**3.2 Cardiac troponins**

284 Progress in Hemodialysis – From Emergent Biotechnology to Clinical Practice

Although ESR is widely used in the general population as an inflammation marker, it was judged to be of no clinical utility in chronic hemodialysis patients in the mid-1980s. So ESR has seldom been studied in patients on hemodialysis. However, in 2001, it was proposed that after correction of ESR values according to Hct levels in hemodialysis patients, Hctcorrected ESR could serve to select the inflammation-afflicted hemodialysis patients from those without this comorbid state (Borawski& Mysliwic, 2001). Supporting that study, while no relationship between ESR and carotid artery intima-media thickness was found, a relationship in hemodialysis patients without comorbidities was found between Hctcorrected ESR and carotid artery intima-media thickness, beyond other inflammatory markers, CRP, and fibrinogen. Although larger additional studies are needed to determine the potential value of Hct-corrected ESR as an inflammatory marker for early-onset atherosclerosis, this relationship may again reflect the role of non-specific inflammation in

In the normal population, increased activity of procoagulant proteins including factor VII and fibrinogen is associated with coronary risk. Factor VII coagulant activity and markers of thrombin activation are elevated in patients with chronic renal failure and correlate positively with serum triglycerides and the acute phase reactants interleukin 6 and fibrinogen and negatively with serum albumin (Tomson, 2000). The presence of generalized endothelial dysfunction in uraemic patients is also suggested by higher plasma levels of fibrinogen, endothelin and other factors. The relationship between carotid artery intimamedia thickness and fibrinogene in hemodialysis patients without comorbidities may reflect the role of fibrinogene in early-onset atherosclerosis as one of the best-studied inflammation

Left ventricular hypertrophy is a well-known potent predictor of CV mortality in patients on renal replacement therapy (Ma et al., 1992). This may result either from pressure overload, causing increased tensile stress, or from volume overload, causing increased shear stres (Tomson, 2000). Recently published results demonstrated that even with good control of hypertension and anaemia, conventional hemodialysis is associated with significant left ventricular hypertrophy. And high prevalence of CV disease was positively associated with

In the study assessing the predictive markers of CV risk in asymptomatic hemodialysis patients, in total, 113 hemodialysis patients were included. Demographic, anthropometric, clinical, and laboratory data were collected. Silent myocardial damage was defined by elevated cardiac troponin I values above cutoff values. Cardiac troponin I concentrations were below cutoff value in 103 (91.2%) patients (group 1), whereas 10 (8.8%) patients (group 2) had elevated concentrations. Group 1 patients had higher levels of hemoglobin and highdensity lipoprotein cholesterol and lower C-reactive protein and tumor necrosis factor-alpha levels, as well as less incidence of left ventricular hypertrophy, when compared to group 2 patients. Diabetes mellitus, left ventricular hypertrophy, uncontrolled blood pressure, normalized protein equivalent of total nitrogen appearence, hemoglobin and tumor necrosis

**2.2 Hematocrit-corrected erythrocyte sedimentation rate (Hct-corrected ESR)** 

CV risk of the 'healthy' hemodialysis patients ( Zumrutdal et al., 2005).

**2.3 Fibrinogene** 

markers (Zumrutdal et al., 2005).

**3.1 Left ventricular hypertrophy** 

left ventricular hypertrophy in hemodialysis population.

**3. Cardiac markers** 

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

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 (Zumrutdal AO et al., 2000).

Determinants of Cardiovascular Risk in Hemodialysis Patients Without Significant Comorbidities 287

interleukin-6, in the pathogenesis of elevated beta2 microglobulin, and its role as a potential initiator of the inflammatory response were discussed (Vraetz et al., 1999; Xie & Yi, 2003). Recently, a study comparatively evaluated the effect of hemodialysis and peritoneal dialysis on oxidative stress and inflammatory biomarkers and the associated factors. It found similar degrees of inflammaton and oxidative stress activation in both groups. In that study, beta2 microglobulin was one of the parameters which correlated to oxidative stress and inflammatory biomarkers. It was negatively correlated both with total antioxidant capacity in hemodialysis patients and with superoxide dismutase in peritoneal dialysis patients

Previously, for what was probably the first time in the available literature, we provided data about the association between beta2 microglobulin and early-onset atherosclerosis in hemodialysis patients without comorbidities (Zumrutdal et al., 2005). In our study, the only parameter correlated with beta2 microglobulin was time on hemodialysis therapy. At that time, we speculated that the relationship we found might be casual (inflammatory) or just an epiphenomenon, and added that further follow up studies were needed to elucidate the importance of beta2 microglobulin as a new nontraditional cardiovascular risk factor in hemodialysis patients. Subsequently, few studies have evaluated the association of beta 2 microglobulin levels with clinical outcome in dialyzed patients. The patients were divided into two groups according to their serum beta2 microglobulin levels (lower beta2 microglobulin group, n=245 and higher beta2 microglobulin group, n=245) and followedup. During the follow-up period of 40±15 months, there were 91 all-cause deaths, and out of them, 36 were from CV disease. All cause mortality in the higher beta2 microglobulin group was significantly higher compared to that in the lower beta2 microglobulin group. And serum beta2 microglobulin level was a significant predictor of mortality in hemodialysis patients, independent of hemodialysis duration, diabetes, malnutrition and chronic

A few studies also supported the correlation between serum beta2 microglobulin levels and various cardiovascular risk factors, including CRP, in hemodialysis patients (Kuragano et al., 2010). And recently, beta2 microglobulin has been suggested to be a novel biomarker of peripheral arterial disease and an independent predictor of aortic stiffness in atherosclerosis, in the general population (Wilson et al., 2007). Additionally, higher serum beta2 microglobulin levels were proposed to be a novel marker to distinguish levels of risk in

All of those findings strongly support the role of beta2 microglobulin in CV risk of hemodialysis patients, and it seems it will be a potential new CV risk marker in the future. Further studies are needed to clarify the importance of beta2 microglobulin as a CV risk

**5. Determinants of cardiovascular risk in nondiabetic hemodialysis patients**  Diabetes is not only a traditional risk factor for CV disease, but also one of the most common causes of end-stage renal disease. While a decline in CV deaths has occurred in the general population, a similar trend has not been observed in dialysis patients. This discrepancy is in part due to the demographics of patients about to be started on dialysis: about 40 percent are diabetic. Also, the average age of hemodialysis patients is approximately 60 years and about 20 percent are over 75 years, and many patients have underlying cardiac disease

acute heart failure patients with creatinine ≤ 3mg/dl (Kawai et al., 2010).

factor in hemodialysis patients without comorbidities.

(Filiopoulos et al., 2009).

inflammation (Okuno et al., 2009).

Subsequent studies showed that frequently positive T test results in hemodialysis patients were likely due to use of the older and less specific troponin T assay with some crossreactivity to skeletal muscle (Yeun&Kaysen, 2000). And with the use of the latest generation assays, accumulated data from groups of renal failure patients have suggested that elevated levels of both troponin T and I in asymptomatic hemodialysis patients could be associated with added CV risk, including general mortality. Most of the recent studies supported the troponin tests as predictive markers of asymptomatic atherosclerosis and silent myocardial damage in hemodialysis patients (Kanderian& Francis, 2006; Kanwar et al., 2006).

The carotid artery intima-media thickness measurement has been proposed as a method for establishing risk stratification for CV events. To the best of our knowledge, we were the first to examine the relationship between serum cardiac troponin I level and early onset atherosclerosis in a selected subgroup of hemodialysis patients without any clinical evidence of either atherosclerosis or comorbidities. Based on those results, the increased serum cardiac troponin I level was positively correlated with the carotid intima-media thickness and seemed to be a valuable predictive marker for the assessment of CV risk in asymptomatic hemodialysis patients (Zumrutdal et al., 2005). Also, a possible association was found between elevated serum cardiac troponins and inflammatory markers such as CRP, fibrinogen and Hct-corrected ESR. The association between carotid intima-media thickness, serum cardiac troponin I levels and inflammatory parameters needs to be clarified with further studies. Although the underlying pathophysiology of elevated cardiac troponins is still not clearly understood, it may reflect ongoing, often subclinical, myocardial damage or microinfarctions that are partially independent of acute ischaemic injury. So serum cardiac troponin elevations might be very effective in elucidating cardiac risks of hemodialysis patients without any clinical evidence of atherosclerosis and comorbidities.

In conclusion, in addition to traditional risk factors such as age and male sex, non-specific inflammation may play a key role in the progression of atherosclerosis in patients on hemodialysis without comorbidities. Although it is well-established that end-stage renal failure is a state of chronic systemic inflammation, both nondialysis-related factors and the dialysis procedure per se may be responsible for this high risk. Beta2 microglobulin and serum cardiac troponins may be the potential new additions for CV risk in this group of patients. Further studies are needed to determine whether there is a causal relationship.
