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

Circulating trimethylamine -oxide (TMAO) predicts poor cardiovascular outcomes in patients with chronic kidney disease (CKD). Accumulation of serum TMAO has been observed in CKD patients; however, the mechanisms contributing to this finding have been inadequately explored. The purpose of this study was to investigate the mechanisms responsible for TMAO accumulation in the setting of decreased kidney function using a CKD mouse model. Mice were fed a diet supplemented with 0.2% adenine to induce CKD, which resulted in increased serum TMAO concentrations (females: CKD 29.4 ± 32.1M vs. non-CKD 6.9 ± 6.1 M, < 0.05; males: CKD 18.5 ± 13.1 M vs. non-CKD 1.0 ± 0.5M, < 0.001). As anticipated, accumulation of circulating TMAO was accompanied by a decrease in renal clearance (females: CKD 5.2 ± 3.8 l/min vs. non-CKD 90.4 ± 78.1l/min, < 0.01; males: CKD 10.4 ± 8.1 l/min vs. non-CKD 260.4 ± 134.5l/min; < 0.001) and fractional excretion of TMAO. Additionally, CKD animals exhibited an increase in hepatic flavin monooxygenase (FMO)-mediated formation of TMAO (females: CKD 125920 ± 2181 pmol/mg per 60 minutes vs. non-CKD 110299 ± 4196 pmol/mg per 60 minutes, < 0.001; males: CKD 131286 ± 2776 pmol/mg per 60 minutes vs. non-CKD 74269 ± 1558 pmol/mg per 60 minutes, < 0.001), which likely resulted from increased FMO3 expression in CKD mice. The current study provides evidence that both decreased renal clearance and increased hepatic production of TMAO may contribute to increments in serum TMAO in the setting of CKD. Hepatic FMO activity may represent a novel therapeutic target for lowering circulating TMAO in CKD patients.

The absorption, deposition, and excretion of zinc65 was studied in mice, rats, and dogs. When zinc65 was fed to the animals it was poorly absorbed, but its long biologic half-life made even the small portion absorbed physiologically significant. Absorption was obviated by feeding large quantities of nonradioactive carrier zinc. Injected zinc65 chloride first was deposited, preferably in the pancreas, liver, and spleen, with only minor deposition in muscle and in the brain. Subsequently, a large proportion was transferred to bone. The chief means of excretion was in feces, presumably via pancreatic secretion. Injected nonradioactive zinc or treatment with 2,3-dimercaptopropanol (BAL), Versene, or cadmium ion failed to alter body burden significantly. Cadmium, however, decreased soft tissue zinc65 deposition and increased accretion by the skeleton. Blood activity fell rapidly and less than .01% of the dose injected remained in the blood after 1 day. Renal excretion of zinc65 rose as plasma concentration fell and clearance ratios in excess of 1.0 were noted, indicating probable renal secretion.

American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) created the Surgical Risk Calculator, to allow physicians to offer patients a risk-adjusted 30-day surgical outcome prediction. This tool has not yet been validated in plastic surgery. A retrospective analysis of all plastic surgery-specific complications from a quality assurance database from September 2013 through July 2015 was performed. Patient preoperative risk factors were entered into the ACS Surgical Risk Calculator, and predicted outcomes were compared with actual morbidities. The difference in average predicted complication rate versus the actual rate of complication within this population was examined. Within the study population of patients with complications (n=104), the calculator accurately predicted an above average risk for 20.90% of serious complications. For surgical site infections, the average predicted risk for the study population was 3.30%; this prediction was proven only 24.39% accurate. The actual incidence of any complication within the 4924 patients treated in our plastic surgery practice from September 2013 through June 2015 was 1.89%. The most common plastic surgery complications include seroma, hematoma, dehiscence and flap-related complications. The ACS Risk Calculator does not present rates for these risks. While most frequent outcomes fall into general risk calculator categories, the difference in predicted versus actual complication rates indicates that this tool does not accurately predict outcomes in plastic surgery. The ACS Surgical Risk Calculator is not a valid tool for the field of plastic surgery without further research to develop accurate risk stratification tools.