Contrast-induced nephropathy: How high the risk?

Despite stacks of review articles and analyses, results from several clinical trials, and the best efforts of the keenest minds in renal imaging, contrast-induced nephropathy remains a mystery. Some experts say it is because available data are open to interpretation. Others suspect unintentional or perhaps unavoidable bias at work.

Most contrast-induced nephropathy research has been conducted in the coronary angiography setting and extrapolated to radiology. But key differences exist. Patients undergoing CT scans tend to be in better health and experience a lower incidence of CIN compared with heart catheterization patients.

Of particular concern for radiologists is the safety profile of low-osmolar contrast media relative to more expensive iso-osmolar contrast media in CT. The osmolality of IOCM is equal to that of blood, whereas the osmolality of LOCM is two to three times higher. High-osmolality media checks in with an osmolality that is five or more times higher than ICOM.

"The science is not there. We wouldn't have a controversy if the facts were clear-cut. Some very smart people have very different opinions. And those who tell you they know the answers may not be objective," said Dr. Michael Rudnick, chief of the renal electrolyte and hypertension division at the University of Pennsylvania Health System.

NEPHRIC ON TRIAL

Contrast-induced nephropathy-acute deterioration of renal function after exposure to contrast media-is measured by serum creatinine levels in a blood test. Most of the time serum creatinine returns to normal levels within two weeks, but an extremely small percentage of patients wind up on kidney dialysis, which is associated with a significantly higher mortality rate. Patients in this latter group had severe chronic kidney disease, usually from diabetes, prior to receiving contrast and are usually close to starting dialysis.

The influential multicenter NEPHRIC Trial, published in The New England Journal of Medicine in 2003, indicated that iodixanol (Visipaque), the only IOCM agent available in the U.S., was significantly safer than the LOCM iohexol (Omnipaque) in high-risk patients undergoing coronary angiography.1 After these results were published, many radiology departments began using iodixanol with CT in high-risk patients instead of LOCM, but they now are questioning their policies in light of new studies that cast doubt on the NEPRHIC findings.

"We were persuaded by initial studies to make the change. But ultimately, some studies contradicted that research. The results did not hold," said Dr. William Bush, director of genitourinary radiology at the University of Washington Medical Center in Seattle.

Risk of CIN is lower than 2% in the general population and highest for patients who have impaired renal function in combination with diabetes. The estimated glomular filtration rate, using serum creatinine measurements, is thought to be more accurate than serum creatinine level alone for measuring risk for CIN. Those with glomular filtration rates from 60 to 30 mL/min have a 10% to 20% risk of CIN, and those with GFR less than 30 mL/min have a 40% to 50% risk.2 In-hospital mortality rates are as high as 35% for patients who need dialysis.

But despite the safety profile for LOCM relative to widespread use, concerns about CIN are growing. These trends, cited in Kidney International, show why:

• In the last two decades, CT scanning utilization has risen by 800%.

• The number of cardiac catheterization procedures in the U.S. rose by almost 400% from the late 70s to the late 90s.

• The U.S. Renal Data System notes a "relentless increase in kidney failure," projecting a 90% increase by 2010.

• An estimated 194 million people have diabetes worldwide. This figure is expected to grow by 75% by 2025. 3

STRAIGHT ANSWERS

Almost everything about CIN is subject to debate, including its definition, methods for measuring the condition, causative agents, the mechanism for damage, the best means of prevention, and its true effect on mortality rates.

Many studies define CIN as relative increase in serum creatinine from baseline by 25% or a rise in absolute terms of 0.5 mg/dL or more from baseline. A group assembled by the Brussels-based International Society of Nephrology has been working on standardizing a definition. A consensus is expected this year.

The number of new analyses, clinical trials, and opinion papers on various aspects of CIN are almost too numerous to count, and it can be difficult to compare the results.

Patient populations and type of contrast used vary. Strategies for preprocedure prophylaxis, which has a huge impact on safety, differ widely. For example, pharmaceutical agents may or may not be administered, and types of hydration protocols used could sway results one way or the other. Quality of trial design is also variable.

"There are all kinds of bias," said Dr. Richard Solomon, chief of nephrology at the University of Vermont in Burlington. "Some studies eliminate bias, involve more patients, have a blinded design, and randomize patients. These trials lead to better, more believable results."

But many clinical trials are financed by the contrast media manufacturers, and some leading experts receive speaking and consulting fees from particular companies.

The effect of osmolality is one key factor investigated in clinical trials. The NEPHRIC Trial compared IOCM to one particular LOCM (iohexol). LOCM are different in structure, and a number of researchers speculate that other types of LOCM could be safer than iohexol.

Reports of adverse events to the FDA indicate incidence of CIN is highest in patients who receive iohexol and lowest for those who get iopamidol (Isovue), according to an analysis performed by Solomon and published in Investigative Radiology in mid-2006. 4 This analysis demonstrated less of a difference between iohexol and other LOCM.

Differences between iodixanol and iopamidol were not significant for high-risk patients undergoing coronary angiography in CARE, a new randomized clinical trial of more than 400 patients. Results were presented by Solomon at the Transcatheter Cardiovascular Therapeutics scientific symposium in November 2006.5

Furthermore, the ICON trial, presented at the same meeting,6 found little difference between iodixanol and another LOCM, ioxaglate (Hexabrix), for high-risk patients in the angiography setting. This study was sponsored by New York-based not-for-profit Cardiovascular Research Foundation, which is funded by foundations and corporations (Table 1).

But another new trial, RECOVER, funded by the Korean government, showed iodixanol was significantly less nephrotoxic than ioxaglate in coronary angiography.7 This finding was especially marked for patients with both diabetes and renal failure.

"Over the past four years, the NEPHRIC Trial has largely driven the practice of how cardiologists and radiologists use contrast agents. We are sitting now on the cusp of all these other studies becoming public. With the possible exception of the Asian trial, the new studies are not able to reproduce what was in the NEJM paper," said Dr. Richard Katzberg, distinguished professor of radiology at the University of California, Davis.

RISKS AND BENEFITS

Katzberg and others theorize that risks are greater with intra-arterial administration in heart catheterization procedures than with intravenous application during CT.

"One of the major insights we have gained in recent years is that intra-arterial adverse outcomes are not transferable to intravenous outcomes. The cardiac angiography world is markedly different from the daily intravenous CT contrast world," Katzberg said.

The multicenter IMPACT Trial, one of the first randomized controlled trials to focus on CIN in radiology, found little difference between the IOCM iodixanol and the LOCM iopamidol in patients with moderate to severe renal impairment undergoing CT.8

During angiography, contrast is injected directly into the arterial system, which may result in a direct toxic effect, whereas with intravenous administration, there is a dilution effect that could minimize risk of CIN, explained Dr. Dushyant Sahani, director of CT at Massachusetts General Hospital and an IMPACT investigator.

Volume and rate of injection in CT are standardized, and typically only one bolus is administered, whereas in angiography, several boluses might be delivered and procedures are more complex, Sahani said.

But Dr. Peter Aspelin, a nephrologist and lead author of the NEPRHIC Trial, noted that with CT, a bolus with a higher dose is injected in a short period, and this is potentially more toxic than a slow infusion of smaller doses. Therefore, administration in CT could actually be more dangerous than in coronary angiography.

Aspelin also said the risk of CIN may be lower in the CT population due to differences in health, because those who undergo coronary angiography also have a higher frequency of decreased renal function.

Some have raised questions about the IMPACT study methodology. Most patients had serum creatinine levels between 1.5 and 1.9 mg/dL, and only 18 of 153 patients registered serum creatinine of 2 mg/dL or greater. Just 36 patients had diabetes.

"It is not too surprising that the overall risk of CIN was low in the study. The patients had elevated, but not strongly elevated serum creatinine," said Dr. James Ellis, a professor of radiology at the University of Michigan in Dearborn.

The authors of the IMPACT Trial note that given the low prevalence of CIN in the study group, it would take 3800 patients to detect a 50% reduction in incidence with a particular agent, far more than the 153 patients who were in the study group.

"It seems likely that it doesn't matter much what you use when patients are at fairly low risk. The incidence of CIN is low, and it is hard to tell one agent from another. When the risk is higher, either because of renal function alone, other comorbidities, or intra-arterial use, the answer is still uncertain, and there are small studies supporting either version of the story," said Ellis, who is also vice chair of the American College of Radiology Drugs and Contrast Committee.

Rudnick points out that initial studies comparing HOCM and LOCM were not able to show a difference in nephrotoxicity, but the advantages of the low-osmolar agent became obvious when sicker populations were compared. He views the LOCM/IOCM debate in the same light.

"You would only demonstrate the superiority of iso-osmolar agents in patients who are at highest risk," Rudnick said. "It remains an unsettled question. But because there may be a benefit in using the iso-osmolar agent, that is the media I will use in my high-risk patients."

Others believe there is not enough evidence about osmolality in relation to CIN to support preferential use of IOCM. On top of the lack of evidence, IOCM iodixanol has been associated with more late skin reactions, so there may be advantages in selecting a different agent, accounting to Dr. Henrik Thomsen, chair of radiology at the Copenhagen University Hospital at Herlev.

A QUESTION OF VISCOSITY?

Some researchers believe differences in risk could be due to the viscosity of various agents, as shown in animal studies. A recent retrospective Swedish study of 57,000 patients found that the risk of developing renal failure was actually much higher with the IOCM iodixanol than the LOCM ioxaglate and iohexol.12 Researchers speculated the results reflected IOCM's higher viscosity.

But while the patients involved in the study did have renal failure, they were not confirmed to have CIN, so the cause of the kidney impairment is unclear. The results of this retrospective study contradict findings of more trusted prospective randomized controlled trials.

When contrast media are warmed to body temperature, the higher viscosity pretty much disappears, according to Bush. But questions remain.

"We have to hold judgment and be very cautious in leaping to viscosity as the mechanism for CIN," he said.

SOCIETAL VERDICT

Writing in European Radiology, Thomsen noted the large number of reviews and guidelines published on CIN in recent years. Despite the high volume of literature on the subject, he concluded guidelines have not resulted in better understanding of CIN but have caused confusion and uncertainty.13

"Inconsistency in clinical studies is a real problem," Thomsen wrote.

Only a handful of randomized controlled trials have been undertaken, and further research is needed. Although the European Society of Urogenital Radiology last reviewed its guidelines in 1999, there is not enough evidence to warrant an update, Thomsen said.

The ACR last reviewed the subject in a 2003 contrast media manual, which advised administration of either LOCM or IOCM in high-risk patients.14 (See Table 2 for CIN risk factors.)

The Canadian Radiology Society published consensus guidelines on CIN prevention in 2006. Experts recommended IOCM or LOCM for patients with GFR lower than 60 mL/min and avoidance of HOCM in these patients.15 This year, the association plans to conduct another contrast media safety review, which most likely will also cover risks associated with gadolinium contrast used in MR.

Associations stress the importance of precautionary measures. For example, the ACR manual recommends use of preventive methods for patients with an estimated GFR of less than 60 mL/min and advises that the risk of CIN is greatest for those with a GFR lower than 30 mL/min.

The manual stresses adequate hydration as a major precaution for high-risk patients.

Experts agree that hydration helps, although there is much disagreement about the exact hydration methods that are most effective. Other prevention methods include administration of pharmaceutical agents and discontinuation of nephrotoxic medications prior to the study (see accompanying story).

Radiologists at the University of Washington and the University of Indiana said they are still using IOCM for high-risk patients, but they acknowledged that a review of policies in light of new evidence might be warranted in the near future.

Massachusetts General Hospital policy advises use of LOCM for patients with serum creatinine under 1.9 mg/dL. Patients with elevated creatinine under this threshold are well hydrated and receive less contrast. Serum creatinine is checked after the procedure. Those with rates above 1.9 mg/dL are typically imaged with an alternative imaging study.

There is not enough evidence for iso-osmolar media to make the radical change of switching all patients with borderline renal function, according to Sahani.

"The cost did not justify use of that agent without solid data available in CT," he said.

Cost issues are particularly relevant in the community setting, said Dr. Michael Kelly, chief of radiology at the Carolinas Medical Center.

To help clarify the IOCM/LOCM debate, Kelly said he invited the contrast media companies in to make their cases.

"We let them duke it out," he said.

In Kelly's environment, most of the patients have serum creatinine levels in the 1.2 mg/dL to the 1.5 mg/dL range, and cases beyond 2 mg/dL are very rare.

After hearing both sides of the story, Kelly's department decided that the literature was not clear enough. The department decided to continue a policy that generally advises use of LOCM rather than IOCM in CT.

Furthermore, the center is going to take part in a Bracco-sponsored clinical trial comparing iopamidol with iodixanol in diabetic and renally impaired patients.

When performing CT, radiologists should first ask if they can obtain the clinical answer without using contrast, Bush said. For example, it is possible to follow a lymphoma patient nicely without IV contrast.

"You get a prettier picture with contrast, but for the most part you can get by without it," he said.

The University of Washington also pays more attention to screening patients. A manual creatinine clearance calculator (see image) produced by GE Healthcare uses factors like gender, body weight, and serum creatinine levels to more accurately determine risk for CIN. Calculations are based on National Kidney Foundation guidelines.

"The slide rule calculator estimates clearance, helping to pick up people who do not have much muscle mass," Bush said. "We picked up patients who had worse function than serum creatinine levels indicated and then modified patient management."

Bush's radiology department also invested in a $5000 machine that measures serum creatinine levels in the blood. Before the purchase, patients who showed up for a CT study and needed a serum creatinine check would be sent to the lab, a costly practice that delayed the CT study. Now with the machine right in the CT department, there is no reluctance to check serum creatinine onsite, Bush said. The system has proven to be a good tool for educating techs and other faculty about renal function and nephrotoxicity. He stressed the need to stick with evidence-based practice for both prevention protocols and choice of contrast media, as this will lead to better, more cost-effective care.

"It is important that radiologists continually reevaluate CT protocols as scanners get faster. Keep watching the evidence. Don't latch onto a decision at this point and never think about changing it. Be prepared to look again one month down the road," Bush said.

Ms. Hayes is feature editor of Diagnostic Imaging.

References

• Aspelin P, Aubry P, Fransson SG, et al. Nephrotoxic effects in high risk patients undergoing angiography. NEJM 2003; 348(6):491-499.

• Katzberg RW. Contrast medium-induced nephrotoxicity: Fact or fantasy? Presented at Stanford University's annual multidetector row CT meeting, June 2006:53.

• Katzberg RW and Haller C. Contrast-induced nephrotoxicity: Clinical landscape. Kidney Int 2006;69:S3-S7.

• Solomon R, DuMouchel W. Contrast media and nephropathy: Findings from systematic analysis and Food and Drug Administration reports of adverse effects. Invest Radiol 2006;41(8):651-660.

• Solomon R, Natarajan M, Doucet S, et al. The Cardiac Angiography in Renally Impaired Patients (CARE) study: A randomized, double-blind trial of contrast-induced nephropathy (CIN) in high-risk patients. Presented at the Cardiovascular Research Foundation's annual Transcatheter Cardiovascular Therapeutics meeting, October 2006.

• Mehran R. ICON: Ionic versus nonionic Contrast to Obviate worsening Nephropathy after angioplasty in chronic renal failure patients (ICON), presented at the Cardiovascular Research Foundation's annual Transcatheter Cardiovascular Therapies meeting, October 2006.

• Jo SH, Youn TJ, Koo BK, et al. Renal toxicity evaluation and comparison between Visipaque (iodixanol) and Hexabrix (ioxaglate) in patients with renal insufficiency undergoing coronary angiography. J Am College Cardiol 2006;48(5)2006:924-930.

• Barrett BJ, Katzberg RW, Thomsen HS, 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(11):815-821.

• Chalmers N. Comparison of iodixanol and iohexol in renal impairment. Br J Radiol 1999;72:701-703.

• Hardiek K, Kathol RE, Ogden C, et al. Double blind randomized comparison of iopamidol 370 and iodixanol 320: Renal response in diabetic subjects. Presented at annual meeting of the Radiology Society of North America, November 2003:541.

• Tepel M, Aspelin P, Lameire N. Contrast-induced nephropathy: A clinical and 12. evidence-based approach. Circulation 2006;113:1799-1806.

• Liss P, Persson PB, Hansell P, et al. Renal failure in 57,925 patients undergoing coronary procedures using iso-osmolar or low-osmolar contrast media. Kidney Int 2006;70(10):1811-1817.

• Thomsen HS, Morcos SK. Contrast-medium induced nephropathy: Is there a new consensus? A review of published guidelines. Eur Radiol 2006;16(8):1835-1840.

• King BF, Segal AJ, Berg GR, et al. Contrast nephrotoxicity. Manual on contrast media 5.0. Reston, VA: American College of Radiology 2003:21-25.

• Benko A, Fraser-Hill M, Magner P, et al. Guidelines for the prevention of contrast induced nephropathy. Canadian Association of Radiologists website www.car.ca, 2006:1-16.13:1799-1806.

Bibliography

• Barrett BJ, Parfrey PS. Preventing nephropathy induced by contrast medium. NEJM 2006;354(4):379-385.

• Bettmann MA. Contrast medium-induced nephropathy: Critical review of the existing clinical evidence. Nephrol Dial Transplant 2005;20[Suppl]1:i12-17.

• Deray G. Letters to the editor: Iodixanol and chronic kidney disease. J Invasive Cardiol 2006;18:84.

• Katzberg RW. Urography into the 21st century: New contrast media, renal handling imaging characteristics, and nephrotoxicity. Radiology 1997; 204:297-312.

• Kellum J, Leblanc M, Venkataraman R. Acute renal failure. Clin Evid 2006;15:1-22.

• McCollough, PA, Bertrand ME, Brinker JA, et al. A meta-analysis of the renal safety of isomolar iodixanol compared with low-osmolar contrast media. JACC 2006;48(4):693-699.

• Rao QA, Newhouse JH. Risk of nephropathy after intravenous administration of contrast material: A critical literature analysis. Radiology 2006;239(2):392-397.

• Rudnick M, Kesselheim A, Goldfarb S. Contrast-induced nephropathy: How it develops, how to prevent it. Cleve Clin J Med 2006;73(1):75-87.

• Solomon R. The role of osmolality in the incidence of contrast-induced nerphropathy: A systematic review of angiographic contrast media in high-risk patients. Kidney Int 2005;68:2256-2263.

Disclosures, in alphabetical order:

Dr. Aspelin has received speaking fees from GE Healthcare and Schering.

Dr. Richard Katzberg is a consultant for Bracco.

Dr. Michael J. Kelley is about to join a clinical trial sponsored by Bracco. Company is funding a research assistant. No personal financial relationship.

Dr. Michael Rudnick is a consultant for GE Healthcare.

Dr. Dushyant Sahani receives research grant support from GE Healthcare.

Dr. Richard Solomon is a consultant for Bracco.

Experts offer strategies for CIN prevention

Tips include reviewing image protocols, avoiding dehydration, and selecting appropriate agent

It's not possible to eliminate risk of contrast-induced nephropathy through use of a particular contrast agent or prophylactic medication. But the precautions below can help, according to Dr. William Bush, director of genitourinary radiology at the University of Washington Medical Center in Seattle.

• Review imaging protocols. Is there truly a need for intravenous contrast? Can the contrast amount be reduced for the CT scan?

• Screen patients. Identify those at higher risk with serum creatinine tests.

• Enhance the screening process. Test serum creatinine, plus estimated creatinine clearance or estimated glomular filtration rate.

• Avoid dehydration.

• Hydrate early.

• Consider hydration with bicarbonate solution.

• Hydrate after a contrast-enhanced study.

• Consider medications to mitigate nephrotoxicity, such as N-acetylcysteine (Mucomyst)

• Select the most appropriate contrast agent. LOCM and IOCM have benefits over HOCM in diabetic patients with renal insufficiency. Some studies show the nonionic iso-osmolar dimer (iodixanol) is beneficial for diabetic patients with renal insufficiency (GFR is less than 60 mL/min). Question whether all nonionic LOCM are actually equal in terms of nephrotoxicity. Also, consider whether a nonionic, monomeric LOCM might be just as effective in reducing risk of CIN as IOCM.

• Stay abreast of evidence. CIN prevention is a moving target and needs to be reevaluated by imaging practices as new studies become available. -EH