RESUMO
OBJECTIVES: Hypocalcemia, hypomagnesemia, and hyperphosphatemia are common electrolyte disturbances in perinatal asphyxia (PA). Different reasons have been proposed for these electrolyte disturbances. This study investigated the effect of the urinary excretion of calcium (Ca), magnesium (Mg), and phosphorus (P) on the serum levels of these substances in babies who were treated using therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE) caused by PA. This study sheds light on the pathophysiology that may cause changes in the serum values of these electrolytes. METHODS: This study included 21 healthy newborns (control group) and 38 patients (HIE group) who had undergone therapeutic hypothermia due to HIE. Only infants with a gestational age of 36 weeks and above and a birth weight of 2000 g and above were evaluated. The urine and serum Ca, Mg, P, and creatinine levels of all infants were evaluated at 24, 48, and 72 h. RESULTS: The lower serum Ca value and the higher serum P value of the HIE group were found to be statistically significant compared to the control group (p<0.05). There was no significant difference in serum Mg values between the groups. However, hypomagnesemia was detected in five patients from the HIE group. The urine excretion of FeCa and FeMg at 24 h, and FeP excretion at 48 and 72 h were found to be significantly higher in the HIE group compared to the control group. CONCLUSIONS: This study determined that the urinary excretion of Ca, Mg, and P has an effect on the serum Ca, Mg, and P levels of infants with HIE.
Assuntos
Hiperfosfatemia/etiologia , Hipocalcemia/etiologia , Hipotermia Induzida/métodos , Hipóxia Encefálica/complicações , Erros Inatos do Transporte Tubular Renal/etiologia , Cálcio/análise , Cálcio/sangue , Feminino , Humanos , Hiperfosfatemia/fisiopatologia , Hipocalcemia/fisiopatologia , Hipotermia Induzida/estatística & dados numéricos , Hipóxia Encefálica/epidemiologia , Hipóxia Encefálica/fisiopatologia , Recém-Nascido , Magnésio/análise , Magnésio/sangue , Masculino , Fosfatos/análise , Fosfatos/sangue , Estudos Prospectivos , Erros Inatos do Transporte Tubular Renal/fisiopatologia , Estatísticas não ParamétricasRESUMO
BACKGROUND: Chronic kidney disease (CKD) affects approximately 15% of adults in the USA. As CKD progresses, urinary phosphate excretion decreases and results in phosphate retention and, eventually, hyperphosphatemia. As hyperphosphatemia is associated with numerous adverse outcomes, including increased cardiovascular mortality, reduction in phosphorus concentrations is a guideline-recommended, established clinical practice. Dietary phosphate restriction, dialysis, and phosphate binders are currently the only options for phosphate management. However, many patients with hyperphosphatemia have phosphorus concentrations >5.5 mg/dL, despite treatment. SUMMARY: This review pre-sents recent advances in the understanding of intestinal phosphate absorption and therapeutic implications. Dietary phosphate is absorbed in the intestine through two distinct pathways, paracellular absorption and transcellular transport. Recent evidence indicates that the paracellular route accounts for 65-80% of total phosphate absorbed. Thus, the paracellular pathway is the dominant mechanism of phosphate absorption. Tenapanor is a first-in-class, non-phosphate binder that inhibits the sodium-hydrogen exchanger 3 or solute carrier family 9 member 3 (SLC9A3) encoded by the SLC9A3 gene, and blocks paracellular phosphate absorption. Key Messages: Targeted inhibition of sodium-hydrogen exchanger 3 effectively reduces paracellular permeability of phosphate. Novel therapies that target the paracellular pathway may improve phosphate control in chronic kidney disease.
Assuntos
Hiperfosfatemia/tratamento farmacológico , Absorção Intestinal , Intestino Delgado/fisiopatologia , Isoquinolinas/uso terapêutico , Fosfatos/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Sulfonamidas/uso terapêutico , Animais , Transporte Biológico , Humanos , Hiperfosfatemia/etiologia , Hiperfosfatemia/fisiopatologia , Insuficiência Renal Crônica/complicações , Trocador 3 de Sódio-Hidrogênio/antagonistas & inibidoresRESUMO
The sodium-dependent phosphate transporters Pit 1 and Pit 2 belong to the solute carrier 20 (SLC20) family of membrane proteins. They are ubiquitously distributed in the human body. Their crucial function is the intracellular transport of inorganic phosphate (Pi) in the form of H2 PO4- . They are one of the main elements in maintaining physiological phosphate homeostasis. Recent data have emerged that indicate novel roles of Pit 1 and Pit 2 proteins besides the well-known function of Pi transporters. These membrane proteins are believed to be precise phosphate sensors that mediate Pi-dependent intracellular signaling. They are also involved in insulin signaling and influence cellular insulin sensitivity. In diseases that are associated with hyperphosphatemia, such as diabetes and chronic kidney disease (CKD), disturbances in the function of Pit 1 and Pit 2 are observed. Phosphate transporters from the SLC20 family participate in the calcification of soft tissues, mainly blood vessels, during the course of CKD. The glomerulus and podocytes therein can also be a target of pathological calcification that damages these structures. A few studies have demonstrated the development of Pi-dependent podocyte injury that is mediated by Pit 1 and Pit 2. This paper discusses the role of Pit 1 and Pit 2 proteins in podocyte function, mainly in the context of the development of pathological calcification that disrupts permeability of the renal filtration barrier. We also describe the mechanisms that may contribute to podocyte damage by Pit 1 and Pit 2.
Assuntos
Hiperfosfatemia/metabolismo , Rim/metabolismo , Fosfatos/metabolismo , Podócitos/metabolismo , Insuficiência Renal Crônica/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/metabolismo , Calcificação Vascular/metabolismo , Homeostase , Humanos , Hiperfosfatemia/patologia , Hiperfosfatemia/fisiopatologia , Rim/patologia , Rim/fisiopatologia , Masculino , Podócitos/patologia , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/fisiopatologia , Calcificação Vascular/patologia , Calcificação Vascular/fisiopatologiaRESUMO
Chronic kidney disease (CKD) is common in geriatric cats, and is characterised in the majority of cases by tubulointerstitial inflammation and fibrosis. Hyperphosphataemia is a frequent complication of CKD and is independently associated with severity of renal fibrosis and disease progression. Transforming growth factor-beta 1 (TGF-ß1) signalling is thought to be a convergent pathway which mediates the progression of renal fibrosis in CKD. The aims of this study were to explore the interaction between increased extracellular phosphate and the TGF-ß1 signalling pathway by investigating: (a) the effect of a commercially available, phosphate-restricted, diet on urinary TGF-ß1 excretion in cats with CKD; and (b) the role of increased extracellular phosphate in regulating proliferation, apoptosis, and expression of genes related to TGF-ß1 signalling and extracellular matrix (ECM) production in feline proximal tubular epithelial cells (FPTEC) and cortical fibroblasts from cats with azotaemic CKD (CKD-FCF). The dietary intervention study revealed no effect of dietary phosphate restriction on urinary active TGF-ß1 excretion after 4-8 weeks (P=0.98), despite significantly decreasing serum phosphate (P<0.001). There was no effect of increased growth media phosphate concentration (from 0.95mM to 2mM and 3.5mM) on proliferation (P=0.99) and apoptotic activity in FPTEC (P=0.22), or expression of genes related to ECM production and the TGF-ß1 signalling pathway in FPTEC and CKD-FCF (P>0.05). These findings suggest the beneficial effects of dietary phosphate restriction on progression of feline CKD may not occur through modulation of renal TGF-ß1 production, and do not support a direct pro-fibrotic effect of increased extracellular phosphate on feline renal cells.
Assuntos
Doenças do Gato/fisiopatologia , Hiperfosfatemia/veterinária , Rim/patologia , Insuficiência Renal Crônica/veterinária , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Doenças do Gato/patologia , Gatos , Células Cultivadas , Dieta/veterinária , Células Epiteliais/metabolismo , Fibrose/induzido quimicamente , Hiperfosfatemia/patologia , Hiperfosfatemia/fisiopatologia , Túbulos Renais Proximais/metabolismo , Fosfatos/administração & dosagem , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/fisiopatologia , Transdução de Sinais/genética , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/urinaRESUMO
Phosphate in both inorganic and organic form is essential for several functions in the body. Plasma phosphate level is maintained by a complex interaction between intestinal absorption, renal tubular reabsorption, and the transcellular movement of phosphate between intracellular fluid and bone storage pools. This homeostasis is regulated by several hormones, principally the parathyroid hormone, 1,25-dihydroxyvitamin D and fibroblast growth factor 23. Abnormalities in phosphate regulation can lead to serious and fatal complications. In this review phosphate homeostasis and the aetiology, pathophysiology, clinical features, investigation and management of hypophosphataemia and hyperphosphataemia will be discussed.
Assuntos
Osso e Ossos/metabolismo , Hiperfosfatemia/sangue , Hipofosfatemia/sangue , Absorção Intestinal , Fosfatos/sangue , Reabsorção Renal , Animais , Biomarcadores/sangue , Osso e Ossos/fisiopatologia , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Homeostase , Humanos , Hiperfosfatemia/diagnóstico , Hiperfosfatemia/fisiopatologia , Hiperfosfatemia/terapia , Hipofosfatemia/diagnóstico , Hipofosfatemia/fisiopatologia , Hipofosfatemia/terapia , Hormônio Paratireóideo/sangue , Vitamina D/análogos & derivados , Vitamina D/sangueRESUMO
IMPACT STATEMENT: This review summarizes the work on transcellular intestinal phosphate absorption, arguing why this pathway is not the predominant pathway in humans consuming a "Western" diet. We then highlight the recent evidence which is strongly consistent with paracellular intestinal phosphate absorption mediating the bulk of intestinal phosphate absorption in humans.
Assuntos
Absorção Intestinal/fisiologia , Fosfatos/farmacocinética , Fósforo na Dieta/farmacocinética , Animais , Ensaios Clínicos como Assunto , Dieta Ocidental , Eletroquímica , Enterócitos/efeitos dos fármacos , Enterócitos/metabolismo , Humanos , Hiperfosfatemia/etiologia , Hiperfosfatemia/fisiopatologia , Hiperfosfatemia/terapia , Absorção Intestinal/efeitos dos fármacos , Isoquinolinas/uso terapêutico , Camundongos , Camundongos Knockout , Niacinamida/uso terapêutico , Compostos Orgânicos/química , Fosfatos/urina , Coelhos , Ratos , Proteínas Recombinantes/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/fisiopatologia , Sódio/fisiologia , Trocador 3 de Sódio-Hidrogênio/antagonistas & inibidores , Trocador 3 de Sódio-Hidrogênio/deficiência , Trocador 3 de Sódio-Hidrogênio/fisiologia , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/antagonistas & inibidores , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/deficiência , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/fisiologia , Sulfonamidas/uso terapêuticoRESUMO
Hyperphosphatemia is a serious complication in patients with chronic kidney disease (CKD), and is associated with more rapid progression as well as higher risk of mortality, and higher rate of cardiovascular disease accidents. CKD patients are usually advised to adopt a low phosphate diet in addition to phosphate-lowering medications, if necessary. However, there is a lack of awareness of the dietary sources of phosphate, especially hidden phosphate intake from phosphate additives in processed foods and carbonated beverages. Appropriate nutritional education could be an effective solution in reducing phosphate toxicity without introducing an additional pill burden or malnutrition.
Assuntos
Doenças Cardiovasculares/metabolismo , Hiperfosfatemia/metabolismo , Fósforo na Dieta/uso terapêutico , Insuficiência Renal Crônica/metabolismo , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Fator de Crescimento de Fibroblastos 23 , Humanos , Hiperfosfatemia/complicações , Hiperfosfatemia/epidemiologia , Hiperfosfatemia/fisiopatologia , Desnutrição/complicações , Desnutrição/epidemiologia , Desnutrição/fisiopatologia , Fósforo na Dieta/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/fisiopatologia , Fatores de RiscoRESUMO
BACKGROUND: Highly Active Antiretroviral Therapy (HAART) has been implicated in renal dysfunction with hypophosphataemia. OBJECTIVE: We prospectively evaluated renal phosphate excretion during HAART use. METHOD: Newly diagnosed human immunodeficiency virus (HIV)-infected individuals were treated with Tenofovir disoproxil fumarate/Emtricitabine/Efavirenz (TDF/FTC/EFV), n=33; Zidovudine/Lamivudine/Nevirapine (ZDV/3TC/NVP), n=53; and Zidovudine/Lamivudine/Efavirenz (ZDV/3TC/EFV), n=16. Creatinine and phosphate were assayed in blood and urine simultaneously at baseline, 1, 3, 6 and 9 months. Glomerular filtration rate (eGFR), fractional phosphate excretion and reabsorption (FEPi % and TRP), and the ratio of tubular maximum reabsorption of phosphate (TmP) to GFR (TmP/GFR) were estimated. RESULTS: At baseline, eGFR showed moderate chronic kidney disease (mean: 35.50 ± 2.02, 33.14 ± 1.63, and 39.97±1.84 ml/min/1.73m2 in the 3 groups respectively); 54 (52.9%) patients had hyperphosphataemia (>1.4mmo/L); 43 (42.2%) had normophosphataemia (0.6-1.4mmol/L); 5 (4.9%) had hypophosphataemia (<0.6mmol/L). eGFR improved significantly from 1 month (≥60, 58.65 ± 1.11, and 51.76 ±1.59 ml/min/1.73m2; p=0.04, <0.001, 0.67 respectively), with a relapse at 9 months in TDFtreated subjects (50.10 ± 1.89 ml/min/1.73m2). TDF/FTC/EFV resulted in significantly greater reduction in plasma phosphate than ZDV/3TC/NVP (p=0.031), but not significantly different from ZDV/3TC/EFV (p=0.968). Similarly, ZDV/3TC/EFV resulted in significantly greater reduction in plasma phosphate than ZDV/3TC/NVP (p=0.036). FEP% progressively increased with HAART duration, more in TDF-treated and ZDV/3TC/EFV-treated groups than ZDV/3TC/NVP (p=0.014); TRP was elevated (>0.86), implying non-maximal phosphate reabsorption. TmP/GFR values were elevated, (>1.35mmol/l). CONCLUSION: HIV causes kidney dysfunction with reduced phosphate excretion resulting in hyperphosphataemia but HAART improves renal function. Prolonged use of TDF can cause renal toxicity with hypophosphataemia as fractional excretion progressively increased with duration of therapy unlike ZDV/3TC/NVP. The use of different third agents (either NVP or EFV) in zidovudine-based therapy results in significantly different plasma phosphate levels; ZDV/3TC/EFV, like TDF/FTC/EFV, resulted in significantly greater decline in plasma phosphate than ZDV/3TC/NVP. Thus, Evafirenz (EVF) may have similar or synergistic adverse effects with tenofovir disoproxil fumarate (TDF).
Assuntos
Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , Hiperfosfatemia/fisiopatologia , Rim/efeitos dos fármacos , Insuficiência Renal Crônica/fisiopatologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Terapia Antirretroviral de Alta Atividade/métodos , Sinergismo Farmacológico , Feminino , Taxa de Filtração Glomerular , Infecções por HIV/complicações , Humanos , Hiperfosfatemia/sangue , Hiperfosfatemia/etiologia , Hiperfosfatemia/urina , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nigéria , Fosfatos/metabolismo , Estudos Prospectivos , Eliminação Renal/efeitos dos fármacos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/urina , Adulto JovemRESUMO
OBJECTIVE: Secondary hyperparathyroidism (sHPT) is one of the most serious complications in patients on long-term hemodialysis. These patients may suffer from metabolic bone diseases, severe atherosclerosis, and undesirable cardiovascular events. Endoscopic parathyroidectomy with autotransplantation is a treatment option for those who do not respond to clinical management. This study aimed to investigate practical use of a self-made device in parathyroid autotransplantation for patients with sHPT, and to compare this device with ordinary surgical scissors. METHODS: A total of 15 patients with sHPT were treated with endoscopic parathyroidectomy and autotransplantation. Pieces of parathyroid tissue were squeezed in our self-made device and injected into the brachioradialis muscle. Sixteen patients with sHPT who were treated with traditional parathyroid transplantation served as controls. Serum levels of parathyroid hormone, alkaline phosphatase, calcium, phosphorus and intact parathyroid hormone were measured before and after surgery. RESULTS: Preoperative symptoms were alleviated, and serum parathyroid hormone and alkaline phosphatase levels, hyperphosphatemia, and hypercalcemia were improved or normalized in all of the patients in both groups. Pathological examinations showed that parathyroid cells remained active. CONCLUSION: Application of our squeezing device is an economic, effective, and safe method in endoscopic parathyroidectomy and autotransplantation for patients with sHPT.
Assuntos
Endoscopia/instrumentação , Hiperparatireoidismo Secundário/cirurgia , Falência Renal Crônica/complicações , Glândulas Paratireoides/cirurgia , Paratireoidectomia/métodos , Adulto , Idoso , Fosfatase Alcalina/sangue , Cálcio/sangue , Coristoma/metabolismo , Endoscopia/métodos , Feminino , Antebraço , Humanos , Hipercalcemia/sangue , Hipercalcemia/fisiopatologia , Hipercalcemia/prevenção & controle , Hiperparatireoidismo Secundário/sangue , Hiperparatireoidismo Secundário/etiologia , Hiperparatireoidismo Secundário/fisiopatologia , Hiperfosfatemia/sangue , Hiperfosfatemia/fisiopatologia , Hiperfosfatemia/prevenção & controle , Injeções Intramusculares , Falência Renal Crônica/sangue , Falência Renal Crônica/fisiopatologia , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético , Glândulas Paratireoides/metabolismo , Glândulas Paratireoides/patologia , Hormônio Paratireóideo/sangue , Diálise Renal , Transplante AutólogoRESUMO
Hypocalcemia and hyperphosphatemia are the pathognomonic biochemical features of hypoparathyroidism, and result directly from lack of parathyroid hormone (PTH) action on the kidney. In the absence of PTH action, the renal mechanisms transporting calcium and phosphate reabsorption deregulate, resulting in hypocalcemia and hyperphosphatemia. Circulating calcium negatively regulates PTH secretion. Hypocalcemia causes neuromuscular disturbances ranging from epilepsy and tetany to mild paresthesia. Circulating phosphate concentration does not directly regulate PTH secretion. Hyperphosphatemia is subclinical, but chronically promotes ectopic mineralization disease. Vitamin D-thiazide treatment leads to ectopic mineralization and renal damage. PTH treatment has the potential for fewer side effects.
Assuntos
Hipoparatireoidismo/fisiopatologia , Rim/fisiopatologia , Humanos , Hiperfosfatemia/etiologia , Hiperfosfatemia/fisiopatologia , Hipocalcemia/etiologia , Hipocalcemia/fisiopatologia , Hipoparatireoidismo/complicações , Hipoparatireoidismo/tratamento farmacológico , Nefropatias/etiologia , Nefropatias/fisiopatologia , Nefropatias/prevenção & controle , Hormônio Paratireóideo/uso terapêuticoRESUMO
In chronic kidney disease (CKD), high serum phosphate concentration is associated with cardiovascular disease and deterioration in renal function. In early CKD, the serum phosphate concentration is normal due to increased fractional excretion of phosphate. Our premise was that high phosphate intake even in patients with early CKD would result in an excessive load of phosphate causing tubular injury and accelerating renal function deterioration. In CKD 2-3 patients, we evaluated whether increased phosphaturia accelerates CKD progression. To have a uniform group of patients with early CKD, 95 patients with metabolic syndrome without overt proteinuria were followed for 2.7 ± 1.6 years. The median decline in eGFR was 0.50 ml/min/1.73 m2/year. Patients with a more rapid decrease in eGFR had greater phosphaturia. Moreover, the rate of decrease in eGFR inversely correlated with the degree of phosphaturia. Additionally, phosphaturia independently predicted renal function deterioration. In heminephrectomized rats, a high phosphate diet increased phosphaturia resulting in renal tubular damage associated with inflammation, oxidative stress and low klotho expression. Moreover, in rats with hyperphosphatemia and metabolic syndrome antioxidant treatment resulted in attenuation of renal lesions. In HEK-293 cells, high phosphate promoted oxidative stress while melatonin administration reduced ROS generation. Our findings suggest that phosphate loading in early CKD, results in renal damage and a more rapid decrease in renal function due to renal tubular injury.
Assuntos
Hipofosfatemia Familiar/fisiopatologia , Rim/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antioxidantes/metabolismo , Linhagem Celular , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Glucuronidase/metabolismo , Células HEK293 , Humanos , Hiperfosfatemia/metabolismo , Hiperfosfatemia/fisiopatologia , Hipofosfatemia Familiar/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Proteínas Klotho , Masculino , Melatonina/farmacologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Fosfatos/metabolismo , Proteinúria/metabolismo , Proteinúria/fisiopatologia , Ratos , Ratos Wistar , Ratos Zucker , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Adulto JovemRESUMO
In caring for patients with chronic kidney disease, it is important to prevent and treat hyperphosphatemia with a combination of dietary restrictions and phosphorus binders. This review describes the pathophysiology and control of hyperphosphatemia and the different classes of phosphorus binders with respect to their availability, cost, side effects, and scenarios in which one class of binder may be more beneficial than another.
Assuntos
Quelantes/uso terapêutico , Hiperfosfatemia/fisiopatologia , Fósforo/sangue , Insuficiência Renal Crônica/sangue , Humanos , Hiperfosfatemia/etiologia , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapiaRESUMO
Phosphate homeostasis is primarily maintained in the renal proximal tubules, where the expression of sodium/phosphate cotransporters (Npt2a and Npt2c) is modified by the endocrine actions of both fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH). However, the specific contribution of each regulatory pathway in the proximal tubules has not been fully elucidated in vivo. We have previously demonstrated that proximal tubule-specific deletion of the FGF23 coreceptor Klotho results in mild hyperphosphatemia with little to no change in serum levels of FGF23, 1,25(OH)2D3, and PTH. In the present study, we characterized mice in which the PTH receptor PTH1R was specifically deleted from the proximal tubules, either alone or in combination with Klotho ( PT-PTH1R-/- and PT-PTH1R/KL-/-, respectively). PT-PTH1R-/- mice showed significant increases in serum FGF23 and PTH levels, whereas serum phosphate levels were maintained in the normal range, and Npt2a and Npt2c expression in brush border membrane (BBM) did not change compared with control mice. In contrast, PT-PTH1R/KL-/- mice displayed hyperphosphatemia and an increased abundance of Npt2a and Npt2c in the renal BBM, along with increased circulating FGF23 levels. While serum calcium was normal, 1,25(OH)2D3 levels were significantly decreased, leading to extremely high levels of PTH. Collectively, mice with a deletion of PTH1R alone in proximal tubules results in only minor changes in phosphate regulation, whereas deletion of both PTH1R and Klotho leads to a severe disturbance, including hyperphosphatemia with increased sodium/phosphate cotransporter expression in BBM. These results suggest an important interplay between the PTH/PTH1R and FGF23/Klotho pathways to affect renal phosphate handling in the proximal tubules.
Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Glucuronidase/metabolismo , Hiperfosfatemia/sangue , Túbulos Renais Proximais/metabolismo , Hormônio Paratireóideo/sangue , Fosfatos/sangue , Reabsorção Renal , Animais , Calcitriol/sangue , Cálcio/sangue , Células Cultivadas , Fator de Crescimento de Fibroblastos 23 , Predisposição Genética para Doença , Glucuronidase/deficiência , Glucuronidase/genética , Hiperfosfatemia/genética , Hiperfosfatemia/fisiopatologia , Túbulos Renais Proximais/fisiopatologia , Proteínas Klotho , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Receptor Tipo 1 de Hormônio Paratireóideo/deficiência , Receptor Tipo 1 de Hormônio Paratireóideo/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIc/metabolismo , Regulação para CimaRESUMO
Medial artery calcification, a hallmark of type 2 diabetes mellitus and chronic kidney disease (CKD), is known as an independent risk factor for cardiovascular mortality and morbidity. Hyperphosphatemia associated with CKD is a strong stimulator of vascular calcification but the molecular mechanisms regulating this process remain not fully understood. We showed that calcification was induced after exposing Sprague-Dawley rat aortic explants to high inorganic phosphate level (Pi , 6 mM) as examined by Alizarin red and Von Kossa staining. This calcification was associated with high Tissue-Nonspecific Alkaline Phosphatase (TNAP) activity, vascular smooth muscle cells de-differentiation, manifested by downregulation of smooth muscle 22 alpha (SM22α) protein expression which was assessed by immunoblot analysis, immunofluorescence, and trans-differentiation into osteo-chondrocyte-like cells revealed by upregulation of Runt related transcription factor 2 (Runx2), TNAP, osteocalcin, and osteopontin mRNA levels which were determined by quantitative real-time PCR. To unravel the possible mechanism(s) involved in this process, microRNA (miR) expression profile, which was assessed using TLDA technique and thereafter confirmed by individual qRT-PCR, revealed differential expression 10 miRs, five at day 3 and 5 at day 6 post Pi treatment versus control untreated aortas. At day 3, miR-200c, -155, 322 were upregulated and miR-708 and 331 were downregulated. After 6 days of treatment, miR-328, -546, -301a were upregulated while miR-409 and miR-542 were downregulated. Our results indicate that high Pi levels trigger aortic calcification and modulation of certain miRs. These observations suggest that mechanisms regulating aortic calcification might involve miRs, which warrant further investigations in future studies.
Assuntos
Calcificação Fisiológica/genética , Hiperfosfatemia/genética , MicroRNAs/genética , Insuficiência Renal Crônica/genética , Fosfatase Alcalina/genética , Animais , Desdiferenciação Celular/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hiperfosfatemia/fisiopatologia , Proteínas dos Microfilamentos/genética , Proteínas Musculares/genética , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Osteocalcina/genética , Fosfatos/farmacologia , Ratos , Insuficiência Renal Crônica/fisiopatologiaRESUMO
BACKGROUND AND OBJECTIVES: Prior studies have shown that sevelamer attenuates progression of arterial calcification and may reduce the risk of death compared with calcium-based phosphate binders. In clinical practice, however, sevelamer is used not only as an alternative but also as an add-on therapy in patients already being treated with calcium-based phosphate binders. We analyzed the Dialysis Outcomes and Practice Patterns Study (DOPPS) data to test the hypothesis that the initiation of sevelamer is associated with improved survival in patients on hemodialysis treated with calcium-based phosphate binders. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We included 12,564 patients from DOPPS phase 3 and phase 4 (2005-2011) who were prescribed calcium-based phosphate binders at baseline or before sevelamer treatment. Mortality risk was assessed using a sequential stratification method to identify as-yet-untreated patients who were appropriately matched to the newly treated patients on the basis of their risk of death. RESULTS: Of 12,564 patients, 2606 were subsequently treated with sevelamer hydrochloride or sevelamer carbonate. After beginning sevelamer therapy, mean serum phosphorus levels decreased by 0.3 mg/dl in the first 4 months and gradually decreased thereafter. We matched 2501 treated patients with at least one as-yet-untreated patient. Patients treated with sevelamer had a 14% lower risk for mortality compared with as-yet-untreated patients (hazard ratio, 0.86; 95% confidence interval, 0.76 to 0.97). Similar results were observed in the sensitivity analyses when changing the matching calipers or the treated and as-yet-untreated ratios, and by using propensity score matching. CONCLUSIONS: The use of sevelamer as an add-on or alternative therapy to calcium-based phosphate binders is associated with improved survival in patients on maintenance hemodialysis.
Assuntos
Quelantes/uso terapêutico , Hiperfosfatemia/tratamento farmacológico , Rim/efeitos dos fármacos , Fosfatos/sangue , Diálise Renal , Insuficiência Renal Crônica/terapia , Sevelamer/uso terapêutico , Idoso , Austrália , Biomarcadores/sangue , Quelantes/efeitos adversos , Substituição de Medicamentos , Quimioterapia Combinada , Europa (Continente) , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Hiperfosfatemia/sangue , Hiperfosfatemia/mortalidade , Hiperfosfatemia/fisiopatologia , Rim/metabolismo , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nova Zelândia , América do Norte , Padrões de Prática Médica , Pontuação de Propensão , Modelos de Riscos Proporcionais , Estudos Prospectivos , Diálise Renal/efeitos adversos , Diálise Renal/mortalidade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Sevelamer/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
Tumor lysis syndrome (TLS) is a life-threatening disorder that is an oncologic emergency. Risk factors for TLS are well-known, but the current literature shows case descriptions of unexpected acute TLS. Solid tumors and untreated hematologic tumors can lyse under various circumstances in children and adults. International guidelines and recommendations, including the early involvement of the critical care team, have been put forward to help clinicians properly manage the syndrome. Advanced practice nurses may be in the position of triaging and initiating treatment of patients with TLS, and need a thorough understanding of the syndrome and its treatment.
Assuntos
Hiperfosfatemia/diagnóstico , Hiperfosfatemia/fisiopatologia , Hiperuricemia/fisiopatologia , Enfermagem Oncológica/normas , Síndrome de Lise Tumoral/diagnóstico , Síndrome de Lise Tumoral/fisiopatologia , Desequilíbrio Hidroeletrolítico/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Hiperfosfatemia/enfermagem , Hiperuricemia/diagnóstico , Hiperuricemia/enfermagem , Lactente , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Fatores de Risco , Síndrome de Lise Tumoral/enfermagem , Desequilíbrio Hidroeletrolítico/diagnóstico , Desequilíbrio Hidroeletrolítico/enfermagem , Adulto JovemRESUMO
BACKGROUND: Mineral and bone disorder (MBD), especially hyperphosphatemia, is an independently risk factor for adverse prognosis in patients with chronic kidney disease (CKD). However, CKD-MBD among Chinese population was poorly studied. This study aimed to investigate the status of MBD and its association with cardiovascular parameters in Chinese patients with predialysis CKD. METHODS: Chinese Cohort Study of Chronic Kidney Disease (C-STRIDE) is a prospective multicenter cohort study involving predialysis CKD patients in China. Markers of MBD, including serum phosphorus, calcium, and intact parathyroid hormone, were measured in baseline samples at the patients' entry. The association between serum phosphorus and abdominal aortic calcification (AAC), left ventricular hypertrophy (LVH) were examined by logistic regression models. RESULTS: Altogether 3194 predialysis patients with mean estimated glomerular filtration of 51.8 ± 33.1 ml.min-1.1.73 m-2 were included. The proportion of patients with hyperphosphatemia were 2.6%, 2.9%, 6.8%, and 27.1% in CKD Stages 3a, 3b, 4, and 5, respectively. Moreover, 71.6% of the patients with hyperphosphatemia did not receive any phosphate-binder (PB). Lateral abdominal X-rays were obtained in 2280 patients, 9.8% of the patients were diagnosed as having AAC. Altogether 2219 patients had data of echocardiography, and 13.2% of them were diagnosed with LVH. Multivariate logistic regression analysis showed that serum phosphorus was independently associated with the presence of AAC and LVH. CONCLUSIONS: In Chinese patients with CKD, the percentage of hyperphosphatemia is comparable to that of other countries while the usage of PBs is suboptimal. The prevalence of vascular calcification in Chinese patients is relatively lower compared with the Caucasian population.
Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Adolescente , Adulto , Idoso , China , Distúrbio Mineral e Ósseo na Doença Renal Crônica/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/metabolismo , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Hiperfosfatemia/sangue , Hiperfosfatemia/metabolismo , Hiperfosfatemia/fisiopatologia , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fósforo/sangue , Estudos Prospectivos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/metabolismo , Calcificação Vascular/sangue , Calcificação Vascular/metabolismo , Calcificação Vascular/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: We have sought to explore the impact of dietary Pi intake on human age related health in the pSoBid cohort (n=666) to explain the disparity between health and deprivation status in this cohort. As hyperphosphataemia is a driver of accelerated ageing in rodent models of progeria we tested whether variation in Pi levels in man associate with measures of biological ageing and health. RESULTS: We observed significant relationships between serum Pi levels and markers of biological age (telomere length (p=0.040) and DNA methylation content (p=0.028), gender and chronological age (p=0.032). When analyses were adjusted for socio-economic status and nutritional factors, associations were observed between accelerated biological ageing (telomere length, genomic methylation content) and dietary derived Pi levels among the most deprived males, directly related to the frequency of red meat consumption. CONCLUSIONS: Accelerated ageing is associated with high serum Pi levels and frequency of red meat consumption. Our data provide evidence for a mechanistic link between high intake of Pi and age-related morbidities tied to socio-economic status.
Assuntos
Envelhecimento/fisiologia , Dieta , Rim/fisiopatologia , Fosfatos/sangue , Classe Social , Adulto , Metilação de DNA , Feminino , Humanos , Hiperfosfatemia/sangue , Hiperfosfatemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , TelômeroRESUMO
Hypophosphatasia is the inborn error of metabolism characterized by low serum alkaline phosphatase activity (hypophosphatasaemia). This biochemical hallmark reflects loss-of-function mutations within the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). TNSALP is a cell-surface homodimeric phosphohydrolase that is richly expressed in the skeleton, liver, kidney and developing teeth. In hypophosphatasia, extracellular accumulation of TNSALP natural substrates includes inorganic pyrophosphate, an inhibitor of mineralization, which explains the dento-osseous and arthritic complications featuring tooth loss, rickets or osteomalacia, and calcific arthopathies. Severely affected infants sometimes also have hypercalcaemia and hyperphosphataemia due to the blocked entry of minerals into the skeleton, and pyridoxine-dependent seizures from insufficient extracellular hydrolysis of pyridoxal 5'-phosphate, the major circulating form of vitamin B6, required for neurotransmitter synthesis. Autosomal recessive or dominant inheritance from ~300 predominantly missense ALPL (also known as TNSALP) mutations largely accounts for the remarkably broad-ranging expressivity of hypophosphatasia. High serum concentrations of pyridoxal 5'-phosphate represent a sensitive and specific biochemical marker for hypophosphatasia. Also, phosphoethanolamine levels are usually elevated in serum and urine, though less reliably for diagnosis. TNSALP mutation detection is important for recurrence risk assessment and prenatal diagnosis. Diagnosing paediatric hypophosphatasia is aided by pathognomic radiographic changes when the skeletal disease is severe. Hypophosphatasia was the last type of rickets or osteomalacia to await a medical treatment. Now, significant successes for severely affected paediatric patients are recognized using asfotase alfa, a bone-targeted recombinant TNSALP.
Assuntos
Osso e Ossos/diagnóstico por imagem , Epilepsia/fisiopatologia , Hipercalcemia/fisiopatologia , Hiperfosfatemia/fisiopatologia , Hipofosfatasia/fisiopatologia , Fosfatase Alcalina/genética , Transplante de Medula Óssea , Terapia de Reposição de Enzimas , Terapia Genética , Humanos , Hipofosfatasia/diagnóstico , Hipofosfatasia/genética , Hipofosfatasia/terapia , Mutação , RadiografiaRESUMO
AIMS: Hyperphosphatemia is associated with accelerated vascular endothelial dysfunction in patients with chronic kidney disease (CKD). The purpose of this study is to investigate the molecular mechanisms underlying hyperphosphatemia-caused endothelial dysfunction. MAIN METHODS: The metabolic fingerprinting of human umbilical vein endothelial cells (HUVECs) subjected to hyperphosphatemia was characterized using an integrated metabolomics approach. HUVECs cultured in physiologically simulated hyperphosphatemia with or without phosphonoformic acid, a sodium-dependent phosphate transporter inhibitor (N=6) were collected for metabolomics analysis. Multivariate principle component analysis and partial least squares discriminant analysis were applied to analyze the metabolic data. The key metabolites were confirmed by quantitative analysis using liquid chromatography coupled with tandem mass spectrometer (LC-MS/MS). KEY FINDINGS: 36 metabolites were significantly altered in HUVECs following the challenges of hyperphosphatemia mimic, involving several metabolic pathways (all P<0.05). Among them, ornithine increased significantly in the HUVECs mediated by hyperphosphatemia mimic, and its levels positively correlated with cell apoptosis rate (r=0.674, P=0.002), and several additional metabolites in multiple metabolic pathways. The changes in the levels of ornithine and other several metabolites were supported by subsequent quantitative analyses using LC-MS/MS. Further study demonstrated that the increase in ornithine level may result from the increased expression of arginase 2 in HUVECs, which mediates the hydrolysis of arginine to form ornithine. SIGNIFICANCE: This is the first study demonstrating ornithine a key molecule mediating hyperphosphatemia-induced apoptosis of ECs. Arginase 2 may be a therapeutic target for hyperphosphatemia-associated cardiovascular events.