Prolonged catheter survival in patients with acute kidney injury on continuous renal replacement therapy using a less thrombogenic micropatterned polymer modification.

BACKGROUND: Continuous renal replacement therapy (CRRT) has been increasingly used in critically ill patients with acute kidney injury (AKI). One of the major properties that likely influence the catheter lifespan includes its surface specificity. We hypothesized that the improvement of blood-surface interaction by a reactive polymer film coating might reduce thrombogenic events in the vascular access device and subsequently lead to prolonged catheter survival in this clinical setting. METHODS: We compared, in a randomized study, the clinical application of two temporary catheters (TCs): one surface-modified double-lumen catheter (smDLC) and one standard sDLC with identical geometry and flow design. Efficacy end points were defined as the ability to complete at least 72 h CRRT without interruption due to TC dysfunction and ability to achieve blood flow rates of ≥150 mL/min. Safety end points were defined as the occurrence of catheter-related (CR) bacteraemia or other CR complications. RESULTS: We evaluated 236 critically ill patients (264 TCs) with AKI on CRRT (continuous venovenous haemodiafiltration) with age (mean±SD) of 56.9±17.9 years. The clinical investigation revealed that the number of hours before TC removal according to clinical requirements was significantly higher with smDLC as compared with sDLC (131±38 vs 113±21 h; P=0.004). Temporary catheter dysfunction occurred in 5% for smDLC and 14% for sDLC; P=0.001. Thrombosis of smDLC and sDLC was observed in 2.3 episodes per 1000 TC-days [95% confidence interval (CI), 1.9-2.5] and 4.2 episodes per 1000 TC-days (95% CI, 4.0-4.4), respectively; P=0.021. The blood flow rate was 221±29 mL/min vs 187±36 mL/min for smDLC and sDLC, respectively; P=0.012. Compared with the overall mean of TC dysfunction or thrombosis, the relative risk of premature removal (<72 h) was 0.43 (95% CI, 0.13-0.98; P=0.041) for smDLC and 2.51 (95% CI, 1.04-9.22; P=0.034) for sDLC with a significantly higher catheter-related bacteraemia rate in this latter group (P=0.008). CONCLUSION: Micropatterned surface coating with a polyurethane polymer significantly increased TC survival with lower dysfunction rate, lower thrombotic events and better bacteriological barrier than sDLC in critically ill patients with AKI necessitating CRRT.

Oxidized LDL modulates apoptosis of regulatory T cells in patients with ESRD.

Increased levels of oxidized low-density lipoproteins (oxLDL) contribute to the increased risk for atherosclerosis, which persists even after adjusting for traditional risk factors, among patients with ESRD. Regulatory T cells (CD4+/CD25+ Tregs), which down-regulate T cell responses to foreign and self-antigens, are protective in murine atherogenesis, but whether similar immunoregulation occurs in humans with ESRD is unknown. Because cellular defense systems against oxLDL involve proteolytic degradation, the authors investigated the role of oxLDL on proteasome activity of CD4+/CD25+ Tregs in patients with ESRD. CD4+/CD25+ Tregs isolated from uremic patients' peripheral blood, especially that of chronically hemodialyzed patients, failed to suppress cell proliferation, exhibited cell-cycle arrest, and entered apoptosis by altering proteasome activity. Treating CD4+/CD25+ Tregs with oxLDL or uremic serum ex vivo decreased the number and suppressive capacity of CD4+/CD25+ Tregs. In vitro, oxLDL promoted the accumulation of p27Kip1, the cyclin-dependent kinase inhibitor responsible for G1 cell cycle arrest, and increased apoptosis in a time- and concentration-dependent manner. In summary, proteasome inhibition by oxLDL leads to cell cycle arrest and apoptosis, dramatically affecting the number and suppressive capacity of CD4+/CD25+ Tregs in chronically hemodialyzed patients. This response may contribute to the immune dysfunction, microinflammation, and atherogenesis observed in patients with ESRD.

Influence of CD4+/CD25+ regulatory T cells on atherogenesis in patients with end-stage kidney disease.

Atherosclerosis, which is influenced by both traditional and nontraditional cardiovascular risk factors and has been characterized as an inflammatory process, is considered to be the main cause of the elevated cardiovascular risk associated with chronic kidney disease. The inflammatory component of atherosclerosis can be separated into an innate immune response involving monocytes and macrophages that respond to the excessive uptake of lipoproteins and an adaptive immune response that involves antigen-specific T cells. Concurrent with the influx of immune cells to the site of atherosclerotic lesion, the role of the adaptive immune response gradually increases. One of those cells are represented by the CD4+/CD25+ Tregs, which play indispensable roles in the maintenance of natural self-tolerance and negative control of pathological, as well as physiological, immune responses. Altered self-antigens such as oxidized LDLs may induce the development of CD4+/CD25+ Tregs with atheroprotective properties. However, atherosclerosis may be promoted by an imbalance between regulatory and pathogenic immunity that may be represented by the low expression of the forkhead box transcription factor (Foxp3) in CD4+/CD25+ Tregs. Such a defect may break immunologic tolerance and alter both specific and bystander immune suppression, leading to exacerbation of plaque development. Patients with end-stage kidney disease (ESKD) display a cellular immune dysfunction and accelerated atherosclerosis. Uremic solutes that accumulate during ESKD may be involved in these processes. In patients with ESKD and especially in those that are chronically hemodialyzed, oxidative stress induced by oxidized LDLs may increase CD4+/CD25+ Treg sensitivity to Fas-mediated apoptosis as a consequence of specific dysregulation of IL-2 expression. This review will focus on the current state of knowledge regarding the influence of CD4+/CD25+ Tregs on atherogenesis in patients with ESKD, and the potential effect of statins on the circulating number and the functional properties of these cells.

Oxidized low-density lipoproteins activate CD4+ T cell apoptosis in patients with end-stage renal disease through Fas engagement.

Oxidized LDL (oxLDL) are cytotoxic to vascular cells, but their possible toxic action on T cells from patients with ESRD has not been evaluated. oxLDL concentrations were measured and compared in patients who were on long-term hemodialysis (HD), in patients who had ESRD and were on continuous ambulatory peritoneal dialysis, in nondialyzed patients with chronic kidney disease, and in age- and gender-matched control subjects. In parallel, the proliferative capacity of CD69+/CD4+ T cells and their rate of apoptosis, IL-2 expression, and intracellular expression of Bcl-2 and Bax were determined in vitro. The oxLDL concentrations were significantly higher in HD patients (all P = 0.001). Upon phytohemagglutinin stimulation, CD69+/CD4+ T cells from HD patients proliferated significantly less than those from the other patients' group (both P < 0.001). oxLDL but not the native LDL were led to CD69+/CD4+ T cells' program cell death in a dosage- and time-dependent manner through Fas pathway (P = 0.001). Cell surface Fas expression was followed by DNA fragmentation when CD69+/CD4+ T cells from HD patients or control subjects were cultured with oxLDL (200 microg/ml; 31 +/- 3 versus 25 +/- 3%; P = 0.001). In the presence of oxLDL, CD69+/CD4+ T cells from HD patients expressed significantly lower IL-2 levels, which strongly correlated with a decrease in the antiapoptotic Bcl-2 and conversely with an increase in the proapoptotic Bax expression. In conclusion, these data suggest that, in HD patients, exposure of activated CD4+ T cells to oxLDL leads to Fas-mediated apoptosis in association with inhibition of IL-2 expression. Subsequently, this may favor activation of mitochondria-dependent apoptotic pathways, leading to activated CD4+ T cell dysfunction.

Rethinking the triggering inflammatory processes of chronic periaortitis.

Chronic periaortitis (CP) is an uncommon inflammatory disease which primarily involves the infrarenal portion of the abdominal aorta. However, CP should be regarded as a generalized disease with three different pathophysiological entities, namely idiopathic retroperitoneal fibrosis (RPF), inflammatory abdominal aortic aneurysm and perianeurysmal RPF. These entities share similar histopathological characteristics and finally will lead to fibrosis of the retroperitoneal space. Beside fibrosis, an infiltrate with variable chronic inflammatory cell is present. The majority of these cells are lymphocytes and macrophages as well as vascular endothelial cells, most of which are HLA-DR-positive. B and T cells are present with a majority of T cells of the T-helper phenotype. Cytokine gene expression analysis shows the presence of interleukin (IL)-1alpha, IL-2, IL-4, interferon-gamma and IL-2 receptors. Adhesion molecules such as E-selectin, intercellular adhesion molecule-1 and the vascular cell adhesion molecule-1 were also found in aortic tissue, and may play a significant role in CP pathophysiology. Although CP pathogenesis remains unknown, an exaggerated inflammatory response to advanced atherosclerosis (ATS) has been postulated to be the main process. Autoimmunity has also been proposed as a contributing factor based on immunohistochemical studies. The suspected allergen may be a component of ceroid, which is elaborated within the atheroma. We review the pathogenesis and the pathophysiology of CP, and its potential links with ATS. Clinically relevant issues are summarized in each section with regard to the current working hypothesis of this complex inflammatory disease.

Guidelines for the clinical management of atrial fibrillation: a practical perspective.

PURPOSE: Since the management of atrial fibrillation may be difficult in the individual patient, our purpose was to develop simple clinical recommendations to help the general internist manage this common clinical problem. DATA SOURCES: Systematic review of the literature with evaluation of data-related evidence and framing of graded recommendations. DATA SYNTHESIS: Atrial fibrillation affects some 1% of the population in Western countries and is linked to a significant increase in morbidity and mortality. The management of atrial fibrillation requires individualised evaluation of the risks and benefits of therapeutic modalities, relying whenever possible on simple and validated tools. The two main points requiring a decision in clinical management are 1) whether or not to implement thromboembolic prevention therapy, and 2) whether preference should be given to a "rate control" or "rhythm control" strategy. Thromboembolic prophylaxis should be prescribed after individualised risk assessment: for patients at risk, oral anticoagulation with warfarin decreases the rate of embolic complications by 60% and aspirin by 20%, at the expense of an increased incidence of haemorrhagic complications. "Rate control" and "rhythm control" strategies are probably equivalent, and the choice should also be made on an individualised basis. To assist the physician in making his choices for the care of an atrial fibrillation patient we propose specific tables and algorithms, with graded recommendations. CONCLUSIONS: On the evidence of data from the literature we propose simple algorithms and tables for the clinical management of atrial fibrillation in the individual patient.

Early T cell activation correlates with expression of apoptosis markers in patients with end-stage renal disease.

ABSTRACT. End-stage renal failure (ESRF) and chronic hemodialysis (HD) induce a state of immunodeficiency that involves T cell-mediated responses. A decreased T cell number combined with a reduced T cell lifespan and an increased T cell activation might play a role in the immune impairment associated with ESRF and chronic HD. Increased T cell activation associated with immunodeficiency suggests that activated T cells may be driven to apoptosis. To test this hypothesis, CD3+ T cell activation (CD69) and apoptosis (annexin V, CD95 (Fas), and DNA fragmentation) were analyzed in a case control study after blood draw sampling (ex vivo), in culture conditions, and after phytohemagglutinin or anti-CD3 stimulation. Ex vivo evaluation of T cells showed an increased number of activated CD69+ T cells in chronic HD patients (142 +/- 5 cells/mm3) compared with patients with ESRF (115 +/- 2 cells/mm3, P = 0.04) and controls (74 +/- 2 cells/mm3, P = 0.0006). These data were confirmed in culture conditions and after stimulation. Similarly, annexin V and CD95 (Fas)-positive T cells were more numerous in both patient groups than in controls, irrespective of the experimental conditions (P < or = 0.005 for both markers), and their percentage was always significantly higher in chronic HD patients than in patients with ESRF. The amount of DNA fragmentation was also significantly higher in the cultured resting T cells of chronic HD patients (37 +/- 3%) than in those of patients with ESRF (25 +/- 3%) and controls (20 +/- 2%) (P = 0.01). Percentage of cultured resting T cells expressing both CD69 and annexin V markers was higher in chronic HD patients (17 +/- 4%) than in patients with ESRF (10 +/- 4%) and controls (6 +/- 2%), (P = 0.005). After stimulation (phytohemagglutinin or anti-CD3), CD69+ T cell apoptosis increased by 2.4-fold in chronic HD patients compared with 1.8-fold in patients with ESRF and only 1.2-fold in controls (P = 0.001). T cells from chronic HD patients and patients with ESRF thus showed an aberrant state of early activation that contrasted with an increased proportion of annexin V and CD95 (Fas)-positive T cells engaged in apoptosis, as confirmed by DNA fragmentation. Increased susceptibility to early activated T cell apoptosis is not only associated with uremia, but is also enhanced by HD procedure. This may account for the T lymphopenia, progressive immunodeficiency, and increased infection risk seen in these patients.