N-Acetylcysteine and Contrast-Induced Nephropathy
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The primary end point of the study by Marenzi et al. (June 29 issue)1 was the occurrence of contrast-medium–induced nephropathy, defined as an increase in the serum creatinine concentration of 25% or more from the baseline value within the 72-hour period after primary angioplasty. The reported incidence of contrast-medium–induced nephropathy varies widely among studies, since increases in the level of serum creatinine and the interval after the administration of contrast medium are not uniform among studies. In the Rapid Protocol for the Prevention of Contrast-Induced Renal Dysfunction (RAPPID) trial,2 contrast-medium–induced nephropathy was defined as a 25% increase in the serum creatinine level either 2 or 4 days after the administration of contrast medium. Briguori et al.3 and Tepel et al.4 define contrast-medium–induced nephropathy as an increase in serum creatinine of at least 0.5 mg per deciliter 48 hours after contrast administration. In their recent review article, Barrett and Parfrey5 state that serum creatinine levels peak 3 days after the administration of contrast medium and that appreciable nephropathy probably will not develop unless the serum creatinine level increases by more than 0.5 mg per deciliter within 24 hours.
Thus, given its clinical relevance, a consensus regarding the definition of contrast-medium–induced nephropathy is urgently needed. Meanwhile, we should take care before comparing the incidence of this complication among trials.
Pablo Aguiar-Souto, M.D.
Sara Valero-González, M.D.
Juan F. Oteo Domínguez, M.D.
Puerta de Hierro University Hospital
28035 Madrid, Spain
aguiarsouto@hotmail.com
References
Marenzi G, Assanelli E, Marana I, et al. N-acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med 2006;354:2773-2782.
Baker CSR, 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;41:2114-2118.
Briguori C, Colombo A, Violante A, et al. Standard vs double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity. Eur Heart J 2004;25:206-211.
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;343:180-184.
Barrett BJ, Parfrey PS. Preventing nephropathy induced by contrast medium. N Engl J Med 2006;354:379-386.
To the Editor: Marenzi et al. report that N-acetylcysteine reduces the risk of contrast-medium–induced nephropathy after primary angioplasty for acute myocardial infarction with ST-segment elevation. However, these results may not be generally applicable. The in-hospital mortality rate in the control group (11%) was much higher than the rate of 4 to 5% typically reported in recent randomized studies and large registries.1,2 The authors further report that 5% of patients in the control group required renal-replacement therapy; this very frequent use of dialysis was possibly explained by the authors' liberal threshold for this method of treatment.3
We compared the findings of Marenzi and colleagues with our experience in a large teaching hospital. Among 1174 consecutive patients who underwent primary angioplasty, only 3 (0.3%) required dialysis. In the study by Marenzi et al., the mean volume of contrast medium ranged from 253 to 274 ml. At our center, the mean (±SD) volume was 156±70 ml. We think it is likely that in a more typical population of patients with myocardial infarction and ST-segment elevation, no difference in clinical outcome would have been observed, particularly had contrast medium been used more judiciously.
Arik Wolak, M.D.
Carlos Cafri, M.D.
Doron Zahger, M.D.
Soroka University Medical Center
Beer Sheva 84101, Israel
arikwt@bgu.ac.il
References
Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003;361:13-20.
McNamara RL, Wang Y, Herrin J, et al. Effect of door-to-balloon time on mortality in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2006;47:2180-2186.
Marenzi G, Lauri G, Assanelli E, et al. Contrast-induced nephropathy in patients undergoing primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 2004;44:1780-1785.
To the Editor: Marenzi and colleagues report a reduction in the incidence of contrast-medium–induced nephropathy and in-hospital mortality associated with primary angioplasty among patients receiving N-acetylcysteine. Nevertheless, there was no difference in the incidence of acute renal failure requiring renal-replacement therapy, a relevant clinical predictor of mortality related to renal impairment induced by contrast medium.1,2 This finding suggests that the difference in in-hospital mortality might have been related more to depressed left ventricular function than to renal impairment. Thus, it would be of interest to know the initial hemodynamic status and renal function of the patients in whom cardiogenic shock and heart failure leading to death occurred, especially because the control group had a surprisingly high mortality rate.
In addition, the combined end point calls for careful review. The definition used may not be correct, since the requirement for mechanical ventilation depended on cardiogenic shock, the main cause of death in the study.
Although the authors reported a dose-dependent protective effect of N-acetylcysteine, the two N-acetylcysteine groups had similar rates of contrast-medium–induced nephropathy (15% in the standard-dose group and 8% in the high-dose group, P=0.13), renal-replacement therapy, and death.
Domingo C. Balderramo, M.D.
Hospital Clínic
08036 Barcelona, Spain
dcbalde@clinic.ub.es
References
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;103:368-375.
Gruberg L, Mehran R, Dangas G, et al. Acute renal failure requiring dialysis after percutaneous coronary interventions. Catheter Cardiovasc Interv 2001;52:409-416.
To the Editor: The article by Tepel et al.1 on the use of N-acetylcysteine to prevent contrast-agent–induced reductions in renal function provoked a flurry of studies — unfortunately with widely differing results. Research does not obey the democratic rule of the majority, so it does not help to count the number of patients, as a great number of meta-analyses have done. The original study and most of the follow-up studies were conducted on the basis of measurements of serum creatinine. Marenzi et al. provide information on the estimated creatinine clearance in addition to the serum creatinine concentration after angioplasty in patients with acute myocardial infarction. However, a study involving volunteers (admittedly not a study involving patients with acute renal failure) provided indirect evidence that N-acetylcysteine affects tubular creatinine transport.2 As a result, the serum concentration of creatinine was decreased, but not that of cystatin C, a marker of the glomerular filtration rate that is not affected by tubular transport or by other confounders that render the measurement of creatinine somewhat problematic.
It would be helpful if Marenzi and colleagues could show that in their study the concentrations of cystatin C, as an independent marker of the glomerular filtration rate, moved in parallel with those of serum creatinine.
Eberhard Ritz, M.D.
Ruperto-Carola University Heidelberg
D-69120 Heidelberg, Germany
prof.e.ritz@t-online.de
References
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;343:180-184.
Hoffmann U, Fischereder M, Kruger B, Drobnik W, Kramer BK. The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable. J Am Soc Nephrol 2004;15:407-410.
The authors reply: Regarding the comments of Ritz, the means to measure cystatin C were not available in our institution at the time of our study, and the results of the study by Hoffmann et al. had not yet been published when we designed our study. Although these may be limitations, it is possible that N-acetylcysteine has a protective effect when oxidative stress induced by ischemia and reperfusion plays a role in pathogenesis but has little or no effect when oxidative stress is absent, as is the case in healthy subjects. Moreover, beyond a direct renal effect, the cardioprotective properties of N-acetylcysteine may help prevent contrast-medium–induced nephropathy, resulting in improved left ventricular function and renal hemodynamics.
The mortality rate in our control group was higher than that in other recent randomized trials. However, the numerous exclusion criteria used in such trials, which often do not enroll high-risk patients, may explain their invariably lower mortality rate as compared with the rates in primary angioplasty registries. Indeed, a mortality rate between 9.3 and 10.8% was reported in some recent studies, reflecting, as in our study, "real-world" clinical practice.1,2,3
We agree with Aguiar-Souto and colleagues that because of the variety of definitions of contrast-medium–induced nephropathy (absolute or relative increases in creatinine 24, 48, or rarely 72, 96, or 120 hours after exposure to contrast medium), a consensus is needed. Indeed, because creatinine peaks between the fourth and fifth day, contrast-medium–induced nephropathy may be missed in many patients if one relies only on measurements made during the first 48 hours.4
We used hemodialysis and hemofiltration as renal-replacement therapies. However, of the nine patients who received renal-replacement therapy (2.5%), only one (0.3%) underwent hemodialysis, whereas the remaining eight (2.3%) underwent hemofiltration, which was mainly started earlier than the "standard" indication for hemodialysis because of overt pulmonary congestion. Thus, renal-replacement therapy was not directly correlated with the occurrence of acute renal failure.
The amount of contrast medium used in our study was similar to that reported by others and reflects our practice of primary percutaneous coronary intervention, including left ventriculography performed to assess left ventricular function and to exclude ventricular septal defect and mitral-valve regurgitation; optimal stent deployment, which often requires an increased number of angiographic projections in order to reduce the risk of thrombosis; and the use of thrombus aspiration or distal protection systems in case of a large thrombus burden. Indeed, a recent study comparing clinical and procedural characteristics among hospitals, mostly regarding elective percutaneous coronary intervention, invariably reported a contrast volume of more than 200 ml.5
Finally, the difference in the primary end point and the other clinical end points between the two N-acetylcysteine groups was significant when analyzed by the Mantel–Haenszel chi-square test for trend, suggesting a dose-dependent protective effect of N-acetylcysteine.
Giancarlo Marenzi, M.D.
Gianfranco Lauri, M.D.
Antonio L. Bartorelli, M.D.
Centro Cardiologico Monzino
20138 Milan, Italy
giancarlo.marenzi@ccfm.it
References
Carrabba N, Santoro GM, Balzi D, et al. In-hospital management and outcome in women with acute myocardial infarction (data from the AMI-Florence Registry). Am J Cardiol 2004;94:1118-1123.
Zahn R, Vogt A, Zeymer U, et al. In-hospital time to treatment of patients with acute ST elevation myocardial infarction treated with primary angioplasty: determinants and outcome: results from the registry of percutaneous coronary interventions in acute myocardial infarction of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausarzte. Heart 2005;91:1041-1046.
Yamaguchi J, Kasanuki H, Ishii Y, et al. Prognostic significance of serum creatinine concentration for in-hospital mortality in patients with acute myocardial infarction who underwent successful primary percutaneous coronary intervention (from the Heart Institute of Japan Acute Myocardial Infarction Registry). Am J Cardiol 2004;93:1526-1528.
McCullough PA, Soman SS. Epidemiology and predictors of contrast-induced nephropathy. In: Bartorelli AL, Marenzi G, eds. Contrast-induced nephropathy: in interventional cardiovascular medicine. London: Taylor & Francis, 2005:19-33.
Moscucci M, Share D, Smith D, et al. Relationship between operator volume and adverse outcome in contemporary percutaneous coronary intervention practice: an analysis of a quality-controlled multicenter percutaneous coronary intervention clinical database. J Am Coll Cardiol 2005;46:625-632.
Thus, given its clinical relevance, a consensus regarding the definition of contrast-medium–induced nephropathy is urgently needed. Meanwhile, we should take care before comparing the incidence of this complication among trials.
Pablo Aguiar-Souto, M.D.
Sara Valero-González, M.D.
Juan F. Oteo Domínguez, M.D.
Puerta de Hierro University Hospital
28035 Madrid, Spain
aguiarsouto@hotmail.com
References
Marenzi G, Assanelli E, Marana I, et al. N-acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med 2006;354:2773-2782.
Baker CSR, 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;41:2114-2118.
Briguori C, Colombo A, Violante A, et al. Standard vs double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity. Eur Heart J 2004;25:206-211.
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;343:180-184.
Barrett BJ, Parfrey PS. Preventing nephropathy induced by contrast medium. N Engl J Med 2006;354:379-386.
To the Editor: Marenzi et al. report that N-acetylcysteine reduces the risk of contrast-medium–induced nephropathy after primary angioplasty for acute myocardial infarction with ST-segment elevation. However, these results may not be generally applicable. The in-hospital mortality rate in the control group (11%) was much higher than the rate of 4 to 5% typically reported in recent randomized studies and large registries.1,2 The authors further report that 5% of patients in the control group required renal-replacement therapy; this very frequent use of dialysis was possibly explained by the authors' liberal threshold for this method of treatment.3
We compared the findings of Marenzi and colleagues with our experience in a large teaching hospital. Among 1174 consecutive patients who underwent primary angioplasty, only 3 (0.3%) required dialysis. In the study by Marenzi et al., the mean volume of contrast medium ranged from 253 to 274 ml. At our center, the mean (±SD) volume was 156±70 ml. We think it is likely that in a more typical population of patients with myocardial infarction and ST-segment elevation, no difference in clinical outcome would have been observed, particularly had contrast medium been used more judiciously.
Arik Wolak, M.D.
Carlos Cafri, M.D.
Doron Zahger, M.D.
Soroka University Medical Center
Beer Sheva 84101, Israel
arikwt@bgu.ac.il
References
Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003;361:13-20.
McNamara RL, Wang Y, Herrin J, et al. Effect of door-to-balloon time on mortality in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2006;47:2180-2186.
Marenzi G, Lauri G, Assanelli E, et al. Contrast-induced nephropathy in patients undergoing primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 2004;44:1780-1785.
To the Editor: Marenzi and colleagues report a reduction in the incidence of contrast-medium–induced nephropathy and in-hospital mortality associated with primary angioplasty among patients receiving N-acetylcysteine. Nevertheless, there was no difference in the incidence of acute renal failure requiring renal-replacement therapy, a relevant clinical predictor of mortality related to renal impairment induced by contrast medium.1,2 This finding suggests that the difference in in-hospital mortality might have been related more to depressed left ventricular function than to renal impairment. Thus, it would be of interest to know the initial hemodynamic status and renal function of the patients in whom cardiogenic shock and heart failure leading to death occurred, especially because the control group had a surprisingly high mortality rate.
In addition, the combined end point calls for careful review. The definition used may not be correct, since the requirement for mechanical ventilation depended on cardiogenic shock, the main cause of death in the study.
Although the authors reported a dose-dependent protective effect of N-acetylcysteine, the two N-acetylcysteine groups had similar rates of contrast-medium–induced nephropathy (15% in the standard-dose group and 8% in the high-dose group, P=0.13), renal-replacement therapy, and death.
Domingo C. Balderramo, M.D.
Hospital Clínic
08036 Barcelona, Spain
dcbalde@clinic.ub.es
References
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;103:368-375.
Gruberg L, Mehran R, Dangas G, et al. Acute renal failure requiring dialysis after percutaneous coronary interventions. Catheter Cardiovasc Interv 2001;52:409-416.
To the Editor: The article by Tepel et al.1 on the use of N-acetylcysteine to prevent contrast-agent–induced reductions in renal function provoked a flurry of studies — unfortunately with widely differing results. Research does not obey the democratic rule of the majority, so it does not help to count the number of patients, as a great number of meta-analyses have done. The original study and most of the follow-up studies were conducted on the basis of measurements of serum creatinine. Marenzi et al. provide information on the estimated creatinine clearance in addition to the serum creatinine concentration after angioplasty in patients with acute myocardial infarction. However, a study involving volunteers (admittedly not a study involving patients with acute renal failure) provided indirect evidence that N-acetylcysteine affects tubular creatinine transport.2 As a result, the serum concentration of creatinine was decreased, but not that of cystatin C, a marker of the glomerular filtration rate that is not affected by tubular transport or by other confounders that render the measurement of creatinine somewhat problematic.
It would be helpful if Marenzi and colleagues could show that in their study the concentrations of cystatin C, as an independent marker of the glomerular filtration rate, moved in parallel with those of serum creatinine.
Eberhard Ritz, M.D.
Ruperto-Carola University Heidelberg
D-69120 Heidelberg, Germany
prof.e.ritz@t-online.de
References
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;343:180-184.
Hoffmann U, Fischereder M, Kruger B, Drobnik W, Kramer BK. The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable. J Am Soc Nephrol 2004;15:407-410.
The authors reply: Regarding the comments of Ritz, the means to measure cystatin C were not available in our institution at the time of our study, and the results of the study by Hoffmann et al. had not yet been published when we designed our study. Although these may be limitations, it is possible that N-acetylcysteine has a protective effect when oxidative stress induced by ischemia and reperfusion plays a role in pathogenesis but has little or no effect when oxidative stress is absent, as is the case in healthy subjects. Moreover, beyond a direct renal effect, the cardioprotective properties of N-acetylcysteine may help prevent contrast-medium–induced nephropathy, resulting in improved left ventricular function and renal hemodynamics.
The mortality rate in our control group was higher than that in other recent randomized trials. However, the numerous exclusion criteria used in such trials, which often do not enroll high-risk patients, may explain their invariably lower mortality rate as compared with the rates in primary angioplasty registries. Indeed, a mortality rate between 9.3 and 10.8% was reported in some recent studies, reflecting, as in our study, "real-world" clinical practice.1,2,3
We agree with Aguiar-Souto and colleagues that because of the variety of definitions of contrast-medium–induced nephropathy (absolute or relative increases in creatinine 24, 48, or rarely 72, 96, or 120 hours after exposure to contrast medium), a consensus is needed. Indeed, because creatinine peaks between the fourth and fifth day, contrast-medium–induced nephropathy may be missed in many patients if one relies only on measurements made during the first 48 hours.4
We used hemodialysis and hemofiltration as renal-replacement therapies. However, of the nine patients who received renal-replacement therapy (2.5%), only one (0.3%) underwent hemodialysis, whereas the remaining eight (2.3%) underwent hemofiltration, which was mainly started earlier than the "standard" indication for hemodialysis because of overt pulmonary congestion. Thus, renal-replacement therapy was not directly correlated with the occurrence of acute renal failure.
The amount of contrast medium used in our study was similar to that reported by others and reflects our practice of primary percutaneous coronary intervention, including left ventriculography performed to assess left ventricular function and to exclude ventricular septal defect and mitral-valve regurgitation; optimal stent deployment, which often requires an increased number of angiographic projections in order to reduce the risk of thrombosis; and the use of thrombus aspiration or distal protection systems in case of a large thrombus burden. Indeed, a recent study comparing clinical and procedural characteristics among hospitals, mostly regarding elective percutaneous coronary intervention, invariably reported a contrast volume of more than 200 ml.5
Finally, the difference in the primary end point and the other clinical end points between the two N-acetylcysteine groups was significant when analyzed by the Mantel–Haenszel chi-square test for trend, suggesting a dose-dependent protective effect of N-acetylcysteine.
Giancarlo Marenzi, M.D.
Gianfranco Lauri, M.D.
Antonio L. Bartorelli, M.D.
Centro Cardiologico Monzino
20138 Milan, Italy
giancarlo.marenzi@ccfm.it
References
Carrabba N, Santoro GM, Balzi D, et al. In-hospital management and outcome in women with acute myocardial infarction (data from the AMI-Florence Registry). Am J Cardiol 2004;94:1118-1123.
Zahn R, Vogt A, Zeymer U, et al. In-hospital time to treatment of patients with acute ST elevation myocardial infarction treated with primary angioplasty: determinants and outcome: results from the registry of percutaneous coronary interventions in acute myocardial infarction of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausarzte. Heart 2005;91:1041-1046.
Yamaguchi J, Kasanuki H, Ishii Y, et al. Prognostic significance of serum creatinine concentration for in-hospital mortality in patients with acute myocardial infarction who underwent successful primary percutaneous coronary intervention (from the Heart Institute of Japan Acute Myocardial Infarction Registry). Am J Cardiol 2004;93:1526-1528.
McCullough PA, Soman SS. Epidemiology and predictors of contrast-induced nephropathy. In: Bartorelli AL, Marenzi G, eds. Contrast-induced nephropathy: in interventional cardiovascular medicine. London: Taylor & Francis, 2005:19-33.
Moscucci M, Share D, Smith D, et al. Relationship between operator volume and adverse outcome in contemporary percutaneous coronary intervention practice: an analysis of a quality-controlled multicenter percutaneous coronary intervention clinical database. J Am Coll Cardiol 2005;46:625-632.