Urine Biomarkers of Kidney Tubule Health and Risk of Incident CKD in Persons Without Diabetes: The ARIC, MESA, and REGARDS Studies.

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 m2 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 m2. 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.

This study analyzed 3 cohorts (ARIC, MESA, and REGARDS) of adults without diabetes or prevalent chronic kidney disease (CKD) to determine the associations of 5 urinary biomarkers of kidney tubulointerstitial health with incident CKD, independent of traditional measures of kidney health. Meta-analysis of results from all 3 cohorts suggested that higher baseline levels of urine alpha-1-microglobulin were associated with incident CKD at follow-up. Results from individual cohorts suggested that in addition to alpha-1-microglobulin, monocyte chemoattractant protein-1, kidney injury molecule-1, and epidermal growth factor may also be associated with the development of CKD. These findings underscore the importance of kidney tubule interstitial health in defining risk of CKD independent of creatinine and urine albumin.

Serum Metabolomic Markers of Protein-Rich Foods and Incident CKD: Results From the Atherosclerosis Risk in Communities Study.

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 m2 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.

In this study, we aimed to identify associations between protein-rich foods (fish, nuts, legumes, red and processed meat, eggs, and poultry) and serum metabolites, which are small biological molecules involved in metabolism. Metabolites significantly associated with a protein-rich food individually and collectively improved the discrimination of the respective protein-rich food, suggesting that these metabolites should be prioritized in future diet biomarker research. We also studied associations between significant diet-related metabolites and incident kidney disease. One fish-related metabolite was associated with a lower kidney disease risk. This finding supports the recent nutritional guidelines recommending a Mediterranean diet, which includes fish as the main dietary protein source.

Ultra-processed food exposure and adverse health outcomes: umbrella review of epidemiological meta-analyses.

OBJECTIVE: To evaluate the existing meta-analytic evidence of associations between exposure to ultra-processed foods, as defined by the Nova food classification system, and adverse health outcomes. DESIGN: Systematic umbrella review of existing meta-analyses. DATA SOURCES: MEDLINE, PsycINFO, Embase, and the Cochrane Database of Systematic Reviews, as well as manual searches of reference lists from 2009 to June 2023. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Systematic reviews and meta-analyses of cohort, case-control, and/or cross sectional study designs. To evaluate the credibility of evidence, pre-specified evidence classification criteria were applied, graded as convincing ("class I"), highly suggestive ("class II"), suggestive ("class III"), weak ("class IV"), or no evidence ("class V"). The quality of evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) framework, categorised as "high," "moderate," "low," or "very low" quality. RESULTS: The search identified 45 unique pooled analyses, including 13 dose-response associations and 32 non-dose-response associations (n=9 888 373). Overall, direct associations were found between exposure to ultra-processed foods and 32 (71%) health parameters spanning mortality, cancer, and mental, respiratory, cardiovascular, gastrointestinal, and metabolic health outcomes. Based on the pre-specified evidence classification criteria, convincing evidence (class I) supported direct associations between greater ultra-processed food exposure and higher risks of incident cardiovascular disease related mortality (risk ratio 1.50, 95% confidence interval 1.37 to 1.63; GRADE=very low) and type 2 diabetes (dose-response risk ratio 1.12, 1.11 to 1.13; moderate), as well as higher risks of prevalent anxiety outcomes (odds ratio 1.48, 1.37 to 1.59; low) and combined common mental disorder outcomes (odds ratio 1.53, 1.43 to 1.63; low). Highly suggestive (class II) evidence indicated that greater exposure to ultra-processed foods was directly associated with higher risks of incident all cause mortality (risk ratio 1.21, 1.15 to 1.27; low), heart disease related mortality (hazard ratio 1.66, 1.51 to 1.84; low), type 2 diabetes (odds ratio 1.40, 1.23 to 1.59; very low), and depressive outcomes (hazard ratio 1.22, 1.16 to 1.28; low), together with higher risks of prevalent adverse sleep related outcomes (odds ratio 1.41, 1.24 to 1.61; low), wheezing (risk ratio 1.40, 1.27 to 1.55; low), and obesity (odds ratio 1.55, 1.36 to 1.77; low). Of the remaining 34 pooled analyses, 21 were graded as suggestive or weak strength (class III-IV) and 13 were graded as no evidence (class V). Overall, using the GRADE framework, 22 pooled analyses were rated as low quality, with 19 rated as very low quality and four rated as moderate quality. CONCLUSIONS: Greater exposure to ultra-processed food was associated with a higher risk of adverse health outcomes, especially cardiometabolic, common mental disorder, and mortality outcomes. These findings provide a rationale to develop and evaluate the effectiveness of using population based and public health measures to target and reduce dietary exposure to ultra-processed foods for improved human health. They also inform and provide support for urgent mechanistic research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023412732.

Plasma Biomarkers and Incident CKD Among Individuals Without Diabetes.

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 m2 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.

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.

Coffee Consumption May Mitigate the Risk for Acute Kidney Injury: Results From the Atherosclerosis Risk in Communities Study.

Introduction: Coffee is one of the most frequently consumed beverages worldwide and has been found to have a wide assortment of health benefits. Although habitual coffee consumption is associated with a lower incidence of chronic kidney disease, an association between coffee and acute kidney injury (AKI) has not yet been revealed. Methods: In the Atherosclerosis Risk in Communities (ARIC) Study, a prospective cohort study of 14,207 adults aged 45 to 64 years, coffee consumption (cups/d) was assessed at a single visit via food frequency questionnaires and compared with incident AKI defined by hospitalization with an AKI-related International Classification of Diseases code. Results: In ARIC, there were 1694 cases of incident AKI in a median of 24 follow-up years. Higher coffee consumption was associated with lower AKI risk versus no consumption (hazard ratio [HR] <1 cup/d: 0.92 [95% CI: 0.79-1.08]; 1 cup/d: 1.08 [95% CI: 0.94-1.24]; 2 to 3 cups/d: 0.83 [95% CI: 0.72-0.95]; >3 cups/d: 0.83 [95% CI: 0.71-0.96]; reference: never, P = 0.003). Trends for AKI risk across coffee categories remained significant after multivariable adjustment for age, sex, race-center, education, total daily energy intake, physical activity, smoking, alcohol intake, diet quality (Dietary Approaches to Stop Hypertension [DASH] score), systolic blood pressure (BP), diabetes status, use of antihypertensive agents, estimated glomerular filtration rate (eGFR), and body mass index (BMI) (P = 0.02). Conclusion: Higher coffee intake was associated with a lower risk of incident AKI and could present an opportunity for cardiorenal protection through diet. Further evaluation of the physiological mechanisms underlying the cardiorenal protective effects of coffee consumption is necessary.

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.

Metabolite Biomarkers of CKD Progression in Children.

BACKGROUND AND OBJECTIVES: Metabolomics facilitates the discovery of biomarkers and potential therapeutic targets for CKD progression. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated an untargeted metabolomics quantification of stored plasma samples from 645 Chronic Kidney Disease in Children (CKiD) participants. Metabolites were standardized and logarithmically transformed. Cox proportional hazards regression examined the association between 825 nondrug metabolites and progression to the composite outcome of KRT or 50% reduction of eGFR, adjusting for age, sex, race, body mass index, hypertension, glomerular versus nonglomerular diagnosis, proteinuria, and baseline eGFR. Stratified analyses were performed within subgroups of glomerular/nonglomerular diagnosis and baseline eGFR. RESULTS: Baseline characteristics were 391 (61%) male; median age 12 years; median eGFR 54 ml/min per 1.73 m2; 448 (69%) nonglomerular diagnosis. Over a median follow-up of 4.8 years, 209 (32%) participants developed the composite outcome. Unique association signals were identified in subgroups of baseline eGFR. Among participants with baseline eGFR ≥60 ml/min per 1.73 m2, two-fold higher levels of seven metabolites were significantly associated with higher hazards of KRT/halving of eGFR events: three involved in purine and pyrimidine metabolism (N6-carbamoylthreonyladenosine, hazard ratio, 16; 95% confidence interval, 4 to 60; 5,6-dihydrouridine, hazard ratio, 17; 95% confidence interval, 5 to 55; pseudouridine, hazard ratio, 39; 95% confidence interval, 8 to 200); two amino acids, C-glycosyltryptophan, hazard ratio, 24; 95% confidence interval 6 to 95 and lanthionine, hazard ratio, 3; 95% confidence interval, 2 to 5; the tricarboxylic acid cycle intermediate 2-methylcitrate/homocitrate, hazard ratio, 4; 95% confidence interval, 2 to 7; and gulonate, hazard ratio, 10; 95% confidence interval, 3 to 29. Among those with baseline eGFR <60 ml/min per 1.73 m2, a higher level of tetrahydrocortisol sulfate was associated with lower risk of progression (hazard ratio, 0.8; 95% confidence interval, 0.7 to 0.9). CONCLUSIONS: Untargeted plasma metabolomic profiling facilitated discovery of novel metabolite associations with CKD progression in children that were independent of established clinical predictors and highlight the role of select biologic pathways.

A Low-Sodium DASH Dietary Pattern Affects Serum Markers of Inflammation and Mineral Metabolism in Adults with Elevated Blood Pressure.

BACKGROUND: The blood pressure-lowering effects of the Dietary Approaches to Stop Hypertension (DASH) dietary pattern and reduced sodium intake are well established. The effects on other biomarkers related to vascular health are of interest and might assist in explaining the effects of the DASH diet and sodium reduction. OBJECTIVES: We hypothesized that a low-sodium DASH diet improves (lowers) biomarkers of inflammation [C-reactive protein (CRP) and soluble urokinase plasminogen activator receptor (suPAR)] and mineral metabolism [phosphorus and fibroblast growth factor-23 (FGF23)]. METHODS: We conducted a secondary analysis of the DASH-Sodium trial using frozen serum samples. This controlled feeding study randomly assigned 412 adults (≥22 y) with elevated blood pressure (120-159/80-95 mmHg) to consume either a DASH diet or control diet. Within each arm, participants received 3 sodium levels [low (1150 mg), intermediate (2300 mg), high (3450 mg)] in random sequence, each for 30 d. To maximize contrast, samples collected at the end of the low-sodium DASH (n = 198) and high-sodium control (n = 194) diets were compared. Between-diet differences in serum CRP, suPAR, phosphorus, and FGF23 concentrations were assessed using linear regression adjusted for age, sex, race, income, education, smoking status, and BMI. RESULTS: CRP concentrations did not differ between groups (P = 0.83), but suPAR was higher after the low-sodium DASH diet than the high-sodium control [geometric mean 2470 pg/mL (95% CI: 2380, 2560 pg/mL), compared with 2290 pg/mL (95% CI: 2210, 2380 pg/mL); P = 0.006]. Phosphorus was higher after the low-sodium DASH diet [geometric mean 3.50 mg/dL (95% CI: 3.43, 3.57 mg/dL)] compared with the high-sodium control diet [geometric mean 3.39 mg/dL (95% CI: 3.33, 3.46 mg/dL); P = 0.04]. FGF23 was also higher after the low-sodium DASH diet [geometric mean 35.3 pg/mL (95% CI: 33.3, 37.3 pg/mL) compared with 28.2 pg/mL (95% CI: 26.6, 29.8 pg/mL); P < 0.001]. CONCLUSIONS: Contrary to our hypothesis, biomarkers of inflammation and mineral metabolism were increased or unchanged by a low-sodium DASH diet compared with a high-sodium control diet in adults with elevated blood pressure.

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.

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 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.

Alternative kidney filtration markers and the risk of major macrovascular and microvascular events, and all-cause mortality in individuals with type 2 diabetes in the ADVANCE trial.

BACKGROUND: Creatinine-based estimated glomerular filtration rate (eGFR) is biased in the setting of obesity and other conditions. Alternative kidney filtration markers may be useful in adults with diabetes, but few studies examined the associations with risk of clinical outcomes. METHODS: In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, we evaluated whether baseline levels and change in eGFR based on creatinine (Cr), cystatin c (Cys), ß2 -microglobulin (B2M), eGFRCr-Cys , and the average of three estimates (eGFRCr-Cys-B2M ) assessed in 7217 participants at baseline and a random sample of 640 participants at the 1-year visit are associated with clinical outcomes. We examined associations with major macrovascular and microvascular events together and separately and all-cause mortality using Cox regression models, adjusting for established risk factors. RESULTS: Over a median follow-up of 5 years, 1313 major macrovascular (n = 748) and microvascular events (n = 637), and 743 deaths occurred. Lower levels of eGFR based on all filtration markers individually and combined were associated with 1.4 to 3.0 times higher risk of major macrovascular and microvascular events (combined and separately) and all-cause mortality. Per 30% decline in eGFRCys , eGFR Cr-Cys , and eGFRCr-Cys-B2M were associated with a >2-fold higher risk of all clinical outcomes. CONCLUSIONS: In adults with type 2 diabetes, baseline levels of eGFR based on alternative filtration markers and per 30% decline in eGFRCys , eGFR Cr-Cys , and eGFRCr-Cys-B2M were associated with clinical outcomes. Measurement of alternative filtration markers, particularly B2M in adults with type 2 diabetes may be warranted.

Survival advantage of cohort participation attenuates over time: results from three long-standing community-based studies.

PURPOSE: Cohort participants usually have lower mortality rates than nonparticipants, but it is unclear if this survival advantage decreases or increases as cohort studies age. METHODS: We used a 1975 private census of Washington County, Maryland, to compare mortality among cohort participants to nonparticipants for three cohorts, Campaign Against Cancer and Stroke (CLUE I), Campaign Against Cancer and Heart Disease (CLUE II), and Atherosclerosis Risk In Communities (ARIC) initiated in 1974, 1989, and 1986, respectively. We analyzed mortality risk using time-truncated Cox regression models. RESULTS: Participants had lower mortality risk in the first 10 years of follow-up compared with nonparticipants (fully adjusted average hazard ratio [95% confidence intervals] were 0.72 [0.68, 0.77] in CLUE I, 0.69 [0.65, 0.73] in CLUE II, and 0.74 [0.63, 0.86] in ARIC), which persisted over 20 years of follow-up (0.81 [0.78, 0.84] in CLUE I, 0.87 [0.84, 0.91] in CLUE II, and 0.90 [0.83, 0.97] in ARIC). This lower average hazard for mortality among participants compared with nonparticipants attenuated with longer follow-up (0.99 [0.96, 1.01] after 30+ years in CLUE I, 1.02 [0.99, 1.05] after 30 years in CLUE II, and 0.95 [0.89, 1.00] after 30+ years in ARIC). In ARIC, participants who did not attend visits had higher mortality, but those who did attend visits had similar mortality to the community. CONCLUSIONS: Our results suggest the volunteer selection for mortality in long-standing epidemiologic cohort studies often diminishes as the cohort ages.

Adherence to a Mediterranean-style eating pattern and risk of diabetes in a U.S. prospective cohort study.

BACKGROUND: A Mediterranean-style eating pattern is consistently associated with a decreased diabetes risk in Mediterranean and European populations. However, results in U.S. populations are inconsistent. The objective of this study was to assess whether a Mediterranean-style eating pattern would be associated with diabetes risk in a large, nationally representative U.S. cohort of black and white men and women. METHODS: Participants from the Atherosclerosis Risk in Communities study prospective cohort without diabetes, cardiovascular disease, or cancer at baseline (visit 1, 1987-1989; n = 11,991) were included (mean age 54 years, 56% female, 75% white). Alternate Mediterranean Diet scores (aMed) were calculated using the mean dietary intake self-reported at visit 1 and visit 3 (1993-1995) or visit 1 only for participants censored before visit 3. Participants were followed from visit 1 through 31 December 2016 for incident diabetes. We used Cox regression models to characterize associations of aMed (quintiles as well as per 1-point higher) with incident diabetes adjusted for energy intake, age, sex, race and study center, and education (Model 1) for all participants then stratified by race and body mass index (BMI). Model 2 included potential mediating behavioral and clinical measures associated with diabetes. Results are presented as hazard ratios and 95% confidence intervals. RESULTS: Over a median follow-up of 22 years, there were 4024 incident cases of diabetes. Higher aMed scores were associated with lower diabetes risk [Model 1: 0.83 (0.73-0.94) for Q5 vs Q1 (p-trend < 0.001) and 0.96 (0.95-0.98) for 1-point higher]. Associations were stronger for black vs white participants (interaction p < 0.001) and weaker for obese vs normal BMI (interaction p < 0.01). Associations were attenuated but statistically significant in Model 2. CONCLUSIONS: An eating pattern high in fruits, vegetables, whole grains, legumes, nuts, and fish, and moderate in alcohol was associated with a lower risk of diabetes in a community-based U.S.

Diet quality, change in diet quality and risk of incident CVD and diabetes.

OBJECTIVE: The objective of this study was to assess the prospective association between diet quality, as well as a 6-year change in diet quality, and risk of incident CVD and diabetes in a community-based population. DESIGN: We used Cox regression models to estimate the prospective association between diet quality, assessed using the Healthy Eating Index (HEI)-2015 and the Alternative HEI (AHEI)-2010 scores, as well as change in diet quality, and incident CVD and diabetes. SETTING: The ARIC Study recruited 15 792 black and white men and women (45-64 years) from four US communities. PARTICIPANTS: We included 10 808 study participants who reported usual dietary intake via FFQ at visit 1 (1987-1989) and who had not developed CVD, diabetes, or cancer at baseline. RESULTS: Overall, 3070 participants developed CVD (median follow-up of 26 years) and 3452 developed diabetes (median follow-up of 22 years) after visit 1. Higher diet score at the initial visit was associated with a significantly lower risk of CVD (HR per 10 % higher HEI-2015 diet quality score: 0·90 (95 % CI: 0·86, 0·95) and HR per 10 % higher AHEI-2010 diet quality score: 0·96 (95 % CI: 0·93, 0·99)). We did not observe a significant association between initial diet score and incident diabetes. There were no significant associations between change in diet score and CVD or diabetes risk in the overall study population. CONCLUSIONS: Higher diet quality assessed using HEI-2015 and AHEI-2010 was strongly associated with lower CVD risk but not diabetes risk within a middle-aged, community-based US population.

Alcohol Consumption and Incident Kidney Disease: Results From the Atherosclerosis Risk in Communities Study.

OBJECTIVE(S): Moderate alcohol consumption has been found to be associated with lower risk of coronary heart disease and myocardial infarction, which share similar risk factors and pathophysiology with chronic kidney disease (CKD). However, there is inconsistent evidence on the association between alcohol consumption and CKD. DESIGN AND METHODS: We conducted a prospective analysis of 12,692 participants aged 45-64 years from the Atherosclerosis Risk in Communities (ARIC) study. We categorized participants into 6 alcohol consumption categories: never drinkers, former drinkers, ≤1 drink per week, 2 to 7 drinks per week, 8 to 14 drinks per week, and ≥15 drinks per week based on food frequency questionnaire responses at visit 1 (1987-1989). Incident CKD was defined as estimated glomerular filtration rate <60 mL/minute/1.73 m2 accompanied by ≥25% estimated glomerular filtration rate decline, a kidney disease-related hospitalization or death or end-stage renal disease. RESULTS: During a median follow-up of 24 years, there were 3,664 cases of incident CKD. Current drinkers were more likely to be men, whites, and to have a higher income level and education level. After adjusting for total energy intake, age, sex, race-center, income, education level, health insurance, smoking, and physical activity, there was no significant association between being a former drinker and risk of incident CKD. Participants who drank ≤1 drink per week, 2 to 7 drinks per week, 8 to 14 drinks per week, and ≥15 drinks per week had, respectively, a 12% (hazard ratio [HR]: 0.88, 95% confidence interval [CI]: 0.79-0.97), 20% (HR: 0.80, 95% CI: 0.72-0.89), 29% (HR: 0.71, 95% CI: 0.62-0.83), and 23% (HR: 0.77, 95% CI: 0.65-0.91) lower risk of CKD compared with never drinkers. CONCLUSION(S): Consuming a low or moderate amount of alcohol may lower the risk of developing CKD. Therefore, moderate consumption of alcohol may not likely be harmful to the kidneys.

Association Between Dietary Patterns and Kidney Function in Patients With Chronic Kidney Disease: A Cross-Sectional Analysis of the German Chronic Kidney Disease Study.

OBJECTIVE: In the general population, "healthy" dietary patterns are associated with improved health outcomes, but data on associations between observance of specific dietary patterns and kidney function in patients with chronic kidney disease (CKD) are sparse. METHODS: Dietary intake was evaluated using food frequency questionnaires in patients with moderately severe CKD under nephrology care enrolled into the observational multicenter German CKD study. The Dietary Approaches to Stop Hypertension (DASH) diet score, Mediterranean diet score, and German Food Pyramid Index (GFPI) were calculated and their association with estimated glomerular filtration rate (eGFR) and albuminuria was assessed by multivariable linear regression analysis, adjusted for gender, age, body mass index, energy intake, smoking status, alcohol intake, education, high-density lipoprotein-cholesterol (HDL- cholesterol), low-density lipoprotein-cholesterol (LDL-cholesterol), hypertension, and diabetes mellitus. RESULTS: A total of 2,813 patients (41% women; age 60.1 ± 11.6 years) were included in the analysis. High DASH diet score and GFPI were associated with lower systolic blood pressure and lower intake of antihypertensive medication, higher HDL, and lower uric acid levels. Mediterranean-style diet was associated with lower prevalence of diabetes mellitus. Higher DASH and Mediterranean diet scores were associated with higher eGFR (ß-coefficient = 1.226, P < .001; ß-coefficient = 0.932, P = .007, respectively). In contrast, GFPI was not associated with eGFR. For the individual components of the dietary patterns, higher intake of nuts and legumes, cereals, fish, and polyunsaturated fats was associated with higher eGFR and higher intake of dairy, composed of low- and whole-fat dairy, was associated with lower eGFR. No association was found between dietary patterns and albuminuria. CONCLUSION: Higher observance of the DASH or Mediterranean diet, but not German food pyramid recommendations, was associated with higher eGFR among patients with CKD. Improving dietary habits may offer an opportunity to better control comorbidities and kidney function decline in patients with CKD.

Novel associations between blood metabolites and kidney function among Bogalusa Heart Study and Multi-Ethnic Study of Atherosclerosis participants.

INTRODUCTION: Chronic kidney disease (CKD) is a major public health challenge given its high global prevalence and associated risks of cardiovascular disease and progression to end stage renal disease. Although it is known that numerous metabolic changes occur in CKD patients, identifying novel metabolite associations with kidney function may enhance our understanding of the physiologic pathways relating to CKD. OBJECTIVES: The objective of this study was to elucidate novel metabolite associations with kidney function among participants of two community-based cohorts with carefully ascertained metabolomics, kidney function, and covariate data. METHODS: Untargeted ultrahigh-performance liquid chromatography-tandem mass spectrometry was used to detect and quantify blood metabolites. We used multivariate adjusted linear regression to examine associations between single metabolites and creatinine-based estimated glomerular filtration rate (eGFRcr) among 1243 Bogalusa Heart Study (BHS) participants (median eGFRcr: 94.4, 5th-95th percentile: 66.0-119.6 mL/min/1.73 m2). Replication, determined by statistical significance and consistent effect direction, was tested using gold standard measured glomerular filtration rate (mGFR) among 260 Multi-Ethnic Study of Atherosclerosis (MESA) participants (median mGFR: 72.0, 5th-95th percentile: 43.5-105.0 mL/min/1.73 m2). All analyses used Bonferroni-corrected alpha thresholds. RESULTS: Fifty-one novel metabolite associations with kidney function were identified, including 12 from previously unrelated sub-pathways: N6-carboxymethyllysine, gulonate, quinolinate, gamma-CEHC-glucuronide, retinol, methylmalonate, 3-hydroxy-3-methylglutarate, 3-aminoisobutyrate, N-methylpipecolate, hydroquinone sulfate, and glycine conjugates of C10H12O2 and C10H14O2(1). Significant metabolites were generally inversely associated with kidney function and smaller in mass-to-charge ratio than non-significant metabolites. CONCLUSION: The 51 novel metabolites identified may serve as early, clinically relevant, kidney function biomarkers.

Hospitalization Risk among Older Adults with Chronic Kidney Disease.

INTRODUCTION: Chronic kidney disease (CKD) risk staging is based on estimated glomerular filtration rate (eGFR) and albumin-creatinine ratio (ACR). However, the relationship between all-cause hospitalization risk and the current CKD staging system has not been well studied among older adults, despite a high prevalence of CKD and a high risk of hospitalization in old age. METHODS: Among 4,766 participants of the Atherosclerosis Risk in Communities study, CKD was staged according to Kidney Disease Improving Global Outcomes (KDIGO) criteria, using creatinine-based eGFR (eGFRcr) and ACR. Incidence rates of all-cause hospitalization associated with each CKD risk group were analyzed using negative binomial regression. Additionally, cause-specific hospitalization risks for cardiovascular, infectious, kidney, and other diseases were estimated. The impacts of using cystatin C-based eGFR (eGFRcys) to estimate the prevalence of CKD and risks of hospitalization were also quantified. RESULTS: Participants experienced 5,548 hospitalizations and 29% had CKD. Hospitalization rates per 1,000 person-years according to KDIGO risk categories were 208-223 ("low risk"), 288-376 ("moderately increased risk"), 363-548 ("high risk"), and 499-1083 ("very high risk"). The increased risk associated with low eGFR and high ACR persisted in adjusted analyses, examinations of cause-specific hospitalizations, and when CKD was staged by eGFRcys or eGFRcr-cys, a combined equation based on both creatinine and cystatin C. In comparison to eGFRcr, staging by eGFRcys increased the prevalence of CKD to 50%, but hospitalization risks remained similarly high. DISCUSSION/CONCLUSION: In older adults, decreased eGFR, increased ACR, and KDIGO risk stages based on a combination of these measures, were strong risk factors for hospitalization. These relationships were consistent, regardless of the marker used to estimate GFR, but the use of cystatin C resulted in a substantially higher prevalence of CKD than the use of creatinine. Older adults in the population with very high risk stages of CKD have hospitalization rates exceeding 500 per 1,000 person-years.