Elizabeth Ankers

Vitamin D–binding protein modifies the vitamin D–bone mineral density relationship

Studies examining the relationship between total circulating 25‐hydroxyvitamin D [25(OH)D] levels and bone mineral density (BMD) have yielded mixed results. Vitamin D–binding protein (DBP), the major carrier protein for 25(OH)D, may alter the biologic activity of circulating vitamin D. We hypothesized that free and bioavailable 25(OH)D, calculated from total 25(OH)D, DBP, and serum albumin levels, would be more strongly associated with BMD than levels of total 25(OH)D. We measured total 25(OH)D, DBP, and serum albumin levels in 49 healthy young adults enrolled in the Metabolic Abnormalities in College‐Aged Students (MACS) study. Lumbar spine BMD was measured in all subjects using dual‐energy X‐ray absorptiometry. Clinical, diet, and laboratory information also was gathered at this time. We determined free and bioavailable (free + albumin‐bound) 25(OH)D using previously validated formulas and examined their associations with BMD. BMD was not associated with total 25(OH)D levels (r = 0.172, p = .236). In contrast, free and bioavailable 25(OH)D levels were positively correlated with BMD (r = 0.413, p = .003 for free, r = 0.441, p = .002 for bioavailable). Bioavailable 25(OH)D levels remained independently associated with BMD in multivariate regression models adjusting for age, sex, body mass index, and race (p = .03). It is concluded that free and bioavailable 25(OH)D are more strongly correlated with BMD than total 25(OH)D. These findings have important implications for vitamin D supplementation in vitamin D–deficient states. Future studies should continue to explore the relationship between free and bioavailable 25(OH)D and health outcomes.

Bioavailable Vitamin D Is More Tightly Linked to Mineral Metabolism than Total Vitamin D in Incident Hemodialysis Patients

Prior studies showed conflicting results regarding the association between 25-hydroxyvitamin D (25(OH)D) levels and mineral metabolism in end-stage renal disease. In order to determine whether the bioavailable vitamin D (that fraction not bound to vitamin D binding protein) associates more strongly with measures of mineral metabolism than total levels, we identified 94 patients with previously measured 25(OH)D and 1,25-dihydroxyvitamin D (1,25(OH)2D) from a cohort of incident hemodialysis patients. Vitamin D binding protein was measured from stored serum samples. Bioavailable 25(OH)D and 1,25(OH)2D were determined using previously validated formulae. Associations with demographic factors and measures of mineral metabolism were examined. When compared with whites, black patients had lower levels of total, but not bioavailable, 25(OH)D. Bioavailable, but not total, 25(OH)D and 1,25(OH)2D were each significantly correlated with serum calcium. In univariate and multivariate regression analysis, only bioavailable 25(OH)D was significantly associated with parathyroid hormone levels. Hence, bioavailable vitamin D levels are better correlated with measures of mineral metabolism than total levels in patients on hemodialysis.

Genetic Variation in APOL1 Associates with Younger Age at Hemodialysis Initiation

African Americans have a markedly higher incidence of ESRD compared with other racial groups. Two variants in the APOL1 gene, to date observed only among individuals of recent African ancestry, associate with increased risk for renal disease among African Americans. Here, we investigated whether these risk alleles also associate with age at initiation of chronic hemodialysis. We performed a cross-sectional study of 407 nondiabetic African Americans with ESRD who participated in the Accelerated Mortality on Renal Replacement (ArMORR) study, a prospective cohort of incident chronic hemodialysis patients. African Americans carrying two copies of the G1 risk allele initiated chronic hemodialysis at a mean age of 49.0 ± 14.9 years, which was significantly younger than both subjects with one copy of the G1 allele (55.9 ± 16.7 years; P = 0.014) and subjects without either risk allele (61.8 ± 17.1 years; P = 6.2 × 10(-7)). The association between the presence of the G1 allele and age at initiation of hemodialysis remained statistically significant after adjusting for sociodemographic and other potential confounders. We did not detect an association between the G2 risk allele and age at initiation of hemodialysis, but the sample size was limited. In conclusion, genetic variations in APOL1 identify African Americans that initiate chronic hemodialysis at a younger age. Early interventions to prevent progression of kidney disease may benefit this high-risk population.

Shorter dialysis times are associated with higher mortality among incident hemodialysis patients.

There is an association between hemodialysis session length and mortality independent of the effects of session duration on urea clearance. However, previous studies did not consider changes in session length over time nor did they control for the influence of time-dependent confounding. Using data from a national cohort of 8552 incident patients on thrice-weekly, in-center hemodialysis, we applied marginal structural analysis to determine the association between session length and mortality. Exposure was based on prescribed session length with the outcome being death from any cause. On the 31st day after initiating dialysis, the patients were considered at-risk and remained so until death, censoring, or completion of 1 year on dialysis. On primary marginal structural analysis, session lengths <4 h were associated with a 42% increase in mortality. Sensitivity analyses showed a dose-response relationship between session duration and mortality, and a consistency of findings across prespecified subgroups. Our study suggests that shorter hemodialysis sessions are associated with higher mortality when marginal structural analysis was used to adjust for time-dependent confounding. Further studies are needed to confirm these findings and determine causality.

Association Between Long-term Blood Pressure Variability and Mortality Among Incident Hemodialysis Patients

BACKGROUND Blood pressure variability (BPV) is one putative risk factor for cardiovascular disease and mortality in hemodialysis patients. The purposes of this study are to identify a suitable metric of long-term BPV in this population and determine whether an association between BPV and all-cause mortality exists. STUDY DESIGN Retrospective cohort study. SETTINGS & PARTICIPANTS Patients from the Accelerated Mortality on Renal Replacement (ArMORR) cohort who were adult, incident to hemodialysis at any Fresenius Medical Care unit between June 2004 and August 2005, and had suitable blood pressure data were studied (n = 6,961). PREDICTOR Predialysis blood pressures measured between dialysis days 91 and 180 were used to determine each patients absolute level of, trend in (slope over time), and variability in blood pressure. OUTCOME All-cause mortality beginning immediately after day 180 and continuing through day 365 or until censoring (median follow-up, 185 days). RESULTS Of the 4 candidate BPV metrics, only average residual-intercept ratio adequately distinguished BPV from absolute blood pressure level and temporal blood pressure trend. In the primary analysis, each SD increase in systolic and diastolic BPV was associated with adjusted hazard ratios for all-cause mortality of 1.13 (95% confidence interval, 1.03 to 1.23) and 1.15 (95% confidence interval, 1.06 to 1.26), respectively. Results were consistent across multiple sensitivity analyses in which inclusion and exclusion criteria and timing of blood pressure measurements were varied. LIMITATIONS Contingency of results on the validity of mathematic description of BPV; potential for misclassification bias and residual confounding. CONCLUSIONS Provided the mathematical descriptions of BPV are valid, the data suggest that systolic and diastolic BPV is associated with all-cause mortality in incident hemodialysis patients. Additional study is necessary to confirm and generalize findings, assess the interplay between systolic and diastolic BPV, and assess causality.

Nutritional Vitamin D Supplementation in Dialysis: A Randomized Trial

BACKGROUND AND OBJECTIVES Vitamin D (25-hydroxyvitamin D; 25[OH]D) deficiency is common in patients initiating long-term hemodialysis, but the safety and efficacy of nutritional vitamin D supplementation in this population remain uncertain. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This randomized, placebo-controlled, parallel-group multicenter trial compared two doses of ergocalciferol with placebo between October 2009 and March 2013. Hemodialysis patients (n=105) with 25(OH)D levels ≤32 ng/ml from 32 centers in the Northeast United States were randomly assigned to oral ergocalciferol, 50,000 IU weekly (n=36) or monthly (n=33), or placebo (n=36) for a 12-week treatment period. The primary endpoint was the achievement of vitamin D sufficiency (25[OH]D >32 ng/ml) at the end of the 12-week treatment period. Survival was assessed through 1 year. RESULTS Baseline characteristics were similar across all arms, with overall mean±SD 25(OH)D levels of 21.9±6.9 ng/ml. At 12 weeks, vitamin D sufficiency (25[OH]D >32 ng/ml) was achieved in 91% (weekly), 66% (monthly), and 35% (placebo) (P<0.001). Mean 25(OH)D was significantly higher in both the weekly (49.8±2.3 ng/ml; P<0.001) and monthly (38.3±2.4 ng/ml; P=0.001) arms compared with placebo (27.4±2.3 ng/ml). Calcium, phosphate, parathyroid hormone levels, and active vitamin D treatment did not differ between groups. All-cause and cause-specific hospitalizations and adverse events were similar between groups during the intervention period. Lower all-cause mortality among ergocalciferol-treated participants was not statistically significant (hazard ratio, 0.28; 95% confidence interval, 0.07 to 1.19). CONCLUSIONS Oral ergocalciferol can increase 25(OH)D levels in incident hemodialysis patients without significant alterations in blood calcium, phosphate, or parathyroid hormone during a 12-week period.

Association of Hemoglobin Variability and Mortality among Contemporary Incident Hemodialysis Patients

BACKGROUND AND OBJECTIVES Evidence exists that variability in hemoglobin may be an independent risk factor for mortality among hemodialysis patients. These observations were based on a 1996 cohort, a time when anemia management differed greatly from present. Design, settings, participants and measurements: A retrospective cohort study of patients incident to Fresenius Medical Care units between 2004 and 2005 (n = 6644). Hemoglobin variability (Hgb-Var) was defined for each subject as the residual SD of a linear regression model of time on hemoglobin. RESULTS The mean (SD) of Hgb-Var was 1.13 (0.55) g/dl. In the primary analysis, each g/dl increase of Hgb-Var was associated with an adjusted hazard ratio (95% confidence interval) for all-cause mortality of 1.11 (0.92 to 1.33). No significant interaction with Hgb-Var and mortality was found on the basis of age (P = 0.22), arterial disease (P = 0.45), Hgb slope (P = 0.68), or mean Hgb (P = 0.78). When Hgb-Var was defined by a regression model that included a quadratic term for time (enabling descriptions of curvilinear hemoglobin trajectories), model fit was greatly improved (P for difference <0.001). The corresponding adjusted hazard ratio (95% confidence interval) for all-cause mortality was 1.17 (0.93 to 1.49). CONCLUSIONS Hgb-Var was not found to be associated with all-cause mortality when examined in a contemporary incident hemodialysis population. More research is needed to determine whether differences in these findings compared with prior analyses relate to temporal trends in anemia management or from differences in the relationship between Hgb-Var and outcomes among incident versus prevalent hemodialysis patients.

Klotho Variants and Chronic Hemodialysis Mortality

Patients with end‐stage renal disease (ESRD) suffer exceptionally high mortality rates in their first year of chronic hemodialysis. Both vitamin D and fibroblast growth factor (FGF)‐23 levels correlate with survival in these patients. Klotho is a protein in the vitamin D/FGF‐23 signaling pathway that has been linked with accelerated aging and early mortality in animal models. We therefore hypothesized that genetic variation in the Klotho gene might be associated with survival in subjects with ESRD. We tested the association between 12 single nucleotide polymorphisms (SNPs) in the Klotho gene and mortality in a cohort of ESRD patients during their first year on hemodialysis (n = 1307 white and Asian). We found a significant association between the CC genotype of one tag SNP, rs577912, and increased risk for 1‐yr mortality (RR, 1.76; 95% CI, 1.19–2.59; p = 0.003). This effect was even more marked among patients who were not treated with activated vitamin D supplementation (HR, 2.51; 95% CI, 1.18–5.34; p = 0.005). In lymphoblastoid cell lines derived from HapMap subjects, the CC genotype was associated with a 16–21% lower Klotho expression compared with the AA/AC genotype. Our data suggest that a specific Klotho variant (rs577912) is linked to survival in ESRD patients initiating chronic hemodialysis and that therapy with activated vitamin D may modify this risk.

Effect of Race/Ethnicity on Hypertension Risk Subsequent to Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) prevalence is greater in racially/ethnically diverse groups compared with non-Hispanic white populations. Although race has been shown to modify other cardiovascular disease risk factors in postpartum women, the role of race/ethnicity on GDM and subsequent hypertension has yet to be examined. The aim of this study was to evaluate the impact of race/ethnicity in relation to GDM and subsequent hypertension in a retrospective analysis of women who delivered at Massachusetts General Hospital from 1998 to 2007. Multivariate analyses were used to determine the associations between GDM and (1) race/ethnicity, (2) hypertension, and (3) the interaction with hypertension and race/ethnicity. Women were monitored for a median of 3.8 years from the date of delivery. In our population of 4,010 women, GDM was more common in nonwhite participants (p<0.0001). GDM was also associated with hypertension subsequent to delivery after adjusting for age, race, parity, first-trimester systolic blood pressure, body mass index, maternal gestational weight gain, and preeclampsia (hazard ratio [HR] 1.75, 95% confidence interval [CI] 1.28 to 2.37, p=0.0004). Moreover, Hispanic (HR 3.25, 95% CI 1.85 to 5.72, p<0.0001) and white (HR 1.68, 95% CI 1.10 to 2.57, p=0.02) women with GDM had greater hypertension risk relative to their race/ethnicity-specific counterparts without GDM in race-stratified multivariable analyses. In conclusion, Hispanic women compared with white women have an increased risk of hypertension. Hispanic and white women with GDM are at a greater risk for hypertension compared with those without GDM. Because the present study may have had limited power to detect effects among black and Asian women with GDM, further research is warranted to elucidate the need for enhanced hypertension risk surveillance in these young women.

Carbamylation of Serum Albumin and Erythropoietin Resistance in End Stage Kidney Disease

BACKGROUND AND OBJECTIVES The mechanisms underlying erythropoietin resistance are not fully understood. Carbamylation is a post-translational protein modification that can alter the function of proteins, such as erythropoietin. The hypothesis of this study is that carbamylation burden is independently associated with erythropoietin resistance. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In a nonconcurrent prospective cohort study of incident hemodialysis patients in the United States, carbamylated albumin, a surrogate of overall carbamylation burden, in 158 individuals at day 90 of dialysis initiation and erythropoietin resistance index (defined as average weekly erythropoietin dose [U] per kg body weight per hemoglobin [g/dl]) over the subsequent 90 days were measured. Linear regression was used to describe the relationship between carbamylated albumin and erythropoietin resistance index. Logistic regression characterized the relationship between erythropoietin resistance index, 1-year mortality, and carbamylation. RESULTS The median percent carbamylated albumin was 0.77% (interquartile range=0.58%-0.93%). Median erythropoietin resistance index was 18.7 units/kg per gram per deciliter (interquartile range=8.1-35.6 units/kg per gram per deciliter). Multivariable adjusted analysis showed that the highest quartile of carbamylated albumin was associated with a 72% higher erythropoietin resistance index compared with the lowest carbamylation quartile (P=0.01). Increasing erythropoietin resistance index was associated with a higher risk of death (odds ratio per unit increase in log-erythropoietin resistance index, 1.69; 95% confidence interval, 1.06 to 2.70). However, the association between erythropoietin resistance index and mortality was no longer statistically significant when carbamylation was included in the analysis (odds ratio, 1.44; 95% confidence interval, 0.87 to 2.37), with carbamylation showing the dominant association with death (odds ratio for high versus low carbamylation quartile, 4.53; 95% confidence interval, 1.20 to 17.10). CONCLUSION Carbamylation was associated with higher erythropoietin resistance index in incident dialysis patients and a better predictor of mortality than erythropoietin resistance index.