Elevated serum levels of soluble adhesion molecules predict death in pre-dialysis patients: association with malnutrition, inflammation, and cardiovascular disease

Peter Stenvinkel1,, Bengt Lindholm1,2, Mikael Heimbürger3 and Olof Heimbürger1

1 Divisions of Renal Medicine, and 2 Baxter Novum, Department of Clinical Science, and 3 Department of Rheumatology Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden



   Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Atherosclerotic cardiovascular disease, malnutrition, and increased levels of pro-inflammatory cytokines are common features in patients with chronic renal failure, and contribute to the high mortality rate observed in these patients. A diverse group of soluble cellular adhesion molecules (CAM) (sVCAM-1, sICAM-1 and sE-selectin) are expressed on the surface of vascular endothelial cells in response to pro-inflammatory cytokines and may play an important role in the atherogenic process.

Methods. Serum levels of sVCAM-1, sICAM-1 (n=87) and sE-selectin (n=71) were analysed in a cohort of 88 patients (50±1 years) with chronic renal failure. The presence of malnutrition (subjective global assessment (SGA) and serum albumin), inflammation (C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-{alpha}), and serum hyaluronan), and cardiovascular disease (CVD) were assessed at a time-point close to the start of dialysis treatment (GFR 7±1 ml/min). Blood lipid parameters were also assessed.

Results. Significant correlations were observed between Log high-sensitivity CRP (hsCRP) and sVCAM-1 (R=0.39; P<0.01) and sICAM-1 (R=0.47; P<0.001) levels but not between Log hsCRP and sE-selectin levels in 60 patients examined with a hsCRP assay. Also serum concentrations of Log hyaluronan correlated significantly to sVCAM-1 (R=0.34; P<0.01) and sICAM-1 (R=0.29; P<0.05) levels. Malnourished patients (SGA>1) had elevated serum concentrations of sVCAM-1 (1436±94 vs 1105± 53 ng/ml; P<0.01) compared to well-nourished patients (SGA 1). Patients with clinical signs of CVD (n=26) had elevated serum levels of sICAM-1 (282±18 vs 242±9 ng/ml; P<0.05) compared to 61 patients without signs of CVD. Plasma Log lipoprotein (a) (Lp(a)) levels correlated significantly with sVCAM-1 (R=0.30; P<0.01). Survival analysis by the Cox regression model showed that elevated sICAM-1 was, independent of age, SGA, CVD, and Log CRP, significantly related to an increased mortality rate.

Conclusions. Elevated serum concentrations of soluble adhesion molecules are found in pre-dialysis patients who are malnourished, inflamed, and have signs of cardiovascular disease. These data also suggest that sICAM-1 is an independent predictor of mortality in pre-dialysis patients. Further studies are needed to determine if inflammation causes accelerated atherogenesis via effects on soluble adhesion molecules or if elevated serum levels of soluble adhesion molecules are merely markers of endothelial activation in patients with chronic renal failure.

Keywords: cardiovascular disease; inflammation; Lp(a); malnutrition; mortality; soluble adhesion molecules



   Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with chronic renal failure (CRF) undergoing renal replacement therapy [1]. Protein–energy malnutrition with muscle wasting has been shown to be associated with increased cardiovascular mortality in haemodialysis (HD) patients [2] and low serum albumin concentrations are associated with increased mortality risk in patients on renal replacement therapy [3]. However, serum albumin is to a large extent influenced by factors other than malnutrition, and high concentrations of acute-phase proteins such as C-reactive protein (CRP) are correlated with low serum albumin levels in malnourished patients [4,5].

Several groups have recently reported that increased CRP is a strong risk factor for death [68], cardiovascular mortality [7], and hospitalization [9] in HD patients. Furthermore, we have recently reported on a strong association between malnutrition, inflammation, and atherosclerosis in pre-dialysis patients [10]. Plasma levels of pro-inflammatory cytokines (interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-{alpha})) have been reported to be elevated in CRF [11,12] and has been shown to be associated with both increased mortality [12,13] and malnutrition [14,15]. Based on these findings it could be speculated that pro-inflammatory cytokines, generated in response to cardiac failure, infections, and other inflammatory stimuli, cause muscle wasting, accelerated atherosclerosis, and an increased cardiovascular mortality in CRF patients [16,17].

The mechanism(s) by which elevated levels of pro-inflammatory cytokines may cause accelerated atherosclerosis are not well understood. However, one key event in the development of atherosclerosis is the adhesion of leukocytes to the vascular endothelium [18,19]. In large part, these processes are mediated by a diverse group of cellular adhesion molecules (CAM) (ICAM-1, VCAM-1 and E-selectin) which are expressed on the surface of vascular endothelial cells in response to pro-inflammatory cytokines. Raised concentrations of circulating adhesion molecules are found in a variety of disorders [20] and may indicate endothelial activation and increased interaction with leukocytes. It is of interest that recent prospective data from non-renal patient populations strongly suggest that endothelial activation and inflammation occurs early in the atherosclerotic process and that high serum levels of adhesion molecules may predict future cardiovascular events [21,22]. Serum levels of adhesion molecules have previously been reported to be elevated in patients with CRF [23,24]. However, it is not known whether or not CRF patients with signs of malnutrition, inflammation or CVD have elevated serum levels of soluble adhesion molecules. The aim of the present study was therefore to examine serum levels of soluble adhesion molecules in a cohort of pre-dialysis patients that previously had been characterized with respect to the presence of inflammation, malnutrition, and CVD.



   Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Eighty-eight patients enrolled in a prospective study were studied. Part of this patient material has previously been described [10,25,26]. Their mean patient age (SEM) was 50±1 years (range 23–70 years). The cause of CRF was diabetic nephropathy in 26 patients, chronic glomerulonephritis in 33, polycystic kidney disease in 14, nephrosclerosis in three, and other or unknown aetiologies in 12 patients. Twenty-six of the patients (30%) had clinical signs, or a previous history, of cerebrovascular, cardiovascular and/or peripheral vascular disease (CVD). Of the 26 patients, 10 had suffered from cerebrovascular disease (stroke); 10 had had one or more myocardial infarctions; 10 had clinical signs of ischaemic heart disease (angina pectoris); six had peripheral ischaemic atherosclerotic vascular disease, and two patients had a history of an aortic aneurysm. The level of residual renal function, estimated by the mean of creatinine and urea clearance, was 7±1 ml/min (range 2–15 ml/min). Most patients were on antihypertensives (beta blockers, calcium-channel blockers, frusemide, and angiotensin-converting enzyme (ACE inhibitors) as well as other commonly used drugs in terminal CRF such as phosphate and potassium binders as well as vitamin B, C and D supplementation.

Patients were interviewed and examined close to the start of dialysis treatment. After an overnight fast, venous blood samples were drawn for analysis of serum albumin, CRP, creatinine, urea, cholesterol, triglycerides, lipoprotein(a) (Lp(a)), high-sensitivity CRP (hsCRP) (n=60), serum hyaluronan (n=72), TNF-{alpha} (n=55), sICAM-1, sVCAM-1 (n=87) and sE-selectin (n=71). Blood samples for analysis of hsCRP, hyaluronan, TNF-{alpha}, and soluble adhesion molecules were stored at -70° before analysis. Nutritional status was recorded on the same occasion using subjective global assessment (SGA). Nutritional assessment with SGA was not performed in five of the patients.

Forty-six of the patients (52%) started peritoneal dialysis (PD), 40 patients (45%) started HD and two patients (3%) received a renal transplant before dialysis treatment was initiated. Survival was determined after a median follow-up period of 22 months (range 1–46 months) and the effects of sICAM-1, age, CVD, SGA, and Log CRP were determined by the Cox regression method, and the relative risk of death was calculated. Survival was measured from the day of examination until death or censoring, which was made at the end of the follow-up (28 March 2000). Thirty-seven patients received a kidney transplant subsequent to entering the study and were censored at the time-point of transplantation. The Ethics Committee of Karolinska Institutet at Huddinge University Hospital approved the study. All patients gave informed consent to participate in the study.

Analyses
After thawing, the levels of sICAM-1, sVCAM-1, and sE-selectin were determined by commercially available ELISA kits and standards (R&D Systems Europe Ltd, Abingdon, UK). Duplicate analyses were performed and the average value was used for data analysis. The correlations (R value) between the two analyses were 0.982 (sVCAM-1), 0.923 (sICAM-1), and 0.964 (sE-selectin) respectively. Determinations of albumin (bromcresol purple), CRP (turbidometry), cholesterol, triglycerides, urea, and creatinine were performed by routine procedures in the Department of Clinical Chemistry, Huddinge Hospital. The detection limit of CRP was 10 mg/l and all values <10 mg/l were, in the statistical evaluation, treated as 9 mg/l. However, in 60 of the patients CRP was also evaluated by hsCRP (nephelometry) and exact values of CRP were obtained. Plasma Lp(a) levels were analysed using a two-site immunoradiometric assay (Pharmacia, Uppsala, Sweden). TNF-{alpha} was measured by photometric enzyme-linked immunosorbent assay (ELISA) obtained from Boerhinger Mannheim (Mannheim, Germany). The limit of detection in serum was 5 pg/ml. Serum hyaluronan was measured by radioimmunoassay (RIA) (Pharmacia Diagnostics AB, Uppsala, Sweden). SGA was used to evaluate the overall protein–energy nutritional status as previously described [27,28]. SGA includes six subjective assessments, three based on the patient's history of weight loss, incidence of anorexia, and incidence of vomiting, and three based on the subjective grading of muscle wasting, presence of oedema, and loss of subcutaneous fat. From these assessments each patient was given a score that reflected the nutritional status as follows: 1, normal nutritional status (n=53); 2, mild malnutrition (n=24); 3, moderate malnutrition (n=6); and 4, severe malnutrition (n=0).

Statistical methods
All results are given as mean±SEM. The non-parametric Mann–Whitney U-test or Student's unpaired t test was used to test differences between patients. Correlations were tested by regression analysis. Not-normally distributed variables were log-transformed before entering regression analysis. Survival analysis was made by the Kaplan–Meier and Cox regression analyses. A two-tailed P value <0.05 was considered to be statistically significant.



   Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
All basal clinical and biochemical data of the 88 pre-dialysis patients are given in Table 1Go. Mean serum concentrations of sICAM-1, sVCAM-1, and sE-selectin are also summarized in Table 1Go. No differences in sVCAM-1 (1236±63 vs 1247±92 ng/ml), sICAM-1 (250±11 vs 262±13 ng/ml), or sE-selectin (58±4 vs 54±5 ng/ml) levels were observed between males and females respectively. Moreover, no significant differences in sVCAM-1 (1394±129 vs 1182±51 ng/ml) or sICAM-1 (262±17 vs 251±10 ng/ml) concentrations were observed between diabetic and non-diabetic patients, whereas significantly elevated levels of sE-selectin (68±7 vs 52±3 ng/ml; P<0.05) were found in the diabetic patient group. GFR (as estimated by the mean of creatinine and urea clearance) did not differ significantly between well-nourished and malnourished patients (8±1 vs 6±1 ml/min). Furthermore, no difference in estimated GFR was observed between patients with and those without signs of CVD (7±1 vs 7±1 ml/min) or with normal or elevated CRP concentrations (7±1 vs 6±1 ml/min) respectively. Estimated GFR did not correlate significantly with either sVCAM-1 (R=-0.23; P=0.07), sICAM-1 (R=-0.11; NS), or sE-selectin (R=-0.05; NS) levels. No correlations were found between age and sVCAM-1 (R=0.04; NS), sICAM-1 (R=0.11; NS) and sE-selectin (R=0.05; NS) levels, respectively.


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Table 1. Clinical and biochemical characteristics of the 88 pre-dialysis patients

 
Adhesion molecules and inflammation
Significantly elevated sVCAM-1 (1458±119 vs 1148±50 ng/ml; P<0.01) concentrations were found in 26 patients with elevated CRP (>=10 mg/l), whereas no significant difference in sICAM-1 or sE-selectin levels were observed between patients with elevated or normal CRP concentrations. Log-transformed CRP correlated with sVCAM-1 (R=0.28; P<0.01), sICAM-1 (R=0.21; P=0.05), and sE-selectin (R=0.24; P<0.05) levels respectively. However, in 60 patients, in which an exact CRP value was available, Log hsCRP correlated significantly with sVCAM-1 (R=0.39; P<0.01) and sICAM-1 (R=0.47; P<0.001) levels but not to sE-selectin (R=0.19, NS) concentrations. In 55 patients the pro-inflammatory cytokine TNF-{alpha} correlated significantly with sVCAM-1 (R=0.36; P<0.01), sICAM-1 (R=0.29; P<0.05), and sE-selectin (R=0.39; P<0.01) levels. Likewise, Log hyaluronan (n=72) correlated with sVCAM-1 (R=0.34; P<0.01) and sICAM-1 (R=0.29; P<0.05) concentrations, but not with sE-selectin levels.

Adhesion molecules and nutritional status
Significantly elevated serum concentrations of sVCAM-1 (1436±94 vs 1105±53 ng/ml; P<0.01) were observed in 30 malnourished patients (SGA 2–3) compared to 53 well-nourished patients (SGA 1). On the other hand, no significant differences were observed in sICAM-1 and sE-selectin levels when comparing malnourished and well-nourished patients. Weak, but significant, negative correlations were observed between serum albumin and sVCAM-1 (R=-0.26; P<0.05) and sICAM-1 (R=-0.27; P<0.05) concentrations respectively, whereas no significant correlation was observed between serum albumin and sE-selectin levels.

Adhesion molecules and blood lipid variables
No significant relations were observed between serum cholesterol and triglyceride levels and any adhesion molecule. However, as shown in Figure 1Go, a significant positive relationship was observed between Log plasma Lp(a) and sVCAM-1 (R=0.30; P<0.01) concentrations, whereas no significant relationships were observed between Log plasma Lp(a) vs sICAM-1 and sE-selectin levels respectively.



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Fig. 1. Correlation between plasma Lp(a) and sVCAM-1 (R=0.30; P<0.01) in 88 pre-dialysis patients. Note that plasma Lp(a) was log-transformed before entering the regression analysis.

 

Adhesion molecules, cardiovascular disease and outcome
Twenty-six patients with clinical signs of CVD had significantly elevated concentrations of sICAM-1 (282±18 vs 242±9 ng/ml; P<0.05) compared to 61 patients without signs of CVD, whereas the serum levels of sVCAM-1 and sE-selectin did not differ significantly between the two groups. Following a median follow-up period of 22 months (range 1–46 months) 16 of the 88 patients had died. Non-survivors had significantly elevated sVCAM-1 (1459±86 vs 1191±59 ng/ml; P<0.01) and sICAM-1 (316±21 vs 240±9 ng/ml; P<0.001) concentrations compared with survivors. On the other hand, sE-selectin levels did not differ (65±8 vs 55±3 ng/ml) significantly between the two groups. Survival by Kaplan–Meier plot, dividing patients into quartiles, showed a significantly (Chi-square 12.3; P<0.01) better survival rate in patients with the lowest sICAM-1 concentrations (Figure 2Go). On the other hand, sVCAM-1 levels were not significantly (Chi-square 7.1; P=0.12) associated with the mortality rate. In a Cox regression model, including five independent variables (age, CVD, SGA, Log CRP, and sICAM-1), only SGA (P<0.01) and sICAM-1 (P<0.01) were independent predictors of mortality (Table 2Go).



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Fig. 2. Survival by Kaplan–Meier plot of 87 pre-dialysis patients divided into quartiles. Twenty-one patients in quartile 4 (sICAM-1>284 ng/ml) had significantly (Log rank test P<0.01) higher mortality rate than 22 patients in quartile 1 (sICAM-1 <197 ng/ml). The mortality rate in 44 patients in quartiles 2 and 3 (sICAM-1 197–284 ng/ml) did not differ significantly from the rate in patients in quartile 1, whereas a significant (Log rank test P<0.05) lower mortality rate was observed in this group of patients when compared to patients in quartile 4.

 

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Table 2. Effect of age, CVD, SGA, Log CRP, and sICAM-1 on the survival in pre-dialysis patients

 



   Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Elevated serum concentrations of soluble adhesion molecules have previously been documented in undialysed patients with CRF as well as in patients treated by peritoneal dialysis or HD [23,24,29]. However, to the best of our knowledge, this is the first study that have demonstrated that CRF patients with signs of malnutrition, inflammation, and CVD have elevated serum levels of adhesion molecules compared with a group of CRF patients without these complications, but with a similar renal function. The cause(s) of elevated serum levels of soluble adhesion molecules in CRF patients are probably multifactorial, involving both inadequate clearance and enhanced synthesis/release. Results presented by Bonomini et al. [24] have demonstrated that serum concentrations of adhesion molecules increase with the progressive decline in renal function, suggesting that inadequate clearance might be an important contributor to elevated serum levels of adhesion molecules in CRF. However, in the present study no significant relationships were observed between residual renal function and serum levels of adhesion molecules, which might be explained by the fact that only patients with advanced CRF were evaluated.

The present data clearly suggest that, in addition to inadequate clearance, also enhanced synthesis/release might contribute to elevated serum concentrations of adhesion molecules in CRF. Indeed, it has repeatedly been demonstrated that pro-inflammatory cytokines, which are a common phenomenon in CRF patients [11,12], can up-regulate the expression of adhesion molecules from endothelial cells [30,31]. The prevalence of elevated CRP levels were increased among our patients, which confirms the findings of previous studies [4,79]. In the present study we found significant correlations between CRP and adhesion molecules, which suggests that inflammation may be a major cause of elevated serum levels of these proteins in CRF patients. Our results confirm those obtained in the Physicians Health Study, in which the strongest correlate of sICAM-1 levels was CRP [21]. In addition, we found significant correlations between two other inflammatory markers, TNF-{alpha} and serum hyaluronan, and soluble adhesion molecules, suggesting that the circulating levels of these molecules may be regarded as markers for the extent of an inflammatory process. However, it should be emphasized that some proportion of soluble adhesion molecules may also arise from non-endothelial cells such as fibroblasts, lymphocytes, hepatocytes, and smooth-muscle cells. Further studies are therefore needed to investigate if these cells also may contribute to elevated serum levels of adhesion molecules in CRF.

We have recently demonstrated serum hyaluronan to be associated with the presence of inflammation, malnutrition, and CVD and also to be a predictor of mortality in CRF [26]. Elevated serum concentrations of hyaluronan has repeatedly been reported in a variety of inflammatory conditions [32,33] and pro-inflammatory cytokines [32,34,35] and bacterial lipopolysaccharides [35] have been shown to stimulate hyaluronan production. In the present study we found significant relationships between serum hyaluronan and sVCAM-1 and sICAM-1 levels respectively. Similarly, in a recent report it was demonstrated that high serum hyaluronan concentrations were associated with increased levels of sICAM-1 in patients with alcoholic hepatitis [36]. In this respect, it is of interest that Oertli et al. [37] have shown that hyaluronan displays pro-inflammatory effects by directly stimulating the expression of VCAM-1 and ICAM-1 in mouse epithelial cells, suggesting that hylauronan plays an important role in leukocyte adhesion. Moreover, Mohamadzadeh et al. [35] have recently demonstrated that elevated hyaluronan levels result in increased CD44-dependent adhesive interaction, which could suggest that elevated concentrations of hyaluronan per se may accelerate atherogenesis and increase the risk of CVD. It has recently been demonstrated that acute-phase responses are closely related to atherogenic cardiovascular risk factors [7,10], hospitalization [9] and cardiovascular death [7] in CRF patients. It is therefore reasonable to speculate that one mechanism by which inflammation may cause accelerated atherogenesis in CRF patients is by a stimulatory effect on soluble adhesion molecules.

In the present patient material we found significantly elevated levels of sICAM-1 in CRF patients with CVD. Indeed, there is an increasing body of evidence that has documented that soluble adhesion molecules may play an important role in the genesis of CVD by affecting thrombosis, leukocyte infiltration, smooth-muscle proliferation, and cell migration [3840]. Moreover, a cross-sectional study has also demonstrated that adhesion molecules are elevated among patients with atherosclerosis [41]. Finally, elevated levels of adhesion molecules have been demonstrated in patients with coronary heart disease [42], and high levels of sICAM-1 have recently been shown to be a prognostic risk factor for future cardiovascular events in both men [21,22] and women [43]. The results of the present study accord with these findings and demonstrate that an elevated serum concentration of sICAM-1 is an independent predictor of mortality in CRF patients (Table 2Go). However, as the present patient numbers were small, this association should be interpreted with caution and further prospective studies, in larger patient numbers, are needed to confirm this finding.

Lp(a), a known risk factor of premature atherosclerosis [44], has consistently been shown to be elevated in pre-dialysis and dialysis patients [25,45,46]. Cressman et al. [46] have shown that Lp(a) may be an independent risk factor for CVD in HD patients, whereas others [10,47] have found that the apolipoprotein(a) isoform size may be more predictive for cardiovascular complications than Lp(a) levels per se. The mechanism(s) underlying the atherogenicity of Lp(a) have not yet been fully elucidated. In the present study we found a significant correlation between plasma Lp(a) levels and sVCAM-1. Thus it could be speculated that one mechanism by which Lp(a) may cause atherogenesis in CRF is by a stimulatory effect on soluble adhesion molecules. In this respect it is of interest that Allen et al. [48] have demonstrated that Lp(a) stimulates the production of VCAM-1 in cultured human coronary artery endothelium. As leukocyte recruitment to the vessel is an important early event in atherogenesis it could thus be speculated that this endothelial cell-activating effect of Lp(a) may play an important role in the initiation of atherogenic disease. Further studies are needed to investigate whether this intriguing mechanism for accelerated atherogenesis in renal disease is valid or not.

In summary, the present cross-sectional results have demonstrated that inflammation, malnutrition, and cardiovascular disease are related to elevated serum levels of soluble adhesion molecules in predialysis patients and that elevated sICAM-1 levels predict mortality. As inflammation and malnutrition are common features observed in dialysis patients with atherosclerotic cardiovascular disease, further research is needed to investigate if a chronic inflammatory response may cause accelerated atherosclerosis via a stimulatory effect on soluble adhesion molecules.



   Acknowledgments
 
We acknowledge the skilled technical assistance of Ms Inger Sjödin, Ms Anne-Sofie Jonsson and Ms Ann Lif. This study was supported by Trone-Holsts Foundation, funds from Karolinska Institutet, a grant from Hospal, and the Baxter Extramural Grant Program.



   Notes
 
Correspondence and offprint requests to: Peter Stenvinkel MD, Department of Renal Medicine K56, Huddinge University Hospital, S-141 86 Huddinge, Sweden. Back



   References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
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Received for publication: 2.11.99
Revision received 9. 6.00.