In our prior studies, we demonstrated that high-intensity exercise exacerbates renal medullary hypoxia in murine models of SCT, promoting the sickling of red blood cells and vascular injury within the renal medulla.1 The hypoxia induced by SCT has further been shown to result in degradation of the tumor-suppressor SMARCB1, which provides renal medullary cells a survival advantage in a hypoxic environment.2 This provides a mechanism linking strenuous exercise, hypoxia, and tumor initiation. While SCT is generally considered benign, exertional complications such as rhabdomyolysis and hematuria are well-documented, suggesting that environmental stressors like intense exercise may have underappreciated consequences in this population.
To further validate our hypothesis that vigorous intensity physical activity is linked to RMC development, we prospectively surveyed 39 patients with RMC at two academic centers using a validated physical activity questionnaire derived from the National Health and Nutrition Examination Survey (NHANES). Their responses were compared to a nationally representative cohort of over 7,000 individuals without RMC. The questionnaire distinguished between sedentary, moderate, and vigorous physical activity across occupational and recreational settings.
Patients who reported engaging in vigorous intensity physical activity had significantly higher odds of RMC diagnosis compared to the general population. Specifically, those with vigorous occupational activity had nearly three times the odds (OR 2.91, 95% CI 1.50–5.66; p=0.002), and those with vigorous recreational activity had over four times the odds (OR 4.02, 95% CI 1.85–8.74; p<0.001), after adjusting for age, sex, and race. To corroborate self-reported data, we analyzed body composition. We found that patients endorsing vigorous activity had significantly higher skeletal muscle mass indices and lower subcutaneous fat biomarkers consistent with sustained high-intensity physical exertion.
This study is the first prospective investigation linking a modifiable lifestyle factor to RMC risk. While causality cannot be established from observational data alone, the findings align with preclinical evidence and raise important clinical considerations. In young patients with SCT who present with renal masses, a history of vigorous physical activity may serve as a red flag warranting closer evaluation for RMC.
These findings may also inform future public health policies and screening practices. Given that SCT is present in approximately 8% of African Americans and that many individuals remain unaware of their carrier status, targeted education and screening efforts may be warranted, particularly for those engaging in high-intensity sports or military training. Individuals with SCT should be educated about the risks associated with vigorous intensity activity and adopt training regimens that consist of gradual progression, avoiding extreme conditions (e.g., excessive heat, high humidity, high altitude), active recovery to allow pH restoration and lactate clearance, and hydration.
In conclusion, our study adds to the growing body of evidence suggesting that vigorous physical activity may serve as an environmental risk factor in RMC development among individuals with sickle hemoglobinopathies. These insights underscore the need for personalized risk assessment and reinforce the importance of understanding gene-environment interactions in rare cancers like RMC.
Written by:
- Daniel D. Shapiro, MD, FACS, Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI; William S. Middleton Memorial Veterans Hospital, Madison, WI
- Pavlos Msaouel, MD, PhD, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX; David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas, MD Anderson Cancer Center, Houston, TX; The University of Texas MD Anderson Cancer Center, UTHealth Houston Graduate School of Biomedical Sciences (GSBS), Houston, TX
- Shapiro DD, Soeung M, Perelli L, Dondossola E, Surasi DS, Tripathi DN, et al. Association of High-Intensity Exercise with Renal Medullary Carcinoma in Individuals with Sickle Cell Trait: Clinical Observations and Experimental Animal Studies. Cancers. 2021;13:6022.
- Soeung M, Perelli L, Chen Z, Dondossola E, Ho IL, Carbone F, et al. SMARCB1 regulates the hypoxic stress response in sickle cell trait. Proc Natl Acad Sci U S A. 2023;120:e2209639120.