What is the optimal management plan for a patient with IgA nephropathy to slow progression to end‑stage renal disease while minimizing treatment toxicity?

Management of IgA Nephropathy

All patients with IgA nephropathy and proteinuria >0.5 g/day should receive maximally tolerated ACE inhibitor or ARB therapy with blood pressure control as first-line treatment, and those with persistent proteinuria >0.75-1 g/day after 90 days of optimized supportive care should be considered for targeted-release budesonide (if UPCR >1.5 g/g) or systemic glucocorticoids (if eGFR ≥30 ml/min/1.73 m²), with SGLT2 inhibitors added as adjunctive therapy to slow progression to end-stage renal disease. 1, 2, 3

Initial Management: Optimized Supportive Care

Renin-Angiotensin System Blockade

• Initiate ACE inhibitor or ARB therapy for all patients with proteinuria >0.5 g/day, regardless of hypertension status (Grade 1B recommendation). 4, 3
• Maximize the tolerated dose before considering additional therapies. 3
• This remains the cornerstone of treatment and must be optimized for at least 90 days before escalating therapy. 1

Blood Pressure Targets

• Target blood pressure <130/80 mmHg for patients with proteinuria <1 g/day. 3
• Target blood pressure <125/75 mmHg (or <120/70 mmHg per most recent guidelines) for patients with proteinuria >1 g/day. 1, 3, 5

Lifestyle Modifications

• Restrict dietary sodium to <2.0 g/day. 3
• Implement smoking cessation, weight control, and regular exercise. 3
• Consider dietary protein restriction based on proteinuria severity and kidney function. 3

Treatment Goal

• Reduce proteinuria to <1 g/day, which serves as a surrogate marker for improved kidney outcomes and reduced progression to end-stage renal disease. 1, 4

Second-Line Immunosuppressive Therapy

Patient Selection Criteria

Consider immunosuppression only when all of the following are met:

• Proteinuria remains >0.75-1 g/day after at least 90 days of optimized supportive care. 1, 4
• eGFR ≥30 ml/min/1.73 m². 1
• Absence of contraindications (see below). 1

Targeted-Release Budesonide (Preferred Option)

Targeted-release budesonide is the preferred immunosuppressive agent for eligible patients due to its superior safety profile compared to systemic corticosteroids. 2

• FDA-approved for primary IgA nephropathy with UPCR >1.5 g/g. 1, 2
• Reduces proteinuria by 34% at 9 months with significantly fewer serious adverse events than systemic corticosteroids. 1, 2
• Targets gut-associated lymphoid tissue with reduced systemic exposure. 3
• Monitor proteinuria every 3 months and eGFR every 3-6 months. 2
• Target 50% reduction in proteinuria by 6 months and <1 g/day by 12 months. 2, 3

Systemic Glucocorticoids (Alternative Option)

If budesonide is not available or UPCR <1.5 g/g:

• Consider 6-month course of glucocorticoids (prednisone equivalent ≥0.5 mg/kg/day). 1
• The TESTING trial showed reduction in composite kidney outcomes (28.8% vs 43.1% placebo) over median 4.2-year follow-up. 1
• Critical caveat: Serious adverse events are significantly higher with systemic steroids, including 4 fatalities in the TESTING trial despite pneumocystis prophylaxis. 1

Mandatory Prophylaxis with Systemic Glucocorticoids

When using systemic glucocorticoids:

• Pneumocystis jirovecii pneumonia prophylaxis. 1
• Gastroprotection. 1
• Bone protection according to local guidelines. 1

Absolute Contraindications to Glucocorticoids

Avoid glucocorticoids entirely in patients with: 1

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

Adjunctive Therapies to Slow CKD Progression

SGLT2 Inhibitors (Strongly Recommended)

Add SGLT2 inhibitors to RAS blockade for all eligible patients to reduce kidney failure risk. 3, 5

• The DAPA-CKD trial subanalysis of 270 IgAN patients demonstrated significant reduction in kidney failure risk. 3, 6
• SGLT2 inhibitors provide additional proteinuria reduction and slow eGFR decline independent of glucose-lowering effects. 7, 6, 8
• This represents a paradigm shift toward combining therapies targeting both immune and CKD components. 8

Emerging Therapies

Additional options now available or under evaluation: 1, 5, 8

• Sparsentan (dual endothelin-1 and angiotensin II receptor blocker) - FDA approved
• Iptacopan (complement factor B inhibitor) - FDA approved
• Various complement inhibitors in clinical trials

Therapies NOT Recommended

The following should not be used routinely in IgAN: 1, 4

• Azathioprine
• Cyclophosphamide (except rapidly progressive IgAN with >50% crescents)
• Calcineurin inhibitors
• Rituximab
• Fish oil (no longer recommended despite previous guideline support) 1
• Mycophenolate mofetil in non-Chinese patients 1
• Tonsillectomy in non-Japanese patients 1

Special Population Exception

• Chinese patients: Consider mycophenolate mofetil 1.5 g/day as glucocorticoid-sparing agent for proteinuria >1 g/day with active histologic features. 1, 2

Special Clinical Scenarios

Rapidly Progressive/Crescentic IgAN

For patients with >50% crescents and rapid GFR decline:

• Use aggressive immunosuppression with cyclophosphamide plus glucocorticoids. 1, 3
• This is the only indication for cyclophosphamide in IgAN. 1

IgAN with Minimal Change Disease Features

• Treat according to minimal change disease guidelines, not standard IgAN protocols. 1

IgAN with Acute Kidney Injury from Gross Hematuria

• Focus on supportive care for AKI. 1
• Consider repeat biopsy if no improvement within 2 weeks after hematuria cessation. 1

Monitoring Strategy

Treatment Response Assessment

• Monitor proteinuria, blood pressure, and eGFR regularly. 4, 3
• Target 25% proteinuria reduction at 3 months, 50% at 6 months, and <1 g/day by 12 months. 3
• Monitor for 40% or greater decline in eGFR over 2-3 years as surrogate outcome for kidney failure. 3

Critical Implementation Points

The evidence for glucocorticoid benefit is relatively weak, and the risk of serious adverse events including death is substantial. 1 The TESTING trial was terminated early due to high rates of serious infections despite prophylaxis. 1 This underscores the importance of:

1. Ensuring truly maximal supportive care for at least 90 days before considering immunosuppression. 1
2. Preferentially using targeted-release budesonide when UPCR >1.5 g/g due to superior safety profile. 2
3. Having detailed risk-benefit discussions with patients, particularly those with eGFR <50 ml/min/1.73 m². 1
4. Considering clinical trial enrollment for high-risk patients. 1

The new treatment paradigm combines therapies targeting both immune dysregulation (budesonide, glucocorticoids, complement inhibitors) and CKD progression (SGLT2 inhibitors, sparsentan) in parallel to preserve long-term kidney survival. 8