Effects of Empagliflozin on Urine Biomarkers in EMPA-KIDNEY.

RATIONALE & OBJECTIVE: Sodium/glucose cotransporter 2 (SGLT2) inhibitors substantially slow progression of chronic kidney disease and reduce the risk of acute kidney injury, but their effects on kidney physiology are incompletely understood. This study assessed the effects of empagliflozin on a comprehensive set of urinary tubular and glomerular biomarkers. STUDY DESIGN: Randomized controlled trial. SETTING & PARTICIPANTS: 2,752 participants from EMPA-KIDNEY. EXPOSURE: Empagliflozin, 10 mg daily, versus placebo. OUTCOME: Urine biomarkers indexed to urinary creatinine and averaged across on-study time points. Urine biomarkers included markers of glomerular disease (albumin, total protein); proximal tubular reabsorption (α1-microglobulin [A1M]); 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 urinary albumin by 19% (95% CI, -24% to -14%), total protein by 7% (-11% to -2%), and UMOD by 63% (-65% to -61%). It increased A1M 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% to 4%]), KIM-1 (2% [-1% to 6%]), and MCP-1 (0 [-4% to 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 estimated glomerular filtration rate (eGFR) and/or albuminuria. Exploratory mediation analyses suggest that reductions in albuminuria and UMOD accounted for 32% (15% to 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. CONCLUSIONS: SGLT2 inhibition imparts a large and sustained reduction in urinary 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. PLAIN-LANGUAGE SUMMARY: Sodium/glucose cotransporter 2 inhibitors or "flozins" are medications that prevent kidney failure and acute kidney injury in a broad range of patients with kidney disease. However, exactly how these drugs exert their kidney protective effects is incompletely understood. In a large clinical trial involving patients with varying causes of kidney disease, empagliflozin reduced excretion of 2 common proteins in the urine (albumin and uromodulin). The substantial reduction in uromodulin was unexpected and is of particular interest because uromodulin is manufactured in a later part of the kidney beyond the site of action of empagliflozin. New experiments are needed to understand these results and assess whether the effect on uromodulin can explain the benefits of flozins for the kidney.