الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Cardiovascular diseases remain the major cause of morbidity and mortality in chronic kidney disease patients. However, the traditional risk factors cannot explain the extraordinary increase in morbidity and mortality among CKD. Therefore; other non-traditional risk factors such as endothelial dysfunction has been studied.
Endothelial dysfunction (ED) represents an obligatory, prodromal phase in the atherosclerotic process. Endothelial dysfunction may be also responsible for accelerated atherosclerosis in patients with CKD. Endothelial dysfunction is characterized by shift of the action of the endothelium towards reduced vasodilatation and a proinflammatory state denoting impairment of endothelium-dependent vasodilatation.
The etiology of ED is complex and involves dysregulation of multiple pathways. The hallmark of endothelial dysfunction is impaired nitric oxide-mediated endothelial-dependent vasodilatation.
The adipose tissue is a complex organ with function far beyond the mere storage of energy. Indeed, it secretes a number of adipokines. Visfatin is the most recently identified adipose tissue cytokine. In recent years, a cross-talk between secreted bioactive molecules (adipokines) and endothelial function has been discovered and the issue is intensively investigated.
Fetuin-A which is synthesized by the liver, has been identified as a circulating inhibitor of calcification. Recently, ED was found to be independently associated with fetuin-A. Fetuin-A may be one of the contributing factors for the development of ED in CKD patients. In addition, fetuin-A 256Ser/ Ser (allele G) might affect serum fetuin- A levels.
The aim of the present work is to study novel markers of ED in patients with different stages of CKD through:
Studying the role of visfatin and fetuin-A as novel markers of ED in patients with different stages of CKD.
Studying the relation between fetuin-A gene polymorphisms and the susceptibility to ED in patients with CKD in different stages.
Identifying the effect of fetuin-A gene polymorphisms on the level of serum fetuin-A.
Finding the correlation between serum visfatin and serum fetuin-A as novel markers of ED and the level of NO (nitrite /nitrate) as a settled marker of endothelial dysfunction.
In order to achieve these goals, the present study included sixty patients at different stages of CKD with age range from 18 to 60 years old. All patients were non-diabetic and arranged in five groups according to the stage of CKD assessed GFR from stage 1 to 5 representing the groups from I to V. Each group included twelve patients. Also, twelve matched healthy volunteers with matched age and sex were included to serve as the control group (groupVI).Following proper selection of patients and control subjects, complete history taking and careful physical examination were performed and the following laboratory tests were done for all of them:
• Determination of serum visfatin and serum fetuin-A using enzyme linked immunosorbant assay (ELISA).
• Genotyping for the common functional polymorphisms on fetuin- A (Thr256Ser) using polymerase chain reaction (PCR) technique.
• Estimation of NO (nitrite / nitrate) by chemical method.
• Estimation of serum levels of glucose, triglycerides, total cholesterol and HDL-cholesterol by enzymatic colorimetric methods. LDL-cholesterol was then calculated using Friedewald’s formula.
• Estimation of serum creatinine using a modified Jaffe method by colorimetry.
• Estimation of GFR from serum creatinine levels using Cockcraft and Gault(C&G) formula.
The present study showed:
A statistically significant elevation of serum total nitrate and nitrite and serum visfatin in CKD patients compared to controls, while serum fetuin-A showed statistically significant decrease in CKD patients compared to the control group. When the different stages of CKD were compared to the control group, the study revealed that; serum total nitrate and nitrite levels were significantly increased in all stages of CKD, while serum visfatin was significantly increased in stages 2 to 5 of CKD. Serum fetuin-A showed significant decrease in stages 2 to 5 of CKD. In stage 1 CKD, both serum visfatin and fetuin-A showed insignificant changes.
There was no statistically significant difference between the studied CKD cases and the control group as regards to the frequencies of the three genotypes of fetuin–A(C G); Thr256Ser polymorphism. In both CKD patients and the control group, the distribution of the fetuin-A (C G);Thr256Ser gene polymorphisms did not show significant correlation with low serum fetuin-A levels.
A significant positive correlation was found between serum levels of total nitrate and nitrite and serum levels of (visfatin, triglycerides, total cholesterol, LDL-cholesterol), while A significant negative correlation was found between serum levels of total nitrate and nitrite and serum levels of (fetuin-A and HDL-cholesterol) in CKD patients.
A significant positive correlation was found between serum levels of visfatin and serum levels of (triglycerides, total cholesterol, LDL-cholesterol), while a significant negative correlation was found between serum levels of visfatin and fetuin-A in CKD patients.
A significant negative correlation was found between serum levels of fetuin-A and serum levels of (triglycerides, total cholesterol and LDL-cholesterol), while a significant positive correlation was found between serum levels of fetuin-A and HDL-cholesterol in CKD patients.
Stepwise regression analysis was done in the current study; according to this model the strongest predictors of endothelial dysfunction were found to be serum visfatin and HDL-cholesterol as they could explain significantly 52% of the changes in total nitrate and nitrite.
By plotting receiver-operating characteristic (ROC) curve for the diagnosis of early stages of CKD (stages 1 and 2; groups I and II); the sensitivity and specificity of serum total nitrate and nitrite were 87%% and 91% respectively at the cut-off value of 53.54 umol/l, the sensitivity and specificity of serum visfatin were 62.5% and 75% respectively at the cut-off value of 35 ng/ml and the sensitivity and specificity of serum fetuin-A were 54.2% and 91.7% respectively at the cut-off value of 0.27 g/l.