How should I initially manage a patient with primary membranous nephropathy who has sub-nephrotic proteinuria (~1 g/day)?

Management of Primary Membranous Nephropathy with 1 g/day Proteinuria

Do not use immunosuppressive therapy in patients with primary membranous nephropathy and proteinuria of 1 g/day—manage exclusively with conservative supportive care. 1, 2

Initial Management Strategy

Your patient requires optimized conservative therapy only, which should include:

• RAS blockade (ACE inhibitor or ARB) titrated to maximum tolerated dose, targeting blood pressure <130/80 mmHg 2, 3
• Sodium restriction to <2 g/day to enhance antiproteinuric effects 2, 3
• Statin therapy for hyperlipidemia management 2
• Continue this regimen for at least 6 months before any consideration of escalation 1, 2

Why Immunosuppression is Contraindicated

The evidence is clear that at this level of proteinuria, the risks of immunosuppression clearly exceed any potential benefits 2. Specifically:

• Current guidelines explicitly state that immunosuppressive therapy is not required in patients with proteinuria <3.5 g/day, serum albumin >30 g/L, and eGFR >60 mL/min/1.73 m² 1
• Immunosuppressive agents (cyclophosphamide, calcineurin inhibitors, rituximab) carry substantial risks including infections, malignancy, nephrotoxicity, and infertility 1, 2
• The KDIGO guideline's recommendation to withhold immunosuppression in non-nephrotic patients is based on the understanding that one-third of membranous nephropathy patients experience spontaneous remission 1, 2

Expected Natural History

Your patient has an excellent prognosis with conservative management:

• Spontaneous remission occurs in 20-30% of patients with sub-nephrotic proteinuria, particularly in women 2
• Patients with sustained sub-nephrotic proteinuria have a progression rate of only -0.93 mL/min/year, compared to -3.52 mL/min/year in those who develop nephrotic syndrome 4
• The probability of progression to ESRD is low when proteinuria remains <4 g/day 2
• Waiting 6-12 months to observe disease trajectory does not compromise long-term outcomes provided kidney function remains stable 2

Monitoring Protocol

Follow your patient closely with:

• Spot urine protein-to-creatinine ratio and serum creatinine every 3-6 months 3
• Anti-PLA2R antibody levels if available, though a single measurement should not drive treatment decisions 1
• Watch for development of nephrotic syndrome—the majority who progress do so within the first year 4

When to Escalate to Immunosuppression

Consider immunosuppressive therapy only after ≥6 months of optimized conservative care AND when any of the following develops:

• Proteinuria persistently >4 g/day and remains >50% of baseline without progressive decline 1, 2
• Severe, disabling, or life-threatening nephrotic syndrome manifestations (marked edema, recurrent infections, thromboembolic events) 1, 2
• Serum creatinine rises ≥30% within 6-12 months AND eGFR remains ≥25-30 mL/min/1.73 m², with no alternative cause 1, 2

Critical Pitfalls to Avoid

• Do not start immunosuppression solely based on kidney biopsy diagnosis without meeting clinical criteria 2
• Do not assume treatment failure before 12 months—remission may be delayed up to 18-24 months with a mean time of approximately 15 months 2
• Corticosteroid monotherapy has no demonstrated effect on renal survival or remission rates in membranous nephropathy 2
• Do not interpret anti-PLA2R antibody levels at a single time point—longitudinal trends are what matter 1

Adjunctive Measures

• Exclude secondary causes of membranous nephropathy (malignancy, autoimmune disease, infections, drug exposure) in all biopsy-proven cases 2
• Assess thromboembolic risk, though prophylactic anticoagulation is typically reserved for nephrotic syndrome with serum albumin <2.5 g/dL 1