Sodium-Glucose Cotransporter-2–inhibitors in Adult Patients With Alport Syndrome

Introduction: Alport syndrome (AS) is a genetically heterogenous kidney disease characterized by microhematuria, proteinuria, and progressive chronic kidney disease (CKD). Although early renin-angiotensin system inhibitors (RASi) are standard of care, evidence on sodium-glucose cotransporter-2 inhibitors (SGLT2i) in AS is limited. Thus, this study evaluated SGLT2i effects in adult patients with AS. Methods: We conducted a retrospective, observational study, including patients with genetically confirmed AS with significant proteinuria treated with combined RASi + SGLT2i. Clinico-laboratory data were collected longitudinally and compared with the preceding decade on stable RASi alone. Chronic estimated glomerular filtration rate (eGFR) and proteinuria slopes, changes in time-averaged proteinuria, subgroups responses, and secondary SGLT2i effects were assessed. Results: Eighteen adult patients with AS (mean age: 54.3 ± 15.4 years; baseline eGFR: 61.9 ± 26.5 ml/min per 1.73 m2; median proteinuria: 1010.0 [521.8–1662.5] mg/g) initiated RASi + SGLT2i therapy. Over 24.5 ± 13.5 months, the chronic eGFR slope improved significantly (−3.48 to +0.72 ml/min per 1.73 m2/yr, P < 0.001). Time-averaged proteinuria decreased by 24.1% (P = 0.005), and longitudinal proteinuria slope improved (P = 0.038). Subgroup analyses confirmed consistent responses among patients with heterozygous COL4A3/COL4A4 carriers, normal body mass index (BMI), and preserved renal function. Secondary effects included increases in hemoglobin and bicarbonate, alongside reduction in serum uric acid and weight loss. Three nonserious adverse events occurred, and no patient progressed to kidney failure (KF). Conclusion: This real-world study suggests a potential nephroprotective role of SGLT2i in adult patients with AS, including heterozygous COL4A3/COL4A4 carriers. Benefits appeared independent of baseline BMI and renal function, supporting consideration of earlier initiation. Prospective studies are required to validate these findings and refine treatment timing.