Hypovitaminosis D and Progression of CKD

Chapter 24

Hypovitaminosis D and Progression of CKD Rajnish Mehrotra Kidney Research Institute and Harborview Medical Center, University of Washington, Seattle, WA, United States

Chapter Outline 1 Introduction 2 Vitamin D and progression of kidney disease 2.1 Experimental data 2.2 Human studies

251 252 252 254

3 Racial differences in hypovitaminosis D and as an explanatory factor for racial disparities in progression of kidney disease 4 Conclusions References

258 258 258

1 INTRODUCTION Vitamin D is a fat-soluble vitamin that plays a central role in calcium homeostasis (Fig. 24.1) [1]. The primary sources for vitamin D in humans include natural production in skin that requires sufficient exposure to ultraviolet light in sunlight, and intake of fortified foods and/or supplements [2–4]. With increasing urbanization around the world and the use of sunscreens to reduce risk for skin cancer, many individuals are increasingly dependent upon intake of fortified foods and/or supplements to ensure vitamin D sufficiency [5–7]. The risk of vitamin D insufficiency or deficiency is further amplified in individuals with chronic illnesses that limit physical activity and hence, time under sunlight and/or intakes of foods rich in vitamin D. 1,25 dihydroxy vitamin D is the biologically active form of vitamin D and exerts endocrine effects to serve as a key regulator for calcium homeostasis. For this, vitamin D has to first undergo 25-hydroxylation in the liver and 1-α hydroxylation in the kidney (Fig. 24.1) [1]. 1,25 dihydroxy vitamin D binds to the nuclear vitamin D receptor where it affects DNA transcription as the effector mechanism for its biologic effects. The half-life of 1,25 dihydroxy vitamin D is very short; hence, measurement of blood levels of 25-hydroxy vitamin D that has a considerably longer half-life is the most reliable way to assess vitamin D sufficiency [8,9]. The enzyme 1-α hydroxylase is also present in many cell types in the body, where vitamin D can exert autocrine and/or paracrine effects following the local 1-α hydroxylation of 25-hydroxy vitamin D. This local 1-α hydroxylation is dependent upon the availability of sufficient amounts of the substrate, 25-hydroxy vitamin D, and hence thought to be more sensitive to low circulating levels of 25-hydroxy vitamin D. 25-hydroxy vitamin D is also a vitamin D receptor agonist albeit with a significantly lower affinity but enough to directly exert biologic effects without 1-α hydroxylation [8]. Finally, the enzyme CYP24A1, inactivates both 25-hydroxy and 1,25-di-hydroxy vitamin D by converting them to 24,25 dihydroxy vitamin D and calcitrioic acid, respectively (Fig. 24.1). Consistent with the central importance of vitamin D in calcium homeostasis, the most widely accepted consequence of vitamin D deficiency is rickets in children [10–12]. A large and expanding body of evidence suggests that the health consequences of insufficient vitamin D levels may be apparent at higher serum levels of 25-hydroxy vitamin D than what results in rickets and may be substantially more widespread than that arising from abnormal calcium homeostasis [13]. Hence, observational studies have indicated that starting at about serum 25-hydroxy vitamin D levels <30 ng/mL (<75 nmol/L) the serum parathyroid hormone levels are progressively higher, suggesting these cut-offs to be the threshold below which the body triggers potentially maladaptive compensatory mechanisms [14]. Using this threshold, only less than half of the adult population in the United States has sufficient serum vitamin D levels [15,16]. There is evidence that shows that vitamin D is immunomodulatory, has antiinflammatory and antiproliferative effects, and may affect glucose homeostasis and blood presChronic Kidney Disease in Disadvantaged Populations. http://dx.doi.org/10.1016/B978-0-12-804311-0.00024-8 Copyright © 2017 Elsevier Inc. All rights reserved.

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FIGURE 24.1  Vitamin D metabolism in humans. FGF-23, Fibroblast growth factor-23; UV, ultraviolet.

sure. Cohort studies suggest that sufficient vitamin D levels may be associated with a lower risk of fatal and nonfatal cardiovascular events, diabetes, infections, cancer, falls, and cognitive decline [17–36]. However, there is limited high-level evidence from randomized controlled clinical studies to support the assertion that such substantial health benefits accrue with vitamin D supplementation. There are several large ongoing clinical trials, such as the VITAL in the United States (NCT01169259; n = 25,874) and D-Health in Australia (n = 21,315) that will bridge gaps in our understanding on the effects of vitamin D supplementation on primary prevention of cardiovascular disease, cancer, or reducing all-cause mortality [37,38]. Patients with chronic kidney disease (CKD) have lower levels of circulating 25-hydroxy vitamin D than those in the general population and this is likely secondary to lower physical activity resulting in lower exposure to sunlight, dietary restrictions of foods that are fortified with vitamin D, such as dairy products, and urinary loss of 25-hydroxy vitamin D and its binding protein in patients with proteinuric diseases [14,39,40]. Furthermore, there is lower conversion of 25-hydroxy vitamin D to 1,25 dihydroxy vitamin D because of inhibition of 1-α hydroxylase activity from higher circulating fibroblast growth factor-23 and with progressive kidney disease, and loss of functioning renal mass [41]. Thus, both lower circulating 25-hydroxy vitamin D levels and lower conversion to the biologically active form may lead to significant clinical consequences. As in the general population, cohort studies have indicated a higher risk for death in patients with lower serum 25-hydroxy vitamin D levels [42–48]. This chapter examines the evidence for the contribution of hypovitaminosis D to the progression of kidney disease and explores the hypothesis that racial differences in the prevalence of hypovitaminosis D would explain the racial disparities in progression of kidney disease in the United States.

2  VITAMIN D AND PROGRESSION OF KIDNEY DISEASE 2.1  Experimental data There is a large body of experimental evidence for the pleiotropic effects of vitamin D, some of which suggest a potential role for vitamin D in slowing progression of kidney disease. These include: (1) suppression of renin-angiotensin aldosterone system; (2) antiinflammatory and antioxidative effects; (3) antiproliferative effects; and (4) protecting podocytes against injury.

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2.1.1  Suppression of Renin-Angiotensin-Aldosterone System Renin is a protease synthesized and secreted by the juxtaglomerular cells in the kidney and it cleaves angiotensinogen to angiotensin I. 1,25 dihydroxy vitamin D3 suppresses the transcription of renin gene by blocking the activity of cyclic adenosine monophosphate response element in the promoter region of the gene [49]. Consistent with these findings, vitamin D-receptor null mice have significantly higher plasma renin activity and angiotensin II levels, hypertension, cardiac hypertrophy, and increased water intake; administration of 1,25 dihydroxy vitamin D3 leads to suppression of renin [50]. Administration of paracalcitol in rats with 5/6ths nephrectomy has been shown to result in significantly lower mRNA and protein expression for renin, renin receptor, and vascular endothelial growth factor along with improvement in histologic and functional measures of kidney function [51]. Similarly, coadministration of aliskerin and paracalcitol in diabetic rats is associated with significantly lower mRNAs for renin, angiotensin II, and angiotensin type 1 receptor than either one alone [52]. Analogous to these animal studies, cohort studies have demonstrated an inverse relationship between circulating vitamin D and renin levels both in patients with hypertension and CKD [53–55]. Treatment of patients with end-stage renal disease undergoing hemodialysis with secondary hyperparathyroidism with calcitriol decreases plasma renin activity and angiotensin II levels [56]. These and other lines of evidence suggest that vitamin D deficiency may result in activation of the renin-angiotensinaldosterone system and offers one putative pathway for renoprotection with vitamin D supplementation.

2.1.2  Antiinflammatory and Antioxidative Effects Binding of vitamin D to the nuclear vitamin D receptor affects the transcription of up to 200 genes, many of which modulate inflammation and the immune system and include nuclear factor of activated T-cells, nuclear factor kappa-light-chain enhancer of activated B (NF-kB), and several cytokines [57]. This, in turn, affects the functions of B and T lymphocytes and influences the phenotype and function of antigen presenting cells and dendritic cells [57]. There is also evidence that some of the immunomodulatory effects of vitamin D are exerted by its effects on macrophages including chemotaxis and expression of interleukin-1 β, interleukin-6, tumor necrosis factor α, toll-like receptors, cathelicidin microbial peptide, human b defensin 4, and cytochrome P450 family 27 polypeptide 1 [17,58–60]. Animal studies suggest that the antiinflammatory effects of vitamin D extends to the kidneys [61,62]. Administration of vitamin D reduces glomerular infiltration of inflammatory cells in animal models of primary glomerular diseases [62,63]. Similarly, in a mouse model of obstructive uropathy, paracalcitol has significant antiinflammatory effects by inhibiting T-cells and macrophage infilitration and proinflammatory cytokines [64]. In rats with streptozotocin-induced diabetes, calcitriol and paracalcitol reduce total kidney mRNA expression of interleukin-6, monocyte chemoattractant protein-1 (MCP-1), and interleukin-18 while also reducing glomerular infiltration of macrophages and glomerular cell activation of nuclear factor-kB [65]. Vitamin D also has antioxidative effects and lowers high-glucose induced reactive oxygen species and p22(phox), a nicotinamide adenine dinucleotide phosphate oxidase subunit both in vitro in cultured endothelial cells and in vivo in femoral arteries of diabetic rats with early nephropathy [66]. In diabetic rats, treatment with moxacalcitol decreases the expression of nuclear factor-kB, nicotinamide adenine dinucleotide phosphate oxidase, Kelch-like erythroid cell-derived protein with CNC homology-associated protein (Keap 1), and restores nuclear factor erythroid 2-related factor (Nrf2), all together leading to reduction in intrarenal oxidative stress [67]. Combination therapy with paricalcitol and aliskerin in diabetic rats is associated with lower circulating oxidant, malondialdehyde, and higher antioxidants (glutathione, glutathione oxidase, and superoxide dismutase) [52]. These observations suggest that vitamin D deficiency may potentiate intrarenal inflammation and oxidative stress, which may be attenuated by supplementation. This provides another plausible mechanistic pathway for hypovitaminosis D to contribute to progression of kidney disease.

2.1.3  Antifibrotic Effects Several lines of evidence lend support to the direct antifibrotic effects of vitamin D. Incubation of active vitamin D with cultured renal fibroblasts results in an inhibition of the expression of type I collagen and thrombospondin-1 in cultured renal fibroblasts [68]. Furthermore, it suppresses transforming growth factor-β induced transformation of renal interstitial fibroblasts to myofibroblasts, a precursor to expansion of extracellular matrix, through the induction of hepatocyte growth factor [68]. In various experimental studies, treatment with vitamin D has been shown to result in lower mRNA and protein expression of type I and III collagen, fibronectin, and transforming growth factor β along with reduction in the magnitude of glomerulosclerosis and/or interstitial fibrosis in animal models of streptozotocin-induced diabetes, ischemic reperfusion

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injury, gentamicin-induced renal injury, and obstructive uropathy [65,69–74]. While suggestive of antifibrotic effects in the kidney, it is important to note that these studies demonstrate the potential therapeutic effects of vitamin D rather than the deleterious effects of vitamin D deficiency.

2.1.4  Protecting Podocytes Against Injury Podocytes, which are the visceral epithelial cells, comprise the main filtration barrier in the glomerulus. These cells express vitamin D receptor [75] and both in vitro and in vivo studies demonstrate that vitamin D protects the podocytes from injury. The phenotype of podocytes to serve as a filtration barrier is dependent upon the expression of several proteins including nephrin and podocalyxin. While the incubation of glomerular epithelial cells with high glucose results in downregulation of these proteins, treatment with active vitamin D not only prevents the decrease in expression of nephrin but also upregulation in the expression of podocalyxin [76]. Knockdown of vitamin D receptor in podocyte cell cultures abrogates the vitamin D-stimulated upregulation of podocalyxin [76]. Furthermore, active vitamin D suppresses high-glucose induced apoptosis of podocytes by inhibiting p38- and ERK-mediated proapoptotic pathways [77]. Animal studies have demonstrated that treatment with active vitamin D results in reduction in proteinuria and prevents podocyte loss, likely from reducing podocyte apoptosis, in 5/6th nephrectomized rats, with puromycin, and in animal models of type 1 and 2 diabetes [51,62,69,72,78–81]. Transgenic DBA/2J mice with upregulated vitamin D receptor and strepotozotocin-induced diabetes experience less severe albuminuria than wild type mice and are highly responsive to treatment with doxercalciferol with marked decrease in podocyte loss and apoptosis, glomerular fibrosis, and albuminuria [77]. This indicates that the podocyte-protective effects of vitamin D are mediated through its binding with vitamin D receptor and provides a mechanistic insight into its antiproteinuric effects in human studies.

2.2  Human studies The foregoing discussion illustrates that there are several plausible mechanistic pathways for hypovitaminosis D to contribute to progressive kidney damage and raises the possibility that vitamin D supplementation may have therapeutic efficacy to slow the progression of kidney disease. This section summarizes the data for the role of vitamin D in human kidney disease.

2.2.1  Effect on Proteinuria Many kidney diseases are associated with proteinuria and observational studies have consistently demonstrated a graded association with urinary protein excretion and progression of kidney disease. Several cross-sectional studies have demonstrated an inverse association between circulating serum 25-hydroxy vitamin D and albuminuria both in the general population and in children and adults with CKD [82–86]. There is also evidence from PREVEND, a population-based prospective cohort study, that individuals with hypovitaminosis D are significantly more likely to develop incident microalbuminuria over an average of 10 years of follow-up [87]. When stratified for dietary sodium intake, the risk for incident microalbuminuria was primarily seen in individuals with high dietary sodium intake [87]. Similar findings have been reported in prospective cohort studies of patients with type 1 diabetes whereby those with 25-hydroxy vitamin D <20 ng/mL had a 65% higher risk of developing microalbuminuria over up to 16 years of follow-up compared to those with levels ≥30 ng/ mL [88]. These findings, in conjunction with experimental evidence discussed earlier, raise the possibility that vitamin D supplementation may be useful in the primary prevention of microalbuminuria. There is also interest in the possibility that vitamin D may have antiproteinuric effects allowing it to be used either as an adjunctive therapy in patients treated with maximally tolerated doses of angiotensin converting enzyme inhibitors and/ or angiotensin receptor blockers or in those with contraindications for such use. This premise has been examined in several randomized controlled clinical trials with the primary outcome being the effect on urinary protein excretion or in posthoc analyses (Table 24.1) [89–95]. As is evident, there is heterogeneity in test results but the preponderance of evidence suggests that treatment with active vitamin D (calcitriol or paracalcitol) may have antiproteinuric efficacy. A metaanalysis synthesizing the available data from clinical trials indicates that the benefit is modest (16% reduction); patients treated with vitamin D had a 2.7-fold higher odds for decrease in urinary protein excretion [96]. There is also evidence to suggest that this benefit is independent of the effect of vitamin D on mineral metabolism, consistent with experimental studies. Despite the evidence from observational studies associating the degree of proteinuria with loss of kidney function, there is concern that not all antiproteinuric therapies may translate into slowing progression of kidney disease (such as seen with combining angiotensin converting enzyme inhibitors and angiotensin receptor blockers) [97]. Hence, it is imperative to validate the role of vitamin D supplementation in slowing reduction in glomerular filtration rate or progression to end-stage renal disease in adequately powered clinical trials.

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TABLE 24.1 Summary of Randomized Controlled Trials Testing the Effects of Vitamin D Supplementation on the Reduction of Proteinuria Author, Year

Sample Size

Diabetes Mellitus (%)

RAAS Blockers (%)

Baseline Albuminuria (mg/g)

Baseline eGFR (mL/ min/1.73 m2)

Agarwal, 2005 [89]

195

58

69

Paracalcitol vsersus placebo

Not available

Alborzi, 2008 [90]

24

69

100

Paracalcitol 1 µg versus paracalcitol 2 µg versus. placebo

Fishbane, 2009 [91]

61

58

91

De Zeeuw, 2010 [92]

281

100

Thadhani, 2012 [93]

121

Liu, 2012 [94]

50

Krairttichai, 91 2012 [95]

Intervention

Follow-Up

Key Finding

24 ± 8 23 ± 7

24 weeks

In this posthoc analyses pooling results from 3 trials, 31% of treated patients had reduction in dipstick proteinuria, compared to 15% with placebo

72 (30, 172) 39 (18, 82) 241 (57, 1022)

48 ± 9 47 ± 13 44 ± 12

1 month

At end of followup, the albuminuria decreased among patients treated with paracalcitol (0.52−0.54 × baseline) but increased with placebo (1.35 × baseline) (P = 0.0005)

Paracalcitol 1 µg versus placebo

2.8 ± 3.6a 2.6 ± 2.1a

40 ± 24 35 ± 18

6 months

Paracalcitol resulted in 18% reduction in proteinuria compared with 3% increase with placebo (P = 0.04)

100

Paracalcitol 1 µg versus paracalcitol 2 µg versus placebo

71 (33, 139) 68 (28, 133) 73 (30, 128)

40 ± 15 42 ± 18 39 ± 17

24 weeks

The difference in change in albuminuria with paracalcitol (−16%) and placebo (−3%) did not reach statistical significance (P = 0.07)

57

82

Paracalcitol 2 µg versus placebo

223 (43, 855) 119 (28, 750)

31 (24, 43) 36 (26, 42)

48 weeks

Adjusted mean change in log urine albumin-creatinine ratio was 0.15 (−0.11, 0.42) with paracalcitol and 0.28 (0.03, 0.53) with placebo (P = 0.43)

0

100

Calcitriol 0.5 µg 2 per week versus no treatment

1.4 (1.1, 1.9)b 1.2 (1.0, 1.6)b

83 ± 36 78 ± 28

48 weeks

While the proteinuria decreased in patients treated with calcitriol (−19%), it increased in the untreated patients (+21%) (P = 0.03)

100

57

Calcitriol 0.5 µg 2 per week versus no treatment

3.7 ± 2.2a 3.4 ± 2.1a

38 ± 18 37 ± 17

16 weeks

While proteinuria decreased in patients treated with calcitriol (−19%), it increased in the untreated group (+10%) (P < 0.01)

eGFR, Estimated glomerular filtration rate; RAAS, renal angiotensin aldosterone system. a Protein–creatinine ratio, g/g. b 24-h urine protein excretion.

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2.2.2  Effect on Kidney Function and/or Progression to End-Stage Renal Disease The definitive evidence that hypovitaminosis D contributes to progression of kidney disease would be randomized, controlled clinical trials that demonstrate that vitamin D supplementation reduces risk for progression to end-stage renal disease. To date, no such studies exist and in this section, the evidence providing a rationale for such studies to be undertaken will be summarized. Experimental studies provide support for the presence of several putative reno-protective mechanisms dependent on and independent of reduction in proteinuria. In addition, cross-sectional and longitudinal cohort studies and Mendelian randomization studies suggest that vitamin D deficiency may result in hypertension [98–101]. Hypertension is a key risk factor for progression of kidney disease and provides another mechanistic pathway whereby hypovitaminosis D may contribute to loss of kidney function. Limited clinical trials to date, however, have been unable to consistently demonstrate any significant antihypertensive effects with vitamin D supplementation [102]. Whether vitamin D supplementation has antihypertensive effects in patients with CKD has not yet been systematically examined. The evidence from putative mechanistic pathways has been bolstered now with numerous cohort studies that have demonstrated a consistent association of lower circulating 25-hydroxy vitamin D levels with more rapid decline in glomerular filtration and/or need for dialysis in adults and children with diabetic or nondiabetic CKD [47,86,103–109]. In contrast, posthoc analyses of most randomized controlled trials have not been able to demonstrate any beneficial effect of vitamin D supplementation on retarding progression of kidney disease (Table 24.2) [89,90,94,95,110–116]. Indeed, two clinical trials have raised concern that treatment with paracalcitol may paradoxically be associated with a more rapid loss of kidney function when assessed by estimated glomerular filtration rate [92,93]. It is possible that this apparent worsening in kidney function when using estimating equations may be from a paracalcitol-induced increase in creatinine production and a higher serum creatinine without any perceptible change in measured kidney function [117]. A recent metaanalysis of these posthoc analyses of clinical trials was unable to demonstrate evidence for either benefit or harm from vitamin D supplementation on rate of progression of kidney disease [118]. Given this body of evidence, it remains unclear whether hypovitaminosis D contributes to progression of kidney disease and/or if vitamin D supplementation would be renoprotective.

TABLE 24.2 Summary of posthoc Data From Randomized Controlled Trials on the Effects of Vitamin D Supplementation on the Rate of Decline of Kidney Function and Need for Dialysis Author, Year

Sample Size

Diabetes Mellitus (%)

RAAS Blockers (%)

Intervention

Baseline eGFR (mL/ min/1.73 m2)

Follow-Up

Key Finding

Calciferols Rucker, 2009 [110]

128

Vitamin D3

3 months

There was no significant difference in change in eGFR between the treated and untreated patients (−0.7 vs. +0.3 mL/min/1.73 m2)

Basturk, 2011 [111]

48

Cholecalciferol versus no treatment

3 months

There was no significant change in eGFR between treated and untreated patients (+0.4 vs. −2.0 mL/min/1.73 m2)

Shroff, 2012 [112]

47 Children

0

Not known

Ergocalciferol versus placebo

47 ± 8 48 ± 9

12 months

The mean annualized change in eGFR was −2.1 ± 1.1 versus 1.6 ± 0.9 mL/min/1.73 m2 in ergocalciferol versus placebo treated patients (P = 0.82)

Not known

Alfacalcidol versus placebo

32 ± 11 33 ± 12

2 years

There was no significant difference in change in creatinine clearance with alphacalcidol versus placebo (−5.7 ± 6.8 vs. −4.0 ± 2.0 mL/min, respectively) (P = 0.94); 8 of the 89 treated patients progressed to ESRD compared with 8 of 87 patients treated with placebo

Active vitamin D compounds Hamdy, 1995 [113]

176

Not known

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TABLE 24.2 Summary of posthoc Data From Randomized Controlled Trials on the Effects of Vitamin D Supplementation on the Rate of Decline of Kidney Function and Need for Dialysis (cont.) Diabetes Mellitus (%)

RAAS Blockers (%)

Intervention

Baseline eGFR (mL/ min/1.73 m2)

Follow-Up

Key Finding

55

Not known

Not known

Doxercalciferol versus placebo

25 ± 9 25 ± 7

24 weeks

There was no significant difference in the change in creatinine clearance with doxercalciferol versus. placebo (+1% vs. −1.8%) (P = NS); one patient in each group progressed to ESRD

Rix, 2004 [115]

36

42

Not known

Alfacalcidol versus placebo

49 ± 20a 36 ± 13a

18 months

There was no significant difference in the decline in creatinine clearance between groups treated with alphacalcidol or placebo (P = 0.66)

Agarwal, 2005 [89]

118

58

69

Paracalcitol versus placebo

24 ± 8 23 ± 7

24 weeks

No significant difference in mean change in eGFR with paracalcitol versus placebo (−2.5 ± 0.54 vs. −3.0 ± 0.53 mL/min/1.73 m2)

Coyne, 2006 [116]

220

59

Not known

Paracalcitol versus placebo

23 ± 8 23 ± 8

24 weeks

No significant difference in mean change in eGFR with paracalcitol versus placebo (−2.5 ± 0.5 vs. –1.6 ± 0.5 mL/min/1.73 m2) (P = 0.19)

Alborzi, 2008 [90]

24

69

100

Paracalcitol 1 µg versus paracalcitol 2 µg versus placebo

48 ± 9 47 ± 13 44 ± 12

1 month

No significant difference in mean change in eGFR with paracalcitol 1 µg or 2 µg or placebo (+6.9, +5.3, −5.6, respectively)

De Zeeuw, 2010 [92]

281

100

100

Paracalcitol 1 µg versus paracalcitol 2 µg versus placebo

40 ± 15 42 ± 18 39 ± 17

24 weeks

There was a dose dependent decrease in eGFR (placebo, 0.1 vs. paracalcitol 2 µg, 7.6 mL/ min/1.73 m2); 6 of 188 treated patients progressed to ESRD, compared with 1 of 93 with placebo

Thadhani, 2012 [93]

121

57

82

Paracalcitol 2 µg versus placebo

31 (24, 43) 36 (26, 42)

48 weeks

There was a decrease in GFR with paracalcitol compared to placebo [−4.1 (−5.9, −2.3) vs. +0.5 (−1.3, 2.3)] (P < 0.001); 6 patients progressed to ESRD with paracalcitol compared to 1 with placebo

Liu, 2012 [94]

50

0

100

Calcitriol 0.5 µg 2 per week versus no treatment

83 ± 36 78 ± 28

48 weeks

There was no significant difference in the change in eGFR with calcitriol versus placebo [−3.2 (−8, +1) vs. +0.03 (−4.9, +4.9) mL/min/1.73 m2]

Krairttichai, 2012 [95]

91

100

57

Calcitriol 0.5 µg 2 per week versus no treatment

38 ± 18 37 ± 17

16 weeks

There was no significant difference in change in eGFR in the treated or the untreated patients

Author, Year

Sample Size

Coburn, 2004 [114]

eGFR, Estimated glomerular filtration rate; RAAS, renal angiotensin aldosterone system. a Creatinine clearance.

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3  RACIAL DIFFERENCES IN HYPOVITAMINOSIS D AND AS AN EXPLANATORY FACTOR FOR RACIAL DISPARITIES IN PROGRESSION OF KIDNEY DISEASE Racial disparities in progression of kidney disease are well established in numerous developed countries including the United States and stem primarily from genetic (e.g., high-risk APOL1 gene polymorphisms in African Americans) and socio-economic factors, including challenges in access to care [119–123]. It is also well-established that in the United States, the prevalence of vitamin D deficiency is substantially higher among African Americans and Hispanics, including among those with CKD [16,42,44,104,124–126]. This represents a combination of reduced production of previtamin D in the skin from reduced efficacy of ultraviolet light with increasing amount of melanin in dark-skinned individuals, and lower intake of dairy products that are fortified with vitamin D. An intriguing question that follows is whether some of the disparities in progression of kidney disease could be explained by a higher prevalence of hypovitaminosis D in racial/ethnic minorities. At this time, there is no definitive evidence for such a link. Cohort studies have demonstrated that accounting for differences in vitamin D levels between African Americans and Whites attenuates the difference in the risk for progression of kidney disease [104]. Furthermore, African Americans have higher serum parathyroid hormone levels than Whites and as administration of supraphysiologic doses of vitamin D is the first-line therapy for the treatment of secondary hyperparathyroidism, African Americans undergoing maintenance dialysis receive significantly higher weekly doses of vitamin D than Whites [127–130]. African Americans undergoing maintenance dialysis have a lower risk for death than Whites and it has been posited that the lower risk for death among Blacks undergoing maintenance dialysis is from the higher cumulative dose of vitamin D that they receive [130]. While plausible, these studies are insufficient to conclude that hypovitaminosis D is a significant contributor to the racial disparities in progression of kidney disease or for the lower risk of death among African Americans.

4 CONCLUSIONS There is a large body of experimental and epidemiologic evidence that supports the notion that vitamin D has numerous pleiotropic effects, some of which may be renoprotective. Studies to date demonstrate that vitamin D supplementation has a modest antiproteinuric effect but none shows that it can slow the rate of loss of kidney function. There are racial differences in the prevalence and severity of hypovitaminosis D and racial disparities in the rate of progression of kidney disease; but whether hypovitaminosis D contributes to these racial disparities remains unproven at this time.

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