Membranous Nephropathy: Causes, Symptoms, Treatment

Membranous Nephropathy: Causes, Symptoms, Treatment

Membranous nephropathy (MN) is a chronic autoimmune kidney disease and one of the most common causes of nephrotic syndrome in adults.

It is characterised by immune-mediated damage to (and thickening of) the glomerular basement membrane (GBM), leading to significant proteinuria, oedema, and a risk of kidney function decline (i.e. worsening CKD). It does not normally cause acute kidney injury (AKI).

Advances in immunology—particularly the discovery of antibodies such as anti-PLA2R—have significantly improved diagnosis, risk stratification, and treatment decisions.

This article provides an in-depth overview for expert patients seeking a deeper understanding of membranous nephropathy.

Causes

Membranous nephropathy is classified as primary (idiopathic) or secondary, depending on the underlying cause.

Primary (Autoimmune) Membranous Nephropathy

• Accounts for approximately 70–80% of cases
• Caused by autoantibodies targeting podocyte antigens, most commonly:
  • Phospholipase A2 receptor (PLA2R) – most frequent
  • Thrombospondin type-1 domain-containing 7A (THSD7A) – less common
• Immune complex deposition leads to complement activation and podocyte injury

Secondary Membranous Nephropathy

Associated with identifiable conditions, including:

• Autoimmune diseases (e.g. systemic lupus erythematosus, SLE)
• Chronic infections (hepatitis B, hepatitis C, syphilis)
• Malignancies (especially solid tumours in older adults)
• Medications (NSAIDs, certain biological agents)
• Environmental or toxin exposures

Identifying secondary causes is critical, as treatment focuses on the underlying condition.

Symptoms

Symptoms of membranous nephropathy often develop gradually and are primarily related to nephrotic-range proteinuria.

Common symptoms include:

• Peripheral oedema (legs, ankles, feet)
• Periorbital swelling, especially in the morning
• Foamy or frothy urine due to protein loss
• Fatigue and weakness
• Weight gain from fluid retention

Less common but clinically significant features:

• Hypercoagulability, increasing the risk of venous thrombosis
• Hyperlipidaemia
• Increased susceptibility to infections

Some patients may be asymptomatic initially and diagnosed through routine laboratory testing.

Diagnosis

Diagnosis of membranous nephropathy involves a combination of laboratory testing, serological markers, and usually a kidney biopsy.

Laboratory Tests

• Heavy proteinuria (uACR > 220 mg/mmol)
• Hypoalbuminaemia
• Elevated cholesterol and triglycerides
• Variable kidney function (normal to reduced GFR)

Serological (Immune System) Testing

• Anti-PLA2R antibodies (highly specific for primary MN)
• Anti-THSD7A antibodies (in selected cases)
• Autoimmune and infectious screening to rule out secondary causes

Kidney biopsy of membranous nephropathy, with arrow showing thickened GBM

Kidney Biopsy

• Confirms the diagnosis when needed
• Shows immune complex deposition along the glomerular basement membrane
• Helps assess chronicity and prognosis

In some cases with classic features and positive PLA2R antibodies, biopsy may be deferred.

Treatment

Treatment of membranous nephropathy is individualised and based on risk of progression, severity of proteinuria, and kidney function.

If MN is secondary, you start by removing or treating the cause.

Supportive (Conservative) Therapy

First-line for low-risk patients:

• Renin–angiotensin system blockade (ACE inhibitors or ARBs) and SGLT2is
• Blood pressure control
• Dietary sodium restriction
• Diuretics for oedema
• Statins for dyslipidaemia
• Anticoagulation in selected high-risk patients

Immunosuppressive Therapy

Indicated for moderate- to high-risk disease or worsening kidney function:

• Rituximab (increasingly first-line due to favourable safety profile)
• Cyclophosphamide plus corticosteroids (Ponticelli regimen)
• Calcineurin inhibitors (tacrolimus or cyclosporin)

Treatment response is often monitored using proteinuria levels and PLA2R antibody titers.

Complications

Untreated or progressive membranous nephropathy may lead to:

• Chronic kidney disease (CKD)
• End-stage renal failure (ESRF) requiring dialysis or transplant
• Thromboembolic events (renal vein thrombosis (can be bilateral), DVT, pulmonary embolism (PE))
• Serious infections
• Long-term cardiovascular risk due to persistent nephrotic syndrome

Early recognition and risk-adapted therapy can significantly reduce complications.

Outlook (Prognosis)

The prognosis of membranous nephropathy is highly variable.

• Up to 30–40% of patients experience spontaneous remission
• Approximately 30–40% develop progressive kidney disease over 10–15 years
• Prognosis is influenced by:
  • Degree and persistence of proteinuria
  • Kidney function at diagnosis
  • Response to treatment
  • Antibody levels (e.g., declining PLA2R levels predict remission)

With modern therapies—particularly targeted immunotherapy—long-term outcomes for membranous nephropathy have improved substantially.