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 Overview of Nephrotic Syndrome Nephrotic syndrome is urinary excretion of > 3 g of protein/day due to a glomerular disorder plus edema and hypoalbuminemia. It is more common among children and has both primary and secondary... read more .
Etiology of Membranous Nephropathy
Membranous nephropathy is usually idiopathic, but it may be secondary to any of the following:
Medications (eg, gold therapy, penicillamine, nonsteroidal anti-inflammatory drugs [NSAIDs])
Infections (eg, hepatitis B or C virus infection, syphilis, HIV infection)
Autoimmune disorders (eg, systemic lupus erythematosus [SLE])
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 ) 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 , 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... read more , breast Breast Cancer Breast cancers are most often epithelial tumors involving the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis... read more , 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 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 ; 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 .
Membranous nephropathy is rare in children and, when it occurs, is usually due to hepatitis B virus infection, SLE, or autoimmune thyroid disease.
Renal vein thrombosis Renal Vein Thrombosis Renal vein thrombosis is thrombotic occlusion of one or both main renal veins, resulting in acute kidney injury or chronic kidney disease. Common causes include nephrotic syndrome, primary hypercoagulability... read more 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.
Symptoms and Signs of Membranous Nephropathy
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 of Membranous Nephropathy
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 renal 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 .
Proteinuria is in the nephrotic range in 80% of patients. Laboratory testing is done as indicated for nephrotic syndrome Overview of Nephrotic Syndrome Nephrotic syndrome is urinary excretion of > 3 g of protein/day due to a glomerular disorder plus edema and hypoalbuminemia. It is more common among children and has both primary and secondary... read more . 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 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 medications... read more ).
Electron microscopic features in immunologic glomerular disorders
Diagnosis of cause
Evaluation of patients diagnosed with membranous nephropathy 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 older
Consideration of drug-induced membranous nephropathy
Antinuclear antibody testing
The search for occult cancer is usually limited to age-appropriate screening Cancer Screening Cancer can sometimes be detected in asymptomatic patients via regular physical examinations and screening tests. (See also Overview of Cancer.) Physical examinations for cancers of the thyroid... read more .
Treatment of Membranous Nephropathy
Control of nephrotic-range proteinuria and/or edema with diuretics
Treatment of secondary causes of nephrotic syndrome as indicated
Immunosuppressive therapy for patients with symptomatic idiopathic membranous nephropathy at high risk of progression
Kidney transplantation for patients with end-stage kidney 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 should be treated with diuretics.
Patients with hypertension should be given an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB); these medications may also benefit patients without hypertension by reducing proteinuria.
Immunosuppressants should be considered only for patients with symptomatic idiopathic membranous nephropathy and for those most at risk of progressive disease. While there is no strong evidence that immunosuppressive therapy has a long-term benefit for patient or kidney survival, it appears to improve rates of remission and possibly progression to end-stage kidney disease (ESKD) (1, 2, 3 Treatment references Membranous nephropathy is deposition of immune complexes on the glomerular basement membrane (GBM) with GBM thickening. Cause is usually unknown, although secondary causes include medications... read more ). 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, chlorambucil is no longer preferred because of other therapeutic options with better safety profiles. Most experts favor use of a combination of rituximab and corticosteroids (2 Treatment references Membranous nephropathy is deposition of immune complexes on the glomerular basement membrane (GBM) with GBM thickening. Cause is usually unknown, although secondary causes include medications... read more ). Alternatives to rituximab include a calcineurin inhibitor and cyclophosphamide. The choice of agent is guided by disease severity and anti-PLA2R antibody levels.
Therapies of unproven long-term value include IV immune globulin and nonsteroidal anti-inflammatory drugs (NSAIDs).
Kidney transplantation Kidney Transplantation Kidney transplantation is the most common type of solid organ transplantation. (See also Overview of Transplantation.) The primary indication for kidney transplantation is End-stage renal failure... read more is an option for patients with end-stage kidney disease. Membranous nephropathy recurs in about 10% of patients, with loss of graft in up to 50%.
1. von Groote TC, Williams G, Au EH, et al: Immunosuppressive treatment for primary membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev 11(11):CD004293, 2021. doi: 10.1002/14651858.CD004293.pub4
2. Fervenza FC, Appel GB, Barbour SJ, et al: Rituximab or cyclosporine in the treatment of membranous nephropathy. N Engl J Med 381(1):36-46, 2019. doi: 10.1056/NEJMoa1814427
3. Ponticelli C, Altieri P, Scolari F, et al: A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. J Am Soc Nephrol 9(3):444, 1998. doi: 10.1681/ASN.V93444
Prognosis for Membranous Nephropathy
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 kidney 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 . 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
Membranous nephropathy is usually idiopathic; however, 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 symptoms of nephrotic syndrome and treat hypertension initially with angiotensin inhibition.
Consider immunosuppressive therapy only for patients with idiopathic membranous nephropathy who are at risk for progression.