RESUMO
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.
Assuntos
Meios de Contraste/toxicidade , Mitofagia/efeitos dos fármacos , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Adenina/análogos & derivados , Adenina/toxicidade , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular , Meios de Contraste/química , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Iodo/química , Iohexol/toxicidade , Túbulos Renais/citologia , Potencial da Membrana Mitocondrial , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirolimo/farmacologia , Ácidos Tri-Iodobenzoicos/toxicidadeRESUMO
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 pâ¯≤â¯.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.
Assuntos
Meios de Contraste/toxicidade , Células-Tronco Mesenquimais/efeitos dos fármacos , Cordão Umbilical/citologia , Apoptose/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Genes p53/efeitos dos fármacos , Humanos , Iohexol/toxicidade , Iopamidol/toxicidade , Análise em Microsséries , Gravidez , Transcriptoma/efeitos dos fármacosRESUMO
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.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Meios de Contraste/toxicidade , Modelos Animais de Doenças , Iohexol/toxicidade , Mitocôndrias/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Ácidos Tri-Iodobenzoicos/toxicidade , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Testes de Função Renal , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Mitocôndrias/ultraestrutura , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismoRESUMO
BACKGROUND: Contrast induced nephropathy (CIN) is the commonest cause of iatrogenic renal injury and its incidence has increased with the advent of complex endovascular procedures. Evidence suggests that ascorbic acid (AA) has a nephroprotective effect in percutaneous coronary interventions when contrast media are used. A variety of biomarkers (NGAL, NGAL:creatinine, mononuclear cell infiltration, apoptosis and RBP-4) in both the urine and kidney were assayed using a mouse model of CIN in order to determine whether AA can reduce the incidence and/or severity of renal injury. METHODS: Twenty-four BALB/c mice were divided into 4 groups. Three groups were exposed to high doses of contrast media (omnipaque) in a well-established model of CIN, and then treated with low or high dose AA or placebo (saline). CIN severity was determined by measurement of urinary neutrophil gelatinase-associated lipocalin (NGAL):creatinine at specific time intervals. Histological analysis was performed to determine the level of mononuclear inflammatory infiltration as well as immunohistochemistry to determine apoptosis in the glomeruli by staining for activated caspase-3 and DNA nicking (TUNEL assays). Reverse transcriptase PCR (rtPCR) of mRNA transcripts prepared from mRNA extracted from mouse kidneys was also performed for both lipocalin-2 (Lcn2) encoding NGAL and retinol binding protein-6 (RBP4) genes. NGAL protein expression was also confirmed by ELISA analysis of kidney lysates. RESULTS: Urinary NGAL:creatinine ratio was significantly lower at 48 h with a 44% and 62% (204.3µg/mmol versus 533.6µg/mmol, p = 0.049) reduction in the low and high dose AA groups, respectively. The reduced urinary NGAL:creatinine ratio remained low throughout the time period assessed (up to 96 h) in the high dose AA group. In support of the urinary analysis ELISA analysis of NGAL in kidney lysates also showed a 57% reduction (12,576 ng/ml versus 29,393 ng/ml) reduction in the low dose AA group. Immunohistochemistry for apoptosis demonstrated decreased TUNEL and caspase-3 expression in both low and high dose AA groups. CONCLUSIONS: Ascorbic acid reduced the frequency and severity of renal injury in this murine model of CIN. Further work is required to establish whether AA can reduce the incidence of CIN in humans undergoing endovascular procedures.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Meios de Contraste/toxicidade , Iohexol/toxicidade , Rim/efeitos dos fármacos , Injúria Renal Aguda/metabolismo , Animais , Apoptose/efeitos dos fármacos , Caspase 3/efeitos dos fármacos , Caspase 3/metabolismo , Creatinina/urina , Modelos Animais de Doenças , Procedimentos Endovasculares , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Rim/metabolismo , Rim/patologia , Lipocalina-2/efeitos dos fármacos , Lipocalina-2/metabolismo , Lipocalina-2/urina , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Plasmáticas de Ligação ao Retinol/efeitos dos fármacos , Proteínas Plasmáticas de Ligação ao Retinol/metabolismoRESUMO
In this study, we demonstrate for the first time, that a discrete metal-oxo cluster α-/ß-K6P2W18O62 (WD-POM) exhibits superior performance as a computed tomography (CT) contrast agent, in comparison to the standard contrast agent iohexol. A toxicity evaluation of WD-POM was performed according to standard toxicological protocols using Wistar albino rats. The maximum tolerable dose (MTD) of 2000 mg/kg was initially determined after oral WD-POM application. The acute intravenous toxicity of single WD-POM doses (1/3, 1/5, and 1/10 MTD), which are at least fifty times higher than the typically used dose (0.015 mmol W kg-1) of tungsten-based contrast agents, was evaluated for 14 days. The results of arterial blood gas analysis, CO-oximetry status, electrolyte and lactate levels for 1/10 MTD group (80% survival rate) indicated the mixed respiratory and metabolic acidosis. The highest deposition of WD-POM (0.6 ppm tungsten) was found in the kidney, followed by liver (0.15 ppm tungsten), for which the histological analysis revealed morphological irregularities, although the renal function parameters (creatinine and BUN levels) were within the physiological range. This study is the first and important step in evaluating side effects of polyoxometalate nanoclusters, which in recent years have shown a large potential as therapeutics and contrast agents.
Assuntos
Meios de Contraste , Tungstênio , Ratos , Animais , Meios de Contraste/toxicidade , Tungstênio/toxicidade , Tomografia Computadorizada por Raios X/métodos , Rim/diagnóstico por imagem , Iohexol/toxicidade , Ratos WistarRESUMO
The COVID-19 pandemic resulted in increasing the usage of iodinated contrast media (ICM), and thus an increase in the prevalence of ICM-contaminated wastewater. While ICM is generally safe, this has the potential to be problematic because as medical wastewater is treated and disinfected, various ICM-derived disinfection byproducts (DBPs) may be generated and released into the environment. However, little information was available about whether ICM-derived DBPs are toxic to aquatic organisms. In this study, the degradation of three typical ICM (iopamidol, iohexol, diatrizoate) at initial concentration of 10 µM and 100 µM in chlorination and peracetic acid without or with NH4+ was investigated, and the potential acute toxicity of treated disinfected water containing potential ICM-derived DBPs on Daphnia magna, Scenedesmus sp. and Danio rerio was tested. The degradation results suggested that only iopamidol was significantly degraded (level of degradation >98%) by chlorination, and the degradation rate of iohexol and diatrizoate were significantly increased in chlorination with NH4+. All three ICM were not degraded in peracetic acid. The toxicity analysis results indicate that only the disinfected water of iopamidol and iohexol by chlorination with NH4+ were toxic to at least one aquatic organism. These results highlighted that the potential ecological risk of ICM-contained medical wastewater by chlorination with NH4+ should not be neglected, and peracetic acid may be an environment-friendly alternative for the disinfection of wastewater containing ICM.
Assuntos
COVID-19 , Compostos de Iodo , Scenedesmus , Poluentes Químicos da Água , Animais , Humanos , Iohexol/toxicidade , Iohexol/análise , Iopamidol , Desinfecção/métodos , Diatrizoato/análise , Daphnia , Peixe-Zebra , Ácido Peracético , Águas Residuárias/toxicidade , Pandemias , Meios de Contraste/toxicidade , Meios de Contraste/análise , Água/análise , Poluentes Químicos da Água/toxicidade , Poluentes Químicos da Água/análise , HalogenaçãoRESUMO
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.
Assuntos
Desinfetantes , Iodo , Poluentes Químicos da Água , Purificação da Água , Animais , Bromodesoxiuridina/análise , Cloro/análise , Meios de Contraste/análise , Meios de Contraste/toxicidade , Diatrizoato/análise , Dimetil Sulfóxido , Desinfetantes/toxicidade , Halogenação , Humanos , Iodo/toxicidade , Iohexol/análise , Iohexol/toxicidade , Iopamidol/análise , Iopamidol/toxicidade , Irritantes/toxicidade , Camundongos , Solventes/toxicidade , Água , Poluentes Químicos da Água/análise , Purificação da Água/métodos , Raios XRESUMO
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.
Assuntos
Meios de Contraste/toxicidade , Células Epiteliais/efeitos dos fármacos , Rim/efeitos dos fármacos , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Corantes , Células Epiteliais/citologia , Iohexol/análogos & derivados , Iohexol/toxicidade , Rim/citologia , Ratos , Sais de Tetrazólio , Tiazóis , Ácidos Tri-Iodobenzoicos/toxicidade , Azul TripanoRESUMO
BACKGROUND: The increasing number of endovascular procedures made aware of a kidney disease induced by contrast media (CM). Contrast-induced nephropathy (=âCIN) can develop in 0.6-44â% of the treated patients by angiography andâ/âor endovascular intervention. The incidence in high-risk patients ranges from 50 to 70â%. In most cases CIN is inconspicuous and reversible. But pre-existing chronic kidney disease, diabetes mellitus, age and variable different risk factors (e.âg., 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 100â 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 (=âglomerular filtration rate). Inclusion criteria were a serum creatinine level ≥â1.5âmg% and a GFR ≤â60âmLâ/âmin. Those parameters were measured twice pre-interventionally, and one time 48-72 âhours 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 1.77âmg%â±â0.75 âstandard deviation (SD) pre-interventionally; postinterventional measurement exposed a creatinine level of 1.74âmg%â±â0.74âSD as mean of both collectives. GFR (preinterventional 39.64âmLâ/âminâ±â12.48âSD) increased non-significantly to 45.48âmLâ/âminâ±â16.82âSD. 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.
Assuntos
Angiografia , Angioplastia com Balão , Meios de Contraste/toxicidade , Iohexol/análogos & derivados , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Falência Renal Crônica/diagnóstico por imagem , Falência Renal Crônica/terapia , Testes de Função Renal , Obstrução da Artéria Renal/diagnóstico por imagem , Obstrução da Artéria Renal/terapia , Ácidos Tri-Iodobenzoicos/toxicidade , Idoso , Idoso de 80 Anos ou mais , Angiografia/economia , Angioplastia com Balão/economia , Meios de Contraste/administração & dosagem , Meios de Contraste/economia , Análise Custo-Benefício , Creatinina/sangue , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Iohexol/economia , Iohexol/toxicidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Ácidos Tri-Iodobenzoicos/economiaRESUMO
Globally, acute kidney injury (AKI) is associated with significant mortality and an enormous economic burden. Whereas iron is essential for metabolically active renal cells, it has the potential to cause renal cytotoxicity by promoting Fenton chemistry-based oxidative stress involving lipid peroxidation. In addition, 1,25-dihydroxyvitamin D3 (calcitriol), the active form of vitamin D, is reported to have an antioxidative role. In this study, we intended to demonstrate the impact of vitamin D on iron-mediated oxidant stress and cytotoxicity of Vero cells exposed to iohexol, a low osmolar iodine-containing contrast media in vitro. Cultured Vero cells were pretreated with 1,25-dihydroxyvitamin D3 dissolved in absolute ethanol (0.05%, 2.0 mM) at a dose of 1 mM for 6 hours. Subsequently, iohexol was added at a concentration of 100 mg iodine per mL and incubated for 3 hours. Total cellular iron content was analysed by a flame atomic absorption spectrophotometer at 372 nm. Lipid peroxidation was determined by TBARS (thiobarbituric acid reactive species) assay. Antioxidants including total thiol content were assessed by Ellman's method, catalase by colorimetric method, and superoxide dismutase (SOD) by nitroblue tetrazolium assay. The cells were stained with DAPI (4',6-diamidino-2-phenylindole), and the cytotoxicity was evaluated by viability assay (MTT assay). The results indicated that iohexol exposure caused a significant increase of the total iron content in Vero cells. A concomitant increase of lipid peroxidation and decrease of total thiol protein levels, catalase, and superoxide dismutase activity were observed along with decreased cell viability in comparison with the controls. Furthermore, these changes were significantly reversed when the cells were pretreated with vitamin D prior to incubation with iohexol. Our findings of this in vitro model of iohexol-induced renotoxicity lend further support to the nephrotoxic potential of iron and underpin the possible clinical utility of vitamin D for the treatment and prevention of AKI.
Assuntos
Antioxidantes/farmacologia , Calcitriol/farmacologia , Iohexol/toxicidade , Rim/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Chlorocebus aethiops , Estresse Oxidativo/efeitos dos fármacos , Células VeroRESUMO
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.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Cateterismo Cardíaco , Meios de Contraste/toxicidade , Tomografia Computadorizada por Raios X , Ácidos Tri-Iodobenzoicos/toxicidade , Idoso , Intervalos de Confiança , Creatinina/sangue , Feminino , Humanos , Injeções Intra-Arteriais , Injeções Intravenosas , Iohexol/análogos & derivados , Iohexol/toxicidade , Iopamidol/análogos & derivados , Iopamidol/toxicidade , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Ensaios Clínicos Controlados Aleatórios como Assunto , RiscoRESUMO
In the literature, there have been no studies showing clear results on how radio-contrast pharmaceuticals would affect intact disc tissue cells. In this context, it was aimed to evaluate the effects of iopromide and gadoxetic acid, frequently used in the discography, on intact lumbar disc tissue in pharmaco-molecular and histopathological level. Primary cell cultures were prepared from the healthy disc tissue of the patients operated in the neurosurgery clinic. Except for the control group, the cultures were incubated with the indicated radio-contrast agents. Cell viability, toxicity and proliferation indices were tested at specific time intervals. The cell viability was quantitatively analysed. It was also visually rechecked under a fluorescence microscope with acridine orange/propidium iodide staining. Simultaneously, cell surface morphology was analysed with an inverted light microscope, while haematoxylin and eosin (H&E) staining methodology was used in the histopathological evaluations. The obtained data were evaluated statistically. Unlike the literature, iopromide or gadoxetic acid did not have any adverse effects on the cell viability, proliferation and toxicity (P < 0.05). Although this study reveals that radio-contrast pharmaceuticals used in the discography, often used in neurosurgical practice, can be safely used, it should be remembered that this study was performed in an in vitro environment.
Assuntos
Meios de Contraste/toxicidade , Gadolínio DTPA/toxicidade , Disco Intervertebral/efeitos dos fármacos , Iohexol/análogos & derivados , Adulto , Sobrevivência Celular/efeitos dos fármacos , Meios de Contraste/farmacologia , Gadolínio DTPA/farmacologia , Humanos , Disco Intervertebral/diagnóstico por imagem , Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/induzido quimicamente , Degeneração do Disco Intervertebral/diagnóstico por imagem , Degeneração do Disco Intervertebral/patologia , Iohexol/farmacologia , Iohexol/toxicidade , Dor Lombar/induzido quimicamente , Dor Lombar/patologia , Vértebras Lombares/efeitos dos fármacos , Vértebras Lombares/patologia , Cultura Primária de CélulasRESUMO
OBJECTIVE: Although there are various experimental pancreatic models in animals, only a few studies have evaluated how intraductal pressure and contrast agent affect the development of pancreatitis after endoscopic retrograde cholangiopancreatograpy (ERCP). MATERIALS AND METHODS: The rats were randomly divided into seven groups (n = 8/group). The rats in all groups underwent laparotomy and their biliopancreatic ducts were cannulated transduodenally using a 24G catheter. In the control group, group 1, the biliopancreatic ducts of the rats were not infused with any fluid. The biliopancreatic ducts of the rats in groups 2, 3, and 4 were infused with 0.5 ml isotonic NaCl solution at 10, 2, and 50 mmHg, respectively. Groups 5, 6, and 7 were given 0.5 ml of 50% diluted contrast agent at 10, 25, and 50 mmHg, respectively. The serum amylase, aspartate aminotransferase (AST), lactic dehydrogenase (LDH), and C-reactive protein (CRP) were measured 24 h after the procedure. Pancreatic tissue was also evaluated histopathologically. RESULTS: Pancreatitis due to the contrast agent was noted when comparing the low pressure isotonic NaCl group and the low pressure contrast group (p < 0.05). Based on serum amylase and CRP values, there was a positive correlation between the severity and frequency of acute pancreatitis and pressure (p < 0.01). AST and LDH levels increased in all of the groups that underwent the procedure; however, no correlation was detected with increasing pressure or with the use of contrast agent (p > 0.05). Both pancreatic edema and the inflammatory cell infiltration score were elevated in isotonic NaCl and contrast group (p < 0.05); however, necrosis was not significantly changed (p > 0.05). CONCLUSION: The results of this study suggest that the main mechanism for preventing pancreatitis after ERCP is to minimize trauma to the pancreatic canal, to cannulate the pancreas only when it is necessary, and to give contrast agent under low pressure when it is needed.
Assuntos
Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Meios de Contraste/toxicidade , Iohexol/análogos & derivados , Ductos Pancreáticos/efeitos dos fármacos , Pancreatite Necrosante Aguda/induzido quimicamente , Amilases/sangue , Animais , Aspartato Aminotransferases/sangue , Proteína C-Reativa/metabolismo , Feminino , Pressão Hidrostática , Iohexol/toxicidade , L-Lactato Desidrogenase/sangue , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Pancreatite Necrosante Aguda/enzimologia , Pancreatite Necrosante Aguda/patologia , Ratos , Ratos Sprague-Dawley , Cloreto de Sódio/farmacologiaRESUMO
OBJECTIVES: Contrast-induced acute kidney injury is a prevalent cause of renal failure, and the noninvasive tools to monitor its progress are lacking. We applied intravoxel incoherent motion (IVIM) DWI to measure the progressive changes in kidney diffusion and perfusion of CI-AKI. METHODS: Twenty-four rats received Iopromide (370 mg/ml, 1600 mg iodine/kg) to induce CI-AKI. IVIM DWI was performed on rats (n = 6) at 24 h prior to and 12, 24, 48, 72, and 96 h after the injection using a 3.0 T MRI scanner. The progressive changes in the diffusion (D) and perfusion parameters (D* and f) were studied in the cortex (CO), outer medulla (OM), and inner medulla (IM). For the histology group (n = 18), three rats were sacrificed at each time point. RESULTS: In the CO, D reduced progressively from 24 to 48 h (P < 0.001) and increased starting from 72 h (P < 0.001). However, D decreased until to 72 h in the medulla (P < 0.001) and increased starting from 96 h (P < 0.001). D* decreased to the bottom at 24 h in the cortex and medulla (P = 0.037) and started to recover at 48 h (P = 0.007). f decreased in the cortex and medulla in an early stage (12 h) (P = 0.035) of CI-AKI and then ascended in the later stage (72 h) (P = 0.017). The H & E staining showed different degrees of serial pathological change including cloudy swelling, atrophy, even necrosis, and interstitial vasodilation of tubule epithelial cells and glomerulus cells. CONCLUSION: Our study demonstrates the feasibility of using IVIM DWI to monitor the progress of CI-AKI, implying that IVIM DWI is a useful biomarker in the staging of CI-AKI.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico por imagem , Meios de Contraste/toxicidade , Imagem de Difusão por Ressonância Magnética/métodos , Iohexol/análogos & derivados , Animais , Progressão da Doença , Iohexol/toxicidade , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Magnetic resonance arthrography, a procedure through which contrast agents containing gadolinium and/or iopromide are administered intra-articularly, has become a useful tool in musculoskeletal diagnosis. Nevertheless, despite being considered safe for systemic use, certain tissue toxicities have been identified for both drugs. In this study, the effects of short-term exposure of human primary chondrocyte cell cultures to gadolinium and/or iopromide contrast agents were examined by assaying for stage-specific embryonic antigen-1 (SSEA-1) protein expression (a chondrogenic differentiation marker), cell viability, toxicity, and proliferation. METHODS: Human articular chondrocytes were grown in monolayer culture and were exposed to iopromide and/or gadolinium diethylenetriamine-pentaacetate (Gd-DPT) for 2 and 6 h. Cell cultures with no drug exposure were used as the control group. Cell differentiation status was assessed according to SSEA-1 protein expression. Contrast agent effects on cell viability and proliferation were analyzed using MTT analysis. Further, changes in cell morphology in relation to the control group were evaluated using inverted light microscopy, environmental scanning electron microscopy (ESEM), and 3-tesla magnetic resonance imaging. The obtained data were statistically compared. RESULTS: When compared with the control group, both SSEA-1 protein expression and cell proliferation were lowest in the Gd-DPT group (P = 0.000). There was a statistically significant correlation between SSEA-1 expression and MTT results (rho = 0.351; P = 0.003). CONCLUSIONS: Nevertheless, the data obtained from in vitro experiments may not directly correspond to clinical applications. However, the mere fact that a drug used solely for diagnostic purposes may repress chondrocyte cell proliferation should be carefully considered by clinicians.
Assuntos
Condrócitos/efeitos dos fármacos , Meios de Contraste/toxicidade , Gadolínio DTPA/toxicidade , Iohexol/análogos & derivados , Artrografia , Condrócitos/ultraestrutura , Gadolínio DTPA/análogos & derivados , Humanos , Iohexol/toxicidade , Imageamento por Ressonância Magnética , Cultura Primária de Células , Testes de ToxicidadeRESUMO
Contrast-induced nephropathy (CIN) is a leading cause of hospital-acquired acute kidney injury as a result of iodinated contrast-media use for diagnostic purposes. Pathophysiology remains unclear. In the present study iopromide was administered to New Zealand white rabbits without any prior intervention. Oxidative stress was assessed in blood and tissue level at three anatomical kidney areas (medullary, cortical, juxtamedullary). Histopathological evaluation was also performed. Serum creatinine and urea increased in the CIN groups over 25% at two hours after administration and returned to baseline at 48 h. In kidney tissues, a significant reduction (40%) of catalase in renal cortexes of the CIN groups was observed. Necrosis and tubular vacuolization was also noted that correlated with urea and creatinine levels. Lipid peroxidation decreased at 10 h after administration (>45%) and remained low even at 48 h. Plasma protein carbonyls were significantly increased (67%) in 2 h and dropped later. Serum levels of creatinine and urea at 24 and 48 h significantly correlated with the Total Antioxidant Activity and lipid peroxidation, respectively. Oxidative stress is shown to be involved in CIN development in the rabbit, with more pronounced effects to be confined to the cortex and outer stripe of the outer medulla.
Assuntos
Meios de Contraste/toxicidade , Iohexol/análogos & derivados , Nefropatias/induzido quimicamente , Rim/patologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Biomarcadores , Creatinina/sangue , Iohexol/toxicidade , Rim/metabolismo , Nefropatias/patologia , Masculino , Oxirredução , Coelhos , Distribuição Aleatória , Ureia/sangueRESUMO
AIM: There has been a rise in contrast-induced acute kidney injury (CI-AKI). We examined the role of platelet-to-lymphocyte ratio (PLR) in predicting CI-AKI episodes in patients with myocardial infarction (MI) and diabetes. METHODS: A total of 719 patients with diabetes and MI were enrolled. Study population was divided into: group 1 (n = 615) without CI-AKI and group 2 (n = 104) with CI-AKI. RESULTS: Patients with CI-AKI had higher in-hospital mortality and a longer in-hospital stay. Median PLR was higher in patients with CI-AKI. Receiver operating characteristic analysis indicated PLR to be a good predictive tool in assessing the risk of CI-AKI. PLR was an independent predictor of CI-AKI (OR: 1.22; p < 0.0001). CONCLUSION: These results suggest potential role for PLR as a biomarker of CI-AKI among diabetic patients with MI who undergo percutaneous coronary intervention.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Plaquetas/citologia , Meios de Contraste , Diabetes Mellitus/patologia , Linfócitos/citologia , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Idoso , Área Sob a Curva , Angiografia Coronária , Creatinina/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Iohexol/química , Iohexol/toxicidade , Masculino , Pessoa de Meia-Idade , Razão de Chances , Curva ROC , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnósticoRESUMO
Contrast-induced acute kidney injury (CI-AKI) is an iatrogenic renal injury and associated with substantial morbidity and mortality in susceptible individuals. Despite extensive study of a variety of agents for renal protection, limited strategies have been shown to be effective in the reduction of CI-AKI. O-linked ß-N-acetylglucosamine (O-GlcNAc) is a post-translational regulatory modification of intracellular proteins and governs the function of numerous proteins, both cytosolic and nuclear. Increasing evidence suggests that O-GlcNAc levels are increased in response to stress and that acute augmentation of this reaction is cytoprotective. However, the underlying mechanisms by which augmented OGlcNAc signaling provides renoprotection against contrast media insults is still unknown. Here, we investigated the effect of augmented O-GlcNAc signaling via glucosamine on CI-AKI and explored the underlying molecular mechanisms, particularly its relationship with PI3-kinase (PI3K)/Akt signaling. We used a novel and reliable CI-AKI model consisting of 5/6 nephrectomized (NE) rats, and a low-osmolar contrast media (iohexol, 10mL/kg, 3.5gI) injected via the tail vein after dehydration for 48h. The results showed that augmented O-GlcNAc signaling by glucosamine prevented the kidneys against iohexol-induced injury characterized by the attenuation of renal dysfunction, tubular damage, apoptosis and oxidative stress. Furthermore, this renoprotection was blocked by treatment with alloxan, an O-GlcNAc transferase inhibitor. Augmented O-GlcNAc signaling also increased the protein expression levels of phospho-Akt (Ser473, but not Thr308 and Thr450), phospho-GSK-3ß, Nrf2, and Bcl-2, and decreased the levels of Bax and cleaved caspase-3. Both alloxan and specific inhibitors of PI3K (Wortmannin and LY294002) blocked the protection of glucosamine via inhibiting Akt signaling pathway. We further identified O-GlcNAcylated Akt through immunoprecipitation and western blot. We confirmed that Akt was modified by O-GlcNAcylation, and glucosamine pretreatment increased the O-GlcNAcylation of Akt. Collectively, the results demonstrate that glucosamine induces renoprotection against CI-AKI through augmented O-GlcNAc and activation of PI3K/Akt signaling, making it a promising strategy for preventing CI-AKI.
Assuntos
Acetilglucosamina/farmacologia , Apoptose/efeitos dos fármacos , Meios de Contraste/toxicidade , Iohexol/toxicidade , Substâncias Protetoras/farmacologia , Injúria Renal Aguda , Animais , Avaliação Pré-Clínica de Medicamentos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Estresse Oxidativo , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Transdução de SinaisAssuntos
Meios de Contraste/toxicidade , Angiografia Coronária/efeitos adversos , Iohexol/análogos & derivados , Falência Renal Crônica/induzido quimicamente , Falência Renal Crônica/complicações , Revascularização Miocárdica/efeitos adversos , Ácidos Tri-Iodobenzoicos/toxicidade , Estudos de Coortes , Creatinina/sangue , Seguimentos , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Iohexol/toxicidade , Falência Renal Crônica/mortalidade , Testes de Função Renal , Análise Multivariada , Valor Preditivo dos Testes , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de RiscoRESUMO
OBJECTIVE: Contrast media (CM) are a major cause of nephropathy in high-risk patients. The aim of this study was to examine the effects of carnitine (CAR) in advanced nephrotoxicity due to CM administration in rats with glycerol-induced renal functional disorder. METHODS: 40 rats were divided randomly into five groups (n = 8): (1) healthy group; (2) glycerol only (GLY); (3) glycerol and CM (GLY + CM); (4) glycerol, CM and 200 mg kg(-1) carnitine (CAR200, Carnitene(®); Sigma-tau/Santa Farma, Istanbul, Turkey); and (5) glycerol, CM and 400 mg kg(-1) carnitine (CAR400). Kidney injury was induced with a single-dose, intramuscular injection of 10 ml kg(-1) body weight (b.w.) of GLY. CAR was administered intraperitoneally. CM (8 ml kg(-1) b.w. iohexol, Omnipaque™; Opakim Medical Products, Istanbul, Turkey) was infused via the tail vein to the rats in Groups 3-5. RESULTS: l-carnitine administration significantly decreased serum creatinine and blood urea nitrogen levels. Superoxide dismutase and glutathione activity increased significantly in the treatment groups compared with the nephrotoxic groups. CAR400 significantly reduced malondialdehyde levels to healthy levels. In the treatment groups, tumour necrosis factor (TNF)-α, transforming growth factor 1ß, interleukin 1ß and caspase-3 gene expression decreased compared with the nephrotoxic groups. TNF-α and nuclear factor kappa-beta (NF-κB) protein expression increased after CM and CAR administration reduced both TNF-α and NF-κB expressions. Histopathologically, hyaline and haemorrhagic casts and necrosis in proximal tubules increased in the nephrotoxicity groups and decreased in the CAR groups. CONCLUSION: The results reveal that l-carnitine protects the oxidant/antioxidant balance and decreases proinflammatory cytokines and apoptosis in CM-induced nephrotoxicity in rats with underlying pathology. ADVANCES IN KNOWLEDGE: Depending on the underlying kidney pathologies, the incidence of CM-induced nephropathy (CIN) increases. Therefore, this is the best model to represent clinically observed CIN.