An Imaging Biomarker for Assessing Hepatic Function in Patients With Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: We aimed to evaluate the potential of hepatobiliary phase magnetic resonance imaging (MRI) as parameter for assessment of hepatocellular function in patients with primary sclerosing cholangitis (PSC). METHODS: We collected data from 111 patients (83 male, 28 female; median, 44 years old), from March 2012 through March 2016, with a confirmed diagnosis of PSC who underwent MRI evaluation before and after injection (hepatobiliary phase) of a hepatocyte-specific contrast agent (gadoxetate disodium). Signal intensities were measured in each liver segment. Mean relative enhancement values were calculated and correlated with findings from liver functions tests, prognostic scoring systems (model for end-stage liver disease [MELD] score; Mayo risk score; Amsterdam-Oxford-PSC score), abnormalities detected by endoscopic retrograde cholangiopancreatography (using the Amsterdam cholangiographic classification system), and clinical endpoints (liver transplantation, cholangiocarcinoma, liver-related death). Our primary aim was to associate relative enhancement values with liver function and patient outcomes. RESULTS: Most patients had moderate-stage disease and had intermediate levels of risk (median MELD score, 8 and median Mayo score, 0.27). Clinical endpoints were reached by 21 patients (6 developed cholangiocarcinoma, 8 underwent liver transplantation, and 7 patients died). The highest levels of correlations were observed for relative enhancement 20 min after contrast injection and level of alkaline phosphatase (r = -0.636), bilirubin (r = -0.646), albumin (r = 0.538); as well as international normalized ratio (r = 0.456); MELD score (r = -0.587); Mayo risk score (r = -0.535), and Amsterdam-Oxford model score (r = -0.595) (P < .0001). Relative enhancement correlated with all clinical endpoints (all P < .05). A cutoff relative enhancement value of 0.65 identified patients with a clinical endpoint with 73.9% sensitivity 92.9% specificity (area under the receiver operating characteristic curve, 0.901; likelihood ratio, 10.34; P < .0001). CONCLUSIONS: In an analysis of 111 patients with PSC, we found MRI-measured relative enhancement, using a hepatocyte-specific contrast agent, to identify patients with clinical outcomes with 73.9% sensitivity 92.9% specificity. Long-term, multicenter studies are needed to further evaluate this marker of PSC progression.

Preparation of gadolinium doped carbon dots for enhanced MR imaging and cell fluorescence labeling.

Gadolinium doped carbon dots (Gd-CDs) were prepared as a dual-modal imaging agent for enhanced MR imaging and cell fluorescence imaging. The Gd-CDs were synthesized via one-step solvent free technique with Gd-DTPA and l-arginine as the Gd and carbon sources with a quantum yield of 57.78%. The Gd-CDs exhibited good crystal structure, excellent aqueous dispersity, high colloidal stability, intense fluorescence and low cytotoxicity. The bio-TEM images revealed that the Gd-CDs could be easily internalized by cancer cells and escape from the endosomes. Furthermore, the Gd-CDs demonstrated wonderful multi-color fluoresence cell labeling ability at various excitation wavelength and much better MR contrast effect compared with commercial Gd-DTPA with a high r1 relaxivity value 6.27 mM-1s-1. In addition, Gd-CDs exhibited brighter MR signal than Gd-DTPA in the animal MR imaging test. Finally, the Gd-CDs also indicated low long-term toxicity by the serum biochemistry analysis. Thus, these results indicated that Gd-CDs would be an excellent dual-modal imaging probe for enhanced MR imaging and fluorescence imaging.

Chimeric mouse model for MRI contrast agent evaluation.

PURPOSE: While rodents are the primary animal models for contrast agent evaluation, rodents can potentially misrepresent human organ clearance of newly developed contrast agents. For example, gadolinium (Gd)-BOPTA has ~50% hepatic clearance in rodents, but ~5% in humans. This study demonstrates the benefit of chimeric mice expressing human hepatic OATPs (organic anion-transporting polypeptides) to improve evaluation of novel contrast agents for clinical use. METHODS: FVB (wild-type) and OATP1B1/1B3 knock-in mice were injected with hepatospecific MRI contrast agents (Gd-EOB-DTPA, Gd-BOPTA) and nonspecific Gd-DTPA. T1 -weighted dynamic contrast-enhanced MRI was performed on mice injected intravenously. Hepatic MRI signal enhancement was calculated per time point. Mass of gadolinium cleared per time point and percentage elimination by means of feces and urine were also measured. RESULTS: Following intravenous injection of Gd-BOPTA in chimeric OATP1B1/1B3 knock-in mice, hepatic MRI signal enhancement and elimination by liver was more reflective of human hepatic clearance than that measured in wild-type mice. Gd-BOPTA hepatic MRI signal enhancement was reduced to 22% relative to wild-type mice. Gd-BOPTA elimination in wild-type mice was 83% fecal compared with 32% fecal in chimeric mice. Hepatic MRI signal enhancement and elimination for Gd-EOB-DTPA and Gd-DTPA were similar between wild-type and chimeric cohorts. CONCLUSION: Hepatic MRI signal enhancement and elimination of Gd-EOB-DTPA, Gd-BOPTA, and Gd-DTPA in chimeric OATP1B1/1B3 knock-in mice closely mimics that seen in humans. This study provides evidence that the chimeric knock-in mouse is a more useful screening tool for novel MRI contrast agents destined for clinical use as compared to the traditionally used wild-type models.

A synthetic cartilage extracellular matrix model: hyaluronan and collagen hydrogel relaxivity, impact of macromolecular concentration on dGEMRIC.

OBJECTIVE: To develop and characterize the MR properties of a synthetic model for cartilage extra-cellular matrix using hydrogels and to determine the concentration dependence of spin-lattice (T1) and spin-spin (T2) relaxation times of hydrogels and their glycosaminoglycan and collagen components in the presence and absence of gadopentetate dimeglumine (Gd-DTPA) for use in dGEMRIC. MATERIALS AND METHODS: T1 and T2 measurements were made at 3 Tesla on a range of gelatin (i.e., collagen) and hyaluronan (i.e., glycosaminoglycan) solutions (6.25-100 g/l), alone, together in a composite, and as dityramine-bridged hydrogels. Relaxivity was calculated as a function of macromolecular concentration. RESULTS: Even at the highest concentrations, gelatin and hyaluronan solutions had T1 and T2 values significantly larger than those reported for cartilage. Only composite hydrogels with gelatin and hyaluronan concentrations naturally found in cartilage resulted in T1 values, but not T2 values, representative of cartilage. Relaxivities were slightly dependent on both hyaluronan concentration (R1 = 0.0027 l g(-1) s(-1); R2 = 0.025 l g(-1) s(-1)) and gelatin concentration (R1 = 0.0032 l g(-1) s(-1); R2 = 0.020 l g(-1) s(-1)) alone and as a composite (R1 = 0.0068 l g(-1) s(-1); R2 = 0.101 l g(-1) s(-1)). Gd-DTPA relaxivities were dependent upon macromolecular concentration and varied by 14-32% (R1 = 4.24 to 5.55 mM(-1) s(-1); R2 = 4.60 to 6.27 mM(-1) s(-1)) over the range of cartilage biochemistry. CONCLUSIONS: Without the contrast agent, hyaluronan and gelatin, alone or in a composite, have a very small impact on the relaxivities of the model system. The impact on R1 was approximately tenfold less than on R2. In contrast, macromolecular concentrations above 50 g/l significantly impacted Gd-DTPA relaxivity and should be accounted for when measuring the glycosaminoglycan content of cartilage in vivo using dGEMRIC.

Simple method for quantification of gadolinium magnetic resonance imaging contrast agents using ESR spectroscopy.

To develop an estimation method of gadolinium magnetic resonance imaging (MRI) contrast agents, the effect of concentration of Gd compounds on the ESR spectrum of nitroxyl radical was examined. A solution of either 4-oxo-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPONE) or 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL) was mixed with a solution of Gd compound and the ESR spectrum was recorded. Increased concentration of gadolinium-diethylenetriamine pentaacetic acid chelate (Gd-DTPA), an MRI contrast agent, increased the peak-to-peak line widths of ESR spectra of the nitroxyl radicals, in accordance with a decrease of their signal heights. A linear relationship was observed between concentration of Gd-DTPA and line width of ESR signal, up to approximately 50 mmol/L Gd-DTPA, with a high correlation coefficient. Response of TEMPONE was 1.4-times higher than that of TEMPOL as evaluated from the slopes of the lines. The response was slightly different among Gd compounds; the slopes of calibration curves for acua[N,N-bis[2-[(carboxymethyl)[(methylcarbamoyl)methyl]amino]ethyl]glycinato(3-)]gadolinium hydrate (Gd-DTPA-BMA) (6.22 µT·L/mmol) and gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid chelate (Gd-DOTA) (6.62 µT·L/mmol) were steeper than the slope for Gd-DTPA (5.45 µT·L/mmol), whereas the slope for gadolinium chloride (4.94 µT·L/mmol) was less steep than that for Gd-DTPA. This method is simple to apply. The results indicate that this method is useful for rough estimation of the concentration of Gd contrast agents if calibration is carried out with each standard compound. It was also found that the plot of the reciprocal square root of signal height against concentrations of contrast agents could be useful for the estimation if a constant volume of sample solution is taken and measured at the same position in the ESR cavity every time.

Imaging-Based Staging of Hepatic Fibrosis in Patients with Hepatitis B: A Dynamic Radiomics Model Based on Gd-EOB-DTPA-Enhanced MRI.

Accurate grading of liver fibrosis can effectively assess the severity of liver disease and help doctors make an appropriate diagnosis. This study aimed to perform the automatic staging of hepatic fibrosis on patients with hepatitis B, who underwent gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging with dynamic radiomics analysis. The proposed dynamic radiomics model combined imaging features from multi-phase dynamic contrast-enhanced (DCE) images and time-domain information. Imaging features were extracted from the deep learning-based segmented liver volume, and time-domain features were further explored to analyze the variation in features during contrast enhancement. Model construction and evaluation were based on a 132-case data set. The proposed model achieved remarkable performance in significant fibrosis (fibrosis stage S1 vs. S2-S4; accuracy (ACC) = 0.875, area under the curve (AUC) = 0.867), advanced fibrosis (S1-S2 vs. S3-S4; ACC = 0.825, AUC = 0.874), and cirrhosis (S1-S3 vs. S4; ACC = 0.850, AUC = 0.900) classifications in the test set. It was more dominant compared with the conventional single-phase or multi-phase DCE-based radiomics models, normalized liver enhancement, and some serological indicators. Time-domain features were found to play an important role in the classification models. The dynamic radiomics model can be applied for highly accurate automatic hepatic fibrosis staging.

Synthesis, in vitro and in vivo studies of Gd-DTPA-XDA-D1-Glc(OH) complex as a new potential MRI contrast agent.

A new type of dendritic molecules Gd-DTPA-XDA-D1-Glc(OH), which work as a functionalized ligand coordinating gadolinium(III) ion at the center of their frameworks with two glucose moieties on the molecular surfaces, were readily synthesized with high yield. The structures were established by IR, (1)H, (13)C NMR, and mass spectral studies. Its bio-distribution patterns were evaluated on rats.

Gadolinium Deposition in the Brain: Current Updates.

Gadolinium-based contrast agents (GBCAs) are commonly used for enhancement in MR imaging and have long been considered safe when administered at recommended doses. However, since the report that nephrogenic systemic fibrosis is linked to the use of GBCAs in subjects with severe renal diseases, accumulating evidence has suggested that GBCAs are not cleared entirely from our bodies; some GBCAs are deposited in our tissues, including the brain. GBCA deposition in the brain is mostly linked to the specific chelate structure of the GBCA: linear GBCAs were responsible for brain deposition in almost all reported studies. This review aimed to summarize the current knowledge about GBCA brain deposition and discuss its clinical implications.

Compound-specific recording of gadolinium pollution in coastal waters by great scallops.

Gadolinium-based contrast agents (GBCAs), routinely used in magnetic resonance imaging (MRI), end up directly in coastal seawaters where gadolinium concentrations are now increasing. Because many aquatic species could be sensitive to this new pollution, we have evaluated the possibility of using shellfish to assess its importance. Gadolinium excesses recorded by scallop shells collected in Bay of Brest (Brittany, France) for more than 30 years do not reflect the overall consumption in GBCAs, but are largely controlled by one of them, the gadopentetate dimeglumine. Although its use has been greatly reduced in Europe over the last ten years, gadolinium excesses are still measured in shells. Thus, some gadolinium derived from other GBCAs is bioavailable and could have an impact on marine wildlife.

Mass fluxes and spatial trends of xenobiotics in the waters of the city of Halle, Germany.

The behaviour and the effects of xenobiotics including pharmaceuticals and fragrances in the environment are widely unknown. In order to improve our knowledge, field investigations and modelling approaches for the entire area of the city of Halle/Saale, Germany, were performed. The distribution of the concentration values and mass fluxes are exemplified using indicators such as Bisphenol A, t-Nonylphenol, Carbamacepine, Galaxolide, Tonalide, Gadolinium and isotopes. Concentrations at a magnitude of ng/L to microg/L were found ubiquitously in the ground and surface waters. Using the concentration values, the impact of the city concerning the indicators was not always evident. Only the assessment of the mass fluxes shows significant urban impacts along the city passage. The calculation of the mass fluxes shows increasing values for all investigated xenobiotics during the city passage; only Bisphenol A stagnates. A balance model of water and indicator mass fluxes was built up for the entire city area.

Feasibility of 10-Minute Delayed Hepatocyte Phase Imaging Using a 30° Flip Angle in Gd-EOB-DTPA-Enhanced Liver MRI for the Detection of Hepatocellular Carcinoma in Patients with Chronic Hepatitis or Cirrhosis.

OBJECTIVES: To compare 10-minute (min) delayed hepatocyte phase imaging (HPI) using a 30° flip angle (FA) (10m-FA30) and 20-min delayed HPI using a 10° FA (20m-FA10) or 30° FA (20m-FA30) in Gd-EOB-DTPA-enhanced MRI in patients with chronic hepatitis or cirrhosis, in terms of lesion-to-liver contrast-to-noise ratio (CNR) for hepatocellular carcinoma (HCC) and detection sensitivity for focal hepatic lesions (FHLs). MATERIALS AND METHODS: One hundred and four patients with 168 HCCs and 55 benign FHLs who underwent Gd-EOB-DTPA-enhanced MRI with 10m-FA30, 20m-FA10, and 20m-FA30 were enrolled. Patients were divided into two groups according to the Child-Pugh classification: group A with chronic hepatitis or Child-Pugh A cirrhosis and group B with Child-Pugh B or C cirrhosis. Lesion-to-liver CNR for HCCs was compared between 10m-FA30 and 20m-FA10 or 20m-FA30 for each group. The presence of FHLs was evaluated using a four-point scale by two independent reviewers, and the detection sensitivity was analyzed. RESULTS: In group A, the CNR for HCCs (n = 86) on 10m-FA30 (165.8 ± 99.7) was significantly higher than that on 20m-FA10 (113.4 ± 71.4) and lower than that of 20m-FA30 (210.2 ± 129.3). However, there was no significant difference in the sensitivity of FHL detection between 10m-FA30 (mean 95.0% for two reviewers) and 20m-FA10 (94.7%) or 20m-FA30 (94.7%). In group B, the CNR (54.0 ± 36.4) for HCCs (n = 57) and the sensitivity (94.2%) of FHL detection for 10m-FA30 were significantly higher than those for 20m-FA10 (41.8 ± 36.4 and 80.8%, respectively) and were not different from those for 20m-FA30 (62.7 ± 44.4 and 93.3%, respectively). CONCLUSION: The diagnostic performance of 10m-FA30 was similar to or higher than 20m-FA10 or 20m-FA30 in both groups A and B. This finding indicates that 10m-FA30 could replace 20-min delayed HPI regardless of patient liver function and reduce the delay time by 10 minutes.

Tracing gadolinium-based contrast agents from surface water to drinking water by means of speciation analysis.

In recent decades, a significant amount of anthropogenic gadolinium has been released into the environment as a result of the broad application of contrast agents for magnetic resonance imaging (MRI). Since this anthropogenic gadolinium anomaly has also been detected in drinking water, it has become necessary to investigate the possible effect of drinking water purification on these highly polar microcontaminats. Therefore, a novel highly sensitive method for speciation analysis of gadolinium is presented. For that purpose, the hyphenation of hydrophilic interaction liquid chromatography (HILIC) and inductively coupled plasma-mass spectrometry (ICP-MS) was employed. In order to enhance the detection power, sample introduction was carried out by ultrasonic nebulization. In combination with a novel HILIC method using a diol-based stationary phase, it was possible to achieve superior limits of detection for frequently applied gadolinium-based contrast agents below 20pmol/L. With this method, the contrast agents Gd-DTPA, Gd-DOTA and Gd-BT-DO3A were determined in concentrations up to 159pmol/L in samples from several waterworks in a densely populated region of Germany alongside the river Ruhr as well as from a waterworks near a catchment lake. Thereby, the direct impact of anthropogenic gadolinium species being present in the surface water on the amount of anthropogenic gadolinium in drinking water was shown. There was no evidence for the degradation of contrast agents, the release of Gd(3+) or the presence of further Gd species.

Myocardial magnetic resonance imaging contrast agent concentrations after reversible and irreversible ischemic injury.

BACKGROUND: Discrepant reports have been published recently regarding the relationship of contrast-enhanced magnetic resonance image intensities to reversible and irreversible ischemic injury. Unlike image intensities, contrast agent concentrations provide data independent of the MRI technique. We used electron probe x-ray microanalysis (EPXMA) to simultaneously examine concentrations of Gd, Na, P, S, Cl, K, and Ca over a range of myocardial injuries. Methods and Results- Reversible and irreversible injury were studied in 38 rabbits divided into 4 groups defined by occlusion and reperfusion time, as well as time the animals were euthanized. Gd-DTPA was administered, and the hearts were excised and rapidly frozen, cryosectioned, freeze-dried, and examined by EPXMA in up to 3 regions: remote, infarcted, and at risk but not infarcted. Infarcted regions were defined by anti-myoglobin antibody or triphenyltetrazolium chloride staining. Regions at risk were defined by fluorescent microparticles administered during occlusion. Compared with remote regions, in acutely infarcted regions, Gd was increased (235+/-24%, P<0.005) in the same 50 x 100-microm areas in which Na was increased (154+/-5%, P<0.001) and K was decreased (52+/-8%, P<0.001). Similarly, in chronically infarcted regions, Gd was increased (472+/-78%, P<0.001) in areas in which Na was increased (332+/-28%, P<0.001) and K was decreased (47+/-5%, P<0.001). Also compared with remote regions, however, concentrations of Gd, Na, and K were not elevated after reperfusion in regions that were at risk but not infarcted (P=NS). CONCLUSIONS: Regional elevations in myocardial MRI contrast agent concentrations are exclusively associated with irreversible ischemic injury defined histologically and by regional electrolyte concentrations.

1H NMRD profiles and ESR lineshapes of Gd(III) complexes: a comparison between the generalized SBM and the stochastic Liouville approach.

A complete description of the T1-NMRD profiles and the ESR lineshape of Gd(III) complexes (S = 7/2) was presented using second-order perturbation theory (GSBM) by Zhou et al. [J. Magn. Reson. 167 (2004) 147]. This report compares the GSBM with the stochastic Liouville approach (SLA) to determine the validity of the closed analytical expressions of NMRD and the ESR lineshape functions. Both approaches give the same results at high fields while a very small divergence is observed for X- and W-band ESR lineshapes when the magnitude of the perturbation term times the correlation time approaches the limit of the perturbation regime, DeltaZFStau(f) approximately 0.1. There was a clear discrepancy between the theoretical GSBM X-band spectrum and the recorded ESR spectrum of the Gd(III) MS-325+HSA complex. This is probably due to a slow-motion effect caused by a slow modulation of the ZFS interaction. The characteristic correlation time of this slow modulation is in the range of 150 ps, which therefore cannot be due to the reorientational motion of the whole MS-325 + HSA complex.

Distinguishing intrahepatic cholangiocarcinoma from poorly differentiated hepatocellular carcinoma using precontrast and gadoxetic acid-enhanced MRI.

PURPOSE: We aimed to gain further insight in magnetic resonance imaging characteristics of mass-forming intrahepatic cholangiocarcinoma (mICC), its enhancement pattern with gadoxetic acid contrast agent, and distinction from poorly differentiated hepatocellular carcinoma (pHCC). METHODS: Fourteen mICC and 22 pHCC nodules were included in this study. Two observers recorded the tumor shape, intratumoral hemorrhage, fat on chemical shift imaging, signal intensity at the center of the tumor on T2-weighted image, fibrous capsule, enhancement pattern on arterial phase of dynamic study, late enhancement three minutes after contrast injection (dynamic late phase), contrast uptake on hepatobiliary phase, apparent diffusion coefficient, vascular invasion, and intrahepatic metastasis. RESULTS: Late enhancement was more common in mICC (n=10, 71%) than in pHCC (n=3, 14%) (P < 0.001). A fat component was observed in 11 pHCC cases (50%) versus none of mICC cases (P = 0.002). Fibrous capsule was observed in 13 pHCC cases (59%) versus none of mICC cases (P < 0.001). On T2-weighted images a hypointense area was seen at the center of the tumor in 43% of mICC (6/14) and 9% of pHCC (2/22) cases (P = 0.018). Other parameters were not significantly different between the two types of nodules. CONCLUSION: The absence of fat and fibrous capsule, and presence of enhancement at three minutes appear to be most characteristic for mICC and may help its differentiation from pHCC.

On the philosophy of optimizing contrast agents. An analysis of 1H NMRD profiles and ESR lineshapes of the Gd(III)complex MS-325+HSA.

A generalization of the modified SBM theory is developed in closed analytical form. The theory is applied to describe the paramagnetically enhanced water proton spin-lattice relaxation rates of the aqueous-systems containing a gadolinium(S=7/2) complex(MS-325) in the presence or absence of human serum albumin (HSA). MS-325 binds to HSA: in the absence of the protein the reorientational time, tauR, is short, but when HSA is added tauR becomes much longer. In this way, the effect of reorientational motion, static (Delta s), and transient (Delta t) zero-field splitting (ZFS) interactions on both the water proton relaxivity and the Gd ESR lineshapes are investigated. Two dynamic models of electron spin relaxation are presented, characterized by transient and static ZFS-interactions. X-, Q-, and W-bands ESR spectra of MS-325+HSA are analyzed in order to describe the effect on the electron spin system upon binding to a macromolecule. A computer program based on this theory is developed which calculates solvent water proton T1 NMRD profiles and the corresponding X-, Q-, U-, and W-bands ESR lineshapes.

Investigation of microenvironmental factors influencing the longitudinal relaxation times of drugs and other compounds.

The aim of this study was to investigate the microenvironmental factors likely to influence the longitudinal relaxation time of MR visible drugs or compounds in vivo at 1.5 T. The relative influence that viscosity, albumin and paramagnetic contrast agent concentrations have on the observed longitudinal relaxation times of three 19F MR detectable drugs and compounds have been investigated. Our data show that for 5-fluorouracil, flucloxacillin and tetrafluorosuccinic acid-containing phantoms, the presence of albumin at normal physiological concentrations will have relaxation effects of the same order of magnitude as that of a commonly clinically administered contrast agent, gadolinium diethylenetriamine pentaacetic acid. The contribution of viscosity is shown, in the examples studied here, to be of minor importance, contributing less than 6.5% to the observed relaxation effects. It is also demonstrated that in the presence of competitive binding of other ligands for common binding sites on albumin, the 19F longitudinal relaxation time of 5-fluorouracil can increase by up to 340% from its value in the absence of the competing ligand. The relevance of the findings to in vivo studies is discussed.

Urine profiles and kidney histology after intravenous injection of ionic and nonionic radiologic and magnetic resonance contrast media in normal rats.

RATIONALE AND OBJECTIVES: Previous studies showed that both high-osmolality and low-osmolality iodinated contrast media cause temporary albuminuria and enzymuria (presence of enzymes in urine) in normal rats. Whether the same is true with ionic high-osmolality and nonionic low-osmolality magnetic resonance (MR) contrast media is unknown. We studied urine profiles and histology after intravenous injection of four types of contrast media in rats with normal kidneys. METHODS: Urine profiles were monitored 4, 24, 48, and 72 hr after intravenous injection of saline, diatrizoate, iohexol, gadopentetate dimeglumine, and gadodiamide (4.59 mmol/kg of body weight) in normal rats. Each group included 20 male rats. After sacrifice, both kidneys were removed for examination by light microscopy (LM) and electron microscopy (EM). RESULTS: All four contrast agents caused a temporary (< 22 hr) increase in the excretion of albumin (2-5 times) and of cytoplasmic (30-100 times) and brush border (10-100 times) renal enzymes when compared with saline. The degree of albuminuria correlated well (r = 0.90) with the osmolality of the injected media, whereas the increased level of enzymuria was unrelated to the osmolality. No major differences in the enzymuric effects of the four agents were noted. LM revealed vacuoles in all kidneys exposed to radiologic contrast media but not in kidneys exposed to MR contrast media or saline. Slight vacuolation was revealed by EM after the use of MR contrast media, and significant vacuolation was evident via EM after the use of radiologic contrast media. No difference between ionic and nonionic media within each drug group was detected by either LM or EM. CONCLUSIONS: Transient renal effects are induced by both ionic and nonionic high-osmolality and low-osmolality radiologic and MR contrast media in normal rats. Both osmotic (e.g., albuminuria) and chemotoxic (e.g., enzymuria) mechanisms seem to be involved. From a morphologic point of view, the chemotoxic mechanisms seem to be of major importance.

Quantification of gadodiamide as Gd in serum, peritoneal dialysate and faeces by inductively coupled plasma atomic emission spectroscopy and comparative analysis by high-performance liquid chromatography.

An inductively coupled plasma atomic emission spectroscopy (ICP-AES) method for determination of gadodiamide as Gd in serum, peritoneal dialysate and faeces was developed. The within-day and between-day precision for determination of Gd in serum and peritoneal dialysate were 0.60-2.9 and 1.8-4.4%, respectively, and the accuracy was 98.0-99.3%. The quantification limits in serum and peritoneal dialysate were 6.5 and 1.6 microM Gd, respectively. The within-day and between-day precision determination of gadolinium in faeces were 1.0-5.3 and 2.2-7.9%, respectively, and the accuracy was 104-116%. The quantification limit was 11 nmol Gd/g dry weight. For the high-performance liquid chromatography (HPLC) method, the within-day precision in determination of gadodiamide in peritoneal dialysate was 1.2% and the accuracy was 103%. The quantification limit was 0.9 microM Gd. Comparative analysis of gadodiamide in serum and peritoneal dialysate from severely impaired renal patients by ICP-AES and HPLC revealed no metabolism of chelator or transmetallation of gadolinium, even in samples obtained as long as 7 days after dosing. Furthermore, the ICP-AES determination of Gd in faeces allows for the determination of faeces content of Gd corresponding to less than 0.1% of a clinical dosage of a Gd-based contrast medium.

[Evaluation of the elimination and safety of gadodiamide injection in patients with hemodialysis].

We performed this study to evaluate the safety and elimination of gadodiamide injection in patients with hemodialysis (HD). The subjects were 10 patients on maintenance HD therapy, after receiving gadodiamide injection for magnetic resonance imaging (MRI) examination. The patients' mean age was 59.4 +/- 3.5 years, and their mean hemodialysis period was 70.6 +/- 20.4 months. Diseases for MRI examination were liver tumor (n=2), gallbladder tumor (n=1), renal tumor (n=3), pancreas tumor (n=1), abdominal aortic aneurysm (n=1), and arteriosclerosis obliterans (n=2). HD was performed routinely three times a week for 4 hours. Cellulose triacetate (CTA) membranes were used for 5 patients, polysulphone (PS) for 3 patients and polyester-polymer alloy (PEPA) for 2 patients. Serum levels of gadodiamide were analyzed before and after the first and second HD, and before the third and fourth HD. At the first HD, the concentration of gadodiamide in dialysate was analyzed every hour. Gadodiamide was eventually eliminated over time; 74.1% of the gadodiamide was dialyzed after the first HD and 98.8% after the third HD. There were no significant changes in the removal rate and laboratory parameters between each membrane. The present study suggests that gadodiamide could be removed by HD therapy efficiently thereby indicating that gadodiamide injection is possible in patients with HD.