RESUMEN
The protein α-Klotho acts as transmembrane co-receptor for fibroblast growth factor 23 (FGF23) and is a key regulator of phosphate homeostasis. However, α-Klotho also exists in a circulating form, with pleiotropic, but incompletely understood functions and regulation. Therefore, we undertook a genome-wide association study (GWAS) meta-analysis followed by Mendelian randomization (MR) of circulating α-Klotho levels. Plasma α-Klotho levels were measured by enzyme-linked immunosorbent assay (ELISA) in the Ludwigshafen Risk and Cardiovascular Health and Avon Longitudinal Study of Parents and Children (mothers) cohorts, followed by a GWAS meta-analysis in 4376 individuals across the two cohorts. Six signals at five loci were associated with circulating α-Klotho levels at genome-wide significance (P < 5 × 10-8), namely ABO, KL, FGFR1, and two post-translational modification genes, B4GALNT3 and CHST9. Together, these loci explained >9% of the variation in circulating α-Klotho levels. MR analyses revealed no causal relationships between α-Klotho and renal function, FGF23-dependent factors such as vitamin D and phosphate levels, or bone mineral density. The screening for genetic correlations with other phenotypes followed by targeted MR suggested causal effects of liability of Crohn's disease risk [Inverse variance weighted (IVW) beta = 0.059 (95% confidence interval 0.026, 0.093)] and low-density lipoprotein cholesterol levels [-0.198 (-0.332, -0.063)] on α-Klotho. Our GWAS findings suggest that two enzymes involved in post-translational modification, B4GALNT3 and CHST9, contribute to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability. Subsequent evidence from MR analyses on α-Klotho levels suggest regulation by mechanisms besides phosphate-homeostasis and raise the possibility of cross-talk with FGF19- and FGF21-dependent pathways, respectively. Significance statement: α-Klotho as a transmembrane protein is well investigated along the endocrine FGF23-α-Klotho pathway. However, the role of the circulating form of α-Klotho, which is generated by cleavage of transmembrane α-Klotho, remains incompletely understood. Genetic analyses might help to elucidate novel regulatory and functional mechanisms. The identification of genetic factors related to circulating α-Klotho further enables MR to examine causal relationships with other factors. The findings from the first GWAS meta-analysis of circulating α-Klotho levels identified six genome-wide significant signals across five genes. Given the function of two of the genes identified, B4GALNT3 and CHST9, it is tempting to speculate that post-translational modification significantly contributes to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability.
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Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Factores de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/metabolismo , Glucuronidasa/metabolismo , Proteínas Klotho , Estudios Longitudinales , Fosfatos/metabolismoRESUMEN
Patients with combined cardiac and renal diseases are particularly challenging in the routine clinical practice due to the substantial risk profile for increased morbidity and mortality. As cardiorenal patients have often been underrepresented in randomized, controlled interventional trials, guideline recommendations regarding the choice of treatment are often weaker for these individuals than for cardiovascular patients without chronic kidney disease. Furthermore, there are limitations in the approval of certain medications depending on the kidney function. This review addresses some considerations in crucial treatment areas for patients with cardiovascular diseases, whose treatment is significantly influenced by concomitant chronic kidney disease.
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Fibrilación Atrial , Enfermedades Cardiovasculares , Insuficiencia Renal Crónica , Humanos , Fibrilación Atrial/tratamiento farmacológico , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/terapia , Enfermedades Cardiovasculares/terapia , Enfermedades Cardiovasculares/complicacionesRESUMEN
Ischaemic heart disease, sudden cardiac death and arrhythmias, heart failure, stroke and peripheral arterial disease make up >50% of the causes of death in advanced chronic kidney disease (CKD). Calcification of the vascular tree and heart valves is partially related to these complications and has received growing attention in the literature. However, the main focus of research has been on the pathophysiology and consequences of vascular calcification, with less attention being paid to valvular calcification (VC) and its impact on the survival of CKD patients. Although VC has long been seen as an age-related degenerative disorder with minimal functional impact, several studies proved that it carries an increased risk of death and clinical consequences different from those of vascular calcification. In dialysis patients, the annual incidence of aortic valve calcification is nearly 3.3% and the reported prevalence of aortic and mitral VC varies between 25% and 59%. Moreover, calcification of both valves occurs 10-20 years earlier in CKD patients compared with the general population. Therefore, the purpose of this review is to summarize the current knowledge on the pathophysiology and relevance of VC in CKD patients, and to highlight specific clinical consequences and potential therapeutic implications.
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Estenosis de la Válvula Aórtica/complicaciones , Válvula Aórtica/patología , Calcinosis/complicaciones , Enfermedades de las Válvulas Cardíacas/etiología , Insuficiencia Renal Crónica/fisiopatología , Calcificación Vascular/complicaciones , Enfermedades de las Válvulas Cardíacas/patología , Humanos , PronósticoRESUMEN
BACKGROUND: Chronic heart failure is one of the most common medical conditions, affecting more than 23 million people worldwide. Despite established guideline-based, multidrug pharmacotherapy, chronic heart failure is still the cause of frequent hospitalisation, and about 50% die within five years of diagnosis. OBJECTIVES: To assess the effectiveness and safety of ivabradine in individuals with chronic heart failure. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and CPCI-S Web of Science in March 2020. We also searched ClinicalTrials.gov and the WHO ICTRP. We checked reference lists of included studies. We did not apply any time or language restrictions. SELECTION CRITERIA: We included randomised controlled trials in which adult participants diagnosed with chronic heart failure were randomly assigned to receive either ivabradine or placebo/usual care/no treatment. We distinguished between type of heart failure (heart failure with a reduced ejection fraction or heart failure with a preserved ejection fraction) as well as between duration of ivabradine treatment (short term (< 6 months) or long term (≥ 6 months)). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, extracted data, and checked data for accuracy. We calculated risk ratios (RR) using a random-effects model. We completed a comprehensive 'Risk of bias' assessment for all studies. We contacted authors for missing data. Our primary endpoints were: mortality from cardiovascular causes; quality of life; time to first hospitalisation for heart failure during follow-up; and number of days spent in hospital due to heart failure during follow-up. Our secondary endpoints were: rate of serious adverse events; exercise capacity; and economic costs (narrative report). We assessed the certainty of the evidence applying the GRADE methodology. MAIN RESULTS: We included 19 studies (76 reports) involving a total of 19,628 participants (mean age 60.76 years, 69% male). However, few studies contributed data to meta-analyses due to inconsistency in trial design (type of heart failure) and outcome reporting and measurement. In general, risk of bias varied from low to high across the included studies, with insufficient detail provided to inform judgement in several cases. We were able to perform two meta-analyses focusing on participants with heart failure with a reduced ejection fraction (HFrEF) and long-term ivabradine treatment. There was evidence of no difference between ivabradine and placebo/usual care/no treatment for mortality from cardiovascular causes (RR 0.99, 95% confidence interval (CI) 0.88 to 1.11; 3 studies; 17,676 participants; I2 = 33%; moderate-certainty evidence). Furthermore, we found evidence of no difference in rate of serious adverse events amongst HFrEF participants randomised to receive long-term ivabradine compared with those randomised to placebo, usual care, or no treatment (RR 0.96, 95% CI 0.92 to 1.00; 2 studies; 17,399 participants; I2 = 12%; moderate-certainty evidence). We were not able to perform meta-analysis for all other outcomes, and have low confidence in the findings based on the individual studies. AUTHORS' CONCLUSIONS: We found evidence of no difference in cardiovascular mortality and serious adverse events between long-term treatment with ivabradine and placebo/usual care/no treatment in participants with heart failure with HFrEF. Nevertheless, due to indirectness (male predominance), the certainty of the available evidence is rated as moderate.
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Fármacos Cardiovasculares/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Ivabradina/uso terapéutico , Sesgo , Fármacos Cardiovasculares/efectos adversos , Fármacos Cardiovasculares/economía , Enfermedades Cardiovasculares/mortalidad , Quimioterapia Adyuvante , Enfermedad Crónica , Tolerancia al Ejercicio/efectos de los fármacos , Femenino , Insuficiencia Cardíaca/mortalidad , Humanos , Ivabradina/efectos adversos , Ivabradina/economía , Masculino , Persona de Mediana Edad , Placebos/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Volumen SistólicoRESUMEN
Importance: Intravenous iron enables rapid correction of iron-deficiency anemia, but certain formulations induce fibroblast growth factor 23-mediated hypophosphatemia. Objective: To compare risks of hypophosphatemia and effects on biomarkers of mineral and bone homeostasis of intravenous iron isomaltoside (now known as ferric derisomaltose) vs ferric carboxymaltose. Design, Setting, and Participants: Between October 2017 and June 2018, 245 patients aged 18 years and older with iron-deficiency anemia (hemoglobin level ≤11 g/dL; serum ferritin level ≤100 ng/mL) and intolerance or unresponsiveness to 1 month or more of oral iron were recruited from 30 outpatient clinic sites in the United States into 2 identically designed, open-label, randomized clinical trials. Patients with reduced kidney function were excluded. Serum phosphate and 12 additional biomarkers of mineral and bone homeostasis were measured on days 0, 1, 7, 8, 14, 21, and 35. The date of final follow-up was June 19, 2018, for trial A and May 29, 2018, for trial B. Interventions: Intravenous administration of iron isomaltoside, 1000 mg, on day 0 or ferric carboxymaltose, 750 mg, infused on days 0 and 7. Main Outcomes and Measures: The primary end point was the incidence of hypophosphatemia (serum phosphate level <2.0 mg/dL) between baseline and day 35. Results: In trial A, 123 patients were randomized (mean [SD] age, 45.1 [11.0] years; 95.9% women), including 62 to iron isomaltoside and 61 to ferric carboxymaltose; 95.1% completed the trial. In trial B, 122 patients were randomized (mean [SD] age, 42.6 [12.2] years; 94.1% women), including 61 to iron isomaltoside and 61 to ferric carboxymaltose; 93.4% completed the trial. The incidence of hypophosphatemia was significantly lower following iron isomaltoside vs ferric carboxymaltose (trial A: 7.9% vs 75.0% [adjusted rate difference, -67.0% {95% CI, -77.4% to -51.5%}], P < .001; trial B: 8.1% vs 73.7% [adjusted rate difference, -65.8% {95% CI, -76.6% to -49.8%}], P < .001). Beyond hypophosphatemia and increased parathyroid hormone, the most common adverse drug reactions (No./total No.) were nausea (iron isomaltoside: 1/125; ferric carboxymaltose: 8/117) and headache (iron isomaltoside: 4/125; ferric carboxymaltose: 5/117). Conclusions and Relevance: In 2 randomized trials of patients with iron-deficiency anemia who were intolerant of or unresponsive to oral iron, iron isomaltoside (now called ferric derisomaltose), compared with ferric carboxymaltose, resulted in lower incidence of hypophosphatemia over 35 days. However, further research is needed to determine the clinical importance of this difference. Trial Registration: ClinicalTrials.gov Identifiers: NCT03238911 and NCT03237065.
Asunto(s)
Anemia Ferropénica/tratamiento farmacológico , Disacáridos/efectos adversos , Compuestos Férricos/efectos adversos , Hematínicos/efectos adversos , Hipofosfatemia/inducido químicamente , Maltosa/análogos & derivados , Adulto , Anemia Ferropénica/complicaciones , Biomarcadores/sangre , Biomarcadores/orina , Disacáridos/uso terapéutico , Femenino , Compuestos Férricos/uso terapéutico , Cefalea/inducido químicamente , Hematínicos/uso terapéutico , Humanos , Hipofosfatemia/epidemiología , Incidencia , Masculino , Maltosa/efectos adversos , Maltosa/uso terapéutico , Persona de Mediana Edad , Náusea/inducido químicamente , Fosfatos/sangre , Fosfatos/orinaRESUMEN
BACKGROUND: Various epidemiological studies linked high fibroblast growth factor 23 (FGF23) levels with cardiovascular events in chronic kidney disease (CKD). It remains enigmatic whether high FGF23 exerts adverse cardiovascular effects, or whether it reflects detrimental effects of residual confounders. Earlier studies adjusted for CKD-mineral bone disease (CKD-MBD) regulators of FGF23 rather than for recently discovered non-CKD-MBD regulators, among which iron deficiency and heart failure are of particular importance. Moreover, they used c-terminal FGF23 (cFGF23) assays rather than more specific intact FGF23 (iFGF23) assays. METHODS: The CARE FOR HOMe study analyzed plasma ferritin, iFGF23, cFGF23 and N-terminal proBNP (NT-proBNP) along with conventional risk factors, among 575 CKD G2-G4 patients to determine the interaction between FGF23, its non-CKD-MBD regulators, and incident cardiovascular events in CKD patients. The participants were followed up for 5.1 ± 2.1 years for the occurrence of atherosclerotic events and hospitalization for acute decompensated heart failure. RESULTS: cFGF23 correlated strongly with high iFGF23 (r = 0.607), fairly with high NT-proBNP (r = 0.453) and weakly with low ferritin (r = -0.207); correlation coefficients of iFGF23 with NT-proBNP and ferritin were numerically lower. In Kaplan-Meier analyses, both endpoints were predicted by cFGF23 and iFGF23. In Cox regression models, cFGF23 remained an outcome predictor after adjustment for conventional risk factors and ferritin. This prediction was largely eliminated when further adjusting for NT-proBNP. iFGF23 was less consistently associated with adverse outcome in partly adjusted models, and failed to predict outcome in fully adjusted models. CONCLUSION: In summary, iron deficiency and heart failure affect plasma FGF23. As adjustment for NT-proBNP virtually eliminates the association between plasma FGF23 and predefined outcome, we speculate that high FGF23, rather than exerting detrimental cardiovascular effects, mirrors prevalent heart disease.
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Factores de Crecimiento de Fibroblastos/sangre , Insuficiencia Cardíaca/epidemiología , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Insuficiencia Renal Crónica/complicaciones , Anciano , Femenino , Factor-23 de Crecimiento de Fibroblastos , Estudios de Seguimiento , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/etiología , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Prevalencia , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Insuficiencia Renal Crónica/sangre , Medición de Riesgo/métodos , Factores de RiesgoRESUMEN
Canonical Wnt signalling activity is a major player in physiological and adaptive bone metabolism. Wnt signalling is regulated by soluble inhibitors, with sclerostin being the most widely studied. Sclerostin's main origin is the osteocyte and its major function is blockade of osteoblast differentiation and function. Therefore, sclerostin is a potent inhibitor of bone formation and mineralization. Consequently, blocking sclerostin via human monoclonal antibodies (such as romosozumab) represents a promising perspective for the treatment of (postmenopausal) osteoporosis. However, sclerostin's physiology and the effects of sclerostin monoclonal antibody treatment are not limited to the skeleton. Specifically, the potential roles of sclerostin in chronic kidney disease (CKD) and associated pathologies covered by the term chronic kidney disease and mineral bone disorder (CKD-MBD), which also includes accelerated cardiovascular calcification, warrant specific attention. CKD-MBD is a complex disease condition in which sclerostin antibodies may interfere at different levels and influence the multiform interplay of hyperparathyroidism, renal osteodystrophy and vascular calcification, but the clinical sequelae remain obscure. The present review summarizes the potential effects of sclerostin blockade in CKD-MBD. We will address and summarize the urgent research targets that are being identified and that need to be addressed before a valid risk-benefit ratio can be established in the clinical setting of CKD.
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Enfermedades Óseas/tratamiento farmacológico , Proteínas Morfogenéticas Óseas/efectos adversos , Enfermedades Cardiovasculares/inducido químicamente , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/tratamiento farmacológico , Calcificación Vascular/inducido químicamente , Proteínas Adaptadoras Transductoras de Señales , Marcadores Genéticos , Humanos , PronósticoRESUMEN
PURPOSE: Fibroblast growth factor-23 (FGF23) is critical for phosphate homeostasis. Considering the high prevalence of vitamin D deficiency and the association of FGF23 with adverse outcomes, we investigated effects of vitamin D3 supplementation on FGF23 concentrations. METHODS: This is a post-hoc analysis of the Styrian Vitamin D Hypertension trial, a single-center, double-blind, randomized, placebo-controlled trial, conducted from 2011 to 2014 at the Medical University of Graz, Austria. Two hundred subjects with 25(OH)D concentrations < 30 ng/mL and arterial hypertension were randomized to receive either 2800 IU of vitamin D3 daily or placebo over 8 weeks. Primary outcome was the between-group difference in FGF23 levels at study end while adjusting for baseline values. RESULTS: Overall, 181 participants (mean ± standard deviation age, 60.1 ± 11.3; 48% women) with available c-term FGF23 concentrations were considered for the present analysis. Mean treatment duration was 54 ± 10 days in the vitamin D3 group and 54 ± 9 days in the placebo group. At baseline, FGF23 was significantly correlated with serum phosphate (r = 0.135; p = 0.002). Vitamin D3 supplementation had no significant effect on FGF23 in the entire cohort (mean treatment effect 0.374 pmol/L; 95% confidence interval - 0.024 to 0.772 pmol/L; p = 0.065), but increased FGF23 concentrations in subgroups with baseline 25(OH)D concentrations below 20 ng/mL (n = 70; mean treatment effect 0.973 pmol/L; 95% confidence interval - 0.032 to 1.979 pmol/L; p = 0.019) and 16 ng/mL (n = 40; mean treatment effect 0.593 pmol/L; 95% confidence interval 0.076 to 1.109; p = 0.022). CONCLUSIONS: Vitamin D3 supplementation had no significant effect on FGF23 in the entire study cohort. We did, however, observe an increase of FGF23 concentrations in subgroups with low baseline 25(OH)D.
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Colecalciferol/administración & dosificación , Colecalciferol/sangre , Suplementos Dietéticos , Factores de Crecimiento de Fibroblastos/sangre , Factores de Crecimiento de Fibroblastos/efectos de los fármacos , Austria , Estudios de Cohortes , Método Doble Ciego , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Chronic obstructive pulmonary disease (COPD) and coronary heart disease (CHD) often occur together. However, COPD is underdiagnosed among CHD patients. OBJECTIVES: This study investigated the prevalence of COPD and relevant pulmonary function test (PFT) impairments in patients with acute myocardial infarction (AMI). METHODS: Patients undergoing coronary angiography for AMI were prospectively included. Body plethysmography, lung diffusing capacity, blood gas analysis, and echocardiography were performed. The following patient subgroups were compared: with versus without COPD, ST elevation myocardial infarction (STEMI) versus non-STEMI (NSTEMI). The prevalence of PFT impairments was also recorded. RESULTS: A total of 100 patients (51 with NSTEMI, 49 with STEMI) were included. Twenty patients had diagnosed COPD, of whom 15 were diagnosed for the first time; 80% of all COPD patients were not receiving COPD therapy. Patients with COPD had higher maximum creatine kinase (p = 0.008) and troponin T (p = 0.054) levels than those without COPD. Hypoxaemia was more common in COPD patients (lower oxygen saturation [p = 0.008] and partial pressure of oxygen [PaO2] [p = 0.005]). PaO2 was significantly lower in STEMI compared with NSTEMI (p = 0.017). Independent of a COPD diagnosis, 65 patients had relevant PFT impairments. CONCLUSIONS: The high prevalence of undiagnosed COPD and relevant pulmonary function impairments in this cohort of patients with AMI, and the fact that pulmonary disease was untreated in the majority of COPD patients, highlight the importance of a general pulmonary workup of patients with AMI. Furthermore, patients with CHD should undergo screening for COPD, given the fact that COPD patients had larger infarction size.
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Infarto del Miocardio/complicaciones , Intervención Coronaria Percutánea , Pletismografía Total/métodos , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Análisis de los Gases de la Sangre/métodos , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Mortalidad Hospitalaria/tendencias , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Infarto del Miocardio/mortalidad , Infarto del Miocardio/cirugía , Prevalencia , Pronóstico , Estudios Prospectivos , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Sistema de Registros , Factores de Riesgo , Tasa de Supervivencia/tendenciasRESUMEN
BACKGROUND AND OBJECTIVES: Dyspnea is one of the most disturbing symptoms for patients with chronic obstructive pulmonary disease (COPD) or heart failure (HF). This study investigated dyspnea triggers and factors associated with worsening dyspnea in patients with COPD or HF. METHODS: COPD support group members and HF patients with reduced ejection fraction (HFrEF) and no airway obstruction answered a questionnaire describing different weather conditions (rising/falling air pressure, sunny, foggy, rainy, windy, snowy, hazy, high ozone levels, and airborne pollen) and environmental circumstances (cooking, grilling, perfumes, cigarette smoke, gasoline odor, and flower scents) and were asked to estimate the occurrence and severity of dyspnea under these conditions using predefined scales. RESULTS: 230 patients with COPD and 90 with HFrEF (left ventricular ejection fraction 34 ± 10%, Tiffeneau index > 70%) were analyzed. COPD patients reported dyspnea more often than HF patients in almost all weather and environmental conditions (p = 0.004 to p < 0.001), with the exception of outdoor floral scents and cigarette smoke. Severe to very severe dyspnea was reported more in COPD versus HF in all weather and environmental conditions except sunny weather (p = 0.01 to p < 0.001). COPD was associated with more severe dyspnea than HF in all conditions (all p < 0.001). CONCLUSIONS: Dyspnea was triggered by a variety of weather and other environmental triggers in patients with COPD and occurred more often than in HF patients under the same conditions. Foggy weather and exposure to perfumes were associated with severe dyspnea in the majority of COPD patients, but only a minority of HF patients.
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Disnea/etiología , Exposición a Riesgos Ambientales/efectos adversos , Contaminantes Ambientales/efectos adversos , Insuficiencia Cardíaca/complicaciones , Pulmón/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Tiempo (Meteorología) , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Disnea/diagnóstico , Disnea/fisiopatología , Femenino , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Perfumes/efectos adversos , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Factores de Riesgo , Índice de Severidad de la Enfermedad , Humo/efectos adversosRESUMEN
BACKGROUND: Fibroblast growth factor 23 (FGF23) regulates phosphate metabolism by increasing renal phosphate excretion and decreasing 1.25-dihydroxyvitamin D synthesis. Reports about hypophosphatemia in patients with chronic obstructive pulmonary disease (COPD) suggest altered phosphate metabolism. Therefore, we hypothesized that disturbances in phosphate-regulatory hormones such as FGF23 and parathyroid hormone (PTH) are present in COPD patients. METHODS: We investigated 40 COPD patients (63.5 ± 9.9 years, 27 male), each matched with two age- and sex-matched controls without any primary lung disease. COPD patients underwent lung function testing in advance. All patients had a glomerular filtration rate (GFR) > 60 mL/min/1.73m2. We measured concentrations of intact FGF23 (iFGF23) and c-terminal FGF23 (c-term FGF23), phosphate, parathyroid hormone (PTH) and C-reactive protein (CRP) levels in COPD patients and controls. RESULTS: Phosphate (1.0 ± 02 vs. 1.1 ± 0.2 mmol/L; p = 0.027), PTH (54.2 ± 29.4 vs. 68.7 ± 31.8 pg/mL; p = 0.002) and iFGF23 (46.3 ± 29.0 vs. 57.5 ± 33.5 pg/mL; p = 0.026 ) levels were significantly lower in COPD patients compared with controls. There was a significant negative correlation between c-term FGF23 and total lung capacity (r = - 0.4; p = 0.01), and between c-term FGF23 and CRP in COPD patients (r = 0.48; p = 0.002). iFGF23 and c-term FGF23 were positively correlated with phosphate and PTH in the control group. CONCLUSION: We confirmed lower average serum phosphate levels in COPD patients compared with controls. However, our data do not suggest a causative role for FGF23 or PTH in COPD because levels of both phosphate-lowering hormones appear to be adaptively decreased as well. Therefore, further investigations are needed to identify the pathogenesis of low phosphate levels in patients with COPD and the relationship between phosphate-regulatory hormones and disease progression.
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Factores de Crecimiento de Fibroblastos/sangre , Hormona Paratiroidea/sangre , Fosfatos/sangre , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Estudios de Cohortes , Estudios Transversales , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND/AIMS: The association between serum alkaline phosphatase (ALP) with adverse cardiovascular outcomes, in Chronic Kidney Disease (CKD) patients has previously been reported and may be a result of increased vascular calcification and inflammation. Here we report, for the first time, the effects of pharmacologic epigenetic modulation on levels of ALP and kidney function via a novel oral small molecule BET inhibitor, apabetalone, in CKD patients. METHODS: A post-hoc analysis evaluated patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2, who participated in the apabetalone phase 2 randomized controlled trials (SUSTAIN and ASSURE). 48 CKD subjects with a history of cardiovascular disease (CVD) were treated with 100mg twice-daily of 24 and 26 weeks of apabetalone or placebo. ALP and eGFR were measured prior to randomization and at final visits. RESULTS: Patients who received apabetalone (n=35) versus placebo (n=13) over 6 months showed significantly (p=0.02) lowered serum ALP -14.0% (p<0.0001 versus baseline) versus -6.3% (p=0.9 versus baseline). The eGFR in the apabetalone group increased by 3.4% (1.7 mL/min/1.73 m2) (p=0.04 versus baseline) and decreased by 5.8% (2.9 mL/min/1.73 m2) (p=0.6 versus baseline) in the placebo group. Apabetalone was well tolerated. CONCLUSION: A post-hoc analysis of CKD subjects from the SUSTAIN and ASSURE randomized controlled trials demonstrated favorable effects of apabetalone on ALP and eGFR, and generated the hypothesis that epigenetic modulation by BET inhibition may potentially offer a novel therapeutic strategy to treat CVD and progressive kidney function loss in CKD patients. This is being examined in the phase III trial BETonMACE.
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Fosfatasa Alcalina/sangre , Epigénesis Genética/efectos de los fármacos , Quinazolinonas/farmacología , Insuficiencia Renal Crónica/tratamiento farmacológico , Adulto , Anciano , Fosfatasa Alcalina/genética , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/etiología , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Proteínas , Quinazolinonas/uso terapéutico , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/fisiopatologíaRESUMEN
PURPOSE: Fear of physical activity (FoPA) has been suggested as a psychological barrier to exercise-based cardiac rehabilitation and everyday physical activity (PA) in patients with heart failure (HF). We evaluated the recently developed Fear of Activity in Situations-Heart Failure (FActS-HF) questionnaire that assesses affective/cognitive fear reactions to situations of varying PA intensities. METHODS: The FActS-HF was given to 132 ambulatory patients with stable HF (67 ± 12 years, 80% men). In 121 participants with valid FActS-HF data, the questionnaire's dimensionality was investigated. Psychometric properties were determined in terms of reliability and validity. We assessed convergent and discriminant correlations of FoPA with anxiety, kinesiophobia, and depression. External validation criteria encompassed clinical variables and objectively assessed accelerometer measures of everyday PA in a subsample of 61 participants. RESULTS: The FActS-HF measures a unidimensional construct (i.e., FoPA) based on items presenting varying PA intensities (i.e., the more intense the PA, the stronger the fear response). The scale demonstrated good 2-week stability (r tt = 0.82) and excellent internal consistency reliability (α = 0.97). FoPA was moderately to strongly associated with anxiety and kinesiophobia, and weakly to moderately associated with state/trait depression, supporting convergent and discriminant validity, respectively. High FoPA was associated with feeling uninformed about HF, comorbidities, non participitation to cardio fitness groups, and less stair climbing, as measured by accelerometry. CONCLUSION: The FActS-HF is a reliable and valid instrument to measure FoPA in patients with HF and provides a promising tool for further research and practice.
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Ejercicio Físico/psicología , Miedo/psicología , Insuficiencia Cardíaca/psicología , Encuestas y Cuestionarios , Adulto , Anciano , Anciano de 80 o más Años , Ansiedad/psicología , Depresión/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Psicometría , Reproducibilidad de los ResultadosRESUMEN
Whether to initiate oral anticoagulant therapy in advanced chronic kidney disease patients with atrial fibrillation remains debatable. Although randomized trial data are lacking, observational studies yield controversial results. Keskar and colleagues analyzed data from a Canadian health care system and found that in elderly chronic kidney disease patients with atrial fibrillation, oral anticoagulant therapy did not prevent ischemic strokes, induced hemorrhages, but prolonged life. These paradoxical findings emphasize the dire need for an adequately powered randomized trial.
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Anticoagulantes , Fibrilación Atrial , Canadá , Humanos , Insuficiencia Renal Crónica , Accidente CerebrovascularRESUMEN
Background: Calcific uraemic arteriolopathy (CUA, calciphylaxis) is a rare disease predominantly in dialysis patients and associated with high mortality. Painful skin ulcerations and calcification of cutaneous arterioles characterize calciphylaxis. Methods: We established an observational, Internet-based registry allowing online notification for all German CUA cases. The registry recorded data about patient characteristics, biochemistry and therapies. Blood samples were stored in a central biobank. Results: Between 2006 and 2015, 253 CUA patients were recorded: median age 70 [interquartile range (IQR) 61-76] years, 60% females and 86% ( n = 207) dialysis patients, translating into an estimated annual incidence rate of 0.04% in German dialysis patients. Fifty-two per cent received vitamin K antagonists (VKAs) prior to CUA. Skin lesions were localized in 71% on the legs or gluteal region. In dialysis CUA patients median total serum calcium was 2.20 (IQR 2.06-2.37) mmol/L, phosphorus 1.67 (IQR 1.35-2.03) mmol/L, intact parathyroid hormone 147 (IQR 72-276) pg/mL and fetuin-A 0.21 (IQR 0.16-0.26) g/L (normal range 0.35-0.95). Median sclerostin, osteoprotegerin, TRAP5b, bone-specific alkaline phosphatase and c-terminal FGF23 levels were all elevated. The most frequently recorded therapeutic procedures in dialysis CUA patients were as follows: wound debridement (29% of cases), stopping VKA (25%), lowering calcium supply (24%), sodium thiosulphate (22%), application of vitamin K (18%), increase of dialysis duration/frequency (17%) and stoping active vitamin D (16%). Conclusions: Approximately 50% of CUA patients used VKA. Our data suggest that uncontrolled hyperparathyroidism is not the key determinant of calciphylaxis. Therapeutic strategies were heterogeneous. The experience of the German registry will help substantially to initiate a large-scale multinational CUA registry.
Asunto(s)
Calcifilaxia/diagnóstico , Fallo Renal Crónico/terapia , Sistema de Registros/estadística & datos numéricos , Diálisis Renal/efectos adversos , Vitamina K/antagonistas & inhibidores , Anciano , Calcifilaxia/tratamiento farmacológico , Calcifilaxia/etiología , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Masculino , Persona de Mediana EdadAsunto(s)
Calcifilaxia , Edad de Inicio , Calcifilaxia/diagnóstico , Calcifilaxia/etiología , Calcifilaxia/patología , Calcifilaxia/terapia , Desbridamiento , Diagnóstico Diferencial , Humanos , Enfermedades Renales/complicaciones , Microvasos/patología , Pronóstico , Factores de Riesgo , Tiosulfatos/uso terapéutico , Vitamina K 1/uso terapéuticoRESUMEN
Cardiovascular calcification is both a risk factor and contributor to morbidity and mortality. Patients with chronic kidney disease (and/or diabetes) exhibit accelerated calcification of the intima, media, heart valves and likely the myocardium as well as the rare condition of calcific uraemic arteriolopathy (calciphylaxis). Pathomechanistically, an imbalance of promoters (e.g. calcium and phosphate) and inhibitors (e.g. fetuin-A and matrix Gla protein) is central in the development of calcification. Next to biochemical and proteinacous alterations, cellular processes are also involved in the pathogenesis. Vascular smooth muscle cells undergo osteochondrogenesis, excrete vesicles and show signs of senescence. Therapeutically, measures to prevent the initiation of calcification by correcting the imbalance of promoters and inhibitors appear to be essential. In contrast to prevention, therapeutic regression of cardiovascular calcification in humans has been rarely reported. Measures to enhance secondary prevention in patients with established cardiovascular calcifications are currently being tested in clinical trials.
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Insuficiencia Renal Crónica/metabolismo , Calcificación Vascular/metabolismo , Animales , Calcio/metabolismo , Senescencia Celular , Humanos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Fosfatos/metabolismo , Insuficiencia Renal Crónica/patología , Factores de Riesgo , Calcificación Vascular/patología , Calcificación Vascular/prevención & controlRESUMEN
Calcific uraemic arteriolopathy (CUA), or calciphylaxis, is a rare disease predominantly occurring in comorbidity with dialysis. Due to the very low frequency of CUA, prospective studies on its management are lacking and even anecdotal reports on treatment remain scarce. Therefore, calciphylaxis is still a challenging disease with dismal prognosis urgently requiring adequate strategies for diagnosis and treatment.In an attempt to fill some of the current gaps in evidence on various, highly debated and controversial aspects of dialysis-associated calciphylaxis, 13 international experts joined the 1st Consensus Conference on CUA, held in Leuven, Belgium on 21 September 2015. The conference was supported by the European Calciphylaxis Network (EuCalNet), which is a task force of the ERA-EDTA scientific working group on Chronic Kidney Disease-Mineral and Bone Disorders (CKD-MBD). After an intense discussion, a 9-point Likert scale questionnaire regarding 20 items on calciphylaxis was anonymously answered by each participant. These 20 items addressed unsolved issues in terms of diagnosis and management of calciphylaxis. On the one hand, the analysis of the expert opinions identified areas of general consensus, which might be a valuable aid for physicians treating such a disease with less experience in the field. On the other hand, some topics such as the pertinence of skin biopsy and administration of certain treatments revealed divergent opinions. The aim of the present summary report is to provide some guidance for clinicians who face patients with calciphylaxis in the current setting of absence of evidence-based medicine.
Asunto(s)
Calcifilaxia/patología , Calcifilaxia/prevención & control , Evaluación de Necesidades , Manejo de la Enfermedad , Medicina Basada en la Evidencia , HumanosRESUMEN
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.