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1.
Transplant Proc ; 51(5): 1397-1401, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31155177

RESUMO

OBJECTIVE: In dialysis patients, cinacalcet could be an effective alternative to parathyroidectomy for treating hyperparathyroidism. In the present study, we aimed to determine the characteristics of subjects with persistent hyperparathyroidism who require parathyroidectomy despite the use of cinacalcet. METHODS: Nine kidney transplant patients (7 men, 2 women; mean age 53.2 [SD, 8.9] years) who had tertiary hyperparathyroidism were reviewed in a single center. Pre- and postcinacalcet levels of calcium, phosphorous, intact parathyroid hormone (iPTH), and renal function were analyzed to evaluate the effect of cinacalcet treatment in these patients. The baseline parameters before cinacalcet treatment were compared in patients who did and did not undergo parathyroidectomy. RESULTS: Cinacalcet reduced serum calcium levels in all patients (11.48 [SD, 0.73] mg/dL to 10.20 [0.70] mg/dL; P = .008). Serum phosphorous levels significantly increased from 2.28 (SD, 0.77) mg/dL to 3.02 (SD, 0.65) mg/dL (P = .03). The iPTH levels in 7 patients decreased, while the mean level remained unchanged in total subjects. The iPTH levels increased even with cinacalcet treatment in 2 patients. In 3 patients, serum calcium levels abruptly increased after cinacalcet withdrawal. Five patients who showed persistent hypercalcemia due to hyperparathyroidism underwent parathyroidectomy. These 5 patients had significantly different characteristics compared with 4 patients who did not undergo parathyroidectomy: hypercalcemia (11.92 [SD, 0.68] mg/dL vs 10.93 [SD, 0.26] mg/dL; P = .02), hypophosphatemia (1.74 [SD, 0.36] mg/dL vs 2.95 [SD, 0.58] mg/dL; P = .03), and hyperparathyroidism (252.2 [SD, 131.4] pg/dL vs 101.5 [SD, 18.4] pg/dL; P = .02). CONCLUSION: Cinacalcet reduced hypercalcemia due to hyperparathyroidism in the transplant patients. However, patients who had pre-existing higher iPTH, hypercalcemia, and hypophosphatemia needed parathyroidectomy. Therefore, cinacalcet could be considered an alternative to parathyroidectomy in selected patients.


Assuntos
Calcimiméticos/uso terapêutico , Cinacalcete/uso terapêutico , Hiperparatireoidismo/tratamento farmacológico , Transplante de Rim , Adulto , Idoso , Feminino , Humanos , Hipercalcemia/etiologia , Hiperparatireoidismo/etiologia , Masculino , Pessoa de Meia-Idade , Diálise Renal/efeitos adversos , Estudos Retrospectivos
2.
Ren Fail ; 41(1): 326-333, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31014177

RESUMO

BACKGROUND: Secondary hyperparathyroidism (SHPT) is associated with high incidences of cardiovascular disease, bone fracture, and mortality. This study was conducted to demonstrate the effectiveness of cinacalcet treatment on chronic kidney disease-mineral bone disorder (CKD-MBD) markers in chronic hemodialysis patients with severe SHPT. METHODS: In phase 1, 30 adult HD patients were randomized to cinacalcet or control groups for 12 weeks to explore the achievement of >30% reduction of iPTH. In phase 2, 45 patients were participated to further explore the effect of cinacalcet on CKD-MBD parameters for 24-week follow up and 12 additional weeks after cinacalcet discontinuation. RESULTS: In phase 1, the baseline serum iPTH levels were not different [1374 (955, 1639) pg/mL in the control group vs. 1191 (1005, 1884) pg/mL in the cinacalcet group], the percentage of patients achieving iPTH target were significantly higher in the treatment group [80% vs. 13%, p = .001]. In phase 2, the significant reductions of iPTH, FGF-23, tartrate-resistant acid phosphatase 5b, and slightly decreased size of parathyroid gland and stabilized vascular calcification were observed at 24-week follow up and markedly rebounded after discontinuation of cinacalcet. CONCLUSIONS: The effectiveness of cinacalcet were still obviously demonstrated even in chronic HD patients with severe SHPT. In addition, the improvements of bone markers and FGF-23, and stabilization of vascular calcification were observed. Therefore, cinacalcet can provide salutary effects on CKD-MBD in severe SHPT and might be an initially effective PTH-lowering therapy prior to surgical parathyroidectomy as well as an alternative treatment in the patients unsuitable for surgery. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02056730. Date of registration: February 4, 2014.


Assuntos
Calcimiméticos/uso terapêutico , Cinacalcete/uso terapêutico , Hiperparatireoidismo Secundário/tratamento farmacológico , Falência Renal Crônica/terapia , Diálise Renal/efeitos adversos , Adulto , Cálcio/sangue , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Seguimentos , Humanos , Hiperparatireoidismo Secundário/sangue , Hiperparatireoidismo Secundário/diagnóstico , Hiperparatireoidismo Secundário/etiologia , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Fósforo/sangue , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
3.
PLoS One ; 14(3): e0213774, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30875390

RESUMO

BACKGROUND: Calcimimetics have been shown to be effective and safe therapies for the treatment of secondary hyperparathyroidism (sHPT), a serious complication of disordered mineral metabolism associated with dialysis-dependent chronic kidney disease. Etelcalcetide, a recently approved intravenous calcimimetic, reduces serum parathyroid hormone (PTH), calcium, phosphorus, and fibroblast growth factor-23 concentrations. Here we report the first integrated safety profile of etelcalcetide using pooled data from five pivotal clinical trials. METHODS: This analysis included data from patients receiving hemodialysis with moderate to severe sHPT enrolled in two randomized, placebo-controlled trials; a randomized active-controlled (with cinacalcet) trial; and two single-arm, open-label extension trials. Patients initially received etelcalcetide intravenously 5 mg three times weekly (TIW) after hemodialysis; with potential dose increases of 2.5 or 5 mg at 4-week intervals to a maximum dose of 15 mg TIW, depending on serum PTH and calcium levels. The nature, frequency, and severity of treatment-emergent adverse events (AEs) and changes in laboratory parameters were assessed. RESULTS: Overall, we evaluated 1023 patients from the placebo-controlled trials, 683 from the active-controlled trial, and 1299 from open-label extensions. The frequency and nature of common treatment-emergent AEs reported for the etelcalcetide arm were consistent among the placebo-controlled and active-controlled trials. The most common AEs were those related to mineral metabolism (decreased blood calcium, hypophosphatemia, muscle spasms) or gastrointestinal abnormalities (diarrhea, nausea, vomiting). Hypocalcemia leading to discontinuation of either calcimimetic was experienced in ≤ 1% of patients. CONCLUSIONS: This integrated safety assessment of etelcalcetide across placebo- and active-controlled trials showed an overall favorable risk/benefit profile, with safety similar to that of cinacalcet. Consistent with its mechanism of action, the most important risks associated with etelcalcetide were serum calcium reductions and hypocalcemia-related AEs; no new safety findings were identified in the pooled long-term extension trials.


Assuntos
Calcimiméticos/uso terapêutico , Cálcio/metabolismo , Hiperparatireoidismo Secundário/tratamento farmacológico , Peptídeos/uso terapêutico , Diálise Renal , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Fósforo/metabolismo , Prognóstico
4.
Langenbecks Arch Surg ; 404(1): 71-79, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30729318

RESUMO

INTRODUCTION: Tertiary hyperparathyroidism (tHPT), i.e., persistent HPT after kidney transplantation, affects 17-50% of transplant recipients. Treatment of tHPT is mandatory since persistently elevated PTH concentrations after KTx increase the risk of renal allograft dysfunction and osteoporosis. The introduction of cinacalcet in 2004 seemed to offer a medical treatment alternative to parathyroidectomy (PTx). However, the optimal management of tHPT remains unclear. METHODS: A retrospective analysis was performed on patients receiving a kidney transplantation (KT) in two academic centers in the Netherlands. Thirty patients undergoing PTx within 3 years of transplantation and 64 patients treated with cinacalcet 1 year after transplantation for tHPT were included. Primary outcomes were serum calcium and PTH concentrations 1 year after KT and after PTx. RESULTS: Serum calcium normalized in both the cinacalcet and the PTx patients. PTH concentrations remained above the upper limit of normal (median 22.0 pmol/L) 1 year after KT, but returned to within the normal range in the PTx group (median 3.7 pmol/L). Side effects of cinacalcet were difficult to assess; minor complications occurred in three patients. Re-exploration due to persistent tHPT was performed in three (10%) patients. CONCLUSION: In patients with tHPT, cinacalcet normalizes serum calcium, but does not lead to a normalization of serum PTH concentrations. In contrast, PTx leads to a normalization of both serum calcium and PTH concentrations. These findings suggest that PTx is the treatment of choice for tHPT.


Assuntos
Calcimiméticos/uso terapêutico , Cinacalcete/uso terapêutico , Hiperparatireoidismo/terapia , Transplante de Rim , Paratireoidectomia , Complicações Pós-Operatórias/terapia , Adulto , Feminino , Humanos , Hiperparatireoidismo/diagnóstico , Hiperparatireoidismo/etiologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Resultado do Tratamento
5.
Drugs ; 79(5): 501-513, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30811012

RESUMO

Significant advances in immunosuppressive therapies have been made in renal transplantation, leading to increased allograft and patient survival. Despite improvement in overall patient survival, patients continue to require management of persistent post-transplant hyperparathyroidism. Medications that treat persistent hyperparathyroidism include vitamin D, vitamin D analogues, and calcimimetics. Medication side effects such as hypocalcemia or hypercalcemia, and adynamic bone disease, may lead to a decrease in the drugs. When medical management fails to control persistent post-transplant hyperparathyroidism, treatment is a parathyroidectomy. Surgical techniques are not uniform between centers and surgeons. Undergoing the surgery may include a subtotal technique or a technique including total parathyroid gland resection with partial heterotopic gland reimplantation. In addition, there are possible post-surgical complications. The ideal treatment for persistent post-transplant hyperparathyroidism is the treatment and prevention of the condition while patients are being managed for their late-stage chronic kidney disease and end-stage renal disease.


Assuntos
Doenças Ósseas/terapia , Hiperparatireoidismo/terapia , Transplante de Rim/efeitos adversos , Doenças Ósseas/etiologia , Doenças Ósseas/prevenção & controle , Calcimiméticos/uso terapêutico , Humanos , Hiperparatireoidismo/etiologia , Hiperparatireoidismo/prevenção & controle , Hiperparatireoidismo Secundário/etiologia , Paratireoidectomia , Transplante Homólogo , Resultado do Tratamento , Vitamina D/uso terapêutico
6.
Pediatr Clin North Am ; 66(1): 179-207, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30454743

RESUMO

Hypophosphatemic rickets, mostly of the X-linked dominant form caused by pathogenic variants of the PHEX gene, poses therapeutic challenges with consequences for growth and bone development and portends a high risk of fractions and poor bone healing, dental problems and nephrolithiasis/nephrocalcinosis. Conventional treatment consists of PO4 supplements and calcitriol requiring monitoring for treatment-emergent adverse effects. FGF23 measurement, where available, has implications for the differential diagnosis of hypophosphatemia syndromes and, potentially, treatment monitoring. Newer therapeutic modalities include calcium sensing receptor modulation (cinacalcet) and biological molecules targeting FGF23 or its receptors. Their long-term effects must be compared with those of conventional treatments.


Assuntos
Raquitismo Hipofosfatêmico/diagnóstico , Raquitismo Hipofosfatêmico/tratamento farmacológico , Raquitismo Hipofosfatêmico/genética , Calcimiméticos/uso terapêutico , Criança , Diagnóstico Diferencial , Hormônio do Crescimento/uso terapêutico , Humanos , Mutação , Fosfatos/uso terapêutico , Vitamina D/uso terapêutico
7.
Surgery ; 165(1): 135-141, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30413324

RESUMO

BACKGROUND: Since 2004, end-stage renal disease related hyperparathyroidism patients are treated mainly with cinacalcet, which ceased to be subsidized through the Australian Pharmaceutical Benefits Scheme in 2015. We aimed to investigate the impact of these changes on the treatment strategy in the Australian end-stage renal disease population. METHODS: The following groups were formed according to the date of parathyroidectomy: A, before calcimimetics; B, during the era of calcimimetics; and C, after cinacalcet removal by the Australian Pharmaceutical Benefits Scheme. The primary outcome was time from start of dialysis to parathyroidectomy. Regression analysis was used to examine trends in parathyroidectomy rates. RESULTS: Between 1998 and 2016, 195 parathyroidectomies were performed. Median time to referral was 69 (33-123), 67 (31-110) and 44 (23-102) months for groups A, B, and C, respectively (P = .55). Parathyroidectomy rates increased throughout the years (CI 0.09-1.13, R2=0.27, P = .02). A trend toward a dip in parathyroidectomy rates was seen during the era of cinacalcet (P = .08). Median preoperative parathyroid hormone levels increased significantly (842 [418-1,553] versus 1,040 [564-1,810] versus 1,350 [1,037-1,923] pg/mL, for groups A, B, and C, respectively [P < .01]). CONCLUSION: Parathyroidectomy rates seem to vary according to the availability of cinacalcet. This change in treatment strategy is accompanied with increased preoperative parathyroid hormone levels, reflecting delayed surgery and increased disease severity.


Assuntos
Calcimiméticos/uso terapêutico , Cinacalcete/uso terapêutico , Hiperparatireoidismo Secundário/terapia , Seguro de Serviços Farmacêuticos , Falência Renal Crônica/complicações , Paratireoidectomia/estatística & dados numéricos , Adulto , Idoso , Austrália , Feminino , Humanos , Hiperparatireoidismo Secundário/etiologia , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Análise de Regressão , Índice de Gravidade de Doença , Tempo para o Tratamento
9.
Am J Surg ; 217(1): 146-151, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29929906

RESUMO

BACKGROUND: Cinacalcet is an effective treatment for renal hyperthyroidism when traditional medical therapy has failed. We studied the impact of pre-operative cinacalcet administration on post-surgical outcomes. METHODS: A retrospective analysis was performed of patients from 2002 to 2017 diagnosed with renal hyperparathyroidism requiring parathyroidectomy to evaluate the need for post-operative supplementation and outcomes. RESULTS: 102 patients were identified; 34 patients were treated with cinacalcet prior to undergoing parathyroidectomy. The cinacalcet treatment cohort (CT) demonstrated a greater duration of renal replacement therapy (p = 0.03) relative to the untreated cohort (NC). NC had greater proportion receiving peritoneal dialysis (p=<0.0001) compared to other forms of renal replacement, greater pre-operative PTH levels (p = 0.001) and greater decrease in PTH after resection (p = 0.0086). Post-operative vitamin D supplementation was more frequent in the CT group (p = 0.02). After propensity matching for pre-operative PTH and duration of renal replacement therapy, there were no differences in post-operative supplementation or outcomes. CONCLUSIONS: Cinacalcet patients may have advanced disease. These patients have longer duration of renal failure and higher PTH levels. After propensity matching, no significant differences were noted in terms of need for supplementation or outcomes.


Assuntos
Calcimiméticos/uso terapêutico , Cinacalcete/uso terapêutico , Hiperparatireoidismo Secundário/tratamento farmacológico , Hiperparatireoidismo Secundário/cirurgia , Falência Renal Crônica/complicações , Paratireoidectomia , Adulto , Idoso , Feminino , Humanos , Hiperparatireoidismo Secundário/etiologia , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , Pontuação de Propensão , Diálise Renal , Estudos Retrospectivos , Resultado do Tratamento
10.
Medicine (Baltimore) ; 97(45): e13128, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30407334

RESUMO

RATIONALE: Calcium-sensing receptor (CaSR) mutations can cause life-threatening neonatal severe hyperparathyroidism (NSHPT). The medical management of NSHPT is often challenging and complex. Here, we present a case of NSHPT caused by a novel homozygous CaSR mutation. PATIENT CONCERNS: A Chinese female infant presented with poor feeding, constipation, severe hypotonia, and periodic bradycardia. Biochemistry tests revealed markedly elevated serum levels of Ca and parathyroid hormone (PTH). DIAGNOSES: Genetic sequencing revealed a previously undescribed CaSR mutation in exon 3 (c.242T>A; p.I81K). A diagnosis of NSHPT secondary to homozygously inherited familial hypocalciuric hypercalcemia syndrome was established. INTERVENTIONS: Cinacalcet was administered after the common treatments (low-calcium intake, hydration, and furosemide), calcitonin, and pamidronate therapy all failed. OUTCOMES: Serum Ca decreased and stabilized with cinacalcet therapy. During a 10-month follow-up, total calcium was maintained within the high-normal range and PTH was normalized. LESSONS: A trial of cinacalcet therapy might be undertaken in cases of NSHPT while definitive results of the genetic analysis are awaited.


Assuntos
Calcimiméticos/uso terapêutico , Cinacalcete/uso terapêutico , Hiperparatireoidismo Primário/genética , Doenças do Recém-Nascido/genética , Receptores de Detecção de Cálcio/genética , Cálcio/sangue , Feminino , Testes Genéticos , Homozigoto , Humanos , Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/tratamento farmacológico , Lactente , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/tratamento farmacológico , Mutação , Hormônio Paratireóideo/sangue
11.
BMC Pediatr ; 18(1): 340, 2018 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-30376845

RESUMO

BACKGROUND: Neonatal severe primary hyperparathyroidism (NSHPT) is a rare autosomal recessive disorder of calcium homeostasis, characterized by striking hyperparathyroidism, marked hypercalcemia and hyperparathyroid bone disease. We report the case of a newborn with a novel homozygous mutation of the CaSR, treated by successful subtotal parathyroidectomy, who had an acute presentation of the disease, i.e. out-of hospital cardiorespiratory arrest. . CASE PRESENTATION: A 8-day-old female newborn was admitted to the NICU of University of Bari "Aldo Moro" (Italy) after a cardiorespiratory arrest occurred at home. Severe hypercalcemia was found and different drug therapies were employed (Furosemide, Cinacalcet and bisphosphonate), as well as hyperhydration, until subtotal parathyroidectomy, was performed at day 32. Our patient's mutation was never described before so that a strict and individualized long-term follow-up was started. CONCLUSIONS: This case of NSHPT suggests that a near-miss event, labelled as a possible case of SIDS, could also be due to severe hypercalcemia and evidentiates the difficulties of the neonatal management of NSHPT. Furthermore, the identification of the specific CaSR mutation provides the substrate for prenatal diagnosis.


Assuntos
Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/genética , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/genética , Mutação , Receptores de Detecção de Cálcio/genética , Conservadores da Densidade Óssea/uso terapêutico , Calcimiméticos/uso terapêutico , Cinacalcete/uso terapêutico , Ácido Clodrônico/uso terapêutico , Difosfonatos/uso terapêutico , Feminino , Hidratação , Furosemida/uso terapêutico , Genes Recessivos , Homozigoto , Humanos , Hiperparatireoidismo Primário/terapia , Recém-Nascido , Doenças do Recém-Nascido/terapia , Paratireoidectomia
12.
Clin Ther ; 40(12): 2099-2111, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30473399

RESUMO

PURPOSE: Secondary hyperparathyroidism (SHPT) is a serious complication that increases the risk of bone disorders in patients with chronic kidney disease (CKD) undergoing hemodialysis. Etelcalcetide is the first injectable calcimimetic approved for treatment of SHPT, which reduces bone turnover markers and suppresses intact fibroblast growth factor 23 (iFGF-23). This study aimed to explore the associations between etelcalcetide-induced changes in circulating factors and serum iFGF-23 levels. METHODS: This study was a post hoc analysis of data from a previous multicenter, open-label study of etelcalcetide administered to 191 Japanese patients with SHPT undergoing hemodialysis for 52 weeks. Correlations were analyzed between changes from baseline in serum iFGF-23 and serum intact parathyroid hormone (iPTH), corrected calcium, phosphate, bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase-5b (TRACP-5b), and 1α,25-dihydroxyvitamin D (1,25[OH]2D) levels at 1, 2, 3, 6, and 12 months. Akaike's Information Criterion (AIC) was calculated using serum iPTH, corrected calcium, phosphate, BAP, TRACP-5b, and 1,25(OH)2D levels as potential predictor variables at each time point. Four models with the smallest AIC at the 3-month time point were chosen as the fitted models to predict changes in iFGF-23 levels, and stepwise multivariate analysis was performed to determine the predictor variables with the greatest contribution to the change in iFGF-23 levels by calculating the partial coefficients of determination. FINDINGS: The etelcalcetide-induced reduction in iFGF-23 was positively correlated with serum levels of corrected calcium and phosphate and negatively with BAP. By calculating the AIC, corrected calcium, phosphate, iPTH, BAP, and TRACP-5b were suggested to be predictors of iFGF-23 levels. Stepwise multivariate analysis found that phosphate, corrected calcium, BAP, and TRACP-5b correlated with iFGF-23, in order from strongest to weakest. IMPLICATIONS: These results suggest that etelcalcetide effectively lowered iFGF-23 and that this reduction may occur via improvements in phosphate, corrected calcium, BAP, and TRACP-5b. Etelcalcetide is thus a promising calcimimetic for decreasing iFGF-23 and improving bone turnover in patients with CKD undergoing hemodialysis with severe SHPT, in addition to decreasing PTH itself. JapicCTI identifier: 142,665.


Assuntos
Remodelação Óssea/efeitos dos fármacos , Calcimiméticos/uso terapêutico , Peptídeos/uso terapêutico , Administração Intravenosa , Idoso , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Renal , Insuficiência Renal Crônica/terapia
13.
Nat Rev Endocrinol ; 15(1): 33-51, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30443043

RESUMO

The Ca2+-sensing receptor (CaSR) is a dimeric family C G protein-coupled receptor that is expressed in calcitropic tissues such as the parathyroid glands and the kidneys and signals via G proteins and ß-arrestin. The CaSR has a pivotal role in bone and mineral metabolism, as it regulates parathyroid hormone secretion, urinary Ca2+ excretion, skeletal development and lactation. The importance of the CaSR for these calcitropic processes is highlighted by loss-of-function and gain-of-function CaSR mutations that cause familial hypocalciuric hypercalcaemia and autosomal dominant hypocalcaemia, respectively, and also by the fact that alterations in parathyroid CaSR expression contribute to the pathogenesis of primary and secondary hyperparathyroidism. Moreover, the CaSR is an established therapeutic target for hyperparathyroid disorders. The CaSR is also expressed in organs not involved in Ca2+ homeostasis: it has noncalcitropic roles in lung and neuronal development, vascular tone, gastrointestinal nutrient sensing, wound healing and secretion of insulin and enteroendocrine hormones. Furthermore, the abnormal expression or function of the CaSR is implicated in cardiovascular and neurological diseases, as well as in asthma, and the CaSR is reported to protect against colorectal cancer and neuroblastoma but increase the malignant potential of prostate and breast cancers.


Assuntos
Calcimiméticos/uso terapêutico , Hipercalcemia/congênito , Hipercalciúria/genética , Hipocalcemia/genética , Hipoparatireoidismo/congênito , Nefrolitíase/genética , Receptores de Detecção de Cálcio/genética , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença/epidemiologia , Humanos , Hipercalcemia/tratamento farmacológico , Hipercalcemia/genética , Hipercalcemia/fisiopatologia , Hipercalciúria/tratamento farmacológico , Hipercalciúria/fisiopatologia , Hipocalcemia/tratamento farmacológico , Hipocalcemia/fisiopatologia , Hipoparatireoidismo/tratamento farmacológico , Hipoparatireoidismo/genética , Hipoparatireoidismo/fisiopatologia , Incidência , Masculino , Mutação/genética , Nefrolitíase/tratamento farmacológico , Nefrolitíase/fisiopatologia , Prognóstico , Receptores de Detecção de Cálcio/efeitos dos fármacos , Medição de Risco , Resultado do Tratamento
15.
BMJ Case Rep ; 20182018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30158262

RESUMO

The case of a 61-year-old female patient with a long-standing history of bipolar affective disorder treated medically with lithium therapy for the past two decades. In late 2012, the patient was diagnosed with hyperparathyroidism secondary to lithium therapy. The patient underwent parathyroidectomy in August 2013. During surgery, only two glands were conclusively located and removed. This resulted in a reduction in the patient's plasma total calcium levels and parathyroid hormone. The psychiatric management of the bipolar affective disorder was reviewed, and lithium discontinued as a result of the findings. Over the following year, a variety of different mood stabilisers were trialled, however none were found to successfully maintain the patient's mental health. In August 2014, the patient was admitted with a severe depressive relapse of her bipolar affective disorder. Her admission tests showed hypercalcaemia, which may also have contributed to her mood symptoms and mental state deterioration. The patient was reviewed by the endocrinology team and subsequently commenced on cinacalcet treatment (30 mg twice a day). Over the following months, the patient's plasma total calcium levels returned to within normal range. The patient's depressive symptomatology gradually improved with a combination of physical and pharmacological treatments.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Calcimiméticos/uso terapêutico , Cinacalcete/uso terapêutico , Hiperparatireoidismo/diagnóstico , Carbonato de Lítio/efeitos adversos , Diagnóstico Diferencial , Feminino , Humanos , Hiperparatireoidismo/sangue , Hiperparatireoidismo/induzido quimicamente , Hiperparatireoidismo/tratamento farmacológico , Pessoa de Meia-Idade
16.
J Int Med Res ; 46(11): 4578-4585, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30027791

RESUMO

OBJECTIVE: Secondary hyperparathyroidism (SHPT) is a major complication in patients with chronic kidney disease (CKD). SHPT is related to chronic kidney disease-mineral bone disorder, leading to increased morbidity and mortality. Etelcalcetide is intravenously administered at the end of hemodialysis (HD). Etelcalcetide differs from the oral calcimimetic cinacalcet because it reduces gastrointestinal adverse events, thereby improving therapeutic effects. Etelcalcetide has only been approved by the U.S. Food and Drug Administration for several months. Therefore, there have only been a few reports regarding treatment of SHPT using etelcalcetide. This study aimed to evaluate the efficacy of etelcalcetide in patients on HD with SHPT. METHODS: Nine patients on HD (four men and five women, aged 58 ± 10 years) were enrolled in this study. All of the patients received etelcalcetide (5-10 mg, three times a week after HD). The observation period was 4.4 ± 1.0 months. RESULTS: All of the patients showed a significant reduction in serum parathyroid hormone levels during the observation period (-59% ± 20%). No significant adverse effects were observed. CONCLUSIONS: Although this study had an uncontrolled small group and a short observation period, our results suggest that etelcalcetide could be a promising agent for SHPT treatment.


Assuntos
Calcimiméticos/uso terapêutico , Hiperparatireoidismo Secundário/tratamento farmacológico , Peptídeos/uso terapêutico , Diálise Renal , Idoso , Fosfatase Alcalina/sangue , Cálcio/sangue , Feminino , Humanos , Hiperparatireoidismo Secundário/sangue , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Fósforo/sangue
17.
J Clin Endocrinol Metab ; 103(11): 3993-4004, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30060226

RESUMO

Background: Primary hyperparathyroidism (PHPT), the most common cause of hypercalcemia, is most often identified in postmenopausal women. The clinical presentation of PHPT has evolved over the past 40 years to include three distinct clinical phenotypes, each of which has been studied in detail and has led to evolving concepts about target organ involvement, natural history, and management. Methods: In the present review, I provide an evidence-based summary of this disorder as it has been studied worldwide, citing key concepts and data that have helped to shape our concepts about this disease. Results: PHPT is now recognized to include three clinical phenotypes: overt target organ involvement, mild asymptomatic hypercalcemia, and high PTH levels with persistently normal albumin-corrected and ionized serum calcium values. The factors that determine which of these clinical presentations is more likely to predominate in a given country include the extent to which biochemical screening is used, vitamin D deficiency is present, and whether parathyroid hormone levels are routinely measured in the evaluation of low bone density or frank osteoporosis. Guidelines for parathyroidectomy apply to all three clinical forms of the disease. If surgical guidelines are not met, parathyroidectomy can also be an appropriate option if no medical contraindications are present. If either the serum calcium or bone mineral density is of concern and surgery is not an option, pharmacological approaches are available and effective. Conclusions: Advances in our knowledge of PHPT have guided new concepts in diagnosis and management.


Assuntos
Medicina Baseada em Evidências/métodos , Hipercalcemia/etiologia , Hiperparatireoidismo Primário/terapia , Hormônio Paratireóideo/metabolismo , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/fisiologia , Conservadores da Densidade Óssea/uso terapêutico , Calcimiméticos/uso terapêutico , Cálcio/sangue , Cálcio/metabolismo , Medicina Baseada em Evidências/normas , Comportamento Alimentar/fisiologia , Feminino , Humanos , Hipercalcemia/sangue , Hipercalcemia/fisiopatologia , Hiperparatireoidismo Primário/complicações , Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/fisiopatologia , Masculino , Osteoporose/sangue , Osteoporose/diagnóstico , Osteoporose/fisiopatologia , Glândulas Paratireoides/metabolismo , Glândulas Paratireoides/cirurgia , Hormônio Paratireóideo/sangue , Paratireoidectomia/normas , Pós-Menopausa/psicologia , Guias de Prática Clínica como Assunto , Fatores Sexuais , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/diagnóstico , Deficiência de Vitamina D/fisiopatologia
18.
Semin Dial ; 31(5): 440-444, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30009474

RESUMO

Secondary hyperparathyroidism (SHPT), commonly encountered in patients receiving maintenance dialysis, is associated with numerous adverse outcomes, including mortality. Calcimimetics, agents that act on the calcium sensing receptor (CaSR), were designed to overcome limitations in the use of vitamin D sterols to treat SHPT, and have demonstrated efficacy in reducing levels of PTH in randomized trials. Currently available calcimimetics include oral cinacalcet and the recently approved intravenously administered agent, etelcalcetide. While cinacalcet is an allosteric modulator of the CaSR, etelcalcetide acts as a direct CaSR agonist. Etelcalcetide's properties allow it to be administered intravenously thrice weekly at the end of a hemodialysis treatment session. Etelcalcetide has recently been shown to be more potent than cinacalcet in reducing PTH levels. However, etelcalcetide appears, like cinacalcet, to cause gastrointestinal intolerance. Additionally, etelcalcetide, which appears to reduce calcium substantially more than cinacalcet does, can prolong the QTc electrocardiographic interval. While etelcalcetide is very effective at reducing PTH levels, the current climate of dialysis cost containment in the United States may limit its widespread use. This review compares and contrasts the pharmacologic characteristics of cinacalcet and etelcalcetide, discusses the results of clinical trials involving these drugs, and posits implications for their use for clinical practice.


Assuntos
Calcimiméticos/uso terapêutico , Cinacalcete/uso terapêutico , Hiperparatireoidismo Secundário/tratamento farmacológico , Peptídeos/uso terapêutico , Calcimiméticos/efeitos adversos , Cinacalcete/efeitos adversos , Humanos , Hormônio Paratireóideo/sangue , Peptídeos/efeitos adversos
19.
Kidney Int ; 94(4): 818-825, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30049473

RESUMO

Secondary hyperparathyroidism (SHPT) leads to cardiovascular calcification, which affects survival and quality of life in patients with chronic kidney disease. Cinacalcet is used to control SHPT, but it may induce gastrointestinal symptoms, resulting in lower adherence and insufficient dosages. Therefore, a need exists to develop new calcimimetics that cause fewer gastrointestinal symptoms. Here we conducted a phase 3, randomized, double-blind, double-dummy trial for a head-to-head comparison of the efficacy and safety of evocalcet, a new oral calcimimetic, to the established cinacalcet. Japanese patients with SHPT on hemodialysis were randomized to receive evocalcet or cinacalcet (317 patients each) for 30 weeks. The primary efficacy endpoint was non-inferiority of evocalcet to cinacalcet in the proportion of patients achieving a mean intact parathyroid hormone level of 60 to 240 pg/mL from week 28 to 30 (non-inferiority margin, -15%, per protocol set analyses). In the evocalcet and cinacalcet groups, 72.7% and 76.7%, respectively, achieved the target intact parathyroid hormone level (between-group difference: -4.0% [95% confidence interval -11.4%, 3.5%], for non-inferiority). The incidence of gastrointestinal-related adverse events was 18.6% and 32.8%, respectively (between-group difference: -14.2% [-20.9%, -7.5%], significant for superiority). Thus, the non-inferiority of evocalcet to cinacalcet in suppressing intact parathyroid hormone with fewer gastrointestinal-related adverse events was demonstrated. Hence, evocalcet may be a favorable alternative to existing calcimimetics for management of SHPT.


Assuntos
Calcimiméticos/uso terapêutico , Cinacalcete/uso terapêutico , Hiperparatireoidismo Secundário/tratamento farmacológico , Naftalenos/uso terapêutico , Pirrolidinas/uso terapêutico , Idoso , Calcimiméticos/efeitos adversos , Cinacalcete/efeitos adversos , Método Duplo-Cego , Feminino , Gastroenteropatias/induzido quimicamente , Humanos , Hiperparatireoidismo Secundário/sangue , Japão , Masculino , Pessoa de Meia-Idade , Naftalenos/efeitos adversos , Hormônio Paratireóideo/sangue , Pirrolidinas/efeitos adversos , Diálise Renal , Insuficiência Renal Crônica/terapia
20.
Drug Des Devel Ther ; 12: 1589-1598, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29910605

RESUMO

Secondary hyperparathyroidism (sHPT) is a frequently occurring severe complication of advanced kidney disease. Its clinical consequences include extraskeletal vascular and valvular calcifications, changes in bone metabolism resulting in renal osteodystrophy, and an increased risk of cardiovascular morbidity and mortality. Calcimimetics are a cornerstone of parathyroid hormone (PTH)-lowering therapy, as confirmed by the recently updated 2017 Kidney Disease: Improving Global Outcomes chronic kidney disease - mineral and bone disorder clinical practice guidelines. Contrary to calcitriol or other vitamin D-receptor activators, calcimimetics reduce PTH without increasing serum-calcium, phosphorus, or FGF23 levels. Etelcalcetide is a new second-generation calcimimetic that has been approved for the treatment of sHPT in adult hemodialysis patients. Whereas the first-generation calcimimetic cinacalcet is taken orally once daily, etelcalcetide is given intravenously thrice weekly at the end of the hemodialysis session. Apart from improving drug adherence, etelcalcetide has proven to be more effective in lowering PTH when compared to cinacalcet, with an acceptable and comparable safety profile. The hope for better gastrointestinal tolerance with intravenous administration did not come true, as etelcalcetide did not significantly mitigate the adverse gastrointestinal effects associated with cinacalcet. Enhanced adherence and strong reductions in PTH, phosphorus, and FGF23 could set the stage for a future large randomized controlled trial to demonstrate that improved biochemical control of mineral metabolism with etelcalcetide in hemodialysis patients translates into cardiovascular and survival benefits and better health-related quality of life.


Assuntos
Calcimiméticos/uso terapêutico , Hiperparatireoidismo Secundário/tratamento farmacológico , Peptídeos/uso terapêutico , Diálise Renal , Cinacalcete/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Adesão à Medicação , Guias de Prática Clínica como Assunto
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