RESUMEN
OBJECTIVE: The aim of the study was to investigate the effect of aerobic exercise on markers of bone metabolism in overweight and obese nondialysis-dependent patients with chronic kidney disease. METHODS: This is a post-hoc study with 39 sedentary patients (55.5 ± 8.3 years, body mass index 31.2 ± 4.4 kg/m2, estimated glomerular filtration rate 26.9 ± 11.7 mL/minute) who were randomly assigned to the aerobic exercise group (n = 24) or the control group (n = 15). The aerobic training (walking) was prescribed according to ventilatory threshold and was performed 3 times per week during 24 weeks. Carboxylated and undercarboxylated osteocalcin (GLA and GLU), sclerostin and tartrate-resistant acid phosphatase isoform 5b (TRAP-5b), parathyroid hormone, total alkaline phosphatase (AP), body composition, cardiorespiratory, and functional capacity tests were measured at baseline and after the follow-up. RESULTS: At baseline, carboxylated osteocalcin (GLA) and undercarboxylated osteocalcin (GLU) were inversely correlated with estimated glomerular filtration rate (r = -0.64; r = -0.38, respectively). Both osteocalcin fragments were positively correlated with total AP (GLA: r = 0.36; GLU: r = 0.53). An inverse correlation was found between GLA and sclerostin with body fat (r = -0.36; r = -0.46, respectively). GLU was negatively correlated with markers of muscle mass (r = -0.34). TRAP-5b and sclerostin were inversely correlated with 6-minute walk test and time up and go test, respectively (r = -0.34; r = -0.35, respectively). After 24 weeks, all physical capacity parameters increased in the exercise group (P < .001). Except for total AP that increased after 24 weeks in the exercise group (P < .05), no other changes were observed in both groups in relation to the bone metabolism biomarkers investigated. CONCLUSION(S): In this post-hoc study, the aerobic training used did not promote relevant changes in the bone metabolism markers investigated.
Asunto(s)
Biomarcadores/sangre , Huesos/metabolismo , Ejercicio Físico , Obesidad/sangre , Sobrepeso/sangre , Insuficiencia Renal Crónica/sangre , Fosfatasa Alcalina/sangre , Composición Corporal , Índice de Masa Corporal , Estudios Transversales , Femenino , Tasa de Filtración Glomerular , Fuerza de la Mano , Humanos , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/terapia , Osteocalcina/sangre , Sobrepeso/complicaciones , Sobrepeso/terapia , Hormona Paratiroidea/sangre , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/terapia , Fosfatasa Ácida Tartratorresistente/sangreRESUMEN
Chronic Kidney Disease (CKD)-Mineral and Bone Disorder (CKD-MBD) is a complex disease that is not completely understood. However, some factors secreted by the osteocytes might play an important role in its pathophysiology. Therefore, we evaluated the bone expression of proteins in a group of patients with CKD 2-3, CKD 4, and CKD 5 on dialysis and healthy individuals. We also tested several bone remodeling markers, and correlated these levels with bone biopsy findings. As expected, as serum calcium decreased, serum phosphate, alkaline phosphatase, fibroblast growth factor-23 (FGF-23), parathyroid hormone, and osteoprotegerin increased, as CKD progressed. Additionally, there was a gradual increase in bone resorption associated with a decrease in bone formation and impairment in bone mineralization. Bone expression of sclerostin and parathyroid hormone receptor-1 seemed to be increased in earlier stages of CKD, whereas FGF-23 and phosphorylated ß-catenin had increased expression in the late stages of CKD, although all these proteins were elevated relative to healthy individuals. Immunohistochemical studies showed that FGF-23 and sclerostin did not co-localize, suggesting that distinct osteocytes produce these proteins. Moreover, there was a good correlation between serum levels and bone expression of FGF-23. Thus, our studies help define the complex mechanism of bone and mineral metabolism in patients with CKD. Linkage of serum markers to bone expression of specific proteins may facilitate our understanding and management of this disease.
Asunto(s)
Remodelación Ósea , Huesos/metabolismo , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/sangre , Osteocitos/metabolismo , Insuficiencia Renal Crónica/sangre , Proteínas Adaptadoras Transductoras de Señales , Adulto , Anciano , Biomarcadores/sangre , Biopsia , Proteínas Morfogenéticas Óseas/metabolismo , Huesos/patología , Calcio/sangre , Estudios de Casos y Controles , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/diagnóstico , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/terapia , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Marcadores Genéticos , Humanos , Masculino , Persona de Mediana Edad , Osteocitos/patología , Osteoprotegerina/sangre , Hormona Paratiroidea/sangre , Fosforilación , Receptor de Hormona Paratiroídea Tipo 1/metabolismo , Diálisis Renal , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/terapia , Índice de Severidad de la Enfermedad , beta Catenina/metabolismoRESUMEN
STUDY OBJECTIVES: Restless legs syndrome (RLS) is a highly prevalent sleep disease among patients on hemodialysis. The physiopathology is still unclear, and may be multifactorial. Because of the association between iron metabolism and chronic kidney disease-mineral and bone disorders (CKD-MBD), we hypothesized that both factors would be associated with RLS. METHODS: We have evaluated hemodialysis patients, in a face-to-face interview for the diagnosis and severity of RLS, as measured by the International Restless Legs Syndrome Study Group. Clinical, demographic, and biochemical characteristics were measured. RESULTS: Out of 101 adult patients included, RLS was found in 29 (28.7%). Adjusted multinomial regression analysis revealed that age older than 35 years, transferrin saturation less than 47%, serum ferritin level less than 700 ng/mL, hemoglobin level less than 9.8 g/dL, serum phosphate level higher than 5.2 mg/dL, FGF-23 higher than 2,000 RU/mL, and C-reactive protein less than 1.24 mg/dL were independently associated with RLS. RLS was classified as mild, moderate, severe, and very severe in 3.4%, 41.7%, 44.8%, and 10.1% of patients, respectively. Scores of severity correlated significantly with erythropoietin dose/kg/w (p = 0.046), phosphate (p = 0.003), and inversely with serum albumin (p = 0.003) and calcium (p = 0.008). Phosphate and 25(OH)-vitamin D correlated with transferrin saturation. Patients with severe/very severe symptoms were mostly women, presented with lower serum iron, ionic calcium, and serum albumin levels and higher levels of serum phosphate, and higher percentage of 25(OH)-vitamin D deficiency and levels of FGF-23 higher than 2,000 RU/mL than did those with mild/moderate symptoms. CONCLUSIONS: CKD-MBD factors besides iron metabolism are associated with RLS in patients on hemodialysis, providing new insights into the understanding of RLS in this population.
Asunto(s)
Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/complicaciones , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/metabolismo , Diálisis Renal , Síndrome de las Piernas Inquietas/complicaciones , Síndrome de las Piernas Inquietas/metabolismo , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Masculino , Persona de Mediana Edad , Minerales/metabolismo , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/terapia , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Chronic kidney disease (CKD) affects 10-15% of adult population worldwide. Incident patients on hemodialysis, mainly those on urgent-start dialysis at the emergency room, have a high mortality risk, which may reflect the absence of nephrology care. A lack of data exists regarding the influence of baseline factors on the mortality of these patients. The aim of this study was to evaluate the clinical and laboratory characteristics of this population and identify risk factors that contribute to their mortality. PATIENTS AND METHODS: We studied 424 patients who were admitted to our service between 01/2006 and 12/2012 and were followed for 1 year. We analyzed vascular access, risk factors linked to cardiovascular disease (CVD) and mineral and bone disease associated with CKD (CKD-MBD), and clinical events that occurred during the follow-up period. Factors that influenced patient survival were evaluated by Cox regression analysis. RESULTS: The patient mean age was 50 ± 18 years, and 58.7% of them were male. Hypertension was the main cause of primary CKD (31.8%). Major risk factors were smoking (19.6%), dyslipidemia (48.8%), and CVD (41%). Upon admission, most patients had no vascular access for hemodialysis (89.4%). Biochemical results showed that most patients were anemic with high C-reactive protein levels, hypocalcemia, hyperphosphatemia, elevated parathyroid hormone and decreased 25-hydroxy vitamin D. At the end of one year, 60 patients died (14.1%). These patients were significantly older, had a lower percentage of arteriovenous fistula in one year, and low levels of 25-hydroxy vitamin D. CONCLUSIONS: The combined evaluation of clinical and biochemical parameters and risk factors revealed that the mortality in urgent-start dialysis is associated with older age and low levels of vitamin D deficiency. A lack of a permanent hemodialysis access after one year was also a risk factor for mortality in this population.
Asunto(s)
Servicio de Urgencia en Hospital , Diálisis Renal , Insuficiencia Renal Crónica/mortalidad , Insuficiencia Renal Crónica/terapia , Adulto , Anciano , Proteína C-Reactiva/análisis , Enfermedades Cardiovasculares/complicaciones , Femenino , Humanos , Hipertensión/complicaciones , Masculino , Persona de Mediana Edad , Mortalidad , Nefrología/estadística & datos numéricos , Admisión del Paciente , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Factores de Riesgo , Fumar , Sobrevivientes , Vitamina D/análogos & derivados , Vitamina D/sangre , Deficiencia de Vitamina DRESUMEN
BACKGROUND: Fibroblast growth factor 23 (FGF23), a phosphate-regulating hormone is an established cardiovascular risk factor. Recently, FGF23 has been related to inflammation. Lupus is an inflammatory disease, and whether FGF23 is associated with Lupus nephritis (LN) activity is unknown. MATERIALS AND METHODS: We studied 15 pre-menopausal patients with recent LN diagnose (⩽2months) and compared them to 1:1 age-matched healthy control group. We measured serum levels of intact FGF23, interleukin-6 (IL-6), tumor necrosis factor α (TNFα), and urinary levels of monocyte chemotactic protein (MCP1). RESULTS: LN patients (29.5±10years) presented proteinuria of 4.7±2.9g/day, and estimated glomerular filtration rate of 37 (31-87)ml/min/1.73m2. They demonstrated higher FGF23 levels when compared to healthy controls [106.7 (80.3-179) vs. 33.6 (25.8-60.9) pg/ml, p<0.001]. FGF23 levels correlated with urinary MCP1 (r=0.62, p<0.001), serum TNFα (r=0.58, p<0.001) and serum IL-6 (r=0.46, p=0.01). Only the correlation between FGF23 and MCP1 remained significant after adjustments for 25(OH) vitamin D and renal function. CONCLUSION: Newly diagnosed LN patients demonstrated elevated FGF23 levels that were positively correlated to urinary MCP1, independently of vitamin D levels and kidney function. If FGF23 may predict clinical outcomes in LN warrants further evaluation.
Asunto(s)
Factores de Crecimiento de Fibroblastos/sangre , Nefritis Lúpica/sangre , Premenopausia/sangre , Adolescente , Adulto , Quimiocina CCL2/sangre , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Nefritis Lúpica/fisiopatología , Vitamina D/sangreRESUMEN
PURPOSE: Hyperleptinemia and metabolic acidosis (MA) are frequently observed in patients on hemodialysis (HD). While the role of leptin in patients on HD is not completely understood, HD only partially corrects MA. Both leptin and acidosis have effect on bone disease. The goal of the present study was to evaluate the effects of MA correction on chronic kidney disease-mineral and bone disorder laboratory parameters and leptin levels. METHODS: Forty-eight patients on HD, aged 43±19 years, were prospectively studied. Individual adjustments in the bicarbonate dialysate concentration were made to maintain pre-dialysis concentration≥22 mEq/l. Blood gas analysis was done monthly for 4 months (M1-M4). RESULTS: From M0 to M4, serum albumin increased (from 3.5 ±0.3 to 4.0±0.3 g/l, p<0.0001) while ß2 microglobulin decreased (from 27.6±8.3 to 25.8±6.8 µg/ml, p=0.025). Serum leptin decreased in all but three patients, as well as leptin/adiponectin ratio (p<0.0001). There was a decrease in ionized serum calcium (from 5.0±0.5 to 4.7±0.5 mg/dl, p =0.002) and an increase in parathyroid hormone (PTH) [from 191 (85, 459) to 446 pg/ml (212, 983), p<0.0001] and in serum phosphate (from 5.4±1.4 to 5.8±1.1 mg/dl, p=0.048). CONCLUSION: MA correction in HD patients can decrease leptin, an atherogenic marker. The impact of such treatment extends to uremic bone disease, as decrease in serum calcium and increase in PTH. However, this could be an undesirable effect because it may aggravate a secondary hyperparathyroidism. Whether the reduction in leptin levels has impact on outcomes in patients on hemodialysis deserves further investigation.
Asunto(s)
Acidosis/terapia , Bicarbonatos/sangre , Soluciones para Diálisis/química , Fallo Renal Crónico/terapia , Leptina/sangre , Diálisis Renal , Acidosis/sangre , Adiponectina/sangre , Adulto , Bicarbonatos/administración & dosificación , Análisis de los Gases de la Sangre , Calcio/sangre , Femenino , Humanos , Concentración de Iones de Hidrógeno , Fallo Renal Crónico/sangre , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Fosfatos/sangre , Estudios Prospectivos , Albúmina Sérica/metabolismo , Factores Sexuales , Adulto Joven , Microglobulina beta-2/sangreRESUMEN
High phosphate intake is known to aggravate renal osteodystrophy along various pathogenetic pathways. Recent studies have raised the possibility that dysregulation of the osteocyte Wnt/ß-catenin signaling pathway is also involved in chronic kidney disease (CKD)-related bone disease. We investigated the role of dietary phosphate and its possible interaction with this pathway in an experimental model of adynamic bone disease (ABD) in association with CKD and hypoparathyroidism. Partial nephrectomy (Nx) and total parathyroidectomy (PTx) were performed in male Wistar rats. Control rats with normal kidney and parathyroid function underwent sham operations. Rats were divided into three groups and underwent pair-feeding for 8 weeks with diets containing either 0.6% or 1.2% phosphate: sham 0.6%, Nx+PTx 0.6%, and Nx+PTx 1.2%. In the two Nx+PTx groups, serum creatinine increased and blood ionized calcium decreased compared with sham control group. They also presented hyperphosphatemia and reduced serum parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) levels. Fractional urinary excretion of phosphate increased in Nx+PTx 1.2% rats despite lower PTH and FGF23 levels than in sham group. These biochemical changes were accompanied by a decrease in bone formation rates. The Nx+PTx 1.2% group had lower bone volume (BV/TV), higher osteoblast and osteocyte apoptosis, and higher SOST and Dickkopf-1 gene expression than the Nx+PTx 0.6% group. Nx+PTx 0.6% rat had very low serum sclerostin levels, and Nx+PTx 1.2% had intermediate sclerostin levels compared with sham group. Finally, there was a negative correlation between BV/TV and serum sclerostin. These results suggest that high dietary phosphate intake decreases bone volume in an experimental model of CKD-ABD, possibly via changes in SOST expression through a PTH-independent mechanism. These findings could have relevance for the clinical setting of CKD-ABD in patients who low turnover bone disease might be attenuated by optimal control of phosphate intake and/or absorption.
Asunto(s)
Enfermedades Óseas/etiología , Enfermedades Óseas/metabolismo , Proteínas Morfogenéticas Óseas/metabolismo , Fósforo Dietético/metabolismo , Insuficiencia Renal Crónica/complicaciones , Animales , Análisis Químico de la Sangre , Peso Corporal , Proteínas Morfogenéticas Óseas/sangre , Huesos/metabolismo , Huesos/patología , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Marcadores Genéticos , Masculino , Osteoblastos/metabolismo , Osteocitos/metabolismo , Fosfatos/metabolismo , RatasRESUMEN
BACKGROUND: Mineral bone disorder (MBD) is an early complication of chronic kidney disease (CKD), with complex interactions in the bone-kidney-energy axis. These events lead to impaired bone remodelling, which in turn is associated with cardiovascular disease. Recently, we reported on a positive effect of phosphate binder treatment on bone remodelling markers and a reduction in serum FGF-23 levels in predialysis-CKD patients. The goal of the present study of this trial was to examine the effects of phosphate binders on energy-regulating hormones and Wnt pathway. METHODS: In this present post hoc analysis of the above randomized, open-label, 8-week trial, which compared the effects of increasing doses of sevelamer-HCl or calcium acetate on various CKD-MBD parameters in 40 normophosphatemic CKD Stage 3-4 patients, we measured serum sclerostin, Dickkopf-1, leptin, adiponectin and serotonin concentrations. RESULTS: Serum sclerostin, Dickkopf-1 and leptin were elevated at baseline despite normal calcium, phosphorus levels and daily urinary phosphorus excretion. There were significant and positive correlations between sclerostin and FGF-23, as well between leptin and Dickkopf-1. Treatment with both phosphate binders led to a significant decrease in phosphate overload. However, sevelamer-HCl, but not with calcium acetate, led to a significant decrease in serum FGF-23, sclerostin and leptin, and to a significant increase in bone alkaline phosphatase levels. CONCLUSIONS: Early stages of CKD are associated with an impairment of the Wnt pathway, as reflected by elevated sclerostin, and a dysregulation of energy-regulating hormones. Many of these disturbances can be ameliorated by phosphate binder treatment, more with sevelamer-HCl than with calcium acetate.
Asunto(s)
Acetatos/farmacología , Biomarcadores/sangre , Enfermedades Óseas/metabolismo , Metabolismo Energético/fisiología , Poliaminas/farmacología , Insuficiencia Renal Crónica/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Adiponectina/sangre , Densidad Ósea/efectos de los fármacos , Enfermedades Óseas/tratamiento farmacológico , Proteínas Morfogenéticas Óseas/sangre , Compuestos de Calcio/farmacología , Quelantes/farmacología , Femenino , Factor-23 de Crecimiento de Fibroblastos , Marcadores Genéticos , Humanos , Péptidos y Proteínas de Señalización Intercelular/sangre , Leptina/sangre , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/tratamiento farmacológico , Serotonina/sangre , SevelamerRESUMEN
BACKGROUND: Studies that have conducted bone biopsies after kidney transplantation are scarce, and the results are conflicting. METHODS: We evaluate the bone histomorphometry, in vitro proliferation, and alkaline phosphatase expression in osteoblasts isolated from bone biopsies from 27 kidney transplant patients. The patients had preserved renal function and were treated with the same immunosuppressive therapy, receiving a minimum dose of corticosteroids. RESULTS: The biochemical analysis revealed that 41% of the patients presented with hypercalcemia, 26% presented with hypophosphatemia, and hypovitaminosis D was detected in 63%. The histomorphometric analysis showed a reduced trabecular number and increased trabecular separation, mineral apposition rate, and mineralization lag time, as well as higher osteoid surface, osteoblastic surface, resorption surface, and osteoclastic surface and a lower mineralizing surface, compared with the controls. Based on the TMV classification, bone turnover was normal in 48%, high in 26%, and low in 26% of patients. Bone mineralization was delayed in 48% of the patients, and 58% of the patients with hypovitaminosis D presented with delayed bone mineralization. Bone volume was low in 37% of the patients. The osteoblasts from patients exhibited a higher degree of proliferation compared with those from controls. CONCLUSION: Eight-two percent of our patients presented with alterations in at least one of the TMV parameters. Persistence of hyperparathyroidism, hypovitaminosis D, and immunosuppressive drugs may have influenced osteoblast function, which would explain many of the bone alterations found in these patients.
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Enfermedades Óseas/etiología , Hipercalcemia/etiología , Hipofosfatemia/etiología , Trasplante de Riñón/efectos adversos , Adulto , Fosfatasa Alcalina/metabolismo , Calcificación Fisiológica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Complicaciones Posoperatorias/etiología , Vitamina D/análogos & derivados , Vitamina D/sangreRESUMEN
PURPOSE: To characterize the potential sexual dimorphism of bone in response to exercise. METHODS: Young male and female Wistar rats were either submitted to 12 weeks of exercise or remained sedentary. The training load was adjusted at the mid-trial (week 6) by the maximal speed test. A mechanical test was performed to measure the maximal force, resilience, stiffness, and fracture load. The bone structure, formation, and resorption were obtained by histomorphometric analyses. Type I collagen (COL I) mRNA expression and tartrate-resistant acid phosphatase (TRAP) mRNA expression were evaluated by quantitative real-time PCR (qPCR). RESULTS: The male and female trained rats significantly improved their maximum speed during the maximal exercise test (main effect of training; p<0.0001). The male rats were significantly heavier than the females, irrespective of training (main effect of sex; p<0.0001). Similarly, both the weight and length of the femur were greater for the male rats when compared with the females (main effect of sex; p<0.0001 and p<0.0001, respectively). The trabecular volume was positively affected by exercise in male and female rats (main effect of training; pâ=â0.001), whereas the trabecular thickness, resilience, mineral apposition rate, and bone formation rate increased only in the trained males (within-sex comparison; p<0.05 for all parameters), demonstrating the sexual dimorphism in response to exercise. Accordingly, the number of osteocytes increased significantly only in the trained males (within-sex comparison; p<0.05). Pearson's correlation analyses revealed that the COL I mRNA expression and TRAP mRNA expression were positively and negatively, respectively, related to the parameters of bone remodeling obtained from the histomorphometric analysis (râ=â0.59 to 0.85; p<0.05). CONCLUSION: Exercise yielded differential adaptations with respect to bone structure, biomechanical proprieties, and molecular signaling in male and female rats.
Asunto(s)
Fémur/fisiología , Osteocitos/fisiología , Condicionamiento Físico Animal/fisiología , ARN Mensajero/genética , Fosfatasa Ácida/genética , Fosfatasa Ácida/metabolismo , Animales , Biomarcadores/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Elasticidad , Femenino , Fémur/anatomía & histología , Fémur/citología , Fracturas Óseas/prevención & control , Expresión Génica , Dureza , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Osteocitos/citología , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Factores Sexuales , Fosfatasa Ácida TartratorresistenteRESUMEN
BACKGROUND: Cardiac remodeling in uremia is characterized by left ventricular hypertrophy, interstitial fibrosis and microvascular disease. Cardiovascular disease is the leading cause of death in uremic patients, but coronary events alone are not the prevalent cause, sudden death and heart failure are. We studied the cardiac remodeling in experimental uremia, evaluating the isolated effect of parathyroid hormone (PTH) and phosphorus. METHODS: Wistar rats were submitted to parathyroidectomy (PTx) and 5/6 nephrectomy (Nx); they also received vehicle (V) and PTH at normal (nPTH) or high (hPTH) doses. They were fed with a poor-phosphorus (pP) or rich-phosphorus (rP) diet and were divided into the following groups: 'Sham': G1 (V+normal-phosphorus diet (np)) and 'Nx+PTx': G2 (nPTH+pP), G3 (nPTH+rP), G4 (hPTH+pP) and G5 (hPTH+rP). After 8 weeks, biochemical analysis, myocardium morphometry and arteriolar morphological analysis were performed. In addition, using immunohistochemical analysis, we evaluated angiotensin II, α-actin, transforming growth factor-beta (TGF-ß) and nitrotyrosine, as well as fibroblast growth factor-23 (FGF-23), fibroblast growth factor receptor-1 (FGFR-1) and runt-related transcription factor-2 (Runx-2) expression. RESULTS: Nx animals presented higher serum creatinine levels as well as arterial hypertension. Higher PTH levels were associated with myocardial hypertrophy and fibrosis as well as a higher coronary lesion score. High PTH animals also presented a higher myocardial expression of TGF-ß, angiotensin II, FGF-23 and nitrotyrosine and a lower expression of α-actin. Phosphorus overload was associated with higher serum FGF-23 levels and Runx-2, as well as myocardial hypertrophy. FGFR-1 was positive in the cardiomyocytes of all groups as well as in calcified coronaries of G4 and G5 whereas Runx-2 was positive in G3, G4 and G5. CONCLUSION: In uremia, PTH and phosphorus overload are both independently associated with major changes related to the cardiac remodeling process, emphasizing the need for a better control of these factors in chronic kidney disease.
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Enfermedades Cardiovasculares/etiología , Fibrosis/etiología , Hormona Paratiroidea/metabolismo , Fósforo Dietético/metabolismo , Uremia/complicaciones , Uremia/fisiopatología , Animales , Biomarcadores/metabolismo , Enfermedades Cardiovasculares/patología , Fibrosis/patología , Técnicas para Inmunoenzimas , Masculino , Nefrectomía/efectos adversos , Hormona Paratiroidea/administración & dosificación , Paratiroidectomía/efectos adversos , Fósforo Dietético/administración & dosificación , Ratas , Ratas WistarRESUMEN
BACKGROUND: Fibroblast growth factor 23 (FGF23) concentrations increase early in chronic kidney disease (CKD), and the influence of current CKD-mineral and bone disorder (MBD) therapies on serum FGF23 levels is still under investigation. METHODS: In this post-hoc analysis of a randomized clinical trial, phosphate binders and calcitriol were washed out of 72 hemodialysis patients who were then submitted to bone biopsy, coronary tomography and biochemical measures, including FGF23. They were randomized to receive sevelamer or calcium acetate for 1 year and the prescription of calcitriol and the calcium concentration in the dialysate were adjusted according to serum calcium, phosphate and PTH and bone biopsy diagnosis. RESULTS: At baseline, bone biopsy showed that 58.3% had low-turnover bone disease, whereas 38.9% had high-turnover bone disease, with no significant differences between them with regard to FGF23. Median baseline FGF23 serum levels were elevated and correlated positively with serum phosphate. After 1 year, serum FGF23 decreased significantly. Repeated measures ANOVA analysis showed that the use of a 3.5-mEq/l calcium concentration in the dialysate, as well as the administration of calcitriol and a calcium-based phosphate binder were associated with higher final serum FGF23 levels. CONCLUSIONS: Taken together, our results confirm that the current CKD-MBD therapies have an effect on serum levels of FGF23. Since FGF23 is emerging as a potential treatment target, our findings should be taken into account in the decision on how to manage CKD-MBD therapy.
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Enfermedades Óseas/tratamiento farmacológico , Huesos/patología , Calcinosis/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Soluciones para Diálisis/uso terapéutico , Factores de Crecimiento de Fibroblastos/sangre , Factores de Crecimiento de Fibroblastos/efectos de los fármacos , Fallo Renal Crónico/terapia , Acetatos/administración & dosificación , Acetatos/farmacología , Adulto , Análisis de Varianza , Biopsia , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/farmacología , Enfermedades Óseas/complicaciones , Enfermedades Óseas/patología , Calcitriol/administración & dosificación , Calcitriol/farmacología , Calcio/administración & dosificación , Calcio/farmacología , Compuestos de Calcio/administración & dosificación , Compuestos de Calcio/farmacología , Quelantes/administración & dosificación , Quelantes/farmacología , Soluciones para Diálisis/química , Femenino , Factor-23 de Crecimiento de Fibroblastos , Estudios de Seguimiento , Humanos , Fallo Renal Crónico/complicaciones , Masculino , Persona de Mediana Edad , Fosfatos/sangre , Poliaminas/administración & dosificación , Poliaminas/farmacología , Sevelamer , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND AND OBJECTIVES: Fibroblast growth factor 23 (FGF-23) has emerged as a new factor in mineral metabolism in chronic kidney disease (CKD). An important regulator of phosphorus homeostasis, FGF-23 has been shown to independently predict CKD progression in nondiabetic renal disease. We analyzed the relation between FGF-23 and renal outcome in diabetic nephropathy (DN). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: DN patients participating in a clinical trial (enalapril+placebo versus enalapril+losartan) had baseline data collected and were followed until June 2009 or until the primary outcome was reached. Four patients were lost to follow-up. The composite primary outcome was defined as death, doubling of serum creatinine, and/or dialysis need. RESULTS: At baseline, serum FGF-23 showed a significant association with serum creatinine, intact parathyroid hormone, proteinuria, urinary fractional excretion of phosphate, male sex, and race. Interestingly, FGF-23 was not related to calcium, phosphorus, 25OH-vitamin D, or 24-hour urinary phosphorus. Mean follow-up time was 30.7±10 months. Cox regression showed that FGF-23 was an independent predictor of the primary outcome, even after adjustment for creatinine clearance and intact parathyroid hormone (10 pg/ml FGF-23 increase = hazard ratio, 1.09; 95% CI, 1.01 to 1.16, P=0.02). Finally, Kaplan-Meier analysis showed a significantly higher risk of the primary outcome in patients with FGF-23 values of >70 pg/ml. CONCLUSIONS: FGF-23 is a significant independent predictor of renal outcome in patients with macroalbuminuric DN. Further studies should clarify whether this relation is causal and whether FGF-23 should be a new therapeutic target for CKD prevention.
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Albuminuria/sangre , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/sangre , Factores de Crecimiento de Fibroblastos/sangre , Anciano , Albuminuria/tratamiento farmacológico , Albuminuria/etiología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Biomarcadores/sangre , Brasil , Distribución de Chi-Cuadrado , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/etiología , Progresión de la Enfermedad , Método Doble Ciego , Quimioterapia Combinada , Enalapril/uso terapéutico , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Estimación de Kaplan-Meier , Losartán/uso terapéutico , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Bone disease is a common disorder of bone remodeling and mineral metabolism, which affects patients with chronic kidney disease. Minor changes in the serum level of a given mineral can trigger compensatory mechanisms, making it difficult to evaluate the role of mineral disturbances in isolation. The objective of this study was to determine the isolated effects that phosphate and parathyroid hormone (PTH) have on bone tissue in rats. Male Wistar rats were subjected to parathyroidectomy and 5/6 nephrectomy or were sham-operated. Rats were fed diets in which the phosphate content was low, normal, or high. Some rats received infusion of PTH at a physiological rate, some received infusion of PTH at a supraphysiological rate, and some received infusion of vehicle only. All nephrectomized rats developed moderate renal failure. High phosphate intake decreased bone volume, and this effect was more pronounced in animals with dietary phosphate overload that received PTH infusion at a physiological rate. Phosphate overload induced hyperphosphatemia, hypocalcemia, and changes in bone microarchitecture. PTH at a supraphysiological rate minimized the phosphate-induced osteopenia. These data indicate that the management of uremia requires proper control of dietary phosphate, together with PTH adjustment, in order to ensure adequate bone remodeling.
Asunto(s)
Huesos/efectos de los fármacos , Hormona Paratiroidea/farmacología , Animales , Enfermedades Óseas Metabólicas , Remodelación Ósea/efectos de los fármacos , Huesos/metabolismo , Humanos , Enfermedades Renales , Fallo Renal Crónico/sangre , Masculino , Glándulas Paratiroides/efectos de los fármacos , Glándulas Paratiroides/metabolismo , Hormona Paratiroidea/sangre , Paratiroidectomía , Fosfatos/sangre , Ratas , Ratas Wistar , Insuficiencia Renal/metabolismo , Uremia/metabolismoRESUMEN
BACKGROUND AND OBJECTIVES: Levels of parathyroid hormone (PTH) and the phosphaturic hormone FGF23, a fibroblast growth factor (FGF) family member, increase early in chronic kidney disease (CKD) before the occurrence of hyperphosphatemia. This short-term 6-wk dose titration study evaluated the effect of two phosphate binders on PTH and FGF23 levels in patients with CKD stages 3 to 4. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Patients were randomized to receive over a 6-wk period either calcium acetate (n = 19) or sevelamer hydrochloride (n = 21). RESULTS: At baseline, patients presented with elevated fractional excretion of phosphate, serum PTH, and FGF23. During treatment with both phosphate binders there was a progressive decline in serum PTH and urinary phosphate, but no change in serum calcium or serum phosphate. Significant changes were observed for FGF23 only in sevelamer-treated patients. CONCLUSIONS: This study confirms the positive effects of early prescription of phosphate binders on PTH control. Prospective and long-term studies are necessary to confirm the effects of sevelamer on serum FGF23 and the benefits of this decrease on outcomes.
Asunto(s)
Acetatos/uso terapéutico , Enfermedades Óseas Metabólicas/tratamiento farmacológico , Quelantes/uso terapéutico , Factores de Crecimiento de Fibroblastos/sangre , Hiperparatiroidismo Secundario/tratamiento farmacológico , Enfermedades Renales/tratamiento farmacológico , Hormona Paratiroidea/sangre , Poliaminas/uso terapéutico , Adulto , Biomarcadores/sangre , Enfermedades Óseas Metabólicas/sangre , Enfermedades Óseas Metabólicas/etiología , Compuestos de Calcio/uso terapéutico , Enfermedad Crónica , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Hiperparatiroidismo Secundario/sangre , Hiperparatiroidismo Secundario/etiología , Enfermedades Renales/sangre , Enfermedades Renales/complicaciones , Masculino , Persona de Mediana Edad , Fosfatos/sangre , Proyectos Piloto , Sevelamer , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Vascular calcification (VC) is commonly seen in patients with chronic kidney disease (CKD). Elevated levels of phosphate and parathormone (PTH) are considered nontraditional risk factors for VC. It has been shown that, in vitro, phosphate transforms vascular smooth muscle cells (VSMCs) into calcifying cells, evidenced by upregulated expression of runt-related transcription factor 2 (Runx2), whereas PTH is protective against VC. In addition, Runx2 has been detected in calcified arteries of CKD patients. However, the in vivo effect of phosphate and PTH on Runx2 expression remains unknown. METHODS: Wistar rats were submitted to parathyroidectomy, 5/6 nephrectomy (Nx) and continuous infusion of 1-34 rat PTH (at physiological or supraphysiological rates) or were sham-operated. Diets varied only in phosphate content, which was low (0.2%) or high (1.2%). Biochemical, histological, immunohistochemistry and immunofluorescence analyses were performed. RESULTS: Nephrectomized animals receiving high-PTH infusion presented VC, regardless of the phosphate intake level. However, phosphate overload and normal PTH infusion induced phenotypic changes in VSMCs, as evidenced by upregulated aortic expression of Runx2. High-PTH infusion promoted histological changes in the expression of osteoprotegerin and type I collagen in calcified arteries. CONCLUSIONS: Phosphate, by itself is a potential pathogenic factor for VC. It is of note that phosphate overload, even without VC, was associated with overexpression of Runx2 in VSMCs. The mineral imbalance often seen in patients with CKD should be corrected.
Asunto(s)
Aorta Torácica/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Hormona Paratiroidea/metabolismo , Fósforo/metabolismo , Uremia/metabolismo , Animales , Aorta Torácica/patología , Calcinosis/epidemiología , Calcinosis/metabolismo , Calcinosis/patología , Colágeno Tipo I/metabolismo , Modelos Animales de Enfermedad , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Nefrectomía , Osteoprotegerina/metabolismo , Paratiroidectomía , Fenotipo , Fósforo/administración & dosificación , Fósforo Dietético , Ratas , Ratas Wistar , Factores de Riesgo , Uremia/patologíaRESUMEN
BACKGROUND: Hyperphosphatemia and disturbances in calcium or parathyroid hormone (PTH) metabolism contribute to the high incidence of cardiovascular disease and renal osteodystrophy in chronic renal failure (CRF). We evaluated the effect of hyperphosphatemia on the cardiovascular system, on renal function, and on bone in experimental uremia. METHODS: Wistar rats were submitted to parathyroidectomy (PTx) and 5/6 nephrectomy (Nx) with minipump implantation, delivering 1-34 rat PTH (physiologic rate), or were sham-operated and received vehicle. Only phosphorus content (low-phosphorus (LP) 0.2%; high-phosphorus (HP) 1.2%) differentiated diets. We divided the groups as follows: PTx +Nx +LP; sham + LP; PTx + Nx + HP; and sham + HP. Tail-cuff pressure and weight were measured weekly. After 2 months, biochemical, arterial, and myocardial histology and bone histomorphometry were analyzed. RESULTS: Heart weight normalized to body weight (heart weight/100 g body weight) was higher in PTx + Nx + HP rats (PTx + Nx + HP = 0.36 +/- 0.01 vs. sham + HP = 0.29 +/- 0.01, PTx + Nx + LP = 0.32 +/- 0.01, sham + LP = 0.28 +/- 0.01) (P < 0.05). Serum creatinine levels were higher in PTx + Nx + HP rats than in PTx + Nx + LP rats (1.09 +/- 0.13 vs. 0.59 +/- 0.03 mg/dL) (P < 0.05). Levels of PTH did not differ significantly between the groups. Myocardial and arterial histology detected no vascular calcification or fibrosis. Bone histomorphometry revealed an association, unrelated to uremia, between HP diets and decreased trabecular connectivity. CONCLUSION: Myocardial hypertrophy, impaired renal function, and adverse effects on bone remodeling were associated with hyperphosphatemia and were not corrected by PTH replacement. Although no vascular calcification was observed in this model, we cannot rule out an adverse effect of hyperphosphatemia on the vascular bed. Our finding underscores the importance of phosphorus control in reducing morbidity and mortality in CRF patients.