What is the first‑line treatment for Class V (membranous) lupus nephritis in an adult patient with systemic lupus erythematosus who is otherwise medically stable?

First-Line Treatment for Class V (Membranous) Lupus Nephritis

Treatment Strategy Based on Proteinuria Severity

For Class V lupus nephritis with nephrotic-range proteinuria, the first-line treatment is glucocorticoids combined with mycophenolate mofetil (MMF), along with renin-angiotensin system blockade and hydroxychloroquine. 1

Low-Level Proteinuria (Non-Nephrotic Range)

If your patient has subnephrotic proteinuria (<3.5 g/day or protein-creatinine ratio <3 g/g), immunosuppressive therapy is not indicated unless driven by extrarenal lupus manifestations 1:

• Renin-angiotensin system blockade (ACE inhibitor or ARB) for blood pressure control and antiproteinuric effect 1
• Hydroxychloroquine (maximum 6-6.5 mg/kg ideal body weight daily) universally recommended 1
• Monitor closely for worsening proteinuria or complications (thrombosis, dyslipidemia, edema) 1

Nephrotic-Range Proteinuria (≥3.5 g/day)

This is where immunosuppression becomes essential, as Class V lupus nephritis with heavy proteinuria does not spontaneously remit (unlike primary membranous nephropathy) and carries significant risk of progression to kidney failure (10-30% of patients) 1:

Primary Regimen

Glucocorticoids + Mycophenolate Mofetil (MMF) 1:

• MMF is the reasonable first choice for nephrotic-range proteinuria in Class V lupus nephritis 1
• Pooled data from studies showed prednisone plus MMF had similar efficacy to cyclophosphamide in lowering proteinuria after 6 months 1
• Dosing: MMF 2-3 grams daily (or mycophenolic acid analogs) 1
• Glucocorticoid regimen: Moderate or reduced-dose preferred over high-dose protocols 1

Alternative First-Line Options

If MMF cannot be used, the 2024 KDIGO guidelines provide these alternatives with varying levels of evidence 1:

• Cyclophosphamide + glucocorticoids: Small RCT showed 60% remission rate (vs. 27% with prednisone alone), with better maintenance of remission compared to calcineurin inhibitors 1
• Calcineurin inhibitors (CNIs) + glucocorticoids: Small RCT showed 84% remission with cyclosporine, though 40% relapsed within a year of discontinuation 1
• Triple therapy (glucocorticoids + tacrolimus + low-dose MMF): Resulted in higher complete remission rate (33.1% vs. 7.8% with cyclophosphamide/azathioprine) 1

Essential Supportive Care (All Patients)

Regardless of proteinuria level, all Class V patients require 1:

• Hydroxychloroquine (maximum 6-6.5 mg/kg ideal body weight daily) 1
• Renin-angiotensin system blockade for blood pressure control and proteinuria reduction 1
• Meticulous blood pressure control 1
• Monitor and treat complications: thrombosis prophylaxis if indicated, dyslipidemia management, edema control 1

Response Assessment Timeline

Expect gradual improvement over months, not weeks 1:

• 3 months: Stabilization of creatinine or initial reduction in proteinuria expected 1
• 6-12 months: Primary response assessment window 1
• Complete response: Proteinuria <0.5 g/g (50 mg/mmol) with stable/improved kidney function 1
• Partial response: ≥50% reduction in proteinuria to <3 g/g (300 mg/mmol) with stable/improved kidney function 1

Critical Caveats

Fertility considerations: If fertility preservation is a concern, avoid cyclophosphamide and favor MMF or CNIs, though MMF is teratogenic and requires discontinuation before conception 1, 2

If initial therapy fails: Consider switching to cyclophosphamide for 6 months if MMF is ineffective 1

Relapse risk with CNIs: While CNIs show high initial response rates (84%), they have a 40% relapse rate within one year of discontinuation, whereas cyclophosphamide maintains remission longer 1

Pregnancy planning: Leflunomide (an alternative maintenance agent) must be discontinued for at least 2 years before conception 1