some omit i.v. methylprednisolone, others use alkylating agent and corticosteroids
concurrently, rather than cyclically, for a longer duration.
226, 227, 228
However, the long-term efficacy and safety of these regimens are less well-established
than the cyclical regimen.
229
The safety and efficacy of i.v. cyclophosphamide-based regimens for treatment of IMN
have not been sufficiently evaluated to warrant any recommendations. One small (underpowered)
controlled trial in progressive IMN was negative.
230
The evidence is insufficient to make any recommendations regarding the use of i.v.
compared to oral cyclophosphamide.
A complete or partial remission of nephrotic syndrome is associated with an excellent
long-term prognosis; therefore, persisting remission of the nephrotic state is an
acceptable surrogate end-point to assess overall efficacy of treatment.
Treated patients may continue to enter complete or partial remission for as long as
12–18 months following completion of the regimen, so it is reasonable to wait this
period of time before deciding whether the initial treatment has been unsuccessful
(see Recommendations 7.6.1 and 7.6.2), providing that serum albumin levels or kidney
function are not deteriorating, and that morbid events have not supervened. During
the period of observation, patients should continue to receive ACE-I or ARBs, other
antihypertensives, and other supportive therapies as clinically indicated. In comparative
studies, cyclophosphamide has a superior safety profile compared to chlorambucil.
There is low-quality evidence that cyclophosphamide can lead to more frequent and
longer remissions than chlorambucil. Cumulative toxicities of alkylating agents can
be significant and require careful monitoring by the treating physician. A recent
study of the use of cyclophosphamide- or chlorambucil-based regimens in IMN has raised
concerns regarding safety, given a reported adverse-event rate that exceeded 80%.
231
This is in contrast to the older long-term RCT of cyclical alkylating agents and steroids,
where the regimens were well-tolerated with an acceptably low frequency of serious
adverse events.
229, 232, 233
Risks of this regimen are now known to be increased if alkylating agents are used
in patients with reduced renal function, older age, and/or concomitant comorbidities
as evidenced in this recent report.
Since the decline in GFR in IMN is often very gradual, especially in the absence of
massive proteinuria, any acceleration of the rate of decline indicates the possibility
of a superimposed disease process (such as crescentic glomerulonephritis or acute
interstitial nephritis, which is often drug-related) that might dictate a change in
treatment approach. A repeat kidney biopsy is necessary to identify these conditions.
Relapses of nephrotic syndrome occur in about 25% of patients treated with the “Ponticelli”
regimen. A similar fraction of patients with spontaneous remissions also will relapse
(see treatment of relapses in IMN in Section 7.7).
An open-label RCT utilizing a 6-month course of chlorambucil and steroids in alternating
monthly cycles was initiated in the 1980s (see Table 15 for the description of the
regimen).
229, 232, 233
After 10 years of follow-up, 92% of the treated (n=42) and 60% of the control (n=39)
patients were alive with normal kidney function (P=0.0038). There was remission in
61% (40% complete remission) and 33% (5% complete remission) in the two groups. In
another RCT,
234
this same regimen was compared to one where steroids alone were used for the entire
6-month period (chlorambucil was substituted with oral prednisolone 0.5 mg/kg/d).
A significantly higher proportion of patients in the chlorambucil arm were in remission
in the first 3 years. The difference was lost at 4 years, probably because of a small
number of at-risk cases. The duration of remission was also longer in those treated
with chlorambucil. Another RCT
235
compared the same combination of chlorambucil and steroids to one in which chlorambucil
had been replaced with oral cyclophosphamide (2.5 mg/kg/d). Remission of nephrotic
syndrome was noted with equal frequency in the two arms (82% vs. 93% P=0.116) (Online
Suppl Tables 22–25). However, severe adverse effects leading to discontinuation of
therapy occurred more frequently in the chlorambucil group compared to the cyclophosphamide
group (12% vs. 4%). Other small trials and several meta-analyses and systematic reviews
have indicated that the alkylating agents are associated with a higher remission rate,
although the long-term benefits on kidney function could not be demonstrated.
204, 236, 237, 238, 239, 240
A more recent open-label study
204
gave similar results to the initial trials of Ponticelli. Quality of life, as measured
by a visual analog scale, was significantly better in the treatment group throughout
the follow-up period. The complication rate was not different in the two groups.
One small open-label RCT (N=29) examined the efficacy of cyclophosphamide for 12 months
plus moderate-dose steroids in IMN patients considered to be at high risk of progression
(based on urinary IgG and urine β2 microglobulin levels) that previously indicated
these patients would have an increase in SCr levels by >25%, and reach a SCr >1.5 mg/dl
(>133 μmol/l) or have an increase of >50% from baseline. The study compared an early-start
group (urinary abnormalities at baseline) vs. the group started only after SCr had
risen by >25–50%. They found a more rapid remission in proteinuria in early-start
patients, but no differences between the two groups in overall remission rates, SCr
levels, average proteinuria, relapse rates, or adverse events after 6 years.
241
This study agrees with earlier observational studies from the same authors, and supports
an initial conservative treatment approach in IMN patients. However, toxicity with
this specific approach has been reported to be substantially increased by both prolonging
its duration and by selecting patients with impaired kidney function (SCr >1.5 mg/dl
[>133 μmol/l]). The overall evidence for this approach is moderate.
241, 242, 243
The adverse effects of alkylating-cytotoxic agents are substantial, and include gonadal
toxicity, bladder carcinoma, bone marrow hypoplasia, leukemogenesis, and serious opportunistic
infections (Table 16). The balance of risk and benefit may be altered by patient-dependent
factors, such as age and comorbidities. Table 17 lists some of the contraindications
to the use of the cyclical alkylating-agent/steroid regimen. Cyclophosphamide has
a more favorable side-effect profile compared to chlorambucil. The available evidence
does not suggest a beneficial effect of i.v. cyclophosphamide on the course of IMN,
and its use is not recommended. Based on limited pharmacokinetic data, the dose of
alkylating agents should be reduced when GFR declines, in order to avoid bone-marrow
toxicity. Azathioprine does not favorably influence the course of IMN, either alone
or with corticosteroids.
244, 245, 246
Evidence from studies of immunosuppressed patients with diseases other than IMN indicates
that patients on corticosteroids should receive prophylaxis for Pneumocystis jiroveci
with trimethoprim-sulfamethoxazole. Those at risk for osteoporosis (e.g., elderly
or postmenopausal females) should also receive bisphosphonates, unless these are contraindicated,
such as an eGFR <30 ml/min per 1.73 m2 (see also Chapter 1).
Deterioration of kidney function in IMN is usually slow, and development of advanced
CKD most often takes several years of persistent high-level proteinuria. A rapid deterioration
of kidney function in the absence of massive proteinuria (e.g., >15 g/d) usually indicates
the superimposition of another pathologic process, such as acute bilateral renal-vein
thrombosis, a superimposed crescentic GN, or acute interstitial nephritis. A repeat
kidney biopsy is the most appropriate tool to identify any pathology changes that
may require a change in treatment. In patients with severe proteinuria (>10–15 g/d),
however, an acute decline in kidney function (<50% reduction in GFR) can be seen,
possibly as a result of hemodynamic changes. This usually reverses with remission
of the nephrotic state, and hence does not require a change in the therapeutic approach.
Prospective controlled studies of the use of immunosuppressive agents for treatment
of patients with IMN and impaired renal function (e.g., eGFR 30–60 ml/min per 1.73 m2)
are very limited. The current evidence is insufficient to make any specific recommendation
in this group of patients. The hematological toxicity of alkylating agents can be
heightened in subjects with impaired renal function, and the nephrotoxicity of CNI
in those with already impaired renal function remains a concern. These agents should
be used with caution in patients with IMN and chronically reduced renal function.
RESEARCH RECOMMENDATIONS
Clinical, pathological, and biological markers are needed to identify patients who
will benefit most from therapy, and also to avoid unnecessary drug exposure risk to
the rest. There is a lack of evidence to guide ideal dosing to minimize drug toxicity,
especially the gonadal and bladder toxicity of cyclophosphamide.
RCTs are needed to compare alkylating agents or CNIs to MMF, rituximab, or adrenocorticotropic
hormone (ACTH) as initial therapy of IMN with nephrotic syndrome (with or without
impaired renal function at diagnosis).
Studies are needed to determine the value of renal pathology and urinary biomarkers
in predicting prognosis and/or treatment responsiveness.
Serial anti-PLA2R antibodies and urinary biomarkers (such as urinary IgG, β2-microglobulin)
should be measured in natural history studies, and in all future treatment trials
for IMN, in order to assess their value in determining spontaneous remission, response
to treatment, and prognosis.
7.4:
Alternative regimens for the initial therapy of IMN: CNI therapy
7.4.1: We recommend that cyclosporine or tacrolimus be used for a period of at least
6 months in patients who meet the criteria for initial therapy (as described in Recommendation
7.2.1), but who choose not to receive the cyclical corticosteroid/alkylating-agent
regimen or who have contraindications to this regimen. (See Table 18 for specific
recommendations for dosage during therapy.) (1C)
7.4.2: We suggest that CNIs be discontinued in patients who do not achieve complete
or partial remission after 6 months of treatment. (2C)
7.4.3: We suggest that the dosage of CNI be reduced at intervals of 4–8 weeks to a
level of about 50% of the starting dosage, provided that remission is maintained and
no treatment-limiting CNI-related nephrotoxicity occurs, and continued for at least
12 months. (2C)
7.4.4: We suggest that CNI blood levels be monitored regularly during the initial
treatment period, and whenever there is an unexplained rise in SCr (>20%) during therapy.
(Not Graded) (See Table 18 for specific CNI-based regimen dosage recommendations.)
RATIONALE
There is low- to moderate-quality evidence to support a recommendation for CNI therapy
(cyclosporine or tacrolimus) as an alternative to cyclical corticosteroid/alkylating-agent
therapy in IMN (Online Suppl Tables 28–31). There is low-quality evidence to suggest
that a minimum of 6 months therapy with CNI should be employed, which should be continued
for at least 6–12 months if there is a beneficial effect on proteinuria, based on
the high relapse rates if therapy is discontinued early. The suggested dosage regimens
for CNIs in IMN are given in Table 18.
Cyclosporine
Early uncontrolled studies suggested an initial benefit, but a high relapse rate,
with cyclosporine in IMN.
247, 248
In a single-blind, randomized controlled study, 51 patients with steroid-resistant
MN were treated with low-dose prednisone plus cyclosporine and compared to placebo
plus prednisone.
249
Complete and partial remissions in proteinuria were seen in 69% of the patients, but
the relapse rate when cyclosporine was discontinued was high, approximately 45% of
the end of 1 year. Observational data from the German Cyclosporine in NS Study Group
suggests that prolonging cyclosporine treatment for 1 year results in higher (34%)
complete remission at 1 year, and more sustained rate of remissions.144 Current recommendations,
for patients who respond to cyclosporine, are to continue treatment for at least 1
year.182 Prolonged low-dose cyclosporine (∼1.5 mg/kg/d) could be considered for long-term
maintenance of patients who achieve a complete or partial remission, especially in
patients at high risk for relapse.
250
Regular monitoring of cyclosporine blood concentration as well as kidney function
is often recommended, according to data accumulated from experiences in kidney transplantation.
There is no evidence in patients with IMN to indicate optimal cyclosporine blood levels.
Cyclosporine levels usually regarded as nontoxic are 125–175 ng/ml [104–146 nmol/l]
(C0, trough level) or 400–600 ng/ml [333–500 nmol/l] (C2, 2-hour post-dose level).182
Online Suppl Tables 28–31 summarize studies using cyclosporine.
208, 247, 251, 252, 253
There has been only one small RCT using cyclosporine in patients with high-grade proteinuria
and progressive kidney failure.
251
At the time of initiation of treatment, mean CrCl was 55 ml/min, and mean proteinuria
11 g/d. After 12 months of treatment with cyclosporine, there was a significant reduction
in proteinuria, and the rate of loss of kidney function decreased from −2.4 to −0.7 ml/min/mo,
whereas, in those receiving placebo, there was no change: −2.2 to −2.1 ml/min/mo (P
<0.02). This improvement was sustained in ∼50% of the patients for up to 2 years after
cyclosporine was stopped.
208, 247, 251, 252, 253
Tacrolimus
In an RCT using tacrolimus monotherapy in IMN, patients with normal kidney function
(n=25) and mean proteinuria (∼8 g per 24 hours) received tacrolimus (0.05 mg/kg/d)
over 12 months with a 6-month taper, and were compared to conservatively treated controls
(n=23).
254
After 18 months, the probability of remission was 94% in the tacrolimus group but
only 35%, in the control group. Six patients in the control group and only one in
the tacrolimus group reached the secondary end-point of a 50% increase in SCr.
254
Almost half of the patients relapsed after tacrolimus was withdrawn, similar to patients
treated with cyclosporine. There is only low-quality evidence to support prolonged
use of low-dose tacrolimus to maintain remission; the safety of this approach is uncertain.
226, 227, 229, 230, 233, 234, 235, 238, 240, 242, 243, 255, 256, 257, 258
Comparison Studies of CNIs vs. Alkylating Agents
An RCT in IMN patients of Asian ancestry has compared tacrolimus (n=39) for 6–9 months
to oral cyclophosphamide (n=34) for 4 months (both groups received prednisone tapered
off over 8 months).
259
The results indicated no difference between treatments in terms of partial or complete
remission of proteinuria (79% vs. 69%), or adverse events at 12 months of follow-up.
Relapses occurred in approximately 15% of both groups. These data support the use
of tacrolimus, short-term (with or without concomitant steroids) as an alternative
to an oral alkylating-agent regimen.
254
However, the long-term efficacy of a tacrolimus-based regimen for IMN remains uncertain.
259
Use of CNIs in Patients with Reduced Renal Function
The nephrotoxicity of CNIs can be enhanced in the presence of pre-existing renal functional
impairment. Cyclophosphamide-based regimens may be preferred in this situation, but
dose reduction of the alkylating agent is advisable. There is weak evidence for preferring
CNI or alkylating agent–based regimens in this group of patients. An RCT examining
this controversial area is in progress (ISRCTN99959692). The use of other agents,
including rituximab, MMF, and/or ACTH in this group of subjects is worthy of further
study, but the evidence is currently insufficient to make any specific recommendations.
The evidence concerning the value of quantification of the degree of interstitial
fibrosis and/or tubular atrophy in renal biopsy as a guide for the choice of treatment
regimens for IMN is presently insufficient to make any recommendations.
RESEARCH RECOMMENDATIONS
RCTs are needed in IMN to assess the efficacy, safety, and risks of long-term CNI
therapy.
Studies are needed to determine the value of monitoring blood levels of CNIs during
therapy of IMN.
7.5:
Regimens not recommended or suggested for initial therapy of IMN
7.5.1: We recommend that corticosteroid monotherapy not be used for initial therapy
of IMN. (1B)
7.5.2: We suggest that monotherapy with MMF not be used for initial therapy of IMN.
(2C)
BACKGROUND
A number of treatments, other than combined therapy of corticosteroid/alkylating agents
or CNIs, have been tried as initial therapy in IMN (meeting the criteria outline in
Recommendation 7.2.1). However, none of these have been shown in appropriately sized
RCTs to be consistently effective and safe, and therefore are not recommended as “first-line”
initial therapy in IMN.
RATIONALE
Corticosteroid Monotherapy
There is moderate-quality evidence to recommend not using corticosteroid monotherapy
for inducing remissions or delaying the onset of progressive CKD in IMN. An early
study reported that a 2- to 3-month course of high-dose, alternate-day prednisone
resulted in a significant reduction compared to placebo in progression to kidney failure,
although there was no sustained effect on proteinuria.
260
A subsequent RCT in patients with IMN, using an identical corticosteroid regimen vs.
placebo, showed no improvement during drug exposure, or over a 3-year follow-up in
either proteinuria or kidney function (SCr). An additional RCT comparing a 6-month
course of prednisone given on alternate days (n=81) to no specific treatment (n=77)
showed no significant benefit of corticosteroid treatment alone, in either induction
of remission or preservation of kidney function, even after the data were adjusted
to include only patients with proteinuria at entry >3.5 g per 24 hours.
261
Nevertheless, retrospective studies conducted in subjects of Asian (Japanese) ancestry
have suggested possible benefits for steroid monotherapy.
262
These analyses could be confounded by unmeasured variables and failure to subject
patients to an observation period prior to initiation of therapy. The negative RCTs
mentioned included too few Asian subjects for subanalysis.
MMF (Online Suppl Tables 32–34)
MMF as initial therapy in IMN has not been shown in RCTs to be consistently effective
for inducing remissions or delaying the onset of progressive CKD. Thirty-two patients
with IMN and impairment of kidney function (SCr >1.5 mg/dl [>133 μmol/l]) were treated
with oral MMF 1 g twice daily for 12 months, in combination with corticosteroids,
and compared to 32 patients—historical controls treated for the same duration with
oral cyclophosphamide in combination with corticosteroids (cyclophosphamide; 1.5 mg/kg/d).
263
Cumulative incidences of remission of proteinuria at 12 months were 66% with MMF vs.
72% with cyclophosphamide (P=0.3). Adverse effects occurred at a similar rate in the
two groups, but relapses were very much more common with MMF, and relapses were noted
even while on treatment.
263
There have been two small RCTs that have compared MMF plus steroids to the Ponticelli
regimen of an alkylating agent (cyclophosphamide or chlorambucil) plus steroids.
In one study of 20 low risk-of-progression adults that were all drug-naïve with nephrotic
syndrome due to IMN, the efficacy of a regimen of MMF plus corticosteroids was compared
to a modified Ponticelli regimen (with chlorambucil).
264
There was no significant difference in the proportion of patients achieving remission:
64% with MMF, 67% with the modified Ponticelli regimen. The frequency of relapses
and incidence of infections were similar in both groups. There was more leucopenia
with the modified Ponticelli regimen, compared to MMF. In the other small RCT264A
21 drug naïve IMN patients, MMF plus steroids was compared to the Ponticelli regimen.
The complete or partial response rate was 64% (7/11) in the MMF versus 80% (8/10)
with the alkylating/steroid regimen. In a short follow-up period no patience relapsed
in the MMF group and only one in the Ponticelli regimen (NS).
By contrast, in a pilot RCT in a low risk-of-progression adults that were all drug
naïve with nephrotic syndrome due to IMN, the efficacy of a MMF based monotherapy
regimen (no concomittantt steroids) was compared to conservative therapy alone. This
study randomized 36 patients with IMN and nephrotic syndrome to conservative therapy
(RAS blockade, statins, low-salt and low-protein diet, and diuretics) plus MMF (2 g/d,
without concomitant steroids) (n=19) or conservative therapy alone (n=17) for 12 months.
265
The probability of a complete or partial remission did not differ between the two
groups after 12 months.
Thus, while a regimen of MMF plus steroids might have comparable efficacy to the standard
regimen of cyclical alkylating agents and steroids, the present evidence is conflicting,
of low quality, and only short-term. The high frequency of relapses with MMF substantially
reduces enthusiasm regarding this approach to therapy of IMN.
263
Monotherapy with MMF appears to be ineffective.
265
Rituximab
As yet, there are no RCTs using rituximab for initial therapy of IMN, although large
observational studies have provided encouraging data. A pilot study used four weekly
doses of rituximab (375 mg/m2) in eight nephrotic patients with IMN and followed them
for 1 year.
266, 267
Proteinuria significantly decreased at 12 months, and kidney function remained stable
in all patients. Adverse effects were reported as mild. An observational study from
the same investigators suggested that rituximab is likely to be most effective in
patients with minimal degrees of tubulointerstitial injury.
268
A prospective observational study in 15 patients with IMN and proteinuria >4 g per
24 hours—despite ACE-I/ARB use for >3 months and systolic blood pressure <130 mm Hg—has
been reported.
269
At 6 months, patients who remained with proteinuria >3 g per 24 hours, and in whom
total CD19+ B-cell count was >15 cells/μl, received a second identical course of rituximab.
Baseline proteinuria of 13.0 ± 5.7 g per 24 hours (range 8.4–23.5) decreased to 9.1±7.4 g,
9.3±7.9 g, 7.2±6.2 g, and 6.0±7.0 g per 24 hours (range 0.2–20) at 3, 6, 9, and 12
months, respectively (mean ± SD). The mean decline in proteinuria from baseline to
12 months was 6.2±5.1 g/d and was statistically significant (P=0.002). Rituximab was
well-tolerated, and was effective in reducing proteinuria in some patients with IMN.
The complete and partial remission rate was almost 60%, higher than would have been
expected based on known spontaneous remission rates.
Another observational study used circulating B-cell counts to guide dosing, significantly
reducing total dose of rituximab.
270
At 1 year, the proportion of patients who achieved disease remission was identical
to that of 24 historical patients who were given a standard rituximab protocol of
four weekly doses of 375 mg/m2.
More recently, another prospective observational study in 20 patients with IMN and
baseline persistent proteinuria >5.0 g/d received rituximab (375 mg/m2 weekly for
four doses), with retreatment at 6 months regardless of proteinuria response.
271
Baseline proteinuria of 11.9 g/d decreased to 4.2 g/d and 2.0 g/d at 12 and 24 months,
respectively, while CrCl increased from 72.4 to 88.4 ml/min per 1.73 m2 at 24 months.
Among 18 patients who completed 24 months of follow-up, four achieved complete remission,
12 achieved partial remission (complete plus partial remission of 80%). One patient
relapsed during follow-up. More than 50% of the patients in this pilot trial had not
responded to prior therapy. No short-term toxicity of rituximab was observed. This
study also reinforced the observation, made with alkylating agent/corticosteroid therapy
that proteinuria declines gradually, and many months may be required for proteinuria
to reach its nadir.
An RCT is needed to confirm these encouraging results, but the findings indicate a
high probability that rituximab has beneficial actions on the disease process. The
long-term relapse rate is unknown but in the short term, it appears to be low.
271
Due to the lack of RCTs, no specific recommendations can be made regarding the use
of rituximab for initial therapy of IMN.
ACTH (Online Suppl Tables 26–27)
One observational study and one small RCT provide preliminary, low-quality evidence
for the use of long-acting ACTH as initial therapy in IMN.
Depot synthetic ACTH (Synacthen®) administered for 1 year in an observational study
decreased proteinuria in patients with IMN.
272, 273
More recently, a small open-label pilot RCT compared i.v. methylprednisolone and oral
corticosteroids plus a cytotoxic agent (n=16) vs. synthetic ACTH (n=16) as initial
therapy in IMN, and found them to be of similar efficacy, at least over short-term
follow-up.
274
Side-effects associated with the use of synthetic ACTH included dizziness, glucose
intolerance, diarrhea, and the development of bronze-colored skin, which resolved
after the end of therapy. Larger, more-powerful RCTs are required before synthetic
ACTH can be recommended for initial therapy of IMN. Preliminary reports of uncontrolled
studies showing a similar effect of native, intact (porcine) ACTH in a gel formulation
have very recently appeared, but no RCTs have yet been conducted with this formulation
of ACTH. Until broader and more powerful RCTs are performed, no recommendations can
be made for the use of ACTH (synthetic or intact) for initial therapy of IMN.
RESEARCH RECOMMENDATIONS
Larger RCTs with longer follow-up are needed to test MMF and corticosteroids vs. established
regimens as initial therapy.
An RCT is needed to compare rituximab to cyclical corticosteroid/alkylating-agent
therapy or CNIs for initial treatment of IMN with nephrotic syndrome.
An RCT is needed to compare synthetic or native (intact, porcine) ACTH in gel form
with cyclical corticosteroid/alkylating-agent therapy or CNIs for initial treatment
of IMN with nephrotic syndrome.
7.6:
Treatment of IMN resistant to recommended initial therapy
7.6.1: We suggest that patients with IMN resistant to alkylating agent/steroid-based
initial therapy be treated with a CNI. (2C)
7.6.2: We suggest that patients with IMN resistant to CNI-based initial therapy be
treated with an alkylating agent/steroid-based therapy. (2C)
BACKGROUND
The results of trials using an initial cyclical treatment alternating steroids and
an alkylating agent or an initial CNI have shown excellent kidney survival and a high
rate of remission, even in the long term.
204, 233, 234, 235, 249, 254, 275
However, 9–28% of patients are treatment-resistant (fail to achieve a remission) to
steroids and alkylating-agent therapy, and approximately 25% of patients are treatment-resistant
to CNI therapy. Patients who fail to achieve a complete or partial remission of nephrotic
syndrome should be considered for additional therapy if no contraindication to such
treatment exists. The response to alternative therapeutic strategies in treatment-resistant
disease cannot presently be predicted with any degree of accuracy. Failure to respond
to one regimen does not reliably predict a failure to respond to another regimen.
RATIONALE
Unresponsiveness to initial therapy is observed in 10–30% of patients following a
complete course of treatment. There is low-quality evidence to suggest that failure
to respond to one regimen does not reliably predict failure to respond to another
regimen.
If there is no remission following cyclical treatment with an alkylating agent/corticosteroid
regimen, an alternative is to use CNIs. Cyclosporine is the best studied, although
tacrolimus has also been shown to induce a high initial rate of remission, comparable
to the overall response rate observed with combined steroids and alkylating agents,
particularly after a prolonged administration and associated with moderate doses of
steroids.
249
Many treatment-resistant patients also have deteriorating kidney function. There has
been only one small RCT using cyclosporine in patients with high-grade proteinuria
(>10 g/d) and progressive kidney failure (initial CrCl approximately 55 ml/min). It
showed a significant reduction in the rate of loss of kidney function with cyclosporine.
251
For those patients who receive a CNI for initial therapy and show no response after
a period of at least 6 months, we suggest treatment with an alkylating agent–based
regimen, using the same regimen as for initial therapy. However, adverse effects of
treatment may be more frequent in patients with established or progressing kidney
impairment. A randomized trial examining the relative safety and efficacy of conservative,
alkylating agent or CNI therapy in this group of subjects with IMN is in progress
in the UK (ISRCTN 99959692), the results of which could alter recommendations in this
area.
In patients with kidney impairment,
243, 251
bone marrow is more susceptible to the toxic effect of alkylating agents, and there
may also be heightened susceptibility to infections. Therefore, it is recommended
not to exceed daily doses for chlorambucil of 0.1 mg/kg and cyclophosphamide of 1.5 mg/kg
in patients with SCr >2.0 mg/dl [>177 μmol/l]
276
and to limit the total duration of therapy to <6 months. A higher incidence of side-effects
with this regimen is to be expected. The use of CNIs in this group of subjects may
also be associated with worsening renal function due to nephrotoxicity.
The roles of MMF, rituximab, or ACTH in patients resistant to both alkylating agent–based
and CNI-based regimens remain undefined; there have been no RCTs.
111, 205, 263, 265, 272, 274, 277
Additional causative factors should be considered when there is deteriorating renal
function in IMN. Rapidly progressive renal failure may occur from an acute hypersensitivity
interstitial nephritis in IMN patients receiving diuretics, antibiotics, or nonsteroidal
anti-inflammatory drugs. A superimposed crescentic GN associated with anti-GBM antibodies
or ANCA can also rarely develop in those patients with high-grade proteinuria.
278, 279
Kidney biopsy is often necessary to confirm the diagnosis, and complete recovery of
kidney function may follow a course of high-dose oral prednisone in those with acute
hypersensitivity interstitial nephritis or intensive immunosuppression in those with
crescentic disease (see Chapters 13 and 14).
Finally, pulses of i.v. methylprednisolone as monotherapy should not be used for treatment
of resistant disease, unless the steady evolution of IMN is interrupted by a rapidly
progressive course, and an extracapillary (crescentic) GN superimposed on IMN is shown
by kidney biopsy.
RESEARCH RECOMMENDATIONS
RCTs are needed to assess risks and benefits of rituximab, MMF, and ACTH in the treatment
of IMN patients resistant to first-line therapy.
RCTs are needed to assess risks and benefits of the cyclical alkylating agent/corticosteroid
regimen or with a CNI regimen in IMN patients with impaired or deteriorating kidney
function.
7.7:
Treatment for relapses of nephrotic syndrome in adults with IMN
7.7.1: We suggest that relapses of nephrotic syndrome in IMN be treated by reinstitution
of the same therapy that resulted in the initial remission. (2D)
7.7.2: We suggest that, if a 6-month cyclical corticosteroid/alkylating-agent regimen
was used for initial therapy (see Recommendation 7.3.1), the regimen be repeated only
once for treatment of a relapse. (2B)
BACKGROUND
Clinical trials using cyclical treatment of alternating steroids and alkylating agents
or CNIs in IMN have shown excellent kidney survival in those subjects with complete
or partial remission, even in the long term. However, relapses of nephrotic syndrome
occur in 25–30% of patients within 5 years of discontinuation of therapy with alkylating
agents, and 40–50% of patients within 1 year of discontinuation of CNIs. For those
patients who show a complete or partial remission and then a relapse of nephrotic
syndrome, a second course of treatment can be given.
280
RATIONALE
There is very low–quality evidence to suggest that responses to re-treatment of a
relapse are similar to those observed after the first treatment.
There is moderate-quality evidence to suggest that there are significant risks of
neoplasia induction, opportunistic infections, and gonadal damage when alkylating
agents are used for an extended period.
If there is a relapse of nephrotic syndrome in IMN following remission, reintroduction
of a corticosteroid/alkylating-agent regimen or CNIs will often, but not uniformly,
induce another remission.
Most data on repeated courses of immunosuppressive therapy relate to patients in whom
relapses occurred after a partial remission, and with normal kidney function.
281, 282
There are no RCTs to guide therapy for patients with IMN who relapse after a first
course of therapy and have kidney impairment.
283
Cancer induction is a major concern when alkylating agents are used for an extended
period. Cumulative doses of more than 36 g of cyclophosphamide (equivalent to 100 mg
daily for 1 year) were associated with a 9.5-fold increased risk of bladder cancer,
in patients with Wegener granulomatosis. Extended courses have also been associated
with an increased risk of lymphoproliferative, myelodysplastic, and leukemic disorders.
284
Because of this, repeated courses (more than two) of cyclical alkylating-agent therapy
are not advised.
Mild relapses (redevelopment of subnephrotic proteinuria after a complete remission)
do not require any specific treatment, and should be managed conservatively. Blood
pressure should be kept <125/75 mm Hg and an ACE-I or ARB should be used as the first
line of treatment (see Chapter 1).
Other agents such as MMF, rituximab, or ACTH might be considered for treatment of
relapses in IMN. There is some observational evidence that rituximab may be beneficial
in patients relapsing whenever the dose of CNI is reduced (CNI dependency),
285
but the evidence is currently insufficient to make any specific recommendations.
RESEARCH RECOMMENDATION
RCTs are needed to examine the efficacy and safety of MMF, rituximab, or ACTH in relapsing
patients with IMN.
7.8:
Treatment of IMN in children
7.8.1: We suggest that treatment of IMN in children follows the recommendations for
treatment of IMN in adults. (2C) (See Recommendations 7.2.1 and 7.3.1.)
7.8.2: We suggest that no more than one course of the cyclical corticosteroid/alkylating-agent
regimen be given in children. (2D)
BACKGROUND
IMN in children is uncommon, and usually presents as nephrotic syndrome or asymptomatic
proteinuria. IMN contributes less than 5% of cases of nephrotic syndrome in children.
286, 287
Most cases (>75%) of MN in children are secondary to chronic viral infections (e.g.,
hepatitis B), autoimmune diseases (SLE, thyroiditis), or drugs.
RATIONALE
There is low-quality evidence to suggest children with IMN should be treated with
the same regimens as adults, with appropriate dosage modification.
Most knowledge of the natural history of IMN in children, treatment options, and long-term
outcome is derived from small, uncontrolled observational studies
288
that suggest a relatively high spontaneous remission rate, and a low incidence of
ESRD. Children with IMN will not usually require more than conservative therapy, unless
they are severely symptomatic, as they seem to have a higher spontaneous remission
rate than adults. For children with severe symptomatic disease, the same drug combinations
used in adults are suggested, with appropriate dosage adjustments.
289
Most of these protocols use chlorambucil 0.15–0.2 mg/kg/d or cyclophosphamide 2 mg/kg/d
for 8–12 weeks, with alternate-day prednisone. The risk for gonadal toxicity with
chlorambucil and cyclophosphamide is greater in boys than in girls, and is related
to both the duration and total dose of treatment.
290
The cumulative dose of cyclophosphamide should not exceed 200 mg/kg in order to avoid
gonadal toxicity.
There are no data on the use of CNIs in children with IMN; the use of CNIs is based
only on the evidence from adults RCTs. MMF, rituximab, or ACTH has not been studied
in children (see also Table 19).
RESEARCH RECOMMENDATION
The absence of RCTs of treatment of IMN in children makes treatment recommendations
and suggestions moot. RCTs are needed to compare the use of alkylating agents and
CNIs for initial therapy of IMN children with nephrotic syndrome.
7.9:
Prophylactic anticoagulants in IMN
7.9.1: We suggest that patients with IMN and nephrotic syndrome, with marked reduction
in serum albumin (<2.5 g/dl [<25 g/l]) and additional risks for thrombosis, be considered
for prophylactic anticoagulant therapy, using oral warfarin. (2C)
BACKGROUND
IMN seems to constitute a special hazard for venous thromboembolism and spontaneous
vascular thrombosis (such as deep venous thrombosis or pulmonary artery embolism/thrombosis),
even more so than other causes of nephrotic syndrome (see also Chapter 1).
301, 302, 303
This may also apply to other types of primary GN associated with severe nephrotic
syndrome; the evidence base, however, is lacking. There have been no RCTs of prophylactic
anticoagulation in IMN with nephrotic syndrome.
301, 302, 303
RATIONALE
There is very low–quality evidence to suggest the use of prophylactic anticoagulation
with warfarin in patients with IMN and severe nephrotic syndrome. However, based on
Markov modeling of anticipated benefits and risks derived from observational studies,
prophylactic anticoagulation might be considered when the serum albumin concentration
is <2.0–2.5 g/dl (<20–25 g/l) with one or more of the following: proteinuria >10 g/d;
BMI >35 kg/m2; prior history of thromboembolism; family history of thromboembolism
with documented genetic predisposition; NYHA class III or IV congestive heart failure;
recent abdominal or orthopedic surgery; prolonged immobilization.
301, 302, 303
Treatment with warfarin should always be preceded by a short period of treatment with
heparin (fractionated or unfractionated) in sufficient dosage to obtain prolongation
of the clotting time. Dosage adjustments for fractionated heparin may be required
if kidney function is impaired. Due to insufficient experience with the use of newer
oral or parenteral anticoagulants in nephrotic syndrome, no recommendations can be
made regarding their use for prophylaxis of thrombosis. The duration of prophylactic
anticoagulation needed for optimal benefit compared to risk is not known, but it seems
reasonable to continue therapy for as long as the patient remains nephrotic with a
serum albumin <3.0 g/dl (<30 g/l).
RESEARCH RECOMMENDATION
An RCT is needed of prophylactic warfarin in patients with nephrotic syndrome with/without
additional risk for thromboembolism in IMN patients.
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