What is the initial treatment for lupus nephritis?

Initial Treatment for Lupus Nephritis

For proliferative lupus nephritis (Class III or IV), initiate treatment with mycophenolic acid (MPA) or low-dose intravenous cyclophosphamide combined with glucocorticoids, as these regimens offer the best efficacy-to-toxicity ratio and preserve long-term renal function. 1

Diagnostic Prerequisites

Obtain a renal biopsy before initiating immunosuppressive therapy to confirm the diagnosis and classify disease severity using the ISN/RPS 2003 classification system, as clinical and serological findings cannot reliably predict histological patterns. 1

First-Line Treatment Regimens by Class

Class III or IV Lupus Nephritis (Proliferative)

The KDIGO 2024 guidelines provide four equally recommended first-line options, all combined with glucocorticoids: 1

1. Mycophenolic acid analogs (MPAA) - Target dose of mycophenolate mofetil 2-3 g/day for 6 months 2
2. Low-dose intravenous cyclophosphamide - Total cumulative dose of 3 g over 3 months 2
3. Belimumab plus either MPAA or low-dose cyclophosphamide - Consider for patients with repeated flares or high risk of progression 1
4. MPAA plus calcineurin inhibitor (CNI) - When eGFR >45 mL/min/1.73 m², particularly effective for nephrotic-range proteinuria 1, 2

Choose MPA-based regimens preferentially for patients at high risk of infertility or with prior cyclophosphamide exposure. 1, 2

Reserve high-dose cyclophosphamide (0.5-0.75 g/m² monthly for 6 months) for patients at high risk for kidney failure, defined by reduced GFR, histological crescents or fibrinoid necrosis, and severe interstitial inflammation. 2

Class V Lupus Nephritis (Membranous)

For pure Class V with nephrotic-range proteinuria (>1 g/24h despite RAAS blockade), use MPA combined with oral glucocorticoids as initial treatment. 1

Glucocorticoid Dosing Strategy

The KDIGO 2024 guidelines outline three acceptable glucocorticoid regimens, with reduced-dose schemes preferred when both renal and extrarenal manifestations show satisfactory improvement: 1

Reduced-dose scheme (preferred when feasible):

• Methylprednisolone IV pulses: 0.25-0.5 g/day for up to 3 days initially 1
• Oral prednisone: Start 0.5-0.6 mg/kg/day (max 40 mg), taper to 2.5 mg/day by week 13-14 1
• Target ≤5 mg/day by 6 months 2

Alternative ACR recommendation:

• Three consecutive methylprednisolone IV pulses (500-750 mg each) 2
• Followed by oral prednisone 0.3-0.5 mg/kg/day for up to 4 weeks 2
• Taper to ≤7.5 mg/day by 3-6 months 2

Essential Adjunctive Therapies

All patients with lupus nephritis should receive: 2

• Hydroxychloroquine - Dose not exceeding 5 mg/kg/day, adjusted for GFR 2
• ACE inhibitors or ARBs - For all patients with UPCR >500 mg/g or hypertension 2
• Statins - Based on lipid levels and 10-year cardiovascular risk 2

Treatment Goals and Monitoring Timeline

Target complete renal response defined as: 1, 2

• UPCR <50 mg/mol (<500-700 mg/g) 1, 2
• Normal or near-normal renal function (within 10% of normal GFR if previously abnormal) 1

Expected response timeline: 2

• 25% reduction in proteinuria by 3 months
• 50% reduction by 6 months
• Complete clinical response by 12 months

Partial response (≥50% reduction in proteinuria) is acceptable if complete response not achieved, as both complete and partial responses significantly improve long-term patient and kidney survival compared to non-responders. 3

Maintenance Therapy

After completing initial therapy (typically 6 months), transition to maintenance immunosuppression for at least 3 years: 1, 4

• MPAA (preferred) - Continue at lower doses (1-2 g/day) if used for induction 1, 2
• Azathioprine (alternative) - 2 mg/kg/day, particularly for patients planning pregnancy or intolerant of MPAA 1, 2
• Low-dose prednisone - Maintain at 2.5-5 mg/day as needed for disease control 2, 4

Azathioprine as maintenance therapy increases disease relapse risk compared to MMF (RR 1.75), so MMF maintenance is preferred when MMF was used for induction. 5

Management of Treatment Failure

For inadequate response or treatment failure, consider: 1, 2

• Switching from MPA to cyclophosphamide or vice versa 1
• Adding rituximab 1
• Assessing medication adherence and therapeutic drug monitoring 2
• Re-biopsy to evaluate for transformation to chronic disease 1

Critical Caveats

Common pitfalls to avoid:

• Do not delay renal biopsy - Clinical parameters alone cannot guide appropriate therapy selection 1
• Avoid excessive glucocorticoid exposure - Use reduced-dose regimens when clinically appropriate to minimize long-term toxicity including infection, osteoporosis, and metabolic complications 1, 6
• Do not use azathioprine for induction therapy - It is inferior to standard regimens and associated with increased flare rates 1, 2
• Pregnancy planning requires medication adjustment - Switch to pregnancy-compatible agents (azathioprine, hydroxychloroquine) without reducing treatment intensity 1

MMF demonstrates superior safety compared to IV cyclophosphamide with significantly less alopecia (RR 0.29) and ovarian failure (RR 0.36), though with increased diarrhea (RR 2.42), making it preferable for young women of childbearing age. 5