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Chronic kidney disease (CKD) can be defined as the progressive loss of renal function, characterized by a decreased glomerular filtration rate (GFR). The etiology of CKD in childhood is mainly associated with congenital anomalies of the kidneys and urinary tract (CAKUT) and with glomerular diseases. The goal of this study was to investigate the hemostasis and oxidative stress in pediatric CKD of different etiologies. Fifty-four CKD children and adolescents and 52 controls were enrolled in this study. The evaluation of hemostasis was carried out by determination of D-dimer (D-Di) and plasminogen activator inhibitor (PAI-1) plasma levels, while oxidative stress was evaluated by thiobarbituric acid reactive substance (TBARS) levels, protein carbonyl content, plasma antioxidant capacity (MTT), and ascorbate. The D-Di was increased in CAKUT stage 3 or 4 patients compared with those with glomerular disease. PAI-1 was increased in patients with glomerular disease compared with CAKUT. Carbonyl protein content was higher in the control group compared with glomerular disease stage 3 or 4 patients. Our findings showed that the reduction in GFR is associated with a state of hypercoagulability. The analysis of integrated networks showed an expansion of connections among hemostatic and oxidative stress markers in CKD children and adolescents compared with controls.

Within the spectrum of sickle cell disease (SCD) are sickle cell anemia (SCA), presence of hemoglobin SS (HbSS), hemoglobin SC disease (HbSC), and sickle cell β-thalassemia (Sβ-thal). Asymmetric dimethylarginine (ADMA) competitively inhibits the binding of arginine to NOS, reducing NO production. In patients with HbSS, increased levels of ADMA have been reported, as well as changes in many hemostatic biomarkers, including the plasminogen activator inhibitor type 1 (PAI-1). We hypothesized that high levels of ADMA and PAI-1 may be associated with more severe SCD. Thus, ADMA and PAI-1 levels were determined in 78 individuals including 38 adult patients with SCD and 40 control subjects. Higher levels of ADMA were shown in HbSS and Sβ-thal patients compared to controls. Concerning PAI-1, all patients showed high levels of PAI-1 compared to controls. As a role of NO in the pathogenesis of SCD has already been established, we concluded that high levels of ADMA should compromise, at least in part, NO synthesis, resulting in endothelial dysfunction. Elevated plasma levels of PAI-1 in all patients may indicate not only endothelial dysfunction but also a hypofibrinolytic state favoring thrombotic complications. Finally, high levels of ADMA and PAI-1 may be associated with more severe SCD.

Objectives We carried out a longitudinal study to compare leukotriene B4 (LTB4), lipoxin A4 (LXA4), and resolvin D1 (RvD1) levels in pregnant women with risk factors for PE — who did (N = 11) or did not develop (N = 17) this clinical condition. Design & Methods For both groups, plasma levels of the lipid mediators were measured using immunoassays at 12–19, 20–29, and 30–34 weeks of gestation. Results LTB4 tended to be upregulated throughout gestation in women who developed PE. Moreover, this increase was significant at 30–34 weeks. Although LXA4 levels also tended to be higher in the PE group, this difference was not significant for the evaluated gestational periods. Pregnant women with PE had lower RvD1 levels and a low RvD1/LTB4 ratio at 30–34 weeks, compared to those in the normotensive pregnant women. Contrarily, RvD1 levels increased at weeks 12–19 in pregnant women who developed PE. Particularly, LXA4 and RvD1 levels were higher at 30–34 weeks than those at 20–29 weeks considering both groups of women. We observed an interaction between the gestational outcome and the gestational period in case of RvD1. Conclusions The imbalance among LTB4, LXA4, and RvD1 levels in these preeclamptic women is consistent with the excessive inflammation that underlies the pathogenesis of PE. Although our data highlight the potential for the use of these lipid mediators as clinical markers for PE development, future longitudinal studies must be carried out to confirm these findings.

Within the spectrum of sickle cell disease (SCD) are sickle cell anemia (SCA), presence of hemoglobin SS (HbSS), hemoglobin SC disease (HbSC), and sickle cell β-thalassemia (Sβ-thal). Asymmetric dimethylarginine (ADMA) competitively inhibits the binding of arginine to NOS, reducing NO production. In patients with HbSS, increased levels of ADMA have been reported, as well as changes in many hemostatic biomarkers, including the plasminogen activator inhibitor type 1 (PAI-1). We hypothesized that high levels of ADMA and PAI-1 may be associated with more severe SCD. Thus, ADMA and PAI-1 levels were determined in 78 individuals including 38 adult patients with SCD and 40 control subjects. Higher levels of ADMA were shown in HbSS and Sβ-thal patients compared to controls. Concerning PAI-1, all patients showed high levels of PAI-1 compared to controls. As a role of NO in the pathogenesis of SCD has already been established, we concluded that high levels of ADMA should compromise, at least in part, NO synthesis, resulting in endothelial dysfunction. Elevated plasma levels of PAI-1 in all patients may indicate not only endothelial dysfunction but also a hypofibrinolytic state favoring thrombotic complications. Finally, high levels of ADMA and PAI-1 may be associated with more severe SCD.

Aim This study was aimed at investigating platelet-derived microparticles (PMP), endothelium cell-derived microparticles (EMP) and von Willebrand factor (VWF) according to renal function and time post-transplant. We found this study relevant because unusual biomarkers seem to be a promising tool to evaluate chronic renal disease and post-transplant monitoring. Methods Ninety-one renal transplant recipients (RTx) were allocated into groups according to creatinine plasma levels (C1 120 months). EMP and PMP levels were assessed by flow cytometry and VWF levels were evaluated by enzyme-linked immunosorbent assay. Results Platelet-derived microparticle levels were higher in C1 group compared with C2 (P = 0.00). According to diameter, small PMP and EMP (≤0.7 μm) were also higher in C1 group, all values of P less than 0.05. T1 and T2 groups have shown high EMP levels and a predominance of big microparticle (>0.7 μm) compared with T4 group, all values of P less than 0.05. Higher VWF levels were observed among RTx with creatinine ≥1.4 mg/dL compared with other RTx, P = 0.01. Conclusion The results showed that PMP, EMP and VWF are promising markers to evaluate endothelial function in RTx. These biomarkers could play a major role in monitoring patients after renal transplant.

Problem Omega-3 and omega-6 fatty acids can be endogenously converted into mediators with pro-inflammatory (eg, leukotriene B4/LTB4) or anti-inflammatory/pro-resolving activities (eg, resolvin D1/RvD1 and maresin 1/MaR1). Recent data indicate an imbalance of LTB4 and MaR1 levels in pre-eclampsia (PE), but the relative production of these mediators, including RvD1, and the role of these mediators in the disease pathogenesis remain unclear. Therefore, this study aimed to investigate the plasma levels of LTB4, RvD1, and MaR1 in pregnant women with or without PE and non-pregnant controls and their association with clinical/laboratory parameters of PE women. Method of study LTB4, RvD1, and MaR1 plasma levels were measured by competitive enzyme immunoassay in 19 non-pregnant, 20 normotensive pregnant, and 21 PE women. Results Plasma concentrations of LTB4 were higher and RvD1 were lower in PE women than in normotensive pregnant women, who presented higher levels of LTB4 and similar levels of RvD1 to non-pregnant women. MaR1 levels did not differ among the groups. Pre-eclampsia women had decreased RvD1/LTB4 and MaR1/LTB4 ratios. Considering only the PE group, positive correlations were observed among all the mediators tested, between LTB4 and white blood cell count and between RvD1 and creatinine levels. However, all lipid mediators correlated negatively with body mass index before pregnancy. LTB4 also correlated negatively with maternal age. Conclusion Our findings suggest that the PE state results in systemic overproduction of LTB4 in relation to RvD1 and MaR1, and that these lipid mediators may be involved with the disease pathogenesis.

We have recently investigated the association between the risk of developing PE and clinical, hemostatic, inflammatory and genetic parameters of 108 severe preeclamptic women. A multivariate logistic regression analysis was performed to assess what variables are independent risk factors for PE. Univariate analysis was performed including the variables in age, smoking condition, multiple pregnancy, blood group, phenotypes and alleles of IL-4, IL-5, IL-10, IL-6, IL-8, IL-12, IL-1β, IFN-γ, TNF-α, and the plasma levels of FVII, FVIIa, FVIIa-AT, FVIII, FVW, ADAMTS13, D-Di, PAI-1, ADMA. Those variables whose P

Preeclampsia (PE) is associated with a hypercoagulability state. According to the gestational age (GA) at the onset of the disease, PE has been classified as early (GA34weeks) and late (GA≥34weeks). It has been admitted that early PE is associated with ischemic placental lesions, while in late PE an adequate or slightly impaired placentation occurs, which suggests that the two clinical forms have distinct etiology. Tissue factor (TF) binds and activates plasma factor VII triggering the coagulation. The inhibitor antithrombin (AT), along with tissue factor pathway inhibitor, acts as an inhibitor of the FVIIa-TF pathway. Once the TF-FVIIa complex is formed, the binding and transfer of FVIIa to AT is facilitated and FVIIa activity is inhibited.We evaluated the FVIIa-AT complex levels in pregnant women with early and late severe PE (sPE), in order to verify if this biomarker can be useful for discriminating the two forms of the disease.We evaluated 26 pregnant with severe early PE and 19 pregnant with severe late PE. FVIIa-AT levels were measured by STACLOT® (Diagnostica Stago). Statistical analysis was done by Mann-Whitney test.Increased FVIIa-AT levels were found in early sPE [148.4pM (137.1)] compared to late sPE [95.9pM (66.5)] (P=0.046), which suggests a higher pro-coagulant state when PE onset occurs before 34weeks of gestation.These pioneer data allow inferring the relevance of FVIIa-AT as a device for early sPE diagnosis. However, the clinical relevance of FVIIa-AT complex surely needs to be fully clarified.

Background Genetic, immune and environmental factors are involved in preeclampsia (PE) etiopathogenesis. Considering that hypertension and poor placental perfusion are important features in PE, polymorphisms in the angiotensin-converting enzyme (ACE) and estrogen nuclear receptor 1 (ESR1) genes could be involved in the predisposition and/or development of the disease. The aim of this study was to evaluate if polymorphisms in ACE and ESR1 genes were associated with PE occurrence. Material and Methods This case-control study included 209 Brazilian pregnant women (107 with severe PE and 102 normotensive controls). The polymorphisms were investigated by polymerase chain reaction (PCR) followed by polyacrylamide gel electrophoresis. Results No significant difference between PE versus normotensive pregnant women, as well as early versus late PE, was observed when compared the allelic and genotypic frequencies of insertion/deletion polymorphism in intron 16 of the ACE gene and the single nucleotide polymorphisms (SNPs - rs2234693 and rs9340799) of the ESR1 gene. Conclusion This pioneer study involving Brazilian women showed no association among the studied polymorphisms and PE, which suggests that ins/del ACE and SNPs ESR1 do not contribute to this disease occurrence in Brazil.

Sickle cell disease, the most common genetic blood disorder in the world, has high clinical variability, negatively impacts quality of life and contributes to early mortality. Sickled erythrocytes cause blood flow obstruction, hemolysis, and several hemostatic changes that promote coagulation. These events, in turn, induce chronic inflammation, characterized by elevated plasma levels of pro-inflammatory markers, which aggravates the already unfavorable state of the circulatory system. Empirical evidence indicates that the hemostatic and inflammatory systems continuously interact with each other and thereby further propagate the hypercoagulability and inflammatory conditions. In this review article, we discuss the pathophysiological aspects of sickle cell disease and the hemostatic and inflammatory changes that underlie its pathogenesis.

Introduction: Endothelial dysfunction may contribute to hypercoagulable and inflammation states presents in renal transplant, chronic kidney disease (CKD) and its causes. These disorders can be evaluated by markers, such as thrombomodulin (TM), von Willebrand factor (vWF) and interleukin 6 (IL-6). Objectives: The aim of this study was to assess TM, vWF and IL-6 in renal transplant recipients (RTR) and associate their plasma levels with primary cause of end-stage renal disease (ESRD) and allograft function. Methods: 160 RTR were grouped according to the primary cause of CKD (G1: glomerulopathy; G2: hypertensive nephrosclerosis; G3: diabetic nephropathy; and G4: other causes/unknown etiology); creatinine plasma levels (C1 < 1.4 and C2 ≥ 1.4 mg/dl); and the estimated glomerular filtration rate (eGFR) (R1< 60 and R2 ≥ 60 ml/min/1.73 m2). TM and vWF were determined by the enzyme-linked immunosorbent assay (ELISA) and IL-6 by flow cytometry. The results were presented as median, minimum and maximum; p-value < 0.05 was considered statistically significant. Results: TM levels were significantly higher in the G1 group compared to the others (G1: 8.38; G2: 5.51; G3: 5.88; G4: 6.33 ng/ml, p < 0.0001), and in the R1 group compared to R2 (R1: 6.65; R2: 6.19 ng/ml, p = 0.02). The concentration of IL-6, measured by the mean fluorescence intensity, was higher in C2 group when compared to C1 (C1: 7.9; C2: 13.35, p = 0.03). There was no difference in vWF levels among groups. TM correlated positively with IL-6 and creatinine, and negatively with eGFR. IL-6 also correlated positively with vWF. Conclusion: TM and IL-6 can be identified as potential markers for evaluating renal graft function. TM was more related to the primary cause of CKD compared to vWF and IL-6. RESUMO Introdução: A disfunção endotelial pode contribuir para estados de hipercoagulabilidade e inflamação presentes no transplante renal e na doença renal crônica (DRC) e suas causas, podendo ser avaliada por marcadores como trombomodulina (TM), fator de von Willebrand (FvW) e interleucina 6 (IL-6). Objetivos: Avaliar TM, FvW e IL-6 em receptores do transplante renal (RTR) e associar seus níveis com a causa primária de DRC pré-transplante e função do enxerto. Métodos: Foram alocados 160 RTR em grupos de acordo com a causa primária da DRC (G1: glomerulopatias; G2: nefroesclerose hipertensiva; G3: nefropatia diabética; e G4: outras causas/etiologia desconhecida), os níveis plasmáticos de creatinina (C1 < 1.4 e C2 ≥ 1.4 mg/dl) e o ritmo de filtração glomerular estimado (eRFG) (R1< 60 e R2 ≥ 60 ml/min/1.73 m2). A TM e o FvW foram determinados pelo ensaio de imunoabsorção enzimática (ELISA) e a IL-6, por citometria de fluxo. Os resultados foram apresentados como mediana, mínimo e máximo; p < 0,05 foi considerado significativo. Resultados: Níveis de TM foram significativamente maiores no grupo G1 em comparação com os demais (G1: 8,38; G2: 5,51; G3: 5,88; G4: 6,33 ng/ml, p < 0,0001), e no grupo R1 comparado com o R2 (R1: 6,65; R2: 6,19 ng/ml, p = 0,02). A concentração de IL-6, avaliada pela intensidade média de fluorescência, foi maior no grupo C2 quando comparada com o C1 (C1: 7,9; C2: 13,35, p = 0,03). Não houve diferença entre os grupos para o FvW. TM correlacionou-se positivamente com IL-6 e creatinina e negativamente com eRFG. A IL-6 foi positivamente correlacionada com o FvW. Conclusão: TM e IL-6 podem ser apontadas como potenciais marcadores para avaliar a função do enxerto renal. A TM relacionou-se mais com a causa primária da DRC, se comparada com FvW e IL-6.

Background Preeclampsia (PE) is a pregnancy disease associated with oxidative stress and endothelial dysfunction. It can be classified according to the severity and onset-time of clinical symptoms (early PE: Methods We evaluated markers of oxidative stress (thiobarbituric acid reactive substances-TBARs and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)-MTT) and endothelial lesion (thrombomodulin-TM) in early (N = 24) and late severe PE(N = 22) and normotensive pregnant women(N = 26). Results MTT levels were higher in early sPE than in normotensive pregnancy (P = 0.03). No difference was found comparing late sPE versus normotensive pregnancy, and early sPE versus late sPE. TM levels were higher in early sPE comparing to late sPE women (P = 0.05), but no difference was found between early or late sPE versus normotensive groups. TBARs levels did not differ significantly among the three groups. These data suggest that endothelial lesion and the antioxidant status are more pronounced in early sPE. Moreover, lipid peroxidation might be an early event in PE, stimulating a compensatory antioxidant defense later in pregnancy. Conclusions Longitudinal studies involving pregnant women with risk factors for PE development and including other methods for oxidative stress and endothelial lesion determination should be conducted in order to better evaluate the role of these processes in PE pathogenesis.

INTRODUCTION: Dengue virus (DENV) infection has been considered a major public health problem in tropical countries. The unavailability of serologic testing in public health centers might adversely impact patients' outcome. OBJECTIVE: This study aimed to evaluate the accuracy of mean platelet volume (MPV) and aspartate aminotransferase (AST) to platelet ratio index (APRI) as laboratory markers of DENV infection that could be used to differentiate primary and secondary infections. METHODS: We assessed laboratory results from 503 patients with positive rapid test for DENV infection. RESULTS: Severe thrombocytopenia and increased liver involvement were observed in patients with DENV heterotypic secondary infection. Our data suggest that APRI was able to distinguish patients with primary and secondary infection (p = 0.006) with a relevant sensitivity (75%), specificity (76%) and a cut-off of 1.06. A total of 80 out of 105 (76%) patients with primary DENV infection had APRI ≤ 1.06, and 12 (75%) with secondary DENV infection had APRI > 1.06. On the other hand, MPV did not show significance in the differentiation of types of infection, coming up with poor area under the receiver operating characteristic (ROC) curve (0.61). CONCLUSION: APRI seems to be a powerful tool for early identification of DENV secondary infection cases in health centers. RESUMO INTRODUÇÃO: A infecção pelo vírus da dengue (DENV) é considerada um grande problema de saúde pública nos países tropicais. A indisponibilidade de testes sorológicos em centros de saúde pública pode afetar negativamente o prognóstico do paciente. OBJETIVO: Este estudo teve como objetivo avaliar a precisão do volume médio de plaquetas (MPV) e o índice da relação de aspartato aminotransferase (AST) sobre plaquetas (APRI) como marcadores laboratoriais de infecção por DENV, que poderiam ser utilizados para diferenciar infecções primárias e secundárias. MÉTODOS: Foram avaliados os resultados laboratoriais de 503 pacientes com teste rápido positivo para infecção por DENV. RESULTADOS: Foram observadas trombocitopenia grave e disfunção hepática em pacientes com infecção secundária heterogênea por DENV. Nossos dados sugerem que o APRI foi capaz de distinguir os pacientes com infecção primária e secundária (p = 0, 006), com relevante sensibilidade (75%) e especificidade (76%) e corte de 1, 06. Um total de 80 de 105 (76%) pacientes com infecção primária por DENV tinha APRI ≤ 1, 06; e 12 (75%) com infecção secundária por DENV, APRI > 1, 06. Por outro lado, o MPV não mostrou significância na diferenciação de tipos de infecção, apresentando baixo valor da área sob a curva de característica de operação do receptor (ROC) (0, 61). CONCLUSÃO: APRI parece ser uma ferramenta poderosa para identificação precoce de casos de infecção secundária de DENV em centros de saúde.

Background Asymmetric Dimethylarginine (ADMA) is a modified amino acid formed when intracellular arginine is methylated by methyltransferases that are widely distributed throughout the body. Nitric oxide (NO) is produced from l -arginine in a reaction catalyzed by three distinct isoforms of NO synthase (NOS). NO has emerged as a mediator involved in maintenance of vascular tonus, blood pressure regulation, inhibition of platelet aggregation, leukocyte and endothelial cell interaction and vascular permeability. ADMA is an important inhibitor that competes with NOS and compromises NO synthesis. Objective This review aims to compile articles involving renal and cardiovascular diseases in which plasma ADMA was assessed in order to clarify its role in these diseases. Conclusion Although current knowledge suggests that ADMA has a role in the onset of cardiovascular and renal diseases, its actions are poorly understood. Clarifying its biochemical mechanisms is essential for improving disease management and promoting better quality of life for these patients.

Kidney transplantation is the key for patients with end-stage renal disease, improving quality of life and longer survival. However, kidney transplant triggers an intense inflammatory response and alters the hemostatic system, but the pathophysiological mechanisms of these changes are not completely understood. The aim of this cross-sectional cohort study was to investigate hemostatic biomarkers in Brazilian renal transplanted patients according to renal function and time after transplantation. A total of 159 renal transplanted patients were enrolled and D-Dimer (D-Di), Thrombomodulin (TM), von Willebrand Factor (VWF), and ADAMTS13 plasma levels were assessed by ELISA. An increase of D-Di was observed in patients with higher levels of creatinine. ADAMTS13 levels were associated with creatinine plasma levels and D-Di levels with Glomerular Filtration Rate. These results suggested that D-Di and ADAMTS13 can be promising markers to estimate renal function. ADAMTS13 should be investigated throughout the posttransplant time to clarify the participation of this enzyme in glomerular filtration and acceptance or rejection of the graft in Brazilian transplanted patients.

Aim The maintenance of stable graft function in renal transplanted recipients (RTR) is a challenge for healthcare staff. The ideal biomarkers must have significative predictive values to monitor the intricate renal function response triggered after renal transplantation. The main purpose in this study was to evaluate the regulatory and pro-inflammatory cytokines as biomarkers of allograft function in living-related renal transplant patients. Methods Regulatory and pro-inflammatory cytokine plasma levels were measured by flow cytometry in 120 living-related renal transplanted patients categorized into three groups according to creatinine plasma levels: creatinine less than 1.4 mg/dL (C1), creatinine within 1.4-2.0mg/dL (C2) and more than 2.0 mg/dL (C3). Patients were also classified as “low” or “high” cytokine producers. Clinical data were obtained from patients’ medical record. Results We have found a peak of regulatory cytokines in RTR with low creatinine levels as well as a peak of IL-6 pro-inflammatory cytokine in patients with high creatinine levels. C1 and C3 groups showed a mixed pro-inflammatory (IL-8, IL-6, IL-1β, TNF-α, IL-12 and IFN-γ) and regulatory (IL-4, IL-5 and IL-10) cytokine pattern and C2 had a predominant pro-inflammatory profile. C3 group showed a higher frequency of high pro-inflammatory cytokine producers compared to C1. Conclusion Our data suggest that regulatory cytokines IL-4, IL-5 and IL-10 could be good biomarkers associated with stable renal function, while pro-inflammatory cytokines seems to be potential markers in RTR related to high creatinine plasma levels, specially IL-6 despite of its borderline values. Copyright © 2017 John Wiley & Sons, Ltd.

This prospective study aimed to evaluate the influence of the -351A/G XbaI polymorphism in the estrogen receptor-alpha (ESR-1) gene on global cognitive scores of a community sample of healthy oldest-old individuals within one year of follow up. Methods The individuals were categorized in two groups according to the presence or absence of cognitive decline. Cognitive data were related to genetic information. Results The XbaI -351 AA genotype was more common among cognitive decliners, while -351G allele carriers showed cognitive stability or improvement. Conclusion These results suggest that ESR-1 could be associated with one-year cognitive decline in healthy oldest-old individuals, since the estrogen pathway may be involved with neuroprotection, even in healthy brain aging. RESUMO Neste estudo prospectivo foi avaliada a influência do polimorfismo -351A/G XbaI do gene do receptor de estrogênio alfa (ESR-1) sobre o desempenho cognitivo global em idosos muito idosos (≥ 75 anos) saudáveis durante um ano. Métodos Os indivíduos foram divididos em dois grupos de acordo com a presença ou ausência de declínio cognitivo. Dados cognitivos foram relacionados à informação genética. Resultados O genótipo XbaI -351 AA foi mais comum entre indivíduos que apresentaram declínio cognitivo, enquanto carreadores do alelo -351G demonstraram estabilidade ou melhora cognitiva. Conclusão Estes resultados sugerem que ESR-1 poderia estar associado ao declínio cognitivo em curto prazo em idosos saudáveis, possivelmente por meio de propriedades neuroprotetoras do estrogênio, mesmo em cérebros idosos saudáveis.

Background Preeclampsia (PE) is characterized by hypertension and proteinuria. A predisposition to endothelial dysfunction, which may trigger abnormal activation of the hemostatic and/or inflammatory systems, is thought to play a crucial part in pathogenesis of PE. We investigated the relationship between hemostatic and inflammatory parameters in women with severe PE. Methods D-Dimer, PAI-1, IL-8, IL-6, TNF-α, and IFN-γ concentrations were measured in 59 pregnant women with severe PE (sPE), 49 normotensive pregnant and 48 non-pregnant women. Results D-Dimer and PAI-1 were higher in women with sPE compared to normotensive pregnant and non-pregnant women. IL-8, IL-6, and IFN-γ also were higher in women with sPE compared to normotensive pregnant women. However, only IL-6 and IFN-γ were higher in women with sPE compared to non-pregnant women. Moreover, D-Dimer and PAI-1 showed an elevated area under ROC curve proving to be excellent for discriminating sPE. Correlation analysis showed a weak correlation between D-Dimer and IL-8 and between PAI-1 and IFN-γ in sPE. Conclusion D-Di and PAI-1 concentrations showed to be an important tool for monitoring sPE.

Background There may be a relationship between endothelial dysfunction, coagulation activation and nitric oxide (NO) synthesis in women with mild and severe preeclampsia (PE). Methods Plasma thrombomodulin (TM), D-Dimer (D-Di), cyclic guanosine monophosphate (cGMP) and placental nitric oxide synthase activity (NOS) were investigated in 21 normotensive pregnant women (G1), 22 pregnant women with mild PE (G2) and 20 pregnant women with severe PE (G3). Results TM and D-Di were significantly increased in G3 compared to G1 (P = 0.001 and P = 0.006, respectively) and G2 (P = 0.001, in both cases). However, there was no significant difference when G1 was compared to G2. For total NOS, calcium independent NOS, calcium dependent NOS no significant difference was observed among the groups studied. Conclusions TM and D-Di levels are raised in women with severe PE compared to normotensive pregnant women and women with mild PE. While increased TM levels may reflect endothelial dysfunction, raised D-Di levels indicate a hypercoagulable state. NO assessed by 2 indirect methods did not show any significant difference among the groups studied. Due to current limitations with in vitro NO measurements and interferences associated with NO bioavailability, particularly in PE, such findings should not be over-interpreted.

Preeclampsia (PE) is a multi-system disorder of human pregnancy, whose etiology remains poorly understood. Preeclamptic women are known to have an increased hypercoagulable state that result in excess fibrin deposition in several organs, which compromises their function. Tissue factor (TF) is the main physiological initiator of blood coagulation and its activity is regulated by a specific inhibitor known as Tissue factor pathway inhibitor (TFPI). Based on the important role of TF and TFPI in hemostasis, we hypothesize that their levels may change in the severe PE contributing to exacerbate hypercoagulable state. Some studies have assessed the balance between TF and TFPI in preeclamptic women, but results are inconsistent. Therefore, the aim of this study was to examine these inconsistencies and to assess TF and TFPI plasma levels in three groups of age matched women; pregnant with severe PE (n = 60), normotensive pregnant (n = 50) and normotensive non-pregnant women (n = 50). There was not significantly different among the three groups for TF plasma levels; severe PE women: 338.4 pg/mL (248.1-457.6), normotensive pregnant women: 301.5 pg/mL (216.4-442.9) and normotensive non-pregnant women 393 pg/mL (310.3-522.9). TFPI plasma levels were higher in severe PE comparing to normotensive pregnant women and normotensive non-pregnant women, 115.8 ng/mL (75-149.8); 80.3 ng/mL (59.6-99.7) and 74.5 ng/mL (47.1-98.0), respectively No difference was found between normotensive pregnant women and normotensive non-pregnant women. As for gestational age, a significant difference in TFPI levels was found between severe PE and normotensive pregnant women up to the 33rd week of pregnancy (p = 0.001), and severe PE and non-pregnant women up to the 34th (p = 0.01). In summary, our results indicated that TF plasma levels did not vary in the studied groups, while TFPI plasma levels were significantly increased in severe PE compared to normotensive pregnant and normotensive non-pregnant women. So, our data do not explain the exacerbated hypercoagulability state observed in severe PE. Further studies evaluating genes expression, TF activity and antigen, total and free TFPI and TFPI-2, both in plasma and obstetric tissues, throughout the pregnancy in PE (mild and severe forms) are required.

Introduction Preeclampsia (PE) is a multifactorial disease characterized by high blood pressure and proteinuria after the 20th week of pregnancy. PE is associated with fibrin deposition in placental microcirculation and intrauterine fetal growth retardation. We evaluated FVIII activity, VWF and ADAMTS13 plasma levels, according to O and “non O” blood groups, in women with severe PE (sPE). Methods This case-control study included 140 women; 55 pregnant with sPE, 35 normotensive pregnant and 50 non-pregnant women. VWF and ADAMTS13 antigen levels were assessed by ELISA (American Diagnostica). FVIII activity was measured by automated coagulometric method (Dade Behring) and ABO blood groups phenotyping was performed by indirect technique. Results FVIII activity and VWF levels were significantly higher comparing either sPE to normotensive pregnant (P = 0.01; P = 0.05) and to non-pregnant women (P = 0.00 in both cases) or normotensive pregnant and non-pregnant women (P = 0.00 in both cases). A significant decrease in ADAMTS13 levels was observed comparing either sPE to normotensive pregnant (P = 0.02) and non-pregnant women (P = 0.00) or normotensive pregnant and non-pregnant women (P = 0.00). FVIII activity and VWF levels were associated to O and “non O” blood groups only in non-pregnant women. Conclusions The increase of FVIII activity and VWF levels and the decrease of ADAMTS13 in sPE are not associated to O and “non O” blood groups. These alterations in hemostatic markers in sPE largely surpass those physiologically determined by ABO blood groups influence and may have masked the effect of O and “non O” groups in this disease. A concomitant analysis of VWF levels and ADAMTS13 activity and antigenic levels will be important to clarify the imbalance between these parameters found in sPE in the present study.

A plethora of evidence exists to show that endothelial perturbations underlie many of the clinical features of pre-eclampsia (P-EC), and consequently the markers signifying endothelial disturbance exhibit a rise in plasma. Among others, plasma thrombomodulin (TM) level rises significantly. TM is a transmembrane glycoprotein expressed abundantly on the endothelium of the microvasculature. It neutralizes the thrombotic potential of thrombin, mediating this anticoagulant effect through activation of protein C. Endothelial injury results in a localized loss of TM with a focal impairment of protein C activation and resultant thrombotic tendency. Mainly expressed on the endothelial cells, a small amount of TM is found in plasma with levels rising in certain pathological conditions. Although elevation in levels of TM can be due to endothelial TM proteolysis secondary to endothelial insult, ineffective clearance may account for this in renal and hepatic dysfunction. In P-EC not only is there ongoing endothelial injury, but renal function is also affected. To establish the cause of elevated TM level in P-EC, three groups of pregnant women were investigated. It appears that the elevation in plasma TM is not related to renal or hepatic dysfunction in P-EC. It is more likely that plasma TM is derived from placental or vascular endothelial cells subsequent to activation or damage, confirming the hypothesis that damage to vascular endothelial cells is the primary underlying cause of P-EC.

HELLP syndrome was first described in 1982 by Weinstein et al. and the term HELLP refers to an acronym used to describe the clinical condition that leads to hemolysis, elevated liver enzymes and low platelets. The syndrome frequency varies from 0.5 to 0.9% pregnancies and manifests preferentially between the 27th and 37th week of gestation. Approximately 30% of cases occur after delivery. Although the etiopathogenesis of this syndrome remains unclear, histopathologic findings in the liver include intravascular fibrin deposits that presumably may lead to hepatic sinusoidal obstruction, intrahepatic vascular congestion, and increased intrahepatic pressure with ensuing hepatic necrosis, intraparenchymal and subcapsular hemorrhage, and eventually capsular rupture. Typical clinical symptoms of HELLP syndrome are pain in the right upper quadrant abdomen or epigastric pain, nausea and vomiting. However, this syndrome can present nonspecific symptoms and the diagnosis may be difficult to be established. Laboratory tests and imaging exams are essential for differential diagnosis with other clinical conditions. Treatment of HELLP syndrome with corticosteroids, targeting both lung maturation of the fetus is still an uncertain clinical value. In conclusion, three decades after the tireless efforts of Dr. Weinstein to characterize HELLP syndrome, it remains a challenge to the scientific community and several questions need to be answered for the benefit of pregnant women.

Preeclampsia (PE) is characterized by hypertension and proteinuria, occurring after the 20th week of pregnancy in women who have had no previous symptoms. The disease progresses with generalized vasoconstriction and endothelial dysfunction. Clinically, it is important to diagnose the severe form of the disease (sPE), in which blood pressure and proteinuria are much higher. Recently, the gestational age (GA) of the onset of PE has led to the classification of this disease as early (GA

Preeclampsia (PE) is characterized by hypertension and proteinuria after the 20th week gestation. The aim of this study was to investigate whether platelet count (PC) and platelet indices (mean platelet volume (MPV), platelet distribution width (PDW), and plateletcrit (PCT)) could predict severe form of preeclampsia (sPE).Three groups were evaluated; G1-pregnant with sPE (N = 29); G2-normotensive pregnant (N = 28) and Group 3: non-pregnant women (N = 30). Platelet parameters were obtained using the same automatic blood cells count. Statistical analysis was performed by analysis of variance, t-test, and receiver operating characteristic (ROC) curve. P ≤ 0.05 was considered significant.Lower PC and PCT were observed in sPE comparing to normal pregnant (P = 0.031 and 0.035, respectively) and to non-pregnant women (P0.001 and 0.004, respectively). PDW was higher in sPE comparing to normotensive pregnant (P = 0.028) and to non-pregnant women (P0.001). MPV was higher in sPE comparing to normotensive pregnant and non-pregnant women (P = 0.05 and P0.001, respectively). Analysis from the ROC curve and its areas for each variable showed that the parameters have regular diagnostic significance, except for PCT, considered as not good for this purpose.PC emerges as a good candidate for sPE diagnosis, since it is a simple and habitually done method, with lower cost and greater accessibility in the clinical laboratory. Further studies evaluating sequential PC and platelet indices throughout pregnancy are necessary to clarify the role of platelet parameters in PE development and severity.

Preeclampsia (PE) is a multifactorial pregnancy-specific syndrome which represents one of the leading causes of maternal mortality worldwide. Inherited thrombophilia have been investigated as risk factor for the development of PE and it is currently known that ABO blood group may impact haemostatic balance, having the non-O blood groups (A, B or AB) subjects increased risk for thrombus formation, as compared to those of group O. We performed a systematic review of the literature for published studies investigating whether ABO blood groups could influence PE developing. A sensitive search of four databases identified 45 unique titles. The retrieved papers were assessed independently by authors and a rigorous process of selection and data extract was conduct. Methodological quality of the included studies was also evaluated. Two studies met eligibility criteria. As a main finding of our systematic review, an association between the AB blood group and the occurrence of PE was detected based on two original studies. Considering the role of ABO blood groups on the hemostatic process and thrombus formation, special attention should be given to pregnant patients carrying the AB blood group in order to prevent the syndrome and improve prognosis.

Preeclampsia (PE) is characterized by hypertension and proteinuria. It has been classified in early or late according to gestational age at the onset of disease. Endothelial dysfunction plays a crucial part in its pathogenesis. NO is a potent vasodilator and ADMA is its endogenous inhibitor. We have assessed maternal ADMA levels. ADMA were increased in early [0.66μmol/L] versus late sPE [0.47μmol/L] (P=0.001) and versus normotensive pregnant [0.48μmol/L] (P=0.001). Our findings suggest that high ADMA levels in early sPE could compromise NO synthesis contributing to endothelial dysfunction, leading to impaired placentation and the onset of this disease.

Although preeclampsia causes high maternal/fetal morbidity and mortality, the etiology of this multi-system disorder still remains to be elucidated. Herein, we have characterized the cytokine plasma levels in severe preeclamptic women compared to normotensive pregnant and non-pregnant women, aiming to better understand the immunological network and its clinical significance for the pathogenesis and severity of preeclampsia. A total of 219 women were selected. The study population was composed of three groups referred as severe preeclamptic, normotensive pregnant and non-pregnant women. Cytokine plasma levels were determined using commercially available kits, Cytometric Beads Array – CBA to quantify TNF-α, IFN-γ, IL-4, IL-5, IL-10, IL-1β, IL-6, IL-8 and IL-12. Our findings demonstrated that severe preeclamptic state is associated with high levels of pro-inflammatory cytokines IL-8, IL-6, and IFN-γ (P

CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior Mesmo após o transplante renal bem-sucedido, complicações podem ocorrer levando à perda do enxerto ou até mesmo à morte. Dentre as principais complicações associadas, podemos citar aquelas que cursam com a disfunção endotelial e alterações da hemostasia, ambas associadas à redução da sobrevida do enxerto. Assim, o objetivo geral foi avaliar os marcadores endoteliais (endocan, homocisteína) e hemostáticos (atividade de ADAMTS13 e geração de trombina) em pacientes receptores do transplante renal (RTR) e correlacioná-los com a evolução do enxerto. Foram incluídos 115 RTR, avaliados em delineamento transversal, distribuídos em subgrupos de acordo com a função de filtração renal [creatinina sérica (C1 ≤1,4 e C2 >1,4 mg/dL) e ritmo de filtração glomerular estimado – eRFG (R1 ≤60 e R2 >60 mL/min/1,73m2] e com o tempo após o transplante [T1: 3 a 24; T2: 25 a 60; T3: 61 a 120 e T4: acima de 120 meses pós-transplante]. Uma análise longitudinal prospectiva também foi realizada por meio da avaliação de prontuários médicos por um período de seguimento de 5 anos. A endocan foi mensurada pelo método de ELISA. A avaliação dos níveis de homocisteína foi feita por ensaio enzimático-colorimétrico e a determinação da atividade de ADAMTS13 por transferência de energia de ressonância de fluorescência. O teste de geração de trombina (TGT) foi realizado pelo método CAT (Calibrated Automated Thrombogram) utilizando baixa (LTF) e alta (HTF) concentração do fator tissular. Níveis elevados de endocan e homocisteína foram observados entre os RTR com pior função de filtração renal (subgrupos C2 e R1), se comparados aos RTR com melhor função de filtração (subgrupos C1 e R2). Quanto ao tempo pós-transplante, os pacientes com transplante recente apresentaram níveis mais elevados de endocan (subgrupo T1) do que os demais RTR, o mesmo não sendo observado para Homocisteína. Não foram observadas diferenças significativas em relação aos valores da atividade de ADAMTS13 entre os subgrupos. Menor geração de trombina foi observada entre os pacientes com pior função de filtração renal (subgrupo C2), se comparado aos RTR com função de filtração preservada (subgrupo C1). De acordo com o tempo pós-transplante, os pacientes com maior tempo pós-transplante (subgrupos T3 e T4) apresentaram níveis mais elevados de trombina se comparados aos RTR com menor tempo pós-transplante (subgrupos T1 e T2). Correlações positivas foram encontradas para o potencial endógeno de trombina (ETP) e pico (em LTH e HTF) versus triglicerídeos e tempo pós-transplante. Os modelos de regressão linear mostraram que o tempo pós-transplante foi um preditor independente da geração de trombina avaliado por ETP. A avaliação longitudinal prospectiva mostrou que dentre as complicações mais frequentes após 5 anos de seguimento foram: infecções urinárias e respiratórias; rejeição ao enxerto e neoplasias. Ao avaliar a influência dos marcadores mensurados na fase transversal do estudo e sua associação com episódios de rejeição ao enxerto a longo prazo, não foram observadas diferenças significativas. Finalmente, os dados analisados em conjunto permitem concluir que as dosagens da endocan, homocisteína e o teste de geração de trombina mostraram ser ferramentas promissoras para diagnosticar e monitorar alterações endoteliais e hemostáticas entre os pacientes transplantados renais ao longo do tempo. No entanto, novos estudos são necessários para melhor compreensão das possíveis associações entre tais marcadores e a ocorrência de rejeição a longo prazo. Even after successful kidney transplantation, complications can occur leading to allograft loss or even death. Among the main associated complications, we can mention those occurring due to endothelial dysfunction and hemostasis alterations, both associated with reduced allograft survival. Thus, our objective was to evaluate endothelial (endocan, homocysteine) and hemostatic (ADAMTS13 activity and thrombin generation) markers in renal transplant recipients (RTR) and correlate them with allograft evolution. One hundred and fifteen RTRs were included, evaluated in a cross-sectional design, distributed into subgroups according to renal filtration function [creatinine levels (C1 ≤1.4 and C2 >1.4 mg/dL) and estimated glomerular filtration rate – eRFG ( R1 ≤60 and R2 >60 mL/min/1.73m2] and with time after transplantation [T1: 3 to 24; T2: 25 to 60; T3: 61 to 120 and T4: over 120 months post-transplant ] A prospective longitudinal analysis was also performed through the evaluation of medical records for a follow-up period of 5 years. Endocan was measured by the ELISA method. The evaluation of homocysteine levels was performed by enzymatic-colorimetric assay and the determination of ADAMTS13 activity by fluorescence resonance energy transfer. Thrombin generation test (TGT) was performed by the CAT (Calibrated Automated Thrombogram) method using low (LTF) and high (HTF) concentrations of tissue factor. Higher levels of endocan and homocysteine were observed among RTR with worse renal filtration function (subgroups C2 and R1), compared to RTR with better filtration function (subgroups C1 and R2). As for post-transplant time, patients with recent transplantation had higher levels of endocan (T1 subgroup) than the other RTRs, the same not being observed for homocysteine, whose values did not differ in relation to this variable. No significant differences were observed for ADAMTS13 activity values between the subgroups. Lower thrombin generation was observed among patients with worse renal filtration function (C2 subgroup), compared to RTR with preserved filtration function (C1 subgroup). According to post-transplant time, patients with longer post-transplant time (T3 and T4 subgroups) had higher levels of thrombin compared to RTR with shorter post-transplant time (T1 and T2 subgroups). Positive correlations were found for endogenous thrombin potential (ETP) and peak (in LTH and HTF) versus triglycerides and post-transplant time. Linear regression models showed that post-transplant time was an independent predictor of thrombin generation assessed by ETP. The prospective longitudinal evaluation showed that among the most frequent complications after 5 years of follow-up were urinary and respiratory infections; allograft rejection and neoplasms. When evaluating the influence of the markers measured in the cross-sectional phase of the study and their association with long term allograft rejection episodes, no significant differences were observed. Finally, all the data analyzed together allow us to conclude that endocan, homocysteine and the thrombin generation test showed to be promising tools for diagnosing and monitoring endothelial and hemostatic changes among kidney transplant patients over time. Further studies are needed to better understand the possible associations between such markers and the occurrence of long-term rejection.

CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior A doença renal crônica (DRC) é caracterizada pela perda progressiva da função até a falência renal. A DRC é menos frequente em crianças que em adultos. Na infância, as principais causas incluem malformações congênitas dos rins e trato urinário (CAKUT), seguida por glomerulopatias, além de doenças císticas e tubulopatias. Existem fatores que propiciam o avanço da DRC como; estresse oxidativo, disfunção endotelial e inflamação. Esta última promove injúrias teciduais que impossibilitam a homeostase do parênquima renal, retro-alimentando o processo inflamatório que consequentemente agrava a DRC. Com o presente estudo, objetivou-se avaliar marcadores inflamatórios como a Interleucina 17 (IL-17), Interleucina 33 (IL-33), Quimiocina CXC 16 (CXCL16), Anexina A1 (AnxA1), Interleucina 4 (IL-4), Interleucina 10 (IL-10), Relação neutrófilo-linfócito (RNL), Relação neutrófilo-linfócito derivada (dRNL), Relação linfócito-monócito (RLM) e o Índice de resposta à inflamação sistêmica (Siri) em pacientes pediátricos com DRC, de acordo com as diferentes etiologias/estágios. Foram avaliadas 85 crianças distribuídas em sete grupos, sendo; Grupo IA: crianças com DRC causada por glomerulopatias em estágio 1 ou 2; Grupo IB: crianças com DRC causada por glomerulopatias em estágio 3 ou 4; IIA: crianças com DRC causada por CAKUT em estágio 1 ou 2; IIB: crianças com DRC causada por CAKUT em estágio 3 ou 4; III: crianças com DRC causada por outras etiologias em estágio 3 ou 4. Além disso, foi criado um grupo mais amplo composto por todos os pacientes com DRC, incluindo os estágios de 1 ao 4 (Grupo IV), e por fim um grupo controle (Grupo V), composto por indivíduos saudáveis com idades compatíveis aos pacientes pediátricos As concentrações séricas dos marcadores inflamatórios foram determinados pela técnica de imunoensaio enzimático e os índices derivados do hemograma foram determinados por meio de cálculos com parâmetros do hemograma obtidos do banco de dados do projeto original. Os resultados revelaram redução sérica dos marcadores IL-17, IL-33 e CXCL16 nos pacientes com DRC (incluindo todo os estágios da doença) em relação ao controle. A AnxA1, IL-4 e IL-10 não apresentaram diferenças entre os dois grupos. A RLM apresentou-se reduzida nos pacientes com DRC em comparação ao controle, e o Siri aumentado nos pacientes com DRC quando comparado ao controle. Para os índices RNL e dRNL não houve diferenças entre os pacientes com DRC versus controle. Os mediadores pró-inflamatórios como IL-17 e CXCL16 apresentaram-se promissores nos pacientes com DRC e também os índices derivados do hemograma, como a RLM e o Siri refletiram o status pró-inflamatório nestes pacientes do estudo. Chronic kidney disease (CKD) is characterized by progressive loss of function leading to kidney failure. CKD is less common in children than in adults. In childhood, the main causes include congenital abnormalities of the kidneys and urinary tract (CAKUT), followed by glomerulopathies, in addition to cystic diseases and tubulopathies. There are factors that favor the advancement of CKD such as; oxidative stress, endothelial dysfunction and inflammation. The latter promotes tissue injuries that make homeostasis of the renal parenchyma impossible, feeding back the inflammatory process that consequently aggravates the CKD. The present study aimed to evaluate inflammatory markers such as Interleukin 17 (IL-17), Interleukin 33 (IL-33), Chemokine CXC 16 (CXCL16), Annexin A1 (AnxA1), Interleukin 4 (IL-4), Interleukin 10 (IL-10), Neutrophil-lymphocyte ratio (NLR), Neutrophil-lymphocyte-ratio-derived (dNLR) , Lymphocyte-monocyte ratio (LMR) and Systemic Inflammation Response Index (Siri) in pediatric patients with CKD, according to the different etiologies/stages. Eighty-five children were divided into seven groups and evaluated, namely; Group IA: children with CKD caused by glomerulopathies in stage 1 or 2; Group IB: children with CKD caused by glomerulopathies in stage 3 or 4; IIA: children with CKD caused by CAKUT in stage 1 or 2; IIB: children with CKD caused by CAKUT in stage 3 or 4; III: children with CKD caused by other etiologies in stage 3 or 4. In addition, a broader group was created, comprising all patients with CKD, including stages 1 to 4 (Group IV), and finally a control group (Group V), composed of healthy individuals with ages compatible with pediatric patients Serum concentrations of inflammatory markers were determined by the enzyme immunoassay technique and indices derived from the blood count were determined through calculations with blood count parameters obtained from the original project database. The results revealed a reduction in serum markers IL-17, IL-33 and CXCL16 in patients with CKD (including all stages of the disease) compared to control. AnxA1, IL-4 and IL-10 showed no differences between the two groups. LMR was reduced in patients with CKD compared to control, and Siri increased in patients with CKD compared to control. For the NLR and dNLR indices there were no differences between patients with CKD versus control. Pro-inflammatory mediators such as IL-17 and CXCL16 were showing promise in patients with CKD, as well as blood count-derived indices such as LMR and Siri reflected the pro-inflammatory state of the study patients.

A pré-eclâmpsia (PE) é uma doença exclusivamente gestacional e multissistêmica. Ela é caracterizada pelo aumento da pressão arterial (≥140/90 mmHg), com ou sem a presença de proteinúria, a partir da 20ª semana de gestação. Sabe-se que a placenta desempenha importante papel na patogênese dessa doença. Durante a gestação, o processo de placentação libera importantes fatores angiogênicos, como o fator de crescimento placentário (PlGF), fator angiogênico, e tirosina quinase fms solúvel tipo 1 (sFlt-1), fator antiangiogênico, que atuam durante este processo e em todo o decorrer da gestação. Estudos demonstraram que durante uma gestação com PE, as concentrações de PlGF diminuem já no início da gestação enquanto as de sFlt-1 aumentam. E a razão entre essas duas concentrações podem estabelecer indícios que auxiliam na predição da PE. A fim de determinar a importância desses níveis e sua eficácia na predição da PE, este estudo objetivou avaliar as concentrações de PlGF e sFlt-1 nas gestantes com PE e nas normotensas realizando um estudo transversal e um estudo longitudinal. No estudo transversal, realizado com gestantes com PE grave e normotensas, os níveis de sFlt-1 foram maiores nas gestantes com PE grave (p