What is the treatment approach for lupus nephritis?

Treatment of Lupus Nephritis

For proliferative lupus nephritis (Class III/IV), mycophenolic acid (MMF 3 g/day for 6 months) or low-dose intravenous cyclophosphamide (total 3 g over 3 months) combined with glucocorticoids are the recommended first-line treatments, with both having similar efficacy and the best efficacy-to-toxicity ratio. 1

Diagnostic Prerequisites

Treatment must be guided by kidney biopsy to determine the ISN/RPS histologic class, as clinical and serological tests cannot accurately predict renal pathology. 1, 2

• Biopsy is indicated for proteinuria ≥0.5 g/24h (or UPCR ≥500 mg/g), especially with glomerular hematuria and/or cellular casts 1, 2
• The ISN/RPS 2003 classification system should be used to assess active and chronic glomerular/tubulointerstitial changes 1

Universal Background Therapy (All Patients)

Before discussing class-specific treatment, all lupus nephritis patients should receive:

• Hydroxychloroquine for all patients unless contraindicated 1, 2
• Renin-angiotensin system blockade (ACE inhibitors or ARBs) for proteinuria ≥0.5 g/24h to reduce proteinuria by approximately 30% and delay progression 1, 2
• Blood pressure control targeting ≤130/80 mmHg 1

Class-Specific Induction Treatment

Class III/IV Proliferative Lupus Nephritis (Active Disease)

Initial therapy options (choose one): 1

Option 1: Mycophenolic Acid (Preferred for most patients)

• MMF target dose: 3 g/day for 6 months 1
• Combined with glucocorticoids (see below)

Option 2: Low-Dose Cyclophosphamide

• Total dose 3 g IV over 3 months 1
• Alternative: 0.75-1 g/m² monthly for 6 months or oral 2-2.5 mg/kg/day 1
• Combined with glucocorticoids

Glucocorticoid regimen (for both options): 1

• Three consecutive pulses of IV methylprednisolone 500-750 mg
• Followed by oral prednisone 0.5 mg/kg/day for 4 weeks
• Taper to ≤10 mg/day by 4-6 months

For patients with adverse prognostic factors (acute deterioration in renal function, substantial cellular crescents, fibrinoid necrosis), higher-dose cyclophosphamide regimens should be considered. 1

Alternative for selected patients without adverse features: Azathioprine 2 mg/kg/day may be used when MMF or cyclophosphamide are contraindicated, not tolerated, or unavailable, though it carries higher flare risk. 1

Class V Membranous Lupus Nephritis (Pure)

Treatment is guided by proteinuria severity: 1

For nephrotic-range proteinuria (>3 g/24h):

• MMF (target 3 g/day for 6 months) plus oral prednisone (0.5 mg/kg/day) is recommended as initial treatment based on better efficacy-to-toxicity ratio 1
• Alternative options: cyclophosphamide, calcineurin inhibitors (cyclosporine, tacrolimus), or rituximab for non-responders 1
• Voclosporin (a calcineurin inhibitor) has shown efficacy with median time to reduce proteinuria to <0.5 mg/mg of 3.6 months 1

For proteinuria 1-3 g/24h despite renin-angiotensin blockade:

• Immunosuppressive treatment is recommended 1

For low-level proteinuria (<1 g/24h):

• Continue renin-angiotensin blockade, hydroxychloroquine, and blood pressure control
• Monitor closely; consider immunosuppression if proteinuria worsens or complications develop 1

Class I/II (Minimal/Mesangial)

Immunosuppressive treatment is generally not required. 1

Class VI (Advanced Sclerosis)

Prepare for renal replacement therapy rather than immunosuppression (≥90% glomerular sclerosis). 1

Maintenance Therapy

After achieving response to induction (at 6 months), continue with maintenance therapy for at least 3 years: 1

Preferred options:

• MPA at lower doses (MMF target 2 g/day) plus low-dose prednisone (5-7.5 mg/day) 1
• Azathioprine 2 mg/kg/day plus low-dose prednisone (5-7.5 mg/day) 1

Key principle: If MPA was used for induction, MPA should be used for maintenance. 1

Alternative maintenance options if MPA and azathioprine cannot be used: calcineurin inhibitors, mizoribine, or leflunomide 1

Treatment Failures and Refractory Disease

For patients failing MPA or cyclophosphamide:

• Switch to the other agent (if MPA failed, try cyclophosphamide; if cyclophosphamide failed, try MPA) 1
• Rituximab is suggested for refractory cases 1
• Belimumab (10 mg/kg IV) added to standard therapy has shown efficacy in lupus nephritis, achieving 43% primary efficacy renal response at Week 104 versus 32% with placebo 3

Treatment Response Monitoring

Treatment response should be evaluated systematically: 2

• At 3 months: Expect ≥25% reduction in proteinuria
• At 6 months: Expect ≥50% reduction in proteinuria to subnephrotic levels (<3 g/g)
• At 12 months: Target proteinuria <0.5-0.7 g/g (complete response) or ≥50% reduction with stable kidney function (partial response)

Complete response definition: 1, 2

• UPCR <50 mg/mol (or <0.5 g/g)
• Normal or near-normal renal function (within 10% of normal GFR if previously abnormal)

Partial response definition: 1, 2

• ≥50% reduction in proteinuria to subnephrotic levels
• Normal or near-normal renal function

Ongoing monitoring should include: 2

• Urine sediment analysis
• UPCR or 24-hour proteinuria
• Serum creatinine and eGFR
• Immunologic markers (anti-dsDNA, C3, C4) at each visit

Special Populations

Pregnancy

For pregnant patients with active lupus nephritis: 1

• Glucocorticoids at doses necessary to control disease activity
• Azathioprine (≤2 mg/kg/day) can be added if needed, despite Category D listing
• Hydroxychloroquine for mild systemic activity
• Avoid: MMF, cyclophosphamide, and methotrexate (teratogenic)
• For persistently active Class III/IV with crescents, consider delivery after 28 weeks for viable fetus 1

Anticipating pregnancy: Switch to appropriate medications without reducing treatment intensity. 1

Thrombotic Microangiopathy

If thrombotic microangiopathy is present on biopsy:

• Treat primarily with plasma exchange therapy 1
• Measure ADAMTS13 activity and calculate PLASMIC score to distinguish TTP 2
• Initiate plasma exchange and glucocorticoids while awaiting results if high clinical suspicion 2

Critical Pitfalls to Avoid

• Do not delay biopsy: Clinical parameters cannot predict histologic class accurately 1
• Do not undertreat Class V with nephrotic syndrome: Unlike primary membranous nephropathy, heavy proteinuria in Class V lupus nephritis does not spontaneously remit and requires immunosuppression 1
• Do not continue failing therapy: If no response by 6 months, switch agents rather than persist 1
• Do not stop maintenance therapy prematurely: Continue for at least 3 years to prevent flares 1
• Do not use teratogenic agents in pregnancy: MMF and cyclophosphamide must be avoided 1