Acute transient renal insufficiency after exposure to radiocontrast agents has been well described. The incidence varies among studies depending on the definition and the patient population studied.1 One of the more commonly accepted definitions for radiocontrast-induced nephropathy (RCIN) is a greater than 25% increase in serum creatinine within 48 hours of contrast exposure.2 Risk factors for RCIN include baseline renal dysfunction, congestive heart failure, diabetes mellitus, dehydration, peripheral vascular disease, hypertension, multiple myeloma and treatment with nephrotoxic drugs.1,3,4 RCIN has been associated with increased morbidity and mortality.5 Various agents and different strategies for the prevention of RCIN have been investigated.6–10 The only preventive measures that have been validated in the setting of coronary angiography are pre- and post-procedure hydration.8 N-acetylcysteine, an antioxidant agent with few side effects, was shown to have clinical benefit in preventing RCIN if administered orally for 24 hours before and after computerized tomography studies.11 Patients undergoing cardiac catheterization receive, on average, a higher volume of contrast agent, are usually older and have variable hemodynamic conditions compared to patients undergoing regular computerized tomography. Accordingly, we studied the potential benefit of oral N-acetylcysteine in preventing renal dysfunction in patients undergoing cardiac catheterization. Methods Patients. Fifty-five consecutive patients scheduled for coronary angiography after July 2000 (with a persistent and stable serum creatinine above 1.2 mg/dl [involving at least 2 measurements pre-catheterization] or a creatinine clearance below 50 ml per minute) were enrolled in the study. Creatinine clearance was estimated based on the Cockroft-Gault equation using each patient’s serum creatinine concentration, weight, age and sex.12 All patients received four doses of 600 mg N-acetylcysteine, twice on the day before, once in the morning prior to cardiac catheterization, and once after catheterization. Fifty-five consecutive patients with serum creatinine level above 1.2 mg/dl in one year prior to July 2000 were identified as the control group. All patients in both groups received intravenous hydration according to the discretion of the attending cardiologist. All hydration protocols involved 0.45% or 0.9% saline at 0.5–1.0 ml/kg/hour for 6–12 hours prior to and after the procedure. Patients who were on hemodialysis prior to the coronary catheterization were excluded. Data recorded prospectively, including the amount and type of contrast are listed in Table 1. Angiography protocol. Angiography was performed on digital imaging systems. Routinely 10 coronary angiograms and a left ventriculogram were performed. The type of contrast media used (ionic versus non-ionic), and the need for same-sitting ad hoc coronary intervention were left to the discretion of the invasive cardiologist. After the angiography or coronary intervention, patients were kept under observation for 6 more hours with intravenous hydration. Serum creatinine was measured 24 and 48 hours after angiography. The occurrence of RCIN, defined as > 25% and/or > 0.5 mg/dl increase from baseline creatinine, was recorded. The occurrence of any radiographic-contrast-induced nephropathy requiring dialysis in the month after angiography was noted. Statistical analysis. Baseline characteristics were compared between both groups using t-test for continuous variables and Chi-square test for categorical variables. All continuous variables will be presented in the form of mean ± standard deviation. Categorical variables will be presented as a percentage from total patient population. A multiple logistic-regression analysis was performed to examine the effect of N-acetylcysteine, with adjustment of all baseline characteristics. All statistical data analyses were performed using SAS statistical software, version 8.1 (Cary, North Carolina). Results Demographics and procedural variables for both the treatment and control groups are shown in Table 1. Comparison of the pre-procedural variables revealed no significant difference between the treatment and the control groups except for baseline creatinine and weight. The treatment group had a trend towards higher weights (88 vs. 81.6 kg; p = 0.064) and a significantly higher baseline creatinine (2.0 ± 0.7 vs. 1.8 ± 0.4 mg/dl; p = 0.04). Pre-procedural blood urea nitrogen (BUN) and bicarbonate were similar between both groups. The total amount of peri-procedural intravenous hydration was similar in both groups. (860 ml [± 45] vs. 800 ml [± 53]; p = 0.15). The distribution of the type of fluid was similar between both groups. Thirty-four of 55 and 32/55 patients in the treatment and control group received 0.9% saline while the rest received 0.45% saline (p = 0.2). Similar amounts of contrast media were given in both groups (144 cc vs. 134 cc; p = 0.5). The use of non-ionic contrast media was similar in both groups (14/55 vs. 8/55; p = 0.153). The rest of the patients received ionic contrast media. The number of patients that underwent a coronary intervention was similar between both groups (16/55 vs. 14/55; p = 0.4). All coronary interventions were done in the same sitting after the coronary angiography. The mean change in creatinine after 48 hours was -0.4 ± 0.3 versus +0.1 ± 0.3 mg/dl for treatment and control groups respectively (p 2 mg/dl, the benefit of N-acetylcysteine (Figures 1 and 2) was more pronounced (-0.4 ± 0.4) vs. +0.5 ± 0.3) mg/dl; p 1.2 mg/dl) undergoing computerized tomography studies.11 In the 42 patients that received N-acetylcysteine, the mean serum creatinine concentration decreased significantly (p 2 mg/dl benefited more from prophylactic administration of N-acetylcysteine than did patients with creatinine less than 2.0. The results of our study are different from what was reported by Boccalandro, probably due to multiple confounding factors. Our patients received a less amount of contrast and almost half the amount of hydration. Also, fewer patients had diabetes and hypertension, both factors known to be risk factors for RCIN. Results of both studies could be reconciled in the conclusion that high-risk patients who have not received enough hydration prior to contrast studies may benefit from acetylcysteine.26 There were several limitations to our study. First, it was not randomized, and used historical controls. Second, it included a small number of subjects, especially those with higher levels of serum creatinine. Third, although the total amount of hydration given to each group was similar, there was no standard protocol for hydration. While the study subjects and controls were recruited from different time periods, strategies for treating cardiac catheterization patients with chronic renal insufficiency were unchanged over these time periods except for the use of N-acetylcysteine. While non-ionic contrast was used more frequently in N-acetylcysteine patients, we do not believe that this affected our results because the difference was small, statistically not significant and because other studies have suggested that non-ionic contrast does not prevent RCIN.27,28 We conclude that in addition to adequate intravenous hydration, N-acetylcysteine is of benefit to patients with baseline renal dysfunction undergoing cardiac catheterization. Larger randomized trials are needed to confirm this finding. Also, its benefit in the subgroups of creatinine > 2 mg/dl versus
1. Deray G. Nephrotoxicity of contrast media. Nephrol Dial Transplant 1999;14:2602‚Äì2606. 2. Porter GA. Contrast associated nephropathy. Am J Cardiol 1989;64:22‚Äì26. 3. Gussenhoven MJ, Ravensbergen J, van Bockel, et al. Renal dysfunction after angiography: A risk factor analysis in patients with peripheral vascular disease. J Cardiovasc Surg 1991;32:81‚Äì86. 4. Lautin EM, Freeman NJ, Schoenfeld AH, et al. Radiocontrast-associated renal dysfunction: Incidence and risk factors. Am J Roentgenol 1991;157:49‚Äì58. 5. Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality. JAMA 1996;275:1489‚Äì1494. 6. Katholi RE, Taylor GJ, McCann WP, et al. Nephrotoxicity from contrast media: Attenuation with theophylline. Radiology 1995;195:17‚Äì22. 7. Erley CM, Duda SH, Schlepckow S, et al. Adenosine antagonist theophylline prevents the reduction of glomerular filtration rate after contrast media application. Kidney Int 1994;45:1425‚Äì1431. 8. Solomon R, Werner C, Mann D, et al. Effects of saline, mannitol, and furosemide on acute decreases in renal function induced by radiocontrast agents. N Engl J Med 1994;331:1416‚Äì1420. 9. Kurnik BR, 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‚Äì680. 10. Kini AS, Mitre CA, Kim M, et al. A protocol for prevention of radiographic contrast nephropathy during percutaneous coronary intervention: effect of selective Dopamine receptor agonist Fenoldopam. Cathet Cardiovasc Intervent 2002;55:169‚Äì173. 11. Tepel M, Van der Giet M, Schwarzfeld C, et al. Prevention of radiographic-contrast-agent-induced reduction in renal function by N-acetylcysteine. N Engl J Med 2000;343:180‚Äì184. 12. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31‚Äì41. 13. Gerlach AT, Pickworth KK. Contrast medium-induced nephrotoxicity: Pathophysiology and prevention. Pharmacotherapy 2000;20: 540‚Äì548. 14. Heyman SM, Reichman J, Brezis M. Pathophysiology of radiocontrast nephropathy. A role for medullary hypoxia. Invest Radiol 1999;34:685‚Äì691. 15. Schwab SJ, Hlatky MA, Pieper KS, et al. Contrast nephrotoxicity: A randomized controlled trial of a nonionic and an ionic radiographic contrast agent. N Engl J Med 1989;320:149. 16. Weisberg LS, Kurnik PB, Kurnik BRC. Risk of radiocontrast nephropathy in patients with and without diabetes mellitus. Kidney Int 1994;45:259‚Äì265. 17. Abizaid AS, Clark CE, Mintz GS, et al. Effects of dopamine and aminophylline on contrast-induced acute renal failure after coronary angioplasty in patients with preexisting renal insufficiency. Am J Cardiol 1999;83:260‚Äì263. 18. Morales PA, Hayes JV, Bailey SR. Contrast-induced nephropathy: Fenoldopam, a new agent to decrease acute renal insufficiency (Abstr). Am J Cardiol 2000;86(Suppl):8A. 19. Kini A, Mitre C, Kamran M. Preliminary experience with a Fenoldopam, a new renal vasodilator, in reducing radio contrast nephropathy during percutaneous coronary intervention (Abstr). Am J Cardiol 2000; 86(Suppl:8A. 20. Briguori C, Manganelli F, Scarpato P, et al. Acetylcysteine and contrast agent-associated nephrotoxicity. J Am Coll Cardiol 2002;40:403‚Äì409. 21. Shyu K, Cheng J, Kuan P. Acetylcysteine protects against acute renal damage in patients with abnormal renal function undergoing a coronary procedure. J Am Coll Cardiol 2002;40:1383. 22. Diaz-Sandoval LJ, Kosowsky BD, Losordo DW. Acetylcysteine to prevent angiography related renal tissue injury (the APART trial). Am J Cardiol 2002;89:356‚Äì358. 23. Boccalandro F, Amhad M, Smalling RW, Sdringola S. Oral acetylcysteine does not protect renal function from moderate to high doses of intravenous radiographic contrast. Cathet Cardiovasc Intervent 2003;58:336‚Äì341. 24. Kay J, Chow WH, Chan TM, et al. Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention. JAMA 2003;289:553‚Äì558. 25. Safirstein R, Andrade L, Vieira JM. Acetylcysteine and nephrotoxic effects of radiographic contrast agents ‚Äî A new use for an old drug. N Engl J Med 2000;343:210‚Äì212. 26. Dean LS. Protection from contrast-induced nephropathy. Is the Answer in? Cathet Cardiovasc Intervent 2003;58:342‚Äì343. 27. Katholi RE, Taylor GJ, Woods WT, et al. Nephrotoxicity of nonionic low-osmolality versus ionic high-osmolality contrast media: A prospective double blind randomized comparison in human beings. Radiology 1993:186:183‚Äì187. 28. Barrett BJ, Parfrey PS, Vavasour HM, et al. A comparison of non-ionic, low-osmolality radiocontrast agents with ionic, high-osmolality agents during cardiac catheterization. N Engl J Med 1992;326:431‚Äì436.