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4 Vitamin D Supplementation in CKD Patients: Effects on Skeletal Muscle Functions

4 Vitamin D Supplementation in CKD Patients: Effects on Skeletal Muscle Functions

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290



P. Chauveau and M. Aparicio



In the RCTs and meta-analyses concerning vitamin D supplementation and CKD

patients, skeletal muscle mass and function and risks of falls were not included

among the potential targets of the different forms of active and nutritional vitamin

D in systems outside of bone and mineral metabolism. Only relatively scarce observational and case-controls studies have dealt with the effects of vitamin D supplementation on skeletal muscle mass and function and the resulting quality of life,

independence and ability to perform activity of daily living.

In a retrospective and cross-sectional study, hemodialysis patients supplemented

with calcitriol or with its analogue paricalcitol, had larger muscle size and greater

muscle strength than non-treated patients [27]. In an other study concerning stage

3-4 CKD patients and stage 5 CKD patients on peritoneal dialysis, all with vitamin

D deficiency, physical performance tests, static and dynamic balance tests and isometric strength tests improved in both groups after vitamin D replacement [28]. In

a recent randomized controlled trial, patients on hemodialysis with low 25(OH)D

levels received oral cholecalciferol or placebo for 6 months. At the end of the follow-up period, patients allocated to cholecalciferol had higher levels of 25(OH)D

and 1,25(OH)2D and a greater reduction in phosphorus levels compared with the

placebo group. However, there was no significant difference between the two groups

in serum PTH levels, tests of functional capacity, muscle strength and health-related

quality of life [29].

Given the impact of falls and fractures on morbidity and mortality of patients, it

would be important to have some information on a potentially preventive effect of

vitamin D supplementation on the risk of falls, to our knowledge no randomized

controlled trials have been performed in this field.



16.4.2



Insulin Resistance and Vitamin D Supplementation

in CKD Patients



Skeletal muscle is a highly metabolic tissue that responds to a large range of hormones, so the impact of vitamin D deficiency on skeletal muscle is not limited to the

alteration of force and locomotion, it may also concern muscle metabolism pathways, specifically its sensitivity to insulin.

Insulin resistance (IR) is closely and independently associated with increased

cardio-vascular risk, as part of the metabolic syndrome [30]. Insulin resistance is

also associated with increased skeletal muscle protein breakdown contributing to

the uremic muscle wasting, this latter could explain the accelerated loss of lean

body mass observed in patients with type II diabetes compared to hemodialysis

patients without diabetes [31]. The post receptor defect in the insulin-receptor signaling pathway in skeletal muscle, which is the likely primary abnormality results

from a number of reversible factors, one of them is vitamin D deficiency.

Several observational studies have confirmed, in the general population, a significant association between vitamin D status and insulin sensitivity. Low circulating

25(OH)D levels are negatively associated with various measures of glucose metabo-



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Vitamin D and Muscle in Chronic Kidney Disease



291



lism such as homeostasis model assessment of insulin resistance (HOMA-IR), fasting

glucose as well as insulin levels reflecting a state of hyperinsulinemia confirmed by

clamp studies. In prospective studies, vitamin D deficiency is associated with a longterm risk of developing insulin resistance and is highly prevalent in patients with type

II diabetes. The pathophysiology of type II diabetes includes a range of reversible

factors, among them vitamin D deficiency could play an important role by affecting

both insulin sensitivity and insulin secretory capacity independently of PTH, calcitriol

and intracellular calcium.

Moreover, evidence from in vitro studies suggests that vitamin D may improve

insulin sensitivity by increasing the expression of insulin receptors via effects on

Akt and on early steps of insulin signaling pathway.

In the Third National Health and Nutrition Examination Survey (NHANES III)

which included more than 14,000 participants, Vitamin D and kidney function had

independent, inverse association with insulin resistance, as in the general population, although vitamin D was altered at a later stage than insulin sensitivity in the

course of renal failure, on this different grounds, vitamin D supplementation should

be a logical treatment of this dreadful complication [32]. Unfortunately, only few

small studies have been performed on the effects of vitamin D supplementation on

insulin resistance in CKD patients.

Mixed results of vitamin D supplementation on glucose metabolism and insulin

sensitivity and insulin secretion have been reported in experimental animal models

and in CKD patients [33–35]. Moreover, in these different studies, there was no

assessment to compare the outcomes of muscle mass and function on the one hand

with the outcome of insulin sensitivity in response to supplementation with vitamin

D on the other hand, obviously larger well-designed trials devoted to this topic are

needed.



16.5



Conclusions



Clinical muscular consequences of vitamin D deficit have been described some

decades ago in the general population, mostly in the elderly, as well as in CKD

patients, likewise molecular mechanisms by which vitamin D impacts on muscle

mass and function have been elucidated. It could appear that supplementation with

various forms of vitamin D should be a reasonably safe, simple and potentially

effective intervention, actually, a significant improvement in muscle performance is

frequently observed with this treatment in the elderly. If results of vitamin D supplementation on muscle function are rather convincing in the elderly, the results are

more questionable in CKD patients.

A few years ago, a meta-analysis including 76 trials concluded to the unproven

efficacy of vitamin D supplementation in CKD patients except positive effects on

some biochemical indices [26]. Since then, although multiple observational studies

and clinical trials have confirmed the impact of vitamin D supplementation on PTH

levels, there are not enough data to draw conclusions about the effects of this therapy



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P. Chauveau and M. Aparicio



on patients’ outcomes, including mortality, and a fortiori on muscle disorders and

their mechanical and metabolic consequences. Large, well-designed, randomized

controlled trials are still requested to assess the possible benefits of vitamin D supplementation on skeletal muscle in CKD patients.



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vitamin D compounds in chronic kidney disease. Ann Intern Med. 2007;147(12):840–53.

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strength, functional ability and balance in peritoneal dialysis patients with vitamin D deficiency. Clin Nephrol. 2011;76:110–6.

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Soc Nephrol. 2013;8(7):1143–9.

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Third National Health and Nutrition Examination Survey. Kidney Int. 2007;71(2):134–9.

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Chapter 17



Vitamin D Deficiency and Infection

in Chronic Kidney Disease

Jean-Paul Viard



Abstract Infections are an important cause of morbidity and mortality in chronic,

particularly end stage, renal disease. Uremia and dialysis are associated with

immune impairment at multiple levels: decreased innate and adaptive immunity,

increased inflammation. The role of vitamin D in the regulation of immune functions, particularly as an enhancer of innate immunity and as an anti-inflammatory

agent, is now well recognized. Since vitamin D deficiency is frequent in patients

with chronic kidney disease, several studies examined the relationships between

vitamin D insufficiency and immune impairment or infectious diseases in this population. Vitamin D deficiency could contribute to decreased innate immunity and

increased inflammation or immune cell activation, including through modulating

the microbiome and intestinal permeability. Convincing data from epidemiological

studies have associated vitamin D deficiency with inflammation, all-cause mortality, cardiovascular and infectious outcomes. However, intervention studies are still

needed to validate the causality relationship and determine whether vitamin D supplementation can reduce infections in chronic kidney disease patient.

Keywords Vitamin D • Chronic kidney disease • Infection • Immune responses •

Inflammation



17.1



Introduction



Vitamin D has been studied in chronic kidney disease (CKD) for many years

because of the disturbances of its metabolism and their consequences on mineral

and bone homeostasis. Among extra-skeletal effects of vitamin D, its role as a

potential regulator of immune functions and inflammation has more recently been

extensively studied. In large epidemiological studies conducted in the general



J.-P. Viard, MD

UF de Thérapeutique en Immuno-infectiologie, Hơtel-Dieu, Paris, France

e-mail: jean-paul.viard@htd.aphp.fr

© 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_17



295



296



J.-P.Viard



population, vitamin D deficiency has been associated with an increased susceptibility to infections, especially tuberculosis and respiratory tract infections) [1, 2], and,

although this remains debated, vitamin D supplementation could reduce the risk of

some of these infections [3].

Since patients with CKD (and other chronic conditions) have a higher morbidity

and mortality burden from, in particular, infectious (and cardiovascular) diseases,

the role of vitamin D deficiency in the pathogeny of these complications has been

examined, and supplementation trials have been implemented. This chapter will

examine whether and why vitamin D deficiency could be considered a risk factor for

infection in CKD, and whether there is any evidence that vitamin D supplementation may reduce infections in CKD patients.



17.2



Chronic Kidney Disease, Infection, Immune

Impairment and Inflammation



Infections are an important cause of morbidity and mortality in CKD [4]. For example, a single-center study in France showed that, over a 7-month observation period,

30 % of critical care unit admission of patients with CKD were linked to bacterial

infections [5]. In particular, patients with end-stage renal disease (ESRD) accumulate factors leading to an increased risk of infection, such as malnutrition, comorbidities (such as diabetes), the presence of vascular access devices, but also immune

dysfunction [4, 6]. Of note, it has been shown in the US dialysis population that,

while infection-related deaths have decreased over the last years, infection-related

hospitalizations have not and failed to decrease with the decline of catheter use [7].

The impairment of host response to pathogens in CKD therefore appears as a plausible underlying risk factor, while risk factors linked to dialysis procedures have

been progressively reduced [6, 7].

Impaired immune functions are a feature of CKD and ESRD [6, 8], as exemplified by the lower response rate to vaccines and the accelerated decline of antibody

titers in ESRD patients. Uremia reduces innate host responses to pathogens, through

negative effects on the activation and function of monocytes (decreased TLR and

costimulatory molecules expression, reactive oxygen species release and phagocytosis) and neutrophils (decreased phagocytosis). Adaptive immunity is also impaired

through the reduction of antigen presentation (by dendritic cells, macrophages and

B cells), an altered distribution of T cell subpopulations (abnormal CD4/CD8 ratio,

reduction of the naive and central-memory compartments), increased T-cell apoptosis and a shift towards the production of Th2 cytokines.

It is interesting to note that many of the immune abnormalities found in CKD are

reminiscent of the immune phenotype found, of course at different degrees, in other

conditions such as extreme ageing [9] and HIV infection [10]. CKD, ageing and

HIV infection also have in common that immune impairment is paralleled by persistent inflammation and the consequences thereof, mediated by an increased production of proinflammatory cytokines and chronic cell activation [4, 6, 9, 10].



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297



Much attention has recently been paid to the link that could exist between

immune impairment and chronic inflammation on the one hand, and the impact of

dysbiosis and bacterial translocation form the gut, on the other hand [11]. Among

other conditions, both CKD [6, 12] and HIV infection [13] appear as promising

fields of investigation in this emerging research area. In CKD patients [6, 12], bacterial compounds (endotoxin, ribosomal DNA) have been detected in the blood stream

of patients, and correlate with the intensity of systemic inflammation assessed

through the levels of soluble biomarkers such as C-reactive protein, interleukin-6

and monocyte activation markers. Interestingly, the levels of endotoxin/lipopolysaccharide increase with the progression of CKD, reaching the highest levels in patients

on dialysis, being then an independent predictor of mortality. Several studies have

also documented disorders in the gut microbiome of CKD patients, with a dominance of bacteria with urease, uricase and p-cresol-producing activities and a

decrease of species with butyrate-producing activities, resulting in an increased production in gut-derived uremic toxins (e.g. indoxyl sulfate and p-cresyl sulfate),

which in turn activate leucocytes and inflammatory cytokine production.



17.3

17.3.1



Possible Role of Vitamin D Deficiency in the Immune

Dysfunction of CKD

Vitamin D and Immunity



Vitamin D is increasingly recognized as an important factor of immune regulation

because virtually all immune cells are equipped with the vitamin D receptor and are

able to activate 25-hydroxy vitamin D [14–16].

17.3.1.1



Vitamin D and Innate Immunity



Epithelial cells and monocytes/macrophages express both toll-like receptors (TLR),

recognizing ligands originating from pathogens, CYP27B1, a cytochrome component that activates 25-hydroxyvitamin D [25(OH)D] through 1α-hydroxylation, and

the vitamin D receptor (VDR) [14–16]. This makes an intracrine system that plays

an important role in the production de of bactericidal peptides, such as cathelicidin,

with largely proven activity against Mycobacterium tuberculosis, and β-defensin

4A. Activation of TLRs induces the synthesis of bactericidal peptides via CYP27B1

transcription, binding of 1,25-dihydroxyvitamin D [1,25(OH)2D] to the VDR, and

formation of a heterodimer with the retinoid X receptor (RXR), that regulates the

expression of vitamin D-responsive genes.

Vitamin D induces proliferation and cytokine production in natural killer (NK)

cells. Vitamin D also induces autophagy in macrophages. Autophagy is a finely

regulated phenomenon that is important in the defence against pathogens,

particularly intracellular pathogens such as viruses and mycobacteria. In a



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