What is the initial treatment for lupus nephritis with hematuria?

Initial Treatment for Lupus Nephritis with Hematuria

For lupus nephritis presenting with hematuria, initiate treatment with glucocorticoids plus mycophenolic acid analogs (MPA) as the preferred first-line regimen, as hematuria typically indicates proliferative disease (Class III or IV) requiring aggressive immunosuppression. 1

Diagnostic Confirmation

• Obtain a renal biopsy before starting immunosuppressive therapy to confirm the diagnosis and classify disease severity using the ISN/RPS 2003 classification system, as hematuria with proteinuria strongly suggests proliferative lupus nephritis. 2
• Glomerular hematuria with cellular casts and proteinuria ≥0.5 g/24 hours are indications for urgent biopsy. 1

First-Line Treatment Options for Proliferative Disease

The KDIGO 2024 guidelines provide four equally recommended first-line regimens for Class III or IV lupus nephritis, all combined with glucocorticoids: 1

1. Mycophenolic acid analogs (MPAA) - preferred option (target dose: 2-3 g/day for 6 months) 3
2. Low-dose intravenous cyclophosphamide (total dose 3 g over 3 months) 3
3. Belimumab plus either MPAA or low-dose cyclophosphamide 1
4. MPAA plus calcineurin inhibitor (CNI) when eGFR >45 ml/min per 1.73 m² 1

Choosing Between Options

• MPA is preferred for patients at high risk of infertility or those with prior cyclophosphamide exposure. 1
• Intravenous cyclophosphamide is preferred for patients with difficulty adhering to oral regimens or those at high risk for kidney failure (reduced GFR, crescents, fibrinoid necrosis, severe interstitial inflammation). 1, 3
• Triple therapy with belimumab may be preferred for patients with repeated kidney flares or high risk for progression to kidney failure. 1

Glucocorticoid Regimen

Use a reduced-dose glucocorticoid scheme when both renal and extrarenal manifestations show satisfactory improvement: 1

• Methylprednisolone IV pulses: 0.25-0.5 g/day for up to 3 days as initial treatment 1
• Oral prednisone equivalent: Start at 0.5-0.6 mg/kg/day (max 40 mg) 1
• Taper schedule: Reduce to 15 mg by week 5-6, then to 5 mg by week 11-12, and <2.5 mg by week 25+ 1
• Target dose: ≤5 mg/day by 6 months 2

The reduced-dose scheme is preferred over high-dose or moderate-dose schemes to minimize glucocorticoid toxicity while maintaining efficacy. 1

Essential Adjunctive Therapies

All patients with lupus nephritis must receive: 2

• Hydroxychloroquine (dose not to exceed 5 mg/kg/day, adjusted for GFR) 3
• ACE inhibitors or ARBs for all patients with UPCR >500 mg/g or hypertension 3
• Statins based on lipid levels and cardiovascular risk 3

Treatment Goals and Monitoring Timeline

Expected response timeline: 2

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

Maintenance Therapy

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

• MPA is the recommended maintenance agent (1-2 g/day) 1
• Azathioprine (2 mg/kg/day) is an alternative for patients who cannot tolerate MPA or are planning pregnancy 1, 3
• Continue low-dose prednisone (2.5-5 mg/day) when needed to control disease activity 3

Management of Treatment Failure

If inadequate response by 6-12 months, consider: 2

• Switching from MPA to cyclophosphamide or vice versa
• Adding rituximab
• Assessing medication adherence
• Re-biopsy to evaluate for transformation to chronic disease

Critical Pitfalls to Avoid

• Do not delay renal biopsy - hematuria with proteinuria requires urgent histological confirmation 2
• Avoid excessive glucocorticoid exposure - use reduced-dose schemes when possible 1
• Do not use azathioprine for induction therapy - it is inferior to MPA or cyclophosphamide 1
• Adjust medications appropriately for pregnancy planning - switch to azathioprine if pregnancy is contemplated 3