What is the initial management for a patient with lupus nephritis?

Recent Management of Lupus Nephritis

For initial management of lupus nephritis, start with mycophenolic acid analogs (MPAA) plus glucocorticoids as first-line therapy for proliferative disease (Class III/IV), with belimumab or calcineurin inhibitors as add-on options for high-risk patients. 1

Initial Therapy Selection by Disease Class

Proliferative Lupus Nephritis (Class III/IV)

The KDIGO 2024 guidelines establish four equally acceptable first-line regimens for Class III and IV disease: 1

• Mycophenolic acid analogs (MPAA) + glucocorticoids (preferred for most patients) 1, 2
• Low-dose intravenous cyclophosphamide + glucocorticoids 1
• Belimumab + MPAA or cyclophosphamide + glucocorticoids (triple therapy) 1, 2
• MPAA + calcineurin inhibitor (voclosporin, tacrolimus, or cyclosporine) + glucocorticoids 1, 2

Patient-Specific Treatment Selection

For patients at high risk of infertility (prior cyclophosphamide exposure), MPAA-based regimens are preferred over cyclophosphamide 1

For patients with preserved kidney function (eGFR >45) and nephrotic-range proteinuria due to extensive podocyte injury, calcineurin inhibitor-based regimens (MPAA + CNI) should be strongly considered 1, 2

For patients with repeated kidney flares or high risk for progression to kidney failure due to severe chronic kidney disease, triple immunosuppressive therapy with belimumab + glucocorticoids + either MPAA or reduced-dose cyclophosphamide is preferred 1, 2

For patients who may have difficulty adhering to oral regimens, intravenous cyclophosphamide can be used 1

Membranous Lupus Nephritis (Class V)

For pure Class V with nephrotic-range proteinuria (>1 g/24h), MPAA combined with oral glucocorticoids is recommended as initial treatment 1

For Class 3+5 (mixed proliferative and membranous), treat according to the proliferative component using the same algorithm as pure Class III/IV disease, since the proliferative component drives management decisions 2

Glucocorticoid Regimen

The KDIGO 2024 guidelines recommend a reduced-dose glucocorticoid protocol to minimize toxicity: 1, 2

• Initial pulse therapy: Methylprednisolone 250-500 mg IV daily for up to 3 days 2
• Followed by oral prednisone taper starting at weight-based dosing and tapering over 24+ weeks 1
• Target: Taper to <5 mg/day by week 25 and beyond 1

Essential Adjunctive Therapies

Hydroxychloroquine is mandatory for all patients with lupus nephritis to reduce flares and improve long-term outcomes 1, 2

ACE inhibitor or ARB is required for proteinuria control and blood pressure management 2

Maintenance Therapy

After completion of initial therapy (typically 6 months), patients should be placed on MPAA for maintenance (mycophenolate mofetil 750-1000 mg twice daily or mycophenolic acid 540-720 mg twice daily) 1, 2

The total duration of initial immunosuppression plus maintenance should be at least 36 months 1, 2

Azathioprine is an alternative to MPAA for maintenance in patients who do not tolerate MPAA, lack access to MPAA, or are considering pregnancy 1

Glucocorticoids should be tapered to the lowest possible dose during maintenance, with discontinuation considered after patients maintain complete clinical renal response for ≥12 months 1

Patients treated with triple immunosuppressive regimens (belimumab or CNI-based) can continue with triple therapy as maintenance 1, 2

Monitoring Protocol

Intensive early monitoring every 2-4 weeks for the first 2-4 months should include: 2

• Serum creatinine and eGFR 2
• Urine protein-to-creatinine ratio 2
• Urinalysis with microscopy 2
• Complement levels (C3, C4) 2
• Anti-dsDNA antibodies 2
• Complete blood count 2
• Blood pressure and weight 2

Treatment Response Definitions

Complete response (target outcome): Proteinuria <0.5 g/g, stable or improved kidney function (±10-15% of baseline), achieved within 6-12 months 1, 2

Partial response: ≥50% reduction in proteinuria to <3 g/g, stable or improved kidney function, within 6-12 months 1, 2

No response: Failure to achieve partial or complete response within 6-12 months 1, 2

Management of Inadequate Response

If response is unsatisfactory at 6-12 months, follow this algorithmic approach: 1

1. Verify adherence to treatment 1
2. Ensure adequate dosing by measuring plasma drug levels if applicable 1
3. Switch to alternative agent: For MPAA failures, switch to cyclophosphamide; for cyclophosphamide failures, switch to MPAA 1
4. Consider rituximab for patients with persistent disease activity or inadequate response to initial standard-of-care therapy 1

Evidence from Belimumab Trials

The FDA-approved belimumab for lupus nephritis based on Trial 5, which demonstrated that belimumab 10 mg/kg IV plus standard therapy achieved significantly higher rates of Primary Efficacy Renal Response at Week 104 (43% vs 32%, OR 1.6, p=0.031) and Complete Renal Response (30% vs 20%, OR 1.7, p=0.017) compared to placebo plus standard therapy 3

Common Pitfalls to Avoid

Do not use azathioprine or leflunomide as first-line therapy for proliferative lupus nephritis, as these alternatives are associated with inferior efficacy, increased rate of disease flares, and/or increased drug toxicities 1

Do not delay treatment while awaiting biopsy results if clinical suspicion is high, but immunosuppressive treatment should ultimately be guided by diagnostic renal biopsy 1

Do not continue ineffective therapy beyond 6-12 months without reassessing and switching regimens 1