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Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical and genetic heterogeneity. Applied to one of the worldwide largest cohorts of patients with NPH, genetic analysis encompassing targeted and whole exome sequencing identified disease-causing variants in 600 patients from 496 families with a detection rate of 71%. Of 788 pathogenic variants, 40 known ciliopathy genes were identified. However, the majority of patients (53%) bore biallelic pathogenic variants in NPHP1. NPH-causing gene alterations affected all ciliary modules defined by structural and/or functional subdomains. Seventy six percent of these patients had progressed to kidney failure, of which 18% had an infantile form (under five years) and harbored variants affecting the Inversin compartment or intraflagellar transport complex A. Forty eight percent of patients showed a juvenile (5-15 years) and 34% a late-onset disease (over 15 years), the latter mostly carrying variants belonging to the Transition Zone module. Furthermore, while more than 85% of patients with an infantile form presented with extra-kidney manifestations, it only concerned half of juvenile and late onset cases. Eye involvement represented a predominant feature, followed by cerebellar hypoplasia and other brain abnormalities, liver and skeletal defects. The phenotypic variability was in a large part associated with mutation types, genes and corresponding ciliary modules with hypomorphic variants in ciliary genes playing a role in early steps of ciliogenesis associated with juvenile-to-late onset NPH forms. Thus, our data confirm a considerable proportion of late-onset NPH suggesting an underdiagnosis in adult chronic kidney disease.

BACKGROUND Tacrolimus pharmacokinetics in obese (Ob) patients has been poorly studied. In this article, the authors explored the impact of obesity on tacrolimus exposure in kidney transplant recipients (KTRs) and estimated a more suitable initial dosage in this population. METHODS A retrospective, observational, monocentric case-control study was performed in obese KTRs (BMI > 30 kg/m2) who received tacrolimus between 2013 and 2017 (initial dose: 0.15 mg/kg/d) (actual weight). Nonobese (Nob) controls (BMI

BACKGROUND AND AIMS Chronic kidney disease (CKD) is considered as a public health problem. Almost 20%–25% of patients with end-stage kidney disease have been reported with an undetermined kidney disease (UKD) in large national registry. Recent data have shown that the number of monogenic disease-causing variants among patients with CKD is about 20%–30%. Monogenic disease-causing variants are underdiagnosed. We performed whole exome sequencing on patients in our centre with UKD. METHOD All patients gave their written informed consent for genetic testing. Whole exome sequencing by next-generation sequencing was proposed in routine care practice to patient with UKD between January 2019 and December 2021. High and reproducible coverage achieved by our sequencing approach enabled copy-number variation (CNV) analysis. All patients with inconclusive biopsy results were included. Only one patient from the same pedigree was included. We excluded patients with a typical presentation of ADPKD, familial IgA nephropathy, patients with typical presentation of Gitelman or Bartter syndrome or established genetic diagnosis in the family. RESULTS A total of 211 adult patients were included (120 males) with a median age of 48 years (range 37–62 years). Of these, 50 patients were treated with haemodialysis, 34 patients had a kidney transplantation. A total of 156 had self-declared Caucasian. Consanguinity was reported by 12 patients and suspected in 11 patients. Family history of kidney disease was present in 108 patients with both first and second degree affected in 38 patients. Kidney biopsy were inconclusive in 62 patients. Kidney biopsy was impossible in 57 incidents patients with CKD during the study period. A WES was performed first to avoid kidney biopsy in nine patients. A negative genetic testing prior to the WES with gene panel has been performed in 31 patients. We detected 27 monogenic renal disorders in 73 patients with either pathogenic or likely pathogenic variants and 5 copy number variants among 211 patients (37%). The glomerular disease represent the first yielded diagnostic subgroup in which Alport diseases (COL4A3/4/5) represent the dominant diagnostic (COL4A4 n = 18; COL4A3 n = 12; COL4A5 n = 7; TTC21B n = 3; APOL1 = 2; INF2 n = 2; PAX2 n = 2; TRPC6 n = 2; TREX1 n = 1; COQ8B n = 1; NPHS1 n = 1). Tubulointerstitial diseases is the second yielded diagnostic subgroup (UMOD n = 7; NPHP1 n = 2; NPHP3 n = 1; CCL5 n = 1; HNF1B n = 1; CNM4 n = 1; KCNJ1 n = 1). Cystic disease and CAKUT is the third yielded diagnostic subgroup (PKHD1 n = 3; DNAJB11 n = 2; VHL n = 1; PKD1 n = 1; GREB1L n = 1; PBX1 n = 1). In addition, we find two patients with pathogenic complement variation (CFH et C3), one patient with TTR amyloidosis and one patient with familial renal glucosuria (SLC5A2). Six of the nine patients with WES first to avoid renal biopsy, have positive diagnostic (five Alport disease and one APOL1 nephropathy). Interestingly, one of these nine patients had a WES for nephrotic syndrome during type-I diabetes and a dialysis sister with undetermined glomerular disease and consanguineous parents, which detected a known variation in TTC21B gene (P209L) at a heterozygote state that did not explain the nephrotic syndrome. We performed Sanger sequencing for her sister and revealed the same variation at a homozygous state and explain her renal phenotype. Among 57 patients with impossible kidney biopsy, the WES was positive for 18 patients. The diagnostic yield of WES was higher in consanguineous patients (P = 0.04) and familial history of kidney disease (P CONCLUSION WES identified a molecular diagnosis in almost 40% of patients with UKD in our centre. An exome first may have a high diagnostic yielded and avoid an invasive procedure like kidney biopsy or when it is impossible. WES must be included as a standard of care for patients with UKD.

International audience; End stage kidney disease increase the risk of COVID-19 related death but how the kidney replacement strategy should be adapted during the pandemic is unknown. Chronic hemodialysis makes social distancing difficult to achieve. Alternatively, kidney transplantation could increase the severity of COVID-19 due to therapeutic immunosuppression and contribute to saturation of intensive care units. For these reasons, kidney transplantation was suspended in France during the first epidemic wave. Here, we retrospectively evaluated this strategy by comparing the overall and COVID-19 related mortality in kidney transplant recipients and candidates over the last three years. Cross-interrogation of two national registries for the period 1 March and 1 June 2020, identified 275 deaths among the 42812 kidney transplant recipients and 144 deaths among the 16210 candidates. This represents an excess of deaths for both populations, as compared with the same period the two previous years (mean of two previous years: 253 in recipients and 112 in candidates). This difference was integrally explained by COVID-19, which accounted for 44% (122) and 42% (60) of the deaths in recipients and candidates, respectively. Taking into account the size of the two populations and the geographical heterogeneity of virus circulation, we found that the excess of risk of death due to COVID-19 was similar for recipients and candidates in high viral risk area but four-fold higher for candidates in the low viral risk area. Thus, in case of a second epidemic wave, kidney transplantation should be suspended in high viral risk areas but maintained outside those areas, both to reduce the excess of deaths of candidates and avoid wasting precious resources.

International audience

International audience; There are no studies which have compared the risk of severe Covid-19 and related mortality between transplant recipients and non-transplant patients. We enrolled two groups of patients hospitalized for Covid-19, i.e., kidney transplant recipients from the French Registry of Solid Organ Transplant (n=306) and a single-center cohort of non-transplant patients (n=795). An analysis was performed among subgroups matched for age and risk factors for severe Covid-19 or mortality. Severe Covid-19 was defined as admission (or transfer) to an intensive care unit, need for mechanical ventilation, or death.Transplant recipients were younger and had more comorbidities compared to non-transplant patients. They presented with higher creatinine levels and developed more episodes of acute kidney injury. After matching, the 30-day cumulative incidence of severe Covid-19 did not differ between KTR and non-transplant patients; however, 30-day Covid-19-related mortality was significantly higher in KTR (17.9% versus 11.4%, respectively, p=0.038). Age >60 years, cardiovascular disease, dyspnea, fever, lymphopenia, and C-reactive protein (CRP) were associated with severe Covid-19 in univariate analysis, whereas transplant status and serum creatinine levels were not. Age >60 years, hypertension, cardiovascular disease, diabetes, CRP >60 mg/L, lymphopenia, kidney transplant status (HR=1.55), and creatinine level >115 µmol/L (HR=2.32) were associated with Covid-19-related mortality in univariate analysis. In multivariable analysis, cardiovascular disease, dyspnea, and fever were associated with severe disease, whereas age >60 years, cardiovascular disease, dyspnea, fever, and creatinine level>115 µmol/L retained their independent associations with mortality. Kidney transplant recipients had a higher Covid-19-related mortality compared to non-transplant hospitalized patients.

Notwithstanding the ongoing coronavirus disease-2019 (Covid-19) pandemic, information on its clinical presentation and prognosis in recipients of a kidney transplant remain scanty. The aim of this registry-based observational study was to explore characteristics and clinical outcomes of recipients of kidney transplants included in the French nationwide Registry of Solid Organ Transplant Recipients with Covid-19. Covid-19 was diagnosed in symptomatic patients who had a positive PCR assay for SARS-CoV-2 or having typical lung lesions on imaging. Clinical and laboratory characteristics, management of immunosuppression, treatment for Covid-19, and clinical outcomes (hospitalization, admission to intensive care unit, mechanical ventilation, or death) were recorded. Risk factors for severe disease or death were determined. Of the 279 patients, 243 were admitted to hospital and 36 were managed at home. The median age of hospitalized patients was 61.6 years; most had comorbidities (hypertension, 90.1%; overweight, 63.8%; diabetes, 41.3%; cardiovascular disease, 36.2%). Fever, cough, dyspnea, and diarrhea were the most common symptoms on admission. Laboratory findings revealed mild inflammation frequently accompanied by lymphopenia. Immunosuppressive drugs were generally withdrawn (calcineurin inhibitors: 28.7%; antimetabolites: 70.8%). Treatment was mainly based on hydroxychloroquine (24.7%), antiviral drugs (7.8%), and tocilizumab (5.3%). Severe Covid-19 occurred in 106 patients (46%). Forty-three hospitalized patients died (30-day mortality 22.8%). Multivariable analysis identified overweight, fever, and dyspnea as independent risk factors for severe disease, whereas age over 60 years, cardiovascular disease, and dyspnea were independently associated with mortality. Thus, Covid-19 in recipients of kidney transplants portends a high mortality rate. Proper management of immunosuppression and tailored treatment of this population remain challenging., Graphical abstract

BackgroundCoronavirus disease 2019 (COVID-19) is an emerging infectious disease, related to severe acute respiratory syndrome coronavirus 2 infection. Few data are available in patients with end-stage renal disease (ESRD).MethodsWe conducted an observational cohort study of COVID-19 patients at 11 dialysis centres in two distinct districts of France to examine the epidemiological and clinical characteristics of COVID-19 in this population, and to determine risk factors of disease severity (defined as a composite outcome including intensive care unit admission or death) and mortality.ResultsAmong the 2336 patients enrolled, 5.5% had confirmed COVID-19 diagnosis. Of the 122 patients with a follow-up superior to 28 days, 37% reached the composite outcome and 28% died. Multivariate analysis showed that oxygen therapy on diagnosis and a decrease in lymphocyte count were independent risk factors associated with disease severity and with mortality. Chronic use of angiotensin II receptor blockers (ARBs) (18% of patients) was associated with a protective effect on mortality. Treatment with azithromycin and hydroxychloroquine (AZT/HCQ) (46% of patients) were not associated with the composite outcome and with death in univariate and multivariate analyses.ConclusionsCOVID-19 is a severe disease with poor prognosis in patients with ESRD. Usual treatment with ARBs seems to be protective of critical evolution and mortality. There is no evidence of clinical benefit with the combination of AZT/HCQ.

Classically, kidney transplantation (KT) consists of heterotopic implantation of the renal graft in the iliac fossa with vascular anastomosis on the iliac vessel and reimplantation of the graft ureter in the bladder of the recipient. However, a wide range of variations exist in both vascular anastomosis and urinary diversion that the non-transplant surgeon should know. For any pelvic surgery in a KT patient, the non-transplant surgeon should preoperatively evaluate the anatomy of the graft, its vascularization and its urinary tract. The transplant ureter should be identified and secured by preoperative JJ stenting whenever needed. For any surgery, maintenance and control of both immunosuppressive treatment and renal function is crucial. The advice or even the assistance of a transplant surgeon should be required because any damage to vascularization or urinary drainage of the renal graft could have dramatic and definitive consequences on graft function.

Las estenosis del ureter son un problema frecuente en urologia. La diversidad de los tipos de estenosis, unicas o multiples, largas o cortas, intrinsecas o extrinsecas, refleja la variedad de las etiologias de estenosis ureterales (iatrogenicas, postirradiacion, traumaticas, infecciosas, extrinsecas, etc.). El diagnostico de una obstruccion es facil en caso de estenosis completa, pero puede ser mas dificil en caso de estenosis intermitente o parcial. En esta ultima situacion, es preferible limitar el numero de pruebas complementarias. El objetivo del tratamiento es evitar una perdida de nefronas y la atrofia renal. A la diversidad de las etiologias y de los tipos de estenosis ureterales responde la pluralidad de las tecnicas de tratamiento, desde la endoscopia hasta la cirugia abierta o laparoscopica. La eleccion de la tecnica depende de la evaluacion de las capacidades de recuperacion del rinon, de las caracteristicas de la estenosis, de la etiologia de la estenosis, de la experiencia del cirujano y de la operabilidad del paciente. Asi, a pesar de una tasa de exito claramente inferior a la de la cirugia, la endoscopia permitiria tratar las estenosis ureterales cortas con una menor morbilidad. Para la cirugia abierta o laparoscopica hay diversas tecnicas: reimplantacion ureteral, reemplazo ileal, autotrasplante o nefrectomia. Es preciso conocer bien la anatomia del ureter y en particular su vascularizacion. El principio de la anastomosis sin tension es prioritario para aumentar las posibilidades de exito de esta cirugia.

International audience; Cyst infection is a common complication of autosomal dominant polycystic kidney disease (ADPKD). Diagnosis is challenging with standard imaging techniques. We aimed to evaluate the diagnostic performance of [F-18] fluorodeoxyglucose positron emission tomography-computed tomography (18-FDG PET-CT) for the diagnosis of cyst infections among ADPKD patients, in comparison with computed tomography (CT) and magnetic resonance imaging (MRI). All APKD patients who underwent 18-FDG PET-CT for suspected cyst infection between 2006 and 2013 in a French teaching hospital were included. Diagnosis of cyst infection was retained a posteriori on an index of clinical suspicion. 18-FDG PET-CT findings were was considered to be positive in cases of cyst wall hypermetabolism. CT or MRI findings were were considered to be positive in cases of cyst wall thickening (and enhancement if contrast medium was injected) and infiltration of the adjacent fat. A control group of ADPKD patients with 18-FDG PET-CT performed for other reasons was included. Thirty-two 18-FDG PET-CT scans were performed in 24 ADPKD patients with suspected cyst infection. A diagnosis of cyst infection was retained in 18 of 32 cases: 14 with positive 18-FDG PET-CT findings, and four false negatives. There were no false positives and no hypermetabolism of cyst walls in nine ADPKD control patients. 18-FDG PET-CT had a sensitivity of 77%, a specificity of 100%, and a negative predictive value of 77%. 18-FDG PET-CT allowed a differential diagnosis in three patients. In contrast, CT had a sensitivity of 7% and a negative predictive value of 35% (p < 0.001 vs. 18-FDG PET-CT). Only eight MRI scans were performed. The diagnostic performance of 18-FDG PET-CT is superior to that of CT in cyst infections, for comparable radiation doses and with no injection of nephrotoxic contrast medium, in ADPKD patients. (C) 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Introduction Durant la pandemie de COVID-19, peu d’informations concernant la presentation clinique et le pronostic de cette infection chez les patients transplantes d’organe ont ete rapportees. Description Nous avons mis en place un registre francais sous l’egide de la Societe francophone de transplantation pour recenser tous les cas de patients transplantes developpant une infection a SARS-CoV-2 a partir du 1er mars 2020. Methodes L’infection a ete diagnostiquee chez des patients avec un frottis positif en RT-PCR ou en presence de lesions pulmonaires typiques. Les caracteristiques cliniques et biologiques, la gestion de l’immunosuppression, le traitement du COVID-19 et l’evolution de la maladie ont ete colliges. La severite etait definie par : admission ou transfert en reanimation, ventilation mecanique ou deces. Resultats Sur les 279 patients transplantes renaux recenses dans le Registre, 243 ont ete admis a l’hopital et 36 ont ete pris en charge a domicile. L’âge des patients hospitalises etait de 61,6 ans et la plupart presentaient des comorbidites (hypertension : 90 % ; surpoids : 64 % ; diabete : 41 % ; maladies cardiovasculaires : 36 %). La fievre, la toux, la dyspnee et la diarrhee etaient les symptomes les plus frequents. Les anti-metabolites etaient interrompus dans 70,8 des cas. Le traitement a comporte de l’hydroxychloroquine dans 25 % des cas, un antiviral pour 7,8 % des patients et du tocilizumab chez 5,3 %. Des formes severes de COVID-19 sont survenues chez 106 patients (46 %). Quarante-trois patients sont decedes (taux de mortalite a 30 jours : 22,8 %). Une analyse multivariable a permis d’identifier le surpoids, la fievre et la dyspnee comme facteurs de risque independants de maladie severe, alors que l’âge > 60 ans, un antecedent de maladie cardiovasculaire et la dyspnee etaient independamment associes a la mortalite. Conclusion Les transplantes renaux developpant une infection a SARS-Cov-2 ont un taux de mortalite eleve. La bonne gestion de l’immunosuppression et une prise en charge adaptee restent un defi.

Objectifs L’endothelium allogenique du donneur constitue une interface entre le donneur et le receveur. Le vieillissement et les facteurs de risques cardiovasculaires presents dans le microenvironnement de ces transplants issus de donneurs marginaux contribuent a l’inflammation endotheliale et a la senescence vasculaire et peuvent avoir un effet deletere sur la reponse immunitaire du receveur ainsi que la fonction du greffon. Methodes La fraction vasculaire stromale (SVF) du tissu adipeux peri-renal (PRAT-SVF) preleve chez le donneur a ete isolee apres digestion enzymatique. Les cellules progenitrices endotheliales (ECFC) ont ete isolees par selection immuno-magnetique (CD144 + ) a partir de la PRAT-SVF prelevee chez 2 donneurs marginaux et 2 optimaux. Ces cellules ont ete amplifiees en culture. Le profil phenotypique et transcriptionnel des ECFC a ete etudie en cytometrie de flux et en qRT-PCR. Ces ECFC ont ete utilisees comme cibles pour evaluer l’activite endotheliotoxique d’anticorps circulants de receveurs presentant un rejet humoral, ainsi que l’effet pro-senescent des facteurs paracrines presents dans le liquide de perfusion de transplants marginaux. Resultats Ces travaux apportent une premiere preuve de faisabilite de l’isolement des cellules endotheliales de donneurs issues de PRAT-SVF. Ces cellules presentent un potentiel clonogenique d’expansion en culture ainsi qu’une expression des antigenes endotheliaux et HLA. Nous apportons ici la preuve que ces ECFC de SVF, amplifiees en culture, sont des cibles pertinentes permettant le depistage chez le receveur d’anticorps circulants anti-donneur et le monitoring d’anticorps anti-ABO lors de la desensibilisation humorale lors des transplantations ABO-incompatibles. Ces cellules endotheliales ont montre un profil inflammatoire et senescent accru en reponse a une stimulation par le liquide de perfusion de donneurs marginaux, montrant l’effet deletere du microenvironnement paracrine propre aux donneurs a criteres elargis. Conclusion Ce travail identifie une nouvelle strategie non invasive, qui utilise les ECFC issues de la PRAT-SVF comme un modele d’etude permettant d’indexer la reponse d’anticorps anti-endotheliaux en transplantation renale, et d’evaluer l’impact des facteurs paracrines qui caracterisent les donneurs marginaux sur la vulnerabilite vasculaire associee a la moindre survie de ces transplants.

Hepatitis E virus (HEV) genotype 3 is endemic in Europe and hyperendemic in southern France. Recent reports of a high prevalence of HEV RNA in blood donations and in culinary specialties from this geographical area confirmed the endemicity of HEV and sources of viral transmission in this geographical area. HEV causes acute and chronic hepatitis in solid organ transplant recipients. Since March 2012, we have implemented systematic HEV serological testing in our cohort of kidney transplant recipients (KTRs) in Marseille in southeastern France. The aim of our study was to assess HEV exposure in this cohort between March 2012 and May 2014. During these 27 months, we found that 39% of the patients who underwent kidney transplantation had an anti-HEV IgG response using a sensitive microplate enzyme immunoassay. This seroprevalence was approximately 43% at both 1 and 8 years after, using the same assay. In addition, systematic HEV serological testing detected 6 cases of HEV infection among 578 KTRs (1%) during the 27 months of the study, with 5 at an acute stage and 1 at a chronic stage. In conclusion, continuous HEV monitoring in this population is useful for better understanding the epidemiology of HEV in France, because these patients are a well-monitored population. Moreover, HEV monitoring in KTRs is clinically relevant because HEV represents a clinical threat in these patients. Nevertheless, HEV serological testing may be more fruitful for identifying HEV infections when performed in cases of biological liver abnormalities than when performed systematically.

International audience; Background: Nocardiosis is a rare disease with polymorphic presentations. The epidemiology and clinical presentation could change with the increasing number of immunocompromised patients. Methods: The medical records and microbiological data of patients affected by nocardiosis and treated at the university hospitals of Marseille between 2004 and 2014 were analyzed retrospectively. Results: The cases of 34 patients infected by Nocardia spp during this period were analyzed. The main underlying conditions were transplantation (n = 15), malignancy (n = 9), cystic fibrosis (n = 4), and immune disease (n = 3); no immunodeficiency condition was observed for three patients. No case of AIDS was observed. At diagnosis, 61.8% had received steroids for over 3 months. Four clinical presentations were identified, depending on the underlying condition: the disseminated form (50.0%) and the visceral isolated form (26.5%) in severely immunocompromised patients, the bronchial form (14.7%) in patients with chronic lung disease, and the cutaneous isolated form (8.8%) in immunocompetent patients. Nocardia farcinica was the main species identified (26.5%). Trimethoprim-sulfamethoxazole was prescribed in 68.0% of patients, and 38.0% underwent surgery. Mortality was 11.7%, and the patients who died had disseminated or visceral nocardiosis. Conclusions: The clinical presentation and outcome of nocardiosis depend on the patient's initial immune status and underlying pulmonary condition. Severe forms were all iatrogenic, occurring after treatments altering the immune system. (C) 2017 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

Background. Cytomegalovirus (CMV) antiviral drug resistance constitutes an increasing challenge in transplantation. Foscarnet is usually proposed when resistance for ganciclovir is suspected, but its use is limited by its nephrotoxicity. Case Presentation. We report a case of multiresistant CMV disease in a kidney transplant recipient. Foscarnet was prescribed after ganciclovir treatment failure in a patient with two mutations in the UL97 viral gene. Foscarnet induced biopsy-proven kidney crystal precipitation that resulted in severe acute transplant failure and nephrotic syndrome. Despite a large decrease in immunosuppression, CMV disease was not controlled and a salvage therapy with Brincidofovir (BCV), which is an oral lipid conjugate of cidofovir with limited nephrotoxicity, was attempted. Clinical and virological remission was observed after a 21-day course of BCV, despite mild and reversible liver toxicity. However, a new relapse could not be effectively cured by BCV due to a new mutation in the UL54 gene, which is known to confer resistance to cidofovir. A new course of foscarnet finally resulted in prolonged CMV remission. Herein, we present a review of foscarnet nephropathy cases in solid-organ transplanted patients. Conclusions. This unique case highlights the potential benefit of BCV use during resistant CMV infection, although mutations in the UL54 gene may limit its therapeutic efficacy. These findings need to be confirmed in clinical trials.

International audience; no abstract

International audience; no abstract

Background In kidney transplantation, the conditions of organ preservation following removal influence function recovery. Current static preservation procedures are generally based on immersion in a cold-storage solution used under atmospheric air (approximately 78 kPa N2, 21 kPa O2, 1 kPa Ar). Research on static cold-preservation solutions has stalled, and modifying the gas composition of the storage medium for improving preservation was considered. Organoprotective strategies successfully used noble gases and we addressed here the effects of argon and xenon on graft preservation in an established preclinical pig model of autotransplantation. Methods The preservation solution Celsior saturated with pure argon (Argon-Celsior) or xenon (Xenon-Celsior) at atmospheric pressure was tested versus Celsior saturated with atmospheric air (Air-Celsior). The left kidney was removed, and Air-Celsior (n = 8 pigs), Argon-Celsior (n = 8) or Xenon-Celsior (n = 6) was used at 4 °C to flush and store the transplant for 30 h, a duration that induced ischemic injury in our model when Air-Celsior was used. Heterotopic autotransplantation and contralateral nephrectomy were performed. Animals were followed for 21 days. Results The use of Argon-Celsior vs. Air-Celsior: (1) improved function recovery as monitored via creatinine clearance, the fraction of excreted sodium and tubulopathy duration; (2) enabled diuresis recovery 2–3 days earlier; (3) improved survival (7/8 vs. 3/8 pigs survived at postoperative day-21); (4) decreased tubular necrosis, interstitial fibrosis, apoptosis and inflammation, and preserved tissue structures as observed after the natural death/euthanasia; (5) stimulated plasma antioxidant defences during the days following transplantation as shown by monitoring the “reduced ascorbic acid/thiobarbituric acid reactive substances” ratio and Hsp27 expression; (6) limited the inflammatory response as shown by expression of TNF-alpha, IL1-beta and IL6 as observed after the natural death/euthanasia. Conversely, Xenon-Celsior was detrimental, no animal surviving by day-8 in a context where functional recovery, renal tissue properties and the antioxidant and inflammation responses were significantly altered. Thus, the positive effects of argon were not attributable to the noble gases as a group. Conclusions The saturation of Celsior with argon improved early functional recovery, graft quality and survival. Manipulating the gas composition of a preservation medium constitutes therefore a promising approach to improve preservation. Electronic supplementary material The online version of this article (doi:10.1186/s12967-016-0795-y) contains supplementary material, which is available to authorized users.

Introduction Les fortes doses parenterales de corticoides (ou boli) font partie de la premiere ligne de traitement des rejets aigus prouves histologiquement. Peu d’etudes ont evalue le rationnel de l’administration preemptive (avant les resultats histologiques) de boli de corticoides en cas de suspicion de rejet chez les transplantes renaux (TR). Patients/Materiels et methodes Nous avons mene une etude observationnelle retrospective monocentrique de suivi de cohorte, incluant tous les patients TR hospitalises au CHU de Marseille entre 2009 et 2014 presentant une insuffisance renale aigue (IRA) sans cause urologique, vasculaire, infectieuse ou toxique, indiquant une 1re ponction biopsie du transplant. Les caracteristiques cliniques, biologiques, immunologiques et anatomopathologiques ont ete recueillies a l’inclusion. La duree mediane de suivi etait de 49 [35–66] mois. Les TR qui ont recu de boli de corticoides preemptifs constituaient le groupe « strategie preemptive ». Observation/Resultats Deux-cent quarante-trois TR ont ete inclus, 17 % ont beneficie d’une « strategie preemptive ». Parmi eux 51 % ont recu des boli sans diagnostic final de rejet histologiquement prouve. En cas de rejet, la strategie preemptive etait associee a un gain median d’administration de boli de 5 jours. Dans le groupe « strategie preemptive », les facteurs associes au diagnostic de rejet histologiquement prouve etaient, d’une part, la severite de l’IRA (p = 0,002), et d’autre part, des caracteristiques immunologiques telles qu’un antecedent de rejet (p = 0,032), une immunisation anti-HLA contre le donneur (p = 0,041) ou un traitement immunosuppresseur moindre (p = 0,045). Il a ete observe dans les suites des boli de corticoides une incidence de 20 % de diabetes induits et 10 % de pneumocystoses. La strategie preemptive de boli de corticoides chez les patients avec diagnostic prouve de rejet n’etait pas independamment associee en analyse multivariee, a la survie du transplant censuree sur les deces bien que significative en analyse univariee (p = 0,002). Chez ces patients, les facteurs pronostiques independants de perte du transplant etaient la severite de l’IRA initiale (Hazard Ratio = 2,67 ; p = 0,001) et un diagnostic de rejet medie par anticorps (Hazard Ratio = 1,43 ; p = 0,012). Discussion Il s’agit d’une etude retrospective. Neanmoins il s’agit a notre connaissance de la premiere etude ayant analyse l’impact de la prescription preemptive de boli de corticoides, a l’ere de la definition moderne du rejet humoral. Conclusion Les benefices de la « strategie preemptive » d’administration de boli de corticoides en cas d’IRA sans cause evidente semblent limites chez les TR. Ces resultats sont a confirmer de maniere prospective.

In patients with CKD, not only renal but also, nonrenal clearance of drugs is altered. Uremic toxins could modify the expression and/or activity of drug transporters in the liver. We tested whether the uremic toxin indoxyl sulfate (IS), an endogenous ligand of the transcription factor aryl hydrocarbon receptor, could change the expression of the following liver transporters involved in drug clearance: SLC10A1, SLC22A1, SLC22A7, SLC47A1, SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCB11, ABCC2, ABCC3, ABCC4, ABCC6, and ABCG2. We showed that IS increases the expression and activity of the efflux transporter P-glycoprotein (P-gp) encoded by ABCB1 in human hepatoma cells (HepG2) without modifying the expression of the other transporters. This effect depended on the aryl hydrocarbon receptor pathway. Presence of human albumin at physiologic concentration in the culture medium did not abolish the effect of IS. In two mouse models of CKD, the decline in renal function associated with the accumulation of IS in serum and the specific upregulation of Abcb1a in the liver. Additionally, among 109 heart or kidney transplant recipients with CKD, those with higher serum levels of IS needed higher doses of cyclosporin, a P-gp substrate, to obtain the cyclosporin target blood concentration. This need associated with serum levels of IS independent of renal function. These findings suggest that increased activity of P-gp could be responsible for increased hepatic cyclosporin clearance. Altogether, these results suggest that uremic toxins, such as IS, through effects on drug transporters, may modify the nonrenal clearance of drugs in patients with CKD.

International audience; BACKGROUND: Severe leptospirosis occurs mainly in a tropical environment and includes icterus, acute renal failure and hemorrhages. These bleedings, which are mainly a consequence of acute homeostatic disturbances, can also reveal simultaneous diseases. Coinfections with other tropical diseases have been previously reported during leptospirosis. To our knowledge, invasive amebiasis, which can induce gastrointestinal bleedings, has never been described in the course of severe leptospirosis. CASE PRESENTATION: In this report, we describe a case of a 60 year-old man living in Reunion Island (Indian Ocean, France) admitted to our intensive care unit for severe Leptospira interrogans serovar icterohaemorrhagiae infection with neurological, renal, liver and hematological involvement. Two lower gastrointestinal bleedings occurred 7 and 15 days after admission. The first episode was promoted by hemostatic disturbances while the second bleeding occurred during low-dose heparin therapy. Colonoscopy revealed a pseudo-tumoral inflammatory mass of the recto-sigmoid junction. Histological examination found trophozoites inside mucinous exudate suggestive of Entamoeba histolytica. Amoebic serology was strongly positive whereas careful detection of cysts or trophozoites on saline-wet mount was negative in three consecutive samples of stools. Amoxicillin followed by metronidazole therapy, combined with supportive care, led to an improvement in the clinical and biological patient's condition and endoscopic appearances. CONCLUSION: Clinicians should be aware that gastrointestinal bleeding during severe leptospirosis could not solely be the consequences of hemostatic disturbances. Careful endoscopic evaluation that may reveal curable coinfections should also be considered.

Introduction Les rejets humoraux limitent la survie des transplants renaux. Si les transcrits natural killers (NK) sont associes aux rejets medies par anticorps specifiques du donneur (DSA), le role de la cytotoxicite NK-dependante des anticorps (ADCC-NK) demeure peu explore. Nous avons evalue le lien entre l’ADCC-NK de patients transplantes renaux et leur pronostic renal. Nous avons egalement developpe un test in vitro evaluant l’ADCC-NK comme mecanisme de toxicite des anticorps anti-HLA specifiques du donneur (DSA), independamment du complement. Patients et methodes L’activation ADCC-NK a ete evaluee en cytometrie de flux (marquage CD3− CD56+ CD16+ CD107a+ en presence de rituximab et de cibles cellulaires CD20+) ex vivo au sein d’une cohorte de 148 transplantes a plus de 3 ans de greffe. Notre test in vitro de cytometrie de flux evalue la liaison des DSA au Fc recepteur CD16 des cellules NK. Il reflete le niveau de degranulation NK contre des cibles allogeniques exposees a des serums contenant des DSA. Il a ete correle aux donnees biopsiques de 22 transplantes immunises ou non. Resultats Chez les patients transplantes, la reponse NK est preservee avec une grande variabilite interindividuelle. Une fonction renale alteree (DFG Discussion Notre etude suggere un impact independant et negatif d’une bonne reponse ADCC-NK sur l’evolution de la fonction renale. Cette donnee observationnelle est a rapprocher de notre test in vitro qui montre la forte capacite d’activation NK des DSA via CD16. Ces resultats soulignent le role possible de l’ADCC-NK dans les rejets humoraux DSA+ C4d negatifs. Conclusion L’interaction entre NK et DSA est un champ nouveau dans la physiopathologie des rejets humoraux. L’impact des DSA liant CD16 sur la survie du greffon reste neanmoins a evaluer.

International audience; BACKGROUND: Controlling alloimmune humoral response is a challenge in transplantation. Few studies have evaluated the impact of maintenance immunosuppression on blood humoral parameters. MATERIAL/METHODS: We performed a post-hoc analysis on 307 kidney transplant recipients included in a prospective randomized trial comparing tacrolimus/mycophenolate mofetil (Tac/MMF) vs. cyclosporine/azathioprine (CsA/AZA), both used with antithymocyte globulin induction and steroids. Humoral parameters were analyzed at D0, D15, and M12. RESULTS: IgG, IgA, and IgM levels decreased significantly as soon as D15 in both groups (-35%, -26%, and -35% respectively, vs. D0). At M12, although peripheral B-cell counts did not differ between the groups, Tac/MMF regimen was associated with lower IgG, IgA, and IgM levels than CsA/AZA (-5.9%, -14.6%, and -34%, respectively). Hypogammaglobulinemia at D15 was not associated with an increased risk of infections during the first year. The proportion of HLA-sensitized patients decreased in the Tac/MMF group (15.9% at D0 and 6.7% at M12, p=0.02) and remained stable in the CsA/AZA group (10.3% at D0 and 8.9% at M12, p=0.5). More patients sensitized at baseline became non-sensitized at M12 with Tac/MMF than with CsA/AZA. CONCLUSIONS: Our results suggest humoral immunosuppression is better with Tac/MMF than with CsA/AZA during the first year of kidney transplantation.

Hepatitis E virus (HEV) is an emerging cause of acute hepatitis in Europe, particularly in southern France, and HEV is a new causative agent of chronic hepatitis and cirrhosis in immunocompromised patients. However, the data regarding HEV infection after kidney transplantation are still scarce with respect to the clinical issues that have been raised, and no study has specifically focused on kidney transplant recipients. This study described the clinical features and outcomes of HEV infections in a cohort of kidney transplant recipients living in southeastern France. The epidemiological, clinical, and virological characteristics of HEV infections diagnosed by PCR over a 53-month period were retrospectively analyzed in a cohort of 1,350 kidney transplant recipients monitored at the Marseille University Hospital. Sixteen HEV infections were diagnosed, all of which were autochthonous and involved genotype 3 viruses (HEV-3). Chronic infections occurred in 80% of these patients and resolved in half of the cases after a median time of 39 months. The rate of HEV clearance was 54% after a decrease in the dose of immunosuppressants. One patient developed liver cirrhosis 14 months after infection and experienced acute rejection after a decrease in the dose of immunosuppressants. Autochthonous HEV-3 infections in kidney transplant recipients progress to chronicity in most cases and might be complicated by early liver cirrhosis. Chronic HEV infection can resolve following the reduction of immunosuppressive therapy, but ribavirin may be required if reduction of the immunosuppressant dose is not associated with HEV clearance or is inappropriate for the patient management. J. Med. Virol. 85:462–471, 2013. © 2012 Wiley Periodicals, Inc.

Background Circulating CD34(+) cells, a population that includes endothelial progenitors, participate in the maintenance of endothelial integrity. Better understanding of the mechanisms that regulate their survival is crucial to improve their regenerative activity in cardiovascular and renal diseases. Chemokine-receptor cross talk is critical in regulating cell homeostasis. We hypothesized that cell surface expression of the chemokine fractalkine (FKN) could target progenitor cell injury by Natural Killer (NK) cells, thereby limiting their availability for vascular repair. Methodology/principal findings We show that CD34(+)-derived Endothelial Colony Forming Cells (ECFC) can express FKN in response to TNF-α and IFN-γ inflammatory cytokines and that FKN expression by ECFC stimulates NK cell adhesion, NK cell-mediated ECFC lysis and microparticles release in vitro. The specific involvement of membrane FKN in these processes was demonstrated using FKN-transfected ECFC and anti-FKN blocking antibody. FKN expression was also evidenced on circulating CD34(+) progenitor cells and was detected at higher frequency in kidney transplant recipients, when compared to healthy controls. The proportion of CD34(+) cells expressing FKN was identified as an independent variable inversely correlated to CD34(+) progenitor cell count. We further showed that treatment of CD34(+) circulating cells isolated from adult blood donors with transplant serum or TNF-α/IFN-γ can induce FKN expression. Conclusions Our data highlights a novel mechanism by which FKN expression on CD34(+) progenitor cells may target their NK cell mediated killing and participate to their immune depletion in transplant recipients. Considering the numerous diseased contexts shown to promote FKN expression, our data identify FKN as a hallmark of altered progenitor cell homeostasis with potential implications in better evaluation of vascular repair in patients.

Introduction La glomerulonephrite a depots de C3 (GNC3) resulte d’anomalies de la voie alterne du complement et est caracterisee par des depots glomerulaires predominants de C3. Les frequences respectives de recidive de GNC3 (GNC3r) et de perte du transplant renal apres recidive sont de 66 % et 50 %. Deux cas de GNC3r traites apres transplantation par eculizumab (anticorps monoclonal anti-C5) ont ete decrits [1] . Un an apres traitement, un cas presentait une amelioration histologique, le second, une amelioration biologique. Nous rapportons un troisieme cas de traitement par eculizumab pour GNC3r. Patients et methodes Un homme de 17 ans a beneficie d’une premiere transplantation renale pour GNC3 a partir de sa demi-sœur. L’exploration quantitative des proteines de la voie alterne du complement etait normale avant transplantation. Quarante-deux jours apres, le patient presente une elevation de la creatininemie a 220 μmol/L versus 166 μmol/l (j22), et une micro-hematurie, sans proteinurie. L’examen anatomo-pathologique du transplant montre une GNC3r debutante (depots endomembraneux diffus exclusifs de C3). La creatininemie s’eleve progressivement jusqu’a 280 μmol/L (j64), sans proteinurie et les depots de C3 progressent, sans proliferation. Nous debutons a j77 un traitement par eculizumab apres nouvelle exploration des proteines de la voie alterne du complement, vaccination anti-meningococcique et antibioprophylaxie par oracilline, a raison de 900 mg par semaine pendant 4 semaines puis 1200 mg tous les 14 jours. La creatininemie s’eleve jusqu’a 330 μmol/L (j91) puis, entre les 3e et 7e injections d’eculizumab, diminue progressivement jusqu’a 126 μmol/L (j138), lors du dernier suivi. Discussion et conclusion Nous rapportons un cas de GNC3r precoce, dont l’evolution renale est favorable apres 61 jours de traitement par eculizumab. L’amelioration renale reste a confirmer et la duree du traitement, a definir. Les dernieres explorations du complement ont montre une concentration diminuee du facteur I et une mutation heterozygote du facteur I, rarement associee aux GNC3.

Introduction Les resistances du cytomegalovirus (CMV) posent des difficultes therapeutiques croissantes en transplantation. En cas de mutation UL97 rendant le virus resistant au ganciclovir (GCV), le foscavir (FCV) est utilise, au prix d’une possible nephrotoxicite. Les ressources therapeutiques deviennent alors limitees. Le brincidofovir (BCV) pourrait constituer une nouvelle alternative. Observation Une patiente de 46 ans seronegative pour le CMV a beneficie d’une premiere transplantation renale avec un donneur seropositif. Les suites ont ete simples (creatininemie : 100 μmol/L). Elle a recu une prophylaxie par valganciclovir pendant 6 mois. Sept mois apres la greffe, elle a ete eu une primo-infection a CMV (antigenemie a 2160 cellules/200 000), avec atteinte digestive et hematologique traitee avec succes par GCV IV pendant 8 semaines. Une premiere recidive est survenue et une nouvelle cure de GCV a echoue. Une analyse genetique a confirme les mutations A594 V et L595S dans le gene UL97. Le FCV a ete instaure avec une bonne efficacite virologique, mais au 26e jour la patiente a developpe une insuffisance renale aigue glomerulaire severe (creatininemie : 450 μmol/L, proteinurie : 5 g/j). Une biopsie a revele des cristaux de FCV dans les glomerules, tubules et arterioles du greffon. Le FCV a ete stoppe (antigenemie negative). La creatininemie s’est stabilisee a 150 μmol/L. Une semaine apres l’arret, une deuxieme recidive digestive a ete a nouveau traitee par GCV associe aux immunoglobulines polyvalentes IV sans efficacite (PCR a 20 000 copies/mL). La PCR pour l’EBV etait egalement faiblement positive. Le BCV per os a 200 mg/semaine a ete introduit. La PCR est devenue negative en 10 jours de traitement. Le BCV a ete stoppe a 3 semaines devant une toxicite digestive et hepatique moderee. Discussion Le BCV est un nouvel antiviral, analogue nucleotidique, prodrogue du cidofovir, ayant une action sur les virus a ADN bicatenaire. Son efficacite a ete demontree en prophylaxie primaire du CMV apres allogreffe de mœlle. Contrairement au cidofovir, le BCV n’est pas un substrat du transporteur tubulaire OAT1 limitant sa nephrotoxicite. Conclusion Malgre ce resultat encourageant, une evaluation plus large de l’efficacite et de la tolerance du BCV en transplantation renale est necessaire.

Introduction L’angiomatose bacillaire est une infection opportuniste rare apres transplantation d’organe solide (moins de 30 cas rapportes dans la litterature). La maladie, causee par Bartonella henselae (Bh) ou Bartonella quintana, decrite pour la premiere fois en 1983 chez un patient infecte par le VIH [1] , a ete rapportee en 1990 chez un transplante cardiaque [2] . Nous rapportons le cas d’une angiomatose bacillaire apres transplantation renale. Patients et methodes Dix mois apres une troisieme transplantation renale, un homme de 41 ans presente une lesion cutanee sous-labiale de croissance rapide puis fievre et amaigrissement. On note un syndrome inflammatoire, une cholestase anicterique, une thrombopenie et une insuffisance renale aigue. L’evolution clinique et biologique est defavorable sous ceftriaxone. Le scanner thoraco-abdo-pelvien montre des epanchements pleuraux, des adenomegalies mediastinales et du hile hepatique, et une hepatomegalie. L’examen anatomo-pathologique de la lesion cutanee revele une reaction inflammatoire granulomateuse a predominance histiocytaire avec proliferation vasculaire. La coloration de Warthin–Starry confirme la presence de bacilles intrahistiocytaires. Bh est identifiee par PCR et sequencage uniquement sur les extraits ADN de la biopsie cutanee. La serologie et la culture sont negatives. Le western blot confirme la presence d’antigenes seriques de Bh. La reprise de l’anamnese revele des griffures de chat deux mois avant l’episode. L’antibiotherapie par erythromycine permet d’obtenir une apyrexie en 5 jours et une normalisation biologique en 10 jours. Nous avions elimine une endocardite. Discussion et conclusion Bh compte parmi les ≈ 60 % d’agents pathogenes humains d’origine zoonotique. Son reservoir est le chat. Bh est une bacterie ubiquitaire et fastidieuse. Il faut savoir evoquer l’angiomatose bacillaire chez des patients transplantes d’organes solides, presentant des lesions cutanees volontiers uniques, une fievre et des adenopathies. Les risques d’infection zoonotique peuvent etre reduits par l’education des patients. La connaissance des zoonoses ainsi que l’utilisation des techniques de biologie moleculaire sont necessaires pour diagnostiquer les infections a Bh.

Introduction : la réponse allo-immune médiée par les anticorps constitue un facteur pronostic important des transplants rénaux. Les fortes doses parentérales de corticoïdes (ou boli) font partie de la première ligne de traitement des rejets aigus prouvés histologiquement. Peu d’études ont évalué le rationnel de l’administration préemptive (avant les résultats histologiques) de boli de corticoïdes en cas de suspicion de rejet chez les transplantés rénaux (TR).Matériel et méthodes : nous avons mené une étude observationnelle rétrospective de suivi de cohorte, incluant tous les patients TR hospitalisés au CHU de Marseille entre 2009 et 2014 et qui présentaient une insuffisance rénale aiguë (IRA), indiquant une 1ère ponction biopsie du transplant (PBT). Les caractéristiques cliniques, biologiques, immunologiques et anatomopathologiques ont été recueillies à l’inclusion, la durée de suivi était de 3 ans. Les TR qui ont reçu de boli de corticoïdes préemptifs constituaient le groupe « stratégie préemptive ».Résultats : parmi les 243 TR de notre cohorte, 17% ont bénéficié d’une « stratégie préemptive ». Parmi eux 51% ont reçu des boli mais sans diagnostic de rejet posé. La survie des transplants censurée sur les décès à 3 ans de suivi était statistiquement moins bonne dans le groupe “stratégie préemptive” (p=0,004). Dans ce groupe, les facteurs associés à un diagnostic de rejet étaient, d’une part la sévérité de l’insuffisance rénale aigue, et d’autre part des caractéristiques immunologiques telles qu’un antécédent de rejet, une immunisation anti-HLA contre le donneur ou un traitement immunosuppresseur moindre. Il a été observé dans les suites des boli de corticoïdes 20% de diabète induit et 10% de pneumocystoses. L’administration préemptive de boli de corticoïdes, bien que très significative en analyse univariée, n’était pas indépendamment associée à la survie du transplant en multivariée. Les facteurs pronostics indépendants de perte du transplant étaient la gravité de la fonction rénale initiale, un diagnostic de rejet médié par les anticorps. Conclusion : le rapport bénéfice-risque défavorable de la « stratégie préemptive » d’administration de boli de corticoïdes lors d’un rejet devrait être confirmé par des études prospectives d’effectifs plus larges.