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Polycyclic aromatic hydrocarbons (PAHs) are an organic chemical family produced during incomplete combustion of organic materials. Besides, PAHs are associated with different detrimental health effects. Therefore, this research was aimed to assess the association between PAHs exposure, metabolic syndrome (MetS) prevalence, and cardiovascular risk in a Mexican population. Urinary 1-hydroxypyrene (1-OHP) was the exposure biomarker quantified. MetS prevalence was defined using the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) and the International Diabetes Federation (IDF) criteria. Also, we used the atherogenic index of plasma (AIP) as a cardiovascular risk biomarker. The mean urinary 1-OHP level quantified was 2.50 ± 1.25 µmol/mol creatinine. The MetS prevalence found was 35% ( n  = 222) and 31% ( n  = 197) using NCEP ATP III and IDF criteria, respectively. The mean AIP value was 0.32 ± 0.15. Furthermore, the data analysis showed robust associations between PAH exposure (urinary 1-OHP concentrations), MetS prevalence, and cardiovascular risk (AIP). The real significance of the findings in this study needs to be clarified completely, as MetS and cardiovascular diseases represent a critical challenge in contaminated zones of developing countries such as Mexico.

Purpose of Review: The growing burden of cardiovascular diseases has become a significant concern in both adult and youth populations. Urinary biomarkers of kidney function could provide useful insights that may aid in the early identification of individuals at higher risk of adverse cardiovascular outcomes. This systematic review aimed to assess associations between urinary biomarkers of kidney function and different measures of cardiovascular health., Recent Findings: PubMed, Scopus, and EBSCOhost were searched for articles published between January 2018 and December 2023. Studies exploring associations between urinary kidney biomarkers (alpha-1 microglobulin (uA1M), neutrophil gelatinase-associated lipocalin (uNGAL), uromodulin (uUMOD) and CKD273 classifier) and measures of cardiovascular health (blood pressure and markers of target organ damage) were included. We identified 1186 articles, with 22 studies eligible for inclusion. Among 12 studies reporting associations between uA1M and measures of cardiovascular health, six studies indicated positive associations with office blood pressure and three studies observed associations with different markers of target organ damage. Out of the nine studies that explored the link between uUMOD and cardiovascular health parameters, four found negative associations between uUMOD and blood pressure. With regard to uNGAL, only two out of the seven studies analysed reported varying associations with blood pressure, while neither of the two studies focusing on CKD273 observed any statistically significant results. Biomarkers of kidney tubule function, represented by uA1M and uUMOD, are relevant in the setting of cardiovascular health and should be assessed for utilisation in clinical practice to identify adverse cardiovascular outcomes at an early stage allowing for timely intervention., Competing Interests: Declarations. Human and Animal Rights and Informed Consent: This article does not contain any studies with human or animal subjects performed by any of the authors. Conflict of Interest: The authors declare no competing interests., (© 2025. The Author(s).)

Objective: To analyze the relationship between 24-hour urinary calcium (24 h UCa) level and the risk of end-stage kidney disease (ESKD), cardiovascular disease (CVD), and all-cause mortality. Methods: In the Chinese Cohort Study of Chronic Kidney Disease, we examined 3 375 patients aged 18-74 years with CKD stages 1-4. Kaplan-Meier survival and Cox proportional hazard regression models were used to test a time-to-event association between levels of 24 h UCa and incidence of ESKD, CVD, and all-cause mortality. Results: During a follow-up of 4.17 (3.37, 5.20) years, 179, 145, 104 and 38 ESKD events occurred in <0.60, 0.60-, 1.20-, ≥2.32 mmol 24 h UCa groups. Higher levels of 24 h UCa (1.20-,≥2.32 mmol) were independently associated with a lower incidence of ESKD events in patients with CKD, with HR (95% CI ) of 0.71 (0.54-0.93) and 0.43 (0.29-0.64), respectively. No significant associations with CVD and all-cause mortality endpoints were detected. Conclusion: Among patients with CKD, levels of 24 h UCa displayed an association with the risk of ESKD among patients with CKD stages 1-4.

Background and Aims: Moderate wine consumption has been associated with lower cardiovascular disease (CVD) risk in older populations. However, wine consumption information through self-reports is prone to measurement errors inherent to subjective assessments. The aim of this study was to evaluate the association between urinary tartaric acid, an objective biomarker of wine consumption, and the rate of a composite clinical CVD event., Methods: A case-cohort nested study was designed within the PREDIMED trial with 1232 participants: 685 incident cases of CVD and a random subcohort of 625 participants (including 78 overlapping cases). Wine consumption was registered using validated food frequency questionnaires. Liquid chromatography-tandem mass spectrometry was used to measure urinary tartaric acid at baseline and after one year of intervention. Weighted Cox regression models were used to estimate hazard ratios (HRs) of CVD., Results: Tartaric acid was correlated with self-reported wine consumption at baseline [r = 0.46 (95% CI 0.41; 0.50)]. Five categories of post hoc urinary tartaric acid excretion were used for better representation of risk patterns. Concentrations of 3-12 and 12-35 μg/mL, which reflect ∼3-12 and 12-35 glasses/month of wine, were associated with lower CVD risk [HR 0.62 (95% CI 0.38; 1.00), P = .050 and HR 0.50 (95% CI 0.27; 0.95), P = .035, respectively]. Less significant associations between self-reported wine consumption and CVD risk were observed., Conclusions: Light-to-moderate wine consumption, measured through an objective biomarker (tartaric acid), was prospectively associated with lower CVD rate in a Mediterranean population at high cardiovascular risk., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: To test the hypothesis that the association of formula-estimated sodium intake from spot urine with cardiovascular disease is independent of spot urinary sodium concentration., Methods: We included 435 336 participants in the UK Biobank whose sodium intake was estimated from spot urine using INTERSALT, Kawasaki, and Tanaka formulas. Hazard ratios for cardiovascular disease (CVD) events and deaths were estimated using Cox proportional-hazard model adjusted for multiple covariates. Penalized Cox regression was used to assess nonlinear relations. Hazard ratios were recalculated after replacement of the sodium concentration term with sex-specific mean values (women: 67.5 mmol/l; men: 89.8 mmol/l) to assess how other components of the formulas influenced these associations., Results: Forty-four thousand two hundred and sixty-eight CVD events and 3251 CVD deaths occurred during a median follow-up of 12 years. The mean estimated sodium intake was 143 (SD = 35), 178 (52), and 147 (33) mmol/day based on INTERSALT, Kawasaki, and Tanaka formulas, respectively. For CVD incidence, linear inverse associations were observed for INTERSALT and Tanaka estimates [hazard ratios (95% CIs) for every 50 mmol increase in estimated sodium intake: 0.9 (0.83-0.97) and 0.93 (0.89- 0.97); P -linear = 0.0047 and 0.0021], and a U-shaped association for the Kawasaki estimates ( P -nonlinear = 0.0026). When the sodium concentration term was fixed, inverse associations were seen for all formulas [0.86 (0.77-0.95), 0.96 (0.93-0.99) and 0.94 (0.89-0.99) for INTERSALT, Kawasaki, and Tanaka; P linear = 0.0054, 0.0166 and 0.0188]. For CVD mortality, no association was observed, but a nonlinear association was identified for the INTERSALT equation ( P -nonlinear = 0.0287) after fixing the sodium concentration., Conclusion: These formula-estimated sodium intakes were associated with CVD incidence and mortality independently of spot urinary sodium concentration. We recommend these formulas not be used in studies associating sodium intake with CVD outcomes to avoid generating misleading evidence., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Further evidence is required regarding the influence of metal mixture exposure on mortality. Therefore, we employed diverse statistical models to evaluate the associations between eight urinary metals and the risks of all-cause and cardiovascular mortality., Methods: We measured the levels of 8 metals in the urine of adults who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. Based on follow-up data, we determined whether they died and the reasons for their deaths. We estimated the association between urine metal exposure and all-cause mortality using Cox regression, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) models. Additionally, we used a competing risk model to estimate the relationship between metal exposure and cardiovascular mortality., Results: Among the 14,305 individuals included in our final analysis, there were 2,066 deaths, with 1,429 being cardiovascular-related. Cox regression analysis showed that cobalt (Co) (HR: 1.21; 95% CI: 1.13, 1.30) and antimony (Sb) (HR: 1.26; 95% CI: 1.12, 1.40) were positively associated with all-cause mortality (all P for trend <0.001). In the competing risk model, Co (HR: 1.29; 95% CI: 1.12, 1.48), lead (Pb) (HR: 1.18; 95% CI: 1.03, 1.37), and Sb (HR: 1.44; 95% CI: 1.18, 1.75) were significantly associated with an increased risk of cardiovascular mortality (all P for trend <0.001). Sb, Pb, cadmium (Cd), and molybdenum (Mo) had the highest weight rankings in the final WQS model. All metals showed a complex non-linear relationship with all-cause mortality, with high posterior inclusion probabilities (PIPs) in the final BKMR models., Conclusions: Combining all models, it is possible that Sb may have a more stable impact on all-cause and cardiovascular mortality. Meaningful metal effects in individual statistical models still require careful attention., Competing Interests: none., (Copyright: © 2024 Cheng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Phthalates have been linked to cardiovascular risk factors. Exposure to chemicals with endocrine disrupting properties during the pubertal period can interfere with normal endocrine processes. This study aims to determine whether adolescent urinary concentrations of phthalate metabolites are associated with indices of overweight and cardiovascular risk in 13-15-year-old children. In this Dutch observational cross-sectional cohort study, 101 adolescents were included (mean age 14.4 ± 0.8 years), 55 were boys. The concentrations of 13 phthalate metabolites were measured in morning urine samples. Levels of cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, fasting insulin, fasting glucose, leptin, and adiponectin were measured. The children's height, weight, waist circumference, hip circumference, and blood pressure were measured. Higher urinary mono-ethyl phthalate concentrations were associated with higher BMI and a larger hip circumference. In girls, higher urinary mono-hydroxy-iso-nonyl phthalate concentrations were associated with higher levels of lipids and obesogenic traits. In boys, higher concentrations of urinary phthalate metabolites were associated with lower LDL-C. The results of this explorative study suggest that higher levels of phthalate metabolites are associated with higher levels of lipids and obesogenic traits in 13-15-year-old girls., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This study was to estimate the associations of volatile organic compounds (VOCs) exposure with the prevalence of total and specific cardiovascular disease (CVD) among the general adult population. This cross-sectional study analyzed 15 urinary VOC metabolites in the general population using the 2011-2016 National Health and Nutrition Examination Survey ( n  = 5,213). The weighted study population with 47.0 years median age, was primarily female (51.2%). The prevalence of total CVD in the overall population was 7.9%. The single-exposure analyzes of AAMA, ATCA, CEMA, CYMA, DHBMA, 3HPMA, and 3MHA +4MHA were significantly associated with increased prevalence of total CVD. Qgcomp regression consistently showed that urinary VOCs-mixed exposure was positively correlated with the prevalence of total and specific CVDs (chronic heart failure, angina, and stroke), and highlighted each VOCs metabolite weights and direction. The similar results were observed for the WQS regression using mixed analysis methods. In conclusion, exposure to VOCs increases CVD prevalence and advances the identification of risk factors for CVD for environmental study.

The impact of metal exposure on cardiovascular diseases has become an increasingly concerning topic. To date, few studies have investigated the relationship between the copper-to-zinc ratio and CVD (Cardiovascular disease). This China multi-ethnic cohort study explored the association between the copper-to-zinc ratio and CVD in Chinese adults. The study included a sample size of 9878 people. Logistic regression analysis was used to examine the correlation between urinary copper, urinary zinc, and the copper-to-zinc ratio and CVD prevalence. Restricted cubic spline (RCS) analysis was used to investigate the potential dose-response relationships among copper-to-zinc ratio, urinary copper, urinary zinc, and CVD prevalence. In addition, the least absolute shrinkage and selection operator (LASSO) regression method was used to identify significant risk factors associated with CVD, leading to the development of a nomogram. The predictive performance of the nomogram model for CVD was assessed using the receiver operating characteristic (ROC) curve and the area under the curve (AUC). Compared with the copper-to-zinc ratio in Q1, the copper-to-zinc ratio in Q4 was associated with CVD after adjusting for all potential confounders (Model 3) (Q4, odds ratio [OR] 0.608, 95% confidence interval [CI] 0.416-0.889, P = 0.010). After adjusting for all potential confounders (Model 3), urinary copper levels in Q4 were associated with CVD (Q4, odds ratio [OR] 0.627, 95% confidence interval [CI] 0.436-0.902, P = 0.012). No significant difference was found between urinary zinc levels and CVD. The RCS showed a linear dose-response relationship between the copper-to-zinc ratio and CVD (P for overall = 0.01). The nomogram based on the influencing factors examined with LASSO showed good predictive power, and the AUC was 76.3% (95% CI 73.7-78.9%). Our results suggest that there is a significant linear negative correlation between the copper-to-zinc ratio and CVD in Chinese adults and that it has good predictive value for CVD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: To assess the association between urinary albumin-to-creatinine ratio (UACR) categories within the normal range with mortality and adverse cardiovascular outcomes., Materials and Methods: PubMed and Embase were systematically searched for real-world evidence studies. Studies were manually evaluated according to predefined eligibility criteria. We included prospective and retrospective cohort studies of the association between UACR categories <30 mg/g and cardiovascular outcomes or mortality. Published information regarding study design, participants, UACR categorization, statistical methods, and results was manually collected. Two UACR categorization approaches were defined: a two-category (UACR <10 mg/g vs. 10-30 mg/g) and a three-category division (UACR <5 mg/g vs. 5-10 and 10-30 mg/g). A random effects meta-analysis was performed on studies eligible for the meta-analysis., Results: In total, 22 manuscripts were identified for the systematic review, 15 of which were eligible for the meta-analysis. The results suggest an association between elevated UACR within the normal to mildly increased range and higher risks of all-cause mortality, cardiovascular death, and coronary heart disease, particularly in the range of 10-30 mg/g. Compared with UACR <10 mg/g, the hazard ratio [HR (95% confidence interval, CI)] for UACR between 10 and 30 mg/g was 1.41 (1.15, 1.74) for all-cause mortality and 1.56 (1.23, 1.98) for coronary heart disease. Compared with UACR <5 mg/g, the risk of cardiovascular mortality for UACR between 10 and 30 mg/g was more than twofold [HR (95% CI): 2.12 (1.61, 2.80)]. Intermediate UACR (5-10 mg/g) was also associated with a higher risk of all-cause mortality [HR (95% CI): 1.14 (1.05, 1.24)] and cardiovascular mortality [HR (95% CI): 1.50 (1.14, 1.99)]., Conclusions: We propose considering higher UACR within the normoalbuminuric range as a prognostic factor for cardiovascular morbidity and mortality. Our findings underscore the clinical significance of even mild increases in albuminuria., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background/Objectives: Cardiovascular diseases are the primary cause of global morbidity and mortality, with cardiovascular health (CVH) remaining well below the ideal level and showing minimal improvement in the U.S. population over recent years. Bisphenol A (BPA), a pervasive environmental contaminant, has emerged as a potential contributor to adverse cardiovascular outcomes. This cross-sectional study delves into the impact of BPA exposure on achieving optimal CVH, as assessed by the Life's Essential 8 metric, among U.S. adults. Methods: Analyzing data from 6635 participants in the National Health and Nutrition Examination Survey (NHANES) collected between 2005 and 2016, BPA exposure was quantified through urinary BPA levels, while optimal CVH was defined using the American Heart Association's Life's Essential 8 criteria, scoring between 80 and 100. Multivariable logistic regression and propensity score matching were employed to evaluate the association between BPA exposure and CVH. Results: This study reveals that individuals in the highest tertile of urinary BPA levels were 27% less likely to attain optimal CVH compared with those in the lowest tertile (OR, 0.73; 95% CI: 0.59-0.92). This negative association persisted across diverse demographics, including age, sex, and race, mirrored in the link between urinary BPA levels and health factor scores. Conclusions: The findings underscore the potential benefits of reducing BPA exposure in enhancing the prevalence of optimal CVH and mitigating the burden of cardiovascular disease. Given the widespread use of BPA, ongoing monitoring of BPA's impact on CVH is essential. Further studies are necessary to elucidate the long-term and causative connections between BPA and CVH. These insights contribute to understanding the complex interplay between environmental factors and CVH outcomes, informing targeted interventions to mitigate cardiovascular disease risk within the population.

Background: The overall understanding of the correlations between mortality risk and phytoestrogens in general population remains limited. We examined the association between urinary phytoestrogen levels and all-cause and cardiovascular mortality based on the National Health and Nutrition Examination Survey (NHANES)., Methods: Weighted Cox proportional hazard regression models were employed to calculate adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs). Nonlinear relationships were assessed using multivariable-adjusted restricted cubic splines (RCS)., Results: In the fully adjusted model, the highest quartiles of urinary genistein levels were correlated with significantly elevated all-cause (HR = 1.36, 95%CI: 1.16-1.59) and cardiovascular (HR = 1.58, 95%CI: 1.20-2.09) mortality. Urinary enterolactone levels in the third quartile were associated with reduced all-cause (HR = 0.77, 95%CI: 0.65-0.90) and cardiovascular (HR = 0.74, 95%CI: 0.55-0.99) mortality. In the highest quartiles of urinary daidzein levels, the cardiovascular mortality was significantly increased (HR = 1.44, 95%CI: 1.09-1.90). RCS showed an non-linear relationship between urinary daidzein levels and all-cause mortality ( P = 0.04)., Conclusion: In the context of a nationally representative sample, genistein exhibited associations with elevated all-cause and cardiovascular mortality, whereas enterolactone showed an association with reduced mortality. The dose-response relationship between urinary daidzein levels and all-cause mortality as well as sex-specific disparities in the impact of phytoestrogen levels should be considered., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xuan, Zhao, Zhou, Guo, Pan, Wang and He.)

Background: Exposure to metals has been associated with cardiovascular disease (CVD) end points and mortality, yet prospective evidence is limited beyond arsenic, cadmium, and lead. In this study, we assessed the prospective association of urinary metals with incident CVD and all-cause mortality in a racially diverse population of US adults from MESA (the Multi-Ethnic Study of Atherosclerosis)., Methods: We included 6599 participants (mean [SD] age, 62.1 [10.2] years; 53% female) with urinary metals available at baseline (2000 to 2001) and followed through December 2019. We used Cox proportional hazards models to estimate the adjusted hazard ratio and 95% CI of CVD and all-cause mortality by baseline urinary levels of cadmium, tungsten, and uranium (nonessential metals), and cobalt, copper, and zinc (essential metals). The joint association of the 6 metals as a mixture and the corresponding 10-year survival probability was calculated using Cox Elastic-Net., Results: During follow-up, 1162 participants developed CVD, and 1844 participants died. In models adjusted by behavioral and clinical indicators, the hazard ratios (95% CI) for incident CVD and all-cause mortality comparing the highest with the lowest quartile were, respectively: 1.25 (1.03, 1.53) and 1.68 (1.43, 1.96) for cadmium; 1.20 (1.01, 1.42) and 1.16 (1.01, 1.33) for tungsten; 1.32 (1.08, 1.62) and 1.32 (1.12, 1.56) for uranium; 1.24 (1.03, 1.48) and 1.37 (1.19, 1.58) for cobalt; 1.42 (1.18, 1.70) and 1.50 (1.29, 1.74) for copper; and 1.21 (1.01, 1.45) and 1.38 (1.20, 1.59) for zinc. A positive linear dose-response was identified for cadmium and copper with both end points. The adjusted hazard ratios (95% CI) for an interquartile range (IQR) increase in the mixture of these 6 urinary metals and the corresponding 10-year survival probability difference (95% CI) were 1.29 (1.11, 1.56) and -1.1% (-2.0, -0.05) for incident CVD and 1.66 (1.47, 1.91) and -2.0% (-2.6, -1.5) for all-cause mortality., Conclusions: This epidemiological study in US adults indicates that urinary metal levels are associated with increased CVD risk and mortality. These findings can inform the development of novel preventive strategies to improve cardiovascular health., Competing Interests: None.

The exposure to modifiable risk factors at young ages have been linked to premature fatal and non-fatal cardiovascular and kidney outcomes. The use of urinary metabolomics has shown strong predictability of kidney function and cardiovascular disease (CVD). We therefore determined the associations between estimated glomerular filtration rate (eGFR) and urinary metabolites in young adults with and without CVD risk factors. Apparently healthy Black and White sexes were included (aged 20-30 years) and categorised by the presence or absence of risk factors, i.e., obesity, physical inactivity, smoking, excessive alcohol intake, masked hypertension, hyperglycemia, dyslipidemia and low socio-economic status, forming the CVD risk group (N = 1036), CVD risk clusters (i.e. presenting with 1 CVD risk factor (N = 344), 2 CVD risk factors (N = 360) and 3 + CVD risk factors (N = 332)) and the control group (N = 166). eGFR was calculated with CKD-EPI equations. A targeted metabolomics approach using liquid chromatography-tandem mass spectrometry was used to measure amino acids and acylcarnitines. Lower cystatin C-based eGFR were indicated in the CVD risk group, 2 and 3 + CVD risk clusters compared to the control group (all P ≤ 0.033). In the CVD risk group, eGFR associated positively with histidine, lysine, asparagine, glycine, serine, glutamine, dimethylglycine, threonine, alanine, creatine, cystine, methionine, tyrosine, pyroglutamic acid, leucine/isoleucine, aspartic acid, tryptophan, glutamic acid, free carnitine, acetylcarnitine, propionylcarnitine, isovalerylcarnitine, octanoylcarnitine and decanoylcarnitine (all P ≤ 0.044), with similar results found in the CVD risk clusters, particularly the 2 CVD risk cluster. eGFR was positively associated with metabolites linked to aromatic amino acid and branched-chain amino acid metabolism, energy metabolism and oxidative stress. These findings may indicate altered reabsorption of these metabolites or altered metabolic regulation to preserve renal health in the setting of CVD risk factors at this young age without established CVD., (© 2024. The Author(s).)

Background: High-sodium and low-potassium intakes are associated with a higher risk of hypertension and cardiovascular disease, but there are limited data on the circulating metabolomics profiles of 24-h urinary sodium and potassium excretions in free-living individuals., Objectives: We aimed to characterize the metabolomics signatures of a high-sodium and low-potassium diet in a cross-sectional study., Methods: In 1028 healthy older adults from the Women's and Men's Lifestyle Validation Studies, we investigated the association of habitual sodium and potassium intakes measured by 2 to 4 24-h urine samples with plasma metabolites (quantified using liquid chromatography-tandem mass spectrometry) and metabolomic pathways. Our primary exposures were energy-adjusted 24-h urinary sodium excretion, potassium excretion, and sodium-to-potassium ratio, calculated based on energy expenditure derived from the doubly labeled water method. We then assessed the partial correlations of their metabolomics scores, derived from elastic net regressions, with cardiometabolic biomarkers., Results: Higher sodium excretion was associated with 38 metabolites including higher piperine, phosphatidylethanolamine, and C5:1 carnitine. In pathway analysis, higher sodium excretion was associated with enhanced biotin and propanoate metabolism and enhanced degradation of lysine and branched-chain amino acids (BCAAs). Metabolites associated with higher potassium and lower sodium-to-potassium ratio included quinic acid and proline-betaine. After adjusting for confounding factors, the metabolomics score for sodium-to-potassium ratio positively correlated with fasting insulin (Spearman's rank correlation coefficient ρ = 0.27), C-peptide (ρ = 0.30), and triglyceride (ρ = 0.46), and negatively with adiponectin (ρ = -0.40), and high-density lipoprotein cholesterol (ρ = -0.42)., Conclusions: We discovered metabolites and metabolomics pathways associated with a high-sodium diet, including metabolites related to biotin, propanoate, lysine, and BCAA pathways. The metabolomics signature for a higher sodium low-potassium diet is associated with multiple components of elevated cardiometabolic risk., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Aims/hypothesis: Non-adherence to medication is a frequent barrier in the treatment of patients with type 2 diabetes mellitus, potentially limiting the effectiveness of evidence-based treatments. Previous studies have mostly relied on indirect adherence measures to analyse outcomes based on adherence. The aim of this study was to use LC-MS/MS in urine-a non-invasive, direct and objective measure-to assess non-adherence to cardiometabolic drugs and analyse its association with kidney and cardiovascular outcomes., Methods: This cohort study includes 1125 participants from the PROVALID study, which follows patients with type 2 diabetes mellitus at the primary care level. Baseline urine samples were tested for 79 cardiometabolic drugs and metabolites thereof via LC-MS/MS. An individual was classified as totally adherent if markers for all drugs were detected, partially non-adherent when at least one marker for one drug was detected, and totally non-adherent if no markers for any drugs were detected. Non-adherence was then analysed in the context of cardiovascular (composite of myocardial infarction, stroke and cardiovascular death) and kidney (composite of sustained 40% decline in eGFR, sustained progression of albuminuria, kidney replacement therapy and death from kidney failure) outcomes., Results: Of the participants, 56.3% were totally adherent, 42.0% were partially non-adherent, and 1.7% were totally non-adherent to screened cardiometabolic drugs. Adherence was highest to antiplatelet and glucose-lowering agents and lowest to lipid-lowering agents. Over a median (IQR) follow-up time of 5.10 (4.12-6.12) years, worse cardiovascular outcomes were observed with non-adherence to antiplatelet drugs (HR 10.13 [95% CI 3.06, 33.56]) and worse kidney outcomes were observed with non-adherence to antihypertensive drugs (HR 1.98 [95% CI 1.37, 2.86])., Conclusions/interpretation: This analysis shows that non-adherence to cardiometabolic drug regimens is common in type 2 diabetes mellitus and negatively affects kidney and cardiovascular outcomes., (© 2024. The Author(s).)

Objectives: We examined the associations of self-reported exposures, and urinary metabolites related to household pesticide with cardiovascular disease (CVD) mortality in older adults based on the 2007 to 2014 waves of National Health and Nutrition Examination Survey (NHANES)., Methods: Information on application and urinary metabolites related to household pesticide exposure were collected. We estimated the risks of household pesticide exposure, urinary metabolites with subsequent incident CVD death using Cox proportional hazards regression models. The indirect effects of urinary metabolites and effect modifications were examined., Results: The participants who reported exposure to household pesticide had a higher risk of incident CVD death (adjusted HR 1.40, 95% CI 1.08 to 1.81). Per 1-log10 increase in urinary N, N-diethyl-3-methylbenzamide (DEET) related to household insect repellents was associated with a higher risk of incident CVD death (adjusted HR 1.97, 95% CI 1.14 to 3.40). Urinary DEET explained 4.21% of the total association between household pesticide exposure and CVD death risk. The participants who persisted a low level of health diet exhibited pronounced CVD death risks with household pesticide exposures., Conclusions: Exposure to household pesticide, especially household insect repellents, was consistently associated with an elevated CVD death risk in older adults. A heatlhy diet could partly attenuate the associations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chlorophenols are widespread environmental organic pollutants with harmful effects on human beings. Although relationships between chlorophenols and various dysfunctions/diseases have been reported, the contribution of chlorophenols exposure to mortalities is underdetermined. In this cohort study, we included 4 types of urinary chlorophenols, aiming to estimate associations of chlorophenols exposure with all-cause and cause-specific mortalities. Urinary chlorophenols were examined at baseline of National Health and Nutrition Examination Survey (NHANES) 2003-2010, and adjusted for the urinary creatinine level. Associations between chlorophenols and mortalities were estimated using COX regression analyses, results were shown as hazard ratio (HR) and 95% confidence interval (95% CI). By dividing participants into four subgroups based on quartiles of urinary levels of chlorophenols, associations between mortalities and categorical variables of chlorophenols were estimated. Furthermore, the quantile g-computation analysis was used to estimate the joint effects of 4 chlorophenols on mortalities. Among 5817 adults (2863 men), 1034 were deceased during the follow-up. After adjusted for confounders, 2,4,5-trichlorophenol (2,4,5-TCP) was found to be positively associated with both all-cause (HR = 1.46; 95% CI: 1.16, 1.84) and cardiovascular disease (CVD) mortalities (HR = 1.60; 95% CI: 1.00, 2.55). Compared to the subgroup of the lowest level of chlorophenols, participants in subgroups of higher 2,4,5-TCP levels showed higher risk of all-cause mortality (P-value for trend = 0.003). For CVD mortality, HRs in subgroups of higher levels of 2,4-dichlorophenol (2,4-DCP) and 2,4,6-trichlorophenol (2,4,6-TCP) were statistically significant (P-values for trend were 0.017 for 2,4-DCP and 0.049 for 2,4,6-TCP). The HRs (95% CI) of joint effects of 4 chlorophenols were 1.11 (1.01, 1.21) and 1.32 (1.10, 1.57) for all-cause and CVD-specific mortalities, and 2,4,5-TCP showed the highest weight in joint effects. All of these findings implied that among 4 urinary chlorophenols we included, 2,4,5-TCP might be a sensitive one in associations with mortalities among general populations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aim: Parabens are widely used as antimicrobial preservatives in personal care products. Studies investigating obesogenic or cardiovascular effects of parabens show discordant results, while data on preschool children are lacking. Paraben exposure during early childhood could have profound cardiometabolic effects later in life., Methods: In this cross-sectional study paraben concentrations [methyl (MeP), ethyl (EtP), propyl (PrP), butyl (BuP)] were measured by ultra-performance liquid chromatography/tandem mass spectrometry in 300 urinary samples of 4-6-year-old children of the ENVIRONAGE birth cohort. Paraben values below the limit of quantitation (LOQ) were imputed by censored likelihood multiple imputation. The associations between log-transformed paraben values and cardiometabolic measurements (BMI z-scores, waist circumference, blood pressure and retinal microvasculature) were analyzed in multiple linear regression models with a priori selected covariates. Effect modification by sex was investigated by including interaction terms., Results: Geometric means (geometric SD) of urinary MeP, EtP, and PrP levels above the LOQ were 32.60 (6.64), 1.26 (3.45), and 4.82 (4.11) μg/L, respectively. For BuP more than 96% of all measurements were below the LOQ. Regarding the microvasculature, we found direct associations between MeP and central retinal venular equivalent (β = 1.23, p = 0.039) and PrP with the retinal tortuosity index (x10 3) (β = 1.75, p = 0.0044). Furthermore, we identified inverse associations between MeP and ∑parabens with BMI z-scores (β = -0.067, p = 0.015 and β = -0.070, p = 0.014 respectively), and EtP with mean arterial pressure (β = -0.69, p = 0.048). The direction of association between EtP and BMI z-scores showed evidence for sex-specific differences with a direct trend in boys (β = 0.10, p = 0.060)., Conclusions: Already at young age paraben exposure is associated with potentially adverse changes in the retinal microvasculature., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Our study aims to investigate the association of urinary IPM3 and cardio-cerebrovascular diseases (CVD) in general adults. A total of 1775 participants were enrolled from the National Health and Nutrition Examination Surveys. Urinary levels of IPM3 were measured by LC/MS as exposure to isoprene. The associations between isoprene exposure and the risk of CVD were evaluated by restricted cubic splines based on multivariable logistic regression models. The prevalence of CVD was significantly higher across IPM3 quartiles. Comparing with the lowest quartile, the highest quartile was associated with 2.47-fold risk of CVD (odds ratio: 2.47, 95% confidence interval: 1.40-4.39, P = 0.002). Restricted cubic spline confirmed that the levels of urinary IPM3 were linearly associated with cardio-cerebrovascular diseases, angina and heart attack, while nonlinearly related to CHF and CAD. In conclusion, the urinary IPM3, as a long-term isoprene exposure, was associated with the presence of cardio-cerebrovascular diseases, including CHF, CAD, angina, and heart attack., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Neutrophil gelatinase-associated lipocalin (NGAL) is expressed in atherosclerotic plaques and implicated in the development of cardiovascular diseases. Peripheral arterial disease (PAD) is an atherosclerotic disease that often results in major cardiovascular events. This study aimed to prospectively examine the potential of urine NGAL (uNGAL) in predicting worsening PAD status and major adverse limb events (MALE). Baseline urine NGAL (uNGAL) and urine creatinine (uCr) concentrations were measured in PAD (n = 121) and non-PAD (n = 77) patients. Levels of uNGAL were normalized for urine creatinine (uNGAL/uCr). Outcomes included worsening PAD status, which was defined as a drop in ankle brachial index (ABI) > 0.15, and major adverse limb events (MALE), which was defined as a need for surgical revascularization or amputations. PAD patients had 2.30-fold higher levels of uNGAL/uCr [median (IQR) 31.8 (17.0-62.5) μg/g] in comparison to non-PAD patients [median (IQR) 73.3 (37.5-154.7) μg/g] (P = 0.011). Multivariate cox analysis showed that uNGAL/uCr levels were independently associated with predicting worsening PAD status and MALE outcomes. Cumulative survival analysis, over follow up period, demonstrated a direct correlation between elevated uNGAL/uCr levels and PAD disease progression and MALE outcomes. These data demonstrate an association between elevated uNGAL/uCr levels and worsening PAD disease status and MALE outcomes, indicating its potential for risk-stratification of PAD patients., (© 2022. The Author(s).)

[Figure: see text].

Arginine (Arg) and lysine (Lys) moieties of proteins undergo various post-translational modifications (PTM) including enzymatic N G - and N ε -methylation and non-enzymatic N G - and N ε -glycation. In a large cohort of stable kidney transplant recipients (KTR, n = 686), high plasma and low urinary concentrations of asymmetric dimethylarginine (ADMA), an abundant PTM metabolite of Arg, were associated with cardiovascular and all-cause mortality. Thus, the prediction of the same biomarker regarding mortality may depend on the biological sample. In another large cohort of stable KTR (n = 555), higher plasma concentrations of N ε -carboxymethyl-lysine (CML) and N ε -carboxyethyl-lysine (CEL), two advanced glycation end-products (AGEs) of Lys, were associated with higher cardiovascular mortality. Yet, the associations of urinary AGEs with mortality are unknown. In the present study, we measured 24 h urinary excretion of Lys, CML, and furosine in 630 KTR and 41 healthy kidney donors before and after donation. Our result indicate that lower urinary CML and lower furosine excretion rates are associated with higher mortality in KTR, thus resembling the associations of ADMA. Lower furosine excretion rates were also associated with higher cardiovascular mortality. The 24 h urinary excretion rate of amino acids and their metabolites decreased post-donation (varying as little as - 24% for CEL, and as much as - 62% for ADMA). For most amino acids, the excretion rate was lower in KTR than in donors pre-donation [except for S-(1-carboxyethyl)-L-cysteine (CEC) and N G -carboxyethylarginine (CEA)]. Simultaneous GC-MS measurement of free amino acids, their PTM metabolites and AGEs in urine is a non-invasive approach in kidney transplantation., (© 2021. The Author(s).)

Background: The urinary C-peptide/creatinine ratio (UCPCR) is low in patients with type 1 diabetes mellitus, but it has not been well characterized in patients with type 2 diabetes mellitus (T2DM). We aimed to measure the UCPCRs in patients with T2DM and explore the relationships among UCPCR, insulin resistance (IR), and chronic vascular complications of diabetes., Methods: A cross-sectional study was performed of 1299 Chinese hospitalized patients with T2DM. Binary logistic regression was used to evaluate the relationships between the chronic vascular complications of diabetes and UCPCR. K-means analysis was used to allocate participants to subgroups with five to six variables (age at diagnosis, body mass index [BMI], glycosylated hemoglobin, homoeostasis model assessment 2-estimated beta-cell function (HOMA2-B), and HOMA2-insulin resistance (HOMA2-IR), with or without UCPCR)., Results: UCPCR positively correlated with HOMA2-IR (r = 0.448, P < .001). After adjustment for sex, age, duration of diabetes, and other cardiovascular risk factors, UCPCR was positively associated with diabetic kidney disease (DKD) (odds ratio [OR] = 1.198, 95% CI 1.019-1.408, P = .029) and coronary heart disease (CHD) (OR = 1.312, 95% CI 1.079-1.594, P = .006). When UCPCR was added, cluster analysis using the six variables identified five subgroups of T2DM, characterized by differing age at diagnosis, BMI, beta-cell function, IR, and prevalence of vascular complications., Conclusions: UCPCR is positively associated with IR, DKD, and CHD and represents a promising biomarker that could refine the classification of T2DM., (© 2021 Ruijin Hospital, Shanghai JiaoTong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Diagnostic tests including echocardiography, albuminuria, electrocardiogram (ECG), high-sensitivity troponin I (hs-TnI), and N-terminal prohormone brain natriuretic peptide (NT-proBNP) have been suggested as cardiovascular (CV) risk predictors in type 2 diabetes. We studied the separate and combined prognostic yield of these risk markers., Methods: In all, 1030 patients with type 2 diabetes were recruited from specialized clinics in this prospective cohort study. Full echocardiographic evaluation was feasible in 886 patients in sinus rhythm with adequate image quality. ECG was performed in 998 patients. Albuminuria was measured in 1009 and NT-proBNP/hs-TnI in 933 patients. The end point was a composite of CV events., Results: The median follow-up was 4.7 years (interquartile range: 4.0-5.3), and 174 patients experienced a CV disease event. All considered markers, except hs-TnI, were significantly (P < .001) associated with the outcome: abnormal echocardiogram (hazard ratio 2.40 [1.70-3.39]), albuminuria 2.01 (1.47-2.76), abnormal ECG (2.27 [1.66-3.08]), high NT-proBNP (>150 pg/mL) 3.05 (2.11-4.40), and hs-TnI 1.12 (0.79-1.59). After adjusting for clinical variables, all remained significantly associated with the end point. However, after adjusting for each other, only NT-proBNP >150 pg/mL remained significantly associated with the end point (2.07 [1.28-3.34], P < .001). Measured by C-statistics, model performance was highest with log 2 (NT-proBNP) (0.70 [0.65-0.75]) and similar to clinical variables alone (0.71 [0.67-0.76]). Combining all risk markers only resulted in a very limited increase in C-statistics (0.69 [0.64-0.74])., Conclusions: This study identified NT-proBNP over echocardiography, ECG, and albuminuria in risk prediction in patients with type 2 diabetes. The diagnostic yield in considering more than one risk marker was limited in this population., (© 2021 Ruijin Hospital, Shanghai JiaoTong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Data are limited with regard to the association between low-grade albuminuria (below the threshold of microalbuminuria) and high cardiovascular risk in normoalbuminuric Chinese adults free of cardiovascular disease (CVD)., Methods: A total of 32 650 participants aged over 40 years from seven regional centers in China were included in this study. The single-void first morning urine sample was collected to measure the urinary albumin to creatinine ratio (UACR) and the data were divided into sex-specific quartiles. The Framingham Risk Score (FRS) was used to identify participants at high risk of developing coronary heart disease (CHD) over the next 10 years and the association between low-grade albuminuria and high 10-year Framingham risk for CHD (FRS ≥20%) was investigated., Results: Among males and females, the prevalence of cardiometabolic risk factors (diabetes, hypertension, and dyslipidemia) increased markedly with the elevation of UACR quartiles. Logistic regression analysis showed that the odds ratios (ORs) for high 10-year risk of CHD increased significantly from the second quartile in males (UACR: 4.78 ~ 7.53 mg/g, OR = 1.21, 95% confidence interval [CI]: 1.05-1.40) and the third quartile in females (UACR: 9.13 ~ 15.04 mg/g, OR = 3.07, 95% CI: 1.75-5.40). Stratified analysis showed that in males, the association was especially pronounced in elderly, overweight/obese participants and those without diabetes and hypertension whereas in females, the association was especially pronounced in elderly, overweight/obese participants and those without diabetes and with hypertension., Conclusions: Low-grade albuminuria was significantly associated with high 10-year cardiovascular risk among CVD-free and normoalbuminuric Chinese adults., (© 2021 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

This study aimed to explore the associations between renal-related and arterial stiffness biomarkers with all-cause and expanded cardiovascular disease (CVD) mortality in a general Taiwanese population. This prospective community-based cohort study included 4883 subjects aged ≥ 20 years who were followed up until December 31, 2016. Renal-related biomarkers consisted of blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), and urine albumin-to-creatinine ratio (UACR). Arterial stiffness biomarker consisted of brachial-ankle pulse wave velocity (baPWV). The death status of the subjects was ascertained by matching information from death records with the identification number and date of birth of the subjects. Cox proportional hazard models with restricted cubic splines estimated the hazard ratios and 95% confidence intervals for all-cause mortality and expanded CVD mortality. During a mean 8.3 years of follow up, 456 deaths were recorded, 146 of which were due to expanded CVD mortality. The multivariable-adjusted hazard ratios of all-cause mortality was 1.53 (95% CI 1.21-1.94) for BUN (≥ 20 mg/dL vs. < 20 mg/dL), 1.57 (1.15-2.14) for eGFR (< 90 mL/min/1.73 m 2 vs. ≥ 90 mL/min/1.73 m 2 ), 1.55 (1.25-1.92) for UACR (≥ 30 mg/g vs. < 30 mg/g), and 1.75 (1.14-2.67) for baPWV (≥ 1400 cm/s vs. < 1400 cm/s). The expanded CVD mortality was 1.89 (95% CI 1.30-2.73) for BUN (≥ 20 mg/dL vs. < 20 mg/dL), 2.28 (1.13-4.57) for eGFR (< 90 mL/min/1.73 m 2 vs. ≥ 90 mL/min/1.73 m 2 ), 2.13 (1.52-2.99) for UACR (≥ 25 mg/g vs. < 25 mg/g), and 15.73 (2.14-115.61) for baPWV (≥ 1400 cm/s vs. < 1400 cm/s). High levels of BUN, UACR, and baPWV and low levels of eGFR showed high risks with all-cause and expanded CVD mortality. Our study provides insights into screening tests to target populations at high risk of premature death due to CVD.

Background: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous organic compounds associated with chronic disease in epidemiologic studies, though the contribution of PAH exposure on fatal outcomes in the U.S. is largely unknown., Objectives: We investigated urinary hydroxylated PAH metabolites (OH-PAHs) with all-cause and cause-specific mortality in a representative sample of the U.S. population., Methods: Study participants were ≥20 years old from the National Health and Nutrition Examination Survey 2001-2014. Concentrations (nmol/L) of eight OH-PAHs from four parent PAHs (naphthalene, fluorene, phenanthrene, pyrene) were measured in spot urine samples at examination. We identified all-cause, cancer-specific, and cardiovascular-specific deaths through 2015 using the National Death Index. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between ΣOH-PAHs and mortality endpoints. We assessed potential heterogeneity by age, gender, smoking status, poverty, and race/ethnicity. Additionally, we examined the overall mixture effect using quantile g-computation., Results: In 9,739 eligible participants, there were 934 all-cause deaths, 159 cancer-specific deaths, and 108 cardiovascular-specific deaths (median 6.75 years follow-up). A log10 increase in ΣOH-PAHs was associated with higher all-cause mortality (HRadj = 1.39 [95%CI: 1.21, 1.61]), and possibly cancer-specific mortality (HRadj = 1.15 [95%CI: 0.79, 1.69]), and cardiovascular-specific mortality (HRadj = 1.49 [95%CI: 0.94, 2.33]). We observed substantial effect modification by age, smoking status, gender, and race/ethnicity across mortality endpoints. Risk of cardiovascular mortality was higher for non-Hispanic blacks and those in poverty, indicating potential disparities. Quantile g-computation joint associations for a simultaneous quartile increase in OH-PAHs were HRadj = 1.15 [95%CI: 1.02, 1.31], HRadj = 1.41 [95%CI: 1.05, 1.90], and HRadj = 0.98 [95%CI: 0.66, 1.47] for all-cause, cancer-specific, and cardiovascular-specific mortalities, respectively., Discussion: Our results support a role for total PAH exposure in all-cause and cause-specific mortality in the U.S. population., Competing Interests: The authors have declared that no competing interests exist.

Diabetes mellitus is a disease of dysregulated blood glucose homeostasis. The current pandemic of diabetes is a significant driver of patient morbidity and mortality, as well as a major challenge to healthcare systems worldwide. The global increase in the incidence of diabetes has prompted researchers to focus on the different pathogenic processes responsible for type 1 and type 2 diabetes. Similarly, increased morbidity due to diabetic complications has accelerated research to uncover pathological changes causing these secondary complications. Albuminuria, or protein in the urine, is a well-recognised biomarker and risk factor for renal and cardiovascular disease. Albuminuria is a mediator of pathological abnormalities in diabetes-associated conditions such as nephropathy and atherosclerosis. Clinical screening and diagnosis of diabetic nephropathy is chiefly based on the presence of albuminuria. Given the ease in measuring albuminuria, the potential of using albuminuria as a biomarker of cardiovascular diseases is gaining widespread interest. To assess the benefits of albuminuria as a biomarker, it is important to understand the association between albuminuria and cardiovascular disease. This review examines our current understanding of the pathophysiological mechanisms involved in both forms of diabetes, with specific focus on the link between albuminuria and specific vascular complications of diabetes.

Background: Epidemiological evidence has shown that serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations, a diagnostic biomarker for heart failure, are positively associated with cardiovascular risk. Since NT-proBNP in serum is excreted in urine, it is hypothesized that urinary NT-proBNP concentrations are correlated with serum concentrations and linked with cardiovascular risk in the general population., Methods: A total of 3060 community-dwelling residents aged ≥ 40 years without history of cardiovascular disease (CVD) were followed up for a median of 8.3 years (2007-2015). Serum and urinary concentrations of NT-proBNP at baseline were compared. The hazard ratios (HRs) and their 95% confidence intervals (CIs) for the association between NT-proBNP concentrations and the risk of developing CVD were computed using the Cox proportional hazards model., Results: The median values (interquartile ranges) of serum and urinary NT-proBNP concentrations at baseline were 56 (32-104) pg/mL and 20 (18-25) pg/mL, respectively. There was a strong quadratic correlation between the serum and urinary concentrations of NT-proBNP (coefficient of determination [R 2 ] = 0.72): urinary concentrations of 20, 27, and 43 pg/mL were equivalent to serum concentrations of 55, 125, and 300 pg/mL, respectively. During the follow-up period, 170 subjects developed CVD. The age- and sex-adjusted risk of CVD increased significantly with higher urinary NT-proBNP levels (P for trend < 0.001). This association remained significant after adjustment for traditional cardiovascular risk factors (P for trend = 0.009). The multivariable-adjusted risk of developing CVD almost doubled in subjects with urinary NT-proBNP of ≥ 43 pg/mL as compared to those with urinary NT-proBNP of ≤ 19 pg/mL (HR 2.07, 95% CI 1.20-3.56)., Conclusions: The present study demonstrated that urinary NT-proBNP concentrations were well-correlated with serum concentrations and were positively associated with cardiovascular risk. Given that urine sampling is noninvasive and does not require specially trained personnel, urinary NT-proBNP concentrations have the potential to be an easy and useful biomarker for detecting people at higher cardiovascular risk.

Arginine residues in proteins can be singly or doubly methylated post-translationally. Proteolysis of arginine-methylated proteins provides monomethyl arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). ADMA and SDMA are considered cardiovascular risk factors, with the underlying mechanisms being not yet fully understood. SDMA lacks appreciable metabolism and is almost completely eliminated by the kidney, whereas ADMA is extensively metabolized to dimethylamine (DMA), with a minor ADMA fraction of about 10% being excreted unchanged in the urine. Urinary DMA and ADMA are useful measures of whole-body asymmetric arginine-dimethylation, while urinary SDMA serves as a whole-body measure of symmetric arginine-dimethylation. In renal transplant recipients (RTR), we previously found that higher plasma ADMA concentrations and lower urinary ADMA and SDMA concentrations were associated with a higher risk of all-cause mortality. Yet, in this RTR collective, no data were available for urinary DMA. For the present study, we additionally measured the excretion rate of DMA in 24-h collected urine samples of the RTR and of healthy kidney donors in the cohort, with the aim to quantitate whole-body asymmetric (ADMA, DMA) and symmetric (SDMA) arginine-dimethylation. We found that lower DMA excretion rates were associated with higher all-cause mortality, yet not with cardiovascular mortality. In the healthy donors, kidney donation was associated with considerable decreases in ADMA (by - 39%, P < 0.0001) and SDMA (by - 21%, P < 0.0001) excretion rates, yet there was no significant change in DMA (by - 9%, P = 0.226) excretion rate. Our results suggest that protein-arginine dimethylation is altered in RTR compared to healthy kidney donors and that it is pronouncedly shifted from symmetric to asymmetric arginine-dimethylation, with whole-body protein-arginine dimethylation being almost unaffected.

Background: Although sodium increases the risk of coronary artery disease and hypertension, whether sodium also impacts other cardiovascular disease (CVD) and its risk factors is less clear. We examined the causal role of urinary sodium in these CVDs and risk factors using Mendelian randomization., Methods: We identified strong, independent single nucleotide polymorphisms (SNPs) of urinary sodium from the most up to date genome wide association studies (GWAS) (n = 446,237) and applied them to GWAS of stroke and its subtypes (40,585 cases and 406,111 non-cases), atrial fibrillation (60,620 cases and 970,216 non-cases) and heart failure (47,309 cases and 930,014 non-case). We assessed the impact of sodium on these diseases and associated risk factors using inverse variance weighting. Sensitivity analyses included weighted median, contamination mixture method, MR-PRESSO, and multivariable Mendelian randomization., Results: Higher log transformed urinary sodium was associated with higher risk of stroke (odds ratio (OR) 1.45, 95% confidence interval (CI) 1.01 to 2.08), ischemic stroke (OR 1.60 95% CI 1.12 to 2.30), heart failure (OR 1.77 95% CI 1.19 to 2.62), and type 2 diabetes (OR 4.17 95% CI 1.53 to 11.35). Sensitivity analyses produced directionally similar estimates., Conclusion: Higher sodium likely increases stroke, heart failure and type 2 diabetes risk. Our study further supports public health policies to minimize population sodium intake, so as to reduce the associated disease burden., Competing Interests: Conflict of interest None., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Evidence from previous studies has shown that exposure to metals is associated with cardiovascular disease (CVD). However, the association between metal mixtures and CVD risk and the potential mechanisms in epidemiologic studies remain unclear. The data of 14,795 adults who participated in the U.S. National Health and Nutrition Examination Survey (NHANES) 1999-2016 were analyzed. Multivariate logistic regression was performed to investigate the associations between urinary metal levels and CVDs. Weighted quantile sum (WQS) regression was performed to examine the effects of mixed metals on CVDs. Multivariate linear regression and mediation analysis were conducted to explore the associations between metals and blood lipids. Urinary cadmium (Cd) was significantly associated with an increased total CVD risk and with individual CVD risk. The odds ratio (OR) for CVD in the highest quartile of the WQS index was 1.43 (95% confidence interval [CI]: 1.19, 1.71). One augmented urinary Cd concentration unit (Log10) was associated with a 0.93 mg/dL decrease in HDL cholesterol, a 1.34 mg/dL increase in LDL cholesterol and a 1.30 mg/dL increase in total cholesterol in the fully adjusted model. Mediation analysis showed that HDL cholesterol mediated 4.91% of the association between urinary Cd and the prevalence of CVD. Our findings suggest that urinary Cd and metal mixtures were significantly and positively associated with CVD. The downregulation of HDL cholesterol might play a significant role in mediating Cd exposure-associated CVD risk increases., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Albuminuria is an established risk marker for both cardiovascular and renal outcomes. In this study, we expected to use portable and inexpensive test strips to detect urine albumin level for risk stratification in cardiovascular and renal outcomes among rural Thai community., Objective: To evaluate the relationship between urine albumin dipstick and cardiovascular and renal complications in rural Thai population., Methods: We conducted a retrospective study in 635 rural Thai adults who tested urine albuminuria by using commercial urine albumin dipstick and the Micral-albumin test II strips at baseline. The subjects were divided into normoalbuminuria (albumin < 20 mg/L), microalbuminuria (albumin 20-200 mg/L), or macroalbuminuria (Urine dipstick at least 1+ or albumin > 200 mg/L). We collected data on the incidences of primary composite outcomes including cardiovascular or renal morbidity and mortality. Incident density and cox regression were analyzed to evaluate the association between albuminuria status and primary composite outcome., Results: During an average 14-year follow-up, 102 primary composite events occurred including 59 (13.1%), 32 (20.6%) and 11 (39.3%) among 452, 155, and 28 subjects with normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively. Incident densities of primary composite outcome were elevated continually according to the degree of albuminuria (9.36, 17.11 and 38.12 per 1000 person-years). Compared with the subjects without albuminuria, subjects with microalbuminuria and macroalbuminuria at baseline had higher risk for primary composite outcome in univariate model. After multivariate analysis was performed, the effect of macroalbuminuria was only persisted with 3.13-fold risk (adjusted HR 3.13; 95% CI 1.40-6.96, P= 0.005)., Conclusion: Albuminuria from semi-quantitative methods is an important factor predicting cardiovascular and renal risk among subjects in Thai rural population. Our findings support to also incorporating urine albumin dipstick into assessments of cardiovascular risk in the general population.

Introduction: Urine alpha-1-microglobulin (Uα1m) elevations signal proximal tubule dysfunction. In ambulatory settings, higher Uα1m is associated with acute kidney injury (AKI), progressive chronic kidney disease (CKD), cardiovascular (CV) events, and mortality. We investigated the associations of pre- and postoperative Uα1m concentrations with adverse outcomes after cardiac surgery., Methods: In 1,464 adults undergoing cardiac surgery in the prospective multicenter Translational Research Investigating Biomarker Endpoints for Acute Kidney Injury (TRIBE-AKI) cohort, we measured the pre-and postoperative Uα1m concentrations and calculated the changes from pre- to postoperative concentrations. Outcomes were postoperative AKI during index hospitalization and longitudinal risks for CKD incidence and progression, CV events, and all-cause mortality after discharge. We analyzed Uα1m continuously and categorically by tertiles using multivariable logistic regression and Cox proportional hazards regression adjusted for demographics, surgery characteristics, comorbidities, baseline estimated glomerular filtration rate, urine albumin, and urine creatinine., Results: There were 230 AKI events during cardiac surgery hospitalization; during median 6.7 years of follow-up, there were 212 cases of incident CKD, 54 cases of CKD progression, 269 CV events, and 459 deaths. Each 2-fold higher concentration of preoperative Uα1m was independently associated with AKI (adjusted odds ratio [aOR] = 1.36, 95% confidence interval 1.14-1.62), CKD progression (adjusted hazard ratio [aHR] = 1.46, 1.04-2.05), and all-cause mortality (aHR = 1.19, 1.06-1.33) but not with incident CKD (aHR = 1.21, 0.96-1.51) or CV events (aHR = 1.01, 0.86-1.19). Postoperative Uα1m was not associated with AKI (aOR per 2-fold higher = 1.07, 0.93-1.22), CKD incidence (aHR = 0.90, 0.79-1.03) or progression (aHR = 0.79, 0.56-1.11), CV events (aHR = 1.06, 0.94-1.19), and mortality (aHR = 1.01, 0.92-1.11)., Conclusion: Preoperative Uα1m concentrations may identify patients at high risk of AKI and other adverse events after cardiac surgery, but postoperative Uα1m concentrations do not appear to be informative., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Urinary peptides gained significant attention as potential biomarkers especially in the context of kidney and cardiovascular disease. In this manuscript the recent literature since 2015 on urinary peptide investigation in human kidney and cardiovascular disease is reviewed. The technology most commonly used in this context is capillary electrophoresis coupled mass spectrometry, in part owed to the large database available and the well-defined dataspace. Several studies based on over 1000 subjects are reported in the recent past, especially examining CKD273, a classifier for assessment of chronic kidney disease based on 273 urine peptides. Interestingly, the most abundant urinary peptides are generally collagen fragments, which may have gone undetected for some time as they are typically modified via proline hydroxylation. The data available suggest that urinary peptides specifically depict inflammation and fibrosis, and may serve as a non-invasive tool to assess fibrosis, which appears to be a key driver in kidney and cardiovascular disease. The recent successful completion of the first urinary peptide guided intervention trial, PRIORITY, is expected to further spur clinical application of urinary peptidomics, aiming especially at early detection of chronic diseases, prediction of progression, and prognosis of drug response., (© 2020 Wiley-VCH GmbH.)

Protein-bound uremic toxins (PBUTs) are bioactive microbiota metabolites originated exclusively from protein fermentation of the bacterial community resident within the gut microbiota, whose composition and function is profoundly different in the chronic kidney disease (CKD) population. PBUTs accumulate in the later stages of CKD because they cannot be efficiently removed by conventional hemodialysis due to their high binding affinity for albumin, worsening their toxic effects, especially at the cardiovascular level. The accumulation of uremic toxins, along with oxidative stress products and pro-inflammatory cytokines, characterizes the uremic status of CKD patients which is increasingly associated to a state of immune dysfunction including both immune activation and immunodepression. Furthermore, the links between immune activation and cardiovascular disease (CVD), and between immunodepression and infection diseases, which are the two major complications of CKD, are becoming more and more evident. This review summarizes and discusses the current state of knowledge on the role of the main PBUTs, namely indoxyl sulfate and p-cresyl sulfate, as regulators of immune response in CKD, in order to understand whether a microbiota modulation may be useful in the management of its main complications, CVD, and infections. Summarizing the direct effects of PBUT on immune system we may conclude that PCS seemed to be associated to an immune deficiency status of CKD mainly related to the adaptative immune response, while IS seemed to reflect the activation of both innate and adaptative immune systems likely responsible of the CKD-associated inflammation. However, the exact role of IS and PCS on immunity modulation in physiological and pathological state still needs in-depth investigation, particularly in vivo studies.

Noninvasive biomarkers are required for addressing crucial clinical needs. The ideal biomarker should be easily accessible and provide a unique characteristic for a healthy status or a pathological condition. In the last years, microRNAs (miRNAs) have been proposed as promising tissue-based biomarkers for several diseases such as cancer and cardiovascular diseases. Recently, miRNAs have shown great potential as novel noninvasive biomarkers, due to their high stability in human body fluids such as serum, plasma, and urine. Furthermore, many other noncoding RNAs (ncRNAs) such as long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) have shown to be novel biomarkers as well. The aim of this exciting research field is to offer novel tools, allowing translational scientists to develop new strategies for diagnosis, screening, and monitoring of diseases. In this book chapter, the miRandola database and its applications will be introduced. The database offers the possibility to explore information on ncRNAs as noninvasive biomarkers, manually extracted from scientific literature and public available resources.

Background: Although prostate cancer is a leading cause of cancer death, its aetiology is not well understood. We aimed to identify novel biochemical factors for prostate cancer incidence and mortality in UK Biobank., Methods: A range of cardiovascular, bone, joint, diabetes, renal and liver-related biomarkers were measured in baseline blood samples collected from up to 211,754 men at recruitment and in a subsample 5 years later. Participants were followed-up via linkage to health administrative datasets to identify prostate cancer cases. Hazard ratios (HRs) and 95% confidence intervals were calculated using multivariable-adjusted Cox regression corrected for regression dilution bias. Multiple testing was accounted for by using a false discovery rate controlling procedure., Results: After an average follow-up of 6.9 years, 5763 prostate cancer cases and 331 prostate cancer deaths were ascertained. Prostate cancer incidence was positively associated with circulating vitamin D, urea and phosphate concentrations and inversely associated with glucose, total protein and aspartate aminotransferase. Phosphate and cystatin-C were the only biomarkers positively and inversely, respectively, associated with risk in analyses excluding the first 4 years of follow-up. There was little evidence of associations with prostate cancer death., Conclusion: We found novel associations of several biomarkers with prostate cancer incidence. Future research will examine associations by tumour characteristics.

The predictive value of traditional cardiovascular risk estimators is limited, and young and elderly populations are particularly underrepresented. We aimed to investigate the urine metabolome and its association with cardiovascular risk to identify novel markers that might complement current estimators based on age. Urine samples were collected from 234 subjects categorized into three age-grouped cohorts: 30-50 years (cohort I, young), 50-70 years (cohort II, middle-aged), and > 70 years (cohort III, elderly). Each cohort was further classified into three groups: (a) control, (b) individuals with cardiovascular risk factors, and (c) those who had a previous cardiovascular event. Novel urinary metabolites linked to cardiovascular risk were identified by nuclear magnetic resonance in cohort I and then evaluated by target mass spectrometry quantification in all cohorts. A previously identified metabolic fingerprint associated with atherosclerosis was also analyzed and its potential risk estimation investigated in the three aged cohorts. Three different metabolic signatures were identified according to age: 2-hydroxybutyrate, gamma-aminobutyric acid, hypoxanthine, guanidoacetate, oxaloacetate, and serine in young adults; citrate, cyclohexanol, glutamine, lysine, pantothenate, pipecolate, threonine, and tyramine shared by middle-aged and elderly adults; and trimethylamine N-oxide and glucuronate associated with cardiovascular risk in all three cohorts. The urinary metabolome contains a metabolic signature of cardiovascular risk that differs across age groups. These signatures might serve to complement existing algorithms and improve the accuracy of cardiovascular risk prediction for personalized prevention. KEY MESSAGES: • Cardiovascular risk in the young and elderly is underestimated. • The urinary metabolome reflects cardiovascular risk across all age groups. • Six metabolites constitute a metabolic signature of cardiovascular risk in young adults. • Middle-aged and elderly adults share a cardiovascular risk metabolic signature. • TMAO and glucuronate levels reflect cardiovascular risk across all age groups.

Results of this paper provide evidence that chronic long-term exposure to organophosphorus insecticides poses a significantly higher health risk for US women than for men, based on dialkylphosphate biomarker data from NHANES cycles 2003-2012. The risk of cardiovascular disease for female non-smokers aged 60-85 years in the highest dimethylthiophosphate (DMTP) urinary concentration quartile is 3.0 (odds ratio, OD = 3.0, 95%CI 1.4-6.4) times higher than that in the lowest quartile. Women with higher urinary DMTP concentrations also have significantly higher risk of asthma at the ages 6-39 years and an apparently higher risk of chronic bronchitis at the ages 60-85. Overall cancer risk is significantly higher for female non-smokers aged 60-85 years in the higher urinary DMTP quartiles (OD = 2.7, 95% CI 1.3-5.9). Increasing risks of breast cancer for female smokers and prostate cancer for male smokers aged 60-85 years with higher exposure to organophosphorus insecticides in the US are also significant., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aim: The association between urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), an oxidative stress marker, and the incidence of cardiovascular disease (CVD) has not been confirmed because no previous studies evaluated 24-hour 8-OHdG excretion levels in the general population. We aimed to confirm the association between 24-hour urinary 8-OHdG levels and CVD risk among Japanese men and women., Methods: A nested case-control study was performed based on a 24-hour urine collection in a community-based cohort study performed from 1996 to 2005. Seventy-six cases (55 men and 21 women) who experienced their first CVD incidence during the follow-up period (median: 5.9 years) were recruited. The controls were frequency-matched 1:2, with each case for sex, age, area of residence, and baseline year. The 8-OHdG level was measured by enzyme-linked immunosorbent assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression models adjusted for body mass index, ethanol intake, smoking status, and estimated glomerular filtration rate., Results: The geometric mean and geometric standard deviation (SD) of 8-OHdG levels (nmol/day) for cases and controls were 35.5 (1.55) and 35.5 (1.54) for men and 32.1 (1.35) and 25.0 (1.39) for women, respectively. The multivariable OR (95% CI) of CVD incidence according to the 1-SD increment of the log-transformed 8-OHdG level was 2.08 (0.99-4.37) for women. The multivariable ORs (95% CIs) for the 1st (lowest) and 4th versus 2nd quartile according to 8-OHdG for men were 3.29 (1.02-10.61) and 2.77 (0.96-7.96), respectively., Conclusion: A high 8-OHdG level tended to be associated with CVD incidence among women.

Cardiovascular disease (CVD) begins early in children with chronic kidney disease (CKD). Reduced nitric oxide (NO) bioavailability has been associated with increased CVD in CKD patients. Children tend to have more exposure to acrylamide, one of the most common toxins in food. We aimed to determine whether urinary levels of acrylamide metabolites N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA) and N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-cysteine (GAMA) are associated with CV risk markers in children with CKD. Data on 112 children and adolescents ages three to 18 years old with CKD stage G1-G4 are reported. We observed that 24 h ambulatory blood pressure monitoring (ABPM) abnormalities were greater, and left ventricular (LV) mass and ambulatory arterial stiffness index (AASI) were higher in children with CKD stage G2-G4 versus G1. Patients with CKD stage G2-G4 had a lower urinary acrylamide level, but a higher AAMA-to-GAMA ratio than those with CKD stage G1. Urinary acrylamide level was negatively associated with high systolic blood pressure (SBP) and diastolic BP (DBP) load on 24 h ABPM. Lower urinary levels of acrylamide, AAMA, and GAMA were correlated with LV mass. Additionally, GAMA are superior to AAMA related to NO-related parameters, namely citrulline and symmetric dimethylarginine (SDMA). This study suggests that determinations of urinary acrylamide level and its metabolites in the early stages of pediatric CKD may identify patients at risk of CVD. Further studies should clarify mechanisms underlying acrylamide exposure to define the treatment for protection against CVD.

Background: Hyperuricemia has long been associated with increased cardiovascular risk, and arterial stiffness is proposed as a mediator. The present study is aimed at examining the associations of uric acid (UA) in blood and urine with arterial stiffness in a Chinese cohort., Methods: A total of 2296 participants (mean age: 43.0 years) from our previously established cohort of Hanzhong Adolescent Hypertension Study were included. The participants were classified as subjects with or without arterial stiffness, which was defined as brachial-ankle pulse wave velocity (baPWV) ≥ 1400 cm/s and/or carotid intima-media thickness (CIMT) ≥ 0.9 mm. Multivariate regression analyses were used to examine the relationship between serum and urinary UA and the risk of arterial stiffness after adjusting for age, gender, systolic blood pressure, fasting glucose, BMI, heart rate, total cholesterol, and triglycerides., Results: baPWV was positively correlated with urinary uric acid/creatinine ratio (uUA/Cre) ( β = 0.061, P < 0.001), while CIMT was correlated with uUA/Cre ( β = 0.085, P < 0.001) and fractional excretion of uric acid (FEUA) ( β = 0.044, P = 0.033) in all subjects. In addition, uUA/Cre was significantly associated with the risk of high baPWV [1.032 (1.019-1.045)] and arterial stiffness [1.028 (1.016-1.040)]., Conclusion: Our study showed that urinary UA excretion was significantly associated with the risk of arterial stiffness in Chinese adults. These findings suggest that UA, especially urinary UA, may be used as a simple, noninvasive marker for early detection of arterial stiffness in otherwise healthy subjects., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2020 Yang Wang et al.)

Background: Emerging evidence has identified cardiovascular system as a potential target of Bisphenol A (BPA). Although a few studies have revealed the relationship between BPA and the risk of several cardiovascular diseases (CVD) outcomes and CVD risk factors, no published studies have investigated the link between urinary BPA and the risk of stroke., Methods: Data were derived from the United States National Health and Nutrition Examination Surveys (NHANES), with a representative sample aged ≥20 years (n = 9139) from 2003 to 2014. We performed multivariable logistic regression model to estimate associations between quartiles and natural logarithm transformed urinary BPA concentrations and five specific CVD outcomes and total CVD., Results: In quartile analysis, highest level of urinary BPA was associated with increased prevalence of myocardial infarction (MI) (OR = 1.73, 95% CI = 1.11-2.69) and stroke (OR = 1.61, 95% CI = 1.09-2.36), when compared with those at the lowest quartile. Per unit (μg/g creatinine) increment in ln-transformed BPA concentration was shown to be significantly associated with 19%, 19%, 25%, 29%, 20%, and 16% increased odds ratios of prevalence of congestive heart failure, coronary heart disease (CHD), angina pectoris, MI, stroke and total CVD among total participants, respectively. Similar associations were found in males rather than in females., Conclusion: We provided the premier evidence of positive relationship between urinary BPA concentration and stroke in U.S., Population: Urinary BPA levels were also positively correlated with congestive heart failure, CHD, angina pectoris, MI, as well as total CVD. These associations were more evident in males. Well-coordinated and prospective studies are warranted to gain the human effects of BPA on CVD., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Albuminuria is a risk factor for cardiovascular events in diabetic patients, but it is unknown whether proteinuria is also a risk factor for cardiovascular events in these patients., Methods: The Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial was performed between 2002 and 2008 to examine the efficacy of low-dose aspirin therapy for the primary prevention of cardiovascular events in type 2 diabetes patients. After the JPAD trial was completed, we continued to follow up the patients until 2015. Among the 2536 patients participating in the JPAD study, 42 were excluded because proteinuria was not checked at registration. We divided the patients into two groups: proteinuria group (n = 446; proteinuria ± or greater) and non-proteinuria groups (n = 2048; proteinuria -). We compared the incident rate of cardiovascular events between the two groups., Results: During the observation period [median, 10.3 (10.2-10.5) years], 332 patients had a first cardiovascular event. Among 332 patients, 136 patients had cerebrovascular events and 54 patients had acute myocardial infarction. The incidence rate of cardiovascular events was significantly higher in the proteinuria group compared with the non-proteinuria group (HR 1.75, 95%CI 1.36-2.23, p < 0.0001). The incidence rate of cerebrovascular events was also significantly higher in the proteinuria group than in the non-proteinuria group (HR 1.71, 95%CI 1.14-2.49, p = 0.0064). The Cox proportional hazards model revealed that proteinuria was independently associated with cardiovascular events in diabetic patients without a history of cardiovascular events after adjusting for age, gender, body mass index, hemoglobin A1c level, duration of diabetes, and estimated glomerular filtration rate., Conclusions: Proteinuria was independently associated with the incidence of primary cardiovascular events in diabetic patients. Proteinuria detected by the dipstick test, which is simple and inexpensive, is useful as a first step in the risk assessment of diabetic patients., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Objective: Haptoglobin is an acute-phase reactant with pleiotropic functions. We aimed to study whether urine haptoglobin may predict risk of mortality in people with type 2 diabetes., Research Design and Methods: We employed a transethnic approach with a cohort of Asian origin (Singapore) ( N = 2,061) and a cohort of European origin (France) ( N = 1,438) included in the study. We used survival analyses to study the association of urine haptoglobin with risk of all-cause and cause-specific mortality., Results: A total of 365 and 525 deaths were registered in the Singapore cohort (median follow-up 7.5 years [interquartile range 3.5-12.8]) and French SURDIAGENE cohort (median follow-up 6.8 years [interquartile range 4.3-10.5], respectively. Singapore participants with urine haptoglobin in quartiles 2 to 4 had higher risk for all-cause mortality compared with quartile 1 (unadjusted hazard ratio [HR] 1.47 [95% CI 1.02-2.11], 2.28 [1.62-3.21], and 4.64 [3.39-6.35], respectively). The association remained significant in quartile 4 after multiple adjustments (1.68 [1.15-2.45]). Similarly, participants in the French cohort with haptoglobin in quartile 4 had significantly higher hazards for all-cause mortality compared with quartile 1 (unadjusted HR 2.67 [2.09-3.42] and adjusted HR 1.49 [1.14-1.96]). In both cohorts, participants in quartile 4 had a higher risk of mortality attributable to cardiovascular disease and infection but not malignant tumor., Conclusions: Urine haptoglobin predicts risk of mortality independent of traditional risk factors, suggesting that it may potentially be a novel biomarker for risk of mortality in patients with type 2 diabetes., (© 2019 by the American Diabetes Association.)