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4 Vitamin D Supplementation in CKD Patients: Effects on Skeletal Muscle Functions
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 . 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 . 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 .
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.
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 . 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 . 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-
Vitamin D and Muscle in Chronic Kidney Disease
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 . 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
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 . 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
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 and Muscle in Chronic Kidney Disease
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Vitamin D Deficiency and Infection
in Chronic Kidney Disease
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 •
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
© Springer International Publishing Switzerland 2016
P.A. Ureña Torres et al. (eds.), Vitamin D in Chronic Kidney Disease,
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 .
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.
Chronic Kidney Disease, Infection, Immune
Impairment and Inflammation
Infections are an important cause of morbidity and mortality in CKD . 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 . 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 .
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  and HIV infection . 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].
Vitamin D Deficiency and Infection in Chronic Kidney Disease
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 . Among
other conditions, both CKD [6, 12] and HIV infection  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.
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].
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