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1.
Kidney Blood Press Res ; 47(4): 229-238, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35086103

RESUMO

BACKGROUND AND AIMS: Inflammation and endothelial damage play a pivotal role in Fabry disease (FD) manifestations. In daily clinical practice, FD is mainly monitored by traditional biomarkers of target organ injury, such as serum creatinine and proteinuria, which provide no information about inflammation and endothelial damage. MATERIALS AND METHODS: We investigated the serum levels of 3-nitrotyrosine (3-NT), an oxidative stress biomarker, and of growth differentiation factor-15 (GDF-15) and syndecan-1 in classical FD patients on enzyme replacement therapy (ERT) for at least 6 months and their relationship with Fabry-related cardiac and renal manifestations. RESULTS: Fifty-two classical FD patients (37 females) on ERT for 62.0 ± 27.5 months were included in the study. The main clinical manifestations included nephropathy (67.3%) and cardiomyopathy (21.1%). Serum levels of 3-NT, syndecan-1, and GDF-15 were 33.3 (4.8-111.1) nmol/mL, 55.7 (38.8-74.9) ng/mL, and 541.8 (392.2-784.4) pg/mL, respectively. There was a direct correlation between interventricular septal thickness and serum GDF-15 (r = 0.59; p < 0.001) and syndecan-1 (r = 0.30, p = 0.04). Among kidney parameters, there was a significant correlation between estimated glomerular filtration rate and GDF-15 (r = -0.61; p < 0.001), as well as between 24 h proteinuria and syndecan-1 (r = 0.28; p = 0.04). Serum GDF-15 levels were significantly higher in patients with cardiomyopathy (p = 0.03) as well in those with both nephropathy and cardiomyopathy (p = 0.02) than in patients without these comorbidities. Serum GDF-15 levels were also significantly higher in patients who started ERT at an older age (≥40 years). In multivariate analysis, syndecan-1, 3-NT, GDF-15, time on ERT, and arterial pressure differentiated Fabry patients with both cardiac and renal involvement from those without these manifestations. CONCLUSIONS: GDF-15 and syndecan-1 were associated with parameters of cardiac and renal involvement in classic FD patients on ERT. Their potential association with residual risk and disease outcomes should be investigated.


Assuntos
Doença de Fabry , Nefropatias , Biomarcadores , Terapia de Reposição de Enzimas , Doença de Fabry/complicações , Doença de Fabry/tratamento farmacológico , Feminino , Fator 15 de Diferenciação de Crescimento , Humanos , Inflamação/tratamento farmacológico , Nefropatias/complicações , Proteinúria/tratamento farmacológico , Sindecana-1/uso terapêutico , alfa-Galactosidase/uso terapêutico
2.
Toxicol Appl Pharmacol ; 414: 115412, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33484708

RESUMO

COVID-19 is a pandemic with no end in sight. There is only one approved antiviral agent but global stocks are deemed insufficient. Despite in vitro antiviral activity, clinical trials of chloroquine and hydroxychloroquine were disappointing, and they may even impair outcomes. Chloroquine causes zebroid deposits reminiscent of Fabry disease (α-galactosidase A deficiency) and endothelial cells are key targets of COVID-19. We have explored the effect of chloroquine on cultured endothelial cells and its modulation by recombinant α-galactosidase A (agalsidase). Following dose-response studies, 0.5 µg/mL chloroquine was added to cultured human endothelial cells. Neutral red and Lysotracker were used to assess lysosomes. Cytotoxicity was evaluated by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) - MTT assay and cell stress by assessing reactive oxygen species (ROS) and nitric oxide (NO). In endothelial cells, chloroquine induced dose-dependent cytotoxicity at in vitro test concentrations for COVID-19 therapy. At a sublethal concentration, chloroquine significantly induced the accumulation of acid organelles (P < 0.05), increased ROS levels, and decreased NO production (P < 0.05). These adverse effects of chloroquine on endothelial cell biology were decreased by agalsidase-ß (P < 0.05). Chloroquine-induced endothelial cell cytotoxicity and stress is attenuated by agalsidase-ß treatment. This suggests that endothelial cell injury may contribute to the failure of chloroquine as therapy for COVID-19 and may be at least in part related to causing dysfunction of the lysosomal enzyme α-galactosidase A.


Assuntos
Tratamento Farmacológico da COVID-19 , Cloroquina/efeitos adversos , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cloroquina/administração & dosagem , Cloroquina/uso terapêutico , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Doença de Fabry/induzido quimicamente , Humanos , Pandemias , Espécies Reativas de Oxigênio , SARS-CoV-2
3.
Cochrane Database Syst Rev ; 7: CD006663, 2016 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-27454104

RESUMO

BACKGROUND: Anderson-Fabry disease is an X-linked defect of glycosphingolipid metabolism. Progressive renal insufficiency is a major source of morbidity, additional complications result from cardio- and cerebro-vascular involvement. Survival is reduced among affected males and symptomatic female carriers.This is an update of a Cochrane review first published in 2010, and previously updated in 2013. OBJECTIVES: To evaluate the effectiveness and safety of enzyme replacement therapy compared to other interventions, placebo or no interventions, for treating Anderson-Fabry disease. SEARCH METHODS: We searched the Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register (date of the most recent search: 08 July 2016). We also searched 'Clinical Trials' on The Cochrane Library, MEDLINE, Embase and LILACS (date of the most recent search: 24 September 2015). SELECTION CRITERIA: Randomized controlled trials of agalsidase alfa or beta in participants diagnosed with Anderson-Fabry disease. DATA COLLECTION AND ANALYSIS: Two authors selected relevant trials, assessed methodological quality and extracted data. MAIN RESULTS: Nine trials comparing either agalsidase alfa or beta in 351 participants fulfilled the selection criteria.Both trials comparing agalsidase alfa to placebo reported on globotriaosylceramide concentration in plasma and tissue; aggregate results were non-significant. One trial reported pain scores measured by the Brief Pain Inventory severity, there was a statistically significant improvement for participants receiving treatment at up to three months, mean difference -2.10 (95% confidence interval -3.79 to -0.41; at up to five months, mean difference -1.90 (95% confidence interval -3.65 to -0.15); and at up to six months, mean difference -2.00 (95% confidence interval -3.66 to -0.34). There was a significant difference in the Brief Pain Inventory pain-related quality of life at over five months and up to six months, mean difference -2.10 (95% confidence interval -3.92 to -0.28) but not at other time points. Death was not an outcome in either of the trials.One of the three trials comparing agalsidase beta to placebo reported on globotriaosylceramide concentration in plasma and tissue and showed significant improvement: kidney, mean difference -1.70 (95% confidence interval -2.09 to -1.31); heart, mean difference -0.90 (95% confidence interval -1.18 to -0.62); and composite results (renal, cardiac, and cerebrovascular complications and death), mean difference -4.80 (95% confidence interval -5.45 to -4.15). There was no significant difference between groups for death; no trials reported on pain.Only two trials compared agalsidase alfa to agalsidase beta. One of them showed no significant difference between the groups regarding adverse events, risk ratio 0.36 (95% confidence interval 0.08 to 1.59), or any serious adverse events; risk ratio 0.30; (95% confidence interval 0.03 to 2.57).Two trials compared different dosing schedules of agalsidase alfa. One of them involved three different doses (0.2 mg/kg every two weeks; 0.1 mg/kg weekly and; 0.2 mg/kg weekly), the other trial evaluated two further doses to the dosage schedules: 0.4 mg/kg every week and every other week. Both trials failed to show significant differences with various dosing schedules on globotriaosylceramide levels. No significant differences were found among the schedules for the primary efficacy outcome of self-assessed health state, or for pain scores.One trial comparing agalsidase alfa to agalsidase beta showed no significant difference for any adverse events such as dyspnoea and hypertension.The methodological quality of the included trials was generally unclear for the random sequence generation and allocation concealment. AUTHORS' CONCLUSIONS: Trials comparing enzyme replacement therapy to placebo show significant improvement with enzyme replacement therapy in regard to microvascular endothelial deposits of globotriaosylceramide and in pain-related quality of life. There is, however, no evidence identifying if the alfa or beta form is superior or the optimal dose or frequency of enzyme replacement therapy. With regards to safety, adverse events (i.e., rigors, fever) were more significant in the agalsidase beta as compared to placebo. The long-term influence of enzyme replacement therapy on risk of morbidity and mortality related to Anderson-Fabry disease remains to be established. This review highlights the need for continued research into the use of enzyme replacement therapy for Anderson-Fabry disease.


Assuntos
Terapia de Reposição de Enzimas/métodos , Doença de Fabry/tratamento farmacológico , Isoenzimas/administração & dosagem , alfa-Galactosidase/administração & dosagem , Doença de Fabry/enzimologia , Feminino , Humanos , Masculino , Medição da Dor , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes , Fatores de Tempo , Triexosilceramidas/análise , Triexosilceramidas/sangue
4.
Kidney Int ; 87(5): 1039-45, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25493951

RESUMO

Chronic kidney disease--mineral bone disorder (CKD-MBD) is a complex syndrome influenced by various factors, such as age, CKD etiology, uremic toxins, and dialysis modality. Although extensively studied in hemodialysis (HD) patients, only a few studies exist for peritoneal dialysis (PD) patients. Since most of these older studies contain no bone biopsy data, we studied the pattern of renal osteodystrophy in 41 prevalent PD patients. The most common presentation was adynamic bone disease (49%). There was a significant inverse association between serum sclerostin (a Wnt/ß-catenin pathway inhibitor that decreases osteoblast action and bone formation) and the bone formation rate. Bone alkaline phosphatase had the best sensitivity and specificity to detect both high- and low-turnover diseases. The comparison between nondiabetic PD and HD patients, matched by age, gender, parathyroid hormone level, and length of dialysis, revealed low 25-hydroxyvitamin D levels, worse bone mineralization, and low bone turnover in the nondiabetic PD group. Thus, adynamic bone disease was the most frequent type of renal osteodystrophy in PD patients. Sclerostin seems to participate in the pathophysiology of adynamic bone disease and bone alkaline phosphatase was the best serum marker of bone turnover in these patients.


Assuntos
Biomarcadores/sangue , Proteínas Morfogenéticas Ósseas/sangue , Remodelação Óssea , Distúrbio Mineral e Ósseo na Doença Renal Crônica/fisiopatologia , Diálise Peritoneal , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Osso e Ossos/patologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/patologia , Estudos Transversais , Feminino , Marcadores Genéticos , Humanos , Falência Renal Crônica/terapia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Calcificação Vascular
5.
Calcif Tissue Int ; 97(2): 179-92, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26087714

RESUMO

Chronic kidney disease (CKD) is generally associated with disturbances of mineral and bone metabolism. They contribute to the development of vascular calcification (VC), a strong, independent predictor of cardiovascular risk. Pyrophosphate (PPi), an endogenous inhibitor of hydroxyapatite formation, has been shown to slow the progression of VC in uremic animals. Since in patients with CKD treatment is usually initiated for already existing calcifications, we aimed to compare the efficacy of PPi therapy with that of the phosphate binder sevelamer, using a uremic apolipoprotein-E knockout mouse model with advanced VCs. After CKD creation or sham surgery, 12-week-old female mice were randomized to one sham group and four CKD groups (n = 18-19/group). Treatment was initiated 8 weeks after left nephrectomy allowing prior VC development. Uremic groups received either intraperitoneal PPi (high dose, 1.65 mg/kg or low dose, 0.33 mg/kg per day), oral sevelamer (3 % in diet), or placebo treatment for 8 weeks. Both intima and media calcifications worsened with time in placebo-treated CKD mice, based on both quantitative image analysis and biochemical measurements. Progression of calcification between 8 and 16 weeks was entirely halted by PPi treatment, as it was by sevelamer treatment. PPi did not induce consistent bone histomorphometry changes. Finally, the beneficial vascular action of PPi probably involved mechanisms different from that of sevelamer. Further studies are needed to gain more precise insight into underlying mechanisms and to see whether PPi administration may also be useful in patients with CKD and VC.


Assuntos
Difosfatos/administração & dosagem , Calcificação Vascular/patologia , Animais , Apolipoproteínas E/deficiência , Modelos Animais de Doenças , Progressão da Doença , Infusões Parenterais , Camundongos , Camundongos Knockout , Insuficiência Renal Crônica/complicações , Uremia/complicações , Calcificação Vascular/prevenção & controle
6.
J Bone Miner Metab ; 32(6): 636-44, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24442863

RESUMO

Vascular calcification (VC) is a risk factor for cardiovascular mortality in the setting of chronic kidney disease (CKD). Pyrophosphate (PPi), an endogenous molecule that inhibits hydroxyapatite crystal formation, has been shown to prevent the development of VC in animal models of CKD. However, the possibility of harmful effects of exogenous administration of PPi on bone requires further investigation. To this end, we examined by histomorphometry the bone of CKD mice after intraperitoneal PPi administration. After CKD creation or sham surgery, 10-week-old female apolipoprotein-E knockout (apoE(-/-)) mice were randomized to one non-CKD group or 4 CKD groups (n = 10-35/group) treated with placebo or three distinct doses of PPi, and fed with standard diet. Eight weeks later, the animals were killed. Serum and femurs were sampled. Femurs were processed for bone histomorphometry. Placebo-treated CKD mice had significantly higher values of osteoid volume, osteoid surface and bone formation rate than sham-placebo mice with normal renal function. Slightly higher osteoid values were observed in CKD mice in response to very low PPi dose (OV/BV, O.Th and ObS/BS) and, for one parameter measured, to high PPi dose (O.Th), compared to placebo-treated CKD mice. Treatment with PPi did not modify any other structural parameters. Mineral apposition rates, and other parameters of bone formation and resorption were not significantly different among the treated animal groups or control CKD placebo group. In conclusion, PPi does not appear to be deleterious to bone tissue in apoE(-/-) mice with CKD, although a possible stimulatory PPi effect on osteoid formation may be worth further investigation.


Assuntos
Apolipoproteínas E/genética , Densidade Óssea/efeitos dos fármacos , Soluções para Diálise/farmacologia , Difosfatos/farmacologia , Fêmur/metabolismo , Diálise Peritoneal/métodos , Insuficiência Renal Crônica/terapia , Calcificação Vascular/prevenção & controle , Animais , Densidade Óssea/genética , Feminino , Fêmur/patologia , Camundongos , Camundongos Knockout , Diálise Peritoneal/efeitos adversos , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Calcificação Vascular/etiologia , Calcificação Vascular/genética , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia
7.
Kidney Int ; 84(3): 491-500, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23594676

RESUMO

Elevated serum phosphate and fibroblast growth factor 23 (FGF23) levels are associated with cardiovascular disease (CVD) in patients with chronic renal failure (CRF). The phosphate-binder sevelamer has been shown to decrease both phosphate and FGF23, but limited data indicate that sevelamer improves CRF-related CVD, such as diastolic dysfunction, left ventricular hypertrophy (LVH), and aortic stiffness. To gain additional information, we measured the effects of sevelamer on CVD in a murine model of CRF. Groups of CRF and sham-operated mice received regular chow or 3% sevelamer-HCl in the chow for 14 weeks, starting 6 weeks after the initiation of CRF or sham operation. After the first 8 weeks of sevelamer treatment, CRF mice had decreased serum phosphate levels and an improved aortic systolic expansion rate, pulse-wave velocity, and diastolic function, although LVH remained unchanged. Following an additional 6-week course of sevelamer, LVH had not progressed. The FGF23 serum level was not reduced by sevelamer until after 14 weeks of treatment. In multiple regression analysis, serum phosphate, but not FGF23, was independently correlated with LV diastolic function and mass. Thus, sevelamer first improved aortic stiffness and diastolic dysfunction and secondarily prevented LVH in mice with CRF. The phosphate-lowering, rather than FGF23-lowering, effect appears to be responsible for the observed cardiovascular improvement.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Falência Renal Crônica/tratamento farmacológico , Poliaminas/farmacologia , Poliaminas/uso terapêutico , Rigidez Vascular/efeitos dos fármacos , Animais , Sistema Cardiovascular/fisiopatologia , Quelantes/farmacologia , Quelantes/uso terapêutico , Diástole/efeitos dos fármacos , Diástole/fisiologia , Modelos Animais de Doenças , Feminino , Fator de Crescimento de Fibroblastos 23 , Hipertrofia Ventricular Esquerda/fisiopatologia , Rim/metabolismo , Falência Renal Crônica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fosfatos/metabolismo , Análise de Onda de Pulso , Análise de Regressão , Sevelamer , Rigidez Vascular/fisiologia
8.
J Clin Med ; 11(23)2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36498703

RESUMO

Renal osteodystrophy (ROD) is a common complication of end-stage kidney disease that often starts early with loss of kidney function, and it is considered an integral part in management of patients with chronic kidney disease (CKD). Adynamic bone (ADB) is characterized by suppressed bone formation, low cellularity, and thin osteoid seams. There is accumulating evidence supporting increasing prevalence of ADB, particularly in early CKD. Contemporarily, it is not very clear whether it represents a true disease, an adaptive mechanism to prevent bone resorption, or just a transitional stage. Several co-players are incriminated in its pathogenesis, such as age, diabetes mellitus, malnutrition, uremic milieu, and iatrogenic factors. In the present review, we will discuss the up-to-date knowledge of the ADB and focus on its impact on bone health, fracture risk, vascular calcification, and long-term survival. Moreover, we will emphasize the proper preventive and management strategies of ADB that are pivotal issues in managing patients with CKD. It is still unclear whether ADB is always a pathologic condition or whether it can represent an adaptive process to suppress bone resorption and further bone loss. In this article, we tried to discuss this hard topic based on the available limited information in patients with CKD. More studies are needed to be able to clearly address this frequent ROD finding.

9.
Nephron Clin Pract ; 117(4): c363-72, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21071960

RESUMO

AIMS: To assess (a) plasma osteopontin (pOPN) in a cohort of chronic kidney disease (CKD) patients; (b) the relationship between pOPN and aortic calcification and stiffness, and (c) the association between pOPN and the overall and cardiovascular mortality risk. METHODS: pOPN, the abdominal aortic calcification score and pulse wave velocity (PWV) were determined in 94 CKD patients (68 ± 13 years; 60% males; 31% at CKD stages 2-3, 31% at stages 4-5, 38% at stage 5D), prospectively followed for mortality. RESULTS: pOPN was higher in CKD patients than in controls. Interleukin (IL)-6 (r(2) = 0.086; p = 0.004), CRP (r(2) = 0.046; p = 0.038), iPTH (r(2) = 0.065; p = 0.014), albumin (r(2) = 0.210; p < 0.0001) and statin use (r(2) = 0.038; p = 0.059) were associated with pOPN. There was no association between pOPN and the aortic calcification score or PWV. During follow-up (969 ± 405 days), 32 patients died. In crude analysis, pOPN >167 ng/ml predicted overall and cardiovascular mortality (p = 0.02 and 0.01, respectively), but this effect was lost after adjustment for albumin or IL-6. CONCLUSIONS: pOPN is elevated from the early stages of CKD onward. We found no associations between pOPN and the aortic calcification score or the PWV. The positive association between pOPN and clinical outcomes was dependent of the patients' inflammatory status.


Assuntos
Falência Renal Crônica/sangue , Falência Renal Crônica/diagnóstico , Osteopontina/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Coortes , Feminino , Seguimentos , Humanos , Falência Renal Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida/tendências
10.
Clinics (Sao Paulo) ; 76: e1821, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33624705

RESUMO

OBJECTIVES: This study aimed to evaluate the potential anti-inflammatory effects of vitamin D supplementation under uremic conditions, both in vivo and in vitro, and its effects on the parameters of mineral metabolism. METHODS: Thirty-two hemodialysis patients were randomly assigned to receive placebo (N=14) or cholecalciferol (N=18) for six months. Serum levels of calcium, phosphate, total alkaline phosphatase, intact parathyroid hormone (iPTH), and vitamin D were measured at baseline and after three and six months. The levels of fibroblast growth factor-23 (FGF-23), interleukin-1ß (IL-1ß), and high-sensitivity C-reactive protein (hs-CRP) were also measured at baseline and at six months. Human monocytes were used for in vitro experiments and treated with cholecalciferol (150 nM) and uremic serum. Cell viability, reactive oxygen species (ROS) production, and cathelicidin (CAMP) expression were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, dichloro-dihydro-fluorescein diacetate assay, and real time-quantitative polymerase chain reaction, respectively. RESULTS: Both patient groups were clinically and biochemically similar at baseline. After six months, the levels of vitamin D and iPTH were higher and lower, respectively, in the cholecalciferol group than in the placebo group (p<0.05). There was no significant difference between the parameters of mineral metabolism, such as IL-1ß and hs-CRP levels, in both groups. Treatment with uremic serum lowered the monocyte viability (p<0.0001) and increased ROS production (p<0.01) and CAMP expression (p<0.05); these effects were counterbalanced by cholecalciferol treatment (p<0.05). CONCLUSIONS: Thus, cholecalciferol supplementation is an efficient strategy to ameliorate hypovitaminosis D in hemodialysis patients, but its beneficial effects on the control of secondary hyperparathyroidism are relatively unclear. Even though cholecalciferol exhibited anti-inflammatory effects in vitro, its short-term supplementation was not effective in improving the inflammatory profile of patients on hemodialysis, as indicated by the IL-1ß and hs-CRP levels.


Assuntos
Colecalciferol , Deficiência de Vitamina D , Anti-Inflamatórios/uso terapêutico , Colecalciferol/uso terapêutico , Suplementos Nutricionais , Fator de Crescimento de Fibroblastos 23 , Humanos , Hormônio Paratireóideo/uso terapêutico , Diálise Renal , Vitamina D
11.
Mol Genet Genomic Med ; 9(5): e1666, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33835733

RESUMO

BACKGROUND: Family genetic testing of patients newly diagnosed with a rare genetic disease can improve early diagnosis of family members, allowing patients to receive disease-specific therapies when available. Fabry disease, an X-linked lysosomal storage disorder caused by pathogenic variants in GLA, can lead to end-stage renal disease, cardiac arrhythmias, and stroke. Diagnostic delays are common due to the rarity of the disease and non-specificity of early symptoms. Newborn screening and screening of at-risk populations, (e.g., patients with hypertrophic cardiomyopathy or undiagnosed nephropathies) can identify individuals with Fabry disease. Subsequent cascade genotyping of family members may disclose a greater number of affected individuals, often at younger age than they would have been diagnosed otherwise. METHODS: We conducted a literature search to identify all published data on family genetic testing for Fabry disease, and discussed these data, experts' own experiences with family genetic testing, and the barriers to this type of screening that are present in their respective countries. RESULTS: There are potential barriers that make implementation of family genetic testing challenging in some countries. These include associated costs and low awareness of its importance, and cultural and societal issues. Regionally, there are barriers associated with population educational levels, national geography and infrastructures, and a lack of medical geneticists. CONCLUSION: In this review, the worldwide experience of an international group of experts of Fabry disease highlights the issues faced in the family genetic testing of patients affected with rare genetic diseases.


Assuntos
Doença de Fabry/genética , Testes Genéticos/métodos , Doença de Fabry/diagnóstico , Testes Genéticos/normas , Humanos , Linhagem
12.
Kidney Int ; 77(6): 550-6, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20016471

RESUMO

Chronic inflammation associated with chronic kidney disease predicts all-cause and cardiovascular mortality in hemodialysis patients. Here we sought to evaluate the association between plasma levels of the inflammatory mediator interleukin-6 (IL-6) and mortality and aortic calcification/stiffness in 125 patients at different stages (2-5D) of chronic kidney disease. Using multivariate linear regression, we found that plasma IL-6 was independently associated with C-reactive protein, albumin and the stage of chronic kidney disease, but not the aortic calcification score or pulse wave velocity. During follow-up studies (median of 829 days), 38 patients died, 22 from cardiovascular events. Plasma IL-6 significantly predicted overall and cardiovascular mortality; this association persisted after multiple adjustments or restricting the analysis to pre-dialysis patients. Moreover, IL-6 was a significantly better predictor of mortality than C-reactive protein, albumin or tumor necrosis factor-alpha. Hence, plasma IL-6 independently predicted overall and cardiovascular mortality in patients at different stages of chronic kidney disease; however, whether lowering plasma IL-6 will affect the outcome of chronic kidney disease will require more direct evaluation.


Assuntos
Fatores Imunológicos/sangue , Interleucina-6/sangue , Falência Renal Crônica/sangue , Falência Renal Crônica/mortalidade , Diálise Renal/efeitos adversos , Idoso , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Feminino , Seguimentos , Humanos , Inflamação/sangue , Falência Renal Crônica/complicações , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/sangue , Fatores de Necrose Tumoral/sangue
13.
Nephrol Dial Transplant ; 25(8): 2596-602, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20190248

RESUMO

BACKGROUND: Chronic kidney disease (CKD) is associated with accelerated atherosclerosis and an inadequate inflammatory response which may account for the high morbidity and mortality observed in this population. In vitro and preclinical evidence suggests that the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) might be involved in both the atherosclerosis pathway and modulation of the inflammatory response. The aim of the present study was thus to (i) determine serum levels of soluble TRAIL (sTRAIL) in a cohort of CKD patients, (ii) assess the relationship between sTRAIL and other inflammatory biomarkers (C-reactive protein and albumin) and (iii) evaluate the association between serum sTRAIL levels and the mortality risk. METHODS: One hundred and thirty patients (mean +/- SD age: 67 +/- 12; 62% males; 8% at CKD stage 2, 26% at stage 3, 27% at stage 4, 8% at stage 5 and 31% at stage 5D) were assayed for sTRAIL and the selected biochemical parameters and then prospectively monitored for mortality. RESULTS: CKD stage 5D patients had significantly lower serum sTRAIL levels (median: 46 pg/ml) than patients at CKD stages 2 and 3 (median: 62 pg/ml) or stages 4 and 5 (median: 71 pg/ml). There was no correlation between serum sTRAIL and the estimated glomerular filtration rate (GFR) (r(2) = 0.017, P = 0.22) in pre-dialysis patients. In a multivariate regression analysis, the body mass index (beta = 1.48, P = 0.001) and the serum C-reactive protein (CRP) level (beta = -8.841, P < 0.0001) were independently associated with serum sTRAIL. During follow-up (mean: 772 +/- 286 days), 36 patients died (19 from cardiovascular events, 8 from infectious events and 9 from other causes). The lowest sTRAIL levels (first tertile) were associated with the worst all-cause survival (P = 0.010). Cox regression analyses (with non-cumulative models including age, albumin and CRP as covariates) confirmed the low serum sTRAIL level (first tertile) as an independent predictor of all-cause mortality. CONCLUSIONS: Circulating sTRAIL is a negative marker for inflammation and is inversely associated with the mortality risk in CKD patients. Further studies are needed to better understand the role of sTRAIL as an inflammatory marker and to confirm its protective role in the CKD population.


Assuntos
Inflamação/sangue , Nefropatias/sangue , Nefropatias/mortalidade , Ligante Indutor de Apoptose Relacionado a TNF/sangue , Idoso , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Doença Crônica , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Albumina Sérica/metabolismo , Taxa de Sobrevida
14.
Nephrol Dial Transplant ; 25(4): 1183-91, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19914995

RESUMO

BACKGROUND: Uraemic toxins are considered to be emerging mortality risk factors in chronic kidney disease (CKD) patients. p-Cresol (a prototype protein-bound uraemic retention solute) has been shown to exert toxic effects in vitro. Recently, it has been demonstrated that p-cresol is present in plasma as its sulphate conjugate, p-cresylsulphate. The present study evaluated the distribution of free and total p-cresylsulphate and sought to determine whether these parameters were associated with vascular calcification, arterial stiffness and mortality risk in a cohort of CKD patients. METHODS: One hundred and thirty-nine patients (mean +/- SD age: 67 +/- 12; males: 60%) at different stages of CKD (8% at Stage 2, 26.5% at Stage 3, 26.5% at Stage 4, 7% at Stage 5 and 32% at Stage 5D) were enrolled in this study. RESULTS: Baseline total and free p-cresylsulphate presented an inverse relationship with renal function and were significantly associated with vascular calcification. During the study period (mean follow-up period: 779 +/- 185 days), 38 patients died [including 22 from cardiovascular (CV) causes]. In crude survival analyses, free (but not total) p-cresylsulphate was shown to be a predictor of overall and CV death. Higher free p-cresylsulphate levels (>0.051 mg/100 mL; median) were associated with mortality independently of well-known predictors of survival such as age, vascular calcification, anaemia and inflammation. CONCLUSIONS: Serum levels of free and total p-cresylsulphate (the main in vivo circulating metabolites of p-cresol) were elevated in later CKD stages. However, only free p-cresylsulphate seems to be a predictor of survival in CKD.


Assuntos
Biomarcadores/sangue , Cresóis/sangue , Falência Renal Crônica/mortalidade , Ésteres do Ácido Sulfúrico/sangue , Idoso , Feminino , Humanos , Falência Renal Crônica/sangue , Masculino , Valor Preditivo dos Testes , Taxa de Sobrevida
15.
Semin Dial ; 22(4): 433-7, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19708996

RESUMO

Chronic kidney disease (CKD) is associated with both extensive vascular calcification and abnormal bone remodeling, namely renal osteodystrophy. Moreover, there is increasing evidence for a close relationship between bone and vessel function. Pathological vascular calcification has been recently recognized as an active, cell-mediated process with similarities to physiological skeletal mineralization. Accordingly, we described the concept of vascular remodeling, in analogy to bone remodeling. In this review, we discuss the role of uremic toxins in the cross-talk between bone and vessel, and emphasize their potential contribution to the development of both vascular and bone remodeling disorders in patients with CKD.


Assuntos
Desmineralização Patológica Óssea/etiologia , Remodelação Óssea/fisiologia , Calcinose/etiologia , Uremia/complicações , Uremia/metabolismo , Doenças Vasculares/etiologia , Humanos , Toxinas Biológicas/fisiologia , Uremia/fisiopatologia
16.
Clin Kidney J ; 11(1): 89-98, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29423208

RESUMO

BACKGROUND: Advanced glycation end products (AGEs) have been related to the pathogenesis of cardiovascular diseases (CVD), chronic kidney disease (CKD) and diabetes mellitus. We sought to investigate the binding capacity of sevelamer to both AGEs and uremic serum in vitro and then test this pharmaceutical effect as a potential vascular anti-inflammatory strategy. METHODS: AGEs were prepared by albumin glycation and characterized by absorbance and electrophoresis. Human endothelial cells were incubated in culture media containing AGEs and uremic serum with or without sevelamer. Receptor for advanced glycation end product (RAGE) expression was evaluated through immunocytochemistry and western blot to explore the interactions between AGEs and the endothelium. Inflammatory and endothelial dysfunction biomarkers, such as interleukin 6 (IL-6) and IL-8, monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1) and serum amyloid A (SAA) were also measured in cell supernatant. The chemotactic property of the supernatant was evaluated. RESULTS: AGEs significantly induced the expression of RAGE, inflammatory and endothelial activation biomarkers [IL-6, (P < 0.005); IL-8, MCP-1, PAI-1 and SAA (P < 0.001)] and monocyte chemotaxis as compared with controls. In addition, AGEs increased the levels of inflammatory biomarkers, which were observed after 6 h of endothelial cell incubation with uremic serum [IL-6 (P < 0.001) IL-8, MCP-1 and PAI-1 (P < 0.05)]. On the other hand, after 6 h of endothelial cell treatment with sevelamer, RAGE expression (P < 0.05) and levels of inflammatory biomarkers [IL-6 and IL-8 (P < 0.001), MCP-1 (P < 0.01), PAI-1 and SAA (P < 0.005)] significantly decreased compared with the AGEs/uremic serum treatment alone. CONCLUSIONS: Sevelamer decreased both endothelial expression of RAGE and endothelial dysfunction biomarkers, induced by AGEs, and uremic serum. Further studies are necessary for a better understanding of the potential protective role of sevelamer on uremic serum and AGEs-mediated endothelial dysfunction.

17.
PLoS One ; 13(5): e0197994, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29799857

RESUMO

PURPOSE: Osteoblasts and adipocytes are derived from mesenchymal stem cells. An imbalance in the differentiation of these lineages could affect the preservation of bone integrity. Several studies have suggested the importance of this imbalance in the pathogenesis of osteoporosis after kidney transplant (KT), but the role of bone marrow adiposity in this process is not well known, and if the treatment with the anti-absorptive (zoledronic acid-ZA) drugs could attenuate bone loss. Thus, our objective was compare bone marrow adiposity, osteoblasts and osteocytes before and after KT, verify an association between bone remodeling process (Turnover, Volume, and Mineralization-TMV classification), the osteocyte sclerostin expression to evaluate if there is a role of Wnt pathway, as well as the effect of ZA on these cells. METHODS: We studied 29 new living-donor KT patients. One group received ZA at the time of KT plus cholecalciferol for twelve months, and the other group received only cholecalciferol. Bone biopsies were performed at baseline and after 12 months of treatment. Histomorphometric evaluation was performed in bone and bone marrow adipocytes. Sclerostin (Scl) expression in osteocytes was evaluated by immunohistochemistry. RESULTS: Some bone marrow adiposity parameters were increased before KT. After KT, some of them remained increased and they worsened with the use of ZA. In the baseline, lower bone Volume and Turnover, were associated with increased bone marrow adiposity parameters (some of them). After KT, both groups showed the same associations. Osteocyte Scl expression after KT decreased with the use of ZA. We observed also an inverse association between bone adiposity parameters and lower osteocyte sclerostin expression 12 months after KT. CONCLUSION: In conclusion, the present study suggests that KT fails to normalize bone marrow adiposity, and it even gets worse with the use of ZA. Moreover, bone marrow adiposity is inversely associated with bone Volume and Turnover, which seems to be accentuated by the antiresorptive therapy.


Assuntos
Adiposidade/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Difosfonatos/farmacologia , Imidazóis/farmacologia , Transplante de Rim , Vitamina D/farmacologia , Adulto , Medula Óssea/fisiologia , Remodelação Óssea/efeitos dos fármacos , Calcificação Fisiológica/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Osteócitos/efeitos dos fármacos , Osteócitos/metabolismo , Proteína 1 de Leucemia Linfocítica Aguda de Células T/metabolismo , Adulto Jovem , Ácido Zoledrônico
18.
Toxins (Basel) ; 9(4)2017 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-28420181

RESUMO

Recently, the clinical and experimental evidences that support the toxic effects of indoxyl sulfate, a protein-bound uremic toxin in chronic kidney disease (CKD) patients, has been discussed. In this panorama, the authors described several in vitro and in vivo studies, suggesting that indoxyl sulfate may play a part in the pathogenesis of low turnover bone disease. However, the discussion claims the need for relevant clinical studies in CKD patients whose bone turnover biomarkers and bone histomorphometry were assessed in order to demonstrate the association between serum levels of indoxyl sulfate and bone turnover. We would like to underline the availability of this clinical data to support the concept that indoxyl sulfate may play a part in the pathogenesis of low turnover bone disease in CKD patients.


Assuntos
Indicã/sangue , Toxinas Biológicas/sangue , Biomarcadores , Humanos , Insuficiência Renal Crônica
19.
Am J Kidney Dis ; 48(3): 430-6, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16931216

RESUMO

BACKGROUND: Adynamic bone disease is a type of renal osteodystrophy characterized by low bone turnover and paucity of bone cells. It was proposed that a new type of this disease featuring high osteoclastic resorption without parathyroid hormone stimulus and designated adynamic bone disease variant occurs in hemodialysis patients. The present study is designed to evaluate the frequency and characteristics of both diseases in a large series of bone biopsy specimens. METHODS: We reviewed 1,160 bone biopsy specimens from hemodialysis patients. Specimens in which adynamic bone disease was diagnosed were selected and categorized as classic or variant based on osteoclastic surface. RESULTS: In 218 bone biopsy specimens (18.8%), adynamic bone disease was identified, whereas the variant form was identified in 35 specimens (38.8%). Biopsy specimens categorized as the variant form were from patients who were younger and had greater phosphorus and parathyroid hormone levels. Histologically, the variant form presented greater osteoid volume, fibrosis volume, osteoid surface, osteoblast surface, and eroded surface. Similarly, values for all dynamic parameters were greater in the variant group. Osteoclastic surface correlated with phosphorus level, parathyroid hormone level, and osteoblast surface. Age and osteoblast surface were identified as independent determinants of the variant form. CONCLUSION: Adynamic bone disease variant seems to occur in younger hemodialysis patients with greater levels of parathyroid hormone, which acts on cell-covered bone surfaces. It probably is a transitional phase from low- to high-turnover status, rather than a true entity within the spectrum of renal osteodystrophy.


Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica/etiologia , Diálise Renal/efeitos adversos , Adulto , Idade de Início , Biópsia , Osso e Ossos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Hormônio Paratireóideo/fisiologia , Estudos Retrospectivos
20.
Clinics ; Clinics;76: e1821, 2021. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1153986

RESUMO

OBJECTIVES: This study aimed to evaluate the potential anti-inflammatory effects of vitamin D supplementation under uremic conditions, both in vivo and in vitro, and its effects on the parameters of mineral metabolism. METHODS: Thirty-two hemodialysis patients were randomly assigned to receive placebo (N=14) or cholecalciferol (N=18) for six months. Serum levels of calcium, phosphate, total alkaline phosphatase, intact parathyroid hormone (iPTH), and vitamin D were measured at baseline and after three and six months. The levels of fibroblast growth factor-23 (FGF-23), interleukin-1β (IL-1β), and high-sensitivity C-reactive protein (hs-CRP) were also measured at baseline and at six months. Human monocytes were used for in vitro experiments and treated with cholecalciferol (150 nM) and uremic serum. Cell viability, reactive oxygen species (ROS) production, and cathelicidin (CAMP) expression were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, dichloro-dihydro-fluorescein diacetate assay, and real time-quantitative polymerase chain reaction, respectively. RESULTS: Both patient groups were clinically and biochemically similar at baseline. After six months, the levels of vitamin D and iPTH were higher and lower, respectively, in the cholecalciferol group than in the placebo group (p<0.05). There was no significant difference between the parameters of mineral metabolism, such as IL-1β and hs-CRP levels, in both groups. Treatment with uremic serum lowered the monocyte viability (p<0.0001) and increased ROS production (p<0.01) and CAMP expression (p<0.05); these effects were counterbalanced by cholecalciferol treatment (p<0.05). CONCLUSIONS: Thus, cholecalciferol supplementation is an efficient strategy to ameliorate hypovitaminosis D in hemodialysis patients, but its beneficial effects on the control of secondary hyperparathyroidism are relatively unclear. Even though cholecalciferol exhibited anti-inflammatory effects in vitro, its short-term supplementation was not effective in improving the inflammatory profile of patients on hemodialysis, as indicated by the IL-1β and hs-CRP levels.


Assuntos
Humanos , Deficiência de Vitamina D , Colecalciferol/uso terapêutico , Hormônio Paratireóideo/uso terapêutico , Vitamina D , Diálise Renal , Suplementos Nutricionais , Anti-Inflamatórios
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