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Background: Bladder cancer (BCa) is more common in men and presents differences in molecular subtypes based on sex. Fibroblast growth factor receptor 3 (FGFR3) mutations are enriched in the luminal papillary muscle-invasive BCa (MIBC) and non-MIBC subtypes. Objective: To determine whether FGFR3 mutations initiate BCa and impact BCa male sex bias. Design, setting, and participants: We developed a transgenic mouse model expressing the most frequent FGFR3 mutation, FGFR3-S249C, in urothelial cells. Bladder tumorigenesis was monitored in transgenic mice, with and without carcinogen exposure. Mouse and human BCa transcriptomic data were compared. Intervention: Mutant FGFR3 overexpression in mouse urothelium and siRNA knockdown in cell lines, and N-butyl-N(4-hydroxybutyl)-nitrosamine (BBN) exposure. Outcome measurements and statistical analysis: Impact of transgene dosage on tumor frequency, synergy with BBN treatment, and FGFR3 pathway activation were analyzed. The sex-specific incidence of FGFR3-mutated tumors was evaluated in mice and humans. FGFR3 expression in FGFR3-S249C mouse urothelium and in various human epithelia was measured. Mutant FGFR3 regulation of androgen (AR) and estrogen (ESR1) receptor activity was evaluated, through target gene expression (regulon) and reporter assays. Results and limitations: FGFR3-S249C expression in mice induced low-grade papillary BCa resembling human luminal counterpart at histological, genomic, and transcriptomic levels, and promoted BBN-induced basal BCa formation. Mutant FGFR3 expression levels impacted tumor incidence in mice, and mutant FGFR3–driven human tumors were restricted to epithelia presenting high normal FGFR3 expression levels. BCa male sex bias, also found in our model, was even higher in human FGFR3-mutated tumors compared with wild-type tumors and was associated with higher AR and lower ESR1 regulon activity. Mutant FGFR3 expression inhibited both ESR1 and AR activity in mouse tumors and human cell lines, demonstrating causation only between FGFR3 activation and low ESR1 activity in tumors. Conclusions: Mutant FGFR3 initiates luminal papillary BCa formation and favors BCa male sex bias, potentially through FGFR3-dependent ESR1 downregulation. Patients with premalignant lesions or early-stage BCa could thus potentially benefit from FGFR3 targeting. FGFR3 expression level in epithelia could account for FGFR3-driven carcinoma tissue specificity. Patient summary: By developing a transgenic mouse model, we showed that gain-of-function mutations of FGFR3 receptor, among the most frequent genetic alterations in bladder cancer (BCa), initiate BCa formation. Our results could support noninvasive detection of FGFR3 mutations and FGFR3 targeting in early-stage bladder lesions.

International audience; In low-risk myelodysplastic syndrome (LR-MDS), erythropoietin (EPO) is widely used for the treatment of chronic anemia. However, initial response to EPO has time-limited effects. Luspatercept reduces red blood cell transfusion dependence in LR-MDS patients. Here, we investigated the molecular action of luspatercept (RAP-536) in an in vitro model of erythroid differentiation of MDS, and also in a in vivo PDX murine model with primary samples of MDS patients carrying or not SF3B1 mutation. In our in vitro model, RAP-536 promotes erythroid proliferation by increasing the number of cycling cells without any impact on apoptosis rates. RAP-536 promoted late erythroid precursor maturation while decreasing intracellular reactive oxygen species level. RNA sequencing of erythroid progenitors obtained under RAP-536 treatment showed an enrichment of genes implicated in positive regulation of response to oxidative stress and erythroid differentiation. In our PDX model, RAP-536 induces a higher hemoglobin level. RAP-536 did not modify variant allele frequencies in vitro and did not have any effect against leukemic burden in our PDX model. These results suggest that RAP-536 promotes in vivo and in vitro erythroid cell differentiation by decreasing ROS level without any remarkable impact on iron homeostasis and on mutated allele burden.

International audience; Background Fluid removal can reduce the burden of fluid overload after initial resuscitation. According to the Frank-Starling model, iatrogenic hypovolemia should induce a decrease in cardiac index. We hypothesized that inadequate refilling detected by haemoconcentration during fluid removal or an increase in cardiac index (CI) during passive leg raising (PLR) could predict CI decrease during mechanical fluid removal with continuous renal replacement therapy (CRRT).Methods We conducted a single-centre prospective diagnostic accuracy study. The primary objective was to investigate the diagnostic performance of plasma protein concentration variations in detecting a CI decrease >= 12% during mechanical fluid removal. Secondary objective was to assess other predictive factors of CI change. The attending physician prescribed a fluid removal challenge consisting of a mechanical fluid removal challenge of 500 mL for one hour. Plasma protein concentration, haemoglobin level, PLR and transpulmonary thermodilution were done before and after the fluid removal challenge.Results We included 69 adult patients between December 2016 and April 2020. Sixteen patients had a significant CI decrease (23% [95% CI 14-35]). Haemoconcentration and PLR before fluid removal challenge or CI trending failed to predict CI decrease.Conclusion Haemoconcentration variables, preload dependence status and CI trending failed to predict CI decrease during fluid removal challenge.[GRAPHICS]

Background We determine the benefit of pulsed methylprednisolone for improving kidney function in patients with sarcoidosis tubulointerstitial nephritis. Methods We conducted a multicenter, prospective, randomized, open-label, controlled trial in patients with biopsy-proven acute tubulointerstitial nephritis caused by sarcoidosis at 21 sites in France. Patients were randomly assigned to receive a methylprednisolone pulse 15 mg/kg/day for 3 days, then oral prednisone (MP group) or oral prednisone 1 mg/kg/day alone (PRD group). The primary end point was a positive response at 3 months, defined as a doubling of estimated glomerular filtration rate (eGFR) compared with the eGFR before randomization. Results We randomized 40 participants. Baseline eGFR before PRD was 22 mL/min/1.73m2 {interquartile range [IQR], 16–44} and before MP was 25 mL/min/1.73m2 (IQR, 22–36) (P = .3). The two groups did not differ in underlying pathological lesions, including mean percentage of interstitial fibrosis and intensity of interstitial infiltrate. In the intent-to-treat population, the median eGFR at 3 months did not significantly differ between the PRD and MP groups: 45 (IQR, 34–74) and 46 (IQR, 39–65) mL/min/1.73m2. The primary end point at 3 months was achieved in 16 of 20 (80%) PRD patients and 10 of 20 (50%) MP patients (P = .0467). The eGFR was similar between the two groups after 1, 3, 6, and 12 months of treatment. For both groups, eGFR at 1 month was strongly correlated with eGFR at 12 months (P Conclusion Compared with a standard oral steroid regimen, intravenous MP may have no supplemental benefit for renal function in patients with tubulointerstitial nephritis caused by sarcoidosis. Trial Registration: ClinicalTrials.gov: NCT01652417; EudraCT: 2012–000149-11

National audience; INTRODUCTION: In a context of tension on the number of available kidney transplants compared to the number needed, the practices of refusal of transplants in the Rennes transplantation center were evaluated. MATERIALS AND METHODS: The donors completely refused by our team (no kidney accepted for any Rennes recipient) between January 1st 2012 and December 31st 2015 were identified from the national CRISTAL registry. The outcome of these refused transplants (possible transplantation in another center), the data of the recipients (from Rennes and other centers) and the data of the donors (refused and then finally accepted) were extracted. The outcome of recipients (from Rennes and other centers) was compared: graft survival (censored on death) and patient survival (not censored on cessation of function). The Kidney Donor Profile Index (KDPI) score was calculated and its usefulness studied. RESULTS: Among the 203 rejected donors, 172 (85 %) were accepted for transplantation in another center; 89% of these grafts were functional at one year. In univariate analysis, Rennes recipients transplanted after a refusal had a better graft survival (censored on death) than recipients transplanted in another center with the refused graft (p < 0.001). The main limitation of this analysis is the non-comparability of the groups. The KDPI score was significantly associated with graft survival (censored on death). Of the 151 Rennes patients who had a refusal, 3% were still on the waiting list at the end of the observation period, the others spent a median additional time on dialysis of 220 days (Q1-Q3 81-483). CONCLUSION: Rennes recipients transplanted after a first refusal seem to have a better graft survival (censored on death) than recipients from other centers transplanted with refused grafts. This is to be weighed against the additional time on dialysis and even the risk of non-transplantation.

International audience; BACKGROUND: Intratumor heterogeneity (ITH) is a key feature in clear cell renal cell carcinomas (ccRCCs) that impacts outcomes such as aggressiveness, response to treatments, or recurrence. In particular, it may explain tumor relapse after surgery in clinically low-risk patients who did not benefit from adjuvant therapy. Recently, single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool to unravel expression ITH (eITH) and might enable better assessment of clinical outcomes in ccRCC. OBJECTIVE: To explore eITH in ccRCC with a focus on malignant cells (MCs) and assess its relevance to improve prognosis for low-risk patients. DESIGN, SETTING, AND PARTICIPANTS: We performed scRNA-seq on tumor samples from five untreated ccRCC patients ranging from pT1a to pT3b. Data were complemented with a published dataset composed of pairs of matched normal and ccRCC samples. INTERVENTION: Radical or partial nephrectomy on untreated ccRCC patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Viability and cell type proportions were determined by flow cytometry. Following scRNA-seq, a functional analysis was performed and tumor progression trajectories were inferred. A deconvolution approach was applied on an external cohort, and Kaplan-Meier survival curves were estimated with respect to the prevalence of malignant clusters. RESULTS AND LIMITATIONS: We analyzed 54 812 cells and identified 35 cell subpopulations. The eITH analysis revealed that each tumor contained various degrees of clonal diversity. The transcriptomic signatures of MCs in one particularly heterogeneous sample were used to design a deconvolution-based strategy that allowed the risk stratification of 310 low-risk ccRCC patients. CONCLUSIONS: We described eITH in ccRCCs, and used this information to establish significant cell population-based prognostic signatures and better discriminate ccRCC patients. This approach has the potential to improve the stratification of clinically low-risk patients and their therapeutic management. PATIENT SUMMARY: We sequenced the RNA content of individual cell subpopulations composed of clear cell renal cell carcinomas and identified specific malignant cells the genetic information of which can be used to predict tumor progression.

International audience; PURPOSE: Using large French retrospective study cohort of chemotherapy-naïve metastatic castration-resistant prostate cancer patients (mCRPC; n = 10,308) comparing survival between patients who initiated abiraterone (ABI; 64%) and those initiating enzalutamide (ENZ; 36%), the present objective was to describe treatment patterns in the 2 years following initiation. METHOD: Using the national health data system (SNDS) from 2014 to 2018, we first explored the number of treatment lines, and secondly, patterns of patient management using state sequence analysis; cluster analyses were performed on the 0 to 12 month and 13 to 24 month periods. Age, Charlson score, and duration of androgen deprivation therapy (ADT) were obtained for each cluster in the first year of follow-up. RESULTS: Patients with only 1 treatment line accounted for 52%. In the 0 to 12 month sequence analysis, the main clusters among ABI/ENZ new users involved patients who continued the initial treatment (54% of 65% respectively) and discontinued active treatment (14.5% for both). Less than 2 years exposure to ADT prior to ABI/ENZ initiation was frequently observed for noncontrolled mCRPC, as shown in the death and switch from ABI/ENZ to docetaxel clusters. The clusters for a switch ABI/ENZ to ENZ/ABI involved 6% to 11% of the patients. CONCLUSION: Our study suggested fairly similar patterns between ABI and ENZ initiation. The cluster of patients with active treatment discontinuation needs to be further investigated, as well as factors influencing therapeutic choice. Better understanding for the use of second-generation hormone therapy in mCRPC in real life, could improve its implementation by clinicians in the early stages of prostate cancer.

National audience; OBJECTIVE: Neurogenic bladders can suffer from overactivity, underactivity or dyssynergia depending on the level of the initial lesion. These symptoms can lead to severe alterations of the upper urinary tract. One of the first-line treatments is the transcutaneous tibial posterior stimulation (TTNS), which was demonstrated to be efficient on urodynamics. But it is an invasive, expensive and sometimes not patient-accepted examination, contrary to the uroflowmetry. The aim of this study is to assess the feasibility of a follow-up with a uroflowmetry when treated by TTNS and show that the maximum flow rate increased after treatment, displaying a better detrusor contraction. METHODS: In total, 38 patients with neurogenic bladder undergoing a 12-weeks TTNS treatment and with 2 uroflowmetries interpretable before and after treatment were included. The maximum flow rate (Qmax), the urinated volume and the post-void residual (PVR) were retrieved from the uroflowmetry, and the USP-score and the urinary discomfort were asked at each appointment. RESULTS: Qmax is increased from 17,53ml/s to 18,26ml/s, as well as the PVR (from 76,97ml to 79,16ml). Urinated volume is decreased from 241,4ml to 193,66ml. Patients feel enhanced after TTNS according to the decrease in the USP-score and the urinary discomfort scale. CONCLUSION: The increase of the cystomanometric capacity and the delay of the detrusor overactivity due to TTNS explains the reduction of the urinated volume and the increase of PVR. Increased Qmax might show a better voluntary bladder contraction, with a restraint due to the lack of abdominal pressure measurement during voiding.

Background: Genetic factors play an important role in prostate cancer (PCa) susceptibility.Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry.Design, setting, and participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry.Outcome measurements and statistical analysis: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness.Results and limitations: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10-4).Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry.Patient summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.

International audience; Introduction: APOL1, GSTM1 risk variants, and sickle cell trait (SCT) are associated with chronic kidney disease (CKD) among African Americans (AAs). Nevertheless, such evidence remains scarce in sub-Saharan Africa (SSA) populations.Methods: In a cross-sectional study, we evaluated the prevalence of these risk variants and their association with estimated glomerular filtration rate (eGFR), albuminuria, and CKD in urban (n = 587) and rural (n = 730) adults from South-Kivu, DR Congo (DRC). Furthermore, we evaluated APOL1 recessive model (high risk [HR] vs. low risk [LR]), SCT carriage, and the active versus inactive GSTM1 genotypes.Results: The frequencies of the APOL1 G1 and G2 alleles were 8.7% and 9.1%, respectively, and 3.2% carried the HR genotype. SCT and GSTM1 null allele frequencies were 3.8% and 51.2%, respectively. APOL1 HR was associated with lower eGFR (P = 0.047, odds ratio [OR] = 4). Individuals with SCT exhibited lower eGFR (P = 0.018), higher albuminuria (P = 0.032), and 2.4× increased risk of CKD (P = 0.031). APOL1 HR and SCT were synergistically associated with lower eGFR (Pinteraction = 0.012). The GSTM1 null allele was not significantly associated with any renal outcomes.Conclusion: Our study highlighted the impact of APOL1 and SCT variants on poorer renal outcomes in the DRC and advocates for further genetic studies in SSA settings.

International audience; BackgroundThe Keynote-045 trial illustrates that the long-term benefit (LTB) of treatment does not always translate to improved progression-free survival (PFS). Milestone survival and flexible parametric survival model with cure (FPCM) have been proposed as complementary statistical approaches to more comprehensively evaluate LTBs of treatments.ObjectiveThe current study compares milestone survival and FPCM analyses to evaluate treatment effects of immune checkpoint inhibitor (ICI) phase III trials.Design, setting, and participantsIndividual patient data, from initial and follow-up analyses of Keynote-045 (urothelial cancer) and Checkmate-214 (advanced renal cell carcinoma), were reconstructed for PFS.Outcome measurements and statistical analysisEach trial was reanalyzed using the Cox proportional hazard regression and two complementary methods (milestone survival and FPCM) to estimate treatment impact on the LTB.Results and limitationsFor each trial, there was evidence of nonproportional hazards. For the long-term analysis of the Keynote-045 trial, FPCM identified a time-dependent effect on PFS, but the Cox model found no statistical difference in PFS (hazard ratio, 0.90; 95% confidence interval, 0.75–1.08). Milestone survival and FPCM identified improvements in the LTB fractions. This was consistent with the results from the reanalysis of Keynote-045, based on the shorter follow-up, although the LTB fraction was not retained. The increase in PFS in Checkmate-214 was identified by both Cox model and FPCM. Experimental treatment-dependent improvement in the LTB fraction was demonstrated using milestone survival and FPCM. The LTB fraction estimated with FPCM was consistent with the results from the reanalysis of the shorter follow-up period.ConclusionsAlthough ICIs show substantial shifts toward LTBs in terms of PFS, based on a conventional Kaplan-Meier or Cox model analysis, our approach provides an alternative assessment of benefit-risk ratios for new therapeutics and facilitates communicating risk to patients. Kidney patients treated with ICIs can be counseled that they are potentially cured, but future work will need to definitively validate this conclusion.

International audience; The objective of this study was to determine the proportion of phase 3 clinical trials investigating a systemic therapy for patients with prostate, breast, lung, or colorectal cancer that excluded patients with Chronic Kidney Disease (CKD) and the exclusion criteria chosen, if any. A search was conducted using the ClinicalTrials.gov database to identify eligible studies. Of the 268 included trials, 185 (69%) had at least one renal exclusion criteria. Of these 185 trials, 116 (63%) had an undefined exclusion criterion. Only disease site was associated with exclusion of patients with CKD in the univariate analysis, but no factors in the multivariate analysis. There are several potential barriers to including patients with CKD in clinical trials. Nevertheless, solutions can be proposed to allow the inclusion of these patients. This would allow them to access to innovative therapeutic strategies, but also allow a better applicability of trial results to this patient population.

International audience; There is growing evidence that ion channels are critically involved in cancer cell invasiveness and metastasis. However, the molecular mechanisms of ion signaling promoting cancer behavior are poorly understood and the complexity of the underlying remodeling during metastasis remains to be explored. Here, using a variety of in vitro and in vivo techniques, we show that metastatic prostate cancer cells acquire a specific Na+ /Ca2+ signature required for persistent invasion. We identify the Na+ leak channel, NALCN, which is overexpressed in metastatic prostate cancer, as a major initiator and regulator of Ca2+ oscillations required for invadopodia formation. Indeed, NALCN-mediated Na+ influx into cancer cells maintains intracellular Ca2+ oscillations via a specific chain of ion transport proteins including plasmalemmal and mitochondrial Na+ /Ca2+ exchangers, SERCA and store-operated channels. This signaling cascade promotes activity of the NACLN-colocalized proto-oncogene Src kinase, actin remodeling and secretion of proteolytic enzymes, thus increasing cancer cell invasive potential and metastatic lesions in vivo. Overall, our findings provide new insights into an ion signaling pathway specific for metastatic cells where NALCN acts as persistent invasion controller.

Background : Cisplatin-based combination chemotherapy before surgery is the standard of care for muscle-invasive bladder cancer. However, the optimal chemotherapy modalities have not been precisely defined to date. Patients and Methods : In the VESPER trial, patients received after randomization either gemcitabine and cisplatin (GC, 4 cycles) or methotrexate, vinblastine, doxorubicin and cisplatin (dose dense [dd]-MVAC, 6 cycles). Creatinine clearance (CrCl) was calculated before each cycle according to the Cockroft and Gault formula. Definition criteria for local control after neoadjuvant chemotherapy included pathological complete response (ypT0N0), pathological downstaging ( Results : A total of 2,128 cycles of chemotherapy were delivered, including 2,120 (99.6%) with cisplatin. Full doses of cisplatin were given in 1866 (88%) cycles. Twenty-three (4.7%) patients had to stop chemotherapy (12 GC, 11 dd-MVAC) because of renal failure. No difference in CrCl median values was observed between the two regimens during the first four cycles. A mild decrease occurred thereafter in patients treated with two additional cycles of dd-MVAC. A minimum total dose of 270 mg/m2 for cisplatin was mandatory to optimize pathological complete responses. Conclusion : At least 4 cycles of cisplatin-based chemotherapy should be delivered before cystectomy. Increasing the number of cycles beyond 4 cycles does not lead to a clinically significant deterioration in renal function but without obvious gain on local control. MicroAbstractCGC : A deep analysis of data from a randomized trial of perioperative chemotherapy in muscle-invasive bladder cancer shows that a minimum number of 4 cycles is required to optimize the chances of pathological complete response at cystectomy. Increasing the number beyond 4 cycles does not lead to a clinically significant deterioration in renal function without any obvious gain on pathological complete response.

International audience; Introduction: Tubulointerstitial nephritis (TIN) and uveitis (TINU) syndrome is a rare disease. The renal prognosis is generally thought to be better in children with TINU syndrome than in adults. However, data are scarce. We aimed to investigate the long-term renal prognosis in a French cohort of children with TINU syndrome.Methods: We performed a national retrospective study including 23 French pediatric nephrology centers enrolling patients with TINU syndrome diagnosed between January 2000 and December 2018.Results: A total of 46 patients were included (52% female, median age 13.8 years). At diagnosis of TIN, the median estimated glomerular filtration rate (eGFR) was 30.6 ml/min per 1.73 m2 (4.9-62.8). The median time between diagnosis of uveitis and TIN was 0.4 months (-4.1; +17.1). All patients had anterior uveitis, but 12 (29%) were asymptomatic. Nearly all patients (44 of 46) received steroid treatment, and 12 patients (26%) received a second-line therapy. At last follow-up (median 2.8 years), the median eGFR was 87.5 ml/min per 1.73 m2 (60.3-152.7) and

Background: Alterations of renal hemodynamics play an essential role in renal homeostasis and kidney diseases. Recent data indicated that semaphorin 3C (SEMA3C), a secreted glycoprotein involved in vessel development, can modulate renal vascular permeability in acute kidney injury, but whether and how it might impact systemic and renal hemodynamics is unknown. Objectives: The objective of the study was to explore the effect of SEMA3C on systemic and renal hemodynamics. Methods: SEMA3C recombinant protein was administered intravenously in two-month-old wild-type mice, and the variations of mean arterial pressure, heart rate, renal blood flow, and renal vascular resistance were measured and analyzed. Results: Acute administration of SEMA3C induced (i) systemic hemodynamic changes, including mean arterial pressure decrease and heart rate augmentation; (ii) renal hemodynamic changes, including reduced vascular resistance and elevated renal blood flow. Continuous perfusion of SEMA3C had no significant effect on systemic or renal hemodynamics. Conclusion: SEMA3C is a potent vasodilator affecting both systemic and renal hemodynamics in mice.

International audience; Purpose: the purpose of this multicenter study was to evaluate the clinical success at three months of prostate artery embolization (PAE), assess PAE safety in centers with various experiences and identify factors associated with PAE success.Patients and methods: this multicenter, retrospective study included patients who underwent PAE for lower urinary tract symptoms (LUTS) including those with indwelling urinary catheter. PAE clinical success was defined as either 25% improvement of the International Prostate Symptom Score (IPSS) or 1-point improvement of quality of life (QoL) score, or catheter removal at three months. Multivariable analyses were performed using a logistic regression adjusted on patient variables, technical parameters and center experience in PAE.Results: a total of 383 men (mean age, 68.4±9.7 [standard deviation] years; range: 46-94) with LUTS, including 99 (25.8%) patients with indwelling urinary catheter, were included in seven centers from January 2017 to March 2019. Five patients reported major complications (1.3%), three (0.8%) penile ulceration, three (0.8%) acute urinary retention, one (0.3%) prostatic abscess, and 56 (14.6%) minor complications. Follow up data were available for 271 patients (center 1: n= 159; other centers: n= 112). Clinical success was reported in 232 patients (85.6%). In multivariable analyses, presence of cardiovascular comorbidities (diabetes, stroke history, myocardial infarction and lower limb artery disease) was the single independent variable inversely associated with PAE clinical success (odds ratio= 0.396; 95% confidence interval: 0.17-0.91; P= 0.029). There was no center effect.Conclusion: our results show that PAE is safe and effective in centers with various PAE experiences. Cardiovascular comorbidity is the single independent variable associated with PAE failure.

International audience; Mutations in the apically located kidney Na-K-2Cl cotransporter NKCC2 cause type I Bartter syndrome, a life-threatening kidney disorder. We previously showed that transport from the ER represents the limiting phase in NKCC2 journey to the cell surface. Yet very little is known about the ER quality control components specific to NKCC2 and its disease-causing mutants. Here, we report the identification of Golgi alpha1, 2-mannosidase IA (ManIA) as a novel binding partner of the immature form of NKCC2. ManIA interaction with NKCC2 takes place mainly at the cis-Golgi network. ManIA coexpression decreased total NKCC2 protein abundance whereas ManIA knock-down produced the opposite effect. Importantly, ManIA coexpression had a more profound effect on NKCC2 folding mutants. Cycloheximide chase assay showed that in cells overexpressing ManIA, NKCC2 stability and maturation are heavily hampered. Deleting the cytoplasmic region of ManIA attenuated its interaction with NKCC2 and inhibited its effect on the maturation of the cotransporter. ManIA-induced reductions in NKCC2 expression were offset by the proteasome inhibitor MG132. Likewise, kifunensine treatment greatly reduced ManIA effect, strongly suggesting that mannose trimming is involved in the enhanced ERAD of the cotransporter. Moreover, depriving ManIA of its catalytic domain fully abolished its effect on NKCC2. In summary, our data demonstrate the presence of a ManIA-mediated ERAD pathway in renal cells promoting retention and degradation of misfolded NKCC2 proteins. They suggest a model whereby Golgi ManIA contributes to ERAD of NKCC2, by promoting the retention, recycling, and ERAD of misfolded proteins that initially escape protein quality control surveillance within the ER.

International audience; Introduction: This study aimed to assess if an interference effect could blunt the neuromuscular gains induced by a same-session combined rehabilitation in hemodialysis (HD) patients. Methods: Patients exercised twice a week, for 16 weeks, over their HD sessions. They were either always trained with resistance and endurance exercises (continuous training, “CONT”) or alternatively with 1 week of resistance alternated with 1 week of endurance (discontinuous training, “DISC”). Adherence and workload were continuously recorded. Short Physical Performance Battery (SPPB) score, one-leg balance test, and handgrip and quadriceps strength were evaluated before and after training intervention. Results: Adherence to both programs was high (>90%). SPPB score had significantly improved (CONT: +1.5 point, DISC: +1.2 pt, p < 0.001), like one-leg balance test (CONT: +3.7 s, DISC: +5.5 s, p < 0.05), handgrip strength of exercised (CONT: +5.5 kg, DISC: +5.6 kg, p < 0.001) and of nonexercised arm (CONT: +4.4 kg, DISC: +2.8 kg, p < 0.01) as well as maximal quadriceps strength (+22 N·m for dominant and +29 N·m for nondominant leg in both groups, p < 0.001) bearing no difference between the trainings. Conclusion: Same-session combined training does not induce an interference effect in HD patients and temporal separation of exercises does not optimize strength gains. These practical data may be relevant for clinicians and practitioners to alternate endurance and resistance exercises.

International audience; Background and objectives Kidney impairment of ANCA-associated vasculitides can lead to kidney failure. Patients with kidney failure may suffer from vasculitis relapses but are also at high risk of infections and cardiovascular events, which questions the maintenance of immunosuppressive therapy. Design, setting, participants, & measurements Patients with ANCA-associated vasculitides initiating long-term dialysis between 2008 and 2012 in France registered in the national Renal Epidemiology and Information Network registry and paired with the National Health System database were included. We analyzed the proportion of patients in remission off immunosuppression over time and overall and event-free survival on dialysis (considering transplantation as a competing risk). We compared the incidence of vasculitis relapses, serious infections, cardiovascular events, and cancers before and after dialysis initiation. Results In total, 229 patients were included: 142 with granulomatous polyangiitis and 87 with microscopic polyangiitis. Mean follow-up after dialysis initiation was 4.6±2.7 years; 82 patients received a kidney transplant. The proportion of patients in remission off immunosuppression increased from 23% at dialysis initiation to 62% after 5 years. Overall survival rates on dialysis were 86%, 69%, and 62% at 1, 3, and 5 years, respectively. Main causes of death were infections (35%) and cardiovascular events (26%) but not vasculitis flares (6%). The incidence of vasculitis relapses decreased from 57 to seven episodes per 100 person-years before and after dialysis initiation ( P =0.05). Overall, during follow-up, 45% of patients experienced a serious infection and 45% had a cardiovascular event, whereas 13% experienced a vasculitis relapse. Conclusions The proportion of patients with ANCA-associated vasculitis in remission off immunosuppression increases with time spent on dialysis. In this cohort, patients were far less likely to relapse from their vasculitis than to display serious infectious or cardiovascular events. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_11_08_CJN03190321.mp3

International audience; Background and objectives The fact that metabolism and immune function are regulated by an endogenous molecular clock that generates circadian rhythms suggests that the magnitude of ischemia reperfusion, and subsequent inflammation on kidney transplantation, could be affected by the time of the day. Design, setting, participants, & measurements We evaluated 5026 individuals who received their first kidney transplant from deceased heart-beating donors. In a cause-specific multivariable analysis, we compared delayed graft function and graft survival according to the time of kidney clamping and declamping. Participants were divided into those clamped between midnight and noon ( ante meridiem [ am ] clamping group; 65%) or clamped between noon and midnight ( post meridiem [ pm ] clamping group; 35%), and, similarly, those who underwent am declamping (25%) or pm declamping (75%). Results Delayed graft function occurred among 550 participants (27%) with am clamping and 339 (34%) with pm clamping (adjusted odds ratio, 0.81; 95% confidence interval, 0.67 to 0.98; P =0.03). No significant association was observed between clamping time and overall death-censored graft survival (hazard ratio, 0.92; 95% confidence interval, 0.77 to 1.10; P =0.37). No significant association of declamping time with delayed graft function or graft survival was observed. Conclusions Clamping between midnight and noon was associated with a lower incidence of delayed graft function, whereas declamping time was not associated with kidney graft outcomes.

International audience; Introduction: The search for the 'perfect' renal replacement therapy has been paralleled by the search for the perfect biomarkers for assessing dialysis adequacy. Three main families of markers have been assessed: small molecules (prototype: urea); middle molecules (prototype β2-microglobulin); comprehensive and nutritional markers (prototype of the simplified assessment, albumin levels; composite indexes as malnutrition-inflammation score). After an era of standardization of dialysis treatment, personalized dialysis schedules are increasingly proposed, challenging the dogma of thrice-weekly hemodialysis.Areas covered: In this review, we describe the advantages and limitations of the approaches mentioned above, focusing on the open questions regarding personalized schedules and incremental hemodialysis.Expert opinion: In the era of personalized dialysis, the assessment of dialysis adequacy should be likewise personalized, due to the limits of 'one size fits all' approaches. We have tried to summarize some of the relevant issues regarding the determination of dialysis adequacy, attempting to adapt them to an elderly, highly comorbidity population, which would probably benefit from tailor-made dialysis prescriptions. While no single biomarker allows precisely tailoring the dialysis dose, we suggest using a combination of clinical and biological markers to prescribe dialysis according to comorbidity, life expectancy, residual kidney function, and small and medium-size molecule depuration.

International audience; Eosinophilic granulomatosis with polyangiitis (EGPA), previously called Churg-Strauss syndrome, is a small to medium-sized systemic necrotizing vasculitis characterized by eosinophil-rich tissue infiltrates and granulomatous lesions. EGPA belongs to the larger subgroup of ANCA-associated vasculitides (AAV). However, EGPA is characterized by a distinct biological and clinical presentation when compared with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). EGPA is typically characterized by late onset asthma, nasal and sinus-related symptoms, peripheral neuropathy and prominent peripheral blood eosinophilia.1 The prevalence of ANCA positivity in EGPA is about 40%, with predominant perinuclear staining, and exhibits an anti-MPO specificity in approximatively 65% of cases.1,2 Unlike GPA and MPA, where kidney involvement is a central feature, nephropathy is not considered a prominent aspect in patients with EGPA.1,3 For this reason, the nephrologist is not usually regarded as a key player in the care of EGPA patients. The case reported here dispels this misconception by demonstrating that, in selected cases, nephrological expertise may play an active role in patient management.

PurposeThe emergence of new communication media such as digital contents are progressively replacing more traditional medias in the field of educational programs. Our purpose was to assess urologist in training aspirations regarding urological education.MethodsMembers of a national urologist in training association were sent an anonymous online questionnaire regarding their medical formation in the field of urology. Responders interest for urological sub-specialty or education support (new tools and traditional support) were evaluated through a 5-point Likert scale.ResultsOverall, 109 young urologists (26%) responded to the survey. Most of the respondents worked during their training in an academic hospital (n = 89, 82%). The three favorite tools for training chosen by the responders were: videos, workshop or masterclass, and podcasts (responders very interested were respectively n = 64 (58.7%), n = 50 (45.9%), and n = 49 (45%)). E-mail newsletters were reported as the less useful educational tool by participants (n = 38, 34.9%). Participants were very interested in improving their surgical skills and their radiological knowledge. Responders who were the most attracted by PCa were much more looking to improve their systemic treatment and radiological knowledges.ConclusionsUrologic-oncology was a priority regarding education for urologists in training. A majority of participants expressed a lack in their surgical education, revealing a reduced OR access and underlining utilization of new tools such as simulation. New digital contents such as social media or podcast achieved high interest for the participants, instead of more traditional media. There is a need that educational content evolve and uses new digital media., ButDans la formation médicale, les nouveaux médias de communication tels que les contenus numériques se développent très rapidement et tendent à remplacer les médias plus traditionnels. Notre objectif était d’évaluer les aspirations des urologues en matière de formation en onco-urologie.MatérielLes membres de l’Associations française des urologues en formation ont répondu à un questionnaire en ligne anonyme concernant leur formation en onco-urologie. L’intérêt des participants pour les différents moyens de formation ainsi que pour les spécialités d’organes ont été évalués avec une échelle de Likert à 5-points.RésultatsAu total, 109 urologues en formation ont répondu à l’enquête (26 %). La plupart ont effectué leur formation exclusivement dans un hôpital universitaire (n = 89, 82 %). Les trois outils de formation préférés des participants étaient : les supports vidéo, les ateliers ou masterclass, et les podcast (étaient très intéressés respectivement n = 64 (59 %), n = 50 (46 %) et n = 49 (45 %)). Les newsletters ont été considérées comme l’outil éducatif le moins utile (n = 39, 35 %). Les participants étaient très intéressés par l’amélioration de leurs compétences chirurgicales et de leurs connaissances radiologiques. Les participants qui s’intéressaient le plus au cancer de la prostate cherchaient à consolider leurs connaissances sur les traitements systémiques ainsi qu’en radiologie.ConclusionL’onco-urologie est une priorité pour les urologues en formation. Les nouveaux contenus numériques tels que les réseaux sociaux ou les podcasts ont suscité un grand intérêt chez les participants, supplantant les médias plus traditionnels. Il est nécessaire que le contenu éducatif évolue et se repose sur les nouveaux médias numériques.

Aim Optimal management of bladder cancer requires an accurate, standardised and timely pathological diagnosis, and close communication between surgeons and pathologists. Here, we provide an update on pathology reporting standards of transurethral resections of the bladder and cystectomies. Methods We reviewed recent literature, focusing on developments between 2013 and 2021. Results Published reporting standards developed by pathology organizations have improved diagnosis and treatment. Tumor sub-staging and subtyping has gained increased attention. Lymph nodes continue to be an area of debate, and their staging has seen minor modifications. Several tasks, particularly regarding specimen preparation (“grossing”), are not yet standardized and offer opportunity for improvement. Molecular classification is rapidly evolving, but currently has only limited impact on management. Conclusion Pathological reporting of bladder cancer is continuously evolving and remains challenging in some areas. This review provides an overview of recent major developments, with a particular focus on published reporting standards.

Purpose To evaluate the impact of COVID-19 pandemic on functional urology procedures in France. Methods A prospective study was conducted within 11 secondary and tertiary referral centers in France. Patients aged > 18 years who were diagnosed with a functional urology disease before the national lockdown (March 17th, 2020) and who required a surgery were included. Study period went from March 17th to September 30th 2020. The included interventions were listed according to the guidelines for functional urology enacted by the French Association of Urology and delay of reoperation was compared to the guidelines’ delay. The primary outcome was the number of procedures left unscheduled at the end of the study period. Descriptive statistics were performed. Results From March 17th 2020 to September 3 rd 2020, 1246 patients with a previous diagnosis of a functional urological disease requiring a surgery were included. The mean follow-up was 140.4 days (± 53.4). Overall, 316 interventions (25.4%) were maintained whereas 74 (5.9%) were canceled, 848 (68.1%) postponed and 8 patients (0.6%) died. At the end of the follow-up, 184 patients (21.7%) were still not rescheduled. If the intervention was postponed, the mean delay between the initial and final date was 85.7 days (± 64.4). Conclusion Overall, more than two thirds of interventions had to be postponed and the mean delay between the initial and final date was about three months.

International audience; Although vasopressin V1B receptor (V1BR) mRNA has been detected in the kidney, the precise renal localization as well as pharmacological and physiological properties of this receptor remain unknown. Using the selective V1B agonist d[Leu4, Lys8]VP, either fluorescent or radioactive, we showed that V1BR is mainly present in principal cells of the inner medullary collecting duct (IMCD) in the male rat kidney. Protein and mRNA expression of V1BR were very low compared with the V2 receptor (V2R). On the microdissected IMCD, d[Leu4, Lys8]VP had no effect on cAMP production but induced a dose-dependent and saturable intracellular Ca2+ concentration increase mobilization with an EC50 value in the nanomolar range. This effect involved both intracellular Ca2+ mobilization and extracellular Ca2+ influx. The selective V1B antagonist SSR149415 strongly reduced the ability of vasopressin to increase intracellular Ca2+ concentration but also cAMP, suggesting a cooperation between V1BR and V2R in IMCD cells expressing both receptors. This cooperation arises from a cross talk between second messenger cascade involving PKC rather than receptor heterodimerization, as supported by potentiation of arginine vasopressin-stimulated cAMP production in human embryonic kidney-293 cells coexpressing the two receptor isoforms and negative results obtained by bioluminescence resonance energy transfer experiments. In vivo, only acute administration of high doses of V1B agonist triggered significant diuretic effects, in contrast with injection of selective V2 agonist. This study brings new data on the localization and signaling pathways of V1BR in the kidney, highlights a cross talk between V1BR and V2R in the IMCD, and suggests that V1BR may counterbalance in some pathophysiological conditions the antidiuretic effect triggered by V2R activation.NEW & NOTEWORTHY Although V1BR mRNA has been detected in the kidney, the precise renal localization as well as pharmacological and physiological properties of this receptor remain unknown. Using original pharmaceutical tools, this study brings new data on the localization and signaling pathways of V1BR, highlights a cross talk between V1BR and V2 receptor (V2R) in the inner medullary collecting duct, and suggests that V1BR may counterbalance in some pathophysiological conditions the antidiuretic effect triggered by V2R activation.

Acute kidney injury (AKI) is a common complication observed in half of intensive care unit patients. Associated with a poor short-term outcome, AKI seems to be associated with an increased risk of chronic kidney disease (CKD) in survivors. Due to the diversity of pathophysiological processes involved in the development of AKI and the identification of risk factors that are mostly inaccessible to human intervention, the therapeutic management of AKI remains limited.The aim of this study is twofold: (1) to confirm the long-term impact of AKI and (2) to identify iatrogenic risk factors potentially involved in the development of AKI.We analysed several databases composed of ICU patients and used statistical methods adapted to the longitudinal format and the competition situation.We identified AKI as an independent factor in the occurrence of CKD. Among the risk factors analysed, we found an impact of invasive mechanical ventilation via positive end-expiratory pressure, central venous pressure and hypercapnia on the risk of developing AKI. We observed that trajectories of chloremia, in particular increasing ones, were more associated with AKI. We reported for the first time the negative renal impact of amoxicillin urinary crystal.In total, our work has confirmed the long-term renal impact of AKI, including in patients who recover their renal function at discharge. Among the therapeutic interventions performed in the ICU: mechanical ventilation, changes in blood chloride levels and the use of high-dose antibiotics seem to increase the risk of renal failure., L'insuffisance rénale aiguë (IRA) est une complication observée chez 50% des patients admis en réanimation. Impactant fortement le pronostic à court terme, l'IRA semble aussi associé à un sur risque de maladie rénale chronique (MRC). Du fait de l'importante diversité des processus physiopathologiques impliqués dans le développement de l'IRA et l'identification de facteur de risque majoritairement non accessibles à une intervention humaine, la gestion thérapeutique de l'IRA reste à ce jour limitée.L'objectif de ce travail est double : (1) confirmer l'impact à long terme de l'IRA et (2) identifier des facteurs de risque iatrogène potentiellement impliqué dans le développement de l'IRA. Pour cela, plusieurs bases de données composées essentiellement de patients admis en unité de soins critiques ont été analysée à partir de méthodes statistiques adaptées au format longitudinal de certaines covariables et à la situation de compétition.Nous avons identifié que l'IRA est un facteur indépendant de survenue de MRC. Parmi les facteurs de risque analysés, nous avons mis en évidence un impact de la ventilation mécanique invasive via la pression expiratoire positive, la pression veineuse centrale et l'hypercapnie sur le risque de développer une IRA. Nous avons observé que certaines trajectoires de chlorémie, en particulier celles croissantes étaient plus associées à l'IRA. Nous avons rapporté pour la 1ère fois l'impact négatif au niveau rénal de la formation de critaux d'amoxicilline.Au total, notre travail a permi de confirmer l'impact renal à long terme de l'IRA y compris chez les patients récupérant ad integrum une fonction rénale. Parmi les interventions thérapeutiques réalisées en réanimation : la ventilation mécanique, les modifications de chlorémie et l'utilisation de forte dose d'antibiotiques semblent majorer le risque de défaillance rénale.

International audience; Low Dose Rate Brachytherapy (LDR-BT) is a technique for treating localized prostate cancer by implanting radioactive seeds. In conventional practice, the delivery of seeds is performed using transrectal ultrasonography (TRUS) imaging for implant guidance and checked using computed-tomography for post-implant dosimetry. In the case of TRUS, accuracy can be compromised due to sub-optimal imaging. Magnetic Resonance Imaging (MRI), however, is known to provide better soft-tissue contrast, therefore, increasing the ability to detect small lesions; for that reason, the integration of intraoperative MRI in BT workflows has been investigated over the last two decades. The fusion of preoperative MR-images during TRUS-brachytherapy is possible. However, the image registration process introduces a source of uncertainty. Manual, real-time intra-operative LDR-BT is challenging under MRI due to confined space and procedural workflows. This motivates the development of MRI-compatible robots for prostate BT, with potential advantages of improved source placement accuracy and final dosimetry. In this paper, the state-of-art of technological components in MRI compatible robots, especially for LDR-BT, has been presented. This systematic review helps us to position an ongoing Cooperative Brachytherapy project, developing a real-time MRI-guided robot for adaptive LDR-BT. The design approach includes integrating separate modules: imaging, dose planning, needles, and robot.

International audience; Monoclonal gammopathies of renal significance (MGRS) encompass a remarkable variety of kidney diseases that result from intrinsic nephrotoxic properties of certain monoclonal Igs or their subunits. Effective disease-modifying treatments rely on the targeting of a malignant B-cell clone that may be demonstrable but often is quite hypothetical. Hence, convincing arguments for the genuine monoclonal character of the causative mono-isotypic Ig tissue deposits is needed for design of appropriate treatment strategies. The purpose of this article was to critically analyze distinct situations of suspected MGRS that occur in the practice of pathologists, nephrologists, hematologists, and immunologists. A particular focus of interest is the group of conditions known as proliferative glomerulonephritis with mono-isotypic immunoglobulin deposits (PGNMIDs), which illustrates the difficulties and ambiguities surrounding a definitive assignment of MGRS status.

To compare transcorporal vs bulbar artificial urinary sphincter (AUS) implantation in men with fragile urethra and to investigate the risk factors of AUS explantation in this population. The charts of all male patients who had an AUS implantation between 2004 and 2020 in 16 centers were reviewed retrospectively. The primary endpoint was device explantation-free survival. Only patients with a fragile urethra were included in the present analysis. Fragile urethra was defined as a urethra carrying a high risk of cuff erosion because of prior radiotherapy and/or history of AUS explantation and/or history of urethral stricture surgery. The patients were divided in two groups according to the implantation site: bulbar vs transcorporal. 464 patients were included for analysis. 88 patients underwent a transcorporal AUS implantation and 376 underwent a bulbar AUS implantation. Explantation-free survival was similar in both groups (estimated 5-year explantation free survival rates 55.3% vs. 58.4%; p=0.98). In the subgroup of patients with a history of previous AUS explantation, transcorporal approach tended to bring longer explantation-free survival (2-year explantation-free survival: 61.9% vs. 58.2%; p=0.096). In multivariate analysis, the only risk factor of shorter explantation-free survival was the history of previous AUS explantation (HR=2.65; p=0.01). Transcorporal AUS implantation was not associated with longer explantation-free survival. History of previous AUS explantation was the only risk factor associated with shorter explantation-free survival and this subgroup of patients may be the only one to draw benefits of transcorporal AUS implantation.

International audience; Background: Long-term psychosocial outcomes and health-related quality of life (HRQOL) in adults with pediatric onset of frequently relapsing or steroid-dependent idiopathic nephrotic syndrome (FRNS or SDNS) remain to be determined.Methods: In this prospective cohort study, 59 adults with pediatric onset of FRNS/SDNS and persistent active glomerular disease in adulthood completed the GEDEPAC-2 questionnaire exploring 11 well-being domains. Data were compared to the French general population (FGP) with standardized incidence ratio ([SIR]; adjusted for period, age, gender). Regression models were performed to identify predictive factors of psychosocial well-being.Results: In 82% of cases, the questionnaire was completed while the participants (n = 59; 47 men; median age = 32 years; median number of relapses = 13) were in complete remission (under specific therapy in 76% of cases). Participants had higher educational degree than in the FGP (SIR = 6.3; p < 0.01) and more frequently a managerial occupation (SIR = 3.1; p < 0.01). Social integration was acceptable with regard to marital status and experience of sexual intercourse, but experiences of discrimination were far more frequent (SIR = 12.5; p < 0.01). The SF-12 mental component summary (MCS) score was altered (Z-score = - 0.6; p < 0.01) and mean multidimensional fatigue inventory (MFI-20) global fatigue score appeared high (12). Transfer from pediatric to adult healthcare was followed by a period of discontinued care for 33% of participants. Multivariate analysis revealed a close relationship between MFI-20, physical health, and MCS.Conclusions: This study shows that pediatric onset FRNS and SDNS may have a long-term negative impact on mental HRQOL and highlights the impact of fatigue, which is often not adequately considered in routine care.

International audience; Exostosin (EXT) 1 and EXT2 proteins are recently discovered major components of the subepithelial deposits in a subset of patients with membranous nephropathy (MN).1,2 Although the detection of EXT1/2 seems to be a distinctive feature of MN related to systemic lupus erythematosus (SLE),1 the exact frequency of EXT-positive, SLE-associated MN (SLE-MN) and its potential clinical significance are not well determined.Here, we retrospectively evaluated 86 consecutive patients with biopsy-proven pure class 5 SLE-MN diagnosed between January 2010 and December 2018 in 2 nephropathology centers (La Pitié Salpêtrière and Tenon hospitals) in Paris, France; mixed classes (3 + 5 and 4 + 5 of the 2003 ISN/Renal Pathology Society classification)3 were excluded.

Context Understanding men’s values and preferences in the context of personal, physical, emotional, relational, and social factors is important in optimising patient counselling, facilitating treatment decision-making, and improving guideline recommendations. Objective To systematically review the available evidence regarding the values, preferences, and expectations of men towards the investigation and treatment (conservative, pharmacological, and surgical) of male lower urinary tract symptoms (LUTS). Evidence acquisition We searched electronic databases until August 31, 2020 for quantitative and qualitative studies that reported values and preferences regarding the investigation and treatment of LUTS in men. We assessed the quality of evidence and risk of bias using the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) and GRADE Confidence in the Evidence from Reviews of Qualitative Research (CERQual) approaches. Evidence synthesis We included 25 quantitative studies, three qualitative studies, and one mixed-methods study recruiting 9235 patients. Most men reported urodynamic testing to be acceptable, despite discomfort or embarrassment, as it significantly informs treatment decisions (low certainty evidence). Men preferred conservative and less risky treatment options, but the preference varied depending on baseline symptom severity and the risk/benefit characteristics of the treatment (moderate certainty). Men preferred pharmacological treatments with a low risk of erectile dysfunction and those especially improving urgency incontinence (moderate certainty). Other important preference considerations included reducing the risk of acute urinary retention or surgery (moderate certainty). Conclusions Men prefer lower-risk management options that have fewer sexual side effects and are primarily effective at improving urgency incontinence and nocturia. Overall, the evidence was rated to be of low to moderate certainty. This review can facilitate the treatment decision-making process and improve the trustworthiness of guideline recommendations. Patient summary We thoroughly reviewed the evidence addressing men’s values and preferences regarding the management of urinary symptoms and found that minimising adverse effects is particularly important. Further research to understand other factors that matter to men is required.

International audience; There are no countrywide data regarding the utilization of same-day-discharge (SDD) surgery for robot-assisted radical prostatectomy (RARP). We aimed to evaluate the annual number of SDD RARP procedures in France and to compare postoperative outcomes in SDD versus non-SDD centers. Data for all 9651 patients undergoing RARP in France in 2020 were extracted from the central database of the national healthcare system. Endpoints were length of hospital stay, patient age, center volume, lymph node dissection, and the hospital readmission rate. Overall, 184 SDD cases (1.9%) were reported in 14.2% of RARP centers. The annual RARP and SDD RARP caseload ranged from 41 to 485, and from one to 47, respectively, in SDD centers. SDD was significantly associated with higher-volume centers (p < 0.001). No difference in readmission rate (7.9% vs 5.1%; p = 0.141) was observed for SDD versus non-SDD centers. Direct stay costs were estimated at €1457 in SDD centers compared to €2021 in non-SDD centers. The main limitation is the lack of detailed patient characteristics and readmission causes. This annual nationwide analysis suggests that SDD RARP remains infrequently used in routine practice in France despite being associated with comparable short-term outcomes after RARP and potential cost benefits. Patient summary: We evaluated the use of robot-assisted removal of the prostate (RARP) with same-day hospital discharge in France for men with prostate cancer. In 2020, only 1.9% of the 9651 RARP procedures involved same-day discharge, even though the data show that this approach has lower costs and comparable safety.

International audience; The kidneys, by equilibrating the outputs to the inputs, are essential for maintaining constant the volume, pH and electrolyte composition of the internal milieu. Inability to do so, either because of an internal kidney dysfunction (primary alteration) or because some external factors (secondary alteration) would lead to pathologies, more or less severe, leading to modification of these parameters and affecting the functions of other organs. Alterations of the functions of the collecting duct (CD), the most distal part of the nephron, have been extensively studied and have led to a better diagnosis, a better management of the related diseases and the development of therapeutic tools. Thus, dysfunctions of principal cells specific transporters such as ENaC or AQP2 or its receptors (mineralocorticoid or vasopressin receptors) caused by mutations or by compounds present in the environment (lithium, antibiotics…) has been demonstrated in a variety of syndromes (Liddle, pseudohypoaldosteronism type-1, diabetes insipidus…) affecting salt, potassium and water balance. In parallel, studies of specific transporters (H+-ATPase, anion exchanger 1) in intercalated cells as revealed the mechanisms of related tubulopathies like distal renal distal tubular acidosis or Sjögren syndrome.In this review, we will recapitulate the mechanisms of most of the primary and secondary alteration of the ion transport system of the CD to provide a better understanding of these diseases and highlight how a targeted perturbation may affect many different pathways due to the strong crosstalk and entanglements between the different actors (transporters, cell types).

International audience; A recent article described a thickening of the glomerular basement membrane (GBM) along with changes in the expression of key components of the extracellular matrix in 6-month-old NPHS2-Cre transgenic mice, which express the Cre recombinase specifically in podocytes. This transgenic line has been widely used to characterize the implication of candidate genes in glomerular diseases in younger mice. Using a different mouse strain (C57BL/6J) than the previous report (129S6/SvEvTac), we sought to characterize 3- and 6-month-old NPHS2-Cre+/- mice in control and pathological conditions. At baseline, there was no difference in renal function and histology between control and NPHS2-Cre+/- mice. Notably, GBM thickness evaluated by transmission electron microscopy was similar between the two groups. We then induced an immune-mediated severe glomerular insult, the anti-glomerular basement membrane glomerulonephritis model (anti-GBM-GN) in 3-month-old control and NPHS2-Cre+/- mice. NPHS2-Cre+/- mice exhibited the same alterations in renal function and structure as control mice. In summary, our study strongly suggests that NPHS2-Cre+/- transgenic mice on a C57BL/6J background can be safely used for podocyte-specific gene inactivation in control conditions and in the anti-GBM-GN model.

Background Myostatin and activin A induce muscle wasting by activating the ubiquitin proteasome system and inhibiting the Akt/mammalian target of rapamycin pathway. In chronic kidney disease (CKD), myostatin and activin A plasma concentrations are increased, but it is unclear if there is increased production or decreased renal clearance. Methods We measured myostatin and activin A concentrations in 232 CKD patients and studied their correlation with estimated glomerular filtration rate (eGFR). We analyzed the myostatin gene (MSTN) expression in muscle biopsies of hemodialysis (HD) patients. We then measured circulating myostatin and activin A in plasma and the Mstn and Inhba expression in muscles, kidney, liver and heart of two CKD mice models (adenine and 5/6 nephrectomy models). Finally, we analyzed whether the uremic toxin indoxyl sulfate (IS) increased Mstn expression in mice and cultured muscle cells. Results In patients, myostatin and activin A were inversely correlated with eGFR. MSTN expression was lower in HD patients’ muscles (vastus lateralis) than in controls. In mice with CKD, myostatin and activin A blood concentrations were increased. Mstn was not upregulated in CKD mice tissues. Inha was upregulated in kidney and heart. Exposure to IS did not induce Mstn upregulation in mouse muscles and in cultured myoblasts and myocytes. Conclusion During CKD, myostatin and activin A blood concentrations are increased. Myostatin is not overproduced, suggesting only an impaired renal clearance, but activin A is overproduced in the kidney and heart. We propose to add myostatin and activin A to the list of uremic toxins.

The present study aimed to assess long-term functional outcomes of children with anorectal malformations (ARMs) across a network of expert centers in France.Retrospective cross-sectional study of patients ages 6-30 years that had been surgically treated for ARM. Patient and ARM characteristics (eg, level, surgical approach) and functional outcomes were assessed in the different age groups.Among 367 patients, there were 155 females (42.2%) and 212 males (57.8%), 188 (51.2%) cases with, and 179 (48.8%) higher forms without, perineal fistula. Univariate and multivariate statistical analyses with logistic regression showed correlation between the level of the rectal blind pouch and voluntary bowel movements (odds ratio [OR] = 1.84 [1.31-2.57], P 0.001), or soiling (OR = 1.72 [1.31-2.25], P 0.001), which was also associated with the inability to discriminate between stool and gas (OR = 2.45 [1.28-4.67], P = 0.007) and the presence of constipation (OR = 2.97 [1.74-5.08], P 0.001). Risk factors for constipation were sacral abnormalities [OR = 2.26 [1.23-4.25], P = 0.01) and surgical procedures without an abdominal approach (OR = 2.98 [1.29-6.87], P = 0.01). Only the holding of voluntary bowel movements and soiling rates improved with age.This cross-sectional study confirms a strong association between anatomical status and functional outcomes in patients surgically treated for ARM. It specifically highlights the need for long-term follow-up of all patients to help them with supportive care.

Kidney transplant injury processes are associated with molecular changes in kidney tissue, primarily related to immune cell activation and infiltration. How these processes are reflected in the circulating immune cells, whose activation is targeted by strong immunosuppressants, is poorly understood. To study this, we analyzed the molecular alterations in 384 peripheral blood samples from four European transplant centers, taken at the time of a kidney allograft biopsy, selected for their phenotype, using RNA-sequencing. In peripheral blood, differentially expressed genes in 136 rejection and 248 no rejection samples demonstrated upregulation of glucocorticoid receptor and nucleotide oligomerization domain-like receptor signaling pathways. Pathways enriched in antibody-mediated rejection (ABMR) were strongly immune-specific, whereas pathways enriched in T cell-mediated rejection were less immune related. In polyomavirus infection, upregulation of mitochondrial dysfunction and interferon signaling pathways was seen. Next, we integrated the blood results with transcriptomics of 224 kidney allograft biopsies which showed consistently upregulated genes per phenotype in both blood and biopsy. In single-cell RNASeq (scRNASeq) analysis of seven kidney allograft biopsies, the consistently overexpressed genes in ABMR were mostly expressed by infiltrating leukocytes in the allograft. Similarly, in peripheral blood scRNASeq analysis, these genes were overexpressed in ABMR in immune cell subtypes. Furthermore, overexpression of these genes in ABMR was confirmed in independent cohorts in blood and biopsy. Thus, our results highlight the immune activation pathways in peripheral blood leukocytes at the time of kidney allograft pathology, despite the use of current strong immunosuppressants, and provide a framework for future therapeutic interventions. ispartof: KIDNEY INTERNATIONAL vol:102 issue:1 pages:183-195 ispartof: location:United States status: published

BACKGROUND: Published algorithms for identifying chronic kidney disease in healthcare claims databases have poor performance except in patients with renal replacement therapy. We propose and describe an algorithm to identify all stage chronic kidney disease in a French healthcare claims databases and assessed its performance by using data from the Renal Epidemiology and Information Network registry and the French Childhood Cancer Survivor Study cohort.METHODS: A group of experts met several times to define a list of items and combinations of items that could be related to chronic kidney disease. For the French Childhood Cancer Survivor Study cohort, information on confirmed chronic kidney disease cases extracted from medical records was considered the gold standard (KDIGO definition). Sensitivity, specificity, and positive and negative predictive value and kappa coefficients were estimated. The contribution of each component of the algorithm was assessed for 1 and 2 years before the start of renal replacement therapy for confirmed end-stage kidney disease in the Renal Epidemiology and Information Network registry.RESULTS: The algorithm’s sensitivity was 78%, specificity 97.4%, negative predictive value 98.4% and positive predictive value 68.7% in French Childhood Cancer Survivor Study cohort and the kappa coefficient was 0.79 for agreement with the gold standard. The algorithm 93.6% and 55.1% of confirmed incident end-stage kidney disease cases from the Renal Epidemiology and Information Network registry when considering 1 year and 2 years, respectively, before renal replacement therapy start.CONCLUSIONS: The algorithm showed good performance among younger patients and those with end-stage kidney disease in the twol last years prior to renal replacement therapy. Future research will address the ability of the algorithm to detect early chronic kidney disease stages and to classify the severity of chronic kidney disease., Contexte: Les algorithmes publiés pour identifier les patients avec une maladie rénale chronique (MRC) dans les bases de données médico-administratives ont de mauvaises performances, sauf chez les patients traités par suppléance. Nous proposons et décrivons un algorithme permettant d’identifier les patients MRC de tout stade dans la base française du Système National de Données de Santé et d’évaluer sa performance en utilisant les données du registre du Réseau d’épidémiologie et d’information rénales (REIN) et de la cohorte Français Childhood Cancer Survivor Study (FCCSS).Méthodes : Un groupe d’experts s’est réuni à plusieurs reprises pour définir une liste de variables et des combinaisons variables qui pourraient être liés à la MRC. Pour la cohorte FCCSS, l’information sur les cas confirmés de MRC extraits des dossiers médicaux a été considérée comme la référen (définition de KDIGO). La sensibilité, la spécificité et les coefficients de prédiction positifs et négatifs (PPV, VAN) et kappa ont été estimés. La contribution de chaque composante de l’algorithme a été évaluée à 1 et 2 ans avant le début de la suppléance à partir du registre REIN.Résultats : La sensibilité de l’algorithme était de 78%, la spécificité de 97,4%, la VPN de 98,4% et la VPP de 68,7% dans la cohorte FCCSS et le coefficient kappa était de 0,79 pour l’accord avec la référence. L’algorithme a permis de détecter 93,6% et 55,1% des cas incidents du registre REIN en considérant 1 an et 2 ans, respectivement, avant le début de la suppléance.Conclusions : L’algorithme a montré de bonnes performances chez les patients plus jeunes et ceux atteints de MRC au cours des deux dernières années précédant la suppléance. Les recherches futures porteront sur la capacité de l’algorithme à détecter les premiers stades de l’IRC et à classer la gravité de l’IRC.

International audience; We describe herein the case of a 65-year-old patient on chronic hemodialysis with a medical history of idiopathic thrombocytopenia who experienced numerous episodes of severe thrombocytopenia with no specific diagnosis. Further analysis of the evolution of the platelet count showed that cyclic thrombocytopenia occurred after each injection of recombinant erythropoietin (rHu-EPO). Exploration of the involved mechanisms revealed the presence of a rHu-EPO-dependent anti-GPIV/IIIb antibody associated with a significant increase in GPIV/IIIb expression on her platelets after the addition of rHu-EPO. EPO was discontinued and the patient was treated with roxadustat with favorable results on her hemoglobin and platelet counts.

International audience; Rationale: Automated peritoneal dialysis (APD) treatment for end-stage kidney disease affords patients a degree of autonomy in everyday life. Clinical investigations of their energy expenditure (EE) are usually based on resting EE, which could mask day and night variations in EE. The aim of this study, therefore, was to compare the components of EE in APD patients and healthy control (C) subjects.& nbsp; Material and method: Patients treated with APD for more than 3 months were compared with C volunteers matched for age and lean body mass (LBM). Biochemical analyses were performed and body composition was determined by DEXA to adjust EE to LBM. Total EE, its different components and respiratory quotients (RQ) were measured by a gas exchange method in calorimetric chambers. Spontaneous total and activity-related EE (AEE) were also measured in free-living conditions over 4 days by a calibrated accelerometer and a heart rate monitor.& nbsp; Results: APD (n = 7) and C (n = 7) patients did not differ in age and body composition. REE did not differ between the two groups. However, prandial increase in EE adjusted for dietary energy intake was higher in APD patients (+57.5 +/- 12.71 kcal/h) than in C subjects (+33.8 +/- 10.5 kcal/h, p = 0.003) and nocturnal decrease in EE tended to be lower in APD patients undergoing dialysis sessions (- 4.53 +/- 8.37 kcal/h) than in subjects (- 11.8 +/- 7.69 kcal/h, p = 0.059). Resting RQ (0.91 +/- 0.09 vs 0.81 +/- 0.04, p = 0.032) and nocturnal RQ (0.91 +/- 0.09 vs 0.81 +/- 0.04, p = 0.032) were significantly higher in APD patients, indicating a preferential use of glucose substrate potentially absorbed across the peritoneum. AEE was lower in APD patients (595.9 +/- 383.2 kcal/d) than in C subjects (1205.2 +/- 370.5 kcal/d, p = 0.011). In contrast, energy intakes were not significantly different (1986 +/- 465 vs 2083 +/- 377 kcal/d, p = 0.677).& nbsp; Conclusion: Although the two groups had identical resting EE, APD patients had a higher prandial increase in EE, a lower activity-related EE and higher resting and nocturnal RQ than healthy subjects. (C)& nbsp;2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism

Introduction Childhood IgA nephropathy (cIgAN) is a primary glomerulonephritis clinically characterized by microscopic hematuria and proteinuria, the presence of which may potentially overlap with Alport syndrome. Interestingly, earlier studies suggested that familial IgAN could be linked to the chromosome 2q36 region, also the coding region for collagen type 4 alpha 3/4 (COL4A3/A4). Methods To investigate a possible relationship or phenocopy between Alport syndrome and cIgAN, COL4A3, COL4A4, and COL4A5 exons were sequenced in 36 cIgAN patients. Clinical data and treatment were collected retrospectively. COL4A3/A4/A5 variants were classified according to American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) guidelines. Results Four of 36 cIgAN patients were affected by ACMG class 4/5 COL4A3 heterozygous variants (COL4A3-cIgAN). We found no COL4A4 or COL4A5 variant. Despite having rare and deleterious COL4A3 variants, 3 of 4 COL4A3-cIgAN children developed clinical and biologic features of active IgAN rather than Alport syndrome. Response to intensive immunosuppressive treatment was favorable, leading to a reduction of endocapillary and extracapillary proliferation lesions. High levels of immune immunoglobulin G and A (IgG/IgA) complexes, reduction of proteinuria, and gradual stabilization of estimated glomerular filtration rate (eGFR) argued against Alport syndrome. Nevertheless, COL4A3-cIgAN patients seemed predisposed to a more serious IgAN presentation compared with the non‒COL4A3-cIgAN group, with more glomerulosclerosis and a lower eGFR over time. One of the 4 patients underwent kidney transplant with subsequent IgAN recurrence. Conclusions Predisposition factors for developing serious cIgAN flare-up should be considered for cIgAN with COL4A3 pathologic heterozygous variants. COL4A3 variants, usually responsible for Alport syndrome in adults, should not automatically exclude an immunosuppressive regimen in cIgAN. Moreover, evidence of an ACMG class 4/5 COL4A3 variant in early-stage cIgAN could be a helpful tool for stratifying severity of cIgAN beyond the Oxford classification., Graphical abstract

International audience; Since the first attempt at extracorporeal renal replacement therapy, renal replacement therapy has been constantly improved. In the field of hemodialysis, substantial efforts have been made to improve toxin removal and biocompatibility. The advent of hemodiafiltration (HDF) and, more recently, of mid cut-off membranes have contributed to management of patients with end-stage renal disease (ESRD). Although several uremic toxins have been discovered, we know little about the clinical impact of their clearance in hemodialysis patients. In addition, a great deal of progress has been made in the areas of filtration and diffusion, but the adsorptive properties of hemodialysis membranes remain under-studied. The mechanism of action of adsorption is based on the attraction between the polymer of the dialysis membrane and the solutes, through hydrophobic interactions, ionic or electrostatic forces, hydrogen bonds or van der Waals forces. Adsorption on the dialysis membrane depends on the membrane surface, pore size, structure and electric load. Its involvement in toxin removal and biocompatibility is significant, and is not just an epiphenomenon. Diffusive and convective properties cannot be improved indefinitely and high permeability membranes, despite their high performance in the clearance of many toxins, have several limitations for long-term use in hemodialysis. This review will discuss why adsorption should be reconsidered and better characterized to improve efficiency and adequacy of dialysis.

Context: The role of overactive bladder (OAB) treatment in women beyond antimuscarinics has been evaluated extensively. Beta-3 agonists, botulinum toxin-A (BTX-A), and nerve stimulation are indicated in these patients. However, data on male patients in this clinical scenario are scarce.Objective: The aim of this systematic review was to evaluate the evidence on treatment options beyond antimuscarinics in men with OAB.Evidence acquisition: A search of PubMed, EMBASE, Scopus, Web of science, Cochrane Central Register of Controlled Trials, and Cochrane Central Database of Systematic Reviews databases was performed for relevant articles published between January 2000 and October 2020, using the following Medical Subject Headings: "male/man," "LUTS," "overactive bladder," "storage symptoms," "urgency," "nocturia," "incontinence," "beta-3 agonist," "PDE-5 inhibitors," "botulinum toxin," "sacral nerve stimulation/neurostimulation," "percutaneous/transcutaneous tibial nerve stimulation," "PTENS," and "combination therapy." Evidence acquisition was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. PROSPERO registration number is CRD42020201223.Evidence synthesis: Overall, 24 studies were retrieved. In male OAB, mirabegron (MIRA) is the most intensively investigated pharmacological option. A pooled analysis of five randomized clinical trials (RCTs), including 1187 patients, concluded that MIRA 50 mg was associated with a greater reduction in frequency versus placebo (-0.37, 95% confidence interval [CI]: -0.74, -0.01, p < 0.05). A pooled analysis of three RCTs, including 1317 male patients, has also shown that the addition of MIRA 50 mg in men receiving the alpha(1)-blocker tamsulosin improved the mean number of micturitions per day (-0.27, 95% CI: -0.46 to -0.09, p < 0.05), urgency episodes (-0.50, 95% CI: -0.77 to -0.22, p < 0.05), total OAB symptom score (-0.66, 95% CI: -1.00 to -0.38, p < 0.05), and mean volume voided (+10.76 ml, 95% CI: 4.87-16.64, p < 0.05). MIRA treatment is well tolerated in men. Other pharmacological treatment options, such as phosphodiesterase-5 (PDE-5) inhibitors, should be considered investigational. BTX-A seems to be effective as third-line treatment in male OAB patients. A higher rate of intermittent self-catheterization (5-42%) is observed in male than in female patients. Data on nerve stimulation are scarce.Conclusions: MIRA has the most robust data in terms of safety and efficacy in this patient population. Preliminary data in men suggest that BTX-A is indicated as an interventional treatment. Evidence for PDE-5 inhibitors and nerve stimulation is too limited to provide recommendations. Future studies in this population should aim to better define the best treatment sequence and to identify predictors for treatment response and failure, to determine a therapeutic approach tailored to patients' characteristics.Patient summary: Overactive bladder is highly prevalent in men. Mirabegron 50 mg is the treatment option supported by the highest level of evidence when antimuscarinics failed. Botulinum toxin A injections seems to be an effective treatment as interventional option. Roles of nerve stimulation and phosphodiesterase inhibitors in male OAB patients are still to be defined. (C) 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.

BACKGROUND We seek to evaluate whether ischemia extent (unilateral or bilateral) impacts spatiotemporal and neuromuscular gait parameters differently in patients with peripheral arterial disease and presenting intermittent claudication (PAD-IC). METHODS Two groups of PAD-IC patients: unilateral (Unilat-IC; n = 15), bilateral (Bilat-IC; n = 15) and a group of control subjects with similar risk factors (n = 15) were evaluated during a constant load treadmill walking test. Spatiotemporal parameters and neuromuscular activation in tibialis anterior and gastrocnemius medialis were recorded. Patients were instructed to describe their pain during walking test, and three phases were analysed: pain-free, onset of pain and maximum pain in PAD-IC patients. FINDINGS Single leg stance in the asymptomatic leg of Unilat-IC increases and becomes higher than the symptomatic leg and the Bilat-IC legs at maximum pain. Step time is higher and cadence is lower in PAC-IC than in controls. Tibialis anterior activation peak in Unilat-IC continuously decreases between phases and becomes lower than in Bilat-IC during maximum pain. Tibialis anterior activation time is higher in Bilat-IC and in the asymptomatic leg than in the symptomatic of Unilat-IC during all the phases. Gastrocnemius medialis activation peak in Bilat-IC decreases with pain. Gastrocnemius medialis activation time in the symptomatic leg of Unilat-IC presents a significant decrease between pain-free and maximum pain phases. INTERPRETATION Ischemia impacts gait in PAD-IC patients differently according to its extent between legs compared to controls. Imbalance between legs in Unilat-IC induces compensatory mechanism and an asymmetrical pattern. Bilat-IC should not be simply considered as a 'double' Unilat-IC when evaluating gait.

We performed a post hoc analysis of data from phase 3 and 4 studies to evaluate the efficacy of silodosin 8mg in patients with severe lower urinary tract symptoms (LUTS) related to benign prostatic obstruction (BPO). The presence of two or more of the following criteria was adopted to define severity: total International Prostate Symptom Score (IPSS) 20-35, quality of life (QoL) score 5-6, maximum urinary flow

International audience; Abstract Several studies have reported WDR73 mutations to be causative of Galloway–Mowat syndrome, a rare disorder characterised by the association of neurological defects and renal-glomerular disease. In this study, we demonstrate interaction of WDR73 with the INTS9 and INTS11 components of Integrator, a large multiprotein complex with various roles in RNA metabolism and transcriptional control. We implicate WDR73 in two Integrator-regulated cellular pathways; namely, the processing of uridylate-rich small nuclear RNAs (UsnRNA), and mediating the transcriptional response to epidermal growth factor stimulation. We also show that WDR73 suppression leads to altered expression of genes encoding cell cycle regulatory proteins. Altogether, our results suggest that a range of cellular pathways are perturbed by WDR73 loss-of-function, and support the consensus that proper regulation of UsnRNA maturation, transcription initiation and cell cycle control are all critical in maintaining the health of post-mitotic cells such as glomerular podocytes and neurons, and preventing degenerative disease.