Metabolic reprogramming in chronic kidney disease-cardiovascular disease comorbidity: from molecular mechanisms to therapeutic strategies

Chronic kidney disease (CKD) and cardiovascular disease are bidirectionally linked, with metabolic reprogramming as a central pathophysiological nexus. This review examines metabolic disturbances underlying CKD-CVD comorbidity, including energy metabolism disorders, mitochondrial dysfunction, lipid and glucose dysregulation, and mineral metabolism abnormalities. The gut microbiota-metabolic axis contributes through depletion of short-chain fatty acids, accumulation of trimethylamine N-oxide, and production of uremic toxins. These changes compromise intestinal barrier integrity and sustain systemic inflammation. Downstream consequences include oxidative stress, NLRP3 inflammasome activation, cardiac and renal fibrosis, vascular calcification, and endothelial dysfunction. We critically distinguish validated interventions from speculative strategies. SGLT2 inhibitors and GLP-1 receptor agonists have established cardiorenal protection in large randomized trials, with effects extending beyond glycemic control. By contrast, gut microbiota modulation, mitochondria-targeted therapies, and several anti-inflammatory and anti-fibrotic strategies remain at the preclinical or early-phase clinical stage, and a number of mechanistically attractive interventions have failed in confirmatory trials. We also outline areas of contradictory evidence and unresolved questions. Future directions include multi-omics integration, metabolic phenotype-based stratification, and rational drug development targeting central metabolic nodes. The review provides mechanistic insights into metabolic-immune-inflammatory crosstalk in CKD-CVD and highlights priorities for translation.