Publications by authors named "Elisabeth Cassuto"

39 Publications

Characteristics of T and NK-cell Lymphomas After Renal Transplantation: a French National Multicentric Cohort Study.

Transplantation 2021 Feb 3. Epub 2021 Feb 3.

Department of Transplantation, Nephrology and Clinical Immunology, HCL Hôpital Edouard Herriot, and Université de Lyon, France Department of Hematology, HCL Centre Hospitalier Lyon Sud, and Université de Lyon, France CRCL, INSERM U1052, Pierre-Bénite, France CIRI, INSERM U1111, Lyon, France French PTLD Registry, University Hospital of Strasbourg, France Renal Transplantation Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital, Paris, France Department of Nephrology, AP-HM Hôpital de la Conception, Marseille, France Department of Nephrology and Transplantation, Hôpital Hôtel Dieu, Nantes, France Transplant Unit, Nephrology Department, University Hospital, Reims, France Transplant Unit, Department of Nephrology, University Hospital, Rennes, France Department of Nephrology, Transplantation, Dialysis and Apheresis, Bordeaux University Hospital, Bordeaux, France Department of Nephrology and Transplantation, Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin Bicetre, France Transplant Unit, Nephrology Department, University Hospital, Lille, France Transplant Unit, Nephrology Department, Besançon University Hospital, Besançon, France Transplant Unit, Nephrology Department, University Hospital, Amiens, France Nephrology Department, CHU Clermont-Ferrand, Clermont-Ferrand, France Department of Nephrology, Dupuytren Hospital, Limoges, France Department of Urology, Nephrology and Transplantation, Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Paris Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Paris (AP-HP), Groupe Hospitalier Henri-Mondor, Créteil, France Nephrology Department, CHU de Caen, Caen, France Transplant Unit, Nephrology Department, Dijon University Hospital, Dijon, France Department of Nephrology, University Hospital, Grenoble, France Department of Nephrology, Dialysis and Transplantation, Lapeyronie University Hospital, Montpellier, France Transplant Unit, Nephrology Department, Nancy University Hospital, Nancy, France epartment of Nephrology and Renal Transplantation, Hospital Pasteur, Nice, France Urgences Néphrologiques et Transplantation Rénale, Assistance Publique-Hôpitaux de Paris (AP-HP), Tenon Hospital, Paris, France Department of Nephrology and Transplantation, Assistance Publique-Hôpitaux de Paris (AP-HP), Saint Louis Hospital, Paris, France Department of Nephrology Dialysis and Kidney Transplantation, CHU de Poitiers, Poitiers, France Nephrology, Dialysis and Renal Transplantation Department, Hôpital Nord, CHU de Saint-Etienne, France Nephrology, Dialysis and Renal Transplantation Department, Centre Hospitalier Régional Universitaire Tours, France INSERM U955, Université Paris-Est, and Department of pathology, APHP Hôpital Henri Mondor, Créteil, France Department of Hematology, APHP Hôpital Pitié-Salpétrière, Paris, France. Etablissement Français du Sang, Lyon, France Department of Nephrology and Transplantation, University Hospital of Strasbourg, France.

Background: Posttransplant Lymphoproliferative Disorders (PTLD) encompass a spectrum of heterogeneous entities. Because the vast majority of cases PTLD arise from B cells, available data on PTLD of T or NK phenotype (T/NK-cell PTLD) are scarce, which limits the quality of the management of these patients.

Methods: All adult cases of PTLD diagnosed in France were prospectively recorded in the national registry between 1998 and 2007. Crosschecking the registry data with 2 other independent national databases identified 58 cases of T/NK-cell PTLD. This cohort was then compared with: i) the 395 cases of B-cell PTLD from the registry, and of ii) a cohort of 148 T/NK-cell lymphomas diagnosed in nontransplanted patients.

Results: T/NK-cell PTLD occurred significantly later after transplantation and had a worse overall survival than B-cell PTLD. Two subtypes of T/NK-cell PTLD were distinguished: i) cutaneous (28%) and ii) systemic (72%), the latter being associated with a worse prognosis. Compared with T/NK-cell lymphomas of nontransplanted patients, overall survival of systemic T/NK-cell PTLD was worse (HR: 2.64[1.76-3.94]; p<0.00001).

Conclusions: This difference, which persisted after adjustment on tumoral mass, histological subtype, and extension of the disease at diagnosis could be explained by the fact that transplanted patients were less intensively treated and responded less to chemotherapy.
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http://dx.doi.org/10.1097/TP.0000000000003568DOI Listing
February 2021

A Randomized Prospective Study Comparing Anti-T-Lymphocyte Igs to Basiliximab in Highly Sensitized Kidney Transplant Patients.

Kidney Int Rep 2020 Aug 2;5(8):1207-1217. Epub 2020 Jun 2.

Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, INSERM U1043, IFR-BMT, University Paul Sabatier, Toulouse, France.

Background: Two prospective studies that were performed before the era of highly sensitive solid-phase assays have shown a lower incidence of acute rejection in highly sensitized kidney-transplant patients given polyclonal antibodies compared with those given anti-CD25 monoclonal antibodies.

Methods: This prospective pilot randomized French multicenter study aimed to compare anti-T-lymphocyte Ig (ATLG) ( = 32) and basiliximab ( = 27) in highly sensitized kidney-transplant patients without preformed donor-specific antibodies (pDSAs) as assessed by a Luminex Single-Antigen flow bead assay. Only patients with a calculated panel reactive antibody ≥50%, with at least 1 antibody with a mean fluorescence intensity ≥5000 and without a historical pDSA and without a pDSA on the day of transplantation were included.

Results: Treatment failure as defined by biopsy-proven acute rejection, patient lost to follow-up, graft loss, and death was observed in 18.8% (95% confidence interval [CI], 8.9%-37.1%) and 18.8% (95% CI, 8.9%-37.1%) in patients who received ATLG and 14.8% (95% CI, 5.8%-34.8%) and 28.2% (95% CI, 14.2%-51.2%) of patients who received basiliximab, respectively at 6 ( = 0.66) and 12 ( = 0.62) months post-transplantation. One T cell-mediated rejection was observed in ATLG-treated patients (3.1%). One antibody-mediated rejection due to a donor-specific antibody (DSA) occurred in basiliximab-treated patients (3.7%). Patient survival, graft survival, kidney parameters, and infection rate were similar in the 2 groups.

Conclusion: This pilot study indicates that in highly sensitized kidney-transplant patients without pDSAs, both ATLG and basiliximab can be used efficiently and safely. However, because of the lack of power, these results should be interpreted with caution.
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http://dx.doi.org/10.1016/j.ekir.2020.05.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403559PMC
August 2020

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

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

Centre Hospitalier Universitaire de Nantes, Nantes, France.

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

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

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

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

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

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

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

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

Monitoring of CMV-Specific Cell-Mediated Immunity in Kidney Transplant Recipients With a High Risk of CMV Disease (D+/R-): A Case Series.

Transplant Proc 2020 Jan - Feb;52(1):204-211. Epub 2019 Dec 27.

Service de Néphrologie-Dialyse-Transplantation, CHU de Nice, Université Côte d'Azur, Nice, France; Laboratoire d'Immunologie, CHU de Nice, Université Côte d'Azur, Nice, France. Electronic address:

Cytomegalovirus (CMV) is the most common viral pathogen in kidney transplant recipients (KTRs), and CMV disease impacts patient and graft survivals. CMV-specific CD8 T cell mediated-immunity (CMI) may help to assess the risk of CMV disease and to adapt preventive treatment strategies. High-risk KTRs with CMV seropositive donors/seronegative recipients (D+/R-) were prospectively monitored after CMV prophylaxis discontinuation and during the first year post transplant for CMV viremia (World Health Organization standardization) and CMI (QuantiFERON-CMV). We analyzed the ability of CMI test to predict either subsequent spontaneous viral clearance or CMV disease after prophylaxis discontinuation in patients with asymptomatic viremia. We enrolled 12 consecutive (D+/R-) KTRs. Eleven patients developed a viremia during follow-up, but 7 of them (64%) exhibited a spontaneous viral clearance. At viremia onset, 6 of 11 patients (55%) had a positive CMI test, and all of them (6 of 6, 100%) had subsequent spontaneous viral clearance, compared with only 1 of 5 patients (20%) displaying a nonreactive CMI (P = .02). This latter patient exhibited a positive CMI test 15 days after viremia onset. Four of the 11 patients (36%) developed a CMV disease, and their CMI either remained nonreactive or became positive only after antiviral treatment. We conclude that D+/R- KTRs with asymptomatic viremia after prophylaxis discontinuation may benefit from QuantiFERON-CMV to predict when positive for the spontaneous viral clearance or when persistently negative or the development of a CMV disease.
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http://dx.doi.org/10.1016/j.transproceed.2019.11.002DOI Listing
June 2020

Ribavirin for Hepatitis E Virus Infection After Organ Transplantation: A Large European Retrospective Multicenter Study.

Clin Infect Dis 2020 Aug;71(5):1204-1211

Department of Virology, INSERM U1043, IFR-BMT, University Paul Sabatier, Toulouse, France.

Background: Ribavirin is currently recommended for treating chronic hepatitis E virus (HEV) infection. This retrospective European multicenter study aimed to assess the sustained virological response (SVR) in a large cohort of solid organ transplant (SOT) recipients with chronic HEV infection treated with ribavirin monotherapy (N = 255), to identify the predictive factors for SVR, and to evaluate the impact of HEV RNA mutations on virological response.

Methods: Data from 255 SOT recipients with chronic HEV infection from 30 European centers were analyzed. Ribavirin was given at the median dose of 600 (range, 29-1200) mg/day (mean, 8.6 ± 3.6 mg/kg/day) for a median duration of 3 (range, 0.25-18) months.

Results: After a first course of ribavirin, the SVR rate was 81.2%. It increased to 89.8% when some patients were offered a second course of ribavirin. An increased lymphocyte count at the initiation of therapy was a predictive factor for SVR, while poor hematological tolerance of ribavirin requiring its dose reduction (28%) and blood transfusion (15.7%) were associated with more relapse after ribavirin cessation. Pretreatment HEV polymerase mutations and de novo mutations under ribavirin did not have a negative impact on HEV clearance. Anemia was the main adverse event.

Conclusions: This large-scale retrospective study confirms that ribavirin is highly efficient for treating chronic HEV infection in SOT recipients and shows that the predominant HEV RNA polymerase mutations found in this study do not affect the rate of HEV clearance.This large-scale retrospective study that included 255 solid organ transplant recipients confirms that ribavirin is highly efficient for treating chronic hepatitis E virus (HEV) infection and shows that HEV RNA polymerase mutations do not play a role in HEV clearance.
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http://dx.doi.org/10.1093/cid/ciz953DOI Listing
August 2020

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

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

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

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

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

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

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

Induction Therapy in Elderly Kidney Transplant Recipients With Low Immunological Risk.

Transplantation 2020 03;104(3):613-622

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

Background: In nonimmunized patients, similar rejection rates are observed for patients who have undergone thymoglobulin (antithymocyte globulins [ATG]) or basiliximab (BSX) therapy. While ATG may improve delayed graft function, it may also be associated with higher infection rates and malignancy risk. We compared survival and clinical outcomes in elderly recipients with low immunological risk according to their induction therapy.

Methods: We conducted a multicentric study on nonimmunized patients ≥65 years of age receiving a first kidney transplant between 2010 and 2017. The principal outcome was patient and graft survival. Secondary outcomes were cumulative probabilities of infection, first acute rejection episode, malignancy, de novo donor specific antibody, posttransplant diabetes (PTD), cardiac complications, estimated glomerular filtration rate, and occurrence of delayed graft function. Cox, logistic, or linear statistical models were used depending on the outcome studied, and models were weighted on the propensity scores.

Results: Two hundred and four patients were included in the BSX group and 179 in the ATG group with the average age of 71.0 and 70.5 years, respectively. Patient and graft survival at 3 years posttransplantation were 74% (95% CI, 65%-84%) and 68% (95% CI, 60%-78%) in ATG and BSX group, respectively, without significant difference. Occurrence of PTD was significatively higher in BSX group (23% versus 15%, P = 0.04) due to higher trough levels of Tacrolimus on month 3 (9.48 versus 7.30 ng/mL, P = 0.023). There was no difference in other evaluated outcomes.

Conclusions: In elderly recipients, ATG does not lead to poorer outcomes compared with BSX and could permit lower trough levels of Tacrolimus, thus reducing occurrence of PTD.
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http://dx.doi.org/10.1097/TP.0000000000002804DOI Listing
March 2020

Epitope load identifies kidney transplant recipients at risk of allosensitization following minimization of immunosuppression.

Kidney Int 2019 06 5;95(6):1471-1485. Epub 2019 Mar 5.

Laboratoire d'Immunologie et Histocompatibilité Hôpital Saint-Louis, Paris, France; INSERM UMRs 1160, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.

Human leukocyte antigen (HLA) mismatching and minimization of immunosuppression are two major risk factors for the development of de novo donor-specific antibodies, which are associated with reduced kidney graft survival. Antibodies do not recognize whole HLA antigens but rather individual epitopes, which are short sequences of amino acids in accessible positions. However, compatibility is still assessed by the simple count of mismatched HLA antigens. We hypothesized that the number of mismatched epitopes, or ("epitope load") would identify patients at the highest risk of developing donor specific antibodies following minimization of immunosuppression. We determined epitope load in 89 clinical trial participants who converted from cyclosporine to everolimus 3 months after kidney transplantation. Twenty-nine participants (32.6%) developed de novo donor specific antibodies. Compared to the number of HLA mismatches, epitope load was more strongly associated with the development of donor specific antibodies. Participants with an epitope load greater than 27 had a 12-fold relative risk of developing donor-specific antibodies compared to those with an epitope load below that threshold. Using that threshold, epitope load would have missed only one participant who subsequently developed donor specific antibodies, compared to 8 missed cases based on a 6-antigen mismatch. DQ7 was the most frequent antigenic target of donor specific antibodies in our population, and some DQ7 epitopes appeared to be more frequently involved than others. Assessing epitope load before minimizing immunosuppression may be a more efficient tool to identify patients at the highest risk of allosensitization.
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http://dx.doi.org/10.1016/j.kint.2018.12.029DOI Listing
June 2019

Safety of Everolimus With Reduced Calcineurin Inhibitor Exposure in De Novo Kidney Transplants: An Analysis From the Randomized TRANSFORM Study.

Transplantation 2019 09;103(9):1953-1963

Department of Renal Medicine, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia.

Background: The safety profiles of standard therapy versus everolimus with reduced-exposure calcineurin inhibitor (CNI) therapy using contemporary protocols in de novo kidney transplant recipients have not been compared in detail.

Methods: TRANSFORM was a randomized, international trial in which de novo kidney transplant patients were randomized to everolimus with reduced-exposure CNI (N = 1014) or mycophenolic acid (MPA) with standard-exposure CNI (N = 1012), both with induction and corticosteroids.

Results: Within the safety population (everolimus 1014, MPA 1012), adverse events with a suspected relation to study drug occurred in 62.9% versus 59.2% of patients given everolimus or MPA, respectively (P = 0.085). Hyperlipidemia, interstitial lung disease, peripheral edema, proteinuria, stomatitis/mouth ulceration, thrombocytopenia, and wound healing complications were more frequent with everolimus, whereas diarrhea, nausea, vomiting, leukopenia, tremor, and insomnia were more frequent in the MPA group. The incidence of viral infections (17.2% versus 29.2%; P < 0.001), cytomegalovirus (CMV) infections (8.1% versus 20.1%; P < 0.001), CMV syndrome (13.6% versus 23.0%, P = 0.044), and BK virus (BKV) infections (4.3% versus 8.0%, P < 0.001) were less frequent with everolimus. CMV infection was less common with everolimus versus MPA after adjusting for prophylaxis therapy in the D+/R- subgroup (P < 0.001). Study drug was discontinued more frequently due to rejection or impaired healing with everolimus, and more often due to BKV infection or BKV nephropathy with MPA.

Conclusions: De novo everolimus with reduced-exposure CNI yielded a comparable incidence, though a distinctly different pattern, of adverse events versus current standard of care. Both regimens are safe and effective, yet their distinct profiles may enable tailoring for individual kidney transplant recipients.
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http://dx.doi.org/10.1097/TP.0000000000002626DOI Listing
September 2019

Pharmacokinetics of Prolonged-Release Once-Daily Formulations of Tacrolimus in De Novo Kidney Transplant Recipients: A Randomized, Parallel-Group, Open-Label, Multicenter Study.

Adv Ther 2019 02 14;36(2):462-477. Epub 2018 Dec 14.

Service de Néphrologie, Dialyse, Aphérèses et Transplantation, CHU Grenoble Alpes, Grenoble, France.

Introduction: Different prolonged-release formulations of tacrolimus are available. To date, the pharmacokinetic (PK) profile of LCP-tacrolimus (LCPT; Envarsus) has not been compared with PR-Tac (Advagraf) in de novo kidney transplant recipients. These profiles will guide clinical recommendations for the initiation and dose titration strategies of once-daily tacrolimus formulations.

Methods: This randomized, parallel-group, open-label, multicenter PK study randomized 75 de novo, adult, white kidney transplant recipients to LCPT 0.17 mg/kg/day (n = 37) or PR-Tac 0.20 mg/kg/day (n = 38) for 4 weeks. Dose adjustments were permitted to target a pre-defined therapeutic range based on measured trough blood concentrations.

Results: PK analysis (days 1, 3, 7 and 14) included 68 patients (LCPT, n = 33; PR-Tac, n = 35). Similar proportions of patients were within the pre-defined therapeutic tacrolimus trough blood concentration range, with < 12% in each group having below-target trough levels over the study period. LCPT demonstrated ~ 30% greater relative bioavailability [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 1.32 (p = 0.007); day 7, 1.25 (p = 0.051); day 14, 1.43 (p = 0.002)] and ~ 30% lower peak-to-trough percentage fluctuation of blood concentration [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 0.70 (p < 0.001); day 7, 0.68 (p < 0.001); day 14, 0.73 (p = 0.004)] in addition to longer time to maximum blood concentration (t), lower maximum concentration (C) and a consistently lower daily dose (~ 40% dose reduction with LCPT vs. PR-Tac by day 28). Safety profiles were similar.

Conclusion: In de novo kidney transplant recipients, prolonged-release formulations of tacrolimus can reach therapeutic concentrations in the immediate post-transplant period. LCPT has greater relative bioavailability and lower peak-to-trough fluctuation compared with PR-Tac.

Trial Registration: Registered at ClinicalTrials.gov; study number NCT02500212.

Funding: Chiesi Farmaceutici S.p.A.
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http://dx.doi.org/10.1007/s12325-018-0855-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824349PMC
February 2019

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

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

Centre Hospitalier Universitaire de Nantes, Nantes, France.

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

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

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

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

Actinomycosis: An infrequent disease in renal transplant recipients?

Transpl Infect Dis 2018 Dec 11;20(6):e12970. Epub 2018 Aug 11.

Department of Nephrology and Transplant Federation, François Mitterrand University Hospital, Dijon, France.

Actinomycosis is a rare and heterogeneous infection involving Gram-positive anaerobic bacteria, which are commensals in the oral cavity and digestive tract. Only four cases of actinomycosis in renal transplant recipients have been reported to date. We performed a retrospective study in French renal transplantation centers to collect data about actinomycosis, patients, and transplantation. Seven cases were reported between 2000 and 2017; mean age was 55.7 years, and prevalence of actinomycosis was 0.02%. Median time between transplantation and infection was 104 months (4-204 months). Locations of actinomycosis were cervicofacial (n = 2), pulmonary (n = 2), abdominopelvic (n = 2), or cutaneous (n = 1). Two patients (28.5%) had acute kidney injury. Diagnosis was made possible by microbiology (71%) or histopathology (filaments and sulfur granules) (14%) of the infection site. The suspected gate of entry for the infection was dental (57%), abdominal (28.5%) or through the sinuses (14%). All patients were treated with amoxicillin for 30-200 days (median duration of 115 days), and clavulanic acid was added for 28.5% of cases. Three patients (43%) required surgery. All patients, except one, recovered completely after a few months. Actinomycosis is a rare, slow, progressive disease in French renal transplant recipients. The location and clinical features of this infection are miscellaneous. Global and renal outcomes do not seem to be affected by actinomycosis.
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http://dx.doi.org/10.1111/tid.12970DOI Listing
December 2018

Factors associated with Health-Related Quality of Life in Kidney Transplant Recipients in France.

BMC Nephrol 2018 04 27;19(1):99. Epub 2018 Apr 27.

Laboratoire de Santé Publique, Faculté de Médecine, Université Aix-Marseille, 3279, Marseille, EA, France.

Background: Health-Related Quality of Life (HRQoL) assessment after kidney transplantation has become an important tool in evaluating outcomes. This study aims to identify the associated factors with HRQoL among a representative sample size of Kidney Transplant Recipients (KTR) at the time of their inclusion in the study.

Methods: Data of this cross-sectional design is retrieved from a longitudinal study conducted in five French kidney transplant centers in 2011, and included KTR aged 18 years with a functioning graft for at least 1 year. Measures include demographic, psycho-social and clinical characteristics. To evaluate HRQoL, the Short Form-36 Health Survey (SF-36) and a HRQoL instrument for KTR (ReTransQol) were administered. Multivariate linear regression models were performed.

Results: A total of 1424 patients were included, with 61.4% males, and a mean age of 55.7 years (±13.1). Demographic and clinical characteristics were associated with low HRQoL scores for both questionnaires. New variables were found in our study: perceived poor social support and being treated by antidepressants were associated with low scores of Quality of Life (QoL), while internet access was associated with high QoL scores.

Conclusion: The originality of our study's findings was that psycho-social variables, particularly KTR treated by antidepressants and having felt unmet needs for any social support, have a negative effect on their QoL. It may be useful to organize a psychological support specifically adapted for patients after kidney transplantation.
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http://dx.doi.org/10.1186/s12882-018-0893-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5921567PMC
April 2018

Effects of cyclosporine A pretreatment of deceased organ donors on kidney graft function (Cis-A-rein): study protocol for a randomized controlled trial.

Trials 2018 Apr 17;19(1):231. Epub 2018 Apr 17.

Université Côte d'Azur, Service de Réanimation Polyvalente, Hôpital Pasteur 2, Nice, France.

Background: Renal transplantation represents the treatment of choice of end-stage kidney disease. Delayed graft function (DGF) remains the most frequent complication after this procedure, reaching more than 30%. Its prevention is essential as it impedes early- and long-term prognosis of transplantation. Numerous pharmacological interventions aiming to prevent ischemia-reperfusion injuries failed to reduce the rate of DGF. We hypothesize that cyclosporine as an early preconditioning procedure in donors would be associated with decreased DGF.

Methods: The Cis-A-rein study is an investigator-initiated, prospective, multicenter, double-blind, randomized, controlled study performed to assess the effects of a donor preconditioning with cyclosporine A on kidney grafts function in transplanted patients. After randomization, a brain dead donor will receive 2.5 mg kg of cyclosporine A or the same volume of 5% glucose solution. The primary objective is to compare the rate of DGF, defined as the need for at least one dialysis session within the 7 days following transplantation, between both groups. The secondary objectives include rate of slow graft function, mild and severe DGF, urine output and serum creatinine during the first week after transplantation, rate of primary graft dysfunction, renal function and mortality at 1 year. The sample size (n = 648) was determined to obtain 80% power to detect a 10% difference for rate of DGF at day 7 between the two groups (30% of the patients in the placebo group and 20% of the patients in the intervention group).

Discussion: Delayed graft function is a major issue after renal transplantation, impeding long-term prognosis. Cyclosporine A pretreatment in deceased donors could improve the outcome of patients after renal transplantation.

Trial Registration: ClinicalTrials.gov, ID: NCT02907554 Registered on 20 September 2016.
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http://dx.doi.org/10.1186/s13063-018-2597-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905107PMC
April 2018

Pharmacokinetic Therapeutic Drug Monitoring of Advagraf in More Than 500 Adult Renal Transplant Patients, Using an Expert System Online.

Ther Drug Monit 2018 06;40(3):285-291

University of Limoges, UMR 1248.

Background: Immunosuppressant Bayesian dose adjustment (ISBA) is an online expert system, routinely used by approximately 140 transplantation centers in the world for the dose adjustment of immunosuppressive drugs in transplant patients. This system determines the area under the curve (AUC) of the drug by pharmacokinetic modeling and Bayesian estimation. The purpose of this study was to analyze tacrolimus exposure after administration of its modified-release formulation (Advagraf) in kidney allograft recipients, to optimize its therapeutic drug monitoring.

Methods: This is a retrospective study of exposure indices measured locally [trough tacrolimus concentration (C0), C0/dose] or estimated through ISBA (AUC, AUC/dose, AUC/C0), of their evolution over posttransplantation time, and of the correlations between them.

Results: A total of 922 requests posted by 28 different centers for routine Advagraf adjustment in 530 different patients treated with Advagraf were studied. The exposure to, and dose requirement of, tacrolimus significantly increased across the first posttransplant months before reaching steady state. The AUC:C0 ratio (on which C0 monitoring is implicitly based) was stable across the different posttransplant periods, although with high interindividual variability. C0-AUC correlation was stronger in the late than in the early posttransplant period (r = 0.75 versus 0.63; P = 0.0075). Using the regression equations obtained, AUC ranges corresponding to different applicable C0 target ranges were calculated to guide dose adjustment. When one of the doses recommended was administered, the following AUC was significantly more often in the predicted target ranges (P < 0.0001).

Conclusions: This study improves our knowledge of Advagraf pharmacokinetic variability and relations between exposure indices and the scientific background of the expert service provided through the ISBA Web site.
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http://dx.doi.org/10.1097/FTD.0000000000000503DOI Listing
June 2018

Comparative clinical trial of the variability factors of the exposure indices used for the drug monitoring of two tacrolimus formulations in kidney transplant recipients.

Pharmacol Res 2018 03 8;129:84-94. Epub 2017 Dec 8.

Transplant Unit, University Hospital, Nice, France.

Background: Several studies found differences in tacrolimus whole blood trough levels (C0) or area-under-the curve (AUC) between the twice-daily (Tac-BID) and once-daily (Tac-OD) formulations given to kidney transplant recipients at equal doses. As C0 is widely used as a surrogate of the AUC for individual dose adjustment, this study investigated the correlation and proportionality between C0 and the 24h-AUC, depending on the formulation, time post-transplantation, pharmacogenetics traits and other individual characteristics.

Methods: 45 adult kidney transplant recipients were randomized to receive either Tac OD or Tac BID. On days 8±1 (D8) and 90±3 (month 3, M3), blood samples were collected over 24h in both groups. Tacrolimus concentrations were determined using HPLC-MS/MS and common CYP3A5, CYP3A4 and ABCB1 genotypes characterized using allelic discrimination assays. Tacrolimus population pharmacokinetics was studied in the two patient groups using the Iterative Two Stage (ITS) technique, considering a one-compartment model with two gamma laws to describe the absorption phase. Bayesian estimation based on the C0, C1h and C3h concentrations was employed to estimate individual Tac AUC and AUC (for Tac BID), or AUC (for Tac OD). Multiple linear regression was used to evaluate the influence of Tac formulation, post-transplantation period, recipient gender, existing glucose metabolism disorders, and CYP3A5, CYP3A4 and ABCB1 genotypes on C0, AUC and the AUC-to-trough concentration ratios.

Results: The Full Analysis Set comprised 22 patients on Tac OD and 20 on Tac BID. Tac exposure indices as well as their time evolution were similar in the two groups. Multi-linear modeling analysis showed that the Tac dose was higher with Tac-OD than Tac-BID, on D8 than at M3 and in CYP3A5 expressors (p<0.0001 for all). No such influence was found on C0 or C24h, while the AUC was significantly higher on D8 than at M3. The AUC/C0 ratio was not affected by the drug formulation and the polymorphisms studied, but it was significantly lower on D8 than at M3 (p=7.8×10). In contrast, both the post-transplantation period (p=1.53×10), and CYP3A5 expression (p=0.003) had a significant influence on the AUC/C24h ratio, explaining 19% and 12% of its variability, respectively. Consistently, for both Tac formulations, the AUC was better correlated with C24h than C0, and for Tac-BID the AUC was better correlated with C12h than C0.

Conclusions: This study confirms that the precisely timed 12h- or 24h-post-dose blood concentration (as opposed to the vaguely defined 'trough level') is a convenient surrogate of the 24h-AUC of tacrolimus for the two TAC formulations over the first 3 months post-transplantation. Still, for a given C24h value, AUC was higher on D8 and in CYP3A5 expressors. Bayesian estimation of AUC for TAC BID and AUC for TAC OD is feasible using only 3 time points within the first 3h, thus giving access to the actual overall exposure.
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http://dx.doi.org/10.1016/j.phrs.2017.12.005DOI Listing
March 2018

Adherence to and Acceptance of Once-Daily Tacrolimus After Kidney and Liver Transplant: Results From OSIRIS, a French Observational Study.

Transplantation 2016 10;100(10):2099-2106

1 Hôpital Pasteur, Nice, France.2 Hôpital Saint Eloi, Montpellier, France.3 CHU Nantes, Nantes, France.4 Hôpital Rangueil, Toulouse, France.5 Hôpital Necker, Paris, France.6 Hôpital de Jour, Villejuif, France.7 Groupe Hospitalier Henri Mondor, Créteil, France.8 CHU Bordeaux, Bordeaux, France.9 Hôpital Europeen Georges Pompidou, Paris, France.10 CHU Amiens-Picardie, Amiens, France.11 Mapi, Lyon, France.12 Hôpital Claude Huriez, Lille, France.13 Hôpital d'adultes de Brabois, Vandoeuvre Les Nancy, France.

Background: Adherence to immunosuppressive treatments is a major concern in transplanted patients.

Methods: This 6-month French observational, longitudinal, prospective study aimed to assess patient adherence to and acceptance of once-daily tacrolimus (Advagraf) initiation in kidney and liver transplant recipients. Data from 1106 patients initiating once-daily tacrolimus during posttransplant follow-up were analyzed. Adherence and acceptance were assessed using self-administered questionnaires at inclusion and at 3 and 6 months.

Results: Mean age was 52.4 ± 13.2 years, 61.5% were men. For 94.9% of patients, once-daily tacrolimus was prescribed after switching from twice-daily tacrolimus. At inclusion, 20.9% of patients reported good treatment adherence, 72.0% minor nonadherence, and 7.1% were nonadherent. Mean general acceptance score (range, 0-100) was 77.7 (±24.7). At 3 months, adherence was improved in 21.1%, unchanged in 69.2%, and worsened in 9.7% of patients. Mean general acceptance score was 75.4 (±26.5). General acceptance score was improved in 28.0%, unchanged in 39.4%, and worsened in 32.7% of patients. At 6 months, similar changes in adherence and acceptance were observed. Higher general acceptance score at month 3 was significantly associated with better adherence at month 6.

Conclusions: Conversion to once-daily tacrolimus led to an improved rate of adherence at month 3 in more than 20% of patients and a worsened rate of adherence in less than 10% of patients.
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http://dx.doi.org/10.1097/TP.0000000000001307DOI Listing
October 2016

Dosing of Enteric-Coated Mycophenolate Sodium Under Routine Conditions: An Observational, Multicenter Study in Kidney Transplantation.

Ann Transplant 2016 Apr 28;21:250-61. Epub 2016 Apr 28.

Department of Nephrology and Organ Transplantation, Hospital de Rangueil, Paul Sabatier University, INSERM U1043, IFR-BMT, Toulouse, France.

BACKGROUND Dosing of enteric-coated mycophenolate sodium (EC-MPS) should be adjusted to reflect concomitant immunosuppression, but it is largely undocumented whether such modifications are carried out during routine clinical practice. MATERIAL AND METHODS MyLIFE was an observational study of adult kidney-only or kidney-pancreas transplant patients starting -EC-MPS at 33 French transplant centers. Data were collected at first EC-MPS dose and 6 months later. The primary objective was to describe initial EC-MPS dosing according to concomitant immunosuppression. RESULTS There were 461 patients analyzed (174 started EC-MPS by month 1 post-transplant ['de novo'] and 287 started EC-MPS >1 month post-transplant ['maintenance']), receiving cyclosporine (CsA) (n=76), tacrolimus (n=363), or a mammalian target of rapamycin (mTOR) inhibitor (n=22). Mean (SD) starting dose was 1130 (511) mg/day, 1006 (441) mg/day, and 769 (300) mg/day in the CsA, tacrolimus, and mTOR inhibitor groups, respectively (p=0.003). In the de novo subpopulation, the starting dose was 1440 mg/day in 66.7% (14/21) of CsA-treated patients and 71.9% (110/153) of tacrolimus-treated patients, with an intensified dose of 2160 mg/day in 28.6% (6/21) and 8.5% (13/153), respectively. There was a non-significant trend to a higher rate of biopsy-proven acute rejection in patients receiving CsA versus tacrolimus or an mTOR inhibitor (p=0.082). Adverse events with a suspected relation to EC-MPS occurred in 21.0%, 23.1%, and 9.1% of the CsA, tacrolimus, and mTOR inhibitor subpopulations, respectively. CONCLUSIONS EC-MPS is usually initiated at the dose recommended for de novo CsA-treated kidney transplant patients, then titrated downwards as required. An early intensified regimen is not used frequently. The EC-MPS dose is modified in <20% of de novo patients to account for concomitant tacrolimus therapy instead of CsA administration.
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http://dx.doi.org/10.12659/aot.896213DOI Listing
April 2016

Prospective, multicenter, controlled study of quality of life, psychological adjustment process and medical outcomes of patients receiving a preemptive kidney transplant compared to a similar population of recipients after a dialysis period of less than three years--The PreKit-QoL study protocol.

BMC Nephrol 2016 Jan 19;17:11. Epub 2016 Jan 19.

ITUN and Inserm U1064, Nantes University, CHU Nantes, Nantes, France.

Background: Treatment of end stage renal disease has an impact on patients' physical and psychological health, including quality of life (QoL). Nowadays, it is known that reducing the dialysis period has many advantages regarding QoL and medical outcomes. Although preemptive transplantation is the preferred strategy to prevent patients undergoing dialysis, its psychological impact is unknown. Moreover, transplantation can be experienced in a completely different manner among patients who were on dialysis and those who still had a functioning kidney at the time of surgery. Longitudinal data are often collected to allow analyzing the evolution of patients' QoL over time using questionnaires. Such data are often difficult to interpret due to the patients' changing standards, values, or conceptualization of what the questionnaire is intended to measure (e.g. QoL). This phenomenon is referred to as response shift and is often linked to the way the patients might adapt or cope with their disease experience. Whether response shift is experienced in a different way among patients who were on dialysis and those who still had a functioning kidney at time of surgery is unknown and will be studied in the PreKit-QoL study (trial registration number: NCT02154815). Understanding the psychological impact of pre-emptive transplantation is an important issue since it can be associated with long-term patient and graft survival.

Methods/design: Adult patients with a pre-emptive transplantation (n = 130) will be prospectively included along with a control group of patients with a pre-transplant dialysis period < 36 months (n = 260). Only first and single kidney transplantation will be considered. Endpoints include: comparison of change between groups in QoL, anxiety and depressive disorders, perceived stress, taking into account response shift. These criteria will be evaluated every 6 months prior to surgery, at hospital discharge, at three and six months, one and two years after transplantation.

Discussion: The PreKit-QoL study assesses and compares the evolution of QoL and other psychological criteria in preemptive and dialyzed patients taking patients' adaptation into account through response shift analyses. Our study might help to conceive specific, adapted educational programs and psychological support to prevent a possible premature loss of the kidney as a consequence of non-compliance in patients that may be insufficiently prepared for transplantation.

Trial Registration: ClinicalTrials.gov identifier NCT02154815 , registered on May 28, 2014.
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http://dx.doi.org/10.1186/s12882-016-0225-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719683PMC
January 2016

Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization.

Nat Commun 2015 Oct 21;6:8666. Epub 2015 Oct 21.

Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases, 75015 Paris, France.

Ciliopathies are a large group of clinically and genetically heterogeneous disorders caused by defects in primary cilia. Here we identified mutations in TRAF3IP1 (TNF Receptor-Associated Factor Interacting Protein 1) in eight patients from five families with nephronophthisis (NPH) and retinal degeneration, two of the most common manifestations of ciliopathies. TRAF3IP1 encodes IFT54, a subunit of the IFT-B complex required for ciliogenesis. The identified mutations result in mild ciliary defects in patients but also reveal an unexpected role of IFT54 as a negative regulator of microtubule stability via MAP4 (microtubule-associated protein 4). Microtubule defects are associated with altered epithelialization/polarity in renal cells and with pronephric cysts and microphthalmia in zebrafish embryos. Our findings highlight the regulation of cytoplasmic microtubule dynamics as a role of the IFT54 protein beyond the cilium, contributing to the development of NPH-related ciliopathies.
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http://dx.doi.org/10.1038/ncomms9666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617596PMC
October 2015

PREventing Delayed Graft Function by Driving Immunosuppressive InduCtion Treatment (PREDICT-DGF): study protocol for a randomized controlled trial.

Trials 2015 Jun 23;16:282. Epub 2015 Jun 23.

ITUN and Inserm U1064, Nantes University, 30 Boulevard Jean Monnet, Nantes, 44035, France.

Background: In kidney transplantation, the use of Anti-Thymocyte Globulins (ATG) as induction therapy has been described as a possible treatment for reducing the prevalence of Delayed Graft Function (DGF). ATG possesses pharmaceutical proprieties that could help control the lesions caused by ischemia reperfusion injury. However, other studies have questioned this potential protective effect. We hypothesized that the benefits related to ATG for reducing DGF prevalence may be higher and more consistently recognized if only patients with high DGF risk are considered. We recently proposed a scoring system entitled DGFS (Delayed Graft Function Score) for such stratification of kidney transplant recipients according to their risk of DGF. Using the DGFS calculation, we aim to determine whether a short course of ATG can decrease the incidence of DGF in comparison with Basiliximab in kidney transplant recipients with low immunological risk but high DGF risk.

Methods: We conduct a phase IV, open label, randomized, multicentric and prospective study, to compare ATG in parallel with a control group treated by Basiliximab. The 1:1 randomized allocation of patients between groups is stratified on the clinical center, and on the hypothermic machine-perfusion device. We aimed to include a total of 384 patients to achieve a statistical power at 0.80. The study was initiated at the Nantes University hospital in July 2014, with data collection continuing until April 2018, and publication of the results proposed for 2019.

Discussion: The main expected benefits of this study are i) the reduction of unjustified ATG over-prescriptions associated with serious adverse events, ii) the reduction of chance losses related to ATG under-prescription, iii) the decrease in the incidence of DGF which was described as a risk factor of graft failure and patient death, and iv) the reduction in hospitalization duration and number of post transplantation dialysis sessions, both being associated with reduced medical costs. In conclusion, the current study is innovative by proposing a more efficient and personalized induction therapy.

Trial Registration: The study was registered in the Clinical Trials Registry (# NCT02056938, February 5, 2014), and in the European Clinical Trials Database (EudraCT #2014-000332-42, January 30, 2014).
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http://dx.doi.org/10.1186/s13063-015-0807-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477597PMC
June 2015

C3 nephritic factor can be associated with membranous glomerulonephritis.

Pediatr Nephrol 2015 Feb 14;30(2):353-5. Epub 2014 Nov 14.

Inserm U1091, Genetics of Renal Development and Diseases, UNS Université Nice Sophia Antipolis, 28, avenue de Valrose, 06000, Nice, France,

Background: C3 nephritic factor (C3NeF) has been described in association with membranoproliferative glomerulonephritis and is involved in 80 % of cases of dense deposit disease. C3NeF is an immunoglobulin G (IgG) autoantibody which binds to the complement component 3 (C3) convertase C3bBb, thereby inhibiting its decay and leading to massive C3 cleavage. Commonly associated with C3NeF are low C3 levels, decreased total haemolytic complement (CH50) and normal C4 levels. C3NeF patients often present with proteinuria, haematuria and high blood pressure. Evolution to end-stage renal disease is common. Treatment consists of steroids and/or immunosuppressants, with variable efficiency. Renal transplantation is marked by histological recurrence, leading to higher rates of allograft loss.

Cases: We report C3NeF in association with membranous glomerulonephritis type 3-4 in two unrelated children. We also demonstrate that, under adequate immunosuppressive therapy, proteinuria is significantly lowered, blood pressure is kept within normal range and long-term renal function remains normal.

Conclusions: C3NeF can be associated with membranous glomerulonephritis in children. Clinical presentation is mild, and mid-term outcome is favourable under adequate therapy. However, complement anomalies persist for several years.
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http://dx.doi.org/10.1007/s00467-014-3004-3DOI Listing
February 2015

Visceral leishmaniasis due to Leishmania infantum with renal involvement in HIV-infected patients.

BMC Infect Dis 2014 Oct 30;14:561. Epub 2014 Oct 30.

Department of Internal Medicine, Nice University Hospital, Nice, France.

Background: We describe histological, clinical findings and outcomes of renal involvement during Leishmania infantum infection in four HIV-infected patients in South France and North Italy hospital settings.

Cases Presentation: Four HIV-infected Caucasian patients (age 24-49) performed renal biopsy during episodes of visceral leishmaniasis. They presented severe immunosuppression, frequent relapses of visceral leishmaniasis during a follow-up period of several years and partial or complete recovery of renal function after anti-parasitic treatment. Main clinical presentations were nephrotic or nephritic syndrome and/or acute renal failure secondary to membranoproliferative type III glomerulonephritis or acute interstitial nephritis. Clinical outcome was poor, probably as a consequence of insufficient immuno-virological control of the HIV infection.

Conclusions: Our findings suggest that the main histological findings in case of renal involvement due to Leishmania infantum infection in HIV-infected patients are type III MPGN and acute interstitial nephritis, with a histological specificity similar to that observed in canine leishmaniasis. Poor immune status in HIV-infected patients, altering the capacity for parasite clearance, and prolonged course of chronic active VL in this population may lead to the development of specific renal lesions.
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http://dx.doi.org/10.1186/s12879-014-0561-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4216653PMC
October 2014

Effect of N-acetylcysteine pretreatment of deceased organ donors on renal allograft function: a randomized controlled trial.

Transplantation 2015 Apr;99(4):746-53

1 Medico-Surgical Intensive Care Unit, Saint-Roch University Hospital, University of Medicine, Nice, France. 2 Nephrology and renal transplantation Unit, Archet University hospital of Nice, Nice, France. 3 Coordination of Procurement and Transplantation Unit, Cimiez University hospital of Nice, Nice, France.

Background: Antioxidant donor pretreatment is one of the pharmacologic strategy proposed to prevent renal ischemia-reperfusion injuries and delayed graft function (DGF). The aim of the study was to investigate whether a donor pretreatment with N-acetylcysteine (NAC) reduces the incidence of DGF in adult human kidney transplant recipients.

Methods: In this randomized, open-label, monocenter trial, 160 deceased heart-beating donors were allowed to perform 236 renal transplantations from September 2005 to December 2010. Donors were randomized to receive, in a single-blind controlled fashion, 600 mg of intravenous NAC 1 hr before and 2 hr after cerebral angiography performed to confirm brain death. Primary endpoint was DGF defined by the need for at least one dialysis session within the first week or a serum creatinine level greater than 200 μmol/L at day 7 after kidney transplantation.

Results: The incidence of DGF was similar between donors pretreated with or without NAC (39/118; 33% vs. 30/118; 25.4%; P = 0.19). Requirement for at least one dialysis session was not different between the NAC and No NAC groups (17/118; 14.4% vs. 14/118; 11.8%, P = 0.56). The two groups had comparable serum creatinine levels, estimated glomerular filtration rates, and daily urine output at days 1, 7, 15, and 30 after kidney transplantation as well as at hospital discharge. No difference in recipient mortality nor in 1-year kidney graft survival was observed.

Conclusion: Donor pretreatment with NAC does not improve delayed graft function after kidney transplantation.
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http://dx.doi.org/10.1097/TP.0000000000000395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376274PMC
April 2015

Renal Function and NODM in De Novo Renal Transplant Recipients Treated with Standard and Reduced Levels of Tacrolimus in Combination with EC-MPS.

J Transplant 2012 25;2012:941640. Epub 2012 Nov 25.

Transplant Center, University of Colorado Denver, Aurora, CO 80045, USA.

Information is lacking concerning concomitant administration of enteric-coated mycophenolate sodium with tacrolimus (EC-MPS+Tac) in renal transplant recipients (RTxR). In this 6-month, prospective, open-label, multicenter study, de novo RTxR were randomized (1 : 1) to low-dose (LD) or standard-dose (SD) Tac with basiliximab, EC-MPS 720 mg bid, and steroids. Primary objective was to compare renal function at 6-month posttransplantation. Secondary objectives were to compare the incidences of biopsy-proven acute rejection (BPAR), graft loss and death, and new-onset diabetes mellitus (NODM). 292 patients (LD n = 151, SD n = 141) were included. Mean Tac levels were at the low end of the target range in standard-exposure patients (SD, n = 141) and exceeded target range in low-exposure patients (LD = 151) throughout the study. There was no significant difference in mean glomerular filtration rate (GFR) between treatments (ITT-population: 63.6 versus 61.0 mL/min). Incidence of BPAR was similar (10.6% versus 9.9%). NODM was significantly less frequent in LD Tac (17% versus 31%; P = 0.02); other adverse effects (AEs) were comparable. EC-MPS+Tac (LD/SD) was efficacious and well tolerated with well-preserved renal function. No renal function benefits were demonstrated, possibly related to poor adherence to reduced Tac exposure.
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http://dx.doi.org/10.1155/2012/941640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3512323PMC
December 2012

Factors predictive of medication nonadherence after renal transplantation: a French observational study.

Transplantation 2013 Jan;95(2):326-32

CHU de Bordeaux, Hôpital Pellegrin, Service de Néphrologie et Transplantation Rénale, Bordeaux, France.

Background: There have been few prospective studies on the natural history of nonadherence (NA) in kidney transplant recipients (KTRs) over time. The objective of this study was to prospectively evaluate the rate of and risk factors for NA in a French cohort of KTRs.

Method: A total of 312 KTRs from eight French transplantation centers were included in this prospective, noninterventional cohort study. A computer-learning software package (the Organ Transplant Information System) was made available to all patients.

Results: Using the four-item Morisky scale, we showed that 17.3%, 24.1%, 30.7%, and 34.6% of patients were nonadherent at posttransplant month 3 (M3), M6, M12, and M24, respectively. Young age was predictive of NA at M6, M12, and M24. Surprisingly, simple treatment regimens including a small number of doses per day and a small number of tablets per day were associated with NA at M3 and M12, respectively. Other factors predictive of NA included failure to use the Organ Transplant Information System software package at M6 and patient reports of adverse events at M12 and M24. Importantly, we observed that physicians underestimated the prevalence of adverse events when compared to patient self-reporting.

Conclusion: Our observed rate of medication NA in France is consistent with rates reported in previous studies. We found variability in NA risk factors over time as well as an unexpected risk factor (simple treatment regimens). These findings will be useful in developing effective adherence-promoting interventions.
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http://dx.doi.org/10.1097/TP.0b013e318271d7c1DOI Listing
January 2013

Everolimus plus early tacrolimus minimization: a phase III, randomized, open-label, multicentre trial in renal transplantation.

Transpl Int 2012 May 26;25(5):592-602. Epub 2012 Mar 26.

Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary.

There is increasing interest in tacrolimus-minimization regimens. ASSET was an open-label, randomized, 12-month study of everolimus plus tacrolimus in de-novo renal-transplant recipients. Everolimus trough targets were 3-8 ng/ml throughout the study. Tacrolimus trough targets were 4-7 ng/ml during the first 3 months and 1.5-3 ng/ml (n = 107) or 4-7 ng/ml (n = 117) from Month 4. All patients received basiliximab induction and corticosteroids. The primary objective was to demonstrate superior estimated glomerular filtration rate (eGFR; MDRD-4) at Month 12 in the tacrolimus 1.5-3 ng/ml versus the 4-7 ng/ml group. Secondary endpoints included incidence of biopsy-proven acute rejection (BPAR; Months 4-12) and serious adverse events (SAEs; Months 0-12). Statistical significance was not achieved for the primary endpoint (mean eGFR: 57.1 vs. 51.7 ml/min/1.73 m(2)), potentially due to overlapping of achieved tacrolimus exposure levels (Month 12 mean ± SD, tacrolimus 1.5-3 ng/ml: 3.4 ± 1.4; tacrolimus 4-7 ng/ml: 5.5 ± 2.0 ng/ml). BPAR (months 4-12) and SAE rates were comparable between groups (2.7% vs. 1.1% and 58.7% vs. 51.3%; respectively). Everolimus-facilitated tacrolimus minimization, to levels lower than previously investigated, achieved good renal function, low BPAR and graft-loss rates, and an acceptable safety profile in renal transplantation over 12 months although statistically superior renal function of the 1.5-3 ng/ml tacrolimus group was not achieved.
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http://dx.doi.org/10.1111/j.1432-2277.2012.01465.xDOI Listing
May 2012

A multicenter, randomized trial of increased mycophenolic acid dose using enteric-coated mycophenolate sodium with reduced tacrolimus exposure in maintenance kidney transplant recipients.

Clin Nephrol 2012 Feb;77(2):126-36

Department of Nephrology, Dialysis and Organ Transplantation, Hôpital Rangueil, Toulouse, France.

Mycophenolic acid (MPA) dose is frequently reduced in tacrolimus-treated kidney transplant patients, but alternatively the recommended MPA dose can be maintained with reduced tacrolimus exposure. In a 6-month, multicenter, randomized, openlabel study, maintenance kidney transplant patients receiving MPA (mycophenolate mofetil 1g/d or enteric-coated mycophenolate sodium (EC-MPS) 720 mg/d) and tacrolimus were randomized to convert to EC-MPS 1,440 mg/d with reduced tacrolimus (n = 46), or receive EC-MPS 720 mg/d with unchanged tacrolimus (n = 48). Mean estimated GFR (eGFR, aMDRD) at Month 6 was 49.1 ± 11.1 and 44.7 ± 11.5 ml/min/1.73 m2 in the EC-MPS 1,440 mg and 720 mg groups, respectively (p = 0.07). The primary endpoint, change in eGFR from Day 0 to Month 6, was 2.48 ± 0.95 ml/min/1.73 m2 with EC-MPS 1,440 mg and -0.48 ± 0.93 ml/min/1.73 m2 with EC-MPS 720 mg (difference 2.96 ml/min/1.73 m2; 95% CI 0.32 - 5.60; p = 0.028). There were no deaths, graft losses or acute rejections. Adverse events were more frequent with EC-MPS 1,440 mg than 720 mg (66.7% vs. 44.7%, p = 0.034). Adverse events with suspected relation to EC-MPS occurred in 26.7% and 21.3% of patients, respectively (p = 0.59). Conversion of kidney transplant patients to increased MPA dosing using EC-MPS 1,440 mg/d, with reduced tacrolimus exposure, appears an effective immunosuppression strategy and may improve renal function. Adverse events overall, but not those with a suspected relation to EC-MPS, were higher with ECMPS 1,440 mg/d.
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http://dx.doi.org/10.5414/CN107227DOI Listing
February 2012

Efficacy and safety of de novo or early everolimus with low cyclosporine in deceased-donor kidney transplant recipients at specified risk of delayed graft function: 12-month results of a randomized, multicenter trial.

Transpl Int 2010 Nov 19;23(11):1084-93. Epub 2010 Aug 19.

Service de Néphrologie et Transplantation Rénale, Hôpital Hôtel Dieu, Nantes, France.

Immediate or early use of proliferation signal inhibitor (PSI)/mammalian target of rapamycin (mTOR) inhibitor therapy can avoid high exposure to calcineurin inhibitors but concerns exist relating to the risk of delayed graft function (DGF) and impaired wound healing with the mTOR sirolimus. CALLISTO was a 12-month, prospective, multicenter, open-label study. Deceased-donor kidney transplant patients at protocol-specified risk of DGF were randomized to start everolimus on day 1 (immediate everolimus, IE; n = 65) or week 5 (delayed everolimus, DE; n = 74). Incidence of the primary endpoint (biopsy-proven acute rejection, BPAR; graft loss, death, DGF, wound healing complications related to transplant surgery or loss to follow-up) was 64.6% and 66.2% in the IE and DE groups, respectively, at month 12 (P = 0.860). The overall incidence of BPAR was 20.1%. Median estimated glomerular filtration rate was 48 ml/min/1.73 m(2) and 49 ml/min/1.73 m(2) in the IE and DE groups, respectively, at month 12. DGF and wound healing complications were similar between groups. Adverse events led to study drug discontinuation in 17 IE patients (26.2%) and 28 DE patients (37.8%) (NS). In conclusion, introduction of everolimus immediately or early posttransplant in DGF-risk patients is associated with good efficacy, renal function and safety profile. There seems no benefit in delaying initiation of everolimus.
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http://dx.doi.org/10.1111/j.1432-2277.2010.01094.xDOI Listing
November 2010