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.

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.

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.

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.

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.

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.

[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.

Overexpression of the polarity protein PAR-3 in clear cell renal cell carcinoma is associated with poor prognosis.

The partition-defective 3 (PAR-3) protein is implicated in the development and maintenance of cell polarity and is associated with proteins that mediate the changes in cytoskeleton organization required for cell polarity establishment. In this work, we used two original primary cell lines (R-180 and R-305) derived from clear cell Renal Cell Carcinoma (ccRCC) surgical specimens of a patient with unfavorable clinical course (R-180 cells) and a patient with favorable prognosis (R-305 cells) to identify genetic and molecular features that may explain the survival difference of the two patients. The cytogenetic analysis of these cell lines revealed that the PARD3 gene was amplified only in the R-180 cell line that was derived from an aggressive ccRCC. PARD3 gene amplification was associated with overexpression of the encoded protein and altered cytoskeleton organization. Consistently, PARD3 knockdown in R-180 cells restored the cytoskeleton organization and reduced cell migration in comparison to non-transfected cells. Immunohistochemical analysis of ccRCC samples from a cohort of 96 patients with a follow-up of 6 years revealed that PAR-3 overexpression was correlated with poor survival. Our results suggest that PAR-3 has a role in the clinical aggressiveness of ccRCC, possibly by promoting cell migration.

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.

[Renin-angiotensin system and urological cancers]. / Système rénine-angiotensine et cancers urologiques.

INTRODUCTION: A controversy animates the literature on the potential role of the renin-angiotensin system (RAS) in tumorogenesis. The objective of this review was to determine the involvement of this pathway in cancer, and more specifically in urological cancers. MATERIAL AND METHOD: We made a systematic review of articles referenced in Pubmed, using the following keywords alone or combined: cancer, renin, angiotensin, VEGF, AT1R, antagonists of angiotensin-2 receptors, inhibitors of angiotensinogen converting. RESULTS: Many types of cancers overexpress AT1-R in their tumoral tissues (breast, stomach, bladder, astrocytoma, glioblastoma, ovary, uterus, pancreas, kidney, prostate, adrenal gland). Ang-II can induce VEGF-A expression and promote neoangiogenesis, but also can trigger different molecular pathways involved in cell proliferation or inhibit apoptosis. Several xenograft murin models demonstrated anti-tumoral efficacy of RAS blockers, alone or using combined therapies, targeting angiogenesis and slowing down tumor growth. Retrospective studies in patients have also revealed a better progression-free survival and a better response to therapies in those treated with RAS blockers. CONCLUSION: Many data seem to demonstrate the involvement of the RAS in carcinogenesis, as well as anti-tumoral effect of RAS blockers in addition to anti-cancer treatments. Clinical data are now expected to confirm these experimental findings.

[The laparoscopic nephrectomy for polycystic kidney is feasible and reproducible]. / La néphrectomie laparoscopique pour rein polykystique est faisable et reproductible.

PURPOSE: The aim of our study was to report our experience of laparoscopic nephrectomy in patients with polycystic kidney disease. MATERIAL: Between December 2007 and February 2012, we performed 39 consecutive laparoscopic nephrectomies in patients with polycystic kidneys. All patients were operated by a transperitoneal approach. RESULTS: Patients had a mean age of 55 with an average BMI of 25 kg/m(2). Eighty-seven percent were ASA III and 77% were on dialysis. In most of the cases, the indication concerned patients who were candidates to a renal transplantation to make space for graft implantation. Operative time was 167 minutes with a mean blood loss of 200 mL. Two open conversions were necessary (splenic injury and difficulty of dissection of the renal pedicle). Fifteen percent of patients were transfused. There were 11 complications (28%) among which five were major (Clavien ≥ 3). Mean length of stay was 5.2 days. CONCLUSION: Our study showed that laparoscopic nephrectomy for polycystic kidney is feasible and reproducible. We systematically offer it when indicated.

[Description of medicosocial profiles of pharmacodependent subjects consulting addictology centres using a computerized database]. / Description de profils médicosociaux de sujets pharmacodépendants consultant en addictologie à partir d'une base de données informatique.

INTRODUCTION: Lots of similar vulnerabilities to substance use disorders are described in the literature: clinical, genetics, family, environment, etc. Although, when we follow up patients, we know perfectly well that there are also differences due to the substance mainly causing addiction. But we found very little research on the differences between various substance use disorders according to the substance mainly causing dependence. HYPOTHESIS: Our main hypothesis was that significant differences do not exist in medical and social data between patients with substance use disorders according to the substance mainly used. We expected to find significant differences between illegal substance use disorders (opiates, cocaine, cannabis) and legal substance use disorders (BZD, alcohol). OBJECTIVE: Our study aimed to identify differences between patients with substance related disorders in medical and social data according to the main addictive substance. MATERIAL AND METHOD: A specific software has been created by the CEIP and the Department of Addictology of Nantes University Hospital. Anonymous data were gathered and all patients gave their written consent. This database has been declared to CNIL (number 1350706). All data have been directly collected by the physician during medical consultation. The following data were recorded during the first medical examination: age, sex, illicit substance use, prior criminal record or psychiatric disorders, prior addictive behaviours among relatives and/or friends, family history (divorce, separation, abandonment). Other data were gathered prospectively: socioprofessional insertion, marital status, drug prescriptions (time and duration). RESULTS: We found significant differences in social (age, sex) and medical data (prior psychiatric disorders) between patients according to the substance causing dependence. We identified five profiles depending on the substance: cannabis, cocaine, heroin, alcohol and benzodiazepine. DISCUSSION: We clearly identified different types of patient's profiles according to substances mainly causing addiction. These differences can modify our strategies of prevention and treatment, so as to meet patients' needs better.

[The neutrophil gelatinase-associated lipocalin, or LCN 2, marker of aggressiveness in clear cell renal cell carcinoma]. / La neutrophil gelatinase-associated lipocalin, ou LCN 2, facteur d'agressivité dans le carcinome rénal à cellules claires (CRCC).

OBJECTIVE: To determine the prognostic significance of the neutrophil gelatinase-associated lipocalin (NGAL) and the matrix metalloproteinase 9 (MMP-9) in clear cell renal cell carcinoma (CCRCC). PATIENTS AND METHODS: NGAL and MMP-9 expression were quantified by immunohistochemistry in clear renal cell carcinoma tissues and in sera by Enzyme Linked Immunosorbent Assay (Elisa). Results were associated with clinicopathologic data. RESULTS: Seventy-four patients operated for CCRCC in Rennes between 2003 and 2009 were included. High concentrations of NGAL-MMP-9 complex in serum were associated with short progression free survival (PFS) (33.3 months versus 47.3 months, P=0.016) and poor overall survival (42.5 months versus 51.9 months, P<0.047). High NGAL concentrations in serum were also associated with shorter PFS (13.6 months versus 41.6 months, P=0.04). However, no NGAL expression was observed in renal tumor cells. Interestingly, NGAL was expressed by neutrophils infiltrating CCRCC and we showed that the density of NGAL expressing neutrophils was associated with pejorative PFS and survival (36.9months versus 56.1 months, P<0.006). CONCLUSION: In this study, we showed the pejorative significance of NGAL-MMP-9 complex and NGAL rates in serum of CCRCC. We also confirmed that density of NGAL expressing neutrophils in CCRCC was associated with poor outcome.

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.

Angiotensin-2 receptors (AT1-R and AT2-R), new prognostic factors for renal clear-cell carcinoma?

BACKGROUND: The growth factor Angiotensin-2 signals through Angiotensin receptor type 1 (AT1-R) in a broad range of cell types and tumours and through the type-2 receptor (AT2-R) in a more restricted group of cell types. Although numerous forms of cancer have been shown to overexpress AT1-R, expression of AT1-R and AT2-R by human renal clear-cell carcinoma (RCCC) is not well understood. In this study, the expression of both angiotensin receptors was quantified in a retrospective series of RCCC and correlated with prognostic factors. METHODS: Angiotensin receptor type 1 and AT2-R expressions were quantified on tumour tissues by immunohistochemistry (IHC), western blot and quantitative reverse transcriptase PCR (qRT-PCR). IHC results were correlated to Fuhrman's grade and patient progression-free survival (PFS). RESULTS: A total of 84 RCCC were analysed. By IHC, AT1-R and AT2-R were expressed to a greater level in high-grade tumours (AT1-R: P<0.001, AT2-R: P<0.001). Univariate analysis showed a correlation between PFS and AT1-R or AT2-R expression (P=0.001). By multivariate analysis, only AT2-R expression correlated with PFS (HR 1.021, P=0.006) and cancer stage (P<0.001). By western blot, AT1-R and AT1-R were also found to be overexpressed in higher Fuhrman's grade (P<0.01 and P=0.001 respectively). By qRT-PCR, AT1-R but not AT2-R mRNA were downregulated (P=0.001 and P=0.118, respectively). CONCLUSION: Our results show that AT1-R and AT2-R proteins are overexpressed in the most aggressive forms of RCCC and that AT2-R expression correlates with PFS. AT1-R or AT2-R blockage could, therefore, offer novel directions for anti-RCCC therapy.