Chronic kidney disease (CKD) is a multisystem disease with lifelong consequences and a significant shorter expected lifespan, of which highly accelerated cardiovascular disease (CVD) is the leading cause of mortality. The accumulation of toxic organic metabolites, so called “uremic toxins” that are eliminated by healthy kidneys via the urine, plays a central role in the pathophysiology of CKD-induced vasculopathy, but knowledge on uremic toxin-driven aberrant signaling pathways is limited. Previous research, primarily focusing on the effect of selective uremic toxin removal, has failed to improve clinical outcomes in CKD. A comprehensive, in-depth insight in the signaling pathways disturbed by uremic toxins in CKD-induced CVD is mandatory. In this impulse project, we will focus on the pediatric CKD population because it offers a unique opportunity to elucidate the CKD-related CVD per se in comparison to the adult population, as confounding pre-existing factors such as diabetes, hypertension, smoking, and aging are non-existent. 

As a first aim we will investigate the association between large scale plasma uremic toxin profiles and clinical markers of vasculopathy (i.e. aorta stiffness/distensibility) in pediatric CKD using a recently established local database (WP1). Secondly, we will explore the association between plasma uremic toxin concentrations and histological markers of CKD-induced vasculopathy (such as inflammation, vascular aging, and endothelial disintegration) present on parietal peritoneal and omental arteriolar tissue samples from children with CKD (prior to dialysis initiation) from the International Pediatric Peritoneal Biobank (University of Heidelberg) (WP2). The plasma uremic toxin profile will be compared with the ready-to-use multi-omics data derived from the micro-dissected omental arterioles and endothelial cells in this existing biobank, to comprehensively identify the key aberrant signaling events related to uremic toxin accumulation (WP3). To strengthen the FWO-FKM application that will follow this impulse project, we aim to establish and validate a genetically manipulated CKD zebrafish model with cardiovascular and kidney read-outs, with use of CRISPR-Cas9 technology, starting from our preliminary experiments (WP4). Based on the results of WP1-3, this model will be a unique tool for high throughout testing of innovative therapeutic strategies in CKD-induced vasculopathy. 

Altogether, this impulse project will result in the identification of key uremic toxin-driven clinical and molecular signaling pathways involved in pediatric CKD-induced vasculopathy. These data will be indispensable for the application of larger fundamental and translational grant applications (initially FWO-FKM 2024) within a sustainable research trajectory. The suggested research tract has the potential to speed up the search for new diagnostic and therapeutic markers and targets in CKD, urgently needed in both pediatric and adult CKD, to ultimately improve patient outcome and quality of life.