Advances in IgA Nephropathy Treatment and Treatment Decision Algorithms
All patients with IgAN and proteinuria ≥0.5 g/day should immediately start ACE inhibitor or ARB therapy, and those with persistent proteinuria ≥0.75-1 g/day after 90 days of optimized supportive care should add SGLT2 inhibitors, with targeted-release budesonide or complement inhibitors reserved for high-risk patients with eGFR ≥30 mL/min/1.73 m².
Initial Risk Stratification
At diagnosis, assess three key parameters to determine treatment intensity:
- Proteinuria level (24-hour urine or spot protein-to-creatinine ratio) 1
- eGFR to establish baseline kidney function 1
- Blood pressure as both a risk factor and treatment target 1
Dynamic reassessment every 3 months is critical, as risk profiles change with treatment 1. The Oxford MEST-C score provides prognostic information but should not dictate immunosuppression decisions 1.
Treatment Algorithm: Stepwise Approach
Step 1: Universal Supportive Care (All Patients)
Lifestyle modifications form the foundation:
- Dietary sodium restriction 1
- Smoking cessation 1
- Weight control and regular exercise 1
- Avoid nephrotoxins 2
No other specific dietary interventions (including protein restriction in early disease) have proven benefit 1.
Step 2: RAS Blockade (Proteinuria ≥0.5 g/day)
Initiate ACE inhibitor or ARB immediately when proteinuria exceeds 0.5 g/day 1, 3:
- Strong recommendation (1B evidence) for proteinuria ≥1 g/day 1
- Weaker recommendation (2D evidence) for proteinuria 0.5-1 g/day 1, 3
- Titrate upward to maximally tolerated dose targeting proteinuria <1 g/day 1, 3
Blood pressure targets:
Critical pitfall: The 2012 KDIGO guidelines recommended starting RAS blockade only at proteinuria ≥1 g/day, but the 2021 update lowered this threshold to 0.5 g/day—do not delay treatment 1.
Avoid dual ACE inhibitor/ARB therapy: The STOP-IgAN trial showed no additional benefit and increased hyperkalemia risk 1.
Step 3: Add SGLT2 Inhibitor (Major Advance)
After maximizing RAS blockade, add an SGLT2 inhibitor for patients with persistent proteinuria:
- The DAPA-CKD trial included 695 patients with glomerulonephritis (16% of cohort) and demonstrated a 36% reduction (HR 0.64) in the composite outcome of 50% eGFR decline or kidney failure when dapagliflozin was added to ACE inhibitor/ARB 1
- EMPA-KIDNEY included >800 patients with IgAN and showed benefit even with eGFR as low as 20 mL/min/1.73 m² 1
This represents a paradigm shift: SGLT2 inhibitors should now be considered standard supportive care alongside RAS blockade 1, 4, 5.
Implementation barrier: Insurance coverage remains inconsistent despite strong evidence 1.
Step 4: Define High-Risk Status After 90 Days
Reassess after 3 months (≥90 days) of optimized supportive care 1:
High-risk criteria = proteinuria ≥0.75-1 g/day despite:
- Maximally tolerated ACE inhibitor or ARB 1
- SGLT2 inhibitor (when available) 1
- Blood pressure at target 1
- Lifestyle modifications 1
Patients meeting high-risk criteria should be offered clinical trial enrollment as first priority 1.
Step 5: Immunosuppression for High-Risk Patients
Eligibility Criteria (ALL must be met):
- Proteinuria ≥1 g/day after ≥90 days optimized supportive care 1
- eGFR ≥50 mL/min/1.73 m² (recommendation strength 2C) 1
- No absolute contraindications 1
First-Line Immunosuppression: Targeted-Release Budesonide (Nefecon)
This represents the most significant recent advance in IgAN-specific therapy:
- The NEFIGAN trial demonstrated proteinuria reduction and eGFR stabilization with targeted delivery to gut-associated lymphoid tissue 6, 5
- Substantially fewer systemic adverse effects compared to systemic corticosteroids 6, 5
- Approved by regulatory agencies based on surrogate endpoints 5
- Should replace systemic corticosteroids as first-line immunosuppression 4, 5
Alternative: Systemic Corticosteroids (if targeted-release budesonide unavailable)
6-month Pozzi protocol (2C evidence) 1, 3:
- IV methylprednisolone 1g for 3 consecutive days at months 1,3, and 5
- PLUS oral prednisone 0.5 mg/kg on alternate days for 6 months
Evidence: An Italian trial showed 10-year renal survival of 97% with corticosteroids versus 53% without immunosuppression 1. However, the TESTING trial demonstrated significant treatment-related morbidity and mortality with high-dose systemic corticosteroids 1.
Absolute Contraindications to Systemic Corticosteroids:
- eGFR <30 mL/min/1.73 m² 1, 7
- Uncontrolled diabetes or metabolic syndrome 1, 7
- Obesity (BMI >30 kg/m²) 1
- Active or latent infections (tuberculosis, hepatitis B/C, HIV) 1, 7
- Severe osteoporosis 1
- Uncontrolled psychiatric disease 1
- Active peptic ulceration 1
Use extreme caution or avoid entirely in these populations 1. Adverse effects are more likely when eGFR <50 mL/min/1.73 m² 1.
Step 6: Emerging Therapies for High-Risk Patients
Several novel agents are now approved or in late-stage development:
Sparsentan (Dual Endothelin/Angiotensin Receptor Blocker):
Iptacopan (Complement Factor B Inhibitor):
- Approved for targeting complement pathway 5
- Represents mechanistic advance beyond traditional immunosuppression 5, 8
Other Investigational Agents:
- Complement inhibitors (various targets) 1, 6, 4, 8
- B-cell targeting therapies (BAFF inhibitors) 6, 4, 8
- Hydroxychloroquine 1
- Atrasentan (endothelin antagonist) 1, 4
The treatment landscape is rapidly evolving toward combination therapy targeting both immune and CKD components simultaneously 5.
Special Clinical Scenarios
Crescentic IgAN (Rapidly Progressive Disease)
Definition: >50% crescents on biopsy with rapidly progressive renal deterioration 1, 3, 7.
Treatment: Aggressive immunosuppression regardless of eGFR 1, 3, 7:
- Corticosteroids PLUS cyclophosphamide 1, 3, 7
- Treat analogously to ANCA-associated vasculitis 1, 3, 7
- This is the ONLY indication for cyclophosphamide in IgAN 1
IgA Deposition with Minimal Change Disease Pattern
Nephrotic syndrome with foot process effacement on electron microscopy:
- Treat as primary minimal change disease with high-dose corticosteroids 1, 3, 7
- Do NOT follow standard IgAN algorithm 1
IgAN with Acute Kidney Injury During Macroscopic Hematuria
- Supportive care if biopsy shows only acute tubular necrosis and intratubular erythrocyte casts 1
- Repeat biopsy if no improvement after 5 days 1
Therapies to AVOID
Strong evidence against the following interventions:
- Mycophenolate mofetil: No benefit in non-Chinese patients (2C recommendation against) 1, 7. May be considered as glucocorticoid-sparing agent in Chinese patients only 1, 7
- Cyclophosphamide or azathioprine combined with corticosteroids: Except for crescentic disease (2D recommendation against) 1, 7
- Calcineurin inhibitors (cyclosporine, tacrolimus): Not recommended 1
- Rituximab: Not recommended 1
- Antiplatelet agents: No benefit (2C recommendation against) 1, 3, 7
- Tonsillectomy: Not recommended in non-Japanese patients (2C recommendation against) 1, 3, 7
- Fish oil: Weak evidence, inconsistent benefit (2D suggestion only) 1, 3
- Any immunosuppression if eGFR <30 mL/min/1.73 m²: Except crescentic disease 1, 7
Monitoring Strategy
Every 3 months during treatment:
For patients on corticosteroids, monitor for:
Proteinuria reduction to <1 g/day is a validated surrogate marker for improved kidney outcomes 1, 3, 7.
Key Paradigm Shifts in Recent Years
Lower threshold for RAS blockade: From ≥1 g/day (2012) to ≥0.5 g/day (2021) 1
SGLT2 inhibitors as standard supportive care: No longer experimental, should be added routinely 1, 4, 5
Targeted-release budesonide replacing systemic corticosteroids: Dramatically improved safety profile 6, 4, 5
Complement inhibitors and novel biologics: Multiple mechanistic targets now available 5, 8
Combination therapy approach: Targeting immune and CKD components simultaneously rather than sequentially 5
Acceptance of surrogate endpoints: Proteinuria and eGFR slope changes over 2-3 years now accepted by regulators, accelerating drug development 5