What is the treatment approach for a patient with IgA nephropathy, considering the severity of the disease and presence of risk factors such as significant proteinuria and impaired renal function?

Treatment of IgA Nephropathy

All patients with IgA nephropathy should begin with optimized supportive care including maximally tolerated RAS blockade (ACE inhibitors or ARBs), blood pressure control, and lifestyle modifications for at least 90 days before considering immunosuppression. 1

Initial Risk Stratification and Supportive Care

Baseline Assessment

• Assess proteinuria, blood pressure, and eGFR at diagnosis to determine progression risk 1
• Exclude secondary causes including systemic lupus erythematosus, liver disease, and inflammatory bowel disease 2
• Consider using the International IgAN Prediction Tool (available at Calculate by QxMD) for individualized risk assessment, which is superior to proteinuria alone for treatment decisions 1, 3

Optimized Supportive Care (First-Line for ALL Patients)

• Initiate ACE inhibitor or ARB therapy when proteinuria >0.5 g/day, regardless of blood pressure status 1
• Uptitrate RAS blockade to maximally tolerated doses targeting proteinuria <1 g/day 1
• Blood pressure targets: <130/80 mmHg if proteinuria <1 g/day; <125/75 mmHg if proteinuria >1 g/day 1
• Dietary sodium restriction to <2.0 g/day (<90 mmol/day) 1
• Lifestyle modifications: smoking cessation, weight control, regular exercise, and cardiovascular risk reduction 1

Continue this supportive care regimen for a minimum of 90 days before reassessing for immunosuppression. 1

Immunosuppression Decision Algorithm

When to Consider Glucocorticoids

If proteinuria remains >0.75-1 g/day after at least 90 days of optimized supportive care AND eGFR ≥30 ml/min/1.73 m², consider a 6-month course of glucocorticoid therapy. 1

Absolute Contraindications to Glucocorticoids

Avoid glucocorticoids entirely or use with extreme caution in patients with: 1

• eGFR <30 ml/min/1.73 m²
• Diabetes mellitus
• Obesity (BMI >30 kg/m²)
• Latent infections (viral hepatitis, tuberculosis, HIV)
• Secondary disease (liver cirrhosis)
• Active peptic ulceration
• Uncontrolled psychiatric disease
• Severe osteoporosis

Important caveat: The clinical benefit of glucocorticoids in IgAN is not definitively established, and treatment-associated morbidity and mortality have been documented. 1 Enrollment in clinical trials should be strongly preferred over glucocorticoid therapy when available. 1

Immunosuppressive Agents NOT Recommended

Standard IgAN (Non-Crescentic)

• Do NOT use mycophenolate mofetil (MMF) in non-Chinese patients 1
• MMF may be considered as a glucocorticoid-sparing agent only in Chinese patients 1
• Do NOT use cyclophosphamide or azathioprine (except in crescentic IgAN) 1
• Do NOT use calcineurin inhibitors (cyclosporine, tacrolimus) 1
• Do NOT use rituximab 1
• Do NOT perform tonsillectomy in non-Japanese patients 1

Adjunctive Therapies with Weak Evidence

• Fish oil may be considered for persistent proteinuria >1 g/day despite optimized supportive care, though evidence is weak 1
• Antiplatelet agents are NOT recommended 1

Special Clinical Scenarios

Crescentic IgAN (Rapidly Progressive)

Define crescentic IgAN as >50% of glomeruli with crescents on biopsy plus rapidly progressive renal deterioration. 1

• Treat with corticosteroids PLUS cyclophosphamide, analogous to ANCA vasculitis treatment 1
• This is the ONLY indication for cyclophosphamide in IgAN 1

IgA Deposits with Minimal Change Disease Pattern

• Treat as minimal change disease with corticosteroids if nephrotic syndrome is present with pathological findings of minimal change disease and mesangial IgA deposits 1

Acute Kidney Injury with Macroscopic Hematuria

• Provide general supportive care if biopsy shows only acute tubular necrosis and intratubular erythrocyte casts 1
• Perform repeat kidney biopsy if no improvement after 5 days from onset of kidney function worsening 1

Emerging Therapies Under Investigation

Several novel therapies are currently being evaluated in clinical trials and may become available: 1

• SGLT2 inhibitors (showing promise across proteinuric kidney diseases)
• Sparsentan and atrasentan (endothelin receptor antagonists)
• Enteric-coated budesonide (targeted-release corticosteroid)
• Complement inhibitors
• B-cell targeted therapies
• Hydroxychloroquine

Patients should be offered participation in clinical trials whenever available, as this may provide access to more effective and safer therapies than conventional glucocorticoids. 1

Critical Monitoring Parameters

During Supportive Care Phase

• Monitor proteinuria, blood pressure, and eGFR every 3 months 1
• Proteinuria reduction to <1 g/day is a surrogate marker of improved kidney outcomes and a reasonable treatment target 1

During Immunosuppression

• Recognize that adverse treatment effects are more likely in patients with eGFR <50 ml/min/1.73 m² 1
• Proteinuria frequently recurs after cessation of corticosteroid therapy 1
• A full 6-month trial is NOT required to determine treatment response; assess earlier for futility 1

Common Pitfalls to Avoid

• Do not initiate immunosuppression without first optimizing supportive care for at least 90 days 1
• Do not use proteinuria >1 g/day as the sole criterion for immunosuppression; consider the International IgAN Prediction Tool for more accurate risk stratification 3
• Do not use combination corticosteroid plus cyclophosphamide or azathioprine in standard IgAN (only in crescentic disease) 1
• Do not ignore cardiovascular risk factors; sub-nephrotic proteinuria is a well-recognized cardiovascular risk factor requiring lipid management and aggressive cardiovascular risk reduction 1