What is the treatment approach for a young to middle-aged woman from a high-risk ethnic group diagnosed with lupus nephritis, a complication of systemic lupus erythematosus (SLE)?

Treatment Approach for Lupus Nephritis

For a young to middle-aged woman from a high-risk ethnic group with lupus nephritis, initiate treatment with glucocorticoids plus mycophenolic acid analogs (or low-dose IV cyclophosphamide), with hydroxychloroquine as universal background therapy, and consider adding belimumab for moderate-to-severe proliferative disease. 1

Immediate Diagnostic Confirmation

Renal biopsy is indispensable before initiating immunosuppressive therapy to determine the histologic class (ISN/RPS classification), distinguish active inflammation from chronic scarring, and guide treatment intensity 1, 2. The biopsy should be read by an experienced kidney pathologist and include immunofluorescence to identify the characteristic "full house" pattern of immune deposits 1, 3.

• Active proliferative classes (III/IV) require aggressive immunosuppression, while membranous (Class V) may be approached differently depending on proteinuria severity 1
• Class VI (≥90% glomerular sclerosis) requires preparation for renal replacement therapy rather than immunosuppression 1
• The activity and chronicity indices inform prognosis—higher chronicity predicts lower response to immunosuppression 1

Universal Background Therapy (All Patients)

Hydroxychloroquine

All lupus nephritis patients must receive hydroxychloroquine (≤5 mg/kg real body weight) unless contraindicated 1, 4. This reduces flares, prevents damage accrual including renal damage, decreases thrombotic risk, and improves survival 1, 4.

• Requires ophthalmologic screening at baseline, after 5 years, then yearly for retinal toxicity 4
• Should be continued indefinitely—discontinuation significantly increases relapse risk 5, 4

Renin-Angiotensin System Blockade

For proteinuria ≥0.5 g/24 hours, initiate ACE inhibitors or ARBs to reduce intraglomerular pressure 1. This reduces proteinuria by approximately 30% and delays progression to end-stage renal disease 1.

• Target blood pressure ≤130/80 mmHg (≤125/75 mmHg if nephrotic-range proteinuria) 1, 5
• Contraindicated in pregnancy 1
• Consider adding SGLT2 inhibitors in stable patients without acute kidney injury for additional renoprotection 1

Induction Therapy for Active Class III/IV Lupus Nephritis

The 2024 KDIGO guidelines provide four equally recommended first-line options, all combined with glucocorticoids 1:

Option 1: Mycophenolic Acid Analogs (MPAA) - Preferred for Most Patients

• Mycophenolate mofetil 2-3 g/day or mycophenolic acid 1440-2160 mg/day 1, 5
• Level 1B evidence supporting efficacy comparable to cyclophosphamide with better safety profile 1

Option 2: Low-Dose IV Cyclophosphamide

• Euro-Lupus protocol: 500 mg IV every 2 weeks for 6 doses 1
• Reserve for patients with severe disease or when cost/availability favors this option 6
• Critical: Minimize lifetime cyclophosphamide exposure to <36 g to reduce cancer risk 1
• Counsel reproductive-age patients about gonadal toxicity and fertility preservation options 1, 6

Option 3: Belimumab + MPAA or Cyclophosphamide

Consider adding belimumab (10 mg/kg IV on days 0,14,28, then every 28 days) from disease onset in patients with moderate-to-severe proliferative nephritis, defined as NIH activity index >5 plus ≥1 of: chronicity index >2, proteinuria >3 g/24h, or serum creatinine increase >20% 7, 2.

• In the lupus nephritis trial, 43% achieved primary efficacy renal response at Week 104 with belimumab vs 32% with placebo (OR 1.6, p=0.031) 7
• Can also be added at 3 months if inadequate response to standard therapy, or for inability to taper glucocorticoids 5, 2

Option 4: MPAA + Calcineurin Inhibitor (CNI)

• Use when eGFR >45 mL/min/1.73 m² (not severely impaired) 1
• Voclosporin + MMF shows particular benefit for heavy proteinuria (well above nephrotic range) where rapid reduction is needed 2, 8
• Consider for up to 3 years, though long-term use beyond 1 year requires careful monitoring for scarring effects 2

Glucocorticoid Regimen

Use reduced-dose glucocorticoid protocols to minimize toxicity 1:

• Initiate with methylprednisolone pulses 250-1000 mg IV daily for 1-3 days 1, 6
• Follow with oral prednisone 0.5-1 mg/kg/day (maximum 60 mg/day) depending on severity 1, 6
• Never exceed 1 mg/kg/day or 60 mg/day—higher doses do not improve outcomes and accelerate damage 6
• Taper aggressively with goal of ≤7.5 mg/day for maintenance and eventual withdrawal 1, 6, 4

Maintenance Therapy (After Achieving Response)

Transition to maintenance therapy after achieving response (typically by 3-6 months) 5:

• Mycophenolate mofetil 1-2 g/day (or mycophenolic acid 720-1440 mg/day) as preferred agent 5
• Alternative: Azathioprine 1.5-2.5 mg/kg/day if MMF intolerant 5
• Low-dose prednisone ≤10 mg/day 5
• Minimum duration: ≥36 months before considering reduction—early cessation (before 2 years) significantly increases relapse risk 5

Special Consideration: Pure Membranous (Class V) Lupus Nephritis

For Class V with nephrotic-range proteinuria (>3.5 g/24h) 5:

• Treat with corticosteroids plus immunosuppressive agent (MPAA preferred, or cyclophosphamide, or CNI) 5
• Consider triple therapy (corticosteroids + tacrolimus + low-dose MMF) for nephrotic syndrome—shows 33.1% complete remission vs 7.8% with standard therapy 5
• Class V combined with III/IV should be treated as proliferative disease 1

Monitoring Treatment Response

Assess response systematically at defined intervals 5:

• 3 months: ≥25% reduction in proteinuria and stable renal function (±10-15% baseline eGFR)
• 6 months: Partial response (≥50% reduction in proteinuria to <3 g/24h) or complete response (proteinuria <0.5 g/24h with stable renal function)
• 12 months: Aim for complete response (proteinuria <0.5 g/24h)

If inadequate response at 3-4 months: Switch to alternative induction regimen or add belimumab to existing therapy 5, 2. Consider repeat biopsy to distinguish persistent activity from chronicity 5.

Risk Mitigation Strategies

Infection Prevention

• Screen for HBV, HCV, HIV; vaccinate for HBV and pneumococcus 1
• Assess tuberculosis history and consider testing 1
• Consider Pneumocystis jirovecii prophylaxis during intensive immunosuppression 1
• Individualized consideration for recombinant zoster vaccine 1

Cardiovascular Protection

• Manage dyslipidemia—initiate statin therapy if LDL >100 mg/dL 1
• Low-dose aspirin during pregnancy for patients with antiphospholipid antibodies 1, 4

Bone Health

• Calcium and vitamin D supplementation 1
• Bone density assessment and bisphosphonates when appropriate 1

Fertility Preservation

• Gonadotropin-releasing hormone agonists (leuprolide) during cyclophosphamide therapy 1
• Sperm/oocyte cryopreservation counseling 1

Critical Pitfalls to Avoid

• Never delay immunosuppressive therapy—glucocorticoids alone are insufficient and lead to prolonged high-dose steroid exposure 6
• Never assume Class II (mesangial) requires immunosuppression—generally does not need aggressive therapy 1
• Never discontinue hydroxychloroquine without specific contraindication—increases flare and damage risk 5, 4
• Never ignore persistent proteinuria—28-50% of patients in complete clinical remission have active histological inflammation, increasing relapse risk if immunosuppression is stopped prematurely 5
• Always exclude infection before escalating immunosuppression in patients with fever or clinical deterioration—SLE patients have 5-fold increased infection mortality 6, 4