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Journal of the American Society of Nephrology : JASN logoLink to Journal of the American Society of Nephrology : JASN
. 2020 Oct 28;32(1):188–198. doi: 10.1681/ASN.2020050625

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

Simon Hsu 1,2,✉, Leila R Zelnick 1,2, Yvonne S Lin 3, Cora M Best 2,4, Bryan Kestenbaum 1,2,5, Kenneth E Thummel 3, Lynn M Rose 6, Andrew N Hoofnagle 2,4, Ian H de Boer 1,2,7
PMCID: PMC7894669  PMID: 33115916

Significance Statement

The pharmacokinetic clearance of 25-hydroxyvitamin D (25[OH]D) is an essential, yet often overlooked, determinant of the concentration of circulating 25(OH)D, the prevailing marker of vitamin-D status. Observational studies have associated markers of low 25(OH)D clearance with poor clinical outcomes and suggest differences in clearance by kidney function and race. In this study, the authors used gold-standard pharmacokinetic methods to show that reduced 25(OH)D clearance is associated with worsening eGFR. They also found that, among participants with normal eGFR, but not among those with CKD or kidney failure, Black participants had higher 25(OH)D clearance compared with White participants. These findings confirm impaired 25(OH)D clearance as a feature of disordered mineral metabolism in kidney disease, and may provide some insight into racial differences in vitamin-D metabolism.

Keywords: chronic kidney disease, catabolism, clearance, end stage kidney disease, racial differences, vitamin D

Abstract

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 (β=−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

The circulating 25-hydroxyvitamin-D (25[OH]D) concentration is the prevailing marker of vitamin-D status. Low concentrations of 25(OH)D define vitamin-D insufficiency and deficiency,1,2 which are common in the general population and in patients with CKD, and have been associated with increased risk of cardiovascular disease and cancer.1,3–9 Sunlight, specific foods, and dietary supplements are well-known sources of vitamin D that contribute to 25(OH)D production. However, few human studies have addressed another key determinant of 25(OH)D concentration, 25(OH)D clearance, which, in this paper, will refer to the pharmacokinetic measurement of the volume of blood from which 25(OH)D is completely removed per unit time, and not exclusively renal clearance.

25(OH)D is converted to the biologically active 1,25-dihydroxyvitamin D (1,25[OH]2D) by cytochrome P450 27B1 (CYP27B1, also known as 1-α hydroxylase), which, in health, occurs primarily in the kidney.10–13 The binding of 1,25(OH)2D to intracellular vitamin-D receptors induces the expression of CYP24A1, an enzyme present in many cell types that metabolizes 25(OH)D to 24,25-dihydroxyvitamin D (24,25[OH]2D), the major circulating product of 25(OH)D clearance.14,15 Lower 24,25(OH)2D concentrations are suggested to be a marker of diminished vitamin D–receptor activation, and are associated with secondary hyperparathyroidism, fractures, and death,16–18 sometimes more strongly than traditional vitamin-D measures such as 25(OH)D.

CKD leads to impaired 1,25(OH)2D production via decreased functional kidney tissue and downregulation of CYP27B1.10,11 However, the effect of CKD on 25(OH)D clearance remains controversial. Observational studies from our group and others have demonstrated an independent and direct correlation between eGFR and 24,25(OH)2D concentration, suggesting impaired 25(OH)D clearance in CKD.16,19–22 Still, others hypothesize that CKD is a state of increased 25(OH)D clearance due to the induction of CYP24A1 by fibroblast growth factor-23 (FGF-23).14 Altogether, the net effect of CKD-related mineral metabolism disorders on 25(OH)D metabolism is unclear, leaving uncertainty in the biologic framework of vitamin-D metabolism. Similar ambiguity surrounds racial heterogeneity in 25(OH)D clearance. Black individuals have lower circulating concentrations of 25(OH)D, but not lower 1,25(OH)2D and calcium concentrations when compared with White individuals,23–25 supporting a hypothesis of reduced 25(OH)D clearance to conserve substrate.

To address these uncertainties, we empirically measured 25(OH)D clearance by deuterated 25(OH)D3 (d-25[OH]D3) infusion in a prospective, pharmacokinetic study of Black or White adults with a wide range of kidney function. We also tested whether vitamin-D supplementation modifies 25(OH)D clearance by remeasuring d-25(OH)D3 clearance in a subset of participants after 12–16 weeks of 2000 IU/d of oral vitamin D3.

Methods

Study Design and Population

Participants were recruited into the pharmacokinetic study from existing registries, recently completed and ongoing research studies, outpatient clinics, and dialysis centers in the Seattle, Washington area from March 2017 to July 2019. Inclusion criteria were age ≥18 years and serum 25(OH)D between 10 and 50 ng/ml. We excluded participants with primary hyperparathyroidism; gastric bypass; tuberculosis; sarcoidosis; current pregnancy; serum calcium >10.1 mg/dl; hemoglobin <10 g/dl; use of vitamin-D3 supplements >400 IU/d, any vitamin-D2 supplements, 1,25(OH)2D3 or an analogue, calcimimetics, and medications known to induce CYP enzymes; current or previous kidney transplant; and inability to provide informed consent. Participants on excluded drugs were allowed to washout before screening. We defined healthy controls as those with eGFR ≥60 ml/min per 1.73 m2 and urine albumin-creatinine ratio (UACR) <30 mg/g, CKD as eGFR <60 ml/min per 1.73 m2 in participants not treated with dialysis, and kidney failure as those on chronic maintenance hemodialysis. This study was approved by the University of Washington Institutional Review Board and the US Food and Drug Administration’s Investigational New Drug program.

Study Protocol

At the baseline study visit, urine samples were collected, an intravenous catheter was placed, and blood was drawn for analysis, which included serum creatinine and vitamin-D metabolites. Then, a single dose of d-25(OH)D3 (26,26,26,27,27,27-D6; ISOTEC, Stable Isotope Division, Sigma-Aldrich, Miamisburg, OH) was administered intravenously over 5 minutes (Supplemental Methods). For each participant, the dose was calculated to achieve a peak d-25(OH)D3 concentration near 5 ng/ml, a quantity that intended reliable detection of circulating d-25(OH)D3 concentrations without altering underlying vitamin-D metabolism. Blood was drawn for serial deuterated vitamin D–metabolite measurements 5 minutes and 4 hours after the infusion was completed. Subsequent study visits took place 1, 4, 7, 14, 21, 28, 42, and 56 days after the baseline visit, and included a single blood draw at each visit for the measurement of deuterated vitamin-D metabolites.

After completing the main study, 20 participants enrolled in a pilot study designed to assess the effect of vitamin-D supplementation on 25(OH)D clearance. These participants received 2000 IU/d of oral vitamin D3 (Carlson Labs, Arlington Heights, IL) for approximately 6 months. After 12–16 weeks of supplementation, a single dose of d-25(OH)D3 was administered intravenously, and serum samples were drawn over 56 days in a similar manner as the parent study.

Measurement of Vitamin-D Metabolites

Plasma concentrations of endogenous, nondeuterated 1,25(OH)2D2, 1,25(OH)2D3, 24,25(OH)2D3, 25(OH)D2, and 25(OH)D3 were determined using immunoaffinity extraction and liquid chromatography–tandem mass spectrometry (LC-MS/MS) as previously described.26,27 Total 25(OH)D was calculated by adding 25(OH)D2 and 25(OH)D3. For each participant at each time point, serum concentrations of d-25(OH)D3 and deuterated 24,25(OH)2D3 (d-24,25[OH]2D3) were measured using liquid-liquid extraction and LC-MS/MS as previously described,16,26,28 except that trideuterated 25(OH)D3 (Medical Isotopes Inc., Pelham, NH) was used as the internal standard for both d-25(OH)D3 and d-24,25(OH)2D3. The between-batch analytical variability for the quantification of each of the analytes in the two assays was 2.71%–24.86% for 0.76–7.81 ng/ml of d-25(OH)D3, and 16.9%–76.4% for 0.02–0.20 ng/ml of d-24,25(OH)2D3 (Supplemental Table 1). All vitamin-D measurements were made at the University of Washington.

Pharmacokinetic Modeling

For each participant, noncompartmental analyses of d-25(OH)D3 and d-24,25(OH)2D3 concentrations versus time were performed using Phoenix WinNonlin (version 8.2; Certara, Princeton, NJ). Peak serum concentration and time to peak concentration (Tmax) were determined on the basis of observed values. The terminal rate constant (k) was estimated from the terminal log-linear concentration versus time points for each participant. The terminal t1/2 was calculated from the equation t1/2=ln2/k. The linear trapezoidal rule was used to calculate the area under the serum concentration-time curve from time=0 to the last observed time point (Clast) (AUC0–t), and the area under the serum concentration-time curve from time=0 was extrapolated to infinity by using AUC0–t+Clast/k. The 25(OH)D clearance was calculated by dividing the administered d-25(OH)D3 dose by the AUC0–∞. For the d-24,25(OH)2D3 concentration versus time data, peak serum concentration and Tmax were determined on the basis of observed values. Given observed variability in 24,25(OH)2D3 concentrations, the terminal rate constant could not be estimated, thus only AUC0–56 was determined. The molar ratio of the AUC0–56 for d-24,25(OH)2D3 to that of d-25(OH)D3 (AUC ratio) was calculated.

Covariates

Age, sex, race/ethnicity, smoking status, and comorbidities were self-reported by participants using standardized questionnaires.29–31 Details on the measurements of other clinical covariates are provided in the Supplemental Methods.

Laboratory measurements were obtained from serum and urine samples that were stored at −80°C, with the exception of intact parathyroid hormone (PTH) and UACR, which were assayed immediately after the study visit. General chemistries, urine albumin, and creatinine were measured on a Beckman Coulter DxC autoanalyzer (Beckman Coulter, Brea, CA). PTH was measured with the Beckman Coulter DxI automated immunoassay, intact FGF-23 was measured using the Kainos immunoassay (Kainos Laboratories, Tokyo, Japan), and vitamin D binding globulin (VDBG) was measured by an LC-MS/MS assay.32–34 UACR was quantified from a single-voided urine sample. The eGFR was calculated using the creatinine-only Chronic Kidney Disease Epidemiology Collaboration equation.35

Statistical Analyses

We examined interrelationships of 25(OH)D clearance with covariates using boxplots, scatterplots, and Pearson correlation coefficients. 25(OH)D clearance and other pharmacokinetic measures between the healthy controls, those with CKD, and those with kidney failure were compared using linear regression with Huber–White robust SEM. Specifically, the null hypothesis of equal pharmacokinetic measures across all kidney-disease groups was tested via a global Wald test of the kidney-disease group terms. We used linear regression to evaluate associations between eGFR and 25(OH)D clearance in an unadjusted model, and after adjustment for age, sex, race, and estimated blood volume. The same approach was used to test differences in mean 25(OH)D clearance in Black participants compared with White participants with adjustment for eGFR. We excluded two participants with extreme 25(OH)D clearance values (919 and 801 ml/d) from our main linear regression analyses, but included them in sensitivity analyses. Interactions were tested by the Wald test of product terms for eGFR and race, and for kidney-disease group and race.

For the subset of participants who received vitamin-D3 supplementation, we compared baseline with postsupplementation pharmacokinetic measures, including 25(OH)D clearance, using paired t tests. We used linear regression to assess the relationship between the change in serum total 25(OH)D concentration to vitamin-D3 supplementation and 25(OH)D clearance (mean of d-25[OH]D3 clearances at baseline and during supplementation).

All analyses were conducted with R version 3.6.1 (R Foundation for Statistical Computing). The nominal level of significance was defined as P<0.05 (two tailed).

Results

Participant Characteristics

Of 123 screened participants, 34 were excluded (Supplemental Figure 1). One participant withdrew after enrollment and one was excluded for incomplete sample collection, leaving 87 participants for analysis. The mean age of the participating cohort was 64±11 years; 41% were female and 30% were Black (Table 1). There were 43 healthy controls with a mean eGFR of 85±15 ml/min per 1.73 m2. A total of 24 participants had nondialysis CKD, with a mean eGFR of 42±13 ml/min per 1.73 m2, and 20 participants had kidney failure treated with hemodialysis. Racial distribution was similar across kidney-disease groups by design, with 28%–33% Black participants in each group. Baseline total 25(OH)D concentrations were similar in the three kidney-disease groups.

Table 1.

Baseline characteristics of participants in the Clearance of 25-hydroxyvitamin D in Chronic Kidney Disease Study

Characteristics Healthy Controls (n=43) CKD (n=24) Kidney Failure (n=20)
Age (yr), mean (SD) 64 (10) 67 (11) 58 (9)
Female, n (%) 24 (56) 8 (33) 4 (20)
Race, n (%)
 White 31 (72) 16 (67) 14 (70)
 Black 12 (28) 8 (33) 6 (30)
Hypertension, n (%) 15 (35) 17 (71) 14 (70)
Diabetes, n (%) 7 (16) 13 (54) 9 (45)
Ever smoker, n (%) 19 (44) 10 (42) 8 (40)
RAAS-I use, n (%) 11 (26) 14 (58) 1 (5)
Statin use, n (%) 13 (30) 13 (54) 6 (30)
Vitamin-D3 supplement use (≤400 IU), n (%) 6 (14) 1 (4) 1 (5)
Systolic BP (mm Hg), mean (SD) 125 (16) 127 (34) 124 (19)
BMI (kg/m2), mean (SD) 29.3 (7.1) 29.3 (6.5) 30.0 (7.2)
EBV (L), mean (SD) 4.9 (0.9) 5.2 (1.0) 5.5 (1.3)
Total 25(OH)D (ng/ml), mean (SD) 23 (8) 25 (9) 24 (10)
PTH (pg/ml), median (IQR) 60 (44–71) 89 (48–156) 456 (289–739)
FGF-23 (pg/ml), median (IQR) 58 (52–70) 106 (75–140) 2477 (665–8726)
Calcium (mg/dl), mean (SD) 9.2 (0.3) 9.2 (0.3) 8.9 (0.7)
Albumin (g/dl), mean (SD) 4.1 (0.3) 4.0 (0.3) 4.0 (0.3)
VDBG (μg/ml), mean (SD) 217 (30) 217 (30) 241 (39)
eGFR (ml/min per 1.73 m2), mean (SD) 85 (15) 42 (13) N/A
UACR (mg/g), median (IQR) 3 (0–14) 28 (7–178) N/A
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RAAS-I, renin-angiotensin-aldosterone system inhibitor; EBV, estimated blood volume; IQR, interquartile range; N/A, not applicable.

All 20 participants with kidney failure received hemodialysis with a median of 629 (interquartile range, 432–1121) days on dialysis. Fifteen participants dialyzed through an arteriovenous fistula, three through an arteriovenous graft, and two through a tunneled dialysis catheter. The two most common etiologies of kidney failure were diabetes (n=7) and polycystic kidney disease (n=4).

25(OH)D Clearance

The Tmax for d-25(OH)D3 was reached at 5 minutes after the infusion was completed for all participants, after which d-25(OH)D3 concentrations declined over time (Figure 1). Mean 25(OH)D clearances were 360±108, 313±86, and 263±163 ml/d in healthy controls, those with CKD, and those with kidney failure, respectively (P=0.02; Table 2). Mean 25(OH)D t1/2 were 21.9±5.7, 25.5±6.5 and 35.6±8.1 days (P<0.01), and the molar AUC ratio of d-24,25(OH)2D3 to d-25(OH)D3 were 0.12±0.04, 0.08±0.03, 0.03±0.03 in healthy controls, those with CKD, and those with kidney failure, respectively (P<0.01). There was a weak correlation between 25(OH)D clearance with estimated blood volume (r=0.33) and VDBG concentration (r=−0.29), and no significant correlation with age (r=−0.03), body mass index (BMI; r=0.19), serum albumin concentration (r=0.07), or baseline total 25(OH)D concentration (r=−0.21). There were no differences in 25(OH)D clearance by sex or diabetes status. Racial differences were notable only among healthy controls, among whom Black participants had higher mean 25(OH)D clearance compared with White participants (416±84 versus 339±110 ml/d) (Figure 2).

Figure 1.

Figure 1.

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Concentration-time curves of deuterated vitamin D3 metabolites. (A) Healthy controls, (B) participants with CKD, and (C) participants with kidney failure. The dots indicate the mean; the vertical whiskers indicate the SD in each direction.

Table 2.

Pharmacokinetic parameters of d-25(OH)D3

Parameter Healthy Controls (n=43) CKD (n=24) Kidney Failure (n=20) P Value
Dose administered (µg) 25 (5) 26 (5) 26 (6) 0.2
Clearance (ml/d) 360 (108) 313 (86) 263 (163) 0.02
t1/2 (d) 21.9 (5.7) 25.5 (6.5) 35.6 (8.1) <0.01
Cmax (ng/ml) 9.4 (1.2) 9.9 (1.7) 11.8 (7.6) 0.19
AUC ratioa 0.12 (0.04) 0.08 (0.03) 0.03 (0.03) <0.01
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Data are presented as mean (SD). Cmax, maximum serum concentration.

a

AUC ratio: ratio of the molar area under the curve for d-24,25(OH)2D3 to that of d-25(OH)D3.

Figure 2.

Figure 2.

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25(OH)D clearance by kidney-disease group and race. The center horizontal line in each box indicates the median; top and bottom box borders indicate the first and third quartiles, respectively. The vertical whiskers depict the most extreme observation within 1.5 times the interquartile range of the nearest quartile; dots show all points lying beyond 1.5 times the interquartile range of the nearest quartile.

In unadjusted models, each 10 ml/min per 1.73 m2 lower eGFR was associated with a −14 (95% CI, −19 to −8) ml/d lower 25(OH)D clearance in all study participants. However, the size of this association differed by race, with estimates of −20 (95% CI, −29 to −12) ml/d for Black participants and −10 (95% CI, −16 to −4) ml/d for White participants (P for interaction=0.03; Supplemental Figure 2). After adjustment for age, sex, race, and estimated blood volume, every 10 ml/min per 1.73 m2 lower eGFR was associated with −17 (95% CI, −21 to −12) ml/d 25(OH)D clearance in all participants, −21 (95% CI, −30 to −12) ml/d among Black participants, and −15 (95% CI, −20 to −10) ml/d among White participants (P=0.05 for eGFR-race interaction). Similar results were obtained when adjusting for BMI instead of estimated blood volume, and in sensitivity analyses that included the two outlier participants (Supplemental Table 2).

In unadjusted models, Black race was associated with 41 (95% CI, −1 to 83) ml/d higher 25(OH)D clearance compared with White race in all participants, and 92 (95% CI, 41 to 144) ml/d higher clearance among healthy controls (P=0.03 for kidney-disease group–race interaction). In models adjusted for age, sex, estimated blood volume, and eGFR, Black race was associated with 22 (95% CI, −12 to 56) ml/d higher 25(OH)D clearance compared with White race in all participants, and 71 (95% CI, 16 to 125) ml/d higher clearance among healthy controls (P=0.05 for kidney-disease group–race interaction). In sensitivity analyses that included the two outlier participants, the adjusted association between Black race and 25(OH)D clearance among healthy controls was no longer statistically significant (26 ml/d higher for Black compared with White race; 95% CI, −32 to 84 ml/d; Supplemental Table 2).

Vitamin-D3 Supplementation Pilot Study

Of the 20 participants who enrolled in the supplement study, one withdrew and one was excluded due to serum d-25(OH)D3 concentrations suggesting an error in d-25(OH)D3 administration, leaving 18 participants for analysis (Supplemental Figure 1). Ten participants were healthy controls, with a mean eGFR of 89±12 ml/min per 1.73 m2, and eight participants had nondialysis CKD, with a mean eGFR of 37±13 ml/min per 1.73 m2 (Supplemental Table 3). Sixty percent of healthy controls and 50% of participants with CKD were Black. The baseline total 25(OH)D was lower in healthy controls compared with the CKD group. Total 25(OH)D increased by 16 ng/ml and 14 ng/ml after 12–16 weeks of oral vitamin-D3 supplementation in the control and CKD groups, respectively.

Mean 25(OH)D clearance was 372±106 ml/d at baseline and 385±128 ml/d after oral vitamin-D3 supplementation (Table 3). The mean change in 25(OH)D clearance after supplementation was 13.9 (95% CI, −33 to 60) ml/d. When stratified by kidney-disease group, there was no significant difference in change in 25(OH)D clearance after vitamin-D3 supplementation (Figure 3). Lower 25(OH)D clearance was associated with a larger increase in serum total 25(OH)D concentration with vitamin-D3 supplementation (Supplemental Figure 3).

Table 3.

Pharmacokinetic parameters of d-25(OH)D3 in the vitamin D3–supplemented cohort

Parameters Baseline, Mean (SD) After Supplement, Mean (SD) Difference (after supplement to baseline), Estimate (95% CI) P Value
All (n=18)
 Clearance (ml/d) 372 (106) 385 (128) 14 (−33 to 60) 0.54
 t1/2 (d) 23.2 (7.1) 23.0 (8.2) −0.2 (−3.8 to 3.4) 0.91
 Cmax (ng/ml) 9.6 (1.3) 9.8 (1.4) 0.1 (−0.4 to 0.6) 0.55
 AUC ratioa 0.11 (0.05) 0.11 (0.06) −0.01 (−0.03 to −0.02) 0.63
CKD (n=8)
 Clearance (ml/d) 317 (88) 322 (88) 5 (−45 to 55) 0.81
 t1/2 (d) 27.7 (5.2) 28.9 (7.6) 1.2 (−5.1 to 7.4) 0.67
 Cmax (ng/ml) 9.1 (1.6) 9.2 (1.2) 0.2 (0.6 to 1.0) 0.61
 AUC ratioa 0.08 (0.03) 0.06 (0.02) −0.02 (−0.04 to 0.002) 0.07
Healthy controls (n=10)
 Clearance (ml/d) 415 (101) 436 (135) 21 (−63 to 105) 0.58
 t1/2 (d) 19.5 (6.4) 18.3 (5.1) −1.3 (−6.3 to 3.8) 0.58
 Cmax (ng/ml) 10.1 (1.2) 10.2 (1.4) 0.1 (−0.6 to 0.9) 0.76
 AUC ratioa 0.14 (0.05) 0.14 (0.05) 0.01 (−0.03 to 0.05) 0.73
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Cmax, maximum serum concentration.

a

AUC ratio: ratio of the molar area under the curve for d-24,25(OH)2D3 to that of d-25(OH)D3.

Figure 3.

Figure 3.

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25(OH)D clearance with and without vitamin-D3 supplementation in the vitamin D3–supplemented cohort. The center horizontal line in each box indicates the median; top and bottom box borders indicate the first and third quartiles, respectively. The vertical whiskers depict the most extreme observation within 1.5 times the interquartile range of the nearest quartile; dots show all points lying beyond 1.5 times the interquartile range of the nearest quartile. The spaghetti plot lines show individual changes in 25(OH)D clearance compared with without vitamin D3 supplementation.

Discussion

Using direct pharmacokinetic measurements, we show that lower eGFR is strongly associated with lower 25(OH)D clearance. We further show that Black race is associated with higher 25(OH)D clearance in persons without kidney disease, but similar 25(OH)D clearance in the presence of CKD or kidney failure. In our pilot study, oral vitamin-D3 supplementation did not change 25(OH)D clearance, although lower 25(OH)D clearance was associated with a larger increase in serum total 25(OH)D concentration after supplementation.

Based on d-25(OH)D3 kinetics, we provide conclusive evidence that the net effect of CKD-related factors, including elevated concentrations of FGF-23 and PTH on 25(OH)D metabolism, is markedly reduced clearance (Figure 4). This was hypothesized as early as 1974, when Gray et al.20 reported longer t1/2 of radiolabeled 25(OH)D in ten patients on hemodialysis compared with healthy controls. Evidence has since grown to include associations between low eGFR and reduced concentrations of metabolic products of 25(OH)D clearance in multiple cohorts,16,19 confirmed now using gold-standard methods. Our results contradict the concept that lower serum 25(OH)D concentrations seen in CKD are due to greater 25(OH)D clearance.

Figure 4.

Figure 4.

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Feedback regulation of vitamin-D metabolism. PTH induces the CYP27B1-mediated conversion of 25(OH)D to 1,25(OH)2D, and inhibits the CYP24A1-mediated clearance of 25(OH)D to 24,25(OH)2D. Through classic negative feedback, 1,25(OH)2D suppresses PTH release and promotes CYP24A1-mediated 25(OH)D clearance. FGF-23 is secreted in response to 1,25(OH)2D, and in a feedback loop, inhibits CYP27B1-mediated 1,25(OH)2D synthesis and induces CYP24A1.

We observed serum 25(OH)D t1/2s similar to prior 25(OH)D tracer studies, generally reported at 2–3 weeks in healthy individuals and 6 weeks in persons with kidney failure.20,36–41 Because steady state for a drug is reached at about four to five t1/2s for that drug, our findings suggest clinicians should optimally remeasure 25(OH)D concentrations approximately 12 weeks after supplementation in normal individuals and up to 26 weeks in persons with kidney failure.

One proposed mechanism for reduced 25(OH)D clearance in CKD is reduced glomerular filtration of 25(OH)D, which decreases its delivery to intracellular CYP24A1 in proximal tubules.42 Additionally, 1,25(OH)2D concentrations decline substantially during CKD, leading to reduced CYP24A1 expression.15,43 25(OH)D clearance declined in tandem with eGFR, but participants with kidney failure still had approximately 73% of the 25(OH)D clearance seen in healthy controls. Extrarenal pathways, such as hepatic conjugation, P-glycoprotein 1–mediated efflux, and extrarenal CYP24A1 activity, may be dominant modes of 25(OH)D clearance in kidney failure.44–48 Protein carbamylation is a post-translational modification to proteins like albumin that leads to their functional impairment and increases with eGFR decline as a result of constant urea exposure.49,50 Assuming carbamylation impairs albumin’s ability to bind 25(OH)D, one would expect an increase in free circulating 25(OH)D and thus 25(OH)D clearance. Because we observed a decrease in 25(OH)D clearance with worsening eGFR, this phenomenon appears unlikely to explain our study findings, although we acknowledge the previous assumption as a limitation of our study.

The higher 25(OH)D clearance seen in Black compared with White participants with normal eGFR was surprising. Despite lower 25(OH)D concentrations, Black individuals do not have lower 1,25(OH)2D or serum calcium concentrations, in part due to higher PTH concentration and lower urinary calcium excretion.23–25,51 A reduced 25(OH)D clearance in Black race would fit into a paradigm of conserving 25(OH)D, but, in fact, we observed the opposite. There are a few possible explanations for this. First, higher CYP24A1-mediated 25(OH)D clearance may contribute to lower concentrations of 25(OH)D, perhaps driven by higher 1,25(OH)2D.25 This is consistent with a study reporting a nominally shorter t1/2 of an oral dose of d-25(OH)D in West African men compared with men from the United Kingdom, although this finding was not statistically significant.36 Second, higher 25(OH)D clearance in Black race could occur through non-CYP24A1-mediated pathways, which would reconcile our results with reports of lower circulating 24,25(OH)2D concentrations in Black compared with White populations.16 Third, differences in VDBG genotype and associated 25(OH)D binding affinities may account for racial differences in 25(OH)D clearance.52,53 Lastly, our data may be chance observations and not representative of the general Black population.

We observed no correlation between serum 25(OH)D concentrations and its clearance (r=−0.21), and no change in 25(OH)D clearance with oral vitamin-D3 supplementation. This was a pilot study, and confidence intervals do not exclude relevant induction of 25(OH)D clearance with supplementation, but our results suggest 25(OH)D concentration alone may not play a significant role in 25(OH)D elimination. Others have shown that vitamin-D supplementation does not change the tightly regulated 1,25(OH)2D concentration,54,55 likely leaving CYP24A1 expression unaffected. Larger studies are needed to confirm our findings, but our data offer support for the notion that serum 25(OH)D poorly reflects tissue-level vitamin-D activity, for which other biomarkers may be superior.16,17,56

Randomized trials show that the biologic response to vitamin-D treatment is highly heterogeneous.57–60 Our finding of an inverse correlation between 25(OH)D clearance and the increase in serum total 25(OH)D response to supplementation (r=−0.41) suggests 25(OH)D clearance may modify the vitamin-D treatment response. Future studies should assess surrogate measures of 25(OH)D clearance, such as the ratio of 24,25(OH)2D3 to 25(OH)D3,17,56,61 which may enhance interpretation of vitamin-D supplementation trials and improve the clinical evaluation and management of impaired vitamin-D metabolism in CKD.

Two participants had unusually high 25(OH)D clearances (919 and 801 ml/d), serum 25(OH)D <10 ng/ml, hypocalcemia, secondary hyperparathyroidism, and BMI >40 kg/m2. These participants may have CYP24A1 hyperactivity, or increased 25(OH)D clearance through CYP24A1-independent pathways mediated by morbid obesity. Although we could not specifically identify any obvious explanations for these findings, there is likely something substantially different about them with respect to their 25(OH)D clearances that are not related to eGFR or race that we felt justified their exclusion from linear regression models assessing these risk factors. In sensitivity analyses including both of these participants, our eGFR results were similar; however, because both of these outliers are White, their inclusion in our models significantly altered the results by race, which supports a cautious interpretation of the reported racial differences in 25(OH)D clearance.

To our knowledge, this is the only study dedicated to determining 25(OH)D clearance across a broad range of kidney function and by race. This is in contrast to prior 25(OH)D tracer studies that have either been small, limited to predominantly White participants, or used an oral tracer, which is subject to variation in bioavailability between participants.20,36–41 Other strengths include gold-standard pharmacokinetic methods, the use of an intravenous tracer, and relatively large sample size.

This study also has important limitations. First, race was self-reported rather than genetically determined. Second, although we assume that reduced 25(OH)D clearance in CKD occurs primarily through reduced CYP24A1 activity, other catabolic pathways for 25(OH)D have been described and may be altered in kidney disease.62,63 Third, the molar AUC ratio of d-24,25(OH)2D3 to d-25(OH)D3 should ideally be calculated with AUCs extrapolated to infinite time. However, due to limited and variable data for d-24,25(OH)2D3, especially for participants with kidney failure, the molar AUC ratio was calculated using the AUC to the last measured time point (day 56). If the t1/2 of d-24,25(OH)2D3 increases with kidney dysfunction, as seen with d-25(OH)D3, the molar AUC ratios are likely to be underestimated. Fourth, although the methods used in this study represent state-of-the-art techniques, it is possible that the change from protons to deuterium atoms in the tracer of 25(OH)D3 alters the clearance of 25(OH)D3 by changing its affinity for metabolic enzymes or binding proteins. Whereas this could potentially lead to differences in pharmacokinetic values compared with other studies that use different tracers, it is unlikely to bias the key within-study findings of differences in 25(OH)D clearance by kidney function and race we observed. Lastly, although our supplementation pilot study was null, 25(OH)D clearance still varied significantly for many individuals before and after vitamin-D3 supplementation (Figure 3). If this is due to measurement error of 25(OH)D clearance rather than inherent intraindividual variability, then our reported associations may be stronger than they appear due to misclassification that is most likely nondifferential.

Using gold-standard pharmacokinetic methods, we demonstrated that reduced 25(OH)D clearance and decreased formation of 24,25(OH)2D3 are features of disordered mineral metabolism in patients with CKD and kidney failure. We observed higher 25(OH)D clearance in Black as compared with White participants with normal eGFR, although future studies are needed confirm our findings and explore potential mechanisms. Oral vitamin-D3 supplementation did not modify 25(OH)D clearance, although 25(OH)D clearance was inversely correlated with total 25(OH)D response to supplementation. Surrogate measures of 25(OH)D clearance may help clinicians better assess and treat vitamin D deficiency.

Disclosures

A.N. Hoofnagle reports receiving other from DiaSorin and personal fees from Kilpatrick Townsend & Stockton LLP, outside the submitted work. B. Kestenbaum reports receiving personal fees from Reata Pharmaceuticals, outside the submitted work. All remaining authors have nothing to disclose.

Funding

This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grants R01DK099199 (primary funding source), R01DK099199-S1, 2T32DK007467-36, and P30DK040561; National Center for Advancing Translational Sciences grant UL1 TR002319; National Institute of General Medical Sciences grant R01GM63666; and a Northwest Kidney Centers unrestricted grant. K. Thummel reports receiving National Institute of General Medical Sciences grants, during the conduct of the study. A. Hoofnagle reports receiving National Institute of Diabetes and Digestive and Kidney Diseases grants and Karst Waters Institute grants, during the conduct of the study. I. de Boer reports receiving National Institute of Diabetes and Digestive and Kidney Diseases grants, during the conduct of the study. L. Zelnick reports receiving National Institutes of Health grants, during the conduct of the study.

Supplementary Material

Supplemental Data
ASN.2020050625SupplementaryData.pdf (366.5KB, pdf)

Acknowledgments

We thank Richard Senderoff for his guidance with preparation and regulatory approval of the deuterated 25(OH)D3 material, Kidney Research Institute research coordinators and staff, and the study participants. We thank Carlson Labs for supplying vitamin D3 supplements at research cost.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Dr. Yvonne S. Lin, Dr. Kenneth E. Thummel, Dr. Lynn M. Rose, Dr. Andrew N. Hoofnagle, and Dr. Ian H. de Boer designed the study; Dr. Andrew N. Hoofnagle and Dr. Ian H. de Boer carried out experiments; Dr. Simon Hsu, Dr. Leila R. Zelnick, and Dr. Yvonne S. Lin analyzed the data; Dr. Simon Hsu and Dr. Yvonne S. Lin made the figures; Dr. Simon Hsu drafted and revised the paper; and all authors approved the final version of the manuscript.

Footnotes

Published online ahead of print. Publication date available at www.jasn.org.

Supplemental Material

This article contains the following supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2020050625/-/DCSupplemental.

Supplemental Methods.

Supplemental Table 1. Analytical variability of the assays, expressed as between-batch coefficient of variation (CV%) of vitamin D metabolites.

Supplemental Table 2. Sensitivity analysis of associations of eGFR and race with 25(OH)D clearance in the full study population versus excluding two outlier participants.

Supplemental Table 3. Characteristics of the vitamin D3 supplemented cohort.

Supplemental Figure 1. Participant flow in the Clearance of 25-hydroxyvitamin D in CKD Study.

Supplemental Figure 2. Relationship between eGFR with 25-hydroxyvitamin D clearance by race.

Supplemental Figure 3. Linear regression depicting the relationship of 25-hydroxyvitamin D response to vitamin D3 supplementation with mean 25-hydroxyvitamin D clearance in the vitamin D3 supplemented cohort.

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