RESUMO
AIMS: Renal osteodystrophy occurs in the early stages of chronic kidney disease (CKD) and progresses during loss of kidney function. Fibroblast growth factor (FGF)-23 and sclerostin, both produced by osteocytes, are increased in blood of patients with CKD. The aim of this study was to analyze the impact of decline in kidney function on FGF-23 and sclerostin protein expression in bone and to study their relationship with their serum levels and bone histomorphometry. MATERIALS AND METHODS: 108 patients aged 25 - 81 years (mean ± SD: 56 ± 13 years) underwent anterior iliac crest biopsies after double-tetracycline labeling. Eleven patients were CKD-2, 16 were CKD-3, 9 were CKD-4 - 5, and 64 CKD-5D. Patients were on hemodialysis for 49 ± 117 months. 18 age-matched patients without CKD were included as controls. Immunostaining was performed on undecalcified bone sections to quantify FGF-23 and sclerostin expression. Bone sections were also evaluated by histomorphometry for bone turnover, mineralization, and volume. RESULTS: FGF-23 expression in bone correlated positively with CKD stages (p < 0.001) increasing from 5.3- to 7.1-fold starting at CKD-2. No difference in FGF-23 expression was seen between trabecular and cortical bone. Sclerostin expression in bone correlated positively with CKD stages (p < 0.001) with an increase from 3.8- to 5.1-fold starting at CKD-2. This increase was progressive and significantly greater in cortical than cancellous bone. FGF-23 and sclerostin in blood and bone were strongly associated with bone turnover parameters. Expression of FGF-23 in cortical bone correlated positively with activation frequency (Ac.f) and bone formation rate (BFR/BS) (p < 0.05), while sclerostin correlated negatively with Ac.f, BFR/BS, and osteoblast and osteoclast numbers (p < 0.05). FGF-23 trabecular and cortical expressions correlated positively with cortical thickness (p < 0.001). Sclerostin bone expression correlated negatively with parameters of trabecular thickness and osteoid surface (p < 0.05). CONCLUSION: These data show a progressive increase in FGF-23 and sclerostin in blood and bone associated with decrease in kidney function. The observed relationships between bone turnover and sclerostin or FGF-23 should be considered when treatment modalities are developed for management of turnover abnormalities in CKD patients.
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Distúrbio Mineral e Ósseo na Doença Renal Crônica , Falência Renal Crônica , Insuficiência Renal Crônica , Humanos , Osso e Ossos , Remodelação Óssea , Fatores de Crescimento de Fibroblastos , Falência Renal Crônica/complicações , Osteogênese , Insuficiência Renal Crônica/complicaçõesRESUMO
INTRODUCTION: Renal osteodystrophy (ROD) develops early in chronic kidney disease (CKD) and progresses with loss of kidney function. While intact parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3 (1,25D), and fibroblast growth factor-23 (FGF-23) levels are usually considered the primary abnormalities in ROD development, the role of serum activin A elevations in CKD and its relationships to ROD have not been explored. The aims of this study were to evaluate serum activin A at different CKD stages, and to establish the relationships between activin A, bone biomarkers, and bone histomorphometric parameters. MATERIALS AND METHODS: 104 patients with CKD stages 2 - 5D underwent bone biopsies. We measured in the serum activin A, BSAP, DKK1, FGF-23, α-Klotho, intact PTH, sclerostin, TRAP-5b, and 1,25D. Biochemical results were compared across CKD stages and with 19 age-matched controls with normal kidney function. RESULTS: Median activin A levels were increased in all stages of CKD compared to controls from 544 pg/mL in CKD 2 (431 - 628) to 1,135 pg/mL in CKD 5D (816 - 1,456), compared to 369 pg/mL in controls (316 - 453, p < 0.01). The increase of activin A in CKD 2 (p = 0.016) occurred before changes in the other measured biomarkers. Activin A correlated with intact PTH and FGF-23 (r = 0.65 and 0.61; p < 0.01) and with histomorphometric parameters of bone turnover (BFR/BS, Acf, ObS/BS and OcS/BS; r = 0.47 - 0.52; p < 0.01). These correlations were comparable to those found with intact PTH and FGF-23. CONCLUSION: Serum activin A levels increase starting at CKD 2 before elevations in intact PTH and FGF-23. Activin A correlates with bone turnover similar to intact PTH and FGF-23. These findings suggest a role for activin A in early development of ROD.
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Ativinas/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/sangue , Insuficiência Renal Crônica/sangue , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Proteínas Morfogenéticas Ósseas/sangue , Remodelação Óssea , Estudos de Casos e Controles , Distúrbio Mineral e Ósseo na Doença Renal Crônica/etiologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/fisiopatologia , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Marcadores Genéticos , Taxa de Filtração Glomerular , Glucuronidase/sangue , Humanos , Subunidades beta de Inibinas , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Falência Renal Crônica/sangue , Proteínas Klotho , Masculino , Pessoa de Meia-Idade , Fator de Transcrição PAX5/sangue , Hormônio Paratireóideo/sangue , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/fisiopatologia , Índice de Gravidade de Doença , Fosfatase Ácida Resistente a Tartarato/sangue , Vitamina D/análogos & derivados , Vitamina D/sangueRESUMO
BACKGROUND AND OBJECTIVES: Currently, there is no consensus whether dual-energy X-ray absorptiometry (DXA) or quantitative computed tomography (QCT) can be used to screen for osteoporosis or osteopenia in CKD-5D patients. This study uses iliac bone histology, the "gold standard" for bone volume evaluation, to determine the utility of DXA and QCT for low bone mass screening in CKD-5D patients. PATIENTS AND METHODS: A cross-sectional study of patients with CKD-5D employing iliac crest bone biopsies to assess bone volume by histology and comparing results to bone mineral density (BMD) measurements of the hip and spine by DXA and QCT. Pearson's correlation, linear regression, and receiver operating characteristics curve analyses were performed. RESULTS: 46 patients (mean age 51 years, 52% women, median dialysis vintage 46 months) had bone biopsies, DXA, and QCT scans. 37 patients (80%) had low bone volume by histology. DXA and QCT BMD values (g/cm2) were very highly correlated at the femoral neck (ρ = 0.97) and total hip (ρ = 0.97), and to a lesser degree at the spine (ρ = 0.65). DXA and QCT t-scores were also highly correlated, but QCT t-scores were systematically greater than DXA t-scores (1.1 S.D. on average at the femoral neck) leading to less recognition of osteopenia and osteoporosis by QCT. A t-score below -1 by DXA at the femoral neck (i.e., osteopenic or osteoporotic) showed 83% sensitivity and 78% specificity relative to low bone volume by histology. A QCT t-score below -1 did not reach acceptable diagnostic levels of sensitivity and specificity. CONCLUSIONS: DXA and QCT provide nearly identical areal BMD measures at the hip. However, QCT t-scores are consistently higher than DXA t-scores resulting in less diagnosis of osteoporosis or osteopenia. DXA results showed acceptable diagnostic sensitivity and specificity for low bone volume by histology and can be used for diagnosis of osteopenia and osteoporosis in patients with CKD-5D.
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Absorciometria de Fóton/estatística & dados numéricos , Densidade Óssea/fisiologia , Doenças Ósseas Metabólicas/diagnóstico por imagem , Osteoporose/diagnóstico por imagem , Insuficiência Renal Crônica/complicações , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia/métodos , Estudos Transversais , Feminino , Colo do Fêmur/diagnóstico por imagem , Humanos , Ílio/patologia , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Estudos Prospectivos , Curva ROC , Sensibilidade e Especificidade , Coluna Vertebral/diagnóstico por imagem , Adulto JovemRESUMO
BACKGROUND: Fibroblast growth factor-23 (FGF-23) is a hormone principally produced by osteocytes/osteoblasts. In patients with chronic kidney disease (CKD), FGF-23 levels are usually elevated and can reach up to 300 - 400 times the normal range. FGF-23 is regulated by local bone-related and systemic factors, but the relationship between circulating FGF-23 concentrations and bone remodeling and mineralization in CKD has not been well characterized. In the current study, we examined the relationship between FGF-23 levels and bone histomorphometry parameters in adult patients with renal osteodystrophy. MATERIAL AND METHODS: 36 patients on dialysis (CKD-5D) underwent bone biopsies after tetracycline double labeling. Blood drawings were done at time of biopsy to determine serum levels of markers of bone and mineral metabolism. RESULTS: Patients with high bone turnover had higher values of serum FGF-23 than patients with low bone turnover. FGF-23 levels correlated with activation frequency (ρ = 0.60, p < 0.01) and bone formation rate (ρ = 0.57, p < 0.01). Normal mineralization was observed in 90% of patients with FGF-23 levels above 2,000 pg/mL. Furthermore, FGF-23 correlated negatively with mineralization lag time (ρ = -0.69, p < 0.01) and osteoid maturation time (ρ = -0.46, p < 0.05) but not with osteoid thickness (ρ = 0.08, ns). Regression analysis showed that FGF-23 was the only independent predictor of mineralization lag time. FGF-23 correlated with cancellous bone volume (ρ = 0.38, p < 0.05) but did not predict it. CONCLUSION: Circulating FGF-23 concentrations may reflect alterations in ongoing bone formation along with active mineralization, but not exclusively in bone formation or mineralization. Abnormal mineralization lag time (> 100 days) was mainly seen in patients with FGF-23 levels less than 2,000 pg/mL, while very high levels of FGF-23 are associated with normal mineralization lag time.
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Remodelação Óssea/fisiologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/sangue , Fatores de Crescimento de Fibroblastos/sangue , Diálise Renal , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/patologia , Adulto , Idoso , Biomarcadores/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/patologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/terapia , Estudos Transversais , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Masculino , Pessoa de Meia-Idade , Osteogênese/fisiologia , Insuficiência Renal Crônica/terapiaRESUMO
Abnormal bone turnover is common in CKD, but its effects on bone quality remain unclear. We qualitatively screened iliac crest bone specimens from patients on dialysis to identify those patients with low (n=18) or high (n=17) bone turnover. In addition, we obtained control bone specimens from 12 healthy volunteers with normal kidney function. In the patient and control specimens, Fourier transform infrared spectroscopy and nanoindentation quantified the material and mechanical properties of the specimens, and we used bone histomorphometry to assess parameters of bone microstructure and bone formation and resorption. Compared with high or normal turnover, bone with low turnover had microstructural abnormalities such as lower cancellous bone volume and reduced trabecular thickness. Compared with normal or low turnover, bone with high turnover had material and nanomechanical abnormalities such as reduced mineral to matrix ratio and lower stiffness. These data suggest that turnover-related alterations in bone quality may contribute to the diminished mechanical competence of bone in CKD, albeit through different mechanisms. Therapies tailored specifically to low- or high-turnover bone may treat renal osteodystrophy more effectively.
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Osso e Ossos/metabolismo , Distúrbio Mineral e Ósseo na Doença Renal Crônica/etiologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/metabolismo , Nefropatias/complicações , Índice de Gravidade de Doença , Adulto , Idoso , Fenômenos Biomecânicos , Biópsia , Densidade Óssea , Osso e Ossos/patologia , Estudos de Casos e Controles , Doença Crônica , Feminino , Humanos , Nefropatias/terapia , Pessoa de Meia-Idade , Diálise Renal , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
BACKGROUND: Determination of parathyroid hormone (PTH) level is the most commonly used surrogate marker for bone turnover in patients with stage 5 chronic kidney disease on dialysis therapy (CKD-5D). The objective of this study is to evaluate the predictive value of various PTH measurements for identifying low or high bone turnover rate. STUDY DESIGN: Diagnostic test study. SETTINGS & PARTICIPANTS: 141 patients with CKD-5D from 15 US hemodialysis centers. INDEX TESTS: Intact PTH, PTH 1-84, and PTH ratio (ratio of level of PTH 1-84 to level of large carboxy-terminal PTH fragments). REFERENCE TEST OR OUTCOME: Bone turnover determined using bone histomorphometry. OTHER MEASUREMENTS: Demographic and treatment-related factors, serum calcium and phosphorus. RESULTS: Patients presented histologically with a broad range of bone turnover abnormalities. In white patients with CKD-5D (n = 70), PTH ratio <1.0 added to intact PTH level <420 pg/mL increased the positive predictive value for low bone turnover from 74% to 90%. In black patients (n = 71), adding PTH ratio <1.2 to intact PTH level <340 pg/mL increased the positive predictive value for low bone turnover from 48% to 90%. Adding PTH ratio >1.6 to intact PTH level of 340-790 pg/mL increased the positive predictive value for high bone turnover from 56% to 71%. LIMITATIONS: Because the research protocol called for carefully controlled blood specimen handling, blood drawing and routine specimen handling might be less stringent in clinical practice. By limiting study participation to black and white patients with CKD-5D, we cannot comment on the roles of intact PTH, PTH 1-84, and PTH ratio in other racial/ethnic groups. CONCLUSION: In black patients with CKD-5D, the addition of PTH ratio to intact PTH measurements is helpful for diagnosing low and high bone turnover. In white patients with CKD-5D, it aids in the diagnosis of low bone turnover.
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Distúrbio Mineral e Ósseo na Doença Renal Crônica/diagnóstico , Hormônio Paratireóideo/sangue , Algoritmos , Cálcio/sangue , Humanos , Imunoensaio , Falência Renal Crônica/sangue , Falência Renal Crônica/terapia , Fósforo/sangue , Valor Preditivo dos Testes , Diálise RenalRESUMO
Two adult patients living with AIDS presented with severe bone pain associated with tenofovir (TDF) use. Both were unable to walk without assistance and were severely restricted in their movement due to the bone pain. Both had mild renal impairment, Fanconi syndrome, and bone mineral density (BMD) loss. Bone pain and inability to walk were reversible with the cessation of TDF and supplementation with Vitamin D(3), calcium, and phosphate. These cases appear to be examples of the severity of BMD loss associated with TDF use and suggest not only attention to renal function with TDF use, but also monitoring of alkaline phosphatase (bone fraction) and plasma phosphorus as indicators of BMD loss.
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Adenina/análogos & derivados , Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , HIV-1 , Limitação da Mobilidade , Organofosfonatos/efeitos adversos , Osteoporose/induzido quimicamente , Dor/induzido quimicamente , Absorciometria de Fóton , Adenina/efeitos adversos , Adulto , Fosfatase Alcalina/sangue , Terapia Antirretroviral de Alta Atividade/métodos , Bicarbonatos/sangue , Conservadores da Densidade Óssea/uso terapêutico , Síndrome de Fanconi/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/diagnóstico , Osteoporose/tratamento farmacológico , Osteoporose/prevenção & controle , Dor/diagnóstico , Dor/tratamento farmacológico , Dor/prevenção & controle , TenofovirRESUMO
Although rarely used to diagnose and manage patients with osteoporosis, bone biopsies are performed to establish bone quality, including degree of mineralization and microarchitecture; to assess bone turnover and bone loss mechanisms; and to analyze treatment effects on bone structure and bone turnover. Bone biopsies are also the only method to diagnose mineralization defect or frank osteomalacia. Due to the availability of antiresorptive agents and anabolic drugs, determining bone turnover and bone-loss mechanisms is critical to appropriate treatment regimen selection. Bone biopsies establish the safety and efficacy of new therapeutic modalities. Further, new techniques such as molecular morphometry (in situ hybridization and immunohistochemistry) and analysis of bone content and crystal perfection have been applied to undecalcified bone and elucidated pathogenetic mechanisms or abnormalities in bone microstructure.
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Osso e Ossos/patologia , Osteoporose/patologia , Biópsia , Conservadores da Densidade Óssea/uso terapêutico , Reabsorção Óssea/diagnóstico , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/patologia , Osso e Ossos/metabolismo , Diagnóstico Diferencial , Humanos , Osteomalacia/diagnóstico , Osteomalacia/patologia , Osteoporose/diagnóstico , Osteoporose/tratamento farmacológicoRESUMO
BACKGROUND: Osteoporotic fractures commonly occur after low-energy trauma in postmenopausal women with reduced bone quantity documented by low bone mineral density (BMD). Low-energy fractures, however, have also been reported to occur in premenopausal women with normal or near-normal BMD, suggesting the existence of a bone quality abnormality. METHODS: Bone quality and quantity were evaluated in a cross-sectional study of three groups of premenopausal white females: (1) twenty-five subjects with low-energy fracture(s) and BMD in the normal range (t-scores > -2.0), (2) eighteen subjects with low-energy fracture(s) and BMD in the osteoporotic range (t-scores ≤ -2.5), and (3) fourteen healthy volunteers (controls). Bone quality was assessed with use of Fourier transform infrared spectroscopy and histomorphometry in iliac crest bone samples obtained from all subjects; bone quantity was assessed by dual x-ray absorptiometry and histomorphometry. RESULTS: The collagen crosslinking ratio in the non-low-BMD subjects with fractures was 13% greater than the ratio in the low-BMD subjects with fractures and 14% greater than the ratio in the controls (p < 0.001 for both). Cancellous bone volume was 29% greater (p < 0.01) and trabecular separation was 31% less (p < 0.01) in the non-low-BMD subjects with fractures than in the low-BMD subjects with fractures; the values in the non-low-BMD subjects did not differ from those in the controls. Bone turnover did not differ among the groups, and osteomalacia was not present in any subject. Thus, the non-low-BMD subjects with fractures maintained bone quantity, but the collagen crosslinking ratio, a parameter of bone quality, was abnormal. In contrast, the low-BMD subjects with fractures did not have this collagen crosslinking abnormality but did have abnormal bone quantity. CONCLUSIONS: This study highlights a collagen crosslinking abnormality in patients with low-energy fractures and nonosteoporotic t-scores. Reports have indicated that altered collagen crosslinking is associated with subnormal fracture resistance. A finding of nonosteoporotic bone mass in a patient with low-energy fractures would justify assessment of bone material quality, which currently requires a bone biopsy. Further studies are needed to search for possible noninvasive tests to diagnose abnormal crosslinking. Since no specific therapies for abnormal collagen crosslinking are currently available, studies are also needed to explore novel therapeutic modalities to reverse the underlying collagen crosslinking abnormality. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Assuntos
Densidade Óssea/fisiologia , Matriz Óssea/fisiopatologia , Doenças do Colágeno/fisiopatologia , Osteoporose/fisiopatologia , Fraturas por Osteoporose/fisiopatologia , Pré-Menopausa/fisiologia , Adulto , Matriz Óssea/patologia , Estudos de Casos e Controles , Colágeno/química , Doenças do Colágeno/etiologia , Doenças do Colágeno/patologia , Estudos Transversais , Feminino , Humanos , Osteoporose/patologia , Fraturas por Osteoporose/etiologia , Fraturas por Osteoporose/patologiaRESUMO
Renal osteodystrophy occurs early during loss of kidney function. There are 26 million American patients with chronic kidney disease (CKD), and almost all patients with CKD stage 5 have abnormal bone histology. Six hundred and thirty bone biopsies from adult CKD-5 patients on dialysis were evaluated by histomorphometry and analyzed using the turnover (T), mineralization (M), and volume (V) classification. There were racial differences; whites exhibited predominantly low turnover (62%), whereas blacks showed mostly normal or high turnover (68%). A mineralization defect was observed in only 3% of patients. In whites, cancellous bone volume was low, normal, or high in approximately the same number of patients, whereas in blacks, cancellous bone volume was high in two-thirds of the patients. More than 80% of blacks and whites with low cancellous bone volume had thin trabeculae owing to low bone formation. Cortical thickness was low in half the whites, whereas it was normal in three-quarters of blacks. Cortical porosity was high in 50% of whites, whereas three-quarters of blacks had high porosity. In summary, the TMV system gives relevant information. It should be expanded to include the architecture of cancellous and cortical bone. There are racial differences. Low bone volume and low bone turnover are more frequent than heretofore appreciated, whereas mineralization defects nowadays are observed rarely in adults. These findings call for an adjustment of the current therapeutic paradigm that takes into consideration race and risk of low bone volume and turnover. The latter have been shown to be associated with increased vascular calcifications.
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População Negra/etnologia , Osso e Ossos/patologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/etnologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/patologia , População Branca/etnologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Remodelação Óssea/fisiologia , Osso e Ossos/fisiopatologia , Calcificação Fisiológica/fisiologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/complicações , Distúrbio Mineral e Ósseo na Doença Renal Crônica/fisiopatologia , Feminino , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/etnologia , Falência Renal Crônica/patologia , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão/fisiologia , Porosidade , Adulto JovemRESUMO
Renal osteodystrophy is characterized by abnormalities in bone turnover, mineralization, and bone volume. The effects of treatment modalities for renal osteodystrophy on bone should be analyzed with respect to these abnormalities. The major treatment modalities for renal osteodystrophy include phosphate binders, vitamin D compounds, and calcimimetics. Aluminum-containing phosphate binders have been shown to be toxic to bone secondary to their effects on bone turnover, mineralization, and bone volume. The use of calcium-based phosphate binders has been associated with the development of adynamic bone disease (low bone turnover), bone loss, and worsening of vascular calcifications. New nonaluminum, noncalcium phosphate binders have been developed (sevelamer hydrochloride and lanthanum carbonate). These agents show a potential for improvement in bone turnover and bone volume. Patients with renal osteodystrophy are deficient in calcitriol and often in calcidiol. Calcidiol deficiency has been underappreciated and deserves to be addressed in the treatment of patients with renal osteodystrophy. Calcitriol replacement therapy by daily oral administration is associated with frequent episodes of hypercalcemia and suppression of bone turnover in patients with stages 3 to 5 chronic kidney disease. Pulse oral or intravenous calcitriol administration induces frequent episodes of hypercalcemia or hyperphosphatemia, respectively, and achieves the same degree of correction of bone abnormalities. There are no data on the effects of paricalcitol or doxercalciferol on human bone. Experimental data, however, show that these two analogues and maxacalcitol may control serum parathyroid hormone levels without suppressing bone turnover. Calcimimetics lower parathyroid hormone levels and bone turnover.
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Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Calcificação Fisiológica/efeitos dos fármacos , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Osso e Ossos/patologia , Calcitriol/administração & dosagem , Calcitriol/farmacologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/patologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/fisiopatologia , Cinacalcete , Humanos , Lantânio/farmacologia , Naftalenos/farmacologia , Hormônio Paratireóideo/sangue , Fosfatos/metabolismo , Poliaminas/farmacologia , Sevelamer , Vitamina D/farmacologiaRESUMO
BACKGROUND AND OBJECTIVES: The effects of calcitriol and paricalcitol on circulating levels of intact parathyroid hormone, parathyroid hormone-(1-84), the large carboxy-terminal-parathyroid hormone fragments, and the parathyroid hormone-(1-84)/carboxy-terminal-parathyroid hormone fragments were studied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In the longitudinal study, 31 hemodialysis patients who were receiving intravenous calcitriol or paricalcitol were followed for 6 to 8 wk. After a washout period, patients were treated with the other vitamin D compound for 6 to 8 wk. Plasma intact parathyroid hormone and parathyroid hormone-(1-84) were measured, and the parathyroid hormone ratio was calculated. In the cross-sectional study, results of intact parathyroid hormone, parathyroid hormone-(1-84), and parathyroid hormone ratio were compared between patients who were treated with paricalcitol (n = 49) versus no vitamin D therapy (n = 44). RESULTS: In the longitudinal study, the parathyroid hormone ratio was significantly lower in patients who were treated with calcitriol and higher with paricalcitol treatment compared with values that were obtained during washout. In the cross-sectional study, intact parathyroid hormone levels were identical in both groups, whereas parathyroid hormone-(1-84) and thus parathyroid hormone ratio values were higher in patients who were given paricalcitol than in patients who were not receiving vitamin D. CONCLUSIONS: These data show that at similar intact parathyroid hormone values, the active parathyroid hormone-(1-84) compound is lower with calcitriol than with paricalcitol treatment. This finding might be relevant for choice of vitamin D compound in patients with stage 5 chronic kidney disease.
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Ergocalciferóis/farmacologia , Hiperparatireoidismo Secundário/tratamento farmacológico , Nefropatias/sangue , Hormônio Paratireóideo/sangue , Fragmentos de Peptídeos/sangue , Adulto , Idoso , Calcitriol , Doença Crônica , Estudos Transversais , Feminino , Humanos , Hiperparatireoidismo Secundário/sangue , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Diálise RenalRESUMO
A historical look at research in hyperphosphataemia of chronic kidney disease over the last 40 years shows remarkable advances in our understanding of this abnormality and in the technology used to manage it. Phosphate binders, which have become a mainstay in the management of hyperphosphataemia, have evolved from the early use of aluminium gels to calcium salts, to novel, non-absorbed, aluminium-free, calcium-free agents such as sevelamer hydrochloride, and to magnesium-, iron-, and lanthanum-based compounds. With recent advances, clinical management of this complication of chronic renal disease is evolving from adequate care to optimal care, such that new standards in phosphorous management are being set, and various parameters of patient care are being integrated to optimize outcomes and minimize side effects. This paper provides a historical view of the clinical management of hyperphosphataemia, and looks to advances in treatment that are changing the course of renal bone disease management.
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Falência Renal Crônica/fisiopatologia , Distúrbios do Metabolismo do Fósforo/terapia , Acetatos/uso terapêutico , Compostos de Cálcio , Humanos , Fósforo/sangue , Distúrbios do Metabolismo do Fósforo/etiologiaRESUMO
In the early stages of renal failure, hyperparathyroidism develops as a compensatory mechanism to control serum levels of calcium, phosphorus and calcitriol. As kidney disease progresses, this ability to maintain mineral homeostasis is lost, leading to the development of renal osteodystrophy (ROD). Over the past decade, the pattern of ROD seen in patients with chronic kidney disease (CKD) has changed. Previously, the majority of patients had mixed uraemic osteodystrophy or aluminium-related osteomalacia. The decreased use of aluminium-based phosphate binders, coupled with improvements in the management of hyperphosphataemia, led to a reduction in the prevalence of these types of ROD. Since the mid-1990s, there has been an increase in the prevalence of adynamic bone disease as a result of increased suppression of parathyroid hormone through the use of calcium-based phosphate binders and calcitriol therapy. Adynamic bone disease is also associated with several clinical factors, such as older age, use of continuous ambulatory peritoneal dialysis and the presence of diabetes mellitus, as well as the use of calcitriol therapy. Studies of calcium metabolism in patients with CKD have shown that adynamic bone disease is a distinct clinical condition that leads to hypercalcaemia via mechanisms different from that seen in high-turnover bone disease. As high calcium x phosphorus product has been associated with soft tissue and vascular calcifications, and increased mortality, optimizing bone health may be an important way of reducing cardiovascular risk in patients with CKD. To do this, novel, effective, non-calcium, non-aluminium phosphate binders will be necessary.
Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica/etiologia , Falência Renal Crônica/complicações , Calcinose/etiologia , Cálcio/metabolismo , HumanosRESUMO
Vitamin D is an important hormone for mineral homeostasis and the proper formation and maintenance of bone. In addition, vitamin D has broader functions in the body that expand its traditionally known role in mineral balance. In chronic renal failure, calcitriol deficiency contributes to the development and progression of secondary hyperparathyroidism, bone disorders, and altered mineral metabolism. Recent revelations of the broader role of vitamin D also suggest calcitriol deficiency may contribute to decreased cardiac and immune function in chronic renal failure patients. Research on vitamin D has led to a more complete understanding of the actions of vitamin D at the transcriptional level and with respect to the clinical use of vitamin D and its analogs to control parathyroid hormone overactivity and to replace the other D hormone-dependent actions in patients with renal failure. Limitations of vitamin D and its metabolites include hypercalcemia, hyperphosphatemia and suppression of bone turnover with the risk of adynamic bone disease. Vitamin D analogs may offer greater selectivity and potentially greater safety as compared to calcitriol because of their altered relative potency on calcium and phosphorus metabolism. This review focuses on the current understanding of the biological actions of vitamin D and its analogs and the rationale for treating patients with chronic renal failure.
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Falência Renal Crônica/tratamento farmacológico , Vitamina D/análogos & derivados , Vitamina D/uso terapêutico , HumanosRESUMO
Bone biopsy is the gold standard for diagnosing the type and severity of renal osteodystrophy (ROD) in end-stage renal disease (ESRD) patients. In this article we review the indications, techniques, and complications of this minimally invasive procedure. The importance of careful preparation is emphasized.
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Biópsia por Agulha/métodos , Osso e Ossos/patologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/patologia , Biópsia por Agulha/efeitos adversos , Doenças Ósseas/patologia , HumanosRESUMO
Kidney transplantation corrects most of the metabolic abnormalities that cause renal osteodystrophy. However, many transplanted patients develop osteoporosis and other bone lesions that are related, at least in part, to their immunosuppressive regimen. The precise histologic patterns of bone disease after transplantation are not well defined. In a study designed to investigate this issue, 57 adult posttransplant patients agreed to undergo bone biopsies and blood drawings. There were 32 men and 25 women, mean age 45 +/- 2 yr, who had received a kidney transplantation 5.6 +/- 0.8 yr before biopsy. History of bone pain, fractures, and avascular necrosis was found in 22, 12, and 7 patients, respectively. Serum creatinine was 1.68 +/- 0.1 mg/dl, 21% of patients were hypercalcemic, 63.2% had elevated parathyroid hormone (PTH) (>65 pg/ml), and 91.2% had normal calcitriol levels. Cancellous bone volume/tissue volume was below normal compared to age- and gender-matched control subjects in 56.1% of patients. Bone turnover (activation frequency) was low in 45.6%, normal in 28.1%, and elevated in 26.3% of patients. Bone formation rate/bone surface was low in 59.7%, normal in 35%, and elevated in 5. 3% of the patients. Erosion surface/bone surface was high in 21.1% of patients. Mineralization was prolonged in 87.5% of patients, including 9 patients with osteomalacia and 12 patients with focal osteomalacia. Cumulative and maintenance doses of prednisone and time elapsed since transplantation correlated negatively with bone volume and bone turnover (r = -0.32 to -0.59, P < 0.05 to 0.01), whereas cumulative doses of cyclosporine or azathioprine, age, gender, or serum PTH levels did not. Regression analysis identified prednisone as the main factor responsible for low bone volume and bone turnover (r = 0.54 and r = 0.43, P < 0.01). No factors were found to predict delayed mineralization. The present study shows that low bone volume, low bone turnover, and generalized or focal osteomalacia are frequent histologic features in transplanted patients. The effects of age, gender, PTH, and cyclosporine on bone volume and bone turnover are apparently overridden by the prominent effects of glucocorticoids. The prevalence of mineralization defect in the presence of normal serum levels of calcidiol and calcitriol suggests vitamin D resistance and deserves further study.
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Remodelação Óssea/fisiologia , Osso e Ossos/metabolismo , Imunossupressores/efeitos adversos , Transplante de Rim , Osteomalacia/etiologia , Prednisona/efeitos adversos , Adulto , Análise de Variância , Biópsia , Densidade Óssea/fisiologia , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Estudos Prospectivos , Análise de Regressão , Fatores de TempoRESUMO
BACKGROUND: Evidence derived from healthy subjects suggests that African Americans have higher serum parathyroid hormone (PTH) levels and decreased bone responsiveness to PTH than Caucasians. African American patients with end-stage renal disease (ESRD) also have higher serum PTH than Caucasians. Studies that correlate intact PTH (iPTH) levels with bone turnover in ESRD patients were performed in a predominantly Caucasian population. METHODS: In this study, serum iPTH and bone histomorphometric data were analyzed for racial differences in 76 ESRD patients (Caucasian = 48, African Americans = 28). Bone turnover was determined by histomorphometric measurement of activation frequency in all patients. RESULTS: Age, duration of dialysis, and calcium and phosphorus levels were similar between the two groups. iPTH levels (pg/mL; mean +/- SE) were significantly higher in the African American group (534 +/- 79 vs. 270 +/- 46, P < 0.01). Also, alkaline phosphatase levels (IU/L) were significantly higher in the African American group (162 +/- 31 vs. 144 +/- 43, P < 0.01). Correlations between PTH levels and activation frequency were r = 0.60, P < 0.01 in Caucasians and r = 0.22, P = NS in African Americans. The mean PTH level in African American patients with histologic findings of low bone turnover was 460 +/- 115 vs. 168 +/- 41 in Caucasian patients with similar bone turnover (P < 0.01). In patients with low bone turnover, African Americans had significantly higher osteoid volume and thickness, number of osteoblasts and osteoclasts, erosion surface, peritrabecular fibrosis, and single-label surface than Caucasians. However, erosion depth, bone formation rate per osteoblast and mineralization apposition rate were similar between the two groups. CONCLUSION: There is no correlation between iPTH and bone turnover in African Americans with ESRD. A substantial number of African American patients with low bone turnover have very high serum PTH levels. Bone histomorphometric results reveal differences in remodeling dynamics and responses to PTH between African American and Caucasian patients. Further studies utilizing newer PTH measurement assays are needed to better delineate the correlation between PTH and bone turnover in the various racial groups.