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1.  Invited Commentary: Quantifying Salt in Urine—A Complex Solution 
American Journal of Epidemiology  2013;177(11):1193-1195.
Reduction of dietary sodium intake has been identified as a priority to reduce the worldwide burden of hypertension and cardiovascular disease. Dietary sodium intake is most precisely ascertained by using timed urine collection. Casual urine sodium measurements are relatively easy to perform, but their relationship to timed urine sodium measurements is unclear. In this issue of the Journal, Brown et al. (Am J Epidemiol. 2013;177(11):1180–1192) report the development and validation of equations to estimate 24-hour urine sodium excretion from casual urine samples. Their study included a large number of participants on 2 continents, a well-collected gold standard, separate discovery and validation samples, and relevant covariates. The resulting equations represent the best available methods to estimate dietary sodium intake from casual urine samples. However, the study is limited by evidence of a suboptimal model fit, restriction to people 20–59 years of age in North America and Europe, and exclusion and adjustment that further limit external validity. In addition, individual-level correlations of estimated and measured 24-hour urine sodium excretion were modest. Properly applied, the results will facilitate tracking of dietary sodium intake within populations over time and identification of communities for which dietary sodium restriction is most likely to be beneficial. Further work is needed to extend estimation to additional populations and improve individual-level assessment.
PMCID: PMC3664340  PMID: 23673248
cardiovascular disease; diagnostic test; dietary sodium; estimation techniques; hypertension; sodium; urinary sodium
2.  Assessment of Physical Activity in Chronic Kidney Disease 
Physical activity (PA) plays important roles in the development of kidney disease and its complications; however, the validity of standard tools for measuring PA is not well understood.
Study Design
We investigated the performance of several readily-available and widely-used PA and physical function questionnaires, individually and in combination, against accelerometry among a cohort of CKD participants.
Setting and Participants
Forty-six participants from the Seattle Kidney Study, an observational cohort study of persons with CKD, completed the PA Scale for the Elderly, Human Activity Profile (HAP), Medical Outcomes Study SF-36 questionnaire, and the Four Week PA History Questionnaire (FWH). We simultaneously measured PA using an Actigraph GT3X accelerometer over a 14-day period. We estimated the validity of each instrument by testing its associations with log-transformed accelerometry counts. We used the Akaike information criterion to investigate the performance of combinations of questionnaires.
All questionnaire scores were significantly associated with log-transformed accelerometry counts. The HAP correlated best with accelerometry counts (r2=0.32) followed by the SF-36 (r2=0.23). Forty-three percent of the variability in accelerometry counts data was explained by a model that combined the HAP, SF-36 and FWH.
A combination of measurement tools can account for a modest component of PA in patients with CKD; however, a substantial proportion of physical activity is not captured by standard assessments.
PMCID: PMC3496802  PMID: 22739659
chronic kidney disease; physical activity; accelerometry; questionnaires
3.  Relation of Vitamin D and Parathyroid Hormone to Cardiac Biomarkers and to Left Ventricular Mass (From the Cardiovascular Health Study) 
The American journal of cardiology  2012;111(3):418-424.
Vitamin D and parathyroid hormone (PTH) may impact cardiovascular health among individuals with kidney disease and in the general population. We investigated associations of serum 25-hydroxyvitamin D (25OHD) and PTH concentrations with a comprehensive set of biochemical, electrocardiographic and echocardiographic measurements of cardiac structure and function in the Cardiovascular Health Study. A total of 2,312 subjects who were free of cardiovascular disease at baseline were studied. Serum 25OHD and intact PTH concentrations were measured using mass-spectrometry and a 2-site immunoassay. Outcomes were N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac troponin T, electrocardiographic measures of conduction, and echocardiographic measures of left ventricular mass and diastolic dysfunction. At baseline, subjects had a mean age of 73.9±4.9 years, 69.7% were female and 21% had chronic kidney disease (CKD; glomerular filtration rate <60ml/min). Mean (SD) 25OHD was 25.2 (10.2) ng/ml and median PTH was 51 pg/ml (range 39–65 pg/ml). After adjustment, 25OHD was not associated with any of the biochemical, conduction, or echocardiographic outcomes. Serum PTH levels ≥ 65 pg/ml were associated with greater NT-proBNP, cardiac troponin T and left ventricular mass in subjects with CKD. The regression coefficients were: 120 (36.1, 204 pg/ml), 5.2 (3.0, 7.4 pg/ml) and 17 (6.2, 27.8 g) (p-value <0.001). In subjects with normal kidney function, PTH was not associated with the outcomes. Among older adults with CKD, PTH excess is associated with higher NT-pro-BNP, cardiac troponin T, and left ventricular mass. In conclusion, these findings suggest a role for PTH in cardiovascular health and the prevention of cardiac diseases.
PMCID: PMC3546140  PMID: 23168286
Vitamin D; parathyroid hormone; cardiac biomarkers; left ventricular mass; epi-demiology
4.  Fibroblast Growth Factor–23 and Cardiac Structure and Function 
Fibroblast growth factor–23 (FGF‐23) is a phosphaturic factor previously associated with left ventricular hypertrophy and systolic dysfunction among individuals with chronic kidney disease. Whether FGF‐23 acts directly to induce left ventricular hypertrophy, potentially independent of its klotho coreceptor, remains uncertain. We investigated associations of FGF‐23 with cardiac structural abnormalities among individuals with a broad range of kidney function and explored potential biological mechanisms using cardiac magnetic resonance imaging and histology in klotho‐null mice, an established model of constitutively elevated FGF‐23.
Methods and Results
Among 887 participants with coronary artery disease in the Heart and Soul Study, FGF‐23 was modestly associated with worse left ventricular ejection fraction (−1.0% per standard deviation increase in lnFGF‐23; standard error, 0.4%), but was not associated with the overall prevalence of concentric hypertrophy (odds ratio, 1.5; CI, 0.9 to 2.4) or eccentric hypertrophy (odds ratio, 1.1; CI, 0.9 to 1.3). FGF‐23 was only associated with concentric hypertrophy among individuals with diminished kidney function (eGFR <60 mL/min per 1.73 m2; odds ratio, 2.3; CI, 1.0 to 5.3; P‐interaction=0.28). Comparing klotho‐null with wild‐type mice, null mice did not have greater left ventricular mass (P=0.37) or a lower ejection fraction (P=0.94).
Together, our results suggest that FGF‐23 is unlikely to have major effects on cardiovascular structure and function among patients free of substantial chronic kidney disease, and these effects may not be independent of the klotho coreceptor.
PMCID: PMC3959672  PMID: 24525546
chronic kidney disease; hypertrophy; structure
5.  A Prospective Study of Frailty in Nephrology-Referred Patients With CKD 
Frailty is a construct developed to characterize a state of reduced functional capacity among older adults. However, there are limited data describing the prevalence or consequences of frailty among middle-aged CKD patients.
Study Design
Observational study
Setting & Participants
336 non-dialysis-dependent stage 1–4 CKD patients with eGFR< 90ml/min/1.73m2 (by the CKD-EPI [CKD Epidemiology Collaboration] serum creatinine–based equation) or evidence of microalbuminuria enrolled in the Seattle Kidney Study, a clinic-based cohort study. Findings were compared to community dwelling older adults in the Cardiovascular Health Study.
Prevalence and determinants of frailty in addition to its association with the combined outcome of all-cause mortality or renal replacement therapy.
We defined frailty according to established criteria as ≥3 of the following characteristics: slow gait, weakness, unintentional weight loss, exhaustion, and low physical activity. We estimated kidney function using serum cystatin C concentrations (eGFRcys) to minimize confounding due to relationships of serum creatinine levels with muscle mass and frailty.
The mean age of the study population was 59 years and mean eGFRcys was 51 ml/min/1.73m2. The prevalence of frailty (14.0%) was twice that of the much older non-CKD reference population (P<0.01). The most common frailty components were physical inactivity and exhaustion. After adjustment including diabetes, eGFRcys categories of <30 and 30–44 ml/min/1.73m2 were associated with a 2.8 (95% CI, 1.3–6.3) and 2.1 (95% CI, 1.0–4.7)-fold greater prevalence of frailty compared to GFRcys ≥60 ml/min/1.73m2. There were 63 events during a median of 987 days of follow-up. After adjustment, the frailty phenotype was associated with an estimated 2.5 (95% CI, 1.4–4.4)- fold greater risk of death or dialysis.
Cross-sectional study design obscures inference regarding temporal relationships between CKD and frailty.
Frailty is relatively common among middle-aged CKD patients and is associated with lower eGFRcys as well as increased risk of death or dialysis.
PMCID: PMC3491110  PMID: 22770927
6.  Relationships Between Serum and Urine Phosphorus with All-Cause and Cardiovascular Mortality: the Osteoporotic Fractures in Men (MrOS) Study 
Serum phosphorus is associated with cardiovascular disease (CVD) in the general population but may not comprehensively reflect phosphorus homeostasis. Whether urine phosphorus/creatinine ratio (UPi/UCr, a marker of intestinal absorption) or urine fractional excretion of phosphorus (FePi, a marker of urinary phosphorus handling) is associated with risk of mortality or CVD is uncertain.
Study Design
Prospective observational study.
Setting and Participants
1,325 community-dwelling men aged ≥65 years.
Serum phosphorus, UPi/UCr, and FePi.
All-cause and CVD death.
Mean age was 74±6 years, eGFR was 75±16 ml/min/1.73m2, and serum phosphorus was 3.2±0.4 mg/dL. During 9.3 years median follow-up, there were 364 deaths (120 CVD deaths). After adjustment for demographics, CVD risk factors, and kidney function, the risks of all-cause death in the highest quartiles of serum phosphorus (≥3.6 mg/dL), UPi/UCr, and FePi were 1.63 (95% CI 1.23-2.17), 1.22 (95% CI 0.90-1.65), and 0.88 (95% CI 0.64-1.23), respectively. Results were similar for CVD death. Results were also similar irrespective of eGFR above or below 60 ml/min/1.73m2.
Older, all male cohort. Few had advanced CKD. Specimens were collected in the morning after an overnight fast.
In community-living older men, higher serum phosphorus is associated with all-cause and CVD death. In contrast, UPi/UCr and FePi were not. These findings do not support using UPi/UCr or FePi as adjuvant measures to predict risk of mortality or CVD in the general population.
PMCID: PMC3815620  PMID: 23261120
Phosphorus; urine phosphorus; mortality; cardiovascular disease; kidney disease; geriatrics
7.  Dietary phosphorus is associated with a significant increase in left ventricular mass 
Kidney international  2013;83(4):707-714.
Dietary phosphorus consumption has risen steadily in the United States. Oral phosphorus loading alters key regulatory hormones and impairs vascular endothelial function which may lead to an increase in left ventricular mass (LVM). We investigated the association of dietary phosphorus with LVM in 4,494 participants from the Multi-Ethnic Study of Atherosclerosis, a community-based study of individuals free of known cardiovascular disease. The intake of dietary phosphorus was estimated using a 120-item food frequency questionnaire and the LVM was measured using magnetic resonance imaging. Regression models were used to determine associations of estimated dietary phosphorus with LVM and left ventricular hypertrophy (LVH). Mean estimated dietary phosphorus intake was 1,167 mg/day in men and 1,017 mg/day in women. After adjustment for demographics, dietary sodium, total calories, lifestyle factors, comorbidities, and established LVH risk factors, each quintile increase in the estimated dietary phosphate intake was associated with an estimated 1.1 gram greater LVM. The highest gender-specific dietary phosphorus quintile was associated with an estimated 6.1 gram greater LVM compared to the lowest quintile. Higher dietary phosphorus intake was associated with greater odds of LVH among women, but not men. These associations require confirmation in other studies.
PMCID: PMC3612378  PMID: 23283134
Phosphorus; phosphate; diet; consumption; left ventricular mass; left ventricular hypertrophy
8.  Associations of Socioeconomic Status and Processed Food Intake with Serum Phosphorus in Community-Living Adults: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Higher serum phosphorus concentrations are associated with cardiovascular disease events and mortality. Low socioeconomic status is linked with higher serum phosphorus, but the reasons are unclear. Poor individuals disproportionately consume inexpensive processed foods commonly enriched with phosphorus-based food preservatives. Accordingly, we hypothesized that excess intake of these foods accounts for a relationship between lower socioeconomic status and higher serum phosphorus.
Cross-sectional analysis.
Setting and Participants
We examined a random cohort of 2,664 participants with available phosphorus measurements in the Multi-Ethnic Study of Atherosclerosis, a community-based sample of individuals free of clinically apparent cardiovascular disease from across the United States.
Predictor Variables
Socioeconomic status, the intake of foods commonly enriched with phosphorus additives (processed meats, sodas) and frequency of fast food consumption.
Fasting morning serum phosphorus concentrations.
In unadjusted analyses, lower income and lower educational achievement categories were associated with modestly higher serum phosphorus (by 0.02 to 0.10 mg/dL, P < 0.05 for all). These associations were attenuated in models adjusted for demographic and clinical factors, almost entirely due to adjustment for female gender. There were no statistically significant associations of processed meat intake or frequency of fast-food consumption with serum phosphorus in multivariable-adjusted analyses. In contrast, each serving per day higher soda intake was associated with 0.02 mg/dl lower serum phosphorus (95% confidence interval, −0.04, −0.01).
Greater intake of foods commonly enriched with phosphorus additives was not associated with higher serum phosphorus in a community-living sample with largely preserved kidney function. These results suggest that excess intake of processed and fast foods may not impact fasting serum phosphorus concentrations among individuals without kidney disease.
PMCID: PMC3321388  PMID: 22217539
phosphorus; socioeconomic status; nutrition
9.  Paricalcitol does not improve glucose metabolism in patients with stage 3-4 chronic kidney disease 
Kidney international  2012;83(2):323-330.
Patients with chronic kidney disease are often insulin resistant and glucose intolerant; abnormalities that promote cardiovascular disease. Administration of 1,25-dihydroxyvitamin D (calcitriol) has improved glucose metabolism in patients with end stage renal disease. We conducted a randomized, placebo-controlled clinical trial to test whether paricalcitol, a 1,25-dihydroxyvitamin D analogue, changes glucose tolerance in earlier stages of chronic kidney disease. In a cross-over design, 22 non-diabetic patients with estimated glomerular filtration rates of stage 3-4 chronic kidney disease and fasting plasma glucose 100-125 mg/dL were given daily oral paricalcitol for 8 weeks and matching placebo for 8 weeks, separated by an 8-week washout period. The order of interventions was random and blinded to both participants and investigators. Paricalcitol significantly reduced serum concentrations of parathyroid hormone, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D while significantly increasing serum concentrations of fibroblast growth factor-23 and 24,25-dihydroxyvitamin D. Paricalcitol, however, had no significant effect on glucose tolerance (the primary outcome measure), insulin sensitivity, beta-cell insulin response, plasma free fatty acid suppression, or urinary F2-isoprostane excretion. Thus, despite substantial effects on vitamin D metabolism, paricalcitol did not improve glucose metabolism in non-diabetic patients with stage 3-4 chronic kidney disease.
PMCID: PMC3509239  PMID: 22913981
10.  Fibroblast Growth Factor-23 and Death, Heart Failure, and Cardiovascular Events in Community-Living Individuals: the Cardiovascular Health Study 
To determine the associations of FGF23 with death, HF, and CVD and investigate the influence of CKD in a general community-living population.
FGF23 increases renal phosphorus excretion and inhibits vitamin D activation. In ESRD, high FGF23 levels are associated with mortality. The associations of FGF23 with death, heart failure (HF), and cardiovascular disease (CVD) in teh general population are unknown.
Plasma FGF23 was measured in 3,107 community-living persons ≥ 65 years in 1996–97, and participants were followed through 2008. HF and CVD events were adjudicated by a panel of experts. Associations of FGF23 with each outcome were evaluated using Cox proportional hazards models, and we tested whether associations differed by CKD status.
Both lower eGFR and higher urine ACR were associated with high FGF23 at baseline. During 10.5 years (median) follow-up, there were 1,730 deaths, 697 incident HF events, and 797 incident CVD events. Although high FGF23 concentrations were associated with each outcome in combined analyses, the associations were consistently stronger for those with CKD (P interactions all < 0.006). In the CKD group (n=1,128), the highest FGF23 quartile had adjusted hazards ratios (HR) of 1.87 (1.47, 2.38) for all-cause death, 1.94 (1.32, 2.83) for incident HF, and 1.49 (1.02, 2.18) for incident CVD events compared to the lowest quartile. Corresponding HRs in those without CKD (n=1,979) were 1.29 (1.05, 1.59), 1.37 (0.99, 1.89), and 1.07 (0.79, 1.45).
FGF23, a hormone involved in phosphorous and vitamin D homeostasis, is independently associated with all-cause death and incident HF in community-living older persons. These associations appear stronger in persons with CKD.
PMCID: PMC3396791  PMID: 22703926
Fibroblast growth factor-23; kidney disease; mineral metabolism; cardiovascular disease; heart failure; elderly
11.  Insulin Resistance, Cystatin C, and Mortality Among Older Adults 
Diabetes Care  2012;35(6):1355-1360.
Insulin resistance is a risk factor for cardiovascular and noncardiovascular diseases. Impaired kidney function is linked with insulin resistance and may affect relationships of insulin resistance with health outcomes.
We performed a cohort study of 3,138 Cardiovascular Health Study participants (age ≥65 years) without diabetes. Insulin sensitivity index (ISI) was calculated from fasting and 2-h postload insulin and glucose concentrations. Associations of ISI and fasting insulin concentration with all-cause mortality were tested using Cox proportional hazards models, adjusting for demographic variables, prevalent cardiovascular disease, lifestyle variables, waist circumference, and LDL cholesterol. Subsequent models were additionally adjusted for or stratified by glomerular filtration rate estimated using serum cystatin C (eGFR).
A total of 1,810 participants died during the 14.7-year median follow-up. Compared with the highest quartile of ISI, the lowest quartile (most insulin resistant) was associated with 21% (95% CI 6–41) and 11% (−3 to 29) higher risks of death without and with adjustment for eGFR, respectively. Compared with the lowest quartile of fasting insulin concentration, the highest quartile was associated with 22% (4–43) and 4% (−12 to 22) higher risks of death without and with adjustment for eGFR, respectively. Similar attenuation by eGFR was observed when blood pressure, triglycerides, HDL cholesterol, and C-reactive protein were included in models.
Insulin resistance measured as ISI or fasting insulin concentration is associated with increased risk of death among older adults, adjusting for conventional confounding characteristics. Impaired kidney function may mediate or confound this relationship.
PMCID: PMC3357240  PMID: 22432118
12.  Variation in Oral Calcitriol Response in Patients With Stage 3-4 CKD 
Oral calcitriol lowers parathyroid hormone (PTH) concentrations among patients who have chronic kidney disease (CKD); however, treatment response is highly variable. We evaluated whether patient characteristics affect the PTH response to oral calcitriol among non-dialysis CKD patients in a clinic-based setting.
Cohort study.
This study included 379 new oral calcitriol users in the Veterans’ Affairs Northwest Health Network. All had stages 3-4 CKD, hyperparathyroidism, and a serum PTH measurement before and 1-6 months after initiating oral calcitriol.
Patient-level characteristics hypothesized to affect calcitriol response: race, body size, concurrent medications, and kidney function.
Relative reduction in serum PTH concentration after starting oral calcitriol.
Data were abstracted from the Veterans’ Affairs Northwest Health Network (VISN 20) Data Warehouse, which includes electronic pharmacy and laboratory records.
Mean estimated GFR was 30 ml/min/1.73m2 and mean initial PTH concentration was 199 pg/mL. Regular dose (0.25 ug/day) and low-dose (<0.25 ug/day) oral calcitriol were associated with, on average, 23% and 13% relative reductions in serum PTH concentrations, respectively. After adjustment for calcitriol dosage, initial PTH concentration, and time to follow-up measurement, African American race was associated with a blunted calcitriol response (geometric mean final PTH value, 26% higher; 95% CI, 8%-47%). A serum albumin concentration <3.5 g/dL was also associated with a diminished calcitriol response (geometric mean final PTH, 19% higher; 95% CI, 6%-35%). Although numbers were small, concurrent use of benzodiazepenes and non-activated vitamin D supplements were associated with a significantly greater PTH response.
Clinic-based study is limited by availability of PTH measurements after starting calcitriol. Study among a predominantly older, male population.
Among patients with stages 3-4 CKD, African American race and low serum albumin are associated with a diminished PTH response to oral calcitriol.
PMCID: PMC3328668  PMID: 22285224
Activated vitamin D; calcitriol; parathyroid hormone; hyperparathyroidism; drug metabolism
13.  Serum 25-Hydroxyvitamin D Concentration and Risk for Major Clinical Disease Events in a Community-Based Population of Older Adults 
Annals of internal medicine  2012;156(9):627-634.
Circulating concentrations of 25-hydroxyvitamin D [25-(OH)D] are used to define vitamin D deficiency. Current clinical 25-(OH)D targets based on associations with intermediate markers of bone metabolism may not reflect optimal levels for other chronic diseases and do not account for known seasonal variation in 25-(OH)D concentration.
To evaluate the relationship of 25-(OH)D concentration with the incidence of major clinical disease events that are pathophysiologically relevant to vitamin D.
Cohort study.
The Cardiovascular Health Study conducted in 4 U.S. communities. Data from 1992 to 2006 were included in this analysis.
1621 white older adults.
Serum 25-(OH)D concentration (using a high-performance liquid chromatography–tandem mass spectrometry assay that conforms to National Institute of Standards and Technology reference standards) and associations with time to a composite outcome of incident hip fracture, myocardial infarction, cancer, or death.
Over a median 11-year follow-up, the composite outcome occurred in 1018 participants (63%). Defining events included 137 hip fractures, 186 myocardial infarctions, 335 incidences of cancer, and 360 deaths. The association of low 25-(OH)D concentration with risk for the composite outcome varied by season (P = 0.057). A concentration lower than a season-specific Z score of −0.54 best discriminated risk for the composite outcome and was associated with a 24% higher risk in adjusted analyses (95% CI, 9% to 42%). Corresponding season-specific 25-(OH)D concentrations were 43, 50, 61, and 55 nmol/L (17, 20, 24, and 22 ng/mL) in winter, spring, summer, and autumn, respectively.
The observational study was restricted to white participants.
Threshold concentrations of 25-(OH)D associated with increased risk for relevant clinical disease events center near 50 nmol/L (20 ng/mL). Season-specific targets for 25-(OH)D concentration may be more appropriate than static targets when evaluating health risk.
Primary Funding Source
National Institutes of Health.
PMCID: PMC3632351  PMID: 22547472
14.  The Risk of Infection-Related Hospitalization With Decreased Kidney Function 
Moderate kidney disease may predispose to infection. We sought to determine whether decreased kidney function, as estimated by serum cystatin C, was associated with the risk of infection-related hospitalization in older individuals.
Study Design
Cohort Study.
Setting & Participants
5,142 Cardiovascular Health Study participants with measured serum creatinine and cystatin C and without eGFR <15 ml/min/1.73 m2 at enrollment.
The primary exposure of interest was estimated glomerular filtration rate using serum cystatin C (eGFRSCysC).
Infection-related hospitalizations during a median follow-up of 11.5 years.
In adjusted analyses, eGFRSCysC categories of 60–89, 45–59, and 15–44 ml/min/1.73 m2 were associated with 16%, 37%, and 64% greater risk of all-cause infection-related hospitalization, respectively, compared with an eGFRSCysC ≥90 ml/min/1.73 m2. When cause specific infection was examined, an eGFRSCysC of 15–44 ml/min/1.73 m2 was associated with an 80% greater risk of pulmonary and 160% greater risk of genitourinary infection compared with an eGFRSCysC ≥90 ml/min/1.73 m2.
No measures of urinary protein, study limited to principal discharge diagnosis.
Lower kidney function, estimated using cystatin C, was associated with a linear and graded risk of infection-related hospitalization. These findings highlight that even moderate degrees of reduced kidney function are associated with clinically significant higher risks of serious infection in older individuals.
PMCID: PMC3288732  PMID: 21906862
renal disease; chronic kidney disease; infection; clinical epidemiology
15.  The serum 24,25-dihydroxyvitamin D concentration, a marker of vitamin D catabolism, is reduced in chronic kidney disease 
Kidney international  2012;82(6):693-700.
Chronic kidney disease is characterized, in part, as a state of decreased production of 1,25-dihydroxyvitamin D (1,25(OH)2D); however, this paradigm overlooks the role of vitamin D catabolism. We developed a mass spectrometric assay to quantify serum concentration of 24,25-dihydroxyvitamin D (24,25(OH)2D), the first metabolic product of 25-hydroxyvitamin D (25(OH)D) by CYP24A1, and determined its clinical correlates and associated outcomes among 278 participants with chronic kidney disease in the Seattle Kidney Study. For eGFRs of 60 or more, 45–59, 30–44, 15–29, and under 15 ml/min/1.73m2, the mean serum 24,25(OH)2D concentrations significantly trended lower from 3.6, 3.2, 2.6, 2.6, to 1.7 ng/ml, respectively. Non-Hispanic Black race, diabetes, albuminuria, and lower serum bicarbonate were also independently and significantly associated with lower 24,25(OH)2D concentrations. The 24,25(OH)2D concentration was more strongly correlated with that of parathyroid hormone than was 25(OH)D or 1,25(OH)2D. A 24,25(OH)2D concentration below the median was associated with increased risk of mortality in unadjusted analysis, but this was attenuated with adjustment for potential confounding variables. Thus, chronic kidney disease is a state of stagnant vitamin D metabolism characterized by decreases in both 1,25(OH)2D production and vitamin D catabolism.
PMCID: PMC3434313  PMID: 22648296
16.  Seasonal Variation in 25-Hydroxyvitamin D Concentrations in the Cardiovascular Health Study 
American Journal of Epidemiology  2011;174(12):1363-1372.
Low circulating concentrations of 25-hydroxyvitamin D (25(OH)D) are associated with adverse health outcomes in diverse populations. However, 25(OH)D concentrations vary seasonally with varying exposure to sunlight, so single measurements may poorly reflect long-term 25(OH)D exposure. The authors investigated cyclical trends in average serum 25(OH)D concentrations among 2,298 individuals enrolled in the Cardiovascular Health Study of community-based older adults (1992–1993). A sinusoidal model closely approximated observed 25(OH)D concentrations and fit the data significantly better than did a mean model (P < 0.0001). The mean annual 25(OH)D concentration was 25.1 ng/mL (95% confidence interval: 24.7, 25.5), and the mean peak-trough difference was 9.6 ng/mL (95% confidence interval: 8.5, 10.7). Male sex, higher latitude of study site, and greater physical activity levels were associated with larger peak-trough difference in 25(OH)D concentration (each P < 0.05). Serum concentrations of intact parathyroid hormone and bone-specific alkaline phosphatase also varied in a sinusoidal fashion (P < 0.0001), inversely to 25(OH)D. In conclusion, serum 25(OH)D varies in a sinusoidal manner, with large seasonal differences relative to mean concentration and laboratory evidence of biologic sequelae. Single 25(OH)D measurements might not capture overall vitamin D status, and the extent of misclassification could vary by demographic and behavioral factors. Accounting for collection time may reduce bias in research studies and improve decision-making in clinical care.
PMCID: PMC3276302  PMID: 22112344
alkaline phosphatase; parathyroid hormone; seasons; vitamin D
17.  Kidney Function Decline in the Elderly: Impact of Lipoprotein-Associated Phospholipase A2 
American Journal of Nephrology  2011;34(6):512-518.
Background: Whether lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are associated with kidney function decline has not been well studied. Methods: We investigated associations of Lp-PLA2 antigen and activity with kidney function decline and rapid decline over 5.7 years in the Cardiovascular Health Study (n = 4,359). We estimated kidney function by cystatin C (eGFRcys) in repeated measures, and defined rapid decline as ≥3 ml/min/1.73 m2 per year. We stratified by baseline preserved GFR (≥60 ml/min/1.73 m2). Results: Mean age was 72 ± 5 years. Average eGFRcys decline was −1.79 ml/min/1.73 m2 (SD = 2.60) per year. Among persons with preserved GFR, compared to the lowest quartile of Lp-PLA2 antigen, eGFRcys decline was faster among persons in the second, β −0.31 (95% CI −0.52, −0.10), third −0.19 (–0.41, 0.02) and fourth quartiles −0.26 (–0.48, −0.04) after full adjustment. Persons in the highest quartile of Lp-PLA2 antigen had increased odds of rapid decline 1.34 (1.03, 1.75), compared to the lowest. There was no significant association between levels of Lp-PLA2 activity and eGFRcys decline or rapid decline. Associations were not statistically significant among persons with low eGFR (<60 ml/min/1.73 m2) at baseline. Conclusion: Higher levels of Lp-PLA2 antigen but not activity were significantly associated with faster rates of kidney function decline. These findings may suggest a novel vascular pathway for kidney disease progression.
PMCID: PMC3225232  PMID: 22056971
Chronic kidney disease; Elderly; Estimated GFR; Kidney decline; Lipoprotein-associated phospholipase A2
18.  Vitamin D, Parathyroid Hormone and Sudden Cardiac Death: Results from the Cardiovascular Health Study 
Hypertension  2011;58(6):1021-1028.
Recent studies have demonstrated greater risks of cardiovascular events and mortality among persons who have lower 25-hydroxyvitamin D (25-OHD) and higher parathyroid hormone (PTH) levels. We sought to evaluate the association between markers of mineral metabolism and sudden cardiac death (SCD) among the 2,312 participants from the Cardiovascular Health Study who were free of clinical cardiovascular disease at baseline. We estimated associations of baseline 25-OHD and PTH concentrations individually and in combination with SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, and kidney function. During a median follow-up of 14 years, there were 73 adjudicated SCD events. The annual incidence of SCD was greater among subjects who had lower 25-OHD concentrations: 2 events per 10,000 for 25-OHD ≥ 20 ng/ml and 4 events per 10,000 for 25-OHD < 20 ng/ml. Similarly, SCD incidence was greater among subjects who had higher PTH concentrations: 2 events per 10,000 for PTH ≤ 65 pg/ml and 4 events per 10,000 for PTH > 65 pg/ml. Multivariate adjustment attenuated associations of 25-OHD and PTH with SCD. Finally, 267 participants (11.7% of the cohort) had high PTH and low 25-OHD concentrations. This combination was associated with a more than 2-fold risk of SCD after adjustment (hazard ratio 2.19, 95% confidence interval 1.17, 4.10, p=0.017) compared to participants with normal levels of PTH and 25-OHD. The combination of lower 25-OHD and higher PTH concentrations appears to be associated independently with SCD risk among older adults without cardiovascular disease.
PMCID: PMC3337033  PMID: 22068871
Sudden cardiac death; Vitamin D; Parathyroid hormone; Elderly; Risk Factors
Vitamin D deficiency and parathyroid hormone (PTH) excess are common among older adults and may adversely impact cardiovascular health. We evaluated associations of 25-hydroxyvitamin D (25-OHD) and PTH concentrations, separately, and in combination, with incident cardiovascular events and mortality during 14 years of follow-up in the Cardiovascular Health Study.
Methods and results
We studied 2,312 participants who were free of cardiovascular disease at baseline. We measured 25-OHD and intact PTH from previously frozen serum using mass spectrometry and a two-site immunoassay. Outcomes were adjudicated cases of myocardial infarction, heart failure, cardiovascular death, and all cause mortality. There were 384 participants (17%) who had serum 25-OHD concentrations <15 ng/ml and 570 (25%) who had serum PTH concentrations ≥ 65 pg/ml. After adjustment, each 10-ng/ml lower 25-OHD concentration was associated with a 9% greater (95% CI 2% to 17% greater) relative hazard of mortality and a 25% greater (95% CI 8% to 44% greater) relative hazard of myocardial infarction. Serum 25-OHD concentrations <15 ng/ml, were associated with a 29% greater (95% CI 5% to 55% greater) risk of mortality. Serum PTH concentrations ≥ 65 pg/ml were associated with a 30% greater risk of heart failure (95% CI 6% to 61% greater), but not other outcomes. There was no evidence of an interaction between serum 25-OHD and PTH concentrations and cardiovascular events.
Among older adults, 25-OHD deficiency is associated with myocardial infarction and mortality; PTH excess is associated with heart failure. Vitamin D and PTH might influence cardiovascular risk through divergent pathways.
PMCID: PMC3210558  PMID: 21939825
Vitamin D; parathyroid hormone; myocardial infarction; cardiovascular death; heart failure; mortality; mineral metabolism
20.  Association of Serum Phosphate Levels with Aortic Valve Sclerosis and Annular Calcification: the Cardiovascular Health Study 
To evaluate mineral metabolism markers as potential risk factors for calcific aortic valve disease.
Mineral metabolism disturbances are common among older people and may contribute to cardiac valvular calcification. Associations of serum mineral metabolism markers with cardiac valvular calcification have not been evaluated in a well-characterized general population of older adults.
We measured serum levels of phosphate, calcium, parathyroid hormone, and 25-hydroxyvitamin D in 1,938 Cardiovascular Health Study participants who were free of clinical cardiovascular disease and who underwent echocardiography measurements of aortic valve sclerosis (AVS), mitral annular calcification (MAC), and aortic annular calcification (AAC). We used logistic regression models to estimate associations of mineral metabolism markers with AVS, MAC, and AAC after adjustment for relevant confounding variables, including kidney function.
The respective prevalences of AVS, MAC, and AAC were 54%, 39%, and 44%. Each 0.5 mg/dl higher serum phosphate concentration was associated with a greater adjusted odds of AVS (odds ratio 1.17, 95% confidence interval 1.04 to 1.31, p = 0.01), MAC (odds ratio 1.12, 95% confidence interval 1.00 to 1.26, p =0.05), and AAC (odds ratio 1.12, 95% confidence interval 0.99 to 1.25, p = 0.05). In contrast, serum calcium, parathyroid hormone, and 25-hydroxyvitamin D concentrations were not associated with aortic or mitral calcification.
Higher serum phosphate levels within the normal range are associated with valvular and annular calcification in a community-based cohort of older adults. Phosphate may be a novel risk factor for calcific aortic valve disease and warrants further study.
PMCID: PMC3147295  PMID: 21737022
Phosphate; Aortic Valve; Mitral Valve; Calcification; Epidemiology
21.  Cystatin C and Albuminuria as Risk Factors for Development of CKD Stage 3: The Multi-Ethnic Study of Atherosclerosis (MESA) 
The growing burden and morbidity of chronic kidney disease (CKD) warrant effective strategies for identifying those at increased risk. We examined the association of cystatin C and albuminuria with development of CKD stage 3.
Study Design
Prospective observational study.
Setting and Participants
5,422 participants from the Multi-Ethnic Study of Atherosclerosis with estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73m2.
Participants were categorized into four mutually exclusive groups: presence or absence of microalbuminuria (albumin-creatinine ratio >17 and > 25 µg/mg in men and women, respectively) in those with or without cystatin C ≥ 1.0 mg/L.
Outcomes and Measurements
Incident CKD stage 3 was defined as eGFR < 60 ml/min/1.73m2 at the 3rd or 4th visit and an annual decline of > 1 ml/min/1.73 m2. Poisson regression was used to evaluate incident rate ratios in unadjusted and adjusted analyses that include baseline eGFR.
Mean age was 61 years, 49% were men, 38% white, 11% had diabetes, 13.7% had cystatin C ≥ 1mg/L, 8.4% had microalbuminuria, and 2.7 % had cystatin C ≥ 1 mg/L with microalbuminuria. 554 (10%) participants developed CKD stage 3 over a median follow-up of 4.7 years and the adjusted incidence rate ratios (95% CI) were 1.57 (1.19–2.07), 1.37 (1.13–1.66), and 2.12 (1.61–2.80) in those with microalbuminuria, cystatin C ≥ 1 mg/L, and both, respectively, compared to those with neither.
Relatively short follow up and absence of measured GFR.
Cystatin C and microalbuminuria are independent risk factors for incident CKD stage 3 and could be useful as screening tools to identify those at increased risk.
PMCID: PMC3090544  PMID: 21296473
22.  Glucose, Insulin, and Incident Hypertension in the Multi-Ethnic Study of Atherosclerosis 
American Journal of Epidemiology  2010;172(10):1144-1154.
Diabetes mellitus and hypertension commonly coexist, but the nature of this link is not well understood. The authors tested whether diabetes and higher concentrations of fasting serum glucose and insulin are associated with increased risk of developing incident hypertension in the community-based Multi-Ethnic Study of Atherosclerosis. At baseline, 3,513 participants were free of hypertension, defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or use of antihypertensive medications to treat high blood pressure. Of these, 965 participants (27%) developed incident hypertension over 4.7 years’ median follow-up between 2002 and 2007. Compared with participants with normal baseline fasting glucose, those with impaired fasting glucose and diabetes had adjusted relative risks of hypertension of 1.16 (95% confidence interval (CI): 0.96, 1.40) and 1.41 (95% CI: 1.17, 1.71), respectively (P = 0.0015). The adjusted relative risk of incident hypertension was 1.08 (95% CI: 1.04, 1.13) for each mmol/L higher glucose (P < 0.0001) and 1.15 (95% CI: 1.05, 1.25) for each doubling of insulin (P = 0.0016). Further adjustment for serum cystatin C, urinary albumin/creatinine ratio, and arterial elasticity measured by tonometry substantially reduced the magnitudes of these associations. In conclusion, diabetes and higher concentrations of glucose and insulin may contribute to the development of hypertension, in part through kidney disease and arterial stiffness.
PMCID: PMC3004765  PMID: 20961972
diabetes mellitus; glucose; hypertension; insulin; kidney; nephrology
23.  Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels 
Human Molecular Genetics  2010;19(21):4296-4303.
Serum calcium levels are tightly regulated. We performed genome-wide association studies (GWAS) in population-based studies participating in the CHARGE Consortium to uncover common genetic variations associated with total serum calcium levels. GWAS of serum calcium concentrations was performed in 20 611 individuals of European ancestry for ∼2.5 million genotyped and imputed single-nucleotide polymorphisms (SNPs). The SNP with the lowest P-value was rs17251221 (P = 2.4 * 10−22, minor allele frequency 14%) in the calcium-sensing receptor gene (CASR). This lead SNP was associated with higher serum calcium levels [0.06 mg/dl (0.015 mmol/l) per copy of the minor G allele] and accounted for 0.54% of the variance in serum calcium concentrations. The identification of variation in CASR that influences serum calcium concentration confirms the results of earlier candidate gene studies. The G allele of rs17251221 was also associated with higher serum magnesium levels (P = 1.2 * 10−3), lower serum phosphate levels (P = 2.8 * 10−7) and lower bone mineral density at the lumbar spine (P = 0.038), but not the femoral neck. No additional genomic loci contained SNPs associated at genome-wide significance (P < 5 * 10−8). These associations resemble clinical characteristics of patients with familial hypocalciuric hypercalcemia, an autosomal-dominant disease arising from rare inactivating mutations in the CASR gene. We conclude that common genetic variation in the CASR gene is associated with similar but milder features in the general population.
PMCID: PMC2951868  PMID: 20705733
24.  Alcohol consumption and kidney function decline in the elderly 
Nephrology Dialysis Transplantation  2010;25(10):3301-3307.
Background. Alcohol consumption appears to be protective for cardiovascular disease; however, its relationship with kidney disease is unclear.
Methods. This prospective cohort study included 4343 subjects from the Cardiovascular Health Study, a longitudinal, community-based cohort of persons aged ≥65 from four US communities. We used previously defined categories based on weekly alcohol consumption: none, former, <1 drink, 1–6 drinks, 7–13 drinks and ≥14 drinks. Cystatin C was measured at baseline, year 3 and year 7; eligible subjects had at least two measures. Estimated GFRcys was calculated from cystatin C. The primary outcome was rapid kidney function as an annual estimated GFR (eGFRcys) loss >3 mL/min/1.73 m2/year.
Results. Eight percent of the cohort reported former alcohol use and 52% reported current alcohol consumption. During a mean follow-up of 5.6 years, 1075 (25%) participants had rapid kidney function decline. In adjusted logistic regression models, there was no association between alcohol use and kidney function decline (odds ratio, 95% confidence interval: none = reference; former = 1.18, 0.89–1.56; <1 drink = 1.20, 0.99–1.47; 1–6 = 1.18, 0.95–1.45; 7–13 = 1.10, 0.80–1.53; >14 = 0.89, 0.61–1.13). Results were similar with kidney function decline as a continuous outcome.
Conclusions. Our results suggest that moderate alcohol consumption has neither adverse nor beneficial effects on kidney function. Although clinicians will need to consider the potential deleterious effects associated with alcohol consumption, there does not appear to be a basis for recommending that older adults discontinue or initiate light to moderate alcohol consumption to protect against kidney disease.
PMCID: PMC2948837  PMID: 20400446
alcohol; kidney disease; outcomes; progression
25.  Common genetic determinants of vitamin D insufficiency: a genome-wide association study 
Wang, Thomas J. | Zhang, Feng | Richards, J. Brent | Kestenbaum, Bryan | van Meurs, Joyce B. | Berry, Diane | Kiel, Douglas | Streeten, Elizabeth A. | Ohlsson, Claes | Koller, Daniel L. | Palotie, Leena | Cooper, Jason D. | O'Reilly, Paul F. | Houston, Denise K. | Glazer, Nicole L. | Vandenput, Liesbeth | Peacock, Munro | Shi, Julia | Rivadeneira, Fernando | McCarthy, Mark I. | Anneli, Pouta | de Boer, Ian H. | Mangino, Massimo | Kato, Bernet | Smyth, Deborah J. | Booth, Sarah L. | Jacques, Paul F. | Burke, Greg L. | Goodarzi, Mark | Cheung, Ching-Lung | Wolf, Myles | Rice, Kenneth | Goltzman, David | Hidiroglou, Nick | Ladouceur, Martin | Hui, Siu L. | Wareham, Nicholas J. | Hocking, Lynne J. | Hart, Deborah | Arden, Nigel K. | Cooper, Cyrus | Malik, Suneil | Fraser, William D. | Hartikainen, Anna-Liisa | Zhai, Guangju | Macdonald, Helen | Forouhi, Nita G. | Loos, Ruth J.F. | Reid, David M. | Hakim, Alan | Dennison, Elaine | Liu, Yongmei | Power, Chris | Stevens, Helen E. | Jaana, Laitinen | Vasan, Ramachandran S. | Soranzo, Nicole | Bojunga, Jörg | Psaty, Bruce M. | Lorentzon, Mattias | Foroud, Tatiana | Harris, Tamara B. | Hofman, Albert | Jansson, John-Olov | Cauley, Jane A. | Uitterlinden, Andre G. | Gibson, Quince | Järvelin, Marjo-Riitta | Karasik, David | Siscovick, David S. | Econs, Michael J. | Kritchevsky, Stephen B. | Florez, Jose C. | Todd, John A. | Dupuis, Josee | Hypponen, Elina | Spector, Timothy D.
Lancet  2010;376(9736):180-188.
Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D insufficiency has been linked to a number of extraskeletal disorders, including diabetes, cancer, and cardiovascular disease. Determinants of circulating 25-hydroxyvitamin D (25-OH D) include sun exposure and dietary intake, but its high heritability suggests that genetic determinants may also play a role.
We performed a genome-wide association study of 25-OH D among ∼30,000 individuals of European descent from 15 cohorts. Five cohorts were designated as discovery cohorts (n=16,125), five as in silico replication cohorts (n=9,366), and five as de novo replication cohorts (n=8,378). Association results were combined using z-score-weighted meta-analysis. Vitamin D insufficiency was defined as 25-OH D <75 nmol/L or <50 nmol/L.
Variants at three loci reached genome-wide significance in the discovery cohorts, and were confirmed in the replication cohorts: 4p12 (overall P=1.9 × 10-109 for rs2282679, in GC); 11q12 (P=2.1 × 10-27 for rs12785878, near DHCR7); 11p15 (P=3.3 × 10-20 for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (P=6.0 × 10-10 for rs6013897). A genotype score was constructed using the three confirmed variants. Those in the top quartile of genotype scores had 2- to 2.5-fold elevated odds of vitamin D insufficiency (P≤1 × 10-26).
Variants near genes involved in cholesterol synthesis (DHCR7), hydroxylation (CYP2R1, CYP24A1), and vitamin D transport (GC) influence vitamin D status. Genetic variation at these loci identifies individuals of European descent who have substantially elevated risk of vitamin D insufficiency.
PMCID: PMC3086761  PMID: 20541252

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