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In the psychiatric setting, therapeutic drug monitoring and genotyping for cytochrome P450 (CYP) polymorphisms help to ensure and maintain therapeutic drug levels. In this study, the authors extended the therapeutic drug monitoring and genotyping protocol routinely used in their psychiatric clinic to primary care patients treated with antidepressants. They examined the variation in serum concentrations and assessed the role of CYP polymorphisms, wrong dosing, and noncompliance in deviating serum concentrations. Of 227 serum concentrations obtained, 127 (56%) were more than 20% outside therapeutic ranges. Of these 127 cases, 64 (50%) were congruous with aberrant CYP2D6 or CYP2C19 genotypes, incorrect dosing, or a pharmacy record suggesting noncompliance. Prevalence of aberrant CYP2D6 and CYP2C19 genotypes did not differ significantly between the investigated primary care patients and 751 secondary care users of antidepressants. The therapeutic drug monitoring and the genotyping findings resulted in recommendations to physicians to alter the medication strategy of 146 (64%) patients. These results strongly suggest that the rationale for therapeutic drug monitoring and CYP genotyping when prescribing antidepressants in secondary care also applies to the primary care setting. [ABSTRACT FROM AUTHOR]

Introduction: Patients poisoned with paracetamol are treated with acetylcysteine. In patients without hepatocellular injury, an increased prothrombin time or international normalized ratio has been observed during acetylcysteine administration. The international normalized ratio is preferred as it is a standardized calculation of prothrombin time independent of reagents and machinery. Since the prothrombin time and international normalized ratio are used as markers of liver injury in patients with paracetamol poisoning, it is important to assess the magnitude of the effect of acetylcysteine treatment on the prothrombin time and international normalized ratio. The aim of this narrative review is to describe the effect of acetylcysteine on the prothrombin time and international normalized ratio., Methods: Embase, PubMed and Web of Science were searched to identify the effect of acetylcysteine on coagulation factors II, VII, IX or X, the prothrombin time and the international normalized ratio in in vitro and in vivo studies in healthy subjects and clinical studies involving both those poisoned with paracetamol and surgical patients. The search terms employed were acetylcysteine combined with prothrombin time, international normalized ratio, coagulation or haemostasis., Results: The search identified a total of 2,471 articles, of which 19 studies were included. Six in vitro and/or in vivo studies, five clinical studies in paracetamol-poisoned patients and eight clinical studies in surgical patients were included. Acetylcysteine caused a 15-30% increase in prothrombin time and international normalized ratio. This increase was dose-dependent and was caused by a decrease in the activity of coagulation factors II, VII, IX and X. The effect of acetylcysteine on the increased prothrombin time and international normalized ratio was more prominent after the high loading dose but remained present during the lower maintenance dose of acetylcysteine. The effect was observed in both in vitro and in vivo studies and confirmed in clinical studies in paracetamol-poisoned patients without hepatic injury. Studies in surgical patients treated with acetylcysteine showed conflicting results. Twelve of the 13 clinical studies suffered from risk of bias, limiting the value of these studies., Discussion: The moderate 15-30% increase in the international normalized ratio induced by acetylcysteine is especially important in hospitals using the international normalized ratio as a marker for hepatotoxicity due to paracetamol poisoning and underlines the need for the international normalized ratio to be assessed at admission., Conclusion: Acetylcysteine treatment leads to an estimated 15-30% increase in prothrombin time and international normalized ratio in both experimental studies and paracetamol-poisoned patients. Isolated increases in prothrombin time and international normalized ratio during acetylcysteine infusion are common and do not necessarily reflect liver dysfunction or liver injury.

Introduction: In patients admitted to the intensive care unit (ICU), muscle mass is inversely associated with mortality. Although muscle mass can be estimated with 24-h urinary creatinine excretion (UCE), its use for risk prediction in individual patients is limited because age-, sex-, weight- and length-specific reference values for UCE are lacking. The ratio between measured creatinine clearance (mCC) and estimated glomerular filtration rate (eGFR) might circumvent this constraint. The main goal was to assess the association of the mCC/eGFR ratio in ICU patients with all-cause hospital and long-term mortality., Methods: The mCC/eGFR ratio was determined in patients admitted to our ICU between 2005 and 2021 with KDIGO acute kidney injury (AKI) stage 0-2 and an ICU stay ≥ 24 h. mCC was calculated from UCE and plasma creatinine and indexed to 1.73 m 2 . mCC/eGFR was analyzed by categorizing patients in mCC/eGFR quartiles and as continuous variable., Results: Seven thousand five hundred nine patients (mean age 61 ± 15 years; 38% female) were included. In-hospital mortality was 27% in the lowest mCC/eGFR quartile compared to 11% in the highest quartile (P < 0.001). Five-year post-hospital discharge actuarial mortality was 37% in the lowest mCC/eGFR quartile compared to 19% in the highest quartile (P < 0.001). mCC/eGFR ratio as continuous variable was independently associated with in-hospital mortality in multivariable logistic regression (odds ratio: 0.578 (95% CI: 0.465-0.719); P < 0.001). mCC/eGFR ratio as continuous variable was also significantly associated with 5-year post-hospital discharge mortality in Cox regression (hazard ratio: 0.27 (95% CI: 0.22-0.32); P < 0.001)., Conclusions: The mCC/eGFR ratio is associated with both in-hospital and long-term mortality and may be an easily available index of muscle mass in ICU patients., (© 2024. The Author(s).)

Background: NGAL and Cystatin C (CysC) as biomarkers for the early detection of AKI are subject to both pathophysiological, as well as patient related heterogeneity. The aim of this study was to investigate the timeline of plasma levels of NGAL and CysC during the first seven days of ICU admission in a mixed ICU population and to relate these to AKI severity during ICU stay. Via these means we aimed to bring clarity to the previously reported heterogeneity of these renal biomarkers., Methods: Prospective Observation Cohort. Consecutive patients admitted to adult ICU at an academic hospital in the Netherlands between 18-02-2014 and 31-03-2014 were included. Urine output, serum creatinine, plasma NGAL and CysC were recorded during the first seven days of ICU admission. Biomarker expression was analyzed based on KDIGO score and time of AKI diagnosis., Results: 335 patients were included, 110 met KDIGO criteria for AKI. NGAL and CysC plasma levels were higher in AKI patients compared to non-AKI, high variability in individual values resulted in 56% of AKI patients having a false negative, and 32% of non-AKI patients having a false positive. Individual biomarker levels were variable, and no pattern based on KDIGO score was observed., Conclusions: Plasma NGAL and CysC as biomarkers for the early AKI detection may be subject to pathophysiological, and patient related heterogeneity. Further understanding of individual biomarker profiles may help in their application amongst mixed ICU populations., Trial Registration: The need for informed consent was waived by the Institutional Ethical Review Board of the University Medical Center Groningen (METc 2013 - 174) by Prof. dr. W.A. Kamps on May 17th 2013., (© 2024. The Author(s).)

Background: Creatinine is the most widely used test to estimate the glomerular filtration rate (GFR), but muscle mass as key determinant of creatinine next to renal function may confound such estimates. We explored effects of 24-h height-indexed creatinine excretion rate (CER index) on GFR estimated with creatinine (eGFR Cr ), muscle mass-independent cystatin C (eGFR Cys ), and the combination of creatinine and cystatin C (eGFR Cr-Cys ) and predicted probabilities of discordant classification given age, sex, and CER index., Methods: We included 8076 adults enrolled in the PREVEND study. Discordant classification was defined as not having eGFR Cr  <60 mL/min per 1.73 m 2 when eGFR Cys was <60 mL/min/1.73 m 2 . Baseline effects of age and sex on CER index were quantified with linear models using generalized least squares. Baseline effects of CER index on eGFR were quantified with quantile regression and logistic regression. Effects of annual changes in CER index on trajectories of eGFR were quantified with linear mixed-effects models. Missing observations in covariates were multiply imputed., Results: Mean (SD) CER index was 8.0 (1.7) and 6.1 (1.3) mmol/24 h per meter in male and female participants, respectively (P difference  < 0.001). In male participants, baseline CER index increased until 45 years of age followed by a gradual decrease, whereas a gradual decrease across the entire range of age was observed in female participants. For a 70-year-old male participant with low muscle mass (CER index of 2 mmol/24 h per meter), predicted baseline eGFR Cr and eGFR Cys disagreed by 24.7 mL/min/1.73 m 2 (and 30.1 mL/min/1.73 m 2 when creatinine was not corrected for race). Percentages (95% CI) of discordant classification in male and female participants aged 60 years and older with low muscle mass were 18.5% (14.8-22.1%) and 15.2% (11.4-18.5%), respectively. For a 70-year-old male participant who lost muscle during follow-up, eGFR Cr and eGFR Cys disagreed by 1.5, 5.0, 8.5, and 12.0 mL/min/1.73 m 2 (and 6.7, 10.7, 13.5, and 15.9 mL/min/1.73 m 2 when creatinine was not corrected for race) at baseline, 5 years, 10 years, and 15 years of follow-up, respectively., Conclusions: Low muscle mass may cause considerable overestimation of single measurements of eGFR Cr . Muscle wasting may cause spurious overestimation of repeatedly measured eGFR Cr . Implementing muscle mass-independent markers for estimating renal function, like cystatin C as superior alternative to creatinine, is crucial to accurately assess renal function in settings of low muscle mass or muscle wasting. This would also eliminate the negative consequences of current race-based approaches., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: Vitamin B12 deficiency in children may be associated with (severe) neurological manifestations, therefore recognition is important. Diagnosing vitamin B12 deficiency in children is challenging. This study aimed to investigate plasma methylmalonic acid, holotranscobalamin, and total cobalamin in children 0-18 years of age and to estimate age-dependent reference intervals., Methods: Plasma vitamin B12 markers were measured in collected plasma samples of 170 children 0-18 years visiting a local primary care laboratory. All had within-reference hemoglobin and MCV values. Pediatric plasma vitamin B12 biomarkers were measured and reference values were derived thereof., Results: Plasma methylmalonic acid was higher in young children, in particular between 1 and 6 months of age; total cobalamin and holotranscobalamin were highest from 0.5 to 4 years and decreased till 10 years of age. Plasma holotranscobalamin was highly correlated with plasma total cobalamin; their ratio was independent of age. Plasma methylmalonic acid was slightly more related to total cobalamin than to holotranscobalamin. A large proportion of mainly young children would be misclassified when adult references are applied., Conclusions: Pediatric reference values for cobalamin markers are necessary to allow for early recognition and monitoring of children suspect of (clinical) cobalamin deficiency., Impact: We analyzed three plasma vitamin B12 status markers, i.e., total cobalamin, holotranscobalamin, and methylmalonic acid, in the plasma of 170 children 0-18 years of age and were able to derive reference intervals thereof. Recognition of vitamin B12 deficiency in children is important but challenging as pediatric reference intervals for plasma vitamin B12 status markers, particularly plasma holotranscobalamin, are not well described. We think that our results may help early recognition and monitoring of children suspect of (clinical) vitamin B12 deficiency., (© 2021. The Author(s).)

Background: Accurate measurement of kidney function in patients with neuromuscular disorders is challenging. Cystatin C, a marker not influenced by skeletal muscle degradation, might be of clinical value in these patients. Methods: We consecutively enrolled 39 patients with neuromuscular disorders. We investigated the association of the eGFR, based on plasma creatinine and Cystatin C, with clinical and biochemical variables associated with kidney function, namely age and galectin-3. Results: Creatinine-based eGFR was 242 (±80) and Cystatin C-based eGFR was 110 (±23) mL/min/1.73 m 2 . Cystatin C-based eGFR was associated with age (β -0.63 p < 0.0001) and galectin-3 levels (β -0.43 p < 0.01), while creatinine-based eGFR was not (β -0.22 p = 0.20; β -0.28 p = 0.10). Sensitivity analyses in Duchenne and Becker patients revealed the same results: Cystatin C-based eGFR was associated with age (β -0.61 p < 0.01) and galectin-3 levels (β -0.43 p = 0.05), while creatinine-based eGFR was not (β -0.32 p = 0.13; β -0.34 p = 0.14). Conclusions: These data indicate that estimation of renal function in patients with neuromuscular disorders cannot reliably be achieved with creatinine, while Cystatin C appears a reasonable alternative. Since a large proportion of patients with neuromuscular disorders develops heart failure, and requires heart failure medication, adequate monitoring of renal function is warranted., Competing Interests: The UMCG, which employs the authors, has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc., Novo Nordisk, and Roche. RdB received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche., (Copyright © 2021 Screever, Kootstra-Ros, Doorn, Nieuwenhuis, Meulenbelt, Meijers and de Boer.)

Background and Objectives: High dietary acid load may accelerate a decline in kidney function. We prospectively investigated whether dietary acid load is associated with graft outcomes in kidney transplant recipients, and whether venous bicarbonate mediates this association., Design, Setting, Participants, & Measurements: We used data from 642 kidney transplant recipients with a functioning graft ≥1 year after transplantation. Net endogenous acid production was estimated using food frequency questionnaires and, alternatively, 24-hour urinary urea and potassium excretion to estimate net endogenous acid production. We defined the composite kidney end point as a doubling of plasma creatinine or graft failure. Multivariable Cox regression analyses, adjusted for potential confounders, were used to study the associations of dietary acid load with the kidney end point. We evaluated potential mediation effects of venous bicarbonate, urinary bicarbonate excretion, urinary ammonium excretion, titratable acid excretion, and net acid excretion on the association between net endogenous acid production and the kidney end point., Results: The median net endogenous acid production using food frequency questionnaires and net endogenous acid production using urinary excretion were 40 (interquartile range, 35-45) and 54 (interquartile range, 44-66) mEq/day, respectively. During a median follow-up of 5.3 years (interquartile range, 4.1-6.0), 121 (19%) participants reached the kidney end point. After multivariable adjustment, net endogenous acid production using food frequency questionnaires and net endogenous acid production using urinary excretion (per SD higher) were independently associated with higher risk for kidney end point (hazard ratio, 1.33; 95% confidence interval, 1.12 to 1.57, P =0.001 and hazard ratio, 1.44; 95% confidence interval, 1.24 to 1.69, P <0.001, respectively). Baseline venous bicarbonate mediated 20% of the association between net endogenous acid production using food frequency questionnaires and the kidney end point. Baseline venous bicarbonate, urinary ammonium excretion, and net acid excretion mediated 25%, -14%, and -18%, respectively, of the association between net endogenous acid production using urinary excretion and the kidney end point., Conclusions: Higher dietary acid load was associated with a higher risk of doubling of plasma creatinine or graft failure, and this association was partly mediated by venous bicarbonate, urinary ammonium, and net acid excretion., (Copyright © 2021 by the American Society of Nephrology.)

Background: Self-reported alcohol consumption is an established risk factor for cardiovascular disease (CVD). Carbohydrate deficient transferrin (CDT) is an established objective marker of excessive alcohol consumption, but data on its prospective association with CVD are lacking. We aimed to evaluate the associations of self-reported alcohol consumption and CDT (expressed as %CDT, a more reliable marker than absolute CDT levels) with CVD risk., Materials and Methods: In the PREVEND prospective study of 5,206 participants (mean age, 53 years; 47.7% males), alcohol consumption by self-reports, absolute CDT measured using the Siemens nephelometric assay and %CDT calculated as the percentage of total transferrin concentrations, were assessed at baseline. Alcohol consumption was classified into 5 categories: abstention (reference), light, light-moderate, moderate and heavy alcohol consumption.Hazard ratios (HRs) (95% confidence intervals [CI]) for first CVD events were estimated., Results: Mean (SD) of %CDT was 1.59 (0.54) %. During a median follow-up of 8.3 years, 326 first CVD events were recorded. Compared with abstainers, the multivariable-adjusted HRs (95% CIs) of CVD for light, light-moderate, moderate and heavy alcohol consumption were 0.66 (0.46-0.95), 0.83 (0.62-1.11), 0.83 (0.61-1.14) and 0.80 (0.48-1.36), respectively. Light alcohol consumption was associated with reduced coronary heart disease risk 0.62 (0.40-0.96), whereas light-moderate alcohol consumption was associated with reduced stroke risk 0.45 (0.24-0.83). The association of %CDT with CVD risk was not significant., Conclusions: Our findings confirm the established association between self-reported light to moderate alcohol consumption and reduced CVD risk. However, %CDT within the normal reference range may not be a risk indicator for CVD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Folate analysis in plasma is affected by hemolysis, which can lead to biased results. However, the degree of hemolysis that is considered acceptable is unclear. We explored the relationship between folate concentration and degree of hemolysis. Heparin plasma samples (N=77, hemolysis index ≤10 μmol/L) were spiked with increasing amounts of corresponding patient-specific hemolysate. Subsequently, the folate concentration and hemolysis index were measured using two Roche Cobas platforms, and their incremental relationship was investigated. The folate concentration ranged from 2.9 to 30.9 nmol/L with a median (interquartile range) of 11.4 (8.6-19.1) nmol/L. The linear relationship between the increments in folate concentration and hemolysis index was approximated by the function y=1.86x+1.56 (R 2 =0.996), where x represents the laboratory-specific critical difference in folate concentration, which can be calculated from the analytical variation of the employed folate assay(s), and y represents the hemolysis threshold. The hemolysis threshold did not significantly differ between the tertiles of plasma folate concentration ( P =0.10). In conclusion, we have provided an evidence-based approach that can be used to reliably interpret folate concentrations in hemolytic samples, independent of the patient's folate status.

Purpose: Although thyroid hormones are irrefutably implicated in cardiovascular physiology, the impact of within-reference range variations of thyroid function on cardiovascular disease (CVD) remains unclear. Elucidating this is important, since it could foster preventive treatment and reduce global CVD burden. We therefore investigated the impact of within-reference range variations of thyroid function on all-cause and cardiovascular mortality., Methods: We included community-dwelling individuals aged 28-75 years from a prospective cohort study, without known use of thyroid-affecting therapy and with thyrotropin within reference range. Associations of thyroid function with mortality were quantified using Cox models and adjusted for sociodemographic and cardiovascular risk factors., Results: Mean (SD) age of the 6,054 participants (52.0% male) was 53.3 (12.0) years. During 47,594 person-years of follow-up, we observed 380 deaths from all causes and 103 from CVDs. Although higher thyrotropin was not associated with all-cause mortality (adjusted HR 1.02, 95% CI 0.92-1.14), point estimates for cardiovascular mortality diverged toward increased risk in younger (<72 years) participants (1.31, 1.00-1.72) and decreased risk in elderly (≥72 years) (0.77, 0.56-1.06). Higher free thyroxine (FT 4 ) was associated with all-cause mortality (1.18, 1.07-1.30) and with cardiovascular mortality only in elderly (1.61, 1.19-2.18), but not in younger participants (1.03, 0.78-1.34). Higher free triiodothyronine (FT 3 ) was associated with all-cause mortality in females only (1.18, 1.02-1.35). FT 3 was not associated with cardiovascular mortality (0.91, 0.70-1.18)., Conclusions: Community-dwelling elderly individuals with high-normal thyroid function are at increased risk of all-cause and cardiovascular mortality, reinforcing the need of redefining the current reference ranges of thyroid function.

Background: Methylmalonic acid (MMA) is best known for its use as a functional marker of vitamin B12 deficiency. However, MMA concentrations not only depend on adequate vitamin B12 status, but also relate to renal function and endogenous production of propionic acid. Hence, we aimed to investigate to what extent variation in MMA levels is explained by vitamin B12 and eGFR and whether MMA levels are associated with mortality if vitamin B12 and eGFR are taken into account., Methods: A total of 1533 individuals (aged 60-75 years, 50% male) were included from the Lifelines Cohort and Biobank Study. Individuals were included between 2006 and 2013, and the total follow-up time was 8.5 years., Results: Median [IQR] age of the study population was 65 [62-69] years, 50% was male. At baseline, median MMA concentration was 170 [138-216] nmol/L, vitamin B12 290 [224-362] pmol/L, and eGFR 84 [74-91] mL/min/1.73 m2. Log 2 vitamin B12, log 2 eGFR, age, and sex were significantly associated with log 2 MMA in multivariable linear regression analyses (model R 2  = 0.22). After a total follow-up time of 8.5 years, 72 individuals had died. Log 2 MMA levels were significantly associated with mortality (hazard ratio [HR] 1.67 [95% CI 1.25-2.22], P < 0.001). Moreover, we found a significant interaction between MMA and eGFR with respect to mortality (P interaction  < 0.001)., Conclusions: Only 22% of variation in MMA levels was explained by vitamin B12, eGFR, age, and sex, indicating that a large part of variation in MMA levels is attributable to other factors (e.g., catabolism, dietary components, or gut microbial production). Higher MMA levels are associated with an increased risk for mortality, independent of vitamin B12, eGFR, and sex. This association was more pronounced in individuals with impaired renal function.

C-peptide measurement may represent a better index of pancreatic β-cell function compared to insulin. While insulin is mainly cleared by liver, C-peptide is mainly metabolized by kidneys. The aim of our study was to evaluate the association between baseline plasma C-peptide level and the development of type 2 diabetes independent of glucose and insulin levels and to examine potential effect-modification by variables related to kidney function. We included 5176 subjects of the Prevention of Renal and Vascular End-Stage Disease study without type 2 diabetes at baseline. C-peptide was measured in plasma with an electrochemiluminescent immunoassay. Cox proportional hazards regression was used to evaluate the association between C-peptide level and type 2 diabetes development. Median C-peptide was 722 (566-935) pmol/L. During a median follow-up of 7.2 (6.0-7.7) years, 289 individuals developed type 2 diabetes. In multivariable-adjusted Cox regression models, we observed a significant positive association of C-peptide with the risk of type 2 diabetes independent of glucose and insulin levels (hazard ratio (HR): 2.35; 95% confidence interval (CI): 1.49-3.70). Moreover, we found significant effect modification by hypertension and albuminuria ( p < 0.001 and p = 0.001 for interaction, respectively), with a stronger association in normotensive and normo-albuminuric subjects and absence of an association in subjects with hypertension or albuminuria. In this population-based cohort, elevated C-peptide levels are associated with an increased risk of type 2 diabetes independent of glucose, insulin levels, and clinical risk factors. Elevated C-peptide level was not independently associated with an increased risk of type 2 diabetes in individuals with hypertension or albuminuria.

Socioeconomic health inequalities are an important global public health problem. However, it is not well known to what extent socioeconomic inequalities culminate in impaired vitamin status and whether this is mediated by diet. We, therefore, aimed to assess vitamin status in a population already at increased risk of micronutrient deficiency, i.e., elderly with high and low socioeconomic status (SES), and to investigate whether potential differences therein were mediated by diet quality. Vitamin status in 1605 individuals (60-75 years) from the Lifelines- Micronutrients and Health inequalities in Elderly (MINUTHE) Study was assessed by measuring folic acid and the vitamins B6, B12, D, A, E, and K. Multinomial logistic and linear regression analyses were applied to test the associations between SES and vitamin status. Mediation analysis was used to explore the interrelationship between SES, diet quality, and vitamin status. Low SES was associated with poorer status of vitamin B6, vitamin B12, and, notably, folic acid. Moreover, multivitamin deficiencies were more prevalent in the low SES group. Diet quality was found to mediate the associations of SES with folic acid (for 39.1%), vitamin B6 (for 37.1%), and vitamin B12 (for 37.2%). We conclude that low SES is a risk factor for a spectrum of vitamin deficiencies. Diet quality can partially explain the socioeconomic differences in vitamin status, suggesting that policymakers can mitigate socioeconomic inequality in nutritional status through improving diet quality.

Objective: To evaluate associations of high-sensitivity cardiac troponin-T (cTnT) with cardiovascular disease (CVD), heart failure (HF), and mortality in community-dwelling women and men., Participants and Methods: A total of 8226 adults from the Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort (1997-1998) were enrolled in a prospective observational study (mean age: 49 years; 50.2% women). Sex-specific associations of cTnT levels with future clinical outcomes were evaluated using adjusted Cox-regression models., Results: Measurable cTnT levels (≥3 ng/L) were detected in 1102 women (26.7%) and in 2396 men (58.5%). Baseline cTnT levels were associated with a greater risk of developing CVD in women than men [Hazard ratio (HR women ), 1.48 per unit increase in log 2 -cTnT; 95% CI, 1.21 to 1.81 vs HR men , 1.20; 95% CI, 1.07 to 1.35; P interaction <.001]. Similar sex-related differences were observed for HF (P interaction = .005) and mortality (P interaction = .008). Further, compared with referent category (cTnT <3 ng/L), women with cTnT levels greater than or equal to 6 ng/L had a significantly increased risk for CVD (HR, 2.30; 95% CI, 1.45 to 3.64), HF (HR, 2.86; 95% CI, 1.41 to 5.80), and mortality (HR, 2.65; 95% CI, 1.52 to 4.61), whereas men with cTnT levels greater than or equal to 6 ng/L had a significantly increased risk only for CVD (HR, 1.51; 95% CI, 1.07 to 2.13)., Conclusion: Baseline cTnT levels were associated with future CVD, HF, and mortality in both sexes, and these associations were stronger in women. Future studies are needed to determine the value of cTnT in early diagnosis of CVD, particularly in women., (Copyright © 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background Moderate alcohol consumption has been associated with a lower risk of cardiovascular disease (CVD) and all-cause mortality compared with heavy drinkers and abstainers. To date, studies have relied on self-reported consumption, which may be prone to misclassification. Urinary ethyl glucuronide (EtG) is an alcohol metabolite and validated biomarker for recent alcohol consumption. We aimed to examine and compare the associations of self-reported alcohol consumption and EtG with CVD and all-cause mortality. Methods and Results In 5676 participants of the PREVEND (Prevention of Renal and Vascular End-Stage Disease) study cohort, EtG was measured in 24-hour urine samples and alcohol consumption questionnaires were administered. Participants were followed up for occurrence of first CVD and all-cause mortality. Cox proportional hazards regression models, adjusted for age, sex, and CVD risk factors, were fitted for self-reported consumption, divided into 5 categories: abstention, 1 to 4 units/month (reference), 2 to 7 units/week, 1 to 3 units/day, and ≥4 units/day. Similar models were fitted for EtG, analyzed as both continuous and categorical variables. Follow-up times differed for CVD (8 years; 385 CVD events) and all-cause mortality (14 years; 724 deaths). For both self-reported alcohol consumption and EtG, nonsignificant trends were found toward J-shaped associations between alcohol consumption and CVD, with higher risk in the lowest (hazard ratio for abstention versus 1-4 units/month, 1.42; 95% CI, 1.02-1.98) and highest drinking categories (hazard ratio for ≥4 units/day versus 1-4 units/month, 1.11; 95% CI, 0.68-1.84). Neither self-report nor EtG was associated with all-cause mortality. Conclusions Comparable associations with CVD events and all-cause mortality were found for self-report and EtG. This argues for the validity of self-reported alcohol consumption in epidemiologic research.

High concentrations of high-density lipoprotein (HDL) cholesterol are likely associated with a lower risk of posttransplantation diabetes mellitus (PTDM). However, HDL particles vary in size and density with yet unestablished associations with PTDM risk. The aim of our study was to determine the association between different HDL particles and development of PTDM in renal transplant recipients (RTRs). We included 351 stable outpatient adult RTRs without diabetes at baseline evaluation. HDL particle characteristics and size were measured by nuclear magnetic resonance (NMR) spectroscopy. During 5.2 (IQR, 4.1‒5.8) years of follow-up, 39 (11%) RTRs developed PTDM. In multivariable Cox regression analysis, levels of HDL cholesterol (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.40-0.94 per 1SD increase; p = 0.024) and of large HDL particles (HR 0.68, 95% CI 0.50-0.93 per log 1SD increase; p = 0.017), as well as larger HDL size (HR 0.58, 95% CI 0.36-0.93 per 1SD increase; p = 0.025) were inversely associated with PTDM development, independently of relevant covariates including, age, sex, body mass index, medication use, transplantation-specific parameters, blood pressure, triglycerides, and glucose. In conclusion, higher concentrations of HDL cholesterol and of large HDL particles and greater HDL size were associated with a lower risk of PTDM development in RTRs, independently of established risk factors for PTDM development.

Whether the affinity of serum vitamin E with total lipids hampers the appropriate assessment of its association with age-related risk factors has not been investigated in epidemiological studies. We aimed to compare linear regression-derived coefficients of the association of non-indexed and total lipids-indexed vitamin E isoforms with clinical and laboratory characteristics pertaining to the lipid, metabolic syndrome, and one-carbon metabolism biological domains. We studied 1429 elderly subjects (non-vitamin supplement users, 60-75 years old, with low and high socioeconomic status) from the population-based LifeLines Cohort and Biobank Study. We found that the associations of tocopherol isoforms with lipids were inverted in total lipids-indexed analyses, which may be indicative of overcorrection. Irrespective of the methods of standardization, we consistently found positive associations of α-tocopherol with vitamins of the one-carbon metabolism pathway and inverse associations with characteristics related to glucose metabolism. The associations of γ-tocopherol were often opposite to those of α-tocopherol. These data suggest that tocopherol isoforms and one-carbon metabolism are related, with beneficial and adverse associations for α-tocopherol and γ-tocopherol, respectively. Whether tocopherol isoforms, or their interplay, truly affect the one-carbon metabolism pathway remains to be further studied.

Background: Acute kidney injury (AKI) is a common complication in patients during intensive care unit (ICU) admission. AKI is defined as an increase in serum creatinine (SCr) and/or a reduction in urine output. SCr is a marker of renal function with several limitations, which led to the search for biomarkers for earlier AKI detection. Our aim was to study the predictive value of plasma neutrophil gelatinase-associated lipocalin (NGAL) at admission as a biomarker for AKI progression during the first 48 h of ICU admission in an unselected, heterogeneous ICU patient population., Methods: We conducted a prospective observational study in an academic tertiary referral ICU population. We recorded AKI progression in all ICU patients during the first 48 h of ICU admission in a 6-week period. Plasma NGAL was measured at admission but levels were not reported to the attending clinicians. As possible predictors of AKI progression, pre-existing AKI risk factors were recorded. We examined the association of clinical parameters and plasma NGAL levels at ICU admission with the incidence and progression of AKI within the first 48 h of the ICU stay., Results: A total of 361 patients were included. Patients without AKI progression during the first 48 h of ICU admission had median NGAL levels at admission of 115 ng/mL [interquartile range (IQR) 81-201]. Patients with AKI progression during the first 48 h of ICU admission had median NGAL levels at admission of 156 ng/mL (IQR 97-267). To predict AKI progression, a multivariant model with age, sex, diabetes mellitus, body mass index, admission type, Acute Physiology and Chronic Health Evaluation score and SCr at admission had an area under the receiver operating characteristics (ROC) curve of 0.765. Adding NGAL to this model showed a small increase in the area under the ROC curve to 0.783 (95% confidence interval 0.714-0.853)., Conclusions: NGAL levels at admission were higher in patients with progression of AKI during the first 48 h of ICU admission, but adding NGAL levels at admission to a model predicting this AKI progression showed no significant additive value., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Observational studies suggest that high dairy intake is associated with a lower blood pressure (BP)., Objective: We aimed to investigate the effect of a high-dairy diet (HDD) as compared with a low-dairy diet (LDD) on BP in overweight middle-aged adults., Methods: Fifty-two overweight men and women were included in a randomized crossover intervention study. Each subject consumed 2 isocaloric diets for 6 wk, an LDD (≤1 dairy portion per day) and an HDD (6 or 5 reduced-fat dairy portions for men and women, respectively), with a 4-wk washout period in between the diets during which the subjects consumed their habitual diet. BP was measured at the start and at the end of the intervention diets. The effect of the intervention study was evaluated by 2-sample t tests. Mixed-model analyses were used for adjustment for the potential influence of changes in dietary protein and mineral intake and risk factors for hypertension including body weight and plasma cholesterol., Results: Consumption of an HDD as compared with an LDD resulted in a reduction of both systolic BP (mean ± SD: 4.6 ± 11.2 mm Hg, P < 0.01) and diastolic BP (3.0 ± 6.7 mm Hg, P < 0.01). In further analyses, these reductions appeared dependent on the concomitant increase in calcium intake., Conclusions: This intervention study shows that an HDD results in a reduction of both systolic and diastolic BP in overweight middle-aged men and women. If the results of our study are reproduced by other studies, advice for high dairy intake may be added to treatment and prevention of high BP. This trial was registered at trialregister.nl as NTR4899., (Copyright © American Society for Nutrition 2019.)

Background: Folate functions as an enzyme co-factor within the one-carbon metabolic pathway, providing key metabolites required for DNA synthesis and methylation. Hence, insufficient intake of folate can negatively affect health. As correct interpretation of folate status is dependent on a well-established reference interval, we set out to perform a new estimation following the restandardization of the Roche folate assay against the international folate standard., Materials and Methods: The folate reference interval was estimated using samples obtained from the Dutch population-based Lifelines cohort. The reference interval was estimated using two methods: a nonparametric estimation combined with bootstrap resampling and by fitting the data to a gamma distribution. The lower reference limit was verified in a patient cohort by combined measurement of folate and homocysteine., Results: Dependent on the method used for estimation and in- or exclusion of individuals younger than 21 years of age, the lower reference limit ranged from 6.8 to 7.3 nmol/L and the upper reference limit ranged from 26 to 38.5 nmol/L. Applying a lower reference limit of 7.3 nmol/L resulted in the following percentage of folate deficiencies over a period of 12 months: general practitioner 15.5% (IQR 4.0%), general hospital 12.8% (IQR 5.3%), academic hospital 9.6% (IQR 4.3%)., Conclusions: We estimated the folate reference interval in the Dutch general population which is not affected by a folic acid fortification program and verified the obtained lower reference limit by homocysteine measurements. Based on our results, we propose a folate reference interval independent of age of 7.3-38.5 nmol/L.

Background: Low circulating magnesium (Mg) is associated with an increased risk of developing type 2 diabetes mellitus (T2DM). We aimed to study the performance of a nuclear magnetic resonance (NMR)-based assay that quantifies ionized Mg in EDTA plasma samples and prospectively investigate the association of Mg with the risk of T2DM., Methods: The analytic performance of an NMR-based assay for measuring plasma Mg was evaluated. We studied 5747 subjects free of T2DM at baseline in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study., Results: Passing⁻Bablok regression analysis, comparing NMR-measured ionized Mg with total Mg measured by the Roche colorimetric assay, produced a correlation of r = 0.90, with a slope of 1.08 (95% CI: 1.00⁻1.13) and an intercept of 0.02 (95% CI: -0.02⁻0.08). During a median follow-up period of 11.2 (IQR: 7.7⁻12.0) years, 289 (5.0%) participants developed T2DM. The association of NMR-measured ionized Mg with T2DM risk was modified by sex (P interaction = 0.007). In women, we found an inverse association between Mg and the risk of developing T2DM, independent of adjustment for potential confounders (HR: 1.80; 95% CI: 1.20⁻2.70). In men, we found no association between Mg and the risk of developing T2DM (HR: 0.90; 95%: 0.67⁻1.21)., Conclusion: Lower NMR-measured plasma ionized Mg was independently associated with a higher risk of developing T2DM in women, but not in men., Competing Interests: E.J.J., I.S., J.D.O., and M.A.C. are employees of LabCorp.

Background: Previous studies have reported low circulating concentrations of pyridoxal-5-phospate (PLP) in renal transplant recipients (RTRs). It is unknown whether this is because of low intake or altered handling, and it is also unknown whether variation in circulating concentrations of PLP influences long-term outcome. Objective: We compared vitamin B-6 intake and circulating PLP concentrations of RTRs with those of healthy controls and investigated long-term clinical implications of vitamin B-6 deficiency in stable outpatient RTRs. Design: In a longitudinal cohort of 687 stable RTRs (57% male; mean ± SD age: 53 ± 13 y) with a median (IQR) follow-up of 5.3 y (4.8-6.1 y) and 357 healthy controls (47% male; age 54 ± 11 y), baseline vitamin B-6 was measured as plasma PLP by high-performance liquid chromatography (HPLC). Vitamin B-6 deficiency was defined as PLP <20 nmol/L, and insufficiency as PLP 20-30 nmol/L. Dietary intake was assessed by validated food-frequency questionnaires. Results: At inclusion [5.3 y (1.8-12.1 y) after transplantation], the mean vitamin B-6 intakes in RTRs and healthy controls were 1.77 ± 0.49 and 1.85 ± 0.56 mg/d, respectively ( P = 0.23). In these groups, the median plasma PLP concentrations were 29 nmol/L (17-50 nmol/L) and 41 nmol/L (29-60 nmol/L), respectively ( P < 0.001). Accordingly, deficiency was present in 30% of RTRs compared with 11% of healthy controls. PLP concentrations were inversely associated with glucose homeostasis variables and inflammation variables (all P < 0.01). During follow-up, 149 (21%) RTRs died and 82 (12%) developed graft failure. In RTRs, vitamin B-6 deficiency was associated with considerably higher mortality risk (HR 2.14; 95% CI: 1.48, 3.08) than a sufficient vitamin B-6 status, independent of potential confounders. No associations were observed for graft failure ( P = 0.18). Conclusions: Vitamin B-6 deficiency is common in RTRs and does not seem to be a consequence of inadequate intake. In addition, this deficient state is clinically relevant and independently associated with an increased risk of mortality in RTRs. The cohort on which the study was based [TransplantLines Food and Nutrition Biobank and Cohort Study (TxL-FN)] was registered at clinicaltrials.gov as NCT02811835., (© 2017 American Society for Nutrition.)

Objective: Both hypokalemia and hyperkalemia are associated with disease progression in patients with chronic kidney disease (CKD). It is unclear whether similar associations are present in the general population. Our aim was to examine the association of plasma potassium with risk of developing CKD and the role of diuretics in this association in a population-based cohort., Research Design and Methods: We studied 5,130 subjects free of CKD at baseline of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, a prospective, population-based cohort of Dutch men and women aged 28-75 years. Hypokalemia was defined as plasma potassium <3.5 mmol/L, and hyperkalemia as plasma potassium ≥5.0 mmol/L. Risk of CKD was defined as de novo development of eGFR <60 ml/min/1.73m2 and/or albuminuria >30 mg/24h., Results: Mean baseline plasma potassium was 4.4±0.3 mmol/L. The prevalences of hypokalemia and hyperkalemia were 0.5% and 3.8%, respectively; 3.0% of the subjects used diuretics. During a median follow-up of 10.3 years (interquartile range: 6.3-11.4 years), 753 subjects developed CKD. The potassium-CKD association was modified by diuretic use (Pinteraction = 0.02). Both hypokalemia without (HR, 7.74, 95% CI, 3.43-17.48) or with diuretic use (HR, 4.32, 95% CI, 1.77-10.51) were associated with an increased CKD risk as compared to plasma potassium 4.0-4.4 mmol/L without diuretic use. Plasma potassium concentrations ≥3.5 mmol/L were associated with an increased CKD risk among subjects using diuretics (Ptrend = 0.01) but not among subjects not using diuretics (Ptrend = 0.74)., Conclusion: In this population-based cohort, hypokalemia was associated with an increased CKD risk, regardless of diuretic use. In the absence of hypokalemia, plasma potassium was not associated with an increased CKD risk, except among subjects using diuretics.

Aims: Heart failure (HF) is a common manifestation of patients with primary and secondary causes of iron overload, whereas in patients with established HF iron deficiency impairs outcome. Whether iron stores, either depleted or in overload, amplify the risk for new-onset HF among healthy individuals is unknown. The present study aimed to assess whether markers of iron status or the iron-regulatory hormone hepcidin are associated with new-onset HF or cardiovascular (CV) events in the general population., Methods and Results: In 6386 subjects from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) trial, a prospective, community-based, cohort study, markers of iron status and the iron-regulatory hormone hepcidin were measured. Mean age was 53.1 ± 12.0 years, and 50.7% of the cohort was female. During a median follow-up of 8.3 (interquartile range 7.8-8.9) years, 199 subjects (3.1%) were newly diagnosed with HF, 456 (7.1%) experienced a CV event, and 356 (5.6%) died from all causes. A higher annual HF incidence per ferritin quartile was observed in women (P < 0.001), but not in men (P for interaction 0.032). Multivariable analyses demonstrated ferritin levels to remain independently predictive for new-onset HF in women only (P = 0.024). This association persisted within strata defined by markers of the metabolic syndrome, markers of inflammation, or other markers of iron homeostasis, including hepcidin. No association between ferritin or hepcidin and incident CV events or all-cause mortality was observed in either sex., Conclusions: Increased serum ferritin levels independently amplify the risk for new-onset HF in women in the community., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Anemia, iron deficiency anemia (IDA), and iron deficiency (ID) are highly prevalent in renal transplant recipients (RTR). Anemia is associated with poor outcome, but the role of ID is unknown. Therefore, we aimed to investigate the association of ID, irrespective of anemia, with all-cause mortality in RTR. Cox regression analyses were used to investigate prospective associations. In 700 RTR, prevalences of anemia, IDA, and ID were 34%, 13%, and 30%, respectively. During follow-up for 3.1 (2.7-3.9) years, 81 (12%) RTR died. In univariable analysis, anemia [HR, 1.72 (95%CI: 1.11-2.66), P = 0.02], IDA [2.44 (1.48-4.01), P < 0.001], and ID [2.04 (1.31-3.16), P = 0.001] were all associated with all-cause mortality. In multivariable analysis, the association of anemia with mortality became weaker after adjustment for ID [1.52 (0.97-2.39), P = 0.07] and disappeared after adjustment for proteinuria and eGFR [1.09 (0.67-1.78), P = 0.73]. The association of IDA with mortality attenuated after adjustment for potential confounders. In contrast, the association of ID with mortality remained independent of potential confounders, including anemia [1.77 (1.13-2.78), P = 0.01]. In conclusion, ID is highly prevalent among RTR and is associated with an increased risk of mortality, independent of anemia. As ID is a modifiable factor, correction of ID could be a target to improve survival., (© 2016 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

Background: Bilirubin has anti-oxidative and anti-inflammatory properties, which may explain its proposed protective effects on the development of cardiometabolic disorders. Glucocorticoids affect heme oxygenase regulation in vitro, which plays a key role in bilirubin production. Effects of variations in glucocorticoid exposure on circulating bilirubin levels in humans are unknown. Here we tested whether a higher hydrocortisone replacement dose affects circulating bilirubin in hypopituitary patients., Materials and Methods: A randomized double-blind cross-over study (ClinicalTrials.gov, number NCT01546992) was performed in 47 patients with secondary adrenal failure [10-week exposure to a higher hydrocortisone dose (0·4-0·6 mg/kg body weight) vs. 10 weeks of a lower hydrocortisone dose (0·2-0·3 mg/kg body weight)]., Results: Plasma total bilirubin was increased by 10% from 7 to 8 μM in response to the higher hydrocortisone dose (P = 0·033). This effect was inversely related to age (P = 0·042), but was unaffected by sex, obesity and (replacement for) other hormonal insufficiencies. The higher hydrocortisone dose also resulted in lower alkaline phosphatase (P = 0·006) and aspartate aminotransferase activities (P = 0·001)., Conclusion: Bilirubin is modestly increased in response to higher glucocorticoid exposure in humans, in conjunction with lower alkaline phosphatase and aspartate aminotransferase activities, which are supposed to represent biomarkers of a pro-inflammatory state and enhanced liver fat accumulation., (© 2016 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been linked with an increased risk of type 2 diabetes, but their relationships with cardiovascular disease (CVD) are uncertain. We aimed to assess the associations of ALT and AST with CVD risk and determine their potential utility for CVD risk prediction., Methods: ALT and AST measurements were made at baseline in the PREVEND prospective cohort involving 6899 participants aged 28-75 years without pre-existing CVD., Results: During 10.5 years of follow-up, 729 CVD events were recorded. Serum aminotransferases were strongly correlated with each other and each weakly correlated with several cardiovascular risk markers. ALT and AST were each approximately log-linearly associated with CVD risk. In analyses adjusted for conventional risk factors, the hazard ratios (95% CIs) for CVD per 1 standard deviation increase in loge ALT and loge AST were 0.87 (0.79-0.94; P = 0.001) and 0.91 (0.84-0.98; P = 0.017) respectively. The associations remained consistent after additional adjustment for several potential confounders including alcohol consumption, fasting glucose, and C-reactive protein, with corresponding hazard ratios of 0.88 (0.80-0.96; P = 0.003) and 0.92 (0.84-0.99; P = 0.029). The inverse associations persisted within normal ranges of the aminotransferases. Adding ALT or AST to a CVD risk prediction model containing established risk factors did not improve the C-index or net reclassification., Conclusions: Available data suggest the liver aminotransferases are each inversely, independently, and approximately log-linearly associated with CVD risk. Nonetheless, they provide no significant improvement in CVD risk assessment beyond conventional CVD risk factors., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background and Aims: Hyponatremia has been associated with an increased mortality risk in the general population. Diabetes is a condition predisposing for elevated levels of arginine vasopressin (AVP) and heart failure, both common causes of hyponatremia. These factors, however, are also associated with an increased mortality risk. We aimed to investigate whether serum sodium is associated with cardiovascular and all-cause mortality in type 2 diabetes and whether these associations could be explained by copeptin, a surrogate for AVP, or NT-proBNP, a marker for heart failure., Methods: Patients with type 2 diabetes participating in the observational ZODIAC study were included. Cox regression analyses were used to investigate the association of serum sodium with mortality., Results: We included 1068 patients (age 67 ± 12 years, 45% male, serum sodium 142 ± 3 mmol/L). After 15 years of follow-up, 519 patients (49%) died, with 225 cardiovascular deaths (21%). In univariable analyses, serum sodium, copeptin, and NT-proBNP were all significantly associated with cardiovascular and all-cause mortality. These associations remained significant after combination of these markers in a multivariable model. Serum sodium and NT-proBNP remained significantly associated with mortality after further adjustment for potential confounders, whereas copeptin lost significance after adjustment for SCr and ACR., Conclusion: Low serum sodium was associated with an increased risk of cardiovascular and all-cause mortality in type 2 diabetes. Moreover, these associations were not explained by copeptin and NT-proBNP. Whether low serum sodium itself leads to poor outcome or is a marker for (unidentified) co-morbidity severity or use of specific medications remains to be elucidated., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Combined data suggest a bimodal association of alanine aminotransferase (ALT) with mortality in the general population. Little is known about the association of ALT with mortality in patients with type 2 diabetes. We therefore investigated the association of ALT with all-cause, cardiovascular and noncardiovascular mortality in patients with type 2 diabetes., Design: A prospective study was performed in patients with type 2 diabetes, treated in primary care, participating in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study. Cox regression analyses were performed to determine the associations of log2 -transformed baseline ALT with all-cause, cardiovascular and noncardiovascular mortality., Results: In 1187 patients with type 2 diabetes (67 ± 12 years, 45% female), ALT levels were 11 (8-16) U/L. During median follow-up for 11.1 (6.1-14.0) years, 553 (47%) patients died, with 238 (20%) attributable to cardiovascular causes. Overall, ALT was inversely associated with all-cause mortality (hazard ratio [HR] 0.81; 95% confidence interval [CI] 0.72-0.92), independently of potential confounders. This was less attributable to cardiovascular mortality (HR 0.87; 95% CI 0.72-1.05), than to noncardiovascular mortality (HR 0.77; 95% CI 0.65-0.90). Despite the overall inverse association of ALT with mortality, it appeared that a bimodal association with all-cause mortality was present with increasing risk for levels of ALT above normal (P = 0.003)., Discussion: In patients with type 2 diabetes, low levels of ALT are associated with an increased risk of all-cause mortality, in particular noncardiovascular mortality, compared to normal levels of ALT, while risk again starts to increase when levels are above normal., (© 2015 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Alkaline phosphatase (ALP) has been suggested to be associated with cardiovascular disease (CVD) risk, however, important aspects of the association, such as shape and independence from established risk factors, have yet to be characterized in detail. We assessed the association of ALP with CVD risk and determined its utility for CVD risk prediction., Methods: Alkaline phosphatase activity was measured at baseline in the PREVEND prospective cohort involving 6,974 participants aged 28-75 years without pre-existing CVD. Hazard ratios (95% confidence intervals [CI]) and measures of risk discrimination and reclassification were assessed., Results: During a median follow-up of 10.5 years, 737 participants developed CVD. Serum ALP was correlated with several risk markers for CVD, with strongest correlations for age (r = 0.30; P < 0.001), gamma-glutamyltransferase (r = 0.26; P < 0.001), and C-reactive protein (CRP) (r = 0.25; P < 0.001). There was a non-linear "J-shaped" relationship between ALP and CVD risk. In analyses adjusted for conventional risk factors, the hazard ratio (95% CI) for CVD in a comparison of the top quintile versus bottom quintiles 1-4 of ALP values was 1.34 (1.14 to 1.56; P<0.001), which persisted after additional adjustment for potential confounders 1.33 (1.13 to 1.55; P<0.001). However, the association was somewhat attenuated after adjustment for CRP 1.24 (1.05 to 1.45; P=0.009). Addition of information on ALP to a CVD risk prediction model containing established risk factors did not improve the C-index or net reclassification., Conclusions: Available evidence suggests a non-linear association between ALP activity and CVD risk, which is partly dependent on CRP. Taking account of conventional risk factors, additional information on ALP does not improve CVD risk assessment.

Background: Little is known about optimal protein intake after transplantation. The aim of this study was to prospectively investigate associations of urinary urea excretion, a marker for protein intake, with graft failure and mortality in renal transplant recipients (RTR) and potential effect modification by body mass index (BMI) and estimated glomerular filtration rate (eGFR)., Methods: Urinary urea excretion was measured in repeated 24-hr urine collections between 6 and 18 months after transplantation., Results: In total, 940 RTR were included. During 4.4 (2.3-7.8) years of follow-up for graft failure and 4.8 (2.5-8.3) years for all-cause mortality, 78 RTR developed graft failure and 158 RTR died. Urinary urea excretion was not associated with graft failure in the overall population, but was inversely associated with graft failure in RTR with BMI less than 25 kg/m (hazard ratio [HR], 0.64 [0.28-1.50] and 0.27 [0.09-0.83] for the second and third tertiles, respectively, P < 0.001), and in RTR with eGFR of 45 mL per min per 1.73 m or higher (HR, 0.34 [0.15-0.79], P = 0.015 and HR, 0.31 [0.11-0.86], P = 0.025 for the second and third tertiles, respectively), both independent of potential confounders. Compared to the first tertile, RTR in the second and third tertiles of urinary urea excretion were at a lower risk of all-cause mortality (HR, 0.47 [0.32-0.69]; P < 0.001 and HR, 0.42 [0.26-0.68]; P < 0.001, respectively), independent of potential confounders. Body mass index and eGFR did not influence this association., Conclusion: Urinary urea excretion, a marker for protein intake, was inversely related to graft failure in RTR with BMI less than 25 kg/m and in RTR with an eGFR of 45 mL per min per 1.73 m or higher. In addition, urinary urea excretion was inversely related to mortality.

Background: The value of measuring levels of gamma glutamyltransferase (GGT) for the prediction of first cardiovascular events is uncertain. We aimed to determine whether adding information on GGT values to conventional cardiovascular risk factors is associated with improvement in prediction of CVD risk., Methods: Circulating GGT levels were measured at baseline in the PREVEND prospective cohort study. We included 6969 participants without a prevalent history of CVD. Hazard ratios (95% confidence intervals [CI]) and measures of risk discrimination for CVD outcomes (e.g., C-index) and reclassification (i.e., net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5%to <7.5%), and high (≥7.5%) risk were assessed., Results: During a median follow-up of 10.5 years, 735 incident CVD events were recorded. Loge GGT was linearly associated with CVD risk. In analyses adjusted for conventional plus several potential cardiovascular risk factors, the hazard ratio (95% CI) for CVD per 1 standard deviation increase in loge GGT was 1.24 (1.12-1.37; P < 0.001), which was attenuated somewhat after further adjustment for C-reactive protein 1.18 (1.06-1.30; P = 0.002). Addition of information on GGT to a CVD risk prediction model containing conventional risk factors was associated with a C-index change of 0.0003 (-0.0015 to 0.0022; P = 0.73) and a net reclassification improvement of 1.19% (-0.11-2.49%; P = 0.07) for the categories of predicted 10-year CVD risk., Conclusions: In the general population, adding GGT to conventional CVD risk factors is unlikely to improve prediction of first-ever cardiovascular events., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Not all obese subjects have an adverse metabolic profile predisposing them to developing type 2 diabetes or cardiovascular disease. The BioSHaRE-EU Healthy Obese Project aims to gain insights into the consequences of (healthy) obesity using data on risk factors and phenotypes across several large-scale cohort studies. Aim of this study was to describe the prevalence of obesity, metabolic syndrome (MetS) and metabolically healthy obesity (MHO) in ten participating studies., Methods: Ten different cohorts in seven countries were combined, using data transformed into a harmonized format. All participants were of European origin, with age 18-80 years. They had participated in a clinical examination for anthropometric and blood pressure measurements. Blood samples had been drawn for analysis of lipids and glucose. Presence of MetS was assessed in those with obesity (BMI ≥ 30 kg/m2) based on the 2001 NCEP ATP III criteria, as well as an adapted set of less strict criteria. MHO was defined as obesity, having none of the MetS components, and no previous diagnosis of cardiovascular disease., Results: Data for 163,517 individuals were available; 17% were obese (11,465 men and 16,612 women). The prevalence of obesity varied from 11.6% in the Italian CHRIS cohort to 26.3% in the German KORA cohort. The age-standardized percentage of obese subjects with MetS ranged in women from 24% in CHRIS to 65% in the Finnish Health2000 cohort, and in men from 43% in CHRIS to 78% in the Finnish DILGOM cohort, with elevated blood pressure the most frequently occurring factor contributing to the prevalence of the metabolic syndrome. The age-standardized prevalence of MHO varied in women from 7% in Health2000 to 28% in NCDS, and in men from 2% in DILGOM to 19% in CHRIS. MHO was more prevalent in women than in men, and decreased with age in both sexes., Conclusions: Through a rigorous harmonization process, the BioSHaRE-EU consortium was able to compare key characteristics defining the metabolically healthy obese phenotype across ten cohort studies. There is considerable variability in the prevalence of healthy obesity across the different European populations studied, even when unified criteria were used to classify this phenotype.

Background: As yet little is known about the effect of delayed separation of whole blood stored at room temperature on the stability of the kidney function markers creatinine and cystatin C., Methods: We used plasma samples of 45 patients with a wide range of creatinine and cystatin C concentration. Samples were sent by post as whole blood, and differences in creatinine and cystatin C concentrations when measured (by enzymatic assay and PETIA, respectively) in plasma separated shortly after blood withdrawal or in plasma obtained after delayed separation at 24, 48 and 72 h. Intra- and inter-assay variability was assessed and total change limit was calculated to assess analyte stability., Results: Total change limit was 3.3% for creatinine and 3.9% for cystatin C. In whole blood creatinine and cystatin C remained stable up to 48 h. Delayed separation of whole blood did not induce more variability in measured concentrations of both analytes. Glomerular filtration rate estimated with the CKD-EPI equations showed less than 3 mL/min/1.73 m² difference when using creatinine or cystatin C concentration measured in plasma separated up to 48 h after blood withdrawal compared to plasma separated shortly after blood withdrawal. The new CKD-EPI equation that uses creatinine as well as cystatin C to estimate GFR showed even at 72 h less than 3 mL/min/1.73 m² difference., Conclusions: Creatinine and cystatin C remain stable in whole blood stored at room temperature up to 48 h before separation, and changes in these analytes during this time period do not affect variability and eGFR., (© 2013.)

Observational studies on dietary or circulating magnesium and risk of hypertension have reported weak-to-modest inverse associations, but have lacked measures of actual dietary uptake. Urinary magnesium excretion, an indicator of intestinal magnesium absorption, may provide a better insight in this association. We examined 5511 participants aged 28 to 75 years free of hypertension in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, a prospective population-based cohort study. Circulating magnesium was measured in plasma and urinary magnesium in two 24-hour urine collections, both at baseline. Incident hypertension was defined as blood pressure ≥140 mm Hg systolic or ≥90 mm Hg diastolic, or initiation of antihypertensive medication. During a median follow-up of 7.6 years (interquartile range, 5.0-9.3 years), 1172 participants developed hypertension. The median urinary magnesium excretion was 3.8 mmol/24 hour (interquartile range, 2.9-4.8 mmol/24 hour). Urinary magnesium excretion was associated with risk of hypertension in an inverse log-linear fashion, and this association remained after adjustment for age, sex, body mass index, smoking status, alcohol intake, parental history of hypertension, and urinary excretion of sodium, potassium, and calcium. Each 1-unit increment in ln-transformed urinary magnesium excretion was associated with a 21% lower risk of hypertension after multivariable adjustment (adjusted hazard ratio, 0.79; 95% confidence interval, 0.71-0.88). No associations were observed between circulating magnesium and risk of hypertension. In conclusion, in this cohort of men and women, urinary magnesium excretion was inversely associated with risk of hypertension across the entire range of habitual dietary intake.

The cytochrome P450 enzymes (CYP) 2C19 and 2D6 are involved in the metabolism of many psychotropic drugs. Variability in enzyme activity results in variable metabolic capacities, affecting the metabolism of substrates. The metabolic ratio (MR) of drugs metabolized via these enzymes may therefore reflect the enzyme's activity and/or genotype. To serve as an example for different groups of medications, the selective serotonin reuptake inhibitor venlafaxine, the tricyclic antidepressant amitriptyline, and the antipsychotic risperidone were studied to examine a possible correlation between the MRs of these drugs and the CYP2C19 and/or CYP2D6 genotype. For this purpose data from routine genotyping and serum level analysis were used. The relationships between the observed metabolic ratios and CYP2D6 and/or CYP2C19 genotype were characterized using nonparametric statistical analysis. A clear correlation was observed between the CYP2D6 genotype and the metabolic ratio of venlafaxine. Genotyping of individuals with a log(MR) < -0.6 or a log(MR) > 0.2 would include all patients with an aberrant genotype but would result in a reduction of 52% of genotyping reactions. Slow metabolism of amitriptyline is correlated with a log(MR) > 0.4. Genotyping only those subjects with a log(MR) > 0.4 would result in 88% fewer genotyping reactions. For risperidone, genotyping individuals with a log(MR) > 0.4 would include all CYP2D6 poor metabolizers while reducing the number of genotyping reactions by 93%. According to these data, correlations exist between the log(MR) of venlafaxine, amitriptyline, and risperidone and the genotype of the CYP enzymes involved in their metabolism. From the ranges of log(MR) defined here, a high percentage of aberrant metabolizers can be detected even when patients are not routinely genotyped. Thus, the metabolic ratio may serve as an indication of when genotyping should be considered.

Background: The atypical antipsychotic drug clozapine is metabolized by CYP1A2. The activity of CYP1A2 is highly variable and is among others dependent on smoking habits. Certain genotypes of CYP1A2 have been associated with increased inducibility/activity of CYP1A2. However, the relevance of genotyping for these mutations in a clinical setting has not yet been demonstrated., Methods: In this study, the CYP1A2 *1F, *1C and *1D genotypes of 58 schizophrenic patients on clozapine treatment were correlated with clozapine serum concentrations corrected for dose and weight or concentration/dosage ratios., Results: The allele frequency of *1F and *1D was 67% and 6%, respectively. With an allele frequency of 1%, the occurrence of *1C was very low. Multivariate analysis of variance did not reveal any significant correlations between CYP1A2 genotypes and clozapine clearance in these subjects, although a possible effect of the *1D allele cannot be excluded in this study., Conclusion: Although this study was performed using samples from a limited number of patients, routine genotyping of CYP1A2 *1F, *1C or *1D polymorphisms for their effect on metabolic capacity is, at least in Caucasians, not yet indicated.