What is the appropriate management and treatment for a patient diagnosed with IGA (Immunoglobulin A) nephropathy?

Management of IgA Nephropathy

All patients with IgA nephropathy should receive optimized supportive care as first-line therapy, consisting of maximally tolerated ACE inhibitor or ARB therapy for proteinuria >0.5 g/day, blood pressure control targeting <125/75 mmHg if proteinuria >1 g/day, and cardiovascular risk reduction—with glucocorticoids reserved only for high-risk patients who have persistent proteinuria ≥1 g/day despite at least 90 days of maximal supportive care and eGFR ≥30 ml/min/1.73 m². 1, 2

Initial Assessment and Risk Stratification

• Confirm diagnosis with kidney biopsy showing mesangial IgA deposition and obtain MEST-C histologic scoring for prognostic information 1
• Assess baseline risk using the International IgAN Prediction Tool, which incorporates clinical and histologic features to estimate progression risk 1, 2
• Identify variant forms that require different management: IgAN with minimal change disease, acute kidney injury from gross hematuria, or rapidly progressive glomerulonephritis with >50% crescents 1

First-Line Treatment: Optimized Supportive Care (All Patients)

This is the foundation of therapy and must be maximized for at least 90 days before considering any immunosuppression. 1, 2

RAS Blockade

• Initiate ACE inhibitor or ARB for all patients with proteinuria >0.5 g/day, regardless of blood pressure status (Grade 1B) 1, 2
• Titrate to maximally tolerated doses before considering additional interventions 1, 3
• Do not use dual ACE inhibitor and ARB therapy as there are no data supporting this approach and it increases adverse effects 1

Blood Pressure Management

• **Target <125/75 mmHg** if proteinuria >1 g/day 1, 2
• Target <130/80 mmHg if proteinuria <1 g/day 3

Lifestyle and Cardiovascular Risk Reduction

• Dietary sodium restriction to <2.0 g/day (<90 mmol/day) 3
• Smoking cessation, weight control, and regular exercise 1, 2
• Assess and manage cardiovascular risk factors including hyperlipidemia 1, 2

Emerging Supportive Therapies

• Consider SGLT2 inhibitors as add-on therapy to ACE inhibitor/ARB, based on evidence from DAPA-CKD and EMPA-KIDNEY trials showing benefit in chronic kidney disease patients including those with glomerulonephritis 1, 4

Second-Line Treatment: Immunosuppression for High-Risk Patients

Patient Selection Criteria

Consider glucocorticoids only if ALL of the following are met: 1, 2

• Proteinuria remains ≥1 g/day (some guidelines use ≥0.75 g/day threshold) after at least 90 days of optimized supportive care
• eGFR ≥30 ml/min/1.73 m² (preferably ≥50 ml/min/1.73 m² to minimize toxicity risk)
• No contraindications to glucocorticoid therapy

Glucocorticoid Regimen

• 6-month course of glucocorticoid therapy (Grade 2B recommendation) 1, 2
• Prednisone equivalent ≥0.5 mg/kg/day with appropriate prophylaxis 1
• Include Pneumocystis jirovecii pneumonia prophylaxis, gastroprotection, and bone protection according to local guidelines 1

Critical Contraindications and High-Risk Situations

Avoid or use extreme caution with glucocorticoids in: 1, 5

• eGFR <50 ml/min/1.73 m² (significantly increased toxicity risk)
• eGFR <30 ml/min/1.73 m² (absolute avoidance recommended)
• Uncontrolled diabetes or metabolic syndrome
• Advanced age with frailty
• Obesity
• Latent infections (tuberculosis, HIV, hepatitis B or C)

Evidence and Limitations

The TESTING trial showed benefit on kidney outcomes but was terminated early due to serious adverse events including 4 fatalities despite prophylaxis, highlighting that the risk-benefit profile must be individually discussed with each patient. 1 The clinical benefit of glucocorticoids remains not fully established and should be given with extreme caution. 1

Alternative and Emerging Therapies

FDA-Approved Targeted Therapy

• Enteric-coated budesonide (nefecon) received FDA accelerated approval in December 2021 for primary IgA nephropathy with UPCR >1.5 g/g, showing 34% reduction in proteinuria at 9 months with potentially fewer systemic adverse effects than traditional corticosteroids 1, 4

Population-Specific Considerations

• Chinese patients: Consider mycophenolate mofetil as a glucocorticoid-sparing agent 1, 2, 3
• Japanese patients: Consider tonsillectomy 1, 2

Clinical Trial Enrollment

Strongly consider enrollment in clinical trials evaluating novel therapies including: 1, 2, 4

• SGLT2 inhibitors
• Sparsentan (dual endothelin-1 and angiotensin II receptor blocker)
• Atrasentan (endothelin receptor blocker)
• Complement inhibitors (e.g., iptacopan, a factor B inhibitor)
• Hydroxychloroquine
• B-cell targeting therapies

Special Clinical Situations

Rapidly Progressive IgAN (Crescentic)

• Defined by: Extensive crescent formation (>50% of glomeruli) with declining GFR, typically without gross hematuria 1
• Treatment: Cyclophosphamide and glucocorticoids following protocols for ANCA-associated vasculitis 1, 2
• Important caveat: Presence of crescents without GFR decline does not constitute rapidly progressive IgAN but requires close monitoring 1

IgAN with Minimal Change Disease Features

• Treat according to minimal change disease guidelines rather than standard IgAN protocols 1

Acute Kidney Injury from Gross Hematuria

• Supportive care for AKI is the primary management 1
• Consider repeat kidney biopsy if kidney function fails to improve within 2 weeks after hematuria cessation 1

Therapies NOT Recommended for Routine Use

Do not use the following in standard IgAN management: 2, 3

• Azathioprine
• Cyclophosphamide (except in rapidly progressive IgAN)
• Calcineurin inhibitors
• Rituximab
• Mycophenolate mofetil (except in Chinese patients)
• Tonsillectomy (except in Japanese patients)
• Fish oil supplements

Treatment Goals and Monitoring

Primary Treatment Target

• Reduce proteinuria to <1 g/day as a surrogate marker for improved kidney outcomes, now accepted by FDA as a valid endpoint 1, 2, 3

Monitoring Schedule

• Proteinuria: Every 3 months during and after treatment 2, 5, 3
• eGFR: Every 3-6 months to assess kidney function trajectory 2, 5, 3
• Blood pressure: At each clinical visit 3
• Adverse effects: Particularly infections, glucose intolerance, and weight gain if on immunosuppression 5

Critical Pitfalls to Avoid

• Do not initiate immunosuppression without first optimizing supportive care for at least 90 days 2, 3
• Do not use glucocorticoids in patients with eGFR <30 ml/min/1.73 m² due to unacceptable toxicity risk 1
• Do not rely solely on histologic findings or prediction tools to determine treatment; use serial assessments over time combining clinical, laboratory, and histologic factors 1
• Do not use the Oxford MEST-C score alone to determine when glucocorticoid therapy should be commenced as there is insufficient evidence for this approach 1
• Recognize that IgAN typically progresses slowly over years to decades, making it challenging to demonstrate treatment benefit in short-term trials, but recent data show that even patients with proteinuria <0.88 g/g have 20% risk of kidney failure within 10 years 1, 6