American Journal of Kidney Diseases

Deoxycholic Acid, a Metabolite of Circulating Bile Acids, and Coronary Artery Vascular Calcification in CKD

Published:August 09, 2017DOI:


      Vascular calcification is common among patients with chronic kidney disease (CKD), and it is associated with all-cause and cardiovascular disease mortality. Deoxycholic acid, a metabolite of circulating bile acids, is elevated in CKD and induces vascular mineralization and osteogenic differentiation in animal models.

      Study Design

      Cohort analysis of clinical trial participants.

      Setting & Participants

      112 patients with moderate to severe CKD (estimated glomerular filtration rate, 20-45 mL/min/1.73 m2) who participated in a randomized controlled study to examine the effects of phosphate binders on vascular calcification.


      Serum deoxycholic acid concentration.


      Baseline coronary artery calcification (CAC) volume score and bone mineral density (BMD) and change in CAC volume score and BMD after 9 months.


      Deoxycholic acid was assayed in stored baseline serum samples using liquid chromatography−tandem mass spectrometry, CAC was measured using a GE-Imitron C150 scanner, and BMD was determined using computed tomographic scans of the abdomen with calibrated phantom of known density.


      Higher serum deoxycholic acid concentrations were significantly correlated with greater baseline CAC volume and lower baseline BMD. After adjusting for demographics, coexisting illness, body mass index, estimated glomerular filtration rate, and concentrations of circulating markers of mineral metabolism, including serum calcium, phosphorus, vitamin D, parathyroid hormone, and fibroblast growth factor 23, a serum deoxycholic acid concentration > 58 ng/mL (the median) was positively associated with baseline CAC volume (β = 0.71; 95% CI, 0.26-1.16; P = 0.003) and negatively associated with baseline BMD (β = −20.3; 95% CI, −1.5 to −39.1; P = 0.04). Serum deoxycholic acid concentration > 58 ng/mL was not significantly associated with change in CAC volume score after 9 months (β = 0.06; 95% CI, −0.09 to 0.21; P = 0.4). The analysis for the relationship between baseline deoxycholic acid concentrations and change in BMD after 9 months was not statistically significant, but was underpowered.


      The use of nonfasting serum samples is a limitation because deoxycholic acid concentrations may vary based on time of day and dietary intake. Few trial participants with complete data to evaluate the change in CAC volume score (n = 75) and BMD (n = 59). No data for changes in deoxycholic acid concentrations over time.


      Among patients with moderate to severe CKD, higher serum deoxycholic acid concentrations were independently associated with greater baseline CAC volume score and lower baseline BMD.

      Index Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to American Journal of Kidney Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Saran R.
        • Li Y.
        • Robinson B.
        • et al.
        US Renal Data System 2015 annual data report: epidemiology of kidney disease in the United States.
        Am J Kidney Dis. 2016; 67: S1-S434
        • Go A.S.
        • Chertow G.M.
        • Fan D.
        • McCulloch C.E.
        • Hsu C.Y.
        Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.
        N Engl J Med. 2004; 351: 1296-12305
        • Kuznik A.
        • Mardekian J.
        • Tarasenko L.
        Evaluation of cardiovascular disease burden and therapeutic goal attainment in US adults with chronic kidney disease: an analysis of National Health and Nutritional Examination Survey data, 2001-2010.
        BMC Nephrol. 2013; 14: 132
        • Gargiulo R.
        • Suhail F.
        • Lerma E.V.
        Cardiovascular disease and chronic kidney disease.
        Dis Mon. 2015; 61: 403-413
        • Russo D.
        • Palmiero G.
        • De Blasio A.P.
        • Balletta M.M.
        • Andreucci V.E.
        Coronary artery calcification in patients with CRF not undergoing dialysis.
        Am J Kidney Dis. 2004; 44: 1024-1030
        • Braun J.
        • Oldendorf M.
        • Moshange W.
        • Heidler R.
        • Zeitler E.
        • Luft F.C.
        Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients.
        Am J Kidney Dis. 1996; 27: 394-401
        • Gorriz J.L.
        • Molina P.
        • Cerveron M.J.
        • et al.
        Vascular calcification in patients with nondialysis CKD over 3 years.
        Clin J Am Soc Nephrol. 2015; 10: 654-666
        • Watanabe R.
        • Lemos M.M.
        • Manfredi S.R.
        • Draibe S.A.
        • Canziani M.E.
        Impact of cardiovascular calcification in nondialyzed patients after 24 months of follow-up.
        Clin J Am Soc Nephrol. 2010; 5: 189-194
        • Chen J.
        • Budoff M.J.
        • Reilly M.P.
        • et al.
        Coronary artery calcification and risk of cardiovascular disease and death among patients with chronic kidney disease.
        JAMA Cardiol. 2017; 2: 189-194
        • Zeb I.
        • Ahmadi N.
        • Molmar M.A.
        • et al.
        Association of coronary artery calcium score and vascular dysfunction in long-term hemodialysis patients.
        Hemodial Int. 2013; 17: 216-222
        • Shantouf R.S.
        • Budoff M.J.
        • Ahmadi N.
        • et al.
        Total and individual coronary artery calcium scores as independent predictors of mortality in hemodialysis patients.
        Am J Nephrol. 2010; 31: 419-425
        • Bostrom K.
        • Watson K.E.
        • Horn S.
        • Wortham C.
        • Herman I.M.
        • Demer L.L.
        Bone morphogenetic protein expression in human atherosclerotic lesions.
        J Clin Invest. 1993; 91: 1800-1809
        • Jono S.
        • McKee M.D.
        • Murry C.E.
        • et al.
        Phosphate regulation of vascular smooth muscle cell calcification.
        Circ Res. 2000; 87: E10-E17
        • Lanzer P.
        • Moehm M.
        • Sorribas V.
        • et al.
        Medial vascular calcification revisted: review and perspectives.
        Eur Heart J. 2014; 35: 1515-1525
        • Jimenez F.
        • Monte M.J.
        • El-Mir M.Y.
        • Pascual M.J.
        • Marin J.J.
        Chronic renal failure-induced changes in serum and urine bile acid profiles.
        Dig Dis Sci. 2002; 47: 2398-2406
        • Gai Z.
        • Chu L.
        • Hiller C.
        • et al.
        Effect of chronic renal failure on the hepatic, intestinal, and renal expression of bile acid transporters.
        Am J Physiol Renal Physiol. 2014; 306: F130-F137
        • Miyazaki M.
        • Miyazaki-Anzai S.
        • Masuda M.
        • Kremoser C.
        Deoxycholic acid contributes to chronic kidney disease-dependent vascular calcification.
        Circulation. 2013; 128 ([abstract]): A14937
        • Cariou B.
        • Staels B.
        FXR: a promising target for the metabolic syndrome?.
        Trends Pharmacol Sci. 2007; 28: 236-243
        • Miyazaki-Anzai S.
        • Levi M.
        • Kratzer A.
        • Ting T.C.
        • Lewis L.B.
        • Miyazaki M.
        Farnesoid X receptor activation prevents the development of vascular calcification in ApoE-/- mice with chronic kidney disease.
        Circ Res. 2010; 106: 1807-1817
        • Hambruch E.
        • Miyazaki-Anzai S.
        • Hahn U.
        • et al.
        Synthetic farnesoid X receptor agonists induce high-density lipoprotein-mediated transhepatic cholesterol efflux in mice and monkeys and prevent atherosclerosis in cholesteryl ester transfer protein transgenic low-density lipoprotein receptor (-/-) mice.
        J Pharmacol Exp Ther. 2012; 343: 556-567
        • Miyazaki-Anzai S.
        • Masuda M.
        • Levi M.
        • Keenan A.L.
        • Miyazaki M.
        Dual activation of the bile acid nuclear receptor FXR and G-protein-coupled receptor TGR5 protects mice against atherosclerosis.
        PLoS One. 2014; 9: e108270
        • Kiel D.P.
        • Kauppila L.I.
        • Cupples L.A.
        • Hannan M.T.
        • O’Donnell C.J.
        • Wilson P.W.
        Bone loss and progression of abdominal aortic calcification over a 25 year period: the Framingham Heart Study.
        Calcif Tissue Int. 2001; 68: 271-276
        • Hak A.E.
        • Pols H.A.
        • van Hemert A.M.
        • Hofman A.
        • Witteman J.C.
        Progression of aortic calcification is associated with metacarpal bone loss during menopause: a population-based longitudinal study.
        Arterioscler Thromb Vasc Biol. 2000; 20: 1926-1931
        • Schulz E.
        • Arfai K.
        • Lui X.
        • Sayre J.
        • Gilsanz V.
        Aortic calcification and the risk of osteoporosis and fractures.
        J Clin Endocrinol Metab. 2004; 89: 4246-4253
        • Naves M.
        • Rodriguez-Garcia M.
        • Diaz-Lopez J.B.
        • Gomez-Alonso C.
        • Cannata-Andia J.B.
        Progression of vascular calcifications is associated with greater bone loss and increased bone fractures.
        Osteoporos Int. 2008; 19: 1161-1166
        • Szulc P.
        • Kiel D.P.
        • Delmas P.D.
        Calcifications in the abdominal aorta predict fractures in men: MINOS study.
        J Bone Miner Res. 2008; 23: 95-102
        • Tanko L.B.
        • Christiansen C.
        • Cox D.A.
        • Geiger M.J.
        • McNabb M.A.
        • Cummings S.R.
        Relationship between osteoporosis and cardiovascular disease in postmenopausal women.
        J Bone Miner Res. 2005; 20: 1912-1920
        • London G.M.
        • Marty C.
        • Marchais S.J.
        • Geurin A.P.
        • Metivier F.
        • De Vernejoul M.C.
        Arterial calcifications and bone histomorphometry in end-stage renal disease.
        J Am Soc Nephrol. 2004; 15: 1943-1951
        • Adragao T.
        • Herberth J.
        • Monier-Faugere M.-C.
        • et al.
        Low bone volume – a risk factor for coronary calcifications in hemodialysis patients.
        Clin J Am Soc Nephrol. 2009; 4: 450-455
        • Rodriguez-Garcia M.
        • Gomez-Alonso C.
        • Naves-Diaz M.
        • Diaz-Lopez J.B.
        • Diaz-Corte C.
        • Cannata-Andia J.B.
        Asturias Study Group. Vascular calcifications, vertebral fractures and mortality in haemodialysis patients.
        Nephrol Dial Transplant. 2009; 24: 239-246
        • Malluche H.H.
        • Blomquist G.
        • Monier-Faugere M.C.
        • Cantor T.L.
        • Davenport D.L.
        High parathyroid hormone level and osteoporosis predict progression of coronary artery calcification in patients on dialysis.
        J Am Soc Nephrol. 2015; 26: 2534-2544
        • Park J.C.
        • Kovesdy C.P.
        • Duong U.
        • et al.
        Association of serum alkaline phosphatase and bone mineral density in maintenance hemodialysis patients.
        Hemodial Int. 2010; 14: 182-192
        • Toussaint N.D.
        • Lau K.K.
        • Strass B.J.
        • Polkinghorn K.R.
        • Kerr P.G.
        Associations between vascular calcification, arterial stiffness and bone mineral density in chronic kidney disease.
        Nephrol Dial Transplant. 2008; 23: 586-593
        • Tomiyama C.
        • Carvalho A.B.
        • Higa A.
        • Jorgett V.
        • Draine S.A.
        • Canziani M.E.
        Bone formation rate in CKD patients not yet in dialysis treatment.
        J Bone Miner Res. 2010; 25: 499-504
        • London G.M.
        Bone-vascular cross-talk.
        J Nephrol. 2012; 25: 619-625
        • Block G.A.
        • Wheeler D.C.
        • Persky M.S.
        • et al.
        Effect of phosphate binders in moderate CKD.
        J Am Soc Nephrol. 2012; 23: 1407-1415
        • Spiegel D.M.
        • Raggi P.
        • Mehta R.
        • et al.
        Coronary and aortic calcifications in patients new to dialysis.
        Hemodial Int. 2004; 8: 265-272
        • Callister T.Q.
        • Raggi P.
        • Cooil B.
        • Lippolis N.J.
        • Russo D.J.
        Effect of HMG-CoA reductase inhibitors on coronary artery disease as assessed by electron-beam computed tomography.
        N Engl J Med. 1998; 339: 1972-1978
        • Walter P.
        • Ron D.
        The unfolded protein response: from stress pathway to homeostatic regulation.
        Science. 2011; 334: 1081-1086
        • Duan X.
        • Zhou Y.
        • Teng X.
        • Tang C.
        • Qi Y.
        Endoplasmic reticulum stress-mediated apoptosis is activated in vascular calcification.
        Biochem Biophys Res Commun. 2009; 387: 694-699
        • Funamota T.
        • Sekimoto T.
        • Murakami T.
        • Kurogi S.
        • Imaizumi K.
        • Chosa E.
        Roles of the endoplasmic reticulum stress transducer OASIS in fracture healing.
        Bone. 2011; 49: 724-732
        • Liu J.
        • Hoppman N.
        • O’Connell J.R.
        • et al.
        A functional haplotype in EIF2AK3, an ER stress sensor, is associated with lower bone mineral density.
        J Bone Miner Res. 2012; 27: 331-341
        • Wu Y.
        • Yang M.
        • Fan J.
        • et al.
        Deficiency of osteoblastic ARL6ip5 impaired osteoblast differentiation and enhanced osteoclastogenesis via disturbance of ER calcium homeostasis and induction of ER stress mediated apoptosis.
        Cell Death Dis. 2014; 16: 5e1464
        • Hino S.
        • Kondo S.
        • Yoshinaga K.
        • et al.
        Regulation of ER molecular chaperone prevents bone loss in a murine model of osteoporosis.
        J Bone Miner Metab. 2010; 28: 131-138
        • Uhlig K.
        • Berns J.S.
        • Kestenbaum B.
        • et al.
        KDOQI US commentary on the 2009 KDIGO clinical practice guideline for the diagnosis, evaluation, and treatment of CKD-mineral bone disorder (CKD-MBD).
        Am J Kidney Dis. 2010; 55: 773-799
        • Smith D.H.
        • Gullion D.M.
        • Nichols G.
        • Keith D.S.
        • Brown J.B.
        Cost of medical care for chronic kidney disease and comorbidity among enrollees in a large HMO population.
        J Am Soc Nephrol. 2004; 15: 1300-1306
        • Yoshimoto S.
        • Loo T.M.
        • Atarashi K.
        • et al.
        Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome.
        Nature. 2013; 499: 97-101
        • Engelking L.R.
        • Dasher C.A.
        • Hirschowitz B.I.
        Within-day fluctuations in serum bile-acid concentrations among normal control subjects and patient with hepatic disease.
        Am J Clin Pathol. 1980; 73: 196-201