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Contrast Medium–Induced Acute Kidney Injury: Comparison of Intravenous and Intraarterial Administration of Iodinated Contrast Medium
CLINICAL STUDY
Contrast Medium–Induced Acute Kidney Injury: Comparison of Intravenous and Intraarterial Administration of Iodinated Contrast Medium Ronald P. Karlsberg, MD, Suhail Y. Dohad, MD, and Rubin Sheng, MD, MPH, for the Iodixanol Peripheral Computed Tomographic Angiography Study Investigator Panel
ABSTRACT Purpose: To compare the incidence of contrast medium–induced acute kidney injury (AKI) after intravenous (IV) administration of iodixanol for computed tomographic (CT) angiography versus intraarterial (IA) injection of iodixanol or low osmolar contrast medium (LOCM) for digital subtraction angiography (DSA) within the same population suspected of peripheral arterial occlusive disease (PAOD). Materials and Methods: CT angiography was performed with IV iodixanol 320 mgI/mL. After a washout period of 3–14 days, DSA was performed with IA iodixanol or LOCM. Serum creatinine was measured at baseline and 24 hours after administration. Contrast medium–induced AKI was defined by a serum creatinine increase of at least 25% versus baseline at 24 hours. Data were analyzed with 2 statistics. Results: Mean baseline serum creatinine values were comparable between CT angiography with IV contrast medium and DSA with IA contrast medium (93.3 mol/L ⫾ 52.92 vs 92.8 mol/L ⫾ 61.70). The incidence of AKI for CT angiography after IV iodixanol administration was 7.6% (20 of 264), which was not statistically different than the 8.7% incidence (22 of 253) for DSA with IA iodixanol or LOCM (P ⫽ .641). In the 143 patients who received only iodixanol for both procedures, incidences of contrast medium–induced AKI were comparable after IV (7.0%) and IA (5.6%) administration (P ⫽ .626). Conclusions: The rates of contrast medium–induced AKI are not statistically different between IV iodixanol for CT angiography and IA iodixanol or another LOCM for DSA in the same population with suspected PAOD.
ABBREVIATIONS AKI ⫽ acute kidney injury, DSA ⫽ digital subtraction angiography, IA ⫽ intraarterial, IV ⫽ intravenous, LOCM ⫽ low osmolar contrast medium, PAOD ⫽ peripheral arterial occlusive disease
Iodinated contrast agent administration during radiographic examinations is known to cause acute kidney injury (AKI), particularly when patients have one or more risk factors
From the Cardiovascular Research Institute of Southern California (R.P.K., S.Y.D.), Cedars Sinai Heart Institute, Los Angeles, California; and Clinical Research and Development (R.S.), GE Healthcare Medical Diagnostics, Princeton, New Jersey. Received July 19, 2010; final revision received March 14, 2011; accepted March 20, 2011. Address correspondence to R.P.K., 414 N. Camden Dr., Beverly Hills, CA 90024; E-mail: [email protected] R.S. is a paid employee of GE Healthcare Medical Diagnostics (Princeton, New Jersey), which organized and conducted the study. R.P.K. and S.Y.D. were investigators in the trial. Neither of the other authors has identified a conflict of interest. © SIR, 2011 J Vasc Interv Radiol 2011; 22:1159 –1165 DOI: 10.1016/j.jvir.2011.03.020
such as renal insufficiency, dehydration, diabetes mellitus, congestive heart failure, age older than 75 years, use of nonsteroidal antiinflammatory drugs, or history of severe cardiovascular disease. The reported incidence of contrast medium–induced AKI varies widely in the literature. In several prospective, randomized clinical trials (1–7), the incidence of contrast medium–induced AKI after administration of iodixanol was significantly lower than that associated with low osmolar contrast media (LOCM) in patients at high risk with baseline serum creatinine values of 1.5 mg/dL or higher. However, in several other studies (8 –11), incidences of contrast medium–induced AKI were similar after administration of iodixanol versus LOCM. Although the different results from these clinical trials may be associated with a number of factors (ie, contrast medium– induced AKI definitions, subject population, risk factors, or standardization of blood sample collection after contrast
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medium administration), the controversy of iodixanol versus LOCM use with respect to the occurrence of AKI remains incompletely defined. Peripheral arterial occlusive disease (PAOD) is a slowly progressing disease that primarily affects the elderly population. When the disease is advanced to the stage of limiting lifestyle, a revascularization procedure may be warranted. Intraarterial (IA) digital subtraction angiography (DSA) was conventionally performed to accurately depict and characterize the level, multiplicity, and severity of a stenosis before a percutaneous intervention or surgery. However, noninvasive imaging techniques, such as intravenous (IV) contrast-enhanced computed tomographic (CT) angiography, have been increasingly used to avoid an invasive procedure, which is associated with higher risks and costs. Studies have been conducted in recent years to compare the diagnostic accuracy of CT angiography with IA DSA in patients with carotid and lower-extremity arterial disease (12–14). The results indicate that CT angiography is an accurate modality with high diagnostic value. The IA DSA and IV CT angiography procedures require administration of iodinated contrast media, which may cause AKI. However, it is unsure whether IV administration of contrast media will result in less AKI than IA injection because of extended circulation and dilution of the contrast medium in the bloodstream before it reaches the arterial system and kidneys. The purpose of the present report is to directly compare the incidence of contrast medium–induced AKI between IV administration of iodixanol for contrast-enhanced CT angiography and subsequent IA administration of iodixanol or LOCM for DSA in the same population of patients with suspected PAOD who were enrolled in this prospective, multicenter study evaluating the diagnostic accuracy of CT angiography.
tissue loss (dry necrosis only) located at the lower calf or foot region with a femoral and popliteal pulse but no pedal pulse (ie, Fontaine stage III–IV) or (iii) ankle-brachial index of less than 0.7 indicative of infragenicular arterial disease, measured no more than 3 months before inclusion in the study. Patients with a history of type I diabetes mellitus, allergies to any iodinated contrast agent, cellulitis, and/or acute nondry necrosis on either lower leg requiring immediate antibiotic therapy, and those with a clinically active, serious, or life-threatening disease or a life expectancy of less than 3 months, were excluded from the study. Patients who (i) were pregnant or lactating, (ii) were being evaluated for the patency of a previously created surgical peripheral bypass surgery graft, (iii) presented with acute limb ischemia or arterioembolic disease, (iv) were scheduled to undergo a surgical or nonsurgical intervention, (v) were expecting a change of PAOD conditions between the CT angiography and IA DSA procedures, or (vi) were unable or unwilling to discontinue metformin therapy at the time of the study procedure were also excluded from the study.
MATERIALS AND METHODS This was a retrospective evaluation of data on contrast medium–induced AKI from an open-label, multicenter study. The study was originally designed to assess efficacy of IV CT angiography in patients who were clinically indicated to undergo an IA DSA procedure with or without percutaneous intervention based on medical need.
Study Patients The study population consisted of adults (age ⱖ 18 y) with suspected PAOD referred for IA DSA of the abdominal aorta and/or bilateral iliac and lower-extremity arteries. PAOD was suspected in the setting of (i) intermittent claudication with a walking distance less than 200 meters (ie, Fontaine stage IIb). Claudication was located in the gluteal/ thigh region with weak or absent femoral and distal pulses or in the calf muscle with weak or absent popliteal pulse indicative of supragenicular arterial disease. PAOD was also suspected in the setting of (ii) rest pain and/or ischemic
Study Procedures Because dehydration has been shown to increase the risk of contrast medium–induced AKI, each subject was well hydrated. A standard hydration protocol was used in this study, before and after IV CT angiography or IA DSA procedures, according to the following regimens. (i) Oral fluid intake (ⱖ 1–2 L recommended) was encouraged, but solid food was to be avoided for 3 hours before the CT angiography procedure and for at least 6 hours before the IA DSA procedure. (ii) IV hydration, preferably with a minimum of 800 –1,000 mL normal-strength saline solution (0.9%) was recommended to start at least 4 hours before, and continuing for at least 6 hours after, each procedure. The administration flow rate was 100 –125 mL/h or 1–2 mL/kg body weight per hour depending on the subject’s condition and total duration of IV hydration given. CT angiography of the abdominal aorta and runoff was initially performed with IV administration of iodixanol 320 mgI/mL (Visipaque; GE Healthcare; Princeton, New Jersey) via a power injector at a flow rate of 3– 4 mL/s. A total dose of approximately 170 –200 mL per patient was administered. Safety evaluation included monitoring of injection site reactions, electrocardiography, vital signs, and physical examination changes, and the occurrence of adverse events. Serum creatinine measurements were part of the clinical laboratory evaluations performed at baseline and 24 hours ⫾ 4 after the administration of iodixanol. If necessary, additional hydration was given after the CT angiography procedure at the discretion of the investigator. Other procedure-related medications were administered for renal protection at the discretion of the clinicians or according to the standard of practice at the study site. After a washout period of 3–14 days after the CT angiography procedure, IA DSA was performed according to the normal study site standard procedure for all patients
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Figure 1.
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Study design. (Available in color online at www.jvir.org.)
(Fig 1). The selection of the contrast agent for the IA DSA procedure, volume of contrast medium administered, hydration regimen before and after the IA DSA procedure, and use of N-acetylcysteine were consistent with the normal practice of the catheterization laboratory at the study site. A nonselective IA DSA examination was performed in every patient, with the catheter tip located above both renal arteries. The image coverage range was from the level of the renal artery down to the level of the ankle. Additional selective images could be obtained at the discretion of the clinician. Percutaneous intervention could be performed at the same sitting based on the patient’s medical need. Similarly, serum creatinine measurements were obtained before the IA DSA procedure and 24 hours ⫾ 4 after administration of the contrast agent. The safety assessments were the same as those performed for CT angiography. The study protocol was approved by the institutional review board or independent ethics committee at each study site. Written informed consent was obtained from all patients before any study procedure began. The study was conducted in full accordance with the Declaration of Helsinki, the Good Clinical Practice Consolidated Guideline approved by the International Conference on Harmonization, and any applicable national and local laws and regulations.
Statistical Methods Demographic data and the incidence of contrast medium– induced AKI were summarized by using descriptive statistics. Contrast medium–induced AKI was defined as a laboratory-measured serum creatinine increase from baseline of at least 25% at 24 hours after administration of the iodinated contrast agent. Only patients with serum creatinine measurements at baseline and 24 hours after administration were included in the analysis. In the IA DSA phase, patients also had to have the specific contrast agent recorded to be included in the analysis. Patients who received iodixanol and one type of LOCM in the same IA DSA procedure were removed from the analysis because they could not be categorized in either group. Statistical comparisons were made between (i) IV iodixanol for CT angiography and IA iodixanol or LOCM for DSA based on the occurrence of AKI and the average volume of contrast agent administered during each procedure; (ii) IV iodixanol for CT angiography and IA iodixanol for DSA based on the occurrence of AKI; (iii) IV iodixanol for CT angiography and IA LOCM for DSA based on the occurrence of AKI;
Table 1. Demographic Characteristics
Variable Sex Female Male Race Asian Black Caucasian Hispanic/Latino Other Age (y) Mean ⫾ SD Range Median
CT Angiography, n ⴝ 264
IA DSA, n ⴝ 253
96 (36.4) 168 (63.6)
93 (36.8) 160 (63.2)
2 (0.8) 42 (15.9) 204 (77.3) 14 (5.3) 2 (0.8)
2 (0.8) 40 (15.8) 197 (77.9) 12 (4.7) 2 (0.8)
64.7 ⫾ 10.93 39.0–88.0 65.0
64.4 ⫾ 10.81 39.0–87.0 64.0
Note.—Values in parentheses are percentages. DSA ⫽ digital subtraction angiography; IA ⫽ intraarterial.
and (iv) IA iodixanol vs IA LOCM for DSA based on the occurrence of AKI. 2 statistics were used for categoric variable comparisons. A P value lower than .05 was considered to represent a statistically significant difference. Additionally, changes in serum creatinine level of 25% or more compared with baseline value were analyzed, along with whether patients with AKI following CT angiography with IV contrast medium overlapped with those with AKI following DSA with IA contrast medium.
RESULTS A total of 271 patients received iodixanol for CT angiography. Of these, 263 patients underwent the DSA procedure with IA administration of iodixanol or the study center– specific LOCM. Complete serum creatinine levels were available for 264 of the 271 patients who underwent CT angiography, and for 253 of the 263 patients who underwent DSA with IA contrast medium. Demographic characteristics were similar for patients treated with IV iodixanol in the CT angiography phase and IA iodixanol or LOCM in the DSA phase (Table 1). Among patients who underwent DSA with IA contrast medium, 147 (57.4%) received iodixanol, 103 (40.7%) received LOCM (iopamidol [Bracco, Princeton, New Jersey], n ⫽ 91; ioversol [Mallinckrodt, St. Louis,
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Table 2. Summary of Serum Creatinine Outcomes
Variable Baseline (mol/L) Mean ⫾ SD Median Range 24-Hour follow-up (mol/L) Mean ⫾ SD Median Range Difference vs baseline (mol/L) Mean ⫾ SD Median Range Change from baseline (n) Decrease ⱖ 25% Change ⬍ 25% Increase ⱖ 25
CT Angiography, n ⴝ 264
IA DSA, n ⴝ 253
93.3 ⫾ 52.92 80.0 27.0–513
92.8 ⫾ 61.70 80.0 18.0–628
96.2 ⫾ 51.58 88.0 18.0–460
91.3 ⫾ 36.31 80.0 18.0–318
2.9 ⫾ 26.99 0 ⫺301 to 195
⫺1.5 ⫾ 41.33 0 ⫺531 to 44.0
5 (1.9) 239 (90.5) 20 (7.6)
7 (2.8) 224 (88.5) 22 (8.7)
Figure 2. Incidence of AKI following IV CT angiography and IA DSA: 7.6% (20 of 264) of patients developed AKI following IV iodixanol for CT angiography and 8.7% (22 of 253) of patients developed AKI following IA iodixanol or LOCM for DSA. The difference in incidence was not statistically significant (P ⫽ .641). (Available in color online at www.jvir.org.)
Note.—Values in parentheses are percentages. DSA ⫽ digital subtraction angiography; IA ⫽ intraarterial.
Missouri], n ⫽ 7; iohexol [GE Healthcare], n ⫽ 3; and iopromide [Berlex, Montville, New Jersey], n ⫽ 2), and three (1.9%) received iodixanol and one other LOCM. A total of 143 patients who received iodixanol and 101 patients who received LOCM in the IA DSA phase had complete serum creatinine measurements for the CT angiography and IA DSA procedures. The contrast agent administered to patients undergoing CT angiography was determined by imaging time for each patient to cover the scan range from the level of the renal artery to the ankle level as specified by the protocol. The mean volume of contrast medium administered was 170 mL ⫾ 18 (range, 120 –200 mL). The volume of contrast agent administered during the IA DSA procedure was determined by the standard of practice at each study site and procedural requirements. The mean volume administered was 235 mL ⫾ 99 (range, 38 –589 mL) among the 250 patients who had the volume administered recorded. The variation in the range of volume administered reflected selective placement of catheters for IA DSA in some patients and percutaneous interventional procedures in other patients. The difference in mean contrast agent volume between the two procedures was statistically significant (P ⬍ .001). The patient population had relatively normal baseline renal function, as indicated by mean serum creatinine levels of 93.3 mol/L ⫾ 52.92 (SD) at the baseline observation before CT angiography and 92.8 mol/L ⫾ 61.70 at the baseline observation before IA DSA (Table 2). Contrast medium–induced AKI developed in 7.6% of patients after IV iodixanol for CT angiography (20 of 264) and 8.7% of patients after IA administration of iodixanol or LOCM for
Figure 3. Incidence of AKI following IV iodixanol for CT angiography versus IA iodixanol for DSA. Among the 143 patients who received iodixanol and had complete serum creatinine measurements in both study phases, AKI developed in 10 patients (7.0%) following IV contrast medium administration for CT angiography, compared with eight patients (5.6%) following IA contrast medium administration for DSA. The difference in incidence was not statistically significant (P ⫽ .626). (Available in color online at www.jvir.org.)
IA DSA (22 of 253). The difference was not statistically significant (P ⫽ .641; Fig 2). Among patients who received iodixanol for both procedures, the incidence of AKI was comparable between IV administration for CT angiography and IA administration for DSA (7% [10 of 143] vs 5.6% [eight of 143]; P ⫽ .626; Fig 3). Patients who received IV iodixanol for CT angiography had a lower incidence of AKI (6.9%; seven of 101) compared with those who received IA LOCM for the DSA procedure (13.9%; 14 of 101), but this difference did not reach statistical significance (P ⫽ .107). Further analysis showed that there was no overlap of patients with a 25% increase in serum creatinine level versus baseline between the IA DSA phase and the CT angiography phase. Approximately 90% of patients had a serum creatinine level change of less than 25% versus baseline. In addition to those with an increase of 25% or more in serum creatinine level, fewer than 3% of patients
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showed at least a 25% decrease from baseline level. In patients who received IA iodixanol, the incidence of AKI was 5.6% (eight of 143), compared with an incidence of 13.9% (14 of 101) for those who received IA LOCM (P ⫽ .026). This statistical difference is largely a result of injection of a single LOCM, iopamidol (14.6% [13 of 89]; P ⫽ .020).
DISCUSSION IV administration of contrast agent, in theory, is associated with a lower incidence of AKI compared with IA administration, as a result of the longer circulation route and increased dilution of contrast agent in the bloodstream before it can reach the arterial system and then the kidneys for excretion. However, several studies (15–17) have indicated that contrast medium–induced AKI rates after IV administration are actually similar to those seen after IA administration. In addition, a recent retrospective report from the Mayo Clinic (18) found that a greater mortality rate was associated with IV contrast medium–induced AKI compared with IA contrast medium–induced AKI. The present study offered an opportunity to compare the incidence of contrast medium–induced AKI (defined as a serum creatinine level increase of ⱖ 25% vs baseline at 24 h after administration) between IV administration of iodixanol for CT angiography and IA injection of iodixanol or LOCM for DSA in the same population with suspected PAOD. The study data demonstrated that the overall incidences of contrast medium–induced AKI were 7.6% and 8.7%, respectively, for IV and IA contrast agent administration. The difference between the incidences of contrast medium–induced AKI after IV and IA administration of contrast agent was not statistically significant. This confirms some findings that the occurrence of contrast medium–induced AKI has no association with the injection route of iodinated contrast medium. In a subset analysis, we also found that, among patients who received iodixanol for both the IV and IA administration, there was a comparable incidence of AKI (7% vs 6%), despite the potential provocation associated with the IV contrast agent being administered first, which, in theory, could increase the risk of AKI in the second procedure. A potential explanation for this is that the 3-day washout period between procedures in the study design was sufficient to eliminate the carryover effect from the contrast agent administration in the first procedure. On the other hand, the incidence of contrast medium–induced AKI tended to be lower among patients who received an IV administration of iodixanol for CT angiography compared with those who received IA administration of LOCM for IA DSA (7% vs 14%), but this difference did not reach statistical significance. Another analysis to evaluate the potential overlap of contrast medium–induced AKI in patients during the IV and IA phases confirmed that the cases of AKI in the IA
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DSA phase were completely different from those in the CT angiography phase. This indicates that patients with relatively normal renal function are at very low risk for consequential contrast medium–induced AKI, and that the changes from baseline level in serum creatinine are generally transient and do not warrant avoidance of diagnostic studies that use contrast media. Analysis of the incidences of contrast medium–induced AKI in patients who received IA iodixanol versus another LOCM raises the issue that iodixanol has the potential to be a better contrast agent for IA DSA, irrespective of patient baseline risk level. The difference in incidences of contrast medium–induced AKI was statistically significant (P ⫽ .026) in favor of iodixanol (5.6%; eight of 143) versus LOCM (13.9%; 14 of 101). The difference was largely caused by injection of a single LOCM, iopamidol (14.6% [13 of 89]; P ⫽ .020). This indicates that iodixanol may have less effect on the kidneys than other contrast media, independent of baseline risk. This finding is pending further verification from prospectively designed studies There was a statistically significant difference in the mean contrast agent volume administered for CT angiography versus IA DSA. This was because the CT angiography procedure had a fixed contrast protocol and IA DSA followed routine practice at the site, which could also combine percutaneous intervention with diagnosis in the same setting. However, the maximum volume of contrast agent administered for IA DSA was more than 10 times higher than the minimum volume administered. Therefore, it is problematic to estimate the impact of volume difference on the incidence of contrast medium–induced AKI between the two procedures. The incidences of contrast medium–induced AKI after IV or IA contrast medium administration in the present study are consistent with the range of 4%– 8.5% evident in previous trials of IV administration of iodixanol (4,8 –10) and the range of 0%–21.8% in trials of IA administration that used a more rigorous serum creatinine sampling schedule in patients at high risk (1–3,5–7,11,19). However, they are relatively high in consideration that most patients in the study had normal baseline renal function and that contrast medium–induced AKI is more frequently seen in patients with renal impairment, especially when the impairment is caused by diabetic nephropathy (1–3,5–11, 20). One possible explanation for this is that some normal fluctuation of serum creatinine values might have caused overestimation of contrast medium–induced AKI. To ascertain the level of “background noise” that might be responsible for the incidence of contrast medium–induced AKI in this study, we specifically analyzed serum creatinine change versus baseline and categorized cases with at least a 25% decrease, less than 25% change, and at least a 25% increase. We found that approximately 90% of patients had less than a 25% fluctuation in serum creatinine level. Fewer than 3% of patients had a 25% or greater decrease in serum creatinine value compared with baseline. These findings are consistent with the recent suggestion by Newhouse and colleagues
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(21) that some of contrast medium–induced AKI may be caused by normal serum creatinine variation irrespective of contrast agent administration. In addition, Bruce and colleagues (22) also found, in a retrospective study of 11,588 patients undergoing contrast-enhanced CT or noncontrast CT, that the incidence of contrast medium–induced AKI in the noncontrast group was 5.9%, suggesting the aforementioned background noise. However, more than 7% of patients in the present study experienced an increase of serum creatinine of at least 25% versus baseline measurement. We believe this difference of more than 4% between increase and decrease of serum creatinine level represents the true incidence of contrast medium– induced AKI in this population of patients with relatively normal renal function. There are limitations associated with the present study. First, it is a post-hoc report of renal safety data collected during a trial to compare the efficacy of CT angiography versus IA DSA for evaluation of PAOD. The CT angiography procedure followed a strict protocol whereas the IA DSA procedure was conducted according to the standards of practice at each site, which represents the reality of clinical practice rather than the controlled environment of a clinical trial. Patients were not randomized to receive iodixanol or LOCM during the IA DSA procedure. The analyses of contrast medium–induced AKI were planned and conducted after the completion of the study, and therefore no power calculations were performed with respect to the incidence of contrast medium–induced AKI. Second, serum creatinine samples were collected only at baseline and 24 hours ⫾ 4 after administration, and any cases of contrast medium–induced AKI that may have developed after 24 hours would not have been captured. In addition, serum creatinine measurement is known to have limitations in accurately measuring renal function because it is influenced greatly by the patient’s sex, muscle mass, nutritional status, and age. Use of estimated glomerular filtration rate to assess renal function has been suggested by medical societies to address these limitations (23). However, depending on the different mathematical formulas used to measure estimated glomerular filtration rate, the results may vary considerably. Currently, there is no recognized definition of the magnitude of change of estimated glomerular filtration rate in relation to AKI after administration of a contrast agent. Third, although the hydration protocol was provided to all investigator sites, the actual hydration data for individual patients were not collected, and therefore no correlation could be assessed between cases of contrast medium–induced AKI and hydration status. Potential discretionary hydration may have impacted the relevance of the study results. Finally, the higher volume of contrast agent administered during IA procedures might have been responsible for the slightly higher incidence of contrast medium–induced AKI attributable to the IA route than to the IV route. Consequently, we conclude that the incidence of contrast medium–induced AKI is not significantly differ-
ent between IV administration of iodixanol for CT angiography and IA administration of iodinated contrast media in patients with suspected PAOD but relatively normal renal function. Further prospective study is warranted to clarify the potential effects of contrast agent volume on the route of administration and to examine the trend of higher incidences of contrast medium–induced AKI with LOCM in IA DSA compared with IV iodixanol in CT angiography.
ACKNOWLEDGMENTS The authors thank the Iodixanol Peripheral CT Angiography Study Investigator Panel (sites that enrolled 10 or more patients are marked by an asterisk): Raye Bellinger, MD, Sacramento, CA*; Layne Yonehiro, MD, Pensacola, FL*; David S. Lu, MD, Los Angeles, CA*; Frederick Weiland, MD, Sacramento, CA*; Wilfrido Castaneda-Zuniga, MD, New Orleans, LA*; J. Kevin Smith, MD, Birmingham, AL*; Joseph Andriole, MD, Orlando, FL*; Patrick Cambier, MD; Safety Harbor, FL; Kenneth Murphy, MD, Syracuse, NY; Albert Sam II, MD, Baton Rouge, LA; John Nosher, MD, New Brunswick, NJ: John Colleran, DO, St. Petersburg, FL; Steven Rose, MD, San Diego, CA; H. Paul Singh, MD, Grand Rapids, MI; Andrew Benko, MD, Fleurimont, QC, Canada; John Reid, MD, Vancouver, BC, Canada; Stephan Wicky, MD, Boston, MA; Riyaz Bashir, MD, Toledo, OH; Linda Harris, MD, Buffalo, NY; Kenneth Johnson, MD, Dallas, TX; Gregory Mishkel, MD, Springfield, IL; Steven Brantley, MD, Marietta, GA; Srinivasa Prasad, MD, San Antonio, TX; Mark Sands, MD, Cleveland, OH; Laurence Needleman, MD, Philadelphia, PA; Tara Catanzano, MD, New Haven, CT; Robert Beasley, MD, Miami, FL; Huger Richardson, MD, Columbia, SC; and Dennis Kay, MD, New Orleans, LA.
REFERENCES 1. Chalmers N, Jackson RW. Comparison of iodixanol and iohexol in renal impairment. Br J Radiol 1999; 72:701–703. 2. Aspelin P, Aubry P, Fransson SG, Strasser R, Willenbrock R, Berg KJ; NEPHRIC Study Investigators. Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med 2003; 348:491– 499. 3. Jo SH, Youn TJ, Koo BK, et al. Renal toxicity evaluation and comparison between Visipaque (iodixanol) and Hexabrix (ioxaglate) in patients with renal insufficiency undergoing coronary angiography. The RECOVER study: a randomized controlled trial. J Am Coll Cardiol 2006; 48:924 –930. 4. Nguyen S, Suranyi P, Ravenel J, et al. Iso-osmolality versus low-osmolality iodinated contrast medium at intravenous contrast-enhanced CT: effect on kidney function. Radiology 2008; 248:97–105. 5. Nie B, Cheng WJ, Li YF, et al. A prospective, double-blind, randomized, controlled trial on the efficacy and cardiorenal safety of iodixanol vs. iopromide in patients with chronic kidney disease undergoing coronary angiography with or without percutaneous coronary intervention. Cathet Cardiovasc Interv 2008; 72:958 –965. 6. Rudnick MR, Davidson C, Laskey W, Stafford JL, Sherwin PF; VALOR Trial Investigators. Nephrotoxicity of iodixanol versus ioversol in patients with chronic kidney disease: the Vispaque Angiography/Interventions with Laboratory Outcomes in Renal Insufficiency (VALOR) trial. Am J Heart 2008; 156:776 –782.
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7. Hardiek KJ, Katholi RE, Robbs RS, Katholi CE. Renal effects of contrast media in diabetic patients undergoing diagnostic or interventional coronary angiography. J Diabetes Complications 2008; 22:171–177. 8. Barrett BJ, Katzberg RW, Thomsen HS, et al. Contrast-induced nephropathy in patients with chronic kidney disease undergoing computed tomography: a double-blind comparison of iodixanol and iopamidol. Invest Radiol 2006; 41:815– 821. 9. Kuhn MJ, Chen N, Sahani DV, et al. The PREDICT study: a randomized double-blind comparison of contrast-induced nephropathy after low- or isoosmolar contrast agent exposure. AJR Am J Roentgenol 2008; 191:151–157. 10. Thomsen HS, Morcos SK, Erley CM, et al. The ACTIVE trial: comparison of the effects on renal function of iomeprol-400 and iodixanol-320 in patients with chronic kidney disease undergoing abdominal computed tomography. Invest Radiol 2008; 43:170 –178. 11. Solomon RJ, Natarajan MK, Doucet S, et al. Cardiac angiography in renally impaired patients (CARE) study: a randomized double-blind trial of contrast-induced nephropathy in patients with chronic kidney disease. Circulation 2007; 115:3189 –3196. 12. Koelemay MJW, Nederkoorn PJ, Reitsma JB, Majoie CB. Systematic review of computed tomographic angiography for assessment of carotid artery disease. Stroke 2004; 35:2306 –2312. 13. Heijenbrok-Kal MH, Kock MCJM, Hunink MGM. Lower extremity arterial disease: multidetector CT angiography meta-analysis. Radiology 2007; 245:433– 439. 14. Sun Z. Diagnostic accuracy of multisclice CT angiography in peripheral arterial disease. J Vasc Interv Radiol 2006; 17:1915–1921.
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15. 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. 16. Mitchell AM, Kline JA. Contrast nephropathy following computed tomography angiography of the chest for pulmonary embolism in the emergency department. J Thromb Haemost 2007; 5:50 –54. 17. Polena S, Yang S, Alam R, et al. Nephropathy in critically ill patients without preexisting renal disease. Proc West Pharmacol Soc 2008; 48: 134 –135. 18. From AM, Bartholmai BJ, Williams AW, Cha SS, McDonald FS. Mortality associated with nephropathy after radiographic contrast exposure. Mayo Clin Proc 2008; 83:1095–1100. 19. Juergens CP, Winter JP, Nguyen-Do P, et al. Nephrotoxic effects of iodixanol and iopromide in patients with abnormal renal function receiving N-acetylcysteine and hydration before coronary angiography and intervention: a randomized trial. Intern Med J 2008; 39:25–31. 20. Katzberg RW, Haller C. Contrast-induced nephrotoxicity: clinical landscape. Kidney Int Suppl 2006; 100(Suppl):S3–S7. 21. Newhouse JH, Kho D, Rao QA, Starren J. Frequency of serum creatinine changes in the absence of iodinated contrast material: implications for studies of contrast nephrotoxicity. AJR Am J Roentgenol 2008; 191:376 –382. 22. Bruce RJ, Djamali A, Shinki K, et al. Background fluctuation of kidney function versus contrast-induced nephrotoxicity. AJR Am J Roentgenol 2009; 192:711–718. 23. American College of Radiology. ACR Manual on Contrast Media, version 7. Reston, VA: ACR, 2010.
Contrast Medium–Induced Acute Kidney Injury: Comparison of Intravenous and Intraarterial Administration of Iodinated Contrast Medium Ronald P. Karlsberg, MD, Suhail Y. Dohad, MD, and Rubin Sheng, MD, MPH, for the Iodixanol Peripheral Computed Tomographic Angiography Study Investigator Panel
ABSTRACT Purpose: To compare the incidence of contrast medium–induced acute kidney injury (AKI) after intravenous (IV) administration of iodixanol for computed tomographic (CT) angiography versus intraarterial (IA) injection of iodixanol or low osmolar contrast medium (LOCM) for digital subtraction angiography (DSA) within the same population suspected of peripheral arterial occlusive disease (PAOD). Materials and Methods: CT angiography was performed with IV iodixanol 320 mgI/mL. After a washout period of 3–14 days, DSA was performed with IA iodixanol or LOCM. Serum creatinine was measured at baseline and 24 hours after administration. Contrast medium–induced AKI was defined by a serum creatinine increase of at least 25% versus baseline at 24 hours. Data were analyzed with 2 statistics. Results: Mean baseline serum creatinine values were comparable between CT angiography with IV contrast medium and DSA with IA contrast medium (93.3 mol/L ⫾ 52.92 vs 92.8 mol/L ⫾ 61.70). The incidence of AKI for CT angiography after IV iodixanol administration was 7.6% (20 of 264), which was not statistically different than the 8.7% incidence (22 of 253) for DSA with IA iodixanol or LOCM (P ⫽ .641). In the 143 patients who received only iodixanol for both procedures, incidences of contrast medium–induced AKI were comparable after IV (7.0%) and IA (5.6%) administration (P ⫽ .626). Conclusions: The rates of contrast medium–induced AKI are not statistically different between IV iodixanol for CT angiography and IA iodixanol or another LOCM for DSA in the same population with suspected PAOD.
ABBREVIATIONS AKI ⫽ acute kidney injury, DSA ⫽ digital subtraction angiography, IA ⫽ intraarterial, IV ⫽ intravenous, LOCM ⫽ low osmolar contrast medium, PAOD ⫽ peripheral arterial occlusive disease
Iodinated contrast agent administration during radiographic examinations is known to cause acute kidney injury (AKI), particularly when patients have one or more risk factors
From the Cardiovascular Research Institute of Southern California (R.P.K., S.Y.D.), Cedars Sinai Heart Institute, Los Angeles, California; and Clinical Research and Development (R.S.), GE Healthcare Medical Diagnostics, Princeton, New Jersey. Received July 19, 2010; final revision received March 14, 2011; accepted March 20, 2011. Address correspondence to R.P.K., 414 N. Camden Dr., Beverly Hills, CA 90024; E-mail: [email protected] R.S. is a paid employee of GE Healthcare Medical Diagnostics (Princeton, New Jersey), which organized and conducted the study. R.P.K. and S.Y.D. were investigators in the trial. Neither of the other authors has identified a conflict of interest. © SIR, 2011 J Vasc Interv Radiol 2011; 22:1159 –1165 DOI: 10.1016/j.jvir.2011.03.020
such as renal insufficiency, dehydration, diabetes mellitus, congestive heart failure, age older than 75 years, use of nonsteroidal antiinflammatory drugs, or history of severe cardiovascular disease. The reported incidence of contrast medium–induced AKI varies widely in the literature. In several prospective, randomized clinical trials (1–7), the incidence of contrast medium–induced AKI after administration of iodixanol was significantly lower than that associated with low osmolar contrast media (LOCM) in patients at high risk with baseline serum creatinine values of 1.5 mg/dL or higher. However, in several other studies (8 –11), incidences of contrast medium–induced AKI were similar after administration of iodixanol versus LOCM. Although the different results from these clinical trials may be associated with a number of factors (ie, contrast medium– induced AKI definitions, subject population, risk factors, or standardization of blood sample collection after contrast
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medium administration), the controversy of iodixanol versus LOCM use with respect to the occurrence of AKI remains incompletely defined. Peripheral arterial occlusive disease (PAOD) is a slowly progressing disease that primarily affects the elderly population. When the disease is advanced to the stage of limiting lifestyle, a revascularization procedure may be warranted. Intraarterial (IA) digital subtraction angiography (DSA) was conventionally performed to accurately depict and characterize the level, multiplicity, and severity of a stenosis before a percutaneous intervention or surgery. However, noninvasive imaging techniques, such as intravenous (IV) contrast-enhanced computed tomographic (CT) angiography, have been increasingly used to avoid an invasive procedure, which is associated with higher risks and costs. Studies have been conducted in recent years to compare the diagnostic accuracy of CT angiography with IA DSA in patients with carotid and lower-extremity arterial disease (12–14). The results indicate that CT angiography is an accurate modality with high diagnostic value. The IA DSA and IV CT angiography procedures require administration of iodinated contrast media, which may cause AKI. However, it is unsure whether IV administration of contrast media will result in less AKI than IA injection because of extended circulation and dilution of the contrast medium in the bloodstream before it reaches the arterial system and kidneys. The purpose of the present report is to directly compare the incidence of contrast medium–induced AKI between IV administration of iodixanol for contrast-enhanced CT angiography and subsequent IA administration of iodixanol or LOCM for DSA in the same population of patients with suspected PAOD who were enrolled in this prospective, multicenter study evaluating the diagnostic accuracy of CT angiography.
tissue loss (dry necrosis only) located at the lower calf or foot region with a femoral and popliteal pulse but no pedal pulse (ie, Fontaine stage III–IV) or (iii) ankle-brachial index of less than 0.7 indicative of infragenicular arterial disease, measured no more than 3 months before inclusion in the study. Patients with a history of type I diabetes mellitus, allergies to any iodinated contrast agent, cellulitis, and/or acute nondry necrosis on either lower leg requiring immediate antibiotic therapy, and those with a clinically active, serious, or life-threatening disease or a life expectancy of less than 3 months, were excluded from the study. Patients who (i) were pregnant or lactating, (ii) were being evaluated for the patency of a previously created surgical peripheral bypass surgery graft, (iii) presented with acute limb ischemia or arterioembolic disease, (iv) were scheduled to undergo a surgical or nonsurgical intervention, (v) were expecting a change of PAOD conditions between the CT angiography and IA DSA procedures, or (vi) were unable or unwilling to discontinue metformin therapy at the time of the study procedure were also excluded from the study.
MATERIALS AND METHODS This was a retrospective evaluation of data on contrast medium–induced AKI from an open-label, multicenter study. The study was originally designed to assess efficacy of IV CT angiography in patients who were clinically indicated to undergo an IA DSA procedure with or without percutaneous intervention based on medical need.
Study Patients The study population consisted of adults (age ⱖ 18 y) with suspected PAOD referred for IA DSA of the abdominal aorta and/or bilateral iliac and lower-extremity arteries. PAOD was suspected in the setting of (i) intermittent claudication with a walking distance less than 200 meters (ie, Fontaine stage IIb). Claudication was located in the gluteal/ thigh region with weak or absent femoral and distal pulses or in the calf muscle with weak or absent popliteal pulse indicative of supragenicular arterial disease. PAOD was also suspected in the setting of (ii) rest pain and/or ischemic
Study Procedures Because dehydration has been shown to increase the risk of contrast medium–induced AKI, each subject was well hydrated. A standard hydration protocol was used in this study, before and after IV CT angiography or IA DSA procedures, according to the following regimens. (i) Oral fluid intake (ⱖ 1–2 L recommended) was encouraged, but solid food was to be avoided for 3 hours before the CT angiography procedure and for at least 6 hours before the IA DSA procedure. (ii) IV hydration, preferably with a minimum of 800 –1,000 mL normal-strength saline solution (0.9%) was recommended to start at least 4 hours before, and continuing for at least 6 hours after, each procedure. The administration flow rate was 100 –125 mL/h or 1–2 mL/kg body weight per hour depending on the subject’s condition and total duration of IV hydration given. CT angiography of the abdominal aorta and runoff was initially performed with IV administration of iodixanol 320 mgI/mL (Visipaque; GE Healthcare; Princeton, New Jersey) via a power injector at a flow rate of 3– 4 mL/s. A total dose of approximately 170 –200 mL per patient was administered. Safety evaluation included monitoring of injection site reactions, electrocardiography, vital signs, and physical examination changes, and the occurrence of adverse events. Serum creatinine measurements were part of the clinical laboratory evaluations performed at baseline and 24 hours ⫾ 4 after the administration of iodixanol. If necessary, additional hydration was given after the CT angiography procedure at the discretion of the investigator. Other procedure-related medications were administered for renal protection at the discretion of the clinicians or according to the standard of practice at the study site. After a washout period of 3–14 days after the CT angiography procedure, IA DSA was performed according to the normal study site standard procedure for all patients
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Figure 1.
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Study design. (Available in color online at www.jvir.org.)
(Fig 1). The selection of the contrast agent for the IA DSA procedure, volume of contrast medium administered, hydration regimen before and after the IA DSA procedure, and use of N-acetylcysteine were consistent with the normal practice of the catheterization laboratory at the study site. A nonselective IA DSA examination was performed in every patient, with the catheter tip located above both renal arteries. The image coverage range was from the level of the renal artery down to the level of the ankle. Additional selective images could be obtained at the discretion of the clinician. Percutaneous intervention could be performed at the same sitting based on the patient’s medical need. Similarly, serum creatinine measurements were obtained before the IA DSA procedure and 24 hours ⫾ 4 after administration of the contrast agent. The safety assessments were the same as those performed for CT angiography. The study protocol was approved by the institutional review board or independent ethics committee at each study site. Written informed consent was obtained from all patients before any study procedure began. The study was conducted in full accordance with the Declaration of Helsinki, the Good Clinical Practice Consolidated Guideline approved by the International Conference on Harmonization, and any applicable national and local laws and regulations.
Statistical Methods Demographic data and the incidence of contrast medium– induced AKI were summarized by using descriptive statistics. Contrast medium–induced AKI was defined as a laboratory-measured serum creatinine increase from baseline of at least 25% at 24 hours after administration of the iodinated contrast agent. Only patients with serum creatinine measurements at baseline and 24 hours after administration were included in the analysis. In the IA DSA phase, patients also had to have the specific contrast agent recorded to be included in the analysis. Patients who received iodixanol and one type of LOCM in the same IA DSA procedure were removed from the analysis because they could not be categorized in either group. Statistical comparisons were made between (i) IV iodixanol for CT angiography and IA iodixanol or LOCM for DSA based on the occurrence of AKI and the average volume of contrast agent administered during each procedure; (ii) IV iodixanol for CT angiography and IA iodixanol for DSA based on the occurrence of AKI; (iii) IV iodixanol for CT angiography and IA LOCM for DSA based on the occurrence of AKI;
Table 1. Demographic Characteristics
Variable Sex Female Male Race Asian Black Caucasian Hispanic/Latino Other Age (y) Mean ⫾ SD Range Median
CT Angiography, n ⴝ 264
IA DSA, n ⴝ 253
96 (36.4) 168 (63.6)
93 (36.8) 160 (63.2)
2 (0.8) 42 (15.9) 204 (77.3) 14 (5.3) 2 (0.8)
2 (0.8) 40 (15.8) 197 (77.9) 12 (4.7) 2 (0.8)
64.7 ⫾ 10.93 39.0–88.0 65.0
64.4 ⫾ 10.81 39.0–87.0 64.0
Note.—Values in parentheses are percentages. DSA ⫽ digital subtraction angiography; IA ⫽ intraarterial.
and (iv) IA iodixanol vs IA LOCM for DSA based on the occurrence of AKI. 2 statistics were used for categoric variable comparisons. A P value lower than .05 was considered to represent a statistically significant difference. Additionally, changes in serum creatinine level of 25% or more compared with baseline value were analyzed, along with whether patients with AKI following CT angiography with IV contrast medium overlapped with those with AKI following DSA with IA contrast medium.
RESULTS A total of 271 patients received iodixanol for CT angiography. Of these, 263 patients underwent the DSA procedure with IA administration of iodixanol or the study center– specific LOCM. Complete serum creatinine levels were available for 264 of the 271 patients who underwent CT angiography, and for 253 of the 263 patients who underwent DSA with IA contrast medium. Demographic characteristics were similar for patients treated with IV iodixanol in the CT angiography phase and IA iodixanol or LOCM in the DSA phase (Table 1). Among patients who underwent DSA with IA contrast medium, 147 (57.4%) received iodixanol, 103 (40.7%) received LOCM (iopamidol [Bracco, Princeton, New Jersey], n ⫽ 91; ioversol [Mallinckrodt, St. Louis,
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Table 2. Summary of Serum Creatinine Outcomes
Variable Baseline (mol/L) Mean ⫾ SD Median Range 24-Hour follow-up (mol/L) Mean ⫾ SD Median Range Difference vs baseline (mol/L) Mean ⫾ SD Median Range Change from baseline (n) Decrease ⱖ 25% Change ⬍ 25% Increase ⱖ 25
CT Angiography, n ⴝ 264
IA DSA, n ⴝ 253
93.3 ⫾ 52.92 80.0 27.0–513
92.8 ⫾ 61.70 80.0 18.0–628
96.2 ⫾ 51.58 88.0 18.0–460
91.3 ⫾ 36.31 80.0 18.0–318
2.9 ⫾ 26.99 0 ⫺301 to 195
⫺1.5 ⫾ 41.33 0 ⫺531 to 44.0
5 (1.9) 239 (90.5) 20 (7.6)
7 (2.8) 224 (88.5) 22 (8.7)
Figure 2. Incidence of AKI following IV CT angiography and IA DSA: 7.6% (20 of 264) of patients developed AKI following IV iodixanol for CT angiography and 8.7% (22 of 253) of patients developed AKI following IA iodixanol or LOCM for DSA. The difference in incidence was not statistically significant (P ⫽ .641). (Available in color online at www.jvir.org.)
Note.—Values in parentheses are percentages. DSA ⫽ digital subtraction angiography; IA ⫽ intraarterial.
Missouri], n ⫽ 7; iohexol [GE Healthcare], n ⫽ 3; and iopromide [Berlex, Montville, New Jersey], n ⫽ 2), and three (1.9%) received iodixanol and one other LOCM. A total of 143 patients who received iodixanol and 101 patients who received LOCM in the IA DSA phase had complete serum creatinine measurements for the CT angiography and IA DSA procedures. The contrast agent administered to patients undergoing CT angiography was determined by imaging time for each patient to cover the scan range from the level of the renal artery to the ankle level as specified by the protocol. The mean volume of contrast medium administered was 170 mL ⫾ 18 (range, 120 –200 mL). The volume of contrast agent administered during the IA DSA procedure was determined by the standard of practice at each study site and procedural requirements. The mean volume administered was 235 mL ⫾ 99 (range, 38 –589 mL) among the 250 patients who had the volume administered recorded. The variation in the range of volume administered reflected selective placement of catheters for IA DSA in some patients and percutaneous interventional procedures in other patients. The difference in mean contrast agent volume between the two procedures was statistically significant (P ⬍ .001). The patient population had relatively normal baseline renal function, as indicated by mean serum creatinine levels of 93.3 mol/L ⫾ 52.92 (SD) at the baseline observation before CT angiography and 92.8 mol/L ⫾ 61.70 at the baseline observation before IA DSA (Table 2). Contrast medium–induced AKI developed in 7.6% of patients after IV iodixanol for CT angiography (20 of 264) and 8.7% of patients after IA administration of iodixanol or LOCM for
Figure 3. Incidence of AKI following IV iodixanol for CT angiography versus IA iodixanol for DSA. Among the 143 patients who received iodixanol and had complete serum creatinine measurements in both study phases, AKI developed in 10 patients (7.0%) following IV contrast medium administration for CT angiography, compared with eight patients (5.6%) following IA contrast medium administration for DSA. The difference in incidence was not statistically significant (P ⫽ .626). (Available in color online at www.jvir.org.)
IA DSA (22 of 253). The difference was not statistically significant (P ⫽ .641; Fig 2). Among patients who received iodixanol for both procedures, the incidence of AKI was comparable between IV administration for CT angiography and IA administration for DSA (7% [10 of 143] vs 5.6% [eight of 143]; P ⫽ .626; Fig 3). Patients who received IV iodixanol for CT angiography had a lower incidence of AKI (6.9%; seven of 101) compared with those who received IA LOCM for the DSA procedure (13.9%; 14 of 101), but this difference did not reach statistical significance (P ⫽ .107). Further analysis showed that there was no overlap of patients with a 25% increase in serum creatinine level versus baseline between the IA DSA phase and the CT angiography phase. Approximately 90% of patients had a serum creatinine level change of less than 25% versus baseline. In addition to those with an increase of 25% or more in serum creatinine level, fewer than 3% of patients
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showed at least a 25% decrease from baseline level. In patients who received IA iodixanol, the incidence of AKI was 5.6% (eight of 143), compared with an incidence of 13.9% (14 of 101) for those who received IA LOCM (P ⫽ .026). This statistical difference is largely a result of injection of a single LOCM, iopamidol (14.6% [13 of 89]; P ⫽ .020).
DISCUSSION IV administration of contrast agent, in theory, is associated with a lower incidence of AKI compared with IA administration, as a result of the longer circulation route and increased dilution of contrast agent in the bloodstream before it can reach the arterial system and then the kidneys for excretion. However, several studies (15–17) have indicated that contrast medium–induced AKI rates after IV administration are actually similar to those seen after IA administration. In addition, a recent retrospective report from the Mayo Clinic (18) found that a greater mortality rate was associated with IV contrast medium–induced AKI compared with IA contrast medium–induced AKI. The present study offered an opportunity to compare the incidence of contrast medium–induced AKI (defined as a serum creatinine level increase of ⱖ 25% vs baseline at 24 h after administration) between IV administration of iodixanol for CT angiography and IA injection of iodixanol or LOCM for DSA in the same population with suspected PAOD. The study data demonstrated that the overall incidences of contrast medium–induced AKI were 7.6% and 8.7%, respectively, for IV and IA contrast agent administration. The difference between the incidences of contrast medium–induced AKI after IV and IA administration of contrast agent was not statistically significant. This confirms some findings that the occurrence of contrast medium–induced AKI has no association with the injection route of iodinated contrast medium. In a subset analysis, we also found that, among patients who received iodixanol for both the IV and IA administration, there was a comparable incidence of AKI (7% vs 6%), despite the potential provocation associated with the IV contrast agent being administered first, which, in theory, could increase the risk of AKI in the second procedure. A potential explanation for this is that the 3-day washout period between procedures in the study design was sufficient to eliminate the carryover effect from the contrast agent administration in the first procedure. On the other hand, the incidence of contrast medium–induced AKI tended to be lower among patients who received an IV administration of iodixanol for CT angiography compared with those who received IA administration of LOCM for IA DSA (7% vs 14%), but this difference did not reach statistical significance. Another analysis to evaluate the potential overlap of contrast medium–induced AKI in patients during the IV and IA phases confirmed that the cases of AKI in the IA
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DSA phase were completely different from those in the CT angiography phase. This indicates that patients with relatively normal renal function are at very low risk for consequential contrast medium–induced AKI, and that the changes from baseline level in serum creatinine are generally transient and do not warrant avoidance of diagnostic studies that use contrast media. Analysis of the incidences of contrast medium–induced AKI in patients who received IA iodixanol versus another LOCM raises the issue that iodixanol has the potential to be a better contrast agent for IA DSA, irrespective of patient baseline risk level. The difference in incidences of contrast medium–induced AKI was statistically significant (P ⫽ .026) in favor of iodixanol (5.6%; eight of 143) versus LOCM (13.9%; 14 of 101). The difference was largely caused by injection of a single LOCM, iopamidol (14.6% [13 of 89]; P ⫽ .020). This indicates that iodixanol may have less effect on the kidneys than other contrast media, independent of baseline risk. This finding is pending further verification from prospectively designed studies There was a statistically significant difference in the mean contrast agent volume administered for CT angiography versus IA DSA. This was because the CT angiography procedure had a fixed contrast protocol and IA DSA followed routine practice at the site, which could also combine percutaneous intervention with diagnosis in the same setting. However, the maximum volume of contrast agent administered for IA DSA was more than 10 times higher than the minimum volume administered. Therefore, it is problematic to estimate the impact of volume difference on the incidence of contrast medium–induced AKI between the two procedures. The incidences of contrast medium–induced AKI after IV or IA contrast medium administration in the present study are consistent with the range of 4%– 8.5% evident in previous trials of IV administration of iodixanol (4,8 –10) and the range of 0%–21.8% in trials of IA administration that used a more rigorous serum creatinine sampling schedule in patients at high risk (1–3,5–7,11,19). However, they are relatively high in consideration that most patients in the study had normal baseline renal function and that contrast medium–induced AKI is more frequently seen in patients with renal impairment, especially when the impairment is caused by diabetic nephropathy (1–3,5–11, 20). One possible explanation for this is that some normal fluctuation of serum creatinine values might have caused overestimation of contrast medium–induced AKI. To ascertain the level of “background noise” that might be responsible for the incidence of contrast medium–induced AKI in this study, we specifically analyzed serum creatinine change versus baseline and categorized cases with at least a 25% decrease, less than 25% change, and at least a 25% increase. We found that approximately 90% of patients had less than a 25% fluctuation in serum creatinine level. Fewer than 3% of patients had a 25% or greater decrease in serum creatinine value compared with baseline. These findings are consistent with the recent suggestion by Newhouse and colleagues
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(21) that some of contrast medium–induced AKI may be caused by normal serum creatinine variation irrespective of contrast agent administration. In addition, Bruce and colleagues (22) also found, in a retrospective study of 11,588 patients undergoing contrast-enhanced CT or noncontrast CT, that the incidence of contrast medium–induced AKI in the noncontrast group was 5.9%, suggesting the aforementioned background noise. However, more than 7% of patients in the present study experienced an increase of serum creatinine of at least 25% versus baseline measurement. We believe this difference of more than 4% between increase and decrease of serum creatinine level represents the true incidence of contrast medium– induced AKI in this population of patients with relatively normal renal function. There are limitations associated with the present study. First, it is a post-hoc report of renal safety data collected during a trial to compare the efficacy of CT angiography versus IA DSA for evaluation of PAOD. The CT angiography procedure followed a strict protocol whereas the IA DSA procedure was conducted according to the standards of practice at each site, which represents the reality of clinical practice rather than the controlled environment of a clinical trial. Patients were not randomized to receive iodixanol or LOCM during the IA DSA procedure. The analyses of contrast medium–induced AKI were planned and conducted after the completion of the study, and therefore no power calculations were performed with respect to the incidence of contrast medium–induced AKI. Second, serum creatinine samples were collected only at baseline and 24 hours ⫾ 4 after administration, and any cases of contrast medium–induced AKI that may have developed after 24 hours would not have been captured. In addition, serum creatinine measurement is known to have limitations in accurately measuring renal function because it is influenced greatly by the patient’s sex, muscle mass, nutritional status, and age. Use of estimated glomerular filtration rate to assess renal function has been suggested by medical societies to address these limitations (23). However, depending on the different mathematical formulas used to measure estimated glomerular filtration rate, the results may vary considerably. Currently, there is no recognized definition of the magnitude of change of estimated glomerular filtration rate in relation to AKI after administration of a contrast agent. Third, although the hydration protocol was provided to all investigator sites, the actual hydration data for individual patients were not collected, and therefore no correlation could be assessed between cases of contrast medium–induced AKI and hydration status. Potential discretionary hydration may have impacted the relevance of the study results. Finally, the higher volume of contrast agent administered during IA procedures might have been responsible for the slightly higher incidence of contrast medium–induced AKI attributable to the IA route than to the IV route. Consequently, we conclude that the incidence of contrast medium–induced AKI is not significantly differ-
ent between IV administration of iodixanol for CT angiography and IA administration of iodinated contrast media in patients with suspected PAOD but relatively normal renal function. Further prospective study is warranted to clarify the potential effects of contrast agent volume on the route of administration and to examine the trend of higher incidences of contrast medium–induced AKI with LOCM in IA DSA compared with IV iodixanol in CT angiography.
ACKNOWLEDGMENTS The authors thank the Iodixanol Peripheral CT Angiography Study Investigator Panel (sites that enrolled 10 or more patients are marked by an asterisk): Raye Bellinger, MD, Sacramento, CA*; Layne Yonehiro, MD, Pensacola, FL*; David S. Lu, MD, Los Angeles, CA*; Frederick Weiland, MD, Sacramento, CA*; Wilfrido Castaneda-Zuniga, MD, New Orleans, LA*; J. Kevin Smith, MD, Birmingham, AL*; Joseph Andriole, MD, Orlando, FL*; Patrick Cambier, MD; Safety Harbor, FL; Kenneth Murphy, MD, Syracuse, NY; Albert Sam II, MD, Baton Rouge, LA; John Nosher, MD, New Brunswick, NJ: John Colleran, DO, St. Petersburg, FL; Steven Rose, MD, San Diego, CA; H. Paul Singh, MD, Grand Rapids, MI; Andrew Benko, MD, Fleurimont, QC, Canada; John Reid, MD, Vancouver, BC, Canada; Stephan Wicky, MD, Boston, MA; Riyaz Bashir, MD, Toledo, OH; Linda Harris, MD, Buffalo, NY; Kenneth Johnson, MD, Dallas, TX; Gregory Mishkel, MD, Springfield, IL; Steven Brantley, MD, Marietta, GA; Srinivasa Prasad, MD, San Antonio, TX; Mark Sands, MD, Cleveland, OH; Laurence Needleman, MD, Philadelphia, PA; Tara Catanzano, MD, New Haven, CT; Robert Beasley, MD, Miami, FL; Huger Richardson, MD, Columbia, SC; and Dennis Kay, MD, New Orleans, LA.
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