interleukin-8 and Renal-Insufficiency

In the pathophysiology of acute respiratory distress syndrome (ARDS), the increase in capillary and alveolar permeability caused by various humoral mediators and resultant pulmonary interstitial edema play major roles. In this study, the efficacy of continuous hemodiafiltration using a cytokine-adsorbing hemofilter with a membrane made of polymethylmethacrylate (PMMA-CHDF) in the treatment of ARDS patients was investigated.. Fifty-one patients with a diagnosis of ARDS complicated by renal failure and without prior steroid therapy were enrolled in this study. Changes in respiratory index (RI), positive end-expiratory pressure, central venous pressure (CVP) and blood levels of TNFalpha, IL-6 and IL-8 before/after blood purification for 3 days as well as the cumulative water balance during the 3-day treatment and 28-day cumulative survival rate were compared between 2 patient groups. One group underwent PMMA-CHDF and the other intermittent hemodialysis (IHD) without water removal for elimination of metabolites and continuous hemofiltration (CHF) for fluid management.. Blood purification for 3 days significantly decreased blood levels of cytokines and successfully removed water without changing CVP in the PMMA-CHDF group, but not in the IHD+CHF group. Significant correlations between changes in blood levels of cytokines (IL-6 and IL-8) and changes in RI were demonstrated in the PMMA-CHDF group. The 28-day cumulative survival rate in the PMMA-CHDF group (68.8%) was significantly higher than that in the IHD+CHF group (36.8%).. Cytokine removal therapy with PMMA-CHDF is expected to be useful as a new therapeutic modality in ARDS patients for non-renal indications.

Topics: Cytokines; Hemodiafiltration; Humans; Immunomodulation; Interleukin-6; Interleukin-8; Membranes, Artificial; Polymethyl Methacrylate; Renal Insufficiency; Respiratory Distress Syndrome; Survival Rate; Tumor Necrosis Factor-alpha

Precision medicine aims to change treatment from a "one-size-fits-all" approach to customized therapies based on the individual patient. Applying a precision medicine approach to a heterogeneous condition, such as the cardiopulmonary bypass (CPB)-induced inflammatory response, first requires identification of homogeneous subgroups that correlate with biological markers and postoperative outcomes. As a first step, we derived clinical phenotypes of the CPB-induced inflammatory response by identifying patterns in perioperative clinical variables using machine learning and simulation tools. We then evaluated whether these phenotypes were associated with biological response variables and clinical outcomes.. This single-center, retrospective cohort study used Cleveland Clinic registry data from patients undergoing cardiac surgery with CPB from January 2010 to March 2020. Biomarker data from a subgroup of patients enrolled in a clinical trial were also included. Patients undergoing emergent surgery, off-pump surgery, transplantation, descending thoracoabdominal aortic surgery, and planned ventricular assist device placement were excluded. Preoperative and intraoperative variables of patient baseline characteristics (demographics, comorbidities, and laboratory data) and perioperative data (procedural data, CPB duration, and hemodynamics) were analyzed to derive clinical phenotypes using K-means-based consensus clustering analysis. Proportion of ambiguously clustered was used to assess cluster size and optimal cluster numbers. After clusters were formed, we summarized perioperative profiles, inflammatory biomarkers (eg, interleukin [IL]-6 and IL-8), kidney biomarkers (eg, urine neutrophil gelatinase-associated lipocalin [NGAL] and IL-18), and clinical outcomes (eg, mortality and hospital length of stay). Pairwise standardized difference was reported for all summarized variables.. Of 36,865 eligible cardiac surgery cases, 25,613 met inclusion criteria. Cluster analysis derived 3 clinical phenotypes: α, β, and γ. Phenotype α (n = 6157 [24%]) included older patients with more comorbidities, including heart and kidney failure. Phenotype β (n = 10,572 [41%]) patients were younger and mostly male. Phenotype γ (n = 8884 [35%]) patients were 58% female and had lower body mass index (BMI). Phenotype α patients had worse outcomes, including longer hospital length of stay (mean = 9 days for α versus 6 for both β [absolute standardized difference {ASD} = 1.15] and γ [ASD = 1.08]), more kidney failure, and higher mortality. Inflammatory biomarkers (IL-6 and IL-8) and kidney injury biomarkers (urine NGAL and IL-18) were higher with the α phenotype compared to β and γ immediately after surgery.. Deriving clinical phenotypes that correlate with response biomarkers and outcomes represents an initial step toward a precision medicine approach for the management of CPB-induced inflammatory response and lays the groundwork for future investigation, including an evaluation of the heterogeneity of treatment effect.

Topics: Acute Kidney Injury; Biomarkers; Cardiopulmonary Bypass; Female; Humans; Interleukin-18; Interleukin-8; Lipocalin-2; Male; Phenotype; Renal Insufficiency; Retrospective Studies

Novel aptamer-based technologies can identify >7000 analytes per sample, offering a high-throughput alternative to traditional immunoassays in biomarker discovery. However, the specificity for distinct proteins has not been thoroughly studied in the context of CKD.. We assessed the use of SOMAscan, an aptamer-based technology, for the quantification of eight immune activation biomarkers and cystatin C among 498 African American Study of Kidney Disease and Hypertension (AASK) participants using immunoassays as the gold standard. We evaluated correlations of serum proteins as measured by SOMAscan versus immunoassays with each other and with iothalamate-measured GFR. We then compared associations between proteins measurement with risks of incident kidney failure and all-cause mortality.. Six biomarkers (IL-8, soluble TNF receptor superfamily member 1B [TNFRSF1B], cystatin C, soluble TNF receptor superfamily member 1A [TNFRSF1A], IL-6, and soluble urokinase-type plasminogen activator receptor [suPAR]) had non-negligible correlations (. SOMAscan is an efficient and relatively reliable technique for quantifying IL-8, TNFRSF1B, cystatin C, and TNFRSF1A in CKD and detecting their potential associations with clinical outcomes.. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_02_23_CJN11700921.mp3.

Topics: Biomarkers; Cystatin C; Female; Glomerular Filtration Rate; Humans; Interleukin-8; Male; Receptors, Tumor Necrosis Factor; Receptors, Urokinase Plasminogen Activator; Renal Insufficiency; Renal Insufficiency, Chronic

To investigate the long-term prognostic significance of baseline plasma IL-8 levels in a group of well-characterized male patients presenting with acute coronary syndrome.. IL-8 is a cytokine that has been implicated in the pathogenesis of atherosclerosis and acute coronary syndrome. Elevated plasma levels have been reported in patients with acute coronary syndrome.. Baseline plasma IL-8 levels were measured in 180 male patients with acute coronary syndrome who were referred for coronary angiography and followed prospectively for the development of all-cause mortality for 5 years.. In a multivariate model that included a wide variety of baseline clinical, laboratory and angiographic parameters in the selection process, baseline plasma IL-8 levels (analyzed as a continuous variable) emerged as a significant predictor of all-cause mortality at 5 years (HR, 1.43; 95% CI, 1.08-1.88; p = 0.0123). Furthermore, in 3 additional multivariate models that also included in the selection process a number of contemporary biomarkers with established prognostic efficacy in ACS (i.e., NT-proBNP, hs-CRP, hemoglobin and RDW), IL-8 remained an independent predictor of all-cause mortality at 5 years.. Elevated baseline plasma levels of IL-8 are associated with an increased risk of long-term all-cause mortality in patients with acute coronary syndrome. Furthermore, this association is independent of a variety of clinical, laboratory and angiographic variables, including contemporary biomarkers with established prognostic efficacy in acute coronary syndrome.

Topics: Acute Coronary Syndrome; Age Factors; Aged; Atherosclerosis; Biomarkers; C-Reactive Protein; Coronary Angiography; Coronary Artery Disease; Erythrocytes; Follow-Up Studies; Glomerular Filtration Rate; Heart Failure; Hemoglobins; Humans; Interleukin-8; Kaplan-Meier Estimate; Male; Middle Aged; Mortality; Multivariate Analysis; Myocardial Infarction; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Prospective Studies; Renal Insufficiency

Free light chains (LCs) are among the many ligands that bind to cubilin/megalin for endocytosis via the clathrin-dependent endosomal/lysosomal pathway. Receptor associated protein (RAP), is a 39 kDA high-affinity, chaperone-like ligand for megalin that assists in the proper folding and functioning of megalin/cubilin. Although RAP is known to inhibit ligand binding to megalin/cubilin, its effect on LC endocytosis has not been shown directly.. We investigated whether RAP can block the endocytosis of LC in cultured human proximal tubule cells and whether this can prevent LC cytotoxicity. Immunofluorescence microscopy and flow cytometry showed that fluorescently labeled LC endocytosis was markedly inhibited in HK-2 cells pretreated with human RAP. The effect of RAP was dose-dependent, and was predominantly on endocytosis as it had no effect on the small acid-washable fraction of LC bound to cell membrane. RAP significantly inhibited LC induced cytokine production and phosphorylation of ERK1/2 and p38 MAPK. Prolonged exposure to LC for 48 h resulted in epithelial-to-mesenchymal transformation in HK-2 cells as evidenced by marked reduction in the expression of the epithelial cell marker E-cadherin, and increased the expression of the mesenchymal marker α-SMA, which was also prevented by RAP in the endocytosis medium.. RAP inhibited LC endocytosis by ∼88% and ameliorated LC-induced cytokine responses and EMT in human PTCs. The results not only provide additional evidence that LCs endocytosis occurs via the megalin/cubilin endocytic receptor system, but also show that blocking LC endocytosis by RAP can protect proximal tubule cells from LC cytotoxicity.

Topics: Cell Line; Endocytosis; Epithelial-Mesenchymal Transition; Humans; Immunoglobulin Light Chains; Interleukin-6; Interleukin-8; Kidney Tubules, Proximal; LDL-Receptor Related Protein-Associated Protein; Low Density Lipoprotein Receptor-Related Protein-2; Multiple Myeloma; Renal Insufficiency

Antibody (Ab)-dependent cellular cytotoxicity (ADCC) is considered to be a relevant mechanism of action of Ab-based tumor therapies. However, knowledge about ADCC capacity of dialysis patients (DP) is limited. The aim of our study was to investigate if ADCC capacity of effector cells obtained from DP differed from those of healthy individuals (HI).. First, we performed ADCC assays with isolated polymorphonuclear cells (PMN) and peripheral blood mononuclear cells (PBMC), mediated by the epidermal growth factor receptor Ab cetuximab or panitumumab. As cetuximab is of human IgG1 and panitumumab of human IgG2 isotype, both Abs differ in their affinity to Fcγ receptors and effector cell recruitment.. Using PMN as effectors, ADCC levels via panitumumab proved to be higher than via cetuximab, but did not differ between DP and HI. In contrast, IgG2-mediated ADCC with PBMC from DP was significantly enhanced compared to HI. IgG2 Abs predominantly bind to FcγRIIa. Within the PBMC, monocytes are the only cytotoxic cells physiologically expressing this receptor. ADCC experiments with isolated monocytes confirmed them to be the pivotal cells for the observed effect. Analysis of monocytes' Fc receptor expression demonstrated no difference between DP and HI, but monocytes of DP proved to be numerically increased and appeared preactivated.. Our studies implicate that ADCC capacity is not impaired in DP and that it might particularly be reasonable to apply human IgG2 Abs as therapeutics for these patients.

Topics: Antibodies; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibody-Dependent Cell Cytotoxicity; Cell Line, Tumor; Cetuximab; Humans; Immunoglobulin G; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Monocytes; Neutrophils; Panitumumab; Receptors, Fc; Renal Dialysis; Renal Insufficiency

Ischemia-reperfusion injury is a leading cause of acute renal failure and a major determinant in the outcome of kidney transplantation. Here we explored systemic gene therapy with a modified adenovirus expressing Interleukin (IL)-13, a cytokine with strong anti-inflammatory and cytoprotective properties. When ischemia was induced we found that the IL-13 receptor is expressed in both the normal and experimental kidneys. Prior to the induction of ischemia, rats received adenovirus-IL-13, control adenovirus or saline. IL-13 plasma levels increased more than 50-fold in adenovirus-IL-13 treated animals, confirming successful IL-13 gene delivery. Histological analysis showed decreased tubular epithelial cell damage with adenovirus-IL-13 therapy, accompanied by reduced kidney injury molecule-1 expression. Interstitial infiltration by neutrophils and macrophages was reduced by half as was interstitial fibrosis and expression of alpha-smooth muscle actin. IL-13 treatment significantly diminished the expression of E-selectin, IL-8, MIP-2, TNF-alpha and MCP-1 mRNA. These results suggest that the use of systemic IL-13 gene therapy may be useful in reducing renal tubulointerstitial damage and inflammation caused by ischemia-reperfusion.

Topics: Animals; Cell Proliferation; Chemokine CCL2; Chemokine CXCL2; Down-Regulation; E-Selectin; Epithelial Cells; Fibrosis; Genetic Therapy; Interleukin-13; Interleukin-8; Ki-67 Antigen; Kidney Tubules; Macrophages; Neutrophils; Rats; Rats, Inbred Strains; Receptors, Interleukin-13; Renal Insufficiency; Reperfusion Injury; RNA, Messenger; Tumor Necrosis Factor-alpha

The relationship between cytokine concentrations and transplant-related complications has been studied in bone marrow transplant patients. The changes in TNF-alpha, IL-1 and IL-6 concentrations after transplantation are well documented in the literature but this is not the case for IL-8. The purpose of the present study was to investigate prospectively the plasma concentration of these cytokines and their relationship to transplant-related complications.. Pro-inflammatory cytokine (TNF-alpha, IL-1, IL-6 and IL-8) levels in plasma were determined in a group of 53 patients undergoing hematopoietic progenitor transplantation. Plasma samples were collected weekly from day -7 to day +35 and stored at -70 degrees C until assayed by ELISA. The major transplant-related toxicities registered were: veno-occlusive disease (VOD), acute graft-versus-host disease (GVHD), infectious episodes, renal failure and mucositis.. In spite of the great variability of plasma cytokine profiles between the different patients, we came to various conclusions. Patients' TNF-alpha and IL-1 concentrations correlated well over time. IL-6 and IL-8 profiles were similar and correlated well with febrile episodes. In some cases, an increase in IL-6 preceded hematologic recovery. In our study, increased levels of TNF-alpha, IL-6 and especially IL-8 correlated with hepatic or renal dysfunction as evaluated by increased bilirubin and creatinine in plasma, while pulmonary complications correlated only with increased IL-6 levels. Allogeneic transplant patients had a tendency to have higher TNF-alpha concentrations than autologous transplant patients, probably because an allogeneic transplant is associated with more transplant-related toxicity. Basal disease usually had no effect on cytokine profiles.. IL-6 and IL-8 were the only cytokines studied whose increase correlated with febrile episodes. High IL-8 values may be a useful predictor of renal dysfunction and pulmonary disease and seems to trigger off high IL-6 levels. Plasma TNF-alpha and IL-1 concentrations during the posttransplant period have not been shown to be predictive of the development of transplant-related complications, and none of the profiles was recognized to be specific for a particular complication in this study.

Topics: Adolescent; Adult; Biomarkers; Bone Marrow Transplantation; Communicable Diseases; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Prospective Studies; Renal Insufficiency; Transplantation, Autologous; Transplantation, Homologous

To estimate canine interleukin-8 (cIL-8) levels in blood plasma samples, a sandwich enzyme linked immunosorbent assay (ELISA) was established. For the development of the sandwich ELISA, polyclonal anti-cIL-8 (capturing), biotinylated anti-cIL-8 (developing) antibodies and glutathione-S-transferase/cIL-8 (GST/cIL-8) fusion protein as an antigen were used. cIL-8 in the fusion protein of GST/cIL-8 was detected in a dose dependent manner. The lowest limit of GST/cIL-8 detectable by this method was 2 ng/ml of GST/cIL-8 (containing; 0.470 ng/ml of cIL-8). IL-8 levels in the plasma samples from apparently healthy dogs were less than 0.470 ng/ ml. Higher levels of IL-8 were detected in the plasma samples of dogs with cystitis, dermatitis, and gastric cancer. These results suggest that the determination of cIL-8 by the sandwich ELISA is useful in diagnosis of inflammatory diseases in dogs.

Topics: Animals; Biomarkers; Cystitis; Dermatitis; Dog Diseases; Dogs; Enzyme-Linked Immunosorbent Assay; Female; Glutathione Transferase; Indicators and Reagents; Inflammation; Interleukin-8; Male; Orchiectomy; Recombinant Fusion Proteins; Reference Values; Renal Insufficiency; Sensitivity and Specificity; Stomach Neoplasms