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Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical and genetic heterogeneity. Applied to one of the worldwide largest cohorts of patients with NPH, genetic analysis encompassing targeted and whole exome sequencing identified disease-causing variants in 600 patients from 496 families with a detection rate of 71%. Of 788 pathogenic variants, 40 known ciliopathy genes were identified. However, the majority of patients (53%) bore biallelic pathogenic variants in NPHP1. NPH-causing gene alterations affected all ciliary modules defined by structural and/or functional subdomains. Seventy six percent of these patients had progressed to kidney failure, of which 18% had an infantile form (under five years) and harbored variants affecting the Inversin compartment or intraflagellar transport complex A. Forty eight percent of patients showed a juvenile (5-15 years) and 34% a late-onset disease (over 15 years), the latter mostly carrying variants belonging to the Transition Zone module. Furthermore, while more than 85% of patients with an infantile form presented with extra-kidney manifestations, it only concerned half of juvenile and late onset cases. Eye involvement represented a predominant feature, followed by cerebellar hypoplasia and other brain abnormalities, liver and skeletal defects. The phenotypic variability was in a large part associated with mutation types, genes and corresponding ciliary modules with hypomorphic variants in ciliary genes playing a role in early steps of ciliogenesis associated with juvenile-to-late onset NPH forms. Thus, our data confirm a considerable proportion of late-onset NPH suggesting an underdiagnosis in adult chronic kidney disease.

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) (n = 32) and basiliximab (n = 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 (P = 0.66) and 12 (P = 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 de novo 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., Graphical abstract

BackgroundMost 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.MethodsThe 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.ResultsAmong 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.ConclusionsOur 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.

International audience; 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.

BACKGROUND Posttransplant lymphoproliferative disorders (PTLDs) 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 (hazard ratio: 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.

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.

Cytomegalovirus (CMV) is a latent infection in most infected individuals, but can be pathogenic in immunocompromised kidney transplant recipients. ASP0113 is a DNA-based vaccine for the prevention of CMV-related mortality and end-organ disease in transplant recipients. The efficacy, safety, and immunogenicity of ASP0113 was assessed in a phase 2, double-blind, placebo-controlled study in CMV-seronegative kidney transplant recipients receiving a kidney from a CMV-seropositive donor. Transplant recipients were randomized (1:1) to receive 5 doses of ASP0113 (5 mg; n = 75) or placebo (n = 74) on Days 30/60/90/120/180 posttransplant, and they received prophylactic valganciclovir/ganciclovir 10-100 days posttransplant. The primary endpoint was the proportion of transplant recipients with CMV viremia ≥1000 IU/mL from Day 100 through to 1 year after the first study vaccine injection. There was no statistically significant difference in the primary endpoint between the ASP0113 and placebo groups (odds ratio 0.79, 95% confidence interval 0.43-1.47; P = .307). There were similar numbers of transplant recipients with treatment-emergent adverse events between groups; however, more transplant recipients reported injection site pain in the ASP0113 group compared with placebo. ASP0113 did not demonstrate efficacy in the prevention of CMV viremia in this CMV-seronegative kidney transplant population, but demonstrated a safety profile similar to placebo. ClinicalTrials.gov registration number: NCT01974206.

International audience; 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.

International audience; 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.

Background: Post-transplant diabetes is a frequent and serious complication of kidney transplantation. There is currently no treatment to prevent or delay the disease. Nevertheless, identification of risk factors make possible to target a population at risk to develop de novo diabetes. We hypothesized that a short term treatment with Vildagliptin may prevent new onset diabetes after transplantation (NODAT) in high-risk patients. Methods: This is a multicenter double-blind placebo-controlled randomized clinical trial. Patients undergoing first kidney transplantation will be included in 10 French transplant center. Included patients will be randomized (1:1) to receive either vildagliptin 100 or 50 mg/day (depending on glomerular filtration rate) during 2 months (the first dose being administered before entering the operating blocks) or placebo. Additional antidiabetic therapy could be administered according to glycemic control. The primary outcome is the proportion of diabetic patients 1 year after transplantation, defined as patients receiving a diabetic treatment, or having a fasting glucose above 7 mmol/l, or/and with an abnormal oral glucose tolerance test. Secondary outcomes include the glycated hemoglobin, the occurrence of acute rejection, infection, graft loss and patient death at 3 months, 6 months and 12 months after transplantation. The results will be correlated to clinical and general characteristics of the patient, cardiovascular history, nephropathy, dialysis history, transplantation data, biological data, the health-related quality of life and the cost-effectiveness of prevention of diabetes with vildagliptin. Discussion: There are only few data concerning pharmacological prevention of post-transplant diabetes. If our hypothesis is verified, our results will have a direct application in clinical practice and could limit diabetes-associated morbidity, reduce cardiovascular complications, increase quality of life of renal transplant patients, and consequently promote graft and patient survival. Our results may possibly serve for non-transplant patients carrying a high-risk of diabetes associated with other co-morbidities. Trial registration: ClinicalTrials.gov, NCT02849899 Registered on 8 February 2016. Keywords: Diabetes prevention; Vildagliptin; kidney transplantation; randomized controlled trial.

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

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.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.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 (P0.0001).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.

International audience; 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.

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., A prospective, randomized, single-blind study of donor treatment with N-acetylcysteine prior to procurement shows that antioxidant treatment does not influence early renal allograft function for organs from brain-dead donors. Alternative approaches will be necessary to prevent delayed graft function.

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 24 h 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, C1 h and C3 h concentrations was employed to estimate individual Tac AUC0-12h and AUC12-24h (for Tac BID), or AUC0–24h (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, AUC0–24h 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 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 C24 h value, AUC0–24h was higher on D8 and in CYP3A5 expressors. Bayesian estimation of AUC0-12h for TAC BID and AUC0–24h for TAC OD is feasible using only 3 time points within the first 3 h, thus giving access to the actual overall exposure.

Background. Two large, prospective studies (12-03; OSAKA) compared the efficacy and tolerability of prolonged-release versus immediate-release tacrolimus in kidney transplant patients also receiving mycophenolate mofetil and low-dose corticosteroids (without induction therapy). Methods. Data were combined into one database to compare results over 24 weeks using 3 alternative endpoints: biopsy-confirmed acute rejection (BCAR); the Food and Drug Administration composite endpoint (graft loss, SCAR, and loss to follow-up), and the European Medicines Agency composite endpoint (graft loss, BCAR, and graft dysfunction). The 95% confidence intervals were calculated (10% noninferiority margin). Results. Overall, 633 patients received prolonged-release tacrolimus (12-03, n = 331; OSAKA, n = 302) and 645 received immediate-release tacrolimus (n = 336; n = 309). Baseline characteristics were comparable. Proportionately more patients receiving prolonged-release tacrolimus had trough levels of 5-15 ng/mL on day 1 (60.8%) and 2 (56.6%) versus immediate-release tacrolimus (42.5% and 43.9%, respectively, both P < .001). Efficacy of prolonged-release and immediate-release tacrolimus were similar as assessed by BCAR (13.9% vs 14.1%, respectively), European Medicines Agency composite endpoint (40.3% vs 38.3%) and US Food and Drug Administration composite endpoint (21.5% vs 19.8%). Conclusions. Novel efficacy endpoints as required by the European Medicines Agency and US Food and Drug Administration demonstrate noninferiority of prolonged-release versus immediate-release tacrolimus. Significantly more patients treated with prolonged release tacrolimus versus immediate-release tacrolimus achieved trough levels of 5 to 15 ng/mL early after transplantation.

One hundred ninety-seven patients received anti-T-lymphocyte globulins Fresenius, mycophenolate mofetil and delayed cyclosporine, and were randomized to ≥6-month corticosteroids (+CS; n = 99) or no CS (−CS; n = 98). One- and five-year actual graft survival (censored for death) was 93.2% and 86.4% in the +CS group versus 94.9% and 89.8% in the −CS group (5-year follow-up, p = 0.487). Freedom from clinical rejection was 86.9% and 81.8% versus 74.5% and 74.5% (p = 0.144), respectively, at 1 and 5 years; 5-year freedom from biopsy-proven rejection was 88.9% versus 83.7% (p = 0.227). More late first rejections occurred in the +CS group. Significantly lower 5-year graft survival in patients experiencing rejection was observed for +CS (55.6% vs. 92.0%; p = 0.005) with 8/18 versus 2/25 graft losses. Renal function at 5 years was stable and comparable (median serum creatinine, 159 vs. 145 µmol/L; creatinine clearance, 53.5 vs. 56.6 mL/min). More +CS patients developed diabetes, dyslipidemia and malignancies. Rejections in −CS patients occurred early after transplantation and did not impair long-term renal function. In patients receiving CS, rejections occurred later and with a higher risk for subsequent graft failure. A similar and not inferior 5-year efficacy profile and a reduced morbidity were observed in CS-free patients compared to patients who received CS for at least 6 months.

BACKGROUND The predictive value of anti-M-type phospholipase A2 receptor (PLA2R1) autoantibodies for membranous nephropathy (MN) recurrence after renal transplantation remains controversial. METHODS Our aim was to monitor anti-PLA2R1 IgG4 activity using a sensitive enzyme-linked immunosorbent assay in 15 kidney transplant recipients with MN, and to test the correlation between antibody titres and MN recurrence. RESULTS Five patients never exhibited anti-PLA2R1 antibodies, and one of them relapsed. Ten patients (67%) had IgG4 anti-PLA2R1 antibodies at the time of transplantation and during follow-up. The presence of IgG4 anti-PLA2R1 antibodies at the time of kidney transplantation does not imply MN recurrence (P = 0.600, n = 15). However, a positive IgG4 anti-PLA2R1 activity during follow-up (>Month 6) was a significant risk factor for MN relapse (P = 0.0048, n = 10). Indeed, four patients had persistent IgG4 anti-PLA2R1 activity after transplantation and relapsed. Among them, one was successfully treated with rituximab. Another had persistently high IgG4 anti-PLA2R1 activity and exhibited a histological relapse but no proteinuria while on treatment with renin-angiotensin system inhibitors. In contrast, the six other patients who did not relapse exhibited a decrease of their IgG4 anti-PLA2R1 activity following transplant immunosuppression, including two with proteinuria due to biopsy-proven differential diagnoses. A weak transplant immunosuppressive regimen was also a risk factor of MN recurrence (P = 0.0048, n = 10). Indeed, the six patients who received both an induction therapy and a combined treatment with calcineurin inhibitors/mycophenolate exhibited a decrease of IgG4 anti-PLA2R1 activity and did not relapse, while the four patients who did not receive this strong immunosuppressive treatment association had persistently high IgG4 anti-PLA2R1 activity and relapsed. CONCLUSION The monitoring of IgG4 anti-PLA2R1 titres during follow-up helps to predict MN recurrence, and a strong immunosuppressive treatment of anti-PLA2R1 positive patients may prevent recurrence.

Aristolochic acid (AA) causes aristolochic acid nephropathy (AAN), first described in women in Belgium accidently prescribed Aristolochia fangchi in a slimming treatment, and also Balkan endemic nephropathy (BEN), through probable dietary contamination with Aristolochia clematitis seeds. Both nephropathies have a high risk of urothelial cancer, with AA being the causative agent. In tissues of AAN and BEN patients, a distinct DNA adduct, 7-(deoxyadenosin-N6-yl)-aristolactam I (dA-AAI), has been detected. DNA adducts can be removed through DNA repair, they can result in mutations through erroneous DNA replication or they can cause cell death. The dA-AAI adduct induces AT to TA transversions in the tumor-suppressor TP53 gene in experimental systems, matching TP53 mutations observed in urothelial tumors from AAN cancer cases. Using thin-layer chromatography 32P-postlabeling and mass spectrometric analysis we report the detection of dA-AAI in renal DNA from 11 Belgian AAN patients over 20 years after exposure to AA had ceased. Our results showed that dA-AAI is an established biomarker of AA exposure, and that this biomarker can be demonstrated to be persistent decades after a distinct AA exposure. Further, the persistence of dA-AAI adducts appears to be a critical determinant for the AA mutational fingerprint frequently found in oncogenes and tumor suppressor genes recently identified by whole genome sequencing of AA-associated urothelial tumors. The potential for exposure to AA worldwide is high; the unprecedented long-term persistence of dA-AAI provides a useful long-term biomarker of exposure and attests to the role of AA in human urothelial malignancy.

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

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

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. 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

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.

International audience; 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.

Summary 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 m2 and 49 ml/min/1.73 m2 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.

International audience; BACKGROUND: To define the role of mammalian target of rapamycin inhibitors in kidney transplantation, we compared efficacy and safety of two immunosuppressive regimens-a calcineurin inhibitor-free regimen with depletive induction versus a calcineurin inhibitor-based regimen. METHODS: De novo renal allograft recipients were randomized before transplantation to receive sirolimus (SRL; n=71, group A) or tacrolimus (n=70, group B). All patients received mycophenolate mofetil and corticosteroids. In group A, patients received rabbit antithymocyte globulin induction. In group B, antithymocyte globulin therapy could be given in case of delayed graft function. The estimated glomerular filtration rate (GFR) (Nankivell's formula) at month 12 was the primary endpoint. RESULTS: GFR showed no significant difference at month 12, with 56.1 in group A versus 58.4 mL/min/1.73 m in group B. In functioning grafts, renal function was significantly better in the SRL group, with higher GFR values at months 1, 2, 3, 6, and 9 (P

The management of anemia after kidney transplantation remains poorly explored. The Management of Anemia in French Kidney Transplant Patients (MATRIX) study is an observational study conducted in 10 academic hospitals among kidney-transplant patients designed to evaluate the prevalence, associated factors and management of post-transplant anemia. Over two consecutive weeks, 418 recipients (males: 248; age: 50.8+/-12.7 years) were included, all were transplanted for more than six months. Mean serum creatinine (Scr) was 152+/-67 micromol/l and mean hemoglobin (Hb) was 12.4+/-1.8 g/dl (males: 12.8+/-1.9 g/dl; females 11.9+/-1.6 g/dl). Irrespective of the delay following transplantation, 23% of patients (n=95) were severely anemic (Hb < or = 11 g/dl). Eighteen percent of the patients received an antianemic treatment (10% oral iron, 7% erythropoiesis stimulating agents (ESA), 4% folic acid) and only 35% of the severely anemic patients were actually treated (n=33). A significantly-negative correlation was observed between eGFR and Hb levels (R= -0.347, p

Rituximab is emerging as a potent therapeutic option in chronic inflammatory diseases associated with a prominent humoral component. Recent studies have demonstrated that chronic inflammatory infiltrate organize progressively themselves into ectopic lymphoid tissues (tertiary lymphoid organs; TLOs) supporting a local humoral immune response. In the present study, we evaluated the impact of rituximab therapy on TLOs associated with chronic active antibody-mediated rejection, a prototypic humoral chronic inflammatory condition.Renal allografts removed for terminal chronic rejection were prospectively collected in four transplantation centers over 4 years. Among 38 grafts collected, two were explanted after rituximab therapy for chronic active antibody-mediated rejection. Clinical characteristics and circulating B cell count were recorded for these two patients. The composition and the microarchitecture of the inflammatory infiltrate were analyzed by flow cytometry and immunohistochemistry. Organotypic cultures were performed to evaluate the intragraft production of alloantibody. Levels of expression of BAFF (Blys, CD257) were evaluated by quantitative reverse transcriptase-polymerase chain reaction.Despite the complete depletion of circulating B cells in peripheral blood, TLOs were evidenced in the interstitium of both explanted grafts. Their functionality was assessed by the demonstration of a persistent local production of alloantibody. BAFF, a potent survival factor for B cells, was found to be overexpressed (both at the gene and the protein levels) in chronically rejected grafts when compared with normal kidneys and lymph nodes.In certain patients, inflammatory microenvironment provides BAFF-dependent paracrine survival signal to B-cells in TLOs, allowing them to escape rituximab-induced apoptosis, thereby thwarting therapeutic efficiency.

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., Nephrophthisis (NPH) is a common manifestation of ciliopathy diseases. Here the authors identify mutations in intraflagellar transport 54 (IFT54) in patients with NPH and discover an extra-ciliary role for IFT54 in regulating cytoplasmic microtubule dynamics, that contributes to the pathophysiology of this disease.

Resume Objectifs. – L'effet des anticalcineurines sur le metabolisme osseux reste controverse. Nous avons voulu comparer l'action de la ciclosporine-A (CsA) et du tacrolimus (FK506) sur le metabolisme osseux des transplantes renaux. Methodes. – La population etudiee (n = 28 dont 10 femmes et 18 hommes) a ete choisie parmi 94 patients transplantes au CHU de Nice entre 1996 et 1999. Les criteres d'exclusion comprenaient un nombre de transplantations superieur a 1 (n = 8) et un nombre de rejet superieur a 1 (n = 2). Les patients sous CsA et ceux traites par FK506 ont ete apparies pour l'âge, le sexe, l'index de masse corporelle, la duree de transplantation, et le statut estrogenique chez les femmes. La dose cumulee de corticoides a ete calculee et la densite minerale osseuse (DMO) a ete mesuree au talon et a l'avant-bras. Les concentrations seriques de calcium, phosphore, parathormone (PTH), creatinine, estradiol, telopeptide-C (CTX) ainsi que des metabolites de la vitamine D de meme que l'activite serique de la phosphatase alcaline osseuse (PALC) ont ete mesures. Resultats. – Malgre l'appariement des patients, la duree d'hemodialyse etait plus longue dans le groupe FK506 que CsA. La dose cumulee de corticoides etait similaire dans les deux groupes. Il n'existait pas de difference entre les deux groupes en ce qui concerne les DMO et les parametres du metabolisme phosphocalcique si ce n'est une tendance de la concentration serique de CTX et de l'activite de la PALC osseuse a etre plus eleves dans le groupe FK506 (p = 0,08). L'estradiolemie, en revanche, etait significativement plus basse dans le groupe FK506 que CsA (p = 0,02). Conclusions. – Les effets deleteres sur le metabolisme osseux tant de l'hypoestrogenie que de la plus longue periode d'exposition a l'hyperparathyroidie dans le groupe FK506 ont peut-etre ete contrebalances par un effet favorable du tacrolimus sur le metabolisme osseux. Cela est une hypothese qui demande a etre verifiee par des etudes longitudinales controlees.

Resume Nous rapportons 2 cas de greffes renaux sous tacrolimus ayant presente un syndrome douloureux des genoux au premier et troisieme mois de greffe. Le tacrolimus est un immunosuppresseur agissant, comme la cyclosporine, par inhibition de l’activite phosphatasique de la calcineurine. Ce syndrome semble similaire a celui decrit en 1989 avec la cyclosporine. La scintigraphie osseuse montre des hyperfixations des epiphyses douloureuses, et l’imagerie par resonance magnetique des modifications du signal en faveur d’un œdeme medullaire. Si les taux residuels de tacrolimus ne sont pas trop eleves, la diminution de posologie ne semble pas toujours necessaire. L’evolution est favorable en quelques mois. La surveillance radiologique doit eliminer une osteonecrose. Les hypotheses pathogeniques sont evoquees. L’utilisation du tacrolimus etant encore recente, il est utile que les observations similaires soient rapportees.

We report a case of longitudinal tibial fracture as the first manifestation of bone insufficiency in a 50-year-old patient who had received a renal transplant 12 years earlier. The epidemiological, clinical, and imaging features of these fractures are reviewed. Bone loss occurs in the long term in about half of renal transplant recipients. The main causes are preexisting renal osteodystrophy; glucocorticoid therapy; and hyperparathyroidism, whether residual or secondary to imperfect graft function. The effects of cyclosporine therapy on bone metabolism remain unclear. Identification of patients at very high risk of fracture and available options for early prophylaxis are discussed.

Resume Nous rapportons un cas de fracture de contrainte longitudinale du tibia revelant une insuffisance osseuse chez un patient de 50 ans, transplante renal a l’âge de 38 ans. Les particularites epidemiologiques et cliniques de ce type de fracture de contrainte sont resumees, ainsi que les indications de l’imagerie. L’insuffisance osseuse apres transplantation renale est un probleme frequent, concernant jusqu’a 1 patient sur 2 a long terme. Les principales causes sont l’osteodystrophie renale preexistante, la corticotherapie, l’hyperparathyroidie residuelle ou secondaire a une fonction imparfaite du greffon. Le role de la ciclosporine sur le metabolisme osseux reste encore imprecis. Les criteres de selection des patients les plus a risque de fracture et les possibilites de traitement preventif precoce sont discutes.

Background. Induction therapy with antithymocyte globulin (ATG) reduces the incidence of acute rejection after transplantation. A study was undertaken to assess the efficacy and safety of ATG induction on tacrolimus-based and cyclosporine A (CsA)-based therapies compared with immediate tacrolimus triple therapy in kidney transplant recipients. Methods. In a 6-month, open-label, randomized, prospective study conducted in 30 European centers, 555 renal transplant patients were randomly assigned to tacrolimus triple therapy (Tac triple, n=185), ATG induction with tacrolimus (ATG-Tac, n= 186), or ATG induction with CsA microemulsion (ATG-CsA, n=184); all were combined with azathioprine, and corticosteroids. The primary endpoint was incidence and time to first acute rejection episode confirmed by biopsy. Results. Patient demographics and clinical parameters at baseline were similar. Patient and graft survival rates were similar in all groups. The incidence of clinically apparent acute rejection was significantly higher (P=0.003) for Tac triple (33.0%) compared with ATG-Tac (22.6%) and the incidence for ATG-Tac was significantly lower (P=0.004) than for ATG-CsA (37.0%). The incidences of acute rejection confirmed by biopsy (primary endpoint) were 25.4%, 15.1%, and 21.2% for Tac triple, ATG-Tac, and ATG-CsA, respectively (Tac triple vs. ATG-Tac, P=0.004). The incidences of corticosteroid-resistant acute rejection were 7.0% (Tac triple), 4.8% (ATG-Tac), and 10.9% (ATG-CsA) (ATG-Tac vs. ATG-CsA, P=0.038). In the ATG groups, the incidences of leukopenia, thrombocytopenia, serum sickness, fever, and cytomegalovirus infection were significantly higher (P

We report the 6-year radiographic follow-up of a phalangeal brown tumor in a patient with severe hyperparathyroidism secondary to chronic renal failure treated with hemodialysis. The phalangeal lesion increased in size during the first 3 years, until the patient finally accepted to undergo parathyroidectomy. The initial radiographic change was a small intracortical lytic area. Two years later, an expansile cystic lesion was visible in the phalanx, and computed tomography showed a cortical defect. Ossification of the lesion occurred over the 2.5 years following parathyroidectomy. The epidemiology, radiographic changes and post-treatment evolution of brown tumor in dialysed patients is reviewed. Surgical parathyroidectomy is the standard treatment for brown tumor complicating secondary hyperparathyroidism. The usefulness and limitations of treatment with vitamin D analogs, recently reported in a few case reports, are discussed.

Introduction Le deficit en cobalamine C (cblC) est la plus frequente erreur innee du metabolisme de la vitamine B12. Cette pathologie est souvent revelee dans l’enfance, avec une symptomatologie neurologique predominante. Quelques cas de microangiopathies thrombotiques (MAT) renales liees au deficit en cblC ont ete prealablement rapportes, chez l’enfant mais aussi l’adolescent et l’adulte jeune, mais le tableau renal de cette maladie reste mal defini. Cette etude a pour objectif de decrire et d’analyser comparativement les specificites anatomopathologiques des atteintes renales liees au deficit en cblC. Patients et methodes Il s’agit d’une etude retrospective multicentrique incluant 7 patients atteints d’un deficit en cblC et ayant beneficie d’une biopsie renale. Les caracteristiques cliniques et biologiques ainsi que l’evolution ont ete recueillies. Chaque biopsie a ete relue de maniere centralisee et les 7 cas ont ete compares a 16 controles presentant une MAT d’une autre etiologie. Resultats Les patients inclus avaient entre 6 et 26 ans lors des premieres manifestations. Tous presentaient un tableau de MAT avec insuffisance renale aigue et proteinurie, et 5 necessitaient le recours a l’epuration extrarenale. L’etude histologique revelait une MAT arteriolo-glomerulaire chez tous les patients. Apres comparaison avec le groupe controle, un aspect en chainettes de la membrane basale glomerulaire et des depots glomerulaires parietaux d’IgM apparaissaient significativement plus frequents au cours des MAT liees a un deficit en cblC. L’evolution sous traitement par hydroxycobalamine a montre une resolution de l’hemolyse chez 6/6 patients traites et un sevrage de la dialyse chez 3/4 patients. Discussion Le diagnostic de deficit en cblC doit etre evoque devant un tableau de MAT, meme a l’âge adulte. Les atteintes histologiques comprennent des lesions typiques de MAT arteriolo-glomerulaire aigue ou chronique, un aspect en chainettes de la membrane basale glomerulaire et des depots d’IgM. Le role de l’hyperhomocysteinemie et de l’hypomethioninemie est evoque dans les lesions endotheliales et l’agregation plaquettaire. Conclusion Les MAT associees au deficit en cblC sont une entite rare qu’il faut savoir evoquer chez l’enfant mais aussi le jeune adulte devant une hyperhomocysteinemie et une histologie typique afin de rapidement mettre en route un traitement adapte.

Aristolochic acid (AA) causes aristolochic acid nephropathy (AAN), first described in women in Belgium accidently prescribed Aristolochia fangchi in a slimming treatment, and also Balkan endemic nephropathy (BEN), through probable dietary contamination with Aristolochia clematitis seeds. Both nephropathies have a high risk of urothelial cancer, with AA being the causative agent. In tissues of AAN and BEN patients, a distinct DNA adduct, 7-(deoxyadenosin-N6-yl)-aristolactam I (dA-AAI), has been detected. DNA adducts can be removed through DNA repair, they can result in mutations through erroneous DNA replication or they can cause cell death. The dA-AAI adduct induces AT to TA transversions in the tumor-suppressor TP53 gene in experimental systems, matching TP53 mutations observed in urothelial tumors from AAN cancer cases. Using thin-layer chromatography 32P-postlabeling and mass spectrometric analysis we report the detection of dA-AAI in renal DNA from 11 Belgian AAN patients over 20 years after exposure to AA had ceased. Our results showed that dA-AAI is an established biomarker of AA exposure, and that this biomarker can be demonstrated to be persistent decades after a distinct AA exposure. Further, the persistence of dA-AAI adducts appears to be a critical determinant for the AA mutational fingerprint frequently found in oncogenes and tumor suppressor genes recently identified by whole genome sequencing of AA-associated urothelial tumors. The potential for exposure to AA worldwide is high; the unprecedented long-term persistence of dA-AAI provides a useful long-term biomarker of exposure and attests to the role of AA in human urothelial malignancy.

The occurrence of aortoiliac lesions with renal transplantation is an increasingly common combination that causes problems regarding operative strategy and indications for aortoiliac reconstruction and renal transplantation. To gain greater insight into these problems we undertook a retrospective multicenter study based on data from 24 kidney transplantation centers in France. A total of 83 patients who underwent both aortoiliac reconstruction and kidney transplantation were enrolled. Patients were divided into two groups according to the order in which the two procedures were performed. Group I included 36 patients in whom aortoiliac reconstruction was performed before kidney transplantation-either during the same procedure (6 patients) or as separate procedures (30 patients). Group II included 47 patients in whom aortoiliac reconstruction was performed after kidney transplantation. The mean age was 49.9 years. There were 43 abdominal aortic aneurysms (51.8%), 36 occlusive aortoiliac lesions (43.4%), and 4 aortoiliac dissections (4.8%). Prosthetic bypass grafting was performed in 72 cases (86.8%), transluminal angioplasty in 6 cases (7.2%), endarterectomy in 3 cases (3.6%), and arterial autograft bypass in 1 case. Renal transplant protection was used during aortoiliac clamping in only 3 patients in group II (7.3%). One month after the second procedure (i.e., kidney transplantation in group I and aortoiliac reconstruction in group II), creatinemia was200 micromol/L in 27 patients (87.1%) in group I and in 37 patients (88.1%) in group II. The graft survival rate was 86.1% in group I and 89.3% in group II. The overall postoperative morbidity rate was 36.1% (13 cases) in group I and 36.1% (17 cases) in group II. One year after the second procedure creatinemia was200 micromol/L in 29 patients (93.5%) in group I and 36 patients (93%) in group II. The graft survival rate was 86.1% in group I and 85.1% in group II. The outcome of kidney transplantation is comparable regardless of whether the procedure is performed alone or in association with aortoiliac reconstruction. This finding indicates that kidney transplantation should be performed in patients presenting indications for prior aortoiliac reconstruction. The outcome of aortoiliac reconstruction without graft protection in kidney transplant patients is comparable to the outcome of conventional aortoiliac reconstruction in patients with native kidneys.

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.

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 novoRTxR 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 (LDn=151, SDn=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.

International audience; Atypical hemolytic and uremic syndrome (aHUS) is a severe disease strongly associated with genetic abnormalities in the complement alternative pathway. In renal posttransplantation, few data are available on recurrence risk and graft outcome according to genetic background in aHUS patients. The aim of this study was to identify risk factors for recurrence and transplant outcome and, in particular, the role of complement gene abnormalities. We retrospectively studied 57 aHUS patients who had received 71 renal transplants. A mutation in complement gene was identified in 39 (68%), in factor H (CFH), factor I (CFI), membrane cofactor-protein (MCP), C3 and factor B (CFB). At 5 years, death-censored graft survival was 51%. Disease recurrence was associated with graft loss (p = 0.001). Mutations in complement genes were associated with higher risk of recurrence (p = 0.009). Patients with CFH or gain of function (C3, CFB) mutations had a highest risk of recurrence. M-TOR inhibitor was associated with significant risk of recurrence (p = 0.043) but not calcineurin inhibitor immunosuppressive treatment (p = 0.29). Preemptive plasmatherapy was associated with a trend to decrease recurrence (p = 0.07). Our study highlights that characterization of complement genetic abnormalities predicts the risk of recurrence-related graft loss and paves the way for future genetically based individualized prophylactic therapeutic strategies.

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.

Many sources of foreign or semi foreign cells, known as microchimerism (Mc), can be found in healthy individuals. We have recently shown in women with end stage renal disease (ESRD) that Mc frequencies and levels are exacerbated prior to kidney transplantation. Is Mc arising from pregnancy a protective factor for renal diseases explaining lower incidence in women? Is Mc helpful in slowing down disease progression? However, natural Mc is not the only actor as post blood transfusion Mc is also found at high levels in women with ESRD. The difficulty is therefore to distinguish the different types of Mc and this is made even more complicated when the recipient receives a potentially chimeric organ. What part does each source of chimerism play in disease and transplant fate, and can one decipher each role knowing that one chimerism may hide another?

Background Posttransplant anemia may be a major determinant of chronic allograft nephropathy. However, the impact of correcting anemia on graft function remains controversial. Methods A 3-year follow-up of an open-label, multicenter, randomized controlled trial involving kidney transplantation recipients examined whether sustained maintenance of target hemoglobin (Hb) concentrations at a high level (12.5–13.5 g/dL, n = 64) with either darbepoetin alfa or epoetin beta pegol would slow the graft function decline rate as the primary efficacy endpoint, compared with maintenance of a low Hb concentration (10.5–11.5 g/dL, n = 63). Results The mean blood pressures in the two groups were well controlled throughout the study. In the high Hb group, mean Hb concentrations increased to >12 g/dL at 3 months, reaching the target range at 18 months. At the end of this study (36 months), the mean Hb concentration was 12.8 ± 0.7 g/dL in the high Hb group and 11.5 ± 1.2 g/dL in the low Hb group. The decline rate of the estimated glomerular filtration (eGFR) rate was considerably greater in the low Hb group (ΔeGFR, −5.1 ± 9.5 mL/min/1.73 m2) than in the high Hb group (−1.0 ± 8.4 mL/min/1.73 m2) (P = 0.02). Of note, only a few high Hb patients developed cardiovascular events and returned to hemodialysis, but the low Hb patients did not. Conclusion This prospective study suggests that correcting anemia to the target Hb level range (12.5–13.5 g/dL) slows renal function deterioration by >3 years in the chronic phase of allograft nephropathy.

International audience; BACKGROUND & AIMS: Hepatitis E virus (HEV) infection can cause chronic hepatitis in recipients of solid organ transplants. However, the factors that contribute to chronic infection and the outcomes of these patients are incompletely understood. We performed a retrospective analysis of data from 17 centers from Europe and the United States that described the progression, outcomes, and factors associated with development of chronic HEV infection in recipients of transplanted solid organs. METHODS: We studied data from 85 recipients of solid organ transplants who were infected with HEV. Chronic HEV infection was defined by the persistent increases in levels of liver enzymes and polymerase chain reaction evidence of HEV in the serum and/or stool for at least 6 months. RESULTS: Fifty-six patients (65.9%) developed chronic hepatitis. Univariate analysis associated liver transplant, shorter times since transplant, lower levels of liver enzymes and serum creatinine, lower platelet counts, and tacrolimus-based immunosuppressive therapy (rather than cyclosporin A) with chronic hepatitis. On multivariate analysis, the independent predictive factors associated with chronic HEV infection were the use of tacrolimus rather than cyclosporin A (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.49-1.97; P = .004) and a low platelet count at the time of diagnosis with HEV infection (OR, 1.02; 95% CI, 1.001-1.1; P = .04). Of patients with chronic hepatitis, 18 (32.1%) achieved viral clearance after the dose of immunosuppressive therapy was reduced. No HEV reactivation was observed after HEV clearance. CONCLUSIONS: HEV infection causes chronic hepatitis in more than 60% of recipients of solid organ transplants. Tacrolimus therapy is the main predictive factor for chronic hepatitis. Dose reductions of immunosuppressive therapy resulted in viral clearance in more than 30% of patients.