Abstract: FR-PO420
Uremic Toxins and Extracellular Vesicles as Drivers of Cardiovascular Disease in CKD
Session Information
- Pediatric Nephrology - I
November 04, 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
- Behrens, Felix, Institute of Physiology, Charité – Universitätsmedizin Berlin, Berlin, Germany
- Holle, Johannes, Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité – Universitätsmedizin Berlin, Berlin, Germany
- Chen, Chia-Yu, Experimental and Clinical Research Center (ECRC), a cooperation of Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
- Krause, Benjamin Christoph, Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Berlin, Germany
- Kriegel, Fabian L., Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Berlin, Germany
- Peters, Lisa, Institute of Physiology, Charité – Universitätsmedizin Berlin, Berlin, Germany
- Ginsbach, Laura Frieda, Institute of Physiology, Charité – Universitätsmedizin Berlin, Berlin, Germany
- Kaiser, Toralf, German Rheumatism Research Centre (DRFZ), Berlin, Germany
- Durek, Pawel, German Rheumatism Research Centre (DRFZ), Berlin, Germany
- Lehmann, Katrin, German Rheumatism Research Centre (DRFZ), Berlin, Germany
- Michalick, Laura, Institute of Physiology, Charité – Universitätsmedizin Berlin, Berlin, Germany
- Kirwan, Jennifer A., Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, Berlin, Germany
- Forslund, Sofia Kirke, Experimental and Clinical Research Center (ECRC), a cooperation of Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
- Wilck, Nicola, Experimental and Clinical Research Center (ECRC), a cooperation of Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
- Mashreghi, Mir-Farzin, German Rheumatism Research Centre (DRFZ), Berlin, Germany
- Müller, Dominik, Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité – Universitätsmedizin Berlin, Berlin, Germany
- Löber, Ulrike, Experimental and Clinical Research Center (ECRC), a cooperation of Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
- Kuebler, Wolfgang M., Institute of Physiology, Charité – Universitätsmedizin Berlin, Berlin, Germany
- Simmons, Szandor, Institute of Physiology, Charité – Universitätsmedizin Berlin, Berlin, Germany
Background
Cardiovascular disease (CVD) is the main cause of death in chronic kidney disease (CKD). However, the pathogenesis of CVD in CKD remains incompletely understood. We hypothesized that microbiome-derived uremic toxins (UTs) trigger the release of endothelial (EC-) and immune cell (IC)-derived extracellular vesicles (EVs), promoting endothelial damage and CVD.
Methods
We recruited a cohort of 94 children (mean age 10.9 years) at different stages of CKD, including patients on dialysis and after kidney transplantation (KTx), and age-matched healthy donors, offering the unique opportunity to analyze cardiovascular effects of CKD and metabolite-EV interaction in the absence of age-related confounders like diabetes and metabolic syndrome. Plasma metabolomics for 31 tryptophan-derived UTs were performed. Plasma EVs were analyzed by nanoparticle tracking analysis, flow cytometry and small RNA sequencing. EV release from PBMCs was assessed upon UT exposure.
Results
UTs of indole and kynurenine pathways were stage-dependently increased in children with CKD. Indoxyl sulfate (IS) increased 21-fold in peritoneal dialysis (PD) patients compared to healthy donors. Similar trends were seen in hemodialysis (HD), while more subtle increments were seen in CKD without dialysis and UT levels after KTx were almost normal. PD patients had elevated levels of total plasma EVs compared to healthy donors and KTx patients. Macrophage- (3-fold) and T-cell-derived EVs (6-fold) were increased in CKD without dialysis compared to healthy donors, while EC-EVs were reduced after KTx in longitudinal follow-ups and cross-sectionally comparing HD and KTx (3-fold). Sequencing revealed several differentially regulated microRNAs in EVs from CKD patients, including miR-16-5p, miR-19b-3p, miR-106a-5p, miR-451a and miR-4485. In vitro, IS dose-dependently increased EV release from PBMCs.
Conclusion
Increased levels of microbiome-derived UTs and subsequent EV release from ICs and ECs may present both a biomarker and a pathomechanism in CKD that may drive or contribute to long-term CVD.
Funding
- Government Support – Non-U.S.