Early-Life Sugar Restriction During the First 1000 Days and Adult Kidney Disease: A Natural Experiment with Phenotypic and Metabolomic Mediation

BackgroundThe first 1000 days from conception to age 2 years represent a critical window for kidney development, during which nutritional exposures may have lifelong programming effects. Whether early-life sugar restriction reduces long-term kidney disease risk remains unknown. MethodsUsing the UK sugar rationing policy (1942-1953) as a natural experiment, we compared risks of chronic kidney disease (CKD) and acute kidney injury (AKI) among 64,942 UK Biobank participants born around the rationing period. Duration of early-life exposure was categorised. Cox proportional hazards models estimated hazard ratios (HRs). Negative control analyses included non-UK-born UK Biobank participants and the Chinese CHARLS cohort. Mediation analyses integrated clinical phenotypes and metabolomic profiles. FindingsCompared with never-exposed individuals, those exposed to sugar rationing throughout the first 1000 days (in utero to age 2 years) had lower risks of CKD (adjusted HR 0.78, 95% CI 0.66-0.93) and AKI (0.79, 0.69-0.90). Negative control analyses showed null associations. Mediation analyses indicated that metabolic efficiency (basal metabolic rate), body composition (fat-free mass), and lipid metabolism mediated 4-9% of the protective association. A distinct metabolomic signature characterised by higher polyunsaturated fatty acids and lower VLDL subfractions was identified. InterpretationSugar restriction during the first 1000 days is associated with lower risks of CKD and AKI in adulthood, partially mediated by favorable metabolic efficiency, body composition, and lipid profiles. These findings identify early-life sugar exposure as a modifiable developmental programming factor for lifelong kidney health and support public health strategies to reduce added sugar intake during pregnancy and early childhood. FundingNational Natural Science Foundation of China, and others