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DOI:10.2214/AJR.07.2356
AJR 2007; 189:687-692
© American Roentgen Ray Society

Original Research

IV N-Acetylcysteine and Emergency CT: Use of Serum Creatinine and Cystatin C as Markers of Radiocontrast Nephrotoxicity

Pierre-Alexandre Poletti1, Patrick Saudan2, Alexandra Platon1, Bernadette Mermillod1, Anna-Maria Sautter3, Bernard Vermeulen4, François P. Sarasin4, Christoph D. Becker1 and Pierre-Yves Martin2

1 Department of Radiology, University Hospital of Geneva, 24, rue Micheli-du-Crest, 1211 Genève 14, Switzerland.
2 Service of Nephrology, University Hospital of Geneva, Geneva, Switzerland.
3 Service of Clinical Pharmacology and Pharmacy, University Hospital of Geneva, Geneva, Switzerland.
4 Emergency Center, University Hospital of Geneva, Geneva, Switzerland.

Received September 21, 2006; accepted after revision April 7, 2007.

 
Supported by a grant for Research and Development of the University Hospital of Geneva.

Address correspondence to P. A. Poletti (pierre-alexandre.poletti{at}hcuge.ch).


Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
OBJECTIVE. The purpose of this study was to assess the effect of IV administration of N-acetylcysteine (NAC) on serum levels of creatinine and cystatin C, two markers of renal function, in patients with renal insufficiency who undergo emergency contrast-enhanced CT.

SUBJECTS AND METHODS. Eighty-seven adult patients with renal insufficiency who underwent emergency CT were randomized to two groups. In the first group, in addition to hydration, patients received a 900-mg injection of NAC 1 hour before and another immediately after injection of iodine contrast medium. Patients in the second group received hydration only. Serum levels of creatinine and cystatin C were measured at admission and on days 2 and 4 after CT. Nephrotoxicity was defined as a 25% or greater increase in serum creatinine or cystatin C concentration from baseline value.

RESULTS. A 25% or greater increase in serum creatinine concentration was found in nine (21%) of 43 patients in the control group and in two (5%) of 44 patients in the NAC group (p = 0.026). A 25% or greater increase in serum cystatin C concentration was found in nine (22%) of 40 patients in the control group and in seven (17%) of 41 patients in the NAC group (p = 0.59).

CONCLUSION. On the basis of serum creatinine concentration only, IV administration of NAC appears protective against the nephrotoxicity of contrast medium. No effect is found when serum cystatin C concentration is used to assess renal function. The effect of NAC on serum creatinine level remains unclear and may not be related to a renoprotective action.

Keywords: contrast media • CT • emergency radiology • N-acetylcysteine • nephrotoxicity


Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Nephrotoxicity is a major complication of IV administration of iodine contrast medium. It is usually defined as acute impairment of renal function occurring within 3 days of injection [1–7]. An increase in serum creatinine concentration that is at least 25% of the baseline value is generally considered indicative of radiocontrast nephrotoxicity [1, 2, 4, 6–9]. Some authors [2, 3] consider a higher threshold (> 50%) to define clinically important (severe) acute renal failure. Other criteria have been used, such as an absolute increase of at least 44 µmol/L (0.5 mg/dL) in serum creatinine concentration [10, 11]. Various trials [4, 5, 9, 10] have shown that combined with hydration, twice-daily oral administration of 600 mg of N-acetylcysteine (NAC) the day before and the day of injection of iodine contrast medium may prevent nephrotoxicity in patients with chronic renal failure. Results reported in 2006 [12] suggested that IV and oral NAC may prevent radiocontrast nephropathy with a dose-dependent effect and may improve hospital outcome. When time constraints preclude oral prophylaxis, IV administration of a large dose (150 mg/kg) of NAC immediately before injection of iodine contrast medium followed by an additional dose of 50 mg/kg over the subsequent 4 hours has been advocated for imaging of patients at risk of radiocontrast nephrotoxicity. Randomized controlled studies have shown that with NAC prophylaxis a smaller number of patients have an increase in serum creatinine concentration after injection of contrast medium [8]. Those findings make it tempting to recommend NAC for every patient receiving contrast medium, particularly in emergencies. Other studies [11, 13, 14], however, did not corroborate the findings, and the actual effect of NAC in preventing radiocontrast nephrotoxicity is still subject to controversy [14–16]. Serum creatinine level is known to be an imperfect indicator of glomerular filtration rate (GFR) because other factors, such as diet, tubular secretion of creatinine, muscular mass, age, and sex, also influence creatinine concentration [17–19]. Moreover, in acute renal failure, serum creatinine concentration is a poor indicator of renal function [20].

Another serum marker investigated for evaluating renal failure is cystatin C. Cystatin C is a nonglycosylated protein (cysteine proteinase) produced at a constant rate by nucleated cells. It is freely filtered by the glomeruli and not secreted or reabsorbed as an intact molecule. Cystatin C has been found to be a better indicator of GFR than serum creatinine level in particular circumstances, such as very low or very high muscle mass, cirrhosis, and critical illness [21–25]. Cystatin C appears to be more sensitive than creatinine in detection of mild decreases in GFR, making it an earlier indicator of acute renal failure [26]. Nevertheless, cystatin C cannot be considered an ideal marker of renal function because it is influenced by non-GFR-dependent factors, such as age, sex, obesity, smoking, thyroid dysfunction, and microinflammation [27, 28].

Assessment of the effectiveness of NAC may be influenced by the method used for estimating renal function. Oral administration of NAC to healthy volunteers not receiving injections of contrast medium has been found to reduce serum creatinine concentration without affecting cystatin C level [29]. It is possible that creatinine metabolism, unlike cystatin C metabolism, is affected by NAC and that the observed reduction in serum creatinine concentration after administration of NAC without variation in cystatin C level may not reflect improvement in GFR [29]. Therefore, cystatin C may be better suited than creatinine to evaluation of the renoprotective role of NAC after administration of contrast medium. To our knowledge, in no previous study have investigators specifically analyzed serum concentrations of both creatinine and cystatin C for assessment of the renoprotective effect of NAC before injection of iodine contrast medium. The goal of this study was to evaluate how IV administration of NAC affects both serum creatinine and cystatin C levels in patients undergoing emergency CT with injection of iodine contrast medium.


Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The subjects were 100 adult patients with a serum creatinine concentration greater than 106 µmol/L (1.2 mg/dL) admitted consecutively to our emergency department during daytime hours. The value greater than 106 µmol/L was chosen to identify risk of radiocontrast nephrotoxicity because 106 µmol/L is the upper limit of normal at our institution, and that was the value selected for the same purpose in another study [11]. The patients needed emergency CT within 12 hours of admission. Exclusion criteria were pregnancy, end-stage renal failure necessitating dialysis, suspicion of acute renal obstruction (complicated renal colic), asthma, severe cardiac failure or hemodynamically unstable condition contraindicating IV hydration, and nonurgent indications for CT. Demographic, clinical, and technical data on the patients are shown in Table 1.


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  		TABLE 1: Demographic, Clinical, and Technical Data on Patients

 

All patients underwent CT with the same nonionic low-osmolality iodine contrast medium (iopromide, Ultravist 300, Schering). A bolus of 2 mL/kg body weight was used for nonneurologic indications, and a standard dose of 100 mL was used for brain imaging or suspicion of pulmonary embolism. Injection was performed at a rate of 3 mL/s. None of the patients included in the study underwent a second contrast-enhanced procedure in the 4 days after admission. The study protocol was approved by both the institutional review board of our hospital (IRB 02–147) and the National Agency for Therapeutic Products. Informed written consent was obtained from all patients or their legal representatives.

Study Protocol
Each patient was assigned to receive 0.45% saline solution IV at a rate of 5 mL/kg body weight over the course of the hour before CT and followed at a rate of 1 mL/kg body weight for 12 hours after CT. This protocol was adapted from the study of Solomon et al., who found hydration to have a beneficial effect in preventing contrast-induced renal dysfunction [30]. Patients were randomized to two groups by serial enrollment. In the first group, a vial containing 900 mg of NAC (Fluimucil, Zambon) was diluted in a 50-mL solution of 5% glucose and administered IV 1 hour before CT. A second vial containing 900 mg of NAC was mixed into the 0.45% saline perfusion administered IV after completion of CT at a rate of 1 mL/kg body weight per hour for 12 hours. In the second group, the same procedure was performed, but the vials contained placebo (50 mL of 0.9% NaCl) instead of NAC. An independent pharmacist labeled the pairs of vials containing NAC and placebo only with numbers. Therefore, both patients and investigators were blinded to the contents of the vials.

Serum creatinine and cystatin C concentrations were measured before the first administration of NAC or placebo (day 0, baseline) and on days 2 and 4 after CT. Serum creatinine concentration was measured by the Jaffe kinetic method at 41°C with an LX20 analyzer (Beckman Coulter). Serum cystatin C concentration was measured by immunonephelometric assay. Serum cystatin C concentration was measured in milligrams per liter. At our institution, serum cystatin C concentration is considered normal up to a maximal value of 1.55 mg/L.


Figure 1
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  		Fig. 1A —Time evolution of markers of glomerular filtration rate in each patient. Thick horizontal lines indicate mean concentrations, vertical lines indicate 95% CI, and dotted lines indicate patients with missing data. Graphs show creatinine concentration after CT in N-acetylcysteine (A) and control (B) groups.

 


Figure 2
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  		Fig. 1B —Time evolution of markers of glomerular filtration rate in each patient. Thick horizontal lines indicate mean concentrations, vertical lines indicate 95% CI, and dotted lines indicate patients with missing data. Graphs show creatinine concentration after CT in N-acetylcysteine (A) and control (B) groups.

 


Figure 3
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  		Fig. 1C —Time evolution of markers of glomerular filtration rate in each patient. Thick horizontal lines indicate mean concentrations, vertical lines indicate 95% CI, and dotted lines indicate patients with missing data. Graphs show cystatin C level after CT in N-acetylcysteine (C) and control (D) groups. Dashed line indicates maximum normal value of cystatin C (1.55 mg/L). Triangles indicate patients in whom cystatin C values were not obtained at both day 2 and day 4.

 


Figure 4
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  		Fig. 1D —Time evolution of markers of glomerular filtration rate in each patient. Thick horizontal lines indicate mean concentrations, vertical lines indicate 95% CI, and dotted lines indicate patients with missing data. Graphs show cystatin C level after CT in N-acetylcysteine (C) and control (D) groups. Dashed line indicates maximum normal value of cystatin C (1.55 mg/L). Triangles indicate patients in whom cystatin C values were not obtained at both day 2 and day 4.

 
Outcome Measures
The primary endpoints of the study were mean increase in creatinine and cystatin C concentrations on days 2 and 4 after CT and peak increase (maximal value from day 2 to day 4). Secondary endpoints were proportion of patients in whom nephrotoxicity developed after CT, defined as a 25% or greater increase from baseline at any point over the 2 days for each marker, and proportion of patients in whom severe nephrotoxicity (≥ 50% increase from baseline for each marker) developed. The proportion of patients with an at least 25% increase in both markers also was assessed for each group.

Statistical Analysis
Data were described with mean ± SD. Results for the NAC and control groups were compared by use of Student's t test for quantitative data and Fisher's exact test for proportions. A 95% CI was calculated for differences between group means (NAC – placebo). A negative value for the difference was in favor of NAC. Statistical significance was p < 0.05. All tests were two-tailed. Statistical analyses were performed with statistical software (version 1990, BMDP). Graphs were made with S-Plus software (version 3.4, MathSoft). A correlation coefficient between creatinine and cystatin C was calculated with the Pearson's product moment correlation coefficient method. Creatinine and cystatin C measurements were taken into account at each time point for all patients.


Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Data Collection
Of the 100 patients included in the protocol, four had a rapid decline in general condition and underwent immediate surgery without CT, and one died before CT was performed. Of the 95 remaining patients, six died before day 2 of the study, and two patients left the hospital after CT was performed and were lost to follow-up. Data analysis in this study was restricted to the 87 patients who underwent serum creatinine analysis 2 days after CT. Of the 13 patients excluded, seven belonged to the control group, and six were in the NAC group. Of the 87 patients included in the study, seven had no final (day 4) serum measurement: three died before the last measurement (day 4) was performed, one was transferred to another hospital, and three left the hospital and were lost to follow-up. Therefore, a 4-day creatinine measurement was obtained for 80 patients. For technical reasons, cystatin C analysis was not performed on day 0 for two patients, on day 2 for 10 patients, and on day 4 for five patients.

Data Analysis
No significant difference was found in the two groups in comparisons of admission blood pressure values and the presence of hypovolemia. Twelve (14%) of 87 patients who underwent follow-up had diabetes. Nephrotoxicity (at least 25% increase in creatinine or cystatin C level) was found in two (16%) of the patients with diabetes and in nine (12%) of the 75 patients without diabetes. The difference between the groups was not statistically significant (p = 0.82). The differences in percentages of patients treated with diuretics, nonsteroidal antiinflammatory drugs, and angiotensin-converting enzyme inhibitors also were not statistically significant (Table 1).

The mean serum creatinine concentration on day 0 for all patients was 147 µmol/L (1.66 mg/dL), ranging from 110 to 318 µmol/L (1.24–3.6 mg/dL). Variations in serum creatinine and cystatin C concentrations from day 0 to day 4 after CT are illustrated in Figures 1A, 1B, 1C, and 1D. At baseline, significant correlation (r =0.51, p < 0.001) was found between serum creatinine and cystatin C concentrations, and this correlation became enhanced (r =0.74, p < 0.001) at 48 hours. Within the NAC group, correlations between serum creatinine and cystatin C concentrations were present at baseline (r =0.44, p = 0.002) and 48 hours after CT (r =0.72, p < 0.001) (Figs. 2A and 2B). Within the control group, correlations between serum creatinine and cystatin C were present at baseline (r = 0.64, p < 0.001) and at 48 hours (r =0.78, p < 0.001) (Figs. 2C and 2D).


Figure 5
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  		Fig. 2A —Scatterplots show relative increase in creatinine and cystatin C concentrations from baseline (day 0). Two usual thresholds (25% and 50%) are depicted for both markers. Points on diagonal have equal increase for both markers. Graphs show increase for N-acetylcysteine group on day 2 (A) and day 4 (B) after CT.

 

Figure 6
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  		Fig. 2B —Scatterplots show relative increase in creatinine and cystatin C concentrations from baseline (day 0). Two usual thresholds (25% and 50%) are depicted for both markers. Points on diagonal have equal increase for both markers. Graphs show increase for N-acetylcysteine group on day 2 (A) and day 4 (B) after CT.

 

Figure 7
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  		Fig. 2C —Scatterplots show relative increase in creatinine and cystatin C concentrations from baseline (day 0). Two usual thresholds (25% and 50%) are depicted for both markers. Points on diagonal have equal increase for both markers. Graphs show increase for control group on day 2 (C) and day 4 (D) after CT.

 

Figure 8
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  		Fig. 2D —Scatterplots show relative increase in creatinine and cystatin C concentrations from baseline (day 0). Two usual thresholds (25% and 50%) are depicted for both markers. Points on diagonal have equal increase for both markers. Graphs show increase for control group on day 2 (C) and day 4 (D) after CT.

 

Between day 0 and day 2 after CT, serum creatinine concentration decreased a mean of 15.5 ± 31.8 µmol/L in the NAC group and 0.8 ± 40.6 µmol/L in the control group (between-groups difference, –14.7; 95% CI, –30.2 to 0.8). No significant difference was found in mean cystatin C concentration in either group (between-groups difference, mean value; 95% CI, –0.24 to 0.20). On day 4, serum creatinine concentration decreased a mean of 20.0 ± 35.7 µmol/L in the NAC group and 6.9 ± 55.6 µmol/L in the control group (between-groups difference, –13.1; 95% CI, –33.7 to 7.5). No significant difference was found in mean cystatin C concentration in either group (between-groups difference, mean value; 95% CI, –0.27 to 0.17). For peak serum creatinine concentration, a decrease of 10.3 ± 32.9 µmol/L was found in the NAC group compared with an increase of 6.1 ± 56 µmol/L in the control group (between-groups difference, mean value; 95% CI, –35.9 to 3.1). The peak cystatin C concentration increased 0.07 and 0.12 mg/L in the two groups (between-groups difference, mean value; 95% CI, –0.27 to 0.17). None of the observed differences in creatinine and cystatin C concentrations was statistically significant (Table 2).


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  		TABLE 2: Creatinine and Cystatin C Increases on Days 2 and 4 Compared with Day 0

 

The number of patients in whom nephrotoxicity, based on two thresholds (25% and 50%) of increases in serum creatinine and cystatin C concentrations, had developed by day 2 or day 4 after CT is shown in Table 2. A 25% or greater increase in peak creatinine concentration occurred in two (5%) of 44 NAC patients and in nine (21%) of 43 control patients (p = 0.026). There were no other significant differences between the two groups. A 25% or greater increase in both creatinine and cystatin C concentrations was found in 3% of the NAC group and in 11% of the control group on day 2 after CT. On day 4, these proportions were 0% (0/38) and 9% (3/35). A 50% or greater increase in both creatinine and cystatin C concentrations was found in only one patient, a control subject, on day 4 (Figs. 2A, 2B, 2C, and 2D). This patient, who had preexisting non-insulin-dependent diabetes and liver cirrhosis, was admitted because of acute arterial occlusion of a limb. He died of multiple organ failure 5 days after admission. No side effects attributable to NAC administration were found in our patient population.


Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The aim of this study was to evaluate the renoprotective effect of NAC in patients with renal insufficiency who undergo emergency contrast-enhanced CT. We first analyzed changes in serum creatinine and cystatin C concentrations in NAC and placebo groups after injection of contrast medium. A 25% increase in both values was chosen as the indicator of radiocontrast-induced reduction in renal function. This percentage has been used in several studies of creatinine concentration as an indicator of renal function [3, 5, 12, 14]. In studies in which creatinine and cystatin C concentrations were compared, the same percentage change in concentrations of both markers was considered representative of a significant decrease in renal function [31].

We found that after injection of contrast medium, the mean serum creatinine concentration was lower, but not significantly lower, in the NAC group than in the control group. Our recruitment criteria consisted of admission to the emergency department with an elevated serum creatinine level and no clinical suspicion of obstructive renal disease. Therefore, unlike the populations in most previous studies [4, 8, 10], our study population was not limited to patients with chronic renal failure who did not receive diuretic or antiinflammatory therapy, and this choice of population might be a limitation of our study. The possibility that the observed diminution in serum creatinine level in the NAC group was underestimated cannot be excluded. No difference was found in the means for the two groups with regard to serum cystatin C concentration. These findings substantiate the hypothesis that a reduction in serum creatinine level after NAC administration may reflect not improvement in GFR but alterations in creatinine metabolism [29].

The scattering of the values reported in Figures 2A, 2B, 2C, and 2D for serum creatinine and cystatin C concentrations must be highlighted. In many patients, we found serum creatinine elevation between day 2 and day 4 while cystatin C remained stable. In both groups we found higher correlations between serum creatinine and cystatin C concentrations 48 hours after CT compared with baseline. This finding probably can be explained by the differing rates of increase in creatinine and cystatin C concentrations in emerging acute renal failure. This difference between rates of increase in these two markers has been found in episodes of acute renal failure occurring in ICUs [31]. Forty-eight hours after CT, correlation between serum creatinine and cystatin C concentrations was slightly higher in the control group (0.78) than in the NAC group (0.72) because NAC altered serum creatinine but not cystatin C level.

Our findings raise the problem of finding an ideal marker of renal function, especially in the case of acute renal failure. Current definitions that rely on changes in serum creatinine concentration and urine output have been shown insufficiently sensitive and specific [32]. The usefulness of serum cystatin C concentration as a marker of acute renal failure has to be assessed. Data showing the value of this marker in the diagnosis and monitoring of impaired renal function are scarce [22].

Because of difficulties in assessing impairment of renal function in acute conditions, we used different combinations and thresholds of serum creatinine and cystatin C elevations to evaluate radiocontrast nephrotoxicity in the two groups of patients. Our data showed that the proportions of patients with a 25% or greater increase in peak serum creatinine level after injection of contrast medium were 25% in the placebo group and 5% in the NAC group. These findings are in agreement with those of previous studies [4, 6, 8–10, 29, 33]. In most of those studies, NAC was administered orally to patients with chronic renal failure at a total dose of 2,400 mg in four doses before and after administration of contrast medium. Although NAC is well-absorbed orally, first-pass metabolism decreases its bioavailability to approximately 20% compared with IV administration [34]. First-pass metabolism, however, delivers more glutathione, which may be the key element in preventing nephrotoxicity, thus increasing its efficacy with the IV dose [34]. In three studies [8, 12, 35], NAC was administered IV to patients undergoing cardiac catheterization or intervention with higher volumes of contrast media. One study [8] showed a protective effect with a very high dose of NAC (150 mg/kg). Another study [35] showed no protective effect with a lower dose (1,000 mg IV). In a more recent study [12], a possible dose-dependent protective effect was found when a 1,200-mg IV bolus plus 1,200-mg oral dose was compared with the standard four 600-mg oral doses and with a placebo. In the current study, we chose 1,800 mg IV divided in two doses, which corresponds to 75% of the oral dose. We postulated that this dosage should provide NAC exposure at least equivalent to the oral dosage. Our results confirm that NAC administrated immediately IV before injection of iodine contrast medium has the same effect on serum creatinine concentration as that previously reported by groups using oral NAC preparation.

A significant difference in the peak increase in serum creatinine concentration (maximal value from day 2 to day 4) between patients who received NAC and the control group was found when a threshold of greater than 25% was used to define nephrotoxicity. We found no difference between the groups in proportion of patients with a 25% or greater increase in serum cystatin C concentration after injection of contrast medium. However, one of the limitations of our study was that the number of patients with severe nephrotoxicity after administration of contrast medium was too small to allow a comparison between the two groups. This low incidence of severe and clinically relevant impairment of renal function was probably due to the 1-hour saline hydration received by our patients before contrast injection and emphasizes the importance of hydration in the prevention of radiocontrast nephrotoxicity, as previously shown [30].

In conclusion, despite the technical limitations, the results of this study suggest that IV administration of NAC immediately before and after injection of iodine contrast medium may reduce the transient elevation (≥ 25%) in serum creatinine level but does not affect serum cystatin C level, another marker of renal function. These findings cast serious doubt on whether the observed action of NAC on serum creatinine level has a renoprotective property. It may be that the renoprotective effect can be attributed to a non-GFR-related effect on creatinine metabolism [29]. Studies designed to clarify the value of NAC in radiocontrast nephrotoxicity should not be limited to analysis of serum creatinine level and should consider additional indicators of renal function.


Acknowledgments
 
We acknowledge Josette Simon and Farshid Sadeghipour for their contributions to this work.


References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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