Abstract
Cardiovascular disease is the leading cause of death in chronic kidney disease (CKD), largely driven by accelerated atherosclerosis and vascular calcification. These complications cannot be fully explained by traditional cardiovascular risk factors, indicating that CKD-specific mechanisms may contribute to persistent vascular inflammation. Trained immunity, a long-lasting functional reprogramming of innate immune cells mediated by metabolic and epigenetic remodeling, has emerged as a plausible mechanistic framework linking uremic toxin accumulation to cardiovascular injury. However, the level of evidence differs substantially across individual toxins. Indoxyl sulfate currently has the most direct evidence for classical trained immunity, whereas the evidence for p-cresyl sulfate, homocysteine, S-adenosylhomocysteine, and parts of trimethylamine N-oxide (TMAO) biology remains more indirect or hypothesis-generating. Uremic toxins may therefore act as endogenous danger signals that potentially prime monocytes, macrophages, and endothelial cells toward a hyper-inflammatory state. Because these trained phenotypes may be epigenetically durable, conventional dialysis and downstream anti-inflammatory therapies may be insufficient to reverse cardiovascular risk in CKD. This review summarizes the graded mechanistic evidence potentially linking uremic toxin-induced trained immunity to atherosclerosis and vascular calcification and discusses emerging therapeutic strategies targeting toxin burden, metabolic pathways, epigenetic remodeling, and myeloid-specific drug delivery. These approaches remain investigational in this setting, and evidence that they specifically modify uremic toxin-induced trained immunity in patients is currently lacking.