Comprehensive Therapy for IgA Nephropathy
Foundation: Optimized Supportive Care (First-Line for All Patients)
All patients with IgA nephropathy must receive optimized supportive care as the cornerstone of management, with RAS blockade initiated for any patient with proteinuria >0.5 g/day regardless of blood pressure status. 1
Core Supportive Measures
- ACE inhibitors or ARBs are mandatory first-line therapy for proteinuria >0.5 g/day, even in normotensive patients (Grade 1B recommendation) 1
- Blood pressure targets: Aim for 125/75 mmHg in patients with proteinuria >1 g/day 2
- SGLT2 inhibitors should be added to ACE/ARB therapy based on compelling evidence from DAPA-CKD and EMPA-KIDNEY trials, which showed significant kidney protection in glomerulonephritis patients 1
- Dietary sodium restriction to <2.0 g/day (<90 mmol/day) 1
- Cardiovascular risk management including lipid control, smoking cessation, weight optimization, and regular exercise 1
Critical caveat: Dual ACE inhibitor and ARB therapy provides no additional benefit and increases hyperkalemia risk—avoid this combination 1
Second-Line: Immunosuppressive Therapy for High-Risk Patients
Patient Selection Criteria
Consider immunosuppression only when proteinuria remains >0.75-1 g/day after at least 90 days of maximally optimized supportive care. 1
Systemic Corticosteroids (Traditional Approach)
- 6-month course of glucocorticoids may be considered (Grade 2B) for high-risk patients with eGFR ≥30 mL/min/1.73 m² 1
- Absolute contraindications where glucocorticoids should be avoided entirely: 1
- eGFR <30 mL/min/1.73 m²
- Diabetes mellitus
- Obesity (BMI >30 kg/m²)
- Latent infections (hepatitis B/C, tuberculosis, HIV)
- Liver cirrhosis
- Active peptic ulceration
- Uncontrolled psychiatric disease
- Severe osteoporosis
Important limitation: The TESTING trial showed efficacy in reducing proteinuria (average 2.4 g/day at baseline) but at the expense of significant treatment-associated morbidity and mortality from infections 1, 3
Targeted-Release Budesonide (Preferred Immunosuppressive Option)
Budesonide (nefecon) is now FDA-approved and represents a safer alternative to systemic corticosteroids with significantly fewer serious adverse events. 3, 2
- Indication: Primary IgA nephropathy with UPCR >1.5 g/g despite optimized supportive care 3
- Efficacy: Reduces proteinuria by 34% at 9 months 3
- Safety advantage: Targets gut-associated lymphoid tissue with minimal systemic exposure, avoiding the severe infectious complications seen with systemic steroids 3, 4
- Monitoring protocol: 3
- Target 50% proteinuria reduction by 6 months
- Target <1 g/day proteinuria by 12 months
- Monitor proteinuria every 3 months
- Monitor eGFR every 3-6 months
Other Immunosuppressive Agents (Limited Indications)
Not Recommended for Routine Use
The following agents are explicitly NOT recommended for general IgAN management: 1, 2
- Azathioprine: No benefit demonstrated 1
- Calcineurin inhibitors (CNIs): Not recommended 1
- Rituximab: Not recommended 1
- Cyclophosphamide: Reserved ONLY for rapidly progressive IgAN with extensive crescents (>50% of glomeruli) and declining GFR 1, 2
Population-Specific Exceptions
- Mycophenolate mofetil (MMF): May be used as a glucocorticoid-sparing agent in Chinese patients only at 1.5 g/day for proteinuria >1 g/day with active histologic features 1, 3, 2
- Tonsillectomy: May be considered in Japanese patients only 1, 2
Emerging and Novel Therapies Currently in Development
FDA-Approved Novel Agents
- Sparsentan: Dual endothelin-1 and angiotensin II receptor blocker, now approved 1, 5
- Iptacopan: Complement factor B inhibitor, recently approved 5
Therapies Under Active Investigation
Multiple novel agents are in clinical trials targeting different pathogenic mechanisms: 1
- Complement inhibitors: Various agents targeting the complement cascade 1
- Atrasentan: Endothelin receptor antagonist 1
- Hydroxychloroquine: Being evaluated for immunomodulation 1
- B-cell targeting therapies: Agents targeting B-cell development and BAFF (B-cell activating factor crucial for IgA synthesis) 1, 4
Special Clinical Situations
Rapidly Progressive IgAN
For patients with extensive crescent formation (>50% of glomeruli) and rapidly declining GFR, use cyclophosphamide plus glucocorticoids immediately. 1, 2
IgAN with Minimal Change Disease Features
Treat according to minimal change disease protocols, not standard IgAN management. 1
Nephrotic-Range Proteinuria
Manage as high-risk IgAN if mesangioproliferative features are present; if secondary FSGS features predominate, address underlying causes (obesity, hypertension). 1
Treatment Goals and Monitoring Strategy
Primary Treatment Target
Reduce proteinuria to <1 g/day—this serves as a validated surrogate marker for improved kidney outcomes. 1, 2
Monitoring Schedule
Clinical Trial Enrollment
All high-risk patients who remain at risk despite maximal supportive care should be offered enrollment in clinical trials whenever available. 1
Practical Treatment Algorithm
All patients: Start optimized supportive care (ACE/ARB + SGLT2 inhibitor, BP control, lifestyle modifications) 1
After 90 days: Reassess proteinuria 1
- If <0.75 g/day: Continue supportive care only
- If ≥0.75-1 g/day: Patient is high-risk, proceed to step 3
High-risk patients with eGFR ≥30 mL/min/1.73 m²: 1, 3
- First choice: Targeted-release budesonide (if UPCR >1.5 g/g)
- Alternative: 6-month systemic corticosteroid course (only if no contraindications)
- Best option: Enroll in clinical trial
- Chinese patients: Consider MMF as steroid-sparing agent
- Japanese patients: Consider tonsillectomy
- Rapidly progressive disease: Immediate cyclophosphamide + glucocorticoids