Mitophagy Plays a Protective Role in Iodinated Contrast-Induced Acute Renal Tubular Epithelial Cells Injury.

BACKGROUND/AIMS: Contrast induced-acute kidney injury (CI-AKI) is one of the most common causes of acute kidney injury (AKI) in hospitalized patients. Mitophagy, the selective elimination of mitochondria via autophagy, is an important mechanism of mitochondrial quality control in physiological and pathological conditions. In this study, we aimed to determine effects of iohexol and iodixanol on mitochondrial reactive oxygen species (ROS), mitophagy and the potential role of mitophagy in CI-AKI cell models. METHODS: Cell viability was measured by cell counting kit-8. Cell apoptosis, mitochondrial ROS and mitochondrial membrane potential were detected by western blot, MitoSOX fluorescence and TMRE staining respectively. Mitophagy was detected by the colocalization of LC3-FITC with MitoTracker Red, western blot and electronic microscope. RESULTS: The results showed that mitophagy was induced in human renal tubular cells (HK-2 cells) under different concentrations of iodinated contrast media. Mitochondrial ROS displayed increased expression after the treatment. Rapamycin (Rap) enhanced mitophagy and alleviated contrast media induced HK-2 cells injury. In contrast, autophagy inhibitor 3-methyladenine (3-MA) down-regulated mitophagy and aggravated cells injury. CONCLUSIONS: Together, our finding indicates that iohexol and iodixanol contribute to the generation of mitochondrial ROS and mitophagy. The enhancement of mitophagy can effectively protect the kidney from iodinated contrast (iohexol)-induced renal tubular epithelial cells injury.

Safety of cerebral angiography and neuroendovascular therapy in patients with chronic kidney disease.

PURPOSE: Contrast-induced nephropathy is a common clinical concern in patients undergoing neuroendovascular procedures, especially in those with pre-existent kidney disease. We aimed to define the incidence of contrast-induced nephropathy in these high-risk patients in our practice. METHODS: We analyzed data retrospectively from patients undergoing neuroendovascular procedures at two academic medical centers over a 4-year period. Contrast-induced nephropathy was determined by an absolute increase in serum creatinine of 0.5 mg/dL or a rise from its baseline value by ≥ 25%, at 48-72 h after exposure to contrast agent after excluding other causes of renal impairment. High-risk patients were identified as those with pre-procedural estimated glomerular filtration rate < 60 mL/min irrespective of creatinine level, corresponding to stages 3-5 of chronic kidney disease. RESULTS: One hundred eighty-five high-risk patients undergoing conventional cerebral angiography and neuroendovascular interventions were identified. Only 1 out of 184 (0.54%) high-risk patients developed contrast-induced nephropathy. That one patient had stage 5 chronic kidney disease and multiple other risk factors. CONCLUSION: We have observed a very low rate of renal injury in patients with chronic kidney disease, traditionally considered high risk for neuroendovascular procedures. Multiple factors may be responsible in the risk reduction of contrast-induced nephropathy in this patient population.

Comparison of iohexol and iodixanol induced nephrotoxicity, mitochondrial damage and mitophagy in a new contrast-induced acute kidney injury rat model.

Recent progress in angiography and interventional therapy has revived interest in comparison of nephrotoxicity of low-or iso-osmolar contrast media, but detailed mechanisms and effective treatments of contrast-induced acute kidney injury (CI-AKI) remain elusive. We established a new model of CI-AKI and compared the nephrotoxicity of iohexol and iodixanol with a focus on renal oxidative stress, mitochondrial damage and mitophagy. Our results showed that 48-h dehydration plus furosemide injection before iohexol administration successfully induced CI-AKI in rats. Compared with iodixanol, iohexol induced a greater decrease in renal function, more severe morphological damage and mitochondrial ultrastructural changes, an increased number of apoptotic cells, decreased antioxidative enzymes with activation of NLRP3 inflammasome in renal tissue. Renal contrast media kinetics showed the immediate excretion of iohexol and the transient renal accumulation of iodixanol. Plasma mtDNA Tc numbers were positively correlated with markers of renal mitochondrial disruption but negatively correlated with the level of serum creatinine and the score of tubular injury. Of note, iodixanol appeared to induce a stronger activation of mitophagy than iohexol, evidenced by greater protein levels of LC3II and PINK1/Parkin in the renal tissue of iodixanol-treated rats. Taken together, our results indicate that iohexol induced more severe nephrotoxicity than iodixanol in vivo due to apoptosis, destruction of antioxidative defense machinery, activation of NLRP3 inflammasome, mitochondrial damage and mitophagy. Plasma mtDNA may serve as a biological marker for renal mitochondrial disruption and damage in CI-AKI. Antioxidative defense and mitophagy are involved in the process of CI-AKI and may be promising targets of therapies.

Ectopically expressed glutaredoxin ROXY19 negatively regulates the detoxification pathway in Arabidopsis thaliana.

BACKGROUND: Glutaredoxins (GRXs) are small proteins which bind glutathione to either reduce disulfide bonds or to coordinate iron sulfur clusters. Whereas these well-established functions are associated with ubiquitously occurring GRXs that encode variants of a CPYC or a CGFS motif in the active center, land plants also possess CCxC/S-type GRXs (named ROXYs) for which the biochemical functions are yet unknown. ROXYs physically and genetically interact with bZIP transcription factors of the TGA family. In Arabidopsis, ectopically expressed ROXY19 (originally named GRX480 or GRXC9) negatively regulates expression of jasmonic acid/ethylene-induced defense genes through an unknown mechanism that requires at least one of the redundant transcription factors TGA2, TGA5 or TGA6. RESULTS: Ectopically expressed ROXY19 interferes with the activation of TGA-dependent detoxification genes. Similar to the tga2 tga5 tga6 mutant, 35S:ROXY19 plants are more susceptible to the harmful chemical TIBA (2,3,5-triiodobenzoic acid). The repressive function of ROXY19 depends on the integrity of the active site, which can be either CCMC or CPYC but not SSMS. Ectopic expression of the related GRX ROXY18/GRXS13 also led to increased susceptibility to TIBA, indicating potential functional redundancy of members of the ROXY gene family. This redundancy might explain why roxy19 knock-out plants did not show a phenotype with respect to the regulation of the TIBA-induced detoxification program. Complementation of the tga2 tga5 tga6 mutant with either TGA5 or TGA5C186S, in which the single potential target-site of ROXY19 had been eliminated, did not reveal any evidence for a critical redox modification that might be important for controlling the detoxification program. CONCLUSIONS: ROXY19 and related proteins of the ROXY gene family can function as negative regulators of TGA-dependent promoters controlling detoxification genes.

Diagnostic evaluation of patients with nonimmediate cutaneous hypersensitivity reactions to iodinated contrast media.

BACKGROUND: Nonimmediate hypersensitivity reactions to iodinated contrast media (CM) are common. Allergological evaluation is necessary to confirm the diagnosis and to find a tolerated alternative. The aim of this study was to establish the role of skin testing and the drug provocation test (DPT) in the diagnosis of nonimmediate reactions to CM. METHODS: Skin intradermal testing and patch testing with delayed readings were carried out with different CM (iobitridol, iomeprol, iodixanol, iohexol, ioversol, iopramide and ioxaglate). Single-blind placebo-controlled DPT was carried out in those cases with a negative skin test. In seven cases, a skin biopsy was obtained from positive skin tests and positive DPT. RESULTS: Of the 161 subjects evaluated, 34 (21.1%) were skin-test positive, 21 (50%) to Iomeprol, 7 (16.7%) to Iodixanol, 5 (11.9%) to Iobitridol, 4 (9.5%) to Ioxaglate, 3 (7.1%) to Iohexol and 1 (2.4%) to Iopramide. DPT was positive in 44 cases (34.6%) that were skin-test negative, 38 (76%) to Iodixanol, 8 (16%) to Iomeprol and 4 (8%) to Iohexol. Of 78 cases (48.4%) with confirmed hypersensitivity, 34 (43.6%) were identified by skin testing and 44 (56.4%) by DPT. Skin biopsies showed a perivascular mononuclear cell infiltrate, mainly in the dermis, with higher levels of CD4 than CD8 T lymphocytes, with expression of activation markers and skin homing receptors. CONCLUSION: Patients with nonimmediate reactions to CM were identified by skin testing in 43.6% and by DPT in 56.4%. The method to confirm the diagnosis differed depending on the CM involved.

Iodixanol activation of mast cells: Implications in the pathogenesis of iodixanol-induced delayed cutaneous adverse reactions.

Iodinated contrast media (ICM) is widely used in radiological examination and interventional therapy. In the commonly used ICM, iodixanol is considered to be the safer one. However, compared with other ICMs, it has a higher incidence of delayed cutaneous adverse reactions. The underlying mechanisms are unclear. In this study, mice with positive allergic reactions were selected based on the mouse clinical allergy symptom score and skin and blood samples taken 1, 6, 24, 48, and 72 h after ICMs (6 g iodine/kg) injection for histological and blood analyses. ICMs-induced pseudo-allergic reactions were investigated through in vivo intravital vascular imaging and passive cutaneous anaphylaxis (PCA) not mediated by IgE and through, calcium imaging degranulation of mast cells (MCs), and western blot assays in vitro. Results shows iodixanol-induced systemic anaphylaxis caused severe extravasation of plasma proteins and degranulation of skin MCs, and increased levels of plasma histamine, cytokines and inflammatory chemokines. Mechanistically, iodixanol increases degranulation of MCs and promotes the synthesis of inflammatory factors by activating PLC-γ and PI3K-related pathways. Trigonelline inhibit iodixanol-induced MC-related pseudo-allergic reactions in vitro and in vivo. These results suggest that mice in the iodixanol group had a higher incidence of delayed cutaneous reactions, characterized by cytokine release over time and delayed cutaneous MC degranulation. Iodixanol's delayed cutaneous adverse reactions may be due to a delayed phase of MC-related pseudo-allergic reactions. Trigonelline revealed anti-allergic activity in iodixanol-induced MC-related pseudo-allergic reactions.

The effects of the iodinated X-ray contrast media iodixanol, iohexol, iopromide, and ioversol on the rat kidney epithelial cell line NRK 52-E.

Nephrotoxicity, associated with the administration of iodinated X-ray contrast media (ICM), continues to be a major side effect in a significant number of vulnerable patients undergoing diagnostic X-ray imaging procedures. The molecular mechanisms underlying these adverse effects on the kidneys are unclear despite several decades of investigation. Side effects are more common after exposure to high-osmolar compared with low-osmolar ICM, suggesting that osmolality may be an important physical-chemical property related to nephrotoxicity. This investigation in cultured NRK 52-E cells, a cell line of renal origin, compares the in vitro toxicity of the iso-osmolal ICM iodixanol with the low-osmolal ICM iohexol, iopromide, and ioversol. The cellular toxicity was evaluated with the trypan blue exclusion assay, the MTT assay, and incidences of cell death. A qualitative assessment of vacuolation of the cultured NRK 52-E cells was taken as a measure of intracellular uptake of ICM. A difference in cell death incidence was observed between the iso-osmolal iodixanol and the low-osmolal iohexol, iopromide, and ioversol contrast media, with the iso-osmolal iodixanol having the least effect in each of the in vitro systems tested. The osmolality of the contrast media appeared to be the major cause for the observed in vitro toxicity.

[Effectiveness of nephroprotection by the selection of contrast media used during vascular interventions in patients with chronic renal failure?]. / Ist Nephroprotektion durch die Auswahl des Röntgen-Kontrastmittels im Rahmen von Gefäßinterventionen bei vorbestehender Niereninsuffizienz möglich?

BACKGROUND: The increasing number of endovascular procedures made aware of a kidney disease induced by contrast media (CM). Contrast-induced nephropathy (= CIN) can develop in 0.6-44 % of the treated patients by angiography and / or endovascular intervention. The incidence in high-risk patients ranges from 50 to 70 %. In most cases CIN is inconspicuous and reversible. But pre-existing chronic kidney disease, diabetes mellitus, age and variable different risk factors (e. g., PAOD) can induce irreversible renal impairment. The purpose of the presented trial is to investigate incidence, predictors, and out-come of CIN in chronic renal failure patients using two different CM; one non-ionic isoosmolar -iodixanol and the other non-ionic low-osmolar iopromide. METHODS: To evaluate the incidence of CIN after endovascular diagnostics and intervention two collectives of 100  patients with chronic renal insufficiency were treated with different contrast media (CM). Inclusion followed prospectively in two collectives. One collective received iopromide (Ultravist™, Bayer Health Care, Lever-kusen, Germany), and the second hundred patients received iodixanol (Visipaque™, Nycomed Amersham, Princeton, New Jersey). Demographics, comorbidities, procedure-related data were completed by serum creatinine levels and GFR (= glomerular filtration rate). Inclusion criteria were a serum creatinine level ≥ 1.5 mg% and a GFR ≤ 60 mL / min. Those parameters were measured twice pre-interventionally, and one time 48-72  hours after the endovascular procedure. RESULTS: Collectives were homogenous and comparable concerning pre-existing risk factors, age and gender. Renal function stayed at a constant level and was independent of contrast medium selection, repectively. Average creatinine levels ranged around 1.77 mg% ±â€Š0.75  standard deviation (SD) pre-interventionally; postinterventional measurement exposed a creatinine level of 1.74 mg% ±â€Š0.74 SD as mean of both collectives. GFR (preinterventional 39.64 mL / min ±â€Š12.48 SD) increased non-significantly to 45.48 mL / min ±â€Š16.82 SD. Pre-existing chronic kidney disease had no effect on renal function parameters; no other risk factors could be evaluated. CONCLUSION: According to cost-effectiveness a low-osmolar monomeric contrast medium (LOCM) is a sufficient selection, under careful renal function control.

Predicting cardiotoxicity propensity of the novel iodinated contrast medium GE-145: Ventricular fibrillation during left coronary arteriography in pigs.

BACKGROUND: Severe side effects caused by iodinated radiographic contrast media (CM) are rare, but can occur in high risk patients and during percutaneous coronary intervention. To minimize this risk a new nonionic CM with low inherent osmolality has been designed, giving room for a relatively high concentration of favorable electrolytes in the isotonic formulation. PURPOSE: To test a new radiographic CM (GE-145) in a pig model of cardiotoxicity by comparing its ventricular fibrillation (VF) propensity and hemodynamic effects to that of iodixanol. MATERIAL AND METHODS: Test agents were injected into the left anterior descending coronary artery (LAD) of pigs through an inflated balloon catheter (injection volume 25 ml, injection rate 0.4 ml/s, maximum injection time 62.5 s). Series 1: GE-145 (338 mg I/ml) + 45 mM NaCl and iodixanol (321 mg I/ml) + 19 mM NaCl were injected in five pigs. Series 2: GE-145 (320 mg I/ml) + 45 mM NaCl + 0.1, 0.3, or 0.7 mM CaCl2 and iodixanol (320 mg I/ml) + 19 mM NaCl + 0.3 mM CaC2 (Visipaque) were injected in six pigs. RESULTS: Iodixanol + NaCl caused VF in 6 of 13 injections (46%) after 60.3±7.5 s (mean ± SD). GE-145 + NaCl did not cause any VF in 13 injections (0%) (P<0.05). Iodixanol + 19 mM NaCl + 0.3 mM CaCl2 caused VF in 9 of 9 injections (100%) after 61±4 s. GE-145 + 45 mM NaCl + 0.1, 0.3, or 0.7 mM CaCl2 did not cause any VF during or after 9 injections of each agent (0%) (P<0.05). The least hemodynamic effects were seen with GE-145 + 45 mM NaCl + 0.7 mM CaCl2. CONCLUSION: In this model of direct administration of CM into the LAD of anesthetized pigs, the tested GE-145 formulations had a significantly lower propensity to induce VF than iodixanol with electrolytes. Favorable hemodynamic properties of GE-145 can be achieved by optimizing concentrations of sodium and calcium.

GE-145, a new low-osmolar dimeric radiographic contrast medium.

BACKGROUND: Contrast-induced nephrotoxicity is a significant risk when using radiographic contrast media clinically, especially in high risk patients. Consequently, there is a need for a new contrast agent with improved clinical safety with regards to nephrotoxicity. PURPOSE: To evaluate the physicochemical properties as well as the preclinical safety and biodistribution parameters of the newly developed radiographic contrast medium GE-145. MATERIAL AND METHODS: Standard methods for radiographic contrast media were used for evaluation of physicochemical properties. The acute toxicity in rats was studied at 8, 10, and 12.5 gI/kg, the clinical chemistry parameters were determined, and histology of the kidneys was performed. Biodistribution was studied in rats using ¹²³I-labeled GE-145. RESULTS: GE-145 is more hydrophilic than iodixanol and has a considerably lower osmolality. The viscosity is similar to that of iodixanol and the protein binding is low. The acute toxicity is similar to that of iodixanol and the biodistribution is similar to that of other radiographic contrast media, showing mainly renal excretion. Kidney histology showed a moderate reversible vacuolization, similar to that of iodixanol. CONCLUSION: GE-145 exhibits similar preclinical properties to other dimeric radiographic contrast media. In addition, the low osmolality enables an iso-osmolar formulation containing a significantly higher concentration of electrolytes than Visipaque.

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.

Iodixanol, constriction of medullary descending vasa recta, and risk for contrast medium-induced nephropathy.

PURPOSE: To determine whether a type of contrast medium (CM), iodixanol, modifies outer medullary descending vasa recta (DVR) vasoreactivity and nitric oxide (NO) production in isolated microperfused DVR. MATERIALS AND METHODS: Animal handling conformed to the Animal Care Committee Guidelines of all participating institutions. Single specimens of DVR were isolated from rats and perfused with a buffered solution containing iodixanol. A concentration of 23 mg of iodine per milliliter was chosen to mimic that expected to be used in usual examinations in humans. Luminal diameter was determined by using video microscopy, and NO was measured by using fluorescent techniques. RESULTS: Iodixanol led to 52% reduction of DVR luminal diameter, a narrowing that might interfere with passage of erythrocytes in vivo. Vasoconstriction induced by angiotensin II was enhanced by iodixanol. Moreover, iodixanol decreased NO bioavailability by more than 82%. Use of 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (a superoxide dismutase mimetic) prevented both vasoconstriction with iodixanol alone and increased constriction with angiotensin II caused by CM. CONCLUSION: Iodixanol in doses typically used for coronary interventions constricts DVR, intensifies angiotensin II-induced constriction, and reduces bioavailability of NO. CM-induced nephropathy may be related to these events and scavenging of reactive oxygen species might exert a therapeutic benefit by preventing the adverse effects that a CM has on medullary perfusion.

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.

Asialoerythropoietin prevents contrast-induced nephropathy.

Strategies to prevent contrast-induced nephropathy (CIN) are suboptimal. Erythropoietin was recently found to be cytoprotective in a variety of nonhematopoietic cells, so it was hypothesized that the nonhematopoietic erythropoietin derivative asialoerythropoietin would prevent CIN. Nephropathy was induced in rats by injection of the radiocontrast medium Ioversol in addition to inhibition of prostaglandin and nitric oxide synthesis. Administration of a single dose of asialoerythropoietin before the induction of nephropathy significantly attenuated the resulting renal dysfunction and histologic renal tubular injury. Contrast-induced apoptosis of renal tubular cells was inhibited by asialoerythropoietin both in vivo and in vitro, and this effect was blocked by a Janus kinase 2 (JAK2) inhibitor in vitro. Furthermore, phospho-JAK2/signal transducer and activator of transcription 5 (STAT5) and heat-shock protein 70 increased after injection of asialoerythropoietin, suggesting that the effects of asialoerythropoietin may be mediated by the activation of the JAK2/STAT5 pathway. Overall, these findings suggest that asialoerythropoietin may have potential as a new therapeutic approach to prevent CIN given its ability to preserve renal function and directly protect renal tissue.

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.

Signs in vector-electrocardiography (VECG) predicting the fibrillatory propensity of iodixanol and mannitol solutions after injection into the left coronary artery of pigs.

RATIONALE AND OBJECTIVES: To find signs in vector-electrocardiography (VECG) predicting the ventricular fibrillatory propensity (VF-PROP) of iodixanol and mannitol solutions after injection into the left coronary artery (LCA) of pigs. MATERIALS AND METHODS: Five plasma-isotonic solutions perfused LCA: Iod 320 + Na/Ca (iodixanol 320 mg I/mL, 19 mM NaCl, 0.3 mM CaCl(2)), Iod 320 + Mann (iodixanol 320 mg I/mL, 50 mM mannitol), Mann + Na/Ca (240 mM mannitol, 19 mM NaCl, 0.3 mM CaCl(2)), Mann (275 mM mannitol), and Ringer (representing "physiologic electrolytes"). The first two solutions have at 37 degrees C viscosity 13 mPas and the others <1 mPas. In eight pigs, 20 mL of each solution was injected twice for 10 seconds, and in 15 pigs, each solution was injected for 11-40 seconds (0.5 mL/second) through a wedged catheter in the LCA. If ventricular fibrillation (VF) occurred, injection was stopped and heart was defibrillated. If VF did not occur, perfusion period was 40 seconds. A higher frequency of VF and a shorter period from start of injection until start of VF gave a solution a higher ranking of VF-PROP. RESULTS: The 10-second injections caused no VF. Ringer and Iod 320 + Na/Ca caused no VF after 40-second injections, whereas the other solutions caused VF. Ranking the solutions from lowest to highest VF- PROP gave: Ringer = Iod 320 + Na/Ca < Iod 320 + Mann < Mann + Na/Ca < Mann. Prolongation of QRS time and QTc time were the only VECG signs that showed significant differences (P < .05) between all solutions and correctly ranked the VF-PROP of all solutions in both animal groups. CONCLUSION: The results fit with the concept that a more physiologic electrolyte composition and a higher viscosity of a test solution will, after start of injection of that solution into LCA, delay changes in the electrolyte composition in myocardial interstitial fluid and also delay start of VF. If a plasma isotonic contrast medium (CM) with lower viscosity than that of iodixanol at 320 mgI/mL were created, we conclude that such a CM should have electrolyte composition closer to that of Ringer than present composition (19 mM NaCl and 0.3 mM CaC1(2)) to counteract the effects of faster diffusion of nonphysiologic electrolyte composition from the low-viscosity CM to myocardial interstitial fluid.

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.