Increasingly wide usage of radiographic contrast agents in diagnostic and interventional procedures results in contrast nephropathy, which is one of the important causes of iatrogenic acute renal failure. The increase in mortality, morbidity, and hospital costs in these patients makes prevention of this condition essential.1 However, the mechanism of contrast-related renal failure is complicated and not clearly understood. The renal medullary hypoxia caused by osmotic and hemodynamic changes due to contrast agents can lead to the formation of reactive oxygen radicals.2,3 Due to possible role of reactive oxygen radicals in the pathogenesis, it was suggested that acetylcysteine, which has an antioxidant effect could prevent contrast nephropathy. Tepel et al4 were the first to hypothesize that acetylcysteine taken orally concomitantly with hydration was more effective in preventing contrast nephropathy than hydration alone in patients who underwent elective computerized tomography with a non-ionic, low-osmolality contrast agent at a fixed dose. In this prospective and randomized study, we investigated whether oral acetylcysteine together with hydration was more effective than hydration alone or not in patients who were planned to undergo elective diagnostic coronary angiography with serum creatinine values >1.3 mg/dL.
In this study, we prospectively enrolled 50 consecutive patients scheduled for elective diagnostic coronary angiography with chronic impairment of renal function (serum creatinine concentration >1.3 mg/dL) and stable serum creatinine concentrations. The indication for angiography was determined by individual cardiologists. Coronary angiography was performed in standard fashion through the femoral approach. Concomitant coronary interventions were not performed. A random-allocation table was used to assign patients to receive either oral acetylcysteine and intravenous saline (0.9% NaCl) or intravenous saline alone. Acetylcysteine was given orally at a dose of 600 mg twice daily, on the day before and on the day of administration of the contrast agent, for a total of 2 days (acetylcysteine group). Thus, if randomized to the acetylcysteine group, patients received a total of 2400 mg of acetylcysteine. Total daily dosage of acetylcysteine was based on the previous report.4 The patients in the other group did not receive acetylcysteine (control group). Saline was given intravenously at a rate of 1 mL/kg/h for 12 hours before and 12 hours after administration of contrast agent to both groups. The patients were allowed to take oral fluids throughout the study. The serum creatinine and blood urea nitrogen values were measured immediately before and at the forty-eighth hour after the procedure. Patients with acute renal failure, those with end-stage renal failure on regular dialysis, those with clinically evident heart failure, those having allergy against contrast agents, those with serious hepatic dysfunction, and those planned to undergo percutaneous coronary interventions were not enrolled to the study. Patients were not allowed to take nephrotoxic drugs (NSAIDs, aminoglycoside) during the study. The same low osmolality contrast agent (ioxaglat) was used for all patients. Contrast nephropathy was defined as an increase more than 0.5 mg/dL in serum creatinine at forty-eighth hour post-procedure compared with baseline values. The end point of the study was set as the difference in the incidence of contrast nephropathy between two groups.
Values were given as mean ± SD. Student's t, Paired t, Fisher exact test and χ2 tests were used for statistical analysis. P value less than 0.05 was accepted as significant. Kolmogorov-Smirnov test was used to test the accordance of the data with normal distribution. Data showing abnormal distribution was normalized after adjustment to Logarithm 10.
Of the 50 patients enrolled in the study, 25 were in the acetylcysteine group, and the rest 25 were in the control group.
The baseline clinical features of the patients were similar in both groups (Table 1). Regarding the concomitant drug usage, the agents that could influence renal hemodynamics (angiotensin converting enzyme inhibitors, calcium antagonists, diuretics) were taken into account.
The mean age of all patients was 61.4 ± 11.9 (35-78). Mean serum creatinine and blood urea nitrogen levels of all patients before the procedure were 1.7 ± 0.5 mg/dL and 71.6 ± 34.8 mg/dL, respectively.
Mean baseline serum creatinine concentration was 1.6 ± 0.4 mg/dL in the acetylcysteine group and 1.8 ± 0.6 mg/dL in the control group. Forty-eight hours after the procedure, serum creatinine values showed a decrease in both groups, but they were not significant (1.5 ± 1.0 mg/dL and 1.7 ± 0.8 mg/dL in the acetylcysteine and control groups, respectively). The decrease in serum creatinine values compared with baseline values was not statistically significant in both groups. The changes in serum creatinine values compared with pre-procedure values were 0.098 ± 0.140 mg/dL and 0.017 ± 0.140 mg/dL in the acetylcysteine and control groups, respectively (Table 2).
Whereas the mean baseline blood urea nitrogen concentration was 69.9 ± 32.8 mg/dL in the acetylcysteine group, it was 73.4 ± 37.2 mg/dL in the control group. These values showed a decrease at forty-eighth hour after the procedure, but there was no significant difference between the groups (62.9 ± 39.8 mg/dL and 69.6 ± 31.0 mg/dL in the acetylcysteine and control groups, respectively). The decrease in blood urea nitrogen values compared with baseline values was not statistically significant in both groups. The changes between pre- and post-procedure serum urea nitrogen levels were 6.96 ± 4.94 mg/dL in the acetylcysteine group and 3.80 ± 5.76 mg/dL in the control group (Table 3).
Contrast nephropathy defined as an increase more than 0.5 mg/dL in serum creatinine at forty-eighth hour post-procedure compared with baseline values was observed in 10% of all patients (n = 5). A total of 3 patients in the acetylcysteine group (12%) and of 2 patients in the control group (8%) developed contrast nephropathy (P > 0.05) (Fig. 1).
Among all study population, 2 of the 4 patients (50%) with baseline serum creatinine concentration more than 2.5 mg/dL and only 3 of the 46 patients (6.5%) with baseline serum creatinine concentration less than 2.5 mg/dL developed contrast nephropathy (P = 0.04) (Fig. 2). Two of the 16 patients (12.5%) with diabetes mellitus and 3 of the 34 patients (8.8%) without diabetes mellitus developed contrast nephropathy (P > 0.05).
Treatment strategies did not change the incidence of contrast nephropathy in patients having diabetes mellitus and high baseline serum creatinine values. Dialysis was not required for patients with contrast nephropathy during the follow-up period. Four of the patients in the acetylcysteine group (16%) and 3 of the patients in the control group (12%) experienced gastrointestinal disturbances (P > 0.05).
In this prospective and randomized study, we observed that oral acetylcysteine administered concomitantly with hydration was not more effective than hydration alone in the prevention of contrast nephropathy when used before elective diagnostic coronary angiography in patients with renal dysfunction. Similarly, we did not determine the protective effect of acetylcysteine in patient subgroups with diabetes mellitus and high baseline serum creatinine values. We found that a high baseline serum creatinine value was a risk factor for the development of contrast nephropathy. Moreover, we also determined that dialysis was rarely required for contrast nephropathy and the side effects due to acetylcysteine were limited to the irritation of the gastrointestinal tract.
Tepel et al4 were the first to demonstrate that oral acetylcysteine administered concomitantly with hydration was more effective than hydration alone in the prevention of contrast nephropathy in patients with chronic renal failure after computerized tomography procedure with a non-ionic, low osmolality contrast agent at a fixed dose. In their study, contrast nephropathy was seen in a total of 10 patients (12%) and the incidence was lower in the acetylcysteine group compared with control (2% vs. 21%, P = 0.01). We performed a prospective and randomized study to determine if acetylcysteine had the same protective effect in patients who were planned to undergo elective diagnostic coronary angiography and had renal dysfunction. Although the study designs were similar, the obtained results had differences. There may be several reasons for these differences.
Acetylcysteine may be ineffective in preventing the development of contrast nephropathy at high contrast doses. The results of a study performed by Briguori et al5 support this contention. In this study, the protective effect of acetylcysteine on contrast nephropathy was evaluated in 183 patients with renal insufficiency that underwent elective coronary and/or peripheral angiography and/or angioplasty. When patients who received low doses of contrast (<140 mL) were evaluated, it was observed that contrast nephropathy developed in 5 of 60 patients (8.5%) in the control group but it was not seen in any of the 60 patients in the acetylcysteine group (P = 0.02). However, there was no difference in the incidences of contrast nephropathy between groups including the patients who received high doses of contrast (≥140 mL) (18.8% in acetylcysteine group, 16% in control group, P = 0.78).
The other reason may be that the given dose of the prophylactic acetylcysteine was inadequate. The results of another study performed by Briguori et al6 support this opinion. Among the patients with baseline creatinine level greater than or equal to 1.5 mg/dL and taking a non-ionic, low osmolality contrast agent during coronary and/or peripheral diagnostic procedures, contrast nephropathy developed less frequently in the group taking double dose of acetylcysteine (1200 mg twice a day) plus 0.45% NaCl infusion than in the group taking standard dose of acetylcysteine (600 mg twice a day) plus 0.45% NaCl.6
Concomitant drugs may influence the results. Because some patients in our study required additional drugs due to their clinical status, we did not limit concomitant drug usage. But the drugs received during the study might have influenced the renal hemodynamics and reduced the possible beneficial effects of acetylcysteine.
The difference in osmolalities of the intravenous hydration solutions might be another reason. It was shown in some studies that isotonic (0.9%) NaCl was superior to half-isotonic (0.45%) NaCl for protection from contrast nephropathy.7
Our study had some limitations. We did not record the contrast volumes given to the patients. Patient population was small and it was a single-center study. These factors might lower the statistical power of the study. Although the impairment in renal functions after contrast administration occurs after 48 hours in some patients, we evaluated the renal functions only at the forty-eighth hour after the procedure. The underlying etiology of the chronic renal impairment and the effect of acetylcysteine on different pathologies were not investigated.
Just like our study, acetylcysteine was not found to provide additional protection against contrast nephropathy in many studies.8-10 On the other hand, in accordance with the findings of Tepel et al, there are studies that demonstrated that acetylcysteine was effective.6,11-14 Moreover, in some studies, it was suggested that acetylcysteine was effective only in settings where low doses of contrast agents were used, as stated above.5 Recently, Duong et al15 conducted a meta-analysis to assess the overall effect of acetylcysteine in preventing radiocontrast-induced nephropathy. Their results showed a statistically significant benefit from using prophylactic acetylcysteine for patients with chronic renal impairment undergoing contrast-mediated procedures to prevent radiocontrast-induced nephropathy.
Our results show that oral acetylcysteine does not reduce the risk of contrast nephropathy when used before elective diagnostic coronary angiography in patients with renal dysfunction. However, acetylcysteine continues to draw attention in the prevention of contrast nephropathy because it is a non-expensive, easily obtainable, easily administered, and reliable drug.
1. McCullough PA, Wolyn R, Rocher LL, et al. Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality. Am J Med
2. Bakris GL, Lass N, Gaber AO, et al. Radiocontrast medium induced declines in renal function: a role for oxygen free radicals. Am J Physiol
3. Baliga R, Ueda N, Walker PD, et al. Oxidant mechanisms in toxic acute renal failure. Am J Kidney Dis
4. Tepel M, van der Giet M, Schwarzfeld C, et al. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med
5. Briguori C, Manganelli F, Scarpato P, et al. Acetylcysteine and contrast agent associated nephrotoxicity. J Am Coll Cardiol
6. Briguori C, Colombo A, Violante A, et al. Standard vs double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity. Eur Heart J
7. Mueller C, Buerkle G, Buettner HJ, et al. Prevention of contrast media associated nephropathy: Randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med
8. Durham JD, Caputo C, Dokko J, et al. A randomized controlled trial of N-acetylcysteine to prevent contrast nephropathy in cardiac angiography. Kidney Int
9. 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
10. Allaqaband S, Tumuluri R, Malik AM, et al. Prospective randomized study of N-acetylcysteine, fenoldopam, and saline for prevention of radiocontrast induced nephropathy. Catheter Cardiovasc Interv
11. Baker CS, Wragg A, Kumar S, et al. A rapid protocol for the prevention of contrast induced renal dysfunction: The RAPPID study. J Am Coll Cardiol
12. 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
13. Kay J, Chow WH, Chan TM, et al. Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography
and intervention. JAMA
14. Diaz-Sandoval LJ, Kosowsky BD, Losordo DW. Acetylcysteine to prevent angiography related renal tissue injury (The APART trial). Am J Cardiol
15. Duong MH, MacKenzie TA, Malenka DJ. N-Acetylcysteine prophylaxis significantly reduces the risk of radiocontrast-induced nephropathy: comprehensive meta-analysis. Catheter Cardiovasc Interv