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Background and Objectives: Acute kidney injury (AKI) remains a significant complication following major cardiac surgery. Marinobufagenin (MBG), a cardiotonic steroid involved in sodium balance and blood pressure regulation, has been linked to organ damage after ischemia-reperfusion events. This pilot, prospective study investigates the utility of circulating MBG to improve AKI risk assessment in cardiac surgery patients as a stand-alone biomarker and after inclusion in a validated risk model (STS-AKI score). Materials and Methods: We included 45 patients undergoing elective cardiac surgery. The MBG levels were measured preoperatively and at 4, 8, and 12 h post-surgery. The AKI was defined according to the KDIGO guidelines. Statistical analyses assessed the diagnostic and prognostic utility of MBG and its integration with the STS-AKI score. Results: An AKI occurred in 26.7% of the patients. The STS-AKI score performed well in this cohort (AUC: 0.736). The MBG levels displayed a decreasing trend in the whole population after surgery (p = 0.02). However, in the AKI patients, MBG increased at 4 and 8 h before decreasing at 12 h post-surgery. The MBG changes from the baseline to 8 h and from 8 to 12 h post-surgery showed a remarkable diagnostic accuracy for an AKI (AUCs: 0.917 and 0.843, respectively). Integrating these MBG changes with the STS-AKI score significantly improved the model performance, including discrimination, calibration, and risk reclassification. Conclusions: The MBG measurement, particularly any dynamic changes post-surgery, enhances AKI risk stratification in cardiac surgery patients. Integrating MBG with the STS-AKI score offers more accurate risk predictions, potentially leading to better patient management and outcomes.
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Lesión Renal Aguda , Biomarcadores , Bufanólidos , Procedimientos Quirúrgicos Cardíacos , Humanos , Lesión Renal Aguda/etiología , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/sangre , Lesión Renal Aguda/prevención & control , Bufanólidos/sangre , Masculino , Femenino , Estudios Prospectivos , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Anciano , Medición de Riesgo/métodos , Proyectos Piloto , Persona de Mediana Edad , Biomarcadores/sangre , Prueba de Estudio Conceptual , Complicaciones Posoperatorias/sangre , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/diagnósticoRESUMEN
BACKGROUND AND AIMS: Obesity without metabolic alterations (Metabolically Healthy Obesity, MHO) is a condition with a risk of death and cardiovascular disease lower than that of obesity associated with metabolic alterations (Metabolically Unhealthy Obesity, MUO) and similar to that of healthy non obese individuals. Inflammation is considered as a key risk factor mediating the adverse health outcomes in obesity. METHODS AND RESULTS: We compared circulating levels of thirteen major cytokines and adipokines and the expression profiles of fifteen pro-inflammatory and two anti-inflammatory genes in visceral and subcutaneous adipose tissue in a series of 16 MHO patients and in 32 MUO patients that underwent bariatric surgery. MHO was defined according to the most applied definition in current literature. Serum levels of a large set of major cytokines and adipokines did not differ between MHO and MUO patients (p ≥ 0.15). Analyses of the expression profile of pro-inflammatory and anti-inflammatory genes in subcutaneous and visceral adipose tissue failed to show differences between MHO and MUO patients (p ≥ 0.07). Sensitivity analyses applying two additional definitions of MHO confirmed the results of the primary analysis. CONCLUSION: In a series of metabolically healthy obese patients neither circulating levels of major cytokines and adipokines nor the gene expression profile of a large set of pro-inflammatory and anti-inflammatory genes in subcutaneous and visceral fat differed from those in metabolically unhealthy obese patients.
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Síndrome Metabólico , Obesidad Metabólica Benigna , Humanos , Obesidad/diagnóstico , Obesidad/genética , Inflamación/diagnóstico , Inflamación/genética , Biomarcadores/metabolismo , Obesidad Metabólica Benigna/diagnóstico , Obesidad Metabólica Benigna/genética , Obesidad Metabólica Benigna/complicaciones , Citocinas/genética , Adipoquinas/genéticaRESUMEN
Background: Acute Kidney Injury (AKI) is a frequent, dangerous complication in patients undergoing cardiopulmonary bypass (CPB) with oxidative stress playing a crucial role. In this pilot study we evaluated the possible role of the selenoprotein-p1 (SEPP1), a circulating, anti-oxidant selenium transporter, as a predictive biomarker of AKI in this population setting. Methods: Circulating SEPP1 was measured in the blood of 45 patients before surgery and at 4 h, 8 h and 12 h after CPB by Enzyme-Linked Immunosorbent Assay (ELISA). Results: SEPP1 increased from 69 [IQR 39-85] to 3263 [IQR 1886.2-5042.7] ng/mL (p for trend < 0.0001). AKI occurred in 26.7% of patients. In these individuals, an earlier and more prominent increase in SEPP1 was observed at 4 h and 8 h, as compared with those not experiencing AKI (difference between trends p < 0.0001). Logistic regression analyses evidenced 4 h and 8 h SEPP1 as significantly associated with AKI (OR 1.035; 95% CI 1.002-1.068; p = 0.03 and 1.011; 95% CI 1.002-1.021; p = 0.02, respectively). ROC analyses displayed a remarkable discriminatory capacity of early SEPP1 measurements in identifying AKI (AUCs ranging from 0.682 to 0.854; p from 0.04 to < 0.0001). In addition, 12 h-SEPP1 showed diagnostic capacity to identify patients reaching a secondary composite endpoint including major adverse kidney events (MAKEs). Conclusions: Findings from this pilot, exploratory study suggest that early SEPP1 measurement after CPB may hold great potential for improving renal risk stratification in cardiac surgery patients. Further studies in wider and more heterogeneous cohorts are needed to generalize these findings and to evaluate a possible applicability in daily practice.
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Neuropeptide Y (NPY) is a 36-amino-acid peptide member of a family also including peptide YY and pancreatic polypeptide, which are all ligands to Gi/Go coupled receptors. NPY regulates several fundamental biologic functions including appetite/satiety, sex and reproduction, learning and memory, cardiovascular and renal function and immune functions. The mesenteric circulation is a major source of NPY in the blood in man and this peptide is considered a key regulator of gut-brain cross talk. A progressive increase in circulating NPY accompanies the progression of chronic kidney disease (CKD) toward kidney failure and NPY robustly predicts cardiovascular events in this population. Furthermore, NPY is suspected as a possible player in accelerated cognitive function decline and dementia in patients with CKD and in dialysis patients. In theory, interfering with the NPY system has relevant potential for the treatment of diverse diseases from cardiovascular and renal diseases to diseases of the central nervous system. Pharmaceutical formulations for effective drug delivery and cost, as well as the complexity of diseases potentially addressable by NPY/NPY antagonists, have been a problem until now. This in part explains the slow progress of knowledge about the NPY system in the clinical arena. There is now renewed research interest in the NPY system in psychopharmacology and in pharmacology in general and new studies and a new breed of clinical trials may eventually bring the expected benefits in human health with drugs interfering with this system.
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Disfunción Cognitiva , Hipertensión Renal , Insuficiencia Renal Crónica , Disfunción Cognitiva/etiología , Humanos , Neuropéptido Y , Receptores de Neuropéptido Y , Diálisis Renal , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/terapia , Factores de RiesgoRESUMEN
BACKGROUND: Serum gamma-glutamyltransferase (GGT) is a liver enzyme involved in the metabolism of glutathione (GSH), a major antioxidant in humans. GGT is a risk factor for mortality in young and middle-aged individuals but this association has been poorly investigated in the elderly. METHODS: We studied the relationship between GGT and all-cause mortality and tested whether oxidized low-density lipoproteins (oxLDL) modify this association in a cohort of 1038 elderly individuals. RESULTS: During the observation time (median 9 years), 401 individuals died. In a Cox regression model adjusting for potential confounders, GGT was an independent risk factor for all-cause mortality [HR (20U/L increase in serum GGT): 1.11, 95% CI 1.02-1.21, P = 0.02]. Furthermore, increasing levels of oxLDL amplified the risk excess for all-cause mortality associated with GGT (P for the effect modification = 0.003). CONCLUSIONS: In the elderly, serum GGT is an independent risk factor for all-cause mortality and circulating oxLDL amplify the magnitude of this association.
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Lipoproteínas LDL , gamma-Glutamiltransferasa , Anciano , Biomarcadores , Humanos , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Factores de RiesgoRESUMEN
Background: The fibroblast growth factor 23 (FGF23) response to phosphate load is suppressed in adiponectin gene null mice and substantially amplified in mice overexpressing the same gene and vitamin D receptor (VDR) activation markedly enhances FGF23 gene expression. Methods: We performed an analysis of the static (baseline adiponectin levels) and dynamic (fluctuations in adiponectin levels) interactions of serum adiponectin with the FGF23 response to paricalcitol and placebo in the setting of a double-blind, randomized clinical trial in chronic kidney disease (CKD) patients (NCT01680198). Results: As compared with placebo, VDR activation by paricalcitol markedly increased serum FGF23 levels (P < 0.001), and such an increase was amplified in patients in the 4th adiponectin quartile as compared with other quartiles (P = 0.009) while no such an effect was noted in the placebo group (P = 0.49). Both baseline adiponectin (P for interaction = 0.009) and fluctuations in adiponectin levels following paricalcitol and placebo (P for interaction = 0.003) strongly modified the difference in the FGF23 response to these treatments. These interactions were specific because no similar effect modification by other factors with the FGF23 response to VDR activation was found. Furthermore, in a global correlation analysis, adiponectin and FGF23 were interrelated independent of the estimated glomerular filtration rate and other potential confounders (ß = 0.22, P = 0.003). Conclusions: Adiponectin is a strong modifier of the FGF23 response to VDR activation in CKD patients. The adiponectin-FGF23 link discovered in genetically engineered mice is of mechanistic relevance in the FGF23 response to VDR activation in CKD patients.
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Adiponectina/metabolismo , Ergocalciferoles/farmacología , Factores de Crecimiento de Fibroblastos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Receptores de Calcitriol/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Adiponectina/sangre , Adiponectina/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Conservadores de la Densidad Ósea/farmacología , Método Doble Ciego , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/genética , Tasa de Filtración Glomerular , Humanos , Masculino , Ratones , Persona de Mediana Edad , Fosfatos/metabolismo , Receptores de Calcitriol/genética , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/fisiopatología , Transducción de Señal , Adulto JovenRESUMEN
Insulin resistance (IR) is an early metabolic alteration in chronic kidney disease (CKD) patients, being apparent when the glomerular filtration rate is still within the normal range and becoming almost universal in those who reach the end stage of kidney failure. The skeletal muscle represents the primary site of IR in CKD, and alterations at sites beyond the insulin receptor are recognized as the main defect underlying IR in this condition. Estimates of IR based on fasting insulin concentration are easier and faster but may not be adequate in patients with CKD because renal insufficiency reduces insulin catabolism. The hyperinsulinemic euglycemic clamp is the gold standard for the assessment of insulin sensitivity because this technique allows a direct measure of skeletal muscle sensitivity to insulin. The etiology of IR in CKD is multifactorial in nature and may be secondary to disturbances that are prominent in renal diseases, including physical inactivity, chronic inflammation, oxidative stress, vitamin D deficiency, metabolic acidosis, anemia, adipokine derangement, and altered gut microbiome. IR contributes to the progression of renal disease by worsening renal hemodynamics by various mechanisms, including activation of the sympathetic nervous system, sodium retention, and downregulation of the natriuretic peptide system. IR has been solidly associated with intermediate mechanisms leading to cardiovascular (CV) disease in CKD including left ventricular hypertrophy, vascular dysfunction, and atherosclerosis. However, it remains unclear whether IR is an independent predictor of mortality and CV complications in CKD. Because IR is a modifiable risk factor and its reduction may lower CV morbidity and mortality, unveiling the molecular mechanisms responsible for the pathogenesis of CKD-related insulin resistance is of importance for the identification of novel therapeutic targets aimed at reducing the high CV risk of this condition.
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Resistencia a la Insulina/fisiología , Insuficiencia Renal Crónica/metabolismo , Progresión de la Enfermedad , Técnica de Clampeo de la Glucosa , Humanos , Inflamación/complicaciones , Inflamación/metabolismo , Estrés Oxidativo/fisiología , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/fisiopatología , Deficiencia de Vitamina D/complicacionesRESUMEN
BACKGROUND: Hyperuricemia associates with atherosclerosis complications, but it is uncertain whether this relationship is causal in nature. The urate transporter GLUT9 (encoded by the SLC2A9 gene) is a major genetic determinant of serum uric acid level in humans. Because polymorphisms are distributed randomly at mating (Mendelian randomization), studies based on GLUT9 polymorphisms may provide unconfounded assessment of the nature of the link between uric acid and atherosclerosis. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Family-based study including 449 individuals in 107 families in a genetically homogeneous population in Southern Italy. FACTOR: Serum uric acid level, rs734553 allele, and age. OUTCOME: Ultrasound biomarkers of atherosclerosis (intima-media thickness [IMT] and internal diameter) and pulse wave velocity (PWV). RESULTS: Serum uric acid level was dose-dependently associated with the T allele of rs734553, a polymorphism in SLC2A9 (P=8×10(-6)). Serum uric acid level was a strong modifier of the relationship between age and IMT in fully adjusted analyses (ß=0.33; P=0.01), whereas no such relationship was found for internal diameter (ß=-0.15; P=0.3) or PWV (ß=0.10; P=0.6). The T allele coherently associated with carotid IMT, internal diameter, and PWV and emerged as an even stronger modifier of the age-IMT and age-internal diameter relationships in both crude and fully adjusted (ß=0.40 [P<0.001] and ß=0.48 [P=0.003], respectively) analyses. LIMITATIONS: This is a hypothesis-generating study. CONCLUSIONS: Results in this family-based study implicate uric acid as an important modifier of the age-dependent risk for atherosclerosis. Trials testing uric acid-lowering interventions are needed to prove this hypothesis.
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Enfermedades de las Arterias Carótidas/sangre , Enfermedades de las Arterias Carótidas/genética , Marcadores Genéticos/fisiología , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Ácido Úrico/sangre , Rigidez Vascular/fisiología , Adulto , Alelos , Biomarcadores/sangre , Enfermedades de las Arterias Carótidas/epidemiología , Grosor Intima-Media Carotídeo , Estudios Transversales , Femenino , Humanos , Hiperuricemia/sangre , Hiperuricemia/epidemiología , Hiperuricemia/genética , Italia/epidemiología , Masculino , Persona de Mediana Edad , Polimorfismo Genético/genética , Factores de Riesgo , Rigidez Vascular/genética , Adulto JovenRESUMEN
BACKGROUND: Many publications report the prevalence of chronic kidney disease (CKD) in the general population. Comparisons across studies are hampered as CKD prevalence estimations are influenced by study population characteristics and laboratory methods. METHODS: For this systematic review, two researchers independently searched PubMed, MEDLINE and EMBASE to identify all original research articles that were published between 1 January 2003 and 1 November 2014 reporting the prevalence of CKD in the European adult general population. Data on study methodology and reporting of CKD prevalence results were independently extracted by two researchers. RESULTS: We identified 82 eligible publications and included 48 publications of individual studies for the data extraction. There was considerable variation in population sample selection. The majority of studies did not report the sampling frame used, and the response ranged from 10 to 87%. With regard to the assessment of kidney function, 67% used a Jaffe assay, whereas 13% used the enzymatic assay for creatinine determination. Isotope dilution mass spectrometry calibration was used in 29%. The CKD-EPI (52%) and MDRD (75%) equations were most often used to estimate glomerular filtration rate (GFR). CKD was defined as estimated GFR (eGFR) <60 mL/min/1.73 m(2) in 92% of studies. Urinary markers of CKD were assessed in 60% of the studies. CKD prevalence was reported by sex and age strata in 54 and 50% of the studies, respectively. In publications with a primary objective of reporting CKD prevalence, 39% reported a 95% confidence interval. CONCLUSIONS: The findings from this systematic review showed considerable variation in methods for sampling the general population and assessment of kidney function across studies reporting CKD prevalence. These results are utilized to provide recommendations to help optimize both the design and the reporting of future CKD prevalence studies, which will enhance comparability of study results.
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Biomarcadores/análisis , Tasa de Filtración Glomerular , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/fisiopatología , Muestreo , Adulto , Calibración , Europa (Continente)/epidemiología , Humanos , PrevalenciaRESUMEN
BACKGROUND: Neuropeptide Y (NPY) is a neurotransmitter expressed in both the central and peripheral nervous systems, which is involved in regulating a multitude of physiological processes ranging from arterial pressure, energy balance, the immune response and inflammation and renal electrolyte transport. In a cohort of chronic kidney disease (CKD) patients, we recently showed that high plasma NPY levels predict renal disease progression independently of hypertension and other risk factors but the causal nature of this association remains unproven. METHODS: In the same cohort of the previous study, we tested the relationship of NPY gene variability, as assessed by five single nucleotide polymorphisms (SNPs) that explained the whole gene variability, with the incidence rate of a predefined combined renal endpoint (dialysis/transplantation/estimated glomerular filtration rate reduction >30%) over a median follow up of 36âmonths (inter-quartile range 35-37âmonths) in 735 ethnically homogeneous patients with stage 2-5 CKD. RESULTS: Two variants [rs16131 (recessive model for the T risk allele: TT, n â=â563; CT + CC, n â=â172) and rs16140 (dominant model for the G risk allele: GG + CG, n â=â413; CC, n â=â322)] were coherently associated with the incidence rate of renal events [hazard ratio (HR) ranging from 1.39 to 1.57, P â≤â0.015] and this was also true when the two SNPs were jointly introduced into the same Cox model ( P â≤â0.043). The analysis of the biological interaction showed a significant synergism between the NPY rs16131 and rs16140 variants. Indeed, patients harboring NPY rs16131 TT and NPY rs16140 GG + CG risk genotypes had a much higher HR of renal events [HR: 1.80, 95% confidence interval (CI):1.16-2.79, P â=â0.009] than that expected in the absence of biological interaction under both the additive and multiplicative models and the attributable proportion due to interaction (AP) was 25% and 38% on crude and adjusted analyses, respectively. CONCLUSION: This study, based on the Mendelian randomization approach and using NPY gene variants as instrumental variables to test the link between NPY and CKD progression, is in line with findings indicating that high plasma NPY levels predict an increased risk for renal events and lend support to the hypothesis that NPY is causally involved in renal disease progression.
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Neuropéptido Y , Insuficiencia Renal Crónica , Humanos , Neuropéptido Y/genética , Insuficiencia Renal Crónica/complicaciones , Genotipo , Polimorfismo de Nucleótido Simple , Progresión de la EnfermedadRESUMEN
INTRODUCTION: Diabetic kidney disease (DKD) is a major complication in patients with diabetes and the main contributor to the chronic kidney disease (CKD) global burden. Oxidative stress is a crucial factor in DKD pathogenesis but the role of the antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) and its molecular regulators has been poorly investigated in man. RESEARCH DESIGN AND METHODS: In this case-control study, we analyzed the roles of Nrf2, a transcription factor shielding cells from oxidative stress, its repressor Kelch-like ECH-associated protein 1 (Keap1) and six microRNAs (miRNAs) that potentially suppress Nrf2. We categorized 99 participants into 3 groups: 33 non-dialysis patients with type 2 diabetes with DKD, 33 patients with type 2 diabetes without DKD and 33 control subjects and quantified the gene expression (messenger RNA (mRNA)) levels of Nrf2, Keap1 and 6 miRNAs. Moreover, we studied the correlation between gene expression levels and clinical indicators of kidney health. RESULTS: In patients with diabetes with DKD, Nrf2 mRNA levels were significantly lower than in patients without DKD (p=0.01) and controls (p=0.02), whereas no difference in Nrf2 expression levels existed between patients without DKD and controls. Conversely, in patients with and without DKD, Keap1 expression levels were significantly higher than in controls. Of the six miRNAs studied, miRNA 30e-5p showed differential expression, being markedly reduced in patients with DKD (p=0.007). Nrf2 mRNA levels directly correlated with estimated glomerular filtration rate (eGFR) in patients with DKD (r=0.34, p=0.05) and in a formal mediation analysis the eGFR emerged as the first factor in rank for explaining the difference in Nrf2 mRNA levels between patients with and without DKD. CONCLUSIONS: The observed dysregulation in the Nrf2-Keap1 axis and the unique expression pattern of miRNA30e-5p in DKD underscore the need for more focused research in this domain that can help identify novel intervention strategies for DKD in patients with type 2 diabetes.
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Diabetes Mellitus Tipo 2 , MicroARNs , Humanos , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Riñón/patología , MicroARNs/genética , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , ARN Mensajero/genéticaRESUMEN
Background: Biomarkers development for prognostication or prediction of perioperative myocardial disease is critical for the evolution of treatment options in patients undergoing cardiac surgery. The aim of our prospective monocentric study was to investigate the role of selenoprotein 1 (SEEP 1) as a potential biomarker for assessing the risk of myocardial injury after cardiac surgery. Methods: Circulating SEPP1 was measured in the blood of 45 patients before surgery and at 4 h, 8 h and 12 h after CPB by enzyme-linked immunosorbent assay (ELISA); (3) Results: circulating SEPP-1 levels measured 4 h after surgery were strongly correlated with CK-MB levels measured at 48 h (R = 0.598, p < 0.0001) and at 72 h (R = 0.308, p = 0.05). Close correlations were also found between 4 h SEPP-1 and Hs-c troponin values measured at 24 h (R = 0.532, p < 0.0001), 48 h (R = 0.348, p = 0.01) and 72 h (R = 0.377, p = 0.02), as well as with cardiopulmonary bypass (CPB) (R = 0.389, p = 0.008) and cross-clamp time (R = 0.374, p = 0.001); (4) Conclusions: Early SEPP1 measurement after CPB may hold great potential for identifying cardiac surgery patients at risk of developing perioperative myocardial injury.
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BACKGROUND: Resistin is a major adipose tissue cytokine implicated in insulin resistance, inflammation and vascular damage. This cytokine is raised in patients with end-stage kidney disease (ESKD) but the relationship between resistin and major clinical outcomes has not been investigated in this population. METHODS: We studied the mutual relationship between resistin and the two major adipokines (adiponectin and leptin) and the interaction between resistin and adiponectin (ADPN) and all-cause and cardiovascular (CV) mortality in a cohort of 231 haemodialysis patients followed up for 57 ± 44 months. RESULTS: Plasma resistin was substantially raised in ESKD patients when compared with healthy subjects (P < 0.001). On univariate analysis, resistin was related inversely to ADPN (r = -0.14, P = 0.04) and directly to C-reactive protein (r = 0.15, P = 0.03), but was largely independent of leptin (r = 0.08, P = 0.24) and the HOMA-IR index (r = -0.04, P = 0.51). During the follow-up, 165 patients died (96 for CV causes). On both univariate (all-cause mortality: P = 0.004; CV mortality P < 0.001) and multivariate (all-cause mortality: P = 0.01; CV mortality P < 0.001) Cox regression analyses, the effect of resistin on study outcomes was closely dependent on ADPN levels. There was a consistent excess risk for all-cause (P = 0.002) and CV mortality (P = 0.003) by plasma resistin (20 ng/mL) in patients in the first ADPN tertile, but no risk excess for these outcomes was apparent in patients in the third tertile. CONCLUSION: This study indicates that resistin predicts death and fatal CV events depending on plasma ADPN levels. These findings underscore the importance of the interaction among adipokines for the prediction of adverse clinical outcomes in ESKD.
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Adiponectina/sangre , Biomarcadores/sangre , Enfermedades Cardiovasculares/mortalidad , Fallo Renal Crónico/fisiopatología , Resistina/sangre , Tejido Adiposo/metabolismo , Proteína C-Reactiva/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Resistencia a la Insulina , Leptina/sangre , Masculino , Persona de Mediana Edad , Análisis de Regresión , Diálisis Renal , Tasa de SupervivenciaRESUMEN
Genetic association studies, testing the relationship between genetic variants and disease status, are useful tools for identifying genes that grant susceptibility to complex disorders. In such studies, an inadequate sample size may provide unreliable results: a small sample is unable to accurately describe the population, whereas a large sample makes the study expensive and complex to run. However, in genetic association studies, the sample size calculation is often overlooked or inadequately assessed for the small number of parameters included. In light of this, herein we list and discuss the role of the statistical and genetic parameters to be considered in the sample size calculation, show examples reporting incorrect estimation and, by using a genetic software program, we provide a practical approach for the assessment of the adequate sample size in a hypothetical study aimed at analyzing a gene-disease association.
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Although the gut microbiota is known to affect body weight, its relationship with overweight/obesity is unclear. Our aim was to characterize microbiota composition in a cohort from the southernmost area of Italy. We investigated whether an altered gut microbiota could play an etiological role in the pathogenesis of overweight/obesity. A total of 163 healthy adults were enrolled. Microbiome analysis was performed via 16S rRNA gene sequencing. We found significant phylum variations between overweight (N = 88) and normal-weight (N = 75) subjects. Bacteroidetes and Proteobacteria were higher in overweight participants (p = 0.004; p = 0.03), and Firmicutes and Verrucomicrobia were lower (p = 0.02; p = 0.008) compared to normal-weight participants. Additionally, Akkermansia and Bifidobacterium (genus level) were significantly lower in the overweight group, as well as Akkermansia muciniphila at the species level. The Firmicutes/Bacteroidetes ratio (F/B ratio), an index of dysbiosis, was found to be inversely associated with BMI in linear and logistic regression models (p = 0.001; p = 0.005). The association remained statistically significant after adjustment for potential confounders. This cross-sectional study contributes to defining the gut microbiota composition in an adult population living in southern Italy. It confirms the relationship between overweight susceptibility and the dysbiosis status, highlighting the possible etiological role of the F/B ratio in disease susceptibility.
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Microbioma Gastrointestinal , Sobrepeso , Adulto , Humanos , Sobrepeso/complicaciones , Microbioma Gastrointestinal/genética , Disbiosis/microbiología , ARN Ribosómico 16S/genética , Estudios Transversales , Obesidad/complicaciones , Firmicutes/genética , Bacteroidetes/genética , Verrucomicrobia , Heces/microbiologíaRESUMEN
BACKGROUND: Left ventricular hypertrophy (LVH) and insulin resistance (IR) are frequent complications of end-stage renal disease (ESRD). The ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) gene, whose variability has been repeatedly associated with IR, codes for a membrane glycoprotein which inhibits insulin-receptor signalling. METHODS: We investigated the relationship of ENPP1 variability, as indicated by 10 single nucleotide polymorphisms (SNPs) representative of the gene haploblock structure, with left ventricular mass and geometry (by echocardiography) in an ethnically homogeneous series of 238 Caucasian ESRD patients. RESULTS: ENPP1 rs1974201 and rs9402349 polymorphisms were coherently associated (P ranging from 0.04 to 0.005) with indicators of left ventricular (LV) myocardial hypertrophy (mean wall thickness) and concentric remodelling (relative wall thickness and LV mass-to-volume ratio) but unrelated with the cavitary component of the LV (left ventricular end-diastolic volume). As compared to individuals carrying the alternative genotypes, the risk of LV concentric remodelling was approximately doubled in major allele homozygous for rs1974201 [odds ratio (OR) of GG versus GC + CC: 2.31, 95% confidence interval (CI): 1.30-4.12, P = 0.004] and rs9402349 (OR of AA versus AC + CC: 1.91, 95% CI: 1.02-3.56, P = 0.04) polymorphisms. CONCLUSIONS: Coherent associations exists between echocardiographic parameters of LV myocardial hypertrophy and concentric remodelling and ENPP1 variability in ESRD patients. These data support the hypothesis that IR is a relevant factor in the pathogenesis of myocardiopathy in this population.
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Predisposición Genética a la Enfermedad/epidemiología , Hipertrofia Ventricular Izquierda/genética , Resistencia a la Insulina/genética , Fallo Renal Crónico/genética , Hidrolasas Diéster Fosfóricas/genética , Pirofosfatasas/genética , Remodelación Ventricular/genética , Anciano , Distribución de Chi-Cuadrado , Estudios de Cohortes , Ecocardiografía/métodos , Femenino , Genotipo , Pruebas de Función Cardíaca , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/epidemiología , Incidencia , Fallo Renal Crónico/epidemiología , Fallo Renal Crónico/terapia , Pruebas de Función Renal , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Polimorfismo Genético , Pronóstico , Diálisis Renal/métodos , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Población Blanca/genéticaRESUMEN
BACKGROUND: Left ventricular hypertrophy (LVH) is a major cardiovascular (CV) complication in patients with kidney failure, and an association between polymorphisms in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene, a genetic marker of insulin resistance, and LVH and Left ventricular (LV) concentric remodelling has been recently documented in these patients. Aims. Since myocardial fibrosis is a prominent feature in LVH induced by insulin resistance, we tested the hypothesis that the interaction between ENPP1 rs1974201 and rs9402349 polymorphisms and the tissue inhibitor of metalloproteinases (TIMP-1)--a pro-fibrotic protein which inhibits extracellular matrix degradation--is implicated in concentric LVH and diastolic dysfunction in a cohort of 223 dialysis patients. RESULTS: Both ENPP1 polymorphisms rs1974201 and rs9402349 were in Hardy-Weinberg equilibrium in dialysis patients. In an analysis stratified by ENPP1, rs1974201 polymorphism, circulating levels of TIMP-1 in GG patients were coherently associated with two markers of concentric remodelling [relative wall thickness (RWT) and LV mass-to-volume ratio] as well as with a marker of diastolic dysfunction (E/A ratio) (P ranging from 0.005 to 0.02), whereas no such associations existed in CC or CG patients. These observations suggest that the rs1974201 modifies the relationship between TIMP-1 and LV geometry and diastolic dysfunction. Accordingly, in a multiple regression model, an identical increase of TIMP-1 (100 ng/mL) was associated with an increase of 22% in RWT, 14% in LV mass-to-volume ratio and 29% in E/A ratio in GG patients but with almost no change (from -0.22 to -3.78%) in these echocardiographic indices in the remaining patients (P for the effect modification ≤ 0.024). The rs9402349 did not modify the relationship between TIMP-1 and LV geometry and function. CONCLUSIONS: In dialysis patients, the ENPP1 rs1974201 polymorphism modifies the association between TIMP-1 and LV geometry and diastolic function. These results are consistent with the hypothesis that insulin resistance is involved not only in LVH but also in myocardial fibrosis, an alteration of primary importance in the high risk of this population.
Asunto(s)
Cardiomiopatías/etiología , Marcadores Genéticos/genética , Hipertrofia Ventricular Izquierda/etiología , Resistencia a la Insulina/genética , Insuficiencia Renal/complicaciones , Inhibidor Tisular de Metaloproteinasa-1/sangre , Disfunción Ventricular Izquierda/etiología , Cardiomiopatías/diagnóstico , Estudios de Cohortes , Ecocardiografía , Femenino , Estudios de Seguimiento , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico , Masculino , Persona de Mediana Edad , Hidrolasas Diéster Fosfóricas/genética , Polimorfismo Genético/genética , Pronóstico , Pirofosfatasas/genética , Remodelación VentricularRESUMEN
BACKGROUND: Polymorphisms in the FTO (fat-mass and obesity-associated) gene have been associated with the body mass index, cancer, type 2 diabetes and hypertension. METHODS: We investigated the relationship between 17 tag single-nucleotide polymorphisms (SNPs) and all-cause mortality in three cohorts of dialysis patients (CREED-1, North Apulian and CREED-2 cohorts; n = 783) and in one cohort of stage 2-5 CKD patients (n = 757). RESULTS: We first explored the association between the 17 tag SNPs and all-cause mortality in the CREED-1 cohort and found that patients with the A allele of the FTO rs708259 polymorphism had an elevated risk of mortality (hazard ratio, HR: 1.52, 95% confidence interval (CI) 1.11-2.08; P = 0.008). Similarly, the A allele was associated with an increased risk of death also in the other two dialysis cohorts (North Apulian cohort, risk: +23%; CREED-2 cohort, risk: +21%). The elevated risk portended by this allele was even higher in the stage 2-5 CKD cohort (+97%). However, the risk of mortality associated with the A allele in the three confirmatory cohorts failed to achieve formal statistical significance. In a meta-analysis including the four cohorts (n = 1540; total deaths, n = 381), individuals with the A allele had a 42% excess risk of death (HR: 1.42, 95% CI 1.14-1.76, P = 0.002). CONCLUSION: The A allele of the FTO rs708259 polymorphism is an independent predictor of all-cause mortality in patients with CKD of various severity. These data support our hypothesis that the FTO gene may be a relevant genetic risk factor for mortality in this population.