What is the recommended management approach for IgA nephropathy, including blood pressure targets, use of an angiotensin‑converting enzyme inhibitor or angiotensin receptor blocker, addition of a sodium‑glucose cotransporter‑2 inhibitor, and criteria for initiating immunosuppressive therapy such as persistent proteinuria of at least one gram per day or rapid decline in estimated glomerular filtration rate?

Management of IgA Nephropathy

All patients with IgA nephropathy and proteinuria >0.5 g/day must begin with at least 90 days of maximally optimized supportive care—including uptitrated ACE-inhibitor or ARB, SGLT2 inhibitor, strict blood pressure control (<120/70 mmHg), and sodium restriction to <2 g/day—before any immunosuppression is considered. 1, 2

Initial Supportive Care (First-Line Therapy for All Patients)

Renin-Angiotensin System Blockade

• Start ACE-inhibitor or ARB immediately when proteinuria exceeds 0.5 g/day, regardless of whether blood pressure is elevated 3, 1
• Uptitrate to the maximum tolerated dose to achieve the greatest antiproteinuric effect, not merely blood pressure reduction 3, 1
• Continue uptitration even when blood pressure is already controlled because the goal is maximal proteinuria reduction 1
• Do not discontinue if serum creatinine rises ≤30% from baseline—this modest early rise actually predicts better long-term renal protection 1
• Discontinue only if kidney function deteriorates >30% or refractory hyperkalemia develops 1
• Dual ACE-inhibitor plus ARB therapy is contraindicated because it provides no additional renal benefit and increases hyperkalemia risk 1

Blood Pressure Targets

• Target systolic BP <120 mmHg (standardized office measurement) for most adults 1, 4
• If proteinuria is <1 g/day, aim for BP <130/80 mmHg 3
• If proteinuria is >1 g/day, aim for the more aggressive target of BP <125/75 mmHg 3, 1

SGLT2 Inhibitor Addition

• Add an SGLT2 inhibitor (dapagliflozin or empagliflozin) to baseline ACE-inhibitor/ARB therapy—this combination markedly reduces proteinuria and slows eGFR decline 1, 4
• SGLT2 inhibitors represent a major advance in supportive care and should be instituted before considering any immunosuppression 1

Dietary and Lifestyle Modifications

• Restrict dietary sodium to <2.0 g/day (<90 mmol/day) to augment antiproteinuric effects 1, 2
• Use loop diuretics for volume control; add thiazide-type diuretics when diuretic resistance occurs 1
• Implement smoking cessation, weight control, regular exercise, and cardiovascular risk reduction 1, 2, 4

Risk Stratification After 90 Days of Optimized Supportive Care

High-risk patients warranting immunosuppression consideration are defined by:

• Persistent proteinuria >0.75–1 g/day despite at least 90 days (3–6 months) of maximally optimized supportive care 3, 1, 2
• Baseline eGFR ≥30 ml/min/1.73 m² (preferably ≥50 ml/min/1.73 m²)—benefit of immunosuppression is uncertain or harmful below this threshold 3, 1

The therapeutic goal is proteinuria <1 g/day, which serves as a surrogate marker for improved renal outcomes 3, 1, 2

Immunosuppressive Therapy: Corticosteroids

Indications for Corticosteroid Therapy

Offer a 6-month course of corticosteroids when:

• Proteinuria remains >1 g/day after 3–6 months of optimized supportive care 3, 1, 2
• eGFR is ≥50 ml/min/1.73 m² (some guidelines accept ≥30 ml/min/1.73 m², but toxicity risk increases substantially below 50) 3, 1
• No absolute contraindications are present 3, 1

Recommended Corticosteroid Regimen

• Intravenous methylprednisolone 1 g daily for 3 days at months 1,3, and 5 3, 1
• Plus oral prednisone 0.8–1 mg/kg/day for 2 months, then taper by 0.2 mg/kg/day per month over the remaining 4 months 3, 1
• Italian trials using this regimen demonstrated 97% 10-year renal survival versus 53% without immunosuppression 3, 1

Absolute Contraindications to Corticosteroids

Do not use corticosteroids in patients with:

• eGFR <30 ml/min/1.73 m² (use only with extreme caution, if at all) 3, 1
• Diabetes mellitus 3, 1
• Obesity (BMI >30 kg/m²) 3, 1
• Active or latent infections (tuberculosis, hepatitis B/C, HIV) 3, 1
• Uncontrolled psychiatric disease 3, 1
• Severe osteoporosis 3, 1
• Active peptic ulceration 3, 1
• Liver cirrhosis or other secondary disease 3, 1

The risk/benefit profile of glucocorticoids must be individually discussed with each patient, recognizing that adverse treatment effects are substantially more likely when eGFR is <50 ml/min/1.73 m² 3, 1

Immunosuppressive Agents NOT Recommended

Agent	Recommendation	Evidence
Mycophenolate mofetil	Not recommended in non-Chinese patients; may be used as glucocorticoid-sparing agent in Chinese patients only	[3,1,2]
Cyclophosphamide or azathioprine	Not recommended except in crescentic IgAN with >50% crescents and rapidly progressive renal deterioration	[3,1,2]
Calcineurin inhibitors (cyclosporine, tacrolimus)	Not recommended—lack of proven benefit	[3,1,2]
Rituximab	Not recommended—no demonstrated efficacy	[3,1,2]
Tonsillectomy	Not recommended in non-Japanese patients	[3,1,2]
Antiplatelet agents	Not recommended	[3]
Fish oil	May be considered but evidence is weak	[3]

Special Clinical Scenarios

Crescentic IgA Nephropathy (Rapidly Progressive)

• Define crescentic IgAN as >50% of glomeruli with crescents on biopsy plus rapidly progressive renal deterioration 3, 1
• Treat with corticosteroids plus cyclophosphamide using a regimen analogous to ANCA-associated vasculitis 3, 1

IgA Deposits with Minimal Change Disease Pattern

• Treat as minimal change disease with corticosteroids if nephrotic syndrome is present and kidney biopsy shows mesangial IgA deposits with otherwise minimal change histology 3, 1

Acute Kidney Injury with Macroscopic Hematuria

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

Emerging Therapies and Clinical Trial Participation

Strongly encourage enrollment in clinical trials whenever available 3, 1, 2. Emerging therapies under investigation include:

• Enteric-coated budesonide (recently received FDA accelerated approval for primary IgAN with urine protein-to-creatinine ratio >1.5 g/g) 2, 4
• Complement inhibitors (e.g., iptacopan) 3, 1, 4
• Sparsentan (dual endothelin-angiotensin receptor antagonist) 3, 1, 4
• Atrasentan 3, 1
• B-cell targeted therapies 3, 1
• Hydroxychloroquine 3, 1

These novel agents may offer superior efficacy and safety compared with conventional systemic corticosteroids 3, 1

Monitoring and Management of Adverse Effects

• Monitor serum creatinine and potassium frequently while on ACE-inhibitor/ARB therapy 1
• Instruct patients to hold ACE-inhibitor/ARB and diuretics during intercurrent illnesses that cause volume depletion (e.g., gastroenteritis, febrile illness) 1
• Manage hyperkalemia with potassium-wasting diuretics or potassium-binding agents to allow continuation of RAS blockade 1
• Correct metabolic acidosis when serum bicarbonate is <22 mmol/L 1
• Monitor proteinuria, blood pressure, and eGFR every 3 months during the supportive care phase 1, 2

Critical Pitfalls to Avoid

• Never initiate immunosuppression before completing ≥90 days of optimized supportive care (maximal RAS blockade, SGLT2 inhibitor, BP control, sodium restriction) 1, 2
• Avoid corticosteroids in patients with eGFR <30 ml/min/1.73 m² or multiple comorbidities—harms outweigh benefits 3, 1
• Do not discontinue ACE-inhibitor/ARB for creatinine rises ≤30% from baseline, as this early rise predicts better long-term outcomes 1
• Do not rely solely on Oxford MEST-C score or crescent count to decide on immunosuppression—current evidence does not support these histologic features as independent treatment triggers in the absence of clinical risk factors 1
• Do not use dual ACE-inhibitor plus ARB therapy—it increases harm without additional benefit 1