What is the optimal management of an adult with IgA nephropathy, hypertension, proteinuria and decreased estimated glomerular filtration rate?

Management of IgA Nephropathy

All patients with IgA nephropathy, hypertension, proteinuria, and decreased eGFR should begin with at least 90 days of maximally tolerated ACE inhibitor or ARB therapy, strict blood pressure control, and sodium restriction before considering any immunosuppressive therapy. 1, 2

Initial Supportive Care (First 90 Days Minimum)

RAS Blockade

• Start an ACE inhibitor or ARB immediately and uptitrate to the maximally tolerated dose, regardless of blood pressure, when proteinuria exceeds 0.5 g/day 1, 2
• Continue uptitrating even if blood pressure is controlled, as the goal is maximal antiproteinuric effect, not just blood pressure reduction 1
• Do not stop ACE inhibitor/ARB if serum creatinine rises up to 30% from baseline, as this modest increase predicts better long-term renal protection 1, 3
• Only discontinue if kidney function continues to worsen beyond 30% or refractory hyperkalemia develops 1
• Dual ACE inhibitor and ARB therapy is NOT recommended due to lack of additional benefit and increased risk of hyperkalemia 1

Blood Pressure Targets

• Target systolic blood pressure <120 mmHg using standardized office measurement for most adult patients 1
• If proteinuria is <1 g/day, aim for <130/80 mmHg 1
• If proteinuria is >1 g/day, aim for the more aggressive target of <125/75 mmHg 1

Sodium Restriction and Lifestyle

• Restrict dietary sodium to <2.0 g/day (<90 mmol/day) to enhance antiproteinuric effects 1, 2
• Implement smoking cessation, weight control, and regular exercise 2
• Use loop diuretics as needed for volume management, adding thiazide-type diuretics for synergistic effect if resistant 1

SGLT2 Inhibitors - Emerging Standard

• Add an SGLT2 inhibitor (dapagliflozin or empagliflozin) to baseline ACE inhibitor/ARB therapy, as this combination significantly reduces proteinuria and slows eGFR decline even after corticosteroid treatment 1, 4
• SGLT2 inhibitors are particularly effective in patients with proteinuria >0.5 g/g and those with relatively rapid eGFR decline 4
• This represents a major advance in supportive care that should be implemented before considering immunosuppression 1

Risk Stratification After 90 Days of Optimal Supportive Care

High-Risk Criteria Requiring Immunosuppression Consideration

• Proteinuria persistently >0.75-1 g/day despite 90 days of maximally optimized supportive care (including ACE inhibitor/ARB at maximum dose, SGLT2 inhibitor, blood pressure control, and sodium restriction) 1, 2
• eGFR ≥30 ml/min/1.73 m² (immunosuppression has uncertain benefit and higher toxicity below this threshold) 1, 2

Target Proteinuria Goals

• The treatment target is proteinuria <1 g/day, which serves as a surrogate marker for improved kidney outcomes 1, 2
• However, achieving proteinuria <0.5 g/day provides substantially better long-term renal survival than 0.5-1.0 g/day 5
• Even patients with "low-risk" proteinuria of 0.44-0.88 g/g have approximately 20-30% risk of kidney failure within 10 years, emphasizing the importance of aggressive proteinuria reduction 6

Immunosuppressive Therapy Decision

When to Use Corticosteroids

Offer a 6-month course of corticosteroid therapy if:

• Proteinuria remains >1 g/day after 3-6 months of optimized supportive care 1, 2
• eGFR is ≥50 ml/min/1.73 m² (preferably ≥30 ml/min/1.73 m²) 1
• No contraindications exist (see below) 1, 2

Corticosteroid Regimen

The most effective regimen based on available evidence is high-dose pulse therapy 1:

• Intravenous methylprednisolone 1 gram for 3 days at months 1,3, and 5 1
• Plus oral prednisone 0.8-1 mg/kg/day for 2 months, then taper over the remaining 4 months 1
• This 6-month regimen showed 97% 10-year renal survival versus 53% without immunosuppression in Italian trials 1

Absolute Contraindications to Corticosteroids

• eGFR <30 ml/min/1.73 m² (use with extreme caution) 1, 2
• Diabetes mellitus 1, 2
• Obesity 1, 2
• Active or latent infections 1, 2
• Uncontrolled psychiatric disease 1, 2
• Severe osteoporosis 1, 2
• Active peptic ulceration 1, 2

Agents NOT Recommended

• Mycophenolate mofetil in non-Chinese patients 1, 2
• Cyclophosphamide or azathioprine (except in crescentic IgAN with >50% crescents) 1, 2
• Calcineurin inhibitors 1, 2
• Rituximab 1, 2
• Tonsillectomy in non-Japanese patients 1, 2

Special Clinical Scenarios

Crescentic IgA Nephropathy

• Defined as >50% of glomeruli with crescents plus rapidly progressive renal deterioration 1, 2
• Treat with corticosteroids plus cyclophosphamide using a regimen similar to ANCA-associated vasculitis 1, 2, 7
• Distinguish from acute tubular necrosis, which requires supportive therapy only 7

IgAN with Minimal Change Pattern

• If nephrotic syndrome is present with minimal change histology on biopsy, treat as minimal change disease with corticosteroids 2, 7

Monitoring Strategy

During Supportive Care Phase

• Monitor proteinuria, blood pressure, and eGFR every 3 months 2
• Assess serum creatinine and potassium frequently when on ACE inhibitor/ARB 1
• Counsel patients to hold ACE inhibitor/ARB and diuretics during intercurrent illnesses causing volume depletion 1

Managing Hyperkalemia

• Use potassium-wasting diuretics and/or potassium-binding agents to maintain normal potassium levels, allowing continuation of RAS blockade 1
• Treat metabolic acidosis if serum bicarbonate is <22 mmol/L 1

Clinical Trial Participation

• Strongly encourage enrollment in clinical trials whenever available, as novel therapies (enteric-coated budesonide, complement inhibitors, sparsentan, B-cell targeted therapies) may provide superior efficacy and safety compared to conventional corticosteroids 1, 2

Critical Pitfalls to Avoid

1. Do not start immunosuppression without first optimizing supportive care for at least 90 days, including maximal RAS blockade, SGLT2 inhibitor, blood pressure control, and sodium restriction 1, 2

2. Do not use corticosteroids in patients with eGFR <30 ml/min/1.73 m² or multiple comorbidities, as adverse effects outweigh benefits 1, 2

3. Do not discontinue ACE inhibitor/ARB for creatinine increases up to 30%, as this initial decline predicts better long-term outcomes 1, 3

4. Do not assume patients with proteinuria <1 g/day are "low risk" – they still have substantial lifetime risk of kidney failure and require aggressive supportive care 6, 5

5. Do not use the Oxford MEST-C score or crescent count alone to determine immunosuppression, as there is insufficient evidence supporting these pathologic features for treatment decisions 1