Ishir Bhan

Vitamin D–Binding Protein and Vitamin D Status of Black Americans and White Americans

BACKGROUND Low levels of total 25-hydroxyvitamin D are common among black Americans. Vitamin D-binding protein has not been considered in the assessment of vitamin D deficiency. METHODS In the Healthy Aging in Neighborhoods of Diversity across the Life Span cohort of blacks and whites (2085 participants), we measured levels of total 25-hydroxyvitamin D, vitamin D-binding protein, and parathyroid hormone as well as bone mineral density (BMD). We genotyped study participants for two common polymorphisms in the vitamin D-binding protein gene (rs7041 and rs4588). We estimated levels of bioavailable 25-hydroxyvitamin D in homozygous participants. RESULTS Mean (±SE) levels of both total 25-hydroxyvitamin D and vitamin D-binding protein were lower in blacks than in whites (total 25-hydroxyvitamin D, 15.6±0.2 ng per milliliter vs. 25.8±0.4 ng per milliliter, P<0.001; vitamin D-binding protein, 168±3 μg per milliliter vs. 337±5 μg per milliliter, P<0.001). Genetic polymorphisms independently appeared to explain 79.4% and 9.9% of the variation in levels of vitamin D-binding protein and total 25-hydroxyvitamin D, respectively. BMD was higher in blacks than in whites (1.05±0.01 g per square centimeter vs. 0.94±0.01 g per square centimeter, P<0.001). Levels of parathyroid hormone increased with decreasing levels of total or bioavailable 25-hydroxyvitamin D (P<0.001 for both relationships), yet within each quintile of parathyroid hormone concentration, blacks had significantly lower levels of total 25-hydroxyvitamin D than whites. Among homozygous participants, blacks and whites had similar levels of bioavailable 25-hydroxyvitamin D overall (2.9±0.1 ng per milliliter and 3.1±0.1 ng per milliliter, respectively; P=0.71) and within quintiles of parathyroid hormone concentration. CONCLUSIONS Community-dwelling black Americans, as compared with whites, had low levels of total 25-hydroxyvitamin D and vitamin D-binding protein, resulting in similar concentrations of estimated bioavailable 25-hydroxyvitamin D. Racial differences in the prevalence of common genetic polymorphisms provide a likely explanation for this observation. (Funded by the National Institute on Aging and others.).

Vitamin D Therapy and Cardiac Structure and Function in Patients With Chronic Kidney Disease: The PRIMO Randomized Controlled Trial

CONTEXT Vitamin D is associated with decreased cardiovascular-related morbidity and mortality, possibly by modifying cardiac structure and function, yet firm evidence for either remains lacking. OBJECTIVE To determine the effects of an active vitamin D compound, paricalcitol, on left ventricular mass over 48 weeks in patients with an estimated glomerular filtration rate of 15 to 60 mL/min/1.73 m(2). DESIGN, SETTING, AND PARTICIPANTS Multinational, double-blind, randomized placebo-controlled trial among 227 patients with chronic kidney disease, mild to moderate left ventricular hypertrophy, and preserved left ventricular ejection fraction, conducted in 11 countries from July 2008 through September 2010. INTERVENTION Participants were randomly assigned to receive oral paricalcitol, 2 μg/d (n =115), or matching placebo (n = 112). MAIN OUTCOME MEASURES Change in left ventricular mass index over 48 weeks by cardiovascular magnetic resonance imaging. Secondary end points included echocardiographic changes in left ventricular diastolic function. RESULTS Treatment with paricalcitol reduced parathyroid hormone levels within 4 weeks and maintained levels within the normal range throughout the study duration. At 48 weeks, the change in left ventricular mass index did not differ between treatment groups (paricalcitol group, 0.34 g/m(2.7) [95% CI, -0.14 to 0.83 g/m(2.7)] vs placebo group, -0.07 g/m(2.7) [95% CI, -0.55 to 0.42 g/m(2.7)]). Doppler measures of diastolic function including peak early diastolic lateral mitral annular tissue velocity (paricalcitol group, -0.01 cm/s [95% CI, -0.63 to 0.60 cm/s] vs placebo group, -0.30 cm/s [95% CI, -0.93 to 0.34 cm/s]) also did not differ. Episodes of hypercalcemia were more frequent in the paricalcitol group compared with the placebo group. CONCLUSION Forty-eight week therapy with paricalcitol did not alter left ventricular mass index or improve certain measures of diastolic dysfunction in patients with chronic kidney disease. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00497146.

Classifying and Predicting Errors of Inpatient Medication Reconciliation

BackgroundFailure to reconcile medications across transitions in care is an important source of potential harm to patients. Little is known about the predictors of unintentional medication discrepancies and how, when, and where they occur.ObjectiveTo determine the reasons, timing, and predictors of potentially harmful medication discrepancies.DesignProspective observational study.PatientsAdmitted general medical patients.MeasurementsStudy pharmacists took gold-standard medication histories and compared them with medical teams’ medication histories, admission and discharge orders. Blinded teams of physicians adjudicated all unexplained discrepancies using a modification of an existing typology. The main outcome was the number of potentially harmful unintentional medication discrepancies per patient (potential adverse drug events or PADEs).ResultsAmong 180 patients, 2066 medication discrepancies were identified, and 257 (12%) were unintentional and had potential for harm (1.4 per patient). Of these, 186 (72%) were due to errors taking the preadmission medication history, while 68 (26%) were due to errors reconciling the medication history with discharge orders. Most PADEs occurred at discharge (75%). In multivariable analyses, low patient understanding of preadmission medications, number of medication changes from preadmission to discharge, and medication history taken by an intern were associated with PADEs.ConclusionsUnintentional medication discrepancies are common and more often due to errors taking an accurate medication history than errors reconciling this history with patient orders. Focusing on accurate medication histories, on potential medication errors at discharge, and on identifying high-risk patients for more intensive interventions may improve medication safety during and after hospitalization.

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.

Effect of an Electronic Medication Reconciliation Application and Process Redesign on Potential Adverse Drug Events A Cluster-Randomized Trial

BACKGROUND Medication reconciliation at transitions in care is a national patient safety goal, but its effects on important patient outcomes require further evaluation. We sought to measure the impact of an information technology-based medication reconciliation intervention on medication discrepancies with potential for harm (potential adverse drug events [PADEs]). METHODS We performed a controlled trial, randomized by medical team, on general medical inpatient units at 2 academic hospitals from May to June 2006. We enrolled 322 patients admitted to 14 medical teams, for whom a medication history could be obtained before discharge. The intervention was a computerized medication reconciliation tool and process redesign involving physicians, nurses, and pharmacists. The main outcome was unintentional discrepancies between preadmission medications and admission or discharge medications that had potential for harm (PADEs). RESULTS Among 160 control patients, there were 230 PADEs (1.44 per patient), while among 162 intervention patients there were 170 PADEs (1.05 per patient) (adjusted relative risk [ARR], 0.72; 95% confidence interval [CI], 0.52-0.99). A significant benefit was found at hospital 1 (ARR, 0.60; 95% CI, 0.38-0.97) but not at hospital 2 (ARR, 0.87; 95% CI, 0.57-1.32) (P = .32 for test of effect modification). Hospitals differed in the extent of integration of the medication reconciliation tool into computerized provider order entry applications at discharge. CONCLUSIONS A computerized medication reconciliation tool and process redesign were associated with a decrease in unintentional medication discrepancies with potential for patient harm. Software integration issues are likely important for successful implementation of computerized medication reconciliation tools.

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.

First Trimester Vitamin D, Vitamin D Binding Protein, and Subsequent Preeclampsia

Previous studies report an association between vitamin D deficiency and hypertension, including the pregnancy-specific disorder preeclampsia. Circulating vitamin D is almost entirely bound to vitamin D binding protein, which increases 2-fold during pregnancy and previous studies have not examined vitamin D binding protein or free vitamin D levels. We performed a nested case-control study within the Massachusetts General Hospital Obstetric Maternal Study, measuring first trimester total 25-hydroxyvitamin D (25[OH]D) and vitamin D binding protein and calculating free 25(OH)D levels. We compared these levels from pregnancies complicated by subsequent preeclampsia (cases, n=39) with those from normotensive pregnancies (controls, n=131). First trimester total 25(OH)D levels were similar in cases and controls (27.4±1.9 versus 28.8±0.80 ng/mL; P=0.435). Despite an association between higher first trimester blood pressures and subsequent preeclampsia, first trimester total 25(OH)D was not associated with first trimester systolic (r=0.11; P=0.16) or diastolic blood pressures (r=0.03; P=0.72). Although there was a trend toward increased risk of preeclampsia with 25(OH)D levels <15 ng/mL (odds ratio: 2.5 [95% CI: 0.89 to 6.90]), this was attenuated after adjustment for body mass index and other covariates (odds ratio: 1.35 [95% CI: 0.40 to 4.50]). First trimester vitamin D binding protein and free 25(OH)D levels were similar in cases and controls and were not associated with first trimester blood pressures. These data suggest that first trimester total and free 25(OH)D levels are not independently associated with first trimester blood pressure or subsequent preeclampsia.

Association Between Iodinated Contrast Media Exposure and Incident Hyperthyroidism and Hypothyroidism

BACKGROUND Sudden exposure to high iodide levels may cause thyroid dysfunction. Despite compelling biological plausibility and clinical implication, the association between iodinated contrast media exposure and incident hyperthyroidism and hypothyroidism has not been rigorously studied. METHODS We performed a nested case-control study of patients treated between January 1, 1990, and June 30, 2010, who did not have preexisting hyperthyroidism or hypothyroidism. In parallel analyses, incident hyperthyroid or hypothyroid cases were defined by a change in thyrotropin level from normal (at baseline) to low or high (follow-up measurement). Euthyroid controls were selected using an incidence density sampling approach and were matched to cases on the basis of age, sex, race/ethnicity, estimated glomerular filtration rate, follow-up thyrotropin measurement date, and interval between baseline and the follow-up thyrotropin measurement date. Iodinated contrast media exposure was assessed using claims data for contrast-enhanced computed tomography or cardiac catheterization. RESULTS In total, 178 and 213 incident hyperthyroid and hypothyroid cases, respectively, were matched to 655 and 779 euthyroid controls, respectively. Iodinated contrast media exposure was associated with incident hyperthyroidism (odds ratio [OR], 1.98; 95% CI, 1.08-3.60), but a statistically significant association with incident hypothyroidism was not observed (OR, 1.58; 95% CI, 0.95-2.62). In prespecified secondary analysis, iodinated contrast media exposure was associated with incident overt hyperthyroidism (follow-up thyrotropin level ≤ 0.1 mIU/L; OR, 2.50; 95% CI, 1.06-5.93) and with incident overt hypothyroidism (follow-up thyrotropin level >10 mIU/L; OR, 3.05; 95% CI, 1.07-8.72). CONCLUSION Iodinated contrast media exposure is associated with subsequent development of incident hyperthyroidism and incident overt hypothyroidism.

Vitamin D reduces left atrial volume in patients with left ventricular hypertrophy and chronic kidney disease

BACKGROUND Left atrial enlargement, a sensitive integrator of left ventricular diastolic function, is associated with increased cardiovascular morbidity and mortality. Vitamin D is linked to lower cardiovascular morbidity, possibly modifying cardiac structure and function; however, firm evidence is lacking. We assessed the effect of an activated vitamin D analog on left atrial volume index (LAVi) in a post hoc analysis of the PRIMO trial (clinicaltrials.gov: NCT00497146). METHODS AND RESULTS One hundred ninety-six patients with chronic kidney disease (estimated glomerular filtration rate 15-60 mL/min per 1.73 m(2)), mild to moderate left ventricular hypertrophy, and preserved ejection fraction were randomly assigned to 2 μg of oral paricalcitol or matching placebo for 48 weeks. Two-dimensional echocardiography was obtained at baseline and at 24 and 48 weeks after initiation of therapy. Over the study period, there was a significant decrease in LAVi (-2.79 mL/m(2), 95% CI -4.00 to -1.59 mL/m(2)) in the paricalcitol group compared with the placebo group (-0.70 mL/m(2) [95% CI -1.93 to 0.53 mL/m(2)], P = .002). Paricalcitol also attenuated the rise in levels of brain natriuretic peptide (10.8% in paricalcitol vs 21.3% in placebo, P = .02). For the entire population, the change in brain natriuretic peptide correlated with change in LAVi (r = 0.17, P = .03). CONCLUSIONS Forty-eight weeks of therapy with an active vitamin D analog reduces LAVi and attenuates the rise of BNP. In a population where only few therapies alter cardiovascular related morbidity and mortality, these post hoc results warrant further confirmation.

Therapeutic Effects of Vitamin D Analogs on Cardiac Hypertrophy in Spontaneously Hypertensive Rats

Vitamin D inhibits renin expression and blocks the compensatory induction of renin associated with the use of renin-angiotensin system inhibitors. Here we test the therapeutic effects of two commonly used vitamin D analogs and their combination with losartan on the development of left ventricular hypertrophy. One-month-old male spontaneously hypertensive rats were treated with vehicle, losartan, paricalcitol, doxercalciferol, a combination of losartan and paricalcitol, or a combination of losartan and doxercalciferol for 2 months. Blood pressure was markedly reduced by losartan, but not by paricalcitol or doxercalciferol alone. Echocardiograpy demonstrated a 65 to 80% reduction in left ventricular wall thickness with losartan, paricalcitol, or doxercalciferol monotherapy and almost complete prevention of left ventricular hypertrophy with the combination therapies. Attenuation of cardiac and cardiomyocyte hypertrophy, and suppression of atrial and brain natriuretic peptides, were most marked in the combination therapy groups. These changes were well correlated with left ventricular gene and microRNA expression profiles in the different treatment groups. Renal and cardiac renin expression was markedly increased in losartan-treated animals, but nearly normalized with combination therapy. The same vitamin D analogs suppressed plasma renin activity in patients receiving chronic hemodialysis. These data demonstrate that vitamin D analogs have potent antihypertrophic activity in part via suppression of renin in the kidney and heart, and combination of these analogs with losartan achieves much better therapeutic effects because of the blockade of the compensatory renin increase.