Platelet activation, coagulation activation and C-reactive protein in simultaneous samples from the vascular access and peripheral veins of haemodialysis patients.

INTRODUCTION: Most studies of haemodialysis (HD) patients compare venous blood samples from controls with samples from the vascular access (VA) of HD patients. We hypothesised that VA samples may be more prothrombotic compared with venous samples. METHODS: Samples were taken simultaneously from the VA and the contralateral antecubital vein, from 26 patients immediately before HD. Platelet function was assessed by (1) flow cytometric measurement of P-selectin expression and fibrinogen binding (±ADP) and 2) Ultegra rapid platelet function assay. Plasma soluble P-selectin, von Willebrand factor antigen, high sensitivity C-reactive Protein (hs-CRP), thrombin-antithrombin III complex and D-dimer measured by ELISA. RESULTS: Thrombin receptor activating peptide-induced platelet aggregation (P < 0.001) and hs-CRP (P < 0.001) were higher in VA compared with venous samples. Unstimulated platelet fibrinogen binding (P = 0.016) and ADP-stimulated P-selectin expression (P = 0.008) were lower in VA compared with venous samples. The significant difference in hsCRP persisted when patients taking and not taking antiplatelet therapy were analysed separately, but platelet activation remained significantly different only in the nonantiplatelet group. CONCLUSION: There are statistically significant differences between sampling sites, although samples from the VA do not appear to be more pro-thrombotic. Future studies comparing HD patients with controls should ensure uniformity of sampling sites to prevent inaccurate conclusions being drawn.

Early referral strategies for management of people with markers of renal disease: a systematic review of the evidence of clinical effectiveness, cost-effectiveness and economic analysis.

BACKGROUND: Chronic kidney disease (CKD) is a long-term condition and has been described as the gradual loss of kidney function over time. Early in the disease process, people with CKD often experience no symptoms. For a long time, CKD has been an underdiagnosed condition. Even in the absence of symptoms, CKD appears to add significantly to the burden of cardiovascular disease and death and, for an important minority, can progress to kidney failure. OBJECTIVE: To systematically review the evidence of the clinical effectiveness and cost-effectiveness of early referral strategies for management of people with markers of renal disease. DATA SOURCES: Electronic searches of 12 major databases (such as MEDLINE, EMBASE, CINAHL, etc.) were conducted for the time period of 1990 to April 2008 to identify studies comparing early referral to other care options for people with CKD. Additional searching was performed in the NHS Economic Evaluation Database to support the cost-effectiveness literature review. REVIEW METHODS: Two authors reviewed all titles, abstracts and full papers to select relevant literature. A Markov model was constructed to represent the natural history of CKD. The model allowed cohorts to be tracked according to estimated glomerular filtration rate (eGFR) status and the presence of other complications known to influence CKD progression and the incidence of cardiovascular events. RESULTS: From 36 relevant natural history studies, CKD was found to be, despite marked heterogeneity between studies, a marker of increased risk of mortality, renal progression and end-stage renal disease. Mortality was generally high and increased with stage of CKD. After adjustment for comorbidities, the relative risk of mortality among those with CKD identified from the general population increased with stage. For clinical populations, the relative risk was higher. All three outcomes increased as eGFR fell. Only seven studies, and no randomised controlled trials, were identified as relevant to assessing the clinical effectiveness of early referral strategies for CKD. In the five retrospective studies constructed from cohorts starting on renal replacement therapy (RRT), mortality was reduced in the early referral group (more than 12 months prior to RRT) even as late as 5 years after initiation of RRT. Only two studies included predialysis participants. One study, in people screened for diabetic nephropathy, reported a reduction in the decline in renal function associated with early referral to nephrology specialists (eGFR decline 3.4 ml/min/1.73 m(2)) when compared with a similar group that had no access to nephrology services until dialysis was required (eGFR decline 12.0 ml/min/1.73 m(2)). The second study, among a group of veterans with two creatinine levels of at least 140 mg/dl, reported that a composite end point of death or progression was lower in the group receiving nephrology follow-up than in those receiving only primary care follow-up. The greatest effect was observed in those with stage 3 or worse disease after adjustment for comorbidities, age, race, smoking and proteinuria {stage 3: hazard ratio (HR) 0.8 [95% confidence interval (CI) 0.61 to 0.9)]; stage 4: HR 0.75 (95% CI 0.45 to 0.89)}. In the base-case analysis, all early referral strategies produced more quality-adjusted life-years (QALYs) than referral upon transit to stage 5 CKD (eGFR 15 ml/min/1.73 m(2)). Referral for everyone with an eGFR below 60 ml/min/1.73 m(2) (stage 3a CKD) generated the most QALYs and, compared with referral for stage 4 CKD (eGFR < 30 ml/min/1.73 m(2)), had an incremental cost-effectiveness ratio of approximately 3806 pounds per QALY. LIMITATIONS: Because of a lack of data on the natural history of CKD in individuals without diabetes, and a lack of evidence on the costs and effects of early referral, the Markov model relied on many assumptions. The findings were particularly sensitive to changes in eGFR decline rates and the relative effect of early referral on CKD progression and cardiovascular events; the latter parameter being derived from a single non-randomised study. CONCLUSIONS: Despite substantial focus on the early identification and proactive management of CKD in the last few years, we have identified significant evidence gaps about how best to manage people with CKD. There was some evidence to suggest that the care of people with CKD could be improved and, because these people are at risk from both renal and cardiovascular outcomes, strategies to improve the management of people with CKD have the potential to offer an efficient use of health service resources. Given the number of people now being recognised as having markers of kidney impairment, there is an urgent need for further research to support service change.

Systematic review of the effectiveness of preventing and treating Staphylococcus aureus carriage in reducing peritoneal catheter-related infections.

OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of (1) alternative strategies for the prevention of Staphylococcus aureus carriage in patients on peritoneal dialysis (PD) and (2) alternative strategies for the eradication of S. aureus carriage in patients on PD. DATA SOURCES: Major electronic databases were searched up to December 2005 (MEDLINE Extra up to 6 January 2006). REVIEW METHODS: Electronic searches were undertaken to identify published and unpublished reports of randomised controlled trials and systematic reviews evaluating the effectiveness of preventing and treating S. aureus carriage on peritoneal catheter-related infections. The quality of the included studies was assessed and data synthesised. Where data were not sufficient for formal meta-analysis, a qualitative narrative review looking for consistency between studies was performed. RESULTS: Twenty-two relevant trials were found. These fell into several groups: the first split is between prophylactic trials, aiming to prevent carriage, and trials which aimed to eradicate carriage in those who already had it; the second split is between antiseptics and antibiotics; and the third split is between those that included patients having the catheter inserted before dialysis started and people already on dialysis. Many of the trials were small or short-term. The quality was often not good by today's standards. The body of evidence suggested a reduction in exit-site infections, but this did not seem to lead to a significant reduction in peritonitis, although to some extent this reflected insufficient power in the studies and a low incidence of peritonitis in them. The costs of interventions to prevent or treat S. aureus carriage are relatively modest. For example, the annual cost of antibiotic treatment of S. aureus carriage per identified carrier of S. aureus was estimated at 179 pounds (73 pounds screening and 106 pounds cost of antibiotic). However, without better data on the effectiveness of the interventions, it is not clear whether such costs are offset by the cost of treating infections and averting changes from peritoneal dialysis to haemodialysis. Although treatment is not expensive, the lack of convincing evidence of clinical effectiveness made cost-effectiveness analysis unrewarding at present. However, consideration was given to the factors needed in a hypothetical model describing patient pathways from methods to prevent S. aureus carriage, its detection and treatment and the detection and treatment of the consequences of S. aureus (e.g. catheter infections and peritonitis). Had data been available, the model would have compared the cost-effectiveness of alternative interventions from the perspective of the UK NHS, but as such it helped identify what future research would be needed to fill the gaps. CONCLUSIONS: The importance of peritonitis is not in doubt. It is the main cause of people having to switch from peritoneal dialysis to haemodialysis, which then leads to reduced quality of life for patients and increased costs to the NHS. Unfortunately, the present evidence base for the prevention of peritonitis is disappointing; it suggests that the interventions reduce exit-site infections, but not peritonitis, although this may be due to trials being in too small numbers for too short periods. Trials are needed with larger numbers of patients for longer durations.

The induction of transplantation tolerance by intrathymic (i.t.) delivery of alloantigen: a critical relationship between i.t. deletion, thymic export of new T cells and the timing of transplantation.

Intrathymic (i.t.) injection of donor alloantigens has proved to be an effective strategy for the induction of tolerance. However, the mechanisms by which tolerance is induced and maintained after transplantation remain unclear. In this report we show that tolerance to donor cardiac allografts can be induced across a MHC class I difference by i.t. injection of donor splenocytes and transient T cell depletion. Furthermore, using H-2K(b)-specific TCR transgenic mice (BM3), we demonstrate that prolonged deletion of donor-reactive thymocytes was essential to induce tolerance by i.t. injection and this was dependent upon donor cells persisting in the thymus. Examination of the kinetics of thymic export following i.t. injection revealed that prolonged deletion of thymocytes was required to delay export of new T cells to the periphery until the time of transplantation. Importantly, after transplantation donor cell persistence in the thymus and i.t. deletion were no longer necessary to maintain tolerance. The graft itself or cells from the graft was responsible for maintaining tolerance at this stage. These findings reveal that multiple mechanisms are responsible for the induction and maintenance phases of tolerance to alloantigens in vivo after i.t. delivery, and that a complex inter-relationship between donor cell persistence in the thymus, i.t. deletion, thymic export of T cells and the timing of transplantation is involved.

Deletion of alloantigen-reactive thymocytes as a mechanism of adult tolerance induction following intrathymic antigen administration.

Direct injection of foreign antigen into the adult thymus is a potent route of antigen delivery for the induction of tolerance in vivo. In this report, we demonstrate that tolerance to C57BL/10 (H2b/BL10) alloantigens can be induced in CBA/Ca (H2k/CBA) mice by intrathymic (IT) administration of BL10 spleen leukocytes coincident with transient peripheral immunomodulation of CD4+ T cells using a depleting anti-CD4 monoclonal antibody. T cell receptor (TCR) transgenic mice (BM3.6; H2k) expressing a CD8-independent TCR specific for H2Kb were used as recipients to facilitate investigation of the mechanisms responsible for tolerance induction by allowing visualization of events in the thymus following IT injection. IT administration of 5 x 10(7) BL10 spleen leukocytes and concomitant transient peripheral T cell depletion in BM3.6 mice resulted in a substantial H2Kb-specific deletion of transgenic-TCR+ (tg-TCR) thymocytes which was dependent on the level of tg-TCR expression. IT deletion and the failure to export CD8+ T cells to the peripheral lymphoid organs correlated with the induction of tolerance to H2Kb; TCR transgenic mice that had received IT injection of BL10 splenocytes and peripheral T cell depletion accepted a H2Kb+ cardiac allograft indefinitely. Analysis of tolerant BM3.6 mice revealed that there were low numbers of CD8+ T cells in the periphery giving rise to a substantially reduced reactivity in vitro despite the fact that no donor cells or IT deletion were observed in the thymi of the majority of tolerant mice. These results demonstrate for the first time that IT injection of foreign alloantigen into an adult thymus results in the deletion of thymocytes expressing a TCR specific for the injected alloantigen and suggest that this is an important mechanism of tolerance induction following IT injection of alloantigen in vivo. Furthermore, analysis of tolerant TCR-transgenic mice suggests that IT deletion is not required for the maintenance of tolerance, and that peripheral mechanisms enforce continued hyporesponsiveness to H2Kb following transplantation.

Characteristics of 3H-tifluadom binding in guinea-pig brain membranes.

3H-Tifluadom labels specifically recognition sites of opioid kappa receptors. Membranes of guinea-pig whole brain bind 3H-tifluadom with two affinities, in contrast to the cerebellum where almost all opioid sites are kappa.