Trimethylamine N-Oxide and Cardiovascular Events in Hemodialysis Patients
Open accessAbstract
Cardiovascular disease causes over 50% of the deaths in dialysis patients, and the risk of death is higher in white than in black patients. The underlying mechanisms for these findings are unknown. We determined the association of the proatherogenic metabolite trimethylamine N-oxide (TMAO) with cardiovascular outcomes in hemodialysis patients and assessed whether this association differs by race. We measured TMAO in stored serum samples obtained 3-6 months after randomization from a total of 1232 white and black patients of the Hemodialysis Study, and analyzed the association of TMAO with cardiovascular outcomes using Cox models adjusted for potential confounders (demographics, clinical characteristics, comorbidities, albumin, and residual kidney function). Mean age of the patients was 58 years; 35% of patients were white. TMAO concentration did not differ between whites and blacks. In whites, 2-fold higher TMAO associated with higher risk (hazard ratio [95% confidence interval]) of cardiac death (1.45 [1.24 to 1.69]), sudden cardiac death [1.70 (1.34 to 2.15)], first cardiovascular event (1.15 [1.01 to 1.32]), and any-cause death (1.22 [1.09 to 1.36]). In blacks, the association was nonlinear and significant only for cardiac death among patients with TMAO concentrations below the median (1.58 [1.03 to 2.44]). Compared with blacks in the same quintile, whites in the highest quintile for TMAO (≥135 μM) had a 4-fold higher risk of cardiac or sudden cardiac death and a 2-fold higher risk of any-cause death. We conclude that TMAO concentration associates with cardiovascular events in hemodialysis patients but the effects differ by race.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Of the 19 data points, the study in blacks by Shafi et al affected the heterogeneity; removal of the data in blacks resulted in a pooled RR of 1.70 (95% CI, 1.52, 1.91; P<0.001; P heterogeneity=0.9; I2=0%; fixed-effect model).
“Of the 19 data points, the study in blacks by Shafi et al22 affected the heterogeneity; removal of the data in blacks22 resulted in a pooled RR of 1.70 (95% CI, 1.52, 1.91; P<0.001; P heterogeneity=0.9; I2=0%; fixed‐effect model; Figure S1A).”
From Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies (2017) · cites this paper as [22]
An original study reported a nonlinear association of TMAO and cardiovascular events in blacks.
“An original study reported data separately for whites and blacks; a nonlinear association of TMAO and cardiovascular events was shown in blacks.22”
From Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies (2017) · cites this paper as [22]
In sensitivity analysis replacing RRs for all-cause mortality in these publications, the pooled RR was 1.69 (95% CI, 1.52, 1.89; P<0.001; P heterogeneity=0.6; I2=0%).
“we also performed a sensitivity analysis for the 18 data when we replaced RRs for all‐cause mortality in these publications7, 10, 22, 26; the pooled RR was 1.69 (95% CI, 1.52, 1.89; P<0.001; P heterogeneity=0.6; I2=0%).”
From Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies (2017) · cites this paper as [22]
Inconsistent associations between TMAO-related metabolites and MACE outcomes and death have been observed.
“inconsistent associations have also been observed.10, 22”
From Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies (2017) · cites this paper as [22]
One study showed a significant association of high TMAO levels and elevated risk of outcomes in whites but not in blacks.
“One study showed a significant association of high TMAO levels and elevated risk of outcomes in whites but not in blacks.22”
From Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies (2017) · cites this paper as [22]
The study by Shafi et al consisted of hemodialysis patients with a substantially high mean TMAO value of 101.9 μmol/L among total participants.
“Nonetheless, median values of TMAO concentrations in healthy individuals were reported as ranges of 3 to 6 μmol/L,8, 17, 18, 19 and the study by Shafi et al22 consisted of hemodialysis patients with the substantially high mean vale of TMAO (101.9 μmol/L among total participants).”
From Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies (2017) · cites this paper as [22]
Inclusion of data from black hemodialysis patients influenced the heterogeneity of results in this study.
“As previously reported that the associations of TMAO and risk of cardiovascular events in hemodialysis patients differed by race,22 the inclusion of data in black hemodialysis patients influenced the heterogeneity of results in our study.”
From Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies (2017) · cites this paper as [22]
In HEMO study participants, higher TMAO concentrations were associated with a higher risk of sudden cardiac death, first cardiovascular event, and any-cause death, particularly in whites.
“In HEMO study participants, higher TMAO concentrations were associated with a higher risk of sudden cardiac death, first cardiovascular event, and any-cause death, particularly in whites [46].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [46]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk
Tang, W. H. W., Wang, Z., Levison, B. S., Koeth, R. A., Britt, E. B., Fu, X., Wu, Y., & Hazen, S. L. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1109400 · Cited by 3,402 · see citing works
Tang, W. H. W., Wang, Z., Kennedy, D. J., Wu, Y., Buffa, J. A., Agatisa-Boyle, B., Li, X. S., Levison, B. S., & Hazen, S. L. (2015) · Circulation Research · doi:10.1161/circresaha.116.305360 · Cited by 1,223 · see citing works
Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden
Stubbs, J. R., House, J. A., Ocque, A. J., Zhang, S., Johnson, C., Kimber, C., Schmidt, K., Gupta, A., Wetmore, J. B., Nolin, T. D., et al. (2016) · Journal of the American Society of Nephrology · doi:10.1681/asn.2014111063 · Cited by 450 · see citing works
Clinical subtypes of Alzheimer’s disease
Petersen, R. C. (1998) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000051199 · Cited by 223 · see citing works
Kim, R. B., Morse, B. L., Djurdjev, O., Tang, M., Muirhead, N., Barrett, B., Holmes, D. T., Madore, F., Clase, C. M., Rigatto, C., et al. (2016) · Kidney International · doi:10.1016/j.kint.2016.01.014 · Cited by 179 · see citing works
Flagged first, then by citations
Research works printed but not linked: 31
- [1]United States Renal Data System : 2015 USRDS annual data report: Epidemiology of kidney disease in the United States, Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2015 [Google Scholar]
- [2]Foley RN, Parfrey PS, Sarnak MJ: Epidemiology of cardiovascular disease in chronic renal disease. J Am Soc Nephrol 9[Suppl]: S16–S23, 1998 [PubMed] [Google Scholar]
- [3]Himmelfarb J, Ikizler TA: Hemodialysis. N Engl J Med 363: 1833–1845, 2010 [DOI] [PubMed] [Google Scholar]
- [4]Longenecker JC, Coresh J, Powe NR, Levey AS, Fink NE, Martin A, Klag MJ: Traditional cardiovascular disease risk factors in dialysis patients compared with the general population: the CHOICE Study. J Am Soc Nephrol 13: 1918–1927, 2002 [DOI] [PubMed] [Google Scholar]
- [5]Kucirka LM, Grams ME, Lessler J, Hall EC, James N, Massie AB, Montgomery RA, Segev DL: Association of race and age with survival among patients undergoing dialysis. JAMA 306: 620–626, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [6]Agodoa L, Eggers P: Racial and ethnic disparities in end-stage kidney failure-survival paradoxes in African-Americans. Semin Dial 20: 577–585, 2007 [DOI] [PubMed] [Google Scholar]
- [7]Crews DC, Sozio SM, Liu Y, Coresh J, Powe NR: Inflammation and the paradox of racial differences in dialysis survival. J Am Soc Nephrol 22: 2279–2286, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [8]Parekh RS, Zhang L, Fivush BA, Klag MJ: Incidence of atherosclerosis by race in the dialysis morbidity and mortality study: a sample of the US ESRD population. J Am Soc Nephrol 16: 1420–1426, 2005 [DOI] [PubMed] [Google Scholar]
- [9]Wolf M, Betancourt J, Chang Y, Shah A, Teng M, Tamez H, Gutierrez O, Camargo CA Jr, Melamed M, Norris K, Stampfer MJ, Powe NR, Thadhani R: Impact of activated vitamin D and race on survival among hemodialysis patients. J Am Soc Nephrol 19: 1379–1388, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [10]Meyer TW, Hostetter TH: Approaches to uremia. J Am Soc Nephrol 25: 2151–2158, 2014 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [11]Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL: Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472: 57–63, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [13]Hai X, Landeras V, Dobre MA, DeOreo P, Meyer TW, Hostetter TH: Mechanism of Prominent Trimethylamine Oxide (TMAO) Accumulation in Hemodialysis Patients. PLoS One 10: e0143731, 2015 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [14]Kalim S, Clish CB, Wenger J, Elmariah S, Yeh RW, Deferio JJ, Pierce K, Deik A, Gerszten RE, Thadhani R, Rhee EP: A plasma long-chain acylcarnitine predicts cardiovascular mortality in incident dialysis patients. J Am Heart Assoc 2: e000542, 2013 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [15]Kaysen GA, Johansen KL, Chertow GM, Dalrymple LS, Kornak J, Grimes B, Dwyer T, Chassy AW, Fiehn O: Associations of Trimethylamine N-Oxide With Nutritional and Inflammatory Biomarkers and Cardiovascular Outcomes in Patients New to Dialysis. J Ren Nutr 25: 351–356, 2015 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [17]Meyer TW, Sirich TL, Hostetter TH: Dialysis cannot be dosed. Semin Dial 24: 471–479, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [18]Depner TA: Uremic toxicity: urea and beyond. Semin Dial 14: 246–251, 2001 [DOI] [PubMed] [Google Scholar]
- [19]Eknoyan G, Beck GJ, Cheung AK, Daugirdas JT, Greene T, Kusek JW, Allon M, Bailey J, Delmez JA, Depner TA, Dwyer JT, Levey AS, Levin NW, Milford E, Ornt DB, Rocco MV, Schulman G, Schwab SJ, Teehan BP, Toto R; Hemodialysis (HEMO) Study Group : Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl J Med 347: 2010–2019, 2002 [DOI] [PubMed] [Google Scholar]
- [20]Shafi T, Jaar BG, Plantinga LC, Fink NE, Sadler JH, Parekh RS, Powe NR, Coresh J: Association of residual urine output with mortality, quality of life, and inflammation in incident hemodialysis patients: the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) Study. Am J Kidney Dis 56: 348–358, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [21]Mao M, Matimba A, Scordo MG, Gunes A, Zengil H, Yasui-Furukori N, Masimirembwa C, Dahl ML: Flavin-containing monooxygenase 3 polymorphisms in 13 ethnic populations from Europe, East Asia and sub-Saharan Africa: frequency and linkage analysis. Pharmacogenomics 10: 1447–1455, 2009 [DOI] [PubMed] [Google Scholar]
- [22]Furnes B, Feng J, Sommer SS, Schlenk D: Identification of novel variants of the flavin-containing monooxygenase gene family in African Americans. Drug Metab Dispos 31: 187–193, 2003 [DOI] [PubMed] [Google Scholar]
- [23]Yvan-Charvet L, Ranalletta M, Wang N, Han S, Terasaka N, Li R, Welch C, Tall AR: Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice. J Clin Invest 117: 3900–3908, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [24]Bentley AR, Chen G, Shriner D, Doumatey AP, Zhou J, Huang H, Mullikin JC, Blakesley RW, Hansen NF, Bouffard GG, Cherukuri PF, Maskeri B, Young AC, Adeyemo A, Rotimi CN: Gene-based sequencing identifies lipid-influencing variants with ethnicity-specific effects in African Americans. PLoS Genet 10: e1004190, 2014 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [25]Deo RC, Reich D, Tandon A, Akylbekova E, Patterson N, Waliszewska A, Kathiresan S, Sarpong D, Taylor HA Jr, Wilson JG: Genetic differences between the determinants of lipid profile phenotypes in African and European Americans: the Jackson Heart Study. PLoS Genet 5: e1000342, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [28]Kalantar-Zadeh K, Norris KC: Is the malnutrition-inflammation complex the secret behind greater survival of African-American dialysis patients? J Am Soc Nephrol 22: 2150–2152, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [29]Muntinghe FL, Verduijn M, Zuurman MW, Grootendorst DC, Carrero JJ, Qureshi AR, Luttropp K, Nordfors L, Lindholm B, Brandenburg V, Schalling M, Stenvinkel P, Boeschoten EW, Krediet RT, Navis G, Dekker FW: CCR5 deletion protects against inflammation-associated mortality in dialysis patients. J Am Soc Nephrol 20: 1641–1649, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [30]Kovesdy CP, Kalantar-Zadeh K: Do genes allow inflammation to kill or not to kill? J Am Soc Nephrol 20: 1429–1431, 2009 [DOI] [PubMed] [Google Scholar]
- [31]Mente A, Chalcraft K, Ak H, Davis AD, Lonn E, Miller R, Potter MA, Yusuf S, Anand SS, McQueen MJ: The Relationship Between Trimethylamine-N-Oxide and Prevalent Cardiovascular Disease in a Multiethnic Population Living in Canada. Can J Cardiol 31: 1189–1194, 2015 [DOI] [PubMed] [Google Scholar]
- [32]Greene T, Beck GJ, Gassman JJ, Gotch FA, Kusek JW, Levey AS, Levin NW, Schulman G, Eknoyan G: Design and statistical issues of the hemodialysis (HEMO) study. Control Clin Trials 21: 502–525, 2000 [DOI] [PubMed] [Google Scholar]
- [33]Shastri S, Tangri N, Tighiouart H, Beck GJ, Vlagopoulos P, Ornt D, Eknoyan G, Kusek JW, Herzog C, Cheung AK, Sarnak MJ: Predictors of sudden cardiac death: a competing risk approach in the hemodialysis study. Clin J Am Soc Nephrol 7: 123–130, 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [34]Rocco MV, Yan G, Gassman J, Lewis JB, Ornt D, Weiss B, Levey AS; Hemodialysis Study Group; The National Institutes of Health-funded Hemodialysis. Health Care Financing Administration : Comparison of causes of death using HEMO Study and HCFA end-stage renal disease death notification classification systems. Am J Kidney Dis 39: 146–153, 2002 [DOI] [PubMed] [Google Scholar]
- [35]Donders AR, van der Heijden GJ, Stijnen T, Moons KG: Review: a gentle introduction to imputation of missing values. J Clin Epidemiol 59: 1087–1091, 2006 [DOI] [PubMed] [Google Scholar]
Cited by
Sorted by citations
Dietary metabolism, the gut microbiome, and heart failure
Tang, W. H. W., Li, D. Y., & Hazen, S. L. (2019) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0108-7 · Cited by 789 · see citing works
Schiattarella, G. G., Sannino, A., Toscano, E., Giugliano, G., Gargiulo, G., Franzone, A., Trimarco, B., Esposito, G., & Perrino, C. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehx342 · Cited by 563 · see citing works
Heianza, Y., Ma, W., Manson, J. E., Rexrode, K. M., & Qi, L. (2017) · Journal of the American Heart Association · doi:10.1161/jaha.116.004947 · Cited by 544 · see citing works
Trimethylamine N-oxide: the good, the bad and the unknown.
Velasquez, M., Ramezani, A., Manal, A., & Raj, D. (2016) · Toxins · doi:10.3390/toxins8110326 · Cited by 504 · see citing works
Li, X. S., Obeid, S., Klingenberg, R., Gencer, B., Mach, F., Räber, L., Windecker, S., Rodondi, N., Nanchen, D., Muller, O., et al. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehw582 · Cited by 479 · see citing works
l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans
Koeth, R. A., Lam-Galvez, B. R., Kirsop, J., Wang, Z., Levison, B. S., Gu, X., Copeland, M. F., Bartlett, D., Cody, D. B., Dai, H. J., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci94601 · Cited by 327 · see citing works
TMAO is Associated with Mortality: Impact of Modestly Impaired Renal Function
Gruppen, E. G., Garcia, E., Connelly, M. A., Jeyarajah, E. J., Otvos, J. D., Bakker, S. J. L., & Dullaart, R. P. F. (2017) · Scientific Reports · doi:10.1038/s41598-017-13739-9 · Cited by 146 · see citing works
Farhangi, M. A., Vajdi, M., & Asghari-Jafarabadi, M. (2020) · Nutrition Journal · doi:10.1186/s12937-020-00592-2 · Cited by 72 · see citing works
Johnson, C., Prokopienko, A. J., West, R. E., Nolin, T. D., & Stubbs, J. R. (2018) · Drug Metabolism and Disposition · doi:10.1124/dmd.118.081646 · Cited by 31 · see citing works
Ventricular arrhythmias in mouse models of diabetic kidney disease
Laurita, K. R., Khan, S., McMahon, T., Dennis, A. T., Li, V., Gaivin, R., Sapa, H., Fu, J.-D., & Schelling, J. R. (2021) · Scientific Reports · doi:10.1038/s41598-021-99891-9 · Cited by 8 · see citing works
- Authors
- Shafi, T., Powe, N. R., Meyer, T. W., Hwang, S., Hai, X., Melamed, M. L., Banerjee, T., Coresh, J., & Hostetter, T. H.
- Affiliations
- Johns Hopkins University (US)
- University of California, San Francisco (US)
- VA Palo Alto Health Care System (US)
- Department of Medicine and
- Case Western Reserve University (US)
- Albert Einstein College of Medicine (US)
- Corresponding author
- Shafi, Tariq
- Hwang, Seungyoung
- Coresh, Josef
- ORCID
- Venue
- Journal of the American Society of Nephrology
- Published
- 2016-07-19
- Volume
- 28
- Issue
- 1
- Pages
- 321-331
- ISSN
- 1046-6673 (ISSN-L)
- 1533-3450
- PMC
- PMC5198291
- OpenAlex
- W2478068820
- Cited by
- 164
- References
- 5
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 12 · 2023: 14 · 2022: 19 · 2021: 21 · 2020: 25 · 2019: 15 · 2018: 21 · 2017: 15 · 2016: 3 · 2012: 1
- FWCI
- 18.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of the American Society of Nephrology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR001073)
- Agency for Healthcare Research and Quality (R01 HS008365)
- National Heart, Lung, and Blood Institute (R01HL062985)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK080123, R03DK104012, K23DK083514, R01DK059616)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Nephrology › Dialysis and Renal Disease Management
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- trimethylamine N-oxide, hemodialysis, cardiovascular events, sudden cardiac death, cardiovascular mortality, all-cause mortality, racial differences, end-stage renal disease
- MeSH terms
- Cardiovascular Diseases, Female, Renal Dialysis, Humans, Male, Methylamines, Middle Aged, Prospective Studies, Black People, White People
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
