Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden

Abstract

Trimethlyamine-N-oxide (TMAO) was recently identified as a promoter of atherosclerosis. Patients with CKD exhibit accelerated development of atherosclerosis; however, no studies have explored the relationship between TMAO and atherosclerosis formation in this group. This study measured serum concentrations and urinary excretion of TMAO in a CKD cohort (n=104), identified the effect of renal transplant on serum TMAO concentration in a subset of these patients (n=6), and explored the cross-sectional relationship between serum TMAO and coronary atherosclerosis burden in a separate CKD cohort (n=220) undergoing coronary angiography. Additional exploratory analyses examined the relationship between baseline serum TMAO and long-term survival after coronary angiography. Serum TMAO concentrations demonstrated a strong inverse association with eGFR (r 2 =0.31, P,0.001). TMAO concentrations were markedly higher in patients receiving dialysis (median [interquartile range], 94.4 mM [54.8-133.0 mM] for dialysis-dependent patients versus 3.3 mM [3.1-6.0 mM] for healthy controls; P,0.001); whereas renal transplantation resulted in substantial reductions in TMAO concentrations (median [min-max] 71.2 mM [29.2-189.7 mM] pretransplant versus 11.4 mM [8.9-20.2 mM] posttransplant; P=0.03). TMAO concentration was an independent predictor for coronary atherosclerosis burden (P=0.02) and predicted long-term mortality independent of traditional cardiac risk factors (hazard ratio, 1.26 per 10 mM increment in TMAO concentration; 95% confidence interval, 1.13 to 1.40; P,0.001). In conclusion, serum TMAO concentrations substantially increase with decrements in kidney function, and this effect is reversed by renal transplantation. Increased TMAO concentrations correlate with coronary atherosclerosis burden and may associate with long-term mortality in patients with CKD undergoing coronary angiography. Patients with CKD have a high prevalence of cardiovascular comorbidities, which primarily contributes to the exceedingly high mortality in this group. 1,2 For example, the 5-year survival for ESRD patients receiving dialysis is approximately 35%, with .50% of the mortality in this group resulting directly from cardiovascular causes. 1 It is well established that CKD patients exhibit a disproportionate burden of atherosclerosis as compared with individuals having normal kidney function. [2][3][4][5] Furthermore, a higher prevalence of traditional risk factors for the development of atherosclerosis, such as hypertension, diabetes and hyperlipidemia, only partially accounts for the accelerated atherosclerosis in CKD patients, leading to the hypothesis that unique risk factors must be present in this population. 6,7

Trimethylamine N‐Oxide Promotes Vascular Inflammation Through Signaling of Mitogen‐Activated Protein Kinase and Nuclear Factor‐κB

“…The dose of TMAO used produced an initial spike in circulating levels to ≈100 μmol/L over the first hour, which returned essentially to near baseline levels ≈5 hours after injection in mice fed a normal chow diet (data not shown). 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. At 30 minutes after intraperitoneal injection of TMAO, aortas were harvested and then assessed for changes in activation of p38 mitogen‐activated protein kinase, extracellular signal–related kinase 1/2, and p65 NF‐κB, all of which have been shown to play substantial roles in cellular inflammation contributing to the development of atherosclerosis 18, 20, 21, 22, 23, 24.…”

Trimethylamine N-Oxide as a Novel Therapeutic Target in CKD

“…16 They confirmed the graded rise in circulating TMAO levels with progressive renal dysfunction and added evidence to show the resolution of high TMAO after kidney transplantation. Importantly, they also provided independent validation of the prognostic role of TMAO in an independent cohort of patients with CKD and confirmed the direct correlation between atherosclerotic burden and TMAO levels in CKD.…”

Gut bacteria-derived molecules as mediators and markers in cardiovascular diseases. The role of the gut-blood barrier

“…What is more, TMAO plasma concentration is increased in patients with CKD and is connected with all-cause mortality in CKD patients' sub-population. Therefore, TMAO may be considered as an independent risk factor of cardiovascular complications and CAD progress [44,45]. TMAO can also be used as an independent marker of early atherosclerosis, expressed as carotid intima-media complex thickness [46].…”

“…Trimethylamine N-oxide (TMAO) Sterol metabolism, modulation and promotion of atherosclerosis [17] Augmentation of angiotensin II effects [18] Intravascular inflammation [19] Inhibition of beta-oxidation in heart muscle cells [20] Increased platelet reactivity [21] Diabetes development [22] Increased mortality in CAD and peripheral atherosclerosis [39,40] Correlation with all-cause mortality and MACE [41] Poor prognosis in ACS [42] Secondary risk stratification in ACS [43] CAD progression and higher CV risk in CKD [44,45] Increased rate of CV complications of diabetes [50] Hydrogen sulphide Vasoconstriction or vasorelaxation [27,38] Blood pressure regulation -hypotensive action [6,28] Cytoprotection, proangiogenic action (experimental models)…”