Effects of Empagliflozin on Urine Biomarkers in EMPA-KIDNEY

Background: Sodium-glucose co-transporter-2 (SGLT2) inhibitors substantially slow progression of CKD, but their renoprotective mechanisms are incompletely understood. Urine biomarkers have been developed to understand the role of kidney tubules in kidney disease progression. Methods: The effects of empagliflozin 10mg daily vs placebo on urine biomarkers indexed to urine creatinine were assessed using spot samples in 2752 participants from EMPA-KIDNEY at baseline, 2 months, and 18 months. Urine biomarkers included albumin, total protein, and markers of proximal tubular reabsorption (alpha-1 microglobulin [α1M]); functional reserve (epidermal growth factor [EGF], uromodulin [UMOD]); injury/inflammation (kidney injury molecule-1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL]) and; ischaemia/stress (dickkopf-3 [DKK-3], monocyte chemoattractant protein-1 [MCP-1]). Results: Empagliflozin reduced urine albumin by 19% (95%CI: -24,-14%), total protein by 7% (-11,-2%), and UMOD by 63% (-65,-61%). Empagliflozin increased α1M by 29% (25,34%), DKK-3 by 22% (16,29%), and NGAL by 7% (0,13%) (Fig 1). Overall, there were no significant effects of empagliflozin on EGF, KIM-1, and MCP-1. The magnitude of effects on biomarker concentrations were similar at 2 and 18 months. The large reductions in UMOD were evident regardless of diabetes status and primary cause of kidney disease and appeared to be greater with higher eGFR and lower albuminuria (Fig 2). Conclusion: SGLT2 inhibition increased urine biomarkers reabsorbed by proximal tubules and substantially reduced thick ascending limb-derived UMOD, without affecting other markers of tubular functional reserve, injury, and ischemia. The mechanisms of UMOD reduction require further investigation. Funding: Commercial Support - Boehringer Ingelheim, Eli Lilly and others; Clinicaltrials.gov: NCT03594110Absolute values indicate geometric mean (SE) in mg/g.