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Open Access 18.04.2020 | Nephrology - Original Paper

Interleukin 6 is a better predictor of 5-year cardiovascular mortality than high-sensitivity C-reactive protein in hemodialysis patients using reused low-flux dialyzers

verfasst von: Le Viet Thang, Nguyen Duc Loc, Nguyen Trung Kien, Nguyen Huu Dung, Dao Bui Quy Quyen, Nguyen Minh Tuan, Do Manh Ha, Truong Quy Kien, Nguyen Thi Thuy Dung, Diem Thi Van, Nguyen Van Duc, Nguyen Thi Thu Ha, Pham Quoc Toan, Vu Xuan Nghia

Erschienen in: International Urology and Nephrology | Ausgabe 6/2020

Abstract

Purpose

In this study, we focused on the role of elevated serum interleukin 6 (IL-6) concentration in predicting 5-year cardiovascular mortality in hemodialysis patients using low-flux dialyzer reuse.

Materials and methods

We measured serum IL-6 concentrations in 236 hemodialysis patients (138 males and 98 females) to predict 5-year cardiovascular mortality. We assessed the baseline demographics of all patients who had a mean age of 44 years and a median hemodialysis duration of 38.5 months. We divided all patients into two equal groups based on the serum IL-6 concentration: G1 (n = 118) with serum IL-6 concentration < 6.78 pg/L and G2 (n = 118) with serum IL-6 concentration ≥ 6.78 pg/L.

Results

After the 5-year follow-up, 45 patients died due to cardiovascular causes (19.1%). Lipid disorder, hemoglobin, serum albumin, β2-M, and IL-6 concentration were independent risk factors for predicting cardiovascular mortality during the 60-month follow-up in hemodialysis patients. Based on the Kaplan–Meier analysis, we realized that patients with a higher interleukin 6 concentration (G2) had a significantly higher cardiovascular mortality rate than patients in G1 (log-rank test p < 0.001). Serum IL-6 concentration was a better predictor of 5-year cardiovascular mortality than high-sensitivity C-reactive protein in hemodialysis patients using low-flux dialyzer reuse (AUC = 0.818; p < 0.001; cut-off value: 8.055 pg/mL, Se = 77.8%, Sp = 78.5%).

Conclusion

Serum IL-6 concentration was a better predictor of 5-year cardiovascular mortality than high-sensitivity C-reactive protein in maintenance hemodialysis patients using low-flux dialysis reuse.

Share the first co-author: Nguyen Duc Loc.

The original article has been revised due to retrospective Non Open Access.

A correction to this article is available online at https://doi.org/10.1007/s11255-020-02513-y.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Introduction

Interleukin 6 (IL-6) is an interleukin that acts as both a proinflammatory cytokine and an anti-inflammatory myokine. IL-6 is an important mediator of the acute-phase response. IL-6 can be secreted by macrophages in response to specific microbial molecules. IL-6 is responsible for stimulating acute-phase protein synthesis, as well as the production of neutrophils in bone marrow [1]. IL-6 stimulates inflammatory and autoimmune processes in many diseases, including acute and chronic kidney diseases [2, 3]. IL-6 has a molecular weight of 21 kDa and is difficult to dialyze using low-flux membranes, but IL-6 can be reduced when patients undergo hemodiafiltration [4, 5]. Elevated serum IL-6 concentration is common in patients with chronic kidney diseases, including maintenance hemodialysis (HD) patients [6‐9]. Because elevated IL-6 concentration in maintenance HD patients is associated with more negative than positive effects, many authors have found ways to reduce serum IL-6 in patients [10‐13]. In Vietnam, using a low-flux dialyzer with six reuses is common, so the measurement of serum IL-6 concentration and its relationship with cardiovascular mortality rate in HD patients need to be clarified. In this study, we focused on the predictive value of serum IL-6 compared to that of high-sensitivity C-reactive protein (hs-CRP) concentration for 5-year cardiovascular mortality in HD patients treated with a low-flux dialyzer with six reuses.

Subjects and methods

Subjects

In our study, we included 878 patients with a maintenance HD duration greater than 3 months using low-flux dialyzer reuse from three hemodialysis centers in Vietnam, including the Hemodialysis Center, Bach Mai Hospital, Hanoi; the Department of Nephrology and Hemodialysis, Military Hospital 103, Hanoi; and the Department of Hemodialysis, An Sinh Hospital, Ho Chi Minh city from April 2013 to April 2018. We excluded 642 patients with signs of infection (hs-CRP ≥ 10 mg/L; white blood cell count ≥ 10 G/L; or neutrophil percentage ≥ 70%) or malignancy and those who were not treated with a low-flux dialyzer. Patients with hepatitis B and/or hepatitis C were also excluded. The remaining 236 maintenance hemodialysis patients provided written informed consent before participation in our study. The enrolled patients had been treated with three sessions weekly using low-flux (Polyflux 14L) dialyzer reuse to reach the total Kt/V target, which was calculated using the Daugirdas formula [14]. Each dialysis session lasted between 3.5 and 4.5 h to achieve the target of total Kt/V ≥ 1.2 per session, and the treatments were performed three times weekly. Reuse of dialyzer was performed six times in all patients (the procedure is regulated by Vietnam’s Ministry of Health) as follows: reuse of dialyzer was performed by a professional, trained technician. After finishing the dialysis session, the dialyzer was immediately transferred to the washing room. The dialyzer was cleaned by hand using RO water for 30 min. Next, the dialyzer was soaked and disinfected with 0.7% peracetic acid solution and stored in a professional refrigerator at a temperature of 2–8 °C. Before being used for the dialysis patient, the dialyzer was washed again with RO water for 30 min, and it was confirmed that there was no peracetic acid in the dialyzer by a peracetic acid 2000 test strip.

We assessed patients to determine the cause of kidney failure and carpal tunnel syndrome. We diagnosed residual kidney function according to the method described by Daugirdas [14] and diagnosed lipid disorders according to the KDIGO Clinical Practice Guideline for Lipid Management in CKD (2013) [15]. Patients were followed up for 60 months (from April 2013 to April 2018) to determine cardiovascular mortality. Cardiovascular mortality in our patients was defined as death attributable to myocardial ischemia and infarction, heart failure, cardiac arrest, or cerebrovascular accident [16]. All of these patients died at our hospitals.

We divided all patients into two equal groups based on the serum IL-6 concentration: G1 (n = 118) with serum IL-6 concentration < 6.78 pg/L and G2 (n = 118) with serum IL-6 concentration ≥ 6.78 pg/L. We also used hs-CRP, duration of hemodialysis, serum albumin, and serum β2-microglobulin (β2-M) to predict 5-year cardiovascular mortality in our study.

Biochemical assays and other measurements

Peripheral blood was collected prior to the second dialysis session of the week to measure hematological and biochemical indices, such as hemoglobin, blood urea nitrogen, creatinine, albumin, β2-M, and hs-CRP.

Serum IL-6 concentration was measured using the enzyme-linked immunosorbent assay (ELISA) method at the time of enrollment (using the DRG International, Inc., USA Human IL-6 ELISA Kit). The minimum detectable dose of IL-6 was typically < 1.0 pg/mL.

Statistical methods

All the data were tested for normality by the Kolmogorov–Smirnov test. In cases of a normal distribution, continuous data are represented by the mean and standard deviation and were analyzed by Student’s t test. All the non-normally distributed data are represented by the median (25 percentiles–75 percentiles) and were analyzed by the Mann–Whitney U test. Categorical data are presented as frequencies with percentages and were analyzed using the Chi-square test. Pearson correlation was used to measure the degree of the association between linearly related variables, and Spearman rank correlation was used to measure the degree of association between the non-parametric variables. The receiver-operating characteristic (ROC) curves with the area under the curve (AUC) were calculated to predict cardiovascular mortality of the patients after a 5-year follow-up. Multivariate adjusted regression analysis was performed to identify the predictor of cardiovascular mortality (using backward selection procedure). Survival curves were assessed using Kaplan–Meier analysis and evaluated using the log-rank test. Statistical analysis was performed using the Statistical Package for the Social Science (SPSS) version 20.0 (Chicago, IL, USA). A p value < 0.05 was considered significant.

Results

Table 1 shows the baseline characteristics of all patients. There were 138 males and 98 females with a mean age of 44 years and a median HD duration of 38.5 months. When comparing the demographic and laboratory characteristics between the 2 IL-6 concentration groups (Group 1 and Group 2), we found that there was no difference in the subject’s basic characteristics, such as the mean age, sex, BMI, hypertension, anemia, residual kidney function, or some laboratory indices, such as hemoglobin and creatinine concentration.

Table 1

Clinical characteristics and laboratory parameters of the studied patients (n = 236)

	Total (n = 236)	Group 1 (IL-6 < 6.78 pg/mL), (n = 118)	Group 2 (IL-6 ≥ 6.78 pg/mL), (n = 118)	p for trend
Age (years)	44.47 ± 14.65	43.49 ± 14.54	45.45 ± 14.76	0.306
Male (n, %)	138 (58.5)	67 (56.8)	71 (60.2)	0.597
Duration of hemodialysis (months)	38.5 (22–66)	36 (21–56)	40 (22–74.25)	0.046
BMI	19.05 ± 2.35	18.9 ± 2.17	19.19 ± 2.52	0.346
Hypertension (n, %)	181 (76.7)	86 (72.9)	95 (80.5)	0.166
Carpal tunnel syndrome (n, %)	16 (6.8)	4 (3.4)	12 (10.2)	0.038
Etiology (n, %)
CGN	167 (70.8)	84 (71.2)	83 (70.3)	0.805
Chronic pyelonephritis	29 (12.3)	16 (13.6)	13 (11)
Diabetic nephropathy	24 (10.2)	10 (8.5)	14 (11.9)
Others	16 (6.8)	8 (6.8)	8 (6.8)
Residual kidney function (n, %)	58 (24.6)	31 (26.3)	27 (22.9)	0.545
Lipid disorder (n, %)	155 (65.7)	69 (58.4)	86 (72.9)	0.02
Urea (mmol/L)	28.64 ± 6.65	28.38 ± 6.38	28.89 ± 6.92	0.554
Creatinine (µmol/L)	824 (651.75–981)	773 (618.75–980)	835.5 (710–983)	0.183
Albumin (g/L)	38.88 ± 3.63	39.69 ± 3.58	38.08 ± 3.52	0.001
Hs-CRP (mg/L)	0.4 (0.2–0.6)	0.3 (0.1–0.6)	0.5 (0.2–0.7)	0.046
Hemoglobin (g/L)	102.52 ± 18.78	102.28 ± 16.08	102.75 ± 21.21	0.847
Anemia (n, %)	198 (83.9)	102 (86.4)	96 (81.4)	0.288
β2-M (mg/L)	60.85 (43.95–74.72)	60.6 (45.77–70.52)	61.9 (41.67–78.47)	0.035
IL-6 (pg/mL)	6.77 (5.67–8.96)	5.67 (5.16–6.13)	8.96 (7.52–10.8)	< 0.001
Cardiovascular cause mortality (n, %)	45 (19.1)	9 (7.6)	36 (30.5)	< 0.001

BMI body mass index, CGN chronic glomerulonephritis, hs-CRP high-sensitivity C-reactive protein, β2-M beta-2-microglobulin, IL-6 interleukin 6

Our study also showed that the duration of HD was longer and that the proportions of carpal tunnel syndrome and lipid disorder were higher as serum IL-6 concentrations increased (from Group 1 to Group 2, p < 0.05). In particular, the proportion of cardiovascular mortality in group 2 was significantly higher than that in group 1 (30.5% compared to 7.6%), with a p value < 0.001. In addition, the concentrations of hs-CRP and beta 2-microglobulin (β2-M) were higher, and the concentration of serum albumin was lower in the group of patients with higher serum IL-6 concentrations than in those with lower serum IL-6 concentrations (p < 0.05).

There were moderate positive correlations between serum IL-6 concentration and duration of HD (r = 0.141), serum hs-CRP (r = 0.169), and β2-M concentration (r = 0.121) with p < 0.05 (Table 2).

Table 2

Correlation between serum IL-6 concentration and duration of hemodialysis, hs-CRP, and β2-M (n = 236)

Variables	IL-6 (pg/mL)		Correlation equation
Variables	r	p	Correlation equation
Duration of hemodialysis (months)	0.141	0.03	IL-6 = 0.016* Duration of hemodialysis + 7.154
Serum hs- CRP (mg/L)	0.169	0.009	IL-6 = 1.388* Serum hs- CRP + 7.273
β2-M (mg/L)	0.121	0.046	IL-6 = 0.021* β2-M + 6.622

hs-CRP high-sensitivity C-reactive protein, β2-M beta-2-microglobulin, IL-6 interleukin 6

The results in Table 3 show that lipid disorders, hemoglobin, serum albumin, β2-M, and IL-6 concentrations were independent risk factors for predicting cardiovascular mortality over 60 months in hemodialysis patients.

Table 3

Multivariate logistic regression analysis showing prognostic factors of cardiovascular mortality in hemodialysis patients during the 5-year follow-up (n = 236)

Variable	Adjusted hazard ratio	95% Cl	p
No residual kidney function	4.034	0.956–17.02	0.058
Lipid disorder	0.351	0.119–1.037	0.004
Albumin	0.865	0.761–0.984	0.027
Hemoglobin (g/l)	0.977	0.955–1.00	0.046
β2-M (mg/L)	1.037	1.011–1.063	0.004
IL-6 (pg/ml)	1.643	1.380–1.958	< 0.001

β2-M beta-2-microglobulin, IL-6 interleukin 6

Based on the ROC curve model, serum IL-6 concentration had a better predictive value for cardiovascular mortality than duration of HD, hs-CRP, albumin, and β2-M in maintenance HD patients during the 60-month follow-up (AUC = 0.818; p < 0.001; cut-off value: 8.055 pg/mL, sensitivity of 77.8%, and specificity of 78.5%) (Fig. 1).

As the result of Kaplan–Meier analysis in Fig. 2, we realized that patients with a higher IL-6 concentration (Group 2) had a significantly higher cardiovascular mortality rate than patients in Group 1 (log-rank test, p < 0.001).

Discussion

The median IL-6 concentration in our study was 6.77 pg/mL (Table 1). Elevated serum IL-6 concentrations have been reported in many previous studies. Tbahriti et al. [17] studied 40 maintenance HD patients and found that the serum IL-6 concentration was 8.2 ± 0.22 pg/mL. Babaei et al. [9] studied the concentrations of serum IL-6 in 80 HD patients (the mean duration of HD was 68 months). The results showed that the mean serum IL-6 concentration was 3.79 ± 0.37 pg/mL, which was higher than that of the control group (80 healthy people, p < 0.05). Jin et al. [18] studied serum IL-6 concentrations in 20 HD patients with a mean dialysis duration of 24.9 months. The results showed that the mean concentration of serum IL-6 was 5.2 ± 0.4 pg/mL, which was also higher than that of the control group (20 healthy people, p < 0.01). From these results, we concluded that elevated serum IL-6 concentrations were common in HD patients. However, serum IL-6 concentrations and the proportion of elevated IL-6 were very different in various studies, which reflected that serum IL-6 concentrations in HD patients depend on various factors.

IL-6 acts as a mediator in the notification of the occurrence of some emergent events and is a warning signal in the event of tissue damage. In addition to immune-mediated cells, mesenchymal cells, endothelial cells, fibroblasts, and many other cells are involved in the production of IL-6 in response to various stimuli [19]. The immediate and transient expression of IL-6 is also generated in response to environmental stress factors. This expression triggers an alarm signal and activates host-defense mechanisms against stress. Because of the range of IL-6 biological activities and its pathological role in various diseases described above, it was anticipated that IL-6 targeting would constitute a novel treatment strategy for various immune-mediated diseases, including chronic kidney disease [19]. The pathophysiology involved in the development of chronic inflammation in chronic kidney disease (CKD) patients, as well as maintenance HD patients, has not yet been completely elucidated. Eleftheriadis T [20] noted the reasons for inflammation in HD patients, including uremia, the HD procedure, chronic renal failure complications, and therapeutic interventions for their treatment. Acquired immunity disturbances in HD patients result in malnutrition–inflammation–atherosclerosis syndrome, reduced quality of life, and reduced survival time.

Our results showed that the concentration of IL-6 in group 2 was higher than that in group 1. There were some reasons for the elevated IL-6 concentrations in group 2, including a longer duration of HD (p = 0.046), a higher ratio of carpal tunnel syndrome (CTS) (p = 0.038), and a higher ratio of lipid disorder (p = 0.02). CTS is a common complication of long-term dialysis therapy [14, 16]. The duration of dialysis therapy is an independent and statistically significant risk factor in the development of CTS. A long duration of HD, CTS and lipid disorder increased atherosclerosis and eventually led to increased concentrations of serum IL-6 in the patients in our study.

In this study, we found that an elevated serum IL-6 concentration was related to an increase in serum hs-CRP, serum β2-M concentration (inflammatory markers in acute-phase reactants), and duration of HD (Tables 2, 3). Inflammation occurs due to many causes. There are causes related to patients such as comorbidities, oxidizing agents, infections, and genetic or immune factors. There are reasons related to the quality of dialysis equipment, such as membranes and dialysate quality [21]. Some theories about the occurrence of inflammatory processes in HD patients include the retention of proinflammatory molecules after hemodialysis that should be removed by the kidneys or the excessive stimulation of oxidation; finally, the dialysis process stimulates antigen presentation directly or indirectly through contaminants [22]. The consequences of the inflammatory process are related to the increase in dialysis-related chronic disease manifestations such as carpal tunnel syndrome (Table 1). Many previous authors have also confirmed that malnutrition–inflammation–atherosclerosis (MIA) syndrome is common in patients with chronic kidney disease with and without dialysis [23‐25]. Atherosclerosis is both a chronic inflammatory condition and a disorder of lipid metabolism in CKD patients (65.7% of patients had lipid disorders in our study, Table 1). The results of our study were also consistent with the findings of the above authors and reaffirmed the relationship between inflammation and malnutrition in HD patients.

Among nearly 900 dialysis patients, we only selected 236 patients who met the selection criteria (especially no acute inflammatory infection; no HBV/HCV infection) to participate in our study. We recorded 45 patients with cardiovascular deaths (19.1%) during the 5-year follow-up (Table 1). In this study, we used the serum IL-6 concentration to predict cardiovascular mortality in HD patients and compared its performance with the predictive values of dialysis time, serum albumin, hs-CRP, and β2-M concentration. Through these comparisons, we wanted to determine the prognostic value of IL-6, an inflammatory marker that appears earlier and could be targeted to reduce concentrations by IL-6 antagonists, unlike a commonly used inflammatory marker such as hs-CRP. Our results showed that lipid disorders, hemoglobin, serum albumin, β2-M, and IL-6 concentrations were independent risk factors for predicting cardiovascular mortality in hemodialysis patients during the 60-month follow-up (Table 3). Based on the ROC curve model, the serum IL-6 concentration had a better predictive value for cardiovascular mortality than duration of HD, hs-CRP, albumin, and β2-M in maintenance HD patients during the 60-month follow-up (AUC = 0.818; p < 0.001; cut-off value: 8.055 pg/mL, Se = 77.8%, Sp = 78.5%) (Fig. 1). After IL-6 is synthesized in a local lesion in the initial stage of inflammation, it moves to the liver through the bloodstream, followed by the rapid induction of an extensive range of acute-phase proteins, including CRP and β2-M [19]. On the other hand, IL-6 reduces the production of fibronectin, albumin, and transferrin [19]. The gold standard among the micro-inflammatory markers in HD patients is C-reactive protein, because it is easy to measure and a good predictor of short-term mortality, and CRP has become a routine test in HD units to warn of inflammation [26‐28]. The predicted value of plasma CRP for cardiovascular mortality has been mentioned by the previous authors. Sameiro-Faria M [26] confirmed that CRP and triglycerides (TGs) are significant predictors of death in HD patients after a 2-year follow-up. Ishii J [27] concluded that CRP can be used as a predictor of long-term mortality in HD patients. In this study, we used serum IL-6 concentration to predict cardiovascular mortality in HD patients, because IL-6 was probably associated with more causes of inflammation than CRP [29, 30].

According to the result of Kaplan–Meier analysis (Fig. 2), we realized that patients with higher IL-6 concentrations (Group 2) had a significantly higher cardiovascular mortality rate than patients in Group 1 (log-rank test, p < 0.001). However, in this study, we could not isolate the roles of various factors, such as the duration of HD, hs-CRP, and albumin, in the risk of death in dialysis patients.

Conclusion

In conclusion, serum IL-6 concentration was a better predictor of 5-year cardiovascular mortality than hs-CRP in maintenance HD patients using low-flux dialysis reuse.

Limitations

Although our studies have shown that serum IL-6 concentration has a high value in predicting cardiovascular mortality in maintenance HD patients, a limitation of the study is that IL-6 was assessed once, so we could not clearly analyze changes in serum IL-6 concentration or the effect of changes in IL-6 concentration on complications or cardiovascular mortality in HD patients.

Acknowledgements

In this study, we had been strongly supported by clinical application funding of our local hospital and university to complete our research.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest, financial, or otherwise.

Ethics approval

This study was approved by the Ethical Committee of Vietnam Military 103 hospital (No.1939/QĐ/BVQY103), An Sinh Hospital (No.564/QĐ/BVAS), and Bach Mai Hospital (No.1231/QĐ/BVBM).

Human and animal rights

Animals did not participate in this research. All human research procedures were following the ethical standards of the committee responsible for human experimentation (institutional and national), and with the Helsinki Declaration of 1975, as revised in 2008.

Informed consent was obtained from all participants.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Titel: Interleukin 6 is a better predictor of 5-year cardiovascular mortality than high-sensitivity C-reactive protein in hemodialysis patients using reused low-flux dialyzers
verfasst von: Le Viet Thang
Nguyen Duc Loc
Nguyen Trung Kien
Nguyen Huu Dung
Dao Bui Quy Quyen
Nguyen Minh Tuan
Do Manh Ha
Truong Quy Kien
Nguyen Thi Thuy Dung
Diem Thi Van
Nguyen Van Duc
Nguyen Thi Thu Ha
Pham Quoc Toan
Vu Xuan Nghia
Publikationsdatum: 18.04.2020
Verlag: Springer Netherlands
Erschienen in: International Urology and Nephrology / Ausgabe 6/2020
Print ISSN: 0301-1623
Elektronische ISSN: 1573-2584
DOI: https://doi.org/10.1007/s11255-020-02461-7

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