Study Reinforces Concern about CIN
 Richard J. Solomon, M.D. University of Vermont College of Medicine |
 Michael A. Bettmann, M.D. Wake Forrest University Baptist Medical Center |
A recent study linking contrast-induced nephropathy (CIN) to long-term adverse events is causing some radiologists to question whether the research mischaracterizes the role of intravenous contrast—thereby discouraging its use.
Although research has long established a link between acute kidney injury and poor long-term outcomes, a causal relationship to CIN has not been conclusively confirmed.
In the study published in the June 2009 issue of the Clinical Journal of the American Society of Nephrology (CJASN) researchers again asserted that developing acute kidney injury after exposure to CIN is associated with worse one-year outcomes, particularly death, heart attack and stroke.
“Until this study, the assumption has always been that patients who develop kidney injury are in some way sicker to begin with,” said lead author Richard J. Solomon, M.D., a professor of medicine at the University of Vermont College of Medicine and director of the division of nephrology at Fletcher Allen Health Care in Burlington, Vermont. “Kidney injury was thought to be a flag that marks the patient as sick and not as likely to survive.”
CIN Patients Exhibit Great Number of Adverse Events
In the current study, researchers used data from the 2007 Cardiac Angiography in Renally Impaired Patients (CARE) trial—a randomized, prospective trial comparing two contrast agents—iopamidol and iodixanol—in preventing CIN. Dr. Solomon, also the lead author on the CARE study, and colleagues, conducted a follow-up study on 294 of the original 414 CARE participants one year or more after contrast exposure. In the double-blind comparison of the two contrast agents, researchers examined the incidence of adverse events between patients who developed CIN and those who did not.
Researchers discovered that the incidence of adverse events overall was significantly lower in iopamidol recipients than in iodixanol recipients (27 percent vs. 36 percent), as was the incidence of major adverse events (11 percent vs. 15 percent) respectively.
Of the 294 patients, 31 percent experienced adverse events while 13 percent experienced major adverse events including death, stroke, myocardial infarction or end-stage renal disease that required dialysis. For all definitions of CIN, the incidence of adverse events was significantly greater in CIN patients (42 percent vs. 46 percent) than non-CIN patients (26 percent vs. 29 percent) respectively, according to the study.
Because the CARE trial was supported by a grant from Bracco Diagnostics, Inc., which manufactures iopamidol, Michael A. Bettmann, M.D., offers a word of caution concerning the study. Dr. Solomon is also a paid consultant for Bracco.
“It is important to keep in mind that if a researcher has financial backing from a company, then invariably the article is likely to show that the agent produced by that company is better than or at least as good as the comparator agent,” said Dr. Bettmann, a professor and vice-chair for Interventional Services, Department of Radiology at Wake Forrest University Baptist Medical Center in Winston-Salem, N.C.
In response, Dr. Solomon replied: “This paper isn’t about contrast agents—it’s about the relationship between kidney injury to long-term outcomes,” he said. “We used data from a trial that randomized subjects to two different contrast agents. The randomization process controls for the baseline risk-factor burden. The difference in long-term outcomes in subjects with less CIN implies a causal relationship, not a lower risk factor burden.”
Radiologists Question Cardiac Connection to CIN
A small but growing number of radiologists who question the assumption that intravenous CT contrast is linked to CIN are now asking whether the actual link lies with administering arterial contrast during coronary procedures.
The CJASN analysis is a very logical and well done, and I think the conclusions are valid,” said Jeffrey H. Newhouse, M.D., of the Department of Radiology at Columbia-Presbyterian Medical Center in New York. “However, I think it’s important to caution everyone that this is a group of patients who had cardiac catheterization. You cannot make the automatic assumption that the same results will occur in patients who receive contrast intravenously.”
Mischaracterizing the study lead radiologists to exaggerate the risk that contrast actually carries, said Dr. Newhouse.
“To assume these results would be the same if contrast was administered intravenously is not valid,” said Dr. Newhouse, who presented the multisession course, “Intravenous Contrast Media and Contrast-Induced Nephropathy: What is the Risk,” at RSNA 2009.
Dr. Solomon agrees that the risk of CIN could be overestimated for intravenous contrast and that there is very little data on long-term outcomes with intravenous contrast.
“Less data doesn’t mean it doesn’t happen, but the evidence is not nearly as strong for intravenous use with CT,” said Dr. Solomon. “However, CIN does occur with intravenous contrast and when examined in large databases, research has shown that patients who develop CIN following intravenous contrast have worse short- and long-term outcomes.
Different CIN Definitions Questioned
The study’s methodology was also questioned by Dr. Bettmann who pointed out that different definitions of CIN are used in the original CARE study vs. the current study and that 120 of the patients included in the initial study were not included in the one-year follow up.
“It’s an odd statistical analysis,” said Dr. Bettmann, who presented “Intra-arterial Contrast Media and Contrast-Induced Nephropathy: Significance and Prevention,” as part of the RSNA 2009 Genitourinary Series, “Contrast Material and the Kidneys—Issues and Controversies Concerning Contrast-induced Nephropathy and Nephrogenic System Fibrosis.”
“The study starts with data showing no difference between two contrast agents and ends up with new results through different definitions of CIN than were used originally to show there are differences between the contrast agents,” said Dr. Bettmann.
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 percent or more. The study did not prove a significant difference between the groups.
In the follow-up study, Dr. Solomon and colleagues defined CIN as a rise in SCr of 0.3 mg/dL and relative increases in cystatine C, which Dr. Solomon said has repeatedly shown to have greater sensitivity and specificity for acute kidney injury compared to creatinine.
Researchers used three definitions of CIN based on rises in cystatin C: 15 percent or greater, 20 percent or greater and 25 percent or greater. By all definitions, iopamidol recipients in the follow-up trial had a lower incidence of CIN compared with iodixanol recipients, the study showed.
"Furthermore, in 350 patients of the original CARE study, cystatin C changes showed that there was a difference in the incidence of acute kidney injury between the two arms of the study, confirming the non statistically significant trend that was evident in the original trial using creatinine levels,” said Dr. Solomon.
The cystatin C definitions were considered clinically valid because they were significantly associated with a doubling of one-year adverse events, said Dr. Solomon. “The two-fold increase in adverse events in patients with acute kidney injury is consistent with other observations in literature of the impact of acute kidney injury on these same adverse events.”
In terms of the patient cohort, Dr. Solomon said the 120 patients lost to follow-up were not different clinically or demographically from the 294 in the current study. “The baseline characteristics of the original patients were similar to those in the follow-up cohort reducing the likelihood th qat there was a bias created by the loss of these patients.”
Alternative Markers Part of Future CIN Research
The more sensitive definitions should be included as primary outcomes in future randomized trials for CIN prevention and long-term adverse events should be included as secondary trial outcomes, suggested Dr. Solomon.
Alternative markers will see more use because of the statistical power associated with them, predicts Dr. Solomon. “We know that defining kidney injury by creatinine change is very imprecise,” said Dr. Solomon.
“In light of my research and reading, I suggest that radiologists consider raising the creatinine threshold for CIN as it would be diagnosed if the patient’s creatinine changed,” said Dr. Newhouse.