Significance Statement Controlling chronic inflammatory processes, which are a major risk factor for cardiovascular disease, is of outstanding importance in CKD to reduce the rate of CKD-associated morbidity. This investigation connects microbial dysbiosis and bacterial metabolite imbalance to a proinflammatory immune cell signature. The fact that these dysbiosis-driven immunologic changes are already detectable in children with CKD, in whom comorbidities usually found in adults are absent, highlights the importance and specificity of CKD-related microbiota-immune interaction for chronic inflammation. Personalized dietary interventions and microbiota-targeted therapies may be a promising area of research to improve the prognosis of young and old patients with CKD. Background CKD is characterized by a sustained proinflammatory response of the immune system, promoting hypertension and cardiovascular disease. The underlying mechanisms are incompletely understood but may be linked to gut dysbiosis. Dysbiosis has been described in adults with CKD; however, comorbidities limit CKD-specific conclusions. Methods We analyzed the fecal microbiome, metabolites, and immune phenotypes in 48 children (with normal kidney function, CKD stage G3–G4, G5 treated by hemodialysis [HD], or kidney transplantation) with a mean±SD age of 10.6±3.8 years. Results Serum TNF-α and sCD14 were stage-dependently elevated, indicating inflammation, gut barrier dysfunction, and endotoxemia. We observed compositional and functional alterations of the microbiome, including diminished production of short-chain fatty acids. Plasma metabolite analysis revealed a stage-dependent increase of tryptophan metabolites of bacterial origin. Serum from patients on HD activated the aryl hydrocarbon receptor and stimulated TNF-α production in monocytes, corresponding to a proinflammatory shift from classic to nonclassic and intermediate monocytes. Unsupervised analysis of T cells revealed a loss of mucosa-associated invariant T (MAIT) cells and regulatory T cell subtypes in patients on HD. Conclusions Gut barrier dysfunction and microbial metabolite imbalance apparently mediate the proinflammatory immune phenotype, thereby driving the susceptibility to cardiovascular disease. The data highlight the importance of the microbiota-immune axis in CKD, irrespective of confounding comorbidities.