Membranous nephropathy (MN) is a kidney disorder that affects the glomeruli, the specialized filtering units within the kidneys. It is one of the most frequent causes of nephrotic syndrome in adults. The disease is characterized by the thickening of the glomerular basement membrane (GBM) due to immune system activity. This damage impairs the kidney’s ability to filter blood, causing large amounts of protein to leak into the urine. If left unmanaged, MN can lead to progressive loss of kidney function.
Understanding the Mechanism
Membranous nephropathy is an immune-mediated disease that targets the kidney’s filtration apparatus. The glomerulus contains specialized cells called podocytes, which act as a final barrier to prevent proteins from escaping the bloodstream. MN involves the deposition of immune complexes (antibodies bound to antigens) along the outer surface of the glomerular basement membrane, directly beneath the podocytes.
These immune deposits trigger a localized immune response, including the activation of the complement system. This activation results in the formation of the Membrane Attack Complex (MAC), which damages the podocytes. This damage disrupts the integrity of the slit diaphragms, structures between the podocyte foot processes that normally block protein passage.
The disruption of the filtration barrier allows large plasma proteins, particularly albumin, to escape into the urine. This excessive protein leakage is known as proteinuria. Over time, the continuous immune attack causes the glomerular basement membrane to thicken, a hallmark feature seen on kidney biopsy, ultimately impairing the kidney’s ability to clean waste from the blood.
Primary and Secondary Causes
Membranous nephropathy is categorized into primary and secondary forms based on its origin. Primary MN, or idiopathic MN, accounts for 75% to 80% of all cases and occurs without an identifiable underlying systemic disease. This form is considered an autoimmune disorder.
The most common cause of primary MN involves the production of autoantibodies against the M-type phospholipase A2 receptor (PLA2R). This receptor is expressed on the surface of the podocytes. Anti-PLA2R antibodies bind to the receptor, forming the immune complexes responsible for the damage. Circulating anti-PLA2R antibodies are found in 70% to 80% of patients with primary MN.
Secondary MN makes up the remaining 20% to 25% of cases and develops as a result of another systemic disease or exposure. Common causes include:
- Autoimmune conditions like systemic lupus erythematosus.
- Certain infections, particularly Hepatitis B.
- Cancers.
- Specific medications such as non-steroidal anti-inflammatory drugs (NSAIDs).
Symptoms and Clinical Presentation
The clinical presentation of membranous nephropathy often includes the characteristic features of nephrotic syndrome. One of the most noticeable symptoms is edema, or swelling, which typically begins in the feet and ankles. Fluid retention can also manifest as puffiness around the eyes, especially upon waking.
The excessive loss of albumin, the main protein in the blood, leads to hypoalbuminemia (abnormally low protein levels). This lack of protein causes fluid to leak out of the blood vessels and into the surrounding tissues, resulting in generalized swelling. Patients often report foamy or frothy urine, a direct consequence of the heavy proteinuria.
MN is also associated with a disturbance in lipid metabolism, resulting in high levels of cholesterol and triglycerides (hyperlipidemia). Hypertension, or high blood pressure, may develop due to fluid retention and kidney damage. Fatigue is another common symptom.
Diagnosis and Treatment Strategies
Diagnosis of membranous nephropathy requires a multi-step approach to confirm the disease and rule out secondary causes. A definitive diagnosis relies on a kidney biopsy, where a small tissue sample is examined under a microscope. This allows visualization of immune deposits and the characteristic thickening of the glomerular basement membrane, confirming the pathological pattern.
Supporting laboratory tests include blood work to check kidney function (creatinine levels) and assess hypoalbuminemia. A urine test quantifies proteinuria, often measured as a protein-to-creatinine ratio. The discovery of the PLA2R antigen introduced a blood test to detect circulating anti-PLA2R antibodies, which can diagnose primary MN without a biopsy in specific cases where kidney function is normal.
Treatment involves both supportive care and disease-specific interventions. Supportive therapy focuses on managing the symptoms of nephrotic syndrome and protecting the kidneys from further damage:
- Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) reduce protein loss and control blood pressure.
- Diuretics manage edema.
- Statins lower high cholesterol levels.
For patients at high risk for progressive kidney failure, disease-specific treatment aimed at suppressing the immune system is necessary. Immunosuppressive therapy is reserved for those with heavy, persistent proteinuria or declining kidney function. Common regimens include the modified Ponticelli protocol (corticosteroids combined with an alkylating agent like cyclophosphamide) or newer treatments using the B-cell depleting agent rituximab. Rituximab targets the B-cells responsible for producing anti-PLA2R antibodies.