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

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 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<0.0001 for all). No such influence was found on C0 or C24h, while the AUC0-24h was significantly higher on D8 than at M3. The AUC0-24h/C0 ratio was not affected by the drug formulation and the polymorphisms studied, but it was significantly lower on D8 than at M3 (p=7.8×10-5). In contrast, both the post-transplantation period (p=1.53×10-4), and CYP3A5 expression (p=0.003) had a significant influence on the AUC0-24h/C24h ratio, explaining 19% and 12% of its variability, respectively. Consistently, for both Tac formulations, the AUC0-24h was better correlated with C24h than C0, and for Tac-BID the AUC0-12h 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, 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 3h, thus giving access to the actual overall exposure.

ADHERE: randomized controlled trial comparing renal function in de novo kidney transplant recipients receiving prolonged-release tacrolimus plus mycophenolate mofetil or sirolimus.

ADHERE was a randomized, open-label, Phase IV study comparing renal function at Week 52 postkidney transplant, in patients who received prolonged-release tacrolimus-based immunosuppressive regimens. On Days 0-27, patients received prolonged-release tacrolimus (initially 0.2 mg/kg/day), corticosteroids, and mycophenolate mofetil (MMF). Patients were randomized on Day 28 to receive either prolonged-release tacrolimus plus MMF (Arm 1) or prolonged-release tacrolimus (≥25% dose reduction on Day 42) plus sirolimus (Arm 2). The primary endpoint was glomerular filtration rate by iohexol clearance (mGFR) at Week 52. Secondary endpoints included eGFR, creatinine clearance (CrCl), efficacy failure (patient withdrawal or graft loss), and patient/graft survival. Tolerability was analyzed. The full-analysis set comprised 569 patients (Arm 1: 287; Arm 2: 282). Week 52 mean mGFR was similar in Arm 1 versus Arm 2 (40.73 vs. 41.75 ml/min/1.73 m2 ; P = 0.405), as were the secondary endpoints, except composite efficacy failure, which was higher in Arm 2 versus 1 (18.2% vs. 11.5%; P = 0.002) owing to a higher postrandomization withdrawal rate due to adverse events (AEs) (14.4% vs. 5.2%). Results from this study show comparable renal function between arms at Week 52, with fewer AEs leading to study discontinuation with prolonged-release tacrolimus plus MMF (Arm 1) versus lower dose prolonged-release tacrolimus plus sirolimus (Arm 2).

Comparison of the AN69ST Membrane versus Citrate-Enriched Dialysate on Clotting Events during Hemodialysis without Systemic Anticoagulation.

BACKGROUND: The optimal management of anticoagulation in hemodialyzed patients with a high risk of bleeding is controversial. METHODS: We compared premature termination of dialysis caused by clotting events between AN69ST membranes (G1) and 0.8 mmol/L citrate-enriched dialysate (G2). The number of sessions that had increased venous pressure (VP) and variations in urea-reduction ratio (URR) were analyzed. RESULTS: Six hundred and two sessions were analyzed in 259 patients: 22.4% had sessions that ended prematurely (25% in G1 and 19.1% in G2, p = ns, OR 0.60 [0.34-1.08], p = 0.08). The increase in VP was lower in G2 (23 vs. 70, p < 0.001). URR was higher in G2 (0.56 vs. 0.60, p < 0.001). CONCLUSION: Clotting events that led to the termination of dialysis were comparable in the 2 groups. However, UUR was better in G2, and the number of patients with increased VP in the sessions was lower in G2. SHORT SUMMARY: Our study compared the effects of the AN69ST membrane and citrate-enriched dialysate on clotting events during the dialysis of 259 patients with a high risk of bleeding. URR was significantly better and fewer cases of increased VP occurred in the citrate group compared to the AN69 ST group. No significant difference was observed regarding the need to prematurely terminate a dialysis session.

Cannabinoid receptor 1 is a major mediator of renal fibrosis.

Chronic kidney disease, secondary to renal fibrogenesis, is a burden on public health. There is a need to explore new therapeutic pathways to reduce renal fibrogenesis. To study this, we used unilateral ureteral obstruction (UUO) in mice as an experimental model of renal fibrosis and microarray analysis to compare gene expression in fibrotic and normal kidneys. The cannabinoid receptor 1 (CB1) was among the most upregulated genes in mice, and the main endogenous CB1 ligand (2-arachidonoylglycerol) was significantly increased in the fibrotic kidney. Interestingly, CB1 expression was highly increased in kidney biopsies of patients with IgA nephropathy, diabetes, and acute interstitial nephritis. Both genetic and pharmacological knockout of CB1 induced a profound reduction in renal fibrosis during UUO. While CB2 is also involved in renal fibrogenesis, it did not potentiate the role of CB1. CB1 expression was significantly increased in myofibroblasts, the main effector cells in renal fibrogenesis, upon TGF-ß1 stimulation. The decrease in renal fibrosis during CB1 blockade could be explained by a direct action on myofibroblasts. CB1 blockade reduced collagen expression in vitro. Rimonabant, a selective CB1 endocannabinoid receptor antagonist, modulated the macrophage infiltrate responsible for renal fibrosis in UUO through a decrease in monocyte chemoattractant protein-1 synthesis. Thus, CB1 has a major role in the activation of myofibroblasts and may be a new target for treating chronic kidney disease.

Protein A immunoadsorption cannot significantly remove the soluble receptor of urokinase from sera of patients with recurrent focal segmental glomerulosclerosis.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a serious disease, the pathogenesis of which is unknown. Its recurrence after transplantation (Tx) and its partial remission after treatment with immunoadsorption (IA) on a protein A column indicate the existence of a circulating factor responsible for the disease that is able to bind to a protein A column. Recently, the soluble receptor of urokinase (suPAR) was described as the factor responsible for FSGS. We tested the capacity of suPAR to bind to protein A and to be eliminated by IA. METHODS: We measured suPAR in eluates of protein A columns from seven patients with recurrent FSGS after Tx (rFSGS) treated with IA, and in the serum of 13 patients with rFSGS and 11 healthy donors (HDs). Additionally, the plasma of these patients was immunoadsorbed in vitro on a protein A Sepharose column, and we quantified suPAR in the eluates and in pre- and post-column samples. RESULTS: The concentration of suPAR was higher in the plasma of patients with rFSGS than that of HD patients. However, the concentration of suPAR was similar before and after IA on protein A for the rFSGS and HD samples. The suPAR concentration was very low in the eluates from protein A columns incubated with plasma from HD or rFSGS patients. However, 85% of rFSGS patients showed a decrease in immunoglobulin G and proteinuria. CONCLUSIONS: Thus, suPAR does not significantly bind to protein A in vitro or in vivo.

[Necessary but sometimes complicated coordination of healthcare procedures. The example of chronic renal failure]. / Une coordination des soins nécessaire mais parfois compliquée. Exemple de l'insuffisance rénale chronique.

Chronic renalfailure (CRF), one of several disorders involving progressive loss of function of a vital organ, is a paradigm for medical/paramedical coordination networks, especially in view of the explosion of the geriatric CRF/dialysis population. An efficient network is crucial in this setting, given the very high incidence of CRF, its cost, its impact on employment, quality of life and quality of care; and the progression from medical treatment to replacement therapy (peritoneal or hemodialysis) and, eventually, organ transplantation from a living or deceased donor. There is a constant flow of patients entering and exiting care pathways between community practices (public or private), hospitals (general or teaching), medical laboratories, pharmacies (commuity and hospital) and a large number of allied health professions (nurses, social workers, dieticians, physiotherapists, secretaries, etc.). In the predialytic stage of CRF the goal of the network is to establish the diagnosis, slow disease progression, prevent or treat the many potentially complications, inform patients and their families, and postpone the need for dialysis and transplantation. When renal replacement therapy becomes necessary, the choice between peritoneal dialysis and hemodialysis follows strict rules and requires a more technical approach, with predominant involvement of the nephrologist. Finally, transplantation is highly hospital-centered, but patient monitoring in the community requires an approach very similar to that of the predialytic stage, with the involvement of specialists in internal medicine/general practitioners, as the potential complications cover a very broad field of disciplines (infectious, cardiovascular, metabolic, cancer). CRF is a major public health problem that requires a network-based approach involving multiple specialties and skills, the most difficult problem being its coordination. A similar approach can probably be extrapolated to other patients with chronically failing major organs (liver, lungs, heart).

Liver-kidney recipients with chronic viral hepatitis C treated with interferon-alpha.

Antiviral therapy with interferon-alpha (IFN-alpha) and pegylated IFN-alpha (PEG-IFN-alpha) for chronic hepatitis C (HCV)-infected kidney recipients remains controversial. IFN-alpha is not recommended in most cases because it induces severe acute graft rejection. However, IFN-alpha, as PEG-IFN-alpha, is associated with a more pronounced immune response, and is well tolerated in HCV-infected liver recipients without causing graft rejection. In combined liver-kidney transplant (LKT) recipients, IFN-alpha has been occasionally used and appears to be well tolerated. All LKT recipients with a functioning kidney and liver having a HCV replication and who needed IFN-alpha therapy have been included in the study. The occurrence of liver and/or renal acute rejection as well as the HCV replication has been collected. A total of 12 LKT patients treated with PEG-IFN-alpha plus ribavirin have been studied. No acute rejection was observed. Renal function remained stable during and after discontinuing treatment, without any graft dysfunction. Two patients had a partial viral response and four had a sustained viral response. All patients, whatever their viral response, had decreased liver-enzyme levels. Response to PEG-IFN-alpha therapy was correlated with steroid dose and transaminase level when PEG-IFN-alpha was started. These data suggest that the combination therapy of PEG-IFN-alpha plus ribavirin did not have a higher risk of acute kidney-graft rejection after liver-kidney transplantation.

Surgical prevention and management of vascular complications of kidney transplantation.

The main surgical changes in kidney procurement, preparation, and transplantation procedures occurred 20 years ago and were undertaken despite the inability to design randomized studies. The objective was to assess the evolution of vascular complications after kidney transplantation in a setting of surgical preventive measures in a historical series. A monocentric series of 3129 consecutive kidney transplantations performed over 3 decades was reviewed. The occurrence of arterial or venous thromboses, stenoses, and aneurysms was analyzed in relation with kidney procurement, preparation, and transplantation techniques. Vascular complications occurred in 13.5% of the recipients with a mean 3-year decrease in kidney graft function. The transplantation of a right kidney without renal vein extension, multiple renal arteries, ex vivo vascular repairs, and end-to-end arterial anastomoses were the unfavorable surgical vascular factors. It was possible to manage Transplant Renal Artery Stenosis (TRAS) nonsurgically in 80% of the cases. The prevention of vascular complications begins from the time of organ procurement by skilled surgeons. The aims of organ preparation are to evaluate the vascular risk, select the organs, and to simplify the anatomical constraints of vascular implantations. The three surgical steps of kidney transplantation are determinant in postoperative vascular complications and the duration of graft function.

Maturity onset diabetes of the young: clinical characteristics and outcome after kidney and pancreas transplantation in MODY3 and RCAD patients: a single center experience.

The diabetes and renal phenotype of patients with maturity-onset diabetes of the young (MODY) on a transplantation waiting list is not known; neither is their outcome after pancreas (PT) and/or kidney transplantation (KT). Between 2002 and 2009, we screened 50 of 150 patients referred for kidney and pancreas transplantation to the Kremlin-Bicêtre center for HNF1B and HNF1A mutations if one or more of the following criteria was present (i) an atypical history of diabetes (ii) diabetes with at least one affected parent or two affected relatives, (iii) an absence of auto-antibodies at diagnosis (iv) a persistent secretion of fasting C peptide (v) a personal or a family history of renal cysts or dysplasia. Their phenotype and their outcome were analyzed. Four HNF1A (MODY3) and eight HNF1B mutations [renal cysts and diabetes (RCAD)] were identified. All MODY3 patients had diabetic nephropathy, but only 50% of RCAD patients. Four patients underwent a kidney and pancreas transplantation and two a kidney transplant alone. After 4.1 ± 1.1 years of follow-up, 83% of patients still have a functioning kidney and 75% a functioning pancreas. PT can be proposed with good results for MODY3 and RCAD patients.

Dendritic cells secrete the immunosuppressive HLA-G molecule upon CTLA4-Ig treatment: implication in human renal transplant acceptance.

CTLA4-Ig (Belatacept) is a new recombinant molecule that interferes with the signal of T lymphocyte activation and prevents acute rejection after renal transplantation. HLA-G acts as a naturally tolerogenic molecule in humans. In this study, we analyzed whether HLA-G contributes to CTLA4-Ig-mediated graft acceptance. Our results demonstrate that patients treated with CTLA4-Ig displayed significantly higher soluble HLA-G (sHLA-G) plasma concentrations (72 +/- 14 ng/ml) than patients treated with calcineurin inhibitors (5 +/- 1 ng/ml) or healthy donors (5 +/- 5 ng/ml). Notably, sHLA-G purified from plasma of CTLA4-Ig-treated patients was biologically active as it inhibited allogeneic T cell proliferation in vitro. Dendritic cells (DC) were identified as one of the cellular sources of sHLA-G in CTLA4-Ig-treated patients. Supporting this observation, we showed that DC generated in vitro in presence of CTLA4-Ig released sHLA-G in response to allostimulation. These CTLA4-Ig-treated DC acted as tolerogenic APC through sHLA-G secretion as they suppressed T cell alloproliferation, which could be restored by using a neutralizing anti-HLA-G Ab. These data define a novel pathway by which CTLA4-Ig immunomodulates allogenic response through posttranscriptional regulation of HLA-G expression in DC. CTLA4-Ig-mediated HLA-G release appears as a critical factor in T cell alloresponse inhibition, thereby contributing to the immunosuppressive effect and graft acceptance.

Report of depressive symptoms on waiting list and mortality after liver and kidney transplantation: a prospective cohort study.

BACKGROUND: Little research has explored pre-transplantation psychological factors as predictors of outcome after liver or kidney transplantation. Our objective is to determine whether report of depressive symptoms on waiting list predicts outcome of liver and kidney transplantation. METHODS: Patients on waiting list for liver or kidney transplantation were classified for report or non-report of depressive symptoms on waiting list. 339 were transplanted 6 months later on average, and followed prospectively. The main outcome measures were graft failure and mortality 18 months post-transplantation. RESULTS: Among the 339 patients, 51.6% reported depressive symptoms on waiting list, 16.5% had a graft failure and 7.4% died post-transplantation.Report of depressive symptoms on waiting list predicted a 3 to 4-fold decreased risk of graft failure and mortality 18-months post-transplantation, independently from age, gender, current cigarette smoking, anxiety symptoms, main primary diagnosis, UNOS score, number of comorbid diagnoses and history of transplantation. Data were consistent for liver and kidney transplantations. Other baseline predictive factors were: for graft failure, the main primary diagnosis and a shorter length since this diagnosis, and for mortality, older age, male gender and the main primary diagnosis. CONCLUSION: Further studies are needed to understand the underlying mechanisms of the association between report of depressive symptoms on waiting list and decreased risk of graft failure and mortality after transplantation.

Efficacy and safety of the H1N1 monovalent vaccine in renal-transplant recipients and dialysis patients.

BACKGROUND: The (H1N)1v influenza virus infection emerged in 2009 as a serious disease in targeted populations. Herein, we report on the tolerability and efficacy of (anti-H1N1)v vaccination in dialysis and transplant patients. METHODS: 18 renal-transplant recipients (RTR) and 19 dialysis patients (DP) [12 patients treated with peritoneal dialysis (PDP), 7 patients treated with haemodialysis (HDP)] were enrolled. DPs received one monovalent H1N1 adjuvanted-vaccine injection, and RTRs received two unadjuvanted vaccine injections within a 21-day period. Serologic response was defined as a haemagglutination inhibition titre of > 40 (seroprotection) and/or at least a four-fold increase in antibody titre from baseline (seroconversion). RESULTS: Seroprotection rate after vaccination was greater in DPs than RTRs (p = 0.007), as was seroconversion (p = 0.001). Serologic response was similar in PDPs and HDPs. CONCLUSIONS: Serologic response was satisfactory in DPs, whichever dialysis mode (DPD or HDP). It was low in RTRs as compared to DPs.

Five-year safety and efficacy of belatacept in renal transplantation.

Belatacept is a first-in-class co-stimulation blocker in development for primary maintenance immunosuppression. A Phase II study comparing belatacept with cyclosporine (CsA) for prevention of acute rejection and protection of renal function in kidney transplant recipients demonstrated similar efficacy and significantly higher measured GFR at 1 year for belatacept, but the incidence of posttransplantation lymphoproliferative disorder was higher. Here, we present the results for the extension of this trial, which aimed to assess long-term safety and efficacy of belatacept. Seventy-eight of 102 patients who were receiving belatacept and the 16 of 26 who were receiving CsA completed the long-term extension period. GFR remained stable in patients who were receiving belatacept for 5 years, and the incidences of death/graft loss or acute rejection were low. The frequencies of serious infections were 16% for belatacept and 27% for CsA, and neoplasms occurred in 12% of each group. No patients who were treated with belatacept and one patient who was treated with CsA developed posttransplantation lymphoproliferative disorder during the follow-up period. Serious gastrointestinal disorders occurred more frequently with belatacept (12% belatacept versus 8% CsA), and serious cardiac disorders occurred more frequently with CsA (2% belatacept versus 12% CsA). Pharmacokinetic analyses showed consistent exposure to belatacept over time. CD86 receptor saturation was higher in patients who were receiving belatacept every 4 weeks (74%) compared with every 8 weeks (56%). In conclusion, this study demonstrated high patient persistence with intravenous belatacept, stable renal function, predictable pharmacokinetics, and good safety with belatacept over 5 years.

[History of medical progress in renal transplantation: a review of 3,000 consecutive kidney grafts at Bicetre-Kremlin, Bicetre University Hospital - France]. / Histoire du progrès médical en transplantation rénale. A propos d'une série de 3 000 transplantations consécutives réalisées dans le CHU de Bicêtre.

Major medical progress has been made in the field of renal transplantation over the last 40 years, thanks to advances in areas such as metabolism, immunology, therapeutics, and pathology. This progress has been accompanied by important changes in French legislation that governs organ harvest and transplantation, as well as the institutions that regulate organ allocation. Patient and graft survival have both increased markedly, although long-term improvements have been somewhat offset by complications, including adverse effects of immunosuppression. On average recipients are older than in the past and some recipients are now dying from age-related comorbidities despite having functional grafts.

[Use of new non-nephrotoxic immunosuppressive drugs in kidney transplantation, especially after ischemia-reperfusion injury]. / Utilisation de nouvelles molécules immunosuppres- sives non néphrotoxiques en transplantation rénale, en particulier après lésions d'ischémie-reperfusion.

Medium- and long-term renal graft survival depends on 4 main factors: the quality of the harvested graft, ischemia-reperfusion injury during harvesting and re-implantation, rejection, and the nephrotoxicity of certain drugs (especially immunosuppressants) used in this setting. The most nephrotoxic immunosuppressive drugs are the anticalcineurins (cyclosporine A and tacrolimus), a class discovered in the late 1970s and currently representing a basic component of all immunosuppressive protocols for solid organ graft recipients. The renal tubular and vascular toxicity of anticalcineurins is due to their immunosuppressive mechanism: they block the calcineurin pathway and thereby prevent transmission of the first signal from the T cell receptor to the nucleus, which normally triggers cytokine synthesis, New non-nephrotoxic immunosuppressants are therefore needed, especially for grafts of poor quality or subject to severe ischemia-reperfusion injury. Attention is turning to "old " molecules such as anti-thymocyte globulins, but exciting new immunosuppressants are now appearing. Alefacept is a fusion protein that binds to the immunological synapse-associated molecule CD2, which normally interacts with LFA-3. Belatacept, another fusion protein, blocks the T cell second signal CD 28-B7.1/B7.2. Finally, new chemical agents are being developed, such as sautrasporine, a tyrosine kinase inhibitor, and tofacitinib, a Jak inhibitor.

Expanding the criteria of renal kidneys for transplantation: use of donors with acute renal failure.

BACKGROUND: Increased numbers of patients waiting for renal transplantation have led to widening selection criteria for grafts. Thus, we have evaluated the outcome of transplanted kidneys procured in the presence of acute renal failure (ARF). METHODS: Transplant patients (n = 52) with a kidney procured with ARF were studied. Clinical data from donors and recipients, serum creatinine (SCr), creatinine clearance [estimated glomerular filtration rate (eGFR)], cold ischaemia duration, time to urine flow recovery or renal function recovery, and the number of haemodialysis sessions, were collected retrospectively. RESULTS: Mean donor age was 45.7 +/- 12.7 years, and the mean SCr at the time of harvesting was 276.3 +/- 104.2 micromol/l. Recipients' mean age was 51.1 +/- 12.1 years. After transplantation, recovery of renal function was observed after 7.6 +/- 7.1 days, and required 1.9 +/- 3.0 haemodialysis sessions. SCr was 124.6 +/- 49.5 micromol/l, and eGFR was 56.2 +/- 19.8 ml/min at last follow-up. eGFR was significantly lower if the donor's death was due to stroke or cerebral haemorrhage (CH), or if the donors had previous cardiovascular disease (CVD) (P < 0.02). Patients with eGFR of <50 ml/min (n = 23) had donors who were older, and whose cause of death was more frequently related to CVD factors or to CH/stroke (P < 0.03). There were no significant differences between the two groups regarding age of recipient, gender of the donor or recipient, cold ischaemia time, occurrence of cardiac arrest, collapse or acute rejection. Linear regression analysis indicated that donor age and occurrence of acute rejection were independent factors associated with eGFR. CONCLUSIONS: ARF before organ procurement does not have a negative effect on subsequent renal function. However, old age, CVD risk factors or CH, and late renal function recovery after transplantation are correlated with subsequent lower renal function. Thus, renal grafts with ARF can be used for renal transplantations.

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.

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.

Daclizumab versus antithymocyte globulin in high-immunological-risk renal transplant recipients.

Nondepleting anti-CD25 monoclonal antibodies (daclizumab) and depleting polyclonal antithymocyte globulin (Thymoglobulin) both prevent acute rejection, but these therapies have not been directly compared in a high-risk, HLA-sensitized renal transplant population. We randomly assigned 227 patients, who were about to receive a kidney graft from a deceased donor, to either Thymoglobulin or daclizumab if they met one of the following risk factors: current panel reactive antibodies (PRA) >30%; peak PRA >50%; loss of a first kidney graft from rejection within 2 yr of transplantation; or two or three previous grafts. Maintenance immunosuppression comprised tacrolimus, mycophenolate mofetil, and steroids. Compared with the daclizumab group, patients treated with Thymoglobulin had a lower incidence of both biopsy-proven acute rejection (15.0% versus 27.2%; P = 0.016) and steroid-resistant rejection (2.7% versus 14.9%; P = 0.002) at one year. One-year graft and patient survival rates were similar between the two groups. In a comparison of rejectors and nonrejectors, overall graft survival was significantly higher in the rejection-free group (87.2% versus 75.0%; P = 0.037). In conclusion, among high-immunological-risk renal transplant recipients, Thymoglobulin is superior to daclizumab for the prevention of biopsy-proven acute rejection, but there is no significant benefit to one-year graft or patient survival.

Progressive increase of anxiety and depression in patients waiting for a kidney transplantation.

Because of the increasing duration of the waiting-list period for kidney transplantation, we hypothesized that this period was associated with a progressive increase in depressive and anxious symptoms in patients waitlisted for a kidney transplantation. In a prospective naturalistic follow-up cohort study, 390 patients on a waiting list for kidney transplant were assessed for anxiety and depression at the time of inclusion on the waiting list, 12 months later, 24 months later, and 3 months after transplantation. The Beck Depression Inventory-Short Version (Short-BDI) and the State and Trait Anxiety Inventory (STAI) were used for this assessment. We found that in this sample, anxious and depressive symptoms progressively increased before transplantation and showed a marked decrease after transplantation. We conclude that to limit anxious and depressive symptoms in patients waiting for a kidney transplantation, the duration of the waiting list period should be reduced as far as possible.

Co-signals in organ transplantation.

PURPOSE OF REVIEW: The nonimmune effects of currently used immunosuppressive drugs result in a high incidence of late graft loss due to nephrotoxicity and death. As an immune-specific alternative to conventional immunosuppressants, new biotechnology tools can be used to block the costimulation signal of T-cell activation. RECENT FINDINGS: Many experimental studies, particularly preclinical studies in nonhuman primates, have focused on blocking 'classical' B7/CD28 and CD40/CD40L pathways, which are critical in primary T-cell activation, but also on new B7/CD28 and TNF/TNF-R pathways families of costimulatory molecules that can deliver positive or negative costimulation signals to regulate the alloimmune response. SUMMARY: Belatacept is a new fusion protein derived from CTLA4-Ig that can be used to prevent acute rejection in renal transplantation instead of calcineurin inhibitors. Belatacept can also prevent acute rejection efficiently in humans and, more interestingly, can improve renal function and cardiovascular risk factors in this population.