Vigorous physical activity as a potential environmental risk factor in renal medullary carcinoma

Purpose: Renal medullary carcinoma (RMC) is a rare but aggressive kidney cancer affecting young individuals with sickle hemoglobinopathies. Prior retrospective case-control and mouse modeling studies suggest a mechanism linking vigorous intensity physical activity to increased RMC risk in individuals with sickle hemoglobinopathies. This study aimed to prospectively investigate the association between vigorous intensity exercise and RMC. Materials and methods: This study used a validated questionnaire to prospectively assess reported physical activity in a large cohort of patients with RMC compared to the activity of individuals without RMC. Between 2022 and 2024, patients with RMC (N = 39) were prospectively surveyed using the validated Physical Activity Questionnaire from the National Health and Nutritional Examination Survey and compared to responses of a national cohort of healthy individuals (N = 7148). This questionnaire is designed to distinguish between vigorous, moderate, and sedentary activity. To further validate the questionnaire, we performed body-composition analysis to determine if patients reporting vigorous activity had increased skeletal muscle mass and decreased subcutaneous adipose tissue. Results: Individuals had higher odds of RMC diagnosis if reporting vigorous intensity physical activity at work (OR 2.91, 95% CI 1.50–5.66; P = 0.002) or recreationally (OR 4.02, 95% CI 1.85–8.74; P < 0.001) after adjusting for age, biologic sex, and race. Body composition analysis confirmed that patients reporting vigorous physical activity were more likely to have a higher skeletal muscle mass index (median 54.3 vs. 41.2 cm²/m²; P = 0.01) compared to patients not reporting vigorous physical activity. Conclusion: These results prospectively support the association between vigorous physical activity and RMC in individuals with sickle hemoglobinopathies.