Pro-inflammatory and pro-oxidant diets and CKD risk across cardiovascular–kidney–metabolic syndrome stages: a multi-omics mediation analysis

<i>Background & Purpose</i>: While inflammation and oxidative stress contribute to renal injury, evidence linking dietary inflammatory/antioxidant potential to chronic kidney disease (CKD) incidence remains limited. We investigated associations of the Energy-adjusted Dietary Inflammatory Index (E-DII) and the Composite Dietary Antioxidant Index (CDAI) with CKD risk across Cardiovascular-Kidney-Metabolic (CKM) stages, and elucidated underlying mechanisms through multi-omics profiling. <i>Methods</i>: in this prospective analysis of 179 493 UK Biobank participants, dietary indices were derived from 24 hour recalls. Incident CKD was ascertained through health records. Cox models assessed associations, stratified by CKM stages (0-4), with mediation analyses incorporating proteomic (<i>n</i> = 18 836) and metabolomic (<i>n</i> = 93 416) profiles. All analyses were adjusted for sociodemographic, lifestyle, and clinical factors, and genetic risk scores. <i>Results</i>: during a median 13.2 year follow-up (5799 incident CKD cases), both anti-inflammatory (E-DII < 0; adjusted HR, 0.88, 95% CI: 0.83-0.93) and antioxidant (CDAI ≥ 0; adjusted HR, 0.91; 95% CI: 0.86-0.97) diets were found to exhibit protective effects against CKD <i>versus</i> pro-inflammatory and pro-oxidant diets. Effects were most pronounced in early CKM stages (stages 0-2 <i>vs.</i> 3-4; both <i>P</i>-interactions < 0.05). Combined anti-inflammatory and antioxidant diets conferred maximal protection (adjusted HR, 0.85, 95% CI: 0.80-0.91), corresponding to a 2.5 year delay in CKD onset. Mechanistically, proteomic (56.9%) and metabolomic (60.6%) signatures mediated the E-DII-CKD association, predominantly through the degree of unsaturation (38.7%), FSTL3 (34.8%), and SPON2 (23.2%). <i>Conclusions</i>: pro-inflammatory and pro-oxidant diets synergistically increase CKD risk, particularly in the early CKM stages, while anti-inflammatory/antioxidant diets confer protection <i>via</i> multi-omics pathways linked to lipid metabolism and the extracellular matrix. These findings advocate for CKM stage-specific dietary interventions and integration of multi-omics biomarkers into CKD prevention.