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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).

September 2022

Kidney


  1. The Feasibility and User-Experience of a Digital Health Intervention Designed to Prevent Weight Gain in New Kidney Transplant Recipients-The ExeRTiOn2 Trial
    Frontiers in Nutrition. 2022;9:887580

    Study Details

    Aims: This study aimed to investigate the feasibility, acceptability and experience of a digital healthcare intervention (DHI) which was designed to prevent weight gain following kidney transplantation, and provide important insights for a future multi-centre trial design.
    Interventions: Participants were randomised to either the DHI intervention group or the usual care group.
    Participants: 17 kidney transplant recipients.
    Outcomes: Primary feasibility endpoints were screening, recruitment, adherence, retention, safety and hospitalisations, as well as experience and engagement with the DHI. Secondary endpoints included anthropometrics, arterial stiffness, bioimpedance, 6-minute walk distance and questionnaires completed at each study visit.

    CET Conclusion

    Reviewer: Dr Liset Pengel, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    The small, mixed-methods, randomised controlled trial explored the feasibility, acceptability and user experience of a 12-week digital intervention aimed at preventing weight gain in kidney transplant recipients. Seventeen participants were randomised to the intervention and usual care groups according to a computer-generated list. A formal power calculation was not conducted due to the explorative nature of the study but a target sample of 50 participants was set. Due to COVID-19, recruitment was stopped early and follow-up of patients was limited resulting in missing data. Seventeen patients were randomised and four patients dropped out of the study over the 12-month study period. The adherence rate to the study intervention was 67%. There were no serious adverse events. Thirteen participants from both groups completed individual interviews that explored their experiences regarding the intervention and participation in the trial. The analysis identified four themes regarding the study intervention experience, i.e. ‘optimizing participant recruitment’, ‘the impact of COVID-19’, ‘engagement with the ExeRTiOn DHI (study intervention) is a choice’ and ‘mechanisms of action associated with a positive study experience’. Integration of qualitative and quantitative results suggests that an RCT using the ExeRTiOn DHI is feasible and acceptable to new kidney transplant recipients.

    Abstract

    Half of kidney transplant recipients (KTRs) gain more than 5% of their body weight in the first year following transplantation. KTRs have requested support with physical activity (PA) and weight gain prevention, but there is no routine care offered. There are few high-quality studies investigating the clinical value of diet, PA or combined interventions to prevent weight gain. The development and evaluation of theoretically informed complex-interventions to mitigate weight gain are warranted. The aims of this mixed-methods randomized controlled trial (RCT) were to explore the feasibility, acceptability and user-experience of a digital healthcare intervention (DHI) designed to prevent post-transplant weight gain, in preparation for a large multi-center trial. New KTRs (<3 months) with access to an internet compatible device were recruited from a London transplant center. The usual care (UC) group received standard dietary and PA advice. The intervention group (IG) received access to a 12-week DHI designed to prevent post-transplant weight gain. Primary feasibility outcomes included screening, recruitment, retention, adherence, safety and hospitalizations and engagement and experience with the DHI. Secondary outcomes (anthropometrics, bioimpedance, arterial stiffness, 6-minute walk distance and questionnaires) were measured at baseline, 3- and 12-months. 38 KTRs were screened, of which 32 (84.2%) were eligible, and of those 20 (62.5%) consented, with 17 participants (85%) completing baseline assessment (Median 49 years, 58.8% male, Median 62 days post-transplant). Participants were randomized using a computer-generated list (n = 9 IG, n = 8 UC). Retention at 12-months was 13 (76.4%) (n = 6 IG, n = 7 UC). All a priori progression criteria were achieved. There were no associated adverse events. Reflexive thematic analysis revealed four themes regarding trial participation and experience whilst using the DHI. Halting recruitment due to COVID-19 resulted in the recruitment of 40% of the target sample size. Mixed-methods data provided important insights for future trial design. A definitive RCT is warranted and welcomed by KTRs. Clinical Trial Registration: www.clinicalTrials.gov, identifier: NCT03996551.
  2. Pregnancy after living kidney donation, a systematic review of the available evidence and a review of the current guidance
    American Journal of Transplantation. 2022;[record in progress]

    Study Details

    Aims: The aim of this study was to identify all available evidence investigating pregnancy complications post-living kidney donation, and to compare the quality and consistency of guidelines focusing on pregnancy in living kidney donors.
    Interventions: A literature search was conducted on Embase, PubMed, MEDLINE, society webpages and guideline registries. Three independent reviewers performed the initial screening of study titles and abstracts. Eligibility assessment of full-text articles and data extraction were carried out by two independent reviewers. The methodological quality of the included studies were assessed using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool.
    Participants: 16 studies were included in the review.
    Outcomes: The main outcomes of interest were post-donation pregnancy complications, and the risk of adverse maternal, fetal and neonatal outcomes.

    CET Conclusion

    Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This systematic review summarises the literature and guidelines relating to pregnancy following living kidney donation. The authors identified 16 studies reporting on 1399 post-donation pregnancies. Whilst the risk of pre-eclampsia increased post-donation, it is in keeping with an unselected general population. No difference was found in risk of other pregnancy or foetal complications. Guidelines were found to be generally consistent in advice. Methodology appears good, with well-described searches across a number of databases and screening by 3 reviewers. Risk of bias was assessed with the Robins-I tool and found to be low-moderate in most studies. Of note, studies were published over a long period (35 years) so it is perhaps not clear how relevant results of early studies are to today’s practice. Overall, the authors graded the certainty of evidence in risk of hypertension and pre-eclampsia as “low” and for other foetal outcomes as “very low”, reflecting the quality and size of the underlying evidence. This paper provides a very good summary of the evidence (and limitations thereof) regarding post-donation pregnancy.

    Abstract

    Understanding and communicating the risk of pregnancy complications post-living kidney donation is imperative as the majority of living kidney donors (LKD) are women of childbearing age. We aimed to identify all original research articles examining complications in post-donation pregnancies and compared the quality and consistency of related guidelines. We searched Embase, MEDLINE, PubMed, society webpages and guideline registries for English-language publications published up until 18/12/2020. Ninety-three articles were screened from which 16 studies were identified, with a total of 1,399 post-donation pregnancies. The outcome of interest, post-donation pregnancy complications, was not calculable, and only a narrative synthesis of the evidence was possible. The absolute risk of pre-eclampsia increased from ~1-3% pre-donation (lower than the general population) to ~4-10% post-donation (comparable to the general population). The risks of adverse foetal and neonatal outcomes were no different between post-donation and pre-donation pregnancies. Guidelines and consensus statements were consistent in stating the need to inform LKDs of their post-donation pregnancy risk, however the depth and scope of this guidance was variable. Whilst the absolute risk of pregnancy complications remains low post-donation, a concerted effort is required to better identify and individualise risk in these women, such that consent to donation is truly informed.
  3. Perfusate Composition and Duration of Ex-Vivo Normothermic Perfusion in Kidney Transplantation: A Systematic Review
    Transplant International. 2022;35:10236

    Study Details

    Aims: This study aimed to summarise the evidence for optimal perfusate constituents and duration of ex-vivo normothermic perfusion (EVNP) in the context of renal transplantation.
    Interventions: A literature search was conducted on Embase, Medline, Scopus and BIOSIS Previews. Studies were screened by two independent reviewers.
    Participants: 24 studies were included in the review.
    Outcomes: The main outcomes of interest were perfusate composition and perfusion duration.

    CET Conclusion

    Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This is a well-conducted systematic review in Ex-Vivo Normothermic Perfusion (EVNP) of kidneys. It was registered with the PROSPERO system (CRD42021231381). A wide search was undertaken in multiple databases and two independent authors screened references. 24 studies were included, spanning both animal and human kidney studies. A variety of perfusate compositions are assessed in the included studies and the outcomes are not standardised. In combination, these factors make the included studies very heterogenous and not suitable for any summative analysis. The perfusate most commonly used in clinical studies primarily consisted of Ringer’s lactate and O-negative packed red cells. Accepting that the included studies are heterogenous and include pre-clinical and animal studies, this is a well-written and thorough review of this subject.

    Abstract

    Ex-vivo normothermic perfusion (EVNP) is an emerging strategy in kidney preservation that enables resuscitation and viability assessment under pseudo-physiological conditions prior to transplantation. The optimal perfusate composition and duration, however, remain undefined. A systematic literature search (Embase; Medline; Scopus; and BIOSIS Previews) was conducted. We identified 1,811 unique articles dating from January 1956 to July 2021, from which 24 studies were deemed eligible for qualitative analysis. The perfusate commonly used in clinical practice consisted of leukocyte-depleted, packed red blood cells suspended in Ringer's lactate solution with Mannitol, dexamethasone, heparin, sodium bicarbonate and a specific nutrient solution supplemented with insulin, glucose, multivitamins and vasodilators. There is increasing support in preclinical studies for non-blood cell-based perfusates, including Steen solution, synthetic haem-based oxygen carriers and acellular perfusates with supraphysiological carbogen mixtures that support adequate oxygenation whilst also enabling gradual rewarming. Extended durations of perfusion (up to 24 h) were also feasible in animal models. Direct comparison between studies was not possible due to study heterogeneity. Current evidence demonstrates safety with the aforementioned widely used protocol, however, extracellular base solutions with adequate oxygenation, supplemented with nutrient and metabolic substrates, show promise by providing a suitable environment for prolonged preservation and resuscitation. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021231381, identifier PROSPERO 2021 CRD42021231381.
  4. Efficacy and Safety of Direct-Acting Antivirals in Kidney Transplantation From HCV-Viremic Donors to Negative Recipients: A Meta-Analysis
    Frontiers in Medicine. 2022;9:802686

    Study Details

    Aims: The aim of this study was to assess the efficacy and safety of direct-acting antiviral agents (DAAs) in renal transplantation from hepatitis C virus (HCV) positive donors to HCV negative recipients.
    Interventions: Electronic databases including PubMed, Embase, and Web of Science were searched. Study selection and data extraction were performed by two independent reviewers. The Methodological Index for Non-Randomized Studies (MINORS) was used to assess the methodological quality of the included studies.
    Participants: 16 studies were included in the meta-analysis.
    Outcomes: The primary endpoint was the percentage of sustained virological response at week 12 post-treatment (SVR12). The secondary endpoints included the percentages of HCV transmission from donors to recipients, adverse events, and severe adverse events (SAEs).

    CET Conclusion

    Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This systematic review and meta-analysis summarises the literature on the use of direct-acting antivirals (DAAs) in kidney transplant recipients undergoing transplant from a HCV positive donor. The authors identify 16 studies in 454 recipients. Pooled analysis showed a sustained virological response at week 12 of 100%. Rate of adverse events was found to be 1.9%, with no patients experiencing serious adverse events related to DAAs. The authors conclude that DAAs are highly effective and safe for use in this patient population. Methodology appears sound, with a comprehensive search strategy undertaken by 2 reviewers across a number of databases and comprehensive risk of bias assessment undertaken. Studies were all non-randomised or observational in nature, but assessed to have a relatively low risk of bias overall. Given the non-randomised nature of the included studies, use of a fixed-effects analysis is questionable but given the lack of heterogeneity is unlikely to impact the findings significantly.

    Abstract

    Background: With the development of direct-acting antiviral agents (DAAs), the research on kidney transplantation from Hepatitis C virus (HCV)-viremic donors to HCV-negative recipients has grown. The objective of this comprehensive analysis was to evaluate the efficacy and safety of DAAs in kidney transplantation from HCV-viremic donors to negative recipients. Methods: Multiple databases were searched for a systematic and comprehensive up to March 2022. The primary outcomes included the percentage of sustained virological response at week 12 after the end of treatment (SVR12), adverse events (AEs; any grade), and severe adverse events (SAEs) as the endpoints. Publication bias was examined by using the funnel plots and Egger's test. Results: In total, 16 studies with 454 subjects were included in the study and the pooled estimate of SVR12, AEs, and SAEs rates were 100.0% (95% CI: 99.2-100.0), 1.9%(95%CI: 0.0-4.9), and 0.0% (95%CI: 0.0-1.5). Subgroup analysis showed that pooled SVR12 rates were 100.0% (95%CI: 99.6-100.0) for genotype (GT)1a and 96.3% (95%CI: 83.3-100.0) for GT2; 100.0% (95%CI: 98.9-100.0) for DAAs treatments; and 100.0% (95%CI: 98.2-100.0) for prophylaxis subgroup. Egger's tests showed that no publication bias was found in this study. Conclusion: This comprehensive analysis showed the high efficacy and safety of DAAs in kidney transplantation from HCV-viremic donors to HCV-negative recipients. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=246541.
  5. The Effects of Free Heme on Functional and Molecular Changes During Ex Vivo Normothermic Machine Perfusion of Human Kidneys
    Frontiers in Immunology. 2022;13:849742

    Study Details

    Aims: This secondary analysis of a randomised controlled trial aimed to measure free heme levels during normothermic machine perfusion (NMP) and assess their influence on kidney function, and also to determine any correlation with inflammatory and stress related gene expression.
    Interventions: Kidneys in the original trial were randomly assigned receive either ex vivo normothermic perfusion (EVNP) or remain in static cold storage.
    Participants: 42 kidneys that underwent 1 hour normothermic machine perfusion (NMP).
    Outcomes: Levels of free heme, correlation of free heme levels and pRBC age with perfusion parameters and with inflammatory and stress related gene expression.

    CET Conclusion

    Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This paper reports a secondary analysis of an RCT of normothermic machine perfusion of the kidney prior to transplantation. The authors measured the level of free heme in the perfusate during 1 hour of NMP in a series of 42 DCD kidneys, and related this to perfusion parameters or gene expression. They found that significant levels of free heme are present in the perfusate even during short periods of NMP, and these correlate with the age of the RBC used for perfusion. However, there was no association between levels of free heme and gene expression. As this is a secondary analysis and the number are small with a short perfusion duration, it is unclear whether these findings truly reflect the clinical effects of high levels of free heme in the perfusate, or whether differences in outcome could be detected in a larger sample. Certainly, the age of red cells is likely to be important, and will also effect oxygen carrying capacity and delivery during NMP. Whilst this does not appear to have a major impact during short periods of NMP, it is possible that it will be more significant during longer duration perfusions.

    Abstract

    Normothermic machine perfusion (NMP) is a technique of kidney preservation designed to restore cellular metabolism after cold ischemia. Kidneys are perfused with an oxygenated banked red blood cell (RBC) based solution for 1h at 36degreeC. During NMP, RBCs can become damaged, releasing free heme into the perfusate. This can act as a damage-associated molecular pattern (DAMP) activating inflammatory signalling pathways. The aim of this study was to measure the levels of free heme during NMP, assess the effect on kidney function and determine any association with inflammatory and stress related gene expression. Levels of free heme were measured in perfusate samples from a series of donation after circulatory death (DCD) kidneys undergoing NMP as part of a randomised controlled trial (RCT). The age of RBCs and levels of free heme were correlated with perfusion parameters. Changes in gene expression were analysed in a series of kidneys declined for transplantation using the NanoString nCounter Organ Transplant Panel and qRT-PCR. Older units of RBCs were associated with higher levels of free heme and levels increased significantly during NMP (Pre 8.56 +/- 7.19microM vs 26.29 +/- 15.18microM, P<0.0001). There was no association with levels of free heme and perfusion parameters during NMP (P > 0.05). Transcriptional and qPCR analysis demonstrated the upregulation of differentially expressed genes associated with apoptosis (FOS and JUN), inflammatory cytokines (IL-6, SOCS3, ATF3), chemokines (CXCL8, CXCL2, CC3/L1) and oxidative stress (KLF4) after NMP. However, these did not correlate with levels of free heme (P >0.05). A significant amount of free heme can be detected in the perfusate before and after NMP particularly when older units of red cells are used. Although transcriptional analysis demonstrated significant upregulation of genes involved with apoptotic, inflammatory and oxidative pathways these were not associated with high levels of free heme.
  6. Face-to-Face Mentoring, Remotely Supervised Home Exercise Prehabilitation to Improve Physical Function in Patients Awaiting Kidney Transplantation: A Randomized Clinical Trial
    Frontiers in Psychology. 2022;13:831445

    Study Details

    Aims: This study aimed to investigate the feasibility, safety, and effectiveness of face-to-face mentoring, remotely supervised home exercise prehabilitation to optimize the physical functions of end-stage renal disease (ESRD) patients, and provide a guideline basis for home prehabilitation exercises for patients awaiting renal transplantation.
    Interventions: Participants were randomised to 12 weeks of home exercise prehabilitation or to 12 weeks without home exercise prehabilitation.
    Participants: 55 patients awaiting kidney transplantation.
    Outcomes: The primary endpoints were 6-min walk test (6MWT) walking distance, 6MWT measured distance compliance percentage, grip strength, 5 repetition-sit-to-stand test (5R-STS), and 4-m gait speed. Secondary endpoints were hospital anxiety, depression, and quality of life.

    CET Conclusion

    Reviewer: Dr Liset Pengel, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    The small randomised controlled trial explored the feasibility and safety of a home prehabilitation exercise programme for patients with end-stage renal disease who are estimated to be within 12 weeks of receiving their first kidney transplant. A sample size calculation was based on improvement in the 6-minute walk test (6MWT) and indicated that a minimum of 40 patients were needed. Fifty-five patients were randomised but no details were given regarding the randomisation process and whether allocation was concealed. The prehabilitation intervention was a 12-week programme consisting of aerobic exercise, functional resistance training and stretching exercises. Eighteen out of 55 patients dropped out (7 and 11 patients from the prehabilitation and control groups, respectively) because of loss of interest, time conflicts or loss of contact, leaving 37 patients in the analysis. The primary outcomes 6MWT, handgrip, 5-repetition sit-to-stand test and 4-m gait speed all improved significantly from baseline to post-intervention in the prehabilitation group. However, the between-group analyses showed no significant differences for any of these outcomes post-intervention. The authors suggest that future studies need to evaluate the effectiveness of each exercise type further in a larger trial.

    Abstract

    Objective: This study aims to explore the feasibility, safety, and effectiveness of home exercise prehabilitation on a new social platform for remote guidance to optimize the physical function of patients with end-stage renal disease awaiting kidney transplantation and provide scientific guidance on home prehabilitation exercises for patients awaiting kidney transplantation. Methods: The subjects of this randomized clinical trial were randomly divided into the test and control groups. The control group maintained their exercise habits, while the trial group was given a 12-week personalized home prehabilitation exercise prescription (aerobic exercise + functional resistance exercise + flexibility exercise) on a new social platform with remote guidance. The participants' physical and cardiorespiratory fitness, quality of life, and psychological functioning were assessed before and after the intervention. The 6-min walk test (6MWT) walking distance and its percentage of attainment, the handgrip, the 5 repetition-sit-to-stand test, and the 4-m gait speed were used as primary outcome indicators, while the Short Form Health Survey SF-36 (health survey summary table) and the Hospital Anxiety and Depression scale were used as the secondary outcome indicators. Results: After 12 weeks of intervention, the changes in the 6MWT measured distance (+ 44.9 +/- 40.2, P = 0.001) and the percentage of 6MWT measured distance achieved (+ 6.8 +/- 5.7, P = 0.001), the handgrip (+ 2.7 +/- 4.3, P = 0.028), the 5-sit-to-stand test (-1.1 +/- 1.4, P = 0.005), and the 4-m walking speed (-0.3 +/- 0.4, P < 0.001) of the test group (n = 21) improved significantly. In the control group (n = 16), the changes in the 6MWT measured distance (-13.1 +/- 57.2), the 6MWT measured distance attainment percentage (-2.1 +/- 9.1), the handgrip (-0.1 +/- 2.5), the 5-sit-to-stand test value (0.6 +/- 2.2), and the 4-m walking speed (0.2 +/- 0.5) showed no significant difference. No significant improvement in anxiety, depression, and SF-36 was noted in both the test and control groups. Conclusion: The remote coaching of home exercise pre-habilitation on a new social platform significantly improves the physical and cardiopulmonary fitness of patients with end-stage renal disease awaiting kidney transplantation. This treatment is safe and feasible in this population.
  7. Cyclic photodynamic therapy delays first onset of actinic keratoses in renal transplant recipients: a 5-year randomized controlled trial with 12-month follow-up
    Journal of the European Academy of Dermatology & Venereology. 2022;[record in progress]

    Study Details

    Aims: This study aimed to report the 6-year follow-up data of a randomised controlled trial investigating whether cyclic photodynamic therapy (PDT) was effective in reducing or delaying the development of actinic keratoses (AK) in kidney transplant patients with no baseline skin dysplasia.
    Interventions: Participants were randomly assigned to receive split-side PDT of the face, dorsal forearm and hand, with the contralateral side serving as untreated control.
    Participants: 46 renal transplant recipients with no previous or current AK, keratinocyte carcinoma (KC) or PDT treatment.
    Outcomes: The main outcomes of interest were total number of AKs, time to onset of first AK in the treatment areas, and number of non-melanoma skin cancers including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).

    CET Conclusion

    Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This letter to the editor describes long-term follow-up of a randomised controlled trial of cyclic photodynamic therapy for actinic keratosis (AK) protection in renal transplant recipients with no baseline dysplasia. Patients in the study arm were treated on the face, forearm and hand at 6-month intervals for 5 years, with the contralateral side acting as a control. AK lesions appeared earlier in untreated skin (median 28 vs. 40 months) with lower probability of AK-free skin. There were no differences in incidence of SCC or BCC. These findings are interesting, although the sample is too small to determine a difference in eventual skin cancers. It should be noted that of the 46 patients recruited, only 70% attended all study visits reducing power further. Nevertheless, the findings suggest that PDT does reduce the speed and number of AK lesions developing in renal transplant recipients, and may be of use particularly in high-risk patients and regions.

Lung


  1. Impact of Lung Function Decline on Mortality in Lung Transplant Recipients: Long-Term Results From the L-CsA-i Study for the Prevention of Bronchiolitis Obliterans Syndrome
    Frontiers in Medicine. 2022;9:897581

    Study Details

    Aims: This study aimed to determine the association between forced expiratory volume in one second (FEV1) and risk of mortality in patients following lung transplantation, using the 10-year follow up data from the PARI Study No. 12011.201.
    Interventions: Participants in the original trial were randomised to receive either liposomal Cyclosporine A inhalation (L-CsA-i) or placebo.
    Participants: 130 lung transplant recipients.
    Outcomes: The main outcomes of interest were the association between the course of post-transplant FEV1 over time and the risk of mortality, time to progression to allograft dysfunction and survival.

    CET Conclusion

    Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This paper presents post hoc analyses from a previously published RCT. The original RCT investigated inhaled liposomal ciclosporin-A in the prevention of Bronchiolitis Obliterans Syndrome (BOS) after lung transplantation. 10-year follow up is now available for all 130 of the included patients. A strong association was found between baseline FEV1 and mortality risk and each 1% drop from baseline FEV1 was associated with 3.5% increased risk for mortality. The individual trajectories in lung function were highly variable between patients, however it seems that post-transplant FEV1 is a valid predictor of mortality and could be used to institute pre-emptive treatment.

    Expert Review

    Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    Clinical Impact Rating : ☆☆☆☆☆ (0 of 5)
    This paper presents some long term follow up from a previously published RCT of inhaled liposomal cyclosporine A in lung transplantation. The original study closed prior to reaching the target patient inclusion due to very slow accumulation of cases (Neurohr et al 2022). The paper by Kneidinger et al presents post hoc analyses from the RCT. The authors used the collected data to explore the relationship between decline in FEV1 and mortality in patients with single and double lung transplant. Whilst patients were included in the trial they had FEV1 measurements every 2 months, and for this analysis they were requested every 6 months up to ten years from inclusion. Complete data was retrieved for 91% of included patients, and reduced data for the remaining patients, censored at the last study visit. Mean follow up was 61 months. On average, FEV1 deteriorated over time but the trajectory for showed a great deal of diversity between patients. A highly significant correlation was found between the relative drop in FEV1 compared to baseline and mortality. In broad terms a 1% reduction in FEV1 compared to baseline, related to 3.4% higher mortality risk. In cox regression analysis, type of transplant was the only significant independent predictor of mortality; with recipients of single lung transplants having increased risk of progression. A significant amount of lung function must be lost before chronic lung allograft dysfunction can be diagnosed. Understanding the decline in FEV1 might allow early intervention and improvement in patient care through modification of the underlying process. Decline in FEV1 from baseline could also be used as a reliable surrogate outcome for mortality in clinical trials. References Neurohr, C. ; Kneidinger, N. ; Ghiani, A. ; et al. A randomized controlled trial of liposomal cyclosporine A for inhalation in the prevention of bronchiolitis obliterans syndrome following lung transplantation. American Journal of Transplantation. 2022;22(1):222-229

    Abstract

    Background: Chronic lung allograft dysfunction (CLAD) is defined by a progressive loss of FEV1 and is associated with premature mortality. The aim of this study was to investigate the direct association between FEV1 decline and risk of mortality in patients after lung transplantation (LTx). Methods: 10-year follow up data from lung transplant recipients participating in randomized placebo-controlled clinical trial investigating the role of liposomal Cyclosporine A for inhalation (L-CsA-i) in the prevention of bronchiolitis obliterans syndrome (NCT01334892) was used. The association between the course of FEV1 over time and the risk of mortality was assessed using joint modeling and Cox regression analysis. Results: A total of 130 patients were included. Predictors of FEV1 decline were a higher absolute FEV1 at baseline and male sex. The joint model analysis indicated a significant association of change of FEV1 and risk of mortality (p < 0.001), with a predicted 3.4% increase in mortality risk for each 1% decline in FEV1. Significant predictors of a progressive phenotype were single LTx and treatment with placebo (as opposed to L-CsA-i). At the end of follow-up, 82 patients (63.1%) were still alive. Cox regression analyses for mortality identified only single LTx as a predictor of higher risk. Conclusion: Based on our observation of a close association between FEV1 and mortality over a period of 10 years we suggest FEV1 as a valid predictor of mortality and a suitable surrogate endpoint in the investigation of early interventions.

Various


  1. Pregnancy and neonatal outcomes in women receiving calcineurin inhibitors: A systematic review and meta-analysis
    British Journal of Clinical Pharmacology. 2022;88(9):3950-3961

    Study Details

    Aims: This study aimed to evaluate the effect of calcineurin inhibitors (CNIs) on pregnancy and neonatal outcomes.
    Interventions: Electronic databases including PubMed/MEDLINE and EMBASE were searched. Studies were screened by two independent reviewers. The quality of the included studies was assessed using the Newcastle–Ottawa Scale.
    Participants: 98 studies were included in the review.
    Outcomes: The main outcomes of interest were pregnancy outcomes (rates of induced abortion, spontaneous abortion, preeclampsia, gestational hypertension, gestational diabetes, C-section and maternal death during pregnancy) and neonatal outcomes (rates of live birth, preterm delivery, low birth weight, major congenital malformations, stillbirth and neonatal death).

    CET Conclusion

    Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This was a well-conducted systematic review that searched multiple databases and was registered with the PROSPERO system (CRD42021291249). Two independent authors screened studies for inclusion. A large number of studies were included (98) and all were observational in design, including 5,355 pregnancies in 4,450 patients. Study quality was assessed using the Newcastle-Ottawa Scale, but it is not clear if this was completed in duplicate. Studies were subdivided into immune-mediated inflammatory diseases and organ transplant recipients, further subdivided by organ type. Multiple pregnancy outcomes are investigated with pooled estimates and metaregression analysis to identify contributory factors. The pooled rates of pre-term delivery, low birth rate and pre-eclampsia were 3-4 times higher for patients on CNI than the general population. However, rates of induced and spontaneous abortion were lower, and there was no increase in gestational diabetes or major congenital malformations. Cyclosporin use was significantly associated with gestational hypertension and pre-eclampsia, itself related to higher rates of pre-term delivery. Heterogeneity was statistically assessed as moderate to severe. The study also found significant publication bias for most pregnancy and neonatal outcomes, but this issue is not addressed in any way. Altogether the study suggests that CNI-treated patients must be considered as a higher risk group. Unfortunately, there is not clear information on CNI dosing regimens or emergency versus elective caesarean section. Despite the weaknesses, the paper does have a large population and clearly presents summary rates from multiple studies for pregnancy and neonatal outcomes, particularly for organ transplant recipients.

    Abstract

    AIMS: Calcineurin inhibitors (CNIs) are often used for solid organ transplantation recipients or patients with immune-mediated diseases. This systematic review and meta-analysis aims to understand how CNIs affect pregnancy and neonatal outcomes. METHODS Electronic databases were searched for observational studies assessing pregnancy and neonatal outcomes in CNI-treated patients. The pooled rate of each outcome was determined. Metaregression was conducted to identify contributing factors to the outcomes. RESULTS We analysed 98 studies with a total of 5355 pregnancies in 4450 CNI-treated patients. The pooled rates of live birth and spontaneous abortion were 82.1% (95% confidence interval [CI] 76.7-86.4%) and 11.7% (95% CI 8.7-15.5%), respectively. The rates of preterm delivery (33.2%, 95% CI 29.2-37.5%), low birth weight (35.8%, 95% CI 27.7-44.8%) and preeclampsia (13.5%, 95% CI 9.4-19.2%) were 3-4 times higher than the rates of general population. Nearly half of the CNI-treated patients required caesarean delivery (43.5%, 95% CI 36.9-50.3%). The rates of stillbirth, neonatal and maternal death were 4.2% (95% CI 2.8-6.2%), 2.9% (95% CI 1.8-4.8%) and 2.3% (95% CI 1.3-4.1%), respectively. Metaregression showed that preeclampsia was significantly associated with the risks of preterm delivery and low birth weight. Older maternal age, prepregnancy hypertension and cyclosporine use increased the risk of preeclampsia. CONCLUSION Given the higher mortalities in CNI-treated patients and their children than the general averages, their pregnancy is considered high risk. The risks of preterm delivery and low birth weight were primarily attributed to preeclampsia. Since prepregnancy hypertension increased its risk, an appropriate preconception blood pressure management may improve their outcomes.
  2. Promoting deceased organ and tissue donation registration in family physician waiting rooms (RegisterNow-1): a pragmatic stepped-wedge, cluster randomized controlled registry trial
    BMC Medicine. 2022;20(1):75

    Study Details

    Aims: This study aimed to investigate whether the RegisterNow-1 intervention was effective in promoting organ donation registration in family physician offices.
    Interventions: All participating family physician offices began with usual care, then after every two weeks, one office (which was randomly assigned) started the intervention until all offices delivered the intervention.
    Participants: 6 family physician offices in Canada.
    Outcomes: The primary endpoint was the percentage of patients registered for organ/tissue donation within 7 days of visit. The secondary endpoints were registration within 1 day, 14 days and 30 days of physician visit.

    CET Conclusion

    Reviewer: Dr Liset Pengel, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This is a cross-sectional stepped-wedge cluster randomized controlled registry trial to evaluate an intervention that addresses barriers and enablers to organ donation registration versus no intervention in family physician waiting rooms. All family physician offices began with usual care and then every two weeks, one office (randomly assigned based on computer-generated random numbers) started the intervention until all offices were exposed to the intervention. The intervention was delivered at practice level and members of the public were involved in the design and conduct of the trial. A sample size calculation was based on detecting a 10% absolute increase in donor registrations. During the intervention period there were n=12,484 patient visits to a physician and n=12,132 patient visits during the control period. The percentage of patients that registered for organ or tissue donation was similar between the groups (46% in the control period versus 48% in the intervention period). Staff interviews revealed five themes regarding barriers and enablers to deliver the intervention, which can help to improve the intervention further.

    Abstract

    BACKGROUND The shortage of available organs for life-saving transplants persists worldwide. While a majority support donating their organs or tissue when they die, many have not registered their wish to do so. When registered, next of kin are much more likely to follow-through with the decision to donate. In many countries, most people visit their family physician office each year and this setting is a promising, yet underused, site where more people could register for deceased organ donation. Our primary aim was to evaluate the effectiveness of an intervention to promote organ donation registration in family physician's offices. METHODS We developed an intervention to address barriers and enablers to organ donation registration that involved physician office reception staff inviting patients to register on a tablet in the waiting room while they waited for their appointment. We conducted a cross-sectional stepped-wedge cluster randomized controlled registry trial to evaluate the intervention. We recruited six family physician offices in Canada. All offices began with usual care and then every two weeks, one office (randomly assigned) started the intervention until all offices delivered the intervention. The primary outcome was registration for deceased organ donation in the provincial organ registration registry, assessed within the 7 days of the physician visit. At the end of the trial, we also conducted interviews with clinic staff to assess any barriers and enablers to delivering the intervention. RESULTS The trial involved 24,616 patient visits by 13,562 unique patients: 12,484 visits in the intervention period and 12,132 in the control period. There was no statistically significant difference in the percentage of patients registered for deceased organ donation in the intervention versus control period (48.0% vs 46.2%; absolute difference after accounting for the secular trend: 0.12%; 95% CI: - 2.30, 2.54; p=0.92). Interviews with clinic staff indicated location of the tablet within a waiting room, patient rapport, existing registration, confidence and motivation to deliver the intervention and competing priorities as barriers and enablers to delivery. CONCLUSIONS Our intervention did not increase donor registration. Nonetheless, family physician offices may still remain a promising setting to develop and evaluate better interventions to increase organ donation registration. Trial registration: Nct03213171.