scholarly journals Osteoclast-Released Wnt-10b Underlies Cinacalcet Related Bone Improvement in Chronic Kidney Disease

2019 ◽  
Vol 20 (11) ◽  
pp. 2800 ◽  
Author(s):  
Cai-Mei Zheng ◽  
Yung-Ho Hsu ◽  
Chia-Chao Wu ◽  
Chien-Lin Lu ◽  
Wen-Chih Liu ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Bone Loss ◽  
Bone Fractures ◽  
Bone Mineralization ◽  
Critical Role ◽  
Beta Catenin ◽  
Mineral Density ◽  
High Turnover

Secondary hyperparathyroidism (SHPT) relates to high turnover bone loss and is responsible for most bone fractures among chronic kidney disease (CKD) patients. Changes in the Wingless/beta-catenin signaling (Wnt/β-catenin) pathway and Wnt inhibitors have been found to play a critical role in CKD related bone loss. A calcimimetic agent, cinacalcet, is widely used for SHPT and found to be similarly effective for parathyroidectomy clinically. A significant decrease in hip fracture rates is noted among US hemodialysis Medicare patients since 2004, which is probably related to the cinacalcet era. In our previous clinical study, it was proven that cinacalcet improved the bone mineral density (BMD) even among severe SHPT patients. In this study, the influence of cinacalcet use on bone mass among CKD mice was determined. Cinacalcet significantly reduced the cortical porosity in femoral bones of treated CKD mice. It also improved the whole-bone structural properties through increased stiffness and maximum load. Cinacalcet increased femoral bone wingless 10b (Wnt10b) expression in CKD mice. In vitro studies revealed that cinacalcet decreased osteoclast bone resorption and increased Wnt 10b release from osteoclasts. Cinacalcet increased bone mineralization when culturing the osteoblasts with cinacalcet treated osteoclast supernatant. In conclusion, cinacalcet increased bone quantity and quality in CKD mice, probably through increased bone mineralization related with osteoclast Wnt 10b secretion.

Bone mineral density and biochemical markers of bone metabolism in predialysis patients with chronic kidney disease

2016 ◽  
Vol 64 (4) ◽  
pp. 861-866 ◽  
Author(s):  
Nuri Fidan ◽  
Ayca Inci ◽  
Melahat Coban ◽  
Cevval Ulman ◽  
Seyhun Kursat
Keyword(s):  
Bone Mineral Density ◽  
Chronic Kidney Disease ◽  
Alkaline Phosphatase ◽  
Kidney Disease ◽  
Bone Loss ◽  
Bone Mineral ◽  
Serum Alkaline Phosphatase ◽  
Mineral Density ◽  
T Score ◽  
Z Scores

The aim of the study was to evaluate the usefulness of serum bone turnover markers (BTM) and bone mineral density (BMD) determined by dual-energy X-ray absorptiometry (DEXA) in predialysis patients with chronic kidney disease (CKD). We enrolled 83 patients with CKD, 41 (49.4%) males, 42 (50.6%) females, with mean estimated glomerular filtration rate (eGFR) 23.90±12 (range=6.0–56.0). BMD of the lumbar spine (LS) (anteroposterior, L2 through L4), femoral neck (FN) and femoral trochanter (FT) were measured by DEXA. Biochemical BTM, including calcium (Ca), phosphorus (P), intact parathyroid hormone (PTH), serum specific alkaline phosphatase (serum AP), bone-specific AP (BSAP), plasma bicarbonate and 25-hydroxy-vitamin D (25hD) were used for the prediction of BMD loss. T score results of LS and FN were worse than FT. BMD levels were lower in females than in males (all p<0.05). According to different BMD T score levels, patients with age ≥65 years and patients in menopause were significantly more osteopenic (p=0.026) and there was no relation between different BMD T scores and presence of diabetes (p=0.654). A positive correlation was identified between the BMD of FN T-Z scores (r=0.270, p=0.029, r=0.306, p=0.012), FT T-Z scores (r=0.220, p=0.076, r:0.250, p=0.043) and serum HCO3, while the correlation with serum alkaline phosphatase (AP) and BSAP was considered to be negative. No statistically significant association was found between BMD of all the measured skeletal sites and eGFR. Loss of BMD was identified mostly in females over ≥65 years of age and after menopause. Higher serum levels of BSAP and AP can be determined in the advanced stages of renal failure and they reflect fracture risk of the femur, but not spine. Measurements of BMD by DEXA are useful to demonstrate bone loss, but not technical enough to distinguish the quantity of bone loss between different stages of CKD.

scholarly journals The Pathophysiologic Role of Gelsolin in Chronic Kidney Disease: Focus on Podocytes

2021 ◽  
Vol 22 (24) ◽  
pp. 13281
Author(s):  
Chia-Jung Yu ◽  
Dian W. Damaiyanti ◽  
Shian-Jang Yan ◽  
Chih-Hsing Wu ◽  
Ming-Jer Tang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Critical Role ◽  
Physiological Role ◽  
Small Gtpase ◽  
Common Finding ◽  
Puromycin Aminonucleoside ◽  
Filtration Barrier

Chronic kidney disease (CKD) is normally related to proteinuria, a common finding in a compromised glomerular filtration barrier (GFB). GFB is a structure composed of glomerular endothelial cells, the basement membrane, and the podocytes. CKD with podocyte damage may be associated with actin cytoskeleton reorganization, resulting in podocyte effacement. Gelsolin plays a critical role in several diseases, including cardiovascular diseases and cancer. Our current study aimed to determine the connection between gelsolin and podocyte, and thus the mechanism underlying podocyte injury in CKD. Experiments were carried out on Drosophila to demonstrate whether gelsolin had a physiological role in maintaining podocyte. Furthermore, the survival rate of gelsolin-knocked down Drosophila larvae was extensively reduced after AgNO3 exposure. Secondly, the in vitro podocytes treated with puromycin aminonucleoside (PAN) enhanced the gelsolin protein expression, as well as small GTPase RhoA and Rac1, which also regulated actin dynamic expression incrementally with the PAN concentrations. Thirdly, we further demonstrated in vivo that GSN was highly expressed inside the glomeruli with mitochondrial dysfunction in a CKD mouse model. Our findings suggest that an excess of gelsolin may contribute to podocytes damage in glomeruli.

scholarly journals Different Effects of Empagliflozin on Markers of Mineral-Bone Metabolism in Diabetic and Non-Diabetic Patients with Stage 3 Chronic Kidney Disease

Medicina ◽  
2021 ◽  
Vol 57 (12) ◽  
pp. 1352
Author(s):  
Anna Masajtis-Zagajewska ◽  
Tomasz Hołub ◽  
Katarzyna Pęczek ◽  
Agnieszka Makówka ◽  
Michał Nowicki
Keyword(s):  
Chronic Kidney Disease ◽  
Calcium Phosphate ◽  
Kidney Disease ◽  
Bone Metabolism ◽  
Bone Fractures ◽  
Sglt2 Inhibitor ◽  
Diabetic Patients ◽  
Mineral Density ◽  
Increased Risk ◽  
Fgf 23

Background and objectives: Treatment with sodium–glucose co-transporter 2 (SGLT2) inhibitors decrease tubular reabsorption of phosphate, which may explain the reduction of bone mineral density and an excess of bone fractures observed in some studies with this class of drugs. Since an increased risk of bone fractures may also be a result of diabetes itself, our study aimed to compare the effect of empagliflozin on the markers of mineral-bone metabolism between diabetic (DKD) and non-diabetic (ND-CKD) patients with stage 3 chronic kidney disease (CKD). Materials and Methods: Forty-two patients with stage 3 CKD and A2 albuminuria, including 18 with DKD and 24 ND-CKD, were investigated. All subjects received 10 mg empagliflozin for 7 days. Serum calcium, phosphate, parathormone (PTH), calcitriol, bone alkaline phosphatase (BAP), FGF-23 and urine calcium, phosphate, albumin and the renal tubular maximum reabsorption rate of phosphate to the glomerular filtration rate (TmP-GFR) were measured before and after empagliflozin administration. Differences in biomarkers response to empagliflozin between DKD and ND-CKD were the main measures of outcome. Results: There was a significant increase of PTH, FGF-23 and phosphate in DKD but not in ND-CKD whereas BAP and TmP/GFR did not change in either group. The reduction of albuminuria was only significant in ND-CKD. Conclusions: The effect of SGLT2 inhibitor on serum mineral and bone markers and on albuminuria in patients with CKD may be differently modified by the presence of diabetes mellitus.

scholarly journals Molecular Abnormalities Underlying Bone Fragility in Chronic Kidney Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Yoshiko Iwasaki ◽  
Junichiro James Kazama ◽  
Masafumi Fukagawa
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Bone Cells ◽  
Bone Fractures ◽  
Bone Mineralization ◽  
Bone Fragility ◽  
Pathological Process ◽  
Mineral And Bone Disorder ◽  
Molecular Abnormalities ◽  
Skeletal Resistance

Prevention of bone fractures is one goal of therapy for patients with chronic kidney disease-mineral and bone disorder (CKD-MBD), as indicated by the Kidney Disease: Improving Global Outcomes guidelines. CKD patients, including those on hemodialysis, are at higher risk for fractures and fracture-related death compared to people with normal kidney function. However, few clinicians focus on this issue as it is very difficult to estimate bone fragility. Additionally, uremia-related bone fragility has a more complicated pathological process compared to osteoporosis. There are many uremia-associated factors that contribute to bone fragility, including severe secondary hyperparathyroidism, skeletal resistance to parathyroid hormone, and bone mineralization disorders. Uremia also aggravates bone volume loss, disarranges microarchitecture, and increases the deterioration of material properties of bone through abnormal bone cells or excess oxidative stress. In this review, we outline the prevalence of fractures, the interaction of CKD-MBD with osteoporosis in CKD patients, and discuss possible factors that exacerbate the mechanical properties of bone.

scholarly journals A novel calcimimetic evocalcet for the management of secondary hyperparathyroidism with little effect on the gastrointestinal tract and cyp isozymes in vivo and in vitro

2020 ◽  
Vol 22 (3) ◽  
pp. 27-33
Author(s):  
Lilit V. Egshatyan
Keyword(s):  
Chronic Kidney Disease ◽  
Parathyroid Hormone ◽  
Kidney Disease ◽  
Secondary Hyperparathyroidism ◽  
Safety Margin ◽  
Receptor Activation ◽  
Study Phase ◽  
Mineral Density ◽  
Cyp Isozymes

In the treatment of secondary hyperparathyroidism of end-stage chronic kidney disease, vitamin D receptor activation and allosteric modulators of the calcium-sensing receptor - inhibit glandular hyperplasia; reduce parathyroid hormone levels, impact on bone turnover and mineral density. Cinacalcet, an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism in chronic kidney disease. Nevertheless, some patients remain refractory to the treatment, as the dose of cinacalcet cannot be sufficiently increased due to gastrointestinal symptoms and it strong inhibits of cytochrome P450 (CYP) 2D6. In order to resolve this issue, was develop a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of chronic kidney disease induced by 5/6 nephrectomy, and in multicenter, open-label study phase 3, and in clinical practice oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone. Evocalcet also demonstrated the less induction of emesis and gastro-intestinal effects, and its pharmacological effects were observed at lower doses because of its higher bioavailability than cinacalcet. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro. These findings suggest that evocalcet can be a better alternative to cinacalcet with a wider safety margin.

scholarly journals Bone fragility in patients with chronic kidney disease

2020 ◽  
Vol 9 (4) ◽  
pp. R93-R101
Author(s):  
Martine Cohen-Solal ◽  
Thomas Funck-Brentano ◽  
Pablo Ureña Torres
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Fracture Risk ◽  
Bone Mineralization ◽  
Imaging Techniques ◽  
Bone Diseases ◽  
Special Focus ◽  
Type I ◽  
Mineral Density ◽  
Bone Specific Alkaline Phosphatase

Mineral and bone diseases (MBD) are predominant in patients with chronic kidney disease (CKD) and lead to several bone manifestations, from pain to skeletal fractures. Cumulative traditional clinical risk factors, such as age and gender, in addition to those related to CKD, enhance the risk of comorbidity and mortality related to fractures. Despite great advances in understanding MBD in CKD, clinical and biological targets are lacking, which leads to under-management of fractures. Optimal PTH control results in a net improvement in defining the levels of bone remodeling. In addition, circulating biomarkers such as bone-specific alkaline phosphatase and cross-linked collagen type I peptide will also provide additional information about remodeling rate, bone mineralization and the evaluation of fracture risk. Imaging techniques identify patients at risk by measurement of bone mineral density by DEXA or by high peripheral QCT, which allow the discrimination of trabecular and cortical bone. Here, we have reviewed the literature related to epidemiology and the pathophysiological role of mineral and biochemical factors involved in CKD-MBD with a special focus on fracture risk. We also provide an algorithm that could be used for the management of bone diseases and to guide treatment decisions. Finally, the combined expertise of clinicians from various disciplines is crucial for the best prevention of fractures.

scholarly journals A phosphate and calcium-enriched diet promotes progression of 5/6-nephrectomy-induced chronic kidney disease in C57BL/6 mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
J. Radloff ◽  
N. Latic ◽  
U. Pfeiffenberger ◽  
C. Schüler ◽  
S. Tangermann ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Calcium Phosphate ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Time Course ◽  
Bone Mineralization ◽  
Fibroblast Growth Factor 23 ◽  
Functional Decline ◽  
Left Ventricular ◽  
Normal Diet

AbstractC57BL/6 mice are known to be rather resistant to the induction of experimental chronic kidney disease (CKD) by 5/6-nephrectomy (5/6-Nx). Here, we sought to characterize the development of CKD and its cardiac and skeletal sequelae during the first three months after 5/6-Nx in C57BL/6 mice fed a calcium- and phosphate enriched diet (CPD) with a balanced calcium/phosphate ratio. 5/6-NX mice on CPD showed increased renal fibrosis and a more pronounced decrease in glomerular filtration rate when compared to 5/6-Nx mice on normal diet (ND). Interestingly, despite comparable levels of serum calcium, phosphate, and parathyroid hormone (PTH), circulating intact fibroblast growth factor-23 (FGF23) was 5 times higher in 5/6-Nx mice on CPD, relative to 5/6-Nx mice on ND. A time course experiment revealed that 5/6-Nx mice on CPD developed progressive renal functional decline, renal fibrosis, cortical bone loss, impaired bone mineralization as well as hypertension, but not left ventricular hypertrophy. Collectively, our data show that the resistance of C57BL/6 mice to 5/6-Nx can be partially overcome by feeding the CPD, and that the CPD induces a profound, PTH-independent increase in FGF23 in 5/6-Nx mice, making it an interesting tool to assess the pathophysiological significance of FGF23 in CKD.

scholarly journals Soluble Fas affects erythropoiesis in vitro and acts as a potential predictor of erythropoiesis-stimulating agent therapy in patients with chronic kidney disease

2020 ◽  
Vol 318 (4) ◽  
pp. F861-F869
Author(s):  
Daniela Mendes Chiloff ◽  
Danilo Candido de Almeida ◽  
Maria A. Dalboni ◽  
Maria Eugênia Canziani ◽  
Sunil K. George ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Glomerular Filtration Rate ◽  
Kidney Disease ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Dependent Manner ◽  
Potential Predictor ◽  
Soluble Fas ◽  
Esa Therapy

Serum soluble Fas (sFas) levels are associated with erythropoietin (Epo) hyporesponsiveness in patients with chronic kidney disease (CKD). Whether sFas could predict the need for erythropoiesis-stimulating agent (ESA) usage and its influence in erythropoiesis remain unclear. We evaluated the relation between sFas and ESA therapy in patients with CKD with anemia and its effect on erythropoiesis in vitro. First, we performed a retrospective cohort study with 77 anemic patients with nondialysis CKD. We performed in vitro experiments to investigate whether sFas could interfere with the behavior of hematopoietic stem cells (HSCs). HSCs were isolated from umbilical cord blood and incubated with recombinant sFas protein in a dose-dependent manner. Serum sFas positively correlated with Epo levels ( r = 0.30, P = 0.001) but negatively with hemoglobin ( r = −0.55, P < 0.001) and glomerular filtration rate ( r = −0.58, P < 0.001) in patients with CKD at baseline. Elevated sFas serum levels (4,316 ± 897 vs. 2,776 ± 749, P < 0.001) with lower estimated glomerular filtration rate (26.2 ± 10.1 vs. 33.5 ± 14.3, P = 0.01) and reduced hemoglobin concentration (11.1 ± 0.9 vs. 12.5 ± 1.2, P < 0.001) were identified in patients who required ESA therapy compared with patients with non-ESA. Afterward, we detected that the sFas level was slight correlated with a necessity of ESA therapy in patients with nondialysis CKD and anemia. In vitro assays demonstrated that the erythroid progenitor cell frequency negatively correlated with sFas concentration ( r = −0.72, P < 0.001). There was decreased erythroid colony formation in vitro when CD34+ HSCs were incubated with a higher concentration of sFas protein (1.56 ± 0.29, 4.33 ± 0.53, P < 0.001). Our findings suggest that sFas is a potential predictor for ESA therapy in patients with nondialysis CKD and that elevated sFas could affect erythropoiesis in vitro.

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