Association of malnutrition-inflammation score, dialysis-malnutrition score and serum albumin with novel risk factors for cardiovascular diseases in hemodialysis patients

Abstract

Background: This study was designed to investigate the associations between malnutrition-inflammation score (MIS), dialysis-malnutrition score (DMS) and serum albumin with novel risk factors for cardiovascular diseases (CVD) in hemodialysis (HD) patients. Methods: In this cross-sectional study, 291 HD patients were randomly selected from among 2302 adult HD patients in Tehran HD centers. The MIS and DMS were determined during one of the dialysis sessions in these patients. In addition, 4 mL blood was obtained before dialysis and analyzed for serum albumin and novel risk factors for CVD, including C-reactive protein (CRP), soluble intercellular adhesion molecule type 1 (sICAM-1), soluble vascular cell adhesion molecule type 1 (sVCAM-1), sE-selectin, malondialdehyde (MDA), nitric oxide (NO), endothelin-1 and lipoprotein (a) [Lp (a)]. Results: MIS and DMS were significantly positively correlated with serum CRP (p < 0.01) and sICAM-1 (p < 0.01), whereas serum albumin concentration was significantly negatively correlated with serum CRP (p < 0.01) and sICAM-1 (p < 0.01). There were no significant correlations between MIS, DMS and serum albumin with serum concentrations of sVCAM-1, sE-selectin, MDA, NO, endothelin-1 and Lp (a). Conclusion: This study indicates that protein-energy wasting indicators in HD patients are associated with serum CRP and sICAM-1, as two CVD risk factors.

• Cardiovascular diseases
• dialysis-malnutrition score
• hemodialysis
• malnutrition-inflammation score
• protein-energy wasting
• serum albumin

Introduction

The mortality of hemodialysis (HD) patients is unacceptably high.1 Among several risk factors contributing to this condition, cardiovascular diseases (CVD) is the most important cause of mortality. A marked increase in CVD incidence and death rates has been reported in dialysis patients as compared to an age-matched general population.2–4 Although end-stage renal disease is associated with a higher prevalence of traditional risk factors for CVD, such as lipid abnormalities, hypertension and diabetes, they cannot explain high frequency of CVD in these patients.5 In the general population, over-nutrition and obesity is associated with the risk of CVD, whereas in HD patients, protein-energy wasting (PEW) increases the risk of CVD.6^,7 However, it is not known which nontraditional (or novel) risk factors for CVD in HD patients are associated with PEW and increase the risk of CVD in HD patients with PEW. Therefore, this study was designed to investigate the associations between some PEW indicators, including malnutrition-inflammation score (MIS), dialysis-malnutrition score (DMS) and serum albumin, with novel risk factors for CVD in HD patients.

Materials and methods

For this cross-sectional study, using systematic sampling, we randomly selected 291 HD patients from among 2302 eligible adult HD patients in 50 HD centers in Tehran. Inclusion criteria were age ≥18 years and being on HD for at least six months, while exclusion criteria were HIV infection and hepatitis B. Underlying causes of renal failure in the participating patients were diabetes mellitus (39%), hypertension (28%), urinary infection (9%), polycystic kidney disease (5.5%), nephrolithiasis (2.5%), nephrotic syndrome (2%) and other or unknown causes (14%).

Eighty-nine percent of participating patients were on HD treatments three times a week (four hours per session), while 11% patients had treatments twice weekly. All patients enrolled were hemodialyzed using polysulfone capillary dialyzers and bicarbonate dialysate. The study protocol was approved by the Ethics Committee of the National Nutrition and Food Technology Research Institute of Iran. The study was in adherence with the Declaration of Helsinki. Written informed consent was obtained from all patients.

The DMS is based on the seven original SGA components with a fully quantitative scoring system.8 Each DMS component was rated on a scale of 1 (normal) to 5 (very severe). The sum of all seven DMS components ranges from 7 to 35; a higher total score reflects a more severe degree of PEW.8 The HD patients were categorized into two groups based on DMS: (1) patients with normal status or without PEW (score of 7–13) and (2) patients with PEW (score of ≥14).9

The MIS consists of the seven original SGA components and also three new items (BMI and serum concentrations of albumin and total iron binding capacity) with a fully quantitative and comprehensive scoring system.10 Each MIS component has four levels of severity from 0 (normal) to 3 (very severe). The sum of all 10 MIS components ranges from 0 to 30; a higher total score represents a more severe degree of PEW.10 The HD patients were categorized into two groups based on MIS: (1) patients with normal status or without PEW (score of 0–7) and (2) patients with PEW (score of ≥8).9

In our study, before beginning the study, for evaluating the degree of reproducibility, the DMS and MIS forms were completed by a trained physician for a subset of 16 HD patients. After one week, the DMS and MIS were repeated on the same subset without reference to the first evaluation. The correlation coefficients between the two sets of DMS and MIS were 0.80 (p < 0.01) and 0.87 (p < 0.01), respectively, denoting an acceptable degree of reproducibility.

Patients’ height and weight were determined at the end of one of the dialysis sessions. In addition, after a 12 - to 14-hour fast, 4 mL blood was obtained from each patient before dialysis. After clotting at room temperature (20–25 °C), blood samples were centrifuged at 2000 rpm for 10 minutes. The sera were separated into small aliquots and were frozen at −70 °C until they were used.

Serum creatinine, urea and albumin were assessed using commercial kits (Pars-Azmoon, Tehran, Iran) with the aid of a selectra 2 autoanalyzer (Vital Scientific, Spankeren, The Netherlands). Coefficients of variation (CV) for these biochemical parameters were less than 3%. In this study, HD patients according to serum albumin were classified into two groups11: (1) patients with normal serum albumin (≥3.8 g/dL) and (2) patients with low serum albumin (<3.8 g/dL).

The serum concentration of high sensitive C-reactive protein (hs-CRP) and lipoprotein (a) [Lp (a)] were determined using enzyme-linked immunosorbent assay (ELISA) kits (Dignostics Biochem Canada, London, Canada). The CVs for serum hs-CRP and Lp (a) were 4.6 and 5.4, respectively.

The serum soluble intercellular adhesion molecule type 1 (sICAM-1), soluble vascular cell adhesion molecule type 1 (sVCAM-1) and sE-selectin were measured using ELISA kits (Diaclone, Besancon, France). The CVs for serum sICAM-1, sVCAM-1 and sE-selectin were 3.5, 6.3 and 6.7, respectively. Serum concentration of malondialdehyde (MDA) was assessed using colorimetry method by commercial kits (Cayman Chemical, Ann Arbor, MI) with a CV of 4.6%. Serum nitric oxide (NO) concentration was determined using the colorimetry method by commercial kits (Active Motif, Tokyo, Japan) with a CV of 7.8%. Serum endothelin-1 concentration was measured using ELISA kits (Biomedica, Vienna, Austria) with a CV of 8.5%.

Dialysis adequacy, based on the Kt/V index, was determined for each patient by a Kt/V calculator, using information recorded in patient files, including predialysis blood urea nitrogen (BUN) concentration, postdialysis BUN, the dialysis session length, postdialysis weight and ultrafiltration volume12; of the 291 HD patients, information regarding their Kt/V index was available only for 246 HD patients.

Statistical analysis

Statistical analysis of the data was performed using the Statistical Package for the Social Sciences (SPSS, Inc., Chicago, IL) for windows version 21.0. All quantitative parameters had normal distribution according to the Kolmogorov–Smirnov test. Pearson’s correlation coefficient was used to determine associations between quantitative variables. We used t-test to compare quantitative parameters between two groups. A p value ≤0.05 was considered statistically significant. Quantitative data are displayed as the mean ± standard error.

Results

Characteristics of HD patients are listed in Table 1. MIS and DMS were significantly positively correlated with serum CRP (p < 0.01) and sICAM-1 (p < 0.01), whereas there were no significant correlations between MIS and DMS with serum concentrations of sVCAM-1, sE-selectin, MDA, NO, endothelin-1 and Lp (a) (Table 2). In addition, serum concentrations of CRP (p < 0.001) and sICAM-1 (p < 0.01) were significantly higher in HD patients with PEW based on MIS or DMS in comparison with those without PEW, whereas there were no significant differences in serum concentrations of sVCAM-1, sE-selectin, MDA, NO, endothelin-1 and Lp (a) between the two groups (Table 3).

Table 1. Characteristics of the HD patients.

Characteristics	All patients (n = 291)
Age (years)
18–40	45 (15.5%)
41–60	99 (34%)
>60	147 (50.5%)
Sex
Men	164 (56%)
Women	127 (44%)
Dialysis vintage (years)
≤1	60 (21%)
1–5	149 (51%)
5–10	61 (21%)
>10	21 (7%)
Dialysis adequacy (Kt/V)
<1.2	113 (46%)
≥1.2	133 (54%)
Serum creatinine (mg/dL)	9 ± 0.2
Serum urea (mg/dL)	123 ± 1.7

Note: Serum creatinine and urea are presented as mean ± standard error (SE).

Table 2. Correlations of PEW indicators with novel risk factors for CVD in the HD patients.

Parameters	MIS	DMS	Serum albumin
hs-CRP	r = 0.25 (p < 0.01)	r = 0.25 (p < 0.01)	r = −0.32 (p < 0.01)
sICAM-1	r = 0.25 (p < 0.01)	r = 0.23 (p < 0.01)	r = −0.16 (p < 0.01)
sVCAM-1	NS	NS	NS
sE-selectin	NS	NS	NS
MDA	NS	NS	NS
NO	NS	NS	NS
Endothelin-1	NS	NS	NS
Lp (a)	NS	NS	NS

Note: NS: nonsignificant.

Table 3. Serum concentrations of novel risk factors for CVD in the HD patients based on various PEW indicators.

	MIS		DMS		Serum albumin
Parameters	Normal	PEW	Normal	PEW	Normal	Low
hs-CRP (mg/L)	4.7 ± 0.3	6.2 ± 0.2^a	4.5 ± 0.3	6.2 ± 0.2^a	5 ± 0.2	7 ± 0.4^b
sICAM-1 (ng/mL)	614 ± 19	690 ± 21^b	597 ± 19	691 ± 20^b	643 ± 15	721 ± 42^c
sVCAM-1 (ng/mL)	762 ± 35	818 ± 35	764 ± 39	810 ± 32	777 ± 26	874 ± 72
sE-selectin (ng/mL)	27 ± 1	24 ± 1	27 ± 1.5	24 ± 1	25 ± 1	25 ± 4
MDA (µmol/L)	5.7 ± 0.1	5.9 ± 0.1	5.7 ± 0.1	5.8 ± 0.1	5.8 ± 0.1	5.7 ± 0.2
NO (µmol/L)	44 ± 1	41.5 ± 1	43.5 ± 1	42 ± 1	42 ± 0.6	46 ± 1.8
Endothelin-1 (pg/mL)	27.5 ± 2	27 ± 2	26 ± 2	28 ± 2	27 ± 2	32 ± 4.5
Lp (a) (mg/dL)	34 ± 2	31 ± 2	35 ± 3	30 ± 2	32 ± 2	35 ± 4

Notes: All values are presented as mean ± SE.

^ap < 0.001 versus normal.

^bp < 0.01 versus normal.

^cp = 0.05 versus normal.

Serum albumin concentration was significantly negatively correlated with serum CRP (p < 0.01) and sICAM-1 (p < 0.01), whereas there were no significant correlations between serum albumin with serum concentrations of sVCAM-1, sE-selectin, MDA, NO, endothelin-1 and Lp (a) (Table 2). Furthermore, serum concentrations of CRP (p < 0.01) and sICAM-1 (p = 0.05) were significantly higher in HD patients with low serum albumin as compared to those with normal serum albumin, whereas there were no significant differences in serum concentrations of sVCAM-1, sE-selectin, MDA, NO, endothelin-1 and Lp (a) between the two groups (Table 3).

Discussion

In HD patients, the most important cause of mortality is CVD and approximately 50% of deaths are related to CVD.2^,3 Some studies have indicated that PEW is associated with CVD in HD patients and increases the presence of CVD or cardiovascular mortality.13^,14 However, traditional risk factors for CVD, such as lipid abnormalities, hypertension and diabetes cannot explain high frequency of CVD in these patients.5 Therefore, this study was designed to investigate the associations of MIS, DMS and serum albumin with novel risk factors for CVD in HD patients.

It has been shown that each 10-unit increase in MIS and DMS was associated with an increased mortality risk of 10.4- and 7.7-fold in HD patients, respectively.15 Our study showed that from among novel risk factors of CVD including serum CRP, sICAM-1, sVCAM-1, sE-selectin, MDA, NO, endothelin-1 and Lp (a), serum concentrations of CRP, as a systemic inflammation marker and sICAM-1, as a vascular inflammation marker, were significantly positively correlated with MIS and DMS, as two indicators of PEW, and HD patients with higher MIS or DMS had higher serum CRP and sICAM-1. According to the available literature, no study has investigated the association of MIS and DMS with various nontraditional (or novel) risk factors of CVD in HD patients. In this field, only Demir et al. showed that patients with higher MIS had higher serum CRP and VCAM-1.16

It has been shown that each 1-g/dL decrease in serum albumin was associated with a 7.2-fold increased mortality risk in HD patients.15 Our study indicated that serum albumin, as an indicator of PEW, was significantly negatively correlated with serum concentrations of CRP and sICAM-1 and HD patients with lower serum albumin had higher serum CRP and sICAM-1. In agreement with our research, various studies showed that serum albumin was negatively associated with serum CRP.17^,18 According to the available literature, only one study with small sample size has investigated the association of serum albumin with cell adhesion molecules.19 In contrast to our research, this study found no significant correlation between serum albumin with serum ICAM-1 concentration.19

HD patients have a high prevalence of inflammation and PEW, and these two conditions often occur concomitantly in HD patients.7^,10 In HD patients, chronic inflammation may result from the repeated contact of blood mononuclear cells with dialysis tubes and dialyzer membranes, impurities in the dialysis water and/or dialysis solution, oxidative and carbonyl stress, increased release and decreased clearance of inflammatory cytokines.7 Inflammation may mediate PEW through suppressing appetite and increasing skeletal muscle protein breakdown.20^,21

Chronic inflammation increases the release of inflammatory cytokines such as interleukin-6 and tumor necrosis factor-α by leukocytes, and these inflammatory cytokines increase the synthesis of systemic inflammation markers such as CRP and vascular inflammation markers such as sICAM-1, sVCAM-1 and sE-selectin.22^,23

Serum CRP is a strong predictor of mortality, especially cardiovascular mortality in HD patients.24 CRP has been shown to stimulate the synthesis of monocyte chemotactic protein-1 and upregulate cell adhesion molecules (or vascular inflammation markers) on the surface of the endothelial cells.25 These processes lead to the migration of monocytes to subendothelial layer. The monocytes differentiate into macrophages and scavenge the oxidized low-density lipoproteins. Consequently, the macrophages are converted to foam cells and result in atherosclerosis.25^,26 Therefore, vascular inflammation markers have a central role in the pathogenesis and progression of atherosclerosis according to above-mentioned mechanism and are associated with increased cardiovascular mortality.22^,27^,28 In conclusion, this study indicates that PEW indicators in HD patients are associated with serum CRP and sICAM-1, as two CVD risk factors.

Acknowledgements

The authors thank the staff of the Tehran hemodialysis centers for their invaluable assistance and the staff of the research laboratory of Research Institute for Endocrine Sciences for their technical assistance.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

This study was supported by National Nutrition and Food Technology Research Institute of Iran.