Kidney function measures and cardiovascular outcomes in people with diabetes: the Hoorn Diabetes Care System cohort.

AIMS/HYPOTHESIS: Both manifestations of kidney disease in diabetes, reduced eGFR (ml/min per 1.73 m2) and increased urinary albumin/creatinine ratio (UACR, mg/mmol), may increase the risk of specific CVD subtypes in adults with diabetes. METHODS: We assessed the prospective association between annually recorded measures of eGFR and UACR and the occurrence of myocardial infarction (MI), CHD, stroke, heart failure (HF) and cardiovascular mortality in 13,657 individuals with diabetes (53.6% male, age 62.3±12.1 years) from the Hoorn Diabetes Care System cohort, using data obtained between 1998 and 2018. Multivariate time-dependent Cox regression models adjusted for cardiovascular risk factors were used to estimate HRs and 95% CI. Associations of eGFR were adjusted for UACR values and vice versa. Effect modification by sex was investigated for all associations. RESULTS: After a mean follow-up period of 7 years, event rates per 1000 person-years were 3.08 for MI, 3.72 for CHD, 1.12 for HF, 0.84 for stroke and 6.25 for cardiovascular mortality. Mildly reduced eGFR (60-90 ml/min per 1.73 m2) and moderately to severely reduced eGFR (<59 ml/min per 1.73 m2) were associated with higher risks of MI (HR 1.52; 95% CI 1.10, 2.12 and HR 1.69; 95% CI 1.09, 2.64) and CHD (HR 1.67; 95% CI 1.23, 2.26 and HR 2.01; 95% CI 1.34, 3.02) compared with normal eGFR (>90 ml/min per 1.73 m2). Mildly reduced eGFR was associated with a higher risk of stroke (HR 2.53; 95% CI 1.27, 5.03). Moderately increased UACR (3-30 mg/mmol) and severely increased UACR (>30 mg/mmol) were prospectively associated with a higher cardiovascular mortality risk in men and women (HR 1.87; 95% CI 1.41, 2.47 and HR 2.78; 95% CI 1.78, 4.34) compared with normal UACR (<3 mg/mmol). Significant effect modification by sex was observed for the association between UACR and HF. Because there were a limited number of HF events within the category of UACR >30 mg/mmol, categories were combined into UACR <3.0 and >3.0 mg/mmol in the stratified analysis. Women but not men with UACR >3.0 mg/mmol had a significantly higher risk of HF compared with normal UACR (HR 2.79; 95% CI 1.47, 5.28). CONCLUSIONS/INTERPRETATION: This study showed differential and independent prospective associations between manifestations of early kidney damage in diabetes and several CVD subtypes, suggesting that regular monitoring of both kidney function measures may help to identify individuals at higher risk of specific cardiovascular events.

Alcohol consumption in relation to cardiovascular diseases and mortality: a systematic review of Mendelian randomization studies.

The causal effects of alcohol-in-moderation on cardiometabolic health are continuously debated. Mendelian randomization (MR) is an established method to address causal questions in observational studies. We performed a systematic review of the current evidence from MR studies on the association between alcohol consumption and cardiometabolic diseases, all-cause mortality and cardiovascular risk factors. We performed a systematic search of the literature, including search terms on type of design and exposure. We assessed methodological quality based on key elements of the MR design: use of a full instrumental variable analysis and validation of the three key MR assumptions. We additionally looked at exploration of non-linearity. We reported the direction of the studied associations. Our search yielded 24 studies that were eligible for inclusion. A full instrumental variable analysis was performed in 17 studies (71%) and 13 out of 24 studies (54%) validated all three key assumptions. Five studies (21%) assessed potential non-linearity. In general, null associations were reported for genetically predicted alcohol consumption with the primary outcomes cardiovascular disease (67%) and diabetes (75%), while the only study on all-cause mortality reported a detrimental association. Considering the heterogeneity in methodological quality of the included MR studies, it is not yet possible to draw conclusions on the causal role of moderate alcohol consumption on cardiometabolic health. As MR is a rapidly evolving field, we expect that future MR studies, especially with recent developments regarding instrument selection and non-linearity methodology, will further substantiate this discussion.

Magnesium intake and vascular structure and function: the Hoorn Study.

PURPOSE: Circulating and dietary magnesium have been shown to be inversely associated with the prevalence of cardiovascular disease (CVD) and mortality in both high and low-risk populations. We aimed to examine the association between dietary magnesium intake and several measures of vascular structure and function in a prospective cohort. METHODS: We included 789 participants who participated in the vascular screening sub-cohort of the Hoorn Study, a population-based, prospective cohort study. Baseline dietary magnesium intake was estimated with a validated food frequency questionnaire and categorised in energy-adjusted magnesium intake tertiles. Several measurements of vascular structure and function were performed at baseline and most measurements were repeated after 8 years of follow-up (n = 432). Multivariable linear and logistic regression was performed to study the cross-sectional and longitudinal associations of magnesium intake and intima-media thickness (IMT), augmentation index (Aix), pulse wave velocity (PWV), flow-mediated dilatation (FMD), and peripheral arterial disease (PAD). RESULTS: Mean absolute magnesium intake was 328 ± 83 mg/day and prior CVD and DM2 was present in 55 and 41% of the participants, respectively. Multivariable regression analyses did not demonstrate associations between magnesium intake and any of the vascular outcomes. Participants in the highest compared to the lowest magnesium intake tertile demonstrated in fully adjusted cross-sectional analyses a PWV of -0.21 m/s (95% confidence interval -1.95, 1.52), a FMD of -0.03% (-0.89, 0.83) and in longitudinal analyses an IMT of 0.01 mm (-0.03, 0.06), an Aix of 0.70% (-1.69, 3.07) and an odds ratio of 0.84 (0.23, 3.11) for PAD CONCLUSION: We did not find associations between dietary magnesium intake and multiple markers of vascular structure and function, in either cross-sectional or longitudinal analyses.

Fibroblast growth factor 23 and new-onset chronic kidney disease in the general population: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study.

BACKGROUND: Fibroblast growth factor 23 (FGF23), a phosphate-regulating hormone that increases early in the course of chronic kidney disease (CKD), is associated with disease progression in patients with established CKD. Here we aimed to investigate the association between plasma FGF23 and new-onset CKD in the general population. METHODS: We included 5253 individuals without CKD who participated in the Prevention of Renal and Vascular Endstage Disease study, a prospective, population-based cohort. Multi-variable Cox regression was used to study the association of plasma C-terminal FGF23 with new-onset CKD, defined as a combined endpoint of estimated glomerular filtration rate (eGFR) <60 mL/min/ 1.73 m2, urinary 24-h albumin excretion (UAE) >30 mg/24 h or both, or with all-cause mortality. RESULTS: The median baseline FGF23 was 68 [interquartile range (IQR) 56-85] RU/mL, eGFR was 95 ± 13 mL/min/1.73 m2 and UAE was 7.8 (IQR 5.8-11.5) mg/24 h. After follow-up of 7.5 (IQR 7.2-8.0) years, 586 participants developed CKD and 214 participants died. A higher FGF23 level was associated with new-onset CKD, independent of risk factors for kidney disease and parameters of bone and mineral homoeostasis {fully adjusted hazard ratio (HR) 1.25 [95% confidence interval (CI) 1.10-1.44] per doubling of FGF23; P = 0.001}. In secondary analyses, FGF23 was independently associated with new-onset eGFR <60 mL/min/1.73 m2 [adjusted HR 1.28 (95% CI 1.00-1.62); P = 0.048] or with UAE >30 mg/24 h [adjusted HR 1.24 (95% CI 1.06-1.45); P = 0.01] individually. A higher FGF23 level was also associated with an increased risk of all-cause mortality [fully adjusted HR 1.30 (95% CI 1.03-1.63); P = 0.03]. CONCLUSIONS: High FGF23 levels are associated with an increased risk of new-onset CKD and all-cause mortality in this prospective population-based cohort, independent of established CKD risk factors.

Combined low vitamin D and K status amplifies mortality risk: a prospective study.

OBJECTIVE: To explore the association of both plasma vitamin D and K concentrations with all-cause mortality, cardiovascular mortality, and cardiovascular events in the general population. METHODS: We studied 4742 participants of the Prevention of REnal and Vascular ENd-Stage Disease (PREVEND) Study. At baseline, vitamin D and K status was determined by measurement of 25-hydroxyvitamin D [25(OH)D] and dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP), respectively. Patients were categorized into: 25(OH)D < 50 or ≥ 50 nmol/L and dp-ucMGP < 361 or ≥ 361 pmol/L with 25(OH)D > 75 nmol/L and dp-ucMGP < 361 pmol/L as reference. Cause of death was coded according to International Classification of Diseases 9&10 codes from the 2001-2003 examination until date of death/event or censoring date (January 1st, 2017). RESULTS: Mean age was 52.6 ± 11.9 years and 2513 (53%) were female. During a median of 14.2 year follow-up, 620 participants died of which 142 were due to cardiovascular causes. Combined low vitamin D and K status was present in 970 participants (20%) and was associated with a greater risk of all-cause mortality compared to high vitamin D and high vitamin K status group (n = 1424) after adjusting for potential confounders: hazard ratio 1.46 (95% confidence intervals 1.12-1.90). We observed similar trends, albeit non-significant for cardiovascular mortality, and cardiovascular events: 1.42 (0.79-2.55), 1.28 (0.93-1.77), respectively. CONCLUSIONS: Combined low vitamin D and K status are associated with increased all-cause mortality risk and possibly with cardiovascular mortality and cardiovascular events compared with adequate vitamin D and K status. Future studies should investigate the effect of combined vitamin D and K supplementation on clinical outcomes.

The role of serum and dietary advanced glycation endproducts in relation to cardiac function and structure: The Hoorn Study.

BACKGROUND AND AIMS: This study aims to investigate the relationship of serum and dietary advanced glycation endproducts (AGEs) with cardiac function and structure after eight years of follow-up. METHODS AND RESULTS: We included 370 Hoorn Study participants (aged 66.4 ± 6.1, 47% women). Serum protein-bound AGEs [Nε-(carboxymethyl)lysine, Nε-(carboxyethyl)lysine, and pentosidine], as well as echocardiography to assess left atrium volume index (LAVI), left ventricle ejection fraction (LVEF), and left ventricle mass index (LVMI), were measured at baseline and after 8 years of follow-up. Dietary AGEs [Nε-(carboxymethyl)lysine and Nε-(carboxyethyl)lysine] were estimated at baseline with a validated food-frequency questionnaire and an AGEs database. Increased pentosidine [-1.4% (-2.6;-0.2)] and overall serum AGEs Z-scores over time [-2.1% (-3.8;-0.5)] were associated with decreased LVEF at follow-up, adjusted for confounders. Glucose metabolism status was an effect modifier (P-for-interaction = 0.04). In participants with impaired glucose metabolism, but not type 2 diabetes, increased pentosidine was associated with decreased LVEF [-4.2 (-8.0;-0.3)%]. Higher dietary Nε-(carboxyethyl)lysine [1.9 (0.1; 3.7)%] and overall dietary AGEs Z-scores [2.1 (0.1; 4.2)%] were associated with higher LVEF at follow-up. However, prior cardiovascular disease (CVD) was an effect modifier (P = 0.02). We found a stronger, non-significant, association of higher dietary (carboxyethyl)lysine with higher LVEF at follow-up in participants without CVD [2.3 (-0.1; 4.7)%] compared to participants with CVD [0.6 (-2.1; 3.4)%]. CONCLUSION: Overall serum AGEs were longitudinally associated with impaired systolic function. Future research should focus on including changes in dietary AGEs intake over time and the relation of dietary AGEs with cardiac measures needs to be established in intervention studies using low AGEs diets.

Natriuretic peptides for the detection of diastolic dysfunction and heart failure with preserved ejection fraction-a systematic review and meta-analysis.

BACKGROUND: An overview of the diagnostic performance of natriuretic peptides (NPs) for the detection of diastolic dysfunction (DD) and heart failure with preserved ejection fraction (HFpEF), in a non-acute setting, is currently lacking. METHODS: We performed a systematic literature search in PubMed and Embase.com (May 13, 2019). Studies were included when they (1) reported diagnostic performance measures, (2) are for the detection of DD or HFpEF in a non-acute setting, (3) are compared with a control group without DD or HFpEF or with patients with heart failure with reduced ejection fraction, (4) are in a cross-sectional design. Two investigators independently assessed risk of bias of the included studies according to the QUADAS-2 checklist. Results were meta-analysed when three or more studies reported a similar diagnostic measure. RESULTS: From 11,728 titles/abstracts, we included 51 studies. The meta-analysis indicated a reasonable diagnostic performance for both NPs for the detection of DD and HFpEF based on AUC values of approximately 0.80 (0.73-0.87; I2 = 86%). For both NPs, sensitivity was lower than specificity for the detection of DD and HFpEF: approximately 65% (51-85%; I2 = 95%) versus 80% (70-90%; I2 = 97%), respectively. Both NPs have adequate ability to rule out DD: negative predictive value of approximately 85% (78-93%; I2 = 95%). The ability of both NPs to prove DD is lower: positive predictive value of approximately 60% (30-90%; I2 = 99%). CONCLUSION: The diagnostic performance of NPs for the detection of DD and HFpEF is reasonable. However, they may be used to rule out DD or HFpEF, and not for the diagnosis of DD or HFpEF.

Modifiable lifestyle factors and heart failure: A Mendelian randomization study.

BACKGROUND: Lifestyle factors may be important targets in the prevention of heart failure. The current knowledge on the relationship between lifestyle factors and heart failure originates mostly from observational studies. The objective of this study was to investigate causal associations of multiple lifestyle factors with heart failure risk by using Mendelian randomization. METHODS: We obtained summary statistics data for single nucleotide polymorphisms associated with the following 5 lifestyle factors at genome-wide significance in genome-wide association studies of European-descent individuals: smoking, alcohol consumption, coffee consumption, physical activity, and sleep duration. The corresponding data for heart failure were acquired from a genome-wide association study comprising 47,309 cases and 930,014 controls of European ancestry. For the primary analyses, we used the inverse-variance weighted method. RESULTS: Genetic predisposition to smoking initiation (ever smoked regularly) was robustly associated with a higher odds of heart failure (odds ratio: 1.28; 99% CI: 1.21-1.35). Genetically predicted longer sleep duration was associated with a lower odds of heart failure (odds ratio per hour/day: 0.73; 99% CI: 0.60-0.89). We found no associations of alcohol consumption, coffee consumption, and physical activity with heart failure. CONCLUSIONS: This Mendelian randomization study showed that smoking initiation increases heart failure risk, whereas longer sleep duration decreases the risk of heart failure. Sleep duration should be regarded as novel risk factor in heart failure prevention guidelines. The potential causal role of alcohol and coffee consumption and physical activity for heart failure warrants further investigation in future larger Mendelian randomization analyses.

The Association of Vitamin D and Vitamin K Status with Subclinical Measures of Cardiovascular Health and All-Cause Mortality in Older Adults: The Hoorn Study.

BACKGROUND: A low vitamin D and K status has been associated with increased cardiovascular disease (CVD) risk but the evidence of their combined effect on cardiovascular health is limited. OBJECTIVES: Our study aimed to investigate the prospective association of vitamin D and K status with subclinical measures of cardiovascular health and all-cause mortality among a population of Dutch Caucasians. METHODS: We performed an observational prospective study on 601 participants of the Hoorn Study (mean ± SD age: 70 ± 6 y, 50.4% women, BMI: 27.2 ± 4.0 kg/m2), of whom 321 underwent an echocardiogram in 2000-2001 and 2007-2009. Vitamin D and K status was assessed at baseline by serum 25-hydroxyvitamin D [25(OH)D] and plasma desphospho-uncarboxylated matrix-gla protein (dp-ucMGP)-high concentrations indicate low vitamin K status. Vital status was assessed from baseline until 2018. We studied the association of categories of 25(OH)D (stratified by the clinical cutoff of 50 mmol/L) and dp-ucMGP (stratified by the median value of 568 pmol/L) with echocardiographic measures using linear regression and with all-cause mortality using Cox regression, adjusted for confounders. RESULTS: Compared with markers of normal vitamin D and K status, markers of low vitamin D and K status were prospectively associated with increased left ventricular mass index (5.9 g/m2.7; 95% CI: 1.8, 10.0 g/m2.7). Participants with low vitamin D and K status were also at increased risk of all-cause mortality with an HR of 1.64 (95% CI: 1.12, 2.39) compared with normal vitamin D and K status. CONCLUSIONS: A combination of low vitamin D and K status is associated with adverse cardiac remodeling and increased risk of all-cause mortality in men and women. Future studies should investigate whether vitamin D and K supplementation could help to improve cardiovascular health and to decrease CVD risk.

Joint association of vitamins D and K status with long-term outcomes in stable kidney transplant recipients.

BACKGROUND: Kidney transplant recipients (KTRs) experience substantial survival benefit compared with dialysis patients. However, their mortality and graft failure risk remain high. KTRs are often low in micronutrient status, including vitamins D and K. We investigated the association of both vitamins D and K status, and vitamin D treatment with all-cause mortality and death-censored graft failure. METHODS: We studied 461 KTRs from a single-centre study at median 6.1 years after transplantation. At baseline, vitamins D and K concentrations were measured by 25-hydroxyvitamin D [25(OH)D] and dephosphorylated uncarboxylated matrix gla protein (dp-ucMGP) and patients were categorized into: 25(OH)D <50/≥50 nmol/L and median dp-ucMGP <1057/≥1057 pmol/L. RESULTS: Mean age was 52 ± 12 years, and 122 KTRs (26%) had low vitamins D and K status. During median 9.8 years follow-up, 128 patients (28%) died and 48 (10%) developed death-censored graft failure. Low vitamins D and K status was associated with 2.33 (1.26-4.30) [hazard ratio (95% confidence interval)] increased mortality risk and 3.25 (1.17-9.08) increased graft failure risk compared with KTR with 25(OH)D ≥50 nmol/L and dp-ucMGP <1057 pmol/L. Dp-ucMGP was strongly associated with mortality (per 500 pmol/L increase): 1.41 (1.08-1.41) for vitamin D treatment versus no treatment 1.07 (0.97-1.18), and graft failure 1.71 (1.17-2.49) for vitamin D treatment versus 1.19 (1.05-1.36) no treatment, P-interaction <0.07 for vitamin D treatment (n = 44). CONCLUSIONS: Combined vitamins D and K deficiency are highly prevalent and are associated with increased mortality and graft failure risk compared with high vitamins D and K status. Low vitamin K status was strongly associated with an increased risk of premature mortality and graft failure for patients treated with vitamin D versus no vitamin D treatment.

High dephospho-uncarboxylated matrix Gla protein concentrations, a plasma biomarker of vitamin K, in relation to frailty: the Longitudinal Aging Study Amsterdam.

PURPOSE: No previous study has evaluated the relationship between vitamin K and frailty. Thus, we assessed the relationship between vitamin K status and frailty over 13 years in the Longitudinal Aging Study Amsterdam (LASA). METHODS: Prospective cohort study with 644 community-dwelling adults ≥ 55 years from the LASA cohort. In 2002-2003, plasma desphospho-uncarboxylated matrix Gla protein (dp-ucMGP) was measured as marker of vitamin K status through a sandwich ELISA. Frailty was measured at baseline and in four follow-up examinations with the LASA Frailty Index (LASA-FI), which was used as both a continuous and a dichotomous measure (FI ≥ 0.25), as indicator of the degree of frailty and frailty risk, respectively. Statistical analyses were performed with multivariable generalized estimating equations using the lowest dp-ucMGP tertile, reflecting a high vitamin K status, as reference. RESULTS: The mean (SD) age was 59.9 (2.9) years, and 54% were female. Compared with the lowest tertile, the medium and highest dp-ucMGP tertile were associated with a higher degree of frailty [1.40, 95% confidence interval (0.01-2.81) and 1.62, (0.18-3.06), respectively. P trend: 0.03]. Additionally, the medium and highest dp-ucMGP tertile had a higher odds ratio of frailty [1.75 (1.11-2.77) and 1.63 (1.04-2.57), respectively]. The degree of frailty increased over time, but the differences by dp-ucMGP tertiles existed since baseline and remained stable during follow-up. CONCLUSIONS: Baseline plasma low vitamin K status was associated with a greater degree of frailty and frailty risk in this cohort of older adults, which highlights the importance of ensuring an optimal nutritional status of this vitamin to prevent frailty in later life.

Moderate and heavy alcohol consumption are prospectively associated with decreased left ventricular ejection fraction: The Hoorn Study.

BACKGROUND AND AIMS: Data on the prospective relationship of alcohol consumption at more moderate levels with systolic and diastolic function are scarce. We aimed to examine the prospective association of alcohol consumption with echocardiographic measures of cardiac structure and function, in individuals with and without type 2 diabetes (T2DM). METHODS AND RESULTS: We included 778 participants from the Hoorn Study (aged 68.4 ± 7.2 years, 49% women), a population-based prospective cohort study, oversampled for people with impaired glucose metabolism or T2DM. Self-reported alcohol consumption was collected at baseline with a validated food-frequency questionnaire and categorized into: none (0/week), light (>0-≤30 g/week), light-to-moderate (>30-≤70 g/week), moderate (>70-≤140 g/week), and heavy drinkers (>140 g/week). Echocardiography was performed at baseline (N = 778) and after 8 years follow-up (N = 404). Multiple linear regression was used to study the association between alcohol consumption and echocardiographic measures (left ventricular ejection fraction (LVEF), left atrial volume index (LAVI) and left ventricular mass index (LVMI)), adjusted for confounders. Moderate and heavy alcohol consumption were associated with a decreased LVEF of -3.91% (CI: -7.13;-0.69) for moderate and -4.77% (-8.18;-1.36) for heavy drinkers compared to light drinkers. No associations were found between alcohol consumption, LVMI and LAVI. Modified Poisson regression showed a trend that higher alcohol consumption amounts were associated with a higher risk of incident systolic dysfunction (LVEF≤50%) (P-for-trend 0.058). CONCLUSION: The findings provide longitudinal evidence that moderate and heavy alcohol consumption are associated with decreased LVEF and trend towards a higher risk of incident LV systolic dysfunction, compared to light drinkers.

Urinary Ethyl Glucuronide Can Be Used as a Biomarker of Habitual Alcohol Consumption in the General Population.

BACKGROUND: Alcohol consumption is a frequently studied risk factor for chronic diseases, but many studies are hampered by self-report of alcohol consumption. The urinary metabolite ethyl glucuronide (EtG), reflecting alcohol consumption during the past 72 h, is a promising objective marker, but population data are lacking. OBJECTIVE: The objective of this study was to assess the reliability of EtG as a marker for habitual alcohol consumption compared with self-report and other biomarkers in the general population. METHODS: Among 6211 participants in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort, EtG concentrations were measured in 24-h urine samples. EtG was considered positive when concentrations were ≥100 ng/mL. Habitual alcohol consumption was self-reported by questionnaire (categories: no/almost never, 1-4 units per month, 2-7 units per week, 1-3 units per day or ≥4 units per day). Plasma HDL cholesterol concentration, erythrocyte mean corpuscular volume (MCV), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase (GGT) were determined as indirect biomarkers of alcohol consumption. Sensitivity, specificity, positive and negative predictive value, and proportions of agreement between reported consumption and EtG were calculated. To test the agreement of EtG concentration and alcohol consumption in categories, linear regression analysis was performed. In addition, the association between EtG concentrations and indirect biomarkers was analyzed. RESULTS: Mean age was 53.7 y, and 52.9% of participants men. Of the self-reported abstainers, 92.3% had an EtG concentration <100 ng/mL. Sensitivity was 66.3%, positive predictive value was 96.3%, and negative predictive value was 47.4%. The proportion of positive agreement was 78.5%, and the proportion of negative agreement was 62.7%. EtG concentrations were linearly associated with higher categories of alcohol consumption (P-trend < 0.001), adjusted for age, sex, and renal function. EtG was positively related to MCV, HDL cholesterol, and GGT but not to AST and ALT concentrations. CONCLUSIONS: This study shows that urinary EtG is in reasonable agreement with self-reported alcohol consumption and therefore can be used as an objective marker of habitual alcohol consumption in the general population.

Vitamin K Dependent Proteins in Kidney Disease.

Patients with chronic kidney disease (CKD) have an increased risk of developing vascular calcifications, as well as bone dynamics impairment, leading to a poor quality of life and increased mortality. Certain vitamin K dependent proteins (VKDPs) act mainly as calcification inhibitors, but their involvement in the onset and progression of CKD are not completely elucidated. This review is an update of the current state of knowledge about the relationship between CKD and four extrahepatic VKDPs: matrix Gla protein, osteocalcin, growth-arrest specific protein 6 and Gla-rich protein. Based on published literature in the last ten years, the purpose of this review is to address fundamental aspects about the link between CKD and circulating VKDPs levels as well as to raise new topics about how the interplay between molecular weight and charge could influence the modifications of circulating VKDPs at the glomerular level, or whether distinct renal etiologies have effect on VKDPs. This review is the output of a systematic literature search and may open future research avenues in this niche domain.

Prevention and treatment of hyperphosphatemia in chronic kidney disease.

Hyperphosphatemia has consistently been shown to be associated with dismal outcome in a wide variety of populations, particularly in chronic kidney disease (CKD). Compelling evidence from basic and animal studies elucidated a range of mechanisms by which phosphate may exert its pathological effects and motivated interventions to treat hyperphosphatemia. These interventions consisted of dietary modifications and phosphate binders. However, the beneficial effects of these treatment methods on hard clinical outcomes have not been convincingly demonstrated in prospective clinical trials. In addition, exposure to high amounts of dietary phosphate may exert untoward actions even in the absence of overt hyperphosphatemia. Based on this concept, it has been proposed that the same interventions used in CKD patients with normal phosphate concentrations be used in the presence of hyperphosphatemia to prevent rise of phosphate concentration and as an early intervention for cardiovascular risk. This review describes conceptual models of phosphate toxicity, summarizes the evidence base for treatment and prevention of hyperphosphatemia, and identifies important knowledge gaps in the field.

Association of Vitamin D Metabolites With Arterial Function in the Hemodialysis Fistula Maturation Study.

BACKGROUND: Disturbances in vitamin D metabolism are common in patients with end-stage renal disease and may contribute to vascular dysfunction. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: We evaluated 558 of 602 participants at baseline of the Hemodialysis Fistula Maturation (HFM) Study, a 7-center prospective cohort study of a cohort of patients with chronic kidney disease awaiting arteriovenous fistula (AVF) creation surgery. FACTOR: 4 vitamin D metabolites measured with liquid chromatography-tandem mass spectroscopy from samples obtained within 4 weeks prior to AVF surgery. OUTCOMES: Vasodilator functions and measurements of arterial stiffness. MEASUREMENTS: Trained HFM Study personnel measured brachial artery flow-mediated dilation, nitroglycerin-mediated dilation, and carotid-femoral and carotid-radial pulse wave velocities (PWVs) prior to AVF creation. We evaluated associations after basic adjustment for sex, age, and clinical site and more fully adjusted additionally for baseline education, smoking, body mass index, diabetes, dialysis status, and medication use. RESULTS: Mean participant age was 55±13 (SD) years and 65% were receiving maintenance dialysis. None of the vitamin D metabolites were significantly associated with flow-mediated dilation, carotid-femoral PWV, or carotid-radial PWV in basic or fully adjusted analyses. Higher serum concentrations of bioavailable vitamin D and 1,25-dihydroxyvitamin D were associated with 0.62% and 0.58% greater nitroglycerin-mediated dilation values, respectively, in basic models; however, these associations were no longer statistically significant with full adjustment. There were no significant associations of vitamin D metabolites with carotid-femoral or carotid-radial PWV in fully adjusted analyses. LIMITATIONS: Cross-sectional ascertainment of vitamin D metabolites and vascular functions late during the course of kidney disease. CONCLUSIONS: Serum concentrations of vitamin D metabolites are not associated with vasodilator functions or vascular stiffness at baseline in a cohort study of patients with chronic kidney disease awaiting AVF creation surgery. Laboratory measurements of vitamin D metabolites are unlikely to provide useful information regarding vascular functions in this setting.

Renal Clearance of Mineral Metabolism Biomarkers.

CKD leads to disturbances in multiple interrelated hormones that regulate bone and mineral metabolism. The renal handling of mineral metabolism hormones in humans is incompletely understood. We determined the single-pass renal clearance of parathyroid hormone, fibroblast growth factor 23, vitamin D metabolites, and phosphate from paired blood samples collected from the abdominal aorta and renal vein in 17 participants undergoing simultaneous right and left heart catheterization and estimated associations of eGFR with the renal elimination of metabolites. The mean age ±SD of the study population was 71.4±10.0 years and 11 participants (65%) were male. We found a relatively large mean±SD single-pass renal extraction of parathyroid hormone (44.2%±10.3%) that exceeded the extraction of creatinine (22.1%±7.9%). The proportionate renal extraction of parathyroid hormone correlated with eGFR. The renal extraction of fibroblast growth factor 23 was, on average, lower than that of parathyroid hormone with greater variability across individuals (17.1%±19.5%). There were no differences in the mean concentrations of vitamin D metabolites across the renal vein and artery. In summary, we demonstrate substantial single-pass renal extraction of parathyroid hormone at a rate that exceeds glomerular filtration. Impaired renal clearance of parathyroid hormone may contribute to secondary hyperparathyroidism in CKD.

[Determinants of vitamin D supplement use among community-dwelling older adults]. / Determinanten van vitamine D- gebruik door thuiswonende ouderen.

OBJECTIVE: We estimated the prevalence of vitamin D supplement use and determinants of vitamin D use in community-dwelling adults≥70 year. METHOD: In April 2013, in multiple cities in the Netherlands we determined the use of vitamin D supplements among 215 community-dwelling older adults. The questionnaire consisted of questions about demographics, knowledge about vitamin D, vitamin D use and reasons for (not) using vitamin D supplements. Vitamin D use is defined as self-reported vitamin D during at least part of the year. RESULTS: The mean age was 79±6.5 year and 63% was female. Self-reported -vitamin D supplement use was 28% among free-living older adults. Only 11 individuals (5%) used vitamin D as advised by the Dutch Health Council (20 µg per day). Logistic regression analyses indicated that women, adults with a higher education level and adults with multiple vitamin D related disorders/fractures were more prevalent vitamin D users. CONCLUSION: Despite the advice of the Dutch Health Council, the use of vitamin D supplements among free-living older adults≥70 year is very low. Older adults are not convinced of the benefits of using vitamin D supplements. The general practitioner could play a crucial role in providing information about vitamin D supplementation among older adults.

Parathyroid hormone and cardiovascular disease events: A systematic review and meta-analysis of prospective studies.

BACKGROUND: Parathyroid hormone (PTH) excess might play a role in cardiovascular health. We therefore conducted a systematic review and meta-analysis to evaluate the association between PTH and cardiovascular disease (CVD) events, and intermediate outcomes. METHODS: We conducted a systematic and comprehensive database search using MEDLINE and Embase between 1947 and October 2012. We included English-language prospective studies that reported risk estimates for PTH and CVD events, and intermediate outcomes. The characteristics of study populations, exposure, and outcomes of total CVD events, fatal and non-fatal CVD events were reported, and a quality assessment was conducted. Results were extracted for the highest versus lowest PTH concentrations, and meta-analyses were carried out using random effects models. RESULTS: The systematic literature search yielded 5770 articles, and 15 studies were included. Study duration ranged between 2 and 14 years. All studies were performed primarily in whites with a mean age between 55 and 75 years. The meta-analyses included 12 studies, of which 10 investigated total CVD events; 7, fatal CVD events; and 3, non-fatal CVD events. PTH excess indicated an increased risk for total CVD events: pooled HR (95% CI), 1.45 (1.24-1.71). The results for fatal CVD events and non-fatal CVD events were: HR 1.50 (1.18-1.91) and HR 1.48 (1.14-1.92). Heterogeneity was moderately present; however, sensitivity analyses for follow-up duration, prior CVD, or PTH as dichotomous values showed similar results. CONCLUSIONS: The meta-analysis indicates that higher PTH concentrations are associated with increased risk of CVD events.

Role of vitamin D in the development of insulin resistance and type 2 diabetes.

Vitamin D deficiency is mainly a consequence of insufficient sunlight induced vitamin D production in the skin and has been associated with various chronic diseases including type 2 diabetes. Experimental data have shown that vitamin D is important for glucose induced insulin secretion, improves insulin resistance, and exerts anti-inflammatory actions. Epidemiological studies have largely documented that a poor vitamin D status is associated with higher risk of insulin resistance and type 2 diabetes. The majority of randomized controlled trials (RCTs) in healthy or prediabetic individuals have, however, failed to demonstrate relevant vitamin D effects on insulin resistance or diabetes incidence. In patients with type 2 diabetes, a few RCTs reported some moderate effects of vitamin D on glycemic control and insulin resistance. While these findings warrant further in-depth studies, the current evidence is insufficient to recommend vitamin D supplementation for the prevention or treatment of type 2 diabetes.