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  • Huang HJ
  • Schechtman K
  • Askar M
  • Bernadt C
  • Mitter B
  • et al.
Transplantation. 2024 Mar 1;108(3):777-786 doi: 10.1097/TP.0000000000004841.
CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This pilot study recruited lung transplant recipients at 2 sites, and randomised them to standard immunosuppression (Tac, MMF, Pred) or a belatacept-based regimen (Tac, Belatacept and pred). The hypothesis was that belatacept-based immunosuppression might reduce the incidence of donor-specific antibodies (DSA), leading to a reduction in the risk of chronic lung allograft dysfunction (CLAD). The study was stopped after recruitment of 27 patients due to 3 deaths in the belatacept arm. Causes of death varied – 2 patients died from COVID-19 infection, one from CLAD related to infection, one from PTLD, one from pulmonary embolus and one from haemothorax. The authors ascribe 4 of these deaths to viral infections. No differences were seen in incidence of CLAD or development of DSA. It is very difficult to interpret these results given the small numbers, but clearly the authors were correct in stopping the study and switching patients to standard immunosuppression. The relationship of four of the deaths to viral infection would suggest that the immunosuppressive regimen may have contributed, and in the absence of any detectable clinical benefit, the conclusion that this regimen is unsafe in lung transplant recipients seem justified.
Aims: This study aimed to evaluate the feasibility and inform the design of an RCT investigating the efficacy and safety of belatacept following lung transplantation
Interventions: Participants were randomly assigned to either continue standard-of-care immunosuppression or switch to belatacept.
Participants: 27 lung transplant recipients.
Outcomes: The primary outcome was to assess the feasibility of randomising 80% of eligible patients within 4 hours posttransplantation. The primary outcome was later changed to survival following the cessation of treatment with belatacept.
Follow Up: 1 year posttransplantation.
BACKGROUND:

Chronic lung allograft dysfunction (CLAD) is the leading cause of death beyond the first year after lung transplantation. The development of donor-specific antibodies (DSA) is a recognized risk factor for CLAD. Based on experience in kidney transplantation, we hypothesized that belatacept, a selective T-cell costimulatory blocker, would reduce the incidence of DSA after lung transplantation, which may ameliorate the risk of CLAD.

METHODS:

We conducted a pilot randomized controlled trial (RCT) at 2 sites to assess the feasibility and inform the design of a large-scale RCT. All participants were treated with rabbit antithymocyte globulin for induction immunosuppression. Participants in the control arm were treated with tacrolimus, mycophenolate mofetil, and prednisone, and participants in the belatacept arm were treated with tacrolimus, belatacept, and prednisone through day 89 after transplant then converted to belatacept, mycophenolate mofetil, and prednisone for the remainder of year 1.

RESULTS:

After randomizing 27 participants, 3 in the belatacept arm died compared with none in the control arm. As a result, we stopped enrollment and treatment with belatacept, and all participants were treated with standard-of-care immunosuppression. Overall, 6 participants in the belatacept arm died compared with none in the control arm (log rank P  = 0.008). We did not observe any differences in the incidence of DSA, acute cellular rejection, antibody-mediated rejection, CLAD, or infections between the 2 groups.

CONCLUSIONS:

We conclude that the investigational regimen used in this pilot RCT is associated with increased mortality after lung transplantation.

  • Leino AD
  • Magee JC
  • Kershaw DB
  • Pai MP
  • Park JM
J Clin Pharmacol. 2024 Mar;64(3):334-344 doi: 10.1002/jcph.2352.

Tacrolimus is widely reported to display diurnal variation in pharmacokinetic parameters with twice-daily dosing. However, the contribution of chronopharmacokinetics versus food intake is unclear, with even less evidence in the pediatric population. The objectives of this study were to summarize the existing literature by meta-analysis and evaluate the impact of food composition on 24-hour pharmacokinetics in pediatric kidney transplant recipients. For the meta-analysis, 10 studies involving 253 individuals were included. The pooled effect sizes demonstrated significant differences in area under the concentration-time curve from time 0 to 12 hours (standardized mean difference [SMD], 0.27; 95% confidence interval [CI], 0.03-0.52) and maximum concentration (SMD, 0.75; 95% CI, 0.35-1.15) between morning and evening dose administration. However, there was significant between-study heterogeneity that was explained by food exposure. The effect size for minimum concentration was not significantly different overall (SMD, -0.09; 95% CI, -0.27 to 0.09) or across the food exposure subgroups. A 2-compartment model with a lag time, linear clearance, and first-order absorption best characterized the tacrolimus pharmacokinetics in pediatric participants. As expected, adding the time of administration and food composition covariates reduced the unexplained within-subject variability for the first-order absorption rate constant, but only caloric composition significantly reduced variability for lag time. The available data suggest food intake is the major driver of diurnal variation in tacrolimus exposure, but the associated changes are not reflected by trough concentrations alone.

  • Dong C
  • Song Z
  • Sun C
  • Wang K
  • Zhang W
  • et al.
BACKGROUND:

Optimizing the immunosuppressive regimen is essential to improve the long-term outcomes of pediatric liver transplant recipients.

METHODS:

We conducted a prospective, randomized, open-label study to compare the safety and efficacy of 2 treatment approaches during pediatric liver transplantation: tacrolimus monotherapy following basiliximab induction (the study group) and a dual regimen of tacrolimus plus steroids (the control group). A total of 150 patients were enrolled, with 75 patients allocated to each group.

RESULTS:

In both groups, recipients achieved graft and recipient overall survival rates exceeding 93%, with no statistically significant differences between them. However, the study group exhibited a significantly lower incidence of acute cellular rejection (ACR), delayed occurrence of ACR, and an improved ACR-free survival rate at 2 y compared with the control group. Notably, the study group also showed a significant reduction in the incidence of de novo donor-specific antibodies at 3-mo and 2-y posttransplant. Furthermore, 6 mo after the transplant, the study group demonstrated significant improvements in weight-for-age Z score and height-for-age Z score. No notable differences were observed in postoperative complications or the incidence of liver fibrosis between the 2 groups.

CONCLUSIONS:

Basiliximab induction combine with tacrolimus (TAC) monotherapy is a safe and effective immunosuppressive regimen to reduce the episodes of ACR without influencing the development of liver fibrosis and graft and recipient survival rate after pediatric liver transplantation.

  • Sharif A
  • Chakkera H
  • de Vries APJ
  • Eller K
  • Guthoff M
  • et al.
Nephrol Dial Transplant. 2024 Feb 28;39(3):531-549 doi: 10.1093/ndt/gfad258.

Post-transplantation diabetes mellitus (PTDM) remains a leading complication after solid organ transplantation. Previous international PTDM consensus meetings in 2003 and 2013 provided standardized frameworks to reduce heterogeneity in diagnosis, risk stratification and management. However, the last decade has seen significant advancements in our PTDM knowledge complemented by rapidly changing treatment algorithms for management of diabetes in the general population. In view of these developments, and to ensure reduced variation in clinical practice, a 3rd international PTDM Consensus Meeting was planned and held from 6-8 May 2022 in Vienna, Austria involving global delegates with PTDM expertise to update the previous reports. This update includes opinion statements concerning optimal diagnostic tools, recognition of prediabetes (impaired fasting glucose and/or impaired glucose tolerance), new mechanistic insights, immunosuppression modification, evidence-based strategies to prevent PTDM, treatment hierarchy for incorporating novel glucose-lowering agents and suggestions for the future direction of PTDM research to address unmet needs. Due to the paucity of good quality evidence, consensus meeting participants agreed that making GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) recommendations would be flawed. Although kidney-allograft centric, we suggest that these opinion statements can be appraised by the transplantation community for implementation across different solid organ transplant cohorts. Acknowledging the paucity of published literature, this report reflects consensus expert opinion. Attaining evidence is desirable to ensure establishment of optimized care for any solid organ transplant recipient at risk of, or who develops, PTDM as we strive to improve long-term outcomes.

  • Li Z
  • Wang X
  • Li D
  • Cheng S
  • Guo H
  • et al.
BMC Nephrol. 2024 Feb 6;25(1):48 doi: 10.1186/s12882-024-03467-4.
PURPOSE:

This study aimed to investigate the association between cytochrome P450 (CYP) 3A4*22 and cytochrome P450 oxidoreductase (POR)*28 variations and the pharmacokinetics of tacrolimus.

METHODS:

Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science (SCI), MEDLINE, and Embase were systematically searched from inception to August 2022. The outcomes were weight-adjusted daily dose and dose-adjusted trough concentration (C0/Dose).

RESULTS:

The study included 2931 renal transplant recipients from 18 publications. Weight-adjusted daily dose of CYP3A4*1/*1 carriers was 0.04 (WMD = 0.04, 95% CI: 0.02 to 0.06), 0.03 (WMD = 0.03, 95% CI: 0.02 to 0.05), 0.02 (WMD = 0.02, 95% CI: 0.01 to 0.03), or 0.02 mg/kg/day (WMD = 0.02, 95% CI: 0.00 to 0.04) higher than CYP3A4*22 carriers in Caucasians at 1 month, 3 months, 6 months, or 12 months post-transplantation. Conversely, C0/Dose was lower for CYP3A4*1/*1 carriers at 3 days (SMD = -0.35, 95% CI: -0.65 to -0.06), 1 month (SMD = -0.67, 95% CI: -1.16 to -0.18), 3 months (SMD = -0.60, 95% CI: -0.89 to -0.31), 6 months (SMD = -0.76, 95% CI: -1.49 to -0.04), or 12 months post-transplantation (SMD = -0.69, 95% CI: -1.37 to 0.00). Furthermore, C0/Dose of POR*1/*1 carriers was 22.64 (WMD = 22.64, 95% CI: 2.54 to 42.74) or 19.41 (ng/ml)/(mg/kg/day) (WMD = 19.41, 95% CI: 9.58 to 29.24) higher than POR*28 carriers in CYP3A5 expressers at 3 days or 7 days post-transplantation, and higher in Asians at 6 months post-transplantation (SMD = 0.96, 95% CI: 0.50 to 1.43).

CONCLUSIONS:

CYP3A4*22 variant in Caucasians restrains the metabolism of tacrolimus, while POR*28 variant in CYP3A5 expressers enhances the metabolism of tacrolimus for renal transplant recipients. However, further well-designed prospective studies are necessary to substantiate these conclusions given some limitations.

  • Klein A
  • Toll A
  • Stewart D
  • Fitzsimmons WE
Am J Transplant. 2024 Feb;24(2):250-259 doi: 10.1016/j.ajt.2023.09.019.
CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This interesting study evaluates the use of real-world registry data as a control cohort, combined with propensity matching, for evaluation of long-term outcomes in a clinical trial. The authors use the BENEFIT study as an example, comparing outcomes from the belatacept and original control arms to two registry-based arms – cyclosporine-treated controls, and a tacrolimus-based control group. They demonstrate that the registry-based controls have very similar 5-year graft survival to the original control cohort, resulting in similar conclusions to the original trial. Registry-based approaches to clinical trials may help to make trials more efficient, particularly when the patient cohort is rare or long-term follow-up is required. There are some obvious limitations – outcomes are limited to those included in the registry data, and in order to apply study inclusion/exclusion criteria to the registry cohort, the criteria must be reliably recorded in the registry. A natural extension to this approach may be use of synthetic data, which would circumvent some of the data privacy concerns of using real patient data.
Aims: The aim of this study was to test the feasibility and value of using real-world registry data as a control cohort to compare drug treatment effects to those observed in the BENEFIT study.
Interventions: Participants in the BENEFIT study were randomised to receive either more intensive or less intensive regimens of BELA-based immunosuppressive therapy, or to cyclosporine.
Participants: 1443 kidney transplant recipients.
Outcomes: The main outcomes of interest were covariate-adjusted overall and death-censored graft survival and patient survival at 3- and 5-years posttransplant.
Follow Up: 5 years posttransplantation

To address the challenges of assessing the impact of a reasonably likely surrogate endpoint on long-term graft survival in prospective kidney transplant clinical trials, the Transplant Therapeutics Consortium established a real-world evidence workgroup evaluating the scientific value of using transplant registry data as an external control to supplement the internal control group. The United Network for Organ Sharing retrospectively simulated the use of several distinct contemporaneous external control groups, applied multiple cause inference methods, and compared treatment effects to those observed in the BENEFIT study. Applying BENEFIT study enrollment criteria produced a smaller historical cyclosporine control arm (n = 153) and a larger, alternative (tacrolimus) historical control arm (n = 1069). Following covariate-balanced propensity scoring, Kaplan-Meier 5-year all-cause graft survivals were 81.3% and 81.7% in the Organ Procurement and Transplantation Network (OPTN) tacrolimus and cyclosporine external control arms, similar to 80.3% observed in the BENEFIT cyclosporine treatment arm. Five-year graft survival in the belatacept-less intensive arm was significantly higher than the OPTN controls using propensity scoring for comparing cyclosporine and tacrolimus. Propensity weighting using OPTN controls closely mirrored the BENEFIT study's long-term control (cyclosporine) arm's survival rate and the less intensive arm's treatment effect (significantly higher survival vs control). This study supports the feasibility and validity of using supplemental external registry controls for long-term survival in kidney transplant clinical trials.

  • van den Born JC
  • Meziyerh S
  • Vart P
  • Bakker SJL
  • Berger SP
  • et al.
Transplantation. 2024 Feb 1;108(2):556-566 doi: 10.1097/TP.0000000000004776.
CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This multicentre trial from the Netherlands randomised de novo renal transplant recipients to one of three immunosuppression strategies – standard care, early steroid withdrawal or tacrolimus minimisation at 6 months. The study was designed to demonstrate non-inferiority in renal function at 24 months, and met the primary endpoint, with no difference seen between the three groups. There was a higher incidence of acute rejection in the early steroid withdrawal group, but no increase in DSA formation. In general, study design is good although unblinded, with centralised randomisation and intent-to-treat analysis. Withdrawal rate was around 25% in each arm at 24 months. Inclusion criteria are fairly broad for an immunosuppression minimisation study, allowing recipients up to 80 years of age, PRA up to 75% and first or second transplants. One notable exclusion criteria was for type 1 diabetic recipients; the authors do not provide a rationale for this.
Aims: The aim of this trial was to compare standard immunosuppression with two immunosuppression minimisation strategies in de novo kidney transplant recipients.
Interventions: Participants were randomised to one of three groups: the early steroid withdrawal arm, the standard-dose tacrolimus arm, and the tacrolimus minimisation arm.
Participants: 295 de novo kidney transplant recipients.
Outcomes: The primary outcome was kidney function at 24 months posttransplantation. The secondary outcomes were patient survival, treated rejection, kidney failure, discontinuation of study medication for more than 6 weeks, and treatment failure.
Follow Up: 24 months
BACKGROUND:

Evidence on the optimal maintenance of immunosuppressive regimen in kidney transplantation recipients is limited.

METHODS:

The Amsterdam, LEiden, GROningen trial is a randomized, multicenter, investigator-driven, noninferiority, open-label trial in de novo kidney transplant recipients, in which 2 immunosuppression minimization strategies were compared with standard immunosuppression with basiliximab, corticosteroids, tacrolimus, and mycophenolic acid. In the minimization groups, either steroids were withdrawn from day 3, or tacrolimus exposure was reduced from 6 mo after transplantation. The primary endpoint was kidney transplant function at 24 mo.

RESULTS:

A total of 295 participants were included in the intention-to-treat analysis. Noninferiority was shown for the primary endpoint; estimated glomerular filtration rate at 24 mo was 45.3 mL/min/1.73 m 2 in the early steroid withdrawal group, 49.0 mL/min/1.73 m 2 in the standard immunosuppression group, and 44.7 mL/min/1.73 m 2 in the tacrolimus minimization group. Participants in the early steroid withdrawal group were significantly more often treated for rejection ( P = 0.04). However, in this group, the number of participants with diabetes mellitus during follow-up and total cholesterol at 24 mo were significantly lower.

CONCLUSIONS:

Tacrolimus minimization can be considered in kidney transplant recipients who do not have an increased immunological risk. Before withdrawing steroids the risk of rejection should be weighed against the potential metabolic advantages.

  • Bredewold OW
  • van Oeveren-Rietdijk AM
  • Florijn B
  • Rotmans JI
  • de Fijter JW
  • et al.
Transpl Immunol. 2024 Feb;82:101976 doi: 10.1016/j.trim.2023.101976.

Belatacept, a modified form of CTLA-Ig that blocks CD28-mediated co-stimulation of T cells, is an immune-suppressant that can be used as an alternative to calcineurin inhibitors (CNIs). In kidney transplant recipients, belatacept has been associated with improved renal function and reduced cardiovascular toxicity. Monocytes as well as T-lymphocytes play causal roles in the pathophysiology of atherosclerotic disease. We hypothesized that the beneficial impact of the use of belatacept over CNIs on cardiovascular risk could be partly explained by the impact of belatacept therapy on these circulating leukocytes. Hence, we phenotyped circulating leukocytes in transplanted patients with a stable renal function that were randomized between either continuation of CNI or conversion to belatacept in two international studies in which we participated. In 41 patients, we found that belatacept-treated patients consistently showed lower numbers of B-lymphocytes, T-lymphocytes as well as CD14-negative monocytes (CD14NM), especially in non-diabetic patients. Our observation that this decrease was associated to plasma concentrations of TNFα is consistent with a model where CD14NM-production of TNFα is diminished by belatacept-treatment, due to effects on the antigen-presenting cell compartment.

  • Venkatakrishnan G
  • Kathirvel M
  • Sivasankara Pillai Thankamony Amma B
  • Muraleedharan AK
  • Mathew JS
  • et al.
HPB (Oxford). 2024 Feb;26(2):171-178 doi: 10.1016/j.hpb.2023.10.017.
BACKGROUND:

To compare the safety and efficacy of once-daily tacrolimus (ODT) versus twice-daily tacrolimus (BDT) in adult live donor liver transplantation (LDLT).

METHODS:

In this open-labelled randomized trial, 174 adult patients undergoing LDLT were randomized into ODT or BDT, combined with basiliximab induction and mycophenolate mofetil (steroid-free regimen). Tacrolimus was started at a total dose of 1 mg and the trough level was aimed at 3-7 ng/ml. The primary endpoint was eGFR at 1,3- and 6 months post-transplant, using CKD- EPI equation. Secondary endpoints included biopsy-proven acute rejection (BPAR), metabolic complications, post-operative bilio-vascular complications and patient survival.

RESULTS:

There was no statistically significant difference in eGFR between the two groups at 6 months (ODT -96 ± 19, BDT -91 ± 21, p value-0.164). BPAR was comparable (18/84 in ODT, 19/88 in BDT, p value-0.981). For a similar dosage of tacrolimus, the median trough tacrolimus levels attained were significantly lower for ODT than BDT during the first-month post-transplant (p value-0.001). Metabolic complications due to immunosuppression, post-operative bilio-vascular complications and patient survival was similar between the two groups at 6 months.

CONCLUSION:

Once-daily tacrolimus has similar renal safety and efficacy as twice-daily tacrolimus when used in combination with basiliximab induction and mycophenolate in adult LDLT.

  • Passerini M
  • Nayfeh T
  • Yetmar ZA
  • Coussement J
  • Goodlet KJ
  • et al.
Clin Microbiol Infect. 2024 Feb;30(2):170-177 doi: 10.1016/j.cmi.2023.10.008.
BACKGROUND:

Whether trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis prevents nocardiosis in solid organ transplant (SOT) recipients is controversial.

OBJECTIVES:

To assess the effect of TMP-SMX in the prevention of nocardiosis after SOT, its dose-response relationship, its effect on preventing disseminated nocardiosis, and the risk of TMP-SMX resistance in case of breakthrough infection.

METHODS:

A systematic review and individual patient data meta-analysis.

DATA SOURCES:

MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Science Core Collection, and Scopus up to 19 September 2023.

STUDY ELIGIBILITY CRITERIA:

(a) Risk of nocardiosis between SOT recipients with and without TMP-SMX prophylaxis, or (b) sufficient details to determine the rate of TMP-SMX resistance in breakthrough nocardiosis.

PARTICIPANTS:

SOT recipients.

INTERVENTION:

TMP-SMX prophylaxis versus no prophylaxis.

ASSESSMENT OF RISK OF BIAS:

Risk Of Bias In Non-randomized Studies-of Exposure (ROBINS-E) for comparative studies; dedicated tool for non-comparative studies.

METHODS OF DATA SYNTHESIS:

For our primary outcome (i.e. to determine the effect of TMP-SMX on the risk of nocardiosis), a one-step mixed-effects regression model was used to estimate the association between the outcome and the exposure. Univariate and multivariable unconditional regression models were used to adjust for the potential confounding effects. Certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

RESULTS:

Individual data from three case-control studies were obtained (260 SOT recipients with nocardiosis and 519 uninfected controls). TMP-SMX prophylaxis was independently associated with a significantly decreased risk of nocardiosis (adjusted OR = 0.3, 95% CI 0.18-0.52, moderate certainty of evidence). Variables independently associated with an increased risk of nocardiosis were older age, current use of corticosteroids, high calcineurin inhibitor concentration, recent acute rejection, lower lymphocyte count, and heart transplant. Breakthrough infections (66/260, 25%) were generally susceptible to TMP-SMX (pooled proportion 98%, 95% CI 92-100).

CONCLUSIONS:

In SOT recipients, TMP-SMX prophylaxis likely reduces the risk of nocardiosis. Resistance appears uncommon in case of breakthrough infection.