SP696SOLUBLE TLR4 IN HEMODIALYSIS PATIENTS

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INTRODUCTION AND AIMS: Patients on hemodialysis (HD) present several factors, such as chronic inflammation, immune dysfunction, malnutrition and anemia, that make them a high-risk population. Subclinical inflammation is characterized by an imbalance between pro- and anti- inflammatory molecules, such as IL-1, IL-6, IL-10, TNF-a and molecules of TGF-beta superfamily. Among them, Toll-like receptors (TLRs) play a fundamental role in the innate immune system by triggering proinflammatory pathways in response to different stimuli. TLR4, the best-characterized TLR, binds to LPS leading to a downstream signaling cascade with activation of the NF-κB pathway, which, in turn, activates the transcription of many proinflammatory genes. Recently, a soluble form of extracellular TLR4 domain (sTLR4) has been characterized, which has shown the ability to attenuate TLR4 signalling. However, while it is known that in HD there is an increased expression of TLR4 on monocytes and neutrophils, there are no data on the presence of sTLR4 and its possible meaning. METHODS: We performed a cross-sectional study, enrolling clinically stable uremic patients undergoing HD at least for 6 months. Sex-matched healthy subjects were the control group. We evaluated clinical and biochemical data, including age, dialysis modality, dialysis vintage, body mass index (BMI), serum levels of phosphate, albumin, transferrin, lymphocyte count, C-reactive protein (CRP) and dialysis adequacy. Body composition was studied by BCM Body Composition Monitor (FMC, Bad Homburg, Germany) and was expressed as a three-compartment model, providing overhydration (OH), lean tissue index (LTI), and fat tissue index (FTI). In each patient, before after the hemodialysis session, serum was withdrawn and tested for sTLR4 levels by ELISA (Quantikine; R&D Systems, Minneapolis, MN, USA). RESULTS: We enrolled forty patients (68.2±16.3 years, twenty-five males) with a median dialysis vintage of 41 months. Mean BMI was 24.7±4.8 kg/m2; nine patients were diabetic. At the time of enrollment all patients were undergoing thrice-weekly 4-hour HD. Mean LTI and FTI were 13.8±3.2 and 9.9±5.6 kg/m2, respectively, which corresponded to LTI/BMI of 0.58±0.16 and FTI/BMI of 0.39±0.16. Ten healthy subjects (48.1±12.7 years, four males; BMI 26.5±2.3 kg/m2, p=0.3 vs. HD) constituted the control group (C). sTLR4 serum levels were higher in HD patients than in C without statistical significance (0.28±0.23 vs 0.13±0.14 ng/ml). There were not significant differences between predialysis and post-dialysis sTLR4 values (0.52±0.22 ng/ml). Univariate regression analysis showed a significant direct association between predialysis sTLR4 and BMI, FTI (r=0.55) and CRP levels (r=0.52), whereas there was a significant inverse association with LTI and albumin (r=-0.4). In multivariate analysis sTLR4 resulted still directly associated with FTI (p=0.038). CONCLUSIONS: In clinically stable HD patients sTLR4 resulted associated with inflammatory and nutritional parameters. sTLR4, by its modulatory effects on TLR-4 mediated signalling, could be a part of the counter-regulatory system developed to regulate inflammation in HD.

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