Usefulness of serum interleukin-18 in predicting cardiovascular mortality in patients with chronic kidney disease--systems and clinical approach.
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ABSTRACT:
SUBMITTER: Formanowicz D
PROVIDER: S-EPMC4680867 | biostudies-other | 2015 Dec
REPOSITORIES: biostudies-other
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Project description:Structure-based molecular designs play a critical role in the context of next generation drug development. Besides their fundamental scientific aspects, the findings established in this approach have significant implications in the expansions of target-based therapies and vaccines. Interleukin-18 (IL-18), also known as interferon gamma (IFN-γ) inducing factor, is a pro-inflammatory cytokine. The IL-18 binds first to the IL-18α receptor and forms a lower affinity complex. Upon binding with IL-18β a hetero-trimeric complex with higher affinity is formed that initiates the signal transduction process. The present study, including structural and molecular dynamics simulations, takes a close look at the structural stabilities of IL-18 and IL-18 receptor-bound ligand structures as functions of time. The results help to identify the conformational changes of the ligand due to receptor binding, as well as the structural orders of the apo and holo IL-18 protein complexes.
| S-EPMC7392904 | biostudies-literature
Project description:BackgroundConflicting results have been reported from studies evaluating serum uric acid (SUA) levels as an independent risk factor for cardiovascular mortality in patients with chronic kidney disease (CKD).MethodsWe systematically searched MEDLINE, Web of Science, and bibliographies of retrieved articles to identify studies reporting on the association between SUA levels and cardiovascular mortality in patients with CKD. Random-effects models were used to calculate the pooled hazard ratios (HR) and corresponding 95% confidence intervals (CI).ResultsWe included 11 studies with an overall sample of 27,081 patients with CKD in this meta-analysis. By meta-analysis, restricted to 7 studies (n?=?11,050), patients with the highest SUA were associated with an increased risk of cardiovascular mortality (HR 1.47, 95% CI 1.11-1.96) compared with patients with the lowest SUA. There was no indication of publication bias or significant heterogeneity (I2 =?40.4%; P?=?0.109). Meta-analysis of 10 studies (n?=?26,660) indicated that every 1?mg/dl increase in SUA levels increased a 12% risk in cardiovascular mortality (HR 1.12, 95% CI 1.02-1.24), with significant heterogeneity (I2 =?79.2%, P?<?0.001).ConclusionsHigher SUA levels are associated with significantly increased risk of cardiovascular mortality in patients with CKD. More designed studies, especially randomized controlled trials, should be conducted to determine whether high SUA levels is a potentially modifiable risk factor for cardiovascular mortality in patients with CKD.
| S-EPMC6330757 | biostudies-literature
Project description:BackgroundInterleukin-18 is a proinflammatory cytokine, the activity of which is regulated by its natural inhibitor, IL-18 binding protein (IL-18BP). Elevated circulating levels of IL-18 have been observed in patients with systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD), two conditions associated with dysregulated innate immune responses. This study examines the expression and function of IL-18 and IL-18BP in K/BxN serum transfer arthritis (STA), a model that is uniquely dependent on innate immune responses.MethodsNaïve and serum transfer-induced arthritis (STA) wild-type (WT) mice were used to examine the articular levels of IL-18 and IL-18BP mRNA by RT-qPCR. The cellular sources of IL-18BP in the joints were determined by using Il18bp-tdTomato reporter knock-in mice. The incidence and severity of arthritis, including mRNA levels of different cytokines, were compared in IL-18BP or IL-18 knock-out (KO) mice and their WT littermates.ResultsIL-18 and IL-18BP mRNA levels were significantly increased in arthritic as compared to normal joints. Synovial neutrophils, macrophages, and endothelial cells represented the cellular sources of IL-18BP in arthritic joints, whereas IL-18BP production was limited to endothelial cells in non-inflamed joints. The incidence and severity of arthritis were similar in IL-18BP KO and IL-18 KO compared to their WT littermates. Transcript levels of different inflammatory cytokines were not different in the two KO mouse lines compared to WT mice.ConclusionAlthough IL-18 and IL-18BP levels were increased in arthritic joints, our results show that the IL-18/IL-18BP balance is not involved in the regulation of STA.
| S-EPMC10320286 | biostudies-literature
Project description:BackgroundHigh circulating interleukin (IL)-18 level predicts a higher hospitalization rate among dialysis patients, possibly through cardiovascular mechanisms; however, whether higher IL-18 level is associated with mortality in dialysis patients is less clear. In addition, its impacts on left ventricular (LV) function are also unknown. We conducted a cohort study to examine the impacts of IL-18 level on LV function and prognosis among clinically stable hemodialysis patients.MethodsClinically stable patients undergoing maintenance hemodialysis (? 3 months) were prospectively enrolled from December 2008 to January 2009, and were followed up for 31 months. The enrolled patients (41% male, 66.4 ± 10.9 years of age) received 2-dimensional echocardiography and myocardial deformation (strain) analysis, including LV peak systolic longitudinal strain (GLS) and circumferential strain (CS). Laboratory measurements were also performed. Cox regression analysis was used to investigate prognostic factors.ResultsSeventy-five patients were stratified into 2 groups by the median value of IL-18 (654.2 pg/ml). Between these 2 groups, there was no significant difference in baseline characteristics including LV ejection fraction. The high IL-18 group had a worse LV systolic function as demonstrated by reduced GLS and CS. Seventeen patients (22.7%) died during the follow-up period. Multivariate Cox regression analysis showed that low serum albumin, the presence of hypertension, high serum IL-18, and less negative GLS (>-15%) were independently associated with all-cause mortality. No significant interaction between IL-18 and less negative GLS was noted in the final Cox model.ConclusionHemodialysis patients with high IL-18 levels tend to have worse LV systolic function and higher mortality rate. However, elevated serum IL-18 level is predictive of poor prognosis among stable hemodialysis patients, independently of LV dysfunction. This suggests an additional value of IL-18 to echocardiographic study in predicting all-cause mortality, and IL-18 may be helpful in early risk stratification of hemodialysis patients.
| S-EPMC3943737 | biostudies-literature
Project description:BACKGROUND:Despite pre-kidney-transplant cardiovascular (CV) assessment being routine care to minimise perioperative risk, the utility of such assessment is not well established. The study reviewed the evaluation and outcome of a standardised CV assessment protocol. METHODS:Data were analysed for 231 patients (age 53.4 ± 12.9 years, diabetes 34.6%) referred for kidney transplantation between 1/2/2012-31/12/2014. One hundred forty-three patients were high-risk (age > 60 years, diabetes, CV disease, heart failure, peripheral vascular disease) and offered dobutamine stress echocardiography (DSE); 88 patients were low-risk and offered ECG and echocardiography with/without exercise treadmill test. RESULTS:At the end of follow-up (579 ± 289 days), 35 patients underwent kidney transplantation and 50 were active on the waitlist. There were 24 events (CV or death), none were perioperative. One hundred fifteen patients had DSE with proportionally more events in DSE-positive compared to DSE-negative patients (6/34 vs. 7/81, p = 0.164). In 42 patients who underwent coronary angiography due to a positive DSE or ischaemic heart disease symptoms, 13 (31%) had events, 6 were suspended, 11 removed from waitlist, 3 wait-listed, 1 transplanted and 17 still undergoing assessment. Patients with significant coronary artery disease requiring intervention had poorer event-free survival compared to those without intervention (56% vs. 83% at 2 years, p = 0.044). However, the association became non-significant after correction for CV risk factors (HR = 3.17, 95% CI 0.51-19.59, p = 0.215). CONCLUSIONS:The stratified CV risk assessment protocol using DSE in all high-risk patients was effective in identifying patients with coronary artery disease. The coronary angiograms identified the event-prone patients effectively but coronary interventions were not associated with improved survival.
| S-EPMC5759801 | biostudies-literature
Project description:Review: Interleukin-18 (IL-18) is a proinflammatory cytokine that promotes various innate immune processes related to infection, inflammation, and autoimmunity. Patients with systemic juvenile idiopathic arthritis and adult-onset Still's disease exhibit chronic excess of serum IL-18, which is associated with a high incidence of macrophage activation syndrome (MAS), although the mechanisms of IL-18 regulation in such diseases remain largely unknown. Similar elevation of serum IL-18 and susceptibility to MAS/hemophagocytic lymphohistiocytosis (HLH) have been reported in monogenic diseases such as X-linked inhibitor of apoptosis deficiency (i.e., X-linked lymphoproliferative syndrome type 2) and NLRC4-associated autoinflammatory disease. Recent advances in molecular and cellular biology allow the identification of other genetic defects such as defects in CDC42, PSTPIP1, and WDR1 that result in high serum IL-18 levels and hyperinflammation. Among these diseases, chronic excess of serum IL-18 appears to be linked with severe hyperinflammation and/or predisposition to MAS/HLH. In this review, we focus on recent findings in inflammatory diseases associated with and probably attributable to chronic excess of serum IL-18 and describe the clinical and therapeutical relevance of understanding the pathology of this group of diseases.
| S-EPMC9358977 | biostudies-literature
Project description:Interleukin-6 (IL-6) has been identified as an important pro-inflammatory factor involved in mediating the severity of chronic kidney disease (CKD). This study sought to determine the effect of plasma IL-6 levels on atherosclerotic cardiovascular disease (ASCVD) and cardiovascular mortality risk scores in Javanese CKD patients. We also analyzed the frequency of IL-6 G174C single nucleotide polymorphism (SNP) in the population. This study was a cross-sectional study involving seventy-three patients of Javanese ethnic origin with stable chronic kidney disease. We assessed the ASCVD risk score, cardiovascular mortality score, genotyping of IL-6 G174C SNP, and plasma IL-6 levels in these patients. The genotype distribution and allele frequencies of the IL-6 G174C SNP were predominated by the G genotype/allele (GG: 97.26%, GC: 1.37%, CC: 1.37%, G-allele: 97.95%, and C-allele: 2.05%). Despite the fact that plasma IL-6 levels did not directly affect cardiovascular mortality risk, further analysis revealed its direct effect on the ASCVD risk score (path coefficient = 0.184, p = 0.043, 95% CI = 0.018-0.380), which in turn affected cardiovascular mortality risk (path coefficient = 0.851, p = <0.01, 95% CI = 0.714-0.925). In conclusion, plasma IL-6 levels play important roles on ASCVD risk and cardiovascular mortality risk in Javanese patients with CKD.
| S-EPMC9323412 | biostudies-literature
Project description:Background:Multiple sclerosis (MS) is a chronic demyelinating disorder of central nervous system. Although the definite pathogenesis of MS has not been understood, crucial role of environmental and genetic risk factors has been proposed. Propose:To determine the serum level of interleukin-18 (IL-18) as well as gene polymorphisms of IL-18 (rs1946518, rs360719, and rs187238). Methods:In this case-control study, 110 MS patients diagnosed according to the McDonald criteria and 110 healthy individuals were recruited. IL-18 gene polymorphisms were genotyped by polymerase chain reaction high-resolution melt test, and IL-18 serum level was determined by enzyme-linked immunosorbent assay technique. Results:The mean age of the MS patients (89 females and 21 males) and the control group (89 females and 21 males) was 30.3 ± 9.25 and 30.28 ± 9.13 years, respectively. The mean serum levels of IL-18 in MS patients and healthy individuals were 341.56 ± 39.22 Pg/Ml and 146.52 ± 29.30 Pg/Ml, respectively (P < 0.001). The genotype of rs1946518 (but not rs360719 and rs187238) was significantly different between groups (P = 0.037 and P = 0.069, respectively). Conclusion:In this study, we showed the significant higher IL-18 serum level and significant different frequencies of two polymorphisms of IL-18 in MS patients. These results show the important roles of IL-18 in MS pathogenesis. However, more studies are needed to verify our results in larger sample size.
| S-EPMC6839318 | biostudies-literature
Project description:BACKGROUND:The cytokine interleukin-18 was originally identified as an interferon-?-inducing proinflammatory factor; however, there is increasing evidence to suggest that it has non-immunological effects on physiological functions. We previously investigated the potential pathophysiological relationship between interleukin-18 and dyslipidemia, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis, and suggested interleukin-18 as a possible novel treatment for not only these diseases but also for cancer immunotherapy. Before clinical application, the effects of interleukin-18 on the kidney need to be determined. In the current study, we examined the kidney of interleukin-18 knockout (Il18-/-) mice and the effects of interleukin-18 on the kidney following intravenous administration of recombinant interleukin-18. METHODS:Il18-/- male mice were generated on the C57Bl/6 background and littermate C57Bl/6 Il18+/+ male mice were used as controls. To assess kidney damage, serum creatinine and blood urea nitrogen levels were measured and histopathological analysis was performed. For molecular analysis, microarray and quantitative reverse transcription PCR was performed using mice 6 and 12 weeks old. To evaluate the short- and long-term effects of interleukin-18 on the kidney, recombinant interleukin-18 was administered for 2 and 12 weeks, respectively. RESULTS:Compared with Il18+/+ mice, Il18-/- mice developed kidney failure in their youth-6 weeks of age, but the condition was observed to improve as the mice aged, even though dyslipidemia, arteriosclerosis, and higher insulin resistance occurred. Analyses of potential molecular mechanisms involved in the onset of early kidney failure in Il18-/- mice identified a number of associated genes, such as Itgam, Nov, and Ppard. Intravenous administration of recombinant interleukin-18 over both the short and long term showed no effects on the kidney despite significant improvement in metabolic diseases. CONCLUSIONS:Short- and long-term administration of interleukin-18 appeared to have no adverse effects on the kidney in these mice, suggesting that administration may be a safe and novel treatment for metabolic diseases and cancer.
| S-EPMC5842592 | biostudies-literature
Project description:IntroductionIndividuals with metabolic syndrome (MetS) are at increasing risk of coronary artery disease (CAD). We investigated the common metabolic perturbations of CAD and MetS via serum metabolomics to provide insight into potential associations.MethodsNon-targeted serum metabolomics analyses were performed using ultra high-performance liquid chromatography coupled with Q Exactive hybrid quadrupole-orbitrap high-resolution accurate mass spectrometry (UHPLC-Q-Orbitrap HRMS) in samples from 492 participants (272 CAD vs. 121 healthy controls (HCs) as cohort 1, 55 MetS vs. 44 HCs as cohort 2). Cross-sectional data were obtained when the participants were recruited from the First Affiliated Hospital of Zhengzhou University. Multivariate statistics and Student's t test were applied to obtain the significant metabolites [with variable importance in the projection (VIP) values >1.0 and p values <0.05] for CAD and MetS. Logistic regression was performed to investigate the association of identified metabolites with clinical cardiac risk factors, and the association of significant metabolic perturbations between CAD and MetS was visualized by Cytoscape software 3.6.1. Finally, the receiver operating characteristic (ROC) analysis was evaluated for the risk prediction values of common changed metabolites.ResultsThirty metabolites were identified for CAD, mainly including amino acids, lipid, fatty acids, pseudouridine, niacinamide; 26 metabolites were identified for MetS, mainly including amino acids, lipid, fatty acids, steroid hormone, and paraxanthine. The logistic regression results showed that all of the 30 metabolites for CAD, and 15 metabolites for MetS remained significant after adjustments of clinical risk factors. In the common metabolic signature association analysis between CAD and MetS, 11 serum metabolites were significant and common to CAD and MetS outcomes. Out of this, nine followed similar trends while two had differing directionalities. The nine common metabolites exhibiting same change trend improved risk prediction for CAD (86.4%) and MetS (90.9%) using the ROC analysis.ConclusionSerum metabolomics analysis might provide a new insight into the potential mechanisms underlying the common metabolic perturbations of CAD and MetS.
| S-EPMC8498335 | biostudies-literature