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1
Department of Clinical Radiology, Westfalian Wilhelms-University of Muenster,
Albert-Schweitzer-Str. 33, D-48129 Münster,
Germany.
2
Department of Radiology, Karlsruhe, Academic Teaching Hospital of Freiburg,
Germany.
3
Department of Internal Medicine, Westfalian Wilhelms-University of Muenster,
Germany.
4
Schering, Berlin, Germany.
Received February 21, 2001;
accepted after revision July 23, 2001.
Supported in part by Schering, Berlin, Germany.
Abstract
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SUBJECTS AND METHODS. Eleven patients with end-stage renal failure who required ongoing hemodialysis were enrolled in our prospective study. Gadobutrol (1 mol/L) was injected IV at randomly assigned doses of either 0.1 or 0.3 mmol of gadolinium per kilogram of body weight for contrast-enhanced MR imaging. Hematology, clinical chemistry, and vital signs were closely monitored at baseline and during an observation period of 120 hr after the IV injection of gadobutrol. To calculate the dialysability, blood samples were drawn before and after each of three hemodialysis sessions. Additional arterial and venous blood sampling was performed during the first hemodialysis session after 30 and 90 min.
RESULTS. No gadobutrol-related changes in hematology, clinical chemistry, or vital signs were detected at either dose level during the observation period. The mean and the standard deviation for the eliminated fraction of gadobutrol was 68.2% ± 12.7% after a 3-hr hemodialysis session using a 1.2 m2 low-flux polysulfone membrane. After three consecutive hemodialysis sessions, the total amount of gadobutrol eliminated increased to 98.0% ± 1.8%. The mean clearance rates of gadobutrol were 126.1 ± 17.8 mL/min and 126.6 ± 24.5 mL/min at 30 and 90 min, respectively.
CONCLUSION. Gadobutrol is effectively removed by three hemodialysis sessions using a low-flux polysulfone membrane. Our study documents initial evidence that gadobutrol can be used safely in hemodialysis patients.
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The electrically neutral, highly concentrated gadolinium chelate gadobutrol is already approved as an MR contrast agent in Europe, Canada, Australia, and New Zealand. Compared with extracellular MR contrast agents that have a gadolinium concentration of 0.5 mol/L, the highly concentrated gadobutrol (gadolinium concentration, 1.0 mol/L) offers the potential of a sharper bolus peak and an increased first-pass gadolinium concentration in blood after an IV bolus injection because of the reduced injection volume [18,19,20,21]. In a rabbit model, the concentration in the common carotid artery was found to be about 30% higher after a fast-bolus injection of the 1 mol/L gadobutrol solution than after a fast-bolus injection of the 0.5 mol/L concentration at a dose of 0.3 mmol of gadolinium per kilogram of body weight (Mühler A et al., presented at the International Society of Magnetic Resonance in Medicine and European Society for Magnetic Resonance in Medicine and Biology meeting, August 1995).
T2-weighted brain perfusion studies in rats documented an increased sensitivity to perfusion alterations after the administration of gadobutrol at higher doses (0.3-0.4 mmol/kg of body weight) and higher concentrations [20]. Preliminary results of a human cerebral perfusion study designed as an intra-individually controlled randomized two-period crossover comparative study of two concentrations of gadobutrol (0.5 and 1.0 mmol/L) in healthy volunteers documented the advantages of the 1 mol/L formulation (Benner T et al., presented at the ISMRM meeting, April 2000).
T1-weighted first-pass cardiac studies in a rabbit model that required small doses of gadolinium (0.03 mmol per kg of body weight) did not show that 1 mol/L dose of gadobutrol had any advantages over 0.5 mol/L dose of extracellular MR contrast agents [22]. The tiny injection volume of 150 µL probably masked the advantage of sharper bolus profiles attainable with the more highly concentrated gadolinium chelate [22].
However, several first-pass human studies such as perfusion imaging and MR angiography are currently under investigation. Higher doses of concentrated extracellular MR contrast agents seem to be diagnostically useful, or multiple injections of smaller doses up to the safety limit may be required for these studies [20, 23,24,25,26,27]. Nevertheless, a possibility to consider is whether higher concentrations of gadolinium chelates might degrade the quality of MR angiograms because of an increased incidence of susceptibility artifacts [28].
Because few studies of the renal tolerance for the 1 mol/L gadobutrol solution in patients with chronic renal failure have been reported, and because clinical experience with highly concentrated MR contrast agents (gadolinium, > 0.5 mol /L) is lacking in patients requiring ongoing hemodialysis treatment, a prospective evaluation of their safety profile and dialysability is critical for future use of gadobutrol in this patient population [29].
The purpose of our study was to investigate the safety and dialysability of gadobutrol (gadolinium, 1.0 mol /L) at randomly assigned doses of 0.1 or 0.3 mmol of gadolinium per kilogram of body weight in patients with end-stage renal failure who required hemodialysis treatment.
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Study Design
The objective of the randomized open-label study was to evaluate the safety
and dialysability of 1 mol/L of gadobutrol after an IV injection at randomly
assigned doses of either 0.1 or 0.3 mmol of gadolinium per kilogram of body
weight in patients with chronic renal failure who required hemodialysis
treatment. As the primary variable, the decrease in serum gadobutrol
concentration after each hemodialysis session was evaluated. Physical
examinations, vital signs, adverse events, serious adverse events, and
extensive clinical laboratory tests were defined as secondary variables.
Adverse events were defined as any illness, sign, symptom, or unfavorable
change in the clinical status that appeared or worsened after the start of
study (e.g., headache, nausea, or dizziness). Adverse events during the
clinical study that were fatal or life-threatening, resulted in serious or
permanent damage to health, required intervention to prevent permanent
impairment or damage, or necessitated or extended a stay in the hospital were
classified as serious adverse events (e.g., myocardial infarction or
life-threatening bleeding). A causal relationship to the trial medication had
to be assessed and documented for both adverse events and serious adverse
events.
Patients
The study was approved by the institutional review board and ethics
committee. Fully informed and signed consent was obtained from each patient at
least 24 hr before the study. A total of 11 patients with end-stage renal
failure (six men and five women; age range, 23-65 years; median age, 42 years)
who required hemodialysis treatment, were willing and able to continue study
participation, and had any indication for contrast-enhanced MR imaging were
enrolled. Five patients received the lower dose of gadobutrol—0.1 mmol
of gadolinium per kilogram of body weight—and six patients received the
higher dose—0.3 mmol of gadolinium per kilogram of body weight.
The patients' end-stage renal failure was attributable to hemolytic-uremic syndrome (n = 1), chronic vesicourethral reflux (n = 1), polycystic renal disease (n = 2), Goodpasture's syndrome (n = 1), chronic glomerulonephritis (n = 4), amyloidosis (n = 1), and diabetic nephropathy (n = 1). Five patients (46%) had undergone kidney transplantation and were receiving regular dialysis because of a nonfunctioning transplant. Chronic renal failure was associated with hypertension and coronary heart disease in eight (73%). All patients had negligible urine output. No restriction of medication or fluid was required before the study. MR imaging was performed on a 1.5-T scanner (Magnetom Vision; Siemens Medical Systems, Iselin, NJ) to exclude the possibility of abdominal tumor (n = 7), cerebral tumor (n = 1), parathyroid tumor (n = 1), or aortic aneurysm (n = 1) and for staging of pancreatic adenocarcinoma (n = 1).
Exclusion Criteria
Excluded from the study were patients who were younger than 18 years old,
pregnant, or lactating; patients who had received any investigational drug
within 30 days before the study; and patients who had received any contrast
material within 5 days before the study or would receive it during the
observation period. Other exclusion criteria for patients were substantially
fluctuating laboratory parameters (e.g., attributable to chemotherapy or
radiation therapy), instability of clinical findings with an unpredictable
clinical course during the observation time, acute renal failure, a
functioning transplant, a history of severe adverse reaction to drugs or
contrast agents, a history of severe anaphylactoid allergy to any other
allergen, surgery scheduled during the observation period, and any
contraindication to MR examination.
Monitoring
All patients were followed up over three successive hemodialysis sessions.
The first session was started within 2 hr after the MR study; the second, 2
days later; and the third, another 2 days after that. For each 3-hr
hemodialysis session, a 1.2 m2 low-flux polysulfone membrane (F6S;
Fresenius Medical Care, Bad Homburg, Germany) was used. For vascular access,
all patients underwent fistula cannulation with two needles. Blood flow was
constant during hemodialysis sessions (range, 150-250 mL/min; mean ±
SD, 211.3 ± 28.9 mL/min). Dialysate flow was 500 mL/min. Physical
examinations, monitoring of vital signs, and sampling of venous blood were
performed at baseline and before and after each hemodialysis session after the
IV injection of gadobutrol. Blood samples were analyzed for hematology
(leukocytes, erythrocytes, hemoglobin, hematopoietic substances, mean
corpuscular volume, and thrombocytes) and clinical chemistry (urea-nitrogen,
total protein, albumin, sodium, potassium, calcium, iron, total bilirubin,
alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase,
-glutamyl-transferase, 
-amylase, C-reactive protein, creatinine,
cystatin C, and ß2-microglobulin).
To assess the dialysability of gadobutrol, blood sampling was performed before and after each dialysis treatment. Additional arterial and venous blood samples were drawn during the first hemodialysis session at 30 and 90 min after the start of the session. For quantitative evaluation, gadolinium ion concentration was measured using inductively coupled plasma atomic emission spectrometry (Plasma 1000; Perkin Elmer, Überlingen, Germany). For each patient, the serum gadolinium concentration after injection and before dialysis was set as 100%. The relative gadolinium amounts in serum after the dialysis sessions were calculated according to the following formula: (gadolinium concentration before dialysis — gadolinium concentration after dialysis) / gadolinium concentration before dialysis x 100%. The detection limit of this method was 0.01 µg of gadolinium per milliliter.
The gadobutrol clearance was calculated during first hemodialysis session at 30 and 90 min by this formula: Clearance = {(gadobutrol concentration in the arterial blood line [in mg/mL]) — gadobutrol concentration in the venous blood line [in mg/mL]}: gadobutrol concentration in the arterial blood) x the blood flow at sampling time [in mL/min].
Statistical Analysis
For descriptive statistical analysis, the range, mean, and SD of clinical
chemistry parameters in serum were calculated. In addition, the mean and SD of
the individual differences from baseline values to postinjection values were
determined. The clinical course of each patient was analyzed by two
experienced nephrologists. No inferential statistics were performed because of
the small number of patients in each dosage group (n 
6).
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-amylase rose continuously to 73.6 µmol/L and 10,969 nkat/L 216 hr
postinjection, respectively. Another patient experiencing an acute episode of
his previously known sclerosing cholangitis showed a steady increase in
alkaline phosphatase and in -glutamyl-transferase from 7,352 nkat/L and
2,901 nkat/L at baseline, respectively, up to 14,470 nkat/L and 4,734 nkat/L
96 hr postinjection after hemodialysis. One serious adverse event occurred in a 40-year-old man who was hospitalized because of recurrent hemoptysis. On day 4 of the observation period, a biopsy of the patient's upper right bronchus was performed during a scheduled bronchoscopy. The intervention was complicated by bleeding that could be locally controlled. The bleeding resulted in a drop of hemoglobin and hematocrit from 6.5 and 0.4 mmol/L at baseline, respectively, to 5.2 and 0.3 mmol/L 96 hr postinjection. The patient was transferred to the intensive care unit and recovered well. At no time was the patient's bleeding life-threatening. No hemodynamic changes or prolongation of hospitalization resulted, and the serious adverse event was considered not drug-related.
A 3-hr hemodialysis session using a 1.2 m2 low-flux polysulfone membrane resulted in a mean and SD for the eliminated fraction of gadobutrol of 68.2% ± 12.7%. After the second and third hemodialysis sessions, the total amount of eliminated gadobutrol increased to 94.1% ± 4.3% and 98.0% ± 1.8%, respectively (Fig. 1). The higher mean blood flow and the lower mean body weight in the low-dose group (0.1 mmol of gadolinium per kilogram of body weight) compared to the high-dose group (0.3 mmol of gadolinium per kilogram per body weight) resulted in increased fractions of eliminated gadobutrol at 30, 90, and 180 min of the first hemodialysis treatment (Table 1). After 30 and 90 min of the first hemodialysis session, the mean and SD of gadobutrol clearances were 126.1 ± 17.8 mL/min and 126.6 ± 24.5 mL/min, respectively (Fig. 2).
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In this initial study, the new highly concentrated MR contrast agent gadobutrol (1 mol/L) appears to be safe at doses of either 0.1 or 0.3 mmol of gadolinium per kilogram of body weight in patients with end-stage renal failure requiring hemodialysis. These data are consistent with previous studies in hemodialysis patients for extracellular gadolinium chelates (gadolinium, 0.5 mol/L), such as gadopentetate dimeglumine, gadodiamide, and gadoteridol [9, 10, 12, 15].
The dialysability of gadolinium chelates depends on the characteristics of the contrast agent and the dialysis equipment [30, 31]. Agent characteristics are molecular weight, shape, charge, degree of aggregation, and protein-binding capacity. Molecular weight, which is comparable for gadopentetate dimeglumine, gadodiamide, gadoteridol, and gadobutrol, is considered the most important factor for extracellular gadolinium chelates [30, 31]. The concentration of the contrast agent might not have any potential effect on hemodialysis. The characteristics of hemodialysis (membrane type and surface area, blood flow rate, dialysate flow rate, and duration of treatment) may vary considerably from institution to institution [30]. Therefore, the few clinical studies with other extracellular gadolinium chelates (gadolinium, 0.5 mol/L) were each performed under varying conditions [9, 10, 12, 15].
The present data indicate that the highly concentrated gadobutrol can be effectively removed by hemodialysis. The mean elimination of 68.2% after a 3-hr hemodialysis session and 98.0% after three hemodialysis sessions (a total of 9 hr of hemodialysis), is comparable to other extracellular gadolinium chelates (gadolinium, 0.5 mol/L). At the August 1995 meeting of the International Society of Magnetic Resonance in Medicine and European Society for Magnetic Resonance in Medicine and Biology, La France et al. reported a body clearance rate of 98% for gadoteridol (0.3 mmol of gadolinium per kilogram of body weight) after three hemodialysis sessions using a cellulose acetate membrane. Choyke et al. [14] reported an anephric patient who underwent a 4-hr hemodialysis session 16 hr after the injection of gadopentetate dimeglumine (gadolinium, 0.1 mmol/kg of body weight) whose elimination rate during the observation period was 92.7%. Data on blood and dialysate flow and on the pore size and area of the membrane are missing in both reports. Krahe et al. [12] performed three 3-hr sessions of hemodialysis (using Fresenius F60 high-flux membrane with blood flow of 250 mL/min) in 10 patients after the injection of gadopentetate dimeglumine (gadolinium, 0.1 mmol/kg body weight) resulting in a mean elimination rate of 97%. In another study by Joffe et al. [9], a mean of 68.0% ± 5.7% of gadodiamide (gadolinium, 0.1 mmol/kg of body weight) administered IV was eliminated after the first hemodialysis session (4-hr session using low-flux biocompatible membranes). After the fourth hemodialysis session, 1% of the injected dose was still in the extracellular fluid space [9]. These findings with comparable extracellular gadolinium chelates are very similar to our data indicating that no change in dialysis schedule of hemodialysis patients is required after the IV injection of the highly concentrated gadobutrol.
However, the type of hemodialysis membrane is considered one of the main factors influencing the dialysability of a substance [30]. In the literature, comparisons regarding the types of membrane associated with the clearance of gadolinium chelates is limited. Using a cellulose diacetate membrane (FB-210-U; Nipro Medical Products, Osaka, Japan; pore size, 3.8 nm; area, 2.1 m2), the mean clearance of gadopentetate dimeglumine was 175.8-185.8 mL/min compared with 120.5-130.1 mL/min using a cellulose triacetate membrane (FB-210-M; Nipro Medical Products; pore size, 7.0 nm; area, 2.1 m2). The elimination rate was 62.2% at 2 hr and 81.1% at 4 hr with the diacetate (210-U) membrane and 76.1% at 2 hr and 91.1% at 4 hr with the triacetate (210-M) membrane (dialysate flow, 500 mL/min; blood flow, 200 mL/min) [31]. The mean clearance of 126.1 ± 17.8 mL/min (30 min into the first hemodialysis session) and 126.6 ± 24.5 mL/min (90 min into the first hemodialysis session) indicates an efficient elimination of gadobutrol from serum using a 1.2 m2 low-flux polysulfone membrane. The wide range of clearance data in the literature is based on different conditions of dialysis equipment, but the data on the final elimination rates and guidelines for hemodialysis of gadolinium chelates are comparable. However, our data are also confirmed by in vitro studies of comparable extracellular gadolinium chelates (gadolinium, 0.5 mol/L) requiring 12-14 hr of hemodialysis to remove 97% of the initial dose [2].
Our study is limited by the small number of patients in each dosage groups of gadobutrol (gadolinium, 0.1 or 0.3 mmol/kg of body weight). A descriptive statistical analysis based on calculated measures had to be performed, and calculation of significance had to be excluded. No feces collection was performed to exclude extrarenal elimination of gadobutrol. However, in vivo studies in patients with impaired renal function indicate an excretion rate in feces of less than 2% of extracellular gadolinium chelates during an observation period of 120 hr [9, 12, 32]. Therefore, extrarenal elimination of extracellular gadolinium chelates is negligible in patients with impaired renal function [9].
In conclusion, these initial results document that 1 mol/L of gadobutrol appears to be a safe MR contrast agent at doses of either 0.1 or 0.3 mmol of gadolinium per kilogram of body weight in patients requiring hemodialysis. When low-flux polysulfone dialyzers are used, gadobutrol is effectively removed after three dialysis sessions, and no change in the dialysis schedule is required. These data may not apply to peritoneal dialysis because the flow dynamics are different, and therefore, separate in vivo studies need to be performed.
Acknowledgments
We thank Elke Einck and Birgit Fahrenkamp for image acquisition.
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= 0.3 mmol of gadolinium per kilogram of body weight.