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Published online before print December 22, 2004, 10.1148/radiol.2342040023
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(Radiology 2005;234:399-408.)
© RSNA, 2004

Contrast Media

Contrast-enhanced MR Angiography of the Renal Arteries: Blinded Multicenter Crossover Comparison of Gadobenate Dimeglumine and Gadopentetate Dimeglumine1

Mathias Prokop, MD, Günther Schneider, MD, Angelo Vanzulli, MD, Mathias Goyen, MD, Stefan G. Ruehm, MD, Philippe Douek, MD, Massimo Daprà, PhD, Gianpaolo Pirovano, MD, Miles A. Kirchin, PhD and Alberto Spinazzi, MD

1 From the Department of Radiology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3508 GA, the Netherlands (M.P.); Department of Diagnostic Radiology, University Hospital, Homburg, Germany (G.S.); Department of Radiology, Ospedale Niguarda Ca’ Granda, Milan, Italy (A.V.); Department of Diagnostic and Interventional Radiology, University Hospital, Essen, Germany (M.G., S.G.R.); Department of Diagnostic and Therapeutic Imaging, Hôpital Cardio-Vasculaire, Lyon, France (P.D.); Worldwide Medical Affairs, Bracco Imaging, Milan, Italy (M.D., M.A.K., A.S.); and Worldwide Medical Affairs, Bracco Diagnostics, Princeton, NJ (G.P., A.S.). Received January 6, 2004; revision requested March 4; revision received April 16; accepted May 24. Address correspondence to M.P. (e-mail: m.prokop@azu.nl).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To prospectively and intraindividually compare 0.1 mmol/kg gadobenate dimeglumine with 0.2 mmol/kg gadopentetate dimeglumine for contrast material–enhanced magnetic resonance (MR) angiography of the renal arteries.

MATERIALS AND METHODS: Institutional review board approval was granted by each of three participating centers. The study accorded with international standards for good clinical practice and Declaration of Helsinki and subsequent amendments. Patients gave written informed consent before enrollment. Patients (n = 34) underwent two MR angiographic examinations more than 48 hours but less than 12 days apart. Gadobenate dimeglumine followed by gadopentetate dimeglumine was administered in 18 patients; the order of administration was reversed in 16 patients. A 1.5-T MR imager was used with a phase-encoded three-dimensional spoiled breath-hold pulse sequence. Two blinded independent readers qualitatively assessed randomized subtracted maximum intensity projection images. A three-point scale for diagnostic quality (0, poor; 1a or 1p, moderate; and 2a or 2p, adequate [a and p refer, respectively, to absence and presence of vascular lesions]) was used to score each of nine segments of the abdominal aorta and both renal arteries (possible overall score, 18). Quantitative assessment (vessel signal-to-noise ratio [SNR], vessel-muscle contrast-to-noise ratio [CNR]) of source images was performed for regions of interest in supra-, juxta-, and infrarenal aorta segments and psoas muscle. Data were tested with analysis of variance for two-period crossover design. Interreader agreement was evaluated with Cohen {kappa} statistics.

RESULTS: No difference in mean image quality between the two contrast agents was observed; scores for gadobenate dimeglumine and gadopentetate dimeglumine were 15.15 and 15.23 for reader 1 and 16.77 and 17.01 for reader 2. The order of contrast material administration likewise produced no quality differences: readers 1 and 2 reported scores of 14.4 ± 4.2 (standard deviation) and 16.7 ± 2.3, respectively, when gadobenate dimeglumine was given first, and 15.2 ± 1.8 and 16.6 ± 1.6, respectively, when gadopentetate dimeglumine was given first. Results of quantitative evaluation showed increasing SNR and CNR with gadobenate dimeglumine in segments at progressively lower levels of the aorta, but increases in SNR and CNR at the infrarenal aorta (48.3 vs 40.6 and 44.2 vs 36.4, respectively) were not significant (P = .05 for both).

CONCLUSION: Gadobenate dimeglumine at a dose of 0.1 mmol/kg is comparable to gadopentetate dimeglumine at 0.2 mmol/kg for contrast-enhanced renal MR angiography.

© RSNA, 2004


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Contrast material–enhanced magnetic resonance (MR) angiography is widely considered one of the noninvasive methods of choice for diagnostic evaluation of the renal arteries,with numerous authors reporting sensitivity and specificity values of 90% or more for the depiction of hemodynamically significant stenoses (≥50%) with this technique in comparison with digital subtraction angiography (1–14). However, whereas the results and overall approach to imaging are often similar between studies, the dose of contrast agent used may vary widely. In the studies just cited, the dose used ranged from approximately 0.1 mmol per kilogram body weight in three studies (3,5,9) to approximately 0.15–0.30 mmol/kg in the remainder. In an early study aimed at establishing the optimum dose of gadolinium chelate for contrast-enhanced MR angiography of the renal arteries, it was determined that a dose of 0.2 mmol/kg was appropriate (15), while more-recent review articles recommend doses of 0.2–0.3 mmol/kg to achieve satisfactory image quality (16,17). The need for doses as high as 0.3 mmol/kg (approximately 60 mL for a patient with average body size), however, may greatly affect the overall examination costs, and increased costs may be a concern particularly if procedures are not adequately reimbursed.

Gadobenate dimeglumine (MultiHance; Bracco Imaging, Milan, Italy) is a gadolinium chelate that has been approved in Europe for MR imaging of the central nervous system and liver and that is being investigated for applications in MR angiography. Compared with conventional gadolinium chelates of the type used in the previously mentioned studies (1–15), gadobenate dimeglumine possesses a twofold greater T1 relaxivity when measured in human plasma at 0.47 T (9.7 L · mmol–1 · sec–1, compared with 4.3–5.0 L · mmol–1 · sec–1). This increased T1 relaxivity originates from a capacity for weak and transient interaction with serum albumin (18,19). Early intraindividual crossover studies to evaluate the potential of gadobenate dimeglumine for enhanced vascular imaging revealed significantly (P < .05) higher and longer-lasting signal intensity of the abdominal aorta with gadobenate dimeglumine than with gadopentetate dimeglumine (Magnevist; Schering, Berlin, Germany), with both contrast agents administered at the same dose and injection rate (20). In a more recent study (21) in which these agents were compared intraindividually at equal doses in the runoff vasculature, similar results revealed significantly (P < .05) greater vascular enhancement after gadobenate dimeglumine, particularly in the smaller and more distal vessels. In the renal arteries, Völk et al (22) demonstrated a significantly (P < .05) greater signal-to-noise ratio (SNR) with 0.1 mmol/kg gadobenate dimeglumine compared with 0.1 mmol/kg gadopentetate dimeglumine by using a parallel group study design, with 15 patients per group. In this same study, no substantial difference in SNR was noted between 0.05 mmol/kg gadobenate dimeglumine and 0.1 mmol/kg gadopentetate dimeglumine or between 0.1 mmol/kg gadobenate dimeglumine and 0.2 mmol/kg gadopentetate dimeglumine. Völk et al (22), however, did not use an intraindividual crossover design. Thus, the purpose of our study was to prospectively and intraindividually compare gadobenate dimeglumine at a dose of 0.1 mmol/kg with gadopentetate dimeglumine at a dose of 0.2 mmol/kg for contrast-enhanced MR angiography of the renal arteries.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
The study was a phase II randomized crossover comparison of gadobenate dimeglumine (0.1 mmol/kg) and gadopentetate dimeglumine (0.2 mmol/kg) for MR angiography of the renal arteries conducted at three centers in Europe. Institutional review board approval was granted at each center, and the study was conducted in accordance with international standards of good clinical practice and the World Medical Association Declaration of Helsinki (Helsinki, Finland, 1964) and subsequent amendments (Tokyo, Japan, 1975; Venice, Italy, 1983; Hong Kong, 1989; and Somerset West, Republic of South Africa, 1996). All patients gave written informed consent before enrollment in the study.

Patients
A total of 41 patients (20 men, 21 women) with a mean age of 59.1 years ± 13.6 (standard deviation [SD]) and age range of 23–92 years, who were known or suspected to have renal artery stenosis and who had been referred for MR angiography of the renal arteries, were enrolled in a consecutive manner at each center.

Patients were ineligible for the study if they had received an investigational drug within 30 days prior to admission to the study or any other contrast agent within 48 hours prior to administration of either of the two study agents or if they were expected to receive any other contrast agent before a 24-hour follow-up examination. Similarly, patients with class III or IV congestive heart failure according to the New York Heart Association classification or with other medical conditions or circumstances (eg, claustrophobia, hypersensitivity to gadolinium, pacemaker) that would substantially decrease our chances of obtaining reliable data were ineligible, as were women who were breast-feeding or in whom the possibility of pregnancy could not be excluded.

Eligible patients were divided prospectively into two groups to receive two contrast-enhanced MR angiographic examinations with either gadobenate dimeglumine or gadopentetate dimeglumine as the first injection. Twenty-one patients were randomized to group A, to receive 0.1 mmol/kg gadobenate dimeglumine as the first injection and 0.2 mmol/kg gadopentetate dimeglumine as the second injection, and the remaining 20 patients were randomized to group B, to receive 0.2 mmol/kg gadopentetate dimeglumine as the first injection and 0.1 mmol/kg gadobenate dimeglumine as the second injection. All 41 eligible patients received at least one injection of MR contrast agent, and all were included in an analysis of safety.

Six patients (three from group A and three from group B) prematurely terminated the study during the first MR examination, and data from these patients were excluded from the final analysis. Of the three patients excluded from group A, one patient (aged 92 years) withdrew because of physical exhaustion, one withdrew informed consent, and another withdrew because of an adverse event (mild nausea) after administration of the test bolus and prior to administration of the full study dose of gadobenate dimeglumine. The three patients excluded from group B all withdrew informed consent after administration of the first MR contrast agent (gadopentetate dimeglumine). One of these three patients withdrew consent after experiencing a number of mild adverse events that occurred after the first contrast-enhanced examination, while the other two patients simply changed their minds about continuing the study. A fourth patient from group B, who had previously undergone renal transplantation, was also excluded, because too few artery segments remained for evaluation. Comparison of the two contrast agents for contrast efficacy (ie, contrast enhancement) therefore was performed in 34 patients: 18 patients in group A (nine women with a mean age of 57.8 years ± 10.4 and age range of 49–79 years, and nine men with a mean age of 60.3 years ± 12.1 and age range of 38–81 years) and 16 patients in group B (nine women with a mean age of 54.2 years ± 18.7 and age range of 23–83 years, and seven men with a mean age of 61.6 years ± 9.7 and age range of 46–71 years). There were no significant age or sex differences between the two groups (P > .05). Although creatinine values were not available for all patients, prior medical history indicated that 11 patients in group A and six patients in group B had renal disease (renal artery stenosis in five patients; renal failure, insufficiency, and/or hypertension in six patients; and renal cyst, suspected left kidney aplasia, immunoglobulin-A nephropathy, nephritic syndrome, proteinemia, and shrunken kidney in one patient each).

MR Angiography
At each of the three participating centers, contrast-enhanced MR angiography was performed with a 1.5-T MR imaging system (Magnetom Vision [n = 22], Magnetom Symphony [n = 5], or Magnetom Sonata [n = 7]; Siemens Medical Systems, Erlangen, Germany). Each MR imaging system was equipped with a gradient of at least 20 mT/m, a phased-array surface coil, and an MR angiographic software package. Imaging in all patients was performed in the coronal plane by applying a sequential three-dimensional phase-encoded spoiled sequence during breath holding and with the following parameters: repetition time msec/echo time msec of 4.60/1.80 (Magnetom Vision), 4.00–4.80/1.65–1.80 (Magnetom Symphony), or 2.50–4.60/0.88–1.80 (Magnetom Sonata); flip angle of 30°–45° (Magnetom Vision) or 25°–45° (Magnetom Symphony and Magnetom Sonata). For each patient, the field of view was adjusted to include both kidneys, the left and right renal arteries, and the suprarenal to infrarenal abdominal aorta and was in all cases 338–500 x 350–500 mm. For most patients, the common iliac arteries were also included in the field of view. The matrix size ranged from 256 x 256 (for two of 34 patients, or one patient per group) to 174–240 x 512 (for the remaining 32 patients). Fat suppression was employed at one center for six of seven patients imaged with a Magnetom Sonata system, with which a higher gradient strength (40 mT/m) was available. The section thickness was 1.00–2.86 mm for 32 of 34 patients, with a slightly larger section thickness of 3.33 mm for the remaining two patients. A total of 28 or 32 sections were acquired in 30 of 34 patients, and either 48 (n = 2) or 88 (n = 2) sections were acquired in the remaining four patients. The number of excitations was one in all cases, and the total time for acquisition was 18 seconds for two patients, 21–24 seconds for 29 patients, and 27–31 seconds for three patients.

All patients underwent both unenhanced and contrast-enhanced MR angiography in each session with these parameters. The unenhanced examination was performed to permit postexamination image subtraction (of unenhanced images from contrast-enhanced images) for subsequent evaluation of diagnostic image quality. For the contrast-enhanced examinations, the delay between the start of intravenous contrast agent injection and the start of the acquisition was calculated for each examination on the basis of the circulation time in each patient. For this calculation, dynamic single-section imaging of the abdominal aorta at the level of the renal arteries was performed for approximately 60 seconds at a frequency of one image every 2 seconds by using a transverse T1-weighted two-dimensional gradient-echo sequence. The time it took for the automatically injected 2-mL test bolus of contrast agent to arrive was determined from the resulting time–signal intensity curve for each patient according to the equation TD = TTpeak, where TD is the calculated delay between start of contrast agent injection and start of acquisition, and TTpeak is the time to peak signal intensity. Image acquisition began with the injection of the 2-mL test bolus.

The two contrast-enhanced examinations conducted in each patient were performed with the same MR imaging system and with identical sequence parameters, and care was taken to ensure that the vascular territory imaged during the second examination was as closely comparable as possible with that visualized during the first examination.

The contrast agent for each examination was administered intravenously (in a cubital vein [31 of 34 patients] or hand vein [three of 34 patients]) at an injection rate of 2 mL/sec by using a power injector and a 20-gauge needle. Gadobenate dimeglumine was administered at a dose of 0.1 mmol/kg (corresponding to 0.2 mL/kg of a 0.5 mol/L formulation) and gadopentetate dimeglumine at a dose of 0.2 mmol/kg (corresponding to 0.4 mL/kg of a 0.5 mol/L formulation). The mean administered volumes of gadobenate dimeglumine and gadopentetate dimeglumine were 15.0 mL ± 3.0 (range, 11.0–22.5 mL) and 30.3 mL ± 6.0 (range, 22.0–45.0 mL), respectively, corresponding to mean injection times of 7.6 seconds ± 1.4 for gadobenate dimeglumine and 15.1 seconds ± 3.0 for gadopentetate dimeglumine. In all patients, the contrast agent injection was followed by a 20-mL saline flush. The investigators who conducted the examinations (M.P., M.G., S.G.R., P.D.) were in all cases blinded to the specific contrast agent administered. The mean overall interval between the two contrast-enhanced examinations in each patient was 100.3 hours ± 81.3. For patients in group A, the mean interval between examinations was 119.4 hours ± 102.6. However, this group contained two patients for whom the interval between examinations exceeded 11 days (265 and 451 hours). For the remaining patients in group A, the mean interval between examinations was 89.6 hours ± 47.1 (range, 41.7–192.3 hours). For patients in group B, the mean interval between examinations was 78.7 hours ± 40.9 (range, 44.7–167.7 hours).

Image Evaluation
Qualitative assessment.—Qualitative assessment of contrast efficacy for all available MR imaging studies was performed on site by the principal investigator at each center (M.P., M.G., P.D.) and off site by two independent radiologists (G.S., A.V.). Each of the radiologists involved in the study had at least 8 years of experience with contrast-enhanced renal MR angiography. Both on-site and off-site assessments were performed in a fully blinded fashion. The off-site evaluation was performed at a dedicated reading center, with the study images displayed in electronic format and in randomized order. Both source images and maximum intensity projection images obtained with postprocessing (subtraction of unenhanced images from contrast-enhanced images) were available for evaluation. The two off-site readers performed their blinded evaluations independently and without any knowledge of the results of on-site assessments.

The evaluation criteria were identical for both on-site investigators and off-site readers. Qualitative assessment was performed only for images considered to be technically adequate and in which the selected field of view covered the left and right renal arteries, the left and right kidneys, and the suprarenal to infrarenal abdominal aorta.

To achieve as balanced and objective an evaluation as possible, qualitative assessment was performed by both the on-site investigators and off-site readers for a total of nine independent vessel segments covering the entire vascular territory of interest. The vessel segments evaluated were defined as follows (Fig 1): segment I, suprarenal abdominal aorta; segment II, juxtarenal aorta (including the part approximately 2 cm above and below the renal arteries and any accessory renal arteries); segment III, infrarenal aorta down to the bifurcation; segment IV, proximal third of the renal arteries (left and right); segment V, middle third of the renal arteries (left and right); and segment VI, distal third of the renal arteries (left and right). Accessory renal arteries and proximally bifurcated renal arteries, if present, were similarly divided into proximal, middle, and distal segments and assessed together with each principal renal artery segment.



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  		Figure 1. Schema shows segmentation of the renal vasculature used in qualitative evaluations.

 
For each of the nine vessel segments, an image quality score between 0 and 2 was assigned, with the scores defined as follows: 0, poor diagnostic information, impossible to detect or exclude vascular lesions; 1a, moderate diagnostic information, vascular lesions possibly absent; 1p, moderate diagnostic information, vascular lesions possibly present; 2a, adequate diagnostic information, vascular lesions definitely absent; and 2p, adequate diagnostic information, vascular lesions definitely present.

A total image quality score was thereafter determined for each patient and each contrast-enhanced MR angiographic examination as the sum of the numeric scores assigned to each of the nine vessel segments. Thus, the total image quality score for each contrast-enhanced examination ranged from 0 (poor diagnostic information for all nine segments) to 18 (adequate diagnostic information for each of the nine segments). A comparison of the summed scores for the left and right renal arteries (proximal, middle, and distal segments of each artery) was also performed according to the same criterion. For this evaluation, the summed image quality score ranged from 0 to 6. For purposes of assessment, vascular lesions were defined as any vascular abnormality (eg, stenosis, occlusion, or aneurysm) of the abdominal aorta and/or renal arteries. Only arterial enhancement was assessed; no scoring was performed for renal venous enhancement. Image artifacts, if present, were noted, but no specific scoring for artifacts was performed, since the assessment of artifacts was inherent in the overall evaluation of image quality.

Quantitative assessment.—Quantitative evaluation of contrast enhancement was performed by a single off-site blinded reader (G.S.) on the basis of signal intensity measurements determined for regions of interest (ROIs) positioned on source images. Evaluation was performed only when ROIs could successfully be placed on both the abdominal aorta and psoas muscle on each image. Images were excluded from assessment only if the psoas muscle was not adequately depicted. Circular ROIs of approximately 0.5 cm2 were placed on suprarenal, juxtarenal, and infrarenal segments of the abdominal aorta (ie, in positions superior, adjacent, and inferior to the level of the renal arteries) and, where visible, on the left or right psoas muscle on the same image. For each contrast-enhanced examination, the ROIs were placed on these three levels of the abdominal aorta at the positions of maximum signal intensity enhancement within the contrast agent bolus. Hence, the signal intensity value recorded within each ROI for each contrast-enhanced examination was the maximum attained for that level of the aorta. SNR and contrast-to-noise ratio (CNR) were determined according to the following equations: SNR = SIa/NO, and CNR = (SIa – SIm)/NO, where SIa is the signal intensity measured in the ROI positioned in the abdominal aorta, SIm is the signal intensity measured in the ROI positioned on the psoas muscle on the same image, and NO is noise, defined as the SD of signal intensity measured in the ROI on the psoas muscle.

Safety Assessments
The safety of the two study agents was evaluated by means of complete physical examination and measurement of vital signs (blood pressure and pulse) before and after each contrast-enhanced examination and monitoring for adverse events throughout the study period, from the time the patient signed the informed consent form until the end of the follow-up examination at least 48 hours after the second contrast-enhanced examination. Adverse events were classified by the principal investigators (M.P., M.G., P.D.) as either serious (ie, death, or life-threatening incident requiring or prolonging hospitalization) or not serious (rated as mild, moderate, or severe). The relationship of each adverse event to the study agent was classified as definite, probable, possible, none, or unknown.

Statistical Analysis
Statistical evaluation to establish the noninferiority of 0.1 mmol/kg gadobenate dimeglumine compared with 0.2 mmol/kg gadopentetate dimeglumine was performed with qualitative data by using statistical software (SAS, version 8.2; SAS Institute, Cary, NC). Differences between the two contrast agents were calculated as the difference between the least squares means for 0.2 mmol/kg gadopentetate dimeglumine and for 0.1 mmol/kg gadobenate dimeglumine by using an analysis of variance (ANOVA) method appropriate for a two-period crossover design with terms for period, sequence, and treatment effects (23,24).

An evaluation was performed of the power of the study to demonstrate the noninferiority, with regard to contrast efficacy, of 0.1 mmol/kg gadobenate dimeglumine compared with 0.2 mmol/kg gadopentetate dimeglumine. It was assumed that the average overall image quality score for the group of images obtained with 0.2 mmol/kg gadopentetate dimeglumine was 16. The noninferiority margin for the difference between the two groups (0.1 mmol/kg gadobenate dimeglumine vs 0.2 mmol/kg gadopentetate dimeglumine) was then defined as –10% of this score (–1.6). Assuming an SD of 3.0 for this difference, then noninferiority with more than 85% of power can be demonstrated for 34 patients in a crossover study design by using a two-tailed test with {alpha} = .05. Noninferiority, then, would be demonstrated if the lower limit for the 95% confidence interval (CI) for the difference is greater than –1.6.

Agreement between the two off-site readers for image quality was determined by calculating the Cohen {kappa} statistic (25) and 95% CI.

Statistical comparison of the quantitative values of SNR and CNR determined for the two contrast-enhanced examinations was performed by using ANOVA for a crossover design. Differences in trend were evaluated by means of ANOVA for repeated measures. Differences were considered statistically significant with P < .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Qualitative Assessment
The images from all 34 study patients were considered to be technically adequate and to cover the required field of view.

The overall mean image quality scores determined by the on-site investigators and off-site readers 1 and 2 are shown in Table 1. Although off-site reader 1 reported slightly lower overall image quality scores compared with off-site reader 2 and the on-site investigators, in each case the image quality scores for 0.2 mmol/kg gadopentetate dimeglumine and 0.1 mmol/kg gadobenate dimeglumine were similar. Analysis by means of ANOVA for a two-period crossover design revealed that the period, sequence, and treatment effects were not statistically significant (P > .05) (Table 1). Confirmation of the comparability of image quality was achieved by testing for statistical noninferiority: The results for evaluations by the on-site investigators and each of the two off-site readers showed that the lower 95% confidence limit for the difference in image quality score between 0.1 mmol/kg gadobenate dimeglumine and 0.2 mmol/kg gadopentetate dimeglumine was, in each case, greater than –1.6 (0.72, –1.04, and –0.40, respectively). These results indicated comparable image quality for 0.1 mmol/kg gadobenate dimeglumine and 0.2 mmol/kg gadopentetate dimeglumine when assessed on the basis of individual vessel segment scores by using a crossover study design.


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  		TABLE 1. Total Image Quality Score according to Contrast Agent

 
The results of a comparison of the overall image quality scores reported for the two contrast agents according to the order of their administration (whether at the first or the second contrast-enhanced MR angiographic examination) are presented in Table 2. Interestingly, both off-site readers reported slightly better overall image quality scores for both contrast agents with administration at the second contrast-enhanced examination, compared with scores with administration at the first examination. Neither off-site reader, however, noted any qualitative evidence of residual contrast enhancement from the first contrast-enhanced examination during the acquisition of unenhanced images in the second examination, even among the patients with renal insufficiency or another form of renal disease. Whereas for off-site reader 1 and the on-site investigators, the images obtained with administration of gadobenate dimeglumine followed by gadopentetate dimeglumine produced overall mean image quality scores that were lower than the corresponding scores for the gadopentetate dimeglumine–gadobenate dimeglumine examination sequence (14.8 vs 15.6 and 16.8 vs 17.4, respectively), the opposite pattern was observed for off-site reader 2 (17.0 vs 16.8, respectively). Comparison of summed image quality scores for the right and left renal arteries alone revealed no clear differences in interpretation. Off-site reader 1 reported scores of 4.7 ± 2.0 and 4.7 ± 1.0 for the right renal artery and 4.0 ± 1.9 and 4.6 ± 1.3 for the left renal artery for gadobenate dimeglumine– and gadopentetate dimeglumine–enhanced images, respectively, from the first examination. The scores for corresponding images from the second examination were 5.1 ± 1.3 and 4.8 ± 1.5 (right renal artery) and 5.0 ± 1.7 and 4.8 ± 1.6 (left renal artery). For off-site reader 2, the scores were 5.5 ± 0.9 and 5.8 ± 0.6 (right renal artery) and 5.4 ± 1.1 and 5.1 ± 1.1 (left renal artery) for gadobenate dimeglumine–enhanced images and gadopentetate dimeglumine–enhanced images from the first examination, and 5.5 ± 0.9 and 5.7 ± 0.6 (right renal artery) and 5.4 ± 1.3 and 5.7 ± 0.6 (left renal artery) for images from the second examination.


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  		TABLE 2. Total Image Quality Score according to Contrast Agent Administration at First or Second Examination

 
A detailed evaluation of agreement between the two off-site readers for diagnostic image quality was performed by means of Cohen {kappa} statistics (Table 3). Overall, strong agreement between the two blinded readers was noted, particularly for the juxta- and infrarenal aorta and proximal renal arteries, both for evaluation of each arterial segment individually and for combined evaluation of all segments of the aorta and both proximal renal arteries. Agreement was not as strong for other segments, however, particularly the distal renal arteries. Analysis of interreader agreement according to the contrast agent revealed slightly better results with 0.1 mmol/kg gadobenate dimeglumine for evaluation of all individual segments except the left proximal renal artery and for all evaluations of combined segments. Examples of image quality improvement with enhanced contrast from 0.1 mmol/kg gadobenate dimeglumine or 0.2 mmol/kg gadopentetate dimeglumine are presented in Figures 2–4.


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  		TABLE 3. Reader Agreement for Diagnostic Image Quality according to Contrast Agent and Arterial Segment

 


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  		Figure 2a. Coronal three-dimensional time-resolved MR angiograms (4.6/1.8, 30° flip angle) of the abdominal aorta and renal arteries in a 79-year-old woman (a) after injection of 0.1 mmol/kg gadobenate dimeglumine and (b) after injection of 0.2 mmol/kg gadopentetate dimeglumine. Aneurysm of the infrarenal abdominal aorta (solid arrow) and stenosis of the left proximal renal artery (open arrow) are depicted equally well on both anteroposterior maximum intensity projection images. Better depiction of the inferior mesenteric artery (arrowhead) and more intense and homogeneous signal intensity enhancement above and below the aortic bifurcation, however, are apparent in a.

 


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  		Figure 2b. Coronal three-dimensional time-resolved MR angiograms (4.6/1.8, 30° flip angle) of the abdominal aorta and renal arteries in a 79-year-old woman (a) after injection of 0.1 mmol/kg gadobenate dimeglumine and (b) after injection of 0.2 mmol/kg gadopentetate dimeglumine. Aneurysm of the infrarenal abdominal aorta (solid arrow) and stenosis of the left proximal renal artery (open arrow) are depicted equally well on both anteroposterior maximum intensity projection images. Better depiction of the inferior mesenteric artery (arrowhead) and more intense and homogeneous signal intensity enhancement above and below the aortic bifurcation, however, are apparent in a.

 


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  		Figure 3a. Coronal three-dimensional time-resolved MR angiograms (2.5/0.9, 45° flip angle) of the abdominal aorta and renal arteries in a 60-year-old woman (a) after injection of 0.1 mmol/kg gadobenate dimeglumine and (b) after injection of 0.2 mmol/kg gadopentetate dimeglumine. Stenoses (arrows) of both the right and left proximal renal arteries are depicted on both maximum intensity projection images.

 


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  		Figure 3b. Coronal three-dimensional time-resolved MR angiograms (2.5/0.9, 45° flip angle) of the abdominal aorta and renal arteries in a 60-year-old woman (a) after injection of 0.1 mmol/kg gadobenate dimeglumine and (b) after injection of 0.2 mmol/kg gadopentetate dimeglumine. Stenoses (arrows) of both the right and left proximal renal arteries are depicted on both maximum intensity projection images.

 


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  		Figure 4a. Coronal three-dimensional time-resolved MR angiograms (4.6/1.8, 45° flip angle) of the abdominal aorta and renal arteries in a 50-year-old man (a) after injection of 0.1 mmol/kg gadobenate dimeglumine and (b) after injection of 0.2 mmol/kg gadopentetate dimeglumine. Early branching (arrows) of the segmental renal arteries is well depicted on both maximum intensity projection images.

 


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  		Figure 4b. Coronal three-dimensional time-resolved MR angiograms (4.6/1.8, 45° flip angle) of the abdominal aorta and renal arteries in a 50-year-old man (a) after injection of 0.1 mmol/kg gadobenate dimeglumine and (b) after injection of 0.2 mmol/kg gadopentetate dimeglumine. Early branching (arrows) of the segmental renal arteries is well depicted on both maximum intensity projection images.

 
In their evaluations of overall image quality, none of the on-site investigators and neither off-site blinded reader noted any major difference between the two agents in terms of the ability to detect vascular lesions or any evidence of increased image artifacts with one agent compared with the other. Although the aim of the study was to compare the two contrast agents for enhanced image quality, the overall incidence of vascular lesions among our study patients (ie, the percentage of patients with at least one arterial segment assigned a score of 2p) as determined at contrast-enhanced MR angiography by the on-site investigators was 32.4% (11 of 34) for 0.2 mmol/kg gadopentetate dimeglumine and 41.2% (14 of 34) for 0.1 mmol/kg gadobenate dimeglumine. The corresponding percentages as determined by off-site readers 1 and 2 were slightly higher, at 50.0% (17 of 34) and 55.9% (19 of 34), respectively, for 0.2 mmol/kg gadopentetate dimeglumine, and 70.6% (24 of 34) and 58.8% (20 of 34), respectively, for 0.1 mmol/kg gadobenate dimeglumine.

Quantitative Assessment
Quantitative evaluation of ROIs placed on the suprarenal aorta was performed in all 34 patients after administration of gadopentetate dimeglumine and in 33 of 34 patients after administration of gadobenate dimeglumine. The patient who was not evaluated after gadobenate dimeglumine administration was excluded because the visible psoas muscle was not large enough for satisfactory positioning of an ROI. Quantitative evaluation of ROIs placed on the juxtarenal aorta by using the same criteria was possible in 33 of 34 patients after administration of both gadopentetate dimeglumine and gadobenate dimeglumine, while evaluation in ROIs placed on the infrarenal aorta was possible in 21 of 34 patients after administration of gadopentetate dimeglumine and in 23 of 34 patients after administration of gadobenate dimeglumine. Complete quantitative evaluation in ROIs positioned successfully at all three levels of the abdominal aorta and on the corresponding psoas muscle on each image at both contrast-enhanced examinations was possible in 18 of 34 patients.

Results of a comparison of SNR and CNR values among patients with ROIs placed in the same position on images from both contrast-enhanced examinations are given in Table 4. Almost identical mean values for both SNR and CNR were observed in the suprarenal aorta for 0.1 mmol/kg gadobenate dimeglumine and 0.2 mmol/kg gadopentetate dimeglumine. Apparent differences were noted between the two contrast agents, however, at lower levels of the abdominal aorta: Whereas only slightly higher SNR and CNR values were obtained with gadopentetate dimeglumine for ROIs positioned on the juxta- and infrarenal aorta, an apparent trend toward increasing SNR and CNR with distance traveled down the abdominal aorta was noted with gadobenate dimeglumine. The differences in SNR and CNR between 0.1 mmol/kg gadobenate dimeglumine and 0.2 mmol/kg gadopentetate dimeglumine were most pronounced at the level of the infrarenal aorta, where marginal superiority for 0.1 mmol/kg gadobenate dimeglumine was demonstrated (P = .05 for differences in both SNR and CNR). Results of ANOVA revealed that neither period nor sequence effects were significant (P > .05) for either SNR or CNR (Table 4). Evaluation of the trends in SNR and CNR after gadobenate dimeglumine and gadopentetate dimeglumine was performed for the 18 patients with valid measurements at each of the three levels of the abdominal aorta at both examinations. For these patients, the overall differences in trend between 0.1 mmol/kg gadobenate dimeglumine and 0.2 mmol/kg gadopentetate dimeglumine were again suggestive of better performance with gadobenate dimeglumine (P = .07 for both ratios).


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  		TABLE 4. Comparison of SNR and CNR Values in the Abdominal Aorta according to Contrast Agent and Segment

 
Safety Assessments
A total of 11 adverse events were reported by three (7.3%) of the 41 patients enrolled in the study. Two patients experienced adverse events that were considered to be probably related to the contrast agent administered: One patient, a 55-year-old man, reported mild nausea, which was considered to be probably related to administration of gadobenate dimeglumine; and the second patient, a 43-year-old man, experienced nine mild events (asthenia, headache, pain, hypertension, an increase in serum creatinine from 5.5 to 6.7 mg/100 mL, arthralgia, myalgia, dysuria, and renal pain), all of which were considered to be probably related to administration of gadopentetate dimeglumine. Neither patient completed the second contrast-enhanced examination and neither was included in the evaluation of contrast enhancement. The third patient who experienced an adverse event was an 83-year-old woman who developed a cholesterol embolus that was considered to be serious but not to be related to the administration of a contrast agent. There were no effects on vital signs or results of physical examination that were considered clinically important.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
REFERENCES
 
At present, no MR imaging contrast agent has been approved in the United States specifically for contrast-enhanced MR angiography. Nevertheless, contrast-enhanced MR angiography is widely considered the technique of choice for the demonstration of hemodynamically significant renal artery stenosis and is believed to offer accuracy superior to that of minimally invasive techniques such as ultrasonography (26,27), scintigraphy (10,26), and unenhanced MR angiography (2,5) and comparable with that of much more invasive techniques such as conventional angiography (2–6,8,9,11–13,27–30). Although comparable sensitivity and specificity for the detection of hemodynamically significant stenosis recently have been demonstrated for multi–detector row computed tomography (31), inherent disadvantages of this approach are the exposure of the patient to ionizing radiation and large volumes of iodinated contrast material (16,17,32).

The gadolinium-based contrast agents currently in widespread use for contrast-enhanced MR angiography of the renal vasculature (gadopentetate dimeglumine, gadodiamide, gadoteridol, gadoversetamide, and gadoterate meglumine) have different structures and pharmacokinetic properties but possess similar T1 relaxivities of 4.3–5.0 L · mmol–1 · sec–1 in human plasma at 0.47 T (19). These agents are available as 0.5 mol/L formulations and are generally employed at doses of 0.1–0.3 mmol/kg, with investigators in most studies advocating doses of 0.2 mmol/kg and higher (1,2,7,10–12,15–17,28,31). A more recently developed agent, gadobutrol, is available as a 1.0 mol/L formulation but has a relaxivity of only 5.6 L · mmol–1 · sec–1 (33). Compared with these agents, gadobenate dimeglumine has a roughly twofold higher T1 relaxivity in blood (9.7 L · mmol–1 · sec–1) because the contrast-effective moiety is able to interact weakly and transiently with serum albumin (18,19). It is not surprising, therefore, that the results of the present highly standardized intraindividual crossover comparison show that gadobenate dimeglumine at a dose of 0.1 mmol/kg is comparable with gadopentetate dimeglumine at a dose of 0.2 mmol/kg for contrast-enhanced MR angiography of the renal arteries. Indeed, these findings might have been envisaged on the basis of the results of previous studies of contrast-enhanced MR angiography, in which gadobenate dimeglumine at a dose of 0.1 mmol/kg was found to be superior to gadopentetate dimeglumine at an equivalent dose in healthy volunteers (20,21) and to both gadopentetate dimeglumine and gadoterate meglumine at equivalent doses in patients (22,34,35). Of note in the present study is that qualitative and quantitative evaluation was performed intraindividually in 34 patients. Previous studies in which gadobenate dimeglumine was compared with other agents for contrast-enhanced MR angiography in patients have involved either parallel dose groups of just 15 or 28 patients (22,35) or an intraindividual dose group of just five patients (34). An intraindividual crossover study design may be more valid for use in demonstrating the potential clinical usefulness of gadobenate dimeglumine, since the comparison with gadopentetate dimeglumine is performed in the same patient. Previous studies (20,21) have highlighted the advantage of adopting an intraindividual study design.

Concerning the level of interreader agreement, this was highest for both contrast agents for the juxtarenal and infrarenal segments of the aorta and the left and right proximal renal arteries, and, overall, for 0.1 mmol/kg gadobenate dimeglumine compared with 0.2 mmol/kg gadopentetate dimeglumine. Since renal artery stenosis associated with generalized atherosclerosis is the most common pathologic condition of the renal arteries and is typically associated with the ostial and proximal portions of the renal arteries rather than the distal renal arteries (7,12,16,17,36), these findings further establish that a gadobenate dimeglumine dose of 0.1 mmol/kg is qualitatively comparable to a gadopentetate dimeglumine dose of 0.2 mmol/kg. With regard to the distal renal arteries, a lower level of agreement was noted between off-site blinded readers, despite similar overall mean image quality scores. It is likely that the lower level of agreement between readers is a consequence of the smaller size of the distal renal arteries compared with the proximal renal arteries and the lower level of contrast enhancement in these segments in certain patients (17).

Quantitative evaluation in the present study revealed higher SNR and CNR values with 0.1 mmol/kg gadobenate dimeglumine compared with 0.2 mmol/kg gadopentetate dimeglumine at the level of the infrarenal aorta (P = .05 for both ratios). Similarly, analysis of the trend toward increasing SNR and CNR in lower-level segments in the abdominal aorta led to findings that were suggestive of better signal intensity enhancement with 0.1 mmol/kg gadobenate dimeglumine (P = .07 for both ratios). Völk et al (22) previously suggested that a potential advantage of gadobenate dimeglumine over gadopentetate dimeglumine at an equal injection rate may be an improved bolus geometry that derives from the smaller bolus volume injected. Moreover, it is well established that greater arterial signal intensity enhancement is achieved with the improved geometry of a more compact contrast material bolus (17). The findings of the present study support these observations, in that the values for both mean injection volume and mean injection time for 0.1 mmol/kg gadobenate dimeglumine (15.0 mL ± 3.0 and 7.6 seconds ± 1.4, respectively) were roughly half of the values for 0.2 mmol/kg gadopentetate dimeglumine at a constant identical injection rate of 2 mL/sec. It is important to note that the acquisition of high-quality images with gadobenate dimeglumine was achieved without the introduction of any k-space modulation artifacts, since the contrast agent bolus, although smaller and more compact than that of gadopentetate dimeglumine, was long enough to provide homogeneous contrast agent concentration throughout the image acquisition time.

In addition to the benefit from a more compact bolus, the higher SNR and CNR with 0.1 mmol/kg gadobenate dimeglumine in the more distal regions of the abdominal aorta possibly derive in part from the weak and transient interaction of the gadolinium chelate with serum albumin. Previous studies have similarly demonstrated improved signal intensity enhancement with gadobenate dimeglumine compared with gadopentetate dimeglumine in more peripheral vascular territories (21,35), and it is possible that the interaction between gadobenate dimeglumine and serum albumin contributes to a reduction in the rate of contrast agent extravasation, compared with that observed with gadopentetate dimeglumine and other agents that have no affinity for serum proteins. Unfortunately, serum albumin measurements were not performed for the patients in the present study, and thus further work is needed to investigate more fully the reasons for the higher SNR and CNR with 0.1 mmol/kg gadobenate dimeglumine in the more distal regions of the abdominal aorta. Further work is also necessary to explain why slightly higher quality scores were ascribed by each assessor to the images obtained at the second contrast-enhanced examination rather than the first, regardless of the order in which the two contrast agents were administered. Neither the on-site investigators nor the off-site readers noted any qualitative evidence of residual contrast enhancement from the first contrast-enhanced examination during the acquisition of unenhanced images in the second examination, even among patients who had some form of renal disease, in whom a reduced rate of elimination of contrast agent might be expected (37,38). Hence, it was a curious finding that the image quality scores for the second examination were in all cases superior to the scores for the first examination.

A possible limitation of the present study is the absence of a reference standard technique, such as conventional digital subtraction angiography, with which to compare the relative accuracies of 0.1 mmol/kg gadobenate dimeglumine and 0.2 mmol/kg gadopentetate dimeglumine for the depiction and grading of stenoses. On the other hand, the results of numerous studies have demonstrated the excellent diagnostic accuracy of contrast-enhanced MR angiography for the grading of renal artery stenoses, accuracy that has led to its largely having replaced conventional angiography in most centers (1–14,31). Our decision not to use digital subtraction angiography as the reference standard was based on the established high accuracy of contrast-enhanced MR angiography for the detection of renal artery stenoses, plus the fact that patients were already undergoing two diagnostic imaging procedures. The appropriateness of this decision was borne out by the results of the study and, in particular, by the high level of interreader agreement about diagnostic image quality. A phase III clinical trial to determine the accuracy of unenhanced and gadobenate dimeglumine–enhanced MR angiography against conventional digital subtraction angiography for the detection of renal artery stenosis is currently underway.

Finally, it should be noted that for many patients in this study, the field of view was relatively large and contained both the heart and external iliac arteries. In routine clinical practice, a smaller field of view is often used to increase spatial resolution and, thus, the accuracy of detection of renal artery stenoses (12). However, since the primary emphasis of the present study was to compare 0.1 mmol/kg gadobenate dimeglumine with 0.2 mmol/kg gadopentetate dimeglumine for contrast enhancement rather than diagnostic effectiveness, the larger field of view selected by the on-site investigators was not considered inappropriate.

In conclusion, the results of the present study confirm earlier findings (39,40) that gadobenate dimeglumine at a dose of 0.1 mmol/kg provides image quality comparable to that achievable with gadopentetate dimeglumine at a dose of 0.2 mmol/kg (22). The use of a lower dose and lower injection volume may be clinically advantageous, particularly in patients in whom renal function is compromised.


   ACKNOWLEDGMENTS
 
The authors thank Ningyan Shen, MD, PhD, Franca Heiman, MSc, Usha Halemane, MSc, MBA, and Riccardo Spezia, MSc, for their contributions to the statistical analysis of the data.


   FOOTNOTES
 
Abbreviations: ANOVA = analysis of variance, CI = confidence interval, CNR = contrast-to-noise ratio, ROI = region of interest, SD = standard deviation, SNR = signal-to-noise ratio

Author contributions: Guarantors of integrity of entire study, A.S., G.P.; study concepts, A.S., G.P.; study design, G.P., M.D.; literature research, M.A.K.; clinical studies, M.G., S.G.R., P.D., M.P.; data acquisition, M.A.K., G.S., A.V., M.G., S.G.R., P.D., M.P.; data analysis/interpretation, M.A.K., M.D., G.S., A.V.; statistical analysis, M.A.K.; manuscript preparation, M.A.K.; manuscript definition of intellectual content, M.A.K., M.P., A.S., G.P.; manuscript editing and revision/review, M.A.K., M.P.; manuscript final version approval, all authors


   REFERENCES
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 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
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