Vitamin D in Chronic Kidney Disease

583 Pages·2016·10.18 MB·English

by  Pablo A. Ureña Torres

Vitamin D
in Chronic
Kidney Disease
Pablo A. Ureña Torres
Mario Cozzolino
Marc G. Vervloet
Editors
123
Vitamin D in Chronic Kidney Disease

Pablo A. Ureña Torres (cid:129) Mario Cozzolino
Marc G. Vervloet
Editors
Vitamin D in Chronic
Kidney Disease
Editors
Pablo A. Ureña Torres Marc G. Vervloet
Ramsay-Générale de Santé VU University Medical Center
Clinique du Landy Amsterdam
Saint Ouen The Netherlands
France
Mario Cozzolino
San Paolo Hospital
DiSS University of Milan
Milan
Italy
ISBN 978-3-319-32505-7 ISBN 978-3-319-32507-1 (eBook)
DOI 10.1007/978-3-319-32507-1
Library of Congress Control Number: 2016952637
© Springer International Publishing Switzerland 2016
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Foreword
Chronic kidney disease (CKD) is a global public health problem, affecting up to
10 % of the world’s population and increasing in prevalence and adverse outcomes.
The progressive loss of kidney function is invariably complicated by disorders of
bone and mineral metabolism and cardiovascular disease, resulting in premature
death. The disturbances in mineral metabolism begin early in the course of progres-
sive CKD with a reduced capacity to fully excrete a phosphate load and to convert
vitamin D into the biological active 1,25-dihydroxy-vitamin-D, resulting in a com-
pensatory secondary hyperparathyroidism, elevated levels of FGF23, and disturbed
klotho levels in addition to hyperphosphatemia, vitamin D defi ciency, bone disease,
and extraskeletal calcifi cations. During the past decade there has been a substantial
focus on the pathophysiology and the interrelations between and the understanding
of the fundamental mechanisms, which are involved in the regulation of the many
hormones and factors employed in the disturbances in CKD-mineral and bone dis-
order (CKD-MBD). The new knowledge comes both from clinical and experimental
studies, and the need for confi rmatory randomized clinical trials is often stressed.
A distinguished group of contributors under the editorship of Dr. Pablo Ureña
Torres have produced an extremely concise synopsis on some of the major areas of
importance in the fi eld of vitamin D. Thus, this textbook updates in a relevant and
clear way all aspects of vitamin D in CKD with special focus on metabolism, mea-
surements of the different analogs and metabolites, assessment of vitamin D status,
physiological and pathophysiological actions, non-classical pleiotropic benefi cial
and or deleterious effects, and on the endemic insuffi ciency or defi ciency in CKD. A
section is dedicated to the effects of vitamin D defi ciency and treatment in kidney
transplantation. Finally, the last part reviews the therapeutical aspects of vitamin D
supplementation and the use of vitamin D analogs in CKD. The purpose of this text-
book is to provide a state-of-the-art overview of both basic and clinical aspects of
v
vitamin D in CKD-MBD. The chapters are written in a very clear-cut and updated
way to enlighten the novice and to extend the knowledge of clinicians and clinical
investigators of the recent progress in the many exiting aspects of vitamin D in CKD.
Klaus Olgaard , MD
Nephrological Department P 2132
University of Copenhagen
Rigshospitalet, 9 Blegdamsvej
DK 2100 Copenhagen , Denmark
Introd uction
I n the actual and revolutionary “numerical” era we are living, the writing of a classical
textbook on vitamin D might appear relegated to a second- or third-line priority, prob-
ably even lower for geek peoples. In addition, since the exploding and exponentially
increasing number of vitamin D publications appearing every week, it is highly prob-
able that many of the data presented in this book will be already obsolete at the moment
of its release. Nevertheless, the growing interest manifested by the general public and
health caregivers for all aspects of vitamin D, including metabolism, measurement and
assessment of vitamin D status, physiological actions, unexpected pleiotropic benefi -
cial/deleterious effects, and the endemic insuffi ciency/defi ciency status observed in
patients with chronic kidney disease (CKD), as well as the lack of high-quality and
evidence-based guidelines, motivate us to embark in this exciting adventure.
This textbook is divided into fi ve major sections: the fi rst one considers the metab-
olism of vitamin D in normal and pathological situations, the assessment of vitamin
D status based on actual methods of measuring vitamin D molecules as well as its
binding protein, and the epidemiology of vitamin D defi ciency in CKD worldwide.
The second section discusses the classical biological and biochemical effects of vita-
min D on mineral and bone metabolism in case of CKD. The third section reviews
the non-classical and potential pleiotropic effects of vitamin D in CKD. The fourth
section is dedicated to the metabolism of vitamin D and the effects of vitamin D treat-
ment in CKD benefi cing of a kidney graft. Finally, the fi fth section reviews the thera-
peutical aspects of vitamin D supplementation and the use of vitamin D analogs in
CKD. In the next pages, I will summarize, in a non-exhaustively manner, the most
relevant issues developed here by internationally renowned experts on vitamin D.
Generalities, Measurement, and Epidemiology
We believed that we knew everything about vitamin D physiology, however, in the
fi rst chapter Drs. Zierold and DeLuca reminded us that there are still many unan-
swered questions. Vitamin D is a pro-hormone synthesized in the skin from the
vii
viii Introduction
precursor 7-dehydrocholesterol by the action of sunlight. Low amounts of vitamin D
are p resent in food, fortifi ed dairy, and fi sh oils. Vitamin D undergoes two-step bio-
activation process required to produce its active form. It is converted in 25-hydroxyvi-
tamin D in the liver by 25-hydroxylation, followed by the conversion to 1,25(OH) D
2
by the 1α-hydroxylase in kidney under very tightly regulated physiological condi-
tions. 1,25(OH) D is responsible for maintaining adequate serum calcium and phos-
2
phate levels, which are essential for a healthy mineral and bone metabolism. In
addition, 1,25(OH) D plays an important role in many biological non-calcemic func-
2
tions throughout the body. 1,25(OH) D must bind to the vitamin D receptor to carry
2
out its functions. The highly active and lipid-soluble 1,25(OH) D is inactivated by the
2
24-hydroxylase, which is the enzyme responsible for the major catabolic pathway
that ultimately results in the water-soluble calcitroic acid for excretion in the urine.
Regulation of key players in vitamin D metabolism is reciprocal and very tight. The
activating enzyme 1α-hydroxylase and the catabolic enzyme 24-hydroxylase are
reciprocally regulated by PTH, 1,25(OH) D, and fi broblast growth factor 23 (FGF23).
2
C hronic kidney disease (CKD) leads to an altered vitamin D metabolism, mainly
a decreased production and circulating levels of 1,25(OH) D . Several mechanisms
2
contribute to this phenomenon, including decreased renal mass, decreased delivery
of DBP-bound 25-hydroxyvitamin D to the 1α-hydroxylase enzyme, inhibition of
1α-hydroxylase activity by FGF23 and uremic toxins, reduced renal tubular megalin
expression, reduced intestinal absorption of vitamin D, and fi nally increased 1,25(OH) D
2
degradation by FGF23-stimulated 24-hydroxylase activity. These alterations are asso-
ciated with abnormalities of calcium and phosphate metabolism, an increased risk of
cardiovascular calcifi cations, and signifi cant high morbidity and mortality rates.
V itamin D defi ciency and insuffi ciency is a global health problem and Dr. Metzger
and Stengel elegantly reviewed this issue in case of CKD. They emphasized the fact
that there is not a clear-cut defi nition of vitamin D status in CKD patients. Currently,
it is defi ned as a circulating 25(OH)D level below 20 ng/ml (50 nmol/L), which has
been recognized as a major risk factor for bone and mineral disorders and has been
related to increased risk of non-skeletal health outcomes including mortality, diabe-
tes, and cardiovascular disease. A greater prevalence of defi ciency is expected in
patients with CKD because they are older and more likely to have dark skin, obesity,
and associated comorbidities such as diabetes and hypertension. In clinical-based
studies, the mean circulating 25(OH)D levels ranged from 18 to 29 ng/ml for
patients with non-end-stage renal disease, and from 12 to 32 ng/ml for those on
dialysis. Large population-based clinical studies, however, are inconsistent regard-
ing the association between kidney function and vitamin D level. While some stud-
ies reported signifi cant positive, and independent association between glomerular
fi ltration rate and circulating 25(OH)D values, others showed low levels only in
advanced CKD stages. Other studies show no or even an inverse association, with
paradoxically higher serum levels of 25(OH)D in individuals with moderate CKD
than in those without CKD. Whether the observed relations are direct and causal, or
indirect because of confounders, is not established. Only few studies examined the
relations between proteinuria or albuminuria and circulating 25(OH)D levels and
generally reported signifi cant negative associations.
Introduction ix
Dr. Adriana Dusso extensively treats the complex genomic and non-genomic
actions of vitamin D, and their modifi cation by CKD. She pointed out that the most
characterized calcitriol/VDR genomic actions include the suppression of PTH syn-
thesis, the stimulation of the phosphaturic hormone FGF23, the longevity gene
klotho, the calcium channel TRPV6 in enterocytes, the rate-limiting step in intesti-
nal calcium absorption, the parathyroid calcium sensing receptor, and the receptor
of the canonical Wnt pathway LRP5 in bone, all essential effectors for normal skel-
etal development and mineralization. The “non-genomic” actions of vitamin D
occur within minutes of exposure to calcitriol. Some of these not yet well-
characterized rapid actions involve the cytosolic VDR, although other potential vita-
min D receptors have been identifi ed. These rapid actions regulate intracellular
calcium fl uxes, the degree of protein phosphorylation, stability and/or processing of
microRNAs, acetylation and subcellular localization, which, by affecting protein
function, greatly modify classical and non-classical direct and indirect genomic
signals.
C KD is a state in which there is resistance to the action of many hormones
including 1,25(OH) D . As vitamin D requires binding to the VDR to exert its phys-
2 3
iological role, the resistance to the action of vitamin D, which has never been clearly
defi ned, may partially be explained by a disturbed VDR function. Here, Dr. Bover
et al. made a comprehensible and in-depth review of VDR in CKD. They stressed
out that the uremic ultrafi ltrate contains chemical compounds that signifi cantly
reduced the VDR interaction with DNA binding and with the VDRE. When normal
VDR were incubated with uremic ultrafi ltrate, they lose 50 % of their maximal bind-
ing capacity to the VDRE. Beyond altered receptor interaction with target genes,
decreased MRN expression and VDR concentration in target organs, such as in the
parathyroid glands, the osteoblasts, and the intestine, might also explain the dimin-
ished biological action of vitamin D in CKD. Various mechanisms have been pro-
posed to explain the decrease of VDR in CKD: First, 1,25(OH) D is known to
2 3
upregulate its own receptor; consequently, the low circulating calcitriol levels leads
to VDR downregulation. Second, SHPT may decrease VDR concentration of in
CKD, as suggested by the fact that PTH downregulates the VDR and VDR messen-
ger RNA and also blocks 1,25(OH) D - induced upregulation of rat intestinal and
2 3
renal VDR. Third, uremic ultrafi ltrate in normal animals suppresses VDR synthesis,
possibly at translational sites, and consequently accumulation of uremic toxins in
CKD may reduce VDR concentration. They fi nally revised the development of new
VDR activators that would induce unique conformational changes in the VDR that
allow them being more specifi c and selective, and probably with improved biologi-
cal profi le for therapeutic application.
U ndoubtedly, measuring 25(OH)D is actually one of the most relevant, frequent,
and debated dosage in daily clinical practice. Indeed, this is the most employed
measurement to assess global vitamin D status. In this book, Dr. Cavalier et al.
describe the potential clinical and biological indications and methods available to
measure vitamin D molecules including cholecalciferol, 25(OH)D, and 1,25 and
24,25 vitamin D in CKD as well in the general population. They also critically
revised the measurement and utility assessing circulating vitamin D binding protein