Soluble tumor necrosis factor receptor 1 and 2 predict outcomes in advanced chronic kidney disease : a prospective cohort study

Background : Soluble tumor necrosis factor receptors 1 (sTNFR1) and 2 (sTNFR2) have been associated to progression of renal failure, end stage renal disease and mortality in early stages of chronic kidney disease (CKD), mostly in the context of diabetic nephropathy. The predictive value of these markers in advanced stages of CKD irrespective of the specific causes of kidney disease has not yet been defined. In this study, the relationship between sTNFR1 and sTNFR2 and the risk for adverse cardiovascular events (CVE) and all-cause mortality was investigated in a population with CKD stage 4-5, not yet on dialysis, to minimize the confounding by renal function. Patients and methods : In 131 patients, CKD stage 4-5, sTNFR1, sTNFR2 were analysed for their association to a composite endpoint of all-cause mortality or first non-fatal CVE by univariate and multivariate Cox proportional hazards models. In the multivariate models, age, gender, CRP, eGFR and significant comorbidities were included as covariates. Results : During a median follow-up of 33 months, 40 events (30.5%) occurred of which 29 deaths (22.1%) and 11 (8.4%) first non-fatal CVE. In univariate analysis, the hazard ratios (HR) of sTNFR1 and sTNFR2 for negative outcome were 1.49 (95% confidence interval (CI): 1.28-1.75) and 1.13 (95% CI: 1.06-1.20) respectively. After adjustment for clinical covariables (age, CRP, diabetes and a history of cardiovascular disease) both sTNFRs remained independently associated to outcomes (HR: sTNFR1: 1.51, 95% CI: 1.30-1.77; sTNFR2: 1.13, 95% CI: 1.06-1.20). A subanalysis of the non-diabetic patients in the study population confirmed these findings, especially for sTNFR1. Conclusion : sTNFR1 and sTNFR2 are independently associated to all-cause mortality or an increased risk for cardiovascular events in advanced CKD irrespective of the cause of kidney disease

Hepatitis C infection among injecting drug users attending the National Drug Treatment Centre.

The aim of this research was to quantify the sero-prevalence of antibody to hepatitis C among injecting drug-users and establish whether the harm minimisation programme had had an impact on infection with hepatitis C. A group (n=272) of injecting drug users attending the National Drug Treatment Centre were tested for antibody to hepatitis C virus with a second-generation EIA test. The overall sero-prevalence was found to be 84%. The results suggested that female injecting drug users were involved in greater at-risk behaviour than their male counterparts in relation to hepatitis C, since a significantly higher proportion of females tested positive than males. In relation to the duration of intravenous drug misuse, the researchers found that in patients who had been injecting for two years or more, the sero-prevalence was 95%, while in those with a duration of less than two years it was only 70%. The authors concluded that, in spite of harm reduction programmes, needle sharing continued to occur among drug users during their first two years of injecting

Mechanism of induction of tolerance to tumour-necrosis-factor (TNF): No involvement of modulators of TNF bioavailability or receptor-binding.

The repetitive administration of low doses of hTNF to mice induces tolerance to the lethal effects of mTNF. The underlying mechanism is unknown. In this study we have investigated whether changes in bioavailability and receptor binding could account for the observed differences. To that end we compared the pharmacokinetics of mTNF, the antibody response to TNF, the levels of soluble TNF receptors and the receptor binding of TNF in tolerant and control mice. No differences in pharmacokinetic parameters were observed. An antibody response towards hTNF occurred but the antibodies did not neutralize the mTNF used as a challenge. Furthermore, tolerance failed to protect mice against lethality induced by TNF in the presence of galactosamine, where 100- to 1000-fold lower dose of TNF is required. Also, tolerance could be induced in athymic nude mice where the antibody response is absent. These results show that the mechanism of induction of tolerance is not due to an antibody response. No differences in levels of soluble receptors or receptor binding could be observed in tolerant vs control mice. We conclude that the induction of tolerance involves mechanisms operating at the post-receptor pathways