Impact of hypoxia and reoxygenation on the extra/intracellular metabolome and on transporter expression in a human kidney proximal tubular cell line.

INTRODUCTION: Ischemia-reperfusion injury (IRI) induces several perturbations that alter immediate kidney graft function after transplantation and may affect long-term graft outcomes. Given the IRI-dependent metabolic disturbances previously reported, we hypothesized that proximal transporters handling endo/exogenous substrates may be victims of such lesions. OBJECTIVES: This study aimed to determine the impact of hypoxia/reoxygenation on the human proximal transport system through two semi-targeted omics analyses. METHODS: Human proximal tubular cells were cultured in hypoxia (6 or 24 h), each followed by 2, 24 or 48-h reoxygenation. We investigated the transcriptomic modulation of transporters. Using semi-targeted LC-MS/MS profiling, we characterized the extra/intracellular metabolome. Statistical modelling was used to identify significant metabolic variations. RESULTS: The expression profile of transporters was impacted during hypoxia (y + LAT1 and OCTN2), reoxygenation (MRP2, PEPT1/2, rBAT, and OATP4C1), or in both conditions (P-gp and GLUT1). The P-gp and GLUT1 transcripts increased (FC (fold change) = 2.93 and 4.11, respectively) after 2-h reoxygenation preceded by 24-h hypoxia. We observed a downregulation (FC = 0.42) of y+LAT1 after 24-h hypoxia, and of PEPT2 after 24-h hypoxia followed by 2-h reoxygenation (FC = 0.40). Metabolomics showed that hypoxia altered the energetic pathways. However, intracellular metabolic homeostasis and cellular exchanges were promptly restored after reoxygenation. CONCLUSION: This study provides insight into the transcriptomic response of the tubular transporters to hypoxia/reoxygenation. No correlation was found between the expression of transporters and the metabolic variations observed. Given the complexity of studying the global tubular transport systems, we propose that further studies focus on targeted transporters.

Substrate binding and lipid-mediated allostery in the human organic anion transporter 1 at the atomic-scale.

The Organic Anion Transporter 1 is a membrane transporter known for its central role in drug elimination by the kidney. hOAT1 is an antiporter translocating substrate in exchange for a-ketoglutarate. The understanding of hOAT1 structure and function remains limited due to the absence of resolved structure of hOAT1. Benefiting from conserved structural and functional patterns shared with other Major Facilitator Superfamily transporters, the present study intended to investigate fragments of hOAT1 transport function and modulation of its activity in order to make a step forward the understanding of its transport cycle. µs-long molecular dynamics simulation of hOAT1 were carried out suggesting two plausible binding sites for a typical substrate, adefovir, in line with experimental observations. The well-known B-like motif binding site was observed in line with previous studies. However, we here propose a new inner binding cavity which is expected to be involved in substrate translocation event. Binding modes of hOAT1 co-substrate α-ketoglutarate were also investigated suggesting that it may bind to highly conserved intracellular motifs. We here hypothesise that α-ketoglutarate may disrupt the pseudo-symmetrical intracellular charge-relay system which in turn may participate to the destabilisation of OF conformation. Investigations regarding allosteric communications along hOAT1 also suggest that substrate binding event might modulate the dynamics of intracellular charge relay system, assisted by surrounding lipids as active partners. We here proposed a structural rationalisation of transport impairments observed for two single nucleotide polymorphisms, p.Arg50His and p.Arg454Gln suggesting that the present model may be used to transport dysfunctions arising from hOAT1 mutations.

Current diagnostic and clinical issues of screening for dihydropyrimidine dehydrogenase deficiency.

Fluoropyrimidine drugs (FP) are the backbone of many chemotherapy protocols for treating solid tumours. The rate-limiting step of fluoropyrimidine catabolism is dihydropyrimidine dehydrogenase (DPD), and deficiency in DPD activity can result in severe and even fatal toxicity. In this review, we survey the evidence-based pharmacogenetics and therapeutic recommendations regarding DPYD (the gene encoding DPD) genotyping and DPD phenotyping to prevent toxicity and optimize dosing adaptation before FP administration. The French experience of mandatory DPD-deficiency screening prior to initiating FP is discussed.

Insights into the structure and function of the human organic anion transporter 1 in lipid bilayer membranes.

The human SLC22A6/OAT1 plays an important role in the elimination of a broad range of endogenous substances and xenobiotics thus attracting attention from the pharmacological community. Furthermore, OAT1 is also involved in key physiological events such as the remote inter-organ communication. Despite its significance, the knowledge about hOAT1 structure and the transport mechanism at the atomic level remains fragmented owing to the lack of resolved structures. By means of protein-threading modeling refined by µs-scaled Molecular Dynamics simulations, the present study provides the first robust model of hOAT1 in outward-facing conformation. Taking advantage of the AlphaFold 2 predicted structure of hOAT1 in inward-facing conformation, we here provide the essential structural and functional features comparing both states. The intracellular motifs conserved among Major Facilitator Superfamily members create a so-called "charge-relay system" that works as molecular switches modulating the conformation. The principal element of the event points at interactions of charged residues that appear crucial for the transporter dynamics and function. Moreover, hOAT1 model was embedded in different lipid bilayer membranes highlighting the crucial structural dependence on lipid-protein interactions. MD simulations supported the pivotal role of phosphatidylethanolamine components to the protein conformation stability. The present model is made available to decipher the impact of any observed polymorphism and mutation on drug transport as well as to understand substrate binding modes.

Perfusate Metabolomics Content and Expression of Tubular Transporters During Human Kidney Graft Preservation by Hypothermic Machine Perfusion.

BACKGROUND: Ischemia-related injury during the preimplantation period impacts kidney graft outcome. Evaluating these lesions by a noninvasive approach before transplantation could help us to understand graft injury mechanisms and identify potential biomarkers predictive of graft outcomes. This study aims to determine the metabolomic content of graft perfusion fluids and its dependence on preservation time and to explore whether tubular transporters are possibly involved in metabolomics variations. METHODS: Kidneys were stored on hypothermic perfusion machines. We evaluated the metabolomic profiles of perfusion fluids (n = 35) using liquid chromatography coupled with tandem mass spectrometry and studied the transcriptional expression of tubular transporters on preimplantation biopsies (n = 26), both collected at the end of graft perfusion. We used univariate and multivariate analyses to assess the impact of perfusion time on these parameters and their relationship with graft outcome. RESULTS: Seventy-two metabolites were found in preservation fluids at the end of perfusion, of which 40% were already present in the native conservation solution. We observed an increase of 23 metabolites with a longer perfusion time and a decrease of 8. The predictive model for time-dependent variation of metabolomics content showed good performance (R 2 = 76%, Q 2 = 54%, accuracy = 41%, and permutation test significant). Perfusion time did not affect the mRNA expression of transporters. We found no correlation between metabolomics and transporters expression. Neither the metabolomics content nor transporter expression was predictive of graft outcome. CONCLUSIONS: Our results call for further studies, focusing on both intra- and extratissue metabolome, to investigate whether transporter alterations can explain the variations observed in the preimplantation period.

A single Bayesian estimator for iohexol clearance estimation in ICU, liver failure and renal transplant patients.

AIMS: Iohexol clearance has been proposed to estimate the glomerular filtration rate (GFR). A population pharmacokinetics (popPK) model was developed from heterogeneous patients. A Bayesian estimator (MAP-BE) based on a limited sampling strategy (LSS) was derived and evaluated in external patients. METHODS: Full pharmacokinetic data (7-12 samples) from 172 patients receiving iohexol for measurement of their GFR (unstable and stable ICU patients, liver failure patients and kidney transplant patients) were split into development (n = 136) and validation (n = 36) datasets. A PopPK model was developed in Monolix and was used to develop MAP-BE based on LSS. Its performance for GFR estimation was evaluated in the validation set. RESULTS: A two-compartment model with first-order elimination best described the data. The final model included the type of patients on volume of distribution (Vd), clearance and intercompartmental constants, serum creatinine on clearance and body weight on Vd. The best LSS included samples at 0.1-1-9 h exhibiting a relative mean prediction error (MPE) (RMSE) = -3.7% (14.3%) and better performance than the Bröchner-Mortensen formula (-3.0%/17%). Split by type of patients, the highest interindividual variability and imprecision was observed in unstable ICU patients (MPE (RMSE) = 3.7% (18.8%)) while the best performances were obtained for renal transplant patients (MPE (RMSE) = 1.0% (5.8%)). All LSS that included samples before 9 hours for the third sample were associated with an increased imprecision. CONCLUSION: A single MAP-BE of iohexol based on a three-sample LSS for four heterogeneous populations was developed and allowed accurate estimation of GFR in kidney transplant patients, slightly biased in stable ICU patients and slightly imprecise in unstable ICU patients.

Kinetic Glomerular Filtration Rate Equations in Patients With Shock: Comparison With the Iohexol-Based Gold-Standard Method.

OBJECTIVES: Static glomerular filtration rate formulas are not suitable for critically ill patients because of nonsteady state glomerular filtration rate and variation in the volume of distribution. Kinetic glomerular filtration rate formulas remain to be evaluated against a gold standard. We assessed the most accurate kinetic glomerular filtration rate formula as compared to iohexol clearance among patients with shock. DESIGN: Retrospective multicentric study. SETTING: Three French ICUs in tertiary teaching hospitals. PATIENTS: Fifty-seven patients within the first 12 hours of shock. MEASUREMENTS AND MAIN RESULTS: On day 1, we compared kinetic glomerular filtration rate formulas with iohexol clearance, with or without creatinine concentration correction according to changes in volume of distribution and ideal body weight. We analyzed three static glomerular filtration rate formulas (Cockcroft and Gault, modification of diet in renal disease, and Chronic Kidney Disease-Epidemiology Collaboration), urinary creatinine clearance, and seven kinetic glomerular filtration rate formulas (Jelliffe, Chen, Chiou and Hsu, Moran and Myers, Yashiro, Seelhammer, and Brater). We evaluated 33 variants of these formulas after applying corrective factors. The bias ranged from 12 to 47 mL/min/1.73 m2. Only the Yashiro equation had a lower bias than urinary creatinine clearance before applying corrective factors (15 vs 20 mL/min/1.73 m2). The corrected Moran and Myers formula had the best mean bias, 12 mL/min/1.73 m2, but wide limits of agreement (-50 to 73). The corrected Moran and Myers value was within 30% of iohexol-clearance-measured glomerular filtration rate for 27 patients (47.4%) and was within 10% for nine patients (15.8%); other formulas showed even worse accuracy. CONCLUSIONS: Kinetic glomerular filtration rate equations are not accurate enough for glomerular filtration rate estimation in the first hours of shock, when glomerular filtration rate is greatly decreased. They can both under- or overestimate glomerular filtration rate, with a trend to overestimation. Applying corrective factors to creatinine concentration or volume of distribution did not improve accuracy sufficiently to make these formulas reliable. Clinicians should not use kinetic glomerular filtration rate equations to estimate glomerular filtration rate in patients with shock.

A Machine Learning Approach to Estimate the Glomerular Filtration Rate in Intensive Care Unit Patients Based on Plasma Iohexol Concentrations and Covariates.

OBJECTIVE: This work aims to evaluate whether a machine learning approach is appropriate to estimate the glomerular filtration rate in intensive care unit patients based on sparse iohexol pharmacokinetic data and a limited number of predictors. METHODS: Eighty-six unstable patients received 3250 mg of iohexol intravenously and had nine blood samples collected 5, 30, 60, 180, 360, 540, 720, 1080, and 1440 min thereafter. Data splitting was performed to obtain a training (75%) and a test set (25%). To estimate the glomerular filtration rate, 37 candidate potential predictors were considered and the best machine learning approach among multivariate-adaptive regression spline and extreme gradient boosting (Xgboost) was selected based on the root-mean-square error. The approach associated with the best results in a ten-fold cross-validation experiment was then used to select the best limited combination of predictors in the training set, which was finally evaluated in the test set. RESULTS: The Xgboost approach yielded the best performance in the training set. The best combination of covariates comprised iohexol concentrations at times 180 and 720 min; the relative deviation from these theoretical times; the difference between these two concentrations; the Simplified Acute Physiology Score II; serum creatinine; and the fluid balance. It resulted in a root-mean-square error of 6.2 mL/min and an r2 of 0.866 in the test set. Interestingly, the eight patients in the test set with a glomerular filtration rate < 30 mL/min were all predicted accordingly. CONCLUSIONS: Xgboost provided accurate glomerular filtration rate estimation in intensive care unit patients based on two timed blood concentrations after iohexol intravenous administration and three additional predictors.

Effects of Ischemia-Reperfusion on Tubular Cell Membrane Transporters and Consequences in Kidney Transplantation.

Ischemia-reperfusion (IR)-induced acute kidney injury (IRI) is an inevitable event in kidney transplantation. It is a complex pathophysiological process associated with numerous structural and metabolic changes that have a profound influence on the early and the late function of the transplanted kidney. Proximal tubular cells are particularly sensitive to IRI. These cells are involved in renal and whole-body homeostasis, detoxification processes and drugs elimination by a transporter-dependent, transcellular transport system involving Solute Carriers (SLCs) and ATP Binding Cassettes (ABCs) transporters. Numerous studies conducted mainly in animal models suggested that IRI causes decreased expression and activity of some major tubular transporters. This could favor uremic toxins accumulation and renal metabolic alterations or impact the pharmacokinetic/toxicity of drugs used in transplantation. It is of particular importance to understand the underlying mechanisms and effects of IR on tubular transporters in order to improve the mechanistic understanding of IRI pathophysiology, identify biomarkers of graft function or promote the design and development of novel and effective therapies. Modulation of transporters' activity could thus be a new therapeutic opportunity to attenuate kidney injury during IR.

Potential drug-drug interactions associated with drugs currently proposed for COVID-19 treatment in patients receiving other treatments.

Patients with COVID-19 are sometimes already being treated for one or more other chronic conditions, especially if they are elderly. Introducing a treatment against COVID-19, either on an outpatient basis or during hospitalization for more severe cases, raises the question of potential drug-drug interactions. Here, we analyzed the potential or proven risk of the co-administration of drugs used for the most common chronic diseases and those currently offered as treatment or undergoing therapeutic trials for COVID-19. Practical recommendations are offered, where possible.

Assessment of the glomerular filtration rate (GFR) in kidney transplant recipients using Bayesian estimation of the iohexol clearance.

Background Plasma iohexol clearance (CLiohexol) is a reference technique for glomerular filtration rate (GFR) determination. In routine practice, CLiohexol is calculated using one of several formulas, which have never been evaluated in kidney transplant recipients. We aimed to model iohexol pharmacokinetics in this population, evaluate the predictive performance of three simplified formulas and evaluate whether a Bayesian algorithm improves CLiohexol estimation. Methods After administration of iohexol, six blood samples were drawn from 151 patients at various time points. The dataset was split into two groups, one to develop the population pharmacokinetic (POPPK) model (n = 103) and the other (n = 48) to estimate the predictive performances of the various GFR estimation methods. GFR reference values (GFRref) in the validation dataset were obtained by non-compartmental pharmacokinetic (PK) analysis. Predictive performances of each method were evaluated in terms of bias (ME), imprecision (root mean square error [RMSE]) and number of predictions out of the ±10% or 15% error interval around the GFRref. Results A two-compartment model best fitted the data. The Bayesian estimator with samples drawn at 30, 120 and 270 min allowed accurate prediction of GFRref (ME = 0.47%, RMSE = 3.42%), as did the Brøchner-Mortensen (BM) formula (ME = - 0.0425%, RMSE = 3.40%). With both methods, none of the CL estimates were outside the ±15% interval and only 2.4% were outside the ±10% for the BM formula (and none for the Bayesian estimator). In patients with GFR ≤30 mL/min/1.73 m2, the BM formula performed very well, while the Bayesian method could not be evaluated in depth due to too small a number of patients with adequate sampling times. Conclusions GFR can be estimated with acceptable accuracy in kidney transplant patients using the BM formula, but also using a Bayesian algorithm.

Hypercalcemia is associated with a poor prognosis in lymphoma a retrospective monocentric matched-control study and extensive review of published reported cases.

The prognostic significance of hypercalcemia in lymphoma has only been studied on small series to date. We conducted a retrospective, monocentric, matched-control study that aimed to compare the outcome of patients diagnosed with any histological subtype of lymphoma associated with hypercalcemia, at diagnosis or relapse, with a group of controls matched for histological and prognostic factors. Sixty-two and 118 comparable patients treated between 2000 and 2016 were included in hypercalcemia and control cohorts, respectively. Hypercalcemia was found mainly at diagnosis (71%) in higher-risk patients (prognosis scores ≥ 3, 76%) and those with diffuse large B cell lymphoma (67.7%), stage III/IV disease (91.9%), and elevated LDH (90.3%). Two-year progression-free survival (PFS) was shorter in the hypercalcemia than control cohort [30.1% (95% confidence interval (95% CI) 18.3-41.9) vs 63.9% (95% CI 5.1-72.7), p < 0.001]. Two-year overall survival (OS) was 40.6% (95% CI 28.1-53.1) and 77.7% (95% CI 70.1-85.3) in the hypercalcemia and control cohorts, respectively (p < 0.001). Hypercalcemia was independently associated with poor PFS [HR = 2.5 (95% CI 1.4-3.5)] and OS [HR = 4.7 (95% CI 2.8-7.8)] in multivariate analysis. Among the 40 patients who received autologous stem cell transplantation (ASCT), hypercalcemia was still associated with shorter OS [2-year OS: 65% (95% CI 40.1-89.9) vs 88.0 (95% CI 75.3-100), p = 0.04]. Hypercalcemia may be associated with chemo-resistance, given its impact on PFS and OS. Hence, these data suggest that alternate strategies for lymphoma patients with hypercalcemia should be developed.

Toxicities associated with chemotherapy regimens containing a fluoropyrimidine: A real-life evaluation in France.

AIMS: Despite fluoropyrimidines (FPs) constituting the main component of the chemotherapy combination protocols in 50% of chemotherapies for solid tumour treatments, incidence data for FP-related toxicity are poorly documented in real life. This study evaluated the number of patients receiving FP-based chemotherapies in France, along with the true incidence of FP-related serious adverse effects (SAEs) before the recent mandatory dihydropyrimidine dehydrogenase (DPD)-screening was introduced by French health authorities, DPD being the rate-limiting enzyme of 5-fluorouracil (5-FU) catabolism. METHODS: Exhaustive data on the number of patients treated with FP-based chemotherapy in 2013-2014 were collected in the Centre-Val de Loire region of France. True incidence of SAEs was extracted from a cohort of 513 patients with incident solid tumours receiving first-line FP-based chemotherapy. RESULTS: After extrapolation at national level, we estimated that 76,200 patients are currently treated annually with 5FU (53,100 patients, 62% digestive system-related versus 26% breast cancers versus 12% head and neck cancers) or capecitabine (23,100 patients, 45% digestive system-related versus 37% breast cancers versus 18% non-documented). Earlier (in the first two cycles) the SAE incidence rate was 19.3% (95% confidence interval (CI) 16-23%) including one toxic death (0.2%, 95%CI 0-1%). SAE incidence rate was 32.2% (95%CI 28-36%) over the first 6 months of treatment. Incidence of death, life-threatening prognosis or incapacity/disability was 1.4% (95%CI 0.4-2.4%) and 1.6% (95%CI 0.5-2.6%) during first two cycles and first 6 months, respectively. CONCLUSION: These data highlight the significant public health issue related to FP toxicity, with around 1200 patients developing FP-related life-threatening prognosis or incapacity/disability annually in France, including 150 toxic deaths. It is hoped that DPD-deficiency screening will reduce such iatrogenic events and eradicate toxic deaths.

[Pharmacogenetics for patient care in France: A discipline that evolves!] / La pharmacogénétique au service du soin en France : une discipline qui évolue !

Pharmacogenetics, which concepts are known for a long time, is entering a new period at least as far as its practical applications for patients are concerned. In recent years there have been more and more initiatives to promote widespread dissemination, and health authorities are increasingly incorporating these concepts into drug labels. In France, the national network of pharmacogenetics (RNPGx) works to promote these activities, both with health actors (biologists, clinicians) and health authorities. This article reviews the current situation in France and the milestones of the year 2018. It highlights recent advances in this field, in terms of currently recommended analyses, sharing of information or technological developments, and the prospects for future developments in the near future from targeted pharmacogenetics to eventually preemptive approaches.

[Measurement of glomerular filtration rate using a reference method]. / Mesure du débit de filtration glomérulaire par méthode de référence.

Direct measurement methods of glomerular filtration rate (GFR) are considered as the gold standard to assess kidney function. Following the withdrawal of the Proinuline Serb® specialty by the French National Health Surveillance Agency, iohexol remains the most suitable marker to replace inulin as the marker for GFR in France. The assay is performed by high performance liquid chromatography (HPLC) coupled with ultraviolet (UV) detection or by mass spectrometry. Plasma clearance measurement is the protocol of choice: single-sample protocols dominate, but multiple-sample protocols may be more accurate in specific situations to improve accuracy. In some cases, urinary clearance protocols may be proposed. National and international recommendations suggest using a GFR measurement as a confirmatory test in cases where the creatinine-based estimated GFR is inappropriate, ie clinical situations characterized by a significant alteration of muscle mass or volume distribution. The indications retained by the working group were graded according to the level of recommendations. The essential indications are the evaluation of living kidney donor, the monitoring of kidney allograft function at one year post-transplantation, drugs with narrow therapeutic range (anticoagulant, chemotherapy) in patients with inadequate estimation of GFR by creatinine and clinical research.

Glomerular Hyper- and Hypofiltration During Acute Circulatory Failure: Iohexol-Based Gold-Standard Descriptive Study.

OBJECTIVE: To assess glomerular filtration rate in the early phase of acute circulatory failure by measuring iohexol plasma clearance. DESIGN: Interventional prospective multicentric study. SETTING: Three French ICUs in tertiary teaching hospitals. PATIENTS: Patients with acute circulatory failure within 12 hours after ICU admission. INTERVENTIONS: IV administration of a nontoxic 5-mL dose of iohexol. Collection of nine arterial blood samples over 24 hours for iohexol plasma concentration measurements. Iohexol clearance calculation with a population pharmacokinetic model. Iohexol clearance was an estimation of the mean glomerular filtration rate over 24 hours. MEASUREMENTS AND MAIN RESULTS: Among 99 included patients, we could calculate iohexol clearance for 85. The median iohexol clearance was 31 mL/min (interquartile range, 16-44). According to iohexol clearance, 41 patients (48%) had severe hypofiltration (clearance, < 30 mL/min), 29 (34%) had moderate hypofiltration, and 10 (12%) had mild hypofiltration (clearance, 30-60 and 60-90 mL/min, respectively). Four patients (5%) had normal glomerular filtration rate, and only one (1%) showed hyperfiltration (clearance, > 130 mL/min). Urinary creatinine clearance underestimated renal impairment in one patient out of two; the bias of iohexol clearance toward 24-hour urinary creatinine clearance over the same period was -18.1 mL/min (limits of agreement, -73.5 to 37.4). CONCLUSIONS: We demonstrated the feasibility of iohexol clearance measurement in unstable critically ill patients. Normal kidney function is exceptional during the early phase of acute circulatory failure. Glomerular filtration rate estimation by urinary creatinine clearance frequently fails to detect renal impairment. Hyperfiltration is very infrequent.

[Dihydropyrimidine dehydrogenase deficiency screening for management of patients receiving a fluoropyrimidine: Results of two national practice surveys addressed to clinicians and biologists]. / Intérêts et limites de la recherche du déficit en dihydropyrimidine déshydrogénase dans le suivi des patients traités par fluoropyrimidines : résultats de deux enquêtes nationales de pratiques réalisées auprès des médecins et des biologistes.

Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of early severe toxicities induced by fluoropyrimidines (FP). The French Group of Clinical Oncopharmacology (GPCO)-Unicancer and the French Pharmacogenetics Network (RNPGx) initiated two surveys, one addressed to oncologists, the other to biologists, in order to evaluate routine practices regarding DPD deficiency screening at national level, as well as compliance, motivations and obstacles for implementation of these tests. These anonymized online surveys were performed with the logistic assistance of the Francophone Federation of Digestive Oncology (FFCD) and the support of numerous medical and biological societies. The surveys were conducted in 2016-2017 before the creation of the French INCa/HAS expert panel, which contributed to the drafting of rules and recommendations for DPD deficiency screening published in December 2018. In all, 554 questionnaires from clinicians were analyzed (23% participation) and 35 from biologists. The main arguments raised by clinicians for justifying the limited practice of DPD deficiency screening were: the lack of recommendations from medical societies or Health Authorities, delays in obtaining results, and the lack of adequate reimbursement by the health insurance system. The goal of these surveys was to provide the French Health Authorities with an overview on nationwide DPD-deficiency screening practices and thus help to design recommendations for the standardization and improvement of the management and safety of cancer patients receiving FP-based chemotherapy.

The Key Role of Warm and Cold Ischemia in Uterus Transplantation: A Review.

Introduction: Uterus transplantation (UTx) is a promising treatment for uterine infertility that has resulted in several births since 2014. Ischemia is a key step in organ transplantation because it may lead to changes jeopardizing graft viability. Method: We performed a systematic review of animal and human studies relating to uterine ischemia. Results: We retained 64 studies published since 2000. There were 35 studies in animals, 24 in humans, and five literature reviews. Modest preliminary results in large animals and humans are limited but encouraging. In small animals, pregnancies have been reported to occur after 24 h of cold ischemia (CI). In ewes, uterine contractions have been detected after 24 h of CI. Furthermore, it has been shown in animals that uterine tolerance to CI and to warm ischemia (WI) can be increased by pharmacological products. In women, mean CI time in studies of births from uteri obtained from live donors was between 2 h 47 min and 6 h 20 min from a deceased donor; with only one birth in this case. Muscle contractions have also been demonstrated in myometrial samples from women, after six or more hours of CI. Conclusion: The uterus seems to be able to tolerate a prolonged period of CI, of at least six hours. Studies of the ischemia tolerance of the uterus and ways to improve it are essential for the development of UTx, particularly for procedures using grafts from deceased donors.

Arginine Vasopressin and Posterior Reversible Encephalopathy Syndrome Pathophysiology: the Missing Link?

Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological entity characterized by a typical brain edema. Its pathogenesis is still debated through hypoperfusion and hyperperfusion theories, which have many limitations. As PRES occurs almost exclusively in clinical situations with arginine vasopressin (AVP) hypersecretion, such as eclampsia and sepsis, we hypothesize that AVP plays a central pathophysiologic role. In this review, we discuss the genesis of PRES and its symptoms through this novel approach. We theorize that AVP axis stimulation precipitates PRES development through an increase in AVP secretion or AVP receptor density. Activation of vasopressin V1a receptors leads to cerebral vasoconstriction, causing endothelial dysfunction and cerebral ischemia. This promotes cytotoxic edema through hydromineral transglial flux dysfunction and may increase endothelial permeability, leading to subsequent vasogenic brain edema. If our hypothesis is confirmed, it opens new perspectives for better patient monitoring and therapies targeting the AVP axis in PRES.

A study of the association between UGT1A1*28 variant allele of UGT1A1 gene and colonic phenotype of sporadic colorectal cancer.

INTRODUCTION: The transcriptional activity of the UGT1A1 gene is modulated by a variable number of repetitions of the dinucleotide (TA) within its promoter region. By comparison to the most common allele (TA)6 (UGT1A1*1), decreased activity is observed with increasing TA repetitions. The aim of this study was to determine whether the presence of the variant allele UGT1A1*28, harbouring seven TA repetitions, (TA)7, in the homozygous state, is associated with precancerous colonic lesions and/or with specific colorectal cancer characteristics. MATERIAL AND METHODS: All patients treated for colorectal cancer in a tertiary care centre, between January 2009 and December 2013, who had routine UGT1A1 genotyping for irinotecan dose-adjustment were included. Data were retrospectively collected. RESULTS: 292 patients were enrolled, including 23 UGT1A1*28/*28 homozygous (7.9%), 137 wild type homozygous (46.9%) and 132 heterozygous (45.2%). There were no significant differences in phenotypic colonic characteristics between homozygous and heterozygous patients carrying the UGT1A1*28 allele as compared to *1/*1 homozygous. Patients treated with aspirin were significantly more common in the UGT1A1*28/*28 homozygous group than in the other groups (7/23 (30.4%) compared to 22/269 (8.2%), p = 0.001). CONCLUSION: Dinucleotide polymorphism in the promoter region of the UGT1A1 gene is not associated with a specific colonic phenotype in patients with sporadic colorectal cancer.