Risk factors for hip and vertebral fractures in chronic kidney disease: the CRIC study.

Fracture risk is high in chronic kidney disease (CKD) and underlying pathophysiology and risk factors may differ from the general population. In a cohort study of 3939 participants in the Chronic Renal Insufficiency Cohort (CRIC), we used Cox regression to test associations of putative risk factors with the composite of first hip or vertebral fracture assessed using hospital discharge codes. Mean age was 58 years, 45% were female, 42% were Black, and 13% were Hispanic. There were 82 hip and 24 vertebral fractures over a mean (SD) 11.1 (4.8) years (2.4 events per 1000 person-years [95% CI: 2.0, 2.9]). Measured at baseline, diabetes, lower body mass index (BMI), steroid use, proteinuria, and elevated parathyroid hormone (PTH) were each associated with fracture risk after adjusting for covariates. Lower time-updated estimated glomerular filtration rate (eGFR) was associated with fractures (HR 1.20 per 10 mL/min/1.73m2 lower eGFR; 95% CI: 1.04, 1.38) as were lower time-updated serum calcium and bicarbonate concentrations. Among time-updated categories of kidney function, hazard ratios (95% CI) for incident fracture were 4.53 (1.77, 11.60) for kidney failure treated with dialysis and 2.48 (0.86, 7.14) for post-kidney transplantation, compared with eGFR ≥60. Proton pump inhibitor use, dietary calcium intake, measures of vitamin D status, serum phosphate, urine calcium and phosphate, and plasma fibroblast growth factor-23 were not associated with fracture risk. In conclusion, lower eGFR in CKD is associated with higher fracture risk, which was highest in kidney failure. Diabetes, lower BMI, steroid use, proteinuria, higher serum concentrations of PTH, and lower calcium and bicarbonate concentrations were associated with fractures and may be modifiable risk factors.

The Vitamin D Metabolite Ratio Is Associated With Volumetric Bone Density in Older Men.

CONTEXT: Serum 25-hydroxyvitamin D (25(OH)D) is the current marker of vitamin D adequacy, but its relationship with bone health has been inconsistent. The ratio of 24,25-dihydroxyvitamin D3 to 25(OH)D3 (vitamin D metabolite ratio or VMR) is a marker of vitamin D that has been associated with longitudinal changes in bone mineral density (BMD) and fracture risk. OBJECTIVE: High-resolution peripheral quantitative computed tomography (HR-pQCT) provides information on bone health beyond standard dual-energy x-ray absorptiometry, in that it measures volumetric BMD (vBMD) as well bone strength. The relationship of the VMR with vBMD and bone strength remains unknown. METHODS: We evaluated the associations of the VMR and 25(OH)D3 with vBMD and bone strength in the distal radius and tibia, assessed by HR-pQCT in 545 older men participating in the Osteoporotic Fractures in Men (MrOS) Study. Primary outcomes were vBMD and estimated failure load (EFL, a marker of bone strength) at the distal radius and tibia. RESULTS: The mean age was 84 ± 4 years, 88.3% were White, and 32% had an estimated glomerular filtration rate <60 mL/min/1.73 m2. In adjusted models, each twofold higher VMR was associated with a 9% (3%, 16%) higher total vBMD and a 13% (5%, 21%) higher EFL at the distal radius. Results were similar at the distal tibia. 25(OH)D3 concentrations were not associated with any of the studied outcomes. CONCLUSION: Among older men, a higher VMR was associated with greater vBMD and bone strength while 25(OH)D3 was not. The VMR may serve as a valuable marker of skeletal health in older men.

Vitamin D supplementation in people with chronic kidney disease.

Vitamin D supplements have long been advocated for people with chronic kidney disease based on data from observational studies among the general population and people with chronic kidney disease. These data consistently suggested that higher circulating concentrations of 25-hydroxyvitamin D are associated with improved fracture, cardiovascular, cancer, and mortality outcomes. In the past few years, large clinical trials have been conducted to assess the effects of vitamin D supplements on a range of clinically relevant outcomes. Most of these studies were performed in the general population, but they also enrolled people with chronic kidney disease. Virtually all of these trials were negative and contradicted the observational data. In this review, the key observational data and clinical trials are summarized, and potential explanations for the discrepancies between these studies are discussed.

Vitamin D Metabolites and Risk of Cardiovascular Disease in Chronic Kidney Disease: The CRIC Study.

Background The ratio of 24,25-dihydroxyvitamin D3/25-hydroxyvitamin D3 (vitamin D metabolite ratio [VDMR]) may reflect functional vitamin D activity. We examined associations of the VDMR, 25-hydroxyvitamin D (25[OH]D), and 1,25-dihydroxyvitamin D (1,25[OH]2D) with cardiovascular disease (CVD) in patients with chronic kidney disease. Methods and Results This study included longitudinal and cross-sectional analyses of 1786 participants from the CRIC (Chronic Renal Insufficiency Cohort) Study. Serum 24,25-dihydroxyvitamin D3, 25(OH)D, and 1,25(OH)2D were measured by liquid chromatography-tandem mass spectrometry 1 year after enrollment. The primary outcome was composite CVD (heart failure, myocardial infarction, stroke, and peripheral arterial disease). We used Cox regression with regression-calibrated weights to test associations of the VDMR, 25(OH)D, and 1,25(OH)2D with incident CVD. We examined cross-sectional associations of these metabolites with left ventricular mass index using linear regression. Analytic models adjusted for demographics, comorbidity, medications, estimated glomerular filtration rate, and proteinuria. The cohort was 42% non-Hispanic White race and ethnicity, 42% non-Hispanic Black race and ethnicity, and 12% Hispanic ethnicity. Mean age was 59 years, and 43% were women. Among 1066 participants without prevalent CVD, there were 298 composite first CVD events over a mean follow-up of 8.6 years. Lower VDMR and 1,25(OH)2D were associated with incident CVD before, but not after, adjustment for estimated glomerular filtration rate and proteinuria (hazard ratio, 1.11 per 1 SD lower VDMR [95% CI, 0.95-1.31]). Only 25(OH)D was associated with left ventricular mass index after full covariate adjustment (0.6 g/m2.7 per 10 ng/mL lower [95% CI, 0.0-1.3]). Conclusions Despite modest associations of 25(OH)D with left ventricular mass index, 25(OH)D, the VDMR, and 1,25(OH)2D were not associated with incident CVD in chronic kidney disease.

Effects of very low carbohydrate ketogenic diets on skeletal health.

PURPOSE OF REVIEW: Very low carbohydrate ketogenic diet (KD) therapy has been associated with skeletal demineralization in children with drug-resistant epilepsy, but the cause of this association is unclear. Recently, interest in the KD has grown owing to its potential benefits for other illnesses including cancer, type 2 diabetes, obesity, and polycystic kidney disease. Summaries of the best available evidence regarding effects of a KD on skeletal health are lacking. RECENT FINDINGS: Recent rodent studies found that a KD can harm the growing skeleton, which corroborates most but not all studies in pediatric patients. Proposed mechanisms include chronic metabolic acidosis and depressed osteoanabolic hormones. Relative to other weight-reducing diets, a weight-reducing KD for treatment of obesity and/or type 2 diabetes in adults has not been associated with adverse skeletal effects. By contrast, recent evidence suggests that adaptation to a eucaloric KD may impair bone remodeling in elite adult athletes. Discrepancies in the literature may relate to differences between study populations and in diet formulation. SUMMARY: Attention to skeletal health is warranted when using KD therapy given the uncertainty in the literature and suggestive harms in certain populations. Future research should focus on potential mechanisms of injury.

Metabolism and pharmacokinetics of vitamin D in patients with cystic fibrosis.

Patients with cystic fibrosis (CF) commonly have lower circulating concentrations of 25-hydroxyvitamin D (25(OH)D) than healthy populations. We comprehensively compared measures of vitamin D metabolism among individuals with CF and healthy control subjects. In a cross-sectional study, serum from participants with CF (N = 83) and frequency-matched healthy control subjects by age and race (N = 82) were analyzed for: 25(OH)D2 and 25(OH)D3, 1α,25-dihydroxyvitamins D2 and D3 (1α,25(OH)2D2 and 1α,25(OH)2D3), 24,25-dihydroxyvitamin D3 (24,25(OH)2D3), 4ß,25-dihydroxyvitamin D3 (4ß,25(OH)2D3), 25-hydroxyvitamin D3-3-sulfate (25(OH)D3-S), and 25-hydroxyvitamin D3-3-glucuronide (25(OH)D3-G). In a 56-day prospective pharmacokinetic study, ∼25 µg deuterium-labeled 25(OH)D3 (d6-25(OH)D3) was administered intravenously to participants (N = 5 with CF, N = 5 control subjects). Serum was analyzed for d6-25(OH)D3 and d6-24,25(OH)2D3, and pharmacokinetic parameters were estimated. In the cross-sectional study, participants with CF had similar mean (SD) total 25(OH)D concentrations as control subjects (26.7 [12.3] vs. 27.7 [9.9] ng/mL) and had higher vitamin D supplement use (53% vs. 22%). However, participants with CF had lower total 1α,25(OH)2D (43.6 [12.7] vs. 50.7 [13.0] pg/mL), 4ß,25(OH)2D3 (52.1 [38.9] vs. 79.9 [60.2] pg/mL), and 25(OH)D3-S (17.7 [11.6] vs. 30.1 [12.3] ng/mL) (p < 0.001 for all). The pharmacokinetics of d6-25(OH)D3 and d6-24,25(OH)D3 did not differ between groups. In summary, although 25(OH)D concentrations were comparable, participants with CF had lower 1α,25(OH)2D, 4ß,25(OH)2D3, and 25(OH)D3-S concentrations than healthy controls. Neither 25(OH)D3 clearance, nor formation of 24,25(OH)2D3, appears to account for these differences and alternative mechanisms for low 25(OH)D in CF (i.e., decreased formation, altered enterohepatic recirculation) should be explored.

The plasma free fraction of 25-hydroxyvitamin D3 is not strongly associated with 25-hydroxyvitamin D3 clearance in kidney disease patients and controls.

Circulating 25-hydroxyvitamin D [25(OH)D] concentration is used to monitor vitamin D status. Plasma protein binding may influence the 25(OH)D dose-response to vitamin D treatment through a direct relationship between the plasma unbound ("free") fraction and clearance of 25(OH)D. We previously evaluated 25(OH)D3 clearance in relation to kidney function using intravenous administration of deuterium labeled 25(OH)D3. In this follow up study, we determined the free fraction of 25(OH)D3 in plasma (i.e., percent free 25(OH)D3) and the serum concentration and haplotype of vitamin D binding protein in these participants. We hypothesized that the percent free 25(OH)D3 would be positively associated with 25(OH)D3 clearance and would mediate associations between clearance and vitamin D binding protein (GC) haplotypes. Participants were mean (SD) age 64 (10) years and included 42 individuals with normal kidney function (controls), 24 individuals with chronic kidney disease, and 19 individuals with kidney failure on hemodialysis. Free plasma 25(OH)D2 and 25(OH)D3 concentrations were quantified with a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Because there is no reference measurement procedure for free 25(OH)D, we compared the new method with a widely-used predictive equation and a commercial immunoassay. The percent free 25(OH)D3 determined by predictive equation was weakly associated with 25(OH)D3 clearance (R = 0.27; P = 0.01). However, this association was absent when percent free 25(OH)D3 was determined using LC-MS/MS-measured free and total 25(OH)D3 concentrations. Method comparison uncovered a negative bias in immunoassay-measured free 25(OH)D concentrations among participants with kidney failure, so immunoassay results were not used to evaluate the association between percent free 25(OH)D3 and clearance. GC2 haplotype carriage was associated with 25(OH)D3 clearance. Among individuals with 2 relative to no GC2 alleles, clearance was 87 (95% CI: 15-158) mL/d greater. However, in contrast with the literature, GC2 carriage was not significantly related to DBP concentration or the percent free 25(OH)D3 (either predicted or measured). In conclusion, the free fraction of 25(OH)D3 is not strongly associated with 25(OH)D3 clearance but may explain small differences in clearance according to GC haplotype.

Biomarkers of Vitamin D Metabolism and Hip and Vertebral Fracture Risk: The Multi-Ethnic Study of Atherosclerosis.

Studies on associations between biomarkers of vitamin D metabolism and fracture risk have focused predominantly on White or elderly populations and may not be generalizable to relatively healthy multiethnic populations. We tested associations of total 25-hydroxyvitamin D (25[OH]D), the ratio of 24,25-dihydroxyvitamin D3 to 25-hydroxyvitamin D3 (vitamin D metabolite ratio, VDMR), parathyroid hormone (PTH), and fibroblast growth factor-23 (FGF-23) concentrations measured in serum with risk of hip and vertebral fractures in the Multi-Ethnic Study of Atherosclerosis (MESA). Serum 25-hydroxyvitamin D2 and D3 and 24,25-dihydroxyvitamin D3 were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The study cohort of 6466 participants was without clinically apparent cardiovascular disease and was 39% White, 27% Black, 22% Hispanic, and 12% Chinese. The mean age was 62 years, and 53% were female. There were 128 hip and vertebral fractures over a mean follow-up of 14.2 years. 25(OH)D, the VDMR, PTH, and FGF-23 were not significantly associated with fracture risk after adjustment for demographics, diabetes, smoking, systolic blood pressure, body mass index, medication use, albuminuria, and estimated glomerular filtration rate. Principal component analysis did not suggest differences in linear combinations of 25(OH)D, the VDMR, PTH, and FGF-23 between participants who experienced fractures and those who did not. We did not observe significant interaction between race and ethnicity and any biomarker of vitamin D metabolism on fracture risk. In conclusion, none of the four serum biomarkers of vitamin D metabolism investigated showed a significant association with fracture risk in relatively healthy multiethnic populations. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Converting a mAb downstream process from batch to continuous using process modeling and process analytical technology.

The biopharmaceutical market is driving the revolution from traditional batch processes to continuous manufacturing for higher productivity and lower costs. In this work, a batch mAb downstream process has been converted into an integrated continuous process with the combination of multiple techniques. For process intensification, two batch mode unit operations (protein A capture chromatography, ultrafiltration/diafiltration) were converted into continuous ones; for continuity, surge tanks were used between adjacent steps, and level signals were used to trigger process start or stop, forming a holistic continuous process. For process automation, manual operations (e.g., pH and conductivity adjustment) were changed into automatic operation and load mass was controlled with process analytical technology (PAT). A model-based simulation was applied to estimate the loading conditions for the continuous capture process, resulting in 21% resin capacity utilization and 28% productivity improvement as compared to the batch process. Automatic load mass control of cation exchange chromatography (CEX) was achieved through a customized in-line protein quantity monitoring system, with a difference of less than 1.3% as compared to off-line analysis. Total process time was shortened from 4 days (batch process) to less than 24 hours using the continuous downstream process with the overall productivity of 23.8 g mAb per day for the bench-scale system. Comparable yield and quality data were obtained in three test runs, indicating a successful conversion from a batch process to a continuous process. The insight of this work could be a reference to other similar situations.

Clinical and biomarker modifiers of vitamin D treatment response: the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Different 25-hydroxyvitamin D [25(OH)D] thresholds for treatment with vitamin D supplementation have been suggested and are derived almost exclusively from observational studies. Whether other characteristics, including race/ethnicity, BMI, and estimated glomerular filtration rate (eGFR), should also influence the threshold for treatment is unknown. OBJECTIVES: The aim was to identify clinical and biomarker characteristics that modify the response to vitamin D supplementation. METHODS: A total of 666 older adults in the Multi-Ethnic Study of Atherosclerosis (MESA) were randomly assigned to 16 wk of oral vitamin D3 (2000 IU/d; n = 499) or placebo (n = 167). Primary outcomes were changes in serum parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations from baseline to 16 wk. RESULTS: Among 666 participants randomly assigned (mean age: 72 y; 53% female; 66% racial/ethnic minority), 611 (92%) completed the study. The mean (SD) change in PTH was -3 (16) pg/mL with vitamin D3 compared with 2 (18) pg/mL with placebo (estimated mean difference: -5; 95% CI: -8, -2 pg/mL). Within the vitamin D3 group, lower baseline 25-hydroxyvitamin D [25(OH)D] was associated with a larger decline in PTH in a nonlinear fashion. With baseline 25(OH)D ≥30 ng/mL as the reference, 25(OH)D <20 ng/mL was associated with a larger decline in PTH with vitamin D3 supplementation (-10; 95% CI: -15, -6 pg/mL), whereas 25(OH)D of 20-30 ng/mL was not (-2; 95% CI: -6, 1 pg/mL). A segmented threshold model identified a baseline 25(OH)D concentration of 21 (95% CI: 13, 31) ng/mL as an inflection point for difference in change in PTH. Race/ethnicity, BMI, and eGFR did not modify vitamin D treatment response. There was no significant change in 1,25(OH)2D in either treatment group. CONCLUSIONS: Of characteristics most commonly associated with vitamin D metabolism, only baseline 25(OH)D <20 ng/mL modified the PTH response to vitamin D supplementation, providing support from a clinical trial to use this threshold to define insufficiency. This trial was registered at clinicaltrials.gov as NCT02925195.

Validation of the 24,25-dihydroxyvitamin D3 to 25-hydroxyvitamin D3 ratio as a biomarker of 25-hydroxyvitamin D3 clearance.

The formation of 24,25-dihydroxyvitamin D (24,25(OH)2D) from 25-hydroxyvitamin D (25(OH)D) is the primary mechanism for the metabolic clearance of 25(OH)D, and is regulated by tissue-level vitamin D activity. The ratio of 24,25(OH)2D3 to 25(OH)D3 in blood (vitamin D metabolite ratio, VDMR) is postulated to be a marker of 25(OH)D3 clearance, however this has never been tested. We measured baseline 24,25(OH)2D3 and 25(OH)D3 concentrations in 87 participants by liquid chromatography-tandem mass spectrometry. Following an infusion of deuterated 25(OH)D3, blood samples for each participant were collected over 56 days and analyzed for deuterated vitamin D metabolites. 25(OH)D3 clearance and the deuterated metabolite-to-parent AUC ratio (ratio of the AUC of deuterated 24,25(OH)2D3 to that of deuterated 25(OH)D3) were calculated. We compared the VDMR with these two measures using correlation coefficients and linear regression. Participants had a mean age of 64 ± 11years, 41 % were female, 30 % were self-described Black, 28 % had non-dialysis chronic kidney disease (CKD) and 23 % had kidney failure treated with hemodialysis. The VDMR was strongly correlated with 25(OH)D3 clearance and the deuterated metabolite-to-parent AUC ratio (r = 0.51 and 0.76, respectively). Adjusting for 25(OH)D3 clearance or the deuterated metabolite-to-parent AUC ratio in addition to clinical covariates, lower VDMR was observed in participants with CKD and kidney failure than in healthy controls; in Black than White participants; and in those with lower serum albumin. Our findings validate the VDMR as a measure of 25(OH)D3 clearance. This relationship was biased by characteristics including race and kidney disease, which warrant consideration in studies assessing the VDMR.

Serum Vitamin D: Correlates of Baseline Concentration and Response to Supplementation in VITAL-DKD.

CONTEXT: The effect of daily vitamin D supplementation on the serum concentration of vitamin D (the parent compound) may offer insight into vitamin D disposition. OBJECTIVE: To assess the total serum vitamin D response to vitamin D3 supplementation and whether it varies according to participant characteristics. To compare results with corresponding results for total serum 25-hydroxyvitamin D [25(OH)D], which is used clinically and measured in supplementation trials. DESIGN: Exploratory study within a randomized trial. INTERVENTION: 2000 International Units of vitamin D3 per day (or matching placebo). SETTING: Community-based. PARTICIPANTS: 161 adults (mean ± SD age 70 ± 6 years; 66% males) with type 2 diabetes. MAIN OUTCOME MEASURES: Changes in total serum vitamin D and total serum 25(OH)D concentrations from baseline to year 2. RESULTS: At baseline, there was a positive, nonlinear relation between total serum vitamin D and total serum 25(OH)D concentrations. Adjusted effects of supplementation were a 29.2 (95% CI: 24.3, 34.1) nmol/L increase in serum vitamin D and a 33.4 (95% CI: 27.7, 39.2) nmol/L increase in serum 25(OH)D. Among those with baseline 25(OH)D < 50 compared with ≥ 50 nmol/L, the serum vitamin D response to supplementation was attenuated (15.7 vs 31.2 nmol/L; interaction P-value = 0.02), whereas the serum 25(OH)D response was augmented (47.9 vs 30.7 nmol/L; interaction P-value = 0.05). CONCLUSIONS: Vitamin D3 supplementation increases total serum vitamin D and 25(OH)D concentrations with variation according to baseline 25(OH)D, which suggests that 25-hydroxylation of vitamin D3 is more efficient when serum 25(OH)D concentration is low.

The Multi-Ethnic Study of Atherosclerosis individual response to vitamin D trial: Building a randomized clinical trial into an observational cohort study.

The INdividual response to VITamin D (INVITe) trial was a randomized, placebo-controlled, parallel group trial of vitamin D3 supplementation (2000 IU daily) designed to determine clinical and genetic characteristics that modify the response to vitamin D supplementation. To enhance internal and external validity and reduce cost, the INVITe trial was nested within the Multi-Ethnic Study of Atherosclerosis (MESA), an ongoing prospective observational cohort study. The INVITe trial enrolled a community-based population of 666 racially and ethnically diverse participants from January 2017 to April 2019. This represents 30% of 2210 MESA participants approached for screening, and 96% of those found to be eligible. Barriers to enrollment included delayed initiation of the trial relative to scheduled MESA study visits, a lower number of available MESA participants than expected, and a high prevalence (18%) of high-dose vitamin D supplementation (>1000 IU daily, an exclusion criterion). The final study visit was attended by 611 participants (92%), and median adherence was 98%. Our experience suggests that integration of a randomized trial into an existing observational cohort study may leverage strengths of the source population and enhance enrollment, retention, and adherence, although with limited enrollment capacity. The INVITe trial will use rigorously-collected data to advance understanding of individual determinants of vitamin D response.

Vitamin D in human serum and adipose tissue after supplementation.

BACKGROUND: Serum 25-hydroxyvitamin D [25(OH)D] concentration is an indicator of vitamin D exposure, but it is also influenced by clinical characteristics that affect 25(OH)D production and clearance. Vitamin D is the precursor to 25(OH)D but is analytically challenging to measure in biological specimens. OBJECTIVES: We aimed to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantification of vitamins D3 and D2 in serum and to explore the potential of circulating vitamin D as a biomarker of exposure in supplementation trials. METHODS: The method was validated using guideline C62-A from the Clinical and Laboratory Standards Institute and was applied in 2 pilot clinical trials of oral vitamin D3 supplementation. Pilot study 1 included 22 adults randomly assigned to placebo or 2000 IU/d. Blood was collected at baseline, 1, 3, 6, and 12 mo. Pilot study 2 included 15 adults randomly assigned to 2000 or 4000 IU/d. Blood and subcutaneous (SUBQ) adipose tissue were collected at baseline and 3 mo. RESULTS: In study 1, mean change (baseline to 3 mo) in serum vitamin D3 was -0.1 ng/mL in the placebo group and 6.8 ng/mL in the 2000 IU/d group (absolute difference: 6.9; 95% CI: 4.5, 9.3 ng/mL). In study 2, mean change (baseline to 3 mo) in serum vitamin D3 was 10.4 ng/mL in the 2000 IU/d group and 22.2 ng/mL in the 4000 IU/d group (fold difference: 2.15; 95% CI: 1.40, 3.37). Serum and adipose tissue vitamin D3 concentrations were correlated, and the dose-response of vitamin D3 in adipose mirrored that in serum. CONCLUSIONS: We validated a sensitive, robust, and high-throughput LC-MS/MS method to quantify vitamins D3 and D2 in serum. Serum and SUBQ adipose tissue vitamin D3 concentrations increased proportionally to dose with 3 mo of daily supplementation.These trials were registered at clinicaltrials.gov as NCT00552409 (pilot study 1) and NCT01477034 (pilot study 2).

Differences in 25-Hydroxyvitamin D Clearance by eGFR and Race: A Pharmacokinetic Study.

BACKGROUND: Conversion of 25-hydroxyvitamin D (25[OH]D) to the active form of vitamin D occurs primarily in the kidney. Observational studies suggest 25(OH)D clearance from the circulation differs by kidney function and race. However, these potential variations have not been tested using gold-standard methods. METHODS: We administered intravenous, deuterated 25(OH)D3 (d-25[OH]D3) in a pharmacokinetic study of 87 adults, including 43 with normal eGFR (≥60 ml/min per 1.73 m2), 24 with nondialysis CKD (eGFR <60 ml/min per 1.73 m2), and 20 with ESKD treated with hemodialysis. We measured concentrations of d-25(OH)D3 and deuterated 24,25-dihydroxyvitamin D3 at 5 minutes and 4 hours after administration, and at 1, 4, 7, 14, 21, 28, 42, and 56 days postadministration. We calculated 25(OH)D clearance using noncompartmental analysis of d-25(OH)D3 concentrations over time. We remeasured 25(OH)D clearance in a subset of 18 participants after extended oral vitamin-D3 supplementation. RESULTS: The mean age of the study cohort was 64 years; 41% were female, and 30% were Black. Mean 25(OH)D clearances were 360 ml/d, 313 ml/d, and 263 ml/d in participants with normal eGFR, CKD, and kidney failure, respectively (P=0.02). After adjustment for age, sex, race, and estimated blood volume, lower eGFR was associated with reduced 25(OH)D clearance (ß=-17 ml/d per 10 ml/min per 1.73 m2 lower eGFR; 95% CI, -21 to -12). Black race was associated with higher 25(OH)D clearance in participants with normal eGFR, but not in those with CKD or kidney failure (P for interaction=0.05). Clearance of 25(OH)D before versus after vitamin-D3 supplementation did not differ. CONCLUSIONS: Using direct pharmacokinetic measurements, we show that 25(OH)D clearance is reduced in CKD and may differ by race. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Clearance of 25-hydroxyvitamin D in Chronic Kidney Disease (CLEAR), NCT02937350; Clearance of 25-hydroxyvitamin D3 During Vitamin D3 Supplementation (CLEAR-PLUS), NCT03576716.

Race, Ancestry, and Vitamin D Metabolism: The Multi-Ethnic Study of Atherosclerosis.

CONTEXT: A comprehensive characterization of racial/ethnic variations in vitamin D metabolism markers may improve our understanding of differences in bone and mineral homeostasis and the risk of vitamin D-related diseases. OBJECTIVE: Describe racial/ethnic differences in vitamin D metabolism markers and their associations with genetic ancestry. DESIGN, SETTING, PARTICIPANTS: In a cross-sectional study within the Multi-Ethnic Study of Atherosclerosis (MESA), we compared a comprehensive panel of vitamin D metabolism markers across self-reported racial/ethnic groups of Black (N = 1759), White (N = 2507), Chinese (N = 788), and Hispanic (N = 1411). We evaluated associations of proportion African and European ancestry with this panel of markers in Black and Hispanic participants using ancestry informative markers. Latent class analysis evaluated associations between patterns of vitamin D measurements with race/ethnicity. RESULTS: Compared with Black participants, White participants had significantly higher serum concentrations of 25-hydroxyvitamin D and fibroblast growth factor-23; lower concentrations of parathyroid hormone and 1,25-dihydroxyvitamin D; circulating vitamin D metabolite ratios suggesting lower CYP27B1 and higher CYP24A1 activity; higher urinary concentrations of calcium and phosphorus with higher urinary fractional excretion of phosphorus; and differences in vitamin D binding globulin haplotypes. Higher percent European ancestry was associated with higher 25-hydroxyvitamin D and lower parathyroid hormone concentrations among Black and Hispanic participants. Latent classes defined by vitamin D measurements reflected these patterns and differed significantly by race/ethnicity and ancestry. CONCLUSIONS: Markers of vitamin D metabolism vary significantly by race/ethnicity, may serve to maintain bone and mineral homeostasis across ranges of 25-hydroxyvitamin D production, and be attributable, at least partly, to genetic ancestry.