What is the latest International Pediatric Nephrology Association (IPNA) and International Society of Nephrology (ISN) protocol for managing IgA nephritis in a patient who is non‑responsive to oral steroids and angiotensin‑converting enzyme (ACE) inhibitor therapy?

Management of IgA Nephropathy Non-Responsive to Oral Steroids and ACE Inhibitors

For patients with IgA nephropathy who fail to respond to oral steroids and ACE inhibitors, the next step depends critically on the clinical presentation: if there is rapidly progressive crescentic disease (>50% crescents on biopsy with rapidly deteriorating kidney function), treat with cyclophosphamide plus steroids analogous to ANCA vasculitis; otherwise, consider alternative therapies including fish oil, SGLT2 inhibitors, or sparsentan, while avoiding MMF, azathioprine, and calcineurin inhibitors in non-crescentic disease.

Clinical Assessment and Risk Stratification

First, determine if this represents crescentic IgAN versus persistent proteinuric disease:

Crescentic IgAN (Rapidly Progressive)

• Definition: >50% of glomeruli with crescents on biopsy AND rapidly progressive renal deterioration 1
• Treatment: Steroids plus cyclophosphamide (CYC), analogous to ANCA vasculitis protocol 1
• This is the only scenario where cyclophosphamide is recommended in IgAN
• Consider repeat kidney biopsy if there is rapidly deteriorating kidney function (doubling of serum creatinine over 1-2 months) without massive proteinuria 1

Non-Crescentic IgAN with Persistent Proteinuria

If the patient has persistent proteinuria ≥1 g/day despite 3-6 months of optimized supportive care (ACE inhibitors/ARBs and blood pressure control) and GFR >50 ml/min per 1.73 m², the initial recommendation was a 6-month course of corticosteroid therapy 1, 2, 1. However, since your patient has already failed oral steroids, the guideline framework becomes more limited.

What NOT to Use (Critical Pitfalls)

The KDIGO guidelines are explicit about avoiding certain therapies in non-crescentic IgAN:

• Do NOT use corticosteroids combined with cyclophosphamide or azathioprine (unless crescentic) 1, 2
• Do NOT use MMF in IgAN 1, 2
• Do NOT use immunosuppressive therapy if GFR <30 ml/min per 1.73 m² (unless crescentic) 1, 2
• Do NOT use calcineurin inhibitors (cyclosporine, tacrolimus) for standard IgAN 1
• Do NOT use antiplatelet agents 1

Alternative Treatment Options for Steroid-Refractory Disease

1. Fish Oil (Omega-3 Fatty Acids)

• Suggested for persistent proteinuria ≥1 g/day despite 3-6 months of optimized supportive care 1
• This is a low-toxicity option with weak evidence (Grade 2D)
• Represents a reasonable next step given the limited alternatives

2. Newer Therapies (2025 KDIGO Update)

The most recent 2025 KDIGO guideline 3 introduces important new options:

SGLT2 Inhibitors (Grade 2B):

• Suggested for patients at risk of progressive loss of kidney function
• Can be added to existing RAS blockade
• Evidence from large CKD trials that included IgAN patients
• Caveat: Most trial patients had long-standing disease and low eGFR; benefit uncertain in younger patients with eGFR >60 ml/min per 1.73 m²

Sparsentan (Grade 2B):

• Dual endothelin-1 and angiotensin II receptor blocker
• Should replace (not add to) the ACE inhibitor
• Where approved, suggested for patients at risk of progressive kidney function loss
• Represents a novel mechanism targeting both pathways

Reduced-Dose Systemic Glucocorticoids (Grade 2B):

• If standard-dose steroids failed, consider the TESTING trial regimen: methylprednisolone 0.4 mg/kg/day (maximum 32 mg/day) for 2 months, then taper by 4 mg/day monthly for total 6-9 months 3
• Must combine with:
  • Pneumocystis jirovecii prophylaxis
  • Antiviral prophylaxis if hepatitis B carrier
  • Gastroprotection and bone protection
• Contraindications: eGFR <30 ml/min per 1.73 m², diabetes/prediabetes, obesity, latent infections, active peptic ulcer, uncontrolled psychiatric illness, osteoporosis, cataracts 3

Pediatric-Specific Considerations (IPNA 2025)

The 2025 IPNA clinical practice recommendations 4 acknowledge that pediatric IgAN management is controversial with little high-quality evidence. Children present more acutely (often with synpharyngitic macrohematuria) and have more intense inflammation histologically. The IPNA guideline emphasizes:

• Pediatric IgAN differs from adult disease in presentation and histology
• Management must account for higher disease activity and longer life expectancy in children
• There is critical need for pediatric-specific clinical trials
• Current adult trial data cannot be directly extrapolated to children

Special Clinical Scenarios

Nephrotic Syndrome with IgAN

• If biopsy shows minimal change disease pattern with mesangial IgA deposits, treat as minimal change disease 1
• This is a distinct entity requiring different management

AKI with Macroscopic Hematuria

• If no improvement after 5 days, perform repeat kidney biopsy 1
• If biopsy shows only acute tubular necrosis and intratubular erythrocyte casts, provide general supportive care 1

Practical Algorithm for Your Patient

1. Verify adequate trial of initial therapy: Confirm patient received 3-6 months of maximally tolerated ACE inhibitor/ARB with blood pressure target <130/80 mmHg (or <125/75 mmHg if proteinuria >1 g/day) 1

2. Assess for crescentic disease: If rapidly progressive with >50% crescents, initiate cyclophosphamide plus steroids immediately

3. If non-crescentic and GFR >30 ml/min per 1.73 m²:

   • First-line addition: SGLT2 inhibitor (dapagliflozin or empagliflozin) 3
   • Alternative: Switch ACE inhibitor to sparsentan (where approved) 3
   • Adjunctive: Add fish oil 1
   • Consider: Reduced-dose glucocorticoid regimen if no contraindications 3

4. If GFR <30 ml/min per 1.73 m²: Avoid immunosuppression unless crescentic; focus on supportive care and prepare for renal replacement therapy

Key Monitoring Parameters

• Proteinuria reduction: Target 25% by 3 months, 50% by 6 months
• Blood pressure: Maintain <130/80 mmHg (or <125/75 mmHg if proteinuria >1 g/day)
• eGFR: Monitor for stabilization or improvement
• Watch for steroid toxicity if using reduced-dose regimen

The evidence base for steroid-refractory IgAN remains limited, and the 2012 KDIGO guidelines 1, 2 explicitly recommend against most traditional immunosuppressive combinations. The 2025 updates 3, 4 provide newer options (SGLT2 inhibitors, sparsentan) that represent the most evidence-based next steps for patients who have failed initial therapy.