Sequencing and Individualizing Treatments for IgA Nephropathy

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

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EP: 14.Sequencing and Individualizing Treatments for IgA Nephropathy

Evolution of Treatment Sequencing in IgA Nephropathy

Emerging Risk-Stratified Treatment Paradigm

The approach to IgA nephropathy management is evolving from a one-size-fits-all model to a personalized, risk-stratified framework:

Foundation Therapy (All Patients)

• Optimized supportive care: Maximal tolerated renin-angiotensin-aldosterone system blockade remains the cornerstone for all patients
• SGLT2 inhibition: Increasingly incorporated as standard foundation therapy regardless of risk category
• Comprehensive risk factor management: Blood pressure control, metabolic management, and lifestyle optimization

Risk-Based Treatment Escalation

Low-Risk Patients

• Defining characteristics: Proteinuria < 1g/day, stable estimated glomerular filtration rate (eGFR), minimal histological activity
• Approach: Foundation therapy with surveillance
• Monitoring focus: Detection of disease progression requiring therapy escalation

Moderate-Risk Patients

• Defining characteristics: Persistent proteinuria 1-3 g/day despite supportive care, mild eGFR decline
• First escalation: Targeted therapies addressing specific disease mechanisms
  • APRIL/BAFF pathway inhibitors for patients with elevated galactose-deficient IgA1 (Gd-IgA1)
  • Complement-targeted therapies for those with complement activation biomarkers
• Sequencing principle: Mechanism-specific targeted therapy before broader immunosuppression

High-Risk Patients

• Defining characteristics: Nephrotic-range proteinuria, rapid eGFR decline, crescentic features
• Approach: More aggressive initial therapy, potentially combining:
  • Short-course corticosteroids for rapid anti-inflammatory effect
  • Targeted therapy for long-term disease modification
  • Consideration of multitargeted approaches addressing multiple pathogenic pathways

Biomarker-Guided Sequential Therapy

• Initial biomarker assessment: Evaluation of Gd-IgA1 levels, autoantibodies, complement markers
• Dynamic reassessment: Periodic biomarker monitoring to guide subsequent therapeutic decisions
• Response-based adjustment: Sequential therapy modification based on the following:
  • Proteinuria reduction thresholds
  • eGFR trajectory stabilization
  • Biomarker normalization
  • Patient-reported outcomes

This evolving approach represents a significant advancement from traditional protocols, emphasizing precision medicine principles and mechanism-based therapeutic selection rather than uniform treatment escalation.