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Although cold ischemia time has been widely studied in renal transplantation area, there is no consensus on its precise relationship with the transplantation outcomes. To study this, we sampled data from 3839 adult recipients of a first heart-beating deceased donor kidney transplanted between 2000 and 2011 within the French observational multicentric prospective DIVAT cohort. A Cox model was used to assess the relationship between cold ischemia time and death-censored graft survival or patient survival by using piecewise log-linear function. There was a significant proportional increase in the risk of graft failure for each additional hour of cold ischemia time (hazard ratio, 1.013). As an example, a patient who received a kidney with a cold ischemia time of 30h presented a risk of graft failure near 40% higher than a patient with a cold ischemia time of 6h. Moreover, we found that the risk of death also proportionally increased for each additional hour of cold ischemia time (hazard ratio, 1.018). Thus, every additional hour of cold ischemia time must be taken into account in order to increase graft and patient survival. These findings are of practical clinical interest, as cold ischemia time is among one of the main modifiable pre-transplantation risk factors that can be minimized by improved management of the peri-transplantation period.

Delayed graft function (DGF) is a common complication in kidney transplantation and is known to be correlated with short- and long-term graft outcomes. Here we explored the possibility of developing a simple tool that could predict with good confidence the occurrence of DGF and could be helpful in current clinical practice. We built a score, tentatively called DGFS, from a French multicenter and prospective cohort of 1844 adult recipients of deceased donor kidneys collected since 2007, and computerized in the Données Informatisées et VAlidées en Transplantation databank. Only five explicative variables (cold ischemia time, donor age, donor serum creatinine, recipient body mass index, and induction therapy) contributed significantly to the DGF prediction. These were associated with a good predictive capacity (area under the ROC curve at 0.73). The DGFS calculation is facilitated by an application available on smartphones, tablets, or computers at www.divat.fr/en/online-calculators/dgfs. The DGFS should allow the simple classification of patients according to their DGF risk at the time of transplantation, and thus allow tailored-specific management or therapeutic strategies.

Objectives To assess the long term outcomes of transplantation using expanded criteria donors (ECD; donors aged ≥60 years or aged 50-59 years with vascular comorbidities) and assess the main determinants of its prognosis. Design Prospective, population based cohort study.Setting Four French referral centres.Participants Consecutive patients who underwent kidney transplantation between January 2004 and January 2011, and were followed up to May 2014. A validation cohort included patients from another four referral centres in France who underwent kidney transplantation between January 2002 and December 2011. Main outcome measures Long term kidney allograft survival, based on systematic assessment of donor, recipient, and transplant clinical characteristics; preimplantation biopsy; and circulating levels of donor specific anti-HLA (human leucocyte antigen) antibody (DSA) at baseline.Results The study included 6891 patients (2763 in the principal cohort, 4128 in the validation cohort). Of 2763 transplantations performed, 916 (33.2%) used ECD kidneys. Overall, patients receiving ECD transplants had lower allograft survival after seven years than patients receiving transplants from standard criteria donors (SCD; 80% v 88%, P<0.001). Patients receiving ECD transplants who presented with circulating DSA at the time of transplantation had worse allograft survival after seven years than patients receiving ECD kidneys without circulating DSA at transplantation (44% v 85%, P<0.001). After adjusting for donor, recipient, and transplant characteristics, as well as preimplantation biopsy findings and baseline immunological parameters, the main independent determinants of long term allograft loss were identified as allocation of ECDs (hazard ratio 1.84 (95% confidence interval 1.5 to 2.3); P<0.001), presence of circulating DSA on the day of transplantation (3.00 (2.3 to 3.9); P<0.001), and longer cold ischaemia time (>12 h; 1.53 (1.1 to 2.1); P=0.011). Recipients of ECD kidneys with circulating DSA showed a 5.6-fold increased risk of graft loss compared with all other transplant therapies (P<0.001). ECD allograft survival at seven years significantly improved with screening and transplantation in the absence of circulating DSA (P<0.001) and with shorter (<12 h) cold ischaemia time (P=0.030), respectively. This strategy achieved ECD graft survival comparable to that of patients receiving an SCD transplant overall, translating to a 544.6 allograft life years saved during the nine years of study inclusion time.Conclusions Circulating DSA and cold ischaemia time are the main independent determinants of outcome from ECD transplantation. Allocation policies to avoid DSA and reduction of cold ischaemia time to increase efficacy could promote wider implement of ECD transplantation in the context of organ shortage and improve its prognosis.

There is extensive literature with comparisons between Anti-Thymocyte Globulin (ATG) and Basiliximab (BSX) as induction therapy in kidney transplant recipients. The purpose of our benchmarking study was to describe the consequences in terms of practices in 6 transplantation centers of a French prospective cohort. We included adult patients who received a first or second kidney graft between 2013 and 2019 (n = 4157). We used logistic regressions to identify characteristics associated with the use of ATG or BSX. Use of ATG between the centers ranged from 41% to 75%. We observed different factors associated with the treatment decision. Compared to a first transplant, performing a second graft was the only factor significantly associated with the choice of ATG in all centers. The AUC ranged from 0.67 to 0.91, indicating that the centers seemed to define their own rules. As a result, for patients with the same low immunological risk, the probability of receiving ATG varied from 7% to 36%. We stratified the analyses according to two periods, from 2013 to 2015 and from 2016 to 2019. A similar heterogeneity was observed, and in some cases ATG indications between the centers were inverted. The heterogeneity of induction therapy practices did not decrease in France, even if the reated literature is prolific. This illustrates the necessity to improve the literature by using meta-analyses of recent studies stratified by graft and patient profiles.

After the first year post transplantation, prognostic mortality scores in kidney transplant recipients can be useful for personalizing medical management. We developed a new prognostic score based on 5 parameters and computable at 1-year post transplantation. The outcome was the time between the first anniversary of the transplantation and the patient's death with a functioning graft. Afterwards, we appraised the prognostic capacities of this score by estimating time-dependent Receiver Operating Characteristic (ROC) curves from two prospective and multicentric European cohorts: the DIVAT (Données Informatisées et VAlidées en Transplantation) cohort composed of patients transplanted between 2000 and 2012 in 6 French centers; and the STCS (Swiss Transplant Cohort Study) cohort composed of patients transplanted between 2008 and 2012 in 6 Swiss centers. We also compared the results with those of two existing scoring systems: one from Spain (Hernandez et al.) and one from the United States (the Recipient Risk Score, RRS, Baskin-Bey et al.). From the DIVAT validation cohort and for a prognostic time at 10 years, the new prognostic score (AUC = 0.78, 95%CI = [0.69, 0.85]) seemed to present significantly higher prognostic capacities than the scoring system proposed by Hernandez et al. (p = 0.04) and tended to perform better than the initial RRS (p = 0.10). By using the Swiss cohort, the RRS and the the new prognostic score had comparable prognostic capacities at 4 years (AUC = 0.77 and 0.76 respectively, p = 0.31). In addition to the current available scores related to the risk to return in dialysis, we recommend to further study the use of the score we propose or the RRS for a more efficient personalized follow-up of kidney transplant recipients.

Lactococcus lactis is a lactic acid bacterium of major importance for food fermentation and biotechnological applications. The ability to manipulate its genome quickly and easily through competence for DNA transformation would accelerate its general use as a platform for a variety of applications. Natural transformation in this species requires the activation of the master regulator ComX. However, the growth conditions that lead to spontaneous transformation, as well as the regulators that control ComX production, are unknown. Here, we identified the carbon source, nitrogen supply, and pH as key factors controlling competence development in this species. Notably, we showed that these conditions are sensed by three global regulators (i.e., CcpA, CodY, and CovR), which repress comX transcription directly. Furthermore, our systematic inactivation of known signaling systems suggests that classical pheromone-sensing regulators are not involved. Finally, we revealed that the ComX-degrading MecA-ClpCP machinery plays a predominant role based on the identification of a single amino-acid substitution in the adaptor protein MecA of a highly transformable strain. Contrasting with closely-related streptococci, the master competence regulator in L . lactis is regulated both proximally by general sensors and distantly by the Clp degradation machinery. This study not only highlights the diversity of regulatory networks for competence control in Gram-positive bacteria, but it also paves the way for the use of natural transformation as a tool to manipulate this biotechnologically important bacterium.

Old studies reported a worse outcome for second transplant recipient (STR) than for first transplant recipient (FTR) mainly due to non-comparable populations with numbers confounding factors. More recent analysis, based on improved methodology by using multivariate regressions, challenged this generally accepted idea: the poor prognosis for STR is still under debate. To assess the long-term patient-and-graft survival of STR compared to FTR, we performed an observational study based on the French DIVAT prospective cohort between 1996 and 2010 (N = 3103 including 641 STR). All patients were treated with a CNI, an mTOR inhibitor or belatacept in addition to steroids and mycophenolate mofetil for maintenance therapy. Patient-and-graft survival and acute rejection episode (ARE) were analyzed using Cox models adjusted for all potential confounding factors such as pre-transplant anti-HLA immunization. We showed that STR have a higher risk of graft failure than FTR (HR = 2.18, p = 0.0013) but that this excess risk was observed after few years of transplantation. There was no significant difference between STR and FTR in the occurrence of either overall ARE (HR = 1.01, p = 0.9675) or steroid-resistant ARE (HR = 1.27, p = 0.4087). The risk of graft failure following second transplantation remained consistently higher than that observed in first transplantation after adjusting for confounding factors. The rarely performed time-dependent statistical modeling may explain the heterogeneous conclusions of the literature concerning second transplantation outcomes. In clinical practice, physicians should not consider STR and FTR equally.

Determining early surrogate markers of long-term graft outcome is important for optimal medical management. In order to identify such markers, we used clinical information from a cross-validated French database (Données Informatisées et VAlidées en Transplantation) of 2169 kidney transplant recipients to construct a composite score 1 year after transplantation. This Kidney Transplant Failure Score took into account a series of eight accepted pre- and post-transplant risk factors of graft loss, and was subsequently evaluated for its ability to predict graft failure at 8 years. This algorithm outperformed the traditional surrogates of serum creatinine and the estimated graft filtration rate, with an area under the receiver–operator characteristic curve of 0.78. Validation on an independent database of 317 graft recipients had the same predictive capacity. Our algorithm was also able to stratify patients into two groups according to their risk: a high-risk group of 81 patients with 25% graft failure and a low-risk group of 236 patients with an 8% failure rate. Thus, although this clinical composite score predicts long-term graft survival, it needs validation in different patient groups throughout the world.

Abstract Nowadays, the growing human population exacerbates the need for sustainable resources. Inspiration and achievements in nutrient production or human/animal health might emanate from microorganisms and their adaptive strategies. Here, we exemplify the benefits of lactic acid bacteria (LAB) for numerous biotechnological applications and showcase their natural transformability as a fast and robust method to hereditarily influence their phenotype/traits in fundamental and applied research contexts. We described the biogenesis of the transformation machinery and we analyzed the genome of hundreds of LAB strains exploitable for human needs to predict their transformation capabilities. Finally, we provide a stepwise rational path to stimulate and optimize natural transformation with standard and synthetic biology techniques. A comprehensive understanding of the molecular mechanisms driving natural transformation will facilitate and accelerate the improvement of bacteria with properties that serve broad societal interests. The authors review the advantages of using natural DNA transformation to genetically improve lactic acid bacteria for human benefits by providing a step-by-step strategy to predict and trigger this natural gene exchange process.

Background In kidney transplantation, the use of Anti-Thymocyte Globulins (ATG) as induction therapy has been described as a possible treatment for reducing the prevalence of Delayed Graft Function (DGF). ATG possesses pharmaceutical proprieties that could help control the lesions caused by ischemia reperfusion injury. However, other studies have questioned this potential protective effect. We hypothesized that the benefits related to ATG for reducing DGF prevalence may be higher and more consistently recognized if only patients with high DGF risk are considered. We recently proposed a scoring system entitled DGFS (Delayed Graft Function Score) for such stratification of kidney transplant recipients according to their risk of DGF. Using the DGFS calculation, we aim to determine whether a short course of ATG can decrease the incidence of DGF in comparison with Basiliximab in kidney transplant recipients with low immunological risk but high DGF risk. Methods We conduct a phase IV, open label, randomized, multicentric and prospective study, to compare ATG in parallel with a control group treated by Basiliximab. The 1:1 randomized allocation of patients between groups is stratified on the clinical center, and on the hypothermic machine-perfusion device. We aimed to include a total of 384 patients to achieve a statistical power at 0.80. The study was initiated at the Nantes University hospital in July 2014, with data collection continuing until April 2018, and publication of the results proposed for 2019. Discussion The main expected benefits of this study are i ) the reduction of unjustified ATG over-prescriptions associated with serious adverse events, ii ) the reduction of chance losses related to ATG under-prescription, iii ) the decrease in the incidence of DGF which was described as a risk factor of graft failure and patient death, and iv ) the reduction in hospitalization duration and number of post transplantation dialysis sessions, both being associated with reduced medical costs. In conclusion, the current study is innovative by proposing a more efficient and personalized induction therapy. Trial registration The study was registered in the Clinical Trials Registry (# NCT02056938 , February 5, 2014), and in the European Clinical Trials Database (EudraCT #2014-000332-42, January 30, 2014).