Influence of hematocrit on hemostasis in continuous venovenous hemofiltration during acute renal failure

Influence of hematocrit on hemostasis in continuous venovenous hemofiltration during acute renal failure.BackgroundHematocrit plays a major role in primary hemostasis by influencing blood viscosity and platelet adhesion. During continuous venovenous hemofiltration (CVVH), it is suspected that an increased hematocrit is accompanied by an activation of hemostasis and frequently leads to thromboses in the extracorporeal system. In order to examine this hypothesis, we studied the influence of hematocrit on hemostasis during CVVH.MethodsFourteen patients (8 men and 6 women, mean age 65 ± 10 years) with acute renal failure undergoing CVVH were prospectively enrolled. Polysulfone hemofilters (AV 600®; Fresenius, Oberursel, Germany) were used in all of the patients; blood flow rates were adjusted to 120 ml/min. No blood products and coagulation-related medication, except unfractionated heparin, were applied. Study exclusion criteria included a history of thromboembolism and artificial heart valves. Hemostasis activation markers (fibrinopeptide A, thrombin-antithrombin III complex, β-thromboglobulin, platelet retention) and hematocrit values were determined before and at three-day intervals during the course of CVVH treatment.ResultsThe mean hematocrit value ( ± sem) was 29 ± 1% (range, 22 to 35%). Patients with hematocrit values of less than 30% (N = 7) were compared with patients with higher hematocrit values (>30%, N = 7). The patients with a lower hematocrit (<30%) showed a stronger activation of hemostasis during CVVH when compared with those with a higher hematocrit (>30%), as indicated by a tendency toward higher values for fibrinopeptide A (25 ± 8 vs. 14 ± 5 ng/ml, P = 0.35), thrombin-antithrombin III complex (15 ± 4 vs. 10 ± 2 ng/ml, P = 0.66), and a higher β-thromboglobulin/creatinine ratio (0.62 ± 0.17 vs. 0.48 ± 0.12, P = 0.8).ConclusionContrary to our hypothesis, hematocrit values of more than 30% are not accompanied by an increased hemostasis activation during CVVH. Concerning hemostasis activation, hematocrit values between 30 and 35% may be suitable for patients on CVVH

Pressure oscillation regulates human mesangial cell growth and collagen synthesis

Abstract-Experimental renal disease models establish glomerular hypertension as a crucial determinant in glomerulosclerosis progression and demonstrate that glomerular capillary pressure reduction delays sclerosis development. An oscillating pressure (OP) chamber was constructed as an in vitro model to study human mesangial cells. Cell cultures were grown under atmospheric pressure (AP) and a controlled OP corresponding to intraglomerular capillary pressure. We show that OP significantly decreases mesangial cell proliferation within 24 hours and attenuates DNA synthesis throughout a 7-day period. To explore the effects of OP on cell metabolism, cell-associated and medium-secreted extracellular (CA and EC, respectively) collagen synthesis were measured by [ 3 H]proline incorporation. In subconfluent cultures, total CA and EC collagen synthesis was unaffected by OP, while in confluent cultures total EC collagen [ 3 H]proline incorporation was increased. To determine whether OP influenced mesangial cell growth induction, the effects of increasing glucose in the cell culture media were investigated. Our data show that the high glucose growth stimulatory effect on cell number and DNA synthesis was suppressed by OP. Under high glucose conditions, total CA collagen synthesis was increased in confluent cultures, whereas the EC collagen fraction remained unchanged. In these cultures, OP caused an additional increase in CA collagen synthesis. This study shows that mesangial cell growth and collagen synthesis are influenced by hyperbaric OP, supporting the hypothesis that glomerular capillary pressure plays a role in progressive glomerulosclerosis development. 1-4 Experimental models have shown that changes in intracapillary pressure are accompanied by a loss of afferent arteriole glomerular capillary pressure autoregulation. 5 Furthermore, therapeutic interventions with angiotensin-converting enzyme inhibitors and low protein diets that reduce glomerular intracapillary pressure can attenuate progression of glomerulosclerosis. 6,7 Nevertheless, compelling evidence has not yet been collected about the direct pathophysiologic effects of glomerular intracapillary pressure on intrinsic glomerular cells. A stretch/relaxation model (eg, by cyclic stretch/relaxation of culture plate undersurfaces) has been developed from observations of isolated glomeruli, in which glomerular volume progressively increases with enhanced perfusion pressure. 8 -10 In such studies, shear forces profoundly affect mesangial cell (MC) growth, matrix synthesis, and intermediary filament distribution. Mesangial structures with inherent centripetal forces are maintained by specific MC properties, including a smooth muscle cell phenotype, contractility, and contact points with the capillary basal membrane. 14 Furthermore, the unique central localization of MCs in the glomerular tuft, direct connection to the blood compartment, and absence of an intervening basement membrane support the notion that in addition to shear forces, intraglomerular pressure changes may mediate MC injury. Methods Establishment of Human MC Cultures Human MC isolation and primary cell culture maintenance are described in detail elsewhere

Neutrophil Extracellular Traps Promote NLRP3 Inflammasome Activation and Glomerular Endothelial Dysfunction in Diabetic Kidney Disease

Diabetes mellitus is a metabolic disease largely due to lifestyle and nutritional imbalance, resulting in insulin resistance, hyperglycemia and vascular complications. Diabetic kidney disease (DKD) is a major cause of end-stage renal failure contributing to morbidity and mortality worldwide. Therapeutic options to prevent or reverse DKD progression are limited. Endothelial and glomerular filtration barrier (GFB) dysfunction and sterile inflammation are associated with DKD. Neutrophil extracellular traps (NETs), originally identified as an innate immune mechanism to combat infection, have been implicated in sterile inflammatory responses in non-communicable diseases. However, the contribution of NETs in DKD remains unknown. Here, we show that biomarkers of NETs are increased in diabetic mice and diabetic patients and that these changes correlate with DKD severity. Mechanistically, NETs promote NLRP3 inflammasome activation and glomerular endothelial dysfunction under high glucose stress in vitro and in vivo. Inhibition of NETs (PAD4 inhibitor) ameliorate endothelial dysfunction and renal injury in DKD. Taken together, NET-induced sterile inflammation promotes diabetes-associated endothelial dysfunction, identifying a new pathomechanism contributing to DKD. Inhibition of NETs may be a promising therapeutic strategy in DKD

YB-1 mediates TNF-induced pro-survival signaling by regulating NF-κ\kappaB activation

Cell fate decisions regulating survival and death are essential for maintaining tissue homeostasis; dysregulation thereof can lead to tumor development. In some cases, survival and death are triggered by the same receptor, e.g., tumor necrosis factor (TNF)-receptor 1 (TNFR1). We identified a prominent role for the cold shock Y-box binding protein-1 (YB-1) in the TNF-induced activation and nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-$\kappa$B) p65. In the absence of YB-1, the expression of TNF receptor-associated factor 2 (TRAF2), a central component of the TNF receptor signaling complex required for NF-$\kappa$B activation, is significantly reduced. Therefore, we hypothesized that the loss of YB-1 results in a destabilization of TRAF2. Consistent with this hypothesis, we observed that YB-1-deficient cells were more prone to TNF-induced apoptotic cell death. We observed enhanced effector caspase-3 activation and could successfully rescue the cells using the pan-caspase inhibitor zVAD-fmk, but not necrostatin-1. Taken together, our results indicate that YB-1 plays a central role in promoting cell survival through NF-$\kappa$B activation and identifies a novel mechanism by which enhanced YB-1 expression may contribute to tumor development

Resistin serum levels are increased but not correlated with insulin resistance in chronic hemodialysis patients

Background/Aims: Insulin resistance is a well-known phenomenon in uremia. Resistin, a recently discovered insulin inhibitor secreted by adipocytes, is associated with obesity and insulin resistance in mice. Adiponectin, also secreted by adipocytes, is known to reduce insulin resistance in humans. The aim of the present study was to address the hypothesis that changes in resistin or adiponectin serum levels may relate to body composition and to insulin resistance in patients with end-stage renal disease. Methods: In a cross-sectional study, 33 non-diabetic patients ( 24 males and 9 females, mean age 61.5 +/- 15.8 years) with end-stage renal disease on chronic hemodialysis (treatment duration 41 +/- 31 months) that lacked signs of infection were enrolled. The control group consisted of 33, matched for age, sex and body mass index (BMI), healthy volunteers ( 22 males, 11 females, mean age 62.6 +/- 12.1 years). BMI (kg/m(2)) was calculated from body weight and height. Body fat (%) was measured by means of bioelectrical impedance. Blood samples were taken always in the morning after a 12-hour fasting period before and after the hemodialysis session. Resistin and adiponectin serum concentrations were measured by enzyme immunoassays and insulin by an electrochemiluminescence immunoassay. The posttreatment values were corrected regarding the hemoconcentration. The homeostasis model assessment index (HOMA-R) was calculated as an estimate of insulin resistance from the fasting glucose and insulin serum levels. Results: Pre-treatment resistin serum levels were significantly increased in hemodialysis patients compared to healthy controls (19.2 +/- 6.2 vs. 3.9 +/- 1.8 ng/ml; p < 0.001). Hemodialysis did not alter resistin levels, as pre- and post-treatment levels were not different when corrected for hemoconcentration (19.2 +/- 6.2 vs. 18.7 +/- 5.0 ng/ml; p = 0.54). Adiponectin levels were also increased in hemodialysis patients compared to healthy controls (25.4 +/- 21.5 vs. 10.5 +/- 5.9 mu g/ml; p < 0.001). A significant inverse correlation was observed between the serum adiponectin levels before the hemodialysis session on the one hand and the BMI ( r = - 0.527, p = 0.002), the HOMA-R ( r = - 0.378, p < 0.05) and the fasting insulin levels ( r = - 0.397, p < 0.05) on the other. However, no significant correlation was observed between serum resistin levels on the one hand versus HOMA-R index (3.2 +/- 3.9 mmol center dot mu IU/ml; r = - 0.098, p = 0.59), insulin levels (13.3 +/- 14.4 mU/l; r = - 0.073, p = 0.69), glucose levels ( 89 +/- 13 mg/dl; r = - 0.049, p = 0.78), BMI (25.6 +/- 3.7 kg/m(2); r = - 0.041, p = 0.82) and body fat content (26.4 +/- 8.4%; r = - 0.018, p = 0.94) on the other hand. Conclusion: Resistin serum levels are significantly elevated in non-diabetic patients with end-stage renal disease that are treated by hemodialysis. The hemodialysis procedure does not affect the resistin levels. Along with previous observations in patients with renal insufficiency in the pre-dialysis stage, our findings implicate an important role of the kidney in resistin elimination. However, increased resistin serum levels in hemodialysis patients are not related to reduced insulin sensitivity encountered in uremia. Copyright (C) 2005 S. Karger AG, Basel

The low-frequency radio telescope NenuFAR

International audienceNenuFAR is a new, large low-frequency radio telescope, in construction and commissioning at the Nançay Radioastronomy Observatory, that starts to provide high sensitivity observations in the 10-85 MHz range. NenuFAR’s 1938 dual polarization antennas are connected to a suite of receivers allowing the instrument to operate, simultaneously if needed, in 4 distinct modes : as a standalone beamformer, a standalone imager, a waveform snapshots recorder, and a giant low-frequency station of the LOFAR array. We provide here an overview of the antennas, receivers, data products, operation and scientific context of the instrument