Overview of IgA Nephropathy (IgAN)
IgA nephropathy is the most common immune-mediated glomerular disease worldwide, affecting approximately 200,000 persons in the US, with up to 50% developing kidney failure within 10 years of diagnosis if inadequately treated. 1
Clinical Presentation
IgAN typically presents in younger adults (mean age 34-45 years) with several distinct patterns:
- Asymptomatic microscopic hematuria with proteinuria (60% of cases) - detected incidentally on urinalysis 1
- Synpharyngitic hematuria (up to 30%) - episodic visible hematuria occurring concurrently with upper respiratory or gastrointestinal infections 1
- Nephrotic syndrome (<5%) - rare presentation requiring differentiation between IgAN variant versus coexistent minimal change disease 2
- Rapidly progressive glomerulonephritis (<5%) - defined as ≥50% decline in eGFR over ≤3 months with extensive glomerular crescent formation 2
The disease shows highest incidence in East Asia and predominantly affects young adults, making early recognition critical to prevent lifetime kidney failure 1.
Diagnosis
Adults with suspected IgAN and proteinuria ≥0.5 g/day should undergo kidney biopsy. 1 The diagnostic hallmark is IgA-dominant or co-dominant immune deposits in the glomerular mesangium on immunofluorescence staining 1.
Diagnostic Workup
Initial evaluation must include:
- Quantification of proteinuria (24-hour urine or protein-to-creatinine ratio)
- Assessment for secondary causes: lupus nephritis, IgA vasculitis, infection-related glomerulonephritis, cirrhosis, inflammatory bowel disease, celiac disease, viral hepatitis, and autoimmune diseases 1
- Histological MEST-C scoring on biopsy to predict prognosis 3
Management
The 2025 KDIGO guidelines fundamentally restructured IgAN treatment around preventing lifetime kidney failure rather than accepting slow progression 2.
Foundation: Supportive Care (All Patients)
All patients with IgAN must receive optimized maximally tolerated RAS inhibition (ACE inhibitor or ARB) targeting blood pressure <120/70 mm Hg (Recommendation 1.4.4.1; 1B) 2. This forms the absolute foundation unless contraindicated by hypotension, bilateral renal artery stenosis, or hyperkalemia 2.
Additional supportive measures:
- Dietary sodium <2 g/day
- Smoking cessation
- Weight control and exercise
- Blood pressure optimization 1
Disease-Modifying Therapies (Patients at Risk of Progressive Kidney Function Loss)
The treatment algorithm now includes multiple mechanistically distinct therapies that can be combined:
First-Line Immunomodulation
For patients at risk of progression, initiate targeted-release budesonide (Nefecon) for 9 months where approved (Recommendation 1.4.3.1; 2B) 2. This acts on gut-associated lymphoid tissue to reduce pathogenic galactose-deficient IgA1 production 4.
Alternative: If Nefecon unavailable, use reduced-dose systemic glucocorticoids - 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 (Recommendation 1.4.3.2; 2B) 2. This regimen is based on the TESTING trial and must be combined with:
- Pneumocystis jirovecii prophylaxis
- Antiviral prophylaxis in hepatitis B carriers
- Gastroprotection
- Bone protection 2
Critical caveat: Systemic glucocorticoid toxicity increases substantially with eGFR <30 ml/min per 1.73 m², diabetes/prediabetes, obesity, latent infections, active peptic ulceration, uncontrolled psychiatric illness, osteoporosis, or cataracts 2.
Nephroprotective Add-On Therapies
Add SGLT2 inhibitor for all patients at risk of progression (Recommendation 1.4.4.3; 2B) 2. Note uncertainty exists for younger patients with eGFR >60 ml/min per 1.73 m² as landmark trials enrolled patients with long-standing disease and lower eGFR 2.
Consider sparsentan (dual endothelin-1 and angiotensin II receptor antagonist) where approved (Recommendation 1.4.4.2; 2B) 2. Sparsentan must replace, not be added to, RAS inhibition 2.
Complement Inhibition
Iptacopan (complement factor B inhibitor) represents a newly approved option targeting alternative complement cascade activation in glomerular injury 4.
Therapies NOT Recommended
The 2025 guideline explicitly does not recommend: antiplatelet agents, anticoagulants, azathioprine, cyclophosphamide (except rapidly progressive IgAN), calcineurin inhibitors, rituximab, or fish oil 2.
Exception for Chinese patients: Mycophenolate mofetil and hydroxychloroquine may be considered as glucocorticoid-sparing agents based on trials conducted in this population, but insufficient evidence exists for other ethnicities 2.
Special Clinical Scenarios
Rapidly Progressive IgAN: Treat with cyclophosphamide and systemic glucocorticoids per KDIGO 2024 ANCA-Associated Vasculitis guideline 2. Rituximab has insufficient evidence 2.
Acute Kidney Injury with Visible Hematuria: Focus on supportive care; consider repeat biopsy if no improvement within 2 weeks of hematuria cessation 2.
Childbearing: Discontinue RAS inhibitors, SGLT2 inhibitors, sparsentan, and Nefecon before conception. Optimize blood pressure with pregnancy-compatible medications. Consider trial of immunomodulation pre-conception to achieve disease control. Systemic glucocorticoids may be used during pregnancy, but Nefecon is not advised 2.
Nephrotic Syndrome: Differentiate between IgAN variant (treat as standard IgAN) versus coexistent minimal change disease (treat as MCD) 2.
Common Pitfalls
- Delaying kidney biopsy in patients with proteinuria ≥0.5 g/day - early diagnosis is critical for lifetime kidney preservation 1
- Inadequate RAS blockade optimization before adding other therapies - maximally tolerated dosing is essential 2
- Using sparsentan with RAS inhibitors - these must not be combined 2
- Prescribing systemic steroids without antimicrobial prophylaxis - infectious complications are substantial 2
- Applying therapies proven only in Chinese populations (mycophenolate, hydroxychloroquine) to other ethnicities 2