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NDT Advance Access originally published online on February 17, 2006
Nephrology Dialysis Transplantation 2006 21(6):1633-1639; doi:10.1093/ndt/gfl037
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Dialysis and Transplantation

Relationship between serum albumin level before initiating haemodialysis and angiographic severity of coronary atherosclerosis in end-stage renal disease patients

Nobuhiko Joki1, Hiroki Hase1, Yuri Tanaka1, Yasunori Takahashi2, Tomokatsu Saijyo1, Hiroyaou Ishikawa1, Yoji Inishi1, Yoshihiko Imamura2, Hisao Hara1, Taro Tsunoda1 and Masato Nakamura1

1 Division of Cardiology and Nephrology, Toho University Ohashi Hospital, Tokyo and 2 Division of Dialysis Center, Nissan Tamagawa Hospital, Tokyo, Japan

Correspondence and offprint requests to: Nobuhiko Joki, MD, PhD, FJSIM, Division of Cardiology and Nephrology, Toho University Ohashi Medical Center, 2-17-6, Ohashi, Meguro-ku, Tokyo 153-8515, Japan. Email: joki{at}oha.toho-u.ac.jp



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. In patients with chronic kidney disease (CKD), although strong associations have been observed between malnutrition and atherosclerosis, the relationship between serum albumin concentration and angiographic changes of coronary artery disease (CAD) remains poorly explored. The goal of the present study was, in patients with CKD, to clarify the relationship between the angiographic severity of CAD and serum albumin concentration reflecting either inflammation or nutrition or both.

Methods. In this study, 100 end-stage renal disease (ESRD) patients were enrolled, who commenced long-term dialysis therapy at our hospital and underwent coronary angiography within 3 months of the first haemodialysis (HD) session. Mean age was 63±11 years, 20% of the subjects were female and 62% had diabetes. Severity of CAD was evaluated in terms of (i) number of vessels exhibiting CAD (≥75% stenosis) and (ii) Gensini score (GS). Clinical characteristics and laboratory findings were recorded at initiation of long-term HD therapy. We then evaluated a possible association with the presence and degree of CAD.

Results. Sixty-four patients exhibited signs of CAD. Forty-one among them (64%) had multivessel disease. On univariate logistic regression analysis, age, diabetes and hypoalbuminaemia were significantly associated with multivessel CAD. Univariate linear regression analysis demonstrated a positive correlation of age and diabetes with GS, and an inverse correlation of BMI and serum albumin level with GS. Stepwise regression analysis showed age and serum albumin level to be independently associated with multivessel CAD and GS. The ROC curves demonstrated best cut-off levels of age and albumin for predicting multivessel CAD to be 70 years and 3.15 g/dl, respectively.

Conclusion. Hypoalbuminaemia at the initiation of dialysis is an important predictor of advanced CAD, particularly in male and in diabetic patients. It may reflect mainly a state of inflammation. However, malnutrition as a confounding factor cannot be entirely excluded.

Keywords: albumin; BMI; coronary angiography; coronary atherosclerosis; Gensini score; haemodialysis initiation



   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Cardiovascular complications due to accelerated coronary atherosclerosis represent the main cause of morbidity and mortality in patients undergoing long-term haemodialysis (HD) treatment [1]. As accelerated coronary atherosclerosis is already observed prior to initiation of dialysis therapy [2,3], the K/DOQI guidelines recommend screening for coronary artery disease (CAD) at the initiation of chronic renal replacement therapy (RRT) [4].

Serum albumin concentration at the start of chronic dialysis therapy is a good predictor of prognosis [5]. Serum albumin is considered as a marker of nutritional status, and recent studies have demonstrated an association between hypoalbuminaemia, malnutrition, inflammation and atherosclerosis in patients with chronic renal failure, independent of dialysis therapy [6]. Moreover, in dialysis patients, the HEMO study demonstrated that serum albumin is closely associated with the prevalence of CAD, which was defined as the presence of angina, history of admission for ischaemic heart disease and ischaemic signs on electrocardiography [7]. However, little is known regarding the association of serum albumin with angiographic changes of coronary atherosclerosis in patients with chronic kidney disease (CKD).

The goal of the present study was to identify a possible relationship between angiographic severity of coronary atherosclerosis and serum albumin in patients with CKD. We had two objectives in planning this study. The first was to conduct investigations at the initiation of dialysis therapy according to the K/DOQI guidelines, which recommend screening for CAD at that point in time. The second was to evaluate the degree of CAD more precisely using coronary angiography. Our goal was to define the levels of hypoalbuminaemia that could be useful in predicting severe CAD, and hence future cardiac events.



   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Study design and patients
The present study was cross-sectional in design. Between August 1992 and December 2003, 266 consecutive patients with end-stage renal disease (ESRD) were admitted to Toho University Ohashi Hospital for initiation of chronic dialysis therapy. Of these 266 patients, 100 were enrolled in the study. Eligibility criteria were as follows: (i) ESRD resulting from CKD, regardless of primary disease, (ii) chronic dialysis therapy initiated at our hospital, (iii) coronary angiography performed within 3 months of the first HD session, (iv) clinical, biological and haematological data obtained immediately before the first HD session. Mean age was 63±11 years, 20% of patients were female and 62% had diabetes. Patient characteristics are shown in Table 1. The vascular access in 99% of the patients was a forearm AV fistula. An informed consent was obtained from all 100 patients prior to enrollment in the study. The Committee on Clinical Research of Toho University Ohashi Medical Center approved the study protocol.


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  		Table 1. Demographic, clinical and laboratory characteristics of 100 ESRD patients at the initiation of RRT

 
Data collection
We evaluated the possible associations between clinical characteristics and laboratory parameters at the initiation of chronic HD therapy and the degree of coronary atherosclerosis. In order to focus on the association between the uraemic states in the predialytic phase of CKD with the severity of coronary atherosclerosis, we recorded the clinical characteristics of all the patients immediately prior to initial HD. First, all patients were interviewed to obtain data on age, gender, smoking habits, type of primary renal disease, presence or absence of chest symptoms, previous hospitalizations for cardiac failure and/or ischaemic heart disease, and history of hypertension, atherosclerosis, cerebrovascular disease and peripheral artery disease. Blood pressure was also recorded in the supine position and blood samples were drawn immediately before the first HD session. Serum albumin concentration was analysed using antigen–antibody complex assay. The body mass index (BMI) at dry weight was calculated using the following formula: weight in kilograms divided by the square of the height in metres. As shown in Table 1, mean concentration of albumin was 3.2 g/dl and mean BMI was 21.6. Estimated glomerular filtration rate (GFR) was calculated by using the MDRD method [8].

Severity of coronary atherosclerosis
In line with K/DOQI guidelines [3], we assessed CAD routinely at the initiation of dialysis, regardless of symptoms [9,10]. Coronary angiography was performed within 3 months of starting HD. A written informed consent was obtained from all 100 study patients prior to performing coronary angiography for screening purposes. According to the results of coronary artery cine film, the severity of coronary atherosclerosis was evaluated (i) according to the number of diseased vessels and (ii) numerically using the Gensini score (GS) [11]. This evaluation was performed by three physicians who were unaware of study design and purpose. The number of diseased vessels was defined as the number of major coronary artery branches exhibiting CAD, and patients were accordingly divided into two groups, those with single-vessel disease and those with multivessel disease. CAD was defined clinically significant if angiographically determined narrowing exceeded 75% of the normal reference segment. As shown in Table 2, the mean GS was 31±35 (range 0–156). Normal coronary arteries (GS = 0) were found in 25 ESRD patients (25%). Forty-one percent of our patients had multivessel disease and 23% had single-vessel disease. The remaining 11% of the subjects had coronary atherosclerosis with <75% stenosis angiographically.


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  		Table 2. Angiographic coronary artery features in 100 ESRD patients at the initiation of dialysis therapy

 
Definitions
Chest symptoms
These included not only typical angina pectoris (precordial chest pain, discomfort and oppression precipitated by exertion or stress and relieved by rest or nitrates), but also atypical angina pectoris.

Myocardial infarction (MI)
Prior admission for myocardial infarction.

Coronary revascularization therapy (CRT)
Prior admission for coronary revascularization therapy.

Peripheral artery disease (PAD)
Presence of symptoms>Fontain grade III at the initiation of HD.

Cerebrovascular disease (CVD)
Prior admission for cerebral bleeding or cerebral infarction.

Statistical analysis
Data have been expressed as mean±SD. For the analysis of the association of factors with coronary atherosclerosis, Pearson's univariate regression analyses were performed between clinical factors and GS. Dummy variables were used for gender (0 for female, 1 for male), primary disease causing ESRD (0 for non-diabetic nephropathy, 1 for diabetic nephropathy) and smoking history (0 for negative, 1 for positive). We also performed univariate logistic regression analysis to determine which clinical factors associated with multivessel CAD had a strong influence on prognosis [12]. Subsequently, to determine the factors independently associated with GS and multivessel CAD, stepwise multivariate regression analysis was performed using factors that had significant association in the univariate analysis. Moreover, receiver operating characteristic (ROC) curves of age and serum albumin concentration, which were selected as independent factors from stepwise regression analyses, were drawn to determine the best cut-off for prediction of multivessel CAD. Finally, we evaluated the magnitude of risk for complicating multivessel CAD by comparing patient groups. Patients were divided into the following four groups on the basis of whether their age and serum albumin concentration was over or below the cut-off levels: group 1, albumin ≥3.2 g/dl and age <70 years; group 2, albumin ≥3.2 g/dl and ≥70 years; group 3, albumin ≤3.1 g/dl and age <70 years and group 4, albumin ≤3.1 g/dl and age ≥70 years. P-values of <0.05 were considered statistically significant. All statistical analyses were performed using StatView for Windows version 5.0 (SAS Institute, Cary, NC), and ROC curves were analysed using SPSS II for Windows version 11.0 (SPSS Japan Inc., Tokyo).



   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Patient characteristics (Table 1)
Mean age was similar to that previously reported at the initiation of dialysis in the entire Japanese dialysis patients population [13]. However, our study population of 100 patients was composed of a higher percentage of men and patients with diabetic nephropathy [13]. Approximately, one third of the patients had a history of MI, and one fourth had received CRT. Clinical characteristics are shown in Table 1. Table 2 summarizes coronary artery angiographic findings. Figure 1 shows GS in histogram form.


Figure 1
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  		Fig. 1. Distribution of the Gensini score in 100 ESRD patients at the initiation of dialysis therapy.

 
Univariate analysis of factors associated with GS and multivessel CAD
As shown in Table 3, GS, reflecting severity of coronary atherosclerosis, was well correlated with age and diabetic nephropathy. It was inversely associated with nutritional status, based on BMI and serum albumin. In logistic regression analysis, age, diabetic nephropathy and serum albumin were also powerful predictors of multivessel CAD (Table 3). Other traditional risk factors such as smoking habits, blood pressure and lipid parameters showed no correlation with GS and multivessel CAD. Figure 2 shows the three associations which were significant.


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  		Table 3. Univariate analysis of factors potentially associated with coronary artery disease atherosclerosis

 

Figure 2
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  		Fig. 2. Relationship between Gensini score (GS) and age (A), serum albumin (B) and BMI (C). GS was well correlated with age (r = 0.231, P = 0.021) and was inversely associated with albumin (r = –0.281, P = 0.005) and BMI (r = –0.224, P = 0.025).

 
Stepwise multiple regression analysis for factors independently associated with coronary atherosclerosis
Table 4 summarizes the results of stepwise regression analysis between GS and four factors selected from univariate analysis. Age and albumin were identified as independent factors associated with severity of coronary atherosclerosis. Table 5 shows an association between multivessel CAD and age, albumin and diabetic nephropathy.


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  		Table 4. Stepwise regression analysis of independent factors associated with GS (r2 = 0.12)

 

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  		Table 5. Stepwise regression analysis of independent factors associated with multivessel CAD (r2 = 0.26)

 
Cut-off level for detecting multivessel CAD
The ROC curves were drawn to determine the cut-off levels of age and albumin for detecting multivariate coronary atherosclerosis. ROC curves for age and albumin as predictors of multivessel CAD are shown in Figure 3. The area under the ROC curve was 0.651 (standard error 0.058, 95% CI 0.538–0.764) for age, and 0.715 (standard error 0.054, 95% CI 0.610–0.821) for albumin. The optimum cut-off points for age and albumin were determined to be 70 years (sensitivity 49%, specificity 83%) and 3.15 g/dl (sensitivity 68%, specificity 73%), respectively.


Figure 3
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  		Fig. 3. The ROC curves were drawn to determine the cut-off levels of age (A) and albumin (B) for detecting multivariate coronary atherosclerosis. The area under the ROC curve was 0.651 (SE 0.058, 95% CI 0.538–0.764) for age, and 0.715 (SE 0.054, 95% CI 0.610–0.821) for albumin.

 
Risk of complicating multivessel CAD in four groups stratified by age and serum albumin
Finally, we performed logistic regression analysis to compare the odds of complicating multivessel CAD between four patient groups stratified by levels of age and albumin. As summarized in Table 6, in diabetic patients, the risk of complicated multivessel CAD was 33 times higher in group 4 than in group 1. Groups 2 and 3 also had a significantly higher risk compared with group 1. In non-diabetic patients, the risk of complicated multivessel CAD was 108 times higher in group 4 than in group 1 (P = 0.002). Groups 2 and 3 had a 3 times and 4.5 times higher risk, respectively; however, this increase was not statistically significant.


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  		Table 6. Prevalence of complicated multivessel CAD in four patient groups by age and albumin

 


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
The current study provides evidence that reduced serum albumin concentration is closely and independently associated with GS, which is a quantitative expression of the angiographic severity of coronary atherosclerosis. Moreover, an increase of 1 g/dl in albumin level was associated with a significant reduction (odds ratio, 0.24 per 1 g/dl increase) in the risk of multivessel CAD. These relationships were independent of traditional risk factors such as age and diabetes. We sought a cut-off point of serum albumin concentration that would predict multivessel CAD, a complication that has a strong impact on cardiac mortality in the clinical setting even after successful coronary revascularization therapy [12]. A serum albumin concentration of 3.15 g/dl was the best cut-off point for predicting multivessel CAD. By combining age with albumin level at the initiation of HD, it was possible to precisely predict the presence of multivessel CAD in diabetic and non-diabetic ESRD patients. On the basis of these results, serum albumin concentration at initiation of dialysis therapy appears to be a new marker for predicting CAD. More severe coronary atherosclerosis might explain the observed increase in cardiovascular mortality in patients with hypoalbuminaemia.

Our results are consistent with those of many previous reports. An inverse relationship between serum albumin level and cardiovascular mortality has been reported in the general population and in patients with diabetes. The National Health and Nutrition Examination Survey reported that serum albumin level less than 4.2 g/dl was associated with greater risk of stroke and death in the US general population [14]. Moreover, in diabetic patients with coronary heart disease, which was defined as definite, probable or silent myocardial infarction or definite coronary heart disease, death was significantly associated with lower levels of serum albumin independent of traditional risk factors [15]. In dialysis patients, Foley et al. [16] demonstrated that a 1 g/dl decrease in mean serum albumin level was independently associated with a relative risk increase of 5.29 for de novo ischaemic heart disease, and of 4.24 for recurrent ischaemic heart disease. This observation suggests that low serum albumin level has a strong relation with atherosclerotic disease and clinical events. A close association of serum albumin with morphological atherosclerotic changes has also recently been shown in dialysis patients. Carotid intima-media thickness, a marker for subclinical atherosclerosis, has been demonstrated to be inversely related to serum albumin concentration in HD [17] and peritoneal dialysis [18] patients. Moreover, carotid plaques are often found in malnourished patients with chronic renal failure (CRF). Stenvinkel et al. [6] were the first to demonstrate that patients in predialysis chronic renal failure with carotid plaques had lower serum albumin concentrations. Considering several reports of a synchronous development of carotid and coronary atherosclerosis in dialysis patients [19,20], it is beyond doubt that hypoalbuminaemia is adversely associated with severity of radiological coronary atherosclerosis in patients with CKD.

The current study indicated that an albumin concentration of 3.15 g/dl was the best cut-off level for predicting the presence of multivessel CAD. Beddhu et al. [7] recently demonstrated an association of various serum albumin levels with the presence of CAD diagnosed on the basis of symptoms, past history and non-invasive examinations. Interestingly, in that study, a serum albumin level of 3.1–3.6 g/dl conferred a significantly greater risk for CAD compared with the reference level of ≥4.0 g/dl; this finding is in accordance with our own results. An association between serum albumin and cardiovascular mortality has also been reported by several studies. Owen et al. [5] demonstrated that hypoalbuminaemia was a strong predictor of subsequent death in dialysis patients; a serum albumin level of 3.0–3.4 g/dl was associated with significantly greater risk of death compared with the reference level (4.0–4.4 g/dl). Kalantar-Zadeh et al. [21] also clearly showed that the risk of cardiovascular mortality was approximately two times higher in dialysis patients with a serum albumin of 3.0–3.19 g/dl compared with those with levels of 3.8 g/dl and higher. These observations indicate that a serum albumin of 3.15 g/dl as used in our study is a reasonable cut-off level. Not surprisingly, further decreases in albumin concentrations are associated with more advanced coronary atherosclerosis and cardiovascular mortality.

Notably, Kaysen et al. [22] and another group [23,24] recently demonstrated that sequential measurements of serum albumin were able to predict more precisely the chronic inflammation and clinical events than single measurements. Thus, a decrease in serum albumin of >0.3 g/dl that persists for 6 weeks is associated with the presence of chronic inflammation which suppresses the albumin synthesis [22]. We believe that the complex syndrome of malnutrition, inflammation and atherosclerosis is at the basis of the observation of a close association between hypoalbuminaemia and severe coronary atherosclerosis in the ESRD patients of the present study. It appears reasonable to assume that sequential measurements of serum albumin might lead to an even more reliable prediction of coronary atherosclerosis. Unfortunately, in our study population no repeat measurements were available to confirm this hypothesis.

An important limitation of the present study was that inflammation markers such as C-reactive protein (CRP), whose importance as a predictor of cardiovascular outcome has been shown by others [25], were not measured. We did not include this marker as a possible contributor to atherosclerosis because, we could not obtain complete CRP data for all patients. In addition, CRP was not evaluated in all the cases by a highly-sensitive assay, which is the gold standard for evaluating the atherogenetic process, because the time span of this study was nearly 10 years. Another limitation of our study was a patient selection bias since the percentage of men (80%) and patients with diabetic nephropathy (62%) was higher than that for the entire Japanese dialysis patient population. Despite these limitations, we believe that our main finding, namely an inverse relationship between serum albumin concentration and degree of coronary atherosclerosis, is a new and informative observation. Concerning possible mechanisms, recent data have demonstrated an association between hypoalbuminaemia, malnutrition, inflammation and atherosclerosis in CRF patients independent of dialysis therapy [6]. Another hypothesis implies serum albumin as a potential scavenger of radical oxygen species. Hypoalbuminaemia would decrease serum antioxidant capacity and thereby, favour the noxious effects of oxidative stress on various tissues, including the arterial vessel wall [26]. These data suggest that hypoalbuminaemia is more appropriately viewed as a composite parameter reflecting both malnutrition and increased acute-phase inflammation, given that albumin also is a negative acute-phase reactant [6,27–30].

In conclusion, our study demonstrates that the serum albumin concentration at the initiation of dialysis was closely associated not only with the presence of clinical signs of atherosclerotic disease or events, but also with angiographic evidence of coronary atherosclerosis, particularly in male and in diabetic patients. Hence, even in the predialytic phase of chronic renal failure, hypoalbuminaemia is an excellent reflection of CAD, and even may have a role in accelerating coronary atherosclerosis, probably in the context of the complex syndrome of malnutrition, inflammation and oxidative stress. In order to reduce the cardiovascular mortality rate in CKD patients, nephrologists should attempt to reduce the complex abnormalities associated with malnutrition, inflammation and oxidative stress.



   Acknowledgments
 
Portions of this manuscript were published in abstract form (Nephrology Dialysis Transplantation). The authors gratefully acknowledge the staff of the Cardiovascular Division of Toho University Ohashi Hospital for their helpful suggestions and for collecting the clinical data.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Received for publication: 4.11.05
Accepted in revised form: 23. 1.06


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