What is the recommended management for IgA nephropathy?

Management of IgA Nephropathy

All patients with IgA nephropathy and proteinuria >0.5 g/day should receive optimized supportive care with ACE inhibitors or ARBs, blood pressure control to <120/70 mmHg, SGLT2 inhibitors, and consideration of targeted immunosuppression based on risk stratification after 3-6 months of maximal supportive therapy. 1, 2

Initial Risk Assessment and Supportive Care Foundation

Baseline Evaluation

• Quantify proteinuria at diagnosis and monitor during follow-up 1
• Assess eGFR and blood pressure as primary prognostic markers 1
• High-risk progression is defined as proteinuria >0.75-1 g/day despite ≥90 days of optimized supportive care 1
• Treatment target is proteinuria reduction to <1 g/day 1

First-Line Supportive Care (All Patients)

Renin-Angiotensin System Blockade:

• Use ACE inhibitor or ARB (not both) as first-line therapy when proteinuria ≥1 g/day 1
• Consider ACE inhibitor or ARB if proteinuria is 0.5-1 g/day 1
• Titrate upward to maximally tolerated dose to achieve proteinuria <1 g/day 1
• Do not use dual ACE inhibitor and ARB therapy due to lack of benefit and hyperkalemia risk 1

Blood Pressure Management:

• Target BP <120/70 mmHg for all patients (updated from older guidelines) 2
• Older guidelines suggested <130/80 mmHg for proteinuria <1 g/day and <125/75 mmHg for proteinuria >1 g/day 1

SGLT2 Inhibitors:

• Add SGLT2 inhibitor to ACE inhibitor/ARB as contemporary supportive care 1, 2, 3, 4
• DAPA-CKD trial showed 36% reduction (hazard ratio 0.64) in primary outcome of 50% eGFR reduction or kidney failure in glomerulonephritis patients 1
• EMPA-KIDNEY trial included >800 IgAN patients with eGFR as low as 20 mL/min 1

Behavioral Modifications:

• Dietary sodium restriction to <2 g/day 1, 2
• Smoking cessation, weight control, regular exercise 2

Duration of Supportive Care Before Escalation

• Provide 3-6 months of optimized supportive care before considering immunosuppression 1
• Reassess proteinuria, eGFR trajectory, and blood pressure control at 3-6 months 1

Immunosuppressive Therapy for High-Risk Patients

Indications for Immunosuppression

Consider immunosuppression if:

• Persistent proteinuria ≥1 g/day despite 3-6 months of optimized supportive care 1
• eGFR ≥50 mL/min/1.73 m² (some guidelines suggest ≥30 mL/min/1.73 m²) 1
• Average proteinuria in trials showing benefit was 2.4 g/day 1

Glucocorticoid Therapy

Recommendation:

• 6-month course of glucocorticoid therapy for high-risk patients meeting above criteria 1
• Italian trial showed 10-year renal survival of 97% vs 53% with corticosteroids vs no immunosuppression 1

Contraindications and Cautions - Avoid or Use Extreme Caution in:

• eGFR <30 mL/min/1.73 m² 1
• Diabetes mellitus 1
• Obesity (BMI >30 kg/m²) 1
• Latent infections (viral hepatitis, tuberculosis, HIV) 1
• Secondary disease (liver cirrhosis) 1
• Active peptic ulceration 1
• Uncontrolled psychiatric disease 1
• Severe osteoporosis 1
• Advanced age 1
• Metabolic syndrome 1

Regimens:

• IV methylprednisolone 1 g for 3 days, followed by oral prednisone 0.8-1 mg/kg/day for 2 months, then taper by 0.2 mg/kg/day per month for 4 months 1
• Meta-analysis suggests shorter-term high-dose therapy (prednisone ≥30 mg/day or high-dose pulse IV methylprednisolone with duration <1 year) may be more effective 1

Important Caveat:

• TESTING trial showed efficacy but with significant treatment-associated morbidity and mortality 1
• Adverse effects are more likely with eGFR <50 mL/min/1.73 m² 1
• Detailed risk-benefit discussion required with each patient 1

Novel Immunosuppressive Therapies

Targeted-Release Budesonide (Nefecon):

• Approved therapy targeting gut-associated lymphoid tissue 2, 3, 4, 5
• Reduces formation of IgA-containing immune complexes 2
• Consider as alternative to systemic glucocorticoids 2, 3, 4

Complement Inhibition:

• Iptacopan (complement factor B inhibitor) - approved therapy 2, 3
• Decreases immune complex-mediated glomerular injury 2, 4

Dual Endothelin-Angiotensin Receptor Blockade:

• Sparsentan - approved therapy 2, 3, 4
• Can be used alone or in combination with SGLT2 inhibitor 2
• Manages IgAN-induced nephron loss 2

Therapies NOT Recommended

Do NOT Use:

• Mycophenolate mofetil (MMF) in non-Chinese patients 1
  • Exception: May use as glucocorticoid-sparing agent in Chinese patients 1
• Cyclophosphamide (except in crescentic IgAN) 1
• Azathioprine (except in crescentic IgAN) 1
• Calcineurin inhibitors 1
• Rituximab 1
• Antiplatelet agents 1
• Tonsillectomy in non-Japanese patients 1
  • Exception: Consider in Japanese patients 1

Fish Oil:

• Weak recommendation for persistent proteinuria ≥1 g/day despite optimized supportive care 1

Special Clinical Presentations

IgAN with Minimal Change Disease Features

• Treat as minimal change disease with corticosteroids 1
• Nephrotic patients showing MCD pathology with mesangial IgA deposits require MCD treatment protocol 1

Crescentic IgAN (Rapidly Progressive)

Definition:

• Crescents in >50% of glomeruli with rapidly progressive renal deterioration 1

Treatment:

• Use steroids and cyclophosphamide analogous to ANCA vasculitis treatment 1
• This is the ONLY indication for cyclophosphamide in IgAN 1

IgAN with Acute Kidney Injury from Macroscopic Hematuria

• Provide general supportive care if biopsy shows only acute tubular necrosis and intratubular erythrocyte casts 1
• Perform repeat kidney biopsy if no improvement after 5 days from onset 1

Nephrotic Syndrome in IgAN

• May reflect coexistent secondary FSGS (obesity, uncontrolled hypertension) or extensive glomerulosclerosis 1
• Manage as high-risk IgAN if mesangioproliferative features present 1

Clinical Trial Consideration

All high-risk patients should be offered enrollment in clinical trials given current uncertainty over safety and efficacy of existing immunosuppressive options 1

Monitoring and Dynamic Risk Assessment

• Perform dynamic assessment of patient risk over time 1
• Decisions regarding immunosuppression may change based on response to supportive care 1
• Monitor proteinuria, eGFR trajectory, blood pressure, and microscopic hematuria 1
• Oxford Classification MEST-C score has insufficient evidence for determining immunosuppression initiation 1
• Presence and number of crescents insufficient for treatment decisions alone 1

Contemporary Treatment Paradigm

The modern approach combines therapies targeting different mechanisms: 3, 4

1. Immune components: Targeted-release budesonide, complement inhibitors, B-cell targeted strategies
2. CKD progression: SGLT2 inhibitors, sparsentan, RAS blockade
3. Risk-stratified approach: Induction phase for active disease, maintenance phase for chronic management 6