Treatment of Class IV Lupus Nephritis
All patients with active Class IV lupus nephritis should receive glucocorticoids combined with one of four equally recommended first-line options: mycophenolic acid analogs (MPAA), low-dose intravenous cyclophosphamide, belimumab plus MPAA or cyclophosphamide, or MPAA plus a calcineurin inhibitor when eGFR >45 mL/min/1.73 m² 1.
Initial Immunosuppressive Therapy
The 2024 KDIGO guidelines provide four equivalent first-line treatment options 1:
- Mycophenolic acid analogs (MPAA): Mycophenolate mofetil 2-3 g/day orally (or mycophenolic acid 1.44-2.16 g/day) 1, 2
- Low-dose intravenous cyclophosphamide: 500 mg every 2 weeks for 6 doses (total 3 g over 3 months) 1, 2
- Belimumab combination therapy: Belimumab 10 mg/kg IV every 2 weeks for 3 doses, then every 4 weeks, combined with either MPAA or low-dose cyclophosphamide 1
- MPAA plus calcineurin inhibitor: Voclosporin 23.7 mg twice daily plus MPAA (when eGFR >45 mL/min/1.73 m²), or tacrolimus/cyclosporine when voclosporin unavailable 1, 3
Choosing Between First-Line Options
For patients at high risk of infertility (prior cyclophosphamide exposure, desire for future fertility): Prioritize MPAA-based regimens over cyclophosphamide 1.
For patients with adherence concerns: Intravenous cyclophosphamide may be preferred over oral medications 1.
For patients with nephrotic-range proteinuria and preserved kidney function: The combination of MPAA plus calcineurin inhibitor demonstrates superior efficacy 1, 4.
For patients with severe disease (reduced GFR, crescents, fibrinoid necrosis, severe interstitial inflammation): Consider high-dose intravenous cyclophosphamide 0.5-0.75 g/m² monthly for 6 months instead of low-dose regimen 1.
Glucocorticoid Regimen
Use reduced-dose glucocorticoids following methylprednisolone pulses to minimize toxicity while maintaining efficacy 1, 5:
Induction Protocol
- Methylprednisolone IV pulses: 250-500 mg/day for 1-3 days initially (dose based on disease severity and body weight) 1, 2
- Oral prednisone: Start at 0.5-0.6 mg/kg/day (maximum 40 mg/day) for weeks 0-2 1, 2
Tapering Schedule (Reduced-Dose Regimen)
- Weeks 3-4: 0.3-0.4 mg/kg/day 1
- Weeks 5-6: 15 mg/day 1
- Weeks 7-8: 10 mg/day 1
- Weeks 9-10: 7.5 mg/day 1
- Weeks 11-12: 5 mg/day 1
- Target by 3-6 months: ≤7.5 mg/day 1
- Long-term maintenance: <5 mg/day 1, 2
The reduced-dose glucocorticoid regimen achieves equivalent efficacy with significantly fewer serious adverse events compared to traditional high-dose regimens 5. Repeated methylprednisolone pulses enhance clinical response while allowing lower oral glucocorticoid doses 6.
Essential Adjunctive Therapies
All patients must receive 1:
- Hydroxychloroquine: ≤5 mg/kg/day (adjusted for eGFR), continued long-term to reduce flares and improve outcomes 1, 2
- ACE inhibitors or ARBs: For all patients with proteinuria >500 mg/g or hypertension 1
- SGLT2 inhibitors: Consider for renoprotection in stable patients without AKI 1
Monitoring Protocol
Initial intensive monitoring every 2-4 weeks for the first 2-4 months 1, 2:
- Serum creatinine and eGFR
- Urine protein-to-creatinine ratio
- Urinalysis with microscopy
- Serum albumin
- Complement levels (C3, C4)
- Anti-dsDNA antibodies
- Complete blood count
- Blood pressure and body weight
Adjust monitoring frequency based on treatment response thereafter 1.
Treatment Goals and Response Assessment
Target complete clinical response by 12 months 1:
- Urine protein-to-creatinine ratio <0.5-0.7 mg/mg
- eGFR ≥60 mL/min/1.73 m² or no confirmed decrease >20% from baseline
- Stable or improving kidney function
Interim milestones 1:
- By 3 months: ≥25% reduction in proteinuria with evidence of improvement
- By 6 months: ≥50% reduction in proteinuria (partial response)
For patients with nephrotic-range proteinuria at baseline, extend these timeframes by 6-12 months before considering treatment failure 1.
Management of Inadequate Response
If treatment goals are not met, systematically evaluate 1:
- Assess medication adherence
- Perform therapeutic drug monitoring (especially for MPAA)
- Rule out intercurrent infections or other complications
- Consider repeat kidney biopsy to assess disease activity versus chronicity 2
For refractory disease, switch to an alternative first-line regimen or consider rituximab 1000 mg on days 0 and 14 1.
Preventive Measures to Minimize Treatment Complications
Infection prophylaxis 1:
- Screen for hepatitis B, hepatitis C, HIV, and tuberculosis before treatment
- Pneumocystis jirovecii prophylaxis during intensive immunosuppression
- Consider recombinant zoster vaccine
- Hepatitis B vaccination if seronegative
Fertility preservation (before cyclophosphamide exposure) 1:
- GnRH agonists (leuprolide) during cyclophosphamide therapy
- Sperm/oocyte cryopreservation
- Minimize lifetime cyclophosphamide exposure to <36 g 1
Bone protection 1:
- Calcium and vitamin D supplementation
- Bone mineral density assessment
- Bisphosphonates when appropriate
Cardiovascular risk reduction 1:
- Statin therapy based on lipid levels and cardiovascular risk assessment
- Blood pressure optimization
- Low-dose aspirin during pregnancy
Maintenance Therapy
After achieving treatment goals, transition to maintenance immunosuppression 1:
- MPAA 1-2 g/day (preferred if used successfully for induction) 1
- Azathioprine 2 mg/kg/day (preferred if pregnancy contemplated) 1
- Low-dose prednisone 2.5-5 mg/day as needed for disease control 1
- Continue hydroxychloroquine long-term 1
Duration of maintenance therapy: Continue for at least 3-5 years in complete clinical response before considering gradual withdrawal (glucocorticoids first, then immunosuppressives), but maintain hydroxychloroquine indefinitely 1.
Critical Pitfalls to Avoid
Do not use calcineurin inhibitors when eGFR ≤45 mL/min/1.73 m² due to increased nephrotoxicity risk 1.
Do not exceed 80 mg/day of prednisone regardless of body weight 1.
Do not switch therapy prematurely in patients showing gradual improvement, especially those with baseline nephrotic-range proteinuria 1.
Do not discontinue hydroxychloroquine even after achieving remission 1.