Abstract: FR-PO717
Quantification of Uremic Toxins in Pediatric CKD: A Potential Biomarker and Mechanistic Driver of Cardiorenal Syndrome
Session Information
- Pediatric Nephrology - 1
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pediatric Nephrology
- 1900 Pediatric Nephrology
Authors
- Dalpathadu, Heshini, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
- Wade, Andrew W., Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada
Background
Cardiovascular disease is the leading cause of morbidity and mortality among pediatric chronic kidney disease (CKD) patients. This pathological interaction between the heart and kidneys, known as cardiorenal syndrome (CRS), may be caused by the accumulation of uremic toxins. Compared to adults, CRS is understudied in pediatric patients, and consequently, their composition and levels of uremic toxins are not well established. Currently, there are no definitive clinical guidelines for treating cardiovascular complications in pediatric CKD patients. Furthermore, findings from adults cannot be extrapolated to children due to the presence of preexisting cardiac (and chronic) disease in this population.
Methods
To address this gap in knowledge of CRS in children, we collected blood samples longitudinally from pediatric patients (mean age 8.3±4.9 years; 58.3% males and 41.7% females). These included 3 CKD patients with cardiac dysfunction, 3 CKD patients with resolved cardiac dysfunction, and 6 control patients who had CKD without cardiac dysfunction. Cardiac dysfunction was defined as cardiac ejection fraction <50%.
Results
In children with CKD and no cardiac dysfunction (n=13), concentrations of indoxyl sulfate (IS) and fibroblast growth factor-23 (FGF23) were 355.1±147.9 ng/mL and 54.1±45.5 ng/mL, which are 24-fold lower and 42-fold higher, respectively than levels seen in adults. Levels of p-cresyl sulfate (4.0±1.3 ng/mL) and trimethylamine N-oxide (34.1±11.5 ng/mL) (n=28) were not significantly different from adults. In patients with CKD and ongoing cardiac dysfunction (n=3), IS and FGF23 concentrations increased to 3,245.3±431 ng/mL and 2,206.7±974.9 ng/mL, respectively. The levels of IS and FGF23 normalized in children whose cardiac dysfunction resolved (n=5). We further investigated these findings using an in vitro model. Human induced pluripotent stem cells were differentiated to beating cardiomyocytes and exposed to IS (4000-8000 ng/mL). Following exposure, initial results show that the beating rate decreased from 52±15 to 26±7 beats per minute.
Conclusion
Our results highlight important pediatric differences in the serum concentrations of IS and FGF23. Our in vitro model recapitulates the effects of uremic toxins on cardiac function and provides insight into the mechanism of cardiorenal syndrome.