Vitamin D Status and Kidney Function Decline in HIV-Infected Men: A Longitudinal Study in the Multicenter AIDS Cohort Study.
ABSTRACT: Vitamin D may play an important role in a range of disease processes. In the general population, lower vitamin D levels have been associated with kidney dysfunction. HIV-infected populations have a higher risk of chronic kidney disease. Few studies have examined the link between lower vitamin D levels and kidney function decline among HIV-infected persons. We investigated the associations of serum 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] with kidney function decline in a cohort of HIV-infected white and black men under highly active antiretroviral therapy treatment in the vitamin D ancillary study of the Multicenter AIDS Cohort Study. The associations of 25(OH)D and 1,25(OH)2D with annual change in estimated glomerular filtration rate (eGFR) were evaluated using linear mixed effects models. This study included 187 whites and 86 blacks with vitamin D measures and eGFR ?60?ml/min/1.73?m2 at baseline. Over a median follow-up of 8.0 years, lower 25(OH)D levels were significantly associated with faster eGFR decline in whites (adjusted annual change in eGFR, tertile 1: -2.06?ml/min/1.73?m2 vs. tertile 3: -1.23?ml/min/1.73?m2, p trend .03), while no significant association was detected in blacks. Lower 1,25(OH)2D was associated with faster kidney function decline in both whites and blacks, although the estimates were not statistically significant. In conclusion, lower 25(OH)D levels were significantly associated with faster eGFR decline in a cohort of HIV-infected white men, but not in those with black ancestry. Further research is warranted to investigate the association of 25(OH)D and 1,25(OH)2D with kidney function decline in larger and ethnically diverse populations.
Project description:Background:Interpretation of serum vitamin D biomarkers across pregnancy is complex due to limited understanding of pregnancy adaptations in vitamin D metabolism. During pregnancy, both gestational age and serum 25-hydroxyvitamin D [25(OH)D] concentrations may influence the concentrations of 1,25-dihydroxyvitamin D [1,25(OH)2D], 24,25-dihydroxyvitamin D [24,25(OH)2D], and parathyroid hormone (PTH). Objective:We aimed to identify predictors of change in serum 25(OH)D across gestation in pregnant adolescents and to assess the contribution made by cholecalciferol (vitamin D3) supplementation. We sought to determine whether gestational age and 25(OH)D concentration interacted to affect serum 1,25(OH)2D, 24,25(OH)2D, or PTH. Methods:Pregnant adolescents (n = 78, 59% African American, mean ± SD age: 17 ± 1 y) living in Rochester, NY (latitude 43°N) were supplemented with 200 IU or 2000 IU vitamin D3/d and allowed to continue their daily prenatal supplement that contained 400 IU vitamin D3. Serum was collected at study entry (18 ± 5 wk of gestation), halfway through study participation, and at delivery (40 ± 2 wk). Serum concentrations of the biochemical markers were modeled with linear mixed-effects regression models. Results:Vitamin D3 supplement intake and season of delivery determined change in 25(OH)D across pregnancy. Fall-winter delivery was associated with a decline in 25(OH)D unless vitamin D3 supplement intake was >872 IU/d. The interaction of gestational age and 25(OH)D affected 24,25(OH)2D concentrations. For a given 25(OH)D concentration, model-predicted serum 24,25(OH)2D increased across gestation except when 25(OH)D was <13 ng/mL. Below this threshold, 24,25(OH)2D was predicted to decline over time. Mean serum 1,25(OH)2D was elevated (>100 pg/mL) throughout the study. Conclusion:Our results suggest that when maternal serum 25(OH)D was low, its catabolism into 24,25(OH)2D decreased or remained stable as pregnancy progressed in order to maintain persistently elevated serum 1,25(OH)2D. Furthermore, in adolescents living at latitude 43°N, standard prenatal supplementation did not prevent a seasonal decline in 25(OH)D during pregnancy. This study was registered at clinicaltrials.gov as NCT01815047.
Project description:BACKGROUND:Vitamin D deficiency, determined by blood levels of 25-hydroxyvitamin D [25(OH) D, i.e. the major vitamin D form in blood], has been shown to associate with all-cause mortalities. We recently demonstrated that blood levels of 1,25-dihydroxyvitamin D [1,25(OH)2D, i.e. the active vitamin D] were significantly lower in non-survivors compared to survivors among sepsis patients. Unexpectedly, despite the well documented roles of 1,25(OH)2D in multiple biological functions such as regulation of immune responses, stimulation of antimicrobials, and maintenance of barrier function, 1,25(OH)2D supplementation failed to improve disease outcomes. These previous findings suggest that, in addition to 1,25(OH)2D deficiency, disorders leading to the 1,25(OH)2D deficiency also contribute to mortality among sepsis patients. Therefore, this study investigated the mechanisms leading to sepsis-associated 1,25(OH)2D deficiency. METHODS:We studied mechanisms known to regulate kidney 25-hydroxylvitamin D 1?-hydroxylase which physiologically catalyzes the conversion of 25(OH) D into 1,25(OH)2D. Such mechanisms included parathyroid hormone (PTH), insulin-like growth factor 1 (IGF-1), fibroblast growth factor 23 (FGF-23), and kidney function. RESULTS:We demonstrated in both human subjects and mice that sepsis-associated 1,25(OH)2D deficiency could not be overcome by increased production of PTH which stimulates 1?-hydroxylase. Further studies showed that this failure of PTH to maintain blood 1,25(OH)2D levels was associated with decreased blood levels of IGF-1, increased blood levels of FGF-23, and kidney failure. Since the increase in blood levels of FGF-23 is known to associate with kidney failure, we further investigated the mechanisms leading to sepsis-induced decrease in blood levels of IGF-1. Our data showed that blood levels of growth hormone, which stimulates IGF-1 production in liver, were increased but could not overcome the IGF-1 deficiency. Additionally, we found that the inability of growth hormone to restore the IGF-1 deficiency was associated with suppressed expression and signaling of growth hormone receptor in liver. CONCLUSIONS:Because FGF-23 and IGF-1 have multiple biological functions besides their role in regulating kidney 1?-hydroxylase, our data suggest that FGF-23 and IGF-1 are warranted for further investigation as potential agents for the correction of 1,25(OH)2D deficiency and for the improvement of survival among sepsis patients.
Project description:<h4>Background</h4>Limited data suggest that lead (Pb), cadmium (Cd), and uranium (U) may disrupt vitamin D metabolism and inhibit production of 1,25-dihydroxyvitamin D [1,25(OH)2D], the active vitamin D metabolite, from 25-hydroxyvitamin D [25(OH)D] in the kidney.<h4>Objectives</h4>We evaluated the association between blood lead (BPb) and urine arsenic (As), Cd, molybdenum (Mo), thallium (Tl), and U with markers of vitamin D metabolism [25(OH)D and 1,25(OH)2D].<h4>Methods</h4>We conducted a cross-sectional study of 512 adolescents in Torreón, a town in Mexico with a Pb smelter near residential areas. BPb was measured using atomic absorption spectrometry. Urine As, Cd, Mo, Tl, and U were measured using inductively coupled plasma mass spectrometry. Serum 25(OH)D and 1,25(OH)2D were measured using a chemiluminescent immunoassay and a radioimmunoassay, respectively. Multivariable linear models with vitamin D markers as the outcome were used to estimate associations of BPb and creatinine-corrected urine As and metal concentrations with serum vitamin D concentrations, controlling for age, sex, adiposity, smoking, socioeconomic status, and time outdoors.<h4>Results</h4>Serum 25(OH)D was positively associated with urine Mo and Tl [1.5 (95% CI: 0.4, 2.6) and 1.2 (95% CI: 0.3, 2.1) ng/mL higher with a doubling of exposure, respectively]. Serum 1,25(OH)2D was positively associated with urine As and U [3.4 (95% CI: 0.9, 5.9) and 2.2 (95% CI: 0.7, 3.7) pg/mL higher, respectively], with little change in associations after additional adjustment for serum 25(OH)D. Pb and Cd were not associated with 25(OH)D or 1,25(OH)2D concentrations.<h4>Conclusions</h4>Overall, our findings did not support a negative effect of As or metal exposures on serum 1,25(OH)2D concentrations. Additional research is needed to confirm positive associations between serum 1,25(OH)2D and urine U and As concentrations and to clarify potential underlying mechanisms.
Project description:Preoperative anemia is considered an independent risk factor of poor clinical outcome in cardiac surgical patients. Low vitamin D status may increase anemia risk.We investigated 3,615 consecutive patients scheduled for cardiac surgery to determine the association between preoperative anemia (hemoglobin [Hb] <12.5 g/dL) and circulating levels of the vitamin D metabolites 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25[OH]2D).Of the study cohort, 27.8 % met the criteria for anemia. In patients with deficient 25OHD levels (<30 nmol/l) mean Hb concentrations were 0.5 g/dL lower than in patients with adequate 25OHD levels (50.0-125 nmol/l; P<0.001). Regarding 1,25(OH)2D, mean Hb concentrations were 1.2 g/dL lower in the lowest 1,25(OH)2D category (<40 pmol/l) than in the highest 1,25(OH)2D category (>70 pmol/l; P<0.001). In multivariable-adjusted logistic regression analyses, the odds ratios for anemia of the lowest categories of 25OHD and 1,25(OH)2D were 1.48 (95%CI:1.19-1.83) and 2.35 (95%CI:1.86-2.97), compared with patients who had adequate 25OHD levels and 1,25(OH)2D values in the highest category, respectively. Anemia risk was greatest in patients with dual deficiency of 25OHD and 1,25(OH)2D (multivariable-adjusted OR = 3.60 (95%CI:2.40-5.40). Prevalence of deficient 25OHD levels was highest in anemia of nutrient deficiency, whereas low 1,25(OH)2D levels were most frequent in anemia of chronic kidney disease.This cross-sectional study demonstrates an independent inverse association between vitamin D status and anemia risk. If confirmed in clinical trials, preoperative administration of vitamin D or activated vitamin D (in case of chronic kidney disease) would be a promising strategy to prevent anemia in patients scheduled for cardiac surgery.
Project description:Elevated serum 1,25-dihydroxyvitamin D (1,25(OH)2D) concentrations have been reported among cohorts of recurrent calcium (Ca) kidney stone-formers and implicated in the pathogenesis of hypercalciuria. Variations in Ca and vitamin D metabolism, and excretion of urinary solutes among first-time male and female Ca stone-formers in the community, however, have not been defined.In a 4-year community-based study we measured serum Ca, phosphorus (P), 25-hydroxyvitamin D (25(OH)D), 1,25(OH)2D, 24,25-dihydroxyvitamin D (24,25(OH)2D), parathyroid hormone (PTH), and fibroblast growth factor-23 (FGF-23) concentrations in first-time Ca stone-formers and age- and gender frequency-matched controls.Serum Ca and 1,25(OH)2D were increased in Ca stone-formers compared to controls (P = 0.01 and P = 0.001). Stone-formers had a lower serum 24,25(OH)2D/25(OH)D ratio compared to controls (P = 0.008). Serum PTH and FGF-23 concentrations were similar in the groups. Urine Ca excretion was similar in the two groups (P = 0.82). In controls, positive associations between serum 25(OH)D and 24,25(OH)2D, FGF-23 and fractional phosphate excretion, and negative associations between serum Ca and PTH, and FGF-23 and 1,25(OH)2D were observed. In SF associations between FGF-23 and fractional phosphate excretion, and FGF-23 and 1,25(OH)2D, were not observed. 1,25(OH)2D concentrations associated more weakly with FGF-23 in SF compared with C (P <0.05).Quantitative differences in serum Ca and 1,25(OH)2D and reductions in 24-hydroxylation of vitamin D metabolites are present in first-time SF and might contribute to first-time stone risk.
Project description:<h4>Background and objectives</h4>Low circulating 25-hydroxyvitamin D [25(OH)D] and high sodium intake are both associated with progressive albuminuria and renal function loss in CKD. Both vitamin D and sodium intake interact with the renin-angiotensin-aldosterone system. We investigated whether plasma 25(OH)D or 1,25-dihydroxyvitamin D [1,25(OH)2D] is associated with developing increased albuminuria or reduced renal function and whether these associations depend on sodium intake.<h4>Design, setting, participants, & measurements</h4>Baseline plasma 25(OH)D and 1,25(OH)2D were measured by liquid chromatography tandem mass spectrometry, and sodium intake was assessed by 24-hour urine collections in the general population-based Prevention of Renal and Vascular End-Stage Disease cohort (n=5051). Two primary outcomes were development of urinary albumin excretion >30 mg/24 h and eGFR (creatinine/cystatin C-based CKD Epidemiology Collaboration) <60 ml/min per 1.73 m(2). Participants with CKD at baseline were excluded. In Cox regression analyses, we assessed associations of vitamin D with developing increased albuminuria or reduced eGFR and potential interaction with sodium intake.<h4>Results</h4>During a median follow-up of 10.4 (6.2-11.4) years, 641 (13%) participants developed increased albuminuria, and 268 (5%) participants developed reduced eGFR. Plasma 25(OH)D was inversely associated with increased albuminuria (fully adjusted hazard ratio [HR] per SD higher, 0.86; 95% confidence interval [95% CI], 0.78 to 0.95; P=0.003) but not reduced eGFR (HR, 0.99; 95% CI, 0.87 to 1.12; P=0.85). There was interaction between 25(OH)D and sodium intake for risk of developing increased albuminuria (P interaction =0.03). In participants with high sodium intake, risk of developing increased albuminuria was inversely associated with 25(OH)D (lowest versus highest quartile: adjusted HR, 1.81; 95% CI, 1.20 to 2.73, P<0.01), whereas this association was nonsignificant in participants with low sodium intake (HR, 1.29; 95% CI, 0.94 to 1.77; P=0.12). Plasma 1,25(OH)2D was not significantly associated with increased albuminuria or reduced eGFR.<h4>Conclusions</h4>Low plasma 25(OH)D is associated with higher risk of developing increased albuminuria, particularly in individuals with high sodium intake, but not of developing reduced eGFR. Plasma 1,25(OH)2D is not associated with risk of developing increased albuminuria or reduced eGFR.
Project description:Hypercalcemia occurs in up to 4% of the population in association with malignancy, primary hyperparathyroidism, ingestion of excessive calcium and/or vitamin D, ectopic production of 1,25-dihydroxyvitamin D [1,25(OH)2D], and impaired degradation of 1,25(OH)2D. The ingestion of excessive amounts of vitamin D3 (or vitamin D2) results in hypercalcemia and hypercalciuria due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] that bind to the vitamin D receptor, albeit with lower affinity than the active form of the vitamin, 1,25(OH)2D, and the formation of 5,6-trans 25(OH)D, which binds to the vitamin D receptor more tightly than 25(OH)D. In patients with granulomatous disease such as sarcoidosis or tuberculosis and tumors such as lymphomas, hypercalcemia occurs as a result of the activity of ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in macrophages or tumor cells and the formation of excessive amounts of 1,25(OH)2D. Recent work has identified a novel cause of non-PTH-mediated hypercalcemia that occurs when the degradation of 1,25(OH)2D is impaired as a result of mutations of the 1,25(OH)2D-24-hydroxylase cytochrome P450 (CYP24A1). Patients with biallelic and, in some instances, monoallelic mutations of the CYP24A1 gene have elevated serum calcium concentrations associated with elevated serum 1,25(OH)2D, suppressed PTH concentrations, hypercalciuria, nephrocalcinosis, nephrolithiasis, and on occasion, reduced bone density. Of interest, first-time calcium renal stone formers have elevated 1,25(OH)2D and evidence of impaired 24-hydroxylase-mediated 1,25(OH)2D degradation. We will describe the biochemical processes associated with the synthesis and degradation of various vitamin D metabolites, the clinical features of the vitamin D-mediated hypercalcemia, their biochemical diagnosis, and treatment.
Project description:Objective:Genetic studies have identified four Qatari genotypes: Q1 Arab, Bedouin; Q2 Asian/Persian; Q3 African; and a fourth admixed group not fitting into the previous 3 groups. This study was undertaken to determine if there was an increased risk of deficiency of vitamin D and its metabolites associated with differing genotypes, perhaps due to genetic differences in skin pigmentation. Methods:398 Qatari subjects (220 type 2 diabetes and 178 controls) had their genotype determined by Affymetrix 500?k SNP arrays. Total values of 1,25-dihydroxyvitamin D (1,25(OH)2D), 25-hydroxyvitamin D (25(OH)D), 24,25-dihydroxyvitamin D (24,25(OH)2D), and 25-hydroxy-3epi-vitamin D (3epi-25(OH)D) concentrations were measured by the LC-MS/MS analysis. Results:The distribution was as follows: 164 (41.2%) genotyped Q1, 149 (37.4%) genotyped Q2, 31 (7.8%) genotyped Q3, and 54 (13.6%) genotyped "admixed." Median levels of 25(OH)D and 3epi-25(OH)D did not differ across Q1, Q2, Q3, and "admixed" genotypes, respectively. 1,25(OH)2D levels were lower (p < 0.04) between Q2 and the admixed groups, and 24,25(OH)2D levels were lower (p < 0.05) between Q1 and the admixed groups. Vitamin D metabolite levels were lower in females for 25(OH)D, 1,25(OH)2D (p < 0.001), and 24,25(OH)2D (p < 0.006), but 3epi-25(OH)D did not differ (p < 0.26). Diabetes prevalence was not different between genotypes. Total 1,25(OH)2D (p < 0.001), total 24,25(OH)2D (p < 0.001), and total 3epi-25(OH)D (p < 0.005) were all significantly lower in diabetes patients compared to controls whilst the total 25(OH)D was higher in diabetes than controls (p < 0.001). Conclusion:Whilst 25(OH)D levels did not differ between genotype groups, 1,25(OH)2D and 24,25(OH)2D were lower in the admixed group, suggesting that there are genetic differences in vitamin D metabolism that may be of importance in a population that may allow a more targeted approach to vitamin D replacement. This may be of specific importance in vitamin D replacement strategies with the Q2 genotype requiring less, and the other genotypes requiring more to increase 1,25(OH)2D. Whilst overall the group was vitamin D deficient, total 25(OH)D was higher in diabetes, but 1,25(OH)2D, 24,25(OH)2D, and 3epi-25(OH)D were lower in diabetes that did not affect the relationship to genotype.
Project description:The purpose of the present study was to measure six vitamin D metabolites and to find the association between vitamin D deficiency and coronary artery diseases in diabetes (T2DM_CAD). Four groups [control (n?=?50), type 2 diabetes (T2DM, n?=?71), coronary artery diseases (CAD, n?=?28), T2DM_CAD (n?=?38)] of total 187 subjects were included in the study. Six vitamin D metabolites (D2, D3, 25(OH)D2, 25(OH)D3, 1,25(OH)2D2, 1,25(OH)2D3), total 25(OH)D and total 1,25(OH)2D were measured by UPLC/APCI/HRMS method in these subjects. Although all the vitamin D metabolites were significantly decreased in T2DM_CAD as compared to both control and T2DM subjects (p?<?0.05), only two metabolites i.e., 25(OH)D3 and total 25(OH)D were significantly (p?<?0.05) decreased in the T2DM subjects as compared with the control subjects (p?<?0.05). Vitamin D3, 1,25(OH)2D2, 25(OH)D, and 1,25(OH)2D levels were significantly decreased in T2DM_CAD subjects as compared with CAD subjects (p?<?0.05). Further, multiple logistic regression analysis revealed that total 25(OH)D and total 1,25(OH)2D can be used to predict T2DM (OR 0.82.95% CI 0.68-0.99; p?=?0.0208) and T2DM with CAD (OR 0.460, 95% CI 0.242-0.874; p?=?0.0177), respectively. Our data concludes that lower concentration of 1,25(OH)2D is associated with type 2 diabetes coexisting with coronary artery diseases in South Indian subjects.
Project description:The protein 1?-hydroxylase (CYP27B1) was expressed in liver and omega-3 fatty acid (FA) elevated 1,25-dihydroxyvitamin D [1,25(OH)2D] levels in dialysis patients. The aim of this study was to determine whether omega-3 FA and cholecalciferol have effects on vitamin D metabolism related to CYP27B1 and 24-hydroxylase (CYP24) activities in the kidney and liver of 5/6 nephrectomy (Nx) rats. Male Sprague-Dawley rats were divided into the following groups: sham control, 5/6 Nx, 5/6 Nx treated with cholecalciferol, 5/6 Nx treated with omega-3 FA, and 5/6 Nx treated with cholecalciferol/omega-3 FA. CYP27B1 and CYP24 expression were measured in the liver and kidney. Further, 1,25(OH)2D and 25-hydroxyvitamin D [25(OH)D] levels were measured in serum. Among Nx groups, 1,25(OH)2D and 25(OH)D levels were lowest in the 5/6 Nx group. CYP24 expression was increased in the kidney of the 5/6 Nx rat model, which was found to be reversed by omega-3 FA or cholecalciferol/omega-3 FA supplementation. Decreased CYP27B1 expression was observed in the liver of the 5/6 Nx rats and its expression was recovered by supplementation with cholecalciferol/omega-3 FA. In conclusion, omega-3 FA and cholecalciferol may synergistically increase 1,25(OH)2D levels by inhibiting CYP24 expression in the kidney and liver and activating CYP27B1 expression in the liver of 5/6 Nx rats.