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Background: Consumption of ultra-processed food, which is manufactured food that is high in additives and sparse in intact foods, is adversely associated with cardiovascular health, primarily in non-US study populations. We aimed to estimate the association between ultra-processed food consumption and incident hypertension in middle-aged adults in the United States., Methods and Results: We included 8923 ARIC (Atherosclerosis Risk in Communities) study participants who were hypertension free at baseline and had complete dietary, covariate, and hypertension data from visit 1 (1987-1989). Over a median (25th, 75th percentile) follow-up of 13 (6-21) years, 79% of participants developed hypertension. Participants in the highest quartile of ultra-processed food consumption had 15% higher risk of incident hypertension than those in the lowest quartile (hazard ratio [HR], 1.15 [95% CI, 1.08-1.23]). Participants in the highest quartile of consumption of sugar-sweetened beverages, red and processed meat, and margarine had 16% (HR, 1.16 [95% CI, 1.08-1.24]; p-trend <0.001), 10% (HR, 1.10 [95% CI, 1.03-1.19]; P trend = 0.005), and 6% (HR, 1.06 [95% CI, 0.99, 1.45]; P trend = 0.045) higher risk of incident hypertension, respectively, when compared with the lowest quartiles of consumption. Each additional serving of minimally or unprocessed food was associated with a 2% lower risk of incident hypertension (HR, 0.98 [95% CI, 0.98, 0.99], P <0.001)., Conclusions: High consumption of ultra-processed foods, specifically of sugar-sweetened beverages, red and processed meat, and margarine, was associated with a higher incidence of hypertension, whereas minimally or unprocessed food consumption was associated with lower hypertension risk.

Background: Interest in plant-based eating has increased alongside increased variety and availability of highly processed plant-based meat and dairy alternatives. The impact of the shifting commercial landscape and public interest in plant-based eating on dietary intake is unknown., Objectives: To examine trends in the consumption and composition of plant-based diets in the United States adults., Methods: Serial cross-sectional data from the National Health and Nutrition Examination Survey were used to assess trends in the proportion of United States adults aged ≥20 y consuming a plant-based diet (defined as ≥50% total protein from plants on a 24-h dietary recall) from 1999-2000 to 2017-March 2020 (n = 51,698). Trends in processing level (percentage energy intake from ultraprocessed foods) and diet quality [Healthy Eating Index (HEI)-2020 scores] were assessed in the subset of adults consuming plant-based diets (n = 8327)., Results: The proportion of United States adults consuming plant-based diets increased from 14.4% (95% CI: 12.9%, 16.0%) to 17.2% (95% confidence interval [CI]: 15.5%, 19.1%; P = 0.005 for trend). In all survey cycles, ultraprocessed foods accounted for the majority of energy intake, and ultraprocessed food intake in plant-based diets did not significantly change over time [50.7% kcal (95% CI: 47.3%, 54.1%) in 1999-2000 compared with 52.7% kcal (95% CI: 49.7%, 55.6%) in 2017-March 2020; P for trend = 0.34]. The quality of plant-based diets, measured by HEI-2020 scores, improved from 52.1 (95% CI: 49.7, 54.6) to 55.8 (95% CI: 54.1, 57.5; P for trend <0.001)., Conclusions: Between 1999 and March 2020, the proportion of United States adults consuming a plant-based diet increased. Among people consuming plant-based diets, ultraprocessed foods contributed most to energy intake and there was no sustained change in intake over time. The mean diet quality was low but improved modestly., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background: Patients with chronic kidney disease (CKD) are encouraged to choose refined grains instead of whole grains as part of the low-phosphorus diet for managing chronic kidney disease-mineral and bone disorders (CKD-MBD). However, there is no direct evidence indicating that limiting whole grains has a beneficial impact on CKD outcomes., Methods: This study analyzed Chronic Renal Insufficiency Cohort data in two ways, namely cross-sectional examination of CKD-MBD biomarkers and prospective examination of health outcomes. A total of 4,067 (cross-sectional) and 4,331 (prospective) participants were included. The primary exposure was reported intake of whole grains (analyzed as servings/day, servings/1,000kcal, and refined grain servings/whole grain servings). CKD-MBD biomarkers included serum phosphorus, fibroblast growth factor-23, parathyroid hormone, calcitriol, and calcium. Outcomes included cardiovascular events, kidney failure, and all-cause mortality., Results: In adjusted models, reported intake of whole grains was associated with higher phosphorus intake and serum phosphorus when assessed crudely (serving/day), but not when analyzed in relation to energy. Higher intake of refined grain relative to whole grains was associated (all models) with higher risk of kidney failure (Model 4: 1.01, 95% CI 1.00 to 1.02; P=0.01, all-cause mortality (Model 4: 1.01, 95% CI 1.00 to 1.01; P=0.01), and cardiovasulcar disease except for the fully adjusted model. Higher dietary density was associated with lower mortality in models adjusted for demographic and clinical factors including kidney function, but not in the fully adjusted model that futher adjusted for dietary factors., Conclusion: Intake of whole grains was not associated with CKD-MBD biomarkers. Intake of whole grains in relation to refined grains was associated with lower risk of cardiovascular disease, kidney failure, and mortality. The results of this study put into question the long-standing practice of restricting whole grains in patients with chronic kidney disease., (Copyright © 2024 by the American Society of Nephrology.)

Purpose of Review: Plant-based diets are associated with a lower risk of hypertension, diabetes, cardiovascular disease, and mortality. Using the most recent evidence, we critically appraised the role of plant-based diets in primary and secondary prevention of chronic kidney disease (CKD) with a focus on key nutritional factors (dietary acid load, phosphorus, potassium, sodium, and fiber)., Recent Findings: In healthy individuals, observational studies found that greater intake of plant protein and higher adherence to plant-based diets (overall, healthful, and provegetarian) was associated with a lower risk of CKD. In those with CKD, plant-based diets were associated with a lower risk of mortality, improved kidney function, and favorable metabolic profiles (fibroblast growth factor-23, uremic toxins, insulin sensitivity, inflammatory biomarkers). Only few studies reported nutrient content of plant-based diets. These studies found that plant-based diets had lower dietary acid load, lower or no significant difference in phosphorus and sodium, and higher potassium and fiber. One study reported that vegetarian diets were associated with severe vitamin D deficiency compared to nonvegetarian diets., Summary: Plant-based diets provide several benefits for prevention and management of CKD, with little risk for individuals with CKD. Incorporation of vitamin D rich foods in plant-based diets may be helpful., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Numerous studies have shown inverse associations between serum magnesium (Mg) and risk of cardiovascular disease (CVD), but studies of dietary Mg have not been consistent., Aim: To examine the association of a Mg-rich diet score with risks of CVD, coronary heart disease (CHD), and ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study., Methods: There were 15,022 Black and White adults without prevalent CVD at baseline (1987-89) included in this analysis. Diet was assessed at two visits 6 years apart using an interviewer-administered 66-item food frequency questionnaire. A Mg-rich diet score was created that included servings of whole grain products, nuts, vegetables, fruit, legumes, coffee, and tea. Cox proportional hazard regression evaluated associations of incident CVD, CHD and stroke across quintiles of Mg-rich diet score, adjusting for demographics, lifestyle factors, and clinical characteristics., Results: Over >30 years of follow-up, there were 3,531 incident CVD events (2,562 CHD, 1,332 ischemic stroke). Participants who consumed more Mg-rich foods were older, female, White, had lower blood pressure, fewer were not current smokers, and more reported being physically active. A Mg-rich diet was inversely associated with incident CVD (HRQ5 vs Q1=0.87, 95%CI: 0.77-0.98, ptrend=0.02) CHD (HRQ5 vs Q1=0.82, 95%CI: 0.71-0.95, ptrend=0.01); however, the diet-stroke association was null (HRQ5 vs Q1=1.00, 95%CI: 0.82-1.22, ptrend=0.97)., Conclusions: Consuming a diet including Mg-rich foods, such as whole grains, nuts, vegetables, fruits, legumes, coffee and tea, is associated with lower risk of CVD and CHD, but not ischemic stroke., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Our aim was to conduct an umbrella review of evidence from meta-analyses of observational studies investigating the link between sugar-sweetened beverage consumption and human health outcomes. Using predefined evidence classification criteria, we evaluated evidence from 47 meta-analyses encompassing 22,055,269 individuals. Overall, 79% of these analyses indicated direct associations between greater sugar-sweetened beverage consumption and higher risks of adverse health outcomes. Convincing evidence (class I) supported direct associations between sugar-sweetened beverage consumption and risks of depression, cardiovascular disease, nephrolithiasis, type 2 diabetes mellitus, and higher uric acid concentrations. Highly suggestive evidence (class II) supported associations with risks of nonalcoholic fatty liver disease and dental caries. Out of the remaining 40 meta-analyses, 29 were graded as suggestive or weak in the strength of evidence (classes III and IV), and 11 showed no evidence (class V). These findings inform and provide support for population-based and public health strategies aimed at reducing sugary drink consumption for improved health.

Background & Aims: Plant-based diets are associated with a lower risk of chronic diseases. Large-scale proteomics can identify objective biomarkers of plant-based diets, and improve our understanding of the pathways that link plant-based diets to health outcomes. This study investigated the plasma proteome of four different plant-based diets [overall plant-based diet (PDI), provegetarian diet, healthful plant-based diet (hPDI), and unhealthful plant-based diet (uPDI)] in the Atherosclerosis Risk in Communities (ARIC) Study and replicated the findings in the Framingham Heart Study (FHS) Offspring cohort., Methods: ARIC Study participants at visit 3 (1993-1995) with completed food frequency questionnaire (FFQ) data and proteomics data were divided into internal discovery (n = 7690) and replication (n = 2543) data sets. Multivariable linear regression was used to examine associations between plant-based diet indices (PDIs) and 4955 individual proteins in the discovery sample. Then, proteins that were internally replicated in the ARIC Study were tested for external replication in FHS (n = 1358). Pathway overrepresentation analysis was conducted for diet-related proteins. C-statistics were used to predict if the proteins improved prediction of plant-based diet indices beyond participant characteristics., Results: In ARIC discovery, a total of 837 diet-protein associations (PDI = 233; provegetarian = 182; hPDI = 406; uPDI = 16) were observed at false discovery rate (FDR) < 0.05. Of these, 453 diet-protein associations (PDI = 132; provegetarian = 104; hPDI = 208; uPDI = 9) were internally replicated. In FHS, 167/453 diet-protein associations were available for external replication, of which 8 proteins (PDI = 1; provegetarian = 0; hPDI = 8; uPDI = 0) replicated. Complement and coagulation cascades, cell adhesion molecules, and retinol metabolism were over-represented. C-C motif chemokine 25 for PDI and 8 proteins for hPDI modestly but significantly improved the prediction of these indices individually and collectively (P value for difference in C-statistics<0.05 for all tests)., Conclusions: Using large-scale proteomics, we identified potential candidate biomarkers of plant-based diets, and pathways that may partially explain the associations between plant-based diets and chronic conditions., Competing Interests: Conflict of interest All authors have no conflicts of interests to disclose., (Copyright © 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Aims/hypothesis: Understanding the impact of the overall construct of ultra-processed foods on diabetes risk can inform dietary approaches to diabetes prevention. In this study, we aimed to evaluate the association between ultra-processed food consumption and risk of diabetes in a community-based cohort of middle-aged adults in the USA. We hypothesised that a higher intake of ultra-processed foods is associated with a higher risk of incident diabetes., Methods: The study included 13,172 participants without diabetes at baseline (1987-1989) in the Atherosclerosis Risk in Communities (ARIC) study. Dietary intake was assessed with a 66-item semiquantitative food frequency questionnaire, and foods were categorised by processing level using the Nova classification system. Ultra-processed food was analysed categorically (quartiles of energy-adjusted intake) and continuously (per one additional serving/day). We used Cox regression to evaluate the association of ultra-processed food intake with risk of diabetes with adjustment for sociodemographic characteristics, total energy intake, health behaviours and clinical factors., Results: Over a median follow-up of 21 years, there were 4539 cases of incident diabetes. Participants in the highest quartile of ultra-processed food intake (8.4 servings/day on average) had a significantly higher risk of diabetes (HR 1.13; 95% CI 1.03, 1.23) compared with participants in the lowest quartile of intake after adjustment for sociodemographic, lifestyle and clinical factors. Each additional serving of ultra-processed food consumed daily was associated with a 2% higher risk of diabetes (HR 1.02; 95% CI 1.00, 1.04). Highest quartile consumption of certain ultra-processed food groups, including sugar- and artificially sweetened beverages, ultra-processed meats and sugary snacks, was associated with a 29%, 21% and 16% higher risk of diabetes, respectively, compared with the lowest quartile., Conclusions/interpretation: We found that a higher intake of ultra-processed food was associated with higher risk of incident diabetes, particularly sugar- and artificially sweetened beverages, ultra-processed meats and sugary snacks. Our findings suggest interventions reducing ultra-processed food consumption and specific food groups may be an effective strategy for diabetes prevention., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: The Dietary Approaches to Stop Hypertension (DASH) diet reduces blood pressure, but the mechanisms underlying DASH diet-blood pressure relations are not well understood. Proteomic measures may provide insights into the pathophysiological mechanisms through which the DASH diet reduces blood pressure., Methods: The DASH (1994-1996) and DASH-Sodium (1997-1999) trials were multicenter, randomized-controlled feeding trials. Proteomic profiling was conducted in serum collected at the end of the feeding period (DASH, N = 215; DASH-Sodium, N = 390). Multivariable linear regression models were used to identify interactions between 71 DASH diet-related proteins and changes in systolic and diastolic blood pressure. Estimates were meta-analyzed across both trials. Elastic net models were used to identify proteins that predict changes in blood pressure., Results: Ten significant interactions were identified [systolic blood pressure: seven proteins; diastolic blood pressure: three proteins], which represented nine unique proteins. A high level of renin at the end of the feeding period was associated with greater reductions in diastolic blood pressure in individuals consuming the control than DASH diets. A high level of procollagen c-endopeptidase enhancer 1 (PCOLCE) and collagen triple helix repeat-containing protein 1 (CTHRC1) were associated with greater reductions in systolic blood pressure in individuals consuming the DASH than control diets, and with elevations in systolic blood pressure in individuals consuming the control diets (P for interaction for all tests < 0.05). Elastic net models identified six additional proteins that predicted change in blood pressure., Conclusions: Several novel proteins were identified that may provide some insight into the relationship between the DASH diet and blood pressure., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Circulating α1-acid glycoprotein (AGP) and C-reactive protein (CRP) are commonly measured to assess inflammation, but these biomarkers fail to reveal the complex molecular biology of inflammation. We mined the maternal plasma proteome to detect proteins that covary with AGP and CRP. In 435 gravida predominantly in <12-week gestation, we correlated the relative quantification of plasma proteins assessed via a multiplexed aptamer assay (SOMAScan ® ) with AGP and CRP, quantified by immunoassay. We defined a plasma inflammasome as protein correlates meeting a false discovery rate <0.05. We examined potential pathways using principal component analysis. A total of 147 and 879 of 6431 detected plasma proteins correlated with AGP and CRP, respectively, of which 61 overlapped with both biomarkers. Positive correlates included serum amyloid, complement, interferon-induced, and immunoregulatory proteins. Negative correlates were micronutrient and lipid transporters and pregnancy-related anabolic proteins. The principal components (PCs) of AGP were dominated by negatively correlated anabolic proteins associated with gestational homeostasis, angiogenesis, and neurogenesis. The PCs of CRP were more diverse in function, reflecting cell surface and adhesion, embryogenic, and intracellular and extra-hepatic tissue leakage proteins. The plasma proteome of AGP or CRP reveals wide proteomic variation associated with early gestational inflammation, suggesting mechanisms and pathways that merit future research.

Background: High dietary calcium and phosphorus may accelerate vascular calcification, but epidemiological data are inconsistent. Most of those studies assessed diet at one point and have not been systematically evaluated., Objectives: The purpose of this study was to assess the associations of dietary calcium and phosphorus intakes in middle age with coronary artery and extra-coronary calcification at older age., Methods: We studied 1,914 participants from the ARIC (Atherosclerosis Risk In Communities) study (mean age 80.5 years) without coronary heart disease who underwent chest computed tomography scans at visit 7 (2018-2019) and completed a 66-item food frequency questionnaire at 2 earlier visits (visit 1 [1987-1989] and visit 3 [1993-1995]). Dietary calcium and phosphorus intakes were averaged between these 2 visits. Calcification was quantified by the Agatston score in coronary artery, ascending aorta, descending aorta, aortic valve ring, aortic valve, and mitral valve., Results: Dietary calcium intake was inversely associated with coronary artery and ascending aorta calcification, whereas the association was not significant for other measures of extra-coronary calcification. For example, the highest vs lowest quartile of calcium intake showed an adjusted OR of 0.66 (95% CI: 0.45-0.98) for coronary artery calcification (Agatston score ≥75th percentile). Dietary phosphorus intake demonstrated similar results, but the magnitude of the association was weaker than dietary calcium intake., Conclusions: Dietary calcium and phosphorus intakes at middle age were not positively associated with vascular and valvular calcification at over 75 years old. Our findings did not support the link between a calcium or phosphorus-rich diet and vascular and valvular calcification., Competing Interests: The ARIC study has been funded in whole or in part with federal funds from the 10.13039/100000050National Heart, Lung, and Blood Institute, 10.13039/100000002National Institutes of Health, 10.13039/100000016Department of Health and Human Services, under contract numbers (75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, 75N92022D00005). This specific study was supported by R01HL136592 (multiple PIs: Drs Matsushita and Blaha). Dr Rebholz was supported by a grant from the 10.13039/100000050National Heart, Lung, and Blood Institute (R01 HL153178). Dr Nohara was supported by grants-in-aid from the International Research Fund for Subsidy of Kyusyu University School of Medicine Alumni, Japan. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Objective: Plant-based dietary patterns emphasize plant foods and minimize animal-derived foods. We investigated the association between plant-based dietary patterns and diabetes in a community-based U.S. sample of Black and White adults., Research Design and Methods: We included middle-aged adults from the Atherosclerosis Risk in Communities (ARIC) study without diabetes at baseline who completed a food-frequency questionnaire (n = 11,965). We scored plant-based diet adherence according to three indices: overall, healthy, and unhealthy plant-based diet indices. Higher overall plant-based diet index (PDI) scores represent greater intakes of all plant foods and lower intakes of animal-derived foods. Higher healthy plant-based diet index (hPDI) scores represent greater healthy plant food intake and lower intakes of animal-derived and unhealthy plant foods. Higher unhealthy plant-based diet index (uPDI) scores represent greater unhealthy plant food intake and lower intakes of animal-derived and healthy plant foods. We used Cox regression to estimate hazard ratios (HRs) for incident diabetes (defined according to self-reported diagnosis, medication use, or elevated blood glucose) associated with each index., Results: Over a median follow-up of 22 years, we identified 4,208 cases of diabetes among subjects. Higher PDI scores were associated with a lower risk of diabetes (quintile 5 vs. 1 HR 0.89 [95% CI 0.80, 0.98]; Ptrend = 0.01). hPDI scores were also inversely associated with diabetes risk (quintile 5 vs. 1 HR 0.85 [95% CI 0.77, 0.94]; Ptrend < 0.001). uPDI scores were not associated with diabetes risk., Conclusions: A dietary pattern that minimizes animal-derived foods and emphasizes plant foods may reduce diabetes risk., (© 2024 by the American Diabetes Association.)

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., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Tubulointerstitial damage is a feature of early chronic kidney disease (CKD), but current clinical tests capture it poorly. Urine biomarkers of tubulointerstitial health may identify risk of CKD., Study Design: Prospective cohort (Atherosclerosis Risk in Communities [ARIC]) and case-cohort (Multi-Ethnic Study of Atherosclerosis [MESA] and Reasons for Geographic and Racial Differences in Stroke [REGARDS])., Setting & Participants: Adults with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m 2 and without diabetes in the ARIC, REGARDS, and MESA studies., Exposures: Baseline urine monocyte chemoattractant protein-1 (MCP-1), alpha-1-microglobulin (α1m), kidney injury molecule-1, epidermal growth factor, and chitinase-3-like protein 1., Outcome: Incident CKD or end-stage kidney disease., Analytical Approach: Multivariable Cox proportional hazards regression for each cohort; meta-analysis of results from all 3 cohorts., Results: 872 ARIC participants (444 cases of incident CKD), 636 MESA participants (158 cases), and 924 REGARDS participants (488 cases) were sampled. Across cohorts, mean age ranged from 60 ± 10 to 63 ± 8 years, and baseline eGFR ranged from 88 ± 13 to 91 ± 14 mL/min/1.73 m 2 . In ARIC, higher concentrations of urine MCP-1, α1m, and kidney injury molecule-1 were associated with incident CKD. In MESA, higher concentration of urine MCP-1 and lower concentration of epidermal growth factor were each associated with incident CKD. In REGARDS, none of the biomarkers were associated with incident CKD. In meta-analysis of all 3 cohorts, each 2-fold increase α1m concentration was associated with incident CKD (HR, 1.19; 95% CI, 1.08-1.31)., Limitations: Observational design susceptible to confounding; competing risks during long follow-up period; meta-analysis limited to 3 cohorts., Conclusions: In 3 combined cohorts of adults without prevalent CKD or diabetes, higher urine α1m concentration was independently associated with incident CKD. 4 biomarkers were associated with incident CKD in at least 1 of the cohorts when analyzed individually. Kidney tubule health markers might inform CKD risk independent of eGFR and albuminuria., (© 2024 The Authors.)

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., (Copyright © 2023. Published by Elsevier Inc.)

Background: The Dietary Approaches to Stop Hypertension (DASH) diet score lowers blood pressure (BP). We examined interactions between genotype and the DASH diet score in relation to systolic BP., Methods: We analyzed up to 9 420 585 single nucleotide polymorphisms in up to 127 282 individuals of 6 population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (n=35 660) and UK Biobank (n=91 622) and performed European population-specific and cross-population meta-analyses., Results: We identified 3 loci in European-specific analyses and an additional 4 loci in cross-population analyses at P interaction <5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency, 0.03) and the DASH diet score ( P interaction =4e-8; P for heterogeneity, 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg ( P interaction =9.4e-7) and 0.20±0.06 mm Hg ( P interaction =0.001) in Cohorts for Heart and Aging Research in Genomic Epidemiology and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants ( P =4e-273) and cis-DNA methylation quantitative trait loci variants ( P =1e-300). Although the closest gene for rs117878928 is MTHFS , the highest narrow sense heritability accounted by single nucleotide polymorphisms potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1., Conclusions: We demonstrated gene-DASH diet score interaction effects on systolic BP in several loci. Studies with larger diverse populations are needed to validate our findings., Competing Interests: Disclosures None.

Rationale & Objective: While urine excretion of nitrogen estimates the total protein intake, biomarkers of specific dietary protein sources have been sparsely studied. Using untargeted metabolomics, this study aimed to identify serum metabolomic markers of 6 protein-rich foods and to examine whether dietary protein-related metabolites are associated with incident chronic kidney disease (CKD)., Study Design: Prospective cohort study., Setting & Participants: A total of 3,726 participants from the Atherosclerosis Risk in Communities study without CKD at baseline., Exposures: Dietary intake of 6 protein-rich foods (fish, nuts, legumes, red and processed meat, eggs, and poultry), serum metabolites., Outcomes: Incident CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m 2 with ≥25% estimated glomerular filtration rate decline relative to visit 1, hospitalization or death related to CKD, or end-stage kidney disease)., Analytical Approach: Multivariable linear regression models estimated cross-sectional associations between protein-rich foods and serum metabolites. C statistics assessed the ability of the metabolites to improve the discrimination of highest versus lower 3 quartiles of intake of protein-rich foods beyond covariates (demographics, clinical factors, health behaviors, and the intake of nonprotein food groups). Cox regression models identified prospective associations between protein-related metabolites and incident CKD., Results: Thirty significant associations were identified between protein-rich foods and serum metabolites (fish, n = 8; nuts, n = 5; legumes, n = 0; red and processed meat, n = 5; eggs, n = 3; and poultry, n = 9). Metabolites collectively and significantly improved the discrimination of high intake of protein-rich foods compared with covariates alone (difference in C statistics = 0.033, 0.051, 0.003, 0.024, and 0.025 for fish, nuts, red and processed meat, eggs, and poultry-related metabolites, respectively; P  < 1.00 × 10 -16 for all). Dietary intake of fish was positively associated with 1-docosahexaenoylglycerophosphocholine (22:6n3), which was inversely associated with incident CKD (HR, 0.82; 95% CI, 0.75-0.89; P  = 7.81 × 10 -6 )., Limitations: Residual confounding and sample-storage duration., Conclusions: We identified candidate biomarkers of fish, nuts, red and processed meat, eggs, and poultry. A fish-related metabolite, 1-docosahexaenoylglycerophosphocholine (22:6n3), was associated with a lower risk of CKD., (© 2024 The Authors.)

Cow's milk is frequently included in the human diet, but the relationship between milk intake and type 2 diabetes (T2D) remains controversial. Here, using data from the Hispanic Community Health Study/Study of Latinos, we show that in both sexes, higher milk intake is associated with lower risk of T2D in lactase non-persistent (LNP) individuals (determined by a variant of the lactase LCT gene, single nucleotide polymorphism rs4988235 ) but not in lactase persistent individuals. We validate this finding in the UK Biobank. Further analyses reveal that among LNP individuals, higher milk intake is associated with alterations in gut microbiota (for example, enriched Bifidobacterium and reduced Prevotella) and circulating metabolites (for example, increased indolepropionate and reduced branched-chain amino acid metabolites). Many of these metabolites are related to the identified milk-associated bacteria and partially mediate the association between milk intake and T2D in LNP individuals. Our study demonstrates a protective association between milk intake and T2D among LNP individuals and a potential involvement of gut microbiota and blood metabolites in this association., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The benefits of plant-based diets may depend on the type of plant. To determine the associations of healthy and unhealthy plant-based diet types on risk of hospitalization with respiratory infections or any infection, we used dietary intake data reported in a food frequency questionnaire from the Atherosclerosis Risk in Communities Study to calculate a plant-based diet index (PDI), a healthy PDI (HPDI), and an unhealthy PDI (UPDI). Cox regression was used to calculate hazard ratios for the associations of the three plant-based diet indices with the risk of hospitalization with respiratory infections and any infection-related hospitalization. Comparing the highest to lowest quintiles, HPDI was associated with a lower risk of hospitalization with respiratory infections (HR 0.86, 95% CI: 0.75, 0.99), and a lower risk of hospitalization with any infections (HR 0.87, 95% CI: 0.78, 0.97). The PDI was associated with a lower risk of hospitalization with any infections (HR 0.86, 95% CI: 0.76, 0.96). Significant associations were not observed with the UPDI. Adults with a high PDI and HPDI had a lower risk of hospitalization with any infections, whereas adults with a high HPDI had lower risk of hospitalizations with respiratory infections.

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., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Biomarkers of kidney disease progression have been identified in individuals with diabetes and underlying chronic kidney disease (CKD). Whether or not these markers are associated with the development of CKD in a general population without diabetes or CKD is not well established., Study Design: Prospective observational cohort., Setting & Participants: In the Atherosclerosis Risk in Communities) study, 948 participants were studied., Exposures: The baseline plasma biomarkers of kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein-1 (MCP-1), soluble urokinase plasminogen activator receptor (suPAR), tumor necrosis factor receptor 1 (TNFR-1), tumor necrosis factor receptor 2 (TNFR-2), and human cartilage glycoprotein-39 (YKL-40) measured in 1996-1998., Outcome: Incident CKD after 15 years of follow-up defined as ≥40% estimated glomerular filtration rate decline to <60 mL/min/1.73 m 2 or dialysis dependence through United States Renal Data System linkage., Analytical Approach: Logistic regression and C statistics., Results: There were 523 cases of incident CKD. Compared with a random sample of 425 controls, there were greater odds of incident CKD per 2-fold higher concentration of KIM-1 (OR, 1.49; 95% CI, 1.25-1.78), suPAR (OR, 2.57; 95% CI, 1.74-3.84), TNFR-1 (OR, 2.20; 95% CI, 1.58-3.09), TNFR-2 (OR, 2.03; 95% CI, 1.37-3.04). After adjustment for all biomarkers, KIM-1 (OR, 1.42; 95% CI, 1.19-1.71), and suPAR (OR, 1.86; 95% CI, 1.18-2.92) remained associated with incident CKD. Compared with traditional risk factors, the addition of all 6 biomarkers improved the C statistic from 0.695-0.731 ( P  < 0.01) and using the observed risk of 12% for incident CKD, the predicted risk gradient changed from 5%-40% (for the 1st-5th quintile) to 4%-44%., Limitations: Biomarkers and creatinine were measured at one time point., Conclusions: Higher levels of KIM-1, suPAR, TNFR-1, and TNFR-2 were associated with higher odds of incident CKD among individuals without diabetes., Plain-Language Summary: For people with diabetes or kidney disease, several biomarkers have been shown to be associated with worsening kidney disease. Whether these biomarkers have prognostic significance in people without diabetes or kidney disease is less studied. Using the Atherosclerosis Risk in Communities study, we followed individuals without diabetes or kidney disease for an average of 15 years after biomarker measurement to see if these biomarkers were associated with the development of kidney disease. We found that elevated levels of KIM-1, suPAR, TNFR-1, and TNFR-2 were associated with the development of kidney disease. These biomarkers may help identify individuals who would benefit from interventions to prevent the development of kidney disease., (© 2023 The Authors.)

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/1.73m 2 ; tertile 3 vs tertile 1, HR, 2.61; 95% CI, 1.32-5.18) but not stages 3a-5 (eGFR<60mL/min/1.73m 2 ; 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., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: N-terminal pro-brain-type natriuretic peptide (NT-proBNP) is a marker of cardiac wall stress and is a predictor of cardiovascular disease. Higher diet quality is associated with lower risk of cardiovascular disease. The association between diet quality and subclinical cardiovascular disease assessed by NT-proBNP is uncharacterized. We investigated the associations between diet quality, using Healthy Eating Index-2015 (HEI-2015), and NT-proBNP from the National Health and Nutrition Examination Survey (NHANES) 1999-2004., Methods: We included 9,782 adults from NHANES 1999-2004 without self-reported cardiovascular disease. The HEI-2015 ranges from 0 to 100, with higher scores indicating better diet quality. The HEI-2015 was categorized into sex-specific quintiles. Regression models were used to quantify associations between the overall HEI-2015 score and its 13 components with log-transformed NT-proBNP. The beta coefficients were converted to percent differences., 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, those in the highest vs. lowest HEI-2015 quintile had an 8.5% (95% CI: -14.6% to -2.0%) lower NT-proBNP level. There was a dose-response association between HEI-2015 and NT-proBNP (P value for trend = 0.01). Each 1-unit higher in sodium and added sugars score indicating lower intake was associated with lower NT-proBNP by 7.7% (95% CI: -12.8% to -2.2%) and 6.5% (95% CI: -12.0% to -0.7%), respectively., Conclusion: Higher diet quality, especially lower intakes of sodium and added sugars, was associated with lower serum levels of NT-proBNP., Competing Interests: R.H. Christenson reports a relationship with The Journal of Applied Laboratory Medicine that includes: employment. R.H. Christenson reports a relationship with American Association for Clinical Chemistry that includes: employment. E. Selvin reports a relationship with Diabetes Care that includes: employment. E. Selvin reports a relationship with Diabetologia that includes: employment. E. Selvin reports a relationship with American Heart Association that includes: employment. C.M. Rebholz reports a relationship with Diabetes Care that includes: employment. C.M. Rebholz reports a relationship with American Heart Association that includes: employment. R.H. Christenson reports a relationship with Quidel Medical that includes: consulting or advisory. R.H. Christenson reports a relationship with Roche Diagnostics that includes: consulting or advisory. R.H. Christenson reports a relationship with Siemens Healthineers that includes: consulting or advisory. R.H. Christenson reports a relationship with Beckman Coulter that includes: consulting or advisory. R.H. Christenson reports a relationship with Sphingotech that includes: consulting or advisory. R.H. Christenson reports a relationship with Pixcell Medical that includes: consulting or advisory. E. Selvin reports a relationship with Wolters Kluwer that includes: speaking and lecture fees. R.H. Christenson reports a relationship with Siemens Healthineers that includes: speaking and lecture fees. R.H. Christenson reports a relationship with Roche Diagnostics that includes: speaking and lecture fees. R.H. Christenson reports a relationship with Beckman Coulter that includes: speaking and lecture fees. R.H. Christenson reports a relationship with Sphingotech GHB that includes: speaking and lecture fees. R.H. Christenson reports a relationship with Quidel Medical that includes: speaking and lecture fees. E. Selvin reports a relationship with Foundation for the National Institutes of Health that includes: funding grants. J.B. Echouffo-Tcheugui reports a relationship with National Institutes of Health that includes: funding grants. E. Selvin reports a relationship with National Institutes of Health that includes: funding grants. C.M. Rebholz reports a relationship with National Heart Lung and Blood Institute that includes: funding grants. E. Selvin reports a relationship with American Diabetes Association that includes: employment. E. Selvin reports a relationship with Roche Diagnostics Corporation that includes: non-financial support., (© 2023 The Author(s).)

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 log 2 -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., (© 2023. The Author(s).)

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, <0.05 for all tests)., Conclusions: We identified metabolites that were associated with BP lowering in response to dietary interventions., Registration: URL: https://www., Clinicaltrials: gov/ct2/show/NCT03403166; Unique identifier: NCT03403166 (DASH trial). URL: https://www., Clinicaltrials: gov/ct2/show/NCT00000608; Unique identifier: NCT00000608 (DASH-Sodium trial)., Competing Interests: Disclosures None.

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., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

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 <0.05, there were 71 proteins that were different between the DASH diet and control diet in the DASH and DASH-Sodium trials. Nineteen proteins were validated in the ARIC study. The 19 proteins collectively improved the prediction of the DASH diet intervention in the feeding studies (range of difference in C statistics, 0.267-0.313; P <0.001 for both tests) and the DASH diet score in the ARIC study (difference in C statistics, 0.017; P <0.001) beyond participant characteristics. 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.

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 (Aβ 42/40 ) 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., (© 2023. The Author(s).)

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., (© 2022 the Alzheimer's Association.)

Background: Dietary consumption has traditionally been studied through food intake questionnaires. Metabolomics can be used to identify blood markers of dietary protein that may complement existing dietary assessment tools., Objectives: We aimed to identify associations between 3 dietary protein sources (total protein, animal protein, and plant protein) and serum metabolites using data from the Atherosclerosis Risk in Communities Study., Methods: Participants' dietary protein intake was derived from a food frequency questionnaire administered by an interviewer, and fasting serum samples were collected at study visit 1 (1987-1989). Untargeted metabolomic profiling was performed in 2 subgroups (subgroup 1: n = 1842; subgroup 2: n = 2072). Multivariable linear regression models were used to assess associations between 3 dietary protein sources and 360 metabolites, adjusting for demographic factors and other participant characteristics. Analyses were performed separately within each subgroup and meta-analyzed with fixed-effects models., Results: In this study of 3914 middle-aged adults, the mean (SD) age was 54 (6) y, 60% were women, and 61% were Black. We identified 41 metabolites significantly associated with dietary protein intake. Twenty-six metabolite associations overlapped between total protein and animal protein, such as pyroglutamine, creatine, 3-methylhistidine, and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid. Plant protein was uniquely associated with 11 metabolites, such as tryptophan betaine, 4-vinylphenol sulfate, N -δ-acetylornithine, and pipecolate., Conclusions: The results of 17 of the 41 metabolites (41%) were consistent with those of previous nutritional metabolomic studies and specific protein-rich food items. We discovered 24 metabolites that had not been previously associated with dietary protein intake. These results enhance the validity of candidate markers of dietary protein intake and introduce novel metabolomic markers of dietary protein intake., (© 2023 The Author(s).)

Background: High ultra-processed food consumption is associated with higher risk of CKD. However, there is no biomarker for ultra-processed food, and the mechanism through which ultra-processed food is associated with CKD is not clear. Metabolomics can provide objective biomarkers of ultra-processed food and provide important insights into the mechanisms by which ultra-processed food is associated with risk of incident CKD. Our objective was to identify serum metabolites associated with ultra-processed food consumption and investigate whether ultra-processed food-associated metabolites are prospectively associated with incident CKD., Methods: We used data from 3751 Black and White men and women (aged 45-64 years) in the Atherosclerosis Risk in Communities study. Dietary intake was assessed using a semiquantitative 66-item food frequency questionnaire, and ultra-processed food was classified using the NOVA classification system. Multivariable linear regression models were used to identify the association between 359 metabolites and ultra-processed food consumption. Cox proportional hazards models were used to investigate the prospective association of ultra-processed food-associated metabolites with incident CKD., Results: Twelve metabolites (saccharine, homostachydrine, stachydrine, N2, N2-dimethylguanosine, catechol sulfate, caffeine, 3-methyl-2-oxovalerate, theobromine, docosahexaenoate, glucose, mannose, and bradykinin) were significantly associated with ultra-processed food consumption after controlling for false discovery rate <0.05 and adjusting for sociodemographic factors, health behaviors, eGFR, and total energy intake. The 12 ultra-processed food-related metabolites significantly improved the prediction of ultra-processed food consumption (difference in C statistics: 0.069, P <1×10 -16 ). Higher levels of mannose, glucose, and N2, N2-dimethylguanosine were associated with higher risk of incident CKD after a median follow-up of 23 years., Conclusions: We identified 12 serum metabolites associated with ultra-processed food consumption and three of them were positively associated with incident CKD. Mannose and N2, N2-dimethylguanosine are novel markers of CKD that may explain observed associations between ultra-processed food and CKD., Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023&#95;03&#95;08&#95;CJN08480722.mp3., (Copyright © 2023 by the American Society of Nephrology.)

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 <60 mL/min/1.73 m 2 . In a sensitivity analysis, incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m 2 and <75% of baseline rate., Results: 25 570 participants were included in the primary outcome analysis and 4944 (19.3%) developed incident CKD during follow-up (weighted median 11.3 years). In multivariable adjusted models, higher levels of total seafood n-3 PUFAs were associated with a lower incident CKD risk (relative risk per interquintile range 0.92, 95% confidence interval 0.86 to 0.98; P=0.009, I 2 =9.9%). In categorical analyses, participants with total seafood n-3 PUFA level in the highest fifth had 13% lower risk of incident CKD compared with those in the lowest fifth (0.87, 0.80 to 0.96; P=0.005, I 2 =0.0%). Plant derived α linolenic acid levels were not associated with incident CKD (1.00, 0.94 to 1.06; P=0.94, I 2 =5.8%). Similar results were obtained in the sensitivity analysis. The association appeared consistent across subgroups by age (≥60 v <60 years), estimated glomerular filtration rate (60-89 v ≥90 mL/min/1.73 m 2 ), hypertension, diabetes, and coronary heart disease at baseline., Conclusions: Higher seafood derived n-3 PUFA levels were associated with lower risk of incident CKD, although this association was not found for plant derived n-3 PUFAs. These results support a favourable role for seafood derived n-3 PUFAs in preventing CKD., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest and declare: support from Australian National Health and Medical Research Council Career Development Fellowship and the University of New South Wales Safety Net Fellowship for the submitted work; MM reports research funding from Resolve to Save Lives, World Health Organisation and North western University, and support as invited speaker in the Nordic Dairy Congress 2022. CMR and LMS report research funding from the US National Institute of Health (NIH). CMR reports participation on the Data Safety Monitoring Boards of the SUPER and ADEPT trials and leadership role as associate editor of Diabetes Care. ACvW reports research funding from Jaap Schouten Foundation. JMG reports research funding from Jaap Schouten Foundation, EU Horizon 2020, and Ministry of Health, Welfare and Sports, The Netherlands, and leadership role as the Vice President of the Dutch Health Council. EKH reports research funding from Dutch Kidney Foundation. FI and NGF receive the MRC Epidemiology Unit core support. NGF reports research fundings from the NIHR Cambridge Biomedical Research Centre Theme on Nutrition, Diet and Lifestyle. JT declares conference support from the University of Antioquia, Colombia and possession of stocks from Orion Pharma. MU declares possession of stocks from Orion Pharma. WSH declares possession of stock in OmegaQuant Analytics, LLC (a laboratory that offers blood fatty acid testing to healthcare providers, researchers and consumers). PSS reports research funding from the National Health and Medical Research Council of Australia and honoraria from Biogen Australia and Roche Australia. ACW reports research funding from the US Department of Agriculture/Agricultural Research Service, NIH, National Cattlemen’s Beef Association and Hass Avocado Board Avocado Nutrition Research Center. JA has received research honoraria for lectures from AstraZeneca and Novartis, and has participated in the advisory board for AstraZeneca and Boerhinger Ingelheim, unrelated to the present study. UR reports research funding from Swedish Research Council Forma and Swedish Diabetes Foundation. RM reports research funding from the US NIH, Gates Foundation, Nestle and Danone, and consulting fees from Development Initiatives with leadership role as chair of the Independent Expert Group, Global Nutrition Report. AT declares as co-chair of ClinGen Gout Genetic Curation Panel and reports research funding from the US National Institute of Health; AK reports research funding from the German Research Foundation. DM reports research funding from the US NIH, the Gates Foundation, The Rockefeller Foundation, Vail Innovative Global Research, and the Kaiser Permanente Fund at East Bay Community Foundation; personal fees from Acasti Pharma and Barilla; scientific advisory board, Beren Therapeutics, Brightseed, Calibrate, Elysium Health, Filtricine, HumanCo, Instacart, January Inc., Perfect Day, Tiny Organics, and (ended) Day Two, Discern Dx, and Season Health; stock ownership in Calibrate and HumanCo; and chapter royalties from UpToDate. No other relationships or activities that could appear to have influenced the submitted work were reported., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (Copyright © 2022 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

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 m 2 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., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

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).

Rationale & Objective: 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., Study Design: Prospective cohort., Setting & Participants: The cohort included 3,799 Atherosclerosis Risk in Communities study participants with serum samples available for measurement at visit 1 (1987-1989)., Exposure: Baseline serum levels of 318 metabolites., Outcomes: Incident KFRT, kidney failure (KFRT, estimated glomerular filtration rate <15 mL/min/1.73 m 2 , or death from kidney disease)., Analytical Approach: Because 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., Results: 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., Limitations: Inability to determine if the metabolites cause or are a consequence of changes in kidney function., Conclusions: 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., (© 2022 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.)

Background: Greater adherence to plant-based diets is associated with a lower risk of incident chronic kidney disease (CKD). Metabolomics can help identify blood biomarkers of plant-based diets and enhance understanding of underlying mechanisms., Objectives: Using untargeted metabolomics, we aimed to identify metabolites associated with 4 plant-based diet indices (PDIs) (overall PDI, provegetarian diet, healthful PDI, and unhealthful PDI) and incident CKD in 2 subgroups within the Atherosclerosis Risk in Communities study., Methods: We calculated 4 PDIs based on participants' responses on an FFQ. We used multivariable linear regression to examine the association between 4 PDIs and 374 individual metabolites, adjusting for confounders. We used Cox proportional hazards regression to evaluate associations between PDI-related metabolites and incident CKD. Estimates were meta-analyzed across 2 subgroups (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., Results: We identified 82 significant PDI-metabolite associations (overall PDI = 27; provegetarian = 17; healthful PDI = 20; unhealthful PDI = 18); 11 metabolites overlapped across the overall PDI, provegetarian diet, and healthful PDI. The addition of metabolites improved prediction of those in the highest quintile as opposed to the lower 4 quintiles of PDIs compared with participant characteristics alone (range of differences in C-statistics = 0.026-0.104; P value ≤ 0.001 for all tests). Six PDI-related metabolites (glycerate, 1,5-anhydroglucitol, γ-glutamylalanine, γ-glutamylglutamate, γ-glutamylleucine, γ-glutamylvaline), involved in glycolysis, gluconeogenesis, pyruvate metabolism, and γ-glutamyl peptide metabolism, were significantly associated with incident CKD and improved prediction of incident CKD beyond the CKD prediction model (difference in C-statistics for 6 metabolites = 0.005; P value = 0.006)., Conclusions: In a community-based study of US adults, we identified metabolites that were related to plant-based diets and predicted incident CKD. These metabolites highlight pathways through which plant-based diets are associated with incident CKD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background and Objectives: Mitochondrial DNA copy number is a biomarker of mitochondrial function, which has been hypothesized to contribute to pathogenesis of CKD through podocyte injury, tubular epithelial cell damage, and endothelial dysfunction. The prospective association of mitochondrial DNA copy number with CKD progression has not been previously evaluated., Design, Setting, Participants, & Measurements: Chronic Renal Insufficiency Cohort study participants had serum levels of mitochondrial DNA copy number calculated from probe intensities of mitochondrial single nucleotide polymorphisms genotyped on the Illumina HumanOmni 1-Quad Array. CKD progression was defined as kidney failure or halving of eGFR from baseline. Cox proportional hazards models were used to calculate hazard ratios for mitochondrial DNA copy number and risk of CKD progression., Results: Among 2943 participants, mean age was 58 years, 45% were women, and 48% self-identified as Black. There were 1077 patients who experienced CKD progression over a median follow-up of 6.5 years. The incidence rate of CKD progression was highest for those in the lowest tertile of mitochondrial DNA copy number (tertile 1, 58.1; tertile 2, 50.8; tertile 3, 46.3 per 1000 person-years). Risk for CKD progression was higher for participants with lower levels of mitochondrial DNA copy number after adjustment for established risk factors (for tertile 1 versus 3, hazard ratio, 1.28 [95% confidence interval, 1.10 to 1.50]; for tertile 2 versus 3, hazard ratio, 0.99 [95% confidence interval, 0.85 to 1.16]; trend P =0.002). Similar results were seen among those with albuminuria (for tertile 1 versus 3, hazard ratio, 1.24; 95% confidence interval, 1.05 to 1.47), but there were no statistically significant associations among individuals without albuminuria (for tertile 1 versus 3, hazard ratio, 1.04; 95% confidence interval, 0.70 to 1.53; interaction P <0.001)., Conclusions: These findings suggest lower mitochondrial DNA copy number is associated with higher risk of CKD progression, independent of established risk factors among patients with CKD., (Copyright © 2022 by the American Society of Nephrology.)