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3 Inconsistencies in the Association of Vitamin D with Race Disparities in CKD
concentrations than whites, with the prevalence of 25(OH)D deficiency in the US
being over 80 % in blacks . 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 . 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 . 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) . DBP acts as a serum reservoir to
stabilize 25(OH)D concentrations . DBP also aids in reabsorption of 25(OH)D
filtered by the glomerulus . 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 . 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 . 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. ). 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 .
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
DBP concentrations in homozygotes
Adapted from Ref. 
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
Vitamin D and Racial Differences in Chronic Kidney Disease
enter cells and exert biological activity . 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 . 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.
The Paradox of Racial Differences in Vitamin D
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) . 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 . 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 , 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 , 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
. 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 . 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 . 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 .
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 . 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
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 . In this study, cases included 381 black, 192 Hispanic, 113
Asian, 46 American Indian, and 400 white women with incident fractures. One
Vitamin D and Racial Differences in Chronic Kidney Disease
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 .
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 . 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 . 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
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
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 . 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 . 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 . 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
Vitamin D and Racial Differences in Chronic Kidney Disease
Total 25(OH)D=bound + free fraction
and whites are similar even though total 25(OH)D concentrations are lower in
blacks . 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  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.
Vitamin D effects
• Calcium homeostasis
• Bone mineral density
• Inhibit RAAS activation
• Decrease inflammation
• Promote insulin sensitivity
• Enhance endothelial health
• Reduce cardiac hypertrophy
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
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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