2. Epidemiology
• Children
< 5% of pediatric patients undergoing biopsy for NS.
• Adults
Most common cause of nephrotic syndrome in adults
30% all biopsies for nephrotic syndrome
• Older population
50% of all biopsies for nephrotic syndrome
In patients >60yrs;associated with malignancy in 20-30%
3. Epidemiology
• 2nd /3rd common cause of ESRD within primary GN group
• USRDS 2002 - 2006:
[0.4% ESRD was due to Idiopathic Membranous GN]
• Has been reported in < 1 year old and > 90 years old.
but uncommon in < 30 years old.
• Peak age 30-40 and 40-50 years
• M:F- 2-3:1
• Caucasians > Asians > African-Americans > Hispanics
6. Advances in membranous nephropathy:
success stories of a long journey
• MN is characterized by an accumulation of
immune deposits on the outer aspect of the
glomerular basement membrane.
• In the rat model described by Heymann in 1959,
the target antigen of antibodies is megalin, a
multiligand receptor expressed in the rat
glomerulus but absent from the human
glomerulus.
Clinical Exp Pharmacol Physiol;2011 Jul;38(7):410-6
7. Advances in membranous nephropathy:
success stories of a long journey
• First podocyte antigen:Neutral Endopeptidase
(NEP) in neonatal alloimmune MN
Debiek H et al;NEJM 346;2053 – 2060,2002
• 70% of patients with MN contain an
autoantibody to podocyte antigen PLA2R
Beck LH et al;NEJM 361:11-21,2009
8. Advances in membranous nephropathy:
success stories of a long journey
• In addition to podocyte antigens, recently it
was shown that some patients with childhood
MN had both circulating cationic bovine
serum albumin (BSA) and anti-BSA antibodies,
with BSA being present in immune deposits.
• This suggests that food antigens may be
involved in MN
Clinical Exp Pharmacol Physiol;2011 Jul;38(7):410-6
11. Light Microscopy
• Early MN:
a glomerulus from a
patient with severe
nephrotic syndrome
and early MN exhibiting
normal architecture and
peripheral capillary
basement membranes
of normal thickness
12. Light Microscopy
• Morphologically
advanced MN:
uniform increase in the
thickness of the
glomerular capillary
walls throughout the
glomerulus without any
increase in glomerular
cellularity
13. Light Microscopy
• Morphologically more
advanced MN –
discrete spikes of matrix
emanating from the
outer surface of the
basement membrane
(arrow) indicative of
advanced MN
14. Immunofluorescence
• A glomerulus with
diffuse, finely granular
deposition of IgG along
the outer surface of all
capillary walls
(pathognomonic)
• TBM staining – common
in secondary especially
lupus
15. Electron Microscopy
• Early (stage II) disease:
glomerular capillary wall with
discrete electron-dense deposits
on the subepithelial surface of
the basement membrane (BM)
corresponding to granular
deposits of IgG detected by
immunofluorescence microscopy
(asterisks) with effacement of
overlying podocyte foot
processes.
• Small extensions of BM between
deposits (arrows) are also evident
and represent the projections
that are seen as spikes by light
microscopy
16. Electron Microscopy
More advanced disease(stage III):
• two glomerular capillary loops
showing involvement of
(arrows) the BM by the
immune complex deposition.
• There is prominent membrane
synthesis surrounding and
incorporating these deposits
into the BM (corresponding to
the spikes seen on silver-
stained histologic
preparations).
17. Electron Microscopy
Advanced MN (stage IV):
• BM is diffusely
thickened
• Scattered electron-
dense immune deposits
(arrows) are present
throughout its thickness
in addition to scattered
subepithelial deposits.
20. Secondary MN
• Represents 20% to 30% of all cases
• In women between the ages of 20 and 50 years, a high
index of suspicion is warranted for underlying lupus.
• This diagnosis can be particularly difficult to make because
the majority of these patients have no systemic symptoms
and serologic markers of SLE are often absent.
• Membranous lupus accounts for 8% to 27% of cases of
lupus nephritis
21. Secondary MN
Malignant Neoplasia
• In adults, regardless of age, most common secondary cause of MN
• Colon,kidney, and lung are the most common primary sites.
HBV associated MN -
• a common secondary cause in endemic countries.
• In children, HBVassociated MN most commonly presents as the
nephrotic syndrome and usually follows a benign course.
• In adults, progressive renal impairment is a more common
outcome.
• Hypocomplementemia is present in approximately 50% of cases of
MN with HBV.
22. Secondary MN
Drugs
• MN secondary to drugs usually resolves after
discontinuation of the offending agent.
• The time to resolution, however, varies
significantly from as early as 1 week (e.g., for
NSAIDs) to several years for gold or d-
penicillamine.
23. Membranous nephropathy and renal transplantation
• Recurrence rate -10 to 45%
• The mean time to recurrence, which typically presents as
nephrotic range proteinuria, is approximately 10 months.
• Affected patients appear to have more aggressive initial
disease as evidenced by progression to ESRD at a mean of
four years
• Incidence of allograft loss at 10 years due to recurrent
disease - 12.5 percent.
33. Relapse After Complete Remission or
Partial Remission
Complete remission -
• Relapse rate -25% to 40% with unpredictable time line..
• Great majority of patients will relapse only with sub-nephrotic range proteinuria
and will maintain stable long term kidney function with conservative management
alone.
Partial Remission -
• Relapse rate is as high as 50%
• Achievement of either a complete or partial remission, however, significantly slows
progression and increases renal survival.
• A recent review of 348 nephrotic MN patients documented a 10-year renal
survival in patients with a complete remission of 100%; with partial remission,
90%; and with no remission, only 45%
Treatment related partial remission has same long term implication as that of
spontaneous one
41. Non-Immunosuppressive Therapy
• Conservative management is directed at control of
edema, hypertension, hyperlipidemia, and
proteinuria and is similar to that used for nephrotic
syndrome of any etiology.
• For patients with proteinuria of more than 1 g/day, the
target for blood pressure is 125/75 mm Hg.
• Even patients at low risk for progression should be
treated with ACEI or ARBs because this may reduce
proteinuria and offer additional renal protection with
little chance of significant adverse effects.
42. Non-Immunosuppressive Therapy
• Low-salt diet to achieve the maximum benefit from RAS blockade.
• Patients with significant proteinuria almost always have elevated
serum cholesterol and triglyceride levels.
• Although it is not proven,use of statins to reduce LDL to 100 mg/dl
or lower is recommended.
• Dietary protein intake restriction to 0.8 g/kg body weight per day
of high quality protein with additional dietary protein (gram per
gram) to correct for urinary losses.
• Protein restriction must be carefully monitored in nephrotic
patients to avoid malnutrition
43. Prophylactic Anticoagulation
• Patients with severe nephrotic syndrome are at increased risk for thromboembolic
complications, and prophylactic anticoagulation has been shown in retrospective
reviews to be beneficial in reducing fatal thromboembolic episodes without a
concomitant increase in the risk of bleeding.
• However, no RCT has ever been done. Hence, there is no current consensus about
prophylactic anticoagulation.
• Certain clinical scenarios do have a higher likelihood of such an event and thus
deserve more careful physician monitoring.
• These include patients with severe and persistent nephrotic syndrome (proteinuria
>10 g/day and serum albumin <2.5 g/day).
• The majority of practicing nephrologists, however, still wait until a primary
thromboembolic event has occurred before using anticoagulants.
46. Corticosteroids
• There have been three RCTs of corticosteroids in the
treatment of idiopathic MN.
• The overall consensus has been no significant long-term
beneficial effect on proteinuria, rate of disease progression,
or renal survival.
• The use of oral corticosteroids as a single agent for the
treatment of MN is therefore not recommended.
• The one exception may be the Asian population, in which
long-term observational studies have indicated
improvement in both proteinuria and renal function
preservation with use of corticosteroids as monotherapy
Shiiki H et al;Kidney Int. 2004;65:1400-1407.
47.
48.
49.
50.
51.
52.
53.
54. Alkylating agents
(Summary)
• Cyclophosphamide used in combination with corticosteroids appears to be
effective in the treatment of patients with nephrotic-range proteinuria
due to idiopathic MN, especially if renal function is well preserved at the
time of initiation of therapy.
• This combination may work even in those with impaired renal function,
but the supporting data are much less compelling, adverse effects are
higher, and the likelihood of benefit is reduced, especially in patients with
advanced renal failure (GFR <30 ml/min).
• The favorable effects are maintained beyond the 1-year treatment period,
but relapse rates approach 35% by 2 years.
• The adverse effects of cyclophosphamide when it is used long term are
the major drawbacks to the universal application of this form of therapy.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67. MMF
• In a small retrospective study in
corticosteroid-resistant Asian MN patients, a
higher response with MMF was observed,
partial remission rate approaching 50%,
possibly related to the ethnic characteristics of
the population studied.
• The role of MMF in the treatment of MN is
currently uncertain.
68. Eculizumab
• Eculizumab is a humanized anti-C5 monoclonal
antibody designed to prevent the cleavage of C5
into its proinflammatory byproducts.
• An RCT in 200 patients with MN that compared
this agent with placebo during a total of 16 weeks
showed no significant effect on proteinuria or
renal function, but effective complement
inhibition was not achieved.
Appel G et al;J Am Soc Nephrol. 2002;13:668A
MN in childhood is more often secondary (such as due to hepatitis B virus)
Because only 20% of all patients with MN progress to ESRD, the real incidence of MN is approximately 2300 patients per year in the United States or about 8 patients per million population per year.
In about two thirds of patients, however, no obvious etiologic agent or condition can be identified.
These discoveries should lead to improved therapies.
In recent years, two major antigens have been identified in human membranous nephropathy (MN). The first is neutral endopeptidase (NEP), the alloantigen involved in neonatal cases of MN that occur in newborns from NEP-deficient mothers. The second is the M-type phospholipase A(2) receptor (PLA(2) R), the first autoantigen identified in idiopathic MN in the adult. Megalin, NEP and PLA(2) R are all expressed on the podocyte surface, where they can serve as targets for circulating antibodies, leading to in situ immune complex formation, complement activation and proteinuria.
through charge-dependent binding to the anionic glomerular capillary wall and in situ formation of immune complexes.
In the earliest stages of the disease, the glomeruli and interstitium appear normal by light microscopy, and the diagnosis is made by immunohistology and electron microscopy
Leukocyte infiltration is absent in glomeruli in MN, probably because chemotactic products of complement activation follow filtration forces into the urinary space rather than diffusing backward into the capillary lumenAlthough similar deposits at other sites may induce proliferation of glomerular endothelial and, particularly, mesangial cells, podocytesin vivo seem terminally differentiated and rarely proliferate. 6 As a result, the pathologic lesion of MN is characterized only by changes in podocytes and basement membrane without any associated glomerularhypercellularity.The presence of significant mesangialhypercellularity suggests immune deposit formation in the mesangium and is more consistent with a secondary MN, such as class V lupus nephritis
Later lucencies may develop in the GBM as immune deposits are resorbed, resulting in some areas of the GBM appearing as double contours by silver methenamineCrescent formation is rare unless there is concurrent anti GBM orANCA diseasestaining.
Predominant IgG subclass in idiopathic MN is IgG4. Positive staining for IgG1 or IgG3, IgA, or IgM or significant staining in the glomerularmesangium suggests lupus as an underlying mechanism. Complement C3 is also present in about 50% of patients and usually reflects staining for C3c, a breakdown product of C3b that is rapidly cleared. Consequently, positive C3 staining probably reflects active, ongoing immune deposit formation and complement activation at the time of the biopsy, whereas the absence of C3 suggests that the process of forming deposits has ceased.
Although these changes clearly reflect the severity and duration of disease, they do not correlate well with clinical manifestations or outcome
macroscopic hematuria and red cell casts are rare and suggest a different glomerular pathologic process.C3 anaanca normal
Crescents rare only asso with anti GBM,ANCA
Recently, other biomarkers including urinary α1-microglobulin, β2-microglobulin, IgM, and IgG have also been strongly associated with progression These markers measured together at a single time point have a higher positive predictive value than proteinuria alone, but none has yet been validated in an independent data set.
First the baseline proteinuria in this study from the Mayo clinic a lot of years ago. 104 patients were divided into 3 groups according to the baseline proteinuria. You can see that the survival probability according to this baseline proteinuria. As you can see only one patient with subnephroticproteinuria progressed to ESRD and patients with more than 10 g of proteinuria at baseline had the worst prognosis.As the severity of proteinuria at presentation increases, the frequency of spontaneous remission appears to decrease.
But probably the best predictor of risk of progression to ESRD is obtained by combining the amount of proteinuria and the duration of this proteinuria. This was the predictive model proposed by Cattran some years ago. The measure, the amount of proteinuria for a period of at least 6 months and these are the results they got. As you know patients with less than 4 g/day over 6 months are classified as low risk of progression to ESRD. When the proteinuria ranges between 4-8 g/day they are classified as medium risk. When the proteinuria is more than 8 g or they have a decline in renal function, they are at high risk of progression; it means that their probability of developing ESRD is between 66-80%.
Female sex and lower grade (non-nephrotic) proteinuria at presentation are the only two features associated with a higher likelihood of spontaneous remission
Another good predictor of renal outcome is the occurrence of remission. This is the study from the Toronto GN Registry for 348 patients classified according to the occurrence of the complete, partial or no remission and you can see in the graph of survival free from renal failure that no patient with complete remission entered ESRD and the worst prognosis is for patients with no remission
This was confirmed by this Spanish study very recently published. 380 patients were followed and they were not treated initially and as you can see, 33% entered in remission and no patient within remission entered ESRD and about 20% of patients with no remission developed ESRD. Just to point out, to underline that the time to achieve remission is 15 months and another important factor is that the principal predictor factor of occurrence of spontaneous remission is a progressive decrease of more than 50% of proteinuria during the first year of follow up.
The natural cause of idiopathic membranous nephropathy is well known. You know that one third of the patients enter complete and spontaneous remission, another third enter partial remission and remain subnephrotic and the last third progress to ESRD
Relapses have been reported up to 20 years after the primary
So to conclude, patients with more than 4 g/day with or without renal insufficiency must be treated but when? Probably immediately if there is a renal insufficiency that is a creatinine more than 2-3 mg% or severe complications of nephrotic syndrome. They must be treated before 6-12 months if there is no decrease in proteinuria whilst receiving conservative treatments and probably after this period waiting for remission if there is an decrease in proteinuria. So other results recommend a more restrictive policy postponing treatment until renal function declines.
It is recommended that both RAS blockade and lipid control be initiated early in the MN patients, although reaching a goal of complete remission or even partial remission in patients at higher risk of progression (with persistent proteinuria >5 g/24 h) with conservative treatment alone is unlikely.
The most well-known regimen with alkylating agents was proposed by Professor Ponticelli, it’s very well-known
you know that it is a 6 month alternating cyclophosphamide or chlorambucil and steroids. The cumulative dose of cyclophosphamide is between 13-15g for one course of this treatment. The ten-year follow up results were published in 1995 and as you know, there were two control groups with supportive therapy and a group treated with chlorambucil and chlorambucil improved the rate of remission from 38-83% and there was also a very high rate of renal survival. These results were very recently confirmed by this group from India by Jha. He randomized his patients into two groups treated with cyclophosphamide or conservative therapy and again the remission rate was very high since it was 72%. An excellent renal survival rate of 89%. The relapse rate was higher than in the Ponticelli trial.
These two trials included patients with medium risk to progress to ESRD but alkylating agents as has well been demonstrated that they can be effective in patients with renal failure. In this study from the Netherlands patients were treated with cyclophosphamide and this was compared with the controlled history group of 24 patients and we can see that the rate of remission was very high and the renal survival was also very high; 86% at 5 years compared with 32% of the control group. The rate of relapse was relatively high. The same results were obtained in the Spanish trial.
But obviously alkylating agents are toxic. Two main side effects; infertility and cancer risk. Infertility depends on the cumulative dose and on the age of the patients and the cancer risk, extensively studied in vasculitis, depends on the cumulative dose and on the length of follow up. Just to remind you that one course of treatment with the Ponticelli regimen is 13-15 g and the regimen proposed by the Netherlands group the oral cyclophosphamide, the cumulative dose is 30g
Time to remission with use of cyclosporine variesfrom a few weeks to several months. This suggests that if nosignificant reduction in proteinuria (<40%) is noted within 3 to4 months, a change in therapy may be warranted.
the first control trial was presented by Cattran some years ago. 51 patients were randomized between these two groups; cyclosporine plus prednisolone or cyclosporine alone with an average follow-up of 78 weeks. The rate of remission was very good but there was a high rate of relapses after discontinuation of cyclosporine mainly within the first year.
The same results were obtained with tacrolimus in two studies from Spain; a pilot study and a randomized trial. In this randomized trial the rate of remission comparing monotherapy with tacrolimus in the control group was similar to that obtained with cyclosporine 72% but again a very high rate of relapses mainly within the first 4 months after discontinuation
The exact mechanism of action of this agent in MN is unknown but likely unrelated to corticosteroid effects because corticosteroids alone are not beneficial in MN.1 to 2 mg weekly intramuscularly for a year.
and one controlled trial by Ponticelli some years ago. 32 patients were randomized between the two groups; alkylating agents or ACTH for one year. As you can see the results were very similar in terms of remission only that with ACTH the number of complete remissions was higher but the results on proteinuria and renal function were very similar.
we have two pilot studies the first one published in Italy that was a small study with 8 patients treated with four weekly doses of rituximab and we can see an important reduction of the proteinuria, more than 50% of fall of proteinuria.
The study by Fervenza confirmed these results. It was a pilot study with a different regimen 1 g every two weeks and treatment rescue at 6 months if CD20 increased and there was also an important fall in proteinuria, 53% of remission and two patients entered ESRD.An RCT needs to be done before widespread use of this agent is advocated, given its very high cost and unknown long-term toxici
The first one is a control study from France. 36 patients were randomized into a control group and into an MMF group; 1 g twice daily. There was no difference in terms of proteinuria or kidney function between the two groups. So no evidence of efficacy for MMF. The proteinuria and renal function was stable and similar in the two groups during follow up.
How to treat? Probably cytotoxic agents, we know they are the most extensively studied agents and they may be used as first line of therapy in the moderate or high risk group. Calcineurin inhibitors may be used if the patient presents the risk of side effects with cyclophosphamide or if these drugs are used the two drugs are not mutually exclusive and may follow sequentially if the first one chosen does not induce remission or if there are severe side effects. Nevertheless rituximab and ACTH and MMF might have a role in the management of the disease given the lack of toxic gonadal, bladder and renal effects. Hopefully an improved understanding of the disease will facilitate the development of specific therapy.
These approaches are not mutually exclusive and can be used in sequence if the first one chosen does not succeed in inducing a remission or adverse effects are untenable. Ideally, one should leave 2 to 3 months between treatment regimens to help immune system recovery
