(See also Overview of Nephrotic Syndrome.)
The M-type phospholipase A2 receptor (PLA2R) in the glomerular podocyte has been identified as the major target antigen in deposited immune-complexes.
Membranous nephropathy mostly affects adults, in whom it is a common cause of nephrotic syndrome.
Membranous nephropathy is usually idiopathic, but it may be secondary to any of the following:
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.
Membranous nephropathy 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 membranous nephropathy and is usually asymptomatic, but may manifest with flank pain, hematuria, and hypertension. It may progress to pulmonary embolism.
Diagnosis is suggested by development of nephrotic syndrome, particularly in patients who have potential causes of membranous nephropathy. The diagnosis is confirmed by biopsy.
Proteinuria is in the nephrotic range in 80%. Laboratory testing is done as indicated for nephrotic syndrome. The glomerular filtration rate (GFR), if measured, is normal or decreased.
Immune complexes are seen as dense deposits on electron microscopy (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.
Identifying presence or absence of PLA2R antibody and the subclass of IgG deposits may help to differentiate idiopathic from secondary membranous nephropathy. For example, the deposits in idiopathic are PLA2R antibody positive and predominantly IgG 4, whereas PLA2R antibody is typically negative and IgG 1 and 2 predominate in malignancy-associated membranous nephropathy (1).
Medium-sized subepithelial dense deposits are seen on transmission electron microscopy in late stage I disease (×10,200).
Spikes of basement membrane silver-staining material protrude from the basement membrane (high-power oil-immersion view, Jones silver stain, original magnification ×1000).
Diffuse coarsely granular IgG deposition along glomerular capillary walls (immunofluorescence with anti-IgG, original magnification ×100).
Evaluation of patients diagnosed with membranous nephropathy usually includes the following:
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).
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 years 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 years.
Risk of progression to renal failure is highest among patients with
Primary treatment is that of the causes. Among patients with idiopathic membranous nephropathy, 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 angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB); these drugs may also benefit patients without hypertension by reducing proteinuria.
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 historically, a common regimen included corticosteroids, followed by chlorambucil. However, this regimen is not often used currently (see the Cochrane abstract review Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome). There is no strong evidence that adults with nephrotic syndrome have a long-term benefit from treatment with immunosuppressive drugs. Most experts favor use of combinations of cyclophosphamide and corticosteroids because of their better safety profile. More recent evidence has suggested a benefit in using rituximab (1).
Therapies of unproven long-term value include IV immune globulin and nonsteroidal anti-inflammatory drugs (NSAIDs).
Kidney transplantation is an option for patients with end-stage renal disease. Membranous nephropathy recurs in about 10% of patients, with loss of graft in up to 50%.
Although membranous nephropathy 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.
Drugs Mentioned In This Article
|Drug Name||Select Trade|