Acetylcysteine May Protect Against Contrast-Induced Renal Dysfunction
Abstract & Commentary
Synopsis: In patients with chronic renal insufficiency, oral acetylcysteine combined with intravenous hydration was better than placebo and hydration in reducing the incidence of contrast-induced acute reduction in renal function. If borne out in larger studies and/or expanded to other patient groups (e.g., acute renal failure), this may become an important intervention prior to intravascular contrast agent administration.
Source: Tepel M, et al. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000;343:180-184.
Iodinated radiographic contrast agents for intravascular administration have long been known to be nephrotoxic. Fortunately, the nephrotoxicity usually is of no clinical significance; however, some patients may develop clinically relevant renal dysfunction, even leading to chronic renal failure and dialysis. Patients with pre-existing renal dysfunction (especially when caused by diabetes mellitus) are particularly at higher risk. Also at higher risk are patients taking concomitant nephrotoxic drugs and patients who receive large doses of contrast media. Dehydration, cardiovascular disease, hypertension, and hyperuricemia have also been considered risk factors.1 Nephrotoxicity can be reduced by hydrating the patient with intravenous saline before and after the administration of contrast media. Attempts to improve upon saline administration alone by adding other drugs such as mannitol, furosemide, theophylline, calcium antagonists, dopamine, and atrial natriuretic peptide have not proven successful.
Tepel and colleagues, citing evidence that reactive oxygen species may play a causative role in contrast-agent-induced nephrotoxicity, administered the antioxidant acetylcysteine in a prospective, placebo-controlled, randomized trial in high-risk patients and demonstrated a protective effect of the drug.
Study subjects were to undergo elective CT studies during which they received 75 mL intravenously of the nonionic low-osmolality contrast agent iopromide (300 mg/ml, Ultravist-300, Schering, Berlin, Germany). Subjects had a serum creatinine above 1.2 mg/dL or a calculated creatinine clearance of less than 50 mL per minute. All had a history of known chronic renal failure and stable serum creatinine; the stability of the serum creatinine was tested in the week prior to contrast agent administration. All patients were given half-normal (0.45%) saline intravenously at 1 mL/kg/h for 12 hours before and after the contrast agent administration. Oral fluids were allowed as desired. The study group of 41 patients received 600 mg acetylcysteine orally twice daily on the day before and the day of contrast agent administration. The control group of 42 patients received placebo. Serum creatinine was measured immediately before and two and six days after the dose of contrast agent. An acute contrast-agent-induced reduction in renal function was defined as an increase in serum creatinine of at least 0.5 mg/dL at the 48-hour post-contrast measurement.
In the control group, mean serum creatinine increased from 2.4 ± 1.3 before contrast to 2.6 ± 1.5 mg/dL at 48 hours, a change that was not statistically significant. In the acetylcysteine group, mean serum creatinine decreased from 2.5 ± 1.3 to 2.1 ± 1.3 mg/dL, a fall that was statistically significant (P < 0.001). There was no statistical difference in creatinine between the control and acetylcysteine groups before contrast agent administration, but the change in creatinine levels at 48 hours was significantly different (P < 0.001). An acute contrast-agent-induced reduction in renal function (as defined above) occurred in nine (21%) of the control group but in only one (2%) of the acetylcysteine group (significant at the P = 0.01 level). In these 10 patients, serum creatinine was still elevated on day 6 by 0.5 ± 0.6 mg/dL. Similar numbers of patients in both groups reported temporary gastrointestinal disturbances and dizziness.
To explain their results, Tepel et al point to the vasodilatory action of acetylcysteine as possibly counteracting the vasoconstriction caused by contrast agent administration, and to its antioxidant properties as possibly counteracting the direct toxic effects of contrast agents. The reader interested in more details of the possible biochemical mechanisms for the drug’s effects are referred to an accompanying editorial.2
Comment by James H. Ellis, MD
This interesting paper may lead to a method of reducing the nephrotoxic effects of iodinated radiographic contrast agents by oral administration of the drug acetylcysteine in combination with intravenous hydration. Tepal et al had great success in reducing the incidence of contrast-induced acute decrease in renal function by the combination of oral acetylcysteine and saline hydration compared to saline hydration alone. Indeed, within two weeks of publication, we began seeing patients in our institution in whom their internists had ordered acetylcysteine prior to obtaining CT. (Acetylcysteine is better known by its various trade names including Mucomyst [Bristol-Myers Squibb, Princeton, NJ] and Mucosil [Dey, Napa, Calif].)
On the technical side, it should be noted that the amount of contrast agent administered to the patients for CT scans was relatively small (75 mL of a 300 mg/ml nonionic agent) compared to the larger doses frequently used in abdominopelvic CT in my experience. Hopefully, the results will generalize to the larger doses. Also, patients with serum creatinine as low as 1.2 mg/dL were included, which would be within the range of normal at our institution. (Tepal et al do not give their normal range for serum creatinine.) These small points don’t detract from the overall message that use of acetylcysteine is successful in preventing acute contrast agent nephrotoxicity in a group of high-risk (chronic renal insufficiency) patients. If confirmed, this could expand the range of patients who could benefit from the advantages of receiving intravenous contrast agents.
Besides the above technical caveats, there are a few other important general issues to bring up. As noted above in the abstract, other drugs have been extolled for this purpose in the past, only to fall out of favor when additional studies were completed. The work of Tepel et al was performed on a small number of patients (83 total), especially given the low incidence of clinically significant renal failure caused by contrast agents. Indeed, none of the patients required dialysis, and no long-term outcome information about the patients is reported. Are we treating a laboratory value and not a patient, especially when a rise as little as 0.5 mg/dL in serum creatinine is used as the definition of contrast-induced renal injury? Granted, this value is often used in research studies because we want to be sensitive in detecting renal injury, yet typically such a small change is not important clinically, especially since most patients eventually return to baseline. Nonetheless, we do not know in advance which patients may develop clinically significant renal failure following contrast administration, so a method of prevention would be of great value.
That raises the next question. Without larger studies, we cannot assess the cost-effectiveness of this intervention. What will be the cost per episode of renal insufficiency saved? What is the risk of administering the drug to large populations? What is the correct group of patients to receive the drug (e.g., with creatinine above 1.5, or 2.0, or everybody)? Tepel et al only tested patients who had stable chronic renal failure. Patients with acute renal failure were excluded. Thus, we have as yet no evidence as to whether acetylcysteine may protect patients in acute renal failure from contrast-induced nephrotoxicity. These questions will require substantial future research, but such investigations will be based on this promising work of Tepel et al.
References
1. Committee on drugs and contrast media. In: Manual on Iodinated Contrast Media. 4th ed. Reston, Va: American College of Radiology; 1999:20.
2. Safirstein R, et al. Acetylcysteine and nephrotoxic effects of radiographic contrast agents: A new use for an old drug. N Engl J Med 2000;343:210-212.
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