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La transplantation pulmonaire (TxP) constitue le traitement ultime de l’insuffisance respiratoire terminale et concerne environ 400 patients par an en France. Les indications de TxP restent dominées par la fibrose pulmonaire et la bronchopneumopathie chronique obstructive. La TxP est une activité complexe qui fait appel à de nombreuses expertises et soulève plusieurs problématiques menaçant potentiellement son efficience et sa pérennité. Parmi celles-ci, l’adéquation entre l’offre et la demande de greffons pulmonaires, l’organisation du prélèvement et de la greffe, la vitalité de la recherche clinique et translationnelle en TxP. L’Académie nationale de médecine souhaite dans ce rapport : (1) faire un état des lieux de l’activité de TxP en France et de la recherche clinique et fondamentale adossée à cette activité, en appréciant les points forts et les points faibles de chaque item ; (2) proposer des recommandations pour optimiser l’activité et des pistes d’amélioration. Ce rapport, qui couvre les données actuelles connues dans la thématique de la TxP en France, met en lumière les principales problématiques en relation avec cette activité parmi lesquelles la lourde organisation de la TxP, la préservation limitée du greffon et la fragilisation des équipes. Il avance des propositions portant sur le soin et la recherche visant à optimiser et garantir la poursuite et le développement de cette pratique pour les années à venir, avec notamment l’encouragement l’ouverture de plateforme mutualisée de conditionnement des greffons ou la création d’un réseau réunissant les centres de transplantation pulmonaires français.

La greffe de rein d’un donneur vivant représente la meilleure chance de survie à long terme du greffon (+15 % à 10 ans). Aussi doit-elle être évoquée en priorité chez tout patient insuffisant rénal chronique susceptible d’être transplanté. Si les bénéfices sont évidents pour le receveur, les risques chez le donneur doivent être identifiés afin de donner une information objective et transparente pour que le donneur prenne sa décision en toute conscience. Le bilan se fait en plusieurs étapes successives avec des examens de coût et de complexité progressivement croissants, ce qui explique sa durée (4 à 6 mois) et le fait qu’il n’aboutit à une greffe qu’une fois sur trois. Il explore, d’une part, la faisabilité de la greffe (absence de contre-indication médicale, immunologique ou chirurgicale), d’autre part, les risques pour le donneur, essentiellement le risque à long terme d’insuffisance rénale terminale qui est très faible mais néanmoins majoré. D’après les recommandations internationales KDIGO, le débit de filtration glomérulaire mesuré (mDFG) doit être supérieur à 90mL/min/1,73m2, un mDFG inférieur à 60mL/min/1,73m2 contre-indiquant le prélèvement. Un mDFG intermédiaire doit être interprété en fonction de l’âge et de certains facteurs de risques. Il importe donc que le donneur soit régulièrement suivi sur le plan médical et psychologique après le prélèvement et que les données recueillies soient renseignées dans le logiciel Cristal de l’Agence de biomédecine.

We report results of a phase 2, randomized, multicenter, open‐label, two‐arm study evaluating the safety and efficacy of eculizumab in preventing acute antibody‐mediated rejection (AMR) in sensitized recipients of living‐donor kidney transplants requiring pretransplant desensitization (NCT01399593). In total, 102 patients underwent desensitization. Posttransplant, 51 patients received standard of care (SOC) and 51 received eculizumab. The primary end point was week 9 posttransplant treatment failure rate, a composite of: biopsy‐proven acute AMR(Banff 2007 grade IIor III; assessed by blinded central pathology); graft loss; death; or loss to follow‐up. Eculizumab was well tolerated with no new safety concerns. No significant difference in treatment failure rate was observed between eculizumab (9.8%) and SOC(13.7%; P =.760). To determine whether data assessment assumptions affected study outcome, biopsies were reanalyzed by central pathologists using clinical information. The resulting treatment failure rates were 11.8% and 21.6% for the eculizumab and SOCgroups, respectively (nominal P =.288). When reassessment included grade I AMR, the treatment failure rates were 11.8% (eculizumab) and 29.4% (SOC; nominal P =.048). This finding suggests a potential benefit for eculizumab compared with SOCin preventing acute AMRin recipients sensitized to their living‐donor kidney transplants (EudraCT2010‐019630‐28). In this study of terminal complement inhibition to prevent acute antibody‐mediated rejection in living‐donor kidney transplant recipients with preformed donor‐specific antibodies, prophylactic eculizumab does not significantly reduce the treatment failure rate compared with standard of care, but biopsy reanalysis suggests a benefit for eculizumab in preventing AMR in these patients. See the article by Glotz et al on page 2865.

The presence of preformed donor‐specific antibodies in transplant recipients increases the risk of acute antibody‐mediated rejection (AMR). Results of an open‐label single‐arm trial to evaluate the safety and efficacy of eculizumab in preventing acute AMRin recipients of deceased‐donor kidney transplants with preformed donor‐specific antibodies are reported. Participants received eculizumab as follows: 1200 mg immediately before reperfusion; 900 mg on posttransplant days 1, 7, 14, 21, and 28; and 1200 mg at weeks 5, 7, and 9. All patients received thymoglobulin induction therapy and standard maintenance immunosuppression including steroids. The primary end point was treatment failure rate, a composite of biopsy‐proved grade II/III AMR(Banff 2007 criteria), graft loss, death, or loss to follow‐up, within 9 weeks posttransplant. Eighty patients received transplants (48 women); the median age was 52 years (range 24‐70 years). Observed treatment failure rate (8.8%) was significantly lower than expected for standard care (40%; P <.001). By 9 weeks, 3 of 80 patients had experienced AMR, and 4 of 80 had experienced graft loss. At 36 months, graft and patient survival rates were 83.4% and 91.5%, respectively. Eculizumab was well tolerated and no new safety concerns were identified. Eculizumab has the potential to provide prophylaxis against injury caused by acute AMRin such patients (EudraCT2010‐019631‐35). In this study of terminal complement inhibition to prevent antibody‐mediated rejection in deceased‐donor kidney transplant recipients with donor‐specific antibodies, the treatment failure rate for eculizumab is low compared with the expected rate for standard of care, suggesting that terminal complement inhibition has the potential to prevent acute AMR in patients sensitized to their donors. See the companion article by Marks et al on page 2876.

La maltraitance à enfants a longtemps été ignorée. Les récents plans ministériels prévoient de nombreuses mesures de protection dont le déploiement d’unités d’accueil pédiatriques des enfants en danger (UAPED). Malgré toutes ces avancées, le diagnostic reste sous-estimé dans le secteur de la santé avec une prévalence de l’ordre de 1 enfant sur 10 dans les pays à hauts revenus, toutes catégories de maltraitance confondues. La fréquence de décès serait de 1 enfant tous les 5jours en France. Les violences subies durant l’enfance représentent une lourde perte de chance en termes d’espérance de vie, de santé, de développement et d’insertion. Le rapport est limité aux maltraitances physiques chez l’enfant (MPE) et n’aborde donc pas les maltraitances sexuelles. Le maître-mot est la nécessité d’hospitaliser l’enfant pour une protection immédiate, une évaluation multidisciplinaire, les soins et l’alerte des autorités en temps utile. Les résultats de l’étude montrent une réelle prise de conscience de la MPE dans le secteur pédiatrique. Toutefois, le diagnostic peut être sous-estimé et banalisé chez l’enfant, ce qui signifie que l’étiologie « traumatisme infligé » doit être évoquée largement par le médecin quel que soit son lieu d’intervention. Il y a une amélioration nette de la formation dans ce domaine. Toutefois, le rapport met en évidence une insuffisance persistante des moyens humains dans les secteurs des UAPED, de médecine scolaire, de PMI et de pédopsychiatrie. Le psychotraumatisme doit être pris en charge à court, moyen et long terme. Le diagnostic différentiel permet d’éliminer toutes les étiologies confondantes telles que traumatisme accidentel, maladie rare ou autres. Tout médecin doit pouvoir être guidé, accompagné et protégé pour les situations de MPE. Les médecins référents « Violences » des conseils départementaux de l’Ordre des médecins (CDOM) doivent avoir une compétence dans le domaine de la MPE. L’Académie nationale de médecine propose 6 recommandations : une hospitalisation prioritaire de tout enfant victime ou suspect de MPE jusqu’à ce que tous les éléments du diagnostic soient établis ; un renforcement des moyens humains des UAPED en y intégrant un temps de pédopsychiatrie ; un renforcement du repérage des situations à risque dès la maternité ; un renforcement de la protection et de l’accompagnement des médecins afin que ceux-ci n’hésitent plus à signaler les situations de MPE ; l’extension du périmètre du numéro 119 aux médecins et personnels de santé ; la création d’un registre national pour suivre l’épidémiologie et juger de l’efficacité des mesures prises.

Nous présentons les principes et la méthodologie d’un projet de réforme du financement de la recherche par le ministère chargé de la santé. L’objectif est d’aligner l’attribution de ces fonds, appelés MERRI, sur les pratiques internationales en la fondant sur des critères objectifs de qualité scientifique et de besoin médical. Une minorité de ces fonds serait attribuée aux hôpitaux sur une base concurrentielle et le reste sur une base contractuelle pluriannuelle, en utilisant des canaux de distribution sûrs et transparents. Un préciput substantiel serait alloué aux établissements. Cette réforme, qui vise à améliorer l’efficacité du financement de la recherche hospitalière en France, est très attendue par l’ensemble des chercheurs et des cliniciens.

La recherche clinique correspond aux études scientifiques réalisées sur la personne humaine, en vue du développement des connaissances biologiques ou médicales. Afin d‘améliorer la compétitivité et l’attractivité de la France dans ce domaine, nous avons identifié un certain nombre de freins : lourdeurs administratives, capacités réduites à inclure rapidement, absence de disponibilité des investigateurs pour la recherche, difficultés à obtenir des financements académiques et à en disposer, difficultés d’adaptation rapide aux nouvelles technologies de santé et aux nouvelles méthodologies, prise en compte insuffisante des attentes des patients au regard de la recherche clinique. A la suite de ces constats, nous avons identifié 20 pistes de réflexion et émis 5 recommandations fortes : 1-Limiter et mesurer les délais règlementaires et surtout post- règlementaires en simplifiant les démarches administratives pour s’adapter à la compétition internationale. 2-Structurer, financer et recenser des réseaux, registres, cohortes et centres de ressources biologiques pour inclure rapidement. 3-Réuniversitariser et remédicaliser la gouvernance des CHU et des DRCI. 4-Restructurer l’organisation des CHU autour de pôles Hospitalo-universitaires intégrant des services de soins, des laboratoires et des équipes de recherche et disposant de moyens pour remettre la recherche au cœur des CHU et redonner du sens et de l’attractivité au métier d’hospitalo-universitaire. 5-Instituer au sein du ministère de la Santé une gouvernance médicale (le COHR) de la recherche hospitalière financée par les MERRI en réformant profondément la procédure d’allocation des moyens en la fondant sur des critères objectifs de qualité scientifique et de besoin medical.

The aim of this study was the evaluation of the safety and efficacy of unilateral subretinal injection of the adeno-associated vector (AAV) serotypes 2 and 4 (AAV2/4) RPE65-RPE65vector in patients with Leber congenital amaurosis (LCA) associated with RPE65gene deficiency. We evaluated ocular and general tolerance and visual function up to 1 year after vector administration in the most severely affected eye in nine patients with retinal degeneration associated with mutations in the RPE65gene. Patients received either low (1.22 × 1010to 2 × 1010vector genomes [vg]) or high (between 3.27 × 1010and 4.8 × 1010vg) vector doses. An ancillary study, in which six of the original nine patients participated, extended the follow-up period to 2–3.5 years. All patients showed good ophthalmological and general tolerance to the rAAV2/4-RPE65-RPE65vector. We observed a trend toward improved visual acuity in patients with nystagmus, stabilization and improvement of the visual field, and cortical activation along visual pathways during fMRI analysis. OCT analysis after vector administration revealed no retinal thinning, except in cases of macular detachment. Our findings show that the rAAV2/4.RPE65.RPE65 vector was well tolerated in nine patients with RPE65-associated LCA. Efficacy parameters varied between patients during follow-up.

In a 24‐month, multicenter, open‐label, randomized trial, 715 de novokidney transplant recipients were randomized at 10–14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732versus −1.5(1.5) mL/min/1.732(p = 0.116). Biopsy‐proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNIoverall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus‐treated patients (2.6%, p < 0.001) but similar to cyclosporine‐treated patients (8.8%, p = 0.755). Reporting on de novodonor‐specific antibodies (DSA) was limited but suggested more frequent anti‐HLAClass I DSAunder everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI(8.4%). In conclusion, conversion to everolimus at 10–14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPARwere low in all groups, but lower with tacrolimus than everolimus. In a multicenter, open‐label, randomized trial of de novokidney transplant recipients, conversion to everolimus at 10–14 weeks posttransplant is associated with similar renal function as in patients who continue to standard tacrolimus or cyclosporine therapy, with low rates of biopsy‐proven acute rejection in all groups, but lower rates with tacrolimus than everolimus.

The aim of this study (ClinicalTrials.gov, NCT01744470) was to determine the efficacy and safety of two different doses of extended-release tacrolimus (TacER) in kidney transplant recipients (KTRs) between 4 and 12 mo after transplantation. Stable steroid-free KTRs were randomized (1:1) after 4 mo: Group A had a 50% reduction in TacER dose with a targeted TacER trough level (C0) >3 μg/L; group B had no change in TacER dose (TacER C07–12 μg/L). The primary outcome was estimated GFR at 1 year. Of 300 patients, the intent-to-treat analysis included 186 patients (group A, n = 87; group B, n = 99). TacER C0was lower in group A than in group B at 6 mo (4.1 ± 2.7 vs. 6.7 ± 3.9 μg/L, p < 0.0001) and 12 mo (5.6 ± 2.0 vs. 7.4 ± 2.1 μg/L, p < 0.0001). Estimated GFR was similar in both groups at 12 mo (group A, 56.0 ± 17.5 mL/min per 1.73 m²; group B, 56.0 ± 22.1 mL/min per 1.73 m²). More rejection episodes occurred in group A than group B (11 vs. 3; p = 0.016). At 1 year, subclinical inflammation occurred more frequently in group A than group B (inflammation score [i] >0: 21.4% vs. 8.8%, p = 0.047; tubulitis score [t] >0: 19.6% vs. 8.7%, p = 0.076; i + t: 1.14 ± 1.21 vs. 0.72 ± 1.01, p = 0.038). Anti-HLA donor-specific antibodies appeared only in group A (6 vs. 0 patients, p = 0.008). TacER C0should be maintained >7 μg/L during the first year after transplantation in low-immunological-risk, steroid-free KTRs receiving a moderate dose of mycophenolic acid.

Acute renal rejection is a major risk factor for chronic allograft dysfunction and long‐term graft loss. We performed a genome‐wide association study to detect loci associated with biopsy‐proven acute T cell–mediated rejection occurring in the first year after renal transplantation. In a discovery cohort of 4127 European renal allograft recipients transplanted in eight European centers, we used a DNApooling approach to compare 275 cases and 503 controls. In an independent replication cohort of 2765 patients transplanted in two European countries, we identified 313 cases and 531 controls, in whom we genotyped individually the most significant single nucleotide polymorphisms (SNPs) from the discovery cohort. In the discovery cohort, we found five candidate loci tagged by a number of contiguous SNPs (more than five) that was never reached in iterative in silicopermutations of our experimental data. In the replication cohort, two loci remained significantly associated with acute rejection in both univariate and multivariate analysis. One locus encompasses PTPRO, coding for a receptor‐type tyrosine kinase essential for B cell receptor signaling. The other locus involves ciliary gene CCDC67, in line with the emerging concept of a shared building design between the immune synapse and the primary cilium. A genome‐wide association study strongly implicates B cell tyrosine kinase PTPROand ciliary gene CCDC67in acute renal allograft rejection.

This large retrospective study shows that positive CMV serostatus of recipient and full HLA class I mismatching are the main determinants of poor graft outcome associated with CMV seropositivity of donor.

Calcineurin inhibitors improve acute rejection rates and short‐term graft survival in renal transplantation, but their continuous use may be deleterious. We evaluated the 5‐year outcomes of sirolimus (SRL) versus cyclosporine (CsA) immunosuppressive treatment. This observational study was an extension of the SPIESSER study where deceased donor kidney transplant recipients were randomized before transplantation to a SRL‐ or CsA‐based regimen and followed up 1 year. Data from 131 (63 SRL, 68 CsA) out of 133 patients living with a functional graft at 1 year were collected retrospectively at 5 years posttransplant. Seventy percent of CsA patients versus 54% of SRL patients were still on the allocated treatment at 5 years (p = 0.091), most discontinuations in each group being due to safety issues. In intent‐to‐treat, mean MDRD eGFR was higher with SRL: 54.2 versus 45.3 mL/min with CsA (p = 0.019); SRL advantage was greater in on‐treatment analyses. There were no differences for patient survival (p = 0.873), graft survival (p = 0.121) and acute rejection (p = 0.284). Adverse events were more frequent with SRL (80% vs. 60%, p = 0.015). Results confirmed the high SRL discontinuation rate due to adverse events. Nevertheless, a benefit was evidenced on renal function in patients (more than 50%) still on treatment at 5 years.

A registry of posttransplant lymphoproliferative disorders (PTLD) was set up for the entire population of adult kidney transplant recipients in France. Cases of PTLD were prospectively enrolled between January 1, 1998, and December 31, 2007. Ten-year cumulative incidence was analyzed in patients transplanted after January 1, 1989. PTLD risk factors were analyzed in patients transplanted after January 1, 1998 by Cox analysis. Cumulative incidence was 1% after 5 years, 2.1% after 10 years. Multivariate analysis showed that PTLD was significantly associated with: older age of the recipient 47–60 years and >60 years (vs. 33–46 years, adjusted hazard ratio (AHR) = 1.87, CI = 1.22–2.86 and AHR = 2.80, CI = 1.73–4.55, respectively, p < 0.0001), simultaneous kidney–pancreas transplantation (AHR = 2.52, CI = 1.27–5.01 p = 0.008), year of transplant 1998–1999 and 2000–2001 (vs. 2006–2007, AHR = 3.36, CI = 1.64–6.87 and AHR = 3.08, CI = 1.55–6.15, respectively, p = 0.003), EBV mismatch (HR = 5.31, CI = 3.36–8.39, p < 0.001), 5 or 6 HLA mismatches (vs. 0–4, AHR = 1.54, CI = 1.12–2.12, p = 0.008), and induction therapy (AHR = 1.42, CI = 1–2.02, p = 0.05). Analyses of subgroups of PTLD provided new information about PTLD risk factors for early, late, EBV positive and negative, polymorphic, monomorphic, graft and cerebral lymphomas. This nationwide study highlights the increased risk of PTLD as long as 10 years after transplantation and the role of cofactors in modifying PTLD risk, particularly in specific PTLD subgroups.

Whether or not a cyclosporine A (CsA)‐free immunosuppressant regimen based on sirolimus (SRL) prevents aortic stiffening and improves central hemodynamics in renal recipients remains unknown. Forty‐four patients (48 ± 2 years) enrolled in the CONCEPT trial were randomized at week 12 (W12) to continue CsA or switch to SRL, both associated with mycophenolate mofetil. Carotid systolic blood pressure (cSBP), pulse pressure (cPP), central pressure wave reflection (augmentation index, AIx) and carotid‐to‐femoral pulse‐wave velocity (PWV: aortic stiffness) were blindly assessed at W12, W26 and W52 together with plasma endothelin‐1 (ET‐1), thiobarbituric acid‐reactive substances (TBARS) and superoxide dismutase (SOD) and catalase erythrocyte activities. At W12, there was no difference between groups. At follow‐up, PWV, cSBP, cPP and AIx were lower in the SRL group. The difference in PWV remained significant after adjustment for blood pressure and eGFR. In parallel, ET‐1 decreased in the SRL group, while TBARS, SOD and catalase erythrocyte activities increased in both groups but to a lesser extent in the SRL group. Our results demonstrate that a CsA‐free regimen based on SRL reduces aortic stiffness, plasma endothelin‐1 and oxidative stress in renal recipients suggesting a protective effect on the arterial wall that may be translated into cardiovascular risk reduction.

Calcineurin inhibitor (CNI) withdrawal has been used as a strategy to improve renal allograft function. We previously reported that conversion from cyclosporine A (CsA) to sirolimus (SRL) 3 months after transplantation significantly improved renal function at 1 year. In the Postconcept trial, 77 patients in the SRL group and 85 in the CsA group were followed for 48 months. Renal function (Cockcroft and Gault) was significantly better at month 48 (M48) in the SRL group both in the intent-to-treat population (ITT): 62.6 mL/min/1.73 m2versus 57.1 mL/min/1.73 m2(p = 0.013) and in the on-treatment population (OT): 67.5 mL/min/1.73 m2versus 57.4 mL/min/1.73 m2(p = 0.002). Two biopsy proven acute rejection episodes occurred after M12 in each group. Graft and patient survival were comparable (graft survival: 97.4 vs. 100%; patient survival: 97.4 vs. 97.6%, respectively). The incidence of new-onset diabetes was numerically increased in the SRL group (7 vs. 2). In OT, three cancers occurred in the SRL group versus nine in the CsA group and mean proteinuria was increased in the SRL group (0.42 ± 0.44 vs. 0.26 ± 0.37; p = 0.018). In summary, the renal benefits associated with conversion of CsA to SRL, at 3 months posttransplantation, in combination with MMF were maintained for 4 years posttransplantation.

The high frequency of allogeneic reactive CD8+ T cells in human and their resistance to immunosuppression might be one of the reasons why successful tolerance-inducing strategies in rodents have failed in primates. Studies on the requirement for T-helper cells in priming CD8+ T-cell responses have led to disparate findings. Recent studies have reported CD8+-mediated allograft rejection independently of T-helper cells; however, the mechanisms that govern the activation of these T cells are far from being elucidated. In this study, we demonstrated that lipopolysaccharide-treated dendritic cells (DCs) were able to induce proliferation and cytotoxic activity of allogeneic CD8+ T cells independently of CD4+ T cells, while adding mycophenolic acid (MPA) to LPS abolished this capacity and resulted in anergic CD8+ T cells that secreted high levels of interleukin-4 (IL-4), IL-5, IL-10, and transforming growth factor-β. Interestingly, we demonstrated that MPA inhibited the LPS-induced synthesis of tumor necrosis factor-α, IL-12, and interferon-γ (IFN-γ) in DCs. Importantly, we found that adding exogenous IFN-γ to MPA restored both the synthesis of cytokines and the ability to activate CD8+ T cells. However, adding IL-12 or tumor necrosis factor-α had no effect. These results suggest that IFN-γ has an important role in licensing DCs to prime CD4-independent CD8 allogeneic T cells via an autocrine loop.

Erythropoietin promotes nephroprotection in animal models of ischemia-reperfusion injury. Neorecormon®and Prevention of Delayed Graft Function (Neo-PDGF) is a French open-label multicenter randomized study to evaluate the effect of high doses of epoetin beta (EPO-?) during the first 2 weeks of renal transplantation on renal function in patients at risk for delayed graft function (DGF). One hundred and four patients were included in the study. Patients randomized in treatment group (A) received four injections of EPO-? (30.000 UI each), given before surgery and at 12 h, 7 days and 14 days posttransplantation. Patients randomized in control group (B) did not receive EPO-?. Immunosuppression included induction with basiliximab and maintenance therapy with steroids, mycophenolate mofetil and tacrolimus. At 1 month posttransplant, the estimated glomerular filtration rate (MDRD formula) was 42.5 ± 19.0 mLmin in the EPO-? group and 44.0 ± 16.3 mLmin in the control group (p ns). The frequency of DGF was similar in both groups (32 vs. 38.8; p ns). No difference in the incidence of serious adverse events was observed. (ClinicalTrials.gov number, NCT00815867.)

Late-onset cytomegalovirus (CMV) disease is a significant problem with a standard 3-month prophylaxis regimen. This multicentre, double-blind, randomized controlled trial compared the efficacy and safety of 200 days' versus 100 days' valganciclovir prophylaxis (900 mg once daily) in 326 high-risk (DR-) kidney allograft recipients. Significantly fewer patients in the 200-day group versus the 100-day group developed confirmed CMV disease up to month 12 posttransplant (16.1 vs. 36.8; p < 0.0001). Confirmed CMV viremia was also significantly lower in the 200-day group (37.4 vs. 50.9; p 0.015 at month 12). There was no significant difference in the rate of biopsy-proven acute rejection between the groups (11 vs. 17, respectively, p 0.114). Adverse events occurred at similar rates between the groups and the majority were rated mild-to-moderate in intensity and not related to study medication. In conclusion, this study demonstrates that extending valganciclovir prophylaxis (900 mg once daily) to 200 days significantly reduces the incidence of CMV disease and viremia through to 12 months compared with 100 days' prophylaxis, without significant additional safety concerns associated with longer treatment. The number needed to treat to avoid one additional patient with CMV disease up to 12 months posttransplant is approximately 5.

Les anticorps monoclonaux (Acm) sont utilisés en pratique médicale courante dans le traitement de nombreuses maladies hématologiques ou inflammatoires. Il est indispensable d’en connaître le rapport bénéfice-risque avant d’utiliser ces traitements. En effet, ils peuvent être à l’origine d’infections, plus ou moins sévères selon la molécule et le protocole utilisés. Leurs cibles moléculaires précises, souvent exprimées par des cellules du système hématopoïétique ou immunitaire, expliquent qu’ils puissent induire, directement ou indirectement, une immunosuppression favorable au développement d’infections opportunistes, ou des réactions allergiques. Des infections graves ont été rapportées, nécessitant une prophylaxie anti-infectieuse et rappelant la nécessité d’une évaluation des risques avant l’instauration du traitement et d’une surveillance rigoureuse par la pharmacovigilance lors du suivi de ces nouvelles thérapeutiques.

Conversion from cyclosporine (CsA) to sirolimus at week 12 after kidney transplantation is associated with a significant improvement in renal function. The aim of this analysis was to investigate the effect of this conversion on interstitial fibrosis (IF), a hallmark of chronic allograft injury, in patients taking part in the CONCEPT trial. This multicenter, prospective, trial included 193 renal recipients randomized at week 12 to switch from CsA to sirolimus or to continue CsA, with mycophenolate mofetil. Routine biopsy with automated, quantified assessment of IF by a program of color segmentation was performed at 1 year in 121 patients. At 1 year, renal function was significantly improved in the conversion group as assessed by estimated GFR (MDRD) and measured GFR. Biopsy results, however, showed no between-group difference in percentage of IF. Calculated GFR at 1 year was significantly associated with the percentage of IF (p = 0.004, R2= 0.07). By multivariate analysis diabetic patients had more fibrosis than non-diabetic patients. In conclusion, although kidney transplant patients converted from CsA to sirolimus showed significant improvement in renal function, we found no difference of IF on 1-year biopsies.

Transplant glomerulopathy (TGP) appears to be a pathogenic feature of chronic antibody-mediated rejection, but the pathogenesis of this histologic entity is still poorly understood. Previous studies suggest the involvement of lymphocytes but the phenotypes of these cells have never been analyzed. Here, we report the first study of mRNAs for specific markers of CD4+ T cells including Th1 (T-bet and INFγ), Th2 (IL4 and GATA3), Treg (Foxp3) and Th17 (IL-17 and RORγt) subsets, cytotoxic CD8 T cells (Granzyme B) and B-cell markers (CD20) in renal biopsies from renal transplant recipients suffering interstitial fibrosis and tubular atrophy (IF/TA) with or without TGP but with a similar inflammatory score and controls including transplant recipients with normal renal function. Only INFγ, T-bet (both functionally defined markers of Th1 CD4 T cells) and granzyme B (a CD8 cytotoxic marker) were significantly more strongly expressed in patients with TGP than in patients without TGP and normal controls. These results indicate a role of an active T-mediated inflammatory and cytotoxic process in the pathogenesis of TGP.

Sirolimus (SRL) allows to minimize the use of cyclosporine (CsA), but de novoadministration after transplantation is associated with various complications. We report a prospective, open-label, multicenter randomized study to evaluate conversion from a CsA- based regimen to a SRL-based regimen 3 months after transplantation. One hundred ninety-two of a total of 237 patients were eligible at 3 months to be converted to SRL (n = 95) or to continue CsA (n = 97). All patients were also given mycophenolate mofetil (MMF) and oral steroids, planned to be discontinued at month 8. The primary endpoint, the clearance estimated according to Cockcroft and Gault at week 52, was significantly better in the SRL group (68.9 vs. 64.4 mL/min, p = 0.017). Patient and graft survival were not statistically different. The incidence of acute rejection episodes, mainly occurring after withdrawal of steroids, was numerically but not statistically higher in the SRL group (17% vs. 8%, p = 0.071). Sixteen patients discontinued SRL, mainly for adverse events (n = 11), and seven patients discontinued CsA for renal failure or acute rejection. Significantly, more patients in the SRL group reported aphthous, diarrhea, acne and high triglyceride levels. Conversion CsA to SRL 3 months after transplantation combined with MMF is associated with improvement in renal function.

Depending on their degree of maturation, costimulatory molecule expression, and cytokine secretion, dendritic cells (DC) can induce immunity or tolerance. DC treated with mycophenolic acid during their maturation (MPA‐DC) have a regulatory phenotype and may therefore provide a new approach to induce allograft tolerance. Purified CD4+T cells stimulated in a human in vitro model of mixed culture by allogeneic MPA‐DC displayed much weaker proliferation than T cells activated by mature DC and were anergic. This hyporesponsiveness was alloantigen‐specific. Interestingly, T cells stimulated by MPA‐DC during long‐term coculture in four 7‐day cycles displayed potent, suppressive activity, as revealed by marked inhibition of the proliferation of naive and preactivated control T cells. These regulatory T cells (Tregs) appeared to have antigen specificity and were contact‐dependent. Tregs induced by MPA‐DC were CD25+glucocorticoid‐induced TNFR+CTLA‐4+CD95+, secreted IL‐5 and large amounts of IL‐10 and TGF‐β, and displayed enhanced forkhead box p3 expression. These results obtained in vitro demonstrate that human MPA‐DC can induce allospecific Tregs that may be exploited in cell therapy to induce allograft tolerance.

Risk factors for new-onset diabetes after transplantation (NODAT) need to be assessed in large cohorts.

Anti‐CD25 monoclonal antibodies are widely used in clinical transplantation to prevent acute allograft rejection. Although their effects on T lymphocytes have been extensively studied, their impact on human dendritic cells (DC) has never been reported. Furthermore, the role of the IL‐2 in DC functions has not yet been fully elucidated. In this study, we confirm that the stimulation of human monocyte‐derived DC with LPS strongly induced the expression of CD25 and that LPS‐matured DC also expressed the β and γ chain of the IL‐2R. We also showed that adding anti‐CD25 monoclonal antibodies to LPS induced a decrease in IL‐12, IL‐1, TNF‐α, IL‐6, and IFN‐γ production and an increase in IL‐10 synthesis by DC compared with stimulation with LPS alone. Furthermore, we showed that these modifications diminished the T helper priming ability of DC and polarized the alloimmune response toward TH2. In contrast, humanized anti‐CD25 monoclonal antibodies did not affect the up‐regulation of CD86, CD80, CD83, HLADR, or CD40 induced upon LPS stimulation. Taken together, this study discloses some previously unrecognized effects of anti‐CD25 monoclonal antibodies on DC that may contribute to their clinical efficacy. In addition, this study also shed some light on the role of the IL‐2 in human DC activation.

Proteinuria is constituted by urinary albumin (UAE) and nonalbumin proteins (NAP). UAE was shown to predict ESRD and death. Whether NAP predicts graft or patient outcome is unknown in renal transplantation. We retrospectively analyzed the impact of UAE and NAP respectively on end-stage renal disease (ESRD) and death in 616 renal transplant recipients. In subjects with proteinuria <0.25 gday, 76 of urine proteins were NAP; in those with >1 gday, 44 of the urine proteins were NAP. Determinants of UAE and NAP were partly different: fasting glucose, body weight, donor cause of death and cyclosporine were significantly associated with NAP (but not UAE); panel reactive antibodies (PRA) and rapamycine were significantly associated with UAE (but not with NAP). NAP expressed as a continuous (HR: per gday: 4.00 2.85-5.63, p < 0.0001) or a categorical (presence vs. absence, HR 29.098.80-96.20, p < 0.0001) parameter and UAE (per gday, HR 1.86 1.24-2.78, p < 0.0001) were risk factors for graft loss in univariate analyses. NAP remained significant even after adjustment on UAE. The presence of NAP (HR: 5.37 2.55-11.34, p < 0.0001) and macroalbuminuria (HR: 4.12 1.65-10.29, p 0.0024) were risk factors for death. Proteinuria is made of various proportions of UAE and NAP in renal transplantation; these two parameters provide different information on graftpatient survival.

To evaluate the efficacy and tolerance of a calcineurin inhibitor (CNI)-free regimen, 145 renal recipients were prospectively randomized to receive either sirolimus (n 71) or cyclosporine (CsA; n 74). All patients received polyclonal antilymphocyte antibodies, mycophenolate mofetil (MMF) and steroids (6 months). The primary endpoint, estimated glomerular filtration rate (eGFR) was not significantly different at 12 months comparing sirolimus- and CsA-treated patients (60 ± 27 vs. 57 ± 21 mLmin). At 12 months, patient and graft survival, incidence of biopsy-proven rejection and rates of steroid withdrawal were not statistically different (97 vs. 97; 90 vs. 93; 14.3 vs. 8.6 and 82.8 vs. 84.1, respectively). Delayed and slow graft function (SGF) was not significantly different (18.6 vs. 12.3 and 11.4 vs. 13.7, respectively). In patients who remained on treatment according to protocol at 12 months, eGFR was significantly higher with sirolimus (69 ± 19 vs. 60 ± 14 mLmin, p 0.01). Overall study drug discontinuation rates were 28.2 with sirolimus and 14.9 with CsA. Adverse events (wound complications, mouth ulcers, diarrhea, hypokalemia, bronchopneumonia) and proteinuria >0.5 g24h (38.8 vs. 5.6, p < 0.001) were significantly more frequent in sirolimus-treated patients. Cytomegalovirus (CMV) infections were significantly less frequent with sirolimus (6 vs. 23, p < 0.01). A CNI-free regimen using sirolimus-MMF can achieve excellent renal function, but patients on sirolimus experienced a high rate of adverse events and study drug discontinuation.

Background: Microalbuminuria and macroalbuminuria constitute risk factors for ESRD and death in non-transplanted populations. Whether microalbuminuria (especially in non-proteinuric patients) and macroalbuminuria constitute risk factors for graft loss and death is presently unknown in renal transplantation.

B-cell posttransplantation lymphoproliferative disorder (B-PTLD) is a rare but severe complication of transplantation, with no consensus on best treatment practice. This prospective trial, the first to test a treatment for PTLD, was designed to evaluate the efficacy and safety of rituximab in patients with B-PTLD after solid organ transplantation (SOT). Fortysix patients were included and 43 patients were analyzed. Patients were eligible if they had untreated B-PTLD that was not responding to tapering of immunosuppression. Treatment consisted of 4 weekly injections of rituximab at 375 mg/m2. At day (d) 80, 37 (86%) patients were alive, and the response rate was 44.2%, including 12 complete response/unconfirmed complete response (CR/CRu). The only factor predictive of a response at d80 was a normal lactate dehydrogenase level (P = .007, odds ratio [OR] = 6.9). At d360, responses were maintained in 68% of patients, and 56% of patients were alive. The overall survival rate at 1 year was 67%. We conclude that rituximab is effective and safe in PTLD, with stable responses at 1 year. The response rate and overall survival might be improved by combining rituximab with other treatments.

Proteinuria 1 year after transplantation is associated with poor renal outcome. It is unclear whether low-grade (<1 g/24 h) proteinuria earlier after transplantation and its short-term change affect long-term graft survival. The effects of proteinuria and its change on long-term graft survival were retrospectively assessed in 484 renal transplant recipients. One- and 3-month proteinuria correlated with donor age, donor cardiovascular death, prolonged cold and warm ischemia times and acute rejection. One- and 3-month proteinuria (per 0.1 g/24 h, hazard ratio (HR): 1.07 and 1.15, p < 0.0001)—especially low-grade proteinuria (HR: 1.20 and 1.26, p < 0.0001)—were powerful, independent predictors of graft loss. Its short-term reduction correlated with arterial pressure (AP) (the lower the 3-month diastolic and 12-month systolic AP, the lower the risk of increasing proteinuria during 1–3 months and 3–12 months periods, respectively: Odds ratio (OR) per 10 MmHg: 0.78, p = 0.01 and 0.85, respectively, p = 0.02), and was associated with decreased long-term graft loss (per 0.1 g/24 h: HR: 0.88 and 0.98, respectively, p < 0.0001), independently of initial proteinuria. Early low-grade proteinuria due to pre-transplant renal lesions, ischemia-reperfusion and immunologic injuries is a potent predictor of graft loss. Short-term reduction in proteinuria is associated with improved long-term graft survival.

Immature dendritic cells (DCs) can induce T-cell hyporesponsiveness, thus interfering with the process of DC maturation in a pro-inflammatory context, may therefore provide a novel approach to inducing allograft tolerance. We have studied the effects of mycophenolic acid (MPA), an immunosuppressive agent currently used in transplantation, using an in vitro model of a mixed human DC/alloreactive CD4+ T lymphocyte culture. DCs differentiated from monocytes were exposed to MPA during maturation. MPA treatment affected the maturation of DCs, and this was reflected both in the impairment of the up-regulation of co-stimulatory molecule expression and the maintained endocytic capacity. However, MPA-DCs exhibited a distinctive microscopic morphology and secreted IL-10 and so could no longer be regarded as immature DC. Moreover, MPA-DCs had a mature phenotype for chemokine receptor expression, exhibiting down-regulation of CCR5 and up-regulation of CCR7. Interestingly, the abilities of the MPA-DCs to induce CD4+ T-cell proliferation in response to alloantigens was impaired not only via direct but also via indirect pathways. The maintenance of endocytosis and the inhibition of syngeneic T-cell activation suggest that these cells could have a potential role to avoid chronic rejection. All these characteristics suggest that MPA-DCs may be used in cell therapy to induce allograft tolerance.

Genetic factors other than HLA have been reported to be associated with the outcome of organ transplantations. Because binding of FasL to its receptor Fas could play an important role in tubulitis and in the death of graft tubular epithelial cells during kidney allograft rejection, a gene polymorphism recently identified in position -671 in the promoter of the TNFRSF6 gene coding for Fas was investigated in donors.

Acute graft rejection remains a major problem in renal transplant recipients, and there is no consensus on the optimal immunosuppressive strategy. Immunoprophylaxis with Thymoglobulin^® or basiliximab has significantly reduced the incidence of acute rejection episodes and graft loss following kidney transplantation. This open, randomized, multicenter study investigated the efficacy and tolerability of basiliximab (20 mg day 0- day 4) plus early cyclosporine from day 0 (n = 50) compared with Thymoglobulin^® plus delayed cyclosporine (n = 50) in adult kidney transplant patients. In addition, all patients received steroids and mycophenolate mofetil (MMF) at standard doses from day 0. Patient and graft survival rates at 12 months were 98 and 94% in the basiliximab group, respectively, compared with 100 and 96% in the Thymoglobulin^® group. The incidences of biopsy-confirmed acute rejection (8.0% in each group) and treatment failure (14% in the basiliximab group vs. 8% in the Thymoglobulin group) were comparable in the two groups. There was a nonsignificant tendency to more dialysis (14 vs. 6%), and fewer cytomegalovirus (CMV) infections (p = 0.005) in the basiliximab group, but the percentage of clinical CMV was not different between the two groups (6 vs. 12%). Both strategies give excellent results, despite the differences in patterns, in nonhyperimmunized patients receiving their first cadaveric renal allograft.

Les excellents résultats de la transplantation au cours des dernières décennies ont mis en évidence de nouveaux défis à résoudre dans les années à venir : (1) Modifier les conditions de conservation des organes prélevés pour en améliorer la qualité. (2) Modifier les stratégies en prenant en compte le déficit immunitaire devant de nouvelles infections comme celle à Sars CoV-2. (3) Mieux comprendre les mécanismes du rejet chronique et en particulier le rôle de l’immunité innée. (4) Repenser les traitements immunosuppresseurs pour prévenir et traiter les rejets chroniques.

L’immunothérapie anti cancéreuse a fait une percée décisive dans les 10 dernières années avec les anticorps anti récepteurs inhibiteurs et les Car-T cells. Néanmoins une réponse clinique durable ne s’observe que chez une minorité de patients. Aussi de nouvelles perspectives doivent être envisagées pour améliorer l’efficacité de l’immunothérapie, telles que : 1 l’augmentation de l’immunogénicité de la tumeur. 2 l’activation de l’immunité innée. 3 le ciblage des lymphocytes T résidants mémoires. 4 l’analyse du rôle du microbiote intestinal.