Prospective, single-centre, randomised controlled trial to evaluate the efficacy and safety of ischaemia-free liver transplantation (IFLT) in the treatment of end-stage liver disease
BMJ Open. 2020;10(5):e035374
INTRODUCTION During conventional liver transplantation (CLT), ischaemia-reperfusion injury (IRI) is inevitable and is associated with complications such as early allograft dysfunction (EAD), primary non-function and ischaemic-type biliary lesions. We have established a novel procedure called ischaemia-free liver transplantation (IFLT). The results from a pilot study suggest that IFLT might prevent IRI and yield better transplant outcomes than CLT. The purpose of this study was to further assess the efficacy and safety of IFLT versus CLT in patients with end-stage liver disease. METHODS AND ANALYSIS This is an investigator-initiated, open-label, phase III, prospective, single-centre randomised controlled trial on the effects of IFLT in patients with end-stage liver disease. Adult patients (aged 18-75 years) eligible for liver transplantation will be screened for participation in this trial and will be randomised between the IFLT group (n=34) and the CLT group (n=34). In the IFLT group, the donor liver will be procured, preserved and implanted with continuous normothermic machine perfusion (NMP). In the CLT group, the donor liver will be procured after a fast cold flush, preserved in 0degreeC-4degreeC solution and implanted under hypothermic and hypoxic conditions. Patients in both groups will be managed according to the standard protocol of our centre. The primary end point is the incidence of EAD after liver transplantation. Intraoperative and postoperative parameters of donor livers and recipients will be observed and recorded, and postoperative liver graft function, complications and recipient and graft survival will be evaluated. After a 12-month follow-up of the last enrolled recipient, the outcomes will be analysed to evaluate the safety and efficacy of IFLT versus CLT in patients with end-stage liver disease. ETHICS AND DISSEMINATION The protocol was reviewed and approved by the Ethics Committee of The First Affiliated Hospital of Sun Yat-sen University. The findings will be disseminated to the public through conference presentations and peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER ChiCTR1900021158.
A Systematic Review of Renal Functional Reserve in Adult Living Kidney Donors
KI Reports. 2020;5(4):448-458
Introduction: The kidney's capacity to increase its glomerular filtration rate (GFR) in response to a higher functional demand is known as the renal functional reserve (RFR). Good short-term outcomes after living kidney donation have led to more acceptance of borderline donors (with hypertension, obesity, older age) due the ongoing shortage of donor organs. Given recent concerns about increased long-term risk in some donor subgroups, better donor stratification is needed. Measurement of RFR could inform assessment of donor risk. Methods: A systematic literature review of studies that assessed RFR in donors pre- and/or post-donation was performed. Given study heterogeneity, descriptive analysis and narrative synthesis was conducted. Results: Sixteen of 3250 identified studies published between 1956 and 2019 met inclusion criteria. Most studies were cross-sectional and conducted before (n = 8) and/or after (n = 16) kidney donation. Methods for measurement of GFR, effective renal plasma flow (ERPF) and RFR were not standardized. Changes in filtration fraction (FF) and ERPF relative to GFR observed after donation varied depending on stimulus used to induce RFR. Overall, RFR fell after donation; however, over the shorter term, RFR was largely preserved in young healthy donors. RFR was more significantly reduced in donors with hypertension, obesity, or older age. Conclusion: Existing data suggest possible blunting of RFR post-donation in older, obese, and hypertensive donors, which may represent increased single-nephron GFR at baseline. The long-term implications of these changes deserve further study to determine utility in informing selection of borderline kidney donors.
Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus From the Transplantion Society Working Group
With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low-level evidence. The number of prospective randomized trials for the treatment of AMR is small, and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated. At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes were discussed. The evidence for different treatments was reviewed, and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented. While it was agreed that the aims of treatment are to preserve renal function, reduce histological injury, and reduce the titer of donor-specific antibody, there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes.
The COVID-19 outbreak in Italy: initial implications for organ transplantation programs
American Journal of Transplantation. 2020;[record in progress]
The spread of Coronavirus Disease 2019 (COVID-19) has already reached a pandemic dimension within few weeks. Italy has been one of the first countries dealing with the outbreak of COVID-19 and severe measures have been adopted to limit viral transmission. The spread of COVID-19 may have several implications in organ transplant activity that physicians should be aware of. The initial experience gained during the COVID-19 outbreak shows that around 10% of infected patients in Italy need intensive care management to overcome the acute respiratory distress syndrome. Due to the exponential rise of infected patients we are now facing an actual risk of saturation of intensive care unit (ICU) beds. A restriction in the number of ICU beds available for both donors and transplant recipients may unfavorably influence the overall donation activity, and eventually lead to a reduced number of transplants. Preliminary Italian data show that a 25% reduction of procured organs has already occurred during the first 4 weeks of COVID-19 outbreak. This underlines the need to closely monitor what will be further happening in ICUs due to the COVID-19 spread in the attempt to preserve transplant activity, especially in Western countries where deceased donors represent the major organ resource.
Randomized Sirolimus-based early calcineurin inhibitor reduction in liver transplantation: impact on renal function
This study was a 5 year follow-up to the SiLVER trial, which explored the long-term use of calcineurin inhibitors (CNI) after liver transplantation (LT) on nephrotoxicity.
Patients from the SiLVER trial were randomized into two groups: Group A - the standard CNI-based mTOR-free immunosuppression (n=264) was compared to Group B - a 50 % reduction of CNI and introduction of the mTOR inhibitor Sirolimus within 4 to 6 weeks after LT (n=261).
525 randomized patients from the SiLVER trial were analysed at 5 years.
The primary outcome was to investigate whether the early CNI reduction in group B as stipulated in the SiLVER study protocol impacts early and late renal outcomes, as measured by eGFR and incidence of chronic kidney disease (CKD). Further to this, the extent of CNI reduction actually achieved and its effect on drug levels and renal outcomes during the full study duration of 5 years was also assessed.
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
This manuscript reports the 5-year renal function outcomes from the large multicenter SILVER study, a randomized controlled trial of early CNI-reduction and mTOR inhibitor use in low-risk liver transplant recipients with HCC. In intention-to-treat analysis, renal function improved in the mTORi arm at 3 months, but this improvement was not sustained and decline in renal function was equivalent at later time-points. The reason for this finding is two-fold – (1) as with previous studies, mTORi was poorly tolerated with 1/3 patients stopping it by 5 years, and (2) reduction in CNI dose was common in the control arm. Per-protocol
analysis suggests a renal function benefit in those who are able to continue on mTORi, but in a real-world population long-term benefit is absent.
BACKGROUND The long-term use of calcineurin inhibitors (CNI) after liver transplantation (LT) is associated with nephrotoxicity. METHODS 5-year follow-up data was retrieved from the randomized controlled multicenter SiLVER trial. Standard CNI-based mTOR-free immunosuppression (group A, n=264) was compared to a 50 % reduction of CNI and introduction of the mTOR inhibitor Sirolimus within 4 to 6 weeks after LT (group B, n=261). RESULTS Median MELD at LT was low with 10 (7 - 15) (group A) and 11 (8 - 15) (group B) in the intention-to-treat approach. CNI dose and CNI trough were reduced by 20% and 8% (group A) versus 55% and 56% (group B) at 3 months post transplantation. Renal function was preserved at 3 months after LT in the Sirolimus arm [eGFR 74 (57-95) versus 67 (55-85) ml/min/1.73m, p=0.004] but was similarly impaired thereafter compared to group A. The per protocol analysis identified LT recipients in group B with concomitant early CNI minimization and Sirolimus treatment >= year 1 with significantly superior eGFR and lowest rate of chronic kidney disease (>= stage 3) from year 1 onwards until study end. Competing risk factors for renal disease (arterial hypertension, fat metabolism disorder and hyperglycemia) were not associated with worse kidney function. CONCLUSIONS Prevention of CNI nephrotoxicity by Sirolimus-based early CNI minimization protects renal function only short-term after LT in the intention-to-treat analysis of this low MELD cohort. Yet, selected LT recipients compliant with early CNI minimization and Sirolimus maintenance achieved better long-term renal outcomes compared to real-world practice.
A prospective, randomized, single-blind, multicentre, phase III study on organ preservation with Custodiol-N solution compared with Custodiol R solution in organ transplantation (kidney, liver and pancreas)
Trials [Electronic Resource]. 2020;21(1):62
BACKGROUND Organ preservation before transplantation is still a challenge. Both the University of Wisconsin and Bretschneider's histidine-tryptophan-ketoglutarate (HTK; Custodiol R) solution are standard for liver, kidney and pancreas preservation. Organ preservation with both solutions is comparable; recently, however, Custodiol R solution has been modified to Custodiol-N according to the needs of today. Thus, our study was defined to study its effect in clinical transplantation. METHODS Patients undergoing kidney transplantation (n = 412) (including approximately 30 combined kidney-pancreas) or liver transplantation (n = 202) receive grafts that have been cold stored in either Custodiol R or Custodiol-N to demonstrate noninferiority of Custodiol-N regarding both graft function and graft injury after transplantation. DISCUSSION Preclinical data have clearly shown that Custodiol-N is superior to Custodiol R in cold static organ preservation via mechanisms including inhibition of hypoxic cell injury, cold-induced cell injury and avoidance of adverse effects during warm exposure to the solution. Further clinical safety data on Custodiol-N for cardioplegia are available. Thus, this study was designed to compare Custodiol R with Custodiol-N for the first time in a prospective, randomized, single-blinded, multicentre, phase III clinical transplantation trial. TRIAL REGISTRATION Eudra-CT, 2017-002198-20. Registered on 28 November 2018.
Portable Normothermic Cardiac Perfusion System in Donation After Cardiocirculatory Death: A Health Technology Assessment
Ontario Health Technology Assessment Series. 2020;20(3):1-90
Background: Heart transplantation is the most effective treatment for people experiencing end-stage heart failure whose quality of life and life expectancy are unacceptable. However, there is a chronic shortage of donor hearts to meet the demand, so it is essential to expand the donor pool and increase supply. Heart donation mainly occurs after brain death (neurological determination of death [NDD]), but it may also be feasible after cardiocirculatory death (when the heart has stopped beating and there is no longer blood flow or a pulse), provided specialized preservation techniques are used. An investigational device, a portable normothermic cardiac perfusion system, could make it possible to procure, preserve, and transport hearts donated after cardiocirculatory death (DCD). We conducted a health technology assessment of a portable normothermic cardiac perfusion system for the preservation and transportation of DCD hearts for adult transplantation. This included an evaluation of the effectiveness, safety, value for money, and budget impact of publicly funding this system, as well as an evaluation of patient preferences and values. Methods: We performed a systematic review of the clinical literature published since 1998 that examined the clinical safety and effectiveness of a portable normothermic cardiac perfusion system for DCD heart transplantation. We assessed the risk of bias of each included study and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We also reviewed the economic evidence published during the same time period for the cost-effectiveness of a portable normothermic cardiac perfusion system for DCD hearts compared with cold storage for NDD hearts. We further estimated the 5-year net budget impact of publicly funding a normothermic cardiac perfusion system for DCD heart transplantation for adults on Ontario's waitlist. To contextualize the potential value of a portable normothermic cardiac perfusion system, we spoke with people waiting for a heart transplant, people who had received a heart transplant, and family members of organ donors. Results: We screened 2,386 clinical citations. One study and two case reports met the inclusion criteria. The survival of recipients of DCD hearts procured with a portable normothermic cardiac perfusion system did not differ significantly from the survival of recipients of hearts donated after NDD at 30 days or 90 days, nor was there a significant difference in cumulative survival at 1 year post-transplant (GRADE Very Low). The occurrence of rejection and graft failure also did not significantly differ between the groups (GRADE Very Low). Cardiac function in the early post-operative period was better in DCD hearts than NDD hearts (GRADE Very Low). There were no differences in outcomes between DCD procurement techniques. The economic literature search yielded 62 citations. One report met the inclusion criteria but was not directly applicable to the Ontario context. Given the lack of clinical and economic evidence on long-term outcomes, we did not conduct a primary economic evaluation. In the budget impact analysis, based on the number of DCD donors under 40 years of age in the last 5 years, we estimated that the increased availability of donor hearts made possible by the technology would result in an additional seven transplants in year 1, increasing to 12 in year 5. The annual net budget impact of publicly funding a normothermic cardiac perfusion system for the transplantation of DCD hearts in Ontario over the next 5 years is about $2.0 million in the first year and about $0.9 million in each of years 2 through 5, yielding a total net budget impact of about $5.6 million. This number increases to about $10.3 million if the transplant volume increases to 18 hearts in year 1 (meaning a subsequent increase of up to 21 hearts in year 5). If transplantation were limited to people who do not qualify for a ventricular assistive device or who qualify but do not wish to receive one, the total 5-year net budget impact would be about $7.9 million.People waiting for a heart transplant or who had received a heart transplant and family members of organ donors expressed no substantial concerns about the potential use of a portable normothermic cardiac perfusion system. They hope that it may increase the number of donor hearts available for transplant. For family members of organ donors, a perfusion system may provide comfort and value if it can increase the successful procurement of donor hearts. Conclusions: Based on very low quality of evidence, the outcomes for recipients of DCD hearts preserved using a portable normothermic cardiac perfusion system appear to be similar to outcomes for recipients of NDD hearts. Owing to a lack of evidence relevant to the Ontario context, we were unable to determine whether a portable normothermic perfusion system may be cost-effective. We estimate that publicly funding a portable normothermic cardiac perfusion system for DCD heart transplantation over the next 5 years will cost about $5.6 million. The people we spoke with believe that the system may increase the number of hearts available for transplant and therefore increase the number of heart transplants that can be done.
Improving medication adherence and outcomes in adult kidney transplant patients using a personal systems approach: SystemCHANGE<sup>TM</sup> results of the MAGIC randomized clinical trial
American Journal of Transplantation. 2020;20(1):125-136
The objective of this study was to determine if a SystemCHANGETM intervention was more efficacious than attention control in increasing immunosuppressive medication adherence and improving outcomes in adult kidney transplant recipients during a 6-month intervention phase and a subsequent 6-month (no intervention) maintenance phase.
Patients were randomly assigned to a 6 month SystemCHANGETM intervention or a no intervention, maintenance phase. The SystemCHANGETM approach taught patients to use person-level quality improvement strategies to link adherence to established daily routines.
There were 89 kidney transplant patients which participated in this study.
Primary outcome was assessed as the average 6-month immunosuppressive medication adherence rate, which was defined as doses taken on time/total doses as measured by the Medication Event Monitoring System SmartCap® (MEMSCap™). The secondary outcome was adherence of immunosuppressive medication at 12 months.
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
This interesting RCT investigates the use of a behavioural intervention (SystemChange) to improve medication adherence following renal transplantation. Patients were randomized to intervention or control, and the authors demonstrate a significant improvement in adherence following the intervention, which importantly is preserved for 6 months after the intervention is complete. Interventions that demonstrate sustained improvement in adherence in transplant recipients are far and few between, so these findings are important. However, it is not clear from this study how easy it would be to implement the intervention outside of the trial setting as it is quite resource intensive. Whilst
the intervention effect was sustained in patients for 6 months after completion, this was with a stipend and continued electronic pill monitoring. It is possible that the effect will reduce over time outside of a trial. A pragmatic real-world trial in more centres would help to answer some of these outstanding questions.
This study determined if a SystemCHANGETM intervention was more efficacious than attention control in increasing immunosuppressive medication adherence and improving outcomes in adult kidney transplant recipients during a 6-month intervention phase and subsequent 6-month (no intervention) maintenance phase. The SystemCHANGETM intervention taught patients to use person-level quality improvement strategies to link adherence to established daily routines, environmental cues and supportive people. Eighty-nine patients (average age 51.8 years, 58% male, 61% African-American) completed the 6-month intervention phase. Using an intent-to-treat analysis, at 6-months, medication adherence for SystemCHANGETM (median 0.91, IQR 0.76-0.96) and attention control (median 0.67, IQR 0.52-0.72) patients differed markedly (difference in medians 0.24, 95% CI 0.13-0.30, p <.001). At the conclusion of the subsequent 6-month maintenance phase, the gap between medication adherence for SystemCHANGETM (median 0.77, IQR 0.56-0.94) and attention control (median 0.60, IQR 0.44-0.73) patients remained large (difference in medians 0.17, 95% CI 0.06-0.33, p = 0.004). SystemCHANGETM patients evidenced lower mean creatinine and BUN at 12 months and more infections at 6 and 12 months. This first fully-powered RCT testing SystemCHANGETM to improve and maintain medication adherence in kidney transplant recipients, demonstrated large, clinically meaningful improvements in medication adherence. This article is protected by copyright. All rights reserved.
Supplemental Cardioplegia During Donor Heart Implantation: A Systematic Review and Meta-Analysis
Annals of Thoracic Surgery. 2020;20:20
BACKGROUND The optimal donor heart preservation and management strategy during heart transplantation remains controversial. Here, we perform a systematic review and meta-analysis of the effect of supplemental cardioplegia administration during donor heart implant for transplantation. METHODS We searched MEDLINE and EMBASE databases until February 2019 for studies comparing patients who received transplants with the donor heart given supplemental cardioplegia or not. Data was extracted by two independent investigators. The main outcomes were early morbidity and mortality. RESULTS Seven retrospective observational studies (four comparing to historical controls) and 3 randomized controlled trials enrolling 1125 patients were included. Supplemental cardioplegia included crystalloid, and blood cardioplegia given continuous retrograde or as terminal "hot shots". Supplemental cardioplegia was associated with improved early mortality (risk ratio [RR]:0.55; 95%CI:0.35 to 0.87; p<0.01), greater rates of spontaneous return of sinus rhythm (RR:2.62; 95%CI:1.50 to 4.56; p<0.01), shorter intensive care stay (MD:-3.4 days; 95%CI:-5.1 to -1.6; p<0.01), and lower incidence of ischemic changes seen on endomyocardial biopsy (RR:0.49; 95%CI:0.35 to 0.69; p<0.01) compared to controls. Mid-term mortality was not different between groups (incident rate ratio:0.80; 95%CI:0.51 to 1.26; p=0.34). CONCLUSIONS Administration of supplemental cardioplegia may be associated with a reduction in organ ischemic injury and shorter intensive care stay as well as improvement in early survival post-transplantation. This strategy may be a simple and cost-effective adjunct to improve outcomes of heart transplantation, especially in an era of increasing use of marginal donor organs. Further investigation will be needed to confirm the findings of this hypothesis-generating study.
A systematic review to identify whether perfusate biomarkers produced during hypothermic machine perfusion can predict graft outcomes in kidney transplantation
Transplant International. 2020;[record in progress]
There is good evidence to support the use of Hypothermic Machine Perfusion (HMP) over static cold storage as the favoured preservation method for deceased donor kidneys. However, the utility of HMP as a tool to assess the viability of kidneys for transplant is unclear. There is a need to determine whether perfusate biomarkers produced during HMP can predict post-transplant outcomes and assess the suitability of organs for transplantation. Three different Databases (MEDLINE, Embase, Transplant Library) were screened to 31 May 2019. Articles were included if a relationship was reported between one or more perfusate biomarkers and post-transplant outcomes. Studies were assessed and graded for methodological quality and strength of evidence. Glutathione S-transferase was the most promising biomarker for predicting delayed graft function, but its predictive ability was at best moderate. Analysis of primary non-function rates was challenging due to low occurrence rates and small sample sizes. Existing studies are limited in quality and have not yielded biomarkers for kidneys undergoing HMP that are able to predict post-transplant outcomes with sufficient accuracy to support routine clinical use. Further studies with larger samples and more robust methodology are needed.