What is the recommended treatment for Class V (membranous) lupus nephritis?

Treatment of Class V (Membranous) Lupus Nephritis

Immediate Treatment Decision Based on Proteinuria Level

For Class V lupus nephritis with nephrotic-range proteinuria (≥3.5 g/day), start combination immunosuppression immediately with glucocorticoids plus mycophenolate mofetil (MMF), along with RAS blockade and hydroxychloroquine. 1

For subnephrotic proteinuria (<3.5 g/day), withhold immunosuppressive agents unless extrarenal lupus manifestations are present; manage with RAS blockade, hydroxychloroquine, and close monitoring for thrombotic complications, dyslipidemia, and edema. 2, 1

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First-Line Immunosuppressive Regimen for Nephrotic-Range Proteinuria

Preferred Initial Therapy

• MMF is the first-choice immunosuppressive agent for Class V disease with nephrotic-range proteinuria. 1
• Dose MMF at 2–3 g daily (or equivalent mycophenolic acid formulations). 1
• Combine with a moderate- or reduced-dose glucocorticoid regimen, not high-dose protocols. 2, 1
• Start prednisone at 0.5 mg/kg/day combined with MMF 2–3 g/day. 3
• Taper prednisone rapidly: aim for ≤5 mg/day by 12 weeks and <2.5 mg/day by 6 months. 3
• Consider 3 days of intravenous methylprednisolone 0.25–0.5 g/day before starting oral prednisone to enable lower oral dosing. 3

Evidence Supporting MMF

• Pooled data from two studies showed prednisone plus MMF achieved proteinuria reduction comparable to cyclophosphamide after 6 months. 2, 1
• Unlike primary membranous nephropathy, heavy proteinuria in Class V lupus nephritis does not spontaneously remit, making immunosuppression necessary. 2

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Alternative First-Line Options When MMF Cannot Be Used

Cyclophosphamide-Based Regimen

• A small RCT demonstrated 60% remission with prednisone plus cyclophosphamide versus 27% with prednisone alone. 2, 1
• Cyclophosphamide maintains remission longer than calcineurin inhibitors, with no relapses within one year compared to 40% relapse rate after CNI discontinuation. 2, 1
• Reserve cyclophosphamide for patients who fail MMF or when fertility preservation is not a concern. 2

Calcineurin Inhibitor-Based Regimen

• Prednisone plus cyclosporine achieved 84% remission in a small RCT, but 40% relapsed within one year after drug withdrawal. 2, 1
• Tacrolimus combined with glucocorticoids is effective for Class V lupus nephritis presenting with nephrotic syndrome. 2, 4
• Tacrolimus 0.1–0.2 mg/kg/day for 6 months resulted in 27.8% complete remission and 50% partial remission at 12 weeks, with faster proteinuria resolution than conventional cytotoxic treatment. 4
• Tacrolimus reduced proteinuria by 76.2% at 12 weeks versus 47.1% with cyclophosphamide or azathioprine controls. 4
• CNIs carry a high relapse risk after discontinuation, limiting their durability compared to cyclophosphamide. 2, 1

Triple Immunosuppression

• Glucocorticoids plus tacrolimus plus low-dose MMF achieved 33.1% complete remission versus 7.8% with glucocorticoids and high-dose cyclophosphamide followed by azathioprine. 2, 1
• This triple therapy is particularly effective for patients with nephrotic-range proteinuria. 2

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Universal Supportive Care for All Class V Patients

• Prescribe hydroxychloroquine at a maximum of 5–6.5 mg/kg ideal body weight daily for all patients. 1, 5
• Initiate RAS blockade (ACE inhibitor or ARB) for blood pressure control and antiproteinuric effect. 2, 1
• Target meticulous blood pressure control to reduce proteinuria and cardiovascular risk. 2, 1
• Monitor routinely for thrombosis, dyslipidemia, and edema, as nephrotic syndrome increases infection and thrombotic risk. 2, 1

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Response Assessment Timeline and Definitions

Expected Timeline

• Therapeutic response evolves over months, not weeks; do not expect rapid improvement. 1
• At approximately 3 months, expect stabilization of renal function and initial decline in proteinuria. 1
• Conduct primary response assessment between 6 and 12 months after starting therapy. 2, 1
• Complete response may take more than 12 months to achieve. 2

Response Definitions

• Complete response: proteinuria <0.5 g/g (50 mg/mmol) with stable or improved kidney function (±10–15% of baseline), without rescue therapy. 2, 1
• Partial response: ≥50% reduction in proteinuria to <3 g/g (300 mg/mmol) with stable or improved kidney function (±10–15% of baseline) within 6–12 months. 2, 1
• No response: failure to meet partial response criteria. 2

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Management of Treatment Failure or Inadequate Response

• If MMF fails to induce response by 6 months, switch to cyclophosphamide for a 6-month course. 1
• If proteinuria worsens or complications develop (thrombosis, dyslipidemia, edema), escalate immunosuppressive therapy. 2
• Do not increase prednisone dose; instead, switch the immunosuppressive agent. 3

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Special Considerations for Fertility and Pregnancy

• Avoid cyclophosphamide in patients desiring future fertility; prefer MMF or calcineurin inhibitors. 1, 5
• MMF is teratogenic and must be stopped before conception; switch to azathioprine 2 mg/kg/day for maintenance if pregnancy is contemplated. 5
• Leflunomide is contraindicated in pregnancy and must be discontinued at least 2 years before attempting conception. 2, 1
• Tacrolimus can be used during pregnancy when treatment options are limited. 6

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Maintenance Therapy After Achieving Response

• Continue MMF at lower doses (1–2 g/day) for maintenance. 5
• Alternatively, switch to azathioprine 2 mg/kg/day if pregnancy is planned. 5
• Maintain low-dose prednisone (2.5–5 mg/day) only when needed to control disease activity. 5
• If MMF and azathioprine cannot be used, consider CNIs, mizoribine, or leflunomide for maintenance. 2

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Common Pitfalls and How to Avoid Them

• Do not use high-dose glucocorticoid protocols (1 mg/kg/day); the reduced-dose scheme (0.5 mg/kg/day maximum 40 mg/day) balances efficacy and toxicity. 1, 3
• Do not continue high-dose prednisone beyond 2–4 weeks without aggressive tapering to minimize cumulative toxicity. 3
• Do not omit intravenous methylprednisolone pulses when using reduced oral doses, as the combination enables lower oral dosing while maintaining efficacy. 3
• Do not expect spontaneous remission of heavy proteinuria in Class V lupus nephritis, unlike primary membranous nephropathy. 2
• Do not rely solely on calcineurin inhibitors for long-term remission, as 40% of patients relapse within one year after discontinuation. 2, 1
• Do not delay immunosuppression in nephrotic-range proteinuria, as 10–30% of Class V patients progress to kidney failure, with risk proportional to proteinuria severity. 2