Treatment of Idiopathic
Membranous Nephropathy
Alexander Usorov, MD
4/21/09
Idiopathic MN
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Leading cause of Nephrotic syndrome in white
adults
Incidence rate has remained constant over 3
decades
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As opposed to IgA Nephropathy and FSGS
2ry MN accounts for up to 1/3rd cases and a/w
autoimmune dz (SLE, Hep B/C, NSAIDs,
neoplasms)
Both IMN and 2ry MN have similar clinical
presentations
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Therefore, r/o 2ry causes first
Clinical Manifestations
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All ages (but rare in children)
All races
M>F 2:1
Peak incidence during 4th and 5th decade of life
NS in 60-70% of pts at the time of presentation
As per Dr. Cattran, about 60% of pts who present with
subnephrotic-range proteinuria will progress to full NS
within 1-2 years from presentation
Microscopic hematuria in 30-40%
Mostly normotensive pts (10-20 % with HTN)
<20% of pts have significant renal insufficiency
Natural History
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MN is a chronic dz with spontaneous remission and
relapses
The rule of 1/3rd:
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Spontaneous remission within the first 2 years after
presentation
Lower rates of spontaneous remission if pts present with
higher degree of proteinuria (ie 8g/24hr)
2nd leading cause of ESRD among 1ry GNs
Increased risk of thromboembolic and CV events
Acute changes in proteinuria or rate of loss of renal fxn
should raise the possibility of a superimposed event
(RVT, crescentic GN, anti-GBM disease)
Figure 1. (A and B) Light microscopy showing segmental sclerosis (arrow; A, periodic acid Schiff stain) and
pinholes (arrow) along the glomerular basement membranes (B, silver stain)
Fervenza, F. C. et al. Clin J Am Soc Nephrol 2008;3:905-919
Copyright ©2008 American Society of Nephrology
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(C and D) Immunofluorescence microscopy showing granular
IgG (C) and C3 (D) along the capillary walls. (E) Electron
microscopy showing subepithelial electron-dense deposits and
basement membrane spikes (arrows) separating the deposits
“Idiopathic” MN ?
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Ronco et al reviewed the rat model of Heymann nephritis
and the role of alloimmunization as a new mechanism of
MN in Seminars of Immunopathology 2007
Hypothesized that antibodies to neutral endopeptidases,
aminopeptidase A, and dipeptidyl peptidase IV or DPPIV
(all expressed in podocytes) are responsible for
“Idiopathic” MN
Salant’s presentation at ASN expanded on that idea
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Could not find more info on this presentation
Prognostic Factors
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Critical point
When and what to use (conservative txt vs
immunosuppressive txt)
Allows to separate pts with good long-term renal survival
from those who are likely to progress
No specific markers available
Current evidence does not support pathology as a helpful
measure outside of making a diagnosis
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Not helpful in establishing prognosis
Not helpful in prediciting response to immunosuppression
Some evidence that urinary excretion ratios of a1microglubulin, b2-micro, IgM, IgG are helpful, but these
tests are not routinely available
Prognostic Factors Cont.
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Currently, the best model for ID of pts at
risk was developed from Toronto
Glomerulonephritis Registry
Initial CrCl, the slope of CrCl, lowest
level of proteinuria during a 6-mo
observation period
Has been validated in Italy and Finland
Prognostic Factors Cont.
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Low risk for progression
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Normal CrCl
Proteinuria <4g/24hr
Stable renal fxn during an observation period
Medium risk (55% probability of developing CRI)
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Normal CrCl
Proteinuria >4g/24 hr but < 8g/24 hr
Stable renal fxn during an observation period
High risk (66-80% probability of progression to Chronic
Renal Failure)
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Persistent proteinuria >8g/24 hr independent of the degree
of renal dysfxn
Prognostic Factors Cont.
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Pts who were never nephrotic or who achieved
CR (proteinuria < 0.3g/24hr with nl renal fxn)
have an excellent long-term renal survival
Troyanov, Cattran et al in KI 2004 found that in
350 MN pts with NS:
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10-year renal survival was 100% in CR, 90% in PR
(>50% reduction in proteinuria, >0.3g/24hr and
<3.5g/24 hr), and 45% in no remission
Loss of GFR: -1.5 ml/min/year in CR, -2 in PR, -10 in
no remission
Treatment Options
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Conservative (nonimmunosuppressive)
Therapy
Immunosuppressive therapy
Conservative Therapy
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Restrict dietary protein intake (0.8g/kg
ideal body weight per day, high quality
protein)
Low salt diet
Target BP <125/75 mm Hg
Control dyslipidemia with statins
ACEI/ARB (weak evidence, largely
inferential)
Immunosuppressive Therapy
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Not used in low-risk group as side effects are likely to
exceed the benefits
Medium risk group first
Steroids – monotherapy, no benefit
Combined with cytotoxic agents:
Ponticelli et al NEJM 1989 showed that 6-mo MTP IV + oral
steroids alternating monthly with chlorambucil was superior
to conservative txt in achieving CR (50% vs 7%) and PR
(31% vs 24%)
10-year follow up showed that 8% of txt pts vs 40% of untxt
pts reached ESRD
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Similar data with same cyclic steroid combo when
chlorambucil was c/w cyclic steroids and oral
cyclophosphamide. (Ponticelli et al JASN 1998)
CR or PR in 82% vs 93% (P=0.116)
Txt with CYC was a/w fewer side effects, but renal fxn
was equally preserved for up to 3 years
Recent trial by Jha et al JASN 2007 looked at 47 pts on
6-mo course of alternating prednisolone and CYC vs 49
pts with supporting txt:
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In txt group, 34 (15 CR + 19 PR) vs 16 (5 CR + 11 PR)
10-yr HD-free survival was 89% vs 65% with similar
incidence of infections in both groups
Long Term Adverse Effects for
CYC
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Fertility
Bladder carcinoma
Myelodysplasia
Risk of malignancy is not increased with
cumulative CYC doses < 36 g, but
increases significantly in pts with CYC
doses > 36 g (Faurschou et al J.
Rheumatology 2008)
Cyclosporine
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Single RCT of 51 pts with MN
Low-dose prednisone + CsA vs prednisone + placebo
26 weeks of txt
21/28 pts (78%) in CsA group vs 5/23 (22%) in placebo
achieved PR or CR
Relapse rate of 40% within 1 year of d/c of therapy
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should not be considered failure of therapy as reintroduction of CsA or
an alternative regimen can induce a remission
Majority of CR occurs after > 6 mo of txt
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If after 3-4 mo of CsA proteinuria is not significantly reduced, it is
unlikely that CsA will be effective
Prolonged low-dose CsA (1.5 mg/kg) has been suggested for
long-term maintenance, with little risk for nephrotoxicity
Tacrolimus
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Praga et al KI 2007 administered TAC
monotherapy to 25 pts with nl renal fxn and
mean proteinuria of 8 g/24 hr for 12 mo with a
6 mo taper vs 23 control pts.
At 18 mo, the probability of remission was 94%
in TAC group vs 35% in controls
2ry endpoint of 50% increase in SCr was
reached by 6 control pts and 1 TAC pt
Relapse rate of about 50% after withdrawal
? Low-dose maintenance long term
High Risk for Progression
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Steroids – no benefit
Combined with cytotoxic agents - no RCT
available
CsA – 1 RCT showing some benefit in 17 pts
after 12 mo of txt (reduction in proteinuria and
slope of renal fxn was reduced from -2.4
ml/min to -0.7 vs -2.2 to -2.1 in control group)
with sustained results in 50% for 2 years after
d/c of CsA
MMF – possible benefit from 3g/day dosing
New Therapies
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ACTH
2 studies by Berg (1 in pts with NS in 2004, and 1 in pts with
MN in 1999) and a pilot study by Ponticelli et al AJKD 2006
16 pts were txt with MTP plus chlorambucil or CYC (group A)
16 pts were txt with ACTH 2 injections per week for 1 year
(group B)
Group A – 5 CR and 10 PR
Group B – 10 CR and 4 PR
Side effects a/w ACTH – dizziness, glucose intolerance,
diarrhea, bronze-colored skin, which resolved after the end
of therapy
Rituximab
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Experimental data suggests that B-cell
activation leads to IgG4 deposition along
the GBM, which leads to injury to the
membrane and thus proteinuria
How about we selectively target B cells
and halt the progression of these “autoantibodies”?
Not a first line therapy
Rituximab Cont
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A systematic review by Bomback et al in this
month’s CJASN
21 studies were included in the final review
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12 were single case reports
9 were case series ranging from 2 to 50 pts
Both 1ry and 2ry MN pts were included
Principally used as a 2nd line therapy except for
one study
Rituximab Cont
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Response rate was as follows
CR 15-20%
PR 35-40%
Similar to RR for alkylating agents (CYC and
chlorambucil) and CNIs (CsA and TAC)
No direct comparisons to older therapy
We need a well-designed RCT comparing
rituximab to standard therapy such as
Ponticelli’s regimen
Rituximab – Future Questions
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Should rituximab be used as a first line therapy?
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No data
Optimal dosing regimen
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Lymphoma protocol used for IMN by Remuzzi (375 mg/m2 weekly x4)
Alternative progocol used by Fervenza’s (1 g on days 1 and 15)
Titrating rituximab to circulating B cells used by Cravedi (1 st dose at 375 mg/m2,
2nd dose was given only if > 5 circulating B cells/mm3 were detected 1 week
after txt)
Long term risks and benefits?
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No long-term data for rituximab in MN is available
Recent reports of PML in MS pts
Possible removal of pathogenic auto-Abs (kidneys from Heymann nephritis rats
were transplanted into non-diseased rats and resolution of subepithelial
deposits was seen)