Highly Variable Sialylation Status of Donor-Specific Antibodies Does Not Impact Humoral Rejection Outcomes

Clinical outcome in antibody-mediated rejection (AMR) shows high inter-individual heterogeneity. Sialylation status of the Fc fragment of IgGs is variable, which could modulate their ability to bind to C1q and/or Fc receptors. In this translational study, we evaluated whether DSA sialylation influence AMR outcomes. Among 938 kidney transplant recipients for whom a graft biopsy was performed between 2004 and 2012 at Lyon University Hospitals, 69 fulfilled the diagnosis criteria for AMR and were enrolled. Sera banked at the time of the biopsy were screened for the presence of DSA by Luminex. The sialylation status of total IgG and DSA was quantified using Sambucus nigra agglutinin-based chromatography. All patients had similar levels of sialylation of serum IgGs (~2%). In contrast, the proportion of sialylated DSA were highly variable (median = 9%; range = 0–100%), allowing to distribute the patients in two groups: high DSA sialylation (n = 44; 64%) and low DSA sialylation (n = 25; 36%). The two groups differed neither on the intensity of rejection lesions (C4d, ptc, and g; p > 0.05) nor on graft survival rates (Log rank test, p = 0.99). in vitro models confirmed the lack of impact of Fc sialylation on the ability of a monoclonal antibody to trigger classical complement cascade and activate NK cells. We conclude that DSA sialylation status is highly variable but has not impact on DSA pathogenicity and AMR outcome

Natalizumab treatment shows low cumulative probabilities of confirmed disability worsening to EDSS milestones in the long-term setting.

Abstract Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance

Inégalités sociales de santé en transplantation rénale.

Reducing social inequalities in health is an important objective internationally. An European transnational index, European Deprivation Index (EDI), estimates the individual experience of social deprivation and allows comparison between regions and countries.This work focuses on the social deprivation estimated by EDI in nephrology. Using EDI, our studies showed that 32% of transplanted patients lived in the most deprived areas. Social deprivation was associated with the increased risk of death in renal transplanted patients.In France, there was heterogeneity between transplant centers regarding living-donor kidney transplantation. Gender and social deprivation estimated by EDI were associated with lower likelihood of LDKT. Number of senior nephrologists or coordinators and the existence of ABO incompatible program could influence the use of LDKT.In France, social deprivation estimated by the EDI is associated with self-care dialysis in end-stage renal disease (ESRD) patients undergoing replacement therapy. Compared with the general population, ESRD patients treated by dialysis experienced a high level of social deprivation.Social inequalities in nephrology could be reduced by early interventions during healthcare pathway. New approaches targeted ESRD patients should be explored at the dialysis or transplantation centers levels.La réduction des inégalités sociales de santé (ISS) est un axe majeur des politiques de santé publiques qui définissent le système de santé d’un pays. L’European Deprivation Index (EDI) est un indice écologique européen, reflétant au mieux l’expérience individuelle de défavorisation sociale, qui permet de réaliser des comparaisons entre régions et pays européens.Ce travail s’est intéressé à l’étude des ISS, estimées par l’EDI, dans le domaine de la néphrologie. A l’aide de l’EDI, nos études ont montré que 32 % des patients transplantés rénaux résidaient dans les zones les plus défavorisées et que leur risque de décès était plus élevé comparativement aux sujets les moins défavorisés.En France, il existe des disparités d’accès à la greffe rénale avec donneur vivant en fonction des centres de greffe. Le sexe féminin et la défavorisation sociale estimée par l’EDI sont associés à une plus faible probabilité de greffe avec donneur vivant. Le nombre de néphrologues et de coordinateurs de greffe par centre ainsi que la réalisation de greffe ABO incompatibles sont des facteurs qui influencent la proportion de greffes avec donneur vivant.Les ISS sont associées à la dialyse autonome en France. Il existe à nouveau une surreprésentation, comparativement à la population générale, de la défavorisation sociale dans la population incidente en dialyse.Les ISS en néphrologie pourraient être réduites par des interventions précoces dans le parcours du patient insuffisant rénal. Il est nécessaire d’élaborer des interventions novatrices individuelles mais aussi au sein des centres de dialyse et de greffe rénale afin d’améliorer l’autonomie du patient et l’accès à la greffe rénale

Health inequalities in kidney transplantation

La réduction des inégalités sociales de santé (ISS) est un axe majeur des politiques de santé publiques qui définissent le système de santé d’un pays. L’European Deprivation Index (EDI) est un indice écologique européen, reflétant au mieux l’expérience individuelle de défavorisation sociale, qui permet de réaliser des comparaisons entre régions et pays européens.Ce travail s’est intéressé à l’étude des ISS, estimées par l’EDI, dans le domaine de la néphrologie. A l’aide de l’EDI, nos études ont montré que 32 % des patients transplantés rénaux résidaient dans les zones les plus défavorisées et que leur risque de décès était plus élevé comparativement aux sujets les moins défavorisés.En France, il existe des disparités d’accès à la greffe rénale avec donneur vivant en fonction des centres de greffe. Le sexe féminin et la défavorisation sociale estimée par l’EDI sont associés à une plus faible probabilité de greffe avec donneur vivant. Le nombre de néphrologues et de coordinateurs de greffe par centre ainsi que la réalisation de greffe ABO incompatibles sont des facteurs qui influencent la proportion de greffes avec donneur vivant.Les ISS sont associées à la dialyse autonome en France. Il existe à nouveau une surreprésentation, comparativement à la population générale, de la défavorisation sociale dans la population incidente en dialyse.Les ISS en néphrologie pourraient être réduites par des interventions précoces dans le parcours du patient insuffisant rénal. Il est nécessaire d’élaborer des interventions novatrices individuelles mais aussi au sein des centres de dialyse et de greffe rénale afin d’améliorer l’autonomie du patient et l’accès à la greffe rénale.Reducing social inequalities in health is an important objective internationally. An European transnational index, European Deprivation Index (EDI), estimates the individual experience of social deprivation and allows comparison between regions and countries.This work focuses on the social deprivation estimated by EDI in nephrology. Using EDI, our studies showed that 32% of transplanted patients lived in the most deprived areas. Social deprivation was associated with the increased risk of death in renal transplanted patients.In France, there was heterogeneity between transplant centers regarding living-donor kidney transplantation. Gender and social deprivation estimated by EDI were associated with lower likelihood of LDKT. Number of senior nephrologists or coordinators and the existence of ABO incompatible program could influence the use of LDKT.In France, social deprivation estimated by the EDI is associated with self-care dialysis in end-stage renal disease (ESRD) patients undergoing replacement therapy. Compared with the general population, ESRD patients treated by dialysis experienced a high level of social deprivation.Social inequalities in nephrology could be reduced by early interventions during healthcare pathway. New approaches targeted ESRD patients should be explored at the dialysis or transplantation centers levels

Place de l'eculizumab dans le traitement des syndromes hémolytiques et urémiques (histoire familiale d'un syndrome hémolytique et urémique atypique lié à une mutation du gène du C3 récidivant après transplantation rénale et traité par eculizumab)

CAEN-BU Médecine pharmacie (141182102) / SudocSudocFranceF

Etude PRETAGREF (prévalence et facteurs associés au tabagisme chez les patients transplantés rénaux)

CAEN-BU Médecine pharmacie (141182102) / SudocSudocFranceF

Vitesse télédiastolique et index de résistance (marqueurs pronostiques de la survie du greffon et du patient transplanté rénal)

TOURS-BU Médecine (372612103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Le sens du mouvement

Panneau d'exposition grand publicLe sens du mouvement. Mouvement, sciences & art

On the role of gravity in shoot gravisensing

A plant accidentally put in a horizontal position rapidly bends and deforms to recover a vertical position. The ability of plants to feel gravity thus plays a key role in their development and adaptation to environmental changes (gravitropism and posture control). A crucial step in this gravisensing occurs in specific cells, the statocytes, which contain dense organites filled with starch granules (amyloplasts). The amyloplasts being denser than the surrounding intracellular fluid, they sediment at the bottom of the cell and are supposed to indicate the direction of gravity with respect to the cells (Morita 2010). However the mechanisms at work in statocytes and the link with the active bending of the plant at the macroscopic scale still need a better understanding (Moulia and Fournier 2009, Blancaflor 2015). In this study, we use an experimental approach to study gravitropic motions at the plant scale, and more specifically to investigate quantitatively the plant sensitivity to gravitropic stimuli and identify the sensed variable (e.g mechanical pressure by amyloplats, velocity or position of the amyloplasts in the cell ….). An original experimental setup called ``gravitron'' has been developed to investigate the response of plant shoots to changes in both gravity intensity and direction. The system is based on an instrumented rotating table allowing full kinematical tracking of the tropic mouvement. These records were then interpreted in term of gravisensitivity using the relevant dimensionless quantity introduced by recent quantitative studies on gravitropic control (Bastien et al. 2013, 2014