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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2020  |  Volume : 31  |  Issue : 6  |  Page : 1206-1216
Interleukin 18 as a new inflammatory mediator in left ventricular hypertrophy in children with end-stage renal disease

1 Department of Pediatric, Pediatric Nephrology and Dialysis Unit, Faculty of Medicine, Assiut University, Assiut, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt
3 Department of Medical Biochemistry, Faculty of Medicine, Assiut University, Assiut, Egypt
4 Department of Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt

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Date of Web Publication29-Jan-2021


Left ventricular hypertrophy (LVH) represents an important determinant of increased cardiovascular morbidity and mortality (CV) in end-stage renal disease (ESRD) patients. The role of inflammatory markers in pathogenesis of LVH in children with ESRD is not fully described. The aim of this study is to evaluate relation of some inflammatory markers [as hs C-reactive protein (hsCRP) and interleukin (IL) 18] with LVH in children with ESRD on regular hemodialysis (HD). This is a cross-sectional study performed on 50 children on regular HD. Demographic data were recorded. Echocardiography was performed at baseline to determine those with LVH. Biochemical parameters: hemoglobin (HB), hsCRP, IL 18, phosphorus, calcium, serum albumin, and lipid profile were evaluated and correlated with LVH. Data were analyzed using Student’s t-test, and logistic regression to determine the relationship between LVH and other variables. LVH was present in 33 (66%) participants. Mean left ventricular mass index was 56.88 ± 22.23 g/m.2.7 Concentric remodeling, concentric hypertrophy, and eccentric hypertrophy were present in 4%, 22%, and 44% of the participants. In univariate analysis, children with LVH had significantly lower levels of HB and serum albumin but higher levels of hsCRP, and IL 18 compared to those without LVH. On multivariate analysis: only hsCRP, and IL 18 were significantly associated with LVH. This study shows that elevated hsCRP and IL-18 are independent determinants of LVH in HD children. Understanding the role of inflammatory molecules in the pathogenesis of LVH in ESRD is important for prediction of high-risk group and implementation of targeted anti-inflammatory therapies.

How to cite this article:
Badawy A, Nigm DA, Ezzat GM, Gamal Y. Interleukin 18 as a new inflammatory mediator in left ventricular hypertrophy in children with end-stage renal disease. Saudi J Kidney Dis Transpl 2020;31:1206-16

How to cite this URL:
Badawy A, Nigm DA, Ezzat GM, Gamal Y. Interleukin 18 as a new inflammatory mediator in left ventricular hypertrophy in children with end-stage renal disease. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2021 Dec 4];31:1206-16. Available from: https://www.sjkdt.org/text.asp?2020/31/6/1206/308329

   Introduction Top

Cardiovascular disease (CVD) is an important issue in children with end-stage renal disease (ESRD) with an estimated 10-to 100-fold increased risk of CV mortality than their age-matched peers.[1],[2] Thus, understanding the mechanisms involved in CVD is considered a significant issue in managing those patients to allow early identification of high-risk group and to optimize their management. Left ventricular hypertrophy (LVH) is considered to be responsible for lethal cardiac consequences such as decrease in coronary reserve and arrhythmias, where increased left ventricular mass index (LVMI) represents an important predictor of increased cardiovascular mortality in chronic kidney disease (CKD) patients.[3] Inflammation is an early event in cardiac stress situations such as pressure and volume overload, and it involves increased release of many cytokines.[4] Among these cytokines, increased interleukin (IL)-18 level was found to be associated with higher rate of hospitalization in dialysis patients, possibly, through CV mechanisms.[4] Evidence from the experimental and clinical studies supports that IL-18 is intimately related to progression of atherosclerosis.[5],[ Moreover, increased IL-18 was found to aggravate cardiac remodeling and contractile function in animal models,[7] where daily administration of IL-18 leads to myocardial dysfunction in healthy mice.[8] In children, hard end points (such as stroke or CV death) are rarely evaluated. Hence, surrogate end points, such as LVH, are more important to be evaluated.[9] Identifying the biological pathways that mediate LVH in uremic children is important and has significant clinical and therapeutic implications. There are few studies on the relation between inflammatory markers and LVH in children suffering ESRD, with IL-18 has not yet been studied in those patients. The aim of the present work is to evaluate the occurrence of LVH in children with ESRD on regular HD and its relation with some inflammatory markers (as hs-CRP, IL-18).

   Patients and Method Top

This study involved fifty children who were on long-term regular hemodialysis (HD) for >6 months in Pediatric Nephrology and Dialysis Unit at Assuit University Children Hospital. At the time of the study, whole number of patients attending the unit for regular HD were 71. Only 50 patients were eligible for inclusion in this study. Inclusion criteria were as follow: age <18 years old, regular HD for at least six months, dry weight was relatively stable, and arteriovenous fistula was used for performance of HD. The age of participating patients ranged from five to 16 years. Patients had received HD three times a week for 4 h each with standard bicarbonate-containing dialysate under standard heparinization. Fresenius 4008-B machines were used with polysulfone high flux filters, pediatric lines, and containing a diasafe device for water pureness. We excluded patients with diabetes, rhythm or conduction abnormality, valvular heart disease, and patients with evidence of infection within the past four weeks of time of enrollment in the study. Clinical characteristics were collected by careful history and examination including height, weight, and blood pressure (BP) measurements: height was measured to the nearest 1.0 cm and weight to the nearest 0.1 kg. Blood pressure was measured in the right arm, with the subject in a relaxed, sitting position. The average of three measurements with a mercury sphygmo-manometer was used for all subjects. It was measured 30 min after midweek HD session was finished, using the nonarteriovenous fistula arm. The mean of blood pressure measured during four last weeks before echo-cardiography was registered. Antihypertensive medications were recorded.

The study was approved by the Institutional Review Board of the Faculty of Medicine, Assiut University. An informed written consent in accordance with Assiut University Ethical Committee guidelines was taken from guardians of all cases.

Sampling and processing

Blood samples were collected from patients who agreed to participate in the study after overnight 12–14 h fasting before midweek session, one week before echocardiography. Five milliliters of blood was obtained from each subject and was divided into ethylenediaminetetraacetic acid tube (2.0 mL) and plain tube (3.0 mL). Complete blood count (CBC) was done on the same day of collection. Serum samples were stored at -20°C until the time of performing the analysis. For all patients, the following investigations were done:

  • CBC: On CELL-DYN 3700
  • Serum urea and creatinine: On Siemens Dimension RL Max
  • hs C-reactive protein (hs CRP): On BN Prospec
  • Serum IL-18 levels were analyzed by ELISA kits according to the manufacturer’s protocols [Human IL-18 ELISA reagent kit (Elab Science), Hongshan district, Wuhai province, China]. The results were represented as pg/mL. All samples were tested in duplicates
  • Lipid profile: On Siemens Dimension RL Max, total cholesterol and triglyceride concentrations were estimated using enzymatic methods (CHOD-PAP and GPO-PAP, respectively; Roche Diagnostics, Mannheim, Germany). HDL cholesterol was determined after precipitation with phosphotungstic acid/magnesium chloride. Low-density lipoprotein (LDL) cholesterol was measured directly with a commercially available direct LDL-Cassay (LDL-C Plus assay; Roche Diagnostics).

Echocardiographic parameters

Echocardiography was done within 2 h–24 h after the midweek dialysis session by experienced echo cardiologist in Cardiology Unit at Assiut University Hospital for Children. Two-dimensionally guided M-mode echocardiography was used. Left ventricular internal dimension (LVID) and interventricular septal and posterior wall thickness (IVST and PWT) were measured at end-diastole and end-systole, according to the American Society of Echocardiography guidelines. LVH was determined according to LVMI, which was calculated using the formula of Devereux et al,[10] modified in accordance with the recommendations of the American Society of Echocardiography:[11] LV mass (g) = 0.8 (1.04 [(LVIDD + PWTD + IVSTD)3- (LVIDD)3] + 0.6). Where,

LVIDD = Left ventricular internal diameter in diastole.

PWTD = Posterior wall thickness in diastole.

IVSTD = Interventricularseptal thickness in diastole.

LVM was normalized for height in meters raised to the allometric power 2.7, to linearize the relation between LVM and height[12] and expressed in g/m2.7 as LVMI. LVH was defined as LVMI exceeding the 95th percentile for gender and age in normal children and adolescents provided by Daniels et al[13] and Khoury et al,[14] but after replacement of chronological age by height age, i.e., the age of a child of the same height growing at the 50th height percentile.[12] The relative wall thickness (RWT) was calculated as posterior wall thickness plus septal thickness, divided by the left ventricular internal diameter RWT was normalized using the formula RWTma = RWTm -0.005 × (age-10) as proposed by de Simone et al,[12] but using height age rather than chronological age to account for growth retardation. The 95th percentile of the normalized RWT was used as cutoff value for defining concentric geometry.[12] Based on the LVMI and normalized RWT measurements, four geometric patterns were described:

  • Normal (normal LVMI and normal RWT)
  • Concentric remodeling (normal LVMI and increased RWT)
  • Eccentric hypertrophy (abnormally increased LVMI and normal RWT)
  • Concentric hypertrophy (abnormally increased LVMI and increased RWT).[15]

   Statistical Analysis Top

The data were analyzed using IBM SPSS Statistics for Windows version 24.0 (IBM Corp., Armonk, NY, USA) and Microsoft Excel 2016 (Microsoft Co., USA). The data were checked for normal distribution by the Kolmogorov–Smirnoff test. The mean and standard deviation were used as descriptive value for quantitative data, while numbers and percentages were used to describe qualitative data. Student’s t-test was used to compare the means between groups. Chi-squared test was used to compare proportions or percentages of qualitative data. Univariate and multivariate regression analysis was done to predict the possible independent risk factors for increased LVMI among ESRD. At first, univariate analysis was performed on the following parameters: age, sex, duration of HD, body mass index, systolic and diastolic BP, comorbidities, hs-CRP, serum albumin, serum creatinine, blood urea, lipid profile, hemoglobin (HB) level, serum calcium, serum phosphorus, and IL 18. Then, variables that showed significant P value (P <0.05) by univariate analysis were utilized for multivariate regression analysis.

For all these tests, the level of significance (P-value) can be explained as:

  • No significance P >0.05
  • Significance P <0.05
  • High significance P <0.001.

   Results Top

The present work has included 50 children (24 male and 26 female patients) on regular HD. The mean age was 12.80 ± 3.86 years, and the mean time of dialysis vintage was 23.96 ± 17.65 months. Among diseases leading to the development of CKD in the examined children, the highest prevalence was congenital abnormalities of the kidney and urinary tract, followed by nephronophthisis, then refluxing ureters, and finally other causes. Number of cases for each etiology are shown in [Table 1]. Cases with a history of glomerulonephritis as an etiology of renal failure were excluded from the study as it may be associated with abnormal inflammatory milieu of the patient.
Table 1: Number and percent of the leading causes for the development of chronic kidney disease in the studied cases.

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Demographic, clinical, echocardiographic, and laboratory characteristics of the studied cases are shown in [Table 2] and [Table 3], where LVH was present in 33 (66%) participants. Mean LVMI was 56.88 ± 22.23 g/m2.7. Concentric remodeling, concentric hypertrophy, and eccentric hypertrophy were present in two (4%), 11 (22%), and 22 (44%) of the participants, respectively.
Table 2: Demographic, clinical, and echocardiographic characteristics of the studied cases.

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Table 3: Laboratory characteristics of the studied cases.

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As shown in [Table 4], HD patients with and without LVH were not significantly different in age and gender. However, systolic, diastolic BP, duration of HD, and associated comorbidities as (heart failure, anemia, and RD) were significantly higher in patients with LVH in comparison with those without LVH. Children with LVH had significantly lower levels of HB and serum albumin but higher levels of hs-CRP and IL-18 compared to those without LVH. Parameters of lipid profile as well as serum Ca and phosphorus were not significantly different between both groups. Data are shown in [Table 5].
Table 4: Comparison of demographic and clinical data between cases with and without left ventricular hypertrophy.

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Table 5: Comparison of laboratory data between cases with and without left ventricular hypertrophy.

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In adjusted logistic regression analyses: systolic BP [odd’s ratio = 1.27 (95% Confidence intervals: 1.33-1.35), P <0.01], diastolic BP [odd’s ratio = 1.16 (95% Confidence intervals:1.03–1.30), P <0.014], duration of dialysis [odd’s ratio = 1.21 (95% confidence intervals: 1.36–1.41), P <0.02], hs-CRP [Odd’s ratio = 1.67 (95% Confidence intervals: 1.25–2.19), P <0.001], and IL-18 [Odd’s ratio = 1.78 (95% Confidence intervals: 1.31–2.41), P <0.001] were associated with LVH. HB level and serum albumin level were not significantly associated with LVH as shown in [Table 6].
Table 6: Adjusted logistic regression analysis for risk factors for left ventricular hypertrophy.

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   Discussion Top

CV events have accounted for up to 41% of all deaths in children with ESRD.[9] There are many determinants of CV morbidity and mortality in HD patients. Among these determinants, LVH has been described as a major risk factor.[16]

In the present work, 66 % of the children with ESRD were found to have LVH. This is in accordance with Bakkaloglu et al[9] and Bakkaloglu et al[17] who found LVH in 48% and 68%, respectively, of their studied uremic children on maintenance peritoneal dialysis. Studies about adult patients with ESRD showed that LVH was present in more than 75% by Foley et al[18] and London et al[19] and up to 87% in a study by Cafka et al.[20] Lower percent of LVH in children may be explained by shorter duration of the disease and HD in this young population. Duration of dialysis was found to be a determinant of increased LVMI in our work. In this study, eccentric left ventricular hypertrophy was the most frequent geometric model (44%) followed by concentric hypertrophy (22%) and then concentric remodeling (4%). This is similar to Adiele et al[21] study on children with ESRD, where eccentric LVH was predominant (33.3%) compared to concentric left ventricular hypertrophy (16.7%). Eccentric LVH is associated with volume over load and high cardiac output,[22] while concentric LVH occurs due to excessive pressure (hypertension) on the ventricular muscles with increased incidence of cardiac ischemia and sudden death.[23] Detection of the pattern of LV geometry is clinically relevant, because such pattern adversely affects prognosis, with higher risk of CV events with concentric LVH.[24] There are varying reports on whether eccentric or concentric LVH is more common in children with ESRD.[24] Generally, reports from the developed part of the world show that concentric hypertrophy is more common as they can afford chronic dialysis and ultra-filtration with resultant marked reduction in volume overload.[22] However, this is not an absolute finding as other authors in Europe and America documented predominance of eccentric LVH.[25]

In the present study, systolic and diastolic BP was found to be significant determinants of increased LVMI. This is in accordance with Bakkaloglu et al,[9] Drozdz et al,[26] Ruggenenti et al,[27] and Monfared et al.[28] Hypertension with volume overload or pressure overload can lead to left ventricular damage, hypertrophy, or ischemia which predispose to cardiac dilatation or dysfunction of cardiac pump. Myocardial hypertrophy leads to intermyo-cardial fibrosis, which can cause dysfunction of cardiac electric system and ventricular arrhythmia, progressive damage of contractility, and rise of myocardial stiffness, resulting in congestive heart failure.[20] This should receive special attention, because BP control could be an easy target to modulate ventricular hypertrophy and so CV morbidity in those uremic children. Better control of volume overload is important issue in this aspect through salt restriction, improving dialysis practice, and ultrafiltration rate to keep dry weight more or less constant. In addition, better control of pressure overload can be achieved through adjustment of antihypertensive drugs as much as possible in this young population. In the present work, duration of dialysis is another determinant of increased LVMI. This should encourage more advance in the pediatric renal transplant practice, especially preemptive one to help to avoid more CV risk.

As regard laboratory data in this work, hsCRP and IL-18 have significant relation with increased LVMI. Positive relation of hs-CRP with increased LVMI is in accordance with Cafka et al,[20] Monfared et al,[28] Zimmermann et al,[29] Nguyen-Khoa et al,[30] Park,[31] Wang et al[32] and Cottone et al.[33] However, Mostovaya et al[34] mentioned that hsCRP was not related to LVMI. All of these studies have described the relationship between hsCRP and LVH in adults. In children on maintenance peritoneal dialysis, Bakkaloglu et al[17] had demonstrated significant difference in hsCRP mean level between those with increased LVMI and those with normal LVMI. However, this is the first time to study such relationship in children on regular HD.

CKD leads to a chronic inflammatory condition which become more severe after initiation of hemodialysis (HD).[35] Such inflammation can lead to adverse left ventricular geometry by altering the equilibrium that regulates cell growth, apoptosis, phenotype, and matrix turnover of cardiac tissue.[36] In addition, cytokines promote cardiac remodeling by stimulating enhancing fetal gene expression and sarcomeric protein synthesis.[37]

The serum concentration of CRP reflects the activity of cytokine-mediated acute phase processes and is roughly proportional to the extent of tissue injury.[38] It specifically affects cell cycle and inflammatory process in cardiac myocytes.[39] This may explain its relation with increased LVMI. Many studies have focused on the use of hs-CRP in the detection of patients at increased risk for CV disease.[40],[41]

Elevation of IL-18 levels was associated with pressure overload and inflammatory states in animal models and was suggested to play a role in cardiac hypertrophy and remodeling in these models.[42] However, this is the first time up to our knowledge to correlate IL-18 with increased LVMI in human patients with ESRD. So, it is suggested that IL-18 play an important role in cardiac remodeling not only in animals but also in humans. Increased levels of circulating IL-18 have proved to be a strong and independent predictor of coronary artery disease and CV death.[6] Thus, it is suggested that IL-18 possibly causes LV dysfunction either indirectly by aggravating coronary atherosclerosis or directly by acting on cardiac myocytes to induce myocardial dysfunction.[8],[43]

In this work, serum albumin was significantly lower in group of increased LVMI than those with normal one. However, multivariate analysis failed to show significant relation. Drozdz et al[26] stated that albumin has correlated on univariate and multivariate analysis with LVMI in their cohort. Albumin is a negative acute-phase reactive protein and its synthesis is actively suppressed as a part of response to inflammation.[44] Hypoalbuminemia represents a well-known marker for cardiac morbidity in patients with ESRD. However, further studies on larger number of patients are needed to detect exact pathophysiology.

As regard HB level, it was found significantly lower in group of increased LVMI than those with normal LVMI. However, multivariate analysis failed to show significant relation. Anemia has been associated with LVH in most echocardiographic studies of adult renal patients. In addition, it was also reported to be a major contributor in cardiacmorbidity and mortality.[20],[45],[46]

Calcium and phosphorus levels show no significant association with LVMI in this work. This is in accordance with Cafka et al[20] However, this is in contrast with Achinger and Ayus[47] and Chue et al,[48] who demonstrated significant association between LVMI and levels of calcium and phosphorus in uremic patients.

Chronic pressure and volume overload in patients with ESRD lead to left ventricular wall stress, contributing to cardiomyopathy and left ventricular failure.[49] In addition, inappropriate activation of nonhemodynamic factors involved in oxidative stress, inflammation, fibrosis, the renin–angiotensin system, and collagen turnover leads to myocardial remodeling.[50] Profiling and correlating different biomarkers of these processes will allow for a better understanding of such non-hemodynamic factors. In addition, patients with significant markers of inflammation or evidence of increased LVMI should receive closer follow-up and early management of sources of malnutrition and inflammation. Control of inflammatory state in such patients may be achieved through proper adjustment of dialysis dose, proper choice of type of dialyzer membrane and modality of dialysis, careful BP control, and meticulous treatment of anemia and hypoalbuminemia. In conclusion, elevated hs-CRP and IL-18 are considered as independent determinants of LVH in HD children. Understanding the role of inflammatory molecules in the pathogenesis of LVH in ESRD is important for prediction of high-risk groups and implementation of targeted anti-inflammatory therapies. Further research on introduction of anti-inflammatory drugs in such patients may add benefit.

There are some limitations in the current study such as the small available sample size, monocentric experience of the study, and the single measurement of IL-18 and hsCRP at the time of echocardiography which did not reflect changes over time. In addition, levels of biomarkers had not been correlated with different geometric types of LVH because of small sample size. Further studies with larger sample size and more frequent follow-up are recommended to confirm such findings.

   Informed Consent Top

Informed written consent was obtained from guardians of all individual participants included in the study in accordance with Assiut University Ethical Committee guidelines.

   Ethical Approval Top

All procedures performed in the study were approved by Assiut University Ethical Committee and were in accordance with the 1964 Helsinki declaration and its later amendments.

Conflict of interest: None declared References

   References Top

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Correspondence Address:
Ahlam Badawy
Department of Pediatrics, Pediatric Nephrology and Dialysis Unit, Faculty of Medicine, Assuit University Children Hospital, Assuit University, Assiut
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DOI: 10.4103/1319-2442.308329

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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