**4.1 Beta 2 microglobulin**

Elevated plasma beta2 microglobulin is a well-known characteristic of chronic renal failure, and among uremic toxins in the middle molecule range, it is certainly one of the most studied compounds. Beta 2 microglobulin is a key component in the genesis of dialysisassociated amyloidosis. The source of the elevated serum beta2 microglobulin has not been explained absolutely in hemodialysis patients. There is controversy as to whether elevated levels are caused predominantly by increased synthesis of beta2 microglobulin, the use of membranes in hemodialysis with different clearance capacities, or diminished renal elimination (Drüeke et al., 2009). Use of middle and high-flux biocompatible membranes was shown to be associated with a notable reduction in beta2 microglobulin and, in some other studies, the systemic inflammatory response, in the general hemodialysis population. However, the role of proinflammatory monocytic cytokines, such as interleukin-1 and

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

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.

Elevated plasma beta2 microglobulin is a well-known characteristic of chronic renal failure, and among uremic toxins in the middle molecule range, it is certainly one of the most studied compounds. Beta 2 microglobulin is a key component in the genesis of dialysisassociated amyloidosis. The source of the elevated serum beta2 microglobulin has not been explained absolutely in hemodialysis patients. There is controversy as to whether elevated levels are caused predominantly by increased synthesis of beta2 microglobulin, the use of membranes in hemodialysis with different clearance capacities, or diminished renal elimination (Drüeke et al., 2009). Use of middle and high-flux biocompatible membranes was shown to be associated with a notable reduction in beta2 microglobulin and, in some other studies, the systemic inflammatory response, in the general hemodialysis population. However, the role of proinflammatory monocytic cytokines, such as interleukin-1 and

damage in hemodialysis patients (Kanderian& Francis, 2006; Kanwar et al., 2006).

**4. Metabolic markers 4.1 Beta 2 microglobulin**  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 (Filiopoulos et al., 2009).

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 inflammation (Okuno et al., 2009).

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

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 factor in hemodialysis patients without comorbidities.
