**1. Introduction**

280 Progress in Hemodialysis – From Emergent Biotechnology to Clinical Practice

Zimmermann J, Herrlinger S, Pruy A , Metzger T, Wanner C (1999). Inflammation enhances

Zoccali C, Mallamaci F, Benedetto FA, Tripepi G, Parlongo S, Cataliotti A, Cutrupi S,

Zoccali C, Benedetto FA, Mallamaci F, Tripepi G, Giacone G, Stancanelli B, Cataliotti A,

patients. *J Am Soc Nephrol* 12, 7 (Jul 2001): 1508-1515.

1999): 648-658

65, 4 (Apr 2004): 1492-1498.

cardiovascular risk and mortality in hemodialysis patients. *Kidney Int* 55, 2 (Feb

Giacone G, Bellanuova I, Cottini E, Malatino LS (2001). Cardiac natriuretic peptides are related to left ventricular mass and function and predict mortality in dialysis

Malatino LS (2004). Left ventricular mass monitoring in the follow-up of dialysis patients: prognostic value of left ventricular hypertrophy progression. *Kidney Int*

> Cardiovascular (CV) disease is a major cause of morbidity and mortality in patients with end-stage renal disease. Traditional risk factors for CV disease include hypertension, smoking, diabetes, dyslipidemia, left ventricular hypertrophy, advanced age and male sex in the general population. Although hemodialysis patients have a high prevalence of many of these factors, they also have nontraditional, or uremia-related, specific factors such as anemia, altered calcium-phosphorus metabolism, inflammation, oxidative stress, nitric oxide synthase inhibitors, hypoalbuminemia, carbamylation, abnormal lipoproteins and hyperhomocysteinemia (Parfrey, 2000; London&Drüeke 1997). So the risk markers that predict CV events in hemodialysis patients may differ from those in the general population.

> This increased CV risk has often been attributed to 'accelerated atherosclerosis' in end-stage renal disease (Cheung, 2000; Kasiske et al., 2000). However, CV causes of death are most prominent in the first years of dialysis and are rare in patients who have been on long term dialysis – the reverse of what would be expected if dialysis itself caused 'accelerated atherosclerosis (Mailloux et al., 1991). Because many patients with end-stage renal disease already have one or more comorbidities and clinically evident vascular disease, it is difficult to determine from clinical or epidemiological studies whether traditional or non-traditional risk factors are more responsible for the high risk of CV events.

> The presence of comorbid disease is an increasingly common problem, being much more prevelant in new patients started on dialysis today than previously (Godkin et al., 2003; Mailloux et al., 1996; Merkus et al., 2000; Miskulin et al., 2009; Wallen et al., 2001). Hemodialysis patients who are under 55 years of age and without diabetes, significant comorbid diseases and obesity are very rare in the general hemodialysis population. For this reason, fewer epidemiological studies which focus on the determinants of CV risk of a relatively 'healthy' hemodialysis population are available. However, it is increasingly appreciated that chronic kidney disease alone is an independent risk factor for the development of CV disease. In this topic review of available data, an overview is presented of CV risk factors in hemodialysis patients without significant comorbidities.

Determinants of Cardiovascular Risk in Hemodialysis Patients Without Significant Comorbidities 283

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

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

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

predictors of early-onset atherosclerosis.

12-month stage were age and male sex.

inflammation in hemodialysis patients without comorbidities.
