Saudi Journal of Kidney Diseases and Transplantation

: 2021  |  Volume : 32  |  Issue : 2  |  Page : 341--347

Using urinary Interleukin-18 as a potential marker for early detection of acute kidney injury in intensive care unit

Riyadh M A. Al-Saegh1, MA Mohanad2, Noor Jameel Khudhair3, Maha A R. Al-Mukhtar4,  
1 Department of Medicine, College of Medicine, University of Kerbala; Al Kafeel Center of Nephrology and Kidney Transplantation, Karbala, Iraq
2 Department of Microbiology, College of Medicine, University of Kerbala, Karbala, Iraq
3 Department of Laboratory, Al Kefeel Super Specialty Hospital, Karbala, Iraq
4 Department of Radiology, Al Kefeel Super Specialty Hospital, Karbala, Iraq

Correspondence Address:
Riyadh M A. Al-Saegh
Department of Medicine, College of Medicine, University of Kerbala, Karbala


Acute kidney injury (AKI) is a potentially life-threatening condition. The injury involves the generation of inflammatory mediators which contribute to the recruitment of leukocytes to the site of inflammation. As those inflammatory mediators are secreted directly into the urine, their detection in urine could serve as potential biomarkers for the diagnosis of early kidney injury. This is a prospective cross-sectional descriptive study. Urinary samples were collected from 170 subjects who were admitted to intensive care unit (ICU) at Alkafeel Super Speciality Hospital from September 2017 to June 2018. They were tested for urinary interleukin-18 (IL-18). Among 98 patients, 20 were excluded depending on exclusion criteria. Seventy-two cases in the control group were included. The urine samples were collected at 24, 48, and 72 h after admission to ICU. AKI was diagnosed according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria. The incidence rate of AKI among 78 patients who were admitted to ICU was 38.46%. Most of the patients with AKI belonged to stage 1 (80%) based on KDIGO guidelines2012. Urinary IL-18 levels were significantly higher (P <0.0001) in the AKI group in comparison with the non-AKI group. The result of receiver operating characteristic analysis showed that the higher area under the curve for urinary IL-18 was 0.946 measured at 24 h before development of AKI (P <0.000), with 87.5% sensitivity and 94.4% specificity. In addition, there was no significant difference of urinary IL-18 levels between the different causes of AKI. The results of the study indicate that urinary IL-18 has an excellent performance in predicting AKI in ICU patients.

How to cite this article:
A. Al-Saegh RM, Mohanad M A, Khudhair NJ, R. Al-Mukhtar MA. Using urinary Interleukin-18 as a potential marker for early detection of acute kidney injury in intensive care unit.Saudi J Kidney Dis Transpl 2021;32:341-347

How to cite this URL:
A. Al-Saegh RM, Mohanad M A, Khudhair NJ, R. Al-Mukhtar MA. Using urinary Interleukin-18 as a potential marker for early detection of acute kidney injury in intensive care unit. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 Jun 27 ];32:341-347
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Full Text


Acute kidney injury (AKI) is a potentially life-threatening condition, and it is associated with elevated short-term morbidity and mortality.[1],[2],[3] It is disabling complication of critical illnesses encountered in 25%–50% of intensive care unit (ICU) admissions.[4],[5] It continues to be a universal public health affecting 13.3 million people every year.[6] AKI is still the most common and most expensive kidney disease in hospitals,[7],[8] therefore, accurately predicting which patients are at the highest risk for AKI progression may allow more rapid and targeted treatment.[9] Clinically, yet there remain no effective indicators for early prediction and diagnosis of AKI, thereby resulting in a particularly high incidence rate and mortality rate of AKI due to delayed efficient treatment methods.[10] Numerous factors contribute to the development of AKI, whether by pathogen invasion during sepsis or organ damage via aseptic insult.[11] Exposures recognized to produce AKI in susceptible patients involve sepsis, heart failure, and major cardiac surgery in the critically patient.[5] AKI is more common in the elderly persons, because the aging patients population have a growing multi-morbidity.[7] Diabetes mellitus (DM) and systemic arterial hypertension (HTN) often coexist, and may modify the outcome of kidney disease.[12] AKI develops due to complex interactions between acute insults, including ischemic and toxic, and ultimate tissue damage, occurring over a cycle of minutes to days.[13] Renal inflammation is a common feature of human AKI.[14] The injury induces the generation of inflammatory media-tors such as cytokines and chemokines by tubular and endothelial cells which contribute to the recruitment of leukocytes into the kidneys.[15]

AKI does not confer any clinical symptoms, so it is difficult to define the time of the renal insult. Increases in serum creatinine (SCr) are associated with risk for mortality; therefore, kidney dysfunction should be captured for early detection and intervention.[16] Presently, AKI is diagnosed by measuring SCr, but this way has many drawbacks, including variability according to age, sex, and dependence on muscle mass, making it unsuitable for early diagnosis. There is also a delay between the occurrence of significant renal damage and increase in SCr level.[17],[18] Its role is questionable in early stages of AKI, as the patients are not in the steady state, hence SCr may not rise up to 48–72 h after the initial insult.[19] Furthermore, administration of drugs that inhibit tubular secretion of Cr or inhibit the renin–angiotensin–aldosterone system can lead to increases in SCr concentrations.[20]

In contrast to SCr, interleukin-18 (IL-18) is a pro-inflammatory cytokine, produced by immune and nonimmune cells, and is excreted in the urine following ischemic proximal tubule injury. Interleukin 18 level increases by several folds in patients who develop kidney injury.[21] IL-18 exhibits characteristics of other pro-inflammatory cytokines, such as increases in cell adhesion molecules, nitric oxide synthesis, and chemokine production.[22] In addition,IL18 induces uremic symptoms secondary to the accumulation of nitrogenous waste substances in the blood.[23] The objectives of the current study are to explore the prognostic value of urinary IL-18 in critically ill patients admitted to ICU in early detection of AKI.


Study design and subjects

This is a prospective observational study in medical intensive care and surgical ICUs of Alkafeel Super Specialty Hospital, Holy Karbala, Iraq, from October 24, 2017, to June 20, 2018. Among 98 patients, 20 patients were excluded and the other 78 patients were included in the study with 72 cases as a control group. All patients had at least one or more predisposing factors for AKI. The urine samples were collected at 24, 48, and 72 h after admission to ICU. The urine samples were stored at -30°C to be tested for IL-18 later on. The patients were monitored for the development of AKI. AKI was diagnosed according to the latest definition of AKI provided by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines in 2012.[7] According to those criteria, the patients were diagnosed and divided into two groups, AKI group and non- AKI group. In addition to daily blood urea and SCr, several hematological and biochemical tests were done. IL-18 level was measured using ELISA technique (Elabscience E-EL-H0253, Texas, USA). One hundred microliters of urine sample were used for measurement of urinary IL-18. The assay was performed according to the manufacturer’s protocol.

Inclusion and exclusion criteria

Of the total of 98 patients, there are 46 have chronic comorbidities in addition to acute predisposing factors to cause AKI. These factors were DM, congestive heart failure, HTN, dehydration, stone and cancers, and advanced age. Acute predisposing factors were severe sepsis, stroke, trauma, high-risk surgery (acute cardiac surgery, including valvular or coronary artery bypass grafting and other vascular surgeries), and bleeding. Risk factors were evaluated at the time of screening, within 24 h of ICU admission. All patients had at least one or more predisposing factors for AKI. All patients were Iraqi citizens. Patients with age <18 years, patients who had experienced AKI before ICU admission and before cardiac surgery, patients who had undergone kidney transplantation, baseline SCr >1.2 mg/dL, patients on chronic dialysis, and patients with urinary tract infection were excluded from this study.[2]

Approval of ethical committee

The local ethical committees approved this study protocol.

 Statistical Analysis

The data of 190 subjects were entered and analyzed by using the IBM SPSS Statistics version 22.0 (IBM Corp., Armonk, NY, USA). The results were presented as mean ± standard deviation. Comparison between the two groups was done with independent sample t-test; ANOVA test was utilized in more than two groups. Categorical data were summarized using absolute values (percentage). The Chi-square test is used for categorical and qualitative variables. In this study, Pearson’s correlation coefficients were calculated between urinary IL-18 and blood urea and SCr levels. Receiver operating characteristic (ROC) curve was used to determine the sensitivity and specificity of urinary IL-18, and area under curve (AUC) for their predictive ability of urinary IL-18. Statistical significance was kept at P <0.05 concentration, and confidence interval was set at 95%.[24]


[Table 1] shows the characteristics of the ICU-admitted patients. The incidence rate of AKI among 78 patients who were admitted to ICU was 38.46% (n = 30), while the remaining 48 (61.5%) patients did not develop AKI. Most of the patients with AKI belonged to stage 1 (80%) based on KDIGO guidelines 2012, as shown in [Table 1]. The systolic and diastolic blood pressure was not significantly different between the two groups, as shown in [Table 1].{Table 1}

The reason for ICU admission was found to play a role in predicting AKI development, with a higher proportion of AKI developed in emergency cases (41.6%) than cases with elective surgeries (27.7%).

Urinary IL-18 levels were significantly higher (P <0.0001) in the AKI group in comparison with the non-AKI group. Thus, urinaryIL-18 was significantly associated with the development of AKI.

The result of ROC analysis in [Figure 1] that showed higher area under the curve (AUC) for urinary IL-18 [IL-18 = 0.946, 95% confidence interval (CI) = 0.899, 0.993] measured at 24 hours before development of AKI (P <0.000), with 87.5% sensitivity and 94.4% specificity, as shown in [Table 2].{Figure 1}{Table 2}


Patients with high probability of AKI were selected, in order to detect the significance of urinary IL-18 precisely in early detection of AKI and its prognosis in ICU patients.[25] This study confirms the high incidence of AKI in ICU patients, as seen in other studies.[19],[20],[26],[27] The patient population was critically ill patients with both medical and surgical conditions, as shown in [Table 1]. The risk factors used in this study for identification of AKI are consistent with previous AKI literature.[25],[28],[29]

Several studies explained that SCr is fluctuations significantly by nonrenal factors and it is unsuitable for early diagnosis.[2],[7],[10],[17],[19]

In contrast to creatinine, another study reported by Moledina et al suggested that IL-18, which is produced in proximal tubular cells in response to kidney injury and excreted in urine, has shown promise for diagnosing acute tubular injury.[30] The human study of Yamanishi et al[31]suggested that IL-18 in the urine is one of the early markers of renal tubular disease.[31] Urinary IL-18 level is very low physiologically and increases by several folds in patients who develop kidney injury.[31]

In this study, the concentration of urinary IL-18 showed statistically significant (P <0.001) elevations in urinary concentrations of IL-18, 24 h before development of AKI in the AKI group compared with the non-AKI group as shown in [Table 3]. In this study, urinary IL-18 showed an earlier predictive role for AKI, compared with the SCr typically used to diagnose AKI. Furthermore, urinary IL-18 helps in the early management and individualization of treatment for AKI, facilitating patient counseling. The temporal change in levels of the IL-18 is very important. The study reported by Liu et al had shown that urinary IL-18 level increased dramatically at 4–6 h, peaked at 12 h, and remained elevated up to 48 h after surgery.[24] In the present study, IL-18 levels at the time of ICU admission had positive significant correlations with SCr (r = 0.249, P = 0.028). This is similar to what have been found in the study obtained by Mohamed Ali et al[17] suggested that IL-18 has a positive significant correlation with SCr and this is attributed to the role of IL-18 in inducement of inflammation and immunity over its key cellular targets including macrophages and T cells which leads to inflammation and succeeding kidney injury.[17]{Table 3}

A number of prospective studies and meta- analyses have shown that urinary IL-18 can predict the clinical onset of AKI moderately well across a wide range of clinical settings, including critically ill patients and patients undergoing cardiac surgery. IL-18 is shown to peak early (0–24 h) after an insult to the kidneys.[32] Recently, Choudhary et al found that day 1 concentration of IL-18 was raised, while renal function was clinically manifesting as a reversible acute increase in SCr concentrations within 48 h.[19] The results of the study could be explained in part by the close relation between IL-18 and inflammation. Inflammation-related cells such as neutrophils and lymphocytes and reflected systemic responses to stress could release IL-18.[24]

The AUC for diagnosis of AKI was 0.946 for urinaryIL-18, considering that IL18 is a mediator of inflammation. A recent meta- analysis also supported our findings: the pooled AUC for IL-18 in prediction of AKI was 0.7 in all populations, and 0.66 in critical care setting. Our finding is in agreement with the literature obtained by Liu et al[24] that suggested the area under the curve of IL-18 (0.79). In a meta- analysis of 23 studies including various clinical settings of AKI, including after cardiac surgery and in ICU, AUC of urinary IL-18 to predict AKI was 0.70 (95% CI, 0.66–0.74).AKI, even if considered a mild or moderate stage, may result in increased morbidity and mortality.[18] Recently, Mishra et al,[2] Altu’ma et al,[3] and Choudhary et al[19] demonstrated that no significant alterations in biomarker level in relation to different AKI etiologies, indicating that a rise in levels is unaffected by the underlying pathology.[2],[19] Furthermore, the highest incidence of AKI in patients with age ≥50 was 59.9%, while in other patients, it was less frequent. From these results, it was observed that older patients are more likely to develop AKI because they accumulate arteriosclerosis, arterial HTN, DM, and heart failure. Physiologically, the elderly people are more susceptible to AKI.[12]

These studies suggest that the increased urinary IL-18 levels predict AKI, thus increasing the importance of early prediction that will help the diagnosis of AKI at the earliest stage. Therefore, urinary IL-18 is a reliable, accurate, simpler, easier alternative to SCr measurement, inexpensive and it has the advantage that it can be readily measured by commercially available ELISA kits. The availability of commercial kits can considerably hasten the development of the test for routine clinical use.

Conflict of interest: None declared.


1Schrezenmeier EV, Barasch J, Budde K, Westhoff T, Schmidt-Ott KM. Biomarkers in acute kidney injury – Pathophysiological basis and clinical performance. Acta Physiol (Oxf) 2017;219:554-72.
2Mishra OP, Rai AK, Srivastava P, et al. Predictive ability of urinary biomarkers for outcome in children with acute kidney injury. Pediatr Nephrol 2017;32:521-7.
3Altu’ma FJ, Dheyauldeen MH, Almukhtar MA, Al Jawad SY, Alsaegh R. The role of serum cystatin C in the early detection of contrast- induced nephropathy after coronary intervention. J Kidney 2017;3:154-9.
4Malhotra R, Kashani KB, Macedo E, et al. A risk prediction score for acute kidney injury in the intensive care unit. Nephrol Dial Transplant 2017;32:814-22.
5Alobaidi R, Basu RK, Goldstein SL, Bagshaw SM. Sepsis-associated acute kidney injury. Semin Nephrol 2015;35:2-11.
6ZukA, Bonventre JV. Acute kidney injury. Annu Rev Med 2016;67:293-307.
7Bienholz A, Wilde B, Kribben A. From the nephrologist’s point of view: Diversity of causes and clinical features of acute kidney injury. Clin Kidney J 2015;8:405-14.
8Sawhney S, Marks A, Fluck N, Levin A, Prescott G, Black C. Intermediate and long-term outcomes of survivors of acute kidney injury episodes: A large population-based cohort study. Am J Kidney Dis 2017;69:18-28.
9Belcher JM, Garcia-Tsao G, Sanyal AJ, et al. Urinary biomarkers and progression of AKI in patients with cirrhosis. Clin J Am Soc Nephrol 2014;9:1857-67.
10Wang C, Zhang J, Han J, Yang Q, Liu J, Liang B. The level of urinary IL-18 in acute kidney injury after cardiopulmonary bypass. Exp Ther Med 2017;14:6047-51.
11Gonul Y, Ozsoy M, Kocak A, et al. Anti- oxidant, antiapoptotic and inflammatory effects of interleukin-18 binding protein on kidney damage induced by hepatic ischemia reperfusion. Am J Med Sci 2016;351:607-15.
12Rigonatto MC, Magro MC. Risk for acute kidney injury in primary health care. Rev Bras Enferm 2018;71:20-5.
13Hayashi H, Sato W, Kosugi T, et al. Efficacy of urinary midkine as a biomarker in patients with acute kidney injury. Clin Exp Nephrol 2017;21: 597-607.
14Kinsey GR, Okusa MD. Role of leukocytes in the pathogenesis of acute kidney injury. Crit Care 2012;16:214.
15Akcay A, Nguyen Q, Edelstein CL. Mediators of inflammation in acute kidney injury. Mediators Inflamm 2009;2009:137072.
16Singbartl K, Kellum JA. AKI in the ICU: Definition, epidemiology, risk stratification, and outcomes. Kidney Int 2012;81:819-25.
17Mohamed Ali OS, Elshaer SS, Anwar HM, Zohni MS. Relevance of cystatin-C, N-acetylglucosaminidase, and Interleukin-18 with the diagnosis of acute kidney injury induced by cadmium in rats. J Biochem Mol Toxicol 2017;31:e21968.
18Arsalan M, Ungchusri E, Farkas R, et al. Novel renal biomarker evaluation for early detection of acute kidney injury after transcatheter aortic valve implantation. Proc (Bayl Univ Med Cent) 2018;31:171-6.
19Choudhary A, Basu S, Dey SK, Rout JK, Das RK, Dey RK. Association and prognostic value of serum cystatin C, IL-18 and uric acid in urological patients with acute kidney injury. Clin Chim Acta 2018;482:144-8.
20Puthumana J, Ariza X, Belcher JM, Graupera I, Ginès P, Parikh CR. Urine interleukin 18 and lipocalin 2 are biomarkers of acute tubular necrosis in patients with cirrhosis: A systematic review and meta-analysis. Clin Gastroenterol Hepatol 2017;15:1003-13.e3.
21Laws RL, Brooks DR, Amador JJ, et al. Biomarkers of kidney injury among Nicaraguan sugarcane workers. Am J Kidney Dis 2016;67: 209-17.
22Dinarello CA, Novick D, Kim S, Kaplanski G. Interleukin-18 and IL-18 binding protein. Front Immunol 2013;4:289.
23Beker BM, Corleto MG, Fieiras C, Musso CG. Novel acute kidney injury biomarkers: Their characteristics, utility and concerns. Int Urol Nephrol 2018;50:705-13.
24Liu Y, Guo W, Zhang J, et al. Urinary interleukin 18 for detection of acute kidney injury: A meta-analysis. Am J Kidney Dis 2013;62:1058-67.
25IBM Statistics for Macintosh Version 25.0. Armonk, NY: IBM Cor; 2017.
26Bouchard J, Acharya A, Cerda J, et al. A prospective international multicenter study of AKI in the intensive care unit. Clin J Am Soc Nephrol 2015;10:1324-31.
27Kellum JA, Sileanu FE, Murugan R, Lucko N, Shaw AD, Clermont G. Classifying AKI by urine output versus serum creatinine level. J Am Soc Nephrol 2015;26:2231-8.
28Basu RK, Wang Y, Wong HR, Chawla LS, Wheeler DS, Goldstein SL. Incorporation of biomarkers with the renal angina index for prediction of severe AKI in critically ill children. Clin J Am Soc Nephrol 2014;9:654-62.
29Joung KW, Jo JY, Kim WJ, et al. Association of preoperative uric acid and acute kidney injury following cardiovascular surgery. J Cardiothorac Vasc Anesth 2014;28:1440-7.
30Moledina DG, Hall IE, Thiessen-Philbrook H, et al. Performance of serum creatinine and kidney injury biomarkers for diagnosing histologic acute tubular injury. Am J Kidney Dis 2017;70:807-16.
31Yamanishi K, Mukai K, Hashimoto T, et al. Physiological and molecular effects of interleukin-18 administration on the mouse kidney. J Transl Med 2018;16:51.
32Nisula S, Yang R, Poukkanen M, et al. Predictive value of urine interleukin-18 in the evolution and outcome of acute kidney injury in critically ill adult patients. Br J Anaesth 2015;114:460-8.
33Al-Tu’ma FJ, Dheyauldeen MH, Al-Saegh RM. Measurement of urinary kidney injury molecule-1 as a predictive biomarker of contrast-induced acute kidney injury. J Contemp Med Sci 2017;3:178-81.