The acetylcysteine study, which was conducted in Hong Kong, involved 200 Chinese patients with stable moderate renal insufficiency who were undergoing elective coronary angiography. They were randomized to receive oral acetylcysteine (Fluimucil® - Zambon Group) 600 mg twice daily or placebo on the day before and the day of angiography. All patients received the nonionic low osmolality contrast agent iopamidol.

Serum creatinine was lower in the acetylcysteine group vs controls in the 48 hours after angiography, with 12% of control patients and 4% of acetylcysteine patients developing a more than 25% increase in serum creatinine levels within 48 hours after contrast administration (p=0.03). Creatinine clearance was significantly increased 2 days after contrast administration with the acetylcysteine treatment but remained similar in the control group. These benefits of acetylcysteine were consistent among various patient subgroups and persisted for at least 7 days. The average length of hospital stay was also cut by 0.5 days in the acetylcysteine group, and there were no major treatment-related adverse effects.

The authors, led by Dr Jay Kay (Grantham Hospital, Hong Kong), note that administration of contrast agents increases the production of nephrotoxic oxygen free radicals and that acetylcysteine acts as an antioxidant, scavenging these free radicals. It also has vasodilatory properties, which could have the additional benefit of improving renal hemodynamics, they add.

They conclude that oral acetylcysteine is a safe, effective, and inexpensive prophylactic treatment against acute renal dysfunction for patients with moderate chronic renal insufficiency undergoing coronary angiography. But they add that larger studies will be needed to see whether this agent can reduce morbidity (ie, acute dialysis) and mortality of nephrotoxicity following the administration of contrast media.

In an accompanying editorial, Dr Gary Curhan (Brigham and Women's Hospital, Boston) notes that previous studies of acetylcysteine in prevention of renal damage associated with contrast media have shown conflicting results.3 "These discrepant results may be due to differences in the timing and dose of acetylcysteine, total amount of contrast agent administered, characteristics of patients, and definition of contrast nephropathy," he says.

Curhan points out that the primary outcome of the study by Kay et al (change in serum creatinine level and creatinine clearance) are imperfect measures of glomerular filtration, so more work needs to be done in this area. He also states that many other questions remain, such as: Why was acetylcysteine not completely protective? Would a higher dose have provided even greater protection? Can more specific agents be developed? And would the addition of allopurinol, which also reduces free radicals, lower risk further?

However, he is positive about the overall results of the new study, saying that it provides "convincing support" for the additional benefit of using acetylcysteine in addition to saline and nonionic contrast agents for patients with reduced renal function undergoing coronary angiography. "Although the absolute clinical benefit is unproven, the reduction in length of hospitalization alone, with the associated costs and risk of nosocomial infection, is sufficient to recommend considering this approach," Curhan concludes.

In the iodixanol study, this third-generation, iso-osmolar, dimeric, nonionic iodinated contrast agent was compared with iohexol, a second-generation monomeric nonionic contrast agent in high-risk patients undergoing angiography. The use of iodixanol resulted in significantly fewer nephrotoxic effects than iohexol.

The study was conducted in 129 patients with stable diabetes mellitus and impaired renal function. Results showed that from day 0 to day 3, the mean peak increase in creatinine was 0.13 mg/dL in the iodixanol group and 0.55 mg/dL in the iohexol group (p=0.001). Of the 64 patients in the iodixanol group, 2 (3%) had an increase in creatinine concentration of 0.5 mg/dL or more, as compared with 17 of the 65 patients (26%) in the iohexol group (p=0.002).

The authors, led by Dr Peter Aspelin (Huddinge University Hospital, Stockholm, Sweden), note that these results confirm previous unblinded data suggesting that iodixanol is associated with a reduced incidence of nephropathy compared with iohexol in high-risk patients. They add that the iodixanol group in this study showed less renal toxicity than other studies of second-generation nonionic contrast mediafor example, iohexol given with drugs that may protect against nephrotoxicity such as acetylcysteine or fenoldopam. "The use of iodixanol alone may eliminate many of the adverse effects or logistic problems created when prophylactic pharmacologic regimens are used," they say.

In an accompanying editorial, Dr Carl M Sandler (University of Texas Medical School at Houston) notes that these findings are important because a beneficial effect of iodixanol on renal function has not previously been conclusively demonstrated in a randomized study.4

He explains that before the late 1960s, all iodinated contrast agents used for radiologic imaging were ionic monomers, which are extremely hyperosmolar relative to plasma. As 1 of the primary mechanisms involved in contrast-medium nephrotoxicity is believed to be arteriolar vasoconstriction in response to the delivery of a large hyperosmotic load to the kidneys, reducing the osmolality of contrast agents is thought to be a way of reducing their nephrotoxicity.

Nonionic contrast agents have substantially lower osmolality than ionic agents, but the first nonionic agent was not stable in solution and so was of only limited clinical usefulness. Second-generation nonionic monomers, such as iohexol, were stable, and, despite being much more expensive than ionic contrast agents, they gained widespread clinical acceptance because they were shown to have many fewer adverse effects than ionic contrast agents, Sandler notes, although lower nephrotoxicity still remains controversial, he adds.

In a meta-analysis of 31 trials comparing ionic and nonionic agents, a statistically significant benefit of the nonionic agents in terms of renal function could be shown only among patients with preexisting renal dysfunction in whom the contrast material was administered intra-arterially.

Sandler notes that although the osmolality of these second-generation agents was substantially lower than that of conventional agents, they were still hyperosmolar relative to plasma. Third-generation nonionic contrast agents reduce osmolality even further by creating a dimer, linking 2 molecules of contrast agent together, and thereby increasing the size of the molecule in solution. Iodixanol is the first dimeric contrast agent in this class and is iso-osmolar.

Sandler points out iodixanol has been shown to reduce pain compared with nonionic monomers when injected into small-caliber arteries for peripheral arteriography, but that the dimeric structure also has the disadvantage of increasing viscosity, which renders the contrast material more difficult to inject with the use of small arteriographic catheters.

He cautions that although the current results with iodixanol are encouraging, one should not conclude that iodixanol is the answer to contrast-agent-induced acute renal dysfunction; since previous clinical studies have yielded conflicting results, there is reason to believe that future studies of iodixanol may provide conflicting data as well.