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PURPOSE OF REVIEW: Chronic kidney disease-mineral and bone disorder (CKD-MBD) has become a global health crisis with very limited therapeutic options. Dentin matrix protein 1 (DMP1) is a matrix extracellular protein secreted by osteocytes that has generated recent interest for its possible involvement in CKD-MBD pathogenesis. This is a review of DMP1 established regulation and function, and early studies implicating DMP1 in CKD-MBD. RECENT FINDINGS: Patients and mice with CKD show perturbations of DMP1 expression in bone, associated with impaired osteocyte maturation, mineralization, and increased fibroblast growth factor 23 (FGF23) production. In humans with CKD, low circulating DMP1 levels are independently associated with increased cardiovascular events. We recently showed that DMP1 supplementation lowers circulating FGF23 levels and improves bone mineralization and cardiac outcomes in mice with CKD. Mortality rates are extremely high among patients with CKD and have only marginally improved over decades. Bone disease and FGF23 excess contribute to mortality in CKD by increasing the risk of bone fractures and cardiovascular disease, respectively. Previous studies focused on DMP1 loss-of-function mutations have established its role in the regulation of FGF23 and bone mineralization. Recent studies show that DMP1 supplementation may fill a crucial therapeutic gap by improving bone and cardiac health in CKD.
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Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/etiología , Proteínas de la Matriz Extracelular/fisiología , Fosfoproteínas/fisiología , Animales , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/metabolismo , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Humanos , Ratones , RatasRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Triangle grass is a liliaceous Chlorophytum perennial herb of ChlorophytumlaxumR.Br. It is distributed mainly in Guangdong and Guangxi Provinces of China. The initial use of triangle grass was mainly to treat bone pain and swelling caused by a fall injury. Triangle grass tablets (NO. Z20070544) are also used as a preparation in our hospital because of their analgesic, anti-inflammatory, anti-snake venom and microcirculation improvement properties and other pharmacological effects (Mei et al., 2006). Triangle grass tablets have been widely used in our hospital to treat patients with bone pain from chronic kidney disease-mineral and bone disorder (CKD-MBD). However, the effects and mechanism of triangle grass on bone metabolism in chronic kidney disease complicated with mineral and bone abnormalities are unclear. AIM OF THE STUDY: The aim of the present study was to investigate the effects of a triangle grass decoction on bone metabolism in CKD-MBD rats. MATERIALS AND METHODS: CKD-MBD model rats were subjected to 5/6 nephrectomy combined with 0.5 g NaH2PO4/rat. Serum blood urea nitrogen (BUN), creatinine (Cr), phosphorus (P), calcium (Ca), and intact parathyroid hormone (iPTH) levels were measured with an automatic biochemical analyser. Bone mineral density was determined with a Viva CT 40 system. Bone morphogenetic protein 7(BMP-7),runt-related transcription factor 2 (Runx2) and Osterix protein levels were measured by Western blot analysis. Kidney, vertebra and thoracic aorta tissue samples were assessed by histopathology and immunohistochemistry (IHC). RESULTS: The degrees of membrane thickening, necrosis, swelling and cast deposition were significantly reduced in high-dose rats and Low-dose rats. Serum BUN levels were significantly reduced in the Pre-H group (P < 0.05). Hypocalcaemia and hyperphos phataemia were detected in triangle grass (P < 0.05, P < 0.05). In addition, iPTH levels were significantly increased in the Pre-H group (P < 0.05). Alkaline phosphatase (ALP)levels were significantly decreased in the Pre-H group (P < 0.05). The bone mineral density was improved in the Pre-H and Pre-L groups. BMP-7 protein levels were significantly increased in the Pre-H group (P < 0.05). The pathological changes in muscle fibres in the thoracic aorta middle membranes were significantly alleviated in rats in the Pre-H and Pre-L groups. Changes in SM22α and SMα-act in protein levels were significantly attenuated in the Pre-H group (P < 0.05, P < 0.05). Changes in Runx2 and Osterix protein levels were also significantly attenuated in the Pre-H and Pre-L groups (P < 0.05, P < 0.05). CONCLUSIONS: Triangle grass can simultaneously ameliorate vertebral bone loss and abnormal calcification in the thoracic aorta. Triangle grass has a definite effect on bone metabolism disorder in CKD-MBD rats.
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Asparagaceae/química , Densidad Ósea/efectos de los fármacos , Huesos/metabolismo , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/tratamiento farmacológico , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/metabolismo , Medicamentos Herbarios Chinos/farmacología , Actinas/metabolismo , Animales , Aorta Torácica/metabolismo , Aorta Torácica/patología , Nitrógeno de la Urea Sanguínea , Proteína Morfogenética Ósea 7/metabolismo , Huesos/efectos de los fármacos , Calcinosis/tratamiento farmacológico , Calcinosis/metabolismo , Calcio/metabolismo , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/etiología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Creatinina/sangre , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/uso terapéutico , Artropatías/tratamiento farmacológico , Artropatías/metabolismo , Masculino , Proteínas de Microfilamentos/metabolismo , Proteínas Musculares/metabolismo , Nefrectomía/efectos adversos , Fósforo/metabolismo , Ratas Wistar , Columna Vertebral/efectos de los fármacos , Columna Vertebral/metabolismo , Factores de Transcripción/metabolismo , Enfermedades Vasculares/tratamiento farmacológico , Enfermedades Vasculares/metabolismoRESUMEN
INTRODUCTION: Chronic kidney disease-mineral and bone disorder (CKD-MBD) leads to increased fracture risk. Iliac crest biopsy remains the gold standard for diagnosing bone disease in CKD. Unfortunately, bone biopsy is rarely performed which is mainly due to the inability of clinicians to perform the procedure. In this paper, we propose a fluoroscopy-guided procedure performed by interventional radiologists as a novel approach to iliac crest biopsy in adult population. We describe the implementation of the procedure and present the first 11 cases of CKD patients who underwent iliac crest biopsy with this new approach. METHODS: A nephrologist already trained in performing iliac crest biopsy initiated the creation of a fluoroscopy-based iliac crest biopsy program. Two interventional radiologists underwent a short training. Patients' demographical, clinical and biochemical data were collected on the day of the biopsy. Complications within the first three months after the procedure were collected from electronical records. RESULTS: IR rapidly mastered the procedure. The use of fluoroscopy allowed a precise localisation of the biopsy site and standardization of the intervention, which ensured specimen quality. The new approach allowed CKD patients to access iliac crest biopsy, which resulted in precise bone disease diagnosis (levels of bone turnover and mineralization) and targeted therapy for each case. There were no complications during, nor within 3 months after the intervention. CONCLUSIONS: We believe this approach will increase the access to iliac crest biopsy for diagnosing bone disease in CKD population. Studies are now needed to evaluate whether CKD patients will benefit from anti-osteoporotic therapy based on the results of iliac crest biopsy.
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Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica , Insuficiencia Renal Crónica , Adulto , Biopsia , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Humanos , Ilion/patología , Radiólogos , Insuficiencia Renal Crónica/patologíaRESUMEN
INTRODUCTION: Mineral and bone disorders (MBD) are major complications of chronic kidney disease (CKD)-related adverse outcomes. The Brazilian Registry of Bone Biopsy (REBRABO) is an electronic database that includes renal osteodystrophy (RO) data. We aimed to describe the epidemiological profile of RO in a sample of CKD-MBD Brazilian patients and understand its relationship with outcomes. METHODS: Between August 2015 and March 2018, 260 CKD-MBD stage 3-5D patients who underwent bone biopsy were followed for 12 to 30 months. Clinical-demographic, laboratory, and histological data were analyzed. Bone fractures, hospitalizations, and death were considered the primary outcomes. RESULTS: Osteitis fibrosa, mixed uremic osteodystrophy, adynamic bone disease, osteomalacia, osteoporosis, and aluminum (Al) accumulation were detected in 85, 43, 27, 10, 77, and 65 patients, respectively. The logistic regression showed that dialysis vintage was an independent predictor of osteoporosis (OR: 1.005; CI: 1.001-1.010; p = 0.01). The multivariate logistic regression revealed that hemodialysis treatment (OR: 11.24; CI: 1.227-100; p = 0.03), previous parathyroidectomy (OR: 4.97; CI: 1.422-17.241; p = 0.01), and female gender (OR: 2.88; CI: 1.080-7.679; p = 0.03) were independent predictors of Al accumulation; 115 patients were followed for 21 ± 5 months. There were 56 hospitalizations, 14 deaths, and 7 fractures during follow-up. The COX regression revealed that none of the variable related to the RO/turnover, mineralization and volume (TMV) classification was an independent predictor of the outcomes. CONCLUSION: Hospitalization or death was not influenced by the type of RO, Al accumulation, or TMV classification. An elevated prevalence of osteoporosis and Al accumulation was detected.
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Biopsia/métodos , Enfermedades Óseas Metabólicas/etiología , Huesos/patología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/complicaciones , Insuficiencia Renal Crónica/complicaciones , Adulto , Aluminio/sangre , Enfermedades Óseas Metabólicas/epidemiología , Brasil/epidemiología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/mortalidad , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/terapia , Femenino , Estudios de Seguimiento , Fracturas Óseas/epidemiología , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Osteoporosis/epidemiología , Paratiroidectomía/efectos adversos , Prevalencia , Estudios Prospectivos , Sistema de Registros , Diálisis Renal/efectos adversos , Resultado del TratamientoRESUMEN
Individuals with chronic kidney disease have elevated levels of oxidative stress and are at a significantly higher risk of skeletal fracture. Advanced glycation end products (AGEs), which accumulate in bone and compromise mechanical properties, are known to be driven in part by oxidative stress. The goal of this study was to study effects of N-acetylcysteine (NAC) on reducing oxidative stress and improving various bone parameters, most specifically mechanical properties, in an animal model of progressive CKD. Male Cy/+ (CKD) rats and unaffected littermates were untreated (controls) or treated with NAC (80 mg/kg, IP) from 30 to 35 weeks of age. Endpoint measures included serum biochemistries, assessments of systemic oxidative stress, bone morphology, and mechanical properties, and AGE levels in the bone. CKD rats had the expected phenotype that included low kidney function, elevated parathyroid hormone, higher cortical porosity, and compromised mechanical properties. NAC treatment had mixed effects on oxidative stress markers, significantly reducing TBARS (a measure of lipid peroxidation) while not affecting 8-OHdG (a marker of DNA oxidation) levels. AGE levels in the bone were elevated in CKD animals and were reduced with NAC although this did not translate to a benefit in bone mechanical properties. In conclusion, NAC failed to significantly improve bone architecture/geometry/mechanical properties in our rat model of progressive CKD.
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Acetilcisteína/administración & dosificación , Antioxidantes/administración & dosificación , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/tratamiento farmacológico , Tibia/efectos de los fármacos , Animales , Caseínas/administración & dosificación , Caseínas/efectos adversos , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/sangre , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/etiología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Productos Finales de Glicación Avanzada/análisis , Humanos , Riñón/efectos de los fármacos , Riñón/fisiopatología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Mutación , Proteínas Nucleares/genética , Estrés Oxidativo/efectos de los fármacos , Hormona Paratiroidea/sangre , Ratas , Tibia/química , Tibia/diagnóstico por imagen , Tibia/patología , Microtomografía por Rayos XAsunto(s)
Hiperparatiroidismo Secundario/patología , Hiperparatiroidismo Secundario/cirugía , Hipocalcemia/diagnóstico , Paratiroidectomía/efectos adversos , Fosfatasa Alcalina/sangre , Calcio/sangre , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/complicaciones , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Estudios Retrospectivos , Factores de Riesgo , Trasplante AutólogoAsunto(s)
Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/diagnóstico , Diálisis/efectos adversos , Huesos Faciales/anomalías , Fallo Renal Crónico/complicaciones , Adulto , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/etiología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Diálisis/métodos , Huesos Faciales/diagnóstico por imagen , Humanos , Hiperparatiroidismo Secundario/complicaciones , Hiperparatiroidismo Secundario/patología , Hiperparatiroidismo Secundario/terapia , Fallo Renal Crónico/patología , Fallo Renal Crónico/terapia , Trasplante de Riñón/métodos , Masculino , Maloclusión/diagnóstico , Maloclusión/etiología , Paratiroidectomía/métodos , Síndrome , Cumplimiento y Adherencia al Tratamiento , Resultado del TratamientoRESUMEN
Chronic kidney disease (CKD) is associated with a wide number of abnormalities in mineral metabolism. Often, these alterations are the leading players in the development of comorbidities associated with CKD, which are risk factors of mortality. In this context, mineral and bone disorder associated with CKD (CKD-MBD) are highlighted, connecting bone, renal, and cardiovascular disorders. Many studies have been led to propose strategies to avoid, reduce, or slow down CKD-MBD progression using different compositions of metallic elements-based P binders such as aluminum, magnesium, or calcium. Magnesium, the aim of this review, has been used by nephrologists to treat CKD-MBD with a variable acceptation due mainly to different results on bone homeostasis. Nowadays, we have new evidence about the efficacy of magnesium supplementation on vascular calcification, renal function, and bone disorders, suggesting potential beneficial effects of Magnesium in the management of CKD-MBD.
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Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/prevención & control , Magnesio/farmacología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/sangre , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Suplementos Dietéticos , Humanos , Magnesio/administración & dosificación , Magnesio/sangreRESUMEN
BACKGROUND: There is little information in haemodialysis (HD) patients on whether temporal changes in serum calcium, phosphate or intact parathyroid hormone (iPTH) are associated with mortality. METHODS: We analysed associations of phosphate, total calcium and iPTH with all-cause and cardiovascular mortality in 8817 incident HD patients from the European second Analyzing Data, Recognizing Excellence and Optimizing Outcomes (AROii) cohort enrolled in 2007-09, which were prospectively followed for a median of 3 years, using time-dependent Cox proportional hazards models. We evaluated changes in risk over time depending on changes in phosphate, calcium or iPTH. RESULTS: The association of phosphate and iPTH with all-cause mortality was U-shaped, with the lowest risk ranges between 1.20 and 1.89 mmol/L for phosphate and between 239 and 710 ng/L for iPTH. For total calcium, the associations were J-shaped, with an increased risk for all-cause mortality at levels >2.36 mmol/L. Lowest risk ranges for cardiovascular mortality did not change markedly for all three parameters. If iPTH was below the lowest risk range at baseline (iPTH <239 ng/L), a subsequent increase in levels was associated with improved survival. For phosphate, an increase or decrease out of the lowest risk range was associated with increased mortality risk. For calcium, this was only the case when the values increased above the lowest risk range. CONCLUSION: In the AROii cohort, the ranges of bone mineral biomarkers associated with the lowest mortality ranges were largely consistent with the current Kidney Disease: Improving Global Outcomes chronic kidney disease-mineral and bone disorder guideline recommendations. Allowing a suppressed iPTH to increase was associated with a lower mortality, whereas shifts of phosphate or calcium outside the lowest risk range increased mortality.
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Calcio/sangre , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/mortalidad , Hormona Paratiroidea/sangre , Fosfatos/sangre , Diálisis Renal/mortalidad , Anciano , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/sangre , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/etiología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Diálisis Renal/efectos adversos , Tasa de SupervivenciaRESUMEN
Medial arterial calcification (MAC) is a major complication of chronic kidney disease (CKD) and an indicator of poor prognosis. Aortic overexpression of tissue-nonspecific alkaline phosphatase (TNAP) accelerates MAC formation. The present study aimed to assess whether a TNAP inhibitor, SBI-425, protects against MAC and improves survival probability in a CKD-mineral and bone disorder (MBD) mouse model. CKD-MBD mice were divided in three groups: vehicle, SBI-10, and SBI-30. They were fed a 0.2% adenine and 0.8% phosphorus diet from 14 to 20 weeks of age to induce CKD, followed by a high-phosphorus (0.2% adenine and 1.8% phosphorus) diet for another 6 weeks. At 14-20 weeks of age, mice in the SBI-10 and SBI-30 groups were given 10 and 30 mg/kg SBI-425 by gavage once a day, respectively, while vehicle-group mice were given distilled water as vehicle. Control mice were fed a standard chow (0.8% phosphorus) between the ages of 8 and 20 weeks. Computed tomography imaging, histology, and aortic tissue calcium content revealed that, compared to vehicle animals, SBI-425 nearly halted the formation of MAC. Mice in the control, SBI-10 and SBI-30 groups exhibited 100% survival, which was significantly better than vehicle-treated mice (57.1%). Aortic mRNA expression of Alpl, encoding TNAP, as well as plasma and aortic tissue TNAP activity, were suppressed by SBI-425 administration, whereas plasma pyrophosphate increased. We conclude that a TNAP inhibitor successfully protected the vasculature from MAC and improved survival rate in a mouse CKD-MBD model, without causing any adverse effects on normal skeletal formation and residual renal function. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Fosfatasa Alcalina/antagonistas & inhibidores , Aorta/efectos de los fármacos , Enfermedades de la Aorta/prevención & control , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Niacinamida/análogos & derivados , Sulfonamidas/farmacología , Calcificación Vascular/prevención & control , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Animales , Aorta/enzimología , Aorta/patología , Enfermedades de la Aorta/enzimología , Enfermedades de la Aorta/etiología , Enfermedades de la Aorta/patología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/complicaciones , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/enzimología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Masculino , Ratones Endogámicos C57BL , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/enzimología , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/enzimología , Miocitos del Músculo Liso/patología , Niacinamida/farmacología , Osteoblastos/efectos de los fármacos , Osteoblastos/enzimología , Osteoblastos/patología , Factores de Tiempo , Calcificación Vascular/enzimología , Calcificación Vascular/etiología , Calcificación Vascular/patologíaAsunto(s)
Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/diagnóstico por imagen , Fallo Renal Crónico/diagnóstico por imagen , Osteítis Fibrosa Quística/diagnóstico por imagen , Adulto , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/complicaciones , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Humanos , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/patología , Masculino , Osteítis Fibrosa Quística/complicaciones , Osteítis Fibrosa Quística/patología , RadiografíaRESUMEN
BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) is commonly associated with mineral and bone metabolism disorders, but these are less frequently studied in non-dialysis CKD patients than in dialysis patients. We examined and described international variation in mineral and bone disease (MBD) markers and their treatment and target levels in Stage 3-5 CKD patients. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Prospective cohort study of 7658 adult patients with eGFR <60mL/min/1.73m2, excluding dialysis or transplant patients, participating in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) in Brazil, France, Germany, and the US. CKD-MBD laboratory markers included serum levels of phosphorus (P), calcium (Ca), intact parathyroid hormone (iPTH), and 25-hydroxyvitamin D (25-D). MBD treatment data included phosphate binders and vitamin D (nutritional and active). Nephrologist survey data were collected on target MBD marker levels. RESULTS: Over two-thirds of the patients had MBD markers measured at time intervals in line with practice guidelines. P and iPTH increased and Ca decreased gradually from eGFR 60-20mL/min/1.73m2 and more sharply for eGFR<20. 25-D showed no relation to eGFR. Nephrologist survey data indicated marked variation in upper target P and iPTH levels. Among patients with P>5.5mg/dL, phosphate binder use was 14% to 43% across the four countries. Among patients with PTH >300pg/mL, use of active (calcitriol and related analogs) vitamin D was 12%-51%, and use of any (active or nutritional) vitamin D was 60%-87%. CONCLUSIONS: Although monitoring of CKD-MBD laboratory markers by nephrologists in CKDopps countries is consistent with guidelines, target levels vary notably and prescription of medications to treat abnormalities in these laboratory markers is generally low in these cross-sectional analyses. While there are opportunities to increase treatment of hyperphosphatemia, hyperparathyroidism, and vitamin D deficiency in advanced CKD, the effect on longer-term complications of these conditions requires study.
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Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Internacionalidad , Anciano , Biomarcadores/sangre , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/sangre , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/fisiopatología , Femenino , Tasa de Filtración Glomerular , Humanos , Masculino , Persona de Mediana Edad , Nefrólogos , Pautas de la Práctica en Medicina , Probabilidad , Encuestas y CuestionariosRESUMEN
Renal osteodystrophy (ROD) occurs as early as chronic kidney disease (CKD) stage 2 and seems ubiquitous in almost all pediatric patients with CKD stage 5. Fibroblast growth factor (FGF)-23, a bone-derived endocrine regulator of phosphate homeostasis, is overexpressed in CKD and disturbs osteoblast differentiation and matrix mineralization. In contrast, C-type natriuretic peptide (CNP) acts as a potent positive regulator of bone growth. In the present study, we infused CNP into uremic rats and observed whether CNP could attenuate ROD through the inhibition of FGF-23 cascades. In uremic rats, CNP administration significantly alleviated renal dysfunction, calcium phosphate metabolic disorders, hypovitaminosis D, secondary hyperparathyroidism, the decrease in bone turnover markers and retarded bone pathological progression. More importantly, within FGF-23/mitogen-activated protein kinase (MAPK) signaling, the fibroblast growth factor receptor-1, Klotho and alternative (STAT-1/phospho-STAT-1) elements were upregulated by CNP, whereas FGF-23, RAF-1/phospho-RAF-1, and downstream (ERK/phospho-ERK and P38/phospho-P38) elements were paradoxically underexpressed in bone tissue. Therefore, CNP exerts a therapeutic effect on ROD through inhibition of FGF-23/MAPK signaling at the RAF-1 level.
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Remodelación Ósea , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/tratamiento farmacológico , Factores de Crecimiento de Fibroblastos/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Péptido Natriurético Tipo-C/administración & dosificación , Animales , Huesos/patología , Calcio/sangre , Diferenciación Celular/efectos de los fármacos , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Modelos Animales de Enfermedad , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/genética , Regulación de la Expresión Génica , Humanos , Riñón/patología , Masculino , Proteínas Proto-Oncogénicas c-raf/genética , Proteínas Proto-Oncogénicas c-raf/metabolismo , Ratas , Ratas Sprague-Dawley , Regulación hacia Arriba , UremiaRESUMEN
BACKGROUND AND OBJECTIVES: Over the past decade, the management of CKD-mineral and bone disorder has changed substantially, altering the pattern of bone disease in CKD. We aimed to evaluate the natural history of kidney bone disease in contemporary kidney transplant recipients and patients on dialysis. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: Sixty one patients on dialysis who were referred to kidney transplantation participated in this prospective cohort study during November 2009 and December 2010. We performed baseline bone biopsies while the patients were on dialysis and repeated the procedure in 56 patients at 2 years after kidney transplantation or 2 years after baseline if transplantation was not performed. Measurements of mineral metabolism and bone turnover, as well as dual energy x-ray absorptiometry scans, were obtained concurrently. RESULTS: A total of 37 out of 56 participants received a kidney transplant, of which 27 underwent successful repeat bone biopsy. The proportion of patients with high bone turnover declined from 63% at baseline to 19% at 2 years after kidney transplantation, whereas the proportion of those with low bone turnover increased from 26% to 52%. Of 19 participants remaining on dialysis after 2 years, 13 underwent successful repeat biopsy. The proportion of patients remaining on dialysis with high bone turnover decreased from 69% to 31%, and low bone turnover increased from 8% to 38%. Abnormal bone mineralization increased in transplant recipients from 33% to 44%, but decreased in patients remaining on dialysis from 46% to 15%. Trabecular bone volume showed little change after transplantation, but low bone volume increased in patients remaining on dialysis. Bone mineral density did not correlate with histomorphometric findings. CONCLUSIONS: Bone turnover decreased over time both in patients remaining on dialysis and in kidney transplant recipients. Bone mineral density and bone biomarkers were not associated with bone metabolism changes detected in bone biopsy specimens.
Asunto(s)
Remodelación Ósea , Huesos/patología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/terapia , Trasplante de Riñón , Absorciometría de Fotón , Adulto , Anciano , Fosfatasa Alcalina/sangre , Biopsia , Densidad Ósea , Huesos/diagnóstico por imagen , Huesos/fisiopatología , Hueso Esponjoso/diagnóstico por imagen , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/diagnóstico por imagen , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteocalcina/sangre , Hormona Paratiroidea/sangre , Periodo Posoperatorio , Periodo Preoperatorio , Estudios Prospectivos , Diálisis Renal , Vitamina D/análogos & derivados , Vitamina D/sangreRESUMEN
Male Cy/+ rats have shown a relatively consistent pattern of progressive kidney disease development that displays multiple key features of late stage chronic kidney disease-mineral bone disorder (CKD-MBD), specifically the development of cortical bone porosity. However, progression of disease in female Cy/+ rats, assessed in limited studies, is more heterogeneous and to date has failed to show development of the CKD-MBD phenotype, thus limiting their use as a practical model of progressive CKD-MBD. Animal and human studies suggest that estrogen may be protective against kidney disease in addition to its established protective effect on bone. Therefore, in this study, we aimed to determine the effect of ovariectomy (OVX) on the biochemical and skeletal manifestations of CKD-MBD in Cy/+ female rats. We hypothesized that OVX would accelerate development of the biochemical and skeletal features of CKD-MBD in female Cy/+ rats, similar to those seen in male Cy/+ rats. Female Cy/+ rats underwent OVX (n = 8) or Sham (n = 8) surgery at 15 weeks of age. Blood was collected every 5 weeks post-surgery until 35 weeks of age, when the rats underwent a 4-day metabolic balance, and the tibia and final blood were collected at the time of sacrifice. OVX produced the expected changes in trabecular and cortical parameters consistent with post-menopausal disease, and negative phosphorus balance compared with Sham. However, indicators of CKD-MBD were similar between OVX and Sham (similar kidney weight, plasma blood urea nitrogen, creatinine, creatinine clearance, phosphorus, calcium, parathyroid hormone, and no cortical porosity). Contrary to our hypothesis, OVX did not produce evidence of development of the CKD-MBD phenotype in female Cy/+ rats.
Asunto(s)
Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Posmenopausia , Animales , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/sangre , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Masculino , Mutación Missense , Proteínas Nucleares/genética , Ovariectomía , Ratas , Tibia/patologíaRESUMEN
BACKGROUND: Klotho is a key regulator of phosphate and Ca2+-transport in the kidney. Recently, we showed that treatment with LP533401 improved bone health in rats with chronic kidney disease (CKD) via the normalization of serum phosphate resulting from the reduced renal expression of phosphate cotransporters, including Klotho. METHODS: We evaluated the effect of LP533401 therapy on Klotho-expression-dependent Ca2+-transporters, renal calcium handling, and the potential consequences for the bone of uremic rats. RESULTS: Treatment with LP533401 and its vehicle resulted in the inhibition of transient receptor potential vanilloid receptor subtypes 5 and 6 (TRPV5, TRPV6) and calbindin (CaBP-28k, CaBP-9k) expression. The compensatory acceleration in renal expression of Na+/Ca2+-exchanger, 25-hydroxyvitamin d-1α-hydroxylase (CYP27B1), the intensification of vitamin D metabolism, and disruption of sophisticated balance between 1,25-dihydroxyvitamin D-serotonin was observed, especially in rats treated with LP533401. The imbalance between 1,25-dihydroxyvitamin D-serotonin levels led to intensified bone remodeling and improvement in bone geometry, mineral status, and strength in animals treated with LP533401. CONCLUSION: The modulation of circulating serotonin and its relation to other regulators of calcium handling can play an important role in calcium homeostasis and bone integrity in CKD rats treated with LP533401.
Asunto(s)
Huesos/efectos de los fármacos , Calcio/metabolismo , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/tratamiento farmacológico , Pirimidinas/farmacología , Uremia/tratamiento farmacológico , Animales , Huesos/metabolismo , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Modelos Animales de Enfermedad , Glucuronidasa/metabolismo , Proteínas Klotho , Masculino , Ratas , Ratas Wistar , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/fisiopatología , Vitamina D/metabolismoRESUMEN
Life expectancy in patients with all stages of chronic kidney disease (CKD) falls far short of that in the general population. Cardiovascular disease is the leading cause of mortality in pediatric patients with CKD. In contrast to the intimal atherosclerotic lesions that characterize cardiovascular disease in the general population, vascular endothelial dysfunction, medial arterial calcification, and cardiac dysfunction contribute to cardiovascular pathological conditions in CKD. The pathogenesis of these lesions, the origins of which can be identified in the absence of traditional cardiovascular risk factors, is incompletely understood. CKD-mediated vascular calcification in CKD is characterized by a transition of vascular smooth muscle cells to an osteoblast-like phenotype and altered bone and mineral metabolism are strongly linked to progressive cardiovascular disease in this population. Renal osteodystrophy therapies, including phosphate binders, vitamin D analogs, and calcimimetics, have an impact on the progression of cardiovascular disease. However, cardiovascular disease has its origins before the development of secondary hyperparathyroidism, and optimal therapeutic regimens that minimize cardiac dysfunction, vascular calcification, and early mortality remain to be defined.
Asunto(s)
Enfermedades Cardiovasculares/tratamiento farmacológico , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/complicaciones , Calcificación Vascular/tratamiento farmacológico , Factores de Edad , Arterias/patología , Huesos/metabolismo , Calcimiméticos/uso terapéutico , Fármacos Cardiovasculares/uso terapéutico , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/patología , Quelantes/uso terapéutico , Niño , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/etiología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Progresión de la Enfermedad , Endotelio Vascular/patología , Humanos , Trasplante de Riñón , Minerales/metabolismo , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/terapia , Túnica Media/patología , Calcificación Vascular/etiología , Calcificación Vascular/patología , Vitamina D/uso terapéuticoRESUMEN
The purpose of the present study was to determine whether fibroblast growth factor (FGF)23 could serve as a novel biomarker for renal osteodystrophy (ROD) progression. A rat model of ROD was induced by left nephrectomy plus intravenous injection of Adriamycin. Serum FGF23 was determined using an enzymelinked immunosorbent assay. Serum level and bone expression of FGF23 were both significantly elevated in the ROD group at 24 h postsurgery. Serum FGF23 was negatively correlated with calcium, phosphate, 25hydroxyvitamin D, conventional bone biomarkers and bone collagen X. More importantly, serum FGF23 was significantly associated with abnormalities in bone formation rate, osteoblasts, osteoclasts, trabecular volume thickness and osteoid volume. Therefore, FGF23 may serve as a novel biomarker for ROD.
Asunto(s)
Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/metabolismo , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Progresión de la Enfermedad , Factores de Crecimiento de Fibroblastos/metabolismo , Animales , Biomarcadores/metabolismo , Huesos/metabolismo , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/sangre , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/fisiopatología , Colágeno Tipo X/metabolismo , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Glucuronidasa/metabolismo , Riñón/patología , Riñón/fisiopatología , Pruebas de Función Renal , Proteínas Klotho , Masculino , Ratas Sprague-Dawley , Receptores de Factores de Crecimiento de Fibroblastos/metabolismoRESUMEN
Renal osteodystrophy (ROD), a group of metabolic bone diseases secondary to chronic kidney disease (CKD), still represents a great challenge to nephrologists. Its management is tailored by the type of bone lesion - of high or low turnover - that cannot be accurately predicted by serum biomarkers of bone remodeling available in daily clinical practice, mainly parathyroid hormone (PTH) and alkaline phosphatase (AP). In view of this limitation, bone biopsy followed by bone quantitative histomorphometry, the gold-standard method for the diagnosis of ROD, is still considered of paramount importance. Bone biopsy has also been recommended for evaluation of osteoporosis in the CKD setting to help physicians choose the best anti-osteoporotic drug. Importantly, bone biopsy is the sole diagnostic method capable of providing dynamic information on bone metabolism. Trabecular and cortical bones may be analyzed separately by evaluating their structural and dynamic parameters, thickness and porosity, respectively. Deposition of metals, such as aluminum and iron, on bone may also be detected. Despite of these unique characteristics, the interest on bone biopsy has declined over the last years and there are currently few centers around the world specialized on bone histomorphometry. In this review, we will discuss the bone biopsy technique, its indications, and the main information it can provide. The interest on bone biopsy should be renewed and nephrologists should be capacitated to perform it as part of their training during medical residency.
Asunto(s)
Huesos/patología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Biopsia/instrumentación , Diseño de Equipo , Humanos , Nefrología , Pautas de la Práctica en MedicinaRESUMEN
Abstract Renal osteodystrophy (ROD), a group of metabolic bone diseases secondary to chronic kidney disease (CKD), still represents a great challenge to nephrologists. Its management is tailored by the type of bone lesion - of high or low turnover - that cannot be accurately predicted by serum biomarkers of bone remodeling available in daily clinical practice, mainly parathyroid hormone (PTH) and alkaline phosphatase (AP). In view of this limitation, bone biopsy followed by bone quantitative histomorphometry, the gold-standard method for the diagnosis of ROD, is still considered of paramount importance. Bone biopsy has also been recommended for evaluation of osteoporosis in the CKD setting to help physicians choose the best anti-osteoporotic drug. Importantly, bone biopsy is the sole diagnostic method capable of providing dynamic information on bone metabolism. Trabecular and cortical bones may be analyzed separately by evaluating their structural and dynamic parameters, thickness and porosity, respectively. Deposition of metals, such as aluminum and iron, on bone may also be detected. Despite of these unique characteristics, the interest on bone biopsy has declined over the last years and there are currently few centers around the world specialized on bone histomorphometry. In this review, we will discuss the bone biopsy technique, its indications, and the main information it can provide. The interest on bone biopsy should be renewed and nephrologists should be capacitated to perform it as part of their training during medical residency.
Resumo A osteodistrofia renal (OR), um grupo de doenças ósseas metabólicas secundárias à doença renal crônica (DRC), ainda representa um grande desafio para os nefrologistas. Seu manejo é individualizado de acordo com o tipo de lesão óssea - de alto ou baixo remodelamento - cujo diagnóstico não pode ser prevista com precisão pelos biomarcadores séricos de remodelação óssea disponíveis na prática clínica diária, principalmente o paratormônio (PTH) e a fosfatase alcalina (FA). Em vista dessa limitação, biópsia óssea seguida de histomorfometria óssea quantitativa, método padrão-ouro para o diagnóstico de OR, ainda é considerado um procedimento de grande importância. A biópsia óssea também é recomendada na avaliação da osteoporose em indivíduos com DRC, a fim de auxiliar na escolha do melhor medicamento anti-osteoporótico. É importante observar que a biópsia óssea é o único método diagnóstico capaz de proporcionar informações dinâmicas sobre o metabolismo ósseo. Os ossos trabecular e cortical podem ser analisados separadamente por meio da avaliação de seus parâmetros estruturais e dinâmicos, espessura e porosidade, respectivamente. A deposição óssea de metais como alumínio e ferro também pode ser detectada. Apesar de suas características singulares, o interesse pela biópsia óssea diminuiu nos últimos anos. Poucos centros em todo o mundo são especializados em histomorfometria óssea. A presente revisão discute a técnica de biópsia óssea, suas indicações e as principais informações que ela pode oferecer. O interesse pela biópsia óssea deve ser renovado e os nefrologistas devem ser capacitados a realizá-la durante o período de residência médica.