الفهرس 
Chapter (1): chronic kidney diseaseOnly 14 pages are availabe for public view
 |  | from | 16 |  |  |
| | | from | 16 | | |
Abstract
Cardiovascular disease (USRDS, 2009), excessive blood volume (Stegmayr, 2003), and systemic inflammation (DeFilippi, et al, 2003; Hocher, et al, 2003) are the major causes of mortality in hemodialysis patients. Early diagnosis and treatment of cardiovascular disease and excessive blood volume and systemic inflammation may lead to improved survival in hemodialysis patients (Yoshihara F, et al., 2005).
For this purpose, a noninvasive biochemical testing method would be ideal to screen for, and monitor cardiac condition, blood volume, and inflammatory status.
Adrenomedullin (AM), a 52-amino-acid peptide derived largely from vascular tissues, has numerous effects within the kidneys and on the cardiovascular and rennin-angiotensin systems (Hinson, J. P., Kapas, S., and Smith, D. M, 2000). These protean actions of adrenomedullin are generally seen as protective against injury due to hypertension, cardiovascular trophic and toxic factors, and infection (Hinson, J. P., Kapas, S., and Smith, D. M, 2000; Eto T, and Kitamura K, 2001). The hormone circulates in higher than normal concentrations in patients with renal impairment and is altered variably by haemodialysis (Yamasaki H, et al., 2001; Suda T, et al., 2002; McGregor DO, et al., 2003; Tokura T, et al., 2003).
Numerous studies showed that plasma AM levels were increased in left ventricular (LV) failure (Øie E, et al., 2010), myocardial infarction (Khan SQ, et al., 2007), and peripheral arterial occlusive disease (Suzuki, et al, 2004), according to the disease severity.
It has been shown that plasma AM levels are increased in hemodialysis patients (Cases, et al, 2000; Tokura, et al, 2001; Yamasaki, et al, 2001; Kanozawa, et al, 2002; Suda, et al, 2002), and that increased AM levels might be involved in the regulation of systemic blood pressure (Tokura, et al, 2001; Yamasaki, et al, 2001) and reflect systemic blood volume (Kanozawa, et al, 2002) in hemodialysis patients and intracardiac pressure in hemodialysis patients with coronary artery disease (Osajima, et al, 2002).
Taken together, there is a possibility that plasma AM level may predict morbidity and mortality through the significant correlation with cardiac condition, systemic blood volume, and inflammatory status (Yoshihara, et al, 2005). However, there are few reports concerning the significance of the plasma AM level in hemodialysis patients with cardiovascular disease.
We hypothesized that plasma AM is a noninvasive biochemical predictor for cardiovascular morbidity in hemodialysis patients with cardiovascular disease. Therefore, we conducted the present study to investigate whether plasma AM reflects cardiac dysfunction, removal of fluid volume by ultrafiltration, and systemic inflammatory status in hemodialysis patients. We also assessed whether cardiovascular morbidity can be predicted by the measurement of AM.
Our study was performed on 60 clinically stable hemodialysis patients (31 females, 29 males; mean age 46 ± 12.67) as well as 60 healthy subjects served as a control subjects (30 females, 30 males; mean age 43.05 ± 13.85 years). To clarify the influence of coronary artery disease (CAD) on the clinical, biochemical, humoral and other variables, we subdivided the patients according to the presence or absence of concomitant CAD and compared these variables between the 2 groups: CAD (n = 30) and Non-CAD (n = 30) hemodialysis patients.
All members of the study were subjected to complete history-taking and clinical examination. Along with complete blood picture, kidney function tests, serum electrolytes, iPTH level, iron study, lipid profile; Plasma measurements of mAM and hs-CRP were determined. In addition, echocardiography (for assessement of systolic and diastolic function) was done.
In the present study, plasma AM concentrations were significantly higher (p<0.001) in hemodialysis patients (267.23 ± 79.67) compared to control subjects (68.43± 35.90)
In the current study, a significant negative correlation was found between mature AM and both systolic blood pressure in hemodialysis patients (r = -0.835, p < 0.001). Plasma adrenomedullin showed significant positive correlation with the number of hypotensive episodes (r = 0.952, p < 0.001) suggesting that AM, may play an important role as vasodilator local hormone in regulation of blood pressure during hemodialysis, especially the occurrence of episodic hypotension.
In the current study, there was a significant and positive correlation between mature AM and delta body weight, one of the markers of circulating blood volume (r = 0.886, p < 0.001)
In our study, we analyzed the presence of fluid overload using the measurement of IVCD which is a non-invasive, simple and fast method that correlates well with right atrial pressure and circulating blood volume.
The mean IVC diameter (± SD) immediately before dialysis was significantly higher in hemodialysis patients than in controls (21.40 ± 7.38 vs 12.99 ± 2.45, p<0.001). There was a significant positive correlation between adrenomedullin and IVC diameter (r = 0.825, p <0.001) in hemodialysis patients.
We evaluated the left ventricular function (systolic and diastolic) in hemodialysis patients just before dialysis (using echocardiography). The main difference between hemodialysis patients and controls which emerged from the results of the present study is the significantly greater mean values of right ventricular diameter (RVD) (p<0.001), left atrial diameter (LAD) (p<0.001), left ventricular diastolic diameter (LVEDD) (p<0.001) and left ventricular posterior wall thickness (LVPWT) (p<0.001) in hemodialysis patients than in controls, a finding consistent with ventricular overloading. The mean left ventricular ejection fraction (EF) was significantly lower in hemodialysis patients than in controls (p<0.001). Doppler analysis of left ventricular diastolic function (mitral inflow velocity profiles) showed that LV diastolic function was significantly impaired in hemodialysis patients compared to control subjects. The impairement was manifest as: nonsignificant decrease in E wave velocity (p>0.05), marked increase in the A wave velocity (p<0.001) and reduced E/A ratio (p<0.001) in hemodialysis patients as compared to controls.
In the present study, plasma mAM level was a useful biochemical marker for cardiac dysfunction in hemodialysis patients. There were no significant differences in plasma mAM level, E/A ratio, S/D ratio, LVEDD, LVESD or LVPWT between hemodialysis patients with CAD and those without CAD, in the present study.
Plasma mAM level was correlated negatively with LVEF (r = -0.850, p< 0.001) as well as systolic blood pressure (r = -0.835, p < 0.001). And positively with removal of fluid volume during hemodialysis (delta body weight) (r = 0.886, p < 0.001), number of hypotensive episodes (r = 0.952, p < 0.001 and IVC diameter (r = 0.825, p <0.001) in the present study.
These results suggested that the increased mature AM level in hemodialysis patients may reflect LV systolic dysfunction, which was defined as reduced LVEF.
In the present study, there was a positive correlation between plasma AM and plasma CRP concentrations (r = 0.607, p <0.001). Thus, plasma AM concentrations may provide an indication of chronic inflammatory status in haemodialysis patients that is independent of other cardiac disease conditions.
Thus, the present results that plasma mAM level reflects not only cardiac dysfunction but also systemic blood volume and inflammatory status might be the possible mechanism how plasma mAM level could become a reliable predictor of cardiovascular morbidity and mortality.
In conclusion, the present results together with other reports showed that plasma levels of AM are elevated in patients with chronic renal failure on regular hemodialysis and increased plasma mature AM level reflects excessive fluid volume, LV dysfunction, and systemic inflammatory status in hemodialysis patients.