What is the recommended initial therapy for a patient with lupus nephritis class IV presenting with nephrotic range proteinuria as the only manifestation of lupus?

Treatment for Class IV Lupus Nephritis with Nephrotic Range Proteinuria

For a patient with lupus nephritis class IV presenting with nephrotic range proteinuria as the only manifestation of lupus, the recommended initial therapy is mycophenolate mofetil (MMF) at a target dose of 2-3 g/day or low-dose intravenous cyclophosphamide (500 mg every 2 weeks for a total of 6 doses), combined with glucocorticoids. 1

Initial Treatment Algorithm

First-Line Immunosuppressive Options:

1. Mycophenolate Mofetil (MMF)
   • Target dose: 2-3 g/day
   • Best efficacy/toxicity ratio for class IV lupus nephritis
   • Particularly effective for nephrotic-range proteinuria
   • Lower risk of ovarian failure compared to cyclophosphamide 2

OR

1. Low-dose Intravenous Cyclophosphamide
   • Dosing: 500 mg every 2 weeks for a total of 6 doses (3 months)
   • Equally effective as MMF in preserving kidney function

Glucocorticoid Regimen:

• Initial IV pulse methylprednisolone: 500-2500 mg total dose (depending on disease severity)
• Followed by oral prednisone: 0.3-0.5 mg/kg/day for up to 4 weeks
• Taper to ≤7.5 mg/day by 3-6 months 1

Adjunctive Therapy:

• Hydroxychloroquine: Should be co-administered at a dose not exceeding 5 mg/kg/day (adjusted for GFR) 1, 3
• ACE inhibitors or ARBs: Recommended for all patients with proteinuria >500 mg/g 1

Alternative Treatment Options

For patients with nephrotic-range proteinuria, consider these alternatives if first-line therapy is contraindicated or ineffective:

1. Combination Therapy:

   • MMF (target dose: 1-2 g/day) with a calcineurin inhibitor (especially tacrolimus) 1
   • Particularly effective for patients with significant proteinuria

2. High-dose Cyclophosphamide:

   • Consider in patients at high risk for kidney failure (reduced GFR, crescents, fibrinoid necrosis, severe interstitial inflammation)
   • Dosing: 0.5-0.75 g/m² monthly for 6 months 1, 3

Monitoring and Treatment Goals

• Initial monitoring: Every 2-4 weeks for first 2-4 months
• Parameters to assess: Proteinuria, serum creatinine, eGFR, albumin, urinary sediment, complement levels, complete blood count 3

Treatment targets:

• 25% reduction in proteinuria by 3 months
• 50% reduction by 6 months
• UPCR target below 500-700 mg/g by 12 months 1

Note: Patients with nephrotic-range proteinuria at baseline may require an additional 6-12 months to reach complete clinical response; prompt switches of therapy are not necessary if proteinuria is improving. 1

Maintenance Therapy

After achieving improvement (typically 6 months):

• Continue MMF at lower dose (1-2 g/day) or switch to azathioprine (2 mg/kg/day, preferred if pregnancy is contemplated)
• Low-dose prednisone (2.5-5 mg/day) as needed
• Continue for at least 3-5 years in complete clinical response 1
• Hydroxychloroquine should be continued long-term 1, 3

Important Considerations and Pitfalls

• Medication adherence: Poor adherence is a common cause of treatment failure; regular assessment is essential 1
• Infection risk: Monitor for infections, especially with combined immunosuppression
• Ovarian toxicity: MMF has significantly lower risk of ovarian failure compared to cyclophosphamide (RR 0.15) 2
• Renal relapse: Higher risk with azathioprine compared to MMF for maintenance therapy 2
• Pregnancy planning: If pregnancy is contemplated, azathioprine is preferred over MMF for maintenance therapy 3

In cases of treatment failure, consider switching to an alternative initial therapy or rituximab (1000 mg on days 0 and 14) 1.