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1.
Cardiovasc Diabetol ; 23(1): 259, 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39026232

RESUMO

BACKGROUND: The main goal of this study was to examine how diabetes, cardiovascular calcification characteristics and other risk factors affect mortality in end-stage renal disease (ESRD) patients in the early stages of hemodialysis. METHODS: A total of 285 ESRD patients in the early stages of hemodialysis were enrolled in this research, including 101 patients with diabetes. Survival time was monitored, and general data, biochemical results, cardiac ultrasound calcification of valvular tissue, and thoracic CT calcification of the coronary artery and thoracic aorta were recorded. Subgroup analysis and logistic regression were applied to investigate the association between diabetes and calcification. Cox regression analysis and survival between calcification, diabetes, and all-cause mortality. Additionally, the nomogram model was used to estimate the probability of survival for these individuals, and its performance was evaluated using risk stratification, receiver operating characteristic, decision, and calibration curves. RESULTS: Cardiovascular calcification was found in 81.2% of diabetic patients (82/101) and 33.7% of nondiabetic patients (62/184). Diabetic patients had lower phosphorus, calcium, calcium-phosphorus product, plasma PTH levels and lower albumin levels (p < 0.001). People with diabetes were more likely to have calcification than people without diabetes (OR 5.66, 95% CI 1.96-16.36; p < 0.001). The overall mortality rate was 14.7% (42/285). The risk of death was notably greater in patients with both diabetes and calcification (29.27%, 24/82). Diabetes and calcification, along with other factors, collectively predict the risk of death in these patients. The nomogram model demonstrated excellent discriminatory power (area under the curve (AUC) = 0.975 at 5 years), outstanding calibration at low to high-risk levels and provided the greatest net benefit across a wide range of clinical decision thresholds. CONCLUSIONS: In patients with ESRD during the early period of haemodialysis, diabetes significantly increases the risk of cardiovascular calcification, particularly multisite calcification, which is correlated with a higher mortality rate. The risk scores and nomograms developed in this study can assist clinicians in predicting the risk of death and providing individualised treatment plans to lower mortality rates in the early stages of hemodialysis.


Assuntos
Causas de Morte , Falência Renal Crônica , Nomogramas , Diálise Renal , Calcificação Vascular , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Estudos Retrospectivos , Calcificação Vascular/mortalidade , Calcificação Vascular/diagnóstico por imagem , Falência Renal Crônica/mortalidade , Falência Renal Crônica/terapia , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Diálise Renal/mortalidade , Medição de Risco , Fatores de Tempo , Idoso , Fatores de Risco , Resultado do Tratamento , Diabetes Mellitus/mortalidade , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/sangue , Adulto , Valor Preditivo dos Testes , Nefropatias Diabéticas/mortalidade , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/terapia , Nefropatias Diabéticas/sangue , Técnicas de Apoio para a Decisão , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/terapia
2.
Clin Exp Nephrol ; 28(6): 557-570, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38396314

RESUMO

BACKGROUND: The optimal dialysate calcium (Ca) concentration for patients undergoing hemodialysis remains inconclusive, particularly concerning cardiovascular protection. METHODS: We conducted a systematic review of 19 randomized controlled trials (RCTs) and a meta-analysis of eight RCTs to determine the optimal dialysate Ca concentration for cardiovascular protection. We compared outcomes in patients receiving maintenance hemodialysis treated with either a low-Ca dialysate (LCD) (1.125 or 1.25 mmol/L) or a high-Ca dialysate (HCD) (1.5 or 1.75 mmol/L). The outcomes were coronary artery calcification score (CACS), all-cause and cardiovascular death, cardiovascular function and structure, and serum biochemical parameters. RESULTS: There was no significant difference between LCD and HCD concerning CACS (standardized mean difference [SMD] = -0.16, 95% confidence interval [CI]: [-0.38, 0.07]), the risk of all-cause death, and cardiovascular death in patients treated with chronic maintenance hemodialysis. Conversely, LCD was associated with a significantly lower intima-media thickness (SMD = -0.49, 95% CI [-0.94, -0.05]) and pulse wave velocity than HCD (SMD = -0.86, 95% CI [-1.21, -0.51]). Furthermore, LCD significantly decreased serum Ca levels (mean difference [MD] = 0.52 mg/dL, 95% CI [0.19, 0.85]) and increased serum parathyroid hormone levels (MD = 44.8 pg/mL, 95% CI [16.2, 73.3]) compared with HCD. Notably, most RCTs examined in our analysis did not include patients receiving calcimimetics. CONCLUSIONS: Our meta-analysis showed no significant differences in cardiovascular calcification and death between LCD and HCD and revealed a paucity of RCTs on dialysate Ca concentrations, including those involving patients on calcimimetics, indicating the urgent need for further studies.


Assuntos
Cálcio , Doenças Cardiovasculares , Soluções para Hemodiálise , Diálise Renal , Humanos , Diálise Renal/efeitos adversos , Cálcio/sangue , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/prevenção & controle , Soluções para Hemodiálise/efeitos adversos , Soluções para Hemodiálise/química , Ensaios Clínicos Controlados Aleatórios como Assunto , Hormônio Paratireóideo/sangue , Pessoa de Meia-Idade , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/prevenção & controle , Resultado do Tratamento
3.
Int J Mol Sci ; 25(18)2024 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-39337709

RESUMO

The burden of chronic kidney disease (CKD) is increasing, posing a serious threat to human health. Cardiovascular calcification (CVC) is one of the most common manifestations of CKD, which significantly influences the morbidity and mortality of patients. The manifestation of CVC is an unusual accumulation of mineral substances containing calcium and phosphate. The main component is hydroxyapatite. Many cells are involved in this process, such as smooth muscle cells (SMCs) and endothelial cells. CVC is an osteogenic process initiated by complex mechanisms such as metabolic disorders of calcium and phosphorus minerals, inflammation, extracellular vesicles, autophagy, and micro-RNAs with a variety of signaling pathways like Notch, STAT, and JAK. Although drug therapy and dialysis technology continue to advance, the survival time and quality of life of CVC patients still face challenges. Therefore, early diagnosis and prevention of CKD-related CVC, reducing its mortality rate, and improving patients' quality of life have become urgent issues in the field of public health. In this review, we try to summarize the state-of-the-art understanding of the progression of CVC and hope that it will help in the prevention and treatment of CVC in CKD.


Assuntos
Insuficiência Renal Crônica , Calcificação Vascular , Humanos , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/patologia , Calcificação Vascular/etiologia , Calcificação Vascular/metabolismo , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Qualidade de Vida , Animais
4.
Ren Fail ; 45(2): 2271069, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37870850

RESUMO

BACKGROUND: Cardiovascular calcification includes cardiac valve calcification (CVC) and vascular calcification. We aimed to analyze risk factors for CVC, and construct a predictive model in maintenance peritoneal dialysis (MPD) patients. METHODS: We retrospectively analyzed MPD patients who began peritoneal dialysis between January 2014 and September 2021. Patients were randomly assigned to the derivation cohort and validation cohort in a 7:3 ratio. The patients in the derivation cohort were divided into the CVC group and non-CVC group. Logistic regression was used to analyze risk factors, then the rms package in R language was used to construct a nomogram model to predict CVC. RESULTS: 1,035 MPD patients were included, with the age of 50.0 ± 14.2 years and 632 males (61.1%). Their median follow-up time was 25 (12, 46) months. The new-onset CVC occurred in 128 patients (12.4%). In the derivation cohort, multivariate logistic regression indicated old age, female, high systolic blood pressure (SBP), high calcium-phosphorus product (Ca × P), high Charlson comorbidity index (CCI) and long dialysis time were independent risk factors for CVC (p < 0.05). We constructed a nomogram model for predicting CVC in the derivation cohort, with a C index of 0.845 (95% CI 0.803-0.886). This model was validated with a C index of 0.845 (95%CI 0.781-0.909) in the validation cohort. CONCLUSION: We constructed a nomogram model for CVC in MPD patients, using independent risk factors including age, sex, SBP, Ca × P, CCI and dialysis time. This model achieved high efficiency in CVC prediction.


Assuntos
Doenças das Valvas Cardíacas , Diálise Peritoneal , Calcificação Vascular , Masculino , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Estudos Retrospectivos , Doenças das Valvas Cardíacas/etiologia , Diálise Peritoneal/efeitos adversos , Calcificação Vascular/etiologia , Fatores de Risco , Valvas Cardíacas
5.
Kidney Int ; 101(3): 574-584, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34767831

RESUMO

Sortilin, an intracellular sorting receptor, has been identified as a cardiovascular risk factor in the general population. Patients with chronic kidney disease (CKD) are highly susceptible to develop cardiovascular complications such as calcification. However, specific CKD-induced posttranslational protein modifications of sortilin and their link to cardiovascular calcification remain unknown. To investigate this, we examined two independent CKD cohorts for carbamylation of circulating sortilin and detected increased carbamylated sortilin lysine residues in the extracellular domain of sortilin with kidney function decline using targeted mass spectrometry. Structure analysis predicted altered ligand binding by carbamylated sortilin, which was verified by binding studies using surface plasmon resonance measurement, showing an increased affinity of interleukin 6 to in vitro carbamylated sortilin. Further, carbamylated sortilin increased vascular calcification in vitro and ex vivo that was accelerated by interleukin 6. Imaging by mass spectrometry of human calcified arteries revealed in situ carbamylated sortilin. In patients with CKD, sortilin carbamylation was associated with coronary artery calcification, independent of age and kidney function. Moreover, patients with carbamylated sortilin displayed significantly faster progression of coronary artery calcification than patients without sortilin carbamylation. Thus, carbamylated sortilin may be a risk factor for cardiovascular calcification and may contribute to elevated cardiovascular complications in patients with CKD.


Assuntos
Insuficiência Renal Crônica , Calcificação Vascular , Proteínas Adaptadoras de Transporte Vesicular , Humanos , Carbamilação de Proteínas , Processamento de Proteína Pós-Traducional , Calcificação Vascular/etiologia
6.
Ter Arkh ; 94(6): 731-737, 2022 Aug 04.
Artigo em Russo | MEDLINE | ID: mdl-36286849

RESUMO

AIM: To clarify the mechanisms of the effect of osteoprotegerin (OPG) and sclerostin on vascular calcification and the state of the cardiovascular system in chronic kidney disease (CKD). MATERIALS AND METHODS: A total of 110 patients aged 18 to 65 years with CKD stages 35D were examined. OPG, sclerostin, intact parathyroid hormone, and serum troponin I were determined using the commercial "Enzyme-linked Immunosorbent Assay Kit for Sclerostin" from Cloude-Clone Corp. (USA) by enzyme-linked immunosorbent assay. RESULTS: An increase in sclerostin and OPG levels was revealed, which significantly correlated with a decrease in glomerular filtration rate, as well as an increase in left ventricle myocardial mass index and peak systolic blood flow in the aortic arch. CONCLUSION: Changes in the regulation of bone-mineral metabolism, in which the proteins inhibitors of bone metabolism, OPG and sclerostin, as well as the interactive interaction between the vascular and skeletal systems, play a decisive role in the development of lesions of the cardiovascular system caused by vascular calcification in CKD.


Assuntos
Insuficiência Renal Crônica , Calcificação Vascular , Humanos , Osteoprotegerina , Proteínas Morfogenéticas Ósseas , Troponina I , Marcadores Genéticos , Calcificação Vascular/diagnóstico , Calcificação Vascular/etiologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Hormônio Paratireóideo
7.
Ter Arkh ; 92(6): 37-45, 2020 Jul 09.
Artigo em Russo | MEDLINE | ID: mdl-33346491

RESUMO

Cardiovascular calcification (CVC) makes a significant contribution to the manifestation of cardiovascular complications in patients with chronic kidney disease. Early CVC markers are currently being actively studied to optimize cardio-renoprotective strategies. We performed a prospective comparative analysis of the following factors: FGF-23, a-Klotho, sclecrostin, phosphate, parathyroid hormone, the estimated glomerular filtration rate (eGFR), central systolic pressure as an independent determinant of CVC. MATERIALS AND METHODS: The study included 131 patients with chronic kidney disease 25D st. Serum levels of FGF-23, Klotho, and sclerostin were evaluated using the ELISA method. Vascular augmentation (stiffness) indices, central arterial pressure (using the SphygmoCor device), calcification of heart valves and the degree of aortic calcification (aortic radiography) were also investigated. The observation period was 2 years. RESULTS: According to the Spearman correlation analysis, the percent of calcification increase and the change in Klotho level are most related. According to ROC analysis, a decrease in serum levels of Klotho by 50 units or more is a significant predictor of an increase in aortic calcification of 50% or more with a sensitivity of 86% and a specificity of 77%. Using logistic regression analysis, it was found that a serum Klotho level 632 pg/L predicts an eGFR below a median level of 48 ml/min/1.73 m2 with a sensitivity of 85.5% and a specificity of 78.5%. Wherein OR 17.477 (CI 95% 8.04637.962; p0.001). CONCLUSION: The factor most associated with CVC is Klotho. Decreased serum level of Klotho is a predictor of aortic calcification. In addition, the initial serum level of Klotho is a predictor of eGFR after 2 years.


Assuntos
Calcinose , Insuficiência Renal Crônica , Biomarcadores , Calcinose/diagnóstico , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos , Taxa de Filtração Glomerular , Glucuronidase , Humanos , Estudos Prospectivos , Insuficiência Renal Crônica/diagnóstico
8.
J Cell Physiol ; 234(4): 4997-5010, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30341898

RESUMO

Vascular calcification is highly prevalent in patients with type 2 diabetes mellitus (T2DM), one of the most common chronic diseases with high morbidity and mortality. In recent years, microRNAs have been widely reported as potential biomarkers for the diagnosis and treatment of T2DM. We hypothesized that miR-128-3p is associated with cardiovascular calcification and insulin resistance (IR) in rats with T2DM by targeting ISL1 via the Wnt pathway. Microarray analysis was adopted to identify differentially expressed genes related to T2DM. T2DM models were induced in rats. Blood samples from normal and T2DM rats were used to detect islet ß-cell function, islet sensitivity, and calcium content. Next, islet tissues were obtained to identify the expression of miR-128-3p, ISL1, and the Wnt signaling pathway- and apoptosis-related genes. Finally, apoptosis of islet ß-cells was determined by flow cytometry. Through microarray analysis of GSE27382 and GSE23343, ISL1 was found to be downregulated in T2DM. In blood samples from T2DM rats, basic biochemical indicators, IR, and calcium content were increased, and islet sensitivity and islet ß-cell function were decreased. Furthermore, upregulation of miR-128-3p and ISL1 gene silencing promoted the expression of Wnt-1, ß-catenin, GSK-3ß, and Bax and the phosphorylation of ß-catenin and GSK-3ß, inhibited c-fos, PDX-1, and Bcl-2 expression, and enhanced cell apoptosis. The key findings of our study demonstrate that miR-128-3p aggravates cardiovascular calcification and IR in T2DM rats by downregulating ISL1 through the activation of the Wnt pathway. Thus, miR-128-3p may serve as a potential target for the treatment of T2DM.


Assuntos
Vasos Coronários/patologia , Diabetes Mellitus Tipo 2/genética , Resistência à Insulina/genética , Proteínas com Homeodomínio LIM/genética , MicroRNAs/genética , Fatores de Transcrição/genética , Calcificação Vascular/genética , Animais , Apoptose/genética , Proliferação de Células/genética , Ratos , Calcificação Vascular/patologia , Via de Sinalização Wnt/genética
9.
Molecules ; 24(24)2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31817119

RESUMO

Phytate (myo-inositol hexaphosphate, InsP6) is an important component of seeds, legumes, nuts, and whole cereals. Although this molecule was discovered in 1855, its biological effects as an antinutrient was first described in 1940. The antinutrient effect of phytate results because it can decrease the bioavailability of important minerals under certain circumstances. However, during the past 30 years, researchers have identified many important health benefits of phytate. Thus, 150 years have elapsed since the discovery of phytate to the first descriptions of its beneficial effects. This long delay may be due to the difficulty in determining phytate in biological media, and because phytate dephosphorylation generates many derivatives (InsPs) that also have important biological functions. This paper describes the role of InsP6 in blocking the development of pathological calcifications. Thus, in vitro studies have shown that InsP6 and its hydrolysates (InsPs), as well as pyrophosphate, bisphosphonates, and other polyphosphates, have high capacity to inhibit calcium salt crystallization. Oral or topical administration of phytate in vivo significantly decreases the development of pathological calcifications, although the details of the underlying mechanism are uncertain. Moreover, oral or topical administration of InsP6 also leads to increased urinary excretion of mixtures of different InsPs; in the absence of InsP6 administration, only InsP2 occurs at detectable levels in urine.


Assuntos
Calcinose/tratamento farmacológico , Calcinose/patologia , Ácido Fítico/uso terapêutico , Animais , Cálcio , Cristalização , Humanos , Fosfatos de Inositol/farmacologia , Ácido Fítico/administração & dosagem
10.
Ter Arkh ; 91(6): 47-56, 2019 Jun 15.
Artigo em Russo | MEDLINE | ID: mdl-36471595

RESUMO

Protein restriction diet (PRD) with ketoanalagues of essential amino acids (KA) combination can improve of chronic kidney disease (CKD) course while, the precise mechanisms of PRD + KAA action in CKD are not known yet. We have conducted a prospective, randomized, controlled study of PRD and KAA patient's group in compare with PRD without KAA group in regarding to serum Klotho and FGF-23 levels in patients with CKD. MATERIALS AND METHODS: The study included 79 CKD 3b-4 stages patients, non - diabetic etiology, used PRD (0.6 g/kg/day). The patients were randomized in two groups: 42 patients, received PRD + KAA (Group 1) and 37 patients continued the PRD without KAA (Group 2). Serum FGF-23 (Human FGF-23 ELISA kit with antibodies to native FGF-23 molecule, Merk Millipore MILLENZFGF-23-32K), Klotho (Human soluble Klotho with antiKlotho monoclonal antibodies, IBL-Takara 27998-96Well) levels, as well as instrumental examination: bioimpedance analysis [assess of muscle body mass (MBM), fat body mass (FBM), body mass index (BMI) and others]; sphygmography [assess of augmentation (stiffness) indices (AI), central (aortal) blood pressure (CBP) by «Sphygmacor¼ device]; as well as echocardiography [assess of cardiac (valvular) calcification score (CCS) and left ventricular myocardium mass index (LVMMI)], were studded in addition to conventional examination. RESULTS AND DISCUSSION: To the end of 14th month of the study the PRD group reached a body mass index (BMI) decrease (p=0.046), including MBM in men (p=0.027) and woman (p=0.044). In addition, higher FGF-23 (p=0.029), and lower Klotho (p=0.037) serum levels were revealed in the PRD group compared to the PRD+KAA group as well as the increase in AI (p=0.034), CCS (p=0.048), and LVMMI (p=0.023). CONCLUSION: Use of PRD + KAA provides adequate nutrition status and more efficient correction of FGF-23 and Klotho imbalance in CKD progression that may contribute to alleviation of both cardiovascular calcification and cardiac remodeling in CKD. Importantly, a prolonged PRD use without supplementation of KAA may lead to malnutrition signs.

11.
Br J Clin Pharmacol ; 84(12): 2867-2876, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30280390

RESUMO

AIMS: SNF472 is a calcification inhibitor being developed for the treatment of cardiovascular calcification in haemodialysis (HD) and in calciphylaxis patients. This study investigated the safety, tolerability and pharmacokinetics (PK) of intravenous (IV) SNF472 in healthy volunteers (HV) and HD patients. METHODS: This is a first-time-in-human, double-blind, randomized, placebo-controlled Phase I study to assess the safety, tolerability and PK of SNF472 after ascending single IV doses in HV and a single IV dose in HD patients. A pharmacodynamic analysis was performed to assess the capability of IV SNF472 to inhibit hydroxyapatite formation. RESULTS: Twenty HV and eight HD patients were enrolled. The starting dose in HV was 0.5 mg kg-1 and the dose ascended to 12.5 mg kg-1 . The dose selected for HD patients was 9 mg kg-1 . Safety analyses support the safety and tolerability of IV SNF472 in HD patients and HV. Most treatment-emergent adverse events were mild in intensity. No clinically significant effects were observed on vital signs or laboratory tests. PK results were similar in HD patients and HV and indicate a lack of significant dialysability. Pharmacodynamic analyses demonstrated that SNF472 administration reduced hydroxyapatite crystallization potential in HD patients who received IV SNF472 9 mg kg-1 by 80.0 ± 2.4% (mean ± standard error of the mean, 95% CI, 75.3-84.8) compared to placebo (8.7 ± 21.0%, P < 0.001, 95% CI, -32.4 to 49.7). CONCLUSION: The results from this study showed acceptable safety and tolerability, and lack of significant dialysability of IV SNF472. It is a potential novel treatment for cardiovascular calcification in end-stage renal disease and calciphylaxis warranting further human studies.


Assuntos
Falência Renal Crônica/terapia , Ácido Fítico/efeitos adversos , Diálise Renal/efeitos adversos , Calcificação Vascular/prevenção & controle , Adulto , Idoso , Cálcio/metabolismo , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Ácido Fítico/farmacocinética , Ácido Fítico/farmacologia
12.
Arterioscler Thromb Vasc Biol ; 37(5): 1005-1011, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28279970

RESUMO

OBJECTIVE: Genome-wide association studies and preclinical studies demonstrated a role of sortilin in lipid metabolism, inflammation, and vascular calcification-all cardiovascular risk factors. We evaluated the association of serum sortilin levels with the risk of major adverse cerebrovascular and cardiovascular events (MACCE) and the severity of abdominal aortic calcification (AAC). APPROACH AND RESULTS: A cohort of community-dwelling men aged ≥50 years (n=830) was assessed. At baseline, sortilin levels were measured by ELISA, and AAC was assessed on lateral spine scans obtained by dual-energy X-ray absorptiometry. Men aged ≥60 years (n=745) were followed up prospectively for the incidence of MACCE. During the median follow-up of 7.9 years, 76 MACCE occurred. The unadjusted incidence of MACCE across increasing sortilin quartiles was 8.0, 7.4, 19.8, and 20.3 per 1000 person-years. In multivariate-adjusted analysis, sortilin associated with increased risk of MACCE (hazard ratio, 1.70 per SD; 95% confidence interval, 1.30-2.20; P<0.001). The third and fourth quartiles associated with 3.42-fold (95% confidence interval, 1.61-7.25; P<0.005) and 3.82-fold (95% confidence interval, 1.77-8.26; P<0.001) higher risk of MACCE compared with the first quartile. High sortilin also predicted MACCE independent of traditional Framingham risk factors. Higher sortilin associated with higher odds of severe AAC (score>5) after adjustment for confounders (odds ratio, 1.43 per SD; 95% confidence interval, 1.10-1.85; P<0.01). The highest sortilin quartile associated with 2-fold higher odds of severe AAC (versus 3 lower quartiles combined). After adjustment for low-density lipoprotein cholesterol, the odds of severe AAC remained significant. CONCLUSIONS: In older men, higher serum sortilin levels associated with higher MACCE risk and severe AAC independently of relevant confounders, including C-reactive protein and low-density lipoprotein cholesterol. This finding, however, needs to be validated in other cohorts.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/sangue , Aorta Abdominal , Doenças da Aorta/sangue , Transtornos Cerebrovasculares/sangue , Cardiopatias/sangue , Calcificação Vascular/sangue , Absorciometria de Fóton , Idoso , Idoso de 80 Anos ou mais , Aorta Abdominal/diagnóstico por imagem , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/epidemiologia , Biomarcadores/sangue , Proteína C-Reativa/análise , Transtornos Cerebrovasculares/diagnóstico , Transtornos Cerebrovasculares/epidemiologia , Distribuição de Qui-Quadrado , LDL-Colesterol/sangue , Ensaio de Imunoadsorção Enzimática , França/epidemiologia , Cardiopatias/diagnóstico , Cardiopatias/epidemiologia , Humanos , Incidência , Estimativa de Kaplan-Meier , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Fatores de Tempo , Regulação para Cima , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/epidemiologia
13.
Clin Exp Nephrol ; 22(6): 1351-1359, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29948444

RESUMO

BACKGROUND: A low protein diet (LPD) with essential amino acid ketoanalogue supplementation (KA) may contribute in improving of chronic kidney disease (CKD), while the exact mechanisms of KA's effect are not established yet. We have conducted a prospective, randomized, controlled comparative study of LPD + KA and LPD alone in relation to serum Klotho, FGF-23 levels in CKD patients. METHODS: 79 non-diabetic CKD 3b-4 stage patients, compliant with LPD diet (0.6 g/kg of body weight/day), had been selected. The patients were randomized into two groups. The first group (42 patients) received LPD + КA. The second group (37 patients) continued the LРD alone. In addition to routine tests, serum Klotho, FGF-23 levels, as well as bioimpedance analysis, sphygmography (stiffness (augmentation) indices (AI), central (aortal) blood pressure) with a «SphygmaCor¼ device; echocardiography (valvular calcification score (VCS) and LVMMI), were performed. RESULTS: There were body mass indices' decrease (p = 0.046), including muscle body mass in men (p = 0.027) and woman (p = 0.044) in the LPD group to the end of study (14th month). In addition, lower FGF-23 (p = 0.029), and higher sKlotho (p = 0.037) were detected in the LPD + KA group compared to the LPD one. The increase in AI (p = 0.034), VCS (p = 0.048), and LVMMI (p = 0.023) was detected more often in the LPD group at the end of study. CONCLUSION: LPD + KA provides support for nutrition status and contributes to more efficient correction of FGF-23 and Klotho abnormalities that may result in cardiovascular calcification and cardiac remodeling decreasing in CKD. At the same time, a prolonged LPD alone may lead to malnutrition.


Assuntos
Aminoácidos Essenciais/administração & dosagem , Dieta com Restrição de Proteínas , Fatores de Crescimento de Fibroblastos/sangue , Glucuronidase/sangue , Insuficiência Renal Crônica/complicações , Dieta com Restrição de Proteínas/efeitos adversos , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Proteínas Klotho , Masculino , Desnutrição/etiologia , Projetos Piloto , Estudos Prospectivos , Insuficiência Renal Crônica/sangue , Calcificação Vascular/etiologia
14.
Semin Cell Dev Biol ; 46: 68-77, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26358815

RESUMO

The presence of cardiovascular calcification significantly predicts patients' morbidity and mortality. Calcific mineral deposition within the soft cardiovascular tissues disrupts the normal biomechanical function of these tissues, leading to complications such as heart failure, myocardial infarction, and stroke. The realization that calcification results from active cellular processes offers hope that therapeutic intervention may prevent or reverse the disease. To this point, however, no clinically viable therapies have emerged. This may be due to the lack of certainty that remains in the mechanisms by which mineral is deposited in cardiovascular tissues. Gaining new insight into this process requires a multidisciplinary approach. The pathological changes in cell phenotype that lead to the physicochemical deposition of mineral and the resultant effects on tissue biomechanics must all be considered when designing strategies to treat cardiovascular calcification. In this review, we overview the current cardiovascular calcification paradigm and discuss emerging techniques that are providing new insight into the mechanisms of ectopic calcification.


Assuntos
Calcinose/metabolismo , Doenças Cardiovasculares/metabolismo , Doença da Artéria Coronariana/metabolismo , Placa Aterosclerótica/metabolismo , Animais , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Valva Aórtica/fisiopatologia , Doenças Cardiovasculares/patologia , Colágeno/metabolismo , Doença da Artéria Coronariana/patologia , Humanos , Inflamação/metabolismo , Modelos Biológicos , Placa Aterosclerótica/patologia
15.
Cell Physiol Biochem ; 42(2): 427-440, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28571029

RESUMO

Calcific disease of the cardiovascular system, including atherosclerotic calcification, medial calcification in diabetes and calcific aortic valve disease, is an important risk factor for many adverse cardiovascular events such as ischemic cardiac events and subsequent mortality. Although cardiovascular calcification has long been considered to be a passive degenerative occurrence, it is now recognized as an active and highly regulated process that involves osteochondrogenic differentiation, apoptosis and extracellular vesicle release. Nonetheless, despite numerous studies on the pathogenesis of cardiovascular calcification, the underlying mechanisms remain poorly understood. High mobility group box 1 (HMGB1), a nuclear protein bound to chromatin in almost all eukaryotic cells, acts as a damage-associated molecular pattern (DAMP) when released into the extracellular space upon cell activation, injury or death. Moreover, HMGB1 also functions as a bone-active cytokine participating in bone remodeling and ectopic calcification pathogenesis. However, studies on the roles of HMGB1 in promoting cardiovascular calcification are limited to date, and the mechanisms involved are still unclear. In this review, we summarize recent studies investigating the mechanism of cardiovascular calcification and discuss multiple roles of HMGB1 in its development.


Assuntos
Estenose da Valva Aórtica/genética , Valva Aórtica/patologia , Calcinose/genética , Complicações do Diabetes/genética , Proteína HMGB1/genética , Esclerose Calcificante da Média de Monckeberg/genética , Animais , Valva Aórtica/metabolismo , Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/fisiopatologia , Remodelação Óssea/genética , Calcinose/metabolismo , Calcinose/fisiopatologia , Diferenciação Celular/genética , Cromatina/genética , Complicações do Diabetes/metabolismo , Complicações do Diabetes/fisiopatologia , Proteína HMGB1/metabolismo , Humanos , Esclerose Calcificante da Média de Monckeberg/metabolismo , Esclerose Calcificante da Média de Monckeberg/fisiopatologia , Ligação Proteica , Transdução de Sinais
16.
Pediatr Nephrol ; 31(2): 195-206, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25735207

RESUMO

Canonical Wnt signaling activity contributes to physiological and adaptive bone mineralization and is an essential player in bone remodeling. Sclerostin is a prototypic soluble canonical Wnt signaling pathway inhibitor that is produced in osteocytes and blocks osteoblast differentiation and function. Therefore, sclerostin is a potent inhibitor of bone formation and mineralization. Accordingly, rodent sclerostin-deficiency models exhibit a strong bone phenotype. Moreover, blocking sclerostin represents a promising treatment perspective against osteoporosis. Beyond the bone field novel data definitely associate Wnt signaling in general and sclerostin in particular with ectopic extraosseous mineralization processes, as is evident in cardiovascular calcification or calciphylaxis. Uremia is characterized by parallel occurrence of disordered bone mineralization and accelerated cardiovascular calcification (chronic kidney disease - mineral and bone disorder, CKD-MBD), linking skeletal and cardiovascular disease-the so-called bone-vascular calcification paradox. In consequence, sclerostin may qualify as an emerging player in CKD-MBD. We present a stepwise review approach regarding the rapidly evolving field sclerostin participation in CKD-MBD. Starting from data originating in the classical bone field we look separately at three major areas of CKD-MBD: disturbed mineral metabolism, renal osteodystrophy, and uremic cardiovascular disease. Our review is intended to help the nephrologist revise the potential importance of sclerostin in CKD by focusing on how sclerostin research is gradually evolving from the classical osteoporosis niche into the area of CKD-MBD. In particular, we integrate the limited amount of available data in the context of pediatric nephrology.


Assuntos
Doenças Ósseas/fisiopatologia , Proteínas Morfogenéticas Ósseas/metabolismo , Osso e Ossos/metabolismo , Doenças Cardiovasculares/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Densidade Óssea/fisiologia , Doenças Ósseas/metabolismo , Remodelação Óssea , Marcadores Genéticos , Humanos , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais
17.
Br J Clin Pharmacol ; 85(4): 796-806, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30632182

RESUMO

AIMS: SNF472 is a calcification inhibitor that is being studied as a novel treatment for calciphylaxis and cardiovascular calcification (CVC). A first study showed acceptable safety and tolerability in a single ascending dose administration in healthy volunteers and a single dose administration in haemodialysis (HD) patients. This study aimed to assess the safety, tolerability, and pharmacokinetics/pharmacodynamics relationship of intravenous SNF472 in HD patients in a multiple ascending dose administration trial with 5 doses tested for 1 week (3 administrations) and 1 dose tested for 4 weeks (12 administrations). METHODS: This double blind, randomized, placebo-controlled Phase 1b study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of SNF472 after repeated administrations to HD patients for up to 28 days. A pharmacodynamic assessment was performed to evaluate the potential for SNF472 to inhibit hydroxyapatite (HAP) formation. Patients were grouped into 2 cohorts, receiving multiple ascending doses for 1 week (1 to 20 mg/kg, Cohort 1) and 1 dose of 10 mg/kg for 4 weeks (Cohort 2) of intravenous SNF472. RESULTS: Physical status, body weight, cardiorespiratory function, body temperature and laboratory parameters were in the normal range. No clinically relevant effects on heart rate or blood pressure were observed. No abnormal electrocardiogram or QTcB period were reported. The peak plasma concentration (7.6, 16.1, 46.0 and 66.9 µg/mL for 3, 5, 12.5 and 20 mg/kg, respectively) was observed at the end of the 4-hour infusion and thereafter concentrations declined rapidly with half-life between 32 and 65 min. SNF472 at 10 mg/kg inhibited dose dependently HAP crystallization in plasma samples after 28 days of treatment (78% inhibition, P < .001). CONCLUSIONS: SNF472 is safe and well tolerated in HD patients after 2 schemes: multiple ascending doses for 1 week and after repeated dosing of 10 mg/kg for 4 weeks. In both schemes, SNF472 inhibits the induction of HAP crystallization. These results provide support for the use of SNF472 as a novel treatment for CVC in end-stage renal disease.


Assuntos
Calcinose/prevenção & controle , Cardiomiopatias/prevenção & controle , Falência Renal Crônica/terapia , Ácido Fítico/administração & dosagem , Diálise Renal/efeitos adversos , Idoso , Calcinose/sangue , Calcinose/etiologia , Cardiomiopatias/sangue , Cardiomiopatias/etiologia , Estudos de Coortes , Relação Dose-Resposta a Droga , Esquema de Medicação , Durapatita/sangue , Feminino , Humanos , Falência Renal Crônica/sangue , Masculino , Pessoa de Meia-Idade , Ácido Fítico/efeitos adversos , Ácido Fítico/farmacocinética , Placebos/administração & dosagem , Placebos/efeitos adversos
18.
Ren Fail ; 36(8): 1244-52, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25019348

RESUMO

BACKGROUND: Vascular calcification significantly increases the rates of cardiovascular mortality in hemodialysis (HD) patients. Abnormalities in mineral metabolism may play a role in the pathogenesis of arterial calcification. Whether patients treated with non-calcium-based phosphate binders had reduced aortic vascular calcification compared to those treated with calcium-based phosphate binders is still unclear. METHODS: We searched multiple databases for studies published through August 2013 that evaluated the effects of non-calcium-based phosphate binders (NCBP) versus calcium-based phosphate binders (CBP) on cardiovascular calcification and bone remodeling among dialysis patients. We summarized test performance characteristics with the use of forest plots, fixed and random effects models, and Egger regression test. RESULTS: Eighteen eligible randomized controlled trials totaling 3676 patients were included. Meta-analysis results showed NCBP could significantly attenuate the progression of coronary artery calcification than CBP (WMD: -144.62, 95% CI: -285.62 to -3.63). The serum calcium levels significant lower in NCPB group than in CPB groups (WMD: -0.26, 95% CI: -0.37 to -0.14), but the serum iPTH levels were significantly higher in NCPB groups (WMD: 57.1, 95% CI: 13.42 to 100.78). The osteoid volume and osteoblast numbers were significant higher in NCPB group than in CPB group (WMD: 1.75, 95% CI: 0.78 to 2.73 for osteoid volume; WMD: 4.49, 95% CI: 1.83 to 7.15 for osteoblast numbers). The Egger regression test also showed no potential publication bias (p = 0.725). CONCLUSIONS: Based on available data, NCBPs have equally effective with CBPs for serum phosphate control. But there was significantly lower incidence of coronary artery calcification and a significant higher bone formatting rate in NCBP groups than in CBP groups. So we recommend NCBPs as phosphate binders for HD patients.


Assuntos
Remodelação Óssea/efeitos dos fármacos , Fosfatos de Cálcio/farmacologia , Fosfatos de Cálcio/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Quelantes/uso terapêutico , Lantânio/farmacologia , Lantânio/uso terapêutico , Poliaminas/farmacologia , Poliaminas/uso terapêutico , Diálise Renal , Calcificação Vascular/prevenção & controle , Biomarcadores/sangue , Cálcio , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sevelamer , Calcificação Vascular/sangue
19.
Antioxidants (Basel) ; 13(5)2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38790628

RESUMO

Lysyl oxidase (LOX)-mediated extracellular matrix crosslinking modulates calcification in atherosclerosis and aortic valve disease; however, this enzyme also induces oxidative stress. We addressed the contribution of LOX-dependent oxidative stress to cardiovascular calcification. LOX is upregulated in human-calcified atherosclerotic lesions and atheromas from atherosclerosis-challenged LOX transgenic mice (TgLOXVSMC) and colocalized with a marker of oxidative stress (8-oxo-deoxyguanosine) in vascular smooth muscle cells (VSMCs). Similarly, in calcific aortic valves, high LOX expression was detected in valvular interstitial cells (VICs) positive for 8-oxo-deoxyguanosine, while LOX and LOXL2 expression correlated with osteogenic markers (SPP1 and RUNX2) and NOX2. In human VICs, mito-TEMPO and TEMPOL attenuated the increase in superoxide anion levels and the mineralization induced by osteogenic media (OM). Likewise, in OM-exposed VICs, ß-aminopropionitrile (a LOX inhibitor) ameliorated both oxidative stress and calcification. Gain- and loss-of-function approaches in VICs demonstrated that while LOX silencing negatively modulates oxidative stress and calcification induced by OM, lentiviral LOX overexpression exacerbated oxidative stress and VIC calcification, effects that were prevented by mito-TEMPO, TEMPOL, and ß-aminopropionitrile. Our data indicate that LOX-induced oxidative stress participates in the procalcifying effects of LOX activity in ectopic cardiovascular calcification, and highlight the multifaceted role played by LOX isoenzymes in cardiovascular diseases.

20.
Transl Res ; 264: 1-14, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37690706

RESUMO

Cardiovascular calcification is a significant public health issue whose pathophysiology is not fully understood. NOR-1 regulates critical processes in cardiovascular remodeling, but its contribution to ectopic calcification is unknown. NOR-1 was overexpressed in human calcific aortic valves and calcified atherosclerotic lesions colocalizing with RUNX2, a factor essential for osteochondrogenic differentiation and calcification. NOR-1 and osteogenic markers were upregulated in calcifying human valvular interstitial cells (VICs) and human vascular smooth muscle cells (VSMCs). Gain- and loss-of-function approaches demonstrated that NOR-1 negatively modulates the expression of osteogenic genes relevant for the osteogenic transdifferentiation (RUNX2, IL-6, BMP2, and ALPL) and calcification of VICs. VSMCs from transgenic mice overexpressing NOR-1 in these cells (TgNOR-1VSMC) expressed lower basal levels of osteogenic genes (IL-6, BMP2, ALPL, OPN) than cells from WT littermates, and their upregulation by a high-phosphate osteogenic medium (OM) was completely prevented by NOR-1 transgenesis. Consistently, this was associated with a dramatic reduction in the calcification of both transgenic VSMCs and aortic rings from TgNOR-1VSMC mice exposed to OM. Atherosclerosis and calcification were induce in mice by the administration of AAV-PCSK9D374Y and a high-fat/high-cholesterol diet. Challenged-TgNOR-1VSMC mice exhibited decreased vascular expression of osteogenic markers, and both less atherosclerotic burden (assessed in whole aorta and lesion size in aortic arch and brachiocephalic artery) and less vascular calcification (assessed either by near-infrared fluorescence imaging or histological analysis) than WT mice. Our data indicate that NOR-1 negatively modulates the expression of genes critically involved in the osteogenic differentiation of VICs and VSMCs, thereby restraining ectopic cardiovascular calcification.


Assuntos
Estenose da Valva Aórtica , Calcificação Vascular , Animais , Humanos , Camundongos , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Interleucina-6/genética , Músculo Liso Vascular/fisiologia , Osteogênese/genética , Pró-Proteína Convertase 9/genética , Regulação para Cima , Calcificação Vascular/genética , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia
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