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Kidney Week

Abstract: SA-PO510

Plasma Metabolomics to Identify Biomarkers and Altered Pathways in ADPKD

Session Information

  • ADPKD: Clinical Studies
    October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic

Authors

  • Baliga, Madhurima, University of Colorado School of Medicine, Aurora, Colorado, United States
  • Klawitter, Jost, University of Colorado, Aurora, Colorado, United States
  • Christians, Uwe, Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado, United States
  • Chonchol, Michel, University of Colorado, Aurora, Colorado, United States
  • Gitomer, Berenice Y., Div. Renal Diseases and Hypertension,, Aurora, Colorado, United States
  • Cadnapaphornchai, Melissa A., Rocky Mountain Pediatric Kidney Center, Rocky Mountain Hospital for Children at Presbyterian St. Luke's Medical Center, Denver, Colorado, United States
  • Klawitter, Jelena, University of Colorado Denver , Aurora, Colorado, United States
Background

Autosomal dominant polycystic kidney disease (ADPKD) is the most commonly inherited kidney disease. Though children with ADPKD show normal renal function prior to adulthood, rapid cyst development is already occurring. In this study, we aimed to identify plasma biomarkers of disease progression in the pediatric ADPKD population.

Methods

Plasma samples from 81 ADPKD patients aged 8-22 years were collected. Samples from healthy children (60 subjects, aged 1-3 years) served as a control. Metabolomic analysis was performed using liquid chromatography-mass spectrometry and differences in biomarkers between healthy subjects and ADPKD patients were evaluated. Additionally, longitudinal analysis of the ADPKD patients was completed over 36 months. Metabolites with a P value < 0.05 and a fold change of 50% or greater were identified as significant. Pathway analysis was conducted on significant metabolites.

Results

Cardiovascular risk markers and intermediates of the methionine cycle (uric acid, allantoin, cysteine, S-adenosyl-homocysteine, methionine sulfoxide), intermediates of the Krebs cycle and glycolysis (pyruvate, α-ketoglutarate, D-glyceraldehyde-3-phosphate), and bile acids (deoxycholic and cholic acids) were increased in plasma in ADPKD patients. An increase in intermediates of tryptophan metabolism (kynurenine, 3-hydroxykunurenine, xanthurenic acid and anthranilic acid) was accompanied by a decrease in nicotinamide in patients with ADPKD. The concentration of pipecolic acid, a diagnostic marker for peroxisome biogenesis disorders such as the renal cystic disorder Zellweger syndrome, was also significantly higher in ADPKD patients. Longitudinal analysis of ADPKD patients showed the above metabolites remained changed at 36 months. For the tryptophan pathway, changes became more pronounced.

Conclusion

Kynurenine metabolism is elevated in children with ADPKD suggesting that its direct targeting via, for example inhibition of the pathway’s regulating enzyme indolamine-2,3-dioxygenase (IDO1), could prevent progression of the disease. Markers of cardiovascular risk were increased in pediatric ADPKD patients compared to healthy subjects. Qualification of these as markers for disease progression could help to risk stratify patients and help identify molecular targets for further therapeutic developments.

Funding

  • NIDDK Support