Frontiers in Bone Metabolism and Disorder in Chronic Kidney Disease

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: closed (15 March 2022) | Viewed by 18722

Special Issue Editors

Department of Nephrology, Herlev and Gentofte Hospital, University of Copenhagen, 2100 Copenhagen, Denmark
Interests: hormonal regulation of calcium; phosphate and vitamin D homeostasis; vascular calcification; molecular mechanisms
Department of Nephrology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
Interests: chronic kidney disease; mineral and bone disorder

Special Issue Information

Dear Colleagues,

Advances are progressively introduced in understanding the complex syndrome of mineral and bone disorder in chronic kidney disease (CKD-MBD), with relevance to not only CKD, but also to general aging and chronic metabolic disease pathogenesis. CKD-MBD is defined by altered sensing and plasma levels of calcium and phosphate along with deranged hormonal levels, with decreased production of the anti-aging αklotho, calcitriol, and increased levels of FGF23 and PTH together with development of bone lesions, vascular and valvular calcification, and kidney fibrosis. Research has suggested that disturbances develop early and progress as kidney function declines. As such, acute kidney injury also has an impact together with the time factor. In addition to the classical calcium and phosphate regulating hormones, new factors related to Wnt and TGFβ signaling, e.g., sclerostin and activin A, have been introduced to play an important role in pathogenesis. Furthermore, our knowledge of the impact of uremic toxins, inflammatory cells, and cytokines is growing. Most interestingly, complex crosstalks between the bone, kidney, parathyroid gland, and vasculature have been identified, as shown by the secretion of factors from the injured kidney and vessels and their multiple targets. Potentially, the pathological interplay may further include the microbiome of the gut and nutritional status. Finally, new concepts of disturbed circadian rhythm and disturbed systems biology in CKD are emerging. 

Dr. Ewa Lewin
Dr. Maria L Mace
Guest Editors

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Keywords

  • Calcium
  • Phosphate
  • PTH
  • Vitamin D
  • FGF23
  • Klotho
  • Renal osteodystrophy
  • Activin A
  • Wnt signaling
  • Circadian rhythm
  • Tissue crosstalk
  • Vascular calcification
  • Inflammation

Published Papers (7 papers)

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Editorial

Jump to: Review

5 pages, 209 KiB  
Editorial
Frontiers in Bone Metabolism and Disorder in Chronic Kidney Disease
by Maria L. Mace and Ewa Lewin
Metabolites 2023, 13(10), 1034; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo13101034 - 26 Sep 2023
Viewed by 870
Abstract
Chronic Kidney Disease (CKD) is a progressive condition that affects 10–15% of the adult population, a prevalence expected to increase worldwide [...] Full article
(This article belongs to the Special Issue Frontiers in Bone Metabolism and Disorder in Chronic Kidney Disease)

Review

Jump to: Editorial

12 pages, 860 KiB  
Review
Shedding Light on the Complex Regulation of FGF23
by Marc G. Vervloet
Metabolites 2022, 12(5), 401; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12050401 - 28 Apr 2022
Cited by 6 | Viewed by 2009
Abstract
Early research has suggested a rather straightforward relation between phosphate exposure, increased serum FGF23 (Fibroblast Growth Factor 23) concentrations and clinical endpoints. Unsurprisingly, however, subsequent studies have revealed a much more complex interplay between autocrine and paracrine factors locally in bone like PHEX [...] Read more.
Early research has suggested a rather straightforward relation between phosphate exposure, increased serum FGF23 (Fibroblast Growth Factor 23) concentrations and clinical endpoints. Unsurprisingly, however, subsequent studies have revealed a much more complex interplay between autocrine and paracrine factors locally in bone like PHEX and DMP1, concentrations of minerals in particular calcium and phosphate, calciprotein particles, and endocrine systems like parathyroid hormone PTH and the vitamin D system. In addition to these physiological regulators, an expanding list of disease states are shown to influence FGF23 levels, usually increasing it, and as such increase the burden of disease. While some of these physiological or pathological factors, like inflammatory cytokines, may partially confound the association of FGF23 and clinical endpoints, others are in the same causal path, are targetable and hence hold the promise of future treatment options to alleviate FGF23-driven toxicity, for instance in chronic kidney disease, the FGF23-associated disease with the highest prevalence by far. These factors will be reviewed here and their relative importance described, thereby possibly opening potential means for future therapeutic strategies. Full article
(This article belongs to the Special Issue Frontiers in Bone Metabolism and Disorder in Chronic Kidney Disease)
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17 pages, 966 KiB  
Review
New Therapeutics Targeting Arterial Media Calcification: Friend or Foe for Bone Mineralization?
by Astrid Van den Branden, Anja Verhulst, Patrick C. D’Haese and Britt Opdebeeck
Metabolites 2022, 12(4), 327; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12040327 - 05 Apr 2022
Cited by 3 | Viewed by 2604
Abstract
The presence of arterial media calcification, a highly complex and multifactorial disease, puts patients at high risk for developing serious cardiovascular consequences and mortality. Despite the numerous insights into the mechanisms underlying this pathological mineralization process, there is still a lack of effective [...] Read more.
The presence of arterial media calcification, a highly complex and multifactorial disease, puts patients at high risk for developing serious cardiovascular consequences and mortality. Despite the numerous insights into the mechanisms underlying this pathological mineralization process, there is still a lack of effective treatment therapies interfering with the calcification process in the vessel wall. Current anti-calcifying therapeutics may induce detrimental side effects at the level of the bone, as arterial media calcification is regulated in a molecular and cellular similar way as physiological bone mineralization. This especially is a complication in patients with chronic kidney disease and diabetes, who are the prime targets of this pathology, as they already suffer from a disturbed mineral and bone metabolism. This review outlines recent treatment strategies tackling arterial calcification, underlining their potential to influence the bone mineralization process, including targeting vascular cell transdifferentiation, calcification inhibitors and stimulators, vascular smooth muscle cell (VSMC) death and oxidative stress: are they a friend or foe? Furthermore, this review highlights nutritional additives and a targeted, local approach as alternative strategies to combat arterial media calcification. Paving a way for the development of effective and more precise therapeutic approaches without inducing osseous side effects is crucial for this highly prevalent and mortal disease. Full article
(This article belongs to the Special Issue Frontiers in Bone Metabolism and Disorder in Chronic Kidney Disease)
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13 pages, 682 KiB  
Review
Bone Fragility in Chronic Kidney Disease Stage 3 to 5: The Use of Vitamin D Supplementation
by Pablo Antonio Ureña Torres, Jean Claude Souberbielle and Martine Cohen Solal
Metabolites 2022, 12(3), 266; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12030266 - 20 Mar 2022
Cited by 3 | Viewed by 3397
Abstract
Frequently silent until advanced stages, bone fragility associated with chronic kidney disease-mineral and bone disease (CKD-MBD) is one of the most devastating complications of CKD. Its pathophysiology includes the reduction of active vitamin D metabolites, phosphate accumulation, decreased intestinal calcium absorption, renal alpha [...] Read more.
Frequently silent until advanced stages, bone fragility associated with chronic kidney disease-mineral and bone disease (CKD-MBD) is one of the most devastating complications of CKD. Its pathophysiology includes the reduction of active vitamin D metabolites, phosphate accumulation, decreased intestinal calcium absorption, renal alpha klotho production, and elevated fibroblast growth factor 23 (FGF23) levels. Altogether, these factors contribute firstly to secondary hyperparathyroidism, and ultimately, to micro- and macrostructural bone changes, which lead to low bone mineral density and an increased risk of fracture. A vitamin D deficiency is common in CKD patients, and low circulating 25(OH)D levels are invariably associated with high serum parathyroid hormone (PTH) levels as well as with bone mineralization defects, such as osteomalacia in case of severe forms. It is also associated with a variety of non-skeletal diseases, including cardiovascular disease, diabetes mellitus, multiple sclerosis, cancer, and reduced immunological response. Current international guidelines recommend supplementing CKD patients with nutritional vitamin D as in the general population; however, there is no randomized clinical trial (RCT) evaluating the effect of vitamin D (or vitamin D+calcium) supplementation on the risk of fracture in the setting of CKD. It is also unknown what level of circulating 25(OH)D would be sufficient to prevent bone abnormalities and fractures in these patients. The impact of vitamin D supplementation on other surrogate endpoints, including bone mineral density and bone-related circulating biomarkers (PTH, FGF23, bone-specific alkaline phosphatase, sclerostin) has been evaluated in several RTCs; however, the results were not always translated into an improvement in long-term outcomes, such as reduced fracture risk. This review provides a brief and comprehensive update on CKD-related bone fragility and the use of natural vitamin D supplementation in these patients. Full article
(This article belongs to the Special Issue Frontiers in Bone Metabolism and Disorder in Chronic Kidney Disease)
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17 pages, 983 KiB  
Review
Molecular Mechanisms of Parathyroid Disorders in Chronic Kidney Disease
by Alia Hassan, Nareman Khalaily, Rachel Kilav-Levin, Morris Nechama, Oded Volovelsky, Justin Silver and Tally Naveh-Many
Metabolites 2022, 12(2), 111; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12020111 - 25 Jan 2022
Cited by 8 | Viewed by 2827
Abstract
Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that induces morbidity and mortality in patients. How CKD stimulates the parathyroid to increase parathyroid hormone (PTH) secretion, gene expression and cell proliferation remains an open question. In experimental SHP, the [...] Read more.
Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that induces morbidity and mortality in patients. How CKD stimulates the parathyroid to increase parathyroid hormone (PTH) secretion, gene expression and cell proliferation remains an open question. In experimental SHP, the increased PTH gene expression is post-transcriptional and mediated by PTH mRNA–protein interactions that promote PTH mRNA stability. These interactions are orchestrated by the isomerase Pin1. Pin1 participates in conformational change-based regulation of target proteins, including mRNA-binding proteins. In SHP, Pin1 isomerase activity is decreased, and thus, the Pin1 target and PTH mRNA destabilizing protein KSRP fails to bind PTH mRNA, increasing PTH mRNA stability and levels. An additional level of post-transcriptional regulation is mediated by microRNA (miRNA). Mice with parathyroid-specific knockout of Dicer, which facilitates the final step in miRNA maturation, lack parathyroid miRNAs but have normal PTH and calcium levels. Surprisingly, these mice fail to increase serum PTH in response to hypocalcemia or uremia, indicating a role for miRNAs in parathyroid stimulation. SHP often leads to parathyroid hyperplasia. Reduced expressions of parathyroid regulating receptors, activation of transforming growth factor α-epidermal growth factor receptor, cyclooxygenase 2-prostaglandin E2 and mTOR signaling all contribute to the enhanced parathyroid cell proliferation. Inhibition of mTOR by rapamycin prevents and corrects the increased parathyroid cell proliferation of SHP. This review summarizes the current knowledge on the mechanisms that stimulate the parathyroid cell at multiple levels in SHP. Full article
(This article belongs to the Special Issue Frontiers in Bone Metabolism and Disorder in Chronic Kidney Disease)
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18 pages, 1398 KiB  
Review
New Insights to the Crosstalk between Vascular and Bone Tissue in Chronic Kidney Disease–Mineral and Bone Disorder
by Maria L. Mace, Søren Egstrand, Marya Morevati, Klaus Olgaard and Ewa Lewin
Metabolites 2021, 11(12), 849; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11120849 - 07 Dec 2021
Cited by 8 | Viewed by 3195
Abstract
Vasculature plays a key role in bone development and the maintenance of bone tissue throughout life. The two organ systems are not only linked in normal physiology, but also in pathophysiological conditions. The chronic kidney disease–mineral and bone disorder (CKD-MBD) is still the [...] Read more.
Vasculature plays a key role in bone development and the maintenance of bone tissue throughout life. The two organ systems are not only linked in normal physiology, but also in pathophysiological conditions. The chronic kidney disease–mineral and bone disorder (CKD-MBD) is still the most serious complication to CKD, resulting in increased morbidity and mortality. Current treatment therapies aimed at the phosphate retention and parathyroid hormone disturbances fail to reduce the high cardiovascular mortality in CKD patients, underlining the importance of other factors in the complex syndrome. This review will focus on vascular disease and its interplay with bone disorders in CKD. It will present the very late data showing a direct effect of vascular calcification on bone metabolism, indicating a vascular-bone tissue crosstalk in CKD. The calcified vasculature not only suffers from the systemic effects of CKD but seems to be an active player in the CKD-MBD syndrome impairing bone metabolism and might be a novel target for treatment and prevention. Full article
(This article belongs to the Special Issue Frontiers in Bone Metabolism and Disorder in Chronic Kidney Disease)
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13 pages, 987 KiB  
Review
Cardiovascular Safety of Anti-Sclerostin Therapy in Chronic Kidney Disease
by Daniel Cejka
Metabolites 2021, 11(11), 770; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11110770 - 10 Nov 2021
Cited by 4 | Viewed by 2431
Abstract
The significance of sclerostin for bone and cardiovascular health in patients with chronic kidney disease (CKD) is complex and incompletely understood. Experimental evidence suggests that anti-sclerostin therapy shows diminished efficacy on bone in the setting of CKD. Limited clinical evidence suggests that the [...] Read more.
The significance of sclerostin for bone and cardiovascular health in patients with chronic kidney disease (CKD) is complex and incompletely understood. Experimental evidence suggests that anti-sclerostin therapy shows diminished efficacy on bone in the setting of CKD. Limited clinical evidence suggests that the osteoanabolic and anti-resorptive activity is attenuated, but hypocalcemia is more prevalent in patients with advanced CKD (eGFR < 30 mL/min) treated with anti-sclerostin (romosozumab) therapy as compared to patients without kidney disease. Furthermore, sclerostin is prominently expressed in uremic arteries. Whether the inhibition of sclerostin has adverse effects on cardiovascular health in CKD is currently unknown. This review summarizes the current understanding of the physiology and pathophysiology of sclerostin in CKD, with a focus on the cardiovascular safety of anti-sclerostin therapy in patients with or without CKD. Full article
(This article belongs to the Special Issue Frontiers in Bone Metabolism and Disorder in Chronic Kidney Disease)
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