Investigators have found evidence to suggest that contrast-induced nephropathy (CIN) has a causal role in the development of long-term adverse events (AEs).

The evidence comes following analysis of data from the Cardiac Angiography in Renally Impaired Patients (CARE) study, a randomized, prospective trial comparing the efficacy of two contrast agents—iopamidol and iodixanol— in preventing CIN. Richard J. Solomon, MD, of the University of Vermont in Burlington, and colleagues gathered follow-up data on 294 of the original 414 CARE participants one year or more after contrast exposure.

“If CIN is causally related to long-term AEs, then a strategy that prevents CIN should reduce long-term AEs, as long as the strategy itself does not alter any other risk factors for those AEs,” Dr. Solomon’s group wrote, noting that neither contrast agent used in the CARE trial has any known effect on baseline risk factors that could contribute to long-term AEs.

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Of the 294 patients, 92 (31%) experienced AEs. Major AEs, including death, stroke, MI, or end-stage renal disease that required dialysis, occurred in 38 subjects (13%). For all definitions of CIN, the incidence of AEs was significantly greater in the CIN patients (42%-46%) than non-CIN patients (26%-29%), according to the report in Clinical Journal of the American Society of Nephrology (2009;4:1162-1169).

Iopamidol more protective

The incidence of AEs overall was significantly lower in iopamidol recipients than in iodixanol recipients (27% vs. 36%), as was the incidence of major AEs (11% vs. 15%).

In the original CARE trial, CIN was defined as a serum creatinine (SCr) increase of 0.5 mg/dL or higher or an increase of 25% or more. Combining the two end points, CIN occurred in 9.8% of iopamidol recipients compared with 12.4% of iodixanol recipients, a nonsignificant difference between the groups.

In the follow-up study, Dr. Solomon’s group defined CIN as a rise in SCr of 0.3 mg/dL and relative increases in cystatin C. Cystatin C has been suggested as a more sensitive marker of acute kidney injury in patients exposed to contrast as well as in ICU and post-renal transplant patients. The researchers used three definitions of CIN based on rises in cystatin C: 15% or greater, 20% or greater, and 25% or greater.

By all definitions, iopamidol recipients in the follow-up cohort had a lower incidence of CIN compared with iodixanol recipients. For example, using a CIN definition of 25% or greater increase in cystatin C, CIN developed in 12.9% of iopamidol recipients compared with 21.8% of iodixanol recipients; moreover, the incidence of AEs was significantly less in the iopamidol (27%) compared with the iodixanol (36%) group.

A causal relationship?

Whether a cause-and-effect relationship exists between CIN and long-term AEs has been unclear. CIN may be more likely to develop in patients who have an increased burden of cardiovascular risk factors before contrast medium exposure and, independent of the development of CIN, have more long-term AEs, the authors explained.

The study’s findings show that the incidence of AEs fell only in the trial arm that experienced a decrease in the incidence of CIN, suggesting that CIN has a causal role in the development of long-term AEs, according to the investigators.

“If CIN is a marker of pre-existing comorbidity burden, then this comorbidity burden should distribute equally between the arms of a randomized, prospective trial of two treatments to prevent CIN,” the authors wrote. “If one arm of such a trial reduces the incidence of CIN, then that arm would not be expected to have fewer long-term AEs if these are related to the preexisting comorbidity burden. Conversely, if both the incidence of CIN and long-term AEs were reduced by one of the treatments, then this would strengthen the hypothesis that CIN is causally related to those AEs.”