Posted March 8, 2023

Pavlos Msaouel, M.D., Ph.D., The University of Texas MD Anderson Cancer Center

Renal Medullary Carcinoma (RMC), a rare and aggressive type of kidney cancer with characteristic sickling (changing shape) of the red blood cells, is known to target young patients of African descent who carry sickle cell trait (S�) or have sickle cell disease (SS).¹ Case reports of the disease suggest that these patients will live less than three years after diagnosis. Several RMC patients have served in the U.S. Armed Forces, leading Dr. Msaouel to propose a model that could explain the pathogenesis of RMC and also explain how the kidneys respond to dehydration and other stressors experienced by Service Members.

With support from a fiscal year 2018 (FY18) Kidney Cancer Research Program (KCRP) Concept Award, Dr. Msaouel was able to confirm his hypothesis that there is a strong association between exercise and renal hypoxia (decreased oxygen in the kidneys) in animals that carried the sickle cell trait. Dr. Msaouel used three groups of mice: 1) mice harboring humanized sickle cell trait (S�), 2) mice harboring humanized sickle cell disease (SS), and 3) mice harboring wild-type human �� hemoglobin.² Both mice with wild-type �� and mice with sickle cell trait (S�) showed normal pathophysiology, which can be compared to human pathophysiology. Further investigation revealed that mice with sickle cell trait had sickling of red blood cells, particularly in the renal inner medulla region of the kidneys. Unlike mice harboring wild-type human �� hemoglobin, researchers were able to confirm that mice with sickle cell trait and mice with sickle cell disease had sickling in their red blood cells after experiencing heavy exercise. To do this, they exercised the mice on a treadmill at a high intensity, then harvested the renal inner medulla of the mice. They then used western blot analysis, which confirmed that in animals that had sickle cell trait, there were regional infarcts (areas of tissue death due to inadequate blood supply) in the kidneys, particularly in the right kidney.

In individuals with sickle cell trait or sickle cell disease, exercise can cause an increase in red blood cell sickling. Throughout the course of this research, increased hypoxia, including exercise-induced hypoxia, was found to be a substantial risk factor for RMC.² These findings may help to establish why RMC is more common in athletic individuals, including Service Members. There are no known risk factors for RMC in individuals with sickle cell trait.² Dr. Msaouel has reported data from mouse studies suggesting that high-intensity exercise is the first modifiable risk factor for RMC in individuals with sickle cell trait. Moreover, RMC presentation is more commonly found in the right than the left kidney.² While both renal arteries are similar in diameter on both kidneys, the right renal artery was discovered to be longer, resulting in a reduced amount of blood flow to the right kidney.² Dr. Msaouel's team reported that the reduced amount of blood flow to the right inner medulla, plus exercise-induced hypoxia increasing red blood cell sickling, led to mice incurring more regional microinfarcts in the right kidney than the left kidney.

To corroborate his findings in mice, Dr. Msaouel leveraged a grant from the National Cancer Institute of the National Institutes of Health to conduct clinical observations to support his hypothesis; findings were published in the November 2021 edition of the journal Cancers. Clinical observations of patients with RMC were first compared to control patients. The standards were set for what constitutes high-intensity physical activity, such as sporting events, bicycling, and weight lifting. Skeletal muscle and subcutaneous adipose were measured via computed tomography imaging. A sensitivity analysis was conducted to ensure variables such as smoking and nutrition did not skew the patients� results. Dr. Msaouel's team reported that results remained consistent, and they concluded that patients with sickle cell trait and sickle cell disease who engage in high-intensity activity were at a higher risk for RMC.

The research performed by Dr. Msaouel and his team has the potential to set a tone for how physicians could counsel their patients in the immediate future. Understanding the impact of exercise on those with sickle cell trait can possibly aid clinical practices in guiding these individuals to prevent RMC development. In addition, identifying patterns like this can lead to earlier diagnostic and better treatment options for RMC patients, particularly those with sickle cell trait and sickle cell disease. Hopefully, early intervention, diagnosis, and treatment of RMC could extend the lives of our Service Members and civilian patients.

Publications:
Shapiro DD, Soeung M, Perelli L, et al. 2021. Association of high-intensity exercise with renal medullary carcinoma in individuals with sickle cell trait: Clinical observations and experimental animal studies. Cancers 13, 6022. https://doi.org/10.3390/cancers13236022.

References:
¹National Organization for Rare Disorders (NORD) - Renal Medullary Carcinoma
²Shah AY, Karam JA, Malouf GG, et al. 2017. Management and outcomes of patients with renal medullary carcinoma: A multicentre collaborative study. BJU International 120:782-792.

Links:
Public and Technical Abstracts: A Novel Mechanism of Pathogenesis for Renal Medullary Carcinoma