Thomas D. Nolin

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.

eCrCl (mL/min) a Warfarin Apixaban b Dabigatran Edoxaban c Rivaroxaban >95 Adjusted dose (INR 2-3) 5 mg b.i.d. 150 mg b.i.d. 60 mg QD d 20 mg QD 51-95 Adjusted dose (INR 2-3) 5 mg b.i.d. 150 mg b.i.d. 60 mg QD 20 mg QD 31-50 Adjusted dose (INR 2-3) 5 mg b.i.d.(eCrCl cut-off 25 mL/min) 150 mg b.i.d. or 110 mg b.i.d. e 30 mg QD 15 mg QD INR, international normalized ratio. a Cockcroft-Gault estimated creatinine clearance (eCrCl). b Apixaban dose modification from 5 mg b.i.d. to 2.5 mg b.i.d. if patient has any two of the following: serum creatinine > _1.5 mg/dL, age > _80 years, or body weight < _60 kg. c In the ENGAGE-AF TIMI 48 study, the dose was halved if any of the following: eCrCl of 30-50 mL/min, body weight < _60 kg, or concomitant use of verapamil or quinidine (potent P-glycoprotein inhibitors). d This dose has not been approved for use by the US Food and Drug Administration in this category of kidney function. e In countries where 110 mg b.i.d. is approved, clinicians may prefer this dose after clinical assessment of thromboembolic vs bleeding risk. This dose has not been approved for use by the US Food and Drug Administration.

Until recently, cardiac toxicity manifesting in the form of arrhythmias related to QT interval prolongation was uncommonly appreciated within the antimicrobial class of drugs, but it was well described among antiarrhythmic agents. Antimicrobials that are associated with QT prolongation include the macrolides/ketolides, certain fluoroquinolones and antimalarials, pentamidine, and the azole antifungals. Although, in most cases, mild delays in ventricular repolarization caused by these drugs are clinically unnoticeable, they may serve to amplify the risk for torsades de pointes (TdP) when prescribed in the setting of other risk factors. Conditions or variables that influence proarrhythmic risk include sex, age, electrolyte derangements, structural heart disease, pharmacokinetic/pharmacodynamic interactions, and genetic predisposition. It is important that clinicians be knowledgeable about drugs with QT liability, as well as the risk factors that increase the probability of TdP. Additionally, because TdP remains a difficult-to-measure adverse event, we must rely upon multiple data sources to determine the risk versus the benefit for newly approved drugs.