**2.1 Acute vs. chronic inflammation**

Initially, the inflammatory response is a defense mechanism to cellular injury or pathogenic invasion. The acute response includes vasodilatation, hyperemia and vascular permeability and can be detected within a relatively short amount of time (minutes to days) via an increase in neutrophils and the presence of fluid protein exudates (Sprague & Khalil, 2009).

Malnutrition, Inflammation and Reverse Epidemiology in Hemodialysis Patients 299

been found in atherosclerotic lesions (Sun et al., 2005), but the antibodies used to detect CRP in this study detected both pCRP and mCRP (Eisenhardt, Habersberger, & Peter, 2009). It has been reported that once pCRP dissociates into mCRP, mCRP stimulates monocytes to a greater extent than pCRP, leads to increased monocyte adhesion, and exerts proinflammatory properties (Eisenhardt, Habersberger, Murphy, et al., 2009). Additionally, mCRP may be more effective at regulating LDL metabolism than pCRP (Ji, Wu, Potempa,

Aside from the primary reason for the patient being placed on hemodialysis, often a disease associated with inflammation, dialysis and the integral pieces of hemodialysis can be sources of inflammation. Kaysen (2009) indicates that the type of vascular access used in dialysis, the insertion of the catheters, biofilm on catheters, bacterial components present in dialysate, and water supply can all be sources of inflammation (Kaysen, 2009). Markers of inflammation associated with vascular access alone include albumin (Chand, Teo, Fatica, & Brier, 2008; Wystrychowski et al., 2009), CRP (Costa et al., 2008; Movilli et al., 2006; Sachdeva, Kovalchuk, Bitzer, & Mokrzycki, 2009), and IL-6 (Costa, et al., 2008; Sachdeva, et al., 2009). As Kaysen (2009) points out, the type of vascular access in HP is associated with mortality (Xue, Dahl, Ebben, & Collins, 2003). Acutely, initial insertion of vascular access, especially catheter or arteriovenous graft (AVG), resulted in transient elevations of CRP and IL-6 whereas arteriovenous fistulas (AVF) did not demonstrate a transient rise in inflammatory markers (Sachdeva, et al., 2009). In regards to chronic inflammation, changing vascular access type from a catheter to AVG was shown to cause an increase in albumin, where as a change from AVG to catheter caused a decrease in albumin (Wystrychowski, et al., 2009). Similarly, catheter and AVG use have been demonstrated to result in elevated levels of CRP and IL-6 and lower levels of albumin than AVF (Costa, et al., 2008; Movilli, et al., 2006). Thus, the type of vascular access has an impact on inflammation levels. An additional impact on inflammation levels is adipose tissue as adipocytes produce IL-6 (Fasshauer, Klein, Lossner, & Paschke, 2003), which is also a strong predictor of mortality in

Qiu, & Zhao, 2006).

**2.3 Causes of inflammation in hemodialysis patients** 

HP (Barreto, et al., 2009; Pecoits-Filho, et al., 2002; Stenvinkel, et al., 2002).

Albumin is the most abundant plasma protein with a half-life of about twenty-one days. It is a negative acute-phase protein that functions to maintain oncotic pressure and act as a transport protein (Carlson, 2004). Normal serum albumin concentration is between 3.5 and 5.2 g/dL, and this reference range is often utilized as a marker of nutritional status in healthy older populations (Carlson, 2004; Covinsky, Covinsky, Palmer, & Sehgal, 2002). The cutoff point for low serum albumin concentration (hypoalbuminemia) has been proposed to be even higher at about 3.9 g/dL in HP (Trivedi, Xiang, & Klein, 2009). However, it must be noted that conclusions derived from measures of serum albumin concentration are not always in agreement with the conclusions derived from clinical assessments regarding nutritional status (Covinsky, et al., 2002). Forty HP with CRP levels below 0.80 mg/dL were evaluated for malnutrition by measuring serum albumin and through the use of the Subjective Global Assessment (SGA) described by Detsky, McLaughlin, and Baker et al. (1987). The SGA was used to determine whether a patient was classified as well-nourished

**3. Malnutrition in hemodialysis patients 3.1 Albumin as a marker of nutritional status** 

Additional responders involved in the inflammatory response are cytokines (Sprague & Khalil, 2009) and acute phase proteins, which reach peak circulating levels within two days in the acute setting (Ceciliani, Giordano, & Spagnolo, 2002). Typically, the inflammatory process ceases when the mechanism responsible for cellular injury is removed, subsequent cellular intermediaries are inhibited, and healing takes place (Sprague & Khalil, 2009). However, in some instances that inflammatory process is not resolved. Thus, the response remains active and proceeds into a chronic process, which can result in necrosis and/or loss of functional tissue.

### **2.2 Markers of inflammation in hemodialysis patients**

In HP the inflammatory response and markers of inflammation, namely CRP and the inflammatory cytokine interleukin-6 (IL-6), are predictive of mortality (Barreto et al., 2009; Pecoits-Filho, Barany, Lindholm, Heimburger, & Stenvinkel, 2002; Stenvinkel, Barany, Heimburger, Pecoits-Filho, & Lindholm, 2002; Yeun, Levine, Mantadilok, & Kaysen, 2000; Zimmermann, Herrlinger, Pruy, Metzger, & Wanner, 1999). In addition to CRP and IL-6, albumin and the inflammatory cytokine tumor necrosis factor-alpha (TNF-) are markers of inflammation commonly found in the literature. Each marker can provide evidence regarding the inflammatory state of HP, but there is debate as to which marker should be used and even debate as to the role in the inflammatory process of certain markers, namely CRP. For example, IL-6 and TNF- are known pro-inflammatory cytokines and are also associated with declining kidney function. Various cells including, macrophages and mast cells, produce TNF- and IL-6 (Sprague & Khalil, 2009). Among the numerous effects of TNF- are the stimulation of a febrile response, up-regulation of other cytokines, such as IL-6, and stimulation of acute phase reactants (Sprague & Khalil, 2009). IL-6, in turn, has pleiotropic effects that include antibody secretion, the acute phase response and has also been shown to be pro-atherogenic, to name a few. However, TNF- and IL-6 are not typically used in clinical medicine and are more often found in research; therefore other means of assessing inflammation are used as these tests can become costly. Conversely, albumin and CRP are measurements of inflammation readily available to physicians. Interestingly, albumin levels are also commonly used to assess nutritional status as both nutrition and inflammation can affect albumin (more on this topic will be presented later in the chapter).

CRP, however, is frequently used to confirm the presence of inflammation, as it is an acute phase protein produced by the liver and greatly regulated by IL-6. Additionally CRP is associated with reduction in nitric oxide production, induces monocyte recruitment and plays a strong role in foam cell formation. However, the causal role of CRP in cardiovascular events is still being debated (Genest, 2010; Lippi, Favaloro, Montagnana, & Franchini, 2010; Sattar & Lowe, 2006) and the use of CRP must be justified as it incurs added cost (Kaysen, 2009). Regardless, it is a marker of inflammation that in the native form consists of five noncovalently bonded subunits and is termed pentameric CRP or pCRP. This is typically the CRP measured in plasma or serum, and is also known as high sensitivity CRP (hsCRP). High sensitivity CRP can dissociate into monomeric CRP (mCRP) after binding with activated platelets (Eisenhardt et al., 2009). New evidence suggests that mCRP, through the interaction of hsCRP with activated platelets, may play a more dominant role in the inflammatory process than hsCRP as mCRP was found to colocalize with macrophages and platelets (Eisenhardt, Habersberger, Murphy, et al., 2009). High sensitivity CRP has also been found in atherosclerotic lesions (Sun et al., 2005), but the antibodies used to detect CRP in this study detected both pCRP and mCRP (Eisenhardt, Habersberger, & Peter, 2009). It has been reported that once pCRP dissociates into mCRP, mCRP stimulates monocytes to a greater extent than pCRP, leads to increased monocyte adhesion, and exerts proinflammatory properties (Eisenhardt, Habersberger, Murphy, et al., 2009). Additionally, mCRP may be more effective at regulating LDL metabolism than pCRP (Ji, Wu, Potempa, Qiu, & Zhao, 2006).
