What is the recommended treatment protocol for proliferative lupus nephritis (ISN/RPS class III, IV or mixed)?

Treatment Protocol for Proliferative Lupus Nephritis (ISN/RPS Class III, IV, or Mixed)

For proliferative lupus nephritis (class III, IV, or mixed), initiate glucocorticoids combined with either mycophenolate mofetil (2–3 g/day) or low-dose intravenous cyclophosphamide (500 mg every 2 weeks × 6 doses) as first-line induction therapy, followed by mycophenolate maintenance for at least 36 months. 1

Induction Therapy (First 6 Months)

Glucocorticoid Regimen

• Start with intravenous methylprednisolone 500–1000 mg daily for 3 consecutive days, followed immediately by oral prednisone. 1
• Begin oral prednisone at 0.5–1.0 mg/kg/day (maximum 80 mg/day) and taper aggressively to <5 mg/day by week 25. 1
• The 2021 KDIGO guidelines represent a major shift toward glucocorticoid-sparing protocols compared to the 2012 recommendations, which allowed higher doses for longer durations. 1

Immunosuppressive Agent Selection (Choose One)

Mycophenolate Mofetil (MMF) – Preferred for Most Patients

• Dose: 2–3 g/day divided twice daily for 6 months. 1
• Superior efficacy in African-American and Hispanic patients compared to cyclophosphamide. 2
• Preferred when fertility preservation is a priority because it avoids cyclophosphamide's gonadotoxicity. 2
• Better safety profile regarding infections and leukopenia compared to high-dose cyclophosphamide. 2, 3

Low-Dose Intravenous Cyclophosphamide (Euro-Lupus Regimen) – Alternative

• Dose: 500 mg IV every 2 weeks for 6 doses (total ≈3 g over 3 months). 1, 2
• Select when adherence to oral medications is uncertain, as IV administration guarantees compliance. 2
• Efficacy equivalent to older high-dose NIH protocol but with markedly reduced toxicity (fewer infections, less leukopenia). 2
• Validation primarily in Caucasian (Western/Southern European) populations; comparative data for non-Caucasian groups are lacking. 2
• Avoid as first-line in patients desiring future fertility without prior cyclophosphamide exposure. 2

Emerging Options (Not Yet Standard First-Line)

• Voclosporin (23.7 mg twice daily) plus MMF: FDA-approved in 2021 for active LN (classes III, IV, V, mixed) with significantly glucocorticoid-sparing benefits. 1
• Belimumab (10 mg/kg IV every 2 weeks × 3 doses, then every 4 weeks) plus MMF or cyclophosphamide: Consider for patients with repeated kidney flares or high risk for progression. 2, 4, 5
• Multitarget therapy (tacrolimus + MMF + glucocorticoids): Shows good efficacy in Asian cohorts but limited validation in diverse populations. 1, 6

Mandatory Adjunctive Therapy During Induction

• Hydroxychloroquine ≤5 mg/kg/day (typically 200–400 mg daily) for all patients unless contraindicated—reduces flare rates, decreases organ damage, and enhances immunosuppression responsiveness. 1, 4
• ACE inhibitor or ARB for proteinuria control and blood pressure management. 1, 4
• Infection prophylaxis: Screen for hepatitis B, hepatitis C, HIV, and tuberculosis; provide Pneumocystis jirovecii prophylaxis; consider recombinant zoster vaccination. 1, 2
• Fertility preservation: Women should receive gonadotropin-releasing hormone agonists (e.g., leuprolide) around cyclophosphamide exposure; men should consider sperm banking. 1, 2
• Bone protection: Supplement calcium and vitamin D; add bisphosphonates when indicated by bone-density assessment. 1, 2

Response Assessment and Treatment Adjustment

Early Milestones

• 8-week milestone: ≥25% reduction in proteinuria and/or normalization of complement C3/C4 predicts favorable response. 2
• 3-month milestone: If proteinuria increases ≥50% or serum creatinine rises, switch to alternative therapy or obtain repeat kidney biopsy. 2, 4
• 6-month milestone: Continue induction for the full 6 months unless clear clinical deterioration occurs. 2
• Approximately 50% of patients achieve definite improvement by 6 months, rising to 65–80% by 12–24 months. 2

Response Definitions

• Complete response: Proteinuria <0.5 g/g (≈50 mg/mmol) with stable or improved kidney function (within ±10–15% of baseline eGFR). 2, 4
• Partial response: ≥50% reduction in proteinuria to subnephrotic levels (<3 g/g) with stable or improved kidney function. 1, 2

Maintenance Therapy (After Achieving Response)

Agent Selection

• Mycophenolate mofetil 1.5–2 g/day (or 750–1000 mg twice daily) is the preferred maintenance agent. 2, 4
• Associated with fewer renal relapses compared to azathioprine. 2
• Superior safety profile relative to continued cyclophosphamide, especially regarding gonadotoxicity. 2

Alternative Maintenance

• Azathioprine 1–2 mg/kg/day may be used when MMF is intolerable, unavailable, or contraindicated (e.g., pregnancy planning). 1, 2, 4
• Higher relapse rates compared to MMF but provides comparable renal-function preservation. 2

Duration and Glucocorticoid Management

• Continue maintenance for a minimum of 3–5 years to reduce the high risk of relapse (typically occurs within 5–6 years). 2
• Taper prednisone to ≤5–7.5 mg/day, aiming for complete withdrawal when disease control permits. 1, 2
• Continue hydroxychloroquine and ACE inhibitor/ARB indefinitely. 2, 4

Management of Refractory or Relapsing Disease

• Verify medication adherence first—non-adherence is the most common cause of apparent treatment failure, especially in young women experiencing steroid side effects. 2
• Switch from MMF to cyclophosphamide, or vice versa, for documented treatment failure. 4
• Add rituximab for refractory disease after failure of standard immunosuppression. 2
• Consider repeat kidney biopsy to evaluate for histologic class change or development of thrombotic microangiopathy. 4

Special Considerations

Class III+V or IV+V (Mixed Proliferative and Membranous)

• Treat according to the proliferative component using the same algorithm as pure class III/IV disease, since the proliferative lesions drive management decisions. 7
• CNI-based regimen (voclosporin + MMF) deserves strong consideration when eGFR >45 mL/min/1.73 m² with heavy proteinuria, as it directly addresses podocyte dysfunction. 7

Severe Nephritic Features

• Prefer cyclophosphamide for patients with rapid GFR decline, >25% of glomeruli showing crescents/necrosis, or acute deterioration in renal function. 1, 2
• Higher initial glucocorticoid doses (up to 1.0 mg/kg/day) may be used in severe renal or extra-renal lupus. 1

Active Tuberculosis

• Delay intensive immunosuppression for 2–4 weeks after starting anti-tuberculosis therapy. 4
• Avoid cyclophosphamide during active TB—it raises serious infection risk approximately six-fold. 4
• Use reduced-dose glucocorticoid protocol (start at 0.3–0.4 mg/kg/day, taper to ≤10 mg/day by month 4). 4

Critical Pitfalls to Avoid

• Premature switching of therapy: Continue induction for the full 6 months unless clear worsening occurs; most responders emerge by 12–24 months. 2
• Inadequate glucocorticoid taper: Failure to reduce steroids below 7.5 mg/day by 3–6 months contributes to organ-damage accumulation. 2
• Using high-dose cyclophosphamide unnecessarily: The Euro-Lupus low-dose regimen (≈3 g total) provides equivalent efficacy with superior safety. 2
• Omitting hydroxychloroquine: This foundational therapy reduces flares, prevents organ damage, and markedly lowers mortality in SLE. 2
• Excessive cumulative cyclophosphamide exposure: Limit lifetime exposure to <36 g to reduce malignancy and infertility risk. 1, 2
• Premature discontinuation of maintenance therapy: Stopping before 36 months increases relapse risk. 4
• Delaying kidney biopsy: Can lead to undertreatment and irreversible kidney damage. 4

Monitoring Protocol

Intensive Early Phase (First 2–4 Months)

• Every 2–4 weeks: Serum creatinine, eGFR, urinalysis with microscopy, urine protein-to-creatinine ratio, complement C3/C4, anti-dsDNA antibodies, complete blood count, blood pressure, and weight. 7
• Monthly neutrophil counts during IV cyclophosphamide therapy (versus weekly for oral formulations). 2

Maintenance Phase

• Every 3 months: Same parameters as intensive phase but less frequently once stable response achieved. 7