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

International audience; Background & aims: Before antiviral therapy, kidney transplant recipients infected with hepatitis B virus (HBV) or hepatitis C virus (HCV) had poor outcomes. Since the 90s, nucleos(t)ide analogues have been widely used in HBV-infected patients, while interferon-based therapy was rarely used in HCV-infected patients. The aim of this study was to assess the impact of HBV and HCV on patient and graft survival, according to viral replication status.Methods: Data from January 1993 to December 2010 were extracted from the French national database CRISTAL. A total of 31,433 kidney transplant recipients were included, of whom 575, 1,060 and 29,798 had chronic hepatitis B, C, or were not infected, respectively.Results: Ten-year survival was lower in HCV-infected (71.3%) than in HBV-infected (81.2%, p = 0.0004) or non-infected kidney transplant recipients (82.7%, p

International audience; Longterm use of a calcineurin inhibitor (CNI)-based regimen is one of the major reasons for chronic renal failure in liver transplantation recipients (LTRs). The Everolimus Liver registry (EVEROLIVER) evaluated renal function in LTRs who were converted to everolimus (EVR). This observational registry included all LTRs receiving EVR across 9 centers from France. Data are being collected in an electronic database over 10 years (12 visits/patient) to evaluate efficacy, renal function (estimated glomerular filtration rate [eGFR]), and safety of EVR use in clinical practice, and the current analysis is reporting up to 60 months of findings. Until September 2017, 1045 patients received EVR after a mean time of 3.6 ± 5.1 years. CNI withdrawal was feasible in 57.7% of patients as of month 60. Mean eGFR improved in patients with baseline eGFR

International audience; The first cases of Severe Acute Respiratory Syndrome coronavirus 2 (SARS‐CoV‐2) occurred in France in early February and in our region (Southwest France) in early March 2020.

International audience; Background - Tacrolimus (TAC) is the cornerstone of immunosuppressive regimen in liver transplantation (LT). Its pharmacokinetics is characterized by a high interpatient and intrapatient variability (IPV) leading to an unpredictable dose-response relationship. The aim of our study was to evaluate the impact of TAC IPV (IPV) on graft and patient outcomes after LT. Methods - We retrospectively analyzed 812 LT recipients treated with TAC. The IPV of TAC concentrations was estimated by calculating the coefficient of variation (CV) of whole blood trough concentrations. Patients were categorized in 2 groups: low IPV (CV < 40%) and high IPV (CV ≥ 40%). Results - There were significantly more neurologic complications (31.2% vs 16.6%, P < 0.001), cardiovascular complications (19.7% vs 9.7%, P < 0.001), and acute renal failure requiring dialysis (8.5% vs 2.2%, P < 0.001) in the high CV group than in the low CV group. Moreover, graft survival was significantly poorer in the high CV group (hazard ratio, 1.42; 95% confidence interval, 1.04-1.95; P = 0.03). A pretransplantation elevated Model for End-Stage Liver Disease score (P < 0.001) and Child-Pugh grade (P < 0.001) were identified as risk factors for presenting a high CV. Conclusions - A high CV of TAC concentrations was found to be predictive of TAC-related toxicity and poorer survival.

International audience; Renal insufficiency can occur in patients with congenital lower urinary tract malformations (LUTM) even when managed during infancy. Data in the current literature concerning this subject remain sparse. The aim of this study was to report the feasibility and long-term results of renal transplantation during adulthood in patients with a congenital LUTM.Methods: A retrospective multicenter study from 3 French renal transplant centers was conducted, including 123 transplantations on 112 patients with LUTM (1996-2016). Graft survival, patient survival, and complications were analyzed. Results were stratified according to the underlying uropathy and the type of initial management during childhood or before transplantation.Results: In this study, patients suffering from posterior urethral valves (n = 49), spina bifida (n = 21), central neurogenic bladder (n = 13), bladder exstrophy (n = 14), prune belly syndrome (n = 12), Hinman syndrome (n = 6), urogenital sinus (n = 4), and other pathologies (n = 4) were included. The mean age at transplantation was 32.1 years old (±11.2). The mean follow-up period was 7.2 years. Patient survival at 1, 5, 10, and 15 years was 97.4%, 93.0%, 89.4%, and 80.0%, respectively. Graft survival at 1, 5, 10, 15, and 20 years was 96.6%, 87.6%, 77.3%, 60.6%, and 36.4%, respectively. Enterocystoplasty and continent urinary diversions exposed grafts to more frequent acute pyelonephritis (P = 0.02). There was no difference in graft survival when transplantation was performed on an enterocystoplasty or urinary diversions compared with a native bladder, provided a well-conducted bladder management.Conclusions: Even though enterocystoplasty and continent urinary diversions exposed grafts to more frequent acute graft pyelonephritis, patient and graft survival rates in LUTM at 10 years were similar to other kidney transplantations on native bladders.

International audience; The PIRCHE (Predicted Indirectly ReCognizable HLA Epitopes) score is an HLA epitope matching algorithm. PIRCHE algorithm estimates the level of presence of T-cell epitopes in mismatched HLA. The PIRCHE-II numbers associate with de novo donor-specific antibody (dnDSA) formation following liver transplantation and kidney allograft survival following renal transplantation. The aim of our study was to assess the PIRCHE-II score in calcineurin inhibitor (CNI)-free maintenance immunosuppression recipients. This was a retrospective study of forty-one liver transplant recipients on CNI-free immunosuppression and with available liver allograft biopsies. Donors and recipients were HLA typed. The HLA-derived mismatched peptide epitopes that could be presented by the recipient's HLA-DRB1 molecules were calculated using PIRCHE-II algorithm. The associations between PIRCHE-II scores and graft immune-mediated events were assessed using receiver operating characteristics curves and subsequent univariate and multivariate analyses. CNI-free patients with cellular rejection, humoral rejection, or severe portal inflammation had higher mean PIRCHE-II scores compared to patients with normal liver allografts. PIRCHE-II score and donor age were independent risk factors for liver graft survival in CNI-free patients (HR: 8.0, 95% CI: 1.3-49, p = .02; and HR: 0.88, 95% CI: 0.00-0.96, p = .007, respectively). PIRCHE-II scores could be predictive of liver allograft survival in CNI-free patients following liver transplantation. Larger studies are needed to confirm these results.

International audience; The impact of preemptive second kidney transplantation (2KT) on graft and patient survival is poorly established. The association between preemptive 2KT (p2KT, N = 93) and outcomes was estimated in a multicenter French cohort of 2KT (N = 1314) recipients using propensity score methods. During the follow-up, there were 274 returns to dialysis and 134 deaths. p2KT was associated with lower death-censored graft loss (HR = 0.39 [0.18-0.88], P = 0.024) and graft failure from any cause including death (HR = 0.42 [0.22-0.80], P = 0.008). Similar associations were observed for death with a functioning graft, although not reaching statistical significance (HR = 0.47 [0.17-1.26], P = 0.13). There was a significant interaction between donor type and p2KT (P for interaction = 0.016). Indeed, p2KT was not significantly associated with the risk of graft failure from any cause including death in living donor 2KT (P = 0.39), whereas the association was substantial in the deceased donor subset (HR = 0.30 [0.14-0.64], P = 0.002). Of note, the adjusted graft survival of p2KT with deceased donor paralleled that of 2KT with living donor, either preemptive or not (93.8% vs. 88.6% at 4 years and 76.1% vs. 70.5% at 8 years, P = 0.13). This large French multicenter study analyzed using propensity scores suggests that p2KT is associated with better graft prognosis.

Background: the aim of the study is to assess the consequences of subclinical rejection on long-term kidney allograft survival. Methods: we performed an observational prospective study including 1307 patients who underwent kidney transplantation in Paris (2005-2010). Clinically stable participants underwent prospective screening biopsies at one year post transplant, with concurrent evaluations of circulating anti-HLA antibodies. Results: the main analysis included 1001 patients. Three distinct groups of patients were identified at the 1-year screening: 727 (73%) patients without rejection, 132 (13%) patients with subclinical T cell-mediated rejection (sTCMR) and 142 (14%) patients with subclinical antibody-mediated rejection (sABMR). Patients with sABMR had the poorest graft survival at 8 years post-transplant (56%) compared with subclinical TCMR (88%) and non-rejection (90%) groups (P

International audience; BACKGROUND: We investigated a novel allotransplantation model using an aortocava patch in ewes. METHODS AND RESULTS: We carried out 10 uterine orthotopic allotransplantations in ewes with end-to-side anastomosis of the aortocava donor patch on the left external iliac vessel recipient. The immunosuppressive protocol was a combination of cyclosporine (10 mg/kg/day) and mycophenolic acid (3 g/day). An estimation of the immunosuppressive therapy exposure was performed by measuring the area under the curve (AUC) of immunosuppressive plasma concentrations. The graft was assessed by vaginoscopy, magnetic resonance imaging (MRI) and second look laparotomy at 6, 8 and 10 weeks, respectively. The median (range) times for cold and warm ischemia were 95 min (75-130) and 91 min (55-165), respectively. All the vascular anastomoses were patent at the end of the surgery. The median AUC of cyclosporine and mycophenolic acid were 1.24 mg h/l (0.34-3.85) and 18.40 mg h/l (3.76-42.35), respectively. Of the 10 ewes receiving a transplant, 6 could be assessed. Cervical biopsies showed signs of necrosis in all six ewes. The MRI results correlated with the macroscopic observations of the 'second look' laparotomy. The aortocava vascular pedicles were thrombosed, adding to the peripheral neovascularization. Graft histology showed endometrial tissue in two out of six ewes. CONCLUSIONS: Mobility of the transplant within the pelvis, the length of the vascular pedicle and rejection can explain the high rate of transplant necrosis. The particular digestive anatomy and physiology of ruminants makes it difficult to administer an optimal immunosuppressive treatment. MRI appears to be a good non-invasive examination for graft estimation.

International audience; Fetal neurons (embryonic age E16) of occipital origin grafted in the visual cortex of albino rats at increasing postnatal stages (P0, P7, P15, P30, P60, P120) can be activated by photic stimulation. Inputs originate from five major areas of the brain ipsilateral to the graft, namely, the claustrum, the periallocortex/proisocortex, the isocortex, the visual thalamus, and some unspecific subthalamic and hypothalamic nuclei. All inputs decrease in number with the age at which grafting was performed. Isocortical afferents exhibit furthermore a progressive laminar shaping. In neonates, layer II-III and layer V-VI neurons contribute equally to the graft input. In adults, grafts receive prominent input (approximately 70-80%) from layer VI neurons whereas layer II-III neurons account for less than 10%. Proportions of layer IV (approximately 2-4%) and layer V (approximately 15-20%) neurons innervating the graft remain stable, irrespective of the age of the recipient. The adult pattern of connectivity between the host brain and the graft establishes in frontal and temporal areas 1 week earlier than in occipital areas. It is nearly completed in postnatal day 15 (P15) grafted recipients. Supragranular neurons would be thus unable to innervate and to make stable synapses at the graft level beyond P15, i.e., when eyes open. Some infragranular neurons (supposedly remnants of the earliest generated cortical cell population) still have this capacity in adults.

Background: Since 2002, allocation policies have changed to allow transplantation using expanded criteria donors (ECD). The aim of this thesis is to assess the outcomes of transplantation using kidneys from expanded criteria donor.Methods: Patients who received kidney allografts on three transplantation centers in Paris between January 1, 2004 and January 1, 2011, were included in this study (N=1613). The type of donor was defined as standard (SCD) or expanded criteria donors (ECD). Clinical, biological, histological parameters and the presence of circulating donor-specific anti-HLA antibodies were screened for all the recipients at the time of transplantation. The main outcome was the kidney allograft loss. Results were replicated in an external validation cohort of 1150 kidneys recipients (Toulouse).Results: The 7-years kidney allograft survival was 80.7% for ECD recipients and 90.9% for SCD recipients (pConclusion: The excellent kidney allograft survival of ECD kidneys incites allocation policies of these kidneys in particular if the recipient has no DSA at the time of transplantation.; Rationnel : Depuis 2002 les politiques d’attribution des greffons ont évolué, permettant la transplantation de greffons rénaux issus de donneurs à critères élargis (ECD). L’objectif de cette thèse est d’étudier les résultats de la transplantation rénale chez les patients recevant un greffon ECD en comparaison des greffons standard (SCD).Méthodes : Les patients ayant reçu un greffon rénal dans 3 centres parisiens entre janvier 2004 et janvier 2011 ont été inclus dans cette étude (n=1613). Les paramètres cliniques, biologiques, histologiques et les anticorps anti-HLA dirigés contre le donneur (DSA) ont été recherchés pour tous les receveurs le jour de la transplantation. Le critère d’évaluation principal était la perte de greffon. Les résultats ont été évalués sur une cohorte indépendante de 1150 patients (Toulouse).Résultats : La survie à 7 ans post-transplantation des greffons issus de donneurs ECD était de 80,8% contre 90,9% dans le groupe de patients greffés avec des reins issus de donneurs SCD (pConclusion : La survie excellente des greffons issus des reins ECD encourage les politiques d’attribution de ces reins et ce d’autant plus que le receveur n’a pas de DSA circulant le jour de la transplantation.

International audience; Objectives: To determine the impact of renal graft nephrectomy on second kidney transplantation survival.Methods: We carried out a retrospective single-center study by analyzing cases performed from January 2000 to December 2011. Retransplanted patients who underwent previous allograft nephrectomy more than 3 months post-transplantation (group 1) were compared with those who did not (group 2) in terms of graft survival, incidences of acute rejection and delayed graft function. Multivariate Cox proportional hazard models were used to assess risk factors of graft loss after retransplantation.Results: Overall, 146 patients were analyzed, including 52 (35.6%) in group 1 and 94 (64.4%) in group 2. Group 1 patients presented a significantly shorter first graft survival (0.8 vs 8.6 years, P < 0.001) and more anti-class I antibodies (90.5% vs 74.2%, P = 0.03). A total of 10 patients (19%) in group 1 and 16 patients (17%) in group 2 had at least one acute rejection episode (P = 0.74). Delayed graft function was observed in 13 patients (25%) in group 1 and 17 patients (18%) in group 2 (P = 0.32). Graft survival at 1, 5 and 10 years was, respectively, 94%, 81% and 58% in group 1, and 99%, 93% and 66% in group 2 (P = 0.10). Graft survival was decreased by increased donor age and serum creatinine, and tended to be associated with post-transplantation presence of anti-class I and II antibodies. Graft nephrectomy was not associated with graft survival in multivariate analysis.Conclusions: Graft nephrectomy, probably a marker of high immunological risk patients, is not a risk factor of increased retransplant failure.

International audience; BACKGROUND: Machine perfusion use has been reported to promote graft outcome in case of donation after cardiac death. Our objective was to evaluate the potential for nuclear magnetic resonance (NMR) to predict graft outcome by analyzing perfusates during machine perfusion time. METHOD: We used a renal autotransplantation model mimicking deceased after cardiac death donors with pigs. Organs were subjected to 60 min of warm ischemia before the hypothermic machine preservation during 22 hr. We studied the correlation between creatinemia after transplantation and the NMR data from perfusates. RESULTS: A metabonomic analysis allowed us to highlight the evolution of several metabolites during perfusion: the concentration of lactate, choline, or amino acids such as valine, glycine, or glutamate increased with time, whereas there was a diminution of total glutathione during this period. The changes in these biomarkers were less severe in the group with the better outcome. Statistical analysis revealed a strong association between the level of those metabolites during machine perfusion and function recovery (Spearman rank ≥0.89; P

International audience; Organ shortage is a major problem in organ transplantation. For this reason, transplantation teams have found it necessary to revisit their organ acceptance criteria. Uncontrolled deceased donors after cardiac arrest could increase the donor pool by 20%, but at the same time there is a greater risk of delayed graft function and primary non‐function. Dual kidney transplantation is an option when single kidney transplantation cannot be carried out because of lack of organ quality. We report for the first time our four first dual kidney transplantation from uncontrolled deceased donors after cardiac arrest with a follow up longer than 1 year. We described graft outcomes until 5 years, and histology at 3 and 12 months after transplantation. All organs were machine perfused in order to assess their quality leading to a single kidney transplantation or dual kidney transplantation decision. After 1 year of follow up, all grafts were functional with a mean estimated glomerular filtration rate of 44.5 ± 3.3 mL/min/1.73 m2, and a mean inulin clearance of 43.7 ± 13.6 mL/mn/1.73 m2. These findings suggest that dual kidney transplantation can represent a viable option for kidneys unsuitable for single kidney transplantation without increasing the rate of surgical complications. Successful transplantation is linked to histological, biological and donor clinical criteria, as well as perfusion parameters.

International audience; During the transplantation procedure, ischemia reperfusion is an inevitable situation characterized by specific pathophysiological processes, which ultimately act synergistically to create injuries in the graft. These injuries are involved in early graft dysfunctions which promote chronic dysfunction and compromise graft outcome. Progresses in immunosuppressive drug regimens now place ischemia reperfusion injury control at the forefont for innovative therapeutic strategy to improve the quality of the graft. This review details these different processes and its consequences on renal graft function underlying the interest of novel therapeutic strategy.

Purpose We report herein the incidence of and factors predisposive to surgical complications (SC) after renal transplantation. Methods Between 2004 and 2008, we performed 200 renal transplantation. We retrospectively studied recipient and donor characteristics, cold ischemia time, surgical revision in the month after transplantation, delayed graft function, surgical complications (vascular, urologic, wound, or bleeding), as well as graft and patient 5-year survival rates. Results Sixty-six surgical complications were reported among 49 patients with a preponderance of urologic complications. We noted 6.1% Clavien I, 1.5% Clavien II, 30.3% Clavien IIIa, 53% Clavien IIIb, and 9.1% Clavien IVa SCs. Vascular complications showed a worse prognosis. Among recipients, dialysis duration before transplantation (40.3 ± 50.8 months in SCs versus 28 ± 26.5 months in the control unaffected group, P = .032) and anti-HLA immunization (34.7 ± 48% versus 21.2 ± 41%, P = .05) appeared to be risk factor. No significant factor was identified among donors, although patients with surgical complications received older transplants than the control popuation (49.7 ± 14.5 years versus 45.5 ± 15.1 years, P = .08). A greater percentage of delayed graft function (30.6 ± 46.6% versus 11.4 ± 31.9%; P = .001) and graft rejection episodes (34.7 ± 48.1% versus 17.9 ± 38.4%, P .013) were observed among the SC compared with the control group. No significant difference in patient (89.5% versus 95.6% confidence interval, CI 95% [0.7–10.0]; P = .14) or graft survival (88.7% versus 91.8%, CI 95% [0.4–3.9] P = .63) was observed between the groups. Conclusion Surgical complications, especially urologic complications appear frequently after renal transplantation. Dialysis duration and pre-transplant immunization were linked to the occurrence of a surgical complication, which did not affect graft or patient survival.

International audience; Atypical hemolytic and uremic syndrome (aHUS) is a severe disease strongly associated with genetic abnormalities in the complement alternative pathway. In renal posttransplantation, few data are available on recurrence risk and graft outcome according to genetic background in aHUS patients. The aim of this study was to identify risk factors for recurrence and transplant outcome and, in particular, the role of complement gene abnormalities. We retrospectively studied 57 aHUS patients who had received 71 renal transplants. A mutation in complement gene was identified in 39 (68%), in factor H (CFH), factor I (CFI), membrane cofactor-protein (MCP), C3 and factor B (CFB). At 5 years, death-censored graft survival was 51%. Disease recurrence was associated with graft loss (p = 0.001). Mutations in complement genes were associated with higher risk of recurrence (p = 0.009). Patients with CFH or gain of function (C3, CFB) mutations had a highest risk of recurrence. M-TOR inhibitor was associated with significant risk of recurrence (p = 0.043) but not calcineurin inhibitor immunosuppressive treatment (p = 0.29). Preemptive plasmatherapy was associated with a trend to decrease recurrence (p = 0.07). Our study highlights that characterization of complement genetic abnormalities predicts the risk of recurrence-related graft loss and paves the way for future genetically based individualized prophylactic therapeutic strategies.

International audience; Optimizing kidney preservation is a primary issue in transplantation, particularly in relation to new donor sources, such as expanded criteria donors (ECDs) and donation after cardiac death (DCD). Kidneys from these donors are highly sensitive to ischemia-reperfusion injuries--the emblematic lesions encountered during transplantation. Despite years of research, static cold storage, with solutions designed in the 1980s, remains the gold standard in kidney transplantation. This kind of preservation, however, is unable to fully protect an ECD or DCD kidney, highlighting the need for novel strategies to improve kidney preservation or promote kidney recovery. This Review provides an overview of the emerging strategies to prevent ischemia-reperfusion injuries in donor kidneys and describes strategies that are aimed at the donor, organ or recipient to improve graft outcome. These approaches include management of donors, preconditioning of the kidney, improvements in organ preservation solutions, postconditioning and regenerative therapies of the kidney graft following transplantation. In addition, machine perfusion provides an interesting opportunity to evaluate kidney graft quality before transplantation. Overall, a combination of therapeutic approaches seem to provide the best outcome, but preclinical studies using relevant models are needed before these approaches can be incorporated into clinical practice.

International audience; A large prospective, open-label, randomized trial evaluated conversion from calcineurin inhibitor (CNI)- to sirolimus (SRL)-based immunosuppression for preservation of renal function in liver transplantation patients. Eligible patients received liver allografts 6-144 months previously and maintenance immunosuppression with CNI (cyclosporine or tacrolimus) since early posttransplantation. In total, 607 patients were randomized (2:1) to abrupt conversion (

International audience; Ischemia/reperfusion injury occurring during liver transplantation is mainly due to the generation of reactive oxygen species (ROS) upon revascularization. Thus, delivery of antioxidant enzymes might reduce the deleterious effects of ROS and improve liver graft initial function. Mangafodipir trisodium (MnDPDP), a contrast agent currently used in magnetic resonance imaging of the liver, has been shown to be endowed with powerful antioxidant properties. We hypothesized that MnDPDP could have a protective effect against liver ischemia reperfusion injury when administrated to the donor prior to harvesting. Livers from Sprague Dawley rats pretreated or not with MnDPDP were harvested and subsequently preserved for 24 h in Celsior® solution at 4°C. Organs were then perfused ex vivo for 120 min at 37°C with Krebs Henseleit solution. In MnDPDP (5 µmol/kg) group, we observed that ATP content was significantly higher at the end of the cold preservation period relative to untreated group. After reperfusion, livers from MnDPDP-treated rats showed better tissue integrity, less hepatocellular and endothelial cell injury. This was accompanied by larger amounts of bile production and higher ATP recovery as compared to untreated livers. The protective effect of MnDPDP was associated with a significant decrease of lipid peroxidation, mitochondrial damage, and apoptosis. Interestingly, MnDPDP-pretreated livers exhibited activation of Nfr2 and HIF-1α pathways resulting in a higher catalase and HO-1 activities. MnDPDP also increased total nitric oxide (NO) production which derived from higher expression of constitutive NO synthase and lower expression of inducible NO synthase. In conclusion, our results show that donor pretreatment with MnDPDP protects the rat liver graft from cold ischemia/reperfusion injury and demonstrate for the first time the potential interest of this molecule in the field of organ preservation. Since MnDPDP is safely used in liver imaging, this preservation strategy holds great promise for translation to clinical liver transplantation.

International audience; Although end-stage renal disease related to AA amyloidosis nephropathy is well characterized, there are limited data concerning patient and graft outcome after renal transplantation. We performed a multicentric retrospective survey to assess the graft and patient survival in 59 renal recipients with AA amyloidosis. The recurrence rate of AA amyloidosis nephropathy was estimated at 14%. The overall, 5- and 10-year patient survival was significantly lower for the AA amyloidosis patients than for a control group of 177 renal transplant recipients (p = 0.0001, 0.028 and 0.013, respectively). In contrast, we did not observe any statistical differences in the 5- and 10- year graft survival censored for death between two groups. AA amyloidosis-transplanted patients exhibited a high proportion of infectious complications after transplantation (73.2%). Causes of death included both acute cardiovascular events and fatal septic complications. Multivariate analysis demonstrated that the recurrence of AA amyloidosis on the graft (adjusted OR = 14.4, p = 0.01) and older recipient age (adjusted OR for a 1-year increase = 1.06, p = 0.03) were significantly associated with risk of death. Finally, patients with AA amyloidosis nephropathy are eligible for renal transplantation but require careful management of both cardiovascular and infectious complications to reduce the high risk of mortality.

International audience; 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 m(2) versus 57.1 mL/min/1.73 m(2) (p = 0.013) and in the on-treatment population (OT): 67.5 mL/min/1.73 m(2) versus 57.4 mL/min/1.73 m(2) (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.

International audience; The purpose of this prospective, nine-center, non-randomized study was to assess the efficacy and safety of Celsior preservation fluid in liver transplantation using unselected donors. As data comparing allograft outcomes following liver transplantation using Celsior and University of Wisconsin (UW) preservation fluids are limited, we also compared our cohort with matched controls selected from the European Liver Transplant Registry (ELTR) who received total liver grafts preserved with UW solution during the same period. One hundred and forty patients who received livers preserved with Celsior were included. The primary endpoint, graft loss at one-yr post-transplantation, was observed in 24 patients (17.1%) which was not significantly different from the 20.0% pre-defined threshold rate (95% confidence interval [CI] 10.9, 23.4; p=0.398). Predictive factors for graft loss on univariate analysis were moderate-to-severe steatosis on the donor graft (5/22 patients with graft loss vs. 8/107 patients without, p=0.046) and duration of warm ischemia (1.4±1.1 h in patients with graft loss vs. 0.9±0.5 h in patients without, p=0.034). Hepatic artery thrombosis and stenosis occurred in seven (5.0%) and six (4.3%) patients, respectively. The comparison of our patients to 420 ELTR controls showed that one-yr graft survival rates (Celsior: 82.9%, 95% CI 75.8, 88.2; UW: 78.6%, 95% CI 74.4, 82.2) and Kaplan-Meier one-yr graft survival distributions (p=0.285) were similar. Within the cold ischemia time achieved in our study, liver preservation with Celsior appeared efficient and safe. Comparison with ELTR patients suggested that liver allograft survival was similar using Celsior or UW solution for preservation of unselected donor grafts.

Communication suite à la séance du 31 mai 2011 "Optimiser la reprise fonctionnelle d'un greffon en attente de transplantation" - 21 pages; National audience; There is a shortage of heart donors. Some available organs are lost through deterioration prior to transplantation. Indeed, from the moment of brain death until reperfusion in the recipient, cardiac grafts (and also kidney, lung and liver grafts) can undergo irreversible damage due to cardioplegia, the harvesting procedure, and hypothermic transport. The noxious phenomena occurring during cold ischaemia and myocardial reperfusion have been studied for more than 40 years. It was long believed that only the ischaemic phase was harmful, through depletion of energy stores, ionic imbalance, and metabolic disruption. We now know that the heart graft can also be damaged during the reperfusion phase, through calcium overload, free radical production, and mitochondrial changes. Preconditioning and post-conditioning procedures are being developed to protect the ischemic organ.

International audience; Tacrolimus, a cornerstone immunosuppressant, is available as a twice-daily formulation (tacrolimus bid). A once-daily prolonged-release formulation (tacrolimus qd) has been developed. This 6-week, randomized, phase 2, multicenter, open-label, prospective trial in primary liver transplant recipients investigated and compared the pharmacokinetics (PK) of tacrolimus for qd and bid formulations. All patients received tacrolimus-based immunosuppression (tacrolimus qd, n = 67; bid, n = 62). PK data were available for 77 patients (tacrolimus qd, n = 45; bid, n = 32). Tacrolimus area under the curve (AUC) from 0 to 24 hours (AUC(0-24) ) at equivalent doses was approximately 50% lower for tacrolimus qd than for bid on day 1 (146 versus 264 ng * h/mL, respectively), but by day 14 was comparable between treatments (324 and 287 ng * h/mL, respectively) with higher tacrolimus qd doses. There was a strong correlation between AUC(0-24) and concentration at 24 hours for tacrolimus qd and bid (r = 0.92 and r = 0.76, respectively). Furthermore, the relationship between these 2 parameters (ie, the slope of the line) was also similar for the 2 formulations. Efficacy endpoints were comparable for both formulations at 6 weeks with no marked differences in incidence, nature, or severity of adverse events between treatments (although the study was not powered to draw efficacy conclusions). These results suggest that targeting the same trough levels will achieve similar total AUC over 24 hours for both tacrolimus qd and tacrolimus bid in de novo liver transplant recipients.

International audience; Allogeneic haematopoietic stem-cell transplantation (HSCT) is the only curative treatment for myelofibrosis. We report an analysis of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) registry including patients with myelofibrosis transplanted between 1997 and 2008. Potential risk factors affecting engraftment, non-relapse mortality (NRM), overall survival (OS) and progression-free survival (PFS) were analysed. One hundred and forty-seven patients, aged 20-68 (median 53) years, diagnosed with primary (53%) or secondary myelofibrosis underwent HSCT; 59% of patients were transplanted from a matched sibling donor. The conditioning regimen was myeloablative in 31% of patients. Ninety percent of the patients engrafted. Factors affecting favourably engraftment were splenectomy before HSCT, human leucocyte antigen (HLA) matched sibling donor, peripheral stem cell use as source of stem cells and absence of pre-transplant thrombocytopenia. Four-year OS, PFS and NRM survival were 39% (95%confidence interval [CI]: 31-50), 32% (95%CI: 24-43) and 39% (95%CI 30-48), respectively. Multivariate analysis indicated that HLA-identical sibling donor, chronic phase disease and splenectomy in men had favourable impact on OS.

Communication suite à la séance du 31 mai 2011 "Optimiser la reprise fonctionnelle d'un greffon en attente de transplantation" - 21 pages; National audience; There is a shortage of heart donors. Some available organs are lost through deterioration prior to transplantation. Indeed, from the moment of brain death until reperfusion in the recipient, cardiac grafts (and also kidney, lung and liver grafts) can undergo irreversible damage due to cardioplegia, the harvesting procedure, and hypothermic transport. The noxious phenomena occurring during cold ischaemia and myocardial reperfusion have been studied for more than 40 years. It was long believed that only the ischaemic phase was harmful, through depletion of energy stores, ionic imbalance, and metabolic disruption. We now know that the heart graft can also be damaged during the reperfusion phase, through calcium overload, free radical production, and mitochondrial changes. Preconditioning and post-conditioning procedures are being developed to protect the ischemic organ.

International audience; OBJECTIVE: To assess the efficacy of partial ossicular chain reconstruction using autologous cartilage. DESIGN: Prospective study (April 1, 1997, through January 1, 2008). SETTING: Tertiary academic children's hospital. PATIENTS: Two hundred forty-eight children (268 ears) underwent partial ossicular chain reconstruction using a shaped block of tragal cartilage interposed between the head of the stapes and an underlay tympanic membrane reconstruction along with tragal cartilage and its perichondrium. MAIN OUTCOME MEASURES: Anatomical and audiologic results were evaluated according to the American Academy of Otolaryngology-Head and Neck Surgery guidelines. χ² Tests and multivariate analysis were used for statistical evaluation. RESULTS: Mean age at surgery was 10.9 years. Single-stage surgery was performed in 124 ears (46.3%) (62.9% for cholesteatomas and 32.3% for retraction pockets). Second-look patients (53.7%) included 93.8% of staged surgery. Audiometric results were available for 222 ears at 1 year and for 78 ears at 5 years. Closure of the average air-bone gap (ABG) to within 20 dB was achieved in 62.2% of ears at 1 year. The mean (SD) preoperative and 1-year postoperative ABGs were 25 (11.8) dB and 18.9 (10.3) dB, respectively. Anatomical results were satisfactory in 87.3%. No cases of extrusion, resorption, or displacement of the cartilage were encountered. No statistically significant difference was found between audiometric results at 1 and 5 years. Multivariate analysis showed a significant negative correlation between preoperative and postoperative ABGs and between postoperative otitis media with effusion and postoperative ABG (P < .05). CONCLUSIONS: Cartilage ossiculoplasty is a reliable technique for partial ossicular replacement. Long-term hearing outcomes remain stable and satisfactory. Preoperative ABG and postoperative otitis media are the predictive factors of the hearing outcome.

The mechanisms underlying tolerance to noninherited maternal Ags (NIMA) are not fully understood. In this study, we designed a double-transgenic model in which all the offspring’s CD8+ T cells corresponded to a single clone recognizing the Kb MHC class I protein. In contrast, the mother and the father of the offspring differed by the expression of a single Ag, Kb, that served as NIMA. We investigated the influence of NIMA exposure on the offspring thymic T cell selection during ontogeny and on its peripheral T cell response during adulthood. We observed that anti-Kb thymocytes were exposed to NIMA and became activated during fetal life but were not deleted. Strikingly, adult mice exposed to NIMA accepted permanently Kb+ heart allografts despite the presence of normal levels of anti-Kb TCR transgenic T cells. Transplant tolerance was associated with a lack of a proinflammatory alloreactive T cell response and an activation/expansion of T cells producing IL-4 and IL-10. In addition, we observed that tolerance to NIMA Kb was abrogated via depletion of CD4+ but not CD8+ T cells and could be transferred to naive nonexposed mice via adoptive transfer of CD4+CD25high T cell expressing Foxp3 isolated from NIMA mice.

International audience; Different models have been developed to understand the biology of skin or to test pharmaceutical/cosmetic products. These models can be in vitro models that possess advantages such as mono and co-culture models in 2D, which are very reproducible, or organotypic models (skin explant and reconstructed skin) that present a 3D organisation. Animal or human in vivo models allow studies that are closer to reality. In virtuo models developed on computers control all known parameters and do not require animals. The major limitations of these models are the lack of 3D structure for in vitro culture, the variability of results from organotypic models, ethical problems inherent to human and animal tests and the presence of numerous unknown parameters in in virtuo systems. Despite their limitations, skin explants seem to be an interesting model for studies. Skin explants may be kept from a few hours to 10-14 days on supports or directly in culture medium. These explants are generally cultivated at 37 °C, 5% CO(2), preferentially in serum-free conditions. Three basic techniques are used to characterise these models: histological stains, proliferation, apoptosis and cytotoxicity tests. Skin explants could be a very convenient model to study wound-healing, inflammation processes, autoimmune diseases, malignant transformation, stress, ageing, and to serve as screening tests.

International audience; A new mycophenolate (MPA) assay based on the enzymatic activity of recombinant type II inosine monophosphate dehydrogenase (the pharmacological target of MPA) with excellent correlation with high-performance liquid chromatography has recently been released for the measurement of MPA plasma levels. This study aimed to (1) compare this new assay with liquid chromatography tandem mass spectrometry (LC-MS/MS) for MPA pharmacokinetic (PK) studies in different populations of allograft recipients given mycophenolate mofetil, (2) develop specific Bayesian estimators for this inhibition assay and test their accuracy, and (3) compare the resulting MPA area under the curve (AUC0-12h) estimates with those of Bayesian estimators developed based on the LC-MS/MS results. Sixty-four adult or pediatric, renal or lung transplant patients who were administered mycophenolate mofetil in association with cyclosporine, tacrolimus, or sirolimus at different post-transplant periods were enrolled as part of different PK studies. Eight hundred ninety-four patients' samples were analyzed in parallel with the enzymatic MPA assay and a reference LC-MS/MS method. Repeated analysis of quality control samples showed a mean difference of 6% between the 2 assays, whereas the results obtained in different populations of transplanted patients showed excellent correlation (r2 > 0.96) and small mean relative differences (2.0%-16.9%). The full profiles obtained with both assays were adequately fitted using either a 2-compartment model with 1 "gamma" absorption phase or a 1-compartment model with 2 gamma inputs. Several PK parameters were significantly affected by the analytical method used. Accurate Bayesian estimators could be specifically developed for the enzymatic MPA assay, using the same 3 concentration-time points (20 minutes, 1 hour, and 3 hours post dose) as with LC-MS/MS, with a median bias versus reference (trapezoidal) AUC0-12h values of -1.3% (range -45.2% to 40.4%), and 83% of the patients within +/-20% of the reference. These Bayesian estimates were significantly higher than those obtained with LC-MS/MS in patients on cyclosporine or sirolimus, but not in patients on tacrolimus.

International audience; The role of allogeneic hematopoietic cell transplantation (alloHCT) in human immunodeficiency virus (HIV)-positive patients is not known. Using the Center for International Blood and Marrow Transplant Research database, we retrospectively evaluated 23 HIV-positive patients undergoing matched sibling donor (n = 19) or unrelated donor (n = 4) alloHCT between 1987 and 2003. The median age at alloHCT was 32 years. Indications for alloHCT were diverse and included malignant (n = 21) and nonmalignant (n = 2) hematologic disorders. Nine patients (39%) underwent transplantation after 1996, the approximate year that highly active antiretroviral therapy became standard treatment. The median time to neutrophil engraftment was 16 days (range, 7 to 30 days), and the cumulative incidences of grade II-IV acute graft-versus-host disease (aGVHD) at 100 days, chronic GVHD (cGVHD), and survival at 2 years were 30% (95% confidence interval [CI] = 14% to 50%), 28% (95% CI = 12% to 48%), and 30% (95% CI = 14% to 50%), respectively. At a median follow-up of 59 months, 6 patients were alive. Survival appears to be better in the patients undergoing alloHCT after 1996; 4 of these 9 patients survived, compared with only 2 of 14 those undergoing transplantation before 1996. These data suggest that alloHCT is feasible for selected HIV-positive patients with malignant and nonmalignant disorders. Prospective studies are needed to evaluate the safety and efficacy of this modality in specific diseases in these patients.

International audience; Remissions of haematological malignancies have been reported after allo-SCT, despite donor cell rejection, suggesting that sustained allogeneic engraftment is not mandatory to obtain a lasting anti-tumour effect. To evaluate the potential benefit from transient post-allo-SCT alloreactivity, we took advantage of the Société Française de Greffe de Moëlle et Thérapie Cellulaire (SFGM-TC) registry to colligate 14 patients with an efficient and long-lasting allogeneic (GVL) effect after allo-SCT for haematological malignancies, despite transient or absent engraftment. None received a second allogeneic graft after autologous recovery. The median duration of remission after autologous reconstitution was 118 (12-252) months. Although we cannot exclude the possibility that some patients were cured before allo-SCT, this retrospective analysis does strongly suggest that an efficient GVL effect can be observed without sustained donor engraftment, and that the transient presence of donor T cells might be sufficient to induce a powerful GVL effect.

International audience; A G-->C polymorphism has been identified in the human cyclooxygenase-2 (COX-2) gene promoter at position -765 with C allele leading to a decreased promoter activity with low prostaglandin E2 (PGE2) production. PGE2 has strong immunomodulatory properties that could influence graft survival. We studied the association between this polymorphism and allograft failure in two independent cohorts of renal transplant recipients (RTRs) including a total of 603 patients. The functional effect of COX-2 gene promoter polymorphism was analyzed by measuring serum levels of PGE2. Median follow-up was 8.7 and 7.9 years for the first and second cohort, respectively. Analysis of 603 patients identified 20 CC (3.3%), 179 GC (29.7%) and 404 GG (67%) carriers. Patients with the GG genotype had significantly higher serum PGE2 concentrations than patients with the C allele. Carriers with a C allele have an independent increased risk of graft loss (hazard ratio (HR) 2.43 [95% CI 1.19-4.97], p = 0.015 for cohort 1; HR 1.72 [95% CI 0.99-3.77], p = 0.051 for cohort 2) compared to GG patients. COX-2 gene promoter polymorphism at position -765 (G-->C) is associated with a higher rate of graft loss in RTRs. Such findings may be used to influence immunosuppressive strategies and optimize patient management.

International audience; In this single-institution study, we compared outcomes in diabetic recipients of living donor (LD) kidney transplants that did vs. did not undergo a subsequent pancreas transplant. Of 307 diabetic recipients who underwent LD kidney transplants from January 1, 1995, through December 31, 2003, a total of 175 underwent a subsequent pancreas after kidney (PAK) transplant; 75 were deemed eligible (E) for, but did not receive (for personal or financial reasons), a PAK, and thus had a kidney transplant alone (KTA); and 57 deemed ineligible (I) for a PAK because of comorbidity also had just a KTA. We analyzed the three groups (PAK, KTA-E, KTA-I) for differences in patient characteristics, glycemic control, renal function, patient and kidney graft survival rates, and causes of death. Kidney graft survival rates (actuarial) were similar in the PAK vs. KTA-E groups at one, five, and 10 yr post-transplant: 98%, 82%, and 67% (PAK) vs. 100%, 84%, and 62% (KTA-E) (p = 0.9). The long-term (greater than four yr post-transplant) estimated glomerular filtration rate (GFR) was higher in the PAK than in the KTA-E group: 53 +/- 20 mL/min (PAK) vs. 43 +/- 16 mL/min (KTA-E) (p = 0.016). The patient survival rates were also similar for the PAK and KTA-E groups. We conclude that the subsequent transplant of a pancreas after an LD kidney transplant does not adversely affect patient or kidney graft survival rates; in fact, it is associated with better long-term kidney graft function.

International audience; BACKGROUND: The type 1 plasminogen activator inhibitor (PAI-1) is involved in the development of fibrosis, and its intrarenal expression is increased in interstitial fibrosis and tubular atrophy (IFTA). Moreover, a 4G/5G polymorphism of the PAI-1 gene has been described associating 4G haplotype with higher PAI-1 plasma activity. We investigated the relationship between the donor and recipient PAI-1 polymorphism and kidney graft survival. METHODS: The PAI-1 genotype was determined for both the 304 donors and the 337 corresponding recipients. In recipients, PAI-1 antigen levels were also determined. We compared 4G/4G donors versus donors with other genotypes. RESULTS: Donor or recipient genotype did not influence the PAI-1 plasma level in recipients. Actuarial kidney graft survival was significantly reduced in the 4G/4G donor group (107 months versus 147.5 months, P = 0.013), while recipient PAI-1 genotype did not show any influence on graft survival. Moreover, graft loss due to IFTA proved significantly higher in the 4G/4G donor group (13% versus 6%, P = 0.03). Multivariate analysis showed that the significant independent variables associated with graft loss were the donor 4G/4G genotype, acute clinical rejection and donor age. CONCLUSION: Our study suggests that donor PAI-1 polymorphism influences kidney graft survival and that the donor 4G/4G genotype is an independent risk factor for graft loss. Prospective studies are needed to confirm these results.

Liver ischemia-reperfusion injury occurring in orthotopic liver transplantation (OLT) may be responsible for early graft failure. Molecular mechanisms underlying initial poor graft function (IPGF) have been poorly documented in human. The purpose of this study was to identify the major transcriptional alterations occurring in human livers during OLT. Twenty-one RNA extracts derived from liver transplant biopsies taken after graft reperfusion were compared with 7 RNA derived from normal control livers. Three hundred seventy-one genes were significantly modulated and classified in molecular pathways relevant to liver metabolism, inflammatory response, cell proliferation and liver protection. Grafts were then subdivided into two groups based on their peak levels of serum aspartate amino transferase within 72 h after OLT (group 1, non-IPGF: 14 patients; group 2, IPGF: 7 patients). The two corresponding data sets were compared using a supervised prediction method. A new set of genes able to correctly classify 71% of the patients was defined. These genes were functionally associated with oxidative stress, inflammation and inhibition of cell proliferation. This study provides a comprehensive picture of the transcriptional events associated with human OLT and IPGF. We anticipate that such alterations provide a framework for the elucidation of the molecular mechanisms leading to IPGF.

International audience; BACKGROUND: The impact of posttransplant anemia (PTA) upon patient and graft survival remains controversial. The aim of this study was to assess the incidence of PTA 1 year after transplantation in patients treated with calcineurin inhibitors and mycophenolate mofetil, and to determine the impact of 1-year PTA upon long-term patient and graft survival. METHODS: Between January 1, 1999, and December 31, 2003, all patients with a functioning graft at 1 year, and who were receiving an immunosuppressive regimen based on calcineurin inhibitors and mycophenolate mofetil, were included in the study (n=339). Anemia was defined according to the World Health Organization criteria, that is, hemoglobin levels less than 13 g/dL for men and less than 12 g/dL for women. RESULTS: One hundred and eight of 339 were anemic at 1 year after transplantation (31.85%; group I). Independent predictors for 1-year anemia are donor's age and serum creatinine at 6 months. At last follow-up, that is, 69.4+/-17.7 months after transplantation, there had been a significant number of deaths in group I (n=7; 6.9%) compared with nonanemic patients (group II) (n=4; 1.73%; P=0.04). Mean allograft survival was significantly better in group II (70.7+/-17.1 months) compared with group I (66.4+/-18.7 months; P=0.03). Also, 12 graft losses (11.1%) were observed in group I and seven occurred in group II (3%; P=0.004). Independent predictors for allograft loss included delayed graft function and serum creatinine at 1 year. CONCLUSION: After kidney transplantation, the occurrence of PTA at 1 year is harmful, in the long term, to patient survival.

International audience; BACKGROUND: The proportion of transplant candidates aged 60 years and over listed on the kidney transplant waiting list is increasing, as is the proportion of potential organ donors of this age. We compared in elderly recipients: kidney graft survival of expanded criteria deceased donor (ECD) to nonexpanded criteria deceased donor (NECD), and survival of patients receiving these grafts to those remaining on the waiting list. METHODS: Between 1996 and 2004, a total of 3001 patients aged 60 years and over were registered on the French kidney transplant waiting list, of which 2099 were transplanted. The data were analyzed using Kaplan-Meier methods and Cox models. RESULTS: ECD was defined as presenting at least one of the following factors: age over 60 years than less (relative risk [RR]=1.26; P=0.02), history of arterial hypertension vs. absence (RR=1.34; P=0.01), history of diabetes mellitus vs. absence (RR=1.6; P=0.01), and death due to cerebrovascular accident vs. other cause (RR=1.3; P=0.01). Patients who did not undergo transplantation had an adjusted risk of death 2.54 times higher than that of transplanted patients of the same age (P

International audience; BACKGROUND: Since 1996, the allocation of grafts in France has been based on a hierarchical three-level system: national, regional and local. The objective of this study was to determine whether the shipment of cadaveric kidneys according to these new exchange rules affects allograft outcome in the Eastern region of France. METHODS: This retrospective study analysed all renal transplants performed in the four centres of the French Eastern region during 3 years (1996 to 1998). All patients were followed up until death, return to dialysis, last information date or the end of June 2003. Information regarding the donors, recipients and treatments, as well as patient and graft outcome, was recorded. Factors associated with graft loss were analysed using Cox proportional hazard methods. RESULTS: 542 transplants were analysed, 287 (53%) kidneys were transplanted locally, 229 (42.2%) kidneys coming from exchanges within the region and 26 (4.8%) from another region. There were statistically significant differences between the four centres for donors' and recipient' characteristics and for immunosuppressive treatment, but there was no difference between centres regarding patient survival (94.4% at 5 years), graft survival (83.7% at 5 years) or death-censored graft survival (87.8% at 5 years). Compared to locally transplanted grafts, shipped grafts had significantly better human leukocyte antigen (HLA) matching (2.5 +/- 1.3 versus 2.1 +/- 1.0 matches, P = 0.0005 but a longer cold ischaemia time (23.2 +/- 7.9 versus 19.2 +/- 7.8 h, P < 0.0001). Three independent factors were associated with a reduced graft survival: at least one acute rejection, delayed graft function and a shipped graft. CONCLUSION: The results of this study suggest that the shipment of cadaveric renal allografts in a regional distribution system is associated with better HLA matching but is a significant predictor of graft loss at 5 years. It would be advisable to restrict graft sharing to patients whose access to transplantation is limited, taking special care to avoid any additional factors having a detrimental effect on the outcome.

International audience; The incidence of skin cancer after organ transplantation is mainly related to type, level, and duration of immunosuppression. The immunosuppressive minimization strategy reduces skin malignancies, but no data are available concerning long-term calcineurin inhibitor (CNI) monotherapy compared with bi- or tritherapy. We studied the benefits of long-term CNI monotherapy (>6 years of exposure) with regard to the incidence of squamous cell carcinomas (SCC) and basal cell carcinomas (BCC) compared with bi- or tritherapy, among first renal allograft adult recipients who were more than 6 years posttransplantation. Among 294 renal transplantations performed between 1986 and 1999, 80 patients received CNI monotherapy (MT) and 86 patients bi- or tritherapy (BTT) with a follow-up of more than 6 years. MT patients were older, had longer follow-up, and fewer biopsy-proven acute rejection episodes. The incidence of SCC was 15.9 SCC/1000 patients/year for MT vs 26.2 for BTT (P = .07). The incidence was significantly lower for patients older than 40 years (22.4 vs 56, respectively; P < .01). The incidence of BCC was 28.3 BCC/1000 patients/year for MT and 10.1 for BTT (P = .05), which failed to show a significant difference in patients older than 40 years (39.7 vs 25, respectively; P = .09). The ratio of SCC/BCC in MT was maintained around 1/2 over time, while it exceeded 2/1 in BTT after 12 years posttransplantation. Patient survival was comparable between the 2 groups. A higher graft survival rate was observed in the MT group. CNI monotherapy should be considered to be a beneficial, safe immunosuppressive minimization strategy for SCC in selected recipients.

International audience; Urinary tract infections (UTIs) and acute pyelonephritis (APN) often occur after renal transplantation, but their impact on graft outcome is unclear. One hundred and seventy-seven consecutive renal transplantations were investigated to evaluate the impact of UTIs and APN on graft function. The cumulative incidence of UTIs was 75.1% and that of APN was 18.7%. UTIs occurred mainly during the first year after transplantation and Escherichia coli, Pseudomonas aeruginosa and Enteroccocus sp. were the most frequent pathogens identified. The risk of developing APN was higher in female (64%) than in male recipients, and was correlated with the frequency of recurrent UTIs (p < 0.0001) and rejection episodes (p = 0.0003). APN did not alter graft or recipient survival, however, compared to patients with uncomplicated UTIs, patients with APN exhibited both a significant increase in serum creatinine and a decrease in creatinine clearance, already detected after 1 year (aMDRD-GFR: APN: 39.5 +/- 12.5; uncomplicated UTI: 54.6 +/- 21.7 mL/min/1.73 m(2), p < 0.01) and still persistent ( approximately - 50%) 4 years after transplantation. Multivariate analysis revealed that APN represents an independent risk factor associated with the decline of renal function (p = 0.034). Therefore, APN may be associated with an enduring decrease in renal graft function.

International audience; OBJECTIVE: To evaluate the complications, the morbidity and mortality of renal transplantation in patients with a vascular prosthesis inserted either prior to or at the same time as renal transplantation. PATIENTS AND METHOD: Between January 2001 and January 2006, six renal transplantations were performed in patients with arterial vascular prostheses or requiring concomitant insertion of a vascular prosthesis during renal transplantation. The mean age was 58 years [range: 47-69 years]. In each case, we evaluated operative difficulties, complications and postoperative course (morbidity, mortality) and the renal functional result. RESULTS: The mean operating time was 230 minutes [range: 130-380 minutes] with a mean blood loss of 390 ml [175-750 ml]. Three patients required another surgical operation for femoral thrombosis, iliofemoral thrombosis and compressive haematoma. The median length of hospital stay was 21 days [range: 9-78 days]. Graft function was restored immediately in all six patients, and one case of graft loss was observed. The morbidity was higher than that usually observed after renal transplantation. With a mean follow-up of 26 months, the vascular and renal results are satisfactory. CONCLUSION: Renal transplantation in patients with a history of vascular prosthesis or requiring replacement of the vascular prosthesis at the same time as renal transplantation can be performed with satisfactory results but with an increased morbidity. The vascular treatment must be part of a multidisciplinary strategy in the context of transplantation.

International audience; We compared the influence of induction therapy on 5-year patient and graft survival as well as on renal function in 100 kidney graft recipients at low immunological risk treated with antilymphocyte globulin (n = 50) versus anti-IL-2R monoclonal antibody (n = 50) in a prospective multicenter study. Long-term immunosuppressive treatment included cyclosporine, mycophenolate mofetil, and a short course of steroids in all patients. Five year graft (86% vs 86%) and patient (94% vs 94%) survivals were identical in both study arms. Moreover, neither serum creatinine or proteinuria were significantly different between the two groups. Our results showed that the choice of the induction therapy seemed to not have a major impact on long-term outcomes among renal recipients at low immunological risk.

International audience; Vascular endothelial cells are the first interface between donor and recipient in organ transplantation. Endothelial cells and smooth muscle cells are key actors of acute and chronic rejection processes in organ allografting, but they also have the capacity to protect themselves from allograft-induced injury. Recent advances in our understanding of the precise mechanisms leading to endothelial dysfunction or, on the contrary, to endothelial protection, suggest that therapeutic interventions targeting endothelial cells could improve allograft survival and have even raised the question of whether such manipulations can be considered with a view to inducing immunological tolerance.

International audience; The transplantation of fetal ventral mesencephalic (FVM) cell suspensions into the brain striatal system is an alternative approach for the treatment of Parkinson's disease (PD). However, one objection to this procedure is the relatively poor survival of implanted cells. Attempts have been made to improve the survival of grafted dopaminergic neurons using glial cell line-derived neurotrophic factor (GDNF). Nevertheless, the clinical application of GDNF is limited, due to the difficulties in administering a protein to the brain tissue and due to the ubiquity of its receptor, thus leading to neurological side effects. A strategy to deliver GDNF in the brain based on the intracerebral implantation of biodegradable poly(D,L-lactic acid-co-glycolic acid) sustained release microspheres has been developed. Such microparticles can be easily implanted by sterotaxy in precise and functional areas of the brain without causing damage to the surrounding tissue. Moreover, the release profile of the GDNF-loaded microspheres showed a sustained release over 56 days of biologically active GDNF at clinically relevant doses. The present study shows that the implantation of GDNF-loaded microspheres at a distance to the site of FVM cells in the 6-hydroxydopamine-lesioned rat model of PD improves dopaminergic graft survival and function. Furthermore, the unloaded and the GDNF-loaded microspheres, when they are mixed with FVM cells, may provide a mechanical support and a 3D environment inducing differentiation and increased function of dopaminergic neurons. Taken together, these results show that GDNF microspheres represent an efficient delivery system for cell transplantation studies.

International audience; Apoptotic leukocytes are endowed with immunomodulatory properties that can be used to enhance hematopoietic engraftment and prevent graft-versus-host disease (GvHD). This apoptotic cell-induced tolerogenic effect is mediated by host macrophages and not recipient dendritic cells or donor phagocytes present in the bone marrow graft as evidenced by selective cell depletion and trafficking experiments. Furthermore, apoptotic cell infusion is associated with TGF-beta-dependent donor CD4+CD25+ T-cell expansion. Such cells have a regulatory phenotype (CD62L(high) and intracellular CTLA-4+), express high levels of forkhead-box transcription factor p3 (Foxp3) mRNA and exert ex vivo suppressive activity through a cell-to-cell contact mechanism. In vivo CD25 depletion after apoptotic cell infusion prevents the apoptotic cell-induced beneficial effects on engraftment and GvHD occurrence. This highlights the role of regulatory T cells in the tolerogenic effect of apoptotic cell infusion. This novel association between apoptosis and regulatory T-cell expansion may also contribute to preventing deleterious autoimmune responses during normal turnover.

International audience; Recent updates of the Edmonton trial have shown that insulin independence is progressively lost in approximately 90% of islet transplant recipients over the first 5 years. Early prediction of islet graft injury could prompt the implementation of strategies attempting to salvage the transplanted islets. We hypothesize that islet damage is associated with the release and detection of insulin mRNA in the circulating blood. Whole blood samples were prospectively taken from 19 patients with type 1 diabetes receiving 31 islet transplants, immediately prior to transplantation and at regular time-points thereafter. After RNA extraction, levels of insulin mRNA were determined by quantitative reverse tran-scriptase-polymerase chain reaction. All patients exhibited a primary peak of insulin mRNA immediately after transplantation, without correlation of duration and amplitude with graft size or outcome. Twenty-five subsequent peaks were observed during the follow-up of 17 transplantations. Fourteen secondary peaks (56%) were closely followed by events related to islet graft function. Duration and amplitude of peaks were higher when they heralded occurrence of an adverse event. Peaks of insulin mRNA can be detected and are often associated with alterations of islet graft function. These data suggest that insulin mRNA detection in the peripheral blood is a promising method for the prediction of islet graft damage.

International audience; BACKGROUND: A bilateral hand allotransplantation was performed in a patient six years ago. Whereas skin is known to be highly immunogenic, grafts have been well accepted up to now. Therefore, here we investigated the putative presence of regulatory T cells in the graft. METHODS: Skin biopsies were performed at different time points and analyzed by immunochemistry. T cells were initially expanded with interleukin (IL)-2. In the latter biopsy, skin was directly analyzed by reverse-transcriptase polymerase chain reaction without any culture. RESULTS: When tested against donor mononuclear cells, donor-primed skin T cells demonstrated unresponsiveness and inhibited donor-directed blood T cell alloresponse. Moreover, their T-cell receptor-Vbeta repertoire was skewed, in contrast to that of peripheral blood T cells. Retrospectively, nuclear FoxP3 expression in skin was measured by immunohistochemistry and was found positive at that time, but appeared to increase with time. This result was supported by the measurement of FoxP3 messenger RNA (mRNA) expression in the latter fresh biopsy, which showed higher levels than that of blood, together with no expression of perforin mRNA, but increased expression of transforming growth factor-beta and IL-10. No FoxP3 mRNA expression was found in the contralateral leg, due to the absence of T cell infiltrate. CONCLUSION: This study shows the presence of the FoxP3 marker, in a well accepted human composite tissue allograft, up to six years posttransplantation. Because a suppressive cytokinic profile was also detected intragraft, in the absence of perforin mRNA expression, our data suggest that regulatory T cells could play a role in the long-term survival of this allograft.