Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: an observational study in three cohorts.

INTRODUCTION: It has been proposed that individual genetic variation contributes to the course of severe infections and sepsis. Recent studies of single nucleotide polymorphisms (SNPs) within the endotoxin receptor and its signaling system showed an association with the risk of disease development. This study aims to examine the response associated with genetic variations of TLR4, the receptor for bacterial LPS, and a central intracellular signal transducer (TIRAP/Mal) on cytokine release and for susceptibility and course of severe hospital acquired infections in distinct patient populations. METHODS: Three intensive care units in tertiary care university hospitals in Greece and Germany participated. 375 and 415 postoperative patients and 159 patients with ventilator associated pneumonia (VAP) were included. TLR4 and TIRAP/Mal polymorphisms in 375 general surgical patients were associated with risk of infection, clinical course and outcome. In two prospective studies, 415 patients following cardiac surgery and 159 patients with newly diagnosed VAP predominantly caused by Gram-negative bacteria were studied for cytokine levels in-vivo and after ex-vivo monocyte stimulation and clinical course. RESULTS: Patients simultaneously carrying polymorphisms in TIRAP/Mal and TLR4 and patients homozygous for the TIRAP/Mal SNP had a significantly higher risk of severe infections after surgery (odds ratio (OR) 5.5; confidence interval (CI): 1.34 - 22.64; P = 0.02 and OR: 7.3; CI: 1.89 - 28.50; P < 0.01 respectively). Additionally we found significantly lower circulating cytokine levels in double-mutant individuals with ventilator associated pneumonia and reduced cytokine production in an ex-vivo monocyte stimulation assay, but this difference was not apparent in TIRAP/Mal-homozygous patients. In cardiac surgery patients without infection, the cytokine release profiles were not changed when comparing different genotypes. CONCLUSIONS: Carriers of mutations in sequential components of the TLR signaling system may have an increased risk for severe infections. Patients with this genotype showed a decrease in cytokine release when infected which was not apparent in patients with sterile inflammation following cardiac surgery.

Quality of sleep in renal transplant recipients and patients on hemodialysis.

BACKGROUND: Sleep disorders are very common in patients with chronic kidney disease and they may not always subside after kidney transplantation. AIM AND METHODS: The aim of this cross-sectional study was to evaluate the self-reported quality of sleep, insomnia problems in particular, and examine the factors that disturb sleep of kidney transplant recipients (KTx: n=152) in comparison to age- and sex-matched patients on dialysis (HD: n=67) and participants with normal renal function (NOR: n=49), through the administration of the Athens Insomnia Scale (AIS) at least six months after transplantation. Clinical and laboratory data, as well as health-related quality of life, depression, anxiety, post-traumatic stress symptoms, and the presence of restless legs syndrome (RLS) and pruritus were investigated in relation to sleep problems. RESULTS: The highest mean AIS score was observed in the transplant patients (KTx: 4.6±13.3 vs. HD: 3.8±8.1 vs. NOR: 2.4±10.2); both KTx and HD patients had a lower quality of sleep compared to participants with normal renal function. Multiple linear regression analysis showed that the determinants of the total AIS score were the frequency of post-traumatic stress symptoms, depression, RLS, diastolic blood pressure, and pain (all p<0.0001). CONCLUSION: Although amelioration of renal function post-transplantation improves several aspects of quality of life, it does not seem to have a beneficial effect on self-reported sleep.