Simultaneous or Sequential Treatment of IgA Nephropathy - Specific Disease Drivers and Non-specific Consequences of Nephron Loss?

The expanding therapeutic armamentarium for IgA nephropathy (IgAN) has brought to the forefront a key strategic dilemma: whether to intervene simultaneously on IgAN-specific pathogenic mechanisms and the downstream, non-specific consequences of nephron loss, or to follow a sequential, stepwise approach in which therapies are added only as residual risk becomes evident. This debate article contrasts these philosophies. Proponents of early, combined treatment, in line with KDIGO 2025 guidance, argue that the traditional paradigm of first maximizing 'supportive' care-renin-angiotensin system blockade, strict blood pressure and sodium control, and more recently SGLT2 inhibitors and mineralocorticoid receptor antagonists-before initiating immunosuppressive or other disease-directed agents embeds harmful delay. They emphasize that IgAN is driven by continuous immune activity, with ongoing production of pathogenic IgA, immune complex formation, complement activation, and glomerular injury that proceeds even when proteinuria is hemodynamically reduced. Once a critical threshold of nephron loss is crossed, self-perpetuating hyperfiltration, fibrosis, and microvascular rarefaction limit reversibility. Advocates of a more sequential strategy highlight heterogeneity in disease course, the risks and costs of polypharmacy, and the need for individualized escalation based on dynamic risk assessment. Together, the opposing yet complementary viewpoints underscore that future algorithms will likely integrate baseline risk stratification, evolving biomarkers of immune activity and chronic damage, and patient preferences to balance early, comprehensive disease control against overtreatment and toxicity in IgAN.