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8 Vitamin D and Estimated Glomerular Filtration Rate
Vitamin D and Progression of Renal Failure
Recently, Agarwal et al.  examined the effect of VDR activation on creatinine
metabolism and measured GFR. A 7-day course of paricalcitol (2 μgr daily)
resulted in an increase in serum creatinine and urine creatinine, while creatinine
clearance did not change. Simultaneous measurement of GFR with iothalamate
was not altered by paricalcitol therapy. Moreover, within 4 days of cessation of
vitamin D therapy, they observed changes in creatinine generation and serum
creatinine reversed back to near the baseline. In other words short term VDR
activation increases creatinine generation and serum creatinine, but it does not
influence the GFR. Hence theses changes have nothing to do with a nephrotoxic
effect of vitamin D on the kidney. How far this anabolic effect of vitamin D
receptor activation may be improving skeletal and myocardial function and have
a beneficial effect on mortality in chronic renal failure patients remains to be
Almost 40 years after the paper by Christiansen et al. describing the deterioration of
renal function during vitamin D treatment there is more than a profuse literature on
the beneficial effect of active and natural vitamin D, on several important aspects of
the progression of a CKD patient towards renal failure .
The major problem is that the vast majority of this pinpointed investigations
in vitro, in vivo and also in man have not been able to answer simple but essential
More and better clinical work using the appropriate methodology such as randomized clinical trials (RCTs)  is needed to e.g. elucidate whether formal repletion at early stage of CKD, nowadays a very common practice in renal centers,
using cholecalciferol or ergocalciferol can prevent the renal, cardiac, and skeletal
complications associated with CKD.
Despite numerous observational data on the association of vitamin D with
decreased cardiovascular related morbidity and mortality three RCT “PRIMO”
“PENNY” and “OPERA” showed no differences on the left ventricular mass index
and function of vitamin D analogs compared to untreated patients.
The demonstration has been made several times that in vitro experiments, experimental studies and simplistic clinical observations/trials become irrelevant when
applied in a proper way to a patient group with moderate to severe renal failure .
It is more than time that the renal community leaves his weak reputation when
evaluating the number of relevant high quality controlled studies performed by the
different disciplines of internal medicine . Natural vitamin D is one of the few
reasonable and evident candidates to be tested in a multicenter, prospective RCT as
a potential protector of the failing kidney in patients with CKD 3 and 4.
Acknowledgement Erik Snelders was a more than relevant help in the realization of this
M. De Broe
1. Levin A, Bakris GL, Molitch M, Smulders M, Tian J, Williams LA, Andress DL. Prevalence
of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney
disease: results of the study to evaluate early kidney disease. Kidney Int. 2007;71(1):31–8.
2. Shroff R, Shanahan C. Klotho: an elixir of youth for the vasculature. JASN. 2011;22:5–7.
3. Christiansen C, Rødbro P, Christensen MS, Hartnack B, Transbøl I. Deterioration of renal
function during treatment of chronic renal failure with 1,25-dihydroxycholecalciferol. Lancet.
1978;2(8092 Pt 1):700–3.
4. Holick MF. Vitamin D, deficiency. N Engl J Med. 2007;357(3):266–81.
5. Shroff R, Knott C, Rees L. The virtues of vitamin D – but how much is too much? Pediatr
6. Shroff R, Wan M, Rees L. Can vitamin D slow down the progression of chronic kidney disease? Pediatr Nephrol. 2012;27(12):2167–73.
7. Makibayshi K, Tatematsu M, Hirata M, et al. A vitamin D analog ameliorates glomerular
injury on rat glomerulonephritis. Am J Pathol. 2001;158(5):1733–41.
8. Panichi V, Migliori M, Taccola D, et al. Effects of 1,25(OH)2D3 in experimental mesangial
proliferative nephritis in rats. Kidney Int. 2001;60(1):87–95.
9. Tian J, Liu Y, Williams LA, de Zeeuw D. Potential role of active vitamin D in retarding the
progression of chronic kidney disease. Nephrol Dial Transplant. 2007;22(2):321–8.
10. Kuhlmann A, Haas CS, Gross ML, Reulbach U, Holzinger M, Schwarz U, Ritz E, Amann K.
1,25-Dihydroxyvitamin D3 decreases podocyte loss and podocyte hypertrophy in the subtotally nephrectomized rat. Am J Physiol Renal Physiol. 2004;286(3):F526–33.
11. Agarwal R. Vitamin D, proteinuria, diabetic nephropathy, and progression of CKD. Clin J Am
Soc Nephrol. 2009;4(9):1523–8.
12. Schwarz U, Amann K, Orth SR, Simonaviciene A, Wessels S, Ritz E. Effect of 1,25(OH)2
vitamin D3 on glomerulosclerosis in subtotally nephrectomized rats. Kidney Int. 1998;53(6):
13. Hirata M, Makibayashi K, Katsumata K, Kusano K, Watanabe T, Fukushima N, Doi T.
22-Oxacalcitriol prevents progressive glomerulosclerosis without adversely affecting calcium
and phosphorus metabolism in subtotally nephrectomized rats. Nephrol Dial Transplant.
14. Alborzi P, Patel NA, Peterson C, Bills JE, Bekele DM, Bunaye Z, Light RP, Agarwal
R. Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized
double-blind pilot trial. Hypertension. 2008;52(2):249–55.
15. Szeto CC, Chow KM, Kwan BC, Chung KY, Leung CB, Li PK. Oral calcitriol for the treatment of persistent proteinuria in immunoglobulin A nephropathy: an uncontrolled trial. Am
J Kidney Dis. 2008;51(5):724–31.
16. de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D, Garimella T, Parving HH, Pritchett
Y, Remuzzi G, Ritz E, Andress D. Selective vitamin D receptor activation with paricalcitol for
reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet. 2010;376(9752):1543–51.
17. Kim MJ, Frankel AH, Donaldson M, Darch SJ, Pusey CD, Hill PD, Mayr M, Tam FW. Oral
cholecalciferol decreases albuminuria and urinary TGF-β1 in patients with type 2 diabetic
nephropathy on established renin-angiotensin-aldosterone system inhibition. Kidney Int.
18. Kumar R. New clinical trials with vitamin D and analogs in renal disease. Kidney Int.
19. de Borst MH, Hajhosseiny R, Tamez H, Wenger J, Thadhani R, Goldsmith DJ. Active vitamin
D treatment for reduction of residual proteinuria: a systematic review. J Am Soc Nephrol.
20. Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D(3) is a negative
endocrine regulator of the renin-angiotensin system. J Clin Invest. 2002;110(2):229–38.
Vitamin D and Progression of Renal Failure
21. Lindner A, Charra B, Sherrard DJ, Scribner BH. Accelerated atherosclerosis in prolonged
maintenance hemodialysis. N Engl J Med. 1974;290(13):697–701.
22. Xiang W, Kong J, Chen S, Cao LP, Qiao G, Zheng W, Liu W, Li X, Gardner DG, Li YC. Cardiac
hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac reninangiotensin systems. Am J Physiol Endocrinol Metab. 2005;288(1):E125–32.
23. Zhou C, Lu F, Cao K, Xu D, Goltzman D, Miao D. Calcium-independent and 1,25(OH)2D3dependent regulation of the renin-angiotensin system in 1alpha-hydroxylase knockout mice.
Kidney Int. 2008;74(2):170–9.
24. Forman JP, Giovannucci E, Holmes MD, Bischoff-Ferrari HA, Tworoger SS, Willett WC,
Curhan GC. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension.
25. Feneis JF, Arora RR. Role of vitamin D in blood pressure homeostasis. Am J Ther.
26. Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, Benjamin EJ, D'Agostino
RB, Wolf M, Vasan RS. Vitamin D deficiency and risk of cardiovascular disease. Circulation.
27. Rostand SG. Vitamin D, blood pressure, and African Americans: toward a unifying hypothesis. Clin J Am Soc Nephrol. 2010;5(9):1697–703.
28. Pilz S, Tomaschitz A, Ritz E, Pieber TR. Vitamin D status and arterial hypertension: a systematic review. Nat Rev Cardiol. 2009;6(10):621–30.
29. Park CW, Oh YS, Shin YS, Kim CM, Kim YS, Kim SY, Choi EJ, Chang YS, Bang
BK. Intravenous calcitriol regresses myocardial hypertrophy in hemodialysis patients with
secondary hyperparathyroidism. Am J Kidney Dis. 1999;33(1):73–81.
30. Kim HW, Park CW, Shin YS, Kim YS, Shin SJ, Kim YS, Choi EJ, Chang YS, Bang
BK. Calcitriol regresses cardiac hypertrophy and QT dispersion in secondary hyperparathyroidism on hemodialysis. Nephron Clin Pract. 2006;102(1):c21–9.
31. Wang AY, Lam CW, Sanderson JE, Wang M, Chan IH, Lui SF, Sea MM, Woo J. Serum
25-hydroxyvitamin D status and cardiovascular outcomes in chronic peritoneal dialysis
patients: a 3-y prospective cohort study. Am J Clin Nutr. 2008;87(6):1631–8.
32. Tamez H, Zoccali C, Packham D, Wenger J, Bhan I, Appelbaum E, Pritchett Y, Chang Y,
Agarwal R, Wanner C, Lloyd-Jones D, Cannata J, Thompson BT, Andress D, Zhang W, Singh
B, Zehnder D, Pachika A, Manning WJ, Shah A, Solomon SD, Thadhani R. Vitamin D reduces
left atrial volume in patients with left ventricular hypertrophy and chronic kidney disease. Am
Heart J. 2012;164(6):902–9.
33. Thadhani R, Appelbaum E, Pritchett Y, Chang Y, Wenger J, Tamez H, Bhan I, Agarwal R,
Zoccali C, Wanner C, Lloyd-Jones D, Cannata J, Thompson BT, Andress D, Zhang W,
Packham D, Singh B, Zehnder D, Shah A, Pachika A, Manning WJ, Solomon SD. Vitamin D
therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO
randomized controlled trial. JAMA. 2012;307(7):674–84.
34. Wang AY, Fang F, Chan J, Wen YY, Qing S, Chan IH, Lo G, Lai KN, Lo WK, Lam CW, Yu
CM. Effect of paricalcitol on left ventricular mass and function in CKD – the OPERA trial.
J Am Soc Nephrol. 2014;25(1):175–86.
35. Goldsmith DJ, Massy ZA, Brandenburg V. The uses and abuses of Vitamin D compounds in
chronic kidney disease-mineral bone disease (CKD-MBD). Semin Nephrol. 2014;34(6):
36. Nakamura S, Ishibashi-Ueda H, Niizuma S, Yoshihara F, Horio T, Kawano Y. Coronary calcification in patients with chronic kidney disease and coronary artery disease. Clin J Am Soc
37. Shroff RC, McNair R, Figg N, Skepper JN, Schurgers L, Gupta A, Hiorns M, Donald AE,
Deanfield J, Rees L, Shanahan CM. Dialysis accelerates medial vascular calcification in part
by triggering smooth muscle cell apoptosis. Circulation. 2008;118(17):1748–57.
38. London GM, Guérin AP, Verbeke FH, Pannier B, Boutouyrie P, Marchais SJ, Mëtivier
F. Mineral metabolism and arterial functions in end-stage renal disease: potential role of
25-hydroxyvitamin D deficiency. J Am Soc Nephrol. 2007;18(2):613–20.
M. De Broe
39. Shroff R, Egerton M, Bridel M, Shah V, Donald AE, Cole TJ, Hiorns MP, Deanfield JE, Rees
L. A bimodal association of vitamin D levels and vascular disease in children on dialysis. J Am
Soc Nephrol. 2008;19(6):1239–46.
40. Shroff RC, Donald AE, Hiorns MP, Watson A, Feather S, Milford D, Ellins EA, Storry C,
Ridout D, Deanfield J, Rees L. Mineral metabolism and vascular damage in children on dialysis. J Am Soc Nephrol. 2007;18(11):2996–3003.
41. Shroff RC, Shanahan CM. The vascular biology of calcification. Semin Dial.
42. Carthy EP, Yamashita W, Hsu A, Ooi BS. 1,25-Dihydroxyvitamin D3 and rat vascular smooth
muscle cell growth. Hypertension. 1989;13(6 Pt 2):954–9.
43. Mathew S, Lund RJ, Chaudhary LR, Geurs T, Hruska KA. Vitamin D receptor activators can
protect against vascular calcification. J Am Soc Nephrol. 2008;19(8):1509–19.
44. Becker LE, Koleganova N, Piecha G, Noronha IL, Zeier M, Geldyyev A, Kökeny G, Ritz E,
Gross ML. Effect of paricalcitol and calcitriol on aortic wall remodeling in uninephrectomized
ApoE knockout mice. Am J Physiol Renal Physiol. 2011;300(3):F772–82.
45. Huybers S, Bindels RJ. Vascular calcification in chronic kidney disease: new developments in
drug therapy. Kidney Int. 2007;72(6):663–5.
46. de Boer IH, Tinker LF, Connelly S, Curb JD, Howard BV, Kestenbaum B, Larson JC, Manson
JE, Margolis KL, Siscovick DS, Weiss NS. Calcium plus vitamin D supplementation and the
risk of incident diabetes in the Women’s Health Initiative. Diabetes Care. 2008;31(4):701–7.
47. de Boer IH. Vitamin D and glucose metabolism in chronic kidney disease. Curr Opin Nephrol
48. Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin
D in obesity. Am J Clin Nutr. 2000;72(3):690–3.
49. Sneve M, Figenschau Y, Jorde R. Supplementation with cholecalciferol does not result in
weight reduction in overweight and obese subjects. Eur J Endocrinol. 2008;159(6):675–84.
50. Rodríguez-Rodríguez E, Ortega RM, González-Rodríguez LG, López-Sobaler AM, UCM
Research Group VALORNUT (920030). Vitamin D deficiency is an independent predictor of
elevated triglycerides in Spanish school children. Eur J Nutr. 2011;50(5):373–8.
51. Motiwala SR, Wang TJ. Vitamin D and cardiovascular risk. Curr Hypertens Rep.
52. Zittermann A, Frisch S, Berthold HK, Götting C, Kuhn J, Kleesiek K, Stehle P, Koertke H,
Koerfer R. Vitamin D supplementation enhances the beneficial effects of weight loss on cardiovascular disease risk markers. Am J Clin Nutr. 2009;89(5):1321–7.
53. Zittermann A, Gummert JF, Börgermann J. The role of vitamin D in dyslipidemia and cardiovascular disease. Curr Pharm Des. 2011;17(9):933–42.
54. Wolf M, Shah A, Gutierrez O, Ankers E, Monroy M, Tamez H, Steele D, Chang Y, Camargo
Jr CA, Tonelli M, Thadhani R. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int. 2007;72(8):1004–13.
55. Zehnder D, Quinkler M, Eardley KS, Bland R, Lepenies J, Hughes SV, Raymond NT, Howie
AJ, Cockwell P, Stewart PM, Hewison M. Reduction of the vitamin D hormonal system in
kidney disease is associated with increased renal inflammation. Kidney Int. 2008;74(10):
56. Tan X, Wen X, Liu Y. Paricalcitol inhibits renal inflammation by promoting vitamin D
receptor-mediated sequestration of NF-kappaB signaling. J Am Soc Nephrol. 2008;19(9):
57. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K,
Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zügel U, Gallo RL, Eisenberg D,
Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL. Toll-like receptor triggering of a
vitamin D-mediated human antimicrobial response. Science. 2006;311(5768):1770–3.
58. Salamon H, Bruiners N, Lakehal K, Shi L, Ravi J, Yamaguchi KD, Pine R, Gennaro
ML. Cutting edge: vitamin D regulates lipid metabolism in Mycobacterium tuberculosis infection. J Immunol. 2014;193(1):30–4.
Vitamin D and Progression of Renal Failure
59. Li Y, Spataro BC, Yang J, Dai C, Liu Y. 1,25-dihydroxyvitamin D inhibits renal interstitial
myofibroblast activation by inducing hepatocyte growth factor expression. Kidney Int.
60. Ito I, Waku T, Aoki M, Abe R, Nagai Y, Watanabe T, Nakajima Y, Ohkido I, Yokoyama K,
Miyachi H, Shimizu T, Murayama A, Kishimoto H, Nagasawa K, Yanagisawa J. A nonclassical
vitamin D receptor pathway suppresses renal fibrosis. J Clin Invest. 2013;123(11):4579–94.
61. Zhang Z, Zhang Y, Ning G, Deb DK, Kong J, Li YC. Combination therapy with AT1 blocker
and vitamin D analog markedly ameliorates diabetic nephropathy: blockade of compensatory
renin increase. Proc Natl Acad Sci U S A. 2008;105(41):15896–901.
62. Mizobuchi M, Morrissey J, Finch JL, Martin DR, Liapis H, Akizawa T, Slatopolsky
E. Combination therapy with an angiotensin-converting enzyme inhibitor and a vitamin D
analog suppresses the progression of renal insufficiency in uremic rats. J Am Soc Nephrol.
63. Tan X, Li Y, Liu Y. Paricalcitol attenuates renal interstitial fibrosis in obstructive nephropathy.
J Am Soc Nephrol. 2006;17(12):3382–93.
64. Tan X, He W, Liu Y. Combination therapy with paricalcitol and trandolapril reduces renal
fibrosis in obstructive nephropathy. Kidney Int. 2009;76(12):1248–57.
65. Zhang Y, Kong J, Deb DK, Chang A, Li YC. Vitamin D receptor attenuates renal fibrosis by
suppressing the renin-angiotensin system. J Am Soc Nephrol. 2010;21(6):966–73.
66. Shroff R, Aitkenhead H, Costa N, Trivelli A, Litwin M, Picca S, Anarat A, Sallay P, Ozaltin F,
Zurowska A, Jankauskiene A, Montini G, Charbit M, Schaefer F, Wühl E; ESCAPE Trial
Group. Normal 25-hydroxyvitamin D levels are associated with less proteinuria and attenuate
renal failure progression in children with CKD. J Am Soc Nephrol. 2015. pii: ASN.2014090947.
[Epub ahead of print].
67. O’Herrin JK, Hullett DA, Heisey DM, Sollinger HW, Becker BN. A retrospective evaluation
of 1,25-dihydroxyvitamin D(3) and its potential effects on renal allograft function. Am
J Nephrol. 2002;22(5–6):515–20.
68. Bertoli M, Luisetto G, Ruffatti A, Urso M, Romagnoli G. Renal function during calcitriol
therapy in chronic renal failure. Clin Nephrol. 1990;33(2):98–102.
69. Perez A, Raab R, Chen TC, Turner A, Holick MF. Safety and efficacy of oral calcitriol
(1,25-dihydroxyvitamin D3) for the treatment of psoriasis. Br J Dermatol. 1996;134(6):
70. Agarwal R, Hynson JE, Hecht TJ, Light RP, Sinha AD. Short-term vitamin D receptor activation increases serum creatinine due to increased production with no effect on the glomerular
filtration rate. Kidney Int. 2011;80(10):1073–9.
71. Palmer SC, Sciancalepore M, Strippoli GF. Trial quality in nephrology: how are we measuring
up? Am J Kidney Dis. 2011;58(3):335–7.
72. Novak JE, Inrig JK, Patel UD, Califf RM, Szczech LA. Negative trials in nephrology: what can
we learn? Kidney Int. 2008;74(9):1121–7.
Vitamin D and Diabetes in Chronic
Emilio González Parra, Maria Luisa González-Casaus,
and Ricardo Villa-Bellosta
Abstract The relation between the kidney and vitamin D is well known. Vitamin D
has also been recognized to regulate endocrine pancreatic function; it stimulates pancreatic beta cells proliferation and insulin secretion. And several studies suggest that
vitamin D status may have a significant role in glucose homeostasis in general, and
on the pathophysiology and progression of metabolic syndrome and type-2 diabetes
in particular. The deficiency in vitamin D is associated with a reduced insulin secretion, which might be an important factor for the susceptibility of developing diabetes.
Vitamin D has been proposed also as a possible therapeutic agent in the prevention
and treatment of type-1 and type-2 diabetes. In diabetic patients at various CKD
stages, circulating 25(OH)D levels are negatively correlated with glycosylated hemoglobin (HbA1c) values, which suggests that increasing circulating vitamin levels may
have a beneficial effect of the glycemic control. Likewise, the activation of the vitamin D receptor (VDR) can reduce proteinuria and contribute to the nephroprotection.
Low circulating 25(OH)D levels in CKD patients have been associated with a higher
risk of all-cause mortality and faster progression of kidney disease. Unfortunately,
the level of evidence to support 25(OH)D therapy for CKD or diabetes mellitus is
low. Several studies of nutritional vitamin D supplementation in patients with CKD
and type-2 diabetes are actually ongoing, although their results are not yet available.
Keywords Uremia • CKD • Diabetes • Proteinuria • Insulin • Insulin resistance •
Pancreas • Vitamin D receptor (VDR) • VDR activators
E. González Parra, MD (*)
Servicio de Nefrología, Universidad Autónoma, Fundación Jiménez Díaz, Madrid, Spain
e-mail: EGParra@idcsalud.es; firstname.lastname@example.org
M.L. González-Casaus, MD
Laboratory of Nephrology and Mineral Metabolism, Biochemistry/Biopathology,
Hospital Central de la Defensa Gomez Ulla, Madrid, Spain
R. Villa-Bellosta, PhD
Department of Nephrology, IIS-Fundación Jiménez Díaz, Madrid, Spain
© Springer International Publishing Switzerland 2016
P.A. Ureña Torres et al. (eds.), Vitamin D in Chronic Kidney Disease,
E. González Parra et al.
Basic Approach Between Diabetes and Vitamin D
Vitamin D is a forms of fat-soluble secosteroids, a type of steroid with a “broken”
ring that is responsible for enhancing intestinal absorption of calcium, phosphate,
magnesium, iron, and zinc. In humans, the most important compounds in this group
are vitamin D3 (also known as cholecalciferol) and vitamin D2 or ergocalciferol
(also found in fungi and plants). Humans receive vitamin D through sunlight exposure and dietary intake. Vitamin D is only found in a limited number of foods, such
as fatty fish, egg yolks, mushrooms, and dietary supplements, and the primary natural source of vitamin D is UVB-radiation-dependent synthesis in the skin. Vitamin
D2 and Vitamin D3 are synthesized through UVB irradiation of ergosterol and
7-dehydrocholesterol, respectively, during sunlight exposure.
Vitamin D2 and D3 are inert and are converted to 25-hydroxyvitamin D or 25(OH)
D (25-hydroxyergocalciferol [25(OH)D2] and 25-hydroxycholecalciferol [25(OH)
D3] or calcidiol, respectively) by the microsomal enzyme vitamin D 25-hydroxylase
in hepatocytes (Fig. 15.1). These two specific vitamin D metabolites are measured
in serum and plasma to determine a patient’s vitamin D status. In the kidney, part of
the calcidiol is converted to calcitriol (1-α,25-dihydroxicholecalciferol or
1,25(OH)2D3)—the biologically active vitamin D metabolite—by 1α-hydroxylase.
The renal production of calcitriol is tightly regulated by calcium, phosphate, serum
levels of both parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23),
and calcitriol itself. Calcitriol has a short half-life (4–6 h) and circulates as a hormone in the blood, promoting healthy bone growth and remodeling and regulating
the concentration of calcium/phosphate in the bloodstream. The 24-hydroxylase
enzyme degrades both 25-hydrovitamin D and calcitriol into biologically inactivate
water-soluble calcitroic acid (see Fig. 15.1).
The active vitamin D metabolite calcitriol mediates its biological effects by binding to the vitamin D receptor (VDR), which is primarily located in the core of target
cells in most organs, including several white blood cells, such as monocytes and
activated T and B cells. Although all vitamin D metabolites bind to the VDR, most
biological effects are likely mediated by calcitriol, as it has the greatest receptor
Accumulating evidence suggests that calcitriol possesses (a) anti-inflammatory
properties : reducing pro-inflammatory cytokines (such as TNFα), increasing
anti-inflammatory cytokines (such as IL-10) and suppressing NF-kB activity;
(b) anti-oxidative effects: reducing reactive oxygen species (ROS) generation and
restoring cellular ROS-scavenging enzyme activity; and (c) anti-hypertrophic and
anti-fibrotic properties : suppressing hypertrophy gene expression and regulating heart extracellular matrix metabolism. (d) Calcitriol also possesses antiatherosclerotic actions by increasing fibrinolysis and inhibition of both foam cell
formation and vascular smooth muscle cell proliferation and migration.
(e) Moreover, calcitriol promotes vascular calcification  via hypercalcemia,
hyperphosphatemia, and by inducing transformation of vascular smooth muscle
cells. In vitro, calcitriol affects the synthesis of neurotrophic factors, nitric oxide
synthesis, and glutathione.
Fig. 15.1 Vitamin D biochemistry and its beneficial or harmful effects. UVB ultraviolet B radiation, 25 OHase vitamin D 25-hydroxylase, 25(OH) D
25-hydrovitamin D, 1 OHase vitamin D 1α-hydroxylase, 1,25(OH)2 D 1,25-hydrovitamin D 24 OHase vitamin D 24-hydroxylase
Vitamin D and Diabetes in Chronic Kidney Disease
E. González Parra et al.
Diabetes mellitus (DM) is a disease characterized by hyperglycemia and is
caused by absolute or relative insulin deficiency, sometimes associated with insulin
resistance. Type-1 diabetes is an autoimmune disease in which the patient’s own
immune system reacts against islet antigens and destroys beta cells. Invarious
immune cells CYP27B1 has been discovered, the 1α-hydroxylase responsible for
the final activation of circulating calcidiol into calcitriol, makes it possible for calcitriol to be produced locally in the immune system itself. T- and B-lymphocytes are
also direct targets of calcitriol. Therefore, the immune-modulating properties of
active calcitriol suggest that vitamin D and its metabolites or analogs could be
potential therapeutic agents for the prevention of type-1 diabetes.
An indirect sign of the importance of vitamin D in the pancreatic function is the
presence of VDR in pancreatic cells, including beta cells. These cells possess the
1-alpha hydroxylase enzyme and can locally produce calcitriol, which is capable of
exerting autocrine/paracrine action. Therefore, vitamin D has been proposed as a
possible therapeutic agent in the prevention and treatment of type-1 and type-2 diabetes. Patients with vitamin D deficiency have a dysfunction of pancreatic beta cells
with impaired insulin secretion and increased tissular resistance to insulin. The role
of vitamin D in insulin secretion appears to be due to a direct effect of this hormone
on the VDR receptor on pancreatic cells, or indirectly through the calcium-binding
proteins. The increase in intracellular calcium increases the conversion of proinsulin to insulin. It also improves tissue sensitivity to insulin. For these reasons, vitamin D deficiency could be responsible for the susceptibility of developing diabetes,
as studies show that vitamin D status is inversely correlated to diabetes.
Type-2 diabetes is associated with exposure of beta cells to chronically elevated
levels of glucose and free fatty acids (FFA)—conditions referred to as glucotoxicity
and lipotoxicity, respectively—leading to oxidative and endoplasmatic reticulum (ER)
stress (see Fig. 15.2). These phenomena result in functional impairment and cell death,
which are mediated through excessive generation of reactive oxygen species (ROS),
mitochondrial dysfunction, and inflammation of pancreatic beta cells. As calcitriol
possesses anti-inflammatory and anti-oxidative effects, this hormone could prevent
detrimental effects such as these. Chronic hyperglycemia is the proximate cause of retinopathy, chronic kidney failure, neuropathies, and macrovascular disease in diabetes.
In type-2 diabetes, beta cells are also adversely affected by chronic hyperglycemia and
secrete less and less insulin, thereby adding to a downward spiral of loss of function.
Both types of diabetes display increased levels of ROS such as free radicals. For
this reason, the onset of diabetes is closely associated with increased oxidative
stress, which also causes of glomerulonephritis in grafted kidneys, rheumatoid
arthritis in joints, and atherosclerosis in vessels. Moreover, the dialysis procedure
contributes to the exacerbation of oxidative stress.
The precise mechanism by which oxidative stress accelerates diabetes complications is only partly understood, but protein damage protein is recognized to be one
contributing factor. In physiological concentration, endogenous ROS production
helps maintaining protein homeostasis. However, when ROS excessively accumulate for prolonged periods of time, it causes chronic oxidative stress and adverse
effects, especially in islet cells that are vulnerable to ROS due to their low intrinsic
Vitamin D and Diabetes in Chronic Kidney Disease
Fig. 15.2 Mechanism of action in diabetes. ROS reactive oxygen species, FFA free fatty acid, Cyt
C cytochrome C, ER endoplasmic reticulum
levels of antioxidant enzymes. For example, in a model of type-2 diabetes, high
glucose concentration increased intracellular peroxide levels in islet cells .
Multiple biochemical pathways and mechanisms of action have been implicated
in the deleterious effects of chronic hyperglycemia and oxidative stress on the function of pancreatic beta cells and vascular and renal tissues. At least six pathways are
emphasized in the literature as being major contributors to ROS, including (1)
α-ketoaldehyde by glyceraldehyde autoxidation, (2) PKC activation, (3) glycation,
(4) sorbitol metabolism, (5) hexosamine metabolism, and (6) oxidative phosphorylation. Chronic exposure of pancreatic beta cells to supra-physiologic concentration
of glucose also causes abnormal insulin secretion and defective insulin gene expression and transcription. The defect in insulin gene expression is due to the loss of a
least two critical proteins (PDX-1 and MafA) that activate the insulin promoter.
Clinical diabetes mellitus is often accompanied by elevated blood levels of cholesterol, triglycerides, and free fatty acid (FFA). Prolonged exposure of pancreatic beta
cells to fatty acids has been reported to inhibit insulin gene expression. Simultaneous
presence of hyperglycemia and elevated fatty acid levels causes accumulation of
cytosolic citrate, the precursors of malonyl-CoA, which inhibits carnitine palmitoyltransferase-1, the enzyme responsible for fatty acid transport into the mitochondria.
Moreover, recent studies have revealed that palmitate inhibits insulin gene expression
by inhibition of insulin promoter activity and increased levels of intracellular
ceramide. However, palmitate-induced generation of ceramide has been reported to
lead to apoptosis (X34), and palmitate-induced apoptosis causes generation of ROS.
E. González Parra et al.
Calcitriol may exert beneficial effects on altered cardiac metabolism in diabetic
cardiomyopathy and improve insulin secretion and sensitivity. The imbalance of
FFA and glucose utilization results in the accumulation of toxic intermediates of
FFA, increased oxidative stress, mitochondrial dysfunction, abnormalities in calcium handling, and subsequently diabetic cardiomyopathy. Calcitriol restores
impaired insulin secretion in vitamin D-deficient rats and activates the expression of
the human insulin receptor gene. Calcitriol improves diabetic cardiomyopathy, regulating peroxisome proliferator-activated receptors and increasing glucose utilization via glucose transporter 4. Moreover, vitamin D-deficient rats activated the
glycolytic pathway and reduced β-oxidation, which is also characteristic of cardiac
remodeling and heart failure .
Finally, expression of receptors for calcitriol and 1α-hydroxylase has been
described in all tissues involved in the pathogenesis of type-2 diabetes, including
pancreatic beta cells, liver, kidney, fat tissue, and muscle . Moreover, the formation of the bioactive metabolite of vitamin D (calcitriol) occurs mainly in the kidney; therefore, disturbance in kidney function could impair the synthesis of calcitriol
and its degradation by 24-hydroxylase, also taking place in kidney.
Relationship Between Vitamin D and Diabetes
in Healthy Populations
Epidemiology of Diabetes Mellitus
Diabetes mellitus is a common chronic disease, with an estimated global prevalence
of 9 % among adults aged >18 as of 2014. In 2012, an estimated 1.5 million deaths
were directly caused by diabetes, and the World Health Organization (WHO) projects that diabetes will be the seventh leading cause of death by 2030. Type-1 diabetes (juvenile or insulin-dependent diabetes mellitus) is an autoimmune disorder in
which the immune system reacts against the pancreatic beta cells, leading to a deficit of insulin. This type mainly affects children and adolescents, and its susceptibility is linked to specific HLA genotypes. Moreover, type 2 diabetes (non
insulin-dependent or adult-onset) results from the body’s ineffective use of insulin,
probably by primary dysfunction in peripheral insulin target organs (mainly liver,
fat, and skeletal muscle), although beta-cell dysfunction is also present. Type-2 diabetes comprises 90 % of people with diabetes around the world, and is largely the
result of excess body weight and physical inactivity.
Relationship Between Vitamin D and Diabetes
Taking into account the important pleiotropic role of vitamin D, suggested by the
presence of VDR, the expression of CYP27B1-hydroxylase in pancreatic beta cells,
and the presence of a vitamin D-responsive element in the human insulin receptor