GLIFAS: SGLT2 Inhibitors in Alport Syndrome, With Domenico Santoro, MD, PhD

For adults with Alport syndrome who still have proteinuria despite renin-angiotensin-aldosterone system (RAAS) blockade, adding a sodium-glucose cotransporter-2 (SGLT2) inhibitor was associated with a modest decline in proteinuria over 12 months. The data come from GLIFAS, a longitudinal observational study conducted at 16 centers in Italy.¹

Domenico Santoro, MD, PhD, full professor of nephrology and director of the Division of Nephrology and Dialysis at the University of Messina in Italy, presented the findings as a late-breaking abstract at the American Society of Nephrology (ASN) Kidney Week 2026 in Denver, Colorado. In an interview with HCPLive, he described the results as hypothesis generating. He said prospective controlled studies are needed to establish any long-term kidney benefit.

Residual Proteinuria in Alport Syndrome Despite RAAS Blockade

“At the moment, the therapy is based on early nephroprotection with RAS blockade. Yet patients, despite maximum targeted dose, have residual proteinuria,” Santoro said.

Alport syndrome is a collagen IV nephropathy caused by pathogenic variants in COL4A3, COL4A4, and COL4A5.¹ Its clinical spectrum ranges from persistent microscopic hematuria to progressive proteinuric chronic kidney disease (CKD).

SGLT2 inhibitors reduced proteinuria and slowed kidney function decline in the major nephrology outcome trials. However, Santoro noted that patients with Alport syndrome were not represented in those trials. Earlier observational work in Alport syndrome has reported albuminuria reductions after starting SGLT2 inhibitors, but those cohorts were younger or smaller and followed patients for limited periods.²,³

GLIFAS Study Design: 101 Adults With Alport Syndrome Across 16 Italian Centers

The GLIFAS investigators enrolled adults with genetically or histologically confirmed Alport syndrome who were on ongoing RAAS blockade. Eligibility required an estimated glomerular filtration rate (eGFR) of 20 to 90 mL/min/1.73 m² and proteinuria of 300 to 5000 mg/day.¹ Data were collected 12 months before SGLT2 inhibitor initiation, at initiation, and at 6 and 12 months after.

Outcomes included 24-hour proteinuria, eGFR trajectories, tolerability, and predictors of response. The team used generalized mixed effects models for proteinuria and linear mixed effects models for eGFR, with each patient serving as their own control.

The 101 patients had a median age of 52 years (interquartile range [IQR], 31-60), and 47.5% were men. Of the 77 patients with genetic confirmation, 45.5% had X-linked inheritance, 31% autosomal dominant, and 7% autosomal recessive. Dapagliflozin was used in 85.8% of patients and empagliflozin in 14.2%.

SGLT2 Inhibitors, Proteinuria, and eGFR in Alport Syndrome

Among 61 patients with complete proteinuria data, median proteinuria rose from 1.2 g/day (IQR, 0.7-2.4) 12 months before treatment to 1.5 g/day (IQR, 0.9-2.6) at SGLT2 inhibitor initiation.¹ After initiation, the trend reversed. Proteinuria fell to 1.26 g/day (IQR, 0.7-2.0) at 6 months and was 1.35 g/day (IQR, 0.6-2.4) at 12 months, a 10% reduction (P = .04).

Men had higher proteinuria, but the proteinuria response did not differ by sex (P = .39 for interaction). Body mass index (BMI), albumin, and genetic background were not associated with response.

Among 72 patients with complete eGFR data, median eGFR declined from 59 mL/min/1.73 m² (IQR, 40-90) 12 months before treatment to 52 mL/min/1.73 m² (IQR, 38-80) at initiation. It was 47 mL/min/1.73 m² (IQR, 33-74) at 6 months and 49 mL/min/1.73 m² (IQR, 31-73) at 12 months. Pre- and post-treatment eGFR trajectories did not differ significantly (P = .79).

Sex did modify eGFR trajectories (P = .03 for interaction): women showed partial recovery, and men showed persistent decline. BMI also modulated eGFR response, while dyslipidemia, albumin, and genetic background did not. No serious adverse events led to discontinuation.

Prospective SGLT2 Inhibitor Trials Needed in Alport Syndrome

The investigators concluded that the findings support SGLT2 inhibitors as add-on nephroprotection for adults with Alport syndrome on RAAS blockade.¹ In his interview, Santoro framed the data more cautiously.

“This finding should be considered hypothesis generating and does not establish a causal or sustained kidney protective effect,” Santoro said.

He said prospective controlled studies are needed to determine long-term benefit. They should also test whether the effect differs by genotype, sex, mode of inheritance, and disease stage.

“Until a few years ago, we had just one treatment for patients with Alport syndrome,” Santoro said. “This is a hope for patients with Alport syndrome to have another option, another treatment.”

Editor’s Note: Santoro reported no relevant disclosures.

References

1. Santoro D; GLIFAS Group. SGLT2 inhibitors in Alport syndrome: a national multicenter study (GLIFAS). Abstract SA-OR075. Presented at: American Society of Nephrology Kidney Week 2026; October 21-25, 2026; Denver, CO. doi:10.1681/ASN.2026mh3dxkvt

2. Boeckhaus J, Gale DP, Simon J, et al. SGLT2-inhibition in patients with Alport syndrome. Kidney Int Rep. 2024;9(12):3490-3500. doi:10.1016/j.ekir.2024.09.014

3. Toso D, Cinquina V, Ritelli M, et al. Sodium-glucose cotransporter-2-inhibitors in adult patients with Alport syndrome. Kidney Int Rep. 2026;11(5):106417. doi:10.1016/j.ekir.2026.106417