What is the initial treatment approach for a patient with Systemic Lupus Erythematosus (SLE) nephritis?

Initial Treatment of SLE Nephritis

For patients with active Class III or IV lupus nephritis, initiate treatment with mycophenolic acid analogs (MPAA) or low-dose intravenous cyclophosphamide combined with glucocorticoids, with consideration of adding belimumab to enhance response rates and facilitate steroid tapering. 1

Diagnostic Foundation

• Obtain a renal biopsy before initiating immunosuppressive therapy to guide treatment decisions, as clinical and serological findings cannot reliably predict histological class 1
• Biopsy should be performed when proteinuria ≥0.5 g/24 hours is present, particularly with glomerular hematuria and/or cellular casts 1
• Use the ISN/RPS 2003 classification system to assess active and chronic glomerular and tubulointerstitial changes 1

Initial Treatment Regimens by Class

Class III/IV Proliferative Lupus Nephritis (with or without Class V)

The 2024 KDIGO guidelines provide four equally recommended first-line options 1:

1. MPAA + glucocorticoids (mycophenolate mofetil target dose 3 g/day for 6 months)
2. Low-dose IV cyclophosphamide + glucocorticoids (total dose 3 g over 3 months)
3. Belimumab + either MPAA or low-dose IV cyclophosphamide + glucocorticoids
4. MPAA + calcineurin inhibitor (CNI) + glucocorticoids when eGFR >45 ml/min/1.73 m² and nephrotic-range proteinuria is present

MPAA-based regimens are preferred for patients at high risk of infertility or those with prior cyclophosphamide exposure 1. The addition of belimumab to conventional therapy shows promise for improving response rates and enabling faster steroid tapering 2.

Glucocorticoid Dosing Strategy

The most recent KDIGO guidelines (2024) recommend reduced-dose glucocorticoid regimens when both renal and extrarenal manifestations show satisfactory improvement 1:

• Initial phase: Methylprednisolone IV pulses (0.25-0.5 g/day for up to 3 days), followed by oral prednisone
• Reduced-dose scheme: Start at 0.5-0.6 mg/kg/day (max 40 mg), taper to 15 mg by week 5-6, then to 5 mg by week 11-12, and <2.5 mg by week 25 1
• This represents a significant departure from older high-dose protocols (0.8-1.0 mg/kg/day) to minimize glucocorticoid-related toxicity 1

Patients with Adverse Prognostic Features

For patients with acute deterioration in renal function, substantial cellular crescents, or fibrinoid necrosis, higher-dose cyclophosphamide (0.75-1 g/m² monthly for 6 months) may be prescribed 1

Pure Class V Membranous Lupus Nephritis

When nephrotic-range proteinuria is present:

• First-line: MPAA (MMF 3 g/day) + oral prednisone (0.5 mg/kg/day) 1
• Alternatives: Cyclophosphamide, calcineurin inhibitors (voclosporin, tacrolimus, cyclosporine), or rituximab for non-responders 1

Milder Disease Without Adverse Features

Azathioprine (2 mg/kg/day) may be considered as an alternative when MPAA or cyclophosphamide are contraindicated, not tolerated, or unavailable, though it carries higher flare risk 1

Universal Adjunctive Therapy

All patients with lupus nephritis should receive hydroxychloroquine regardless of class 1, as it improves long-term outcomes and reduces flare rates 1

Treatment Goals and Monitoring

• Target complete renal response: Proteinuria <0.5 g/24 hours (UPCR <50 mg/mmol) with normal or near-normal renal function 1
• Acceptable partial response: ≥50% reduction in proteinuria to subnephrotic levels with preserved renal function, achieved by 6 months (preferably) but no later than 12 months 1
• The ultimate goals are long-term preservation of renal function, prevention of flares, avoidance of treatment-related harms, and improved quality of life 1

Critical Pitfalls to Avoid

• Do not delay treatment while awaiting biopsy results if clinical presentation strongly suggests active nephritis, as early intervention improves outcomes 3
• Avoid prolonged high-dose glucocorticoids beyond the initial period, as they contribute significantly to morbidity without additional benefit 1
• Do not use cyclophosphamide as first-line in young patients desiring fertility when MPAA is equally effective 1
• Minimize lifetime cyclophosphamide exposure to <36 g to reduce malignancy risk 1

Subsequent Maintenance Therapy

After achieving response with initial treatment, transition to maintenance immunosuppression with MPAA (MMF 2 g/day) or azathioprine (2 mg/kg/day) for at least 3 years combined with low-dose prednisone (5-7.5 mg/day) 1. If initial treatment was MPAA, continue MPAA for maintenance rather than switching to azathioprine 1.