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Membranous Nephropathy

(Membranous Glomerulonephritis)

By

Frank O'Brien

, MD, Washington University in St. Louis

Last full review/revision Jul 2021| Content last modified Jul 2021
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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 blood pressure. 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.

The M-type phospholipase A2 receptor (PLA2R) in the glomerular podocyte has been identified as the major target antigen in deposited immune-complexes.

Etiology

Membranous nephropathy is usually idiopathic, but it may be secondary to any of the following:

  • Drugs (eg, gold, penicillamine, nonsteroidal anti-inflammatory drugs [NSAIDs])

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

  • Autoimmune disorders (eg, systemic lupus erythematosus [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 Overview of Lung Tumors Lung tumors may be Primary Metastatic from other sites in the body Primary tumors of the lung may be Malignant (see table Classification of Primary Malignant Lung Tumors) read more , colon Colorectal Cancer Colorectal cancer is extremely common. Symptoms include blood in the stool and change in bowel habits. Screening using one of several methods is recommended for appropriate populations. Diagnosis... read more Colorectal Cancer , stomach Stomach Cancer Etiology of stomach cancer is multifactorial, but Helicobacter pylori plays a significant role. Symptoms include early satiety, obstruction, and bleeding but tend to occur late in the disease... read more Stomach Cancer , breast Breast Cancer Breast cancer most often involves glandular breast cells in the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis... read more Breast Cancer , or kidney Renal Cell Carcinoma Renal cell carcinoma (RCC) is the most common renal cancer. Symptoms can include hematuria, flank pain, a palpable mass, and fever of unknown origin (FUO). However, symptoms are often absent... read more ; Hodgkin Hodgkin Lymphoma Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more Hodgkin Lymphoma or non-Hodgkin lymphoma Non-Hodgkin Lymphomas Non-Hodgkin lymphomas are a heterogeneous group of disorders involving malignant monoclonal proliferation of lymphoid cells in lymphoreticular sites, including lymph nodes, bone marrow, the... read more Non-Hodgkin Lymphomas ; chronic lymphocytic leukemia Chronic Lymphocytic Leukemia (CLL) Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of phenotypically mature malignant B lymphocytes. Primary sites of disease include peripheral blood, bone marrow... read more ; and melanoma Melanoma Malignant melanoma arises from melanocytes in a pigmented area (eg, skin, mucous membranes, eyes, or central nervous system). Metastasis is correlated with depth of dermal invasion. With spread... read more Melanoma .

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

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 membranous nephropathy (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 membranous nephropathy. The diagnosis is confirmed by biopsy Renal biopsy Biopsy of the urinary tract requires a trained specialist (nephrologist, urologist, or interventional radiologist). Indications for diagnostic biopsy include unexplained nephritic or nephrotic... read more .

Immune complexes are seen as dense deposits on electron microscopy (see the figure Electron microscopic features in immunologic glomerular disorders Electron microscopic features in immunologic glomerular disorders 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... read more 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 glomerular basement membrane (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 membranous nephropathy 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 Diagnosis reference 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... read more Diagnosis reference ).

Electron microscopic features in immunologic glomerular disorders

Electron microscopic features in immunologic glomerular disorders
Membranous Nephropathy

Diagnosis of cause

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).

Diagnosis reference

  • 1. Beck LH , Bonegio RG, Lambeau G: M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 361(1):11, 2009. doi: 10.1056/NEJMoa0810457

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 Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more Chronic Kidney 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

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

  • 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 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.

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 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 Treatment reference 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... read more Treatment reference ).

Therapies of unproven long-term value include IV immune globulin and nonsteroidal anti-inflammatory drugs (NSAIDs).

Treatment reference

Key Points

  • 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.

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