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Dysregulation of the immune system and dietary patterns that increase inflammation can increase the risk for cognitive decline, but the mechanisms by which inflammatory nutritional habits may affect the development of cognitive impairment in aging are not well understood. To determine whether plasma proteins linked to inflammatory diet predict future cognitive impairment, we applied high-throughput proteomic assays to plasma samples from a subset (n = 1528) of Women’s Health Initiative Memory Study (WHIMS) participants (mean [SD] baseline age, 71.3 [SD 3.8] years). Results provide insights into how inflammatory nutritional patterns are associated with an immune-related proteome and identify a group of proteins (CXCL10, CCL3, HGF, OPG, CDCP1, NFATC3, ITGA11) related to future cognitive impairment over a 14-year follow-up period. Several of these inflammatory diet proteins were also associated with dementia risk across two external cohorts (ARIC, ESTHER), correlated with plasma biomarkers of Alzheimer’s disease (AD) pathology (Aβ42/40) and/or neurodegeneration (NfL), and related to an MRI-defined index of neurodegenerative brain atrophy in a separate cohort (BLSA). In addition to evaluating their biological relevance, assessing their potential role in AD, and characterizing their immune-tissue/cell-specific expression, we leveraged published RNA-seq results to examine how the in vitro regulation of genes encoding these candidate proteins might be altered in response to an immune challenge. Our findings indicate how dietary patterns with higher inflammatory potential relate to plasma levels of immunologically relevant proteins and highlight the molecular mediators which predict subsequent risk for age-related cognitive impairment.

We studied the replication and generalization of previously identified metabolites potentially associated with global cognitive function in multiple race/ethnicities and assessed the contribution of diet to these associations.We tested metabolite-cognitive function associations in U.S.A. Hispanic/Latino adults (n = 2222) from the Community Health Study/ Study of Latinos (HCHS/SOL) and in European (n = 1365) and African (n = 478) Americans from the Atherosclerosis Risk In Communities (ARIC) Study. We applied Mendelian Randomization (MR) analyses to assess causal associations between the metabolites and cognitive function and between Mediterranean diet and cognitive function.Six metabolites were consistently associated with lower global cognitive function across all studies. Of these, four were sugar-related (e.g., ribitol). MR analyses provided weak evidence for a potential causal effect of ribitol on cognitive function and bi-directional effects of cognitive performance on diet.Several diet-related metabolites were associated with global cognitive function across studies with different race/ethnicities.Metabolites associated with cognitive function in Puerto Rican adults were recently identified. We demonstrate the generalizability of these associations across diverse race/ethnicities. Most identified metabolites are related to sugars. Mendelian Randomization (MR) provides weak evidence for a causal effect of ribitol on cognitive function. Beta-cryptoxanthin and other metabolites highlight the importance of a healthy diet.

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.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.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 (n1 = 1762; n2 = 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.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).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.

BACKGROUND: The DASH (Dietary Approaches to Stop Hypertension) diets reduced blood pressure (BP) in the DASH and DASH-Sodium trials, but the underlying mechanisms are unclear. We identified metabolites associated with systolic BP or diastolic BP (DBP) changes induced by dietary interventions (DASH versus control arms) in 2 randomized controlled feeding studies—the DASH and DASH-Sodium trials. METHODS: Metabolomic profiling was conducted in serum and urine samples collected at the end of diet interventions: DASH (n=219) and DASH-Sodium (n=395). Using multivariable linear regression models, associations were examined between metabolites and change in systolic BP and DBP. Tested for interactions between diet interventions and metabolites were the following comparisons: (1) DASH versus control diets in the DASH trial (serum), (2) DASH high-sodium versus control high-sodium diets in the DASH-Sodium trial (urine), and (3) DASH low-sodium versus control high-sodium diets in the DASH-Sodium trial (urine). RESULTS: Sixty-five significant interactions were identified (DASH trial [serum], 12; DASH high sodium [urine], 35; DASH low sodium [urine], 18) between metabolites and systolic BP or DBP. In the DASH trial, serum tryptophan betaine was associated with reductions in DBP in participants consuming the DASH diets but not control diets ( P interaction, 0.023). In the DASH-Sodium trial, urine levels of N-methylglutamate and proline derivatives (eg, stachydrine, 3-hydroxystachydrine, N-methylproline, and N-methylhydroxyproline) were associated with reductions in systolic BP or DBP in participants consuming the DASH diets but not control diets ( P interaction, CONCLUSIONS: We identified metabolites that were associated with BP lowering in response to dietary interventions. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03403166 (DASH trial). URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00000608 (DASH-Sodium trial).

Background The Dietary Approaches to Stop Hypertension (DASH) diet is recommended for cardiovascular disease prevention. We aimed to identify protein biomarkers of the DASH diet using data from 2 randomized feeding studies and validate them in an observational study, the ARIC (Atherosclerosis Risk in Communities) study. Methods and Results Large‐scale proteomic profiling was conducted in serum specimens (SomaLogic) collected at the end of 8‐week and 4‐week DASH diet interventions in multicenter, randomized controlled feeding studies of the DASH trial (N=215) and the DASH‐Sodium trial (N=396), respectively. Multivariable linear regression models were used to compare the relative abundance of 7241 proteins between the DASH and control diet interventions. Estimates from the 2 trials were meta‐analyzed using fixed‐effects models. We validated significant proteins in the ARIC study (N=10 490) using the DASH diet score. At a false discovery rate P P Conclusions We identified 19 proteins robustly associated with the DASH diet in 3 studies, which may serve as biomarkers of the DASH diet. These results suggest potential pathways that are impacted by consumption of the DASH diet. Registration URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT03403166, NCT00000608.

Metabolomic signatures of incident diabetes remain largely unclear for the U.S. Hispanic/Latino population, a group with high diabetes burden. We evaluated the associations of 624 known serum metabolites (measured by a global, untargeted approach) with incident diabetes in a subsample (n = 2,010) of the Hispanic Community Health Study/Study of Latinos without diabetes and cardiovascular disease at baseline (2008–2011). Based on the significant metabolites associated with incident diabetes, metabolite modules were detected using topological network analysis, and their associations with incident diabetes and longitudinal changes in cardiometabolic traits were further examined. There were 224 incident cases of diabetes after an average 6 years of follow-up. After adjustment for sociodemographic, behavioral, and clinical factors, 134 metabolites were associated with incident diabetes (false discovery rate–adjusted P < 0.05). We identified 10 metabolite modules, including modules comprising previously reported diabetes-related metabolites (e.g., sphingolipids, phospholipids, branched-chain and aromatic amino acids, glycine), and 2 reflecting potentially novel metabolite groups (e.g., threonate, N-methylproline, oxalate, and tartarate in a plant food metabolite module and androstenediol sulfates in an androgenic steroid metabolite module). The plant food metabolite module and its components were associated with higher diet quality (especially higher intakes of healthy plant-based foods), lower risk of diabetes, and favorable longitudinal changes in HOMA for insulin resistance. The androgenic steroid module and its component metabolites decreased with increasing age and were associated with a higher risk of diabetes and greater increases in 2-h glucose over time. We replicated the associations of both modules with incident diabetes in a U.S. cohort of non-Hispanic Black and White adults (n = 1,754). Among U.S. Hispanic/Latino adults, we identified metabolites across various biological pathways, including those reflecting androgenic steroids and plant-derived foods, associated with incident diabetes and changes in glycemic traits, highlighting the importance of hormones and dietary intake in the pathogenesis of diabetes.

Background Glycated albumin may provide complementary information to hemoglobin A1c (HbA1c). We compared cross-sectional associations of HbA1c and glycated albumin with chronic kidney disease (CKD) in US adults. Methods We included 10 923 adults (9955 without diagnosed diabetes, 968 with a diabetes diagnosis) from the National Health and Nutrition Examination Survey 1999–2004. We examined continuous associations and clinical cut points for HbA1c among those without diabetes ( Results There were J-shaped associations for both glycated albumin and HbA1c with CKD. Persons without a history of diabetes and very low glycated albumin or HbA1c were more likely to have CKD compared to those without diabetes and normoglycemia. The odds ratios (ORs) for CKD were 1.32 (95% CI, 1.12–1.55) for HbA1c 5.7% to 6.4% and 2.04 (95% CI, 1.28–3.25) for HbA1c ≥6.5%. The ORs for glycated albumin were 1.27 (95% CI, 1.06–1.51) and 2.48 (95% CI, 1.50–4.08) for glycated albumin 14.4% to 17.8% and ≥17.9%, respectively. The inclusion of glycated albumin in the model with HbA1c and traditional risk factors modestly but significantly improved the model fit (P value = 0.006). Conclusions Glycated albumin and HbA1c were similarly associated with prevalent CKD. Glycated albumin provides complementary information to HbA1c for prevalent CKD.

Introduction: Older populations have been growing dramatically worldwide. Aging may lead to changes in diet quality. There is a need to better understand dietary intake during late-life and the impact on health outcomes. Hypothesis: We hypothesized that adherence to healthy dietary patterns, i.e., the Dietary Approaches to Stop Hypertension (DASH) and the alternate Mediterranean (aMED) diets, would be associated with lower risk of all-cause mortality. Methods: Atherosclerosis Risk in Communities (ARIC) study participants aged 60-83 years who attended a study visit in 2005-2006 were included (n=1,069). Dietary intake was assessed with a 131-item Willett food frequency questionnaire. Adherence to healthy dietary patterns was assessed using a priori scores for DASH and aMED. We used Cox proportional hazards models to study the association between tertiles of healthy dietary patterns and all-cause mortality through December 31, 2019. Results: There were 452 deaths observed over a median follow-up of 13 years (12,564.3 person-years). Incidence rates were lower in the third tertile, indicating high adherence to healthy dietary patterns (DASH: 32.9 per 1,000 person-years; aMED: 28.5 per 1,000 person-years), compared to the first tertile (DASH: 39.6 per 1,000 person-years; aMED: 40.0 per 1,000 person-years). Participants in the third vs. first tertile for adherence to the DASH and aMED diets had a 22% and 37% lower risk of all-cause mortality, respectively [hazard ratio for DASH: 0.78 (95% CI, 0.62 - 0.98); aMED: 0.63 (95% CI, 0.49 - 0.83)] after adjusting for age, sex, race, study centers and total energy intake. An approximately linear, inverse relationship was observed between healthy dietary patterns and risk of all-cause mortality for both DASH and aMED ( Figure ). Conclusion: Higher adherence to healthy dietary patterns, specifically the DASH and aMED diets, is associated with lower risk of mortality among older adults. Following a healthy diet may improve survival in the aging population.

Introduction: There is a lack of objective biomarkers of dietary intake. Untargeted studies can unbiasedly identify dairy biomarkers and inform the creation of robust dietary assessment tools that integrate questionnaire and biospecimen data. Methods: Dairy products from interviewer-administered questionnaires were categorized as either low-fat or high-fat dairy. Total dairy was a composite of low-fat and high-fat dairy items. Linear regression models were used to assess associations between dairy intake and 360 serum metabolites in the Atherosclerosis Risk in Communities (ARIC) Study (n=3907). Significant associations were then tested for replication in the Bogalusa Heart Study (BHS) (n=819). Results: In the ARIC study, 34 dairy-metabolite associations were identified (total dairy, n = 16; low-fat dairy, n = 10; high-fat dairy, n = 8). Total dairy shared 7 metabolic associations each with low-fat dairy and high-fat dairy. Low-fat dairy was associated with pantothenate, vitamin B5, and the catabolic product of vitamin B6, pyridoxate. High-fat dairy was associated with one amino acid, 3-hydroxy-2-ethylpropionate, and eight lipid metabolites, including myristate (14:0), 10-nonadecenoate (19:1n9), and myristoleate (14:1n5). Of the metabolites available for replication in BHS (total dairy, n = 15; low-fat dairy, n = 9; high-fat dairy, n = 8), 2 total dairy metabolites were replicated and 2 low-fat dairy metabolites were replicated ( Table ). Conclusions: We identified metabolomic markers of total, low-fat, and high-fat dairy. Pantothenate, myristate (14:0), and tiglyl carnitine replicated across two large, diverse study populations, suggesting that they are markers of dairy consumption.

Introduction: The Dietary Approaches to Stop Hypertension (DASH) diet significantly reduced blood pressure (BP) in the DASH and DASH-Sodium trials, but the underlying mechanisms are unclear. Hypothesis: We hypothesized that certain metabolites will be associated with BP reductions. Methods: Metabolomic profiling was conducted at the end of the diet interventions for participants randomly assigned to the DASH or control diet in multicenter, controlled feeding studies: DASH (N=219) and DASH-Sodium trials (N=395). Using multivariable linear regression models to examine the association between metabolites and BP change, we tested for interactions between diet and metabolites for the following comparisons: 1) DASH vs. control diets in the DASH trial, 2) DASH-high sodium vs. control-high sodium diets in the DASH-Sodium trial, and 3) DASH-low sodium vs. control-high sodium diets in the DASH-Sodium trial. Pathway overrepresentation analysis was constructed for significant metabolites. Results: Identified were 65 significant interactions [DASH=12; DASH-high sodium=35; DASH-low sodium=18]. Most amino acids (16/19), cofactors and vitamins (15/15), xenobiotics (9/13), peptides (4/5), and a nucleotide (1/1) were higher in participants consuming the DASH diets vs. the control diets. These metabolites were associated with BP reductions in participants consuming the DASH diets, but not control diets ( Figure ). Many lipid metabolites (10/12) were lower in participants consuming the DASH vs. the control diets. Lipid concentrations were associated with BP elevations in participants consuming the DASH diets and with BP reductions in participants consuming the control diets. Metabolites associated with tocopherol metabolism, ceramides, and pantothenate and CoA metabolism were overrepresented. Conclusions: Using data from randomized feeding studies, we identified metabolites that were associated with BP lowering. These metabolites highlight the pathways through which DASH diet reduced BP.

Introduction: Ultra-processed food (UPF) consumption has an adverse impact on cardiovascular health. Current research is primarily based on non-US study populations. The purpose of our study was to estimate the association between UPF consumption and risk of incident hypertension in a population of middle-aged black and white men and women. Methods: Atherosclerosis Risk in Communities (ARIC) study participants who were hypertension free at baseline and had complete dietary, covariate, and hypertension data from visit 1 (1987 - 1989) were included (n = 8,866). Participants were followed through November 30, 2019 for the development of hypertension defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or recent patient-reported use of blood pressure lowering medication. Processing level was determined using the NOVA classification system. Data were analyzed using three progressively adjusted Cox proportional hazards regression models. Results: 6,960 participants developed hypertension during a median follow-up of 13 years. Participants in the highest quartile of UPF consumption were 9% more likely to develop incident hypertension than those in the lowest quartile (model 2 HR: 1.09; CI: 1.02-1.16; P for trend = 0.01) ( Table ). Participants who were in the highest quartile of sugar-sweetened beverages and red and processed meat consumption had a 20% higher risk of hypertension (model 2 HR, 1.20; CI, 1.12 - 1.28; P for trend Conclusions: High UPF consumption, specifically sugar-sweetened beverages and red and processed meat, was associated with higher risk of hypertension, whereas minimally or unprocessed food consumption was associated with lower hypertension risk.

Background: High dietary calcium and phosphorus intakes may accelerate vascular calcification. A few studies have explored the association of dietary calcium and phosphorus intakes with vascular calcification but reported inconsistent results. Most studies relied on dietary assessment at one time point and evaluated only coronary artery calcification. Aim: To assess the associations of dietary calcium and phosphorus intakes over two time points during middle age with coronary artery and extra-coronary calcification at older age. Methods: We studied 1,940 ARIC participants who underwent chest CT scans at ≥75 years of age in 2018-19 and completed a 66-item food frequency questionnaire at two earlier visits (1987-89 and 1993-95). We calculated the average of dietary calcium and phosphorus intakes across these two visits. Calcification was quantified as Agatston score in coronary arteries, ascending aorta, descending aorta, aortic valve ring, aortic valve, and mitral valve. We ran multivariable linear (for continuous Agatston score) and logistic regression models (for Agatston score >75 th percentile). Results: The mean dietary calcium and phosphorus intake was 659 mg/day and 1,074 mg/day, respectively. Overall, we did not observe any positive associations of dietary calcium intake with vascular/valvular calcification. Rather, we saw its inverse association with ascending aorta calcification (Figure). In contrast, dietary phosphorus was not associated with the calcification of any vascular beds. The results were largely similar in linear regression models and after excluding 332 participants (17%) taking calcium supplements. Conclusion: Dietary calcium intake at middle age was largely neutral in its association with vascular calcification while showing a mild inverse association with ascending aorta calcification at older age. No evident associations were seen for dietary phosphorus. Our findings do not support a concern that a calcium or phosphorus-rich diet may accelerate vascular calcification.

Background: Numerous studies have shown inverse associations between serum magnesium (Mg) levels and risk of cardiovascular disease (CVD), but studies of dietary Mg have not been consistent. Aim: The association of a Mg-rich diet score with risks of incident CVD, coronary heart disease (CHD), and ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study was examined. Methods: There were 15,022 Black and White adults without prevalent CVD included in this analysis. Diet was assessed at two visits using an interviewer-administered 66-item food frequency questionnaire. A Mg-rich diet score was created including whole grain products, nuts, fruits, vegetables, legumes, coffee, and tea. Cox proportional hazard regression evaluated the associations of incident CVD, CHD and stroke through 2019 across quintiles of Mg-rich diet score adjusted for demographic characteristics, lifestyle factors, and clinical characteristics. Results: Participants in the highest quintile of Mg-rich diet score compared to the lowest quintile consumed more servings of Mg-rich foods and fiber and less refined grains, red and processed meat, total fat and saturated fat. Over 30 years of follow up, a Mg-rich diet score was inversely associated with incident CVD (HR Q5 vs Q1 =0.88, 95% CI 0.78-0.99, p trend =0.03) and CHD (HR=0.83, 95% CI 0.72-0.96, p trend =0.01); however the diet-stroke association was null (HR=1.08, 95% CI 1.07-1.09, p trend =0.93) (Table). Conclusions: Consuming a diet rich in whole grains, nuts, fruits and vegetables, legumes, coffee and tea is consistent with a lower long-term risk of CVD and CHD.

Introduction: There is inconsistent evidence on the efficacy of a low-protein diet for patients with chronic kidney disease (CKD) and there is a lack of objective biomarkers of dietary intake. The purpose of this study was to identify plasma metabolites associated with dietary intake of protein among children with CKD and to assess whether protein-related metabolites are associated with CKD progression. Methods: We conducted non-targeted metabolomics using plasma samples from 484 Chronic Kidney Disease in Children (CKiD) participants. Multivariable linear regression estimated the cross-sectional association between 949 known, non-drug metabolites and dietary intake of dairy, nuts and beans, red and processed meat, fish, chicken, and eggs, adjusting for demographic, clinical, and dietary covariates. Cox proportional hazards regression models assessed the prospective association between protein-related metabolites and CKD progression defined as kidney replacement therapy or 50% eGFR reduction, adjusting for demographic and clinical covariates. We used a false discovery rate Results: Fifty-seven unique metabolites were significantly associated with dietary protein intake (dairy: n=21; nuts and beans: n=13; red and processed meat: n=20; fish: n=2; chicken: n=3; eggs: n=0). Among them, ten metabolites were significantly associated with CKD progression (TABLE) , including one amino acid, one cofactor and vitamin, four lipids, two nucleotides, one peptide, and one xenobiotic. 1-(1-enyl-palmitoyl)-2-oleoyl-GPE (P-16:0/18:1) was positively associated with dietary intake of red and processed meat and CKD progression, and 3-ureidopropionate was inversely associated with dietary intake of red and processed meat and CKD progression. Conclusion: Untargeted plasma metabolomic profiling revealed metabolites associated with dietary intake of protein and CKD progression in a pediatric population.

Introduction: N-terminal pro-brain-type natriuretic peptide (NT-proBNP) is widely used as a diagnostic biomarker for heart failure. Higher diet quality is associated with lower risk of cardiovascular disease. However, the association between diet and subclinical cardiovascular disease, as assessed by biomarker concentrations, is less well-studied. Hypothesis: We hypothesized that higher diet quality, assessed by the Healthy Eating Index-2015 (HEI-2015), would be associated with lower serum levels of NT-proBNP. Methods: We included 9,782 adults from the National Health and Nutrition Examination Survey (NHANES), 1999-2004. The HEI-2015 ranges from 0 to 100, with higher scores indicating better diet quality, and was categorized into sex-specific quintiles. Weighted multivariable linear regression models were used to estimate associations between the overall HEI-2015 score as well as its 13 components and log-transformed NT-proBNP. Results: Among 9,782 participants, mean age was 45 years, 48% were men, and 72% were non-Hispanic White adults. After adjusting for sociodemographic characteristics, lifestyle factors, and medical history, persons in the highest HEI-2015 quintile had a 10.0% lower NT-proBNP level compared to those in the lowest HEI-2015 quintile (95% CI: -17.7% to -2.6%). There was a dose-response relationship between HEI-2015 and NT-proBNP ( Figure ). For each 1-unit higher sodium and added sugars score, NT-proBNP was lower by 7.7% and 6.8% respectively (95% CI: -13.8 % to -2.2%, and 95% CI: -13.1% to -0.9% respectively). Conclusion: Higher diet quality, especially lower intakes of sodium and added sugars, was associated with lower serum levels of NT-proBNP.

Peer reviewed: True, Funder: University of New South Wales; FundRef: http://dx.doi.org/10.13039/501100001773, OBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD). DESIGN: Pooled analysis. DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020. STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate. DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis. MAIN OUTCOME MEASURES: Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate

BACKGROUND AND AIMS: Various food groups have been associated with measures of left ventricular geometry and function. Whether the Dietary Approaches to Stop Hypertension (DASH) dietary pattern in mid-life is associated with a favorable cardiac structure and function later in life is unknown. METHODS AND RESULTS: The study population consisted of the Atherosclerosis Risk in Communities study participants free of cardiovascular disease at study visit 3 in 1993 to 1995. Dietary intake was assessed by food frequency questionnaire at study visits 1 (1987–1989) and 3 (1993–1995). Participants who underwent transthoracic echocardiograms at the Jackson field center at visit 3 (n=1,974) and at all field centers at study visit 5 (2011–2013; n=4,651) were included in this study. General linear regression was used to evaluate associations between dietary intake and markers of cardiac structure and function adjusting for potential confounders. Higher DASH score was associated with lower left ventricle mean wall thickness and higher absolute value of longitudinal strain at visit 5 (p(trend)=0.004 and

BACKGROUND: The blood pressure–lowering effects of the Dietary Approaches to Stop Hypertension (DASH) dietary pattern and reduced sodium intake are well established. The effects on other biomarkers related to vascular health are of interest and might assist in explaining the effects of the DASH diet and sodium reduction. OBJECTIVES: We hypothesized that a low-sodium DASH diet improves (lowers) biomarkers of inflammation [C-reactive protein (CRP) and soluble urokinase plasminogen activator receptor (suPAR)] and mineral metabolism [phosphorus and fibroblast growth factor-23 (FGF23)]. METHODS: We conducted a secondary analysis of the DASH-Sodium trial using frozen serum samples. This controlled feeding study randomly assigned 412 adults (≥22 y) with elevated blood pressure (120–159/80–95 mmHg) to consume either a DASH diet or control diet. Within each arm, participants received 3 sodium levels [low (1150 mg), intermediate (2300 mg), high (3450 mg)] in random sequence, each for 30 d. To maximize contrast, samples collected at the end of the low-sodium DASH (n = 198) and high-sodium control (n = 194) diets were compared. Between-diet differences in serum CRP, suPAR, phosphorus, and FGF23 concentrations were assessed using linear regression adjusted for age, sex, race, income, education, smoking status, and BMI. RESULTS: CRP concentrations did not differ between groups (P = 0.83), but suPAR was higher after the low-sodium DASH diet than the high-sodium control [geometric mean 2470 pg/mL (95% CI: 2380, 2560 pg/mL), compared with 2290 pg/mL (95% CI: 2210, 2380 pg/mL); P = 0.006]. Phosphorus was higher after the low-sodium DASH diet [geometric mean 3.50 mg/dL (95% CI: 3.43, 3.57 mg/dL)] compared with the high-sodium control diet [geometric mean 3.39 mg/dL (95% CI: 3.33, 3.46 mg/dL); P = 0.04]. FGF23 was also higher after the low-sodium DASH diet [geometric mean 35.3 pg/mL (95% CI: 33.3, 37.3 pg/mL) compared with 28.2 pg/mL (95% CI: 26.6, 29.8 pg/mL); P

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.

BACKGROUNDMetabolomic profiling in individuals with chronic kidney disease (CKD) has the potential to identify novel biomarkers and provide insight into disease pathogenesis.METHODSWe examined the association between blood metabolites and CKD progression, defined as the subsequent development of end-stage renal disease (ESRD) or estimated glomerular filtrate rate (eGFR) halving, in 1,773 participants of the Chronic Renal Insufficiency Cohort (CRIC) study, 962 participants of the African-American Study of Kidney Disease and Hypertension (AASK), and 5,305 participants of the Atherosclerosis Risk in Communities (ARIC) study.RESULTSIn CRIC, more than half of the measured metabolites were associated with CKD progression in minimally adjusted Cox proportional hazards models, but the number and strength of associations were markedly attenuated by serial adjustment for covariates, particularly eGFR. Ten metabolites were significantly associated with CKD progression in fully adjusted models in CRIC; 3 of these metabolites were also significant in fully adjusted models in AASK and ARIC, highlighting potential markers of glomerular filtration (pseudouridine), histamine metabolism (methylimidazoleacetate), and azotemia (homocitrulline). Our findings also highlight N-acetylserine as a potential marker of kidney tubular function, with significant associations with CKD progression observed in CRIC and ARIC.CONCLUSIONOur findings demonstrate the application of metabolomics to identify potential biomarkers and causal pathways in CKD progression.FUNDINGThis study was supported by the NIH (U01 DK106981, U01 DK106982, U01 DK085689, R01 DK108803, and R01 DK124399).

Novel metabolite biomarkers of kidney failure with replacement therapy (KFRT) may help identify people at high risk for adverse kidney outcomes and implicated pathways may aid in developing targeted therapeutics.Prospective cohort.The cohort included 3,799 Atherosclerosis Risk in Communities study participants with serum samples available for measurement at visit 1 (1987-1989).Baseline serum levels of 318 metabolites.Incident KFRT, kidney failure (KFRT, estimated glomerular filtration rate 15 mL/min/1.73 mBecause metabolites are often intercorrelated and represent shared pathways, we used a high dimension reduction technique called Netboost to cluster metabolites. Longitudinal associations between clusters of metabolites and KFRT and kidney failure were estimated using a Cox proportional hazards model.Mean age of study participants was 53 years, 61% were African American, and 13% had diabetes. There were 160 KFRT cases and 357 kidney failure cases over a mean of 23 years. The 314 metabolites were grouped in 43 clusters. Four clusters were significantly associated with risk of KFRT and 6 were associated with kidney failure (including 3 shared clusters). The 3 shared clusters suggested potential pathways perturbed early in kidney disease: cluster 5 (15 metabolites involved in alanine, aspartate, and glutamate metabolism as well as 5-oxoproline and several gamma-glutamyl amino acids), cluster 26 (6 metabolites involved in sugar and inositol phosphate metabolism), and cluster 34 (21 metabolites involved in glycerophospholipid metabolism). Several individual metabolites were also significantly associated with both KFRT and kidney failure, including glucose and mannose, which were associated with higher risk of both outcomes, and 5-oxoproline, gamma-glutamyl amino acids, linoleoylglycerophosphocholine, 1,5-anhydroglucitol, which were associated with lower risk of both outcomes.Inability to determine if the metabolites cause or are a consequence of changes in kidney function.We identified several clusters of metabolites reproducibly associated with development of KFRT. Future experimental studies are needed to validate our findings as well as continue unraveling metabolic pathways involved in kidney function decline.

Nutritional epidemiology seeks to understand nutritional determinants of disease in human populations using experimental and observational study designs. Though randomized controlled trials provide the strongest evidence of causality, the expense and difficulty of sustaining adherence to dietary interventions are substantial barriers to investigating dietary determinants of kidney disease. Therefore, nutritional epidemiology commonly employs observational study designs, particularly prospective cohort studies, to investigate long-term associations between dietary exposures and kidney disease. Due to the covarying nature and synergistic effects of dietary components, holistic characterizations of dietary exposures that simultaneously consider patterns of foods and nutrients regularly consumed are generally more relevant to disease etiology than single nutrients or foods. Dietary intakes have traditionally been self-reported and are subject to bias. Statistical methods including energy adjustment and regression calibration can reduce random and systematic measurement errors associated with self-reported diet. Novel approaches that assess diet more objectively are gaining popularity but have not yet fully replaced self-report and require refinement and validation in populations with chronic kidney disease. More accurate and frequent diet assessment in existing and future studies will yield evidence to better personalize dietary recommendations for the prevention and treatment of kidney disease.

Rationale & Objective Obesity has been related to risk for chronic kidney disease. However, the associations of different measures of midlife obesity with long-term kidney function trajectories and whether they differ by sex and race are unknown. Study Design Observational study. Setting & Participants 13,496 participants from the Atherosclerosis Risk in Communities (ARIC) Study. Predictors Midlife obesity status as measured by body mass index (BMI), waist-to-hip ratio, and predicted percent fat at baseline. Outcomes Estimated glomerular filtration rate (eGFR) calculated using serum creatinine level measured at 5 study visits, and incident kidney failure with replacement therapy (KFRT). Analytical Approach Mixed models with random intercepts and random slopes for eGFR. Cox proportional hazards models for KFRT. Results Baseline mean age was 54 years, median eGFR was 103 mL/min/1.73 m2, and median BMI was 27 kg/m2. Over 30 years of follow-up, midlife obesity measures were associated with eGFR decline in White and Black women but not consistently in men. Adjusted for age, center, smoking, and coronary heart disease, the differences in eGFR slope per 1-SD higher BMI, waist-to-hip ratio, and predicted percent fat were 0.09 (95% CI, −0.18 to 0.36), −0.25 (95% CI, −0.50 to 0.01), and −0.14 (95% CI, −0.41 to 0.13) mL/min/1.73 m2 per decade for White men; −0.91 (95% CI, −1.15 to −0.67), −0.82 (95% CI, −1.06 to −0.58), and −1.02 (95% CI, −1.26 to −0.78) mL/min/1.73 m2 per decade for White women; −0.70 (95% CI, −1.54 to 0.14), −1.60 (95% CI, −2.42 to −0.78), and −1.24 (95% CI, −2.08 to −0.40) mL/min/1.73 m2 per decade for Black men; and −1.24 (95% CI, −2.08 to −0.40), −1.50 (95% CI, −2.05 to −0.95), and −1.43 (95% CI, −2.00 to −0.86) mL/min/1.73 m2 per decade for Black women. Obesity indicators were independently associated with risk for KFRT for all sex-race groups except White men. Limitations Loss to follow-up during 3 decades of follow-up with 5 eGFR assessments. Conclusions Obesity status is a risk factor for future decline in kidney function and development of KFRT in Black and White women, with less consistent associations among men.

RATIONALE & OBJECTIVE: Current dietary guidelines recommend that chronic kidney disease (CKD) patients restrict individual nutrients, such as sodium, potassium, phosphorus and protein. This approach can be difficult for patients to implement and ignores important nutrient interactions. Dietary patterns are an alternative method to intervene on diet. Our objective was to define the associations of four healthy dietary patterns with risk of CKD progression and all-cause mortality among people with CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 2,403 participants aged 21–74 years with an estimated glomerular filtration rate (eGFR) of 20–70 mL/min/1.73 m(2) and dietary data in the Chronic Renal Insufficiency Cohort (CRIC) study. EXPOSURES: Healthy Eating Index-2015 (HEI-2015), Alternative Healthy Eating Index-2010 (AHEI-2010), alternate Mediterranean diet (aMed), and Dietary Approaches to Stop Hypertension (DASH) diet scores were calculated from food frequency questionnaires. OUTCOMES: 1) CKD progression defined as ≥50% eGFR decline, kidney transplantation, or dialysis and 2) all-cause mortality. ANALYTICAL APPROACH: Cox proportional hazards regression models adjusted for demographic, lifestyle, and clinical covariates to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: There were 855 cases of CKD progression and 773 deaths over a maximum of 14 years. Compared with participants with the lowest adherence, the most highly adherent tertile of AHEI-2010, aMed, and DASH had lower adjusted risk of CKD progression with the strongest results for aMed (HR: 0.75, 95% CI: 0.62–0.90). Compared with participants with the lowest adherence, the highest adherence tertiles for all scores had lower adjusted risk of all-cause mortality for each index (24–31% lower risk). LIMITATIONS: Self-reported dietary intake. CONCLUSIONS: Greater adherence to several healthy dietary patterns is associated with a lower risk of CKD progression and all-cause mortality among people with CKD. Guidance to adopt healthy dietary patterns can be considered as a strategy for managing CKD. INDEX WORDS: dietary patterns, nutrition, kidney disease, renal, mortality

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 (n(1) = 1,806, n(2) = 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

Background: Previous studies have suggested that adherence to healthy dietary patterns during late life may be associated with improved cognition. However, few studies have examined the association between healthy dietary patterns during midlife and incident dementia. Objective: Our study aimed to determine the association between adherence to healthy dietary patterns at midlife and incident dementia. Methods: We included 13,630 adults from the Atherosclerosis Risk in Communities (ARIC) Study in our prospective analysis. We used food frequency questionnaire responses to calculate four dietary scores: Healthy Eating Index-2015 (HEI-2015), Alternative Healthy Eating Index-2010 (AHEI-2010), alternate Mediterranean (aMed) diet, and Dietary Approaches to Stop Hypertension (DASH). Participants were followed until the end of 2017 for incident dementia. Cox regression models adjusted for covariates were used to estimate risk of incident dementia by quintile of dietary scores. Results: Over a median of 27 years, there were 2,352 cases of incident dementia documented. Compared with participants in quintile 1 of HEI-2015, participants in quintile 5 (healthiest) had a 14% lower risk of incident dementia (hazard ratio, HR: 0.86, 95% confidence interval, CI: 0.74–0.99). There were no significant associations of incident dementia with the AHEI-2010, aMed, or DASH scores. There were no significant interactions by sex, age, race, education, physical activity, hypertension, or obesity. Conclusion: Adherence to the HEI-2015, but not the other dietary scores, during midlife was associated with lower risk of incident dementia. Further research is needed to elucidate whether timing of a healthy diet may influence dementia risk.

Type 2 diabetes (T2D) is associated with reduced gut microbiome diversity, although the cause is unclear. Metabolites generated by gut microbes also appear to be causative factors in T2D. We therefore searched for serum metabolites predictive of gut microbiome diversity in 1018 females from TwinsUK with concurrent metabolomic profiling and microbiome composition. We generated a Microbial Metabolites Diversity (MMD) score of six circulating metabolites that explained over 18% of the variance in microbiome alpha diversity. Moreover, the MMD score was associated with a significantly lower odds of prevalent (OR[95%CI] = 0.22[0.07;0.70], P = .01) and incident T2D (HR[95%CI] = 0.31[0.11,0.90], P = .03). We replicated our results in 1522 individuals from the ARIC study (prevalent T2D: OR[95%CI] = 0.79[0.64,0.96], P = .02, incident T2D: HR[95%CI] = 0.87[0.79,0.95], P = .003). The MMD score mediated 28%[15%,94%] of the total effect of gut microbiome on T2D after adjusting for confounders. Metabolites predicting higher microbiome diversity included 3-phenylpropionate(hydrocinnamate), indolepropionate, cinnamoylglycine and 5-alpha-pregnan-3beta,20 alpha-diol monosulfate(2) of which indolepropionate and phenylpropionate have already been linked to lower incidence of T2D. Metabolites correlating with lower microbial diversity included glutarate and imidazole propionate, of which the latter has been implicated in insulin resistance. Our results suggest that the effect of gut microbiome diversity on T2D is largely mediated by microbial metabolites, which might be modifiable by diet.

Background Creatinine-based estimated glomerular filtration rate (eGFR) is biased in the setting of obesity and other conditions. Alternative kidney filtration markers may be useful in adults with diabetes, but few studies examined the associations with risk of clinical outcomes. Methods In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, we evaluated whether baseline levels and change in eGFR based on creatinine (Cr), cystatin c (Cys), β2 -microglobulin (B2M), eGFRCr-Cys , and the average of three estimates (eGFRCr-Cys-B2M ) assessed in 7217 participants at baseline and a random sample of 640 participants at the 1 year visit are associated with clinical outcomes. We examined associations with major macrovascular and microvascular events together and separately, and all-cause mortality using Cox regression models, adjusting for established risk factors. Results Over a median follow-up of 5 years, 1313 major macrovascular (n = 748) and microvascular events (n = 637), and 743 deaths occurred. Lower levels of eGFR based on all filtration markers individually and combined were associated with 1.4 to 3.0 times higher risk of major macrovascular and microvascular events (combined and separately) and all-cause mortality. Per 30% decline in eGFRCys , eGFR Cr-Cys , and eGFRCr-Cys-B2M were associated with a > 2-fold higher risk of all clinical outcomes. Conclusions In adults with type 2 diabetes, baseline levels of eGFR based on alternative filtration markers and per 30% decline in eGFRCys , eGFR Cr-Cys , and eGFRCr-Cys-B2M were associated with clinical outcomes. Measurement of alternative filtration markers, particularly B2M in adults with type 2 diabetes may be warranted. This article is protected by copyright. All rights reserved.

OBJECTIVE: Dietary factors mediate racial disparities in hypertension. However, the physiological mechanisms underlying this relationship are incompletely understood. We sought to assess the association between 1-methylhistidine (1-MH), a metabolite marker of animal protein consumption, and blood pressure (BP) in a community-based cohort of black and white middle-aged adults. METHODS: This analysis consisted of 655 participants of the Bogalusa Heart Study (25% black, 61% women, aged 34–58 years) who were not taking antihypertensive medication. Fasting serum 1-MH was measured using liquid chromatography-tandem mass spectroscopy. Animal food intakes were quantified by food-frequency questionnaires. Multivariable linear regression assessed the association between 1-MH and BP in combined and race-stratified analyses, adjusting for demographic, dietary, and cardiometabolic factors. RESULTS: A significant dose–response relationship was observed for the association of red meat (P-trend

BACKGROUND: Public health recommendations on the benefits and harms of moderate alcohol intake require a thorough and unbiased understanding of all potential effects of various levels and patterns of alcohol consumption. We seek to evaluate the associations between patterns of current and past alcohol consumption with hospitalizations and mortality. METHODS: Data came from a prospective cohort of 12,327 adults (56% women, 78% white, mean age 60 years) participating in the Atherosclerosis Risk in Communities (ARIC) study visit 3 (1993–1995). Current and past alcohol consumption was based on self-report. Hospitalizations and mortality were ascertained through December 31, 2017. Negative binomial and cox proportional hazards regressions were used. RESULTS: 24.8% of the study population reported never drinking, 48.3% reported currently drinking without a history of heavy drinking, 4.2% reported currently drinking with a history of heavy drinking, 19.2% reported being former drinkers without a history of heavy drinking and 3.4% reported being former drinkers with a history of heavy drinking. Compared to those who reported drinking ≤1–7 drinks/week, never drinkers [incident rate ratio (IRR): 1.21 (95% confidence interval 1.13, 1.29] and former drinkers with [IRR: 1.43 (1.26, 1.63)] or without [IRR: 1.21 (1.13, 1.30)] a history of heavy drinking had a positive association with all-cause hospitalization (P

Introduction: Molecular mechanisms underlying the benefits of healthy dietary patterns on chronic diseases are poorly understood. Identifying protein biomarkers of healthy diets can help us characterize biological pathways influenced by diet quality and confirm the validity of established healthy dietary patterns. Objectives: To identify protein biomarkers that are associated with diet quality using four metrics of adherence to dietary guidelines and healthy dietary patterns: the Alternative Healthy Eating Index-2010 (AHEI-2010); the Alternate Mediterranean Diet (aMED); the Dietary Approaches to Stop Hypertension (DASH) diet; and the Healthy Eating Index-2015 (HEI-2015). Methods: We examined 4,877 plasma proteins among 10,593 participants with available proteomics and dietary data from the Atherosclerosis Risk in Communities (ARIC) Study at visit 3 (1993-1995). Dietary intake data were collected through a food frequency questionnaire, and proteins were measured in plasma using an aptamer-based proteomics assay from SomaLogic. We used multivariable linear regression models to examine the association between proteins and each dietary pattern. Results: In the multivariable adjusted model, 276 out of 4,877 proteins (5.7%) were associated with at least one dietary pattern (AHEI: 74; aMED: 37; DASH: 250; HEI: 135; p-value < 0.05/4,877=1.0х10 -5 ) ( Figure ). There were 140 proteins that were associated with only one dietary pattern (AHEI: 6; aMED: 0; DASH: 116; HEI: 18). Conclusion: Large-scale proteomic analysis identified proteins that are representative of a range of healthy dietary patterns and proteins that are specific to single healthy dietary pattern. Future studies are warranted to link diet-related proteins with clinical outcomes.

Introduction: 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 understand the underlying mechanisms. Objectives: Using untargeted metabolomics, we aimed to identify metabolites associated with 4 plant-based diet indices (PDI) [overall PDI, provegetarian, healthful PDI, and unhealthful PDI] and incident CKD in 2 subgroups within the Atherosclerosis Risk in Communities Study. Methods: Participants (n 1 =1,762; n 2 =2,152) reported usual dietary intake using a food frequency questionnaire. We used linear regression models to examine the association between 4 PDIs and 374 individual metabolites. We used Cox regression models to evaluate associations between PDI-related metabolites and incident CKD. Estimates were meta-analyzed across 2 subgroups. We calculated C-statistics to assess whether metabolites improved the prediction of those in the highest quintile vs. lower 4 quintiles of PDIs, and whether PDI-related metabolites predicted incident CKD. 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, and healthful PDI. The addition of metabolites improved prediction of those in the highest quintile vs. lower 4 quintiles of PDIs compared to participant characteristics alone ( P -value ≤0.001 for all tests). Six PDI-related metabolites representing 2 pathways were significantly associated with incident CKD ( Table ) and improved prediction of incident CKD beyond traditional risk factors (difference in C-statistics for all 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 that predicted incident CKD. These metabolites highlight pathways through which plant-based diets are associated with incident CKD.

Lack of biomarkers is a challenge for the accurate assessment of protein intake and interpretation of observational study data. The study aims to identify biomarkers of a protein-rich dietary pattern.The Optimal Macronutrient Intake Trial to Prevent Heart Disease (OmniHeart) trial is a randomized cross-over feeding study which tested three dietary patterns with varied macronutrient content (carbohydrate-rich; protein-rich with about half from plant sources; and unsaturated fat-rich). In 156 adults, differences in log-transformed plasma metabolite levels at the end of the protein- and carbohydrate-rich diet periods using paired t-tests is examined. Partial least-squares discriminant analysis is used to identify a set of metabolites which are influential in discriminating between the protein-rich versus carbohydrate-rich dietary patterns. Of 839 known metabolites, 102 metabolites differ significantly between the protein-rich and the carbohydrate-rich dietary patterns after Bonferroni correction, the majority of which are lipids (n = 35), amino acids (n = 27), and xenobiotics (n = 24). Metabolites which are the most influential in discriminating between the protein-rich and the carbohydrate-rich dietary patterns represent plant protein intake, food or beverage intake, and preparation methods.The study identifies many plasma metabolites associated with the protein-rich dietary pattern. If replicated, these metabolites may be used to assess level of adherence to a similar dietary pattern.

Background Research examining the role of obesity in cardiovascular disease (CVD) often fails to adequately consider heterogeneity in obesity severity, distribution, and duration. Methods and Results We here use multivariate latent class mixed models in the biracial Atherosclerosis Risk in Communities study (N=14 514; mean age=54 years; 55% female) to associate obesity subclasses (derived from body mass index, waist circumference, self‐reported weight at age 25, tricep skinfold, and calf circumference across up to four triennial visits) with total mortality, incident CVD, and CVD risk factors. We identified four obesity subclasses, summarized by their body mass index and waist circumference slope as decline (4.1%), stable/slow decline (67.8%), moderate increase (24.6%), and rapid increase (3.6%) subclasses. Compared with participants in the stable/slow decline subclass, the decline subclass was associated with elevated mortality (hazard ratio [HR] 1.45, 95% CI 1.31, 1.60, P P P =0.0002), and coronary heart disease (HR 1.36, 95% CI 1.14, 1.63, P =0.0008), adjusting for baseline body mass index and CVD risk factor profile. The moderate increase latent class was not associated with any significant differences in CVD risk as compared to the stable/slow decline latent class and was associated with a lower overall risk of mortality (HR 0.85, 95% CI 0.80, 0.90, P P =0.004). Conclusions Consideration of heterogeneity and longitudinal changes in obesity measures is needed in clinical care for a more precision‐oriented view of CVD risk.

Ultraprocessed foods have become readily available in the global food supply in the past few decades. Several adverse health outcomes have been linked with higher consumption of ultraprocessed foods. However, the impact of ultraprocessed foods on chronic kidney disease (CKD) risk remains unknown.Prospective cohort study.14,679 middle-aged adults without CKD at baseline in the Atherosclerosis Risk in Communities (ARIC) study.Ultraprocessed foods consumption (servings per day) calculated using dietary data collected via a food frequency questionnaire at visit 1 and visit 3.Incident CKD defined as estimated glomerular filtration rate (eGFR) 60 mL/min/1.73 mMultivariable-adjusted Cox proportional hazards models were used to assess the association between ultraprocessed foods consumption and CKD. Restricted cubic splines were used to examine the shape of the association.During a median follow-up period of 24 years, there were 4,859 cases of incident CKD. The incidence rate for the highest quartile of ultraprocessed foods consumption was 16.5 (95% CI, 15.6-17.4) per 1,000 person-years and 14.7 (95% CI, 13.9-15.5) per 1,000 person-years for the lowest quartile of consumption. After adjusting for a range of confounders including lifestyle factors, demographic characteristics, and health behaviors, participants in the highest quartile of ultraprocessed foods consumption had a 24% higher risk (HR, 1.24 [95% CI, 1.15-1.35]) of developing CKD compared with those in the lowest quartile. There was an approximately linear relationship observed between ultraprocessed food intake and risk of CKD. By substituting 1 serving of ultraprocessed foods with minimally processed foods, there was a 6% lower risk of CKD observed (HR, 0.94 [95% CI, 0.93-0.96]; P 0.001).Self-reported data and residual confounding.Higher ultraprocessed foods consumption was independently associated with a higher risk of incident CKD in a general population.

Introduction: Mitochondrial DNA copy number (mtDNA-CN) is a biomarker of mitochondrial function that has been associated with chronic kidney disease (CKD) and all-cause mortality in several community-based studies. However, there has been little research on mtDNA-CN and progression of CKD. Hypothesis: We hypothesized that higher mtDNA-CN will be associated with lower risk for CKD progression in a cohort of CKD patients. Methods: A total of 2,943 Chronic Renal Insufficiency Cohort (CRIC) study participants had mtDNA-CN calculated from probe intensities of mitochondrial single nucleotide polymorphisms (SNP) genotyped on the Illumina HumanOmni 1-Quad Array. To correct for batch effects, DNA quality, DNA quantity, and latent confounding factors, mtDNA-CN was regressed on 15 principal components generated from autosomal SNP probe intensity signals. mtDNA-CN residuals were then standardized to a mean of 0 and standard deviation of 1 and used in this analysis. CKD progression was defined as incident end-stage renal disease (ESRD) or halving of eGFR from baseline. Cox proportional hazards models were used to calculate hazard ratios for mtDNA-CN and risk of CKD progression. Results and Conclusions: Compared to patients in the lowest mtDNA-CN tertile, those in the middle tertile [HR=0.78, 95% CI: (0.68, 0.91)] and highest tertile [HR=0.78, 95% CI: (0.67, 0.91)] had a statistically significantly lower risk for CKD progression after adjustment for established risk factors (Table). Similar results were seen in race- and sex-stratified analyses (Table). These findings suggest that mtDNA-CN may have potential clinical utility in improving CKD risk classification. Furthermore, mitochondrial dysfunction has been hypothesized to contribute to renal disease through podocyte injury, tubular epithelial cell damage, and endothelial dysfunction. Future research on the mechanisms underlying mtDNA-CN and CKD progression may lead to novel strategies for CKD management.

Poor diet quality is strongly associated with elevated risk of cardiovascular disease morbidity and mortality. This scientific statement emphasizes the importance of dietary patterns beyond individual foods or nutrients, underscores the critical role of nutrition early in life, presents elements of heart-healthy dietary patterns, and highlights structural challenges that impede adherence to heart-healthy dietary patterns. Evidence-based dietary pattern guidance to promote cardiometabolic health includes the following: (1) adjust energy intake and expenditure to achieve and maintain a healthy body weight; (2) eat plenty and a variety of fruits and vegetables; (3) choose whole grain foods and products; (4) choose healthy sources of protein (mostly plants; regular intake of fish and seafood; low-fat or fat-free dairy products; and if meat or poultry is desired, choose lean cuts and unprocessed forms); (5) use liquid plant oils rather than tropical oils and partially hydrogenated fats; (6) choose minimally processed foods instead of ultra-processed foods; (7) minimize the intake of beverages and foods with added sugars; (8) choose and prepare foods with little or no salt; (9) if you do not drink alcohol, do not start; if you choose to drink alcohol, limit intake; and (10) adhere to this guidance regardless of where food is prepared or consumed. Challenges that impede adherence to heart-healthy dietary patterns include targeted marketing of unhealthy foods, neighborhood segregation, food and nutrition insecurity, and structural racism. Creating an environment that facilitates, rather than impedes, adherence to heart-healthy dietary patterns among all individuals is a public health imperative.

Coffee is one of the most frequently consumed beverages worldwide and has been found to have a wide assortment of health benefits. Although habitual coffee consumption is associated with a lower incidence of chronic kidney disease, an association between coffee and acute kidney injury (AKI) has not yet been revealed.In the Atherosclerosis Risk in Communities (ARIC) Study, a prospective cohort study of 14,207 adults aged 45 to 64 years, coffee consumption (cups/d) was assessed at a single visit via food frequency questionnaires and compared with incident AKI defined by hospitalization with an AKI-related International Classification of Diseases code.In ARIC, there were 1694 cases of incident AKI in a median of 24 follow-up years. Higher coffee consumption was associated with lower AKI risk versus no consumption (hazard ratio [HR] 1 cup/d: 0.92 [95% CI: 0.79-1.08]; 1 cup/d: 1.08 [95% CI: 0.94-1.24]; 2 to 3 cups/d: 0.83 [95% CI: 0.72-0.95];3 cups/d: 0.83 [95% CI: 0.71-0.96]; reference: never,Higher coffee intake was associated with a lower risk of incident AKI and could present an opportunity for cardiorenal protection through diet. Further evaluation of the physiological mechanisms underlying the cardiorenal protective effects of coffee consumption is necessary.

Background Higher ultra-processed food intake has been linked with several cardiometabolic and cardiovascular diseases. However, prospective evidence from US populations remains scarce. Objectives To test the hypothesis that higher intake of ultra-processed foods is associated with higher risk of coronary artery disease. Methods A total of 13,548 adults aged 45-65 y from the Atherosclerosis Risk in Communities study were included in the analytic sample. Dietary intake data were collected through a 66-item FFQ. Ultra-processed foods were defined using the NOVA classification, and the level of intake (servings/d) was calculated for each participant and divided into quartiles. We used Cox proportional hazards models and restricted cubic splines to assess the association between quartiles of ultra-processed food intake and incident coronary artery disease. Results There were 2006 incident coronary artery disease cases documented over a median follow-up of 27 y. Incidence rates were higher in the highest quartile of ultra-processed food intake (70.8 per 10,000 person-y; 95% CI: 65.1, 77.1) compared with the lowest quartile (59.3 per 10,000 person-y; 95% CI: 54.1, 65.0). Participants in the highest compared with lowest quartile of ultra-processed food intake had a 19% higher risk of coronary artery disease (HR: 1.19; 95% CI: 1.05, 1.35) after adjusting for sociodemographic factors and health behaviors. An approximately linear relation was observed between ultra-processed food intake and risk of coronary artery disease. Conclusions Higher ultra-processed food intake was associated with a higher risk of coronary artery disease among middle-aged US adults. Further prospective studies are needed to confirm these findings and to investigate the mechanisms by which ultra-processed foods may affect health.