Membranous Nephropathy

Membranous nephropathy (MN) gets its name from the thickening of the glomerular basement membrane visible under the microscope. Antibodies bind to proteins on the podocyte (filter) surface, immune complexes form, and the basement membrane thickens trying to wall them off.

Types

1. PRIMARY (idiopathic) — 80%:

• Autoimmune
• Driven by anti-PLA2R antibodies (~70%) or anti-THSD7A (~5%)
• Often older men, may follow infections or stress

2. SECONDARY — 20%, always look for these:

• Cancer (especially over age 60) — lung, prostate, breast, colon
• Hepatitis B (and rarely C)
• Lupus (SLE) — class V
• Drugs: NSAIDs, gold, penicillamine, captopril
• Infections: syphilis, malaria
• Other autoimmune: thyroid, sarcoid

IDENTIFYING THE CAUSE MATTERS because treating the underlying problem (cancer, drug, infection) is often the best treatment for the kidney.

Typical Presentation

• Frothy urine
• Leg/ankle swelling (oedema)
• Periorbital swelling in mornings
• Weight gain from fluid
• Tiredness
• Less commonly: blood clots (DVT, PE, renal vein thrombosis) — MN has the highest clot risk of any kidney disease

Investigations

• Urine ACR (very high, often > 300, may be > 1,000)
• Serum albumin (low, often < 25)
• Cholesterol (very high)
• Anti-PLA2R antibody (blood test)
• Anti-THSD7A antibody
• eGFR, creatinine
• Hepatitis B and C, HIV serology
• ANA, complement (exclude lupus)
• Age-appropriate cancer screening: chest X-ray, mammogram, PSA, colonoscopy
• Kidney biopsy if PLA2R negative or atypical

Biopsy

• Light microscopy: thickened basement membrane
• Silver stain: 'spikes' on basement membrane
• Immunofluorescence: granular IgG and C3 along capillary loops
• Electron microscopy: subepithelial deposits, foot process effacement
• PLA2R staining now standard

KDIGO 2021 risk categories — drives treatment decision:

Low Risk

• Normal eGFR
• Proteinuria < 3.5 g/day (or > 50% drop in 6 months on supportive care)
• Albumin > 30

→ Supportive care only, monitor 6 months

Moderate Risk

• eGFR > 60
• Proteinuria 3.5-8 g/day persisting at 6 months

→ Supportive 6 months, then consider rituximab

High Risk

• eGFR < 60 or falling
• Proteinuria > 8 g/day
• Anti-PLA2R titre > 150 RU/mL
• Albumin < 25

→ Immunosuppression sooner

Very High Risk

• Life-threatening nephrotic syndrome
• Rapid eGFR loss

→ Urgent immunosuppression

STEP 1 — SUPPORTIVE CARE (everyone for 3-6 months):

• ACE inhibitor or ARB at maximum tolerated dose
• BP target < 125/75
• Salt restriction < 5 g/day
• Statin (cholesterol is very high)
• Diuretic for oedema (furosemide ± spironolactone)
• Anticoagulation if albumin < 20 g/L (prophylactic warfarin or DOAC — high VTE risk in MN specifically)
• SGLT2 inhibitor (dapagliflozin) — add-on benefit
• Vitamin D (lost in urine)
• Treat secondary causes if found

STEP 2 — IMMUNOSUPPRESSION (if persistent moderate/high risk):

FIRST-LINE (KDIGO 2021): RITUXIMAB

• Two 1 g IV infusions, 2 weeks apart
• May be repeated at 6 months
• Excellent safety profile vs older options
• Now standard of care in UK

ALTERNATIVE: CYCLOPHOSPHAMIDE + STEROIDS (Ponticelli regime)

• 6 months alternating IV methylprednisolone, oral prednisolone, and oral cyclophosphamide
• Effective but more toxic — infection, fertility, malignancy risk
• Reserved for severe disease or rituximab failure

ALTERNATIVE: CALCINEURIN INHIBITORS (tacrolimus, ciclosporin)

• Reduce proteinuria within weeks
• High relapse rate when stopped
• Used as second/third line

Monitoring

• Anti-PLA2R titre falls before urinary proteinuria — early sign of response
• Negative PLA2R = immunological remission
• Aim for partial remission (50% reduction, < 3.5 g/day) within 12 months, complete remission (< 0.3 g/day) within 24 months

Outcomes

• 1/3 spontaneous remission with supportive care only
• 1/3 partial remission with treatment
• 1/3 progress to CKD — but with modern care kidney failure rate is now low (< 10% at 10 years)

Factors Predicting Worse Outcome

• Persistent heavy proteinuria > 8 g/day
• Reduced eGFR at diagnosis
• High anti-PLA2R titre
• Male, older age
• Tubulointerstitial damage on biopsy

Living With MN

• Watch for clots — leg pain, breathlessness, chest pain → urgent assessment
• Avoid prolonged immobility (drive breaks, long flights)
• Annual flu, COVID, 5-yearly pneumococcal vaccines
• Bone protection if on steroids
• Cancer screening as per age and family history (more vigilant after MN diagnosis over 60)
• Pregnancy: best in remission; switch off teratogenic drugs (cyclophosphamide); rituximab and tacrolimus generally OK in pregnancy with planning

Recurrence In Transplant

• ~10-40% recurrence rate
• Pre-transplant anti-PLA2R titre predicts recurrence
• Often responds to rituximab