**4. Cardiovascular disease and hemodialysis patients**

The number of HP patients in the United States is approximately 350,000 with an expectation of reaching 1.5 million by 2016. Most HP have a significant decline in quality of life with two-thirds dying within 5 years of dialysis initiation; a survival rate worse than most cancers (Kilpatrick et al., 2007). Cardiovascular disease (CVD) is a leading cause of death in HP with rates higher than the general population and risk primarily associated with elevated lipids, inflammation, malnutrition, hypertension, hyperhomocysteinemia, obesity, and insulin resistance (Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report, 2002). Most HP patients' elevated lipid profiles are associated with a higher incidence of CVD morbidity and mortality (Vaziri, 2009) and allcause mortality (Tsirpanlis, et al., 2009). Additionally, non-fatal CVD is 10-30 times higher in HP suggesting this population is more prone to heart disease (Nanayakkara & Gaillard, 2010). Though traditional treatment of CVD in HP has demonstrated promise, many large randomized trials in HP have not demonstrated a survival benefit from traditional treatment strategies (Nanayakkara & Gaillard, 2010). The challenge becomes understanding why traditional risk factors are less predictive and whether the progression of disease is so advanced in HP that risk factor management should be different in this patient population. It should be noted however, that traditional and non-traditional risk factors for CVD in HP do have some crossover, complicating our understanding of how risk factor management may assist in disease causation and association. Though this chapter focuses on HP, chronic kidney disease patients who are predialysis share some of the same counter-intuitive findings. Therefore it should be noted that progression of CVD begins well before HP begin dialysis and could be detected as early as stage I CKD. Finally, it has been suggested that plaque accumulation may occur differently in HP. In the general population arterial plaque is more associated with lipid accumulation, but with HP it is more likely to be associated with calcified plaques and increased arterial stenosis (Diepeveen, Wetzels, Bilo, van Tits, & Stalenhoef, 2008). Various research groups, including the National Cholesterol Education Program (NCEP) (Third Report of the National Cholesterol Education Program Expert Panel on Detection,

Malnutrition, Inflammation and Reverse Epidemiology in Hemodialysis Patients 303

studies are deficient, but the few published on this topic have suggested that HP with chronically elevated levels of inflammation, as measured by C-reactive protein (CRP) or interleukin-6 (IL-6), and malnutrition, as measured by albumin, are associated with normal cholesterol values but higher levels of mortality (Chavalitdhamrong, et al., 2007;

Cano et al. (2009) has reported that between 20-60% of HP may have MIC and that patients also have lower body weights, lower BMI, lower albumin levels, lower blood pressure and elevated CRP (Diepeveen, et al., 2008). Albumin has been specifically mentioned as a marker of nutritional status and identified as one of the criteria used to measure PEM which is associated with MIC. The association between hypoalbuminemia (< 3.9 mg/dL) and mortality has been well-established and albumin has been identified as a strong predictor of cardiovascular disease (Kaysen, 2009). Supporting this theory is the fact that most studies reporting on reverse epidemiology report no counter-intuitive findings with HDL. The cholesterol esters in HDL are primarily received from albumin (Vaziri, 2009) and therefore hypoalbuminemia would be associated with low HDL. This is also one possible explanation for why other lipoproteins would be low, yet still associated with a significantly higher mortality rate in HP. Challenging our understanding of how this might impact mortality and cholesterol is that albumin is also used as a measure of inflammation and may not necessarily be related a nutritional etiology (Trivedi, et al., 2009). Finally, CRP along with IL-6 are inflammatory markers that have been associated with higher rates of mortality as well

In a subset of HP a decrease in baseline cholesterol levels, excluding HDL, has been associated with decreases in CVD mortality and all-cause mortality when patients have chronic levels of inflammation and poor nutritional status (Krane et al., 2009). Recent study authors have suggested the need to consider both malnutrition and inflammation simultaneously as albumin has been shown to be affected by inflammation levels. Inflammatory cytokines and acute phase reactants have been reported to decrease appetite, reduced albumin, increase catabolism (Liu et al., 2004) and quite possibly cause lower levels of cholesterol suggesting that low albumin levels may simply be a reflection of inflammation rather than malnutrition. Specifically most lipoproteins seem to be affected by MIC with the exception of HDL. In most studies where HDL was either low or unaffected most patients experience hypoalbuminemia and low protein intake in the diet (Kilpatrick, et al., 2007). Krane et al. (2009) in a study of 1,229 Type II diabetics who were HP reported that high levels of CRP strongly predicted all-cause mortality, sudden death and myocardial infarction when cholesterol levels were both low and high. Yet, when CRP levels were high and cholesterol levels were low, relative risks for CVD related deaths were even greater. It was further reported that CRP level and not LDL level was the variable more likely to predict risk for mortality and cardiovascular events. Another study confirmed the existence of reverse epidemiology in the presence of high inflammation suggesting the inflammation better predicted both morbidity and mortality (Tsirpanlis, et al., 2009). The study authors also reported that nutritional cachexia along with low cholesterol were good nutritional indices for malnutrition and may be the reason low cholesterol levels are associated with

Chmielewski, et al., 2008).

(Bowden & Wilson, 2010).

**5.1 Reverse epidemiology and cholesterol** 

**5. Malnutrition-inflammation complex** 

Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report, 2002) have established that lipids play a significant role in the progression of CVD and with reductions in cholesterol levels there is a similar and graded reduction in risk (Kalantar-Zadeh, et al., 2003). Dyslipidemia characterized in HP is primarily associated with hypertriglyceridemia, low HDL concentrations, elevated levels of LDL, elevated LDL particle numbers, a higher propensity of smaller and denser LDL particles which contain high levels of residual triglycerides, and elevated levels of lipoprotein (a) (Vaziri, 2009). Cholesterol metabolism in HP can be significantly altered by dialysis protocol, lipid controlling medication, malnutrition, and inflammation (Montazerifar, Hashemi, Karajibani, & Dikshit, 2010). HDL can be significantly reduced in HP due to a reduced plasma concentration of ApoA-I and ApoA-II (Bowden, Hebert, Wilson, Gentile, & Lanning, 2007; Vaziri, 2009), reduced transporter proteins such as ABCA-1 (Vaziri, 2009), and the downregulation of enzymatic process associated with HDL maturation (Malgorzewicz et al., 2010). Down-regulation also occurs with HDL paraoxonase which is associated with impaired protection against oxidative stress. Hypertriglyceridemia also occurs in HP, is normally associated with impaired VLDL and is the most prominent dyslipidemic abmormality reported in 70% of HP (Eisenhardt, Habersberger, & Peter, 2009). Additionally, hypertriglyceridemia is associated with increases in IDL, chylomicrons, and chylomicron remnants postprandial (Chmielewski, et al., 2008). Primarily a reduction in lipoprotein lipase, an enzyme associated with binding to VLDL and the release of the corresponding triglycerides, is associated with changes that cause a concomitant increase in plasma triglycerides that seems to correspond with a decrease in VLDL receptors. Finally, LDL in HP is normally more atherogenic as particles are usually smaller, denser and are more likely to be oxidized and engulfed by macrophages leading to more unstable arterial plaques (Kaysen, 2009). Oxidation can further cause LDL to no longer be recognizable to LDL receptors on the cell causing less deposition of LDL in intracellular pools. Less deposition can lead to the same amount of circulating LDL cholesterol being associated with smaller and denser LDL particles which can carry more risk for CVD. Excess LDL cholesterol is then removed from circulation primarily by being engulfed by macrophages which lead to more atherogenic foam cells leading to risk acceleration. Lipoprotein (a) is a LDL-like lipid with higher levels associated with increased risk of CVD and is associated with overproduction of apolipoproteins, specifically apoB. Apolipoprotein B is bound with LDL and is associated with increased numbers of LDL particles.

#### **4.1 Reverse epidemiology**

Though cholesterol metabolism in HP is associated with dyslipidemia and many CVD related deaths are associated with elevated levels of lipoproteins, recent evidence suggests that many HP have normal or reduced plasma cholesterol levels that are associated with a higher rate of mortality (Bowden & Wilson, 2010). CVD related mortality accounts for 40- 45% of all-cause mortality in HP suggesting factors other than lipids may be associated with CVD in this patient population (Dungan, et al., 2007; Tsirpanlis, et al., 2009). Counterintuitive outcomes regarding the role cholesterol may play in disease progression in HP may be affected by chronic inflammation and malnutrition with much of the published literature concerned with MIC (Bowden & Wilson, 2010; Chavalitdhamrong, et al., 2007). The term, though controversial, that has been used in the literature associated with this counter-intuitive finding is reverse epidemiology (Dungan, et al., 2007). Experimental studies are deficient, but the few published on this topic have suggested that HP with chronically elevated levels of inflammation, as measured by C-reactive protein (CRP) or interleukin-6 (IL-6), and malnutrition, as measured by albumin, are associated with normal cholesterol values but higher levels of mortality (Chavalitdhamrong, et al., 2007; Chmielewski, et al., 2008).
