Prior randomized trials and observational studies have generally reported similar outcomes in kidney transplant recipients (KTRs) treated with immediate-release tacrolimus (IR-TAC) versus extended-release tacrolimus (ER-TAC). However, many of these previous studies focused on patients with low immunological risks, had small sample sizes and brief follow-up periods, and excluded outcomes associated with graft loss, such as chronic rejection.

To address these limitations, we conducted a cohort study of 848 KTRs at a single transplantation center who had generally high immunological risks and were treated with either IR-TAC capsules (589 patients, 65.9%) or ER-TAC capsules (289 patients, 34.1%). All patients received their designated maintenance immunosuppressive regimen for at least 3 months post-transplantation. Afterwards, tacrolimus formulation was at the discretion of each patient's transplant nephrologist. For the two treatment groups, we compared the hazards of experiencing a composite outcome of acute or chronic antibody-mediated rejection (AMR), acute or chronic T-cell-mediated rejection, de novo DSA, and/or graft loss over a 3-year period starting at 3 months post-transplantation.

In a multivariable Cox proportional hazards regression model, KTRs treated with IR-TAC capsules had an increased hazard of experiencing the composite outcome when compared to patients treated with ER-TAC capsules; however, this result was not significant (adj HR 1.24, 95% CI .92-1.68, p = .163). Similar results were obtained with inverse probability of treatment weighting (IPTW) using a propensity score (adj HR 1.25, 95% CI .93-1.68, p = .146).

These findings suggest that when compared to IR-TAC capsules, ER-TAC capsules do not reduce the hazard of poor outcomes in KTRs with generally high immunological risks.

Tacrolimus is the most commonly prescribed medication in initial immunosuppressive regimens to prevent acute rejection in kidney transplant recipients (KTRs). Tacrolimus was originally available as an immediate-release formulation (IR-Tac) given twice daily. Extended-release tacrolimus (ER-Tac) given once daily was later developed with the expectation of improved medication adherence. Data from observational studies, which compared outcomes between ER-Tac and IR-Tac in different populations of KTRs including those who are unlikely to be enrolled in randomized clinical trials, have been reported.

To evaluate the incidence of biopsy-proven acute rejection (BPAR) at 12 months together with other outcomes reported in observational studies among adult KTRs who received ER-Tac compared to IR-Tac.

In accordance with the recommendations of the Cochrane Collaboration and the Meta-analysis of Observational Studies in Epidemiology, we systematically reviewed all observational studies that compared clinical outcomes between ER-Tac and IR-Tac in KTRs. The systematic searches were conducted on PubMed, EMBASE, Scopus, and Web of Science without language restriction. Reference lists were also searched and reviewed. Data were extracted for BPAR, graft survival, patient survival, estimated glomerular filtration rate (eGFR), serum creatinine (Scr), creatinine clearance (CrCl), at different times after kidney transplantation (KT). A meta-analysis was performed to integrate the results from the eligible studies. This study is registered with PROSPERO, number CRD42019135705.

From the 1401 articles screened, 10 observational studies in KTRs who received tacrolimus were included. The pooled results showed significantly lower BPAR with ER-Tac than with IR-Tac at 12 months post-KT (5 studies, n = 659; RR, 0.69; 95% CI 0.51-0.95; p = 0.02; I² = 0%). No significant differences in BPAR at other time points after KT were found. Graft survival, patient survival, Scr, and eGFR were comparable between groups at different times over approximately 1 year after transplantation.

Based upon currently available evidence in observational studies, 30% lower risk of BPAR was observed in ER-Tac group compared with IR-Tac group at 12 months post-KT, while there was no significant difference in BPAR risk at any other studied time points. No differences in graft- and patient-survival rates and kidney function were found. Given the limitations of observational studies to make causal inference, as well as quality limitations among the included studies, caution should be exercised in interpreting these findings.

Maintaining the exposure of tacrolimus (Tac) after kidney transplantation (KT) must be necessary to prevent acute rejection (AR) and improve graft survival，but there is still no clear consensus on the optimal Tac target blood concentration and concentration-effect relationship is poorly defined.

We conducted a dose-response meta-analysis to quantitatively assess the association between Tac blood concentration and (AR) or adverse effects after KT. A comprehensive search of PubMed, Embase and Cochrane library databases was conducted to find eligible studies up to 10th September 2018. Unpublished data from patients receiving KT in West China Hospital (Sichuan University, China) were also collected. Both twostage dose-response and one-stage dose-response meta-analysis models were used to improve the statistical power.

A total of 4967 individuals from 10 original studies and 1453 individuals from West China Hospital were eligible for the ultimate analysis. In the two-stage dose-response meta-analysis model, we observed a significant non-linear relationship between Tac blood concentration and AR (P < 0.001) with moderate heterogeneity (I2 = 46.0%, P = 0.08). Tac blood concentration at 8ng/ml was associated with the lowest risk of AR (RR: 0.26, 95%CI: 0.13 - 0.54) by reference to 2ng/ml. Tac concentration at 7.0 - 11.0 ng/ml reduced the risk of AR by at least 70%, 5-14 ng/ml by at least 60%, and 4.5 - 14 ng/ml at least 50%. In the one-stage dose-response model, we also found a strong non-linear relationship between Tac and AR (P < 0.001) with moderate heterogeneity (I2 = 41.2%, P = 0.10). Tac concentration of 7.5 ng/ml was associated with the lowest risk of AR (RR: 0.35, 95%CI: 0.16 - 0.77). The blood concentration at 5.5 - 9.5 ng/ml was associated with the reduced AR by at least 60% and 4.5 - 10.5 ng/ml by at least 50% by reference to 2 ng/ml.

Maintaining Tac blood concentration at 5 - 9.5 ng/ml within the first year may prevent AR most effectively.

PEP Study: Ethics committee N° 393/2004, EudraCT 2004-004209-98. PEP-X Study: Ethics committee amendment application N° 154/01/2008. ClinicalTrials.gov NCT03751332.

This study is to analyze concentration changes of the prolonged-release and shorter-acting formulation of tacrolimus in patients with different CYP3A5 genotypes after kidney transplantation.

A single-factor retrospective analysis was performed in patients underwent allogeneic kidney transplantation with postoperative administration of Advagraf or Prograf in our hospital from May 2013 to June 2014. The CYP3A5 genotypes were determined, and tacrolimus trough concentrations in whole blood were measured within 28days after transplantation. The rates of acute rejection rate, chronic rejection and infection were recorded and compared after one year follow-up after surgery.

The study included 106 patients administered Advagraf (45 cases) or Prograf (61 cases). The low expression genotype of CYP3A5 was detected in 40 (37.7%) patients. A higher dose of Advagraf was required to increase the tacrolimus trough concentrations within 21days after transplantation. Moreover, a higher dose for Advagraf than Prograf was required to increase the tacrolimus trough concentrations in low expression patients. In the low expression patients, Prograf more frequently achieved the target tacrolimus trough concentrations within seven days after transplantation (five days: 7.14% vs. 84%, P=0.001; seven days: 33.33% vs. 77.78%, P=0.001). The patient and kidney graft survival rates one year after transplantation both were 100%. The estimated glomerular filtration rate showed no significant difference between different CYP3A5 phenotypes or formulations of tacrolimus (P>0.05). However, the incidence of infections was higher in the Advagraf group in low expression patients (P<0.05).

Tacrolimus of different formulations had different impact on patients with different CYP3A5 genotypes after kidney transplantation.

The efficacy and safety of tacrolimus twice-a-day (BID) and once-a-day (QD) formulations are similar. However, the available information regarding the initiation and management of tacrolimus QD is sparse and practical information is lacking. A panel of French experts extensively reviewed the available literature on tacrolimus pharmacokinetics, clinical efficacy, and safety in kidney transplantation and, based on their own day-to-day experience, provided the practitioners with practical guidelines for the daily use and management of tacrolimus QD in de novo initiation or early conversion.

A once-daily modified release formulation of oral tacrolimus (Tac QD) has been developed in response to the problem of nonadherence. However, there have been no data available about the efficacy of Tac QD conversion from intravenous Tac (Tac i.v.) in allogeneic hematopoietic stem cell transplantation (allo-SCT). We analyzed the pharmacokinetics (PK) of Tac QD in allo-SCT recipients. A total of 10 patients with hematological malignancies who received allo-SCT from unrelated donors were enrolled. Patients received Tac i.v. at 0.03 mg/kg a day before transplantation. Administration of Tac i.v. was converted to Tac QD at a 1:4 ratio when the patients had recovered from regimen-related gastrointestinal toxicity and could tolerate oral medication. After conversion, six out of 10 patients (60 %) showed a sustained decrease in Tac exposure and required dose adjustment. The conversion from Tac i.v. to Tac QD should be performed under close medical supervision. Area under the curve (AUC) and the trough of Tac QD showed a correlation, and the trough should be maintained above 7.5 ng/ml to provide an adequate AUC. Although four patients received bone marrow from an HLA DRB1 1 antigen-mismatched unrelated donor, no patients developed grade III-IV acute graft-versus-host disease (GVHD). The modification of Tac QD to maintain a whole-blood trough concentration above 7.5 ng/ml may be as effective as Tac BID.

The purpose of this study was to compare once-daily tacrolimus with twice-daily tacrolimus in terms of safety, efficacy, and patient satisfaction.

This prospective, randomized, open-label, multicenter study was conducted at three institutes. Patients in the investigational group were converted from tacrolimus twice daily to the same dose of extended-release tacrolimus once daily at 1 month post-transplantation, while patients in the control group were maintained on tacrolimus twice daily. The efficacies, safeties, and patient satisfaction for the two drugs at 6 months post-transplantation were compared.

Sixty patients were enrolled and randomized to the investigational group (28 of 29 patients completed the study) or the control group (26 of 31 patients completed the study). At 6 months post-transplantation, composite efficacy failure rates including the incidences of biopsy-confirmed acute rejection in the investigational and control groups were 0% and 10.7%, respectively; patient survival was 100% in each group. No difference in estimated glomerular filtration rate values were observed at 6 months post-transplantation (p=0.97). The safety and satisfaction profile (immunosuppressant therapy barrier scale) of once-daily tacrolimus was comparable with that of twice-daily tacrolimus (p=0.35).

Conversion from twice-daily tacrolimus to once-daily tacrolimus one month after transplantation is safe and effective.

According to the clinical trials, Advagraf (ADV) has efficacy and safety profile similar to Prograf (PROG). The aim of this study was to compare the graft functions, dosages, and tacrolimus (TAC) trough level profile curves of patients on de novo PROG and ADV therapy.

The ADV group included 39 de novo renal cases who had received initial immunosuppression (IS) with once-daily TAC (1 × 0.2 mg/kg from day1 after transplantation). We compared them with a PROG group of 38 transplant patients who received equivalent IS with twice-daily TAC (2 × 0.1 mg/kg from day1). In both groups, the IS was combined with antimetabolites and steroids. The mean follow-up time was similar (13.5 ± 7 days) in both groups after renal transplantation until the emission of the patients from our clinic.

TAC mean total daily dose was reduced and whole-blood trough levels decreased over the time in early postoperative days. Only on day 3 and day 4 after transplant, a significant higher adjustment in the ADV dosage was necessary to achieve sufficient TAC trough levels. The average TAC trough level profile curves were similar in PROG and ADV groups, but the individual curves were very different. Mainly in patients on ADV therapy, the initial concentrations were often >30 ng/mL, and in some cases on the 9th posttransplant day decreased to <5 ng/mL, then slowly increased into the required therapeutic range.

The results demonstrate that patients after renal transplantation can be safely treated de novo with ADV. Setting the required therapeutic TAC blood levels may require more attention to avoid the "fluctuations" of trough level profile curve during the early postoperative period. Our data suggest that dose adjustment of ADV can be carried out more carefully compared with PROG on the basis of clinical symptoms and the value of TAC blood levels to avoid acute rejection and toxicity.

Excellent outcomes have been achieved in the field of renal transplantation. A significant reduction in acute rejection has been attained at many renal transplant centers using contemporary immunosuppressive, consisting of an induction agent, a calcineurin inhibitor, an antiproliferative agent plus or minus a corticosteroid. Despite improvements with these regimens, chronic allograft injury and adverse events still persist. The perfect immunosuppressive regimen would limit or eliminate calcineurin inhibitors and/or corticosteroid toxicity while providing enhanced allograft outcomes. Potential improvements to the calcineurin inhibitor class include a prolonged release tacrolimus formulation and voclosporin, a cyclosporine analog. Belatacept has shown promise as an agent to replace calcineurin inhibitors. A novel, fully-human anti-CD40 monoclonal antibody, ASKP1240, is currently enrolling patients in phase 2 trials with calcineurin minimization and avoidance regimens. Another future goal of transplant immunosuppression is effective and safe treatment of allograft rejection. Novel treatments for antibody mediated rejection include bortezomib and eculizumab. Several investigational agents are no longer being pursed in transplantation including the induction agents, efalizumab and alefacept, and maintenance agents, sotrastaurin and tofacitinib. The purpose of this review is to consolidate the published evidence of the effectiveness and safety of investigational immunosuppressive agents in renal transplant recipients.

With effective agents available to prevent posttransplantation acute organ rejection, medication adherence becomes a key factor for successful treatment outcomes after renal transplantation. A once-daily, modified-release oral formulation of tacrolimus has been developed to simplify dosing and improve medication adherence.

Adherence Measurement in Stable Renal Transplant Patients Following Conversion From Prograft to Advagraf is a randomized multicenter controlled trial to evaluate adherence between a tacrolimus once-daily regimen and a tacrolimus twice-daily regimen using an electronic monitor to document drug intake. After enrolment, all patients continued the twice-daily regimen for 3 months and then were randomized 2:1 between the two formulations and followed for 6 months. Adherence was decomposed into patients' persistence and implementation of each regimen.

Two hundred nineteen patients (45% male; 3±2 years after transplantation) were analyzed (145 once daily and 74 twice daily). At 6 months after randomization, 81.5% of the once-daily group and 71.9% of the twice-daily group remained persistent with the treatment (P=0.0824). Among patients who remained engaged with the regimen, 88.2% of the once-daily group and 78.8% of the twice-daily group (P=0.0009) took the prescribed number of daily doses. When the patients took the twice-daily regimen, the average percentage of missed doses was 11.7% in the morning and 14.2% in the evening (P=0.0035).

Regimen implementation of tacrolimus once daily is significantly superior to the twice-daily regimen. There was a residual prevalence of suboptimal adherence that will have to be countered by means other than reformulation and regimen simplification. Electronically compiled dosing histories provide detailed data on patient adherence that can be used for efficient medication management.

For kidney transplant recipients, immunosuppression commonly consists of combination treatment with a calcineurin inhibitor, an antiproliferative agent and a corticosteroid. Many medical centers use a sequential immunosuppression regimen where an induction agent, either an anti-thymocyte globulin or interleukin-2 receptor antibody, is given at the time of transplantation to prevent early acute rejection which is then followed by a triple immunosuppressive maintenance regimen. Very low rejection rates have been achieved at many transplant centers using combinations of these agents in a variety of protocols. Yet, a large number of recipients suffer chronic allograft injury and adverse events associated with drug therapy. Regimens designed to limit or eliminate calcineurin inhibitors and/or corticosteroid use are actively being pursued. An ideal immunosuppressive regimen limits toxicity and prolongs the functional life of the graft. This article contains a critical analysis of clinical data on currently available immunosuppressive strategies and an overview of therapeutic moieties in development.

We initially performed a study to evaluate the safety and efficacy of modified-release tacrolimus (FK506E) in a phase 3, 2-arm, 6-month, randomized, open-label, multicenter trial in Korean living donor de novo kidney transplant recipients. We then performed an extended study to evaluate the long-term safety and efficacy of a FK506E-based regimen up to 45 months posttransplantation in recipients already treated with FK506E.

Initial study was designed as a randomized, open-label, comparative, multicenter study in de novo living donor kidney transplant recipients. The patients were randomized to an FK506E versus a control (FK506) group (1:1). Recipients who completed a 6-month FK506E treatment study were enrolled in the 39-month follow-up study. Primary end-points were patient and graft survivals at posttransplantation 45 months. Secondary end-point was the incidence of a clinical or biopsy-proven acute rejection episode between 6 and 45 months posttransplantation.

In the initial 6-month de novo study 124 enrolled patients were randomized into either the FK506E (n = 62) or the control group (n = 62). The incidence of an acute rejection episode was 19.4% (n = 12) in the FK506E versus 16.1% (n = 10) in the control group (P = .638). There was no mortality or graft failure among the 44 recipients enrolled in this additional 39-month follow-up study. There was 1 patient with biopsy-proven acute cellular rejection episode (2.3%) who underwent steroid pulse therapy with renal function recovery. At the time of study completion 40/44 recipients (90.9%) maintained FK506E treatment.

This 39-month study following the initial 6-month FK506E study period showed an FK506E-based immunosuppressive regimen in living donor kidney transplantation recipients to be safe and effective.