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Abstract: TH-PO405

Microbiome-Related Changes In Autosomal Dominant Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic

Authors

  • Klawitter, Jelena, University of Colorado Denver School of Medicine, Aurora, Colorado, United States
  • Smith, Peter H., University of Colorado Denver School of Medicine, Aurora, Colorado, United States
  • Chonchol, Michel, University of Colorado Denver School of Medicine, Aurora, Colorado, United States
  • Gitomer, Berenice Y., University of Colorado Denver School of Medicine, Aurora, Colorado, United States
  • Christians, Uwe, University of Colorado Denver School of Medicine, Aurora, Colorado, United States
  • Klawitter, Jost, University of Colorado Denver School of Medicine, Aurora, Colorado, United States
Background

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by uncontrolled growth of cysts in the kidney. Many studies have reported immune system activation and infiltration of immune cells in ADPKD. In recent years, more details have emerged about the symbiotic relationship between the immune system and the microbiome. Our previous metabolomics study showed that concentrations of several microbiota-originated metabolites were altered in children with ADPKD. Here, we aimed to identify these metabolites and their contribution to ADPKD severity and progression.

Methods

Indoles and short chain fatty acids (SCFAs) were quantified in 146 patient plasma samples collected at the baseline of HALT-A PKD trial as well as in 80 healthy subjects using liquid chromatography-mass spectrometry assays. Multiple stepwise linear regression was used to calculate the associations between the microbiota-derived metabolites and ADPKD severity and progression (as calculated by the height-corrected total kidney volume (HtTKV) and estimated glomerular filtration rate (eGFR)).

Results

Indole acetic acid (IAA) and 5-hydroxyindole acetic acid (5-HIAA) were not only higher in ADPKD patients as compared to healthy subjects but were also positively associated with HtTKV at baseline (beta=0.201, p=0.013 and beta=0.254; p=0.002, respectively). SCFAs butyrate and hydroxybutyrate were lower in ADPKD patients versus healthy subjects and both negatively associated with HtTKV (beta=-0.181, p=0.004 and beta=-0.317, p<0.001, respectively; all after adjustment for age, race, sex, body mass index, systolic blood pressure). Using the same model, 5-HIAA was shown to associate negatively and butyrate positively with kidney function/ eGFR. Furthermore, baseline para-cresol was the only metabolite that significantly associated with yearly % change in HtTKV, whereas 5-HIAA and butyrate remained associated with yearly change in eGFR in patients with ADPKD.

Conclusion

Alteration in plasma levels of indole metabolites and SCFAs was observed between patients with ADPKD and healthy subjects. Several of these microbiota-derived metabolites associated with the disease severity (HtTKV and/or eGFR) and were predictive of disease progression. Follow-up studies using microbiome-targeted therapy to restore a healthy host-microbiota homeostasis could prove beneficial in patients with ADPKD.

Funding

  • NIDDK Support