**2.1 C-reactive protein (CRP)**

CRP is the best studied inflammation marker associated with CV events. It is the prototypical acute phase response protein produced by the liver under the control of various proinflammatory cytokines, namely interleukin-6, interleukin-1, and tumor necrosis factor-α. Its uniquiness is due to rapid (within 6 hours) and dramatic increases (up to 1000 fold) in circulating concentrations after a cytokine-mediated response to most forms of tissue injury, infection, and inflammation. Moreover, it was shown that plasma half-life (19 hours) and fractional clearance rates of CRP were nearly constant in normal subjects, as well as in patients with infectious, inflammatory, and neoplastic conditions. This marks CRP as a 'precise objective index' of overall inflammatory activity and a surrogate of underlying cytokine stimulus (Arici& Walls, 2001; Pepys&Baltz, 1983; Vigushin et al., 1993).

Several observations have demonstrated that in a significant proportion of hemodialysis patients CRP is elevated for no apparent reason. A wide variety of factors in hemodialysis patients may be responsible for this elevation. First, the uremic state is associated with an altered immune response and uremia per se may cause a proinflammatory status with ongoing acute phase response. Also, extracorporeal circulation of blood during each hemodialysis session may act as a fresh stimulus for acute phase response. Increased cytokine release, the role of dialysis membranes, the dialysate and the patient-specific processes, such as the type of vascular access or unrecognized infections, may also play a role in inciting an inflammatory response (Arici&Walls, 2001; Stenvinkel, 2002a, 2002b).

The predictive value of CRP in CV risk and mortality in hemodialysis patients was shown in numerous studies, and evidence from experimental and clinical studies showed that CRP may contribute directly to the pathogenesis of atherosclerosis and its complications through a variety of mechanisms (Arici&Walls, 2001; Yeun&Kaysen, 2000; Zimmermann et al., 1999).

So it has been suggested that this hepatic–derived protein is not only a marker, but also a mediator, of vascular disease (Lagrand et al., 1997; Torzewski et al., 1998). Although a wide variety of potential sources may be associated with elevated CRP in this patient population, underlying silent CV disease may be one of the possible links for this elevation. So the clear association between CRP and CV disease in the hemodialysis population has added CRP as a new predictive CV risk factor which may actually be in a midway position between traditional and uremia-related CV risk factors (Arici&Walls, 2001).

One of the studies investigated the associations of different risk factors with carotid artery intima-media thickness in non-diabetic hemodialysis patients who had no clinical evidence

Chronic inflammation is one of the well-known non-traditional cardiovascular risk factors in hemodialysis patients. Chronic kidney disease results in a chronic, low-grade inflammatory process that becomes evident even in the early stages of the disease. After the start of dialysis treatment, various factors associated with the dialysis procedure may also contribute to a stronger, more active inflammatory response. All available evidence suggests that chronic inflammation in hemodialysis patients may contribute significantly to the development and progression of CV disease (Filiopoulos&Vlassopoulos, 2009; Stenvinkel,

Although few studies are available concerning the relationship between inflammatory status and CV risk in hemodialysis patients without co-morbid diseases, the studies that do exist in

CRP is the best studied inflammation marker associated with CV events. It is the prototypical acute phase response protein produced by the liver under the control of various proinflammatory cytokines, namely interleukin-6, interleukin-1, and tumor necrosis factor-α. Its uniquiness is due to rapid (within 6 hours) and dramatic increases (up to 1000 fold) in circulating concentrations after a cytokine-mediated response to most forms of tissue injury, infection, and inflammation. Moreover, it was shown that plasma half-life (19 hours) and fractional clearance rates of CRP were nearly constant in normal subjects, as well as in patients with infectious, inflammatory, and neoplastic conditions. This marks CRP as a 'precise objective index' of overall inflammatory activity and a surrogate of underlying

Several observations have demonstrated that in a significant proportion of hemodialysis patients CRP is elevated for no apparent reason. A wide variety of factors in hemodialysis patients may be responsible for this elevation. First, the uremic state is associated with an altered immune response and uremia per se may cause a proinflammatory status with ongoing acute phase response. Also, extracorporeal circulation of blood during each hemodialysis session may act as a fresh stimulus for acute phase response. Increased cytokine release, the role of dialysis membranes, the dialysate and the patient-specific processes, such as the type of vascular access or unrecognized infections, may also play a role in inciting an inflammatory response (Arici&Walls, 2001; Stenvinkel, 2002a, 2002b). The predictive value of CRP in CV risk and mortality in hemodialysis patients was shown in numerous studies, and evidence from experimental and clinical studies showed that CRP may contribute directly to the pathogenesis of atherosclerosis and its complications through a variety of mechanisms (Arici&Walls, 2001; Yeun&Kaysen, 2000; Zimmermann et al., 1999). So it has been suggested that this hepatic–derived protein is not only a marker, but also a mediator, of vascular disease (Lagrand et al., 1997; Torzewski et al., 1998). Although a wide variety of potential sources may be associated with elevated CRP in this patient population, underlying silent CV disease may be one of the possible links for this elevation. So the clear association between CRP and CV disease in the hemodialysis population has added CRP as a new predictive CV risk factor which may actually be in a midway position between

One of the studies investigated the associations of different risk factors with carotid artery intima-media thickness in non-diabetic hemodialysis patients who had no clinical evidence

cytokine stimulus (Arici& Walls, 2001; Pepys&Baltz, 1983; Vigushin et al., 1993).

traditional and uremia-related CV risk factors (Arici&Walls, 2001).

**2. Markers of inflammation** 

2006; Zimmermann et al., 1999).

**2.1 C-reactive protein (CRP)** 

this area also support the role of inflammation.

of atherosclerosis and no comorbidities (Zumrutdal et al., 2005). Seventy-two patients (43 men, 29 women; mean age 34.5 ± 10.6 years, mean time on hemodialysis 47.9 ± 40.0 months) were included in the study. Patients without history or evidence of myocardial, cerebrovascular or peripheral vascular disease, those without diabetes mellitus, and those who had been stabilized on hemodialysis therapy for more than six months and were less than 55 years old were enrolled. Patients were excluded whose chest radiograph showed calcified plaques in the aortic arch, or who had ischaemic findings on electrocardiography and/or ventricular wall motility disorders or valvular calcifications on echocardiography. Additionally, patients with conditions known to be associated with acute-phase responses were excluded. The control group consisted of 40 age-and sex-matched healthy subjects, who had been recruited from hospital staff. Body mass index, triglycerides, lipoprotein (a), fibrinogen, CRP, haematocrit-corrected erythrocyte sedimentation rate, serum cardiac troponin I, beta2 microglobulin, and homocysteine levels were found to be significantly different in patients on hemodialysis compared with control subjects. The mean value of the right and left carotid intima media thickness was 0.59 ± 0.06 mm for patients and 0.53 ± 0.07 mm for control subjects. The difference was significant (p=0.002). The carotid intima-media thickness of patients was correlated with age, body mass index, CRP, haematocrit-corrected erythrocyte sedimentation rate, beta2 microglobulin, serum cardiac troponin I, triglyceride, and fibrinogen. CRP, haematocrit-corrected erythrocyte sedimentation rate, serum cardiac troponin I, and fibrinogen were significantly correlated with each other, but not with beta2 microglobulin. The only parameter correlated with beta2 microglobulin was time on hemodialysis. The mean carotid intima-media thickness was significantly greater in patients with both left ventricular hypertrophy and a CRP level > 6.0 mg/L than it was in those with a CRP level ≤ 6.0 mg/L. In that study, multivariate regression analysis showed that age, CRP, beta2 microglobulin, and left ventricular hypertrophy were independent predictors of carotid artery intima-media thickness. The results of that study supported the hypothesis of an 'accelerated atherogenesis' in the hemodialysis population, even if those patients do not have clinical evidence of atherosclerosis. And CRP was found to be one of the independent predictors of early-onset atherosclerosis.

Most investigations of CV risk in patients on hemodialysis have been cross-sectional in nature and representative of the general hemodialysis population. In the previous study, the same subgroup of hemodialysis patients was followed up over the course of one year and the determinants of the progression of carotid artery intima-media thickness were assessed again (Zumrutdal et al., 2006). Fifty-four of the 72 patients completed the study and retested under the same standardized conditions after 12 months. The findings at 12 months showed that carotid artery intima-media thickness had progressed in 75.9 % patients. Age, CRP, beta2 microglobulin and left ventricular hypertrophy were independently related with baseline carotid artery intima-media thickness. At 12 months, age and CRP were found to be independent variables related with carotid artery intima-media thickness. The independent risk factors related with the change in carotid artery intima-media thickness from baseline to 12-month stage were age and male sex.

According to those results, age and male sex were related to progression of carotid artery intima-media thickness as unavoidable risk factors in this subgroup of the hemodialysis population. That agreed with the results of major clinical and epidemiological studies of the general population. The independent relation between CRP and carotid artery intima-media thickness both at baseline and 12 months supports the additional role of non-specific inflammation in hemodialysis patients without comorbidities.

Determinants of Cardiovascular Risk in Hemodialysis Patients Without Significant Comorbidities 285

factor-alpha were found to be independently associated with silent myocardial damage

In hemodialysis patients without comorbidities, mean carotid intima-media thickness, which reflects generalized atherosclerosis and CV risk, was significantly greater in patients with left ventricular hypertrophy, than it was in patients without left ventricular hypertrophy. Mean carotid intima-media thickness in subjects in the heathy control group was significantly lower than it was in hemodialysis patients both with and without left ventricular hypertrophy. The mean serum cardiac troponin I level in the control group was significantly lower than it was in patients both with and without left ventricular hypertrophy. The mean serum cardiac troponin I level was significantly higher in patients with left ventricular hypertrophy than it was in those without left ventricular hypertrophy (Zumrutdal et al., 2005). The relationship between carotid artery intima-media thickness, serum cardiac troponin I levels and left ventricular hypertrophy may demonstrate that subclinical atherosclerotic changes and/or adaptation may occur along with cardiac alterations. So it may be reasonable to apply early strategies for prevention and treatment of left ventricular hypertrophy in hemodialysis patients before clinically evident CV disease.

Cardiac troponins are the most specific biomarkers for myocardial damage, although they may be elevated in situations other than acute coronary syndrome. Hemodialysis patients often have raised cardiac troponin I and T levels in the absence of acute ischaemic symptoms. The source of this increase has been a point of confusion over the past decade. At the beginning, some authors suggested that this might be related to the cardiac expression of troponins, while others argued for the skeletal muscle as a possible extracardiac source of abnormally elevated cardiac troponins in hemodialysis patients (Bodor et al., 1997; Kals et

In initial experience with two troponin subunits, serum troponin T was elevated more frequently than troponin I in patients with renal failure, and that led the clinicians to question its specificity for the diagnosis of myocardial infarction. Additionally, the poorer specificity of troponin T was attributed to subclinical myocardial injury in the setting of left ventricular hypertrophy or to uremia-induced skeletal muscle expression of the cardiac isoform of troponin T, while cardiac troponin I has been exclusively of cardiac origin and does not express in the skeletal muscle at any developmental stage. Thus, troponin I was proposed to be a better marker of myocardial injury in renal failure than T (Yeun&Kaysen, 2000). However, subsequent studies reported the absence of extracardiac cardiac troponin T expression in truncal skeletal muscle biopsy specimens from patients with end-stage renal failure at the RNA and protein levels (Haller et al., 1998). Another study, based on the electromyographic evaluation of 50 chronic hemodialysis patients, investigated the relationship between increased cardiac troponin T levels and uremic myopathy. Proximalextremity muscles-deltoid, biceps, vastus laterali-, which were the most common targets of uremic myopathy, were studied. Five of 50 patients (10%) had a positive troponin T test, but only 1 of those patients had characteristic electromyographic findings. Totally, 4 of 50 patients (8%) had electromyographic findings characteristic of uremic myopathy. Positive troponin test results were not associated with calcium, phosphate, parathormone levels. There was no association between serum cardiac troponin T levels and uremic myopathy

(Afsar et al., 2009).

**3.2 Cardiac troponins** 

al., 2011; McLaurin et al., 1997).

(Zumrutdal AO et al., 2000).
