Impact of Switching From Immediate- or Prolonged-Release to Once-Daily Extended-Release Tacrolimus (LCPT) on Tremor in Stable Kidney Transplant Recipients: The Observational ELIT Study.

Once-daily extended-release tacrolimus (LCPT) exhibits increased bioavailability versus immediate-release (IR-TAC) and prolonged release (PR-TAC) tacrolimus. Improvements in tremor were previously reported in a limited number of kidney transplant patients who switched to LCPT. We conducted a non-interventional, non-randomized, uncontrolled, longitudinal, prospective, multicenter study to assess the impact of switching to LCPT on tremor and quality of life (QoL) in a larger population of stable kidney transplant patients. The primary endpoint was change in The Essential Tremor Rating Assessment Scale (TETRAS) score; secondary endpoints included 12-item Short Form Survey (SF-12) scores, tacrolimus trough concentrations, neurologic symptoms, and safety assessments. Subgroup analyses were conducted to assess change in TETRAS score and tacrolimus trough concentration/dose (C0/D) ratio by prior tacrolimus formulation and tacrolimus metabolizer status. Among 221 patients, the mean decrease of TETRAS score after switch to LCPT was statistically significant (p < 0.0001 vs. baseline). There was no statistically significant difference in change in TETRAS score after switch to LCPT between patients who had received IR-TAC and those who had received PR-TAC before switch, or between fast and slow metabolizers of tacrolimus. The overall increase of C0/D ratio post-switch to LCPT was statistically significant (p < 0.0001) and from baseline to either M1 or M3 (both p < 0.0001) in the mITT population and in all subgroups. In the fast metabolizers group, the C0/D ratio crossed over the threshold of 1.05 ng/mL/mg after the switch to LCPT. Other neurologic symptoms tended to improve, and the SF-12 mental component summary score improved significantly. No new safety concerns were evident. In this observational study, all patients had a significant improvement of tremor, QoL and C0/D ratio post-switch to LCPT irrespective of the previous tacrolimus formulation administered (IR-TAC or PR-TAC) and irrespective from their metabolism status (fast or slow metabolizers).

Thrombotic microangiopathies after kidney transplantation in modern era: nosology based on chronology.

BACKGROUND: Thrombotic microangiopathies (TMAs) are rare but can be severe in kidney transplant. recipients (KTR). METHODS: We analysed the epidemiology of adjudicated TMA in consecutive KTR during the. 2009-2021 period. RESULTS: TMA was found in 77/1644 (4.7%) KTR. Early TMA (n = 24/77 (31.2%); 1.5% of all KTR) occurred during the first two weeks ((median, IQR) 3 [1-8] days). Triggers included acute antibody-mediated rejection (ABMR, n = 4) and bacterial infections (n = 6). Graft survival (GS) was 100% and recurrence rate (RR) was 8%. Unexpected TMA (n = 31/77 (40.2%); 1.5/1000 patient-years) occurred anytime during follow-up (3.0 (0.5-6.2) years). Triggers included infections (EBV/CMV: n = 10; bacterial: n = 6) and chronic active ABMR (n = 5). GS was 81% and RR was 16%. Graft-failure associated TMA (n = 22/77 (28.6%); 2.2% of graft losses) occurred after 8.8 (4.9-15.5) years). Triggers included acute (n = 4) or chronic active (n = 14) ABMR, infections (viral: n = 6; bacterial: n = 5) and cancer (n = 6). 15 patients underwent transplantectomy. RR was 27%. Atypical (n = 6) and typical (n = 2) haemolytic and uremic syndrome, and isolated CNI toxicity (n = 4) were rare. Two-third of biopsies presented TMA features. CONCLUSIONS: TMA are mostly due to ABMR and infections; causes of TMA are frequently combined. Management often is heterogenous. Our nosology based on TMA timing identifies situations with distinct incidence, causes and prognosis.

Impact of hypoxia and reoxygenation on the extra/intracellular metabolome and on transporter expression in a human kidney proximal tubular cell line.

INTRODUCTION: Ischemia-reperfusion injury (IRI) induces several perturbations that alter immediate kidney graft function after transplantation and may affect long-term graft outcomes. Given the IRI-dependent metabolic disturbances previously reported, we hypothesized that proximal transporters handling endo/exogenous substrates may be victims of such lesions. OBJECTIVES: This study aimed to determine the impact of hypoxia/reoxygenation on the human proximal transport system through two semi-targeted omics analyses. METHODS: Human proximal tubular cells were cultured in hypoxia (6 or 24 h), each followed by 2, 24 or 48-h reoxygenation. We investigated the transcriptomic modulation of transporters. Using semi-targeted LC-MS/MS profiling, we characterized the extra/intracellular metabolome. Statistical modelling was used to identify significant metabolic variations. RESULTS: The expression profile of transporters was impacted during hypoxia (y + LAT1 and OCTN2), reoxygenation (MRP2, PEPT1/2, rBAT, and OATP4C1), or in both conditions (P-gp and GLUT1). The P-gp and GLUT1 transcripts increased (FC (fold change) = 2.93 and 4.11, respectively) after 2-h reoxygenation preceded by 24-h hypoxia. We observed a downregulation (FC = 0.42) of y+LAT1 after 24-h hypoxia, and of PEPT2 after 24-h hypoxia followed by 2-h reoxygenation (FC = 0.40). Metabolomics showed that hypoxia altered the energetic pathways. However, intracellular metabolic homeostasis and cellular exchanges were promptly restored after reoxygenation. CONCLUSION: This study provides insight into the transcriptomic response of the tubular transporters to hypoxia/reoxygenation. No correlation was found between the expression of transporters and the metabolic variations observed. Given the complexity of studying the global tubular transport systems, we propose that further studies focus on targeted transporters.

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.

Blood pressure management and long-term outcomes in kidney transplantation: a holistic view over a 35-year period.

INTRODUCTION: Hypertension is a burden for most kidney transplant recipients. Whether respect of hypertension guidelines results in better outcomes is unknown. METHODS: In this multicenter study, office blood pressure at 12 months following transplantation (i.e., after > 20 outpatient visits), and survival were assessed over 35 years among 2004 consecutive kidney transplant recipients who received a first kidney graft from 1985 to 2019 (follow-up: 26,232 patient-years). RESULTS: Antihypertensive medications were used in 1763/2004 (88.0%) patients. Renin-angiotensin-system blockers were used in 35.6% (47.1% when proteinuria was > 0.5 g/day) and calcium-channel blockers were used in 6.0% of patients. Combined treatment including renin-angiotensin-system-blockers, calcium-channel blockers and diuretics was used in 15.4% of patients receiving ≥ 3 antihypertensive drugs. Blood pressure was controlled in 8.3%, 18.8% and 43.1%, respectively, depending on definition (BP < 120/80, < 130/80, < 140/90 mmHg, respectively) and has not improved since the year 2001. Two-thirds of patients with uncontrolled blood pressure received < 3 antihypertensive classes. Low sodium intake < 2 g/day (vs ≥ 2) was not associated with better blood pressure control. Uncontrolled blood pressure was associated with lower patient survival (in multivariable analyses) and graft survival (in univariate analyses) vs controlled hypertension or normotension. Low sodium intake and major antihypertensive classes had no influence on patient and graft survival. CONCLUSIONS: Pharmacological recommendations and sodium intake reduction are poorly respected, but even when respected, do not result in better blood pressure control, or patient or graft survival. Uncontrolled blood pressure, not the use of specific antihypertensive classes, is associated with reduced patient, and to a lesser extent, reduced graft survival, even using the 120/80 mmHg cut-off.

A Universal Bleeding Risk Score in Native and Allograft Kidney Biopsies: A French Nationwide Cohort Study.

BACKGROUND: The risk of bleeding after percutaneous biopsy in kidney transplant recipients is usually low but may vary. A pre-procedure bleeding risk score in this population is lacking. METHODS: We assessed the major bleeding rate (transfusion, angiographic intervention, nephrectomy, hemorrhage/hematoma) at 8 days in 28,034 kidney transplant recipients with a kidney biopsy during the 2010-2019 period in France and compared them to 55,026 patients with a native kidney biopsy as controls. RESULTS: The rate of major bleeding was low (angiographic intervention: 0.2%, hemorrhage/hematoma: 0.4%, nephrectomy: 0.02%, blood transfusion: 4.0%). A new bleeding risk score was developed (anemia = 1, female gender = 1, heart failure = 1, acute kidney failure = 2 points). The rate of bleeding varied: 1.6%, 2.9%, 3.7%, 6.0%, 8.0%, and 9.2% for scores 0 to 5, respectively, in kidney transplant recipients. The ROC AUC was 0.649 (0.634-0.664) in kidney transplant recipients and 0.755 (0.746-0.763) in patients who had a native kidney biopsy (rate of bleeding: from 1.2% for score = 0 to 19.2% for score = 5). CONCLUSIONS: The risk of major bleeding is low in most patients but indeed variable. A new universal risk score can be helpful to guide the decision concerning kidney biopsy and the choice of inpatient vs. outpatient procedure both in native and allograft kidney recipients.

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.

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).

Machine learning does not outperform traditional statistical modelling for kidney allograft failure prediction.

Machine learning (ML) models have recently shown potential for predicting kidney allograft outcomes. However, their ability to outperform traditional approaches remains poorly investigated. Therefore, using large cohorts of kidney transplant recipients from 14 centers worldwide, we developed ML-based prediction models for kidney allograft survival and compared their prediction performances to those achieved by a validated Cox-Based Prognostication System (CBPS). In a French derivation cohort of 4000 patients, candidate determinants of allograft failure including donor, recipient and transplant-related parameters were used as predictors to develop tree-based models (RSF, RSF-ERT, CIF), Support Vector Machine models (LK-SVM, AK-SVM) and a gradient boosting model (XGBoost). Models were externally validated with cohorts of 2214 patients from Europe, 1537 from North America, and 671 from South America. Among these 8422 kidney transplant recipients, 1081 (12.84%) lost their grafts after a median post-transplant follow-up time of 6.25 years (Inter Quartile Range 4.33-8.73). At seven years post-risk evaluation, the ML models achieved a C-index of 0.788 (95% bootstrap percentile confidence interval 0.736-0.833), 0.779 (0.724-0.825), 0.786 (0.735-0.832), 0.527 (0.456-0.602), 0.704 (0.648-0.759) and 0.767 (0.711-0.815) for RSF, RSF-ERT, CIF, LK-SVM, AK-SVM and XGBoost respectively, compared with 0.808 (0.792-0.829) for the CBPS. In validation cohorts, ML models' discrimination performances were in a similar range of those of the CBPS. Calibrations of the ML models were similar or less accurate than those of the CBPS. Thus, when using a transparent methodological pipeline in validated international cohorts, ML models, despite overall good performances, do not outperform a traditional CBPS in predicting kidney allograft failure. Hence, our current study supports the continued use of traditional statistical approaches for kidney graft prognostication.

End-diastolic velocity mediates the relationship between renal resistive index and the risk of death.

OBJECTIVE: Renal resistive index predicts the risk of death in many populations but the mechanism linking renal resistive index and death remains elusive. Renal resistive index is derived from end-diastolic velocity (EDV) and peak systolic velocity (PSV). However, the predictive value of EDV or PSV considered alone is unknown. METHODS: We conducted a retrospective analysis of 2362 consecutive patients who received a kidney transplant from 1985 to 2017. EDV and PSV were measured at 3 months after transplantation, renal resistive index was calculated, and the risk of death was assessed [median follow-up: 6.25 years (0.25-29.15); total observation period: 13 201 patient-years]. RESULTS: Doppler indices were available in 1721 of 2362 (78.9%) patients (exclusions: 113 who died or returned to dialysis before, 427 with no Doppler studies, 27 with renal artery stenosis, 74 missing values). Among them, 279 (16.4%) had diabetes before transplantation. Mean age was 51.5 ±â€Š14.7, 1097 (63.7%) were male. During follow-up, 217 of 1721 (12.6%) patients died. Renal resistive index and EDV shared many determinants (notably systolic, diastolic and pulse pressure, recipient age and diabetes) unlike renal resistive index and PSV. EDV used as a binary [lowest tertile vs. higher values: (hazard ratio: 2.57 (1.96-3.36), P  < 0.001)] and as a continuous (the lower EDV, the greater the risk of death) variable was significantly associated with the risk of death. This finding was confirmed in multivariable analyses. Prediction of similar magnitude was found for renal resistive index. No association was found between PSV used as a binary or a continuous variable and the risk of death. CONCLUSION: Low EDV explains high renal resistive index, and the mechanism-linking renal resistive index to the risk of death is through low EDV.

Unraveling complexity of antibody-mediated rejections, the mandatory way towards an accurate diagnosis and a personalized treatment.

Antibody-mediated rejection (ABMR) remains one of the most challenging issues after organ transplantation and particularly after kidney transplantation. Despite many progresses during the last decade, ABMR is still the main cause of kidney graft loss and this all over the post- transplant period. In this review, we describe the recent knowledge about molecular and cellular mechanisms involved in ABMR. We focused our report on the role of the complement pathway in the process of ABMR and we give some insights into the role of inflammatory cells, NK lymphocytes and the role of endothelial cells. We further describe the potential role of non-HLA antibodies, of which the importance has been increasingly emphasized in recent years. Overall, this report could be of interest for all physicians who are working in the field of organ transplantation or who are working in the field of immunology. It gives essential information to understand new diagnosis advances and further therapeutic approaches. Antibody-mediated rejection (ABMR) is the leading cause of graft failure ([1,2]). In contrast to T-cell mediated rejection usually sensitive to steroids, active ABMR remains a therapeutic challenge. ABMR diagnosis relies on the presence of renal injuries and donor-specific antibodies (DSA) (HLA and non HLA antibodies) with sometimes the evidence of interaction between DSA and graft endothelium. Regularly revised during expert conferences, ABMR definition is currently categorized as active or chronic active. [3] The emergence of validated molecular assays targeting a better phenotyping of ABMR and the recent advances regarding the detrimental effect of DSA directed against minor antigens open the way to a better assessment of the heterogeneity of ABMR. In this review, we will address new aspects of ABMR regarding its mechanisms, diagnosis and treatments.

Prolonged-Release Once-Daily Formulation of Tacrolimus Versus Standard-of-Care Tacrolimus in de novo Kidney Transplant Patients Across Europe.

Background: Tacrolimus is the calcineurin inhibitor of choice for preventing acute rejection episodes in kidney transplant patients. However, tacrolimus has a narrow therapeutic range that requires regular monitoring of blood concentrations to minimize toxicity. A new once-daily tacrolimus formulation, LCP-tacrolimus (LCPT), has been developed, which uses MeltDose™ drug-delivery technology to control drug release and enhance overall bioavailability. Our study compared dosing of LCPT with current standard-of-care tacrolimus [immediate-release tacrolimus (IR-Tac) or prolonged-release tacrolimus (PR-Tac)] during the 6 months following de novo kidney transplantation. Comparisons of graft function, clinical outcomes, safety, and tolerability for LCPT versus IR-Tac/PR-Tac were also performed. Methods: Standard immunological risk patients with end-stage renal disease who had received a de novo kidney transplant were randomized (1:1) to LCPT (N = 200) or IR-Tac/PR-Tac (N = 201). Results: Least squares (LS) mean tacrolimus total daily dose from Week 3 to Month 6 was significantly lower for LCPT than for IR-Tac/PR-Tac. Although LS mean tacrolimus trough levels were significantly higher for LCPT than IR-Tac/PR-Tac, tacrolimus trough levels remained within the standard reference range for most patients. There were no differences between the groups in treatment failure measures or safety profile. Conclusion: LCPT can achieve similar clinical outcomes to other tacrolimus formulations, with a lower daily dose. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT02432833.

Cryptococcal Meningitis in Kidney Transplant Recipients: A Two-Decade Cohort Study in France.

Cryptococcosis is the third most common cause of invasive fungal infection in solid organ transplant recipients and cryptococcal meningitis (CM) its main clinical presentation. CM outcomes, as well as its clinical features and radiological characteristics, have not yet been considered on a large scale in the context of kidney transplantation (KT). We performed a nationwide retrospective study of adult patients diagnosed with cryptococcosis after KT between 2002 and 2020 across 30 clinical centers in France. We sought to describe overall and graft survival based on whether KT patients with cryptococcosis developed CM or not. Clinical indicators of CNS involvement and brain radiological characteristics were assessed. Eighty-eight cases of cryptococcosis were diagnosed during the study period, with 61 (69.3%) cases of CM. Mortality was high (32.8%) at 12 months (M12) but not significantly different whether or not patients presented with CM. Baseline hyponatremia and at least one neurological symptom were independently associated with CM (p < 0.001). Positive serum cryptococcal antigen at diagnosis was also significantly associated with CM (p < 0.001). On magnetic resonance imaging (MRI), three patterns of brain injury were identified: parenchymal, meningeal, and vascular lesions. Although CM does not affect graft function directly, it entails a grim prognosis.

Outcomes of kidney-transplanted patients with history of intestinal reconstruction of the urinary tract.

Background: Due to increased risk of pyelonephritis, patients with intestinal reconstruction of the lower urinary tract (IRLUT) have long been advised against kidney transplantation. The aim of this study was to compare the outcomes of transplantation between patients with IRLUT and patients with normal LUT (NLUT) using propensity score matching method. Methods: The study included 23 kidney recipients with IRLUT matched to 46 kidney recipients with NLUT using known allograft survival and pyelonephritis risk factors as covariates. One-, 5-, and 10-year graft survival, pyelonephritis, and surgical complications occurrence and graft function were compared. Results: One-, 5-, and 10-year graft survival were 96%, 91%, and 63% in the IRLUT group and 96%, 88%, and 70% in the NLUT group, respectively (p = 0.72). Patients with IRLUT had increased cumulative risk of pyelonephritis at 10 years (70% vs. 19%; log-rank < 0.01) without impacting graft function or rejection occurrence. There was no difference in overall surgical complication, but patients with IRLUT had more urological complications than patients with NLUT (62% vs. 28%; p < 0.01). Conclusions: Our case-control study consolidates the results regarding the safety of transplantation in patients with IRLUT using a strong validated matching method and provides new insights regarding graft function, pyelonephritis, and surgical complications in this population.

Is CD25 blockade optimal in kidney transplant patients treated with basiliximab? A target-mediated drug disposition model.

AIMS: Basiliximab, an anti-CD25 chimeric monoclonal antibody, is approved in prevention of acute kidney transplant rejection. This study aims at investigating target-mediated pharmacokinetics of basiliximab. METHODS: Data from the IDEALE study, where 16 kidney transplant patients were treated with 2 40- or 80-mg basiliximab injections, were reanalysed. Basiliximab pharmacokinetics was described using a population 2-compartment target-mediated drug disposition model with the quasi-steady-state approximation. RESULTS: Volume of distribution was significantly higher in males (P = .029). Estimated baseline target antigen (CD25) level was lower is patients cotreated with cyclosporine (P = .026). CONCLUSION: This analysis allows the first description of the target-mediated nonlinear elimination of basiliximab. Our results suggest that cyclosporine cotreatment is associated with decreased target level and that an optimized dosing regimen may improve basiliximab effects.

Relationship Between Antithymocyte Globulin Concentrations and Lymphocyte Sub-Populations in Kidney Transplant Patients.

BACKGROUND: Rabbit antithymocyte globulins (rATGs) are polyclonal antibodies used to prevent acute cellular rejection in kidney transplantation. Their dosing remains largely empirical and the question of an individualized dose is still unresolved. METHODS: Data from a prospective study in 17 kidney transplant patients were used to develop a model describing the dose-concentration-response relationship of rATG with T-lymphocyte subpopulation counts over time. The model was validated using an independent cohort of kidney transplant patients treated by rATG in the same center. RESULTS: Pharmacokinetics of rATG was described using a two-compartment model integrating a third compartment and a target-mediated elimination for active rATG. The kinetics of CD3+, CD4+, CD8+, and CD3-CD56+ cell counts over time were described by a pharmacokinetic-pharmacodynamic model with transit compartments, integrating both CD3-CD56+-independent and CD3-CD56+-dependent rATG-mediated lymphocyte depletion, and a positive feedback. Elimination of rATG was influenced by age and body surface area, while its distribution was also influenced by body surface area. CD3+ proliferation rate decreased with age and CD3-CD56+-mediated elimination was influenced by the V158F-FCGR3A polymorphism. Binary efficacy and tolerance endpoints were defined as a CD3+ count < 20 mm-3 for at least 7 days and a CD4+ count > 200 mm-3 at 1 year, respectively. Simulations showed that increasing or decreasing the standard 6-mg/kg dose will impact both tolerance and efficacy, while a dose decrease may be beneficial in elderly patients. CONCLUSIONS: Our results can be used to design prospective clinical trials testing dose individualization based on patients' characteristics. CLINICAL TRIAL REGISTRATION: Eudract No. 2009-012673-35.

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.

Implementing a personalized pharmaceutical plan in kidney or liver transplant patients: study protocol for a stepped-wedge cluster randomized trial (GRePH).

BACKGROUND: Nowadays, the main challenge of transplantation is the improvement of long-term care, aiming at reducing treatment-related complications and at decreasing rejection rates. Patients' adherence to both treatment and hygienic-dietary measures is mandatory to achieve these objectives. Adherence to immunosuppressive drugs is estimated to be only 70%. We hypothesized that the implementation of a personalized pharmaceutical plan (PPP) would increase adherence and therefore graft survival. METHODS/DESIGN: This study is a stepped-wedge cluster randomized trial with transplantation units defining clusters. Twelve clusters from 10 university hospitals were recruited. All centres started on the same day in the control phase. Every 7 weeks, one centre will switch to the intervention phase and remain there until the end of inclusions. We plan to recruit 1716 kidney and/or liver transplant patients. The intervention phase consists in setting up the PPP: development of the patient's hospital and community pharmaceutical follow-up. In the hospital, the pharmacist will carry out drug reconciliation upon admission, daily pharmaceutical follow-up of prescriptions and pharmaceutical interviews with the patient in order to explain the modalities of taking immunosuppressive drugs and hygienic-dietary measures. After hospitalization, during the post-transplantation year, pharmaceutical meetings will take place, prior to medical consultations in order to check the patient's understanding of the prescription, his adherence, to remind them of hygienic-dietary measures and to look for adverse effects. The hospital pharmacist will also be in charge of establishing a close link with the community pharmacist (CP) and general practitioner, especially providing discharge medication reconciliation, an e-learning and a checklist. Moreover, prior to each pharmaceutical consultation, the hospital pharmacist will contact the CP to discuss patient adherence. The primary outcome is adherence to immunosuppressive treatments 1 year post-transplantation assessed by using the BAASIS questionnaire and the health insurance data from the national health data system. A medico-economic study will measure the efficiency of this plan. DISCUSSION: GRePH aims to increase adherence of liver and/or kidney transplant patients to their immunosuppressive therapies in order to reduce transplant rejections. To this end, a new clinical pharmacy model, the PPP, will be set up in 10 university hospitals. TRIAL REGISTRATION: ClinicalTrials.gov NCT04295928 . Registered on 5 March 2020.