**5. Possible causes of inflammation**

266 Progress in Hemodialysis – From Emergent Biotechnology to Clinical Practice

Elevated CRP levels have been described in a significant proportion of end-stage-renaldisease patients on hemodialysis or peritoneal dialysis (Arici et al., 2001). About one-third of patients with chronic renal failure have serum CRP concentration > 10 mg/l (Owen et al., 1998). In healthy men, high CRP level has been identified as a risk factor for cardiovascular disease (Ridker et al., 2001). As occurs in the general population, prospective studies point to a correlation between CRP plasma levels and overall and cardio-vascular mortality also in end-stage-renal disease patients (Arici et al., 2001; Ikizler et al., 1999; Noh et al., 1998; Owen et al., 1998; Panichi et al., 2008; Wang et al., 2009; Yeun et al. 2000; Zimmermann et al., 1999).

In dialysis patients, inflammation expressed by high levels of CRP is also associated with low blood hemoglobin and/or resistance to eritropoyesis-stimulating agents (Barany et al., 1997; Bradbury et al., 2009; Gunnel et al., 1999; Owen et al., 1998). This has been attributed to the inhibition of erythropoietin secretion by pro-inflammatory cytokines. Inflammation also contributes to anemia by inducing functional iron deficiency probably blocking the delivery of iron from the reticuloendothelial cells to the hemathopoietic cells. Cytokines may also induce ferritin synthesis directly or by increasing iron uptake into hepatocytes. The increase in ferritin synthesis by hepatocytes and reticuloendothelial cells underlies in the iron storage pool during inflammation. Thus, inflammation among patients with CKD can contribute to anemia and impaired response to erythropoietin. Erythropoietin resistance by itself has been associated with higher short-term mortality in CKD patients (López-Gómez

High concentration of acute phase protein is correlated with low serum albumin in malnourished hemodialysis patients (Kaysen et al., 1997; Qureshi et al., 1998). Low serum albumin concentrations are highly associated with increased mortality risk in patients with renal replacement therapy (Lowrie et al., 1990). Hypoalbuminemia has been traditionally been assumed to result from inadequate protein and calorie intake. However, albumin is a negative acute-phase protein. The synthesis of this protein decreases during inflammation independently of nutritional state. Albumin concentration in dialysis patients is negatively correlated with levels of positive acute-phase protein. Moreover, inflammation and malnutrition data has been associated with the presence of atherosclerotic carotid plaques (Stenvinkel et al., 1999) describing the so called MIA (malnutrition-inflammation-

In summary, inflammation is high prevalent among patients with chronic kidney disease and predicts anemia, malnutrition and CV death. An intriguing question is whether CRP is just a sensitive marker of systemic inflammation or actively contributes to the development and progression of atherosclerotic lesions and, therefore, to the CV damage. Some authors have demonstrated CRP content inside the atherosclerotic lesions, suggesting the active participation in the inflammatory process (Zhang et al., 1999) what hints that inflammation could be the cause rather than the consequence of CV damage. Based on the bad prognosis of patients with markers of inflammation, it is important to try to known the possible causes

of inflammation in this population in order to prevent morbidity and mortality.

atherosclerosis) syndrome in patients with advanced renal failure.

**3. Inflammation and anemia** 

**4. Inflammation and malnutrition** 

et al., 2008).

The causes of inflammation in patients with CKD patients remained unclear over time.

Several studies have attempted to address the question as to whether some factors related to the dialysis technique by itself could induce the inflammatory response. Activation of monocytes with the subsequent enhanced release of inflammatory cytokines can be caused by membrane-induced complement activation, by direct cell-membrane interaction and by dialysis fluids containing endotoxins (Carracedo et al., 2006; Honkanen et al., 1991; Kerr et al., 2007; Schouten et al. 2000).

However, a similar prevalence of inflammation has been described in patients with advanced renal failure not yet on dialysis (Ortega et al., 2002; Panichi et al., 2002; Stenvinkel et al., 1999). An inverse correlation between CRP levels and clearance of creatinine has been observed (Panichi et al., 2002); thus, CRP levels increase as renal function declines. This finding suggests the possibility of a decreased renal clearance of CRP as a cause of an activated acute-phase response in patients with chronic kidney disease. Another possibility could be that uremia by itself could be the cause of inflammation among these patients. However, in another study performed in pre-dialysis patients with a more homogeneous clearance of creatinine (Ortega et al., 2002), a non-normal distribution of CRP levels were detected. That means that only a group of patients with advanced renal failure shows high levels of CRP, whereas other patients with the same degree of renal insufficiency have even normal CRP values. Hence, it seems that uremia by itself is not the unique cause of inflammation. Probably, inflammation could be related to some factors, frequently associated with renal failure, which can worsen with the worsening of renal function. In this study (Ortega et al., 2002), CRP levels were higher in those patients with a previous history of CVD. Comparing with patients with normal CRP levels at baseline, patients with higher levels maintained significant higher levels on follow-up. This group of inflamed patients showed during the study period persistently lower serum albumin, lower blood hemoglobin, needed higher doses of erythropoietin stimulating agents and showed higher hospitalization rate (table 1).


Table 1. Comparison of the evolution of analytical and clinical data between patients with high (Group I) or low (Group II) CRP levels at baseline. Mean ± standard deviation. \*Median (interquartile range).

In summary, at this point we know that inflammation is high prevalent among patients with CKD, that the prevalence is higher among patients with associated CVD, that inflammation tends to increase with the decline of renal function but that only about one third of patients with advance renal function shows persistently high levels of inflammatory

Biomarkers in Chronic Kidney Disease -

ventricular dysfunction such as B-type natriuretic peptide.

the high levels of natriuretic peptides detected in this population.

NT-proBNP is the amino-terminal peptide fragment of the precursor of BNP and shows a close correlation to BNP (Masson et al., 2002). A non-normal distribution of NT-proBNP levels was observed among patients with advanced renal failure, as previously observed

CRP.

The Linkage Between Inflammation, Ventricular Dysfunction and Overhydration 269

Based on the association between inflammation and heart failure in the general population and as myocardial dysfunction is high prevalent among patients with CKD, several authors tried to find an association between inflammation and cardiac disease also in this population. Furthermore, this hypothesis could explain why only some patients (those with more ventricular damage) show high levels of CRP, whereas other patients with similar clearance of creatinine (those with less cardiac disease) could present even normal values of

Some authors (Ates et al., 2005; Kim et al., 2005) have observed an association between CRP and left ventricular hypertrophy or dysfunction among patients with CKD. However, most authors have employed in their studies the measurement of a biochemical marker of

B-type natriuretic peptide (BNP) is a cardiac neurohormone specifically secreted from cardiac ventricles in response to an increased left-ventricular wall tension (Maeda et al., 1998). When end-diastolic filling pressure is increased (related to ventricular dysfunction, hypervolemia or both conditions), the release of BNP is induced. BNP is a potent natriuretic peptide by enhancing renal sodium excretion, reducing so the intravascular volume and, therefore, the end-diastolic volume and pressure. BNP is a strong predictor of systolic and diastolic abnormalities and is a powerful marker for prognosis and risk stratification in the setting of heart failure (Tabbibizar et al., 2002). In the general population, a cut point of about 100 pg/ml can discriminate patients with heart failure from patients without it. BNP is increased among patients with CKD and an inverse correlation between BNP levels and glomerular filtration rate has been observed (McCullough et al., 2003). This increased BNP level among these patients is in part related to the decreased renal clearance as well as the accompanying increased intravascular volume which is usually present in these patients. However, values above a cut-point reflect ventricular dysfunction and predict heart failure also among patients with CKD. In general, as CKD stage advances, a higher cut point of BNP is implied. BNP levels higher than 500 pg/ml usually predict heart failure even in patients with renal failure. Diastolic dysfunction is the most frequent cardiac disease among patients with CKD. In this setting, a small increment in end-diastolic volume lead to an exaggerated increase in diastolic pressure (Mandinov et al., 2000), inducing the release of natriuretic peptide. Probably, this pathophysiological mechanism partly explains the high levels of BNP detected among patients with CKD. In fact, several studies have observed an association between natriuretic peptide levels and echocardiographic data of left ventricular hypertrophy and dysfunction among patients with CKD (Guo et al., 2009; Paniagua et al., 2010; Zocali et al., 2001). Natriuretic peptide levels among patients with CKD predict death, as it occurs in patients with heart failure and normal renal function. Otherwise, some authors (Jacobs et al., 2010) have demonstrated a direct correlation between extracellular water, measured by bioelectrical impedance, and natriuretic peptide in CKD patients, explaining how volume overload can increase end-diastolic volume and, therefore, enddiastolic pressure favoring the release of BNP. Probably both mechanisms, volume overload and myocardial damage, both high prevalent among patients with CKD, could explained

markers. Thus, we could argue that uremia by itself is not the cause of inflammation. It seems that another factor, usually associated with uremia and which usually worsens with the decline of renal function could be the responsible of inflammation in patients with CKD. In the past decade, it has been observed that circulating inflammatory cytokines are elevated in patients with chronic heart failure (Levin et al., 1990) and it has been suggested that cytokines can be in part responsible for cardiac disease progression in these patients (Seta et al., 1996). Some authors have detected elevated plasma levels of endotoxins and cytokines during the acute phase of heart failure and that normalization of endotoxins and cytokines concentration can be achieved using intensive diuretic treatment (Niebauer et al. 1999, Peschel et al. 2003). The authors hypothesized that during acute cardiac decompensation, acute mesenteric venous congestion with subsequently altered gut permeability for endotoxins would lead to translocation of these materials into the circulation inducing the inflammatory response. Thus, the authors highlight that inflammation could be the consequence, rather than the cause of heart failure.
