Developmental origins and environmental determinants of cardiovascular-kidney-metabolic syndrome: A pediatric precision prevention perspective.

Cardiovascular-Kidney-Metabolic Syndrome (CKMS), formally defined by the American Heart Association in 2023, emphasizes the interconnections among chronic kidney disease, cardiovascular disease, obesity, and diabetes. Although CKMS typically manifests in adulthood, accumulating evidence indicates that vulnerability is established early in life through developmental programming shaped by maternal, perinatal, and early-childhood exposures. This review summarizes the developmental origins, environmental determinants, and mechanistic pathways of CKMS, with a particular emphasis on kidney programming and pediatric precision prevention. Recent nationally representative data indicate that CKMS risk-stage (stage ≥1) affects approximately 90% of U.S. adults and 40% of adolescents, highlighting the extensive population burden long before overt clinical disease develops, yet kidney health remains underrecognized within cardiometabolic risk assessment. In children, early metabolic disruption, excess adiposity, and subclinical cardiovascular dysfunction interact with structural or developmental renal vulnerability to accelerate CKD progression and amplify lifelong risk. Evidence from the Developmental Origins of Health and Disease framework demonstrates that maternal malnutrition, metabolic disease, toxicant exposures, preterm birth, and perinatal complications permanently alter nephron endowment, vascular function, and metabolic regulation. Animal studies reveal convergent mechanisms-including oxidative stress, aberrant renin-angiotensin activity, epigenetic modifications, gut microbiota dysbiosis, and sex-specific responses-that predispose offspring to CKMS and highlight targets for early-life reprogramming. Prevention should begin with maternal health and the first 1000 days, incorporating nutritional and lifestyle interventions, early screening for obesity, hypertension, and dyslipidemia, and emerging microbiome- or antioxidant-targeted therapies. Advances in multi-omics, digital health, and AI-enabled monitoring facilitate early risk stratification and precision prevention, although pediatric-specific guidelines remain limited. Viewed through a life-course lens, CKMS represents a gradual, self-reinforcing process rooted in developmental programming and environmental exposures. Integrating maternal and pediatric interventions within a life-course precision prevention framework provides a roadmap to disrupt disease trajectories, reduce intergenerational risk, and promote lifelong cardiovascular, kidney, and metabolic health.