Functional vs Structural Renal Outcomes of SGLT2 Inhibitors in Autosomal Dominant Polycystic Kidney Disease: A Systematic Review of Preclinical and Clinical Evidence.

Abstract

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) provide significant renoprotection in chronic kidney disease, but their efficacy in autosomal dominant polycystic kidney disease (ADPKD) remains unclear.

Objective: To systematically assess preclinical and clinical data regarding the effectiveness, safety, and mechanisms of SGLT2i in ADPKD.

Data sources: PubMed, Embase, and Scopus were searched from database inception to May 2026.

Eligibility criteria: Preclinical polycystic kidney models and clinical trials/observational studies of ADPKD evaluating any SGLT2i.

Methods: Two reviewers independently screened studies and extracted data following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 standards. Bias was evaluated using SYRCLE and relevant clinical tools.

Results: Eleven studies satisfied the inclusion criteria: 4 preclinical rodent models, 1 current randomized controlled trial, and 6 observational/case-based clinical investigations. Preclinical results consistently showed decreased cyst load, inflammation, and fibrosis while also enhancing renal hemodynamics. Emerging clinical evidence demonstrated advantages in managing blood pressure, decreasing proteinuria, and improving metabolic measures, with slight or inconsistent effects on overall kidney volume. Diverse clinical data prevented quantitative meta-analysis.

Relevance to patient care and clinical practice: This review addresses a significant gap by comparing the functional and structural renal outcomes of SGLT2i in ADPKD. It indicates that although SGLT2i provides multi-pathway functional nephroprotection (natriuretic, anti-inflammatory, antifibrotic), structural reduction of cyst growth needs additional clinical validation. These results provide reassurance to clinicians concerning short-term safety and advocate for the use of SGLT2i as effective supplements to control blood pressure, metabolic markers, and proteinuria in ADPKD, regardless of structural kidney alterations.

Conclusion: Preclinical findings suggest that SGLT2i provides renal protection in ADPKD through metabolic, anti-inflammatory, and antifibrotic mechanisms. Nevertheless, well-structured randomized controlled trials are necessary to validate long-term clinical effectiveness and safety.