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Membranous Nephropathy

by Navin Jaipaul, MD, MHS

Membranous nephropathy is deposition of immune complexes on the glomerular basement membrane (GBM) with GBM thickening. Cause is usually unknown, although secondary causes include drugs, infections, autoimmune disorders, and cancer. Manifestations include insidious onset of edema and heavy proteinuria with benign urinary sediment, normal renal function, and normal or elevated BP. Diagnosis is by renal biopsy. Spontaneous remission is common. Treatment of patients at high risk of progression is usually with corticosteroids and cyclophosphamide or chlorambucil.

Membranous nephropathy (MN) mostly affects adults, in whom it is a common cause of nephrotic syndrome (see Overview of Nephrotic Syndrome).

Etiology

MN is usually idiopathic but may be secondary to any of the following:

  • Drugs (eg, gold, penicillamine, NSAIDs)

  • Infections (eg, hepatitis B or C virus infection, syphilis, HIV)

  • Autoimmune disorders (eg, SLE)

  • Thyroiditis

  • Cancer

  • Parasitic diseases (eg, malaria, schistosomiasis, leishmaniasis)

Depending on the patient’s age, 4 to 20% have an underlying cancer, including solid cancers of the lung, colon, stomach, breast, or kidney; Hodgkin or non-Hodgkin lymphoma; chronic lymphocytic leukemia; and melanoma.

MN is rare in children and, when it occurs, is usually due to hepatitis B virus infection or SLE.

Renal vein thrombosis is more frequent in MN and is usually asymptomatic, but may manifest with flank pain, hematuria, and hypertension. It may progress to pulmonary embolism.

Symptoms and Signs

Patients typically present with edema and nephrotic-range proteinuria and occasionally with microscopic hematuria and hypertension. Symptoms and signs of a disorder causing MN (eg, a cancer) may be present initially.

Diagnosis

  • Renal biopsy

  • Evaluation for secondary causes

Diagnosis is suggested by development of nephrotic syndrome, particularly in patients who have potential causes of MN. The diagnosis is confirmed by biopsy.

Proteinuria is in the nephrotic range in 80%. Laboratory testing is done as indicated for nephrotic syndrome. The GFR, if measured, is normal or decreased. Immune complexes are seen as dense deposits on electron microscopy (see see Figure: Electron microscopic features in immunologic glomerular disorders.). Subepithelial dense deposits occur with early disease, with spikes of lamina densa between the deposits. Later, deposits appear within the GBM, and marked thickening occurs. A diffuse, granular pattern of IgG deposition occurs along the GBM without cellular proliferation, exudation, or necrosis.

Electron microscopic features in immunologic glomerular disorders.

Evaluation of patients diagnosed with MN usually includes the following:

  • A search for occult cancer, particularly in a patient who has lost weight, has unexplained anemia or heme-positive stools, or is elderly

  • Consideration of drug-induced MN

  • Hepatitis B and C serologic testing

  • Antinuclear antibody testing

The search for occult cancer is usually limited to age-appropriate screening (eg, colonoscopy for patients age > 50 or with other symptoms or risk factors, mammography for women age > 40, prostate-specific antigen measurement for men age > 50 [age > 40 for blacks], chest x-ray and possibly chest CT for patients at risk of lung cancer).

Prognosis

About 25% of patients undergo spontaneous remission, 25% develop persistent, non-nephrotic–range proteinuria, 25% develop persistent nephrotic syndrome, and 25% progress to end-stage renal disease. Women, children, and young adults with non-nephrotic–range proteinuria and patients with persistently normal renal function 3 yr after diagnosis tend to have little disease progression. More than 50% of patients with nephrotic-range proteinuria who are asymptomatic or who have edema that can be controlled with diuretics will have a partial or complete remission within 3 to 4 yr.

Risk of progression to renal failure is highest among patients with

  • Persistent proteinuria 8 g/day, particularly men age > 50 yr

  • An elevated serum creatinine level at presentation or diagnosis

  • Biopsy evidence of substantial interstitial inflammation

Treatment

  • Treatment of secondary causes and of nephrotic syndrome as indicated

  • Immunosuppressive therapy for patients at high risk of progression

  • Kidney transplantation for patients with end-stage renal disease

Primary treatment is that of the causes. Among patients with idiopathic MN, asymptomatic patients with non-nephrotic–range proteinuria do not require treatment; renal function should be monitored periodically (eg, twice yearly when apparently stable). Patients with nephrotic-range proteinuria who are asymptomatic or who have edema that can be controlled with diuretics should be treated for nephrotic syndrome. Patients with hypertension should be given an ACE inhibitor or angiotensin II receptor blocker; these drugs may also benefit patients without hypertension by reducing proteinuria.

Immunosuppressive therapy

Immunosuppressants should be considered only for patients with symptomatic idiopathic nephrotic syndrome and for those most at risk of progressive disease. However, there is no strong evidence that adults with nephrotic syndrome benefit long-term from immunosuppressive therapy. Older and chronically ill patients are at greater risk of infectious complications due to immunosuppressants. No consensus protocol exists, but one approach uses methylprednisolone 1 g IV for 3 days, after which prednisone 0.5 mg/kg po once/day is given for the next 27 days. The following month, chlorambucil 0.1 to 0.2 mg/kg po once/day is given for 1 mo. These 2 monthly regimens are alternated for a total of 6 mo. This protocol remains controversial (see the Cochrane abstract review There is no strong evidence that adults with nephrotic syndrome have a long-term benefit from treatment with immunosuppressive drugs .) and should be used with caution, especially in the elderly because of the increased risk of infection. Some experts favor use of combinations of cyclophosphamide and corticosteroids because of their better safety profile.

For patients who are intolerant of cytotoxic drugs or who do not respond to them, cyclosporine 4 to 6 mg/kg po once/day for 4 mo may be beneficial. Therapies of unproven long-term value include IV immune globulin and NSAIDs.

Kidney transplantation is an option for patients with end-stage renal disease. MN recurs in about 10% of patients, with loss of graft in up to 50%.

Key Points

  • Although MN is usually idiopathic, patients may have treatable associated disorders, such as cancers, autoimmune disorders, or infections.

  • Initial manifestations are typically those of nephrotic syndrome (eg, edema, nephrotic-range proteinuria, occasionally microscopic hematuria and hypertension).

  • Confirm the diagnosis with renal biopsy and consider associated disorders and causes.

  • Treat nephrotic syndrome and treat hypertension initially with angiotensin inhibition.

  • Consider immunosuppressive therapy only for patients with idiopathic nephrotic syndrome who are at risk for progression.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • CYTOXAN (LYOPHILIZED)
  • LEUKERAN
  • CUPRIMINE
  • MEDROL
  • NEORAL, SANDIMMUNE
  • RAYOS

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