What is the initial treatment approach for lupus nephritis?

Initial Treatment Approach for Lupus Nephritis

The initial treatment for active Class III and Class IV lupus nephritis should be a mycophenolic acid (MPAA)-based regimen with glucocorticoids, particularly in patients at high risk of infertility or those with prior cyclophosphamide exposure. 1

First-Line Treatment Options

Standard First-Line Therapy

• MPAA-based regimen:
  • Mycophenolate mofetil (MMF): 750-1000 mg twice daily
  • Mycophenolic acid (MPA): 540-720 mg twice daily
  • Combined with glucocorticoids:
    • Initial IV pulse methylprednisolone (optional): 500-1000 mg/day for up to 3 days in severe cases
    • Oral prednisone: Starting at 0.5-0.6 mg/kg/day (maximum 40 mg)
    • Taper to ≤7.5 mg/day by 3-6 months

Alternative First-Line Options

• Intravenous cyclophosphamide with glucocorticoids:

  • Indicated for patients who may have difficulty adhering to an oral regimen 1
  • Should be avoided in patients at high risk of infertility

• CNI-based regimen (voclosporin, tacrolimus, or cyclosporine):

  • Preferred in patients with:
    • Relatively preserved kidney function with nephrotic-range proteinuria
    • Inability to tolerate standard-dose MPAA
    • Contraindications to cyclophosphamide 1

• Triple immunosuppressive regimen:

  • Belimumab + glucocorticoids + either MPAA or reduced-dose cyclophosphamide
  • Preferred for patients with:
    • Repeated kidney flares
    • High risk for progression to kidney failure due to severe CKD 1
  • Belimumab has shown significant improvement in Primary Efficacy Renal Response (PERR) compared to standard therapy alone 2

Treatment Response Assessment

Response Definitions

• Complete response:

  • Proteinuria <0.5 g/g (PCR)
  • Stable or improved kidney function (±10-15% of baseline)
  • Usually within 6-12 months of starting therapy 1

• Partial response:

  • ≥50% reduction in proteinuria to <3 g/g (PCR)
  • Stable or improved kidney function
  • Within 6-12 months of starting therapy 1

Expected Timeline for Response

• 25% reduction in proteinuria by 3 months
• 50% reduction by 6 months
• Target UPCR below 500-700 mg/g by 12 months
• Patients with nephrotic-range proteinuria may require 12-24 months for complete response 3

Maintenance Therapy

After completion of initial therapy, patients should be placed on MPAA for maintenance therapy. 1

• MPAA dosing:

  • MMF: 750-1000 mg twice daily
  • MPA: 540-720 mg twice daily 1

• Alternative maintenance option:

  • Azathioprine: For patients who don't tolerate MPAA, lack access to MPAA, or are considering pregnancy 1
  • Note: Disease relapse is probably increased with azathioprine compared to MMF 4

• Duration:

  • Total duration of initial plus maintenance immunosuppression should be ≥36 months 1

• Glucocorticoids:

  • Taper to lowest possible dose
  • Consider discontinuation after complete clinical renal response for ≥12 months 1

Special Considerations

Adjunctive Treatments

• Hydroxychloroquine:

  • Should be co-administered at ≤5 mg/kg/day (adjusted for GFR) 3

• Cardiovascular protection:

  • ACE inhibitors or ARBs for all patients with proteinuria >500 mg/g
  • Statins for persistent dyslipidemia (target LDL <100 mg/dL) 3

Monitoring

• Every 2-4 weeks initially, then adjust based on response
• Monitor for:
  • Infection (major cause of morbidity and mortality)
  • Medication adherence (poor adherence is a common cause of treatment failure)
  • Drug toxicity 3

Common Pitfalls and Caveats

1. Medication adherence issues:

   • Poor adherence is a common cause of treatment failure
   • Consider IV cyclophosphamide for patients with adherence concerns 1

2. Fertility considerations:

   • Avoid cyclophosphamide in patients concerned about fertility
   • MPAA-based regimens are preferred for patients at high risk of infertility 1

3. Premature therapy changes:

   • Avoid switching therapy too early if proteinuria is improving
   • Complete response may take 12-24 months in nephrotic patients 3

4. Inadequate duration of treatment:

   • Maintain immunosuppression for at least 36 months total 1
   • Premature discontinuation increases risk of relapse

5. Excessive glucocorticoid exposure:

   • Taper to lowest effective dose to minimize toxicity
   • Consider discontinuation after 12 months of complete response 1