Standard-dose Tacrolimus Research Articles

Advances in understanding and managing pediatric heart failure and transplant.

This article highlights the most recent advances in a review of the current literature in the field of pediatric heart failure and transplantation. Diagnostically, the identification of new genetic factors has contributed to a deeper understanding of cardiomyopathy in children. Novel medications like sacubitril/valsartan and Sodium-Glucose cotransporter-2 (SGLT2) inhibitors, which are now standard in the adult population are being studied in pediatric population and offer new promise of pediatric heart failure treatment. Ventricular assist devices are more commonly used in cardiomyopathy patients and single ventricle patients as a bridge to transplant. Recent pediatric heart transplant society (PHTS) data demonstrated that waitlist survival improved significantly over the past decades (i) and new treatments such as daratumumab and eculizumab have been used in high-risk populations and demonstrate promising results. TEAMMATE trial is the first multicenter randomized clinical trial (RCT) in pediatric heart transplant (HT) to evaluate the safety and efficacy of everolimus (EVL) and low-dose tacrolimus (TAC) compared to standard-dose TAC and mycophenolate mofetil (MMF). It will provide valuable information about the safety and efficacy of EVL, TAC, and MMF (ii).Donor cell-free DNA has been used more in pediatric transplant recipients and has significantly decreased invasive EMB (iii). This past 5 years have witness dramatic progress in the field of pediatric heart failure and transplantation including more use of mechanical support in heart failure patients with various underlying etiology, especially use of mechanical support in single ventricle patients and the use of sacubitril/valsartan and SGLT2 inhibitors in the pediatric population. The problem of the highly sensitized transplant recipient remains, although novel therapeutics have been added to our toolbox of options to maintain healthy allograft function. Ongoing research aims to further enhance our understanding and management of pediatric heart failure, emphasizing the need for continued innovation in this complex field.

1438-P: Diabetes after Cardiac Transplant with Low-Dose Everolimus and Tacrolimus

Background: Although modern immunosuppressants improve survival post-transplant, they are associated with long-term metabolic complications, such as post-transplant diabetes mellitus (PTDM). Calcineurin inhibitor-sparing regimens using everolimus attenuate some complications such as left ventricular hypertrophy. However, the metabolic effects of everolimus following transplant are less clear. Aims: To compare incidence of diabetes in heart transplant recipients exposed to low-dose everolimus and tacrolimus versus standard-dose tacrolimus. Methods: Post-hoc analysis in participants of a randomised open-label clinical trial of low-dose everolimus and tacrolimus versus standard-dose tacrolimus in heart transplant recipients. Results: There were 39 participants in the trial, mean follow up was 6.4 ± 1.5 years. There was a high rate of pre-existing diabetes (26%) and newly-diagnosed PTDM (36%) during follow-up (Figure 1). Half the patients who developed PTDM in the everolimus-tacrolimus group (n=4/8) ceased diabetes medications during follow-up, which was not observed in patients on standard tacrolimus (n=0/6). Conclusion: This study suggests that treatment with everolimus may improve PTDM outcomes relative to treatment with standard doses of calcineurin inhibitor. These findings should be further studied in prospective randomised trials. Disclosure L.M.Raven: None. C.A.Muir: None. J.Pouliopoulos: None. P.S.Macdonald: Advisory Panel; AstraZeneca, Boehringer Ingelheim Inc., Other Relationship; Novartis. A.Jabbour: None. J.Greenfield: None.

The teammate trial: Study design and rationale tacrolimus and everolimus against tacrolimus and MMF in pediatric heart transplantation using the major adverse transplant event (MATE) score

Currently there are no immunosuppression regimens FDA-approved to prevent rejection in pediatric heart transplantation (HT). In recent years, everolimus (EVL) has emerged as a potential alternative to standard tacrolimus (TAC) as the primary immunosuppressant to prevent rejection that may also reduce the risk of cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD) and cytomegalovirus (CMV) infection. However, the two regimens have never been compared head-to-head in a randomized trial. The study design and rationale are reviewed in light of the challenges inherent in rare disease research. The TEAMMATE trial (NCT03386539, IND 127980) is the first multicenter randomized clinical trial (RCT) in pediatric HT. The primary purpose is to evaluate the safety and efficacy of EVL and low-dose TAC (LD-TAC) compared to standard-dose TAC and mycophenolate mofetil (MMF). Children aged <21 years at HT were randomized (1:1 ratio) at six months post-HT to either regimen, and followed for 30 months. Children with recurrent rejection, multi-organ transplant recipients, and those with an estimated glomerular filtration rate (eGFR) <30 ml/min/1.73m2 were excluded. The primary efficacy hypothesis is that, compared to TAC/MMF, EVL/LD-TAC is more effective in preventing 3 MATEs: acute cellular rejection (ACR), CKD and CAV. The primary safety hypothesis is that EVL/LD-TAC does not have a higher cumulative burden of 6 MATEs (antibody mediated rejection [AMR], infection, and post-transplant lymphoproliferative disorder [PTLD] in addition to the 3 above). The primary endpoint is the MATE score, a composite, ordinal surrogate endpoint reflecting the frequency and severity of MATEs that is validated against graft loss. The study had a target sample size of 210 patients across 25 sites and is powered to demonstrate superior efficacy of EVL/LD-TAC. Trial enrollment is complete and participant follow-up will be completed in 2023. The TEAMMATE trial is the first multicenter RCT in pediatric HT. It is anticipated that the study will provide important information about the safety and efficacy of everolimus- vs tacrolimus-based regimens and will provide valuable lessons into the design and conduct of future trials in pediatric HT.

Renal function after liver transplantation: Real-world experience with basiliximab induction and delayed reduced-dose tacrolimus.

Routine use of delayed reduced-dose calcineurin-inhibitor treatment with induction immunosuppression in liver transplantation to minimize post-operative kidney injury is still scarce. To evaluate real-world experience of basiliximab induction with delayed reduced-dose tacrolimus. In a retrospective cohort study, kidney function was evaluated pre- and postoperatively by measured glomerular filtration rate (mGFR). Adult patients undergoing liver transplantation between 2000 and 2017 were divided into a conventional treatment group (immediate-introduction of tacrolimus, target trough levels 10-15ng/mL, and corticosteroids, n=203) and a revised treatment group (basiliximab induction, reduced-dose tacrolimus, target through levels 5-8ng/mL, delayed until day three, and mycophenolate mofetil 2000mg/day, n=343). Mean mGFR was similar between groups at wait-listing (85.3vs 84.1ml/min/1.73m², p=0.60), but higher in the revised treatment group at 3 (56.8vs 63.4ml/min/1.73m², p=0.004) and 12 months post-transplant (60.9vs 69.7ml/min/1.73m², p<0.001); this difference remained after correcting for multiple confounders and was independent of pre-transplant mGFR. In the revised treatment group, biopsy proven acute rejection rate was lower (38% vs. 21%, p<0.001), and graft-survival better (p=0.01). Basiliximab induction with delayed reduced-dose tacrolimus is associated with less kidney injury when compared to standard-dose tacrolimus, without increased risk of rejection, graft loss or death.

Evaluation of clotrimazole prophylaxis on tacrolimus trough concentrations in kidney transplant recipients.

BackgroundClotrimazole troches are used as prophylaxis against oropharyngeal candidiasis post‐transplant and have limited systemic absorption. Following several occurrences of tacrolimus concentration fluctuations after clotrimazole discontinuation, its use as prophylaxis was discontinued post‐kidney transplant.MethodsWe conducted a retrospective cohort study to evaluate the effect of clotrimazole prophylaxis on tacrolimus trough concentrations post‐kidney transplant. The study included adult patients who received a kidney transplant at Cleveland Clinic Main Campus from August 1, 2019 to July 1, 2020 and were maintained on per‐protocol, standard‐dose tacrolimus through 90 days post‐transplant. Patients were excluded if they received cyclosporine, systemic antifungals, strong CYP3A4 inhibitors or inducers, or a simultaneous multiorgan transplant. The primary objective was to compare tacrolimus trough concentrations before and after completion of clotrimazole prophylaxis. Secondary objectives were to compare the time to first post‐transplant goal tacrolimus trough concentration, the rate of for‐cause allograft biopsies within 90 days after transplant, and the incidence and type of candidiasis within 30 days after transplant, pre‐ and post‐protocol change.ResultsFollowing clotrimazole discontinuation, the median tacrolimus trough concentration decreased from 10.5 ng/ml (IQR 8.4–12.2) to 6.6 ng/ml (IQR 5–8.7, p < 0.0001). No statistically significant differences in the rate of for‐cause allograft biopsies (4.9% vs. 9.7%, p = 0.264) or incidence of candidiasis (1.2% vs. 5.4%, p = 0.217) were observed between those who received clotrimazole and those who did not receive clotrimazole.ConclusionsOur study provides further evidence of a significant drug–drug interaction between tacrolimus and clotrimazole among kidney transplant recipients that can potentially lead to negative allograft outcomes.

Outcomes of Everolimus Plus Standard-Dose Tacrolimus Immunosuppression in De Novo Kidney Transplant: A Retrospective, Single-Center Study of 225 Transplants.

In this study, our aim was to compare the outcomes of everolimus versus mycophenolate mofetil plus standard-dose tacrolimus immunosuppression in patients who received de novo kidney transplant at our center in Fukuoka, Japan. In this retrospective, observational, single-center, inverse probability of treatment weighting analysis study, 225 recipients who underwent kidney transplant at our center between January 2013 and December 2018 were included. The variables considered were recipient age/sex, duration of dialysis, cytomegalovirus mismatch (seronegative recipient and seropositive donor), cause of end-stage renal disease, donor age/sex, and number of HLA mismatches. Our analyses included 85 transplant recipients in the everolimus group and 141 transplant recipients in the mycophenolate mofetil group (n = 226 overall). There were no significant differences between the groups at 1 year for incidence of patient death and allograft loss, biopsy-proven acute rejection, BK virus-associated nephropathy, surgical complications, delayed graft function, and posttransplant diabetes mellitus. Incidence of cytomegalovirus infection and estimated glomerular filtration rate were significantly lower in the everolimus group than in the mycophenolate mofetil group. Posttransplant triglyceride and low-density lipoprotein were higher in the everolimus group than in the mycophenolate mofetil group. Multivariate ordered logistic analysis showed that older donor age and an acute rejection episode, but not induction with everolimus or mean tacrolimus trough concentration throughoutthe firstpostoperative year,were significant risk factors for severity of interstitial fibrosis/tubular atrophy at the 1-year protocol biopsy (P = .004 and P < .001,respectively). Short-term outcomes with everolimus plus standard-dose tacrolimus in recipients of de novo kidney transplant were comparable to those with mycophenolate mofetil plus standard-dose tacrolimus.

Clinical Outcomes of Everolimus With Reduced-Dose Tacrolimus vs Mycophenolate Mofetil With Standard-Dose Tacrolimus in De Novo ABO-Incompatible Kidney Transplant Recipients: 1-Year Follow-up

One of the major barriers for long-term renal graft survival is considered to be calcineurin inhibitor nephrotoxicity, contributing to chronic graft dysfunction. Thus, recent immunosuppressive strategies are focused on regimens that can reduce or avoid exposure to calcineurin inhibitors. Herein, we carried out a small-scale pilot study to assess whether everolimus (EVR) with reduced-dose tacrolimus (Tac) is an acceptable immunosuppressive regimen for patients with de novo ABO-incompatible kidney transplant compared with mycophenolate mofetil (MMF) with standard-dose Tac. This retrospective single-center cohort study included patients who underwent ABO-incompatible kidney transplant at our institution between January 2016 and December 2019. Those whose immunosuppressive regimen was changed by reasons other than rejection during the 1-year follow-up period were excluded. A total of 24 patients were enrolled in this study: 10 patients who received an EVR with reduced-dose Tac regimen and 14 patients who received an MMF with standard-dose Tac regimen. Tac trough levels in the EVR group were significantly lower than those in the MMF group (P < .001). No patients died or lost their grafts during the follow-up period. There were no significant differences in renal function, proteinuria, and prevalence of hyperlipidemia between the 2 groups at 1 year after transplant. There were no significant differences in the incidence of rejection (acute cellular rejection, steroid-resistant acute cellular rejection, acute antibody-mediated rejection) and infection (cytomegalovirus viremia, cytomegalovirus disease, BK viremia, BK virus nephropathy) between the 2 groups. Comparable with MMF with standard-dose Tac, EVR with reduced-dose Tac might be an acceptable immunosuppressive regimen for patients with de novo ABO-incompatible kidney transplant.

Everolimus for the Prevention of Calcineurin-Inhibitor-Induced Left Ventricular Hypertrophy After Heart Transplantation (RADTAC Study)

ObjectivesThis study aimed to determine the safety and efficacy of combined low-dose everolimus and low-dose tacrolimus compared with standard-dose tacrolimus in attenuating left ventricular hypertrophy (LVH) after orthotopic heart transplantation (OHT). BackgroundCalcineurin inhibitors (CNIs) such as tactrolimus are important in preventing cardiac allograft rejection and reducing mortality after OHT. However CNIs are causatively linked to the development of LVH, and are associated with nephrotoxicity and vasculopathy. CNI-sparing agents such as everolimus have been hypothesized to inhibit adverse effects of CNIs. MethodsIn this prospective, randomized, open-label study, OHT recipients were randomized at 12 weeks after OHT to a combination of low-dose everolimus and tacrolimus (the RADTAC group) or standard-dose tacrolimus (the TAC group), with both groups coadministered mycophenolate and prednisolone. The primary endpoint was LVH indexed as the change in left ventricular mass (ΔLVM) by cardiovascular magnetic resonance (CMR) imaging from 12 to 52 weeks. Secondary endpoints included CMR-based myocardial performance, T1 fibrosis mapping, blood pressure, and renal function. Safety endpoints included episodes of allograft rejection and infection. ResultsForty stable OHT recipients were randomized. Recipients in the RADTAC group had significantly lower tacrolimus levels compared with the TAC group (6.5 ± 3.5 μg/l vs. 8.6 ± 2.8 μg/l; p = 0.02). The mean everolimus level in the RADTAC group was 4.2 ± 1.7 μg/l. A significant reduction in LVM was observed in the RADTAC group compared with an increase in LVM in the TAC group (ΔLVM = −13.0 ± 16.8 g vs. 2.1 ± 8.4 g; p < 0.001). Significant differences were also noted in secondary endpoints measuring function and fibrosis (Δ circumferential strain = −2.9 ± 2.8 vs. 2.1 ± 2.3; p < 0.001; ΔT1 mapping values = −32.7 ± 51.3 ms vs. 26.3 ± 90.4 ms; p = 0.003). No significant differences were observed in blood pressure (Δ mean arterial pressure = 4.2 ± 18.8 mm Hg vs. 2.8 ± 13.8 mm Hg; p = 0.77), renal function (Δ creatinine = 3.1 ± 19.9 μmol/l vs. 9 ± 21.8 μmol/l; p = 0.31), frequency of rejection episodes (p = 0.69), or frequency of infections (p = 0.67) between groups. ConclusionsThe combination of low-dose everolimus and tacrolimus compared with standard-dose tacrolimus safely attenuates LVH in the first year after cardiac transplantation with an observed reduction in CMR-measured fibrosis and an improvement in myocardial strain.

Efficacy and Safety of a Quadruple Regimen Compared with Triple Regimens in Patients with Mycophenolic Acid-Related Gastrointestinal Complications After Renal Transplantation: A Short-Term Single-Center Study

BackgroundAt present, there is no ideal conventional triple regimen that can effectively treat gastrointestinal (GI) complications in patients after kidney transplantation. We aimed to investigate the efficacy and safety of a quadruple regimen including standard-dose tacrolimus, low-dose enteric-coated mycophenolate sodium (EC-MPS), low-dose mizoribine (MZR), and corticosteroids, compared with regimens containing standard-dose tacrolimus, corticosteroids, plus either low-dose EC-MPS or standard-dose MZR in patients with mycophenolic acid (MPA)-related GI complications after renal transplantation.Material/MethodsBetween August 2016 and October 2018 in Qilu Hospital of Shandong University, 115 living donor kidney transplant recipients with MPA-related GI complications were enlisted in a single-center, prospective, randomized, control study. Thirty-six recipients were assigned to the low-dose EC-MPS plus low-dose MZR group, 37 recipients were assigned to the low-dose EC-MPS group, and 39 recipients were assigned to the standard-dose MZR group. We analyzed the Gastrointestinal Symptom Rating Scale (GSRS), estimated glomerular filtration rate (eGFR), graft rejection, serum creatinine, human leukocyte antigen (HLA) antibody, and the occurrence of adverse events among the 3 groups.ResultsCompared with baseline, gastrointestinal symptoms improved significantly in all 3 groups. The reduction in mean subscale scores from baseline to month 3 was more significant in the standard-dose MZR group compared with the other 2 groups. The low-dose EC-MPS plus low-dose MZR group had better renal function. The incidence of graft rejection and cytomegalovirus (CMV) and polyomavirus BK (BKV) infection, as well as the incidence of hyperuricemia, in the low-dose EC-MPS plus low-dose MZR group were all significantly reduced.ConclusionsThis quadruple regimen may be equivalent to regimens containing standard-dose tacrolimus, corticosteroids plus either low-dose EC-MPS or standard-dose MZR in improving GI symptoms after kidney transplant, and is also advantageous for kidney function, graft rejection, and the rates of adverse events.

One-year Outcome of Everolimus With Standard-dose Tacrolimus Immunosuppression in De Novo ABO-incompatible Living Donor Kidney Transplantation: A Retrospective, Single-center, Propensity Score Matching Comparison With Mycophenolate in 42 Transplants.

Background.Despite improvement in immunosuppressive therapy, long-term kidney allograft survival remains a major challenge. The outcomes of therapy with everolimus (EVR) and standard-dose tacrolimus (Tac) have not been compared with those of mycophenolate mofetil (MMF) and standard-dose Tac in recipients of de novo ABO-incompatible (ABOi) living donor kidney transplantation (LDKT).Methods.This retrospective, observational, single-center, propensity score matching (PSM) study compared the outcomes of EVR and standard-dose Tac with those of MMF and standard-dose Tac following de novo ABOi LDKT. In total, 153 recipients of ABOi LDKT between January 2008 and March 2018 were screened for inclusion in the study. The variables considered for PSM were: recipient age/sex, duration of dialysis, cytomegalovirus mismatch (seronegative recipient and seropositive donor), cause of kidney disease, donor age/sex, and numbers of mismatches (HLA-A, HLA-B, and HLA-DR). After PSM, there were 21 patients in each group (n = 42 overall).Results.Four patients in the EVR group and 1 patient in the MMF group were withdrawn because of adverse effects. There were no significant differences between the 2 groups in 1-year outcomes regarding patient death, graft loss, delayed graft function, biopsy-proven acute rejection, infection requiring hospital admission, or estimated glomerular filtration rate. The 1-year protocol biopsy showed that the severity of interstitial fibrosis/tubular atrophy was significantly milder in the EVR group than in the MMF group.Conclusions.The findings suggest that the renal efficacy and safety of EVR and standard-dose Tac in recipients of de novo ABOi LDKT are comparable with those of MMF and standard-dose Tac.

Clinical Study of Standard- vs Reduced-Dose Tacrolimus Combined With Generic Mycophenolate Mofetil in De Novo Kidney Transplantation: A Prospective Randomized Trial

BackgroundThe lowering of calcineurin inhibitor exposure is possibly considered as the proper strategy to prevent calcineurin inhibitor–induced nephrotoxicity in kidney transplant. This clinical study was designed to compare the efficacy and tolerability of reduced-dose tacrolimus with standard-dose mycophenolate mofetil (MMF) vs standard-dose tacrolimus with reduced-dose MMF. MethodsA prospective, multicenter, open-label, randomized, and parallel-group clinical trial was conducted at 4 transplant centers in Korea. A total sample size was 108, and eligible patients were randomly assigned in a 1:1 ratio to either reduced-dose tacrolimus with standard-dose MMF (the study group) or standard-dose tacrolimus with reduced-dose MMF (the control group) for 6 months in de novo kidney transplant recipients. Graft function, the incidence of efficacy failure, and adverse events were compared. ResultsThe mean estimated glomerular filtration rate at 6 months post-transplantation was 69.83 ± 16.68 mL/min/1.73 m2 in the study group and 69.92 ± 17.55 mL/min/1.73 m2 in the control group (P > .05). The overall incidence of biopsy-proven acute rejection was 3.64% (n = 2) in the study group, compared to 3.77% (n = 2) in the control group (P > .05). There was no graft loss, death, or loss of follow-up in either group. ConclusionIn conclusion, the results suggest that tacrolimus minimization with standard-dose MMF provides adequate immunosuppression with proper renal function and similar rate of incidence of acute rejection compared with the regimen including standard-dose tacrolimus with reduced-dose MMF.

Efficacy and Safety of a Quadruple Regimen in Patients with Gastrointestinal Complications after Renal Transplantation

Objectives: The aim of this study was to evaluate the efficacy and safety of a quadruple regimen including standard-dose tacrolimus, low-dose enteric-coated mycophenolate sodium (EC-MPS), low-dose mizoribine (MZR), and corticosteroids compared with regimens containing standard-dose tacrolimus, corticosteroids plus either low-dose EC-MPS or standard-dose MZR in patients with mycophenolic acid (MPA)-related GI complications after kidney transplantation. Methods: Between August 2016 and October 2018 in Qilu Hospital of Shandong University, 115 living donor kidney transplantations with MPA-related GI complications were enrolled in a single-center, prospective study. Thirty-six recipients were assigned to the low-dose EC-MPS plus low-dose MZR group. Thirty-seven recipients were assigned to the low-dose EC-MPS group, and thirty-nine recipients were assigned to the standard-dose MZR group. The three groups were compared with the Gastrointestinal Symptom Rating Scale (GSRS), graft rejection, human leukocyte antigen (HLA) antibody, serum creatinine levels, estimated glomerular filtration rate (eGFR), and incidence of adverse effects. Results: A significant improvement in GI symptoms was observed in all three groups compared with baseline. Renal function was better in the low-dose EC-MPS plus low-dose MZR group. The incidence of graft rejection and cytomegalovirus (CMV) and polyomavirus BK (BKV) infection with the incidence of hyperuricemia were all significantly lower in the low-dose EC-MPS plus low-dose MZR group. Conclusions: The quadruple regimen may be not only equivalent to regimens containing standard-dose tacrolimus, corticosteroids plus either low-dose EC-MPS or standard-dose MZR in improving GI symptoms after kidney transplantation but also advantageous for renal function, graft rejection rates, and the incidence of adverse effects. Funding: This study was funded by the Provincial Key Technologies R & D Program of Shandong Province (Grant No. 26010104011025), National Natural Science Foundation of China (Grant No. 81600092), Key Research and Development Plan of Shandong Province (Grant No. 2017GSF218003). Declaration of Interest: The authors declare no competing interests. Ethical Approval: Patients gave their informed consent to be in the study, and the study protocol was approved by the ethics committee of Qilu Hospital of Shandong University, China (2016Qilu Hospital of Shandong University IRB Approval No. 2016041).

Mechanistic analyses in kidney transplant recipients prospectively randomized to two steroid free regimen-Low dose Tacrolimus with Everolimus versus standard dose Tacrolimus with Mycophenolate Mofetil.

Calcineurin inhibitors (CNI), the cornerstone of immunosuppression after transplantation are implicated in nephrotoxicity and allograft dysfunction. We hypothesized that combined low doses of CNI and Everolimus (EVR) may result in better graft outcomes and greater tolerogenic milieu. Forty adult renal transplant recipients were prospectively randomized to (steroid free) low dose Tacrolimus (TAC) and EVR or standard dose TAC and Mycophenolate (MMF) after Alemtuzumab induction. Baseline characteristics were statistically similar. EVR levels were maintained at 3–8 ng/ml. TAC levels were 4.5±1.9 and 6.4±1.5 ng/ml in the TAC+EVR and TAC+MMF group respectively. Follow up was 14±4 and 17±5 months respectively and included protocol kidney biopsies at 3 and 12 months post-transplantation. Rejection-rate was lower in the TAC+EVR group. However patient and overall graft survival, eGFR and incidence of adverse events were similar. TAC+EVR induced expansion of CD4+CD25hiFoxp3+ regulatory T cells as early as 3 months and expansion of IFN-γ+CD4+CD25hiFoxp3+ regulatory T cells at 12 months post-transplant. Gene expression profile showed a trend toward decreased inflammation, angiogenesis and connective tissue growth in the TAC+EVR Group. Thus, greater tolerogenic mechanisms were found to be operating in patients with low dose TAC+EVR and this might be responsible for the lower rejection-rate than in patients on standard dose TAC+MMF. However, further studies with longer follow up and evaluating impact on T regulatory cells are warranted.

Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial.

In a 12-month, multicenter, open-label study, 106 children were randomized at 4 to 6 weeks after kidney transplantation to switch to everolimus with reduced TAC (EVR/rTAC) and steroid elimination from month 5 posttransplant or to continue standard tacrolimus with mycophenolate mofetil (sTAC/MMF) and steroids. The cumulative incidence of a co-primary efficacy end point (biopsy-proven acute rejection [BPAR], graft loss, or death from randomization to month 12) was 10.3% with EVR/rTAC and 5.8% with sTAC/MMF (difference 4.4%; P = .417). BPAR occurred in 9.6% and 5.6% of patients, respectively. Patient and renal allograft survival were 100%. The co-primary end point of mean estimated glomerular filtration rate at month 12 was 76.2 mL/min/1.73 m2 with EVR/rTAC and 72.5 mL/min/1.73 m2 for sTAC/MMF (difference 3.8 mL/min/1.73m2 ; P = .49). One EVR/rTAC patient developed posttransplant lymphoproliferative disease. Longitudinal growth and sexual maturation were equivalent between groups. The randomized drug regimen was discontinued in 34.6% and 13% of patients in the EVR/rTAC and sTAC/MMF groups, respectively (P = .024), and discontinued due to adverse events/infections in 25.0% and 11.1% of patients (P = .062). In conclusion, early conversion of pediatric kidney transplant patients from TAC, MMF, and steroids to EVR/rTAC and steroid withdrawal maintains immunosuppressive efficacy and preserves renal function.

A review on therapeutic drug monitoring of the mTOR class of immunosuppressants: everolimus and sirolimus

Immunosuppression plays a key role in the prevention of organ rejection in transplant recipients and in the treatment of diverse autoimmune disorders. Therapeutic drug monitoring (TDM) for the mammalian target of rapamycin inhibitors (mTOR) class of immunosuppressants is mandatory in the clinical setting because of the narrow therapeutic index, high intersubject pharmacokinetic variability, under- and over-immunosuppression and adverse effects of these drugs. Immunosuppressive drug therapy is frequently individualized based on the organ transplanted, time after transplantation, and transplant centre-specific immunosuppressive protocols. Since predose trough concentrations (Co) correlate well with areas under the curve, Co levels are commonly used as predictable indices when monitoring everolimus and sirolimus. In kidney transplantation, the lowest incidence of adverse events is generally detected when everolimus Co is 3–8 ng/mL in combination therapy with ciclosporin and glucocorticoids. A regimen of mTOR inhibitors + tacrolimus minimization therapy reduced nephrotoxicity better than standard-dose tacrolimus, without significant changes in mortality or biopsy-proven acute rejection. Sirolimus whole blood Co should be set between 5 and 15 ng/mL, depending on the immunological risk, time of conversion and use of other immunosuppressive drugs. As per the Kidney Disease: Improving Global Outcomes recommendations, because of potential nephrotoxicity, the use of sirolimus and ciclosporin should be avoided during the early course of therapy. The evidence-based recommendations discussed in this review are useful for the optimal implementation of TDM in routine clinical practice. Avoiding calibration bias using whole blood calibrators, and the use of an external proficiency testing programme to improve analytical performance are highly recommended.

New Recipes With Known Ingredients: Combined Therapy of Everolimus and Low-dose Tacrolimus in De Novo Renal Allograft Recipients

BackgroundCalcineurin inhibitors (CNIs) are the cornerstones of immunosuppressive management in renal allograft recipients even though their nephrotoxicity may contribute to a reduced long-term graft survival. This has created a great interest in improving immunosuppressive strategies in the early post-transplantation period. Proliferation signal inhibitors (PSIs), such as everolimus, are promising alternatives, although their side effects may have a drawback in de novo renal transplant recipients, for instance, delaying renal function in the presence of renal ischemia/acute tubular necrosis and predisposing to lymphocele development. Study and MethodsA retrospective study was developed to compare the combined therapy of low-dose tacrolimus and everolimus (study group) with mycophenolate mofetil/mycophenolic acid and standard-dose tacrolimus (control group) in the first 3 months post-transplantation. The study's end-points concerned renal graft function, proteinuria, incidence of biopsy-proven acute rejection, surgical complication rates, and incidence of new-onset diabetes after renal transplantation. ResultsThere was no more delayed graft function in the study group and graft function distribution was similar between groups. Median serum creatinine and eGFR were comparable as well as proteinuria levels. Generally, adverse events were rare in both groups and there were no significant statistical differences between them in terms of biopsy-proven acute rejection, surgical complication, and new-onset diabetes after renal transplantation rates. ConclusionDespite the slightly lower tendency for serum creatinine in the study group, renal allograft function wasn't statistically different between groups. Moreover, there weren't more metabolic or surgical complications in the study group. Everolimus may be a choice in tacrolimus-sparing strategies, but a larger study and a longer follow-up are still required.

A Single Center, Open-label, Randomized Pilot Study to Evaluate the Safety and Efficacy of Tacrolimus Modified Release, ADVAGRAF, Versus Tacrolimus Twice Daily, PROGRAF, in Stable Renal Recipients (SINGLE)

BackgroundCompliance with immunosuppressive regimens may affect clinical outcomes in renal transplant recipients. The aim of this study was to assess the safety and efficacy of standard-dose tacrolimus modified-release (TAC-MR) once daily versus tacrolimus (TAC) twice daily in stable renal transplant recipients. MethodsNinety-nine stable renal transplant recipients were randomized to receive standard-dose tacrolimus twice daily or standard-dose modified-release tacrolimus once daily on a 1:1 (mg:mg) basis. The primary end point was the incidence of adverse events (AEs) in both groups. Secondary end points included biopsy-proven acute rejection, graft survival, patient survival, clinical indicators, and change in score of questionnaire. ResultsThe incidence of AEs was not different between the TAC and TAC-MR groups (56.0% vs 53.1%, P > .05). There were no significant differences in mean calculated glomerular filtration rate, blood pressure, glycosylated hemoglobulin (HbA1c), blood concentration of tacrolimus, and drug compliance. The scores of all items in the 36-item short form health survey (SF-36) were not different between groups, except for vitality. With respect to the subject questionnaire, there was no difference in question scores between the two treatment groups. ConclusionA regimen of TAC-MR once daily can be considered as an effective and safe alternative formulation of tacrolimus in stable renal transplant patients.

Autologous bone marrow derived mesenchymal stromal cell therapy in combination with everolimus to preserve renal structure and function in renal transplant recipients.

BackgroundKidney transplantation has improved survival and quality of life for patients with end-stage renal disease. Despite excellent short-term results due to better and more potent immunosuppressive drugs, long-term survival of transplanted kidneys has not improved accordingly in the last decades. Consequently there is a strong interest in immunosuppressive regimens that maintain efficacy for the prevention of rejection, whilst preserving renal structure and function. In this respect the infusion of mesenchymal stromal cells (MSCs) may be an interesting immune suppressive strategy. MSCs have immune suppressive properties and actively contribute to tissue repair. In experimental animal studies the combination of mammalian target of rapamycin (mTOR) inhibitor and MSCs was shown to attenuate allo immune responses and to promote allograft tolerance. The current study will test the hypothesis that MSC treatment, in combination with the mTOR inhibitor everolimus, facilitates tacrolimus withdrawal, reduces fibrosis and decreases the incidence of opportunistic infections compared to standard tacrolimus dose.Methods/design70 renal allograft recipients, 18–75 years old, will be included in this Phase II, open label, randomized, non-blinded, prospective, single centre clinical study. Patients in the MSC treated group will receive two doses of autologous bone marrow derived MSCs IV (target 1,5x106, Range 1-2x106 million MSCs per/kg body weight), 7 days apart, 6 and 7 weeks transplantation in combination with everolimus and prednisolone. At the time of the second MSC infusion tacrolimus will be reduced to 50% and completely withdrawn 1 week later. Patients in the control group will receive everolimus, prednisolone and standard dose tacrolimus. The primary end point is to compare fibrosis by quantitative Sirius Red scoring of MSC treated and untreated groups at 6 months compared to 4 weeks post-transplant. Secondary end points include: composite end point efficacy failure (Biopsy Proven Acute Rejection, graft loss or death); renal function and proteinuria; opportunistic infections; immune monitoring and “subclinical” cardiovascular disease groups by assessing echocardiography in the different treatment groups.DiscussionThis study will provide information whether MSCs in combination with everolimus can be used for tacrolimus withdrawal, and whether this strategy leads to preservation of renal structure and function in renal recipients.Trial registrationNCT02057965.

Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomised trial

Calcineurin inhibitors (CNIs) reduce short-term kidney transplant failure, but might contribute to transplant failure in the long-term. The role of alemtuzumab (a potent lymphocyte-depleting antibody) as an induction treatment followed by an early reduction in CNI and mycophenolate exposure and steroid avoidance, after kidney transplantation is uncertain. We aimed to assess the efficacy and safety of alemtuzumab-based induction treatment compared with basiliximab-based induction treatment in patients receiving kidney transplants. For this randomised trial, we enrolled patients aged 18 years and older who were scheduled to receive a kidney transplant in the next 24 h from 18 transplant centres in the UK. Using minimised randomisation, we randomly assigned patients (1:1; minimised for age, sex, and immunological risk) to either alemtuzumab-based induction treatment (ie, alemtuzumab followed by low-dose tacrolimus and mycophenolate without steroids) or basiliximab-based induction treatment (basiliximab followed by standard-dose tacrolimus, mycophenolate, and prednisolone). Participants were reviewed at discharge from hospital and at 1, 3, 6, 9, and 12 months after transplantation. The primary outcome was biopsy-proven acute rejection at 6 months, analysed by intention to treat. The study is registered at ClinicalTrials.gov, number NCT01120028, and isrctn.org, number ISRCTN88894088. Between Oct 4, 2010, and Jan 21, 2013, we randomly assigned 852 participants to treatment: 426 to alemtuzumab-based treatment and 426 to basiliximab-based treatment. Overall, individuals allocated to alemtuzumab-based treatment had a 58% proportional reduction in biopsy-proven acute rejection compared with those allocated to basiliximab-based treatment (31 [7%] patients in the alemtuzumab group vs 68 [16%] patients in the basiliximab group; hazard ratio (HR) 0·42, 95% CI 0·28-0·64; log-rank p<0·0001). We detected no between-group difference in treatment effect on transplant failure during the first 6 months (16 [4%] patients vs 13 [3%] patients; HR 1·23, 0·59-2·55; p=0·58) or serious infection (135 [32%] patients vs 136 [32%] patients; HR 1·02, 0·80-1·29; p=0·88). During the first 6 months after transplantation, 11 (3%) patients given alemtuzumab-based treatment and six (1%) patients given basiliximab-based treatment died (HR 1·79, 95% CI 0·66-4·83; p=0·25). Compared with standard basiliximab-based treatment, alemtuzumab-based induction therapy followed by reduced CNI and mycophenolate exposure and steroid avoidance reduced the risk of biopsy-proven acute rejection in a broad range of patients receiving a kidney transplant. Long-term follow-up of this trial will assess whether these effects translate into differences in long-term transplant function and survival. UK National Health Service Blood and Transplant Research and Development Programme, Pfizer, and Novartis UK.

Results of a Large Randomized Controlled Trial of Alemtuzumab-Versus Basiliximab-Based Induction Therapy in Kidney Transplantation.

Background Calcineurin inhibitors reduce short-term kidney transplant failure, but may contribute to late transplant loss. The role of alemtuzumab (a potent lymphocyte-depleting antibody) as induction therapy followed by an early reduction in CNI exposure after kidney transplantation is uncertain. The 3C Study aims to assess the efficacy and safety of alemtuzumab (followed by low-dose CNI) compared to basiliximab (with standard dose CNI) among patients receiving kidney transplants. Methods This randomized trial included 852 patients scheduled to receive a kidney transplant who were randomly assigned alemtuzumab-based induction therapy (followed by low-dose tacrolimus and mycophenolate) or basiliximab-based induction therapy (followed by standard-dose tacrolimus, mycophenolate and steroids). The primary outcome is biopsy-proven acute rejection at 6 months. Key secondary outcomes include delayed graft function, steroid resistant rejection, transplant survival, serious infections (defined as opportunistic infections or infection requiring hospitalisation) and cause-specific mortality. Tertiary outcomes include the incidence of the primary outcome in different types of transplant recipient. Results 426 participants were assigned alemtuzumab and 426 to basiliximab. Average age was 51 years and 65% were male. Approximately one-third of transplants followed each of donation after brain death, donation after cardiac death and living donation. During the first 6 months of follow-up, about 100 participants had biopsy-proven acute rejection, about 30 transplants failed and over 250 participants had a serious infection. Conclusion The 3C Study is the largest randomized trial to assess the clinical efficacy and safety of alemtuzumab-based induction in kidney transplantation and the unblinded clinical efficacy results would be presented for the first time during the WTC meeting. With about 100 rejection episodes and 250 serious infections, the study has excellent statistical power to detect clinically important treatment effects. These results should have an important impact on the choice of induction therapy at the time of kidney transplantation. DISCLOSURE:Haynes, R.: Grant/Research Support, Novartis. Harden, P.: Grant/Research Support, Novartis. Landray, M.: Grant/Research Support, Novartis. Baigent, C.: Grant/Research Support, Novartis. Friend, P.: Grant/Research Support, Novartis.