What is the class-wise treatment for Lupus Nephritis?

Lupus Nephritis: Class-Wise Treatment Approach

For Class III/IV lupus nephritis, initiate treatment with glucocorticoids plus mycophenolic acid analogs (2-3 g/day), low-dose intravenous cyclophosphamide, or the combination of belimumab with either agent, as these regimens provide the best efficacy-to-toxicity ratio and are now the standard of care. 1

Class I and II Lupus Nephritis

Class I (Minimal Mesangial) and Class II (Mesangial Proliferative):

• No specific immunosuppressive therapy is required for these classes 2, 3
• Treatment should focus on extrarenal manifestations of lupus 2
• All patients must receive hydroxychloroquine 5 mg/kg actual body weight daily (not exceeding this dose and adjusted for GFR) unless contraindicated 1, 2
• For Class II with proteinuria <1 g/day, no immunosuppression is needed; simply treat extrarenal manifestations 2
• Careful surveillance is essential to detect progression to more severe disease classes 4

Class III and IV Lupus Nephritis (Focal and Diffuse Proliferative)

Initial Induction Therapy (First-Line Options):

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

1. Mycophenolic acid analogs (MPAA) at target dose 2-3 g/day plus glucocorticoids 1
2. Low-dose intravenous cyclophosphamide (500 mg every 2 weeks for 6 doses) plus glucocorticoids 1
3. Belimumab combined with either MPAA or low-dose cyclophosphamide plus glucocorticoids 1
4. MPAA plus calcineurin inhibitor (especially tacrolimus) when eGFR is not severely impaired (≥45 ml/min per 1.73 m²), particularly effective for nephrotic-range proteinuria 1, 5

Glucocorticoid Regimens:

The 2024 KDIGO guidelines now emphasize reduced-dose glucocorticoid protocols 1:

• Start with methylprednisolone IV pulses (250-500 mg/day for up to 3 days) 1
• Follow with oral prednisone using a reduced-dose scheme: 0.5-0.6 mg/kg/day (max 40 mg) for weeks 0-2, then taper to 0.3-0.4 mg/kg by weeks 3-4,15 mg by weeks 5-6,10 mg by weeks 7-8,7.5 mg by weeks 9-10,5 mg by weeks 11-12, and <2.5 mg by week 25 1
• The older high-dose regimen (0.3-0.5 mg/kg/day tapered to ≤7.5 mg/day by 3-6 months) is still acceptable but carries more toxicity 1

Special Considerations for High-Risk Disease:

• Patients with reduced GFR, histological crescents, fibrinoid necrosis, or severe interstitial inflammation can be treated with the above regimens, but high-dose IV cyclophosphamide (0.5-0.75 g/m² monthly for 6 months) may also be considered 1
• MPAA-based regimens are preferred for patients at high risk of infertility 1
• IV cyclophosphamide is useful when adherence to oral regimens is questionable 1

Maintenance Therapy:

After achieving improvement with initial treatment 1:

• Continue with MMF/MPA 1-2 g/day (especially if used for induction) OR azathioprine 2 mg/kg/day (preferred if pregnancy is contemplated) 1
• Combine with low-dose prednisone (2.5-5 mg/day) as needed 1
• Maintain therapy for at least 3-5 years in complete clinical response 1
• Hydroxychloroquine must be continued long-term indefinitely 1, 2

Class V Lupus Nephritis (Membranous)

Pure Class V (Without Proliferative Features):

• For nephrotic-range proteinuria: MMF/MPA at target dose 2-3 g/day combined with pulse IV methylprednisolone (500-2500 mg total) followed by oral prednisone 20 mg/day, tapered to ≤5 mg/day by 3 months 1, 2
• This regimen has the best efficacy-to-toxicity ratio for Class V 1
• Alternative options include IV cyclophosphamide or calcineurin inhibitors (especially tacrolimus) in monotherapy or combined with MMF/MPA, particularly for nephrotic-range proteinuria 1
• For proteinuria <1 g/day without nephrotic syndrome, no specific immunosuppressive therapy may be needed 2

Class V Combined with Class III or IV:

• Treat as Class III/IV disease using the proliferative lupus nephritis protocols described above 3

Maintenance for Class V:

• Continue maintenance immunosuppression for at least 3 years 2
• If MMF/MPA was used for induction, continue MMF/MPA for maintenance 2
• Calcineurin inhibitors can be continued, switched to, or added at the lowest effective dose after considering nephrotoxicity risks 1

Class VI Lupus Nephritis (Advanced Sclerosing)

• Class VI (≥90% globally sclerosed glomeruli) generally requires preparation for renal replacement therapy rather than immunosuppression 3
• Immunosuppressive therapy is not indicated as the kidney damage is irreversible 3

Treatment Goals and Monitoring

Response Targets:

• Proteinuria reduction of ≥25% by 3 months, ≥50% by 6 months 1, 2
• Target urine protein-to-creatinine ratio (UPCR) <500-700 mg/g by 12 months (complete clinical response) 1, 2
• 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

Monitoring Schedule:

• Urinalysis and urine protein quantification every 1-3 months 2
• Serum creatinine and eGFR every 1-3 months 2
• Complement levels (C3, C4) and anti-dsDNA antibodies every 3 months 2

Refractory or Non-Responding Disease

When treatment goals are not met:

• Thoroughly evaluate possible causes including medication adherence and perform therapeutic drug monitoring 1
• Switch to one of the alternative initial therapies listed above 1
• Consider rituximab (1000 mg on days 0 and 14) for active non-responding/refractory disease 1

Essential Adjunctive Therapies (All Classes)

Renoprotection:

• ACE inhibitors or ARBs for all patients with UPCR >500 mg/g or hypertension 1
• SGLT2 inhibitors in stable patients without AKI 1

Infection Prevention:

• Screen for hepatitis B, C, HIV, and tuberculosis 1
• Pneumocystis jirovecii prophylaxis during intensive immunosuppression 1
• Consider recombinant zoster vaccine 1

Bone Protection:

• Calcium and vitamin D supplementation 1
• Bisphosphonates when appropriate based on fracture risk 1

Fertility Preservation:

• Minimize lifetime cyclophosphamide exposure to <36 g 1
• Consider gonadotropin-releasing hormone agonists (leuprolide) or gamete cryopreservation before cyclophosphamide 1

Cardiovascular Risk:

• Statins based on lipid levels and 10-year cardiovascular risk 1
• Optimize blood pressure control 1

Critical Pitfalls to Avoid

• Never delay renal biopsy in patients with proteinuria ≥0.5 g/24 hours plus hematuria or cellular casts, as clinical parameters cannot predict histology 2, 3
• Do not use Class I/II protocols for Class III/IV disease, as this leads to progression to end-stage kidney disease 3, 6
• Avoid high cumulative cyclophosphamide doses (keep lifetime exposure <36 g) to prevent infertility and malignancy risk 1
• Do not abruptly stop therapy after achieving remission; gradual withdrawal after 3-5 years is essential, with hydroxychloroquine continued indefinitely 1, 2
• Never ignore treatment adherence when evaluating non-response; therapeutic drug monitoring is essential 1