Effects of Empagliflozin on Urine Biomarkers in EMPA-KIDNEY
(2025) American Journal of Kidney Diseases — (2025)
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- Rationale & objective: Sodium-glucose co-transporter 2 (SGLT2) inhibitors substantially slow progression of chronic kidney disease and reduce risk of acute kidney injury, but their effects on kidney physiology are incompletely understood. This study sought to assess the effects of empagliflozin on a comprehensive set of urine tubular and glomerular biomarkers. Study design: Randomized controlled trial. Setting & participants: 2,752 participants from EMPA-KIDNEY. Exposure: Empagliflozin 10mg daily versus placebo. Outcome: Urine biomarkers indexed to urine creatinine and averaged across on-study timepoints. Urine biomarkers included markers of glomerular disease (albumin, total protein); proximal tubular reabsorption (alpha-1 microglobulin [α1M]); functional tubular reserve (epidermal growth factor [EGF], uromodulin [UMOD]); tubular injury/inflammation (kidney injury molecule-1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL]) and; tubular ischemia/stress (dickkopf-3 [DKK-3], monocyte chemoattractant protein-1 [MCP-1]). Analytical approach: Mixed model repeated measures. Results: Allocation to empagliflozin reduced urine albumin by 19% (95% CI; -24,-14%), total protein by 7% (-11, -2%), and UMOD by 63% (-65, -61%). It increased α1M by 29% (25, 34%), DKK-3 by 22% (16, 29%), and NGAL by 7% (0, 13%). Overall, there were no significant effects on EGF (1%, -1,4%), KIM-1 (2%, -1,6%), and MCP-1 (0%, -4,3%). The magnitude of effects on biomarker levels was generally similar at 2 and 18 months of follow-up. The large reductions in UMOD were evident regardless of baseline diabetes status, primary cause of kidney disease, and level of eGFR and or albuminuria. Exploratory mediation analyses suggest that reductions in albuminuria and UMOD accounted for 32% (15-52%) of the beneficial effect of empagliflozin on chronic eGFR slope. Limitations: The mediation analyses cannot be used to formally confirm that UMOD reduction is a causal mediator for the kidney benefits of SGLT2 inhibitors. Conclusion: SGLT2 inhibition imparts a large and sustained reduction in urine UMOD, and also increases some biomarkers partially reabsorbed by proximal tubules, without consistently affecting markers of tubular injury. These effects deserve further detailed experimental exploration, particularly the effect on thick ascending limb-derived UMOD, which could represent a novel mechanism of kidney protection.
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Malijan, G. B., Sardell, R. J., Staplin, N., Devuyst, O., Chapman, D., Hill, M., Nägele, N., Moffat, S., Wijayaratne, D., Donovan, K., Zhu, D., Steubl, D., Hauske, S. J., Petrini, M., Ng, S. Y. A., Pontremoli, R., Cherney, D. Z. I., Tuttle, K. R., Landray, M. J., et al. (2025). Effects of Empagliflozin on Urine Biomarkers in EMPA-KIDNEY. American Journal of Kidney Diseases. Accepted/in-press. https://doi.org/10.1053/j.ajkd.2025.10.004 (Original work published 2025)