Key Facts

Membranous nephropathy is an autoimmune disease where antibodies (mainly anti-PLA2R) target podocyte antigens, forming subepithelial immune complexes that activate complement and damage the filtration barrier.

Epidemiology

• Peak incidence: age 50-60 years; M:F 2:1
• Accounts for 25-30% of adult nephrotic syndrome
• Incidence: 1-2 per 100,000/year in the UK
• Rare in children (<5% of nephrotic syndrome)

Aetiology

• Primary (75%): anti-PLA2R antibodies (most common), anti-THSD7A antibodies (~3%)
• Secondary (25%):
  • Malignancy: lung, colon, breast, prostate, lymphoma (especially age >60)
  • Autoimmune: SLE (class V lupus nephritis), RA
  • Infections: hepatitis B, hepatitis C, syphilis, malaria
  • Drugs: NSAIDs, gold, penicillamine, captopril

Pathophysiology

• Anti-PLA2R IgG4 antibodies bind PLA2R on podocyte foot processes
• In situ immune complex formation on the subepithelial surface of GBM
• Complement activation (C5b-9 membrane attack complex) → podocyte injury
• GBM remodelling with spike formation between deposits
• Progressive GBM thickening → nephrotic-range proteinuria

Classic Presentation

• Nephrotic syndrome: peripheral oedema, frothy urine, weight gain
• Insidious onset over weeks to months
• Preserved renal function at diagnosis in most patients

Features

• Heavy proteinuria (often >10g/day)
• Hypoalbuminaemia (<25 g/L)
• Hyperlipidaemia
• Microscopic haematuria (30-50%)

Complications

• Thromboembolism: highest risk of all nephrotic syndromes
  • Renal vein thrombosis (5-8%): flank pain, haematuria, sudden increase in proteinuria
  • DVT/PE
• Infection (loss of immunoglobulins)
• AKI (rare unless complications)

Red Flags

• Age >60 → mandatory malignancy screening (CT chest/abdomen/pelvis)
• Anti-PLA2R negative → higher likelihood of secondary cause
• Low complement → consider SLE or hepatitis
• Constitutional symptoms (weight loss, malaise) → malignancy screen

Bloods

• Anti-PLA2R antibodies: positive in 70-80% of primary MN; titre correlates with disease activity and predicts treatment response
• Anti-THSD7A: if PLA2R negative
• Serum albumin, lipids, U&Es, urine PCR: standard nephrotic syndrome workup
• C3/C4: normal in primary; low in lupus
• ANA, dsDNA: exclude SLE
• Hepatitis B/C serology: mandatory
• Age-appropriate cancer screening: CT CAP, PSA, mammography

Imaging

• Renal USS: normal kidney size
• CT chest/abdomen/pelvis: malignancy screening (age >60 or PLA2R negative)
• Renal Doppler: if renal vein thrombosis suspected

Special Tests

• Renal biopsy (diagnostic):
  • LM: diffuse GBM thickening, GMS stain shows spike pattern
  • IF: granular IgG4 and C3 along GBM
  • EM: subepithelial electron-dense deposits with GBM spike formation
  • PLA2R staining on biopsy: more sensitive than serum antibody

Non-pharmacological

• Risk stratification based on anti-PLA2R titre, proteinuria, and eGFR
• Low risk (proteinuria <3.5g/day, normal eGFR, low PLA2R): observation with supportive care for 6 months
• Dietary sodium restriction, fluid management

Pharmacological

Supportive (all patients):

• ACEi/ARB: maximised for proteinuria reduction
• Statins: for hyperlipidaemia
• Anticoagulation: prophylactic LMWH or warfarin if albumin <20g/L (some advocate <25g/L given high thrombotic risk)

Immunosuppression (high risk or progressive):

• Rituximab 1g IV on days 1 and 15: now considered first-line (MENTOR trial – non-inferior to ciclosporin with better sustained remission)
• Modified Ponticelli regimen: alternating months of IV methylprednisolone/oral prednisolone and oral cyclophosphamide for 6 months
• Calcineurin inhibitors: ciclosporin 3.5-5mg/kg/day or tacrolimus (high relapse rate on cessation)
• Mycophenolate mofetil: limited evidence, used in some centres

Referral Criteria

• All patients with membranous nephropathy → nephrology
• Age >60 or anti-PLA2R negative → malignancy screening
• Thrombotic complications → haematology/anticoagulation clinic

• Rule of thirds: spontaneous remission (30-40%), stable disease (30%), progressive to ESRD (30-40%)
• Anti-PLA2R negative at presentation or early decline: associated with better outcomes
• Spontaneous remission may take up to 3-5 years
• With immunosuppression: 60-80% achieve complete/partial remission
• 5-year renal survival: ~85-90% with modern treatment
• Transplant recurrence: 30-40% but significant graft loss in only ~10%
• Secondary MN: prognosis depends on treating underlying cause

Staging (Ehrenreich-Churg Classification)

MENTOR Trial (2019)

• Rituximab vs ciclosporin for primary membranous nephropathy
• Complete/partial remission at 24 months: rituximab 60% vs ciclosporin 20%
• Rituximab now preferred first-line over CNIs

Anti-PLA2R Antibodies