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: 281–287, 2008. doi: 10.2215/CJN.02590607

C

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 (7–13), 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
NAC’s 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 drug’s 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: 1555-9041/301–0281

2008 sively. cystine. the deacetylation of NAC is so efficient that the concentration of metabolites is 300% to 500% higher than that of NAC (34). has been found to be poor and the actual half-life closer to 6 to 40 min. forming various disulfide compounds. In rats.36 ⫻ 1010 M⫺1sec⫺1. inorganic sulfites. Bioavailability was ⬍5%. Cysteine is the moiety that supplies glutathione’s active sulfhydryl group and plays a critical role as the rate-limiting factor in glutathione synthesis. Biological Actions of NAC The pharmacology of NAC. The antioxidant properties of NAC have been studied exten- Clin J Am Soc Nephrol 3: 281–287. glutamate. NAC is effectively deacetylated by the enzyme acylase I in the intestines and liver (30 –35). administration of NAC has been found to increase renal glutathione levels (48). It generally cannot enter cells. It is clear from these reports that. Conesa et al. such as superoxide anion and hydrogen peroxide.36). a model with reduced medullary blood flow. and labile disulfide protein complexes (34. NAC has other biological actions that might be helpful for preventing CIN. Bursts of oxidative stress occur naturally. Harada et al. The most plausible mechanism of NAC’s putative protective effect against CIN is supplementation of the body’s antioxidant capacity. NAC yields cysteine as one of its metabolites. and the body’s cells and tissues possess antioxidant systems to protect against oxidative damage (37). In the circulation of the portal vein. NAC might work by inducing glutathione synthesis. it is likely that any antioxidant effects it exerts in humans would be indirect. Structure of N-acetylcysteine. reducing production of the vasoconstrictor angiotensin II (52). Only small amounts of NAC were found in circulation despite the intravenous route of administration (29). NAC is a somewhat less effective antioxidant (40). After deacetylation in the intestines and liver. The liberated cysteine molecules can be used by cells as precursors for glutathione production.44). The drug reacts with and deactivates hydroxyl radicals (39. In addition. In addition to its antioxidant properties. yielding NAC thiol radical intermediates and ultimately NAC disulfide (39). NAC is very effective in neutralizing certain free radicals in vitro. For example. with a rate constant of 1. and cysteine. . particularly affecting the kidney’s medullary circulation (53). Heyman and colleagues (55) found that NAC administration in rats resulted in reduced total. When considering the mechanism by which NAC can have a potential benefit in preventing CIN. Moldeus and Cotgreave were able to detect only very small quantities of oxidized drug in circulation. The following discussion will highlight those most relevant to the pathogenesis of CIN. After intravenous injection. The relevance for the kidney is suggested by the demonstration of glutathione depletion in ischemia reperfusion injury (46. By stabilizing nitric oxide. Another recently demonstrated action of NAC is in reducing urinary albumin excretion (56). After oral administration. This circulating cysteine may enter renal cells and serve as a precursor for glutathione production. Regarding other reactive oxygen species. found that NAC was highly bound to plasma and tissue proteins. probably because of extensive first-pass hepatic metabolism. the reaction is rapid. published the first clinical study on this subject in 2000 (57). NAC has a variety of biological actions. In fact. after oral administration. In a study of ARF induced by inferior vena cava obstruction. NAC is almost completely metabolized before entering the systemic circulation.282 Clinical Journal of the American Society of Nephrology Figure 1. 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. with no free drug detectable (23). Vasoconstriction has often been considered as a factor contributing to the pathogenesis of CIN. its poor bioavailability must somehow be reconciled. NAC’s sulfhydryl group may inhibit angiotensin-converting enzyme. the major metabolites entering the circulation include cysteine. 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. and medullary vascular resistance by 7% to 10%. The beneficial therapeutic effects of NAC may well be a result of indirect effects such as induction of glutathione synthesis. homodisulfides of NAC. With intestinal transit and absorption. particularly its deacetylation and poor bioavailability. The vasoconstriction in CIN may be somewhat selective. cortical. Numerous other investigators have confirmed the low bioavailability of oral NAC including slow-release preparations (25–28). Glutathione plays a central role in the body’s defense against cellular oxidative damage (41.40). instead it must be synthesized intracellularly from glycine. Since that time there have been many published studies with great heterogeneity in results. NAC may have a vasodilatory effect in certain situations (49 – 51).47). make clear that the drug’s in vitro effects must be considered separately from its in vivo actions. After exposure to CM there is a surge in oxidative stress that may overwhelm these systems and result in tissue injury (38). several studies have found that NAC prevents glutathione depletion (43. found that NAC reduced medullary vasoconstriction and improved blood flow (54).42). Tepel et al. The poor bioavailability of NAC after oral dosing is the result of extensive first-pass metabolism. In rats. Because NAC is extensively degraded in vivo (as discussed above).

ARF was defined as an increase in SCr of 0. 86.2 mg/dl or creatinine clearance ⬍50 ml/min were studied. presaged the literature that has paralleled this pattern of great heterogeneity of results (58).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.9% in the saline plus NAC group.5 mg/dl or ⱖ25% above the baseline value.0%). generally defined by an increased baseline SCr. Studies generally did not attempt to differentiate ARF induced by CM from other possible causes.5%. 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). However. More remarkable.. a recent review by Bagshaw et al.. There are even fewer examples in which such a small number of studies found a substantial benefit. sodium bicarbonate infusion plus NAC (n ⫽ 108).59 – 61). as has been recently suggested (64). However. or 0. Most published studies have been underpowered to adequately test efficacy end points. and Diaz-Sandoval et al. We found no significant difference in the rate of CIN between the NAC and placebo groups (26. Because clinical heterogeneity has been an important feature of these studies. seven of these reports found a net benefit for NAC in the prevention of CIN. this result would be strengthened by confirmation by other investigators. Publication bias is an important issue to consider with respect to NAC. others reporting no effect.2%. 11 meta-analyses have been published on this subject (66 –76). and 82. ARF developing after contrast exposure has generally been defined as an increase in SCr of ⱖ0. that of Webb et al. a standard dose of NAC (600 mg by intravenous bolus before primary angioplasty and 600 mg orally twice daily for 48 h after angioplasty). However. An increase of 25% in serum creatinine occurred in 9. ARF.Clin J Am Soc Nephrol 3: 281–287.9% saline infusion plus NAC (n ⫽ 111). Therefore. respectively (57.. the risk for death was also reduced by the use of NAC at both dosage strengths (63). were not adequately powered to fully evaluate the spectra of efficacy and safety). The most likely explanation for this find is that NAC may have had a cardioprotective effect.7%. and Marenzi et al. Subjects were randomly assigned to administration of 0. Vaitkus and Brar reported that this appears to be a substantial problem. 487 patients with renal dysfunction were randomized to receive either placebo or NAC 500 mg intravenously before undergoing cardiac catheterization. It should be noted that intravenous NAC is associated with a small risk for anaphylactoid reactions. 2008 some finding substantial benefit for NAC. For this reason the literature on NAC has been so difficult to interpret and synthesize into clinical treatment recommendations. occurred in 21% of placebo subjects compared with 2% in the NAC group (P ⫽ 0. Shyu et al. The remarkable disparity between our results and those of Tepel et al. defined as an increase in SCr of ⱖ0. and further add to the murkiness of the literature on NAC for prevention of CIN.5 mg/dl. Patients were randomized to treatment with placebo. The findings of Marenzi et al. noted the marked heterogeneity in study results.01). the results of meta-anal- .5% in the standard-dose NAC group and by 75. the magnitude of benefit in some of the positive studies was substantial. Shortly after Tepel’s publication. meta-analyses have been performed to increase the probability of explaining the full spectrum of utility for NAC. The authors concluded that NAC was more effective paired with bicarbonate compared with saline hydration (65). In the largest published study. compared with 1. which reports on 354 patients with myocardial infarction undergoing coronary angiography with primary angioplasty (63). 83 patients undergoing contrastenhanced CT scanning were studied.3% versus 22. Studies with negative results outnumber those with positive results by a 2-to-1 margin. Other Studies There are ⬎20 published studies investigating NAC for the prevention of CIN.9% saline plus ascorbic acid plus NAC (n ⫽ 107). ARF was defined as a 25% increase in SCr level. 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). Bagshaw et al. Only subjects with SCr ⬎1. the negative findings carry particular weight. There are few areas in clinical medicine where a treatment has demonstrated such a dramatic magnitude of benefit. This gradient of effect was particularly impressive and not found in prior studies. 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. The risk for CIN was reduced by 54. it is not clear whether meta-analyses are a useful tool to clarify the role of NAC. This dramatic reduction in risk with NAC drew great attention and led to an almost immediate change in clinical practice (57).019) and 10. noting that.3% in the saline plus ascorbic acid plus NAC group. whereas most other studies found no benefit at all... To date. indeed 10 of the 11 meta-analyses found statistically significant heterogeneity to be present. In Tepel’s seminal report. Because of the larger sample size of this study compared with other NAC studies. In contrast to Webb’s findings is the recent publication of NAC in the Prevention of CIN 283 Marenzi et al. our group attempted to reproduce the finding in patients undergoing cardiac angiography. Studies by Tepel et al. 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).5 mg/dl.8% in the high-dose NAC group. or a double dose of NAC (1200 mg by intravenous bolus and 1200 mg orally twice daily for 48 h after intervention). 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. Most of the studies included patient populations at relatively increased risk for CIN..9% in the bicarbonate plus NAC group (P ⫽ 0. by Webb et al. reported that NAC reduced the risk of CIN by 90. among abstracts presented at scientific meetings. Kay et al. Subjects with SCr ⬎1.6%. far fewer negative studies on NAC resulted in publications (78). with 30 to 487 subjects enrolled in each study. 67. stand in stark contrast to the other large study.

85 ⫾ 0. When NAC is to be used.000 mg/L). route of administration. although almost all are inadequately powered. Although NAC shows promise. if possible. 1983 4. Without a more complete understanding of the pathogenesis of CIN. NAC and Measurement of SCr Because almost all studies of NAC in the prevention of CIN defined ARF as a small increase in SCr. A large. Hollenberg NK: Mechanism of renal response to contrast medium in dogs: Decrease in renal function due to hypertonicity. 1987 2. Hudson K. Because the efficacy of NAC has not been completely established. no additional underpowered studies should be performed as they will have no impact on clinical practice. the original Tepel dose should be used (600 mg twice daily on the day before and the day of exposure to contrast). it is difficult to determine whether NAC is truly effective in preventing CIN. This factor is probably responsible for much of the heterogeneity in study results.14 mg/dl to 0. Davidson AJ: Renal hemodynamic effects of contrast media. the decision to perform CM-enhanced tests and procedures on high-risk patients requires a careful balancing of risk and benefit. was the work of Hoffmann et al. there remains controversy about whether the oral or intravenous route of administration of NAC is preferred. Nygren A: Contrast media and regional renal blood flow: A study of the effects of ionic and non-ionic monomeric and dimeric contrast media in the rat. 1968 6. were SCr levels significantly affected. use of NAC in higher-risk patients undergoing CM-enhanced procedures is probably reasonable. Caldicot WJH. Hunt DA. These results indicate that although NAC may have a small effect on measurement of SCr. who studied the effect of NAC in vivo (80). indicating that NAC had no substantive effect on actual renal function. In 2001. They measured SCr using the modified Jaffe method and found no analytic interference for SCr for NAC concentrations of 102 to 600 mg/L. Contrast-enhanced tests and procedures should be avoided. Clin J Am Soc Nephrol 3: 281–287. the reduction in SCr would have been only 0.29 mg/dl (80). Until a well-powered definitive study is performed. The drug is inexpensive. With the remarkable heterogeneity in study results. intravenous hydration should be used where clinically appropriate.5% of patients). The intravenous route of administration is reasonable when oral treatment is not possible. White MD: Direct toxic effect of the . any interference by NAC on measurement of SCr could be problematic. Bakris GL. was unchanged.284 Clinical Journal of the American Society of Nephrology yses probably reflect an overly optimistic view of NAC’s treatment efficacy. 2008 understanding would help in the design of future agents as well as help better guide dose timing. Even at 2 SD below the mean (2. Schick CS. 1999 5. well above what would occur after typical dosing. Only at very high concentrations of NAC (50. its mechanism of action has not been fully elucidated. The oral route of administration is probably acceptable as it is less expensive and avoids the minor risk for anaphylaxis. Treatment Recommendations The only well established treatment for the prevention of CIN is intravenous hydration. In addition to NAC. Schulman G. Knox FG: Renal vasoconstrictive response to contrast medium: The role of sodium balance and the renin-angiotensin system. research on newer agents must continue to be encouraged. used as the assay for GFR. Izzedine and coworkers estimated that plasma NAC levels achieved in the study of Tepel et al. Clinically relevant high-level outcomes should be used. or practice guidelines. Somewhat at odds with these results. A better None. Moreover. In contrast. The magnitude of the change. Haller C: Comparative cytotoxicity of ionic and non-ionic radiocontrast agents on MDCK cell monolayers in vitro. Humes HD. Mertz JI. References 1. 1992 7. The primary end point used in these studies has always been a relatively small increase in SCr. and they tried to approximate this concentration in vitro. however. Katzberg RW.05). a higher dose may be given only on the day of the procedure. Invest Radiol 3: 310 –317. Talner LB. Acta Radiol 378: 123–135. Arend LJ. SCr level was significantly decreased. safe. meta-analyses. Romero JC. was quite small. the small magnitude of change in SCr used to define CIN increases the vulnerability of this outcome measure. decreasing by ⬎50% (79). wellpowered. in high-risk patients when alternative tests are available.13 mg/dl (P ⬍ 0.. 1983 3. At this point in time. preferably multicenter study is needed to clarify the current murky literature and determine the true utility of NAC. Izzedine et al. Fifty volunteers with normal renal function were given NAC 600 mg twice daily for 2 d. Additional areas for research include explorations of NAC’s mechanism of action in CIN and further studies on the pathobiology of CIN. requiring larger sample sizes. Damieno MM. selection of new candidate drugs will remain somewhat arbitrary. extended hospital stays. Spielman WS: Role for intrarenal adenosine in the renal hemodynamic response to contrast media. Alternatively. J Lab Clin Med 110: 406 – 411. or death. Larson JS. Cystatin C. The availability of NAC should not sway these decisions since its efficacy is not clearly established. Mergerian C. and well tolerated by patients. Invest Radiol 18: 74 – 80. and other aspects of treatment. Meggs LG. it is probably not large enough to diminish the value of SCr as a study end point. In particular. Disclosures Research Directions The published literature on NAC in the prevention of CIN is composed of many studies. Nephrol Dial Transplant 14: 342–347. J Lab Clin Med 101: 385–391. would probably have been approximately 465 mg/L.82 ⫾ 0. 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