membranous nephropathy

Membranous Nephropathy

Puneet Arora 21/12/2011

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%

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

PATHOPHYSIOLOGY

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


• 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


• 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

PATHOLOGY

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

Light Microscopy

• Morphologically advanced MN:

uniform increase in the thickness of the glomerular capillary walls throughout the glomerulus without any increase in glomerular cellularity

Light Microscopy

• Morphologically more advanced MN –

discrete spikes of matrix emanating from the outer surface of the basement membrane (arrow) indicative of advanced MN

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

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

Electron MicroscopyMore 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).

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.

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%

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

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.

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.

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.

CLINICAL COURSE, OUTCOMES,AND COMPLICATIONS

Relapse After Complete Remission orPartial 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

EVIDENCE BASED TREATMENT OF MEMBRANOUS NEPHROPATHY

?

• Who to treat?

• When to treat??

• How to treat???

CONSERVATIVE MANAGEMENT How to treat?

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.

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

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.

IMMUNOSUPPRESSIVE THERAPY

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.

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.

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.

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

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membranous nephropathy

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