TAK-242 improves sepsis-associated acute kidney injury in rats by inhibiting the TLR4/NF-κB signaling pathway.

OBJECTIVE: This study was designed to observe the effect of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway activity on sepsis-associated acute kidney injury (SA-AKI), thereby providing new considerations for the prevention and treatment of SA-AKI. METHODS: The rats were divided into Sham, cecal ligation and puncture (CLP), CLP + vehicle, and CLP + TAK-242 groups. Except the Sham group, a model of CLP-induced sepsis was established in other groups. After 24 h, the indicators related to kidney injury in blood samples were detected. The pathological changes in the kidneys were observed by hematoxylin-eosin staining, and tubular damage was scored. Oxidative stress-related factors, mitochondrial dysfunction-related indicators in each group were measured; the levels of inflammatory factors in serum and kidney tissue of rats were examined. Finally, the expression of proteins related to the TLR4/NF-κB signaling pathway was observed by western blot. RESULTS: Compared with the CLP + vehicle and CLP + TAK-242 groups, the CLP + TAK-242 group reduced blood urea nitrogen (BUN), creatinine (Cr), cystatin-C (Cys-C), reactive oxygen species (ROS), malondialdehyde (MDA), and inflammatory factors levels (p < 0.01), as well as increased superoxide dismutase (SOD) activity of CLP rats (p < 0.01). Additionally, TAK-242 treatment improved the condition of CLP rats that had glomerular and tubular injuries and mitochondrial disorders (p < 0.01). Further mechanism research revealed that TAK-242 can inhibit the TLR4/NF-κB signaling pathway activated by CLP (p < 0.01). Above indicators after TAK-242 treatment were close to those of the Sham group. CONCLUSION: TAK-242 can improve oxidative stress, mitochondrial dysfunction, and inflammatory response by inhibiting the activity of TLR4/NF-κB signaling pathway, thereby preventing rats from SA-AKI.

Association between serum sodium level trajectories and survival in patients with heart failure.

AIMS: The effect of changes in serum sodium levels on the survival of patients with heart failure (HF) is unclear. We aimed to analyse the impact of serum sodium level trajectories on survival in intensive care unit (ICU) patients with HF. METHODS: A total of 4760 patients diagnosed with HF between 2001 and 2012 from the Medical Information Mart for Intensive Care III (MIMIC-III) database were extracted. Of these patients, 1132 patients who died within 48 h of ICU admission were excluded, and 3628 patients were included in this retrospective cohort study. Sodium levels were measured at baseline, 6, 12, 18, 24, 30, 36, 42, and 48 h. Patients were divided into hyponatremia, normal, and hypernatremia groups based on baseline sodium levels, and trajectory modelling was performed for each group separately. Group-based trajectory model (GBTM) method was utilized to identify serum sodium levels trajectories. RESULTS: The number of patients with hyponatremia (<135 mmol/L), normal sodium levels (135-145 mmol/L), and hypernatremia (>145 mmol/L) at baseline were 594 (16.37%), 2,738 (75.47%), and 296 (8.16%), respectively. A total of seven trajectory groups were identified, including hyponatremia-slow rise group [initial levels (IL), 128.48 ± 5.42 mmol/L; end levels (EL), 131.23 ± 3.83 mmol/L], hyponatremia-rapid rise to normal group (IL, 132.13 ± 2.18 mmol/L; EL, 137.46 ± 3.68 mmol/L), normal-slow decline group (IL, 137.65 ± 2.15 mmol/L; EL, 134.50 ± 2.54 mmol/L), normal-steady-state group (IL, 139.20 ± 2.26 mmol/L; EL, 139.04 ± 2.58 mmol/L), normal-slow rise group (IL, 140.94 ± 2.37 mmol/L; EL, 143.43 ± 2.89 mmol/L), hypernatremia-rapid decline to normal group (IL, 146.31 ± 1.98 mmol/L; EL, 140.71 ± 3.61 mmol/L), and hypernatremia-slow decline group (IL, 148.89 ± 5.54 mmol/L; EL, 146.28 ± 3.90 mmol/L). The results showed that hyponatremia-slow rise group [hazard ratio (HR) = 1.35; 95% confidence interval (CI), 1.01-1.80, P = 0.040], hyponatremia-rapid rise to normal group (HR = 1.37; 95% CI, 1.11-1.71, P = 0.004), hypernatremia-rapid decline to normal group (HR = 1.46; 95% CI, 1.08-1.97, P = 0.014), and hypernatremia-slow decline group (HR = 1.49; 95% CI, 1.07-2.07, P = 0.018) trajectories were associated with an increased risk of 1-year mortality in HF patients compared with normal-steady-state group. After adjustment for all confounders, hyponatremia-rapid rise to normal group (HR = 1.26, 95% CI; 1.01-1.57, P = 0.038) and hypernatremia-rapid decline to normal group (HR = 1.36; 95% CI, 1.01-1.84, P = 0.047) trajectories were still related to an increased risk of 1-year mortality in patients with HF. CONCLUSIONS: Serum sodium level trajectories were associated with mortality in patients with HF. Association between serum sodium level trajectories and prognosis in patients with HF deserve further study.