Interplay between uromodulin excretion and water balance in the general adult population

Uromodulin is a kidney-specific protein that is excreted in the normal urine. Factors regulating its excretion are unknown. Conflicting studies suggest that water balance may influence uromodulin excretion which, in turn, may cooperate with vasopressin to increase water reabsorption in the distal nephron. We analyzed the interplay between uromodulin excretion and water balance in a healthy adult population. Participants were recruited in a population-based study in Switzerland. The urine uromodulin excretion rate (UUER) (mg/24 h) was measured (ELISA) in parallel with urine osmolality and serum copeptin (pmol/L) (immune-luminometric assay) as a surrogate for vasopressin. Mixed multi-variate linear regression models were used. We included 937 participants with 497 (53.0%) women, median age 47.7 years (32.4-61.6) and 27 (2.8%) with eGFR <60 mL/min/1.73m². In univariate analysis, UUER was positively associated with urine volume (p < 0.001) and negatively with serum copeptin concentration (p < 0.001). In fully adjusted analysis, UUER remained positively associated with urine volume (p = 0.004) but not with serum copeptin concentration (p = 0.224). In univariate analysis, urine osmolality was negatively associated with UUER (p = 0.016). In fully adjusted analysis, namely accounting for serum copeptin and urine volume, urine osmolality was positively associated with UUER (p = 0.001). These results indicate that, in a healthy population, urine uromodulin excretion strongly associates with urine volume and, once accounting for confounding factors, influences urine osmolality in addition to vasopressin/copeptin levels. These data substantiate the role of urine flow in regulating uromodulin excretion and suggest an additive effect of uromodulin on urine concentration, alongside vasopressin.