A preclinical study to investigate the development of nephrogenic systemic fibrosis: a possible role for gadolinium-based contrast media.

OBJECTIVES: Several recent publications have suggested an association between the administration of gadolinium (Gd)-based contrast agents and the occurrence of Nephrogenic Systemic Fibrosis (NSF), an acquired disorder marked by skin thickening and fibrosis occurring in patients with severe renal dysfunction. The aim of this study was to establish a preclinical experimental setting to investigate the possible link between NSF and Gd-based contrast agents, and specifically the role of Gd and/or depletion of endogenous metal ions as possible triggers for NSF. MATERIALS AND METHODS: Thirty-five healthy male rats received repeated intravenous injections of Magnevist (gadopentetate dimeglumine; Gd-DTPA), Omniscan (gadodiamide; Gd-DTPA-BMA), or gadodiamide without caldiamide at a dose of 2.5 mmol Gd/kg body weight over at least 20 days to simulate the exposure to Gd-containing contrast agents in patients with severe renal dysfunction. In addition, caldiamide (the excess ligand in Omniscan) and Gd-ethylenediamine tetraacetic acid (Gd-EDTA) as a positive control, and saline as a negative control were studied. Histopathologic and immunohistochemical analysis of the skin was performed. Gd and zinc concentrations were measured in skin, femur, and liver tissue by atomic emission spectrometry. RESULTS: Rats receiving Gd-EDTA, gadodiamide without caldiamide, and Omniscan developed epidermal ulceration and acanthosis, dermo-epidermal clefts, minimal-to-slight dermal fibrosis, and increased dermal infiltration of different cells, partly positive for CD34 fibrocytes. No such NSF-like macroscopic lesions were observed in the saline, caldiamide, and Magnevist groups. High Gd concentrations in the skin were found in the Gd-EDTA, gadodiamide without caldiamide, and Omniscan groups. In the Magnevist group, Gd levels in the skin were 10-times lower than in the Omniscan-treated animals but elevated compared with saline. CONCLUSIONS: A preclinical experimental setting has been established where NSF-like lesions could be observed. The link between the application of Gd-based contrast media and the induction of NSF-like lesions was established. The data indicate that the observed skin lesions are related to the release of Gd and not to the depletion of endogenous ions. The investigations further suggest potential importance of the stability of Gd-based contrast agents.

Gadofluorine-enhanced magnetic resonance imaging of carotid atherosclerosis in Yucatan miniswine.

OBJECTIVE: The aim of this study was to determine whether gadofluorine, a paramagnetic magnetic resonance imaging (MRI) contrast agent, selectively enhances carotid atherosclerotic plaques in Yucatan miniswine. METHODS: Atherosclerotic plaques were induced in the left carotid arteries (LCA) of Yucatan miniswine (n=3) by balloon denudation and high cholesterol diet. T1-weighted MRI was performed before and 24 hours after gadofluorine injection (at a dose of 100 micromol/kg) to assess the enhancement of the balloon-injured LCA wall relative to healthy, uninjured right carotid artery (RCA) wall. Histopathology was performed to verify the presence and composition of the atherosclerotic plaques imaged with MRI. RESULTS: Gadofluorine was found to enhance LCA atherosclerotic lesions relative to RCA wall by 21% (P<0.025) 24 hours after contrast injection. Enhancement of healthy LCA wall relative to healthy RCA wall was not observed. CONCLUSION: Gadofluorine selectively enhances carotid atherosclerotic plaques in Yucatan miniswine. Gadofluorine appears to be a promising MR contrast agent for detection of atherosclerotic plaques in vivo.

CT angiography with gadolinium-based contrast media.

RATIONALE AND OBJECTIVES: To evaluate the potential use of gadolinium (Gd)-based contrast media, especially that of Gadovist, a 1-molar Gd medium, in computed tomography (CT) and compare our findings with standard iodinated contrast media. MATERIAL AND METHODS: Using a live rabbit and an acrylic CT body phantom for comparative CT imaging of Gd- and I-based media. The images were acquired at 80, 100, and 120 kVp, using fixed standard beam filtration. The phantom study used serial dilutions of the Magnevist and Ultravist 300 (2.4-molar I), whereas the animal study used different volumes of Gadovist, Magnevist (0.5 molar Gd), and Ultravist administered intravenously. RESULTS: At 80 kVp for the same injection volumes of Gadovist and Ultravist, the image contrast enhancement of the aorta with Gadovist was 40% lower than that of Ultravist. In the phantom studies, however, for the same kVp settings the CT image contrast was up to fourfold higher for Gd compared with iodine when comparing the same molar concentrations of the two elements in the solutions. CONCLUSION: These results indicate a potential of Gd-based media for clinical CT angiography and provide incentive for further investigation of this subject.

Detection of atherosclerotic plaque with Gadofluorine-enhanced magnetic resonance imaging.

BACKGROUND: The purpose of this study was to visualize atherosclerotic plaques independently of luminal narrowing using T1-weighted contrast-enhanced MRI. METHODS AND RESULTS: Eight Watanabe heritable hyperlipidemic (WHHL) rabbits, aged 9 to 18 months, and 8 age-matched controls (New Zealand White rabbits) underwent MRI of the aortic arch before and up to 48 hours after injection of 100 micromol/kg Gadofluorine (Schering AG). Additionally, 8 WHHL rabbits were examined with Magnevist (Schering AG). A half-Fourier acquisition single-shot turbo-spin-echo (HASTE) sequence and a T1-weighted inversion-recovery turbo fast, low-angle shot sequence were used for data acquisition. Immediately after the MR examination, the animals were killed, the aorta was stained with Sudan red, and ex vivo imaging of the stained aortic specimens was performed. Additionally, gadolinium concentrations in plaque (Sudan-positive) and normal (Sudan-negative) aortic wall segments were measured. Plain MR imaging revealed no plaques in the aortic arch in either animal group. Enhancement occurred in the aortic wall of all WHHL rabbits examined with Gadofluorine but not in the vessel wall of animals examined with Magnevist and the control group. Sudan red staining demonstrated multiple plaques in the aortic arch of all WHHL rabbits. Ex vivo imaging demonstrated that the area of hyperenhancement matched the area of plaques stained with Sudan red. The gadolinium concentration was 7+/-5 nmol/g for normal aortic wall of the control group and 368+/-30 nmol/g for aortic wall with plaque in WHHL. CONCLUSIONS: Gadofluorine enhances the imaging of atherosclerotic plaques and enables improved plaque detection of even nonstenotic lesions that are not visible on unenhanced MRI.

Lipid-rich atherosclerotic plaques detected by gadofluorine-enhanced in vivo magnetic resonance imaging.

BACKGROUND: MRI of specific components in atherosclerotic plaque may provide information on plaque stability and its potential to rupture. We evaluated gadofluorine in atherosclerotic rabbits using a new MR sequence that allows plaque detection within 1 hour after injection and assessed enhancement in lipid-rich and non-lipid-rich plaques. METHODS AND RESULTS: Twelve rabbits with aortic plaque and 6 controls underwent MRI before and up to 24 hours after gadofluorine injection (50 micromol/kg). Two T1-weighted, segmented gradient-echo sequences (TFL) were compared to enhance vessel wall delineation after injection: (1) an inversion-recovery prepulse (IR-TFL) or (2) a combination of inversion-recovery and diffusion-based flow suppression prepulses (IR-DIFF-TFL). With the use of IR-TFL at 1 hour after injection, the vessel wall was not delineated because of poor flow suppression; at 24 hours after injection, the enhancement was 37% (P<0.01). IR-DIFF-TFL showed significant enhancement after versus before contrast (1 hour: 164% [P<0.005]; 24 hours: 207% [P<0.001]). At 1 hour and 24 hours after injection, the contrast-to-noise ratio was higher with the use of IR-DIFF-TFL than with IR-TFL (1 hour: 13.0+/-7.7 versus -19.8+/-10.3 [P<0.001]; 24 hours: 15.2+/-5.9 versus 11.4+/-8.9, respectively [P=0.052]). There was no enhancement in the vessel wall after gadofluorine injection in the control group. A strong correlation was found (r2=0.87; P<0.001) between the lipid-rich areas in histological sections and signal intensity in corresponding MR images. This suggests a high affinity of gadofluorine for lipid-rich plaques. CONCLUSIONS: Gadofluorine-enhanced MRI improves atherosclerotic plaque detection. The IR-DIFF-TFL method allows early detection of atherosclerotic plaque within 1 hour after gadofluorine injection.

Imaging of myocardial infarction: comparison of magnevist and gadophrin-3 in rabbits.

OBJECTIVES: This study was designed to determine the enhancement profile of a necrosis-specific contrast agent (gadophrin III) in comparison to a standard extracellular agent on T1-weighted magnetic resonance (MR) images in acute and chronic myocardial infarctions (MIs). BACKGROUND: Contrast-enhanced MR imaging demonstrated the ability to accurately quantify infarct size; however, some controversies persist about which contrast medium is best suited. METHODS: Fifteen rabbits underwent thoracotomy and permanent occlusion of a branch of the left coronary artery. Two animals died before imaging, eight were examined 48 h after occlusion and five animals were imaged six weeks following induction of infarction. All animals received 50 micromol/kg of gadophrin-3 24 h before the MR examination. Continuous short-axis views were collected using an inversion recovery turbo fast low angle shot sequence. Imaging was repeated 5 to 10 min following additional injection of 100 micromol/kg of Magnevist. The area of hyperenhancement demarcated following gadophrin-3 injection was compared with the region of hyperenhancement seen on gadophrin-3 plus Magnevist enhanced image using triphenyltetrazolium chloride (TTC) staining as the standard of reference. RESULTS: In acute MI the mean difference in size of hyperenhancement seen on the two different in vivo MR scans was -1.8 +/- 6.0 mm(2) (p > 0.05). Both measurements showed excellent agreement with TTC staining. Chronic MIs showed no enhancement with gadophrin-3, whereas application of Magnevist resulted in hyperenhancement. CONCLUSIONS; Standard extracellular contrast agents do not overestimate the size of acute MI. The combination of gadophrin-3 and Magnevist can distinguish acute and chronic myocardial injury because chronic MIs do not enhance with gadophrin-3.

Comparison of magnetic properties of MRI contrast media solutions at different magnetic field strengths.

RATIONALE AND OBJECTIVES: To characterize and compare commercially available contrast media (CM) for magnetic resonance imaging (MRI) in terms of their relaxivity at magnetic field strengths ranging from 0.47 T to 4.7 T at physiological temperatures in water and in plasma. Relaxivities also were quantified in whole blood at 1.5 T. METHODS: Relaxivities of MRI-CM were determined by nuclear magnetic resonance (NMR) spectroscopy at 0.47 T and MRI phantom measurements at 1.5 T, 3 T, and 4.7 T, respectively. Both longitudinal (T1) and transverse relaxation times (T2) were measured by appropriate spin-echo sequences. Nuclear magnetic resonance dispersion (NMRD) profiles were also determined for all agents in water and in plasma. RESULTS: Significant dependencies of relaxivities on the field strength and solvents were quantified. Protein binding leads to both increased field strength and solvent dependencies and hence to significantly altered T1 relaxivity values at higher magnetic field strengths. CONCLUSIONS: Awareness of the field strength and solvent associated with relaxivity data is crucial for the comparison and evaluation of relaxivity values. Data observed at 0.47 T can thus be misleading and should be replaced by relaxivities measured at 1.5 T and at 3 T in plasma at physiological temperature.

Gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic acid interaction with clinical drugs in rats.

RATIONALE AND OBJECTIVES: To investigate whether the hepatic enhancement characteristics of Gd-EOB-DTPA are influenced by the preapplication of a variety of commonly used clinical pharmaceuticals (eg, antibiotics, antineoplastic drugs, corticosteroids, antiarrhythmia drugs, antianxiety drugs, scopolamine, and xanthine derivatives). MATERIALS AND METHODS: Eleven commercially available drugs (prednisolone, rifampicin, doxorubicin hydrochloride, cisplatin, propranolol hydrochloride, scopolamine butylbromide, theophylline, ampicillin, cefotaxime sodium, verapamil hydrochloride, and diazepam) were intravenously (IV) injected in rats at three to five times the clinical dose (n = 3 or 6 per drug). A control group of rats was given saline (n = 6). Gd-EOB-DTPA (25 micromol Gd/kg IV) was administered to rats 30 minutes after the injections of the clinical drugs. Liver MR imaging was performed with a 2.0 T animal imager before and up to 60 minutes after injection. Enhancement (ENH) (%) and area under the data from time versus enhancement curve (AUD) were calculated. RESULTS Rifampicin was the only drug that significantly decreased the hepatic enhancement by Gd-EOB-DTPA. Both the maximum enhancement of the liver and the AUD were significantly reduced when rifampicin was preinjected. Preinjection of prednisolone, doxorubicin hydrochloride, cisplatin or propranolol hydrochloride yielded a slightly but significant increased maximum enhancement of the liver. Furthermore, the enhancement declined more slowly when these drugs were preadministered, yielding a large AUD. None of the other drugs showed a significant effect on hepatic enhancement. CONCLUSION: Rifampicin exerted a clinically significant decrease on hepatic enhancement by Gd-EOB-DTPA. Prednisolone, doxorubicin hydrochloride, cisplatin, or propranolol hydrochloride slightly but significantly increased the hepatic enhancement by Gd-EOB-DTPA.

Dynamic contrast-enhanced MR imaging of VX2 carcinomas after X-irradiation in rabbits: comparison of gadopentetate dimeglumine and a macromolecular contrast agent.

RATIONALE AND OBJECTIVES: To compare enhancement patterns of gadomer-17 with those of gadopentetate dimeglumine in VX2 carcinomas after irradiation on rabbits. METHODS: Twelve rabbits with VX2 carcinoma in the thigh underwent dynamic contrast-enhanced magnetic resonance (MR) imaging with gadopentetate dimeglumine and gadomer-17 at 24-hour intervals before (n = 12), 3 days (group 1, n = 12), 1 month (group 2, n = 8) and 2 months (group 3, n = 4) after 30 Gy irradiation. After taking postirradiation MR images, 4 rabbits were killed for histopathologic examination at each time interval. The enhancement characteristics in MR imaging and morphology of tumor vessels in histopathologic specimen were assessed. RESULTS: After gadopentetate dimeglumine injection, the enhancement characteristics were not different among tumors before and after irradiation (P > 0.05). For gadomer-17, the enhancement ratios decreased after irradiation. The shape of the curves for tumor enhancement before irradiation was significantly different from curves of group 1(P < 0.05). The specimens from group 3 showed sclerosis and wall thickening in arterioles. CONCLUSIONS: Dynamic contrast-enhanced MR imaging with a gadomer-17 reveals increased capillary permeability at an early phase after irradiation and chronic obliterating vasculopathy at delayed phase.

New contrast media designed for x-ray energy subtraction imaging in digital mammography.

RATIONALE AND OBJECTIVES: In contrast-enhanced dual-energy subtraction imaging 2 images acquired postcontrast media administration at different energies are subtracted to highlight structures hidden in the absence of contrast media. X-ray spectra of the newly developed digital full-field mammography units (GE Senographe 2000 D) are dominated by the emission lines of the Mo or Rh anodes. The K-edge of Zirconium (Zr) is flanked by these 2 emission lines. Thus, the attenuation of Zr should experience a pronounced change of attenuation in parallel with a change of anodes. Under clinically relevant conditions, the contrasting behavior of Zr should be compared with that of other elements having K-edge energies outside the window spanned by the 2 anode emission lines. METHODS: Solutions containing the contrasting elements Br, Y, Zr, I, and Gd were investigated for dual-energy subtraction in digital mammography with the 2 anode/filter settings (Mo/Mo and Rh/Rh). These solutions were investigated in phantom studies in the energy range conventionally used in mammography. Additionally, the contrasting behavior of Zr and I was compared in an in vivo study in rats. RESULTS: The sweeping over the K-edge by alternating between the Mo and Rh anodes increases the detection of Zr in energy subtraction imaging at constant high voltage. This procedure does not lead to sufficient contrast enhancement for iodine-based contrast media which become detectable by increasing the high voltage to 40-49 kV. CONCLUSION: The instrumental and physical data outlined predestine Zr as contrasting element with a high potential for energy subtraction imaging in digital mammography in the energy range conventionally applied.

Dynamic enhancement features of gadophrin-2 on magnetic resonance imaging: an experimental model of VX2 carcinoma and bacterial abscess in rabbit thigh.

RATIONALE AND OBJECTIVES: To determine the dynamic enhancement features of malignant tumor and bacterial abscess in rabbits on magnetic resonance imaging (MRI) after injection of gadolinium mesoporphyrin (gadophrin-2) and to correlate them with histopathologic findings. METHODS: Six VX2 carcinomas and six bacterial abscesses were experimentally induced in either thigh of six rabbits. Dynamic T1-weighted MRI was performed before and 1, 3, 5, 10, 30 minutes and 16, 21, 72 hours after intravenous injection of gadophrin-2 (0.05 mmol/kg). The enhancement ratios of lesions were calculated for each time point. All tumors and abscesses were sectioned along the same plane of MR images for a detailed MRI-histopathologic correlation. RESULTS: In tumors and abscesses, peripheral-rim enhancement appeared on MRI at 1, 3, 5, 10, 30 minutes after injection of gadophrin-2. The lesions showed peripheral enhancement with irregular central enhancement or diffuse enhancement after 16 and 21 hours, and there was diffuse enhancement of the entire lesion after 72 hours. Enhancement ratios in tumor-necrosis mixed area and the pure necrotic area in VX2 carcinoma and the central cavity in bacterial abscess were significantly lower than that in the compact cellular portion in VX2 carcinoma and the wall of abscess at early phase (P < 0.01). On delayed phase MRI, there was no statistical significance in enhancement ratio of three histologic parts of VX2 carcinoma (P > 0.05) and two histologic parts of abscess (P > 0.05). Rapid enhancement at early phase with diminishing signal intensity at delayed phase is indicative of viable compact tumor and delayed strong enhancement is indicative of necrosis. CONCLUSION: It is difficult to distinguish an abscess from a tumor on gadophrin-2 enhanced MRI especially when intratumoral necrosis is prominent. However, the trend and degree of enhancement by gadophrin-2 could be helpful in discrimination between viable tumor and tumor necrosis.

Tissue-specific MR contrast agents.

The purpose of this review is to outline recent trends in contrast agent development for magnetic resonance imaging. Up to now, small molecular weight gadolinium chelates are the workhorse in contrast enhanced MRI. These first generation MR contrast agents distribute into the intravascular and interstitial space, thus allowing the evaluation of physiological parameters, such as the status or existence of the blood-brain-barrier or the renal function. Shortly after the first clinical use of paramagnetic metallochelates in 1983, compounds were suggested for liver imaging and enhancing a cardiac infarct. Meanwhile, liver specific contrast agents based on gadolinium, manganese or iron become reality. Dedicated blood pool agents will be available within the next years. These gadolinium or iron agents will be beneficial for longer lasting MRA procedures, such as cardiac imaging. Contrast enhanced lymphography after interstitial or intravenous injection will be another major step forward in diagnostic imaging. Metastatic involvement will be seen either after the injection of ultrasmall superparamagnetic iron oxides or dedicated gadolinium chelates. The accumulation of both compound classes is triggered by an uptake into macrophages. It is likely that similar agents will augment MRI of atheriosclerotic plaques, a systemic inflammatory disease of the arterial wall. Thrombus-specific agents based on small gadolinium labeled peptides are on the horizon. It is very obvious that the future of cardiovascular MRI will benefit from the development of new paramagnetic and superparamagnetic substances. The expectations for new tumor-, pathology- or receptor-specific agents are high. However, is not likely that such a compound will be available for daily routine MRI within the next decade.

Vascular enhancement in early dynamic liver MR imaging in an animal model: comparison of two injection regimen and two different doses Gd-EOB-DTPA (gadoxetic acid) with standard Gd-DTPA.

OBJECTIVES: To investigate the influence of 2 different doses and injection rates on the enhancement of liver vasculature in Gd-EOB-DTPA enhanced liver MRI compared with the standard dose Gd-DTPA. MATERIALS AND METHODS: This animal experimental study has been approved by the local authorities. In 5 pigs, a time-resolved T1w 3D GRE sequence, and in a second experiment, a single-slice turbo FLASH T1w sequence with 3 frames/s were started each with contrast agent application of Gd-EOB-DTPA and Gd-DTPA. Three sets with different doses were performed with an injection rate of 1 and 2 mL/s which are as follows: A, Standard dose: 25 [mu]mol Gd-EOB-DTPA/kg body-weight (bw); B, Double dose: 50 [mu]mol Gd-EOB-DTPA/kg bw; and C, Standard dose: 100 [mu]mol Gd-DTPA/kg bw. Signal intensities were measured in aorta, vena cava inferior, portal vein, and liver parenchyma, and time-signal-to-noise (SNR)-curves were generated. The increase in SNR from baseline and several perfusion parameters were calculated. Statistical significance was tested with the Wilcoxon rank test at a significance level of P = 0.05. RESULTS: Mean peak enhancement (SNR) in the aorta was not significantly different for set A, B, and C with the same injection rate. Mean peak enhancement in the aorta was significantly higher for set A at 1 mL/s than at 2 mL/s (159.1 vs. 144.4, P = 0.043). Mean peak enhancement in the PV, the vena cava inferior, and the liver parenchyma was significantly lower for set A compared with set B and set C, at both injection speeds. The full width at half max was significantly longer for injection protocols with 1 as compared with 2 mL/s for sets A and set B. Set A with 1 mL/s reached similar values as compared with set C with 2 mL/s for the full width at half max (8.92 vs. 9.40; P = 0.35), for the area-under-the curve (1736.64 vs. 1912.74; P = 0.69) and the maximal signal-to-noise ratio (25.21 vs. 25.37; P = 0.69). CONCLUSION: Despite the lower amount of gadolinium in the standard dose of Gd-EOB-DTPA, the results showed that the arterial enhancement in Gd-EOB-DTPA-enhanced dynamic liver MRI was comparable to Gd-DTPA. This result can be explained mainly by the higher relaxivity. Choosing a lower injection rate additionally supported to compensate for the lower injection volume by stretching the bolus without decreasing the peak. In this respect, an injection rate of 1 mL/s showed better results with regard to the arterial enhancement compared with 2 mL/s.

Increased neovascularization in advanced lipid-rich atherosclerotic lesions detected by gadofluorine-M-enhanced MRI: implications for plaque vulnerability.

BACKGROUND: Inflammation and neovascularization may play a significant role in atherosclerotic plaque progression and rupture. We evaluated gadofluorine-M-enhanced MRI for detection of plaque inflammation and neovascularization in an animal model of atherosclerosis. METHODS AND RESULTS: Sixteen rabbits with aortic plaque and 6 normal control rabbits underwent gadofluorine-M-enhanced MRI. Eight rabbits had advanced atherosclerotic lesions, whereas the remaining 8 had early lesions. Magnetic resonance atherosclerotic plaque enhancement was meticulously compared with plaque inflammation and neovessel density as assessed by histopathology. Advanced plaques and early atheroma were enhanced after gadofluorine-M injection. Control animals displayed no enhancement. After accounting for the within-animal correlation of observations, mean contrast-to-noise ratio was significantly higher in advanced plaques than compared with early atheroma (4.29+/-0.21 versus 3.00+/-0.32; P=0.004). Macrophage density was higher in advanced plaques in comparison to early atheroma (geometric mean=0.50 [95% CI, 0.19 to 1.03] versus 0.25 [0.07 to 0.42]; P=0.05). Furthermore, higher neovessel density was observed in advanced plaques (1.83 [95% CI, 1.51 to 2.21] versus 1.29 [0.99 to 1.69]; P=0.05). The plaque accumulation of gadofluorine-M correlated with increased neovessel density as shown by linear regression analysis (r=0.67; P<0.001). Confocal and fluorescence microscopy revealed colocalization of gadofluorine-M with plaque areas containing a high density of neovessels. CONCLUSIONS: Gadofluorine-M-enhanced MRI is effective for in vivo detection of atherosclerotic plaque inflammation and neovascularization in an animal model of atherosclerosis. These findings suggest that gadofluorine-M enhancement reflects the presence of high-risk plaque features believed to be associated with plaque rupture. Gadofluorine-M plaque enhancement may therefore provide functional assessment of atherosclerotic plaque in vivo.

Stability of gadolinium-based magnetic resonance imaging contrast agents in human serum at 37 degrees C.

OBJECTIVES: Assessment of the complex stability and Gd3+ dissociation rate of all marketed gadolinium-based MRI contrast agents (GBCA) in human serum at pH 7.4 and 37 degrees C. METHODS AND RESULTS: The kinetic profiles of Gd3+ dissociation of GBCAs were determined by incubation for 15 days in human serum from healthy volunteers at a concentration of 1 mmol/L, pH 7.4, and 37 degrees C. The initial rates of Gd3+ release and the amounts of Gd3+ released after 15 days were established by HPLC-ICP-MS analysis. In an attempt to simulate the situation in patients with end-stage renal disease who often have elevated serum phosphate levels, the influence of 10 mmol/L phosphate on Gd3+ dissociation was also investigated.The GBCAs were grouped and ranked in the following order according to their stabilities in native human serum at pH 7.4 and 37 degrees C [% Gd release after 15 days and initial rate (%/d) (95% confidence interval) in brackets]. NONIONIC LINEAR GBCAS: Optimark [21 (19-22) %, 0.44 (0.40-0.51) %/d) and Omniscan [20 (17-20) %, 0.16 (0.15-0.17) %/d]. IONIC LINEAR GBCAS: Magnevist [1.9 (1.2-2.0) %, 0.16 (0.12-0.36) %/d], Multihance [1.9 (1.3-2.1) %, 0.18 (0.13-0.38) %/d], Vasovist [1.8 (1.4-1.9) %, 0.12 (0.11-0.18) %/d], and Primovist [1.1 (0.76-1.2) %, 0.07 (0.05-0.08) %/d]. MACROCYCLIC GBCAS: Gadovist, Prohance, and Dotarem (all < limit of quantification of 0.1%, <0.007%/d).In the presence of additional 10 mmol/L phosphate in serum, the initial Gd release rates of the nonionic linear GBCAs, Omniscan, and Optimark increased about 100-fold, and, after 15 days, the amount of Gd3+ released from these agents was more than 75% higher than in native serum. The initial rates found for the ionic linear GBCAs increased about 12- to 30-fold, but, despite this, increase in the initial rate, the amount of Gd3+ released after 15 days was comparable to that in native serum. The elevated phosphate level did not lead to any measurable release of Gd3+ from the 3 macrocyclic GBCAs. CONCLUSIONS: The release of Gd from all linear Gd3+ complexes in human serum was several orders of magnitude greater than predicted by the conditional stability constants. After 15 days, release of Gd3+ from the nonionic linear GBCAs was about 10 times higher than from the ionic linear GBCAs. Elevated serum phosphate levels accelerated the release of Gd3+ from nonionic linear GBCAs and, to a lesser degree, from the ionic linear GBCAs. All 3 macrocyclic GBCAs remained stable in human serum at both normal and elevated phosphate levels.

Gadolinium-based contrast agents and their potential role in the pathogenesis of nephrogenic systemic fibrosis: the role of excess ligand.

PURPOSE: To investigate the role of excess ligand present in gadolinium (Gd) -based contrast agents in the development of nephrogenic systemic fibrosis (NSF). Using a dosing regimen to simulate the exposure seen in patients with severe renal impairment, we investigated the effect of excess ligand on Gd-deposition and the depletion of endogenous ions. MATERIALS AND METHODS: Gadodiamide and gadoversetamide were formulated with 0%, 5%, and 10% excess ligand. Forty-two, healthy, male Hannover Wistar rats received daily intravenous injections of each formulation over a period of 20 days. At the end of the study, histopathological analysis of the skin was performed and the concentrations of Gd, Zn, and Cu were measured in several tissues. The levels of Zn in the urine were also measured. RESULTS: The most severe skin lesions were observed after injection of formulations containing 0% free ligand and in those animals with the highest Gd concentrations in the skin. There were no significant reductions in the levels of Zn or Cu observed in the skin; however, the levels of Zn in the urine were elevated following administration of formulations with the highest amount of excess ligand. CONCLUSION: Our findings suggest that there is an inverse correlation between the amount of excess ligand present in Gd-containing contrast agents and the amount of Gd in the tissue, and further underline the importance of the inherent stability of these agents in the development of NSF.

Preclinical investigation to compare different gadolinium-based contrast agents regarding their propensity to release gadolinium in vivo and to trigger nephrogenic systemic fibrosis-like lesions.

Recent reports suggest that nephrogenic systemic fibrosis (NSF) is associated with the administration of gadolinium (Gd)-based contrast agents (GBCAs) and in particular with the stability of the Gd-complex. The aim of this investigation was to compare GBCAs and their potential to trigger NSF. Forty-two healthy male rats received repeated intravenous injections of six different GBCAs at high doses to simulate the exposure seen in patients with severe renal dysfunction. Histopathological and immunohistochemical analysis of the skin was performed, and the concentrations of Gd, zinc and copper were measured in several tissues by inductive coupled plasma atomic emission spectroscopy. Macroscopic and histological skin changes similar to those seen in NSF patients were only observed in rats receiving Omniscan. In addition, very high concentrations of Gd were observed in the animals treated with Omniscan, and, to a lesser extent, in animals treated with OptiMARK. Significantly lower levels of Gd were found after the treatment with ionic linear agents and even less after the treatment with macrocyclic agents. The data in this investigation strongly suggest that the stability of the Gd-complex is a key factor for the development of NSF-like symptoms in this experimental setting.