What is the treatment for IgA (Immunoglobulin A) nephropathy in a patient with uncontrolled Diabetes Mellitus (DM) where steroid use is contraindicated?

Treatment of IgA Nephropathy in Patients with Uncontrolled Diabetes Where Steroids Cannot Be Given

In patients with IgA nephropathy and uncontrolled diabetes where steroids are contraindicated, focus exclusively on maximally optimized supportive care with RAS blockade, blood pressure control to target <125/75 mmHg, and consider mycophenolate mofetil (MMF) if the patient is of Chinese ancestry. 1

Why Steroids Are Contraindicated

The KDIGO 2021 guidelines explicitly state that glucocorticoids should be avoided entirely or given with extreme caution in patients with diabetes, as uncontrolled diabetes significantly increases the risk of serious adverse events including infections and metabolic complications. 1 This contraindication is absolute in the context of uncontrolled diabetes, as the risks clearly outweigh any potential benefits. 1

Primary Treatment: Optimized Supportive Care

RAS Blockade (First-Line Therapy)

• Institute ACE inhibitors or ARBs regardless of blood pressure status if proteinuria >0.5 g/day (Grade 1B). 1, 2
• Titrate to maximally tolerated doses before considering any other interventions. 1, 2
• RAS inhibition probably decreases proteinuria (MD -0.71 g/24h) and may preserve kidney function. 3

Blood Pressure Management

• Target blood pressure <125/75 mmHg if proteinuria >1 g/day. 4
• Target <130/80 mmHg if proteinuria <1 g/day. 2
• Strict blood pressure control is critical as it directly impacts disease progression. 1

Additional Supportive Measures

• Dietary sodium restriction to <2.0 g/day (<90 mmol/day). 1
• Dietary protein restriction may be considered based on degree of proteinuria and kidney function. 1
• Cardiovascular risk factor modification including smoking cessation, weight control, and regular physical activity. 1
• Optimize diabetes control (though this is challenging in your scenario, it remains essential). 1

Alternative Immunosuppressive Option: Mycophenolate Mofetil

If the patient is of Chinese ancestry, mycophenolate mofetil may be used as a glucocorticoid-sparing agent. 1, 4

Evidence for MMF in Chinese Patients

• KDIGO 2021 specifically states MMF may be used as a glucocorticoid-sparing agent in Chinese patients with IgAN. 1
• One study showed MMF plus RAS inhibitors lowered risk of progression to ESKD (RR 0.22,95% CI 0.05 to 0.90) and improved remission of proteinuria (RR 2.67,95% CI 1.32 to 5.39). 5
• MMF is not recommended in non-Chinese patients with IgAN. 1

MMF Dosing Considerations

• Studies in Chinese patients used MMF 1.5 g/day combined with lower-dose prednisone (0.4-0.6 mg/kg/day), which provided similar outcomes to higher-dose prednisone alone. 1
• In your case without steroids, MMF monotherapy could be considered if the patient is Chinese, though evidence is weaker. 1

Treatment Algorithm

1. Assess disease severity and prognosis using MEST-C histologic scoring and the International IgAN Prediction Tool. 1

2. Initiate maximally optimized supportive care for at least 90 days:

   • Start ACE inhibitor or ARB, titrate to maximum tolerated dose 1
   • Achieve blood pressure targets 2, 4
   • Implement dietary sodium restriction 1
   • Address cardiovascular risk factors 1

3. Reassess proteinuria after 90 days:

   • If proteinuria <0.75 g/day: Continue supportive care only 1
   • If proteinuria remains >0.75-1 g/day: Patient is high-risk for progression 1

4. For high-risk patients (proteinuria >0.75-1 g/day after 90 days):

   • If Chinese ancestry: Consider MMF as glucocorticoid-sparing agent 1, 4
   • If non-Chinese: Continue optimized supportive care and consider enrollment in clinical trial 1
   • If eGFR <30 mL/min/1.73 m²: Avoid immunosuppression entirely unless rapidly progressive disease 1

Therapies to Avoid

Do not use the following agents in routine IgAN management: 1, 2

• Azathioprine (except after cyclophosphamide in crescentic disease) 1
• Cyclophosphamide (except in rapidly progressive IgAN with >50% crescents) 1
• Calcineurin inhibitors 1
• Rituximab 1
• Fish oil (no longer recommended in updated guidelines) 1

Emerging Therapies to Consider

If available, consider enrollment in clinical trials evaluating: 1

• SGLT2 inhibitors (may augment supportive care approach) 1
• Enteric-coated budesonide (FDA-approved for IgAN with UPCR >1.5 g/g, targets gut-associated lymphoid tissue with potentially fewer systemic effects than oral steroids) 1, 6
• Sparsentan, atrasentan, or complement inhibitors 1

Treatment Goals and Monitoring

Target proteinuria reduction to <1 g/day as a surrogate marker of improved kidney outcomes. 1, 4

Monitoring Parameters

• Proteinuria every 3 months 1, 4
• Blood pressure at each visit 2
• eGFR every 3-6 months 1
• Assess for adverse effects of RAS inhibition (hyperkalemia, acute kidney injury) 3

Critical Pitfalls to Avoid

• Do not initiate immunosuppression without first optimizing supportive care for at least 90 days. 1, 2
• Do not use steroids in patients with uncontrolled diabetes—the infection risk and metabolic complications are prohibitive. 1
• Do not use MMF in non-Chinese patients as routine therapy—evidence does not support efficacy. 1
• Do not overlook the importance of blood pressure control and RAS blockade—these are the cornerstones of therapy. 1, 2
• Do not initiate any immunosuppression if eGFR <30 mL/min/1.73 m² unless rapidly progressive disease with extensive crescents. 1

Special Consideration: Rapidly Progressive Disease

If the patient develops rapidly progressive IgAN (>50% crescents on biopsy with rapidly declining GFR), cyclophosphamide plus steroids may be necessary despite diabetes. 1 In this life-threatening scenario, the benefits may outweigh risks, but this requires careful risk-benefit discussion and intensive monitoring for infectious complications. 1