#623 SGLT2 inhibitors in adult patients with Alport syndrome: a single center Italian experience

Abstract Background and Aims Alport syndrome (AS) is the most common inherited glomerular disease, caused by pathogenic variants in COL4A3, COL4A4, and COL4A5 genes, leading to distinct inheritance patterns. Structural disruption of glomerular basement membrane due to collagen IV gene variants leads to a clinical renal spectrum characterized by microhematuria, glomerular proteinuria, and progressive chronic kidney disease (CKD), often culminating in kidney failure (KF). Proteinuria is a recognized key prognostic marker for KF in AS, and combination therapy with renin-angiotensin system (RAS) blockers and SGLT2 inhibitors (SGLT2i) has recently been recommended in an AS guideline [1] to slow CKD progression. However, a randomized control trial is ongoing, and a retrospective study have evaluated its effect in a young cohort with short mean follow-up period [2]. Thus, this study aimed to evaluate the impact of SGLT2i therapy on proteinuria and estimated glomerular filtration rate (eGFR) in an older AS patients cohort. Method A retrospective, single-center, observational study involving adult patients with a confirmed genetic diagnosis of AS, treated with the maximum tolerated dose of RAS blockers and SGLT2i, following Italian regulatory agency criteria (eGFR 45–90 mL/min with uACR ≥200 mg/g, or eGFR 20–45 mL/min with or without albuminuria). Clinical, histological, and laboratory data were retrospectively collected from 5 years prior to treatment initiation until December 2024, excluding data from the first month of therapy to avoid biases related to the known initial eGFR drop upon SGLT2i initiation. Genetic diagnosis was performed using a next generation sequencing targeted glomerular genes panel. Statistical analyses included Shapiro-Wilk test, paired t-test, linear regressions, and linear mixed model, conducted using R version 4.1.2. Results Out of a cohort of 140 adult patients with AS, 20 received RAS blockers and SGLT2i treatment, and 5 of them were excluded due to a lack of post-treatment data. Baseline characteristics of the remaining 15 patients are summarized in Table 1. All patients were over 40 years of age, with a mean age of 60.4 ± 9.6 years, an eGFR of 54.5 ± 19.5 mL/min/1.73 m², and median proteinuria of 910 mg/day (IQR 340;1610). Most patients (11/15) carried heterozygous variants in COL4A3 or COL4A4 genes. The mean observation period was 17.9 ± 7.4 months, ranging from 6.1 to 32.7 months. Four patients discontinued SGLT2i due to different reasons: diarrhea, symptomatic hypotension, severe eGFR impairment, and KF. As described in Fig. 1a, eGFR slope reduced after treatment initiation (−0.19 mL/min/month before and −0.02 mL/min/month after SGLT2i, p = 0.204). Similarly, while the reduction in proteinuria did not reach statistical significance, a trend toward improvement was observed, with an estimated reduction of 19.5% from baseline (Fig. 1b, p = 0.204). Furthermore, consistent with known SGLT2i effects, haemoglobin levels increased (from 13.9 ± 1.2 to 14.3 ± 1.4, p-value: 0.060) and serum uric acid levels decreased (from 5.9 ± 1.1 to 5.4 ± 1.2, p-value: 0.060), although these changes were not statistically significant. Conclusion This study supports the potential antiproteinuric and nephroprotective effects of SGLT2i in a real-world cohort of older AS patients compared to those reported in literature, predominantly carrying heterozygous COL4A3/COL4A4 variants. Despite a relatively high discontinuation rate, no serious adverse events were observed, and symptoms resolved promptly after treatment cessation. The restricted sample size and single-center design limited the statistical power of the analyses. Nonetheless, randomized control trials (such as DOUBLE PRO-TECT Alport) are essential to better define optimal treatment strategies and timing for SGLT2i initiation in AS.

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