RESUMO
Rodent models are commonly used to evaluate parathyroid hormone (PTH) and PTH-related protein (PTHrP) ligands and analogues for their pharmacologic activities and potential therapeutic utility toward diseases of bone and mineral ion metabolism. Divergence, however, in the amino acid sequences of rodent and human PTH receptors (rat and mouse PTH1Rs are 91% identical to the human PTH1R) can lead to differences in receptor-binding and signaling potencies for such ligands when assessed on rodent vs human PTH1Rs, as shown by cell-based assays in vitro. This introduces an element of uncertainty in the accuracy of rodent models for performing such preclinical evaluations. To overcome this potential uncertainty, we used a homologous recombination-based knockin (KI) approach to generate a mouse (in-host strain C57Bl/6N) in which complementary DNA encoding the human PTH1R replaces a segment (exon 4) of the murine PTH1R gene so that the human and not the mouse PTH1R protein is expressed. Expression is directed by the endogenous mouse promoter and hence occurs in all biologically relevant cells and tissues and at appropriate levels. The resulting homozygous hPTH1R-KI (humanized) mice were healthy over at least 10 generations and showed functional responses to injected PTH analog peptides that are consistent with a fully functional human PTH1R in target bone and kidney cells. The initial evaluation of these mice and their potential utility for predicting behavior of PTH analogues in humans is reported here.
Assuntos
Proteína Relacionada ao Hormônio Paratireóideo , Hormônio Paratireóideo , Receptor Tipo 1 de Hormônio Paratireóideo , Sequência de Aminoácidos , Animais , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Hormônio Paratireóideo/genética , Hormônio Paratireóideo/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/genética , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Ratos , Receptor Tipo 1 de Hormônio Paratireóideo/genética , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Receptores de Hormônios Paratireóideos/genética , Receptores de Hormônios Paratireóideos/metabolismo , Transdução de SinaisRESUMO
Short metacarpals and/or metatarsals are typically observed in pseudohypoparathyroidism (PHP) type Ia (PHP1A) or pseudo-PHP (PPHP), disorders caused by inactivating GNAS mutations involving exons encoding the alpha-subunit of the stimulatory G protein (Gsα). Skeletal abnormalities similar to those in PHP1A/PPHP were present in several members of an extended Belgian family without evidence for abnormal calcium and phosphate regulation. Direct nucleotide sequencing of genomic DNA from an affected individual (190/III-1) excluded GNAS mutations. Instead, whole exome analysis revealed a novel heterozygous A>G change at nucleotide -3 upstream of PTHLH exon 3 that encodes the last two amino acids of the prosequence and the mature PTHrP. The same nucleotide change was also found in her affected mother and maternal aunt (190/II-2, 190/II-1), and her affected twin sons (190/IV-1, 190/IV-2), but not in her unaffected daughter (190/IV-3) and sister (190/III-2). Complementary DNA derived from immortalized lymphoblastoid cells from 190/IV-2 (affected) and 190/IV-3 (unaffected) was PCR-amplified using forward primers located either in PTHLH exon 1 (noncoding) or exon 2 (presequence and most of the prosequence), and reverse primers located in the 3'-noncoding regions of exons 3 or 4. Nucleotide sequence analysis of these amplicons revealed for the affected son 190/IV-2, but not for the unaffected daughter 190/IV-3, a heterozygous insertion of genomic nucleotides -2 and -1 causing a frameshift after residue 34 of the pre/prosequence and thus 29 novel residues without homology to PTHrP or any other protein. Our findings extend previous reports indicating that PTHrP haploinsufficiency causes skeletal abnormalities similar to those observed with heterozygous GNAS mutations. © 2018 American Society for Bone and Mineral Research.
Assuntos
Genes Dominantes , Ossos Metacarpais/patologia , Ossos do Metatarso/patologia , Mutação/genética , Proteína Relacionada ao Hormônio Paratireóideo/genética , Sítios de Splice de RNA/genética , Adulto , Idoso de 80 Anos ou mais , Alelos , Sequência de Bases , DNA Complementar/genética , Feminino , Haploinsuficiência/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismoAssuntos
Obstrução das Vias Respiratórias/psicologia , Deglutição , Medo , Hipocalcemia/diagnóstico , Pseudo-Hipoparatireoidismo/diagnóstico , Adolescente , Cálcio/uso terapêutico , Metilação de DNA , Diagnóstico Diferencial , Humanos , Hipocalcemia/tratamento farmacológico , Hipocalcemia/etiologia , Masculino , Fósforo/sangue , Pseudo-Hipoparatireoidismo/complicações , Pseudo-Hipoparatireoidismo/genética , Pseudo-Hipoparatireoidismo/psicologia , Tireotropina/sangue , Vitamina D/uso terapêutico , Vitaminas/uso terapêutico , Pseudo-HipoparatireoidismoRESUMO
Mutations in the renal sodium-dependent phosphate co-transporters NPT2a and NPT2c have been reported in patients with renal stone disease and nephrocalcinosis, but the relative contribution of genotype, dietary calcium and phosphate to the formation of renal mineral deposits is unclear. We previously reported that renal calcium phosphate deposits persist and/or reappear in older Npt2a-/- mice supplemented with phosphate despite resolution of hypercalciuria while no deposits are seen in wild-type (WT) mice on the same diet. Addition of calcium to their diets further increased calcium phosphate deposits in Npt2a-/-, but not WT mice. The response of PTH to dietary phosphate of Npt2a-/- was blunted when compared to WT mice and the response of the urinary calcium x phosphorus product to the addition of calcium and phosphate to the diet of Npt2a-/- was increased. These finding suggests that Npt2a-/- mice respond differently to dietary phosphate when compared to WT mice. Further evaluation in the Npt2a-/- cohort on different diets suggests that urinary calcium excretion, plasma phosphate and FGF23 levels appear to be positively correlated to renal mineral deposit formation while urine phosphate levels and the urine anion gap, an indirect measure of ammonia excretion, appear to be inversely correlated. Our observations in Npt2a-/- mice, if confirmed in humans, may be relevant for the optimization of existing and the development of novel therapies to prevent nephrolithiasis and nephrocalcinosis in human carriers of NPT2a and NPT2c mutations.
Assuntos
Cálcio da Dieta/farmacologia , Fósforo na Dieta/farmacologia , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/deficiência , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/genética , Animais , Cálcio/urina , Fosfatos de Cálcio/metabolismo , Feminino , Fator de Crescimento de Fibroblastos 23 , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Minerais/metabolismo , Mutação , Fosfatos/sangueRESUMO
BACKGROUND AND OBJECTIVES: Plasma fibroblast growth factor 23 (FGF23) concentrations increase early in the course of CKD in children. High FGF23 levels associate with progression of CKD in adults. Whether FGF23 predicts CKD progression in children is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We tested the hypothesis that high plasma FGF23 is an independent risk factor for CKD progression in 419 children, aged 1-16 years, enrolled in the Chronic Kidney Disease in Children (CKiD) cohort study. We measured plasma FGF23 concentrations at baseline and determined GFR annually using plasma disappearance of iohexol or the CKiD study estimating equation. We analyzed the association of baseline FGF23 with risk of progression to the composite end point, defined as start of dialysis or kidney transplantation or 50% decline from baseline GFR, adjusted for demographics, baseline GFR, proteinuria, other CKD-specific factors, and other mineral metabolites. RESULTS: At enrollment, median age was 11 years [interquartile range (IQR), 8-15], GFR was 44 ml/min per 1.73 m2 (IQR, 33-57), and FGF23 was 132 RU/ml (IQR, 88-200). During a median follow-up of 5.5 years (IQR, 3.5-6.6), 32.5% of children reached the progression end point. Higher FGF23 concentrations were independently associated with higher risk of the composite outcome (fully adjusted hazard ratio, 2.52 in the highest versus lowest FGF23 tertile; 95% confidence interval, 1.44 to 4.39, P=0.002; fully adjusted hazard ratio, 1.33 per doubling of FGF23; 95% confidence interval, 1.13 to 1.56, P=0.001). The time to progression was 40% shorter for participants in the highest compared with the lowest FGF23 tertile. In contrast, serum phosphorus, vitamin D metabolites, and parathyroid hormone did not consistently associate with progression in adjusted analyses. CONCLUSIONS: High plasma FGF23 is an independent risk factor for CKD progression in children.
Assuntos
Progressão da Doença , Fatores de Crescimento de Fibroblastos/sangue , Insuficiência Renal Crônica/sangue , Adolescente , Criança , Feminino , Fator de Crescimento de Fibroblastos 23 , Seguimentos , Taxa de Filtração Glomerular , Humanos , Transplante de Rim , Masculino , Hormônio Paratireóideo/sangue , Fósforo/sangue , Estudos Prospectivos , Diálise Renal , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/terapia , Medição de Risco , Fatores de Risco , Vitamina D/análogos & derivados , Vitamina D/sangueRESUMO
CONTEXT: 1,25-Dihydroxyvitamin D (1,25D) administration and long-term increases in phosphate, PTH, and calcium concentrations are associated with increases in circulating fibroblast growth factor 23 (FGF23); however, whether or not acute changes in serum calcium modulate short-term FGF23 release is unknown. OBJECTIVE/DESIGN: To assess the direct effect of acute changes in calcium and PTH on circulating FGF23 levels. SETTING: A university clinical and translational research center. PATIENTS/PARTICIPANTS: Twelve healthy volunteers and 10 dialysis patients. INTERVENTIONS: Calcium gluconate and sodium citrate were infused for 120 minutes on 2 consecutive days. MAIN OUTCOME MEASURES: Serum levels of ionized calcium, phosphorus, PTH, 1,25D, and plasma C-terminal FGF23 levels were obtained at 0, 13, 30, 60, 90, and 120 minutes during the infusions. RESULTS: During the calcium infusion, serum calcium concentrations increased from 1.33 ± 0.01 to 1.57 ± 0.04 mmol/L (P < .05 from baseline) and from 1.20 ± 0.05 to 1.50 ± 0.03 mmol/L (P < .05 from baseline) in healthy subjects and in dialysis patients, respectively, whereas serum calcium values decreased from 1.33 ± 0.01 to 1.03 ± 0.02 mmol/L (P < .05 from baseline) and from 1.26 ± 0.04 to 1.07 ± 0.03 mmol/L (P < .05 from baseline) in the two groups, respectively during the sodium citrate infusion. PTH levels decreased from 35 (29, 57) to 8 (2,10) pg/mL (healthy subjects) (P < .05 from baseline) and from 292 (109, 423) to 44 (28, 86) pg/mL (dialysis patients) (P < .05 from baseline) during the calcium infusion and rose from 31 (25, 56) to 122 (95, 157) pg/mL and from 281 (117, 607) to 468 (169, 928) pg/mL (P < .05 from baseline) during sodium citrate infusion. Serum 1,25D levels and plasma FGF23 values remained unchanged during both infusions in both groups. CONCLUSIONS: Short-term changes in calcium and PTH levels do not affect FGF23 concentrations in either healthy volunteers or dialysis patients.
Assuntos
Cálcio/sangue , Fatores de Crescimento de Fibroblastos/metabolismo , Falência Renal Crônica/metabolismo , Hormônio Paratireóideo/sangue , Adolescente , Cálcio/administração & dosagem , Citratos/administração & dosagem , Retroalimentação Fisiológica/efeitos dos fármacos , Retroalimentação Fisiológica/fisiologia , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Falência Renal Crônica/terapia , Masculino , Fósforo/sangue , Diálise Renal , Citrato de Sódio , Vitamina D/análogos & derivados , Vitamina D/sangue , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVES: In children with CKD, information is limited regarding the prevalence and determinants of fibroblast growth factor 23 excess and 1,25-dihyroxyvitamin D deficiency across the spectrum of predialysis CKD. This study characterized circulating concentrations of fibroblast growth factor 23 and 1,25-dihyroxyvitamin D, and investigated their interrelationships and associations with GFR and secondary hyperparathyroidism in children with CKD who were enrolled in the Chronic Kidney Disease in Children observational cohort study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Plasma fibroblast growth factor 23 concentrations and determinants of mineral metabolism were measured in 464 children ages 1-16 years with predialysis CKD. GFR was measured by plasma disappearance of iohexol in 70% of participants and estimated by the Chronic Kidney Disease in Children estimating equation using serum creatinine and cystatin C concentrations in the remainder of the participants. Participants were grouped according to CKD stage and by 10-ml/min categories of GFR. RESULTS: Median GFR for the cohort was 45 ml/min per 1.73 m(2) (interquartile range=33-57; range=15-109). Plasma fibroblast growth factor 23 concentration was above the normal range in 67% of participants (with higher levels observed among participants with lower GFR) before higher levels of serum parathyroid hormone and phosphorus were observed. Plasma fibroblast growth factor 23 levels were 34% higher in participants with glomerular disease than in participants with nonglomerular disease, despite similar GFR. Serum phosphorus levels, adjusted for age, were significantly lower at GFR of 60-69 ml/min per 1.73 m(2) than higher GFR, but thereafter they became higher in parallel with fibroblast growth factor 23 as GFR declined. Serum 1,25-dihyroxyvitamin D concentrations were lower in those participants with low GFR values, high fibroblast growth factor 23 levels, 25-hydroxyvitamin D deficiency, and proteinuria. Secondary hyperparathyroidism was present in 55% of participants with GFR<50 ml/min per 1.73 m(2). CONCLUSION: In children with predialysis CKD, high plasma fibroblast growth factor 23 is the earliest detectable abnormality in mineral metabolism, and levels are highest in glomerular diseases.
Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Insuficiência Renal Crônica/sangue , Adolescente , Fatores Etários , Biomarcadores/sangue , Cálcio/metabolismo , Canadá , Criança , Pré-Escolar , Creatinina/sangue , Estudos Transversais , Cistatina C/sangue , Diagnóstico Precoce , Fator de Crescimento de Fibroblastos 23 , Taxa de Filtração Glomerular , Humanos , Hiperparatireoidismo Secundário/sangue , Hiperparatireoidismo Secundário/etiologia , Lactente , Rim/fisiopatologia , Hormônio Paratireóideo/sangue , Fósforo/sangue , Valor Preditivo dos Testes , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia , Índice de Gravidade de Doença , Estados Unidos , Vitamina D/análogos & derivados , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/etiologiaRESUMO
BACKGROUND: The relationship between fibroblast growth factor 23 (FGF23) and vitamin D production and catabolism post-renal transplantation has not been characterized. METHODS: Circulating creatinine, calcium, phosphorus, albumin, parathyroid hormone, FGF23, and 1,25(OH)2 vitamin D (calcitriol) values were obtained pre-transplantation, daily post-operatively for 5 days, and at 6 months post-transplantation in 44 patients aged 16.4 ± 0.4 years undergoing renal transplantation at UCLA from 1 August 2005 through to 30 April 2007. 25(OH) Vitamin D and 24,25(OH)2 vitamin D concentrations were obtained at baseline and on post-operative days 5 and 180, and urinary concentrations of creatinine, phosphorus, and FGF23 were measured on post-operative days 1, 3, 5, and 180. RESULTS: Circulating phosphate concentrations declined more rapidly and the fractional excretion of phosphorus was higher in the first week post-transplantation in subjects with higher FGF23 values. Fractional excretion of FGF23 was low at all time-points. Circulating 1,25(OH)2 vitamin D levels rose more rapidly and were consistently higher in patients with lower FGF23 values; however, 25(OH) vitamin D and 24,25(OH)2 vitamin D values were unrelated to FGF23 concentrations. CONCLUSIONS: Inhibition of renal 1α-hydroxylase, rather than stimulation of 24-hydroxylase, may primarily contribute to the relationship between FGF23 values and calcitriol. The rapid decline in FGF23 levels post-transplantation in our patient cohort was not mediated solely by the filtration of intact FGF23 by the new kidney.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Transplante de Rim , Minerais/metabolismo , Adolescente , Western Blotting , Calcitriol/metabolismo , Cálcio/metabolismo , Criança , Creatinina/metabolismo , Ergocalciferóis/metabolismo , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/urina , Humanos , Falência Renal Crônica/etiologia , Falência Renal Crônica/cirurgia , Masculino , Hormônio Paratireóideo/metabolismo , Fosfatos/urina , Fósforo/metabolismo , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVES: Primary prevention of disordered mineral metabolism in CKD necessitates knowledge of its early pathophysiology. This study evaluated daily fluctuations in mineral metabolites in patients with CKD stages 3 and 4 before and after short-term calcitriol treatment and tested the effects of dietary calcium and calcitriol supplementation on these parameters in the dynamic postprandial setting. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twelve CKD patients received calcitriol (0.25 µg daily for 1 week) with hourly assessments of mineral metabolites made throughout the day and in the context of standardized meals before and after treatment. Calcium content (250 versus 500 mg) in the breakfasts constituted the dietary calcium intervention. Twelve healthy volunteers were used as controls. RESULTS: At baseline, compared with controls, fasting CKD subjects had higher parathyroid hormone and fibroblast growth factor 23 levels and greater fractional excretion of phosphate. After breakfast, urinary calcium excretion increased and parathyroid hormone levels dipped transiently in both groups, but they rose soon thereafter, reaching higher peaks in CKD. Calcitriol decreased fasting parathyroid hormone levels, and when combined with dietary calcium load, it normalized the postprandial parathyroid and calcemic responses. Daily variability in mineral metabolites was preserved in CKD before and after calcitriol. Fibroblast growth factor 23 levels increased after calcitriol, although the response was heterogeneous. CONCLUSIONS: Short-term treatment with calcitriol and dietary calcium supplementation normalizes the parathyroid and calcemic postprandial responses in patients with CKD, in whom the diurnal rhythms of mineral metabolites are preserved. Future studies should investigate the variable fibroblast growth factor 23 response to calcitriol in CKD.
Assuntos
Calcitriol/farmacologia , Cálcio/farmacologia , Insuficiência Renal Crônica/sangue , Vitaminas/farmacologia , Idoso , Calcitriol/uso terapêutico , Cálcio/análise , Cálcio/sangue , Cálcio/urina , Ritmo Circadiano , Suplementos Nutricionais , Fezes/química , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Fosfatos/análise , Fosfatos/sangue , Fosfatos/urina , Período Pós-Prandial , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/urina , Fatores de Tempo , Vitaminas/uso terapêuticoRESUMO
The parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor (PTHR1) in cells of the renal proximal tubule mediates the reduction in membrane expression of the sodium-dependent P(i) co-transporters, NPT2a and NPT2c, and thus suppresses the re-uptake of P(i) from the filtrate. In most cell types, the liganded PTHR1 activates Gα(S)/adenylyl cyclase/cAMP/PKA (cAMP/PKA) and Gα(q/11)/phospholipase C/phosphatidylinositol 1,4,5-trisphosphate (IP(3))/Ca(2+)/PKC (IP(3)/PKC) signaling pathways, but the relative roles of each pathway in mediating renal regulation P(i) transport remain uncertain. We therefore explored the signaling mechanisms involved in PTH-dependent regulation of NPT2a function using potent, long-acting PTH analogs, M-PTH(1-28) (where M = Ala(1,12), Aib(3), Gln(10), Har(11), Trp(14), and Arg(19)) and its position 1-modified variant, Trp(1)-M-PTH(1-28), designed to be phospholipase C-deficient. In cell-based assays, both M-PTH(1-28) and Trp(1)-M-PTH(1-28) exhibited potent and prolonged cAMP responses, whereas only M-PTH(1-28) was effective in inducing IP(3) and intracellular calcium responses. In opossum kidney cells, a clonal cell line in which the PTHR1 and NPT2a are endogenously expressed, M-PTH(1-28) and Trp(1)-M-PTH(1-28) each induced reductions in (32)P uptake, and these responses persisted for more than 24 h after ligand wash-out, whereas that of PTH(1-34) was terminated by 4 h. When injected into wild-type mice, both M-modified PTH analogs induced prolonged reductions in blood P(i) levels and commensurate reductions in NPT2a expression in the renal brush border membrane. Our findings suggest that the acute down-regulation of NPT2a expression by PTH ligands involves mainly the cAMP/PKA signaling pathway and are thus consistent with the elevated blood P(i) levels seen in pseudohypoparathyroid patients, in whom Gα(s)-mediated signaling in renal proximal tubule cells is defective.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Hormônio Paratireóideo/metabolismo , Pseudo-Hipoparatireoidismo/metabolismo , Transdução de Sinais/fisiologia , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/metabolismo , Animais , Células COS , Bovinos , Chlorocebus aethiops , Regulação para Baixo/fisiologia , Humanos , Técnicas In Vitro , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gambás , Osteoblastos/citologia , Osteoblastos/metabolismo , Hormônio Paratireóideo/análogos & derivados , Hormônio Paratireóideo/genética , Fósforo/sangue , Ratos , Sódio/metabolismoRESUMO
CONTEXT: Factors contributing to PTH resistance in dialysis patients remain elusive. OBJECTIVES: The study assessed the skeletal and biochemical response to 46 h of PTH(1-34) infusion in dialysis patients. DESIGN: The study was a prospective, controlled assessment of response to PTH(1-34). SETTING: The study was performed at the University of California, Los Angeles, General Clinical Research Center. PARTICIPANTS: Nineteen dialysis patients and 17 healthy volunteers were studied. INTERVENTION: PTH(1-34) was infused at a rate of 8 pmol/kg x h for 46 h. Bone biopsy was performed in all dialysis patients. MAIN OUTCOME MEASURES: Serum calcium, phosphorus, 1,25-dihydroxyvitamin D, PTH (four separate assays), and FGF-23 were determined at baseline and h 7, 23, 35, and 46 of the infusion. RESULTS: Serum calcium levels rose in healthy volunteers (9.2 +/- 0.1 to 11.9 +/- 0.3 mg/dl; P < 0.01) and in dialysis patients with adynamic/normal bone turnover (9.0 +/- 0.3 to 10.7 +/- 0.7 mg/dl; P < 0.05) but did not change in dialysis patients with high bone turnover. Serum phosphorus levels declined in healthy volunteers (3.9 +/- 0.1 to 3.5 +/- 0.1 mg/dl; P < 0.05) but increased in all dialysis patients (6.7 +/- 0.4 to 8.0 +/- 0.3 mg/dl; P < 0.05). Full-length PTH(1-84) declined in all subjects; however, PTH(7-84) fragments declined only in healthy subjects and in dialysis patients with normal/adynamic bone but remained unchanged in dialysis patients with high bone turnover. CONCLUSIONS: The skeleton of dialysis patients with high bone turnover is resistant to the calcemic actions of PTH. PTH(7-84) may contribute to this phenomenon.
Assuntos
Osso e Ossos/metabolismo , Cálcio/sangue , Falência Renal Crônica/tratamento farmacológico , Hormônio Paratireóideo/uso terapêutico , Fragmentos de Peptídeos/fisiologia , Adolescente , Desenvolvimento Ósseo/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Calcificação Fisiológica/efeitos dos fármacos , Cálcio/urina , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Falência Renal Crônica/patologia , Masculino , Hormônio Paratireóideo/fisiologia , Fósforo/sangue , Diálise Renal , Adulto JovemRESUMO
PURPOSE OF REVIEW: Regulation of calcium and phosphorus levels in the fetus and neonate is critical for proper bone development and mineralization. RECENT FINDINGS: Parathyroid hormone-related peptide plays an important role in transferring calcium across the placenta into the fetal circulation. In contrast, the factors controlling placental phosphate transport have not yet been explored, and numerous studies have indicated that maternal and childhood vitamin D deficiency continues to be a significant clinical concern. SUMMARY: The molecular basis for mineral ion homeostasis in the fetus and child remains incompletely understood. More attention must be paid to identifying and treating maternal, neonatal, and childhood vitamin D deficiency.
Assuntos
Osso e Ossos/metabolismo , Cálcio/metabolismo , Feto/metabolismo , Desenvolvimento Ósseo/fisiologia , Calcitonina/metabolismo , Criança , Feminino , Homeostase , Humanos , Recém-Nascido , Transporte de Íons , Modelos Biológicos , Hormônio Paratireóideo/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Fosfatos/metabolismo , Fósforo/metabolismo , Placenta/metabolismo , Gravidez , Vitamina D/metabolismo , Deficiência de Vitamina D/metabolismoRESUMO
Amino-terminally truncated parathyroid hormone (PTH) fragments are detected to differing degrees by first- and second-generation immunometric PTH assays (PTH-IMAs), and acute changes in serum calcium affect the proportion of these fragments in circulation. However, the effect of chronic calcium changes and different vitamin D doses on these PTH measurements remains to be defined. In this study, 60 pediatric dialysis patients, aged 13.9 +/- 0.7 years, with secondary hyperparathyroidism were randomized to 8 months of therapy with oral vitamin D combined with either calcium carbonate (CaCO(3)) or sevelamer. Serum phosphorus levels did not differ between groups. Serum calcium levels rose from 9.3 +/- 0.1 to 9.7 +/- 0.1 mg/dl during CaCO(3) therapy (p < 0.01 from baseline) but remained unchanged during sevelamer therapy. In the CaCO(3) and sevelamer groups, baseline serum PTH levels (1st PTH-IMA; Nichols Institute Diagnostics, San Clemente, CA) were 964 +/- 75 and 932 +/- 89 pg/ml, and levels declined to 491 +/- 55 and 543 +/- 59 pg/ml, respectively (nonsignificant between groups). Patients treated with sevelamer received higher doses of vitamin D than those treated with CaCO(3). The PTH values obtained by first- and second-generation PTH-IMAs correlated closely throughout therapy and the response of PTH was similar to both PTH-IMAs, despite differences in serum calcium levels.
Assuntos
Carbonato de Cálcio/administração & dosagem , Quelantes/administração & dosagem , Imunoensaio/métodos , Hormônio Paratireóideo/sangue , Poliaminas/administração & dosagem , Vitamina D/administração & dosagem , Adolescente , Adulto , Fosfatase Alcalina/sangue , Cálcio/sangue , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Humanos , Hiperparatireoidismo Secundário/sangue , Hiperparatireoidismo Secundário/tratamento farmacológico , Masculino , Fósforo/sangue , Diálise Renal , SevelamerRESUMO
OBJECTIVE: Most patients with autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib) carry an identical maternally inherited 3-kb microdeletion up-stream of GNAS (STX16del4-6(mat)), which is associated with a methylation loss restricted to exon A/B. STX16del4-6(mat) is not found in sporadic PHP-Ib (sporPHP-Ib) patients, who show broad GNAS methylation changes. Because of the epigenetic differences between both groups, we searched for clinical and/or laboratory differences. PATIENTS AND METHODS: Age at diagnosis, calcium, phosphorus and PTH were analysed in 43 patients with AD-PHP-Ib due to STX16del4-6(mat) and in 22 patients with sporPHP-Ib. RESULTS: All AD-PHP-Ib patients with STX16del4-6(mat) showed only loss of exon A/B methylation. Of the 43 individuals, 26 were symptomatic when diagnosis was established at age 12.1 +/- 1.34 years (mean +/- SEM); laboratory findings at presentation were calcium 1.69 +/- 0.06 mmol/l, phosphorus 2.25 +/- 0.12 mmol/l and PTH 442 +/- 54.1 pg/ml. The remaining 17 individuals with STX16del4-6(mat) were asymptomatic when diagnosed at age 23.5 +/- 3.93 years (calcium 2.18 +/- 0.05 mmol/l, phosphorus 1.63 +/- 0.10 mmol/l, PTH 222 +/- 40.3 pg/ml). Patients with sporPHP-Ib showed methylation changes at two or more GNAS exons, presented at age 10.0 +/- 1.01 years and had, as a group, similar laboratory findings as patients with symptomatic AD-PHP-Ib (calcium 1.51 +/- 0.06 mmol/l, phosphorus 2.65 +/- 0.10 mmol/l, PTH 634 +/- 162.1 pg/ml). However, sporPHP-Ib females appeared to be more severely affected. CONCLUSIONS: Patients with symptomatic AD-PHP-Ib due to STX16del4-6(mat) and sporPHP-Ib have similar changes in calcium, phosphate and PTH. STX16del4-6(mat) often leads to asymptomatic disease and screening of all siblings of affected individuals is therefore advised. The cause of the apparent sexual dimorphism in patients with sporPHP-Ib remains uncertain.
Assuntos
Epigênese Genética/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Pseudo-Hipoparatireoidismo/sangue , Pseudo-Hipoparatireoidismo/genética , Adulto , Idade de Início , Cálcio/sangue , Cromograninas , Metilação de DNA , Éxons/genética , Feminino , Humanos , Masculino , Hormônio Paratireóideo/sangue , Fósforo/sangue , Pseudo-HipoparatireoidismoRESUMO
BACKGROUND: First-generation immunometric assays for "intact" parathyroid hormone (iPTH) also measure large N-terminally truncated PTH fragments, whereas second-generation assays, such as the "bio-intact" PTH (biPTH) assay, measure only full-length biologically active PTH(1-84). This study compared iPTH and biPTH assays during cinacalcet treatment in subjects with secondary HPT receiving dialysis. METHODS: Four hundred and ten subjects were enrolled in a 26-week randomized, double-blind, placebo-controlled trial of oral cinacalcet (or placebo), 30 to 180 mg once daily, and efficacy was assessed using biPTH and iPTH assays. RESULTS: Compared with control treatment, cinacalcet improved the management of secondary HPT. Both biPTH and iPTH decreased by 38%+/- 3% during weeks 13 to 26 in the cinacalcet group; biPTH increased by 23%+/- 4% and iPTH increased by 9.5%+/- 3% in the control group (P < 0.001). Fifty-six percent of cinacalcet subjects and 10% of control subjects had a > or = 30% reduction in biPTH, and 61% and 11%, respectively, had a > or = 30% reduction in iPTH. Significant correlations between biPTH and iPTH levels were observed throughout the study. Both assays correlated similarly with bone-specific alkaline phosphatase levels. The ratio of biPTH to iPTH was maintained at 56% +/- 1% after treatment in both treatment groups. Increasing serum calcium levels were associated with a decreasing ratio of biPTH to (iPTH-biPTH). CONCLUSION: These data show that PTH can be monitored with either iPTH or biPTH assays during therapy with cinacalcet, and that cinacalcet therapy does not exert a major influence on the ratio between PTH(1-84) and large, N-terminally truncated PTH fragments.
Assuntos
Hiperparatireoidismo/sangue , Hiperparatireoidismo/tratamento farmacológico , Imunoensaio/métodos , Naftalenos/administração & dosagem , Hormônio Paratireóideo/sangue , Adulto , Idoso , Cálcio/sangue , Cinacalcete , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/análise , Fósforo/sangue , Resultado do Tratamento , Vitamina D/sangueRESUMO
We describe 2 sisters diagnosed initially with paroxysmal kinesigenic choreoathetosis, a condition characterized by brief episodes of spasms precipitated by sudden movement. However, subsequent testing showed hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone levels consistent with pseudohypoparathyroidism type Ib. This diagnosis was confirmed by genetic testing, which identified a 3-kilobase deletion on chromosome 20q13.3. Our report describes the neurologic presentation, metabolic derangement, and underlying genetic mutation in a family. It also reinforces the importance of metabolic testing in the evaluation of pediatric patients with movement disorders.