RESUMO
Background: Novel creatinine-based equations have recently been proposed but their predictive performance for cardiovascular outcomes in participants at high cardiovascular risk in comparison to the established CKD-EPI 2009 equation is unknown. Method: In 9361 participants from the United States included in the randomized controlled SPRINT trial, we calculated baseline estimated glomerular filtration rate (eGFR) using the CKD-EPI 2009, CKD-EPI 2021, and EKFC equations and compared their predictive value of cardiovascular events. The statistical metric used is the net reclassification improvement (NRI) presented separately for those with and those without events. Results: During a mean follow-up of 3.1 ± 0.9 years, the primary endpoint occurred in 559 participants (6.0%). When using the CKD-EPI 2009, the CKD-EPI 2021, and the EKFC equations, the prevalence of CKD (eGFR <60 ml/min/1.73 m2 or >60 ml/min/1.73 m2 with an ACR ≥30 mg/g) was 37% vs. 35.3% (P = 0.02) vs. 46.4% (P < 0.001), respectively. The corresponding mean eGFR was 72.5 ± 20.1 ml/min/1.73 m2 vs. 73.2 ± 19.4 ml/min/1.73 m2 (P < 0.001) vs. 64.6 ± 17.4 ml/min/1.73 m2 (P < 0.001). Neither reclassification according to the CKD-EPI 2021 equation [CKD-EPI 2021 vs. CKD-EPI 2009: NRIevents: -9.5% (95% confidence interval (CI) -13.0% to -5.9%); NRInonevents: 4.8% (95% CI 3.9% to 5.7%)], nor reclassification according to the EKFC equation allowed better prediction of cardiovascular events compared to the CKD-EPI 2009 equation (EKFC vs. CKD-EPI 2009: NRIevents: 31.2% (95% CI 27.5% to 35.0%); NRInonevents: -31.1% (95% CI -32.1% to -30.1%)). Conclusion: Substituting the CKD-EPI 2009 with the CKD-EPI 2021 or the EKFC equation for calculation of eGFR in participants with high cardiovascular risk without diabetes changed the prevalence of CKD but was not associated with improved risk prediction of cardiovascular events for both those with and without the event.
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Resistant hypertension (RH) is defined in patients who do not meet their blood pressure targets despite the daily intake of three antihypertensive drugs in maximally tolerated dosages. This triple treatment should comprise (1) an angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB), (2) a calcium channel blocker and (3) a diuretic. RH should also be diagnosed in patients on four or more antihypertensive drug classes. Of note, the diagnosis of RH requires the exclusion of non-adherence, "white coat effect", and incorrect BP-measurement.After diagnosing RH, it is important to recommend lifestyle interventions (e.âg. low dietary salt intake, regular physical activity), to pause BP-elevating substances, and to consider the presence of secondary hypertension.Such secondary forms of hypertension primarily include endocrine disorders and renal disease (both acute kidney injury and chronic kidney disease). The leading endocrine cause is primary hyperaldosteronism, the management of which was highlighted in a recent guideline. Other endocrine causes - such as phaeochromocytoma or hypercortisolism - are much less frequent. In contrast, sleep apnoea disorders are now mostly considered as a comorbidity rather than as a cause of secondary hypertension.Treatment options for RH include lifestyle optimisation and escalation of antihypertensive medication. In most patients on triple treatment (ACE-I or ARB plus calcium channel blocker plus diuretic), mineralocorticoid receptor antagonists (MRA) should be the next treatment choice. As MRA may be associated with hyperkalemia (particularly in patients with chronic kidney disease), the concurrent use of potassium-lowering agents such as patiromer may allow a safe long-term treatment. In contrast, novel interventional treatment options in RH such as renal denervation are still controversially discussed.
Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão , Pressão Sanguínea/fisiologia , Humanos , Hiperaldosteronismo , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologiaRESUMO
Anemia and iron deficiency are highly prevalent in chronic kidney disease (CKD) and in chronic heart failure. Both may epidemiologically predict future renal and/or cardiovascular events. However, anemia treatment with either erythropoietin or erythropoiesis-stimulating agents failed to induce a prognostic benefit in either CKD or chronic heart failure. Instead, in the subgroup of chronic dialysis patients, liberal intravenous iron supplementation was beneficial, and ongoing clinical trials are testing the prognostic implication of intravenous iron supplementation in chronic heart failure. Finally, HIF stabilizers are a new treatment option for anemia in chronic kidney disease, and safety studies are currently ongoing in CKD patients. Whether patients suffering from chronic heart failure might also benefit from this treatment is currently unknown.
Assuntos
Anemia Ferropriva , Insuficiência Cardíaca/complicações , Insuficiência Renal Crônica/complicações , Anemia Ferropriva/complicações , Anemia Ferropriva/tratamento farmacológico , Anemia Ferropriva/etiologia , Doença Crônica , Eritropoetina/administração & dosagem , Eritropoetina/uso terapêutico , Hematínicos/administração & dosagem , Hematínicos/uso terapêutico , Humanos , Ferro/administração & dosagem , Ferro/uso terapêutico , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/terapiaAssuntos
Compostos Férricos/administração & dosagem , Fatores de Crescimento de Fibroblastos/sangue , Insuficiência Cardíaca/complicações , Hipofosfatemia/tratamento farmacológico , Maltose/análogos & derivados , Volume Sistólico/efeitos dos fármacos , Biomarcadores/sangue , Fator de Crescimento de Fibroblastos 23 , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipofosfatemia/sangue , Hipofosfatemia/etiologia , Injeções Intravenosas , Maltose/administração & dosagemRESUMO
Background: Since the introduction of sacubitril/valsartan in clinical cardiology, neprilysin has become a major target for heart failure treatment. Plasma neprilysin concentration has been discussed as a novel biomarker that predicts cardiac events. Natriuretic peptides may inhibit plasma neprilysin. As they accumulate in chronic kidney disease (CKD), we hypothesized that high plasma neprilysin loses its predictive role in CKD patients. Methods: We measured plasma levels of neprilysin concentration, neprilysin activity and brain natriuretic peptide (BNP) in 542 CKD G2-G4 patients within the CARE FOR HOMe study. Patients were followed for predefined endpoints of hospitalization for acute decompensated heart failure and incident atherosclerotic cardiovascular events. Results: During 5.1 ± 2.1 years, 63 patients had acute decompensated heart failure and 125 patients had incident atherosclerotic cardiovascular events. In both Kaplan-Meier and multivariate Cox regression analyses, high plasma BNP and low, rather than elevated, neprilysin activity predicted future hospitalization for acute decompensated heart failure; neprilysin concentration was not predictive. Furthermore, only BNP was an independent predictor of incident atherosclerotic cardiovascular events. Conclusions: In line with experimental studies, high natriuretic peptides may inhibit neprilysin activity in CKD. Therefore, high neprilysin activity and concentrations are not predictors of adverse cardiovascular outcome in CKD patients. Thus neprilysin inhibitors should be implemented with caution in patients with advanced CKD.
Assuntos
Biomarcadores/sangue , Insuficiência Cardíaca/diagnóstico , Peptídeo Natriurético Encefálico/sangue , Neprilisina/sangue , Neprilisina/metabolismo , Insuficiência Renal Crônica/complicações , Idoso , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
In experimental myocardial infarction (MI), a rise in cell counts of circulating monocyte subsets contributes to impaired myocardial healing and to atherosclerotic plaque destabilization. In humans, the prognostic role of monocyte subsets in patients suffering ST-elevation MI (STEMI) is still unclear. In the present study, we aimed to determine the kinetics of the 3 monocyte subsets (classical CD14++CD16-, intermediate CD14++CD16+, and nonclassical CD14+CD16++ monocytes), as well as the subset-specific monocyte-platelet aggregates (MPA), in acute STEMI followed by primary percutaneous coronary intervention (PCI), and their relationships with cardiovascular outcomes during a 2-year follow-up.Monocyte subsets and MPA were measured in 100 STEMI patients receiving primary PCI on days 1, 2, 3, 5, and 7 of symptom onset, which were compared with 60 stable coronary heart disease patients and 35 healthy volunteers. From day 1 to day 7, significant increases in the counts of CD14++CD16+ monocytes and CD14++CD16+ MPA were observed, with peak levels on day 2. During a median follow-up of 2.0 years, 28 first cardiovascular events (defined as cardiovascular death, nonfatal ischemic stroke, recurrent MI, need for emergency or repeat revascularization, and rehospitalization for heart failure) were recorded. After adjustment for confounders, CD14++CD16+ monocytosis (day 1 [HR: 3.428; 95% CI: 1.597-7.358; Pâ=â0.002], day 2 [HR: 4.835; 95% CI: 1.106-21.13; Pâ=â0.04], day 3 [HR: 2.734; 95% CI: 1.138-6.564; Pâ=â0.02], and day 7 [HR: 2.647; 95% CI: 1.196-5.861; Pâ=â0.02]), as well as increased levels of CD14++CD16+ MPA measured on all time points (days 1, 2, 3, 5, and 7), had predictive values for adverse cardiovascular events.In conclusion, our data show the expansion of the CD14++CD16+ monocyte subset during acute phase of STEMI has predictive values for 2-year adverse cardiovascular outcomes in patients treated with primary PCI. Future studies will be warranted to elucidate whether CD14++CD16+ monocytes may become a target cell population for new therapeutic strategies after STEMI.
Assuntos
Antígenos CD/análise , Plaquetas/metabolismo , Monócitos , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Idoso , Agregação Celular , China , Angiografia Coronária/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/classificação , Monócitos/metabolismo , Readmissão do Paciente/estatística & dados numéricos , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/métodos , Período Pós-Operatório , Valor Preditivo dos Testes , Recidiva , Reoperação/estatística & dados numéricos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/terapiaRESUMO
BACKGROUND: Treatment of iron deficiency with intravenous (i.v.) iron is a first-line strategy to improve anaemia of chronic kidney disease. Previous in vitro experiments demonstrated that different i.v. iron preparations inhibit differentiation of haematopoietic stem cells to monocytes, but their effect on monocyte differentiation to macrophages and mature dendritic cells (mDCs) has not been assessed. We investigated substance-specific effects of iron sucrose (IS), sodium ferric gluconate (SFG), ferric carboxymaltose (FCM) and iron isomaltoside 1000 (IIM) on monocytic differentiation to M1/M2 macrophages and mDCs. METHODS: Via flow cytometry and microRNA (miRNA) expression analysis, we morphologically and functionally characterized monocyte differentiation to M1/M2 macrophages and mDCs after monocyte stimulation with IS, SFG, FCM and IIM (0.133, 0.266 and 0.533 mg/mL, respectively). To assess potential clinical implications, we compared monocytic phagocytosis capacity in dialysis patients who received either 500 mg IS or IIM. RESULTS: Phenotypically, IS and SFG dysregulated the expression of macrophage (e.g. CD40, CD163) and mDC (e.g. CD1c, CD141) surface markers. Functionally, IS and SFG impaired macrophage phagocytosis capacity. Phenotypic and functional alterations were less pronounced with FCM, and virtually absent with IIM. In miRNA expression analysis of mDCs, IS dysregulated miRNAs such as miR-146b-5p and miR-155-5p, which are linked to Toll-like receptor and mitogen-activated protein kinase signalling pathways. In vivo, IS reduced monocytic phagocytosis capacity within 1 h after infusion, while IIM did not. CONCLUSIONS: This study demonstrates that less stable i.v. iron preparations specifically affect monocyte differentiation towards macrophages and mDCs.
Assuntos
Anemia Ferropriva/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Células Dendríticas/citologia , Compostos de Ferro/administração & dosagem , Macrófagos/citologia , Monócitos/citologia , Anemia Ferropriva/imunologia , Anemia Ferropriva/patologia , Estudos de Casos e Controles , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Dissacarídeos/administração & dosagem , Dissacarídeos/farmacologia , Compostos Férricos/administração & dosagem , Compostos Férricos/farmacologia , Óxido de Ferro Sacarado , Ácido Glucárico/administração & dosagem , Ácido Glucárico/farmacologia , Hematínicos/administração & dosagem , Hematínicos/farmacologia , Humanos , Injeções Intravenosas , Compostos de Ferro/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Maltose/administração & dosagem , Maltose/análogos & derivados , Maltose/farmacologia , MicroRNAs/genética , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Fagocitose/efeitos dos fármacosRESUMO
Human monocytes are a heterogeneous cell population consisting of 3 subsets: classical CD14++CD16-, intermediate CD14++CD16+ and nonclassical CD14+CD16++ monocytes. Via poorly characterized mechanisms, intermediate monocyte counts rise in chronic inflammatory diseases, among which chronic kidney disease is of particular epidemiologic importance. DNA methylation is a central epigenetic feature that controls hematopoiesis. By applying next-generation Methyl-Sequencing we now tested how far the 3 monocyte subsets differ in their DNA methylome and whether uremia induces DNA methylation changes in differentiating monocytes. We found that each monocyte subset displays a unique phenotype with regards to DNA methylation. Genes with differentially methylated promoter regions in intermediate monocytes were linked to distinct immunological processes, which is in line with results from recent gene expression analyses. In vitro, uremia induced dysregulation of DNA methylation in differentiating monocytes, which affected several transcription regulators important for monocyte differentiation (e.g., FLT3, HDAC1, MNT) and led to enhanced generation of intermediate monocytes. As potential mediator, the uremic toxin and methylation inhibitor S-adenosylhomocysteine induced shifts in monocyte subsets in vitro, and associated with monocyte subset counts in vivo. Our data support the concept of monocyte trichotomy and the distinct role of intermediate monocytes in human immunity. The shift in monocyte subsets that occurs in chronic kidney disease, a proinflammatory condition of substantial epidemiological impact, may be induced by accumulation of uremic toxins that mediate epigenetic dysregulation.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Metilação de DNA/genética , Histona Desacetilase 1/genética , Insuficiência Renal Crônica/genética , Proteínas Repressoras/genética , Uremia/genética , Tirosina Quinase 3 Semelhante a fms/genética , Diferenciação Celular/genética , Proteínas Ligadas por GPI/genética , Regulação da Expressão Gênica , Voluntários Saudáveis , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Receptores de Lipopolissacarídeos/genética , Monócitos/metabolismo , Receptores de IgG/genética , Insuficiência Renal Crônica/patologia , S-Adenosil-Homocisteína/metabolismo , Uremia/patologiaRESUMO
Human monocytes are subdivided into classical, intermediate, and nonclassical subsets, but there is no unequivocal strategy to dissect the latter 2 cell types. We show herein that the cell surface marker 6-sulfo LacNAc (slan) can define slan-positive CD14(+)CD16(++) nonclassical monocytes and slan-negative CD14(++)CD16(+) intermediate monocytes. Gene expression profiling confirms that slan-negative intermediate monocytes show highest expression levels of major histocompatibility complex class II genes, whereas a differential ubiquitin signature is a novel feature of the slan approach. In unsupervised hierarchical clustering, the slan-positive nonclassical monocytes cluster with monocytes and are clearly distinct from CD1c(+) dendritic cells. In clinical studies, we show a selective increase of the slan-negative intermediate monocytes to >100 cells per microliter in patients with sarcoidosis and a fivefold depletion of the slan-positive monocytes in patients with hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), which is caused by macrophage colony-stimulating factor (M-CSF) receptor mutations. These data demonstrate that the slan-based definition of CD16-positive monocyte subsets is informative in molecular studies and in clinical settings.
Assuntos
Amino Açúcares/análise , Monócitos/classificação , Receptor de Fator Estimulador de Colônias de Macrófagos/genética , Receptores de IgG/análise , Antígenos CD1/análise , Células Dendríticas/química , Feminino , Citometria de Fluxo , Proteínas Ligadas por GPI/análise , Perfilação da Expressão Gênica , Genes MHC da Classe II , Estudo de Associação Genômica Ampla , Glicoproteínas/análise , Antígenos HLA-D/análise , Humanos , Separação Imunomagnética , Leucoencefalopatias/genética , Leucoencefalopatias/imunologia , Leucoencefalopatias/patologia , Receptores de Lipopolissacarídeos/análise , Masculino , Pessoa de Meia-Idade , Monócitos/química , Monócitos/imunologia , Mutação Puntual , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sarcoidose/imunologia , Sarcoidose/patologia , Adulto JovemRESUMO
BACKGROUND: In cardiogenic shock (CS) renal dysfunction is an important parameter of inadequate end-organ perfusion and an independent predictor of adverse outcome. Early detection of renal dysfunction is therefore important, and novel biomarkers such as Neutrophil Gelatinase-Associated Lipocalin (NGAL), Kidney Injury Molecule 1 (KIM1) and Cystatin C (CysC) have been suggested. However, in high-risk CS patients their role for assessing renal injury has not yet been investigated in comparison to the most widely used serum creatinine. METHODS: This predefined substudy included 190 patients of the randomized Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II)-trial. Blood samples were collected directly during primary percutaneous coronary intervention, one day and two days after randomization. The primary endpoint for outcome assessment was 1 year mortality. RESULTS: Creatinine, NGAL and KIM-1 were significantly higher in non-survivors in comparison to survivors over time in ANOVA (p<0.001; p=0.002 and p=0.04, respectively). In contrast, CysC levels were not associated with the primary endpoint (p=0.15). Receiver operator characteristics revealed that creatinine at any time point had the best predictive value for 1 year mortality. This was also true when comparing creatinine to different equations for glomerular filtration rate. In multivariable Cox-regression analysis creatinine remained the only significant independent predictor of kidney biomarkers of time to death during the first year. CONCLUSIONS: Assessment of novel biomarkers such as CysC, NGAL and KIM-1 or calculation of glomerular filtration rate provide no additional prognostic information in patients with CS complicating acute myocardial infarction in comparison to creatinine.
Assuntos
Injúria Renal Aguda/sangue , Biomarcadores/sangue , Balão Intra-Aórtico/métodos , Infarto do Miocárdio/sangue , Choque Cardiogênico/sangue , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença , Choque Cardiogênico/etiologia , Choque Cardiogênico/terapiaAssuntos
Calcinose/diagnóstico por imagem , Cálcio/análise , Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/química , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X/métodos , Biomarcadores , Calcinose/epidemiologia , Doença da Artéria Coronariana/epidemiologia , Dislipidemias/epidemiologia , Humanos , Hipertensão/epidemiologia , Metanálise como Assunto , Motivação , Estudos Observacionais como Assunto , Guias de Prática Clínica como Assunto , Valor Preditivo dos Testes , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Reprodutibilidade dos Testes , Medição de RiscoAssuntos
Creatinina/sangue , Cistatina C/sangue , Taxa de Filtração Glomerular/fisiologia , Modelos Biológicos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Fatores Etários , Idoso , Biomarcadores/sangue , Estudos de Coortes , Feminino , Seguimentos , Alemanha , Humanos , Masculino , Valor Preditivo dos Testes , Prognóstico , Insuficiência Renal Crônica/mortalidade , Taxa de SobrevidaRESUMO
BACKGROUND: Monocytes are critical in innate immunity and transplantation. Three monocyte subsets exist, CD14(++)CD16(-), CD14(++)CD16(+) and CD14(+)CD16(++) monocytes; cell counts of CD14(++)CD16(+) and CD14(+)CD16(++) monocytes are increased in pre-transplant chronic kidney disease. Interestingly, the effect of immunosuppressants on monocyte heterogeneity has not been well studied. METHODS: The impact of immunosuppressants on monocyte subsets was studied: (i) in 152 kidney transplant (KTx) recipients to characterize subset distribution in the steady state, (ii) in patients after autologous (n = 10) versus allogenic (n = 9) haematopoietic stem cell transplantation (HSCT) to analyse monocyte subset development and (iii) in an in vitro model to compare the effect of immunosuppressants on monocyte subset biology. RESULTS: In KTx, steroid intake was associated with higher total, CD14(++)CD16(-) and CD14(++)CD16(+) monocyte counts, but fewer CD14(+)CD16(++) monocytes, whereas intake of mycophenolate, calcineurin inhibitors (CNI) and mammalian target of rapamycin inhibitors (mTORI) did not affect monocyte (subset) counts. In linear regression analysis, only steroid intake was a significant determinant of monocyte (subset) counts: total monocytes (ß = 0.331; P < 0.001), CD14(++)CD16(-) monocytes (ß = 0.374; P < 0.001), CD14(++)CD16(+) monocytes (ß = 0.221; P = 0.010) and CD14(+)CD16(++) monocytes (ß = -0.169; P = 0.049). After HSCT, CD14(++)CD16(-) monocytes were the first to arise, followed by CD14(++)CD16(+) and later by CD14(+)CD16(++) monocytes. Monocyte subset distribution did not differ significantly in patients after allogenic compared with autologous transplantation. CNI, mycophenolate and methotrexate did not influence monocyte subset development, but modified surface receptor expression (CCR2, HLA-DR, ENG, TEK and TLR4) in allogenic HSCT. CONCLUSION: Chronic low-dose steroids are associated with monocytosis and higher counts of CD14(++)CD16(-) and of proinflammatory CD14(++)CD16(+) monocytes.
Assuntos
Antígenos CD/metabolismo , Imunossupressores/uso terapêutico , Monócitos/classificação , Monócitos/efeitos dos fármacos , Receptores de Superfície Celular/metabolismo , Insuficiência Renal Crônica/terapia , Células Cultivadas , Terapia Combinada , Feminino , Citometria de Fluxo , Regulação da Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Humanos , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Insuficiência Renal Crônica/metabolismo , Transplante Autólogo , Transplante HomólogoRESUMO
BACKGROUND: Angiogenic cytokines fms-like tyrosine kinase-1(sFlt-1) and placental growth factor (PlGF) are associated with increased risk for cardiovascular disease (CVD) in the general population. In this study we examine the association between these vascular endothelial factors and atherosclerosis, cardiovascular outcome, and mortality in chronic kidney disease (CKD) patients. METHODS: Serum level of PlGF and sFlt-1 were measured in 301 patients with CKD, who were followed for up to 4 years. Primary outcomes were CV events and all-cause mortality. Carotid-intima media thickness (CIMT) was used as marker of atherosclerosis. Kaplan-Meier survival curves and the Cox proportional hazard model were used to assess the association of biomarkers and clinical outcomes. RESULTS: Mean (SD) PlGF and sFlt-1 were 5.45 ng/ml (3.76) and 68.6 (28.0) pg/ml, respectively. During the follow up time, 60 patients (19.9%) experienced CV events and 22 patients (7.3%) died. Compared with low PlGF, patients with PlGF above median level had higher CV events (12.7% vs. 27.2%, p = 0.002) and mortality (2.0% vs. 12.6%, p < 0.001). The associations of PlGF and sFlt-1 with CV events were not statistically significant in the fully adjusted model. Higher PlGF was associated with greater death risk (HR = 5.22, 95% CI: 1.49-18.33, p = 0.01), which was robust to adjustment for sFlt-1 and other risk factors. Elevated sFlt-1 level was also an independent predictor of mortality (HR 3.41, 95% CI: 1.49-9.51, p = 0.019). CONCLUSION: In CKD patients not yet on dialysis, higher serum level of PlGF and sFlt-1 are associated with increased mortality, but not CV events.
Assuntos
Doenças Cardiovasculares/mortalidade , Proteínas de Membrana/sangue , Insuficiência Renal Crônica/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Idoso , Aterosclerose/sangue , Aterosclerose/epidemiologia , Biomarcadores , Doenças Cardiovasculares/sangue , Espessura Intima-Media Carotídea , Causas de Morte , Comorbidade , Diabetes Mellitus/epidemiologia , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mortalidade , Estudos Prospectivos , Insuficiência Renal Crônica/mortalidade , Fatores de Risco , Fumar/epidemiologia , Resultado do TratamentoRESUMO
OBJECTIVE: Patients with chronic kidney disease (CKD) display impaired cholesterol efflux capacity and elevated CD14(++)CD16(+) monocyte counts. In mice, dysfunctional cholesterol efflux causes monocytosis. It is unknown whether cholesterol efflux capacity and monocyte subsets are associated in CKD. APPROACH AND RESULTS: In 438 patients with CKD, mediators of cholesterol efflux capacity (high-density lipoprotein cholesterol/apolipoprotein A-I) and monocyte subsets were analyzed as predictors of cardiovascular events. Monocyte subset-specific intracellular lipid content, CD36, CD68, and ABCA1 were measured in a subgroup. Experimentally, we analyzed subset-specific cholesterol efflux capacity and response to oxidized low-density lipoprotein cholesterol stimulation in CKD. Epidemiologically, both low Apo-I and low high-density lipoprotein cholesterol were associated with high CD14(++)CD16(+) monocyte counts in linear regression analyses (apolipoprotein A-I: ß=-0.171; P<0.001; high-density lipoprotein cholesterol: ß=-0.138; P=0.005), but not with counts of other monocyte subsets. In contrast to apolipoprotein A-I or high-density lipoprotein cholesterol, higher CD14(++)CD16(+) monocyte counts independently predicted cardiovascular events (hazard ratio per increase of 1 cell/µL: 1.011 [1.003-1.020]; P=0.007). Experimentally, CD14(++)CD16(+) monocytes demonstrated preferential lipid accumulation, high CD36, CD68, and low ABCA1 expression and, consequently, displayed low cholesterol efflux capacity, avid oxidized low-density lipoprotein cholesterol uptake, and potent intracellular interleukin-6, interleukin-1ß, and tumor necrosis factor-α production. CONCLUSIONS: Taken together, mediators of cholesterol efflux are associated with CD14(++)CD16(+) monocyte counts, which independently predict adverse outcome in CKD.
Assuntos
Apolipoproteína A-I/análise , Doenças Cardiovasculares/epidemiologia , HDL-Colesterol/sangue , Monócitos , Insuficiência Renal Crônica/sangue , Transportador 1 de Cassete de Ligação de ATP/sangue , Idoso , Doenças Cardiovasculares/etiologia , Feminino , Proteínas Ligadas por GPI/análise , Humanos , Imunofenotipagem , Interleucina-1beta/sangue , Interleucina-6/biossíntese , Interleucina-6/sangue , Contagem de Leucócitos , Lipídeos/sangue , Receptores de Lipopolissacarídeos/análise , Lipoproteínas LDL/sangue , Masculino , Pessoa de Meia-Idade , Monócitos/classificação , Estudos Prospectivos , Receptores de IgG/análise , Insuficiência Renal Crônica/complicações , Método Simples-Cego , Fator de Necrose Tumoral alfa/análiseRESUMO
In the general population, HDL cholesterol (HDL-C) is associated with reduced cardiovascular events. However, recent experimental data suggest that the vascular effects of HDL can be heterogeneous. We examined the association of HDL-C with all-cause and cardiovascular mortality in the Ludwigshafen Risk and Cardiovascular Health study comprising 3307 patients undergoing coronary angiography. Patients were followed for a median of 9.9 years. Estimated GFR (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration eGFR creatinine-cystatin C (eGFRcreat-cys) equation. The effect of increasing HDL-C serum levels was assessed using Cox proportional hazard models. In participants with normal kidney function (eGFR>90 ml/min per 1.73 m(2)), higher HDL-C was associated with reduced risk of all-cause and cardiovascular mortality and coronary artery disease severity (hazard ratio [HR], 0.51, 95% confidence interval [95% CI], 0.26-0.92 [P=0.03]; HR, 0.30, 95% CI, 0.13-0.73 [P=0.01]). Conversely, in patients with mild (eGFR=60-89 ml/min per 1.73 m(2)) and more advanced reduced kidney function (eGFR<60 ml/min per 1.73 m(2)), higher HDL-C did not associate with lower risk for mortality (eGFR=60-89 ml/min per 1.73 m(2): HR, 0.68, 95% CI, 0.45-1.04 [P=0.07]; HR, 0.84, 95% CI, 0.50-1.40 [P=0.50]; eGFR<60 ml/min per 1.73 m(2): HR, 1.18, 95% CI, 0.60-1.81 [P=0.88]; HR, 0.82, 95% CI, 0.40-1.69 [P=0.60]). Moreover, Cox regression analyses revealed interaction between HDL-C and eGFR in predicting all-cause and cardiovascular mortality (P=0.04 and P=0.02, respectively). We confirmed a lack of association between higher HDL-C and lower mortality in an independent cohort of patients with definite CKD (P=0.63). In summary, higher HDL-C levels did not associate with reduced mortality risk and coronary artery disease severity in patients with reduced kidney function. Indeed, abnormal HDL function might confound the outcome of HDL-targeted therapies in these patients.
Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , HDL-Colesterol/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/mortalidade , Idoso , Doenças Cardiovasculares/complicações , Angiografia Coronária , Receptores ErbB/sangue , Receptores ErbB/fisiologia , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Insuficiência Renal Crônica/complicaçõesRESUMO
OBJECTIVE: Although homocysteine has been proposed as a cardiovascular risk factor, interventional trials lowering homocysteine have not consistently demonstrated clinical benefit. Recent evidence proposed the homocysteine metabolite S-adenosylhomocysteine (SAH) rather than homocysteine itself as the real culprit in cardiovascular disease. Of note, SAH is predominantly excreted by the kidneys, and cannot be lowered by vitamin supplementation. Due to its cumbersome measurement, data from large studies on the association between SAH, kidney function and cardiovascular disease are not available. METHODS: We recruited 420 apparently healthy subjects into our I Like HOMe FU study. Among all study participants, we assessed parameters of C1 metabolism (homocysteine, SAH and S-adenosylmethionine), renal function (estimated glomerular filtration rate [eGFR]) and subclinical atherosclerosis (common carotid intima-media-thickness [IMT]). eGFR was estimated by the CKD-EPIcreat-cys equation. RESULTS: Traditional cardiovascular risk factors and subclinical atherosclerosis were associated with SAH, but not with homocysteine (IMT vs SAH: r = 0.129; p = 0.010; IMT vs homocysteine: r = 0.009; p = 0.853). Moreover, renal function was more closely correlated with SAH than with homocysteine (eGFR vs SAH: r = -0.335; p < 0.001; eGFR vs homocysteine: r = -0.250; p < 0.001). The association between eGFR and SAH remained significant after adjustment for traditional cardiovascular risk factors. CONCLUSION: In summary, cardiovascular risk factors, subclinical atherosclerosis and eGFR are more strongly associated with SAH than with homocysteine in apparently healthy subjects. Thus, SAH might represent a more promising target to prevent cardiovascular disease than homocysteine.
Assuntos
Aterosclerose/etiologia , Aterosclerose/fisiopatologia , S-Adenosil-Homocisteína/metabolismo , Doenças Assintomáticas , Aterosclerose/complicações , Aterosclerose/metabolismo , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Feminino , Taxa de Filtração Glomerular , Homocisteína/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , S-Adenosilmetionina/metabolismoRESUMO
BACKGROUND: Iron deficiency contributes to anaemia in patients with chronic kidney disease. I.v. iron is therefore widely used for anaemia treatment, although it may induce oxidative stress and activate monocytes. Different i.v. iron preparations are available, but interestingly their substance-specific immunologic effects are poorly studied. METHODS: We analysed the effect of iron sucrose, ferric carboxymaltose, iron isomaltoside 1000, low-molecular-weight iron dextran and ferumoxytol on classical, intermediate and nonclassical monocyte biology. We therefore stimulated in vitro mature monocytes and haematopoietic CD34(+) stem cells during their differentiation into monocytes with different concentrations (0.133, 0.266, 0.533 mg/mL) of i.v. iron preparations. Alterations of monocyte subset distribution, expression of surface markers (CD86, CCR5, CX3CR1), as well as production of pro-inflammatory cytokines (TNF-α, IL-1ß) and reactive oxygen species were measured using flow cytometry. Additionally, we analysed phagocytosis and antigen presentation capacity. RESULTS: We found specific immunologic effects after stimulation with iron sucrose which were not induced by the other iron preparations. Iron sucrose activated monocyte subsets leading to significantly increased CD86 expression. Simultaneously CD16 and CX3CR1 expression and monocytic phagocytosis capacity were decreased. Additionally, differentiation of monocytes from haematopoietic CD34(+) stem cells was almost completely abolished after stimulation with iron sucrose. CONCLUSIONS: Our findings demonstrate that specific immunologic effects of distinct i.v. iron preparations exist. The clinical relevance of these findings requires further investigation.