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1. Introduction By Richard Solomon, MD
2. How to Identify High-risk Patients By Garry Choy, MD, and Sanjay Saini, MD
3. Overall Prevention Strategies By Michael Rudnick, MD, and Richard Solomon, MD
4. Let the Data Decide By Richard Solomon, MD, and Michael Rudnick, MD

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Introduction

By Richard Solomon, MD

Richard Solomon, MD

Contrast-induced nephropathy (CIN) is fast becoming a major concern for radiologists and cardiologists. It is defined as an acute fall in glomerular filtration rate (GFR) estimated from a rise in serum creatinine occurring within 72 hours of contrast exposure in the absence of another renal insult. Physicians are being told that the risk of CIN is increasing in the population and that the consequences of CIN are being increasingly recognized. Why all this noise? First, it is true that an increasing number of individuals are being exposed to iodinated contrast media (CM). This is because of advances in the technical aspects of imaging that make imaging with contrast an increasingly important diagnostic and therapeutic tool. In addition, our population is aging and with aging comes a greater burden of chronic diseases including hypertension, diabetes, kidney disease, and heart disease. It is in this very group of patients that diagnostic imaging and catheter-based interventions are particularly appropriate.

The use of contrast media in diagnostic imaging has increased significantly. In the United States alone, approximately 30 million contrast imaging procedures are performed annually and nearly half of all CT examinations are contrast enhanced (Figure 1). These procedures include a variety of organs systems and interventions.

Figure 1. Number of CT procedures (in millions); total for 2006 is estimated. Source: Arlington Medical Resources, Malvern, Pa.

In addition, there is an increasing use of catheter-based interventions rather than surgical approaches for peripheral vascular disease. Many of these procedures require complicated angioplasties and deployment of stents and require large amounts of contrast media. From the Arlington Medical Resources database, we can see that the interventional procedural growth from 1995 to 2001 was phenomenal (Figure 2). The angioplasty procedures grew from 536,000 in 1995 to over 1,600,000 in 2001. During the same period, stent procedures went from representing 40% of the percutaneous transluminal coronary angioplasty (PTCA) in 1995 to more than 80% in 2001.

Figure 2. Procedures (in thousands); PTCA = percutaneous transluminal coronary angioplasty. Source: Arlington Medical Resources, Malvern, Pa.

More recently, an increase in cardiac CT angiography that parallels the growth in peripheral angiography has occurred. Both groups of patients carry a burden of chronic disease that contributes to an increased risk of contrast-induced nephropathy (CIN).

The consequences of CIN are also being highlighted. Patients who develop CIN stay in the hospital longer, use more hospital resources such as hemodialysis, and have an increase in morbidity.¹ One of the earliest reports,² which retrospectively reviewed approximately 16,000 contrast studies performed over a 1-year period, found that mortality in those who developed CIN was seven times that in a matched group of patients who did not develop CIN. The study group included approximately equal numbers of patients exposed to contrast through radiology procedures (mostly CT) and cardiac procedures. Subsequently, a number of other databases^3-5 has confirmed these observations, at least in cardiac patients. More recently, concern about the impact of CIN on renal function has emerged. It has been appreciated since the early 1970s that patients with severely depressed renal function might end up requiring dialysis following contrast exposure. In some of these patients, renal function would not return to baseline levels and dialysis would be permanent. A recent review of 646 patients with baseline renal insufficiency exposed to contrast media found that the group that developed CIN had a further deterioration in renal function 18 months later, in significantly more patients and to a greater extent compared to those who did not develop CIN.⁶

Figure 3. Number of procedures (in millions). Source: Arlington Medical Resources, Malvern, Pa.

Given the increasing use of contrast media and the parallel increase in risk of CIN in the cohorts exposed to contrast media, efforts to reduce the incidence of CIN are being generated from a number of areas. Manufacturers of imaging equipment are working to improve the speed at which images can be obtained with the result that less contrast media dose is necessary. Injectors are replacing manual administration of contrast, improving the ability to control the dose of contrast delivered. Producers of contrast media are providing data on contrast media safety in a variety of settings, as well as comparative data to help one make an informed choice of contrast medium. Clinical trials with different strategies for the renal or extracorpo-real elimination of contrast media and pharmacologic prophylaxis are providing additional choices for the practitioner. It is in the context of this explosion of data regarding contrast media and nephrotoxicity that this collection of papers is particularly appropriate and timely. In the first article, Sanjay Saini, MD, and Garry Choy, MD, discuss identifying the patients who are at highest risk for CIN. This is followed by an article by Michael Rudnick, MD, and Richard Solomon, MD, dealing with all the strategies for preventing CIN in high risk patients. Included subtopics are the evidence for intravenous fluid administration, the use of antioxidants, vasodilators, and the removal of contrast media by dialysis. The final article addresses the topic of contrast media themselves. What characteristic of contrast media is most related to nephro-toxicity? Do different contrast agents have different potential effects on the kidney, leading to CIN?

Richard Solomon, MD, is professor of medicine and chief, Division of Nephrology, University Health Center, Fletcher Allen Health Care, Burlington, Vt.

References

1. Iakovou I, Dangas G, Mehran R, et al. Impact of gender on the incidence and outcome of contrast-induced nephropathy after percutaneous coronary intervention. J Invasive Cardiol. 2003;15:18-22.
2. Levy E, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality. A cohort analysis. JAMA. 1996;275:1489-1494.
3. Rihal C, Textor SC, Grill DE, et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation. 2002;105:2259-2264.
4. McCullough P, Wolyn R, Rocher LL, et al. Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality. Am J Med. 1997;103:368-375.
5. Gruberg L, Mintz GS, Mehran R, et al. The prognostic implications of further renal function deterioration within 48 h of inter-ventional coronary procedures in patients with pre-existent chronic renal insufficiency. J Am Coll Cardiol. 2000;36:1542-1548.
6. Ijak F, Yousaf M, Sohail I, Alam MG. Long term renal consequences of acute kidney injury related to contrast media. J Am Soc Nephrol. 2006;17:280A.

How to Identify High-risk Patients

Patients requiring prophylactic strategies prior to contrast studies can be determined through a comprehensive medical history, review of medical records, a physical examination, or a serum creatinine level for those with predisposing factors.

By Garry Choy, MD, and Sanjay Saini, MD

Garry Choy, MD	Sanjay Saini, MD

Given the large and increasing number of diagnostic imaging examinations and therapeutic interventions that require intravascular administration of iodinated contrast material, implementation of a prevention strategy for contrast-induced nephropathy (CIN) in every patient receiving iodinated contrast material is neither practical nor medically justified. The first step toward reducing the incidence of CIN, therefore, is the identification of patients at increased and high risk for developing CIN.

Medical conditions predispose certain patients to developing CIN following administration of iodinated contrast material. The important risk factors are summarized in the table.

Risk Factors

The patients at highest risk for developing CIN are those with chronic kidney disease.^1-4 Conversely, the incidence of CIN in patients with normal renal function is very low.⁵ Indeed, the higher the stage of chronic kidney disease, the greater the likelihood that a patient will develop CIN. Although elevated serum creatinine levels have traditionally been regarded as an indicator of renal insufficiency, it is now recognized that elevated creatinine levels, in isolation, are a poor measure of renal function. This is because creatinine is produced by the musculature; its production is higher in men than in women, in younger patients than in the elderly, and in African American patients than in white patients. Therefore, it is now widely held that renal function should be assessed by calculating the estimated glomerular filtration rate (eGFR) using the modification of diet in renal disease equation:

GFR (mL/min/1.73 m2) = 175 x (serum creatinine) – 1.154 x (age) – 0.203 x (0.742 if female) x (1.21 if African American)

Many calculators issued for personal digital assistants and for online use can facilitate rapid calculation of eGFR based on the patient’s recent serum creatinine level plus age, sex, and race. For example, a Web-based calculator from the US National Institutes of Health can be found at http://nkdep.nih.gov/professionals/gfrcalculators.

Diabetes is commonly cited as an important predisposing factor for developing CIN. A number of studies^6-10 have demonstrated, however, that diabetes poses an important risk only when associated with pre-existing renal insufficiency. The incidence of CIN in this population may be as high as 40%.^11,12

Algorithm for evaluating patients at high risk for contrast-induced nephropathy; eGFR=estimated glomerular filtration rate.

Congestive heart failure and dehydration are both volume states that lead to decreased renal perfusion, one of the key mechanisms in the pathogenesis of CIN.^13,14 The renal medulla has a significantly high demand for oxygen; in a state of dehydration, there may be tubular damage mediated by decreased oxygen delivery, increased viscosity, and abnormally high levels of vasoactive substances (such as endothelin) causing vasoconstriction. Furthermore, dehydration can cause an increased concentration of contrast media, as well as reactive oxygen species. This, in turn, can lead to direct nephrotoxic damage.

Laboratory values such as blood urea nitrogen/creatinine ratios, as well as physical examination of the patient, are often useful in determining clinical volume status. Evaluating the volume status of patients undergoing contrast studies can be highly effective in minimizing the risk of CIN. The volume status can often be easily corrected prior to contrast administration. In addition, whenever possible, oral hydration prior to contrast administration should be encouraged. More important, before outpatient CT examinations, patients should not be required to fast.

Increasing numbers of patients have chronic medical problems, and the frequency of imaging in this population is also rising, particularly among the elderly. It is known that GFR decreases with age. As a result, advanced age itself is a predisposing factor in CIN and must be taken into consideration prior to contrast administration.

The renal medulla exhibits a high demand for oxygen, so any perturbation in medullary perfusion can result in ischemic damage. Perturbations in perfusion might result from increased perivascular hydrostatic pressure, high viscosity, or changes in vasoactive substances such as endothelin. Agents impairing medullary vasodilatation, such as nonsteroidal anti-inflammatory drugs (NSAIDs), may also lead to changes in medullary perfusion, thereby worsening CIN. Cisplatin and methotrexate chemotherapy agents, NSAIDs, and aminoglycosides are examples of agents that should be avoided in patients concurrently receiving contrast media.

There is also evidence that high doses of contrast medium and the type of contrast medium may be associated with an increased risk of direct renal injury. Higher risk has been assigned to patients undergoing multiple exposures to intravenous contrast within a 72hour period, as well as to those undergoing studies requiring a high volume of contrast.¹⁴ A number of studies¹⁵ support a direct correlation between the volume of contrast administered and the incidence of CIN. The dose of contrast (grams of iodine per unit of GFR) has been proposed as a more accurate measure of nephrotoxic potential. The tolerable dose depends on the patient and his or her individual baseline renal function, as well as on the coexistence of predisposing factors.⁵

In addition, there is some concern about the use of metformin. By itself, metformin does not cause direct nephrotoxicity; however, should CIN develop, the consequences of abnormally high levels of metformin (leading to metabolic acidosis) can be fatal. Therefore, as a precautionary standard, metformin should be discontinued for all patients undergoing a contrast-enhanced CT scan and resumed 48 hours afterward, unless there is evidence of CIN.¹⁶

Multiple myeloma has been considered a risk factor for CIN. It does not appear, however, to be a significant risk factor when modern contrast agents are used, provided that precautions are taken to ensure that patients are adequately hydrated and not significantly hypocal-cemic.^17,18

Practical Approach

Identifying the high-risk patient starts with obtaining a comprehensive medical history, reviewing medical records, and performing a physical examination prior to contrast studies. If the patient has any of the listed predisposing factors for CIN, it is recommended that a serum creatinine level be obtained in order to calculate eGFR (see figure). When the eGFR is in hand, high-risk patients can be identified and proper CIN prophylaxis can be undertaken. Many studies^14-15 have found that an eGFR of less than 60 mL per minute/1.73 m² results in an elevated risk for contrast nephropathy. As a result, based on the currently available literature, we recommend that, for any patient demonstrating an eGFR of less than 60, preventive measures should be taken.

Diagnostic examinations without contrast administration should be considered, if possible, in those with severely impaired eGFR, such as those with stage IV (eGFR of less than 30) or stage V (eGFR of less than 15) chronic renal disease.

Garry Choy, MD, is a Resident, Department of Radiology, Massachusetts General Hospital, Boston, and Clinical Fellow, Harvard Medical School. Sanjay Saini, MD, is Professor of Radiology at Massachusetts General Hospital, Harvard Medical School, Boston.

References

1. Mueller C, Buerkle G, Buettner HJ, et al. Prevention of contrast media associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med. 2002;162:329-336.
2. Sadeghi HM, Stone GW, Grines CL, et al. Impact of renal insufficiency in patients undergoing primary angioplasty for acute myocardial infarction. Circulation. 2003;108:2769-2775.
3. Parfrey PS, Griffiths SM, Barrett BJ, et al. Contrast material-induced renal failure in patients with diabetes mellitus, renal insufficiency, or both: a prospective controlled study. N Engl J Med. 1989;320:143-149.
4. Muntner P, Coresh J, Klag MJ, et al. Exposure to radiologic contrast media and an increased risk of treated end-stage renal disease. Am J Med Sci. 2003;326:353-359.
5. McCullough PA, Soman SS. Contrast-induced nephropathy. Crit Care Clin. 2005;21:261-280.
6. Berns AS. Nephrotoxicity of contrast media. Kidney Int. 1989;36:730-740.
7. Rudnick MR, Berns JS, Cohen RM, Goldfarb S. Nephrotoxic risks of renal angiog-raphy: contrast media-associated nephrotoxicity and atheroembolism-a critical review. Am J Kidney Dis. 1994;24:713-727.
8. Rudnick MR, Goldfarb S, Wexler L, et al. The Iohexol Cooperative Study. Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial. Kidney Int. 1995;47:254-261.
9. Toprak O, Cirit M, Yesil M, et al. Impact of diabetic and pre-diabetic state on development of contrast-induced nephropathy in patients with chronic kidney disease. Nephrol Dial Transplant. 2007;22:819-826.
10. Manske CL, Sprafka JM, Strony JT, Wang Y. Contrast nephropathy in azotemic diabetic patients undergoing coronary angiography. Am J Med. 1990;89:615-620.
11. Gruberg L, Mintz GS, Mehran R, et al. The prognostic implications of further renal function deterioration within 48 h of interventional coronary procedures in patients with pre-existent chronic renal insufficiency. J Am Coll Cardiol. 2000;36:1542-1548.
12. Tumlin JA, Wang A, Murray PT, Mathur VS. Fenoldopam mesylate blocks reductions in renal plasma flow after radiocontrast dye infusion: a pilot trial in the prevention of contrast nephropathy. Am Heart J. 2002;143:894-903.
13. Lin J, Bonventre J V. Prevention of radiocontrast nephropathy. Curr Opin Nephrol Hypertens. 2005;14:105-110.
14. Barrett BJ, Parfrey PS. Clinical practice. Preventing nephropathy induced by contrast medium. N Engl J Med. 2006;354:379-386.
15. Cigarroa RG, Lange RA, Williams RH, Hillis LD. Dosing of contrast material to prevent contrast nephropathy in patients with renal disease. Am J Med. 1989;86:649-652.
16. McCullough PA, Wolyn R, Rocher LL, et al. Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality. Am J Med. 1997;103:368-375.
17. Elicker BM, Cypel YS, Weinreb JC. IV contrast administration for CT: a survey of practices for the screening and prevention of contrast nephropathy. AJR Am J Roentgenol. 2006;186:1651-1658.
18. van den Berk G, Tonino S, de Fijter C, Smit W, Schultz MJ. Bench-to-bedside review: preventive measures for contrast-induced nephropathy in critically ill patients. Crit Care. 2005;9:361-370.

Overall Prevention Strategies

Proven strategies are limited by insufficient data, but consensus has begun to coalesce around guidelines for the prevention of contrast-induced nephropathy.

By Michael Rudnick, MD, and Richard Solomon, MD

Michael Rudnick, MD	Richard Solomon, MD

Proven strategies are limited by insufficient data, but consensus has begun to coalesce around guidelines for the prevention of contrast-induced nephropathy. Contrast-induced nephropathy (CIN) is unique as a cause of acute kidney injury in that its timing is predictable and its risk factors are well known. These factors make CIN a potentially preventable form of acute kidney injury in which an effective prophylactic strategy would be feasible. Several different interventions have been evaluated for the prevention of CIN. These interventions should be applied primarily to patients who are at high risk for the development of CIN (see Choy and Saini, page 5). In patients who are at low risk for CIN, the avoidance of volume depletion by encouraging liberal oral fluid intake prior to contrast administration and avoidance of nonsteroidal anti-inflammatory drugs (NSAIDs), which may predispose the patient to CIN, are usually sufficient to prevent CIN. For high-risk patients, however, several additional prophylactic strategies are usually applied.

Hydration

It is universally accepted that hydration is effective for the prevention of CIN in high-risk patients. This practice is based on experimental observations of increased contrast-induced reductions in renal blood flow in salt-depleted, compared with salt-repleted, animals, as well as on a reduced risk for CIN.^1,2 Early clinical observations³ suggested that intravenous fluid administration at the time of contrast-media administration resulted in a lower incidence of CIN, compared with incidence for historical patients who underwent similar contrast exposure, but were fluid deprived prior to contrast-media administration. Given the current understanding of the pathogenesis of CIN, there are several mechanisms through which hydration could be an effective prophylactic tool. These include reduction of vasoconstrictive hormones, increased sodium diuresis, diminished tubuloglomerular feedback, dilution of contrast media, decreased tubular cytotoxicity, and protection from reactive oxygen species.⁴ The value of hydration alone, compared with other prophylactic strategies, has been evaluated in a few prospective randomized trials.^5,8 Solomon et al⁶ randomized patients with chronic kidney disease undergoing angiography to either saline alone (0.45% saline delivered intravenously for 12 hours before and 12 hours after contrast media) or to a similar saline regimen with mannitol or furosemide. The incidence of CIN was lowest in the saline alone group (11%), compared with the saline and mannitol group (28%) and the saline and furosemide group (40%).

Although a number of studies have examined the route and duration of fluid administration, there is no consensus as to either of these particulars. Trivedi et al⁹ randomized patients undergoing cardiac angiography to either intravenous saline for 12 hours both before and after contrast or oral fluids taken as desired. CIN occurred in 34.6% of patients who received oral fluids, compared with 3.7% of patients who received intravenous fluids, suggesting that the latter route of administration is superior. In contrast, the PREPARED trial¹⁰ demonstrated that the use of oral fluids, coupled with a brief period of intravenous hydra-tion, resulted in an incidence of CIN similar to that associated with overnight intravenous hydration in chronic kidney disease patients undergoing coronary angiography. Bader et al¹¹ randomized patients receiving contrast media to be given either 2 L of intravenous fluid over 24 hours or 300 mL of intravenous fluid during the radiologic procedure. Glomerular filtration rate (GFR) fell by 34.6 mL per minute in the bolus infusion group and 18.3 mL per minute in the 24-hour infusion group (P<.5), suggesting that slow hydration is more effective than a brief bolus infusion.

The PRINCE trial¹² examined the hypothesis that forced diuresis with maintenance of a normal intravascular volume would result in less CIN. Despite a similar incidence of CIN in patients with and without forced diuresis, it was observed that the incidence of CIN was significantly lower in patients whose urine-flow rates exceeded 150 mL per hour (21.6%) than in those whose flow rates were below 150 mL per hour (46%). Since this was a post-hoc observation, a prospective randomized trial will be needed to determine whether the creation of high urine-flow rates during contrast-media administration is beneficial.

The composition of the fluids to be infused during contrast administration also remains controversial. Infusion of isotonic (0.9%) saline and half-isotonic (0.45%) saline was compared in patients undergoing coronary angiography.¹³ Although the volume of infused fluid was similar in both groups (2 L), the incidence of CIN was significantly lower with isotonic saline (0.7%) than with half-isotonic saline (2%). In two recent studies, isotonic sodium bicarbonate (154 mEq in dextrose and water), infused at a rate of 3 mL per kg per hour for an hour before contrast administration and 6 hours afterward, was compared with isotonic saline (154 mEq in dextrose and water) infused at a similar rate¹⁴ or for 12 hours both before and after contrast administra-tion¹⁵ in high-risk patients undergoing coronary angiogra-phy. In both studies, the incidence of CIN was significantly lower in the patients who received isotonic bicarbonate, compared with isotonic saline. The authors of these studies hypothesized that the superior benefit of bicarbonate was due to a reduction in free-radical oxygen species from alka-lization of the renal tubular fluid. The attractiveness of these findings, if confirmed in additional studies, is the achievement of protection against CIN with a reduced period of intravenous fluid administration. This has logistical advantages, given the outpatient setting for most radiolog-ic studies that use intravascular contrast media.

The table is a summary of prospective randomized trials of different hydration protocols for the prevention of CIN.

N-Acetylcysteine

N-acetylcysteine (NAC) has been demonstrated, in animal studies,¹⁹ to protect against renal injury from ischemia and nephrotoxins. Possible mechanisms for NAC’s protective effects include antioxidation, vasodilation, and prevention of apoptotic cell death.^19,20 NAC was originally demonstrated as protecting against CIN in a study²¹ of 83 patients with chronic kidney disease who were undergoing contrast-enhanced CT. Patients were randomized to receive NAC, 600 mg by mouth, twice daily, a day before and on the day of the study (for a total of four doses), or placebo. CIN developed in 21% of the placebo group, compared with 2% of the NAC group (P=.1). Subsequently, several additional studies¹⁹ confirmed this initial observation, and the use of NAC to prevent CIN was quickly and widely adopted. This protective effect of NAC has also been shown for intravenous administration, potentially eliminating the need for prolonged exposure through oral administration.²²

Following these initial encouraging reports, several studies¹⁹ appeared in which NAC was not shown to have protective value against CIN. As an example, Durham et al²³ randomized 79 patients with chronic kidney disease undergoing coronary angiography to either oral NAC or placebo. There was no significant difference in the incidence of CIN between the two groups (NAC, 26%; placebo, 22%). Currently, there are more than 20 published studies investigating NAC for the prevention of CIN, with 30 to 487 subjects enrolled in each study. Studies with negative results outnumber those with positive results by a two-to-one margin. These conflicting reports of NAC’s prophylactic value have made it difficult to make specific clinical recommendations for NAC in CIN prophylaxis.

Because most of the studies published on NAC for the prevention of CIN are quite small, multiple meta-analyses have been performed to define the full spectrum of NAC’s utility. In a meta-analysis²⁴ of 20 studies involving 2,195 patients, the relative risk of CIN in patients who received NAC was 0.73 (95% confidence interval, 0.52 to 1; P=.08). The investigators in this meta-analysis and others have pointed out that individual studies of NAC show substantial heterogeneity in design and baseline risk factors, making it unclear whether meta-analyses are a useful tool in clarifying the role of NAC.

More recently, trials^25,26 employing higher doses of NAC have been more encouraging. Marenzi et al²⁵ randomized 354 patients undergoing coronary angiography to receive treatment with a placebo; a standard dose of NAC (a 600-mg intravenous bolus before primary angioplasty and 600 mg orally, twice daily, for 48 hours after angioplasty); or a double dose of NAC. The risk for CIN was reduced by 54.5% in the standard-dose NAC group and by 75.8% in the high-dose group.

The value of other antioxidants in CIN prevention remains unclear. For example, a trial²⁷ of ascorbic acid found a prophylactic benefit in predominantly low-risk patients, while another trial¹⁵ found no benefit when it was added to NAC in high-risk patients.

Theophylline

Use of theophylline, an adenosine antagonist, has been suggested to prevent CIN.^28,29 For example, Erley et al²⁹ randomized 39 patients exposed to contrast media to either intravenous theophylline or placebo. Although there were no cases of CIN in either group, the GFR in the placebo group fell from 88 mL per minute at baseline to 75 mL per minute after contrast administration; there was no change in the GFR in the theophylline group. Similar findings have been demonstrated in other studies³⁰ of low-risk patients.

To date, there is no compelling evidence that theophylline prevents CIN in high-risk patients. Furthermore, intravenous theophylline has its own potential risks (ventricular arrhythmias and seizures).

Dialysis and Hemofiltration

Multiple studies³¹ have demonstrated that 60% to 90% of contrast media can be removed effectively after a few hours of hemodialysis. Despite this observation, several studies³¹

evaluating the potential to prevent CIN of hemodialysis following contrast-media exposure have shown no benefit for this strategy. The use of hemofiltration, however, begun 4 to 6 hours before contrast-media exposure and then continued for an additional 18 to 24 hours afterward, has been reported to protect against CIN in high-risk patients.^32,33 This conclusion is questionable, though, since the removal of creati-nine by hemofiltration could, itself, have resulted in the observed lower incidence of CIN.³⁴

Recommendations

Strategies to prevent CIN are limited by insufficient rigorous data. Based upon what is currently available in the literature, the following guidelines are suggested for CIN prevention in high-risk patients.

• All patients should avoid fluid restriction and NSAIDs prior to radiologic examinations employing intravascular contrast media.
• High-risk patients undergoing intravascular contrast administration should receive sodium-containing intravenous fluids prior to, during, and following contrast exposure. Volume expansion with 0.9% saline is more effective than with 0.45% saline, but the evidence demonstrating the superiority of isotonic saline for CIN prevention is limited.
• Isotonic sodium bicarbonate, administered at 3 mL per kg per hour for an hour before and 6 hours after contrast exposure, may offer advantages over similar or longer infusions of saline.
• The use of N-acetylcysteine remains controversial, particularly with doses of 600 mg given orally, twice daily, for 2 days. In high-risk patients, twice that dose might be preferable, particularly combined with intravenous bicarbonate therapy.
• More data are needed before a recommendation can be made on the use of other antioxidants or theophylline.
• Hemodialysis and hemofiltration are not recommended for the majority of high-risk patients or, for that matter, for patients already on dialysis.

Michael Rudnick, MD, is associate professor of medicine and chief, Renal Electrolyte and Hypertension Division, University of Pennsylvania School of Medicine, Philadelphia. Richard Solomon, MD, is professor of medicine and chief, Division of Nephrology, University Health Center, Fletcher Allen Health Care, Burlington, Vt.

References

1. Larson TS, Hudson K, Mertz JI, Romero JC, Knox FG. Renal vasoconstrictive response to contrast medium. The role of sodium balance and the renin-angiotensin system. J Lab Clin Med. 1983;101:385-391.
2. Vari RC, Natarajan LA, Whitescarver SA, Jackson BA, Ott CE. Induction, prevention and mechanisms of contrast media-induced acute renal failure. Kidney Int. 1988;33:699-707.
3. Eisenberg RL, Bank WO, Hedgock MW. Renal failure after major angiography can be avoided with hydration. AJR Am J Roentgenol. 1981;136:859-861.
4. Erley CM. Does hydration prevent radiocontrast-induced acute renal failure? Nephrol Dial Transplant. 1999;14:1064-1066.
5. Wang A, Holcslaw T, Bashore TM, et al. Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism. Kidney Int. 2000;57:1675-1680.
6. Solomon R, Werner C, Mann D, D’Elia J, Silver P. Effects of saline, mannitol and furosemide on acute decreases in renal function induced by radiocontrast agents. N Engl J Med. 1994;331:1416-1420.
7. Weisberg LS, Kurnik PB, Kurnik BR. Risk of radiocontrast nephropathy in patients with and without diabetes mellitus. Kidney Int. 1994;45:259-265.
8. Stone GW, McCullough PA, Tumlin JA, et al. Fenoldopam mesylate for the prevention of contrast-induced nephropathy: a randomized controlled trial. JAMA. 2003;290:2284-2291.
9. Trivedi HS, Moore H, Nasr H, et al. A prospective randomized trial to assess the role of saline hydration on the development of contrast nephrotoxicity. Nephron Clin Pract. 2003;93:c29-c34.
10. Taylor AJ, Hotchkis D, Morse R, McCabe J. PREPARED: preparation for angiography in renal dysfunction: a randomized trial of inpatient vs. outpatient hydration protocols for cardiac catheterization in mild-to-moderate renal dysfunction. Chest. 1998;114:1570-1574.
11. Bader BD, Berger ED, Heede MB, et al. What is the best hydration regimen to prevent contrast media-induced nephrotoxicity? Clin Nephrol. 2004;62:1-7.
12. Stevens MA, McCullough PA, Tobin KJ, et al. A prospective randomized trial of prevention measures in patients at high risk for contrast neprhopathy. Results of the P.R.I.N.C.E. study. J Am Coll Cardiol. 1999;33:403-411.
13. Mueller C, Buerkle G, Buettner HJ, et al. Prevention of contrast media-associated nephropathy. Randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angiograplasty. Arch Intern Med. 2002;162:329-336.
14. Merten G, Burgess W P, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA. 2004;291:2328-2334.
15. Briguori C, Airoldi F, D'Andrea D, et al. Renal insufficiency following contrast media administration trial (REMEDIAL). A randomized comparison of 3 preventive strategies. Circulation. 2007;115:1211-1217.
16. Krasuski R, Beard RM, Geoghagan JD, Thompson CM, Guidera SA. Optimal timing of hydration to erase contrast-associated nephropathy: the other CAN study. J Invasive Cardiol. 2003;15:699-702.
17. Weinstein J, Heyman S, Brezis M. Potential deleterious effect of furosemide in radio-contrast nephropathy. Nephron. 1992;62:413-5.
18. Dussol B, Morange S, Loundoun A, Auguier P, Berland Y. A randomized trial of saline hydration to prevent contrast nephropathy in chronic renal failure patients. Nephrol Dial Transplant. 2006;21:2120-2126.
19. Fishbane S, Durham JH, Marzo K, Rudnick M. N-acetylcysteine in the prevention of radiocontrast-induced nephropathy. J Am Soc Nephrol. 2004;15:251-260.
20. Heyman SN, Goldfarb M, Shina A, Karmeli F, Rosen S. N-acetylcysteine ameliorates renal microcirculation: studies in rats. Kidney Int. 2003;63:634-641.
21. Tepel M, Van Der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med. 2000;343:180-184.
22. Baker CSR, Wragg A, Kumar S, De Palma R, Baker LRI, Knight CJ. A rapid protocol for the prevention of contrast-induced renal dysfunction: the RAPPID Study. J Am Coll Cardiol. 2003;41:2114-2118.
23. Durham JD, Caputo C, Dokko J, et al. A randomized controlled trial of N-acetylcys-teine to prevent contrast nephropathy in cardiac angiography. Kidney Int. 2002;62:2202-2207.
24. Nallamothu BK, Shojania KG, Saint S, et al. Is acetylcysteine effective in preventing contrast-related nephropathy? A meta-analysis. Am J Med. 2004;117:938-947.
25. Marenzi G, Assanelli E, Marana I, et al. N-acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med. 2006;354:2773-2782.
26. Briguori C, Columbo A, Violante A, et al. Standard vs double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity. Eur Heart J. 2004;25:206-211.
27. Spargias I, Alexopoulos E, Kyrzopoulos S, et al. Ascorbic acid prevents contrast-mediated nephropathy in patient with renal dysfunction undergoing coronary angiography or intervention. Circulation. 2004;110:2837-42.
28. Pflueger A, Larson TS, Nath KA, King B F, Gross JM, Knox FG. Role of adenosine in contrast media-induced acute renal failure in diabetes mellitus. Mayo Clin Proc. 2000;75:1275-1283.
29. Erley C, Duda SH, Schlepckow S, et al. Adenosine antagonist theophylline prevents the reduction of glomerular filtration after contrast media application. Kidney Int. 1994;45:1425-1431.
30. Bagshaw SM, Ghali WA. Theophylline for prevention of contrast-induced nephropathy: a systematic review and meta-analysis. Arch Intern Med. 2005;165:1087-1093
31. Sterner G, Frennby B, Kurkus K, Nyman U. Does post-angiographic hemodialysis reduce the risk of contrast medium nephropathy? Scand J Urol Nephrol. 2000;34:323-326.
32. Marenzi G, Marana I, Lauri G, et al. The prevention of radiocontrast-agent-induced nephropathy by hemofiltration. N Engl J Med. 2003;349:1333-1340.
33. Marenzi G, Lauri G, Campodonico J, et al. Comparison of two hemofiltration protocols for prevention of contrast-induced nephropathy in high-risk patients. Am J Med.. 2006;119:155-62.
34. Rudnick MR, Kesselheim A, Goldfarb S. Contrast-induced nephropathy: how it develops, how to prevent it. Cleve Clin J Med. 2006;73:75-78.

Let the Data Decide

The choice of contrast can add significant cost to an examination, so an examination of the data from contrast comparison trials is warranted.

By Richard Solomon, MD, and Michael Rudnick, MD

Richard Solomon, MD	Michael Rudnick, MD

The concept of osmotoxicity is firmly ingrained in the understanding of the nephrotoxicity of contrast media, yet most of the data are from animal studies in which the experimental conditions included administering substances with osmolalities of more than 1,500 mOsm/kg. The concept of osmotoxicity in clinical studies arose from a seminal study by Rudnick et al¹ in which a low-osmolar contrast medium (iohexol) was shown to be less nephrotoxic than a high-osmolar contrast medium in high-risk patients with chronic kidney disease who were undergoing coronary angiography. A subsequent meta-analysis² of clinical trials comparing high-osmolar contrast media (more than 1,500 mOsm/kg) to low-osmolar contrast media (600 to 900 mOsm/kg) confirmed this observation. It is not surprising that in both the prospective trial of Rudnick et al and the meta-analy-sis, no statistically significant differences in nephro-toxicity between high-osmolar and low-osmolar contrast media was found in individuals with normal renal function or when the contrast medium was administered intravenously.

Following the introduction of an iso-osmolar contrast medium into clinical practice, it was not remarkable that studies would soon appear evaluating whether a further reduction in osmolarity would be associated with still more protection against nephro-toxicity. In the first of these studies (the NEPHRIC trial³), high-risk patients undergoing cardiac angiog-raphy (with renal insufficiency and diabetes) were randomized to the low-osmolar contrast medium iohexol or the iso-osmolar contrast medium iodixanol. A significantly lower incidence of contrast-induced nephropathy (CIN) was observed with the iso-osmolar agent (3%) than with the low-osmolar contrast agent (26%).

Since the publication of the NEPHRIC trial, additional prospective randomized trials comparing different low-osmolar contrast media with the iso-osmo-lar contrast agent iodixanol have not consistently found a lower incidence of CIN associated with iso-osmolar contrast. Most of these trials have been conducted with high-risk patients receiving intra-arterial contrast media for cardiac angiography. A limited amount of data are available for patients receiving intravenous contrast media. These trials have been reviewed in two systematic analyses^4,5 of data from prospective trials in high-risk patients and one meta-analysis⁶ of comparative trials conducted by a single pharmaceutical supplier of contrast media.

The comparative trials are listed in Table 1. All trials^3,7-12 involved high-risk patients with renal insufficiency and the intra-arterial administration of contrast media. A reduction of CIN associated with iso-osmo-lar (compared with low-osmolar) contrast media was not uniformly seen in each study. A benefit favoring iso-osmolar contrast was seen when the comparator contrast medium was iohexol or ioxaglate. When the comparator contrast medium was iopamidol or iover-sol, however, no additional protective effect was seen with use of the iso-osmolar contrast agent. In the previously mentioned meta-analysis of comparative trials, iso-osmolar contrast media were superior to low-osmolar contrast media.⁶ This conclusion, however, is based primarily on trials conducted with iohexol and ioxaglate. Over 95% of the cases of CIN in that meta-analysis occurred in trials involving those two agents as comparators. For other low-osmolar contrast media, no differences in nephrotoxicity were found when they were compared with iso-osmolar contrast media.

Systematic analyses^4,11 cast the net wider and included trials to determine the effectiveness of N-acetylcysteine. These trials typically used a single isoosmolar or nonionic low-osmolar contrast medium. Although both systematic analyses found iohexol to be associated with a higher incidence of CIN, compared with other low-osmolar contrast media, caution must be exercised regarding any conclusions, since these were not reviews of prospective trials comparing low-osmolar to iso-osmolar contrast media. One possible explanation for the heterogeneous findings of the prospective studies performed to date is that differences in CIN incidence between iso-osmolar and low-osmolar contrast media may depend upon the specific low-osmolar contrast medium studied. Several low-osmolar contrast media may be as safe for the kidneys as iso-osmolar contrast media. The specific physiochemical properties of contrast media that are responsible for the nephrotoxicity of these agents remain unknown. The lack of uniformity seen for nephrotoxicity in comparisons of low-osmolar and iso-osmolar contrast media raises the question of whether physical and/or chemical properties of contrast media other than osmolarity are implicated in the pathogen-esis of nephrotoxicity. Caution should be exercised in interpreting any single prospective randomized trial, since the presence or absence of differences may be more of a function of study design (for example, power or patients' risk factors) than of differences in nephrotoxicity.

For intravenous contrast media, perhaps the first question to ask is how frequently CIN occurs. A recent publication¹³ that reviewed some older data suggested that there was a very low incidence of CIN with intravenous administration of contrast. This conclusion, however, was based upon studies that used a very insensitive definition of CIN. More recent trials suggest that the incidence of CIN is about 5% in high-risk patients (Table 2), approximately half that seen in patients exposed to intra-arterial contrast.

Given this relatively low incidence of CIN, all prospective randomized trials of preventive strategies are likely to be underpowered, making it difficult to be certain of the conclusions. Nevertheless, the few head-to-head comparisons¹⁴ of intravenous contrast in high-risk patients suggest that low-osmolar and iso-osmolar contrast agents have similar safety profiles.

A number of strategies for reducing the dose of contrast can be used in radiology. Injecting a saline bolus following the contrast injection to push contrast out of the injected limb into the central circulation permits a higher concentration of contrast with a lower overall dose. Using a contrast medium with a high iodine concentration per mL also allows for a smaller volume to be used without sacrificing image quality. As an alternative, diluting contrast media 2:1 or 3:1 will allow less contrast to be used, but will sacrifice image quality. This approach has been successfully used in fistulography in patients with advanced chronic kidney disease. Using power injectors and bolus profiling also helps to control the total volume (and, therefore, dose) of contrast medium administered.

Summary

For both intravenous and intra-arterial use of contrast media in high-risk patients, the data do not support a uniformly significant difference between iso-osmolar and all low-osmolar contrast media. As only a small number of different low-osmolar contrast media have been studied in head-to-head prospective trials with iso-osmolar contrast media, it is not possible to conclude that all low-osmolar contrast media are equal. Indeed, systematic analyses and a meta-analysis suggest otherwise. Therefore, for the high-risk patient, use of an iso-osmolar contrast medium or one of the low-osmolar contrast media with a documented low incidence of CIN is recommended.

You may complete the post-test online at www.cmeuniversity.com. Click on "Find Post-tests by Course" on the navigation menu, and search by project ID 4652. Upon successfully completing the post-test and evaluation, your certificate will be made available immediately.

Richard Solomon, MD, is professor of medicine and chief, Division of Nephrology, University Health Center, Fletcher Allen Health Care, Burlington, Vt. Michael Rudnick, MD, is associate professor of medicine and chief, Renal Electrolyte and Hypertension Division, University of Pennsylvania School of Medicine, Philadelphia.

References

1. Rudnick M, Goldfarb S, Wexler L, et al. Nephropathy of ionic and nonionic contrast media in 1196 patients: a randomized trial. Kidney Int. 1995;47:254-261.
2. Barrett B, Carlisle EJ. Meta-analysis of the relative nephrotoxicity of high- and low-osmolar iodinated contrast media. Radiology. 1993;188:171-178.
3. Aspelin P, Aubry P, Fransson S, Strasser R, Willenbrock R, Berg KJ. Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med. 2003;348:491-499.
4. Solomon R. The role of osmolarity in the incidence of contrast induced nephropathy: a systematic review of angiographic contrast media in high risk patients. Kidney Int. 2005;68:2256-2263.
5. Solomon R, DuMouchel W. Contrast media and nephropathy: findings from systematic analysis and FDA reports of adverse effects. Invest Radiol. In press.
6. McCullough P, Bertrand ME, Brinker JA, Stacul F. A meta-analysis of the renal safety of isosmolar iodixanol compared with low-osmolar contrast media. J Am Coll Cardiol. 2006;48:692-699.
7. Chalmers N, Jackson R W. Comparison of iodixanol and iohexol in renal impairment. Br J Radiol. 1999;72:701-703.
8. Hardiek K, Katholi RE, Robbs RS, Katholi CE. Renal effects of contrast media in diabetic patients undergoing diagnostic or interventional coronary angiography. J Diabetes Complications. 2007. In press.
9. Jo S, Youn TJ, Koo BW, et al. Renal toxicity evaluation and comparison between Visipaque (iodixanol) and Hexabrix (ioxaglate) in patients with renal insufficiency undergoing coronary angiography: the RECOVER Study: a randomized controlled trial. J Am Coll Cardiol. 2006;48:924-930.
10. Rudnick M. Contrast media induced nephrotoxicity. Paper presented at: ASN Clinical Nephrology Conferences; 2005; Philadelphia.
11. Solomon R, Natarajan MK, Doucet S, et al. The CARE (Cardiac Angiography in Renally Impaired Patients) Study: a randomized, double-blind trial of contrast-induced nephropathy in high risk patients. Circulation. 2007;115. In press.
12. Mehran R. Ionic versus non-ionic contrast to obviate worsening nephropathy after angioplasty in chronic renal failure patients. Abstract presented at: Transcatheter Cardiovascular Therapeutics 18th Annual Scientific Symposium; October 23-25, 2006; Washington, DC.
13. Rao Q, Newhouse JH. Risk of nephropathy after intravenous administration of contrast material: a critical literature analysis. Radiology. 2006;239:392-397.
14. Barrett B, Thomsen H, Katzberg R. Nephrotoxicity of low-osmolar iopamidol vs iso-osmolar iodixanol in renally impaired patients: the IMPACT Study. Invest Radiol. 2006;41:815-821.
15. Carraro M, Malalan F, Antonione R, et al. Effects of a dimeric vs a monomeric nonionic contrast medium on renal function in patients with mild to moderate renal insufficiency: a double-blind, randomized clinical trial. Eur Radiol. 1998;8:144-147.
16. Kolehmainen H, Soiva M. Comparison of Xenetrix 300 and Visipaque 320 in patients with renal failure. Eur Radiol. 2003;13:B32.

You may complete the post-test online at www.cmeuniversity.com. Click on "Find Post-tests by Course" on the navigation menu, and search by project ID 4652. Upon successfully completing the post-test and evaluation, your certificate will be made available immediately.