IgA Nephropathy: Diagnosis and Management
Diagnosis
Kidney biopsy is required to definitively diagnose IgA nephropathy and should be performed in adults with proteinuria ≥0.5 g/day who present with hematuria and/or proteinuria. 1
When to Suspect IgA Nephropathy
- Episodic gross hematuria occurring concurrently with upper respiratory or gastrointestinal infections (synpharyngitic hematuria) is present in up to 30% of cases 1
- Persistent microscopic hematuria with proteinuria detected incidentally on urinalysis (approximately 60% of cases) 1
- Nephrotic syndrome (<5% of cases) or rapidly progressive glomerulonephritis (<5% of cases) 1
Initial Workup Before Biopsy
- Quantify proteinuria using spot urine protein-to-creatinine ratio (PCR) or albumin-to-creatinine ratio (ACR) on an early morning sample 2
- Measure serum creatinine and calculate eGFR using the CKD-EPI equation 2
- Document blood pressure at presentation 2
- Exclude secondary causes including systemic lupus erythematosus, liver disease (cirrhosis), inflammatory bowel disease, celiac disease, viral hepatitis, and axial spondyloarthritis 3, 1
- Order serological testing: hepatitis B and C serologies, complement levels (C3, C4), antinuclear antibody, quantitative immunoglobulins, serum and urine protein electrophoresis 2
- Perform renal ultrasound to assess kidney size and rule out obstruction 2
Diagnostic Criteria on Kidney Biopsy
- Mesangial dominant or co-dominant IgA deposits on immunofluorescence microscopy is the definitive diagnostic feature 3
- Electron-dense deposits in the mesangium on electron microscopy, often with C3 co-deposition 3
- Exclude secondary IgA deposition from IgA vasculitis (Henoch-Schönlein purpura), IgA-dominant infection-related glomerulonephritis, and the secondary causes listed above 1
Urinalysis Findings Suggesting Glomerular Disease
- Dysmorphic red blood cells (>80% dysmorphic) or red cell casts indicate glomerular bleeding 4
- Proteinuria >1 g/24 hours (or >1+ on dipstick) warrants nephrology evaluation 4
Risk Stratification
Proteinuria >1 g/day, hypertension, and reduced eGFR at diagnosis predict progressive disease, with 20-40% of patients developing end-stage renal disease within 5-25 years. 5, 6
High-Risk Features
- Proteinuria persistently ≥1 g/day despite optimized supportive care 4, 7
- Elevated serum creatinine or eGFR <60 mL/min/1.73 m² at presentation 5
- Uncontrolled hypertension 5, 6
- Pathological features: glomerulosclerosis, tubular atrophy/interstitial fibrosis, crescents in >50% of glomeruli 5, 4
Intermediate-Risk Features
- Proteinuria 0.5-1 g/day after initial evaluation 7
Low-Risk Features
- Isolated microscopic hematuria or proteinuria <0.5 g/day 6
Initial Management: Optimized Supportive Care (First 3-6 Months)
All patients with proteinuria >0.5 g/day must receive maximally tolerated ACE inhibitor or ARB therapy, strict blood pressure control, and lifestyle modifications before considering immunosuppression. 4, 7
Renin-Angiotensin System (RAS) Blockade
- Start ACE inhibitor or ARB immediately in all patients with proteinuria >0.5 g/day, regardless of blood pressure 4, 7
- Uptitrate to the maximum tolerated dose with the goal of reducing proteinuria to <1 g/day 4, 7
- Accept up to 30% rise in serum creatinine during uptitration as a benign hemodynamic effect; discontinue only if the rise exceeds 30% persistently or refractory hyperkalemia develops 7
- Monitor serum creatinine and potassium monthly during uptitration 7
Blood Pressure Targets
- Target <130/80 mmHg for patients with proteinuria <1 g/day 4
- **Target <125/75 mmHg** for patients with proteinuria >1 g/day 4, 7
- Target <120/70 mmHg according to the most recent 2025 guideline 1
Lifestyle Modifications
- Restrict dietary sodium to <2 g/day (≈90 mmol) to augment antiproteinuric effect of RAS blockade 7, 1
- Smoking cessation 7, 1
- Weight normalization and regular physical activity 7, 1
- Consider moderate protein restriction balanced against nutritional needs 7
Monitoring During Supportive Care Phase
- Check serum creatinine, potassium, and spot urine PCR monthly while uptitrating ACE inhibitor/ARB 7
- Measure blood pressure at each visit 7
- Reassess proteinuria at 3-6 months to determine need for immunosuppression 4, 7
Immunosuppressive Therapy
If proteinuria remains ≥1 g/day after 3-6 months of optimized supportive care, add a 6-month course of corticosteroid therapy in patients with eGFR >50 mL/min/1.73 m². 4, 7
Eligibility Criteria for Corticosteroids
- Persistent proteinuria ≥1 g/day despite 3-6 months of optimized supportive care 4, 7
- eGFR >50 mL/min/1.73 m² 4
- Absence of contraindications: diabetes, obesity (BMI >30), active infection, uncontrolled psychiatric disease, severe osteoporosis 4, 7
Corticosteroid Regimen (Pozzi Protocol)
The preferred regimen is intravenous methylprednisolone 1 g daily for 3 consecutive days at months 1,3, and 5, combined with oral prednisone 0.5 mg/kg every other day for 6 months. 7
- This regimen achieved 10-year renal survival of 97% versus 53% without immunosuppression 7
- Taper oral prednisone by 0.2 mg/kg/day each month over the final 4 months 7
Pre-Treatment Screening
- Screen for latent infections including tuberculosis, hepatitis B and C, and HIV before starting corticosteroids 4, 7
Monitoring During Corticosteroid Therapy
- Monitor monthly for steroid-related adverse effects: hyperglycemia, weight gain, mood changes, bone density loss 7
- Continue monthly proteinuria and renal function assessments 7
Therapies to Avoid in Standard IgA Nephropathy
- Cyclophosphamide or azathioprine: Reserved only for crescentic IgA nephropathy with rapidly progressive renal deterioration 4, 7
- Mycophenolate mofetil: Not recommended based on lack of proven benefit 4, 7
- Tonsillectomy: Should not be performed routinely 4
- Antiplatelet agents or anticoagulants: Not recommended 4, 6
Special Clinical Scenarios
Crescentic IgA Nephropathy (Rapidly Progressive Glomerulonephritis)
Treat with cyclophosphamide and high-dose corticosteroids analogous to ANCA-associated vasculitis when crescents involve >50% of glomeruli and there is rapidly progressive renal deterioration. 4
- This represents <5% of IgA nephropathy cases 1
- Do not wait for 50% crescents if rapid GFR deterioration is occurring with crescents approaching 50%, as sampling error may affect biopsy interpretation 4
Acute Kidney Injury with Macroscopic Hematuria
- Provide general supportive care if kidney biopsy shows only acute tubular necrosis and intratubular erythrocyte casts 4
- Perform repeat kidney biopsy if no improvement occurs within 2 weeks after cessation of hematuria to exclude crescentic disease 4
- The 2013 guideline recommended repeat biopsy after 5 days, but the 2021 guideline extended this to 2 weeks 4
IgA Nephropathy with Minimal Change Disease Features
Treat as minimal change disease with corticosteroids when kidney biopsy shows mesangial IgA deposits but otherwise demonstrates minimal light microscopic changes and diffuse foot-process effacement on electron microscopy. 4
Nephrotic Syndrome
- Distinguish minimal change disease with IgA deposits (treat as above) from nephrotic IgA nephropathy with mesangioproliferative features (treat as high-risk IgA nephropathy) 4
- Nephrotic syndrome occurs in <5% of IgA nephropathy cases 1
Long-Term Management and Monitoring
Continue ACE inhibitor/ARB at maximally tolerated dose indefinitely, with proteinuria and eGFR monitoring every 3-6 months, aiming for sustained proteinuria <1 g/day and ideally <0.5 g/day. 7, 2
Follow-Up Schedule
- Every 3-6 months: Assess proteinuria (spot urine PCR) and eGFR 7, 2
- At each visit: Measure blood pressure and adjust medications to maintain target 7
- Annually at minimum for all patients with confirmed IgA nephropathy 2
Treatment Goals
- Proteinuria <1 g/day is associated with favorable long-term prognosis 7
- Proteinuria <0.5 g/day is the ideal target 7
- Blood pressure <120/70 mmHg per most recent guidelines 1
Emerging Therapies (2025-2026)
- Targeted-release budesonide to decrease formation of IgA-containing immune complexes 1
- Iptacopan to reduce immune complex-mediated glomerular injury 1
- Dual endothelin angiotensin receptor antagonist (sparsentan) alone or combined with SGLT2 inhibitor to manage IgA-induced nephron loss 1
Common Pitfalls to Avoid
- Do not delay kidney biopsy in patients with proteinuria ≥0.5 g/day, as clinical features alone cannot exclude IgA nephropathy or distinguish it from other glomerular diseases 3
- Do not start immunosuppression before completing 3-6 months of optimized supportive care, as many patients will respond to RAS blockade alone 4, 7
- Do not use corticosteroids in patients with eGFR <30 mL/min/1.73 m² unless crescentic disease is present 4
- Do not assume creatinine rise during ACE inhibitor/ARB uptitration is nephrotoxicity; up to 30% rise is acceptable hemodynamic effect 7
- Do not use mycophenolate mofetil as it lacks proven benefit in non-Chinese populations 4, 7