RESUMO
Phosphorus is a vital element for life found in most foods as a natural component, but it is also one of the most used preservatives added during food processing. High serum phosphorus contributes to develop vascular calcification in chronic kidney disease; however, it is not clear its effect in a population without kidney damage. The objective of this in vivo and in vitro study was to investigate the effect of high phosphorus exposure on the aortic and serum levels of miR-145 and its effect on vascular smooth muscle cell (VSMCs) changes towards less contractile phenotypes. The study was performed in aortas and serum from rats fed standard and high-phosphorus diets, and in VSMCs exposed to different concentrations of phosphorus. In addition, miR-145 silencing and overexpression experiments were carried out. In vivo results showed that in rats with normal renal function fed a high P diet, a significant increase in serum phosphorus was observed which was associated to a significant decrease in the aortic α-actin expression which paralleled the decrease in aortic and serum miR-145 levels, with no changes in the osteogenic markers. In vitro results using VSMCs corroborated the in vivo findings. High phosphorus first reduced miR-145, and afterwards α-actin expression. The miR-145 overexpression significantly increased α-actin expression and partially prevented the increase in calcium content. These results suggest that miR-145 could be an early biomarker of vascular calcification, which could give information about the initiation of the transdifferentiation process in VSMCs.
Assuntos
MicroRNAs , Calcificação Vascular , Ratos , Animais , Fósforo/metabolismo , Músculo Liso Vascular , Actinas/metabolismo , Transdiferenciação Celular , MicroRNAs/genética , MicroRNAs/metabolismo , Fenótipo , Calcificação Vascular/genética , Calcificação Vascular/metabolismo , Miócitos de Músculo Liso , Células CultivadasRESUMO
This study was designed to investigate the controversy on the potential role of sKlotho as an early biomarker in Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD), to assess whether sKlotho is a reliable marker of kidney α-Klotho, to deepen the effects of sKlotho on vascular smooth muscle cells (VSMCs) osteogenic differentiation and to evaluate the role of autophagy in this process. Experimental studies were conducted in CKD mice fed a normal phosphorus (CKD+NP) or high phosphorus (CKD+HP) diet for 14 weeks. The patients' study was performed in CKD stages 2-5 and in vitro studies which used VSMCs exposed to non-calcifying medium or calcifying medium with or without sKlotho. The CKD experimental model showed that the CKD+HP group reached the highest serum PTH, P and FGF23 levels, but the lowest serum and urinary sKlotho levels. In addition, a positive correlation between serum sKlotho and kidney α-Klotho was found. CKD mice showed aortic osteogenic differentiation, together with increased autophagy. The human CKD study showed that the decline in serum sKlotho is previous to the rise in FGF23. In addition, both serum sKlotho and FGF23 levels correlated with kidney function. Finally, in VSMCs, the addition of sKlotho prevented osteogenic differentiation and induced autophagy. It can be concluded that serum sKlotho was the earliest CKD-MBD biomarker, a reliable indicator of kidney α-Klotho and that might protect against osteogenic differentiation by increasing autophagy. Nevertheless, further studies are needed to investigate the mechanisms of this possible protective effect.
Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica , Insuficiência Renal Crônica , Humanos , Camundongos , Animais , Proteínas Klotho , Glucuronidase , Osteogênese , Fatores de Crescimento de Fibroblastos , Rim , Fósforo , Minerais , BiomarcadoresRESUMO
INTRODUCTION: MicroRNAs (miRs) regulate vascular calcification (VC), and their quantification may contribute to suspicion of the presence of VC. METHODS: The study was performed in four phases. Phase 1: miRs sequencing of rat calcified and non-calcified aortas. Phase 2: miRs with the highest rate of change, plus miR-145 [the most abundant miR in vascular smooth muscle cells (VSMCs)], were validated in aortas and serum from rats with and without VC. Phase 3: the selected miRs were analyzed in epigastric arteries from kidney donors and recipients, and serum samples from general population. Phase 4: VSMCs were exposed to different phosphorus concentrations, and miR-145 and miR-486 were overexpressed to investigate their role in VC. RESULTS: miR-145, miR-122-5p, miR-486 and miR-598-3p decreased in the rat calcified aortas, but only miR-145 and miR-486 were detected in serum. In human epigastric arteries, miR-145 and miR-486 were lower in kidney transplant recipients compared with donors. Both miRs inversely correlated with arterial calcium content and with VC (Kauppila index). In the general population, the severe VC was associated with the lowest serum levels of both miRs. The receiver operating characteristic curve showed that serum miR-145 was a good biomarker of VC. In VSMCs exposed to high phosphorus, calcium content, osteogenic markers (Runx2 and Osterix) increased, and the contractile marker (α-actin), miR-145 and miR-486 decreased. Overexpression of miR-145, and to a lesser extent miR-486, prevented the increase in calcium content induced by high phosphorus, the osteogenic differentiation and the loss of the contractile phenotype. CONCLUSION: miR-145 and miR-486 regulate the osteogenic differentiation of VSMCs, and their quantification in serum could serve as a marker of VC.
Assuntos
MicroRNAs , Calcificação Vascular , Animais , Humanos , Ratos , Biomarcadores , Cálcio , MicroRNAs/genética , Músculo Liso Vascular , Miócitos de Músculo Liso , Osteogênese/genética , Fósforo , Calcificação Vascular/genéticaRESUMO
X-linked hypophosphataemia (XLH) is the most frequent cause of hypophosphataemia-associated rickets of genetic origin and is associated with high levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23). In addition to rickets and osteomalacia, patients with XLH have a heavy disease burden with enthesopathies, osteoarthritis, pseudofractures and dental complications, all of which contribute to reduced quality of life. This Consensus Statement presents the outcomes of a working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, and provides robust clinical evidence on management in XLH, with an emphasis on patients' experiences and needs. During growth, conventional treatment with phosphate supplements and active vitamin D metabolites (such as calcitriol) improves growth, ameliorates leg deformities and dental manifestations, and reduces pain. The continuation of conventional treatment in symptom-free adults is still debated. A novel therapeutic approach is the monoclonal anti-FGF23 antibody burosumab. Although promising, further studies are required to clarify its long-term efficacy, particularly in adults. Given the diversity of symptoms and complications, an interdisciplinary approach to management is of paramount importance. The focus of treatment should be not only on the physical manifestations and challenges associated with XLH and other FGF23-mediated hypophosphataemia syndromes, but also on the major psychological and social impact of the disease.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Fator de Crescimento de Fibroblastos 23 , Osteoartrite , Síndrome de Emaciação , Adulto , Animais , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Raquitismo Hipofosfatêmico Familiar/genética , Raquitismo Hipofosfatêmico Familiar/metabolismo , Fator de Crescimento de Fibroblastos 23/metabolismo , Humanos , Osteoartrite/diagnóstico , Osteoartrite/tratamento farmacológico , Osteoartrite/genética , Osteoartrite/metabolismo , Qualidade de Vida , Síndrome de Emaciação/diagnóstico , Síndrome de Emaciação/tratamento farmacológico , Síndrome de Emaciação/genética , Síndrome de Emaciação/metabolismoRESUMO
BACKGROUND AND OBJECTIVE: Adequate serum phosphorus levels in patients with chronic kidney disease is essential for their clinical management. However, the control of hyperphosphatemia is difficult because is normally associated with increases in serum PTH. In the present study, the effects of hyperphosphatemia, in the presence of elevated and normal PTH, on cardiac inflammation, hypertrophy and fibrosis in an experimental renal failure model were analyzed. MATERIALS AND METHODS: 4 groups of rats were formed. Two groups underwent total parathyroidectomy (PTx). Rats with Ca <7.5â¯mg/dL and PTHâ¯<â¯50â¯pg/mL underwent 7/8 nephrectomy (CRF) and a subcutaneous pellet was placed that releases PTH 1-34 (5⯵g/kg/day). One group received a diet with normal P (NP) (CRFâ¯+â¯PTxâ¯+â¯rPTHâ¯+â¯NP group) and another with a high P diet (0.9% - HP) (CRFâ¯+â¯PTxâ¯+â¯rPTHâ¯+â¯HP group). Other 2 groups that only had CRF received NP (CRFâ¯+â¯NP) and HP (CRFâ¯+â¯HP) diet. A SHAM group for nephrectomy and parathyroidectomy was also added. After 14 weeks the rats were sacrificed. RESULTS: The groups with a diet high in phosphorus (CRFâ¯+â¯H A and CRFâ¯+â¯PTxâ¯+â¯rPTHâ¯+â¯HP) had a significant reduction in creatinine clearance and also in body weight with an increase in serum phosphorus regardless of parathyroidectomy, but not serum levels of calcium, FGF23 and calcitriol that were 2-3 times higher in the group with secondary hyperparathyroidism (CRFâ¯+â¯HP). The diameter of the cardiomyocytes was greater in the CRFâ¯+â¯HP group, while parathyroidectomy (CRFâ¯+â¯PTxâ¯+â¯rPTHâ¯+â¯HP) significantly reduced them, despite the high and similar serum phosphorus values. TNF-α, Adam17 and cardiac fibrosis at the histological and molecular level showed a similar pattern with increases in the group with severe secondary hyperparathyroidism (CRFâ¯+â¯HP). CONCLUSIONS: Hyperphosphatemia confirmed its importance in the genesis of secondary hyperparathyroidism, but also of kidney damage that was independent of PTH levels. However, inflammation, fibrosis, and cardiomyocyte growth were more closely related to PTH levels, since in the presence of similar severe hyperphosphatemia, parathyroidectomy reduced the values ââof inflammatory parameters, cardiac hypertrophy, and fibrosis.
Assuntos
Hiperparatireoidismo Secundário , Hiperfosfatemia , Falência Renal Crônica , Insuficiência Renal Crônica , Animais , Calcitriol , Cálcio , Cardiomegalia/complicações , Creatinina , Fibrose , Humanos , Hiperparatireoidismo Secundário/complicações , Hiperparatireoidismo Secundário/cirurgia , Hiperfosfatemia/etiologia , Inflamação , Falência Renal Crônica/complicações , Modelos Teóricos , Fósforo , Ratos , Insuficiência Renal Crônica/complicações , Fator de Necrose Tumoral alfaRESUMO
BACKGROUND: In chronic kidney disease, serum phosphorus (P) elevations stimulate parathyroid hormone (PTH) production, causing severe alterations in the bone-vasculature axis. PTH is the main regulator of the receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system, which is essential for bone maintenance and also plays an important role in vascular smooth muscle cell (VSMC) calcification. The discovery of a new RANKL receptor, leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), which is important for osteoblast differentiation but with an unknown role in vascular calcification (VC), led us to examine the contribution of LGR4 in high P/high PTH-driven VC. METHODS: In vivo studies were conducted in subtotally nephrectomized rats fed a normal or high P diet, with and without parathyroidectomy (PTX). PTX rats were supplemented with PTH(1-34) to achieve physiological serum PTH levels. In vitro studies were performed in rat aortic VSMCs cultured in control medium, calcifying medium (CM) or CM plus 10-7 versus 10-9 M PTH. RESULTS: Rats fed a high P diet had a significantly increased aortic calcium (Ca) content. Similarly, Ca deposition was higher in VSMCs exposed to CM. Both conditions were associated with increased RANKL and LGR4 and decreased OPG aorta expression and were exacerbated by high PTH. Silencing of LGR4 or parathyroid hormone receptor 1 (PTH1R) attenuated the high PTH-driven increases in Ca deposition. Furthermore, PTH1R silencing and pharmacological inhibition of protein kinase A (PKA), but not protein kinase C, prevented the increases in RANKL and LGR4 and decreased OPG. Treatment with PKA agonist corroborated that LGR4 regulation is a PTH/PKA-driven process. CONCLUSIONS: High PTH increases LGR4 and RANKL and decreases OPG expression in the aorta, thereby favouring VC. The hormone's direct pro-calcifying actions involve PTH1R binding and PKA activation.
Assuntos
Miócitos de Músculo Liso/metabolismo , Osteoprotegerina/metabolismo , Hormônio Paratireóideo/farmacologia , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Calcificação Vascular/metabolismo , Animais , Hormônios e Agentes Reguladores de Cálcio/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ligantes , Masculino , NF-kappa B/metabolismo , Osteoprotegerina/genética , Ligante RANK/genética , Ratos , Ratos Wistar , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptores Acoplados a Proteínas G/genéticaRESUMO
BACKGROUND: In chronic kidney disease (CKD), increases in serum phosphate and parathyroid hormone (PTH) aggravate vascular calcification (VC) and bone loss. This study was designed to discriminate high phosphorus (HP) and PTH contribution to VC and bone loss. METHODS: Nephrectomized rats fed a HP diet underwent either sham operation or parathyroidectomy and PTH 1-34 supplementation to normalize serum PTH. RESULTS: In uraemic rats fed a HP diet, parathyroidectomy with serum PTH 1-34 supplementation resulted in (i) reduced aortic calcium (80%) by attenuating osteogenic differentiation (higher α-actin; reduced Runx2 and BMP2) and increasing the Wnt inhibitor Sclerostin, despite a similar degree of hyperphosphataemia, renal damage and serum Klotho; (ii) prevention of bone loss mostly by attenuating bone resorption and increases in Wnt inhibitors; and (iii) a 70% decrease in serum calcitriol levels despite significantly reduced serum Fgf23, calcium and renal 24-hydroxylase, which questions that Fgf23 is the main regulator of renal calcitriol production. Significantly, when vascular smooth muscle cells (VSMCs) were exposed exclusively to high phosphate and calcium, high PTH enhanced while low PTH attenuated calcium deposition through parathyroid hormone 1 receptor (PTH1R) signalling. CONCLUSIONS: In hyperphosphataemic CKD, a defective suppression of high PTH exacerbates HP-mediated osteogenic VSMC differentiation and reduces vascular levels of anti-calcifying sclerostin.
Assuntos
Hormônio Paratireóideo/sangue , Fosfatos/sangue , Insuficiência Renal Crônica/sangue , Calcificação Vascular/metabolismo , Animais , Doenças Ósseas Metabólicas/sangue , Proteína Morfogenética Óssea 2/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Calcitriol/sangue , Cálcio/sangue , Cálcio/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/metabolismo , Marcadores Genéticos , Hiperfosfatemia/metabolismo , Rim/efeitos dos fármacos , Masculino , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Nefrectomia , Osteogênese/efeitos dos fármacos , Hormônio Paratireóideo/uso terapêutico , Paratireoidectomia , Fosforilação , Ratos , Ratos Wistar , Vitamina D3 24-Hidroxilase/metabolismoRESUMO
BACKGROUND: Mineral and bone metabolism disorders are common complications in haemodialysis patients that present significant geographical variability. OBJECTIVES: The objective of this study was to assess these disorders for the first time in haemodialysis patients from Peru. METHODS: The study included 1551 haemodialysis patients from 55 centres affiliated with the Social Health System of Peru in the city of Lima. Demographic data, comorbidities, treatments and biochemical parameters were collected from each patient. Serum calcium, phosphorus and PTH levels were categorised according to the recommended ranges in the KDOQI and KDIGO guidelines. RESULTS: The mean age of the patients was 59.5±15.6 years, with a mean time on haemodialysis of 58.0±54.2 months. All patients were dialysed with a calcium concentration in the dialysis fluid of 3.5 mEq/l and 68.9% of patients were prescribed phosphate-binding agents (98.4% of them calcium carbonate). A high percentage of patients showed serum calcium above, and serum phosphorus below, the recommended ranges in the KDOQI guidelines (32.8% and 37.3%, respectively). More than half of the patients had serum PTH values below the recommended ranges of both the KDOQI and KDIGO guidelines (56.4% and 51.6%, respectively). CONCLUSIONS: Patients included in this study were younger than those from other studies and showed both hypophosphataemia and suppressed PTH, probably due to an excessive calcium overload through dialysis fluid and the use of calcium-containing phosphate binding agents.
Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica/metabolismo , Distúrbio Mineral e Ósseo na Doença Renal Crônica/terapia , Diálise Renal , Instituições de Assistência Ambulatorial , Osso e Ossos/metabolismo , Cálcio/metabolismo , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peru , Fósforo/metabolismo , Saúde da População UrbanaRESUMO
Bone loss and increased fractures are common complications in chronic kidney disease. Because Wnt pathway activation is essential for normal bone mineralization, we assessed whether Wnt inhibition contributes to high-phosphorus-induced mineralization defects in uremic rats. By week 20 after 7/8 nephrectomy, rats fed a high-phosphorus diet had the expected high serum creatinine, phosphorus, parathyroid hormone, and fibroblast growth factor 23 (FGF23) levels and low serum calcium. There was a 15% reduction in tibial mineral density and a doubling of bone cortical porosity compared to uremic rats fed a normal-phosphorus diet. The decreases in tibial mineral density were preceded by time-dependent increments in gene expression of bone formation (Osteocalcin and Runx2) and resorption (Cathepsin K) markers, which paralleled elevations in gene expression of the Wnt inhibitors Sfrp1 and Dkk1 in bone. Similar elevations of Wnt inhibitors plus an increased phospho-ß-catenin/ß-catenin ratio occurred upon exposure of the osteoblast cell line UMR106-01 either to uremic serum or to the combination of parathyroid hormone, FGF23, and soluble Klotho, at levels present in uremic serum. Strikingly, while osteoblast exposure to parathyroid hormone suppressed the expression of Wnt inhibitors, FGF23 directly inhibited the osteoblastic Wnt pathway through a soluble Klotho/MAPK-mediated process that required Dkk1 induction. Thus, the induction of Dkk1 by FGF23/soluble Klotho in osteoblasts inactivates Wnt/ß-catenin signaling. This provides a novel autocrine/paracrine mechanism for the adverse impact of high FGF23 levels on bone in chronic kidney disease.
Assuntos
Descalcificação Patológica/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Osteoblastos/metabolismo , Insuficiência Renal Crônica/complicações , Via de Sinalização Wnt , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Calcificação Fisiológica , Cálcio/sangue , Catepsina K/metabolismo , Linhagem Celular Tumoral , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Descalcificação Patológica/etiologia , Modelos Animais de Doenças , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/farmacologia , Glucuronidase/metabolismo , Glucuronidase/farmacologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas Klotho , Masculino , Proteínas de Membrana/metabolismo , Osteoblastos/efeitos dos fármacos , Osteocalcina/metabolismo , Hormônio Paratireóideo/sangue , Fósforo/sangue , Fósforo/metabolismo , Fósforo na Dieta/efeitos adversos , Porosidade , Ratos , Ratos Wistar , Insuficiência Renal Crônica/metabolismo , Tíbia/metabolismo , Tíbia/patologia , Uremia/complicações , Uremia/metabolismo , Proteínas Wnt/antagonistas & inibidores , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/sangueRESUMO
The pathogenesis and management of chronic kidney disease-mineral bone disorders (CKD-MBD) has experienced major changes, but the control of serum phosphorus at all stages of CKD still seems to be a key factor to improve clinical outcomes. High serum phosphorus is the most important uremia-related, non-traditional risk factor associated with vascular calcification in CKD patients and in the general population. Phosphorus may also be one of the key elements linking vascular calcification with low bone turnover. The main hormones and factors that contribute to the kidney regulation of phosphorus and calcium include parathyroid hormone, FGF-23, klotho and 1,25-dihydroxyvitamin D (1,25(OH)2D). Serum phosphorus did not start rising until CKD 3b in contrast with the earlier changes observed with fibroblast growth factor-23 (FGF-23), Klotho, calcitriol and parathyroid hormone (PTH). Despite FGF-23 and PTH having synergic effects regarding phosphorus removal, they have opposite effects on 1,25(OH)2D3. At the same stages of CKD in which phosphorus retention appears to occur, calcium retention also occurs. As phosphorus accumulation is associated with poor outcomes, an important question without a clear answer is at which level-range should serum phosphorus be maintained at different stages of CKD to improve clinical outcomes. There are four main strategies to manage phosphate homeostasis; phosphorus dietary intake, administration of phosphate binder agents, effective control of hyperparathyroidism and to ensure in the CKD 5D setting, an adequate scheme of dialysis. Despite all the available strategies, and the introduction of new phosphate binder agents in the market, controlling serum phosphorus remains challenging, and hyperphosphatemia continues to be extremely common in CKD 5 patients. Furthermore, despite phosphate binding agents having proved to be effective in reducing serum phosphorus, their ultimate effects on clinical outcomes remain controversial. Thus, we still need well-designed, large-scale, placebo-controlled studies to definitively prove that the reduction of serum phosphorus by phosphate binders improves clinical outcomes.
Assuntos
Hiperfosfatemia/prevenção & controle , Fósforo na Dieta/administração & dosagem , Fósforo/sangue , Insuficiência Renal Crônica/complicações , Fator de Crescimento de Fibroblastos 23 , Humanos , Hiperfosfatemia/sangue , Hiperfosfatemia/etiologia , Insuficiência Renal Crônica/sangueRESUMO
Vascular calcification is a frequent cause of morbidity and mortality in patients with CKD and the general population. The common association between vascular calcification and osteoporosis suggests a link between bone and vascular disorders. Because microRNAs (miRs) are involved in the transdifferentiation of vascular smooth muscle cells into osteoblast-like cells, we investigated whether miRs implicated in osteoblast differentiation and bone formation are involved in vascular calcification. Different levels of uremia, hyperphosphatemia, and aortic calcification were induced by feeding nephrectomized rats a normal or high-phosphorus diet for 12 or 20 weeks, at which times the levels of eight miRs (miR-29b, miR-125, miR-133b, miR-135, miR-141, miR-200a, miR-204, and miR-211) in the aorta were analyzed. Compared with controls and uremic rats fed a normal diet, uremic rats fed a high-phosphorous diet had lower levels of miR-133b and miR-211 and higher levels of miR-29b that correlated respectively with greater expression of osteogenic RUNX2 and with lower expression of several inhibitors of osteoblastic differentiation. Uremia per se mildly reduced miR-133b levels only. Similar results were obtained in two in vitro models of vascular calcification (uremic serum and high-calcium and -phosphorus medium), and experiments using antagomirs and mimics to modify miR-29b, miR-133b, and miR-211 expression levels in these models confirmed that these miRs regulate the calcification process. We conclude that miR-29b, miR-133b, and miR-211 have direct roles in the vascular smooth muscle calcification induced by high phosphorus and may be new therapeutic targets in the management of vascular calcification.
Assuntos
MicroRNAs/metabolismo , Músculo Liso Vascular/metabolismo , Uremia/metabolismo , Calcificação Vascular/metabolismo , Receptores de Activinas Tipo II/genética , Receptores de Activinas Tipo II/metabolismo , Animais , Aorta/química , Aorta/metabolismo , Aorta/patologia , Cálcio/análise , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Meios de Cultura , Expressão Gênica , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Nefrectomia , Fósforo/farmacologia , Fósforo na Dieta/administração & dosagem , Ratos , Ratos Wistar , Calcificação Vascular/genéticaRESUMO
BACKGROUND: Abnormalities in serum phosphorus, calcium and parathyroid hormone (PTH) have been associated with poor survival in haemodialysis patients. This COSMOS (Current management Of Secondary hyperparathyroidism: a Multicentre Observational Study) analysis assesses the association of high and low serum phosphorus, calcium and PTH with a relative risk of mortality. Furthermore, the impact of changes in these parameters on the relative risk of mortality throughout the 3-year follow-up has been investigated. METHODS: COSMOS is a 3-year, multicentre, open-cohort, prospective study carried out in 6797 adult chronic haemodialysis patients randomly selected from 20 European countries. RESULTS: Using Cox proportional hazard regression models and penalized splines analysis, it was found that both high and low serum phosphorus, calcium and PTH were associated with a higher risk of mortality. The serum values associated with the minimum relative risk of mortality were 4.4 mg/dL for serum phosphorus, 8.8 mg/dL for serum calcium and 398 pg/mL for serum PTH. The lowest mortality risk ranges obtained using as base the previous values were 3.6-5.2 mg/dL for serum phosphorus, 7.9-9.5 mg/dL for serum calcium and 168-674 pg/mL for serum PTH. Decreases in serum phosphorus and calcium and increases in serum PTH in patients with baseline values of >5.2 mg/dL (phosphorus), >9.5 mg/dL (calcium) and <168 pg/mL (PTH), respectively, were associated with improved survival. CONCLUSIONS: COSMOS provides evidence of the association of serum phosphorus, calcium and PTH and mortality, and suggests survival benefits of controlling chronic kidney disease-mineral and bone disorder biochemical parameters in CKD5D patients.
Assuntos
Biomarcadores/sangue , Osso e Ossos/metabolismo , Cálcio/sangue , Hiperparatireoidismo Secundário/mortalidade , Hormônio Paratireóideo/sangue , Fósforo/sangue , Diálise Renal/mortalidade , Adulto , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Hiperparatireoidismo Secundário/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Insuficiência Renal Crônica/terapia , Taxa de SobrevidaAssuntos
Estudos Observacionais como Assunto/estatística & dados numéricos , Modelos de Riscos Proporcionais , Idoso , Causalidade , Quelantes/uso terapêutico , Terapia por Quelação , Estudos de Coortes , Coleta de Dados , Feminino , Humanos , Hiperparatireoidismo Secundário/sangue , Hiperparatireoidismo Secundário/tratamento farmacológico , Hiperparatireoidismo Secundário/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Estudos Observacionais como Assunto/métodos , Fósforo , Pontuação de Propensão , Diálise Renal/efeitos adversos , Projetos de PesquisaRESUMO
BACKGROUND: Several studies have demonstrated the impact of vascular calcification on morbidity and mortality both in the general and chronic kidney disease populations. The process of vascular calcification involves complex mechanisms including the overexpression of genes and proteins associated with mineralization and increments of reactive oxygen species (ROS). Taking into account previous findings, we decided to analyze in vitro the likely inhibitory effect of natural antioxidants in the process of vascular calcification. METHODS: Primary vascular smooth muscle cells (VSMCs) were cultured with either normal medium or normal medium supplemented with calcium and phosphorus (P + Ca) in combination with several antioxidants. Mineralization, intracellular reactive oxygen species levels and the protein expression of Cbfa1/RUNX2 and Mn-superoxide dismutase-2 (SOD-2) were investigated. RESULTS: Curcumin and silybin were the more effective, inhibiting both ROS increase and VSMC mineralization. Curcumin was able to prevent the increase in Cbfa1/RUNX2 expression, but did not modify SOD-2 expression in the VSMCs cultured with the P + Ca medium. CONCLUSIONS: These findings support the importance of performing further studies in this field, as some antioxidants might have potential benefits in the management of vascular calcification.
Assuntos
Antioxidantes/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Calcificação Vascular/metabolismo , Animais , Antioxidantes/uso terapêutico , Cálcio/farmacologia , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Curcumina/farmacologia , Curcumina/uso terapêutico , Técnicas In Vitro , Músculo Liso Vascular/citologia , Fósforo/farmacologia , Ratos , Ratos Wistar , Silibina , Silimarina/farmacologia , Silimarina/uso terapêutico , Superóxido Dismutase/metabolismoRESUMO
BACKGROUND: Mineral metabolism parameters may play a role in the survival of patients with chronic kidney disease (CKD). METHODS: In the CORES Study, we analysed the association between calcium, phosphorus and PTH and mortality (all-cause and cardiovascular) in 16 173 haemodialysis (HD) patients over 18 years from six Latin American countries, who underwent haemodialysis up to 54 months. Unadjusted, case-mix-adjusted and time-dependent multivariable-adjusted hazard ratio (HR) of death were calculated for categories of serum albumin-corrected calcium (Ca(Alb)), phosphorus and PTH using as 'reference values' the range in which the lowest death rate was observed. Age, gender, vitamin D treatment, diabetes, vintage, vascular access, weight, blood pressure and laboratory variables (serum albumin, haemoglobin, creatinine, ferritin and Kt/V) were used as confounding variables. RESULTS: Low (<9.5 mg/dL) and high (>10.5 mg/dL) Ca(Alb) increased the HR for all-cause mortality. Low (<9.0 mg/dL) Ca(Alb) increased the HR for cardiovascular mortality. High phosphorus (>5.5 mg/dL) increased the HR for both all-cause and cardiovascular mortality. Low phosphorus (<4.0 and <3.0 mg/dL) increased the HR for both all-cause and cardiovascular mortality. Furthermore, low (<150 pg/mL) and high (>500 and >300 pg/mL) PTH increased the HR for both all-cause and cardiovascular mortality. In addition, only phosphorus >6.0 mg/dL increased the HR for cardiovascular hospitalizations. No effect was observed with Ca(Alb) or PTH. CONCLUSIONS: In summary, in 16,173 HD patients, elevated and reduced serum levels of albumin-corrected calcium, phosphorus and PTH levels were associated with increments in all-cause mortality. Similar results were obtained when only cardiovascular mortality was analysed.
Assuntos
Cálcio/sangue , Doenças Cardiovasculares/mortalidade , Falência Renal Crônica/sangue , Falência Renal Crônica/mortalidade , Hormônio Paratireóideo/sangue , Fósforo/sangue , Diálise Renal/mortalidade , Estudos de Coortes , Creatinina/sangue , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , América Latina , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
OBJECTIVE: The aim of this study was to evaluate the effect of 17beta-estradiol, raloxifene, and 1-alpha,25-dihydroxycholecalciferol or calcitriol on bone and lipid metabolism in chronic kidney disease and estrogen insufficiency. METHODS: Six-month-old female Sprague-Dawley rats (n = 48) were ovariectomized and nephrectomized (seven eighths). One week after surgery, the rats were divided into six groups and treated with (1) placebo, (2) 17beta-estradiol 10 microg kg day, (3) raloxifene 1 mg kg day, (4) calcitriol 10 ng kg day, (5) 17beta-estradiol + calcitriol, and (6) raloxifene + calcitriol. A group of untreated animals with chronic kidney disease and normal ovarian function was used as a control group (n = 5). The rats were killed after 8 weeks of treatment. Blood samples were drawn for serum analyses; the right tibia was removed to perform histomorphometric analyses, uteri were used as tissue markers of estrogen replacement, and paraffin-embedded sections of the uterus and the fourth breast were used for histopathologic evaluation. RESULTS: Raloxifene, alone or combined with calcitriol, and 17beta-estradiol combined with calcitriol significantly diminished total cholesterol level compared with placebo. Qualitative histological and histomorphometric analyses showed that both the single treatments and their combinations were able to increase the trabecular connectivity compared with placebo. The less beneficial results were obtained with 17beta-estradiol alone, whereas the more beneficial results were obtained with the combined treatments, particularly with raloxifene and calcitriol. CONCLUSIONS: In summary, this experimental study demonstrates the advantages of replacing both hormonal deficiencies together. The combination of calcitriol and raloxifene, a selective estrogen receptor modulator, showed a better lipid, uterus, and bone profile.
Assuntos
Colesterol/sangue , Estradiol/farmacologia , Estrogênios/deficiência , Nefropatias/complicações , Cloridrato de Raloxifeno/farmacologia , Tíbia/metabolismo , Animais , Atrofia , Conservadores da Densidade Óssea/farmacologia , Calcitriol/farmacologia , Cálcio/sangue , Doença Crônica , Estrogênios/farmacologia , Feminino , Hiperplasia , Glândulas Mamárias Animais/patologia , Tamanho do Órgão , Hormônio Paratireóideo/sangue , Fósforo/sangue , Ratos , Ratos Sprague-Dawley , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Tíbia/patologia , Útero/patologiaAssuntos
Cálcio/efeitos adversos , Quelantes/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Hiperfosfatemia/tratamento farmacológico , Falência Renal Crônica/tratamento farmacológico , Cálcio/metabolismo , Medicina Baseada em Evidências , Humanos , Hiperfosfatemia/complicações , Hiperfosfatemia/metabolismo , Falência Renal Crônica/complicações , Falência Renal Crônica/metabolismo , Fosfatos/metabolismo , Medição de Risco , Resultado do Tratamento , Vitamina D/metabolismoRESUMO
In chronic kidney disease, hyperphosphatemia has been associated to vascular calcifications. Moreover, the rate and progression of vascular calcification have been related with the reduction of bone mass and osteoporotic fractures, hereby suggesting a strong link between vascular calcification and bone loss. Our aim was to prospectively study the effects of high phosphorus diet on bone mass, vascular calcification and gene expression profile of the arterial wall. A rat model of 7/8 nephrectomy fed with normal (0.6%) and moderately high (0.9%) phosphorus diet was used. Biochemical parameters, bone mineral density and vascular calcifications were assessed. A microarray analysis of the aortic tissue was also performed to investigate the gene expression profile. After 20 weeks, the rats fed with a high phosphorus diet showed a significant increase in serum phosphorus, PTH, and creatinine, together with aortic calcification and a decrease in bone mass. The histological analysis of the vascular calcifications showed areas with calcified tissue and the gene expression profile of this calcified tissue showed repression of muscle-related genes and overexpression of bone-related genes, among them, the secreted frizzled related proteins, well-known inhibitors of the Wnt pathway, involved in bone formation. The study demonstrated prospectively the inverse and direct relationship between vascular calcification and bone mass. In addition, the microarrays findings provide new information on the molecular mechanisms that may link this relationship.
Assuntos
Aorta/metabolismo , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Calcinose/induzido quimicamente , Fósforo/efeitos adversos , Doenças Vasculares/induzido quimicamente , Animais , Aorta/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Calcinose/metabolismo , Calcinose/patologia , Densitometria , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Fósforo/administração & dosagem , Ratos , Ratos Wistar , Doenças Vasculares/metabolismo , Doenças Vasculares/patologiaRESUMO
This paper reviews the pathogenesis of hyperphosphataemia and its role in the regulation of parathyroid hormone synthesis and parathyroid cell proliferation in chronic kidney disease. The association between hyperphosphaemia and vascular calcification, and the interventions that can be used to control plasma phosphate are also discussed.