الفهرس 
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Abstract
Accelerated atherosclerosis is the major cause of mortality in patients on chronic haemodialysis (HD). Inflammation, increased oxidative stress and endothelial activation or dysfunction might be the major factors leading to high cardiovascular mortality rate in HD patients. Also C677T mutation of MTHFR might be associated with accelerated atherosclerosis.
Aim. Our study was to clarify the role of inflammation, oxidative stress parameters, endothelial activation or dysfunction and genotyping of MTHFR enzyme which affect the level of homocysteine and there relation to carotid artery intima-media thickness (CIMT) as an indicator of atherosclerosis.
Subject & Methods. 44chronic haemodialysis (HD) patients, and 40 healthy subjects were included in the study. Serum hs-CRP and IL-6 were measured as inflammatory markers, VCAM-1 was measured as marker of endothelial activation and dysfunction, Serum thiobarbituric acid reactive substances (TBARS), nitrite/nitrate, Total peroxides (TP), erythrocyte superoxide dismutase (SOD), Catalase (CAT) activities, Total antioxidant capacity (TAC) and oxidative stress index (OSI) levels were determined as oxidative stress markers., C-IMT was assessed by carotid artery ultrasonography, Genotyping of MTHFR gen which affect the level of homocysteine.
Results. Chronic HD patients had elevated levels of inflammatory markers (hs-CRP and Il-6) , enhanced endothelial activation or dysfunction demonstrated by elevated VCAM-1 as compared by healthy controls, Also they had enhanced oxidative stress indicated by higher levels of nitrite/nitrate, TBARS , TP, OSI and lower levels of SOD, CAT and TAC as compared to controls. HD patients had significantly higher CIMT. There is a significant positive correlation between inflammatory cytokines ( CRP and IL-6), TBARS, Total intric oxide , Total peroxides and OSI with CC-IMT Also a negative correlation between SOD, Catalase and TAC, there is no difference in the genotype of C667T MTHFR between patients and controls, but this mutation especially the TT genotype is associated with development of atherosclerosis as indicated by increase of CC-IMT.
recommendations
Chronic renal failure is a common health problem all over the world. It has its implication on the patient and community, despite the improvement in dialysis technology. Haemodialysis patients experience lower quality of life, significantly greater morbidity, higher hospitalization rates, and higher mortality compared with the general population. The main cause of death is the cardiovascular complications which occur as a result of accelerated atherosclerosis which occurred in a 30-yr-old ESRD patient with the same rate as a 70 to 80-yr-old subject from the nonrenal population.
The accelerated atherosclerosis in those patients occurs due to multiple risk factors. In those patients the classical risk factors such as diabetes, obesity, hypertension, etc are prevalent. However these risk factors alone can not explain the increased incidence of accelerated atherosclerosis. Therefore, much recent interest has focused on nontraditional risk factors. Such as inflammation, malnutrition, oxidative stress, endothelial dysfunction, etc
Chronic renal failure represent as state of microiflammation which continuously occurred due to multiple factors, such as uremic toxins, interaction of circulating mononuclear cells with bioincompatible dialyzers, or contaminated dialysate and vascular access infections.
Proinflammatory molecules play an important role in endothelial dysfunction, providing a link between inflammation, atherogenesis and excessive cardiovascular morbidity and mortality in ESRD patients.
Hs-CRP (highly sensitive CRP) measurement provides an index not only to inflammation in ESRD but also it is a biomarker associated with occurrence of atherosclerosis, as indicated by its positive correlation with CC-IMT and VCAM-1. So hs-CRP is considered as a positive determinant of atherosclerosis in chronic renal failure patients.
IL-6 is unique among proinflammatory cytokines and represents not only a potential agent of organ damage in pathophysiologic conditions but also a potent marker of the overall severity of the inflammation process.
This observation that IL-6 captures almost entirely the predictive power of inflammation in ESRD is in keeping with findings in the general population, in which IL-6 emerged as the sole inflammation marker in ESRD. Its prediction power being almost equal to what can be derived from simultaneous measurements of several other cytokines and CRP.
Also IL-6 considered a marker predicts atherosclerosis as it positively correlated with CC-IMT and VCAM-1. However, although most ESRD patients have elevated IL-6 levels, it should be pointed out that normal or even low plasma levels of IL-6 could be found in dialysis patients, suggesting that genetic factors might be of importance. So, combined measurement of IL-6 and CRP is the most informative indices of inflammation. So IL-6 is considered as a positive determinant of atherosclerosis in ESRD.
Oxidative stress has a big role in accelerated atherosclerosis in ESRD , due to multiple factors and cause multiple events which favor atherosclerosis in ESRD. Several etiologic factors for oxidative stress have been proposed in these patients, including uremia, reaction of the blood with dialyzer membranes and subsequent contaminating with dialysis byproducts, acute or chronic bacterial infections, parenteral administration of ferrous sulfate, limitation in consumption of fruits and vegetables that are rich with antioxidant, vitamins and natural phytochemicals besides the underlying diseases. Furthermore, oxidative stress is responsible for alterations in the composition of lipoproteins that result in oxidation of low-density lipoproteins and the release of short-chain aldehydes, such as malondialdehyde and acceleration of atherosclerosis process.
Oxidative stress is evident in ESRD patients as manifested by the increased level of TBARS, NO , TP, OSI and decreased level of SOD , catalase and TAC. TBARS, NO ,TP and OSI levels are considered as positive determinants of atherosclerosis as they positively correlated with VCAM-1 and CC-IMT. TAC is considered as a negative determinant of atherosclerosis as it negatively correlated with CC-IMT.
Endothelial dysfunction is the early step to atherosclerosis occur in ESRD, and manifested by increased level of soluble vascular adhesion molecule and CC-IMT as a marker of early sub clinical atherosclerosis.
VCAM-1 can be consider as a biochemical marker of atherosclerosis as indicated by the positive correlation between VCAM-1 and CC-IMT.
Atherosclerosis is no longer consider as a simple inert plumbing problem but rather a complex dynamic process that can be modulated and prevented. Pivotal roles of inflammation and oxidative stress in the pathogenesis of endothelial dysfunction ad atherosclerosis may open new exciting opportunities in the way we should manage and prevent cardiovascular disease in ESRD.
Drugs, such as statins, ACE inhibitors, glitazones, vitamin E, and aspirin have antiinflammatory and anti-oxidative stress effects, which might add to their clinical effectiveness in preventing these events. Also these drugs act to interrupt the vicious circle of inflammation, oxidative stress, endothelial activation and increased expression of VCAM-1 to cut the bridge to atherogenesis in renal disease.
It is recommended to shift from the use of bioincompatible dialyzer membrane (Cuprammonium) which is associated with increased inflammation, to the use of a biocompatible membrane (Polysulfon) which is less associated with inflammation and oxidative stress. Moreover, a change from conventional to ultrapure dialysis fluid reduced the inflammation and improved nutritional status in HD.
Specific dialysis techniques should be introduced in an attempt to reduce oxidative stress, such as vitamin E-modified cellulose membranes and haemolipodialys. The blood–membrane interaction can trigger oxidative stress, direct scavenging at the membrane site is an attractive approach. Vitamin E-modified cellulose membranes bear a hyDROPhilic polymer that strongly binds vitamin E. Liposomes interact with blood components at the HD membrane without passage through the membrane itself. In addition, the liposomes can be oxidized themselves acting as a ‘radical sink’.
There is no difference in the percentage of different genotypes of MTHFR enzyme between patients and controls as regard C667T mutation, but this mutation especially the TT genotype is associated with development of atherosclerosis as indicated by the increase of inflammatory, some oxidative stress markers, (VCAM-1 and CC-IMT).
Folic acid and vitamin B12 also must be added to the treatment of those patients especially those with TT genotype to overcome the bad effect of MTHFR mutation hyperhomocysteinemia level which is exaggerated by the kidney function in those patients.