What are the treatment regimens for class I, II, and V lupus nephritis, including diagnosis, follow-up, and assessment of response?

Management of Class I, II, and V Lupus Nephritis

For lupus nephritis classes I, II, and V, treatment should be guided by renal biopsy findings, with specific regimens tailored to each class to optimize outcomes for morbidity, mortality, and quality of life.

Diagnosis and Classification

• Kidney biopsy is essential for all patients with suspected lupus nephritis, particularly with proteinuria ≥0.5 g/24 hours, glomerular hematuria, and/or cellular casts 1
• The International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification system should be used to guide treatment decisions 1
• Testing for antiphospholipid antibodies, anti-dsDNA, anti-C1q antibodies, and complement levels (C3 and C4) should be performed in all patients with suspected lupus nephritis 1

Class I Lupus Nephritis (Minimal Mesangial)

• Class I lupus nephritis generally does not require specific immunosuppressive treatment 1
• Treatment should be guided by extrarenal manifestations of lupus 1
• All patients should receive hydroxychloroquine (5 mg/kg actual body weight daily) unless contraindicated 1, 2
• Regular monitoring for disease activity with urinalysis, serum creatinine, and complement levels every 3-6 months is recommended 1

Class II Lupus Nephritis (Mesangial Proliferative)

• For Class II with proteinuria <1 g/day: No specific immunosuppressive therapy is needed; treat extrarenal manifestations as indicated 1
• For Class II with proteinuria 1-3 g/day: Consider low-dose corticosteroids 1
• For Class II with nephrotic-range proteinuria (>3 g/day): Treat with corticosteroids or calcineurin inhibitors as described for minimal change disease 1
• All patients should receive hydroxychloroquine unless contraindicated 1, 2
• Renin-angiotensin-aldosterone system (RAAS) blockers are recommended for all patients with proteinuria ≥0.5 g/day 1

Class V Lupus Nephritis (Membranous)

• For pure Class V with nephrotic-range proteinuria:
  • First-line treatment: Mycophenolic acid (MPA) or mycophenolate mofetil (MMF) at target dose 2-3 g/day in combination with glucocorticoids 1, 2
  • Initial glucocorticoid regimen: IV methylprednisolone (total dose 500-2500 mg depending on disease severity) followed by oral prednisone (20 mg/day, tapered to ≤5 mg/day by 3 months) 1
• Alternative first-line options:
  • Calcineurin inhibitors (especially tacrolimus) alone or in combination with MMF 1, 2
  • Cyclophosphamide with glucocorticoids 2
• For Class V with subnephrotic proteinuria but >1 g/day despite optimal RAAS blockade for 3 months: Consider immunosuppressive therapy as above 1
• For Class V with proteinuria <1 g/day: RAAS blockade without immunosuppression may be sufficient 1

Follow-up and Monitoring

• Treatment aims for:
  • Reduction in proteinuria of at least 25% by 3 months 1
  • Reduction in proteinuria of at least 50% by 6 months 1
  • UPCR target below 500-700 mg/g by 12 months (complete clinical response) 1
• Patients with nephrotic-range proteinuria at baseline may require an additional 6-12 months to reach complete clinical response 1
• Regular monitoring should include:
  • Urinalysis and urine protein quantification every 1-3 months 1
  • Serum creatinine and estimated GFR every 1-3 months 1
  • Complement levels and anti-dsDNA antibodies every 3 months 1

Assessment of Treatment Response

• Complete response: Proteinuria <0.5 g/24h with normal or near-normal renal function 1
• Partial response: >50% reduction in proteinuria to subnephrotic levels with normal or near-normal renal function 1
• If worsening LN (rising serum creatinine, worsening proteinuria) during the first 3 months of treatment, consider changing to alternative therapy or repeat kidney biopsy 1

Maintenance Therapy

• For patients with Class V who achieve response:
  • Continue maintenance immunosuppression for at least 3 years 1
  • If initial treatment was MMF/MPA, continue with MMF/MPA for maintenance 1
  • If initial treatment was cyclophosphamide, either MMF/MPA or azathioprine can be used for maintenance 1
  • Calcineurin inhibitors can be used at the lowest effective dose for maintenance in Class V 1
• Gradual tapering of immunosuppression should be considered only after sustained complete response 1
• Hydroxychloroquine should be continued indefinitely 1, 2

Treatment of Refractory Disease

• For MMF or cyclophosphamide failures, switch to the other agent 1
• Rituximab may be considered for non-responders to first-line therapies 1, 2
• Combination of MMF with a calcineurin inhibitor (multitarget therapy) may be effective in refractory cases 1

Adjunctive Treatments

• All patients should receive hydroxychloroquine unless contraindicated 1
• RAAS blockade with ACE inhibitors or ARBs for all patients with proteinuria ≥0.5 g/day 1
• Blood pressure control with target ≤130/80 mmHg 2
• Address cardiovascular risk factors and bone health 1