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Cardiovascular disease is more common in patients with chronic kidney disease (CKD), and traditional risk factors do not adequately predict those at risk for cardiovascular (CV) events. Recent evidence suggests elevated trimethylamine N-oxide (TMAO), created by gut microflora from dietary L-carnitine and choline, is associated with CV events. We investigated the relationship of TMAO levels in patients with stages 3b and 4 CKD to ischemic CV events using the CanPREDDICT cohort, a Canada-wide observational study with prospective 3-year follow-up of adjudicated CV events. Baseline samples were obtained for 2529 CKD patients. TMAO, choline, and L-carnitine levels were measured using tandem mass spectrometry. Baseline median TMAO level was high for the whole cohort (20.41 μM; interquartile range [IQR]: 12.82–32.70 μM). TMAO was independently associated with CV events (hazard ratio 1.23; 95% confidence interval: 1.06–1.42 / 1 SD lnTMAO) after adjusting for all potential CV risk factors. Those in the highest TMAO quartile had significantly higher risk of CV events (adjusted hazard ratio 1.59; 95% confidence interval: 1.04–2.43; P = 0.0351) in the analysis of recurring ischemic events. Among those with stage 3b CKD (hazard ratio 1.45; 95% confidence interval: 1.12–1.87 / 1 SD lnTMAO), independent of kidney function, TMAO levels identified those at highest risk for events. Our results suggest that TMAO may represent a new potentially modifiable CV risk factor for CKD patients. Further studies are needed to determine sources of variability and if lowering of TMAO reduces CV risk in CKD.

BACKGROUND In patients with chronic kidney disease (CKD), anemia is associated with left ventricular hypertrophy and adverse cardiovascular and clinical outcomes. Moreover, anemia is associated with a reduction in quality of life, particularly when the hemoglobin level drops below 100 g/l. 1 Thus, the goal of treating anemia in iron-replete patients with erythropoietic-stimulating agents (ESAs) is to reduce the likelihood of cardiovascular events, improve patients’ survival, and improve patients’ quality of life while minimizing any deleterious effects of the drug. Given that ESAs increase blood pressure and have other potential side effects, it is also important to assess whether the quantity of the ESA used might contribute to adverse events such as more rapid deterioration of kidney function, earlier requirement for dialysis, and vascular access failure. It is acknowledged that, if left untreated, patients with severe anemia may require blood transfusions, which have associated risks and costs, and possible implications for patients awaiting a kidney transplant. In light of this, in most developed countries, the question for CKD patients with significant anemia has often not been whether to use ESAs, but when to use them and what target hemoglobin level to aim for. 2 The earliest anemia correction studies in nondialysischronic kidney disease (ND-CKD) and hemodialysis-chronic kidney disease (HD-CKD) patients compared the use of erythropoietin a with placebo. 3–5 Most early studies were not designed and powered to examine clinical outcomes other than quality of life, and no differences were apparent in such other outcomes. Several of the studies showed improvements in quality of life compared with placebo. 3–5 Subsequent randomized control trials (RCTs) have tended to examine the impact of using ESAs to achieve different target hemoglobin level ranges on surrogate endpoints, such as left ventricular (LV) mass, where patients with the lower hemoglobin target would be less likely to require the use of an ESA or would require lower doses to maintain the prespecified lower target hemoglobin. Two RCTs 6,7 in HDCKD patients compared with the use of ESAs to achieve intermediate hemoglobin and high hemoglobin targets. Although both studies showed no difference in progression of LV mass, the higher target hemoglobin led to improved quality of life in some of the domains, but the size of this

Supplemental therapies are treatment strategies to enhancethe responsiveness of erythropoietic-stimulating.agents(ESAs) in the management of anemia in chronic kidneydisease (CKD) patients, including those who exhibitresistance to ESAs. The desired outcome is an improvementin hemoglobin levels, reduction in ESA dose, or both.Although the outcomes of these studies (hemoglobin level,ESA dose) are arguably the relevant outcomes of interest, asthe outcome is not a ‘clinical outcome,’ each of the studies isassigned either a Grade C or D level of evidence.

Anemia management of adult hemodialysis patients in the U.S.: Results from the 1997 ESRD Core Indicators Project.BackgroundThe Health Care Financing Administration's End-Stage Renal Disease (ESRD) Core Indicators Project collects clinical information on prevalent adult patients receiving in-center hemodialysis (HD) care in the United States to assess the quality of care delivered. Although hematocrit values, transferrin saturations, and iron prescription practices have improved over the last five years, we sought to determine whether continued opportunities for improvement of this domain of care exist.MethodsA random sample of 7292 adult in-center HD patients was selected. Dialysis facility staff provided clinical information for the period of October through December 1996 for 6858 (94%) patients; complete laboratory information was available from 4991 (73%) returned forms. Hematocrit values, transferrin saturations, serum ferritin concentrations, epoetin alfa dosing, and iron prescriptions were abstracted from patient medical records to assess anemia management practices.ResultsThe mean hematocrit for this cohort was 32.6 ± 3.5%. Seventy-two percent of patients had hematocrit values> 30%. Forty-two percent had hematocrit values of 33 to 36%, and 10% were severely anemic (hematocrit 100 and> 800 ng/mL, respectively. Nine percent of the sample (N = 434) had a transferrin saturation

the hemoglobin levels used todefine a chronic kidney disease (CKD) patient as anemic arebased on gender-specific values under the 5th percentile foran age of more than 18 years. The data are taken from thethird National Health and Nutrition Examination Survey(NHANES III) data set of the US population, 1988–1994

Clinical Practice Guidelines for the management of anemia associated with chronic kidney disease Braden J. Manns, Colin T. White, Francois Madore, Louise M. Moist, Scott W. Klarenbach, Brendan J. Barrett, Rob N. Foley, Bruce F. Culleton and Marcello Tonelli Division of Nephrology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada; Division of Nephrology, Department of Pediatrics, Faculty of Medicine, British Columbia Children’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada; Division of Nephrology, Department of Medicine, Hopital du Sacre-Cœur de Montreal, Universite de Montreal, Montreal, Quebec, Canada; Department of Medicine, University of Western Ontario, London, Ontario, Canada; Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Department of Medicine, Memorial University, St John’s, Newfoundland and Labrador, Canada and Minneapolis Medical Research Foundation, Minneapolis, Minnesota, USA

Accumulating evidence suggests that periodontal disease is associated with increased risk of cardiovascular disease (CVD). Several mechanisms have been proposed to explain this association. To date, however, a causal relation has not been firmly established. In addition, the extent to which treatment of periodontal disease might result in lower incidence of CVD has not been addressed in any study to date. Further research is needed before recommendations are made regarding monitoring and therapy of periodontal disease.