Future Possibilities for Step Therapy in IgA Nephropathy Treatment

EP: 1.Advancing IgA Nephropathy Care: Emerging Therapies, Unmet Needs, and Economic Considerations

EP: 2.Introduction to IgA Nephropathy

EP: 3.Pathogenesis of IgA Nephropathy: The 4-Hit Cascade, A Proliferation-Inducing Ligand (APRIL), and cytokines

EP: 4.Diagnosing IgA Nephropathy

EP: 5.Signs and Symptoms of IgA Nephropathy

EP: 6.Challenges in Timely Identification of IgA Nephropathy

EP: 7.Clinical Impact of IgA Nephropathy and Quality of Life

EP: 8.Overview of Treatment Landscape for IgA Nephropathy: Standard of Care and KDIGO Guidelines

EP: 9.Current Treatments for IgA Nephropathy and the 4-Hit Cascade

EP: 10.Gaps in Patient Care for IgA Nephropathy

EP: 11.Emerging Anti-BATH- and Anti-APRIL Therapies

EP: 12.Emerging Therapies: Other Strategies and Important Considerations

EP: 13.The Promise of Emerging Therapies for IgA Nephropathy and Future KDIGO Guidelines

EP: 14.Sequencing and Individualizing Treatments for IgA Nephropathy

EP: 15.Measuring Success in IgA Nephropathy in Clinical Practice

EP: 16.Economic Impact of IgA Nephropathy for Patients

EP: 17.Early Diagnosis and Cost Mitigation in IgA Nephropathy

EP: 18.Cost Implications of Modulating IgA Nephropathy Disease Course

EP: 19.Patient-Reported Outcomes in the Treatment of IgA Nephropathy

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EP: 20.Future Possibilities for Step Therapy in IgA Nephropathy Treatment

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.