What are the recommended treatment options for IgA nephropathy?

Treatment of IgA Nephropathy

For adults with IgA nephropathy and proteinuria >0.5 g/day, initiate dual-mechanism therapy: (1) therapies targeting pathogenic IgA production and immune complex formation (targeted-release budesonide or systemic corticosteroids), combined with (2) therapies managing nephron loss consequences (RAS inhibitors, SGLT2 inhibitors, and/or dual endothelin-angiotensin receptor blockers like sparsentan), alongside strict blood pressure control (<120/70 mmHg) and dietary sodium restriction (<2 g/day). 1, 2

Initial Assessment and Risk Stratification

• Confirm diagnosis with kidney biopsy in adults with proteinuria ≥0.5 g/day to exclude secondary causes (IgA vasculitis, infection-related glomerulonephritis, cirrhosis, inflammatory bowel disease, celiac disease) 3

• Quantify proteinuria using 24-hour urine collection or protein-to-creatinine ratio, as this drives treatment decisions and prognosis 4

• Assess progression risk using persistent proteinuria, microscopic hematuria, rate of eGFR decline, and histologic features (mesangial hypercellularity, endocapillary hypercellularity, crescents, tubular atrophy/interstitial fibrosis) 5

Treatment Goals

• Target proteinuria <0.5 g/day, ideally <0.3 g/day with stable eGFR 1

• Achieve blood pressure <120/70 mmHg using antihypertensive medications 3

Foundational Therapy (All Patients with Proteinuria >0.5 g/day)

Lifestyle Modifications

• Dietary sodium restriction to <2 g/day (<90 mmol/day) 4, 3
• Smoking cessation, weight control, and regular exercise 3

RAS Inhibition

• RAS inhibitors (ACE inhibitors or ARBs) probably decrease proteinuria (MD -0.71 g/24h) and should be first-line antihypertensive therapy 6
• Compared to symptomatic treatment alone, RAS inhibition probably decreases proteinuria (MD -1.16 g/24h), decreases serum creatinine (MD -9.37 µmol/L), and increases creatinine clearance (MD 23.26 mL/min) 6

SGLT2 Inhibitors

• SGLT2 inhibitors are now integral to contemporary supportive care, particularly in patients with chronic kidney damage, as they manage consequences of existing nephron loss 1, 5

Dual Endothelin-Angiotensin Receptor Blockade

• Sparsentan (dual endothelin-1 and angiotensin II receptor blocker) has been approved and should be considered, especially in patients with chronic kidney damage 2, 5

Disease-Modifying Immunotherapy (High-Risk Patients)

Targeted-Release Budesonide (Nefecon)

• Targeted-release budesonide is the preferred immunosuppressive approach as it prevents or reduces pathogenic IgA production and immune complex formation with lower systemic toxicity than systemic corticosteroids 1, 2

Systemic Corticosteroids

• Reduced-dose systemic corticosteroids are indicated in high-risk patients when targeted-release budesonide is unavailable, but beneficial effects wane after withdrawal and carry substantial treatment-associated toxicity 1, 5
• Use clinical parameters (degree of proteinuria, persistent microscopic hematuria, rate of eGFR loss) combined with histologic scoring to identify patients most likely to benefit 5

Mycophenolate Mofetil

• In Chinese patients specifically, mycophenolate mofetil can be used to reduce pathogenic IgA production 1

Complement Inhibition

• Iptacopan (complement factor B inhibitor) has been approved and decreases glomerular injury from immune complexes 3, 2

Special Populations and Situations

Children

• Treatment goals for proteinuria should not differ between disease etiologies: target PCR <200 mg/g (<20 mg/mmol) or <8 mg/m²/hour 4

Nephrotic Syndrome, AKI, or RPGN

• Little has changed for these presentations given lack of major clinical trials, but more aggressive immunosuppression is typically warranted 1

Tonsillectomy

• Tonsillectomy may increase remission of proteinuria and hematuria (RR 1.90 and 1.93 respectively) in Japanese patients with IgAN, but evidence is low certainty and findings are inconsistent across other ethnicities 6
• Tonsillectomy is not widely recommended given potential harm and lack of generalizability beyond Japanese populations 6

Treatment Paradigm: Parallel Dual-Target Approach

The new paradigm combines therapies targeting:

1. Immune components (pathogenic IgA production and immune complex formation): targeted-release budesonide, systemic corticosteroids, or mycophenolate mofetil in Chinese patients 1, 2

2. CKD components (consequences of existing nephron loss): RAS inhibitors, SGLT2 inhibitors, and/or sparsentan 1, 2

This parallel approach preserves long-term kidney survival by addressing both active disease and chronic damage simultaneously 2

Monitoring and Adverse Effects

• Monitor hematuria magnitude and persistence as it has prognostic value in IgAN 4

• RAS inhibition adverse events may be no different from placebo or symptomatic treatment, but monitor for hyperkalemia, acute kidney injury, and hypotension 6

• Diuretic therapy for edema should follow standard protocols with loop diuretics as first-line, monitoring for hypokalemia, hyponatremia, and volume depletion 4