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3 Inconsistencies in the Association of Vitamin D with Race Disparities in CKD

3 Inconsistencies in the Association of Vitamin D with Race Disparities in CKD

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O.M. Gutiérrez



134



concentrations than whites, with the prevalence of 25(OH)D deficiency in the US

being over 80 % in blacks [66]. Since melanin absorbs UV light needed to synthesize vitamin D in the skin, this has historically been attributed to higher melanin

skin content in blacks [1]. Prevalence rates of vitamin D deficiency in other populations with high skin pigmentation such as Hispanics and Asian Indians are also

higher than their Caucasian counterparts [66, 67], underscoring the disruptive effect

of melanin in the cutaneous synthesis of vitamin D. Importantly, however, other

biological differences, such as genetically defined differences in vitamin D binding

protein (DBP) levels, also play a critical role in explaining racial differences in circulating 25(OH)D concentrations.

Vitamin D is highly lipophilic, similar to steroid and thyroid hormones that

require protein carriers to circulate in the serum. As a result, less than 1 % of vitamin

D circulates freely [68]. The majority (85–90 %) of circulating vitamin D is instead

tightly bound to DBP—an abundant circulating α-globulin protein produced by the

liver—and the remaining (10–15 %) is bound to albumin with much lower affinity

(referred to as free or bioavailable vitamin D) [68]. DBP acts as a serum reservoir to

stabilize 25(OH)D concentrations [69]. DBP also aids in reabsorption of 25(OH)D

filtered by the glomerulus [69]. These findings indicate that the primary roles of

DBP are to serve as a serum reservoir for vitamin D and provide an efficient mechanism to prevent urinary losses of filtered, unbound 25(OH)D.

Although over 120 variant forms of DBP have been reported, classically three

DBP phenotypes have been described: Gc1S, Gc1F, and Gc2 [70]. Each phenotype

variant is characterized by a different combination of two SNPs (rs4588 and rs7041)

in the DBP (also known as Gc globulin) gene resulting in amino acid substitutions

and differing glycosylation patterns [70]. These phenotypes differ in the associated

concentration of DBP in serum, the affinity of DBP for 25(OH)D and possibly other

characteristics (Table 6.1 adapted from Ref. [71]). DBP phenotypes strongly influence circulating 25(OH)D concentrations, and show marked differences in prevalence among races with black individuals having a higher prevalence of phenotypes

(Gc1F) characterized by very low DBP concentrations than white individuals [72].

The tight affinity of DBP for 25(OH)D has important physiological consequences. This is because the free hormone hypothesis states that hormones liberated

from binding proteins or bound to low-affinity carriers such as albumin are free to



Table 6.1 Common phenotypic variants of vitamin D binding protein (DBP) and their effects on

DBP concentrations and 25-hydroxyvitamin D (25(OH)D) affinity

Phenotype

Gc1F

Gc1S

Gc2



DBP concentrations in homozygotes

Lowest

Highest

Intermediate



25(OH)D affinity

Highest

Intermediate

Lowest



Adapted from Ref. [71]

The three major DBP phenotypes include GC1F, GC1S, and GC2, defined by SNPs rs7041 and

rs4588. The associated nucleotide and amino acid changes are presented, along with known data

on DBP levels in homozygotes and affinity for 25-hydroxyvitamin D



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enter cells and exert biological activity [73]. Consistent with this, experimental data

have shown that DBP inhibits the actions of exogenous vitamin D when added

directly to monocytes or osteoblasts in vitro by blocking intracellular transport of

vitamin D [69, 74–77]. Chun et al. showed that the induction of cathelicidin expression by 25(OH)D in cultured human monocytes was strongly inhibited by adding

DBP to culture media, and that the effects varied according to DBP phenotype, with

the Gc1F phenotype showing markedly different responses as compared to Gc1S or

Gc2 phenotypes [75]. Additionally, free or bioavailable 25(OH)D (that fraction of

25(OH)D which is not bound to DBP) is more strongly associated with classic measures of vitamin D adequacy such as BMD and PTH than total 25(OH)D (which

primarily reflects DBP-bound 25(OH)D) [78, 79]. Collectively, these data indicate

that DBP plays a key role in modulating the bioavailability and end-organ responsiveness of 25(OH)D, with critical implications for assessing vitamin D status in

humans. Standard 25(OH)D assays do not distinguish between relatively inert

25(OH)D bound to DBP and more biologically active 25(OH)D that is free or

loosely bound to albumin. Thus, it is possible that total 25(OH)D reflects total body

stores rather than vitamin bioactivity or sufficiency.



6.3.2



The Paradox of Racial Differences in Vitamin D

and Outcomes



The classical effects of vitamin D on bone and mineral health and its non-classical

effects on cardiovascular function, insulin signaling and immunity support the

notion that vitamin D deficiency should be a prime target of therapy for improving

health disparities, such as the excess risk of CKD and ESRD in blacks vs. whites.

While the breadth of data supporting this viewpoint are compelling, it is instructive

to consider racial differences in the association of vitamin D with the physiological

system(s) that it is most strongly linked with, namely bone and mineral metabolism.

The primary role of vitamin D is to maintain calcium homeostasis (and by extension

skeletal health) [1]. Studies have shown that the efficiency of calcium absorption

from the intestinal lumen is exquisitely sensitive to vitamin D and that in the absence

of sufficient 25(OH)D, intestinal calcium absorption is impaired [80]. When coupled with low dietary calcium intake, this presents the perfect scenario for deficient

calcium incorporation into the bone and impaired bone mineralization. Given that

black individuals on average have both lower circulating 25(OH)D concentrations

and lower dietary calcium intake than whites [66], this would presumably put them

at higher risk for bone disease. However, with the notable exception of the higher

prevalence of rickets in black as compared to white children [81], quite the opposite

has been observed in large, population-based studies.

The vast majority of these studies in fact have shown that black individuals maintain higher BMD than white individuals in both the appendicular and axial skeleton

starting in adolescence and continuing through adulthood [66, 82–93]. Further, black

individuals have lower risk of osteoporosis compared to their white counterparts



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[94]. Similar associations have been noted when examining more sophisticated

measures of bone structure and function. Barbour and colleagues examined the

associations of 25(OH)D with pQCT-derived indices of bone structure in 446 US

white men and 496 men of African descent living in Tobago and found that the

associations of 25(OH)D with parameters of bone mass and strength were modified

by race [95]. Namely, whereas positive linear trends were noted between increasing

25(OH)D categories (<20 ng/ml, 20–29, and ≥30) and cortical vBMD, total BMC,

cortical thickness, and polar and axial strain indexes at the distal radius in white

men, increasing 25(OH)D categories were either not associated or were negatively

associated with these parameters in men of African descent. Similarly, whereas concentrations of 25(OH)D was linearly associated with BMC and cortical thickness

in the tibia of white men, 25(OH)D was not associated with any tibial measures in

men of African descent.

Gutiérrez and colleagues examined cross-sectional associations of 25(OH)D and

whole body BMD in 4,309 white, 2,025 Mexican-American, and 2,081 black participants of the NHANES from 2003 to 2006 [66]. Analogous to the findings of

Barbour et al. the association of 25(OH)D and BMD differed by race—whereas

BMD significantly decreased as 25(OH)D concentrations declined among whites

and Mexican-Americans, no association of 25(OH)D with whole body BMD was

observed among blacks. The relationships between 25(OH)D and PTH were also

modified by race. Whereas inverse associations of 25(OH)D and PTH were noted

above and below a 25(OH)D cut-point commonly used to define vitamin D deficiency (20 ng/ml) in whites and Mexican-Americans, a significant inverse relationship between 25(OH)D and PTH was only observed when 25(OH)D concentrations

were below 20 ng/ml among blacks, with the slope of the relationship being essentially flat above this cut-point. These data suggest that PTH secretion is maximally

suppressed at a lower 25(OH)D threshold in blacks as compared to whites or

Mexican-Americans. Aloia et al. similarly found that the inflection point of PTH

was around a 25(OH)D level of 15 ng/ml among black women vs. 24 ng/ml among

white women in an analysis of women between 20 and 80 years of age [96].

van Ballegooijen and colleagues compared the association of 25(OH)D and volumetric trabecular BMD in white, black, Chinese and Hispanic participants of the

Multi-Ethnic Study of Atherosclerosis [97]. In line with the findings of Gutiérrez

and colleagues, black individuals had the highest mean BMD despite having the

lowest 25(OH)D concentrations of any race or ethnic group. Further, lower circulating 25(OH)D concentrations were associated with lower BMD values in white and

Chinese participants, but not in black or Hispanic participants. In fact, when 25(OH)

D was analyzed on a linear continuous scale, lower 25(OH)D concentrations were

associated with higher BMD in black participants, but not in any other race or ethnic

group.

Racial differences in the relationship between 25(OH)D and bone outcomes

were further highlighted in a case-control study of the associations of 25(OH)D

with incident fracture risk in participants of the Women’s Health Initiative (WHI)

Observational Study [98]. In this study, cases included 381 black, 192 Hispanic, 113

Asian, 46 American Indian, and 400 white women with incident fractures. One



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control was chosen per case matched on age, race/ethnicity, and blood draw date.

Among white participants, women with 25(OH)D concentrations in the highest tertile of 25(OH)D (≥30 ng/mL) had 44 % lower risk of fracture as compared to women

in the lowest tertile of 25(OH)D (<20 ng/mL) in multivariable models adjusted for

clinical factors, physical activity, calcium intake, previous history of fracture and

PTH. In contrast, black women in the highest tertile of 25(OH)D had higher risk of

fracture as compared to the lowest tertile of 25(OH)D in both unadjusted and fullyadjusted models.

A number of investigators have attempted to explain the paradox of why black

individuals have better indexes of bone structure and function and better skeletal

outcomes than white individual despite lower 25(OH)D by arguing that black

individuals compensate for lower 25(OH)D by increasing the secretion of PTH,

the hormone required to convert 25(OH)D to 1,25(OH)2D [35, 99]. While this

helps to maintain calcium homeostasis in the short-term, so the argument goes,

this compensation becomes maladaptive in the long-term because it comes at the

cost of chronically higher PTH concentrations, substantiating the belief that having lower 25(OH)D concentrations (relative to whites) is pathologic in blacks. It

is certainly true that black individuals have higher average PTH concentrations

than whites and that they tend to have higher 1,25(OH)2D concentrations as a

result [100–103]. However, if anything, one would assume that higher PTH and

1,25(OH)2D concentrations would help to keep bone mass similar or only slightly

lower, not higher, in blacks than whites if it were solely a maladaptive compensation for lower 25(OH)D concentrations. Furthermore, differences in BMD by race

have been observed even in the absence of differences in PTH concentrations [93].

Finally, studies have shown that black individuals manifest skeletal resistance to

the bone-resorbing effects of PTH [104, 105], suggesting that higher PTH concentrations may not adversely affect bone strength in black individuals, at least in

comparison to whites [106]. Consistent with this, in a prospective study of black

and white women from four US centers participating in the Study of Osteoporosis

Fractures, the incidence rate of non-spinal fracture was significantly higher in

white women as compared to black women irrespective of baseline bone mineral

content or density [94]. Further, the relative risk of fracture remained substantially

lower in black compared to white women after adjustment for potential confounders (0.43, 95 % confidence interval 0.32–0.57), in line with the findings of other

studies [37–41].

When taken together, the results of these studies may have important implications for the concept of vitamin D adequacy in racially-diverse populations.

Thresholds of vitamin D sufficiency have most commonly been derived from the

mathematical modeling of PTH and/or BMD as a function of 25(OH)D concentrations [107–112] or by determining the 25(OH)D concentration above which fracture risk is minimized [113–116]. However, the results of the studies reviewed

above suggest that optimal concentrations of 25(OH)D determined by these criteria

may not be the same in white individuals as compared to black individuals.

So how do we best account for this paradox? A number of explanations have

been offered including more efficient dietary calcium utilization, better renal



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calcium conservation (perhaps due to higher basal PTH concentrations), and lower

bone turnover in black individuals than white individuals [47, 117]. Even when

taking these factors into account, however, the results of these studies suggest that

optimal concentrations of 25(OH)D may not be the same in white individuals as

compared to black individuals, at least with respect to bone health. Indeed, it is

entirely reasonable to conclude from these data that individuals of more recent

African descent require lower 25(OH)D concentrations to optimize bone and mineral metabolism as compared to their counterparts of European descent. This in turn

begs the question of whether the same is true with respect to the relationships

between 25(OH)D and non-skeletal outcomes such as cardiovascular health, glucose metabolism, immune function and, of greatest relevance to this text, kidney

disease in black individuals. Though supporting evidence is scarce, important clues

may be gleaned from available studies.

In a study of 2,766 non-Hispanic white, 1,736 non-Hispanic black and 1,726

Mexican American participants of NHANES, higher serum concentrations of

25(OH)D were associated with lower odds of diabetes in non-Hispanic whites and

Mexican Americans [48]. In contrast, no associations were noted between serum

concentrations of 25(OH)D and odds of diabetes among blacks overall—in fact, in

some models, higher 25(OH)D was associated with higher odds of diabetes,

though these results should be interpreted cautiously because of the low sample

size of blacks in higher categories of 25(OH)D. Similarly, despite the observation

that 25(OH)D is inversely associated with calcified plaque in population-based

studies of European Americans [34, 118], a study showed that 25(OH)D was positively associated with calcified plaque in African Americans with type 2 diabetes,

suggesting that higher 25(OH)D may have adverse effects on calcified atherosclerotic lesions in black individuals [119]. In the largest study to examine the association of 25(OH)D with coronary heart disease (CHD), Robinson-Cohen et al.

showed that lower total 25D levels were associated with higher risk of CHD in

whites but not blacks [32]. Other reports have shown similar racial heterogeneity

in the association of total 25D with risk of hypertension, fatal stroke and mortality

[4, 14, 31, 48].

The results of these studies should be interpreted in the context of other studies

that showed that lower 25(OH)D concentrations in blacks at least partially explained

racial disparities in hypertension, albuminuria and ESRD prevalence (reviewed

above), supporting the potential mediating role of low vitamin D in disparities in

CKD outcomes by race. Nevertheless, while it appears biologically plausible that

lower 25(OH)D concentrations (relative to whites) are “bad” for blacks and should

be treated, it remains very much unclear at what level of 25(OH)D the excess risk

for chronic disease among blacks begins to manifest. That is to say, while blacks can

and do become vitamin D deficient at some critical threshold of 25(OH)D, whether

that level is the same as for whites remains an open question.

Genetically determined differences in circulating DBP concentrations and, by

extension, 25(OH)D bioavailability, may also be key to understanding inconsistencies in the association of vitamin D with health outcomes by race. Epidemiologic

studies have shown that estimated bioavailable 25(OH)D concentrations in blacks



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Vitamin D and Racial Differences in Chronic Kidney Disease



139



DBP



DBP

25D



25D



DBP



DBP

25D



Bioavailable Fraction



Total 25(OH)D=bound + free fraction



and whites are similar even though total 25(OH)D concentrations are lower in

blacks [72]. A prior study measured total 25(OH)D and DBP concentrations in

stored serum samples from black and white subjects enrolled in Healthy Aging in

Neighborhoods of Diversity across the Life Span Study, a fixed cohort of communitydwelling black and white adults aged 30–64 [72] and demonstrated that blacks,

despite having lower 25(OH)D concentrations than whites, had similar estimated

bioavailable 25(OH)D concentrations. This was mostly due to racially-determined

genetic variations in DBP which impact both the abundance of DBP in the circulation, and DBP-affinity binding constants for 25(OH)D. Specifically, black participants had a higher prevalence of DBP phenotypes associated with very low DBP

levels (Gc1F/1 F) than white participants. These racially-determined variations in

DBP explained a large proportion of lower total 25(OH)D concentrations measured

in blacks vs whites and helped to explain why BMD in blacks poorly correlated with

measures of total 25(OH)D—namely, because low total 25(OH)D concentrations

may be a poor marker of true vitamin D deficiency when levels of DBP are also low,

such as in many black individuals. In contrast, low 25(OH)D concentrations may be

more likely to represent vitamin D deficiency in populations with higher DBP concentrations, such as white individuals (Fig. 6.1). This may explain why low total

25(OH)D concentrations were associated with CVD risk in whites but not blacks in

prior studies and raises important questions about whether bioavailable 25(OH)D—

which demonstrates much less variability by race—may be a better cross-racial

marker of CVD risk.



25D



Albumin

25D

25D



Vitamin D effects

• Calcium homeostasis

• Bone mineral density

• Inhibit RAAS activation

• Decrease inflammation

• Promote insulin sensitivity

• Enhance endothelial health

• Reduce cardiac hypertrophy



Albumin



25D



25D



Fig. 6.1 Vitamin D has pleiotropic effects that promote cardiovascular health. Total

25-hydroxyvitamin D (25(OH)D) represents mostly inert 25(OH)D bound to vitamin D binding

protein (DBP), which may attenuate vitamin D’s physiological effects (small arrow). The bioavailable fraction, in term, better represents the biologically active form of vitamin D (large arrow).

While total 25(OH)D concentrations differ by race, the bioavailable fraction does not seem to differ by race, potentially helping to explain racial heterogeneity in the association of 25(OH)D with

bone and cardiovascular outcomes



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6.4



O.M. Gutiérrez



Conclusions



Vitamin D deficiency has captured a great deal of attention in the ongoing quest to

understand well-known but poorly understood discrepancies in CKD and ESRD

risk by race. The basis for this enthusiasm is well-founded in plausible biological

pathways linking lower 25(OH)D concentrations with cardiovascular and renal

pathology. However, the lingering paradox between lower 25(OH)D concentrations

(relative to whites) in blacks and musculoskeletal health should provide a measure

of caution in rushing to the conclusion that low average 25(OH)D concentrations

are truly detrimental to the overall health of black individuals, especially with

respect to CKD outcomes. New insights into genetically determined differences in

the bioavailability of vitamin D may provide a window into understanding how and

why racial differences in vitamin D metabolism effect disparities in health outcomes by race.



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