Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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. For Permissions, please e-mail: [email protected] 3104 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 3106 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