Faculty Bibliography

PURPOSE/OBJECTIVE:We tested whether short-term vitamin D supplementation improves insulin resistance in patients with kidney disease, a condition with little intrinsic vitamin D activity. METHODS:PubMed, EMBASE and CENTRAL were searched for relevant observational studies and randomized clinical trials (RCTs). Random-effects models were employed for meta-analysis, and effect sizes were summarized as standardized mean difference (SMD) with 95% confidence intervals. Separate analyses were done for RCTs and non-randomized intervention studies (NRIS). RESULTS:Seventeen studies (5 RCTs and 12 NRIS) were included. The meta-analysis population (n = 131) was mostly middle aged (40-50 years), male and non-diabetic, and on hemodialysis. The duration (4-12 weeks) and type of supplementation varied between studies. Among RCTs, compared to placebo, vitamin D supplementation was associated with significant decrease in fasting glucose [SMD -1.13, (-2.11 to -0.11)] and PTH levels [SMD -1.50, (-2.95 to -0.04)] but no difference in fasting insulin levels [SMD 1.32, (-0.15 to 2.79)]. Among NRIS, there was only a significant decrease in PTH levels [SMD -1.68, (-2.55 to -0.82)] between pre- and post-vitamin D treatment levels. CONCLUSIONS:Short-term (4-12 weeks) supplementation with vitamin D is associated with lower fasting glucose levels in ESRD with no change in fasting insulin levels. However, the findings from this study are limited by the studies that were used in the meta-analysis, which were mostly small, used multiple different vitamin D compounds and dosing regimens, and had large heterogeneity, and funnel plots showed that there was a dearth of studies with null or negative finding. Therefore, larger RCTs need to be performed to answer this important clinical question.

BACKGROUND:Chronic metabolic acidosis leads to bone mineral loss and results in lower bone mineral density (BMD), which is a risk factor for osteoporosis-related fractures. The effect of low-level metabolic acidosis on bone density in the general population is unknown. STUDY DESIGN/METHODS:Cross-sectional study. SETTING & PARTICIPANTS/METHODS:9,724 nationally representative adults 20 years or older in NHANES (National Health and Nutrition Examination Survey) 1999-2004. FACTOR/METHODS:Serum bicarbonate level. OUTCOMES/RESULTS:Lumbar and total BMD, as well as low lumbar and total bone mass, defined as 1.0 SD below the sex-specific mean value of young adults. MEASUREMENTS/METHODS:BMD was measured by dual-energy x-ray absorptiometry and serum bicarbonate was measured in all participants. RESULTS:Both men and women with lower serum bicarbonate levels were more likely to be current smokers and had higher body mass index and estimated net endogenous acid production. There was a significant linear trend across quartiles of serum bicarbonate with lumbar BMD in the total population, as well as in sex-specific models (P=0.02 for all 3 models, P=0.1 for interaction). For total BMD, a significant association was seen with serum bicarbonate level for women but not men (P=0.02 and P=0.1, respectively; P=0.8 for interaction), and a significant association was seen for postmenopausal women but not premenopausal women (P=0.02 and P=0.2, respectively; P=0.5 for interaction). Compared with women with serum bicarbonate levels <24mEq/L, those with serum bicarbonate levels ≥27mEq/L had 0.018-g/cm(2) higher total BMD (95% CI, 0.004-0.032; P=0.01) and 31% lower odds of having low total bone mass (OR, 0.68; 95% CI, 0.46-0.99; P=0.049). LIMITATIONS/CONCLUSIONS:Cross-sectional study using a single measurement of serum bicarbonate. Subgroup differences are not definitive. CONCLUSIONS:Lower serum bicarbonate levels are associated with lower BMD in US adults. Further studies should examine whether serum bicarbonate levels should be incorporated into the diagnostic assessment and management of osteoporosis.

BACKGROUND:Abnormalities in mineral homeostasis are ubiquitous in patients on dialysis, and influenced by race. In this study, we determine the race-specific relationship between mineral parameters and mortality in patients initiating hemodialysis. METHODS:We measured the levels of fibroblast growth factor 23 (FGF23) and 25-hydroxyvitamin D (25 D) in 184 African American and 327 non-African American hemodialysis patients who enrolled between 1995 and 1998 in the Choices for Healthy Outcomes in Caring for ESRD Study. Serum calcium, phosphorus, parathyroid hormone (PTH) and total alkaline phosphatase levels were averaged from clinical measurements during the first 4.5 months of dialysis. We evaluated the associated prospective risk of mortality using multivariable Cox proportional hazards models stratified by race. RESULTS:PTH and total alkaline phosphatase levels were higher, whereas calcium, phosphorus, FGF23 and 25 D levels were lower in African Americans compared to those of non-African Americans. Higher serum phosphorus and FGF23 levels were associated with greater mortality risk overall; however, phosphorus was only associated with risk among African Americans (HR 5.38, 95% CI 2.14-13.55 for quartile 4 vs. 1), but not among non-African Americans (p-interaction = 0.04). FGF23 was associated with mortality in both groups, but more strongly in African Americans (HR 3.91, 95% CI 1.74-8.82 for quartiles 4 vs. 1; p-interaction = 0.09). Serum calcium, PTH, and 25 D levels were not consistently associated with mortality. The lowest and highest quartiles of total alkaline phosphatase were associated with higher mortality risk, but this did not differ by race (p-interaction = 0.97). CONCLUSIONS:Aberrant phosphorus homeostasis, reflected by higher phosphorus and FGF23, may be a risk factor for mortality in patients initiating hemodialysis, particularly among African Americans.

Most dialysis patients are vitamin D deficient, including deficiencies in both activated vitamin D (1, 25-dihydroxyvitamin D) and the less active 25-hydroxyvitamin D. These and other abnormalities associated with chronic kidney disease (CKD), if they remain untreated, lead to secondary hyperparathyroidism and bone changes, such as osteitis fibrosa cystica. Activated vitamin D has been proven to decrease parathyroid hormone (PTH) levels in dialysis patients and is currently used for this indication. There are multiple other potential "pleotrophic" effects associated with vitamin D therapy. These include associations with lower all-cause and cardiovascular mortality, lower rates of infections and improved glycemic indexes. Meta-analyses of multiple observational studies have shown activated vitamin D therapy to be associated with improved survival. Observational data also suggest fewer infections and better glucose control. There have been no randomized clinical trials powered to evaluate mortality or other clinical outcomes. Small trials of nutritional vitamin D (ergocalciferol and cholecalciferol) showed increases in 25-hydroxyvitamin D levels without hypercalcemia or hyperphosphatemia, even when given in addition to activated vitamin D therapy. While activated vitamin D therapy is associated with improved outcomes, it also leads to higher fibroblast growth factor 23 (FGF-23) levels, which may be detrimental in dialysis patients. Further research is needed to evaluate whether activated or nutritional vitamin D therapy are beneficial in dialysis patients for outcomes other than secondary hyperparathyroidism.

Non-adherence is common in adolescent and young adult kidney transplant recipients, leading to adverse graft outcomes. The aim of this study was to determine whether adherence to immunosuppressant medications changes during transition from a pediatric to an adult program within the same transplant center. Adherence was assessed for a period of two yr before and two yr after the transfer. Subtherapeutic trough levels of serum tacrolimus and level variability were used as measures of adherence. Twenty-five patients were transitioned between 1996 and 2011 at the median age of 22.3 [IQR 21.6-23.0] yr. Young adults 21-25 yr of age (n = 26) and non-transitioned adolescents 17-21 yr of age (currently followed in the program, n = 24 and those that lost their grafts prior to the transfer, 22) formed the comparison groups. In the transitioned group, adherence prior to the transfer was not significantly different from the adherence after the transfer (p = 0.53). The rate of non-adherence in the group of non-transitioned adolescents who lost their grafts (68%) was significantly higher than in the transitioned group (32%, p = 0.01). In the group of young adults, adherence was not significantly different from the transitioned group (p = 0.27). Thus, transition was not associated with differences in medication adherence in this single-center study. Large-scale studies are needed to evaluate the national data on medication adherence after transfer.

OBJECTIVE:To examine the association between 25-hydroxyvitamin D [25(OH)D] deficiency and anemia in a cohort of otherwise-healthy children and to determine whether race modifies the association between 25(OH)D status and hemoglobin (Hgb). STUDY DESIGN/METHODS:Cross-sectional study of 10,410 children and adolescents ages 1-21 years from the 2001-2006 National Health and Nutrition Examination Survey. Anemia was defined as Hgb less than the 5th percentile for age and sex based on National Health and Nutrition Examination Survey III (1988-1994) data. RESULTS:Lower 25(OH)D levels were associated with increased risk for anemia; <30 ng/mL, adjusted OR 1.93, 95% CI 1.21-3.08, P = .006, and <20 ng/mL, OR 1.47, 95% CI 1.14-1.89, P = .004. In linear regression, small but significant increases in Hgb were noted in the upper quartiles of 25(OH)D compared with the lowest quartile (<20 ng/mL) in the full cohort. Results of race-stratified linear regression by 25(OH)D quartile in white children were similar to those observed in the full cohort, but in black children, an increase in Hgb in the upper 25(OH)D quartiles was only apparent compared with the lowest black race-specific quartile (<12 ng/mL). CONCLUSION/CONCLUSIONS:25(OH)D deficiency is associated with increased risk of anemia in healthy US children, but the 25(OH)D threshold levels for lower Hgb are lower in black children in comparison with white children.

OBJECTIVES/OBJECTIVE:To define vitamin D levels and their association with cognition in subjects with exceptional longevity. DESIGN/METHODS:Cross-sectional. SETTING/METHODS:Community and long-term care facilities. PARTICIPANTS/METHODS:Ashkenazi Jewish subjects (n = 253) with exceptional longevity, with comparison made to the Third National Health and Nutrition Examination Survey (NHANES III) participants aged 70 and older. MEASUREMENTS/METHODS:Serum 25-hydroxyvitamin D levels were measured using liquid chromatography/tandem mass spectrometry analysis. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) and clock drawing test (CDT: command and copy). RESULTS:The median age of the Ashkenazi subjects was 97 (interquartile range (IQR) 95-104). Age-associated rise in the prevalence of vitamin D insufficiency, defined as a serum vitamin D level of less than 30 ng/mL, was noted in NHANES III (P = .001). In the Ashkenazi group with longevity, the rate of vitamin D insufficiency was comparable with that of the NHANES III participants, who were up to 25 years younger. In the cohort with exceptional longevity, 49% demonstrated cognitive impairment as assessed according to MMSE score (impaired cognition, median 9.5 IQR 0-24); normal cognition, median 29 (IQR 18-30) P < .001). Vitamin D insufficiency was more prevalent in those with impaired cognition, defined according to the MMSE (71.8% vs 57.7%, P = .02) and the CDT copy (84.6% vs. 50.6%, P = .02), than in those with normal cognition. This association remained significant after multivariable adjustment in logistic regression models for cognitive assessments made using the MMSE (odds ratio (OR) = 3.2, 95% confidence interval (CI) = 1.1-9.29, P = .03) and the CDT copy (OR = 8.96, 95% CI = 1.08-74.69, P = .04). CONCLUSION/CONCLUSIONS:Higher vitamin D levels may be a marker of delayed aging, because they are associated with better cognitive function in people achieving exceptional longevity.

BACKGROUND:Calcium supplements are widely used among older adults for osteoporosis prevention and treatment. However, their effect on creatinine levels and kidney function has not been well studied. METHODS:We investigated the effect of calcium supplementation on blood creatinine concentration in a randomized controlled trial of colorectal adenoma chemoprevention conducted between 2004-2013 at 11 clinical centers in the United States. Healthy participants (N = 1,675) aged 45-75 with a history of colorectal adenoma were assigned to daily supplementation with calcium (1200 mg, as carbonate), vitamin D3 (1000 IU), both, or placebo for three or five years. Changes in blood creatinine and total calcium concentration were measured after one year of treatment and multiple linear regression was used to estimate effects on creatinine concentrations. RESULTS:After one year of treatment, blood creatinine was 0.013±0.006 mg/dL higher on average among participants randomized to calcium compared to placebo after adjustment for other determinants of creatinine (P = 0.03). However, the effect of calcium treatment appeared to be larger among participants who consumed the most alcohol (2-6 drinks/day) or whose estimated glomerular filtration rate (eGFR) was less than 60 ml/min/1.73 m2 at baseline. The effect of calcium treatment on creatinine was only partially mediated by a concomitant increase in blood total calcium concentration and was independent of randomized vitamin D treatment. There did not appear to be further increases in creatinine after the first year of calcium treatment. CONCLUSIONS:Among healthy adults participating in a randomized clinical trial, daily supplementation with 1200 mg of elemental calcium caused a small increase in blood creatinine. If confirmed, this finding may have implications for clinical and public health recommendations for calcium supplementation. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT00153816.

African Americans have lower 25-hydroxyvitamin D (25(OH)D) levels compared with whites. African Americans also have a higher risk of developing albuminuria and end-stage renal disease but a lower risk of death once they commence hemodialysis compared with whites. Vitamin D levels have been associated with multiple outcomes including albuminuria, progression to end-stage renal disease, and all-cause and cardiovascular mortality. In this review, we examine the evidence linking 25(OH)D to outcomes and the possibility that differential 25(OH)D may explain certain racial differences in outcomes.