Kidney Week

Abstract: FR-PO458

Uromodulin Synthesis Is Reflected by Metabolic Profiles in the General Population

Session Information

• CKD: Risk Factors for Incidence and Progression - II
  November 03, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Chronic Kidney Disease (Non-Dialysis)

• 301 CKD: Risk Factors for Incidence and Progression

Authors

• Boulange, Claire, Metabometrix Ltd, London, United Kingdom

Claire Boulange,

• Olinger, Eric Gregory, University of Zürich, Zürich, Switzerland

Eric Gregory Olinger,

• Kaluarachchi, Manuja, Metabometrix Ltd, London, United Kingdom

Manuja Kaluarachchi,

• Lindon, John C., Metabometrix Ltd, London, United Kingdom

John C. Lindon,

• Tokonami, Natsuko, University of Zurich, Zurich, Switzerland

Natsuko Tokonami,

• Takata, Tomoaki, University of Zurich, Zurich, Switzerland

Tomoaki Takata,

• Devuyst, Olivier, University of Zurich, Zurich, Switzerland

Olivier Devuyst,

Background

Uromodulin (UMOD) is the most abundant protein in mammalian urine, synthesized exclusively along the thick ascending limb (TAL) in the kidney and with highly variable urinary levels in the general population. GWAS associated common variants in the UMOD promoter region, driving higher UMOD production, with increased risk for chronic kidney disease (CKD). UMOD regulates TAL transport but the mechanisms linking UMOD and risk for CKD remain unknown. We hypothesize. We speculate that the production rate of this protein imposes a metabolic burden to the TAL that might be reflected by metabolic profiles.

Methods

Overnight urine was collected from male volunteers (eGFR>80mL/min) and overnight UMOD excretion was determined (14.71±0.60mg, n=279). gender Extreme low (2.79±0.26mg, n=25) and high (34.11±2.14mg, n=25) age-matched UMOD excretion groups were defined and urine was analyzed by ¹H NMR spectroscopy and UPLC-MS. Mitochondrial phenotyping was performed on isolated TAL’s from Umod^-/-, Umod^+/+ and Tg^Umodwt/wt mice on FVB background, mimicking variable UMOD production rates in humans.

Results

Unsupervised principal component analysis evidenced natural clustering of metabolic data for urine samples stratified according to UMOD excretion. Many significant metabolic features were associated with overnight UMOD excretion in both NMR and UPLC-MS datasets. Biological interpretation pinpoint to Metabolic pathways involving these metabolites are related to protein synthesis and degradation, energy metabolism (fatty acid metabolism, citric acid cycle) and oxidative stress. Mitochondrial phenotyping revealed lower oxygen consumption rates and mitochondrial ATP production at baseline in TAL samples from Umod^-/- vs. Umod^+/+ mice; and an increased maximal respiratory capacity in those from Tg^Umodwt/wt vs. Umod^+/+ mice.

Conclusion

These results indicate a particular specific urinary metabolic profile associated with divergent UMOD production in the general population, supported by specific changes in mitochondrial metabolism reflecting uromodulin production in mouse models. The metabolic burden of increased UMOD production may, over time, contribute to CKD susceptibility.

Funding

• Government Support - Non-U.S.