New Insights to the Crosstalk between Vascular and Bone Tissue in Chronic Kidney Disease-Mineral and Bone Disorder.
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ABSTRACT:
SUBMITTER: Mace ML
PROVIDER: S-EPMC8708186 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The chronic kidney disease-mineral and bone disorder (CKD-MBD) syndrome is an extremely important complication of kidney diseases. Here we tested whether CKD-MBD causes vascular calcification in early kidney failure by developing a mouse model of early CKD in a background of atherosclerosis-stimulated arterial calcification. CKD equivalent in glomerular filtration reduction to human CKD stage 2 stimulated early vascular calcification and inhibited the tissue expression of α-klotho (klotho) in the aorta. In addition, osteoblast transition in the aorta was stimulated by early CKD as shown by the expression of the critical transcription factor Runx2. The ligand associated with the klotho-fibroblast growth factor receptor complex, FGF23, was found to be expressed in the vascular media of sham-operated mice. Its expression was decreased in early CKD. Increased circulating levels of the osteocyte-secreted proteins, FGF23, and sclerostin may have been related to increased circulating klotho levels. Finally, we observed low-turnover bone disease with a reduction in bone formation rates more than bone resorption. Thus, the CKD-MBD, characterized by cardiovascular risk factors, vascular calcification, increased circulating klotho, FGF23 and sclerostin levels, and low-turnover renal osteodystrophy, was established in early CKD. Early CKD caused a reduction of vascular klotho, stimulated vascular osteoblastic transition, increased osteocytic secreted proteins, and inhibited skeletal modeling producing the CKD-MBD.
| S-EPMC3836911 | biostudies-literature
Project description:Childhood and adolescence are crucial times for the development of a healthy skeletal and cardiovascular system. Disordered mineral and bone metabolism accompany chronic kidney disease (CKD) and present significant obstacles to optimal bone strength, final adult height, and cardiovascular health. Decreased activity of renal 1 alpha hydroxylase results in decreased intestinal calcium absorption, increased serum parathyroid hormone levels, and high-turnover renal osteodystrophy, with subsequent growth failure. Simultaneously, phosphorus retention exacerbates secondary hyperparathyroidism, and elevated levels contribute to cardiovascular disease. Treatment of hyperphosphatemia and secondary hyperparathyroidism improves growth and high-turnover bone disease. However, target ranges for serum calcium, phosphorus, and parathyroid hormone (PTH) levels vary according to stage of CKD. Since over-treatment may result in adynamic bone disease, growth failure, hypercalcemia, and progression of cardiovascular calcifications, therapy must be carefully adjusted to maintain optimal serum biochemical parameters according to stage of CKD. Newer therapeutic agents, including calcium-free phosphate binding agents and new vitamin D analogues, effectively suppress serum PTH levels while limiting intestinal calcium absorption and may provide future therapeutic alternatives for children with CKD.
| S-EPMC2668632 | biostudies-other
Project description:Chronic kidney disease (CKD)-mineral bone disorder (MBD) is a complex clinical syndrome that begins early during CKD and evolves into one of the deadliest complications of CKD through its effects on the cardiovascular and skeletal systems. Achievement of treatment goals to decrease the risk of accelerated cardiovascular events and fractures has been challenging. We hypothesized that application of quantitative systems pharmacology (QSP) modeling combined with artificial intelligence techniques could improve the management of CKD-MBD with the goal of improving outcomes for patients with CKD. We present the implementation of a reinforcement learning (RL) approach to achieve the prescribed goals for serum calcium, phosphorus, and parathyroid hormone through concurrent dosing of phosphate binders, vitamin D analogs, and calcimimetics by simulation in 80 subjects in Matlab. In silico simulation results demonstrate that the application of a QSP model coupled with RL more effectively and quickly achieves treatment goals even in the setting of inferior simulated subject compliance with medical therapy and identifies key decision variables for therapeutic recommendations.
| S-EPMC9574726 | biostudies-literature
Project description:ObjectiveEpidemiologic studies have suggested a link between chronic systemic inflammation and chronic kidney disease-mineral and bone disorder (CKD-MBD). Additionally, declining renal function is associated with worsening physical and cognitive function, which may potentially be explained by systemic inflammation, CKD-MBD, or both. We hypothesized that inhibiting inflammation with an interleukin-1 (IL-1) trap would improve markers of CKD-MBD as well as physical/cognitive function in patients with moderate-to-severe CKD.MethodsIn a two-site, double-blind trial, 39 patients with stage 3 - 4 CKD completed a randomized trial receiving either the IL-1 trap rilonacept (160 mg/week) or placebo for 12 weeks. The following CKD-MBD markers were assessed in serum before and after the intervention: calcium, phosphorus, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, intact parathyroid hormone (iPTH), and fibroblast growth factor 23 (FGF23). A battery of tests was also administered in a subgroup (n = 23) to assess multiple domains of physical function (endurance, locomotion, dexterity, balance, strength, and fatigue) and cognitive function.ResultsParticipants were 65 ± 10 years of age, 23% female, and had a mean estimated glomerular filtration rate of 38 ± 13 mL/min/1.73m2. There were no changes in serum calcium, phosphorus, any vitamin D metabolite, iPTH, or FGF23 levels (p ? 0.28) with IL-1 inhibition. Similarly, rilonacept did not alter locomotion, dexterity, balance, strength, fatigue, or cognitive function (p ? 0.13). However, endurance (400-m walk time) tended to improve in the rilonacept (-31 s) vs. placebo group (-2 s; p = 0.07).ConclusionsIn conclusion, 12 weeks of IL-1 inhibition did not improve markers of CKD-MBD or physical function.?.
| S-EPMC6595399 | biostudies-literature
Project description:Chronic kidney disease (CKD) mineral and bone disorder (MBD) comprises a triad of biochemical abnormalities (of calcium, phosphate, parathyroid hormone and vitamin D), bone abnormalities (turnover, mineralization and growth) and extra-skeletal calcification. Mineral dysregulation leads to bone demineralization causing bone pain and an increased fracture risk compared to healthy peers. Vascular calcification, with hydroxyapatite deposition in the vessel wall, is a part of the CKD-MBD spectrum and, in turn, leads to vascular stiffness, left ventricular hypertrophy and a very high cardiovascular mortality risk. While the growing bone requires calcium, excess calcium can deposit in the vessels, such that the intake of calcium, calcium- containing medications and high calcium dialysate need to be carefully regulated. Normal physiological bone mineralization continues into the third decade of life, many years beyond the rapid growth in childhood and adolescence, implying that skeletal calcium requirements are much higher in younger people compared to the elderly. Much of the research into the link between bone (de)mineralization and vascular calcification in CKD has been performed in older adults and these data must not be extrapolated to children or younger adults. In this article, we explore the physiological changes in bone turnover and mineralization in children and young adults, the pathophysiology of mineral bone disease in CKD and a potential link between bone demineralization and vascular calcification.
| S-EPMC10817832 | biostudies-literature
Project description:BackgroundChronic kidney disease-mineral and bone disorder (CKD-MBD) in dogs is associated with hypovitaminosis D, increased parathyroid hormone (PTH), and increased fibroblast growth factor-23 (FGF-23) concentrations. Best practice for vitamin D metabolite supplementation in CKD-MBD remains unknown.ObjectiveTo provide an extended-release calcifediol supplement to dogs with CKD and to measure its effects on variables indicative of CKD-MBD.AnimalsTen dogs with International Renal Interest Society stages 2 and 3 CKD.MethodsIn a prospective study, dogs received a calcifediol supplement for 84 days. Serum 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OH]2 D), 24,25-dihydroxyvitamin D (24,25[OH]2 D), creatinine, calcium, phosphorus, PTH, plasma FGF-23 concentrations, and urine profiles were measured monthly during supplementation. Urine calcium to creatinine (UCa/Cr) ratios and fractional excretion of calcium, phosphorus, and sodium were determined.ResultsAll serum vitamin D metabolite concentrations increased significantly by day 84 (P < .001): [25(OH)D (median 249.9 ng/mL; range, 149.7-469.9 ng/mL) compared to baseline (median 50.2 ng/mL; range, 31.3-66.0 ng/mL); 1,25(OH)2 D (median 66.1 pg/mL; range, 56.9-88.1 pg/mL) compared to baseline (median 37.3 pg/mL; range, 29.3-56.7 pg/mL); 24,25(OH)2 D (median 81.4 ng/mL; range, 22.1-151.7 ng/mL) compared to baseline (median 15.4 ng/mL; range, 6.9-40.6 ng/mL)]. There were no significant differences in calcium, phosphorus, PTH concentrations, UCa/Cr or fractional excretion of calcium. No dog developed ionized hypercalcemia. Plasma FGF-23 concentrations increased by day 84 (median 1219 pg/mL; range, 229-8824 pg/mL) compared to baseline (median 798 pg/mL; range, 103-4.145 pg/mL) (P < .01).Conclusions and clinical importanceCalcifediol supplementation for 84 days was well-tolerated in dogs with IRIS stages 2 and 3 CKD. It remains to be determined how long-term supplementation would affect CKD progression and QOL.
| S-EPMC7694821 | biostudies-literature
Project description: Not available
| S-EPMC6513594 | biostudies-literature
Project description:Mineral and bone disorder biomarkers 'normal ranges' are controversial. The aim of the study was to evaluate the association between serum calcium (Ca), phosphate (P), intact parathyroid hormone (iPTH), and 25(OH) vitamin D levels and mortality risk, in a chronic kidney disease (CKD) grade (G) 3b-4 cohort. The Uruguayan National Renal Healthcare Program (NRHP-UY) CKD patients' cohort, included between 1 October 2004 and 1 March 2020 and followed-up until 1 March 2021, was analyzed with the Ethics Committee approval. A total of 6473 patients were analyzed: 56% men, median age 73 (65-79) years, 55% on CKD G3b. At the end of the follow-up, 2459 (37.7%) patients had died (6.4/100 patient-year). There were iPTH data on 2013 patients (younger, with lower estimated glomerular filtration rate (eGFR) and lesser comorbidities). By bivariate Cox analysis the lowest death risk was observed with mean Ca between 9.01 and 10.25 mg/dl, P between 2.76 and 4.0 mg/dl, iPTH ≤ 105 pg/ml, and 25(OH) vitamin D >10 ng/ml. The multivariate Cox regression mortality risk adjusted to age, sex, CKD etiology, diabetes, smoking, cardiovascular comorbidity, blood pressure, proteinuria, eGFR, renin-angiotensin system blockers and vitamin D treatments, serum Ca, P, iPTH, and 25(OH) vitamin D (n = 964) showed that a higher mortality risk was associated with p > 4.00 mg/dl (HR 1.668, CI 95%: 1.201-2.317), iPTH >105 pg/ml (HR 1.386, CI 95%: 1.012-1.989), and 25(OH) vitamin D ≤ 10 ng/ml (HR 1.958, CI 95%: 1.238-3.098) and a lower mortality risk with 1,25(OH)2 vitamin D treatment (HR 0.639, CI 95%: 0.451-0.906). These data may contribute to the precise G3b-4 CKD-MBD biomarkers levels definition.
| S-EPMC9373789 | biostudies-literature
Project description:BackgroundAutoclaving rodent diets is common in laboratory animals, but autoclaving increases the formation of dietary advanced glycation end-products (AGE). We studied the effect of autoclaved (AC) diet alone or in combination with a diet high in bioavailable phosphorus on biochemistries of chronic kidney disease-mineral and bone disorder (CKD-MBD), intestinal gene expression, and oxidative stress.MethodsMale CKD rats (Cy/+) and normal littermates were fed 1 of 3 diets: AC 0.7% phosphorus grain-based diet for 28 weeks (AC); AC diet for 17 weeks followed by non-autoclaved (Non-AC) 0.7% phosphorus casein diet until 28 weeks (AC + Casein); or Non-AC diet for 16 weeks followed by a Non-AC purified diet until 30 weeks (Non-AC + Casein).ResultsAC diets contained ~3× higher AGEs and levels varied depending on the location within the autoclave. Rats fed the AC and AC + Casein diets had higher total AGEs and oxidative stress, irrespective of kidney function. Kidney function was more severely compromised in CKD rats fed AC or AC + Casein compared to Non-AC + Casein. There was a disease-by-diet interaction for plasma phosphorus, parathyroid hormone, and c-terminal fibroblast growth factor-23, driven by high values in the CKD rats fed the AC + Casein diet. Compared to Non-AC + Casein, AC and AC + Casein-fed groups had increased expression of receptor of AGEs and intestinal NADPH oxidase dual oxidase-2, independent of kidney function.ConclusionsAutoclaving rodent diets impacts the progression of CKD and CKD-MBD, highlighting the critical importance of standardizing diets in experiments.
| S-EPMC7228841 | biostudies-literature
Project description:BackgroundChronic kidney disease mineral bone disorder (CKD-MBD) is a condition characterized by alterations of calcium, phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF-23) metabolism that in turn promote bone disorders, vascular calcifications, and increase cardiovascular (CV) risk. Nephrologists' awareness of diagnostic, prognostic, and therapeutic tools to manage CKD-MBD plays a primary role in adequately preventing and managing this condition in clinical practice.MethodsA national survey (composed of 15 closed questions) was launched to inquire about the use of bone biomarkers in the management of CKD-MBD patients by nephrologists and to gain knowledge about the implementation of guideline recommendations in clinical practice.ResultsOne hundred and six Italian nephrologists participated in the survey for an overall response rate of about 10%. Nephrologists indicated that the laboratories of their hospitals were able to satisfy request of ionized calcium levels, 105 (99.1%) of both PTH and alkaline phosphatase (ALP), 100 (94.3%) of 25(OH)D, and 61 (57.5%) of 1.25(OH)2D; while most laboratories did not support the requests of biomarkers such as FGF-23 (intact: 88.7% and c-terminal: 93.4%), Klotho (95.3%; soluble form: 97.2%), tartrate-resistant acid phosphatase 5b (TRAP-5b) (92.5%), C-terminal telopeptide (CTX) (71.7%), and pro-collagen type 1 N-terminal pro-peptide (P1NP) (88.7%). As interesting data regarding Italian nephrologists' behavior to start treatment of secondary hyperparathyroidism (sHPT), the majority of clinicians used KDOQI guidelines (n = 55, 51.9%). In contrast, only 40 nephrologists (37.7%) relied on KDIGO guidelines, which recommended referring to values of PTH between two and nine times the upper limit of the normal range.ConclusionResults point out a marked heterogeneity in the management of CKD-MBD by clinicians as well as a suboptimal implementation of guidelines in Italian clinical practice.
| S-EPMC10784916 | biostudies-literature