RESUMEN
SUMMARY: The hormone fibroblast growth factor 23 (FGF23) is involved in mineral homeostasis but may also have a role in vascular calcification and bone mineralization. In a cohort of 142 patients with CKD stages 2-5D, plasma FGF23 was independently associated with aortic calcification but not with pulse wave velocity or bone mineral density. INTRODUCTION: FGF23 is involved in mineral homeostasis but may also have a role in vascular calcification and bone mineralization. Previous studies related to FGF23 and vascular and bone outcomes have been restricted to dialysis patients. The aim of the present study was to establish whether or not plasma FGF23 is associated with aortic and coronary calcification, arterial stiffness, and bone mineral density in patients with early as well as late stages of CKD. METHODS: In a cohort of 142 patients with CKD stages 2-5D, we made routine biochemistry and intact FGF23 determinations, and assessed aortic and coronary calcification, bone mineral density (BMD), and arterial stiffness by multislice spiral computed tomography and automated pulse wave velocity (PWV). RESULTS: Plasma intact FGF23 levels were elevated in CKD patients; the elevation preceded that of serum phosphate in early-stage CKD. Patients with elevated FGF23 levels had higher aortic and coronary calcification scores than patients with lower FGF23 levels. Multivariate linear regression analysis indicated that only age (p < 0.001) and FGF23 (p = 0.008) were independently associated with aortic calcification score. Plasma FGF23 was neither associated with PWV nor with BMD. CONCLUSION: Our data suggest that plasma FGF23 is an independent biomarker of vascular calcification in patients with various CKD stages including early stages. The association between vascular calcification and FGF23 levels appears to be independent of BMD. It remains to be seen whether this association is independent of bone turnover and bone mass.
Asunto(s)
Densidad Ósea/fisiología , Factores de Crecimiento de Fibroblastos/fisiología , Fallo Renal Crónico/sangre , Calcificación Vascular/sangre , Anciano , Enfermedades de la Aorta/sangre , Enfermedades de la Aorta/etiología , Biomarcadores/sangre , Velocidad del Flujo Sanguíneo/fisiología , Estudios de Cohortes , Enfermedad Coronaria/sangre , Enfermedad Coronaria/etiología , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Tasa de Filtración Glomerular/fisiología , Humanos , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/fisiopatología , Masculino , Persona de Mediana Edad , Tomografía Computarizada Multidetector/métodos , Flujo Pulsátil/fisiología , Índice de Severidad de la Enfermedad , Calcificación Vascular/etiología , Rigidez Vascular/fisiologíaRESUMEN
The non-invasive diagnosis of bone turnover in patients with chronic kidney disease (CKD) remains difficult compared with bone histomorphometry as the gold standard. Most clinicians rely on surrogate markers, mainly serum parathyroid hormone and total alkaline phosphatases, in association with serum calcium and phosphorus. Although very high serum PTH levels generally allow the diagnosis of high bone turnover, slight elevations, normal, or low values cannot allow a reliable distinction between normal or low turnover.
Asunto(s)
Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/diagnóstico , Hormona Paratiroidea/sangre , Biomarcadores/sangre , Femenino , Humanos , MasculinoRESUMEN
The blood pressure of the spontaneously hypertensive rat (SHR) is influenced by the Ca2+ content of its diet. As the SHR's greater dependence on dietary calcium may reflect a defect in intestinal calcium absorption, we measured in vitro unidirectional Ca2+ flux (J) in the duodenum-jejunum (four segments each) of the SHR (n = 6) and the normotensive Wistar-Kyoto rat (WKY; n = 6) by a modified Ussing apparatus. Because of the known and postulated interactions between Ca2+ and Na+ in both intestinal and vascular tissue, we assessed in vivo the influence of a concurrent manipulation of Na+ intake (three levels: 0.25%, 0.45%, and 1.0%) on the blood pressure development of SHRs (n = 35) and WKYs (n = 35), between 6 and 20 wk of age, exposed to three levels of dietary calcium (0.1, 1.0, and 2%). Net calcium flux (Jnet) (mean +/- SEM) was significantly (P less than 0.01) lower in the SHR (-2.8 +/- 6.3 nmol/cm2 X h) than in the WKY (34.6 +/- 8.8 nmol/cm2 X h). The SHR's decreased Jnet resulted from a significantly (P less than 0.03) lower mucosa-to-serosa flux (Jm-s) in the SHR (41.0 +/- 5.6 nmol/cm2 X h) compared with the Jm-s of the WKY (70.1 +/- 9.1 nmol/cm2 X h). Serosa-to-mucosa flux for calcium did not differ between the SHR (43.8 +/- 6.6 nmol/cm2 X h) and the WKY (35.5 +/- 8.0 nmol/cm2 X h). The SHR's decreased (P less than 0.002) Jm-s was confirmed by additional measurements in SHRs and WKYs. Jm-s was 36.2 +/- 3.7 nmol/cm2 X h in the SHRs (n = 11) and 64.4 +/- 6.7 nmol/cm2 X h in the WKYs (n = 9). The provision of an increased dietary Ca2+ (2% by weight) and increased Na+ (1%) to the SHR prevented the emergence of hypertension (P less than 0.001) (mean +/- SEM systolic blood pressure at 20 wk of age; 135 +/- 5 mmHg for the 2% Ca2+, 1% Na+ SHR vs. 164 +/- 2 mmHg for the control diet SHR). Ca2+ (0.1%) and Na+ (0.25%) restriction accelerated the SHR's hypertension (192 +/- 2 mmHg) (P less than 0.001) and was associated with higher pressures in the WKY (146 +/- 4 mmHg in the restricted WKY vs. 134 +/- 4 mmHg in the control WKY). In a parallel group of 24 SHRs and 24 WKYs fed one of three diets (2% Ca2+/1% Na+; 1% Ca2+/0.45% Na+; or 0.1% Ca2+/0.25% Na+), the heart (P < 0.05) and kidney (P = 0.08) weight of the SHRs varied depending on the diet at 20 wk of age. Low Ca2+ and Na+ intake was associated with increased heart weight (1.6+/-0.9 g) compared with the normal diet for SHR (1.51+/-0.07 g). Increased Ca2+ and Na+ intake was associated with a significantly (P = 0.05) lower heart weight in the SHR (1.37+/-0.03 g) and in the WKY (1.35+/-0.06 g) compared with their normal diet controls. These findings show one mechanism for the SHR's depressor response to supplemental dietary Ca2+ and, in part, explain the sodium dependence of calcium's cardiovascular protective effect.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Calcio de la Dieta/administración & dosificación , Mucosa Intestinal/metabolismo , Ratas Endogámicas SHR/fisiología , Ratas Endogámicas/fisiología , Cloruro de Sodio/administración & dosificación , Animales , Transporte Biológico Activo , Peso Corporal/efectos de los fármacos , Calcio de la Dieta/metabolismo , Dieta Hiposódica , Corazón/fisiología , Riñón/fisiología , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas WKYRESUMEN
Abnormalities of intestinal calcium absorption and the vitamin D axis in the spontaneously hypertensive rat (SHR) are controversial. The present report documents a reduction in circulating 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in the 12-14-wk-old male SHR with evidence of its functional significance. Both plasma 1,25(OH)2D3 and mucosa-to-serosa duodenal calcium flux (Jm-s), measured by the Ussing chamber, were significantly lower (approximately 60% of value in Wistar-Kyoto rats [WKY]) in SHR on both normal (1%) and low (0.1%) calcium diets than in corresponding control WKY. Low dietary calcium increased both 1,25(OH)2D3 and Jm-s by approximately 80% in SHR and WKY, with levels of both parameters rising in the SHR to levels found in the WKY under baseline conditions. The latter fact suggests the improbability of intestinal resistance to the action of 1,25(OH)2D3 in the SHR. Plasma 25-hydroxyvitamin D3 (25(OH)D3) was not significantly different between the strains. Intraperitoneal 1,25(OH)2D3 increased Jm-s in 12-14-wk-old SHR to levels observed in equivalent WKY. In 20-24-wk-old SHR, calcium deprivation was associated with significantly reduced Jm-s compared with equivalent WKY. Bone density and bone calcium content in 20-30-wk-old SHR were significantly reduced. In summary, we provide evidence that the SHR was unable to sustain appropriate circulating levels of 1,25(OH)2D3, an impairment which resulted in reduced duodenal calcium absorption.
Asunto(s)
Huesos/metabolismo , Calcio/metabolismo , Hipertensión/metabolismo , Absorción Intestinal , Vitamina D/metabolismo , Animales , Transporte Biológico Activo , Peso Corporal , Calcitriol/sangre , Densitometría , Dieta , Conductividad Eléctrica , Mucosa Intestinal/metabolismo , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Membrana Serosa/metabolismoRESUMEN
The pathogeneses of parathyroid disease in patients with uremia and nonfamilial primary parathyroid hyperplasia are poorly understood. Because of multigland involvement, it has been assumed that these common diseases predominantly involve polyclonal (non-neoplastic) cellular proliferations, but an overall assessment of their clonality has not been done. We examined the clonality of these hyperplastic parathyroid tumors using X-chromosome inactivation analysis with the M27 beta (DXS255) DNA polymorphism and by searching for monoclonal allelic losses at M27 beta and at loci on chromosome band 11q13. Fully 7 of 11 informative hemodialysis patients (64%) with uremic refractory hyperparathyroidism harbored at least one monoclonal parathyroid tumor (with a minimum of 12 of their 19 available glands being monoclonal). Tumor monoclonality was demonstrable in 6 of 16 informative patients (38%) with primary parathyroid hyperplasia. Histopathologic categories of nodular versus generalized hyperplasia were not useful predictors of clonal status. These observations indicate that monoclonal parathyroid neoplasms are common in patients with uremic refractory hyperparathyroidism and also develop in a substantial group of patients with sporadic primary parathyroid hyperplasia, thereby changing our concept of the pathogenesis of these diseases. Neoplastic transformation of preexisting polyclonal hyperplasia, apparently due in large part to genes not yet implicated in parathyroid tumorigenesis and possibly including a novel X-chromosome tumor suppressor gene, is likely to play a central role in these disorders.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 11 , Fallo Renal Crónico/genética , Fallo Renal Crónico/patología , Glándulas Paratiroides/patología , Neoplasias de las Paratiroides/genética , Neoplasias de las Paratiroides/patología , Adulto , Anciano , Southern Blotting , Mapeo Cromosómico , ADN/análisis , ADN de Neoplasias/análisis , Femenino , Humanos , Hiperplasia , Fallo Renal Crónico/complicaciones , Persona de Mediana Edad , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/patología , Neoplasias de las Paratiroides/complicaciones , Polimorfismo Genético , Mapeo Restrictivo , Aberraciones Cromosómicas Sexuales , Cromosoma XRESUMEN
The number of chronic kidney disease (CKD) patients and related adverse outcomes has dramatically increased worldwide in the past decade. Therefore, numerous experimental and clinical studies have recently addressed the underlying mechanisms, in particular the marked increase in cardiovascular mortality. Hyperphosphatemia is a major problem in these patients with advanced stage of CKD. Its control by calcium-containing phosphate binders is effective, but at the price of potentially noxious calcium overload. Sevelamer hydrochloride is a phosphate binder that offers an effective control of hyperphosphatemia as calcium-rich binders but without increase of calcium load. Beyond the control of phosphate, sevelamer seems to exert pleiotropic effects which include the correction of lipid abnormalities and the clearance of some uremic toxins.
Asunto(s)
Quelantes/uso terapéutico , Fallo Renal Crónico/complicaciones , Fosfatos/sangre , Trastornos del Metabolismo del Fósforo/tratamiento farmacológico , Poliaminas/uso terapéutico , Humanos , Fallo Renal Crónico/sangre , Fallo Renal Crónico/inmunología , Trastornos del Metabolismo del Fósforo/sangre , Trastornos del Metabolismo del Fósforo/etiología , Sevelamer , Uremia/sangre , Uremia/complicaciones , Uremia/inmunologíaRESUMEN
Patients with end-stage renal disease often have derangements in calcium and phosphorus homeostasis and resultant secondary hyperparathyroidism (sHPT), which may contribute to the high prevalence of arterial stiffness and hypertension. We conducted a secondary analysis of the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial, in which patients receiving hemodialysis with sHPT were randomly assigned to receive cinacalcet or placebo. We sought to examine whether the effect of cinacalcet on death and major cardiovascular events was modified by baseline pulse pressure as a marker of arterial stiffness, and whether cinacalcet yielded any effects on blood pressure. As reported previously, an unadjusted intention-to-treat analysis failed to conclude that randomization to cinacalcet reduces the risk of the primary composite end point (all-cause mortality or non-fatal myocardial infarction, heart failure, hospitalization for unstable angina or peripheral vascular event). However, after prespecified adjustment for baseline characteristics, patients randomized to cinacalcet experienced a nominally significant 13% lower adjusted risk (95% confidence limit 4-20%) of the primary composite end point. The effect of cinacalcet was not modified by baseline pulse pressure (Pinteraction=0.44). In adjusted models, at 20 weeks cinacalcet resulted in a 2.2 mm Hg larger average decrease in systolic blood pressure (P=0.002) and a 1.3 mm Hg larger average decrease in diastolic blood pressure (P=0.002) compared with placebo. In summary, in the EVOLVE trial, the effect of cinacalcet on death and major cardiovascular events was independent of baseline pulse pressure.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Calcimiméticos/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , Cinacalcet/uso terapéutico , Rigidez Vascular , Adulto , Anciano , Calcimiméticos/farmacología , Enfermedades Cardiovasculares/mortalidad , Cinacalcet/farmacología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Parathyroid hormone (PTH) and calcitonin exert well known effects on the renal tubule which are thought to involve specific hormone receptors and adenyl cyclase. In the intestine, it is not clear whether the action of PTH and calcitonin is only indirect or also direct, and their mechanisms of action are much less well established. In the present study, possible direct effects of PTH and calcitonin on Na+ transport in isolated intestinal epithelial cells of rats were investigated. In the presence of bovine PTH (1.2 I.U/ml) in the incubation medium, the Na+ efflux rate constant (oKNa) of isolated enterocytes was significantly reduced when compared to that in control experiments with the hormone vehicle only. The mean depression of oKNa induced by bovine PTH was 26% as compared to the control (100%) and to that induced by ouabain (4.0 mM) which was 44%. No depressant effect of bovine PTH on oKNa was observed when the isolated enterocytes were incubated with ouabain (4.0 mM). Thus, bovine PTH appeared to inhibit the ouabain-sensitive Na+ pump. When incubating the isolated epithelial cells in an EGTA-containing CA2+-free medium, bovine PTH lost its capacity to inhibit oKNa. Thus, the presence of extracellular Ca2+ appeared necessary for the inhibitory effect of bovine PTH. In contrast to its effect on oKNa, bovine PTH induced no change in net Na+ uptake by isolated enterocytes. Moreover, no significant effect on enterocyte Na+ transport could be demonstrated for salmon or porcine calcitonin at two different concentrations in the incubation medium, Neither bovine PTH nor salmon calcitonin induced significant changes in enterocyte cyclic AMP or cycle GMP concentrations. It was concluded that bovine PTH, but not calcitonin, exerted a directed inhibitory effect on the ouabain-sensitive oKNa of isolated rat enterocytes. The effect of bovine PTH occurred without measurable activation of the cyclic nucleotide system but needed the presence of Ca2+ in the incubation medium to be operative.
Asunto(s)
Calcitonina/farmacología , Yeyuno/metabolismo , Hormona Paratiroidea/farmacología , Sodio/metabolismo , Animales , Transporte Biológico Activo/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Yeyuno/citología , Yeyuno/efectos de los fármacos , Cinética , Masculino , Microscopía Electrónica , Ouabaína/farmacología , RatasRESUMEN
Anemia has been recognized recently as a possible complication of primary hyperparathyroidism. If the hyperparathyroid state can induce anemia in patients with normal kidney function, the extremely high levels of circulating parathyroid hormone usually observed in hyperparathyroidism secondary to chronic renal failure may have an unfavorable influence on the anemia of uremic patients. We investigated the influence of subtotal parathyroidectomy on the severity of the anemia of 18 uremic subjects undergoing long-term hemodialysis therapy. Subtotal parathyroidectomy resulted in a significant increase of mean hematocrit value. RBC count, and hemoglobin level. Serial bone biopsies suggested a relationship between the amount of marrow fibrosis and the improvement of anemia after surgery, but the precise mechanism of this phenomenon is still unknown.
Asunto(s)
Anemia/etiología , Hiperparatiroidismo Secundario/complicaciones , Adulto , Anemia Hipocrómica/etiología , Antígenos , Médula Ósea/patología , Recuento de Eritrocitos , Femenino , Hematócrito , Hemoglobinas/metabolismo , Humanos , Hiperparatiroidismo Secundario/etiología , Fallo Renal Crónico/complicaciones , Masculino , Persona de Mediana Edad , Glándulas Paratiroides/cirugía , Hormona Paratiroidea/inmunología , Estudios RetrospectivosRESUMEN
Cholangiocellular carcinoma developed in two uremic patients with polycystic kidney and liver disease, who had been treated with intermittent hemodialysis for one and nine years. In one case, in situ transformation of the liver cyst epithelium into cholangiocellular carcinoma could be demonstrated. The incidence of cholangiocellular carcinoma in patients undergoing long-term dialysis for polycystic kidney and liver disease, however, has yet to be determined.
Asunto(s)
Adenoma de los Conductos Biliares/complicaciones , Hepatopatías/complicaciones , Neoplasias Hepáticas/complicaciones , Enfermedades Renales Poliquísticas/complicaciones , Transformación Celular Neoplásica , Quistes/complicaciones , Femenino , Humanos , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Diálisis RenalRESUMEN
The nephrology community has progressively recognized that vascular calcification in patients with chronic renal failure is a major problem in terms of morbidity and mortality. This type of soft tissue calcification is not only passive, as thought previously, but implies active processes as well. It results from disturbances of the normal balance between calcification inhibitors and promoters, acting both at the systemic and the local level, and from the phenotypic change of smooth muscle cells towards osteoblast-like calcifying cells in the vessel wall. The recognition of the main factors involved will allow in the future a more appropriate prophylactic and therapeutic approach of this clinically important complication of chronic renal failure.
Asunto(s)
Calcinosis/etiología , Enfermedades Cardiovasculares/etiología , Fallo Renal Crónico/fisiopatología , Enfermedades Vasculares/etiología , Adulto , Calcinosis/sangre , Calcinosis/metabolismo , Calcinosis/patología , Calcinosis/prevención & control , Calcio/sangre , Calcio/metabolismo , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/patología , Enfermedades Cardiovasculares/prevención & control , Niño , Complicaciones de la Diabetes , Femenino , Humanos , Técnicas In Vitro , Fallo Renal Crónico/sangre , Fallo Renal Crónico/complicaciones , Masculino , Miocitos del Músculo Liso/patología , Fenotipo , Fosfatos/metabolismo , Fósforo/sangre , Riesgo , Enfermedades Vasculares/sangre , Enfermedades Vasculares/metabolismo , Enfermedades Vasculares/patología , Enfermedades Vasculares/prevención & controlRESUMEN
An original human parathyroid cell culture model from uremic patients with IIo hyperparathyroidism has been developed, with its main feature being long-term functionally active viability up to 5 months, as assessed by persistent responsiveness to changes of extracellular Ca2+ concentrations ([Ca2+]e). In addition to the inhibitory effect of increasing [Ca2+]e, increasing extracellular phosphate exerted a biphasic effect on parathyroid hormone (PTH) secretion. The presence of the Ca2+-sensing receptor (CaR), on which depends the response to [Ca2+]e and its persistence, has been demonstrated in our culture system both by direct detection and by inhibition of its activity. CaR protein was detected by Western blot analysis with a specific anti-CaR antibody. CaR gene transcripts have been identified by reverse transcription-polymerase chain reaction analysis. mRNA (by in situ hybridization) and protein (by immunocytochemistry) expression were detected for both CaR and PTH. Adding a specific anti-CaR antibody to the medium induced a marked reduction of low [Ca2+]e-stimulated PTH release, which decreased to levels equivalent to those obtained in high [Ca2+]e medium. The described long-term functionality could be due to several factors, including the clustered cell type of culture yielded by our preparation procedure, the growth characteristics of hyperplastic uremic tissue, and the use of a phosphate-rich medium. The present model, because of its long-term functionality, is a unique tool for the exploration of PTH synthesis and secretion and for studies of parathyroid cell growth in vitro.
Asunto(s)
Glándulas Paratiroides/metabolismo , Hormona Paratiroidea/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores de Hormona Paratiroidea/metabolismo , Animales , Calcio/farmacología , División Celular/efectos de los fármacos , Supervivencia Celular , Células Cultivadas , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Hiperparatiroidismo/fisiopatología , Ratones , Glándulas Paratiroides/efectos de los fármacos , Glándulas Paratiroides/ultraestructura , Hormona Paratiroidea/genética , Fósforo/farmacología , ARN Mensajero/análisis , Receptores Sensibles al Calcio , Receptores de Superficie Celular/efectos de los fármacos , Transcripción Genética , Uremia/fisiopatologíaRESUMEN
Type I collagen represents more than 90% of bone matrix. Quantitative analysis of collagen cross-link molecules such as pyridinoline (PYD) provides valuable information on bone resorption rate. We have studied 37 hemodialysis patients who underwent a systematic transiliac bone biopsy for histomorphometry study. Eighteen of them had tetracycline double labeling, allowing to determine dynamic, in addition to static bone parameters. Measurement of serum-free PYD was performed using a new competitive enzyme immunoassay. Serum PYD values were compared with those of three other serum markers of bone metabolism, namely intact PTH (iPTH), bone-specific alkaline phosphatase (bAP), and osteocalcin, for the correlations with bone histomorphometric parameters. Serum PYD levels (mean +/- SD) were significantly higher in dialysis patients than in normal individuals, 90.6 +/- 99.6 nM versus 1.9 +/- 0.4 nM, respectively. Patients with high turnover bone disease had significantly higher serum PYD levels than patients with normal or low bone turnover, 108.8 +/- 108.0 nM versus 34.1 +/- 12.8 nM, respectively. Serum PYD levels were positively correlated with bone resorption parameters including osteoclast surface (r = 0.59, p < 0.0001) and osteoclast number/mm2 (r = 0.61, p < 0.0001), and also with bone formation parameters, osteoblast surface (r = 0.43, p < 0.008), double-labeled surface (r = 0.81, p < 0.001), and BFR (r = 0.91, p < 0.0001). The BFR was better correlated with serum PYD levels than with either serum iPTH or osteocalcin concentrations. However, correlation with serum bAP was comparable.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Aminoácidos/sangre , Huesos/metabolismo , Colágeno/metabolismo , Diálisis Renal/efectos adversos , Adulto , Anciano , Fosfatasa Alcalina/sangre , Resorción Ósea/sangre , Resorción Ósea/diagnóstico , Colágeno Tipo I , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Ilion/patología , Ensayo Inmunorradiométrico , Masculino , Persona de Mediana Edad , Osteoblastos/citología , Osteoblastos/patología , Osteocalcina/sangre , Osteoclastos/citología , Osteoclastos/patología , Hormona Paratiroidea/sangre , Fragmentos de Péptidos/sangre , Péptidos/metabolismo , Procolágeno/sangre , Uremia/fisiopatología , Uremia/terapiaRESUMEN
Abnormalities of calcium metabolism and of its two principal regulating hormones, parathyroid hormone and 1,25-dihydroxyvitamin D3 (calcitriol), have been reported in the spontaneously hypertensive rat (SHR). Reports of abnormal calcitriol metabolism in the SHR by several groups have not provided measurements of tissue calcitriol receptors. Similarly, few data are available as to the parathyroid status of the SHR. In the present study, circulating calcitriol levels and intestinal and parathyroid gland calcitriol receptor status were determined in male SHR and in Wistar-Kyoto (WKY) rats. Parathyroid status was investigated by determination of parathyroid gland mass together with tissue micromorphometry and by quantitative histology of bone as a measure of the biological action of parathyroid hormone. Circulating calcitriol levels were reduced in the 11-week-old SHR compared with the WKY rat (165 +/- 23 vs. 194 +/- 28 pmol/l, p less than 0.01, mean +/- SD). Calcitriol-free ratio was diminished and maximal specific binding capacity for calcitriol was increased in the SHR in parathyroid tissue (172 +/- 4.9 vs. 123 +/- 6.6 fmol/mg protein, p less than 0.01) and in intestinal mucosa with no change of receptor affinity. Plasma ionized calcium (1.29 +/- 0.05 vs. 1.45 +/- 0.35 mmol/l, p less than 0.05) and phosphate (1.5 +/- 0.26 vs. 2.4 +/- 0.03 mmol/l, p less than 0.05) were significantly lower in the SHR. Parathyroid gland mass was increased in the SHR (59 +/- 12 vs. 17 +/- 7 micrograms/100 g body wt, p less than 0.001) as a result of hyperplasia and not hypertrophy. Higher osteoclast numbers were observed in SHR bone (27.6 +/- 0.79 vs. 23.9 +/- 0.66 osteoclasts/mm2, p less than 0.01), suggesting increased parathyroid hormone activity. In summary, in the 11-week-old SHR we observed reduced circulating calcitriol levels together with increased tissue calcitriol receptor numbers, increased parathyroid gland mass, and histological evidence of hyperparathyroidism. It is possible that these abnormalities influence the development of hypertension in the SHR.
Asunto(s)
Calcitriol/metabolismo , Hiperparatiroidismo/metabolismo , Ratas Endogámicas SHR/metabolismo , Ratas Endogámicas/metabolismo , Animales , Huesos/patología , Calcitriol/análisis , Hiperparatiroidismo/patología , Mucosa Intestinal/metabolismo , Intestinos/análisis , Masculino , Glándulas Paratiroides/análisis , Glándulas Paratiroides/metabolismo , Glándulas Paratiroides/patología , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas WKY , Receptores de Calcitriol , Receptores de Esteroides/análisis , Receptores de Esteroides/metabolismoRESUMEN
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.
Asunto(s)
Genes Supresores de Tumor , Hiperparatiroidismo Secundario/etiología , Hiperparatiroidismo Secundario/genética , Receptores de Calcitriol/genética , Uremia/complicaciones , Adulto , Alelos , Secuencia de Bases/genética , Cromosomas , Femenino , Humanos , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Hibridación de Ácido Nucleico , Polimorfismo Genético/genéticaRESUMEN
Epidemiologic findings continue to add to the body of evidence supporting a relationship between calcium intake and blood pressure. These findings also indicate that there is a threshold of the potential protective effect of adequate calcium intake, below which the risk of hypertension increases at a greater rate. The set point of this threshold, estimated at 700-800 mg/d, may be modified by a variety of factors including dietary patterns and components, lifestyle, and genetics. This may explain, at least in part, the heterogeneous response observed in dietary-intervention studies. In animal models of hypertension it was shown that greater amounts of calcium must be given to cause a blood pressure change comparable with that in normal animals, suggesting that in high-risk human populations in which calcium metabolism may be disordered, calcium intake may have to be increased to amounts greater than 700-800 mg/d to demonstrate the blood-pressure-lowering effect. Calcium intake at or above the currently recommended daily allowance of 800 mg could be of potential benefit to certain racial groups, individuals ingesting excessive alcohol, and pregnant women, all of whom generally consume low amounts of calcium and who are at higher risk of developing hypertension.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Calcio de la Dieta/farmacología , Hipertensión/prevención & control , Animales , Calcio de la Dieta/uso terapéutico , Bases de Datos Bibliográficas , Modelos Animales de Enfermedad , Humanos , Ratas , Ratas Endogámicas SHRRESUMEN
Ten patients with a uremic polyneuropathy were investigated. Chronic renal failure was associated with a variety of neuropathies, including an acute axonal neuropathy, a progressive axonal neuropathy with secondary segmental demyelination, and a predominantly demyelinative neuropathy. All patterns were associated with distal degeneration of fibers evidenced by axonal sprouting observed on single-fiber preparations. The etiology of such variations in pathology of uremic neuropathy is still not clearly understood.
Asunto(s)
Enfermedades del Sistema Nervioso/etiología , Uremia/complicaciones , Adolescente , Adulto , Axones/ultraestructura , Biopsia , Femenino , Humanos , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Fibras Nerviosas/patología , Fibras Nerviosas Mielínicas/patología , Enfermedades del Sistema Nervioso/patología , Nervio Sural/patología , Nervio Sural/ultraestructuraRESUMEN
Using a discriminating gradient separation technique combined with careful analysis of lipid and apolipoprotein (apo) composition, serum lipoproteins of 20 chronically uremic patients have been compared with those of 19 normal controls matched for age and sex. In uremic subjects, serum VLDL concentration was markedly increased. These particles were enriched in protein and cholesterol and relatively poor in triglycerides (TG). They contained more frequently apo B-48, and a decreased proportion of apo E. Expressed in percent, total apo C was normal but the ratio of apo C-III2/apo C-III1 was elevated. Uremic IDL, whose serum concentration was markedly increased, were characterized by an increased proportion of protein. Total uremic LDL whose serum concentration was normal, contained less esterified cholesterol (EC) and more TG than normal LDL, their EC/TG ratio being very low. Moreover, the concentration of the mature subfraction of LDL having a mean density of 1.043 g/ml, was markedly decreased in uremic subjects. Taken together, these anomalies indicate a delayed transformation of VLDL into LDL in chronic renal failure. The decreased concentration of total HDL in uremic subjects was more marked in HDL2 (-46%) than HDL3 (-24%). Both uremic HDL2 and HDL3 were relatively enriched in TG, and uremic HDL3 were poorer in EC than normal HDL3.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Apolipoproteínas A/sangre , Apolipoproteínas C/sangre , Lipoproteínas HDL/sangre , Uremia/sangre , Adulto , Apolipoproteína A-I , Apolipoproteína B-48 , Apolipoproteína C-II , Apolipoproteína C-III , Apolipoproteínas B/sangre , Colesterol/sangre , Femenino , Humanos , Lipoproteínas HDL2 , Lipoproteínas HDL3 , Lipoproteínas LDL/sangre , Lipoproteínas VLDL/sangre , Masculino , Persona de Mediana Edad , UltracentrifugaciónRESUMEN
In a black man, recently receiving long-term hemodialysis, a severe, rapidly progressive polyradiculoneuritis (Guillain-Barre syndrome) developed. Routine virologic study revealed a high antimeasles virus antibody titer (1:1280 by hemagglutination-inhibition) which progressively decreased. There was no clinical evidence of measles. Discussed here is the possible relationship between the Guillain-Barre syndrome and clinically inapparent measles associated with and perhaps modified by the uremic state.
Asunto(s)
Virus del Sarampión/inmunología , Polirradiculopatía/etiología , Diálisis Renal , Adulto , Anticuerpos Antivirales/análisis , Clofibrato/uso terapéutico , Humanos , Masculino , Sarampión/diagnóstico , Sarampión/etiología , Factores de Tiempo , Uremia/terapiaRESUMEN
Periarteritis nodosa was observed in three of 266 persistent hepatitis B antigen (HBsAg) carriers undergoing long-term hemodialysis; no cases of necrotizing vasculitis occurred among 384 other patients undergoing dialysis having either no or transient antigenemia. Circulating e antigen, but no e antibody, was found in two of these three patients. The serum level of the third component of complement (C3) was normal in two patients and low in the third. Circulating immune complexes were demonstrated in all three patients, using polyethylene-glycol (PEG) precipitation, PEG-C4, and solid phase C1q tests. HBsAg and anti-hepatitis B antibody (HBsAb) were identified in the PEG precipitates using radioimmunoassay and electron microscopy technics. Direct immunofluorescence performed on a muscle biopsy specimen from one patient was positive for HBsAg, but not for immunoglobulin G (IgG), immunoglobulin M (IgM), C3 or C1q. These data support the hypothesis that circulating immune complexes involving HBsAg may be involved in the pathogenesis of periarteritis nodosa.