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

Luis Russo, MD, MS

Rare Disease Day 2026: Kidney Diseases Enter Optimistic Therapeutic Era

On Rare Disease Day 2026, 4 clinicians share their insights and perspectives on the groundbreaking improvements in the rapidly evolving field of rare kidney diseases.

Despite persistent awareness gaps in rare kidney disease care, a wave of FDA approvals and phase 3 trial successes in 

 alongside updated 2025 KDIGO Practice Guidelines, has fueled growing clinician optimism about a rapidly advancing, disease-modifying treatment era.

Rare kidney diseases remain complex and underrecognized, leaving both patients and clinicians with challenges in early diagnosis, risk stratification, and long-term management. Yet recent scientific advances and regulatory approvals are beginning to reshape the therapeutic landscape.

Momentum in rare kidney disease care has accelerated with multiple FDA approvals supported by pivotal clinical trial data. In IgAN, 

demonstrated significant reductions in proteinuria and preservation of kidney function in the NefIgArd trial, while 

, a dual endothelin-angiotensin receptor antagonist, showed positive outcomes in the PROTECT study. The addition of 

, an endothelin A receptor antagonist, further underscores the diversification of therapeutic strategies in IgAN, with the ALIGN Phase III trial demonstrating clinically meaningful reductions in proteinuria, a key surrogate for slowing disease progression. Iptacopan, a factor B inhibitor targeting the alternative complement pathway, reported encouraging efficacy in the APPLAUSE-IgAN trial, highlighting a precision-based approach to treatment.

In C3G, iptacopan also showed promising results in the 

, alongside other complement-targeted therapies such as 

 and danicopan, reflecting growing opportunities for disease modification in a previously limited treatment space.

These advances are complemented by the updated 

, which provide evidence-based recommendations to support clinicians in diagnosis, monitoring, and treatment selection, fostering a more standardized and patient-centered approach.

Together, these therapies, spanning endothelin-angiotensin signaling modulation, complement inhibition, and targeted anti-inflammatory strategies, illustrate a shift toward precision medicine in rare kidney disease. 

Editor's Note: Norouzi reports relevant disclosures with Calliditas, Travere, Apellis, and others. Appel reports relevant disclosures with Novartis, Travere Therapeutics, and others. Russo reports no relevant disclosures. Arora declares no relevant disclosures.Reference

6 New Kidney Disease Medications Approved in 2025. National Kidney Foundation. Published January 21, 2026. 

https://www.kidney.org/news-stories/6-new-kidney-disease-medications-approved-2025

Sayna Norouzi, MD, Cheung K, Skolnik E, Peleg Y. 2025 KDIGO Guideline Update for IgAN. Hcplive.com. Published January 14, 2026. Accessed February 28, 2026. https://www.hcplive.com/view/2025-kdigo-guideline-update-for-igan

Perkovic V, Barratt J, Rovin BH, et al; APPLAUSE‑IgAN Investigators. 

Alternative complement pathway inhibition with iptacopan in IgA nephropathy.

 N Engl J Med. 2025;392(6):531‑543. doi:10.1056/NEJMoa2410316. Published online 2024 Oct 25.

Kavanagh D, Bomback AS, Vivarelli M, et al. 

Oral iptacopan therapy in patients with C3 glomerulopathy: a randomized, double‑blind, placebo‑controlled, phase 3 study.

 Lancet. 2025;406(10512):1587‑1598. doi:10.1016/S0140‑6736(25)01148‑1.

Lafayette R, et al; NefIgArd Investigators. 

Efficacy and safety of a targeted‑release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2‑year results from a randomized phase 3 trial.

KDIGO IgAN and IgA Vasculitis Work Group; Rovin BH, Barratt J, Cook HT, et al. 

KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV).

 Kidney Int. 2025;108(4S):S1‑S71. doi:10.1016/j.kint.2025.04.004.

Novartis receives FDA accelerated approval for Fabhalta (iptacopan), the first and only complement inhibitor for reduction of proteinuria in adults with primary IgA nephropathy.

Novartis investigational atrasentan Phase III study demonstrates clinically meaningful proteinuria reduction in patients with IgA nephropathy (ALIGN).

Videos

On Rare Disease Day 2026, clinicians share their perspective on the evolving landscape for IgAN and C3G. 

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

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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