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6 24,25-Dihydroxyvitamin D and 1,24,25-Trihydroxyvitamin D

6 24,25-Dihydroxyvitamin D and 1,24,25-Trihydroxyvitamin D

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14



C. Zierold et al.



present in the inner membrane of the mitochondria of target cells. This enzyme,

also known as CYP24A1, is a cytochrome P-450 mixed function monooxygenase

that requires nicotinamide adenine dinucleotide phosphate oxidase (NADPH), ferrodoxin, and ferrodoxin reductase to introduce molecular oxygen on the carbon 24

of 1,25(OH)2D or 25(OH)D. Both metabolites are substrates for the 24-hydroxylase, but the affinity is tenfold higher for 1,25(OH)2D than 25(OH)D, yet the

25(OH)D circulates at 1,000-fold higher concentrations (ng/mL versus pg/mL).

Recently, human patients with infantile idiopathic hypercalcemia were identified

with mutations in the CYP24A1 gene, and found to have accumulation of serum

1,25(OH)2D, further supporting the role of 24-hydroxylase in the clearance of vitamin D metabolites [1, 2, 6].

A biological role for 24-hydroxylated vitamin D metabolites remains

controversial. While inactivation of the active 1,25(OH)2D makes physiological

sense, the role of inactivation of the not-yet-active 25(OH)D has been questioned.

However, that 24-hydroxylation of 25(OH)D decreases the available substrate for

1α-hydroxylation does afford a viable regulatory step. Animals fed a diet with

24,24-difluoro-25-OH-D3 as their sole source of vitamin D for two generations

had normal growth, reproduction and skeletal mineralization. The difluoro compound cannot be 24-hydroxylated, but behaves as 1,25(OH)2D when

1α-hydroxylated, and the metabolism of vitamin D is not unbalanced, yet

24,25(OH)2D is absent. Furthermore, 24-Hydroxylase-null mice were generated

and show 50 % perinatal lethality. Interestingly the mice that survived past weaning were able to catabolize 1,25(OH)2D by an alternate pathway, and showed normal levels of circulating calcium and phosphate. These surviving homozygous

24-hydroxylase-null mice can be bred, and have offspring with abnormal bone

development, which can however be rescued when CYP24/VDR double null

mutants are generated. This can be explained by the fact that 24-hydroxylase-null

dams have elevated levels of 1,25(OH)2D during gestation which cause the bone

abnormalities in the developing offspring when VDR is present. In the absence of

VDR, 1,25(OH)2D cannot carry out its function even though circulating at elevated levels, and the offspring now have normal bone development in spite of the

absence of 24,25(OH)2D. In light of this, 24,25(OH)2D does not appear to be necessary for normal bone development during development, and is likely the product of the first catabolic step for 25(OH)D, with no known function. This confirms

the early conclusions reached using the 24,24-difluoro-25-OH-D as a sole source

of vitamin D [7, 20].

Regulation of key players in vitamin D metabolism is reciprocal and very tight.

The activating enzyme 1α-hydroxylase, and the catabolic enzyme 24-hydroxylase

are reciprocally regulated by PTH, 1,25(OH)2D, and FGF23. PTH up-regulates

1α-hydroxylase when calcium is needed, while at the same time it downregulates

the 24-hydroxylase. When calcium is normalized, 1,25(OH)2D regulates its own

breakdown by activating the 24-hydroxylase, and decreases its synthesis by downregulating the 1α-hydroxylase. FGF23 is increased when phosphorus levels are

elevated, and shuts down further absorption by down-regulating the 1α-hydroxylase

and up-regulating the 24-hydroxylase [2].



1 Vitamin D Metabolism in Normal and Chronic Kidney Disease States



1.7



15



Other Metabolites



Over 33 metabolites of vitamin D have been isolated and identified, and most are

formed only when high doses of vitamin D are administered. The metabolites that

have been isolated under physiological conditions are shown in Fig. 1.5. In addition

to the above mentioned pathways, other important metabolic pathways of vitamin D

that occur at physiologic concentrations are the 23-hydroxylation of 25(OH)D with

subsequent 26-oxidation, and cyclization to form a lactone, and the 26-hydroxylation

of 25(OH)D. Animals maintained on 25(OH)D fluorinated at positions 23, 26, and

27 to prevent hydroxylation at these carbons, were shown to have normal growth,

reproduction, and bone mineralization thus suggesting that the 23- and

26-hydroxylated metabolites do not have important functions in calcium and phosphorus homeostasis, and that these compounds are likely metabolites of another

catabolic pathway that leads to excretion [4, 6].



1.8



C3-Epimer of 25(OH)D



The C3-epimer of 25(OH)D is an isomer of 25(OH)D, having the hydroxyl group

on carbon 3 in the β orientation instead of α. It has been measured in some infant

blood samples, and it can be found at levels similar to or greater than 25(OH)D. Since

its initial detection in pediatric samples, it has also been detected in adults, albeit

less frequently. When present, the C3-epimer can be detected at concentrations

below 10 ng/mL, though in extreme cases levels as high as 30–50 ng/mL have been

found. To date, no physiological role has been attributed to this metabolite, but

increased interest exists as to find why some subjects present with such high circulating amounts while others have none [1].



1.9



24(OH)D2 or 1,24(OH)2D2



Widespread vitamin D deficiency has led to increased use of over-the-counter vitamin D supplements (both vitamin D3 and D2), and prescription strength vitamin D2

supplementation (50,000 IU). Alternate metabolites were observed when either a

single large dose (1,000,000 IU of vitamin D2) or repeated daily doses (1,000–

50,000 IU vitamin D2) were ingested. 24(OH)D2 and 1,24(OH)2D2 were produced

via a pathway that resulted in 24-hydroxylation occurring via a liver 25-hydroxylase,

presumably the CYP27A1 which prefers vitamin D2 as a substrate over vitamin D3.

This alternate pathway has not been observed for vitamin D3 supplements for which

the expected 25(OH)D3 and 1,25(OH)2D3 metabolites were produced even at high

levels of supplementation. 1,24(OH)2D2 was shown to be physiologically active,

and behave similarly to 1,25(OH)2D [21, 22].



16



1.10



C. Zierold et al.



Relation Between Vitamin D, 24(OH)D, and 1,25(OH)2D



Research in the field has over the years consistently and conclusively shown that

1,25(OH)2D is the biologically active, hormonal form of vitamin D. However, the

measurement of inactive 25(OH)D, has commonly been used in studies of disease

association with vitamin D. The conversion of inactive 25(OH)D to active

1,25(OH)2D is a tightly regulated step, and circulating levels of 1,25(OH)2D are not

directly proportional to the circulating 25(OH)D, but are dependent on physiological states, and respective regulatory stimuli. While small increases in 1,25(OH)2D

may result when circulating levels of 25(OH)D increase, due to more substrate

availability, much larger changes of 1,25(OH)2D can result from regulation by the

physiological state, so that for a given serum level of 25(OH)D, levels of 1,25(OH)2D

can vary more than tenfold. Novel methods for a more accurate and precise measurement of 1,25(OH)2D are being developed, and future clinical studies on the

effects of vitamin D should include quantification of not only 25(OH)D, but also

1,25(OH)2D the active effector molecule that binds the VDR, and is responsible for

physiological responses in target cells.



1.11



Conclusions



Vitamin D as synthesized in the skin or ingested in the diet is inactive, and must

undergo two successive hydroxylations to form the active metabolite 1,25(OH)2D.

1,25(OH)2D maintains adequate levels of calcium and phosphorus in the blood by

acting on intestine, kidney, and bone, and is responsible for other non-calcemic

functions. 1,25(OH)2D carries out its functions through the vitamin D receptor. The

25(OH)D that is produced in the first bio-activation step is inactive, but its measurement in serum or plasma has been adopted as an indicator of an individual’s vitamin

D status. 25(OH)D levels have also commonly been used in studies of disease association with vitamin D, yet 1,25(OH)2D has dependably been shown to be the biologically active form. The regulation of 1,25(OH)2D is very tight and largely

dependent on the physiological state surrounding calcium and phosphorus homeostasis, and thus not directly correlated to the levels of 25(OH)D. Though

25-hydroxyvitamin D, 1,25(OH)2D, and the 24-hydroxylated metabolites are the

most important and well-studied, other physiological metabolites of vitamin D exist,

and future research may reveal additional physiologically important metabolites.



References

1. Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol.

2014;21(3):319–29.

2. Christakos S, et al. Vitamin D: metabolism. Endocrinol Metab Clin North Am. 2010;39(2):

243–53.



1 Vitamin D Metabolism in Normal and Chronic Kidney Disease States



17



3. Christakos S, DeLuca HF. Minireview: vitamin D: is there a role in extraskeletal health?

Endocrinology. 2011;152(8):2930–6.

4. DeLuca HF. The vitamin D story: a collaborative effort of basic science and clinical medicine.

FASEB J. 1988;2(3):224–36.

5. DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin

Nutr. 2004;80(6 Suppl):1689S–96.

6. DeLuca HF. Triennial Growth Symposium – Vitamin D: bones and beyond. J Anim Sci.

2014;92(3):917–29.

7. Deluca HF. History of the discovery of vitamin D and its active metabolites. Bonekey Rep.

2014;3:479.

8. Lo CW, et al. Vitamin D absorption in healthy subjects and in patients with intestinal malabsorption syndromes. Am J Clin Nutr. 1985;42(4):644–9.

9. Speeckaert M, et al. Biological and clinical aspects of the vitamin D binding protein

(Gc-globulin) and its polymorphism. Clin Chim Acta. 2006;372(1–2):33–42.

10. Bhan I. Vitamin d binding protein and bone health. Int J Endocrinol. 2014;2014:561214.

11. Yousefzadeh P, Shapses SA, Wang X. Vitamin D binding protein impact on 25-hydroxyvitamin

D levels under different physiologic and pathologic conditions. Int J Endocrinol. 2014;2014:

981581.

12. Zhu JG, et al. CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo. Proc Natl Acad Sci U S A. 2013;110(39):15650–5.

13. Martin A, David V, Quarles LD. Regulation and function of the FGF23/klotho endocrine pathways. Physiol Rev. 2012;92(1):131–55.

14. Renkema KY, et al. Calcium and phosphate homeostasis: concerted interplay of new regulators. Ann Med. 2008;40(2):82–91.

15. Liu S, Quarles LD. How fibroblast growth factor 23 works. J Am Soc Nephrol.

2007;18(6):1637–47.

16. Martin KJ, Gonzalez EA. Long-term management of CKD-mineral and bone disorder. Am

J Kidney Dis. 2012;60(2):308–15.

17. Nigwekar SU, Tamez H, Thadhani RI. Vitamin D and chronic kidney disease-mineral bone

disease (CKD-MBD). Bonekey Rep. 2014;3:498.

18. Vaziri ND, et al. Impaired intestinal absorption of vitamin D3 in azotemic rats. Am J Clin Nutr.

1983;37(3):403–6.

19. Evans RM, Mangelsdorf DJ. Nuclear receptors, RXR, and the Big Bang. Cell. 2014;157(1):

255–66.

20. St-Arnaud R, et al. Deficient mineralization of intramembranous bone in vitamin D-24hydroxylase-ablated mice is due to elevated 1,25-dihydroxyvitamin D and not to the absence

of 24,25-dihydroxyvitamin D. Endocrinology. 2000;141(7):2658–66.

21. Jones G, et al. Isolation and identification of 24-hydroxyvitamin D2 and 24,25-dihydroxyvitamin

D2. Arch Biochem Biophys. 1980;202(2):450–7.

22. Mawer EB, et al. Unique 24-hydroxylated metabolites represent a significant pathway of

metabolism of vitamin D2 in humans: 24-hydroxyvitamin D2 and 1,24-dihydroxyvitamin D2

detectable in human serum. J Clin Endocrinol Metab. 1998;83(6):2156–66.



Chapter 2



Epidemiology of Vitamin D Deficiency

in Chronic Kidney Disease

Marie Metzger and Bénédicte Stengel



Abstract Vitamin D deficiency is common in both the general population and

CKD patients. Currently defined as a circulating 25-dihydroxyvitamin D (25(OH)

D) level below 20 ng/mL (50 nmol/L), it is a major risk factor for bone and mineral

disorders and has been related to increased risk of non-skeletal health outcomes

including mortality, diabetes, and cardiovascular disease. A greater prevalence of

this deficiency is expected in patients with CKD because they are older and more

likely to have dark skin, obesity, and associated comorbidities such as diabetes and

hypertension. In studies of clinical populations, the mean circulating 25(OH)D levels ranged from 18 to 29 ng/mL for patients with non-end-stage CKD and from 12

to 32 ng/mL for those on dialysis. Large population-based and clinical studies, however, describe inconsistent findings about the association between kidney function

and vitamin D level. While some studies report significant, positive, and independents associations between glomerular filtration rate and circulating 25(OH)D values, others show low levels only in advanced CKD stages. Still others show no or

even an inverse association, with paradoxically higher levels of 25(OH)D in individuals with moderate CKD than in those without CKD. Similarly, it remains

unclear whether these discordant relations are direct and causal, or indirect because

of confounders. Only a few studies have examined the relations between proteinuria

or albuminuria and circulating 25(OH)D levels; they generally report significant

negative associations. Potential mechanisms supporting a causal relation between

kidney function and damage and vitamin D are discussed at the end of this chapter.

Keywords Chronic kidney disease • Dialysis • Transplantation • Vitamin D deficiency • Recommendations • Epidemiology • Risk factors • Prevalence • Glomerular

filtration rate • Albuminuria • Proteinuria

M. Metzger, MD (*)

Inserm UMR 1018, Centre de Recherches en Epidémiologie et Santé des Populations (CESP),

Villejuif, France

e-mail: marie.metzger@inserm.fr

B. Stengel, MD, PhD

Center for Research in Epidemiology and Population Health (CESP),

Renal and Cardiovascular Epidemiology Team, University Paris-Saclay,

Paris, France

e-mail: benedicte.stengel@inserm.fr

© Springer International Publishing Switzerland 2016

P.A. Ura Torres et al. (eds.), Vitamin D in Chronic Kidney Disease,

DOI 10.1007/978-3-319-32507-1_2



19



20



2.1



M. Metzger and B. Stengel



Introduction



Vitamin D deficiency is a global issue affecting nearly a billion people across the

globe and across the life span, from childhood to advanced age [1, 2]. According to

a 2014 systematic review of vitamin D status in populations worldwide in 2014,

37 % of the 195 studies included from 44 countries reported mean circulating

25-hydroxy vitamin D levels below 50 nmol/mL (20 ng/mL), the most common

threshold for defining deficiency [3].

Vitamin D is involved in bone and mineral metabolism; its key role in bone

health is consistent with a causal relation [4]. Risks associated with vitamin D deficiency include rickets in children and adolescents [5] and osteomalacia and osteoporosis, which can lead to fractures, in adults and the elderly [6]. Since 2000, many

observational studies, reviewed by Theodoratou et al. [7], have also documented

vitamin D deficiency as a potentially independent risk factor for non-skeletal outcomes including overall mortality, cancer, cardiovascular disease, autoimmune disease, and several other outcomes. In addition, a recent Cochrane meta-analysis of 56

randomized clinical trials (RCTs) showed that vitamin D supplementation slightly

but significantly reduces mortality, especially among the elderly [8]. Several other

RCTs on the effects of vitamin D are ongoing [9]. Whether or not vitamin D is causally related to extraskeletal complications, however, is currently debated. Some

authors argue that the associations observed may have resulted from confounding or

reverse causation [10]. Rather than being a risk factor for these outcomes, vitamin

D deficiency may merely be a marker of poor health status associated with malnutrition and sedentary lifestyle.

Vitamin D deficiency is also common in chronic kidney disease (CKD) [11], and

its role in the development of secondary hyperparathyroidism (SHPT) and CKDrelated bone and mineral disorders (MBD) is well established (see section II of this

book). Supplementation with calciferol, as well as with calcitriol or its analogs, has

proved to be effective in reducing SHPT in patients with CKD, on dialysis or not

[12–14] (but see [15]). Observational studies have also shown associations between

vitamin D deficiency and other CKD complications, including anemia [16], insulin

resistance [17], and inflammation [18]. Moreover, vitamin D deficiency has been

associated with higher risks of overall and cardiovascular mortality in patients with

end-stage [19, 20] and non-end-stage CKD [21], as well as with faster decline in the

glomerular filtration rate (GFR) and earlier progression to end-stage renal disease

(ESRD) [22–25].

This chapter begins with a review of the methods used to assess vitamin D status

and a description of the definitions of deficiency used in studies in the general

population and among patients with CKD. A brief summary of the main findings

about the epidemiology and risk factors of vitamin D deficiency worldwide follows.

We then report the prevalence of vitamin deficiency in patients with non-end-stage

CKD, those on dialysis, and those living with a kidney transplant. Finally, we discuss

whether or not CKD, defined by either increased albuminuria or decreased GFR, is

associated with vitamin D deficiency, independently of other established risk factors.



2



Epidemiology of Vitamin D Deficiency in Chronic Kidney Disease



2.2



21



Assessment of Vitamin D Status and Definition

of Vitamin D Deficiency



Vitamin D status is best assessed by the level of its major circulating form,

25-hydroxyvitamin D (25(OH)D), also called calcidiol [4, 26]. Calcitriol or 1,25

dihydroxyvitamin D (1,25(OH)2D3), the active hormonal form of vitamin D, has a

very short half-life and its concentration is tightly regulated by PTH, calcium, and

phosphate levels (see Chap. 1) and is thus a poor indicator of vitamin D status [1].

Defining normal vitamin D values and comparing mean values or percentages of

abnormal values between studies require a standard definition and a reference assay,

neither of which currently exists. Normal or reference values for a given biological

parameter are usually determined from a large sample of healthy volunteers.

However, the production of 25(OH)D depends on sun exposure to UVB and liver 25

hydroxylation, as well as on endogenous factors such as age and skin color (see

Chap. 6); because its levels therefore vary strongly according to latitude and season,

there is no consensus about this approach. This limitation necessitates caution in the

interpretation of variations in the vitamin D estimates between studies, especially in

light of the lack of standardized assays for it.

Since 2010, various national or international medical societies and expert groups

have published different guidelines for the evaluation, treatment, and prevention of

vitamin D deficiency. Experts establishing recommendations for a level sufficient to

prevent adverse outcomes have considered primarily its bone and mineral action [6,

27, 28]. Some are based on the relation between the circulating levels of 25(OH)D

that reduce PTH level or increase intestinal calcium absorption. Others use findings

from RCTs investigating the vitamin D threshold necessary to prevent hip and nonvertebral fractures [29]. The major definitions currently proposed for vitamin D

deficiency or insufficiency are summarized in Table 2.1.

The threshold of 10 ng/mL (25 nmol/L) for 25(OH)D has long been used to

define low vitamin D values with clinical effects, such as osteomalacia [30, 31].

Most recent guidelines, however, have proposed serum 25(OH)D levels below

20 ng/mL (50 nmol/L) to define vitamin D deficiency in the general population.

Debate nonetheless continues about the definition of sufficiency, particularly

because of the potentially pleiotropic effects of vitamin D. The Institute of Medicine

(IOM) has concluded that values above 20 ng/mL are adequate for all ages and both

genders [27]. The Endocrine Society, on the other hand, considers that optimum

values should exceed 30 ng/mL and suggested defining deficiency as 25(OH)D

below 20 ng/mL and insufficiency by values between 20 and 30 ng/mL (75 nmol/L)

[26]. The discrepancies between guidelines for the minimum level of 25(OH)D

required to be in “good health” and the need for supplementation reflects the low

level of evidence for the extraskeletal effects of vitamin D [32]. Further RCTs are

needed [9] to justify raising the vitamin D threshold, in view of the major economic

and public health consequences of such an action: the levels of supplementation

and/or sun exposure needed to achieve a circulating 25(OH)D concentration ≥30 ng/

mL are far greater than those to exceed 20 ng/mL [30]).



Adult general population (with

exception of pregnant and

lactating women)

General population

Patients at risk for deficiency

Adult general population

Adult patients with or at risk

of bone disease (excluding

those with CKD stage 4–5)

General population

CKD patients

CKD patients



2010



2011



2011



2011



2013



2014

2003

2012



Population

Older adults



Year

2010



a



NR not reported

Inadequate

b

Adequate level in at least 97.5 % of the population of “normal healthy individuals”

c

Low vitamin D status



NICE – UK [83]

KDOQI [35]

KDIGO [33, 34]



US National Academies:

Institute of Medicine[27]

Endocrine Society

Clinical practice guidelines [26]

French osteoporosis research

group [81]

National Osteoporosis Society –

UK [82]



Reference

International Osteoporosis

Foundation [6]

Canadian Medical Association

Osteoporosis Canada [28]



>20



12–20a



NR

15–29

NR



<12



<10c

<15

<20



NR

>30

NR



30–70



30–100



20–50b



<20a

21–29



>30



10–30



Sufficient or

recommended level

>30



10–29



<10



<20



NR



<10



Definitions of Vitamin D status

Insufficient or

Deficient

inadequate

NR

NR



Table 2.1 Definitions of vitamin D status based on circulating 25(OH)D levels (in ng/ml) according to scientific societies, healthcare and medical institutions



22

M. Metzger and B. Stengel



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