Prevention of contrast-induced nephropathy in vascular patients undergoing angiography: A randomized controlled trial of intravenous N-acetylcysteine

From the Society for Vascular Surgery

Prevention of contrast-induced nephropathy in vascular patients undergoing angiography: A randomized controlled trial of intravenous N-acetylcysteine Sheikh Tawqeer Rashid, MA, MBBChir, MRCS, Mahmoud Salman, FRCS, Fiona Myint, FRCS, Daryll M. Baker, FRCS, Surendra Agarwal, FRCS, Paul Sweny, MRCP, and George Hamilton, FRCS, London, United Kingdom Objective(s): Apart from proper hydration, only oral N-acetylcysteine (NAC) has shown efficacy in reducing radiographic contrast media (RCM)-induced acute renal failure, though its benefit has been challenged. We investigated the effect of intravenous (IV) NAC on renal function in patients with vascular disease receiving RCM for angiography. Methods: Single-center, randomized, double-blind, placebo-controlled trial. Based on a previous study, a trial with 44 patients each in placebo and treatment arms would give at least 80% power to show a statistically significant difference at the 5% level. Vascular patients undergoing angiography were consented and segregated into those whose serum creatinine (SC) level was normal or raised (men >1.32 mg/dl; women >1.07 mg/dL). All patients received 500 mL IV normal saline 6 to 12 hours prior to and then after angiography. Groups with normal SC and raised SC were randomly assigned to either 1 g of NAC with normal saline before and after angiography or nothing (placebo). Main outcome measures were change in SC and creatinine clearance (CrCl) as measured 1, 2, and 7 days postangiography (with comparison between active and placebo groups using unpaired t test) and incidence of acute renal decline (>25% or 0.5 mg/dL rise in SC) at 48 hours (with comparison between active and placebo using the Fisher exact test). Results: Forty-six patients received NAC (29 normal SC, 17 raised SC), and 48 received placebo (27 normal SC, 21 raised SC). There was no significant difference in postangiography SC or CrCl at any of the time points measured between NAC and placebo in patients with either normal or raised SC. In the raised SC group, 3 patients from both the NAC and placebo groups suffered acute renal declines. Importantly, at 48 hours, the impaired SC group had a significant reduction in CrCl (–14% ⴞ 41% vs ⴙ18% ⴞ 58%: P ⴝ .0142) and a significant rise in SC (ⴙ7.0 ⴞ 25% vs –1.6% ⴞ 10%; P ⴝ .0246) when compared with the normal SC group. Conclusions: NAC (IV at 1 g) precontrast and postcontrast does not confer any benefit in preventing RCM-induced nephropathy in vascular patients. Patients with pre-existing raised SC have an increased risk of renal impairment as defined by a fall in CrCl and a rise in SC post-RCM when compared with patients with normal SC who appear to benefit from hydration. ( J Vasc Surg 2004;40:1136-41.)

Radiographic contrast media (RCM) are used routinely in procedures such as computed tomography (CT) scanning, angiography, and angioplasty for the evaluation of patients with vascular disease. Some patients develop an acute decline in renal function known as radiocontrastinduced nephropathy (RCIN). This has been defined in a variety of ways,1 but we chose a rise of 25% or 0.5 mg/dL (⬃45 ␮mol/L) in serum creatinine (SC) at 48 hours postRCM to be consistent with other trials of N-acetylcysteine (NAC).2 The incidence varies from 0% to 90%, depending on the presence or absence of various risk factors, including pre-existing renal insufficiency, diabetes mellitus, hypovolemia, the dose and type of contrast agent employed, and the patient’s concurrent intake of potentially nephrotoxic From the University Departments of Vascular Surgery & Nephrology, Royal Free Hospital, London. Competition of interest: none Correspondence: Professor George Hamilton, University Department of Vascular Surgery, Royal Free Hospital, Pond Street, London NW3 2QG (e-mail: [email protected]). 0741-5214/$30.00 Copyright © 2004 by The Society for Vascular Surgery. doi:10.1016/j.jvs.2004.09.026

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drugs.3-5 The postcoronary angiography incidence of RCIN was 14.5% in one study of 1826 unselected patients.6 Postcontrast nephropathy is associated with a mortality of up to 34%.7 Apart from proper hydration, which seems to reduce but not completely prevent the risk of renal injury after RCM administration,8,9 the results of other agents such as dopamine, mannitol, and captopril are equivocal.10-12 Recently, Tepel et al13 found that oral NAC was effective in reducing the risk of RCIN in patients with preexisting renal dysfunction undergoing contrast CT scan. Others have found similar benefit from oral14-16 and intravenous (IV) NAC17; however, several other studies have not found such a benefit.18-25 Oral NAC is not licensed in the United Kingdom, so we used IV NAC. The IV dose comes in 2 g vials. Our pragmatic approach, decided in consultation with the pharmacy department, was to equally divide the 2 g vial so that the patient received 1 g precontrast and 1 g postcontrast. As there is no dose-response or critical toxicity level for NAC in this dosage range, this seemed reasonable and feasible.

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We therefore conducted a prospective, single-center, randomized, double-blind, placebo-controlled trial to investigate the effect of IV NAC on renal function in patients with peripheral vascular disease who would be receiving RCM for angiography or angioplasty. These patients are known to have many risk factors, including diabetes mellitus, pre-existing renal disease, hypertension, and renal artery stenosis, that increase the risk of renal dysfunction developing after RCM administration. NAC is a drug with minimal adverse effects, although it may cause allergic reactions. To our knowledge, there is no study of RCIN and IV NAC in patients with peripheral vascular disease. It is even more important in vascular patients because, undoubtedly, some cases of angiographically induced acute renal failure may be due to cholesterol emboli rather than contrast nephrotoxicity. MATERIAL AND METHODS We invited all patients with peripheral vascular disease going for elective angiography or angioplasty to participate in this trial. Approval was obtained from the Ethics Committee of the Royal Free Hampstead NHS Trust. Patients who consented to participate were subdivided into 2 groups according to their initial SC: a normal SC group and a raised SC group. Normal SC in our hospital is defined as an SC level of less than 120 ␮mol/L (1.32 mg/dL) for men and 97 ␮mol/L (1.07mg/dL) for women. All patients received normal saline (500 mL over 4 to 6 hours) 6 to 12 hours prior to angiography and again after angiography. Both the normal and raised SC groups were randomized to receive either 1 g of NAC in each bag of normal saline or nothing (placebo group). Randomization was performed by the hospital clinical trials pharmacist, and both patient and doctor were blinded. SC and CrCl were measured prior to angiography and again at 1, 2, and 7 days after angiography. Creatinine clearance was done by 24-hour urine collection. Outcome measures were incidence of RCIN, change in SC and CrCl at 1, 2, and 7 days, and any significant morbidity and mortality. We also made note of the volume of contrast; all patients received Omnipaque 300. Statistics The study was conceived in 2001 when only data by the Tepel researchers13 had been published, so this was the only trial that could have been used to power the study. This study showed that NAC reduced the incidence of RCIN from 21% to 2%.13 Based on this data, we calculated that 44 patients each in the placebo and treatment arms would be needed to give at least 80% power to show a statistically significant difference at the 5 % level. Differences in CrCl and SC at days 1, 2 and 7; and differences in continuous risk factors, such as age and contrast dose (see Tables I and II) were assessed using a two-sample t test. The comparison between active and placebo groups in terms of incidence within the group of RCIN, diabetes mellitus, and sex ratio was done using the Fisher exact test.

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The 24-hour urinary creatinine clearance (CrCl) evaluation is a standard test performed routinely in the hospital’s biochemistry department, which is fully and regularly validated. In keeping with other laboratories, the coefficient of variation from repeated 24-hour urine collections is between 11% and 30%. Given that almost all measurements were done whilst the patients were in the hospital and supervised by experienced nurses, we feel confident that our results are around 11%. RESULTS Initially, 103 patients were recruited; however, the angiograms of 7 patients were canceled after they received a randomization number because of unavailability of hospital beds or time in the angiography suite. Two patients declined to proceed with the trial before having angiography because of the unforeseen trouble of continuously providing urine for a 24-hour urine collection. That left 94 patients who were actually recruited into the trial. The age range was 30 to 93 years; 32 patients were women, and 62 were men. Fifty-three interventional procedures (stenting or angioplasty) were performed: 45 infrainguinal (NAC, 23; placebo, 22) and 8 aortoiliac (NAC, 4; placebo, 4). The others were diagnostic procedures: 28 infrainguinal (NAC, 14; placebo, 14), 7 carotid (NAC, 4; placebo, 3), 3 brachial (all placebo), and 3 aortoiliac (NAC, 1; placebo, 2). The mean contrast dose was 143.2 ⫾ 69.38 mL of Omnipaque 300. Thirty-eight patients were in the raised SC group; 56 were in the normal SC group. In the normal SC group, 45 (80%) had an impaired CrCl (⬍100 mL/min); of these, 35 (78%) had significantly impaired CrCl of under 70 mL/min (Fig 1). Forty-six patients received NAC: 29 with normal SC and 17 with raised SC. None of the patients suffered any adverse effects or complications from the NAC. The placebo group consisted of 48 patients: 27 with normal SC and 21 with raised SC. The NAC and placebo groups did not differ significantly in renal function (SC and CrCl), gender, age, body mass index, diabetes mellitus, or dose of contrast (Table I). There was no RCIN in either of the normal SC groups. RCIN developed equally (P ⫽ 1.000) in the raised SC groups, that is 3 (17.6%) of 17 patients in the group that received NAC (one fatality occurred partly due to complications of renal failure) and 3 (14.3%) of 21 in the placebo group (one eventually required dialysis). Among those with raised SC or normal SC, but significantly reduced CrCl (⬍70 mL), RCIN developed in 3 (7.7%) out of 39 in the NAC group compared with 3 (8.8%) out of 34 in the placebo group (P ⫽ 1.000). To exclude missing more subtle degrees of RCIN, we reanalyzed the data using an alternative RCIN definition of a 20% rise in SC within 1 to 7 days of contrast administration. This definition included 5 (8.9%) of the 56 patients in the normal SC group (3 in NAC and 2 in placebo group). For the raised SC group, this definition would have in-

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Table I. Patient profiles of N-acetylcysteine and placebo groups

SC (␮mol/L) CrCl (mL/min) Male/female Age (y) BMI Contrast dose (mL) DM

NAC

Placebo

P

109.9 ⫾ 41.15 50.78 ⫾ 27.51 27:19 72.09 ⫾ 12.34 26.11 ⫾ 4.586 135.4 ⫾ 62.7 17/46

124.3 ⫾ 63.47 61.37 ⫾ 34.42 33:15 68.75 ⫾ 12.32 27.03 ⫾ 4.624 151.2 ⫾ 75.6 13/48

.1985 .1066 .3914 .1930 .3554 .3012 .3777

P values are from the Student t test, except the Fisher exact test was used for gender and DM. NAC, N-acetylcysteine, SC, serum creatinine; CrCl, creatinine clearance; BMI, body mass index; DM, diabetes mellitus.

cluded 9 (23.7%) out of 38 patients (4 in the NAC and 5 in the placebo group. Again, NAC did not appear to be of benefit in reducing RCIN (P ⫽ 1.000). RCIN among the raised SC group was not associated with age, gender, diabetes mellitus, contrast dose, or initial SC or CrCl (Table II). In terms of change in SC or CrCl over days 1, 2, or 7, there was no significant difference between the NAC and placebo groups (Figs 2 and 3). Of interest, at day 2 the raised SC group had a significant decline in renal function compared with the normal SC group (Fig 4): the raised SC group had an SC rise of 7.0% ⫾ 25% compared to a fall of 1.62% ⫾ 10% in the normal SC group (P ⫽ .0246), and CrCl similarly fell by 14% ⫾ 41% in the raised SC patients compared with an increase of 18% ⫾ 58% in the normal SC patients (P ⫽ .0142). Discussion This study represents the first attempt to analyze the impact of NAC on patients with peripheral vascular disease and is also only the second study to use an IV rather than oral dose of NAC. We did not detect any benefit for the use of NAC in the prevention of RCIN. Furthermore, there was no significant difference in the more sensitive measures of change in SC values or even CrCl at any of the time points (1, 2, and 7 days) despite there being no difference between the patient groups for potentially important risk factors such as diabetes and pre-existing renal function (Table I). In a recent review, 8 of the 12 trials using oral NAC likewise found no benefit for NAC,2 whereas the previous trial using intravenous NAC did find it to be of benefit.17 What to make of such conflicting results? Was there something fundamentally different between the trial protocols that could explain this difference? Fishbane et al2 compared positive and negative studies and noted that the studies showing no benefit from NAC had a much lower incidence of RCIN in the placebo group than did those studies showing NAC to be beneficial (11.0% compared to 24.8%). These results suggest that perhaps NAC is only beneficial for those at a high risk of RCIN. This inference was supported by another review that suggested NAC was beneficial in those studies with higher proportions of el-

Table II. Profiles of patients with and without radiocontrast-induced nephropathy among the raised serum creatinine group

SC (␮mol/L) CrCl (mL/min) Male/female Age (y) Contrast dose (mL) DM

RCIN

No RCIN

P

190 ⫾ 53 36 ⫾ 26 3:3 72 ⫾ 10 135 ⫾ 54 3/6

158 ⫾ 58 43 ⫾ 18 21:11 72 ⫾ 9 140 ⫾ 53 10/32

.2112 .4293 .6497 .9523 .8602 .3924

P values are from the Student t test, except the Fisher exact test was used for gender and DM. RCIN, Radiocontrast-induced nephropathy; SC, serum creatinine; CrCl, creatinine clearance; BMI, body mass index; DM, diabetes mellitus.

derly and diabetic patients, high volumes of contrast, and a high osmolality contrast, all known risk factors for RCIN.26 Hence, the first possible explanation for our result is that we had a low-risk population. By choosing to look at all patients undergoing angiography and using CrCl to quantify renal function, we found only 11 patients to have normal renal function (CrCl ⬎100 mL/min). Furthermore, using the CrCl threshold of 70 mL/min, we identified 70 patients with significant renal impairment and, hence, at increased risk of RCIN. On this basis, the incidence of RCIN was 7.7% for the NAC group and 8.8% for the placebo group. Looking only at patients with raised SC, the incidence of RCIN increased to 17.6% for the NAC group and 14.3% for the placebo group (P ⫽ 1.000). In terms of other risk factors identified by Kshirsagar et al,26 we had an elderly population averaging over 70 years, a low incidence of diabetic patients (32%), and used a low volume of contrast (⬍150 mL). It is, therefore, possible that our trial was underpowered, resulting in a type II error, and a larger study confined to exclusively high-risk patients might have shown a benefit from the use of NAC. However, our findings of no significant difference in the changes of SC and CrCl between NAC and placebo groups makes this unlikely. A further important consideration is the dose of NAC. The original Tepel et al13 study used 600 mg twice daily the day before and on the day of the procedure, giving a total dose of 2.4 g. However, because the bioavailability of oral NAC is at most 5% to 10% due to considerable first-pass metabolism,2 the actual dose received by patients with this protocol was at most 0.24 g. Other oral regimens have used similar dosages. The intravenous NAC trial that found benefit used a dosage derived from treating paracetamol overdoses that equates to 150 mg/kg precontrast and 50 mg/kg postcontrast.17 For the average 70kg person, this gives a total dose of 14 g, almost two orders of magnitude greater than the oral regimens and almost one order greater than our dosage of 1 g precontrast and 1 g postcontrast (total ⫽ 2 g). It is not possible to draw any conclusions from the low-dose oral regimens, but the possibility of benefit from a very high-dose IV regimen remains, al-

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Fig 2. Change in serum creatinine (SC) levels over time.

Fig 1. Creatinine clearance (CrCl) distribution for patients with normal serum creatinine and subnormal CrCl.

though this was associated with a 14.6% risk of hypersensitivity and anaphylactoid-type reactions.17 Similarly, the timing of NAC administration in relation to contrast delivery is a factor worth considering. Kshirsagar et al26 suggested NAC treatment the day before improved the benefit of NAC. However, several other studies failed to confirm this.18,19,21,24 Our own protocol of using IV NAC over 4 to 6 hours, starting 6 to 12 hours before and again immediately after contrast administration, did not show benefit, whereas the Baker protocol that used IV NAC immediately before contrast did show benefit.17 To confuse matters further, oral NAC reaches a serum peak about an hour after ingestion27 and has an elimination half-life of 2.27 hours28; therefore, predosing the day before should not theoretically be of benefit. It is possible, however, that NAC’s effects are mediated indirectly through its metabolites—perhaps by the induction of the antioxidant glutathione2—thus, there is no agreement on whether the effect of NAC is immediate or delayed. Another consideration is the patient population. Diabetic patients are known to be at increased risk of RCIN, but the studies have shown conflicting effects from NAC administration: one showed increased benefit,15 and another showed that NAC was harmful to diabetic patients.20 The Tepel researchers’ original population was a nonspecific group undergoing CT. Almost all the other trials were on cardiac patients undergoing coronary angiography. Our study was exclusively for patients with peripheral arterial disease undergoing angiography. Again, the conflicting results among the coronary groups mean that no definitive conclusions can be made even in this group. The route of contrast administration may also be worth investigating further. Angiographic studies have intra-arterial

contrast, whereas in the study by Tepel et al,29 which showed NAC to be of benefit, the contrast was injected intravenously. Our study has reconfirmed a previous finding that patients with normal SC levels may have occult-compromised renal function as defined by CrCl.29 However, these patients are at significantly less risk of renal impairment postcontrast compared with those with a raised SC as demonstrated by the better SC and CrCl results 2 days postcontrast. Why the normal SC group seemed on average to have an improved renal function in terms of SC and CrCl is a matter of speculation, but we assume it to be an effect of hydration. It must be stressed that the definition of RCIN as a 25% rise or a 0.5-mg/dL (⬃45-␮mol/L) increase in SC at 48 hours resulted in no RCIN being found in the normal SC group. This definition was chosen to be consistent with other studies that used NAC. However, a lower RCIN threshold of a 20% rise in SC within 1 to 7 days of contrast1 would have increased the incidence of RCIN to 8.9% of patients in the normal SC group and 23.7% among the raised SC group. Therefore, acute decline in renal function is still found in patients with normal SC though, again, NAC does not appear to be of benefit (P ⫽ 1.000). CONCLUSION So what treatment recommendations regarding NAC can be made from the results of this trial and those that have previously been reported? This was the subject of two recent meta-analyses that were done prior to our trial. The older meta-analysis suggested the continued use of NAC, at least for those with known renal impairment. The reasoning given was that in addition to an overall benefit shown in the meta-analysis, NAC is inexpensive, easy to use, and has a favorable adverse event profile at a low dosage.30 The more recent meta-analysis suggested that the present data are too inconsistent to give a definitive recommendation.

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interim, we believe hydration is clearly important, and it is our own practice to provide periangiographic IV hydration without the use of NAC until a definitive trial reports. We would like to thank Dr Richard Morris and Dr John Emberson from the Department of Primary Care and Population Science for their statistical advice, both in formulating the study design and in analyzing the data afterwards. REFERENCES

Fig 3. Change in creatinine clearance (CrCl) over time

Fig 4. Changes in serum creatinine (SC) and creatinine clearance (CrCl) 2 days postcontrast for raised and normal SC patients.

The results of our trial concur with the conclusion of the latter meta-analysis. An important point was made recently by Hoffmann et al, who looked purely at the impact of NAC on renal function. They showed that NAC decreased SC but without improving cystatin C.31 Although cystatin C is not available at many hospitals, including our own, it is considered a superior marker for renal function compared with creatinine.32 Thus, the Hoffmann et al study raises the possibility that NAC may be affecting creatinine without actually improving renal function at all. The time has come for a large multicenter trial powered to look for clinical end points such as the need for renal replacement therapy, death, and delayed hospital discharge. Is it worth such an effort? We believe so. The need for contrast-based procedures is rising, especially in endovascular surgery, as is the incidence of postcontrast renal failure, which has a reported mortality of 34%.7 In the

1. Lindholt JS. Radiocontrast induced nephropathy. Eur J Vasc Endovasc Surg 2003;25(4):296-304. 2. Fishbane S, Durham JH, Marzo K, Rudnick M. N-acetylcysteine in the prevention of radiocontrast-induced nephropathy. J Am Soc Nephrol 2004;15(2):251-60. 3. Harkonen S, Kjellstrand C. Contrast nephropathy. Am J Nephrol 1981;1(2):69-77. 4. Solomon R. Contrast-medium-induced acute renal failure. Kidney Int 1998;53(1):230-42. 5. Baker CS, Baker LR. Prevention of contrast nephropathy after cardiac catheterisation. Heart 2001;85(4):361-2. 6. McCullough PA, Wolyn R, Rocher LL, Levin RN, O’Neill WW. Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality. Am J Med 1997;103(5):368-75. 7. Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality. A cohort analysis. JAMA 1996;275(19):1489-94. 8. Eisenberg RL, Bank WO, Hedgock MW. Renal failure after major angiography can be avoided with hydration. AJR Am J Roentgenol 1981;136(5):859-61. 9. Solomon R, Werner C, Mann D, D’Elia J, Silva P. Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med 1994;331(21): 1416-20. 10. Kapoor A, Sinha N, Sharma RK, Shrivastava S, Radhakrishnan S, Goel PK, et al. Use of dopamine in prevention of contrast induced acute renal failure—a randomised study. Int J Cardiol 1996;53(3):233-6. 11. Gare M, Haviv YS, Ben Yehuda A, Rubinger D, Bdolah-Abram T, Fuchs S, et al. The renal effect of low-dose dopamine in high-risk patients undergoing coronary angiography. J Am Coll Cardiol 1999; 34(6):1682-8. 12. Effect of angiotensin-converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPP) randomized trial. The Captopril Prevention Project (CAPP) Study Group. Curr Hypertens Rep 1999;1(6):466-7. 13. Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000;343(3):180-4. 14. Diaz-Sandoval LJ, Kosowsky BD, Losordo DW. Acetylcysteine to prevent angiography-related renal tissue injury (the APART trial). Am J Cardiol 2002;89(3):356-8. 15. Kay J, Chow WH, Chan TM, Lo SK, Kwok OH, Yip A, et al. Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention: a randomized controlled trial. JAMA 2003;289(5):553-8. 16. Shyu KG, Cheng JJ, Kuan P. Acetylcysteine protects against acute renal damage in patients with abnormal renal function undergoing a coronary procedure. J Am Coll Cardiol 2002;40(8):1383-8. 17. Baker CS, Wragg A, Kumar S, De Palma R, Baker LR, Knight CJ. A rapid protocol for the prevention of contrast-induced renal dysfunction: the RAPPID study. J Am Coll Cardiol 2003;41(12):2114-8. 18. Allaqaband S, Tumuluri R, Malik AM, Gupta A, Volkert P, Shalev Y, et al. Prospective randomized study of N-acetylcysteine, fenoldopam, and saline for prevention of radiocontrast-induced nephropathy. Catheter Cardiovasc Interv 2002;57(3):279-83. 19. Briguori C, Manganelli F, Scarpato P, Elia PP, Golia B, Riviezzo G, et al. Acetylcysteine and contrast agent-associated nephrotoxicity. J Am Coll Cardiol 2002;40(2):298-303.

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20. Durham JD, Caputo C, Dokko J, Zaharakis T, Pahlavan M, Keltz J, et al. A randomized controlled trial of N-acetylcysteine to prevent contrast nephropathy in cardiac angiography. Kidney Int 2002;62(6):2202-7. 21. Boccalandro F, Amhad M, Smalling RW, Sdringola S. Oral acetylcysteine does not protect renal function from moderate to high doses of intravenous radiographic contrast. Catheter Cardiovasc Interv 2003; 58(3):336-41. 22. Goldenberg I, Shechter M, Matetzky S, Jonas M, Adam M, Pres H, et al. Oral acetylcysteine as an adjunct to saline hydration for the prevention of contrast-induced nephropathy following coronary angiography. A randomized controlled trial and review of the current literature. Eur Heart J 2004;25(3):212-8. 23. Oldemeyer JB, Biddle WP, Wurdeman RL, Mooss AN, Cichowski E, Hilleman DE. Acetylcysteine in the prevention of contrast-induced nephropathy after coronary angiography. Am Heart J 2003;146(6): E23. 24. Vallero A, Cesano G, Pozzato M, Garbo R, Minelli M, Quarello F, et al. [Contrast nephropathy in cardiac procedures: no advantages with prophylactic use of N-acetylcysteine (NAC)]. G Ital Nefrol 2002;19(5): 529-33. 25. Loutrianakis E, Stella D, Hussain A, Lewis B, Steen L, Sochaneld M, et al. Randomized comparison of fenaldopam and n-Acetylcysteine to saline in the prevention of radiocontrast nephropathy [abstract]. J AM Coll Card 41, 327A. 2003.

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26. Kshirsagar AV, Poole C, Mottl A, Shoham D, Franceschini N, Tudor G, et al. N-acetylcysteine for the prevention of radiocontrast induced nephropathy: a meta-analysis of prospective controlled trials. J Am Soc Nephrol 2004;15(3):761-769. 27. Morgan LR, Holdiness MR, Gillen LE. N-Acetylcysteine: its bioavailability and interaction with ifosfamide metabolites. Semin Oncol 1983; 10(1 Suppl 1):56-61. 28. Borgstrom L, Kagedal B, Paulsen O. Pharmacokinetics of N-acetylcysteine in man. Eur J Clin Pharmacol 1986;31(2):217-22. 29. Rashid ST, Agarwal S, Hamilton G. Unmasking renal impairment, using creatinine clearance, in peripheral vascular disease patients with normal serum creatinine [abstract]. Br J Surg 2003;90:619-20. 30. Birck R, Krzossok S, Markowetz F, Schnulle P, van der Woude FJ, Braun C. Acetylcysteine for prevention of contrast nephropathy: metaanalysis. Lancet 2003;362(9384):598-603. 31. Hoffmann U, Fischereder M, Kruger B, Drobnik W, Kramer BK. The value of N-acetylcysteine in the prevention of radiocontrast agentinduced nephropathy seems questionable. J Am Soc Nephrol 2004; 15(2):407-10. 32. Laterza OF, Price CP, Scott MG. Cystatin C: an improved estimator of glomerular filtration rate? Clin Chem 2002;48(5):699-707.

Submitted Jun 27, 2004; accepted Sep 27, 2004.

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