Management of immunosuppressive therapy after functional renal graft failure: results of a practice survey of French-speaking nephrologists / Gestion du traitement immunosuppresseur après arrêt fonctionnel du greffon rénal : résultats d'une enquête de pratique parmi les néphrologues francophones.

The management of patients with kidney transplant failure (KTF) remains a complex process involving multiple stakeholders. A working group of the Transplantation Commission of the French-speaking Society of Nephrology, Dialysis and Transplantation (SFNDT) conducted a survey on the management of immunosuppressants (IS) after KTF among nephrologists at transplant centres and general nephrologists in France, Switzerland and Belgium between March and June 2023. We analysed 232 replies from 58 nephrologists at transplant centres and 174 general nephrologists, aged 43.6 (+10.6) years. In the first three months following KTF, nephrologists reported discontinuing antimetabolite, calcineurin inhibitor (CNI) and corticosteroid treatment in 83%, 39.9% and 25.8% of cases respectively. Conversely, some nephrologists reported that they were continuing to use CNI (14%) and corticosteroids (19.1%) on a long-term basis. The patient's comorbidities associated with the discontinuation of IS treatment are cancer and opportunistic infections as KT's complications and presence of diabetes mellitus at KTF, whereas humoral rejection encourages the IS to be maintained. Transplantectomy is proposed by nephrologists most often for graft intolerance syndrome (86.5%), more rarely to discontinue IS (17.6%) or in the absence of plans of new transplantation (9.3%). In multivariate analyses, the presence of a protocol in the centre facilitated the management of IS by the general nephrologists. The management of IS after AFG by French-speaking nephrologists is heterogeneous. Specific prospective studies are needed to establish new best practice recommendations, based on more robust evidence, which could encourage better adherence by nephrologists.

La prise en charge des patients avec un arrêt fonctionnel du greffon rénal (AFG) reste un processus complexe avec de multiples intervenants. Un groupe de travail de la Société francophone de néphrologie, dialyse et transplantation (SFNDT) a conduit une enquête sur la gestion des traitements immunosuppresseurs (IS) après AFG parmi les néphrologues de centres de transplantation et néphrologues généraux en France, Suisse et Belgique francophone entre mars et juin 2023. Nous avons pu analyser 232 réponses de néphrologues (centres de transplantation N = 58 et généraux N = 174) âgés de 43,6 (± 10,6) ans. Dans les 3 premiers mois suivant l'AFG, les néphrologues déclarent interrompre le traitement par antimétabolites (83 %), inhibiteurs de la calcineurine (ICN) (39,9 %) et corticoïdes (25,8 %). À l'inverse, certains déclarent maintenir les ICN (14 %) et les corticoïdes (19,1 %) au long cours en cas de projet de nouvelle transplantation rénale (TR). La survenue de cancer pendant la TR, d'infections opportunistes dans la dernière année de TR ou à l'initiation de la dialyse, et la présence d'un diabète lors de l'AFG sont associées avec l'arrêt du traitement IS alors que la perte du greffon par rejet humoral incite à le maintenir. En analyse multivariée, la présence d'un protocole dans le centre facilite la gestion des IS par les néphrologues généraux. Enfin, la transplantectomie est proposée par les néphrologues le plus souvent pour un syndrome d'intolérance du greffon (86,5 %), plus rarement pour interrompre les IS (17,6 %) ou en l'absence de projet de nouvelle TR (9,3 %). La gestion des IS après l'AFG par les néphrologues francophones est hétérogène. Des études prospectives spécifiques sont nécessaires afin de formuler de nouvelles recommandations de bonnes pratiques, reposant sur des données probantes plus robustes, qui pourraient encourager une meilleure adhésion par les néphrologues.

Management of immunosuppressive therapy after functional renal graft failure: Results of a practice survey of French-speaking nephrologists / Gestion du traitement immunosuppresseur après arrêt fonctionnel du greffon rénal : résultats d'une enquête de pratique parmi les néphrologues francophones.

The management of patients with kidney transplant failure (KTF) remains a complex process involving multiple stakeholders. A working group of the Transplantation Commission of the French-speaking Society of Nephrology, Dialysis and Transplantation (SFNDT) conducted a survey on the management of immunosuppressants (IS) after KTF among nephrologists at transplant centres and general nephrologists in France, Switzerland and Belgium between March and June 2023. We analysed 232 replies from 58 nephrologists at transplant centres and 174 general nephrologists, aged 43.6 (+10.6) years. In the first three months following KTF, nephrologists reported discontinuing antimetabolite, calcineurin inhibitor (CNI) and corticosteroid treatment in 83%, 39.9% and 25.8% of cases respectively. Conversely, some nephrologists reported that they were continuing to use CNI (14%) and corticosteroids (19.1%) on a long-term basis. The patient's comorbidities associated with the discontinuation of IS treatment are cancer and opportunistic infections as KT's complications and presence of diabetes mellitus at KTF, whereas humoral rejection encourages the IS to be maintained. Transplantectomy is proposed by nephrologists most often for graft intolerance syndrome (86.5%), more rarely to discontinue IS (17.6%) or in the absence of plans of new transplantation (9.3%). In multivariate analyses, the presence of a protocol in the centre facilitated the management of IS by the general nephrologists. The management of IS after AFG by French-speaking nephrologists is heterogeneous. Specific prospective studies are needed to establish new best practice recommendations, based on more robust evidence, which could encourage better adherence by nephrologists.

La prise en charge des patients avec un arrêt fonctionnel du greffon rénal (AFG) reste un processus complexe avec de multiples intervenants. Un groupe de travail de la Société francophone de néphrologie, dialyse et transplantation (SFNDT) a conduit une enquête sur la gestion des traitements immunosuppresseurs (IS) après AFG parmi les néphrologues de centres de transplantation et néphrologues généraux en France, Suisse et Belgique francophone entre mars et juin 2023. Nous avons pu analyser 232 réponses de néphrologues (centres de transplantation N = 58 et généraux N = 174) âgés de 43,6 (± 10,6) ans. Dans les 3 premiers mois suivant l'AFG, les néphrologues déclarent interrompre le traitement par antimétabolites (83 %), inhibiteurs de la calcineurine (ICN) (39,9 %) et corticoïdes (25,8 %). À l'inverse, certains déclarent maintenir les ICN (14 %) et les corticoïdes (19,1 %) au long cours en cas de projet de nouvelle transplantation rénale (TR). La survenue de cancer pendant la TR, d'infections opportunistes dans la dernière année de TR ou à l'initiation de la dialyse, et la présence d'un diabète lors de l'AFG sont associées avec l'arrêt du traitement IS alors que la perte du greffon par rejet humoral incite à le maintenir. En analyse multivariée, la présence d'un protocole dans le centre facilite la gestion des IS par les néphrologues généraux. Enfin, la transplantectomie est proposée par les néphrologues le plus souvent pour un syndrome d'intolérance du greffon (86,5 %), plus rarement pour interrompre les IS (17,6 %) ou en l'absence de projet de nouvelle TR (9,3 %). La gestion des IS après l'AFG par les néphrologues francophones est hétérogène. Des études prospectives spécifiques sont nécessaires afin de formuler de nouvelles recommandations de bonnes pratiques, reposant sur des données probantes plus robustes, qui pourraient encourager une meilleure adhésion par les néphrologues.

Risk Factors for Adverse Outcomes in Kidney Transplants From Donors After Circulatory Death With Normothermic Regional Perfusion: A Systematic Analysis.

BACKGROUND: This study examined 1071 adult primary kidney transplants from the French-controlled donation after the circulatory determination of death (cDCD) program, which uses normothermic regional perfusion (NRP), and involves short cold ischemia times (CIT) and constrained asystole times differing by donor age. METHODS: Logistic regression identified risk factors for primary nonfunction (PNF), delayed graft function (DGF), and graft failure. RESULTS: Risk factors for PNF included donor hypertension, admission for ischemic vascular stroke, and HLA DR mismatches. Risk factors for DGF included functional warm ischemia time >40 min, dialysis >2 y, recipient body mass index of 30 kg/m2 or higher, recipient diabetes, and CIT >10 h. Risk factors for 1-y graft failure included donor hypertension, donor lung recovery, ostial calcification, recipient cardiovascular comorbidities, and HLA DR mismatches. A high donor estimated glomerular filtration rate protected against DGF and graft failure at 1-y. After adjustment restricted to recipient and graft factors and donor age, the risks of PNF, DGF, and graft failure increased with donor age up to 65 y and then remained stable. CONCLUSIONS: The study suggests that cDCD kidney transplants are highly successful, but also that its outcomes are influenced by lung recovery, poor HLA DR matching, and warm ischemia times differing with donor age. Our study identified several risk factors for kidney transplantation failure after cDCD with systematic use of NRP and some of them seem as modifiable variables associated with cDCD transplant outcome.

Prophylactic treatment of FSGS recurrence in patients who relapsed in a previous kidney graft.

BACKGROUND AND HYPOTHESIS: Recurrence of focal segmental glomerulosclerosis (FSGS) is common after kidney transplantation and is classically associated with a significant decrease in graft survival. A major risk factor is a prior history of FSGS recurrence on a previous graft. This analysis reports the impact of a prophylactic treatment of FSGS recurrence in very high-risk patients who experienced a recurrence on a previous graft. METHODS: We performed a retrospective multicentre observational study in 25 French transplantation centres. The inclusion criteria were patients aged more than 18 years who had undergone kidney transplant between December 31, 2004, and December 31, 2020, and who had a history of FSGS recurrence on a previous graft. RESULTS: We identified 66 patients: 40 received prophylactic treatment (PT+), including intravenous cyclosporine and/or rituximab and/or plasmapheresis, and 26 did not receive any prophylactic treatment (PT-). The time to progression to end-stage kidney disease was similar between groups. The PT + group was younger at FSGS diagnosis and at the time of kidney retransplantation and lost their previous graft faster. The overall recurrence rate was 72.7% (76.9% in the PT- group and 70.0% in the PT + group, P = 0.54). At least partial remission was achieved in 87.5% of patients. The 5-year graft survival was 67.7% (95% CI: 53.4 to 78.4%): 65.1% (95%CI: 48.7 to 77.4%) in patients with FSGS recurrence vs. 77.3% (95% CI: 43.8 to 92.3%) in patients without recurrence (P = 0.48). CONCLUSION: Our study suggests that prophylactic treatment should not be used routinely in patients receiving a second transplantation after recurrence of FSGS on a previous graft. The recurrence rate is high regardless of the use of prophylactic treatment. However, the 5-year graft survival remains satisfactory.

Better Rejection-Free Survival at Three Years in Kidney Transplant Recipients With Model-Informed Precision Dosing of Mycophenolate Mofetil.

The clinical impact of individual dose adjustment of mycophenolate mofetil is still debated, due to conflicting results from randomized clinical trials. This retrospective study aimed to compare 3-year rejection-free survival and adverse effects between adult kidney transplant recipients (KTRs) with or without mycophenolate mofetil model-informed precision dosing (MIPD). MIPD is defined here as mycophenolic acid area under the curve (AUC0-12h) estimation using a limited sampling strategy, pharmacokinetic models and Bayesian estimators; dose recommendation to reach AUC0-12h = 45 mg.h/L; using a widely used online expert system. The study, nested in two multicenter prospective cohort studies, focused on patients who received a mycophenolate drug and were followed up for 1-3 years. Mycophenolate mofetil MIPD was prescribed as per local practice, on a regular basis, when deemed necessary, or not at all. The MIPD group included 341 KTRs and the control group 392. At 3 years, rejection-free survival was respectively 91.2% and 80.6% (P < 0.001) and the cumulative incidence of rejection 5.08% vs. 12.7% per patient × year (hazard ratio = 0.49 (0.34, 0.71), P < 0.001), corresponding to a 2.5-fold reduction. Significant association with rejection-free survival was confirmed in patients at low or high risk of rejection (P = 0.017 and 0.013) and in patients on tacrolimus, but not on cyclosporine (P < 0.001 and 0.205). The mycophenolate mofetil MIPD group had significantly more adverse effects, but most occurred before the first AUC0-12h, suggesting some may be the reason why MIPD was ordered.

Impact of Calcineurin Inhibitor-Based Immunosuppression Maintenance During the Dialysis Period After Kidney Transplant Failure on the Next Kidney Graft Outcome: A Retrospective Multicenter Study With Propensity Score Analysis.

The impact of immunosuppressive therapy (IS) strategies after kidney transplant failure (KTF) on potential future new grafts is poorly established. We assessed the potential benefit of calcineurin inhibitor (CNI)-based IS maintenance throughout the dialysis period on the outcome of the second kidney transplant (KT). We identified 407 patients who underwent a second KT between January 2008 and December 2018 at four French KT centers. Inverse probability of treatment weighting was used to control for potential confounding. We included 205 patients with similar baseline characteristics at KTF: a total of 53 received at least CNIs on the retransplant day (G-CNI), and 152 did not receive any IS (G-STOP). On the retransplant date, G-STOP patients experienced a longer pretransplant dialysis time, were more often hyperimmunized, and underwent more expanded-criteria donor KTs than G-CNI patients. During the second KT follow-up period, rejection episodes were similar in both groups. The 10-year survival rates without death and dialysis were 98.7% and 59.5% in G-CNI and G-STOP patients, respectively. In the multivariable analysis, CNI-based IS maintenance was associated with better survival (hazard ratio: 0.08; 95% confidence interval: 0.01-0.58, p = 0.01). CNI-based IS maintenance throughout the dialysis period after KTF may improve retransplantation outcomes.

Tacrolimus Exposure Before and After a Switch From Twice-Daily Immediate-Release to Once-Daily Prolonged Release Tacrolimus: The ENVARSWITCH Study.

LCP-tacrolimus displays enhanced oral bioavailability compared to immediate-release (IR-) tacrolimus. The ENVARSWITCH study aimed to compare tacrolimus AUC0-24 h in stable kidney (KTR) and liver transplant recipients (LTR) on IR-tacrolimus converted to LCP-tacrolimus, in order to re-evaluate the 1:0.7 dose ratio recommended in the context of a switch and the efficiency of the subsequent dose adjustment. Tacrolimus AUC0-24 h was obtained by Bayesian estimation based on three concentrations measured in dried blood spots before (V2), after the switch (V3), and after LCP-tacrolimus dose adjustment intended to reach the pre-switch AUC0-24 h (V4). AUC0-24 h estimates and distributions were compared using the bioequivalence rule for narrow therapeutic range drugs (Westlake 90% CI within 0.90-1.11). Fifty-three KTR and 48 LTR completed the study with no major deviation. AUC0-24 h bioequivalence was met in the entire population and in KTR between V2 and V4 and between V2 and V3. In LTR, the Westlake 90% CI was close to the acceptance limits between V2 and V4 (90% CI = [0.96-1.14]) and between V2 and V3 (90% CI = [0.96-1.15]). The 1:0.7 dose ratio is convenient for KTR but may be adjusted individually for LTR. The combination of DBS and Bayesian estimation for tacrolimus dose adjustment may help with reaching appropriate exposure to tacrolimus rapidly after a switch.

Imlifidase for Kidney Transplantation of Highly Sensitized Patients With a Positive Crossmatch: The French Consensus Guidelines.

Imlifidase recently received early access authorization for highly sensitized adult kidney transplant candidates with a positive crossmatch against an ABO-compatible deceased donor. These French consensus guidelines have been generated by an expert working group, in order to homogenize patient selection, associated treatments and follow-up. This initiative is part of an international effort to analyze properly the benefits and tolerance of this new costly treatment in real-life. Eligible patients must meet the following screening criteria: cPRA ≥ 98%, ≤ 65-year of age, ≥ 3 years on the waiting list, and a low risk of biopsy-related complications. The final decision to use Imlifidase will be based on the two following criteria. First, the results of a virtual crossmatch on recent serum, which shall show a MFI for the immunodominant donor-specific antibodies (DSA) > 6,000 but the value of which does not exceed 5,000 after 1:10 dilution. Second, the post-Imlifidase complement-dependent cytotoxicity crossmatch must be negative. Patients treated with Imlifidase will receive an immunosuppressive regimen based on steroids, rATG, high dose IVIg, rituximab, tacrolimus and mycophenolic acid. Frequent post-transplant testing for DSA and systematic surveillance kidney biopsies are highly recommended to monitor post-transplant DSA rebound and subclinical rejection.

Evaluation of the efficacy of HEMO2life®, a marine OXYgen carrier for Organ Preservation (OxyOp2) in renal transplantation: study protocol for a multicenter randomized trial.

BACKGROUND: Preventing ischemia‒reperfusion injury (IRI) is a major issue in kidney transplantation, particularly for transplant recipients receiving a kidney from extended criteria donors (ECD). The main consequence of IRI is delayed graft function (DGF). Hypoxia is one of the key factors in IRI, suggesting that the use of an oxygen carrier as an additive to preservation solution may be useful. In the OxyOp trial, we showed that the organs preserved using the oxygen carrier HEMO2life® displayed significantly less DGF. In the OxyOp2 trial, we aim to definitively test and quantify the efficacy of HEMO2life® for organ preservation in a large population of kidney grafts. METHODS: OxyOp2 is a prospective, multicenter, randomized, comparative, single-blinded, parallel-group study versus standard of care in renal transplantation. After the selection of a suitable donor according to the inclusion/exclusion criteria, both kidneys will be used in the study. Depending on the characteristics of the donor, both kidneys will be preserved either in static cold storage (standard donors) or on machine perfusion (for ECD and deceased-after-cardiac-death donors (DCD)). The kidneys resulting from one donor will be randomized: one to the standard-of-care arm (organ preserved in preservation solution routinely used according to the local practice) and the other to the active treatment arm (HEMO2life® on top of routinely used preservation solution). HEMO2life® will be used for ex vivo graft preservation at a dose of 1 g/l preservation solution. The primary outcome is the occurrence of DGF, defined as the need for renal replacement therapy during the first week after transplantation. DISCUSSION: The use of HEMO2life® in preservation solutions is a novel approach allowing, for the first time, the delivery of oxygen to organs. Improving graft survival by limiting ischemic lesions is a major public-health goal in the field of organ transplantation. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT04181710 . registered on November 29, 2019.

Early activation and recruitment of invariant natural killer T cells during liver ischemia-reperfusion: the major role of the alarmin interleukin-33.

Over the past thirty years, the complexity of the αß-T cell compartment has been enriched by the identification of innate-like T cells (ITCs), which are composed mainly of invariant natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells. Based on animal studies using ischemia-reperfusion (IR) models, a key role has been attributed to iNKT cells in close connection with the alarmin/cytokine interleukin (IL)-33, as early sensors of cell-stress in the initiation of acute sterile inflammation. Here we have investigated whether the new concept of a biological axis of circulating iNKT cells and IL-33 applies to humans, and may be extended to other ITC subsets, namely MAIT and γδ-T cells, in the acute sterile inflammation sequence occurring during liver transplant (LT). From a prospective biological collection of recipients, we reported that LT was accompanied by an early and preferential activation of iNKT cells, as attested by almost 40% of cells having acquired the expression of CD69 at the end of LT (i.e. 1-3 hours after portal reperfusion), as opposed to only 3-4% of conventional T cells. Early activation of iNKT cells was positively correlated with the systemic release of the alarmin IL-33 at graft reperfusion. Moreover, in a mouse model of hepatic IR, iNKT cells were activated in the periphery (spleen), and recruited in the liver in WT mice, as early as the first hour after reperfusion, whereas this phenomenon was virtually missing in IL-33-deficient mice. Although to a lesser degree than iNKT cells, MAIT and γδ-T cells also seemed targeted during LT, as attested by 30% and 10% of them acquiring CD69 expression, respectively. Like iNKT cells, and in clear contrast to γδ-T cells, activation of MAIT cells during LT was closely associated with both release of IL-33 immediately after graft reperfusion and severity of liver dysfunction occurring during the first three post-operative days. All in all, this study identifies iNKT and MAIT cells in connection with IL-33 as new key cellular factors and mechanisms of acute sterile inflammation in humans. Further investigations are required to confirm the implication of MAIT and iNKT cell subsets, and to precisely assess their functions, in the clinical course of sterile inflammation accompanying LT.

Paving the Way for Personalized Medicine in First Kidney Transplantation: Interest of a Creatininemia Latent Class Analysis in Early Post-transplantation.

Plasma creatinine is a marker of interest in renal transplantation but data on its kinetics in the first days following transplantation are scarce. The aim of this study was to identify clinically relevant subgroups of creatinine trajectories following renal transplantation and to test their association with graft outcome. Among 496 patients with a first kidney transplant included in the French ASTRE cohort at the Poitiers University hospital, 435 patients from donation after brain death were considered in a latent class modeling. Four distinct classes of creatinine trajectories were identified: "poor recovery" (6% of patients), "intermediate recovery" (47%), "good recovery" (10%) and "optimal recovery" (37%). Cold ischemia time was significantly lower in the "optimal recovery" class. Delayed graft function was more frequent and the number of hemodialysis sessions was higher in the "poor recovery" class. Incidence of graft loss was significantly lower in "optimal recovery" patients with an adjusted risk of graft loss 2.42 and 4.06 times higher in "intermediate recovery" and "poor recovery" patients, respectively. Our study highlights substantial heterogeneity in creatinine trajectories following renal transplantation that may help to identify patients who are more likely to experience a graft loss.

Nonskeletal and skeletal effects of high doses versus low doses of vitamin D3 in renal transplant recipients: Results of the VITALE (VITamin D supplementation in renAL transplant recipients) study, a randomized clinical trial.

Vitamin D sufficiency is associated with a reduced risk of fractures, diabetes mellitus, cardiovascular events, and cancers, which are frequent complications after renal transplantation. The VITALE (VITamin D supplementation in renAL transplant recipients) study is a multicenter double-blind randomized trial, including nondiabetic adult renal transplant recipients with serum 25-hydroxy vitamin D (25(OH) vitamin D) levels of <30 ng/mL, which is randomized 12 to 48 months after transplantation to receive high (100 000 IU) or low doses (12 000 IU) of cholecalciferol every 2 weeks for 2 months and then monthly for 22 months. The primary outcome was a composite endpoint, including diabetes mellitus, major cardiovascular events, cancer, and death. Of 536 inclusions (50.8 [13.7] years, 335 men), 269 and 267 inclusions were in the high-dose and low-dose groups, respectively. The serum 25(OH) vitamin D levels increased by 23 versus 6 ng/mL in the high-dose and low-dose groups, respectively (P < .0001). In the intent-to-treat analysis, 15% versus 16% of the patients in the high-dose and low-dose groups, respectively, experienced a first event of the composite endpoint (hazard ratio, 0.94 [0.60-1.48]; P = .78), whereas 1% and 4% of patients in the high-dose and low-dose groups, respectively, experienced an incident symptomatic fracture (odds ratio, 0.24 [0.07-0.86], P = .03). The incidence of adverse events was similar between the groups. After renal transplantation, high doses of cholecalciferol are safe but do not reduce extraskeletal complications (trial registration: ClinicalTrials.gov; identifier: NCT01431430).

Comparison of High-Flux, Super High-Flux, Medium Cut-Off Hemodialysis and Online Hemodiafiltration on the Removal of Uremic Toxins.

INTRODUCTION: Online hemodiafiltration (OL-HDF) and hemodialysis (HD) using high-performance membranes such as adsorptive, medium cut-off (MCO), and super high-flux (SHF) dialyzers have been implemented to enhance the removal of middle molecules (MM). The aim of this study was to compare the efficacy of different dialysis strategies and dialyzers on small solutes and MM reduction ratio (RR) and mass removal. METHODS: We performed a prospective study in 8 HD patients. Each patient underwent 9 dialysis sessions: seven sessions on HD using either Theranova 500™, Elisio 21H™, Renak PS-2.0W™, Filtryzer BK-2.1F™, Vie 21X™, TS-2.1UL™ or FDY 210-GW™ dialyzers and two sessions on OL-HDF using Elisio 21H™ or Renak PS-2.0W™ dialyzers. RESULTS: Urea mass removal and RR were similar between all dialysis strategies. The lowest beta2-microglobulin RR was achieved with Filtryzer BK-2.1F™ HD (p < 0.05). Compared to Elisio 21H™ HD, Renak PS-2.0W™ OL-HDF produced higher beta2-microglobulin mass removal (181 ± 46 vs. 317 ± 161 mg, p < 0.05). Theranova 500™ HD, Vie 21X™ HD, FDY 210-GW™ HD, Elisio 21H™ OL-HDF, and Renak PS-2.0W™ OL-HDF induced higher RR for kappa and lambda FLC, as compared to Elisio 21H™ HD and Filtryzer BK-2.1F™ HD (p < 0.05). Renak PS-2.0W™ OL-HDF achieved higher kappa FLC mass removal compared to Elisio 21H™ HD (563 ± 515 vs. 141 ± 47 mg, p < 0.01) and to Renak PS-2.0W™ HD (563 ± 515 vs. 153 ± 25 mg, p < 0.05). Albumin loss varied from 0.02 ± 0.05 to 7.6 ± 3.8 g/session with Elisio 21H™ HD and Renak PS-2.0W™ OL-HDF, respectively. Compared to all other strategies, Renak PS-2.0W™ OL-HDF induced a significantly higher albumin loss (p < 0.05). CONCLUSION: This study confirms that albumin loss and removal of MM are similar using conventional Elisio 21H™ OL-HDF, MCO-HD, and SHF type V dialyzers. Although Renak PS-2.0W™ OL-HDF provides high performance for MM depuration, this protein-permeable dialyzer should not be used in OL-HDF because of excessive albumin loss.

Absence of Mortality Differences Between the First and Second COVID-19 Waves in Kidney Transplant Recipients.

Introduction: SARS-CoV-2 pandemic evolved in 2 consecutive waves during 2020. Improvements in the management of COVID-19 led to a reduction in mortality rates among hospitalized patients during the second wave. Whether this progress benefited kidney transplant recipients (KTRs), a population particularly vulnerable to severe COVID-19, remained unclear. Methods: In France, 957 KTRs were hospitalized for COVID-19 in 2020 and their data were prospectively collected into the French Solid Organ Transplant (SOT) COVID registry. The presentation, management, and outcomes of the 359 KTRs diagnosed during the first wave were compared to those of the 598 of the second wave. Results: Baseline comorbidities were similar between KTRs of the 2 waves. Maintenance immunosuppression was reduced in most patients but withdrawal of antimetabolite (73.7% vs. 58.4%, P < 0.001) or calcineurin inhibitor (32.1% vs. 16.6%, P < 0.001) was less frequent during the second wave. Hydroxychloroquine and azithromycin that were commonly used during the first wave (21.7% and 30.9%, respectively) but were almost abandoned during the second wave. In contrast, the use of high dose corticosteroids doubled (19.5% vs. 41.6%, P < 0.001). Despite these changing trends in COVID-19 management, 60-day mortality was not statistically different between the 2 waves (25.3% vs. 23.9%; Log Rank, P = 0.48) and COVID-19 hospitalization period was not associated with death due to COVID-19 in multivariate analysis (Hazard ratio 0.89, 95% confidence interval 0.67-1.17, P = 0.4). Conclusion: We conclude that changing of therapeutic trends during 2020 did not reduce COVID-19 related mortality among KTRs. Our data indirectly support the importance of vaccination and neutralizing monoclonal anti-SARS-CoV-2 antibodies to protect KTRS from severe COVID-19.

Impact of targeted hypothermia in expanded-criteria organ donors on recipient kidney-graft function: study protocol for a multicentre randomised controlled trial (HYPOREME).

INTRODUCTION: Expanded-criteria donors (ECDs) are used to reduce the shortage of kidneys for transplantation. However, kidneys from ECDs are associated with an increased risk of delayed graft function (DGF), a risk factor for allograft loss and mortality. HYPOREME will be a multicentre randomised controlled trial (RCT) comparing targeted hypothermia to normothermia in ECDs, in a country where the use of machine perfusion for organ storage is the standard of care. We hypothesise that hypothermia will decrease the incidence of DGF. METHODS AND ANALYSIS: HYPOREME is a multicentre RCT comparing the effect on kidney function in recipients of targeted hypothermia (34°C-35°C) and normothermia (36.5°C-37.5°C) in the ECDs. The temperature intervention starts from randomisation and is maintained until aortic clamping in the operating room. We aim to enrol 289 ECDs in order to analyse the kidney function of 516 recipients in the 53 participating centres. The primary outcome is the occurrence of DGF in kidney recipients, defined as a requirement for renal replacement therapy within 7 days after transplantation (not counting a single session for hyperkalemia during the first 24 hours). Secondary outcomes include the proportion of patients with individual organs transplanted in each group; the number of organs transplanted from each ECD and the vital status and kidney function of the recipients 7 days, 28 days, 3 months and 1 year after transplantation. An interim analysis is planned after the enrolment of 258 kidney recipients. ETHICS AND DISSEMINATION: The trial was approved by the ethics committee of the French Intensive Care Society (CE-SRLF-16-07) on 26 April 2016 and by the competent French authorities on 20 April 2016 (Comité de Protection des Personnes-TOURS-Région Centre-Ouest 1, registration #2016-S3). Findings will be published in peer-reviewed journals and presented during national and international scientific meetings. TRIAL REGISTRATION NUMBER: NCT03098706.

Comparison of the injection of low-molecular weight heparin in the arterial vs. venous blood line for preventing extracorporeal circuit clotting during hemodialysis.

Low-molecular weight heparins (LMWH) are widely used for preventing clotting during hemodialysis (HD). Although injection in the venous blood line is recommended to avoid initial loss of LMWH through the dialyzer, LMWH is still frequently administered in the arterial blood line at the start of dialysis. This study aimed to compare the safety and efficacy of the same enoxaparin dose administered through the venous blood line or arterial blood line. We also evaluated antifactor Xa (aXa) activity according to the injection route and dialysis modalities: high-flux (HF) HD, medium cut-off (MCO) HD, and online hemodiafiltration (OL-HDF). Forty-three patients were studied over 18 consecutive dialysis sessions using a fixed enoxaparin dose (20 or 40 mg), first administered through the arterial blood line bolus and then through the venous blood line for another 18 sessions. Compared to arterial blood line administration, venous blood line bolus resulted in a significant increase in median post-dialysis aXa activity: 0.16 (0.1-0.6) IU/ml versus 0.31 (0.1-1.3) IU/ml, respectively, p = 0.006. After arterial blood line bolus of 40 mg enoxaparin, median post-dialysis aXa activity was significantly lower with OL-HDF compared to HF-HD: 0.14 (0.1-0.35) versus 0.32 (0.15-0.49), p = 0.02. A trend for lower clotting within lines and bubble trap using venous blood line bolus was observed. In conclusion, venous blood line enoxaparin injection is safe in OL-HDF patients. However, in HF-HD and MCO-HD, venous blood line injection of 40 mg enoxaparin may increase overdosing risk. Thus, aXa activity should be monitored in HF-HD and MCO-HD patients at risk of bleeding and/or on vitamin K antagonists and careful surveillance is required when administering a 40 mg enoxaparin dose through the venous blood line route.

HEMO2 life® improves renal function independent of cold ischemia time in kidney recipients: A comparison with a large multicenter prospective cohort study.

BACKGROUND: M101 is an extracellular hemoglobin isolated from a marine lugworm and is present in the medical device HEMO2 life®. The clinical investigation OXYOP was a paired kidney analysis (n = 60) designed to evaluate the safety and performance of HEMO2 life® used as an additive to preservation solution in renal transplantation. The secondary efficacy endpoints showed less delayed graft function (DGF) and better renal function in the HEMO2 life® group but due to the study design cold ischemia time (CIT) was longer in the contralateral kidneys. METHODS: An additional analysis was conducted including OXYOP patients and patients from the ASTRE database (n = 6584) to verify that the decrease in DGF rates observed in the HEMO2 life® group may not be due solely to the shorter CIT but also to HEMO2 life® performance. Kaplan-Meier estimate curves of cumulative probability of achieving a creatinine level below 250 µmol/L were generated and compared in both groups. A Cox model was used to test the effect of the explanatory variables (use of HEMO2 life® and CIT). Finally, a bootstrap strategy was used to randomly select smaller samples of patients and test them for statistical comparison in the ASTRE database. RESULTS: Kaplan-Meier estimate curves confirmed the existence of a relation between DGF and CIT and Cox analysis showed a benefit in the HEMO2 life® group regardless of the associated CIT. Boostrap analysis confirmed these results. CONCLUSIONS: The present study suggested that the better recovery of renal function observed among kidneys preserved with HEMO2 life® in the OXYOP study is a therapeutic benefit of this breakthrough innovative medical device.

Endogenous Interleukin-33 Acts as an Alarmin in Liver Ischemia-Reperfusion and Is Associated With Injury After Human Liver Transplantation.

Ischemia and reperfusion injury is an early inflammatory process during liver transplantation that impacts on graft function and clinical outcomes. Interleukin (IL)-33 is a danger-associated molecular pattern involved in kidney ischemia/reperfusion injury and several liver diseases. The aims were to assess whether IL-33 was released as an alarmin responsible for ischemia/reperfusion injury in a mouse model of warm hepatic ischemia, and whether this hypothesis could also apply in the setting of human liver transplantation. First, a model of warm hepatic ischemia/reperfusion was used in wild-type and IL-33-deficient mice. Severity of ischemia/reperfusion injury was assessed with ALT and histological analysis. Then, serum IL-33 was measured in a pilot cohort of 40 liver transplant patients. Hemodynamic postreperfusion syndrome, graft dysfunction (assessed by model for early allograft scoring >6), renal failure, and tissue lesions on time-zero biopsies were assessed. In the mouse model, IL-33 was constitutively expressed in the nucleus of endothelial cells, immediately released in response to hepatic pedicle clamping without neosynthesis, and participated in the recruitment of neutrophils and tissue injury on site. The kinetics of IL-33 in liver transplant patients strikingly matched the ones in the animal model, as attested by serum levels reaching a peak immediately after reperfusion, which correlated to clinical outcomes including postreperfusion syndrome, posttransplant renal failure, graft dysfunction, and histological lesions of ischemia/reperfusion injury. IL-33 was an independent factor of graft dysfunction with a cutoff of IL-33 at 73 pg/ml after reperfusion (73% sensitivity, area under the curve of 0.76). Taken together, these findings establish the immediate implication of IL-33 acting as an alarmin in liver I/R injury and provide evidence of its close association with cardinal features of early liver injury-associated disorders in LT patients.

Therapeutic education as a tool to improve patient-reported and clinical outcomes after renal transplantation: results of the EPHEGREN multicenter retrospective cohort study.

Patients are not always aware of the inconveniences associated with renal transplantation, which they compare with a « rebirth ¼, and from which they expect complete recovery. Therapeutic education is proposed to prepare patients for their life after transplantation. This study evaluated the impact of pretransplant therapeutic education on patient-reported outcomes and rejection-free survival over the first year. We collected data from 383 renal transplant patients followed-up in seven centers. Patients who benefited from therapeutic education before transplantation (N = 182) were compared with patients who did not (N = 139) for quality-of-life, adherence and adverse events using the Pearson's chi-square test, one-way ANOVA or t-test. The association between therapeutic education and time to acute rejection was investigated using Cox models. The patients who benefited from therapeutic education reported adverse events less frequently (e.g., tremor: 9% vs. 32.4%, P = 0.01) and better quality-of-life (MCS-QOL: 50.7 ± 8.1 vs. 47.7 ± 9.5, P = 0.02; PCS-QOL: 49.1 ± 7.1 vs. 46.0 ± 9.2, P = 0.013). No difference was found on adherence. Rejection-free survival was slightly better in the therapeutic education group (HR = 0.44, 95% CI = [0.19-1.01]). This multicenter retrospective cohort study suggests that integrating therapeutic education to care pathways entails clinical benefit, in terms of quality-of-life, self-reported adverse events and rejection-free survival. Randomized clinical trials are necessary to confirm this.

Allotransplantation Is Associated With Exacerbation of CD8 T-Cell Senescence: The Particular Place of the Innate CD8 T-Cell Component.

Immunosenescence is a physiological process that is associated with changes in the immune system, particularly among CD8 T-cells. Recent studies have hypothesized that senescent CD8 T-cells are produced with chronologic age by chronic stimulation, leading to the acquisition of hallmarks of innate-like T-cells. While conventional CD8 T-cells are quite well characterized, CD8 T-cells sharing features of NK cells and memory CD8 T-cells, are a newly described immune cell population. They can be distinguished from conventional CD8 T-cells by their combined expression of panKIR/NKG2A and Eomesodermin (E), a unique phenotype closely associated with IFN-γ production in response to innate stimulation. Here, we first provided new evidence in favor of the innate character of panKIR/NKG2A(+) E(+) CD8 T-cells in normal subjects, documenting their position at an intermediate level in the innateness gradient in terms of both innate IFN-γ production and diminished mitochondrial mass. We also revealed that CD8 E(+) panKIR/NKG2A(+) T-cells, hereafter referred to as Innate E(+) CD8 T-cells, exhibit increased senescent (CD27(-) CD28(-)) phenotype, compared to their conventional memory counterparts. Surprisingly, this phenomenon was not dependent on age. Given that inflammation related to chronic viral infection is known to induce NK-like marker expression and a senescence phenotype among CD8 T-cells, we hypothesized that innate E(+) CD8 T-cells will be preferentially associated with exacerbated cellular senescence in response to chronic alloantigen exposure or CMV infection. Accordingly, in a pilot cohort of stable kidney allotransplant recipients, we observed an increased frequency of the Innate E(+) CD8 T-cell subset, together with an exacerbated senescent phenotype. Importantly, this phenotype cannot be explained by age alone, in clear contrast to their conventional memory counterparts. The senescent phenotype in CD8 T-cells was further increased in cytomegalovirus (CMV) positive serology transplant recipients, suggesting that transplantation and CMV, rather than aging by itself, may promote an exacerbated senescent phenotype of innate CD8 T-cells. In conclusion, we proposed that kidney transplantation, via the setting of inflammatory stimuli of alloantigen exposure and CMV infection, may exogenously age the CD8 T-cell compartment, especially its innate component. The physiopathological consequences of this change in the immune system remain to be elucidated.