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NDT Advance Access published online on March 29, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm029
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Midregional proadrenomedullin reflects cardiac dysfunction in haemodialysis patients with cardiovascular disease

Fumiki Yoshihara1, Andrea Ernst2, Nils G. Morgenthaler3, Takeshi Horio1, Satoko Nakamura1, Hajime Nakahama1, Hiroto Nakata1, Andreas Bergmann2,3, Kenji Kangawa4 and Yuhei Kawano1

1Division of Hypertension and Nephrology, National Cardiovascular Center, Suita, Osaka, Japan, 2SphingoTec GmbH, Tulpenweg 6, D-16556 Borgsdorf, 3Research Department, B.R.A.H.M.S AG, Neuendorfstrasse 25, D-16761 Hennigsdorf, Germany and 4Research Institute, National Cardiovascular Center, Suita, Osaka, Japan

Correspondence and offprint requests to: Fumiki Yoshihara, MD, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. Email: fyoshi{at}ri.ncvc.go.jp



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Study limitations
 References
 
Background. Although adrenomedullin is an indicator of cardiac dysfunction in haemodialysis patients, the clinical significance of midregional proadrenomedullin has not been elucidated.

Objectives. We evaluated whether midregional proadrenomedullin reflects cardiac dysfunction, systemic inflammation or blood volume in haemodialysis patients.

Methods. Plasma midregional proadrenomedullin, C-reactive protein and delta body weight (indicating excessive blood volume), and two-dimensional as well as Doppler echocardiographic variables were measured just before haemodialysis in 70 patients with cardiovascular disease.

Results. The median value of midregional proadrenomedullin was 1.93 nmol/l before haemodialysis, and these levels were significantly reduced following haemodialysis. Log [midregional proadrenomedullin] was positively correlated with left ventricular end-systolic volume index, diameter of inferior vena cava, C-reactive protein and delta body weight (r = 0.328, r = 0.421, r = 0.356, r = 0.364), and negatively with blood pressure, deceleration time of an early diastolic filling wave, pulmonary venous flow velocity ratio and left ventricular ejection fraction (r = –0.330, r = –0.324, r = –0.479, r = –0.373). Multivariate regression analysis revealed that pulmonary venous flow velocity ratio, diameter of inferior vena cava and C-reactive protein were independently related factors for midregional proadrenomedullin concentration.

Conclusion. Plasma midregional proadrenomedullin levels increase in association with cardiac dysfunction, systemic inflammatory status and systemic blood volume in haemodialysis patients with concomitant cardiovascular disease.

Keywords: cardiac dysfunction; excessive blood volume; haemodialysis; midregional proadrenomedullin; systemic inflammatory status



   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Study limitations
 References
 
Cardiovascular disease [1], excessive blood volume [2] and systemic inflammation [3] are the major causes of mortality in haemodialysis patients. Early diagnosis and treatment of these processes in haemodialysis patients may lead to improved survival. For this purpose, a non-invasive biochemical testing method would be ideal for screening and monitoring cardiac status, blood volume and inflammatory state.

Plasma adrenomedullin levels are elevated in left ventricular (LV) failure [4], myocardial infarction [5] and peripheral arterial occlusive disease [6], and these levels increase according to disease severity. Plasma adrenomedullin levels are additionally increased in haemodialysis patients [7] and these increases may be involved in the regulation of systemic blood pressure [7], and may reflect changes in systemic blood volume [8] in these patients. We also recently reported that adrenomedullin reflects cardiac dysfunction, excessive blood volume and inflammation, thereby proving to be a good predictor of mortality and cardiovascular morbidity in haemodialysis patients with cardiovascular disease [9].

Because adrenomedullin has a short half-life (22 min) in human plasma and is regulated by a proteolytic enzyme [10], the pre-analytical conditions of the plasma samples, particularly the storage temperature, may influence the final test results. Furthermore, several other factors may influence adrenomedullin measurement, including a binding protein that may be present in human plasma, which may have a specific inhibitory effect on the adrenomedullin radioimmunoassay [11]. Also, autocrine or paracrine interactions between adrenomedullin and its receptors in the vicinity of release may lead to a removal of adrenomedullin from the circulation. Taken together, these pre-analytical factors may lead to an underestimation of the true adrenomedullin values by immunoassays.

Adrenomedullin is derived from a larger precursor peptide (prepro-adrenomedullin; 185 amino acids) by posttranslational processing [12]. During the processing of prepro-adrenomedullin, two peptides flank Adrenomedullin: one midregional part of proadrenomedullin (proadrenomedullin 45–92) and the COOH terminus of the molecule (proadrenomedullin 153–185). We have recently reported the technical characterization of this midregional proadrenomedullin (MR-proADM) sandwich immunoassay [13]. In contrast to mature adrenomedullin, MR-proADM is stable in plasma at room temperature for at least 72 h. MR-proADM probably has no physiological effects and its apparent stability may be attributable to this lack of function because only bioactive substances require careful regulation by proteolysis. The released amounts of MR-proADM may directly reflect levels of adrenomedullin. In addition, circulating MR-proADM is unlikely to be influenced by a binding protein, making it suitable for immunometric analysis. Although we recently reported that MR-proADM is increased in patients with cardiovascular disease [13], a more detailed analysis of the relationship between plasma MR-proADM concentration and cardiac function or cardiovascular disease severity is still lacking.

Therefore, we conducted the present study to investigate whether plasma MR-proADM accurately reflects cardiac dysfunction, removal of fluid volume by ultrafiltration, and systemic inflammatory status in haemodialysis patients admitted for evaluation of cardiovascular disease. We also performed pilot work to assess whether MR-proADM levels are predictive of subsequent mortality.



   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Study limitations
 References
 
Patients
Seventy consecutive haemodialysis patients (51 men, 19 women; mean age, 65 ± 10 years), admitted to the National Cardiovascular Center for evaluation of cardiovascular disease, were enrolled in the present study. Patients having atrial fibrillation, overt pulmonary effusion, or pulmonary congestion were excluded from the present study. All patients underwent regular haemodialysis for 3–4 h three times weekly (Monday, Wednesday and Friday). Written informed consent was obtained from all patients. The procedures were in accordance with the Helsinki Declaration of 1975 (and as revised in 1983). After release from our institute, patients were followed up for an average 14.7 months. All-cause deaths were recorded.

Echocardiographic measurement
A skilled echocardiographer without knowledge of the clinical features of the patients performed the echocardiographic studies using a cardiac ultrasound unit (Sonos 5500; Philips Medical Systems, Andover, MA) just prior to haemodialysis treatment, as previously reported [9]. Left ventricular end-diastolic volume index (LVEDVI), left ventricular end-systolic volume index (LVESVI) and left ventricular ejection fraction (LVEF) were calculated using the modified Simpson method according to the recommendations of the American Society of Echocardiography [14].

To assess left ventricular (LV) diastolic function, LV diastolic filling (LV inflow) was examined using Doppler echocardiography. The LV diastolic filling pattern was obtained with the sample volume at the tips of the mitral valve in the apical four-chamber view and was recorded at the end-expiratory phase during quiet breathing. Peak velocity of early diastolic filling (E) and peak velocity of atrial filling (A) were recorded, and the E/A ratio was calculated. The deceleration time (DcT) was measured as the time between the top of the E wave and the point at which the descending part of the E wave or its asymptote crossed the zero line.

After LV inflow velocities were examined, pulmonary venous flow velocities were obtained from the apical four-chamber view and recorded at end-expiration. The pulsed Doppler sample volume was set at 0.5–1.0 cm into the upper right pulmonary vein. Peak forward flow velocities during ventricular systole (S) and diastole (D) were measured, and the S/D ratio was calculated. Echocardiographic parameters were obtained in 51 patients. LV inflow velocities and pulmonary venous flow velocities were obtained in 50 patients, because in the other patients it proved technically difficult to evaluate these variables.

Blood pressure, excessive blood volume, blood sampling and assay for MR-proADM
Blood pressure was measured with a mercury sphygmomanometer in the supine position after supine rest of 5 min or longer before blood sampling. Excessive blood volume before haemodialysis was defined as the fluid volume removal by ultrafiltration during haemodialysis (=delta body weight). Blood was withdrawn through the shunt before and after haemodialysis to measure MR-proADM, and was transferred into a chilled glass tube containing disodium EDTA and aprotinin. The blood was centrifuged immediately at 4°C, and plasma was frozen and stored at –80°C until assay. Plasma levels of MR-proADM were measured using a specific immunoassay system as previously reported [13]. The personnel responsible for measuring MR-proADM were blinded to the clinical and ultrasound status of the patients. Plasma C-reactive protein (CRP) levels were also measured, but only before haemodialysis by using the standardized methods in an autoanalyser.

Blood sampling and the echocardiographic studies were performed just before haemodialysis because of the need to evaluate the relationship between humoral factors and cardiac function in concurrence with excessive blood volume.

Statistical analysis
Data are expressed as means ± SD or using the median and interquartile range. Statistical comparisons were made with the Wilcoxon rank-tests or Mann–Whitney U-tests between two groups. Significant differences between more than two groups were evaluated by Kruskal–Wallis tests with subsequent Scheffe's multiple comparison tests. Because MR-proADM data were not normally distributed, log [MR-proADM] was used in the correlations and regression models. Univariate linear and multivariate stepwise regression analyses were used to detect factors related to two-dimensional, Doppler echocardiographic parameters, plasma CRP concentrations or removal fluid volume to log [MR-proADM]. Event-free curves were estimated by the Kaplan–Meier product-limited method and compared with the Mantel (log-rank) test. The prognostic value of MR-proADM was tested by Cox's proportional-hazards regression analysis. Differences were considered to be statistically significant when the P value was <0.05.



   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Study limitations
 References
 
Clinical characteristics of the study population and echocardiographic findings just before haemodialysis are listed in Tables 1 and 2, respectively. All patients had a normal cardiac sinus rhythm, but each had cardiovascular disease as shown in Table 1.


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  		Table 1. Clinical characteristics of the study population

 

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  		Table 2. Echocardiographic findings just before haemodialysis

 
The median values and interquartile ranges of MR-proADM before and after haemodialysis in patients with cardiovascular disease are shown in Figure 1. Haemodialysis significantly decreased plasma concentrations of MR-proADM.


Figure 1
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  		Fig. 1. Plasma midregional proadrenomedullin (MR-proADM) levels before and after haemodialysis (HD) in patients with cardiovascular disease.

 
In univariate linear regression analysis, log [MR-proADM] was significantly and negatively correlated with systolic blood pressure (SBP), DcT, S/D ratio and LVEF, and positively with LVESVI©, CRP and delta body weight (BW) (Table 3). Multivariate regression analysis revealed that S/D ratio, "diameter of inferior vena cava (IVC)" and CRP were independently related factors for MR-ProAM (Table 3). Log [MR-proADM] tended to be positively correlated with the E/A ratio and LVEDVI, but these did not reach statistical significance.


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  		Table 3. Univariate correlation between log (MR-proADM) and age, echocardiographic findings, C-reactive protein levels and delta body weight in haemodialysis patients

 
To evaluate the possible effects of LV diastolic dysfunction on plasma concentrations of MR-proADM, we compared levels among patients with E/A > 1 and E/A ≤ 1, patients with DcT < 180 ms and DcT ≥ 180 ms, and patients with S/D < 1, 1 ≤ S/D < 2 and S/D ≥ 2. In patients with DcT < 180 ms, plasma MR-proAM concentrations were significantly higher than those with DcT ≥ 180 ms. Furthermore, in patients with S/D < 1, plasma MR-proADM concentrations were significantly greater than in patients with S/D ≥ 2 (Figure 2).


Figure 2
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  		Fig. 2. Midregional proadrenomedullin (MR-proADM) levels in the DcT < 180 (N = 6) and DcT ≥ 180 groups (N = 44), in the E/A > 1 (N = 12) and E/A ≤ 1 groups (N = 38), and in the S/D < 1 (N = 7), 1 ≤ S/D < 2 (N = 35) and S/D ≥ 2 (N = 8) groups.

 
Nine patents died during the 14.7-month follow-up period. Event-free Kaplan–Meier curves comparing MR-proADM cut-off values are shown in Figure 3. We used the median value of MR-proADM (=1.93 nmol/l) as the cut-off in the present study. Seven of 34 patients with MR-proADM levels >1.93 nmol/l died and 2 of 36 with levels of 1.93 nmol/l or lower died during the follow-up period. Patients with greater MR-proADM levels had a greater death rate than those with lower MR-proADM levels (log-rank test, P = 0.0346).


Figure 3
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  		Fig. 3. Kaplan–Meier event-free curves in haemodialysis patients classified according to plasma midregional proadrenomedullin (MR-proADM) level [≤1.93 nmol/l (N = 36; mortality number: 2) or >1.93 nmol/l (N = 34; mortality number: 7)] (log-rank test, P = 0.0346).

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Study limitations
 References
 
In the present study, we showed that (i) the median concentration of MR-proADM was 1.93 nmol/l in a cohort of haemodialysis patients with cardiovascular disease; (ii) plasma MR-proADM concentrations were negatively correlated with blood pressure, DcT, S/D and LVEF, and positively correlated with LVESVI and IVC in these same patients, suggesting that plasma MR-proADM reflects LV diastolic and systolic dysfunction, which were defined as decreases in DcT, S/D and LVEF and increases in LVESVI; (iii) plasma MR-proADM increased in association with systemic inflammatory status and/or removal fluid volume during haemodialysis ultrafiltration; (iv) patients with high MR-proADM had a higher mortality rate than those with low MR-proADM during the 14.7-month follow-up period.

We recently reported a MR-proADM mean value of 0.33 nmol/l in healthy individuals [13]. This was subsequently confirmed in other cohorts of healthy individuals (N.G.M. unpublished data). We did not evaluate MR-proADM concentrations in healthy controls in the present study. Nevertheless, compared with these previous reports, the high median MR-proADM concentration of 1.93 nmol/l in our patients is more than 5-fold higher than in healthy subjects, suggesting that MR-proADM is clearly increased in patients with end-stage renal disease. Because the kidney is the most important clearance organ for circulating peptides such as BNP [15], the correlation coefficient between plasma BNP level and cardiac catheterization data was weakened, despite increased plasma BNP levels in patients with renal dysfunction compared to those with preserved renal function in the intensive care unit. Thus, renal failure resulting in a decrease in peptide clearance may be one possible reason for the increase in plasma MR-proADM concentrations in these patients. In addition, renal failure is well known to cause body fluid retention resulting in volume overload. Volume overload in turn increases shear stress in the arteries of the extremities [16]. Previous reports demonstrated that volume overload by itself increased cardiac biventricular adrenomedullin production [17], and that shear stress also increased adrenomedullin production in vascular endothelial cells [18]. We found a positive correlation between MR-proADM concentration and excessive blood volume in our patients, suggesting that the increased production of adrenomedullin in cardiac ventricles and the vascular endothelium resulted in increased plasma MR-proADM levels in patients with end-stage renal disease.

Plasma MR-proADM concentrations were negatively correlated with systemic blood pressure in our patients. In other studies with haemodialysis patients, plasma adrenomedullin levels have also been reported to be increased and negatively correlated with systemic blood pressure [7]. Given that adrenomedullin has a potent vasodilatory effect, the negative correlation between MR-proADM and systemic blood pressure in the present study suggests that adrenomedullin may be involved in lowering blood pressure in haemodialysis patients. Alternatively, the negative correlation between MR-proADM and systemic blood pressure may be secondary to reduced LV systolic function resulting in low blood pressure in association with an increase in plasma MR-proADM levels.

We previously reported that MR-proADM concentrations are increased in patients with cardiovascular disease [13]. However, there were no data to document the relationship between MR-proADM levels and cardiac function. Here, we report that plasma MR-proADM concentrations related to not only LV systolic dysfunction, which was defined as reduced LVEF, but also to diastolic dysfunction defined as reduced DcT, by the S/D ratio, and by an increased E/A ratio. This suggests that in the present study the plasma MR-proADM concentration may reflect reduced LV systolic and diastolic function. Numerous previous studies showed that plasma adrenomedullin levels were increased in LV failure [4], myocardial infarction [5] and peripheral arterial occlusive disease [6], and these levels increased according to disease severity. Thus, the concomitant cardiovascular disease in our haemodialysis patients may have led to cardiovascular dysfunction, resulting in increased cardiac adrenomedullin production and increased plasma MR-proADM level.

Increasing levels of CRP have been associated with increased risk of death in patients undergoing long-term haemodialysis [3]. In the present study, there was a positive correlation between plasma MR-proAM and plasma CRP concentrations. Previous reports demonstrated that tumour necrosis factor alpha, which is one of the most common inflammation-related cytokines, increased basal secretion of adrenomedullin in a cultured monocyte/macrophage cell line [19]. Furthermore, plasma levels of MR-proADM were markedly increased in patients with sepsis, and these increases may be helpful in individual risk assessment in septic patients [20], where MR-proADM showed an especially strong association with the APACHE II score. Thus, plasma MR-proADM concentrations may provide an indication of chronic inflammatory status in haemodialysis patients that is independent of other cardiac disease conditions.



   Study limitations
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
References
 
Although the results of our survival analysis were limited to a small sample pilot population, elevated plasma MR-proADM concentrations predicted a poorer prognosis in our patients. Since cardiovascular disease [1], excessive blood volume [2] and systemic inflammation [3] are the major causes of mortality in haemodialysis patients, our findings that plasma MR-proADM reflected LV systolic and diastolic dysfunction and excessive blood volume are in concordance with these observations. If these findings are confirmed in a much larger sample study, plasma MR-proADM concentrations in haemodialysis patients may provide a tool for physicians to evaluate the severity of LV dysfunction, excessive blood volume and systemic inflammatory condition, and to manage these problems in haemodialysis patients with cardiovascular diseases. We performed echocardiographical studies to non-invasively evaluate LV diastolic and systolic function and remodelling. This was done instead of left-sided and right-sided catheterizations, which are more precise methods for these evaluations. The echocardiographical studies were performed just before dialysis. Because predialysis volume overload may affect both echocardiographical parameters and plasma levels of MR-proADM, individual differences in delta body weight may have altered the relationship between these parameters and MR-proADM in our patients. Concomitant cardiovascular disease was disproportionately distributed in the present study in that coronary artery disease was more frequent than the other cardiovascular diseases. Furthermore, we did not evaluate possible changes in plasma MR-proADM levels before and after specific management of concomitant cardiovascular diseases or before or after reduction of excessive blood volume during the interval between haemodialysis therapies. Therefore, further investigations should be conducted that will examine these additional factors.

In conclusion, the present results suggest that plasma MR-proADM concentrations may increase in association with cardiac dysfunction, excessive blood volume and systemic inflammation. These levels may provide a possible index of these conditions in haemodialysis patients with concomitant cardiovascular disease. A large prospective population-based study will be necessary to confirm these preliminary observations.



   Acknowledgments
 
This study was supported by the Program for Promotion of Fundamental Studies in Health Sciences of the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 References
 

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  4. Nishikimi T, Saito Y, Kitamura K, et al. (1995) Increased plasma levels of adrenomedullin in patients with heart failure. J Am Coll Cardiol 26:1424–1431.[Abstract]
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  16. Lu X, Zhao JB, Wang GR, Gregersen H, Kassab GS. (2001) Remodeling of the zero-stress state of femoral arteries in response to flow overload. Am J Physiol Heart Circ Physiol 280:H1547–H1559.[Abstract/Free Full Text]
  17. Yoshihara F, Nishikimi T, Horio T, et al. (2000) Ventricular adrenomedullin concentration is a sensitive biochemical marker for volume and pressure overload in rats. Am J Physiol Heart Circ Physiol 278:H633–H642.[Abstract/Free Full Text]
  18. Chun TH, Itoh H, Ogawa Y, et al. (1997) Shear stress augments expression of C-type natriuretic peptide and adrenomedullin. Hypertension 29:1296–1302.[Abstract/Free Full Text]
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Received for publication: 20. 9.06
Accepted in revised form: 9. 1.07


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