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Experimental Studies |
1 From the Department of Diagnostic Radiology (M.C.H., A.G., M.H., B.K.) and Department of Medicine, Division of Nephrology and Hypertension (M.K.K.), University Hospital of Saarland, Homburg/Saar, Germany; and Department of Diagnostic Radiology, University Hospital of Erlangen, Maximiliansplatz 1, 91054 Erlangen, Germany (M.U.). From the 2004 RSNA Annual Meeting. Received April 22, 2004; revision requested June 29; revision received July 21; accepted August 18. Address correspondence to M.U. (e-mail: michael.uder@idr.imed.uni-erlangen.de).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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MATERIALS AND METHODS: LLC-PK1 cells were incubated with ioxithalamate, ioversol, iomeprol-300, iomeprol-150, iodixanol, iotrolan, and hyperosmolar mannitol solutions for 1–24 hours at concentrations from 18.75 to 150 mg of iodine per milliliter. Cytotoxic effects were assessed with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Data were analyzed with one-way analysis of variance; post hoc tests were performed.
RESULTS: At equal iodine concentrations, ioxithalamate showed stronger cytotoxic effects than did other contrast media (MTT conversion for ioxithalamate was 4% vs that for ioversol of 32%, that for iomeprol-300 of 34%, that for iodixanol of 40%, and that for iotrolan of 41% of undamaged control cells at 75 mg of iodine per milliliter, n = 61–90, P < .001); there was no significant difference between low-osmolar monomeric and iso-osmolar dimeric contrast media (P > .05). At equal molarity, dimeric contrast media induced significantly stronger cytotoxic effects than did low-osmolar monomeric contrast media (40% for iodixanol and 41% for iotrolan vs 64% for ioversol and 59% for iomeprol-300 at 98.5 mmol/L, n = 61–75, P < .001). At equimolar concentrations, both dimeric contrast media showed stronger cytotoxic effects than did iso-osmolar formulation of iomeprol-150 (51% for iodixanol and 50% for iotrolan vs 77% for iomeprol-150 at 98.5 mmol/L, n = 35–40, P < .001). Mannitol solutions induced weaker cytotoxic effects than did corresponding contrast media compounds (74% for mannitol-520 vs 34% for iomeprol-300 and 41% for mannitol-1860 vs 4% for ioxithalamate, P < .001).
CONCLUSION: Besides hyperosmolality, direct cytotoxic effects of contrast media molecules contribute to their cytotoxic effects. Results of this study indicate that dimeric contrast media molecules have a greater potential for cytotoxic effects on proximal renal tubular cells in vitro than do monomeric contrast media molecules.
© RSNA, 2005
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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The osmolality of contrast media is considered to play an important role in the pathogenesis of contrast-induced nephropathy. Low-osmolar nonionic contrast media have been shown to have fewer nephrotoxic effects than do high-osmolar ionic contrast media (1,2,8). In addition, findings in a recent study suggest that in high-risk patients the iso-osmolar dimer iodixanol is associated with fewer nephrotoxic effects than are low-osmolar monomeric contrast media (9). This study has caused debate (10), however, and results of another clinical study showed no significant differences between the renal effects of iodixanol and those of monomeric contrast media (11). Therefore, it is not yet clarified whether dimeric iso-osmolar contrast media really exert fewer nephrotoxic effects than do low-osmolar monomeric contrast media.
Researchers in early in vitro studies found evidence for direct renal tubular cell toxic effects of contrast media (12,13). In vitro experiments are a way to examine the cytotoxic effects of contrast media on renal cells because of the absence of confounding variables, which can be found in vivo (eg, hypoxia due to hemodynamic changes or other systemic mechanisms) (14). The finding of fewer in vivo nephrotoxic effects of low-osmolar contrast media, as compared with those of high-osmolar ionic compounds, correlates with their fewer in vitro cytotoxic effects (14). Researchers in previous studies have compared the effects of different classes of contrast media on renal tubular cells only at equal iodine concentrations. To compare the potential for nephrotoxic effects of monomeric and dimeric contrast media molecules, however, it is necessary to compare the contrast media on a molar basis and to control the effects of osmolality. Thus, the purpose of our study was to compare the cytotoxic effects of monomeric and dimeric contrast media at equal iodine concentrations, as well as at equal molarity, on renal tubular cells in vitro, with special regard to osmolality.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Cell Cultures
LLC-PK1 cells that are from a proximal tubular epithelial cell line of porcine origin were obtained from a cell culture collection (American Type Culture Collection, Rockville, Md) and grown in modified medium 199, supplemented with 10% fetal bovine serum (FBS; Invitrogen, Paisley, Scotland), 100 U/mL penicillin, and 100 µg/mL streptomycin (Seromed, Vienna, Austria), at 37°C with a humidified atmosphere of 95% air and 5% CO2. Cells were grown to confluence in flasks (75 cm2) over 6–7 days, treated with trypsin, and seeded into 96 microtiter plates (Greiner, Frickenhausen, Germany). Only confluent cell monolayers with dome formation were studied.
Experimental Solutions
Cells were incubated with either control media (serum-free and phenol red–free medium 199) or various doses of contrast media diluted in serum-free medium 199. Ready-to-use formulations of all contrast media were used. These contrast media included the nonionic dimer iotrolan (Isovist-300; Schering, Berlin, Germany), the nonionic dimer iodixanol (Visipaque 320; Amersham Buchler, Ismaning, Germany), the nonionic monomers iomeprol-300 and iomeprol-150 (Imeron 300 and Imeron 150; Bracco-Byk-Gulden, Konstanz, Germany), the nonionic monomer ioversol (Optiray 300; Mallinckrodt, St Louis, Mo), and the ionic monomer ioxithalamate (Telebrix 300; Guerbet, Sulzbach, Germany). The contrast media we used, with corresponding concentrations and osmolalities, are summarized in the Table.
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Experiments
To assess concentration and time dependency of contrast media–mediated cell injury, we used the low-osmolar nonionic monomer iomeprol-300. The concentrations we used ranged from 18.75 to 150 mg of iodine per milliliter, and the incubation times varied from 1 hour, to 5 hours, to 24 hours (12 specimens were tested for each concentration and incubation time).
To compare the effects of different contrast media, cells were incubated for 24 hours. The numbers of specimens tested at concentrations of 49.25 mmol/L (low) and 98.5 mmol/L (high), respectively, are enclosed within parentheses, for the following contrast media: iodixanol (n = 69 and n = 75), iotrolan (n = 66 and n = 61), ioversol (n = 70 and n = 77), iomeprol-300 (n = 71 and n = 61), and ioxithalamate (n = 77 and n = 90). As a control, cells were incubated with corresponding volumes of a mannitol solution with an osmolality of 1860 mOsm/kg H2O (n = 69 and n = 72) and with an osmolality of 520 mOsm/kg H2O (n = 66 and n = 58) and with saline solution (n = 60 and n = 72). For the evaluation to which amount the osmolality contributes to cell injury, we performed separate experiments in which iodixanol (n = 24 and n = 40), iotrolan (n = 24 and n = 40), and iomeprol-300 (n = 17 and n = 35) were compared with the iso-osmolar formulation iomeprol-150 (n = 18 and n = 35) at concentrations of 49.25 mmol/L (low) and 98.5 mmol/L (high) for 24 hours in the same experiments.
Determination of Cell Injury
Cell viability was assessed by using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl- 2H-tetrazolium bromide (MTT) uptake assay. The conversion of MTT, a tetrazolium salt, into formazan depends on the activity of a group of mitochondrial dehydrogenases and, thus, is an indicator of cell metabolic activity. The MTT assay was performed according to Mosmann (15), with modifications. An equal volume of MTT reagent (5 mg/mL phosphate-buffered saline) was added to the cell supernatant and incubated 4 hours at 37°C. Supernatants were removed, and 100 µL lysis buffer (20% sodium dodecyl sulfate, 33.3% dimethylformamide, 2% acetic acid, pH 4.7) was added per well; plates were shaken at room temperature for 30 minutes, and absorbance was measured at 570 nm, with 630 nm as reference. The measurements were performed automatically by a microplate reader (Dynatech MR 5000; Dynex Technologies, Chantilly, Va). The incubation with the experimental solutions, MTT, and lysis buffer was performed by one author (M.C.H.).
Statistical Analysis
The data are reported as percentage of undamaged control cells and are presented as the mean ± the standard error of the mean. To compare the effects of the contrast media and to compare the contrast media with the mannitol solutions and the NaCl solution, data were analyzed with one-way analysis of variance, followed by analysis with the Tukey post hoc test for multiple comparisons. MTT reduction after incubation with iomeprol-300 at various doses and various incubation times was compared with the reduction in untreated control cells by means of one-way analysis of variance, followed by analysis with the Dunnett post hoc test for multiple comparisons. A difference with a P value < .05 was considered significant. For statistical analysis and graphic representations, statistical software (Prism 3.03, 2002; GraphPad Software, San Diego, Calif) was used.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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At concentrations of 49.25 and 98.5 mmol/L, the dimeric contrast media iodixanol (69% ± 2 and 51% ± 4, n = 24–40) and iotrolan (71% ± 1 and 50% ± 2, n = 24–40) induced a more pronounced inhibition of MTT conversion, as compared with that of iomeprol-150 (81% ± 2 and 77% ± 2, n = 18–35, P < .001) (Fig 5). At a concentration of 98.5 mmol/L, the iso-osmolar compound iomeprol-150 showed a slightly weaker effect on the MTT assay than did iomeprol-300 (69% ± 1 and 77% ± 2 for iomeprol-300 and iomeprol-150, respectively; n = 17–35; P < .05) (Fig 5). At this concentration, the mannitol-520 solution showed an inhibition of MTT conversion at 94% ± 2 of the undamaged control cells.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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This finding, that at equal iodine concentrations the ionic high-osmolar monomer ioxithalamate induced a significantly stronger effect on the tubular cells than did the nonionic low-osmolar monomeric and iso-osmolar dimeric contrast media, is in agreement with results in previous in vitro studies (16–21). Findings in those previous studies indicated a greater nephrotoxic potential of ionic hyperosmolar contrast media when they were compared with nonionic contrast media. The greater in vitro toxic effects of the ionic hyperosmolar contrast media, as compared with those of the nonionic contrast media, correlate with their greater nephrotoxic effects in vivo (8,22). The hyperosmolality of ionic contrast media often is thought to play the pivotal role in the greater nephrotoxic effects of these compounds. To distinguish chemotoxic effects of the contrast media molecules from effects caused by hyperosmolality, we used as controls hyperosmolar mannitol solutions with the same osmolality as iomeprol-300 and ioxithalamate.
Both mannitol solutions showed cytotoxic effects whereby the high-osmolar mannitol solution exerted more pronounced effects than did the low-osmolar solution. Since the mannitol solutions had significantly fewer toxic effects than did the corresponding contrast media, however, the cytotoxic effects of contrast media cannot solely be caused by their hyperosmolality. Furthermore, at a concentration of 98.5 mmol/L, iomeprol-300 showed a slightly stronger effect on the MTT assay than did the iso-osmolar compound iomeprol-150. At this concentration, the mannitol-520 solution induced only a slight inhibition of MTT conversion. Thus, only the small difference between iomeprol-150 and iomeprol-300 is probably caused by the hyperosmolality of iomeprol-300. Our results confirm findings in previous in vitro studies, which have shown that hyperosmolality of contrast media cannot fully explain their cytotoxic effects (18,20,21,23–25) or other contrast-induced side effects (26–29).
Hyperosmolality cannot be the only reason for contrast-induced cytotoxic effects, since in our study the iso-osmolar contrast media also showed cytotoxic effects. When the dimeric iso-osmolar contrast media iodixanol and iotrolan were compared with the monomeric low-osmolar contrast media iomeprol and ioversol at equal iodine concentrations, no significant difference in cytotoxic effects was observed. This finding is in agreement with results in previous studies of renal tubular cell cultures. No significant difference between iohexol and iodixanol was found on the renal epithelial Madin Darby canine kidney (or MDCK) cell line monolayers with regard to cell viability, transmonolayer resistance, and inulin permeability (19). In human renal proximal tubular epithelial (or HRPTE) cells, iomeprol, iopamidol, and iodixanol decreased MTT reduction at 51.4%, 51.9%, and 52.8%, respectively (20). In contrast, iotrolan induced a somewhat more pronounced cell injury than did iohexol, iomeprol, and iopamidol, when they were assessed by using the 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2, 4-disulfophenyl)-2H-tetrazolium, monosodium salt (or WST-8) assay in LLC-PK1 cells (21). Also in the study of Hardiek et al (20), the dimer iodixanol produced a stronger inhibition of MTT conversion than did iomeprol and iopamidol in LLC-PK1 cells at 31%, 52%, and 39% of the undamaged control cells, respectively.
At equal molarity, the dimeric contrast media iotrolan and iodixanol showed a significantly stronger reduction of MTT conversion than did the monomeric contrast media iomeprol-300 and ioversol. To compare the effects of the monomeric and dimeric contrast media molecules, the different osmolalities must be taken into account when compounds with the same iodine concentrations are used. For this reason, we performed experiments with the iso-osmolar compound iomeprol-150, which contains 150 mg of iodine per milliliter. Identical volumes of iomeprol-150 and of the dimeric contrast media contain the same number of contrast media molecules and have almost the same osmolality. Also, with these conditions, the dimeric contrast media showed a significantly more pronounced cytotoxic effect in comparison with that of iomeprol. Therefore, the difference in toxic effects in tubular cells must be attributed to the contrast medium molecule itself or to additives in the contrast medium, because differences in osmolality were excluded in our experiments. Investigators in previous studies (16,20), however, showed that the additives trometamol and edetate calcium disodium did not play a substantial role in the cytotoxic effects of contrast media.
To examine the toxic properties of contrast media in renal tubular cells in vitro, the dilution of the tissue culture media with the use of ready-to-use formulations must be considered. At a concentration of 75 mg of iodine per milliliter, 25% of the culture medium was replaced by contrast media. This replacement could be responsible for toxic effects. The dilution of the growth media by the same volume of isotonic NaCl solution, however, showed a reduction of MTT levels only at 89% ± 1.66. In addition, researchers in earlier studies have shown that the dilution of the growth medium does not explain the contrast-induced cytotoxic effects in cell culture experiments at the concentrations used (23,24).
In our study, LLC-PK1 cells, which are from a proximal tubular epithelial cell line of porcine origin, were used to determine the toxic effects of contrast media on renal tubular cells. LLC-PK1 cells are a well-characterized renal epithelial model system for the investigation of cytotoxic effects of various substances (30,31). Cytotoxic effects of ontrast media also have been investigated in LLC-PK1 cells in previous studies (16,18,20,21). Results in a study of Hardiek et al (20) indicated that human renal proximal tubular cells (HRPTE) respond to contrast media in a manner similar to the way that LLC-PK1 cells respond. Thus, LLC-PK1 cells seem to be a suitable model system for the investigation of cytotoxic effects of contrast media on renal tubular cells.
The contrast media concentrations and incubation times used in our study were chosen carefully with regard to the clinical situation. Contrast media doses administered clinically (even during angiography of the abdominal aorta or the renal arteries) result in plasma concentrations of approximately 10 mg of iodine per milliliter and usually do not exceed 20 mg of iodine per milliliter (14,20). Because contrast media are concentrated in the renal proximal tubules as a result of reabsorption of water, the concentration of contrast media in the renal tubules is much higher than it is in plasma (32). After intravascular administration of contrast media in rabbits, urinary concentrations higher than 100 mg of iodine per milliliter have been measured (33). We compared different contrast media at concentrations of 37.5 and 75 mg of iodine per milliliter. These concentrations are in the range of those that have been used in previous cell culture studies (16,18–21,23,24). In some studies, concentrations of as much as 100–150 mg of iodine per milliliter were used (20,21,23).
In healthy volunteers, contrast media were rapidly excreted almost exclusively by means of renal glomerular filtration (34). The elimination half-life increases progressively, however, with increasing renal impairment (35). In patients with chronic renal failure, the elimination half-life of iopamidol was about 70 hours (36). Furthermore, in patients with contrast-induced nephropathy, a persistent nephrogram after more than 24 hours is a common finding (37). We demonstrated time-dependent cell injury induced by contrast media at incubation times between 1 and 24 hours. The contrast media were compared after an incubation time of 24 hours, which also has been used in several studies on renal tubular cells before (20,38,39). In one study, an incubation time of as much as 3 days was used (25). Therefore, with regard to the high urinary contrast medium concentration and the prolonged exposure of the tubular cells to the contrast medium in patients with renal insufficiency, the concentrations and incubation times used in our study were in the range of those that can occur in clinical situations.
For investigation of contrast-induced cell injury, we used the MTT assay. MTT is a yellow tetrazolium salt that is converted into a blue formazan product by mitochondrial dehydrogenases when it is incubated with living cells. With the assay, detection of very small numbers of living cells is allowed, and the amount of formazan generated is directly proportional to the number of living cells. Only living cells with active mitochondria cleave MTT, in which the amount of formazan generated depends on the level of energy metabolism in the cell (15). Therefore, this assay is an indicator for cell viability, proliferation, and metabolic activity. The MTT assay is a well-established method for assessment of cytotoxic effects of various substances in cell cultures (30,40) and also has been used before to investigate cytotoxic effects of contrast media in some studies (17,20,25). The molecular mechanisms by which contrast media induce direct cytotoxic effects on renal cells are poorly understood. Findings in some studies have suggested that oxidative stress is involved in contrast-induced renal damage (41–44). Researchers in another recent in vitro study, however, have shown toxic effects of contrast media to be dissociated from tubular cell oxidant stress (25). There are also conflicting results with regard to contrast-induced apoptosis in renal tubular cells. Researchers in some studies demonstrated apoptosis in renal tubular cell cultures (21,24,39), whereas investigators in another study found no evidence of contrast-induced apoptosis (20).
Whether dimeric contrast media have fewer nephrotoxic effects than do monomeric contrast media in vivo is a matter of debate. Findings in a clinical study suggested that contrast-induced nephropathy is less likely to develop in high-risk patients when iodixanol is used rather than when low-osmolar nonionic contrast media are used (9). Results in that study are arguably controversial for the following reasons: the small number of patients who developed acute renal failure; the significant differences in proteinuria, in the duration of diabetes, and in the use of angiotensin-converting enzyme inhibitors in the iohexol group compared with the iodixanol group; and the lack of standardized vigorous hydration of the patients (10). Moreover, in another clinical study, Baker et al (45) showed a markedly higher incidence of contrast-induced nephropathy after administration of iodixanol, as compared with the findings in the study of Aspelin et al (9). Furthermore, in a recent clinical trial, no significant differences in the renal effects of iopamidol 370 and iodixanol 320 were observed (11). Katayama et al (46) reported a similar renal tolerability of iodixanol and iomeprol after intraarterial injection. Further studies are required to investigate the effect of dimeric contrast media in comparison with that of monomeric contrast media on renal function in vivo.
Some limitations of our study have to be considered. As in all in vitro experiments, in our study an artificial model system was used to compare the cytotoxic effects of the contrast media. This design does not consider the complex, multifactorial pathogenesis of contrast-induced nephropathy in vivo. In vitro experiments with cultured renal cells, however, are an established method to examine the cytotoxic effects of drugs, especially contrast media, without confounding variables, which can be found in vivo, such as hypoxia caused by hemodynamic changes or other systemic mechanisms (14). Furthermore, the MTT assay used in our study is an indicator for cell viability, proliferation, and metabolic activity. The inhibition of MTT conversion by contrast media observed in our study could be explained not only by a reduced number of viable cells but also by reduced mitochondrial activity. Researchers in two studies have shown indications for contrast-induced mitochondrial dysfunction. Hardiek et al (20) demonstrated an increase in mitochondrial membrane potential by contrast media, and they suggested that a consecutive decrease in dehydrogenase activity could potentially explain the inhibition of MTT conversion by contrast media. Investigators in another study (25) found evidence for contrast-induced mitochondrial damage because of cytochrome c loss into the cell supernatant solution. They suggested that there may be a link between the observed contrast-induced plasma membrane damage and mitochondrial injury (25). The mechanisms by which contrast media exert their cytotoxic effects, however, remain uncertain.
In conclusion, in our study, we demonstrated that, although hyperosmolality contributes to the cytotoxic effects of hyperosmolar contrast media in renal proximal tubular cells, hyperosmolality plays only a minor role in the case of low-osmolar contrast media. Direct cytotoxic effects of the contrast media molecules seem to be the most important factor in the case of low-osmolar and iso-osmolar contrast media. The iso-osmolar dimeric contrast media showed strong cytotoxic effects, which were significantly (P < .001) more pronounced when they were compared with those of the low-osmolar monomeric contrast media at equimolar concentrations. This finding suggests a greater potential for nephrotoxic effects of the dimeric contrast media molecules when they are compared with the monomeric contrast media molecules.
Practical application: The design of our experiments, especially the use of iso-osmolar formulations of monomeric contrast media, allows comparison between the biologic activity of the molecules of different types of contrast media, with exclusion of the physicochemical properties of the solutions, such as osmolality. This may offer a further approach to study which molecular mechanisms cause contrast-induced nephropathy. For clinical practice, the fact that dimeric contrast media molecules are more toxic than monomeric nonionic contrast media molecules in vitro means that one should exercise caution when one is advising radiologists about a preference for use of dimeric contrast media in at-risk patients on the basis of findings in available studies. It seems possible that the different levels of biologic activity of the molecules are especially important in subgroups of patients with certain comorbidities or in whom certain medications are used concomitantly with contrast media and that these patients have been unequally distributed in the few studies with small numbers of these patients so far.
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FOOTNOTES |
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Authors stated no financial relationship to disclose.
See also the editorial by Katzberg in this issue.
Author contributions: Guarantors of integrity of entire study, M.C.H., M.U.; study concepts and design, all authors; literature research, M.C.H.; experimental studies, M.C.H.; data acquisition, M.C.H.; data analysis/interpretation, all authors; statistical analysis, M.C.H., M.U.; manuscript preparation and editing, M.C.H., M.U.; manuscript definition of intellectual content, revision/review, and final version approval, all authors
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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