Membranous Nephropathy
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Direct answer
Membranous nephropathy is a subepithelial immune-complex glomerulopathy and a leading cause of nephrotic syndrome in non-diabetic adults. Most primary cases carry circulating IgG4 autoantibodies against the phospholipase A2 receptor, anti-PLA2R, which supports the diagnosis and guides monitoring. Secondary causes such as lupus, hepatitis B and C, malignancy and drugs must be excluded before the primary form is accepted.
What you must remember
- Histology: subepithelial immune deposits with a spike-and-dome pattern on silver stain, and granular IgG and C3 on immunofluorescence.
- Anti-PLA2R: present in most primary cases, with titre tracking disease activity; antibody-negative cases may have THSD7A or NELL-1 antibodies instead.
- Secondary causes: systemic lupus erythematosus (class V lupus nephritis), hepatitis B and C, syphilis, solid tumours and drugs such as NSAIDs, gold and penicillamine.
- Thrombosis risk: renal vein thrombosis and other venous thromboembolism rise as serum albumin falls very low, so anticoagulation is considered in that setting.
- Low-risk management: supportive care with ACE inhibitors or ARBs, diuretics and statins, with observation, since spontaneous remission occurs in a substantial minority.
- Immunosuppression: reserved for intermediate and high-risk patients, using steroid-alkylator regimens, calcineurin inhibitors or rituximab.
- Monitoring: proteinuria, serum albumin, eGFR and anti-PLA2R titre across the course of therapy.
A stepwise pathway from nephrotic proteinuria to a decision
Consider a 52-year-old man with nephrotic-range proteinuria of about 6 g per day, serum albumin of 2.4 g/dL and a preserved eGFR.
- Confirm and search for secondary causes: the nephrotic picture is confirmed, then antinuclear antibodies, complement levels, hepatitis B and C serology, HIV and syphilis testing, a drug history and an age-appropriate cancer screen are checked.
- Establish the primary form: anti-PLA2R is positive, and the biopsy shows a spike-and-dome pattern with IgG4 deposition, which together establish primary membranous nephropathy.
- Stratify risk: with a preserved eGFR, the decision depends on the level of proteinuria, the trajectory of renal function and the anti-PLA2R titre.
- Treat low risk conservatively: a low-risk patient can be managed with renin-angiotensin blockade, diuretics, statins and observation, with reassessment over months.
- Immunosuppress high risk: a high-risk patient with persistent heavy proteinuria or falling eGFR receives immunosuppression, such as a steroid-alkylator regimen or rituximab.
- Address thrombosis and lipids: because the albumin is very low, the clinician considers thromboprophylaxis, and the lipid profile is treated since hyperlipidaemia is common.
- Stop the cause: if a secondary cause such as a drug is identified, stopping it is the first treatment.
Where the examiner tries to catch you
The examiner's favourite is the link between membranous nephropathy and age-related malignancy.
- Trap: accepting membranous nephropathy in a patient over 60 as primary without screening. Correct: that age should prompt a cancer screen, while a positive anti-PLA2R antibody makes the primary form more likely.
- Trap: treating anti-PLA2R negativity as exclusion. Correct: other antibodies such as THSD7A or NELL-1 may be present.
- Trap: forgetting that calcineurin inhibitors are nephrotoxic. Correct: their use demands careful monitoring of creatinine and blood levels.
- Trap: labelling lupus class V as primary membranous nephropathy. Correct: lupus class V can look identical on light microscopy, so double-stranded DNA antibodies, low complement and extra-renal features must be sought first.
Frequently asked questions
Which antibody is associated with primary membranous nephropathy?
Anti-PLA2R antibodies, directed against the M-type phospholipase A2 receptor on podocytes, are associated with primary membranous nephropathy in most cases. Their titre supports the diagnosis and tracks disease activity, while antibody-negative patients may have other targets such as THSD7A or NELL-1.
What are the secondary causes of membranous nephropathy that must be excluded?
Secondary causes of membranous nephropathy that must be excluded include systemic lupus erythematosus, hepatitis B and C, syphilis, solid tumours and drugs such as NSAIDs, gold and penicillamine. Excluding these before accepting a primary diagnosis is essential, because treating the cause may resolve the nephropathy.
Why is thromboprophylaxis considered in membranous nephropathy?
Thromboprophylaxis is considered in membranous nephropathy because the loss of antithrombin and other proteins in urine, together with hypoalbuminaemia, raises the risk of renal vein thrombosis and other venous events. The risk is greatest when serum albumin falls very low, and anticoagulation is weighed against bleeding risk.
What is the spike and dome pattern in membranous nephropathy?
The spike and dome pattern is a silver-stain appearance in membranous nephropathy, in which new basement membrane material forms spikes between subepithelial immune deposits. It reflects the progressive subepithelial location of the immune complexes and is one of the classic histological hallmarks of the disease.
Which immunosuppressive drugs are used for high-risk membranous nephropathy?
High-risk membranous nephropathy is treated with steroid-alkylator regimens, calcineurin inhibitors or rituximab, chosen according to patient factors and local expertise. The choice weighs the efficacy of each agent against toxicity such as infection, gonadal effects and nephrotoxicity, and response is monitored with proteinuria and anti-PLA2R titre.