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Vitamin D in Chronic Kidney Disease PDF

583 Pages·2016·10.18 MB·English
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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 T his work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. T he use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. T he publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer International Publishing AG Switzerland 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

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Vitamin D deficiency, circulating levels lower than 15 ng/ml, is an epidemic disease worldwide with more than a billion people suffering of it in the beginning of the 21-century. Besides its impact on mineral and bone metabolism, these low vitamin D levels are also associated with a diversity of non
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