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Future Possibilities for Step Therapy in IgA Nephropathy Treatment

Opinion
Video

Panelists discuss how step-therapy for immunoglobulin A (IgA) nephropathy is evolving toward a more personalized approach, starting with optimized supportive care before progressing to targeted therapies based on risk stratification, disease characteristics, and biomarker profiles.

Evolving Step-Therapy Approaches in IgA Nephropathy Management

Anticipated Treatment Algorithm Evolution

As targeted therapies enter clinical practice, the traditional step-therapy approach for IgA nephropathy (IgAN) is likely to evolve toward a more personalized, mechanism-based framework:

Initial Risk Stratification and Baseline Therapy

  • All patients: Optimized supportive care with maximal tolerated renin-angiotensin-aldosterone system (RAAS) blockade and SGLT2 inhibitors as foundation therapy
  • Risk assessment: Comprehensive evaluation using proteinuria levels, estimated glomerular filtration rate (eGFR), blood pressure, and histopathologic features (MEST-C)
  • Biomarker profiling: Where available, assessment of galactose-deficient IgA1 levels, autoantibodies, and complement activation markers

Anticipated Step-Therapy Framework

Step 1: Supportive Care Optimization (3-6 months)

  • Maximal tolerated RAAS inhibition
  • Addition of SGLT2 inhibitors
  • Comprehensive lifestyle modifications and cardiovascular risk management

Step 2: Risk-Stratified Therapeutic Escalation

  • Low-risk patients (proteinuria < 1g/day, stable eGFR):
    • Continue optimized supportive care with monitoring
  • Moderate-risk patients (proteinuria 1-3 g/day despite supportive care):
    • First escalation: APRIL/BAFF inhibitors (sibeprenlimab, povetacicept)
    • Alternative first escalation: Targeted enteric-release budesonide
  • High-risk patients (nephrotic-range proteinuria, rapid eGFR decline):
    • First escalation: Combination of short-course systemic steroids with targeted therapy
    • Mechanism-driven selection: Match therapy to dominant pathophysiologic feature

Step 3: Response Assessment and Adjustment (3-6 months)

  • Adequate response (≥ 30% proteinuria reduction, stable eGFR):
    • Continue effective therapy with potential dose optimization
  • Partial response (15%-30% proteinuria reduction):
    • Augmentation strategy: Add complementary mechanism agent
    • Example: Add complement inhibitor to APRIL inhibitor therapy
  • Inadequate response (< 15% proteinuria reduction, declining eGFR):
    • Switch strategy: Change to alternative pathway inhibitor
    • Intensification: Consider multitargeted approach addressing multiple hits

Step 4: Long-term Management

  • Responders: Potential trial of extended-interval dosing or dose reduction
  • Persistent active disease: Continuous therapy with periodic reassessment
  • Progressive disease: Consider combination approaches targeting multiple pathways

Anticipated Refinements

The step-therapy approach will likely evolve to incorporate:

  • Biomarker-guided therapy selection: Matching treatment to dominant pathogenic mechanism
  • Combination approaches: Rationally designed multiagent regimens targeting different hits
  • Predictive algorithms: Using baseline characteristics to determine optimal therapeutic sequence
  • Duration optimization: Personalized decisions on treatment continuation vs withdrawal

This framework represents the anticipated evolution of IgAN management as experience with targeted therapies grows and biomarker-based patient stratification becomes more sophisticated.

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