Mechanisms of action of the SGLT2 inhibitor canagliflozin on tubular inflammation and damage:A post-hoc mediation analysis of the CANVAS trial

Abstract

AIMS: Exposure of tubular cells to albumin stimulates pro-inflammatory pathways including the release of Monocyte Chemoattractant Protein-1 (MCP-1) which may result in interstitial fibrosis and tubular damage reflected by increased urinary kidney injury molecule-1 (KIM-1). SGLT2 inhibition reduces urine albumin-creatinine ratio (UACR) and small studies suggest it also reduces MCP-1 and KIM-1. We hypothesised that the reduction in KIM-1 observed with the SGLT2 inhibitor canagliflozin is mediated through its effect on UACR and MCP-1. To test this hypothesis, we assessed the proportion of effect of canagliflozin on KIM-1 mediated through its effects on MCP-1 and UACR in patients with type 2 diabetes and albuminuric kidney disease. MATERIAL AND METHODS: KIM-1 and MCP-1 were measured in urine samples of the CANVAS trial at baseline and week 52 with the Mesoscale QuickPlex SQ 120 platform. KIM-1 and MCP-1 were standardized by urinary creatinine. The proportion of mediated effect of canagliflozin through UACR and MCP-1/Cr on KIM-1/Cr was estimated with G-computation. RESULTS: In total, 763 (17.6% of total cohort) patients with micro- or macroalbuminuria were included. Baseline characteristics were well balanced between the canagliflozin and placebo group. At year 1, canagliflozin compared to placebo reduced UACR, MCP-1/Cr, and KIM-1/Cr by 40.4% (95%CI 31.0, 48.4), 18.1% (95%CI 8.9, 26.4), and 30.9% (95%CI 23.0, 38.0), respectively. The proportion of the effect of canagliflozin on KIM-1/Cr mediated by its effect on UACR and in turn on MCP-1/Cr was 15.2% (95%CI 9.4, 24.5). CONCLUSION: Canagliflozin reduces urinary KIM-1 suggesting decreased tubular damage. This effect was partly mediated through a reduction in MCP-1, indicative of reduced tubular inflammation, which was in turn mediated by a reduction in UACR. This post-hoc analysis suggest that urinary albumin leakage may lead to tubular inflammation and induction of injury, and provide mechanistic insight for how canagliflozin may ameliorate tubular damage, but further research is required to confirm these findings. This article is protected by copyright. All rights reserved