Membranous Nephropathy

Membranous nephropathy (MN) is an immune complex glomerulopathy with subepithelial deposits and thickened glomerular basement membrane, and is a leading cause of nephrotic syndrome in non-diabetic adults.

• Primary MN (about 80%): autoantibodies to PLA2R (70 to 80%), THSD7A (2 to 5%), NELL1 and others.
• Secondary MN: hepatitis B and C, syphilis, malaria, SLE, NSAIDs, gold, penicillamine, malignancy (lung, colon, prostate, breast; present in 10% of older patients), sarcoidosis, graft-versus-host disease.
• Peak age 40 to 60, male predominance.
• Natural history: one third remit spontaneously, one third persistent proteinuria, one third progress to ESKD over 10 years.
• Complications: venous thromboembolism (renal vein thrombosis, risk highest with albumin under 25 g/L), infection, hyperlipidaemia, AKI.

• Insidious nephrotic syndrome with oedema, foamy urine, weight gain.
• Often normal or mildly raised blood pressure and preserved GFR.
• Microscopic haematuria in 30 to 50%.
• Pulmonary embolism or flank pain suggest thrombosis.
• Features of secondary causes: rash, arthralgia, weight loss, hepatitis symptoms.

• Proteinuria usually over 3.5 g/day, low albumin, high cholesterol, bland sediment, normal complement.
• Anti-PLA2R antibody (ELISA) positive in primary MN; with typical presentation a positive titre allows diagnosis without biopsy.
• Renal biopsy if antibody negative: granular IgG and C3 along capillary walls, spikes on silver stain, subepithelial deposits on electron microscopy. Dominant IgG1 or IgG3 and mesangial deposits suggest secondary (lupus) disease.
• Screen for secondary causes: hepatitis B/C, HIV, syphilis, ANA, dsDNA, complement, age-appropriate cancer screening, drug review.
• Risk stratification: low (proteinuria under 3.5 g/day, normal GFR), moderate, high (proteinuria over 8 g/day for 6 months, or antibody over 150 RU/mL, falling GFR).

• Supportive for all: ACE inhibitor or ARB maximally tolerated, blood pressure below 125/75 mmHg, sodium restriction, diuretics, statin, SGLT2 inhibitor. Observe low-risk patients for 6 months.
• Anticoagulation: prophylactic warfarin (INR 2 to 3) or apixaban 2.5 to 5 mg twice daily if albumin under 20 to 25 g/L with bleeding risk acceptable.
• Immunosuppression for moderate to high risk disease:
  • Rituximab 1 g on days 1 and 15 (or 375 mg/m2 weekly for 4), first line; remission in 60 to 80%.
  • Modified Ponticelli regimen: alternating monthly methylprednisolone 1 g IV for 3 days then prednisolone 0.5 mg/kg for 27 days, with cyclophosphamide 2 mg/kg orally in months 2, 4 and 6.
  • Tacrolimus 0.05 mg/kg/day (trough 5 to 8 ng/mL) for 6 to 12 months, or ciclosporin 3.5 to 5 mg/kg, with relapse after withdrawal in up to 50%.
• Refractory: obinutuzumab, higher dose rituximab, or combinations.
• Rapid GFR decline: cyclophosphamide with steroids.
• Secondary MN: treat the cause (antivirals for hepatitis B, stop NSAIDs, cancer treatment, lupus therapy).
• Monitor anti-PLA2R antibody (falls before proteinuria resolves), protein excretion, creatinine at 3 monthly intervals.
• Transplant recurrence occurs in 30%.