An in vivo and in vitro model on the protective effect of cilnidipine on contrast-induced nephropathy via regulation of apoptosis and CaMKâ ¡/mPTP pathway.

Contrast-induced nephropathy (CIN) is an acute kidney injury (AKI) observed after the administration of contrast media. Calcium channel blockers (CCBs) have been reported to exert a renal protective effect. This study aims to investigate the role of cilnidipine, a novel CCBs, on CIN by regulating the calcium/calmodulin-dependent protein kinase Ⅱ(CaMKⅡ)/mitochondrial permeability transition pore (mPTP) pathway. Here, iohexol, a representative contrast media, was used to establish CIN model. KN-93 (CaMKⅡ inhibitor) and atractyloside (mPTP opener) were administered in rats, and CaMKⅡ overexpression was used in Human proximal tubular epithelial cells. Markers of renal injury (serum creatinine, blood urea nitrogen, and urinary NAGL), hematoxylin-eosin stain, oxidative stress (ROS, superoxide dismutase [SOD], and malondialdehyde [MDA] levels), cell death (MTT and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling [TUNEL]), mitochondrial function (mPTP, mitochondrial membrane potential [MMP], and ATP) were assessed. Western blots were used to measure the expression levels of Bax/Bcl-2, caspase-3, CaMKⅡ/mPTP signaling pathways. Results showed that cilnidipine markedly improved kidney function, and alleviated tubular cell apoptosis, oxidative stress and mitochondrial damage induced by iohexol in vitro and in vivo. The underlying mechanism may be that cilnidipine relieved CaMKⅡ activation and mPTP opening induced by iohexol. All of these protective effects of cilnidipine were attenuated by CaMKⅡ overexpression and atractyloside (mPTP opener) pretreatment. Moreover, KN-93 (CaMKⅡ inhibitor) treatment showed a similar renal protective effect with cilnidipine, while the protective effect of cilnidipine on kidney in CIN rats was not further suppressed by KN-93 cotreatment. These in vitro and in vivo results point toward the fact that cilnidipine might be a novel therapeutic drug against contrast-induced nephrotoxicity in a CaMKⅡ-dependent manner.

Ox-LDL aggravates contrast-induced injury of renal tubular epithelial cells.

Hypercholesterolemia can aggravate contrast-induced acute kidney injury, and the exacerbation of renal tubular epithelial cell (RTEC) injury is a major cause. However, the exact mechanisms remain obscure. Mitophagy, a type of autophagy, selectively eliminates damaged mitochondria and reduces mitochondrial oxidative stress, which is strongly implicated in cell homeostasis and acute kidney injury. Oxidized low-density lipoprotein (Ox-LDL) is accumulated in hypercholesterolemia and has a cytotoxic effect. This study aimed to determine whether and how ox-LDL exacerbates contrast-induced injury in RTECs and to further explore whether PINK1/Parkin-dependent mitophagy is involved in this process. Iohexol and ox-LDL were used alone or in combination to treat HK-2 cells. Rapamycin pretreatment was utilized to enhance mitophagy. Cell viability, apoptosis, mitochondrial membrane potential (MMP) and mitochondrial reactive oxygen species (mtROS) were detected by cell counting kit-8, TUNEL staining, JC-1 kit and MitoSOX fluorescence, respectively. The expression of mitophagy-related proteins (including PINK1, Parkin, and so on) and cleaved caspase-3 was confirmed by western blot. Colocalization of MitoTracker-labeled mitochondria and LysoTracker-labeled lysosomes was observed by fluorescence microscopy to evaluate mitophagy. The results of our study showed that ox-LDL aggravated MMP decline, mtROS release and apoptosis in iohexol-treated HK-2 cells, accompanied by a further increased autophagy level. Enhancement of PINK1/Parkin-dependent mitophagy by rapamycin alleviated apoptosis and mitochondrial injury in HK-2 cells in response to iohexol under ox-LDL condition. Therefore, our findings indicate that ox-LDL aggravates contrast-induced injury of RTECs by increasing mitochondrial damage and mitochondrial oxidative stress, which may be associated with the relative insufficiency of PINK1/Parkin-dependent mitophagy.

Contrast Agent Selection to Prevent Recurrent Severe Hypersensitivity Reaction to Iodinated Contrast Media Based on Nationwide Database.

OBJECTIVE: To investigate the incidence of severe iodinated contrast media (ICM)-related hypersensitivity reaction (HSR) and to find the optimal alternative ICM to reduce the risk of severe HSR recurrence. METHODS: We retrospectively reviewed 23,383,183 cases of ICM administration between January 2015 and December 2019 from the nationwide health insurance database. We classified ICMs based on generic profiles and the presence of N-(2,3-dihydroxypropyl) carbamoyl side chains. The incidence of severe and recurrent severe HSRs was calculated, and χ2 tests were performed to compare the prevalence of severe HSR according to ICM groups. In addition, logistic regression analyses were used to assess differences between ICM groups. RESULTS: The incidence of severe HSRs was 1.92% (450,067 of 23,282,183). Among 1,875,245 individuals who received ICM twice on different days, severe HSR occurred in 40,850 individuals, and severe HSR recurred in 3319 individuals (8.12%). The risk of recurrence significantly decreased when the ICM changed (9.24% vs 7.08%, P < 0.001), especially when the ICM changed to one with a different side chain (6.74%, P < 0.001). In addition, compared with the reuse of the culprit agent, using combinations of iobitridol/iohexol (odds ratio [OR], 0.696; P = 0.04), iohexol/iopamidol (OR, 0.757; P = 0.007), iopamidol/iohexol (OR, 0.447; P < 0.001), and ioversol/iohexol (OR, 0.683; P = 0.04) reduced the risk of recurrence of severe HSR. CONCLUSIONS: Changing the culprit ICM to that with a different side chain can reduce severe HSR recurrence. The optimal choice of an alternative ICM depends on the causative agent.

Incomplete Recovery from the Radiocontrast-Induced Dysregulated Cell Cycle, Adhesion, and Fibrogenesis in Renal Tubular Cells after Radiocontrast (Iohexol) Removal.

Contrast-induced nephropathy (CIN) is one of the most common causes of acute kidney injury (AKI). However, management is still limited, and the cellular response to radiocontrast removal for CIN remains unclear. This study aimed to explore the latent effects of iohexol in cultured renal tubular cells with or without the removal of iohexol by medium replacement. HK2 renal tubular cells were subcultured 24 h before use in CIN experiments. Three treatment groups were established: the control, a radiocontrast (iohexol)-only group at 75 mg I/mL (I-75), and iohexol exposure for 24 h with culture medium replacement (I-75/M). Cell cycle arrest, fibrogenic mediator assays, cell viability, cell function, and cell-cycle-related protein expression were compared between groups. Iohexol induced numerous changes in HK2 renal tubular cells, such as enlarged cell shape, cell cycle arrest, increased apoptosis, and polyploidy. Iohexol inhibited the expression of cyclins, CDKs, ZO-1, and E-cadherin but conversely enhanced the expression of p21 and fibrosis-related genes, including TGF-ß1, CTGF, collagen I, collagen III, and HIF-1α within 60 hr after the exposure. Except for the recovery from cell cycle arrest and cell cycle gene expression, notably, the removal of iohexol by medium replacement could not fully recover the renal tubular cells from the formation of polyploid cells, the adhesion or spreading, or the expression of fibrosis-related genes. The present study demonstrates, for the first time, that iohexol exerts latent cytotoxic effects on cultured renal tubular cells after its removal, suggesting that these irreversible cell changes may cause the insufficiency of radiocontrast reduction in CIN, which is worth investigating further.

Metabolomic Study on Iohexol-Induced Nephrotoxicity in Rats Based on NMR and LC-MS Analyses.

Iohexol, the raw material of nonionic X-ray computed tomography (X-CT) contrast medium, is usually injected into the vein before CT angiography diagnosis. It is used for angiography, urography, and lymphography. With the advantages of low contrast density and good tolerance, it is currently one of the most popular contrast media. However, the renal toxicity of iohexol seriously affects its safety use. Therefore, it is of great importance to identify new potential diagnostic biomarkers and therapeutic targets in the process of contrast medium-induced acute kidney injury (CI-AKI) in order to safely use iohexol in clinical practice. In this study, in order to understand the metabolic mechanism of CI-AKI, ultra-high-performance liquid chromatography/quadrupole-Orbitrap-mass spectrometry and 1H NMR-based metabolomic techniques were utilized to study the metabolic spectra of kidney, plasma, and urine from CI-AKI rats, and a total of 30 metabolites that were closely related to kidney injury were screened out, which were mainly related to 9 metabolic pathways. The results further indicated that iohexol might intensify kidney dysfunction in vivo by disrupting the metabolic pathways in the body, especially through blocking energy metabolism, amino acid metabolism, and promoting inflammatory reactions.

Effect of Extrinsic Warming of Low-Osmolality CT Contrast Media (Iohexol 350) on Extravasations and Patient Reaction Rates: A Retrospective Study.

BACKGROUND. Extrinsic warming of iodinated CT contrast media to body temperature reduces viscosity and injection pressures. However, studies examining the effect of extrinsic warming on clinical adverse events are limited in number and provide conflicting results. Therefore, consensus practice recommendations have been sparse. OBJECTIVE. The purpose of this study is to compare rates of extravasation, allergic and allergiclike reactions, and physiologic reactions between iohexol 350 mg I/mL warmed to body temperature (37°C) versus this agent maintained at room temperature. METHODS. This retrospective study compared adult patients who received CT examinations using IV iohexol 350 that had either been warmed to body temperature or maintained at room temperature. At our institution, contrast media had historically been warmed to body temperature before a protocol change unrelated to this investigation. Information on the patient and CT examination was extracted from the electronic medical record. Adverse events, including extravasations, allergic and allergiclike reactions, and physiologic reactions, were compared between groups. RESULTS. A total of 3939 patients received contrast media warmed to body temperature before the protocol change; 3933 patients received contrast media at room temperature after the protocol change. The body temperature group experienced 11 (0.28%; 95% CI, 0.14-0.50%) adverse events, all extravasations; the allergic and allergic-like reaction rate was 0.00% (97.5% CI, 0.00-0.09%). The room temperature group experienced 17 (0.43%; 95% CI, 0.25-0.69%) adverse events: 13 (0.33%; 95% CI, 0.17-0.56%) extravasations and four (0.10%; 95% CI, 0.03-0.26%) allergic and allergiclike reactions. No physiologic reaction occurred in either group. The two groups were not different in terms of overall reaction rate (p = .19), extravasation rate (p = .69), allergic and allergiclike reaction rate (p = .06), or physiologic reaction rate (p > .99). Logistic regression adjusting for patient and CT characteristics (age, sex, conventional CT vs CTA, contrast media volume, injection location) showed no significant association of patient group and adverse reaction rate (odds ratio, 2.19; 95% CI, 0.68-7.00). Multivariable regression modeling showed an excess of 0.27 adverse events per 100 patients within the room temperature group, which is below a 0.6% noninferiority margin. CONCLUSION. The data suggest that maintaining iohexol 350 at room temperature is noninferior to warming the agent to body temperature before injection. CLINICAL IMPACT. The resources involved to prewarm iohexol 350 before injection may not be warranted.

A novel contrast-induced acute kidney injury mouse model based on low-osmolar contrast medium.

The contrast-induced acute kidney injury (CI-AKI) has been becoming the third common cause of hospital-acquired acute kidney injury. An ideal animal model is essential for understanding the pathophysiology of CI-AKI. Previous CI-AKI studies were mostly performed on rats with high-osmolar contrast medium (HOCM), which is unsuitable for transgenic researches. This study provides a novel, efficient and reproducible CI-AKI model which was developed in mouse by administrating a low-osmolar contrast medium (LOCM). First of all, we applied the frequently used pretreatments (uninephrectomy and water deprivation), which combined with HOCM on rats could induce CI-AKI, on mice with LOCM. Secondly, we attempted to find a novel pretreatment suitable for mouse and LOCM by combining two classic pretreatments(uninephrectomy, water deprivation and furosemide administration). Finally, we evaluate the kidney damage of the novel model. We found that this mouse model possessed a significant reduction in renal function, severe renal tissue damage, and increased renal tubular cells apoptosis, indicating that LOCM is a feasible inducer for CI-AKI mice model. Taken together, we found that uninephrectomy (UPHT) combined with 24 h water deprivation and furosemide administration 20 min before LOCM (iohexol, 10 ml/kg) application is a feasible pretreatment to establish a novel CI-AKI mouse model.

Involvement of necroptosis in contrast-induced nephropathy in a rat CKD model.

BACKGROUND: The risk of contrast-induced nephropathy (CIN) is high in patients with chronic kidney disease (CKD). However, the mechanism of CIN in CKD is not fully understood. Here, we prepared a clinically relevant model of CIN and examined the role of necroptosis, which potentially cross-talks with autophagy, in CIN. METHODS: In Sprague-Dawley rats, CKD was induced by subtotal nephrectomy (SNx, 5/6 nephrectomy) 4 weeks before induction of CIN. CIN was induced by administration of a contrast medium (CM), iohexol, following administration of indomethacin and N-omega-Nitro-L-arginine methyl ester. Renal function and tissue injuries were assessed 48 h after CM injection. RESULTS: Serum creatinine (s-Cre) and BUN were increased from 0.28 ± 0.01 to 0.52 ± 0.02 mg/dl and from 15.1 ± 0.7 to 29.2 ± 1.2 mg/dl, respectively, after SNx alone. CM further increased s-Cre and BUN to 0.69 ± 0.03 and 37.2 ± 2.1, respectively. In the renal tissue after CM injection, protein levels of receptor-interacting serine/threonine-protein kinase (RIP) 1, RIP3, cleaved caspase 3, and caspase 8 were increased by 64 ~ 212%, while there was reduction in LC3-II and accumulation of p62. Necrostatin-1, an RIP1 inhibitor, administered before and 24 h after CM injection significantly suppressed elevation of s-Cre, BUN and urinary albumin levels, kidney injury molecule-1 expression and infiltration of CD68-positive macrophages in renal tissues after CM injection. CONCLUSION: The results suggest that necroptosis of proximal tubular cells contributes to CIN in CKD and that suppression of protective autophagy by pro-necroptotic signaling may also be involved.

Renal insufficiency following contrast media administration trial III: Urine flow rate-guided versus left-ventricular end-diastolic pressure-guided hydration in high-risk patients for contrast-induced acute kidney injury. Rationale and design.

BACKGROUND: Urine flow rate (UFR)-guided and left-ventricular end-diastolic pressure (LVEDP)-guided hydration regimens have been proposed to prevent contrast-induced acute kidney injury (CIAKI). The REnal Insufficiency Following Contrast MEDIA Administration triaL III (REMEDIAL III) is a randomized, multicenter, investigator-sponsored trial aiming to compare these two hydration strategies. METHODS: Patients at high risk for CIAKI (that is, those with estimated glomerular filtration rate ≤ 45 mL/min/1.73 m2 and/or with Mehran's score ≥11 and/or Gurm's score >7) will be enrolled. Patients will be randomly assigned to (a) LVEDP-guided hydration with normal saline (LVEDP-guided group) and (b) UFR-guided hydration carried out by the RenalGuard system (RenalGuard group). Seven-hundred patients (350 in each arm) will be enrolled. In the LVEDP-guided group the fluid infusion rate will be adjusted according to the LVEDP as follows: 5 mL kg-1 hr-1 for LVEDP ≤12 mmHg, 3 mL kg-1 hr-1 for LVEDP 13-18 mmHg, and 1.5 mL kg-1 hr-1 for LVEDP >18 mmHg. In the RenalGuard group hydration with normal saline plus low-dose of furosemide is controlled by the RenalGuard system, in order to reach and maintain a high (>300 mL/hr) UFR. In all cases, iobitridol (a low-osmolar, nonionic contrast agent) will be administered. RESULTS: The primary endpoint is the composite of CIAKI (i.e., serum creatinine increase ≥25% and/or ≥0.5 mg/dL from the baseline to 48 hr after contrast media exposure) and/or acute pulmonary edema. CONCLUSION: The REMEDIAL III will test the hypothesis that the UFR-guided hydration is superior to the LVEDP-guided hydration to prevent the composite of CIAKI and/or acute pulmonary edema.

AdipoRon, an adiponectin receptor agonist, protects contrast-induced nephropathy by suppressing oxidative stress and inflammation via activation of the AMPK pathway.

BACKGROUND: Contrast-induced nephropathy (CIN), a complication caused by using contrast medium during diagnostic and interventional procedures, occurs frequently and lacks effective treatment. AdipoRon, the agonist of adiponectin receptors, has been shown to benefit many organs including the kidney. This study aimed to investigate the role of AdipoRon in treating CIN. METHODS: CIN model was established via infusing iopromide (1.8 g/kg) in Sprague-Dawley (SD) rats; NRK52E cells were treated with iopromide (5-50 µM). Renal function, renal histopathology, levels of lactate dehydrogenase (LDH) release, cell vitality, oxidative stress and inflammatory markers were measured to evaluate the protective effects of AdipoRon. The level of pAMPK/AMPK was determined by western blot. RESULTS: AdipoRon (50 mg/kg) significantly reversed serum creatinine, blood urea nitrogen, creatinine clearance and urinary kidney injury molecule-1 levels induced by iopromide in SD rats. Besides, it decreased the renal injury score and apoptosis of renal cells. AdipoRon also reversed the changes of antioxidant markers, pro-oxidant and inflammatory markers induced by iopromide. Moreover, the in vitro studies showed that AdipoRon decreased LDH release and increased cell vitality in NRK52E cells treated with iopromide. Then, we demonstrated that the protection of AdipoRon was accompanied by augmented AMPK phosphorylation. Both in vivo and in vitro studies demonstrated that compound c, an AMPK inhibitor, reversed the AdipoRon-mediated improvement in the CIN model. CONCLUSION: Our data indicate that AdipoRon protects against the CIN by suppressing oxidative stress and inflammation via activating the AMPK pathway, showing that AdipoRon might be a potential candidate for the prevention and therapy of CIN.

Contrast-Associated Acute Kidney Injury in Endovascular Thrombectomy Patients With and Without Baseline Renal Impairment.

Background and Purpose- In ischemic stroke, baseline renal impairment is present in 20 to 35% of patients and may increase the risk of contrast-associated acute kidney injury (CA-AKI). We aimed to determine whether endovascular thrombectomy (EVT) patients with baseline renal impairment are at increased risk of CA-AKI. Methods- Consecutive EVT patients were identified from a prospective database. Patients were stratified by estimated glomerular filtration rate. The primary outcome was CA-AKI assessed at 24 to 72 hours following EVT, defined as an increase in serum creatinine of ≥26.5 µmol/L or 1.5× baseline serum creatinine. Secondary outcomes included requirement for renal replacement therapy and 3-month mortality. Results- Three hundred thirty-three EVT patients (201 men; mean±SD age 63.9±15.8 years) were included. The mean±SD iohexol contrast volume used in diagnostic and EVT imaging was 236±77 mL per patient. CA-AKI occurred in 11 (3.3%) patients; none required renal replacement therapy, but 4 of 11 (36.4%) had died by 3 months. Propensity score-adjusted logistic regression showed that estimated glomerular filtration rate <30 mL/(min·1.73 m2) was a significant predictor of CA-AKI (odds ratio, 19.93; 95% CI, 2.33-170.74; P=0.006). The dose of contrast was not associated with an increased risk of CA-AKI (P>0.05). Multiple logistic regression adjusted for potential confounders demonstrated that CA-AKI was independently associated with increased mortality (odds ratio, 4.68; 95% CI, 1.05-20.97; P=0.04). Conclusions- There is utility in obtaining baseline creatinine levels to identify patients at risk of CA-AKI and to establish a diagnosis of CA-AKI in patients with subsequent creatinine rises. However, contrast-requiring diagnostic imaging and EVT should not be delayed by waiting for the results of baseline renal function.

DDAH-2 alleviates contrast medium iopromide-induced acute kidney injury through nitric oxide synthase.

BACKGROUND: Contrast medium-induced acute kidney injury (CI-AKI) is one of the most common causes of hospital-acquired acute renal failure. However, the pathogenesis of CI-AKI remains unclear. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor that is largely metabolised by dimethylarginine dimethylaminohydroxylase (DDAH) in humans. Two isoforms of DDAH exist, namely, DDAH-1 and DDAH-2. In the present study, we examined whether the DDAH-2/ADMA/NOS pathway is involved in the pathogenesis of CI-AKI. METHODS AND RESULTS: Exposure to the contrast medium iopromide led to increase in creatinine and blood urea nitrogen (BUN) levels, accumulation of ADMA, increase in reactive oxygen species (ROS) generation, and an inflammatory response in mice kidney tissue. The injection of adenovirus-harbouring DDAH-2 lowered renal ADMA levels and had a reno-protective effect against contrast-medium injury by decreasing cell apoptosis, ROS, and fibrosis. By contrast, contrast medium-induced renal injury was exacerbated in heterozygous DDAH-2 knockout mice. In the in vitro study, overexpression of DDAH-2 increased the levels of nitrite and intracellular cGMP, while the DDAH-2 knockdown induced the opposite effect. These findings were also observed in the in vivo sample. CONCLUSIONS: Our findings provide the first evidence that the DDAH-2/ADMA/NOS pathway is involved in the pathogenesis of CI-AKI and that the protective effect of DDAH-2 probably arises from the modulation of NOS activity, oxidative stress, and the inflammatory process.

Rate of major adverse renal or cardiac events with iohexol compared to other low osmolar contrast media during interventional cardiovascular procedures.

OBJECTIVE: This study assessed the rate of major adverse renal or cardiac events (MARCE) when iohexol is used during interventional cardiovascular procedures compared to other low osmolar contrast media (LOCMs). BACKGROUND: Interventional cardiovascular procedures are often essential for diagnosis and treatment, the risk of MARCE should be considered. METHODS: Data were derived from the Premier Hospital Database January 1, 2010 through September 30, 2015. Patient encounters with an inpatient primary interventional cardiovascular procedure with a single LOCM (iohexol, ioversol, ioxilan, ioxaglate, or iopamidol) were included. The primary outcome was a composite endpoint of MARCE, which included: renal failure with dialysis, acute kidney injury (AKI) with or without dialysis, contrast induced AKI, acute myocardial infarction, angina, stent occlusion/thrombosis, stroke, transient ischemic attack, or death. Multivariable regression analysis was performed using the hospital fixed-effects specification to assess the relationship between MARCE and iohexol compared to other LOCMs, while controlling for patient demographics, comorbid conditions and reason for hospitalization. As a sensitivity analysis, direct comparisons of iohexol were made to other LOCMs. RESULTS: A total of 458,091 inpatient encounters met inclusion criteria of which 26% used iohexol and 74% used other LOCMs. Results of multivariable modeling revealed no differences in MARCE rates between iohexol and other LOCMs. When direct comparisons of iohexol vs. ioversol and iopamidol were modeled, no differences in MARCE nor the renal component of MARCE were found. CONCLUSIONS: In this retrospective multicenter study, there were no differences in MARCE events with iohexol compared to other LOCMs during inpatient interventional cardiovascular procedures.

A novel rat model of contrast-induced nephropathy based on dehydration.

BACKGROUND: Contrast-induced nephropathy (CIN) is a frequent cause of hospital-acquired acute kidney injury. Previous animal models developed to explore the pathogenesis of CIN were based primarily on surgery or indomethacin treatment. Thus, we sought to explore a novel CIN rat model comparable to the human CIN. METHODS AND RESULTS: Both serum creatinine and tubular injury score were used to assess the successful establishment of the present model. In our study, dehydration duration and the iohexol dosage were found to be the two most important factors to develop a rat CIN model. And, dehydration for 3 days plus furosemide (10 mL/kg) injection before iohexol (15 mL/kg) administration was demonstrated the optimal strategy. Renal injury induced by 15 mL/kg iohexol was almost twice more severe than 10 mL/kg. Moreover, significant renal function decrease, morphological damage and mitochondrial dysfunction occurred as early as 6 h after iohexol injection, not 24 h as previous studies reported. Unexpectedly, we firstly discovered that dehydration after iohexol administration did not increase the extent of renal damage, indicating that hydration after contrast media exposure may be ineffective. CONCLUSIONS: A novel CIN rat model based on dehydration and iohexol exposure was established and validated to assist in understanding and preventing CIN.

CHA2DS2-VASC score as a preprocedural predictor of contrast-induced nephropathy among patients with chronic total occlusion undergoing percutaneous coronary intervention: a single-center experience.

BACKGROUND: The usefulness of the CHA2DS2-VASC risk score (CVRS) in predicting the occurrence of contrast-induced nephropathy (CIN) among patients with chronic total occlusion (CTO) undergoing percutaneous coronary intervention (PCI) remains unclear. METHOD: A total of 239 patients with CTO who underwent PCI were included in this study. They were divided into 3 groups according to the CVRS: low-risk group (1 point, n = 64), intermediate-risk group (2 points, n = 135), and high-risk group (≥3 points, n = 40). Baseline serum creatinine was determined upon admission before the procedure. The serum creatinine level was monitored for 72 h post-procedure to determine the occurrence of CIN. RESULTS: The total incidence of CIN in patients with CTO who underwent PCI was 16.3%. The average CVRS in the CIN group was significantly higher than that in the non-CIN group (3.1 ± 1.2 VS 2.1 ± 1.1, P < 0.001). The incidence of CIN in the high-risk group was 5.6 times higher than that in the low-risk group (37.5% VS 6.3%, P < 0.001). Similar to the Mehran risk score (AUC, 0.754; 95% CI, 0.698-0.810; P < 0.001), the receiver operating characteristic curve analysis showed a good diagnostic value of the CVRS in predicting CIN among patients with CTO who underwent interventional therapy for having CVRS≥3 (sensitivity, 69.2%; specificity, 78.0%; AUC, 0.742; 95% CI, 0.682-0.797; P < 0.001). The multivariate analysis showed that the higher pulse pressure and contrast volume, lower baseline glomerular filtration rate, and CVRS ≥3 were independent predictors of CIN. CONCLUSIONS: The CVRS can be used as a simple pre-procedural predictor of CIN among patients with CTO undergoing PCI.

Renal Safety of Intra-Arterial Treatment after Acute Ischemic Stroke with Multimodal CT Imaging selection.

BACKGROUND: Multimodal computed tomography imaging is used to identify eligible patients for intra-arterial treatment. A concern with this method is the multiple use of iodinated contrast material which presents a possible risk of renal toxicity. We compared the safety of intra-arterial treatment versus intravenous treatment during acute ischemic stroke treatment with a focus on renal safety. METHODS: Adult acute ischemic stroke patients who underwent a baseline Multimodal computed tomography, then intra-arterial treatment and/or intravenous treatment were identified. Primary outcomes were acute kidney injury and changes in serum creatinine at 24-72 hours (Δ serum creatinine). RESULTS: A total of 184 patients received intra-arterial treatment, while 68 received intravenous treatment. There were no differences in mean serum creatinine in the 24-72-hour time period, 24-hour urine volume, or rates of acute kidney injury, dialysis, or mortality. Univariate regression analysis identified diabetes mellitus, operation duration and times of embolectomy as predictors of creatinine increase while the multiple regression model identified diabetes mellitus as the only significant predictor. CONCLUSIONS: There were no significant differences in renal safety between the intra-arterial treatment and intravenous treatment groups. Diabetes mellitus may be a predictor of acute kidney injury. The use of Multimodal computed tomography imaging in the selection of patients who could benefit from endovascular therapy is safe.

Iodixanol versus iopromide in cancer patients: Evidence from a randomized clinical trial.

To assess the safety profile of iso-osmolar contrast medium (CM) versus low osmolar CM in cancer patients with an estimated glomerular filtration rate (eGFR) >60 ml/min. In this multicenter, blind trial of patients seeking a chest-abdomen-pelvis contrast enhanced computed tomography (CT) with iodated CM, participants were centrally randomized to iodixanol or iopromide. Contrast induced nephropathy (CIN) at 24 and/or 72 hr were our primary outcomes. We further considered irreversible CIN, average eGFR percentage variation (%Δ), and adverse events (AEs). Overall, 607 patients were enrolled. Among them, 497 eligible patients were randomized to iodixanol (N: 247) or iopromide (N: 250). No differences emerged by descriptive characteristics. Seven and 3 CIN at 24 hr (p = 0.34) and 8 and 2 CIN at 72 hr (p = 0.11) occurred in the iopromide and iodixanol group, respectively. Within the subgroup of individual patients who developed CIN (N: 17), the event rate was higher in the iopromide arm (p = 0.045). No cases of permanent CIN or significant differences in terms of AEs or GFR %Δ were observed. Our results suggest a more favorable safety profile of iodixanol versus iopromide. Adequately sized trials with similar design are warranted to confirm our findings and clarify the underlying biological mechanisms.

Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial.

BACKGROUND: Intravenous saline is recommended in clinical practice guidelines as the cornerstone for preventing contrast-induced nephropathy in patients with compromised renal function. However, clinical-effectiveness and cost-effectiveness of this prophylactic hydration treatment in protecting renal function has not been adequately studied in the population targeted by the guidelines, against a group receiving no prophylaxis. This was the aim of the AMACING trial. METHODS: AMACING is a prospective, randomised, phase 3, parallel-group, open-label, non-inferiority trial of patients at risk of contrast-induced nephropathy according to current guidelines. High-risk patients (with an estimated glomerular filtration rate [eGFR] of 30-59 mL per min/1·73 m2) aged 18 years and older, undergoing an elective procedure requiring iodinated contrast material administration at Maastricht University Medical Centre, the Netherlands, were randomly assigned (1:1) to receive intravenous 0·9% NaCl or no prophylaxis. We excluded patients with eGFR lower than 30 mL per min/1·73 m2, previous dialysis, or no referral for intravenous hydration. Randomisation was stratified by predefined risk factors. The primary outcome was incidence of contrast-induced nephropathy, defined as an increase in serum creatinine from baseline of more than 25% or 44 µmol/L within 2-6 days of contrast exposure, and cost-effectiveness of no prophylaxis compared with intravenous hydration in the prevention of contrast-induced nephropathy. We measured serum creatinine immediately before, 2-6 days, and 26-35 days after contrast-material exposure. Laboratory personnel were masked to treatment allocation. Adverse events and use of resources were systematically recorded. The non-inferiority margin was set at 2·1%. Both intention-to-treat and per-protocol analyses were done. This trial is registered with ClinicalTrials.gov, number NCT02106234. FINDINGS: Between June 17, 2014, and July 17, 2016, 660 consecutive patients were randomly assigned to receive no prophylaxis (n=332) or intravenous hydration (n=328). 2-6 day serum creatinine was available for 307 (92%) of 332 patients in the no prophylaxis group and 296 (90%) of 328 patients in the intravenous hydration group. Contrast-induced nephropathy was recorded in eight (2·6%) of 307 non-hydrated patients and in eight (2·7%) of 296 hydrated patients. The absolute difference (no hydration vs hydration) was -0·10% (one-sided 95% CI -2·25 to 2·06; one-tailed p=0·4710). No hydration was cost-saving relative to hydration. No haemodialysis or related deaths occurred within 35 days. 18 (5·5%) of 328 patients had complications associated with intravenous hydration. INTERPRETATION: We found no prophylaxis to be non-inferior and cost-saving in preventing contrast-induced nephropathy compared with intravenous hydration according to current clinical practice guidelines. FUNDING: Stichting de Weijerhorst.

Iodixanol versus Iopromide at Coronary CT Angiography: Lumen Opacification and Effect on Heart Rhythm-the Randomized IsoCOR Trial.

Purpose To show that equal coronary lumen opacification can be achieved with iso- and low-osmolar contrast media when it is injected at the same iodine delivery rate with contemporary cardiac computed tomographic (CT) protocols and to investigate the cardiovascular effect of iso-osmolar contrast media and the image quality achieved. Materials and Methods Institutional review board approval and written informed consent were obtained for the Effect of Iso-osmolar Contrast Medium on Coronary Opacification and Heart Rhythm in Coronary CT Angiography, or IsoCOR, trial. Between November 2015 and August 2016, 306 patients (167 [55%] women) at least 18 years old (weight range, 50-125 kg), were prospectively randomized to receive iso-osmolar iodixanol 270 or low-osmolar iopromide 300 contrast media. All coronary segments were assessed for intraluminal opacification and image quality and were compared by using the Student t test. Heart rate, arrhythmia, patient discomfort, and adverse events also were monitored. Results Mean measured coronary attenuation values ± standard deviation were comparable between the iodixanol 270 and iopromide 300 contrast media groups (469 HU ± 167 vs 447 HU ± 166, respectively [P = .241]; 95% confidence interval: -15.1, 60.0), including those from subanalyses. Adjusted for the lower iodine concentration, the mean iodixanol 270 bolus was larger compared with that of iopromide 300 (76.8 mL ± 11.6 vs 69.7 mL ± 10.8, respectively; P < .001). The higher injection rate was associated with higher pressure (777 kPa ± 308 vs 630 kPa ± 252, respectively; P < .001). Although in the iodixanol 270 group patients experienced less heat discomfort (72% vs 86%, respectively; P < .001), no differences in heart rate or rhythm were observed. Conclusion If injected at comparable iodine delivery rates, the iso-osmolar contrast medium iodixanol 270 is not inferior to low-osmolar contrast medium iopromide 300 for assessment of coronary opacification. Iodixanol 270 was associated with less heat discomfort, but did not affect heart rate differently compared with iopromide 300. © RSNA, 2017 Online supplemental material is available for this article.

Immediate Mild Reactions to CT with Iodinated Contrast Media: Strategy of Contrast Media Readministration without Corticosteroids.

Purpose To evaluate premedication protocols involving administration of antihistamine and multidose corticosteroid that have been widely used in prevention of recurrent hypersensitivity reactions (HSRs) to iodinated contrast media (ICM); an evidence-based optimal preventive strategy customized for patients with mild cases has not yet been established. Materials and Methods The outcomes of patients with mild HSR who subsequently underwent contrast material-enhanced computed tomography (CT) between January 2012 and December 2015 were analyzed. For premedication, 4 mg of chlorpheniramine was intravenously administered 30 minutes prior to reexposure to ICM. Logistic regression with generalized estimating equations was used to determine the relationship between premedication and recurrence rate. Results A total of 1178 patients with mild immediate HSR were reexposed to ICM 3533 times. Among these patients, 1056 patients experienced allergylike reactions and 122 patients developed gastrointestinal reactions. With reexposure to the culprit agent without premedication, the recurrence rate was 31.1% (85 of 273 examinations). The recurrence rate decreased to 12% (105 of 872 examinations; P < .001) by only changing the culprit agent and to 7.6% (148 of 1947 examinations; P < .001) by using the combination of changing the ICM and antihistamine premedication. Changing the ICM plus antihistamine premedication was also helpful in reducing the recurrence of gastrointestinal symptoms from 16.1% to 1.8% (P = .020). However, despite changing of the ICM, some combinations of ICM did not show a prophylactic effect. Conclusion A combination of changing the culprit agent and antihistamine premedication resulted in the best preventive outcome for patients with mild immediate HSR. The optimal choice of substitute ICM could be individualized according to the culprit agent.