What is the current standard of care for treating lupus nephritis?

Current Standard of Care for Lupus Nephritis

The 2024 KDIGO guidelines establish mycophenolic acid analogs (MPAA) combined with glucocorticoids as the preferred first-line induction therapy for proliferative lupus nephritis (Class III/IV), followed by MPAA maintenance therapy for at least 36 months total duration. 1

Initial (Induction) Therapy for Proliferative Lupus Nephritis

First-Line Standard Regimen

MPAA-based therapy is the primary recommendation:

• Mycophenolate mofetil (MMF) 1.0-1.5 g twice daily OR mycophenolic acid (MPA) 0.72-1.08 g twice daily 2
• Combined with glucocorticoids: IV methylprednisolone pulses followed by oral prednisone 0.3-0.5 mg/kg/day, tapering to <5 mg/day by week 25 1, 2
• Duration: 6 months of induction therapy 1

Alternative First-Line Options

The 2024 KDIGO guidelines recognize four equally acceptable initial regimens 2:

Low-dose IV cyclophosphamide:

• 500 mg every 2 weeks for 6 doses (total 3 grams) 1, 2
• Preferred when adherence to oral medications is a concern 1
• Should be avoided in patients at high risk for infertility 1

Triple therapy with belimumab:

• Belimumab 10 mg/kg IV every 2 weeks for 3 doses, then every 4 weeks 2
• Combined with either MPAA or reduced-dose cyclophosphamide plus glucocorticoids 1
• Preferred for patients with repeated kidney flares or high risk for progression to kidney failure 1
• FDA-approved based on Trial 5 showing 43% achieved primary efficacy renal response at Week 104 versus 32% with placebo (OR 1.6,95% CI 1.0-2.3, p=0.031) 3

Calcineurin inhibitor (CNI) combination:

• Voclosporin 23.7 mg twice daily, tacrolimus, or cyclosporine 1, 2
• Combined with MPAA and glucocorticoids 1
• Preferred when eGFR >45 mL/min/1.73 m² with nephrotic-range proteinuria likely from podocyte injury 1, 2
• Also preferred for patients intolerant to standard-dose MPAA or unsuitable for cyclophosphamide 1

Special Populations

High infertility risk patients:

• MPAA-based regimen is strongly preferred over cyclophosphamide 1
• Applies to those with moderate-to-high prior cyclophosphamide exposure 1

Adherence concerns:

• IV cyclophosphamide preferred over oral regimens 1

Maintenance Therapy

MPAA is the recommended maintenance agent (Grade 1B) 1:

• MMF 750-1000 mg twice daily OR MPA 540-720 mg twice daily 1, 2
• Total duration of induction plus maintenance should be ≥36 months 1

Azathioprine as alternative:

• 1-2 mg/kg/day for patients who cannot tolerate MPAA, lack access to MPAA, or are planning pregnancy 1, 2
• However, azathioprine probably increases disease relapse compared to MMF (RR 1.75,95% CI 1.20-2.55) 4

Glucocorticoid management during maintenance:

• Taper to lowest possible dose, ideally <7.5 mg/day 1
• Discontinuation can be considered after maintaining complete clinical renal response for ≥12 months 1
• Exception: continue if needed for extrarenal lupus manifestations 1

Triple therapy continuation:

• Patients started on belimumab or CNI-based triple regimens can continue these as maintenance 1

Treatment Response Assessment

Complete response (target outcome):

• Proteinuria <0.5 g/g (50 mg/mmol) on protein-creatinine ratio 1, 2
• Stabilization or improvement in kidney function (±10-15% of baseline) 1
• Achieved within 6-12 months, though may take >12 months 1
• This target provides best long-term prognosis 2

Partial response:

• ≥50% reduction in proteinuria to <3 g/g (300 mg/mmol) 1, 2
• Stabilization or improvement in kidney function 1
• Within 6-12 months of starting therapy 1

No response:

• Failure to achieve partial or complete response within 6-12 months 1

Management of Inadequate Response

Systematic approach when response is unsatisfactory 1:

1. Verify medication adherence 1
2. Ensure adequate dosing by measuring plasma drug levels (mycophenolic acid levels if on MPAA; check infusion records for cyclophosphamide) 1
3. Repeat kidney biopsy if concern for chronicity or alternative diagnosis (e.g., thrombotic microangiopathy) 1
4. Switch to alternative recommended regimen when persistent active disease present 1
5. Consider for refractory disease 1:
   • Addition of rituximab or other biologic therapies 1
   • Extended course of IV pulse cyclophosphamide 1
   • Enrollment in clinical trials if eligible 1

Essential Adjunctive Therapies

Renal protection:

• ACE inhibitors or ARBs for all patients 2
• SGLT2 inhibitors recommended 2

Hydroxychloroquine:

• Recommended for all patients with regular ophthalmological monitoring 1

Infection prophylaxis:

• Screen for HBV, HCV, HIV 2
• Vaccinate for hepatitis B 2

Bone protection:

• Assess bone mineral density 2
• Calcium and vitamin D supplementation 2

Fertility preservation:

• Gonadotropin-releasing hormone agonists 2
• Sperm/oocyte cryopreservation for patients of childbearing age 2

Key Clinical Considerations

The 2024 KDIGO guidelines represent a significant evolution from previous standards, expanding first-line options beyond the traditional MMF versus cyclophosphamide debate to include triple therapy regimens with belimumab and CNI-based combinations 1, 2. This reflects emerging evidence that different patient phenotypes may benefit from tailored initial approaches rather than a one-size-fits-all strategy.

Common pitfall: Using high-dose cyclophosphamide when low-dose regimens are equally effective with less toxicity. The Euro-Lupus low-dose protocol (500 mg every 2 weeks × 6 doses) has replaced older high-dose regimens 1.

Important caveat: While MMF may increase complete disease remission compared to IV cyclophosphamide (RR 1.17,95% CI 0.97-1.42), it also causes more diarrhea (RR 2.42) but less alopecia (RR 0.29) 4. The certainty of evidence remains low to moderate for many comparisons 4.