Cytokines, C-Reactive Protein, and Risk of Incident Hypertension in the REGARDS Study.

BACKGROUND: Hypertension is a highly prevalent cardiovascular disease risk factor that may be related to inflammation. Whether adverse levels of specific inflammatory cytokines relate to hypertension is unknown. The present study sought to determine whether higher levels of IL (interleukin)-1ß, IL-6, TNF (tumor necrosis factor)-α, IFN (interferon)-γ, IL-17A, and CRP (C-reactive protein) are associated with a greater risk of incident hypertension. METHODS: The REGARDS study (Reasons for Geographic and Racial Difference in Stroke) is a prospective cohort study that recruited 30 239 community-dwelling Black and White adults from the contiguous United States in 2003 to 2007 (visit 1), with follow-up 9 years later in 2013 to 2016 (visit 2). We included participants without prevalent hypertension who attended follow-up 9 years later and had available laboratory measures and covariates of interest. Poisson regression estimated the risk ratio of incident hypertension by level of inflammatory biomarkers. RESULTS: Among 1866 included participants (mean [SD] aged of 62 [8] years, 25% Black participants, 55% women), 36% developed hypertension. In fully adjusted models comparing the third to first tertile of each biomarker, there was a greater risk of incident hypertension for higher IL-1ß among White (1.24 [95% CI, 1.01-1.53]) but not Black participants (1.01 [95% CI, 0.83-1.23]) and higher TNF-α (1.20 [95% CI, 1.02-1.41]) and IFN-γ (1.22 [95% CI, 1.04-1.42]) among all participants. There was no increased risk with IL-6, IL-17A, or CRP. CONCLUSIONS: Higher levels of IL-1ß, TNF-α, and IFN-γ, representing distinct inflammatory pathways, are elevated in advance of hypertension development. Whether modifying these cytokines will reduce incident hypertension is unknown.

Associations Between Head Injury and Subsequent Risk of Falls: Results From the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND AND OBJECTIVES: Falls are a leading cause of head injury among older adults, but the risk of fall occurring after a head injury is less well-characterized. We sought to examine the association between head injury and subsequent risk of falls requiring hospital care among community-dwelling older adults. METHODS: This analysis included 13,081 participants in the Atherosclerosis Risk in Communities Study enrolled in 1987-1989 and followed through 2019. The association of head injury (time-varying exposure, self-reported and/or ICD-9/10 code identified) with the risk of subsequent (occurring >1-month after head injury) falls requiring hospital care (ICD-9/10 code defined) was modeled using Cox proportional hazards regression. Secondary analyses included Fine and Gray proportional hazards regression to account for the competing risk of death, analysis of head injury frequency and severity, and formal testing for interaction by age, sex, and race. Models were adjusted for age, sex, race/center, education, military service, alcohol consumption, smoking, diabetes, hypertension, and psychotropic medication use. RESULTS: The mean age of participants at baseline was 54 years, 58% were female, 28% were Black, and 14% had at least one head injury occurring over the study period. Over a median 23 years of follow-up, 29% of participants had a fall requiring medical care. In adjusted Cox proportional hazards models, individuals with head injury had 2.01 (95% CI 1.85-2.18) times the risk of falls compared with individuals without head injury. Accounting for the competing risk of mortality, individuals with head injury had 1.69 (95% CI 1.57-1.82) times the risk of falls compared with individuals without head injury. We observed stronger associations among men compared with women (men: hazard ratio [HR] = 2.60, 95% CI 2.25-3.00; women: HR = 1.80, 95% CI 1.63-1.99, p-interaction <0.001). We observed evidence of a dose-response association for head injury number and severity with fall risk (1 injury: HR = 1.68, 95% CI 1.53-1.84; 2+ injuries: HR = 2.37, 95% CI 1.92-2.94 and mild: HR = 1.97, 95% CI 1.78-2.18; moderate/severe/penetrating: HR = 2.50, 95% CI 2.06-3.02). DISCUSSION: Among community-dwelling older adults followed over 30 years, head injury was associated with subsequent falls requiring medical care. We observed stronger associations among men and with increasing number and severity of head injuries. Whether older individuals with head injury might benefit from fall prevention measures should be a focus of future research.

Cardiovascular Autonomic Function and Incident Chronic Obstructive Pulmonary Disease Hospitalizations in Atherosclerosis Risk in Communities.

Rationale: The autonomic nervous system extensively innervates the lungs, but its role in chronic obstructive pulmonary disease (COPD) outcomes has not been well studied. Objective: We assessed relationships between cardiovascular autonomic nervous system measures (heart rate variability [HRV] and orthostatic hypotension [OH]) and incident COPD hospitalization in the multicenter ARIC (Atherosclerosis Risk In Communities) study. Methods: We used Cox proportional hazards regression models to estimate hazard ratios and 95% confidence intervals between baseline (1987-1989) autonomic function measures (HRV measures from 2-minute electrocardiograms and OH variables) and incident COPD hospitalizations through 2019. Adjusted analyses included demographic data, smoking status, lung function, comorbidities, and physical activity. We also performed analyses stratified by baseline airflow obstruction. Results: Of the 11,625 participants, (mean age, 53.8 yr), 56.5% were female and 26.3% identified as Black. Baseline mean percentage predicted forced expiratory volume in 1 second was 94 ± 17% (standard deviation), and 2,599 participants (22.4%) had airflow obstruction. During a median follow-up time of 26.9 years, there were 2,406 incident COPD hospitalizations. Higher HRV (i.e., better autonomic function) was associated with a lower risk of incident COPD hospitalization. Markers of worse autonomic function (OH and greater orthostatic changes in systolic and diastolic blood pressure) were associated with a higher risk of incident COPD hospitalization (hazard ratio for the presence of OH, 1.5; 95% confidence interval, 1.25-1.92). In stratified analyses, results were more robust in participants without airflow obstruction at baseline. Conclusions: In this large multicenter prospective community cohort, better cardiovascular autonomic function at baseline was associated with a lower risk of subsequent hospitalization for COPD, particularly among participants without evidence of lung disease at baseline.

The association of vitamin D supplementation and serum vitamin D levels with physical activity in older adults: Results from a randomized trial.

BACKGROUND: To assess whether vitamin D3 supplementation attenuates the decline in daily physical activity in low-functioning adults at risk for falls. METHODS: Secondary data analyses of STURDY (Study to Understand Fall Reduction and Vitamin D in You), a response-adaptive randomized clinical trial. Participants included 571 adults aged 70 years and older with baseline serum 25(OH)D levels of 10-29 ng/mL and elevated fall risk, who wore a wrist accelerometer at baseline and at least one follow-up visit and were randomized to receive: 200 IU/day (control), 1000, 2000, or 4000 IU/day of vitamin D3 . Objective physical activity quantities and patterns (total daily activity counts, active minutes/day, and activity fragmentation) were measured for 7-days, 24-h/day, in the free-living environment using the Actigraph GT9x over up to 24-months of follow-up. RESULTS: In adjusted models, physical activity quantities declined (p < 0.001) and became more fragmented, or "broken up", (p = 0.017) over time. Supplementation with vitamin D3 did not attenuate this decline. Changes in physical activity were more rapid among those with baseline serum 25(OH)D <20 ng/mL compared to those with baseline 25(OH)D levels of 20-29 ng/mL (time*baseline 25(OH)D, p < 0.05). CONCLUSION: In low-functioning older adults with serum 25(OH)D levels 10-29 ng/mL, vitamin D3 supplementation of 1000 IU/day or higher did not attenuate declines in physical activity compared with 200 IU/day. Those with baseline 25(OH)D <20 ng/mL showed accelerated declines in physical activity. Alternative interventions to supplementation are needed to curb declines in physical activity in older adults with low serum 25(OH)D.

Patterns of Daily Physical Movement, Chronic Inflammation, and Frailty Incidence.

INTRODUCTION: Low physical activity is a criterion of phenotypic frailty defined as an increased state of vulnerability to adverse health outcomes. Whether disengagement from daily all-purpose physical activity is prospectively associated with frailty and possibly modified by chronic inflammation-a pathway often underlying frailty-remains unexplored. METHODS: Using the Study to Understand Fall Reduction and Vitamin D in You data from 477 robust/prefrail adults (mean age = 76 ± 5 yr; 42% women), we examined whether accelerometer patterns (activity counts per day, active minutes per day, and activity fragmentation [broken accumulation]) were associated with incident frailty using Cox proportional hazard regression. Baseline interactions between each accelerometer metric and markers of inflammation that include interleukin-6, C-reactive protein, and tumor necrosis factor-alpha receptor 1 were also examined. RESULTS: Over an average of 1.3 yr, 42 participants (9%) developed frailty. In Cox regression models adjusted for demographics, medical conditions, and device wear days, every 30 min·d -1 higher baseline active time, 100,000 more activity counts per day, and 1% lower activity fragmentation was associated with a 16% ( P = 0.003), 13% ( P = 0.001), and 8% ( P < 0.001) lower risk of frailty, respectively. No interactions between accelerometer metrics and baseline interleukin-6, C-reactive protein, or tumor necrosis factor-alpha receptor 1 were detected (interaction P > 0.06 for all). CONCLUSIONS: Among older adults who are either robust or prefrail, constricted patterns of daily physical activity (i.e., lower total activity minutes and counts, and higher activity fragmentation) were prospectively associated with higher risk of frailty but not modified by frailty-related chronic inflammation. Additional studies, particularly trials, are needed to understand if this association is causal.

Increases in Circulating and Fecal Butyrate are Associated With Reduced Blood Pressure and Hypertension: Results From the SPIRIT Trial.

Background Short chain fatty acids (SCFAs) are microbially derived end products of dietary fiber fermentation. The SCFA butyrate reduces blood pressure (BP) in mouse models. The association of SCFAs, including butyrate, with BP in humans is unclear, due in part to predominantly cross-sectional analyses and different biospecimens (blood versus fecal) for SCFA measurement. Longitudinal studies including both circulating and fecal SCFAs are lacking. Methods and Results We leveraged existing data from the SPIRIT (Survivorship Promotion In Reducing IGF-1 Trial), which randomized 121 adult cancer survivors with overweight/obesity to a behavioral weight-loss intervention, metformin, or self-directed weight-loss. Of participants with baseline serum and fecal SCFAs measured (n=111), a subset had serum (n=93) and fecal (n=89) SCFA measurements 12 months later. We used Poisson regression with robust error variance to estimate baseline associations of SCFAs with hypertension, and we assessed the percent change in SCFAs from baseline with corresponding 12-month changes in BP using multiple linear regression. Baseline fecal butyrate was inversely associated with prevalent hypertension (standardized PR [95%CI]: 0.71 [0.54, 0.92]). A 10% increase in fecal butyrate from baseline was associated with decreased systolic BP (ß [95%CI]: -0.56 [-1.01, -0.10] mm Hg), and a 10% increase in serum butyrate was associated with decreased systolic (ß [95%CI]: -1.39 [-2.15, -0.63] mm Hg) and diastolic (ß [95%CI]: -0.55 [-1.03, -0.08] mm Hg) BPs. Butyrate associations with systolic BP were linear and not modified by sex, race, or intervention arm. Conclusions Increased serum or fecal butyrate is associated with lowered BP. Butyrate may be a target for SCFA-centered BP-lowering interventions. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02431676.

Effects of a Behavioral Weight Loss Intervention and Metformin Treatment on Serum Urate: Results from a Randomized Clinical Trial.

Background: Lower body mass index (BMI) has been associated with lower serum urate (SU), but only in observational studies. We sought to determine the effects of behavioral weight loss and metformin treatment on SU in a randomized trial. Methods and Findings: The Survivorship Promotion In Reducing IGF-1 Trial (SPIRIT) was a parallel three-arm randomized controlled trial of overweight/obese adult cancer survivors without gout at a single center in Maryland, United States. Participants were randomized to: (1) coach-directed weight loss (behavioral telephonic coaching), (2) metformin (up to 2000 mg daily), or (3) self-directed weight loss (informational brochures; reference group). SU and BMI were assessed at baseline and at 3, 6, and 12 months post-randomization. The 121 participants had a mean ± standard deviation (SD) age of 60 ± 9 years, 79% were female, and 45% were Black. At baseline, BMI was 35 ± 5 kg/m2, and SU was 5.6 ± 1.3 mg/dL. Compared to the self-directed group, at 12 months, the coach-directed group reduced BMI by 0.9 kg/m2 (95% confidence interval (CI): -1.5, -0.4) and metformin reduced BMI by 0.6 kg/m2 (95% CI: -1.1, -0.1). However, compared to the self-directed group, the coach-directed group unexpectedly increased SU by 0.3 mg/dL (95% CI: 0.05, 0.6), and metformin non-significantly increased SU by 0.2 mg/dL (95% CI: -0.04, 0.5); these effects were attenuated when analyses included change in estimated glomerular filtration rate (eGFR). Conclusions: In this randomized trial of cancer survivors without gout, reductions in BMI either increased or did not change SU, potentially due to effects on eGFR. These results do not support a focus on BMI reduction for SU reduction; however, long-term studies are needed. ClinicalTrials.gov Registration: NCT02431676.

Metformin Affects Gut Microbiome Composition and Function and Circulating Short-Chain Fatty Acids: A Randomized Trial.

OBJECTIVE: To determine the longer-term effects of metformin treatment and behavioral weight loss on gut microbiota and short-chain fatty acids (SCFAs). RESEARCH DESIGN AND METHODS: We conducted a 3-parallel-arm, randomized trial. We enrolled overweight/obese adults who had been treated for solid tumors but had no ongoing cancer treatment and randomized them (n = 121) to either 1) metformin (up to 2,000 mg), 2) coach-directed behavioral weight loss, or 3) self-directed care (control) for 12 months. We collected stool and serum at baseline (n = 114), 6 months (n = 109), and 12 months (n = 105). From stool, we extracted microbial DNA and conducted amplicon and metagenomic sequencing. We measured SCFAs and other biochemical parameters from fasting serum. RESULTS: Of the 121 participants, 79% were female and 46% were Black, and the mean age was 60 years. Only metformin treatment significantly altered microbiota composition. Compared with control, metformin treatment increased amplicon sequence variants for Escherichia (confirmed as Escherichia coli by metagenomic sequencing) and Ruminococcus torques and decreased Intestinibacter bartlettii at both 6 and 12 months and decreased the genus Roseburia, including R. faecis and R. intestinalis, at 12 months. Effects were similar in comparison of the metformin group with the behavioral weight loss group. Metformin versus control also increased butyrate, acetate, and valerate at 6 months (but not at 12 months). Behavioral weight loss versus control did not significantly alter microbiota composition but did increase acetate at 6 months (but not at 12 months). Increases in acetate were associated with decreases in fasting insulin. Additional whole-genome metagenomic sequencing of a subset of the metformin group showed that metformin altered 62 metagenomic functional pathways, including an acetate-producing pathway and three pathways in glucose metabolism. CONCLUSIONS: Metformin, but not behavioral weight loss, impacted gut microbiota composition at 6 months and 12 months. Both metformin and behavioral weight loss altered circulating SCFAs at 6 months, including increasing acetate, which correlated with lower fasting insulin. Future research is needed to elucidate whether the gut microboime mediates or modifies metformin's health effects.

Effects of Behavioral Weight Loss and Metformin on IGFs in Cancer Survivors: A Randomized Trial.

CONTEXT: Higher levels of insulin-like growth factor-1 (IGF-1) are associated with increased risk of cancers and higher mortality. Therapies that reduce IGF-1 have considerable appeal as means to prevent recurrence. DESIGN: Randomized, 3-parallel-arm controlled clinical trial. INTERVENTIONS AND OUTCOMES: Cancer survivors with overweight or obesity were randomized to (1) self-directed weight loss (comparison), (2) coach-directed weight loss, or (3) metformin treatment. Main outcomes were changes in IGF-1 and IGF-1:IGFBP3 molar ratio at 6 months. The trial duration was 12 months. RESULTS: Of the 121 randomized participants, 79% were women, 46% were African Americans, and the mean age was 60 years. At baseline, the average body mass index was 35 kg/m2; mean IGF-1 was 72.9 (SD, 21.7) ng/mL; and mean IGF1:IGFBP3 molar ratio was 0.17 (SD, 0.05). At 6 months, weight changes were -1.0% (P = 0.07), -4.2% (P < 0.0001), and -2.8% (P < 0.0001) in self-directed, coach-directed, and metformin groups, respectively. Compared with the self-directed group, participants in metformin had significant decreases on IGF-1 (mean difference in change: -5.50 ng/mL, P = 0.02) and IGF1:IGFBP3 molar ratio (mean difference in change: -0.0119, P = 0.011) at 3 months. The significant decrease of IGF-1 remained in participants with obesity at 6 months (mean difference in change: -7.2 ng/mL; 95% CI: -13.3 to -1.1), but not in participants with overweight (P for interaction = 0.045). There were no significant differences in changes between the coach-directed and self-directed groups. There were no differences in outcomes at 12 months. CONCLUSIONS: In cancer survivors with obesity, metformin may have a short-term effect on IGF-1 reduction that wanes over time.

Gamma gap thresholds and HIV, hepatitis C, and monoclonal gammopathy.

BACKGROUND: An elevated gamma gap (>4 g/dL), the difference between serum total protein and albumin, can trigger testing for chronic infections or monoclonal gammopathy, despite a lack of evidence supporting this clinical threshold. METHODS: Using the National Health and Nutrition Examination Survey (NHANES) 1999-2014, gamma gap was derived in three subpopulations based on availability of testing for human immunodeficiency virus (HIV; N = 25,680), hepatitis C (HCV; N = 45,134), and monoclonal gammopathy of unknown significance (MGUS; N = 6,118). Disease status was confirmed by HIV antibody and Western blot, HCV RNA test, or electrophoresis with immunofixation. Sensitivity, specificity, and likelihood ratios were calculated for different gamma gap thresholds. Area under the curve (AUC) was used to assess performance and cubic splines were used to characterize the relationship between the gamma gap and each disease. RESULTS: Mean gamma gaps of participants with HIV, HCV, or MGUS ranged from 3.4-3.8 g/dL. The AUC was 0.80 (95%CI: 0.75,0.85) for HIV, 0.74 (0.72,0.76) for HCV, and 0.64 (0.60,0.69) for MGUS. An elevated gamma gap of over 4 g/dL corresponded to sensitivities of 39.3%, 19.0%, and 15.4% and specificities of 98.4%, 97.8%, and 95.4% for HIV, HCV, and MGUS, respectively. A higher prevalence of all three diseases was observed at both low and high gamma gaps. DISCUSSION: An elevated gamma gap of 4 g/dL is insensitive for HIV, HCV, or MGUS, but has a high specificity for HIV and HCV, suggesting that the absence of an elevated gamma gap does not rule out HIV, HCV, or MGUS. Conversely, an elevated gap may justify further testing for HIV and HCV, but does not justify electrophoresis in the absence of additional clinical information.

Effects of high-fiber diets enriched with carbohydrate, protein, or unsaturated fat on circulating short chain fatty acids: results from the OmniHeart randomized trial.

BACKGROUND: Short chain fatty acids (SCFAs; e.g., acetate, propionate, and butyrate) are produced by microbial fermentation of fiber in the colon. Evidence is lacking on how high-fiber diets that differ in macronutrient composition affect circulating SCFAs. OBJECTIVES: We aimed to compare the effects of 3 high-fiber isocaloric diets differing in %kcal of carbohydrate, protein, or unsaturated fat on circulating SCFAs. Based on previous literature, we hypothesized that serum acetate, the main SCFA in circulation, increases on all high-fiber diets, but differently by macronutrient composition of the diet. METHODS: OmniHeart is a randomized crossover trial of 164 men and women (≥30 y old); 163 participants with SCFA data were included in this analysis. We provided participants 3 isocaloric high-fiber (∼30 g/2100 kcal) diets, each for 6 wk, in random order: a carbohydrate-rich (Carb) diet, a protein-rich (Prot) diet (protein predominantly from plant sources), and an unsaturated fat-rich (Unsat) diet. We used LC-MS to quantify SCFA concentrations in fasting serum, collected at baseline and the end of each diet period. We fitted linear regression models with generalized estimating equations to examine change in ln-transformed SCFAs from baseline to the end of each diet; differences between diets; and associations of changes in SCFAs with cardiometabolic parameters. RESULTS: From baseline, serum acetate concentrations were increased by the Prot (ß: 0.24; 95% CI: 0.12, 0.35), Unsat (ß: 0.21; 95% CI: 0.10, 0.33), and Carb (ß: 0.12; 95% CI: 0.01, 0.24) diets; between diets, only Prot compared with Carb was significant (P = 0.02). Propionate was decreased by the Carb (ß: -0.10; 95% CI: -0.16, -0.03) and Unsat (ß: -0.10; 95% CI: -0.16, -0.04) diets, not the Prot diet; between diet comparisons of Carb vs. Prot (P = 0.006) and Unsat vs. Prot (P = 0.002) were significant. The Prot diet increased butyrate (ß: 0.05; 95% CI: 0.00, 0.09) compared with baseline, but not compared with the other diets. Increases in acetate were associated with decreases in insulin and glucose; increases in propionate with increases in leptin, LDL cholesterol, and blood pressure; and increases in butyrate with increases in insulin and glucose, and decreases in HDL cholesterol and ghrelin (Ps < 0.05). CONCLUSIONS: Macronutrient composition of high-fiber diets affects circulating SCFAs, which are associated with measures of appetite and cardiometabolic health. This trial was registered at clinicaltrials.gov as NCT00051350.

Prevalence and Risk Factors of Thyroid Dysfunction in Older Adults in the Community.

Prevalence estimates and evidence informing treatment targets for thyroid dysfunction largely come from studies of middle-aged adults. We conducted a cross-sectional analysis to determine the prevalence of thyroid dysfunction and risk factors for abnormal thyroid tests in participants aged ≥65 in the Atherosclerosis Risk in Communities (ARIC) study (N = 5,392). We measured serum concentrations of triiodothyronine (T3), free thyroxine (FT4), thyroid peroxidase antibody (Anti-TPO), and thyroid stimulating hormone (TSH). In this population (58% women, 22% black), 17% reported medication use for thyroid dysfunction. Among those not on treatment, the prevalence of overt and subclinical hypothyroidism was 0.82% and 6.06%, respectively. Overt and subclinical hyperthyroidism affected 0.26% and 0.78%, respectively. Multivariable adjusted TSH, FT4 and T3 levels were 25%, 1.3% and 3.9% lower in blacks compared to whites, respectively. Men were less likely to be anti-TPO positive compared to women (p < 0.001). Former and never smoking were associated with lower T3 and FT4 levels compared to current smoking. The prevalence of thyroid dysfunction in older adults is nearly 25%. Multiple illnesses can interact to contribute to declines in health. Additional attention to thyroid dysfunction and screening in this age group is recommended.

Use of online recruitment strategies in a randomized trial of cancer survivors.

BACKGROUND/AIMS: Despite widespread Internet adoption, online advertising remains an underutilized tool to recruit participants into clinical trials. Whether online advertising is a cost-effective method to enroll participants compared to other traditional forms of recruitment is not known. METHODS: Recruitment for the Survivorship Promotion In Reducing IGF-1 Trial, a community-based study of cancer survivors, was conducted from June 2015 through December 2016 via in-person community fairs, advertisements in periodicals, and direct postal mailings. In addition, "Right Column" banner ads were purchased from Facebook to direct participants to the Survivorship Promotion In Reducing IGF-1 Trial website. Response rates, costs of traditional and online advertisements, and demographic data were determined and compared across different online and traditional recruitment strategies. Micro-trials optimizing features of online advertisements were also explored. RESULTS: Of the 406 respondents to our overall outreach efforts, 6% (24 of 406) were referred from online advertising. Facebook advertisements were shown over 3 million times (impressions) to 124,476 people, which resulted in 4401 clicks on our advertisement. Of these, 24 people ultimately contacted study staff, 6 underwent prescreening, and 4 enrolled in the study. The cost of online advertising per enrollee was $794 when targeting a general population versus $1426 when accounting for strategies that specifically targeted African Americans or men. By contrast, community fairs, direct mail, or periodicals cost $917, $799, or $436 per enrollee, respectively. Utilization of micro-trials to assess online ads identified subtleties (e.g. use of an advertisement title) that substantially impacted viewer interest in our trial. CONCLUSION: Online advertisements effectively directed a relevant population to our website, which resulted in new enrollees in the Survivorship Promotion In Reducing IGF-1 Trial at a cost comparable to traditional methods. Costs were substantially greater with online recruitment when targeting under-represented populations, however. Additional research using online micro-trial tools is needed to evaluate means of more precise recruitment to improve yields in under-represented groups. Potential gains from faster recruitment speed remain to be determined.

Effect of glycemic index and carbohydrate intake on kidney function in healthy adults.

BACKGROUND: Replacing carbohydrate with protein acutely increases glomerular filtration rate (GFR) but is associated with faster, long-term kidney disease progression. The effects of carbohydrate type (i.e. glycemic index, GI) on kidney function are unknown. METHODS: We conducted an ancillary study of a randomized, crossover feeding trial in overweight/obese adults without diabetes or kidney disease (N = 163). Participants were fed each of four healthy, DASH-like diets for 5 weeks, separated by 2-week washout periods. Weight was kept constant. The four diets were: high GI (GI ≥65) with high %carb (58 % kcal) (reference diet), low GI (≤45) with low %carb (40 % kcal), low GI with high %carb; and high GI with low %carb. Plasma was collected at baseline and after each feeding period. Study outcomes were cystatin C, ß2-microglobulin (ß2M), and estimated GFR based on cystatin C (eGFRcys). RESULTS: Mean (SD) age was 52 (11) years; 52 % were women; 50 % were black. At baseline, mean (SD) cystatin C, ß2M, and eGFRcys were 0.8 (0.1) mg/L, 1.9 (0.4) mg/L, and 104 (16) mL/min/1.73 m(2). Compared to the high GI/high %carb diet, reducing GI, %carb, or both increased eGFRcys by 1.9 mL/min/1.73 m(2) (95 % CI: 1.1, 2.7; P < 0.001), 3.0 mL/min/1.73 m(2) (1.9, 4.0; P < 0.001), and 4.5 mL/min/1.73 m(2) (3.5, 5.4; P < 0.001), respectively. Increases in eGFRcys from reducing GI were significantly associated with increases in eGFRcys from reducing %carb (P < 0.001). Results for cystatin C and ß2M reflected eGFRcys. CONCLUSIONS: Reducing GI increased GFR. Reducing %carb by increasing calories from protein and fat, also increased GFR. Future studies on GI should examine the long-term effects of this increase in GFR on kidney injury markers and clinical outcomes. TRIAL REGISTRATION: Clinical Trials.gov, number: NCT00608049 (first registered January 23, 2008).

Effects of Lowering Glycemic Index of Dietary Carbohydrate on Plasma Uric Acid Levels: The OmniCarb Randomized Clinical Trial.

OBJECTIVE: The effects of carbohydrates on plasma uric acid levels are a subject of controversy. We determined the individual and combined effects of carbohydrate quality (the glycemic index) and quantity (the proportion of total daily energy [percentage of carbohydrates]) on uric acid levels. METHODS: We conducted a randomized, crossover trial of 4 different diets in overweight or obese adults without cardiovascular disease (n = 163). Participants consumed each of 4 diets over a 5-week period, each of which was separated by a 2-week washout period. Body weight was kept constant. The 4 diets were high glycemic index (≥65) with high percentage of carbohydrates (58% kcal), low glycemic index (≤45) with low percentage of carbohydrates (40% kcal), low glycemic index with high percentage of carbohydrates, and high glycemic index with low percentage of carbohydrates. Plasma uric acid levels were measured at baseline and after completion of each 5-week period for comparison between the 4 diets. RESULTS: Of the 163 study participants, 52% were women and 50% were non-Hispanic African American subjects; their mean age was 52.6 years, and their mean ± SD uric acid level was 4.7 ± 1.2 mg/dl. Reducing the glycemic index lowered uric acid levels when the percentage of carbohydrates was low (-0.24 mg/dl; P < 0.001) or high (-0.17 mg/dl; P < 0.001). Reducing the percentage of carbohydrates marginally increased the uric acid level only when the glycemic index was high (P = 0.05). The combined effect of lowering the glycemic index and increasing the percentage of carbohydrates was -0.27 mg/dl (P < 0.001). This effect was observed even after adjustment for concurrent changes in kidney function, insulin sensitivity, and products of glycolysis. CONCLUSION: Reducing the glycemic index lowers uric acid levels. Future studies should examine whether reducing the glycemic index can prevent gout onset or flares.

The Gamma Gap and All-Cause Mortality.

BACKGROUND: The difference between total serum protein and albumin, i.e. the gamma gap, is a frequently used clinical screening measure for both latent infection and malignancy. However, there are no studies defining a positive gamma gap. Further, whether it is an independent risk factor of mortality is unknown. METHODS AND FINDINGS: This study examined the association between gamma gap, all-cause mortality, and specific causes of death (cardiovascular, cancer, pulmonary, or other) in 12,260 participants of the National Health and Nutrition Examination Survey (NHANES) from 1999-2004. Participants had a comprehensive metabolic panel measured, which was linked with vital status data from the National Death Index. Cause of death was based on ICD10 codes from death certificates. Analyses were performed with Cox proportional hazards models adjusted for mortality risk factors. The mean (SE) age was 46 (0.3) years and the mean gamma gap was 3.0 (0.01) g/dl. The population was 52% women and 10% black. During a median follow-up period of 4.8 years (IQR: 3.3 to 6.2 years), there were 723 deaths. The unadjusted 5-year cumulative incidences across quartiles of the gamma gap (1.7-2.7, 2.8-3.0, 3.1-3.2, and 3.3-7.9 g/dl) were 5.7%, 4.2%, 5.5%, and 7.8%. After adjustment for risk factors, participants with a gamma gap of ≥3.1 g/dl had a 30% higher risk of death compared to participants with a gamma gap <3.1 g/dl (HR: 1.30; 95%CI: 1.08, 1.55; P = 0.006). Gamma gap (per 1.0 g/dl) was most strongly associated with death from pulmonary causes (HR 2.22; 95%CI: 1.19, 4.17; P = 0.01). CONCLUSIONS: The gamma gap is an independent risk factor for all-cause mortality at values as low as 3.1 g/dl (in contrast to the traditional definition of 4.0 g/dl), and is strongly associated with death from pulmonary causes. Future studies should examine the biologic pathways underlying these associations.

Serum uric acid and the risk of mortality during 23 years follow-up in the Scottish Heart Health Extended Cohort Study.

BACKGROUND: Elevated uric acid is a prevalent condition with controversial health consequences. Observational studies disagree with regard to the relationship of uric acid with mortality, and with factors modifying this relationship. OBJECTIVE: We examined the association of serum uric acid with mortality in 15,083 participants in the Scottish Heart Health Extended Cohort (SHHEC) Study. METHODS: Serum uric acid was measured at study enrollment. Death was ascertained using both the Scottish death register and record linkage. RESULTS: During a median follow-up of 23 years, there were 3980 deaths. In Cox proportional hazards models with sexes combined, those in the highest fifth of uric acid had significantly greater mortality (HR 1.18, 95% CI: 1.06, 1.31) compared with the second fifth, after adjustment for traditional cardiovascular risk factors. This relationship was modified by sex (P-interaction=0.002) with adjusted HRs of 1.69 (95% CI: 1.40, 2.04) and 0.99 (95% CI: 0.86, 1.14) in women and men, respectively. Compared with the second fifth, the highest fifth of uric acid was most associated with kidney-related death (HR: 2.08, 95% CI: 1.31, 3.32). CONCLUSION: Elevated uric acid is associated with earlier mortality, especially in women. Future studies should evaluate mechanisms for these interactions and explore the strong association with renal-related mortality.

Trends in the prevalence of reduced GFR in the United States: a comparison of creatinine- and cystatin C-based estimates.

BACKGROUND: The US prevalence of reduced estimated glomerular filtration rate (eGFR) based on serum creatinine level increased during the decade ending in 2002. National Health and Nutrition Examination Survey (NHANES) cystatin C measurements recently were calibrated to the international standard, allowing for an independent test of the trend in prevalence of reduced eGFR using cystatin C level. STUDY DESIGN: Cross-sectional surveys performed during 2 periods. SETTING & PARTICIPANTS: Nationally representative subsamples of adult participants from NHANES III (1988-1994) and the NHANES 1999-2002 surveys. PREDICTOR: Survey period. OUTCOMES: Prevalence of reduced GFR, defined as eGFR <60 mL/min/1.73 m² based on levels of serum creatinine, cystatin C, or both (eGFRcr, eGFRcys, and eGFRcr-cys), using estimating equations developed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). MEASUREMENTS: Serum cystatin C level, measured from stored samples in 2006, calibrated to the international standard in 2012. RESULTS: Between 1988-1994 and 1999-2002, the prevalence of reduced eGFRcr, eGFRcys, and eGFRcr-cys increased from 4.7% (95% CI, 4.1%-5.3%) to 6.5% (95% CI, 5.9%-7.1%) (P < 0.001), from 5.5% (95% CI, 4.6%-6.5%) to 8.7% (95% CI, 7.5%-10.0%) (P < 0.001), and from 4.4% (95% CI, 3.7%-5.2%) to 7.1% (95% CI, 6.2%-8.0%) (P < 0.001), respectively. The higher prevalence of reduced GFR in the later period was observed in all subgroups of age, race, sex, and GFR categories. After adjusting for changes in the US population by age, sex, race, diabetes, hypertension, and body mass index, prevalence ratios of reduced GFR in the later versus earlier survey were 1.24 (95% CI, 1.09-1.45), 1.34 (95% CI, 1.15-1.67), and 1.33 (95% CI, 1.17-1.65) using eGFRcr, eGFRcys, and eGFRcr-cys, respectively. LIMITATIONS: Likely underascertainment of persons with GFR <15 mL/min/1.73 m²; GFR was estimated and not measured; comparability of laboratory assays based on a calibration subsample. CONCLUSIONS: The prevalence of reduced eGFRcys in the US civilian noninstitutionalized population increased between 1988-1994 and 1999-2002, confirming the increase observed in the prevalence of reduced eGFRcr.

Novel filtration markers as predictors of all-cause and cardiovascular mortality in US adults.

BACKGROUND: New filtration markers, including ß-trace protein (BTP) and ß2-microglobulin (B2M), may, similar to cystatin C, enable a stronger prediction of mortality compared to serum creatinine-based estimated glomerular filtration rate (eGFRcr). We sought to evaluate these mortality associations in a representative sample of US adults. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 6,445 adults 20 years or older from the Third National Health and Nutrition Examination Survey (1988-1994) with mortality linkage through December 31, 2006. PREDICTORS: Serum cystatin C, BTP, and B2M levels and eGFRcr categorized into quintiles, with the highest quintile (lowest for eGFRcr) split into tertiles (subquintiles Q5a-Q5c). OUTCOMES: All-cause, cardiovascular disease, and coronary heart disease mortality. MEASUREMENTS: Demographic- and multivariable-adjusted Cox proportional hazard models. RESULTS: During follow-up, 2,392 deaths (cardiovascular, 1,079; coronary heart disease, 605) occurred. Levels of all 4 filtration markers were associated with mortality risk after adjusting for demographics (P trend<0.02). Adjusted for mortality risk factors, compared to the middle quintile, the highest subquintiles for cystatin C (Q5c: HR, 1.94; 95% CI, 1.43-2.62), BTP (Q5c: HR, 2.14; 95% CI, 1.56-2.94), and B2M (Q5c: HR, 2.58; 95% CI, 1.96-3.41) were associated with increased all-cause mortality risk, whereas the association was weaker for eGFRcr (Q5c: HR, 1.31; 95% CI, 0.84-2.04). Associations persisted for the novel markers and not for eGFRcr at eGFRcr ≥60 mL/min/1.73 m². Trends were similar for cardiovascular disease and coronary heart disease mortality. LIMITATIONS: Single measurements of markers from long-term stored samples. CONCLUSIONS: The strong association of cystatin C level with mortality compared with serum creatinine estimates is shared by BTP and B2M. This supports the utility of alternative filtration markers beyond creatinine when improved risk prediction related to decreased GFR is needed.