Can Neutrophil Gelatinase associated Lipocalin Help Depict Early Contrast Material induced Nephropathy? 1

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1 Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at Original Research n Contrast Media Antonio Lacquaniti, MD Francesco Buemi, MD Rosaria Lupica, MD Claudio Giardina, MD Gabriella Murè, MD Adriana Arena, MD Carmela Visalli, MD Sergio Baldari, MD Carmela Aloisi, MD Michele Buemi, MD Can Neutrophil Gelatinase associated Lipocalin Help Depict Early Contrast Material induced Nephropathy? 1 Purpose: Materials and Methods: To evaluate the utility of serum and urinary neutrophil gelatinase associated lipocalin (NGAL) in depicting an event of contrast material induced nephropathy (CIN) in patients who received iodinated contrast media, gadoterate meglumine, or radiopharmaceutical technetium-99m ( 99m Tc) and to evaluate the protective effect exerted by isotonic saline infusion, sodium bicarbonate administration, or N-acetylcysteine administration. Institutional ethics committee approval was given, and informed consent was obtained. One hundred twenty patients were enrolled in a prospective study and divided into three groups: iomeprol group, magnetic resonance (MR) imaging group (gadoterate meglumine), and renal scintigraphy group ( 99m Tc). They randomly received N- acetylcysteine, physiologic saline, or sodium bicarbonate. Receiver operating characteristic (ROC) analysis, Kaplan- Meier curves, and Cox proportional hazard regression analysis were used. Results: Conclusion: In the MR imaging and renal scintigraphy groups, there were significant changes in serum creatinine and NGAL levels, and there were no cases of CIN. In the iomeprol group, an early rise in NGAL was found, while serum creatinine level changes occurred 24 hours after contrast material administration. At ROC analysis, NGAL showed high sensitivity and specificity (serum NGAL: area under the curve, 0.995; 95% confidence interval [CI]: 0.868, 0.992; urinary NGAL: area under the curve, 0.992; 95% CI: 0.925, 1.000) in identifying CIN 8 hours after iomeprol administration. Regression analysis showed that NGAL independently predicted CIN. Administration of N-acetylcysteine, sodium bicarbonate, or physiologic saline did not influence NGAL level. NGAL depicted CIN in patients who received iodinated contrast material within 8 hours of contrast material administration. 1 From the Department of Internal Medicine (A.L., F.B., R.L., C.A., M.B.), Department of Radiological Sciences (C.G., C.V.), Unit of Nuclear Medicine, Department of Radiological Sciences (G.M., S.B.), and Department of Surgical Science, Unit of Clinical Microbiology, Faculty of Medicine (A.A.), University of Messina, Via Salita Villa Contino 30, Messina, Italy. Received March 9, 2012; revision requested April 30; revision received August 30; accepted September 18; final version accepted September 27. Address correspondence to M.B. ( buemim@unime.it). q RSNA, 2013 Supplemental material: /suppl/doi: /radiol /-/dc1 q RSNA, radiology.rsna.org n Radiology: Volume 267: Number 1 April 2013

2 Contrast material induced nephropathy (CIN) has become the third leading cause of hospital-acquired acute kidney injury, because of an increasing number of patients receiving intravascular injection of iodinated contrast media every year worldwide (1). The risk of CIN in patients with predisposing factors, such as advanced age, preexisting renal disease, congestive heart failure, anterior myocardial infarction, cardiogenic shock, diabetes mellitus, and type and volume of contrast material, is considerably increased (2). The exact mechanism underlying CIN has not yet been completely elucidated but is likely to involve several pathogenic factors. An essential element for developing CIN is thought to be the presence of hypoxia in the renal medulla, as suggested by Brezis and Rosen and Liss et al, who observed an oxygen tension reduction in the medulla Advances in Knowledge Neutrophil gelatinase associated lipocalin (NGAL) is an early biomarker that depicts contrast material induced nephropathy (CIN) within 8 hours of the administration of the contrast agent, with high diagnostic sensitivity and specificity (greater than 95% for urinary and serum NGAL). Serum creatinine level helps identify CIN 48 hours after the administration of the contrast agent, with low sensitivity (41.2%) and specificity (69.8%). Gadoterate meglumine and radiopharmaceuticals, at a dose of 0.2 ml per kilogram of body weight and 700 MBq, respectively, do not cause renal injury; NGAL enables monitoring of the effects of these drugs on the kidney. N-acetylcysteine, physiologic saline, or sodium bicarbonate prevents CIN in the same maer; no significant differences between urinary and serum NGAL were found among these three groups. in rats after injection of low- and isoosmolar contrast agents (3,4). Although great progress has been made in identifying patients at risk and in studying pathophysiologic mechanisms, there are currently no early predictive biomarkers of CIN. Among the contemporary definitions, CIN is characterized by an absolute ( 0.5 mg/dl) and relative increase ( 25%) in serum creatinine level hours after exposure to a contrast agent compared with baseline serum creatinine values, when alternative explanations for renal impairment have been excluded (5). Furthermore, 25% 50% of the increase in creatinine level, which is highly predictive of the development of CIN, most often occurs 24 hours after administration of contrast medium (6,7). To date, a reliable laboratory value or test that recognizes acute renal damage before serum creatinine level increases is still being sought and might be a most helpful tool in initiating proper treatment early. Neutrophil gelatinase associated lipocalin (NGAL) is a 25-kDa protein produced by renal tubular cells in response to different types of injury. NGAL, considered an excellent predictor of kidney injury, rises before any increase occurs in creatinine levels in response to treatments that are potentially harmful to the kidney, thus facilitating a more reliable prediction of renal damage (8,9). NGAL is highly accumulated in the human kidney cortical tubules, blood, and urine after nephrotoxic and ischemic injuries, such as exposure to iodinated contrast material (10). In fact, it has been shown to be capable of earlier Implication for Patient Care NGAL represents an optimal biomarker for the early detection of CIN in patients at increased risk receiving iodinated contrast agents; NGAL could be used to monitor possible risks resulting from the administration of radiopharmaceuticals and gadoterate meglumine. diagnosis in patients undergoing cardiac surgery and CIN after intraarterial iodinated contrast material administration (11,12). A number of approaches to CIN prophylaxis have been used. A widely used prophylaxis for CIN after contrast material administration is based on intravenous volume loading with an isotonic saline infusion (0.9%) (13,14). Hydration with sodium bicarbonate has also been suggested to provide additional renal protection by alkalinizing renal tubular fluid, with decreased tubular damage by scavenging oxygen free radicals (15). Finally, N-acetylcysteine has been the most widely studied of all prophylactic strategies (16). Unfortunately, most studies evaluating these prophylactic measures lacked statistical power and used different types of contrast media, varying definitions of CIN, and several diverse prophylactic measures. The result is a lack of generally accepted guidelines for their use among radiologists, cardiologists, nephrologists, and other involved physicians. The main purpose of the present study was to evaluate the diagnostic power of serum and urinary NGAL in depicting an event of CIN in patients who received iodinated contrast material, gadoterate meglumine, or Published online before print /radiol Content code: Radiology 2013; 267:86 93 Abbreviations: CI = confidence interval CIN = contrast material induced nephropathy GFR = glomerular filtration rate NGAL = neutrophil gelatinase associated lipocalin ROC = receiver operating characteristic Author contributions: Guarantors of integrity of entire study, all authors; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, A.L., F.B., R.L., C.G., A.A., C.V., C.A., M.B.; clinical studies, A.L., F.B., R.L., C.G., G.M., A.A., S.B., C.A., M.B.; statistical analysis, A.L., F.B., R.L., C.G., C.A., M.B.; and manuscript editing, A.L., F.B., R.L., C.G., A.A., S.B., C.A., M.B. Conflicts of interest are listed at the end of this article. Radiology: Volume 267: Number 1 April 2013 n radiology.rsna.org 87

3 Table 1 Prophylactic Arms: Modality and Timing of Treatment Group Drug Route of Administration Before Contrast Material Injection After Contrast Material Injection Physiologic saline 0.9% sodium chloride Intravenous 5 ml/kg over 1 hour before injection 1 ml/kg for 12 hours Sodium bicarbonate 75 ml of 8.4% sodium bicarbonate plus 1 Intravenous 3 ml/kg for 1 hour before injection 1 ml/kg per hour for 6 hours L of 0.9% sodium chloride N-acetylcysteine N-acetylcysteine Oral 1200 mg 1 hour before injection 1200 mg/d for 2 days radiopharmaceutical technetium-99m ( 99m Tc). We also evaluated the protective effect of isotonic saline infusion, sodium bicarbonate administration, or N-acetylcysteine administration. Materials and Methods Institutional ethics committee approval was given, and informed consent was obtained from all participants. This study was conducted in the Department of Radiology and Nephrology at the Medical University of Messina, Italy, between January 2010 and June Our investigation was a single-center prospective study. Patients Patients 18 years and older with impaired renal function (baseline glomerular filtration rate [GFR] 60 ml/ min) who required clinically indicated contrast material enhanced computed tomography (CT), magnetic resonance (MR) imaging with gadoterate meglumine, or renal scintigraphy were considered to be eligible to enroll in the clinical study. Patients with diabetes with good glycemic control (hemoglobin A 1c 7%), patients with hypertension, and patients who had a mild and stable congestive heart failure were also enrolled. Exclusion criteria were age younger than 18 years; severe renal insufficiency (estimated GFR 30 ml/min/1.73 m 2 ); administration of iodinated contrast media within 7 days prior to study entry; history of anaphylaxis to iodinated contrast medium; pregnancy; lactation; acute renal failure; end-stage renal disease requiring dialysis; acute myocardial infarction; patients receiving other potentially nephrotoxic drugs; administration of dopamine, maitol, or theophylline; self-administration of nonstudy N-acetylcysteine or sodium bicarbonate 24 hours prior to enrollment; and administration of nonsteroidal anti-inflammatory drugs other than aspirin within 48 hours prior to enrollment. All types of diuretics were withheld on the day of the procedure. One hundred sixty patients were screened. Forty patients were excluded because of history of reaction to iodinecontaining contrast agents (n = 2), GFR less than 30 ml/min (n = 14), hemoglobin A 1c greater than 7% (n = 8), severe congestive heart failure (n = 10), or intake of potentially nephrotoxic drugs (n = 6). Thus, a group of 120 patients met all eligibility criteria and were enrolled. They were divided into three groups according to the diagnostic examination and then according to the type of contrast agent used. In particular, 60 patients underwent CT with administration of iomeprol (350 mg of iodine per milliliter, nonionic, monomeric, low osmolality [618 mosm per kilogram of H 2 O], low viscosity, high water solubility) (Iomeron; Bracco Diagnostics, Milan, Italy) at doses of 1.5 ml per kilogram of body weight. Thirty patients underwent MR imaging with intravenous administration of gadoterate meglumine (anionic, osmolality of 1350 mosm per kilogram of H 2 O) (Dotarem; Guerbet, Genoa, Italy) at a dose of 0.2 ml/kg. The third group, consisting of 30 patients, underwent renal scintigraphy with the the radiopharmaceutical 99m Tc pentetic acid at a dose of 700 MBq. All patients were instructed to fast for 6 hours before examination and were orally hydrated with 1 L of water in the 10 hours before and 2 L in the 24 hours after the examination. Randomization and Drug Infusion All the patients were randomly assigned into one of three prophylaxes: N-acetylcysteine, physiologic saline, or sodium bicarbonate (Table 1). The patients, physicians, laboratory staff, and the epidemiologist who analyzed the data were not aware of the intervention for each group. Evaluation of Renal Function The parameters used to estimate renal function were serum creatinine level (Cobas Integra, creatinine Jaffe gen2 standardized for isotope dilution mass spectrometry; Roche, Maheim, Germany) and estimation of the GFR by using the Modification of Diet in Renal Disease formula (17). Serum creatinine level was evaluated with blood samples obtained 24 hours before examination and 8, 24, 48, and 72 hours after administration of the contrast agent. The development of CIN, defined as being a percentage increase in serum creatinine level of 25% or more or by an overall increase of at least 44 mmol/l (0.50 mg/dl), in the absence of an alternative cause, was evaluated for each patient (18). NGAL was used to differentiate CIN from non-cin groups 8 hours after iodinated contrast material administration. Collection of Blood and Urine Blood samples were drawn from the cubital vein of each subject before contrast material administration and every hour for 8 hours and at 24 hours. Urine was also collected at these time intervals. Blood samples for NGAL evaluations were collected in chilled blood collection tubes (Vacutainer; Becton Dickinson, Franklin Lakes, NJ) containing 88 radiology.rsna.org n Radiology: Volume 267: Number 1 April 2013

4 Table 2 Patient Demographic, Laboratory, Clinical and Imaging Examination Detanils Parameter MR Imaging Group (n = 30) Renal Scintigraphy Group (n = 30) Iomeprol Group (n = 60) Iomeprol Group Details CIN (n = 23) No CIN (n = 37) P Value Men/women* 16/14 18/12 30/30 13/10 17/20.21 Age of men (y) Age of women (y) Body mass index (kg/m 2 ) Hemoglobin A 1c Diabetes* 14 (46) 15 (50) 17 (28) Hypertension* 20 (66) 18 (60) 46 (77) Heart failure* 10 (33) 8 (26) 18 (30) Serum creatinine level (mg/dl) Estimated GFR (ml/min) Contrast media amount 0.2 ml/kg 700 MBq 1.5 ml/kg ml ml Serum NGAL (ng/ml) Urinary NGAL (ng/ml) ,.0001 Note. Unless otherwise indicated, data are means 6 standard deviations. P values were calculated by using the t test, except where indicated. * Data are numbers of patients, with percentages in parentheses. Calculated by using x 2 test. potassium edetic acid, and the plasma was promptly separated in a centrifuge and immediately tested. For urinary assays, 10 ml of fresh urine was mixed with 1 ml of 10-mmol/L Tris buffer (ph of 8.6) with 0.05% Tween 20 and 0.01% NaN 3 containing protease inhibitors (10 mmol/l benzamidine, 10 mmol/l aminocaproic acid, 20 mmol/l edetic acid, and aprotinin). This mixture was centrifuged at 3000 revolutions per minute for 8 minutes and stored at 280 C until assayed. NGAL was measured in the blood by using a test (Triage NGAL Test; Alere-Biosite, Milan, Italy) which returned results in 15 minutes. Urinary NGAL was tested by using an enzymelinked immunosorbent assay commercially available kit (Antibody Shop, Gentofte, Denmark) according to the manufacturer s instructions. The enzymatic reactions were quantified in an automatic microplate photometer. Serum and urinary NGAL levels were expressed as nanograms per milliliters. Statistical Analysis Statistical analyses were performed with software (MedCalc, version 8.0, MedCalc, Mariakerke, Belgium; Prism, version 5.0, GraphPad, La Jolla, Calif). Data were presented as mean 6 standard deviation for normally distributed values (Kolmogorov- Smirnov test) and median with interquartile range for noormally distributed values. Differences between groups were established by using an unpaired t test for normally distributed values and by using Kruskal-Wallis analysis followed by the Du test for nonparametric values. Dichotomized values were compared by using the x 2 test. Receiver operating characteristic (ROC) analysis was used to calculate the area under the curve for NGAL and to find the best cutoff values capable of identifying CIN. Kaplan-Meier curves were generated to assess incidence of CIN in subjects with serum and urinary NGAL values higher and lower than the optimal ROC-derived cutoff levels. Adjusted risk estimates for endpoint were calculated by using univariate followed by multivariate Cox proportional hazard regression analysis. Exploratory graphic analysis and test of specific violations indicated no departure from the assumption of proportional hazards. Results Patient Baseline Characteristics All 120 patients enrolled (64 men: mean age, 57.7 years [standard deviation]; 56 women: mean age, 60.6 years 6 12; age range for all patients, years) had clinically stable mild chronic kidney disease (serum creatinine level, 1.4 mg/dl ; estimated GFR, 59.3 ml/min 6 9.5). Thirty-eight percent (46 of 120) of patients were diabetic with good glycemic control (hemoglobin A 1c, 5.3% 6 1.6). Seventy percent (84 of 120) of patients were hypertensive. Thirty percent (36 of 120) of patients had congestive heart failure. These conditions were chosen to identify risk of contrast material nephrotoxicity. Patient demographic, laboratory, clinical, and imaging examination details are summarized in Table 2. All three groups were well matched in terms of kidney function, risk factors for CIN, and baseline NGAL. In fact, basal levels of serum and urinary NGAL did not show statistically significant differences between the three groups (iomeprol group: serum NGAL, 89.5 ng/ml ; urinary NGAL, 48.4 ng/ Radiology: Volume 267: Number 1 April 2013 n radiology.rsna.org 89

5 ml ; MR imaging group: serum NGAL, 85.6 ng/ml ; urinary NGAL, 44.1 ng/ml ; renal scintigraphy group: serum NGAL, 89.9 ng/ ml ; urinary NGAL, 49.7 ng/ml ). Figure 1 Differences in NGAL Levels in the MR Imaging and Renal Scintigraphy Groups In the MR imaging and renal scintigraphy groups, changes in serum and urinary NGAL were not statistically significant at 8 and 24 hours, compared with baseline. In these two groups, there was no statistically significant change in serum creatinine level throughout the study period, and there was no evidence of CIN in these groups. NGAL Levels in the Iomeprol Group In the iomeprol group, we found a significant rise in serum NGAL at 8 and 24 hours (112.2 ng/ml [P,.0001] and ng/ml [P =.0004], respectively, vs 89.5 ng/ml at baseline) and in urinary NGAL at 8 and 24 hours (77.7 ng/ml [P,.0001] and 74.7 ng/ml [P,.0001], respectively, vs 48.4 ng/ ml at baseline) after iomeprol administration. After 8 hours, 30 patients had a rise in serum NGAL and 33 patients in urinary NGAL values, compared with baseline. We observed 23 cases of CIN. All of these patients were characterized by a rise of serum NGAL at 8 hours, while only one person had CIN without an increase in urinary NGAL. In these 23 patients, creatinine level did not show statistically significant changes (P =.11) until 48 hours after contrast material administration. More details are provided in Figure E1 (online). Among the 60 patients, CIN was diagnosed in 23 (38%) patients (CIN group) receiving iomeprol, while the remaining 37 (62%) patients (no-cin group) did not develop CIN. None of these patients underwent dialysis after exposure to contrast material. By comparing the two groups on the basis of values of NGAL, a statistically significant difference was shown between CIN and no-cin groups 8 hours Figure 1: Box-and-whisker plots show serum NGAL (sngal), urinary NGAL (ungal), and serum creatinine values before and 8 hours after contrast agent administration in patients with and without CIN. P values were calculated by using the t test. Horizontal lines in boxes = medians. after the procedure (serum NGAL: ng/ml vs ng/ml 6 18, respectively [P,.0001]; urinary NGAL: 102 ng/ml vs 68.1 ng/ml , respectively [P,.0001]). At the same time, there was no significant difference for serum creatinine values (1.6 mg/dl vs 1.5 mg/dl [P =.27]) between CIN and no-cin groups (Fig 1). Characteristics of NGAL as Diagnostic Marker ROC analyses were performed to define the diagnostic profile of serum and urinary NGAL in identifying CIN 8 hours after the administration of the contrast agent (Fig 2). The area under the ROC curve was for serum NGAL and for urinary NGAL. When the cutoff values of serum and urinary NGAL were set at 115 ng/ml and 90 ng/ml, respectively, sensitivity and specificity of the two markers used for the diagnosis were 100% and 87.3% and 94.1% and 97.7%, respectively. More details can be found in Tables E1 and E2 (online). ROC analysis showed an area under the curve for serum creatinine after 48 hours of 0.547, with a best cutoff level of 1.7 mg/dl (sensitivity, 41.2%; specificity, 69.8%). Both serum and urinary NGAL areas were significantly different compared with that of creatinine (P,.001). On the contrary, the difference between the two NGAL areas was not significant (P..05). NGAL and Prediction of CIN We evaluated the decrease in Modification of Diet in Renal Disease GFR at 48 hours after contrast material administration as an endpoint in patients with serum and urinary NGAL levels higher and lower than the optimal ROC cutoff level. Subjects with serum NGAL values higher than 115 ng/ml experienced a significantly faster evolution to endpoint (P =.002), with a hazard ratio of 3.70 (95% confidence interval [CI]: 1.62, 8.45). 90 radiology.rsna.org n Radiology: Volume 267: Number 1 April 2013

6 Figure 2 patients 35% (eight of 23) were in the physiologic saline group, 26% (six of 23) were in the sodium bicarbonate group, and 39% (nine of 23) were in the N-acetylcysteine group; the difference was not statistically significant (P =.61). There was no significant difference in the baseline characteristics among the three preventive groups. Between day 0 and day 2 after iomeprol administration, serum creatinine concentration decreased at a mean of 0.35 mg/dl in the N-acetylcysteine group, without significant differences compared with the other two groups. Furthermore, we did not find any significant differences between urinary and serum NGAL in the three groups (Table 4). Figure 2: ROC curves. Area under the curve for serum NGAL (sngal) and urinary NGAL (ungal) was (95% CI: 0.868, 0.992) and (95% CI: 0.925, 1.000), respectively. The area under the curve for creatinine (Creat) at 48 hours was (P =.58; 95% CI: 0.413, 0.676) with a best cutoff level of 1.7 mg/dl (sensitivity, 41.2%; specificity, 69.8%). Subjects with urinary NGAL values higher than 90 ng/ml showed a significantly faster progression to endpoint (P =.0002), with a hazard ratio of 4.89 (95% CI: 2.09, 11.42). Univariate and Multiple Cox Regression Analysis and Incidence of CIN To identify putative risk factors associated with incidence of CIN, we performed Cox regression analysis; we inserted in the model all variables that were different at baseline in patients who reached the endpoint during the entire follow-up period (age, contrast agent volume, serum NGAL, urinary NGAL, and estimated GFR). Univariate analysis showed that only estimated GFR, serum NGAL, and urinary NGAL were significantly associated with endpoint, whereas age and the amount of contrast material volume did not reach statistical significance. A multiple Cox regression was constructed, with all of the variables found to be significantly associated with endpoint at univariate analysis (serum NGAL, urinary NGAL, and estimated GFR). In addition, age was also inserted in this model because it commonly represents one of the most important risk factors for CIN, although in this population it was not found to be significantly associated with endpoint. Results from this analysis indicated that all of these factors predicted higher risk of CIN onset independently. In detail, the increase of 10 ng/ml of urinary NGAL was associated with a 3% increased risk of CIN (hazard ratio, 1.03; 95% CI: 1.02, 1.04; P =.0001), whereas the increase of 10 ng/ml of serum NGAL increased this risk by 2% (hazard ratio, 1.01; 95% CI: 1.01, 1.03; P =.003). Table 3 summarizes data from univariate and multivariate Cox analysis. CIN Group and Preventive Therapy Throughout the study period, cases of CIN were reported in the iomeprol group only. The primary endpoint (CIN) occurred in 38% (23 of 60) of Discussion A more sensitive and precocious test to indicate acute renal failure after contrast media exposure is still sought after. Current definitions of CIN, which rely on changes in serum creatinine concentration and urine output, have been shown to be insufficiently sensitive and specific (19). The administration of iodinated contrast agent represented an important risk factor for CIN development in our study. Serum creatinine levels showed a statistically significant increase 48 hours after iodinated contrast material administration, whereas NGAL was an early marker, with its elevations observed after only 8 hours. We have also shown that this lipocalin possesses a high diagnostic sensitivity and specificity for detecting CIN. In fact, regression analysis showed that NGAL predicted CIN independently of other potential confounders, including estimated GFR. Furthermore, NGAL would be far more useful, in patient prescreening, prior to iodinated agent administration, than simple estimated GFR value calculated from a Modification of Diet in Renal Disease equation using serum creatinine level. The other aim of this study was to evaluate the renal protective effects Radiology: Volume 267: Number 1 April 2013 n radiology.rsna.org 91

7 Table 3 Univariate and Multivariate Cox Proportional Hazards Regression Model for CIN Parameter Univariate Analysis of N-acetylcysteine, sodium bicarbonate, and physiologic saline in patients who developed CIN. This study suggested no significant difference in the development of CIN between treated groups, without variations of NGAL levels. We observed a decrease in serum creatinine level in the N-acetylcysteine group, but without significant relevance. Hoffma et al (20) observed the same condition and hypothesized that this reduction may reflect alterations in creatinine metabolism, not an improvement in GFR. In the group of patients receiving 99m Tc pentetic acid or gadoterate meglumine, we found no cases of CIN, and NGAL levels did not show any significant change. In the cohort analyzed, gadoterate meglumine was safe probably because it was administered intravenously and at low dose levels. Gadolinium chelates, originally regarded as noephrotoxic, have been recommended to replace iodinated contrast media in patients at risk for acute renal failure. Since then, some gadolinium-based contrast media have been reported to be associated with CIN, especially in patients with advanced renal disease or receiving higher doses and most commonly with intraarterial Multivariate Analysis Hazard Ratio 95% CI P Value Hazard Ratio 95% CI P Value Age , , GFR , , Serum NGAL , , Urinary NGAL , 1.17, , Contrast material amount , Table 4 Iomeprol Group: Prophylactic Therapies Parameter Physiologic Saline (n = 20) Sodium Bicarbonate (n = 20) N-Acetylcysteine (n = 20) No. of patients with CIN Serum NGAL (ng/ml) Urinary NGAL (ng/ml) Bachorzewska-Gajewska H, Malyszko J, Sitniewska E, Malyszko JS, Dobrzycki S. Neutrophil-gelatinase-associated lipocalin and renal function after percutaneinjections (21). Moreover, nephrogenic systemic fibrosis can develop in patients with renal disease who are given at least some of the gadolinium-based MR imaging contrast agents. This has been reported to occur in patients with acute renal disease and not just in chronic renal disease (22). Our study had some limitations. It was a single-center study, and the cohort of patients, especially after randomization, was relatively small. A larger study population could make the results more reliable. The duration of follow-up was deliberately chosen to be relatively brief to focus on the earliest phase. Nevertheless, the primary endpoint was reached by one-third of the participants, and the statistical model was powerful enough to establish independent relationships between NGAL and incidence of CIN. The degree of chronic kidney disease in the present study was mild; therefore, our results should not be generalized for patients with more severe chronic kidney disease. In conclusion, despite these limitations, the results of this study suggest that NGAL is an independent early predictor of CIN with good sensitivity and specificity, while the major risk is represented by iodinated contrast agents. Administration of N-acetylcysteine, sodium bicarbonate, or physiologic saline immediately before and after injection of iodinated contrast material did not influence NGAL level. Disclosures of Conflicts of Interest: A.L. No relevant conflicts of interest to disclose. F.B. No relevant conflicts of interest to disclose. R.L. No relevant conflicts of interest to disclose. C.G. No relevant conflicts of interest to disclose. G.M. No relevant conflicts of interest to disclose. A.A. No relevant conflicts of interest to disclose. C.V. No relevant conflicts of interest to disclose. S.B. No relevant conflicts of interest to disclose. C.A. No relevant conflicts of interest to disclose. M.B. No relevant conflicts of interest to disclose. References 1. 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8 ous coronary interventions. Am J Nephrol 2006;26(3): Schilcher G, Ribitsch W, Otto R, et al. Early detection and intervention using neutrophil gelatinase-associated lipocalin (NGAL) may improve renal outcome of acute contrast media induced nephropathy: a randomized controlled trial in patients undergoing intra-arterial angiography (ANTI-CIN Study). BMC Nephrol 2011;12: Haase-Fielitz A, Bellomo R, Devarajan P, et al. Novel and conventional serum biomarkers predicting acute kidney injury in adult cardiac surgery: a prospective cohort study. Crit Care Med 2009;37(2): Weisbord SD, Palevsky PM. Prevention of contrast-induced nephropathy with volume expansion. Clin J Am Soc Nephrol 2008;3(1): Erley CM. Does hydration prevent radiocontrast-induced acute renal failure? Nephrol Dial Transplant 1999;14(5): Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA 2004;291(19): Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Lierma D, Zidek W. Prevention of radiographic-contrast-agentinduced reductions in renal function by acetylcysteine. N Engl J Med 2000;343(3): Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. A Intern Med 2006; 145(4): Rihal CS, Textor SC, Grill DE, et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation 2002;105(19): Mehta RL, Chertow GM. Acute renal failure definitions and classification: time for change? J Am Soc Nephrol 2003;14(8): Hoffma U, Fischereder M, Krüger B, Drobnik W, Krämer BK. The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable. J Am Soc Nephrol 2004;15(2): Ledneva E, Karie S, Launay-Vacher V, Janus N, Deray G. Renal safety of gadolinium-based contrast media in patients with chronic renal insufficiency. Radiology 2009;250(3): Perazella MA. Nephrogenic systemic fibrosis, kidney disease, and gadolinium: is there a link? Clin J Am Soc Nephrol 2007;2(2): Radiology: Volume 267: Number 1 April 2013 n radiology.rsna.org 93