Contrast-enhanced CT texture analysis for the prediction of delayed graft function following kidney transplantation from cadaveric donors.

OBJECTIVE: Delayed graft function (DGF) is a common complication after transplantation of deceased donor kidneys. The aim of this study was to investigate the feasibility of using computed tomography texture analysis (CT-TA) of the donor kidney to predict delayed graft function (DGF) following kidney transplantation from cadaveric donors. MATERIALS AND METHODS: We made a retrospective review of all consecutive DBD and DCD kidney donors admitted to our institution and their corresponding KTRs between December 2014 and January 2019. We extracted 15 image features from unenhanced CT and contrast-enhanced CT corresponding to first order and second order Haralick textural features. Predictors of DGF were evaluated by univariable and multivariable analysis. Receiver operating characteristic (ROC) analysis was performed and the area under the ROC curve (AUC) to predict DGF was calculated for the predictors. RESULTS: A total of 115 patients were included in the study. DGF occurred in 15 patients (13%). Recipient body mass index (BMI) (P=0.003) and Skewness (P=0.05) represented independent predictors in the multivariate model. The combination of both clinical and textural features in a bivariate model reached a ROC-AUC of 0.79 (95% CI: 0.64-0.94) in predicting the probability of DGF. CONCLUSION: Results from this preliminary study suggest that CT texture analysis might be a promising quantitative imaging tool to help physician predict DFG after kidney transplantation from cadaveric donors. LEVEL OF EVIDENCE: 4/5.

Evolution of sexual functioning of men through treated and untreated depression.

OBJECTIVES: Depression as well as a treatment by antidepressant are factors that may interfere with sexuality. Due to this complex relationship between depression, antidepressant and sexuality, it is difficult to incontestably establish the exclusive accountability of a treatment or of a psychiatric disorder on sexual dysfunctions. The main purpose of the SADD (for Sexuality, Anti-Depressant and Depression) study is to evaluate sexual dysfunctions in depressed men treated with antidepressant or not. METHODS: Participants of this transversal, observational study were men aged over 18 years old, suffering from unipolar major depressive disorder and treated by a psychiatrist, with or without antidepressant. Assessment of sexual functioning through three times: euthymia (before depression), untreated depression and treated depression if applicable was performed based on the ASEX scale. RESULTS: Seventy patients were included. Eight percent of euthymic patients presented a sexual dysfunction (average score on the ASEX=12.4) whereas 56% of untreated patients presented a sexual dysfunction (average total score on the ASEX=17.7) and 62% (34/55) of patients treated with antidepressant (average total score on ASEX=18.5) (P<0.001). Sexual functioning of men receiving treatment is not significantly different to that among men not receiving any antidepressant, even if patients treated with antidepressant reported that they had a better mood than those untreated. CONCLUSIONS: Our results reveal a high prevalence of sexual dysfunction within the framework of major depressive disorder and its treatment and underlines the complex relationship between major depressive disorder, antidepressant and sexuality.

Screening for Fabry disease in male patients with end-stage renal disease in western France.

CONTEXT: Fabry disease is a rare X-linked genetic disease due to pathogenic variants in the GLA gene. Classic Fabry disease is characterized by glycosphingolipids accumulation in all organs including the kidney, resulting in end-stage renal disease in a subset of male patients. Fabry disease should therefore be considered in the differential diagnosis of patients with unexplained end-stage renal disease. OBJECTIVE: We performed a prospective screening study in Western France to determine the prevalence of Fabry disease in a large population of dialyzed and transplanted patients. PATIENTS AND METHODS: Patients meeting the inclusion criteria (males, 18-70 years with end-stage renal disease of unknown or vascular origin) were selected from the REIN® registry and the CRISTAL® database. Screening on filter papers was performed after patient consent was obtained during either a dialysis session or a transplantation follow-up visit. RESULTS: One thousand five hundred and sixty-one end-stage renal disease male patients were screened and 819 consented (dialysis: n=242; transplant: n=577). One single patient was found with decreased alpha-galactosidase levels <25%. GLA sequencing identified the p.Phe113Leu variant in favor of an unknown superimposed kidney disease responsible for end-stage renal disease since this GLA pathogenic variant is associated with a later-onset cardiac form of Fabry disease with minimal kidney involvement. Family cascade genotyping revealed a previously undiagnosed affected brother. CONCLUSION: The prevalence of Fabry disease in end-stage renal disease patients was 0.12%, questioning the efficacy of this screening strategy with respect to the low prevalence. However, beside the benefit for the patient and his family, the increased awareness of Fabry disease among participating nephrologists may be of interest for future patients.

French national health insurance database analysis and field study focusing on the impact of secure prescription pads on zolpidem consumption and sedative drug misuse: ZORRO study protocol.

INTRODUCTION: In recent years, data collected by the French Addictovigilance Network have shown the potential for abuse and addiction associated with zolpidem (the most sold hypnotic drug in France). Since 10 April 2017, new regulations have come into force that require zolpidem to be prescribed on special secure prescription pads, in order to reduce the risk of abuse or misuse. This measure has far-reaching repercussions that are not only limited to the consumption of zolpidem but also extend to the usage of sedative medication on a whole. The objective of the ZOlpidem and the Reinforcement of the Regulation of prescription Orders (ZORRO) study is to evaluate the overall impact of the new regulatory framework requiring zolpidem to be prescribed on special secure prescription pads. Three axes will be evaluated: the number of consumers, the type of consumption (chronic use versus occasional use, problematic consumption versus non-problematic use) and the consumption of other sedative molecules.The study has been registered in the Protocol Registration and Results System under the number NCT03584542 at stage "Pre-results". METHODS AND ANALYSIS: The ZORRO study is an epidemiological, observational, national multicentre, non-controlled, prospective research project supported by the French National Agency for Medicines and Health Products Safety. The evaluation of the impact of the regulatory framework change relative to zolpidem will be done according to two axes: via an epidemiological study of the French National Health Insurance database and by the implementation of field studies of prescribers and consumers of zolpidem. ETHICS AND DISSEMINATION: The Nantes Research Ethics Committee (Groupe Nantais d'Ethique dans le Domaine de la Santé), the Committee for the Protection of the Population and the Committee of Expertise in Research, Studies and Evaluations in the Field of Health approved this study. Results will be presented in national and international conferences and submitted to peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03584542; Pre-results.

Recurrence of Goodpasture syndrome without circulating anti-glomerular basement membrane antibodies after kidney transplant, a case report.

BACKGROUND: Goodpasture Syndrome (GS) is an autoimmune disease caused by the development of auto-antibodies against the Glomerular Basement Membrane (GBM). Linear deposit of immunoglobulins G on the GBM detected by immunofluorescence analysis of renal biopsies is a GS pathognomonic finding. GS is commonly monophasic and its incidence is 1.6 case per million per year. CASE PRESENTATION: This report describes and discusses the case of a 40-year-old woman who one year after allograft kidney transplant, presented with acute pulmonary and renal symptoms of GS, leading to acute graft dysfunction, without circulating anti-GBM antibody detection in laboratory assays. She received a living donor kidney transplant 4 years after the first diagnosis of GS without circulating anti-GBM antibodies, when considered in remission. CONCLUSIONS: In both episodes, the diagnosis of GS was based exclusively on the kidney biopsy that showed rapidly progressing glomerulonephritis with deposition of immunoglobulins G on the GBM. Although rare, the management of patients with GS without circulating anti-GBM antibodies is difficult due to the lack of standardized follow-up guidelines to reduce the risk of GS recurrence after kidney transplantation.

Psychiatric disorders, acne and systemic retinoids: comparison of risks.

BACKGROUND: The link between isotretinoin, treatment of a severe form of acne, and psychiatric disorders remains controversial, as acne itself could explain the occurrence of psychiatric disorders. This study aims at assessing the disproportionality of psychiatric adverse events reported with isotretinoin in the French National PharmacoVigilance Database, compared with other systemic acne treatments and systemic retinoids. MATERIALS AND METHODS: Data were extracted from the French National PharmacoVigilance Database for systemic acne treatments, systemic retinoids and drugs used as comparators. Each report was subjected to double-blind analysis by two psychiatric experts. A disproportionality analysis was performed, calculating the number of psychiatric ADRs divided by the total number of notifications for each drug of interest. RESULTS: Concerning acne systemic treatments: all 71 reports of severe psychiatric disorders involved isotretinoin, the highest proportion of mild/moderate psychiatric adverse events was reported with isotretinoin (14.1%). Among systemic retinoids, the highest proportion of severe and mild/moderate psychiatric events occurred with isotretinoin and alitretinoin. CONCLUSION: Our study raises the hypothesis that psychiatric disorders associated with isotretinoin are related to a class effect of retinoids, as a signal emerges for alitretinoin. Complementary studies are necessary to estimate the risk and further determine at-risk populations.

Predictive Modeling of Tacrolimus Dose Requirement Based on High-Throughput Genetic Screening.

Any biochemical reaction underlying drug metabolism depends on individual gene-drug interactions and on groups of genes interacting together. Based on a high-throughput genetic approach, we sought to identify a set of covariant single-nucleotide polymorphisms predictive of interindividual tacrolimus (Tac) dose requirement variability. Tac blood concentrations (Tac C0 ) of 229 kidney transplant recipients were repeatedly monitored after transplantation over 3 mo. Given the high dimension of the genomic data in comparison to the low number of observations and the high multicolinearity among the variables (gene variants), we developed an original predictive approach that integrates an ensemble variable-selection strategy to reinforce the stability of the variable-selection process and multivariate modeling. Our predictive models explained up to 70% of total variability in Tac C0 per dose with a maximum of 44 gene variants (p-value <0.001 with a permutation test). These models included molecular networks of drug metabolism with oxidoreductase activities and the multidrug-resistant ABCC8 transporter, which was found in the most stringent model. Finally, we identified an intronic variant of the gene encoding SLC28A3, a drug transporter, as a key gene involved in Tac metabolism, and we confirmed it in an independent validation cohort.

Benzodiazepine dependence in subjects with alcohol use disorders: what prevalence?

OBJECTIVE: To our knowledge, no studies have been conducted in France on benzodiazepine (BZD) dependence among outpatients with alcohol use disorders (AUD). Some international studies have been conducted on the consumption of BZD in this specific population, but the comparisons among them are difficult. We aimed to assess the current prevalence of probable benzodiazepine and BZD-like hypnotics (Z-drugs) dependence among outpatients seeking treatment for AUD. METHODS: Participants were patients seeking treatment for AUD for the first time or repeating treatment after more than twelve months. Recruitment took place in seven addiction centres between January and December 2013 in the Nantes region (France). BZD/Z-drug dependence was assessed according to the DSM-IV diagnostic criteria for dependence. This information was gathered through a self-report questionnaire. RESULTS: Among the 1005 patients included in this study, 413 were BZD/Z-drug users (41.1%). Among the 413 patients, 217 were probably dependent on at least one substance, which represents 21.6% of the total population and 52.5% of BZD/Z-drug users. CONCLUSION: BZD/Z-drug dependence represents a public health concern. Prescribers should take the risks into account and keep treatment courses to a minimum.

Increased inhibition of cytochrome P450 3A4 with the tablet formulation of posaconazole.

Being a substrate of the cytochrome P450 3A4 (CYP3A4) isoenzyme, sirolimus metabolism is decreased when posaconazole is administered concomitantly. However, because of the poor bioavailability of the oral suspension of posaconazole with which low plasma concentrations are obtained, CYP3A4 inhibition is weak and a 50-75% dose reduction of sirolimus is sufficient to avoid sirolimus overdosage. The new tablet formulation allows reaching posaconazole concentrations 3-4 fold higher than those obtained with the oral suspension. Based on a case of sirolimus overdosage following posaconazole tablets administration, we modelled the inhibition of sirolimus clearance by posaconazole, and then simulated several dosage regimens of sirolimus taken together with posaconazole tablets. We were able to describe well the interaction, and found a value of IC50 of posaconazole towards sirolimus clearance of 0.68 µg/mL. The simulations showed that even a 80% decrease of the daily dose of sirolimus is unsuitable in many cases with trough concentrations of posaconazole of 2 µg/mL. A decrease of 40% of the dose with spacing administrations of 3 days may be considered. The clinicians and pharmacologists must be warned that the use of posaconazole tablets may result in an inhibition of CYP3A4 of greater magnitude than with the oral suspension.

Long-Term Clinical Impact of Adaptation of Initial Tacrolimus Dosing to CYP3A5 Genotype.

Pretransplantation adaptation of the daily dose of tacrolimus to CYP3A5 genotype is associated with improved achievement of target trough concentration (C0 ), but whether this improvement affects clinical outcomes is unknown. In the present study, we have evaluated the long-term clinical impact of the adaptation of initial tacrolimus dosing according to CYP3A5 genotype: The transplantation outcomes of the 236 kidney transplant recipients included in the Tactique study were retrospectively investigated over a period of more than 5 years. In the Tactique study, patients were randomly assigned to receive tacrolimus at either a fixed dosage or a dosage determined by their genotype, and the primary efficacy end point was the proportion of patients for whom tacrolimus C0 was within target range (10-15 ng/mL) at day 10. Our results indicate that the incidence of biopsy-proven acute rejection and graft survival were similar between the control and the adapted tacrolimus dose groups, as well as between the patients who achieve the tacrolimus C0 target ranges earlier. Patients' death, cancer, cardiovascular events, and infections were also similar, and renal function did not change. We conclude that optimization of initial tacrolimus dose using pharmacogenetic testing does not improve clinical outcomes.

The von Hippel-Lindau tumour suppressor gene: uncovering the expression of the pVHL172 isoform.

BACKGROUND: The von Hippel-Lindau (VHL) gene encodes two mRNA variants. Variant 1 encodes two protein isoforms, pVHL213 and pVHL160, that have been extensively documented in the literature. Variant 2 is produced by alternative splicing of exon 2 and encodes a pVHL isoform of 172 amino acids with a theoretical molecular weight of 19 kDa (pVHL172), the expression of which has never been demonstrated so far due to the absence of suitable antibodies. METHODS: We have generated an anti-pVHL monoclonal antibody (JD-1956) using pVHL172 recombinant protein. We tested the antibody against exogenous or endogenous expressed proteins in different cell lines. We identified the pVHL172 using a silencing RNA strategy. The epitope of the antibody was mapped using a peptide array. RESULTS: We efficiently detected the three different isoforms of pVHL in cell lines and tumorigenic tissues by western blotting and immunohistochemistry and confirmed for the first time the endogenous expression of pVHL172. CONCLUSIONS: The endogenous expression of the three isoforms and particularly the pVHL172 has never been shown before due to a lack of a highly specific antibody since none of the available commercial antibodies distinguish the three isoforms of pVHL in cells or in both normal and cancerous human tissues. Evidence of pVHL172 expression emphasises the need to further study its implication in renal tumorigenesis and VHL disease.

[Urinary stones and bowel diseases: Systematic review]. / Lithiases urinaires et pathologies digestives : une revue de la littérature.

PURPOSE: The aim of the study was to explain the relationship between urinary stones and bowel disease. METHODS: A systematic review was performed on Medline, Embase and Cochrane using following keywords: urinary stones; urolithiasis; bowel; enteric and digestive. The literature selection was based on evidence and practical considerations. RESULTS: Fifty-three articles were selected. Three types of urolthiasis are mainly involved in digestive pathologies: calcium oxalate stones, uric acid and ammonium acid urate stones. Bowel pathologies responsible for stone disease are divided into small bowel diseases, colonic lesions and lack of an oxalate degrading bacteria (Oxalobacter formigenes) in the intestinal flora. Resulting in a decreased urine output, pH, hyperoxaluria, hypocitraturia or a hypomagnesurie. Blood and urinary explorations are the basis of diagnostic management. CONCLUSION: Bowel diseases can be responsible for urolthiasis. Understanding of the mechanisms, and metabolic evaluations can prevent recurrences. Increase fluid intake associated with specific supplementation and diet are the key of the treatment.

Kidney transplant recipients carrying the CYP3A4*22 allelic variant have reduced tacrolimus clearance and often reach supratherapeutic tacrolimus concentrations.

CYP3A4*22 is an allelic variant of the cytochrome P450 3A4 associated with a decreased activity. Carriers of this polymorphism may require reduced tacrolimus (Tac) doses to reach the target residual concentrations (Co). We tested this hypothesis in a population of kidney transplant recipients extracted from a multicenter, prospective and randomized study. Among the 186 kidney transplant recipients included, 9.3% (18 patients) were heterozygous for the CYP3A4*22 genotype and none were homozygous (allele frequency of 4.8%). Ten days after transplantation (3 days after starting treatment with Tac), 11% of the CYP3A4*22 carriers were within the target range of Tac Co (10-15 ng/mL), whereas among the CYP3A4*1/*1 carriers, 40% were within the target range (p = 0.02, OR = 0.19 [0.03; 0.69]). The mean Tac Co at day 10 in the CYP3A4*1/*22 group was 23.5 ng/mL (16.6-30.9) compared with 15.1 ng/mL (14-16.3) in the CYP3A4*1/*1 group, p < 0.001. The Tac Co/dose significantly depended on the CYP3A4 genotype during the follow-up (random effects model, p < 0.001) with the corresponding equivalent dose for patients heterozygous for CYP3A4*22 being 0.67 [0.54; 0.84] times the dose for CYP3A4*1/*1 carriers. In conclusion, the CYP3A4*22 allelic variant is associated with a significantly altered Tac metabolism and carriers of this polymorphism often reach supratherapeutic concentrations.

[Prescription of methylphenidate for children: importance of recommendations to limit misuse]. / Prescription de méthylphénidate chez l'enfant : importance des recommandations pour limiter la consommation problématique.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder appearing during childhood. Multimodal strategies have been developed to treat this disorder, some of them including medication. To this day in France, prescriptions are mainly based on methylphenidate. Ever since this drug was marketed in France in 1995, it has been subject to enhanced monitoring, mainly because of the risk of dependence, abuse, and misuse. The present study aims at assessing (1) whether the recommendations on methylphenidate use for children are being respected, (2) the extent of problematic use of methylphenidate, and (3) the impact of said recommendations being respected on the development of problematic consumption. We studied patients who were treated with methylphenidate in an academic child psychiatry department. We specifically developed a semistructured interview grid for this study. Both parents and children were interviewed. In almost three out of four cases, at least one recommendation had not been followed (52% of patients did not follow the recommendation of stopping use during weekends and holidays). We found an average of 1.6 (range, 0-5) recommendations that were not respected. In almost two out of three cases, the consumption of methylphenidate was problematic; for 40% of children, this meant the search for at least one effect other than the expected therapeutic effects, such as an intellectual, creative, or athletic boosting effect. Approximately one-third of parents also sought an effect other than therapeutic for their child. Conversely, if all of the prescription recommendations were followed, less problematic consumption was observed. Methylphenidate-based treatments must therefore be implemented after a specialist has evaluated the patient and be prescribed following the recommendations. In this context, the treatment's benefits are undeniable.

Ibuprofen dependence: a case report.

Ibuprofen is currently widely prescribed and has not been reported to produce dependence. We report the case of a 17-year old patient who presented many positive psychic symptoms related to a pharmacological dependence. During the treatment, she adjusted herself posology as she developed withdrawal symptoms. Pharmacological evidences (effect on COX-1 and COX-2, FAAH and PPARs) allow us to formulate hypotheses explaining this effect.

[Cytogenetics profiles of renal carcinoma]. / Cytogénétique des carcinomes rénaux.

Renal carcinomas are histologically and prognostically heterogeneous. Genomic as well as chromosomal studies of these tumors have permitted a better comprehension of molecular mechanisms implicated in their development and progression. The most frequent histological subtypes are characterized by recurrent cytogenetic abnormalities, such as the loss of the chromosome 3 short arm involving a VHL gene copy in clear cell renal carcinomas, or trisomies 7 and 17 in papillary renal cell carcinomas. New histological subtypes like renal carcinomas associated with Xp11.2 translocations have also been individualized. Besides diagnosis, some chromosomal aberrations like the loss of a short arm of chromosome 9 in different renal carcinoma histological subtypes have a worse prognostic impact. The identification of chromosomal shuffles contributes in backing histological diagnosis and in precising the individual prognosis of patients. This review describes chromosomal abnormalities associated to renal carcinomas and their impact for an accurate classification of these tumors and the evaluation of their prognosis.