Deoxycholic Acid and Risks of Cardiovascular Events, ESKD, and Mortality in CKD: The CRIC Study

Overview

Journal Kidney Med

Specialty Nephrology

Date 2022 Jan 24

PMID 35072049

Authors

Rebecca Frazier

Xuan Cai

Jungwha Lee

Joshua D Bundy

Anna Jovanovich

Jing Chen

Rajat Deo

James P Lash

Amanda Hyre Anderson

Alan S Go

Harold I Feldman

Tariq Shafi

Eugene P Rhee

Makoto Miyazaki

Michel Chonchol

Tamara Isakova

Affiliations

Soon will be listed here.

Abstract

Rationale & Objective: Elevated levels of deoxycholic acid (DCA) are associated with adverse outcomes and may contribute to vascular calcification in patients with chronic kidney disease (CKD). We tested the hypothesis that elevated levels of DCA were associated with increased risks of cardiovascular disease, CKD progression, and death in patients with CKD.

Study Design: Prospective observational cohort study.

Setting & Participants: We included 3,147 Chronic Renal Insufficiency Cohort study participants who had fasting DCA levels. The average age was 59 ± 11 years, 45.3% were women, 40.6% were African American, and the mean estimated glomerular filtration rate was 42.5 ± 16.0 mL/min/1.73 m.

Predictor: Fasting DCA levels in Chronic Renal Insufficiency Cohort study participants.

Outcomes: Risks of atherosclerotic and heart failure events, end-stage kidney disease (ESKD), and all-cause mortality.

Analytical Approach: We used Tobit regression to identify predictors of DCA levels. We used Cox regression to examine the association between fasting DCA levels and clinical outcomes.

Results: The strongest predictors of elevated DCA levels in adjusted models were increased age and nonuse of statins. The associations between log-transformed DCA levels and clinical outcomes were nonlinear. After adjustment, DCA levels above the median were independently associated with higher risks of ESKD (HR, 2.67; 95% CI, 1.51-4.74) and all-cause mortality (HR, 2.13; 95% CI, 1.25-3.64). DCA levels above the median were not associated with atherosclerotic and heart failure events, and DCA levels below the median were not associated with clinical outcomes.

Limitations: We were unable to measure DCA longitudinally or in urinary or fecal samples, and we were unable to measure other bile acids. We also could not measure many factors that affect DCA levels.

Conclusions: In 3,147 participants with CKD stages 2-4, DCA levels above the median were independently associated with ESKD and all-cause mortality.

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References

Proudfoot D, Skepper J, Hegyi L, Bennett M, Shanahan C, Weissberg P . Apoptosis regulates human vascular calcification in vitro: evidence for initiation of vascular calcification by apoptotic bodies. Circ Res. 2000; 87(11):1055-62. DOI: 10.1161/01.res.87.11.1055. View

Feldman H, Appel L, Chertow G, Cifelli D, Cizman B, Daugirdas J . The Chronic Renal Insufficiency Cohort (CRIC) Study: Design and Methods. J Am Soc Nephrol. 2003; 14(7 Suppl 2):S148-53. DOI: 10.1097/01.asn.0000070149.78399.ce. View

Cipriani S, Mencarelli A, Palladino G, Fiorucci S . FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res. 2009; 51(4):771-84. PMC: 2842143. DOI: 10.1194/jlr.M001602. View

Ku E, Hsu R, Tuot D, Bae S, Lipkowitz M, Smogorzewski M . Magnitude of the Difference Between Clinic and Ambulatory Blood Pressures and Risk of Adverse Outcomes in Patients With Chronic Kidney Disease. J Am Heart Assoc. 2019; 8(9):e011013. PMC: 6512117. DOI: 10.1161/JAHA.118.011013. View

Calabrese E, Baldwin L . Hormesis: U-shaped dose responses and their centrality in toxicology. Trends Pharmacol Sci. 2001; 22(6):285-91. DOI: 10.1016/s0165-6147(00)01719-3. View

Foley R, Murray A, Li S, Herzog C, McBean A, Eggers P . Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999. J Am Soc Nephrol. 2004; 16(2):489-95. DOI: 10.1681/ASN.2004030203. View

Payne C, Weber C, Crowley-Skillicorn C, Dvorak K, Bernstein H, Bernstein C . Deoxycholate induces mitochondrial oxidative stress and activates NF-kappaB through multiple mechanisms in HCT-116 colon epithelial cells. Carcinogenesis. 2006; 28(1):215-22. DOI: 10.1093/carcin/bgl139. View

. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl. 2009; (113):S1-130. DOI: 10.1038/ki.2009.188. View

Yoshimoto S, Loo T, Atarashi K, Kanda H, Sato S, Oyadomari S . Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013; 499(7456):97-101. DOI: 10.1038/nature12347. View

10.

Nunez J, Bayes-Genis A, Zannad F, Rossignol P, Nunez E, Bodi V . Long-Term Potassium Monitoring and Dynamics in Heart Failure and Risk of Mortality. Circulation. 2017; 137(13):1320-1330. DOI: 10.1161/CIRCULATIONAHA.117.030576. View

11.

Mahmoudiandehkordi S, Arnold M, Nho K, Ahmad S, Jia W, Xie G . Altered bile acid profile associates with cognitive impairment in Alzheimer's disease-An emerging role for gut microbiome. Alzheimers Dement. 2018; 15(1):76-92. PMC: 6487485. DOI: 10.1016/j.jalz.2018.07.217. View

12.

Lash J, Go A, Appel L, He J, Ojo A, Rahman M . Chronic Renal Insufficiency Cohort (CRIC) Study: baseline characteristics and associations with kidney function. Clin J Am Soc Nephrol. 2009; 4(8):1302-11. PMC: 2723966. DOI: 10.2215/CJN.00070109. View

13.

Meira-Machado L, Cadarso-Suarez C, Gude F, Araujo A . smoothHR: an R package for pointwise nonparametric estimation of hazard ratio curves of continuous predictors. Comput Math Methods Med. 2014; 2013:745742. PMC: 3876718. DOI: 10.1155/2013/745742. View

14.

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(4):694-9. DOI: 10.1016/j.bbrc.2009.07.085. View

15.

Gai Z, Chu L, Hiller C, Arsenijevic D, Penno C, Montani J . Effect of chronic renal failure on the hepatic, intestinal, and renal expression of bile acid transporters. Am J Physiol Renal Physiol. 2013; 306(1):F130-7. DOI: 10.1152/ajprenal.00114.2013. View

16.

Zhang Y, Lee F, Barrera G, Lee H, Vales C, Gonzalez F . Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci U S A. 2006; 103(4):1006-11. PMC: 1347977. DOI: 10.1073/pnas.0506982103. View

17.

Bundy J, Cai X, Mehta R, Scialla J, de Boer I, Hsu C . Serum Calcification Propensity and Clinical Events in CKD. Clin J Am Soc Nephrol. 2019; 14(11):1562-1571. PMC: 6832040. DOI: 10.2215/CJN.04710419. View

18.

Miyazaki-Anzai S, Masuda M, Levi M, Keenan A, 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(9):e108270. PMC: 4169583. DOI: 10.1371/journal.pone.0108270. View

19.

McGarr S, Ridlon J, Hylemon P . Diet, anaerobic bacterial metabolism, and colon cancer: a review of the literature. J Clin Gastroenterol. 2005; 39(2):98-109. View

20.

Farhana L, Nangia-Makker P, Arbit E, Shango K, Sarkar S, Mahmud H . Bile acid: a potential inducer of colon cancer stem cells. Stem Cell Res Ther. 2016; 7(1):181. PMC: 5134122. DOI: 10.1186/s13287-016-0439-4. View