Although intravenous iodinated contrast media used in some CT exams has long been regarded as potentially harmful to kidneys, two April 2013 Radiology studies found no evidence that patients undergoing CT exams with contrast face an increased risk of kidney injury.
Demonstrating the complexity of the issue, however, a third study appearing in the same issue of Radiology showed that intravenous, low-osmolality iodinated contrast material is a nephrotoxic risk factor, but only in patients with preexisting renal insufficiency. The authors of the first two studies, Robert J. McDonald, M.D., Ph.D., and Jennifer S. McDonald, Ph.D., join the third author, Matthew S. Davenport, M.D., and other experts in a Radiology Podcast discussion of their research and contrast agents in general. (See sidebar).
For many years, the association between intravenous iodinated contrast media and kidney injury was so entrenched that the terms acute kidney injury (AKI) and contrast material-induced nephropathy (CIN), or an increase in serum creatinine (SCr) after a CT exam, were used interchangeably. “Medical dogma currently suggests that intravenous contrast is an extremely common cause of renal injury,” said Dr. Robert McDonald, a radiologist at the Mayo Clinic in Rochester, Minn.
Despite their ability to improve visualization of tissue, contrast agents are often withheld from CT exams due to this concern, and patients with compromised kidney function are frequently discouraged from having these tests. This practice has come under the scrutiny of Dr. Robert McDonald, Dr. Davenport and colleagues who believe that improperly designed studies have led to an overstated risk of renal injury from intravenous iodinated contrast material. Clinical trials in which patients are randomly assigned to receive or not receive contrast could provide answers, but ethical dilemmas over such trials have forced clinicians to instead predominantly rely on studies with no control groups.
“Over the past several decades, well over 1,000 studies have been published on contrast-induced nephropathy that did not include control groups of patients who did not receive contrast,” said Dr. Jennifer McDonald, an assistant professor in the Department of Radiology at the Mayo Clinic. “These uncontrolled studies cannot differentiate cases of true contrast-induced nephropathy from contrast-independent causes of renal injury and are thus of little value in the realm of evidence-based medicine.”
To that end, Dr. Robert McDonald and his Mayo Clinic colleagues recently conducted an extensive review of AKI in patients who underwent contrast-enhanced and unenhanced abdominal, pelvic and thoracic CT. In a study published in the April issue of Radiology, researchers applied analytical tools including propensity score adjustments to simulate a randomized controlled trial on retrospective data and a counterfactual analysis, an experiment designed to test causality.
The Mayo team studied AKI incidence in 53,439 patients who underwent CT scanning between 2001 and 2010. After analyzing 157,140 scans, researchers found no significant difference in AKI risk between patients who had received contrast and those who had not. Analysis of patients who received both an enhanced an unenhanced CT scanning during the study timeframe also showed no significant difference in AKI incidence between the two scan types, suggesting a weak or absent causal association between contrast exposure and kidney injury.
Findings from the first study inspired Mayo researchers to identify and analyze all prior controlled studies of the nephrotoxic effects of IV contrast media. These separate efforts were also published in the April issue of Radiology.
Researchers identified 13 non-randomized studies comprising 25,950 patients. The risk of AKI, death and dialysis was similar between the group that received contrast medium and the control group that did not receive contrast medium. This pattern was observed regardless of IV contrast medium type, diagnostic criteria for AKI or whether patients had diabetes mellitus or renal insufficiency.
“The results of this meta-analysis mirror the findings from our own controlled study,” Dr. Jennifer McDonald said. “These studies comprehensively could not detect an increased incidence of AKI in those patients that received contrast media.”
The Mayo studies and other research suggest that other sources for kidney injury exist in this patient group. Dr. Robert McDonald pointed out that people undergoing CT with contrast are less healthy, on average, than people in the general population.
“There are dozens of other causes of kidney injury that lead to a rise in serum creatinine and, based upon our findings, these contrast-independent causes seem to occur at a similar rate between patients who were exposed to intravenous contrast and those who were not,” he said.
While the Radiology research led by Dr. Davenport determined that intravenously administered low-osmolality iodinated contrast material is an important independent risk factor for post-CT AKI in patients with preexisting renal insufficiency, researchers also determined that many factors other than contrast material can affect post-CT AKI rates.
In their retrospective study, researchers performed CT exams over a 10-year period in 20,242 patients identified with sufficient SCr data. Half of the exams included intravenous contrast material and half did not.
Researchers performed a one-to-one propensity-matched cohort analysis with multivariate analysis of effects. Propensity matching was performed with respect to likelihood of patients receiving intravenous contrast material (36 tested covariates). The primary endpoint was post-CT AKI by using Acute Kidney Injury Network SCr criteria; the secondary endpoint was post-CT AKI by using traditional SCr criteria for contrast material–induced nephrotoxicity. Multivariate subgroup threshold analysis was performed and adjusted for assigned propensity scores.
Intravenous low-osmolality iodinated contrast material had a significant effect on the development of post-CT AKI for patients with pre-CT SCr levels of 1.6 mg/dL or greater, results showed. Patients with stable SCr less than 1.5 mg/dL were not at risk for developing CIN.
“Our data demonstrate that intravenously administered iodinated contrast is indeed nephrotoxic, although only in a small population of patients,” said Dr. Davenport, an assistant professor at the University of Michigan Health System in Ann Arbor. “Only patients with severe renal dysfunction appear to be at significant risk. Each of our studies has shown rather convincingly that the risk is much less common than previously believed.”
Although all three studies share common ground, there is one critical difference, Dr. Davenport said. “Our research shows that there is a risk in patients with severe renal impairment, while Dr. McDonald and colleagues were unable to find such a risk. Resolving this difference has profound clinical implications.”
The Mayo and Michigan findings and other research could help speed a change in thinking among physicians and expand access to potentially life-saving exams for patients.
Paradoxically, patients for whom contrast is withheld are often those who would benefit the most from a contrast-enhanced CT exam. “Without contrast, we are more limited in the information we can provide to the patient and the primary care provider which unfortunately can lead to unnecessary additional CT examinations and delays in diagnosis and/or treatment,” Dr. Robert McDonald said.
There are signs that the Mayo and Michigan studies and other research are helping physicians make more informed decisions, according to David F. Kallmes, M.D., a professor of radiology at the Mayo Clinic and a co-author of both studies who also participates in the Podcast discussion.
“The research has made an impact, and we’re already seeing liberalization in the use of contrast media,” he said.
That could be the lasting impact of all three studies, according to another expert who co-authored an editorial on contrast media in the same Radiology issue and participates in the Podcast. “Wherever the real truth lies, these studies show it is far from what we’ve been thinking in terms of contrast being particularly dangerous,” said Jeffrey H. Newhouse, M.D., of the Department of Radiology, Columbia-Presbyterian Medical Center, N.Y. “It’s only a little dangerous for a small group of people.”
Access the article, “Intravenous Contrast Material–induced Nephropathy: Causal or Coincident Phenomenon?” by Robert J. McDonald, M.D., Ph.D., and Jennifer S. McDonald, Ph.D., at radiology.rsna.org/content/267/1/106.full
Access the article, “Contrast Material–induced Nephrotoxicity and Intravenous Low-Osmolality Iodinated Contrast Material: Risk Stratification by Using Estimated Glomerular Filtration Rate,” by Matthew S. Davenport, M.D., at radiology.rsna.org/content/early/2013/04/07/radiol.13122276.full
Access the editorial, “Quantitating Contrast Medium–induced Nephropathy: Controlling the Controls” by Jeffrey H. Newhouse, M.D., and Arindam RoyChoudhury, Ph.D., at radiology.rsna.org/content/267/1/4.full.
Listen to a Podcast on these studies moderated by Radiology Editor Herbert Y. Kressel, M.D., at radiology.rsna.org/content/267/1/106/suppl/DC2.
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