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Nephrol Dial Transplant (2009) 24: 3103–3107
doi: 10.1093/ndt/gfp306
Advance Access publication 23 June 2009
Acetylcysteine and non-ionic isosmolar contrast-induced
nephropathy—a randomized controlled study
Francesca Ferrario1 , Maria Teresa Barone1 , Giovanni Landoni2 , Augusto Genderini1 ,
Marco Heidemperger1 , Matteo Trezzi1 , Emanuela Piccaluga3 , Paolo Danna3 and Daniele Scorza1
1
Nephrology and Dialysis Ospedale “L. Sacco” Milano, Italy, 2 Department of Anesthesia and Intensive Care, Istituto Scientifico San
Raffaele, Milano, Italy and 3 Cardiology Department Ospedale “L. Sacco” Milano, Italy
Correspondence and offprint requests to: Giovanni Landoni; E-mail: [email protected]
Abstract
Introduction. Intravenous administration of saline and
non-ionic isosmolar contrast media significantly reduces
the incidence of contrast-induced nephropathy, one of
the most common causes of acute renal failure. Results
with oral N-acetylcysteine are conflicting. The aim of
our study was to evaluate the prophylactic role of Nacetylcysteine in patients with stable chronic renal failure
undergoing coronary and/or peripheral angiography and/or
angioplasty.
Methods. We randomized 200 elective, consecutive
patients (mean age 74.9 ± 7.3 years; 65% male, 25%
diabetics) with basal creatinine clearance ≤55 ml/min to
receive oral N-acetylcysteine (600 mg bid the day before
and the day of the procedure plus saline i.v. 0.9% 1 ml/kg/h
12–24 h before and 24 h after the procedure, n = 99) or
placebo and saline at the same time intervals, n = 101. The
contrast medium was non-ionic isosmolar (Iodixanol, Visipaque Amersham Health). Contrast-induced nephropathy
was defined as an increase in serum creatinine >0.5 mg/dl
or >25% within 3 days after the procedure. Serum
creatinine was measured at baseline, 24, 48 and 72 h after
the procedure.
Results. Contrast-induced nephropathy was 8/99 (8.1%)
in the N-acetylcysteine group versus 6/101 (5.9%) in the
placebo group, P = 0.6. No difference was noted in highrisk subgroups such as diabetics (4/25 versus 2/25 P = 0.4)
and those with serum creatinine clearance <42.3 ml/min
(5/54 versus 4/48; P = 0.9).
Conclusion. In our experience, N-acetylcysteine did not
prevent contrast-induced nephropathy in patients receiving isosmolar (iodixanol) contrast media and adequate
hydration.
Keywords: acute renal failure; contrast nephropathy; isosmolar contrast
media; N-acetylcysteine; renal replacement therapy
Introduction
Contrast media-induced nephropathy (CIN) is a recognized
complication in angiographic diagnostic and interventional
procedures and is associated with prolonged hospitalization
and adverse clinical outcome [1]. Its frequency increases
with reduced creatinine clearance, ranging from 5% in those
with mild renal impairment to 50% in those with diabetes
and severe renal insufficiency [2]. The pathophysiological
mechanism of CIN is not well understood. It may be related
to the alteration of renal haemodynamic, to the damage
caused by oxygen free radicals and to the direct toxic effect
of contrast media on tubular cells [3,4].
There is a pressing need to find effective strategies for
the prevention of CIN in high-risk patients in order to improve the outcome of patients receiving angiography and/or
angioplasty. Identification of high-risk population, avoidance of nephrotoxic drugs and the use of small amounts
of low-osmolality contrast media are recognized methods to decrease the incidence of CIN. Only periprocedural hydration is a widely accepted strategy to prevent
CIN [5]. Various prophylactic agents, including calcium
antagonists, theophylline, dopamine, mannitol, endothelin
antagonist and atrial natriuretic peptides, have been tried
to prevent CIN, with few resoundingly positive results
[6–11].
In recent years, N-acetylcysteine (NAC) has been extensively studied. The ability of scavenging a variety
of oxygen-derived free radicals and the improvement of
endothelium-dependent vasodilation are properties of NAC
that may confer protection against CIN [12]. Tepel first reported that NAC may prevent acute renal dysfunction in
patients with chronic kidney disease who are undergoing
procedures requiring the use of a radiocontrast medium
[13]. Several studies on the prophylactic effect of NAC
have been published, with contradictory results [14–25].
Several meta-analyses that explored the role of NAC for
the prevention of CIN have been published without conclusively resolving this issue [26]. Several systematic reviews
on the same clinical topic varied in quality of reporting
C The Author [2009]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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F. Ferrario et al.
and recommendations [27]. The intervention has minimal
toxicity, but the width of the 95% CI remains compatible
with a range from a large benefit to none at all. Further randomized trials are recommended [28]. Data regarding NAC
clinical efficacy are sparse and conflicting and there is still
virtually no definitive evidence of efficacy, especially in
high-risk patients. Moreover, only one study evaluated the
effects of NAC in patients receiving the isosmolar contrast
medium [23].
Therefore, we performed a prospective, randomized clinical study to assess the effect of NAC on the prevention of
CIN in patients with moderate-to-severe chronic renal failure who underwent elective angiography and/or angioplasty
with isosmolar contrast media.
Methods
Study population
The study was carried out according to the principles of the Declaration of
Helsinki. The ethical committee approved the study protocol. The patients
provided written informed consent.
Consecutive eligible patients, 18 years of age or older, scheduled for
elective diagnostic and interventional angiography at a university hospital
were randomly assigned to receive NAC and intravenous saline (0.9%) or
placebo and intravenous saline.
The patients were included if their creatinine clearance was <55 ml/min
as calculated by the Cockcroft Gault formula, were scheduled for elective
coronary and/or peripheral angiography and/or angioplasty and had a
stable renal function as documented by a small ±10% variation in serum
creatinine pre-procedural values when compared to the outpatients values
performed 3–30 days before the procedure.
Exclusion criteria were represented by New York Health Association
status III to IV, ongoing acute myocardial infarction or acute coronary
syndrome, renal replacement therapy, allergy to NAC, need for theophylline, dopamine, fenoldopam, mannitol or nephrotoxic drugs (nonsteroidal anti-inflammatory drugs, fluoroquinolones, aminoglycosides . . .)
within 1 week of the procedure, the presence of clinical signs of dehydration and systemic hypotension.
Protocol
Details of the randomization, created by a computer-generated list, were
contained in a set of sealed, opaque envelopes that were opened after the
patient had signed the consent. As shown in Figure 1, out of the 271 eligible
patients, 56 refused to sign the consent and did not take part in the study.
From the 215 patients who were randomized, we excluded 15 patients
due to the following reasons: 2 patients were later discovered not to fulfil
the inclusion criteria; 4 patients did not undergo the planned procedure;
2 patients had periprocedural pulmonary oedema and 7 patients were lost to
follow-up (left the hospital before completing the planned postprocedural
examination). The two groups received either NAC and intravenous saline
(99 patients) or placebo and saline alone (101 patients). NAC was supplied
as tablets [600 mg twice a day (bid) for 2 days]; placebo was supplied
as tablets containing glucose. They were both administered orally the
day before and the day of the procedure (completing the treatment the
evening of the procedure day) by trained nurses that were not involved in
the patients’ management. All patients received normosaline (0.9%) e.v.
1 ml/kg/h in the 12–24 h before the procedure and in the following 24 h.
Oral clear fluid intake was not restricted before or after the procedure.
All pre-procedural medications were routinely continued on the day of
the procedure.
All patients received isosmolar (290 mOsm/Kg), non-ionic, dimeric
contrast medium [29] (Iodixanolo, Visipaque, Amersham Health, Princeton, NJ, USA).
Study end point
We tested the hypothesis that NAC would reduce the incidence of postprocedural CIN as compared to placebo. The primary end point of the
study was the incidence of CIN following elective diagnostic and inter-
Fig. 1. Flow diagram of randomization.
ventional angiography defined as an increase of serum creatinine levels
of 25% or more and/or 0.5 mg/dl or more from baseline to the maximum
value [13].
Plasmatic creatinine was assayed by our hospital laboratory during the
preprocedural period, and daily for 3 days after the procedure.
Power of the study and statistical analysis
Sample size calculations were based on a two-sided alpha error of 0.05
and 80% power. On the basis of our experience and of previous data
investigating post-procedural CIN in high-risk patients, we anticipated a
20% frequency of CIN by the average incidence in previously published
studies [30] in the standard treatment group and assumed a 50% reduction
after treatment with NAC. We calculated that we would need a sample
size of 80 patients per group. Therefore, the total study population was
2 × 80 = 160 patients. We randomized 215 patients to account for possible
protocol deviations.
Data were stored electronically and analysed by use of Epi Info 2002
software (Center for Disease Control) and SAS software, version 8 (SAS
Institute, Cary, NC, USA). Data analysis was carried out according to a
pre-established analysis plan. Dichotomous data were compared by using
two-tailed χ2 test with the Yates correction or Fisher’s exact test when
appropriate. Continuous measures were compared by analysis of variance
(ANOVA) or the Mann–Whitney U-test when appropriate. Two-sided significance tests were used throughout.
Planned subgroup analysis included patients with clearance creatinine
less than the median value (42.3 ml/min), diabetic patients and those
receiving >140 ml [31] of contrast media volume.
Acetylcysteine and non-ionic isosmolar contrast-induced nephropathy
Table 1. Clinical and biochemical characteristics of 200 patient receiving
N-acetylcysteine plus saline or saline alone for renal protection in elective
diagnostic or interventional angiography
Variables
Age (year)
Female sex, n (%)
Creatinine clearance (ml/min)
MDRD (Modification of Diet in
Renal Disease) (ml/min)
Diabetes mellitus, n (%)
Hypertension, n (%)
Hyperlipidemia, n (%)
Peripheral vascular disease, n (%)
Diuretics, n (%)
Angiotensin-converting enzyme
inhibitors, n (%)
Calcium channel blocker, n (%)
Angiotensin II receptor
inhibitor, n (%)
Left ventricular ejection
fraction < 40%, n (%)
Contrast agent volume (ml)
Pre-procedural hydration (h)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
N-acetylcysteine
(n = 99)
Placebo
(n = 101)
75 ± 7.7
32 (32%)
37 ± 11.5
40 ± 18.5
75 ± 6.9
38 (38%)
40 ± 9.3
45 ± 20.5
25 (25%)
79 (80%)
51 (52%)
24 (24%)
50 (50%)
49 (49%)
25 (25%)
84 (83%)
40 (39%)
29 (29%)
40 (39%)
53(52%)
25 (25%)
7 (7%)
30 (30%)
14 (14%)
7 (7%)
6 (6%)
180 ± 104.4
19 ± 3.9
141 ± 20
79 ± 10
168 ± 103.3
19 ± 4.4
142 ± 20
78 ± 10
Results
Between March 2003 and January 2005, 200 patients were
randomly assigned to receive either NAC or placebo (Figure 1). The overall incidence of CIN was 14/200 (7.0%)
with the two groups of patients having a similar incidence:
8/99 (8.1%) in the NAC group and 6/101 (5.9%) in
the placebo group (P = 0.6). No patient required renal
replacement therapy and no patient died in hospital; no
patient had a prolonged length of hospital stay (>5 days).
The baseline demographics and clinical characteristics
are reported in Table 1. Pre-procedural hydration was similar in the two groups (19 ± 3.9 h in the NAC group versus
19 ± 4.4 h in the placebo group). These 200 patients randomized to receive either NAC (99 patients) or placebo (101
patients) were at a high risk of developing CIN since the
creatinine clearance as calculated by the Cockcroft Gault
formula was 37 ± 11.5 ml/min in the NAC group and 40 ±
9.3 ml/min in the placebo group.
Serum creatinine remained stable from a baseline level
of 1.6 ± 0.69 mg/dl to a peak postoperative value of 1.6 +
0.71 mg/dl (P = 0.9) in the overall population. In those
patients who developed CIN, serum creatine showed a 40%
increase, from 1.5 ± 0.57 to 2.1 ± 0.68 mg/dl. All 14 patients with CIN recovered renal function completely within
15 days. MDRD (Modification of Diet in Renal Disease)
preprocedural and peak postprocedural values were stable
in both groups: from 40 ± 18.5 to 41 + 18.7 (P = 0.9)
ml/min in the NAC group and from 45 ± 20.5 to 47 + 19.3
in the placebo group (P = 0.8).
Subgroup analysis showed that in patients with a creatinine clearance less than the median value (42.3 ml/min), the
incidence of CIN was 5/54 (9.2%) in the NAC group versus
4/48 (8.3%), P = 0.9; in diabetic patients, the incidence of
CIN was 4/25 (16.0%) in the NAC group versus 2/25 (8%),
3105
P = 0.40; in patients receiving >140 ml of contrast media
volume, the incidence of CIN was 6/59 (10.2%) in the NAC
group versus 4/48 (8.3%), P = 0.5.
A post hoc analysis in the overall population showed that
in patients receiving >140 ml contrast media volume, the
incidence of CIN trended towards a higher incidence of
10/107 (9.3%) versus 4/93 (4.3%) in the remaining population (P = 0.1).
Discussion
The principal finding of this randomized double-blind trial
is that NAC failed to show a reduction in the risk of CIN in
high-risk patients receiving low-osmolality contrast media
when compared to placebo.
CIN accounts for 10% of all causes of hospital-acquired
acute renal failure and represents the third most common
cause of in-hospital renal function deterioration after decreased renal perfusion and post-operative renal insufficiency [32].
In a recent retrospective analysis of 7230 consecutive
patients with vascular angiography or intervention, the incidence of CIN was 13.1% in the general population and
19.2% in patients with a glomerular filtration rate (GFR)
<60 ml/min [30]. Although generally mild, CIN can occasionally result in the need for dialysis and increased morbidity and mortality [33].
Probably, a combination of various mechanisms needs to
act in concert to cause CIN. A reduction in renal perfusion
caused by a direct effect of contrast media on the kidney and
toxic effects on the tubular cells are generally recognized
as important [34]. Among the often-discussed mechanisms,
superoxide and perhaps other reactive oxygen species have
been discussed to promote CIN. Reactive oxygen species
are endogenously produced and their levels can increase
during an oxidative stress-like reduction in renal perfusion.
Reactive oxygen species may be significant in mediating
the actions of vasoconstrictors that have been considered
important for the development of CIN [35].
NAC has a number of properties including anti-oxidant
functions and mediation of renal vasodilatation suggesting
a role in preventing CIN [36,37], particularly considering
its low cost, safety and ease of administration.
Tepel was the first who published a randomized trial
about the role of NAC in preventing CIN and reported a
success with this agent [13].
Since then, many randomized controlled trials examined
the effect of NAC on the prevention of CIN in patients with
renal insufficiency; however, conflicting results were observed (Table 2). NAC has been the subject of comprehensive reviews, and there appears to be insufficient evidence
to support the universal use of NAC to prevent CIN.
Recent meta-analyses show a non-significant trend towards benefit in patients with impaired renal function
treated with NAC. The intervention has minimal toxicity,
but the width of the 95% CI remains compatible with a
range from a large benefit to none at all. Further randomized trials of large sample size and with clinical outcomes
will add importantly relevant information to the totality of
evidence and allow the most rational clinical decisions for
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F. Ferrario et al.
Table 2. Randomized controlled trials examining the effect of N-acetylcysteine on prevention of contrast medium-induced nephropathy in patients
with renal insufficiency
Study
Year
Number of patients
GFR/creat
N-acetylcysteine dose
Contrast agent
N-acetylcysteine versus placebo
Tepel
Diaz
Briguori
Shyu
Durham
Allaquaband
Kay
Boccalandro
Tadros
Macneill
Goldemberg
Fung
2000
2002
2002
2002
2002
2002
2003
2003
2003
2003
2004
2004
83
54
183
121
79
85
200
179
110
43
80
91
<50 ml/min
<50 ml/min
<70 ml/min
<40 ml/min
Creatinine >1.7
<60 ml/min
<60 ml/min
<50 ml/min
Creatinine >1.2
Creatinine >1.5
<50 ml/min
Creatinine > 1.7
600 bid × 2 d
600 bid × 2 d
600 bid × 2 d
400 bid × 2 d
1200 bid × 1 d
600 bid × 2 d
600 bid × 2 d
600 bid × 2 d
600 bid × 2 d
600 bid × 2 d
600 tid × 2 d
400 tid × 2 d
Iopromide
Ioxilan
Iopromide
Iopamidol
Iohexol
Iopamidol
Iopamidol
Iodixanol
Iopamidol
Iopromide
Iopromide
Iopromide
2% versus 21%
8% versus 45%
6.5% versus 11%
3.3% versus 24%
26% versus 22%
17% versus 15%
4% versus 12%
13% versus 12%
5% versus 16%
4% versus 30%
10% versus 8%
17% versus 13%
Statistically significant results are in bold.
GFR, glomerular filtration rate; d, day; bid, twice a day; tid, three times a day.
individual patients as well as policy decisions for the health
of the general public [28,38].
In spite of the virtual absence of definitive evidence, the
use of NAC as a renal protective agent has become a nearly
standard practice in many hospitals on the basis of the initial clinical study by Tepel. It is not clear why conflicting
results regarding the protective role of prophylactic NAC
were observed in clinical trials. Firstly, most studies remain
severely underpowered because of the low number of patients. Moreover, an incomplete saline infusion (the only
strategy widely accepted to prevent CIN) was observed and
not all authors specified the amount of hydration performed.
In our trial, all patients received normosaline (0.9%) e.v.
1 ml/kg/h in the 12–24 h before the procedure (mean hydration pre-procedure was 19 h) and in the following 24 h.
Furthermore, oral clear fluid intake was not restricted before or after the procedure.
In the current prospective randomized clinical trial, NAC
failed to prevent CIN in a high-risk population of 200 patients. CIN, defined as a postoperative serum creatinine
level increase of at least 25% and/or ≥0.5 mg/dl, developed in 8.1% of patients treated with NAC plus saline versus 5.9% of patients treated with saline alone.
Moreover, we did not find any significant effect on the
occurrence of CIN with NAC in a high-risk patient subgroup analysis (patients with clearance creatinine less than
the median value, diabetic patients and those receiving
>140 ml of contrast media volume). Nonetheless, due to
the limited size of these subgroups, large studies in specific
subsettings are still justified.
A post hoc analysis in the overall population showed that
in patients receiving >140 ml of contrast media volume, the
incidence of CIN trended towards a higher incidence 10/107
(9.3%) versus 4/93 (4.3%) in the remaining population
(P = 0.1).
It should be emphasized that we used an isosmolar contrast agent (iodixanol) that has entered into clinical practice
after the NEPHRIC [39] study and after the recent metaanalysis of Mc Collough et al. [40]. Interestingly, the only
other trial [23] that studied CIN using iodixanol had similar negative findings. It should be acknowledged that one
recent retrospective report [41] suggested that the risk of de-
veloping renal failure after coronary procedures was higher
when patients received iodixanol than ioxaglate or iohexol.
Limitations
We did not measure GFR in our population and limited our
analysis to MDRD which is not validated for acute changes
in kidney function and serum creatinine (which is known
to be altered by NAC). Beneficial renal effects have been
demonstrated at doses of 600 mg bid [13,18,19,24,25] and
other authors have already studied even lower doses (400
mg bid) with success [15]. A double dose of NAC (1200–
1500 mg bid) was studied with contrasting results [31,42].
While the current study size effectively rules out NAC utility for the prevention of ARF in the study population as a
whole, it would be useful to identify subgroups of patients
with similar characteristics in order to identify lower/higher
risk patients who could benefit from NAC administration.
The volume status could have been better investigated in
this study, for example by the inferior vena cava index [43].
Due to dietary creatinine intake, tubulary secretion of creatinine and variations in the patients’ muscle mass, the use of
serum creatinine may inaccurately estimate the GFR. The
decrease in serum creatinine might reflect either an increase
in creatinine excretion or a decrease in creatinine production attributable to NAC. The creatinine metabolism can be
affected by NAC either through direct activation of creatinine kinase or through reversal of inhibition by free radicals.
N-acetylcysteine itself can directly lower serum creatinine
concentration without improving renal function [44]. We
should also acknowledge that this study is not adequately
powered to exclude any beneficial effect of NAC in this population. In fact our power analysis was based on an anticipated 20% frequency of CIN in the control group, while we
observed a 7% incidence of CIN in the overall population.
Conclusions and clinical implications
In this small, randomized placebo-controlled study, NAC
was not useful to prevent CIN in patients receiving an
isosmolar (iodixanol) contrast medium and adequate
Acetylcysteine and non-ionic isosmolar contrast-induced nephropathy
hydration. Even if the negative finding of this investigation could be, in part, attributed to the low incidence and
severity of CIN in this population, we suggest that hydration
and the use of iodixanol contrast medium could be enough
for renal protection.
Conflict of interest statement. None declared.
References
1. Rihal CS, Textor SC, Grill DE et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention.
Circulation 2002; 105: 2259–2264
2. Curhan GC. Prevention of contrast nephropathy. JAMA 2003; 289:
606–608
3. Heyman SN, Rosenberger C, Rosen S. Regional alteration in renal
haemodynamics and oxygenation: a role in contrast medium-induced
nephropathy. Nephrol Dial Transplant 2005; 20(S1): i6–i11
4. Persson PB, Hansell P, Liss P. Pathophysiology of contrast mediuminduced nephropathy. Kidney Int 2005; 68: 14–22
5. Trivedi HS, Moore H, Nasr S et al. A randomized prospective trial
to assess the role of saline hydration on the development of contrast
nephrotoxicity. Nephron Clin Pract 2003; 93: C29–C34
6. Solomon R, Werner C, Mann D et al. Effects of saline, mannitol
and furosemide on acute to prevent acute decreases in renal function
induced by radiocontrast agents. NEJM 1994; 331: 1416–1420
7. Wang YXJ, Jia YF, Chen KM et al. Radioghraphic contrast mediainduced nephropathy: experimental observations and the protective
effect of calcium channel blockers. Br J Radiol 2001; 74: 1103–1108
8. Wang A, Holcslaw T, Bashore TM et al. Exacerbation of radiocontrast
nephrotoxicity by endothelin receptor antagonism. Kidney Int 2000;
57: 1675–1680
9. Stone GW, McCullough PA, Tumlin JA et al. Fenoldopam mesylate
for the prevention of contrast-induced nephropathy. A randomised
controlled trial. JAMA 2003; 290: 2284–2291
10. Ix JH, McCulloch CE, Chertow GM. Theophylline for the prevention
of radiocontrast nephropathy: a meta-analysis. Nephrol Dial Transplant 2004; 19: 2747–2753
11. Kurnik BRC, Allgren RL, Genter FC et al. Prospective study of
atrial natriuretic peptide for the prevention of radiocontrast-induced
nephropathy. Am J Kidney Dis 1998; 31: 674–680
12. Efrati S, Dishy V, Averbukh M et al. The effect of N-acetylcysteine
on renal function, nitric oxide and oxidative stress after angiography.
Kidney Int 2003; 64: 2182–2187
13. Tepel M, Van Der Giet M, Schwarzfeld C et al. Prevention of
radiographic-contrast-agent-induced reductions in renal function by
acetylcysteine. NEJM 2000; 20: 180–184
14. Vallero A, Cesano G, Pozzato M et al. Nefropatia da contrasto in cardiologia interventistica: assenza di vantaggi con impiego profilattico
di N-Acetilcisteina. GIN 2002; 19: 529–533
15. Shyu KG, Cheng JJ, Kuan P. Acetylcysteine protects against acute
renal damage in patients with abnormal renal function undergoing a
coronary procedure. JACC 2002; 40: 1383–1388
16. Briguori C, Manganelli F, Scarpato P et al. Acetylcysteine and contrast
agent-associated nephrotoxicity. JACC 2002; 40: 298–303
17. Durham JD, Caputo C, Dokko J et al. A randomized controlled trial of
N-acetylcysteine to prevent contrast nephropathy in cardiac angiography. KI 2002; 62: 2202–2207
18. Diaz-Sandoval LJ, Kosowsky BD, Losordo DW. Acetylcysteine to
prevent angiography-related renal tissue injury (The APART Trial).
Am J Cardiol 2002; 89: 356–358
19. Kay J, Chow WH, Chan TM et al. Acetylcysteine for prevention
of acute deterioration of renal function following elective coronary
angiography and intervention. A randomized controlled trial. JAMA
2003; 289: 553–558
20. Fung JW, Szeto CC, Chan WW et al. Effect of N-Acetylcysteine for
prevention of contrast nephropathy in patients with moderate to severe
renal insufficiency: a randomized trial. AJKD 2004; 43: 801–808
3107
21. Webb JG, Pate GE, Humphries KH et al. A randomised controlled
trial of intravenous N-acetylcysteine for the prevention of contrastinduced nephropathy after catheterisation: lack of effect. Am Heart J
2004; 148: 422–429
22. Goldemberg I, Shechter M, Matetzky S et al. Oral acetylcysteine as
an adjunct to saline hydration for the prevention of contrast-induced
nephropathy following coronary angiography. Eur Heart J 2004; 25:
212–218
23. Boccalandro F, Amhad M, Smalling RW et al. Oral acetylcysteine does
not protect renal function from moderate to high doses of intravenous
radiographic contrast. Catheter Cardiovasc Interv 2003; 58: 336–341
24. Tadros GM, Mouhayar EN, Akinwande AO et al. Prevention of
radiocontrast-induced nephropathy with N-acetylcysteine in patients
undergoing coronary angiography. J Invas Cardiol 2003; 15: 311–314
25. MacNeill B, Harding SA, Bazari H et al. Prophylaxis of contrastinduced nephropathy in patient undergoing coronary angiography.
J Invas Cardiol 2003; 60: 458–461
26. Bagshaw SM, Ghali WA. Acetylcysteine for prevention of contrastinduced nephropathy after intravascular angiography: a systematic
review and meta-analysis. BMC Med 2004; 2: 38
27. Biondi-Zoccai GG, Lotrionte M, Abbate A et al. Compliance with
QUOROM and quality of reporting of overlapping meta-analyses on
the role of acetylcysteine in the prevention of contrast associated
nephropathy: case study. BMJ 2006; 332: 202–209
28. Zagler A, Azadpour M, Mercado C et al. N-acetylcysteine and
contrast-induced nephropathy: a meta-analysis of 13 randomized trials. Am Heart J 2006; 151: 140–145
29. Aspelin P, Aubry P, Fransson SG et al. Nephrotoxic effects in highrisk patients undergoing angiography. NEJM 2003; 348: 491–499
30. Dangas G, Iakovou I, Nikolsky E et al. Contrast-induced nephropathy
after percutaneous coronary interventions in relation to chronic kidney
disease and hemodynamic variables. Am J Cardiol 2005; 95: 13–19
31. Briguori C, Colombo A, Violante A et al. Standard vs double dose
of N-acetylcysteine to prevent contrast agent associated nephropathy.
Europ Heart J 2004; 25: 206–211
32. Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am
J Kidney Dis 2002; 39: 930–936
33. Weisbord S. The high cost of acute renal failure following the administration of intravenous contrast media in hospitalised patients. J Am
Soc Nephrol 2002; 13: 447
34. Solomon R. Radiocontrast-induced nephropathy. Semin Nephrol
1998; 18: 551–557
35. Katholi RE, Woods WT Jr, Taylor GJ et al. Oxygen free radicals and
contrast nephropathy. Am J Kidney Dis 1998; 32: 64–71
36. Heyman SN, Goldfarb M, Shina A et al. N-acetylcysteine ameliorates
renal microcirculation: Studies in rats. Kidney Int 2003; 63: 634–641
37. Efrati S, Dishy V, Averbukh M et al. The effect of N-acetylcysteine
on renal function, nitric oxide and oxidative stress after angiography.
Kidney Int 2003; 64: 2182–2187
38. Nallamothu BK, Shojania KG, Saint S et al. Is acetylcysteine effective
in preventing contrast-related nephropathy? A meta-analysis. Am J
Med 2004; 117: 938–947
39. Aspelin Aubry P, Fransson SG et al. Nephrotoxic effects in high-risk
patients undergoing angiography. NEJM 2003; 348: 491–499
40. McCullough PA, Bertrand ME, Brinker JA et al. A meta-analysis of
the renal safety of isosmolar iodixanol compared with low-osmolar
contrast media. J Am Coll Cardiol 2006; 48: 692–629
41. Liss P, Persson PB, Hansell P et al. Renal failure in 57 925 patients
undergoing coronary procedures using iso-osmolar or low-osmolar
contrast media. Kidney Int 2006; 70: 1811–1817
42. Oldemeyer JB, Biddle WP, Wurdeman RL et al. Acetylcysteine in the
prevention of contrast-induced nephropathy after coronary angiography. Am Heart J 2003; 146: 23
43. Toprak O, Cirit M, Yesil M et al. Impact of diabetic and pre-diabetic
state on development of contrast-induced nephropathy in patients
with chronic kidney disease. Nephrol Dial Transplant 2007; 22: 819–
826
44. Toprak O. Interactions between serum creatinine, volume status, Nacetylcysteine and contrast-induced nephropathy. Ren Fail 2006; 28:
265–266
Received for publication: 13.5.08; Accepted in revised form: 29.5.09