Gut Microbiota-Dependent Trimethylamine N -Oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease
Open accessAbstract
Rationale: Trimethylamine- N -oxide (TMAO), a gut microbial-dependent metabolite of dietary choline, phosphatidylcholine (lecithin), and l -carnitine, is elevated in chronic kidney diseases (CKD) and associated with coronary artery disease pathogenesis. Objective: To both investigate the clinical prognostic value of TMAO in subjects with versus without CKD, and test the hypothesis that TMAO plays a direct contributory role in the development and progression of renal dysfunction. Methods and Results: We first examined the relationship between fasting plasma TMAO and all-cause mortality over 5-year follow-up in 521 stable subjects with CKD (estimated glomerular filtration rate, <60 mL/min per 1.73 m 2 ). Median TMAO level among CKD subjects was 7.9 μmol/L (interquartile range, 5.2–12.4 μmol/L), which was markedly higher ( P <0.001) than in non-CKD subjects (n=3166). Within CKD subjects, higher (fourth versus first quartile) plasma TMAO level was associated with a 2.8-fold increased mortality risk. After adjustments for traditional risk factors, high-sensitivity C-reactive protein, estimated glomerular filtration rate, elevated TMAO levels remained predictive of 5-year mortality risk (hazard ratio, 1.93; 95% confidence interval, 1.13–3.29; P <0.05). TMAO provided significant incremental prognostic value (net reclassification index, 17.26%; P <0.001 and differences in area under receiver operator characteristic curve, 63.26% versus 65.95%; P =0.036). Among non-CKD subjects, elevated TMAO levels portend poorer prognosis within cohorts of high and low cystatin C. In animal models, elevated dietary choline or TMAO directly led to progressive renal tubulointerstitial fibrosis and dysfunction. Conclusions: Plasma TMAO levels are both elevated in patients with CKD and portend poorer long-term survival. Chronic dietary exposures that increase TMAO directly contributes to progressive renal fibrosis and dysfunction in animal models.
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- Findingown data
In the non-CKD cohort, continuous log[TMAO] was associated with mortality (adjusted HR=1.21, 95%CI 1.07-1.36, p<0.01).
“a dose-dependent relationship between plasma TMAO levels and mortality risk was observed (log[TMAO]: adjusted HR=1.41, 95%CI 1.23–1.61, p<0.001 for CKD cohort; adjusted HR=1.21, 95%CI 1.07–1.36, p<0.01 for non-CKD cohort).”
Quote in the paperSubstantial claim - Findingown data
In the non-CKD cohort, after adjustment for traditional risk factors, log hsCRP, and log eGFR, elevated TMAO remained predictive of 5-year mortality (adjusted HR 1.47, 95%CI 1.02-2.12, p<0.05).
“as well as after adjusting for traditional risk factors, log-transformed hsCRP, and log-transformed eGFR (adjusted HR 1.47, 95%CI 1.02–2.12, p<0.05, Table 2B).”
Quote in the paperSubstantial claim - Findingown data
In the CKD cohort, with low cystatin C and low TMAO as reference, concomitant high cystatin C and high TMAO was associated with a 3-fold higher mortality risk (HR 3.01, 95%CI 1.97-4.59, p<0.001).
“Using median cohort cut-offs with low cystatin C (<1.4 mg/dL) and low TMAO (<7.9 μM) as reference, those with concomitant high cystatin C and high TMAO had a 3-fold increase in mortality risk (HR 3.01, 95%CI 1.97–4.59, p<0.001).”
Quote in the paperSubstantial claim - Findingown data
CKD subjects had higher TMAO levels than non-CKD subjects (median 7.9 vs 3.4 μM, p<0.001).
“Compared to non-CKD subjects, TMAO levels were elevated in patients with CKD (median TMAO: 7.9 [IQR 5.2–12.4]μM versus 3.4 [IQR 2.3–5.3]μM, p<0.001; Figure 1A).”
Quote in the paperSubstantial claim - Findingown data
In the CKD cohort, continuous log[TMAO] was associated with mortality (adjusted HR=1.41, 95%CI 1.23-1.61, p<0.001).
“a dose-dependent relationship between plasma TMAO levels and mortality risk was observed (log[TMAO]: adjusted HR=1.41, 95%CI 1.23–1.61, p<0.001 for CKD cohort; adjusted HR=1.21, 95%CI 1.07–1.36, p<0.01 for non-CKD cohort).”
Quote in the paperSubstantial claim
- Findingown data
Elevated TMAO was associated with increased tubulointerstitial fibrosis and collagen deposition.
“Importantly, elevated TMAO levels were associated with corresponding increases in tubulointerstitital fibrosis and collagen deposition (Figure 3B–C)”
Quote in the paperSubstantial claim - Findingown data
Among CKD subjects, the median fasting plasma TMAO was 7.9 μM (IQR 5.2-12.4).
“Median TMAO level among CKD subjects was 7.9 μM (interquartile range 5.2–12.4μM)”
Quote in the paperNot a substantial claim - Findingown data
Elevated TMAO was associated with higher 5-year mortality risk among subjects with either normal or elevated cystatin C.
“Elevated TMAO levels are associated with higher 5-year mortality risk among subjects with either normal or elevated cystatin C levels (Figure 2).”
Quote in the paperSubstantial claim - Findingown data
In the non-CKD cohort, with low cystatin C and low TMAO as reference, concomitant high cystatin C and high TMAO was associated with a 3.7-fold higher mortality risk (HR 3.67, 95%CI 2.57-5.23, p<0.001).
“Using median cohort cut-offs with low cystatin C (<0.9 mg/dL) and low TMAO (<3.4μM) as reference, those with concomitant high cystatin C and high TMAO had a 3.7-fold increase in mortality risk (HR 3.67, 95%CI 2.57–5.23, p<0.001).”
Quote in the paperSubstantial claim - Findingown data
In non-CKD subjects with preserved eGFR and normal cystatin C (n=3,151), the mortality findings were similar.
“These findings were similar when restricted to subjects with preserved eGFR (≥60 ml/min/1.73m2) plus normal cystatin C (<1.4mg/dL, n=3,151).”
Quote in the paperNot a substantial claim - Findingown data
Elevated TMAO was associated with Smad3 phosphorylation.
“and phosphorylation of Smad3, an important regulator of the pro-fibrotic TGF-β/Smad3 signaling pathway during fibrotic kidney disease23 (Figure 3E).”
Quote in the paperNot a substantial claim - Findingown data
In the CKD cohort, the highest versus lowest TMAO quartile was associated with a 2.8-fold higher unadjusted 5-year all-cause mortality risk (HR 2.76, 95%CI 1.74-4.37, p<0.001).
“In the CKD cohort, higher TMAO levels (quartiles 4 versus 1) were associated with a 2.8-fold increase in risk for all-cause mortality at 5 years (unadjusted HR 2.76, 95%CI 1.74–4.37, p<0.001).”
Quote in the paperSubstantial claim - Findingown data
In the CKD cohort, above-median TMAO remained associated with mortality after adding cystatin C to the model (adjusted HR 1.45, 95%CI 1.05-2.02, p<0.05).
“as well as with addition of cystatin C to the model (adjusted HR 1.45, 95%CI 1.05–2.02, p<0.05).”
Quote in the paperSubstantial claim - Findingown data
In the CKD cohort, above-median TMAO remained associated with mortality after adjustment for traditional risk factors and log hsCRP (adjusted HR 1.72, 95%CI 1.16-2.34, p<0.001).
“and remained significant after adjusting for traditional risk factors and log-transformed hsCRP (adjusted HR 1.72, 95%CI 1.16–2.34, p<0.001)”
Quote in the paperSubstantial claim - Findingown data
TMAO added significant incremental prognostic value beyond traditional risk factors (NRI 17.26%, p<0.001; AUC 63.26% vs 65.95%, p=0.036).
“TMAO provided significant incremental prognostic value (net reclassification index 17.26%, p<0.001; and differences in area under Receiver Operator Characteristic curve, 63.26% vs. 65.95 %, p=0.036).”
Quote in the paperSubstantial claim - Findingown data
In the CKD cohort, after adjustment for traditional CVD risk factors, log hsCRP, and log eGFR, the highest versus lowest TMAO quartile remained associated with 1.9-fold poorer 5-year survival (adjusted HR 1.93, 95%CI 1.13-3.29, p<0.05).
“After adjusting for traditional CVD risk factors, log-transformed hsCRP, and log-transformed eGFR, higher TMAO levels still were associated with a 1.9-fold poorer 5-year survival (adjusted HR 1.93, 95%CI 1.13–3.29, p<0.05; Table 2, Kaplan-Meier curve shown in Figure 1B).”
Quote in the paperSubstantial claim - Findingown data
TMAO levels in supplemented mice fell within the range seen in CKD subjects (97.5th percentile 77.6 μM; 99th percentile 96.3 μM).
“with TMAO levels observed within the range of values detected among CKD subjects studied (97.5 percentile 77.6μM, 99 percentile 96.3μM).”
Quote in the paperSubstantial claim - Findingown data
After 6 weeks, TMAO levels rose significantly in both TMAO-supplemented and choline-supplemented mice compared with chow-fed mice (p<0.01).
“After 6 weeks we observed significant (p<0.01) increases in TMAO levels in both the TMAO-supplemented and choline-supplemented groups of mice (Figure 3A)”
Quote in the paperSubstantial claim - Findingown data
In the CKD cohort, above-median TMAO (>7.9 μM) was associated with a 1.7-fold higher all-cause mortality risk (HR 1.70, 95%CI 1.25-2.30, p<0.001).
“When stratified according to median levels (7.9 μM), higher TMAO conferred a 1.7-fold increase in risk for all-cause mortality (HR 1.70, 95%CI 1.25–2.30, p<0.001)”
Quote in the paperSubstantial claim - Findingown data
In the non-CKD cohort (n=3,166), the highest versus lowest TMAO quartile predicted 5-year mortality (HR 2.21, 95%CI 1.57-3.12, p<0.001).
“Within the non-CKD cohort (n=3,166), the prognostic value of elevated TMAO (quartile 4 vs 1) remained predictive of 5-year mortality risk (HR 2.21, 95%CI 1.57–3.12, p<0.001)”
Quote in the paperSubstantial claim - Findingown data
Plasma TMAO showed dose-dependent relationships with renal histopathological and functional impairment indices.
“striking dose-dependent relationships were noted between plasma TMAO levels and monitored indices of renal histopathological (Figure 3D, 3F) and functional impairment (Figure 4B).”
Quote in the paperSubstantial claim - Findingown data
TMAO-fed and choline-fed mice had increased kidney injury marker-1 (KIM-1).
“Furthermore, TMAO-fed and choline-fed mice experienced increased kidney injury marker-1 (KIM-1, Figure 4A).”
Quote in the paperSubstantial claim - Findingown data
Extending TMAO or choline feeding to 16 weeks was associated with higher serum cystatin C than in chow-fed mice.
“Extending the TMAO/choline feeding to 16 weeks was associated with increased serum cystatin C levels compared to chow-fed mice (Figure 4C).”
Quote in the paperSubstantial claim - Premisecitation
The kidney clears TMAO.
“TMAO is cleared by the kidney, and prior studies have reported TMAO is elevated in subjects with impaired renal function16–18.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [16] Bain MA Faull R Fornasini G Milne RW Evans AM Accumulation of trimethylamine and trimethylamine-n-oxide in end-stage renal disease patients undergoing haemodialysis Nephrol Dial Transplant 2006 21 1300 1304 16401621 source
Not checked in the free run.
- cites [17] Bain MA Faull R Milne RW Evans AM Oral l-carnitine: Metabolite formation and hemodialysis Curr Drug Metab 2006 7 811 816 17073580 source
Not checked in the free run.
- cites [18] Bell JD Lee JA Lee HA Sadler PJ Wilkie DR Woodham RH Nuclear magnetic resonance studies of blood plasma and urine from subjects with chronic renal failure: Identification of trimethylamine-n-oxide Biochim Biophys Acta 1991 1096 101 107 2001424 source
Not checked in the free run.
- Premisecitation
In a large study of mostly preserved renal function, TMAO predicted three-year major adverse cardiovascular events even after renal function adjustment.
“In one large study of subjects with predominantly preserved renal function, we reported the prognostic value of TMAO for predicting three year risk for major adverse cardiovascular events (MACE = myocardial infarction, stroke or death) remained significant following adjustments for renal function 9.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Tang WH Wang Z Levison BS Koeth RA Britt EB Fu X Wu Y Hazen SL Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk N Engl J Med 2013 368 1575 1584 23614584 PMC3701945 source
Not checked in the free run.
- Premisecitation
TMAO accumulates in people with reduced kidney function.
“TMAO is cleared by the kidney, and prior studies have reported TMAO is elevated in subjects with impaired renal function16–18.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [16] Bain MA Faull R Fornasini G Milne RW Evans AM Accumulation of trimethylamine and trimethylamine-n-oxide in end-stage renal disease patients undergoing haemodialysis Nephrol Dial Transplant 2006 21 1300 1304 16401621 source
Not checked in the free run.
- cites [17] Bain MA Faull R Milne RW Evans AM Oral l-carnitine: Metabolite formation and hemodialysis Curr Drug Metab 2006 7 811 816 17073580 source
Not checked in the free run.
- cites [18] Bell JD Lee JA Lee HA Sadler PJ Wilkie DR Woodham RH Nuclear magnetic resonance studies of blood plasma and urine from subjects with chronic renal failure: Identification of trimethylamine-n-oxide Biochim Biophys Acta 1991 1096 101 107 2001424 source
Not checked in the free run.
- Premisecitation
Gut microbes are required for TMAO formation from trimethylamine-containing nutrients, including choline, phosphatidylcholine, L-carnitine, γ-butyrobetaine, and to a lesser extent betaine.
“Animal model and human clinical studies demonstrate an obligatory role for gut microbiota in TMAO formation from TMA-containing nutrients including choline and phosphatidylcholine9, 10, L-carnitine8, and more recently, γ-butyrobetaine15, and to a lesser degree, the choline oxidation metabolite betaine11.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [9] Tang WH Wang Z Levison BS Koeth RA Britt EB Fu X Wu Y Hazen SL Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk N Engl J Med 2013 368 1575 1584 23614584 PMC3701945 source
Not checked in the free run.
- cites [10] 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 2011 472 57 63 21475195 PMC3086762 source
Not checked in the free run.
- cites [8] Koeth RA Wang Z Levison BS Buffa JA Org E Sheehy BT Britt EB Fu X Wu Y Li L Smith JD DiDonato JA Chen J Li H Wu GD Lewis JD Warrier M Brown JM Krauss RM Tang WH Bushman FD Lusis AJ Hazen SL Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis Nat Med 2013 19 576 585 23563705 PMC3650111 source
Not checked in the free run.
- Premisecitation
Trimethylamine-N-oxide (TMAO) is produced by gut microbes from dietary choline, phosphatidylcholine and L-carnitine.
“Specifically, gut microbiota-mediated metabolism of phosphatidylcholine, choline or L-carnitine each have been shown to ultimately produced trimethylamine-N-oxide (TMAO), and in multiple clinical studies, TMAO levels have been shown to be associated with cardiovascular risks8–10, 13.”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [8] Koeth RA Wang Z Levison BS Buffa JA Org E Sheehy BT Britt EB Fu X Wu Y Li L Smith JD DiDonato JA Chen J Li H Wu GD Lewis JD Warrier M Brown JM Krauss RM Tang WH Bushman FD Lusis AJ Hazen SL Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis Nat Med 2013 19 576 585 23563705 PMC3650111 source
Not checked in the free run.
- cites [9] Tang WH Wang Z Levison BS Koeth RA Britt EB Fu X Wu Y Hazen SL Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk N Engl J Med 2013 368 1575 1584 23614584 PMC3701945 source
Not checked in the free run.
- cites [10] 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 2011 472 57 63 21475195 PMC3086762 source
Not checked in the free run.
- cites [11] Wang Z Tang WH Buffa JA Fu X Britt EB Koeth RA Levison BS Fan Y Wu Y Hazen SL Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-n-oxide Eur Heart J 2014 35 904 910 24497336 PMC3977137 source
Not checked in the free run.
- cites [12] Tang WH Hazen SL The contributory role of gut microbiota in cardiovascular disease J Clin Invest 2014 124 4204 4211 25271725 PMC4215189 source
Not checked in the free run.
- cites [13] Tang WH Wang Z Fan Y Levison BS Hazen JE Donahue L Wu Y Hazen SL Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-n-oxide in patients with heart failure: Refining the gut hypothesis J Am Coll Cardiol 2014 2014 1908 1914 25444145 PMC4254529 source
Not checked in the free run.
- Interpretationreasoning
Elevated systemic TMAO is linked to greater susceptibility to developing CKD.
“Our animal model findings therefore provide a potential mechanistic rationale for the Framingham observational data, and collectively, further link elevated systemic TMAO levels with increased susceptibility for development of CKD.”
Quote in the paperSubstantial claim - Interpretationown data
In animal models, dietary choline or TMAO exposure led to renal tubulointerstitial fibrosis and early dysfunction (elevated cystatin C).
“Third, extending to animal models studies, dietary exposure of either choline or TMAO lead to the development of renal tubulointerstitial fibrosis and early measures of dysfunction (elevated cystatin C).”
Quote in the paperSubstantial claim - Interpretationreasoning
Chronic dietary exposures that raise TMAO appear to directly contribute to progressive renal fibrosis and dysfunction.
“Chronic dietary exposures that increase TMAO appear to directly contribute to progressive renal fibrosis and dysfunction.”
Quote in the paperSubstantial claim - Premisecitation
In a Nurses Health Study sub-study, eating two or more servings of red meat weekly was associated with higher risk of developing microalbuminuria (OR 1.51; 95% CI 1.01-2.26).
“two or more servings of red meat (primary dietary source of L-carnitine) per week were directly associated with enhanced risk for development of microalbuminuria (OR: 1.51; 95% CI: 1.01 to 2.26)34.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [34] Lin J Hu FB Curhan GC Associations of diet with albuminuria and kidney function decline Clin J Am Soc Nephrol 2010 5 836 843 20299364 PMC2863979 source
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- Interpretationown data
Animal model findings offer a potential mechanism for Framingham data linking elevated choline and TMAO to future CKD risk.
“Our animal model findings therefore provide a potential mechanistic rationale for the Framingham observational data, and collectively, further link elevated systemic TMAO levels with increased susceptibility for development of CKD.”
Quote in the paperSubstantial claim
- May combine two claims. 7
- Classified as probably not a substantial claim. 10
May combine two claims.
Findingown dataIn the CKD cohort, TMAO correlated modestly with eGFR (r=-0.48, p<0.001) and cystatin C (r=0.46, p<0.001).
“Overall in the CKD cohort, TMAO modestly correlated with eGFR (r= −0.48, p<0.001) and cystatin C (r=0.46, p<0.001), but did not correlate with hsCRP (r=0.04, p=0.332).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataIn the CKD cohort, TMAO did not correlate with hsCRP (r=0.04, p=0.332).
“Overall in the CKD cohort, TMAO modestly correlated with eGFR (r= −0.48, p<0.001) and cystatin C (r=0.46, p<0.001), but did not correlate with hsCRP (r=0.04, p=0.332).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMultiple clinical studies have linked TMAO levels to cardiovascular risk.
“in multiple clinical studies, TMAO levels have been shown to be associated with cardiovascular risks8–10, 13.”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [8] Koeth RA Wang Z Levison BS Buffa JA Org E Sheehy BT Britt EB Fu X Wu Y Li L Smith JD DiDonato JA Chen J Li H Wu GD Lewis JD Warrier M Brown JM Krauss RM Tang WH Bushman FD Lusis AJ Hazen SL Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis Nat Med 2013 19 576 585 23563705 PMC3650111 source
Not checked in the free run.
- cites [9] Tang WH Wang Z Levison BS Koeth RA Britt EB Fu X Wu Y Hazen SL Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk N Engl J Med 2013 368 1575 1584 23614584 PMC3701945 source
Not checked in the free run.
- cites [10] 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 2011 472 57 63 21475195 PMC3086762 source
Not checked in the free run.
- cites [13] Tang WH Wang Z Fan Y Levison BS Hazen JE Donahue L Wu Y Hazen SL Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-n-oxide in patients with heart failure: Refining the gut hypothesis J Am Coll Cardiol 2014 2014 1908 1914 25444145 PMC4254529 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe data suggest that TMAO formed from dietary choline via gut microbes causally contributes to CKD development and progression and is clinically relevant.
“These studies thus suggest both a causal relationship and clinical relevance of dietary choline-induced, gut microbiota-mediated, TMAO formation in CKD development and progression.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSmad3 is an important regulator of the pro-fibrotic TGF-β/Smad3 signaling pathway in fibrotic kidney disease.
“phosphorylation of Smad3, an important regulator of the pro-fibrotic TGF-β/Smad3 signaling pathway during fibrotic kidney disease23”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [23] Qu X Li X Zheng Y Ren Y Puelles VG Caruana G Nikolic-Paterson DJ Li J Regulation of renal fibrosis by smad3 thr388 phosphorylation Am J Pathol 2014 184 944 952 24485922 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe gut microbiota-dependent product TMAO is associated with higher risk of progressive renal fibrosis and functional impairment, and with poorer long-term survival.
“The gut microbiota-dependent product, TMAO, is associated with both higher risk of progressive renal fibrosis and functional impairment, and poorer long-term survival.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationIn the Framingham Heart Study, baseline elevated choline and TMAO levels were each associated with increased future CKD risk among subjects with normal renal function.
“a recent untargeted metabolomic study from the Framingham Heart Study among subjects with normal renal function identified elevated choline and TMAO levels at baseline were each associated with an increased future risk of developing CKD 33.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] Rhee EP Clish CB Ghorbani A Larson MG Elmariah S McCabe E Yang Q Cheng S Pierce K Deik A Souza AL Farrell L Domos C Yeh RW Palacios I Rosenfield K Vasan RS Florez JC Wang TJ Fox CS Gerszten RE A combined epidemiologic and metabolomic approach improves ckd prediction J Am Soc Nephrol 2013 24 1330 1338 23687356 PMC3736702 source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
Study design and conductcitationNet reclassification and AUC were calculated from Cox models adjusted for traditional risk factors with and without TMAO.
“Net reclassification and area under Receiver Operator Characteristic curve were calculated according to mortality risk estimated using Cox models adjusted for above mentioned traditional risk factors with versus without TMAO as previously described22.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] Pencina MJ D'Agostino RB Sr D'Agostino RB Jr Vasan RS Evaluating the added predictive ability of a new marker: From area under the roc curve to reclassification and beyond Stat Med 2008 27 157 172 17569110 source
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Classified as probably not a substantial claim.
PremisecitationThe C57BL/6J mouse model is known to be relatively resistant to renal injury.
“even in the C57BL/6J mouse model that is known to be relatively resistant to renal injury31.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Walkin L Herrick SE Summers A Brenchley PE Hoff CM Korstanje R Margetts PJ The role of mouse strain differences in the susceptibility to fibrosis: A systematic review Fibrogenesis Tissue Repair 2013 6 18 24294831 PMC3849643 source
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Classified as probably not a substantial claim.
Study design and conductown dataMortality analyses adjusted for traditional risk factors, log hsCRP, and log eGFR.
“Adjustments were made for individual traditional risk factors including age, sex, systolic blood pressure, low-density lipoprotein cholesterol (LDLc), high-density lipoprotein cholesterol (HDLc), smoking, diabetes mellitus, as well as log-transformed hsCRP to predict all-cause mortality risks. Additional adjustment for log-transformed eGFR was also performed.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataFive-year all-cause mortality was ascertained by prospective telephone contact, chart review, and Social Security Death Index interrogation.
“Ascertainment of all-cause mortality at 5-years was performed by prospective telephone contact and chart review plus interrogation of the Social Security Death Index (up to 2011).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCholine is an essential nutrient, so eliminating it entirely from the diet is ill advised and could cause deficiency.
“However, it is important to note that choline is an essential nutrient; therefore, its total elimination from the diet is ill advised, and could result in development of a deficiency state35.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Zeisel SH Choline: Clinical nutrigenetic/nutrigenomic approaches for identification of functions and dietary requirements J Nutrigenet Nutrigenomics 2010 3 209 219 21474952 PMC3085526 source
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May combine two claims.
Interpretationown dataPlasma TMAO is elevated in CKD patients and predicts poorer long-term survival.
“Plasma TMAO levels are both elevated in patients with CKD and portend poorer long-term survival.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductcitationeGFR was calculated using the CKD-EPI creatinine and cystatin C formula.
“Estimated glomerular filtration rate (eGFR) was calculated according to the CKD-EPI creatinine and cystatin C formula20, with CKD defined as eGFR <60 ml/min/1.73m2 (CKD stage 3 or beyond).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Inker LA Schmid CH Tighiouart H Eckfeldt JH Feldman HI Greene T Kusek JW Manzi J Van Lente F Zhang YL Coresh J Levey AS Estimating glomerular filtration rate from serum creatinine and cystatin c N Engl J Med 2012 367 20 29 22762315 PMC4398023 source
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Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationTMAO was measured by stable isotope dilution HPLC with online electrospray ionization tandem mass spectrometry using d9-labeled internal standards.
“Trimethylamine-N-oxide (TMAO) levels were determined by stable isotope dilution high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry (LC/MS/MS) on an AB SCIEX 5500 triple quadrupole mass spectrometer (AB SCIEX, Framingham MA) using d9-(trimethyl)-labeled internal standards as previously described10, 21.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [10] 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 2011 472 57 63 21475195 PMC3086762 source
Not checked in the free run.
- cites [21] Wang Z Levison BS Hazen JE Donahue L Li XM Hazen SL Measurement of trimethylamine-n-oxide by stable isotope dilution liquid chromatography tandem mass spectrometry Anal Biochem 2014 455 35 40 24704102 PMC4167037 source
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The paper relies on this without support.
No prior studies had directly examined long-term mortality risk from TMAO in CKD subjects.
“However, no studies to date have directly looked at the long-term mortality risk of TMAO among CKD subjects.”
The paper relies on this without support.
No prior study had reported a direct role for TMAO in renal functional impairment.
“A direct role for TMAO in impacting renal functional impairment has not been reported.”
The paper relies on this without support.
The mechanism linking CKD to atherosclerotic heart disease is not fully understood.
“Yet the mechanism(s) through which CKD is linked to enhanced atherosclerotic heart disease is not fully elucidated.”
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TMAO levels are associated with cardiovascular disease risks in a variety of cohorts.
“Numerous recent case–control and longitudinal studies have shown a striking association between trimethylamine N‐oxide (TMAO) levels and cardiovascular disease risks in a variety of cohorts.1, 2, 3, 4, 5, 6, 7, 8, 9, 10”
From Trimethylamine N‐Oxide Promotes Vascular Inflammation Through Signaling of Mitogen‐Activated Protein Kinase and Nuclear Factor‐κB (2016) · cites this paper as [9]
Peak plasma TMAO levels from acute TMAO injection were similar to levels in mice chronically exposed to choline-supplemented diet and in some human clinical studies.
“Of note, the peak plasma TMAO levels with this protocol were similar to levels observed in mice chronically exposed to the choline‐supplemented diet (Figure 1C) and in some human clinical studies.9, 10, 17”
From Trimethylamine N‐Oxide Promotes Vascular Inflammation Through Signaling of Mitogen‐Activated Protein Kinase and Nuclear Factor‐κB (2016) · cites this paper as [9]
TMAO is biologically active and has been proposed as a contributor to chronic human diseases such as atherosclerosis.
“Trimethylamine N-oxide (TMAO) is a biologically active molecule and is a putative promoter of chronic diseases including atherosclerosis in humans.”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [109]
Plasma TMAO was strongly associated with long-term mortality in heart failure patients.
“Plasma TMAO concentrations were strongly associated with long-term mortality in heart failure patients, with advanced left-ventricular diastolic dysfunction, and with atherosclerosis burden in patients with atherosclerotic coronary artery disease (100, 101, 109, 111, 120).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [109]
Elevated plasma TMAO predicted five-year mortality after adjustment for traditional risk factors.
“Elevated plasma TMAO concentrations were predictive of five-year mortality risk after adjusting for traditional risk factors, such as high-sensitivity C-reactive protein, glomerular filtration rate, etc.”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [109]
In 521 stable kidney disease patients, fasting plasma TMAO was associated with all-cause mortality.
“In a study of stable patients with kidney disease (n = 521), there was an association between fasting plasma TMAO concentrations and all-cause mortality (109).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [109]
Patients with poor kidney function have elevated plasma TMAO concentrations.
“Patients with poor kidney function have elevated plasma TMAO concentrations (93,109).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [109]
Many studies linking TMAO to heart disease also found that people with higher TMAO had decreased renal function.
“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 <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [109]
In C57BL/6J mice fed high-choline or TMAO-supplemented diets for six weeks, plasma TMAO increased and was associated with increases in tubulointerstitial fibrosis, collagen deposition, and kidney injury marker-1.
“When C57BL/6J mice were fed either a high-choline diet or a diet supplemented with TMAO for six weeks, plasma concentrations of TMAO increased and were associated with corresponding increases in tubulointerstitial fibrosis and collagen deposition, as well as increases in kidney injury marker-1.”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [109]
The mouse study in Section 5.2.2 is the most compelling evidence that TMAO and choline cause renal disease.
“The data from the mouse study discussed in Section 5.2.2 (109) are the most compelling evidence that TMAO (and choline a precursor of TMAO) causes renal disease.”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [109]
Even among patients without severe kidney disease, elevated plasma TMAO indicated poor prognosis.
“Even among patients who did not have severe kidney disease, elevated plasma TMAO concentrations indicated poor prognosis (109).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [109]
When mice were fed these diets for 16 weeks, serum cystatin C rose.
“When mice were fed these diets for 16 weeks, serum cystatin C concentrations rose (a marker of kidney injury) (109).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [109]
Multiple human and animal studies support mechanistic and clinical prognostic associations between TMAO formation and cardiometabolic disease risks.
“multiple human and animal studies supporting both mechanistic and clinical prognostic associations between TMAO formation and cardiometabolic disease risks have been reported8–16.”
From Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential (2018) · cites this paper as [12]
Serum TMAO levels are positively correlated with colorectal cancer in humans.
“Recent human studies have established that the levels of TMAO in serum are positively correlated with impaired renal function, colorectal cancer, and cardiovascular disease (CVD) (8, 10, 17, 18).”
Serum TMAO levels are positively correlated with impaired renal function in humans.
“Recent human studies have established that the levels of TMAO in serum are positively correlated with impaired renal function, colorectal cancer, and cardiovascular disease (CVD) (8, 10, 17, 18).”
Serum TMAO levels are positively correlated with cardiovascular disease in humans.
“Recent human studies have established that the levels of TMAO in serum are positively correlated with impaired renal function, colorectal cancer, and cardiovascular disease (CVD) (8, 10, 17, 18).”
Renal functional decline leads to less efficient excretion and thus heightened levels of trimethylamine/trimethylamine N-oxide.
“Second, renal functional decline leads to less efficient excretion and thus heightened levels of TMA(O)95.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [95]
TMAO is formed from trimethylamine (TMA), which is generated by gut microbiota from dietary choline and phosphatidylcholine (lecithin).
“TMAO is formed from trimethylamine (TMA), which is generated by the action of gut microbiota from dietary choline and phosphatidylcholine (lecithin) [8,9].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [9]
TMAO is either transported to tissues for accumulation as an osmolyte or cleared by the kidney.
“TMAO is then either transported to the tissues for accumulation as an osmolyte or, more commonly, cleared by the kidney [3,9,13,14].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [9]
TMAO is a small colorless amine oxide generated from choline, betaine, and carnitine by gut microbial metabolism.
“Trimethylamine N-oxide (TMAO) is a small colorless amine oxide generated from choline, betaine, and carnitine by gut microbial metabolism.”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [9]
TMAO levels increase with decreasing levels of kidney function and are associated with mortality in patients with chronic kidney disease.
“TMAO levels increase with decreasing levels of kidney function and is associated with mortality in patients with chronic kidney disease.”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [9]
In a prospective cohort study of 521 stable subjects with CKD, elevated plasma TMAO levels were associated with a 2.8-fold increased mortality risk.
“A prospective cohort study of 521 stable subjects with CKD found elevated plasma TMAO levels which were associated with a 2.8-fold increased mortality risk [9].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [9]
C57BL/6J mice fed with choline or TMAO exhibited tubulointerstitial fibrosis, collagen deposition and phosphorylation of Smad3.
“Tang et al. showed that C57BL/6J mice fed with choline or TMAO exhibited tubulointerstitital fibrosis, collagen deposition and phosphorylation of Smad3; an important regulator of the profibrotic transforming growth factor-β/Smad3 signaling pathway [9].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [9]
Blood TMAO level is positively correlated with long-term mortality risk in patients with atherosclerosis, heart failure, and chronic kidney disease.
“The blood TMAO level has been reported to be positively correlated with long‐term mortality risk in patients with atherosclerosis, heart failure, and chronic kidney disease.5, 6, 7”
From Dysbiosis of gut microbiota with reduced trimethylamine-N-oxide level in patients with large-artery atherosclerotic stroke or transient ischemic attack (2015) · cites this paper as [7]
In rat models, primarily renal excretion greater than 95% occurs after radiolabel ingestion.
“The strong relationship between kidney function and TMAO has been recognized in multiple early studies on rat models showing primarily renal excretion greater than 95% after radiolabel ingestion192.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [192]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Cystatin C feeding duration differs between Methods and Results
MinorThe Methods specify a 14-week follow-up for the diet-group comparison of cystatin C, while the Results describe that comparison after 16 weeks of feeding.
“A separate study included C57BL6J mice with ApoE−/− background were fed with the same diet groups for comparing their cystatin C levels at 14 weeks of follow-up using a commercially available mouse enzyme-linked immunosorbent assay (R&D systems, Minneapolis MN).”
“Extending the TMAO/choline feeding to 16 weeks was associated with increased serum cystatin C levels compared to chow-fed mice (Figure 4C).”
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- Authors
- 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.
- Affiliations
- Cleveland State University (US)
- ORCID
- Venue
- Circulation Research
- Published
- 2015-01-30
- Volume
- 116
- Issue
- 3
- Pages
- 448-455
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC4312512
- OpenAlex
- W2150350691
- Cited by
- 1,223
- References
- 43
- Citations by year
- 2026: 92 · 2025: 140 · 2024: 101 · 2023: 128 · 2022: 135 · 2021: 130 · 2020: 125 · 2019: 84 · 2018: 94 · 2017: 80 · 2016: 80 · 2015: 32
- FWCI
- 26.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- EngagedScholarship @ Cleveland State University (Cleveland State University) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR000439)
- National Heart, Lung, and Blood Institute (R01HL103931, P20HL113452, P01HL076491, P01HL098055, R01HL103866)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK106000)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Dialysis and Renal Disease Management
- Keywords
- trimethylamine N-oxide, chronic kidney disease, renal failure, gut microbiota, dietary choline, phosphatidylcholine, L-carnitine, all-cause mortality, prognostic factors, renal fibrosis, cystatin C, cardiovascular risk
- MeSH terms
- Aged, Aged, 80 and over, Animals, Female, Humans, Intestines, Male, Methylamines, Mice, Inbred C57BL, Middle Aged, Prognosis, Risk Factors, Biomarkers, Case-Control Studies, Mice, Renal Insufficiency, Chronic, Renal Insufficiency, Microbiota
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