Sensitivity And Specificity Of Urine Interleukin-18 as an Early Biomarker For Acute Kidney Injury

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1 Volume 2, Issue 4, Page No: Available online : Bio Sc Med 2(4) :20-29 Sensitivity And Specificity Of Urine Interleukin-18 as an Early Biomarker For Acute Kidney Injury F. Heru Irwanto1, Andi Miarta1, Theodorus1, Febri Jaya Gunawan1# 1 Departement of Anesthesiology and Intensive Care Medical Faculty Sriwijaya University/ General Hospital Mohammad Hoesin Palembang, Sumatera Selatan, Indonesia #Correspondence drfebrijayagunawan@gmail.com Received : August 28th 2018 Accepted : November 16th 2018 Abstract Background Incidence of AKI in intensive care unit patients reach 60-70%, and the mortality rate is about 60%. IL-18 is a proinflammatory cytokine which increased in endogenous inflammation process. Studies in human showed that IL-18 concentration increased prior to AKI. The aims of this research is to determine the sensitivity and specificity of Interleukin-18 urine examination as an early biomarker for acute kidney injury. Methods There re total of 66 subjects who met the inclusion criteria. All the subject were checked for the IL-18 urine level with Cloud Clone kit and creatinine serum were also checked 48 hours after admission. Results The results showed in the cut-off point of Pg/mL, urine IL-18 has a sensitivity of 54.3 % and specificity 83.9%, positive predictive value 79.17%, negative predictive value 61.9% and accuracy of 68.18% Conclusions IL-18 urine holds a promise as an early biomarker of AKI and more sensitive and specific as an early biomarker for AKI compared to creatinine serum. Key words : Acute Kidney Injury, Interleukin-18, sensitivity, spesificity Background Incidence of AKI in intensive care patients reaches 60-70%. Changes in serum creatinine values are not sensitive for early diagnose of AKI because serum creatinine takes hours to increase after kidney damage occurs. IL-18 is a proinflammatory cytokine that will increase during

2 inflammatory process. IL-18 levels will increase significantly in patients who experience pre-renal azotemia, urinary tract infections, chronic renal insufficiency, and nephrotic syndrome. Research shows IL-18 concentrations will increase due to AKI.1-3 According to Kidney Disease Improving Global Outcomes (KDIGO) 2012, AKI was defined as an increase in ccr to 26.5 µmol / L within 48 hours, or 1.5 times the initial value in 7 days. However, the guide uses urine output and scr values as staging criteria. In addition, because CSR is influenced by many factors and has low sensitivity and specificity for its relationship with AKI, it is very important to determine other early AKI biomarkers that are more sensitive, specific, and significant. Biomarkers that can be used for early diagnosis of AKI are Cystatin C, IL-18 (Interleukin-18), KIM-1 (Kidney Injury Molecule-1), L-FABP (Liver Fatty Acid Binding Protein), and NGAL (Neutrophil Gelatinase Associated Lipocalin ).4-6 IL-18, known as an inflammatory mediator, is produced by renal tubular epithelium and interstitial macrophages. IL-18 plays an active role in various kidney diseases, such as injury due to reperfusion, transplant rejection, and urinary tract infections. Levels of IL-18 are very physiologically low and increase several-fold in patients who experience AKI. Increased urine IL18 levels in AKI are partly derived from damaged tubules. In a cross-sectional study of humans, urine IL-18 levels increased significantly in patients with AKI compared with people with chronic, urinary tract infections. kidney disease, and nephrotic syndrome.7-10 Furthermore, urine IL-18 is easily measured through commercially available kits, and the tests are fast, reliable, accurate, and relatively inexpensive, thus facilitating practicality as a biomarker for patients with AKI. Methods This diagnostic test was carried out in the ICU, HCU and P1 general hospital of Dr. Mohammad Hoesin Palembang in June until the number of samples was fulfilled. A total of 66 samples were obtained that met the inclusion criteria. All samples were examined for urine IL-18 levels using a Cloud Clone kit and serum creatinine values were examined 48 hours after the patient admitted. The results of the study will be analyzed using the Receiver Operating Characteristic (ROC) curve with SPSS version 25 and MedCalc version 18.6.

3 Results This diagnostic test study had been carried out in the ICU, HCU, and P1 general hospitals of Dr. Mohammad Hoesin Palembang began in June 2018 until August 2018 with the aim of knowing the value of sensitivity and specificity of IL-18 examination compared with serum creatinine examination. The sample of the study was all patients who had just been treated in the ICU, HCU and P1 who met the inclusion and exclusion criteria. The number of samples was 66 samples that met the study inclusion and exclusion criteria. As long as the research continues until completion, no sample withdraws or drops out. From the results of the study it was found that out of 66 samples, 39 (59.1%) were male and 27 (40.9%) were female from 66 samples, the average age was ± with a median age of 50 years. The average age of the male subjects was ± with a median age of 58 years. The average age of female subjects was 47 ± and the median age was 49 years. Of the 66 samples, the majority of respondents were diagnosed with Cerebro Vascular Disease (CVD), which were 15 people (22.7%) followed by obstetrics, intracranial space occupying lession and post digestive surgery patient with 8 subjects each (12.1%). There were 30 people (45.5%) diagnosed with Non-AKI, and 36 subjects (54.5%) experiencing AKI where 22 subjects with a diagnosis of AKI stage 1 (33.3%), subjects with a diagnosis of AKI stage 2 as many as 6 subjects (9.1%) and subjects with a diagnosis of AKI stage 3 were 8 subjects (12.1%). There were 17 samples (77.27%) that had positive values both from the results of IL-18 and serum creatinine and as many as 26 samples (59.1%) which had negative values from both examinations.diagnostic test results in sensitivity, specificity, accuracy, positive likelihood ratio, negative likelihood ratio, positive predictive value, negative predictive value, likelihood ratio test, AUC (Area Under Curve), and reliability test. Analysis of the results using the ROC curve with SPSS version 25.0 software (IBM Corporation and Others, NY, USA) and Epicalc and MedCalc version 18.6 (MedCalc Software, Mariakerke, Belgium). The sensitivity in this study was 48.6% and the specificity in this study was 83.9% which means that IL-18 levels can specifically describe the diagnosis of AKI but are less sensitive.

4 The average value of sample serum creatinine was 2.03 mg / dl with an average value of male serum creatinine level of 1.26 mg / dl and the average value of serum sample creatinine in women was 2.56 mg / dl. From the group of patients with AKI, the mean serum creatinine level was 3.16 mg /dl compared with the group of non-aki patients with an average serum creatinine level of 0.67 mg /dl and the mean serum creatinine level of patients with AKI stage 1 was 1.2 mg / dl, patients with AKI stage 2 was 2.1 mg / dl, patients with AKI stage 3 were 9.2 mg / dl. Table 1. Diagnostic Value of IL-18 Urine Examination The mean value of urine IL-18 levels in the sample was Pg/mL with a mean urine IL-18 level of a male sample was pg / ml and mean urine IL-18 level of a female sample was Pg ml. From the group of patients with AKI, the mean value of urine IL-18 levels was Pg / ml compared with the group of non AKI patients with an average value of urine IL18 levels of Pg / ml. The average value of IL-18 levels the urine of patients with AKI stage 1 was Pg / ml, patients with AKI stage 2 were Pg / ml, patients with stage3 AKI were Pg / ml.

5 IL_ Sensitivity Sensitivity: 48.6 Specificity: 83.9 Criterion: > AUC = P = Specificity 100 Picture 1. ROC curve of IL-18 Urine DISCUSSION AKI is an independent predictor of mortality and length of hospital stay. Severe cases require expensive therapy which slows down therapy which will worsen kidney damage and increase the need of human and financial resources. In 2012, Kidney Disease Improving Global Outcomes (KDIGO) issued a new classification that combines RIFLE and AKIN criteria. KDIGO also defines AKI as an increase in serum creatinine 0.3 mg / dl or more for 48 hours, or an increase in serum creatinine 1.5 mg / dl or more in the last 7 days, or urine output <0.5 ml / kg / hour for 6 hours However, the guide uses urine output and scr values as staging criteria. In addition, because CSR is influenced by many factors and has low sensitivity and specificity for its

6 relationship with AKI, it is very important to determine other early AKI biomarkers that are more sensitive, specific, and significant. Markers that can be used for early diagnosis of AKI are Cystatin C, IL-18 (Interleukin-18), KIM-1 (Kidney Injury Molecule-1), L-FABP (Liver Fatty Acid Binding Protein), and NGAL (Neutrophil Gelatinase Associated Lipocalin ) IL-18 known as an inflammatory mediator, is produced by renal tubular epithelium and interstitial macrophages. IL-18 plays an active role in various kidney diseases, such as reperfusion injury, transplant rejection, and urinary tract infections. Levels of IL-18 are very physiologically low and increase several-fold in patients who experience AKI. Increased urine IL-18 levels in AKI are partly derived from damaged tubules In this study, based on the characteristics of the research subjects it can be seen that the sample of this study is heterogeneous. Research subjects who entered the ICU and HCU, as well as P1 were caused by a variety of medical, surgical, midwifery and neurology cases. The average age of 66 samples was 50 years. This result is the same as the Parikh study which also found an average age of AKI of 50 years with a male population of 52.2%, whereas in Chen's study, it was found that the average age of AKI was 60 years with 66% of men. This may be due to the diverse backgrounds of patients ranging from trauma cases that often occur at a young age to CVD which are more common in old age From 66 samples, 30 subjects (45.5%) diagnosed with Non-AKI, 22 subjects with stage 1 diagnosis of AKI (33.3%), 6 subjects with a diagnosis of AKI stage 2 (9.1 %) and 8 subjects with a diagnosis of AKI stage 3 (12.1%). From this data, the incidence of AKI in stage 1, stage 2 and stage 3 was 54.5%. This incidence is slightly different from the literature on the incidence of AKI in the HCU at 60-70%. The difference in incidence in this study may be due to differences in the number of samples. A pilot study was conducted to obtain an IL-18 cut-off value of> pg / ml which showed positive AKI. The cut-off in this study differs from the research conducted by Haase in 2008 which received a cut-off value of> 750 pg / ml, Endre in 2011 with a cut-off of 154 pg / ml and Doi in 2011 with a cut-off value pg / ml. This cut-off difference is due to the number of samples used as pilot studies. Based on bivariate analysis of the diagnostic values of AKI and IL-18, from 66 study samples 17 samples (77.27%) were found that had positive values both from the results of IL-18

7 and serum creatinine and 26 samples (59.1%) which had negative values from both checks. A total of 5 subjects (22.7%) showed false positives, and 18 subjects (40.9%) who showed false negatives. In this study also found that IL-18 had a sensitivity number of 48.6% and specificity of 83.9%, with an Odds ratio of (95% CI ). This number of odds ratios shows that when IL-18 was obtained> 495 Pg / ml the possibility of diagnosing AKI was times greater. The results of this study are similar to study, which proved that IL-18 can predict AKI with diagnostic odds ratios (OR) 5.1 with sensitivity and specific 0.51 and 0.79 respectively. Xin Lin also found that urine IL-18 levels in pediatric patients (18 years) were more effective in predicting AKI, with a diagnostic OR of compared to for the adult group (p = 0.334); subgroups of early predictive AKI time (12 hours) showed the highest diagnostic OR of 8,176 (95% CI 2,19130,507) among three subgroups Conclussion The incidence of AKI in patients treated in the ICU, HCU and P1 in general hospital of Dr. Mohammad Hoesin Palembang at 54.5%.. Urine IL-18 at levels> Pg / ml has a sensitivity of 48.6%, specificity 83.9%, positive predictive value 77.27%, and negative predictive value 59.09%. References 1. Dirac, PA. Acute Kidney Injury. The ICU Book, 4th ed., Philadelphia: Lippincott, Williams & Wilkins, 2014, pp Holt, NF. Renal Disease. Stoelting's Anesthesia and Coexisting Disease, 6th ed., Philadelphia: Saunders, 2012, pp GE, Morgan, Mikhail MS, et al. Renal Physiology & Anesthesia. Clinical Anesthesiology, 5th ed., McGraw-Hill Companies, Inc, 2013, pp SS, Waikar, and Liu KD. Diagnosis, Epidemiology and Outcomes of Acute Kidney Injury. CJASN, May 2008, cjasn.asnjournals.org/content/3/3/844.full.

8 5. Akcay, Ali, et al. Mediators of Inflammation in Acute Kidney Injury. Mediators of Inflammation, Hindawi, 21 Feb. 2010, doi: /2009/ KDIGO Clinical Practice guidelines for acute kidney injury. Kidney Int Suppl Ren, Hongqi, et al. Assessment of Urinary Kidney Injury Molecule-1 and Interleukin-18 in the Early Post-Burn Period to Predict Acute Kidney Injury for Various Degrees of Burn Injury. BMC Nephrology, BioMed Central, 18 Aug. 2015, bmcnephrol.biomedcentral.com/articles/ /s Lin, X, et al. Urine Interleukin-18 in Prediction of Acute Kidney Injury: a Systemic Review and Meta-Analysis. Journal of Nephrology., U.S. National Library of Medicine, Feb. 2015, 9. Liu, Yan Wei, et al. Urinary Interleukin 18 for Detection of Acute Kidney Injury; A MetaAnalysis. American Journal of Kidney Disease, vol. 2013;62(6): Ãnal, Ertekin Utku. Serum Interleukin-18 as an Early Marker of Acute Kidney Injury Following Open Heart Surgery. Turkish Journal of Thoracic and Cardiovascular Surgery, vol. 22(3): Han, W K, et al. Urinary Biomarkers in the Early Detection of Acute Kidney Injury after Cardiac Surgery. Clinical Journal of the American Society of Nephrology : CJASN., U.S. National Library of Medicine, May 2009, Zheng, Jianyong, et al. Comparison of Urinary Biomarkers for Early Detection of Acute Kidney Injury After Cardiopulmonary Bypass Surgery in Infants and Young Children. SpringerLink, Springer-Verlag, 3 Nov. 2012, link.springer.com/article/ /s Edelstein, C.l. Biomarkers in Acute Kidney Injury. Biomarkers of Kidney Disease, vol. 15, 2017, pp , doi: /b Nakamura, Akihiko, et al. Serum Interleukin-18 Levels Are Associated With Nephropathy and Atherosclerosis in Japanese Patients With Type 2 Diabetes. Diabetes Care, American Diabetes Association, 1 Dec. 2005, care.diabetesjournals.org/content/28/12/ Schrier, Robert W. Pathophysiology of Ischemic Acute Renal Injury. Diseases of the Kidney & Urinary Tract, vol. 2, Wolters Kluwer Health/Lippincott Williams & Wilkins, 2007, pp

9 16. Barash, Paul G. The Renal System and Anesthesia for Urologic Surgery. Clinical Anesthesia, 6th ed., Wolters Kluwer Health/Lippincott Williams & Wilkins, 2013, pp Roesli RM. Diagnosis dan Pengelolaan Gangguan Ginjal Akut. Edisi kedua. Jakarta: Puspa Swara; Hoste, Eric AJ, et al. RIFLE Criteria for Acute Kidney Injury Are Associated with Hospital Mortality in Critically Ill Patients: a Cohort Analysis. Critical Care, BioMed Central, 12 May 2006, ccforum.biomedcentral.com/articles/ /cc Bagshaw SM, George C, Dinu I, Bellomo R. A Multi-Centre Evaluation of the RIFLE criteria for Early Acute Kidney Injury in Critically Ill Patients. Nephrol Dial Transplant 2008;23: Ricci Z, Cruz DN, Ronco C. Classification and staging of acute kidney injury: beyond the RIFLE and AKIN criteria. Nephrology. Vicenza: Macmillan Publishers Limited; Hallan S, Astor B, Lydersen S. Estimating Glomerular Filtration Rate in the General Population: The Second Health Survey of Nord-Trondelag (HUNT II). Nephrol Dial Transplant 2006;21: Geus HR, Betjes MG, Bakker J. Biomarkers for the prediction of acute kidney injury: a narrative review on current status and future challenges. Clin Kidney J 2012;5: Devarajan, Prasad. Emerging Biomarkers of Acute Kidney Injury. Karger Publishers, Karger Publishers, 25 Apr. 2007, Lin, CY, et al. Serum Interleukin-18 at Commencement of Renal Replacement Therapy Predicts Short-Term Prognosis in Critically Ill Patients with Acute Kidney Injury. PloS One, 1 Jan. 2013, europepmc.org/articles/pmc Shi B, Ni Z, Cao L, Zhou M, Mou S, Wang Q, et al. Serum IL-18 is closely associated with renal tubulointerstitial injury and predicts renal prognosis in IgA nephropathy. Mediators Inflamm 2012;2012: J. M. Thurman, A. M. Lenderink, P. A. Royer, et al., C3a is required for the production of CXC chemokines by tubular epithelial cells after renal ishemia/reperfusion, Journal of Immunology, vol. 178, no. 3, pp , 2007.

10 27. C. L. Edelstein, T. S. Hoke, H. Somerset, et al., Proximal tubules from caspase-1-deficient mice are protected against hypoxia-induced membrane injury, Nephrology Dialysis Transplantation, vol. 22, no. 4, pp , Xin C, Yulong X, Yu C, Changchun C, Feng Z, Xinwei M. Urine neutrophil gelatinaseassociated lipocalin and interleukin-18 predict acute kidney injury after cardiac surgery. Ren Fail. 2008; 30(9): Melnikov VY, Ecder T, Fantuzzi G, Siegmund B, Lucia MS, Dinarello CA, Schrier RW, Edelstein CL: Impaired IL-18 processing protects caspase-1deficient mice from ischemic acute renal failure. J Clin Invest 2001, 107: Melnikov VY, Faubel S, Siegmund B, Lucia MS, Ljubanovic D, Edelstein CL: Neutrophilindependent mechanisms of caspase-1- and il-18-mediated ischemic acute tubular necrosis in mice. J Clin Invest 2002, 110: Zulkifli, Zainal R, Lestari MI. Buku panduan usulan penelitian dan tesis. Palembang. Penerbit Unsri Press, 2014.