Transplant Library

Transplant Trial Watch

The Transplant Trial Watch provides a monthly overview of the 10 most important new clinical trials in organ transplantation, selected and reviewed by the Peter Morris Centre for Evidence in Transplantation (Oxford University).
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February 2023

Kidney
Burden of neutropenia and leukopenia among adult kidney transplant recipients: A systematic literature review of observational studies
  • Raval AD
  • Kistler KD
  • Tang Y
  • Vincenti F
Transpl Infect Dis. 2022 Dec 12;e14000 doi: 10.1111/tid.14000.
CET Conclusion
Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: There are some good indicators of best-practice in the process of this systematic review, such as reference to the PRISMA guidelines and searching multiple databases. In addition, conference abstracts were searched to identify further possibly relevant information. However a single author screened abstracts and subsequently full texts for inclusion. Data was extracted by a sole author and validated by another, rather than being extracted in duplicate and then resolved. These are potential sources of bias or error. A formal assessment of study quality was completed, but only by one author. A large number of studies were included (82), with a total patient population of 41,705. Unfortunately, there was a wide variation in the white blood cell and neutrophil thresholds to define leukopenia and neutropenia. WBC<3000/microlitre was most commonly used for leukopenia (15 studies) and neutrophils<1000/microlitre was most commonly used for neutropenia (12 studies). The authors then divide the results by immune induction regimen and length of follow up, which produces a range of rates for leukopenia and neutropenia that is reliant on single studies in many incidences. Whilst this systematic review provides an overview, if a more specific research question had been set at the outset then more firm conclusions could have been drawn.
Study Details
Aims: The aim of this study was to summarise the available evidence regarding the incidence, risk factors and clinical and economic outcomes of leukopenia and neutropenia (L/N) following kidney transplantation.
Interventions: Electronic databases including MEDLINE, Embase, and the Cochrane Library, as well as conference proceedings were searched. Studies were selected for inclusion and data were extracted by a single researcher. The methodological quality of the included studies was assessed using the Newcastle-Ottawa tool for non-randomised studies, Motheral et al checklist for retrospective and registry studies, and the Joanna Briggs Institute Critical Appraisal Checklist for analytical cross-sectional studies.
Participants: 82 studies were included in the review.
Outcomes: Incidence or prevalence of leukopenia/neutropenia, the adjusted risk factors for leukopenia/neutropenia, the association between leukopenia/neutropenia occurring posttransplantation, infection, allograft rejection, graft loss, and mortality, healthcare resource utilization and healthcare costs.
Follow Up: N/A
BACKGROUND:

Leukopenia and neutropenia (L/N) may affect treatment decisions, potentially resulting in poor clinical and economic outcomes among kidney transplant recipients (KTRs). The burden of L/N is poorly quantified systematically. This systematic literature review aimed to summarize the incidence of, risk factors for, and clinical and economic outcomes associated with L/N post-KT.

METHODS:

We systematically searched MEDLINE, Embase, and the Cochrane Library (from database inception-June 14, 2021) and conferences (past 3 years) to identify observational studies examining epidemiology, risk factors, or outcomes associated with L/N among adult KTRs.

RESULTS:

Of 2081 records, 82 studies met inclusion criteria. Seventy-three studies reported the epidemiology of L/N post-KT. Pooled incidence of neutropenia, defined as absolute neutrophil counts (ANC) <1000/μl, ranged from 13% to 48% within 1-year post-transplant; ANC <500/μl ranged from 15% to 20%. Leukopenia, defined as white blood cell counts <3500/μl, was 19% to 83%. Eleven studies reported independent risk factors associated with L/N post-KT. D+/R- cytomegalovirus status, mycophenolic acid (MPA), and tacrolimus use were the most consistent risk factors across studies. Fourteen studies reported L/N-associated clinical outcomes. We noted a trend toward a positive association between neutropenia and acute rejection/opportunistic infections. Mixed findings were noted on the association between L/N and graft failure or mortality. Dosage modifications of valganciclovir, MPA, cotrimoxazole, and anti-thymoglobulin and the need for granulocyte colony-stimulating factor (G-CSF) use were common with L/N.

CONCLUSION:

Findings suggest post-transplant L/N were common and associated with frequent modifications of immunosuppressive agents, requiring G-CSF use, and rejection or opportunistic infections. Findings highlight the need for interventions to reduce risk of L/N post-KT.
Rapamycin and inulin for third-dose vaccine response stimulation (RIVASTIM): Inulin - study protocol for a pilot, multicentre, randomised, double-blinded, controlled trial of dietary inulin to improve SARS-CoV-2 vaccine response in kidney transplant recipients
  • Singer J
  • Tunbridge M
  • Perkins GB
  • Salehi T
  • Ying T
  • et al.
BMJ Open. 2022 Dec 1;12(12):e062747 doi: 10.1136/bmjopen-2022-062747.
CET Conclusion
Reviewer: Mr John Fallon, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This manuscript describes the protocol of an upcoming multi-centre, double blinded RCT of a size larger than many previous RCTs, attempting to assess gut biome effects on vaccine responses. Of the 26 previously conducted RCTs around 50% have demonstrated some beneficial effects of probiotics on vaccine response. It has been commented that the response may be reduced as none of these trials contained patients who had a disrupted microbiome, including immunosuppressed renal recipients. The intervention has been previously demonstrated to improve the gut biome and increase reactivity to parenteral vaccines. The authors propose a well-designed study with sound methodology, containing a clearly defined primary outcome which can be unambiguously tested. The proposed intervention is unlikely to have any serious adverse events and is inexpensive. Based on previous literature it is a study that has good potential.
Study Details
Aims: This study aims to examine whether dietary fibre supplementation will lead to attenuation of gut dysbiosis and promote vaccine responsiveness in renal transplant patients.
Interventions: Patients will be randomly assigned to receive either inulin (active) or maltodextrin (placebo).
Participants: Kidney transplant recipients (age ≥ 18 years).
Outcomes: The primary endpoint is the proportion of participants to achieve in vitro neutralisation of live SARS-CoV-2 virus four weeks after the third dose of the COVID-19 vaccine. Secondary endpoints are safety and tolerability of dietary inulin, vaccine-specific immune cell populations and responses, and the diversity and differential abundance of gut microbiota.
Follow Up: 4- 6 weeks following vaccination.
INTRODUCTION:

Kidney transplant recipients (KTRs) are at an increased risk of hospitalisation and death from COVID-19. Vaccination against SARS-CoV-2 is our primary risk mitigation strategy, yet vaccine effectiveness in KTRs is suboptimal. Strategies to enhance vaccine efficacy are therefore required. Current evidence supports the role of the gut microbiota in shaping the immune response to vaccination. Gut dysbiosis is common in KTRs and is a potential contributor to impaired COVID-19 vaccine responses. We hypothesise that dietary fibre supplementation will attenuate gut dysbiosis and promote vaccine responsiveness in KTRs.

METHODS AND ANALYSIS:

Rapamycin and inulin for third-dose vaccine response stimulation-inulin is a multicentre, randomised, prospective, double-blinded, placebo-controlled pilot trial examining the effect of dietary inulin supplementation prior to a third dose of COVID-19 vaccine in KTRs who have failed to develop protective immunity following a 2-dose COVID-19 vaccine schedule. Participants will be randomised 1:1 to inulin (active) or maltodextrin (placebo control), administered as 20 g/day of powdered supplement dissolved in water, for 4 weeks prior to and following vaccination. The primary outcome is the proportion of participants in each trial arm that achieve in vitro neutralisation of live SARS-CoV-2 virus at 4 weeks following a third dose of COVID-19 vaccine. Secondary outcomes include the safety and tolerability of dietary inulin, the diversity and differential abundance of gut microbiota, and vaccine-specific immune cell populations and responses.

ETHICS AND DISSEMINATION:

Ethics approval was obtained from the Central Adelaide Local Health Network (CALHN) Human Research Ethics Committee (HREC) (approval number: 2021/HRE00354) and the Sydney Local Health District (SHLD) HREC (approval numbers: X21-0411 and 2021/STE04280). Results of this trial will be published following peer-review and presented at scientific meetings and congresses.

TRIAL REGISTRATION NUMBER:

ACTRN12621001465842.
Treatment of early borderline lesions in low immunological risk kidney transplant patients: a Spanish multicenter, randomized, controlled parallel-group study protocol: the TRAINING study
  • Hernández D
  • Vázquez-Sánchez T
  • Sola E
  • Lopez V
  • Ruiz-Esteban P
  • et al.
BMC Nephrol. 2022 Nov 7;23(1):357 doi: 10.1186/s12882-022-02989-z.
CET Conclusion
Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This is a clearly written protocol for a multicentre randomised controlled trial. The hypothesis is that treatment of early borderline lesions (within 3 months of transplant) will prevent or decrease progression of IFTA. The treatment used will be rabbit ATG, so a safety study will be as important as any improvement at a histological level. The study is based on the fact that early, subclinical lesions are an indicator of subsequent drop in graft function and reduced graft survival, and that treatment at this stage will have a positive impact. Length of follow up is 24 months, which should be long enough to assess efficacy and safety in general. Patients will require a 3-month protocol biopsy to then determine whether or not they enter randomisation. The sample size calculation has made reference to previous data and expected dropout rates.
Study Details
Aims: This study aims to investigate the effects of treating early borderline lesions with polyclonal rabbit antithymocyte globulin (Grafalon®) in comparison to conventional therapy, in low immunological risk kidney transplant recipients.
Interventions: Participants will be randomly assigned to either the Grafalon® group or the standard treatment group.
Participants: The study will randomise 80 kidney transplant recipients with low immunological risk.
Outcomes: The primary outcomes are the presence of interstitial fibrosis/tubular atrophy (IFTA) and graft function. The main efficacy outcomes are function and histological lesions.
Follow Up: N/A
BACKGROUND:

Subclinical inflammation, including borderline lesions (BL), is very common (30-40%) after kidney transplantation (KT), even in low immunological risk patients, and can lead to interstitial fibrosis/tubular atrophy (IFTA) and worsening of renal function with graft loss. Few controlled studies have analyzed the therapeutic benefit of treating these BL on renal function and graft histology. Furthermore, these studies have only used bolus steroids, which may be insufficient to slow the progression of these lesions. Klotho, a transmembrane protein produced mainly in the kidney with antifibrotic properties, plays a crucial role in the senescence-inflammation binomial of kidney tissue. Systemic and local inflammation decrease renal tissue expression and soluble levels of α-klotho. It is therefore important to determine whether treatment of BL prevents a decrease in α-klotho levels, progression of IFTA, and loss of kidney function.

METHODS:

The TRAINING study will randomize 80 patients with low immunological risk who will receive their first KT. The aim of the study is to determine whether the treatment of early BL (3rd month post-KT) with polyclonal rabbit antithymocyte globulin (Grafalon®) (6 mg/kg/day) prevents or decreases the progression of IFTA and the worsening of graft function compared to conventional therapy after two years post-KT, as well as to analyze whether treatment of BL with Grafalon® can modify the expression and levels of klotho, as well as the pro-inflammatory cytokines that regulate its expression.

DISCUSSION:

This phase IV investigator-driven, randomized, placebo-controlled clinical trial will examine the efficacy and safety of Grafalon® treatment in low-immunological-risk KT patients with early BL.

TRIAL REGISTRATION:

clinicaltrials.gov : NCT04936282. Registered June 23, 2021, https://clinicaltrials.gov/ct2/show/NCT04936282?term=NCT04936282&amp;draw=2&amp;rank=1 . Protocol Version 2 of 21 January 2022.

SPONSOR:

Canary Isles Institute for Health Research Foundation, Canary Isles (FIISC). mgomez@fciisc.org .
Comparative Study of 2 Extended-Release Tacrolimus Formulations in Kidney Transplantation
  • Cholbi Vives E
  • Espí Reig J
  • Cruz Sánchez A
  • Moreno Maestre E
  • Ventura Galiano A
  • et al.
Transplant Proc. 2022 Nov;54(9):2434-2438 doi: 10.1016/j.transproceed.2022.10.001.
CET Conclusion
Reviewer: Mr John Fallon, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This study was a prospective, randomised parallel single-centre study comparing Advagraft, a brand-name formulation of ER-Tac with a newer generic formulation, Conferoport. The study aimed to assess the safety and efficacy of the two formulations over a 12-month follow-up period after transplantation. Within this small unblinded cohort the authors found no significant difference between the groups in the doses prescribed, the blood tacrolimus levels, blood creatinine levels or proteinuria. In both groups, there was a downward trend over time in the tacrolimus dose and blood level, along with a downward trend in creatinine and proteinuria over the 12 months. There were 4 cases of biopsy-proven acute rejection, 2 in Conferoport (6.5%) and 2 in Advagraft (9.5%). The study duration is limited to 12-months so no assessment of important prolonged duration side-effects such as malignancy can be assessed. While the analysis shows no difference between the formulations, suggesting equivalent safety and efficacy, the small samples size restricts the power of the study, meaning confidence in the generic formulation is currently limited. Clinical impact is limited as the level of evidence produced is not adequate to confidently alter clinical practice currently. However, the possibility of generic formulations could be of financial benefit, as a patient on Advagraf at 6mg per day equates to an annual medication cost of around £3000.
Study Details
Aims: This study aimed to compare the efficacy and safety of the generic ER-Tac (Conferoport) versus the reference ER-Tac (Advagraf) in kidney transplant recipients.
Interventions: Participants were randomised to either the Conferoport group or the Advagraf group.
Participants: 52 kidney transplant recipients.
Outcomes: The main outcomes of interest were tacrolimus dose and levels, proteinuria, creatinine, coefficient of variation, and graft rejection.
Follow Up: 12 months
BACKGROUND:

During the 1900s, tacrolimus became the mainstay immunosuppressive agent to prevent rejection after kidney transplant. Subsequently, an extended-release tacrolimus (ER-Tac) formulation was developed to improve adherence, and its generic version has been marketed over the last years. This study examines the differences in efficacy and safety between the generic ER-Tac (Conferoport) and the reference brand-name drug (Advagraf).

METHODS:

Prospective, randomized and parallel single-center study (May 2020 to June 2021) with 52 kidney transplant recipients who were randomly assigned to 1 of the following groups: study group (Conferoport, n = 31) and control group (Advagraf, n = 21). The variables of interest were collected and analyzed to compare tacrolimus efficacy and safety between them. Demographic characteristics of the patients and clinical donor data were homogeneous in both groups (P > .05).

RESULTS:

No statistically significant differences were found among treatments regarding dosage used, levels, creatinine, and proteinuria (P > .05), with these variables presenting a downward trend during follow-up and, consequently, the improvement of graft function. Analyses also revealed the absence of differences concerning the incidence of acute rejection and intrapatient variability (coefficient of variation) throughout the first year of evolution between both formulations (P > .05). A total of 5 graft losses occurred, 2 resulting from patient death.

CONCLUSIONS:

In our experience, we found no significant differences between the measured parameters in relation to the efficacy and safety profile of both drugs, with generic ER-Tac being an alternative comparable with the reference brand-name ER-Tac.
Lack of Efficacy and Safety of Eculizumab for Treatment of Antibody-Mediated Rejection Following Renal Transplantation
  • Heo S
  • Park Y
  • Lee N
  • Kim Y
  • Kim YN
  • et al.
Transplant Proc. 2022 Oct;54(8):2117-2124 doi: 10.1016/j.transproceed.2022.08.008.
CET Conclusion
Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This is a small randomised controlled trial in Antibody Mediated Rejection (AMR) of renal transplants. Patients with confirmed AMR were randomised to standard care (plasmapheresis and IVI Ig as prescribed by clinicians) or to eculizimab infusion. There were 11 patients included, so a relatively small number, but this would have been dependent on a low number of potential patients to include. The study commenced in 2013 and has only just come to publication. It is not clear that the study was adequately randomised, and there was also the possibility for patients to cross over to the other arm if treatment failed, which further confuses the results and interpretation. There was also considerable variation in additional treatments, such as the use of Campath, Basiliximab, Rituximab and ATG. The main conclusion to draw from this small study is that eculizumab alone did not reverse rejection in any case, prevent progression to chronic AMR or transplant glomerulopathy.
Study Details
Aims: This study aimed to compare the efficacy and safety of eculizumab versus plasmapheresis (PP) and intravenous immunoglobulin therapy (IVIG) in kidney transplant patients with antibody-mediated rejection (AMR).
Interventions: Participants were randomly assigned to receive either eculizumab or standard of care (PP combined with IVIG).
Participants: 11 kidney transplant recipients between 18 and 75 years of age.
Outcomes: The main outcomes of interest were as follows: mean serum creatinine, rejection reversal, graft loss and serious adverse events.
Follow Up: 12 months
BACKGROUND:

We evaluated the efficacy and safety of eculizumab in comparison with plasmapheresis and intravenous immunoglobulin therapy in renal transplant recipients diagnosed with antibody-mediated rejection (AMR).

METHODS:

This was a multicenter, open-label, prospective, randomized analysis. The patients were randomized by therapy type (eg, eculizumab infusions or standard of care [SOC]: plasmapheresis/intravenous immunoglobulin). The patients (ie, eculizumab arm: 7 patients, SOC arm: 4 patients) were evaluated for the continued presence of donor-specific antibodies (DSAs) and C4d (staining on biopsy), as well as histologic evidence, using repeat renal biopsy after treatment.

RESULTS:

The allograft biopsies revealed that eculizumab did not prevent the progression to transplant glomerulopathy. Only 2 patients in the SOC arm experienced rejection reversal, and no graft losses occurred in either group. After AMR treatment, the DSA titers generally decreased compared to titers taken at the time of AMR diagnosis. There were no serious adverse effects in the eculizumab arm.

CONCLUSIONS:

Eculizumab alone cannot treat AMR effectively and does not prevent acute AMR from progressing to chronic AMR or transplant glomerulopathy. However, it should be considered as a potential alternative therapy because it may be associated with decreased DSA levels.
Efficacy of Clonidine as an Adjuvant to Ropivacaine in Transversus Abdominis Plane Block in Adult Renal Transplant Recipients: A Double-blinded Randomized Controlled Trial
  • Nath S
  • Arora MK
  • Chhabra A
  • Baidya DK
  • Subramaniam R
  • et al.
Anesth Essays Res. 2022 Apr-Jun;16(2):231-237 doi: 10.4103/aer.aer_92_22.
CET Conclusion
Reviewer: Mr Keno Mentor, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This randomised controlled trial examines the potential benefit and harm of adding clonidine to the current standard transversus abdominis plan (TAP) block regimen in patients undergoing renal transplantation. The primary endpoint was reduction in patient-controlled morphine consumption in the 24-hour post-operative period, which was shown to be similar between the test and control arms. One of the secondary endpoints, the rate of intra-operative hypotension, was significantly higher in the clonidine group. The mechanism of action and pharmacokinetics of clonidine in TAP blocks is poorly understood, making the effective dose and interaction with other agents difficult to predict. The authors cite several other studies using different doses of clonidine in various surgical scenarios, with conflicting results. The data from this study suggest that there is little benefit from the addition of clonidine to TAP blocks. Furthermore, the harm of intra-operative hypotension, which is a consistent finding in other studies, may have more serious implications in patients undergoing renal transplantation in terms of long-term graft survival.
Study Details
Aims: The aim of this study was to examine if adding clonidine in transversus abdominis plane (TAP) block would reduce the consumption of 24‑h postoperative morphine in adult kidney transplant recipients.
Interventions: Participants were randomised to receive either TAP block with ropivacaine plus clonidine (group RC) or TAP block with ropivacaine (group R) following the induction of anesthesia.
Participants: 40 adult (age 18–65 years) kidney transplant recipients.
Outcomes: The primary endpoint was 24‑h postoperative morphine consumption. The secondary endpoints were requirement for intraoperative fentanyl, postoperative pain, need for rescue analgesia (number of morphine bolus) and side effects.
Follow Up: 24 hours
BACKGROUND AND AIMS:

Transversus abdominis plane (TAP) block has been used to provide analgesia in renal transplant surgery with varying results. This study was designed to assess if the addition of clonidine in TAP block would decrease 24-h postoperative morphine consumption in adult renal transplant recipients.

MATERIALS AND METHODS:

Forty adult patients undergoing renal transplantation under general anesthesia in a tertiary care hospital were randomized into either group RC (TAP block with 20 mL of 0.5% ropivacaine plus 2 μg.kg-1 clonidine) or group R (TAP block with 20 mL 0.5% ropivacaine) after induction of anesthesia. Postoperative analgesia was provided using patient-controlled morphine. The primary outcome was 24-h patient-controlled morphine consumption. The secondary outcomes were a) intraoperative hemodynamics, b) fentanyl and ephedrine requirement, c) postoperative pain using the Visual Analog Scale at 0, 2, 6, 12 and 24 hours, d) time to first postoperative analgesia, e) postoperative hemodynamics, and f) side effects.

RESULTS:

There was no significant difference in postoperative morphine consumption between the groups (25 mg in group RC vs. 28.5 mg in group R) (median interquartile range) (P = 0.439). Postoperative pain scores were comparable between the groups. Intraoperatively, fewer patients required rescue fentanyl in group RC (7 patients) as compared to group R (17 patients) (P = 0.003). Significantly more patients in group RC required ephedrine boluses as compared to group R (9 patients in group RC vs. 2 in group R, P = 0.014).

CONCLUSIONS:

The addition of 2 μg.kg-1 clonidine to ropivacaine in TAP block did not reduce 24-h postoperative morphine consumption after renal transplantation. It reduced the need for intraoperative analgesics but increased the need for intraoperative ephedrine administration.
Liver
Long-Term Effects of Everolimus-Facilitated Tacrolimus Reduction in Living-Donor Liver Transplant Recipients with Hepatocellular Carcinoma
  • Sapisochin G
  • Lee WC
  • Joo DJ
  • Joh JW
  • Hata K
  • et al.
Ann Transplant. 2022 Nov 22;27:e937988 doi: 10.12659/AOT.937988.
CET Conclusion
Reviewer: Mr Keno Mentor, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This study analysed the long-term follow-up data of patients who underwent living donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC) and were enrolled in a previous RCT to receive combination everolimus/reduced tacrolimus or normal dose tacrolimus alone. The authors hypothesised that everolimus combined with reduced tacrolimus would reduce HCC recurrence and CNI-related renal dysfunction, and have similar immunosuppressive efficacy and safety. The original RCT followed the patients up for 12 months and reported similar efficacy and safety data between the 2 groups, with a reduced rate of HCC recurrence in the everolimus/reduced tacrolimus arm. This study followed these two groups of patients and analysed the same outcome measures at 5 years. Although all primary and secondary endpoints were numerically superior in the everolimus/reduced tacrolimus group, none of the differences reported achieved statistical significance. Furthermore, the all-cause 5-year overall survival was also not significantly different. This study essentially found similar outcomes to the original RCT and thus did not show compelling evidence of long-term benefit of the everolimus/reduced tacrolimus regimen in all patients who undergo LDLT. However, a sub-group analysis indicated that this regimen may benefit patients with a greater burden of HCC and who are transplanted outside of Milan criteria.
Study Details
Aims: This follow-up study aimed to report the long term outcomes of a randomised controlled trial investigating the effects of everolimus (EVR) combined with reduced tacrolimus (rTAC) versus a standard TAC (sTAC) regimen in living-donor liver transplant recipients (LDLTRs) with hepatocellular carcinoma (HCC).
Interventions: Participants were randomly assigned to receive either EVR+rTAC or sTAC.
Participants: 117 HCC patients who underwent LDLT.
Outcomes: The primary outcome was HCC recurrence. The secondary efficacy outcomes included incidences of acute and chronic rejections, graft loss, death, ‘composite of drop-out’ [death, withdrawal of consent and lost to follow-up], changes in immunosuppressive regimen, malignancies other than HCC and change in renal function.
Follow Up: 60 months

BACKGROUND The study objective was to evaluate the effect of everolimus (EVR) in combination with reduced tacrolimus (rTAC) compared with a standard TAC (sTAC) regimen on hepatocellular carcinoma (HCC) recurrence in de novo living-donor liver transplantation recipients (LDLTRs) with primary HCC at liver transplantation through 5 years after transplantation. MATERIAL AND METHODS In this multicenter, non-interventional study, LDLTRs with primary HCC, who were previously randomized to either everolimus plus reduced tacrolimus (EVR+rTAC) or standard tacrolimus (sTAC), and who completed the 2-year core H2307 study, were followed up. Data were collected retrospectively (end of core to the start of follow-up study), and prospectively (during the 3-year follow-up study). RESULTS Of 117 LDLTRs with HCC at LT in the core H2307 study (EVR+rTAC, N=56; sTAC, N=61), 86 patients (EVR+rTAC, N=41; sTAC, N=45) entered the follow-up study. Overall HCC recurrence was lower but statistically non-significant in the EVR+rTAC group (3.6% vs 11.5% in sTAC; P=0.136) at 5 years after LT. There was no graft loss or chronic rejection. Acute rejection and death were comparable between treatment groups. Higher mean estimated glomerular filtration rate in the EVR+rTAC group (76.8 vs 65.8 mL/min/1.73 m² in sTAC) was maintained up to 5 years. Reported adverse events were numerically lower in the EVR+rTAC group (41.0% vs 53.5% sTAC) but not statistically significant. CONCLUSIONS Although statistically not significant, early EVR initiation reduced HCC recurrence, with comparable efficacy and safety, and better long-term renal function, than that of sTAC treatment.
Lung
A Randomized, Multicenter, Blinded Pilot Study Assessing the Effects of Gaseous Nitric Oxide in an Ex Vivo System of Human Lungs
  • Hartwig MG
  • Klapper JA
  • Poola N
  • Banga A
  • Sanchez PG
  • et al.
Pulm Ther. 2022 Dec 13;1-13 doi: 10.1007/s41030-022-00209-5.
CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This multicentre pilot study randomised rejected lungs to ex-vivo perfusion (EVLP), EVLP with gaseous nitric oxide (gNO) introduced directly into the perfusate (n=16) or inhaled NO via the ventilator (iNO; n=4). Lungs with gaseous NO demonstrated improved aggregate scores in markers of lung physiology (delta PO2, static compliance and pulmonary vascular resistance), with lower lung weights. No difference was seen in the iNO group. No differences were seen in the assessment of transplantability between groups by any of the observers. As an experimental study, the design was good with randomisation and blinding of outcome assessment in the gNO subgroup (the iNO subgroup was unblinded). The limitations are small numbers (especially in the iNO subgroup) and the discarded nature of the organs which are therefore not comparable to those used in clinical transplantation. Nonetheless, these results warrant further investigation, in particular with regards to post-transplant clinical outcomes of NO delivery during EVLP.
Study Details
Aims: This study aimed to evaluate whether administering exogenous nitric oxide during ex vivo lung perfusion (EVLP) improves lung health.
Interventions: Donor lungs were randomised to receive either gaseous nitric oxide (gNO) plus perfusate or perfusate alone.
Participants: 20 bilateral lungs (16 were included in blinded study and 4 in the open-label study).
Outcomes: The primary outcomes were overall score for lung physiology indicators and total duration of stable EVLP time. The secondary outcomes were measurements of transplantation suitability, lung weight and left atrium partial pressure of oxygen (LAPO2).
Follow Up: 10 hours.
INTRODUCTION:

Normothermic ex vivo lung perfusion (EVLP) is used to evaluate and condition donor lungs for transplantation. The objective of this study was to determine whether administration of exogenous nitric oxide during EVLP contributes to improvement of lung health.

METHODS:

A multicenter, blinded, two-arm, randomized pilot study evaluated the effect of gaseous nitric oxide (gNO) administered during EVLP on donor lungs rejected for transplantation. gNO introduced into the perfusate at 80 parts per million (ppm) was compared with perfusate alone (P). An open-label substudy assessed inhaled nitric oxide gas (iNO) delivered into the lungs at 20 ppm via a ventilator. Primary endpoints were an aggregate score of lung physiology indicators and total duration of stable EVLP time. Secondary endpoints included assessments of lung weight and left atrium partial pressure of oxygen (LAPO2).

RESULTS:

Twenty bilateral donor lungs (blinded study, n = 16; open-label substudy, n = 4) from three centers were enrolled. Median (min, max) total EVLP times for the gNO, P, and iNO groups were 12.4 (8.6, 12.6), 10.6 (6.0, 12.4), and 12.4 (8.7, 13.0) hours, respectively. In the blinded study, median aggregate scores were higher in the gNO group compared to the P group at most time points, suggesting better lung health with gNO (median score range [min, max], 0-3.5 [0, 7]) vs. P (0-2.0 [0, 5] at end of study). In the substudy, median aggregate scores did not improve for lungs in the iNO group. However, both the gNO and iNO groups showed improvements in lung weight and LAPO2 compared to the P group.

CONCLUSIONS:

The data suggest that inclusion of gNO during EVLP may potentially prolong duration of organ stability and improve donor lung health, which warrants further investigation.
Impact of delayed veno-venous extracorporeal membrane oxygenation weaning on postoperative rehabilitation of lung transplantation: a single-center comparative study
  • Li LJ
  • Xu HY
  • Wang XW
  • Jin K
  • Zhang C
  • et al.
J Artif Organs. 2022 Dec 8; doi: 10.1007/s10047-022-01376-7.
CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This single centre study randomised recipients of lung transplants requiring veno-venous ECMO intra-operatively to immediate or delayed weaning of ECMO post-operatively. Delayed ECMO weaning was associated with shorter hospital stay, less primary graft dysfunction and lower incidence of non-invasive ventilation. Whilst the results appear significantly better in the delayed-weaning group, there are some methodical and reporting issues that should be noted. No primary outcome is defined, and no sample size calculation is presented. The method of randomisation is not reported. Outcomes are not clearly defined – for example, the definition of primary graft dysfunction used is not clear. Many of the outcomes showing significant improvement may be subject to treatment biases in the absence of blinding – such as use of non-invasive ventilation and discharge from hospital. The findings are certainly worthy of further investigation in a larger, multicentre sample with more robust design.
Study Details
Aims: This study aimed to evaluate the benefits of delayed weaning of veno-venous extracorporeal membrane oxygenation (VV-ECMO) in lung transplant recipients.
Interventions: Participants were randomised into two groups: the intraoperative VV-ECMO group which included VVECMO weaning immediately after lung transplantation, or the intra- and postoperative group which involved delayed VV-ECMO weaning after lung transplantation.
Participants: 88 lung transplant recipients with VV-ECMO.
Outcomes: The main clinical outcomes of interest were duration of hospital and ICU stay, duration of mechanical ventilation, noninvasive ventilation, respiratory failure, high-flow oxygen mask (auxiliary ventilation after VV-ECMO weaning), and postoperative complications.
Follow Up: Not reported

Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is a reliable and effective extracorporeal life support during lung transplantation (LTx). However, the clinical benefit of delayed VV-ECMO weaning remains unclear. The current study aims to investigate whether delayed weaning of VV-ECMO is more beneficial to the rehabilitation for lung transplant patients. Patients who underwent LTx with VV-ECMO between January 2017 and January 2019 were included. Enrollment of patients was suitable for weaning off ECMO immediately after surgery. Randomization was performed in the operating room. Postoperative outcomes were compared between the two groups. Besides, univariate and multivariable logistic regressions were performed to estimate risk of postoperative complications. Compared to VV-ECMO weaning immediately after LTx, delayed weaning was associated with shorter hospital length of stay (days, 31 vs. 46; P < 0.05), lower incidence of noninvasive ventilation (4.3% vs. 24.4%; P < 0.05), primary graft dysfunction (PGD) (6.4% vs. 29.3%; P < 0.05), atrial fibrillation (AF) (4.3% vs. 22%, P < 0.05), and respiratory failure (4.3% vs. 19.5%; P < 0.05). Multivariable logistic regressions revealed that VV-ECMO weaning after LTx was independently correlated with increased risk of developing PGD [odds ratio (OR), 5.97, 95% CI 1.16-30.74], AF (OR, 6.87, 95% CI 1.66-28.47) and respiratory failure (OR, 6.02, 95% CI 1.12-32.49) by comparison of delayed VV-ECMO weaning. Patients with delayed VV-ECMO weaning are associated with lower complications and short hospital length of stay, while it relates to longer mechanical ventilation. These findings suggest that delayed VV-ECMO after LTx can facilitate rehabilitation.
Various
Shoulder arthroplasty following solid organ transplant: A systematic review and meta-analysis
  • Patel AV
  • Duey AH
  • Stevens AJ
  • Vaghani PA
  • Cvetanovich GL
  • et al.
J Orthop. 2022 Nov 26;35:150-154 doi: 10.1016/j.jor.2022.11.015.
CET Conclusion
Reviewer: Reshma Rana Magar, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This systematic review and meta-analysis compared demographics, functional and radiographic outcomes, and complications of shoulder arthroplasty in solid organ transplant recipients versus non-transplant patients. Studies were assessed for eligibility by two independent reviewers, but whether the data were also extracted in duplicate was not reported. Only 5 studies were included, including two retrospective cohort and three retrospective case series (level of evidence: III and IV respectively), suggesting high risk of bias. Patients in the SOT group had significantly lower visual analog scale (VAS) pain scores (p-value<0.01), but a significantly higher risk of death (p-value<0.01) score. Level of heterogeneity between studies was not reported for meta-analysed outcomes. The findings revealed comparable improvements in range of motion and patient-reported outcomes in SOT patients versus non-transplant patients without a significant increase in complications, leading the authors to conclude that shoulder arthroplasty is a safe option for SOT patients. The authors report a difference in mortality between the two groups, but then report that surgery is safe. From the data presented – we cannot be sure if the excess deaths in the transplant group were due to having a transplant (most likely) or due to undergoing shoulder surgery. You would need a control cohort of transplant patients who did not have shoulder surgery to be sure.
Study Details
Aims: This study aimed to compare the outcomes of shoulder arthroplasty among solid organ transplant (SOT) recipients versus non-transplant patients.
Interventions: A literature search was conducted on PubMed, Scopus, MEDLINE, and Web of Science. Study selection was performed by two independent reviewers. The quality of the included studies was assessed Methodological Index for Nonrandomized Studies (MINORS) criteria.
Participants: 5 studies were included in the review.
Outcomes: The outcomes of interest included preoperative and postoperative forward elevation (FE), external rotation in adduction (ER), and internal rotation (IR); patient-reported outcomes; implant migration and loosening; and death, surgical and medical complications.
Follow Up: N/A
INTRODUCTION:

The purpose of this study is to report a systematic review and meta-analysis of solid organ transplant (SOT) patients undergoing shoulder arthroplasty to compare functional and radiographic outcomes, demographics, and complications with non-transplant patients.

METHODS:

Studies were included if they examined patients undergoing shoulder arthroplasty in the setting of prior solid organ transplantation and included post operative range of motion, patient-reported outcomes, complications, or revisions. Studies were excluded if they were national database analyses or lacked clinical data. Pubmed, MEDLine, Scopus, and Web of Science were queried using relevant search terms in July 2022. Data was pooled, weighted, and a paired t-test and chi-square analysis was performed.

RESULTS:

There were 71 SOT and 159 non-SOT shoulders included in the study. The most common indication for surgery was avascular necrosis (n = 26) in the solid organ transplant group and osteoarthritis (n = 60) in the non-SOT group. Forward elevation, external rotation, ASES, and VAS pain scores improved significantly in both cohorts following surgery. There was no significant difference in age at surgery (p-value = 0.20), postoperative forward elevation (p-value = 0.08), postoperative external rotation (0.84), and postoperative ASES scores (p-value = 0.11) between the two cohorts. VAS pain scores were significantly lower in the SOT cohort (p-value<0.01). The risk of death was significantly higher in the SOT group (p-value<0.01). but the rate of overall complications (p = 0.47), surgical complication (p-value = 0.79), or revision surgery (p-value = 1.00) was not significantly different between the two cohorts.

CONCLUSION:

Shoulder arthroplasty is a safe, effective option in patients following solid organ transplant. There is not an increased risk of adverse outcomes, and SOT patients had comparable range of motion and patient-reported outcomes when compared to their non-SOT peers.

LEVEL OF EVIDENCE:

III.