Luis Sanchez Russo, MD, is a nephrologist affiliating with Advent Health.

Luis Russo, MD, MS

KDIGO 2025 Guides Mechanism-Driven Therapy in IgA Nephropathy

 released by Kidney Disease: Improving Global Outcomes (KDIGO) mark a clear shift toward proactive, mechanism-driven disease management.

HCPLive spoke with Luis Sanchez Russo, MD, MS, a nephrologist at Central Florida Kidney Specialists and AdventHealth, to break down the clinical implications of the updated guidelines.

Pathophysiology of IgA Nephropathy: The 4-Hit Model

“I think the 2025 KDIGO guidelines are very much aligned with where the field is right now,” said Russo. “First, we now understand that this disease is not as benign as we previously thought. Second, for the first time in history, we have mechanism-driven therapeutics available.”

Recent research has aimed to explain the underlying mechanisms of IgAN with the 4-hit hypothesis.

First, circulating galactose-deficient IgA1 (Gd-IgA1) accumulates due to abnormal glycosylation, exposing antigenic sites that trigger pathogenic immune responses. Second, the immune system generates IgG and/or IgA autoantibodies against Gd-IgA1, sustaining immune activation. Third, these antibodies bind Gd-IgA1 to form circulating immune complexes, which persist because clearance mechanisms are overwhelmed. Finally, the complexes deposit in the glomerular mesangium, activating mesangial cells and releasing proinflammatory and profibrotic mediators, driving inflammation, scarring, and progressive nephron loss. Understanding these steps provides the framework for how emerging therapies intervene at multiple points along the disease cascade.

“I think the 2025 KDIGO guidelines are very much aligned with where the field is right now. There are 2 major acknowledgments reflected in these updates,” said Sanchez. “First, we now understand that this disease is not as benign as we previously thought. Second, for the first time in history, we have mechanism-driven therapeutics available.”

Notably, the 2025 KDIGO guideline encourages kidney biopsy in adults with suspected IgAN and proteinuria ≥0.5 g/d, representing a shift from the 2021 guideline, which emphasized reducing proteinuria to <1 g/d.

The guidelines also reinforce proteinuria as a validated surrogate for long-term renal outcomes. Recommended targets have been lowered to <0.5 g/d, with an ideal goal of <0.3 g/d regardless of treatment status, reflecting evidence that persistent proteinuria increases lifetime risk of kidney failure.

A major new concept is the initiation of therapies to prevent or reduce pathogenic IgA production and immune complex formation, alongside treatment strategies to manage the consequences of existing nephron loss.

Emerging therapies now allow clinicians to target multiple stages of the IgAN disease cascade.

Mucosal-directed therapy, such as Nefecon, reduces circulating Gd-IgA1 at its source. APRIL and BAFF pathway inhibitors, including Sibeprenlimab, Atacicept, and Telitacicept, help limit the production of pathogenic autoantibodies. Plasma cell–directed therapy, like Mezagitamab, reduces the formation of circulating immune complexes. Therapies targeting downstream mesangial injury and nephron loss include complement inhibitors such as Iptacopan, endothelin receptor antagonists like Sparsentan and Atrasentan, and SGLT2 inhibitors including Dapagliflozin and Empagliflozin.

Across all stages, ACE inhibitors, ARBs, and optimized blood pressure management remain central to preserving kidney function. Together, these mechanism-based approaches represent a shift toward earlier, targeted intervention across the disease continuum.

In light of the KDIGO guidelines and these mechanism-driven therapeutic landscape, many questions remain unanswered.

“There is a great deal on the horizon. Now that effective treatments are available, it is essential to understand how to use them, how to combine them, and how to sequence them. This is where real-world evidence becomes critically important,” said Russo. “We have extensive pharmaceutical and mechanistic research, but now we need to determine how best to apply these therapies to real patients. That responsibility falls on the nephrology community, to use these medications and generate meaningful real-world data.”

Editor’s Note: Russo reports no relevant disclosures. 

Floege J, Barratt J, Cook HT, et al. Executive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV). 

https://doi.org/10.1016/j.kint.2025.04.003

Barratt J, Mariani LH, Radhakrishnan J, Rizk DV, Tumlin JA, Lafayette RA. Defining Disease Modification in IgA Nephropathy: Toward a Paradigm Shift in Management. 

https://doi.org/10.1016/j.ekir.2025.09.025

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The 2025 KDIGO guidelines guide mechanism-driven therapy in IgA nephropathy, highlighting targeted interventions across the 4-hit disease cascade.

Luis Russo, MD, MS

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