**6. Association between inflammation, overhydratacion and cardiac disease: B-type natriuretic peptide**

Cardiac disease is high prevalent among patients with CKD (Foley et al. ,1995; Hayashi et al., 2006; Levin et al., 1996; Zocali et al., 2004). The typical feature of uremic cardiomyopathy is left ventricular diastolic dysfunction related to left ventricular hypertrophy and left ventricular fibrosis (Ahmed et al., 2007; Losi et al., 2010; Mark et al., 2006). Left ventricular hypertrophy is particularly highly prevalent in end-stage renal disease patients because of hypertension, hyperparathyroidism and increased volume. However, myocardial fibrosis is a specific finding among patients with CKD comparing with patients with isolated hypertension as revealed autopsy studies (Sharer et al., 1999). Probably, volume overload could be a main cause of myocardial fibrosis among these patients as volume overload can produce mechanical stress on the ventricular wall and it has been demonstrated that mechanical factors can induce the activation of the fibroblasts of the myocardium synthesizing the extracellular matrix (MacKenna et al., 2000). Volume overload is present very early in the course of CKD and is the consequence of the inability of the insufficient kidney to eliminate the excess of water and salt. Usually, the increase in extracellular water in the very early course of CKD is modest and may easily be underestimated by clinical examination and can only be proved by accurate measurement of body water volume, as with bioimpedance. Extracellular water excess increases when glomerular filtration rate declines and has emerged as an independent factor in the structural cardiac damage, as a direct relation between extracellular water excess and left ventricular mass has been demonstrated as well as with left ventricular data of diastolic dysfunction (Essig et al., 2008). The authors also highlighted that cardiac remodeling was present at the very early stages of CKD. Over time, structural myocardial alterations progress, leading to diastolic dysfunction. The central disturbance in diastolic dysfunction involves abnormalities in myocardial relaxation and ventricular compliance (Martos et al., 2007). Thus, in order to complete ventricular filling and achieve a sufficient end-diastolic volume, which will provide adequate stroke volume, the left ventricle needs filling pressure higher than normal. Diastolic dysfunction, in fact, means that the left ventricle fills at higher pressure. Echocardiographic data of diastolic dysfunction are the most frequent findings among patients with CKD (Hayashy et al., 2006).

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

**6. Association between inflammation, overhydratacion and cardiac disease:** 

Cardiac disease is high prevalent among patients with CKD (Foley et al. ,1995; Hayashi et al., 2006; Levin et al., 1996; Zocali et al., 2004). The typical feature of uremic cardiomyopathy is left ventricular diastolic dysfunction related to left ventricular hypertrophy and left ventricular fibrosis (Ahmed et al., 2007; Losi et al., 2010; Mark et al., 2006). Left ventricular hypertrophy is particularly highly prevalent in end-stage renal disease patients because of hypertension, hyperparathyroidism and increased volume. However, myocardial fibrosis is a specific finding among patients with CKD comparing with patients with isolated hypertension as revealed autopsy studies (Sharer et al., 1999). Probably, volume overload could be a main cause of myocardial fibrosis among these patients as volume overload can produce mechanical stress on the ventricular wall and it has been demonstrated that mechanical factors can induce the activation of the fibroblasts of the myocardium synthesizing the extracellular matrix (MacKenna et al., 2000). Volume overload is present very early in the course of CKD and is the consequence of the inability of the insufficient kidney to eliminate the excess of water and salt. Usually, the increase in extracellular water in the very early course of CKD is modest and may easily be underestimated by clinical examination and can only be proved by accurate measurement of body water volume, as with bioimpedance. Extracellular water excess increases when glomerular filtration rate declines and has emerged as an independent factor in the structural cardiac damage, as a direct relation between extracellular water excess and left ventricular mass has been demonstrated as well as with left ventricular data of diastolic dysfunction (Essig et al., 2008). The authors also highlighted that cardiac remodeling was present at the very early stages of CKD. Over time, structural myocardial alterations progress, leading to diastolic dysfunction. The central disturbance in diastolic dysfunction involves abnormalities in myocardial relaxation and ventricular compliance (Martos et al., 2007). Thus, in order to complete ventricular filling and achieve a sufficient end-diastolic volume, which will provide adequate stroke volume, the left ventricle needs filling pressure higher than normal. Diastolic dysfunction, in fact, means that the left ventricle fills at higher pressure. Echocardiographic data of diastolic dysfunction are the most frequent findings among

consequence, rather than the cause of heart failure.

**B-type natriuretic peptide** 

patients with CKD (Hayashy et al., 2006).

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 CRP.

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 ventricular dysfunction such as B-type natriuretic peptide.

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 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

Biomarkers in Chronic Kidney Disease -

hypervolemia or both conditions (Ortega, 2005).

inflammation in dialysis patients (figure 3).

Data expressed as mean ± standard error.

The Linkage Between Inflammation, Ventricular Dysfunction and Overhydration 271

participate in the atherosclerotic process inducing CV damage, it has also been suggested that inflammation among patients with CKD could be the consequence, rather than the cause, of an increased left-ventricular filling pressure, related to ventricular dysfunction,

The complex relation between ventricular dysfunction, overhydration and inflammation highlights the importance of strict volume control in patients with CKD. Usually, ventricular dysfunction progress over time. In an interesting longitudinal study performed in hemodialysis patients, a progressive deterioration of left ventricular filling pressure (an index of diastolic dysfunction) was observed in parallel with the progression of left ventricular hypertrophy and a progressive increment in levels of NT-proBNP (Kim et al., 2011). Thus, these results suggest that diastolic dysfunction progress over time among patients with chronic kidney disease. In another longitudinal study performed in hemodialysis patients (Ortega et al., 2009), the effect of strict volume control on the evolution of cardiac biomarker levels over time was analyzed. In this study, the strategy of strict volume control permitted the stabilization of cardiac biomarker levels over time, suggesting that this strategy may prevent further progression of left ventricular hypertrophy, cardiac fibrosis and diastolic dysfunction. Patients with higher biomarker levels at baseline, probably those with more severe myocardial damage, were the most beneficed as NT-proBNP levels could even be reduced over time (figure 2). In these high risk patients, continuous prevention of fluid overload diminished the inflammatory parameters on follow-up, confirming the importance of volume control for preventing

Fig. 2. Evolution over time of NT-proBNP values among patients distributed in high quartile at baseline (NT-proBNP high) and those distributed in other basal quartiles (NT-proBNP).

with CRP (Ortega et al., 2004). Newly, it means that only a group of patients with advanced renal failure shows high levels of natriuretic peptides, whereas other patients with similar creatinine clearance show even normal values. This finding probably reflects the presence of a mixed population among patients with advanced CKD with a group of patients with more severe cardiac disease whereas other patients can achieve the end-stage disease phase with less myocardial damage. But most importantly, a strong correlation between NT-proBNP and CRP levels is found (figure 1), suggesting an association between left-ventricular filling pressure and inflammation among patients with CKD.

Fig. 1. Regression graph demonstrating the correlation between NT-proBNP and C-reactive protein values at baseline (r: 0.7; p< 0.001)

This association between left-ventricular filling pressure and inflammation among CKD patients has been confirmed in subsequent years (Guo et al., 2009; Jacobs et al., 2010; Paniagua et al., 2010). Otherwise, the same studies and other authors (Booth et al., 2010) observed a relationship between cardiac and inflammatory biomarkers and volume overload. An association between volume overload and inflammation had been previously observed among patients on peritoneal dialysis (Woodrow, 2006). Overhydration by itself has emerged as an independent predictor on mortality in chronic hemodialysis patients (Wizemann et al., 2009).

Thus, all these findings show the complex relation between overhydration, malnutrition, inflammation and cardiac biomarkers in CKD patients. Although CRP can actively

with CRP (Ortega et al., 2004). Newly, it means that only a group of patients with advanced renal failure shows high levels of natriuretic peptides, whereas other patients with similar creatinine clearance show even normal values. This finding probably reflects the presence of a mixed population among patients with advanced CKD with a group of patients with more severe cardiac disease whereas other patients can achieve the end-stage disease phase with less myocardial damage. But most importantly, a strong correlation between NT-proBNP and CRP levels is found (figure 1), suggesting an association between left-ventricular filling

Fig. 1. Regression graph demonstrating the correlation between NT-proBNP and C-reactive

This association between left-ventricular filling pressure and inflammation among CKD patients has been confirmed in subsequent years (Guo et al., 2009; Jacobs et al., 2010; Paniagua et al., 2010). Otherwise, the same studies and other authors (Booth et al., 2010) observed a relationship between cardiac and inflammatory biomarkers and volume overload. An association between volume overload and inflammation had been previously observed among patients on peritoneal dialysis (Woodrow, 2006). Overhydration by itself has emerged as an independent predictor on mortality in chronic hemodialysis patients

Thus, all these findings show the complex relation between overhydration, malnutrition, inflammation and cardiac biomarkers in CKD patients. Although CRP can actively

pressure and inflammation among patients with CKD.

protein values at baseline (r: 0.7; p< 0.001)

(Wizemann et al., 2009).

participate in the atherosclerotic process inducing CV damage, it has also been suggested that inflammation among patients with CKD could be the consequence, rather than the cause, of an increased left-ventricular filling pressure, related to ventricular dysfunction, hypervolemia or both conditions (Ortega, 2005).

The complex relation between ventricular dysfunction, overhydration and inflammation highlights the importance of strict volume control in patients with CKD. Usually, ventricular dysfunction progress over time. In an interesting longitudinal study performed in hemodialysis patients, a progressive deterioration of left ventricular filling pressure (an index of diastolic dysfunction) was observed in parallel with the progression of left ventricular hypertrophy and a progressive increment in levels of NT-proBNP (Kim et al., 2011). Thus, these results suggest that diastolic dysfunction progress over time among patients with chronic kidney disease. In another longitudinal study performed in hemodialysis patients (Ortega et al., 2009), the effect of strict volume control on the evolution of cardiac biomarker levels over time was analyzed. In this study, the strategy of strict volume control permitted the stabilization of cardiac biomarker levels over time, suggesting that this strategy may prevent further progression of left ventricular hypertrophy, cardiac fibrosis and diastolic dysfunction. Patients with higher biomarker levels at baseline, probably those with more severe myocardial damage, were the most beneficed as NT-proBNP levels could even be reduced over time (figure 2). In these high risk patients, continuous prevention of fluid overload diminished the inflammatory parameters on follow-up, confirming the importance of volume control for preventing inflammation in dialysis patients (figure 3).

Fig. 2. Evolution over time of NT-proBNP values among patients distributed in high quartile at baseline (NT-proBNP high) and those distributed in other basal quartiles (NT-proBNP). Data expressed as mean ± standard error.

Biomarkers in Chronic Kidney Disease -

CKD patients (Sommerer et al., 2007).

values at baseline (r: 0.4; p= 0.002)

dysfunction (figure 5) (Ortega et al., 2009).

elevations of troponin among patients with CKD.

The Linkage Between Inflammation, Ventricular Dysfunction and Overhydration 273

Cardiac microinfarctions and arrhythmia have also been suggested as possible causes of

More recently, it has been observed that CKD patients with high troponin T concentrations had clear evidence of myocardial dysfunction and raised left ventricular filling pressure (Sharma et al., 2006), supporting that volume and pressure overload can cause excessive ventricular wall tension with resultant myofibrillary damage or cardiomyocites death (Horwich TB et al., 2003). In this way, a strong association between troponin T and NTproBNP has been observed in hemodialysis patients (figure 4) (Ortega et al., 2009) and both troponin T and NT-proBNP levels has been observed to be higher in volume-overloaded

Fig. 4. Regression graph demonstrating the correlation between NT-proBNP and troponin T

Thus, it seems that the increased troponin T in a high proportion of patients with CKD could be related to myocardial injury induced by an increased left ventricular volume especially in those patients with diastolic dysfunction, in whom a small increase in end-diastolic volume produces an exaggerated increment in end-diastolic pressure with the subsequent myocardial damage. Furthermore, in hemodialysis patients, a strategy of strict volume control over time could significantly reduce the troponin T levels especially in those patients with higher biomarker levels at baseline, probably those with more severe myocardial

Fig. 3. Evolution over time of CRP values among patients distributed in high quartile at baseline (CRP high) and those distributed in other basal quartiles (CRP). \* p<0.05 vs baseline levels. Data expressed as mean ± standard error.
