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Vitamin D deficiency has been associated with a number of diseases, including influenza. Whether or not this reflects a causal relationship is unknown. We therefore wanted to examine if supplementation with vitamin D would affect the incidence and severity of influenza-like disease.
Questionnaires on influenza were sent to subjects participating in ongoing placebo-controlled intervention studies with vitamin D supplementation, up until the end of April 2010.
Five hundred and sixty-nine subjects from 10 different clinical trials were included in the study, of whom 289 were randomized to receive vitamin D (1111–6800 IU/day) and 280 to receive placebo. Influenza-like disease during the previous fall/winter was reported in 38 subjects in the vitamin D group and 42 in the placebo group (non-significant), of whom 25 and 26 subjects, respectively, fulfilled our clinical criteria for influenza. In these latter subjects, the duration of illness was significantly longer among those in the vitamin D group than among those in the placebo group (median 7 (range 2–60) days vs median 4 (range 2–18) days; p = 0.007). However, this difference was not statistically significant if all 38 (vitamin D) and 42 (placebo) subjects who reported symptoms were included.
Our results do not support the hypothesis that high doses of vitamin D supplementation will have a pronounced effect on influenza-like disease in populations not targeted for high influenza risk.
PMCID: PMC3917712  PMID: 22026455
H1N1; influenza; randomized clinical trial; vitamin D
2.  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
3.  Apolipoprotein E and kidney function in older adults 
Clinical nephrology  2012;78(3):174-180.
Previous studies suggest that the ε4 and ε2 alleles of apolipoprotein E (APOE) may be associated with decreased and increased risks of CKD, respectively, but there are limited data in older adults. We evaluated the associations of apolipoprotein E alleles with kidney function among older adults in the cardiovascular health study (CHS).
Caucasian participants had APOE allelic analysis and serum creatinine and cystatin C measured at baseline (n = 3,844 for cross sectional analysis) and in follow up (n = 3,226 for longitudinal analysis). APOE variation was evaluated as an additive model with number of ε2, ε3 and ε4 alleles. GFR was estimated using the CKD epidemiology equation (eGFRcreat) and the cystatin C demographic equation (eGFRcys). The primary outcome was CKD defined by eGFR < 60 ml/min/1.73 m2. The secondary outcome was rapid progression defined by annual loss of eGFR > 3 ml/min/1.73 m2.
Mean eGFRcreat was 72 ml/min/1.73 m2 (25% CKD). Compared with the ε3 allele, the APOE ε4 allele was associated with reduced risk of CKD by eGFRcreat: unadjusted odds ratio (OR) and 95% confidence interval (CI) 0.79 (0.67 – 0.93) per allele, fully adjusted OR (95% CI) 0.80 (0.68 – 0.96) per allele. Results were consistent using eGFRcys. There was no association of the ε2 allele with CKD or between the apolipoprotein E gene with rapid progression.
The apolipoprotein ε4 allele was associated with lower odds of CKD in elderly Caucasian individuals. Future research should confirm these findings in other races and explore mechanisms to explain these results.
PMCID: PMC3874583  PMID: 22874105
apolipoprotein E; chronic kidney disease; kidney function; elderly
4.  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
5.  Characterizing and harnessing antibody cross-reactivity for the immunoaffinity purification of analytes prior to multiplexed liquid chromatography-tandem mass spectrometry 
Clinical chemistry  2012;58(12):1711-1716.
Immunoassays for 1α,25-dihydroxyvitamin D [1α,25(OH)2D] lack specificity. We aimed to characterize the cross-reactivity of an anti-1α,25(OH)2D antibody using purified vitamin D metabolites and to use these data to map the chemical features of 1α,25(OH)2D that are important for antibody binding. Additionally, we hypothesized that when combined with isotope dilution-liquid chromatography-tandem mass spectrometry (LC-MS/MS), antibody cross-reactivity could be used to semi-selectively enrich for structurally similar metabolites of vitamin D in a multiplexed assay.
Sample preparation consisted of immunoaffinity enrichment with a solid-phase anti-1α,25(OH)2D antibody and derivatization. Analytes were quantified using LC-MS/MS. Spike-recovery studies were performed using eleven vitamin D metabolites. A novel method for quantifying 25(OH)D2, 25(OH)D3, 24,25(OH)2D3, 1α,25(OH)2D2 and 1α,25(OH)2D3 simultaneously was developed and evaluated, which included deuterated internal standards for each analyte.
The important chemical features of vitamin D metabolites for binding to the antibody were (1) native orientation of the hydroxyl group on carbon C3 in the A-ring, (2) the lack of substitution at carbon C4 in the A-ring, and (3) the overall polarity of the vitamin D metabolite. The new multiplexed method had lower limits of quantification (20% CV) of 0.2 ng/mL, 1.0 ng/mL, 0.06 ng/mL, 3.4 pg/mL and 2.8 pg/mL for 25(OH)D2, 25(OH)D3, 24,25(OH)2D3, 1α,25(OH)2D2 and 1α,25(OH)2D3, respectively. Method comparisons to three other LC-MS/MS methods were acceptable (r2>0.9, intercept
LC-MS/MS can be used to characterize antibody cross-reactivity. We developed and evaluated a multiplexed assay for five vitamin D metabolites using immunoenrichment in a targeted metabolomic assay.
PMCID: PMC3731945  PMID: 22968104
Liquid chromatography-tandem mass spectrometry; immunoaffinity enrichment; multiplexed assay; specificity; hapten mapping; vitamin D metabolism
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
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
Diabetes is the leading cause of kidney disease in the developed world. Over time, the prevalence of diabetic kidney disease (DKD) may increase due to the expanding size of the diabetes population or decrease due to the implementation of diabetes therapies.
To define temporal changes in DKD prevalence in the United States.
Design, Setting, and Participants
Cross-sectional analyses of the Third National Health and Nutrition Examination Survey (NHANES III) from 1988–1994 (N = 15 073), NHANES 1999–2004 (N = 13 045), and NHANES 2005–2008 (N=9588). Participants with diabetes were defined by levels of hemoglobin A1c of 6.5% or greater, use of glucose-lowering medications, or both (n = 1431 in NHANES III; n = 1443 in NHANES 1999–2004; n = 1280 in NHANES 2005–2008).
Main Outcome Measures
Diabetic kidney disease was defined as diabetes with albuminuria (ratio of urine albumin to creatinine >30 mg/g), impaired glomerular filtration rate (<60 mL/min/1.73 m2 estimated using the Chronic Kidney Disease Epidemiology Collaboration formula), or both. Prevalence of albuminuria was adjusted to estimate persistent albuminuria.
The prevalence of DKD in the US population was 2.2% (95% confidence interval [CI], 1.8%–2.6%) in NHANES III, 2.8% (95% CI, 2.4%–3.1%) in NHANES 1999–2004, and 3.3% (95% CI, 2.8%–3.7%) in NHANES 2005–2008 (P<.001 for trend). The prevalence of DKD increased in direct proportion to the prevalence of diabetes, without a change in the prevalence of DKD among those with diabetes. Among persons with diabetes, use of glucose-lowering medications increased from 56.2% (95% CI, 52.1%–60.4%) in NHANES III to 74.2% (95% CI, 70.4%–78.0%) in NHANES 2005–2008 (P<.001); use of renin-angiotensin-aldosterone system inhibitors increased from 11.2% (95% CI, 9.0%–13.4%) to 40.6% (95% CI, 37.2%–43.9%), respectively (P<.001); the prevalence of impaired glomerular filtration rate increased from 14.9% (95% CI, 12.1%–17.8%) to 17.7% (95% CI, 15.2%–20.2%), respectively (P=.03); and the prevalence of albuminuria decreased from 27.3% (95% CI, 22.0%–32.7%) to 23.7% (95% CI, 19.3%–28.0%), respectively, but this was not statistically significant (P=.07).
Prevalence of DKD in the United States increased from 1988 to 2008 in proportion to the prevalence of diabetes. Among persons with diabetes, prevalence of DKD was stable despite increased use of glucose-lowering medications and renin-angiotensin-aldosterone system inhibitors.
PMCID: PMC3731378  PMID: 21693741
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
Purpose of review
Insulin resistance is a known complication of end-stage renal disease that also appears to be present in earlier stages of chronic kidney disease (CKD). It is a risk factor for cardiovascular disease and an important potential therapeutic target in this population. Measurement of insulin resistance is reviewed in the context of known pathophysiologic abnormalities in CKD.
Recent findings
Insulin resistance in CKD is due to a high prevalence of known risk factors (e.g. obesity) and to unique metabolic abnormalities. The site of insulin resistance in CKD is localized to skeletal muscle. Estimates based on fasting insulin concentration may not adequately capture insulin resistance in CKD because they largely reflect hepatic defects and because CKD impairs insulin catabolism. A variety of dynamic tests are available to directly measure insulin-mediated glucose uptake.
Insulin resistance may be an important therapeutic target in CKD. Complementary methods are available to assess insulin resistance, and each method has unique advantages, disadvantages, and levels of complexity. These characteristics, and the likelihood that CKD alters the performance of some insulin resistance measurements, must be considered when designing and interpreting clinical studies.
PMCID: PMC3712903  PMID: 21885970
chronic kidney disease; insulin resistance
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
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
Cohort study.
1621 white older adults.
The observational study was restricted to white participants.
Primary Funding Source
National Institutes of Health.
PMCID: PMC3632351  PMID: 22547472
PMCID: PMC3563259  PMID: 22402937
Peripheral artery disease; Diabetes; Insulin Resistance; Epidemiology
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
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
Background and purpose
PMCID: PMC3226936  PMID: 21998054
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
PMCID: PMC3243937  PMID: 21920948
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
Nephrology Dialysis Transplantation  2010;26(6):1903-1908.
Background. Pentraxin-3 (PTX3), an inflammatory marker thought to be related to vascular inflammation, is elevated in advanced chronic kidney disease (CKD). Whether PTX3 is associated with mild to moderate kidney dysfunction is unknown.
Methods. We tested associations of proteins in the pentraxin family [PTX3, C-reactive protein (CRP) and serum amyloid protein (SAP)] with estimated glomerular filtration rate by cystatin C (eGFRcys) and microalbuminuria among 2824 participants in the Multi-Ethnic Study of Atherosclerosis. Associations were tested using multivariable linear regression with adjustment for demographics (age, gender, annual income), comorbidities (diabetes, hypertension, smoking, body mass index, low-density lipoprotein, high-density lipoprotein, triglycerides, ACE inhibitor and statin use) and systemic inflammation [interleukin-6 (IL-6)].
Results. Among the 2824 participants, mean age was 62 years and mean eGFRcys was 94 mL/min/1.73 m2; 25% were white, 25% Chinese, 25% African-American and 25% Hispanic. Among all participants after full adjustment, higher PTX3 was associated with lower eGFRcys independently of IL-6 (β − 3.0 mL/min/1.73 m2 per unit increase in lnPTX3, P < 0.001). In contrast, CRP and SAP were associated with eGFRcys in demographic adjusted models, but these associations were attenuated after adjustment for comorbidities and IL-6 (lnCRP β − 0.06, P = 0.9; lnSAP β − 0.35, P = 0.7). There was a significant interaction with race/ethnicity (P < 0.001) in the association of PTX3 and eGFRcys. After adjustment for demographics, comorbidities and IL-6, this association was significant in blacks (β − 5.7 mL/min/1.73 m2 per unit increase in lnPTX3, P = 0.002) but not in Hispanics (β − 2.4, P = 0.1), Chinese (β − 0.91, P = 0.5) or whites (β − 0.26, P = 0.9). PTX3 and CRP, but not SAP, had correlations with microalbuminuria in unadjusted models (Spearman coefficients PTX3 0.05, P = 0.005; CRP 0.07, P < 0.001; SAP 0.013, P = 0.5), but these were attenuated after full adjustment.
Conclusions. Endovascular inflammation may be an important mechanism associated with early kidney dysfunction, particularly among blacks. This mechanism appears to be independent of IL-6-regulated pathways.
PMCID: PMC3145399  PMID: 21079193
C-reactive protein; estimated glomerular filtration rate by cystatin; pentraxin-3; race/ethnicity; serum amyloid protein
Archives of internal medicine  2011;171(5):412-420.
Microalbuminuria is a common diagnosis in the clinical care of patients with type 1 diabetes. Long-term outcomes after the development of microalbuminuria are variable.
We quantified the incidence of and risk factors for long-term renal outcomes after the development of microalbuminuria in the DCCT/EDIC Study. The DCCT randomly assigned 1441 persons with type 1 diabetes to intensive or conventional diabetes therapy, and participants were subsequently followed during the observational EDIC Study. During DCCT/EDIC, 325 participants developed incident persistent microalbuminuria (albumin excretion rate [AER] ≥ 30 mg/24hr on two consecutive study visits). We assessed their subsequent renal outcomes, including progression to macroalbuminuria (AER ≥ 300 mg/24hr x2), impaired glomerular filtration rate (estimated GFR < 60 mL/min/1.73m2 x2), and end stage renal disease (ESRD), and regression to normoalbuminuria (AER < 30 mg/24hr x2).
Median follow-up after persistent microalbuminuria diagnosis was 13 years (maximum 23 years). 10-year cumulative incidences of progression to macroalbuminuria, impaired GFR, and ESRD and regression to normoalbuminuria were 28%, 15%, 3%, and 40%, respectively. Albuminuria outcomes were more favorable with intensive diabetes therapy, lower hemoglobin A1c, lack of retinopathy, female gender, lower blood pressure, and lower concentrations of LDL cholesterol and triglyceride. Lower hemoglobin A1c, lack of retinopathy, and lower blood pressure were also associated with decreased risk of impaired GFR.
After the development of persistent microalbuminuria, progression and regression of kidney disease each occur commonly. Intensive glycemic control, lower blood pressure, and a more favorable lipid profile are associated with improved outcomes.
PMCID: PMC3085024  PMID: 21403038
PMCID: PMC3025638  PMID: 21123850
aging; body composition; body size; coronary disease; stroke
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
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

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