Addressing the Pathophysiology of Venous Thrombosis and Chronic Kidney Disease in Sickle Cell Trait Using a Mouse Model

• Renal impairment & enhanced venous thrombosis in Townes sickle trait (AS) mice mimic similar complications in sickle cell trait (SCT) humans

• Nephropathy and increased size of venous thrombi in Townes AS mice are associated with localized sickling of SCT red blood cells.

Sickle cell trait (SCT) is present in subjects who possess a single copy of the bS-globin gene mutation. While most affected individuals are asymptomatic, SCT is a well-established risk factor for venous thrombosis and renal complications, including chronic and end-stage kidney disease. Following prolonged hypoxia, SCT red blood cells (RBCs) can undergo sickling, and hypoxia-mediated RBC sickling can be enhanced by cellular dehydration, hyperosmolarity and/or acidosis. Some or all of these conditions may be encountered in the nidus of venous thrombi and in the medulla of the kidney. We sought to determine if Townes sickle trait (AS) mice develop kidney dysfunction and manifest enhanced venous thrombosis. We demonstrated that the harsh environment within the inner medulla induces RBC sickling in vitro and in vivo, and is associated with kidney-related pathologies, including impaired urinary concentration, albuminuria and declining renal function that closely mimic those seen in human SCT. In the inferior vena cava model of venous thrombosis, extreme and prolonged hypoxia in the core of RBC-rich venous thrombi resulted in irreversible RBC sickling and larger clots in Townes AS mice compared to AA controls. Our results support the use of Townes AS mice in future studies investigating mechanisms of venous thrombosis and chronic kidney disease in SCT.