Background: Chronic kidney disease (CKD) is a major risk factor for cardiovascular disease (CVD). CKD-related chronic inflammation, which is already present in children, contributes to the increased CV risk. The underlying mechanisms are incompletely understood, but gut microbial dysbiosis seems to play an important role. Here, we aimed to describe the cardiovascular phenotype of children with CKD in the absence of confounding comorbidities, which are very common in the adult CKD population.  

Methods: We analyzed the cardiovascular (CV) phenotype by echocardiography, carotid intima-media thickness (cIMT), measurements of office blood pressure (BP) and pulse wave velocity (PWV) in 38 children (normal kidney function, CKD stage G3-G4, 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.

Results: Children with CKD showed increased BP and PWV despite anti-hypertensive medication. Additionally, normalized cIMT values were increased in both CKD and HD groups. Our echocardiographic analysis demonstrated cardiac hypertrophy (left ventricular mass index and diastolic wall thicknesses), together with signs of diastolic dysfunction (increased E/e’). Of note, systolic function was not affected. 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 found a decreased number of mucosa-associated invariant T cells (MAIT) with a shift towards pro-inflammatory states in CKD and HD. Using the OLINK Target 96 Inflammation Panel, we found 55 out of 92 measured proteins to be dysregulated, with for example an increase in TNF, PD-L1 and MCP-1. Lastly, ongoing analysis of the fecal microbiome showed a reduction of alpha-diversity and evenness in the microbiome of children from the HD group.

Conclusion: Even at young age and in the absence of classical CV risk factors seen in adults, CKD leads to pathologies like cardiac hypertrophy, diastolic dysfunction and atherosclerosis. Our analysis revealed a strong pro-inflammatory immune cell profile and reduced microbial diversity in CKD. Thus, the data highlight the importance of the microbiota-immune axis in CKD. Using fecal microbiome transplantation into germ-free mice, we are currently investigating a potential causal link between the CKD microbiome, inflammation and CV risk.