RESUMEN
BACKGROUND: Dialysis patients often take multiple oral medications, leading to a high pill burden. Phosphate binders (PBs) account for a large proportion of this daily pill burden (DPB). The relationship between DPB and mortality risk remains unclear, and we hypothesized that this relationship might be influenced by the proportion of PBs to all medications. METHODS: We divided DPB into those derived from PBs and non-PB drugs and analyzed the association with mortality risk over a 7-year period in 513 chronic hemodialysis patients using a baseline model. RESULTS: The median (interquartile range) DPB from all drugs was 15.8 (11.2-21.0) pills/day/patient, and the median ratio of PB pills to all drug pills was 29.3 (13.7-45.9)% at baseline. During a median observation period of 5.2 years, 161 patients (31.4%) died. Kaplan-Meier analysis showed no significant difference in all-cause mortality between PB users and non-users. However, a significant survival advantage was observed in the highest tertile of DPB from PBs compared to the lowest tertile. Conversely, the highest tertile of DPB from non-PB drugs was associated with worse survival. Consequently, the highest tertile of the ratio of PBs to all pills was associated with better survival. This association remained significant even after adjusting for patient characteristics in the Cox proportional hazards model. However, when serum nutritional parameters were included as covariates, the significant association disappeared. CONCLUSIONS: Dialysis patients prescribed a higher rate of PB pills to all medications exhibited a lower mortality risk, possibly due to their better nutritional status.
Asunto(s)
Fallo Renal Crónico , Diálisis Renal , Humanos , Diálisis Renal/efectos adversos , Estudios de Cohortes , Estudios de Seguimiento , Fósforo , FosfatosRESUMEN
The hormone fibroblast growth factor 23 (FGF23) is secreted from bone and is involved in phosphorus (P) metabolism. FGF23 mainly binds the FGF receptor, which interacts with αKlotho in the kidney or parathyroid and regulates Na-dependent phosphate co-transporter type IIa (NaPi-IIa) and type IIc (NaPi-IIc) expression, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) activity, and parathyroid hormone (PTH) secretion. In this study, we utilized hemi-nephrectomized rats fed a high-P diet (HP Nx), rats subjected to a partial nephrectomy (PN) and rats with doxorubicin-induced renal failure (DXR) as chronic kidney disease (CKD) animal models and analyzed the P metabolism and FGF23 expression in the kidneys in each CKD model. We cultured HK2 cells with a high level of P, 1,25(OH)2D3 or transforming growth factor-ß1 (TGFß1) to investigate the FGF23 expression mechanism. In both the HP Nx and PN rats, the blood FGF23 and PTH levels were increased. However, the 1,25(OH)2D3 level was increased in the HP Nx rats and decreased in the PN rats. In all three animal models, the mRNA expression of αKlotho, NaPi-IIa and NaPi-IIc was decreased, and the mRNA expression of TGFß1, collagen1a1, osteopontin and FGF23 was elevated in the kidney. FGF23 protein and mRNA were expressed at high levels in the extended tubule epithelium, which was an osteopontin-positive region in the HP and PN rats. FGF23 and osteopontin mRNAs were expressed in HK2 cells incubated with TGFß1; however, these levels were not altered in HK2 cells incubated with 1,25(OH)2D3 and high P levels in vitro. Altogether, FGF23 is expressed in the kidneys in CKD model rats. Following stimulation with TGFß1, the injured renal tubular epithelial cells are strongly suspected to express both FGF23 and osteopontin. FGF23 produced in the kidney might contribute to P metabolism in subjects with CKD.
Asunto(s)
Factores de Crecimiento de Fibroblastos/metabolismo , Riñón/metabolismo , Insuficiencia Renal Crónica/metabolismo , Animales , Calcitriol , Línea Celular , Modelos Animales de Enfermedad , Doxorrubicina , Factor-23 de Crecimiento de Fibroblastos , Humanos , Riñón/patología , Nefrectomía , Osteopontina/metabolismo , Fósforo/administración & dosificación , Fósforo/metabolismo , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Ratas Wistar , Insuficiencia Renal Crónica/patología , Factor de Crecimiento Transformador beta1/metabolismo , Regulación hacia ArribaRESUMEN
The inhibitory effect of cinacalcet hydrochloride (cinacalcet) on blood phosphorus (P) levels is widely-accepted. However, this effect is only observed in patients on dialysis. Reduction in parathyroid hormone (PTH) induced by cinacalcet increases blood P levels with decreased urinary P excretion in pre-dialysis patients with chronic kidney disease (CKD). Similar results observed in normal and CKD rats provide a pharmacological validation of the trade-off hypothesis. The lowering effect of cinacalcet on blood P levels in dialysis patients is attributed to decreased P mobilization from the bone caused by the decreased PTH secretion. It is unlikely that this P-lowering effect of cinacalcet would bring any benefits on the enhanced parathyroid gland function and bone metabolism. On the other hand, the P-lowering effect of this drug is considered to contribute to its inhibitory effects on the development and progression of vascular calcification in dialysis patients. Further studies should examine this beneficial cinacalcet effect would lead to the reduction of the mortality risk.
Asunto(s)
Naftalenos/uso terapéutico , Hormona Paratiroidea/metabolismo , Fósforo/metabolismo , Animales , Calcio/metabolismo , Cinacalcet , Humanos , Naftalenos/efectos adversos , Glándulas Paratiroides/efectos de los fármacos , Diálisis Renal , Insuficiencia Renal Crónica/tratamiento farmacológicoRESUMEN
BACKGROUND: Dietary phosphate restriction suppresses parathyroid hormone (PTH) secretion, synthesis, and parathyroid cell proliferation in experimental animals with chronic renal insufficiency (CRI), independently of serum calcium and 1,25(OH)2D3 levels. This study was conducted to examine whether sevelamer hydrochloride (sevelamer), a metal-free phosphate binder, could regress an advanced parathyroid gland (PTG) hyperplasia and enlargement in rats with CRI. METHODS: Male Sprague-Dawley rats were fed a diet containing adenine for 6 weeks to establish CRI. Normal rats and adenine-treated rats were sacrificed to obtain the PTG (baseline group). The adenine diet was changed to a normal diet or diet containing 1 or 3% sevelamer for another 4 weeks. Time course changes of serum levels of calcium, phosphorus, and PTH were measured. At the end of the study, the PTG was weighed and examined histologically. RESULTS: Adenine-treated rats developed severe CRI with marked elevation of serum phosphorus and PTH. The PTG weight markedly increased with enlarged cell volume (i.e. cell hypertrophy) at baseline. Sevelamer treatment rapidly lowered serum phosphorus and PTH levels within 6 days, and after 4 weeks, reduced the PTG weight by 38% compared to adenine-treated rats at baseline. The reduction in PTG weight was due to regression of cell hypertrophy, but not to decreased cell number by apoptosis. Decreased expression of calcium receptor in the PTG at baseline was partially recovered by the sevelamer treatment. CONCLUSIONS: The sevelamer treatment can reduce the PTG weight with a reduction in serum PTH levels via regression of cell hypertrophy but not apoptosis in rats with CRI. Reduced PTG function might contribute to the regression of cell hypertrophy.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Fallo Renal Crónico/complicaciones , Glándulas Paratiroides/patología , Poliaminas/uso terapéutico , Animales , Apoptosis , Calcio/sangre , Modelos Animales de Enfermedad , Femenino , Hiperplasia/tratamiento farmacológico , Hiperplasia/metabolismo , Hiperplasia/patología , Hipertrofia/patología , Inmunohistoquímica , Fallo Renal Crónico/tratamiento farmacológico , Fallo Renal Crónico/metabolismo , Masculino , Tamaño de los Órganos/efectos de los fármacos , Glándulas Paratiroides/efectos de los fármacos , Hormona Paratiroidea/sangre , Fósforo/sangre , Ratas , Ratas Sprague-Dawley , SevelamerRESUMEN
Phosphorus directly controls parathyroid hormone (PTH) synthesis and secretion. Serum levels of the novel phosphate-regulating hormone, fibroblast growth factor 23 (FGF23), are positively correlated with hyperphosphatemia in patients with chronic kidney disease (CKD). Rats were fed a diet containing adenine for 4 weeks to establish CKD. Animals were then offered a diet containing sevelamer hydrochloride (sevelamer) or a normal diet for alternating 2 week periods over 8 weeks. Adenine-treated rats showed marked elevations of serum phosphorus, PTH and FGF23 levels associated with parathyroid hyperplasia and aortic calcification. Serum phosphorus, PTH and FGF23 levels decreased rapidly when sevelamer treatments commenced and recovered rapidly once they were discontinued. However, intermittent treatment with sevelamer successfully inhibited parathyroid hyperplasia and aortic calcification. In conclusion, phosphate-binder treatment can effectively inhibit the elevation of serum FGF23 levels, as well as PTH levels, under conditions of CKD. Setting up a period of reduced serum phosphorus levels, even if it is intermittent, is worthwhile for the inhibition of the development of parathyroid hyperplasia and aortic calcification.
Asunto(s)
Enfermedades de la Aorta/tratamiento farmacológico , Calcinosis/tratamiento farmacológico , Factores de Crecimiento de Fibroblastos/sangre , Hiperparatiroidismo Secundario/tratamiento farmacológico , Fallo Renal Crónico/complicaciones , Glándulas Paratiroides/patología , Hormona Paratiroidea/sangre , Poliaminas/administración & dosificación , Adenina , Animales , Enfermedades de la Aorta/etiología , Calcinosis/etiología , Calcio/sangre , Modelos Animales de Enfermedad , Esquema de Medicación , Hiperparatiroidismo Secundario/sangre , Hiperparatiroidismo Secundario/etiología , Hiperplasia/tratamiento farmacológico , Hiperplasia/etiología , Fallo Renal Crónico/sangre , Fallo Renal Crónico/inducido químicamente , Masculino , Fósforo/sangre , Ratas , Ratas Sprague-Dawley , SevelamerRESUMEN
Circulating levels of calcium ion (Ca(2+)) are maintained within a narrow physiological range mainly by the action of parathyroid hormone (PTH) secreted from parathyroid cells. Parathyroid cells can sense small fluctuations in plasma Ca(2+) levels by virtue of a cell surface Ca(2+) receptor (CaR) that belongs to the superfamily of G-protein-coupled receptors. Calcimimetics are positive allosteric modulators that activate the CaR on parathyroid cells and thereby immediately suppress PTH secretion. Pre-clinical studies with NPS R-568, a first generation calcimimetic compound, have demonstrated that daily oral administration inhibits the elevation of plasma PTH levels and parathyroid gland hyperplasia and ameliorates impaired bone qualities in rats with chronic renal insufficiency. The results of clinical trials with cinacalcet hydrochloride, a second generation calcimimetic compound, have shown that calcimimetics possess lowering effects not only on serum PTH levels but also on serum calcium x phosphorus product levels, a hallmark of an increased risk for cardiovascular death in dialysis patients with end-stage renal disease (ESRD). Thus, calcimimetics have considerable potential as an innovative medical approach to manage secondary hyperparathyroidism associated with ESRD. Indeed, cinacalcet hydrochloride has been approved in several countries and is the first positive allosteric modulator of any G protein-coupled receptor to reach the market.
Asunto(s)
Calcio/metabolismo , Diseño de Fármacos , Hiperparatiroidismo Secundario/tratamiento farmacológico , Receptores Sensibles al Calcio/efectos de los fármacos , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Animales , Calcio/agonistas , Cinacalcet , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Humanos , Hiperparatiroidismo Secundario/sangre , Hiperparatiroidismo Secundario/etiología , Hiperparatiroidismo Secundario/metabolismo , Fallo Renal Crónico/complicaciones , Modelos Biológicos , Estructura Molecular , Naftalenos/uso terapéutico , Glándulas Paratiroides/citología , Glándulas Paratiroides/metabolismo , Hormona Paratiroidea/sangre , Hormona Paratiroidea/metabolismo , Fenetilaminas , Propilaminas , Ratas , Receptores Sensibles al Calcio/genéticaRESUMEN
Calcimimetics are positive allosteric modulators that activate the parathyroid calcium receptor (CaR) and thereby immediately suppress parathyroid hormone (PTH) secretion. Preclinical studies have demonstrated that calcimimetics inhibit PTH secretion and parathyroid gland hyperplasia and ameliorates bone qualities in rats with chronic renal insufficiency. Clinical trials with cinacalcet hydrochloride, a calcimimetic compound, have shown that calcimimetics possess lowering effects not only on serum PTH levels but also on serum phosphorus levels in dialysis patients with secondary hyperparathyroidism (2HPT). Thus, calcimimetics have considerable potential as an innovative medical approach to manage 2HPT. In this review, the similarities are extrapolated between the pharmacological effect of calcimimetics on the set point of Ca-regulated PTH secretion and clinical observations in affected subjects with activating CaR mutations.
Asunto(s)
Naftalenos/farmacología , Hormona Paratiroidea/metabolismo , Receptores Sensibles al Calcio/efectos de los fármacos , Animales , Calcio/fisiología , Cinacalcet , Ensayos Clínicos como Asunto , Depresión Química , Genes Dominantes , Humanos , Hiperparatiroidismo Secundario/sangre , Hiperparatiroidismo Secundario/tratamiento farmacológico , Hipocalcemia/fisiopatología , Mutación , Naftalenos/uso terapéutico , Hormona Paratiroidea/sangre , Fósforo/sangre , Ratas , Receptores Sensibles al Calcio/genéticaRESUMEN
Sevelamer hydrochloride is a non-absorbed calcium- and metal-free phosphate binder that lowers the serum phosphorus levels in hemodialysis patients. Sevelamer contains multiple amines, which are partially protonated and interact with phosphate molecules through ionic and hydrogen bonding. We show the in vitro phosphate binding assay data and the efficacy of sevelamer to lower the serum phosphorus and calcium phosphorus product in several animal models. Furthermore, we indicate the vivid data that sevelamer prevented the ectopic calcification of aorta in adenine induced renal failure model, which represent severe hyperphosphatemia and the related dialysis complications.
Asunto(s)
Compuestos Epoxi/uso terapéutico , Osificación Heterotópica/prevención & control , Polietilenos/uso terapéutico , Adsorción , Animales , Aorta , Calcio/sangre , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Compuestos Epoxi/farmacología , Humanos , Enlace de Hidrógeno , Iones , Fallo Renal Crónico/complicaciones , Osificación Heterotópica/etiología , Fósforo/sangre , Trastornos del Metabolismo del Fósforo/etiología , Trastornos del Metabolismo del Fósforo/prevención & control , Poliaminas , Polietilenos/farmacología , Diálisis Renal/efectos adversos , Factores de Riesgo , SevelamerRESUMEN
BACKGROUND: Dietary phosphate restriction prevents renal function deterioration in animal models. This study examined whether sevelamer hydrochloride (Renagel(R); 'sevelamer' hereafter), a non-calcaemic phosphate binder could slow deterioration of renal function in rats with progressive renal insufficiency. METHODS: Wistar Kyoto male rats were singly injected with normal rabbit serum or rabbit anti-rat glomerular basement membrane serum. Three days later, rats were fed a powder diet containing 0, 1 or 3% sevelamer for 58 days. Time course changes of serum levels of blood urea nitrogen (BUN), creatinine, calcium, phosphorus and parathyroid hormone (PTH) were measured throughout, and creatinine clearance (CCr), kidney calcium content and renal histology examined at the end of the study. RESULTS: Sevelamer partially inhibited elevation of BUN and serum creatinine, and completely inhibited increases in serum phosphorus, PTH and calcium xphosphorus product. Sevelamer significantly prevented the decrease in CCr and kidney calcium content elevation. Kidney calcium content and BUN and serum creatinine were strongly positively correlated, and kidney calcium content and CCr strongly negatively correlated. Kidney calcium content correlated well with serum phosphorus, serum calcium x phosphorus product and PTH, but not serum calcium. Sevelamer treatment partly prevented histological deterioration of both glomerular and tubulointerstitial lesions of the kidney. CONCLUSIONS: The results suggest that sevelamer protects against renal function deterioration by maintaining kidney calcium at a low level as a result of reducing serum phosphorus and PTH.
Asunto(s)
Suplementos Dietéticos , Compuestos Epoxi/farmacología , Fallo Renal Crónico/patología , Fallo Renal Crónico/prevención & control , Polietilenos/farmacología , Animales , Biopsia con Aguja , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Tasa de Filtración Glomerular/efectos de los fármacos , Inmunohistoquímica , Pruebas de Función Renal , Masculino , Fosfatos/metabolismo , Poliaminas , Ratas , Ratas Wistar , Valores de Referencia , Factores de Riesgo , Sensibilidad y Especificidad , SevelamerRESUMEN
BACKGROUND: Hyperphosphatemia is associated with severe complications, including ectopic calcification of soft tissues, secondary hyperparathyroidism, and renal osteodystrophy (ROD). Sevelamer hydrochloride is a nonabsorbed calcium- and metal-free phosphate binder that lowers serum phosphorus levels in hemodialysis patients. This study examined the efficacy of sevelamer in preventing ectopic calcification of soft tissues and ROD in adenine-induced renal failure rats. METHODS: Male, 12-week-old Wistar-Jcl rats were freely fed an adenine diet (0.75 g adenine in 100 g normal diet) for four weeks. After three weeks of the adenine diet, when serum phosphorus levels had significantly increased, the rats were freely fed a normal diet that contained 1% or 2% of sevelamer for another five weeks. Time course changes of serum levels of phosphorus, calcium, and parathyroid hormone (PTH) were measured. At the end of the study, calcium and phosphorus levels in the heart and aorta were measured, and the calcification of kidney, heart, aorta, and stomach were histopathologically examined. The severity of ROD was evaluated by a histopathologic and morphometric analysis of the femurs. RESULTS: Compared with the adenine controls (N = 10), the sevelamer-treated (1%, N = 6; and 2%, N = 10) groups of adenine-induced renal failure rats had reduced serum phosphorus, serum calcium x phosphorus product, and serum PTH levels. Moreover, in the treatment groups, sevelamer suppressed calcification of the aorta media, and also the osteoid volume, fibrosis volume, and porosity ratio of femurs. CONCLUSION: These results suggest that sevelamer treatment might contribute to the suppression of ectopic calcification and ROD.
Asunto(s)
Calcinosis/prevención & control , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/prevención & control , Compuestos Epoxi/farmacología , Fallo Renal Crónico/tratamiento farmacológico , Polietilenos/farmacología , Animales , Calcinosis/sangre , Calcinosis/etiología , Calcio/sangre , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/sangre , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/etiología , Creatinina/sangre , Fallo Renal Crónico/sangre , Fallo Renal Crónico/complicaciones , Masculino , Fósforo/sangre , Poliaminas , Ratas , Ratas Wistar , SevelamerRESUMEN
BACKGROUND: Secondary hyperparathyroidism characterized by hyperplasia of the parathyroid gland (PTG) is a consequence of chronic renal insufficiency (CRI). Dietary phosphate restriction and sevelamer hydrochloride, a calcium-free phosphate binder, suppress parathyroid hormone (PTH) secretion and PTG hyperplasia in experimental animals with CRI, independently of serum calcium and 1,25(OH)(2)D(3) concentrations. In the present study, the effect of sevelamer on PTG cell proliferation in rats with CRI was investigated. METHODS: Seven weeks after a 5/6 nephrectomy, rats were fed a diet containing 0, 1 or 3% sevelamer for 4 weeks, and sham-operated rats were fed a normal diet. Serum calcium, phosphorus, PTH and 1,25(OH)(2)D(3) concentrations were measured. The number of cells positive for proliferating cell nuclear antigen (PCNA) in the maximal two-dimensional PTG area was counted at the end of study. RESULTS: Sevelamer inhibited increases in serum phosphorus, calcium-phosphorus product and PTH concentrations without affecting serum calcium or 1,25(OH)(2)D(3). Sevelamer also suppressed the maximal PTG area and PCNA-positive cells. There was also a strong correlation between the maximal PTG area and serum PTH concentration, and between PCNA-positive cells and the maximal PTG area, as well as between serum phosphorus concentration and PCNA-positive cells. CONCLUSIONS: These results indicate that sevelamer treatment reduces serum phosphorus concentration and could inhibit PTG cell proliferation and prevent PTG hyperplasia.