Analysis of 394,148 participants reveals high physical activity reduces chronic kidney disease risk by 37.6% compared to low activity levels, with moderate activity providing 28% protection. The protective mechanism operates partially through inflammation reduction, as measured by C-reactive protein, white blood cells, and composite inflammation scores accounting for 4-10% of the benefit depending on the marker. Device-measured activity data from accelerometers confirmed these associations, though with somewhat smaller effect sizes than self-reported activity levels. This finding illuminates a concrete biological pathway linking exercise to kidney health beyond traditional risk factors. The inflammation-mediated protection suggests that exercise's anti-inflammatory effects may be particularly valuable for kidney preservation as people age. However, the mediation analysis shows inflammation explains only a modest portion of exercise's total protective effect, indicating other mechanisms like improved blood pressure, glucose metabolism, or direct renal benefits likely contribute substantially. The large cohort size strengthens confidence in these associations, though this preprint awaits peer review and the observational design cannot definitively establish causation. These results support current exercise recommendations while revealing specific inflammatory targets that may guide future kidney disease prevention strategies.