Dr Keno Mentor, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
Mineralocorticoid receptor antagonists (MRA) have been shown to have reno-protective effects in pre-clinical and clinical studies. Their use in the kidney transplant population is limited because of an uncertain risk profile, especially the risk of hyperkalaemia and with respect to potential drug interactions with immunosuppressants. This randomised study investigated the efficacy and safety of eplerenone in the paediatric kidney transplant population. The findings showed a significant reduction in progression of allograft dysfunction over 3 years in the eplerenone group, without an increase in potassium levels. The study is limited by a small sample size (n = 26) and although randomised, an unclear blinding methodology. Thus, like in the adult population, the risk-benefit assessment of MRA use in paediatric transplant patients remains controversial and larger randomised trials are required.
Aims:
This study aimed to examine how long-term eplerenone administration affects paediatric patients with chronic allograft nephropathy (CAN).
Interventions:
Participants were randomised to either receive or not receive eplerenone.
Participants:
26 renal transplant children with biopsy-proven CAN.
Outcomes:
Outcomes of interest included assessment of serum creatinine, serum K, serum Na, estimated glomerular filtration rate (eGFR), spot protein/creatinine, blood pressure (BP), and interstitial fibrosis and tubular atrophy (IFTA) scores at baseline and 36 months, as well as variables associated with eGFR improvement at 36 months.
Follow Up:
36 months
BACKGROUND:
Literature supports the protective role of mineralocorticoid antagonist (MRA) against the renal injury induced by aldosterone in kidney transplant recipients. However, there is limited data available regarding the safety and efficacy of MRAs in pediatric renal transplant patients. Therefore, we aimed to investigate the effect of long-term eplerenone administration in children with chronic allograft nephropathy (CAN).
METHODS:
Twenty-six renal transplant children with biopsy-proven CAN, an estimated glomerular filtration rate (eGFR ) > 40 mL/min per 1.73 m2 and with a significant proteinuria were included. Selected patients were randomly divided into two groups as follows; Group 1 (n = 10) patients received 25 mg/day eplerenone and Group 2 (n = 16) patients did not receive eplerenone for 36 months. Patients were examined in the renal transplant outpatient clinic biweekly for the first month and once a month thereafter. The primary outcome of the patients was compared.
RESULTS:
Mean eGFR stayed stable in group 1 patients, but significantly decreased in group 2 at 36 months (57.53 ± 7.53 vs. 44.94 ± 8.04 mL/min per 1.73 m2 , p = .001). Similarly, spot protein-creatinine ratio was significantly lower in group 1 compared to group 2 patients at 36 months (1.02 ± 7.53 vs. 3.61 ± 0.53, p < .001). Eplerenone associated hyperkalemia was not observed in group 1 patients (4.6 ± 0.2 vs. 4.56 ± 0.3, p = .713).
CONCLUSION:
The long-term eplerenone administration blunted the chronic allograft nephropathy by maintaining a stable eGFR levels and decreasing urine protein-creatinine ratio. Eplerenone associated hyperkalemia was not observed in our study.
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This interesting study looked at the implications of substituting the control arm of a randomised controlled trial with a cohort derived from real-world registry data. The authors applied the same inclusion/exclusion criteria as used in the CRADLE RCT to the CERTAIN registry, and compared the demographics and outcomes seen in the two cohorts. Differences in demographics and outcomes were generally small and not statistically significant, leading the authors to conclude that the use of real-world data as a control in clinical trials is feasible. This is an interesting approach and may be particularly useful in fields where recruitment is challenging due to small numbers or rare conditions, or in situations where equipoise has been lost making randomisation unfeasible. There are drawbacks – the historical nature of controls may mean that subtle changes over time are missed, and the control cohort will only be as good and complete as the quality of the registry data collection. Outcomes will be limited to those reliably collected in the registry.
Aims:
This study aimed to investigate the feasibility of emulating the control arm of a randomised controlled trial in pediatric kidney transplantation (CRADLE trial) with Real‑World Data derived from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry.
Interventions:
Participants in the CRADLE trial were randomised to either continue standard tacrolimus with mycophenolate mofetil and steroids, or to switch to everolimus with reduced tacrolimus and steroid elimination from 5 months following transplantation.
Participants:
608 paediatric kidney transplant recipients (54 from the CRADLE control cohort and 554 from the CERTAIN cohort)
Outcomes:
Patient death, graft loss, biopsy-proven acute rejection (BPAR), kidney transplant function, urinary protein-creatinine ratio, incidence of posttransplant lymphoproliferative disorders (PTLDs), number of patients with any infection, urinary tract infections, anthropometric data and specifc laboratory endpoints of interest.
Follow Up:
12 months
BACKGROUND:
Randomized controlled trials in pediatric kidney transplantation are hampered by low incidence and prevalence of kidney failure in children. Real-World Data from patient registries could facilitate the conduct of clinical trials by substituting a control cohort. However, the emulation of a control cohort by registry data in pediatric kidney transplantation has not been investigated so far.
METHODS:
In this multicenter comparative analysis, we emulated the control cohort (n = 54) of an RCT in pediatric kidney transplant patients (CRADLE trial; ClinicalTrials.gov NCT01544491) with data derived from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, using the same inclusion and exclusion criteria (CERTAIN cohort, n = 554).
RESULTS:
Most baseline patient and transplant characteristics were well comparable between both cohorts. At year 1 posttransplant, a composite efficacy failure end point comprising biopsy-proven acute rejection, graft loss or death (5.8% ± 3.3% vs. 7.5% ± 1.1%, P = 0.33), and kidney function (72.5 ± 24.9 vs. 77.3 ± 24.2 mL/min/1.73 m2 P = 0.19) did not differ significantly between CRADLE and CERTAIN. Furthermore, the incidence and severity of BPAR (5.6% vs. 7.8%), the degree of proteinuria (20.2 ± 13.9 vs. 30.6 ± 58.4 g/mol, P = 0.15), and the key safety parameters such as occurrence of urinary tract infections (24.1% vs. 15.5%, P = 0.10) were well comparable.
CONCLUSIONS:
In conclusion, usage of Real-World Data from patient registries such as CERTAIN to emulate the control cohort of an RCT is feasible and could facilitate the conduct of clinical trials in pediatric kidney transplantation. A higher resolution version of the Graphical abstract is available as Supplementary information.
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This is an interesting study that paves the way for larger studies, with some adaptations. Young adult and adolescent liver transplant recipients were randomised to standard care, or to receive “praise text messages” when their immune suppression drug levels were in range. The study focussed on self-reported levels of confidence in taking medications, and self-reported adherence, which was already very high in the standard care group. There was also a high recognition of the importance of medication adherence. In multivariate analysis, participants in the intervention arm were significantly more likely to report taking their medications on time and as directed. The study was too small to see any endpoints in treatment outcome and there was no significant difference in measures of drug level variation. The intervention was cheap to install in terms of staff time and cost, it was also feasible and acceptable to patients. However, no difference in actual drug levels could be shown in this study, nor clinical outcomes and the self-reported confidence can certainly be confounded. With refinement of the protocol and personalisation of text messages, this could be taken forward to a larger study population.
Aims:
The aim of this study was to investigate the feasibility, acceptability and impact of a brief mobile health (mHealth) intervention on medication adherence among adolescent and young adult (AYA) liver transplant recipients.
Interventions:
Participants were randomised to receive either praise text messages or to usual care.
Participants:
35 adolescent and young adult liver transplant recipients (13–21 years old).
Outcomes:
Self-reported motivation and adherence, and medication level variability index (MLVI).
Follow Up:
1 year
BACKGROUND:
AYA who have undergone liver transplantations often struggle to adhere to their post-transplant immunosuppressant medications, which can lead to serious health complications. The objective of this pilot study is to examine the acceptability and feasibility of a brief mobile health (mHealth) intervention and its impact on medication adherence among AYA liver transplant recipients.
METHODS:
Thirty-five AYAs (13-21 years old) were randomized to either (1) receive praise text messages whenever laboratory results indicated immunosuppressant medications within the expected range or (2) usual care. Motivation for adherence and adherence were assessed via self-report, and a MLVI was calculated based on values abstracted from the electronic health record.
RESULTS:
Multilevel, multivariate models showed significant associations between group assignment and some self-reported motivation and adherence outcomes but not MLVI. Specifically, AYA receiving the praise text messages were significantly more likely to report taking their prescribed doses (OR = 2.49, p = .03), taking their medicine according to the directions (OR = 2.39, p = .04), and being highly confident in taking their medication (OR = 2.46, p = .04), compared with the usual services group. Qualitative responses indicated praise texts were mostly helpful but could be improved.
CONCLUSIONS:
The results suggest texting patients about positive health indicators was acceptable and, with refinement, might promote AYA illness self-management.
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This small single-centre study investigated the role of intraoperative ATG injected directly to the coronary sinus during cardiac transplantation. Patients in both groups also received postoperative ATG infusion, to achieve the same total dose in both groups. The authors claim a significant reduction in the risk of acute rejection in the intraoperative ATG group, as well as a reduction in echocardiographic abnormalities and need of inotropic therapy. Whilst on the face of it, this sounds like a promising intervention, there are significant deficiencies in the methodology and reporting of this study. This study is described as randomised, but from the description in the manuscript it appears to be a sequential cohort study with all intraoperative ATG patients recruited at the end of the study. No power calculation is presented, and there is a real risk of type I error in the acute rejection results. I was unable to replicate the claim of a statistically significant increase in acute rejection – with 2/15 control and 0/15 study patients experiencing rejection, a Fisher exact test gives a p-value of 0.48, rather than the <0.05 reported in the manuscript. The claims of reduced inotrope use and improved echocardiographic function are not backed up with any data. In short, the data presented in the manuscript do not support the conclusion of the authors.
Expert Review
Reviewer:
Prof. Dr. Bart De Geest, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
Conflicts of Interest:
No
Clinical Impact Rating
1
Review:
This prospective single center study was conducted in heart transplant patients receiving donor hearts procured after cardiocirculatory death (category III and category IV according to modified Maastricht classification). Thirty-two orthotopic heart transplant recipients were divided into 2 groups: group 1 included 17 patients who received retrograde antithymocyte globulin infusion via the coronary sinus intraoperatively and immediately after organ procurement and group 2 included 15 patients who received traditional antithymocyte globulin infusion after implantation. Two patients in group 1 were excluded due to early mortality resulting from a surgical complication (bleeding) and from acute renal failure. The first group had less acute rejection episodes than group 2 (0.0% vs 13.3%; P < .05) and graft function was better in these patients. The main limitation of this study is that group assignment was performed based on consecutive order, with group 1 being the last patients of the study period. The study is not a double-blind prospective study and no clear conclusions can be drawn. Furthermore, not all p-values are created equal and p-values obtained in small trials should be interpreted with greater caution.
Aims:
To identify the effects of intraoperative antithymocyte globulin administration on donor hearts following cardiocirculatory death.
Interventions:
Patients were randomized to receive retrograde antithymocyte globulin infusion via coronary sinus intraoperatively and immediately after organ procurement or traditional antithymocyte globulin infusion after implantation.
Participants:
30 patients with orthotropic heart transplants.
Outcomes:
Allograft rejection and graft function.
Follow Up:
30 days.
OBJECTIVES:
Our study was conducted to determine the effects of intraoperative antithymocyte globulin administration on donor hearts procured after cardiocirculatory death. We evaluated the impact of antithymocyte globulin on graft function and related parameters during isothermic blood cardioplegia.
MATERIALS AND METHODS:
In this prospective and randomized single center study, 30 patients with orthotropic heart transplant were divided into 2 groups: group 1 included 15 patients who received retrograde antithymocyte globulin infusion via coronary sinus intraoperatively and immediately after organ procurement and group 2 included 15 patients who received traditional antithymocyte globulin infusion after implantation.
RESULTS:
Study patients had a mean age of 33.8 years (range, 15-56 y). All patients had panel reactive antibody less than 10% except for 3 patients. The cluster of differentiation 3-positive cell count decrease was more than 20%. The inotropic therapy dose required and the myocardial pressure (stiffness) were less for group 1 patients. These patients had less acute rejection episodes than group 2 (0% vs 13.3%; P < .05).
CONCLUSIONS:
Favorable clinical outcomes were observed in terms of less acute rejection episodes and better graft function at least during the early posttransplant period. Intraoperative antithymocyte globulin treatment may have a preventive effect for acute cellular rejection in heart transplant patients.
Dr Liset Pengel, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
The randomised controlled trial tested the hypothesis that a graphic narrative illustrating bronchoscopy for post-LTx surveillance will improve the overall patient satisfaction regarding the quality of patient informed consent and may decrease pre-procedural anxiety and periprocedural discomfort. Adult recipients and paediatric recipients who were in transition to adult care, were scheduled for the first non-sedated surveillance bronchoscopy after their primary lung transplant (median days after transplant ranged from 2-5 days). Based on a table of random numbers and using numbered, sealed envelopes participants were randomised to the standardised informed consent form plus the graphic narrative or the standardised consent form only. The power calculation was based on the primary outcome patient satisfaction and indicated that 60 patients needed to be included in the study. Overall satisfaction with informed consent was significantly higher in the graphic narrative group. Patient anxiety measured before and after informed consent (but before the bronchoscopy) was similar between groups. The patient reported bronchoscopy experience of anxiety, dyspnoea, cough, gagging, pain or discomfort was similar between groups. The graphic narrative may be a simple tool to improve overall patient reported satisfaction with the informed consent form.
Aims:
This study aimed to evaluate if supplementing standard informed consent (IC) with a graphic narrative illustrating bronchoscopy for post-lung transplantation (LTx) surveillance led to improvements on patient satisfaction, periprocedural anxiety and experience.
Interventions:
Patients were randomised to receive either a standard IC form with a graphic narrative illustrating the procedure (intervention group) or a standard IC form alone (control group).
Participants:
60 primary lung transplant recipients.
Outcomes:
The primary outcome was the overall patient satisfaction with the IC process. The secondary outcomes were change in state anxiety level, satisfaction with IC and adverse experience during bronchoscopy.
Follow Up:
Immediately after informed consent.
OBJECTIVE:
This study investigated the effects of supplementing standard informed consent (IC) with a graphic narrative on patient satisfaction, periprocedural anxiety and experience.
METHODS:
Patients due to undergo first conscious surveillance bronchoscopy following lung transplantation were randomized to receive IC with (intervention group) or without (control group) a graphic narrative illustrating the procedure. The primary endpoint was overall patient satisfaction with the IC. Key secondary endpoints were change in state anxiety level, as measured by State Trait Anxiety Inventory, and a questionnaire assessing satisfaction with IC and adverse experience during bronchoscopy (judged by patient and examiners).
RESULTS:
Sixty patients were randomized, and 59 patients were included in the analysis (30 intervention-group; 29 control-group). Overall patient satisfaction was higher in the intervention group 9.5 (25Q-75Q: 8.6-9.8) vs. 8.6 (25Q-75Q: 8.1-9.2), p = 0.028). Change in state anxiety level (before vs after informed consent) was similar between the groups. There were no significant differences in adverse experience during bronchoscopy.
CONCLUSION:
Addition of a graphic narrative illustrating bronchoscopy improved patient satisfaction with IC but did not influence anxiety before and adverse experience during the procedure.
PRACTICE IMPLICATIONS:
Supplementing the IC process with a procedure-specific graphic narrative may be a simple tool to improve patient satisfaction.
Dr Liset Pengel, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
The double-blind randomised controlled trial compared daily 1000 IU with 4000 IU of vitamin D3 in children with CKD stages 3–5 or who were kidney transplant recipients. The primary outcome was the proportion of children who were vitamin D replete (25(OH)D ≥ 30 ng/mL) at 6 months. The sample size calculation showed that 36 patients in each study arm were needed for a statistical power of 90%. Because of the high drop-out rate 98 participants, aged 9-21 years, were enrolled and 80 (81.6%), including 43 kidney transplant recipients, were included in the analysis. Participants were randomised according to a randomisation list prepared by a statistician and the study pharmacist distributed identical containers to the study participants. At 6 months, there was a statistically significant difference in the proportion of participants who were vitamin D replete in the 4000 IU group compared with the 1000 IU group (74.4% versus 33.3%, respectively).
Aims:
The aim of this study was to investigate whether 4000 IU daily of vitamin D was more effective in achieving and maintaining 25-hydroxvitamin D (25(OH)D) levels ≥ 30 ng/mL in children with chronic kidney disease (CKD) stages 3–5, compared to 1000 IU of vitamin D daily.
Interventions:
Participants were randomised to either 1000 IU or 4000 IU of daily vitamin D3.
Participants:
98 paediatric patients who either received a kidney transplant or had an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2.
Outcomes:
The primary endpoint was the percentage of patients who were vitamin D replete at 6 months. Secondary endpoints included the percentage of patients who were vitamin D replete at 3 months, change in vitamin D levels at 3 and 6 months between the two arms, and side effects (hypercalcemia and hypervitaminosis D).
Follow Up:
6 months
BACKGROUND:
Correction of nutritional vitamin deficiency is recommended in children with chronic kidney disease (CKD). The optimal daily dose of vitamin D to achieve or maintain vitamin D sufficiency is unknown.
METHODS:
We conducted a phase III, double-blind, randomized trial of two doses of vitamin D3 in children ≥ 9 years of age with CKD stages 3-5 or kidney transplant recipients. Patients were randomized to 1000 IU or 4000 IU of daily vitamin D3 orally. We measured 25-hydroxvitamin D (25(OH)D) levels at baseline, 3 months and 6 months. The primary efficacy outcome was the percentage of patients who were vitamin D replete (25(OH)D ≥ 30 ng/mL) at 6 months.
RESULTS:
Ninety-eight patients were enrolled: 49 randomized into each group. Eighty (81.6%) patients completed the study and were analyzed. Baseline plasma 25(OH)D levels were ≥ 30 ng/mL in 12 (35.3%) and 12 (27.3%) patients in the 1000 IU and 4000 IU treatment groups, respectively. At 6 months, plasma 25(OH)D levels were ≥ 30 ng/mL in 33.3% (95% CI: 18.0-51.8%) and 74.4% (95% CI: 58.8-86.5%) in the 1000 IU and 4000 IU treatment groups, respectively (p = 0.0008). None of the patients developed vitamin D toxicity or hypercalcemia.
CONCLUSIONS:
In children with CKD, 1000 IU of daily vitamin D3 is unlikely to achieve or maintain a plasma 25(OH)D ≥ 30 ng/mL. In children with CKD stages 3-5, a dose of vitamin D3 4000 IU daily was effective in achieving or maintaining vitamin D sufficiency.
Dr Liset Pengel, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
The randomised controlled trial evaluated the safety and immunogenicity of a standard 3-dose (10 µg) versus a double 3-dose (20 µg) hepatitis B (HepB) vaccine in paediatric liver transplant recipients with immunologic loss who had previously received HepB immunisation. Sample size calculation showed that 68 participants needed to be recruited to allow for 10% dropouts. The trial enrolled 68 participants and 61 participants completed the study. The authors did not describe how the randomisation order was generated or whether allocation to groups was concealed. Humoral response was not significantly different between groups at any time point over 12 months. Cellular response was assessed in 42 participants and showed no statistically significant differences between groups. Safety outcomes were also similar between groups. Participants were categorised as hyporesponders, responders or nonresponders and their baseline characteristics were compared to identify factors associated with immunologic response to vaccination. Early revaccination, lower anti-HBs levels at baseline, and higher tacrolimus trough levels were associated with no seroprotective antibody levels after vaccination.
Aims:
The aim of this study was to compare the safety and immunogenicity of standard three-dose versus double three-dose hepatitis B (HepB) vaccine regimens in paediatric patients following liver transplantation.
Interventions:
Participants were randomly assigned to receive either a standard 3-dose or double 3-dose HepB vaccine.
Safety outcomes included incidence of adverse events. Immunogenicity outcomes included assessment of humoral response and cellular response.
Follow Up:
12 months
A high prevalence of hepatitis B (HepB) antibody loss after liver transplantation (LT) and de novo HepB infection (DNH) was documented, hence revaccination to prevent DNH is crucial. This study aimed to compare the safety and immunogenicity of two HepB vaccine regimens in liver-transplanted children. Liver-transplanted children who were previously immunised but showed HepB surface antibodies (anti-HBs) ≤ 100 mIU/mL were randomised to receive a standard three-dose (SD) and double three-dose (DD) vaccine intramuscularly in months 0-1-6. Anti-HBs and T-cell-specific response to the HepB antigen were assessed. A total of 61 children (54.1% male, aged 1.32 ± 1.02 years) completed the study without any serious adverse reaction. The seroprotective rate was 69.6% vs. 60% (p = 0.368) and 91.3% vs. 85% (p = 0.431) in SD and DD after the first and third 3-dose vaccinations, respectively. The geometric mean titre (95% confidence interval) of anti-HBs in SD and DD were 443.33 (200.75-979.07) vs. 446.17 (155.58-1279.50) mIU/mL, respectively, at completion. Numbers of interferon-γ-secreting cells were higher in hyporesponders/responders than in nonresponders (p = 0.003). The significant factors for the immunologic response to HepB vaccination were anti-HB levels prevaccination, tacrolimus trough levels, and time from LT to revaccination. SD and DD had comparative immunogenicity and were safe for liver-transplanted children who were previously immunised.
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This is a good quality randomised controlled trial in paediatric lung transplantation. The study was double-blinded and conducted in multiple centres. Patients were randomised to either standard immune induction with ATG (plus placebo) or to ATG and Rituximab. The primary outcome was composite graft dysfunction, death or re-listing. Unfortunately, only 11 subjects met criteria for the composite primary outcome, so the study was underpowered to demonstrate all but the most drastic of differences between the study arms. Whilst there was no significant difference in the primary outcome, there was a significantly lower generation of de novo DSA in the Rituximab arm (21% versus 73%). There was no significant difference in adverse event rates. A much larger study, and with longer follow up, is required.
Aims:
The aim of this study was to investigate whether rituximab in addition to rabbit anti-thymocyte globulin induction was effective in reducing the development of de novo donor-specific human leukocyte antigen antibodies (DSA) and improve outcomes, in paediatric lung transplant recipients.
Interventions:
Participants were randomly assigned to either the rituximab group or the placebo group
Participants:
27 paediatric lung transplant patients.
Outcomes:
The primary outcome was a composite of chronic allograft dysfunction, listing for re-transplant or death. The secondary outcomes were the incidence of primary graft dysfunction, antibody-mediated rejection and acute cellular rejection.
Follow Up:
24 months
We conducted a randomized, placebo-controlled, double-blind study of pediatric lung transplant recipients, hypothesizing that rituximab plus rabbit anti-thymocyte globulin induction would reduce de novo donor-specific human leukocyte antigen antibodies (DSA) development and improve outcomes. We serially obtained clinical data, blood, and respiratory samples for at least one year posttransplant. We analyzed peripheral blood lymphocytes by flow cytometry, serum for antibody development, and respiratory samples for viral infections using multiplex PCR. Of 45 subjects enrolled, 34 were transplanted and 27 randomized to rituximab (n = 15) or placebo (n = 12). No rituximab-treated subjects versus five placebo-treated subjects developed de novo DSA with mean fluorescence intensity >2000. There was no difference between treatment groups in time to the primary composite outcome endpoint (death, bronchiolitis obliterans syndrome [BOS] grade 0-p, obliterative bronchiolitis or listing for retransplant). A post-hoc analysis substituting more stringent chronic lung allograft dysfunction criteria for BOS 0-p showed no difference in outcome (p = .118). The incidence of adverse events including infection and rejection episodes was no different between treatment groups. Although the study was underpowered, we conclude that rituximab induction may have prevented early DSA development in pediatric lung transplant recipients without adverse effects and may improve outcomes (Clinical Trials: NCT02266888).
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This manuscript reports long-term outcomes from a randomized controlled trial of tacrolimus versus cyclosporine microemulsion in paediatric liver transplantation. The original study recruited 156 recipients between 1997 and 2000. 81% patients randomized to tacrolimus remained on protocol treatment at study end, compared to just 31% of patients on CsA. Due to the large number of crossovers, the authors sensibly present narrative data. There were numerically fewer deaths from chronic rejection/liver failure, and less cosmetic side effects with tacrolimus. Clearly, the strength of conclusions are limited by the large crossover which precluded statistical analysis. Nonetheless, it appears that CsA is poorly tolerated in this population, supporting the adoption of tacrolimus as first-line immunosuppression seen in most centres.
Aims:
The aim of this study was to report the long-term outcomes of a randomised controlled trial comparing tacrolimus (Tac) and cyclosporine immunosuppression in paediatric liver transplant recipients.
Interventions:
Patients in the original trial were randomised to either a dual Tac regimen (tacrolimus and corticosteroids) or to cyclosporine A microemulsion (CyA-ME) therapy (CyA-ME, corticosteroids and azathioprine).
Participants:
156 paediatric liver transplant recipients.
Outcomes:
The outcomes of interest included time to first rejection episode (acute or chronic), renal function, graft survival, patient survival, posttransplant lymphoproliferative disease (PTLD) incidence, Epstein-Barr virus (EBV) infection, and adverse events.
Follow Up:
14 years
UNLABELLED:
The aim of this study was to determine the long-term efficacy and safety of tacrolimus (Tac) and cyclosporine immunosuppression in pediatric liver transplantation (LTx).
METHODS:
One hundred fifty-six patients who had taken part in a multicenter, randomized, open, parallel study of Tac and corticosteroids versus cyclosporine A microemulsion (CyA-ME), corticosteroids, and azathioprine. Patients were assessed at regular intervals up to 14 y after LTx. Analysis was conducted descriptively.
RESULTS:
In a long-term follow-up, there was a similar incidence of acute rejection (Tac versus CyA-ME, 5 versus 8) and graft loss (5 versus 10). There were 11 deaths in the cohort, which were from infectious complications/malignancy in the Tac group (n = 2/5) and from chronic rejection/liver failure in the CyA-ME group (n = 3/6). A similar incidence of Epstein-Barr virus and posttransplant lymphoproliferative disease was observed (8 versus 8, 3 versus 3). However, there was a greater incidence of cosmetic adverse events in the CyA-ME cohort, with higher incidences of hypertrichosis (8 versus 27) and gum hyperplasia (20 versus 6). Growth improved equally in both groups. Overall, 81% of patients randomized to Tac remained on Tac therapy at study end, compared with 31% of patients randomized to CyA-ME. Common reasons for switching from CyA-ME included steroid-resistant/acute rejection (n = 12/8) and cosmetic changes (n = 8).
CONCLUSIONS:
This study is the first prospective, observational follow-up study of pediatric patients randomized to Tac and CyA-ME to evaluate long-term outcomes. Our analysis was limited by the degree of switchover between the cohorts; however, there were fewer deaths from chronic rejection/liver failure and reduced adverse events with Tac. Long-term use of Tac and Tac combination therapy appears to be safe and effective immunosuppression for pediatric LTx recipients.
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This interesting multicentre study investigates the use of virus-specific T-cell activity for monitoring of immunosuppression (in addition to trough levels) in a paediatric kidney transplant population. The authors conclude that the monitoring strategy is safe and allows a reduction in immunosuppression exposure without compromising clinical outcomes. The primary endpoint of an improvement in eGFR at 24 months was not met. The study suffers from being underpowered – the original sample size calculation only allowed for a power of 50% to detect a 7.5 ml/min difference in GFR. It would be interesting to see larger studies with more conventional immunosuppression, and also in adult populations, to fully evaluate this monitoring strategy.
Aims:
The aim of this study was to determine whether additional steering of immunosuppressive therapy by evaluating virus-specific T cell (Tvis) levels optimizes dosing of immunosuppressants.
Interventions:
Participants were randomised to either the intervention or control group, both of which received trough-level monitoring of immunosuppressive therapy. The intervention group received additional steering of immunosuppressive therapy by Tvis levels.
Participants:
64 paediatric renal transplant recipients.
Outcomes:
The primary outcome was estimated glomerular filtration rate (eGFR). The secondary outcomes were the incidence and number of acute rejections, viral infections, development of donor-specific antibodies, adverse events, serious adverse events, and doses and trough levels of immunosuppressants.
Follow Up:
2 years
BACKGROUND:
Pharmacokinetic monitoring is insufficient to estimate the intensity of immunosuppression after transplantation. Virus-specific T cells correlate with both virus-specific and general cellular immune defense. Additional steering of immunosuppressive therapy by virus-specific T cell levels might optimize dosing of immunosuppressants.
METHODS:
In a multicenter, randomized, controlled trial, we randomized 64 pediatric kidney recipients to a control group with trough-level monitoring of immunosuppressants or to an intervention group with additional steering of immunosuppressive therapy by levels of virus-specific T cells (quantified by cytokine flow cytometry). Both groups received immunosuppression with cyclosporin A and everolimus in the same target range of trough levels. Primary end point was eGFR 2 years after transplantation.
RESULTS:
In the primary analysis, we detected no difference in eGFR for the intervention and control groups 2 years after transplantation, although baseline eGFR 1 month after transplantation was lower in the intervention group versus the control group. Compared with controls, patients in the intervention group received significantly lower daily doses of everolimus and nonsignificantly lower doses of cyclosporin A, resulting in significantly lower trough levels of everolimus (3.5 versus 4.5 µg/L, P<0.001) and cyclosporin A (47.4 versus 64.1 µg/L, P<0.001). Only 20% of patients in the intervention group versus 47% in the control group received glucocorticoids 2 years after transplantation (P=0.04). The groups had similar numbers of donor-specific antibodies and serious adverse events.
CONCLUSIONS:
Steering immunosuppressive therapy by virus-specific T cell levels in addition to pharmacokinetic monitoring seems safe, results in a similar eGFR, and personalizes immunosuppressive therapy by lowering exposure to immunosuppressive drugs, likely resulting in lower drug costs.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER:
IVIST trial, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2009-012436-32 and ISRCTN89806912.
CET Conclusion