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.
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This manuscript reports a secondary analysis of a randomized trial of steroid withdrawal in pediatric renal transplant recipients. The authors report significantly lower incidence of hypertension, lower use of antihypertensive drugs and restoration of the normal circadian rhythm in the steroid withdrawal group. The results are impressive, suggesting a significant benefit which may have an impact on long-term cardiovascular risk. There are some caveats – the sample size is very small (28 patients) and a subset of just 2/3 of the originally recruited patients, leaving the possibility of recruitment bias. The hypertension score used is not validated, and the original study was performed nearly 10 years ago, so the relevance to current-day practice is uncertain.
Expert Review
Reviewer:
John M. Barry, MD, Professor of Urology, Professor of Surgery, Division of Abdominal Organ Transplantation, Oregon Health & Science University, Portland
Conflicts of Interest:
No
Clinical Impact Rating
4
Review:
The key findings in this nicely designed small study of pediatric kidney transplant recipients on triple maintenance immunosuppression with cyclosporine, mycophenolate mofetil and methyl prednisolone were 1) ambulatory blood pressure monitoring (ABPM) is preferred to repeated office blood pressure (BP) measurements for the documentation of hypertension and nocturnal BP rhythms, 2) hypertension score, which includes BP level and number of antihypertensive drugs, is the preferred measurement of response to antihypertensive therapy and 3) when compared with controls, glucocorticoid withdrawal in children with well-preserved renal transplant function was associated with lower artrerial hypertension, lower need for antihypertensive medication, restoration of circadian BP rhythm, decreased body mass index and no reduction of renal function. Are the study results such that the methodology should be applied to future studies for the management of hypertension? Yes. What are the implcations for clinical practice? It's reasonable to attempt gradual glucocorticoid withdrawal in pediatric and adult kidney transplant recipients with stable renal function and no evidence of rejection for the preceding 6 months.
Aims:
An RCT substudy to investigate the impact of steroid withdrawal on blood pressure control and nocturnal blood pressure dipping in pediatric renal transplant recipients.
Interventions:
Late steroid (prednisone) withdrawal (≥1 year posttransplant) was compared with continuous steroid treatment under cyclosporine (CsA)- and mycophenolate mofetil (MMF)-based immunosuppression. Blood pressure was measured using ambulatory blood pressure monitoring (ABPM) over 24 hour monitoring periods in conjunction with a diary of events.
Participants:
28 pediatric renal allograft recipients (first or second transplant; aged <18 years; low immunologic risk; no acute rejection episode within the last 6 months before study entry) with ABPM data (≥40 recordings, including ≥8 nighttime readings).
Outcomes:
Daytime and nighttime blood pressure by ABPM at baseline and Month 15. A hypertension score (based on blood pressure level plus number of antihypertensive treatments) was calculated at baseline and Month 15.
Follow Up:
15 months (equivalent to 12 months after steroid withdrawal)
BACKGROUND:
Variable effects of steroid minimization strategies on blood pressure in pediatric renal transplant recipients have been reported, but data on the effect of steroid withdrawal on ambulatory blood pressure and circadian blood pressure rhythm have not been published so far.
METHODS:
In a prospective, randomized, multicenter study on steroid withdrawal in pediatric renal transplant recipients (n = 42) on cyclosporine, mycophenolate mofetil, and methylprednisolone, we performed a substudy in 28 patients, aged 11.2 ± 3.8 years, for whom ambulatory blood pressure monitoring (ABPM) data were available.
RESULTS:
In the steroid-withdrawal group, the percentage of patients with arterial hypertension, defined as systolic and/or diastolic blood pressure values recorded by ABPM > 1.64 SDS and/or antihypertensive medication, at month 15 was significantly lower (35.7%, p = 0.002) than in controls (92.9%). The need of antihypertensive medication dropped significantly by 61.2% (p < 0.000 vs. control), while in controls, it even rose by 69.3%. One year after steroid withdrawal, no patient exhibited hypertensive blood pressure values above the 95th percentile, compared to 35.7% at baseline (p = 0.014) and to 14.3% of control (p = 0.142). The beneficial impact of steroid withdrawal was especially pronounced for nocturnal blood pressure, leading to a recovered circadian rhythm in 71.4% of patients vs. 14.3% at baseline (p = 0.002), while the percentage of controls with an abnormal circadian rhythm (35.7%) did not change.
CONCLUSIONS:
Steroid withdrawal in pediatric renal transplant recipients with well-preserved allograft function is associated with less arterial hypertension recorded by ABPM and recovery of circadian blood pressure rhythm by restoration of nocturnal blood pressure dipping.
Mr John O'Callaghan, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This is a well conducted and written study that scores moderately on quality assessment. The study was adequately randomised, however it was not blinded after allocation when this could have been possible. The initial graft function (a composite of measures) was not different between groups. EGFR on days 1 and 2 was significantly better in the Eculizumab group. Graft and one-year survival was not different between groups. Importantly there were 4 early graft losses in the Eculizumab group, during a flu-like infection that resulted in renal vein thrombosis in unvaccinated children. There was a reduction in DGF (0 versus 38% in deceased donors) with Eculizumab, but this outcome has not been statistically assessed and we suspect it is not statistically significant, given the small numbers included. There was no difference in acute rejection rate. It is unclear whether any power calculation was done to design the study, and this is possibly why it is small in number and no great differences can be seen between groups. The substantial immune suppression at the time of transplantation in this study seems to have had an overall negative impact through graft loss, although there was an improvement in early graft function in the first 2 days.
Expert Review
Reviewer:
Dr Richard Trompeter, UCL Center for Nephrology, Royal Free Campus, London, UK.
Conflicts of Interest:
No
Clinical Impact Rating
5
Review:
Clinical trials in children undergoing renal transplantation are few and far between, and unless designed as multi centre studies will always be vulnerable to the problem of small numbers and the challenge of adequate double blinding. Having said this, the authors should be commended for attempting to examine a novel method of improving graft function. The problem with ischaemic reperfusion injury is that it is not a single entity and however evaluated will necessarily be different between all patients recruited into a clinical trial, especially a trial that includes deceased and living donor kidneys. The use of an expensive, monoclonal antibody, which blocks complement activation in children who have not been adequately immunised against common infections, is a high-risk strategy, and probably accounts for the significant mortality and morbidity in the eculizumab treated group. I wonder if this risk was specifically explained to parents. Better early graft function compared to the control group would not be considered as adequate justification to recommend such treatment in routine paediatric renal transplantation.
Aims:
To determine whether Eculizumab is an effective agent in the prevention or amelioration of Ischemia-reperfusion injury (IRI) in paediatric kidney transplant recipients.
Interventions:
Patients were randomized to either an intervention group and received eculizumab 700 mg/m2, administered intravenously over one hour after admission to the hospital, versus control group.
Participants:
57 paediatric kidney transplant recipients aged ≤ 18 years.
Outcomes:
Primary measured outcomes included initial graft function and delayed graft function. Secondary measured outcomes included patient and graft survival, rejection, renal function and the banff scores of graft biopsies.
Follow Up:
3 years
Ischemia-reperfusion injury has multiple effects on a transplanted allograft, including delayed or impaired graft function, compromised long-term survival, and an association with an increased incidence of rejection. Eculizumab, a monoclonal antibody blocking terminal complement activation, has been postulated to be an effective agent in the prevention or amelioration of IRI. We performed a single-center prospective, randomized controlled trial involving 57 pediatric kidney transplant recipients between 2012 and 2016. The immunosuppressive protocol included two doses of alemtuzumab; half of the patients were randomized to receive a single dose of eculizumab prior to transplantation. Maintenance immunosuppression was based on a combination of low-dose tacrolimus and mycophenolate, without steroids. Eculizumab-treated patients had a significantly better early graft function, less arteriolar hyalinosis and chronic glomerulopathy on a protocol biopsies taken on day 30, 1 year, and 3 years after transplantation. In the eculizumab group, four non-vaccinated children lost their grafts during the course of a flu-like infection. Eculizumab is associated with better early graft function and improved graft morphology; however, there was an unacceptably high number of early graft losses among the eculizumab-treated children. While a promising strategy, the best approach to complement inhibition remains to be established.
Sir Peter Morris, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This is an important phase I study comparing vaccination with high dose trivalent inactivated influenza vaccine to a standard dose vaccine in paediatric patients between 3-17 years of age and at least 6 months after a solid organ transplant. 38 paediatric recipients were enrolled with a mean age of 11.25 years and were recipients of heart, liver, lung and intestinal transplants, the majority being renal, heart and liver. No severe adverse events were reported and in particular there was no evidence of rejection occurring after vaccination. There were more local symptoms in the high dose group and more systemic symptoms again in the high dose group. However there was a much higher percentage of a significant rise in titre in the high dose group compared to the standard dose group, against H3N2. The authors conclude that the high dose vaccine was well tolerated and may have increased in immunogenicity and recommend that a larger phase II study be carried out.
Expert Review
Reviewer:
Dr Richard Trompeter, UCL Centre for Nephrology, The Royal Free Hospital Campus, London, United Kingdom
Conflicts of Interest:
No
Clinical Impact Rating
4
Review:
There still exists an important balance between morbidity and mortality associated with viral illness versus any potential adverse effects of a vaccine when administered to a paediatric recipient of a solid organ transplant. Any forward step in providing an answer to this question has to be considered a benefit for clinical practice. In this small, two centre, prospective randomized double blind phase 1 study, safety and immunogenicity between a standard dose and a high dose inactivated influenza vaccine were compared for both safety and immunogenicity. Although there were more immediate local and systemic reactions when compared to the group who received the standard vaccine the cohort who received the high dose exhibited an impressive rise in the protective titre to H3N2 suggesting a benefit. Graft rejection was not associated with either form of rejection in this clinical trial.The authors point out important limitations to this study, specifically the small number of patients recruited i.e. 60, and that those who received the high dose vaccine had a higher mean age, possibly affecting immune response. The study was subject to a two week halt rule. This was designed so that the first 15 subjects enrolled could be monitored for allograft rejection, this necessarily delayed enrolment. The authors advocate that a phase 2 trial is now needed to assess immunogenicity of the high dose vaccine in this varied group of solid organ transplant recipients i.e. kidney, liver, heart lung and intestine all of who receive a different immunosuppressive regimen. The international paediatric transplant community should rise to the challenge.
Aims:
To compare standard-dose (SD) versus high-dose (HD) trivalent inactivated influenza vaccine in paediatric solid organ transplant patients.
Interventions:
Patients were randomized to receive 0.5 mL of either the HD (60 µg) or SD (15 µg) trivalent inactivated influenza vaccine (TIV) intramuscularly. Subjects <9 yr. of age received either one or two doses of the vaccine based on the Advisory Committee on Immunization Practices (ACIP) recommendations.
Participants:
38 paediatric patients between the ages of three and seventeen.
Outcomes:
The primary outcome measures were safety and the frequency of solicited local and systemic reactogenicity, adverse events, and serious adverse events. The secondary outcome measures were immunogenicity and the comparison of the geometric mean titer of hemagglutination inhibition titers, percent of children who develop hemagglutination inhibition antibody titers ≥1:40, and percent of children who develop seroconversion.
Follow Up:
180 days
Children who have undergone SOT mount a lower immune response after vaccination with TIV compared to healthy controls. HD or SD TIV in pediatric SOT was given to subjects 3-17 yr and at least six months post-transplant. Subjects were randomized 2:1 to receive either the HD (60 μg) or the SD (15 μg) TIV. Local and systemic reactions were solicited after each vaccination, and immune responses were measured before and after each vaccination. Thirty-eight subjects were enrolled. Mean age was 11.25 yr; 68% male, 45% renal, 26% heart, 21% liver, 5% lung, and 5% intestinal. Twenty-three subjects were given HD and 15 SD TIV. The median time since transplant receipt was 2.2 yr. No severe AEs or rejection was attributed to vaccination. The HD group reported more tenderness and local reactions, fatigue, and body ache when compared to the SD cohort, but these were considered mild and resolved within three days. Subjects in the HD group demonstrated a higher percentage of four-fold titer rise to H3N2 compared to the SD group. HD influenza vaccine was well tolerated and may have increased immunogenicity. A phase 2 trial is needed to confirm.
Dr Lara Danziger-Isakov, Cincinnati Children's Hospital Medical Center, Ohio, United States of America.
Conflicts of Interest:
No
Clinical Impact Rating
2
Review:
A randomized evaluation of fluid intake over a month period between pediatric renal transplant recipients with and without use of an interactive water bottle was performed. The subjects who used the water bottles had significantly increased likelihood that fluid intake goals would be achieved. However, there was no significant impact on laboratory values during the short study. Interestingly, only 50% of the participants in the intervention arm used the water bottle most days, highlighting the difficulty with adherence to proposed interventions even in a more-controlled research setting. The impact of adequate fluid intake on renal graft function is not well-established in the literature as described by the investigators at the onset of the study. Continued exploration of this treatment goal perhaps over an extended period of time may provide further insight into long-term outcomes and the impact of adequate fluid intake in this population.
Hydration is important post-renal transplant to maintain adequate renal perfusion and graft function. Adherence to fluid recommendations is challenging given barriers to staying hydrated. There are no studies of adherence to fluid intake recommendations following pediatric renal transplant. Through this pilot study, we sought to determine whether the use of a commercially available interactive water bottle would lead to better adherence to recommended fluid intake and improved kidney functioning post-transplant relative to standard of care. Participants included 32 youth ages 7-19 ≥1 month post-kidney transplant randomized to the intervention (HydraCoach(®) water bottle) or standard education control group. Laboratory records were reviewed for serum chemistries (Na, BUN, creatinine) at baseline and one-month follow-up, and participants recorded daily fluid intake for 28 days. Those in the intervention group were significantly more likely to meet or exceed their fluid target, but this did not translate into better kidney functioning. Participants in the intervention group largely reported satisfaction with the water bottle and were likely to continue its use. While an interactive water bottle providing real-time feedback may be a promising intervention to help pediatric kidney transplant patients meet fluid goals, it did not appear to impact kidney function.
Dr Arthur Matas, University of Minnesota, United States of America
Conflicts of Interest:
None
Clinical Impact Rating
0
Review:
This manuscript reports the design of a multi-centre prospective, randomised trial to assess whether, in paediatric transplant recipients, adjusting immunosuppression levels by measurement of trough levels plus CMV-virus specific T cells is superior to adjustment of levels by use of troughs alone. The primary end-point is GFR at 2 years. Secondary end-points include the number and severity of CMV infections. In addition, if CMV infection develops, those in the trough based on viral-specific T cells Within the trial, there is a second randomization for those in the measurement of T cells group; those who develop viral infection will be randomized to fixed time treatment vs treatment dependent on There is no preliminary data
BACKGROUND:
After kidney transplantation, immunosuppressive therapy causes impaired cellular immune defense leading to an increased risk of viral complications. Trough level monitoring of immunosuppressants is insufficient to estimate the individual intensity of immunosuppression. We have already shown that virus-specific T cells (Tvis) correlate with control of virus replication as well as with the intensity of immunosuppression. The multicentre IVIST01-trial should prove that additional steering of immunosuppressive and antiviral therapy by Tvis levels leads to better graft function by avoidance of over-immunosuppression (for example, viral infections) and drug toxicity (for example, nephrotoxicity).
METHODS/DESIGN:
The IVIST-trial starts 4 weeks after transplantation. Sixty-four pediatric kidney recipients are randomized either to a non-intervention group that is only treated conservatively or to an intervention group with additional monitoring by Tvis. The randomization is stratified by centre and cytomegalovirus (CMV) prophylaxis. In both groups the immunosuppressive medication (cyclosporine A and everolimus) is adopted in the same target range of trough levels. In the non-intervention group the immunosuppressive therapy (cyclosporine A and everolimus) is only steered by classical trough level monitoring and the antiviral therapy of a CMV infection is performed according to a standard protocol. In contrast, in the intervention group the dose of immunosuppressants is individually adopted according to Tvis levels as a direct measure of the intensity of immunosuppression in addition to classical trough level monitoring. In case of CMV infection or reactivation the antiviral management is based on the individual CMV-specific immune defense assessed by the CMV-Tvis level. Primary endpoint of the study is the glomerular filtration rate 2 years after transplantation; secondary endpoints are the number and severity of viral infections and the incidence of side effects of immunosuppressive and antiviral drugs.
DISCUSSION:
This IVIST01-trial will answer the question whether the new concept of steering immunosuppressive and antiviral therapy by Tvis levels leads to better future graft function. In terms of an effect-related drug monitoring, the study design aims to realize a personalization of immunosuppressive and antiviral management after transplantation. Based on the IVIST01-trial, immunomonitoring by Tvis might be incorporated into routine care after kidney transplantation.
TRIAL REGISTRATION:
EudraCT No: 2009-012436-32, ISRCTN89806912 (17 June 2009).
CET Conclusion