The protective effect of klotho against contrast-associated acute kidney injury via the antioxidative effect.

As oxidative stress is one major factor behind contrast-associated acute kidney injury (CA-AKI), we investigated the protective effect of klotho against CA-AKI via the antioxidative effect. In in vitro experiments, cells (NRK-52E) were divided into the following three groups: control, iopamidol, or iopamidol + recombinant klotho (rKL) groups. Moreover, cell viability was measured with the Cell Counting Kit-8 assay, and oxidative stress was examined with 2',7'-dichlorodihydrofluorescein diacetate fluorescence intensity. RT-PCR and Western blot analysis were performed to assess propidium iodide klotho expression, and Bax-to-Bcl-2 and apoptosis ratios were evaluated with annexin V/Hoechst 33342 staining. Furthermore, we knocked down the klotho gene using siRNA to verify the endogenous effect of klotho. In our in vivo experiments, oxidative stress was evaluated with the thiobarbituric acid-reactive substance assay, and apoptosis was evaluated with the Bax-to-Bcl-2 ratio and cleaved caspase-3 immunohistochemistry. Additionally, cell and tissue morphology were investigated with transmission electron microscopy. In both in vitro and in vivo experiments, mRNA and protein expression of klotho significantly decreased in CA-AKI mice compared with control mice, whereas oxidative stress and apoptosis markers were significantly increased in CA-AKI mice. However, rKL supplementation mitigated the elevated apoptotic markers and oxidative stress in the CA-AKI mouse model and improved cell viability. In contrast, oxidative stress and apoptotic markers were more aggravated when the klotho gene was knocked down. Moreover, we found more cytoplasmic vacuoles in the CA-AKI mouse model using transmission electron microscopy but fewer cytoplasmic vacuoles in rKL-supplemented cells. The present study shows that klotho in proximal tubular cells can protect against CA-AKI via an antioxidative effect.

Cytotoxicity of radiocontrast dyes in human umbilical cord mesenchymal stem cells.

Radiocontrast dyes are used for a wide range of diagnostic procedures for enhancing the image of anatomical structures, pain targets, and vascular uptake. While some of these dyes show toxicity to primary cells, their effect on stem cells, particularly mesenchymal stem cells (MSCs), is unknown. This study investigates the cytotoxic effects of two clinically used radiocontrast dyes, iohexol and iopamidol, on bone marrow and human umbilical cord MSCs. Exposure to these dyes significantly affected morphology of MSCs from both sources, as treated cells appeared transparent and no longer fibroblastoid. Cell viability decreased as determined by trypan blue and Annexin-V/PI staining, in a dose dependent manner with simultaneous loss of CD90 and CD105 concurrent with spontaneous differentiation in MSCs treated with iohexol and iopamidol. In addition, significantly higher cell death was observed in MSCs exposed to iopamidol than iohexol. At a concentration of 1:1, iohexol and iopamidol induced apoptosis in 19% and 92% (<.01) of MSCs, respectively. Global transcriptome analysis of treated MSCs revealed 139 and 384 differentially expressed genes in iohexol vs control and iopamidol vs control at p ≤ .01 and 1.5-fold, respectively. This suggested that iopamidol had more significant effect on the transcription of MSCs. Based on these results a molecular mechanism of radiocontast dye induced cell death via intrinsic apoptosis pathway mediated by p53 was proposed. Since iopamidol was significantly more toxic than iohexol in human MSCs, a more careful examination of safety of radiocontrast dyes for clinical use is warranted.

Transformation of iopamidol during chlorination.

The transformation of the iodinated X-ray contrast media (ICM) iopamidol, iopromide, iohexol, iomeprol, and diatrizoate was examined in purified water over the pH range from 6.5 to 8.5 in the presence of sodium hypochlorite, monochloramine, and chlorine dioxide. In the presence of aqueous chlorine, only iopamidol was transformed. All other ICM did not show significant reactivity, regardless of the oxidant used. Chlorination of iopamidol followed a second order reaction, with an observed rate constant of up to 0.87 M(-1) s(-1) (±0.021 M(-1) s(-1)) at pH 8.5. The hypochlorite anion was identified to be the reactive chlorine species. Iodine was released during the transformation of iopamidol, and was mainly oxidized to iodate. Only a small percentage (less than 2% after 24 h) was transformed to known organic iodinated disinfection byproducts (DBPs) of low molecular weight. Some of the iodine was still present in high-molecular weight DBPs. The chemical structures of these DBPs were elucidated via MSn fragmentation and NMR. Side chain cleavage was observed as well as the exchange of iodine by chlorine. An overall transformation pathway was proposed for the degradation of iopamidol. CHO cell chronic cytotoxicity tests indicate that chlorination of iopamidol generates a toxic mixture of high molecular weight DBPs (LC50 332 ng/µL).

Mutagenicity assessment of two potential impurities in preparations of 5-amino-2,4,6 triiodoisophthalic acid, a key intermediate in the synthesis of the iodinated contrast agent iopamidol.

5-Aminoisophthalic acid and 5-nitroisophthalic acid (5-NIPA) are potential impurities in preparations of 5-amino-2,4,6-triiodoisophthalic acid, which is a key intermediate in the synthesis of the iodinated contrast agent iopamidol. We have studied their mutagenicity in silico (quantitative structure-activity relationships, QSAR) and by the bacterial reverse mutation assay (Ames test). First, the compounds were screened with the tools Derek Nexus™ and Leadscope®. Both compounds were flagged as potentially mutagenic (class 3 under ICH M7). However, contrary to the in silico prediction, neither chemical was mutagenic in the Ames test (plate incorporation method) with or without S9 metabolic activation.

Assessing the skin irritation and sensitizing potential of concentrates of water chlorinated in the presence of iodinated X-ray contrast media.

Chemical disinfection of water provides significant public health benefits. However, disinfectants like chlorine can react with naturally occurring materials in the water to form disinfection byproducts (DBPs). Natural levels of iodine have been reported to be too low in some source waters to account for the levels of iodinated DBPs detected. Iodinated X-ray contrast media (ICM) have been identified as a potential source of iodine. The toxicological impact of ICM present in source water at the time of disinfection has not been fully investigated. Iopamidol, iohexol, iopromide, and diatrizoate are among the ICM most frequently detected in water. In this study, source water containing one of these four ICM was chlorinated; non-chlorinated ICM-containing water samples served as controls. Reactions were conducted at an ICM concentration of 5 µM and a chlorine dose of 100 µM over 72 hr. Water concentrates (20,000-fold) were prepared by XAD-resin/ethyl acetate extraction and DMSO solvent exchange. We used the MatTek® reconstituted human epithelial skin irritation model to evaluate the water concentrates and also assessed the dermal irritation and sensitization potential of these concentrates using the LLNA:BrdU ELISA in BALB/c mice. None of the water concentrates tested (2500X) resulted in a skin irritant response in the MatTek® skin irritation model. Likewise, none of the concentrates (2500X, 1250X, 625X, 312.5X, 156.25X) produced a skin irritation response in mice: erythema was minimal; the maximum increase in ear thickness was less than 25%. Importantly, none of the concentrates produced a positive threshold response for allergic skin sensitization at any concentration tested in the LLNA:BrdU ELISA. We conclude that concentrates of water disinfected in the presence of four different ICM did not cause significant skin irritation or effects consistent with skin sensitization at the concentrations tested.

Subclinical Contrast-Induced Acute Kidney Injury in Patients Undergoing Cerebral Computed Tomography.

INTRODUCTION: The nephrotoxicity of modern contrast media remains controversial. Novel biomarkers of kidney damage may help in identifying a subclinical structural renal injury not revealed by widely used markers of kidney function. OBJECTIVE: The aim of this study was to investigate clinical (contrast-induced acute kidney injury [CI-AKI]) and subclinical CI-AKI (SCI-AKI) after intra-arterial administration of Iodixanol and Iopamidol in patients with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2. METHODS: This is a prospective observational monocentric study. Urinary sample was collected at 4-8 h after contrast medium exposure to measure neutrophil gelatinase associated lipocalin (NGAL) and the product tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 ([TIMP-2] × [IGFBP7]), while blood samples were collected at 24 and 48 h after exposure to measure serum creatinine. RESULTS: One hundred patients were enrolled, of whom 53 were exposed to Iodixanol and 47 to Iopamidol. Patients in Iodixanol and Iopamidol groups were comparable in terms of demographics, pre-procedural and procedural data. No patient developed CI-AKI according KDIGO criteria, while 13 patients reported SCI-AKI after exposure to iodine-based medium contrast (3 patients in Iodixanol group and 10 patients in Iopamidol group), defined by positive results of NGAL and/or [TIMP-2] × [IGFBP7]. A positive correlation was found between NGAL and [TIMP-2] × [IGFBP7] in the analysed population (Spearman's rho 0.49, p < 0.001). In logistic regression analysis, Iopamidol exposure showed higher risk for SCI-AKI compared to Iodixanol (OR 4.5 [95% CI 1.16-17.52], p = 0.030), even after controlling for eGFR and volume of contrast medium used. CONCLUSIONS: This study showed that intra-arterial modern contrast media administration may have a nephrotoxic effect in a population without pre-existing chronic kidney disease. Further investigations on larger scale are warranted to confirm if Iopamidol exposed patients to increased risk of SCI-AKI compared to Iodixanol.

Nephrotoxicity of iso-osmolar iodixanol compared with nonionic low-osmolar contrast media: meta-analysis of randomized controlled trials.

PURPOSE: To compare the nephrotoxicity of iso-osmolar iodixanol with that of nonionic low-osmolar contrast media (CM) (LOCM) in randomized clinical trials. MATERIALS AND METHODS: This meta-analysis was conducted with a systematic search of MEDLINE, EMBASE, BIOSIS, Web of Science, ISI Web of Knowledge, Current Contents Medizin, Cochrane Library (until August 2007), trial registers, conference proceedings, and reference lists to identify studies and with requests from all manufacturers of CM for unidentified studies. Randomized controlled trials assessing serum creatinine levels before and after intravascular application of iodixanol or LOCM were included. The primary outcome measures were the incidence of contrast medium-induced nephropathy (CIN) and change in serum creatinine levels. RESULTS: Twenty-five trials were included. Iodixanol did not significantly reduce the risk of CIN (relative risk [RR], 0.80; 95% confidence interval [CI]: 0.61, 1.04; weighted mean difference in serum creatinine increase, 0.01 mg/dL [0.88 mumol/L]; 95% CI: -0.01, 0.03). There was no significant risk reduction after intravenous administration of the CM (RR, 1.08; 95% CI: 0.62, 1.89); subgroup with preexisting renal insufficiency (RR, 1.07; 95% CI: 0.56, 2.02) or after intraarterial administration (RR, 0.68; 95% CI: 0.46, 1.01); subgroup with preexisting renal insufficiency (RR, 0.59; 95% CI: 0.33, 1.07). However, in patients with intraarterial administration and renal insufficiency, the risk of CIN was greater for iohexol than for iodixanol (RR, 0.38; 95% CI: 0.21, 0.68), whereas there was no difference between iodixanol and the other (noniohexol) LOCM (RR, 0.95; 95% CI: 0.50, 1.78). CONCLUSION: Iodixanol is not associated with a significantly reduced risk of CIN compared with the LOCM pooled together. However, in patients with intraarterial administration and renal insufficiency, iodixanol is associated with a reduced risk of CIN compared with iohexol, whereas no significant difference between iodixanol and other LOCM could be found.

Nephrotoxicity of iodixanol versus iopamidol in patients with chronic kidney disease and diabetes mellitus undergoing coronary angiographic procedures.

BACKGROUND: The choice of radiographic contrast media for use in patients at increased risk of contrast-induced nephropathy (CIN) is of ongoing interest. METHODS: The current study is a prospective, multicenter, randomized, double-blind design comparing the renal effects of the non-ionic, iso-osmolal agent, iodixanol, versus the non-ionic, low-osmolal agent, iopamidol, in 526 subjects with impaired baseline renal function (chronic kidney disease) and diabetes mellitus undergoing diagnostic and/or therapeutic coronary angiographic procedures. The co-primary end points were the peak increase in serum creatinine (SCr) and the incidence of CIN (increase > or =0.5 mg/dL) in SCr from baseline within 3 days of receiving contrast media. RESULTS: In 418 evaluable subjects with complete postcontrast media SCr data, the median peak increase in SCr in the iodixanol arm was 0.10 mg/dL, whereas in the iopamidol arm, the median peak increase was 0.09 mg/dL (P = .13). The overall CIN incidence was 10.5% (11.2% % in the iodixanol arm and 9.8% in the iopamidol arm, P = .7). The volume of contrast media, volume of saline administered, frequency of coronary interventional procedures, and severity of baseline kidney disease and of diabetes mellitus were similar between treatments. CONCLUSIONS: In the present study, the overall rate of CIN in patients with chronic kidney disease and DM undergoing coronary angiographic procedures was 10.5%. There was no significant difference between iodixanol and iopamidol in either peak increase in SCr or risk of CIN.

Reversibility and time-dependency of contrast medium induced inhibition of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) conversion in renal proximal tubular cells in vitro: comparison of a monomeric and a dimeric nonionic iodinated contrast medium.

OBJECTIVES: To evaluate the time-course and reversibility of toxicity of a low-osmolar and an iso-osmolar radiographic contrast medium on renal tubular cell cultures. MATERIALS AND METHODS: LLC-PK1-cells were incubated with iomeprol, iodixanol, and mannitol (4.7-75 mg I/mL, 2-24 hours). Metabolic activity was assessed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide-(MTT) assay. RESULTS: Iomeprol and iodixanol induced a time- and dose-dependent inhibition of MTT conversion (75%-19% and 70%-23% of control for iomeprol and iodixanol, respectively, at concentrations ranging from 4.7 to 75 mg I/mL after an incubation time of 2 hours and 64%-14% and 65%-12% of control after 24 hours). The mannitol induced inhibition of the MTT conversion was significantly weaker than that induced by iomeprol (99%-47% of control at concentrations corresponding to 4.7-75 mg I/mL after an incubation time of 24 hours, P < 0.001). After 24 hours incubation with iomeprol, iodixanol, or mannitol and a recovery time of 2 hours after removal of the test-solutions, there was only a small inhibition of MTT-conversion (89%, 88%, and 95% of control at 75 mg I/mL). CONCLUSIONS: Contrast medium induced cytotoxicity consisted of a reversible part and an irreversible part. There was no difference in cytotoxicity between iomeprol and iodixanol over a broad range of concentrations and incubation-times.

A comparison of the efficacy and safety of iopamidol-370 and iodixanol-320 in patients undergoing multidetector-row computed tomography.

OBJECTIVES: To prospectively compare the effects on heart rate (HR) and contrast enhancement efficacy of iopamidol-370 and iodixanol-320 in contrast-enhanced, multidetector-row computed tomography (CE-MDCT). METHODS: IMPACT is a multicenter, double-blind study involving 166 patients undergoing CE-MDCT of the liver (n = 121) or peripheral arteries (n = 45) randomized to receive equi-iodine doses (40 gI) of iopamidol-370 or iodixanol-320 intravenous at 4 mL/s. CE-MDCT was performed using 16-MDCT scanners according to predefined imaging protocols. HR was measured with the patient in the supine position before and continuously for 5 minutes after contrast medium administration. Mean and peak increases in HR and the proportion of subjects with predefined HR increases (>5 to <10, 10 to <15, 15 to <20, >20 bpm) were compared in the 2 populations. Liver images were assessed by 2 independent, blinded readers for contrast enhancement [Hounsfield unit (HU)], using predefined regions-of-interest during the arterial and portal-venous phase of enhancement. RESULTS: Effects on HR: Eighty-four subjects received iopamidol-370 whereas 82 received iodixanol-320. Mean age, gender distribution, weight, total iodine dose, dose/body weight, concomitant medications and use of beta-blockers were comparable in the 2 groups. Mean baseline HR was similar in the 2 groups (iopamidol-370: 72.3 +/- 12.5 bpm; iodixanol-320: 74.5 +/- 11.9 bpm). Mean changes from baseline to peak postdose were similar in the 2 groups (8.0 +/- 9.3 bpm after iopamidol-370 and 8.4 +/- 14.7 after iodixanol-320, P = 0.72). The proportion of subjects in each group having increases of <5, >5 to <10, 10 to <15, 15 to <20, or >20 bpm was comparable (P = 0.87). Two subjects experienced postcontrast tachycardia (HR increase >70 bpm, peak HR of 146 and 164 bpm), both in the iodixanol-320 group (2.4%). Contrast Enhancement: Of the 121 patients undergoing liver CT, 60 received iopamidol-370 whereas 61 received iodixanol-320. Mean age, gender distribution, weight, total iodine dose, and dose/body weight were comparable in the 2 groups. Iopamidol-370 provided significantly higher HU values in abdominal aorta during the arterial phase of enhancement for both readers [R1: 301.3 +/- 80.2 vs. 273.6 +/- 65.9 HU, 95% confidence interval (6.1-56.8), P = 0.02; R2: 302.0 +/- 73.6 vs. 275.1 +/- 62.9 HU, 95% confidence interval (2.3-51.3), P = 0.03]. No significant difference was observed between the 2 contrast medium during the portal venous phase of enhancement. CONCLUSIONS: When the same injection rate and iodine dose is used, the effects on HR of bolus intravenous injections of iopamidol-370 and iodixanol-320 were similar. Iopamidol-370 provides significantly greater enhancement during the arterial phase and similar enhancement during the portal venous phase compared with iodixanol-320.

Chlor(am)ination of iopamidol: Kinetics, pathways and disinfection by-products formation.

The degradation kinetics, pathways and disinfection by-products (DBPs) formation of iopamidol by chlorine and chloramines were investigated in this paper. The chlorination kinetics can be well described by a second-order model. The apparent second-order rate constants of iopamidol chlorination significantly increased with solution pH. The rate constants of iopamidol with HOCl and OCl- were calculated as (1.66 ± 0.09) × 10-3 M-1 s-1 and (0.45± 0.02) M-1 s-1, respectively. However, the chloramination of iopamidol fitted well with third-order kinetics and the maximum of the apparent rate constant occurred at pH 7. It was inferred that the free chlorine (i.e., HOCl and OCl-) can react with iopamidol while the combined chlorine species (i.e., NH2Cl and NHCl2) were not reactive with iopamidol. The main intermediates during chlorination or chloramination of iopamidol were identified using ultra performance liquid chromatography - electrospray ionization-mass spectrometry (UPLC-ESI-MS), and the destruction pathways including stepwise deiodination, hydroxylation as well as chlorination were then proposed. The regular and iodinated DBPs formed during chlorination and chloramination of iopamidol were measured. It was found that iodine conversion from iopamidol to toxic iodinated DBPs distinctly increased during chloramination. The results also indicated that although chloramines were much less reactive than chlorine toward iopamidol, they led to the formation of much more toxic iodinated DBPs, especially CHI3.

The effects of pharmaceuticals on a unionid mussel (Lampsilis siliquoidea): An examination of acute and chronic endpoints of toxicity across life stages.

The toxicity and bioconcentration of 3 pharmaceuticals (amitriptyline, iopamidol, and sertraline) were examined using multiple life stages (larval, juvenile, and adult) of the unionid mussel Lampsilis siliquoidea. The endpoints examined varied with life stage but included survival, behavior (algal clearance rate, filtering frequency), and oxidative stress. Iopamidol was not toxic at concentrations up to 101 mg/L. Sertraline was the most toxic chemical (50% lethal concentrations [LC50] and effect concentrations [EC50] = 0.02-0.04 mg/L), but exposure did not induce oxidative stress. Glochidia and juveniles were more sensitive than adult mussels. Algal clearance rate in juvenile mussels was the most sensitive endpoint assessed, similar to or lower than the LC50 values for glochidia. However, the compounds examined were not toxic at concentrations detected in the environment. The relative bioconcentration factors were sertraline > amitriptyline > iopamidol. These results suggest that glochidia toxicity could be a screening tool for rapidly assessing the toxicity of chemicals of concern to freshwater mussels. Environ Toxicol Chem 2017;36:1572-1583. © 2016 SETAC.

Hypotonic contrast media is more toxic than isotonic contrast media on endothelial cells in vivo and in vitro.

The aim of the current study was to investigate the cytotoxic effects of hypotonic (iopamidol) and isotonic (iodixanol) contract media (CMs) in vitro and in vivo. A total of 60 Wistar rats were included and were randomly divided into three groups (20 rats per group). Iodixanol (4 g iodine/kg), iopamidol (4 g iodine/kg) or equal volume of normal saline was injected via tail vein. HUVEC and H5V cell viability was determined by Cell Counting Kit­8 agents. Western blotting was performed to detect ATP­binding cassette subfamily G member 1 (ABCG1) expression. For histological analysis, hematoxylin and eosin staining was performed. Plasma endothelin, von Willebrand factor, tissue type plasminogen activator, plasminogen activator inhibitor, D­Dimer, fibrinogen, anti­thrombin III, plasminogen and nitric oxide synthase (NOS) were measured by using ELISA. Both iopamidol and iodixanol treatments deceased cell viability and increased apoptosis of HUVEC and H5V cells, along with downregulated NOS and ABCG1. The injection of iopamidol or iodixanol into rats changed the endothelium­related plasma levels of biomarkers, including endothelin, von Willebrand factor, tissue type plasminogen activator, plasminogen activator inhibitor, D­Dimer, fibrinogen and anti­thrombin III. However, endothelia isolated from rat abdominal aorta in the iodixanol group retained their normal structure, whereas endothelial structure in the iopamidol group was injured and disrupted. The findings in the present study suggested that both hypotonic and isotonic CMs may lead to endothelial dysfunction and thrombin and fibrinolytic system disorder. However, hypotonic CMs may be more toxic than isotonic CMs. Therefore, additional cautions should be taken when selecting hypotonic CMs and their dosages during cardioangiography.

Use of orbitrap-MS/MS and QSAR analyses to estimate mutagenic transformation products of iopamidol generated during ozonation and chlorination.

The effects of two water purification processes (ozonation, and chlorination after ozonation) on the mutagenicity of a solution containing iopamidol (X-ray contrast medium) were investigated by using the Ames assay. No mutagenicity was observed during ozonation. In contrast, mutagenicity was induced by the ozone-treated iopamidol-containing solution after subsequent chlorination, indicating that mutagenic transformation-products (TPs) were generated. Ten of 70 peaks detected on the LC/MS total ion chromatogram (TIC) of the ozone-treated iopamidol-containing solution after chlorination had a positive correlation (r(2) > 0.6) between their peak areas and the observed mutagenicity, suggesting that TPs detected as these peaks may induce mutagenicity. To narrow down the possible contributors to the observed mutagenicity, we compared the areas of the peaks on the TIC-charts with and without chlorination. Of the ten peaks, six were also detected in the ozone-treated iopamidol-containing solution without chlorination, which did not induce mutagenicity, indicating that these peaks were not related to the observed mutagenicity. Accurate m/z values and MS/MS analysis with an orbitrap MS of the remaining four peaks revealed that two of them represented the same TP in the negative and positive ion modes. The three remaining TPs were assessed in four quantitative structure-activity relationship models for predicting Ames mutagenicity. At least one model predicted that two of the three TPs were mutagenic, whereas none of the models predicted that the other TP was a mutagen, suggesting that the former TPs, estimated as N1-acetyl-5-amino-6-chloro-2-iodobenzene-1,3-dicarboxamide and 3-hydroxy-2-{3-[(2-hydroxyethoxy)carbonyl]-2,4,6-triiodo-5-nitrobenzoyl}amino)propanoic acid, could be the candidate compounds that contributed to the observed mutagenicity.

A randomized comparison of the nephrotoxicity of iopamidol and diatrizoate in high risk patients undergoing cardiac angiography.

Three hundred seven high risk patients with renal impairment (serum creatinine greater than or equal to 1.5 mg/dl) were randomized in a double-blind manner to either iopamidol (a nonionic, low osmolar radiocontrast agent) or diatrizoate (a conventional radiocontrast agent) at cardiac angiography with subsequent follow-up study of renal function. Baseline clinical and angiographic variables were similar in the iopamidol (n = 155) and diatrizoate (n = 152) groups. Change in renal function after angiography was less pronounced with iopamidol compared with diatrizoate as measured by mean ( +/- SD) increase in 24 h serum creatinine (0.11 +/- 0.2 versus 0.22 +/- 0.26 mg/dl, p less than 0.001), mean maximal increase in serum creatinine (0.2 +/- 0.44 versus 0.38 +/- 0.73 mg/dl, p less than 0.0001) and percent of patients with a maximal increase in serum creatinine greater than 0.5 mg/dl (8% versus 19%, p less than 0.01). Such differences could not be documented in diabetic patients using insulin. There was no significant difference between agents in the number of patients developing clinically severe acute renal dysfunction. It is concluded that iopamidol is less nephrotoxic than diatrizoate in high risk patients at cardiac angiography. However, the difference in nephrotoxicity is small, of no major clinical significance in the majority of high risk patients and could not be documented in insulin-using diabetic patients. Iopamidol may be the preferred agent in certain patients with advanced renal impairment, but further study is warranted.

Variable effects of radiological contrast media on thrombus growth in a rabbit jugular vein thrombosis model.

We studied the effect of an ionic high osmolar contrast medium (Ioxitalamate), an ionic low osmolar contrast medium (Ioxaglate) and various nonionic low osmolar contrast media (Iopamidol, Iopromide and Iohexol) on thrombus growth in a rabbit jugular vein thrombosis model. Thrombus growth was determined by the accretion of 125I-labeled fibrinogen onto autologous preformed thrombi in rabbit jugular veins at various time-intervals from 15 min up to 10 h after infusion of the study solution. The ionic low osmolar contrast medium markedly inhibited thrombus growth whereas all nonionic low osmolar contrast media promoted thrombus growth. The ionic high osmolar, contrast medium inhibited thrombus growth, but less than the ionic low osmolar contrast medium. Within the group of nonionic contrast media, the Iopamidol associated promotion of thrombus growth was significantly higher than the Iopromide or Iohexol associated effects. The simultaneous administration of the apparently most potent thrombus growth promoting contrast medium (i.e. Iopamidol) and heparin resulted in complete abolishment of the increase in thrombus growth. These results support the claims of prothrombotic properties of nonionic as compared to ionic contrast media and could explain the clinically encountered thromboembolic complications after the use of nonionic low osmolar contrast media.

Ventricular fibrillation during right coronary arteriography with ioxaglate, iohexol and iopamidol in dogs.

Radiograph contrast media (CM) are known to produce myocardial disturbances during cardiac angiography. The most severe electrical disturbance is ventricular fibrillation (VF). Previous studies using prolonged right coronary exposures have demonstrated a higher incidence of VF with dilute low sodium CM than with dilute CM containing more physiologic levels of sodium. In this study the incidence of VF was examined for more conventional concentrations of iopamidol, iohexol and ioxaglate and for sodium supplemented iohexol. The incidence of VF was determined during 25-second injections of contrast media into the canine right coronary artery at a rate of 0.4 mL/sec. Injections of iohexol and iopamidol at concentrations of 160, 240 and 320 mgI/mL produced significantly more VF (P less than .005, Fisher Exact Test) than meglumine/sodium ioxaglate or iohexol supplemented with 20 mM sodium chloride. The time required to produce a 50% incidence of VF with iohexol and iopamidol was significantly related to sodium concentration (r = .92, P less than .01).

The effect of sodium on the fibrillatory propensity of nonionic contrast media.

Removing sodium from standard ionic contrast media markedly increases the incidence of ventricular fibrillation in patients undergoing coronary angiography. Newer nonionic contrast media, iopamidol, iohexol, and ioversol contain only trace amounts of sodium. To determine whether sodium attenuates or potentiates ventricular fibrillation from nonionic contrast media, we measured the prolongation in QT interval and performed programmed electrical stimulation with one, two and three extra ventricular stimuli in 40 dogs during 4-mL intracoronary injections of iopamidol, iohexol, and ioversol. Solutions of each contrast medium with added NaCl at concentrations of 0.225%, 0.45%, and 0.9% were compared with standard contrast media. The addition of NaCl markedly increased the amount of QT interval prolongation produced by each contrast medium. With iopamidol, the amount of QT interval prolongation was 40 +/- 11 msec with standard iopamidol, but was 58 +/- 11 msec with 0.225% NaCl/iopamidol, 84 +/- 17 msec with 0.45% NaCl/iopamidol, and 132 +/- 42 msec with 0.9% NaCl/iopamidol (P less than .001). Similar results were seen with iohexol and ioversol. Ventricular fibrillation was difficult to induce with standard solutions of these agents (even with three extra stimuli), but became progressively easier to induce when NaCl was added. Three extra stimuli produced ventricular fibrillation in zero of 11 dogs with standard iopamidol, zero of 11 with 0.225% NaCl/iopamidol, three of 11 with 0.45% NaCl/iopamidol, and eight of 11 with 0.9% NaCl/iopamidol (P less than .001). Similar results were observed with iohexol and ioversol. The addition of choline chloride or dextrose did not increase ventricular fibrillation and QT interval prolongation. It is concluded that standard preparations of nonionic contrast media have a very low fibrillatory propensity.(ABSTRACT TRUNCATED AT 250 WORDS)