What is the stepwise treatment approach for lupus nephritis?

Stepwise Treatment of Lupus Nephritis

All patients with active Class III or IV lupus nephritis should be treated with glucocorticoids plus one of four equally effective options: mycophenolic acid analogs, low-dose IV cyclophosphamide, belimumab combined with either agent, or mycophenolic acid plus a calcineurin inhibitor (when eGFR >45 mL/min/1.73 m²). 1

Initial Treatment Phase (Induction Therapy)

Glucocorticoid Regimen

• Start with IV methylprednisolone pulses 0.25-0.5 g/day for 1-3 days based on disease severity and progression rate 1
• Follow with oral prednisone at 0.35-1.0 mg/kg/day (maximum 80 mg/day), with reduced-dose regimens (0.5-0.6 mg/kg/day, max 40 mg) showing comparable efficacy with less toxicity 1, 2
• Taper aggressively to ≤10 mg/day by 4-6 months and <5 mg/day by week 25 or beyond 1, 3

Recent pooled analysis demonstrates that low-dose oral glucocorticoids (≤0.5 mg/kg/day) following IV pulses achieve similar renal response rates as high-dose regimens (1.0 mg/kg/day) but with significantly fewer serious adverse events (19.4% vs 31.6%, p<0.001) and infection-related complications (9.8% vs 16.5%, p=0.012). 2 However, one propensity-matched study showed higher complete response rates with higher doses at 12 months (61.8% vs 38.2%), though cumulative damage was similar long-term. 4 The KDIGO 2024 guidelines prioritize reduced-dose regimens to minimize toxicity while maintaining efficacy. 1

Immunosuppressive Agent Selection (Choose ONE)

Option 1: Mycophenolic Acid Analogs (MPAA) - Preferred for most patients 3

• Mycophenolate mofetil (MMF) 1.0-1.5 g twice daily OR mycophenolic acid sodium 0.72-1.08 g twice daily 1
• Preferred for patients at high risk of infertility or those with moderate-to-high prior cyclophosphamide exposure 1
• Duration: 6 months for induction 1

Option 2: Low-Dose IV Cyclophosphamide 1

• 500 mg every 2 weeks for 6 doses (total 3 g over 3 months) 1
• Preferred for patients with adherence concerns to oral regimens 1, 3
• Alternative: Monthly higher doses (0.75-1 g/m²) for 6 months or oral 1.0-1.5 mg/kg/day for 3 months 1
• Minimize lifetime exposure to <36 g to reduce cancer risk 1

Option 3: Belimumab + MPAA or Cyclophosphamide 1

• Belimumab IV 10 mg/kg every 2 weeks for 3 doses, then every 4 weeks 1
• Combined with either MPAA (doses as above) or low-dose IV cyclophosphamide 500 mg every 2 weeks for 6 doses 1, 3
• Duration: Up to 2.5 years 1

Option 4: MPAA + Calcineurin Inhibitor (CNI) 1

• Only when eGFR >45 mL/min/1.73 m² due to nephrotoxicity risk 1
• Voclosporin 23.7 mg twice daily plus MPAA 1, 3
• Alternative: Tacrolimus or cyclosporine when voclosporin unavailable 1, 5
• Duration: Up to 3 years 1
• Particularly effective for nephrotic-range proteinuria 5

Special Considerations for Severe Disease

• Patients with adverse prognostic factors (acute renal function deterioration, substantial cellular crescents, fibrinoid necrosis) may benefit from more aggressive initial therapy 1

Maintenance Treatment Phase (After 6-12 Months)

Primary Maintenance Agent

Mycophenolic acid analogs are the recommended maintenance therapy 3, 5

• MMF 750-1000 mg twice daily OR mycophenolic acid 540-720 mg twice daily 3, 5
• Continue for at least 3-5 years 1, 5

Alternative Maintenance Agent

Azathioprine 1-2 mg/kg/day 3, 5

• Reserved for patients who cannot tolerate MPAA 3
• Associated with higher flare risk compared to MPAA 1

Maintenance Glucocorticoids

• Taper to lowest possible dose, ideally prednisone 2.5-5 mg/day 3, 5

Adjunctive Therapies (ALL Patients)

Renal Protection 1, 3

• ACE inhibitors or ARBs for proteinuria (UPCR >500 mg/g) or hypertension 5
• SGLT2 inhibitors for additional renoprotection in stable patients without AKI 1
• Avoid nephrotoxic agents 1

Infection Prophylaxis 1, 3

• Screen for HBV, HCV, HIV; vaccinate for hepatitis B 1
• Pneumocystis jirovecii prophylaxis during intensive immunosuppression 1
• Assess tuberculosis and herpes zoster history; consider recombinant zoster vaccine 1

Bone Protection 1, 3

• Bone mineral density assessment and fracture risk evaluation 1
• Calcium and vitamin D supplementation 1
• Bisphosphonates when appropriate 1

Fertility Preservation 1, 3

• Gonadotropin-releasing hormone agonists (leuprolide) for patients receiving cyclophosphamide 1
• Sperm/oocyte cryopreservation before treatment 1

Additional Measures 1, 5

• Hydroxychloroquine ≤5 mg/kg/day (adjusted for GFR) for all patients 5
• Statins for persistent dyslipidemia (target LDL <100 mg/dL) 5
• Broad-spectrum sunscreen and limit UV exposure 1
• Individualized contraception counseling 1

Treatment Response Monitoring

Target Outcomes 3

• Complete response (optimal goal): Proteinuria <0.5 g/g (UPCR <50 mg/mmol), normal or near-normal kidney function 3
• Partial response (acceptable): ≥50% reduction in proteinuria to <3 g/g, stable or improved kidney function 3

Timeline Expectations 1, 5

• At 3 months: ≥25% reduction in proteinuria 5
• At 6 months: ≥50% reduction in proteinuria, preferably achieving partial response 1
• At 12 months: Complete or partial response should be achieved 1

Regular Monitoring Parameters 5

• Body weight, blood pressure, serum creatinine, eGFR 5
• Serum albumin, proteinuria, urinary sediment 5
• Serum C3/C4, anti-dsDNA antibody levels, complete blood count 5

Management of Refractory Disease

For non-responders or refractory disease after 6-12 months: 5

• Switch from MPAA to cyclophosphamide or vice versa 1, 5
• Consider rituximab 1000 mg on days 0 and 14 5
• Consider calcineurin inhibitors (especially for Class V nephritis) 5

Class V (Membranous) Lupus Nephritis Modifications

• For nephrotic-range proteinuria: MPAA (MMF 3 g/day for 6 months) plus oral prednisone 0.5 mg/kg/day 1
• Alternative options: Cyclophosphamide, calcineurin inhibitors (tacrolimus, cyclosporine), or rituximab for non-responders 1, 5

Critical Pitfalls to Avoid

• Do not use CNI when eGFR ≤45 mL/min/1.73 m² due to severe nephrotoxicity risk 1
• Do not delay treatment while awaiting biopsy results in rapidly progressive disease 1
• Do not exceed 36 g lifetime cyclophosphamide exposure 1
• Do not abruptly discontinue maintenance therapy before 3 years due to high relapse risk 1, 5