The DESCARTES-Nantes survey of kidney transplant recipients displaying clinical operational tolerance identifies 35 new tolerant patients and 34 almost tolerant patients.

BACKGROUND: Kidney recipients maintaining a prolonged allograft survival in the absence of immunosuppressive drugs and without evidence of rejection are supposed to be exceptional. The ERA-EDTA-DESCARTES working group together with Nantes University launched a European-wide survey to identify new patients, describe them and estimate their frequency for the first time. METHODS: Seventeen coordinators distributed a questionnaire in 256 transplant centres and 28 countries in order to report as many 'operationally tolerant' patients (TOL; defined as having a serum creatinine <1.7 mg/dL and proteinuria <1 g/day or g/g creatinine despite at least 1 year without any immunosuppressive drug) and 'almost tolerant' patients (minimally immunosuppressed patients (MIS) receiving low-dose steroids) as possible. We reported their number and the total number of kidney transplants performed at each centre to calculate their frequency. RESULTS: One hundred and forty-seven questionnaires were returned and we identified 66 TOL (61 with complete data) and 34 MIS patients. Of the 61 TOL patients, 26 were previously described by the Nantes group and 35 new patients are presented here. Most of them were noncompliant patients. At data collection, 31/35 patients were alive and 22/31 still operationally tolerant. For the remaining 9/31, 2 were restarted on immunosuppressive drugs and 7 had rising creatinine of whom 3 resumed dialysis. Considering all patients, 10-year death-censored graft survival post-immunosuppression weaning reached 85% in TOL patients and 100% in MIS patients. With 218 913 kidney recipients surveyed, cumulative incidences of operational tolerance and almost tolerance were estimated at 3 and 1.5 per 10 000 kidney recipients, respectively. CONCLUSIONS: In kidney transplantation, operational tolerance and almost tolerance are infrequent findings associated with excellent long-term death-censored graft survival.

Steroid avoidance with early intensified dosing of enteric-coated mycophenolate sodium: a randomized multicentre trial in kidney transplant recipients.

BACKGROUND: Short-term intensified dosing using enteric-coated mycophenolate sodium (EC-MPS) reduces rejection after kidney transplantation without compromising safety and may facilitate steroid avoidance. METHODS: In a 6-month, multicentre open-label trial, 222 de novo kidney transplant recipients at low-immunological risk were randomized to steroid avoidance or maintenance steroids with interleukin (IL)-2 receptor antibody (IL-2RA) induction, EC-MPS (2160 mg/day to Week 6, 1440 mg/day thereafter) and cyclosporine. RESULTS: The primary end point; treatment failure at Month 6 [biopsy-proven acute rejection (BPAR), graft loss, death or loss to follow-up], occurred in 17.9% (20/112) of steroid-avoidance patients and 14.5% (16/110) of controls (difference 3.4%, 95% confidence interval -6.3 to 13.1, P = 0.47 for superiority testing). BPAR occurred in 11.6 and 7.3% of patients in the steroid-avoidance and control arms, respectively (P = 0.27). Creatinine clearance was similar at Month 6 (steroid-avoidance 56 ± 18 mL/min/1.73 m(2), controls 60 ± 22 mL/min/1.73 m(2), P = 0.34). Cytomegalovirus infection, as reported by investigators, occurred in 12.5% of steroid-avoidance patients and 22.7% of controls (P = 0.045). CONCLUSIONS: A regimen of early intensified EC-MPS dosing with calcineurin inhibitor and IL-2RA induction permits oral steroid avoidance in adult kidney transplant patients at low-immunological risk without compromising efficacy at 6 months' follow-up.

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

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.

Relation between pretransplant magnesemia and the risk of new onset diabetes after transplantation within the first year of kidney transplantation.

BACKGROUND: New-onset diabetes after transplantation (NODAT) is a frequent condition associated with a poor outcome. In kidney transplantation, hypomagnesemia is a frequent posttransplant complication and has been associated with calcineurin inhibitors use. Previous studies have analyzed the relationship between posttransplant hypomagnesemia and the risk of NODAT and provided conflicting conclusions. We conducted an observational study to analyze the relationship between pretransplant magnesemia (Mg) and the risk of NODAT within the first year of kidney transplantation. METHODS: A cohort study was conducted to determine the risk conferred by pretransplant magnesium level on development of NODAT within 1 year posttransplant. First time kidney transplant recipients between January 2005 and December 2010 with more than 6 months of follow-up were included. Mg was measured within the 24 hours preceding kidney transplantation. NODAT was defined according to the American Diabetes Association criteria. RESULTS: Among the 154 patients analyzed, 28 (18.2%) developed NODAT at year 1. NODAT patients had lower levels of pretransplant Mg as compared with non-NODAT patients (P<0.02). When patients were divided into tertiles of Mg level, NODAT developed more frequently in patients in the lower tertile (Mg <2 mg/dL) as compared with patients in the higher tertile (Mg >2.3 mg/dL) (log rank, P<0.05). A multivariate analysis after adjustment to several variables demonstrated pretransplant Mg to be an independent risk factor of NODAT. CONCLUSION: This study supports that a low pretransplant Mg level is an independent risk factor of NODAT in kidney transplant recipients.

Long-term maintenance immunosuppressive regimen with tacrolimus monotherapy.

BACKGROUND: The long-term outcome of kidney transplant recipients on monotherapy with calcineurin inhibitors has been poorly analyzed. This study aimed to describe the long-term outcome of patients on Tac monotherapy (mTac) and to compare this regimen to a standard dual therapy with Tac/MMF. MATERIAL AND METHODS: This retrospective study included 84 consecutive first kidney recipients transplanted between 1998 and 2003 and followed until 2010. Patients were treated with mTac after the 6th month of transplantation. Survival and incidence of adverse events were analyzed and compared to those of patients treated with Tac/MMF as maintenance regimen after the 6th month of transplantation. RESULTS: Mean follow-up of the mTac cohort was 8.7 ± 2.2 years. Overall patient and graft survival of the mTac cohort was 91.3% and 86.6%, respectively, at year 8 posttransplant. Tac monotherapy was started in 93.3% of patients at month 6 posttransplant and maintained in 50% of the cohort at the end of the follow-up period. Incidence of acute rejection (AR) and chronic allograft nephropathy (CAN) were 11.9% and 16.6%, respectively. Kaplan-Meyer analysis did not show any difference in patient and graft survival between mTac patients and patients under Tac/MMF. At year 6, compared to Tac/MMF patients, mTac patients had a significantly lower incidence of AR after the 6th month posttransplant and no difference in CAN, cancer, NODAT, and cardiovascular events incidence. CONCLUSIONS: This work suggests that long-term maintenance immunosuppression with mTac is safe in low-immunological risk patients and should be considered for use especially in patients with MMF intolerance.

Tacrolimus population pharmacokinetic-pharmacogenetic analysis and Bayesian estimation in renal transplant recipients.

OBJECTIVES: The aims of this study were (i) to investigate the population pharmacokinetics of tacrolimus in renal transplant recipients, including the influence of biological and pharmacogenetic covariates; and (ii) to develop a Bayesian estimator able to reliably estimate the individual pharmacokinetic parameters and inter-dose area under the blood concentration-time curve (AUC) from 0 to 12 hours (AUC(12)) in renal transplant patients. METHODS: Full pharmacokinetic profiles were obtained from 32 renal transplant patients at weeks 1 and 2, and at months 1, 3 and 6 post-transplantation. The population pharmacokinetic analysis was performed using the nonlinear mixed-effect modelling software NONMEM version VI. Patients' genotypes were characterized by allelic discrimination for PXR -25385C>T genes. RESULTS: Tacrolimus pharmacokinetics were well described by a two-compartment model combined with an Erlang distribution to describe the absorption phase, with low additive and proportional residual errors of 1.6 ng/mL and 9%, respectively. Both the haematocrit and PXR -25385C>T single nucleotide polymorphism (SNP) were identified as significant covariates for apparent oral clearance (CL/F) of tacrolimus, which allowed improvement of prediction accuracy. Specifically, CL/F decreased gradually with the number of mutated alleles for the PXR -25385C>T SNP and was inversely proportional to the haematocrit value. However, clinical criteria of relevance, mainly the decrease in interindividual variability and residual error, led us to retain only the haematocrit in the final model. Maximum a posteriori Bayesian forecasting allowed accurate prediction of the tacrolimus AUC(12) using only three sampling times (at 0 hour [predose] and at 1 and 3 hours postdose) in addition to the haematocrit value, with a nonsignificant mean AUC bias of 2% and good precision (relative mean square error = 11%). CONCLUSION: Population pharmacokinetic analysis of tacrolimus in renal transplant recipients showed a significant influence of the haematocrit on its CL/F and led to the development of a Bayesian estimator compatible with clinical practice and able to accurately predict tacrolimus individual pharmacokinetic parameters and the AUC(12).

Diabetes mellitus after kidney transplantation: a French multicentre observational study.

BACKGROUND: New-onset diabetes mellitus (NODM)-a common complication of kidney transplantation-is associated with increases in graft loss, morbidity and mortality. METHODS: This is a purely observational study of 527 patients taking a calcineurin inhibitor (CNI), based on data collected at a single routine visit 6-24 months after kidney transplantation. Diabetes was defined according to ADA/WHO guidelines. RESULTS: The mean age of the patients was 47.2 years and 61.1% were men; 49.5% were receiving cyclosporine microemulsion (CsA-ME) and 50.5% tacrolimus (Tac). NODM developed in 7.0% after a median interval of 1.6 months. In CsA-ME-treated patients, the unadjusted cumulative risks of NODM were 5.5% and 8.4% at 1- and 2-year post-transplantation, while in Tac-treated patients, the risks were respectively 17.4% and 21%. Four independent risk factors (RFs) were identified by multivariate analysis: maximum lifetime body mass index>25 [odds ratio (OR)=5.1], pre-transplantation impaired fasting glucose (OR=4.7), hepatitis C status (OR=4.7) and Tac vs CsA-ME treatment (OR=3.0). CONCLUSIONS: NODM is associated with certain RFs present prior to kidney transplantation, and with treatment with Tac as opposed to CsA-ME.

Differential effect of CD28 versus B7 blockade on direct pathway of allorecognition and self-restricted responses.

Immunosuppression with B7 antagonists might have 2 opposite effects: reducing T-cell costimulation through CD28 but also preventing CTLA-4 from transmitting its negative regulatory signal. We therefore hypothesized that a selective blockade of CD28 might be qualitatively different from blocking B7. It was previously reported that CD28 modulation prolongs allograft survival in the rat and reverses induction of experimental autoimmune encephalomyelitis in mice. However, whether CD28 or B7 blockade results in similar immunosuppression on alloimmune and self-restricted responses to soluble antigens has not yet been investigated. Here, we addressed this issue in vitro with antagonist anti-CD28 Fab fragments and in vivo using the modulating anti-rat JJ319 monoclonal antibody. As in the inhibition of B7 with CTLA4 immunoglobulin, anti-CD28 Fab fragments inhibited allogenic T-cell proliferation in mixed cultures. In vivo modulation of CD28 blocked the expansion of alloreactive T cells and promoted their apoptosis. In contrast, selective blockade of CD28 did not modify T-cell proliferative responses and antibody production to soluble antigens, whereas blocking B7 with CTLA4 immunoglobulin did. Our data show that blocking CD28, while leaving CTLA4-B7 interactions undisturbed, inhibits alloreactive CD4+ T-cell expansion but does not modify the response to nominal antigens presented in the context of a self-major histocompatibility complex. That B7 engagement is needed for self-restricted responses whereas engagement of CD28 is not essential adds to the suggestion that another unidentified ligand of B7 might deliver a costimulatory signal in the absence of CD28.