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Plant-based diets are associated with a lower risk of chronic diseases. Large-scale proteomics can identify objective biomarkers of plant-based diets, and improve our understanding of the pathways that link plant-based diets to health outcomes. This study investigated the plasma proteome of four different plant-based diets [overall plant-based diet (PDI), provegetarian diet, healthful plant-based diet (hPDI), and unhealthful plant-based diet (uPDI)] in the Atherosclerosis Risk in Communities (ARIC) Study and replicated the findings in the Framingham Heart Study (FHS) Offspring cohort. ARIC Study participants at visit 3 (1993–1995) with completed food frequency questionnaire (FFQ) data and proteomics data were divided into internal discovery (n = 7690) and replication (n = 2543) data sets. Multivariable linear regression was used to examine associations between plant-based diet indices (PDIs) and 4955 individual proteins in the discovery sample. Then, proteins that were internally replicated in the ARIC Study were tested for external replication in FHS (n = 1358). Pathway overrepresentation analysis was conducted for diet-related proteins. C-statistics were used to predict if the proteins improved prediction of plant-based diet indices beyond participant characteristics. In ARIC discovery, a total of 837 diet-protein associations (PDI = 233; provegetarian = 182; hPDI = 406; uPDI = 16) were observed at false discovery rate (FDR) < 0.05. Of these, 453 diet-protein associations (PDI = 132; provegetarian = 104; hPDI = 208; uPDI = 9) were internally replicated. In FHS, 167/453 diet-protein associations were available for external replication, of which 8 proteins (PDI = 1; provegetarian = 0; hPDI = 8; uPDI = 0) replicated. Complement and coagulation cascades, cell adhesion molecules, and retinol metabolism were over-represented. C-C motif chemokine 25 for PDI and 8 proteins for hPDI modestly but significantly improved the prediction of these indices individually and collectively (P value for difference in C-statistics<0.05 for all tests). Using large-scale proteomics, we identified potential candidate biomarkers of plant-based diets, and pathways that may partially explain the associations between plant-based diets and chronic conditions. [ABSTRACT FROM AUTHOR]

High to moderate levels of physical activity (PA) are associated with low risk of incident cardiovascular disease. However, it is unclear whether the benefits of PA in midlife extend to cardiovascular health following myocardial infarction (MI) in later life. Among 1,111 Atherosclerosis Risk in Communities study participants with incident MI during Atherosclerosis Risk in Communities follow-up (mean age 73 [SD 9] years at MI, 54% men, 21% Black), PA on average 11.9 (SD 6.9) years prior to incident MI (premorbid PA) was evaluated as the average score of PA between visit 1 (1987-1989) and visit 3 (1993-1995) using a modified Baecke questionnaire. Total and domain-specific PA (sport, nonsport leisure, and work PA) was analyzed for associations with composite and individual outcomes of mortality, recurrent MI, and stroke after index MI using multivariable Cox models. During a median follow-up of 4.6 (IQI 1.0-10.5) years after incident MI, 823 participants (74%) developed a composite outcome. The 10-year cumulative incidence of the composite outcome was lower in the highest, as compared to the lowest tertile of premorbid total PA (56% vs. 70%, respectively). This association remained statistically significant even after adjusting for potential confounders (adjusted hazard ratio [aHR] 0.80 [0.67-0.96] for the highest vs. lowest tertile). For individual outcomes, high premorbid total PA was associated with a low risk of recurrent MI (corresponding aHR 0.64 [0.44, 0.93]). When domain-specific PA was analyzed, similar results were seen for sport and work PA. The association was strongest in the first year following MI (e.g., aHR of composite outcome 0.66 [95% CI 0.47, 0.91] for the highest vs. lowest tertile of total PA). Premorbid PA was associated positively with post-MI cardiovascular health. Our results demonstrate the additional prognostic advantages of PA beyond reducing the risk of incident MI. [ABSTRACT FROM AUTHOR]

NT-proBNP is an important predictor of mortality but is inversely related to estimated glomerular filtration rate (eGFR). Whether the prognostic value of NT-proBNP is similar at different levels of kidney function is unknown. We evaluated the association of NT-proBNP with eGFR and its implications for all-cause and cardiovascular mortality risk in the general population. We included adults without prior cardiovascular disease from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. We used linear regression to characterize the cross-sectional associations of NT-proBNP with eGFR. We used Cox regression to assess the prospective associations of NT-proBNP with mortality across categories of eGFR. Among 11,456 participants (mean age 43 years, 48% female, 71% White, 11% Black), there was an inverse association between NT-proBNP and eGFR, which was stronger in those with more impaired kidney function. Per 15-unit decrease in eGFR, NT-proBNP was 4.3-fold higher for eGFR<30; 1.7-fold higher for eGFR 30 to 60, 1.4-fold higher for eGFR 61 to 90, 1.1-fold higher for eGFR 91 to 120 mL/min/1.73 m2. Over a median 17.6 years of follow-up, 2,275 deaths (622 cardiovascular) occurred. Higher NT-proBNP was associated with higher all-cause (HR per doubling of NT-proBNP: 1.20, 95% CI: 1.16-1.25) and cardiovascular mortality (HR: 1.34, 95% CI 1.25-1.44). Associations were similar across eGFR categories (P -interaction >.10). Adults with NT-proBNP≥450 pg/mL and eGFR<60 mL/min/1.73m2 had 3.4-fold higher all-cause mortality and 5.5-fold higher cardiovascular mortality risk, compared to those with NT-proBNP<125 pg/mL and eGFR>90 mL/min/1.73m2. Despite its strong inverse association with eGFR, NT-proBNP has robust associations with mortality across the full range of kidney function in the general US adult population. [Display omitted] [ABSTRACT FROM AUTHOR]

Background Greater adherence to plant-based diets is associated with a lower risk of incident chronic kidney disease (CKD). Metabolomics can help identify blood biomarkers of plant-based diets and enhance understanding of underlying mechanisms. Objectives Using untargeted metabolomics, we aimed to identify metabolites associated with 4 plant-based diet indices (PDIs) (overall PDI, provegetarian diet, healthful PDI, and unhealthful PDI) and incident CKD in 2 subgroups within the Atherosclerosis Risk in Communities study. Methods We calculated 4 PDIs based on participants' responses on an FFQ. We used multivariable linear regression to examine the association between 4 PDIs and 374 individual metabolites, adjusting for confounders. We used Cox proportional hazards regression to evaluate associations between PDI-related metabolites and incident CKD. Estimates were meta-analyzed across 2 subgroups (n 1 = 1762; n 2 = 1960). We calculated C-statistics to assess whether metabolites improved the prediction of those in the highest quintile compared to the lower 4 quintiles of PDIs, and whether PDI- and CKD-related metabolites predicted incident CKD beyond the CKD prediction model. Results We identified 82 significant PDI–metabolite associations (overall PDI = 27; provegetarian = 17; healthful PDI = 20; unhealthful PDI = 18); 11 metabolites overlapped across the overall PDI, provegetarian diet, and healthful PDI. The addition of metabolites improved prediction of those in the highest quintile as opposed to the lower 4 quintiles of PDIs compared with participant characteristics alone (range of differences in C-statistics = 0.026–0.104; P value ≤ 0.001 for all tests). Six PDI-related metabolites (glycerate, 1,5-anhydroglucitol, γ-glutamylalanine, γ-glutamylglutamate, γ-glutamylleucine, γ-glutamylvaline), involved in glycolysis, gluconeogenesis, pyruvate metabolism, and γ-glutamyl peptide metabolism, were significantly associated with incident CKD and improved prediction of incident CKD beyond the CKD prediction model (difference in C-statistics for 6 metabolites = 0.005; P value = 0.006). Conclusions In a community-based study of US adults, we identified metabolites that were related to plant-based diets and predicted incident CKD. These metabolites highlight pathways through which plant-based diets are associated with incident CKD. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2005.03.055 Byline: Brad C. Astor (a)(c), Josef Coresh (a)(b)(c)(d), Gerardo Heiss (e), Dan Pettitt (f), Mark J. Sarnak (g) Abstract: Kidney failure causes anemia and is associated with a very high risk of coronary heart disease (CHD). Mildly to moderately decreased kidney function is far more common and also is associated with an elevated prevalence of anemia and CHD risk. Recent data suggest an even higher risk of CHD when both conditions are present. Author Affiliation: (a) Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (b) Department of Biostatistics, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (c) Welch Center for Prevention, Epidemiology and Clinical Research, The Johns Hopkins University, Baltimore, MD (d) Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (e) Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC (f) Department of Health Economics and Outcomes Research, Amgen, Inc, Thousand Oaks, CA (g) Division of Nephrology, Department of Medicine, Tufts New England Medical Center, Boston, MA Article History: Received 30 November 2004; Accepted 27 March 2005 Article Note: (footnote) The ARIC Study was funded by contracts N01HC55015, N01HC55016, N01HC55018, N01HC55019, N01HC55020, N01HC55021, and N01HC55022 from the National Heart, Lung, and Blood Institute, Bethesda, Md. This work was supported in part by Amgen, Inc, Thousand Oaks, Calif, and by a grant from the American Heart Association Mid Atlantic Affiliate, Baltimore, Md, and by grant T32HL07024-23 from the National Heart, Lung, and Blood Institute (Dr Astor) and by an American Heart Association Established Investigator Award (Dr Coresh). We thank the staff and participants in the ARIC Study for their important contributions. The authors maintained control over the content of the manuscript.

Although immunoassays are the most widely used protein measurement method, aptamer-based methods such as the SomaScan platform can quantify up to 7000 proteins per biosample, creating new opportunities for unbiased discovery. However, there is limited research comparing the consistency of biomarker-disease associations between immunoassay and aptamer-based platforms. In a substudy of the TRIBE-AKI cohort, preoperative and postoperative plasma samples from 294 patients with previous immunoassay measurements were analyzed using the SomaScan platform. Inter-platform Spearman correlations (rs) and biomarker-AKI associations were compared across 30 preoperative and 34 postoperative immunoassay-aptamer pairs. Possible factors contributing to inter-platform differences were examined including target protein characteristics, immunoassay, and SomaScan coefficients of variation, other assay characteristics, and sample storage time. The median rs was 0.54 (interquartile range [IQR] 0.34-0.83) in postoperative samples and 0.41 (IQR 0.21-0.69) in preoperative samples. We observed a trend of greater rs in biomarkers with greater concentrations; the Spearman correlation between the concentration of protein and the inter-platform correlation was 0.64 in preoperative pairs and 0.53 in postoperative pairs. Of proteins measured by immunoassays, we observed significant biomarker-AKI associations for 13 proteins preop and 24 postop; of all corresponding aptamers, 8 proteins preop and 12 postop. All proteins significantly associated with AKI as measured by SomaScan were also significantly associated with AKI as measured by immunoassay. All biomarker-AKI odds ratios were significantly different (P < 0.05) between platforms in 14% of aptamer-immunoassay pairs, none of which had high (rs > 0.50) inter-platform correlations. Although similar biomarker-disease associations were observed overall, biomarkers with high physiological concentrations tended to have the highest-confidence inter-platform operability in correlations and biomarker-disease associations. Aptamer assays provide excellent precision and an unprecedented coverage and promise for disease associations but interpretation of results should keep in mind a broad range of correlations with immunoassays. [ABSTRACT FROM AUTHOR]

Background: In individuals with chronic kidney disease (CKD), healthy dietary patterns are inversely associated with CKD progression. Metabolomics, an approach that measures many small molecules in biofluids, can identify biomarkers of healthy dietary patterns.Objectives: We aimed to identify known metabolites associated with greater adherence to 4 healthy dietary patterns in CKD patients.Methods: We examined associations between 486 known plasma metabolites and Healthy Eating Index (HEI)-2015, Alternative Healthy Eating Index (AHEI)-2010, the Dietary Approaches to Stop Hypertension (DASH) diet, and alternate Mediterranean diet (aMED) in 1056 participants (aged 21-74 y at baseline) in the Chronic Renal Insufficiency Cohort (CRIC) Study. Usual dietary intake was assessed using a semiquantitative FFQ. We conducted multivariable linear regression models to study associations between healthy dietary patterns and individual plasma metabolites, adjusting for sociodemographic characteristics, health behaviors, and clinical factors. We used principal component analysis to identify groups of metabolites associated with individual food components within healthy dietary patterns.Results: After Bonferroni correction, we identified 266 statistically significant diet-metabolite associations (HEI: n = 60; AHEI: n = 78; DASH: n = 77; aMED: n = 51); 78 metabolites were associated with >1 dietary pattern. Lipids with a longer acyl chain length and double bonds (unsaturated) were positively associated with all 4 dietary patterns. A metabolite pattern low in saturated diacylglycerols and triacylglycerols, and a pattern high in unsaturated triacylglycerols was positively associated with intake of healthy food components. Plasmalogens were negatively associated with the consumption of nuts and legumes and healthy fat, and positively associated with the intake of red and processed meat.Conclusions: We identified many metabolites associated with healthy dietary patterns, indicative of food consumption. If replicated, these metabolites may be considered biomarkers of healthy dietary patterns in patients with CKD. [ABSTRACT FROM AUTHOR]

Background: High diet quality is associated with a lower risk of chronic diseases. Metabolomics can be used to identify objective biomarkers of diet quality.Objectives: We used metabolomics to identify serum metabolites associated with 4 diet indices and the components within these indices in 2 samples from African Americans and European Americans.Methods: We studied cross-sectional associations between known metabolites and Healthy Eating Index (HEI)-2015, Alternative Healthy Eating Index (AHEI)-2010, the Dietary Approaches to Stop Hypertension Trial (DASH) diet, alternate Mediterranean diet (aMED), and their components using untargeted metabolomics in 2 samples (n1 = 1,806, n2 = 2,056) of the Atherosclerosis Risk in Communities study (aged 45-64 y at baseline). Dietary intakes were assessed using an FFQ. We used multivariable linear regression models to examine associations between diet indices and serum metabolites in each sample, adjusting for participant characteristics. Metabolites significantly associated with diet indices were meta-analyzed across 2 samples. C-statistics were calculated to examine if these candidate biomarkers improved prediction of individuals in the highest compared with lowest quintile of diet scores beyond participant characteristics.Results: Seventeen unique metabolites (HEI: n = 6; AHEI: n = 5; DASH: n = 14; aMED: n = 2) were significantly associated with higher diet scores after Bonferroni correction in sample 1 and sample 2. Six of 17 significant metabolites [glycerate, N-methylproline, stachydrine, threonate, pyridoxate, 3-(4-hydroxyphenyl)lactate)] were associated with ≥1 dietary pattern. Candidate biomarkers of HEI, AHEI, and DASH distinguished individuals with highest compared with lowest quintile of diet scores beyond participant characteristics in samples 1 and 2 (P value for difference in C-statistics <0.02 for all 3 diet indices). Candidate biomarkers of aMED did not improve C-statistics beyond participant characteristics (P value = 0.930).Conclusions: A considerable overlap of metabolites associated with HEI, AHEI, DASH, and aMED reflects the similar food components and similar metabolic pathways involved in the metabolism of healthy diets in African Americans and European Americans. [ABSTRACT FROM AUTHOR]

Background Beverages are a source of calories and other bioactive constituents but are an understudied aspect of the diet. Different beverages have varying effects on health outcomes. Objectives We created the Healthy Beverage Score (HBS) to characterize participants' beverage patterns and examined its association with chronic kidney disease (CKD) progression, incident cardiovascular disease (CVD), and all-cause mortality among individuals with CKD. Methods We conducted a prospective analysis of 2283 adults aged 21–74 y with a baseline estimated glomerular filtration rate of 20–70 mL · min−1 · 1.73 m−2 from the Chronic Renal Insufficiency Cohort. Diet was assessed using a 124-item FFQ at visit 1 (2003–2008). The HBS, ranging from 7 to 28 possible points, consisted of 7 components, each scored from 1 to 4 based on rank distribution by quartile, except alcohol, which was based on sex-specific cutoffs. Participants were given more points for higher consumption of low-fat milk and of coffee/tea, for moderate alcohol, and for lower consumption of 100% fruit juice, whole-fat milk, artificially sweetened beverages, and sugar-sweetened beverages. CKD progression, incident CVD, and mortality were ascertained through January 2018. We conducted multivariable Cox proportional hazards models. Results There were 815 cases of CKD progression, 285 cases of incident CVD, and 725 deaths over a maximum of 14 y of follow-up. Compared with participants in the lowest tertile of the HBS, participants in the highest tertile had a 25% lower likelihood of CKD progression (HR: 0.75; 95% CI: 0.63, 0.89; P -trend = 0.001) and a 17% lower likelihood of all-cause mortality (HR: 0.83; 95% CI: 0.69, 1.00; P -trend = 0.04) after adjusting for sociodemographic, clinical, and dietary factors. There was no significant trend for incident CVD. Conclusions Among individuals with CKD, a healthier beverage pattern was inversely associated with CKD progression and all-cause mortality. Beverage intake may be an important modifiable target in preventing adverse outcomes for individuals with CKD. [ABSTRACT FROM AUTHOR]

Background: Several distinct plant-based diet indices (PDIs) have been developed to characterize adherence to plant-based diets.Objective: We contrasted 5 PDIs in a community-based cohort by assessing characteristics of the diet and evaluating whether these PDIs are associated with risk of incident hypertension.Methods: Using FFQ data from adults (45-64 y, n = 8041) without hypertension at baseline in the Atherosclerosis Risk in Communities (ARIC) Study, we scored participants' diets using the overall PDI (oPDI), healthy PDI (hPDI), less healthy (unhealthy) PDI (uPDI), provegetarian diet index, and PDI from the Rotterdam Study (PDI-Rotterdam). For the oPDI, provegetarian diet, and PDI-Rotterdam, higher intakes of all or selected plant foods received higher scores. For the hPDI, higher intakes of plant foods identified as healthful received higher scores. For the uPDI, higher intakes of less healthy plant foods received higher scores. All indices scored higher intakes of animal foods lower. We examined agreement between indices, and whether scores on these indices were associated with risk of hypertension using Cox proportional hazard models.Results: The PDIs were moderately-to-strongly correlated and largely ranked subjects consistently, except for the uPDI. Over a median follow-up of 13 y, 6044 incident hypertension cases occurred. When adjusted for sociodemographic characteristics, other dietary factors, and health behaviors, the highest compared with the lowest quintile for adherence to the oPDI, hPDI, and provegetarian diet was associated with a 12-16% lower risk of hypertension (all P-trend <0.05). Highest adherence to the uPDI was associated with a 13% higher risk of hypertension, when clinical factors were further adjusted for (P-trend = 0.03). No significant association was observed with the PDI-Rotterdam. The oPDI, hPDI, and provegetarian diet moderately improved the prediction of hypertension.Conclusions: In middle-aged US adults, despite moderate agreement in ranking subjects across PDIs, operational differences can affect the ability to detect diet-disease associations, such as hypertension. [ABSTRACT FROM AUTHOR]

Background: The Healthy Eating Index-2015 (HEI-2015) score measures adherence to recommendations from the 2015-2020 Dietary Guidelines for Americans. The HEI-2015 was altered from the HEI-2010 by reclassifying sources of dietary protein and replacing the empty calories component with 2 new components: saturated fats and added sugars.Objectives: Our aim was to assess whether the HEI-2015 score, along with 3 other previously defined indices, were associated with incident cardiovascular disease (CVD), CVD mortality, and all-cause mortality.Methods: We conducted a prospective analysis of 12,413 participants aged 45-64 y (56% women) from the Atherosclerosis Risk in Communities (ARIC) Study. The HEI-2015, Alternative Healthy Eating Index-2010 (AHEI-2010), alternate Mediterranean (aMed) diet, and Dietary Approaches to Stop Hypertension Trial (DASH) scores were computed using the average dietary intakes of Visits 1 (1987-1989) and 3 (1993-1995). Incident CVD, CVD mortality, and all-cause mortality data were ascertained from baseline through 31 December, 2017. We used Cox proportional hazards models to estimate HRs and 95% CIs.Results: There were 4509 cases of incident CVD, 1722 cases of CVD mortality, and 5747 cases of all-cause mortality over a median of 24-25 y of follow-up. Compared with participants in the lowest quintile of HEI-2015, participants in the highest quintile had a 16% lower risk of incident CVD (HR: 0.84; 95% CI: 0.76-0.93; P-trend < 0.001), 32% lower risk of CVD mortality (HR: 0.68; 95% CI: 0.58-0.80; P-trend < 0.001), and 18% lower risk of all-cause mortality (HR: 0.82; 95% CI: 0.75-0.89; P-trend < 0.001) after adjusting for demographic and lifestyle covariates. There were similar protective associations for AHEI-2010, aMed, and DASH scores, and no significant interactions by race.Conclusions: Higher adherence to the 2015-2020 Dietary Guidelines for Americans was associated with lower risks of incident CVD, CVD mortality, and all-cause mortality among US adults. [ABSTRACT FROM AUTHOR]

High-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at the time of myocardial infarction (MI) are strong predictors of prognosis. However, whether their premorbid (before MI occurrence) levels are associated with prognosis after incident MI is unknown.Methods: In 1,054 participants from the Atherosclerosis Risk in Communities Study with incident MI, we evaluated premorbid levels of hs-cTnT and NT-proBNP measured on median 5.8 (interquartile interval 3.0-11.5 [mean 5.5]) years prior to incident MI and their associations with subsequent composite and individual outcomes of all-cause mortality, cardiovascular mortality, recurrent MI, heart failure, and stroke.Results: During a median follow-up of 3.0 years after MI, 801 participants developed the composite outcome. Both hs-cTnT and NT-proBNP were independently associated with the composite outcome after incident MI. Among individual outcomes, all-cause mortality, cardiovascular mortality, and heart failure showed significant associations with both cardiac markers. Overall, NT-proBNP demonstrated a more evident relationship than hs-cTnT. Indeed, the addition of premorbid NT-proBNP alone, but not hs-cTnT alone, to conventional predictors at incident MI significantly improved risk prediction of the composite outcome after incident MI (Δc-statistic 0.013 [95% CI 0.005-0.022] from 0.691 with conventional predictors).Conclusions: Premorbid levels of hs-cTnT and NT-proBNP assessed on average 6 years prior to incident MI were associated with adverse outcomes after incident MI. These results further highlight the importance of cardiac health at an earlier stage of life. [ABSTRACT FROM AUTHOR]

Background Adherence to healthy dietary patterns, measured by the Healthy Eating Index (HEI), Alternative Healthy Eating Index (AHEI), and alternate Mediterranean diet (aMed) scores, is associated with a reduced risk of cardiovascular disease. The association between these scores and chronic kidney disease (CKD) is undetermined. Objective We aimed to estimate the association between the HEI, AHEI, and aMed scores and risk of incident CKD. Methods We conducted a prospective analysis in 12,155 participants aged 45–64 y from the Atherosclerosis Risk in Communities (ARIC) Study. We calculated HEI-2015, AHEI-2010, and aMed scores for each participant and categorized them into quintiles of each dietary score. Incident CKD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2 accompanied by ≥25% decline in estimated glomerular filtration rate, a kidney disease–related hospitalization or death, or end-stage renal disease. We used cause-specific hazard models to estimate risk of CKD from the quintile of the dietary score through to 31 December 2017. Results There were 3980 cases of incident CKD over a median follow-up of 24 y. Participants who had higher adherence to the HEI-2015, AHEI-2010, and aMed scores were more likely to be female, have higher educational attainment, higher income level, be nonsmokers, more physically active, and diabetic compared with participants who scored lower. All 3 dietary scores were associated with lower CKD risk (P -trend < 0.001). Participants who were in the highest quintile of HEI-2015 score had a 17% lower risk of CKD (HR: 0.83; 95% CI: 0.74, 0.92) compared with participants in the lowest quintile. Those in quintile 5 of AHEI-2010 and aMed scores, respectively, had a 20% and 13% lower risk of CKD compared with those in quintile 1. Conclusion Higher adherence to healthy dietary patterns during middle age was associated with lower risk of CKD. [ABSTRACT FROM AUTHOR]

Background: Dietary acid load is a clinically important aspect of the diet that reflects the balance between acid-producing foods, for example, meat and cheese, and base-producing foods, for example, fruits and vegetables.Methods: We used metabolomics to identify blood biomarkers of dietary acid load in 2 independent studies of chronic kidney disease patients: the African American Study of Kidney Disease and Hypertension (AASK, n = 689) and the Modification of Diet in Renal Disease (MDRD, n = 356) study. Multivariable linear regression was used to assess the cross-sectional association between serum metabolites whose identity was known (outcome) and dietary acid load (exposure), estimated with net endogenous acid production (NEAP) based on 24-h urine urea nitrogen and potassium, and adjusted for age, sex, race, randomization group, measured glomerular filtration rate, log-transformed urine protein-to-creatinine ratio, history of cardiovascular disease, BMI, and smoking status.Results: Out of the 757 known, nondrug metabolites identified in AASK, 26 were significantly associated with NEAP at the Bonferroni threshold for significance (P < 6.6 × 10-5). Twenty-three of the 26 metabolites were also identified in the MDRD study, and 13 of the 23 (57%) were significantly associated with NEAP (P < 2.2 × 10-3), including 5 amino acids (S-methylmethionine, indolepropionylglycine, indolepropionate, N-methylproline, N-δ-acetylornithine), 2 cofactors and vitamins (threonate, oxalate), 1 lipid (chiro-inositol), and 5 xenobiotics (methyl glucopyranoside, stachydrine, catechol sulfate, hippurate, and tartronate). Higher levels of all 13 replicated metabolites were associated with lower NEAP in both AASK and the MDRD study.Conclusion: Metabolomic profiling of serum specimens from kidney disease patients in 2 study populations identified 13 replicated metabolites associated with dietary acid load. Additional studies are needed to validate these compounds in healthy populations. These 13 compounds may potentially be used as objective markers of dietary acid load in future nutrition research studies. [ABSTRACT FROM AUTHOR]

Background Accurate assessment of dietary intake is essential, but self-report of dietary intake is prone to measurement error and bias. Discovering metabolic consequences of diets with lower compared with higher protein intake could elucidate new, objective biomarkers of protein intake. Objectives The goal of this study was to identify serum metabolites associated with dietary protein intake. Methods Metabolites were measured with the use of untargeted, reverse-phase ultra-performance liquid chromatography–tandem mass spectrometry quantification in serum specimens collected at the 12-mo follow-up visit in the Modification of Diet in Renal Disease (MDRD) Study from 482 participants in study A (glomerular filtration rate: 25–55 mL · min−1 · 1.73 m−2) and 192 participants in study B (glomerular filtration rate: 13–24 mL · min−1 · 1.73 m−2). We used multivariable linear regression to test for differences in log-transformed metabolites (outcome) according to randomly assigned dietary protein intervention groups (exposure). Statistical significance was assessed at the Bonferroni-corrected threshold: 0.05/1193 = 4.2 × 10−5. Results In study A, 130 metabolites (83 known from 28 distinct pathways, including 7 amino acid pathways; 47 unknown) were significantly different between participants randomly assigned to the low-protein diet compared with the moderate-protein diet. In study B, 32 metabolites (22 known from 8 distinct pathways, including 4 amino acid pathways; 10 unknown) were significantly different between participants randomly assigned to the very-low-protein diet compared with the low-protein diet. A total of 11 known metabolites were significantly associated with protein intake in the same direction in both studies A and B: 3-methylhistidine, N-acetyl-3-methylhistidine, xanthurenate, isovalerylcarnitine, creatine, kynurenate, 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPE (P-16:0/20:4), 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (P-18:0/20:4), 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPC (P-16:0/20:4), sulfate, and γ-glutamylalanine. Conclusions Among patients with chronic kidney disease, an untargeted serum metabolomics platform identified multiple pathways and metabolites associated with dietary protein intake. Further research is necessary to characterize unknown compounds and to examine these metabolites in association with dietary protein intake among individuals without kidney disease. This trial was registered at clinicaltrials.gov as NCT03202914. [ABSTRACT FROM AUTHOR]

Background: The Dietary Approaches to Stop Hypertension (DASH) dietary pattern is recommended for cardiovascular disease risk reduction. Assessment of dietary intake has been limited to subjective measures and a few biomarkers from 24-h urine collections. Objective: The aim of the study was to use metabolomics to identify serum compounds that are associated with adherence to the DASH dietary pattern. Design: We conducted untargeted metabolomic profiling in serum specimens collected at the end of 8 wk following the DASH diet (n = 110), the fruit and vegetables diet (n = 111), or a control diet (n = 108) in a multicenter, randomized clinical feeding study (n = 329). Multivariable linear regression was used to determine the associations between the randomized diets and individual log-transformed metabolites after adjustment for age, sex, race, education, body mass index, and hypertension. Partial least-squares discriminant analysis (PLS-DA) was used to identify a panel of compounds that discriminated between the dietary patterns. The area under the curve (C statistic) was calculated as the cumulative ability to distinguish between dietary patterns. We accounted for multiple comparisons with the use of the Bonferroni method (0.05 of 818 metabolites = 6.11 × 10-5). Results: Serum concentrations of 44 known metabolites differed significantly between participants randomly assigned to the DASH diet compared with both the control diet and the fruit and vegetables diet, which included an amino acid, 2 cofactors and vitamins (n = 2), and lipids (n = 41). With the use of PLS-DA, component 1 explained 29.4% of the variance and component 2 explained 12.6% of the variance. The 10 most influential metabolites for discriminating between the DASH and control dietary patterns were N-methylproline, stachydrine, tryptophan betaine, theobromine, 7-methylurate, chiro-inositol, 3-methylxanthine, methyl glucopyranoside, β-cryptoxanthin, and 7-methylxanthine (C statistic = 0.986). Conclusions: An untargeted metabolomic platform identified a broad array of serum metabolites that differed between the DASH diet and 2 other dietary patterns. This newly identified metabolite panel may be used to assess adherence to the DASH dietary pattern. [ABSTRACT FROM AUTHOR]

Background: A high fructose intake has been shown to be associated with increased serum urate concentration, whereas ascorbate (vitamin C) may lower serum urate by competing with urate for renal reabsorption.Objective: We assessed the combined association, as the fructose:vitamin C intake ratio, and the separate associations of dietary fructose and vitamin C intakes on prevalent hyperuricemia.Methods: We conducted cross-sectional analyses of dietary intakes of fructose and vitamin C and serum urate concentrations among Jackson Heart Study participants, a cohort of African Americans in Jackson, Mississippi, aged 21-91 y. In the analytic sample (n = 4576), multivariable logistic regression was used to examine the separate associations of dietary intakes of fructose and vitamin C and the fructose:vitamin C intake ratio with prevalent hyperuricemia (serum urate ≥7 mg/dL), after adjusting for age, sex, smoking, waist circumference, systolic blood pressure, estimated glomerular filtration rate, diuretic medication use, vitamin C supplement use, total energy intake, alcohol consumption, and dietary intake of animal protein. Analyses for individual dietary factors (vitamin C, fructose) were adjusted for the other dietary factor.Results: In the fully adjusted model, there were 17% greater odds of hyperuricemia associated with a doubling of the fructose:vitamin C intake ratio (OR: 1.17; 95% CI: 1.08, 1.28), 20% greater odds associated with a doubling of fructose intake (OR: 1.20; 95% CI: 1.08, 1.34), and 13% lower odds associated with a doubling of vitamin C intake (OR: 0.87; 95% CI: 0.78, 0.97). Dietary fructose and the fructose:vitamin C intake ratio were more strongly associated with hyperuricemia among men than women (P-interaction ≤ 0.04).Conclusion: Dietary intakes of fructose and vitamin C are associated with prevalent hyperuricemia in a community-based population of African Americans. [ABSTRACT FROM AUTHOR]

Background & Aims Proton pump inhibitors (PPI) have been associated with acute kidney injury and recent studies suggest that they may be associated with the risk of chronic kidney disease (CKD). Methods We performed a retrospective analysis using the Stockholm creatinine measurements database, which contains information on diagnoses, dispensation claims, and laboratory test results for all citizens in the Stockholm region from 2007 through 2010. We identified new users of PPIs (n = 105,305) and new users of H 2 blockers (H 2 B; n = 9578); data on renal outcomes were collected for a median 2.7 years. The primary outcome was progression CKD, defined as doubling of creatinine or decrease in estimated glomerular filtration rate of 30% or more. Secondary outcomes were end-stage renal disease and acute kidney injury. Complete collection of repeated PPI and H 2 B dispensations at pharmacies in Sweden allowed modeling the time-dependent risk associated with cumulative PPI exposure. Results Users of PPIs, compared with users of H 2 Bs, had an increased risk for doubled levels of creatinine (1985 events; adjusted hazard ratio [HR], 1.26; 95% CI, 1.05–1.51) and decrease in estimated glomerular filtration rate of 30% or more (11,045 events; 1.26; 95% CI, 1.16–1.36). PPI use also associated with development of end-stage renal disease (HR, 2.40; 95% CI, 0.76–7.58) and acute kidney injury (HR, 1.30; 95% CI, 1.00–1.69). There was a graded association between cumulative exposure to PPIs and risk of CKD progression. This was not the case for cumulative H 2 B use. Conclusions Initiation of PPI therapy and cumulative PPI exposure is associate with increased risk of CKD progression in a large, North European healthcare system. Although consistent, the association was modest in magnitude, and cannot exclude residual confounding. [ABSTRACT FROM AUTHOR]

Background: Individuals with chronic kidney disease, particularly those requiring dialysis, are at high risk of sudden cardiac death (SCD). However, comprehensive data for the full spectrum of kidney function and SCD risk in the community are sparse. Furthermore, newly developed equations for estimated glomerular filtration rate (eGFR) and novel filtration markers might add further insight to the role of kidney function in SCD.Methods: We investigated the associations of baseline eGFRs using serum creatinine, cystatin C, or both (eGFRcr, eGFRcys, and eGFRcr-cys); cystatin C itself; and β2-microglobulin (B2M) with SCD (205 cases through 2001) among 13,070 black and white ARIC participants at baseline during 1990-1992 using Cox regression models accounting for potential confounders.Results: Low eGFR was independently associated with SCD risk: for example, hazard ratio for eGFR <45 versus ≥90mL/(min 1.73m(2)) was 3.71 (95% CI 1.74-7.90) with eGFRcr, 5.40 (2.97-9.83) with eGFRcr-cys, and 5.24 (3.01-9.11) with eGFRcys. When eGFRcr and eGFRcys were included together in a single model, the association was only significant for eGFRcys. When three eGFRs, cystatin C, and B2M were divided into quartiles, B2M demonstrated the strongest association with SCD (hazard ratio for fourth quartile vs first quartile 3.48 (2.03-5.96) vs ≤2.7 for the other kidney markers).Conclusions: Kidney function was independently and robustly associated with SCD in the community, particularly when cystatin C or B2M was used. These results suggest the potential value of kidney function as a risk factor for SCD and the advantage of novel filtration markers over eGFRcr in this context. [ABSTRACT FROM AUTHOR]

Background: Stroke is a leading cause of morbidity and mortality among adults in the U.S. Ideal levels of the Life's Simple 7 (LS7) are associated with lower cardiovascular disease (CVD) and all-cause mortality. However, the association of LS7 with CVD, recurrent stroke, and all-cause mortality after incident stroke is unknown.Methods: We used data from the ARIC study, a cohort of 13,508 adults from four US communities, 45-64 years old at baseline (1987-1989). Cardiovascular hospitalizations and mortality were ascertained in follow-up through December 31st, 2017. We defined cardiovascular health (CVH) based on AHA definitions for LS7 (range 0-14) and categorized CVH into four levels: LS7 0-3, 4-6, 7-9, and ≥10 (ideal LS7), according to prior studies. Outcomes included incident stroke, CVD, recurrent stroke, all-cause mortality, and a composite outcome including all the above. Adjusted hazard ratios (95% CI) were estimated with Cox proportional hazards regression models.Results: Median (25%-75%) follow-up for incident stroke was 28 (18.6-29.2) years. Participants with incident stroke were 55.7 (SD 5.6) years-old at baseline, 53% were women and 35% Black. Individuals with LS7 score ≥10 had 65% lower risk (HR: 0.35; 95% CI: 0.29-0.41) of incident stroke than those with LS7 4-6 (reference group). Of 1,218 participants with incident stroke, 41.2% (n=502) had composite CVD and 68.3% (n=832) died during a median (25%-75%) follow-up of 4.0 (0.76-9.95) years. Adjusted HR (95% CI) for stroke survivors with LS7≥10 at baseline were 0.74 (0.58-0.94) for the composite outcome, 0.38(0.17-0.85) for myocardial infarction, 0.60 (0.40-0.90) for heart failure, 0.63 (0.48-0.84) for all-cause mortality, and 0.65 (0.39-1.08) for recurrent stroke.Conclusions: Good and excellent midlife cardiovascular health are associated with lower risks of incident stroke and CVD after stroke. Clinicians should stress the importance of a healthy lifestyle for primary and secondary CVD prevention. [ABSTRACT FROM AUTHOR]

Background According to a recent meta-analysis, parathyroid hormone (PTH) excess is associated with increased cardiovascular disease (CVD) risk, but existing studies are limited. We examined in a prospective study the association of PTH with the incidence of CVD, taking into account vitamin D and other confounding variables. Methods The ARIC study measured PTH using a second-generation assay (Roche, Indianapolis, IN) in stored serum samples from 1990 to 1992 and related levels in 10,392 adults to incident cardiovascular outcomes (coronary heart disease [n = 808], heart failure [n = 1,294], stroke [n = 586], peripheral artery disease [n = 873], atrial fibrillation [n = 1,190], and CVD mortality [n = 647]) through 2010 (median follow-up 19 years). Results Contrary to the hypothesis, PTH level was not associated positively with any CVD outcome. The associations of incident heart failure, peripheral artery disease, and CVD mortality with PTH actually were weakly inverse ( P trend = .02-.04) in the most fully adjusted models. For example, the hazard ratios across PTH quartiles were 1.00, 1.07, 1.07, and 0.96 ( P trend = .74) for coronary heart disease incidence and were 1.00, 0.69, 0.74, and 0.74 ( P trend = .02) for CVD mortality. Patterns were similar when restricted to participants with normal baseline kidney function. Conclusions This large prospective study failed to support the hypothesis that elevated PTH is an independent risk marker for incident CVD. When our data were added to the previous meta-analysis, the pooled hazard ratio remained statistically significant but weakened. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) is a major source of morbidity and mortality, particularly among the elderly. Magnesium, phosphorus, and calcium are micronutrients traditionally viewed in relation to bone health or chronic kidney disease. However, they also may be associated with risk of cardiovascular disease through a broad range of physiologic roles. Objective: With the use of data from the Atherosclerosis Risk in Communities (ARIC) cohort, we tested the hypotheses that the incidence of HF is greater among individuals with low serum magnesium and those with high serum phosphorus and calcium. Design: A total of 14,709 African Americans (27%) and whites from the ARIC cohort [aged 45-64 y at baseline (1987-1989)] were observed through 2009. Proportional hazards regression was used to explore associations between biomarkers and incident HF. Serum calcium was corrected for serum albumin. Models were adjusted for demographics, behaviors, and physiologic characteristics. Results: A total of 2250 incident HF events accrued over a median follow-up of 20.6 y. Participants in the lowest (≥1.4 mEq/L) compared with the highest (≤1.8 mEq/L) category of magnesium were at greater HF risk (HR: 1.71; 95% CI: 1.46, 1.99). For phosphorus, there appeared to be a threshold whereby only those in the highest quintile were at greater HF risk [HR(Q5 vs Q1): 1.34; 95% CI: 1.16, 1.54]. Higher concentrations of calcium were also associated with greater risk of HF [HR(Q5 vs Q1): 1.24; 95% CI: 1.07, 1.43]. Results were not modified by race, sex, or kidney function and were similar when incident coronary heart disease was included as a time-varying covariate. Conclusions: Low serum magnesium and high serum phosphorus and calcium were independently associated with greater risk of incident HF in this population-based cohort. Whether these biomarkers will be useful candidates for HF risk prediction or targets for prevention remains to be seen. [ABSTRACT FROM AUTHOR]

Using a community-based cohort we studied the association between changes in the estimated glomerular filtration rate (eGFR) over time and the risk of all-cause mortality. We identified 529,312 adults who had at least three outpatient eGFR measurements over a 4-year period from a provincial laboratory repository in Alberta, Canada. Two indices of change in eGFR were evaluated: the absolute annual rate of change (in ml/min per 1.73 m2 per year) and the annual percentage change (percent/year). The adjusted mortality risk associated with each category of change in eGFR was assessed, using stable eGFR (no change) as the reference. Over a median follow-up of 2.5 years there were 32,372 deaths. Compared to the reference participants, those with the greatest absolute annual decline less than or equal to 5 ml/min per 1.73 m2 per year had significantly increased mortality (hazard ratio of 1.52) adjusted for covariates and kidney function at baseline (last eGFR measurement). Participants with the greatest increase in eGFR of 5 ml/min per 1.73 m2 per year or more also had significantly increased mortality (adjusted hazard ratio of 2.20). A similar pattern was found when change in eGFR was quantified as an annual percentage change. Thus, both declining and increasing eGFR were independently associated with mortality and underscore the importance of identifying change in eGFR over time to improve mortality risk prediction. [ABSTRACT FROM AUTHOR]

BACKGROUND: The Modification of Diet in Renal Disease (MDRD) Study equation underestimates measured glomerular filtration rate (GFR) at levels>60 mL/min/1.73 m2, with variable accuracy among subgroups; consequently, estimated GFR (eGFR)⩾60 mL/min/1.73 m2 is not reported by clinical laboratories. Here, performance of a more accurate GFR-estimating equation, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, is reported by level of GFR and clinical characteristics. STUDY DESIGN: Test of diagnostic accuracy. SETTING & PARTICIPANTS: Pooled data set of 3,896 people from 16 studies with measured GFR (not used for the development of either equation). Subgroups were defined by eGFR, age, sex, race, diabetes, prior solid-organ transplant, and body mass index. INDEX TESTS: eGFR from the CKD-EPI and MDRD Study equations and standardized serum creatinine. REFERENCE TEST: Measured GFR using urinary or plasma clearance of exogenous filtration markers. RESULTS: Mean measured GFR was 68±36 (SD) mL/min/1.73 m2. For eGFR<30 mL/min/1.73 m2, both equations have similar bias (median difference compared with measured GFR). For eGFR of 30-59 mL/min/1.73 m2, bias was decreased from 4.9 to 2.1 mL/min/1.73 m2 (57% improvement). For eGFR of 60-89 mL/min/1.73 m2, bias was decreased from 11.9 to 4.2 mL/min/1.73 m2 (61% improvement). For eGFR of 90-119 mL/min/1.73 m2, bias was decreased from 10.0 to 1.9 mL/min/1.73 m2 (75% improvement). Similar or improved performance was noted for most subgroups with eGFR<90 mL/min/1.73 m2, other than body mass index<20 kg/m2, with greater variation noted for some subgroups with eGFR⩾90 mL/min/1.73 m2. LIMITATIONS: Limited number of elderly people and racial and ethnic minorities with measured GFR. CONCLUSIONS: The CKD-EPI equation is more accurate than the MDRD Study equation overall and across most subgroups. In contrast to the MDRD Study equation, eGFR⩾60 mL/min/1.73 m2 can be reported using the CKD-EPI equation. [ABSTRACT FROM AUTHOR]

Background: A substantial portion of the public health burden of heart failure is due to hospitalizations, many of which are for causes other than cardiovascular disease. We assessed whether left ventricular (LV) systolic dysfunction was associated with increased risk of both cardiovascular and noncardiovascular hospitalizations in a community sample of African Americans. Methods: African American participants from the Jackson, MS, site of the Atherosclerosis Risk in Communities (ARIC) study who underwent echocardiography were followed for 12 years. Hospitalization rates among individuals with and without LV systolic dysfunction were compared using negative binomial regression. Results: Among 2,416 participants with echocardiograms, LV systolic dysfunction was found in 61 (2.5%). Participants with LV dysfunction experienced 366 hospitalizations, a rate of 1.27 per person-year, compared with 0.25 per person-year among individuals without LV dysfunction. The incidence rate ratio adjusted for demographics, comorbidities, and other risk factors was 3.11 (95% CI 2.22-4.35). The adjusted rate ratios were 4.76 (95% CI 2.90-7.20) for cardiovascular and 2.67 (95% CI 1.82-3.90) for noncardiovascular diagnoses, with similar findings in the subset of individuals with asymptomatic LV dysfunction. The percentage attributable risks for hospitalizations were 87% and 74% for cardiovascular and noncardiovascular causes (79% and 63% after adjustment). Conclusions: African American individuals with LV dysfunction are at an increased risk of hospitalization due to a wide range of causes, with noncardiovascular hospitalizations accounting for nearly half the increased risk. To the extent that estimates of risk focus on cardiovascular morbidity, they may underestimate the true health burden of LV dysfunction. [ABSTRACT FROM AUTHOR]

Background: Residual kidney function (RKF) is associated with improved survival in peritoneal dialysis patients, but its role in hemodialysis patients is less well known. Urine output may provide an estimate of RKF. The aim of our study is to determine the association of urine output with mortality, quality of life (QOL), and inflammation in incident hemodialysis patients. Study Design: Nationally representative prospective cohort study. Setting & Participants: 734 incident hemodialysis participants treated in 81 clinics; enrollment, 1995-1998; follow-up until December 2004. Predictor: Urine output, defined as producing at least 250 mL (1 cup) of urine daily, ascertained using questionnaires at baseline and year 1. Outcomes & Measurements: Primary outcomes were all-cause and cardiovascular mortality, analyzed using Cox regression adjusted for demographic, clinical, and treatment characteristics. Secondary outcomes were QOL, inflammation (C-reactive protein and interleukin 6 levels), and erythropoietin (EPO) requirements. Results: 617 of 734 (84%) participants reported urine output at baseline, and 163 of 579 (28%), at year 1. Baseline urine output was not associated with survival. Urine output at year 1 indicating preserved RKF, was independently associated with lower all-cause mortality (HR, 0.70; 95% Cl, 0.52-0.93; P = 0.02) and a trend toward lower cardiovascular mortality (HA, 0.69; 95% Cl, 0.45-1.05; P = 0.09). Participants with urine output at baseline reported better QOL and had lower C-reactive protein (P = 0.02) and interleukin 6 (P = 0.03) levels. Importantly, EPO dose was 12,000 U/wk lower in those with urine output at year 1 compared with those without (P = 0.001). Limitations: Urine volume was measured in only a subset of patients (42%), but agreed with self-report (P < 0.001). Conclusions: RKF in hemodialysis patients is associated with better survival and QOL, lower inflammation, and significantly less EPO use. RKF should be monitored routinely in hemodialysis patients. The development of methods to assess and preserve RKF is important and may improve dialysis care. [ABSTRACT FROM AUTHOR]