Treatment of IgA Nephropathy
The cornerstone of IgA nephropathy treatment is optimized supportive care with RAS blockade for all patients with proteinuria >0.5 g/day, followed by consideration of a 6-month glucocorticoid course only in high-risk patients (proteinuria >0.75-1 g/day after 90 days of maximal supportive care and eGFR ≥30 mL/min/1.73 m²), though emerging therapies like SGLT2 inhibitors and targeted-release budesonide are rapidly expanding treatment options. 1
Initial Assessment and Risk Stratification
After biopsy-confirmed diagnosis with MEST-C histologic scoring, assess disease prognosis using clinical parameters rather than histology alone, as neither the MEST-C score nor crescent presence can currently predict treatment response. 1 The International IgAN Prediction Tool provides prognostic information but cannot determine the impact of specific treatment regimens. 1
First-Line: Optimized Supportive Care (All Patients)
RAS Blockade:
- Institute ACE inhibitor or ARB therapy for all patients with proteinuria >0.5 g/day, regardless of hypertension status (Grade 1B). 1
- Maximize the tolerated dose before considering additional therapies. 1
- Do not use dual ACE inhibitor and ARB therapy due to lack of benefit and hyperkalemia risk. 1
Blood Pressure Targets:
Lifestyle Modifications:
- Restrict dietary sodium to <2.0 g/day (<90 mmol/day). 1
- Implement smoking cessation, weight control, and regular exercise. 1
- Consider dietary protein restriction based on proteinuria degree and kidney function. 1
Cardiovascular Risk Management:
- Address all modifiable cardiovascular risk factors. 1
- Consider statin therapy based on lipid levels and cardiovascular risk. 1
Duration: Maintain optimized supportive care for at least 90 days before considering immunosuppression. 1
Second-Line: Glucocorticoid Therapy (High-Risk Patients Only)
Indications:
- Proteinuria persisting at >0.75-1 g/day despite ≥90 days of optimized supportive care. 1
- eGFR ≥30 mL/min/1.73 m² (Grade 2B). 1
Absolute Contraindications to Glucocorticoids:
- eGFR <30 mL/min/1.73 m² (unless rapidly progressive crescentic disease). 1
- Diabetes mellitus. 1
- Obesity (BMI >30 kg/m²). 1
- Latent infections (viral hepatitis, tuberculosis). 1
- Secondary disease (liver cirrhosis). 1
- Active peptic ulceration. 1
- Uncontrolled psychiatric disease. 1
- Severe osteoporosis. 1
Important Caveats:
- The clinical benefit of glucocorticoids in IgAN is not definitively established. 1
- Adverse treatment effects are more likely with eGFR <50 mL/min/1.73 m². 1
- Recent trials have raised concerns about infectious and metabolic toxicity from systemic corticosteroids. 4
- Proteinuria frequently recurs after corticosteroid cessation. 3
- A detailed risk-benefit discussion must occur with each patient before initiating therapy. 1
Treatment Goal:
- Reduce proteinuria to <1 g/day, which serves as a surrogate marker for improved kidney outcomes. 1
Emerging and Approved Therapies
SGLT2 Inhibitors:
- Consider adding to RAS blockade based on evidence from DAPA-CKD and EMPA-KIDNEY trials, which included patients with glomerulonephritis and showed significant reduction in kidney failure risk. 1
- Can be used in patients with eGFR as low as 20 mL/min. 1
Targeted-Release Budesonide (Nefecon):
- Recently received FDA accelerated approval for primary IgA nephropathy with UPCR >1.5 g/g. 5
- Targets gut-associated lymphoid tissue with reduced systemic exposure compared to oral corticosteroids. 6
Other Investigational Agents:
- Sparsentan (dual endothelin-1 and angiotensin II receptor blocker). 1, 6
- Iptacopan (complement factor B inhibitor). 6
- Various complement inhibitors and B-cell targeting therapies. 1
Therapies NOT Recommended for Routine Use
The following immunosuppressive agents are not recommended in IgAN: 1
- Azathioprine (except after cyclophosphamide in crescentic disease). 1
- Cyclophosphamide (except in rapidly progressive IgAN). 1
- Calcineurin inhibitors. 1
- Rituximab. 1
- Mycophenolate mofetil in non-Chinese patients. 1
Special Clinical Scenarios
Rapidly Progressive/Crescentic IgAN (>50% crescents with rapid GFR decline):
- Use glucocorticoids plus cyclophosphamide as aggressive immunosuppression. 1, 3
- This is the only scenario where cyclophosphamide is recommended. 1
Population-Specific Considerations:
- Chinese patients: May use mycophenolate mofetil as a glucocorticoid-sparing agent. 1
- Japanese patients: May consider tonsillectomy in select cases. 1
- These recommendations do not apply to other populations. 1
IgAN with Minimal Change Disease Pattern:
- Treat as minimal change disease with corticosteroids. 1
IgAN with AKI and Macroscopic Hematuria:
- Provide supportive care if biopsy shows only acute tubular necrosis and intratubular erythrocyte casts. 1
- Perform repeat biopsy if no improvement after 5 days. 1
Monitoring and Treatment Targets
Proteinuria Goals:
- 25% reduction by 3 months. 3
- 50% reduction by 6 months. 3
- <1 g/day by 12 months (complete clinical response). 1, 3
Regular Monitoring:
- Track proteinuria, blood pressure, and eGFR to assess treatment response. 5
- A 40% or greater decline in eGFR over 2-3 years represents a surrogate outcome for kidney failure. 1
Critical Clinical Pitfalls to Avoid
- Never initiate glucocorticoids without an adequate trial (90 days minimum) of optimized supportive care. 1, 3
- Never use glucocorticoids in patients with eGFR <30 mL/min/1.73 m² unless rapidly progressive crescentic disease is present. 1, 3
- Never overlook infection prophylaxis (including pneumocystis prophylaxis) during high-dose steroid therapy. 3
- Never use NSAIDs in IgAN patients, as they worsen kidney function and interfere with ACE inhibitor/ARB efficacy. 2
- Never fail to counsel patients about the uncertain long-term benefit and high recurrence rate after glucocorticoid discontinuation. 3
Clinical Trial Enrollment
All patients who remain at high risk despite maximal supportive care should be offered enrollment in clinical trials, as this is the preferred approach given the evolving evidence base and availability of novel targeted therapies. 1