Adherence to Plant-Based Diets and Risk of CKD Progression and All-Cause Mortality: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Studies have shown that generally healthy individuals who consume diets rich in plant foods have a lower risk of incident chronic kidney disease (CKD) and cardiovascular disease. This study investigated the prospective associations of plant-based diets with the risk of CKD progression and all-cause mortality in individuals with CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 2,539 participants with CKD recruited between 2003-2008 into the Chronic Renal Insufficiency Cohort (CRIC) Study. EXPOSURE: Responses on the Diet History Questionnaire were used to calculate scores for the overall plant-based diet index, healthy plant-based diet index, and unhealthy plant-based diet index. OUTCOME: (1) CKD progression defined as≥50% estimated glomerular filtration rate decline from baseline or kidney replacement therapy (dialysis, transplant) and (2) all-cause mortality. ANALYTICAL APPROACH: Cox proportional hazards models to compute hazard ratios and 95% confidence intervals adjusting for lifestyle, socioeconomic, and clinical covariates. RESULTS: There were 977 CKD progression events and 836 deaths during a median follow-up period of 7 and 12 years, respectively. Participants with the highest versus lowest adherence to overall plant-based diets and healthy plant-based diets had 26% (HR, 0.74 [95% CI, 0.62-0.88], P trend<0.001) and 21% (HR, 0.79 [95% CI, 0.66-0.95], P trend=0.03) lower risks of all-cause mortality, respectively. Each 10-point higher score of unhealthy plant-based diets was modestly associated with a higher risk of CKD progression (HR, 1.14 [95% CI, 1.03-1.25) and all-cause mortality (HR, 1.11 [95% CI, 1.00-1.23). LIMITATIONS: Self-reported diet may be subject to measurement error. CONCLUSIONS: Adherence to an overall plant-based diet and a healthy plant-based diet is associated with a reduced risk of all-cause mortality among individuals with CKD. An unhealthy plant-based was associated with an elevated risk of CKD progression and all-cause mortality. PLAIN-LANGUAGE SUMMARY: Plant-based diets are healthful dietary patterns that have been linked to a lower risk of chronic diseases. However, the impact of plant-based diets on clinical outcomes in patients with chronic kidney disease (CKD) is not well established. In 2,539 individuals with CKD, we examined the associations of adherence to 3 different types of plant-based diets with the risks of CKD progression and all-cause mortality. We found that following an overall plant-based diet and a healthy plant-based diet was associated with a lower risk of all-cause mortality. By contrast, following an unhealthy plant-based diet was associated with a higher risk of CKD progression and all-cause mortality. These results suggest that the quality of plant-based diets may be important for CKD management.

Plasma proteins related to inflammatory diet predict future cognitive impairment.

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 (Aß42/40) 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.

Plasma Metabolomics of Dietary Intake of Protein-Rich Foods and Kidney Disease Progression in Children.

OBJECTIVE: Evidence regarding the efficacy of a low-protein diet for patients with CKD is inconsistent and recommending a low-protein diet for pediatric patients is controversial. There is also a lack of objective biomarkers of dietary intake. The purpose of this study was to identify plasma metabolites associated with dietary intake of protein and to assess whether protein-related metabolites are associated with CKD progression. METHODS: Nontargeted metabolomics was conducted in plasma samples from 484 Chronic Kidney Disease in Children (CKiD) participants. Multivariable linear regression estimated the cross-sectional association between 949 known, nondrug metabolites and dietary intake of total protein, animal protein, plant protein, chicken, dairy, nuts and beans, red and processed meat, fish, and eggs, adjusting for demographic, clinical, and dietary covariates. Cox proportional hazards models assessed the prospective association between protein-related metabolites and CKD progression defined as the initiation of kidney replacement therapy or 50% eGFR reduction, adjusting for demographic and clinical covariates. RESULTS: One hundred and twenty-seven (26%) children experienced CKD progression during 5 years of follow-up. Sixty metabolites were significantly associated with dietary protein intake. Among the 60 metabolites, 10 metabolites were significantly associated with CKD progression (animal protein: n = 1, dairy: n = 7, red and processed meat: n = 2, nuts and beans: n = 1), including one amino acid, one cofactor and vitamin, 4 lipids, 2 nucleotides, one peptide, and one xenobiotic. 1-(1-enyl-palmitoyl)-2-oleoyl-glycerophosphoethanolamine (GPE, P-16:0/18:1) was positively associated with dietary intake of red and processed meat, and a doubling of its abundance was associated with 88% higher risk of CKD progression. 3-ureidopropionate was inversely associated with dietary intake of red and processed meat, and a doubling of its abundance was associated with 48% lower risk of CKD progression. CONCLUSIONS: Untargeted plasma metabolomic profiling revealed metabolites associated with dietary intake of protein and CKD progression in a pediatric population.

Nutritional Epidemiology and Dietary Assessment for Patients With Kidney Disease: A Primer.

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.

Ultraprocessed Foods and Kidney Disease Progression, Mortality, and Cardiovascular Disease Risk in the CRIC Study.

RATIONALE & OBJECTIVE: Ultraprocessed foods are widely consumed in the United States and are associated with cardiovascular disease (CVD), mortality, and kidney function decline in the general population. We investigated associations between ultraprocessed food intake and chronic kidney disease (CKD) progression, all-cause mortality, and incident CVD in adults with chronic kidney disease (CKD). STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Chronic Renal Insufficiency Cohort Study participants who completed baseline dietary questionnaires. EXPOSURE: Ultraprocessed food intake (in servings per day) classified according to the NOVA system. OUTCOMES: CKD progression (≥50% decrease in estimated glomerular filtration rate [eGFR] or initiation of kidney replacement therapy), all-cause mortality, and incident CVD (myocardial infarction, congestive heart failure, or stroke). ANALYTICAL APPROACH: Cox proportional hazards models adjusted for demographic, lifestyle, and health covariates. RESULTS: There were 1,047 CKD progression events observed during a median follow-up of 7 years. Greater ultraprocessed food intake was associated with higher risk of CKD progression (tertile 3 vs tertile 1, HR, 1.22; 95% CI, 1.04-1.42; P=0.01 for trend). The association differed by baseline kidney function, such that greater intake was associated with higher risk among people with CKD stages 1/2 (eGFR≥60mL/min/1.73m2; tertile 3 vs tertile 1, HR, 2.61; 95% CI, 1.32-5.18) but not stages 3a-5 (eGFR<60mL/min/1.73m2; P=0.003 for interaction). There were 1,104 deaths observed during a median follow-up of 14 years. Greater ultraprocessed food intake was associated with higher risk of mortality (tertile 3 vs tertile 1, HR, 1.21; 95% CI, 1.04-1.40; P=0.004 for trend). LIMITATIONS: Self-reported diet. CONCLUSIONS: Greater ultraprocessed food intake may be associated with CKD progression in earlier stages of CKD and is associated with higher risk of all-cause mortality in adults with CKD. PLAIN LANGUAGE SUMMARY: Ultraprocessed foods are industrial formulations produced using ingredients and processes that are not commonly used in culinary preparations and contain few, if any, intact unprocessed foods. Ultraprocessed foods are widely consumed in the United States, and high intakes of such foods have been linked to cardiovascular disease, kidney disease, and mortality in the general population. In this study, we found that greater intake of ultraprocessed foods was associated with higher risk of kidney disease progression and mortality in adults with chronic kidney disease. Our findings suggest that patients with kidney disease may benefit from greater consumption of fresh, whole, and homemade or hand-prepared foods and fewer highly processed foods.

Associations of circulating proteins with lipoprotein profiles: proteomic analyses from the OmniHeart randomized trial and the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Within healthy dietary patterns, manipulation of the proportion of macronutrient can reduce CVD risk. However, the biological pathways underlying healthy diet-disease associations are poorly understood. Using an untargeted, large-scale proteomic profiling, we aimed to (1) identify proteins mediating the association between healthy dietary patterns varying in the proportion of macronutrient and lipoproteins, and (2) validate the associations between diet-related proteins and lipoproteins in the Atherosclerosis Risk in Communities (ARIC) Study. METHODS: In 140 adults from the OmniHeart trial, a randomized, cross-over, controlled feeding study with 3 intervention periods (carbohydrate-rich; protein-rich; unsaturated fat-rich dietary patterns), 4,958 proteins were quantified at the end of each diet intervention period using an aptamer assay (SomaLogic). We assessed differences in log2-transformed proteins in 3 between-diet comparisons using paired t-tests, examined the associations between diet-related proteins and lipoproteins using linear regression, and identified proteins mediating these associations using a causal mediation analysis. Levels of diet-related proteins and lipoprotein associations were validated in the ARIC study (n = 11,201) using multivariable linear regression models, adjusting for important confounders. RESULTS: Three between-diet comparisons identified 497 significantly different proteins (protein-rich vs. carbohydrate-rich = 18; unsaturated fat-rich vs. carbohydrate-rich = 335; protein-rich vs. unsaturated fat-rich dietary patterns = 398). Of these, 9 proteins [apolipoprotein M, afamin, collagen alpha-3(VI) chain, chitinase-3-like protein 1, inhibin beta A chain, palmitoleoyl-protein carboxylesterase NOTUM, cathelicidin antimicrobial peptide, guanylate-binding protein 2, COP9 signalosome complex subunit 7b] were positively associated with lipoproteins [high-density lipoprotein (HDL)-cholesterol (C) = 2; triglyceride = 5; non-HDL-C = 3; total cholesterol to HDL-C ratio = 1]. Another protein, sodium-coupled monocarboxylate transporter 1, was inversely associated with HDL-C and positively associated with total cholesterol to HDL-C ratio. The proportion of the association between diet and lipoproteins mediated by these 10 proteins ranged from 21 to 98%. All of the associations between diet-related proteins and lipoproteins were significant in the ARIC study, except for afamin. CONCLUSIONS: We identified proteins that mediate the association between healthy dietary patterns varying in macronutrients and lipoproteins in a randomized feeding study and an observational study. TRIAL REGISTRATION: NCT00051350 at clinicaltrials.gov.

Plasma Protein Biomarkers of Healthy Dietary Patterns: Results from the Atherosclerosis Risk in Communities Study and the Framingham Heart Study.

BACKGROUND: Molecular mechanisms underlying the benefits of healthy dietary patterns are poorly understood. Identifying protein biomarkers of dietary patterns can contribute to characterizing biological pathways influenced by food intake. OBJECTIVES: This study aimed to identify protein biomarkers associated with four indexes of healthy dietary patterns: Healthy Eating Index-2015 (HEI-2015); Alternative Healthy Eating Index-2010 (AHEI-2010); DASH diet; and alternate Mediterranean Diet (aMED). METHODS: Analyses were conducted on 10,490 Black and White men and women aged 49-73 y from the ARIC study at visit 3 (1993-1995). Dietary intake data were collected using a food frequency questionnaire, and plasma proteins were quantified using an aptamer-based proteomics assay. Multivariable linear regression models were used to examine the association between 4955 proteins and dietary patterns. We performed pathway overrepresentation analysis for diet-related proteins. An independent study population from the Framingham Heart Study was used for replication analyses. RESULTS: In the multivariable-adjusted models, 282 out of 4955 proteins (5.7%) were significantly associated with at least one dietary pattern (HEI-2015: 137; AHEI-2010: 72; DASH: 254; aMED: 35; P value < 0.05/4955 = 1.01 × 10-5). There were 148 proteins that were associated with only one dietary pattern (HEI-2015: 22; AHEI-2010: 5; DASH: 121; aMED: 0), and 20 proteins were associated with all four dietary patterns. Five unique biological pathways were significantly enriched by diet-related proteins. Seven out of 20 proteins associated with all dietary patterns in the ARIC study were available for replication analyses, and 6 out of these 7 proteins were consistent in direction and significantly associated with at least 1 dietary pattern in the Framingham Heart Study (HEI-2015: 2; AHEI-2010: 4; DASH: 6; aMED: 4; P value < 0.05/7 = 7.14 × 10-3). CONCLUSIONS: A large-scale proteomic analysis identified plasma protein biomarkers that are representative of healthy dietary patterns among middle-aged and older US adult population. These protein biomarkers may be useful objective indicators of healthy dietary patterns.

Serum Metabolomic Markers of Dairy Consumption: Results from the Atherosclerosis Risk in Communities Study and the Bogalusa Heart Study.

BACKGROUND: Dairy consumption is related to chronic disease risk; however, the measurement of dairy consumption has largely relied upon self-report. Untargeted metabolomics allows for the identification of objective markers of dietary intake. OBJECTIVES: We aimed to identify associations between dietary dairy intake (total dairy, low-fat dairy, and high-fat dairy) and serum metabolites in 2 independent study populations of United States adults. METHODS: Dietary intake was assessed with food frequency questionnaires. Multivariable linear regression models were used to estimate cross-sectional associations between dietary intake of dairy and 360 serum metabolites analyzed in 2 subgroups of the Atherosclerosis Risk in Communities study (ARIC; n = 3776). Results from the 2 subgroups were meta-analyzed using fixed effects meta-analysis. Significant meta-analyzed associations in the ARIC study were then tested in the Bogalusa Heart Study (BHS; n = 785). RESULTS: In the ARIC study and BHS, the mean age was 54 and 48 years, 61% and 29% were Black, and the mean dairy intake was 1.7 and 1.3 servings/day, respectively. Twenty-nine significant associations between dietary intake of dairy and serum metabolites were identified in the ARIC study (total dairy, n = 14; low-fat dairy, n = 10; high-fat dairy, n = 5). Three associations were also significant in BHS: myristate (14:0) was associated with high-fat dairy, and pantothenate was associated with total dairy and low-fat dairy, but 23 of the 27 associations significant in the ARIC study and tested in BHS were not associated with dairy in BHS. CONCLUSIONS: We identified metabolomic associations with dietary intake of dairy, including 3 associations found in 2 independent cohort studies. These results suggest that myristate (14:0) and pantothenate (vitamin B5) are candidate biomarkers of dairy consumption.

Using Machine Learning to Identify Metabolomic Signatures of Pediatric Chronic Kidney Disease Etiology.

BACKGROUND: Untargeted plasma metabolomic profiling combined with machine learning (ML) may lead to discovery of metabolic profiles that inform our understanding of pediatric CKD causes. We sought to identify metabolomic signatures in pediatric CKD based on diagnosis: FSGS, obstructive uropathy (OU), aplasia/dysplasia/hypoplasia (A/D/H), and reflux nephropathy (RN). METHODS: Untargeted metabolomic quantification (GC-MS/LC-MS, Metabolon) was performed on plasma from 702 Chronic Kidney Disease in Children study participants (n: FSGS=63, OU=122, A/D/H=109, and RN=86). Lasso regression was used for feature selection, adjusting for clinical covariates. Four methods were then applied to stratify significance: logistic regression, support vector machine, random forest, and extreme gradient boosting. ML training was performed on 80% total cohort subsets and validated on 20% holdout subsets. Important features were selected based on being significant in at least two of the four modeling approaches. We additionally performed pathway enrichment analysis to identify metabolic subpathways associated with CKD cause. RESULTS: ML models were evaluated on holdout subsets with receiver-operator and precision-recall area-under-the-curve, F1 score, and Matthews correlation coefficient. ML models outperformed no-skill prediction. Metabolomic profiles were identified based on cause. FSGS was associated with the sphingomyelin-ceramide axis. FSGS was also associated with individual plasmalogen metabolites and the subpathway. OU was associated with gut microbiome-derived histidine metabolites. CONCLUSION: ML models identified metabolomic signatures based on CKD cause. Using ML techniques in conjunction with traditional biostatistics, we demonstrated that sphingomyelin-ceramide and plasmalogen dysmetabolism are associated with FSGS and that gut microbiome-derived histidine metabolites are associated with OU.

Plasma metabolites associated with cognitive function across race/ethnicities affirming the importance of healthy nutrition.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. DISCUSSION: Several diet-related metabolites were associated with global cognitive function across studies with different race/ethnicities. HIGHLIGHTS: 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.

Host and gut microbial tryptophan metabolism and type 2 diabetes: an integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies.

OBJECTIVE: Tryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes (T2D), host genetics, diet and gut microbiota. METHOD: We analysed associations between circulating levels of 11 tryptophan metabolites and incident T2D in 9180 participants of diverse racial/ethnic backgrounds from five cohorts. We examined host genome-wide variants, dietary intake and gut microbiome associated with these metabolites. RESULTS: Tryptophan, four kynurenine-pathway metabolites (kynurenine, kynurenate, xanthurenate and quinolinate) and indolelactate were positively associated with T2D risk, while indolepropionate was inversely associated with T2D risk. We identified multiple host genetic variants, dietary factors, gut bacteria and their potential interplay associated with these T2D-relaetd metabolites. Intakes of fibre-rich foods, but not protein/tryptophan-rich foods, were the dietary factors most strongly associated with tryptophan metabolites. The fibre-indolepropionate association was partially explained by indolepropionate-associated gut bacteria, mostly fibre-using Firmicutes. We identified a novel association between a host functional LCT variant (determining lactase persistence) and serum indolepropionate, which might be related to a host gene-diet interaction on gut Bifidobacterium, a probiotic bacterium significantly associated with indolepropionate independent of other fibre-related bacteria. Higher milk intake was associated with higher levels of gut Bifidobacterium and serum indolepropionate only among genetically lactase non-persistent individuals. CONCLUSION: Higher milk intake among lactase non-persistent individuals, and higher fibre intake were associated with a favourable profile of circulating tryptophan metabolites for T2D, potentially through the host-microbial cross-talk shifting tryptophan metabolism toward gut microbial indolepropionate production.

2021 Dietary Guidance to Improve Cardiovascular Health: A Scientific Statement From the American Heart Association.

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.

Plant-based diets and incident cardiovascular disease and all-cause mortality in African Americans: A cohort study.

BACKGROUND: Prior studies have documented lower cardiovascular disease (CVD) risk among people with a higher adherence to a plant-based dietary pattern. Non-Hispanic black Americans are an understudied group with high burden of CVD, yet studies of plant-based diets have been limited in this population. METHODS AND FINDINGS: We conducted an analysis of prospectively collected data from a community-based cohort of African American adults (n = 3,635) in the Jackson Heart Study (JHS) aged 21-95 years, living in the Jackson, Mississippi, metropolitan area, US, who were followed from 2000 to 2018. Using self-reported dietary data, we assigned scores to participants' adherence to 3 plant-based dietary patterns: an overall plant-based diet index (PDI), a healthy PDI (hPDI), and an unhealthy PDI (uPDI). Cox proportional hazards models were used to estimate associations between plant-based diet scores and CVD incidence and all-cause mortality. Over a median follow-up of 13 and 15 years, there were 293 incident CVD cases and 597 deaths, respectively. After adjusting for sociodemographic characteristics (age, sex, and education) and health behaviors (smoking, alcohol intake, margarine intake, physical activity, and total energy intake), no significant association was observed between plant-based diets and incident CVD for overall PDI (hazard ratio [HR] 1.06, 95% CI 0.78-1.42, p-trend = 0.72), hPDI (HR 1.07, 95% CI 0.80-1.42, p-trend = 0.67), and uPDI (HR 0.95, 95% CI 0.71-1.28, p-trend = 0.76). Corresponding HRs (95% CIs) for all-cause mortality risk with overall PDI, hPDI, and uPDI were 0.96 (0.78-1.18), 0.94 (0.76-1.16), and 1.06 (0.86-1.30), respectively. Corresponding HRs (95% CIs) for incident coronary heart disease with overall PDI, hPDI, and uPDI were 1.09 (0.74-1.61), 1.11 (0.76-1.61), and 0.79 (0.52-1.18), respectively. For incident total stroke, HRs (95% CIs) for overall PDI, hPDI, and uPDI were 1.00 (0.66-1.52), 0.91 (0.61-1.36), and 1.26 (0.84-1.89) (p-trend for all tests > 0.05). Limitations of the study include use of self-reported dietary intake, residual confounding, potential for reverse causation, and that the study did not capture those who exclusively consume plant-derived foods. CONCLUSIONS: In this study of black Americans, we observed that, unlike in prior studies, greater adherence to a plant-based diet was not associated with CVD or all-cause mortality.

Association Between Ultraprocessed Food Consumption and Risk of Incident CKD: A Prospective Cohort Study.

RATIONALE & OBJECTIVE: 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. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 14,679 middle-aged adults without CKD at baseline in the Atherosclerosis Risk in Communities (ARIC) study. EXPOSURE: Ultraprocessed foods consumption (servings per day) calculated using dietary data collected via a food frequency questionnaire at visit 1 and visit 3. OUTCOME: Incident CKD defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 accompanied by ≥25% eGFR decline, CKD-related hospitalization or death, or kidney failure with kidney replacement therapy. ANALYTICAL APPROACH: Multivariable-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. RESULTS: 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). LIMITATIONS: Self-reported data and residual confounding. CONCLUSIONS: Higher ultraprocessed foods consumption was independently associated with a higher risk of incident CKD in a general population.

Metabolomics of Dietary Acid Load and Incident Chronic Kidney Disease.

OBJECTIVE: Blood biomarkers of dietary intake are more objective than self-reported dietary intake. Metabolites associated with dietary acid load were previously identified in 2 chronic kidney disease (CKD) populations. We aimed to extend these findings to a general population, replicating their association with dietary acid load, and investigating whether the individual biomarkers were prospectively associated with incident CKD. METHODS: Among 15,792 participants in the Atherosclerosis Risk in Communities cohort followed up from 1987 to 1989 (baseline) to 2019, we evaluated 3,844 black and white men and women with dietary and metabolomic data in cross-sectional and prospective analyses. We hypothesized that a higher dietary acid load (using equations for potential renal acid load and net endogenous acid production) was associated with lower serum levels of 12 previously identified metabolites: indolepropionylglycine, indolepropionate, N-methylproline, N-δ-acetylornithine, threonate, oxalate, chiro-inositol, methyl glucopyranoside, stachydrine, catechol sulfate, hippurate, and tartronate. In addition, we hypothesized that lower serum levels of these 12 metabolites were associated with higher risk of incident CKD. RESULTS: Eleven out of 12 metabolites were significantly inversely associated with dietary acid load, after adjusting for demographics, socioeconomic status, health behaviors, health status, and estimated glomerular filtration rate: indolepropionylglycine, indolepropionate, N-methylproline, threonate, oxalate, chiro-inositol, catechol sulfate, hippurate, methyl glucopyranoside (α + ß), stachydrine, and tartronate. N-methylproline was inversely associated with incident CKD (hazard ratio: 0.95, 95% confidence interval: 0.91, 0.99, P = .01). The metabolomic biomarkers of dietary acid load significantly improved prediction of elevated dietary acid load estimated using dietary data, beyond covariates (difference in C statistics: 0.021-0.077, P ≤ 1.08 × 10-3). CONCLUSION: Inverse associations between candidate biomarkers of dietary acid load were replicated in a general population. N-methylproline, representative of citrus fruit consumption, is a promising marker of dietary acid load and could represent an important pathway between dietary acid load and CKD.

Proteins Associated with Risk of Kidney Function Decline in the General Population.

BACKGROUND: Proteomic profiling may allow identification of plasma proteins that associate with subsequent changesin kidney function, elucidating biologic processes underlying the development and progression of CKD. METHODS: We quantified the association between 4877 plasma proteins and a composite outcome of ESKD or decline in eGFR by ≥50% among 9406 participants in the Atherosclerosis Risk in Communities (ARIC) Study (visit 3; mean age, 60 years) who were followed for a median of 14.4 years. We performed separate analyses for these proteins in a subset of 4378 participants (visit 5), who were followed at a later time point, for a median of 4.4 years. For validation, we evaluated proteins with significant associations (false discovery rate <5%) in both time periods in 3249 participants in the Chronic Renal Insufficiency Cohort (CRIC) and 703 participants in the African American Study of Kidney Disease and Hypertension (AASK). We also compared the genetic determinants of protein levels with those from a meta-analysis genome-wide association study of eGFR. RESULTS: In models adjusted for multiple covariates, including baseline eGFR and albuminuria, we identified 13 distinct proteins that were significantly associated with the composite end point in both time periods, including TNF receptor superfamily members 1A and 1B, trefoil factor 3, and ß-trace protein. Of these proteins, 12 were also significantly associated in CRIC, and nine were significantly associated in AASK. Higher levels of each protein associated with higher risk of 50% eGFR decline or ESKD. We found genetic evidence for a causal role for one protein, lectin mannose-binding 2 protein (LMAN2). CONCLUSIONS: Large-scale proteomic analysis identified both known and novel proteomic risk factors for eGFR decline.

Association of Multiple Plasma Biomarker Concentrations with Progression of Prevalent Diabetic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: Although diabetic kidney disease is the leading cause of ESKD in the United States, identifying those patients who progress to ESKD is difficult. Efforts are under way to determine if plasma biomarkers can help identify these high-risk individuals. METHODS: In our case-cohort study of 894 Chronic Renal Insufficiency Cohort Study participants with diabetes and an eGFR of <60 ml/min per 1.73 m2 at baseline, participants were randomly selected for the subcohort; cases were those patients who developed progressive diabetic kidney disease (ESKD or 40% eGFR decline). Using a multiplex system, we assayed plasma biomarkers related to tubular injury, inflammation, and fibrosis (KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40). Weighted Cox regression models related biomarkers to progression of diabetic kidney disease, and mixed-effects models estimated biomarker relationships with rate of eGFR change. RESULTS: Median follow-up was 8.7 years. Higher concentrations of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were each associated with a greater risk of progression of diabetic kidney disease, even after adjustment for established clinical risk factors. After accounting for competing biomarkers, KIM-1, TNFR-2, and YKL-40 remained associated with progression of diabetic kidney disease; TNFR-2 had the highest risk (adjusted hazard ratio, 1.61; 95% CI, 1.15 to 2.26). KIM-1, TNFR-1, TNFR-2, and YKL-40 were associated with rate of eGFR decline. CONCLUSIONS: Higher plasma levels of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were associated with increased risk of progression of diabetic kidney disease; TNFR-2 had the highest risk after accounting for the other biomarkers. These findings validate previous literature on TNFR-1, TNFR-2, and KIM-1 in patients with prevalent CKD and provide new insights into the influence of suPAR and YKL-40 as plasma biomarkers that require validation.

Association Between Midlife Physical Activity and Incident Kidney Disease: The Atherosclerosis Risk in Communities (ARIC) Study.

RATIONALE & OBJECTIVE: Physical activity is associated with lower risk for cardiovascular disease, diabetes, and hypertension, which have shared risk factor profiles with chronic kidney disease (CKD). However, there are conflicting findings regarding the relationship between physical activity and CKD. The objective was to evaluate the association between physical activity and CKD development over long-term follow-up using the Atherosclerosis Risk in Communities (ARIC) Study. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 14,537 participants aged 45 to 64 years. PREDICTORS: Baseline physical activity status was assessed using the modified Baecke Physical Activity Questionnaire at visit 1 (1987-1989) and categorized according to the 2018 Physical Activity Guidelines for Americans to group participants as inactive, insufficiently active, active, and highly active. OUTCOMES: Incident CKD defined as estimated glomerular filtration rate (eGFR)<60mL/min/1.73m2 at follow-up and≥25% decline in eGFR relative to baseline, CKD-related hospitalization or death, or initiation of kidney replacement therapy. ANALYTICAL APPROACH: Cox proportional hazards regression. RESULTS: At baseline, 37.8%, 24.2%, 22.7%, and 15.3% of participants were classified as inactive, insufficiently active, active, and highly active, respectively. During a median follow-up of 24 years, 33.2% of participants developed CKD. After adjusting for age, sex, race-center, education, smoking status, diet quality, diabetes, coronary heart disease, hypertension, antihypertensive medication, body mass index, and baseline eGFR, higher categories of physical activity were associated with lower risk for CKD compared with the inactive group (HRs for insufficiently active, 0.95 [95% CI, 0.88-1.02]; active, 0.93 [95% CI, 0.86-1.01]; highly active, 0.89 [95% CI, 0.81-0.97]; P for trend = 0.007). LIMITATIONS: Observational design and self-reported physical activity that was based on leisure time activity only. Due to low numbers, participants who were not Black or White were excluded. CONCLUSIONS: Highly active participants had lower risk for developing CKD compared with inactive participants.

Association Between Midlife Obesity and Kidney Function Trajectories: The Atherosclerosis Risk in Communities (ARIC) Study.

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 103mL/min/1.73m2, and median BMI was 27kg/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/1.73m2 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/1.73m2 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/1.73m2 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/1.73m2 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.

Adherence to Healthy Dietary Patterns and Risk of CKD Progression and All-Cause Mortality: Findings From the CRIC (Chronic Renal Insufficiency Cohort) Study.

RATIONALE & OBJECTIVE: Current dietary guidelines recommend that patients with chronic kidney disease (CKD) 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 4 healthy dietary patterns with risk for CKD progression and all-cause mortality among people with CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 2,403 participants aged 21 to 74 years with estimated glomerular filtration rates of 20 to 70mL/min/1.73m2 and dietary data in the Chronic Renal Insufficiency Cohort (CRIC) Study. EXPOSURES: Healthy Eating Index-2015, Alternative Healthy Eating Index-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% estimated glomerular filtration rate 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 (HRs) and 95% CIs. RESULTS: There were 855 cases of CKD progression and 773 deaths during a maximum of 14 years. Compared with participants with the lowest adherence, the most highly adherent tertile of Alternative Healthy Eating Index-2010, aMed, and DASH had lower adjusted risk for 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 for 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 lower risk for 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.