Uromodulin Drop Offers Clues to SGLT2 Kidney Protection, With Greco Malijan, MD

Findings from the EMPA-KIDNEY trial's urine biomarker substudy suggest empagliflozin's kidney-protective effects may reach further into the nephron than previously understood, said G. A sharp, sustained drop in urinary uromodulin may be part of that kidney-protective mechanism, rather than simply a treatment-related effect.

Greco Malijan, MD, MSc, a DPhil researcher in the Renal Studies Group at the University of Oxford's Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), lead author on the analysis, spoke in an interview with HCPLive about the findings published in the American Journal of Kidney Diseases.

The study examined urine tubular biomarkers in 2,752 EMPA-KIDNEY participants randomized to empagliflozin or placebo. SGLT2 inhibitors are known to act in the proximal tubule, with activation of tubuloglomerular feedback considered a key mechanism of kidney protection. But reductions in acute kidney injury risk and kidney function decline among patients with low levels of albuminuria have raised the possibility of additional tubular effects, prompting investigators to examine a broader range of urine biomarkers in EMPA-KIDNEY.

Acute eGFR Dips Were Not Linked to Tubular Injury

Empagliflozin produced the expected early dip in estimated glomerular filtration rate (eGFR), but that dip was not associated with changes in markers of tubular injury or stress.

"We recognize that clinicians and prescribers may hesitate to initiate SGLT2 inhibitors due to this primarily hemodynamic effect," Malijan said. "Hopefully these biomarker findings may help allay concerns regarding these acute changes related to therapy."

A 63% Drop in Uromodulin, From an Unexpected Site

The most striking finding was a 63% reduction in urinary uromodulin, a protein secreted by the thick ascending limb of the loop of Henle, a segment distal to where SGLT2 is expressed. Empagliflozin also reduced urinary albumin by 19% and total protein by 7%.

Because observational studies have linked higher urine uromodulin to better kidney outcomes, while Mendelian randomization studies point in the opposite direction, the finding could have cut either way. Malijan said the randomized analysis was consistent with the latter evidence.

"The data from our randomized analysis actually support the latter and suggest that uromodulin reduction may even be a part of the mechanism of kidney protection," Malijan said.

Levels of alpha-1 microglobulin and dickkopf-3 rose modestly (29% and 22%, respectively). Malijan said these increases were likely related to changes in proximal tubular protein handling rather than tubular injury or stress, a reading reinforced by the absence of meaningful changes in kidney injury molecule-1 and monocyte chemoattractant protein-1; neutrophil gelatinase-associated lipocalin rose only marginally (7%).

Uromodulin and Albuminuria Accounted for 32% of the Kidney Benefit

An exploratory mediation analysis found that reductions in albuminuria and uromodulin together accounted for 32% (95% CI, 15%-52%) of empagliflozin's benefit on chronic eGFR slope. Malijan called the results hypothesis-generating and said the next step is for translational researchers to test whether the uromodulin pathway is a true mechanistic mediator of kidney protection rather than simply a marker that tracks with it.

"SGLT2 inhibitors are standard of care in chronic kidney disease, and they will be widely used globally," Malijan said. "We hope then that the hypothesis generated by our work would trigger exploration by translational researchers using experimental models so that we may actually fully understand the underlying mechanisms of kidney protection of this remarkable class of medication in kidney disease."

Editor's note: EMPA-KIDNEY was sponsored by Boehringer Ingelheim, with additional grant funding from Eli Lilly and Company to the University of Oxford. Several study authors reported grant funding or consultancy fees from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, AstraZeneca, and other pharmaceutical companies; individual disclosures are listed in the published manuscript.

References

1. Malijan GB, Sardell RJ, Staplin N, et al. Effects of Empagliflozin on Urine Biomarkers in EMPA-KIDNEY. Am J Kidney Dis. 2026;87(4):553-563.e1. doi:10.1053/j.ajkd.2025.10.004.

2. Herrington WG, Staplin N, Wanner C, et al; EMPA-KIDNEY Collaborative Group. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388(2):117-127. doi:10.1056/NEJMoa2204233.

3. Ponte B, Sadler MC, Olinger E, et al. Mendelian randomization to assess causality between uromodulin, blood pressure and chronic kidney disease. Kidney Int. 2021;100(6):1282-1291. doi:10.1016/j.kint.2021.08.032.