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Advanced chronic kidney disease populations have elevated trimethylamine N-oxide levels associated with increased cardiovascular events
Open accessAbstract
Cardiovascular disease is more common in patients with chronic kidney disease (CKD), and traditional risk factors do not adequately predict those at risk for cardiovascular (CV) events. Recent evidence suggests elevated trimethylamine N-oxide (TMAO), created by gut microflora from dietary L-carnitine and choline, is associated with CV events. We investigated the relationship of TMAO levels in patients with stages 3b and 4 CKD to ischemic CV events using the CanPREDDICT cohort, a Canada-wide observational study with prospective 3-year follow-up of adjudicated CV events. Baseline samples were obtained for 2529 CKD patients. TMAO, choline, and L-carnitine levels were measured using tandem mass spectrometry. Baseline median TMAO level was high for the whole cohort (20.41 μM; interquartile range [IQR]: 12.82-32.70 μM). TMAO was independently associated with CV events (hazard ratio 1.23; 95% confidence interval: 1.06-1.42 / 1 SD lnTMAO) after adjusting for all potential CV risk factors. Those in the highest TMAO quartile had significantly higher risk of CV events (adjusted hazard ratio 1.59; 95% confidence interval: 1.04-2.43; P = 0.0351) in the analysis of recurring ischemic events. Among those with stage 3b CKD (hazard ratio 1.45; 95% confidence interval: 1.12-1.87 / 1 SD lnTMAO), independent of kidney function, TMAO levels identified those at highest risk for events. Our results suggest that TMAO may represent a new potentially modifiable CV risk factor for CKD patients. Further studies are needed to determine sources of variability and if lowering of TMAO reduces CV risk in CKD.
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“Fifth, most of the study participants were from Europe and the United States and included mainly (approximately of 65–90% of total study participants) whites,10, 19, 20, 23 so that our results might not be applicable to other race/ethnic groups such as Asians and Africans.”
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 [20]
In the citing paper
“Trimethylamine N-oxide (TMAO) is a biologically active molecule and is a putative promoter of chronic diseases including atherosclerosis in humans.”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [61]
In the citing paper
“Many of the studies that identified an association between TMAO and heart disease also found that people with higher TMAO had decreased renal function (61,109).”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [61]
Citations
Cites
A Proportional Hazards Model for the Subdistribution of a Competing Risk
Fine, J. P., & Gray, R. J. (1999) · Journal of the American Statistical Association · doi:10.1080/01621459.1999.10474144 · Cited by 14,290
Pencina, M. J., D' Agostino, R. B., D' Agostino, R. B., & Vasan, R. S. (2008) · Statistics in Medicine · doi:10.1002/sim.2929 · Cited by 6,493
Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease
Wang, Z., Klipfell, E., Bennett, B. J., Koeth, R., Levison, B. S., DuGar, B., Feldstein, A. E., Britt, E. B., Fu, X., Chung, Y.-M., et al. (2011) · Nature · doi:10.1038/nature09922 · Cited by 5,597
Assessing the Performance of Prediction Models: A Framework for Traditional and Novel Measures
Steyerberg, E. W., Vickers, A. J., Cook, N. R., Gerds, T., Gonen, M., Obuchowski, N., Pencina, M. J., & Kattan, M. W. (2010) · Epidemiology · doi:10.1097/ede.0b013e3181c30fb2 · Cited by 5,170
Cox’s regression model for counting processes: A large sample study
Andersen, P. K., & Gill, R. D. (1982) · The Annals of Statistics · doi:10.1214/aos/1176345976 · Cited by 4,419
Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis
Koeth, R. A., Wang, Z., Levison, B. S., Buffa, J. A., Org, E., Sheehy, B. T., Britt, E. B., Fu, X., Wu, Y., Li, L., et al. (2013) · Nature Medicine · doi:10.1038/nm.3145 · Cited by 4,386
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 3,400
Clinical Prediction Models: A Practical Approach to Development, Validation, and Updating
Steyerberg, E. W. (2019) · Statistics for Biology and Health · doi:10.1007/978-3-030-16399-0 · Cited by 3,281
Baigent, C., Landray, M. J., Reith, C., Emberson, J., Wheeler, D. C., Tomson, C., Wanner, C., Krane, V., Cass, A., Craig, J., et al. (2011) · The Lancet · doi:10.1016/s0140-6736(11)60739-3 · Cited by 2,479
Self-citationPencina, M. J., & D’Agostino, R. B. (2004) · Statistics in Medicine · doi:10.1002/sim.1802 · Cited by 1,442
Cited by
Sorted by citations
Microbiota in health and diseases
Hou, K., Wu, Z.-X., Chen, X.-Y., Wang, J.-Q., Zhang, D., Xiao, C., Zhu, D., Koya, J. B., Wei, L., Li, J., et al. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00974-4 · Cited by 3,171
“A trial study using samples obtained from CKD patients displayed higher plasma levels of TMAO in CKD vs nonCKD patients.(314) Persistent low-grade inflammation is augmented due to translocation of bacteria and bacterial products from the gut lumen to blood via increase in intestinal permeability.”
ResultTotal volatile basic nitrogen (TVB-N) and its role in meat spoilage: A review
Bekhit, A. E. A., Holman, B. W. B., Giteru, S. G., & Hopkins, D. L. (2021) · Trends in Food Science & Technology · doi:10.1016/j.tifs.2021.01.006 · Cited by 1,003
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
Epidemiology and risk of cardiovascular disease in populations with chronic kidney disease
Matsushita, K., Ballew, S. H., Wang, A. Y.-M., Kalyesubula, R., Schäeffner, E., & Agarwal, R. (2022) · Nature Reviews Nephrology · doi:10.1038/s41581-022-00616-6 · Cited by 728
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
Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease
Zeisel, S. H., & Warrier, M. (2017) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071816-064732 · Cited by 475
“Many of the studies that identified an association between TMAO and heart disease also found that people with higher TMAO had decreased renal function (61, 109).”
BackgroundLi, 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
Microbial modulation of cardiovascular disease
Brown, J. M., & Hazen, S. L. (2018) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2017.149 · Cited by 440
Wu, K., Yuan, Y., Yu, H., Dai, X., Wang, S., Sun, Z., Wang, F., Fei, H., Lin, Q., Jiang, H., et al. (2020) · Blood · doi:10.1182/blood.2019003990 · Cited by 345
Organic Cation Transporters in Health and Disease
Koepsell, H. (2019) · Pharmacological Reviews · doi:10.1124/pr.118.015578 · Cited by 302
“High plasma TMAO concentrations have been associated with development of chronic kidney and cardiovascular diseases (Brown and Hazen, 2014; Tang et al., 2015; Kim et al., 2016).”
BackgroundQi, J., You, T., Li, J., Pan, T., Xiang, L., Han, Y., & Zhu, L. (2018) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13307 · Cited by 268
“For instance, TMAO exhibited no significant predictive value on CVEs and mortality in a 4-year observational cohort including 235 patients with CKD [40].”
BackgroundInfluentialComplications of chronic kidney disease: current state, knowledge gaps, and strategy for action
Bello, A. K., Alrukhaimi, M. N., Ashuntantang, G., Basnet, S., Correa‐Rotter, R., Douthat, W., Kazancıoğlu, R., Köttgen, A., Nangaku, M., Powe, N. R., et al. (2017) · Kidney International Supplements · doi:10.1016/j.kisu.2017.07.007 · Cited by 304
Xu, K., Xia, G., Lu, J.-Q., Chen, M.-X., Zhen, X., Wang, S., You, C., Nie, J., Zhou, H., & Yin, J. (2017) · Scientific Reports · doi:10.1038/s41598-017-01387-y · Cited by 268
Cardiovascular disease risk factors in chronic kidney disease: A systematic review and meta-analysis
Major, R., Cheng, M. R. I., Grant, R. A., Shantikumar, S., Xu, G., Oozeerally, I., Brunskill, N. J., & Gray, L. J. (2018) · PLoS ONE · doi:10.1371/journal.pone.0192895 · Cited by 254
Trimethylamine- N -Oxide: Friend, Foe, or Simply Caught in the Cross-Fire?
Cho, C. E., & Caudill, M. A. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2016.10.005 · Cited by 220
“Circulating TMAO concentrations were also shown to identify those at the highest risk for cardiovascular events among patients with advanced chronic kidney disease [37].”
BackgroundGut Microbiota-Derived TMAO: A Causal Factor Promoting Atherosclerotic Cardiovascular Disease?
Canyelles, M., Borràs, C., Rotllán, N., Tondo, M., Escolá‐Gil, J. C., & Blanco‐Vaca, F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24031940 · Cited by 218
“Last, the CKD patient results also showed a significant association when eGFR was not included in the adjustment [39], while adjustment for renal function led to divergent results [40,41].”
Gut microbiota in atherosclerosis: focus on trimethylamine N‐oxide
Zhu, Y., Li, Q., & Jiang, H. (2020) · Apmis · doi:10.1111/apm.13038 · Cited by 210
Canyelles, M., Tondo, M., Cedó, L., Farràs, M., Escolá‐Gil, J. C., & Blanco‐Vaca, F. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19103228 · Cited by 197
Gupta, N., Buffa, J. A., Roberts, A. B., Sangwan, N., Skye, S. M., Li, L., Ho, K. J., Varga, J., DiDonato, J. A., Tang, W. H. W., et al. (2020) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.120.314139 · Cited by 187
Li, D., Lu, Y., Yuan, S., Cai, X., He, Y., Chen, J., Wu, Q., He, D., Fang, A., Bo, Y., et al. (2022) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqac074 · Cited by 193
Gut Microbiota and Ischemic Stroke: The Role of Trimethylamine N-Oxide
Nam, H. S. (2019) · Journal of Stroke · doi:10.5853/jos.2019.00472 · Cited by 176
“In patients with advanced chronic kidney disease, an elevated TMAO level was found to be independently associated with MACE risk after adjustment for cardiovascular risk factors.(32,33) Studies examining the relationship between TMAO levels and cardiovascular outcomes have identified kidney function as an important co…”
BackgroundAn overview of renal metabolomics
Kalim, S., & Rhee, E. P. (2016) · Kidney International · doi:10.1016/j.kint.2016.08.021 · Cited by 179
Trimethylamine N-Oxide and Cardiovascular Events in Hemodialysis Patients
Shafi, T., Powe, N. R., Meyer, T. W., Hwang, S., Hai, X., Melamed, M. L., Banerjee, T., Coresh, J., & Hostetter, T. H. (2017) · Journal of the American Society of Nephrology · doi:10.1681/asn.2016030374 · Cited by 164
Bekhit, A. E. A., Giteru, S. G., Holman, B. W. B., & Hopkins, D. L. (2021) · Comprehensive Reviews in Food Science and Food Safety · doi:10.1111/1541-4337.12764 · Cited by 170
Gut Microbiota Dysbiosis and Increased Plasma LPS and TMAO Levels in Patients With Preeclampsia
Wang, J., Gu, X., Yang, J., Wei, Y., & Zhao, Y. (2019) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2019.00409 · Cited by 161
Alisson-Silva, F., Kawanishi, K., & Varki, A. (2016) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2016.07.002 · Cited by 156
“of death in CKD patients, the association between plasma TMAO level and CVD risk in CKD is debated (Kim et al., 2016; Stubbs et al., 2016; Tang et al., 2015).”
Nie, J., Xie, L., Zhao, B.-X., Li, Y., Qiu, B., Zhu, F., Li, G.-F., He, M., Wang, Y., Wang, B., et al. (2018) · Stroke · doi:10.1161/strokeaha.118.021997 · Cited by 163
Pelletier, C. C., Croyal, M., Ene, L., Aguesse, A., Billon‐Crossouard, S., Krempf, M., Lemoine, S., Guebre‐Egziabher, F., Juillard, L., & Soulage, C. O. (2019) · Toxins · doi:10.3390/toxins11110635 · Cited by 156
Impact of Altered Intestinal Microbiota on Chronic Kidney Disease Progression
Castillo-Rodríguez, E., Fernández-Prado, R., Esteras, R., Pérez-Gómez, M. V., Gracia-Iguacel, C., Fernández‐Fernández, B., Kanbay, M., Tejedor, A., Lázaro, A., Ruiz‐Ortega, M., et al. (2018) · Toxins · doi:10.3390/toxins10070300 · Cited by 154
“TMAO levels correlated with evidence of systemic inflammation and was an independent predictor of mortality and CVD in CKD patients [29,30,78,79].”
BackgroundWang, S., Lv, D., Jiang, S., Jiang, J., Liang, M., Hou, F. F., & Chen, Y. (2019) · Clinical Science · doi:10.1042/cs20190171 · Cited by 143
Sun, G., Yin, Z., Liu, N., Bian, X., Yu, R., Su, X., Zhang, B., & Wang, Y. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.09.108 · Cited by 140
Trimethylamine N-oxide impairs pyruvate and fatty acid oxidation in cardiac mitochondria
Makrecka‐Kuka, M., Volska, K., Antone, U., Vilšķe̅rsts, R., Grı̄nberga, S., Bandere, D., Liepinsh, E., & Dambrova, M. (2017) · Toxicology Letters · doi:10.1016/j.toxlet.2016.12.017 · Cited by 143
Impact of Gut Microbiota Composition on Onset and Progression of Chronic Non-Communicable Diseases
Noce, A., Marrone, G., Daniele, F. D., Ottaviani, E., Jones, G. W., Bernini, R., Romani, A., & Rovella, V. (2019) · Nutrients · doi:10.3390/nu11051073 · Cited by 162
“In patients with moderate-severe CKD, TMAO represents an independent predictor of CV mortality [68,69], and its levels are directly proportional to inflammatory biomarkers (such as high-sensitivity C-reactive protein (hs-CRP) and IL-6).”
BackgroundTrimethylamine N -oxide: A harmful, protective or diagnostic marker in lifestyle diseases?
Nowiński, A., & Ufnal, M. (2017) · Nutrition · doi:10.1016/j.nut.2017.08.001 · Cited by 132
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Guasti, L., Galliazzo, S., Molaro, M., Visconti, E., Pennella, B., Gaudio, G. V., Lupi, A., Grandi, A. M., & Squizzato, A. (2020) · Internal and Emergency Medicine · doi:10.1007/s11739-020-02470-5 · Cited by 129
Tomlinson, J. A. P., & Wheeler, D. C. (2017) · Kidney International · doi:10.1016/j.kint.2017.03.053 · Cited by 121
Winther, S. A., Oellgaard, J., Tofte, N., Tarnow, L., Wang, Z., Ahluwalia, T. S., Jorsal, A., Theilade, S., Parving, H., Hansen, T. W., et al. (2019) · Diabetes Care · doi:10.2337/dc19-0048 · Cited by 111
“increases in tubulointerstitial fibrosis and collagen deposition in the kidneys, including elevated cystatin C and kidney injury molecule-1 (26,36).”
BackgroundBrown, J. M., & Hazen, S. L. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r116.765388 · Cited by 108
“In several large human studies, TMAO has been found to be elevated in people suffering with CKD and who are at risk for cardiovascular disease and its adverse events (71-76).”
BackgroundPlatelet Function in CKD: A Systematic Review and Meta-Analysis
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Red meat intake in chronic kidney disease patients: Two sides of the coin
Mafra, D., Borges, N. A., Cardozo, L. F. M. D. F., Anjos, J. S., Black, A. P., Moraes, C., Bergman, P., Lindholm, B., & Stenvinkel, P. (2018) · Nutrition · doi:10.1016/j.nut.2017.08.015 · Cited by 93
Lee, Y., Nemet, I., Wang, Z., Lai, H. T. M., Otto, M. C. D. O., Lemaître, R. N., Fretts, A. M., Sotoodehnia, N., Budoff, M. J., DiDonato, J. A., et al. (2021) · Journal of the American Heart Association · doi:10.1161/jaha.120.020646 · Cited by 95
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Zhou, X., Ji, S., Chen, L., Liu, X., Deng, Y., You, Y., Wang, M., He, Q., Peng, B., Yang, Y., et al. (2024) · Microbiome · doi:10.1186/s40168-024-01826-9 · Cited by 92
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Ye, Z., Lulu, C., Xiangchang, Z., Fang, Q., Binjie, Z., Chunyang, L., Rao, T., & Dongsheng, O. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.929262 · Cited by 91
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BackgroundGut Microbiota and Atherosclerosis
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Lakshmi, G. B. V. S., Yadav, A. K., Mehlawat, N., Jalandra, R., Solanki, P. R., & Kumar, A. (2021) · Scientific Reports · doi:10.1038/s41598-020-80122-6 · Cited by 88
Tang, W. H. W., Li, X. S., Wu, Y., Wang, Z., Khaw, K., Wareham, N. J., Nieuwdorp, M., Boekholdt, S. M., & Hazen, S. L. (2021) · American Heart Journal · doi:10.1016/j.ahj.2021.01.020 · Cited by 92
Zeng, Y., Guo, M., Xia, F., Teng, F., Tan, X., Li, X., Wang, M., Long, Y., & Xu, Y. (2021) · Advances in Nutrition · doi:10.1093/advances/nmab010 · Cited by 94
“Furthermore, increased expression of kidney injury marker-1 (KIM-1) and CysC suggested causality in that experimental mouse model.”
BackgroundMethodInfluentialSnelson, M., Kellow, N. J., & Coughlan, M. T. (2018) · Advances in Nutrition · doi:10.1093/advances/nmy068 · Cited by 89
“Abbreviations used: AhR, aryl hydrocarbon receptor; CKD, chronic kidney disease; CVD, cardiovascular disease; ESRD, end-stage renal disease; GFR, glomerular filtration rate; GLP-1/2, glucagon-like peptide 1/2; HbA1c, glycated hemoglobin; IAA, indole acetic acid; IS, indoxyl sulfate; MCP-1, monocyte chemoattractant pro…”
BackgroundInfluentialLi, T., Gua, C., Wu, B., & Chen, Y. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.12.069 · Cited by 89
Borges, N. A., Stenvinkel, P., Bergman, P., Qureshi, A. R., Lindholm, B., Moraes, C., Stockler-Pinto, M. B., & Mafra, D. (2019) · Probiotics and Antimicrobial Proteins · doi:10.1007/s12602-018-9411-1 · Cited by 83
Identification and Characterization of Trimethylamine-N-oxide Uptake and Efflux Transporters
Teft, W. A., Morse, B. L., Leake, B. F., Wilson, A. S., Mansell, S. E., Hegele, R. A., Ho, R. H., & Kim, R. B. (2016) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.6b00937 · Cited by 83
Self-citationKapetanaki, S., Kumawat, A. K., Persson, K., & Demirel, I. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111864 · Cited by 80
“Patients with chronic kidney disease (CKD) and high TMAO have an increased risk of cardiovascular events and increased mortality [10,11].”
BackgroundYu, D., Shu, X., Rivera, E. S., Zhang, X., Cai, Q., Calcutt, M. W., Xiang, Y., Li, H., Gao, Y., Wang, T. J., et al. (2019) · Journal of the American Heart Association · doi:10.1161/jaha.118.010606 · Cited by 81
“In particular, circulating TMAO level in CKD patients were 5 to 10 times higher than those of general populations (eg, 20 versus 1–4 lmol/L).(9,10,45) Treatment for diseases and potential diet and lifestyle changes after disease diagnosis may have also changed TMAO level, raising concern about reverse causation and co…”
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“These data show that TMA and TMAO production is dependent on gut microbiota and become a potential target to attenuate renal disease progression.”
BackgroundInfluentialGut microbiome and cardiovascular disease
Zhao, Y., & Wang, Z. (2020) · Current Opinion in Cardiology · doi:10.1097/hco.0000000000000720 · Cited by 70
Yamaguchi, Y., Zampino, M., Moaddel, R., Chen, T. K., Tian, Q., Ferrucci, L., & Semba, R. D. (2021) · Metabolomics · doi:10.1007/s11306-020-01762-3 · Cited by 68
Microbiome and Cardiovascular Disease in CKD
Jovanovich, A. J., Isakova, T., & Stubbs, J. R. (2018) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.12691117 · Cited by 71
Chamieh, C. E., Liabeuf, S., & Massy, Z. A. (2022) · Toxins · doi:10.3390/toxins14040280 · Cited by 69
Balancing the Equation: A Natural History of Trimethylamine and Trimethylamine-N-oxide
Loo, R. L., Chan, Q. M., Nicholson, J. K., & Holmes, E. C. (2022) · Journal of Proteome Research · doi:10.1021/acs.jproteome.1c00851 · Cited by 63
Metabolic Abnormalities in Diabetes and Kidney Disease: Role of Uremic Toxins
Koppe, L., Fouque, D. P., & Soulage, C. O. (2018) · Current Diabetes Reports · doi:10.1007/s11892-018-1064-7 · Cited by 62
Lv, Z., Shan, X., Tu, Q., Wang, J., Chen, J., & Yang, Y. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.111100 · Cited by 61
Tacconi, E., Palma, G., Biase, D. D., Luciano, A., Barbieri, M., de Nigris, F., & Bruzzese, F. (2023) · Nutrients · doi:10.3390/nu15030563 · Cited by 62
The dietary source of trimethylamine N-oxide and clinical outcomes: an unexpected liaison
Evans, M., Dai, L., Avesani, C. M., Kublickiene, K. R., & Stenvinkel, P. (2023) · Clinical Kidney Journal · doi:10.1093/ckj/sfad095 · Cited by 68
“In a large study of Canadian CKD patients, circulating TMAO levels independently predicted CVD events over a 3-year follow-up period in CKD3 but not in CKD4 [50].”
BackgroundThe emerging role of gut microbial metabolism on cardiovascular disease
Kasahara, K., & Rey, F. E. (2019) · Current Opinion in Microbiology · doi:10.1016/j.mib.2019.09.007 · Cited by 59
Gut Microbial-Derived Metabolites as Immune Modulators of T Helper 17 and Regulatory T Cells
Calvo‐Barreiro, L., Zhang, L., Abdel‐Rahman, S. A., Naik, S. P., & Gabr, M. T. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24021806 · Cited by 62
Intertwined Relationship of Mitochondrial Metabolism, Gut Microbiome and Exercise Potential
Imdad, S., Lim, W., Kim, J., & Kang, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052679 · Cited by 60
“Gut microbiota-derived metabolites such as TMAO have been found to be elevated in circulation and serve as a strong prognostic marker for unfavorable cardiac events and chronic kidney diseases [209,210].”
BackgroundYang, J. J., Shu, X., Herrington, D. M., Moore, S. C., Meyer, K. A., Ose, J., Menni, C., Palmer, N. D., Eliassen, A. H., Harada, S., et al. (2020) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqaa430 · Cited by 54
Chen, S. X., Jiang, P., Yu, D., Liao, G., Wu, S., Fang, A., Chen, P., Wang, X., Luo, Y., Long, J., et al. (2020) · European Journal of Nutrition · doi:10.1007/s00394-020-02278-1 · Cited by 58
Yang, J. J., Lipworth, L. P., Shu, X., Blot, W. J., Xiang, Y., Steinwandel, M. D., Li, H., Gao, Y., Zheng, W., & Yu, D. (2019) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqz318 · Cited by 53
The Nutritional Supplement L-Alpha Glycerylphosphorylcholine Promotes Atherosclerosis
Wang, Z., Hazen, J. E., Jia, X., Org, E., Zhao, Y., Osborn, L. J., Nimer, N. A., Buffa, J. A., Culley, M. K., Krajcik, D., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413477 · Cited by 52
Li, Y., Lü, H., Guo, J., Zhang, M., Zheng, H., Liu, Y., & Liu, W. (2023) · Annals of Medicine · doi:10.1080/07853890.2023.2215542 · Cited by 54
An Overview of Chronic Kidney Disease Pathophysiology: The Impact of Gut Dysbiosis and Oral Disease
Altamura, S., Pietropaoli, D., Lombardi, F., Pinto, R. D., & Ferri, C. (2023) · Biomedicines · doi:10.3390/biomedicines11113033 · Cited by 64
“Kim et al. reported that the TMAO levels were significantly elevated in CKD, supporting its role as a risk factor in these patients [140].”
BackgroundGessner, A., di Giuseppe, R., Koch, M., Fromm, M. F., Lieb, W., & Maas, R. (2020) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm-2019-1146 · Cited by 51
“Besides the composition of gut microbiome, dietary intake and sex, kidney function is an important determinant of the plasma TMAO concentrations as it is almost exclusively removed from the circulation via renal elimination [11, 15, 20], putatively involving active secretion mechanisms [21–24].”
BackgroundZhang, L., XIE, F., Tang, H., ZHANG, X., Hu, J., Zhong, X., Gong, N., Lai, Y., Zhou, M., Tian, J., et al. (2021) · Translational research · doi:10.1016/j.trsl.2021.10.001 · Cited by 49
The metabolomic quest for a biomarker in chronic kidney disease
Davies, R. (2018) · Clinical Kidney Journal · doi:10.1093/ckj/sfy037 · Cited by 50
“TMAO is derived from the gut microbiota and L-carnitine and choline precursors derived from dietary intake of meat and eggs, and p-cresyl sulphate and sulphate are uraemic toxins derived from the metabolism of amino acids by commensal gut microbiota, consequently greatly influenced by dietary intake [62, 75], and TMAO…”
BackgroundThe Role of Microbiota in Cardiovascular Risk: Focus on Trimethylamine Oxide
Al-Rubaye, H., Perfetti, G., & Kaski, J.-C. (2019) · Current Problems in Cardiology · doi:10.1016/j.cpcardiol.2018.06.005 · Cited by 43
Li, D. Y., & Tang, W. H. W. (2018) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2018.01.008 · Cited by 48
Wiese, G. N., Biruete, A., Moorthi, R. N., Moe, S. M., Lindemann, S. R., & Gallant, K. M. H. (2020) · Journal of Renal Nutrition · doi:10.1053/j.jrn.2020.04.007 · Cited by 46
“Participants (N = 113) consumed a baseline diet for 2 weeks, followed in random order by three experimental diets with higher intake of (1) red meat, (2) white meat, and (3) nonmeat protein.”
MethodTrimethylamine N-oxide: a meta-organismal axis linking the gut and fibrosis
Jang, J. W., Capaldi, E., Smith, T. L., Verma, P., Varga, J., & Ho, K. J. (2024) · Molecular Medicine · doi:10.1186/s10020-024-00895-8 · Cited by 48
“(Kim et al. 2016; Mis-sailidis et al. 2016; Tang et al. 2015a, b) In one prospective cohort study of 521 patients with CKD, TMAO was associated with a 2.8-fold dose-dependent increase in 5-year all-cause mortality.”
BackgroundInfluentialAssociation of Gut Microbiota-Dependent Metabolite Trimethylamine N-Oxide with First Ischemic Stroke
Sun, T., Zhang, Y., Yin, J., Peng, X., Zhou, L., Huang, S., Wen, Y., Cao, B., Chen, L., Li, X., et al. (2020) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.55962 · Cited by 44
Ufnal, M., & Nowiński, A. (2019) · Medical Hypotheses · doi:10.1016/j.mehy.2019.109271 · Cited by 41
Jaikumkao, K., Thongnak, L., Htun, K. T., Pengrattanachot, N., Phengpol, N., Sutthasupha, P., Promsan, S., Montha, N., Sriburee, S., Kothan, S., et al. (2023) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2023.166912 · Cited by 41
Krueger, E. S., Lloyd, T. S., & Tessem, J. S. (2021) · Nutrients · doi:10.3390/nu13082873 · Cited by 41
“CKD progression is associated with elevated TMAO levels such that stage 4 and 5 CKD patients had disproportionately elevated serum TMAO levels compared to stage 1 to 3 CKD patients [145,148,149].”
BackgroundMitchell, S. M., Milan, A. M., Mitchell, C. J., Gillies, N. A., D’Souza, R. F., Zeng, N., Ramzan, F., Sharma, P., Knowles, S. O., Roy, N. C., et al. (2019) · Nutrients · doi:10.3390/nu11092207 · Cited by 40
“Kidney function is an independent risk factor for CVD [54], and impaired renal function is correlated with elevated plasma TMAO concentrations [55,56].”
BackgroundOnyszkiewicz, M., Jaworska, K., & Ufnal, M. (2020) · Experimental Biology and Medicine · doi:10.1177/1535370219900898 · Cited by 39
“It is along with the fact that TMAO is excreted mainly with urine and elevated plasma TMAO level has been widely reported in chronic kidney disease.(114,125,126) It was shown that impaired renal function was the main variable affecting plasma TMAO concentration.”
BackgroundTMAO enhances TNF-α mediated fibrosis and release of inflammatory mediators from renal fibroblasts
Stefania, K., Ashok, K. K., Varghese, G., Katarina, P., & Demirel, I. (2024) · Scientific Reports · doi:10.1038/s41598-024-58084-w · Cited by 42
Zhang, P., Zou, J., Chen, J., Tan, X. Y., Xiang, F., Shen, B., Hu, J.-C., Wang, J., Wang, Y., Yu, J., et al. (2020) · Renal Failure · doi:10.1080/0886022x.2020.1822868 · Cited by 37
Dai, L., Massy, Z. A., Stenvinkel, P., Chesnaye, N. C., Larabi, I. A., Alvarez, J., Caskey, F. J., Torino, C., Porto, G., Szymczak, M., et al. (2022) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqac278 · Cited by 38
Caggiano, G., Stasi, A., Franzin, R., Fiorentino, M., Cimmarusti, M. T., Deleonardis, A., Palieri, R., Pontrelli, P., & Gesualdo, L. (2023) · Toxins · doi:10.3390/toxins15020115 · Cited by 36
Zou, D., Li, Y., & Sun, G. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.751380 · Cited by 34
“Our previous study showed that circulating TMAO levels were increased in a mouse model of diet-induced obesity and that inhibition of TMAO alleviated renal interstitial fibrosis and obesity-associated CKD (Sun et al., 2017).”
BackgroundInfluentialGessner, A., König, J., & Fromm, M. F. (2018) · Scientific Reports · doi:10.1038/s41598-018-25139-8 · Cited by 36
Kanmani, S., Son, T., Kim, K., & Koo, B. (2020) · Microbial Pathogenesis · doi:10.1016/j.micpath.2020.104583 · Cited by 31
Influence of Resveratrol on the Cardiovascular Health Effects of Chronic Kidney Disease
Song, J.-Y., Shen, T.-C., Hou, Y., Chang, J., Lu, C., Liu, W.-C., Chen, P.-J., Chen, B.-H., Zheng, C., & Lu, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176294 · Cited by 28
“Studies have shown that TMAO is independently related to cardiovascular events and that a relationship between TMAO levels and ischemic cardiovascular events exists, especially in CKD Stages 3b and 4 [30].”
BackgroundNovel Perspectives in Chronic Kidney Disease-Specific Cardiovascular Disease
Xu, C., Tsihlis, G., Chau, K., Trinh, K., Rogers, N. M., & Julovi, S. M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052658 · Cited by 30
“Elevated plasma concentrations of these mediators are associated with endothelial dysfunction, CVD, CV events, and mortality in patients with [125] or without CKD [126] (and comprehensively reviewed in [12]).”
BackgroundJaworska, K., Kopacz, W., Koper, M., & Ufnal, M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252312511 · Cited by 32
“However, TMAO is recognized as a uremic toxin whose levels significantly increase with kidney function decline [13,58], suggesting its potential utility as a biomarker for renal toxicity.”
Methyl Donor Nutrients in Chronic Kidney Disease: Impact on the Epigenetic Landscape
Mafra, D., Esgalhado, M., Borges, N. A., Cardozo, L. F. M. F., Stockler-Pinto, M. B., Craven, H., Buchanan, S. J., Lindholm, B., Stenvinkel, P., & Shiels, P. G. (2019) · The Journal of Nutrition · doi:10.1093/jn/nxy289 · Cited by 26
From heart failure and kidney dysfunction to cardiorenal syndrome: TMAO may be a bridge
Zhang, J., Zhu, P., Li, S., Gao, Y., & Xing, Y. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1291922 · Cited by 28
Heinrich‐Sanchez, Y., & Vital, M. (2025) · Annals of Medicine · doi:10.1080/07853890.2025.2525403 · Cited by 27
“Kidney malfunctioning is a risk factor for the development of CVDs, with the accumulation of TMAO providing one of the many links [63].”
Effect of Oat β-Glucan Supplementation on Chronic Kidney Disease: A Feasibility Study
Hill, E., Sapa, H., Negrea, L. A., Bame, K., Hostetter, T. H., Barkoukis, H. D., Dusso, A., & Dobre, M. A. (2019) · Journal of Renal Nutrition · doi:10.1053/j.jrn.2019.06.012 · Cited by 25
Zheng, Y., Tang, Z., Li, Y., Wu, Y., Liu, J., & Xue, J. (2020) · Renal Failure · doi:10.1080/0886022x.2020.1781170 · Cited by 24
“Although cardiovascular diseases are the most common causes of hospitalization in patients with CKD, it has been reported that conventional risk factors such as diabetes, hypertension, and hyperlipidemia do not accelerate vascular stenosis in these patients [6].”
BackgroundInfluential
Metadata
- Authors
- Kim, R. B., Morse, B. L., Djurdjev, O., Tang, M., Muirhead, N., Barrett, B., Holmes, D. T., Madore, F., Clase, C. M., Rigatto, C., Levin, A., Agharazii, M., Blouin, J., Samson, F., Akbarii, A., Cheesman, J., Courtney, J., Hamer, S., Delic, E., Cronin, V., Barré, P., Golden, J., Barrett, B., Langille, E., Adams, S., Morgan, J., Clase, C., Moreau, C., Cooper, S., Forzley, B., Caron, S., Granger, S., Valley, S., Sather, H., Cournoyer, S., Menard, L., Roy, M., Skidmore, H., Beaudry, D., Dionne, J., Chow, J., Sahraei, V., Donnelly, S., Dacouris, N., Marticorena, R., Hemmelgarn, B., Gulewich, S., Hamilton, T., Keown, P., Zalunardo, N., Rogers, D., Tut, R., Paquette, M., Yung, R., Levin, A., Ferguson, N., Tang, M., Chiu, H., Carlson, K., Sioson, L., Perry, T., Sheriff, Z., Rozen, N., Lok, C., Cross, M., Forrester, C., Cotoi, A., Madore, F., Maltais, M., Moist, L., Gallo, K., Langford, S., Slamen, L., Cram, D., Muirhead, N., Edgar, M. J., Gray, T., Edgar, C., Groeneweg, K., McKinnon, E., McRae, E., Blackie, K., Nathoo, B., Lau, K., Parmar, M., Gelinas, S., Leblanc, M., Lépine, L., Rigatto, C., Friesen, D., Soroka, S., Fleet, S., Squires, J., Thanamayooran, S., Binder, M., Hines, C., McNeil, B., McDougall, P., Howard, J., Gillis, D., Hines, K., Tobe, S., Chessman, M., Perkins, N., Agelopoulos, M., Knox, S., Richards, T., Tonelli, M., Szigety, S., Opgenorth, D., Yeates, K., & Mahoney, K.
- Affiliations
- Western University (CA)
- University of British Columbia (CA)
- Memorial University of Newfoundland (CA)
- McMaster University (CA)
- University of Manitoba (CA)
- Corresponding author
- Kim, Richard B.
- ORCID
- Kim, Richard B.
- Morse, Bridget L.
- Holmes, Daniel T.
- Agharazii, Mohsen
- Golden, Jeffrey
- Dionne, Janis
- Hemmelgarn, Brenda
- Keown, Paul
- Zalunardo, Nadia
- Chiu, Helen
- Rozen, Naama
- Lok, Charmaine
- Moist, Louise
- Gallo, Kerri
- Langford, Sarah
- Parmar, Malvinder
- Hines, Christine
- McNeil, Brenda
- Tobe, Sheldon
- Perkins, Nancy
- Tonelli, Marcello
- Opgenorth, Dawn
- Yeates, Karen
- Venue
- Kidney International
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 89
- Issue
- 5
- Pages
- 1144-1152
- ISSN
- 0085-2538 (ISSN-L)
- OpenAlex
- W2300515179
- Cited by
- 179
- References
- 33
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 15 · 2023: 21 · 2022: 19 · 2021: 20 · 2020: 23 · 2019: 15 · 2018: 19 · 2017: 13 · 2016: 6
- FWCI
- 17.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Kidney International (publishedVersion)
- PubMed (publishedVersion)
- Scholarship@Western (Western University) (submittedVersion)
- Funders
- Canadian Institutes of Health Research (MOP-89753)
- Topics
- Health Sciences › Medicine › Nephrology › Dialysis and Renal Disease Management
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- trimethylamine N-oxide, chronic kidney disease, cardiovascular events, ischemic cardiovascular events, gut microbiota, L-carnitine, choline, cardiovascular risk factors
- MeSH terms
- Aged, Aged, 80 and over, Canada, Cardiovascular Diseases, Female, Glomerular Filtration Rate, Humans, Kidney, Male, Methylamines, Middle Aged, Prospective Studies, Risk Factors, Severity of Illness Index, Time Factors, Biomarkers, Up-Regulation, Risk Assessment, Disease-Free Survival, Renal Insufficiency, Chronic, Kaplan-Meier Estimate, Tandem Mass Spectrometry
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