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Abstract: SA-PO626

Single Cell Immune Profiling Reveals Pro-Inflammatory Mechanisms Linked to Dysbiosis and Cardiovascular Disease in Children With CKD

Session Information

  • Pediatric Nephrology - II
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pediatric Nephrology

  • 1800 Pediatric Nephrology

Authors

  • Holle, Johannes, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Anandakumar, Harithaa, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Löber, Ulrike, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Dueck, Anne, Technische Universitat Munchen, Munchen, Bayern, Germany
  • Schlender, Julia, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Sallmon, Hannes, German Heart Institute Berlin, Berlin, Berlin, Germany
  • Behrens, Felix, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Kirwan, Jennifer A., Berlin Institute of Health at Charite, Berlin, Berlin, Germany
  • Oh, Jun, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Engelhardt, Stefan, Technische Universitat Munchen, Munchen, Bayern, Germany
  • Forslund, Sofia Kirke, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Müller, Dominik, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Bartolomaeus, Hendrik, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Wilck, Nicola, German Centre for Cardiovascular Research, partner site Berlin, Berlin, Berlin, Germany
Background

Controlling chronic inflammatory processes as a major risk factor for cardiovascular disease (CVD) is of outstanding importance in chronic kidney disease (CKD) to reduce CKD-associated morbidity. The underlying mechanisms of inflammation in CKD are incompletely understood, but may be linked to gut dysbiosis. We aimed to characterize microbiota-immune interactions in pediatric CKD patients, thus independent of confounding comorbidities frequently seen in adult patients.

Methods

We analyzed the fecal microbiome, metabolites and immune phenotypes in 48 children (normal kidney function, CKD stage G3-G4, G5 treated by hemodialysis (HD) or kidney transplantation) with a mean age of 10.6 ± 3.8 years. We validated and further expanded our knowledge in a second cohort of 38 patients linking cardiovascular phenotypes to single immune cell transcriptomics.

Results

Serum TNF-α and sCD14 were stage-dependently elevated, indicating inflammation, gut barrier dysfunction and endotoxemia. We observed compositional and functional alterations of the microbiome, including a diminished production of short-chain fatty acids. Plasma metabolite analysis revealed a stage-dependent increase of tryptophan metabolites of bacterial origin. Serum from HD patients activated the aryl hydrocarbon receptor and stimulated TNF-α production in monocytes, corresponding to a pro-inflammatory shift from classical to non-classical and intermediate monocytes. Unsupervised analysis of T cells revealed a loss of mucosa-associated invariant T (MAIT) cells and regulatory T cell subtypes in HD patients. Pro-inflammatory immune cell patterns were confirmed and further described using targeted proteomics and CITE-sequencing in the validation cohort.

Conclusion

Gut barrier dysfunction and microbial metabolite imbalance mediate the pro-inflammatory immune phenotype, thereby driving the susceptibility to cardiovascular disease. Thus, the data highlight the importance of the microbiota-immune axis in CKD irrespective of confounding comorbidities. Further investigations are ongoing to highlight the role of microbiome-immune interaction as an emerging treatment target in CKD patients.

Funding

  • Private Foundation Support