Chronic kidney disease (CKD) is a major public health concern that has reached epidemic proportions, affecting ~20 million individuals (~13.1% of the population) in the United States alone. Risk of cardiovascular disease is significantly elevated among patients with CKD; however, this increased cardiovascular risk is only partially explained by traditional risk factors. Vascular dysfunction including arterial stiffening, endothelial dysfunction, and vascular calcification is a common and well-established risk factor and predictor of cardiovascular disease events and all-cause mortality among individuals with CKD. Deoxycholic acid (DCA) is a secondary bile acid derived via gut bacteria transformation of the primary bile acid, cholic acid. In CKD, bile acid levels are elevated and the proportion of DCA is increased compared to its primary bile acid precursor, cholic acid. Data show that DCA is associated with vascular dysfunction, and it is directly toxic to vascular smooth muscle cells inducing vascular calcification through endoplasmic reticulum stress. How circulating DCA and other abundant bile acid (cholic acid, chenodeoxycholic acid, lithocholic acid) levels change as kidney function declines needs further characterization. Moreover, whether circulating DCA and other bile acid (cholic acid, chenodeoxycholic acid, lithocholic acid) levels are associated with meaningful clinical outcomes such as cardiovascular disease events and all-cause mortality is unknown. The objective of this epidemiologic proposal is to assess plasma DCA and other bile acid (cholic acid, chenodeoxycholic acid, lithocholic acid) levels across a full spectrum of kidney function and evaluate the association of circulating DCA and other bile acid (cholic acid, chenodeoxycholic acid, lithocholic acid) levels with cardiovascular disease events and all-cause mortality. We will use baseline data collected from participants in the Randomized Trial of Intensive versus Standard Blood-Pressure Control (SPRINT) and from participants in the Effect of Homocysteine Lowering on Mortality and Vascular Disease in Advanced Chronic Kidney Disease and End-stage Renal Disease (HOST). Together these two unique cohorts include the full spectrum of kidney function from normal estimated glomerular filtration rate to end-stage renal disease as well as adjudicated cardiovascular disease events and all-cause mortality.
The first aim i s to measure levels of plasma DCA and other bile acids (cholic acid, chenodeoxycholic acid, lithocholic acid) among participants in SPRINT, which enrolled patients with normal kidney function and mild-moderate CKD (mean estimated glomerular filtration rate 47 mL/min/1.73 m2), and participants in HOST, which enrolled patients with severe CKD (mean estimated glomerular filtration rate 18 mL/min/1.73 m2) and end-stage renal disease.
The second aim i s to evaluate the association of plasma DCA and other bile acid (cholic acid, chenodeoxycholic acid, lithocholic acid) levels with adjudicated cardiovascular disease events and all-cause mortality. We hypothesize that elevated plasma levels of DCA and other bile acids (cholic acid, chenodeoxycholic acid, lithocholic acid) are common among individuals with CKD and will be associated with greater risk of cardiovascular disease events and all-cause mortality. Previous observations suggest that circulating DCA levels may be modified by diet, exercise, and bile acid sequestrants. Therefore, DCA may be a target for intervention to reduce vascular dysfunction and calcification and improve cardiovascular disease outcomes and premature mortality in CKD.
Vascular dysfunction and calcification are common in CKD and associated with progression to end-stage renal disease, cardiovascular disease, and death. The current proposal will examine the association of abundant circulating bile acids, including deoxycholic acid, a secondary bile acid that is elevated in CKD and linked with endothelial cell toxicity, vascular dysfunction, and vascular calcification, with cardiovascular disease events and all-cause mortality across a full range of kidney function. Because deoxycholic acid levels are potentially modifiable, they may be a target for intervention to reduce vascular dysfunction and calcification, cardiovascular disease events, and death in CKD.
