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![( a ) Intestinal calcium absorption, ( b ) plasma calcium efflux and ( c ) calcium bone accretion in dialysis patients with low- turnover bone disease, mixed uraemic osteodystrophy or hyperparathyroid bone disease. Reproduced from Kurz et al. [20], with permission from Blackwell Publishing.](profile/Hartmut-Malluche/publication/8578248/figure/fig1/AS:280109916409859@1443794816519/a-Intestinal-calcium-absorption-b-plasma-calcium-efflux-and-c-calcium-bone.png)
( a ) Intestinal calcium absorption, ( b ) plasma calcium efflux and ( c ) calcium bone accretion in dialysis patients with low- turnover bone disease, mixed uraemic osteodystrophy or hyperparathyroid bone disease. Reproduced from Kurz et al. [20], with permission from Blackwell Publishing.
Source publication
In the early stages of renal failure, hyperparathyroidism develops as a compensatory mechanism to control serum levels of calcium, phosphorus and calcitriol. As kidney disease progresses, this ability to maintain mineral homeostasis is lost, leading to the development of renal osteodystrophy (ROD). Over the past decade, the pattern of ROD seen in p...
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Renal hyperparathyroidism with attendant osteodystrophy is a frequent and severe morbidity affecting the quality of life of end stage renal failure patients surviving on long-term renal replacement therapy. A small subgroup of these patients with severe cardiorespiratory dysfunction was deemed at very high risk for general anaesthesia (GA). We repo...
Prevention, diagnosis and treatment of renal osteodystrophy are continually evolving. We submitted a postal questionnaire to all Spanish dialysis centres, comprising 30 questions, with the aim of obtaining information about the current management of this entity in Spain. The answers from 171 centres, 63% of the total registered (10,724 patients), w...
Background
Effective control of hyperparathyroidism and renal osteodystrophy in CAPD patients requires a combination of calcitriol and calcium carbonate (CaCO3), but is frequently limited by hypercalcaemia. Reducing dialysate calcium (Ca) concentration may overcome this problem, but had not been examined in a controlled trial.
Methods
45 stable CA...
Objective:
To describe the oral and maxillofacial manifestations of patients diagnosed with chronic kidney disease-mineral and bone disorders.
Study design:
Over a 13-year period, clinicopathologic data of patients diagnosed with CKD-MBD who had oral and maxillofacial alterations were retrieved from the files of 4 Brazilian institutions. Data in...
Citations
... In CKD patients, PTH resistance occurs when PTH regulates sclerostin, so not only the level of PTH but also the level of sclerostin is high [111]. Expression of WNT inhibitors is increased in hyperphosphatemia, but the underlying mechanism is unclear [118]. ...
Background
The WNT/β-catenin system is an evolutionarily conserved signaling pathway that plays a crucial role in morphogenesis and cell tissue formation during embryogenesis. Although usually suppressed in adulthood, it can be reactivated during organ damage and regeneration. Transient activation of the WNT/β-catenin pathway stimulates tissue regeneration after acute kidney injury, while persistent (uncontrolled) activation can promote the development of chronic kidney disease (CKD). CKD-MBD is a clinical syndrome that develops with systemic mineral and bone metabolism disorders caused by CKD, characterized by abnormal bone mineral metabolism and/or extraosseous calcification, as well as cardiovascular disease associated with CKD, including vascular stiffness and calcification.
Objective
This paper aims to comprehensively review the WNT/β-catenin signaling pathway in relation to CKD-MBD, focusing on its components, regulatory molecules, and regulatory mechanisms. Additionally, this review highlights the challenges and opportunities for using small molecular compounds to target the WNT/β-catenin signaling pathway in CKD-MBD therapy.
Methods
We conducted a comprehensive literature review using various scientific databases, including PubMed, Scopus, and Web of Science, to identify relevant articles. We searched for articles that discussed the WNT/β-catenin signaling pathway, CKD-MBD, and their relationship. We also reviewed articles that discussed the components of the WNT/β-catenin signaling pathway, its regulatory molecules, and regulatory mechanisms.
Results
The WNT/β-catenin signaling pathway plays a crucial role in CKD-MBD by promoting vascular calcification and bone mineral metabolism disorders. The pathway’s components include WNT ligands, Frizzled receptors, and LRP5/6 co-receptors, which initiate downstream signaling cascades leading to the activation of β-catenin. Several regulatory molecules, including GSK-3β, APC, and Axin, modulate β-catenin activation. The WNT/β-catenin signaling pathway also interacts with other signaling pathways, such as the BMP pathway, to regulate CKD-MBD.
Conclusions
The WNT/β-catenin signaling pathway is a potential therapeutic target for CKD-MBD. Small molecular compounds that target the components or regulatory molecules of the pathway may provide a promising approach to treat CKD-MBD. However, more research is needed to identify safe and effective compounds and to determine the optimal dosages and treatment regimens.
... Mixed uremic osteodystrophy is a complex disorder in which elevated bone turnover coexists with features of osteomalacia [15-17] ( Figure 1E). The frequency of the two last lesions has decreased consistently in recent decades [18]. More recently, it has been shown that osteoporosis is a frequent feature in patients with CKD-MBD [19-21] that may complicate their outcome. ...
Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD) comprises alterations in calcium, phosphorus, parathyroid hormone (PTH), vitamin D, and fibroblast growth factor-23 (FGF-23) metabolism, abnormalities in bone turnover, mineralization, volume, linear growth or strength, and vascular calcification leading to an increase in bone fractures and vascular disease, which ultimately result in high morbidity and mortality. The bone component of CKD-MBD, referred to as renal osteodystrophy, starts early during the course of CKD as a result of the effects of progressive reduction in kidney function which modify the tight interaction between mineral, hormonal, and other biochemical mediators of cell function that ultimately lead to bone disease. In addition, other factors, such as osteoporosis not apparently dependent on the typical pathophysiologic abnormalities resulting from altered kidney function, may accompany the different varieties of renal osteodystrophy leading to an increment in the risk of bone fracture. After kidney transplantation, these bone alterations and others directly associated or not with changes in kidney function may persist, progress or transform into a different entity due to new pathogenetic mechanisms. With time, these alterations may improve or worsen depending to a large extent on the restoration of kidney function and correction of the metabolic abnormalities developed during the course of CKD. In this paper, we review the bone lesions that occur during both CKD progression and after kidney transplant and analyze the factors involved in their pathogenesis as a means to raise awareness of their complexity and interrelationship.
... Due to non-compressible vessels, standard ankle brachial index or toe brachial index remain inconclusive for diagnosis.Any evidence of signifi cant vascular disease precludes renal transplantation.iii. Bone mineral profi le: Adynamic Bone Disease (ABD) affects > 40% of CKD-V patients and has strong association with vascular calcifi cations, increased incidence of fractures and cardiovascular mortality[35,36]. So, a co-existence of ABDand DM adds on the risk of cardiac complications. ...
Diabetes Mellitus (DM) is a potent risk factor for post-transplant cardiovascular complications and infections. Management of diabetes and its complications in renal transplant recipients is a challenging task. This is a frequently encountered predicament in transplant setups. An erratic glycemic control during dialysis is a predictor of poor graft and patient outcomes after kidney transplantation. Literature review reveals majority studies explaining post-transplant diabetes and its role in graft and patient survival. However, a wide range of opinion exists about the impact of pre-transplant DM on transplant outcomes. Measurement of HbA1c levels is a significant tool for assessment of glycemic control. A target HbA1c level of <7% is recommended for diabetic patients irrespective of presence or absence of Chronic Kidney Disease (CKD). However, diabetic patients with CKD are at risk of hypoglycemia owing to decreased insulin metabolism so it is safe to keep HbA1c levels between 7-8% in this population. Immunosuppressive medications have a strong contributory role in deterioration of glycemic control. So, it is imperative to achieve strict pre-transplant diabetes control in order to avoid post-transplant complications. Post-transplant diabetes mellitus (PTDM) has been a subject of a large number of trials and is not only considered a serious metabolic complication but also a predisposing factor of diabetic nephropathy in transplanted kidney.
... The copyright holder for this preprint this version posted August 6, 2021. ; https://doi.org/10.1101/2021.08.06.455411 doi: bioRxiv preprint inactivity due to PTH resistance, as well as reduced calcitriol levels, and accumulation of uremic toxins (60)(61)(62) . When renal function further deteriorates, the chronically increased PTH levels overcome peripheral PTH resistance and activate the indolent bone cells, leading to high turnover bone disease (osteitis fibrosa) (8) . ...
Patients with advanced chronic kidney disease (CKD) often present with skeletal abnormalities; a condition known as renal osteodystrophy (ROD). While Tissue-nonspecific alkaline phosphatase (TNAP) and PHOSPHO1 are recognized to be critical for bone mineralization, their role in the etiology of ROD is unclear. To address this, ROD was induced in both wild-type and Phospho1 knockout (P1KO) mice using dietary adenine supplementation. The mice presented with hyperphosphatemia, hyperparathyroidism, and elevated levels of FGF23 and bone turnover markers. In particular, we noted that in CKD mice, bone mineral density (BMD) was increased in cortical bone ( p < 0.05) but decreased in trabecular bone ( p < 0.05). These changes were accompanied by decreased TNAP ( p < 0.01) and increased PHOSPHO1 ( p < 0.001) expression in wild-type CKD bones. In P1KO CKD mice, the cortical BMD phenotype was rescued, suggesting that the increased cortical BMD of CKD mice was driven by increased PHOSPHO1 expression. Other structural parameters were also improved in P1KO CKD mice. We further investigated the driver of the mineralization defects, by studying the effects of FGF23, PTH, and phosphate administration on PHOSPHO1 and TNAP expression by primary murine osteoblasts. We found both PHOSPHO1 and TNAP expression to be down-regulated in response to phosphate and PTH. While matrix mineralization was increased with phosphate (Pi), it decreased with PTH and FGF23 had no effect. The in vitro data suggest that the TNAP reduction in CKD-MBD is driven by the hyperphosphatemia and/or hyperparathyroidism noted in these mice, while the higher PHOSPHO1 expression may be a compensatory mechanism in an attempt to protect the bone from hypomineralization. We propose that increased PHOSPHO1 expression in ROD may contribute to the disordered skeletal mineralization characteristic of this progressive disorder.
... However, in patients with CKD, sclerostin levels are often elevated, despite hyperparathyroidism. Hyperphosphataemia increases the expression of WNTinhibitory proteins, although the underlying mechanisms are only poorly understood 112 . Thus, although PTH is a well-characterized suppressor of sclerostin in health, CKD is proposed to lead to 'PTH resistance' in the regulation of sclerostin, resulting in both high PTH and high sclerostin levels 106 . ...
The WNT-β-catenin system is an evolutionary conserved signalling pathway that is of particular importance for morphogenesis and cell organization during embryogenesis. The system is usually suppressed in adulthood; however, it can be re-activated in organ injury and regeneration. WNT-deficient mice display severe kidney defects at birth. Transient WNT-β-catenin activation stimulates tissue regeneration after acute kidney injury, whereas sustained (uncontrolled) WNT-β-catenin signalling promotes kidney fibrosis in chronic kidney disease (CKD), podocyte injury and proteinuria, persistent tissue damage during acute kidney injury and cystic kidney diseases. Additionally, WNT-β-catenin signalling is involved in CKD-associated vascular calcification and mineral bone disease. The WNT-β-catenin pathway is tightly regulated, for example, by proteins of the Dickkopf (DKK) family. In particular, DKK3 is released by 'stressed' tubular epithelial cells; DKK3 drives kidney fibrosis and is associated with short-term risk of CKD progression and acute kidney injury. Thus, targeting the WNT-β-catenin pathway might represent a promising therapeutic strategy in kidney injury and associated complications.
... However, usually the viability of bone cells is not adversely affected for Al 3+ concentrations less than 1 mM (our measurements indicated that Al 3+ concentration was consistently less than this, not shown). In addition, gene expression (i.e., that of collagen, osteocalcin and ALP) can be significantly inhibited, (Malluche, Mawad, & Monier-Faugere, 2004 (Malluche et al., 2004). In addition, various other studies have shown the toxicity of Al 3+ for organ function (e.g., it is associated with chronic renal failure) and also for bone health (Malluche, 2002;Netter et al., 1984). ...
... However, usually the viability of bone cells is not adversely affected for Al 3+ concentrations less than 1 mM (our measurements indicated that Al 3+ concentration was consistently less than this, not shown). In addition, gene expression (i.e., that of collagen, osteocalcin and ALP) can be significantly inhibited, (Malluche, Mawad, & Monier-Faugere, 2004 (Malluche et al., 2004). In addition, various other studies have shown the toxicity of Al 3+ for organ function (e.g., it is associated with chronic renal failure) and also for bone health (Malluche, 2002;Netter et al., 1984). ...
This article describes the use of a novel lactone‐layered double hydroxide polymer network (PN), derived from a poly(lactide‐co‐caprolactone) copolymer, as a controlled ion‐release agent for artificial bone tissue regeneration. The osteogenic cell culture Saos‐2 is used as a test culture to investigate the PN's performance as an extracellular ion‐release agent. The compelling performance of this PN is demonstrated in both growth and osteogenic media compared with a control of cells grown on tissue culture plastic (TCP) without PN. Firstly, the PNs released concentration of magnesium ions over time ranging from 10 to 60 mM after 24 hr, depending on the PN sample. After incubation of Saos‐2 with the PN, while no difference was seen in cell number, there was significant upregulation of bone‐related gene expression at 14 days—~5fold increase in Bone Morphogenetic Protein 2, ~3fold increase in osteopontin and ~2fold increase in collagen Type I. In addition, normalized alkaline phosphatase activity was seen to significantly increase by ~2fold with PN presence. A ~4fold increase in collagen Type I protein expression (via Gomori Trichrome Stain) was observed with PN presence. In addition, a ~4fold increase in phosphate deposits (as seen with Von Kossa staining analysis) was seen with PN presence. It is found that this novel PN material has a significant potential for bone tissue regeneration.
... As chronic kidney disease (CKD) progress, abnormalities in mineral homeostasis occur impairing bone remodeling and mineralization [1][2][3]. Bone abnormalities are found in the majority of patients with CKD stages 3 -5D [1,[4][5][6]. A high incidence of fractures has been reported in patients with abnormal bone turnover [7,8] and fractures are associated with increased mortality [9]. ...
Background:
The diagnosis of renal osteodystrophy is challenging. Bone biopsy is the gold standard, but it is invasive and limited to one site of the skeleton. The ability of biomarkers to estimate the underlying bone pathology is limited. 18F-Sodium Fluoride positron emission tomography (18F-NaF PET) is a noninvasive quantitative imaging technique that allows assessment of regional bone turnover at clinically relevant sites. The hypothesis of this study was, that 18F-NaF PET correlates with bone histomorphometry in dialysis patients and could act as a noninvasive diagnostic tool in this patient group.
Methods:
This was a cross-sectional diagnostic test study. 26 dialysis patients with biochemical abnormalities indicating mineral and bone disorder were included. All the participants underwent a 18F-NaF PET scan and a bone biopsy. Fluoride activity in the PET scan was measured in the lumbar spine and at the anterior iliac crest. Dynamic and static histomorphometric parameters of the bone biopsy were assessed. As histomorphometric markers for bone turnover we used bone formation rate per bone surface (BFR/BS) and activation frequency per year (Ac.f).
Results:
There was a statistically significant correlation between fluoride activity in the 18F-NaF PET scan and histomorphometric parameters such as bone formation rate, activation frequency and osteoclast and osteoblast surfaces and mineralized surfaces. 18F-NaF PET's sensitivity to recognize low turnover in respect to non-low turnover was 76% and specificity 78%. Because of the small number of patients with high turnover, we were unable to demonstrate significant predictive value in this group.
Conclusions:
A clear correlation between histomorphometric parameters and fluoride activity in the 18F-NaF PET scan was established. 18F-NaF PET may possibly be a noninvasive diagnostic tool in dialysis patients with low turnover bone disease, but further research is needed.
... Bone remodeling is dependent on the dynamic balance between bone formation and bone resorption. Excessively high levels of serum PTH lead to an imbalance of these 2 processes and affect bone and mineral metabolism [37,38]. El-Shafey et al. [19] reported that cinacalcet treatment increased the proximal femur BMD in patients with SHPT. ...
Objective:
To assess the long-term effects including all-cause mortality, cardiovascular mortality, and fracture incidence, of cinacalcet on secondary hyperparathyroidism (SHPT) in patients on dialysis.
Methods:
PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched from their inception to October 2018. Randomized controlled trials (RCTs) and cohort design prospective observational studies assessing cinacalcet for the treatment of SHPT in dialysis patients were included. Data extraction was independently completed by 2 authors who determined the methodological quality of the studies and extracted data in duplicate. Study-specific risk estimates were tested by using a fixed effects model.
Results:
A total of 14 articles with 38,219 participants were included, of which 10 RCTs with 7,471 participants and 4 prospective observational studies with 30,748 participants fulfilled the eligibility criteria. Compared with no cinacalcet, cinacalcet administration reduced all-cause mortality (relative risk [RR] 0.91, 95% CI 0.89-0.94, p < 0.001) and cardiovascular mortality (RR 0.92, 95% CI 0.89-0.95, p < 0.001), but it did not significantly reduce the incidence of fractures (RR 0.93, 95% CI 0.87-1.00, p = 0.05).
Conclusions:
The results of this meta-analysis indicated that the treatment of SHPT with cinacalcet may in fact reduce all-cause mortality and cardiovascular mortality among patients receiving maintenance dialysis.
... Patients with chronic kidney disease (CKD) and endstage renal disease (ESRD) suffer from significant alterations in mineral and bone metabolism, including loss of bone mass, increased susceptibility to fractures and increased production of fibroblast growth factor 23 (FGF23) [1][2][3][4]. Elevated circulating FGF23 contributes to cardiovascular disease and mortality [5][6][7][8]. Identifying new molecular mechanisms that contribute to reduced bone mass and FGF23 excess is a critical step toward developing improved therapeutic approaches for patients with CKD. ...
Purpose of review:
Chronic kidney disease (CKD) is a condition associated with bone disease and fibroblast growth factor 23 (FGF23) excess that contributes to cardiovascular mortality. Dentin matrix protein 1 (DMP1) is an established regulator of bone mineralization and FGF23 production in osteocytes. To date, DMP1 function has mainly been studied in the context of hereditary hypophosphatemic rickets diseases. This review describes the role of DMP1 as a potential strong candidate to prevent bone disorders, FGF23 elevation and associated cardiac outcomes in CKD.
Recent findings:
Patients and mice with CKD show impaired osteocyte maturation and impaired regulation of DMP1 and FGF23 in bone. New data suggest that impaired DMP1 production contributes to CKD-associated bone and mineral metabolism disorders and we show that DMP1 repletion improves osteocyte alterations, bone mineralization and partially prevents FGF23 elevation. As a result, mice with CKD show attenuated left ventricular hypertrophy and improved survival.
Summary:
There is an urgent need for new therapeutic strategies to improve bone quality and to lower FGF23 levels in CKD. By preventing osteocyte apoptosis and inhibiting Fgf23 transcription, DMP1 supplementation may represent an ideal approach to improve CKD-associated bone and cardiac outcomes.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0.
... Ca-containing PB are characterized by an optimal cost/effect ratio. But these drugs, if used without control, can induce high Ca-element exposition of patients, facilitate the development and/or progression of extra-osseous calcifications, and bone dynamicity [30]. The use of Mg supplements or of Ca-Mg containing PB could reduce Ca exposition and simultaneously correct Mg levels, frequently low in CKD patients, through exposing to a Mg overload. ...
Secondary hyperparathyroidism (SHPT) is a frequent condition in the presence of chronic kidney disease (CKD). In CKD patients, SHPT is reported to increase both morbidity and mortality, especially cardiovascular. The difficulty in the treatment of SHPT in clinical practice is frequently encountered from a not always adequate conduct of the clinicians and a common non-compliance to the therapy of CKD patients. In this review, the greatest difficulties from clinicians and CKD-patients' point of view in the treatment of SHPT will be addressed, with particular attention to those related to dialysis features, nutritional habits, and medical therapy.
