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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2021  |  Volume : 32  |  Issue : 2  |  Page : 355-363
Plasma neutrophil gelatinase-associated lipocalin and Interleukin-18 as predictors of acute kidney injury in renal transplant recipients: A pilot study


1 Department of Anaesthesia, Institute of Liver and Biliary Sciences, New Delhi, India
2 Department of Anaesthesia, Institute of Liver and Biliary Sciences, New Delhi, India; Department of Anesthesia and Intensive Care Medicine, London North West University NHS Trust, Harrow, United Kingdom
3 Department of Critical Care Medicine, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
4 Department of Anaesthesia, Institute of Liver and Biliary Sciences, New Delhi; Department of Trauma and Emergency (Anesthesia), All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
5 Department of Anesthesia, Dharamshila Narayana Superspeciality Hospital, New Delhi, India
6 Department of Urology, Institute of Liver and Biliary Sciences, New Delhi, India
7 Department of Biochemistry, Institute of Liver and Biliary Sciences, New Delhi, India

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Date of Web Publication11-Jan-2022
 

   Abstract 


Urine neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL- 18) have shown promise for predicting renal graft recovery. However, urinary flow rate variations may cause variable biomarker dilution. Plasma NGAL and IL-18 may form a biomarker panel that may help predict delayed graft function and slow graft function (SGF) in renal transplant recipients within the first two postoperative days earlier than serum creatinine. There are only a few studies in the literature using plasma NGAL for predicting renal graft recovery. Hence, we planned this study. This observational single-center, prospective cohort study was conducted in renal transplant recipients above 18 years of age. In 22 consecutive renal transplant recipients, we collected ethylenediaminetetraacetic acid-plasma samples 1 h before surgery and subsequently at 6 h, 24 h, and 48 h after surgery for NGAL and IL-18 by sandwich enzyme-linked immuno-sorbent assay technique. Serum creatinine was measured as a part of routine transplant protocol. In renal transplant recipients, neither serum levels of NGAL and IL-18 nor their trends could reliably predict SGF. The only significant correlation existed between serum creatinine at day 2 and IL-18 at day 2 with P = 0.023. Serum NGAL did not correlate with serum creatinine in this setting of renal transplantation. Patients with immediate graft function had a greater percentage decrease of creatinine at day 1 and day 2 (P = 0.002 and 0.001) The percentage change in IL-18 at 24 h and 48 h after transplant from baseline could predict the occurrence of early graft loss (EGL) (P = 0.05, 0.04). The cutoffs were -4.12% at day 1 and +3.39% at day 2 with area under receiver operator characteristics of 0.82 and 0.83, respectively. The percentage change in IL-18 may be a useful marker of EGL in renal transplant recipients. Serum NGAL and creatinine were not able to predict EGL.

How to cite this article:
Ponnappan KT, Parveez MQ, Pandey CK, Sharma A, Tandon M, Jain V, Pandey VK, Thomas S. Plasma neutrophil gelatinase-associated lipocalin and Interleukin-18 as predictors of acute kidney injury in renal transplant recipients: A pilot study. Saudi J Kidney Dis Transpl 2021;32:355-63

How to cite this URL:
Ponnappan KT, Parveez MQ, Pandey CK, Sharma A, Tandon M, Jain V, Pandey VK, Thomas S. Plasma neutrophil gelatinase-associated lipocalin and Interleukin-18 as predictors of acute kidney injury in renal transplant recipients: A pilot study. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 Jan 28];32:355-63. Available from: https://www.sjkdt.org/text.asp?2021/32/2/355/335447



   Introduction Top


The use of creatinine as a marker of kidney function has many confounding factors; it rises only after loss of 50% of renal function.[1],[2] Acute kidney injury (AKI) may remain undiagnosed if serum creatinine is the sole diagnostic tool. New markers of AKI, plasma neutrophil gelatinase-associated lipocalin (NGAL), and interleukin-18 (IL-18) may form a biomarker panel to detect kidney injury following successful renal transplantation,[3],[4] and magnitude of their change correlates with the renal graft function.[5] The change in biomarker levels is reported to precede change in creatinine and in the urine output. If graft dysfunction occurs, the biomarker trend could provide a valuable window of opportunity for therapeutic interventions and to evaluate the effectiveness of such interventions.[6]

NGAL is a 25-kDa ligand-binding protein of the lipocalin family, present in human tissues including kidney. NGAL is induced early in ischemic, nephrotoxic injury and in kidney transplantation with graft dysfunction.[6] IL-18 is synthesized as an inactive 23 kDa precursor by several tissues including monocytes, macrophages, and proximal tubular epithelial cells. Urine IL-18 is elevated in patients with acute tubular necrosis, urinary tract infections, chronic renal insufficiency, and prerenal azotemia.[5],[7] Delayed graft function (DGF) and slow graft function (SGF) are associated with poor graft survival at one year. Early prediction of graft dysfunction could help prognosticate and initiate renal protective measures.[8],[9] Urine biomarkers including NGAL and IL-18 have shown promise in this regard, but urinary flow rate variations may cause variable biomarker dilution.[5],[10]

There is scarce literature using plasma NGAL for predicting renal graft recovery. We hypothesized that plasma NGAL and plasma IL-18 can detect reduced renal graft function in renal transplant recipients within the first two postoperative days.


   Methods Top


The study protocol was approved by the ethics committee of the institute (vide IEC/ IRB No 39/5) and registered in clinical trial registry (Clinicaltrials.gov NCT03605264). This observational single-center, prospective cohort study was conducted in renal transplant recipients above 18 years of age. Following informed written consent, 22 patients were enrolled. In the study, patients with sepsis, malignancy, patients previously on immunosuppression, re-transplantation, and pregnant women were excluded [Figure 1] from the study.
Figure 1: Flow diagram of the study protocol.

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Immediate graft function (IGF) was defined as a fall of serum creatinine of 70% at postoperative day 7 after renal transplantation. SGF was defined as a failure of serum creatinine to fall by 70% at postoperative day 7 after renal transplantation. DGF was defined as the use of hemodialysis in the 1st week after renal transplantation. EGL was defined as a need for graft nephrectomy or loss of kidney transplant function resulting in the recipient becoming dialysis dependent within 30 days of kidney transplantation (and never achieving graft function thereafter) or death with a nonfunctioning graft within 30 days.

Clinical regimen

The demographic data were collected for age, gender, height/weight, admission diagnoses, comorbidities, renal replacement therapy history, perioperative adverse events, and for duration and severity of AKI preceding renal transplantation. Anesthesia at the institute is standardized. The urine output was monitored hourly. Ethylenediaminetetraacetic acid-plasma samples were collected 1 h before surgery and subsequently at 6 h, 24 h, and 48 h after surgery. Samples were centrifuged to remove cellular debris, aliquoted into 0.5 mL cryovials, and stored at -80°C. Serum creatinine was measured by a modified Jaffe method (kinetic colorimetric assay) as a part of routine transplant protocol. The intra-assay and inter-assay variability for the Jaffe method ranges from 0.7% to 2.3%. All measurements were performed by personnel blinded to patient information.

Analysis was made for NGAL by Sandwich ELISA, with a sensitivity of 0.1 ng/mL, detection range of 0.16–10 ng/mL, and coefficient of variation of <10%. Standard samples were added to micro-ELISA plates and precoated with human NGAL-specific antibody. IL-18 was measured using sandwich enzyme-linked immunosorbent assay (Elab sciences) with a sensitivity of 9.38 pg/mL, detection range between 15.63 and 1000 pg/mL, and coefficient of variation of <10%.


   Statistical Analysis Top


Data were checked for normalcy of distribution. Data were expressed as mean ± standard SD or median (minimum and maximum value). Categorical variables were compared using Pearson Chi-square test, and continuous variables were compared using Student t-test. Nonnormal continuous variables were compared using the Mann–Whitney U test (unpaired data). Analysis of variance (ANOVA) or Kruskal–Wallis ANOVA was used for repeated measurements. Correlations between the severity or duration of AKI and concentrations of NGAL, IL-18, and creatinine and their combination were evaluated by Pearson’s or Spearman’s correlation test. P ≤0.05 was taken as significant. Logistic regression was used to evaluate the association between risk factors with an event. Multivariate regression analysis was used wherever applicable.


   Results Top


The average age of patients was 38.2 ± 13.4 years with male preponderance (72.7%). The average duration of dialysis before surgery was 41.7 ± 26 months [Table 1]. The most common etiology was hypertension (n = 18) followed by diabetes (n = 3) and IgA nephropathy (n = 1). The median urine output was 75 mL/day, with interquartile range of 0–300 mL, and was similar in SGF and IGF groups [Table 2].
Table 1: Demographics and baseline characteristics of the study patients.

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Table 2: Baseline characteristics: Kidney disease.

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The baseline laboratory parameters including hemoglobin and albumin were 8.9 ± 1.7 and 3.3 ± 0.6, respectively. The baseline creatinine was 4 ± 1.4 (mean ± SD) with the SGF group having a lower starting creatinine than IGF group [Table 3] and [Table 4]. The biomarkers in our study, NGAL and IL-18, had a median range of 279 ng/mL (185–354) and 255 pg/mL (22–688) at baseline. Both were comparable between the SGF and IGF groups. The median cold ischemia time was 2.5 h with IQR between 1.2 and 4.7 h.
Table 3: Baseline laboratory parameters.

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Table 4: Comparison of serum creatinine for slow graft function and immediate graft function groups.

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The serum creatinine, NGAL, and IL-18 were similar between the two groups at baseline, at 6 h postoperative day (POD) 1, and POD 2. The percentage decrease from baseline in the values of creatinine, NGAL, and IL-18 were studied. The percentage decrease was significant for serum creatinine both at day 1 and at day 2, with P = 0.002 and 0.01, respectively [Table 4] and [Table 5].
Table 5: Comparison of NGAL and IL-18 for slow graft function and immediate graft function groups.

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Patients who had dialysis within 1st month after renal transplant had no significant change in serum creatinine and NGAL in the first two days after renal transplantation. However, the change in IL-18 both at POD 1 and POD 2 was significantly less in the group which received dialysis within one month than in patients with IGF.

The correlation between the three parameters was evaluated. While the correlation of serum creatinine at day 2 and IL-18 at day 2 was significant (P = 0.023), we found no correlation of baseline, 6 h, 24 h, and 48 h serum creatinine with NGAL [Table 6]. Similarly, we found no correlation between creatinine and IL-18 at baseline, 6 h, and 24 h [Table 6].
Table 6: Correlation between creatinine, NGAL, and IL-18 (P values).

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The areas under the receiver-operating characteristic curves for predicting dialysis at 1st month were greater with IL-18 compared with creatinine. The percentage decrease in IL- 18 on 1st and 2nd PODs had AUC of 0.82 and 0.83, respectively, compared to the AUC for creatinine change which was 0.667 at both POD 1 and 2. The AUC for change in NGAL levels was 0.49 on POD 1 and for POD 2 [Figure 2] and [Figure 3].
Figure 2: Receiver-operating characteristic curves for requirement of dialysis at 1st month by percentage decrease in creatinine, NGAL, and IL 18 on 1st postoperative day.
NGAL: Neutrophil gelatinase-associated lipocalin, IL-18: Interleukin-18


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Figure 3: Receiver-operating characteristic curves for requirement of dialysis at 1st month by percentage decrease in creatinine, NGAL, and IL-18 on 2nd postoperative days.
NGAL: Neutrophil gelatinase-associated lipocalin, IL-18: Interleukin-18.


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   Discussion Top


The study highlights the emerging role of serum IL-18 in the early prediction of dialysis requirement within one month of renal transplant. The percentage change of IL-18 at POD 1 and day 2 strongly correlated with the need for dialysis within one month of transplant, with AUC of 0.82 and 0.83, respectively.

A recent meta-analysis[6] showed that plasma NGAL was a reliable marker of AKI in the setting of patients undergoing cardiac surgeries with pooled AUC of 0.85 and that serum NGAL was as effective as urinary NGAL in predicting AKI. In another study as well, serum IL-18 was found to be associated with AKI in cardiac surgical patients.[11] Other biomarker, serum IL-18, has been shown to correlate with GFR in patients with diabetes mellitus, tubulointerstitial damage in IgA nephropathy, and in patients with microalbuminuria in systemic lupus erythematosus. IL-18 also correlates with poor sleep quality in peritoneal dialysis patients.[12],[13],[14],[15],[16],[17]

Serum IL-18 has not been studied in the renal transplant patients. Investigators have however studied the successful use of NGAL and IL-18 in the urine for predicting graft function.[5] Urinary biomarkers, although showing good correlation with AKI, may have varying concentrations depending on the urinary flow rate.[10] This is further confounded in the perioperative period by the use of diuretics, which may alter the day-to-day flow rates and the biomarker concentration. Serum markers whereas are independent of urine flow rates.

In a study by Melnikov,[16] a strong correlation of serum IL-18 with ischemia reperfusion injury was seen which was reversed by antiserum IL-18. In our study, although none of the patients had DGF, the percentage change in IL-18 was a useful marker of EGL in renal transplant recipients. The cutoffs were -4.12% at day 1 and +3.39% at day 2 with area under receiver operator characteristics of 0.82 and 0.83, respectively. The tests had a sensitivity of 75% and specificity of 72% on POD1 and 75% and 78% on POD 2.

SGF did not show any correlation with the change in serum creatinine and both NGAL and IL-18 failed to detect SGF. Hall et al[5] in their study found similar results and concluded that serum markers NGAL and IL-18 were not able to distinguish between DGF, SGF, and IGF.

DGF increases the length of stay and has a 40% chance of graft failure in the 1st year.[18],[19] DGF is caused by ischemia reperfusion injury. Terasaki et al first highlighted the improved survival of living donor renal transplants compared to deceased donor transplants on account of lesser ischemia time and therefore less ischemia reperfusion injury.[20] Our study involved living donors, and none of the 22 patients had DGF, possibly due to lesser ischemia reperfusion injury.

SGF is associated with worse outcome compared to patients with IGF.[8],[9] We also classified our patients into SGF and IGF on the basis of fall in serum creatinine from baseline but found that none of the markers including creatinine, NGAL, and IL-18 could reliably detect SGF.

In a study by Mahdavi and Lebkowska, a significant fall in serum NGAL was seen before fall in serum creatinine following renal transplant.[21],[22] In a study by Bataille et al, of 41 renal transplant patients, IGF patients had a significant fall in the NGAL levels compared with those developing DGF.[17] However, in our study, we found no correlation between serum NGAL and SGF. Serum NGAL was inferior to both creatinine and IL-18 in its ability to detect the need for dialysis at one month after renal transplant which is similar to the findings of Mahdavi.[21] We also found no correlation between serum IL-18 and serum creatinine at any time point and also no relationship between SGF and IL-18. Unlike earlier studies that demonstrated a relationship between serum IL-18 and AKI in cardiac surgical patients,[7],[11],[23] no such correlation was observed in our study.

Our study had certain limitations. The sample size was small, and biomarkers were studied for only 48 h after renal transplant. Extending the study for up to a week and increasing the number could have helped characterize the biomarker trends more extensively. We followed the patients for a one-month period, and a longer follow-up may have been more useful. All our patients were live related renal transplant recipients, and the data are not representative of the other techniques of transplantation.


   Conclusions Top


The percentage change in IL-18 may be a useful marker of EGL in renal transplant recipients. Serum NGAL and creatinine were not able to predict EGL.

Conflict of interest: None declared.

Funding: This study was funded by Departmental Funding.

Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent: Informed consent was obtained from all individual participants included in the study.



 
   References Top

1.
Malyszko J, Lukaszyk E, Glowinska I, Durlik M. Biomarkers of delayed graft function as a form of acute kidney injury in kidney transplantation. Sci Rep 2015;5:11684.  Back to cited text no. 1
    
2.
Tung YC, Chang CH, Chen YC, Chu PH. Combined biomarker analysis for risk of acute kidney injury in patients with ST-segment elevation myocardial infarction. PLoS One 2015;10:e0125282.  Back to cited text no. 2
    
3.
Munir MU, Khan DA, Khan FA, Shahab Naqvi SM. Rapid detection of acute kidney injury by urinary neutrophil gelatinase-associated lipocalin after cardiopulmonary bypass surgery. J Coll Physicians Surg Pak 2013;23:103-6.  Back to cited text no. 3
    
4.
Eremenko AA, Minbolatova NM, Kaabak MM, Babenko NN. Neutrophil gelatinase-associated lipocalin (u-NGAL) in the assessment of renal function in patients after kidney allotransplantation. Anesteziol Reanimatol 2014; 59:10-5.  Back to cited text no. 4
    
5.
Hall IE, Yarlagadda SG, Coca SG, et al. IL-18 and urinary NGAL predict dialysis and graft recovery after kidney transplantation. J Am Soc Nephrol 2010;21:189-97.  Back to cited text no. 5
    
6.
Zhou F, Luo Q, Wang L, Han L. Diagnostic value of neutrophil gelatinase-associated lipocalin for early diagnosis of cardiac surgery-associated acute kidney injury: A meta-analysis. Eur J Cardiothorac Surg 2016; 49:746-55.  Back to cited text no. 6
    
7.
Cui LY, Zhu X, Yang S, et al. Prognostic value of levels of urine neutrophil gelatinase-associated lipocalin and interleukin-18 in patients with delayed graft function after kidney transplantation. Transplant Proc 2015; 47:2846-51.  Back to cited text no. 7
    
8.
Gill J, Dong J, Rose C, Gill JS. The risk of allograft failure and the survival benefit of kidney transplantation are complicated by delayed graft function. Kidney Int 2016;89: 1331-6.  Back to cited text no. 8
    
9.
Gołębiewska J, Dębska-Ślizień A, Bułło-Piontecka B, Rutkowski B. Outcomes in renal transplant recipients with lupus nephritis-a single-center experience and review of the literature. Transplant Proc 2016;48:1489-93.  Back to cited text no. 9
    
10.
Trachtenberg F, Barregard L, McKinlay S. The influence of urinary flow rate in children on excretion of markers used for assessment of renal damage: Albumin, gamma-glutamyl transpeptidase, N-acetyl-beta-D –glucosaminidase, and alpha1-microglobulin. Pediatr Nephrol 2008;23:445-56.  Back to cited text no. 10
    
11.
Unal EU. Serum interleukin-18 as an early marker of acute kidney injury following open heart surgery. Turkish J Thorac Cardiovasc Surg 2014;22:483-88.  Back to cited text no. 11
    
12.
Mir M, Rostami A, Hormozi M. Comparison of serum levels of IL-18 in peripheral blood of patients with type II diabetes with nephropathy clinical protests and patients with type II diabetes without nephropathy clinical protests. Diabetes Metab Syndr 2017;11:245-50.  Back to cited text no. 12
    
13.
Shi B, Ni Z, Cao L, et al. Serum IL-18 is closely associated with renal tubulointerstitial injury and predicts renal prognosis in IgA nephropathy. Mediators Inflamm 2012;2012: 728417.  Back to cited text no. 13
    
14.
Wawrocki S, Druszczynska M, Kowalewicz- Kulbat M, Rudnicka W. Interleukin 18 (IL-18) as a target for immune intervention. Acta Biochim Pol 2016;63:59-63.  Back to cited text no. 14
    
15.
Yang JY, Huang JW, Chiang CK, et al. Higher plasma interleukin-18 levels associated with poor quality of sleep in peritoneal dialysis patients. Nephrol Dial Transplant 2007;22: 3606-9.  Back to cited text no. 15
    
16.
Melnikov VY, Ecder T, Fantuzzi G, et al. Impaired IL-18 processing protects caspase-1- deficient mice from ischemic acute renal failure. J Clin Invest 2001;107:1145-52.  Back to cited text no. 16
    
17.
Bataille A, Abbas S, Semoun O, et al. Plasma neutrophil gelatinase-associated lipocalin in kidney transplantation and early renal function prediction. Transplantation 2011;92:1024-30.  Back to cited text no. 17
    
18.
Bonner K, Joshi G, Seibert R, Kayler LK. Association of dialysis duration with outcomes after kidney transplantation in the setting of long cold ischemia time. Transplant Direct 2019;5:e413.  Back to cited text no. 18
    
19.
Butala NM, Reese PP, Doshi MD, Parikh CR. Is delayed graft function causally associated with long-term outcomes after kidney transplantation? Instrumental variable analysis. Transplantation 2013;95:1008-14.  Back to cited text no. 19
    
20.
Terasaki PI, Cecka JM, Gjertson DW, Takemoto S. High survival rates of kidney transplants from spousal and living unrelated donors. N Engl J Med 1995;333:333-6.  Back to cited text no. 20
    
21.
Mahdavi-Mazdeh M, Amerian M, Abdollahi A, Hatmi ZN, Khatami MR. Comparison of serum neutrophil gelatinase-associated lipocalin (NGAL) with serum creatinine in prediction of kidney recovery after renal transplantation. Int J Organ Transplant Med 2012;3:176-82.  Back to cited text no. 21
    
22.
Liu Y, Li HX, Ying ZW, et al. Serum neutrophil gelatinase-associated lipocalin and cystatin c for assessing recovery of graft function in Patients undergoing living-donor kidney transplantation. Clin Lab 2016;62:155- 63.  Back to cited text no. 22
    
23.
Assadi F, Sharbaf FG. Urine KIM-1 as a potential biomarker of acute renal injury after circulatory collapse in children. Pediatr Emerg Care 2019;35:104-7.  Back to cited text no. 23
    

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Correspondence Address:
Ankur Sharma
Department of Trauma and Emergency (Anesthesia), All India Institute of Medical Sciences, Jodhpur - 342 008, Rajasthan
India
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DOI: 10.4103/1319-2442.335447

PMID: 35017329

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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

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



 

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