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8 Vitamin D and Estimated Glomerular Filtration Rate

8 Vitamin D and Estimated Glomerular Filtration Rate

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Vitamin D and Progression of Renal Failure


Recently, Agarwal et al. [70] 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 [3].

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

clinical questions.

More and better clinical work using the appropriate methodology such as randomized clinical trials (RCTs) [71] 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 [72].

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 [71]. 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


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Chapter 15

Vitamin D and Diabetes in Chronic

Kidney Disease

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; egparra@fjd.es

M.L. González-Casaus, MD

Laboratory of Nephrology and Mineral Metabolism, Biochemistry/Biopathology,

Hospital Central de la Defensa Gomez Ulla, Madrid, Spain

e-mail: mlgcasaus@gmail.com

R. Villa-Bellosta, PhD

Department of Nephrology, IIS-Fundación Jiménez Díaz, Madrid, Spain

e-mail: ricardo.villa@fjd.es

© Springer International Publishing Switzerland 2016

P.A. Ureña Torres et al. (eds.), Vitamin D in Chronic Kidney Disease,

DOI 10.1007/978-3-319-32507-1_15




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 [1]: 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 [2]: 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 [3] 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 [4].

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 [5].

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 [6]. 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

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8 Vitamin D and Estimated Glomerular Filtration Rate

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