Publications by authors named "Magali Giral"

117 Publications

Clinical utility of C-peptide measurement after pancreas transplantation with especial focus on early graft thrombosis.

Transpl Int 2021 Mar 18. Epub 2021 Mar 18.

Institut de Transplantation-Urologie-Néphrologie (ITUN), Nantes University Hospital, Nantes, France.

Since the beginning of our pancreas transplant programme, plasma C-peptide was routinely measured daily during the postoperative period. We aimed to evaluate the clinical interest of the C-peptide in the follow-up of pancreas transplantation with a particular look on early graft failure. From 2000 to 2016, 384 pancreas transplantations were evaluated. We collected and compared C-peptide, glycaemia and adjusted C-peptide (aCP; calculated based on C-peptide, glycaemia and creatininaemia) in patients with and without pancreas failure within 30 days after surgery. Variations of glycaemia, C-peptide and aCP between the day before and the day of failure were also recorded. The difference of aCP was significant during the first week after transplantation between patients with thrombosis and those with functional allograft: 63.2 vs. 26.7 on day 1, P = 0.0003; 61.4 vs. 26.7 on day 3, P < 0.0001; 64.8 vs. 5.7 on day 7, P < 0.0001, respectively. Glycaemia had a median increase of 8% on the day of failure, whereas C-peptide and aCP had, respectively, a median decrease of 88% and 83%. C-peptide monitoring after pancreas transplantation may help to identify graft function and early failure. This sensitive biomarker could allow pre-emptive diagnosis of an early thrombotic event allowing the possibility of rescue interventions.
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http://dx.doi.org/10.1111/tri.13866DOI Listing
March 2021

Preformed T cell alloimmunity and HLA eplet mismatch to guide immunosuppression minimization with tacrolimus monotherapy in kidney transplantation: Results of the CELLIMIN trial.

Am J Transplant 2021 Mar 16. Epub 2021 Mar 16.

Kidney Transplant Unit, Nephrology department, Bellvitge University Hospital, IDIBELL, Barcelona University, Barcelona, Spain.

Personalizing immunosuppression is a major objective in transplantation. Transplant recipients are heterogeneous regarding their immunological memory and primary alloimmune susceptibility. This biomarker-guided trial investigated whether in low immunological-risk kidney transplants without pretransplant DSA and donor-specific T cells assessed by a standardized IFN-γ ELISPOT, low immunosuppression (LI) with tacrolimus monotherapy would be non-inferior regarding 6-month BPAR than tacrolimus-based standard of care (SOC). Due to low recruitment rates, the trial was terminated when 167 patients were enrolled. ELISPOT negatives (E-) were randomized to LI (n = 48) or SOC (n = 53), E+ received the same SOC. Six- and 12-month BPAR rates were higher among LI than SOC/E- (4/35 [13%] vs. 1/43 [2%], p = .15 and 12/48 [25%] vs. 6/53 [11.3%], p = .073, respectively). E+ patients showed similarly high BPAR rates than LI at 6 and 12 months (12/55 [22%] and 13/66 [20%], respectively). These differences were stronger in per-protocol analyses. Post-hoc analysis revealed that poor class-II eplet matching, especially DQ, discriminated E- patients, notably E-/LI, developing BPAR (4/28 [14%] low risk vs. 8/20 [40%] high risk, p = .043). Eplet mismatch also predicted anti-class-I (p = .05) and anti-DQ (p < .001) de novo DSA. Adverse events were similar, but E-/LI developed fewer viral infections, particularly polyoma-virus-associated nephropathy (p = .021). Preformed T cell alloreactivity and HLA eplet mismatch assessment may refine current baseline immune-risk stratification and guide immunosuppression decision-making in kidney transplantation.
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http://dx.doi.org/10.1111/ajt.16563DOI Listing
March 2021

Covariates adjustment questioned conclusions of predictive analyses: an illustration with the Kidney Donor Risk Index.

J Clin Epidemiol 2021 Feb 9;135:103-114. Epub 2021 Feb 9.

INSERM UMR 1246 - SPHERE, Nantes University, Tours University, Nantes, France; Centre Hospitalier Universitaire de Nantes, Nantes, France.

Objectives: We aimed to illustrate that considering covariates can lead to meaningful interpretation of the discriminative capacities of a prognostic marker. For this, we evaluated the ability of the Kidney Donor Risk Index (KDRI) to discriminate kidney graft failure risk.

Study Design And Setting: From 4114 French patients, we estimated the adjusted area under the time-dependent ROC curve by standardizing the marker and weighting the observations. By weighting the contributions, we also studied the impact of KDRI-based transplantations on the patient and graft survival.

Results: The covariate-adjusted AUC varied from 55% (95% confidence interval [CI]: 51-60%) for a prognostic up to 1 year post-transplantation to 56% (95% CI: 52-59%) up to 7 years. The Restricted Mean Survival Time (RMST) was 6.44 years for high-quality graft recipients (95% CI: 6.30-6.56) and would have been 6.31 years (95% CI: 6.13-6.46) if they had medium-quality transplants. The RMST was 5.10 years for low-quality graft recipients (95% CI: 4.90-5.31) and would have been 5.52 years (95% CI: 5.17-5.83) if they had medium-quality transplants.

Conclusion: We demonstrated that the KDRI discriminative capacities were mainly explained by the recipient characteristics. We also showed that counterfactual estimations, often used in causal studies, are also interesting in predictive studies, especially regarding the new available methods.
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http://dx.doi.org/10.1016/j.jclinepi.2021.02.007DOI Listing
February 2021

Prognostic value for long-term graft survival of estimated glomerular filtration rate and proteinuria quantified at 3 months after kidney transplantation.

Clin Kidney J 2020 Oct 26;13(5):791-802. Epub 2020 Apr 26.

Department of Nephrology and Kidney Transplantation, Nancy University Hospital, Vandoeuvre-lès-Nancy, France.

Background: The estimated glomerular filtration rate (eGFR) measured at 1 year is the usual benchmark applied in kidney transplantation (KT). However, acting on earlier eGFR values could help in managing KT during the first post-operative year. We aimed to assess the prognostic value for long-term graft survival of the early (3 months) quantification of eGFR and proteinuria following KT.

Methods: The 3-, 6- and 12-month eGFR using the Modified Diet in Renal Disease equation (eGFR) was determined and proteinuria was measured in 754 patients who underwent their first KT between 2000 and 2010 (with a mean follow-up of 8.3 years) in our centre. Adjusted associations with graft survival were estimated using a multivariable Cox model. The predictive accuracy was estimated using the C-index and net reclassification index. These same analyses were measured in a multicentre validation cohort of 1936 patients.

Results: Both 3-month eGFR and proteinuria were independent predictors of return to dialysis (all P < 0.05) and there was a strong correlation between eGFR at 3 and 12 months (Spearman's ρ = 0.76). The predictive accuracy of the 3-month eGFR was within a similar range and did not differ significantly from the 12-month eGFR in either the derivation cohort [C-index 62.6 (range 57.2-68.1) versus 66.0 (range 60.1-71.9), P = 0.41] or the validation cohort [C-index 69.3 (range 66.4-72.1) versus 71.7 (range 68.7-74.6), P = 0.25].

Conclusion: The 3-month eGFR was a valuable predictor of the long-term return to dialysis whose predictive accuracy was not significantly less than that of the 12-month eGFR in multicentre cohorts totalling >2500 patients. Three-month outcomes may be useful in randomized controlled trials targeting early therapeutic interventions.
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http://dx.doi.org/10.1093/ckj/sfaa044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577768PMC
October 2020

Induction therapy in kidney transplant recipients: Description of the practices according to the calendar period from the French multicentric DIVAT cohort.

PLoS One 2020 22;15(10):e0240929. Epub 2020 Oct 22.

Centre Hospitalier Universitaire de Nantes, Nantes, France.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240929PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580969PMC
December 2020

Efficient Expansion of Human Granzyme B-Expressing B Cells with Potent Regulatory Properties.

J Immunol 2020 11 18;205(9):2391-2401. Epub 2020 Sep 18.

CHU Nantes, Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France;

Granzyme B-expressing B cells have been shown to be an important regulatory B cell subset in humans. However, it is unclear which subpopulations of B cells express GZMB under normal conditions and which protocols effectively induce ex vivo expansion of GZMB B cells. We found that in the peripheral blood of normal individuals, plasmablasts were the major B cell subpopulation that expressed GZMB. However, when using an in vitro plasmablast differentiation protocol, we obtained only 2% GZMB B cells. Nevertheless, using an expansion mixture containing IL-21, anti-BCR, CpG oligodeoxynucleotide, CD40L, and IL-2, we were able to obtain more than 90% GZMB B cells after 3 d culture. GZMB B cells obtained through this protocol suppressed the proliferation of autologous and allogenic CD4CD25 effector T cells. The suppressive effect of GZMB B cells was partially GZMB dependent and totally contact dependent but was not associated with an increase in effector T cell apoptosis or uptake of GZMB by effector T cells. Interestingly, we showed that GZMB produced by B cells promoted GZMB B cell proliferation in ERK1/2-dependent manner, facilitating GZMB B cell expansion. However, GZMB B cells tended to undergo apoptosis after prolonged stimulation, which may be considered a negative feedback mechanism to limit their uncontrolled expansion. Finally, we found that expanded GZMB B cells exhibited a regulatory phenotype and were enriched in CD307b, CD258CD72, and CD21loPD-1 B cell subpopulations. Our study, to our knowledge, provides new insight into biology of GZMB B cells and an efficient method to expand GZMB B cells for future cell therapy applications.
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http://dx.doi.org/10.4049/jimmunol.2000335DOI Listing
November 2020

Resurgence of BK virus following Covid-19 in kidney transplant recipients.

Transpl Infect Dis 2021 Feb 23;23(1):e13465. Epub 2020 Sep 23.

Nephrology and Transplantation Department, Centre Hospitalier Universitaire, Nantes, France.

Kidney transplant recipients have been supposed vulnerable to severe Covid-19 infection, due to their comorbidities and immunosuppressive therapies. Mild-term complications of Covid-19 are currently unknown, especially in this population. Herein, we report two cases of BKV replication after non-severe SARS-CoV-2 infection. The first case was a 59-year-old man, transplanted 3 months ago, with recent history of slight BKV viremia (3.3 log DNA copies/ml). Despite strong reduction of maintenance immunosuppression (interruption of mycophenolic acid and important decrease of calcineurin inhibitors), BKV replication largely increased after Covid-19 and viremia persisted at 4.5 log copy/ml few months later. The second case was a 53-year-old woman, transplanted 15 years ago. She had a recent history of BKV cystitis, which resolved with a decrease of MPA dosage. Few weeks after SARS-CoV-2 infection, she presented recurrence of lower urinary tract symptoms. Our reports highlight that SARS-CoV-2 infection, even without severity, could disrupt immune system and particularly lymphocytes, thus leading to viral replication. Monitoring of viral replications after Covid-19 in kidney transplant recipients could permit to confirm these preliminary observations.
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http://dx.doi.org/10.1111/tid.13465DOI Listing
February 2021

Antibiotics versus no therapy in kidney transplant recipients with asymptomatic bacteriuria (BiRT): a pragmatic, multicentre, randomized, controlled trial.

Clin Microbiol Infect 2021 Mar 10;27(3):398-405. Epub 2020 Sep 10.

Department of Nephrology, Universitair Ziekenhuis Antwerpen, Universiteit Antwerpen, Antwerp, Belgium.

Objectives: Many transplant physicians screen for and treat asymptomatic bacteriuria (ASB) during post-kidney-transplant surveillance. We investigated whether antibiotics are effective in reducing the occurrence of symptomatic urinary tract infection (UTI) in kidney transplant recipients with ASB.

Methods: We performed this multicentre, randomized, open-label trial in kidney transplant recipients who had ASB and were ≥2 months post-transplantation. We randomly assigned participants to receive antibiotics or no therapy. The primary outcome was the incidence of symptomatic UTI over the subsequent 12 months.

Results: One hundred and ninety-nine kidney transplant recipients with ASB were randomly assigned to antibiotics (100 participants) or no therapy (99 participants). There was no significant difference in the occurrence of symptomatic UTI between the antibiotic and no-therapy groups (27%, 27/100 versus 31%, 31/99; univariate Cox model: hazard ratio 0.83, 95%CI: 0.50-1.40; log-rank test: p 0.49). Over the 1-year study period, antibiotic use was five times higher in the antibiotic group than in the no-therapy group (30 antibiotic days/participant, interquartile range 20-41, versus 6, interquartile range 0-15, p < 0.001). Overall, 155/199 participants (78%) had at least one further episode of bacteriuria during the follow-up. Compared with the participant's baseline episode of ASB, the second episode of bacteriuria was more frequently caused by bacteria resistant to clinically relevant antibiotics (ciprofloxacin, cotrimoxazole, third-generation cephalosporin) in the antibiotic group than in the no-therapy group (18%, 13/72 versus 4%, 3/83, p 0.003).

Conclusions: Applying a screen-and-treat strategy for ASB does not reduce the occurrence of symptomatic UTI in kidney transplant recipients who are more than 2 months post-transplantation. Furthermore, this strategy increases antibiotic use and promotes the emergence of resistant organisms.
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http://dx.doi.org/10.1016/j.cmi.2020.09.005DOI Listing
March 2021

Time-dependent lymphocyte count after transplantation is associated with higher risk of graft failure and death.

Kidney Int 2020 Sep 3. Epub 2020 Sep 3.

CRTI UMR 1064, Inserm, Université de Nantes, ITUN, CHU Nantes, RTRS Centaure, Nantes, France; Centre Hospitalier Universitaire de Nantes, Nantes, France; Centre d'Investigation Clinique en Biothérapie, Labex IGO, Nantes, France.

The transplantation field requires the identification of specific risk factors associated with the level of immunosuppression. Here, our aim was to analyze the association between the number of circulating lymphocytes, monitored routinely by complete blood cell counts during outpatient visits, and patient and graft survival. In total, 2,999 kidney or combined kidney-pancreas recipients transplanted between 2000 and 2016, from two University hospitals, were enrolled. We investigated the etiological relationship between time-dependent lymphocyte count beyond one year after transplantation and patient and graft survival, viral infection and cancer risk using time-dependent multivariate Cox models. Model 1 considered kidney function at one year and model 2 as time-dependent variable. At the time of inclusion (one year after transplantation), 584 patients (19.4%) had deep lymphopenia (under 750 /mm) and 1,072 (35.7%) had a normal count (over 1,500 /mm). A patient with deep lymphopenia at a given follow-up time had significantly higher risks of graft failure, death and viral infection than comparable patients with a normal lymphocyte count at the same time point. Thus, after the first year of transplantation, the occurrence of deep lymphopenia within a patient's follow-up is a risk factor for long-term graft failure, death and viral infection.
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http://dx.doi.org/10.1016/j.kint.2020.08.010DOI Listing
September 2020

Trajectories of glomerular filtration rate and progression to end stage kidney disease after kidney transplantation.

Kidney Int 2021 01 8;99(1):186-197. Epub 2020 Aug 8.

Université de Paris, INSERM, PARCC, Paris Translational Research Centre for Organ Transplantation, Paris, France; Kidney Transplant Department, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France. Electronic address:

Although the gold standard of monitoring kidney transplant function relies on glomerular filtration rate (GFR), little is known about GFR trajectories after transplantation, their determinants, and their association with outcomes. To evaluate these parameters we examined kidney transplant recipients receiving care at 15 academic centers. Patients underwent prospective monitoring of estimated GFR (eGFR) measurements, with assessment of clinical, functional, histological and immunological parameters. Additional validation took place in seven randomized controlled trials that included a total of 14,132 patients with 403,497 eGFR measurements. After a median follow-up of 6.5 years, 1,688 patients developed end-stage kidney disease. Using unsupervised latent class mixed models, we identified eight distinct eGFR trajectories. Multinomial regression models identified seven significant determinants of eGFR trajectories including donor age, eGFR, proteinuria, and several significant histological features: graft scarring, graft interstitial inflammation and tubulitis, microcirculation inflammation, and circulating anti-HLA donor specific antibodies. The eGFR trajectories were associated with progression to end stage kidney disease. These trajectories, their determinants and respective associations with end stage kidney disease were similar across cohorts, as well as in diverse clinical scenarios, therapeutic eras and in the seven randomized control trials. Thus, our results provide the basis for a trajectory-based assessment of kidney transplant patients for risk stratification and monitoring.
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http://dx.doi.org/10.1016/j.kint.2020.07.025DOI Listing
January 2021

Poor kidney graft survival in anorexia nervosa patients.

Eat Weight Disord 2020 Jul 15. Epub 2020 Jul 15.

Service de Néphrologie Transplantation Dialyse, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.

Background: Anorexia nervosa is a condition associated with poor outcomes in a variety of circumstances such as recurrence of eating disorders, psychiatric disorders, and organ damage.

Objective: In the present study, we first sought to determine the 5-year kidney graft survival in patients with anorexia nervosa and then to evaluate the BMI course and medical complications.

Methods: In this multicenter, retrospective, case-control study, we analyzed the impact of anorexia nervosa on graft outcomes compared to transplant recipients with low or normal BMI.

Results: We enrolled 137 women in this study: 19 with anorexia nervosa, 59 with low BMI (BMI < 18.5 kg/m), and 59 with normal BMI (18.5-24.9 kg/m). Anorexia nervosa was significantly associated with lower graft survival compared to either of the other groups (hazard ratio 5.5 [95% CI 3.4-8.9], p = 0.005); there was no difference in graft survival between patients with low or normal BMI. Cardiovascular complications were more frequent in the anorexia nervosa group (37%) than in patients with low (6%) or normal BMI (7%) (p = 0.001).

Conclusion: We conclude that patients with anorexia nervosa should be considered a high-risk group.

Level Of Evidence: Level III, evidence obtained from well-designed cohort or case-control analytic studies.
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http://dx.doi.org/10.1007/s40519-020-00959-8DOI Listing
July 2020

Diagnostic performance of kSORT, a blood-based mRNA assay for noninvasive detection of rejection after kidney transplantation: A retrospective multicenter cohort study.

Am J Transplant 2021 02 4;21(2):740-750. Epub 2020 Aug 4.

French National Institute of Health and Medical Research (Inserm) Unit 1111, Lyon, France.

The Kidney Solid Organ Response Test (kSORT) blood gene expression assay was developed to noninvasively detect acute rejection (AR) after kidney transplantation. Its performance in a setting with natural disease prevalence has not been evaluated. A retrospective, multicenter cohort study was conducted across all single kidney transplant recipients, transplanted between 2011 and 2015, with samples within the first year after transplantation available in existing biobanks. The primary objective was to determine the diagnostic performance of the kSORT assay to detect AR (T cell-mediated and/or antibody-mediated rejection) as compared to a concomitant renal biopsy. AR was reported on the concomitant biopsy in 188 of 1763 (10.7%) blood samples and any rejection (including borderline changes) in 614 of 1763 (34.8%) blood samples. In 320 of 1763 samples (18.2%) the kSORT risk category was indeterminate. The kSORT assay had no diagnostic value for AR (area under the curve [AUC] 0.51, 95% confidence interval [CI] 0.50-0.56; P = .46) overall, or when considering indication biopsies (N = 487) and protocol-specified biopsies (N = 1276) separately (AUC of 0.53, 95% CI 0.50-0.59, P = .44 and 0.55, 95% CI 0.50-0.61, P = .09, respectively). This large retrospective study utilizing samples obtained under real-world clinical conditions, was unable to validate the kSORT assay for detection of AR in the first year after transplantation.
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http://dx.doi.org/10.1111/ajt.16179DOI Listing
February 2021

Comparison of machine perfusion versus cold storage in kidney transplant recipients from expanded criteria donors: a cohort-based study.

Nephrol Dial Transplant 2020 06;35(6):1043-1070

Centre Hospitalier Universitaire de Nantes, Nantes, France.

Background: Most studies comparing the efficacy of hypothermic machine perfusion (HMP) versus static cold storage (SCS) are based on short-term outcomes. We aimed to better evaluate the mid-term impact of HMP in patients receiving expanded criteria donor (ECD) kidneys.

Methods: The analyses were based on the French Données Informatisées et VAlidées en Transplantation (DIVAT) observational cohort. Patients aged ≥45 years transplanted for the first or second times from an ECD donor since 2010 were studied. Our study reported the graft and/or patient survivals and the incidence of acute rejection episode. The Cox models and the Kaplan-Meier estimators, weighted on the propensity score, were used to study the times-to-events.

Results: Among the 2019 included patients, 1073 were in the SCS group versus 946 in the HMP group. The mean life expectancy with functioning graft was 5.7 years [95% confidence interval (CI) 5.4-6.1] for the HMP cohort followed-up for 8 years post-transplantation versus 6.0 years (95% CI 5.7-6.2) for the SCS group. These mid-term results were comparable in the patients receiving grafts from donors aged ≥70 years and in the transplantations with cold ischaemia time ≥18 h.

Conclusions: Our study challenges the utility of using HMP to improve mid-term patient and graft survival. Nevertheless, the improvement of the short-term outcomes is indisputable. It is necessary to continue technological innovations to obtain long-term results.
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http://dx.doi.org/10.1093/ndt/gfz175DOI Listing
June 2020

The weekend effect in kidney transplantation outcomes: a French cohort-based study.

Transpl Int 2020 09 13;33(9):1030-1039. Epub 2020 Jul 13.

CRTI UMR 1064, Université de Nantes, ITUN, RTRS Centaure, Inserm, Nantes, France.

Numerous studies have reported a weekend effect on outcomes for diseases treated at hospitals. No study has been conducted in France for kidney transplantation. We therefore performed a cohort-based study to evaluate whether outcomes of kidney transplant recipients display a weekend effect. Data were extracted from the French DIVAT cohort. Patients aged 18 years and older, transplanted with a single kidney from deceased donors between 2005 and 2017 were studied. Linear regression, logistic regression, and cause-specific Cox model were used. Among the 6652 studied patients, 4653 patients were transplanted during weekdays (69.9%) versus 1999 during weekends (30.1%). The only statistically significant difference was the percentage of patients with vascular surgical complication(s) at 30 days: 13.3% in the weekend group versus 16.2% in the weekday group 0.79 (95% CI: 0.68; 0.92). We did not observe other significant differences for the other outcomes: patient or graft survival, the risk of acute rejection episodes, the 30-day percentage of urological complications, and the 1-year estimated glomerular filtration rate. Our study highlights a small protective weekend effect with less post-surgery vascular complications compared to weekdays. This paradox might be explained by a different handling of weekend transplantations.
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http://dx.doi.org/10.1111/tri.13653DOI Listing
September 2020

Terminally Differentiated Effector Memory CD8 T Cells Identify Kidney Transplant Recipients at High Risk of Graft Failure.

J Am Soc Nephrol 2020 04 12;31(4):876-891. Epub 2020 Mar 12.

Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France;

Background: Identifying biomarkers to predict kidney transplant failure and to define new therapeutic targets requires more comprehensive understanding of the immune response to chronic allogeneic stimulation.

Methods: We investigated the frequency and function of CD8 T cell subsets-including effector memory (EM) and terminally differentiated EM (TEMRA) CD8 T cells-in blood samples from 284 kidney transplant recipients recruited 1 year post-transplant and followed for a median of 8.3 years. We also analyzed CD8 T cell reactivity to donor-specific PBMCs in 24 patients who had received living-donor kidney transplants.

Results: Increased frequency of circulating TEMRA CD8 T cells at 1 year post-transplant associated with increased risk of graft failure during follow-up. This association remained after adjustment for a previously reported composite of eight clinical variables, the Kidney Transplant Failure Score. In contrast, increased frequency of EM CD8 T cells associated with reduced risk of graft failure. A distinct TEMRA CD8 T cell subpopulation was identified that was characterized by expression of FcRIIIA (CD16) and by high levels of proinflammatory cytokine secretion and cytotoxic activity. Although donor-specific stimulation induced a similar rapid, early response in EM and TEMRA CD8 T cells, CD16 engagement resulted in selective activation of TEMRA CD8 T cells, which mediated antibody-dependent cytotoxicity.

Conclusions: At 1 year post-transplant, the composition of memory CD8 T cell subsets in blood improved prediction of 8-year kidney transplant failure compared with a clinical-variables score alone. A subpopulation of TEMRA CD8 T cells displays a novel dual mechanism of activation mediated by engagement of the T-cell receptor or of CD16. These findings suggest that TEMRA CD8 T cells play a pivotal role in humoral and cellular rejection and reveal the potential value of memory CD8 T cell monitoring for predicting risk of kidney transplant failure.
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http://dx.doi.org/10.1681/ASN.2019080847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191929PMC
April 2020

External Validation of the DynPG for Kidney Transplant Recipients.

Transplantation 2021 02;105(2):396-403

INSERM UMR 1246 - SPHERE, Nantes University, Tours University, Nantes, France.

Background: In kidney transplantation, dynamic prediction of patient and kidney graft survival (DynPG) may help to promote therapeutic alliance by delivering personalized evidence-based information about long-term graft survival for kidney transplant recipients. The objective of the current study is to externally validate the DynPG.

Methods: Based on 6 baseline variables, the DynPG can be updated with any new serum creatinine measure available during the follow-up. From an external validation sample of 1637 kidney recipients with a functioning graft at 1-year posttransplantation from 2 European transplantation centers, we assessed the prognostic performance of the DynPG.

Results: As one can expect from an external validation sample, differences in several recipient, donor, and transplantation characteristics compared with the learning sample were observed. Patients were mainly transplanted from deceased donors (91.6% versus 84.8%; P < 0.01), were less immunized against HLA class I (18.4% versus 32.7%; P < 0.01) and presented less comorbidities (62.2% for hypertension versus 82.7%, P < 0.01; 25.1% for cardiovascular disease versus 33.9%, P < 0.01). Despite these noteworthy differences, the area under the ROC curve varied from 0.70 (95% confidence interval [CI], 0.64-0.76) to 0.76 (95% CI, 0.64-0.88) for prediction times at 1 and 6 years posttransplantation respectively, and calibration plots revealed reasonably accurate predictions.

Conclusions: We validated the prognostic capacities of the DynPG in terms of both discrimination and calibration. Our study showed the robustness of the DynPG for informing both the patient and the physician, and its transportability for a cohort presenting different features than the one used for the DynPG development.
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http://dx.doi.org/10.1097/TP.0000000000003209DOI Listing
February 2021

Tacrolimus- versus sirolimus-based immunosuppression after simultaneous pancreas and kidney transplantation: 5-year results of a randomized trial.

Am J Transplant 2020 06 28;20(6):1679-1690. Epub 2020 Feb 28.

CHU Nantes, Université de Nantes, Institut de Transplantation, Urologie, Néphrologie, Nantes, France.

Tacrolimus, the cornerstone immunosuppression after simultaneous pancreas and -kidney (SPK) transplantation, may exert nephrotoxic and diabetogenic effects. We therefore prospectively compared in an open-label, randomized, monocentric, 5-year follow-up study, a tacrolimus- and a sirolimus-based immunosuppressive regimen. Randomization using the block method allowing a blind allocation was done at the time of surgery. All patients received anti-thymocyte globulin and maintenance therapy with tacrolimus, mycophenolate mofetil, and steroids. At month 3, tacrolimus was continued or replaced by sirolimus. The primary endpoint was kidney and pancreas graft survival at 1 and 5 years. Fifty patients were included in the final analysis in each group. At 1 year, differences for kidney and pancreas graft survival between sirolimus and tacrolimus were 0% (90% confidence interval -4.61% to 4.61%) and 6% (90% confidence interval -6.32% to 18.32%), respectively. There was no difference in renal and pancreas graft survival at 5 years. Thirty-four patients (68%) in the sirolimus group vs three (6%) in the tacrolimus group needed definitive withdrawal of the study drug. Despite noninferiority of sirolimus compared to tacrolimus for kidney and pancreas graft survival, the high rate of sirolimus discontinuation does not favor its use as cornerstone therapy after SPK transplantation (NCT00693446).
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http://dx.doi.org/10.1111/ajt.15809DOI Listing
June 2020

Comparison of longitudinal quality of life outcomes in preemptive and dialyzed patients on waiting list for kidney transplantation.

Qual Life Res 2020 Apr 29;29(4):959-970. Epub 2019 Nov 29.

UMR INSERM 1246, SPHERE "MethodS in Patient-centered outcomes and HEalth ResEarch", Université de Nantes, Université de Tours, 22 Boulevard Benoni Goullin, Nantes, France.

Purpose: The waiting list period for kidney transplantation can be lengthy and associated with a deteriorated health-related quality of life (HRQoL). It might also be experienced differently depending on the experience of renal replacement therapy (preemptive or dialyzed patients), and the type of dialysis. The main objective of this study is to measure and compare HRQoL changes in preemptive, hemodialysis (HD), and peritoneal dialysis (PD) patients during the waiting list period for kidney transplantation.

Methods: A sample of adult patients on kidney transplant waiting list from three French University Hospital centers was recruited. HRQoL was measured using the SF-36 and a specific questionnaire (ReTransQol), which were collected every 6 months before transplantation in preemptive, HD, and PD patients. Mixed-effects models taking into account time and possible confounding factors were used to compare HRQoL changes between the three groups.

Results: Preemptive (n = 230), HD (n = 177), and PD patients (n = 39) were enrolled. The renal replacement therapy modalities, time (time on waiting list and age at registration), and gender were associated with HRQoL changes. The HD and PD patients had a significantly lower perceived HRQoL on Role Physical, Social Functioning, and Role Emotional dimensions than the preemptive patients, with lower scores for PD compared to HD patients. The HRQoL scores of all patients were lower compared to the French general population for all dimensions.

Conclusions: A better understanding of pre-transplantation patients' experience can help improving patient care with adapted educational programs and psychological support depending on the type of renal replacement therapy.
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http://dx.doi.org/10.1007/s11136-019-02372-wDOI Listing
April 2020

CXCR5PD1ICOS Circulating T Follicular Helpers Are Associated With Donor-Specific Antibodies After Renal Transplantation.

Front Immunol 2019 10;10:2071. Epub 2019 Sep 10.

Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.

Donor-specific anti-HLA antibodies (DSAs) are a major risk factor associated with renal allograft outcomes. As a trigger of B cell antibody production, T follicular helper cells (Tfhs) promote DSA appearance. Herein, we evaluated whether circulating Tfhs (cTfhs) are associated with the genesis of antibody-mediated rejection. We measured cTfh levels on the day of transplantation and 1 year after transplantation in blood from a prospective cohort of 237 renal transplantation patients without DSA during the first year post-transplantation. Total cTfhs were characterized as CD4CD45RACXCR5, and the three following subsets of activated cTfh were analyzed: CXCR5PD1, CXCR5PD1ICOS, an CXCR5PD1CXCR3. Immunizing events (previous blood transfusion and/or pregnancy) and the presence of class II anti-HLA antibodies were associated with increased frequencies of activated CXCR5PD1, CXCR5PD1ICOS, and CXCR5PD1CXCR3 cTfh subsets. In addition, ATG-depleting induction and calcineurin inhibitor treatments were associated with a relative increase of activated cTfh subsets frequencies at 1 year post-transplantation. In multivariate survival analysis, we reported that a decrease in activated CXCR5PD1ICOS at 1 year after transplantation in the blood of DSA-free patients was significantly associated with the risk of developing DSA after the first year ( = 0.018, HR = 0.39), independently of HLA mismatches ( = 0.003, HR = 3.79). These results highlight the importance of monitoring activated Tfhs in patients early after transplantation and show that current treatments cannot provide early, efficient prevention of Tfh activation and migration. These findings indicate the need to develop innovative treatments to specifically target Tfhs to prevent DSA appearance in renal transplantation.
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http://dx.doi.org/10.3389/fimmu.2019.02071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746839PMC
October 2020

Prediction system for risk of allograft loss in patients receiving kidney transplants: international derivation and validation study.

BMJ 2019 09 17;366:l4923. Epub 2019 Sep 17.

Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, Paris, France.

Objective: To develop and validate an integrative system to predict long term kidney allograft failure.

Design: International cohort study.

Setting: Three cohorts including kidney transplant recipients from 10 academic medical centres from Europe and the United States.

Participants: Derivation cohort: 4000 consecutive kidney recipients prospectively recruited in four French centres between 2005 and 2014. Validation cohorts: 2129 kidney recipients from three centres in Europe and 1428 from three centres in North America, recruited between 2002 and 2014. Additional validation in three randomised controlled trials (NCT01079143, EudraCT 2007-003213-13, and NCT01873157).

Main Outcome Measure: Allograft failure (return to dialysis or pre-emptive retransplantation). 32 candidate prognostic factors for kidney allograft survival were assessed.

Results: Among the 7557 kidney transplant recipients included, 1067 (14.1%) allografts failed after a median post-transplant follow-up time of 7.12 (interquartile range 3.51-8.77) years. In the derivation cohort, eight functional, histological, and immunological prognostic factors were independently associated with allograft failure and were then combined into a risk prediction score (iBox). This score showed accurate calibration and discrimination (C index 0.81, 95% confidence interval 0.79 to 0.83). The performance of the iBox was also confirmed in the validation cohorts from Europe (C index 0.81, 0.78 to 0.84) and the US (0.80, 0.76 to 0.84). The iBox system showed accuracy when assessed at different times of evaluation post-transplant, was validated in different clinical scenarios including type of immunosuppressive regimen used and response to rejection therapy, and outperformed previous risk prediction scores as well as a risk score based solely on functional parameters including estimated glomerular filtration rate and proteinuria. Finally, the accuracy of the iBox risk score in predicting long term allograft loss was confirmed in the three randomised controlled trials.

Conclusion: An integrative, accurate, and readily implementable risk prediction score for kidney allograft failure has been developed, which shows generalisability across centres worldwide and common clinical scenarios. The iBox risk prediction score may help to guide monitoring of patients and further improve the design and development of a valid and early surrogate endpoint for clinical trials.

Trial Registration: Clinicaltrials.gov NCT03474003.
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http://dx.doi.org/10.1136/bmj.l4923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746192PMC
September 2019

Unique and specific Proteobacteria diversity in urinary microbiota of tolerant kidney transplanted recipients.

Am J Transplant 2020 01 9;20(1):145-158. Epub 2019 Sep 9.

Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.

Host-microbiota interactions can modulate the immune system both at local and systemic levels, with potential consequences for organ transplantation outcomes. In this study, we hypothesized that differences in the urinary microbiome following kidney transplantation would be associated with posttransplantation status: stable, minimally immunosuppressed, or tolerant. One hundred thirteen urine samples from stable (n = 51), minimally immunosuppressed (n = 19), and spontaneously tolerant (n = 16) patients, paired with age-matched controls (n = 27) were profiled and compared to each other at a taxonomic level with special interest in the immunosuppressive regimen. All comparisons and correlations were adjusted on sex and time posttransplantation. Our results highlighted a unique and specific urinary microbiota associated with spontaneous tolerance characterized by a high diversity and a clear Proteobacteria profile. Finally, we report that this profile is (1) impacted by gender, (2) inversely correlated with immunosuppressive drugs (calcineurin inhibitors and mammalian target of rapamycin inhibitors), and (3) stable in time.
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http://dx.doi.org/10.1111/ajt.15549DOI Listing
January 2020

Dynamic predictions of long-term kidney graft failure: an information tool promoting patient-centred care.

Nephrol Dial Transplant 2019 11;34(11):1961-1969

INSERM UMR 1246 - SPHERE, Nantes University, Tours University, Nantes, France.

Background: Informing kidney transplant recipients of their prognosis and disease progression is of primary importance in a patient-centred vision of care. By participating in decisions from the outset, transplant recipients may be more adherent to complex medical regimens due to their enhanced understanding.

Methods: We proposed to include repeated measurements of serum creatinine (SCr), in addition to baseline characteristics, in order to obtain dynamic predictions of the graft failure risk that could be updated continuously during patient follow-up. Adult recipients from the French Données Informatisées et VAlidées en Transplantation (DIVAT) cohort transplanted for the first or second time from a heart-beating or living donor and alive with a functioning graft at 1 year post-transplantation were included.

Results: The model was composed of six baseline parameters, in addition to the SCr evolution. We validated the dynamic predictions by evaluating both discrimination and calibration accuracy. The area under the receiver operating characteristic curve varied from 0.72 to 0.76 for prediction times at 1 and 6 years post-transplantation, respectively, while calibration plots showed correct accuracy. We also provided an online application tool (https://shiny.idbc.fr/DynPG).

Conclusion: We have created a tool that, for the first time in kidney transplantation, predicts graft failure risk both at an individual patient level and dynamically. We believe that this tool would encourage willing patients into participative medicine.
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http://dx.doi.org/10.1093/ndt/gfz027DOI Listing
November 2019

Early Acute Microvascular Kidney Transplant Rejection in the Absence of Anti-HLA Antibodies Is Associated with Preformed IgG Antibodies against Diverse Glomerular Endothelial Cell Antigens.

J Am Soc Nephrol 2019 04 8;30(4):692-709. Epub 2019 Mar 8.

Paris Descartes, Sorbonne Paris Cité University, Paris, France;

Background: Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed.

Methods: We conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR). We developed a crossmatch assay to assess serum reactivity to human microvascular endothelial cells, and used a combination of transcriptomic and proteomic approaches to identify non-HLA Abs.

Results: We identified a highly selected cohort of 38 patients with early acute AMVR. Biopsy specimens revealed intense microvascular inflammation and the presence of vasculitis (in 60.5%), interstitial hemorrhages (31.6%), or thrombotic microangiopathy (15.8%). Serum samples collected at the time of transplant showed that previously proposed anti-endothelial cell Abs-angiotensin type 1 receptor (AT1R), endothelin-1 type A and natural polyreactive Abs-did not increase significantly among patients with AMVR compared with a control group of stable kidney transplant recipients. However, 26% of the tested AMVR samples were positive for AT1R Abs when a threshold of 10 IU/ml was used. The crossmatch assay identified a common IgG response that was specifically directed against constitutively expressed antigens of microvascular glomerular cells in patients with AMVR. Transcriptomic and proteomic analyses identified new targets of non-HLA Abs, with little redundancy among individuals.

Conclusions: Our findings indicate that preformed IgG Abs targeting non-HLA antigens expressed on glomerular endothelial cells are associated with early AMVR, and that cell-based assays are needed to improve risk assessments before transplant.
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http://dx.doi.org/10.1681/ASN.2018080868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442343PMC
April 2019

Lack of impact of pre-emptive deceased-donor kidney transplantation on graft outcomes: a propensity score-based study.

Nephrol Dial Transplant 2019 05;34(5):886-891

Centre Hospitalier Universitaire de Nantes, Nantes, France.

Background: A significant number of studies have compared graft outcomes between patients with Pre-emptive Kidney Transplantation (PreKT) and patients on Dialysis before their Kidney Transplantation (DiaKT). These studies have suffered from the limitation that the DiaKT group is composed of all the dialysed patients, including those placed on a waiting list at the time of their first dialysis session. This seriously questions the comparability of these patients with those placed on the waiting list a long time before the need for renal replacement therapy. The aim of this study was to precisely evaluate the causal effect of PreKT from deceased donors.

Methods: Data were extracted from the multicentric French DIVAT (Données Informatisées et VAlidées en Transplantation) cohort. The DiaKT group was composed of patients placed on the waiting list with an initial intention of pre-emptive transplantation. Cause-specific Cox models with propensity scores (inverse probability weighting) were used to study the patient and graft outcomes.

Results: Among the 1138 included patients, 554 patients were in the PreKT group. The outcomes of the PreKT group were similar compared with the DiaKT group. In particular, the life expectancy with a functioning graft was 8.51 years [95% confidence interval (CI) 8.20-8.81] for the PreKT recipients versus 8.49 years (95% CI 8.15-8.84) for the DiaKT recipients.

Conclusions: Our results challenge the utility of PreKTs from deceased donors, especially with regard to the consequential increase in the waiting list.
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http://dx.doi.org/10.1093/ndt/gfy317DOI Listing
May 2019

Comparison of graft and patient survival according to the transplantation centre policy for 1-year screening biopsy among stable kidney recipients: a propensity score-based study.

Nephrol Dial Transplant 2019 04;34(4):703-711

INSERM UMR 1246 - SPHERE, Nantes University, Tours University, Nantes, France.

Background: The clinical utility of screening biopsies (SBs) at 1 year post-transplantation is still debated, especially for stable kidney graft recipients. Given the heterogeneity in practices between transplantation centres, the objective of this study was to compare graft and patient survival of stable patients according to whether they were followed up in a transplantation centre with or without a policy for having an SB at 1 year post-transplantation.

Materials: From a French multicentre cohort, we studied 1573 kidney recipients who were alive with stable graft function at 1 year post-transplantation, with no acute rejection in their first year post-transplantation.

Results: Using propensity score-based analyses, we did not observe any significant difference in the relative risk for graft failure between patients from centres with a 1-year SB policy and those from other centres [hazard ratio = 1.15, 95% confidence interval (CI) 0.86-1.53]. The corresponding adjusted survival probability at 8 years post-transplantation was 69% (95% CI 61-74%) for patients from centres with a 1-year SB policy versus 74% (95% CI 67-79%) for those from other centres.

Conclusion: A 1-year SB policy for stable patients may not lead to therapeutical benefits for improved graft and patient survival. Further studies examining the benefits versus the risks of a 1-year SB policy are warranted to demonstrate the long-term utility of this intervention.
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http://dx.doi.org/10.1093/ndt/gfy221DOI Listing
April 2019

Analyses of the short- and long-term graft survival after kidney transplantation in Europe between 1986 and 2015.

Kidney Int 2018 11 24;94(5):964-973. Epub 2018 Jul 24.

Department of Microbiology and Immunology, KU Leuven, University of Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium. Electronic address:

The evolution of kidney allograft survival remains insufficiently studied in the context of the changing donor and recipient demographics. Since European data are lacking we performed a cohort study (1986-2015) that, based on the Collaborative Transplant Study, included 108 787 recipients of brain-death kidney donors in 135 hospitals across 21 European countries. We analyzed the hazard rate of kidney failure after transplantation. Between 1986 and 1999, improvement in graft survival was more pronounced in the short term than in the long term: one-, five- and ten-year hazard rates after transplantation declined 64% (95% confidence interval, 61%-66%), 53% (49%-57%) and 45% (39%-50%), respectively. Between 2000 and 2015, hazard rates at one, five and ten years post-transplant declined respectively 22% (12-30%), 47% (36-56%) and 64% (45-76%). Improvement in graft survival in the first five years post-transplant was significantly less since 2000, while improvement after five years was comparable to before. During the 2000-2015 period improvement of graft survival was greater in the long than in the short term. These changes were independent of changing donor and recipient characteristics, and reflect the evolution in global kidney transplant management over the past decades. Unfortunately, after accounting for the evolution of donor and recipient characteristics, we found that short-term improvement in graft survival decreased since 2000, while long-term improvement remained unchanged in Europe. Thus, deceleration of short-term graft survival improvement in more recent years illustrates an unmet need for innovation.
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http://dx.doi.org/10.1016/j.kint.2018.05.018DOI Listing
November 2018

The 1-year Renal Biopsy Index: a scoring system to drive biopsy indication at 1-year post-kidney transplantation.

Transpl Int 2018 Jun 12. Epub 2018 Jun 12.

INSERM UMR 1246 - SPHERE, Nantes University, Tours University, Nantes, France.

Surveillance biopsies after renal transplantation remain debatable. To drive the decision of such intervention, we propose a predictive score of abnormal histology at 1-year post-transplantation, named 1-year Renal Biopsy Index (1-RBI). We studied 466 kidney recipients from the DIVAT cohort alive with a functioning graft and a surveillance biopsy at 1-year post-transplantation. Patients displaying abnormal histology (49%) (borderline, acute rejection, interstitial fibrosis and tubular atrophy [IFTA] grade 2 or 3, glomerulonephritis) were compared to the normal or subnormal (IFTA grade 1) histology group. Obtained from a lasso penalized logistic regression, the 1-RBI was composed of recipient gender, serum creatinine at 3, 6, and 12 month post-transplantation and anticlass II immunization at transplantation (internal validation: AUC = 0.71, 95% CI [0.53-0.83]; external validation: AUC = 0.62, 95% CI [0.58-0.66]). While we could not determinate a threshold able to identify patients at high chance of normal or subnormal histology, we estimated and validated a discriminating threshold capable of identifying a subgroup of 15% of the patients with a risk of abnormal histology higher than 80%. The 1-RBI is computable online at www.divat.fr. The 1-RBI could be a useful tool to standardize 1-year biopsy proposal and may for instance help to indicate one in case of high risk of abnormal histology.
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http://dx.doi.org/10.1111/tri.13290DOI Listing
June 2018

HCMV triggers frequent and persistent UL40-specific unconventional HLA-E-restricted CD8 T-cell responses with potential autologous and allogeneic peptide recognition.

PLoS Pathog 2018 04 30;14(4):e1007041. Epub 2018 Apr 30.

Centre de Recherche en Transplantation et Immunologie (CRTI), UMR1064, INSERM, Université de Nantes, Nantes, France.

Immune response against human cytomegalovirus (HCMV) includes a set of persistent cytotoxic NK and CD8 T cells devoted to eliminate infected cells and to prevent reactivation. CD8 T cells against HCMV antigens (pp65, IE1) presented by HLA class-I molecules are well characterized and they associate with efficient virus control. HLA-E-restricted CD8 T cells targeting HCMV UL40 signal peptides (HLA-EUL40) have recently emerged as a non-conventional T-cell response also observed in some hosts. The occurrence, specificity and features of HLA-EUL40 CD8 T-cell responses remain mostly unknown. Here, we detected and quantified these responses in blood samples from healthy blood donors (n = 25) and kidney transplant recipients (n = 121) and we investigated the biological determinants involved in their occurrence. Longitudinal and phenotype ex vivo analyses were performed in comparison to HLA-A*02/pp65-specific CD8 T cells. Using a set of 11 HLA-E/UL40 peptide tetramers we demonstrated the presence of HLA-EUL40 CD8 αβT cells in up to 32% of seropositive HCMV+ hosts that may represent up to 38% of total circulating CD8 T-cells at a time point suggesting a strong expansion post-infection. Host's HLA-A*02 allele, HLA-E *01:01/*01:03 genotype and sequence of the UL40 peptide from the infecting strain are major factors affecting the incidence of HLA-EUL40 CD8 T cells. These cells are effector memory CD8 (CD45RAhighROlow, CCR7-, CD27-, CD28-) characterized by a low level of PD-1 expression. HLA-EUL40 responses appear early post-infection and display a broad, unbiased, Vβ repertoire. Although induced in HCMV strain-dependent, UL4015-23-specific manner, HLA-EUL40 CD8 T cells are reactive toward a broader set of nonapeptides varying in 1-3 residues including most HLA-I signal peptides. Thus, HCMV induces strong and life-long lasting HLA-EUL40 CD8 T cells with potential allogeneic or/and autologous reactivity that take place selectively in at least a third of infections according to virus strain and host HLA concordance.
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http://dx.doi.org/10.1371/journal.ppat.1007041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945056PMC
April 2018

Poor Patient and Graft Outcome After Induction Treatment by Antithymocyte Globulin in Recipients of a Kidney Graft After Nonrenal Organ Transplantation.

Transplant Direct 2018 Apr 20;4(4):e357. Epub 2018 Mar 20.

Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France.

Background: End-stage renal failure occurs in a substantial number of patients having received a nonrenal transplantation (NRT), for whom a kidney transplantation is needed. The medical strategy regarding the use of immunosuppression (IS) for a kidney graft in patients after an NRT is not well established. The prekidney grafts long-term IS advocates for a mild induction, such as using anti-IL-2R antibodies, whereas addition of new incompatibilities and anti-HLA preimmunization may suggest using stronger IS such as induction by polyclonal antithymocyte globulins (ATG).

Methods: We performed Cox multivariate and propensity score analysis of our validated transplant database to study the impact of the type of induction therapy on kidney graft survival of recipients of a kidney graft after NRT.

Results: We report here that kidney transplantation after NRT treated with an ATG induction has a poorer outcome (kidney and recipient survival) than that with an anti-IL-2R induction. After accounting for potential baseline differences with a multivariate Cox model, or by adjusting on a propensity score, we found that despite patients having received ATG cumulate more risk factors, ATG appears independently involved. As animal-derived biotherapeutics induce antiglycan antibodies and particularly anti-N-glycolylneuraminic acid (Neu5Gc) IgGs which may activate endothelial cells in patients and grafts, we also investigated the magnitude and the nature of the anti-Neu5Gc elicited by the induction and showed that induction was associated with a shift in anti-Neu5Gc IgG repertoire. Possible reasons and mechanisms of a deleterious ATG usage in these patients are discussed.

Conclusions: Our study suggests that ATG induction after a kidney transplantation in recipients already under maintenance IS for a NRT should be used cautiously.
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http://dx.doi.org/10.1097/TXD.0000000000000772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908458PMC
April 2018