Preventing Nephropathy Induced by Contrast Medium
http://www.100md.com
《新英格兰医药杂志》
This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors' clinical recommendations.
A 71-year-old man with type 2 diabetes and hypertension is referred for coronary angiography. His medications include metformin and a thiazide. Before the angiogram, his serum creatinine level is 1.8 mg per deciliter (160 μmol per liter), yielding an estimated glomerular filtration rate of 40 ml per minute per 1.73 m2 of body-surface area. What can be done to reduce the risk that an angiographic contrast medium will worsen his kidney function?
The Clinical Problem
Sensitive tests of kidney function identify mild, transient changes in most patients who have been exposed to intravascular iodinated contrast mediums.1 Clinically important injury (often called contrast-medium–induced nephropathy) is much less common. Cases of contrast-medium–induced nephropathy are usually defined by a fixed (0.5 mg per deciliter ) or proportionate (25 percent) rise in serum creatinine levels after exposure to the contrast medium. However, the clinical importance of such changes, if they are transient, is uncertain. A serum creatinine level itself is a relatively poor measure of kidney function and is influenced by age, sex, and body composition.
In a study by Nash et al.,2 contrast-medium–induced nephropathy was reported to be the third most common cause of acute renal failure in hospitalized patients. In this study, the contrast medium was assumed to be the cause of the renal failure if it was administered in the 24 hours before renal failure and no other major kidney insult was identified. However, exposure to contrast medium may be a contributory rather than a sole cause of acute renal failure; concomitant insults may include low blood volume, surgery, atheroembolic disease, and the presence of other nephrotoxins.
The reported incidence of contrast-medium–induced nephropathy varies among studies, due to differences in definition, background risk, type and dose of contrast medium, imaging procedure, and the frequency of other potential causes of acute renal failure. The status of renal function before administration of a contrast medium is a major determinant of deterioration in function after administration.3 In one study, serum creatinine levels rose by more than 25 percent in 14.5 percent of patients who underwent coronary angiography (95 percent confidence interval, 12.9 to 16.1 percent).3
In the absence of preexisting renal disease, the incidence is much lower. In a large clinical trial, only 8 percent of patients whose baseline serum creatinine level was below 1.5 mg per deciliter (135 μmol per liter) had an increase in the serum creatinine level of more than 0.5 mg per deciliter, and none had an increase of more than 1 mg per deciliter (89 μmol per liter).4
In another study, 0.8 percent of 1826 patients required dialysis after exposure to the contrast medium; the baseline estimated creatinine clearance rate was below 47 ml per minute per 1.73 m2 of body-surface area in all patients requiring dialysis.3 Serum creatinine levels rose by less than 1 mg per deciliter (89 μmol per liter) in 29 percent of those requiring dialysis, indicating advanced preexisting kidney disease. Registry data suggest a 0.44 percent incidence of nephropathy requiring dialysis after percutaneous coronary intervention.5
Risk Factors
Diabetes is a risk factor for deterioration in renal function after angiography.3,6,7 Other factors variably associated with increased rates of acute renal failure after the administration of contrast medium include age over 75 years, periprocedural volume depletion, heart failure, cirrhosis or nephrosis, hypertension, proteinuria, concomitant use of nonsteroidal antiinflammatory drugs, and intraarterial injection. In the setting of acute myocardial infarction or percutaneous coronary intervention, hypotension or use of an aortic balloon pump has been associated with a higher rate of acute renal failure after exposure to a contrast medium.7,8 However, it is uncertain to what extent these factors independently worsen renal function, as opposed to serving as markers for coexisting conditions. High doses of contrast medium also increase the likelihood of renal dysfunction. The tolerable dose of contrast medium depends on kidney function.3,5,9
Prognosis
Contrast-medium–induced nephropathy is usually transient, with serum creatinine levels peaking at 3 days after administration of the medium and returning to baseline within 10 days after administration.8,10 Appreciable nephropathy is unlikely to develop if the serum creatinine level does not increase by more than 0.5 mg per deciliter within 24 hours.11 Few studies report kidney function beyond a few days after exposure to the contrast medium. In one report, 5 of 21 elderly patients with an initial sudden rise in serum creatinine levels after angiography had a final creatinine level of at least 0.5 mg per deciliter above baseline.12 Thirteen to 50 percent of patients requiring dialysis after exposure to a contrast medium may depend on dialysis permanently.3,13
A decline in kidney function after the administration of a contrast medium is associated with a prolonged hospital stay, adverse cardiac events, and high mortality both in the hospital and in the long term.3,6,8,14,15,16 However, the association between these outcomes and the decline in function may be explained at least in part by coexisting conditions, acuteness of illness, or other causes of acute kidney failure, such as atheroembolism.
Pathogenesis
The pathogenesis of contrast-medium–induced nephropathy in humans is not clear. In vitro studies and studies in animals suggest a combination of toxic injury to the renal tubules and ischemic injury partly mediated by reactive oxygen species.17,18 Low blood flow in the medulla, which has a high demand for oxygen, might result from increased perivascular hydrostatic pressure, high viscosity, or changes in vasoactive substances such as endothelin, nitric oxide, and adenosine.10,19 Factors impairing medullary vasodilation, such as nonsteroidal antiinflammatory drugs, may worsen contrast-medium–induced nephropathy.
Strategies and Evidence
Evaluation of Risk
The first steps in reducing the risk of kidney injury are to look for risk factors and review the indications for the administration of contrast medium. Most risk factors can be detected by history taking and physical examination. Factors such as dehydration can be at least partially corrected before exposure to the contrast medium.
The risk of a decline in kidney function after the administration of contrast medium rises exponentially with the number of risk factors present.8,12,14 Validated risk-prediction models, such as the one shown in Table 1, have been developed for patients undergoing percutaneous coronary intervention.7
Table 1. Predicting the Risk of an Acute Decline in Kidney Function after Percutaneous Coronary Intervention.
It is not necessary to measure the serum creatinine levels of every patient before exposure to a contrast medium, but measurements should be made before intraarterial use of the medium and in patients with a history of kidney disease, proteinuria, kidney surgery, diabetes, hypertension, or gout.20 The creatinine clearance rate or the glomerular filtration rate should be estimated from the serum creatinine level, according to either the Cockcroft–Gault21 or the Modification of Diet in Renal Disease22 formula (Table 1) to identify more accurately patients with values below 50 ml per minute per 1.73 m2, who are at increased risk for nephropathy.8 Alternative imaging methods not requiring contrast medium should be considered for use in patients with any risk factors. If contrast medium has to be given, serum creatinine levels should be measured 24 to 48 hours after administration of the contrast medium. Because of the risk of lactic acidosis when contrast-medium–induced nephropathy occurs in a patient with diabetes who is receiving metformin, it is prudent to withhold this agent until the glomerular filtration rate is greater than 40 ml per minute per 1.73 m2 and for the 48 hours before exposure of the patient to the contrast medium.23
Prevention
Protocols for Administration of Fluids
The administration of fluids is recommended to reduce the risk of contrast-medium–induced nephropathy. However, data are lacking that specify the optimal fluid regimen. In one trial, serum creatinine levels increased by more than 0.5 mg per deciliter in nine patients (34.6 percent) given water orally as compared with one (3.7 percent) given intravenous saline for 24 hours beginning 12 hours before administration of the contrast medium, but the trial was stopped early after an unplanned interim examination of the data.24 Prolonged intravenous fluid therapy is difficult to administer for ambulatory procedures. A small trial comparing the use of intravenous fluids for 12 hours (before and after administration of the contrast medium) with oral fluids plus a single intravenous bolus of fluid showed a lesser mean decline in the glomerular filtration rate at 48 hours after administration of the contrast medium (–18.3 vs. –34.6 ml per minute per 1.73 m2) in the group receiving intravenous fluids,25 although another trial did not confirm this result.26 In a study comparing isotonic saline with 0.45 percent saline, each given at 1 ml per kilogram of body weight per hour for 24 hours starting the morning of the procedure involving the contrast medium, a rise in the serum creatinine level of more than 0.5 mg per deciliter within 48 hours after administration of the contrast medium was less likely in patients who were given isotonic saline (0.7 percent vs. 2.0 percent, P=0.04).27
It has been hypothesized that alkalinization of tubular fluid might be beneficial by reducing the levels of pH-dependent free radicals. In one report, the creatinine level was less likely to rise more than 25 percent within two days after the administration of contrast medium in patients who were given an infusion of isotonic sodium bicarbonate than in those given a saline infusion.28 However, there are methodologic concerns about these results. The trial was terminated early because of a lower-than-expected rate of "events" in the bicarbonate group, but the timing of the interim analysis and the stopping rules were not prespecified, and the P value for the difference in event rates (P=0.02) was higher than is standard for stopping a trial early.
N-acetylcysteine
N-acetylcysteine has the potential to reduce the nephrotoxicity of contrast mediums through antioxidant and vasodilatory effects.29 In an initial trial, serum creatinine levels rose by more than 0.5 mg per deciliter in 2 percent of patients who received N-acetylcysteine as compared with 21 percent of patients in the control group (P<0.01).30 This event rate in the control group is unexpectedly high for patients who received low-dose intravenous low-osmolality contrast medium. For the most part, subsequent trials have involved patients with reduced kidney function who underwent coronary angiography. Some have shown a benefit and others have shown a lack of effect; many are limited by low power and a lack of blinding.31,32,33,34 Recent meta-analyses31,32,33,34 suggest some benefit to N-acetylcysteine (pooled odds ratio, 0.54 to 0.73 for contrast nephropathy, defined variably across studies). However, this estimate must be interpreted with caution, given the heterogeneous results of the individual trials, the possibility of publication bias, and the underrepresentation of small negative studies. Also, the effect of N-acetylcysteine on outcomes other than minor changes in serum creatinine levels is unknown. More data are needed before N-acetylcysteine can be strongly recommended for the prevention of contrast-medium–induced nephropathy.
Other Approaches to Prophylaxis
Several other interventions have been proposed to reduce the risk of contrast-medium–induced nephropathy, but data to support them are limited. Forced diuresis with furosemide, mannitol, dopamine, or a combination of these given at the time of exposure to the contrast medium has been associated with similar or higher rates of contrast-medium–induced nephropathy when compared with prophylactic fluids alone.35,36,37,38 Deleterious effects may be explained by negative fluid balance in some instances. In generally small randomized trials, the use of various vasodilators, including dopamine, fenoldopam, atrial natriuretic peptides, calcium blockers, prostaglandin E1, or a nonselective endothelin-receptor antagonist, has not been shown to reduce the risk of contrast-medium–induced nephropathy in comparison with fluid therapy.38,39,40,41,42,43 A small randomized trial showed a lower frequency of an increase of more than 0.5 mg per deciliter in serum creatinine levels in patients given captopril for three days as compared with those given placebo,44 but confirmatory trials are required. In another small trial, serum creatinine levels were significantly less likely to increase (by >25 percent or >0.5 mg per deciliter) within two to five days of administration of the contrast medium in patients who received ascorbic acid as an antioxidant than in those who received placebo.45 The baseline serum creatinine level was lower in the placebo group, and both groups reached a similar level after exposure to the contrast medium.
Theophylline and aminophylline have also been proposed as agents that may reduce the risk of contrast-medium–induced nephropathy. A recent meta-analysis found that the mean rise in serum creatinine levels was significantly lower (by 0.17 mg per deciliter ) at 48 hours after administration of the contrast medium among patients receiving either of these medications than among those receiving placebo.46 However, the clinical importance of this finding is questionable, and there was heterogeneity among studies with regard to changes in serum creatinine levels. Overall, no prophylactic agent has been shown conclusively to prevent clinically important contrast-medium–induced nephropathy.
Hemodialysis or Hemofiltration
The role of hemodialysis in patients at high risk for contrast-medium–induced nephropathy remains uncertain. Among patients with advanced kidney disease (mean creatinine clearance, 26 ml per minute), an increase in serum creatinine levels of at least 25 percent was significantly less common in patients randomly assigned to prophylactic hemofiltration before and after the administration of contrast medium than in those assigned to receive fluid alone (5 percent vs. 50 percent, P<0.001).19 In-hospital death was also significantly less frequent in the hemofiltration group.47 However, the serum creatinine level is directly altered by the intervention, and the relationship between the intervention and the reduced mortality rate is unclear. Thus, the results require confirmation. Given the resources to deliver the intervention, this approach would apply only to the most ill.
Choice of Contrast Mediums
Iodinated contrast mediums can be classified by osmolality (e.g., high-osmolar contrast mediums, such as sodium diatrizoate; low-osmolar mediums, such as iohexol; and iso-osmolar mediums, such as iodixanol). In a meta-analysis of comparative trials, an increase in serum creatinine levels of more than 0.50 mg per deciliter after administration of the contrast medium in patients with reduced kidney function was less frequent with low-osmolar than with high-osmolar mediums (odds ratio, 0.50; 95 percent confidence interval, 0.36 to 0.68).48 Because of the small number of events, no conclusion could be reached about the effects of osmolality on the need for dialysis.
Iso-osmolar contrast mediums have been proposed as an alternative. One randomized trial involving patients with diabetes who have renal impairment showed a significantly lower frequency of increases in creatinine levels of at least 0.5 mg per deciliter with the iso-osmolar agent iodixanol, than with a low-osmolar agent.49 However, the rate of renal deterioration in the group receiving a low-osmolar contrast medium was higher than expected. Similarly, in an open-label trial, a maximal increase in serum creatinine levels of greater than 25 percent within a week after the administration of contrast medium was less common with iodixanol than with iohexol (3.7 percent vs. 10 percent), but a lack of consistent timing for measuring creatinine levels in the two groups may have biased the results.50 In contradistinction, other trials have revealed no significant differences between iodixanol and low-osmolar agents in the rates of renal failure requiring intervention or prolonging hospitalization51 or in mean changes in creatinine levels after administration of contrast medium.52 Further studies are needed before iso-osmolar contrast mediums can be recommended in place of low-osmolar mediums.
Exceeding a volume of contrast medium of 5 ml per kilogram of body weight divided by the serum creatinine level in milligrams per deciliter strongly predicts nephropathy requiring dialysis.5 Table 2 summarizes recommendations regarding interventions commonly used to prevent contrast-medium–induced nephropathy.
Table 2. Summary Recommendations of Interventions Commonly Used to Reduce the Risk of Contrast-Medium–Induced Nephropathy.
Areas of Uncertainty
The pathogenesis of contrast-medium–induced nephropathy remains uncertain. The value of possible preventive strategies (including N-acetylcysteine, vasodilators, and iso-osmolar contrast mediums) in reducing the risk of contrast-medium–induced nephropathy and associated morbidity also remains uncertain.
Guidelines
The European Society of Urogenital Radiology and the American College of Radiology recommend assessment of risk factors including dehydration, heart failure, age greater than 70 years, and concurrent use of nephrotoxic drugs, along with measurement of serum creatinine levels in those at risk for reduced kidney function.23,53 In the presence of risk factors, consideration of alternative imaging techniques, discontinuation of nephrotoxic drugs, and use of low-osmolar or iso-osmolar contrast mediums in limited doses are recommended. Maintaining adequate hydration and the administration of additional fluids are also recommended, but the details of the regimens are not defined. Multiple infusions of contrast medium within a short period of time and the use of mannitol or diuretics are to be avoided. The American guidelines mention the use of N-acetylcysteine or other potential prophylactic drug therapies without specifically recommending these approaches.
Summary and Recommendations
Patients with normal kidney function and no recognized risk factors for contrast-medium–induced nephropathy do not require routine testing or prophylactic intervention before angiography. For patients likely to have reduced kidney function, such as the man described in the vignette, we recommend measurement of the serum creatinine level and estimation of the glomerular filtration rate. If the glomerular filtration rate is less than 50 ml per minute per 1.73 m2, particularly in combination with other risk factors, consideration should be given to alternative imaging approaches. If infusing contrast medium is thought to be warranted, a low-osmolar agent should be used at the minimal dose necessary, and measurement of the serum creatinine level should be repeated 24 to 48 hours after the administration of the contrast medium. Nonsteroidal antiinflammatory drugs and diuretics should be withheld for at least 24 hours before and after exposure to contrast medium, if possible. Metformin should be withheld for 48 hours before the administration of contrast medium and until it is certain that contrast-medium–induced nephropathy has not occurred. Additional fluids should be given; although the optimal regimen is uncertain, available data support a regimen of 0.9 percent saline at 1 ml per kilogram per hour intravenously from up to 12 hours before administration of contrast medium and for up to 12 hours after, with careful observation of fluid balance. The use of N-acetylcysteine is not recommended routinely, given the inconsistent results of clinical trials.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Division of Nephrology, Memorial University of Newfoundland, St. John's, Newf., Canada.
Address reprint requests to Dr. Barrett at the Patient Research Centre, Health Sciences Centre, 300 Prince Philip Dr., St. John's, NL A1B 3V6, Canada, or at bbarrett@mun.ca.
References
Katholi RE, Taylor GJ, McCann WP, et al. Nephrotoxicity from contrast media: attenuation with theophylline. Radiology 1995;195:17-22.
Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Dis 2002;39:930-936.
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.
Rudnick MR, Goldfarb S, Wexler L, et al. Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial: the Iohexol Cooperative Study. Kidney Int 1995;47:254-261.
Freeman RV, O'Donnell MO, Share D, et al. Nephropathy requiring dialysis after percutaneous coronary intervention and the critical role of an adjusted contrast dose. Am J Cardiol 2002;90:1068-1073.
Rihal CS, Textor SC, Grill DE, et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation 2002;105:2259-2264.
Mehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol 2004;44:1393-1399.
Marenzi G, Lauri G, Assanelli E, et al. Contrast-induced nephropathy in patients undergoing primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 2004;44:1780-1785.
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.
Solomon R. Contrast-medium-induced acute renal failure. Kidney Int 1998;53:230-242.
Guitterez NV, Diaz A, Timmis GC, et al. Determinants of serum creatinine trajectory in acute contrast nephropathy. J Interv Cardiol 2002;15:349-354.
Rich MW, Crecelius CA. Incidence, risk factors, and clinical course of acute renal insufficiency after cardiac catheterization in patients 70 years of age or older: a prospective study. Arch Intern Med 1990;150:1237-1242.
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.
Bartholomew BA, Harjai KJ, Dukkipati S, et al. Impact of nephropathy after percutaneous coronary intervention and a method for risk stratification. Am J Cardiol 2004;93:1515-1519.
Dangas G, Iakovou I, Nikolsky E, et al. Contrast-induced nephropathy after percutaneous coronary interventions in relation to chronic kidney disease and hemodynamic variables. Am J Cardiol 2005;95:13-19.
Abizaid AS, Clark CE, Mintz GS, et al. Effects of dopamine and aminophylline on contrast-induced acute renal failure after coronary angioplasty in patients with preexisting renal insuffciency. Am J Cardiol 1999;83:260-263.
Messana JM, Cieslinski DA, Humes HD. Comparison of toxicity of radiocontrast agents to renal tubule cells in vitro. Ren Fail 1990;12:75-82.
Katholi RE, Woods WT Jr, Taylor GL, et al. Oxygen free radicals and contrast nephropathy. Am J Kidney Dis 1998;32:64-71.
Heyman SN, Reichman J, Brezis M. Pathophysiology of radiocontrast nephropathy: a role for medullary hypoxia. Invest Radiol 1999;34:685-691.
Thomsen HS, Morcos SK, Members of the Contrast Media Safety Committee of European Society of Urogenital Radiology (ESUR). In which patients should serum creatinine be measured before iodinated contrast medium administration? Eur Radiol 2005;15:749-754.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41.
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999;130:461-470.
Thomsen HS. Guidelines for contrast media from the European Society of Urogenital Radiology. AJR Am J Roentgenol 2003;181:1463-1471.
Trivedi HS, Moore H, Nasr S, et al. A randomized prospective trial to assess the role of saline hydration on the development of contrast nephrotoxicity. Nephron Clin Pract 2003;93:C29-C34.
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.
Taylor AJ, Hotchkiss D, Morse RW, McCabe J. PREPARED: Preparation for Angiography in Renal Dysfunction: a randomized trial on inpatient vs outpatient hydration protocols for cardiac catheterization in mild-to-moderate renal dysfunction. Chest 1998;114:1570-1574.
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.
Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA 2004;291:2328-2334.
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.
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.
Kshirsagar AV, Poole C, Mottl A, et al. N-acetylcysteine for the prevention of radiocontrast induced nephropathy: a meta-analysis of prospective controlled trials. J Am Soc Nephrol 2004;15:761-769.
Pannu N, Manns B, Lee H, Tonelli M. Systematic review of the impact of N-acetylcysteine on contrast nephropathy. Kidney Int 2004;65:1366-1374.
Bagshaw SM, Ghali WA. Acetylcysteine for prevention of contrast-induced nephropathy after intravascular angiography: a systematic review and meta-analysis. BMC Med 2004;2:38-38.
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.
Weinstein J-M, Heyman S, Brezis M. Potential deleterious effect of furosemide in radiocontrast nephropathy. Nephron 1992;62:413-415.
Solomon R, Werner C, Mann D, D'Elia J, Silva 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.
Stevens MA, McCullough PA, Tobin KJ, et al. A prospective randomized trial of prevention measures in patients at high risk for contrast nephropathy: results of the P.R.I.N.C.E. Study. J Am Coll Cardiol 1999;33:403-411.
Weisberg LS, Kurnik PB, Kurnik BRC. Risk of radiocontrast nephropathy in patients with and without diabetes mellitus. Kidney Int 1994;45:259-265.
Kurnik BR, Allgren RL, Genter FC, Solomon RJ, Bates ER, Weisberg LS. Prospective study of atrial natriuretic peptide for the prevention of radiocontrast-induced nephropathy. Am J Kidney Dis 1998;31:674-680.
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.
Wang A, Holcslaw T, Bashore TM, et al. Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism. Kidney Int 2000;57:1675-1680.
Sketch MH Jr, Whelton A, Schollmayer E, et al. Prevention of contrast media-induced renal dysfunction with prostaglandin E1: a randomized, double-blind, placebo-controlled study. Am J Ther 2001;8:155-162.
Khoury Z, Schlicht JR, Como J, et al. The effect of prophylactic nifedipine on renal function in patients administered contrast media. Pharmacotherapy 1995;15:59-65.
Gupta RK, Kapoor A, Tewari S, Sinha N, Sharma RK. Captopril for prevention of contrast-induced nephropathy in diabetic patients: a randomised study. Indian Heart J 1999;51:521-526.
Spargias K, Alexopoulos E, Kyrzopoulos S, et al. Ascorbic acid prevents contrast-mediated nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention. Circulation 2004;110:2837-2842.
Bagshaw SM, Ghali WA. Theophylline for prevention of contrast-induced nephropathy: a systematic review and meta-analysis. Arch Intern Med 2005;165:1087-1093.
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.
Barrett BJ, Carlisle EJ. Metaanalysis of the relative nephrotoxicity of high- and low-osmolality iodinated contrast media. Radiology 1993;188:171-178.
Aspelin P, Aubry P, Fransson S-G, Strasser R, Willenbrock R, Berg KJ. Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med 2003;348:491-499.
Chalmers N, Jackson RW. Comparison of iodixanol and iohexol in renal impairment. Br J Radiol 1999;72:701-703.
Davidson CJ, Laskey WK, Hermiller JB, et al. Randomized trial of contrast media utilization for high-risk PTCA: the COURT trial. Circulation 2000;101:2172-2177.
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 real insufficiency: a double-blind, randomized clinical trial. Eur Radiol 1998;8:144-147.
American College of Radiology. Manual on contrast media, version 5.0. (Accessed December 30, 2005, at http://www.acr.org/s_acr/sec.asp?CID=2131&DID=16687.)(Brendan J. Barrett, M.B.,)
A 71-year-old man with type 2 diabetes and hypertension is referred for coronary angiography. His medications include metformin and a thiazide. Before the angiogram, his serum creatinine level is 1.8 mg per deciliter (160 μmol per liter), yielding an estimated glomerular filtration rate of 40 ml per minute per 1.73 m2 of body-surface area. What can be done to reduce the risk that an angiographic contrast medium will worsen his kidney function?
The Clinical Problem
Sensitive tests of kidney function identify mild, transient changes in most patients who have been exposed to intravascular iodinated contrast mediums.1 Clinically important injury (often called contrast-medium–induced nephropathy) is much less common. Cases of contrast-medium–induced nephropathy are usually defined by a fixed (0.5 mg per deciliter ) or proportionate (25 percent) rise in serum creatinine levels after exposure to the contrast medium. However, the clinical importance of such changes, if they are transient, is uncertain. A serum creatinine level itself is a relatively poor measure of kidney function and is influenced by age, sex, and body composition.
In a study by Nash et al.,2 contrast-medium–induced nephropathy was reported to be the third most common cause of acute renal failure in hospitalized patients. In this study, the contrast medium was assumed to be the cause of the renal failure if it was administered in the 24 hours before renal failure and no other major kidney insult was identified. However, exposure to contrast medium may be a contributory rather than a sole cause of acute renal failure; concomitant insults may include low blood volume, surgery, atheroembolic disease, and the presence of other nephrotoxins.
The reported incidence of contrast-medium–induced nephropathy varies among studies, due to differences in definition, background risk, type and dose of contrast medium, imaging procedure, and the frequency of other potential causes of acute renal failure. The status of renal function before administration of a contrast medium is a major determinant of deterioration in function after administration.3 In one study, serum creatinine levels rose by more than 25 percent in 14.5 percent of patients who underwent coronary angiography (95 percent confidence interval, 12.9 to 16.1 percent).3
In the absence of preexisting renal disease, the incidence is much lower. In a large clinical trial, only 8 percent of patients whose baseline serum creatinine level was below 1.5 mg per deciliter (135 μmol per liter) had an increase in the serum creatinine level of more than 0.5 mg per deciliter, and none had an increase of more than 1 mg per deciliter (89 μmol per liter).4
In another study, 0.8 percent of 1826 patients required dialysis after exposure to the contrast medium; the baseline estimated creatinine clearance rate was below 47 ml per minute per 1.73 m2 of body-surface area in all patients requiring dialysis.3 Serum creatinine levels rose by less than 1 mg per deciliter (89 μmol per liter) in 29 percent of those requiring dialysis, indicating advanced preexisting kidney disease. Registry data suggest a 0.44 percent incidence of nephropathy requiring dialysis after percutaneous coronary intervention.5
Risk Factors
Diabetes is a risk factor for deterioration in renal function after angiography.3,6,7 Other factors variably associated with increased rates of acute renal failure after the administration of contrast medium include age over 75 years, periprocedural volume depletion, heart failure, cirrhosis or nephrosis, hypertension, proteinuria, concomitant use of nonsteroidal antiinflammatory drugs, and intraarterial injection. In the setting of acute myocardial infarction or percutaneous coronary intervention, hypotension or use of an aortic balloon pump has been associated with a higher rate of acute renal failure after exposure to a contrast medium.7,8 However, it is uncertain to what extent these factors independently worsen renal function, as opposed to serving as markers for coexisting conditions. High doses of contrast medium also increase the likelihood of renal dysfunction. The tolerable dose of contrast medium depends on kidney function.3,5,9
Prognosis
Contrast-medium–induced nephropathy is usually transient, with serum creatinine levels peaking at 3 days after administration of the medium and returning to baseline within 10 days after administration.8,10 Appreciable nephropathy is unlikely to develop if the serum creatinine level does not increase by more than 0.5 mg per deciliter within 24 hours.11 Few studies report kidney function beyond a few days after exposure to the contrast medium. In one report, 5 of 21 elderly patients with an initial sudden rise in serum creatinine levels after angiography had a final creatinine level of at least 0.5 mg per deciliter above baseline.12 Thirteen to 50 percent of patients requiring dialysis after exposure to a contrast medium may depend on dialysis permanently.3,13
A decline in kidney function after the administration of a contrast medium is associated with a prolonged hospital stay, adverse cardiac events, and high mortality both in the hospital and in the long term.3,6,8,14,15,16 However, the association between these outcomes and the decline in function may be explained at least in part by coexisting conditions, acuteness of illness, or other causes of acute kidney failure, such as atheroembolism.
Pathogenesis
The pathogenesis of contrast-medium–induced nephropathy in humans is not clear. In vitro studies and studies in animals suggest a combination of toxic injury to the renal tubules and ischemic injury partly mediated by reactive oxygen species.17,18 Low blood flow in the medulla, which has a high demand for oxygen, might result from increased perivascular hydrostatic pressure, high viscosity, or changes in vasoactive substances such as endothelin, nitric oxide, and adenosine.10,19 Factors impairing medullary vasodilation, such as nonsteroidal antiinflammatory drugs, may worsen contrast-medium–induced nephropathy.
Strategies and Evidence
Evaluation of Risk
The first steps in reducing the risk of kidney injury are to look for risk factors and review the indications for the administration of contrast medium. Most risk factors can be detected by history taking and physical examination. Factors such as dehydration can be at least partially corrected before exposure to the contrast medium.
The risk of a decline in kidney function after the administration of contrast medium rises exponentially with the number of risk factors present.8,12,14 Validated risk-prediction models, such as the one shown in Table 1, have been developed for patients undergoing percutaneous coronary intervention.7
Table 1. Predicting the Risk of an Acute Decline in Kidney Function after Percutaneous Coronary Intervention.
It is not necessary to measure the serum creatinine levels of every patient before exposure to a contrast medium, but measurements should be made before intraarterial use of the medium and in patients with a history of kidney disease, proteinuria, kidney surgery, diabetes, hypertension, or gout.20 The creatinine clearance rate or the glomerular filtration rate should be estimated from the serum creatinine level, according to either the Cockcroft–Gault21 or the Modification of Diet in Renal Disease22 formula (Table 1) to identify more accurately patients with values below 50 ml per minute per 1.73 m2, who are at increased risk for nephropathy.8 Alternative imaging methods not requiring contrast medium should be considered for use in patients with any risk factors. If contrast medium has to be given, serum creatinine levels should be measured 24 to 48 hours after administration of the contrast medium. Because of the risk of lactic acidosis when contrast-medium–induced nephropathy occurs in a patient with diabetes who is receiving metformin, it is prudent to withhold this agent until the glomerular filtration rate is greater than 40 ml per minute per 1.73 m2 and for the 48 hours before exposure of the patient to the contrast medium.23
Prevention
Protocols for Administration of Fluids
The administration of fluids is recommended to reduce the risk of contrast-medium–induced nephropathy. However, data are lacking that specify the optimal fluid regimen. In one trial, serum creatinine levels increased by more than 0.5 mg per deciliter in nine patients (34.6 percent) given water orally as compared with one (3.7 percent) given intravenous saline for 24 hours beginning 12 hours before administration of the contrast medium, but the trial was stopped early after an unplanned interim examination of the data.24 Prolonged intravenous fluid therapy is difficult to administer for ambulatory procedures. A small trial comparing the use of intravenous fluids for 12 hours (before and after administration of the contrast medium) with oral fluids plus a single intravenous bolus of fluid showed a lesser mean decline in the glomerular filtration rate at 48 hours after administration of the contrast medium (–18.3 vs. –34.6 ml per minute per 1.73 m2) in the group receiving intravenous fluids,25 although another trial did not confirm this result.26 In a study comparing isotonic saline with 0.45 percent saline, each given at 1 ml per kilogram of body weight per hour for 24 hours starting the morning of the procedure involving the contrast medium, a rise in the serum creatinine level of more than 0.5 mg per deciliter within 48 hours after administration of the contrast medium was less likely in patients who were given isotonic saline (0.7 percent vs. 2.0 percent, P=0.04).27
It has been hypothesized that alkalinization of tubular fluid might be beneficial by reducing the levels of pH-dependent free radicals. In one report, the creatinine level was less likely to rise more than 25 percent within two days after the administration of contrast medium in patients who were given an infusion of isotonic sodium bicarbonate than in those given a saline infusion.28 However, there are methodologic concerns about these results. The trial was terminated early because of a lower-than-expected rate of "events" in the bicarbonate group, but the timing of the interim analysis and the stopping rules were not prespecified, and the P value for the difference in event rates (P=0.02) was higher than is standard for stopping a trial early.
N-acetylcysteine
N-acetylcysteine has the potential to reduce the nephrotoxicity of contrast mediums through antioxidant and vasodilatory effects.29 In an initial trial, serum creatinine levels rose by more than 0.5 mg per deciliter in 2 percent of patients who received N-acetylcysteine as compared with 21 percent of patients in the control group (P<0.01).30 This event rate in the control group is unexpectedly high for patients who received low-dose intravenous low-osmolality contrast medium. For the most part, subsequent trials have involved patients with reduced kidney function who underwent coronary angiography. Some have shown a benefit and others have shown a lack of effect; many are limited by low power and a lack of blinding.31,32,33,34 Recent meta-analyses31,32,33,34 suggest some benefit to N-acetylcysteine (pooled odds ratio, 0.54 to 0.73 for contrast nephropathy, defined variably across studies). However, this estimate must be interpreted with caution, given the heterogeneous results of the individual trials, the possibility of publication bias, and the underrepresentation of small negative studies. Also, the effect of N-acetylcysteine on outcomes other than minor changes in serum creatinine levels is unknown. More data are needed before N-acetylcysteine can be strongly recommended for the prevention of contrast-medium–induced nephropathy.
Other Approaches to Prophylaxis
Several other interventions have been proposed to reduce the risk of contrast-medium–induced nephropathy, but data to support them are limited. Forced diuresis with furosemide, mannitol, dopamine, or a combination of these given at the time of exposure to the contrast medium has been associated with similar or higher rates of contrast-medium–induced nephropathy when compared with prophylactic fluids alone.35,36,37,38 Deleterious effects may be explained by negative fluid balance in some instances. In generally small randomized trials, the use of various vasodilators, including dopamine, fenoldopam, atrial natriuretic peptides, calcium blockers, prostaglandin E1, or a nonselective endothelin-receptor antagonist, has not been shown to reduce the risk of contrast-medium–induced nephropathy in comparison with fluid therapy.38,39,40,41,42,43 A small randomized trial showed a lower frequency of an increase of more than 0.5 mg per deciliter in serum creatinine levels in patients given captopril for three days as compared with those given placebo,44 but confirmatory trials are required. In another small trial, serum creatinine levels were significantly less likely to increase (by >25 percent or >0.5 mg per deciliter) within two to five days of administration of the contrast medium in patients who received ascorbic acid as an antioxidant than in those who received placebo.45 The baseline serum creatinine level was lower in the placebo group, and both groups reached a similar level after exposure to the contrast medium.
Theophylline and aminophylline have also been proposed as agents that may reduce the risk of contrast-medium–induced nephropathy. A recent meta-analysis found that the mean rise in serum creatinine levels was significantly lower (by 0.17 mg per deciliter ) at 48 hours after administration of the contrast medium among patients receiving either of these medications than among those receiving placebo.46 However, the clinical importance of this finding is questionable, and there was heterogeneity among studies with regard to changes in serum creatinine levels. Overall, no prophylactic agent has been shown conclusively to prevent clinically important contrast-medium–induced nephropathy.
Hemodialysis or Hemofiltration
The role of hemodialysis in patients at high risk for contrast-medium–induced nephropathy remains uncertain. Among patients with advanced kidney disease (mean creatinine clearance, 26 ml per minute), an increase in serum creatinine levels of at least 25 percent was significantly less common in patients randomly assigned to prophylactic hemofiltration before and after the administration of contrast medium than in those assigned to receive fluid alone (5 percent vs. 50 percent, P<0.001).19 In-hospital death was also significantly less frequent in the hemofiltration group.47 However, the serum creatinine level is directly altered by the intervention, and the relationship between the intervention and the reduced mortality rate is unclear. Thus, the results require confirmation. Given the resources to deliver the intervention, this approach would apply only to the most ill.
Choice of Contrast Mediums
Iodinated contrast mediums can be classified by osmolality (e.g., high-osmolar contrast mediums, such as sodium diatrizoate; low-osmolar mediums, such as iohexol; and iso-osmolar mediums, such as iodixanol). In a meta-analysis of comparative trials, an increase in serum creatinine levels of more than 0.50 mg per deciliter after administration of the contrast medium in patients with reduced kidney function was less frequent with low-osmolar than with high-osmolar mediums (odds ratio, 0.50; 95 percent confidence interval, 0.36 to 0.68).48 Because of the small number of events, no conclusion could be reached about the effects of osmolality on the need for dialysis.
Iso-osmolar contrast mediums have been proposed as an alternative. One randomized trial involving patients with diabetes who have renal impairment showed a significantly lower frequency of increases in creatinine levels of at least 0.5 mg per deciliter with the iso-osmolar agent iodixanol, than with a low-osmolar agent.49 However, the rate of renal deterioration in the group receiving a low-osmolar contrast medium was higher than expected. Similarly, in an open-label trial, a maximal increase in serum creatinine levels of greater than 25 percent within a week after the administration of contrast medium was less common with iodixanol than with iohexol (3.7 percent vs. 10 percent), but a lack of consistent timing for measuring creatinine levels in the two groups may have biased the results.50 In contradistinction, other trials have revealed no significant differences between iodixanol and low-osmolar agents in the rates of renal failure requiring intervention or prolonging hospitalization51 or in mean changes in creatinine levels after administration of contrast medium.52 Further studies are needed before iso-osmolar contrast mediums can be recommended in place of low-osmolar mediums.
Exceeding a volume of contrast medium of 5 ml per kilogram of body weight divided by the serum creatinine level in milligrams per deciliter strongly predicts nephropathy requiring dialysis.5 Table 2 summarizes recommendations regarding interventions commonly used to prevent contrast-medium–induced nephropathy.
Table 2. Summary Recommendations of Interventions Commonly Used to Reduce the Risk of Contrast-Medium–Induced Nephropathy.
Areas of Uncertainty
The pathogenesis of contrast-medium–induced nephropathy remains uncertain. The value of possible preventive strategies (including N-acetylcysteine, vasodilators, and iso-osmolar contrast mediums) in reducing the risk of contrast-medium–induced nephropathy and associated morbidity also remains uncertain.
Guidelines
The European Society of Urogenital Radiology and the American College of Radiology recommend assessment of risk factors including dehydration, heart failure, age greater than 70 years, and concurrent use of nephrotoxic drugs, along with measurement of serum creatinine levels in those at risk for reduced kidney function.23,53 In the presence of risk factors, consideration of alternative imaging techniques, discontinuation of nephrotoxic drugs, and use of low-osmolar or iso-osmolar contrast mediums in limited doses are recommended. Maintaining adequate hydration and the administration of additional fluids are also recommended, but the details of the regimens are not defined. Multiple infusions of contrast medium within a short period of time and the use of mannitol or diuretics are to be avoided. The American guidelines mention the use of N-acetylcysteine or other potential prophylactic drug therapies without specifically recommending these approaches.
Summary and Recommendations
Patients with normal kidney function and no recognized risk factors for contrast-medium–induced nephropathy do not require routine testing or prophylactic intervention before angiography. For patients likely to have reduced kidney function, such as the man described in the vignette, we recommend measurement of the serum creatinine level and estimation of the glomerular filtration rate. If the glomerular filtration rate is less than 50 ml per minute per 1.73 m2, particularly in combination with other risk factors, consideration should be given to alternative imaging approaches. If infusing contrast medium is thought to be warranted, a low-osmolar agent should be used at the minimal dose necessary, and measurement of the serum creatinine level should be repeated 24 to 48 hours after the administration of the contrast medium. Nonsteroidal antiinflammatory drugs and diuretics should be withheld for at least 24 hours before and after exposure to contrast medium, if possible. Metformin should be withheld for 48 hours before the administration of contrast medium and until it is certain that contrast-medium–induced nephropathy has not occurred. Additional fluids should be given; although the optimal regimen is uncertain, available data support a regimen of 0.9 percent saline at 1 ml per kilogram per hour intravenously from up to 12 hours before administration of contrast medium and for up to 12 hours after, with careful observation of fluid balance. The use of N-acetylcysteine is not recommended routinely, given the inconsistent results of clinical trials.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Division of Nephrology, Memorial University of Newfoundland, St. John's, Newf., Canada.
Address reprint requests to Dr. Barrett at the Patient Research Centre, Health Sciences Centre, 300 Prince Philip Dr., St. John's, NL A1B 3V6, Canada, or at bbarrett@mun.ca.
References
Katholi RE, Taylor GJ, McCann WP, et al. Nephrotoxicity from contrast media: attenuation with theophylline. Radiology 1995;195:17-22.
Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Dis 2002;39:930-936.
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.
Rudnick MR, Goldfarb S, Wexler L, et al. Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial: the Iohexol Cooperative Study. Kidney Int 1995;47:254-261.
Freeman RV, O'Donnell MO, Share D, et al. Nephropathy requiring dialysis after percutaneous coronary intervention and the critical role of an adjusted contrast dose. Am J Cardiol 2002;90:1068-1073.
Rihal CS, Textor SC, Grill DE, et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation 2002;105:2259-2264.
Mehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol 2004;44:1393-1399.
Marenzi G, Lauri G, Assanelli E, et al. Contrast-induced nephropathy in patients undergoing primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 2004;44:1780-1785.
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.
Solomon R. Contrast-medium-induced acute renal failure. Kidney Int 1998;53:230-242.
Guitterez NV, Diaz A, Timmis GC, et al. Determinants of serum creatinine trajectory in acute contrast nephropathy. J Interv Cardiol 2002;15:349-354.
Rich MW, Crecelius CA. Incidence, risk factors, and clinical course of acute renal insufficiency after cardiac catheterization in patients 70 years of age or older: a prospective study. Arch Intern Med 1990;150:1237-1242.
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.
Bartholomew BA, Harjai KJ, Dukkipati S, et al. Impact of nephropathy after percutaneous coronary intervention and a method for risk stratification. Am J Cardiol 2004;93:1515-1519.
Dangas G, Iakovou I, Nikolsky E, et al. Contrast-induced nephropathy after percutaneous coronary interventions in relation to chronic kidney disease and hemodynamic variables. Am J Cardiol 2005;95:13-19.
Abizaid AS, Clark CE, Mintz GS, et al. Effects of dopamine and aminophylline on contrast-induced acute renal failure after coronary angioplasty in patients with preexisting renal insuffciency. Am J Cardiol 1999;83:260-263.
Messana JM, Cieslinski DA, Humes HD. Comparison of toxicity of radiocontrast agents to renal tubule cells in vitro. Ren Fail 1990;12:75-82.
Katholi RE, Woods WT Jr, Taylor GL, et al. Oxygen free radicals and contrast nephropathy. Am J Kidney Dis 1998;32:64-71.
Heyman SN, Reichman J, Brezis M. Pathophysiology of radiocontrast nephropathy: a role for medullary hypoxia. Invest Radiol 1999;34:685-691.
Thomsen HS, Morcos SK, Members of the Contrast Media Safety Committee of European Society of Urogenital Radiology (ESUR). In which patients should serum creatinine be measured before iodinated contrast medium administration? Eur Radiol 2005;15:749-754.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41.
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999;130:461-470.
Thomsen HS. Guidelines for contrast media from the European Society of Urogenital Radiology. AJR Am J Roentgenol 2003;181:1463-1471.
Trivedi HS, Moore H, Nasr S, et al. A randomized prospective trial to assess the role of saline hydration on the development of contrast nephrotoxicity. Nephron Clin Pract 2003;93:C29-C34.
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.
Taylor AJ, Hotchkiss D, Morse RW, McCabe J. PREPARED: Preparation for Angiography in Renal Dysfunction: a randomized trial on inpatient vs outpatient hydration protocols for cardiac catheterization in mild-to-moderate renal dysfunction. Chest 1998;114:1570-1574.
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.
Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA 2004;291:2328-2334.
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.
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.
Kshirsagar AV, Poole C, Mottl A, et al. N-acetylcysteine for the prevention of radiocontrast induced nephropathy: a meta-analysis of prospective controlled trials. J Am Soc Nephrol 2004;15:761-769.
Pannu N, Manns B, Lee H, Tonelli M. Systematic review of the impact of N-acetylcysteine on contrast nephropathy. Kidney Int 2004;65:1366-1374.
Bagshaw SM, Ghali WA. Acetylcysteine for prevention of contrast-induced nephropathy after intravascular angiography: a systematic review and meta-analysis. BMC Med 2004;2:38-38.
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.
Weinstein J-M, Heyman S, Brezis M. Potential deleterious effect of furosemide in radiocontrast nephropathy. Nephron 1992;62:413-415.
Solomon R, Werner C, Mann D, D'Elia J, Silva 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.
Stevens MA, McCullough PA, Tobin KJ, et al. A prospective randomized trial of prevention measures in patients at high risk for contrast nephropathy: results of the P.R.I.N.C.E. Study. J Am Coll Cardiol 1999;33:403-411.
Weisberg LS, Kurnik PB, Kurnik BRC. Risk of radiocontrast nephropathy in patients with and without diabetes mellitus. Kidney Int 1994;45:259-265.
Kurnik BR, Allgren RL, Genter FC, Solomon RJ, Bates ER, Weisberg LS. Prospective study of atrial natriuretic peptide for the prevention of radiocontrast-induced nephropathy. Am J Kidney Dis 1998;31:674-680.
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.
Wang A, Holcslaw T, Bashore TM, et al. Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism. Kidney Int 2000;57:1675-1680.
Sketch MH Jr, Whelton A, Schollmayer E, et al. Prevention of contrast media-induced renal dysfunction with prostaglandin E1: a randomized, double-blind, placebo-controlled study. Am J Ther 2001;8:155-162.
Khoury Z, Schlicht JR, Como J, et al. The effect of prophylactic nifedipine on renal function in patients administered contrast media. Pharmacotherapy 1995;15:59-65.
Gupta RK, Kapoor A, Tewari S, Sinha N, Sharma RK. Captopril for prevention of contrast-induced nephropathy in diabetic patients: a randomised study. Indian Heart J 1999;51:521-526.
Spargias K, Alexopoulos E, Kyrzopoulos S, et al. Ascorbic acid prevents contrast-mediated nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention. Circulation 2004;110:2837-2842.
Bagshaw SM, Ghali WA. Theophylline for prevention of contrast-induced nephropathy: a systematic review and meta-analysis. Arch Intern Med 2005;165:1087-1093.
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.
Barrett BJ, Carlisle EJ. Metaanalysis of the relative nephrotoxicity of high- and low-osmolality iodinated contrast media. Radiology 1993;188:171-178.
Aspelin P, Aubry P, Fransson S-G, Strasser R, Willenbrock R, Berg KJ. Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med 2003;348:491-499.
Chalmers N, Jackson RW. Comparison of iodixanol and iohexol in renal impairment. Br J Radiol 1999;72:701-703.
Davidson CJ, Laskey WK, Hermiller JB, et al. Randomized trial of contrast media utilization for high-risk PTCA: the COURT trial. Circulation 2000;101:2172-2177.
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 real insufficiency: a double-blind, randomized clinical trial. Eur Radiol 1998;8:144-147.
American College of Radiology. Manual on contrast media, version 5.0. (Accessed December 30, 2005, at http://www.acr.org/s_acr/sec.asp?CID=2131&DID=16687.)(Brendan J. Barrett, M.B.,)