What is the recommended treatment regimen for a patient with lupus nephritis?

Lupus Nephritis Treatment Regimen

First-Line Treatment Selection

For proliferative lupus nephritis (Class III or IV), initiate mycophenolic acid analogs (1.0–1.5 g twice daily) combined with a reduced-dose glucocorticoid regimen as the preferred first-line treatment. 1

The KDIGO guidelines provide four equally effective first-line options for proliferative disease, all combined with glucocorticoids 1:

• Mycophenolic acid analogs (mycophenolate mofetil 1.0–1.5 g twice daily or mycophenolic acid sodium 0.72–1.08 g twice daily) for 6 months 1
• Low-dose intravenous cyclophosphamide (500 mg IV every 2 weeks for 6 doses) 1
• Belimumab (10 mg/kg IV every 2 weeks for 3 doses, then every 4 weeks) combined with mycophenolic acid analogs or low-dose cyclophosphamide—prioritize for patients with repeated kidney flares or high risk for progression to kidney failure 1
• Voclosporin (23.7 mg twice daily) plus mycophenolic acid analogs—prioritize for patients with relatively preserved kidney function (eGFR >45 ml/min per 1.73 m²) and nephrotic-range proteinuria 1, 2

When to Choose Cyclophosphamide Over Mycophenolic Acid

Use intravenous cyclophosphamide for patients with difficulty adhering to oral regimens or those at high risk for kidney failure (reduced GFR, crescents, fibrinoid necrosis, severe interstitial inflammation) 2. Conversely, choose mycophenolic acid for patients at high risk of infertility or those with prior cyclophosphamide exposure 2.

Multitarget Therapy Option

For patients with nephrotic-range proteinuria, consider multitarget therapy combining mycophenolic acid (1-2 g/day) with a calcineurin inhibitor (particularly tacrolimus) plus glucocorticoids 3.

Glucocorticoid Regimen

Use a reduced-dose glucocorticoid protocol to minimize toxicity while maintaining efficacy 1:

• Initial pulse therapy: Methylprednisolone IV 500–750 mg for 3 consecutive days (or 0.25-0.5 g/day for up to 3 days) 1, 2
• Oral prednisone: Start at 0.5 mg/kg/day (maximum 40 mg) for 4 weeks 3, 2
• Tapering schedule: Reduce to ≤10 mg/day by 4–6 months and ≤2.5–5 mg/day by week 21–24 1, 3

Essential Adjunctive Therapies

All patients with lupus nephritis require the following adjunctive treatments 1, 3:

• Hydroxychloroquine: Dose not exceeding 5 mg/kg/day (adjusted for GFR) to reduce renal flares and limit accrual of renal and cardiovascular damage 1, 3, 2
• ACE inhibitors or ARBs: For all patients with proteinuria (UPCR >500 mg/g) or hypertension 1, 3, 2
• Statins: For persistent dyslipidemia with target LDL <100 mg/dl 1, 3

Maintenance Therapy

After completing 6 months of initial therapy, transition to maintenance therapy with mycophenolic acid analogs for at least 36 months total 1:

• Mycophenolate mofetil: Approximately 750–1000 mg twice daily (target dose 1-2 g/day) 1, 3
• Azathioprine: 2 mg/kg/day is an alternative but is associated with higher disease relapse rates 1, 3
• Low-dose prednisone: Continue at 2.5–5 mg/day 3

Treatment Goals and Monitoring

Response Timeline

Monitor for the following treatment milestones 2:

• 3 months: ≥25% reduction in proteinuria 3, 2
• 6 months: ≥50% reduction in proteinuria to subnephrotic levels 1, 3, 2
• 12 months: Complete clinical response (UPCR <50 mg/mmol with normal or near-normal renal function) 1, 2

Monitoring Schedule

Initial intensive monitoring every 2–4 weeks should include 1:

• Serum creatinine, eGFR, serum albumin 1, 3
• Urinalysis, urine protein-to-creatinine ratio 1, 3
• C3/C4, anti-dsDNA antibodies 1, 3
• Complete blood count 1, 3
• Body weight and blood pressure 3

Management of Treatment Failure

If inadequate response by 6–12 months, switch immunosuppressive agents 1, 2:

• Switch from mycophenolic acid analogs to cyclophosphamide, or vice versa 1, 3, 2
• Consider rituximab (1000 mg on days 0 and 14) for persistent disease activity or inadequate response 1, 3
• Assess medication adherence before escalating therapy 2
• Consider repeat kidney biopsy to guide further treatment decisions and evaluate for transformation to chronic disease 1, 2

Critical Pitfalls to Avoid

• Delaying kidney biopsy leads to undertreatment and irreversible kidney damage 1
• Excessive cumulative cyclophosphamide exposure (>36 g lifetime) increases infertility and malignancy risk 1
• Premature discontinuation of maintenance therapy before 36 months increases relapse risk 1
• Inadequate glucocorticoid tapering prolongs toxicity exposure unnecessarily 1

Special Considerations for Class V (Membranous) Lupus Nephritis

For pure Class V lupus nephritis, mycophenolic acid (target dose 2-3 g/day) with glucocorticoids is recommended as initial treatment due to the best efficacy/toxicity ratio 3. Calcineurin inhibitors are particularly effective for Class V nephritis if initial therapy fails 3.