Recent advances in the clinical significance and physiological functions of uromodulin: a narrative review

Uromodulin, also called Tamm-Horsfall protein, is a kidney-specific glycoprotein primarily synthesized in the thick ascending limb of Henle’s loop. This review summarizes recent advances in its multifaceted physiological roles across urinary, interstitial, and circulatory compartments. In urine, It inhibits urinary tract infections and prevents renal stones by modulating calcium/magnesium reabsorption via ion channels. In the interstitium, preclinically and observationally, uromodulin regulates water-salt balance via the sodium-potassium-2-chloride cotransporter 2/sodium-chloride cotransporter (NKCC2/NCC) phosphorylation, influences blood pressure, and exerts dual immunomodulatory effects. Serum uromodulin (sUMOD) exhibits systemic antioxidant activity (preclinical models) and mitigates vascular calcification (in vitro/animal studies), with associations to multiple disease outcomes—suggesting biomarker potential. Despite progress, unresolved questions remain regarding uromodulin’s secretory regulation, post-translational modifications, and therapeutic potential. Key future research priorities are standardizing its detection methods (addressing assay heterogeneity) and clarifying its role in chronic kidney disease (CKD), acute kidney injury (AKI), and cardiovascular diseases. This review comprehensively synthesizes literature to clarify these aspects, emphasizing its physiological roles and observational clinical associations to guide potential clinical translation.Clinical trial number Not applicable.