Contrast-induced nephropathy in computed tomography

Henrik S Thomsen
MD
Professor of Radiology
Department of Diagnostic Radiology
Copenhagen University Hospital
Herlev
Denmark

Administration of contrast media may cause a reduction in renal function, particularly in patients with reduced renal function; the poorer the function the higher the risk. This adverse event, which is called contrast-induced nephropathy (CIN), is often temporary. In some patients, however, CIN might lead to permanent haemodialysis. CIN occurs instantly after administration of the contrast media and, in most cases, kidney function returns to normal within a week or two. However, this temporary dysfunction is correlated with increased morbidity and mortality. Therefore, many efforts have been put into trying to reduce the incidence of CIN. About 50% of the consumption of iodine-based contrast media is used for computed tomography (CT). Recently new CT studies have enlightened this area, which for years had been dominated by angiographic examinations.

Currently available contast agents
More than 25 years ago, Barrett and Carlisle showed that the incidence of CIN was significantly higher after administration of high-osmolar contrast agents (osmolality >1,500 mOsm/kg) than after administration of low-osmolar contrast media (LOCM, osmolality <915 mOsm/kg). Today the question is whether there are any differences in nephrotoxicity among the other available contrast agents, either low-osmolar contrast media or iso-osmolar contrast media (IOCM, osmolality of 290 mOsm/kg). A total of eight nonionic monomers (iohexol, iomeprol, iopamidol, iopentol, ioxilan, iopromide, ioversol and iobiditrol), one ionic dimer (ioxaglate) and one nonionic dimer (iodixanol) are approved for intra‑vascular use (their approved use varies from country to country).

The hypothesis that isotonic contrast media may have better renal tolerance in high-risk patients compared with low-osmolar contrast media has had considerable impact on the scientific community. It has even influenced the recommendations of several guidelines despite the fact that, for a long time, this had only been demonstrated in one single study. Now seven studies have compared a low-osmolar contrast agent with an iso-osmolar contrast agent administered intra-arterially. Two studies were in favour of the nonionic dimer, whereas the remaining five showed no statistically significant difference between the two contrast agents.

Until recently only two studies had compared the renal safety of nonionic dimeric contrast agents with nonionic monomeric contrast agents after intravenous administration. Now two major studies have been performed, with no study being in favour of the nonionic dimer. One study has shown a significantly lower rate of CIN after administration of the monomer, compared with the dimer (see Table 1), and when the results of these two almost identical studies, ACTIVE and IMPACT, are pooled together they show that no patient with reduced renal function (<40 ml/min) in the monomer group developed CIN, whereas six patients did in the dimer group (p < 0.0059).

[[HHE07_table1_R5]]

The IMPACT and ACTIVE studies are the largest prospective, randomised, double-blind studies comparing CIN incidence after intravenous injection of either the dimer contrast agent iodixanol or a non‑ionic monomer (either iopamidol or iomeron). No significant relationship was observed between the occurrence of CIN and age, gender, race, diabetes mellitus, dose by body weight, baseline creatine clearance, intrinsic kidney diseases versus other reasons for reduced kidney function, hypertension and use of concomitant potentially nephrotoxic medications. The true cause of acute renal failure after contrast media injection is difficult to determine clinically, particularly in patients undergoing cardiac angiography, where haemodynamic instability, atheroembolism and the effects of other drugs may all play a role. In this respect, studies comparing agents given intravenously may be less prone to confounding factors for kidney failure other than CIN. However, it must also be noted that small and transient changes in kidney function have been documented in a proportion of patients having CT examinations without contrast and control groups not exposed to contrast.

It has been suggested that the nephrotoxicity of contrast media is a function of dose in relation to level of kidney function at the time of injection. The dose of contrast by necessity varies between patients undergoing cardiac angiography with and without stent placement, and the similarity of trial groups in terms of individual patient dose per unit of kidney function is generally not reported. This is more of an issue when interpreting data from trials with relatively small numbers of subjects per group, where an unreported imbalance might significantly affect the results. Moreover, the dose of contrast is usually reported as injected volume, even though the iodine strength of contrast solutions varies from 140 mgI/ml to up to 400 mgI/ml.

The protocol for the IMPACT and ACTIVE studies called for a fixed and equi-iodine dose of contrast to be given to all participants. This helped reduce the contrast factor, as variability between subjects derived only from body size or level of kidney function. Iodine dose/kg body weight and iodine dose/per unit of creatinine clearance were also equivalently distributed in the IMPACT and ACTIVE studies.

Most trials have not been as rigorous in determining the stability of kidney function among trial participants before contrast administration. It is clearly difficult to say whether CIN is responsible for a decline in kidney function in patients with changing kidney function before contrast. The definition of “stable” kidney function in the ACTIVE and IMPACT studies was based on a review of trial data before unblinding. 

Conclusion
Controversy still exists about differences in nephrotoxicity between the nonionic dimer and the various monomers following their intra-arterial administration. However, it is clear that there is no advantage of using the nonionic dimer for intravenous studies.

These results have major financial implications, as the monomers are cheaper per gram of iodine than the dimer.

Resources

1. Barrett BJ, et al. Contrast induced nephropathy in patients with chronic kidney disease undergoing computed tomography. A double blind �comparison of iodixanol and iopamidol. Invest Radiol 2006;41:815-21.
2. Barrett BJ, Parfery PS. Preventing nephropathy induced by contrast medium. N Engl J Med 2006;354:379-86.
3. Thomsen HS, editor. Contrast media. Safety issues and ESUR guidelines. Heidelberg: Springer Verlag; 2006.
4. Thomsen HS, Morcos SK. Contrast-medium-induced nephropathy: is there a new consensus? A review of published guidelines. Eur Radiol 2006;16:1835-40.