What is the initial treatment for IgA (Immunoglobulin A) nephropathy?

Initial Treatment for IgA Nephropathy

All patients with IgA nephropathy should begin with optimized supportive care, including ACE inhibitor or ARB therapy for those with proteinuria ≥0.5 g/day, with blood pressure targets of <130/80 mmHg (or <125/75 mmHg if proteinuria ≥1 g/day), before considering any immunosuppressive therapy. 1, 2

Step 1: Risk Stratification at Diagnosis

Begin by assessing the patient's risk of progression through:

• Proteinuria level: Measure 24-hour urine protein or spot urine protein-to-creatinine ratio 1, 2
• Blood pressure: Document baseline blood pressure 1, 2
• Kidney function: Measure eGFR 1, 2
• Cardiovascular risk factors: Assess for diabetes, obesity, smoking, hyperlipidemia 1, 3

Step 2: Initiate Optimized Supportive Care (First-Line for ALL Patients)

Blood Pressure and Proteinuria Management

• Start ACE inhibitor or ARB if proteinuria ≥0.5 g/day, regardless of blood pressure status 1, 2, 3
• Titrate upward to maximally tolerated doses to achieve proteinuria <1 g/day 1, 2
• Target blood pressure <130/80 mmHg if proteinuria <1 g/day 1, 2
• Target blood pressure <125/75 mmHg if proteinuria ≥1 g/day 1, 2
• Do NOT use dual ACE inhibitor and ARB therapy together, as this provides no additional benefit and increases hyperkalemia risk 1

Lifestyle Modifications

• Dietary sodium restriction (the only dietary intervention shown to alter outcomes) 1, 3
• Smoking cessation 1, 3
• Weight control and regular exercise 1, 3
• Maintain high fluid intake 4

Additional Supportive Measures

• Consider SGLT2 inhibitor (dapagliflozin or empagliflozin) added to ACE inhibitor/ARB, based on DAPA-CKD and EMPA-KIDNEY trial data showing 36% reduction in kidney failure risk 1
• Manage hyperlipidemia with statins as indicated 3, 4
• Avoid nephrotoxins (NSAIDs, contrast agents when possible) 4

Step 3: Reassess After 90 Days of Optimized Supportive Care

Wait at least 90 days (3 months) on maximally tolerated supportive care before considering immunosuppression 1, 2, 3

Define High-Risk Patients Who May Need Immunosuppression

High-risk patients are those with proteinuria >0.75-1 g/day despite ≥90 days of optimized supportive care 1, 2, 3

Step 4: Consider Immunosuppression for High-Risk Patients (Second-Line)

Corticosteroid Therapy Eligibility Criteria

Only consider corticosteroids if ALL of the following are met:

• Proteinuria persistently ≥1 g/day after 90 days of optimized supportive care 1, 2
• eGFR ≥50 mL/min/1.73 m² (some guidelines suggest ≥30 mL/min/1.73 m²) 1, 2
• Absence of contraindications: diabetes mellitus, obesity, latent infections, advanced age, metabolic syndrome, active peptic ulceration, uncontrolled psychiatric disease, or severe osteoporosis 3

Corticosteroid Regimen (if criteria met)

Use a 6-month course with one of these regimens:

• IV methylprednisolone 1 g for 3 days at months 1,3, and 5, PLUS oral prednisone 0.5 mg/kg on alternate days for 6 months 2
• Oral prednisone starting at 0.8-1 mg/kg/day for 2 months, then reduced by 0.2 mg/kg/day per month for the next 4 months 1

Important caveat: The TESTING trial showed corticosteroids reduce proteinuria and slow eGFR decline but carry significant adverse event risk, including serious infections 5

What NOT to Use

• Do NOT use corticosteroids combined with cyclophosphamide or azathioprine (except in crescentic IgAN) 1, 2
• Do NOT use mycophenolate mofetil (MMF) - multiple trials show no benefit 1, 2
• Do NOT use immunosuppression if eGFR <30 mL/min/1.73 m² (except in crescentic IgAN) 1, 2
• Do NOT use antiplatelet agents or anticoagulants specifically for IgAN 2
• Do NOT perform tonsillectomy as treatment 2

Special Clinical Situations Requiring Immediate Treatment

Crescentic IgA Nephropathy (>50% crescents with rapidly declining GFR)

• Treat immediately with cyclophosphamide PLUS corticosteroids, using protocols similar to ANCA-associated vasculitis 2, 3
• This is the ONLY indication for cyclophosphamide in IgAN 1, 2

IgAN with Minimal Change Disease Features

• Treat according to minimal change disease protocols if kidney biopsy shows mesangial IgA deposition with histologic features otherwise consistent with MCD 2, 3

IgAN with Acute Kidney Injury

• Distinguish acute tubular necrosis (supportive care only) from crescentic IgAN (requires immunosuppression) 6

Common Pitfalls to Avoid

• Do not delay ACE inhibitor/ARB initiation - start immediately when proteinuria ≥0.5 g/day 2
• Do not rush to immunosuppression - wait the full 90 days of optimized supportive care, as many patients respond to supportive measures alone 1
• Do not use corticosteroids in patients with eGFR <50 mL/min/1.73 m² without careful risk-benefit discussion, as adverse events are significantly more likely 1, 3
• Do not use suboptimal blood pressure targets - historical trials used 140/90 mmHg, which is now considered inadequate 1, 2
• Do not forget SGLT2 inhibitors - these are underutilized despite strong evidence for kidney protection 1

Monitoring Treatment Response

Goal: Reduce proteinuria to <1 g/day, which is associated with favorable long-term outcomes regardless of how this is achieved 2, 3

Consider clinical trial enrollment for all high-risk patients, given ongoing uncertainty about optimal immunosuppressive strategies 1, 3