Membranous nephropathy
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This document provides information on membranous nephropathy (MN), including its epidemiology, pathophysiology, pathology, clinical presentation, secondary causes, clinical course and outcomes, and treatment options. It notes that MN is a common cause of nephrotic syndrome in adults. The pathology involves immune complex deposition on the outer aspect of the glomerular basement membrane. Conservative management focuses on controlling edema, hypertension, and proteinuria. Cyclophosphamide combined with corticosteroids can be effective for idiopathic MN with nephrotic-range proteinuria, while the role of mycophenolate mofetil requires further study.
![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](https://image.slidesharecdn.com/membranousnephropathy-111225094601-phpapp02/85/Membranous-nephropathy-3-320.jpg)
Membranous nephropathy
- 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
- 10. PATHOLOGY
- 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.
- 18. Clinical Presentation Presentation: Nephrotic Syndrome: 70-80% Asymptomatic proteinuria : 20-30% Associated findings: Hypertension : 10-20% Renal insufficiency : <10% Microhematuria : 30-40% Renal vein thrombosis : 10-40%
- 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.
- 24. CLINICAL COURSE, OUTCOMES, AND COMPLICATIONS
- 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
- 34. EVIDENCE BASED TREATMENT OF MEMBRANOUS NEPHROPATHY
- 35. • Who to treat? • When to treat?? • How to treat???
- 40. CONSERVATIVE MANAGEMENT How to treat?
- 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.
- 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.
- 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
- 75. THANKYOU
Editor's Notes
- #3: MN in childhood is more often secondary (such as due to hepatitis B virus)
- #4: 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.
- #5: In about two thirds of patients, however, no obvious etiologic agent or condition can be identified.
- #7: These discoveries should lead to improved therapies.
- #8: 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.
- #9: through charge-dependent binding to the anionic glomerular capillary wall and in situ formation of immune complexes.
- #12: 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
- #13: 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
- #14: 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.
- #15: 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.
- #18: Although these changes clearly reflect the severity and duration of disease, they do not correlate well with clinical manifestations or outcome
- #19: macroscopic hematuria and red cell casts are rare and suggest a different glomerular pathologic process.C3 anaanca normal
- #20: Crescents rare only asso with anti GBM,ANCA
- #26: 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.
- #27: 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.
- #29: 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%.
- #30: Female sex and lower grade (non-nephrotic) proteinuria at presentation are the only two features associated with a higher likelihood of spontaneous remission
- #31: 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
- #32: 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.
- #33: 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
- #34: Relapses have been reported up to 20 years after the primary
- #40: 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.
- #43: 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.
- #50: The most well-known regimen with alkylating agents was proposed by Professor Ponticelli, it’s very well-known
- #51: 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.
- #53: 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.
- #54: 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
- #57: 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.
- #59: 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.
- #60: 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
- #61: 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.
- #62: 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.
- #64: 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.
- #65: 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
- #67: 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.
- #74: 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.
- #75: 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