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Abstract: SA-PO170

Variability in Uromodulin Production and Its Response to Water Loading in Healthy Subjects and Patients With Stone Disease

Session Information

Category: Bone and Mineral Metabolism

  • 402 Bone and Mineral Metabolism: Clinical

Authors

  • LaFavers, Kaice Arminda, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States
  • Gaddy, Anna R., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Micanovic, Radmila, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States
  • Williams, James C., Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States
  • Coe, Fredric L., University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States
  • El-Achkar, Tarek M., Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States
  • Worcester, Elaine M., University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States
Background

Uromodulin is a protein made only by the kidney and released in the urine and circulation. This protein has multiple functions and its high abundance in the urine inhibits stone formation. The physiological determinants of uromodulin production are incompletely understood.

Methods

We investigated the dynamic hourly changes in uromodulin levels and the key factors governing its production and release in urine and serum. We specifically tested the effect of water loading, a common intervention prescribed to prevent stone formation. During a two-day period, 17 stone patients and 14 healthy controls were subjected to water loading (day 1) and compared with normal fluid intake (day 2). Uromodulin levels along with other analytes and creatinine were measured by ELISA on timed hourly measurements in the urine and plasma during the period of the study.

Results

Compared to the rate of creatinine excretion, there was a significant variability in the rate of uromodulin secretion within subjects during the hours of the study in both days. Water loading increased urinary uromodulin secretion (35 vs. 9 ug/min at baseline, p <0.0001) in stone formers and healthy controls. Despite high urine volumes, most patients maintained a relatively stable range of urinary uromodulin concentration. Native Western blots for polymerizing and non-polymerizing uromodulin forms suggest that polymerizing uromodulin was the form predominantly produced at higher urinary flow volumes. In addition to urine flow rates, urine sodium excretion and stone disease were significant determinants of increased urinary uromodulin production. Serum uromodulin levels were unaffected by water loading and were not associated with urinary uromodulin.

Conclusion

Increased water intake and high urine volumes enhance the secretion of urinary polymerizing uromodulin, which is likely to be beneficial in stone formers. Our study underscores the differential regulation of serum and urine uromodulin. We propose that in a physiological setting, kidney maintains a stable range of polymerizing urinary uromodulin concentration by increasing uromodulin production in the settings of high urine volumes.

Funding

  • NIDDK Support