Michal L. Melamed

25-Hydroxyvitamin D Levels and the Risk of Mortality in the General Population

BACKGROUND In patients undergoing dialysis, therapy with calcitriol or paricalcitol or other vitamin D agents is associated with reduced mortality. Observational data suggests that low 25-hydroxyvitamin D levels (25[OH]D) are associated with diabetes mellitus, hypertension, and cancers. However, whether low serum 25(OH)D levels are associated with mortality in the general population is unknown. METHODS We tested the association of low 25(OH)D levels with all-cause, cancer, and cardiovascular disease (CVD) mortality in 13 331 nationally representative adults 20 years or older from the Third National Health and Nutrition Examination Survey (NHANES III) linked mortality files. Participant vitamin D levels were collected from 1988 through 1994, and individuals were passively followed for mortality through 2000. RESULTS In cross-sectional multivariate analyses, increasing age, female sex, nonwhite race/ethnicity, diabetes, current smoking, and higher body mass index were all independently associated with higher odds of 25(OH)D deficiency (lowest quartile of 25(OH)D level, <17.8 ng/mL [to convert to nanomoles per liter, multiply by 2.496]), while greater physical activity, vitamin D supplementation, and nonwinter season were inversely associated. During a median 8.7 years of follow-up, there were 1806 deaths, including 777 from CVD. In multivariate models (adjusted for baseline demographics, season, and traditional and novel CVD risk factors), compared with the highest quartile, being in the lowest quartile (25[OH]D levels <17.8 ng/mL) was associated with a 26% increased rate of all-cause mortality (mortality rate ratio, 1.26; 95% CI, 1.08-1.46) and a population attributable risk of 3.1%. The adjusted models of CVD and cancer mortality revealed a higher risk, which was not statistically significant. CONCLUSION The lowest quartile of 25(OH)D level (<17.8 ng/mL) is independently associated with all-cause mortality in the general population.

Prevalence and Associations of 25-Hydroxyvitamin D Deficiency in US Children: NHANES 2001–2004

OBJECTIVES: To determine the prevalence of 25-hydroxyvitamin D (25[OH]D) deficiency and associations between 25(OH)D deficiency and cardiovascular risk factors in children and adolescents. METHODS: With a nationally representative sample of children aged 1 to 21 years in the National Health and Nutrition Examination Survey 2001–2004 (n = 6275), we measured serum 25(OH)D deficiency and insufficiency (25[OH]D <15 ng/mL and 15–29 ng/mL, respectively) and cardiovascular risk factors. RESULTS: Overall, 9% of the pediatric population, representing 7.6 million US children and adolescents, were 25(OH)D deficient and 61%, representing 50.8 million US children and adolescents, were 25(OH)D insufficient. Only 4% had taken 400 IU of vitamin D per day for the past 30 days. After multivariable adjustment, those who were older (odds ratio [OR]: 1.16 [95% confidence interval (CI): 1.12 to 1.20] per year of age), girls (OR: 1.9 [1.6 to 2.4]), non-Hispanic black (OR: 21.9 [13.4 to 35.7]) or Mexican-American (OR: 3.5 [1.9 to 6.4]) compared with non-Hispanic white, obese (OR: 1.9 [1.5 to 2.5]), and those who drank milk less than once a week (OR: 2.9 [2.1 to 3.9]) or used >4 hours of television, video, or computers per day (OR: 1.6 [1.1 to 2.3]) were more likely to be 25(OH)D deficient. Those who used vitamin D supplementation were less likely (OR: 0.4 [0.2 to 0.8]) to be 25(OH)D deficient. Also, after multivariable adjustment, 25(OH)D deficiency was associated with elevated parathyroid hormone levels (OR: 3.6; [1.8 to 7.1]), higher systolic blood pressure (OR: 2.24 mmHg [0.98 to 3.50 mmHg]), and lower serum calcium (OR: −0.10 mg/dL [−0.15 to −0.04 mg/dL]) and high-density lipoprotein cholesterol (OR: −3.03 mg/dL [−5.02 to −1.04]) levels compared with those with 25(OH)D levels ≥30 ng/mL. CONCLUSIONS: 25(OH)D deficiency is common in the general US pediatric population and is associated with adverse cardiovascular risks.

Serum 25-Hydroxyvitamin D Levels and the Prevalence of Peripheral Arterial Disease Results from NHANES 2001 to 2004

Objective—The purpose of this study was to determine the association between 25-hydroxyvitamin D (25(OH)D) levels and the prevalence of peripheral arterial disease (PAD) in the general United States population. Methods and Results—We analyzed data from 4839 participants of the National Health and Nutrition Examination Survey 2001 to 2004 to evaluate the relationship between 25(OH)D and PAD (defined as an ankle-brachial index <0.9). Across quartiles of 25(OH)D, from lowest to highest, the prevalence of PAD was 8.1%, 5.4%, 4.9%, and 3.7% (P trend <0.001). After multivariable adjustment for demographics, comorbidities, physical activity level, and laboratory measures, the prevalence ratio of PAD for the lowest, compared to the highest, 25(OH)D quartile (<17.8 and ≥29.2 ng/mL, respectively) was 1.80 (95% confidence interval: 1.19, 2.74). For each 10 ng/mL lower 25(OH)D level, the multivariable-adjusted prevalence ratio of PAD was 1.35 (95% confidence interval: 1.15, 1.59). Conclusions—Low serum 25(OH)D levels are associated with a higher prevalence of PAD. Several mechanisms have been invoked in the literature to support a potential antiatherosclerotic activity of vitamin D. Prospective cohort and mechanistic studies should be designed to confirm this association.

Vitamin D and cardiovascular disease risk

Purpose of reviewDespite our understanding of how to prevent and treat traditional cardiovascular risk factors, cardiovascular disease remains the leading cause of death of both men and women in the US. Thus, there is widespread interest in a number of emerging nontraditional risk factors for the detection of early cardiovascular disease in order to implement aggressive preventive therapies. 25-Hydroxyvitamin D deficiency has been identified as a potential novel cardiovascular disease risk factor. This review outlines what is known about the association of 25-hydroxyvitamin D levels and cardiovascular disease risk. Recent findingsLow 25-hydroxyvitamin D levels have been associated with the cardiovascular disease risk factors of hypertension, obesity, diabetes mellitus and the metabolic syndrome, as well as cardiovascular disease events including stroke and congestive heart failure. Studies suggest vitamin D deficiency may be a contributor to the development of cardiovascular disease potentially through associations with diabetes or hypertension. SummaryVitamin D deficiency is easy to screen for and easy to treat with supplementation. Further larger observational studies and randomized clinical trials are, however, needed to determine whether vitamin D supplementation could have any potential benefit in reducing future cardiovascular disease events and mortality risk.

Impact of Activated Vitamin D and Race on Survival among Hemodialysis Patients

Contrary to most examples of disparities in health outcomes, black patients have improved survival compared with white patients after initiating hemodialysis. Understanding potential explanations for this observation may have important clinical implications for minorities in general. This study tested the hypothesis that greater use of activated vitamin D therapy accounts for the survival advantage observed in black and Hispanic patients on hemodialysis. In a prospective cohort of non-Hispanic white (n = 5110), Hispanic white (n = 979), and black (n = 3214) incident hemodialysis patients, higher parathyroid hormone levels at baseline were the primary determinant of prescribing activated vitamin D therapy. Median parathyroid hormone was highest among black patients, who were most likely to receive activated vitamin D and at the highest dosage. One-year mortality was lower in black and Hispanic patients compared with white patients (16 and 16 versus 23%; P < 0.01), but there was significant interaction between race and ethnicity, activated vitamin D therapy, and survival. In multivariable analyses of patients treated with activated vitamin D, black patients had 16% lower mortality compared with white patients, but the difference was lost when adjusted for vitamin D dosage. In contrast, untreated black patients had 35% higher mortality compared with untreated white patients, an association that persisted in several sensitivity analyses. In conclusion, therapy with activated vitamin D may be one potential explanation for the racial differences in survival among hemodialysis patients. Further studies should determine whether treatment differences based on biologic differences contribute to disparities in other conditions.

Relation Between Alkaline Phosphatase, Serum Phosphate, and All-Cause or Cardiovascular Mortality

Background— Higher levels of serum alkaline phosphatase (AlkP) are associated with excess mortality in dialysis patients, but whether AlkP is associated with adverse outcomes among people without kidney failure is unknown. Methods and Results— We first analyzed the association between AlkP and cardiovascular outcomes among 4115 participants with a previous myocardial infarction (the Cholesterol And Recurrent Events [CARE] study). Results were validated by analyzing the association between AlkP and mortality in an independent sample of 14 716 adults from the general US population (the Third National Health and Nutrition Examination Survey). A graded, independent association was noted between baseline tertile of AlkP and the adjusted hazard ratio of all-cause mortality in CARE participants (Ptrend=0.02). After adjustment for serum phosphate, hepatic enzymes, and other potential confounders, participants with AlkP in the highest tertile had an adjusted hazard ratio of 1.43 (95% confidence interval 1.08 to 1.89) compared with those in the lowest tertile. Multivariable-adjusted associations between higher AlkP and all-cause and cardiovascular mortality were present in the Third National Health and Nutrition Examination Survey (Ptrend across tertiles of AlkP=0.006 and 0.038, respectively). Findings from both CARE and the Third National Health and Nutrition Examination Survey were similar among individuals with and without evidence of kidney disease, defined by estimated glomerular filtration rate <60 mL · min−1 · 1.73 m−2. Conclusions— We found an independent relation between higher levels of AlkP and adverse outcomes among survivors of myocardial infarction and in a general population sample. The excess risk of death was present in people without evidence of kidney disease and was particularly high among people with higher levels of both AlkP and serum phosphate.

25-Hydroxyvitamin D Levels, Race, and the Progression of Kidney Disease

Black individuals have lower 25-hydroxyvitamin D [25(OH)D] levels and experience a disproportionate burden of ESRD compared with white individuals. Animal studies suggest that vitamin D has renoprotective effects. We evaluated the contribution of low 25(OH)D levels on incidence of ESRD using data from the Third National Health and Nutrition Examination Survey-linked Medicare claims files (n = 13,328). We included baseline (1988 through 1994) measurements of 25(OH)D and assessed the incidence of ESRD through July 31, 2001. Overall, 34% of non-Hispanic black individuals had 25(OH)D levels <15 ng/ml compared with 5% of non-Hispanic white individuals (P < 0.001). During a median of 9.1 yr, 65 participants developed ESRD. After adjustment for demographic, socioeconomic, and clinical and laboratory factors (including diabetes, hypertension, estimated GFR, and albuminuria), participants with 25(OH)D levels <15 ng/ml had a 2.6-fold greater incidence of ESRD than those with levels > or =15 ng/ml (incidence rate ratio 2.64; 95% confidence interval [CI] 1.00 to 7.05; P = 0.05). After adjustment for clinical covariates but not 25(OH)D levels, non-Hispanic black individuals had a 2.83-fold (95% CI 1.03 to 7.77) higher risk for developing ESRD compared with non-Hispanic white individuals. Additional adjustment for 25(OH)D levels reduced the risk by 58% (incidence rate ratio 1.77; 95% CI 0.38 to 8.21). In summary, low 25(OH)D levels associate with development of ESRD even after adjustment for multiple risk factors. Low 25(OH)D levels may account for a substantial proportion of the increased risk for ESRD experienced by black individuals.

Moderate Chronic Kidney Disease and Cognitive Function in Adults 20 to 59 Years of Age: Third National Health and Nutrition Examination Survey (NHANES III)

Previous studies among elderly suggest an association between chronic kidney disease (CKD) and cognitive impairment. The purpose of this study was to determine whether moderate CKD is associated with cognitive performance among young, healthy, ethnically diverse adults. Three computerized cognitive function tests of visual-motor reaction time (Simple Reaction Time), visual attention (Symbol Digit Substitution), and learning/concentration (Serial Digit Learning) were administered to a random sample of participants, aged 20 to 59 yr, who completed initial interviews and medical examination in the Third National Health and Nutrition Examination Survey (NHANES III). Participants for this study (n = 4849) completed at least one cognitive function test. GFR was estimated using the Modification of Diet in Renal Disease (MDRD) equation. Moderate CKD was defined as estimated GFR (eGFR) 30 to 59 ml/min per 1.73 m(2). Unadjusted, residual-adjusted, and multivariate-adjusted logistic regression models were used. The cohort was 49.0% male and 11.6% black, and median (interquartile range) age was 36 yr (27 to 45) and eGFR was 107.9 ml/min per 1.73 m(2) (95.0 to 125.4). There were 31 (0.8%) prevalent cases of moderate CKD. Models were adjusted for residual effects of age, gender, race, diabetes, and other known potential confounders. In multivariate models, moderate CKD was not significantly associated with reaction time but was significantly associated with poorer learning/concentration (odds ratio 2.41; 95% confidence interval 1.30 to 5.63) and impairment in visual attention (odds ratio 2.74; 95% confidence interval 1.01 to 7.40). In summary, among those in a large nationally representative sample of healthy, ethnically diverse 20- to 59-yr-old adults, moderate CKD, reflected by eGFR 30 to 59 ml/min per 1.73 m(2), was significantly associated with poorer performance in visual attention and learning/concentration.

Predictors of serum 25-hydroxyvitamin D concentrations among postmenopausal women: the Women's Health Initiative Calcium plus Vitamin D Clinical Trial

BACKGROUND It is unclear how well surrogate markers for vitamin D exposure (eg, oral intake of vitamin D and estimates of sunlight exposure), with and without consideration of other potential predictors of 25-hydroxyvitamin D [25(OH)D] concentrations, similarly rank individuals with respect to 25(OH)D blood concentrations. OBJECTIVE The objective was to determine how much variation in serum 25(OH)D concentrations (nmol/L) could be explained by a predictive model with the use of different vitamin D surrogate markers (latitude of residence, mean annual regional solar irradiance estimates, and oral sources) and other individual characteristics that might influence vitamin D status. DESIGN A random sample of 3055 postmenopausal women (aged 50-70 y) participating in 3 nested case-control studies of the Womens Health Initiative Calcium plus Vitamin D Clinical Trial was used. Serum 25(OH)D values, assessed at year 1 (1995-2000), and potential predictors of 25(OH)D concentrations, assessed at year 1 or Womens Health Initiative baseline (1993-1998), were used. RESULTS More than half of the women (57.1%) had deficient (<50 nmol/L) concentrations of 25(OH)D. Distributions of 25(OH)D concentrations by level of latitude of residence, mean annual regional solar irradiance, and intake of vitamin D varied considerably. The predictive model for 25(OH)D explained 21% of the variation in 25(OH)D concentrations. After adjustment for month of blood draw, breast cancer status, colorectal cancer status, fracture status, participation in the hormone therapy trial, and randomization to the dietary modification trial, the predictive model included total vitamin D intake from foods and supplements, waist circumference, recreational physical activity, race-ethnicity, regional solar irradiance, and age. CONCLUSIONS Surrogate markers for 25(OH)D concentrations, although somewhat correlated, do not adequately reflect serum vitamin D measures. These markers and predictive models of blood 25(OH)D concentrations should not be given as much weight in epidemiologic studies of cancer risk.

Staging of Chronic Kidney Disease: Time for a Course Correction

Awareness of chronic kidney disease (CKD) has increased in part because of the definitions and treatment guidelines set out by Kidney Disease Outcomes Quality Initiative (KDOQI); however, the staging system set forth by these guidelines has led to several problems and unforeseen consequences. Stages 1 and 2 CKD are difficult to determine using the standard Modification of Diet in Renal Disease (MDRD) estimation of GFR, and their clinical significance in the absence of other risk factors is unclear. Just because microalbuminuria in people without diabetes is a cardiovascular risk factor does not make it kidney disease. Most patients who receive a diagnosis of stage 3 CKD (GFR between 30 and 59 ml/min) are elderly people, and the vast majority of these patients will die before they reach ESRD. The staging system needs to be modified to reflect the severity and complications of CKD. It is suggested that stages 1 and 2 be eliminated and stages 3, 4, and 5, be simply termed moderate impairment, severe impairment, and kidney failure, respectively. In addition, age should be a modifying factor, especially in moderate kidney impairment. These changes would allow identification and treatment of clinically relevant disease and avoidance of what can seem exaggerated prevalence estimates.