Dietary Inflammatory Potential and Chronic Kidney Disease Risk: Exploring the Mediation Effects of Circulating Proteins

Background: While the association between diet-induced inflammation and the risk of cardiovascular disease or cancer has been previously reported, its contribution to chronic kidney disease (CKD) and the underlying biological mechanisms remain unclear. This study aimed to elucidate the mechanistic role of the Dietary Inflammatory Index (DII) in CKD through multi-omics-based mediation analyses and to provide clinically relevant insight. Methods: This study included 158,722 United Kingdom (UK) Biobank participants without underlying CKD (median age 57 years; 53% female). The DII was assessed via a 24-hour dietary recall and categorized into quartiles. Incident CKD was identified using International Classification of Diseases (ICD)-10 and Office of Population Censuses and Surveys Classification of Interventions and Procedures (OPCS)-4 codes. In a sub-cohort with creatinine follow-up, CKD was also defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 . Mediation analyses using proteomics and metabolomics data were conducted to explore potential mechanisms linking diet-induced inflammation to CKD. Individual food item analyses were performed to identify their association with CKD via diet-induced inflammation. Results: During a median of 11.2 years of follow-up, CKD occurred in 4,382 patients. Cox regression revealed that the adjusted hazard ratios for incident CKD were higher in a stepwise fashion across higher DII quartiles (adjusted hazard ratio [aHR] and 95% confidence interval [CI]: Q2, 1.08 [0.99-1.18]; Q3, 1.15 [1.05-1.26]; Q4, 1.17 [1.06-1.29]) relative to Q1 ( P -for-trend <0.001). Similar results were observed with eGFR-defined CKD. Proteomics-based mediation analysis identified death receptor and tumor necrosis factor (TNF) receptor-related proteins as mediators linking diet-induced inflammation to CKD. Metabolomics analysis highlighted omega-3 fatty acids, especially docosahexaenoic acid, as protective mediators. Oily fish intake was inversely associated with CKD risk, while sugar-rich and high-fat dairy consumption showed positive associations, partly through inflammatory pathways. Conclusions: The association between the DII and incident CKD risk may be partly mediated by alterations in circulating protein profiles involving TNF receptor superfamily-related pathways and plasma omega-3 fatty acids. Dietary counseling aimed at lowering the consumption of sugar-rich and high-fat dairy products may be beneficial.