RESUMEN
OBJECTIVES: High prevalence of iron deficiency (ID) and cardiomyopathy have been observed in patients with end-stage kidney disease (ESKD). Our objective was to clarify associations between ID and cardiac remodeling in patients with ESKD. DESIGN AND METHODS: A cross-sectional study was conducted using 1974 Japanese patients with ESKD at the initiation of maintenance dialysis. Levels of hemoglobin (Hb), iron status, and cardiac enlargement as assessed by the cardiothoracic ratio (CTR) were determined immediately before the first hemodialysis session. Circulatory ID was defined as transferrin saturation (TSAT) < 20%, and stored ID was defined as ferritin level <100 ng/dL. RESULTS: The mean age was 67 years. Median CTR was 54.0%. The prevalence of circulatory and stored ID was found to be 38% and 34%, respectively. CTR was higher in patients with circulatory ID than in those without. Even in ESKD patients without overhydration, significant negative association was observed between TSAT and CTR. Higher odds ratios in parallel with higher CTR categories compared with the reference category of CTR <45% were found in patients with TSAT <20% on multinomial analysis, but ferritin did not show any significant associations. The odds ratio for CTR >54% showed an upward trend in patients with TSAT <20% (odds ratio: 1.3) and <10% (odds ratio: 1.6) compared with the reference, even after adjusting for confounding variables such as Hb and ferritin. However, that phenomenon was eliminated by adding usage of an iron agent. CONCLUSIONS: Circulatory ID is closely associated with an enlarged heart independent of ferritin and Hb. Iron supplementation in the predialysis phase of chronic kidney disease may prevent cardiac remodeling independent of Hb level in patients chronic kidney disease.
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Anemia Ferropénica/epidemiología , Cardiomegalia/epidemiología , Fallo Renal Crónico/epidemiología , Anciano , Comorbilidad , Estudios Transversales , Bases de Datos Factuales , Femenino , Humanos , Japón , Masculino , PrevalenciaRESUMEN
Previous clinical and experimental studies have indicated that magnesium may prevent vascular calcification (VC), but mechanistic characterization has not been reported. This study investigated the influence of increasing magnesium concentrations on VC in a rat aortic tissue culture model. Aortic segments from male Sprague-Dawley rats were incubated in serum-supplemented high-phosphate medium for 10 days. The magnesium concentration in this medium was increased to demonstrate its role in preventing VC, which was assessed by imaging and spectroscopy. The mineral composition of the calcification was analyzed using Fourier transform infrared (FTIR) spectroscopic imaging, scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX) mapping. Magnesium supplementation of high-phosphate medium dose-dependently suppressed VC (quantified as aortic calcium content), and almost ablated it at 2.4 mm magnesium. The FTIR images and SEM-EDX maps indicated that the distribution of phosphate (as hydroxyapatite), phosphorus and Mg corresponded with calcium content in the aortic ring and VC. The inhibitory effect of magnesium supplementation on VC was partially reduced by 2-aminoethoxy-diphenylborate, an inhibitor of TRPM7. Furthermore, phosphate transporter-1 (Pit-1) protein expression was increased in tissues cultured in HP medium and was gradually-and dose dependently-decreased by magnesium. We conclude that a mechanism involving TRPM7 and Pit-1 underpins the magnesium-mediated reversal of high-phosphate-associated VC.
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Magnesio/uso terapéutico , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo III/metabolismo , Canales Catiónicos TRPM/metabolismo , Calcificación Vascular/prevención & control , Animales , Aorta , Magnesio/farmacología , Masculino , Microscopía Electrónica de Rastreo , Fosfatos , Ratas Sprague-Dawley , Espectrometría por Rayos X , Espectroscopía Infrarroja por Transformada de Fourier , Técnicas de Cultivo de TejidosRESUMEN
AIM: Vascular calcification (VC) is a risk factor of cardiovascular and all-cause mortality in patients with chronic kidney disease (CKD). CKD-mineral and bone metabolism disorder is an important problem in patients with renal failure. Abnormal levels of serum phosphate and calcium affect CKD-mineral and bone metabolism disorder and contribute to bone disease, VC, and cardiovascular disease. Hypercalcemia is a contributing factor in progression of VC in patients with CKD. However, the mechanisms of how calcium promotes intracellular calcification are still unclear. This study aimed to examine the mechanisms underlying calcium-induced calcification in a rat aortic tissue culture model. METHODS: Aortic segments from 7-week-old male Sprague-Dawley rats were cultured in serum-supplemented medium for 10 days. We added high calcium (HiCa; calcium 3.0 mM) to high phosphate (HPi; phosphate 3.8 mM) medium to accelerate phosphate and calcium-induced VC. We used phosphonoformic acid and the calcimimetic R-568 to determine whether the mechanism of calcification involves Pit-1 or the calcium-sensing receptor. RESULTS: Medial VC was significantly augmented by HPi+HiCa medium compared with HPi alone (300%, pï¼0.05), and was associated with upregulation of Pit-1 protein. Pit-1 protein concentrations in HPi+HiCa medium were greater than those in HPi medium. Phosphonoformic acid completely negated the augmentation of medial VC induced by HPi+HiCa. R-568 had no additive direct effect on medial VC. CONCLUSION: These results indicated that exposure to HPi+HiCa accelerates medial VC, and this is mediated through Pit-1, not the calcium-sensing receptor.
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Aorta/patología , Calcio/efectos adversos , Fosfatos/efectos adversos , Receptores Sensibles al Calcio/metabolismo , Insuficiencia Renal Crónica/fisiopatología , Factor de Transcripción Pit-1/metabolismo , Calcificación Vascular/patología , Animales , Aorta/efectos de los fármacos , Progresión de la Enfermedad , Masculino , Ratas , Ratas Sprague-Dawley , Calcificación Vascular/inducido químicamente , Calcificación Vascular/metabolismoRESUMEN
AIM: High phosphorus conditions promote vascular calcification (VC) in both chronic kidney disease (CKD) patients and experimental models. However, the composition of medial calcification has not been accurately determined, so the objective of this study was to evaluate the mineral composition of calcification in a tissue culture model, not a cell culture system. METHODS: Aortic rings obtained from male Sprague-Dawley rats were incubated in serum-supplemented medium for 10 days. The inorganic phosphate (Pi) concentration of the medium was increased to induce VC, which was assessed by histology, imaging, and spectroscopy. The mineral composition of the calcification was analyzed using Fourier transform infrared (FTIR) spectroscopic imaging, scanning electron microscopy (SEM), and energy dispersive X-ray spectroscopy (EDX) mapping. RESULTS: The calcium content significantly increased only in aortic rings cultured for 10 days in the high-Pi medium (HiP: 3.8 mmol/L). The concentration of the phosphate transporter Pit-1 in the aortic tissue exposed to HiP was higher than that in the control incubated sections. The FTIR images and spectra indicated that PO4(3-) was mostly distributed as hydroxyapatite in the medial calcification of aortic rings cultured in HiP. A small quantity of carbonate was identified. The SEM-EDX overlay map demonstrated that phosphorus and calcium simultaneously accumulated and localized in the area of medial calcification induced by exposure to HiP. CONCLUSION: This is the first report of accurate determination of the chemical composition of aortic medial calcification. Exposure to high Pi concentration augments aortic calcification via an increase in Pit-1, which mainly contains calcium phosphate.
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Aorta/patología , Calcio/metabolismo , Minerales/metabolismo , Modelos Biológicos , Fosfatos/toxicidad , Calcificación Vascular/patología , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Masculino , Microscopía Electrónica de Rastreo , Ratas , Ratas Sprague-Dawley , Espectroscopía Infrarroja por Transformada de Fourier , Calcificación Vascular/inducido químicamente , Calcificación Vascular/metabolismoRESUMEN
BACKGROUND: Hyperphosphataemia is a known contributing factor in the progression of vascular calcification in dialysis patients. The cellular mechanisms underlying phosphate-induced calcification are still unclear despite intense study, so in this study, we investigated the possible involvement of the type III sodium-dependent phosphate cotransporter, Pit-1, in an aortic tissue culture model. METHODS: Aortic segments from 9-week-old male Sprague-Dawley rats were incubated in serum-supplemented medium for 10 days. The phosphate concentration of the medium was elevated to induce calcification, which was assessed by histology and calcium content. Phosphonoformic acid (PFA) was used to inhibit phosphate uptake. The involvement of apoptosis was examined using the terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate (dUTP) nick-end labelling (TUNEL) assay, caspase 3 activation, and inhibition of apoptosis using a general caspase inhibitor. Phenotypic changes in vascular smooth muscle cells (VSMC) were assessed using expression of osteochondrogenic differentiation markers. RESULTS: Medial vascular calcification was induced in aortas cultured in a high phosphate medium. PFA decreased the rates of calcification and apoptosis of VSMC in the media, concomitant with calcification. Caspase inhibitor reduced calcification. No phenotypic transition of VSMC was seen in this model. CONCLUSIONS: These results indicate that phosphate uptake through the type III sodium-dependent phosphate cotransporter, Pit-1, leads to induction of apoptosis and subsequent calcification of VSMC.
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Calcinosis/inducido químicamente , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo III/fisiología , Animales , Aorta/patología , Aorta/fisiología , Apoptosis , Caspasa 3/metabolismo , Foscarnet/farmacología , Etiquetado Corte-Fin in Situ , Masculino , Músculo Liso Vascular/patología , Músculo Liso Vascular/fisiología , Fosfatos/metabolismo , Ratas , Ratas Sprague-Dawley , Técnicas de Cultivo de TejidosRESUMEN
In this part, we reports the experience of treatment by calcimimetics for 3 hemodialyzed patients with refractory secondary hyperparathyroidism. They purchased own expense, and used "Cinacalcet" as calcimimetics (Sensipar(R) 30 mg/tablet, by AMGEN co. Ltd. in USA) . Serum Ca, P, and intact-PTH decreased certainly in 3 cases after cinacalcet therapy. Especially the reduction of intact-PTH is obviously. The any adverse effect did not observed by 30 mg/tablet/day prescription except mild epigastralgia in a case. We were able to experience the marked suppressive effect on parathyroid gland by cinacalcet as calcimimetics in Japanese patients with refractory secondary hyperparathyroidism undergoing hemodialysis.
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Hiperparatiroidismo Secundario/tratamiento farmacológico , Naftalenos/uso terapéutico , Receptores Sensibles al Calcio/agonistas , Anciano , Calcio/sangre , Cinacalcet , Humanos , Hiperparatiroidismo Secundario/sangre , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Fósforo/sangre , Diálisis RenalRESUMEN
BACKGROUND: Controlling hyperplasia of the parathyroid gland (PTG) is important in the management of secondary hyperparathyroidism (SHPT). Regression of the hyperplastic PTG requires a decrease in the number of parathyroid cells (PTCs), so the present study investigated cell death caused by toxic agents or by clinically usable vitamin D metabolites. METHODS: The PTGs of Sprague-Dawley rats, which had been 5/6-nephrectomized and fed a high-phosphate diet for 12 weeks, were treated with two consecutive direct injections (DI) of calcitriol, maxacalcitol, paricalcitol, doxercalciferol or phosphate-buffered saline containing either 0.01% or 90% ethanol (0.01-ET or 90-ET, respectively). Laboratory data, including serum levels of intact parathyroid hormone (intact-PTH), were obtained before and after the treatments. The PTGs were excised 24 h after the final injection and evaluated for PTC apoptosis using light and electron microscopy, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) method and DNA electrophoresis. RESULTS: Treatment with any of the vitamin D metabolites and 90-ET significantly decreased the serum intact-PTH level, but only the latter significantly decreased the serum Ca level. Either treatment markedly increased the number of TUNEL-positive PTCs, but not in PTG treated with 0.01-ET. In PTGs treated with DI of any vitamin D metabolites was there ladder formation on DNA electrophoresis, as well as the characteristic morphological features of apoptosis in both the light and electron microscopic studies. CONCLUSIONS: DI of vitamin D metabolites may be effective in controlling not only the PTH level, but also PTG hyperplasia, in advanced SHPT by, at least in part, apoptosis-induced cell death. Our study was performed in rats.
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Calcitriol/análogos & derivados , Glándulas Paratiroides/efectos de los fármacos , Glándulas Paratiroides/patología , Animales , Apoptosis/efectos de los fármacos , Calcitriol/farmacología , Calcio/sangre , Modelos Animales de Enfermedad , Humanos , Hiperparatiroidismo Secundario/sangre , Hiperparatiroidismo Secundario/tratamiento farmacológico , Hiperparatiroidismo Secundario/patología , Hiperplasia , Masculino , Microscopía Electrónica de Transmisión , Hormona Paratiroidea/sangre , Fósforo/sangre , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Injection of maxacalcitol (OCT) directly into the parathyroid gland (PTG) is a clinically safe and effective treatment for advanced secondary hyperparathyroidism (A-SHPT) resistant to conventional medical treatment. In the present study, the degree of nuclear localization of directly injected OCT in parathyroid cells (PTC) was investigated by microautoradiography (mARG) in a model of A-SHPT. METHODS: The 5/6 nephrectomized Sprague-Dawley rats were fed a high-phosphate and low-calcium diet for 8 weeks and consequently the level of vitamin D receptor (VDR) in their PTC severely decreased. The bilateral PTG were surgically exposed and only the left gland were directly injected with 3H-OCT (DI-3H-OCT). The time course of the changes in both radioactivity and localization of 3H-OCT in the bilateral glands was analysed using a bioimaging analyser system and mARG, respectively. A very high dose of unlabelled calcitriol was administered intravenously (IV-1,25D3) prior to DI-3H-OCT, as a competitive study. RESULTS: Peak radioactivity levels in the directly injected and intact PTG occured immediately and 1 h, respectively, after DI-3H-OCT, and the difference was about 50-fold higher in the treated gland. The of mARG showed a marked concentration of silver grains in the nuclei of PTC in the gland treated with DI-3H-OCT and that concentration was significantly suppressed by IV-1,25D3. CONCLUSIONS: Direct injection of OCT into the PTG enables the administration of the highly concentrated drug for specific binding to nuclear vitamin D binding sites, including VDR of PTC, which markedly suppresses the parathyroid hormone, improves the response to calcium and vitamin D and induces apoptosis in PTC.
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Antineoplásicos/metabolismo , Calcitriol/análogos & derivados , Glándulas Paratiroides/metabolismo , Receptores de Calcitriol/metabolismo , Animales , Antineoplásicos/administración & dosificación , Apoptosis/fisiología , Calcitriol/administración & dosificación , Calcitriol/metabolismo , Calcio/farmacología , Modelos Animales de Enfermedad , Hiperparatiroidismo Secundario/tratamiento farmacológico , Inyecciones , Masculino , Glándulas Paratiroides/citología , Hormona Paratiroidea/fisiología , Unión Proteica , Ratas , Ratas Sprague-Dawley , Uremia/metabolismo , Vitamina D/farmacologíaRESUMEN
Classic pathogeneses of secondary hyperparathyroidism (2HPT), hyperphosphatemia, vitamin D deficiency, and hypocalcemia, have been treated by the administration of phosphorus binders and vitamin D derivatives. However, these therapies have not brought about a successful result. The main reason could be attributed to hypercalcemia resulting from the administration of calcium salts as a phosphorus binder and the calcemic action of vitamin D. To prevent hypercalcemia, non-calcium-containing phosphorus binders and vitamin D analogues, which suppress parathyroid hormone (PTH) secretion with minimum calcemic action, have been developed. Furthermore, calcimimetics that stimulate the calcium-sensing receptor of parathyroid cells and suppress PTH secretion are now under clinical trial. Direct injection therapy of vitamin D analogues or calcimimetics into the parathyroid gland also has been reported. These new strategies are expected to effectively and safely suppress 2HPT, which has been resistant to conventional medical treatments.