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| ORIGINAL ARTICLE |
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| Year : 2013 | Volume
: 18
| Issue : 2 | Page : 116-121 |
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Evaluation of the diagnostic performance of new markers for acute kidney injury associated with contrast administration
M Vijayasimha1, V Vijaya Padma2, Saroj Kumar Das Mujumdar3, P. V. V. Satyanarayana1
1 Department of Biochemistry, Micropath Medical Center, Gurgaon, Haryana, India
2 Department of Biotechnology, Bharathiyar University, Coimbatore, Tamil Nadu, India
3 Department of Radiation Oncology, Salmaniya Medical Complex, Manama, Bahrain
| Date of Web Publication | 6-Sep-2013 |
Correspondence Address:
M Vijayasimha
Department of Biochemistry, Micropath Medical Center, Gurgaon, Haryana
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0971-9903.117802
Background: Contrast-induced nephropathy (CIN) is a form of acute kidney injury (AKI) that is caused by exposure to contrast media in diagnostic imaging and interventional procedures such as angiography. At present serum creatinine is the only standard test for it. A few studies have been published analyzing the potential use of neutrophil-gelatinase-associated lipocalin (NGAL) in AKI.
Aim: The aim of this study is to search for new markers to identify AKI acute renal failure earlier than serum creatinine.
Materials and Methods: We studied 100 consecutive patients with normal serum creatinine undergoing angiographic procedure against Urine NGAL, serum NGAL, serum Cystatin C and urinary interleukin-18 (IL-18) at basal, and 2 h, 4 h, 8 h, 24 h, and 48 h after the angiography.
Results: There was a significant rise in serum NGAL levels at 2 h, 4 h, and 8 h after angiography and in urinary NGAL levels at 4 h, 8 h, and 24 h after the procedure. Cystatin C rose significantly at 8 h and 24 h after the procedure, On the other hand, there was mild rise in urinary Il-18 levels at 24 h, but not significant. The presence of CIN associated with AKI was 13%.
Conclusion: The present study highlighted the importance of serum NGAL, urine NGAL and Cystatin C in detecting AKI associated with contrast administration earlier than serum creatinine. Keywords: Contrast-induced nephropathy, cystatin C, glomerular filtration rate, interleukin-18, kidney injury molecule-1, neutrophil-gelatinase-associated lipocalin
How to cite this article:
Vijayasimha M, Padma V V, Das Mujumdar SK, Satyanarayana P. Evaluation of the diagnostic performance of new markers for acute kidney injury associated with contrast administration. J Mahatma Gandhi Inst Med Sci 2013;18:116-21 |
How to cite this URL:
Vijayasimha M, Padma V V, Das Mujumdar SK, Satyanarayana P. Evaluation of the diagnostic performance of new markers for acute kidney injury associated with contrast administration. J Mahatma Gandhi Inst Med Sci [serial online] 2013 [cited 2023 Mar 29];18:116-21. Available from: https://www.jmgims.co.in/text.asp?2013/18/2/116/117802 |
| Introduction | |  |
Radio-contrast administration is one of the important reasons for acute kidney injury (AKI). AKI is an independent risk factor for mortality in adult and children, [1],[2],[3] even with a small increase in serum creatinine. [4],[5] Radiological procedures requiring intravascular administration of iodinated contrast media are becoming a common source of an iatrogenic disease known as contrast-induced nephropathy (CIN). [6] AKI is defined as an acute impairment of the renal function manifested by an absolute increase in the serum creatinine level of at least 0.5 mg/dl or by a relative increase of at least 25% from the baseline level [7] Now-a-days Cardiologists are being asked more frequently to perform angiography in an increasing number of patients, in which CIN is a potentially serious complication. [8] CIN is at present the third leading cause of hospital-acquired AKI. [9] Increased serum creatinine values typically occur 3-5 days after contrast administration and return to baseline levels within 1-3 weeks, [8] when patients are discharged from the hospital. Unfortunately, serum creatinine is an unreliable indicator during acute changes in the kidney function. [10] A marked reduction in the glomerular filtration rate (GFR) can be present before it is reflected in a rise in serum creatinine levels. All these reasons contribute to significant delay in the diagnosis of AKI associated with contrast administration. Moreover, the renal function may not return to baseline, leading to an increased risk of chronic Kidney Injury. [4] Therefore, new markers that help to identify AKI earlier than serum creatinine are required for timely treatment.
Neutrophil-gelatinase-associated lipocalin (NGAL), a member of the lipocalin family, was originally isolated from the supernatant of activated human neutrophils, [11] but it is also expressed at a low level in human tissue, including the kidney. [12] Due to its small molecular size (25 kDa) and resistance to degradation, NGAL is readily excreted and detected in urine. NGAL is also accumulated in human kidney cortical tubules, blood, and nephortoxic renal injuries. [13] Therefore, NGAL might prove as an early marker for detecting AKI associate with contrast administration. Cystatin C is a 13-kD cysteine protease inhibitor that has gained popularity as an alternative to serum creatinine in the measurement of renal function of the GFR. [13] Cystatin C concentration is independent of age, sex, changes of muscle mass, and nutrition. Therefore, Cystatin C might serve as a new marker for early detection of AKI associated with contrast administration. Interleukin-18 (IL-18), a proinflammatory cytokine that is released in response to injury to the renal tubules, [14],[15] is being investigated in the field of Kidney Injury. IL-18 might serve as an earlier AKI biomarker than serum creatinine in specific population such as patients receiving kidney transplantation, [16] critically ill children, [17] intensive care patients, [18] and patients undergoing cardiac surgery. [19] The objective of this study is to investigate serum and urine NGAL, serum Cystatin C and urinary IL-18 in comparison with serum creatinine, in contrast administered patients and to evaluate the diagnostic performance of their efficiency.
| Materials and Methods | | |
The study was carried out on 100 consecutive patients undergoing coronary angiography procedure. The study was approved by the Ethics Committee of Micropath Medical Center, Gurgaon, Haryana Written informed consent was obtained from each patient before enrolment. All consecutive adult patients undergoing coronary angiographic procedure over a 3 years period from 2009 to 2012 were included. All clinical and biochemical data are shown in [Table 1]. Patients with diabetic mellitus comprised 47 of 28 male and 19 females. Patients with non-diabetic mellitus comprised 53 of 31 male and 22 females. Among diabetic patients, 17 were treated with insulin and the rest with oral hypoglycemic drugs. No angiotension converting enzyme (ACE) inhibitors and angiotension II receptor blockers (ARBs) were used by any of the patients. All subjects were discharged home from the angiography area after 9 h of their procedure with advice to give specimen at scheduled time and encouraged to drink about 2 liters of water at least for the first 24 h. | Table 1: Basal clinical characteristics of patients undergoing angiography
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The coronary angiography was performed by a consultant doctor in a standard manner using femoral artery. We excluded patients with pre-existing chronic kidney disease, serum creatinine greater than 1.5 mg/dl in males and 1.3 mg/dl in females. None of the subjects investigated had received nephrotoxic drugs at least 2 weeks before and during the study period. Before the procedure, all the participating patients were given their urine and blood specimens for investigations such as cholesterol, high density lipoprotein, triglycerides, hemoglobin, HbA1C and fasting blood sugar. Blood pressure (BP) also studied on admission. Each patient was given low osmolar contrast (iodizanol or iopromide) medium. Specific protocols and medications for CIN prevention were not used in this study, but patients were persistently encouraged to drink plenty of fluids and oral fluid intake was maximally encouraged. Serum and urinary NGAL and urinary IL-18 and serum Cystatin C were evaluated before (at basal level), and 2 h, 4 h, 8 h, 24 h, and 48 h after the angiography. Urinary Samples were centrifuged at 2000 g for 5 min and the supernatant stored at −80 deg C.
Serum creatinine was assessed before (at basal level), and 24 h, and 48 h after the procedure using enzymatic method. NGAL was evaluated using a commercially available enzyme-linked immunosorbent assay (BioPorto Diagnostics, Gentofte, Denmark) and the IL-18 was analyzed using the enzyme linked immunosorbent assay (Biosensis, Thebarton, Australia). The Cystatin C was analyzed using commercially available kits from Dade Behring (Deerfield, USA). All tests were performed according to manufactures instruction. For the choice of optimal cut-off, receiver operating characteristic curve were constructed and the Youden index was calculated. [20] The Youden index is defined as follows: (sensitivity + specificity)-1. The best cut-off is the highest Youden index. The commercial statistical software package SPSS11.0 (SPSS, Inc., Chicago, IL, USA) was utilized. Results are evaluated with 95% confidence intervals. The significance level was < 0.05.
| Results | | |
The basal clinical characteristics of patients undergoing angiography are presented in [Table 1]. The present study revealed a significant increase in serum NGAL, at 2 h, 4 h, and 8 h after coronary angiography procedure [Table 2]. Serum NGAL returned to baseline values at 48 h after the angiographic procedure. Urinary NGAL levels were increased at 4 h, 8 h, and 24 h after the procedure. There was a mild increase in serum creatinine at 24 h and milder at 48 h after the angiographic procedure, but there was no significant increase in estimated glomerular filtration rate (eGFR) during 48 h of the procedure [Table 2].{Table 1} | Table 2: Changes in serum and urinary NGAL, Cystatin C, IL-18, eGFR and BP in patients undergoing angiography
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The serum Cytatin C levels increased significantly at 8 h and reaching a peak at 24 h after the procedure. There was a mild increase in urinary IL-18 levels at 24 h after the angiographic procedure, but returned to baseline at 48 h. It was observed that serum NGAL levels before contrast administration were significantly higher in diabetic patients than in non-diabetics (123.81 ± 81.22 vs. 88.11 ± 35.87 ng/ml, P < 0.05). In addition to that the serum NGAL levels were higher in diabetic patients comparison to non-diabetics at 2 h, 4 h, 8 h and 24 h after contrast administration (137.14 ± 87.28 vs. 89.17 ± 45.07 ng/ml, P < 0.05; 127.26 ± 89.21 vs. 8.41 ± 55.13 ng/ml, P < 0.05; 122.34 ± 80.27 vs. 81.27 ± 35.01 ng/ml, P < 0.05; and 125.42 ± 96.58 vs. 88.19 ± 40.74 ng/ml, P < 0.05 respectively). There is no significant difference in urinary NGAL and serum Cystatin C levels in diabetic and non-diabetic patients. Patients with hypertension revealed higher serum NGAL levels at 2 h, and 4 h after contrast administration, than the normal BP patients (124.14 ± 87.28 vs. 81.17 ± 35.61 ng/ml, P < 0.05; and 137.14 ± 97.28 vs. 80.17 ± 42.07 ng/ml, P < 0.05 respectively. As per definition for AKI (>0.5 mg of the baseline levels at 48 h after contrast administration), then the prevalence of AKI was 13%. "The serum creatinine levels at 48 h after the contrast administration were significantly higher in patients with AKI associated with contrast administration then those without AKI (1.40 ± 0.28 vs. 1.1 ± 0.31 mg/dl, P < 0.01). The serum NGAL levels at 2 h after the contrast administration were significantly higher in patients with AKI group associated with contrast administration then those without AKI group (153.76 ± 31.3 vs. 98.7 ± 23.7 ng/ml, P < 0.01). The urine NGAL levels at 4 h after the contrast administration were significantly higher in patients with AKI group associated with contrast administration then those without AKI group (154.76 ± 29.1 vs. 92.5 ± 18.9 ng/ml, P < 0.01). The serum Cystatin C levels at 24 h after the contrast administration were significantly higher in patients with AKI group associated with contrast administration then those without AKI group (2.27 ± 0.6 vs. 0.9 ± 0.1 mg/l, P < 0.01). The eGFR at 48 h after the contrast administration was significantly decreased in patients with AKI associated with contrast administration than those without AKI (65.34 ± 17.68 vs. 84.07 ± 23.41 ml/min, P <0.05). Cystatin C levels were higher at 8 h and 24 h after the contrast administration in patients with AKI than those without AKI.ND: Not determined. Data given are mean values ± SD or median values (minimum-maximum) *P < 0.05 vs. baseline; **P < 0.001 vs. baseline; ***P < 0.001 vs. baseline.
Using the Youden index, the best cut-off value for both serum and urinary NGAL to predict AKI was: 106 ng/ml and P < 0.5 [Figure 1]. The cut-off value for Cystatin C is 1.1 mg/L with diagnostic sensitivity 83% and specificity 91% and P < 0.5. | Figure 1: Receiver operating characteristic showing correlation among serum NGAL (2 h), urinary NGAL (4 h) and Cystatin C (24 h) and Contrast induced AKI, defined as a serum creatinine increase >0.5 mg/dl at 48 h. Using a cutoff value of 106 ng/ml, sensitivity, specificity and area under the ROC curve for prediction of AKI were excellent for serum NGAL at 2 h (96%, 89% and 0.95 respectively). Using a cutoff value of 106 ng/ml, sensitivity, specificity and area under the ROC curve for prediction of AKI were excellent for urinary NGAL at 4 h (95%, 100% and 0.96 respectively).
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| Discussion | | |
RIFLE and acute kidney injury network (AKIN) Criteria: In 2002, the Acute Dialysis Quality Initiatives group proposed a standard definition and classification system for the syndrome of acute renal failure (ARF) through a broad consensus of experts across disciplines and international boundaries. The classification systems coin the acronym RIFLE and have three levels: Risk, injury, and failure; and two outcomes: Persistent ARF (termed loss) and End stage Kidney disease. A unique feature of the RIFLE classification is that it provides retrospectively for three grades of severity of renal dysfunction on the basis of a maximum change in serum creatinine, reflecting changes in GFR or duration and severity of decline in urine output from the baseline. Based on the findings that small alterations of serum creatinine result in adverse outcomes, the AKI International Collaborative Network (AKIN) recently changed the definition of Risk group to include patients with an increase in serum creatinine of 0.3 mg/dl. [21] The proposed diagnostic and staging criteria for ARF are designed to facilitate the acquisition of knowledge and to validate the emerging concepts. Serum creatinine is the most widely used parameter for everyday assessment of GFR, but it has poor sensitivity and specificity in ARF because serum creatinine lags behind both renal injury and renal recovery. [21] Therefore, new promising markers were investigated to find ways to diagnose AKI at the earliest possible time. Serum creatinine levels began to rise within 24 h in 80% of patients, reaching maximum at 48-72 h after contrast administration, returning to baseline after 2 weeks. [22] Parikh et al., found that 72 patients with acute tubular necrosis and delayed graft function significantly higher IL-18 levels than other kidney diseases (urinary tract infection, chronic Kidney Injury, nephritic syndrome or prerenal azotemia). [13] Coca et al. reported that IL-18 generally showed a low sensitivity but high specificity respectively for assessing an AKI diagnosis and risk classification. [23] In our present study, we analyzed urinary Il-18 levels in comparison with serum creatinine levels. There was a mild rise in urinary IL-18 levels at 24 h after contrast administration, but without significance. In conclusion, urinary IL-18 might not serve as an early diagnostic tool for detecting AKI associated with contrast administration.
Serum NGAL at 2 h after contrast administration raised maximally and urinary NGAL raised maximally at 4 h after the contrast administration. The present study revealed that the serum NGAL, urine NGAL, and serum Cystatin C can detect AKI associated with contrast administration earlier than serum creatinine. The area under the curve (AUC) for serum NGAL at 2 h was 0.956 and for urinary NGAL 0.963. AUC for Cystatin C was 0.939. Using the Youden index, the best cut-off value for both serum and urinary NGAL to predict AKI was: 106 ng/ml. The best cut-off value for Cystatin C is 1.1 mg/L with diagnostic sensitivity 83% and specificity 91%. Similar, but not same values were noted by Hirsch et al. in which both urine and plasma NGAL levels served as excellent predictors of CIN both with sensitivity and specificity of 73% and 100% respectively. [24] Bachorzewska-Gajewska et al. found NGAL is a sensitive biomarker of AKI after contrast administrations for coronary angiography. They found a significant rise in serum NGAL at 2 h and 4 h after percutaneous coronary intervention (PCI) and a rise in urinary NGAL at 4 h and 12 h after PCI. [25] A similar study of 25 patients with normal serum creatinine undergoing PCI due to unstable angina revealed a significant rise in serum NGAL after 2 h and 4 h. Urinary NGAL and urinary liver type fatty acid binding protein (L-FABP) also raised significantly after 4 h and remained elevated up to 48 h after PCI. [26]
The prevalence of AKI association with contrast administration is 13%. The reported incidence of AKI due to contrast administration varies widely, ranging from 0 to >50%. [8] This variation results from whether the presence or absence of risk factors (primarily renal insufficiency), amount and type of contrast agent used, the exact radiologic procedure and whether other causes of AKI unrelated to contrast media were excluded. The underlying pathophysiology of CIN is acute tubular necrosis, a type of ARF, although the mechanism by which this occurs is not well understood. [27] The two major theories, based largely upon studies performed in experimental animals, are renal vasoconstriction resulting in medullary hypoxemia and direct cytotoxic effects of the contrast agents. The time of the procedure is very important in determining serum NGAL. [28] An earlier NGAL rise in serum than in urine may be due to the fact that NGAL is released into the circulation probably secondary to inflammatory activation of neutrophils initiated by the contrast agent. In addition to this, it was noted that NGAL is increased in atherosclerotic plaques. [29]
It was suggested the serum Cystatin C may have an advantage over serum creatinine for estimating the GFR; however, with some limitation. [30] Herget-Rosenthal et al. reported that serum Cystatin C is a useful detection marker for ARF and might detect ARF, 1 or 2 days earlier than serum creatinine. [31] Rickli et al. observed that the rise in Cystatin C achieved a maximum 24 h after the application of the contrast agent. [32] There is no significant correlation among age, BP or eGFR observed.
Hence, in our study, we simultaneously analyzed serum NGAL, urinary NGAL, Serum Cystatin C, serum creatinine, eGFR and IL-18 and confirmed their findings.
| Conclusion | | |
The present study revealed that the serum NGAL at 2 h, urine NGAL at 4 h and serum Cystatin C at 24 h after angiographic procedure can detect AKI associated with contrast administration earlier than serum creatinine. Urinary IL-18 is not an early predictive biomarker of CIN. Limitation of this study is that we could not include kidney injury molecule-1 (KIM-1), which is a new marker for AKI and we could have missed patients who developed AKI after 48 h of the procedure. In summary, this is the first study to test the efficiency of new bio-markers in this combination revealing advantages of urinary NGAL and serum NGAL along with Cystatin C.
The present study will add to our scientific knowledge and set the stage for larger studies of these serum NGAL, urinary NGAL, and Cystatin C markers along with new markers such as KIM-1 to strengthen the diagnostic performance of above stated markers in detecting AKI associated with contrast administration.
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[Figure 1]
[Table 1], [Table 2]
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