RESUMEN
UNLABELLED: Chronic kidney disease increases the risk of hip fractures which can be promoted by dementia. We here showed that dementia increased the risk of hip fractures in dialysis patients, but in a similar manner than without dialysis. Attention should be paid to dementia to prevent hip fractures. INTRODUCTION: Hip fractures (HF) are associated with significant morbidity and is further increased in patients with chronic kidney disease (CKD). Dementia, frequent in CKD, might be a risk factor for HF. We here aimed to assess if dementia increased the risk of hip fracture in CKD. METHODS: The study was derived from the French National Database of Hospitalization. Data were obtained over the period 2011-2013. Three populations of subjects >60 years were extracted. Hip fractures, dialysis, and dementia were the main studied factors. The three populations were crossed to estimate the fracture risk based on dementia or dialysis, adjusted for age and gender. The fracture risk was calculated using a multiple logistic regression model. RESULTS: Over this period, 213,180 patients experienced a HF, 660,434 patients were diagnosed for dementia, and 47,430 patients were on dialysis. There was an effect of age and gender on the incidence of HF and dementia. In CKD patients, the risk of HF was significantly higher in demented patients compared to those without dementia: OR 2.0 [95 % CI 1.7-2.4], this being the same for men (OR 2.4 [1.8-3.1]) and women (OR 2.6 [2.0-3.3]) and at any age. However, the adjusted risk for HF in demented patients on dialysis therapy is not different than in demented patients without CKD (OR 1.3 [1.0-1.6]). CONCLUSIONS: Dementia significantly increases the risk of HF in patients on dialysis, but this risk in demented patients is equally high whether receiving dialysis therapy or not. These results highlight dementia as a major risk factor for HF in dialysis and indicate that reduction of fracture risk should include dementia as a risk factor.
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Demencia/complicaciones , Fracturas de Cadera/etiología , Fallo Renal Crónico/complicaciones , Fracturas Osteoporóticas/etiología , Distribución por Edad , Anciano , Anciano de 80 o más Años , Bases de Datos Factuales , Demencia/epidemiología , Femenino , Francia/epidemiología , Fracturas de Cadera/epidemiología , Humanos , Fallo Renal Crónico/epidemiología , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Fracturas Osteoporóticas/epidemiología , Prevalencia , Diálisis Renal , Factores de Riesgo , Distribución por SexoRESUMEN
UNLABELLED: In chronic kidney disease patients with secondary hyperparathyroidism (SHPT), the recommended K/DOQI™ target serum levels of parathyroid hormone (PTH), calcium (Ca) and phosphorus (P) are difficult to reach and maintain stable. We present the results of the French cohort from the European study ECHO which investigated the use and effectiveness of cinacalcet in real-world clinical practice. METHODS: An observational study of the SHPT management in dialysis patients, partially retrospective (from 6 months prior to cinacalcet initiation) and partially prospective (up to 12 months of cinacalcet treatment). RESULTS: Four hundred and eighty-five French patients were enrolled from 44 centres. Cinacalcet was given in combination with active vitamin D treatment (39%) and phosphate binders (87%). After 12 months, the proportion of patients reaching recommended K/DOQI™ target levels had increased from 2.5% to 28.8% for PTH, from 46.8% to 50.1% for Ca, from 40.0% to 49.9% for P and 54.8% to 77.7% for the CaxP product. The proportions of patients using active vitamin D and sevelamer decreased by 6% and 20% respectively. Adverse events were reported in 37 (7.6%) patients, mainly nausea (2.1%), vomiting (2.1%) and dyspepsia (1.2%). CONCLUSIONS: The results of this study are consistent with data from controlled and randomized studies showing that cinacalcet increases the proportion of patients achieving the K/DOQI™ targets for PTH, Ca, P and CaxP in real-world clinical practice.
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Calcimiméticos/uso terapéutico , Hiperparatiroidismo Secundario/tratamiento farmacológico , Naftalenos/uso terapéutico , Anciano , Quelantes/uso terapéutico , Cinacalcet , Femenino , Francia , Humanos , Hiperparatiroidismo Secundario/etiología , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Poliaminas/uso terapéutico , Estudios Prospectivos , Diálisis Renal , Estudios Retrospectivos , Sevelamer , Vitamina D/uso terapéutico , Vitaminas/uso terapéuticoRESUMEN
AIMS: To evaluate the relationship between the severity of secondary hyperparathyroidism (SHPT) - defined in terms of baseline plasma intact parathyroid hormone (iPTH) level - and the magnitude of response to cinacalcet. MATERIALS AND METHODS: In this post hoc analysis, data were pooled from three randomized, placebo-controlled trials in which dialysis patients with iPTH ≥ 300 pg/ml were dose-titrated with cinacalcet or placebo in addition to conventional treatment to achieve iPTH ≤ 250 pg/ml. In 953 patients analyzed (cinacalcet, 545; placebo, 408), baseline iPTH levels were categorized in 100 pg/ml intervals (300 - ≥ 1,000 pg/ml), and the impact of baseline iPTH on changes in iPTH, phosphate (P), calcium (Ca) and calcium- phosphate product (Ca × P) was evaluated. RESULTS: Cinacalcet reduced iPTH (47% reduction), P (9%), Ca (7%), and Ca × P (15%) across all subgroups. For patients receiving cinacalcet, the mean percentage reduction from baseline in iPTH varied from 35 to 55%, being consistently decreased across the severity subgroups. The mean absolute change in iPTH was more pronounced in patients with higher baseline iPTH levels, particularly in the ≥ 1,000 pg/ml subgroup vs. the other subgroups. However, as baseline iPTH levels increased, iPTH ≤ 250 pg/ml was achieved in fewer patients. A trend towards greater absolute change from baseline was observed for P in patients with more severe disease (iPTH ≥ 800 pg/ml) treated with cinacalcet compared with patients with less severe disease (iPTH 300 - < 800 pg/ml). CONCLUSIONS: Cinacalcet lowers plasma iPTH and serum P, Ca and Ca × P levels in dialysis patients with SHPT, regardless of disease severity. Patients with more severe disease experienced greater reductions in PTH and P, but fewer achieved iPTH ≤ 250 pg/ml by the efficacy assessment phase. Use of cinacalcet when baseline PTH is lower may result in more stable control of SHPT and help to control bone and mineral alterations.
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Calcimiméticos/uso terapéutico , Calcio/sangre , Hiperparatiroidismo Secundario/tratamiento farmacológico , Naftalenos/uso terapéutico , Hormona Paratiroidea/sangre , Fosfatos/sangre , Adulto , Anciano , Anciano de 80 o más Años , Cinacalcet , Femenino , Humanos , Hiperparatiroidismo Secundario/sangre , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto JovenRESUMEN
AIMS: The pan-European ECHO observational study evaluated cinacalcet in adult dialysis patients with secondary hyperparathyroidism (SHPT) in "real-world" clinical practice. A sub-analysis compared data for 7 European countries/country clusters: Austria, CEE (Czech Republic and Slovakia), France, Italy, Netherlands, Nordics (Denmark, Finland, Norway, and Sweden), and the UK/Ireland. METHODS: Data on serum intact parathyroid hormone (iPTH), phosphorous, calcium, as well as the usage of cinacalcet, active vitamin D analogues and phosphate binders were compared. RESULTS: 1,865 patients (mean age 58 years) were enrolled: median baseline iPTH levels ranged from 605 pg/ml in Austria to 954 pg/ml in the UK/Ireland. After ~1 year of cinacalcet, median iPTH reductions from baseline ranged from 38% in the UK/Ireland to 58% in the Netherlands. The proportion of patients achieving NKF/K-DOQITM iPTH targets (150 - 300 pg/ml) at Month 12 ranged from 14% in the UK/Ireland to 40% in CEE. In general, use of sevelamer decreased, while use of calcium-based phosphate binders increased, during cinacalcet treatment. Vitamin D changes were more variable. CONCLUSION: The iPTH level at which cinacalcet is initiated in clinical practice differs considerably among different countries: where cinacalcet was started at a lower iPTH level this resulted in better achievement of serum iPTH targets.
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Hiperparatiroidismo Secundario/tratamiento farmacológico , Naftalenos/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Cinacalcet , Europa (Continente) , Femenino , Humanos , Hiperparatiroidismo Secundario/sangre , Fallo Renal Crónico/sangre , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Estudios Prospectivos , Diálisis Renal , Estudios Retrospectivos , Resultado del TratamientoAsunto(s)
Enfermedades Óseas Metabólicas/etiología , Enfermedades Óseas Metabólicas/prevención & control , Fallo Renal Crónico/complicaciones , Enfermedades Metabólicas/etiología , Enfermedades Metabólicas/prevención & control , Minerales/metabolismo , Guías de Práctica Clínica como Asunto , Programas Informáticos , HumanosRESUMEN
Objetivo. Analizar los factores que afectan a la supervivencia de sujetos tratados con hemiartroplastia tras una fractura subcapital de fémur.Material y método. Estudio retrospectivo de 1.196 fracturas subcapitales consecutivas en 1.166 pacientes tratados con hemiartroplastia de Thompson tras una fractura subcapital de fémur entre 1989 y 2001. Se realizó seguimiento clínico de una muestra aleatoria de 220 fracturas; de éstas, 210 casos fueron seguidos al menos dos años o hasta el fallecimiento (95,5%). Se realizó un análisis multivariante del efecto de laedad, el sexo, las enfermedades asociadas, la demora de la intervención quirúrgica y las complicaciones postoperatorias en la supervivencia. Se analizó también la supervivencia de los implantes.Resultados. La mediana de supervivencia fue de 4,5 años. El sexo masculino incrementaba la mortalidad (riesgo relativo [RR]= 2,47; intervalo de confianza para un 95% [IC 95%]: 1,65-3,70; p < 0,001) y también la edad avanzada (RR = 1,04; IC 95%: 1,01-1,07; p = 0,005). La demora de la intervención quirúrgica no afectaba la supervivencia a largo plazo, pero sí a los 6 meses teniendo los operados en el día del ingreso unamortalidad superior a la de los operados en los primeros 10 días tras el ingreso (33,3% frente a 10,4%; odds ratio [OR] = 4,38; IC 95%:1,12-16,5; p = 0,03). Sólo tres implantes fueron retirados, todos ellos por aflojamiento aséptico.Conclusiones. Los factores que más aumentan la mortalidaden este grupo de pacientes son el sexo masculino, laedad y la presencia de enfermedades. Una demora de la intervención de 24 horas puede aumentar la supervivencia a corto plazo. Los implantes rara vez fracasan
Purpose. To analyze the factors that affect the survivorship of subjects treated by hemiarthroplasty after a femoral neck fracture.Materials and methods. This is a retrospective study of1196 consecutive subcapital fractures in 1166 patients treated with a Thompson hemiarthroplasty between 1989 and2001 for a femoral neck fracture. A clinical follow-up was made of a random sample of 220 fractures. Of these, 210 cases were followed up for at least two years or until the patients death (95.5%). A multivariate analysis was carried out of the effect on survivorship of age, gender, associated conditions, delay of surgery and post-op complications. Implant survivorship was also analyzed.Results. Median survivorship was 4.5 years. Male genderhad a higher mortality rate (RR = 2.47, 95% confidence interval: 1.65-3.70; p < 0.001) as did old age (RR = 1.04, CI: 1.01-1.07; p = 0.005). Although, delay of surgery did not affect long-term survivorship, it did affect survivorship at 6 months: patients operated the same day they were admitted had a higher mortality rate than those operated in the first 10 days after admission (33.3% vs. 10.4%; OR = 4.38; CI: 1.12-16.5; p = 0.03). Only three implants had to be explanted,all of them further to aseptic loosening.Conclusions. The factors that most significantly contribute to mortality in this group of patients are male gender, age and the presence of a disease. A 24-hour delay of surgery can increase short-term survivorship. Implants rarely fail (AU)
Asunto(s)
Humanos , Fracturas del Fémur/cirugía , Artroplastia/métodos , Supervivencia , Implantación de Prótesis , Estudios Retrospectivos , Fracturas del Fémur/mortalidadRESUMEN
The extracellular calcium-sensing receptor (CaR) on the parathyroid cell surface negatively regulates secretion of parathyroid hormone (PTH). Its activation by small changes in the extracellular concentration of ionized calcium (ec[Ca2+]) decreases PTH secretion and secondarily bone turnover. CaR is an ideal target for compounds that may be developed to modulate its activity - activating calcimimetics and inhibiting calcilytics. Calcimimetics can amplify the sensitivity of the CaR to ec(Ca2+), thereby suppressing PTH levels and in turn reducing blood Ca++. They dose-dependently reduce the secretion of PTH in cultured parathyroid cells, in animal models and in humans. In uremic animals, these compounds prevent parathyroid cell hyperplasia when given at the onset of the disease and stop cell proliferation if they are administered afterwards, when the hyperplasia already exists. They normalize plasma PTH levels and bone remodeling. In uremic patients undergoing hemodialysis, calcimimetics reduce plasma PTH concentrations in the short (12 weeks) and long (2 years) terms. They also reduce serum levels of calcium-phosphorus product. Calcimimetics are therefore an alternative for the treatment of secondary hyperparathyroidism, particularly in dialysis patients, when increased serum levels of calcium-phosphorus product, the attendant risk of cardiovascular calcification, and its lack of efficacy limit use of the standard treatment.
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Compuestos de Anilina/uso terapéutico , Calcio/agonistas , Hiperparatiroidismo/tratamiento farmacológico , Naftalenos/uso terapéutico , Receptores Sensibles al Calcio/efectos de los fármacos , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/farmacología , Animales , Remodelación Ósea , Células Cultivadas , Cinacalcet , Método Doble Ciego , Femenino , Humanos , Hiperparatiroidismo Primario/tratamiento farmacológico , Hiperparatiroidismo Secundario/tratamiento farmacológico , Hiperplasia , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Naftalenos/administración & dosificación , Naftalenos/farmacología , Glándulas Paratiroides/citología , Glándulas Paratiroides/patología , Hormona Paratiroidea/sangre , Hormona Paratiroidea/metabolismo , Neoplasias de las Paratiroides/tratamiento farmacológico , Fenetilaminas , Propilaminas , Ensayos Clínicos Controlados Aleatorios como Asunto , Ratas , Diálisis Renal , Factores de Riesgo , Factores de Tiempo , Uremia/tratamiento farmacológico , Uremia/terapiaAsunto(s)
Anemia/tratamiento farmacológico , Hiperparatiroidismo/tratamiento farmacológico , Enfermedades Renales/complicaciones , Vasculitis/tratamiento farmacológico , Anemia/sangre , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Calcio/sangre , Humanos , Enfermedades Renales/sangre , Enfermedades Renales/inmunología , Hormona Paratiroidea/sangre , Fósforo/sangre , Vasculitis/inmunologíaRESUMEN
BACKGROUND: Secondary hyperparathyroidism (secondary HPT) in patients with chronic renal failure (CRF) is characterized by parathyroid gland hyperplasia and an intrinsic defect in the recognition of parathyroid hormone (PTH) secretion. Conflicting results have been reported regarding the set point for calcium-regulated PTH release and its modification by calcitriol therapy in hemodialysis patients. Additionally, the effect of calcitriol on the calcium/PTH relationship in predialysis CRF patients with early secondary HPT has not been investigated. Our objective in this controlled study was to investigate the calcium/PTH relationship and to determine the calcium set point in patients with early stages of CRF before and after a 1-year treatment with calcitriol and in normal volunteers. METHODS: Nine patients with an early stage of CRF (GFR between 20 and 50 ml/min x 1.73 m2 b.s.) aged 35-77 years and 13 healthy volunteers (HV) aged 26-60, years were included in the study. All participants were investigated by sequential lowering and raising of serum calcium levels comprising the following phases: blood-ionized calcium (Ca2+) was lowered by about 0.2 mmol/l (3 steps), steady-state hypocalcemia of Ca2+ 0.2 mmol/l below the baseline (step 4), stop of the infusion for 5 minutes (step 5), Ca2+ was raised to about 0.2 mmol/l above baseline (steps 6 and 7), and a steady state hypercalcemia of Ca2+ 0.2 mmol/l above baseline (step 8). Ionized calcium and intact PTH (iPTH) were measured at 30 time points during 240 minutes. The calcium set point was determined using the classical 4-parameter model. The CiCa clamp test was performed before and after a 1-year treatment with 0.5 microg of calcitriol thrice weekly. RESULTS: No differences in the set point were observed between HV and CRF patients with early secondary HPT. Four of 9 patients responded to calcitriol treatment with a decrease in basal serum iPTH levels ("responders"). There was no difference between renal function (GFR 18 +/- 6 vs. 17 +/- 8 ml/min x 1.73 m2 b.s.), set point (Ca2+ 1.07 +/- 0.13 vs. 1.07 +/- 0.06 mmol/l) and suppressibility of PTH secretion (PTHmin% 7.3 +/- 1.6 vs. 8.2 +/- 2.9) in responders vs non-responders, nor did these values change after treatment with calcitriol. PTHmin% decreased significantly in the whole group after treatment (10.4 +/- 8.5 vs. 7.8 +/- 2.4). CONCLUSIONS: Although the calcium set point was not different in predialysis CRF patients with early secondary HPT compared to HV, calcitriol treatment improved the calcium-related suppression of PTH secretion (PTHmin%).
Asunto(s)
Calcitriol/uso terapéutico , Agonistas de los Canales de Calcio/uso terapéutico , Hiperparatiroidismo Secundario/diagnóstico , Fallo Renal Crónico/metabolismo , Hormona Paratiroidea/metabolismo , Adulto , Calcio/sangre , Estudios de Casos y Controles , Citratos , Humanos , Persona de Mediana Edad , Diálisis RenalRESUMEN
Since its discovery in 1923, the parathyroid hormone (PTH), was thought to be the sole hormone capable of stimulating bone resorption, renal tubular calcium reabsorption, calcitriol synthesis, and urinary excretion of phosphate. However, in 1987, the PTHrP (PTH-related peptide), was demonstrated to share most of the biological actions of PTH through the activation of the same receptor. This receptor was cloned in 1992 and named PTH/PTHrP receptor or PTH-R1. Both, PTH and PTHrP bind with great affinity to PTH-R1 and stimulate a signal transduction system involving different G-proteins, phospholipase C, and adenylate cyclase. A third member of the PTH family, the TIP-39 (tuberoinfundibular peptide), binds and activates another PTH receptor (PTH-R2). There is evidence for other PTH receptors, a PTH-R3, probably specific for PTHrP in keratinocytes, kidney, placenta and a PTH-R4 specific for C-terminal PTH fragments. Activating mutations in the PTH-R1 gene cause Jansen type metaphyseal chondrodysplasia, whereas inactivating mutations are responsible for Blomstrand type rare chondrodysplasia and enchondromatosis. The renal and bone PTH-R1 expression is upregulated in vitamin D deficient rats and by endotoxin, interleukin-2, dexamethasone, T3, and TGF beta. On the contrary, PTH, PTHrP, angiotensin-II, IGF-1, PGE2, vitamin D, and chronic renal failure decrease its expression. In conclusions, the biological implications of the identification and cloning of different PTH receptors are at their beginning. The almost ubiquitous distribution of PTHrP and PTH-R1, the numerous PTHrP and PTH fragments, let us suppose the existence of other PTH-related receptors, and a great complexity of the bone and mineral metabolism.
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Huesos/metabolismo , Minerales/metabolismo , Hormona Paratiroidea/fisiología , Hormonas Peptídicas/fisiología , Receptores de Hormona Paratiroidea/fisiología , Animales , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/fisiopatología , Encondromatosis/genética , Endotoxinas/farmacología , Regulación de la Expresión Génica , Sustancias de Crecimiento/fisiología , Humanos , Interleucina-3/fisiología , Fallo Renal Crónico/fisiopatología , Túbulos Renales/metabolismo , Neuropéptidos/fisiología , Osteocondrodisplasias/genética , Proteína Relacionada con la Hormona Paratiroidea , Conformación Proteica , Ratas , Receptor de Hormona Paratiroídea Tipo 1 , Receptores de Hormona Paratiroidea/genética , Transducción de Señal , Deficiencia de Vitamina D/complicacionesRESUMEN
Desde su descubrimiento en el año 1923, la hormona paratiroidea (PTH) era la única capaz de estimular la resorción ósea, la reabsorción tubular de calcio, la eliminación renal de fósforo y la síntesis de calcitriol. Sin embargo, en 1987 se identificó el PTHrP (PTH-related peptide), el cual ejerce la mayoría de las funciones biológicas de la PTH a través del mismo receptor. Ese receptor, PTH/PTHrP o PTH-R1, fue clonado en el 1992. Las dos moléculas, PTH y PTHrP se ligan a él con gran afinidad y estimulan un sistema de transducción que implica la activación de diferentes proteínas G, la fosfolipasa C y la adenilciclasa. Un tercer miembro de la familia PTH, el TIP-39 (tuberoinfundibular peptide), se liga y activa otro receptor de la PTH, el PTH-R2. También, hay evidencias de la existencia de otros receptores de la PTH (PTH-R3, PTH-R4). Las mutaciones activadoras del PTH-R1 provocan la condrodisplasia metafisaria de tipo Jansen y las mutaciones inactivadoras son responsables de otra condrodisplasia rara, la enfermedad de Blomstrand y de ciertas encondromatosis. La expresión del PTH-R1 aumenta en el riñón y el hueso de ratas deficientes en vitamina D y en respuesta a las endotoxinas, la interleuquina-2, la dexametasona, la T3 y el TGFβ. Al contrario, la PTH, el PTHrP, la angiotensina-II, el IGF-1, la PGE2, la vitamina D y la insuficiencia renal crónica la disminuyen. En conclusión, las implicaciones biológicas del clonaje de los receptores de la PTH son innumerables. El hecho que el PTHrP y el PTH-R1 sean ubicuos y el hecho que hay varios fragmentos circulantes del PTHrP y de la PTH, supone la existencia de otros receptores específicos de esos fragmentos y por supuesto que el metabolismo mineral y óseo es mucho más complejo de lo imaginado (AU)
Since its discovery in 1923, the parathyroid hormone (PTH), was thought to be the sole hormone capable of stimulating bone resorption, renal tubular calcium reabsorption, calcitriol synthesis, and urinary excretion of phosphate. However, in 1987, the PTHrP (PTH-related peptide), was demonstrated to share most of the biological actions of PTH through the activation of the same receptor. This receptor was cloned in 1992 and named PTH/PTHrP receptor or PTH-R1. Both, PTH and PTHrP bind with great affinity to PTH-R1 and stimulate a signal transduction system involving different G-proteins, phospholipase C, and denylate cyclase. A third member of the PTH family, the TIP-39 (tuberoinfundibular peptide), binds and activates another PTH receptor (PTH-R2). There is evidence for other PTH receptors, a PTH-R3, probably specific for PTHrP in keratinocytes, kidney, placenta and a PTH-R4 specific for C-terminal PTH fragments. Activating mutations in the PTH-R1 gene cause Jansen type metaphyseal chondrodysplasia, whereas inactivating mutations are responsible for Blomstrand type rare chondrodysplasia and enchondromatosis. The renal and bone PTH-R1 expression is upregulated in vitamin D deficient rats and by endotoxin, interleukin-2, dexamethasone, T3, and TGFβ. On the contrary, PTH, PTHrP, angiotensin-II, IGF-1, PGE2, vitamin D, and chronic renal failure decrease its expression. In conclusions, the biological implications of the identification and cloning of different PTH receptors are at their beginning. The almost ubiquitous distribution of PTHrP and PTH-R1, the numerous PTHrP and PTH fragments, let us suppose the existence of other PTH-related receptors, and a great complexity of the bone and mineral metabolism (AU)
Asunto(s)
Humanos , Animales , Ratas , Huesos/metabolismo , Minerales/metabolismo , Hormona Paratiroidea/fisiología , Proteína Relacionada con la Hormona Paratiroidea , Hormonas Peptídicas/fisiología , Receptor de Hormona Paratiroídea Tipo 1 , Receptores de Hormona Paratiroidea/genética , Receptores de Hormona Paratiroidea/fisiología , Encondromatosis/genética , Endotoxinas/farmacología , Regulación de la Expresión Génica , Sustancias de Crecimiento/fisiología , Interleucina-3/fisiología , Fallo Renal Crónico/fisiopatología , Túbulos Renales/metabolismo , Neuropéptidos/fisiología , Osteocondrodisplasias/genética , Conformación Proteica , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/fisiopatología , Transducción de Señal , Deficiencia de Vitamina D/complicacionesRESUMEN
Parathyroid glands, bones, intestines and kidneys closely regulate ionized extracellular calcium concentration and thereby bone mineral density. This regulation is accomplished by a membrane associated receptor that responds to small changes in the extracellular calcium concentration (Ca2+)ec. The activation of this receptor regulates the secretion of PTH and the urinary excretion of calcium. The cloning of this calcium sensing receptor (RCa) in 1993 has allowed the identification of several hereditary disorders characterized by either a hyperparathyroidism or a hypoparathyroidism, as well as the development of pharmaceutical compounds potentially of interest for the treatment of these diseases. The calcimimetics are able either to directly stimulate the RCa or to make the RCa more sensitive to the effects of (Ca2+)ec. By this way, they decrease the secretion of PTH, but they also stimulate the secretion of calcitonin. The first clinical studies with a first-generation calcimimetic have demonstrated their efficacy lowering plasma intact PTH concentration in uremic patients with secondary hyperparathyroidism. However, the low biodisponibility of these first calcimimetics predict a difficult clinical utilization. The preliminary results obtained with a second-generation calcimimetic, the AMG-073, are very promising and await long term evaluation. The goal of this manuscript is to review the physiological, biological and clinical bases for the development of calcimimetic. Moreover, to try to replace the potential use of these drugs in the context of chronic renal failure and in the treatment of secondary hyperparathyroidism.
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Proteínas de Unión al Calcio/agonistas , Proteínas de Unión al Calcio/antagonistas & inhibidores , Calcio/fisiología , Glándulas Paratiroides/fisiología , Animales , Calcio/orina , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/fisiología , Clonación Molecular , Regulación de la Expresión Génica , Humanos , Hiperparatiroidismo/tratamiento farmacológico , Hipoparatiroidismo/tratamiento farmacológico , Hormona Paratiroidea/biosíntesis , Hormona Paratiroidea/metabolismoRESUMEN
Vitamin D derivatives correct high bone remodeling by decreasing plasma iPTH concentration in uremic patients with secondary hyperparathyroidism. However, without bone biopsy, plasma iPTH alone might not provide sufficient information regarding vitamin D-induced bone changes. Plasma bone-specific alkaline phosphatase (bAP) seems more sensitive than iPTH in assessing the degree of bone remodeling. We prospectively studied the evolution of iPTH and bAP in 14 adult hemodialysis patients treated for 1 year by i.v. alfacalcidol pulses. The mean total alfacalcidol dose was 0.08 +/- 0.02 g/kg/week. Ten patients completed the study, 2 patients had to be parathyroidectomized before week 24 because of hypercalcemia and uncontrolled hyperphosphatemia, and 2 other patients died before week 36. Mean iPTH levels diminished from 826 +/- 300 pg/ml (range 507 - 1,500 pg/ml) at baseline to 436 +/- 371 pg/ml (range 18 - 1,095 pg/ml) after 52 weeks of treatment (48% of decrease). Only 2 patients normalized plasma iPTH levels while 8/10 normalized bAP. Five patients remained with plasma iPTH concentrations higher than 5-fold the normal value. In contrast, plasma bAP levels declined from 47.6 +/- 32.2 ng/ml (range 15.4 - 130.0 ng/ml) at baseline to 17.8 +/- 9.9 ng/ml (range 8.0 +/- 38.0 ng/ml) at week 52 (63% of decrease). Bone histomorphometry was available in 6 patients after 15.8 +/- 5.1 months of alfacalcidol treatment. None of them met the criteria of adynamic bone disease as they had increased bone resorption and marrow bone fibrosis. Bone formation rate was normal in 2 patients and unmeasurable in the other 4. Two patients showed signs of osteomalacia. In conclusion, alfacalcidol preferentially reduced bone formation rate rather than the other histological parameters of secondary hyperparathyroidism. It reduced plasma bAP more efficiently than iPTH.
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Adyuvantes Inmunológicos/administración & dosificación , Fosfatasa Alcalina/sangre , Fosfatasa Alcalina/efectos de los fármacos , Huesos/irrigación sanguínea , Huesos/metabolismo , Hidroxicolecalciferoles/administración & dosificación , Diálisis Renal , Adulto , Anciano , Biomarcadores/sangre , Biopsia , Huesos/patología , Calcio/sangre , Terapia Combinada , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Hormona Paratiroidea/sangre , Fósforo/sangre , Estudios Prospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Arterial hypotension, defined as a systolic blood pressure < 100 mmHg, is the most frequent complication in dialysis patients. Four types of hypotension can be identified: chronic, per-dialytic, hypotensive shock and the hypotension due to an unexpected cause. The pathophysiology is relatively well known when the hypotension is secondary to a decrease in the intravascular volume provoked by a sustained ultrafiltration rate during the dialysis session. However, new mechanisms also appear to play an-important role, namely, the dysfunction of the autonomic nervous system and the plasmatic accumulation of vasoactive substances such as adrenomedullin, nitric oxide, and asymmetric dimethyl arginine. Hypotensive episodes can be responsible of acute vascular complications such as myocardial ischemia, ischemic cerebro-vascular accidents, venous thrombosis (retina vein), intestinal ischemia and the aggravation of lower member arteritis. In the long-term, pre-dialysis hypotension has been found associated with an increased mortality rate. The goal of this article is to review the pathophysiological mechanisms involved in the arterial hypotension of dialysis patients, its treatment and the potential preventive measures.
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Hipotensión/etiología , Diálisis Renal/efectos adversos , Enfermedades del Sistema Nervioso Autónomo/complicaciones , Enfermedades Cardiovasculares/etiología , Humanos , Hipotensión/mortalidad , Hipotensión/prevención & control , Vasodilatadores/sangreRESUMEN
HYPOTHESIS: Parathyroid scanning, based on simultaneous recording of technetium Tc 99m sestamibi and iodine 123 images, is able to identify patients with multiple parathyroid gland disease and is a safe imaging technique for unilateral parathyroid surgery. DESIGN: Scintigraphic criteria of eligibility for unilateral surgery were prospectively tested against findings of conventional bilateral surgery. SETTING: Patients referred to an endocrine surgeon in a university hospital. PATIENTS: Seventy consecutive patients with primary hyperparathyroidism had dual-isotope scanning before conventional surgery. Forty-one patients had scan findings compatible with unilateral surgery, with a single focus of high intensity seen on the anterior and lateral views. The remaining 29 patients had 1 or more criteria of ineligibility: (1) scan findings pointing to multiple gland disease, (2) no well-identified focus, (3) contralateral thyroid nodule requiring surgical management, or (4) family history of hyperparathyroidism or multiple endocrine disease. MAIN OUTCOME MEASURES: Number of enlarged parathyroid glands at surgical inspection and calcemia follow-up. RESULTS: None of the 41 patients, with a single well-defined focus on the scan image, showed evidence of multiple parathyroid involvement. Each parathyroid adenoma was resected from the precise site predicted by the subtraction scan. Nine patients (13%) had surgical findings of multiple parathyroid gland disease. All 9 were ineligible based on preoperative image findings. CONCLUSIONS: Unilateral surgery can be safely offered to 60% of patients with primary hyperparathyroidism, on the basis of simultaneous (99m)Tc-sestamibi and (123)I scanning. This may reduce the length of the operation, anesthesia requirements, and hospital stay, and the risks of hypoparathyroidism and injury to the recurrent laryngeal nerve.
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Hiperparatiroidismo/diagnóstico por imagen , Hiperparatiroidismo/cirugía , Radioisótopos de Yodo , Radiofármacos , Tecnecio Tc 99m Sestamibi , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , CintigrafíaRESUMEN
Most chronic renal failure patients with severe refractory hyperparathyroidism harbor at least one monoclonal parathyroid tumor, but the specific acquired genetic defects that confer this clonal selective advantage remain poorly understood. Somatic inactivation of the vitamin D receptor (VDR) gene could contribute to clonal outgrowth, because a parathyroid cell containing this lesion would have an impaired response to the antiproliferative influence of 1,25-dihydroxyvitamin D3. Furthermore, diminished expression of VDR protein has been described in uremia-associated parathyroid tumors. Therefore, to assess VDR gene inactivation's potential pathogenetic role in this disease, we rigorously analyzed the VDR gene in 59 parathyroid tumors surgically resected from uremic patients. First, Southern blotting and/or PCR analyses of 29 tumor samples from 14 genetically informative patients revealed no allelic losses at the VDR locus. Next, direct DNA sequencing of all VDR splice junctions, associated intronic sequences, and virtually the entire VDR-coding region for all 59 tumors revealed no acquired mutations. Last, 37 tumor DNA samples were subjected to comparative genomic hybridization, and no chromosomal losses in the VDR region (12cen-q12) were observed. These observations suggest that inactivating defects within the VDR gene do not commonly contribute to the primary pathogenesis of severe refractory hyperparathyroidism in uremia.