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Contrast Media |
1 From the Departments of Clinical Radiology (B.T., C.B., P.R., W.H.) and Internal Medicine (K.K., R.M.S.), Westfalian Wilhelms University of Münster, Albert-Schweitzer Str 33, Münster D-48129, Germany; and Schering, Berlin, Germany (V.G.). From the 1998 RSNA scientific assembly. Received November 10, 1999; revision requested January 5, 2000; revision received July 31; accepted August 30. Supported in part by Schering. Address correspondence to B.T. (e-mail: tombach@uni-muenster.de).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Twenty-one patients with impaired renal function were enrolled in this prospective randomized study and classified into two subgroups according to their creatinine clearance: group 1 (n = 12), less than 80 mL/min (<1.33 mL/sec) and greater than 30 mL/min (>0.50 mL/sec); group 2 (n = 9), less than 30 mL/min (<0.50 mL/sec) and not requiring dialysis. Gadobutrol (1.0 mol/L) was injected intravenously at randomly assigned doses of either 0.1 or 0.3 mmol per kilogram of body weight. Changes in vital signs, clinical chemistry, and urinalysis results, including creatinine clearance, were monitored before, at 6 hours, and then every 24 hours until 72 hours (group 1) or 120 hours (group 2) after intravenous injection of gadobutrol. Hematologic results were checked every other day.
RESULTS: No serious adverse event occurred, and no clinically relevant changes in vital signs, hematologic results, clinical chemistry, or urinalysis results were detected in the observation period. Markers for glomerular filtration (creatinine, cystatin C, ß2-microglobulin, creatinine clearance) and tubular function (N-acetyl-ß-D-glucosaminidase, 
1-microglobulin) were unaffected by gadobutrol in both groups.
CONCLUSION: Gadobutrol did not affect renal function and, therefore, proved to be a safe MR contrast agent in patients with impaired renal function. Even in patients with marginal excretory function (creatinine clearance, <30 mL/min [<0.50 mL/sec]), prehydration or treatment with diuretics or hemodialysis are not required after the administration of gadobutrol.
Index terms: Gadolinium • Kidney, failure, 81.699 • Kidney, MR, 81.12143 • Kidney neoplasms, MR, 81.32, 81.12143 • Magnetic resonance (MR), contrast media, 81.12143
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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We found only a few clinical data for patients with preexisting renal insufficiency who received high doses (>0.3 mmol/kg) of extracellular MR contrast agents (0.5 mol/L) (1,33). In a retrospective analysis of 31 patients with preexisting renal insufficiency (serum creatinine, >1.5 mg/dL [>133 µmol/L]), the frequency of contrast material–induced renal failure with iodinated contrast material (n = 9) was 29% compared with 0% for that with gadolinium chelates, including gadopentetate dimeglumine (Magnevist; Schering, Berlin, Germany), gadodiamide (Omniscan; Nycomed, Oslo, Norway), or gadoteridol (ProHance; Bracco, Milan, Italy) at doses of 0.2–0.4 mmol per kilogram of body weight (1). In four patients with renal insufficiency, the high dose of 0.5 mmol/kg of gadoversetamide (Optimarck; Mallinckrodt, St Louis, Mo) resulted in no adverse effect on renal function (33).
Gadobutrol (gadolinium-DO3A-butriol, Gadovist; Schering) is approved for use in Germany, Australia, and Switzerland as an electrically neutral gadolinium chelate for MR imaging. Specific physicochemical properties of gadobutrol allow the preparation of a highly concentrated MR contrast agent for intravenous injection with a gadolinium concentration of 1.0 mol/L, whereas approved commercially available gadolinium chelates are prepared with a gadolinium concentration of 0.5 mol/L (34,35). The 1.0 mol/L concentration provides increased gadolinium concentrations with a sharper bolus peak because of the reduced injection volume, which may be advantageous for first-pass investigations such as perfusion imaging and contrast material–enhanced MR angiography (31,36–38). With regard to renal toxicity, highly concentrated gadolinium chelates (1.0 mol/L) may also result in an increased renal concentration and thus increased renal toxicity during the first pass; however, data in patients with preexisting renal failure are not available, to our knowledge.
The purpose of our study was to determine the renal tolerance of 1.0 mol/L gadobutrol in patients with chronically impaired renal function after intravenous injection of randomly assigned doses of 0.1 and 0.3 mmol/kg.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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hours (35). The median lethal dose of gadobutrol in mice, rats, and dogs is greater than 25, 20, and 6 mmol, respectively. Exact values or ranges could not be determined, because no lethal effects were observed in either mice or rats at maximum administration volume. In healthy volunteers, gadobutrol is safe over a dose range from 0.04 to 0.5 mmol/kg, with urinary excretion rates of 92.5%, 98.0%, and 96.6% for doses of 0.04, 0.1, and 0.4 mmol/kg, respectively, 12 hours after injection. The average renal clearance of gadobutrol is 121 mL/min, close to the normal level of creatinine clearance in humans (35).
Study Design
The objective of this randomized open-label study was to evaluate the safety of gadobutrol administered intravenously at randomly assigned doses of either 0.1 or 0.3 mmol/kg in patients with impaired renal function who underwent MR imaging for any indication. The primary variable was the change in creatinine clearance after contrast material injection. Physical examination findings, vital signs, adverse events, serious adverse events, and extensive clinical laboratory test results were defined as secondary variables. To detect minimal changes in renal function, sensitive indicators of renal injury for both glomerular and tubular damage were determined at several time points.
Adverse events were defined as any illness, sign, symptom, or unfavorable change (eg, headache, nausea, dizziness) in the clinical status that appeared or worsened after the start of the study. Adverse events during the clinical study that were fatal, life threatening, resulted in serious or permanent damage to health, required intervention to prevent permanent impairment or damage, or necessitated or extended the hospital stay were classified as serious adverse events (eg, myocardial infarction, life-threatening bleeding). A causal relationship with the trial medication had to be assessed and documented for both adverse events and serious adverse events.
Patients
This study was approved by our institutional review board and ethics committee. Informed consent was obtained from each patient at least 24 hours before the study. Between October 1996 and February 1998, 21 patients (16 men, five women; age range, 20–76 years; mean age, 59.6 years) with a creatinine clearance of less than 80 mL/min (<1.33 mL/sec) who did not require chronic hemodialysis treatment, were willing and able to continue study participation, and had any indication for contrast-enhanced MR imaging were enrolled.
The 21 patients were classified into two subgroups according to their creatinine clearance: group 1, n = 12, less than 80 and greater than 30 mL/min (>0.50 mL/sec); group 2, n = 9, less than 30 mL/min (<0.50 mL/sec) and did not require dialysis. According to the experience of nephrologists (R.M.S., K.K.), the estimated serum creatinine levels for creatinine clearance values of 80 mL/min (1.33 mL/sec) and 30 mL/min (0.50 mL/sec) are 1.0 mg/dL (88 µmol/L) and 2.9–3.2 mg/dL (256–283 µmol/L), respectively, depending on age, sex, and body weight. Eleven patients were randomly assigned to receive the lower dose of gadobutrol of 0.1 mmol/kg (group 1, n = 6; group 2, n = 5), and 10 patients were assigned to receive the higher dose of 0.3 mmol/kg (group 1, n = 6; group 2, n = 4).
Overall (n = 21), renal impairment was associated with respiratory abnormalities in 29% of patients (chronic bronchitis, chronic obstructive lung disease), cardiovascular abnormalities in 91% (hypertension, coronary heart disease), and endocrine dysfunction in 48% (adrenal gland insufficiency, hyperparathyroidism, hypo- and hyperthyroidism, diabetes). These findings reflected a patient population with severe disease. Four patients had diabetes treated with insulin. All patients received concomitant medication. No restriction of medication or fluid was required before the study, and all patients appeared well hydrated according to clinical signs.
MR imaging was performed with a 1.5-T imager (Magnetom Vision; Siemens, Iselin, NJ) to exclude abdominal empyema (n = 1), renal tumor (n = 2), abdominal tumor (n = 12), metastases (n = 5), or aortic aneurysm (n = 1).
Inclusion and exclusion criteria.—Only patients with a creatinine clearance value of less than 80 mL/min (<1.33 mL/sec) were enrolled in the study. Exclusion criteria were the following: age less than 18 years, pregnancy or lactation in women, treatment with any investigational drug within 30 days before the study, treatment with any contrast material within 5 days before the study or in the observation period, substantial fluctuation of laboratory parameters (eg, as a result of chemotherapy or radiation therapy), clinical instability with unpredictable clinical course during the observation time, organ transplantation, acute renal failure, a history of severe adverse reaction to drugs or contrast agents, a history of severe anaphylactoid allergy to any other allergen, surgery scheduled in the observation period, and any contraindication to MR imaging.
Monitoring.—Results of physical examinations, vital signs, and clinical laboratory tests were recorded at baseline and at 6, 24, 48, and 72 hours after the intravenous injection of gadobutrol. For group 2 patients, additional sampling was performed at 96 and 120 hours. Blood samples were analyzed for hematologic results (leukocytes, erythrocytes, hemoglobin, hematocrit, mean corpuscular volume, thrombocytes) and clinical chemistry (urea nitrogen, total protein, albumin, sodium, potassium, calcium, iron, total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, amylase, cyclic adenosine monophosphate receptor protein), including the markers for glomerular filtration (creatinine, cystatin C, ß2-microglobulin).
Cystatin C and ß2-microglobulin in serum were measured as additional parameters of excretory renal function, which allowed differentiation between laboratory variations and real changes in glomerular filtration rate in cases of fluctuating creatinine values. The serum creatinine level was determined on the basis of the Jaffe reaction, and the creatinine clearance value was calculated as the product of urine creatinine concentration and urine volume divided by the serum creatinine concentration and the collection period (40). Urinalysis was performed to determine total protein, albumin, and the markers for tubular function (N-acetyl-ß-D-glucosaminidase [ß-NAG], 1-microglobulin). The level of 1-microglobulin was measured to assess global tubular damage (proximal and distal); increased ß-NAG excretion indicated proximal tubular damage.
Data Analysis
An increase in serum creatinine level greater than 1.0 mg/dL (>88.4 µmol/L) within 48 hours after intravenous injection of the contrast agent is considered diagnostic of acute renal failure, according to Katzberg (3). For descriptive analysis of serum and urinary clinical chemistry parameters, the following data were calculated: mean, SD, median, range, and 95% CIs. Individual differences between baseline and postinjection values were also calculated: mean, SD, median, and 95% CIs.
The clinical course of each patient was analyzed by the two nephrologists, who were blinded regarding the injected dose of gadobutrol. Therefore, consensus evaluation of results of physical examination, medical and surgical history including current anamnesis, vital signs, and clinical laboratory tests in the observation period was performed individually for each patient by analyzing all available parameters. No inferential statistical analysis was performed owing to the small number of patients in each group (n = 6).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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One group 1 patient (0.3 mmol/kg), who had a 1-year history of urinary retention caused by benign prostatic hyperplasia associated with chronic urinary tract infection and chronic pyelonephritis, was excluded from assessment of the primary variable. A suprapubic urinary catheter caused an inflammation and was removed before the MR investigation. Subsequently, urinary retention, fever, leukocyturia, and bacteriuria occurred within 24 hours after the administration of gadobutrol and persisted for 1 week. The serum creatinine level increased from 1.6 mg/dL (141 µmol/L) at baseline to 1.6 mg/dL (141 µmol/L) at 24 hours, 1.7 mg/dL (150 µmol/L) at 48 hours, 1.87 mg/dL (165 µmol/L) at 72 hours, 2.33 mg/dL (206 µmol/L) at 96 hours, and 2.85 mg/dL (252 µmol/L) at 120 hours. The level returned to baseline within 8 days after high-dose antibiotic therapy.
For all other patients (n = 20), no clinically relevant changes in the glomerular filtration markers of serum creatinine, creatinine clearance, cystatin C, and ß2-microglobulin occurred in the observation period after the injection of gadobutrol. For group 1, the mean serum creatinine concentration was 175.0 µmol/L (low dose) and 158.9 µmol/L (high dose) before administration of gadobutrol and was 183.4 µmol/L (low dose) and 157.2 µmol/L (high dose) at the end of the observation period (72 hours). For group 2, the mean serum creatinine concentration changed from 535.4 to 395.8 µmol/L (low dose) and from 484.4 to 542.5 µmol/L (high dose) during the 120-hour observation period (Fig 1). Furthermore, creatinine clearance values did not decrease in either group at either dose during the observation period (Fig 2). Table 2 presents the follow-up data for both groups for serum creatinine levels and creatinine clearance values in 24-hour intervals of the observation period, regardless of the assigned dose of 0.1 or 0.3 mmol/kg. Figures 3 and 4 present the differences in serum creatinine and creatinine clearance from baseline to postinjection values, regardless of the assigned dose. Urinary parameters, including markers for tubular function (ß-NAG, 1-microglobulin), were unaffected by gadobutrol in both groups (Table 3).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Findings in animal studies with gadopentetate dimeglumine (0.5 mmol/kg) and ex vivo experimental models with high doses of gadopentetate dimeglumine (0.6 mL/kg) suggest a correlation between the excretory function and the dose of MR contrast agent (41,42). Systemic influences and direct nephrotoxicity are discussed, but all effects are transient, reflecting a nonspecific osmotically induced alteration by the contrast agent (41–44). However, the extrapolation of animal data to humans can be misleading. Clinical experience after the injection of 0.5 mol/L extracellular MR contrast agents in patients with chronically impaired renal function is limited (18–26). Data for the renal tolerance of doses as high as 0.5 mmol/kg are available in two prospective studies and one retrospective analysis (1,24,25,33). To our knowledge, however, the renal tolerance of 1.0 mol/L gadolinium chelates as MR contrast agents has not been investigated previously.
The reported stable courses of renal function in patients with preexisting renal impairment document the safety of 1.0 mol/L gadobutrol at randomly assigned doses of 0.1 or 0.3 mmol/kg. Besides some minor fluctuations in individual patients in this study, hematologic results and clinical chemistry, including serum creatinine levels, were unchanged in both groups in the observation period. To improve sensitivity for the detection of glomerular intolerance on the basis of serum creatinine level, which is a less sensitive indicator of renal injury, we monitored additional markers of glomerular filtration (cystatin C, ß2-microglobulin) and calculated creatinine clearance values. No clinically relevant change indicated a gadobutrol-induced impairment of glomerular function.
The glomerular tolerance of gadobutrol at doses of either 0.1 or 0.3 mmol/kg is comparable to that of the clinically approved reference agents gadopentetate dimeglumine, gadodiamide, gadoteridol, and gadoversetamide (19–25,33). Data from the most comprehensive experience with gadopentetate dimeglumine, however, are based on the follow-up of only serum creatinine levels as an indicator of renal impairment, and no creatinine clearance values were calculated (19). On the basis of the definition of acute renal failure according to Katzberg et al (an increase in serum creatinine greater than 1 mg/dL [88.4 µmol/L] in 48 hours), we did not observe any increase in the level of serum creatinine that is diagnostic for acute renal failure (3). Furthermore, tubular function (ß-NAG, 1-microglobulin) was unaffected by gadobutrol in both dose groups. ß-NAG, a lysosomal enzyme located in the proximal tubular cells, is considered a highly sensitive but nonspecific enzyme for detection of renal tubular damage (45). A statistically significant but transient increase due to hyperosmolality was reported after intravenous injection of gadopentetate dimeglumine (19–21).
A limitation of the current study is the small number of patients in each subgroup; therefore, we performed a descriptive data analysis on the basis of calculated measures and could not calculate statistical significance. Nevertheless, findings in this prospective study support reports on the absence of observable nephrotoxicity after the intravenous injection of 0.5 mol/L gadolinium chelates.
In conclusion, gadobutrol did not affect renal function in patients with impaired renal function; therefore, it is a safe MR contrast agent at doses of either 0.1 or 0.3 mmol/kg. After intravenous injection, highly concentrated gadolinium chelates (1.0 mol/L) are well tolerated even in patients with severely reduced renal function (creatinine clearance, <30 mL/min [<0.50 mL/sec]). Prehydration or treatment with hemodialysis or diuretics is not required. Even in patients with marginal excretory function (creatinine clearance, <30 mL/min [<0.50 mL/sec]), hemodialysis treatment did not have to be performed after the injection of gadobutrol. Intraindividual studies are required in the future to compare clinical aspects of the highly concentrated gadobutrol with high doses of 0.5 mol/L gadolinium chelates.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Author contributions: Guarantors of integrity of entire study, all authors; study concepts, V.G., B.T., P.R., R.M.S.; study design, V.G., B.T., R.M.S.; definition of intellectual content, all authors; literature research, B.T., C.B., R.M.S., W.H., V.G.; clinical studies, B.T., C.B., R.M.S., K.K.; experimental studies, B.T., C.B., V.G.; data acquisition, B.T., C.B., R.M.S., K.K.; data analysis, all authors; manuscript preparation, editing, and review, all authors.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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