Abstract
Simple SummaryRenal medullary carcinoma (RMC) is a rare but highly aggressive malignancy that affects individuals of African descent with sickle cell trait (SCT). The driver of RMC pathogenesis is thought to be renal medullary ischemia from red blood cell sickling in the setting of SCT. Currently, no modifiable risk factors for RMC have been identified that explain why certain individuals with SCT develop RMC. Prior studies have demonstrated that high-intensity exercise increases adverse events related to red blood cell sickling. We hypothesized that high-intensity exercise may increase the risk of RMC. We used multiple sources of evidence including retrospective and prospective review of RMC patient exercise activity, objective measurements of skeletal muscle surface area, and measurement of hypoxia levels in the renal medulla of mice with SCT following high or moderate-intensity exercise. Our results suggest that high but not moderate-intensity exercise may be associated with the development of RMC among individuals with SCT.Renal medullary carcinoma (RMC) is a lethal malignancy affecting individuals with sickle hemoglobinopathies. Currently, no modifiable risk factors are known. We aimed to determine whether high-intensity exercise is a risk factor for RMC in individuals with sickle cell trait (SCT). We used multiple approaches to triangulate our conclusion. First, a case-control study was conducted at a single tertiary-care facility. Consecutive patients with RMC were compared to matched controls with similarly advanced genitourinary malignancies in a 1:2 ratio and compared on rates of physical activity and anthropometric measures, including skeletal muscle surface area. Next, we compared the rate of military service among our RMC patients to a similarly aged population of black individuals with SCT in the U.S. Further, we used genetically engineered mouse models of SCT to study the impact of exercise on renal medullary hypoxia. Compared with matched controls, patients with RMC reported higher physical activity and had higher skeletal muscle surface area. A higher proportion of patients with RMC reported military service than expected compared to the similarly-aged population of black individuals with SCT. When exposed to high-intensity exercise, mice with SCT demonstrated significantly higher renal medulla hypoxia compared to wild-type controls. These data suggest high-intensity exercise is the first modifiable risk factor for RMC in individuals with SCT.
Highlights
Renal medullary carcinoma (RMC) is a lethal kidney malignancy that almost exclusively afflicts young individuals of African descent with sickle hemoglobinopathies, predominantly sickle cell trait (SCT), and is associated with red blood cell (RBC) sickling in the renal medulla [1,2,3]
Our multivariable models adjusting for confounders identified on SCMs demonstrated a significant relationship between physical activity index and RMC diagnosis, as well as between higher skeletal muscle (SM) surface area and RMC diagnosis (Figure 1c, Supplementary Tables S4 and S5)
Conditional multivariable logistic regression models again demonstrated a significant relationship between physical activity index and RMC diagnosis as well as SM surface area and RMC diagnosis
Summary
Renal medullary carcinoma (RMC) is a lethal kidney malignancy that almost exclusively afflicts young individuals of African descent with sickle hemoglobinopathies, predominantly sickle cell trait (SCT), and is associated with red blood cell (RBC) sickling in the renal medulla [1,2,3]. Sickle cell trait, which is the predominant sickle hemoglobinopathy affecting patients with RMC in more than 85% of cases, is the most common sickle hemoglobinopathy with a population genotype rate 55 times more prevalent than sickle cell disease [2,3]. Sickle cell trait is found in approximately 300 million individuals worldwide [4], and between 1/20,000 to 1/39,000 will develop RMC [5]. RMC is resistant to traditional targeted therapies used in other renal cell carcinomas (RCCs), and patients have few therapeutic options. There is a critical need to develop new ways to screen, diagnose, and prevent RMC, informed by a better understanding of what drives its unique epidemiology
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