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1.
N Engl J Med ; 2024 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-39453837

RESUMO

BACKGROUND: In the EMPA-KIDNEY trial, empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, had positive cardiorenal effects in patients with chronic kidney disease who were at risk for disease progression. Post-trial follow-up was designed to assess how the effects of empagliflozin would evolve after the discontinuation of the trial drug. METHODS: In the active trial, patients with chronic kidney disease were randomly assigned to receive either empagliflozin (10 mg once daily) or matching placebo and were followed for a median of 2 years. All the patients had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m2 of body-surface area or an eGFR of at least 45 but less than 90 ml per minute per 1.73 m2 with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Subsequently, surviving patients who consented were observed for 2 additional years. No trial empagliflozin or placebo was administered during the post-trial period, but local practitioners could prescribe open-label SGLT2 inhibitors, including open-label empagliflozin. The primary composite outcome was kidney disease progression or cardiovascular death as assessed from the start of the active-trial period to the end of the post-trial period. RESULTS: Of the 6609 patients who had undergone randomization in the active trial, 4891 (74%) were enrolled in the post-trial period. During this period, the use of open-label SGLT2 inhibitors was similar in the two groups (43% in the empagliflozin group and 40% in the placebo group). During the combined active- and post-trial periods, a primary-outcome event occurred in 865 of 3304 patients (26.2%) in the empagliflozin group and in 1001 of 3305 patients (30.3%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.72 to 0.87). During the post-trial period only, the hazard ratio for a primary-outcome event was 0.87 (95% CI, 0.76 to 0.99). During the combined periods, the risk of kidney disease progression was 23.5% in the empagliflozin group and 27.1% in the placebo group; the risk of the composite of death or end-stage kidney disease was 16.9% and 19.6%, respectively; and the risk of cardiovascular death was 3.8% and 4.9%, respectively. There was no effect of empagliflozin on death from noncardiovascular causes (5.3% in both groups). CONCLUSIONS: In a broad range of patients with chronic kidney disease at risk for progression, empagliflozin continued to have additional cardiorenal benefits for up to 12 months after it was discontinued. (Funded by Boehringer Ingelheim and others; EMPA-KIDNEY ClinicalTrials.gov number, NCT03594110; EuDRACT number, 2017-002971-24.).

2.
N Engl J Med ; 388(2): 117-127, 2023 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-36331190

RESUMO

BACKGROUND: The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. METHODS: We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m2 of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m2 with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to <10 ml per minute per 1.73 m2, a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) or death from cardiovascular causes. RESULTS: A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P<0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P = 0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. CONCLUSIONS: Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo. (Funded by Boehringer Ingelheim and others; EMPA-KIDNEY ClinicalTrials.gov number, NCT03594110; EudraCT number, 2017-002971-24.).


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Compostos Benzidrílicos/efeitos adversos , Compostos Benzidrílicos/uso terapêutico , Doenças Cardiovasculares/induzido quimicamente , Creatinina/urina , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Progressão da Doença , Taxa de Filtração Glomerular , Rim/fisiopatologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
3.
J Am Soc Nephrol ; 35(2): 202-215, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38082486

RESUMO

SIGNIFICANCE STATEMENT: SGLT2 inhibitors reduce risk of kidney progression, AKI, and cardiovascular disease, but the mechanisms of benefit are incompletely understood. Bioimpedance spectroscopy can estimate body water and fat mass. One quarter of the EMPA-KIDNEY bioimpedance substudy CKD population had clinically significant levels of bioimpedance-derived "Fluid Overload" at recruitment. Empagliflozin induced a prompt and sustained reduction in "Fluid Overload," irrespective of sex, diabetes, and baseline N-terminal pro B-type natriuretic peptide or eGFR. No significant effect on bioimpedance-derived fat mass was observed. The effects of SGLT2 inhibitors on body water may be one of the contributing mechanisms by which they mediate effects on cardiovascular risk. BACKGROUND: CKD is associated with fluid excess that can be estimated by bioimpedance spectroscopy. We aimed to assess effects of sodium glucose co-transporter 2 inhibition on bioimpedance-derived "Fluid Overload" and adiposity in a CKD population. METHODS: EMPA-KIDNEY was a double-blind placebo-controlled trial of empagliflozin 10 mg once daily in patients with CKD at risk of progression. In a substudy, bioimpedance measurements were added to the main trial procedures at randomization and at 2- and 18-month follow-up visits. The substudy's primary outcome was the study-average difference in absolute "Fluid Overload" (an estimate of excess extracellular water) analyzed using a mixed model repeated measures approach. RESULTS: The 660 substudy participants were broadly representative of the 6609-participant trial population. Substudy mean baseline absolute "Fluid Overload" was 0.4±1.7 L. Compared with placebo, the overall mean absolute "Fluid Overload" difference among those allocated empagliflozin was -0.24 L (95% confidence interval [CI], -0.38 to -0.11), with similar sized differences at 2 and 18 months, and in prespecified subgroups. Total body water differences comprised between-group differences in extracellular water of -0.49 L (95% CI, -0.69 to -0.30, including the -0.24 L "Fluid Overload" difference) and a -0.30 L (95% CI, -0.57 to -0.03) difference in intracellular water. There was no significant effect of empagliflozin on bioimpedance-derived adipose tissue mass (-0.28 kg [95% CI, -1.41 to 0.85]). The between-group difference in weight was -0.7 kg (95% CI, -1.3 to -0.1). CONCLUSIONS: In a broad range of patients with CKD, empagliflozin resulted in a sustained reduction in a bioimpedance-derived estimate of fluid overload, with no statistically significant effect on fat mass. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03594110 ; EuDRACT: 2017-002971-24 ( https://eudract.ema.europa.eu/ ).


Assuntos
Diabetes Mellitus Tipo 2 , Glucosídeos , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Desequilíbrio Hidroeletrolítico , Humanos , Diabetes Mellitus Tipo 2/complicações , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Pressão Sanguínea , Compostos Benzidrílicos/efeitos adversos , Insuficiência Renal Crônica/tratamento farmacológico , Água , Método Duplo-Cego
4.
Artigo em Inglês | MEDLINE | ID: mdl-39277784

RESUMO

BACKGROUND AND HYPOTHESIS: Hyperuricaemia and gout are common in chronic kidney disease (CKD). We aimed to assess the effects of sodium-glucose co-transporter-2 (SGLT2) inhibition on uric acid (urate) and gout in patients with CKD. METHODS: The EMPA-KIDNEY trial randomised 6609 patients with CKD (estimated glomerular filtration rate [eGFR] ≥20 and <90 mL/min/1.73m2) to receive either empagliflozin 10 mg daily or matching placebo over a median of two years follow-up. Serum uric acid was measured at randomisation then 2 and 18 months of follow-up and the effects of empagliflozin were analysed using a pre-specified mixed model repeated measures approach. Participant-reported gout events were analysed in Cox regression models (first events) with the Andersen-Gill extension (total events). A post-hoc composite outcome included new initiation of uric acid lowering therapy or colchicine. EMPA-KIDNEY primary and kidney disease progression outcomes were also assessed in subgroups of baseline serum uric acid. RESULTS: Baseline mean ± SD serum uric acid concentration was 431±114 µmol/L. Allocation to empagliflozin resulted in a study-average between-group difference in serum uric acid of -25.6 (95%CI -30.3,-21.0) µmol/L with larger effects in those with higher eGFR (trend P < 0.001) and without diabetes (heterogeneity P < 0.001). Compared to placebo, empagliflozin did not significantly reduce first or total gout events (HR 0.87, 95%CI 0.74-1.02 for the 595 first events, and 0.86, 0.72-1.03 for the 869 total events) with similar hazard ratios for the post-hoc composite and across subgroups, including by diabetes and eGFR. The effect of empagliflozin on the primary outcome and kidney disease progression outcomes were similar irrespective of baseline level of uric acid. CONCLUSION: SGLT2 inhibition reduces serum uric acid in patients with CKD with larger effects at higher eGFR and in the absence of diabetes. However, the effect on uric acid is modest and did not translate into reduced risk of gout in EMPA-KIDNEY.

5.
Nutr Metab Cardiovasc Dis ; 34(8): 1874-1878, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38664124

RESUMO

BACKGROUND AND AIMS: While serum osteopontin (OPN)'s established role in cardiometabolic risk is recognized, its potential as a predictor of metabolic syndrome (MetS) improvement through a urine assay has not yet been demonstrated. In this study, we propose its potential predictive role over a 12-month period of standard care, with the ability to complement anthropometric measures. METHODS AND RESULTS: Hierarchical clustering revealed a notable association of urinary OPN (uOPN) with MetS criteria and overcame anthropometric measures in predicting the improvement at 12 months (OR of 2.74 [95% CI 1.32 to 6.29]). uOPN significantly contributed to the homogeneity of the nodes in the random forest and ultimately enhanced the performance of anthropometric measures when assessed for accuracy and area under the curve (AUC). CONCLUSION: Our findings offer insights into potential applications in cardiometabolic medicine for uOPN, which is easily detectable in non-invasive biological samples through an affordable assay.


Assuntos
Biomarcadores , Síndrome Metabólica , Osteopontina , Valor Preditivo dos Testes , Urinálise , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/urina , Síndrome Metabólica/sangue , Humanos , Osteopontina/urina , Osteopontina/sangue , Masculino , Feminino , Biomarcadores/urina , Biomarcadores/sangue , Pessoa de Meia-Idade , Fatores de Tempo , Adulto , Resultado do Tratamento , Idoso , Fatores de Risco Cardiometabólico
6.
Nutr Metab Cardiovasc Dis ; 33(8): 1591-1598, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37263913

RESUMO

BACKGROUND AND AIMS: The CHA2DS2-VASc score estimates the risk of cardioembolism in patients with atrial fibrillation (AF). It also predicts vascular events and death in different clinical settings, even in the absence of AF. The R2CHA2DS2-VASc score, obtained by adding the glomerular filtration rate to CHA2DS2-VASc, shows a higher prediction ability for new events and all-cause mortality. The present study aims to assess whether the addition of albuminuria to R2CHA2DS2-VASc score further improves its discrimination ability in predicting all-cause mortality in a sample of high cardiovascular risk population. METHODS AND RESULTS: Prospective, monocentric, observational study, evaluating a subset of 737 subjects consecutively undergoing to coronary angiography at Coronary Unit of Scientific Institute "Casa Sollievo della Sofferenza" from June 2016 to December 2018. The presence of albuminuria was significantly associated with all-cause mortality (p < 0.0001). Any one-point increase of Alb-R2CHA2DS2-VASc score increased mortality of about 1.5-fold (adjusted HR 1.49; 95%CI: 1.37-1.63; p < 0.0001). Considering tertiles of Alb-R2CHA2DS2-VASc, the third tertile showed a 9.5-fold increased risk of mortality (HR 9.52; 95% CI: 5.15-17.60, p < 0.001). Comparing the two scores, the Alb-R2CHA2DS2-VASc score (C-statistic = 0.751; 95%CI: 0.69-0.81) outperformed the R2-CHA2DS2-VASc score (C-statistic = 0.736; 95%CI: 0.68-0.961) in predicting mortality (delta C-statistic = 0.015; 95%CI: 0.001-0.029). The better prediction ability of the Alb-R2CHA2DS2-VASc score was also proven by an IDI of 0.024 (p < 0.0001) and a relative IDI of 24.11% (p < 0.0001), with an NRI = 0.608 (p < 0.00001). CONCLUSIONS: The addition of albuminuria to R2CHA2DS2-VASc significantly and independently predicts the risk of all-cause mortality in a sample of high CV risk patients. Moreover, Alb-R2CHA2DS2-VASc outperforms R2CHA2DS2-VASc.


Assuntos
Fibrilação Atrial , Doenças Cardiovasculares , Acidente Vascular Cerebral , Humanos , Fatores de Risco , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/complicações , Estudos Prospectivos , Albuminúria/diagnóstico , Fibrilação Atrial/epidemiologia , Fatores de Risco de Doenças Cardíacas , Medição de Risco , Acidente Vascular Cerebral/epidemiologia
7.
Nutr Metab Cardiovasc Dis ; 33(1): 185-193, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36411219

RESUMO

BACKGROUND AND AIMS: Inflammation due to the excess of nutrient intake plays an important role in the pathophysiology of metabolic syndrome (MetS). Here, the potential influence of neutrophils and their degranulation markers on MetS improvement upon dietary and behavioral counselling, has been investigated. Specifically, we aimed at investigating their role as potential predictors of metabolic syndrome improvements. METHODS AND RESULTS: patients with MetS (n = 127) received behavioral and dietary recommendations before follow-up at 6 months. Serum levels of matrix metalloproteinases (MMP)8, MMP9, myeloperoxidase (MPO), tissue inhibitor of MMP (TIMP)-1, TIMP-2, TIMP-3 and resistin were tested at baseline. In the whole cohort, baseline levels of proinflammatory MMP8, MMP9 and MPO increased together with the number of MetS criteria. Seventy-three (57%) patients experienced a reduction in MetS-defining criteria at follow-up. With respect to those with no improvement, such individuals showed lower weight and waist circumference at enrolment, less frequent smoking habits, higher levels of triglycerides and lower circulating MMP8. At logistic regression analysis, baseline MMP8 showed negative predictive ability (odds ratio (OR) 0.979 [0.961-0.997]; p = 0.025) against MetS improvement. Such findings hold true even when included in the backward stepwise logistic regression model confirming MMP8 as an independent predictor (OR 0.970 [0.949-0.993]; p = 0.009). Receiver operating characteristic (ROC) curve confirmed the predictive ability of MMP8 combined in a model including baseline MetS criteria and waist circumference. Bootstrap resampling analysis internally validated our findings. CONCLUSION: Improvement of MetS is independently associated with baseline low MMP-8 levels, suggesting a pivotal role for inflammation in metabolic alteration.


Assuntos
Síndrome Metabólica , Humanos , Síndrome Metabólica/diagnóstico , Metaloproteinase 8 da Matriz , Metaloproteinase 9 da Matriz , Neutrófilos/metabolismo , Biomarcadores , Inflamação , Curva ROC , Circunferência da Cintura
8.
Nutr Metab Cardiovasc Dis ; 33(2): 323-330, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36642602

RESUMO

BACKGROUND AND AIMS: Whether the association between very high HDL-cholesterol levels and cardiovascular mortality (CVM) is modulated by some facilitating factors is unclear. Aim of the study was to investigate whether the risk of CVM associated with very high HDL-cholesterol is increased in subjects with hyperuricemia. METHODS AND RESULTS: Multivariable Cox analyses were made in 18,072 participants from the multicentre URRAH study stratified by sex and HDL-cholesterol category. During a median follow-up of 11.4 years there were 1307 cases of CVM. In multivariable Cox models a J-shaped association was found in the whole population, with the highest risk being present in the high HDL-cholesterol group [>80 mg/dL, adjusted hazard ratio (HR), 1.28; 95%CI, 1.02-1.61; p = 0.031)]. However, a sex-specific analysis revealed that this association was present only in women (HR, 1.34; 95%CI, 1.02-1.77; p = 0.034) but not in men. The risk of CVM related to high HDL-cholesterol was much greater in the women with high uric acid (>0.30 mmol/L, HR 1.61; 95%CI, 1.08-2.39) than in those with low uric acid (HR, 1.17; 95%CI, 0.80-1.72, p for interaction = 0.016). In women older than 70 years with hyperuricemia the risk related to high HDL-cholesterol was 1.83 (95%CI, 1.19-2.80, p < 0.005). Inclusion of BMI in the models weakened the strength of the associations. CONCLUSION: Our data indicate that very high HDL-cholesterol levels in women are associated with CVM in a J-shaped fashion. The risk of CVM is increased by concomitant hyperuricemia suggesting that a proinflammatory/oxidative state can enhance the detrimental cardiovascular effects associated with high HDL-cholesterol.


Assuntos
Doenças Cardiovasculares , Hipercolesterolemia , Hiperlipidemias , Hiperuricemia , Masculino , Humanos , Feminino , HDL-Colesterol , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Fatores de Risco , Hiperuricemia/epidemiologia , Ácido Úrico
9.
Int J Mol Sci ; 24(3)2023 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-36769281

RESUMO

The mechanisms by which hyperuricemia induces vascular dysfunction and contributes to cardiovascular disease are still debated. Phenotypic transition is a property of vascular smooth muscle cells (VSMCs) involved in organ damage. The aim of this study was to investigate the effects of uric acid (UA) on changes in the VSMC cytoskeleton, cell migration and the signals involved in these processes. MOVAS, a mouse VSMC line, was incubated with 6, 9 and 12 mg/dL of UA, angiotensin receptor blockers (ARBs), proteasome and MEK-inhibitors. Migration property was assessed in a micro-chemotaxis chamber and by phalloidin staining. Changes in cytoskeleton proteins (Smoothelin B (SMTB), alpha-Smooth Muscle Actin (αSMA), Smooth Muscle 22 Alpha (SM22α)), Atrogin-1 and MAPK activation were determined by Western blot, immunostaining and quantitative reverse transcription PCR. UA exposition modified SMT, αSMA and SM22α levels (p < 0.05) and significantly upregulated Atrogin-1 and MAPK activation. UA-treated VSMCs showed an increased migratory rate as compared to control cells (p < 0.001) and a re-arrangement of F-actin. Probenecid, proteasome inhibition and ARBs prevented the development of dysfunctional VSMC. This study shows, for the first time, that UA-induced cytoskeleton changes determine an increase in VSMC migratory rate, suggesting UA as a key player in vascular remodeling.


Assuntos
Músculo Liso Vascular , Ácido Úrico , Camundongos , Animais , Músculo Liso Vascular/metabolismo , Ácido Úrico/farmacologia , Ácido Úrico/metabolismo , Remodelação Vascular , Antagonistas de Receptores de Angiotensina/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Citoesqueleto/metabolismo , Movimento Celular , Miócitos de Músculo Liso/metabolismo , Células Cultivadas , Proliferação de Células
10.
Int J Mol Sci ; 24(11)2023 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-37298378

RESUMO

Arterial hypertension (AH) is a global challenge that greatly impacts cardiovascular morbidity and mortality worldwide. AH is a major risk factor for the development and progression of kidney disease. Several antihypertensive treatment options are already available to counteract the progression of kidney disease. Despite the implementation of the clinical use of renin-angiotensin aldosterone system (RAAS) inhibitors, gliflozins, endothelin receptor antagonists, and their combination, the kidney damage associated with AH is far from being resolved. Fortunately, recent studies on the molecular mechanisms of AH-induced kidney damage have identified novel potential therapeutic targets. Several pathophysiologic pathways have been shown to play a key role in AH-induced kidney damage, including inappropriate tissue activation of the RAAS and immunity system, leading to oxidative stress and inflammation. Moreover, the intracellular effects of increased uric acid and cell phenotype transition showed their link with changes in kidney structure in the early phase of AH. Emerging therapies targeting novel disease mechanisms could provide powerful approaches for hypertensive nephropathy management in the future. In this review, we would like to focus on the interactions of pathways linking the molecular consequences of AH to kidney damage, suggesting how old and new therapies could aim to protect the kidney.


Assuntos
Hipertensão Renal , Hipertensão , Humanos , Rim/metabolismo , Sistema Renina-Angiotensina , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/metabolismo , Hipertensão Renal/metabolismo
11.
Eur J Clin Invest ; 52(11): e13830, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35778894

RESUMO

BACKGROUND: The CHA2 DS2 -VASc score, widely used to estimate cardioembolic risk in patients with atrial fibrillation (AF), appears to be useful also in predicting vascular adverse events and death in different sets of patients without AF. The R2 CHA2 DS2 -VASc score, which includes renal impairment, allows a better prediction of death and thromboembolism in patients without AF. The aims of our study were to assess, in a large sample of patients at high cardiovascular (CV) risk, (i) the correlation between CHA2 DS2 -VASc and R2 CHA2 DS2 -VASc with all-cause mortality, and (ii) to compare the performances of CHA2 DS2 -VASc and R2 CHA2 DS2 -VASc in predicting all-cause mortality. METHODS: In this single-centre prospective observational study, conducted at the Research Hospital 'Casa Sollievo della Sofferenza' between June 2016 and December 2018, 1017 CV patients at high risk of undergoing coronary angiography were enrolled. RESULTS: CHA2DS2-VASc and R2 CHA2 DS2 -VASc scores significantly associated with all-cause mortality. For each one-point increase in CHA2 DS2 -VASc or R2 CHA2 DS2 -VASc scores, mortality increased by almost 1.5-fold. The R2 CHA2 DS2 -VASc score (C-statistic = 0.71; 95% CI = 0.65-76) outperformed the CHA2 DS2 -VASc score (C-statistic = 0.66; 95% CI = 0.61-0.71) in predicting 4-year mortality (delta C-statistic = 0.05; 95% CI = 0.02-0.07). The better predictive ability of the R-CHA2 DS2 -VASc score was also demonstrated by an IDI = 0.027 (95% CI = 0.021-0.034, p < .00001) and a relative IDI = 62.8% (95% CI = 47.9%-81.3%, p < .00001). The R2 CHA2 DS2 -VASc score correctly reclassified the patients with a NRI = 0.715 (95% = 0.544-0.940, p < .00001). CONCLUSIONS: The CHA2DS2-VASc and R2 CHA2 DS2 -VASc scores are useful predictors of all-cause mortality in subjects at high CV risk, with the R2 CHA2 DS2 -VASc score being the best performer.


Assuntos
Fibrilação Atrial , Doenças Cardiovasculares , Acidente Vascular Cerebral , Fibrilação Atrial/complicações , Doenças Cardiovasculares/epidemiologia , Fatores de Risco de Doenças Cardíacas , Humanos , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/etiologia
12.
Nutr Metab Cardiovasc Dis ; 32(2): 402-409, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34893408

RESUMO

BACKGROUND AND AIM: Three vessels disease (3VD) has been associated with worse prognosis and higher mortality. Chronic kidney disease (CKD) is an independent risk factor for premature death, mostly due to coronary artery disease (CAD). We aim to examine the prognostic impact of 3VD on all-cause mortality in a cohort of high cardiovascular risk subjects undergoing coronary angiography (CA) and to explore whether low eGFR (<60 ml/min/1.73 m2) modulates the risk of all-cause mortality associated to 3VD. METHODS AND RESULTS: One-thousand-seventeen subjects (759 M, mean age 68.4 ± 11 years) consecutive subjects undergoing CA from 2016 to 2018 were evaluated. Subjects were classified according to the severity of CAD as follows: group "three vessels disease" (3VD), and "no three vessels disease" (No 3VD). Serum creatinine was measured to estimate glomerular filtration rate (eGFR). The whole population was divided into 4 groups (A, B, C, D), according to the presence/absence of low eGFR and/or 3VD. One-hundred-fourteen deaths occurred (median follow-up:44 months). The risk of death in subjects with 3VD was almost 2-time higher than subject without 3VD (adjusted HR = 1.61; 95% CI 1.094-2.373, p = 0.0157). Among 4 subgroups, subjects with low eGFR and 3VD (Group D) had the highest risk of death (adjusted HR = 3.881; 95% CI 2.256-6.676, p < 0.0001). CONCLUSIONS: Low eGFR significantly amplifies the risk of all-cause mortality associated to 3VD. Our results strengthen the role of kidney disease as a risk multiplier for cardiovascular and all-cause mortality and highlight the need to prevent its onset and progression.


Assuntos
Doença da Artéria Coronariana , Insuficiência Renal Crônica , Idoso , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Creatinina , Taxa de Filtração Glomerular , Humanos , Pessoa de Meia-Idade , Prognóstico , Insuficiência Renal Crônica/diagnóstico , Fatores de Risco
13.
Nutr Metab Cardiovasc Dis ; 32(5): 1245-1252, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35282979

RESUMO

BACKGROUND AND AIM: The URRAH (URic acid Right for heArt Health) Study has identified cut-off values of serum uric acid (SUA) predictive of total mortality at 4.7 mg/dl, and cardiovascular (CV) mortality at 5.6 mg/dl. Our aim was to validate these SUA thresholds in people with diabetes. METHODS AND RESULTS: The URRAH subpopulation of people with diabetes was studied. All-cause and CV deaths were evaluated at the end of follow-up. A total of 2570 diabetic subjects were studied. During a median follow-up of 107 months, 744 deaths occurred. In the multivariate Cox regression analyses adjusted for several confounders, subjects with SUA ≥5.6 mg/dl had higher risk of total (HR: 1.23, 95%CI: 1.04-1.47) and CV mortality (HR:1.31, 95%CI:1.03-1.66), than those with SUA <5.6 mg/dl. Increased all-cause mortality risk was shown in participants with SUA ≥4.7 mg/dl vs SUA below 4.7 mg/dl, but not statistically significant after adjustment for all confounders. CONCLUSIONS: SUA thresholds previously proposed by the URRAH study group are predictive of total and CV mortality also in people with diabetes. The threshold of 5.6 mg/dl can predict both total and CV mortality, and so is candidate to be a clinical cut-off for the definition of hyperuricemia in patients with diabetes.


Assuntos
Diabetes Mellitus , Hiperuricemia , Diabetes Mellitus/diagnóstico , Humanos , Hiperuricemia/diagnóstico , Fatores de Risco , Ácido Úrico
14.
Eur J Clin Invest ; 51(3): e13403, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32918277

RESUMO

Prediabetes is often observed in patients with Metabolic Syndrome (MetS) and might be associated with metabolic and inflammatory alterations. Here, we investigated whether the inflammatory molecule osteopontin (OPN) might have a prognostic impact in a cohort of MetS patients (n = 85) with baseline normal glycaemia or impaired fasting glucose (IFG) over one year of recommended pharmacological treatments and Mediterranean diet. Patients were then followed up for 12 months with intermediate evaluation after 6 months. At all time points, anthropometric and clinical data were recorded, alongside with haematological and biochemical profiles, including serum concentrations of OPN. As expected, Mediterranean diet improves glycaemic profile in patients with IFG. Baseline serum OPN failed to be associated with baseline anthropometric or biochemical variables. At baseline, higher levels of OPN were shown in patients with IFG as compared to normal glycaemia. Two distinct subgroups of patients in whom OPN decreased or remained stable/increased at follow-up were identified. When higher serum OPN levels were observed at baseline, greater reduction was observed at 1-year follow-up. Reduction in circulating OPN levels was associated with metabolic improvement in terms of blood pressure, LDL-c, HDL-c, and glycaemia. At both univariate and adjusted logistic regression analyses, serum OPN emerged as an independent predictor of glycaemic profile improvement at 1-year follow-up (adjOR 1.05 [1.00-1.10]; P = .041). In conclusion, pharmacological and dietetic interventions improved glycaemic profile in patients with MetS. In particular, glycaemic improvement was demonstrated in patients who also reduce circulating OPN levels. Higher OPN levels at baseline predict normalization of glycaemic profile.


Assuntos
Glicemia/metabolismo , Dieta Mediterrânea , Intolerância à Glucose/dietoterapia , Síndrome Metabólica/dietoterapia , Osteopontina/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Intolerância à Glucose/metabolismo , Humanos , Modelos Logísticos , Masculino , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico
15.
Int J Mol Sci ; 22(9)2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33922865

RESUMO

In recent years, following the publication of results from several RCTs, first on cardiovascular and more recently on renal outcomes, SGLT2is have become the standard of care to prevent diabetic kidney disease and slow its progression. This narrative review focuses on biological mechanisms, both renal and extrarenal, underlying kidney protection with SGLT2is. Furthermore, data from cardiovascular as well as renal outcome trials, mostly conducted in diabetic patients, are presented and discussed to provide an overview of current uses as well as the future therapeutic potential of these drugs.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Animais , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Taxa de Filtração Glomerular , Humanos
16.
Curr Hypertens Rep ; 22(12): 102, 2020 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-33128170

RESUMO

PURPOSE OF REVIEW: In chronic kidney disease (CKD), plasma uric acid levels are increased because of the decrease in glomerular filtration rate. However, in addition to CKD, hyperuricemia is frequently associated with a number of other conditions such as hypertension, type 2 diabetes, obesity, and heart failure, overweight, and cardiovascular disease. RECENT FINDINGS: It is now becoming increasingly clear that, in many clinical conditions, elevated levels of uric acid have a much greater role beyond just causing gout. The present review will summarize current knowledge on the relation between hyperuricemia, CKD, and existing comorbidities, as well as the mechanisms of uric acid-related renal damage. In addition, the role and evidence for urate-lowering therapy in prevention and cardiovascular protection in CKD patients is discussed with a focus on allopurinol and febuxostat. To date, several clinical studies have provided evidence that urate-lowering therapy may help to prevent and delay the decline of renal function in patients with CKD. Use of a xanthine oxidase inhibitor should be considered in patients who are at high renal risk and/or with declining renal function in the presence of hyperuricemia with and without deposition, although additional studies are warranted to define treatment targets. Notwithstanding, the possibility to delay deterioration of renal function in patients with CKD merits consideration.


Assuntos
Diabetes Mellitus Tipo 2 , Hipertensão , Hiperuricemia , Insuficiência Renal Crônica , Supressores da Gota/uso terapêutico , Humanos , Hiperuricemia/complicações , Hiperuricemia/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Resultado do Tratamento
17.
Int J Mol Sci ; 21(12)2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32599713

RESUMO

Recently, there has been a growing interest in epidemiological and clinical studies supporting a pathogenetic role of fructose in cardio-metabolic diseases, especially in children and adolescents. In the present review, we summarize experimental data on the potential biological mechanisms linking fructose and uric acid in the development of insulin resistance, metabolic syndrome, obesity, diabetes, hypertension, non-alcoholic fatty liver disease and chronic renal disease, thereby contributing to an increase in cardiovascular risk at pediatric age.


Assuntos
Doenças Cardiovasculares/etiologia , Diabetes Mellitus/fisiopatologia , Frutose/metabolismo , Hipertensão/complicações , Síndrome Metabólica/complicações , Obesidade/complicações , Ácido Úrico/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Criança , Diabetes Mellitus/metabolismo , Humanos , Hipertensão/metabolismo , Hipertensão/patologia , Resistência à Insulina , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Obesidade/metabolismo , Obesidade/patologia , Fatores de Risco
18.
J Cell Physiol ; 234(7): 10868-10876, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30536556

RESUMO

Renal proximal tubular cells (PTECs) participate in several mechanisms of innate immunity, express toll-like receptors (TLRs), and proinflammatory cytokines. Hyperuricemia may be a promoter of inflammation and renal damage. Angiotensin II (Ang II) modulate immune and inflammatory responses in renal tubular cells. With the aim to evaluate the effect of uric acid (UA) and Ang II on oxidative stress and inflammation mediated by toll-like receptor 4 (TLR4) activation in human PTECs, human kidney 2 (HK2) were incubated for 24 hr with UA (12 mg/dl) and Ang II (10 -7 M). HK2 were pretreated with an antagonist of TLR4 (TAK 242), valsartan or losartan. The genic expression of TLR4, monocyte chemoattractant protein-1 (MCP1), and Nox4 was quantified with reverse transcription polymerase chain reaction, proteins were evaluated with Western blot. The incubation of HK2 either with UA or with Ang II determines an increased expression of TLR4, production of proinflammatory cytokines as MCP1 and pro-oxidants as Nox4 ( p < 0.05). TAK 242 attenuates the expression of MCP1 induced both by UA and Ang II. Valsartan attenuated all the effects we described after exposure to Ang II but not those observed after UA exposure. At variance, pretreatment with losartan, which inhibits UA internalization, attenuates the expression of TLR4, MCP1, and Nox4 in cells previously treated with UA, Ang II, and UA plus Ang II. Proinflammatory pathways are induced in an additive manner by UA and Ang II ( p < 0.05) and might be mediated by TLR4 in PTECs. Renin-angiotensin-aldosterone system (RAAS) activation, hyperuricemia, and innate immunity interplay in the development of chronic tubular damage and the interaction of several nephrotoxic mechanisms blunt the protective effect of RAAS inhibition.


Assuntos
Angiotensina II/toxicidade , Mediadores da Inflamação/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Nefrite/induzido quimicamente , Estresse Oxidativo/efeitos dos fármacos , Receptor 4 Toll-Like/agonistas , Ácido Úrico/toxicidade , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Linhagem Celular , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Humanos , Imunidade Inata/efeitos dos fármacos , Túbulos Renais Proximais/imunologia , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , Nefrite/imunologia , Nefrite/metabolismo , Nefrite/patologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
19.
Eur J Clin Invest ; 49(8): e13128, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31091356

RESUMO

BACKGROUND: Inflammation, overweight and other cardiovascular risk factors might negatively impact on hypertension remission in metabolic syndrome (MetS), independently of the pharmacological treatment. Here, the potential influence of systemic inflammation (assessed by serum high-sensitivity C-reactive protein [hs-CRP]) on hypertension remission will be investigated in a cohort of hypertensive patients with MetS. MATERIAL AND METHODS: Hypertensive patients with MetS (n = 100) were enrolled, treated under current behavior/dietary/pharmacological recommendations and followed up for 12 months. All patients received medications and nutritional advice based on Mediterranean-like dietary pattern in addition to psychological and physical activity counselling. At baseline (T0), 6 (T1) and 12 (T2) months of follow-up, clinical data, haematological and biochemical profiles and serum hs-CRP were measured. RESULTS: As compared to T0, at T2 patients displayed improvements in anthropometric and metabolic profiles. At T2, the hypertension remission rate was 13.0%. Serum hs-CRP did not change overtime in the overall cohort. Surprisingly, patients who experienced hypertension remission were less treated with antihypertensive drugs, but developed a weak improvement in anthropometric measures during follow-up. The hypertension remission group had lower baseline levels of hs-CRP as compared to non-remission. Low baseline hs-CRP (<2 µg/mL, cut-off value identified by ROC curve) predicted hypertension remission, independently of antihypertensive treatment implementation, baseline systolic blood pressure and waist circumference improvement. CONCLUSIONS: Remission of hypertension in MetS is independently associated with baseline low CRP levels, which might suggest a critical role for inflammation in sustaining high blood pressure levels.


Assuntos
Proteína C-Reativa/metabolismo , Hipertensão/sangue , Síndrome Metabólica/sangue , Adulto , Antropometria , Anti-Hipertensivos/uso terapêutico , Estudos de Coortes , Dieta , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/dietoterapia , Hipertensão/tratamento farmacológico , Inflamação/dietoterapia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/dietoterapia , Síndrome Metabólica/tratamento farmacológico , Metaboloma , Pessoa de Meia-Idade , Sobrepeso/complicações , Curva ROC , Remissão Espontânea , Circunferência da Cintura , Adulto Jovem
20.
Medicina (Kaunas) ; 55(6)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31159279

RESUMO

Type 2 diabetes mellitus (T2DM) is the leading cause of chronic kidney disease (CKD). Diabetic nephropathy (DN) is determined by specific pathological structural and functional alterations of the kidneys in patients with diabetes, and its clinical manifestations are albuminuria and decline of glomerular filtration rate (GFR). Apart from renin-angiotensin-aldosterone system (RAAS) inhibitors, no other drugs are currently available as therapy for diabetic kidney disease (DKD). Glucagon-like peptide-1 receptor (GLP-1R) agonists are a new class of anti-hyperglycemic drugs which have been demonstrated to prevent the onset of macroalbuminuria and reduce the decline of GFR in diabetic patients. These drugs may exert their beneficial actions on the kidneys through blood glucose- and blood pressure (BP)-lowering effects, reduction of insulin levels and weight loss. Clinical benefits of GLP-1R agonists were acknowledged due to data from large randomized phase III clinical trials conducted to assess their cardiovascular(CV) safety. These drugs improved renal biomarkers in placebo-controlled clinical studies, with effects supposed to be independent of the actions on glycemic control. In this review, we will focus on the actions of GLP-1R agonists on glucose metabolism and kidney physiology, and evaluate direct and indirect mechanisms through which these drugs may confer renal protection.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Rim/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/uso terapêutico , Humanos , Rim/fisiopatologia , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico
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