Increased Risk of Early-onset Kidney Cancer in Individuals with Non-Alcoholic Fatty Liver Disease Aged 20–39: A Nationwide Cohort Study

Abstract Background: The global incidence of kidney cancer has significantly increased among individuals under 50 years of age. However, genetic predisposition alone does not account for this trend. This study investigated the association between nonalcoholic fatty liver disease (NAFLD) and the risk of early-onset kidney cancer. Methods: We conducted a nationwide cohort study of 5,606,357 Korean individuals aged 20–39 years who underwent national health screening between 2009 and 2012, with follow-up until December 2020. NAFLD was defined using the fatty liver index. Cox proportional hazards models were used to estimate hazard ratios (HRs) for early-onset kidney cancer, adjusting for potential confounders including age, sex, smoking, alcohol intake, physical activity, diabetes, hypertension, obesity, and chronic kidney disease (CKD). Results: During 52.4 million person-years of follow-up, 2,956 cases of early-onset kidney cancer were identified. NAFLD was associated with a higher cumulative incidence (log-rank test P < 0.01) and an increased risk of early-onset kidney cancer (adjusted HR [aHR], 1.46; 95% CI: 1.32–1.61). The association remained consistent across subgroups stratified by age, sex, smoking status, alcohol consumption, obesity, and CKD (all P for interactions > 0.05). The risk was highest among individuals with both NAFLD and obesity (aHR, 95% CI: 2.12, 1.95–2.32; synergy index = 1.34, P < 0.01). Conclusions: NAFLD may serve as an independent risk factor for early-onset kidney cancer. Impact: Given that NAFLD is a modifiable condition, its early detection and management may be a potential strategy to reduce the burden of early-onset kidney cancer, warranting further investigation.