RESUMO
Fibroblast growth factor 23 (FGF23) levels are often elevated in chronic kidney disease (CKD). FGF23 and inflammation are common characteristics in CKD, and both are associated with worse disease progression and the occurrence of complications. The existence of an interaction between FGF23 and inflammation has been suggested, each of which influences the expression and activity of the other, leading to a vicious feedback loop with adverse outcomes, including cardiovascular disease and mortality. In this work, we determined circulating FGF23 levels in a group of patients with CKD stages 3 and 4 subjected to elective femoral endarterectomy due to established peripheral artery disease (PAD), a condition resulting from an athero-inflammatory process, and we studied its associations with different inflammatory markers and mediators. We evaluated its association with serum tumor necrosis factor (TNF)α, interleukin (IL) 6, and IL10, as well as with the gene expression levels of these parameters and A disintegrin and metalloproteinase domain-containing protein (ADAM) 17 in femoral vascular tissue and peripheral blood circulating cells (PBCCs). We also analyzed its association with serum concentrations of C-reactive protein (CRP), the systemic immune inflammation index (SII), and the neutrophil-to-lymphocyte ratio (NLR). Finally, we determined the vascular immunoreactivity of protein TNFα in a subgroup of patients. FGF23 concentrations were independently associated with circulating and PBCC mRNA levels of TNFα. Worst kidney function and diabetes were also found to be contributing to FGF23 levels. Patients with higher levels of FGF23 also had greater vascular immunoreactivity for TNFα.
Assuntos
Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos , Doença Arterial Periférica , Insuficiência Renal Crônica , Humanos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/metabolismo , Doença Arterial Periférica/sangue , Doença Arterial Periférica/metabolismo , Doença Arterial Periférica/etiologia , Masculino , Feminino , Idoso , Fatores de Crescimento de Fibroblastos/sangue , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Proteína ADAM17/metabolismo , Proteína ADAM17/sangue , Proteína ADAM17/genética , Interleucina-6/sangue , Interleucina-10/sangue , Inflamação/sangue , Inflamação/metabolismoRESUMO
Cardiovascular disease is the leading cause of death worldwide. New therapeutic strategies are aimed to modulate the athero-inflammatory process that partially orchestrates underlying vascular damage. Peripheral blood circulating cells include different immune cells with a central role in the development of the atherogenic inflammatory response. The anti-aging protein α-Klotho has been related to protective effects against CVD. KL is expressed in monocytes, macrophages, and lymphocytes where it exerts anti-inflammatory effects. In this work, we analyse the relationships of the levels of inflammatory markers with the expression of the KL gene in PBCCs and with the serum levels of soluble KL in atherosclerotic vascular disease. For this, we conducted a cross-sectional single-center case-control study including a study group of 76 CVD patients and a control group of 16 cadaveric organ donors without medical antecedent or study indicating CVD. Vascular artery fragments and whole blood and serum samples were obtained during elective or organ retrieval surgery. Serum levels of sKL, TNFα and IL10, and gene expression levels of KL, TNF, IL10, NFKB1, DNMT1, and DNMT3A in PBCCs were measured. In these cells, we also determined KL promoter methylation percentage. Histological and immunohistochemical analyses were employed to visualize atherosclerotic lesions and to measure IL10 and TNFα levels in vascular fragments. Patients with CVD presented higher values of proinflammatory markers both at systemic and in the vasculature and in the PBCCs, compared to the control group. In PBCCs, CVD patients also presented lower gene expression levels of KL gene (56.4% difference, P < 0.001), higher gene expression levels of DNMT1 and DNMT3A (P < 0.0001, for both) and a higher methylation status of in the promoter region of KL (34.1 ± 4.1% vs. 14.6 ± 3.4%, P < 0.01). In PBCCs and vasculature, KL gene expression correlated inversely with pro-inflammatory markers and directly with anti-inflammatory markers. sKL serum levels presented similar associations with the expression levels of pro- and anti-inflammatory markers in PBCCs. The differences in KL expression levels in PBCCs and in serum sKL levels with respect to control group was even greater in those CVD patients with macroscopically observable atheromatous plaques. We conclude that promoter methylation-mediated downregulation of KL gene expression in PBCCs is associated with the pro-inflammatory status in atherosclerotic vascular disease.
Assuntos
Aterosclerose , Doenças Cardiovasculares , Aterosclerose/genética , Biomarcadores , Estudos de Casos e Controles , Estudos Transversais , Glucuronidase/metabolismo , Humanos , Inflamação/genética , Inflamação/metabolismo , Interleucina-10 , Proteínas Klotho , Fator de Necrose Tumoral alfa/genéticaRESUMO
INTRODUCTION: Hospital malnutrition is very common and worsens the clinical course of patients while increasing costs. Lacking clinical-economic studies on the implementation of nutrition screening encouraged the evaluation of the CIPA (Control of Food Intake, Protein, Anthropometry) tool. MATERIAL AND METHODS: An open, non-randomized, controlled clinical trial was conducted on patients admitted to internal medicine and general and digestive surgery wards, who were either assigned to a control (standard hospital clinical care) or to an intervention, CIPA-performing ward (412 and 411, respectively; n = 823). Length of stay, mortality, readmission, in-hospital complications, and quality of life were evaluated. Cost-effectiveness was analysed in terms of cost per quality-adjusted life years (QALYs). RESULTS: The mean length of stay was higher in the CIPA group, though not significantly (+ 0.95 days; p = 0.230). On the surgical ward, more patients from the control group moved to critical care units (p = 0.014); the other clinical variables did not vary. Quality of life at discharge was similar (p = 0.53), although slightly higher in the CIPA group at 3 months (p = 0.089). Patients under CIPA screening had a higher mean cost of 691.6 and a mean QALY gain over a 3-month period of 0.0042. While the cost per QALY for the internal medicine patients was 642 282, the results for surgical patients suggest that the screening tool is both less costly and more effective. CONCLUSIONS: The CIPA nutrition screening tool is likely to be cost-effective in surgical but not in internal medicine patients.
RESUMO
Decrease in soluble anti-aging Klotho protein levels is associated to cardiovascular disease (CVD). Diverse studies have shown a bidirectional relationship between Klotho and inflammation, a risk factor for the development of CVD. In this work we aimed to evaluate the association between Klotho and inflammatory cytokines levels in the context of human CVD.The study included 110 patients with established CVD and preserved renal function, and a control group of 22 individuals without previous history of cardiovascular events. Serum Klotho and IL10 levels were significantly lower in the CVD group. Inflammatory status, marked by the TNFα/IL10 ratio and the C-reactive protein (CRP) levels, was significantly increased in the group of patients with established CVD. Soluble Klotho levels were directly correlated with eGFR (r=0.217) and IL10 (r=0.209) and inversely correlated with age (r=-0.261), CRP (r=-0.203), and TNFα/IL10 (r=-0.219). This association with TNFα/IL10 remained significant in age-matched subgroups. Multiple logistic regression analysis showed that age, smoking and the neutrophil-to-lymphocyte ratio (NLR) constituted risk factors for the presence of CVD, while Klotho was a protective factor.In conclusion, in patients with established CVD, the reduction in soluble Klotho is associated with a pro-inflammatory status marked by lower IL10 concentrations and higher TNFα/IL10 ratio and CRP levels.
Assuntos
Biomarcadores , Doenças Cardiovasculares/sangue , Citocinas/sangue , Glucuronidase/sangue , Mediadores da Inflamação/sangue , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/terapia , Estudos de Casos e Controles , Comorbidade , Feminino , Humanos , Proteínas Klotho , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de RiscoRESUMO
Atherosclerosis is a chronic inflammatory disorder affecting the artery wall. Klotho, an anti-aging factor expressed in the vessel walls that participates in the maintenance of vascular homeostasis, can be down-regulated by inflammation. In this proof-of-concept work we seek to characterize the arterial KLOTHO expression in the vascular wall, as well as the serum concentration of this protein, in a group of patients with clinical atherosclerotic disease. In addition, we aim to analyze the relationship between Klotho and inflammation. Vascular samples were obtained from 27 patients with atherosclerotic disease under an elective vascular surgery procedure, and from 11 control subjects (cadaveric organ donation programme). qRT-PCR was performed to analyze the gene expression of KLOTHO, TNF-α, IL-6, and IL-10 Serum levels of soluble KLOTHO were measured by ELISA. As compared with control subjects, serum concentrations and vascular expression of Klotho were lower in patients with atherosclerotic vascular disease, whereas inflammatory status was significantly higher. There was a negative and significant correlation between inflammatory parameters and Klotho. After controlling for the effect of other variables, partial correlation showed a direct relationship between vascular KLOTHO gene expression and IL-10 mRNA levels, whereas there was a negative association with serum LDL concentrations and vascular TNF-α expression. Our study indicates an inverse interrelationship between inflammation and Klotho in atherosclerosis. Further studies are necessary to elucidate whether the inflammatory state causes Klotho deficiency or, on the contrary, reduction of Klotho could be responsible for greater inflammation, and finally, to investigate the potential clinical relevance of this association.
Assuntos
Aterosclerose/genética , Aterosclerose/metabolismo , Expressão Gênica/fisiologia , Glucuronidase/metabolismo , Inflamação/metabolismo , Feminino , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Glucuronidase/deficiência , Glucuronidase/genética , Humanos , Inflamação/genética , Interleucina-10/sangue , Proteínas Klotho , Masculino , Insuficiência Renal Crônica/sangue , Solubilidade , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND AND OBJECTIVES: Paricalcitol, a selective vitamin D receptor activator, is used to treat secondary hyperparathyroidism in kidney transplant patients. Experimental and clinical studies in non-transplant kidney disease patients have found this molecule to have anti-inflammatory properties. In this exploratory study, we evaluated the anti-inflammatory profile of paricalcitol in kidney-transplant recipients. METHODS: Thirty one kidney transplant recipients with secondary hyperparathyroidism completed 3 months of treatment with oral paricalcitol (1µg/day). Serum concentrations and gene expression levels of inflammatory cytokines in peripheral blood mononuclear cells were analysed at the beginning and end of the study. RESULTS: Paricalcitol significantly decreased parathyroid hormone levels with no changes in calcium and phosphorous. It also reduced serum concentrations of interleukin (IL)-6 and tumour necrosis factor-alpha (TNF-α) by 29% (P<0.05) and 9.5% (P<0.05) compared to baseline, respectively. Furthermore, gene expression levels of IL-6 and TNF-α in peripheral blood mononuclear cells decreased by 14.1% (P<0.001) and 34.1% (P<0.001), respectively. The ratios between pro-inflammatory cytokines (TNF-α and IL-6) and anti-inflammatory cytokines (IL-10), both regarding serum concentrations and gene expression, also experienced a significant reduction. CONCLUSIONS: Paricalcitol administration to kidney transplant recipients has been found to have beneficial effects on inflammation, which may be associated with potential clinical benefits.
Assuntos
Anti-Inflamatórios/uso terapêutico , Citocinas/sangue , Ergocalciferóis/uso terapêutico , Hiperparatireoidismo Secundário/tratamento farmacológico , Transplante de Rim , Complicações Pós-Operatórias/tratamento farmacológico , Adulto , Idoso , Anti-Inflamatórios/farmacologia , Proteína C-Reativa/análise , Citocinas/biossíntese , Citocinas/genética , Ergocalciferóis/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hiperparatireoidismo Secundário/sangue , Hiperparatireoidismo Secundário/etiologia , Inflamação , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Receptores de Calcitriol/agonistasRESUMO
BACKGROUND: Malnutrition is highly prevalent in hospitalized patients and results in a worsened clinical course as well as an increased length of stay, mortality, and costs. Therefore, simple nutrition screening systems, such as CIPA (control of food intake, protein, anthropometry), may be implemented to facilitate the patient's recovery process. The aim of this study is to evaluate the effectiveness and cost-effectiveness of implementing such screening tool in a tertiary hospital, consistent with the lack of similar, published studies on any hospital nutrition screening system. METHODS: The present study is carried out as an open, controlled, randomized study on patients that were admitted to the Internal Medicine and the General and Digestive Surgery ward; the patients were randomized to either a control or an intervention group (n = 824, thereof 412 patients in each of the two study arms). The control group underwent usual inpatient clinical care, while the intervention group was evaluated with the CIPA screening tool for early detection of malnutrition and treated accordingly. CIPA nutrition screening was performed upon hospital admission and classified positive when at least one of the following parameters was met: 72 h food intake control < 50%, serum albumin < 3 g/dL, body mass index < 18.5 kg/m2 (or mid-upper arm circumference ≤ 22.5 cm). In this case, the doctor decided on whether or not providing nutrition support. The following variables will be evaluated: hospital length of stay (primary endpoint), mortality, 3-month readmission, and in-hospital complications. Likewise, the quality of life questionnaires EQ-5D-5 L are being collected for all patients at hospital admission, discharge, and 3 months post-discharge. Analysis of cost-effectiveness will be performed by measuring effectiveness in terms of quality-adjusted life years (QALYs). The cost per patient will be established by identifying health care resource utilization; cost-effectiveness will be determined through the incremental cost-effectiveness ratio (ICER). We will calculate the incremental cost per QALY gained with respect to the intervention. DISCUSSION: This ongoing trial aims to evaluate the cost-effectiveness of implementing the malnutrition screening tool CIPA in a tertiary hospital. TRIAL REGISTRATION: Clinical Trial.gov ( NCT02721706 ). First receivevd: March 1, 2016 Last updated: April 8, 2017 Last verified: April 2017.