Water Loading and Uromodulin Secretion in Healthy Individuals and Idiopathic Calcium Stone Formers

Abstract

Background Uromodulin is a protein made only by the kidney and released in urine, circulating in polymerizing and nonpolymerizing forms. This protein's multiple functions include inhibition of stone formation in the urine. The physiological determinants of uromodulin production are incompletely understood. Methods We investigated changes in uromodulin levels and key factors governing its production and release in urine and serum. We performed an experiment to determine whether water loading, a common intervention to prevent stone formation, will alter the rate of uromodulin production. During a 2-day period, 17 stone forming participants and 14 control participants were subjected to water loading (day 1) and normal fluid intake (day 2). Uromodulin levels were measured on timed hourly collections in urine and plasma during the period of the study. Results Water loading increased urinary uromodulin secretion (33±4 versus 10±4 μg/min at baseline, P < 0.0001) in stone formers and control participants. Despite high urine volumes, most participants maintained relatively stable urinary uromodulin concentrations. Native Western blots for polymerizing and nonpolymerizing uromodulin suggest that polymerizing uromodulin was the predominant form at higher urinary flow volumes. Urine flow rates and sodium excretion were significant correlates of urinary uromodulin production. Water loading did not affect serum uromodulin levels, which were also not associated with urinary uromodulin. Conclusions Water loading increases the secretion of polymerizing urinary uromodulin. This increased secretion reduces the variability of urinary uromodulin concentrations despite high urine volumes. Serum uromodulin levels were not affected by this treatment.

The Role of Water in Uromodulin Regulation

“…LaFavers et al studied 17 calcium stone formers and 14 control participants over a 2-day period and examined the impact of a prescribed water loading and ad lib intake on urine volume, raw uromodulin concentration (ng/ml), and uromodulin secretion accounting for the urine rate (ug/min). 7 In the overall cohort, compared with baseline, urine flow rate was higher in the ad lib and water load period by 2.8- and 7.6-fold, respectively. Despite higher urine flow rate, uromodulin concentrations remained relatively stable in most participants, while uromodulin secretion was significantly increased with water loading compared with the baseline and ad lib periods.…”

“…6 In this issue of CJASN , LaFavers et al investigated changes in uromodulin concentrations in response to water loading. 7 This experiment offers new insights into the regulation of uromodulin secretion and its implications on kidney health.…”

Uromodulin biology

“…The association of 24-h uUMOD levels with both UMOD rs12917707 variants (i.e., G and T alleles) was confirmed and subjects with higher uUMOD had higher eGFR [ 113 ]. Interestingly, not only Na + excretion, but also higher urine volume (e.g., following water loading) increased 24-h uUMOD excretion without changing uUMOD concentration [ 114 ].…”