How should IgA nephropathy be diagnosed and managed, including blood pressure targets, proteinuria goals, and the use of angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), corticosteroids, cyclophosphamide, or mycophenolate mofetil?

IgA Nephropathy: Diagnosis and Management

Diagnosis

Kidney biopsy is required for definitive diagnosis in any adult with proteinuria ≥0.5 g/day and suspected IgA nephropathy, demonstrating dominant mesangial IgA1 deposition. 1

• Quantify proteinuria using 24-hour urine collection or spot urine protein-to-creatinine ratio 2
• Measure serum creatinine and calculate eGFR to assess kidney function and determine treatment eligibility 2
• Request Oxford MEST scoring on biopsy specimens, as this provides independent prognostic information beyond clinical features alone 3, 2
• Quantify the percentage of crescents to identify rapidly progressive disease requiring aggressive immunosuppression 2
• Exclude secondary causes including IgA vasculitis, cirrhosis, inflammatory bowel disease, celiac disease, viral hepatitis, and autoimmune diseases 1

Initial Management: Supportive Care (All Patients)

Begin ACE inhibitor or ARB therapy immediately for any patient with proteinuria ≥0.5 g/day, regardless of hypertension status, and titrate upward as tolerated to achieve proteinuria <1 g/day. 3, 2

Blood Pressure Targets

• Target <130/80 mm Hg if proteinuria <1 g/day 3
• Target <125/75 mm Hg if proteinuria ≥1 g/day 3, 2

Lifestyle Modifications

• Restrict dietary sodium to <2.0 g/day 4
• Implement smoking cessation, weight control, and regular exercise 4

Observation Period

• Continue optimized supportive care for 3-6 months before considering immunosuppression 3, 2
• Monitor proteinuria every 3 months during this period to assess response 2

Immunosuppression: When to Escalate

For patients with persistent proteinuria ≥1 g/day after 3-6 months of optimized supportive care AND eGFR >50 ml/min/1.73m², initiate a 6-month course of corticosteroid therapy. 3, 2

Corticosteroid Regimen

The evidence supports corticosteroid monotherapy, with two randomized controlled trials demonstrating benefit compared to ACE inhibitors/ARBs alone in patients with relatively preserved renal function. 3 A large multicenter trial is currently underway to evaluate corticosteroids in patients with broader ranges of kidney function (eGFR 20-70 ml/min/1.73m²). 3

• Use the Pozzi Protocol: 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 2
• You do not need to complete a full 6-month trial before determining response—assess earlier for treatment effect 3
• Note that proteinuria frequently recurs after cessation of corticosteroid therapy, though the guideline does not address this 3

Contraindications to Corticosteroids

• eGFR <30 ml/min/1.73m² (except crescentic disease) 3, 2
• Uncontrolled diabetes or metabolic syndrome 3, 2
• Obesity 3
• Poorly controlled hypertension 3
• Active or latent infections 2
• Advanced age with frailty 2

Monitoring During Corticosteroid Therapy

• Screen for glucose intolerance 2
• Monitor blood pressure closely 2
• Assess infection risk 2
• Monitor weight gain 2

Special Clinical Scenarios

Crescentic IgA Nephropathy (Rapidly Progressive Disease)

Define crescentic IgAN as >50% crescents on biopsy with rapidly progressive renal deterioration, and treat with steroids PLUS cyclophosphamide analogous to ANCA vasculitis, regardless of baseline eGFR. 3, 2

This is the only indication for cyclophosphamide in IgA nephropathy. 3 The usual prohibition against immunosuppression in patients with eGFR <30 ml/min/1.73m² does not apply to crescentic disease. 3, 2

Minimal Change Disease Pattern with IgA Deposits

Treat nephrotic patients showing minimal light microscopic changes with mesangial IgA deposits as minimal change disease, using high-dose corticosteroids as for primary MCD. 3, 2

Acute Kidney Injury with Macroscopic Hematuria

• Perform repeat kidney biopsy if no improvement after 5 days from onset of kidney function worsening 3
• If biopsy shows only acute tubular necrosis and intratubular erythrocyte casts, provide general supportive care only 3

Therapies to AVOID

The evidence is clear on several interventions that should NOT be used:

Do NOT Use:

• Corticosteroids combined with cyclophosphamide or azathioprine (except crescentic disease) 3, 2
• Mycophenolate mofetil (MMF) - no benefit demonstrated in Belgian and American trials 3, 2, 5
• Antiplatelet agents (dipyridamole) - low-quality evidence and poor adherence 3, 2
• Routine tonsillectomy - not recommended unless recurrent tonsillitis with macroscopic hematuria 3, 2
• Immunosuppression if eGFR <30 ml/min/1.73m² (except crescentic disease) 3, 2

Weak Evidence (Consider Only in Select Cases):

• Fish oil - suggested for persistent proteinuria >1 g/day despite optimized supportive care, but evidence is weak (2D recommendation) 3

Emerging Therapies

While the core guidelines focus on traditional approaches, recent evidence supports:

• SGLT2 inhibitors as add-on therapy to RAS blockade, based on DAPA-CKD and EMPA-KIDNEY trials showing significant reduction in kidney failure risk 4
• Targeted-release budesonide (Nefecon) for primary IgAN with urine protein-to-creatinine ratio >1.5 g/g, which targets gut-associated lymphoid tissue with reduced systemic exposure 4

Monitoring and Treatment Goals

• Check proteinuria every 3 months during and after treatment 2
• Monitor eGFR every 3-6 months to assess disease trajectory 2
• Goal: Reduce proteinuria to <1 g/day 3, 2
• Target proteinuria reduction of 25% at 3 months, 50% at 6 months, and complete clinical response (<1 g/day) by 12 months 4

Common Pitfalls

• Do not start immunosuppression without first optimizing supportive care for 3-6 months - this is a critical error that exposes patients to unnecessary toxicity 3, 2
• Do not use corticosteroids in patients with eGFR <50 ml/min/1.73m² unless they have crescentic disease - the risk-benefit ratio is unfavorable 3
• Do not assume all proteinuria is due to IgAN - exclude secondary causes and concurrent conditions like urinary tract infections 1
• Do not use MMF based on older literature - recent high-quality trials have definitively shown no benefit 3, 2
• Evaluate relative contraindications to steroids carefully - obesity, glucose intolerance, and poorly controlled hypertension must be considered at the individual patient level 3