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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 30  |  Issue : 4  |  Page : 1014-1021

Interleukin-18 and vascular endothelial growth factor as predictors for end-stage renal disease


1 Department of Microbiology and Immunology, Faulty of Medicine, Menoufia Universality, Shebin Elkom, Egypt
2 Department of Internal Medicine, Faulty of Medicine, Menoufia Universality, Shebin Elkom, Egypt
3 Menoufia University Hospital, Menoufia University, Menoufia Governorate, Egypt

Date of Submission21-May-2017
Date of Acceptance19-Jul-2017
Date of Web Publication04-Apr-2018

Correspondence Address:
Sara I M. El Shohady
Shebin El Kom City, Menoufia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_352_17

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  Abstract 


Objective
The objective of this study was to evaluate the role of interleukin-18 (IL-18) and vascular endothelial growth factor (VEGF) in end-stage renal disease (ESRD), and the influence of comorbidities like diabetes and viral hepatitis on their levels.
Background
IL-18 and VEGF are inflammatory cytokines playing important roles in the pathogenesis of ESRD and related comorbidities like diabetic nephropathy and viral hepatitis.
Patients and methods
This study was conducted on 96 patients undergoing hemodialysis (25 diabetic patients with hepatic viral infections, 25 diabetic patients without hepatic viral infections, 25 nondiabetic patients with hepatic viral infections, and 21 age-matched and sex-matched healthy individuals as a control group). All patients were subjected to full history taking, clinical examination, and laboratory investigations. Serum IL-18 and VEGF levels were measured for all the study individuals by using enzyme-linked immunosorbent assay technique.
Results
The prevalence of IL-18 and VEGF was higher in diabetic patients and patients with hepatitis comparing with the controls (P = 0.001). A detectable level of IL-18 was found in 100% of diabetic patients with and without viral hepatitis, and in 44% of the ones with only hepatitis (P = 0.001). A detectable level of VEFG was found in 100% of the patients with only diabetes and only hepatitis, and in 80% of the ones with combined diabetes and hepatitis (P = 0.001).
Conclusion
There is high elevation of both IL-18 and VEGF serum levels in ESRD associated with diabetic nephropathy and viral hepatitis. Serum IL-18 is higher in diabetic than hepatic nephropathy, whereas the opposite is seen with VEGF.

Keywords: interleukin-18, renal dialysis, vascular endothelial growth factor


How to cite this article:
A. Makled AF, M. Salem EH, A. El-Khayat AH, A. Emara MM, M. El Shohady SI. Interleukin-18 and vascular endothelial growth factor as predictors for end-stage renal disease. Menoufia Med J 2017;30:1014-21

How to cite this URL:
A. Makled AF, M. Salem EH, A. El-Khayat AH, A. Emara MM, M. El Shohady SI. Interleukin-18 and vascular endothelial growth factor as predictors for end-stage renal disease. Menoufia Med J [serial online] 2017 [cited 2018 Sep 19];30:1014-21. Available from: http://www.mmj.eg.net/text.asp?2017/30/4/1014/229220




  Introduction Top


End-stage renal disease (ESRD) is the last stage of chronic kidney disease which is related with significantly increased morbidity and mortality resulting from cardiovascular disease and infection, representing for 50 and 20%, respectively, of the gross mortality rate in ESRD patients[1]. Diabetic nephropathy (DN) is an advanced kidney disease which is the most prevalent cause of ESRD. It is a dangerous complication of long-term diabetes mellitus (DM) and is a major cause for dialysis in many developing countries[2].

Patients subjected to hemodialysis (HD) are at high risk for acquiring viral infections such as hepatitis B virus (HBV), hepatitis C virus (HCV), and uncommonly, HIV. That is because impaired cellular immunity enhances their susceptibility to infection[3].

Interleukin-18 (IL-18), a strong proinflammatory cytokine with multiproperties, is a member of the IL-1 family of cytokines, which was primarily described as an interferon (IFN-γ) inducing factor produced alternately in several cell types. It takes part in both cellular and humeral responses[4]. IL-18 participates in the progression of nephropathy by its direct effect on kidney function besides its proinflammatory effect[5]. In patients with DN, there is high expression of IL-18 in the serum, urine, and tubular renal cells[6]. Expression of IL-18 is high in chronic hepatitis C infection and in cirrhosis, and this is related to IFN-γ production[7].

Vascular endothelial growth factor (VEGF) is a signal protein produced by cells that induces vasculogenesis and angiogenesis. It is part of the system that returns the oxygen supply back to tissues and cells which are inhibited of oxygenated blood owing to impaired blood circulation[8]. VEGF plays a main role in the formation and preservation of the filtration barrier and is expressed in podocytes and can work through receptors Flt-1 and Flk-1 on endothelial cells[9]. As VEGF plays main role in the formation and preservation of the filtration barrier and is expressed in podocytes and can work through specific receptors on endothelial cells, so increased VEGF levels have been associated with glomerular harmful through hyper filtration, hypertrophy, and proteinuria[9]. There is also high hepatic angiogenesis in chronic HCV and HBV infections which may provide the molecular basis for liver carcinogenesis and participating in increasing the risk of hepatocellular carcinoma in patients with cirrhosis owing to HCV and/or HBV[10]. In the current study, we aimed to evaluate the influence of comorbidities like DM and viral hepatitis on the serum levels of IL-18 and VEGF in patients with ESRD.


  Patients and Methods Top


Study population and selection of patients

This study was approved by the Ethical Committee of Microbiology and Immunology Department, Faculty of Medicine, Menoufia University, in cooperation with Shebin El Kom Fever and Teaching Hospitals during the period from December 2015 to August 2016. Informed consent was obtained from every patient and controls. It involved 96 patients undergoing HD, who were divided into four groups: group I included 25 diabetic patients with hepatic viral infections, group II included 25 diabetic patients without hepatic viral infections, group III included 25 nondiabetic patients with hepatic viral infections, and group IV included 21 age-matched and sex-matched healthy individuals as a control group.

  1. The following were the inclusion criteria: age of the participants was to be in the range from 23 to 70 years, and all must be on HD. Patients with DN and viral hepatic infections, according to each group, were diagnosed by laboratory investigations
  2. The following were the exclusion criteria: infants, young children, and pregnant women, along with the presence of other accompanying diseases, hepatic failure, congenital kidneys, or tumors.


The patients were subjected to the following:

  1. Full history including personal, family and clinical history of DM (type and treatment), type of viral hepatitis, and duration of dialysis and past history of blood transfusion
  2. Clinical examination was conducted with stress on signs and symptoms of kidney and hepatic diseases like jaundice, pallor, edema, hypertension, and proteinuria and palpation of liver, kidney, and spleen
  3. Laboratory investigations:


    1. Kidney function tests; liver function tests; serum phosphorus, calcium (Ca), and iron; and random blood sugar (RBS) tests were done using Cobas Integra 400 autoanalyzer (Roche Diagnostics, Indianapolis, Indiana, USA)
    2. Complete blood count was done using ADVIA 2120 hematology analyzer (Siemens Healthcare Diagnostics, Erlangen, Germany) to estimate hemoglobin (Hb) level, white blood cells (WBCs), and platelets
    3. HCV antibody was detected by enzyme-linked immunosorbent assay (ELISA) third generation (Roche Diagnostics, Mannheim, Germany)
    4. Hb surface antigen (HBsAg) was done by electrochemiluminescence immunoassay (Roche Diagnostics)
    5. Special laboratory investigations included measurement of IL-18 and VEGF levels in the sera of all studied groups done by ELISA.


    Collection of blood samples

    Venous blood samples (5 ml) were aseptically withdrawn in plain vacutainer tubes from all studied groups. The samples were left to clot for 4 h at room temperature and centrifuged at ∼1000 g for 15 min. The clear sera were kept frozen at −80°C. Repeated freeze–thaw cycles were avoided.

    Quantification of interleukin-18 and vascular endothelial growth factor serum levels

    IL-18 and VEGF serum levels were measured by ELISA kit (Boster Biological Technology, Pleasanton, California, USA). Monoclonal antibodies from mouse specific for IL-18 and VEGF had been precoated onto 96-well plates. Standards (Escherichia coli; Immunogenic sequence: Y33-D197 for IL-18 and sf21, A27-R191 for VEGF) and test samples were added to the wells, and biotinylated detection polyclonal antibodies from goat specific for IL-18 and VEGF were added subsequently, which was followed by washing with PBS or tris-buffered saline buffer. Avidin–biotin–peroxidase complex was added, and unbound conjugates were washed away with PBS or tris-buffered saline buffer. Horseradish peroxidase substrate tetramethylbenzidine was used to visualize horseradish peroxidase enzymatic reaction.

    Statistical analysis

    Data collected were tabulated and analyzed by statistical package for the social sciences (SPSS, version 20; SPSS Inc., Chicago, Illinois, USA) on IBM personal computer. The following statistics were applied: descriptive statistics included percentage, mean, SD, and range, and analytic statistics included χ2-test, Fisher's exact test, Student's t-test, Mann–Whitney test, analysis of variance (f) test, Kruskal–Wallis test, post-hoc test, and the receiver operating characteristic (ROC) curves. P value less than 0.05 was considered to be significant. Spearman's correlation coefficient (r) was used to measure the relation between two quantitative variables.


      Results Top


    The mean age was 55.9 ± 11.2 years, with the highest mean age in diabetic patients without viral hepatitis (63.6 ± 3.95 years) and the lowest mean age in the control group (49.0 ± 11.6 years). There was a highly statistically significant difference between the studied groups regarding the age (P = 0.001). The percentage of patients on HD among the studied groups was statistically more in male (63.5%) than female (36.5%). There was a highly statistically significant difference between group I and III regarding viral infections (HCV and HCV/HBV) (P = 0.001). Moreover, there was a highly statistically significant difference between the studied groups regarding the past history of blood transfusion (P = 0.001), as it was higher in patients with viral hepatitis than others. There was a significant difference between groups I and II regarding the type of diabetes (P = 0.037), whereas no significant difference was seen between the studied groups regarding the duration of dialysis, smoking, residence, the treatment of diabetes, and mortality (P > 0.05) [Table 1].
    Table 1: Demographic characteristics and comorbidities of the studied groups

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    Regarding Hb, the mean ± SD in groups I and III (11.6 ± 2.11 and 9.80 ± 1.39, respectively) was higher than in groups II and IV. The mean ± SD of WBCs in group IV (8.14 ± 1.42) was higher than other groups. The mean ± SD of platelet in groups I and III (167.3 ± 71.5 and 150 ± 59.3, respectively) was significantly lower than group IV. The mean ± SD of serum iron in the groups I, II, and III (84.4 ± 381, 87.3 ± 40.5 and 81.0 ± 29.6, respectively) was lower than group IV. The mean ± SD of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in group III was higher than in groups I, II, and IV [Figure 1].
    Figure 1: Mean hemoglobin, white blood cells, platelet, iron, alanine aminotransferase, and aspartate aminotransferase among the studied groups. ALT, alanine aminotransferase; AST, aspartate aminotransferase; Hb, hemoglobin; WBC, white blood cell.

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    Regarding IL-18, all the patients in groups I and II had a detectable level of IL-18, but it was detected in only 44% of patients in group III. For VEGF, all patients in groups II and III had detectable levels of VEGF, whereas it was detected in 80% of patients of group I. IL-18 and VEGF were not detected in control group [Table 2].
    Table 2: Prevalence and mean values of interleukin-18 and vascular endothelial growth factor in pg/ml among the studied groups

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    A highly significant positive correlation was detected between Hb and RBS and the serum level of IL-18 (P = 0.002 and 0.001, respectively). On the contrary, a significant negative correlation was detected in urea, ALT, and AST (P = 0.048, 0.009, and 0.001, respectively) [Table 3].
    Table 3: Pearson's correlation between the serum level of interleukin-18 in pg/ml and serum levels of vascular endothelial growth factor and laboratory investigations among the studied groups

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    A significant positive correlation was detected between urea, ALT, and AST and serum level of VEGF (P = 0.001), whereas a significant negative correlation was in Hb, and RBS (P = 0.013 and 0.001, respectively). On the contrary, there was no relation between age, duration of dialysis, WBC, platelet, serum iron, creatinine, Ca, and phosphorus and serum level of VEGF (P > 0.05) [Table 3].

    In our study, the ROC curve was used to find out the best cutoff points of IL-18 and VEGF in cases of ESRD. IL-18 level at a cutoff of 392 pg/ml had the sensitivity of 81%, the specificity of 100%, positive predictive value (PPV) of 100%, negative predictive value (NPV) of 60%, and accuracy of 85% in detection. VEGF level at a cutoff value of 255.5 pg/ml had the sensitivity of 93%, the specificity of 100%, PPV of 100%, NPV of 81%, and accuracy of 95% in detection [Table 4].
    Table 4: Diagnostic validity of interleukin-18 and vascular endothelial growth factor

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    The mortality rate was 6.6 and 7.1% in patients with IL-18 more than 392 pg/ml and VEGF more than 255.5 pg/ml, respectively [Table 5].
    Table 5: Mortality in the studied patients who were divided into two groups based on the cutoff values of interleukin-18 and vascular endothelial growth factor serum concentrations

    Click here to view



      Discussion Top


    DM is the leading cause of chronic renal failure associated with high level of the inflammatory mediators and is a growing cause of morbidity and mortality. Approximately 31–40% of patients with DM evolve to DN[11]. Viral hepatitis is a liver inflammation with high levels of inflammatory cytokines which may lead to renal damage by a complex of circulating antibodies[12].

    Chronic kidney disease progresses more slowly in women than in men which may be because of the effect of estrogen[13]. This was approved in this study as the percentage of HD in males was more than in female patients. The highest mean age was found in diabetic patients on HD without viral hepatitis (63.6 ± 3.95). This was in agreement with Vijayan et al.[14] who found thatdiabetic patients had higher ages, compared with those with other diseases. Perhaps it was because of decreased exercise trend, gained weight with the age, and decreased efficiency of the cells function.

    Increase in the incidence of type 2 diabetes (T2D) than type 1 diabetes was detected among the studied groups. Similar result was reported by Harvey[15], in Europe, who found increased incidence of nephropathy in patients with T2D but the excess in end-stage renal failure is more disproportional.

    In the current study, the prevalence of HCV infection in diabetic groups was 92%, which was higher than in nondiabetics (48%). This was in agreement with Abdel Aziz et al.[16], in Egypt, who found the prevalence rate of HCV infection among diabetics was 35%, and it was significantly higher than control group. The prevalence of HCV alone (70%) was higher than HCV/HBV coinfection (30%) among patients with HD. The same result was reported by Perumal et al.[17], who showed higher HCV prevalence (15%) than HBV (6%) and HBV/HCV coinfection (2%) among patients with HD. Thabet et al.[18] in Yemen showed significant higher prevalence of HCV than HBV among patients with T2D.

    The current study showed high significant increase of the percentage of blood transfusion in the groups with hepatitis viral infection than other groups. Malhotra et al.[19], in India, found that the risk of viral hepatitis coinfection was greater among patients with chronic renal failure owing to the high frequency of blood transfusions or its products and extracorporeal circulation during HD. There was no significant difference among the studied groups regarding the duration of dialysis and smoking as risk factors. This was similar to Chang et al.[20], who did not show HD duration to be a significant risk factor among the studied groups.

    The mean Hb values in patients with viral hepatitis with and without diabetes were higher than those without viral hepatitis. This might be because of the secretion of erythropoietin from regenerating liver cells or increased iron metabolism[21]. The same result was observed by Fouad et al.[22] in Egypt, who found the mean value of Hb in patients with HCV on maintenance HD (11.4 ± 1.3) was significantly higher than patients without viral infection (8.8 ± 1.2) and both HBV/HCV coinfection (9.0 ± 1.3).

    Patients on maintenance HD have high incidence of various types of infections owing to impaired cellular immunity, neutrophil function, and alteration of microbial flora as uremic or dialysis pericarditis[23]. This fact may explain leukocytosis in the control group. Several factors cause thrombocytopenia in patients with chronic liver disease with HCV like immune dysfunction, hepatic fibrosis or cirrhosis, hypersplenism, bone marrow suppression, and low thrombopoietin levels or activity. This fact emerged in our study, as the platelets count in patients of groups I and III were significantly lower than those in the control group. Similar results were noted byFouad et al.[22].

    Our study approved the fact that T2D is frequently associated with high levels of serum ferritin, as serum iron was significantly higher in the studied groups than in the control group; similarly, Kundu et al.[24] in India and Fouad et al.[22] found that the diabetics and patients with HCV on HD had higher serum iron levels than the controls.

    The present study showed highly significant increase of ALT and AST levels in patients with viral hepatitis compared with those without viral hepatitis. This was in agreement with Sabry et al.[25], who observed that HCV-infected groups had higher levels of ALT levels than groups without viral infection and Fouad et al.[22] showed increased levels of ALT and AST inpatients with HCV infection on HD than non viral hepatitis infected patients reflects the hepatic injury.

    According to the present study, there was highly significant increase of IL-18 serum levels in all studied groups than the control group. In China, Wong et al.[6] reported that IL-18 was higher in patients with DN than the patients without DN. Moreover, El-Sherif et al.[26]showed that serum levels of IL-18 were significantly higher in patients with chronic HCV than healthy controls as IL-18 is a proinflammatory cytokine that is upregulated in HCV infection.

    All diabetic patients with and without viral hepatitis (100%) in this study had a detectable level of IL-18. Fujita et al.[5] in Japan and Liu et al.[27] in China demonstrated that there was an elevation of IL-18 mRNA and protein in urine and serum of patients with T2D, which supports the use of cytokines as markers that mirror the progression of microinflammation and incidence of DN.

    This study showed highly significant increase in VEGF serum level among the studied groups compared with the control. Atta et al.[28], in Egypt, found that patients with HCV had significantly higher plasma VEGF levels than control and Shao et al.[29], in China, found that VEGF in patients with diabetic kidney disease (DKD) was significantly higher than in the controls. VEGF serum level was statistically significant higher in the group with viral hepatitis without diabetes than those with diabetes.

    In the current study, 100% of diabetic patients without viral hepatitis had detectable levels of serum VEGF compared with the control. This was in agreement withShao et al.[29], in China, who found patients with DKD had significantly higher VEGF levels than nondiabetics as controls. Overall, 80% of patients with viral hepatitis with diabetes (group I) and 100% of viral hepatitis patients without diabetes (group III) had detectable levels of serum VEGF. There is an abnormal angiogenesis with elevated level of VEGF in DN[30]. Moreover, the induction of HCV core protein expression enhances the transcriptional level and amount of hypoxia-inducible factor 1α that stimulates angiogenesis, including VEGF[31]. This was in agreement with Abd-El-Moety et al.[32], in Egypt, who noticed significant increased VEGF serum level in patients with chronic hepatitis C infection with nephropathy than those without in the control group.

    In the present study, there was a significant increase in the mean of IL-18 serum level in patients with HCV than in patients with HCV/HBV coinfection, whereas the opposite was seen with VEGF. This result was in agreement with Falasca et al.[33], who showed plasma IL-18 levels were higher in patients with HCV than in those with HBV or in the controls, and Abdel Mohsen et al.[10], who found significantly higher VEGF levels in patients with HBV than those with HCV.

    In the present study, there was a positive correlation between Hb and RBS and IL-18 serum levels. This was in agreement with Esposito et al.[34], who detected that hyperglycemia produces an acute rise of IL-18 concentrations. Moreover, a positive correlation was found between blood urea, ALT, and AST and serum VEGF. Similar result was reported by Lin et al.[35]. However, a negative correlation was found between Hb and VEGF serum level. Adams et al.[36] reported that low Hb level often reflect further advanced disease; this may be associated with hypoxia-induced VEGF expression, with the reduction in Hb, mirroring hypoxia.

    On constructing the ROC curve, the best cutoff value of IL-18 for patients on HD was 392 pg/ml. Serums IL-18 levels showed sensitivity of 81% and a specificity of 100%, with a PPV of 100%. For VEGF, the best cutoff value was 255.5 pg/ml. Serum VEGF levels showed sensitivity of 93% and a specificity of 100% with a PPV of 100%. High sensitivity and specificity of these cutoff points were expressed in the results that have been created on its basis.

    IL-18 and VEGF levels above the cutoff value exhibited increased number of deaths which suggests that IL-18 and VEGF may be predictive factors of mortality in patients subjected to HD[27].


      Conclusion Top


    From this study, we can conclude that IL-18 serum levels increased significantly in patients with DN and viral hepatitis, so it could have an important role in the initiation, development, and progression of nephropathy in diabetics and patients infected with viral hepatitis. VEGF may be considered a predictive factor for progression of the renal condition, with viral hepatitis, through its positive correlation with some renal functions.

    Recommendations

    From this study, we can recommend the following: further research should be conducted on a more wider scale to show the effect of downregulation of IL-18 in the improvement of DKD, and the effect of therapeutic usage of VEGF-antagonist in reversing the state of nephropathy; moreover, significant advantages of serums IL-18 and VEGF in predicting mortality in diabetics and patients with viral hepatitis subjected to HD should be analyzed.

    Financial support and sponsorship

    Nil.

    Conflicts of interest

    There are no conflicts of interest.



     
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        Figures

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Abstract
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Patients and Methods
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