Steroid-Sparing Agents in IgA Nephropathy
In Chinese patients with IgA nephropathy, mycophenolate mofetil (MMF) can be used as a glucocorticoid-sparing agent, while hydroxychloroquine may also be considered; however, there is insufficient evidence to support the use of these agents in non-Chinese populations. 1
Evidence-Based Recommendations by Ethnicity
For Chinese Patients
The KDIGO 2025 guidelines explicitly state that mycophenolate mofetil can be considered as a glucocorticoid-sparing agent in Chinese patients, where controlled trials have been conducted 1. Additionally, hydroxychloroquine may be considered in this population, though the evidence remains limited 1.
Meta-analyses support this approach, showing that MMF increases partial or complete proteinuria remission compared to steroids alone (RR 2.19,95% CI 1.25-3.85) 2. Recent network meta-analyses confirm MMF's efficacy in reducing proteinuria, though it ranks lower than combination therapies 3.
For Non-Chinese Patients
There is insufficient evidence to recommend MMF or hydroxychloroquine as steroid-sparing agents in non-Chinese ethnicities 1. This represents a critical limitation in the current evidence base and reflects the need for ethnicity-specific treatment considerations.
Agents NOT Recommended as Steroid-Sparing Options
The KDIGO 2025 guidelines explicitly state that the following should NOT be used for IgA nephropathy treatment 1:
- Azathioprine
- Cyclophosphamide (except in rapidly progressive IgAN)
- Calcineurin inhibitors
- Rituximab
- Antiplatelet agents
- Anticoagulants
- Fish oil
Despite older meta-analyses suggesting potential benefits of azathioprine 2, 4, the most recent and authoritative KDIGO 2025 guidelines do not support its use 1.
Alternative Approaches to Reduce Steroid Exposure
Targeted-Release Budesonide (Nefecon)
Where approved, a 9-month course of Nefecon is suggested for patients at risk of progressive kidney function loss (KDIGO Recommendation 1.4.3.1, Grade 2B) 1. This targeted ileal-release formulation provides immunosuppression at the mucosal level with reduced systemic steroid exposure, achieving 40-50% proteinuria reduction 5.
Reduced-Dose Systemic Glucocorticoid Regimen
When Nefecon is unavailable, use methylprednisolone 0.4 mg/kg/day (maximum 32 mg/day) for 2 months, then taper by 4 mg/day monthly for 6-9 months total, combined with antimicrobial prophylaxis against Pneumocystis jirovecii 1.
Non-Immunosuppressive Alternatives
These agents reduce the need for high-dose steroids by addressing different disease mechanisms 1, 6:
- Sparsentan (dual endothelin-angiotensin receptor antagonist): Replaces RAS inhibitors, not added to them
- SGLT2 inhibitors: Provide renal protection independent of immunosuppression
- Optimized RAS blockade: Maximally tolerated ACE inhibitor or ARB doses
Critical Caveats
Ethnicity matters: The steroid-sparing evidence for MMF and hydroxychloroquine is specific to Chinese populations and cannot be extrapolated to other ethnicities 1
Avoid contraindicated combinations: Do not use azathioprine, calcineurin inhibitors, or rituximab as steroid-sparing agents despite older literature suggesting potential benefits 1
Risk stratification is essential: Steroid-sparing approaches should only be considered in patients at risk of progressive kidney function loss with proteinuria >0.5 g/day 1, 6
Geographic availability: Nefecon and sparsentan availability varies by region, necessitating alternative strategies where these agents are not approved 1