Deoxycholic Acid And Risks Of Cardiovascular Events, ESKD, And Mortality in CKD: The CRIC Study Ⅱ
Nov 03, 2023
RESULTS Baseline Characteristics
Among the 3,147 participants with fasting DCA levels at the 1-year follow-up visit, which was the baseline visit for the current analyses, the average age was 59 ± 11 years, 45.3% were women, 40.6% were African American, and 48.0% had diabetes (Table S1). The average estimated glomerular filtration rate was 42.5 ± 16.0 mL/min/1.73 m2 . Several participant characteristics varied by DCA quartile (Table 1).
Figure 1. Adjusted hazard ratios for atherosclerotic CVD, heart failure events, ESKD, and mortality according to DCA levels. Adjusted hazard ratios with 95% CIs for (A) atherosclerotic CVD, (B) heart failure events, (C) ESKD, and (D) mortality according to DCA levels. The curve above the y-scale reference line of 1.0 is statistically significant. Models were adjusted for the covariates in model 4, including age, sex, African American race, Hispanic ethnicity, eGFR, log urinary protein, diabetes, SBP, number of antihypertensive medications, current smoking, history of cardiovascular disease, total cholesterol, statin use, log IL-6, log CRP, log FGF23, log PTH, phosphate, calcium, and albumin. The DCA values on the x-axis were back-transformed per 1 SD of log-transformed DCA values. The rug plot at the bottom of the figures displays the number of measurements. Abbreviations: CRP, C-reactive protein; CVD, cardiovascular disease; DCA, deoxycholic acid; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; FGF23, fibroblast growth factor 23; IL-6, interleukin 6; PTH, parathyroid hormone; SBP, systolic blood pressure; SD, standard deviation.
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Higher DCA levels were associated with increased age. lower percentage of African American participants, lower statin use, and higher estimated glomerular filtration rate.higher albumin, higher interleukin-6, and lower fibroblastgrowth factor-23 levels. There was no signifcant association of DCA quartiles with sex, current smoking, body mass index, systolic blood pressure, history of CVD, total cholesterol, number of blood pressure medications, urinary protein, calcium, or C-reactive protein, phosphate, parathyroid hormone. Dietary protein and fat were also not significantly associated with DCA levels (Table S2)After multivariable adjustment of the Tobit regression model, the 2 variables most strongly associated with higher DCA levels were increased age and nonuse of statins(Table S4)
Associations of Fasting DCA Level WithAdjudicated Atherosclerotic and Heart FailureEvents
The associations of DCA with all outcomes were nonlinear(Fig 1). Table 2 shows the associations between DCA and atherosclerotic and heart failure events. In the group with DCA levels below the median (68.45 ng/ml), there were (16.6%) atherosclerotic events with a mean follow-up time of 6.9 years. Among individuals with DCA levels above the median, there were 251 (16.0%) atherosclerotic events with a mean follow-up time of 6.7 years. In both groups, DCA levels were not associated with atherosclerotic events in the unadjusted analysis or the adjusted models (HR 0.88 and 95% CI,0.56-1.40 for model 4 with DCA below the median; HR, 1 .52 and 95% CI, 0.74 3.12 for model 4 with DCA above the median; Fig 1A). In the heart failure analysis, there were 303 (19.3%) events in those with DCA values below the median with a mean follow-up time of 7.1 years. Among individuals with DCA values above the median, there were 272 (17.3%) heart failure events with a mean follow-up time of 7.0 years. Similarly, there were no associations between DCA values and heart failure events in the unadjusted and adjusted analyses (HR, 0.82 and 95% CI, 0.54-1.27 in model 4 with DCA below the median; HR, 1.22 and 95% CI, 0.63- 2.38 in model 4 with DCA above the median; Fig 1B).
Association of Fasting DCA Level With ESKD Table 2 shows the association of fasting DCA level with progression to ESKD. Among participants with baseline DCA levels below the median, there were 456 (29.0%) events with a mean follow-up time of 6.9 years. In this population with DCA levels below the median, DCA levels closer to the median value were associated with lower risk of progression to ESKD (HR, 0.58 and 95% CI, 0.41-0.81 in the unadjusted analysis; HR, 0.62 and 95% CI, 0.44- 0.88 in model 1). However, this association was no longer significant after adjustment for CKD and CVD risk factors (HR, 0.98 and 95% CI, 0.68-1.40 in model 4, Fig 1C).
Among individuals with DCA values above the median, there were 373 (23.7%) events with a mean follow-up time of 7.0 years. In the unadjusted analysis and model 1, there was no significant association between DCA and ESKD. However, after adjustment for CKD and CVD risk factors, the association became significant. Adjustments for bone and mineral factors in model 4 also strengthened this association (HR, 2.67, and 95% CI, 1.51-4.74 in model 4).
Associations of Fasting DCA Level With All-Cause Mortality Table 2 shows the associations of DCA with all-cause mortality. Among individuals with DCA values below the median, there were 408 (25.9%) total deaths with a mean follow-up time of 8.1 years. Low DCA values were not associated with all-cause mortality in the unadjusted analysis or in any of the adjusted models (HR, 1.00 and 95% CI, 0.70-1.43 in model 4, Fig 1D).
Among individuals with DCA values above the median, there were 411 (26.1%) deaths with a mean follow-up time of 7.9 years. High DCA levels were significantly associated with all-cause mortality in the unadjusted analysis and all of the additional models, independent of demographics, renal risk factors, CVD risk factors, inflammatory markers, and markers of mineral metabolism (HR, 2.13 and 95% CI, 1.25-3.64 in model 4). We also investigated the age of the DCA sample on clinical outcomes. We found that adjusting for DCA sample age did not significantly affect the association between DCA and atherosclerotic events, heart failure events, ESKD, or mortality (model 5 in Table S3). DISCUSSION Our study found that in 3,147 participants with CKD stages 2-4, the associations between DCA levels and heart failure and atherosclerotic events, progression to ESKD, and mortality were nonlinear. In multivariable-adjusted models, DCA levels above the median were independently associated with ESKD and all-cause mortality, whereas those below the median were not associated with clinical outcomes after adjustment. Our findings, which will require validation in future studies, provide support for the emerging evidence of the complex effects of bile acids on human health.
Bile acids primarily aid in digestion, although there is growing recognition of their numerous effects throughout the body. Primary bile acids, such as cholic acid, are formed from cholesterol precursors in the liver and are excreted into the intestines to aid in lipid digestion, where a portion is metabolized by intestinal bacteria into secondary bile acids, such as DCA. Most bile acids are reabsorbed in the distal ileum and returned to the liver as part of the enterohepatic circulation. However, a low level remains in the systemic circulation. Many factors are thought to alter the level and composition of bile acids, including diet, medications, and the gut microbiome.6,28,29 A high-fat “Western” diet and alcohol use may increase DCA levels.30,31 CKD may also alter bile acid levels. Prior research has indicated that those with CKD have elevated total bile acids compared with those without CKD and have an increased DCA to cholic acid ratio.3,8,9 We found that among individuals with CKD stages 2-4, elevated DCA levels were most strongly associated with increased age and nonuse of statins after multivariable adjustment. Statins competitively inhibit the activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase, the rate-limiting step in cholesterol synthesis, resulting in lowered cellular cholesterol concentration.32 Bile acids are formed from cholesterol precursors; thus, reducing cholesterol may reduce bile acid synthesis and quantity. The effect of age on DCA levels is unclear, with contradictory reports in the literature.33,34 In contrast to prior studies, we did not find an independent relationship between kidney function and DCA levels.3,8,9 Additional research is needed to examine DCA levels across the full spectrum of kidney function.
In our study, DCA levels were associated with clinical outcomes in a nonlinear or biphasic pattern. This distribution suggests that moderate DCA concentrations may be optimal, whereas more extreme levels may have to deleterious effects. Many biological molecules exhibit this biphasic dose-response curve.35,36 With some substances, a minimum threshold is needed for normal function and yet high levels cause toxicity, creating a middle range of ideal functioning. Because DCA and other bile acids, in addition to their role in digestion, have hormone-like properties with systemic physiologic effects, we speculate that DCA may be harmful at high levels, but some level of DCA above a minimal threshold may be advantageous. Future studies will need to test this hypothesis and further investigate the optimal range of DCA levels.
Prior studies showing that DCA is associated with both beneficial and harmful outcomes in the body support our assertion of an optimal threshold level of DCA. DCA has detergent properties that assist the digestion of dietary lipids and can also affect cellular lipid bilayers. DCA has been shown to disrupt gastrointestinal mucosal barriers, leading to cellular damage and inflammation.37 DCA also generates reactive oxygen species, causing DNA damage and cellular apoptosis, and stimulates the production of proinflammatory, procalcification, and protumorigenic factors.10,11,38,39 In addition, both animal and human studies suggest that elevated DCA levels may contribute to vascular calcification, which may worsen cardiovascular and kidney disease.3,14,40 However, research also suggests that DCA may have favorable effects through the activation of its receptor, the farsenoid X receptor. Farsenoid X receptor activation decreases gluconeogenesis, increases glycolysis, induces hepatic lipoprotein clearance, and reduces fatty acid synthesis, leading to improved glucose tolerance, insulin sensitivity, and lipid profiles.41-44 In addition, in the kidney, farnesoid X receptor activation has been associated with reduced diabetic nephropathy and renal fibrosis.45-47 Thus at low DCA levels, reduced farsenoid X receptor stimulation may worsen metabolic syndrome and kidney disease, but at high levels, DCA may cause cellular damage and vascular calcification and may hasten CKD progression. Additional studies are needed to validate our findings and to further examine the exact mechanisms of beneficial and harmful effects of DCA on kidney function.
In this study, we found that elevated DCA was associated with a higher risk of all-cause mortality but not with atherosclerotic or heart failure events. 2 possibilities may reconcile these disparate findings. First, there may not be a true association of DCA with CVD, and our findings of a significant association of DCA with mortality suggest that elevated DCA may contribute to mortality through mechanisms other than CVD. Second, DCA may be associated with CVD events but not heart failure or atherosclerotic events. Patients with CKD are susceptible to medial arterial calcification, which is associated with arrhythmias and sudden cardiac death instead of atherosclerotic events or heart failure.48,49 Future studies are needed to confirm or refute our findings.
There are several strengths of our study. We used data from the CRIC Study, which is a large, prospective cohort of a diverse patient population with CKD stages 2-4. Given the long follow-up time and many participants in the cohort, we were able to assess clinically relevant outcomes associated with DCA levels. The CRIC Study uses standardized data collection methods, collects many variables, and clinical outcomes are adjudicated. We were also able to measure the fasting DCA levels on most of the CRIC Study participants. However, there are also limitations. We do not have longitudinal data on DCA levels, and thus we do not know the variability of DCA in each participant or how DCA levels over time affect clinical outcomes. We were unable to measure other bile acids and thus could not make conclusions about the total bile acid pool or ratios of bile acids. We were only able to measure serum DCA and not urinary or fecal DCA levels and thus may have an incomplete understanding of patients’ DCA metabolism. We were unable to measure many factors that may affect DCA levels, such as liver disease, alcohol consumption, the gut microbiome, fat malabsorption, certain medications, or complete dietary intake. In addition, the cause of death of many participants was unable to be determined, and outcomes of interest such as sudden cardiac death and arrhythmias were not available.
In conclusion, our study suggests that high DCA levels are associated with the risk of ESKD and all-cause mortality in patients with CKD. Although there are several possible biological mechanisms linking DCA to poor clinical outcomes, there is still much that is unknown about DCA in kidney disease. Further research is needed to validate our findings and to determine the exact role of DCA levels in the pathogenesis of cardiovascular and kidney disease and the clinical effects in patients with CKD.
SUPPLEMENTARY MATERIAL
Supplementary File (PDF) Figure S1: Study population derived from the total CRIC Study population. Item S1: Supplementary Methods. Table S1: Characteristics of all CRIC Study participants who attended the year 1 visit and of the participants included in the study population. Table S2: Associations of dietary protein and fat with log-DCA. Table S3: Associations of fasting DCA level with clinical outcomes, adjusted for age of sample. Table S4: Associations between log-DCA and DCA predictors.
ARTICLE INFORMATION
CRIC Study Investigators: Lawrence J. Appel, MD, MPH, Harold I. Feldman, MD, MSCE, Alan S. Go, MD, Jiang He, MD, PhD, James P. Lash, MD, Robert G. Nelson, MD, PhD, MS, Mahboob Rahman, MD, Panduranga S. Rao, MD, Vallabh O. Shah, PhD, MS, Raymond R. Townsend, MD, and Mark L. Unruh, MD, MS.
Authors’ Full Names and Academic Degrees: Rebecca Frazier, MD, Xuan Cai, MS, Jungwha Lee, PhD, Joshua D. Bundy, PhD, MPH, Anna Jovanovich, MD, Jing Chen, MD, MMSc, MSc, Rajat Deo, MD, MTR, James P. Lash, MD, Amanda Hyre Anderson, PhD, MPH, Alan S. Go, MD, Harold I. Feldman, MD, MSCE, Tariq Shafi, MBBS, MHS, Eugene P. Rhee, MD, Makoto Miyazaki, PhD, Michel Chonchol, MD, and Tamara Isakova, MD, MMSc, on behalf of the CRIC Study Investigators.
Authors’ Affiliations: Division of Nephrology and Hypertension, Department of Medicine (RF, TI), and Center for Translational Metabolism and Health, Institute for Public Health and Medicine (RF, XC, JL, TI), Northwestern University Feinberg School of Medicine, Chicago, Illinois; Jesse Brown Veterans Administration Medical Center, Chicago, Illinois (RF); Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana (JDB, AHA); Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora (AJ, MM, MC); Renal Section, Medicine Service, Rocky Mountain Regional VA Medical Center, Aurora, Colorado (AJ); Division of Nephrology and Hypertension, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana (JC); Division of Cardiology, Electrophysiology Section, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (RD); Division of Nephrology, Department of Medicine, University of Illinois, Chicago (JPL); Comprehensive Clinical Research Unit, Kaiser Permanente Northern California Division of Research, Oakland, California (ASG); Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Biostatistics, Epidemiology, and Informatics, and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (HIF); Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson (TS); and Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston (EPR).
REFERENCES
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