title: 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 μM [54.8-133.0 μM] for dialysis-dependent patients versus 3.3 μM [3.1-6.0 μM] for healthy controls; P<0.001); whereas renal transplantation resulted in substantial reductions in TMAO concentrations (median [min-max] 71.2 μM [29.2-189.7 μM] pretransplant versus 11.4 μM [8.9-20.2 μM] post-transplant; 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 μM 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.
authors.affiliation: The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas; Department of Internal Medicine, Division of Nephrology & Hypertension, University of Kansas Medical Center, Kansas City, Kansas; jstubbs@kumc.edu.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Stubbs
authors.affiliation: Saint Luke's Mid America Heart Institute, Kansas City, Missouri;
authors.forename: John A
authors.initials: JA
authors.lastname: House
authors.affiliation: Department of Pharmacy and Therapeutics, Center for Clinical Pharmaceutical Sciences and.
authors.forename: A Jacob
authors.initials: AJ
authors.lastname: Ocque
authors.affiliation: The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Shiqin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Cassandra
authors.initials: C
authors.lastname: Johnson
authors.affiliation: Department of Internal Medicine, Division of Nephrology & Hypertension, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Cassandra
authors.initials: C
authors.lastname: Kimber
authors.affiliation: The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Kyle
authors.initials: K
authors.lastname: Schmidt
authors.affiliation: The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas; Department of Internal Medicine, Division of Nephrology & Hypertension, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Aditi
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Division of Nephrology, Hennepin County Medical Center, Minneapolis, Minnesota; and.
authors.forename: James B
authors.initials: JB
authors.lastname: Wetmore
authors.affiliation: Department of Pharmacy and Therapeutics, Center for Clinical Pharmaceutical Sciences and Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh Schools of Pharmacy and Medicine, Pittsburgh, Pennsylvania;
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Nolin
authors.affiliation: Saint Luke's Mid America Heart Institute, Kansas City, Missouri; University of Missouri-Kansas City, Kansas City, Missouri.
authors.forename: John A
authors.initials: JA
authors.lastname: Spertus
authors.affiliation: The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas; Department of Internal Medicine, Division of Nephrology & Hypertension, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Alan S
authors.initials: AS
authors.lastname: Yu
mesh_terms: D000368:Aged; D003324:Coronary Artery Disease / Q000097:blood* / Q000150:complications; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008744:Methylamines / Q000097:blood*; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000150:complications / Q000601:surgery*
chemical_list: D008744:Methylamines; C005855:trimethyloxamine
keywords: CKD; ESRD; atherosclerosis; cardiovascular disease; coronary artery disease; mortality