RESUMO
BACKGROUND: There is limited evidence on the association between short-term changes in mineral and bone disorder parameters and survival in maintenance hemodialysis patients. METHODS: We investigated the association between changing patterns of phosphorus, calcium and intact parathyroid hormone levels and all-cause mortality in hemodialysis patients with secondary hyperparathyroidism. Each parameter was divided into three categories (low [L], middle [M] and high [H]), and the changing patterns between two consecutive visits at 3-month intervals were categorized into nine groups (e.g., L-L and M-H). The middle category was defined as 4.0-7.0 mg/dL for phosphorous, 8.5-9.5 mg/dL for calcium and 200-500 pg/mL for intact parathyroid hormone. Adjusted incidence rates and rate ratios were analyzed by weighted Poisson regression models accounting for time-dependent exposures. RESULTS: For phosphorus, shifts from low/high to middle category (L-M/H-M) were associated with a lower mortality compared with the L-L and H-H groups, whereas shifts from middle to low/high category (M-L/M-H) were associated with a higher mortality compared with the M-M group. For calcium, shifts from low/middle to high category (L-H/M-H) were associated with a higher mortality compared with the L-L and M-M groups, whereas shifts from high to middle category (H-M) were associated with a lower mortality compared with the H-H group. For intact parathyroid hormone, shifts from low to middle category (L-M) were associated with a lower mortality compared with the L-L group. CONCLUSIONS: Changes in the 3-month patterns of phosphorus and calcium toward the middle category were associated with lower mortality. Our study also suggests the importance of avoiding hypercalcemia.
Assuntos
Cálcio/sangue , Hiperparatireoidismo Secundário/etiologia , Falência Renal Crônica/sangue , Fósforo/sangue , Diálise Renal , Idoso , Doenças Ósseas , Causas de Morte , Feminino , Humanos , Hipercalcemia , Hiperparatireoidismo Secundário/mortalidade , Hiperfosfatemia , Falência Renal Crônica/complicações , Falência Renal Crônica/mortalidade , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Prognóstico , Estudos Prospectivos , Diálise Renal/efeitos adversos , Diálise Renal/mortalidadeRESUMO
INTRODUCTION: There is limited evidence about the association between calcium and phosphate levels and mortality stratified by intact parathyroid hormone (iPTH) level. METHODS: We investigated whether differences in iPTH level affect the relationship between calcium and phosphate levels and all-cause mortality in hemodialysis patients with secondary hyperparathyroidism (SHPT). Calcium and phosphate levels were categorized as low (< 8.5 mg/dL, < 4.0 mg/dL), medium (≥ 8.5-< 9.5 mg/dL, ≥ 4.0-< 7.0 mg/dL), and high (≥ 9.5 mg/dL, ≥ 7.0 mg/dL), respectively. iPTH levels were grouped into < 300 or ≥ 300 pg/mL. Adjusted incidence rate ratios (aIRRs) were analyzed by weighted Poisson regression. RESULTS: For calcium, patients with higher iPTH (≥ 300 pg/mL) had significantly higher all-cause mortality rates in the high than in the medium category (aIRR 1.99, 95% confidence interval [CI] 1.16-3.42), and tended to have a higher mortality rate in the low category (aIRR 2.04, 95% CI 0.94-4.42). Patients with lower iPTH (< 300 pg/mL) had higher mortality rates in the high than in the medium category (aIRR 1.65, 95% CI 1.39-1.96). For phosphate, the mortality rate was significantly higher in the high than in the medium category in patients with higher and lower iPTH (aIRR 3.23, 95% CI 1.63-6.39 for iPTH ≥ 300 pg/mL; aIRR 1.58, 95% CI 1.06-2.36 for iPTH < 300 pg/mL). CONCLUSION: High calcium and phosphate levels were associated with increased risk of mortality irrespective of iPTH level.
Assuntos
Cálcio/sangue , Hiperparatireoidismo Secundário/sangue , Mortalidade , Hormônio Paratireóideo/sangue , Fosfatos/sangue , Insuficiência Renal Crônica/sangue , Idoso , Doenças Cardiovasculares/mortalidade , Feminino , Humanos , Hiperparatireoidismo Secundário/tratamento farmacológico , Hiperparatireoidismo Secundário/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Estudos Observacionais como Assunto , Diálise Renal , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Estudos RetrospectivosRESUMO
OBJECTIVES: To elucidate the effect of cinacalcet use on all-cause and cause-specific hospitalization outcomes using a prospective cohort of maintenance hemodialysis patients. METHODS: We used data from a prospective cohort of Japanese hemodialysis patients with secondary hyperparathyroidism and examined baseline characteristics as well as longitudinal changes. All patients were cinacalcet-naïve at study enrollment. Further, we used a marginal structural model to account for time-varying confounders on cinacalcet initiation and hospitalization outcomes, and an Andersen-Gill-type recurrent event model to account for any recurring events of hospitalization in the outcome analysis using the weighted dataset. RESULTS: Among the 3,276 patients, cinacalcet treatment was initiated in 1,384 patients during the entire follow-up. Cinacalcet users were slightly younger, included more patients with chronic glomerulonephritis and fewer patients with diabetes, were more likely to have a history of parathyroidectomy, and were more often used receiving vitamin D receptor activator, phosphate binders, and iron supplements. The overall hospitalization analysis yielded a hazard ratio (HR) of 0.97 (95% confidence interval [CI]: 0.80, 1.18). A trend toward a mild protective association was observed for cardiovascular-related hospitalizations (HR: 0.85; 95% CI: 0.64, 1.14). In the subgroup analysis, a protective association was seen due to cinacalcet use for infection-related hospitalizations in the lowest intact parathyroid hormone group (HR: 0.36; 95% CI: 0.14, 0.95). CONCLUSIONS: Cinacalcet initiation in patients on maintenance hemodialysis had no effect on all-cause and cause-specific hospitalizations. Although the overall association was statistically not significant, cinacalcet may have a protective association on cardiovascular-related hospitalization in all patients and infection-related hospitalization in patient with low intact parathyroid hormone.
Assuntos
Cinacalcete/administração & dosagem , Hospitalização , Hiperparatireoidismo/terapia , Diálise Renal , Idoso , Povo Asiático , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
In the original publication of the article, two sentences in the "Results" section were published incorrectly. The corrected texts are provided below.
RESUMO
BACKGROUND: This post-marketing surveillance (PMS) study evaluated the safety and effectiveness of long-term darbepoetin alfa (darbepoetin) for the treatment of renal anemia in Japanese non-dialysis chronic kidney disease patients. METHODS: Patients were treated with darbepoetin and followed up for 3 years. Adverse events (AEs), adverse drug reactions (ADRs), hemoglobin (Hb) levels, and renal function were assessed. Patients were stratified by Hb level at the time of occurrence of cardiovascular-related AEs. Statistical analyses were performed to explore factors affecting the occurrence of AEs, cardiovascular-related AEs, and composite renal endpoints. RESULTS: In the safety analysis set (5547 patients), AEs and ADRs occurred in 44.4 and 7.1% of patients, respectively. Cardiovascular-related AEs were observed in 12.6% of the overall population. The proportion of patients who presented cardiovascular-related AEs was lower among those with a higher Hb level at the time of occurrence. In the effectiveness analysis set (5024 patients), mean Hb levels remained between 10.0 and 10.6 g/dL (Weeks 4-156). Three months after darbepoetin administration, patients with Hb ≥ 11 g/dL presented fewer composite renal endpoints than those with Hb < 11 g/dL (p = 0.0013), and the cumulative proportion of renal survival was higher in those with Hb ≥ 11 g/dL vs. Hb < 11 g/dL (p < 0.0001). CONCLUSIONS: This PMS study showed the safety and effectiveness of long-term use of darbepoetin in a large number of patients. Patients with Hb ≥ 11 g/dL presented fewer composite renal endpoints than those with Hb < 11 g/dL, without an increase in the incidence of cardiovascular-related AEs.
Assuntos
Anemia/tratamento farmacológico , Darbepoetina alfa/administração & dosagem , Hematínicos/administração & dosagem , Rim/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Anemia/sangue , Anemia/diagnóstico , Anemia/epidemiologia , Biomarcadores/sangue , Darbepoetina alfa/efeitos adversos , Esquema de Medicação , Feminino , Hematínicos/efeitos adversos , Hemoglobinas/metabolismo , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Vigilância de Produtos Comercializados , Estudos Prospectivos , Sistema de Registros , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Cinacalcet hydrochloride (cinacalcet), an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). In sharp contrast to vitamin D receptor activators, cinacalcet suppresses SHPT without inducing hypercalcemia or hyperphosphatemia. Nevertheless, some patients remain refractory to SHPT with this agent, as the dose cannot be sufficiently increased due to gastrointestinal symptoms. In order to resolve this issue, we have developed a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of CKD induced by 5/6 nephrectomy, oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone (PTH). With regard to the gastro-intestinal effects, cinacalcet induced a significant delay in gastric emptying in rats, while evocalcet did no marked effects on it. Evocalcet also demonstrated the less induction of emesis compared to cinacalcet in common marmosets. The pharmacological effects of evocalcet were observed at lower doses because of its higher bioavailability than cinacalcet, which may have contributed to the reduced GI tract symptoms. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro liver microsome assay, suggesting a better profile in drug interactions than cinacalcet that inhibits cytochrome P450 (CYP) 2D6. These findings suggest that evocalcet can be a better alternative to cinacalcet, an oral calcimimetic agent, with a wider safety margin.
Assuntos
Calcimiméticos/farmacologia , Trato Gastrointestinal/efeitos dos fármacos , Glândulas Paratireoides/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Administração Oral , Animais , Calcimiméticos/química , Calcimiméticos/farmacocinética , Callithrix , Cinacalcete/farmacologia , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Trato Gastrointestinal/fisiopatologia , Células HEK293 , Humanos , Isoenzimas/metabolismo , Masculino , Estrutura Molecular , Glândulas Paratireoides/enzimologia , Hormônio Paratireóideo/metabolismo , Ratos Wistar , Receptores de Detecção de Cálcio/antagonistas & inibidores , Receptores de Detecção de Cálcio/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Vômito/induzido quimicamenteRESUMO
Cinacalcet HCl (cinacalcet) is a calcimimetic compound, which suppresses parathyroid (PTH) hormone secretion from parathyroid glands in both primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism (SHPT). We previously reported the suppressive effect of cinacalcet on PTH secretion in vivo in a PHPT model mouse, in which parathyroid-targeted overexpression of the cyclin D1 oncogene caused chronic biochemical hyperparathyroidism and parathyroid cell hyperplasia. Although cinacalcet suppressed parathyroid cell proliferation in SHPT in 5/6-nephrectomized uremic rats, its effect on PHPT has not yet been determined. In this study, the effect of cinacalcet on parathyroid cell proliferation was analyzed in PHPT mice. Cinacalcet (1 mg/g) was mixed into the rodent diet and orally administrated to 80-week-old PHPT mice for 10 days before death. 5-Bromo-2'-deoxyuridine (BrdU, 6 mg/day) was infused by an osmotic pump for 5 days before death, followed by immunostaining of the thyroid-parathyroid complex using an anti-BrdU antibody to estimate parathyroid cell proliferation. Compared to untreated PHPT mice, cinacalcet significantly suppressed both serum calcium and PTH. The proportion of BrdU-positive cells to the total cell number in the parathyroid glands increased considerably in untreated PHPT mice (9.5 ± 3.1%) compared to wild-type mice (0.7 ± 0.1%) and was significantly suppressed by cinacalcet (1.2 ± 0.2%). Cinacalcet did not affect apoptosis in the parathyroid cells of PHPT mice. These data suggest that cinacalcet suppressed both serum PTH levels and parathyroid cell proliferation in vivo in PHPT.
Assuntos
Ciclina D1/antagonistas & inibidores , Hiperparatireoidismo Primário/tratamento farmacológico , Naftalenos/uso terapêutico , Glândulas Paratireoides/efeitos dos fármacos , Animais , Apoptose , Proliferação de Células/efeitos dos fármacos , Cinacalcete , Ciclina D1/genética , Ciclina D1/metabolismo , Hiperparatireoidismo Primário/genética , Hiperparatireoidismo Primário/metabolismo , Camundongos , Camundongos Transgênicos , Modelos Animais , Oncogenes/genética , Glândulas Paratireoides/metabolismo , Hormônio Paratireóideo/metabolismoRESUMO
BACKGROUND: Lysophosphatidylcholine (LPC), an atherogenic component of oxidized low-density lipoprotein, has been shown to induce the attenuation of endothelium-dependent vascular relaxation. Although benidipine, a dihydropyridine-calcium channel blocker, is known to have endothelial protective effects, the effects of benidipine on LPC-induced endothelial dysfunction remain unknown. We examined the effects of benidipine on the impairment of endothelium-dependent relaxation induced by LPC. METHODS: Benidipine was administered orally to rats and aortas were then isolated. Aortic rings were treated with LPC and endothelial functions were then evaluated. Additionally, the effects of benidipine on intracellular calcium concentration ([Ca2+]i) and membrane fluidity altered by LPC in primary cultured rat aortic endothelial cells were examined. [Ca2+]i was measured using the fluorescent calcium indicator fura-2. Membrane fluidity was monitored by measuring fluorescence recovery after photobleaching. RESULTS: Treatment with LPC impaired endothelial function. Benidipine prevents the impairment of relaxation induced by LPC. Acetylcholine elicited an increase in [Ca2+]i in fura-2 loaded endothelial cells. The increase in [Ca2+]i was suppressed after exposure to LPC. Plasma membrane fluidity increased following incubation with LPC. Benidipine inhibited the LPC-induced increase in membrane fluidity and impairment of increase in [Ca2+]i. CONCLUSION: These results suggest that benidipine inhibited LPC-induced endothelial dysfunction by maintaining increase in [Ca2+]i. Benidipine possesses membrane stabilization properties in LPC-treated endothelial cells. It is speculated that the preservation of membrane fluidity by benidipine may play a role in the retainment of calcium mobilization. The present findings may provide new insights into the endothelial protective effects of benidipine.
Assuntos
Aorta/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Di-Hidropiridinas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Lisofosfatidilcolinas/química , Administração Oral , Animais , Antioxidantes/metabolismo , Cálcio/metabolismo , Membrana Celular/metabolismo , Células Endoteliais/metabolismo , Recuperação de Fluorescência Após Fotodegradação , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
X-linked hypophosphatemia (XLH), characterized by renal phosphate wasting, is the most common cause of vitamin D-resistant rickets. It has been postulated that some phosphaturic factor plays a causative role in XLH and its murine homolog, the Hyp mouse. Fibroblast growth factor 23 (FGF23) is a physiological phosphaturic factor; its circulatory level is known to be high in most patients with XLH and Hyp mice, suggesting its pathophysiological role in this disease. To test this hypothesis, we treated Hyp mice with anti-FGF23 antibodies to inhibit endogenous FGF23 action. A single injection of the antibodies corrected the hypophosphatemia and inappropriately normal serum 1,25-dihydroxyvitamin D. These effects were accompanied by increased expressions of type IIa sodium-phosphate cotransporter and 25-hydroxyvitamin-D-1alpha-hydroxylase and a suppressed expression of 24-hydroxylase in the kidney. Repeated injections during the growth period ameliorated the rachitic bone phenotypes typically observed in Hyp mice, such as impaired longitudinal elongation, defective mineralization, and abnormal cartilage development. Thus, these results indicate that excess actions of FGF23 underlie hypophosphatemic rickets in Hyp mice and suggest a novel therapeutic potential of the FGF23 antibodies for XLH.
Assuntos
Anticorpos/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/complicações , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/imunologia , Doenças Genéticas Ligadas ao Cromossomo X , Osteomalacia/complicações , Osteomalacia/tratamento farmacológico , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Animais , Anticorpos/administração & dosagem , Anticorpos/farmacologia , Peso Corporal/efeitos dos fármacos , Raquitismo Hipofosfatêmico Familiar/sangue , Raquitismo Hipofosfatêmico Familiar/urina , Feminino , Fator de Crescimento de Fibroblastos 23 , Lâmina de Crescimento/efeitos dos fármacos , Lâmina de Crescimento/patologia , Imuno-Histoquímica , Injeções Subcutâneas , Masculino , Camundongos , Osteomalacia/sangue , Osteomalacia/urina , Tíbia/efeitos dos fármacos , Tíbia/patologia , Fatores de Tempo , Vitamina D/metabolismoAssuntos
Hiperparatireoidismo Secundário/tratamento farmacológico , Falência Renal Crônica/complicações , Naftalenos/farmacologia , Naftalenos/uso terapêutico , Glândulas Paratireoides/efeitos dos fármacos , Receptores de Detecção de Cálcio/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Cinacalcete , Humanos , Falência Renal Crônica/terapia , Ratos , Diálise RenalRESUMO
High serum parathyroid hormone levels are associated with vascular calcification. Cinacalcet is a calcimimetic agent that inhibits parathyroid hormone secretion and is used to treat patients with secondary hyperparathyroidism. Here we measured the effects of oral cinacalcet on calcification of the aorta and heart in rats with a remnant kidney (5/6 nephrectomy) model of uremia that were fed a high-phosphate diet containing lactose to accelerate the process of aortic calcification. Alizarin red staining showed that the smooth muscle in the aortic arch of rats with a remnant kidney was calcified. The tissue levels of calcium and phosphorus in the aorta and hearts of these rats were significantly increased compared to sham-operated rats. Expression of the osteoblastic lineage genes osteocalcin, osteopontin and runt-related gene 2 were also increased in the aorta of these rats. Cinacalcet suppressed these calcification-related changes by reducing serum parathyroid hormone, calcium, phosphorus, and the calcium-phosphorus product. Parathyroidectomy also suppressed calcification in this model. We suggest that cinacalcet inhibits calcification of the aorta and heart in uremic patients with secondary hyperparathyroidism by decreasing serum parathyroid hormone levels.
Assuntos
Aorta/patologia , Calcinose/tratamento farmacológico , Miocárdio/patologia , Naftalenos/farmacologia , Uremia/complicações , Animais , Calcinose/prevenção & controle , Cinacalcete , Modelos Animais de Doenças , Hiperparatireoidismo Secundário , Hormônio Paratireóideo/sangue , RatosRESUMO
Clinical studies have been performed to determine the effect of cinacalcet HCl (cinacalcet), an allosteric modulator of the calcium-sensing receptor (CaR), on primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism of uremia (SHPT). However, no in vitro studies on human parathyroid cells have been reported to date. In this study, the inhibitory effect of cinacalcet on PTH secretion was analyzed in primary cultured parathyroid cells obtained from patients. The investigation involved three PHPT and three SHPT patients subjected to therapeutic parathyroidectomy. Notably, all SHPT patients were resistant to intravenous vitamin D analogue therapy. Removed parathyroid tumors were used for immunohistochemistry and parathyroid cell primary culture. Immunohistochemical analyses revealed diminished expression of CaR and vitamin D receptor (VDR) in all parathyroid tumors. PTH secretion from cultured parathyroid cells of PHPT and SHPT patients was suppressed by extracellular Ca2+ and cinacalcet in a dose-dependent manner. Rates of suppression of PTH secretion in PHPT and SHPT by cinacalcet (1000 nmol/l) were 61% +/- 21% and 61% +/- 19%, respectively. Cinacalcet demonstrates significant potency in the suppression of PTH secretion in primary cultured human parathyroid cells in vitro, despite reduced levels of the target protein, CaR. Data from this in vitro analysis support the clinical application of cinacalcet in PHPT and SHPT therapy.
Assuntos
Naftalenos/farmacologia , Glândulas Paratireoides/efeitos dos fármacos , Glândulas Paratireoides/metabolismo , Hormônio Paratireóideo/metabolismo , Receptores de Detecção de Cálcio/deficiência , Cinacalcete , Humanos , Hiperparatireoidismo Primário , Hiperparatireoidismo Secundário , Imuno-Histoquímica , Glândulas Paratireoides/citologia , Paratireoidectomia , Receptores de Calcitriol/análise , Receptores de Detecção de Cálcio/análise , Receptores de Detecção de Cálcio/metabolismoRESUMO
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.
Assuntos
Proliferação de Células/efeitos dos fármacos , Falência Renal Crônica/complicações , Glândulas Paratireoides/patologia , Poliaminas/uso terapêutico , Animais , Apoptose , Cálcio/sangue , Modelos Animais de Doenças , Feminino , Hiperplasia/tratamento farmacológico , Hiperplasia/metabolismo , Hiperplasia/patologia , Hipertrofia/patologia , Imuno-Histoquímica , Falência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/metabolismo , Masculino , Tamanho do Órgão/efeitos dos fármacos , Glândulas Paratireoides/efeitos dos fármacos , Hormônio Paratireóideo/sangue , Fósforo/sangue , Ratos , Ratos Sprague-Dawley , SevelamerRESUMO
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.
Assuntos
Doenças da Aorta/tratamento farmacológico , Calcinose/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/sangue , Hiperparatireoidismo Secundário/tratamento farmacológico , Falência Renal Crônica/complicações , Glândulas Paratireoides/patologia , Hormônio Paratireóideo/sangue , Poliaminas/administração & dosagem , Adenina , Animais , Doenças da Aorta/etiologia , Calcinose/etiologia , Cálcio/sangue , Modelos Animais de Doenças , Esquema de Medicação , Hiperparatireoidismo Secundário/sangue , Hiperparatireoidismo Secundário/etiologia , Hiperplasia/tratamento farmacológico , Hiperplasia/etiologia , Falência Renal Crônica/sangue , Falência Renal Crônica/induzido quimicamente , Masculino , Fósforo/sangue , Ratos , Ratos Sprague-Dawley , SevelamerRESUMO
Cinacalcet HCl, an allosteric modulator of the calcium-sensing receptor (CaR), has recently been approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, due to its suppressive effect on parathyroid hormone (PTH) secretion. Although cinacalcet's effects in patients with primary and secondary hyperparathyroidism have been reported, the crucial relationship between the effect of calcimimetics and CaR expression on the parathyroid glands requires better understanding. To investigate its suppressive effect on PTH secretion in primary hyperparathyroidism, in which hypercalcemia may already have stimulated considerable CaR activity, we investigated the effect of cinacalcet HCl on PTH-cyclin D1 transgenic mice (PC2 mice), a model of primary hyperparathyroidism with hypo-expression of CaR on their parathyroid glands. A single administration of 30 mg/kg body weight (BW) of cinacalcet HCl significantly suppressed serum calcium (Ca) levels 2 h after administration in 65- to 85-week-old PC2 mice with chronic biochemical hyperparathyroidism. The percentage reduction in serum PTH was significantly correlated with CaR hypo-expression in the parathyroid glands. In older PC2 mice (93-99 weeks old) with advanced hyperparathyroidism, serum Ca and PTH levels were not suppressed by 30 mg cinacalcet HCl/kg. However, serum Ca and PTH levels were significantly suppressed by 100 mg/kg of cinacalcet HCl, suggesting that higher doses of this compound could overcome severe hyperparathyroidism. To conclude, cinacalcet HCl demonstrated potency in a murine model of primary hyperparathyroidism in spite of any presumed endogenous CaR activation by hypercalcemia and hypo-expression of CaR in the parathyroid glands.
Assuntos
Hiperparatireoidismo/metabolismo , Naftalenos/farmacologia , Hormônio Paratireóideo/antagonistas & inibidores , Receptores de Detecção de Cálcio/metabolismo , Envelhecimento , Animais , Cálcio/antagonistas & inibidores , Cálcio/sangue , Cinacalcete , Genes bcl-1 , Hiperparatireoidismo/genética , Hiperparatireoidismo/patologia , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos , Glândulas Paratireoides/efeitos dos fármacos , Glândulas Paratireoides/metabolismo , Hormônio Paratireóideo/sangue , Hormônio Paratireóideo/genética , Hormônio Paratireóideo/metabolismoRESUMO
BACKGROUND: Secondary hyperparathyroidism (HPT) in chronic kidney disease (CKD) is a physiologic response to kidney failure characterized by elevated serum parathyroid hormone (PTH) levels and parathyroid gland enlargement. Calcimimetic agents acting through allosteric modification of the calcium-sensing receptor (CaR) can attenuate parathyroid hyperplasia in rats with secondary HPT. The present study explores the effects of the calcimimetic cinacalcet HCl on parathyroid hyperplasia, apoptosis, and PTH secretion in a rat model of secondary HPT. METHODS: Cinacalcet HCl was gavaged daily (1, 5, or 10 mg/kg) for 4 weeks starting 6 weeks post-5/6 nephrectomy. After dosing, hyperplasia was determined using parathyroid weight and proliferating cell nuclear antigen (PCNA) immunochemistry. Apoptosis was determined using in situ techniques. Serum PTH((1-34)) and blood chemistries were determined throughout the course of the study. RESULTS: Administration of cinacalcet HCl (5 or 10 mg/kg) significantly reduced the number of PCNA-positive cells and decreased parathyroid weight compared with vehicle-treated 5/6 nephrectomized rats. There was no difference in apoptosis from cinacalcet HCl-treated or vehicle-treated animals. Serum PTH and blood ionized calcium levels decreased in cinacalcet HCl-treated animals compared with vehicle-treated controls. CONCLUSION: The results confirm previous work demonstrating that calcimimetic agents attenuate the progression of parathyroid hyperplasia in subtotally nephrectomized rats, extending earlier observations to now include cinacalcet HCl. These results support a role for the CaR in regulating parathyroid cell proliferation. Therefore, cinacalcet HCl may represent a novel therapy for improving the management of secondary HPT.
Assuntos
Hiperparatireoidismo Secundário/tratamento farmacológico , Naftalenos/uso terapêutico , Glândulas Paratireoides/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Cálcio/sangue , Cinacalcete , Hiperparatireoidismo Secundário/sangue , Hiperparatireoidismo Secundário/patologia , Hiperplasia , Masculino , Glândulas Paratireoides/patologia , Hormônio Paratireóideo/sangue , Ratos , Ratos Sprague-DawleyRESUMO
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.
Assuntos
Suplementos Nutricionais , Compostos de Epóxi/farmacologia , Falência Renal Crônica/patologia , Falência Renal Crônica/prevenção & controle , Polietilenos/farmacologia , Animais , Biópsia por Agulha , Modelos Animais de Doenças , Progressão da Doença , Taxa de Filtração Glomerular/efeitos dos fármacos , Imuno-Histoquímica , Testes de Função Renal , Masculino , Fosfatos/metabolismo , Poliaminas , Ratos , Ratos Wistar , Valores de Referência , Fatores de Risco , Sensibilidade e Especificidade , SevelamerRESUMO
Parathyroid cell hyperplasia is commonly observed in patients with chronic renal insufficiency and largely accounts for refractory secondary hyperparathyroidism. Calcimimetics are newly synthesized compounds that activate a calcium receptor on the parathyroid cell and can suppress parathyroid hormone secretion. The calcimimetic compound AMG 073 has been examined in clinical trials, and the data obtained so far demonstrate that the compound can lower the circulating levels of parathyroid hormone and calcium-phosphorus product in patients with secondary hyperparathyroidism. Furthermore, experimental evidence indicates that calcimimetics have the potential to inhibit parathyroid cell proliferation and block the progression of parathyroid hyperplasia. These beneficial effects, especially the potential to control parathyroid cell proliferation, would place calcimimetics among the essential therapeutic agents for treating secondary hyperparathyroidism.
Assuntos
Proteínas de Ligação ao Cálcio/agonistas , Glândulas Paratireoides/citologia , Animais , Cálcio/fisiologia , Divisão Celular/efeitos dos fármacos , Divisão Celular/fisiologia , Humanos , Hormônio Paratireóideo/antagonistas & inibidores , Transdução de SinaisRESUMO
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.
Assuntos
Compostos de Epóxi/farmacologia , Nefrectomia , Glândulas Paratireoides/patologia , Polietilenos/farmacologia , Animais , Calcitriol/sangue , Cálcio/sangue , Divisão Celular/efeitos dos fármacos , Masculino , Nefrectomia/métodos , Tamanho do Órgão/efeitos dos fármacos , Concentração Osmolar , Glândulas Paratireoides/efeitos dos fármacos , Glândulas Paratireoides/metabolismo , Hormônio Paratireóideo/sangue , Fósforo/sangue , Poliaminas , Período Pós-Operatório , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos Sprague-Dawley , SevelamerRESUMO
The secondary hyperparathyroidism that develops in rats with chronic renal insufficiency (CRI) can be totally prevented by activation of the parathyroid Ca(2+) receptor with a calcimimetic compound, when treatment is initiated before parathyroid cell hyperplasia and increased circulating parathyroid hormone levels develop. In clinical practice, however, secondary hyperparathyroidism is usually manifest by the time CRI is diagnosed. This study examined the effects of daily oral gavage or continuous subcutaneous infusion for 8 wk of the calcimimetic NPS R-568 on the progression of established mild or moderate-to-severe secondary hyperparathyroidism in rats with CRI induced by 5/6 nephrectomy. Both oral and infused NPS R-568 completely prevented further hyperplasia but did not reduce total parathyroid cell number below that present at the initiation of treatment. This prevention of cellular proliferation occurred despite increases in plasma phosphate and decreases in Ca(2+) and 1, 25-dihydroxyvitamin D levels, and supports the view that the Ca(2+) receptor is the dominant regulator of parathyroid cell hyperplasia in addition to parathyroid hormone secretion. The clinical implications of these findings suggest that controlling Ca(2+) receptor activity with calcimimetic compounds could be sufficient to manage secondary hyperparathyroidism in CRI.