N-Acetylcysteine in the Prevention of Contrast-Induced

Nephropathy
Steven Fishbane
Winthrop-University Hospital, Mineola, New York, and State University of New York School of Medicine, Stony
Brook, New York
Background and objectives: Contrast-induced nephropathy (CIN) is a common clinical problem that is growing in importance
as an increasing number of tests and procedures that utilize contrast media are performed.
Design, setting, participants, and measurements: The biological and pharmacological properties of n-acetylcysteine (NAC)
are reviewed, as well as the current literature relevant to the ability of NAC to prevent CIN.
Results: After publication of a seminal study by Tepel et al. in 2000, there has been a surge in interest regarding the ability
of NAC to reduce the risk for CIN. Since then a large number of studies, mostly with relatively small sample sizes, have been
published.
Conclusions: The results have been remarkably varied with some studies finding great efficacy with NAC but most finding
no significant benefit.
Clin J Am Soc Nephrol 3: 281287, 2008. doi: 10.2215/CJN.02590607

ontrast-induced nephropathy (CIN) is most precisely

defined as an acute deterioration in renal function
after exposure to, and as a result of, contrast media
(CM). In actuality, however, acute renal failure (ARF) occurring
after procedures associated with contrast administration may
be caused by several different factors including volume depletion, atheroembolic disease, congestive heart failure, and a
functional increase in serum creatinine (SCr) after preprocedure
hydration. Because it is not always possible to clinically differentiate the cause of the renal dysfunction, it may be more
appropriate to term this condition contrast-associated nephropathy.
It is certain that different causes of contrast-associated renal
dysfunction require different preventive strategies. Prevention
of renal failure that is truly caused by contrast requires interventions based on our knowledge of the pathophysiology of
this disorder. Consequences of exposure to CM may include
renal vasoconstriction and redistributed blood flow (1 6), tubular epithelial cell toxicity (disruption of cell integrity, oxygen
radical generation, and apoptosis (713), intratubular obstruction, and hemoglobin oxygen saturation curve shifts. A variety
of therapeutic agents aimed at ameliorating these changes have
been studied. This article discusses one specific agent, n-acetylcysteine (NAC).

Published online ahead of print. Publication date available at www.cjasn.org.

Correspondence: Dr. Steven Fishbane, 200 Old Country Road, #135, Mineola, NY
11501. Phone: 516-663-2169; Fax: 516-663-2179; E-mail: sfishbane@winthrop.org
Copyright 2008 by the American Society of Nephrology

N-Acetylcysteine
NACs primary use in clinical medicine has been as a mucolytic
agent, where inhalation leads to splitting of disulfide linkages
between the glycopeptides in mucus and loosening of obstructive plugs (14,15). In addition, NAC plays an important role in
the treatment of acetaminophen overdose, where administration of large doses results in improved outcomes (16 18). Hepatic metabolism of acetaminophen results in production of
N-acetyl benzoquinoneimine, which depletes cellular glutathione stores, leaving the liver vulnerable to oxidative injury
(19,20). Administration of NAC provides cysteine as a substrate
to replenish glutathione stores and reduce hepatic damage
(21,22).

Pharmacology
N-acetylcysteine is an acetylated derivative of the amino acid
cysteine. The chemical formula is C5H9NO3S, and the molecular mass is 163.2 g/mol (Figure 1). The drug can be administered via oral, intravenous, or respiratory routes. Early studies
of NAC pharmacology were hindered by the complexity of the
analysis. The problem is caused by the drugs highly reactive
sulfhydryl group, which rapidly binds to and reacts with
plasma and tissue proteins, forming disulfide linkages, with
oxidation of the drug (23). The drug may circulate free in
plasma or may become associated with other proteins in a wide
variety of forms (24). Analytic systems testing the concentration
of NAC in plasma must be able to differentiate between reduced and oxidized NAC as well as free and bound NAC
found in proteinaceous complexes in the sample.
Older studies reported NAC to have a plasma half-life of
several hours, but with modern techniques the bioavailability
ISSN: 1555-9041/3010281

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Clinical Journal of the American Society of Nephrology

Figure 1. Structure of N-acetylcysteine.

has been found to be poor and the actual half-life closer to 6 to

40 min. After oral administration, Moldeus and Cotgreave were
able to detect only very small quantities of oxidized drug in
circulation, with no free drug detectable (23). Bioavailability
was 5%, probably because of extensive first-pass hepatic metabolism. Numerous other investigators have confirmed the
low bioavailability of oral NAC including slow-release preparations (2528). After intravenous injection, Harada et al. found
that NAC was highly bound to plasma and tissue proteins,
forming various disulfide compounds. Only small amounts of
NAC were found in circulation despite the intravenous route of
administration (29). It is clear from these reports that, after oral
administration, NAC is almost completely metabolized before
entering the systemic circulation. When considering the mechanism by which NAC can have a potential benefit in preventing
CIN, its poor bioavailability must somehow be reconciled.
The poor bioavailability of NAC after oral dosing is the result
of extensive first-pass metabolism. With intestinal transit and
absorption, NAC is effectively deacetylated by the enzyme
acylase I in the intestines and liver (30 35). The resulting free
amino acid cysteine has a highly reactive sulfhydryl group that
readily reacts with plasma and tissue proteins yielding a variety of sulfur-containing molecules and compounds. In rats, the
major metabolites entering the circulation include cysteine, cystine, inorganic sulfites, homodisulfides of NAC, and labile disulfide protein complexes (34,36). In the circulation of the portal
vein, the deacetylation of NAC is so efficient that the concentration of metabolites is 300% to 500% higher than that of NAC
(34). The liberated cysteine molecules can be used by cells as
precursors for glutathione production.

Biological Actions of NAC

The pharmacology of NAC, particularly its deacetylation and
poor bioavailability, make clear that the drugs in vitro effects
must be considered separately from its in vivo actions. The
beneficial therapeutic effects of NAC may well be a result of
indirect effects such as induction of glutathione synthesis. NAC
has a variety of biological actions. The following discussion will
highlight those most relevant to the pathogenesis of CIN.
The antioxidant properties of NAC have been studied exten-

Clin J Am Soc Nephrol 3: 281287, 2008

sively. Bursts of oxidative stress occur naturally, and the bodys

cells and tissues possess antioxidant systems to protect against
oxidative damage (37). After exposure to CM there is a surge in
oxidative stress that may overwhelm these systems and result
in tissue injury (38). The most plausible mechanism of NACs
putative protective effect against CIN is supplementation of the
bodys antioxidant capacity.
NAC is very effective in neutralizing certain free radicals in
vitro. The drug reacts with and deactivates hydroxyl radicals
(39,40); the reaction is rapid, with a rate constant of 1.36 1010
M1sec1, yielding NAC thiol radical intermediates and ultimately NAC disulfide (39). Regarding other reactive oxygen
species, such as superoxide anion and hydrogen peroxide,
NAC is a somewhat less effective antioxidant (40).
Because NAC is extensively degraded in vivo (as discussed
above), it is likely that any antioxidant effects it exerts in
humans would be indirect. For example, NAC might work by
inducing glutathione synthesis. Glutathione plays a central role
in the bodys defense against cellular oxidative damage (41,42).
It generally cannot enter cells; instead it must be synthesized
intracellularly from glycine, glutamate, and cysteine. Cysteine
is the moiety that supplies glutathiones active sulfhydryl
group and plays a critical role as the rate-limiting factor in
glutathione synthesis. After deacetylation in the intestines and
liver, NAC yields cysteine as one of its metabolites. This circulating cysteine may enter renal cells and serve as a precursor for
glutathione production. In fact, several studies have found that
NAC prevents glutathione depletion (43,44). The relevance for
the kidney is suggested by the demonstration of glutathione
depletion in ischemia reperfusion injury (46,47). In rats, administration of NAC has been found to increase renal glutathione
levels (48).
In addition to its antioxidant properties, NAC has other
biological actions that might be helpful for preventing CIN.
Vasoconstriction has often been considered as a factor contributing to the pathogenesis of CIN. By stabilizing nitric oxide,
NAC may have a vasodilatory effect in certain situations (49
51). In addition, NACs sulfhydryl group may inhibit angiotensin-converting enzyme, reducing production of the vasoconstrictor angiotensin II (52). The vasoconstriction in CIN may be
somewhat selective, particularly affecting the kidneys medullary circulation (53). In a study of ARF induced by inferior vena
cava obstruction, a model with reduced medullary blood flow,
Conesa et al. found that NAC reduced medullary vasoconstriction and improved blood flow (54). Heyman and colleagues
(55) found that NAC administration in rats resulted in reduced
total, cortical, and medullary vascular resistance by 7% to 10%.
Another recently demonstrated action of NAC is in reducing
urinary albumin excretion (56).

Clinical Studies of NAC in the Prevention of

CIN
The salutary properties of NAC described in the previous section form the rationale for why NAC might be helpful in the
prevention of CIN. Tepel et al. published the first clinical study
on this subject in 2000 (57). Since that time there have been
many published studies with great heterogeneity in results,

Clin J Am Soc Nephrol 3: 281287, 2008

some finding substantial benefit for NAC, others reporting no

effect. Most of the studies included patient populations at relatively increased risk for CIN, generally defined by an increased baseline SCr. ARF developing after contrast exposure
has generally been defined as an increase in SCr of 0.5 mg/dl
or 25% above the baseline value. Studies generally did not
attempt to differentiate ARF induced by CM from other possible causes.
In Tepels seminal report, 83 patients undergoing contrastenhanced CT scanning were studied. Only subjects with SCr
1.2 mg/dl or creatinine clearance 50 ml/min were studied.
Randomization was followed by double-blind treatment with
either oral NAC 600 mg twice daily on the day before and the
day of the CT scan or with placebo. ARF, defined as an increase
in SCr of 0.5 mg/dl, occurred in 21% of placebo subjects
compared with 2% in the NAC group (P 0.01). This dramatic
reduction in risk with NAC drew great attention and led to an
almost immediate change in clinical practice (57).
Shortly after Tepels publication, our group attempted to
reproduce the finding in patients undergoing cardiac angiography. Subjects with SCr 1.7 mg/dl were randomized to
double-blind administration of placebo or NAC 1200 mg orally
with doses 1 h before the procedure and 3 h afterwards. ARF
was defined as an increase in SCr of 0.5 mg/dl. We found no
significant difference in the rate of CIN between the NAC and
placebo groups (26.3% versus 22.0%). The remarkable disparity
between our results and those of Tepel et al. presaged the
literature that has paralleled this pattern of great heterogeneity
of results (58).

Other Studies

There are 20 published studies investigating NAC for the

prevention of CIN, with 30 to 487 subjects enrolled in each
study. Studies with negative results outnumber those with
positive results by a 2-to-1 margin. However, the magnitude of
benefit in some of the positive studies was substantial. Studies
by Tepel et al., Shyu et al., Kay et al., and Diaz-Sandoval et al.
reported that NAC reduced the risk of CIN by 90.5%, 86.6%,
67.7%, and 82.2%, respectively (57,59 61). There are few areas
in clinical medicine where a treatment has demonstrated such
a dramatic magnitude of benefit. There are even fewer examples in which such a small number of studies found a substantial benefit, whereas most other studies found no benefit at all.
For this reason the literature on NAC has been so difficult to
interpret and synthesize into clinical treatment recommendations.
Most published studies have been underpowered to adequately test efficacy end points. In the largest published study,
by Webb et al., 487 patients with renal dysfunction were randomized to receive either placebo or NAC 500 mg intravenously before undergoing cardiac catheterization. The study
was terminated prematurely by the Data Safety Monitoring
Committee because of futility and the lack of any trend toward
benefit with NAC treatment (62). Because of the larger sample
size of this study compared with other NAC studies, the negative findings carry particular weight.
In contrast to Webbs findings is the recent publication of

NAC in the Prevention of CIN

283

Marenzi et al., which reports on 354 patients with myocardial

infarction undergoing coronary angiography with primary angioplasty (63). Patients were randomized to treatment with
placebo, a standard dose of NAC (600 mg by intravenous bolus
before primary angioplasty and 600 mg orally twice daily for
48 h after angioplasty), or a double dose of NAC (1200 mg by
intravenous bolus and 1200 mg orally twice daily for 48 h after
intervention). ARF was defined as a 25% increase in SCr level.
The risk for CIN was reduced by 54.5% in the standard-dose
NAC group and by 75.8% in the high-dose NAC group. This
gradient of effect was particularly impressive and not found in
prior studies. More remarkable, the risk for death was also
reduced by the use of NAC at both dosage strengths (63). The
most likely explanation for this find is that NAC may have had
a cardioprotective effect, as has been recently suggested (64).
However, this result would be strengthened by confirmation by
other investigators. It should be noted that intravenous NAC is
associated with a small risk for anaphylactoid reactions. The
findings of Marenzi et al. stand in stark contrast to the other
large study, that of Webb et al., and further add to the murkiness of the literature on NAC for prevention of CIN. Another
recent publication found benefit for the combination of NAC
with intravenous bicarbonate. Briguori and colleagues studied
patients with CKD undergoing coronary or peripheral vascular
procedures (65). Subjects were randomly assigned to administration of 0.9% saline infusion plus NAC (n 111), sodium
bicarbonate infusion plus NAC (n 108), or 0.9% saline plus
ascorbic acid plus NAC (n 107). An increase of 25% in serum
creatinine occurred in 9.9% in the saline plus NAC group,
compared with 1.9% in the bicarbonate plus NAC group (P
0.019) and 10.3% in the saline plus ascorbic acid plus NAC
group. The authors concluded that NAC was more effective
paired with bicarbonate compared with saline hydration (65).
Because most of the studies published on NAC for the prevention of CIN are quite small in size (even the studies of Webb
et al. and Marenzi et al. were not adequately powered to fully
evaluate the spectra of efficacy and safety), meta-analyses have
been performed to increase the probability of explaining the
full spectrum of utility for NAC. To date, 11 meta-analyses have
been published on this subject (66 76), seven of these reports
found a net benefit for NAC in the prevention of CIN. However, a recent review by Bagshaw et al. noted the marked
heterogeneity in study results; indeed 10 of the 11 meta-analyses found statistically significant heterogeneity to be present.
Bagshaw et al. cautioned that pooling of data to arrive at a
summary estimate for treatment efficacy should generally be
avoided in situations where the trials exhibit significant statistical and/or clinical heterogeneity (77). Because clinical heterogeneity has been an important feature of these studies, it is not
clear whether meta-analyses are a useful tool to clarify the role
of NAC.
Publication bias is an important issue to consider with respect to NAC. Vaitkus and Brar reported that this appears to be
a substantial problem, noting that, among abstracts presented
at scientific meetings, far fewer negative studies on NAC resulted in publications (78). Therefore, the results of meta-anal-

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yses probably reflect an overly optimistic view of NACs treatment efficacy.

NAC and Measurement of SCr

Because almost all studies of NAC in the prevention of CIN
defined ARF as a small increase in SCr, any interference by
NAC on measurement of SCr could be problematic. In 2001,
Izzedine et al. reported on in vitro testing of NAC with respect
to its effect on SCr determinations by adding NAC to samples
of human plasma to achieve different concentrations (79). Izzedine and coworkers estimated that plasma NAC levels
achieved in the study of Tepel et al. would probably have been
approximately 465 mg/L, and they tried to approximate this
concentration in vitro. They measured SCr using the modified
Jaffe method and found no analytic interference for SCr for
NAC concentrations of 102 to 600 mg/L. Only at very high
concentrations of NAC (50,000 mg/L), well above what would
occur after typical dosing, were SCr levels significantly affected, decreasing by 50% (79). Somewhat at odds with these
results, was the work of Hoffmann et al., who studied the effect
of NAC in vivo (80). Fifty volunteers with normal renal function
were given NAC 600 mg twice daily for 2 d. Cystatin C, used as
the assay for GFR, was unchanged, indicating that NAC had no
substantive effect on actual renal function. In contrast, SCr level
was significantly decreased. The magnitude of the change,
however, was quite small; a mean decrease in SCr at 4 h after
dosing from 0.85 0.14 mg/dl to 0.82 0.13 mg/dl (P 0.05).
Even at 2 SD below the mean (2.5% of patients), the reduction
in SCr would have been only 0.29 mg/dl (80). These results
indicate that although NAC may have a small effect on measurement of SCr, it is probably not large enough to diminish the
value of SCr as a study end point.

Clin J Am Soc Nephrol 3: 281287, 2008

understanding would help in the design of future agents as

well as help better guide dose timing, route of administration,
and other aspects of treatment. In particular, there remains
controversy about whether the oral or intravenous route of
administration of NAC is preferred. Because the efficacy of
NAC has not been completely established, research on newer
agents must continue to be encouraged.

Treatment Recommendations
The only well established treatment for the prevention of CIN
is intravenous hydration. With the remarkable heterogeneity in
study results, it is difficult to determine whether NAC is truly
effective in preventing CIN. Until a well-powered definitive
study is performed, use of NAC in higher-risk patients undergoing CM-enhanced procedures is probably reasonable. The
drug is inexpensive, safe, and well tolerated by patients. The
oral route of administration is probably acceptable as it is less
expensive and avoids the minor risk for anaphylaxis. However,
the decision to perform CM-enhanced tests and procedures on
high-risk patients requires a careful balancing of risk and benefit. The availability of NAC should not sway these decisions
since its efficacy is not clearly established. Contrast-enhanced
tests and procedures should be avoided, if possible, in high-risk
patients when alternative tests are available.
When NAC is to be used, the original Tepel dose should be
used (600 mg twice daily on the day before and the day of
exposure to contrast). Alternatively, a higher dose may be
given only on the day of the procedure. The intravenous route
of administration is reasonable when oral treatment is not
possible. In addition to NAC, intravenous hydration should be
used where clinically appropriate.

Disclosures
Research Directions
The published literature on NAC in the prevention of CIN is
composed of many studies, although almost all are inadequately powered. The primary end point used in these studies
has always been a relatively small increase in SCr. It is unclear
the extent to which this is a reasonable surrogate for higherlevel outcomes such as need for dialysis, extended hospital
stays, or death. Moreover, the small magnitude of change in
SCr used to define CIN increases the vulnerability of this outcome measure, requiring larger sample sizes. This factor is
probably responsible for much of the heterogeneity in study
results.
At this point in time, no additional underpowered studies
should be performed as they will have no impact on clinical
practice, meta-analyses, or practice guidelines. A large, wellpowered, preferably multicenter study is needed to clarify the
current murky literature and determine the true utility of NAC.
Clinically relevant high-level outcomes should be used.
Additional areas for research include explorations of NACs
mechanism of action in CIN and further studies on the pathobiology of CIN. Without a more complete understanding of the
pathogenesis of CIN, selection of new candidate drugs will
remain somewhat arbitrary. Although NAC shows promise, its
mechanism of action has not been fully elucidated. A better

None.

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