Abstract: FR-PO410
Dysregulation of the Microbiome-Immune Axis Drives Cardiovascular Pathology in Early-Onset CKD
Session Information
- Hypertension and CVD: Basic
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Holle, Johannes, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
- Anandakumar, Harithaa, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
- Dueck, Anne, Technische Universitat Munchen, Munchen, Bayern, Germany
- Schlender, Julia, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
- Vecera, Valentin, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
- Müller, Dominik, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
- Thumfart, Julia, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
- Oh, Jun, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Bartolomaeus, Hendrik, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
- Wilck, Nicola, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
Background
CKD patients have a high risk for cardiovascular disease (CVD). CKD-related chronic inflammation contributes to the increased CV risk. The underlying mechanisms are incompletely understood, but gut microbial dysbiosis seems to play an important role. Here, we describe the cardiovascular and immune phenotype of children with CKD and investigate the induction of these changes by CKD-typical microbiome alterations.
Methods
We analyzed the CV phenotype by echocardiography, carotid intima-media thickness (cIMT), measurements of blood pressure (BP) and pulse wave velocity (PWV) in 38 children (normal kidney function (HC), CKD stage G3-G4 (CKD), G5 treated by hemodialysis (HD)). Additionally, we performed CITE-seq enhanced single cell RNA sequencing (scRNAseq) and flow cytometry of peripheral immune cells, targeted plasma proteomics (OLINK) and shotgun sequencing of the fecal microbiome. Lastly, from a subset of HC and HD kids, we performed fecal microbiota transplantations into GF mice and analyzed the immunophenotype and vascular function.
Results
Children with CKD showed increased BP and PWV. Our echocardiographic analysis demonstrated increased cIMT, cardiac hypertrophy and diastolic dysfunction. Immune cell analysis by flow cytometry revealed a pro-inflammatory profile with a reduction of circulating regulatory T cells. This finding could be confirmed by scRNAseq. Additionally, we identified a stage-dependent dysregulate of transcriptomes within T cell populations from CKD and HD. Using the targeted proteomics of inflammatory markers, we found 55 out of 92 measured proteins to be dysregulated, with for example an increase in TNF, PD-L1 and MCP-1. Transfer of microbiota from HD patients or HC into germ-free recipient mice (C57BL6/J) promoted early signs of immune aging and a reduced endothelial dependent vasorelaxation.
Conclusion
In the absence of traditional CV risk factors, pediatric CKD leads to a measurable alteration of the CV system. Our analysis revealed a pro-inflammatory immune cell profile. Using fecal microbiome transplantation into germ-free mice, we provide preliminary evidence for a causal role of the microbiota in promoting inflammation and CV risk. Thus, the data highlight the importance of the microbiota-immune axis in CKD.