Exploration de la dysfonction chronique d'allogreffe par analyse protéomique urinaire SELDI-TOF

Objectif : la Néphropathie chronique d allogreffe (NCA), principale cause de retour prématuré en dialyse, est diagnostiquée à un stade tardif et irréversible à partir d un examen invasif que représente la biopsie du greffon. Le but de ce travail est de détecter précocement des protéines urinaires prédictives de NCA dès le premier trimestre post-greffe et de valider ces biomarqueurs sur une cohorte de patients indépendants. Matériels et méthodes : l analyse protéomique SELDI-TOF est réalisée à partir de 41 échantillons urinaires prélevés à trois mois de greffe. 3 groupes sont identifiés à 1 an de greffe selon des critères biologiques (valeur de la clcr) et histologiques (Banff 2001) : groupe non NCA (n=14) (clcr > 69 ml/min, grade 0), groupe NCA (n=15) (clcr 69 ml/min). Les biomarqueurs candidats sont détectés en comparant les sous-protéomes du groupe NCA versus non-NCA ( test de caractérisation ). L analyse statistique est réalisée par le test U de Mann et Whitney et l analyse de courbes ROC (p 69 ml/min, chronic Banff score of zero), CAN group (i.e.,clairance creatinine < 50 ml/min, chronic Banff score of 1, 2 or 3), undetermined transplant group (i.e.,clairance creatinine between 50 and 69 ml/min). First testing test detect potential biomarkers comparing proteomics profiles of no-CAN group and CAN group by Mann-Whitney U test and receiver operator characteristic (ROC) curve analysis. Then, these proteins are tested in the training test on the independent undetermined transplant group to assess their predictive accuracy, as the proportion of correct classifications, sensitivity, and specificity. Algorithms are used to increase diagnostic performance by combination of several biomarkers. Results : sixteen biomarkers are predictive of CAN and 2 proteins are associated with a long term allograft survival. The best candidate biomarker demonstrating the highest diagnostic performance to predict CAN is a protein of 8860 Da (Se 93%, Sp 65%, AUC=0.826, p=0,002 with the testing test and Se of 83%, Sp of 66%, PPV of 71% and NPV of 80% in the training test ). The combination of several biomarkers ameliorates diagnostic performance. The algorithm provides a sensitivity of 86.6% and a specificity of 100% using three biomarkers at 8860 Da, 12825 Da and 5811 Da for the diagnosis of CAN within the testing population. With the training population tree performance is a little less powerful (Se of 83%, Sp of 66%, PPV of 71% and NPV of 80%). Conclusion : urinary proteomic profiles analysis with SELDI-TOF, in conjunction with bioinformatics tools, could greatly facilitate the discovery of noninvasive biomarkers of CAN. Identification of these proteins may improve the pathophysiology of CAN.GRENOBLE1-BU Médecine pharm. (385162101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Recherche d un effet protecteur de HLA-G membranaire et soluble vis-à-vis de la toxicité des anticorps anti-HLA dirigés contre le donneur en transplantation rénale

L allo-immunisation post-greffe rénale représente un facteur important de la dysfonction chronique d allogreffe. Le développement de technologies sensibles pour la détection des anticorps soulève la question de la toxicité de ces anticorps. En effet, ceux-ci ne s accompagnent pas toujours d épisodes de rejet, traduisant alors un état d accommodation dont la physiopathologie reste incomprise. Connaissant les propriétés immuno-modulatrices de HLA-G, l objectif de notre étude est de rechercher un effet protecteur de cette molécule vis à vis de la toxicité sur le greffon des anticorps. Notre étude rétrospective a été menée sur les patients non immunisés en pré-greffe receveurs d une allogreffe rénale au CHU de Grenoble entre le 01/01/2005 et le 31/12/2009, divisés en 2 groupes : un groupe immunisé (n=28) regroupant les patients ayant développé des anticorps anti-HLA dirigés contre leur donneur ( donor specific antibodies , DSA) en post-greffe, divisés en 2 sous-groupes : DSA + rejet (n=16) se caractérisant par la survenue d un rejet et DSA + accommodation (n=12) comprenant les patients sans signes de toxicité des DSA ; un groupe non immunisé (n=22) comprenant les patients n ayant pas développé de DSA en post-greffe. Une comparaison de l expression de HLA-G membranaire et soluble a été effectuée à différents temps post-greffe. Notre étude confirme une association positive entre l expression de HLA-G membranaire et la survenue d un état d accommodation en présence de DSA (p=0.042) ainsi qu une tendance à une moindre incidence de (p=NS). Aucun effet protecteur de l isoforme soluble de la molécule n a été mis en évidence.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

Predictive diagnostic of chronic allograft dysfunction using urinary proteomics analysis.

International audienceBACKGROUND: Kidney transplant Chronic Allograft Dysfunction (CAD), a major cause of long-term graft failure, is currently diagnosed at a late and irreversible stage by graft biopsies. Our goal was to identify predictive urinary biomarkers of CAD before renal lesions appeared by analysis of the urine proteomic profile. METHODS/METHODS: Twenty-nine urinary samples withdrawn three months post-transplant were analyzed by SELDI-TOF technology. CAD development was evaluated by serum creatinine level and confirmed by allograft biopsy one year after transplantation. Comparison of protein profile of both groups revealed 18 biomarkers predictive of CAD occurrence. RESULTS: The biomarker demonstrating the highest diagnostic performance was a protein of 8860 Da that predicted CAD with a sensitivity of 93% and a specificity of 65%. Moreover combination of these biomarkers in two multivariate analyses improved the diagnostic potential of CAD. Relevance of these individual biomarkers and a decisional algorithm constituted of 3 proteins was confirmed in an independent cohort of patients with undetermined CAD status one year post-transplant. CONCLUSIONS: These non invasive biomarkers, detected as soon as three months post-grafting, allowed identification of patients who would develop CAD as late as 4 years after graft. Systematic measurement of these biomarkers would greatly improve the management of immunosuppressive therapy of kidney grafted patients

L’apport d’une unité de concertation éthique pour la pratique professionnelle en néphrologie validé par un protocole de recherche

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Severe acute hepatitis after thymoglobulin induction before islet transplantation

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Conversion from everolimus with low-exposure cyclosporine to everolimus with mycophenolate sodium maintenance therapy in kidney transplant recipients: a randomized, open-label multicenter study.

International audienceBACKGROUND: Data in kidney transplant recipients regarding elimination of calcineurin inhibitor (CNI) therapy from a de novo regimen based on low CNI exposure and an mTOR inhibitor are sparse, and restricted to CNI elimination within the first six months post-transplant. MATERIAL/METHODS: In a 12-month, randomized, multicenter, open-label study, kidney transplant patients who had received everolimus, low-exposure cyclosporine and corticosteroids from transplantation to month 12 (with proteinuria <1 g/24 h at month 12) were randomized to convert from cyclosporine to mycophenolate sodium 720 mg/day with increased everolimus exposure (6-10 ng/mL [CNI-free group], n=15) or continue unchanged (everolimus 3-8 ng/mL [CNI group], n=15). RESULTS: Median (range) baseline mGFR was 54 (21-87) mL/min and 37 (range 18-69) mL/min (p=0.053) in the CNI-free and CNI groups, respectively, compared to 56 (18-126) mL/min and 32 (12-63) mL/min at month 12 (p=0.007). The between-group difference in change in mGFR from baseline to month 12 post-conversion (the primary endpoint) was -14.4 mL/min (95% CI -29.3 to 0.6 mL/min, p=0.059 [least squares mean]). Changes in serum creatinine and estimated GFR to month 12 were significantly in favor of CNI-free patients. One CNI patient experienced biopsy-proven acute rejection. Study drug was discontinued due to adverse events in one CNI-free patient (7%) and three CNI-treated patients (20.0%). CONCLUSIONS: Elimination of CNI from a de novo regimen of everolimus with low-exposure CNI at one year post-transplant maintained efficacy and led to a non-significant but clinically relevant improvement in renal function, although patients numbers were low (n=30). Findings from this small study require confirmation in a larger controlled trial

Low incidence of SARS-CoV-2, risk factors of mortality and the course of illness in the French national cohort of dialysis patients

International audienceThe aim of this study was to estimate the incidence of COVID-19 disease in the French national population of dialysis patients, their course of illness and to identify the risk factors associated with mortality. Our study included all patients on dialysis recorded in the French REIN Registry in April 2020. Clinical characteristics at last follow-up and the evolution of COVID-19 illness severity over time were recorded for diagnosed cases (either suspicious clinical symptoms, characteristic signs on the chest scan or a positive reverse transcription polymerase chain reaction) for SARS-CoV-2. A total of 1,621 infected patients were reported on the REIN registry from March 16th, 2020 to May 4th, 2020. Of these, 344 died. The prevalence of COVID-19 patients varied from less than 1% to 10% between regions. The probability of being a case was higher in males, patients with diabetes, those in need of assistance for transfer or treated at a self-care unit. Dialysis at home was associated with a lower probability of being infected as was being a smoker, a former smoker, having an active malignancy, or peripheral vascular disease. Mortality in diagnosed cases (21%) was associated with the same causes as in the general population. Higher age, hypoalbuminemia and the presence of an ischemic heart disease were statistically independently associated with a higher risk of death. Being treated at a selfcare unit was associated with a lower risk. Thus, our study showed a relatively low frequency of COVID-19 among dialysis patients contrary to what might have been assumed