Lupus Nephritis Treatment by Class
Class I and II (Minimal Mesangial and Mesangial Proliferative)
No immunosuppressive therapy is required for Class I and II lupus nephritis. 1
- Supportive care only: These classes generally do not require immunosuppressive treatment 2
- Adjunctive therapy: ACE inhibitors or angiotensin receptor blockers for proteinuria (UPCR >50 mg/mmol) or hypertension 1
- Hydroxychloroquine: Should be administered to all patients at ≤5 mg/kg/day (adjusted for GFR) to reduce renal flares and limit cardiovascular damage 1
Class III and IV (Focal and Diffuse Proliferative Lupus Nephritis)
For Class III or IV lupus nephritis (with or without membranous component), initial treatment should combine glucocorticoids with mycophenolic acid analogs (MPAA), which is the preferred first-line agent. 1
Initial (Induction) Therapy
First-line options (choose one): 1
| Agent | Dosing | Evidence Level |
|---|---|---|
| Mycophenolate mofetil (MMF) | 2-3 g/day for 6 months | 1B (preferred) [1] |
| Low-dose IV cyclophosphamide | 500 mg every 2 weeks × 6 doses (total 3 g over 3 months) | 1B [1] |
| Belimumab + MMF or cyclophosphamide | Standard dosing with either agent above | 1B [1] |
| MMF + calcineurin inhibitor (tacrolimus) | MMF 1-2 g/day + tacrolimus (target trough 5-7 ng/mL) | 1B (especially for nephrotic-range proteinuria; only if eGFR >45 mL/min/1.73m²) [1] |
Alternative options: 1
- High-dose IV cyclophosphamide (0.5-0.75 g/m² monthly × 6 months) for patients at high risk of kidney failure (reduced GFR, crescents, fibrinoid necrosis, severe interstitial inflammation) 1
- Azathioprine 2 mg/kg/day only in selected patients without adverse prognostic factors when MMF or cyclophosphamide are contraindicated, not tolerated, or unavailable (associated with higher flare risk) 1
Glucocorticoid Regimen (Combined with Above)
Reduced-dose glucocorticoid protocol (preferred): 1
| Timeframe | Dosing |
|---|---|
| Initial pulses | Methylprednisolone 500-750 mg IV × 3 days [1] OR 0.25-0.5 g/day up to 3 days [1] |
| Weeks 0-2 | Prednisone 0.5-0.6 mg/kg/day (max 40 mg) [1] |
| Weeks 3-4 | Prednisone 0.3-0.4 mg/kg/day [1] |
| Weeks 5-6 | Prednisone 15 mg/day [1] |
| Weeks 7-8 | Prednisone 10 mg/day [1] |
| Weeks 9-10 | Prednisone 7.5 mg/day [1] |
| Weeks 11-12 | Prednisone 5 mg/day [1] |
| By 3-6 months | Taper to ≤7.5 mg/day [1] |
Key principle: The reduced-dose scheme minimizes cumulative glucocorticoid toxicity while maintaining efficacy when both kidney and extrarenal manifestations show satisfactory improvement 1
Maintenance Therapy
After achieving improvement with induction therapy (at 6-12 months), transition to maintenance immunosuppression: 1
| Agent | Dosing | Duration | Evidence |
|---|---|---|---|
| MMF (preferred if used for induction) | 1-2 g/day | ≥3-5 years | 1A [1] |
| Azathioprine | 2 mg/kg/day | ≥3-5 years | 1A (preferred if pregnancy contemplated; switch ≥3 months before conception) [1] |
| Plus prednisone | 2.5-7.5 mg/day | As needed for disease control | [1] |
Critical evidence: Azathioprine maintenance therapy probably increases disease relapse compared with MMF (RR 1.75,95% CI 1.20 to 2.55; 114 more relapses per 1000 people) 3
Withdrawal strategy: After 3-5 years in complete clinical response, gradual drug withdrawal can be attempted (glucocorticoids first, then immunosuppressive drugs), but hydroxychloroquine should be continued long-term 1
Refractory Disease
For patients failing initial therapy (lack of effect or adverse events), switch treatment: 1
Class V (Membranous Lupus Nephritis)
Pure Class V with Nephrotic-Range Proteinuria
For pure Class V with proteinuria >1 g/24h despite optimal RAAS blockade, MMF combined with glucocorticoids is the preferred initial treatment. 1
First-line therapy: 1
- MMF 2-3 g/day for 6 months
- Plus: Methylprednisolone IV pulses (500-2500 mg total) followed by oral prednisone 20 mg/day, tapered to ≤5 mg/day by 3 months 1
Alternative options: 1
- IV cyclophosphamide (dosing as above) 1
- Calcineurin inhibitors (ciclosporin or tacrolimus) in monotherapy or combined with MMF, particularly for nephrotic-range proteinuria 1
- Rituximab for non-responders 1
Maintenance: Calcineurin inhibitors can be continued at the lowest effective dose after considering nephrotoxicity risks 1
Class V Combined with III or IV
Treat as Class III/IV (see above). 2
Class VI (Advanced Sclerosing Lupus Nephritis)
No immunosuppressive therapy is indicated; prepare for renal replacement therapy. 2
- Class VI involves ≥90% globally sclerosed glomeruli without residual activity 2
- Focus on preparation for dialysis or transplantation rather than immunosuppression 2
Universal Adjunctive Therapies (All Classes)
All patients with lupus nephritis should receive the following adjunctive therapies: 1
| Intervention | Indication | Evidence |
|---|---|---|
| Hydroxychloroquine | All patients unless contraindicated | ≤5 mg/kg/day (adjusted for GFR) to reduce renal flares and cardiovascular damage [1] |
| ACE inhibitor or ARB | UPCR >500 mg/g or hypertension | Mandatory for renoprotection [1] |
| Statins | Persistent dyslipidemia | Target LDL <100 mg/dL (2.58 mmol/L) [1] |
| Calcium + Vitamin D | All patients on glucocorticoids | Bone protection [1] |
| Bisphosphonates | Based on fracture risk assessment | When appropriate [1] |
| Pneumocystis prophylaxis | Individualized based on immunosuppression intensity | Consider during intensive therapy [1] |
| Anticoagulation | Nephrotic syndrome with albumin <20 g/L, especially with antiphospholipid antibodies | Consider prophylactic anticoagulation [1] |
Treatment Goals and Monitoring
Complete clinical response (target by 12 months): 1
- UPCR <500-700 mg/g 1
- Normal or near-normal kidney function (within 10% of normal GFR if previously abnormal) 1
Acceptable milestones: 1
Patients with nephrotic-range proteinuria at baseline may require an additional 6-12 months to reach complete response; prompt therapy switches are not necessary if proteinuria is improving. 1
Critical Pitfalls to Avoid
- Do not delay treatment awaiting complete response criteria—partial response (≥50% reduction in proteinuria to subnephrotic levels with stable renal function) by 6-12 months is acceptable 1
- Minimize lifetime cyclophosphamide exposure to <36 g to reduce cancer risk and ovarian failure 1
- MMF is associated with decreased ovarian failure (RR 0.15,95% CI 0.03 to 0.80) and alopecia (RR 0.22,95% CI 0.06 to 0.86) compared to IV cyclophosphamide 4
- Assess adherence and therapeutic drug monitoring before declaring treatment failure 1
- Switch from MMF to azathioprine ≥3 months before conception if pregnancy is planned 1