Sodium-glucose cotransporter inhibition in polycystic kidney disease: fact or fiction

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary kidney disease. Recent evidence suggests that the pathogenesis of ADPKD is a complex web of abnormal cellular processes including altered cell signaling, disordered cell metabolism, impaired autophagy, increased apoptosis, mitochondrial dysfunction and chronic inflammation. Sodium-glucose cotransporter (SGLT) inhibitors (SGLTi) reduce body weight, blood pressure and blood glucose levels, have kidney and cardiovascular protective activity, and have been reported to decrease inflammation, increase autophagy and improve mitochondrial dysfunction. We now review results from preclinical studies on SGLTi for ADPKD identified through a systematic search of the MEDLINE, Cochrane Library, Embase and PubMed databases. Potential underlying mechanisms for the conflicting results reported as well as implications for clinical translation are discussed, as ADPKD patients were excluded from clinical trials exploring kidney protection by SGLT2 inhibitors (SGLT2i). However, they were not excluded from cardiovascular safety trials or trials for cardiovascular conditions. A post-hoc analysis of the kidney function trajectories and safety of SGLT2i in ADPKD patients enrolled in such trials may provide additional information. In conclusion, SGLT2i are cardio- and nephroprotective in diverse clinical situations. Currently, it is unclear whether ADPKD patients may benefit from SGLT2i in terms of kidney function preservation, and their safety in this population remains unexplored. We propose a roadmap to address this unmet clinical need.

Keywords: SGLT inhibitors; apoptosis; autophagy; canagliflozin; dapagliflozin; polycystic kidney disease.

FIGURE 1:

The suggested mechanisms of polycystic kidney disease (PKD) leading to higher tubular and cystic epithelial cell proliferation with higher cyst index are shown with red arrows. The possible beneficial effects of SGLTi on polycystic kidney disease (PKD) are shown with green arrows as they can interfere in multiple pathological processes of PKD by adjustments in metabolism via their glucosuric effects. SGLTi, sodium–glucose co-transporter inhibitor; HIF, hypoxia-inducible factor.