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Pentraxins Pentraxins are a superfamily of proteins highly conserved during evolution from non-vertebrates to vertebrates and characterized by specific pattern recognition proteins. is subdivided Pentraxin family into two subclasses: short pentraxins & long pentraxins that depend on the length and structure of the molecules. Short pentraxins such as: C-reactive protein(CRP) in humans that produced in the liver. and serum amyloid P (SAP) in mice. Long pentraxins The first cloned long pentraxin is Pentraxin 3 (tumor necrosis factor stimulated gene 14). Other long pentraxins in human are: Pentraxin 4 Neuronal pentraxin 1 Neuronal pentraxin 2. The human PTX3 gene has been localized on chromosome 3 band q25 and is organized in three exons separated by two introns. Pentraxin molecular 3 has size a (40.6 bigger KDa) compared to CRP (21.5 KDa). Long pentraxins are characterized by an unrelated N-terminal domain (amino acids 18-178) coupled to a short PTXlike C-terminal domain (amino acids 179-381). Carboxy-terminal domain contains the canonical pentraxin signature of eight amino acids sequence (HxCxS/TWxS), where X is any amino acid. Release of PTX3 The long PTX3 is rapidly produced and released by diverse cell types : mononuclear phagocytes dendritic cells, endothelial cells & epithelial cells in response to primary inflammatory signals . while it is synthesized de novo in a variety of cells, specific neutrophil granules store PTX3 . Pentraxin 3 production is induced by lipopolysaccharide (LPS), interleukin-1 (IL-1), and tumor necrosis factor-alpha (TNF-α) but not by Interleukin-6 (IL-6) which induce CRP. PTX3 in neutrophils PTX3 in neutrophil granules is mainly in the monomer form and mature glycosylated multimeric forms (pentamers, octamers or decamers) are detected in the supernatants activated neutrophils. of Pentraxin 3 is produced locally in response to proinflammatory stimuli. During inflammation, by matrix metalloprotease, there is production of mediators such as cytokines, lipid mediators, pattern recognition molecules and matrix metalloproteins . Different microorganisms(fungi- bacteriaeviruses) may activate macrophages and dendritic cells through Toll-like receptors. These cells can produce PTX3. PTX3 mRNA is expressed at a late stage of promyelocyte differentiation. Most PTX3 is synthesized at the myelocytes/metamyelocytes stages. However, the source of PTX3 production or release depends on the kind of inflammatory stimulus. Pentraxin 3 is a key component of the humoral arm of the innate immune system and influences the adaptive immunity. 1.Invading pathogens are controlled by both innate and adaptive immune system. 2.Binding of pathogen to TLRs on antigen-presenting cells activate the components of adaptive immunity. 3.Pentraxin 3 bind with high affinity to the complement component C1q thus activating the complement system through the classical pathway. 4.it may protects against unwanted complement activation. 5.The selective recognition of fibroblast growth factor by PTX3 inhibits FGF-2 angiogenic activity. 6.Pentraxin 3 participates in the clearance of apoptotic cells and several microorganisms. PTX3 and pregnancy Pentraxin 3 plays an essential role in female fertility by acting as a nodal point in the extracellular matrix architecture, and its involvement in tissue remodeling. Pentraxin 3 was expressed placentas from pregnancies uncomplicated subjects. in of PTX3 in asthma Pentraxin 3 expression is increased in asthmatic airways. PTX3 cause inhibition of human airway smooth muscle cells migration induced by FGF-2. Thus, PTX3 may play a dual role in allergic asthma. 1. Unlike CRP, PTX3 appears to be more specific for vascular inflammation. 2. Rolph et al (2002) showed a strong expression of PTX3 in human advanced atherosclerotic lesions. 3. PTX3 level has been proposed as a risk predictor for acute myocardial infarction and biomarker of adverse outcome in patients with unstable angina pectoris, myocardial infarction and heart failure. 4. In acute myocardial infarction, PTX3 reaches peak values after 6-8 hours compared to 24 hours for CRP. Pentraxin 3 mRNA is expressed in cortex,medulla and glomeruli of the normal human kidney. Stimulation with IL-1, TNFα, interleukin-17 (IL-17) and CD40 Ligand (CD40L) increases the expression and production of PTX3 by renal epithelial cells. There is a gradual increase of PTX3 concomitent to the decline in glomerular filteration rate (GFR) . Serum levels of PTX3 are elevated in a number of human diseases, such as: 1. myocardial infarction 2. rheumatoid arthritis 3. sepsis and tuberculosis 4. vasculitis 5. inflammatory reaction in the kidney. Therefore, Pentraxin 3 may represent a diagnostic approach unrelated to CRP to the study of inflammatory disease. and autoimmune Chronic kidney disease (CKD) is defined as the presence of kidney damage, manifested by abnormal albumin excretion or decreased kidney function that persist for more than three months. During recent years, the prevalence of CKD has markedly increased and is expected to double continuously every 8 to 10 years. The first task in evaluating the patient with an elevated creatinine level is to categorize the patient's presentation as 1 of 3 possible types of renal failure: post renal failure, prerenal azotemia or intrinsic renal failure. Chronic kidney disease is a complex disease, its progression is associated with a number of serious complications including increased incidence of cardiovascular disease, hyperlipidemia, anemia and metabolic bone disease. STAGE 1 2 GFR, ml/min/1.73 m2 DESCRIPTION Kidney damage with normal or increased GFR. Mostly recognized by albuminuria or structural renal abnormalities. Kidney damage decreased GFR. with ≥90 midly 60-89 3 Moderately decreased GFR. 30-59 4 Severely decreased GFR. 15-29 5 Kidney failure. ‹15 or dialysis Stage5 kidney failure(ESRD) GFR<15 ml/min/1.73m2. is defined as Chronic kidney disease promotes hypertension and dyslipidemia, which in turn can contribute to the progression of renal failure. Approximately 50% of individuals with ESRD die from a cardiovascular cause. In dialysed chronic renal failure patients we can encounter dialysis pericarditis and endocarditis. Pentraxin 3 levels are increased in patients with impaired renal functions. The bigger molecular size for PTX3 (40.6KD) may suggest increased retention in uremia. The Pentraxin 3 may amplify the inflammatory response after being produced both in peripheral tissues and in the kidney. PTX3 may also play a role in the atherogenic process present in chronic kidney disease. PTX3 levels may provide more information on the development and progression of atherosclerosis than non-specific markers like CRP and IL-6. PTX3 is induced in vascular smooth muscle cells by atherogenic modified low-denisty lipoprotein and is present in human atherosclerotic lesions. Pentraxin 3 levels increase rapidly in acute myocardial infarction, reaching a peak ~7 hours after the onset of symptoms. CRP is an acute phase protein and a member of the family of pentraxins. The major part of the CRP present in the plasma comes from the liver and small amount of CRP can be produced locally. CRP may be involved in atherosclerosis by direct influencing process like complement activation, apoptosis, vascular cell activation, monocyte recruitment, lipid accumulation and thrombosis. PTX3 is thought to be more specific to endovascular injury than C-reactive protein. 75subjects were included in this study. They were divided into Control group (Group 1) Patients group (Group 2) 50patients with chronic kidney disease (CKD ) . subdivided into 2 subgroups: 25apparently healthy volunteers Group 2a Group 2b 25 patients with CKD on conservative non dialytic therapy 25 patients with endstage renal disease on maintenance hemodialysis therapy. Exclusion Criteria: Patients with lung disease, rheumatoid arthritis, psoriasis, vasculitis or using immunosuppressive drugs and pregnant females were not included in the present study. To all the studied subjects, the following was done Detailed history taking. Thorough physical examination. 12-lead electrocardiography. Measurment of carotid intima media thickness (CIMT) by ultrasound. Laboratory investigations Serum Glucose Serum Creatinine Serum Albumin High density lipoprotein cholesterol (HDL-C) Serum Triglycerides Serum Urea Serum Uric acid Total serum Cholesterol Low density lipoprotein cholesterol (LDL-C) Serum Alanine aminotransferase(ALT) Determination of high sensitivity C-reactive protein (hs-CRP) by ELISA Estimation of Pentraxin 3 by ELISA 80 70 r = 0.624* p = 0.001 Age 60 50 40 30 20 10 0 0.50 0.55 0.60 0.65 CIMT 0.70 0.75 0.80 70 r = 0.693* p <0.001 60 Age 50 40 30 20 10 0 0.50 0.55 0.60 0.65 CIMT 0.70 0.75 0.80 160 r = 0.412* p = 0.041 140 120 TG 100 80 60 40 20 0 0 5 10 15 CRP 20 25 30 35 120 r = -0.537* p = 0.006 100 LDL-C 80 60 40 20 0 0 5 10 15 CRP 20 25 30 35 15 > 8.46 0 10 ≤ 22.36 9 3 > 22.36 13 22 Efficiency 100.0 62.50 70.0 88.0 40.91 62.86 75.0 65.96 % 100.0 % 40.0 % NPV % PTX3 25 PPV % CRP ≤ 8.46 Specificity (Group1) patients on non-dialytic therapy (Group 2a) Sensitivity Control group 25 10 > 8.46 0 15 ≤ 23.62 16 7 > 23.62 6 18 Efficiency 100.0 71.43 72.0 72.73 75.0 69.57 72.34 % 100.0 % 60.0 % NPV % PTX3 ≤ 8.46 PPV % CRP (Group2b) Specificity (Group1) patients on hemodialysi s Sensitivity Control group 80.0 1. There was a significant decrease in the mean levels of albumin in all the studied chronic renal failure patients when compared to controls. Hypoalbuminemia is due to malnutrition and inflammation in CKD patients. 2.There was a significant increase in hsCRP in patients on hemodialysis therapy when compared to both controls and patients on non-dialytic therapy. The circulating value of CRP reflects ongoing inflammation and/or tissue damage. 3.There was a significant increase in PTX3 in patients on hemodialysis therapy as compared to controls. PTX3 levels may directly reflect the inflammatory status. Since a state of persistant low-grade inflammation is a common feature in hemodialysis patients so PTX3 increased in such patients. 4.There was no correlations between PTX3 and hsCRP in the studied groups. 5. By drawing the ROC curve for hsCRP and PTX3 in patients on non-dialytic therapy (Group 2a), the area under the curve was 0.545 ( p = 0.594) and 0.653 ( p = 0.073) respectively. In patients on hemodialysis therapy (Group 2b), the area under the curve was 0.735 ( p = 0.006) for hsCRP and 0.765 ( p = 0.002) for PTX3. 6.By using the best cut off values, it was found that high sensitivity C-reactive protein showed a better specificity and positive predictive value than PTX3 while PTX3 showed a better sensitivity than hsCRP in the studied two groups of patients. It could be concluded that using both hsCRP and PTX3 complement each other to give better specificity and sensitivity as predictors of inflammation in chronic kidney disease patients.