Tải bản đầy đủ - 0 (trang)
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

Tải bản đầy đủ - 0trang

O.M. Gutiérrez


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





DBP concentrations in homozygotes




25(OH)D affinity




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


Vitamin D and Racial Differences in Chronic Kidney Disease


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.


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


O.M. Gutiérrez

[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


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


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 [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


O.M. Gutiérrez

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


Vitamin D and Racial Differences in Chronic Kidney Disease









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.





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



O.M. Gutiérrez


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.


1. Holick MF. Vitamin D, deficiency. N Engl J Med. 2007;357:266–81.

2. Resnick LM, Muller FB, Laragh JH. Calcium-regulating hormones in essential hypertension.

Relation to plasma renin activity and sodium metabolism. Ann Intern Med. 1986;105:


3. Vaidya A, Williams JS. The relationship between vitamin D and the renin-angiotensin system

in the pathophysiology of hypertension, kidney disease, and diabetes. Metabolism.


4. Judd SE, Nanes MS, Ziegler TR, et al. Optimal vitamin D status attenuates the age-associated

increase in systolic blood pressure in white Americans: results from the third National Health

and Nutrition Examination Survey. Am J Clin Nutr. 2008;87:136–41.

5. Martins D, Wolf M, Pan D, et al. Prevalence of cardiovascular risk factors and the serum

levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and

Nutrition Examination Survey. Arch Intern Med. 2007;167:1159–65.

6. Hypponen E, Boucher BJ, Berry DJ, et al. 25-hydroxyvitamin D, IGF-1, and metabolic syndrome at 45 years of age: a cross-sectional study in the 1958 British Birth Cohort. Diabetes.


7. Hintzpeter B, Mensink GB, Thierfelder W, et al. Vitamin D status and health correlates

among German adults. Eur J Clin Nutr. 2008;62:1079–89.

8. Pasco JA, Henry MJ, Nicholson GC, et al. Behavioural and physical characteristics associated with vitamin D status in women. Bone. 2009;44:1085–91.

9. Forouhi NG, Luan J, Cooper A, et al. Baseline serum 25-hydroxy vitamin d is predictive of

future glycemic status and insulin resistance: the Medical Research Council Ely Prospective

Study 1990–2000. Diabetes. 2008;57:2619–25.

10. Gannage-Yared MH, Chedid R, Khalife S, et al. Vitamin D in relation to metabolic risk factors, insulin sensitivity and adiponectin in a young Middle-Eastern population. Eur

J Endocrinol. 2009;160:965–71.

11. Forman JP, Giovannucci E, Holmes MD, et al. Plasma 25-hydroxyvitamin D levels and risk

of incident hypertension. Hypertension. 2007;49:1063–9.

12. Patel RS, Al Mheid I, Morris AA, et al. Oxidative stress is associated with impaired arterial

elasticity. Atherosclerosis. 2011;218:90–5.


Vitamin D and Racial Differences in Chronic Kidney Disease


13. Al Mheid I, Patel R, Murrow J, et al. Vitamin D status is associated with arterial stiffness and

vascular dysfunction in healthy humans. J Am Coll Cardiol. 2011;58:186–92.

14. Melamed ML, Michos ED, Post W, et al. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med. 2008;168:1629–37.

15. Pilz S, Dobnig H, Fischer JE, et al. Low vitamin d levels predict stroke in patients referred to

coronary angiography. Stroke. 2008;39:2611–3.

16. Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008;117:503–11.

17. Giovannucci E, Liu Y, Hollis BW, et al. 25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med. 2008;168:1174–80.

18. Dobnig H, Pilz S, Scharnagl H, et al. Independent association of low serum 25-hydroxyvitamin

d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch

Intern Med. 2008;168:1340–9.

19. Pilz S, Dobnig H, Nijpels G, et al. Vitamin D and mortality in older men and women. Clin

Endocrinol (Oxf). 2009;71:666–72.

20. Marniemi J, Alanen E, Impivaara O, et al. Dietary and serum vitamins and minerals as predictors of myocardial infarction and stroke in elderly subjects. Nutr Metab Cardiovasc Dis.


21. Pilz S, Marz W, Wellnitz B, et al. Association of vitamin D deficiency with heart failure and

sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography. J Clin Endocrinol Metab. 2008;93:3927–35.

22. Ginde AA, Scragg R, Schwartz RS, et al. Prospective study of serum 25-hydroxyvitamin D

level, cardiovascular disease mortality, and all-cause mortality in older U.S. adults. J Am

Geriatr Soc. 2009;57:1595–603.

23. Kilkkinen A, Knekt P, Aro A, et al. Vitamin D status and the risk of cardiovascular disease

death. Am J Epidemiol. 2009;170:1032–9.

24. Semba RD, Houston DK, Bandinelli S, et al. Relationship of 25-hydroxyvitamin D with allcause and cardiovascular disease mortality in older community-dwelling adults. Eur J Clin

Nutr. 2010;64:203–9.

25. Anderson JL, May HT, Horne BD, et al. Relation of vitamin D deficiency to cardiovascular

risk factors, disease status, and incident events in a general healthcare population. Am

J Cardiol. 2010;106:963–8.

26. Cawthon PM, Parimi N, Barrett-Connor E, et al. Serum 25-hydroxyvitamin D, parathyroid

hormone, and mortality in older men. J Clin Endocrinol Metab. 2010;95:4625–34.

27. Michaelsson K, Baron JA, Snellman G, et al. Plasma vitamin D and mortality in older men:

a community-based prospective cohort study. Am J Clin Nutr. 2010;92:841–8.

28. Hutchinson MS, Grimnes G, Joakimsen RM, et al. Low serum 25-hydroxyvitamin D levels

are associated with increased all-cause mortality risk in a general population: the Tromso

study. Eur J Endocrinol. 2010;162:935–42.

29. Kestenbaum B, Katz R, de Boer I, et al. Vitamin D, parathyroid hormone, and cardiovascular

events among older adults. J Am Coll Cardiol. 2011;58:1433–41.

30. Deo R, Katz R, Shlipak MG, et al. Vitamin D, parathyroid hormone, and sudden cardiac

death: results from the Cardiovascular Health Study. Hypertension. 2011;58:1021–8.

31. Michos ED, Reis JP, Post WS, et al. 25-Hydroxyvitamin D deficiency is associated with fatal

stroke among whites but not blacks: the NHANES-III linked mortality files. Nutrition.


32. Robinson-Cohen C, Hoofnagle AN, Ix JH, et al. Racial differences in the association of

serum 25-hydroxyvitamin D concentration with coronary heart disease events. JAMA.


33. de Boer IH, Levin G, Robinson-Cohen C, et al. Serum 25-hydroxyvitamin D concentration

and risk for major clinical disease events in a community-based population of older adults: a

cohort study. Ann Intern Med. 2012;156:627–34.

34. de Boer IH, Kestenbaum B, Shoben AB, et al. 25-hydroxyvitamin D levels inversely associate

with risk for developing coronary artery calcification. J Am Soc Nephrol. 2009;20:1805–12.


O.M. Gutiérrez

35. Harris SS. Vitamin D, and African Americans. J Nutr. 2006;136:1126–9.

36. Melamed ML, Astor B, Michos ED, et al. 25-hydroxyvitamin D levels, race, and the progression of kidney disease. J Am Soc Nephrol. 2009;20:2631–9.

37. Baron JA, Barrett J, Malenka D, et al. Racial differences in fracture risk. Epidemiology.


38. Farmer ME, White LR, Brody JA, et al. Race and sex differences in hip fracture incidence.

Am J Public Health. 1984;74:1374–80.

39. Moldawer M, Zimmerman SJ, Collins LC. Incidence of osteoporosis in elderly whites and

elderly Negroes. JAMA. 1965;194:859–62.

40. Silverman SL, Madison RE. Decreased incidence of hip fracture in Hispanics, Asians, and

blacks: California Hospital Discharge Data. Am J Public Health. 1988;78:1482–3.

41. Barrett-Connor E, Siris ES, Wehren LE, et al. Osteoporosis and fracture risk in women of

different ethnic groups. J Bone Miner Res. 2005;20:185–94.

42. Glerup H, Mikkelsen K, Poulsen L, et al. Hypovitaminosis D myopathy without biochemical

signs of osteomalacic bone involvement. Calcif Tissue Int. 2000;66:419–24.

43. Schott GD, Wills MR. Muscle weakness in osteomalacia. Lancet. 1976;1:626–9.

44. Bischoff-Ferrari HA, Dietrich T, Orav EJ, et al. Higher 25-hydroxyvitamin D concentrations

are associated with better lower-extremity function in both active and inactive persons aged

> or =60 y. Am J Clin Nutr. 2004;80:752–8.

45. Wicherts IS, van Schoor NM, Boeke AJ, et al. Vitamin D status predicts physical performance and its decline in older persons. J Clin Endocrinol Metab. 2007;92:2058–65.

46. Ensrud KE, Ewing SK, Fredman L, et al. Circulating 25-hydroxyvitamin D levels and frailty

status in older women. J Clin Endocrinol Metab. 2010;95:5266–73.

47. Aloia JF. African Americans, 25-hydroxyvitamin D, and osteoporosis: a paradox. Am J Clin

Nutr. 2008;88:545S–50S.

48. Scragg R, Sowers M, Bell C, et al. Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the

Third National Health and Nutrition Examination Survey. Diabetes Care. 2004;27:2813–8.

49. Gutierrez OM, Isakova T, Andress DL, et al. Prevalence and severity of disordered mineral

metabolism in Blacks with chronic kidney disease. Kidney Int. 2008;73:956–62.

50. Egan KM, Signorello LB, Munro HM, et al. Vitamin D insufficiency among AfricanAmericans in the southeastern United States: implications for cancer disparities (United

States). Cancer Causes Control CCC. 2008;19:527–35.

51. Fiscella K, Winters P, Tancredi D, et al. Racial disparity in blood pressure: is vitamin D a

factor? J Gen Intern Med. 2011;26:1105–11.

52. Fiscella KA, Winters PC, Ogedegbe G. Vitamin D and racial disparity in albuminuria:

NHANES 2001–2006. Am J Hypertens. 2011;24:1114–20.

53. Reis JP, Michos ED, von Muhlen D, et al. Differences in vitamin D status as a possible contributor to the racial disparity in peripheral arterial disease. Am J Clin Nutr.


54. Rostand SG. Ultraviolet light may contribute to geographic and racial blood pressure differences. Hypertension. 1997;30:150–6.

55. Kritchevsky SB, Tooze JA, Neiberg RH, et al. 25-Hydroxyvitamin D, parathyroid hormone,

and mortality in black and white older adults: the health ABC study. J Clin Endocrinol Metab.


56. Williams SK, Fiscella K, Winters P, et al. Association of racial disparities in the prevalence of

insulin resistance with racial disparities in vitamin D levels: National Health and Nutrition

Examination Survey (2001–2006). Nutr Res. 2013;33:266–71.

57. Bertisch SM, Sillau S, de Boer IH, et al. 25-hydroxyvitamin D concentration and sleep duration and continuity: multi-ethnic study of atherosclerosis. Sleep. 2015;38:1305–11.

58. Navaneethan SD, Schold JD, Arrigain S, et al. Low 25-hydroxyvitamin D levels and mortality in non-dialysis-dependent CKD. Am J Kidney Dis. 2011;58:536–43.

59. Fernandez-Juarez G, Luno J, Barrio V, et al. 25 (OH) vitamin D levels and renal disease

progression in patients with type 2 diabetic nephropathy and blockade of the renin-angiotensin system. Clin J Am Soc Nephrol. 2013;8:1870–6.


Vitamin D and Racial Differences in Chronic Kidney Disease


60. Shroff R, Aitkenhead H, Costa N, et al. Normal 25-hydroxyvitamin D levels are associated

with less proteinuria and attenuate renal failure progression in children with CKD. J Am Soc

Nephrol. 2016;27:314–22.

61. de Boer IH, Katz R, Chonchol M, et al. Serum 25-hydroxyvitamin D and change in estimated

glomerular filtration rate. Clin J Am Soc Nephrol. 2011;6:2141–9.

62. Wolf M, Betancourt J, Chang Y, et al. Impact of activated vitamin D and race on survival

among hemodialysis patients. J Am Soc Nephrol. 2008;19:1379–88.

63. Kalantar-Zadeh K, Miller JE, Kovesdy CP, et al. Impact of race on hyperparathyroidism,

mineral disarrays, administered vitamin D mimetic, and survival in hemodialysis patients.

J Bone Miner Res. 2010;25:2724–34.

64. Gutierrez OM. Fibroblast growth factor 23 and disordered vitamin D metabolism in chronic

kidney disease: updating the “trade-off” hypothesis. Clin J Am Soc Nephrol. 2010;5:1710–6.

65. Bringhurst FR, Demay MB, Kronenberg HM. Williams textbook of endocrinology. 12th ed.

Philadelphia: Elsevier Saunders; 2011.

66. Gutierrez OM, Farwell WR, Kermah D, et al. Racial differences in the relationship between

vitamin D, bone mineral density, and parathyroid hormone in the National Health and

Nutrition Examination Survey. Osteoporos Int. 2011;22:1745–53.

67. Awumey EM, Mitra DA, Hollis BW, et al. Vitamin D metabolism is altered in Asian Indians

in the southern United States: a clinical research center study. J Clin Endocrinol Metab.


68. Bikle DD, Gee E, Halloran B, et al. Assessment of the free fraction of 25-hydroxyvitamin D

in serum and its regulation by albumin and the vitamin D-binding protein. J Clin Endocrinol

Metab. 1986;63:954–9.

69. Safadi FF, Thornton P, Magiera H, et al. Osteopathy and resistance to vitamin D toxicity in

mice null for vitamin D binding protein. J Clin Invest. 1999;103:239–51.

70. Braun A, Bichlmaier R, Cleve H. Molecular analysis of the gene for the human vitamin-Dbinding protein (group-specific component): allelic differences of the common genetic GC

types. Hum Genet. 1992;89:401–6.

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

72. Powe CE, Evans MK, Wenger J, et al. Vitamin D-binding protein and vitamin D status of

black Americans and white Americans. N Engl J Med. 2013;369:1991–2000.

73. Mendel CM. The free hormone hypothesis: a physiologically based mathematical model.

Endocr Rev. 1989;10:232–74.

74. Bikle DD, Siiteri PK, Ryzen E, et al. Serum protein binding of 1,25-dihydroxyvitamin D: a

reevaluation by direct measurement of free metabolite levels. J Clin Endocrinol Metab.


75. Chun RF, Lauridsen AL, Suon L, et al. Vitamin D-binding protein directs monocyte responses

to 25-hydroxy- and 1,25-dihydroxyvitamin D. J Clin Endocrinol Metab. 2010;95:3368–76.

76. Chun RF, Peercy BE, Adams JS, et al. Vitamin D binding protein and monocyte response to

25-hydroxyvitamin D and 1,25-dihydroxyvitamin D: analysis by mathematical modeling.

PLoS One. 2012;7:e30773.

77. Zella LA, Shevde NK, Hollis BW, et al. Vitamin D-binding protein influences total circulating levels of 1,25-dihydroxyvitamin D3 but does not directly modulate the bioactive levels of

the hormone in vivo. Endocrinology. 2008;149:3656–67.

78. Powe CE, Ricciardi C, Berg AH, et al. Vitamin D-binding protein modifies the vitamin

D-bone mineral density relationship. J Bone Miner Res. 2011;26:1609–16.

79. Bhan I, Powe CE, Berg AH, et al. Bioavailable vitamin D is more tightly linked to mineral

metabolism than total vitamin D in incident hemodialysis patients. Kidney Int. 2012;82:84.

80. Christakos S, Dhawan P, Porta A, et al. Vitamin D and intestinal calcium absorption. Mol Cell

Endocrinol. 2011;347:25–9.

81. Holick MF. Resurrection of vitamin D deficiency and rickets. J Clin Invest. 2006;


82. Aloia JF, Vaswani A, Ma R, et al. Comparison of body composition in black and white premenopausal women. J Lab Clin Med. 1997;129:294–9.


O.M. Gutiérrez

83. Bachrach LK, Hastie T, Wang MC, et al. Bone mineral acquisition in healthy Asian, Hispanic,

black, and Caucasian youth: a longitudinal study. J Clin Endocrinol Metab. 1999;


84. Nelson DA, Jacobsen G, Barondess DA, et al. Ethnic differences in regional bone density, hip

axis length, and lifestyle variables among healthy black and white men. J Bone Miner Res.


85. Aloia JF, Vaswani A, Delerme-Pagan C, et al. Discordance between ultrasound of the calcaneus and bone mineral density in black and white women. Calcif Tissue Int. 1998;62:481–5.

86. Aloia JF, Vaswani A, Yeh JK, et al. Risk for osteoporosis in black women. Calcif Tissue Int.


87. Bell NH, Shary J, Stevens J, et al. Demonstration that bone mass is greater in black than in

white children. J Bone Miner Res. 1991;6:719–23.

88. Harris SS, Wood MJ, Dawson-Hughes B. Bone mineral density of the total body and forearm

in premenopausal black and white women. Bone. 1995;16:311S–5S.

89. Looker AC, Wahner HW, Dunn WL, et al. Updated data on proximal femur bone mineral

levels of US adults. Osteoporos Int. 1998;8:468–89.

90. Luckey MM, Meier DE, Mandeli JP, et al. Radial and vertebral bone density in white and

black women: evidence for racial differences in premenopausal bone homeostasis. J Clin

Endocrinol Metab. 1989;69:762–70.

91. Pollitzer WS, Anderson JJ. Ethnic and genetic differences in bone mass: a review with a

hereditary vs environmental perspective. Am J Clin Nutr. 1989;50:1244–59.

92. Cauley JA, Gutai JP, Kuller LH, et al. Black-white differences in serum sex hormones and

bone mineral density. Am J Epidemiol. 1994;139:1035–46.

93. Meier DE, Luckey MM, Wallenstein S, et al. Calcium, vitamin D, and parathyroid hormone

status in young white and black women: association with racial differences in bone mass.

J Clin Endocrinol Metab. 1991;72:703–10.

94. Cauley JA, Lui LY, Ensrud KE, et al. Bone mineral density and the risk of incident nonspinal

fractures in black and white women. JAMA. 2005;293:2102–8.

95. Barbour KE, Zmuda JM, Horwitz MJ, et al. The association of serum 25-hydroxyvitamin D

with indicators of bone quality in men of Caucasian and African ancestry. Osteoporos Int.


96. Aloia JF, Chen DG, Chen H. The 25(OH)D/PTH threshold in black women. J Clin Endocrinol

Metab. 2010;95:5069–73.

97. van Ballegooijen AJ, Robinson-Cohen C, Katz R, et al. Vitamin D metabolites and bone

mineral density: the multi-ethnic study of atherosclerosis. Bone. 2015;78:186–93.

98. Cauley JA, Danielson ME, Boudreau R, et al. Serum 25 hydroxyvitamin (OH)D and clinical

fracture risk in a multiethnic Cohort of women: the Women’s health initiative (WHI). J Bone

Miner Res. 2011;26:2378.

99. Dawson-Hughes B. Racial/ethnic considerations in making recommendations for vitamin D

for adult and elderly men and women. Am J Clin Nutr. 2004;80:1763S–6S.

100. Bell NH, Greene A, Epstein S, et al. Evidence for alteration of the vitamin D-endocrine system in blacks. J Clin Invest. 1985;76:470–3.

101. Dawson-Hughes B, Harris S, Kramich C, et al. Calcium retention and hormone levels in

black and white women on high- and low-calcium diets. J Bone Miner Res. 1993;8:779–87.

102. Engelman CD, Fingerlin TE, Langefeld CD, et al. Genetic and environmental determinants

of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels in Hispanic and African

Americans. J Clin Endocrinol Metab. 2008;93:3381–8.

103. Cosman F, Nieves J, Dempster D, et al. Vitamin D economy in blacks. J Bone Miner Res.

2007;22 Suppl 2:V34–8.

104. Cosman F, Morgan DC, Nieves JW, et al. Resistance to bone resorbing effects of PTH in

black women. J Bone Miner Res. 1997;12:958–66.

105. Fuleihan GE, Gundberg CM, Gleason R, et al. Racial differences in parathyroid hormone

dynamics. J Clin Endocrinol Metab. 1994;79:1642–7.

Tài liệu bạn tìm kiếm đã sẵn sàng tải về

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

Tải bản đầy đủ ngay(0 tr)