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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).

May 2022

Kidney


  1. A Randomized Controlled Trial on Safety of Steroid Avoidance in Immunologically Low-Risk Kidney Transplant Recipients
    KI Reports. 2022;7(2):259-269

    Study Details

    Aims: The aim of this study was to investigate whether complete steroid avoidance with tacrolimus/ mycophenolate mofetil (MMF)/ antithymocyte globulin (ATG) induction in immunologically low-risk kidney transplant patients without diabetes leads to a reduction in the incidence of post-transplant diabetes mellitus (PTDM) with good efficacy and safety in two years, in comparison to the standard steroid maintenance regimen.
    Interventions: Participants were randomly assigned to either the steroid avoidance arm or the steroid maintenance arm.
    Participants: 224 low immunological risk kidney transplant recipients.
    Outcomes: The primary outcome was the incidence of PTDM within one year following transplantation. Secondary outcomes included incidence of PTDM and use of antidiabetic agents at 2 years; incidence of biopsy-proven rejection; composite measure of freedom from acute rejection, graft loss, and death; kidney function; occurrence of infections; major cardiovascular events and malignancies; mean doses, mean area under the curve (AUC) of doses, trough levels, and AUCs for immunosuppressants; and use of antihypertensive and lipid-lowering agents.

    CET Conclusion

    Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This multicentre RCT investigated the safety of complete steroid avoidance with maintenance steroid therapy following renal transplantation in low-risk patients. Patients undergoing avoidance received ATG induction, whereas those undergoing maintenance therapy received basiliximab. There were no significant differences in risk of acute rejection, graft or patient survival, or incidence of post-transplant diabetes (PTDM). This leads the authors to conclude that in this patient population, steroid avoidance is safe when used in conjunction with ATG induction and Tac/MMF. There are some points of note. Firstly, 36% of patients in the steroid avoidance arm ended up on oral steroids at 2 years, diluting any potential benefit in intent-to-treat analysis. Secondly, the initial power calculation estimated a risk of PTDM in the control arm of 36%, whereas the observed rate was only 18%, leading to an underpowered study. Finally, the maintenance steroid dose in the control arm after 6 months was a relatively low average of 5-6mg/day. Post-hoc analysis of our own previous meta-analysis suggested that risk of diabetic complications related to steroid maintenance dose, with the benefits of avoidance compared to low-dose steroids being more limited than compared to higher doses.

    Abstract

    Introduction: Steroid-based immunosuppression after transplantation increases the risk of post-transplant diabetes mellitus (PTDM), with adverse effects on patient and graft survival. In the SAILOR study, we investigated the safety and efficacy of complete steroid avoidance in immunologically low-risk kidney recipients without diabetes on the current standard-of-care maintenance regimen with tacrolimus/mycophenolate mofetil (MMF). Methods: In this 2-year, multicenter, open-label trial, a total of 222 patients were randomized to receive either steroid avoidance protocol (tacrolimus/MMF/antithymocyte globulin [ATG] induction [n = 113]) or steroid maintenance protocol (tacrolimus/MMF/prednisolone/basiliximab-induction [n = 109]). Results: At 1 year, no significant differences were found between steroid avoidance and steroid maintenance arms in the incidence of PTDM, the primary end point (12.4% vs. 18.3%, respectively, P = 0.30, CI: 16.3-4.4), or in overall biopsy-proven rejections (15% vs. 13.8%, respectively, P = 0.85). At 2 years, the composite end point of freedom from acute rejection, graft loss, and death (81% vs. 85%, respectively, P = 0.4), kidney function, or adverse events was comparable between the 2 arms. Moreover, 63.9% of the patients in the steroid avoidance arm remained free from steroids at 2 years. Conclusion: The SAILOR study provides further evidence for the feasibility, safety, and efficacy of early steroid-free treatment at 2 years in immunologically low-risk kidney recipients with tacrolimus/MMF maintenance regimen.
  2. Survival for waitlisted kidney failure patients receiving transplantation versus remaining on waiting list: systematic review and meta-analysis
    Bmj. 2022;376:e068769

    Study Details

    Aims: This study aimed to evaluate the survival benefit of kidney transplantation compared to remaining on dialysis for waitlisted kidney failure patients.
    Interventions: A literature search was performed using Ovid Embase, Web of Science, MEDLINE, Cochrane Collection, and ClinicalTrials.gov. Study selection and data extraction were conducted by two independent reviewers. The risk of bias was assessed using the Newcastle-Ottawa Assessment Scale (NOS) for comparative non-randomised studies.
    Participants: 48 studies were included in the review.
    Outcomes: The main outcome of interest was all cause mortality.

    CET Conclusion

    Reviewer: Dr Liset Pengel, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This good quality systematic review and meta-analysis evaluated the survival benefit of kidney transplantation versus remaining on dialysis for waitlisted patients. The review protocol was registered with PROSPERO and a comprehensive literature search was conducted to identify comparative studies. Two independent reviewers screened search results, selected studies, extracted data and assessed the study quality. Overall, the methodological quality of the observational studies was assessed as high quality. Almost all studies (92%) reported a significant long-term (≥1 year) survival benefit from transplantation compared with dialysis. All studies presenting adjusted hazard ratios also reported a survival benefit from kidney transplantation. Meta-analysis of 18 studies showed that kidney transplantation was associated with a 55% lower risk of mortality compared with dialysis. Significant heterogeneity was explored by subgroup analyses, sensitivity analyses and meta-regression analysis however heterogeneity could not be fully explained. The authors note that despite the overall survival benefit for most patients, there may not be a benefit from kidney transplantation for some subgroups.

    Abstract

    OBJECTIVES To investigate the survival benefit of transplantation versus dialysis for waitlisted kidney failure patients with a priori stratification. DESIGN Systematic review and meta-analysis. DATA SOURCES Online databases MEDLINE, Ovid Embase, Web of Science, Cochrane Collection, and ClinicalTrials.gov were searched between database inception and 1 March 2021. INCLUSION CRITERIA All comparative studies that assessed all cause mortality for transplantation versus dialysis in patients with kidney failure waitlisted for transplant surgery were included. Two independent reviewers extracted the data and assessed the risk of bias of included studies. Meta-analysis was done using the DerSimonian-Laird random effects model, with heterogeneity investigated by subgroup analyses, sensitivity analyses, and meta-regression. RESULTS The search identified 48 observational studies with no randomised controlled trials (n=1 245 850 patients). In total, 92% (n=44/48) of studies reported a long term (at least one year) survival benefit associated with transplantation compared with dialysis. However, 11 of those studies identified stratums in which transplantation offered no statistically significant benefit over remaining on dialysis. In 18 studies suitable for meta-analysis, kidney transplantation showed a survival benefit (hazard ratio 0.45, 95% confidence interval 0.39 to 0.54; P<0.001), with significant heterogeneity even after subgroup/sensitivity analyses or meta-regression analysis. CONCLUSION Kidney transplantation remains the superior treatment modality for most patients with kidney failure to reduce all cause mortality, but some subgroups may lack a survival benefit. Given the continued scarcity of donor organs, further evidence is needed to better inform decision making for patients with kidney failure. Study registration: Prospero crd42021247247.
  3. Effect of allopurinol drug use on GFR and proteinuria in patients with renal transplant recipients (ADOPTR study)
    Transplant Immunology. 2022;72:101560

    Study Details

    Aims: The aim of this study was to examine the effect of using allopurinol on renal functions in kidney transplant patients.
    Interventions: Participants were randomly assigned to receive either allopurinol or placebo.
    Participants: 245 renal transplant recipients.
    Outcomes: The main outcomes were the assessment of uric acid, urinary protein creatinin ratio, the modification of diet in renal diseases (MDRD) and C-reactive protein (CRP).

    CET Conclusion

    Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This is a study of a simple intervention in renal transplant recipients but there are significant questions about the methodology. Renal transplant recipients were randomised to receive either 300mg allopurinol once daily, or placebo, with 6 months follow up. Unfortunately, there is no description of the method of randomisation, so this cannot be assessed. Also, there is no description of how the placebo was designed or administered and whether there was sufficient blinding of patients or investigators. There is no power calculation, nor declaration which was the primary outcome set in advance of the study commencing. The study found that taking allopurinol daily for 24 weeks, was associated with a significant reduction in plasma uric acid level, as one might expect. It was also associated with improved urine albumin:creatinine ratio, serum creatinine and eGFR. Despite these apparently significant results, it is not clear that the study was truly randomised, or placebo controlled, and hence questions will remain about the potential for systematic bias affecting the results.

    Abstract

    BACKGROUND Hyperuricemia has been associated with the development of hypertension, cardiovascular, and renal disease. However, there is no data about the effect of lowering uric acid level on renal functions and proteinuria in renal transplant recipients. This study aimed to investigate the effect of allopurinol treatment on renal functions in renal transplant recipients (RTR). METHODS A total of 245 patients with renal transplantation were included in this randomized, placebo-controlled study. Patients were randomized to receive either placebo (121 patients) or 300 mg/day allopurinol (124 patients). We have examined uric acid, urinary protein creatinin ratio, MDRD (the modification of diet in renal diseases) and CRP (C-reactive protein) before and 24 weeks after treatment in both group. RESULTS In the allopurinol group, the mean serum uric acid levels, eGFR (estimated glomerular filtration rate), and creatinine urinary albumin creatinin ratio (UACR) significantly improved (p < 0.001). Also uric acid level was positively correlated with the UACR (r = 0,645 p < 0.001) and negatively correlated with MDRD (r = -0,387 p < 0.05) in allopurinol treatment group. A statistically significant increase in CRP level was observed (p < 0,05) in plasebo group. Multivariate regression analysis showed that uric acid was positively correlated with UACR (r = 0,473, beta = 0.021, p = 0.002) and negatively correlated with MDRD (r = -0554 beta = 0.016, P = 0.001) in allopurinol treatment RTR. CONCLUSION Urate, a salt of uric acid, is lowered by allopurinol treatment resulting in improved eGFR and decreased proteinuria, when compared to the placebo group. Therefore, we suggest that allopurinol therapy should be part of the management of kidney transplant patients with normal kidney function. Long-term follow-up studies will be useful in revealing the effect of uric acid management on kidney functions and proteinuria.
  4. Kidney Autotransplantation for Renal Artery Aneurysm: Case Series and a Systematic Review
    Annals of Vascular Surgery. 2021;77:349.e5-349.e18

    Study Details

    Aims: This paper reports a case series of kidney autotransplantation (KAT) for renal artery aneurysm (RAA). It also includes a systematic review evaluating outcomes of KAT for RAA.
    Interventions: In the systematic review, electronic databases including Medline Ovid, Embase, Cochrane CENTRAL , Web of science and Google scholar were searched. Studies were screened for eligibility by two independent reviewers. The methodological quality of the included studies were also assessed.
    Participants: 102 studies were inclded in the systematic review.
    Outcomes: The main outcomes of interest included postoperative complications, graft loss, and postoperative hospital stay.

    CET Conclusion

    Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This paper is based around a case series of renal auto-transplantation for a rare indication- renal artery aneurysm. In addition, the paper includes a systematic review. The review searched multiple databases, and abstracts were screened in duplicate although it does not appear that data was extracted in duplicate. There is a formal quality assessment of the 102 papers included (66% of which were single case reports). The authors summarise the demographics of included patients and the surgical approaches used. Overall patient and graft outcomes seem acceptable, but a minority of papers reported outcomes beyond 1 year. It would have been useful to see a comparison with endovascular techniques, where this approach could have been technically feasible.

    Abstract

    OBJECTIVES Renal artery aneurysm (RAA) is a rare vascular disease. Kidney autotransplantation (KAT) is the treatment option when endovascular approach is not available. However, the evidence on KAT for RAA is mostly limited to small case series or reports. Here, we describe our 2 center experience of KAT for RAA, and provide the results of our systematic literature review to evaluate the outcomes. METHODS A retrospective 2 center study was conducted in patients undergoing KAT for RAA between 2010 and 2018. Moreover, a systematic review was performed on medical databases to evaluate the outcomes of KAT for RAA. RESULTS Nine patients were surgically treated at our institutions: eight with laparoscopic nephrectomy (LN), and 1 with open followed heterotopic KAT. All RAAs were ex-vivo reconstructed, and in 3 cases a vein graft was used for reconstruction. There were 2 postoperative major complications including 1 graft loss. In the systematic review, 102 studies with 355 patients were included. In 35 patients (9.9%) a minimal invasive approach was performed. The incidence of postoperative major complications and graft loss was 9.4% and 4.1%. CONCLUSIONS Our experiences showed that laparoscopic approach for nephrectomy followed heterotopic KAT was feasible with good postoperative outcomes. KAT is an effective treatment for RAA when endovascular approach is not feasible for interpretation of the outcomes, the quality and sample size of the evidence should be taken into consideration.
  5. Efficacy and Safety of Iguratimod Supplement to the Standard Immunosuppressive Regimen in Highly Mismatched Renal Transplant Recipients: A Pilot Study
    Frontiers in Immunology. 2021;12:738392

    Study Details

    Aims: This study aimed to assess the effect and safety of Iguratimod (IGU) combined with standard immunosuppressive regimen in highly HLA-mismatched kidney transplant patients.
    Interventions: Patients were randomised to either the IGU or non-IGU group.
    Participants: 60 highly HLA-mismatched renal transplant recipients.
    Outcomes: The primary outcomes were biopsy-proven acute rejection and functional allograft survival. The secondary outcomes were the safety profile, donor-specific antibody (DSA) and other indicators.

    CET Conclusion

    Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This small pilot RCT investigated whether the addition of the disease-modifying anti-rheumatoid drug (DMARD) Iguratimod (IGU) can improve outcomes in poorly-mismatched renal transplant recipients. The study itself was unblinded, but nephrologists scoring protocol biopsies were blinded to treatment allocation. Both modified intent-to-treat and per-protocol analyses are reported. Patients receiving IGU had numerically lower incidence of biopsy-proven acute rejection, although not achieving statistical significance due to the small sample size. The results presented do show some promise for the use of IGU following renal transplantation, but larger studies will be required to confirm any benefit. It should be noted that the baseline rate for biopsy-proven acute rejection was relatively high for a Tac/MMF/Pred based regimen (29.6%). Another potential limitation is that patients were only eligible at least 2 weeks post-transplant – anti-inflammatory drugs of this nature may be most effective if given from the day of transplant.

    Abstract

    Iguratimod (IGU) can mitigate the symptoms of rheumatoid arthritis through its anti-inflammatory effects. The objective of this study was to investigate the clinical efficacy and safety of IGU in highly HLA-mismatched renal transplant recipients, in combination with standard immunosuppressive regimen. This pilot study was designed as an open-label, blank-control, randomized clinical trial on patients recruited from a single transplant center in China. Patients who met the inclusion criteria were randomized to the IGU (n=27) and blank control (n=27) groups. IGU was administrated with the conventional triple immunosuppressive protocol for 52 weeks after kidney transplantation. The incidence of biopsy-proven acute rejection rate was 14.8% (4/27) in the IGU group and 29.6% (8/27) in the control group, P = 0.19. The clinical rejection rate was also substantially reduced in the IGU group (3.7% vs. 18.5%, P = 0.08). De novo donor-specific antibody also showed a decline trend in the IGU group after 52 weeks. The graft function and incidence of adverse events were similar between the two groups. In addition, IGU intervention significantly decreased the number of NK cells throughout the follow-up. In conclusion, our study has shown the possibility that IGU could reduce the allograft rejection rate and de novo DSA with appreciable safety in combination with conventional immunosuppressants. Formal clinical trials were warranted based on current findings.

Lung


  1. Feasibility and Usefulness of Self-Hypnosis in Patients Undergoing Double-Lung Transplantation During the Pre- and Postoperative Periods: A Randomized Study
    Journal of Cardiothoracic & Vascular Anesthesia. 2022;[record in progress]

    Study Details

    Aims: This study aimed to investigate whether the implementation of self-hypnosis in a lung transplantation setting leads to improvements in patients’ pain and quality of life.
    Interventions: Participants were randomised to either the self-hypnosis group or the usual care group.
    Participants: 78 patients who needed a double-lung transplant.
    Outcomes: The primary endpoint was pain 1 month posttransplantation. The secondary endpoints included pain, anxiety, coping, catastrophism, quality of life, and compliance with the self-hypnosis technique prior to surgery, in the intensive care unit (ICU) and post-transplantation.

    CET Conclusion

    Reviewer: Dr Liset Pengel, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    The randomised controlled trial evaluated whether self-hypnosis before and after lung transplantation improves pain and quality of life. Patients awaiting a double-lung transplant aged ≥15 years were randomised online according to a computer-generated randomisation sequence. The sample size calculation showed that 78 patients needed to be included in the study for a power of 80%. Participants received at least two teaching sessions by psychologists and anaesthesiologists who underwent the same hypnosis training. Seventy-eight participants were randomised and 61 participants were included in the analysis at 4 months posttransplant. Most participants (77%) used self-hypnosis regularly or occasionally before the transplant but less often after the transplant. Forty-two percent of patients were very enthusiastic about self-hypnosis, which they considered helpful in many circumstances and 68% said that self-hypnosis was difficult to practice alone. There were no statistically significant differences between groups for any of the pain scores, anxiety or quality of life up to 4 months posttransplant. The authors highlight some factors that may have influenced the results including adherence to self-hypnosis, particularly in the immediate posttransplant period, and other stressors.

    Abstract

    OBJECTIVE Hypnosis can reduce pain and anxiety in surgical patients. This study aimed to demonstrate that implementing self-hypnosis in the setting of lung transplantation could improve patients' pain and quality of life. DESIGN A randomized, single-center study. SETTING Foch University Hospital, Suresnes, France. PARTICIPANTS The participants were patients aged 15 years or older who needed a double-lung transplant. Patients were excluded if they participated in only 1 learning self-hypnosis session before transplantation. INTERVENTIONS Patients were included at the time of their final evaluation before inscription on the waiting list. They were taught self-hypnosis at this time and were asked to perform it by themselves before and after transplantation, as frequently as possible. MEASUREMENTS AND MAIN RESULTS The main outcome of the study was self-reported pain 1 month after lung transplantation. Secondary outcomes were self-reported pain, anxiety, coping, catastrophism, and self-reported quality of life evaluated at their registration, 7 days and 1 and 4 months after the transplantation. Seventy-eight patients were included, but only 28 patients in the control group and 33 in the self-hypnosis group were evaluated at the fourth postoperative month. Practice of self-hypnosis was high before transplantation (76.6%), lower after, from 32.3% in the intensive care unit to 51.6% during the last 3 months of the study. Group-time interactions were not statistically significant whatever the concerned outcome, especially pain score at 1 month (p = 0.16). CONCLUSION Implementation of self-hypnosis is possible, but the study failed to demonstrate an improvement in patients' experience, perhaps due to the variable compliance with the technique.
  2. A pilot randomized controlled trial of de novo belatacept-based immunosuppression following anti-thymocyte globulin induction in lung transplantation
    American Journal of Transplantation. 2022;[record in progress]

    Study Details

    Aims: This pilot randomised controlled trial (RCT) aimed to examine the efficacy and safety of belatacept-based immunosuppression following lung transplantation.
    Interventions: Patients were randomised into two arms: the belatacept- based immunosuppression arm, in which patients received tacrolimus, belatacept, and prednisone until day 89 followed by belatacept, mycophenolate mofetil (MMF), and prednisone; or the control arm, where patients received tacrolimus, MMF and prednisone.
    Participants: 27 lung transplant recipients.
    Outcomes: The primary outcome was the feasibility metric of randomising 80% of eligible patients within 4 hours posttransplantation.

    CET Conclusion

    Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This pilot RCT investigated the use of belatacept-based immunosuppression in lung transplant recipients. Standard immunosuppression with Tac/MMF/Pred was compared to belatacept and prednisolone-based immunosuppression in conjunction with tacrolimus for the first 3 months and MMF thereafter. Recruitment was stopped after 3 deaths in the belatacept arm – a further two patients subsequently died. The authors conclude that belatacept-based immunosuppression in lung transplant recipients is associated with excess mortality. The results in such a small number of patients are difficult to interpret – causes of death were different for all 5 recipients (PE, haemothorax, restrictive allograft syndrome, COVID-19 and PTLD). Three deaths related to possible viral infection, which may reflect the overall immunosuppressive burden of the regimen. Given the excess mortality, the DSMB were correct to stop the trial despite the small sample size.

    Abstract

    The development of donor-specific antibodies (DSA) after lung transplantation is common and results in adverse outcomes. In kidney transplantation, Belatacept has been associated with a lower incidence of DSA, but experience with Belatacept in lung transplantation is limited. We conducted a two-center pilot randomized controlled trial of de novo immunosuppression with Belatacept after lung transplantation to assess the feasibility of conducting a pivotal trial. Twenty-seven participants were randomized to Control (Tacrolimus, Mycophenolate Mofetil, and prednisone, n = 14) or Belatacept-based immunosuppression (Tacrolimus, Belatacept, and prednisone until day 89 followed by Belatacept, Mycophenolate Mofetil, and prednisone, n = 13). All participants were treated with rabbit anti-thymocyte globulin for induction immunosuppression. We permanently stopped randomization and treatment with Belatacept after three participants in the Belatacept arm died compared to none in the Control arm. Subsequently, two additional participants in the Belatacept arm died for a total of five deaths compared to none in the Control arm (log rank p = .016). We did not detect a significant difference in DSA development, acute cellular rejection, or infection between the two groups. We conclude that the investigational regimen used in this study is associated with increased mortality after lung transplantation.
  3. Five-Year Outcome of an Early Everolimus-based Quadruple Immunosuppression in Lung Transplant Recipients: Follow-Up of the 4EVERLUNG Study
    Transplantation. 2022;03:08

    Study Details

    Aims: This study aimed to report the five-year outcomes of the 4EVERLUNG study, which compared everolimus-based quadruple low calcineurin inhibitor (CNI) versus standard triple regimen in lung transplant recipients.
    Interventions: Patients were randomised to receive either the everolimus-based quadruple low CNI regimen or the standard triple regimen.
    Participants: Data from 123 out of 130 lung transplant recipients randomised in the 4EVERLUNG study were analysed.
    Outcomes: Renal function, biopsy-proven acute cellular rejection, chronic lung allograft dysfunction [CLAD], death and safety endpoints.

    CET Conclusion

    Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This paper reports the 5-year follow up of a previously published study in lung transplantation. The first publication showed that the addition of everolimus to standard immune suppression regimen allowed the minimisation of CNI exposure. Despite being underpowered, the original publication of the study demonstrated improved eGFR at 12 months, with no change in rejection rates or infectious complications. Over the total 5-year follow-up a substantial proportion (46%) had to switch away from the everolimus arm. There was a significantly increased risk of thromboembolic events in the everolimus arm of the study (24% versus 11%). At 5 years there was no significant difference in GFR between the 2 study arms (in both intention-to-treat and per protocol analysis). There was also no difference in graft survival. It seems that any short-term benefit in renal function is lost over time, whether switching back off everolimus or not. With such a susbtantial proportion changing immune suppression, crossing over and long term follow up with other potential medication changes, it does become difficult to separate effects.

    Abstract

    BACKGROUND Everolimus-based quadruple low calcineurin inhibitor (CNI) maintenance immunosuppression has been shown to be effective in preserving short-term renal function without compromising efficacy or safety after lung transplantation. However, long-term benefit remains unknown. METHODS An investigator-initiated 5-y follow-up analysis of the 4EVERLUNG study (NCT01404325), comparing everolimus-based quadruple low CNI with standard triple regimen, was performed. Patients who remained on the randomized drug regimen until the end of the 5-y observation were analyzed as per protocol (PP) population. Patients in whom the assigned regimen was switched were analyzed as intention-to-treat (ITT) population. RESULTS In total, 123 patients (95%) from the core study were analyzed. During the observation period in 11 patients (19%) of the standard triple regimen and in 30 patients (46%) of the quadruple low CNI regimen, the assigned immunosuppressive regimen was switched (P = 0.002). Estimated glomerular filtration rate at 5-y follow-up did not differ between the groups in both the ITT (56 [48-73] versus 58 [48-69] mL/min; P=0.951) and PP (59 [50-73] versus 59 [48-69] mL/min; P = 0.946) populations. Thromboembolic events occurred more frequently in the quadruple low CNI regimen (ITT: 11% versus 24%, P = 0.048; PP: 11% versus 22%, P = 0.162). There was a trend for a higher chronic lung allograft dysfunction-free survival for the quadruple low CNI regimen in the PP population (P = 0.082). No difference in the graft survival was found. CONCLUSIONS Initiation of an early everolimus-based quadruple low CNI regimen may have no long-term benefit on renal function. The immunosuppressive efficacy and safety profile seems comparable with the standard triple regimen.

Various


  1. Chemoprevention of cutaneous squamous cell carcinoma and its precursors in solid organ transplant recipients using topical sirolimus: a randomized, double-blind, placebo-controlled pilot trial
    Journal of the American Academy of Dermatology. 2022;[record in progress]

    Study Details

    Aims: This study aimed to examine whether topical application of sirolimus could safely reduce the incidence of keratinocyte cancer (KC) in solid organ transplant recipients.
    Interventions: Forearms of patients were randomised to either receive topical Sirolimus or placebo.
    Participants: 29 adult solid organ transplant recipients with a history of basal cell carcinomas or squamous cell carcinomas (SCC) as well as keratotic lesions on the back of the forearms and hands.
    Outcomes: Number of keratotic lesions, change in keratotic lesions, number of intraepidermal carcinoma, and number of SCC.

    CET Conclusion

    Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This small, blinded pilot study randomised transplant recipients with a history of basal and squamous cell carcinoma (BCC/SCC) to apply topical sirolimus to one forearm/hand and placebo to the other for 12 weeks. There was a significant reduction in the risk of keratotic lesions in the sirolimus group at 12 weeks, which resulted in a significant reduction in the risk of intraepithelial carcinomas at 24 months (4 in the sirolimus arm vs. 12 in the placebo arm). Whilst clearly small and underpowered for firm conclusions, this pilot study does provide some evidence of efficacy and feasibility in support of a larger efficacy study.
  2. Donor-Transmitted Cancer in Orthotopic Solid Organ Transplant Recipients: A Systematic Review
    Transplant International. 2021;35:10092

    Study Details

    Aims: This study aimed to synthesise the available evidence on donor-transmitted cancer (DTC) in orthotopic solid organ transplant recipients.
    Interventions: A literature search was performed on PubMed, EMBASE, MEDLINE, Scopus and Web of Science. Study selection and data extraction were carried out by two independent reviewers. The methodological quality of the included studies were assessed using tools published by the Joanna Briggs Institute (JBI).
    Participants: 58 studies were included in the review.
    Outcomes: The main outcomes included patient death, cause of death, cancer remission and cancer recurrence (and time since remission).

    CET Conclusion

    Reviewer: Dr Liset Pengel, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    The systematic review evaluated published evidence on donor transmitted cancer (DTC) in solid organ transplant recipients. The systematic review was registered with PROSPERO. A thorough bibliographic search was developed to identify relevant cohort studies, case-control studies, case series and case reports. Two independent reviewers screened search results, selected studies, extracted data and assessed the study quality. Fifty-eight studies met the inclusion criteria and reported on 73 cases of DTC in liver, lung and heart transplant recipients. Methodological quality of the included studies varied but was overall considered acceptable. Time from transplantation to the diagnosis of DTC ranged from 0 days to 6 years with 66% of cases diagnosed within 1 year and 82% of cases diagnosed within 2 years. The limited evidence showed that mortality was high. The authors make suggestions for clinical practice including surveillance of higher risk patients and management after DTC diagnosis.

    Abstract

    Donor-transmitted cancer (DTC) has major implications for the affected patient as well as other recipients of organs from the same donor. Unlike heterotopic transplant recipients, there may be limited treatment options for orthotopic transplant recipients with DTC. We systematically reviewed the evidence on DTC in orthotopic solid organ transplant recipients (SOTRs). We searched MEDLINE, EMBASE, PubMed, Scopus, and Web of Science in January 2020. We included cases where the outcome was reported and excluded donor-derived cancers. We assessed study quality using published checklists. Our domains of interest were presentation, time to diagnosis, cancer extent, management, and survival. There were 73 DTC cases in liver (n = 51), heart (n = 10), lung (n = 10) and multi-organ (n = 2) recipients from 58 publications. Study quality was variable. Median time to diagnosis was 8 months; 42% were widespread at diagnosis. Of 13 cases that underwent re-transplantation, three tumours recurred. Mortality was 75%; median survival 7 months. Survival was worst in transmitted melanoma and central nervous system tumours. The prognosis of DTC in orthotopic SOTRs is poor. Although re-transplantation offers the best chance of cure, some tumours still recur. Publication bias and clinical heterogeneity limit the available evidence. From our findings, we suggest refinements to clinical practice. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020165001, Prospero Registration Number: CRD42020165001.