Introduction Une altération de l’élimination des cellules mourantes par les macrophages, par efferocytose, contribue à un défaut de résolution de l’inflammation, et cette altération semble commune a différentes pathologies inflammatoires chroniques dont la polyarthrite rhumatoïde (PR). Ainsi, restaurer cette fonction dans les macrophages « pathologiques » afin de réenclencher la résolution de l’inflammation et la réparation tissulaire représente une approche thérapeutique attractive dans le traitement de la PR. Dans cet optique, nous avons évalué les propriétés thérapeutiques d’un sécrétome autologue résolutif dans un modèle pré-clinique et sur des cellules de patients PR. Matériels et méthodes Les macrophages ont été différenciés en présence de M-CSF pendant 7jours à partir de cellules mononucléées circulantes (PBMC) de souris arthritiques, avec ou sans traitement standard, de patients PR ou de volontaires sains (VS) (NCT02839278). La capacité d’efferocytose des macrophages a été évaluée par cytométrie en flux. Les sécrétomes issus des cultures d’efferocytose ont été récoltés et filtrés (0,22μm). Les sécrétomes murins ont été évalués dans le modèle d’arthrite induite au collagène (CIA) par évaluation du score clinique suivi pendant 10jours. Les sécrétomes humains ont été caractérisés par dosage multiplex et analyse lipidomique, et leurs activités par un test d’inhibition de l’activation monocytaire. Résultats Les sécrétomes résolutifs autologues obtenus des macrophages de souris CIA (MRTCIA) permettent de contrôler de l’activité de la maladie après une seule injection (Figure 1a,b) et de façon drastiquement supérieure au méthotrexate (MTX) (Figure 1a-c). De plus, l’activité thérapeutique des sécrétomes n’est pas influencée par les traitements conventionnels MTX±corticoïdes (Figure 1a-c). Ces effets thérapeutiques sont dépendants de la reprogrammation des macrophages aux capacités d’efferocytose accrues, d’une inhibition de l’activation des monocytes et d’une augmentation des lymphocytes Treg (données non présentées), confirmant le réengagement de la résolution de l’inflammation. L’analyse des sérums de patients PR (N=35) confirme le profil inflammatoire avec des taux élevés de cytokines pro-inflammatoires (TNF-a, IL-6, IL-8, IL-1β et IL-12) et de médiateurs lipidiques dérivés des acides gras omega-3, comparés aux VS (n=31). Les monocytes et cellules dendritiques circulants des patients PR présentent une expression élevée de CD40. Cependant, sortis de leur environnement inflammatoire, les macrophages dérivés des monocytes sanguins démontrent des capacités d’efferocytose comparables à celles des VS, et plus particulièrement leurs sécrétomes d’efferocytose présentent une activité inhibitrice de l’activation monocytaire équivalente à celle des sécrétomes de VS (Figure 2). Conclusion Ces données pré-cliniques et translationnelles montrent le potentiel thérapeutique jusqu’à présent non décrit des sécrétomes résolutifs autologues afin de contrôler l‘activité de la maladie. Cette approche continue donc son développement comme traitement de nouvelle génération/bDMARDs dans la PR dans un essai clinique programmé en 2025.

Background: Macrophages are believed to be local and systemic master actors in disease, critically involved in shaping inflammation, and in disease resolution via effective efferocytosis. Impaired efferocytosis, a hallmark of failed inflammation resolution, has been reported in an increasing number of immune-mediated inflammatory diseases, like Rheumatoid Arthritis (RA). Macrophage plasticity and capability for reprogramming, make them an attractive target for novel disease-modifying therapies. While cell-based therapies currently being scrutinized for their unique potential to fulfil a lost function, including macrophage-based therapies, the use of resolution-type macrophage secretome, i.e. the molecules they release, might provide a simpler and yet potentially safer approach to restore homeostasis in RA. Objectives: The present study attempted to understand the inflammatory profile and functionality of RA patient's monocyte-derived macrophages and evaluate their plasticity and capability for reprogramming to resolution-type macrophages as a source of RA patient-derived secretome with therapeutic potential. Methods: Patients being followed up at CHU Besançon between 2015 and 2021 were included in this prospective single center study. Inclusion criteria were 18 to 80 year-old patients with RA according to ACR/EULAR 2010 criteria, with a DAS28 ≥ 2.6, with or without csDMARDS (methotrexate, leflunomide or sulfasalazine), and naïve of biological agents or systemic corticosteroids for 6 months. Blood inflammatory cytokines and lipid mediators were quantified using CBA multiplex and MS analysis, respectively. Blood monocytes from RA patients or healthy donors (HD) were isolated by density gradient, and examined after differentiation into macrophages using M-CSF during 7 days, or not. Inflammatory responses and efferocytosis capacities were analyzed using flow cytometry. Results: A total of 28 patients and 31 HD were included. Evaluating inflammatory mediators, we found pro-inflammatory cytokines TNF-α, IL-6, IL-8, IL-1β and IL-12 increased in RA patient's plasma compared to HD. We also detected a global increase of the pro-inflammatory lipid mediators derived from omega-3 fatty acid in patient plasma, confirming the ongoing systemic inflammatory nature of disease in RA patients. Furthermore, we observed that monocytes and dendritic cells (DC) of RA patients presented higher levels of the co-stimulatory marker CD40, as compared to HD, which was not true on plasmacytoid DC. Thus, we confirm that circulating myeloid cells exhibit an inflammatory profile in RA patients. To evaluate how inflammatory pattern affects the efferocytosis capacities of macrophages, monocytes were differentiated into macrophages and evaluated for their phagocytosis of apoptotic cells. Interestingly, we observed that the efferocytic capacities of patient monocytes-derived macrophages were not impaired ex vivo. This was confirmed by similar expression of membrane engulfment receptors at the macrophage stage. Culturing macrophages with apoptotic cells generate resolution-type macrophages secreting pro-resolutive mediators. Interestingly, when exposed to HD resolution mediators, the efferocytic capacity of RA macrophages could be further increased by 67% [5-303%, min-max]. Our data show that in RA patients, monocytes remained plastic and capable to reprogram into resolution-type macrophages outside of patient inflammatory environment, and with that, could be considered not only a potential target but also a cellular source to generate autologous patient-specific resolution mediator secretome. Conclusion: Our study revealed that despite their inflammatory profile, RA patient monocytes remained plastic and conserved ex vivo their efferocytic capacities, and used to produce patient-specific autologous resolution-type secretome. Further investigations are ongoing to confirm the therapeutic properties of RA patient own macrophage-derived secretomes to be proposed as next generation disease modifying therapeutic modality/bDMARD for RA patients. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: Mélanie COUTURIER MED'INN'Pharma, F-25000 Besançon, France, MED'INN'Pharma, F-25000 Besançon, France, Emilie GAIFFE: None declared, Charline VAUCHY: None declared, Susanne BEHLKE MED'INN'Pharma, F-25000 Besançon, France, Eric Toussirot: None declared, Sylvain PERRUCHE MED'INN'Pharma, F-25000 Besançon, France, MED'INN'Pharma, F-25000 Besançon, France.

Importance Red blood cell transfusion (RBCT) is frequently required in the early post–kidney transplant period, but long-term outcomes associated with RBCT is controversial. Therefore, it may be relevant to investigate the association between RBCT characteristics and transplant outcomes. Objective To study the association between RBC storage duration and transplant outcomes. Design, Setting, and Participants This was a nationwide retrospective cohort study based on data linking between 2 prospective French nationwide registries. Clinical transplant parameters, outcomes, and RBCT characteristics were extracted from the CRISTAL registry of the Agence de la Biomédecine and the national database of the Etablissement Français du Sang. All 12 559 patients having received a first kidney transplant in France between January 1, 2002, and December 31, 2008, were included. Patients were followed up from transplant to graft loss, death with a functional graft, or data retrieval in June 2016. Data were analyzed from April 2019 to June 2022. Exposures Clinical outcomes of transplant recipients who underwent early RBCT were analyzed considering transfusion characteristics. Main Outcomes and Measures Cox proportional hazards regression models were fitted to evaluate transplant failure defined as graft loss or death with a functional graft. Results Among 12 559 patients who underwent kidney transplant, 3483 received an RBCT during the first 14 days posttransplant. The median (IQR) age of patients was 53.0 (41.5-61.2) years, and 1929 patients (55.4%) were male. Median (IQR) follow-up was 7.8 (7.6-8.0) years. In multivariable analysis, longer (vs shorter) storage duration of transfused RBC was associated with a decrease in risk of transplant failure (hazard ratio, 0.99; 95% CI, 0.98-1.00 for each additional storage day; P = .06). Patients transfused with at least 1 RBC unit stored for more than 20 days had a 5% absolute decrease in transplant failure at 3 years and 7% at 5 years compared with those who received RBC stored for less than 20 days. Conclusions and Relevance In this study, longer RBC storage duration was associated with a decreased risk of transplant failure among patients who received kidney transplants and RBC transfusions. Preferential use of RBC with longer storage duration might improve kidney graft survival following transplant and transfusion.

BackgroundAcute rejection persists as a frequent complication after kidney transplantation. Defining an at-risk immune profile would allow better preventive approaches.MethodsWe performed unsupervised hierarchical clustering analysis on pre-transplant immunological phenotype in 1113 renal transplant recipients from the ORLY-EST cohort.ResultsWe identified three immune profiles correlated with clinical phenotypes. A memory immune cluster was defined by memory CD4+T cell expansion and decreased naïve CD4+T cell. An activated immune cluster was characterized by an increase in CD8+T cells and a decreased CD4/CD8 ratio. A naïve immune cluster was mainly defined by increased naïve CD4+T cells. Patients from the memory immune profile tend to be older and to have diabetes whereas those from the activated immune profile were younger and more likely to have pre-transplant exposure to CMV. Patients from the activated immune profile were more prone to experience acute rejection than those from other clusters [(HR=1.69, 95%IC[1.05-2.70], p=0.030) and (HR=1.85; 95%IC[1.16-3.00], p=0.011). In the activated immune profile, those without previous exposure to CMV (24%) were at very high risk of acute rejection (27 vs 16%, HR=1.85; 95%IC[1.04-3.33], p=0.039).ConclusionImmune profile determination based on principal component analysis defines clinically different sub-groups and discriminate a population at high-risk of acute rejection.

Background Red blood cell (RBC) transfusions are frequently required in the early period after kidney transplantation. However, the consequences of RBC transfusions on long-term outcomes are largely unrecognized. Methods We conducted a nationwide French cohort study involving all 31 French kidney transplant centers. Patients having received a first kidney transplant between January 1, 2002 and December 31, 2008 were identified through the national registry of the French BioMedecine Agency (Agence de BioMédecine). Number and date of RBC transfusions were collected from the national database of the French transfusion public service. The primary endpoint was transplant failure defined as graft loss or death with a functional graft. Results Among 12,559 patients included during the study period, 3,483 (28%) were transfused during the first 14 days post-transplant. Median follow-up was 7.6 (7.5-7.8) years. Multivariable analysis determined that post-transplant RBC transfusion was associated with an increased risk in transplant failure (HR 1.650, 95%CI [1.538;1.771] p<0.0001). Both sensitivity and propension score analyses confirmed the previous result. Conclusions Early red blood cell transfusion after kidney transplantation is associated with increased transplant failure.

A premature decline of thymic output in patients with chronic kidney disease (CKD) is associated with a greater risk of infectious and neoplastic events [1, 2], while its evolution after transplantation has an impact on cancer, infections and rejection occurrences [3–5]. In addition, low pre-transplant thymic function is predictive of death after transplantation [6, 7]. Recently a common intergenic variant located in the TCRA/TCRD locus was linked to interindividual variability of thymic output [8]. In the general population, GG homozygous (wild allele) carriers of the rs2204985 polymorphism had better thymopoiesis than AA homozygous (variant) patients. Our work aimed to analyse the allele impact on thymopoiesis in a cohort of CKD patients receiving a kidney transplant. This work involved 550 patients from the ORLY-EST (Influence de l'Orientation de la Re’ponse LYmphocytaire dans l'athe ’rosclerose post-trans-plantation) prospective study [5...

Chronic kidney disease induces disruption of the intestinal epithelial barrier, leading to gut bacterial translocation. Here, we appreciated bacterial translocation by analyzing circulating lipopolysaccharides (LPS) using two methods, one measuring only active free LPS, and the other quantifying total LPS as well as LPS lipid A carbon chain length. This was done in end-stage renal disease (ESRD) patients and healthy volunteers (HV). We observed both higher LPS concentration in healthy volunteers and significant differences in composition of translocated LPS based on lipid A carbon chain length. Lower LPS activity to mass ratio and higher concentration of high-density lipoproteins were found in HV, suggesting a better plasma capacity to neutralize LPS activity. Higher serum concentrations of soluble CD14 and pro-inflammatory cytokines in ESRD patients confirmed this hypothesis. To further explore whether chronic inflammation in ESRD patients could be more related to LPS composition rather than its quantity, we tested the effect of HV and patient sera on cytokine secretion in monocyte cultures. Sera with predominance of 14-carbon chain lipid A-LPS induced higher secretion of pro-inflammatory cytokines than those with predominance of 18-carbon chain lipid A-LPS. TLR4 or LPS antagonists decreased LPS-induced cytokine production by monocytes, demonstrating an LPS-specific effect. Thereby, septic inflammation observed in ESRD patients may be not related to higher bacterial translocation, but to reduced LPS neutralization capacity and differences in translocated LPS subtypes.

Background Few studies have focused on risk stratification for premature death after transplantation. However, stratification of individual risk is an essential step in personalized care. Material and methods We have developed a risk score of early post-transplant death (ORLY score) in a prospective multicentre cohort including 942 patients and validated our model in a retrospective independent replication cohort including 874 patients. Results 60 patients (6.4%) from the prospective cohort died during the first three-year post-transplant. Age, male gender, diabetes, dialysis duration and chronic respiratory failure were associated with early post-transplant death. The multivariable model exhibited good discrimination ability (C-index = 0.78, 95%CI [0.75-0.81]). ORLY score highly predicted early death after transplantation (1.34; 95%CI, 1.22 to 1.48 for each increase of 1 point in score;P < .001). The predictive value of the score in the validation cohort was close to that observed in the experimental cohort (1.41; 95%CI, 1.27 to 1.56 for each increase of 1 point in score;P < .001). Merging the two cohorts, four categories of risk could be individualized: low, 0-5 (n = 522, mean risk, 1%); intermediate, 6-7 (n = 739, mean risk 4.7%); moderate, 8-10 (n = 429, mean risk 10%); and high risk 11-15 (n = 132, mean risk 19%). Conclusions The ORLY score discriminates patients with high risk of early death.

Accelerated thymic involution is a main feature of end-stage renal disease (ESRD)-associated immune senescence. Recent evidences suggest that ESRD-associated immune senescence is associated with adverse outcomes in dialysis patients. However, no study focused on the association between pre-transplant thymic function and patient survival after transplantation. We conducted a prospective, multicenter study to assess whether pre-transplant thymic function measured by recent thymic emigrants (RTE) may predict death after first kidney transplantation. Results were tested in a validation cohort. Nine hundred and sixty-seven incident kidney transplant recipients were included in the prospective study. Mean follow up was 5.1 + 2.9 years. Eighty two patients (8.5%) died during follow up. Lower RTE levels were associated with a higher risk of death (2.53; 95%CI, 1.54-4.39 for each decrease of 1 log in RTE;p< 0.001). Cancer-related death was particularly increased in patients with low RTE levels (4.23; 95%CI, 1.43-12.13;p= 0.007). One hundred and thirty-six patients having received a first kidney transplantation were included in the validation cohort. Lower TREC levels were associated with higher risk of death (1.90; 95%CI, 1.11-3.51 for each decrease of 1 log in RTE;p= 0.025). RTE were not associated with death-censored graft loss. Pre-transplant thymic function is strongly associated with death after transplantation. Attempt to reverse ESRD-related thymic loss may prevent premature death.

Few data are available concerning immune factors involved in the occurrence of new onset diabetes after transplantation (NODAT). Our objective was to determine an immune profile associated with the subsequent development of NODAT. The secondary objective was to build a predictive model of NODAT. We studied a prospective cohort of incident kidney transplant patients to determine whether pre-transplant immune characteristics could be associated with the occurrence of NODAT. 818 patients were included. We observed a significant inverse correlation between BMI and recent thymic emigrants (RTE) % at transplant time (p < 0.001). 177 (17.3%) of 677 non-diabetic patients experienced NODAT in the first year post-transplant. In multivariate analysis, age, body mass index (BMI), use of Tacrolimus, use of anti-thymocyte globulins (ATG), higher B cell count, and lower recent thymic emigrants (RTE) % were associated with NODAT. A differential effect of immune profile was observed in ATG-treated patients and non-ATG-treated patients. B cell count predicts NODAT only in non-ATG-treated patients whereas lower RTE% was associated with NODAT only in ATG-treated patients. Tacrolimus sparing and B cell depletion may efficiently prevent NODAT in selected patients. We identified an immune profile associated with the occurrence of post-transplant diabetes. Further studies should better precise the exact mechanisms involved in this association.

Chronic inflammation in end-stage renal disease (ESRD) is partly attributed to gut bacterial translocation (GBT) due to loss of intestinal epithelium integrity. Increased levels of circulating lipopolysaccharide (LPS) -a surrogate marker of GBT- contribute to maintain a chronic inflammatory state. However, circulating LPS can be neutralized by lipoproteins and transported to the liver for elimination. While ESRD-associated GBT has been widely described, less is known about its changes and impact on clinical outcome after kidney transplantation (KT). One hundred and forty-six renal transplant recipients with serum samples obtained immediately before and 1 year after transplantation (1-Year post KT) were included. Intestinal epithelium integrity (iFABP), total LPS (by measuring 3-hydroxymyristate), LPS activity (biologically active LPS measured by the LAL assay), inflammatory biomarkers (sCD14 and cytokines), lipoproteins and LPS-binding proteins (LBP and phospholipid transfer protein [PLTP] activity) were simultaneously measured. At 1-Year post KT, iFABP decreased but remained higher than in normal volunteers. Total LPS concentration remained stable while LPS activity decreased. Inflammation biomarkers decreased 1-Year post KT. We concomitantly observed an increase in lipoproteins. Higher sCD1 4 levels before transplantation was associated with lower incidence of acute rejection. Although GBT remained stable after KT, the contemporary increase in lipoproteins could bind circulating LPS and contribute concomitantly to neutralization of LPS activity, as well as improvement in ESRD-associated chronic inflammation. Chronic exposure to LPS in ESRD could promote endotoxin tolerance and explain why patients with higher pre-transplant sCD14 are less prompt to develop acute rejection after transplantation.

Background: Randomized studies reported a marginal superiority of polyclonal antithymocyte globulins (ATG, Thymoglobulin®, Sanofi, Gentilly, France, or Fresenius®, Bad Homburg, Germany) to prevent acute rejection compared to monoclonal anti-CD25 antibodies (IL2Ra). Nevertheless, the representativeness and the generalizability of these studies are questionable. Methods: We studied the impact of ATG use in real-life conditions in a multicenter study. Propensity score analysis was performed to address potential confounding by indication. Results: 817 patients were included. Logistic regression revealed that age, male gender, a pre-transplant history of cancer, presence of anti-HLA antibodies, previous kidney transplantation, and transplant center were associated with ATG use. The area under the curve of the propensity score was 0.84 + 0.02. ATG use was not associated with a lower rate of acute rejection (18.2% in ATG-treated patients vs 15.8% in non-ATG-treated patients, p =0.356). Adjustment for propensity score slightly modified the relationship between ATG and acute rejection towards a more neutral effect ( p =0.913). Score match analysis recapitulated the previous result. ATG use was associated with the occurrence of opportunistic infection ( p =0.034). There was no difference in graft loss or death between the two groups. Conclusions: In real-life conditions, ATG does not substantially reduce the risk of acute rejection after kidney transplantation. A better discrimination of patients who may benefit from ATG is required.

Background Post-transplant diabetes is a frequent and serious complication of kidney transplantation. There is currently no treatment to prevent or delay the disease. Nevertheless, identification of risk factors make it possible to target a population at risk of developing de novo diabetes. We hypothesized that a short-term treatment with vildagliptin may prevent new onset diabetes after transplantation (NODAT) in high-risk patients. Methods/design This is a multicenter, double-blind, placebo-controlled randomized clinical trial. Patients undergoing first kidney transplantation will be included from ten French transplant centers. Included patients will be randomized (1:1) to receive either vildagliptin 100 or 50 mg/day (depending on glomerular filtration rate) during 2 months (the first dose being administered before entering the operating theatres) or placebo. Additional antidiabetic therapy could be administered according to glycemic control. The primary outcome is the proportion of diabetic patients 1 year after transplantation, defined as patients receiving a diabetic treatment, or having a fasting glucose above 7 mmol/l, and/or with an abnormal oral glucose tolerance test. Secondary outcomes include glycated hemoglobin, the occurrence of acute rejection, infection, graft loss and patient death at 3 months, 6 months, and 12 months after transplantation. Outcomes will be correlated to clinical and general characteristics of the patient, cardiovascular history, nephropathy, dialysis history, transplantation data, biological data, health-related quality of life, and the cost-effectiveness of prevention of diabetes with vildagliptin. Discussion We have scarce data on the pharmacological prevention of post-transplant diabetes. If our hypothesis is verified, our results will have a direct application in clinical practice and could limit diabetes-associated morbidity, reduce cardiovascular complications, increase quality of life of renal transplant patients, and consequently promote graft and patient survival. Our results may possibly serve for non-transplant patients carrying a high-risk of diabetes associated with other co-morbidities. Trial registration ClinicalTrials.gov, NCT02849899 . Registered on 8 February 2016.

Using pseudo-periodic patterns on the observed target releases usual computer-vision constraints by allowing sub-pixel resolutions together with supra field-of-observation absolute measurement ranges. The allowed range of working distances is also tremendously extended using digital holography.

BACKGROUND:Patients with chronic kidney disease (CKD) are more prone to develop premature age-related diseases. Data on immune senescence are scarce in CKD populations, except in end-stage renal disease and dialysis. We designed a longitudinal prospective study to evaluate immune senescence at different CKD stages and its influence on CKD patient outcomes.METHODS:Clinical and biological data collections were performed on 222 patients at different CKD stages [1-2 (n = 85), 4 (n = 53) and 5 (n = 84)]. Immune senescence biomarkers were measured by cytometry on T cells (CD28, CD57, CD45RA, CD31, γH2A.X) or by quantitative polymerase chain reaction [relative telomere length (RTL)] on peripheral blood mononuclear cells and analysed according to CKD stages and outcomes.RESULTS:CKD was associated with an increase in immune senescence and inflammation biomarkers, as follows: low thymic output (197 ± 25 versus 88 ± 13 versus 73 ± 21 CD4+CD45RA+CD31+ T cells/mm3), an increased proportion of terminally differentiated T cells (CD8+CD28-CD57+) (24 ± 18 versus 32 ± 17 versus 35 ± 19%) restricted to cytomegalovirus-positive patients, telomere shortening (1.11 ± 0.36 versus 0.78 ± 0.24 versus 0.97 ± 0.21 telomere:single copy ratio) and an increase in C-reactive protein levels [median 2.9 (range 1.8-4.9) versus 5.1 (27-9.6) versus 6.2 (3.4-10.5) mg/L]. In multivariate analysis, shorter RTL was associated with death {hazard ratio [HR] 4.12 [95% confidence interval (CI) 1.44-11.75]}. Low thymic output was associated with infections [HR 1.79 (95% CI (1.34-9.58)] and terminally differentiated CD8+ T-cell expansion with a risk of cardiovascular events [CEs; HR 4.86 (95% CI 1.72-13.72)].CONCLUSION:CKD was associated with premature immune ageing. Each of these alterations increased the risk of specific age-related diseases, such as RTL and death, thymic function and infections and terminally differentiated CD8+ T-cell expansion and CEs.

Using pseudo-periodic patterns on the observed target releases usual computer-vision constraints by allowing sub-pixel resolutions together with supra field-of-observation absolute measurement ranges. The allowed range of working distances is also tremendously extended using digital holography.

Les patients en insuffisance rénale chronique (IRC) présentent plus prématurément des pathologies associées au vieillissement (infections, événements cardiovasculaires [ECV]). Les données sur le lien entre IRC et immunosénescence (IS) restent parcellaires principalement limitées au stade d’IRC terminale et de dialyse. Nous avons conduit une étude prospective pour évaluer la présence d’une IS à différents stades d’IRC ainsi que l’impact sur la survenue d’événements cliniques (décès, infections, ECV). Nous avons réalisé l’analyse de biomarqueurs d’IS et relevé les événements cliniques sur 222 patients à différent stade d’IRC (I [n = 85], IV [n = 53], et V [n = 83]) sur une période de 547 ± 265 jours. Les biomarqueurs d’IS comprenaient un immunophénotypage lymphocytaire réalisé par cytométrie (CD3, CD4, CD28, CD57, CD45RA, CD31, γH2A.X), une mesure de la longueur des télomères (RTL) et la quantification de l’expression de KLOTHO lymphocytaire par qPCR ainsi que la mesure de marqueurs de l’inflammation. L’IRC était associée à une inflammation ainsi qu’à une diminution de la thymopoïèse (201 ± 26 vs. 89 ± 13 vs. 72 ± 21 recent thymic emigrant/mm3), une augmentation de la proportion de lymphocyte T au stade terminal de différentiation (24 ± 18 % vs. 32 ± 17 % vs. 36 ± 18 %) principalement chez les CMV positifs, une attrition télomérique (RTL 1,11 ± 0,36 vs. 0,78 ± 0,24 vs. 0,97 ± 0,21) et une hyperexpression lymphocytaire du gène KLOTHO. En analyse multivariée, des télomères longs étaient protecteur vis-à-vis du risque de décès (HR : 0,04 ; IC95 % [0,01–0,55]). Une thymopoïèse diminuée était associé au risque de survenue d’infection (HR : 1,79 ; IC95 % [1,18–2,71]) et l’expansion de lymphocyte T (LT) au stade terminal de différentiation au risque de survenue d’ECV (HR : 2,02 ; IC95 % [1,15–3,55]). Ces résultats confirment l’existence d’un lien entre IS accélérée, urémie, dès le stade IV, et inflammation. C’est la première fois qu’il est décrit une association entre un paramètre d’IS (attrition télomérique, thymopoïèse, LT au stade terminal de différentiation) et la survenue d’événements cliniques (décès, infections, EVC) chez les patients IRC. Certains paramètres d’IS prématurée induite par l’urémie sont associés au risque de survenue d’événements cliniques comme le décès, les épisodes infectieux et les ECV.