Relationship of the Intake of Water and Other Beverages With Renal Endpoints: Cross-Sectional and Longitudinal Data-Observational, Population-Based Study.

OBJECTIVES: The relationship of water intake with kidney function in the population is uncertain. This study investigated cross-sectionally and longitudinally the relationship of the intake of water and other beverages with kidney function within an adult Italian population sample. METHODS: In 4,554 Gubbio Study examinees (54.4% women, age 18-95 years), data collection at baseline included demographics, anthropometry, questionnaires on habitual intakes of water and other beverages (non-water fluids), a timed overnight urine collection, estimated glomerular filtration rate (eGFR), decreased eGFR (<60 mL/minute/1.73 m2), and other variables including urinary markers of diet. At 15-year follow-up, the incidence of renal/kidney replacement therapy, the eGFR change from baseline, and the incidence of decreased eGFR were used as indices of kidney function change over time. RESULTS: In multivariable analyses, higher water intake is independently related to higher urine flow (beta = 0.163, P < .001), lower urine osmolality (beta = 0.184, P < .001), lower eGFR (beta = 0.030, P = .002), and higher prevalence of decreased eGFR (logistic coefficient ± standard error = 1.13 ± 0.32, P < .001). Water intake did not relate to kidney function change over time. Intake of non-water fluids did not independently relate to urinary indices nor to kidney function. CONCLUSIONS: In the general population, water intake relates cross-sectionally to urine flow, urine concentration, and kidney function but it does not relate to kidney function change over time. The intake of other beverages does not relate to urinary indices or kidney function. Results do not support a role of water intake in kidney function decline over time in the population.

Estimation of metabolic syndrome heritability in three large populations including full pedigree and genomic information.

Metabolic syndrome is a complex human disorder characterized by a cluster of conditions (increased blood pressure, hyperglycemia, excessive body fat around the waist, and abnormal cholesterol or triglyceride levels). Any of these conditions increases the risk of serious disorders such as diabetes or cardiovascular disease. Currently, the degree of genetic regulation of this syndrome is under debate and partially unknown. The principal aim of this study was to estimate the genetic component and the common environmental effects in different populations using full pedigree and genomic information. We used three large populations (Gubbio, ARIC, and Ogliastra cohorts) to estimate the heritability of metabolic syndrome. Due to both pedigree and genotyped data, different approaches were applied to summarize relatedness conditions. Linear mixed models (LLM) using average information restricted maximum likelihood (AIREML) algorithm were applied to partition the variances and estimate heritability (h2) and common sib-household effect (c2). Globally, results obtained from pedigree information showed a significant heritability (h2: 0.286 and 0.271 in Gubbio and Ogliastra, respectively), whereas a lower, but still significant heritability was found using SNPs data ([Formula: see text]: 0.167 and 0.254 in ARIC and Ogliastra). The remaining heritability between h2 and [Formula: see text] ranged between 0.031 and 0.237. Finally, the common environmental c2 in Gubbio and Ogliastra were also significant accounting for about 11% of the phenotypic variance. Availability of different kinds of populations and data helped us to better understand what happened when heritability of metabolic syndrome is estimated and account for different possible confounding. Furthermore, the opportunity of comparing different results provided more precise and less biased estimation of heritability.

Osmotic indices and kidney concentrating activity: population-based data on correlates and prognostic power.

Background: Research data are limited on indices of osmotic equilibrium and of kidney concentrating activity (KCA). This study investigated correlates and prognostic power of these indices in a sample of the general population. Methods: Urine osmolality (U-osm), plasma osmolality (P-osm), plasma creatinine and other variables were measured by the Gubbio Study for the 1988-92 exam (baseline). Plasma creatinine and other variables were re-measured in the 2001-07 exam (follow-up). KCA was assessed as the U-osm/P-osm ratio and kidney function as estimated glomerular filtration rate (eGFR). Results: Baseline data were complete in 4220 adults, of whom 852 died before follow-up and 2795 participated in the follow-up. At baseline, the following independent cross-sectional associations were identified: female sex and higher urine flow with lower values of U-osm, P-osm and U-osm/P-osm ratio (P < 0.01); obesity with higher values of U-osm, P-osm and U-osm/P-osm ratio (P < 0.01); older age and lower eGFR with lower U-osm, lower U-osm/P-osm ratio and higher P-osm (P < 0.05); hypertension and smoking with lower U-osm and lower U-osm/P-osm ratio (P < 0.05) but not with P-osm. From baseline to follow-up, the annualized rate was 1.26% for mortality and -0.74 ± 0.76 mL/min × 1.73 m2 for eGFR change. Mortality was independently predicted by baseline U-osm and baseline U-osm/P-osm ratio (hazard ratio for one higher standard deviation was ≤0.91, 95% confidence interval was ≤0.97, P < 0.01), but not by baseline P-osm. The eGFR change was not independently predicted by baseline values of U-osm, P-osm and U-osm/P-osm ratio (P ≥ 0.4). Conclusions: Sex, age, obesity, eGFR, urine flow, hypertension and smoking independently associated with U-osm and KCA. U-osm and KCA independently predicted mortality, but not kidney function change over time.

Low Protein Intake in the Population: Low Risk of Kidney Function Decline but High Risk of Mortality.

OBJECTIVE: This population-based study investigated low protein intake, mortality, and kidney function decline. DESIGN: Observational longitudinal cohort study. SUBJECTS: Target cohort consisted of 4,679 adults participating in 1988-1992 and 2001-2007 examinations of the Gubbio Study (baseline and follow-up). Data collection included overnight urine urea nitrogen (UUN) and other variables at baseline, serum creatinine at baseline and follow-up, and mortality from baseline to follow-up. Three hundred seventy-two persons were excluded for missing data. UUN in the lowest 20% of the distribution was defined as low and used as index of low protein intake. Estimated glomerular filtration rate (eGFR, mL/minute × 1.73 m2) was used as kidney function index. INTERVENTION: None (observational study). MAIN OUTCOME MEASURE: Mortality and eGFR decline are the main outcome measures, and eGFR decline was defined as eGFR change from baseline to follow-up ≤ mean-1 standard deviation (Z-score ≤ -1). RESULTS: Eight hundred seventy-one deaths occurred over 15.9 ± 4.0 years of observation (417 from cardiovascular disease and 276 from neoplastic disease). Low UUN associated with mortality (hazard ratio, HR = 1.31, 95% confidence interval, CI = 1.12/1.53) due to association with mortality from neoplastic disease (HR = 1.33, 95% CI = 1.02/1.76). Mortality-corrected follow-up response rate was 79.9% (n = 2845). Baseline to follow-up eGFR change was -9.9 ± 10.1, and eGFR decline was found in 454 examinees. Low UUN associated with eGFR decline only in subgroup with baseline eGFR <90 (n = 1441, odds ratio = 0.44, 95% CI = 0.22/0.85). Low baseline eGFR interacted with the association between low UUN and eGFR decline (P = .024). CONCLUSION: Low protein intake predicted higher mortality in the whole population and lower incidence of eGFR decline only in subgroup with reduced kidney function.

Diet and Other Modifiable Factors in Long-Term Decline of Kidney Function: Observational and Population-Based Cohort Study.

BACKGROUND: Lower physical activity, lower alcohol intake, higher protein intake, higher sodium intake, and lower potassium intake related to greater kidney function decline over time, according to previous studies. The present study aimed to analyze the cumulative effects of these factors. METHODS: This prospective, observational, population-based cohort study included 3039 adult examinees of the Gubbio study who participated in the baseline exam and 15-year follow-up exam. Kidney function was evaluated as estimated glomerular filtration rate (eGFR). Habitual physical activity in leisure time and habitual alcohol intake were assessed by questionnaires; dietary intakes of protein, sodium, and potassium were assessed by urinary markers. Based on previous reports, each one of the five modifiable factors was scored 0 for the tertile associated with smaller eGFR decline (low risk), 2 for the tertile associated with greater eGFR decline (high risk), and 1 for the intermediate tertile (intermediate risk). A cumulative score was calculated as the sum of the factor-specific scores and used as the main independent variable. RESULTS: The cumulative score ranged from 0 to 10, that is, from low risk for all factors to high risk for all factors (skewness = 0.032, mean ± SD = 5 ± 2). To avoid the bias of low-n analyses, score 0 was re-coded as 1 and score 10 was recoded as 9; after re-coding, the cumulative score ranged from 1 to 9 (skewness = 0.016, mean ± SD = 5 ± 2). The cumulative score related to annualized eGFR change in multi-variable linear regression (slope = -0.027, 95%CI = -0.039/-0.014, p < 0.001); findings were consistent in apparently healthy examinees and other subgroups. De novo incidence of eGFR < 60 mL/min × 1.73 m2 was higher along the cumulative score (p < 0.001). Compared to score 1 (n examinees = 35, adjusted incidence = 2.0%), incidence of low kidney function was 4.5 times higher in score 5 (n examinees = 624, adjusted incidence = 8.9%) and 6.5 times higher in score 9 (n examinees = 86, adjusted incidence = 12.9%). The cumulative score related to incidence of low kidney function in multi-variable logistic regression (odds ratio = 1.19, 95%CI = 1.08/1.32, p < 0.001). CONCLUSIONS: The combination of five modifiable factors predicted large differences in long-term incidence of low kidney function.

Relationship between lifestyle factors and hypertension: a cross-sectional analysis from the Gubbio study.

BACKGROUND: Hypertension (HTN) is a well-established and a major risk factor for cardiovascular disease. Lifestyle behaviours for its prevention and control are recommended within worldwide guidelines. Their relationship with HTN need more investigations. AIM: We aimed to investigate the associations between lifestyle, anthropometric and biological measurements and BP in the Gubbio residential study. METHODS: Cross-sectional analyses were performed using data from Gubbio study. Information concerning lifestyle factors were collected using self-reported questionnaire and were further completed with a baseline clinical examination and blood exams. Three BP measurements were performed following a standard protocol. Age-adjusted and multivariable logistic regressions were used to examine the relationships between lifestyle parameters and HTN separately for each sex. We used heterogeneity test to observe sex differences. RESULTS: There were 3,183 persons included (48% men, 43 ± 17 years old). Mean systolic BP (SBP) was 119 ± 16 mmHg and 10.6% were hypertensives. Age [OR: 129.70 (95%CI: 18.57-905.79) in women and OR: 8.37 (95%CI: 4.01-17.48) (p < 0.0001) in men] and BMI [OR: 2.14 (95%CI: 1.32-3.46) (p = 0.006) in women and OR: 1.81 (95%CI: 1.05-3.12), p = 0.03 in men], were positively associated with SBP in both sexes. Serum uric acid [OR: 3.86 (95%CI: 2.03-7.26), p = 0.04] was positively associated with HTN in women while fasting blood glucose [OR: 3.04 (95%CI: 1.55-5.97), p < 0.001] were associated to HTN only in men. DISCUSSION: In addition to age, BMI is associated with HTN in both sexes while sex differences were observed in the associations between serum uric acid, fasting blood glucose and HTN.

Marital status and long-term cardiovascular risk in general population (Gubbio, Italy).

To investigate whether marital status is associated to long-term major fatal and non-fatal cardiovascular events in men and women from the Gubbio Population Study. The incidence of cardiovascular disease (CVD), including stroke and coronary heart disease (CHD) and CVD death together with all-cause mortality were analyzed. The analysis included 2832 persons (44% men, 54 ± 11 years old). Marital status was defined at entry as married (married or living conjugally) versus unmarried subjects (widowed, separated, divorced or single). Married and unmarried subjects did not differ concerning socio-demographic, anthropometric and biological variables at baseline. Over 191 months median follow-up, the incidence of CHD was lower among married versus unmarried women [HR: 0.63 (95% CI 0.41-0.96)] only; the same was true for CHD mortality [HR: 0.43 (95% CI 0.22-0.84)] and all-cause mortality [HR: 0.75 (95% CI 0.59-0.96)] independently of traditional risk factors (age, SBP, total and HDL cholesterol, cigarette smoke and BMI). In men, marital status was not associated to any of the investigated outcomes. In primary care, marital status should be investigated as it can be associated with long-term CHD and all-cause incidence and mortality risks among women.

Relation of Alcohol Intake to Kidney Function and Mortality Observational, Population-Based, Cohort Study.

Data are conflicting about the effects of alcohol intake on kidney function. This population-based study investigated associations of alcohol intake with kidney function and mortality. The study cohort included adult participants in Exam-1, Exam-2 (6-year follow-up), and Exam-3 (20-year follow-up) of the Gubbio study. Kidney function was evaluated as estimated glomerular filtration rate (eGFR, CKD-Epi equation, mL/min × 1.73 m2). Daily habitual alcohol intake was assessed by questionnaires. Wine intake accounted for >94% of total alcohol intake at all exams. Alcohol intake significantly tracked over time (R > 0.66, p < 0.001). Alcohol intake distribution was skewed at all exams (skewness > 2) and was divided into four strata for analyses (g/day = 0, 1−24, 25−48, and >48). Strata of alcohol intake differed substantially for lab markers of alcohol intake (p < 0.001). In multivariable regression, strata of alcohol intake related cross-sectionally to eGFR at all exams (Exam-1: B = 1.70, p < 0.001; Exam-2: B = 1.03, p < 0.001; Exam-3: B = 0.55, p = 0.010) and related longitudinally to less negative eGFR change from Exam-1 to Exam-2 (B = 0.133, p = 0.002) and from Exam-2 to Exam-3 (B = 0.065, p = 0.004). In multivariable Cox models, compared to no intake, intakes > 24 g/day were not associated with different mortality while an intake of 1−24 g/day was associated with lower mortality in the whole cohort (HR = 0.77, p = 0.003) and in the subgroup with eGFR < 60 mL/min × 1.73 m2 (HR = 0.69, p = 0.033). These data indicate a positive independent association of alcohol intake with kidney function not due to a mortality-related selection.

A report on the Gubbio Study thirty-eight years after its inception.

BACKGROUND: The Gubbio Population Study (Gubbio Study) is a prospective epidemiological study carried out on the resident population of the city of Gubbio, Perugia, Italy. The study's objectives were both of public health nature (the control and awareness of hypertension), and experimental (the role of electrolyte handling at the cellular membrane level and its relation to hypertension). Additional objectives were addressed during the 30+ year activity of the study, in particular the role of kidney dysfunction. METHODS: Three active screenings (exams) were performed beginning 38 years ago: the first (Exam 1) in 1983-1986 (5376 individuals - response rate 92%) and two follow-up exams, were completed between 1989-92 (Exam 2) and 2001-2007 (Exam 3). Data collected include demographics, personal and family medical history, lifestyle (smoking, alcohol, diet and physical activity), education, type of work, anthropometry, blood pressure, pulse rate, blood biochemistry, urine biochemistry and special investigations on cellular electrolyte handling. Additional measurements were performed in selected subgroups of participants. Data on hospitalizations, mortality and causes of death were collected after the completion of Exam 1. RESULTS: The main results of the study, presented in this paper, identify new variables to consider in screening for cardiovascular risk factors, and show the impact that the focused and coordinated effort of a longitudinal program can have on a free-living population'. CONCLUSIONS: The data are of relevance to Public Health and to experimental medicine alike and vouch to the importance of the control of risk factors at the community level.

Sodium intake and kidney function in the general population: an observational, population-based study.

BACKGROUND: The relationships of sodium intake to kidney function within the population have been poorly investigated and are the objective of the study. METHODS: This observational, population-based, cross-sectional and longitudinal study targeted 4595 adult participants of the Gubbio study with complete data at baseline exam. Of these participants, 3016 participated in the 15-year follow-up (mortality-corrected response rate 78.4%). Baseline measures included sodium:creatinine ratio in timed overnight urine collection, used as an index of sodium intake, together with serum creatinine, sex, age and other variables. Follow-up measures included serum creatinine and other variables. Estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) was calculated using serum creatinine, sex and age and was taken as an index of kidney function. RESULTS: The study cohort was stratified in sex- and age-controlled quintiles of baseline urine sodium:creatinine ratio. A higher quintile associated with higher baseline eGFR (P < 0.001). In multivariable analysis, the odds ratio (OR) of Stage1 kidney function (eGFR ≥90 mL/min/1.73 m2) was 1.98 times higher in Quintile 5 compared with Quintile 1 [95% confidence interval (CI) 1.50-2.59, P < 0.001]. The time from baseline to follow-up was 14.1 ± 2.5 years. Baseline to follow-up, the eGFR change was more negative along quintiles (P < 0.001). In multivariable analysis, the OR in Quintile 5 compared with Quintile 1 was 2.21 for eGFR decline ≥30% (1.18-4.13, P = 0.001) and 1.38 for worsened stage of kidney function (1.05-1.82, P = 0.006). Findings were consistent within subgroups. CONCLUSIONS: Within the general population, an index of higher sodium intake associated cross-sectionally with higher kidney function but longitudinally with greater kidney function decline.

Twenty-year cardiovascular and all-cause mortality trends and changes in cardiovascular risk factors in Gubbio, Italy: the role of blood pressure changes.

AIMS: In an observational population study that lasted 20 years, the relationships between mortality trends and changes in cardiovascular risk factor levels were examined. METHODS AND RESULTS: In the town of Gubbio, in central Italy, population surveys for measurement of cardiovascular risk factors were performed 20 years apart. In a subset of the initial cohort (1927 men and 2333 women), mortality data were collected for 20 years. Cardiovascular risk factor levels were compared in individuals in the same age range (20-79 years) examined at the initial survey (1927 men and 2333 women) and at the final survey (1761 men and 2055 women). Age-adjusted rates significantly declined, by 28% among men and 51% among women, for all causes of death, and by 50% among men and 71% among women for cardiovascular disease deaths. Declines were observed in the levels of systolic blood pressure, serum cholesterol, resting heart rate, smoking habits, BMI, plasma glucose (the latter two only in women) and the estimated cardiovascular risk, together with increases in serum high-density lipoprotein cholesterol and in the proportion of treated and controlled hypertensive patients. CONCLUSION: Although similar but less impressive changes were recorded in Italy at large, the existence of the observational study in Gubbio might have motivated the general population and the medical profession towards actions promoting general health.

Cohort profile: The Gubbio Population Study.

The Gubbio Study is a prospective epidemiological study on the population residing in the city of Gubbio, Italy. Original objectives of the study were the control of hypertension and the role of cellular electrolyte handling in hypertension. Other objectives were added during the 30-year activity of the study. The original target cohort consists of individuals aged ≥5 years residing within the medieval walls of the city. To complete family genealogies, individuals residing outside the city were also included. Three active screenings (exams) were conducted. A total of 5376 individuals (response rate 92%) participated in Exam 1 which was performed in 1983-86. Follow-up exams were completed between 1989-92 and 2001-2007. Data categories included demographics, personal and family medical history, lifestyle habits, education, type of work, anthropometry, blood pressure, pulse rate, blood biochemistry, urine biochemistry and special investigations on cellular electrolyte handling. Electrocardiogram, echocardiogram, 24-h ambulatory blood pressure and uroflowmetry were performed in selected subgroups defined by age and/or sex. Data about hospitalizations, mortality and causes of death were collected starting from completion of Exam 1. The study shared the data with other studies.

Typical and atypical coronary heart disease deaths and their different relationships with risk factors. The Gubbio residential cohort study.

OBJECTIVES: The Seven Countries Study showed that fatal coronary heart disease (CHD) with only chronic heart failure, arrhythmia or blocks (atypical CHD, A-CHD) may represent a distinct disease as compared to fatal CHD cases with angina pectoris, acute myocardial infarction (AMI) or sudden death (typical CHD, T-CHD). We aimed at validating this, using identical diagnostic criteria, in a separate residential cohort first examined in 1983-85 in Gubbio, central Italy. MATERIAL AND METHODS: Forced Cox's models were run to assess 9 classic risk factors and their 20-year predictivity of A-CHD versus T-CHD, in the entire cohort or separately for men and women. RESULTS: There were 3229 subjects aged 30-79 years. Entry mean age was slightly higher in women than men although age at death was lower in men than in women for both T-CHD (71.99 ± 11.38 versus 81.20 ± 9.35 years, p<0.0001) and A-CHD (80.22 ± 9.44 versus 84.98 ± 8.13 years, p<0.0001). T-CHDs were predicted by male gender, age, continued smoke, systolic blood pressure (SBP), blood glucose, total and HDL-cholesterol (protective). A-CHDs were predicted by age, continued smoke, SBP, body mass index and blood glucose but neither total nor HDL-cholesterol or gender was significant. In the entire cohort and in men there were predictive differences of T-CHD versus A-CHD fatalities only in relation to age (p<0.01), SBP (p<0.05) and total cholesterol (p<0.01). CONCLUSION: As age, SBP and total cholesterol had a different predictive role of T-CHD versus A-CHD fatalities also in the Gubbio cohort, the possibility is reinforced that a different etiology exists between these entities.

Serum uric acid and eGFR_CKDEPI differently predict long-term cardiovascular events and all causes of deaths in a residential cohort.

OBJECTIVES: Serum uric acid (SUA) and estimated glomerular filtration rate (eGFR) were separately assessed as risk factors for incident coronary hard (CHDH), cardiovascular disease (CVDH) or all-cause (ALL) deaths but never concomitantly in a residential cohort. MATERIAL AND METHODS: Men and women aged 35-74years, totaling 2888 subjects were followed 13.5-19.5years for incident CVDH, CHDH and ALL deaths. Systematic comparisons among different end-points were based on: age, gender, systolic blood pressure (SBP), total and HDL cholesterol, cigarette consumption, body mass index, blood glucose, SUA, eGFR from the Chronic Kidney Disease Prognosis Consortium (eGFR_CKDEPI) and (eGFR_CKDEPI)(2). RESULTS: Significant (p<0.00001) differences in SUA quintiles were seen for SBP, total and HDL cholesterol, body mass index and eGFR_CKDEPI whereas cigarettes and blood glucose were not statistically different. There were increasingly larger proportions of all events in SUA quintiles (0.05>p<0.0001). Among 4 major continuous variables, SUA was largely accurate (ROC>0.610) to predict all end-points whereas eGFR_CKDEPI was the worse univariate predictor. Multivariately, age, gender, SBP and cigarettes were significant predictors for all end-points. Total cholesterol was a significant predictor only for CHDH events. Blood glucose and SUA were contributors for CVDH events (RR, for 1mg/dl of SUA, 1.09, 95%CI 1.01-1.17), CVD deaths (RR 1.11, 95%CI 1.03-1.20) and ALL deaths (RR 1.08, 95%CI 1.03-1.14) whereas (eGFR_CKDEPI)(2) was for ALL deaths only (RR 1.02, 95%CI 1.00-1.04). CONCLUSION: SUA is a predictor of long-term incidence of cardiovascular events and deaths and all-cause mortality and should be considered for risk predictive purposes and instruments whereas eGFR_CKDEPI only predicts all-cause mortality by a U-shaped relation.

Heritability of blood pressure through latent curve trajectories in families from the Gubbio population study.

BACKGROUND AND OBJECTIVES: Prospective investigations on cardiovascular risk factors in populations provide a unique opportunity to dissect time-dependent quantitative complex traits, such as arterial blood pressure (BP), into their polygenic and environmental components. BP heritability analyses were carried out on 2620 patients belonging to 711 nuclear pedigrees that could be followed up throughout 25 years in the Gubbio Population Study. METHODS: Each patient's BP serial measurements were summarized into individual intercepts (expected values at baseline) and slopes (time-related changes), which were predicted through latent curve models. These models considered either age in years or waves (times from the first survey) as time axis and were linked at a family level in the heritability analyses using additive polygenic-common environment-unique error models adjusted for sex, age and clinical variables. RESULTS: The additive genetic effect explained 32-49% of the variance of SBP values at baseline, the wave-dependent analysis with nuclear pedigrees and the sibs-household matrix accounting for higher heritability values. Heritability of DBP baseline value was lower than that of SBP in analyses by age (5-15%), but fell in the same heritability range as SBP on the analysis by waves (36-37%). The BP variation over time (slope) explained by an additive genetic effect ranged from 33 to 43% and from 24 to 25% for SBP and DBP, respectively, in the analysis by age. Shared environment also exerted a significant influence, but explained a smaller portion of the variances (4-17%) for both traits. CONCLUSION: Longitudinal data from the Gubbio population show strong to moderate genetic influences on SBP and DBP baseline values and changes over time with a smaller, though significant, effect of environment.