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1.
Medicine (Baltimore) ; 98(28): e16408, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305454

RESUMO

RATIONALE: The Gitelman's syndrome (GS) is characterized by metabolic alkalosis, hypokalemia, hypomagnesemia, and hypocalciuria. However, the involvement of this deranged electrolyte balance in patients with GS in parathyroid hormone action has not been known. PATIENT CONCERNS: We report a 34-year-old woman with muscle weakness and tetany/seizures caused by electrolyte imbalance. She had hyperphosphatemia and hypocalciuric hypocalcemia in addition to severe hypomagnesemia with low potassium in the absence of metabolic alkalosis. We identified 2 heterozygous mutations in the solute carrier family 12 member 3 gene in this case (c.1732G>A, p.Val578Met and c.2537_38delTT, p.846fs) by targeted sequence for all causative genes of salt-losing tubulopathies. DIAGNOSES: A diagnosis of GS. Hypocalcemia and hyperphosphatemia were suggested to relate with the secondary obstruction of appropriate parathyroid hormone release following severe hypomagnesemia in GS. INTERVENTIONS: She was treated with single oral magnesium oxide administration. OUTCOMES: The electrolyte imbalance including hypocalcemia and hyperphosphatemia were resolved with a remission of clinical manifestations. LESSONS: These observations, in this case, suggest that even severe hypomagnesemia caused by GS was associated with resistance to appropriate parathyroid hormone secretion. Through this case, we recognize that secondary hypoparathyroidism would be triggered by severe hypomagnesemia in GS.


Assuntos
Antiácidos/uso terapêutico , Síndrome de Gitelman/complicações , Síndrome de Gitelman/tratamento farmacológico , Hiperfosfatemia/complicações , Hiperfosfatemia/tratamento farmacológico , Óxido de Magnésio/uso terapêutico , Administração Oral , Adulto , Feminino , Síndrome de Gitelman/genética , Humanos , Hiperfosfatemia/genética
2.
Cell Mol Life Sci ; 76(11): 2077-2091, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30887097

RESUMO

Medial vascular calcification has emerged as a putative key factor contributing to the excessive cardiovascular mortality of patients with chronic kidney disease (CKD). Hyperphosphatemia is considered a decisive determinant of vascular calcification in CKD. A critical role in initiation and progression of vascular calcification during elevated phosphate conditions is attributed to vascular smooth muscle cells (VSMCs), which are able to change their phenotype into osteo-/chondroblasts-like cells. These transdifferentiated VSMCs actively promote calcification in the medial layer of the arteries by producing a local pro-calcifying environment as well as nidus sites for precipitation of calcium and phosphate and growth of calcium phosphate crystals. Elevated extracellular phosphate induces osteo-/chondrogenic transdifferentiation of VSMCs through complex intracellular signaling pathways, which are still incompletely understood. The present review addresses critical intracellular pathways controlling osteo-/chondrogenic transdifferentiation of VSMCs and, thus, vascular calcification during hyperphosphatemia. Elucidating these pathways holds a significant promise to open novel therapeutic opportunities counteracting the progression of vascular calcification in CKD.


Assuntos
Hiperfosfatemia/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais , Calcificação Vascular/metabolismo , Animais , Fosfatos de Cálcio/química , Fosfatos de Cálcio/metabolismo , Transdiferenciação Celular , Condrócitos/metabolismo , Condrócitos/patologia , Regulação da Expressão Gênica , Humanos , Hiperfosfatemia/complicações , Hiperfosfatemia/genética , Hiperfosfatemia/patologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Osteoblastos/metabolismo , Osteoblastos/patologia , Ligante RANK/genética , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Calcificação Vascular/complicações , Calcificação Vascular/genética , Calcificação Vascular/patologia
3.
Adv Exp Med Biol ; 1133: 75-81, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30632117

RESUMO

The incidence of urolithiasis in infants is unknown. The aim of this study was to investigate clinical characteristics, nutrition, calcium, phosphate, 25-hydroxyvitamin D (25(OH)D), alkaline phosphate, and parathyroid hormone in infants with urolithiasis. There were 32 infants (23 boys and 9 girls) of the mean age of 6.4 ± 3.7 months (range 2-12 months), with diagnosis of urolithiasis enrolled into the study. Boys were younger than girls (5.3 vs. 9.1 months, respectively; p < 0.05). The infants were receiving prophylactic vitamin D3. Twenty-one of them were fed with milk formula, 9 were breastfed, and 2 were on a mixed diet. The major clinical symptoms consisted of irritability in 19 (59%) and urinary tract infection in 6 (19%) infants. Hypercalcemia and hyperphosphatemia were detected in the serum in 30 (94%) and 19 (60%) infants, respectively. The serum calcium level was higher in boys than girls (10.8 vs. 9.8 mg/dL, respectively; p < 0.05). Four (12.5%) infants had increased activity of alkaline phosphatase. The serum level of 25(OH)D was high in 3 (9%), low in 2 (6%), and normal in 27 (85%) infants. Parathyroid hormone was low in eight (25%) infants. Hypercalciuria and hyperphosphaturia were found in 11 (34%) boys and 8 (25%) girls. Family history of urolithiasis was positive in eight (25%) infants. We conclude that urolithiasis occurs in infancy more often in boys fed with milk formula and in those who received vitamin D supplementation. Hypercalcemia, hyperphosphatemia, and hypercalciuria are the most common changes present in clinical metabolic tests.


Assuntos
Cálcio/sangue , Urolitíase/diagnóstico , Vitamina D/sangue , Fosfatase Alcalina/sangue , Animais , Feminino , Homeostase , Humanos , Hipercalcemia/complicações , Hipercalciúria/complicações , Hiperfosfatemia/complicações , Lactente , Fórmulas Infantis , Masculino , Leite , Hormônio Paratireóideo/sangue , Vitaminas
5.
In Vivo ; 33(1): 11-16, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30587596

RESUMO

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 , 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 Risco
6.
Atherosclerosis ; 278: 49-59, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30253289

RESUMO

Mineral bone disease (MBD) is a common complication of chronic kidney disease (CKD) characterized by disruption of normal mineral homeostasis within the body. One or more of the following may occur: hypocalcemia, hyperphosphatemia, secondary hyperparathyroidism (SHPT), decreased vitamin D and vascular calcification (VC). The greater the decrease in renal function, the worse the progression of CKD-MBD. These abnormalities may lead to bone loss, osteoporosis and fractures. CKD-MBD is a major contributor to the high morbidity and mortality among patients with CKD. Another well-known complication of CKD is cardiovascular disease (CVD) caused by increased atherosclerosis and VC. CVD is the leading cause of morbidity and mortality in CKD patients. VC is linked to reduced arterial compliance that may lead to widened pulse pressure and impaired cardiovascular function. VC is a strong predicator of cardiovascular mortality among patients with CKD. Elevated phosphorus levels and increased calcium-phosphorus product promote VC. Controlling mineral disturbances such as hyperphosphatemia and SHPT is still considered among the current strategies for treatment of VC in CKD through restriction of calcium based phosphate binders in hyperphosphatemic patients across all severities of CKD along with dietary phosphate restriction and use of calciminetics. Additionally, Vitamin D insufficiency is common in CKD and dialysis patients. The causes are multifactorial and a serious consequence is SHPT. Vitamin D compounds remain the first-line therapy for prevention and treatment of SHPT in CKD. Vitamin D may also have atheroprotective effects on the arterial wall, but clinical studies do not show clear evidence of reduced cardiovascular mortality with vitamin D administration. This review discusses the issues surrounding CKD-MBD, cardiovascular disease and approaches to treatment.


Assuntos
Aterosclerose/complicações , Densidade Óssea , Doenças Ósseas/complicações , Cálcio/metabolismo , Insuficiência Renal Crônica/complicações , Calcificação Vascular/complicações , Animais , Aterosclerose/patologia , Doenças Ósseas/patologia , Osso e Ossos/patologia , Cardiotônicos/farmacologia , Ensaios Clínicos como Assunto , Homeostase , Humanos , Hiperparatireoidismo Secundário/complicações , Hiperparatireoidismo Secundário/patologia , Hiperfosfatemia/complicações , Hiperfosfatemia/patologia , Rim/fisiopatologia , Fosfatos/metabolismo , Diálise Renal , Insuficiência Renal Crônica/patologia , Sevelamer/farmacologia , Calcificação Vascular/patologia , Vitamina D/farmacologia
7.
Expert Opin Pharmacother ; 19(10): 1137-1148, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29985725

RESUMO

INTRODUCTION: Sucroferric oxyhydroxide is a non-calcium, iron-based phosphate binder indicated for the treatment of hyperphosphatemia in patients with chronic kidney disease undergoing dialysis. Areas covered: Herein, the preclinical development and clinical data for sucroferric oxyhydroxide are reviewed, including the key data from the Phase III registration study and the latest evidence from the real-world clinical setting. Expert opinion: Sucroferric oxyhydroxide displays potent phosphate-binding capacity and clinical studies demonstrate its effectiveness for the long-term reduction of serum phosphorus levels in dialysis patients. Observational study data also show that sucroferric oxyhydroxide provides effective serum phosphorus control for hyperphosphatemic patients in the real-world clinical setting. The serum phosphorus reductions with sucroferric oxyhydroxide can be achieved with a relatively low pill burden in comparison with other phosphate binders, which may translate into better treatment adherence in clinical practice. The Phase III data also indicate that sucroferric oxyhydroxide has a favorable impact on other chronic kidney disease-related mineral bone disease parameters, including a fibroblast growth factor-23-lowering effect. Sucroferric oxyhydroxide is well tolerated and associated with low systemic iron absorption, minimizing the potential for iron accumulation or overload. These attributes render sucroferric oxyhydroxide an attractive non-calcium-containing phosphate binder for the treatment of hyperphosphatemia.


Assuntos
Compostos Férricos/uso terapêutico , Hiperfosfatemia/tratamento farmacológico , Sacarose/uso terapêutico , Quelantes/uso terapêutico , Ensaios Clínicos como Assunto , Combinação de Medicamentos , Compostos Férricos/química , Compostos Férricos/farmacocinética , Regulamentação Governamental , Humanos , Hiperfosfatemia/complicações , Fosfatos/sangue , Diálise Renal , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/patologia , Sacarose/química , Sacarose/farmacocinética , Resultado do Tratamento
8.
J Adv Nurs ; 74(10): 2431-2441, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29943430

RESUMO

AIM: To evaluate the effectiveness of a bundled self-management intervention (Taking control of your phosphate with the 4Ds) to improve phosphate control among adults receiving haemodialysis. BACKGROUND: Hyperphosphataemia occurs in end-stage kidney disease and is associated with increased morbidity and mortality. While hyperphosphataemia can be managed through four methods (food, drinks, drugs and dialysis) adherence to these methods is challenging for patients. Studies also tend to focus on one method of phosphate control rather than bundling all methods together into a theoretically driven intervention. DESIGN: A multisite cluster randomized controlled trial with repeated measures. METHODS: Adults receiving haemodialysis with high serum phosphate levels (>1.6 millimoles per litre for at least 3 months) will be cluster randomized to standard care or intervention according to haemodialysis treatment shift. Informed by social cognitive theory, the intervention focuses on improving self-efficacy and incorporates the "teach-back" method of patient education. The intervention brings together essential phosphate control strategies of diet, drinks, drugs (phosphate binders) and dialysis prescription in a 12-week self-management education programme. The primary outcome is serum phosphate level. Secondary outcomes are knowledge of and adherence to phosphate control strategies and self-efficacy for managing kidney disease. DISCUSSION: Efforts to improve phosphate control have been undertaken although the optimal approach remains unclear. This study will make an important contribution to building an evidence base of phosphate control nursing intervention that can be delivered during routine haemodialysis. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry Number ACTRN12617000703303.


Assuntos
Hiperfosfatemia/prevenção & controle , Falência Renal Crônica/terapia , Educação de Pacientes como Assunto/métodos , Fosfatos/sangue , Diálise Renal , Autogestão/métodos , Adulto , Austrália , Protocolos Clínicos , Humanos , Hiperfosfatemia/complicações , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Nova Zelândia , Cooperação do Paciente , Autoeficácia , Comunicação para Apreensão de Informação
9.
Chronobiol Int ; 35(10): 1329-1334, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29947550

RESUMO

Hyperphosphatemia is a common complication of chronic kidney disease (CKD) and is associated with cardiovascular disease (CVD), which has contributed to an increase in mortality of CKD patients. The onset of CVD often varies by time-of-day. Acute myocardial infarction or ventricular arrhythmia occurs most frequently during early morning. Blood pressure (BP) and heart rate circadian rhythms account for the diurnal variations in CVD. Preservation of normal circadian time structure from the cardiomyocyte level to the whole organ system is essential for cardiovascular health and CVD prevention. Independent risk factors, such as reduced heart rate variability (HRV) and increased BP variability (BPV), are particularly prevalent in patients with CKD. Analysis of HRV is an important clinical tool for characterizing cardiac autonomic status, and reduced HRV has prognostic significance for various types of CVD. Circadian BP rhythms are classified as extreme dipper, dipper, non-dipper or riser. It has been reported that nocturnal riser BP pattern contributes to cardiovascular threats. Previous studies have indicated that the circadian rhythm of serum phosphate in CKD patients is consistent with the general population, with the highest diurnal value observed in the early morning hours, followed by a progressive decrease to the lowest value of the day, which occurs around 11:00 am. Rhythm abnormalities have become the main therapeutic target for treating CVD in CKD patients. It has been reported that high levels of serum phosphate are associated with reduced HRV and increased BPV in CKD patients. However, the mechanisms related to interactions between hyperphosphatemia, HRV and BPV have not been fully elucidated. This review focuses on the evidence and discusses the potential mechanisms related to the effects of hyperphosphatemia on HRV and BPV.


Assuntos
Pressão Sanguínea/fisiologia , Ritmo Circadiano/fisiologia , Frequência Cardíaca/fisiologia , Hiperfosfatemia/patologia , Insuficiência Renal Crônica/complicações , Humanos , Hiperfosfatemia/complicações
10.
J Pharmacol Exp Ther ; 366(3): 433-445, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29903718

RESUMO

Patients with chronic kidney disease (CKD) have a markedly increased risk for developing cardiovascular disease. Nontraditional risk factors, such as increased phosphate retention, increased serum fibroblast growth factor 23 (FGF-23), and deficiencies in vitamins D and K metabolism, likely play key roles in the development of vascular calcification during CKD progression. Calcitriol [1,25-(OH)2-D3] is a key transcriptional regulator of matrix Gla protein, a vitamin K-dependent protein that inhibits vascular calcification. We hypothesized that calcitriol treatment would inhibit the development of vascular calcification and this inhibition would be dependent on vitamin K status in a rat model of CKD. Rats were treated with dietary adenine (0.25%) to induce CKD, with either 0, 20, or 80 ng/kg of calcitriol with low or high dietary vitamin K1 (0.2 or 100 mg/kg) for 7 weeks. Calcitriol at both lower (20 ng/kg) and moderate (80 ng/kg) doses increased the severity of vascular calcification, and contrary to our hypothesis this was not significantly improved by high dietary vitamin K1. Calcitriol had a dose-dependent effect on: 1) lowering serum parathyroid hormone, 2) increasing serum calcium, and 3) increasing serum FGF-23. Calcitriol treatment significantly increased aortic expression of the calcification genes Runx2 and Pit-1 These data also implicate impaired vitamin D catabolism in CKD, which may contribute to the development of calcitriol toxicity and increased vascular calcification. The present findings demonstrate that in an adenine-induced rat model of CKD calcitriol treatment at doses as low as 20 ng/kg can increase the severity of vascular calcification regardless of vitamin K status.


Assuntos
Calcitriol/farmacologia , Hiperparatireoidismo Secundário/complicações , Hiperfosfatemia/complicações , Insuficiência Renal Crônica/complicações , Calcificação Vascular/complicações , Calcificação Vascular/metabolismo , Vitamina K/metabolismo , Animais , Modelos Animais de Doenças , Progressão da Doença , Hemodinâmica/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Calcificação Vascular/fisiopatologia , Vitamina K/sangue
12.
J Am Soc Nephrol ; 29(6): 1636-1648, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29654213

RESUMO

Background The high cardiovascular morbidity and mortality of patients with CKD may result in large part from medial vascular calcification, a process promoted by hyperphosphatemia and involving osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Reduced serum zinc levels have frequently been observed in patients with CKD, but the functional relevance of this remains unclear.Methods We performed experiments in primary human aortic VSMCs; klotho-hypomorphic (kl/kl), subtotal nephrectomy, and cholecalciferol-overload mouse calcification models; and serum samples from patients with CKD.Results In cultured VSMCs, treatment with zinc sulfate (ZnSO4) blunted phosphate-induced calcification, osteo-/chondrogenic signaling, and NF-κB activation. ZnSO4 increased the abundance of zinc-finger protein TNF-α-induced protein 3 (TNFAIP3, also known as A20), a suppressor of the NF-κB pathway, by zinc-sensing receptor ZnR/GPR39-dependent upregulation of TNFAIP3 gene expression. Silencing of TNFAIP3 in VSMCs blunted the anticalcific effects of ZnSO4 under high phosphate conditions. kl/kl mice showed reduced plasma zinc levels, and ZnSO4 supplementation strongly blunted vascular calcification and aortic osteoinduction and upregulated aortic Tnfaip3 expression. ZnSO4 ameliorated vascular calcification in mice with chronic renal failure and mice with cholecalciferol overload. In patients with CKD, serum zinc concentrations inversely correlated with serum calcification propensity. Finally, ZnSO4 ameliorated the osteoinductive effects of uremic serum in VSMCs.Conclusions Zinc supplementation ameliorates phosphate-induced osteo-/chondrogenic transdifferentiation of VSMCs and vascular calcification through an active cellular mechanism resulting from GPR39-dependent induction of TNFAIP3 and subsequent suppression of the NF-κB pathway. Zinc supplementation may be a simple treatment to reduce the burden of vascular calcification in CKD.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Falência Renal Crônica/sangue , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/fisiologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Calcificação Vascular/prevenção & controle , Sulfato de Zinco/farmacologia , Animais , Aorta , Transdiferenciação Celular , Células Cultivadas , Suplementos Nutricionais , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Glucuronidase/genética , Humanos , Hidroxietilrutosídeo , Hiperfosfatemia/sangue , Hiperfosfatemia/complicações , Camundongos , NF-kappa B/antagonistas & inibidores , Nefrectomia , Nefrocalcinose/prevenção & controle , Fosfatos , Transdução de Sinais , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Calcificação Vascular/sangue , Calcificação Vascular/etiologia , Zinco/sangue
13.
Clin Exp Nephrol ; 22(4): 967-972, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29536389

RESUMO

BACKGROUND: In dialysis patients, mortality risk due to cardiovascular diseases is remarkably high and prognosis is poor; coronary artery calcification is considered one of the major contributing factors. It is known that hyperphosphatemia is associated with coronary artery calcification. Therefore, controlling serum phosphate level and thereby mitigating vascular calcification could improve the poor prognosis of dialysis patients. However, the optimal phosphate level in dialysis patients remains unknown; hence, this study was planned to compare the effects of two types of non-calcium-based phosphate binders, and examine the effect of strict control of phosphate on coronary artery calcification. METHODS: EPISODE is a randomized, open-label, multi-center, interventional trial with a two-by-two factorial design (UMIN ID: UMIN000023648). This trial will enroll hemodialysis patients who have been on dialysis for at least 3 months with a pre-dialysis serum phosphate level of at least 5.0 mg/dL or at least 6.1 mg/dL, respectively, in those taking or not taking a phosphate binder, as measured during the observation period. Registered patients will be randomized to the sucroferric oxyhydroxide or lanthanum carbonate arm and will receive the assigned drug to reduce serum phosphate to two target levels (3.5-4.5 mg/dL in strict arm and 5.0-6.0 mg/dL in standard arm) for 12 months. The primary endpoint will be percent change in coronary artery calcification score, and the secondary endpoints will include change from baseline serum phosphate and calcium levels, change in renal anemia-related factors, etc. The desired sample size has been calculated to be 200 patients.


Assuntos
Doença da Artéria Coronariana/etiologia , Compostos Férricos/uso terapêutico , Hiperfosfatemia/tratamento farmacológico , Diálise Renal , Sacarose/uso terapêutico , Calcinose , Quelantes , Doença da Artéria Coronariana/prevenção & controle , Combinação de Medicamentos , Humanos , Hiperfosfatemia/complicações , Ferro , Fosfatos , Ensaios Clínicos Controlados Aleatórios como Assunto
15.
PLoS One ; 13(1): e0190978, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29315336

RESUMO

INTRODUCTION: Phosphate level is often deranged during acute illness, regardless of the presence of kidney injury or not. A few studies described that hypophosphatemia may associated with outcome in patients admitted to the burn unit, but the literatures for hyperphosphatemia is limited. Our study aims to evaluate if hyperphosphatemia, one of the sign of severe tissue damage or kidney injury, will associate with mortality of patients with severe burns. MATERIALS AND METHODS: The study was a post hoc analysis of prospectively collected data from patients admitted to the burn unit between September 2006 and December 2011. Patients were stratified into normophosphatemic or hyperphosphatemic group by baseline plasma phosphate level. The primary endpoint is 90-day mortality. RESULTS: Total 301 patients were included (hyperphosphatemia: n = 52; normophosphatemia: n = 249). The hyperphosphatemic group had lower Glasgow Coma Scale, mean arterial blood pressure, hemoglobin level, albumin, and higher TBSA of burns, APACHE II score, ABSI score, Acute kidney injury (AKI), and creatinine. The 90-day mortality was higher in the hyperphosphatemic group than in the normal group (53.8% vs 18.1%, P < .001) and this difference was still significant when adjusting for several confounding factors (hazard ratio, 2.05; 95% CI, 1.17-3.59). Multivariable Cox analysis showed risk factors of mortality included TBSA of burns, hyperphosphatemia, reduced urine output, and APACHE II score. CONCLUSIONS: Our study found in addition to TBSA of burns and inhalation injury, baseline hyperphosphatemia in patients with severe burns is also associated with higher mortality.


Assuntos
Queimaduras/mortalidade , Hiperfosfatemia/complicações , Adulto , Queimaduras/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Sobrevida
16.
Kidney Blood Press Res ; 42(6): 1205-1215, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29227975

RESUMO

BACKGROUND/AIMS: Hyperphosphatemia is one of the most notable features of chronic kidney disease (CKD). Numerous epidemiological and clinical studies have found that high serum phosphate concentrations are associated with calcification in the coronary arteries. However, the mechanisms underlying the vascular calcification induced by high phosphate have not been understood fully. METHODS: Vascular smooth muscle cells (VSMCs) were cultured in high-phosphate media to induce vascular calcification, which was detected by Alizarin red S staining. Gene expression and protein levels of differentiation markers were determined by real-time RT-PCR and western blotting, respectively. Protein levels of phosphorylated NF-κB and TLR4 were detected by western blotting, and the role of NF-κB/TLR4 was further confirmed by using an NF-κB inhibitor or TLR4 siRNA. RESULTS: Our results showed that high-phosphate media induced obvious calcification of VSMCs. Simultaneously, VSMC differentiation was confirmed by the increased expression of bone morphogenetic protein-2 and Runt-related transcription factor 2 and decreased expression of the VSMC-specific marker SM22α, which was accompanied by the increased expression of inflammatory cytokines. Moreover, a significant upregulation of TLR4 and phosphorylated NF-κB was also detected in VSMCs with high-phosphate media. In contrast, VSMC calcification and the increased expression of inflammatory cytokines were markedly attenuated by pretreatment with TLR4 siRNA and pyrrolidine dithiocarbamic acid, an NF-κB inhibitor. CONCLUSION: These data suggest that high-phosphate conditions directly induce vascular calcification via the activation of TLR4/NF-κB signaling in VSMCs. Moreover, inhibition of the TLR4/NF-κB signaling pathway might be a key intervention to prevent vascular calcification in patients with CKD.


Assuntos
Músculo Liso Vascular/metabolismo , Fosfatos/química , Fosfatos/farmacologia , Calcificação Vascular/induzido quimicamente , Células Cultivadas , Humanos , Hiperfosfatemia/complicações , NF-kappa B/metabolismo , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo
17.
Rev. osteoporos. metab. miner. (Internet) ; 9(4): 114-120, nov.-dic. 2017. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-169411

RESUMO

Introducción: En pacientes con enfermedad renal crónica (ERC), la hiperfosfatemia agrava tanto la hiperplasia paratiroidea como la síntesis y secreción de PTH. La mayor hiperplasia se asocia a descensos en la expresión génica de los receptores de calcio (CaSR), vitamina D (VDR) y también de α-Klotho, induciendo resistencia de la glándula paratiroides para responder tanto al tratamiento como a los aumentos de FGF23. Este estudio examinó la posible contribución epigenética del fósforo elevado en agravar el hiperparatiroidismo secundario (HPTS). Material y métodos: Se comparó el grado de metilación mediante pirosecuenciación de bisulfito en secuencias ricas en CpG de los promotores en los genes del CaSR, VDR, PTH y α-Klotho en ADN de glándulas paratiroides de ratas urémicas alimentadas con dieta con contenido normal y elevado en fósforo. Resultados: La dieta rica en fósforo incrementó la expresión de PTH y causó una marcada reducción del grado de metilación en el promotor del gen de PTH. En cambio, las regiones promotoras de los genes de CaSR, VDR y α-Klotho no mostraron diferencias significativas en el porcentaje de metilación entre ambos grupos de ratas, no siendo, por tanto, éste el mecanismo determinante de la disminución de la expresión de estos genes observada en el HPTS. Conclusiones: Las alteraciones epigenéticas inducidas por la dieta rica en fósforo en el HPTS, en particular la hipometilación del gen de la PTH, podrían contribuir a los aumentos que se producen en la síntesis y secreción de esta hormona. La identificación de los mecanismos implicados permitiría diseñar mejores tratamientos para el HPTS en fases tempranas de la ERC (AU)


Introduction: Hyperphosphataemia aggravates both parathyroid hyperplasia and PTH secretion in patients with chronic kidney disease (CKD). Hyperplasia is associated with decreases in calcium receptor expression (CaSR), vitamin D (VDR) and α-Klotho, inducing resistance of the parathyroid gland to respond both to treatment and to increases in FGF23. This study examined the possible epigenetic contributions of raised phosphorus to aggravate secondary hyperparathyroidism (SHPT) in patients with (CRD). Material and methods: The degree of methylation was compared by pyrosequencing of bisulfite in CpGrich sequences of the promoters in the CaSR, VDR, PTH and α-Klotho genes in parathyroid gland DNA from uremic rats fed a normal and high phosphorus diet. Results: The diet rich in phosphorus increased PTH expression and caused a marked reduction in the degree of methylation in the promoter of the PTH gene. In contrast, the promoter regions of the CaSR, VDR and α-Klotho genes did not show significant differences in the percentage of methylation between the two groups of rats. Thus, it was not the determining mechanism for the decrease of the expression of these genes observed in the SHPT. Conclusions: The epigenetic alterations induced by the phosphorus rich diet in SHPT, particularly the PTH gene hypomethylation, could contribute to the increases that occur in the synthesis and secretion of this hormone. The identification of the mechanisms involved would allow better treatments for SHPT to be designed in the early stages of CKD (AU)


Assuntos
Animais , Ratos , Fósforo/uso terapêutico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/genética , Hiperfosfatemia/complicações , Metilação , Modelos Animais , Fósforo/efeitos adversos , Hiperparatireoidismo Secundário/diagnóstico , Hiperparatireoidismo Secundário/genética , Neoplasias das Paratireoides/complicações , Metilação de DNA , Metilação de DNA/genética , Glândulas Paratireoides/patologia , Ratos Wistar , Análise Estatística
18.
J Am Heart Assoc ; 6(11)2017 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-29146611

RESUMO

BACKGROUND: Hyperphosphatemia is a major factor promoting the formation of arterial medial calcification in chronic kidney disease (CKD). However, arterial medial calcification begins to occur during the early stages of CKD, when hyperphosphatemia is not yet apparent. It is predicted that other factors also play a role. The aim of the present study was to determine the role of pro-inflammatory nuclear factor-κB (NF-κB) signaling in smooth muscle cells (SMCs) for phosphate-induced arterial medial calcification in CKD mice. METHODS AND RESULTS: We first sought to establish a novel mouse model of CKD with arterial medial calcification. CKD was induced in DBA/2 mice by feeding them a low concentration of adenine, and these mice were fed a normal or high-phosphorus diet. Severe calcification was seen in CKD mice fed the high-phosphorus diet, while it was undetectable in CKD mice fed the normal phosphorus diet or control mice fed the high-phosphorus diet. Arterial medial calcification was accompanied by phenotypic switching of SMCs into osteogenic cells. Interestingly, NF-κB inhibitors, tempol and triptolide, both reduced arterial medial calcification in CKD mice fed the high-phosphorus diet. Moreover, formation of arterial medial calcification, as well as SMC phenotypic switching, was also markedly attenuated in transgenic mice, in which the NF-κB activity was inhibited selectively in SMCs. Mechanistic studies revealed that Krüppel-like factor 4 was involved in NF-κB-induced SMC phenotypic switching and calcification. CONCLUSIONS: Results of the present studies suggest that the NF-κB signaling in SMCs plays an important role in high phosphate-induced arterial medial calcification in CKD.


Assuntos
Hiperfosfatemia/genética , Fatores de Transcrição Kruppel-Like/genética , Miócitos de Músculo Liso/metabolismo , NF-kappa B/antagonistas & inibidores , Proteínas/farmacologia , Insuficiência Renal Crônica/complicações , Calcificação Vascular/genética , Animais , Western Blotting , Células Cultivadas , Modelos Animais de Doenças , Feminino , Hiperfosfatemia/complicações , Hiperfosfatemia/metabolismo , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Miócitos de Músculo Liso/patologia , Fenótipo , RNA/genética , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Calcificação Vascular/etiologia , Calcificação Vascular/metabolismo
19.
Semin Arthritis Rheum ; 47(3): 451-455, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28779847

RESUMO

INTRODUCTION: Tumoral calcinosis (TC) is a difficult-to-treat complication that can occur during several diseases such as dermatomyositis or genetic hyperphosphatemia. It is a painful and disabling condition that can lead to local complications including joint mobility reduction, cutaneous ulceration and superinfection. For the largest lesions, the treatment relies essentially on surgery. Intravenous sodium thiosulfate (STS) is efficient to treat calciphylaxis in patients undergoing hemodialysis. Local injections of STS seem efficient in superficial calcifications. OBJECTIVE: To report the efficacy and safety of intra-lesional injections of STS in tumoral calcinosis. RESULTS: We report two cases of successful intra-lesional injections of STS. A 44-year-old woman, with a history of dermatomyositis, presenting large subcutaneous calcifications in the right elbow, and a 42-year-old man, with a history of familial tumoral calcinosis, presenting large intramuscular calcifications in the right buttock, received weekly intra-lesional of 1-3g STS injections for 12 and 21 months, respectively. In both cases, the treatment relieved pain and greatly reduced the tumoral calcinosis with a very significant functional improvement without specific adverse effects. In case 1, TC size decreased from 28.7*56.0mm at baseline to 21.5*30.6mm at M12 treatment (59% reduction). In case 2, TC reduced from 167.5*204.3mm at baseline to 86.2*85.2mm at M21 treatment (79% reduction). CONCLUSION: Local injection of STS could be a promising therapeutic strategy for large and deep TC lesions and could therefore be an alternative to surgery.


Assuntos
Calcinose/tratamento farmacológico , Quelantes/administração & dosagem , Dermatomiosite/tratamento farmacológico , Hiperfosfatemia/tratamento farmacológico , Tiossulfatos/administração & dosagem , Adulto , Calcinose/etiologia , Dermatomiosite/complicações , Dermatomiosite/diagnóstico por imagem , Feminino , Humanos , Hiperfosfatemia/complicações , Hiperfosfatemia/genética , Injeções Intralesionais , Imagem por Ressonância Magnética , Masculino , Síndrome de Sjogren/complicações
20.
Am J Kidney Dis ; 70(3): 377-385, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28579423

RESUMO

BACKGROUND: Mild hyperphosphatemia is a putative risk factor for cardiovascular disease [CVD], loss of kidney function, and mortality. Very limited data are available from sizable multicenter kidney transplant recipient (KTR) cohorts assessing the potential relationships between serum phosphorus levels and the development of CVD outcomes, transplant failure, or all-cause mortality. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial, a large, multicenter, multiethnic, controlled clinical trial that provided definitive evidence that high-dose vitamin B-based lowering of plasma homocysteine levels did not reduce CVD events, transplant failure, or total mortality in stable KTRs. PREDICTOR: Serum phosphorus levels were determined in 3,138 FAVORIT trial participants at randomization. RESULTS: During a median follow-up of 4.0 years, the cohort had 436 CVD events, 238 transplant failures, and 348 deaths. Proportional hazards modeling revealed that each 1-mg/dL higher serum phosphorus level was not associated with a significant increase in CVD risk (HR, 1.06; 95% CI, 0.92-1.22), but increased transplant failure (HR, 1.36; 95% CI, 1.15-1.62) and total mortality risk associations (HR, 1.21; 95% CI, 1.04-1.40) when adjusted for treatment allocation, traditional CVD risk factors, kidney measures, type of kidney transplant, transplant vintage, and use of calcineurin inhibitors, steroids, or lipid-lowering drugs. These associations were strengthened in models without kidney measures: CVD (HR, 1.14; 95% CI, 1.00-1.31), transplant failure (HR, 1.72; 95% CI, 1.46-2.01), and mortality (HR, 1.34; 95% CI, 1.15-1.54). LIMITATIONS: We lacked data for concentrations of parathyroid hormone, fibroblast growth factor 23, or vitamin D metabolites. CONCLUSIONS: Serum phosphorus level is marginally associated with CVD and more strongly associated with transplant failure and total mortality in long-term KTRs. A randomized controlled clinical trial in KTRs that assesses the potential impact of phosphorus-lowering therapy on these hard outcomes may be warranted.


Assuntos
Doenças Cardiovasculares , Hiperfosfatemia , Falência Renal Crônica , Transplante de Rim/efeitos adversos , Fósforo/sangue , Complicações Pós-Operatórias , Adulto , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Feminino , Humanos , Hiperfosfatemia/sangue , Hiperfosfatemia/complicações , Hiperfosfatemia/diagnóstico , Falência Renal Crônica/sangue , Falência Renal Crônica/mortalidade , Falência Renal Crônica/cirurgia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/mortalidade , Fatores de Risco , Análise de Sobrevida , Transplantados/estatística & dados numéricos
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