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Exposure of iodinated contrast media (ICM) to X-rays is not uncommon, as contrast media are often stored in close proximity to radiological equipment. However, the interaction between X-rays and ICM is not widely investigated in literature. The present study aims to investigate the chemical stability of iomeprol and iopamidol, two commercial iodinated ICM commonly used in diagnostic imaging, under X-rays exposure. Different formulations of iopamidol and iomeprol (iodine concentration 9 to 400 mgI/mL, volume 50–500 mL) were exposed to three different conditions of X-ray irradiation: i) 1 month storage in CT room (≈5–15 mGy); (ii) low-dose protocol (≈10 mGy); (ii) stressed protocol (≈100 mGy). Unexposed and exposed solutions were characterized by high-performance liquid chromatography in terms of concentration of active pharmaceutical ingredient (API), iodine species and by products. In addition, appearance and colour of the solutions were inspected and pH measured. API concentrations, appearance, colour and pH of the exposed formulations remained unaffected by X-rays. Measured concentrations of iodine species and by products were observed well within the acceptability criteria, i.e. values turned out to be lower than specifications limits established by the manufacturer, considering both release and shelf-life values. Up to 100 mGy X-ray exposure did not induce any alteration of iomeprol and iopamidol formulation, nor a detectable increase in the concentration of iodine species or by-products. Our study strengthens the hypothesis that ICM are stable under X-rays exposure up to 100 mGy. [ABSTRACT FROM AUTHOR]

Chronic hypertension is a major risk factor for preeclampsia (PE), associated with significant maternal and neonatal morbidity. We previously demonstrated that pregnant stroke-prone spontaneously hypertensive rats (SHRSP) display a spontaneous PE-like phenotype with distinct placental, fetal, and maternal features. Here, we hypothesized that supplementation with alpha lipoic acid (ALA), a potent antioxidant, during early pregnancy could ameliorate the PE phenotype in this model. To test this hypothesis, timed pregnancies were established using 10 to 12-week-old SHRSP females ( n = 19-16/group), which were assigned to two treatment groups: ALA (injected intraperitoneally with 25 mg/kg body weight ALA on gestation day (GD1, GD8, and GD12) or control, receiving saline following the same protocol. Our analysis of maternal signs showed that ALA prevented the pregnancy-dependent maternal blood pressure rise (GD14 blood pressure control 169.3 ± 19.4 mmHg vs. 146.1 ± 13.4 mmHg, p = 0.0001) and ameliorated renal function, as noted by the increased creatinine clearance and improved glomerular histology in treated dams. Treatment also improved the fetal growth restriction (FGR) phenotype, leading to increased fetal weights (ALA 2.19 ± 0.5 g vs. control 1.98 ± 0.3 g, p = 0.0074) and decreased cephalization indexes, indicating a more symmetric fetal growth pattern. This was associated with improved placental efficiency, decreased oxidative stress marker expression on GD14, and serum soluble fms-like tyrosine kinase 1 (sFlt1) levels on GD20. In conclusion, ALA supplementation mitigated maternal signs and improved placental function and fetal growth in SHRSP pregnancies, emerging as a promising therapy in pregnancies at high risk for PE.

5-Aminoisophthalic acid and 5-nitroisophthalic acid (5-NIPA) are potential impurities in preparations of 5-amino-2,4,6-triiodoisophthalic acid, which is a key intermediate in the synthesis of the iodinated contrast agent iopamidol. We have studied their mutagenicity in silico (quantitative structure-activity relationships, QSAR) and by the bacterial reverse mutation assay (Ames test). First, the compounds were screened with the tools Derek Nexus™ and Leadscope®. Both compounds were flagged as potentially mutagenic (class 3 under ICH M7). However, contrary to the in silico prediction, neither chemical was mutagenic in the Ames test (plate incorporation method) with or without S9 metabolic activation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The excessive demand for organ transplants has promoted the development of strategies that increase the supply of immune compatible organs, such as xenotransplantation of genetically modified pig organs and the generation of bioartificial organs. We describe a method for the partial replacement of rat endothelial cells for human endothelial cells in a rat's kidney, obtaining as a final result a rat-human bioartificial kidney. First, in order to maintain parenchymal epithelial cells and selectively eliminate rat endothelial cells, three methods were evaluated in which different solutions were perfused through the renal artery: 0.1% sodium dodecyl sulfate (SDS), 0.01% SDS, and hyperosmolar solutions of sucrose. Then, partially decellularized kidneys were recellularized with human endothelial cells and finally transplanted in an anesthetized rat. The solution of 0.1% SDS achieved the highest vascular decellularization but with high degree of damage in the parenchyma side. On the contrary, 0.01% SDS and hyperosmolar solutions achieved a partial degree of endothelial decellularization. TUNEL assays reveal that hyperosmolar solutions maintained a better epithelial cell viability contrasting with 0.01% SDS. Partially decellularized kidneys were then recellularized with human endothelial cells. Histological analysis showed endothelial cells attached in almost all the vascular bed. Recellularized kidney was transplanted in an anesthetized rat. After surgery, recellularized kidney achieved complete perfusion, and urine was produced for at least 90 min posttransplant. Histological analysis showed endothelial cells attached in almost all the vascular bed. Therefore, endothelial decellularization of grafts and recellularization with human endothelial cells derived from transplant recipients can be a feasible method with the aim to reduce the damage of the grafts., Competing Interests: Dr. Claudio Incardona is a medical director of GADOR S.A., (Copyright © 2022 Geraldine Haeublein et al.)

Dried Blood Spots (DBS) represents a promising micro-sampling technique in the field of forensic toxicology to carry out minimally invasive blood sample collection. In DBS, cheap, fast and easy sampling is combined with effortless store and transport. These properties aimed us to develop and validate a quick and easy procedure for the detection of a large and diverse range of emerging and alarming New Psychoactive Substances (NPS). A drop of whole blood sample was collected on a DBS card and dried for 3 h, from which a total of 132 analytes (including NPS, synthetic opioids NSO and metabolites) plus 13 deuterated internal standards could be extracted using 500 μL of a methanol/acetonitrile mixture (3:1, v/v) and subsequently separated and identified by means of ultra-high-performance liquid-chromatography (UHPLC) coupled to high resolution mass spectrometry (HRMS). The extraction efficiency proved to be reproducible with yields ranging from 30% to 100% depending on the different classes of drugs. Trueness, repeatability, and intermediate precision fulfilled acceptance criteria for almost all synthetic opioids, cathinones and hallucinogens (bias and CV% below ±20%); in particular, the aggregate inter-day trueness data showed extremely limited deviation from the expected concentrations (-10% < bias% < +10%) for 114 target analytes out of 132. The calculated limits of detection ranged from 1.3 to 6.3 ng/mL, consistently exceeding the values experimentally tested. Moderate ion suppression was observed for most analytes, partly caused by blood fortification itself. Good stability of the target analytes at -20 °C, 4 °C, and 35 °C on DBS cards after drying was observed, even for long periods of time. Optimal storage condition appeared to be at 4 °C resulting in virtually no drugs degradation for up to 40 days. The novel analytical method based on DBS sampling, verified on venous whole blood real samples previously tested positive with our routine procedure, conveys remarkable potential in analytical toxicology, clinical analysis, and doping control., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Abstract: Acute kidney injury (AKI) is characterized by rapid loss of excretory function and is the clinical manifestation of several disorders affecting the kidney. The aim of the present study was to investigate the mechanism of action of Secretory Leukocyte Proteinase Inhibitor (SLPI) that protects the kidneys form AKI. In vivo and in vitro experiments were performed to assess the effect of SLPI on kidney injury. Animal models of kidney injury was generated by 40 min obstruction of kidney artery and vein (ischemia-reperfusion injury model) or daily administration of 60 mg/kg/day of gentamicine for 5 day (gentamicin-associated AKI model). For in vitro assessment, human renal epithelium HK-2 cells were cultured under serum starvation conditions or with tacrolimus. The administration of SLPI (250 μg/kg, i.p.) reduced elevated plasma creatinine and blood urea nitrogen levels, tissue myeloperoxidase content, and acute tubular necrosis induced by kidney damage. Furthermore, SLPI treatment reduced CD86, CD68, CD14, CCL2, TNFα, and IL-10 transcripts in kidney biopsies. To further analyze a direct effect of SLPI on renal epithelial cells, HK-2 cells from human renal epithelium were cultured under serum starvation conditions or with tacrolimus. Both conditions induced apoptosis of HK-2 cells which was reduced when SLPI was present in the culture medium. Furthermore, SLPI favored the proliferation and migration of HK-2 cells. An analysis of the gene profiles of HK-2 cells treated with calcineurin inhibitors affected inflammatory and non-inflammatory pathways that were reversed by SLPI. Among them, SLPI down modulated the expression of CCL2, SLC5A3, and BECN1 but up-regulated the expression of TLR4, ATF4, ATF6, HSP90B, BBC3 SLC2A1, and TNFRSF10B. Overall, these results suggest that SLPI, in addition to its activity on immune cells, may directly target tubular epithelial cells of the kidney to mediate the nephroprotective activity in AKI., Competing Interests: This work was supported by Fundación del 3er Milenio, ANPCYT PICT2014-2447, PICT2014-2504, PICT2016-0859; UBACYT2018-2021. All authors declare no conflicts of interest except Dr Incardona who is the medical director of GADOR SA. The founding sponsors had no role in the interpretation and writing of the manuscript. The authors report no conflicts of interests., (Copyright © 2021 by the Shock Society.)

Aim: It is important to find biomarkers that identify the graft quality in kidney transplantation. Results & methodology: The level of SLPI in the cold preservation solution was used as a marker to predict early kidney graft function after transplantation. Before transplantation, kidneys were washed and SLPI was measured in the discarded solution. A retrospective analysis showed that patients with delayed graft function or rejection episodes in post-trasplant, had higher SLPI concentrations in the perfusion solution than patients without delayed graft function or rejections. Furthermore, SLPI could discriminate between patients with better or worse estimated glomerular filtration rate among low-risk patients (kidney donor profile index <80). Discussion & conclusion: These results suggest that the SLPI concentration in the perfusion solutions could be a predictor of short-term organ function and a complement to the kidney donor profile index score.

A double-blind randomized controlled trial was performed to compare the safety and efficacy of α-lipoic acid (ALA) in liver transplantation (LT). The grafts were randomized to receive ALA or placebo before the cold ischemia time. Furthermore, patients transplanted with the ALA-perfused graft received 600 mg of intravenous ALA, while patients with the nonperfused graft received the placebo just before graft reperfusion. Hepatic biopsy was performed 2 h postreperfusion. Blood samples were collected before, during and 1 and 2 days after reperfusion. Quantitative polymerase chain reaction (qPCR) analysis was performed on biopsies to assess genes involved in the response to hypoxia, apoptosis, cell growth, survival and proliferation, cytokine production and tissue damage protection. Nine of 40 patients developed postreperfusion syndrome (PRS), but seven of them belonged to the control group. There was a decrease in PHD2 and an increase in alpha subunit of hypoxia-inducible factor-1 (HIF-1α) and baculoviral IAP repeat containing 2 (Birc2) transcript levels in the biopsies from the ALA-treated versus the control group of patients. Additionally, plasma levels of alarmins were lower in ALA-treated patients than control patients, which suggests that ALA-treated grafts are less inflammatory than untreated grafts. These results showed that ALA is safe for use in LT, induces gene changes that protect against hypoxia and oxidative stress and reduces the appearance of PRS., (© 2018 Steunstichting ESOT.)

Organ replacement is an option to mitigate irreversible organ damage. This procedure has achieved a considerable degree of acceptance. However, several factors significantly limit its effectiveness. Among them, the initial inflammatory graft reaction due to ischemia-reperfusion injury (IRI) has a fundamental influence on the short and long term organ function. The reactive oxygen species (ROS) produced during the IRI actively participates in these adverse events. Therapeutic strategies that tend to limit the action of free radicals could result in beneficial effects in transplantation outcome. Accordingly, the anti-oxidant α-lipoic acid (ALA) have been proved to be protective in several animal experimental models and humans. In a clinical trial, ALA was found to decrease hepatic IRI after hepatic occlusion and resection. Furthermore, the treatment of cadaveric donor and recipient with ALA had a protective effect in the short-term outcome in simultaneous kidney and pancreas transplanted patients. These studies support ALA as a drug to mitigate the damage caused by IRI and reinforce the knowledge about the deleterious consequences of ROS on graft injury in transplantation. The goal of this review is to overview the current knowledge about ROS in transplantation and the use of ALA to mitigate it., Competing Interests: The authors declare that Dr. Incardona is the medical director of GADOR SA. The founding sponsors had no role in interpretation and in the writing of the manuscript.

Background: Multiple factors have been implicated in the process of ischemia-reperfusion injury (IRI) in organ transplantation. Among these factors, oxidative damage seems to initiate the injury. α-lipoic acid (ALA) is a potent antioxidant that is used in patients with diabetic polyneuropathy. The aim of the present study was to determine the effect of ALA in patients undergoing simultaneous kidney-pancreas transplant by evaluating the functional recovery of the graft and biochemical markers of IRI., Methods: Twenty-six patients were included in the following groups: (i) untreated control; (ii) donor and recipient (DR) ALA-treated, in which ALA was administered both to the deceased donor and to the recipients; and (iii) recipient ALA-treated group. The expression of inflammatory genes, as observed in biopsies taken at the end of surgery, as well as the serum cytokines, secretory leukocyte protease inhibitor, regenerating islet-derived protein 3β/pancreatitis-associated protein, amylase, lipase, glucose, and creatinine levels were quantified as markers of organ function., Results: The DR group showed high levels of TGFβ and low levels of C3 and TNFα in the kidneys, whereas high levels of C3 and heme oxygenase were identified in pancreas biopsies. Decreases in serum IL-8, IL-6, secretory leukocyte protease inhibitor, and regenerating islet-derived protein 3 β/pancreatitis-associated protein were observed after surgery in the DR group. Serum lipase and amylase were lower in the DR group than in the control and recipient groups. Early kidney dysfunction and clinical pancreatitis were higher in the control group than in either treatment group., Conclusions: These results show that ALA preconditioning is capable of reducing inflammatory markers while decreasing early kidney dysfunction and clinical posttransplant pancreatitis.

Background: Delayed graft function (DGF) remains an important problem after kidney transplantation and reduced long-term graft survival of the transplanted organ. The aim of the present study was to determine if the development of DGF was associated with a specific pattern of inflammatory gene expression in expanded criteria of deceased donor kidney transplantation. Also, we explored the presence of correlations between DGF risk factors and the profile that was found., Methods: Seven days after kidney transplant, a cDNA microarray was performed on biopsies of graft from patients with and without DGF. Data was confirmed by real-time PCR. Correlations were performed between inflammatory gene expression and clinical risk factors., Results: From a total of 84 genes analyzed, 58 genes were upregulated while only 1 gene was downregulated in patients with DGF compared with no DGF (P = 0.01). The most relevant genes fold changes observed was IFNA1, IL-10, IL-1F7, IL-1R1, HMOX-1, and TGF-β. The results were confirmed for IFNA1, IL-1R1, HMOX-1 and TGF-β. A correlation was observed between TGF-β, donor age, and preablation creatinine, but not body mass index (BMI). Also, TGF-β showed an association with recipient age, while IFNA1 correlated with recipient BMI. Furthermore, TGF-β, IFNA1 and HMOX-1 correlated with several posttransplant kidney function markers, such as diuresis, ultrasound Doppler, and glycemia., Conclusions: Overall, the present study shows that DGF is associated with inflammatory markers, which are correlated with donor and recipient DGF risk factors.

Background: Scientific data from current literature demonstrate an incidence of bacteraemia due to tunnelled central venous catheter (tCVC) use accounting for 1.6 / 1000 days per tCVC, with a range of 1.5 to 1.8. In Sicily no data on the incidence of tCVC- related bacteraemia are available. In our hospital, tCVC infection occurs 2.4 times in 1000 days during CVC use. A retrospective analysis carried out from 2006 to 2012 was performed on 650 patients with tunnelled catheters. Of the subjects who received tCVC in our hospital, 90% were destined to undergo haemodialysis in a private health care environment outside our hospital., Materials and Methods: In order to improve the aforementioned infection outcome, we planned and implemented a specific work project. The work project (WP) was subdivided into two steps: 1) The first step was further subdivided into two sub-phases. The first was principally concerned with the implementation of educational courses, conducted directly on the ward and aimed at the implementation of meticulous nursing regimes for the care of tCVC by our health care nurse. The courses were entitled Management of Vascular Access: from doing - to teaching to do!. These educational courses were organized by the Nephrology Department, which takes care of the management and handling of the major complications of tCVCs for the maintenance of haemodialysis. After this first step, the nurses who had participated became the promoters of the second part of the course, which concerned the development of know-how within an outpatient clinic, which deals exclusively with the nursing management of tCVCs. 2) The title of the second phase was Therapeutic Education: self-Care and understanding and managing your venous access at home. The aim of this step was the integration of correct in-hospital care with that available in outsourced private institutions, via the involvement of the patient in the management of their own central venous access. During our training project, a more detailed analysis of the stakeholder as well as a swot analysis on the feasibility of the project were used to determine ad interim and final targets of the study. A summary of operative planning is included to explain in greater detail the study design, timing and costs of the various phases. Risk management and corrective measures adopted during the project are also mentioned and monitoring of the phases is described in relation to the fulfilling of intermediate goals. The prompt correction of mistakes allows for safer realisation of outcomes., Conclusion: From our experience with this work project, we can conclude that a more accurate management of tCVCs can significantly reduce the morbidity and mortality of patients. The project offers a positive cost-benefit balance through a decrease in costs of hospitalisation for tCVC-related infections and other life.threatening conditions related to the use of tCVCs an important goal for any spending review.

Purpose: The arteriovenous fistula (AVF) represents the gold standard for hemodialysis (HD) vascular access. In some critical cases, use of the deep venous circle may represent an alternative approach and venae comitantes could be employed for this purpose., Methods: Sixty patients with chronic renal failure in which the deep venous circle was used to create an AVF were identified; of the 48 who had a direct anastomosis between the brachial artery and vena comitans, 42 had a long-term follow-up (mean follow-up 59 weeks), while six were lost to follow-up., Results: Immediate success (patency and palpable thrill) was achieved in 88% of cases (primary and early failure 12%). Primary accessibility rate was 62%, while 11 patients required a second surgical approach to make the vein accessible to needling. Secondary accessibility rate of 71% was due to surgical revisions. In the 80-week observation period, the complication rate was 10% with irreversible loss of the AVF in all these cases. Cumulative patency was 71% at the 80th week. Including all 42 patients, technical and functional success rate, defined as vein accessibility to needling and chance of an adequate HD treatment, was 62%., Conclusions: AVF employing venae comitantes may represent a suitable alternative in the absence of other vascular accesses for HD.

The dysfunction of a vascular access for hemodialysis and its loss may depend on drainage difficulties of the superficial or deep venation due to hemodynamically significant stenosis or obstruction of a central vein, which generally involve the innominate-subclavian veins or superior vena cava. These alterations are often neglected due to their central and deep location; when there is hemodynamic compensation, they may remain asymptomatic. For these reasons every suspect clinical sign for central vein stenosis (gross arm syndrome or venous hypertension in an arteriovenous fistula) must not be ignored, as timely intervention is essential for functional recovery of the vessel and for the protection of the arteriovenous fistula. The modern imaging techniques ensure thorough diagnostic assessment, while the possibilities of endovascular treatment with interventional radiology allow, in a large proportion of cases, optimal minimally invasive treatment, but above all the recovery of venation in a hemodialyzed patient. We report our experience with multislice computed tomographic angiography (MS-CTA) and reconstruction software for treatment planning of central vein stenosis or obstruction. Forty-nine patients were studied with MS-CTA (GE 16). Images were acquired in the venous phase (120-180 seconds after contrast medium injection) followed by digital vascular reconstruction (AutoBone for bone removal, vessel analysis for caliber and length measurements, thin and curved MIP, MPR). Within a week control phlebography was performed. The venous tree was divided into seven segments and analyzed in a double-blind fashion with a distinction between patent segments, 50-70% stenosis, >70% stenosis, occlusion, and collateral vascular beds. There was excellent correspondence in all the examined segments for patency, >70% stenosis, and occlusion, with high sensitivity (98%), specificity (99.3%), and diagnostic accuracy (99.1%). The binomial test demonstrated a highly significant concordance (alpha=0.99) for all patients and in all vascular segments with the exception of 70% stenoses, in which MS-CTA gave a slight overestimate. In the central venous district, color Doppler ultrasonography may not be as effective as for the peripheral study of arteriovenous fistulae, and second-level imaging techniques such as MS-CTA are more useful. We suggest that endovascular treatment must be preceded by MS-CTA. This examination shows the lesions that may benefit from endovascular treatment and recognizes ''uncrossable'' lesions, ie, the ones that will not benefit from treatment. Moreover, it allows accurate planning of endovascular treatment by showing the lesion type (stenosis or obstruction), the position and extension of the involved vessels, the vessel caliber above and below the lesion, and the possible presence of a collateral vascular bed. MS-CTA with dedicated reconstruction software, if correctly performed and accurately reconstructed, is a precious tool for diagnosis and treatment planning.

Angioplasty is the usual method for the treatment of stenosis of arteriovenous fistulas for hemodialysis, along with fibrinolysis and thrombus aspiration. We evaluated the efficacy and safety of interventional radiology procedures in the treatment of stenosis or occlusion of arteriovenous fistulas. One hundred thirteen patients suffering from malfunction of arteriovenous fistulas underwent interventional radiological procedures (140 treatments). In all patients color-Doppler was performed beforehand. Stenosis at the site of the fistula was found in all patients and was treated with percutaneous transluminal angioplasty (PTA); stenosis at the anastomosis site was found in 63 cases and was treated by angioplasty with a microcatheter. In 40 patients suffering from recent thrombotic occlusion, locoregional thrombolysis and PTA were necessary. Technical and clinical success was achieved in 107 patients (94.6%); in 1 of 6 unsuccessful treatments the procedure had to be interrupted due to the rupture of a vein. Follow-up exams demonstrated primary patency in 92.5%, 71.9% and 49.5% of patients at 6 months, 1 year and 2 years, respectively. In 19 patients (17.7%) hemodynamically significant restenosis was observed, which was treated with multiple PTAs (27 treatments, only 1 of which with a negative outcome), resulting in a 94.2% success rate; only 1 patient had to undergo a fourth PTA. The overall patency rate was 95%, 87.2%, 62.3% at 6 months, 1 year and 2 years, respectively. In our experience immediate success and excellent patency rates were observed, which persisted in the medium and long term. PTA, with thrombolysis and thromboaspiration, is the treatment of choice in cases of malfunctioning arteriovenous fistulas. PTA should always be attempted before making a new surgical access in order to preserve the vascular tree.

In order to estimate the outcome of arteriovenous fistula (AVF) for hemodialysis, we reviewed our experience in the construction of AVFs using the venae comitantes in patients without an adequate superficial venous vascular territory. The study included 34 patients affected by end-stage renal disease in whom an AVF was created using the deep venous system. In 26 of them we performed an anastomosis between the brachial artery and its vena comitans. Immediate success, defined by the presence of a thrill at the end of the anastomosis, was obtained in 84%, while primary failure of the AVF (immediate postoperative failure) occurred in 3 patients (12%). Early failure, defined as failure within 6 weeks of AVF placement, occurred in 4% of patients. Of the 22 patients with a functioning AVF, 8 (36%) subsequently requested a second operation to bring the fistula to the surface. Some of these involved the placement of synthetic grafts for better accessibility. The primary patency of the AVFs was equal to 64%, while the patency after a second intervention was 91%. Among the 26 AVFs created with venae comitantes, total patency at 50 weeks was 62%. Our experience with the placement of prosthetic grafts draining into the venae comitantes has not provided encouraging results. We believe that for adequate exploitation of venae comitantes it is important to use native veins that have to meet specific anatomical and functional requirements. The creation of an AVF with a native vein, taking advantage of the deep venous system, is feasible under the right circumstances.