Extracorporeal liver support in patients with liver failure: a systematic review and meta-analysis of randomized trials
Intensive Care Medicine. 2020;46(1):1-16
This systematic review and meta-analysis of randomized controlled trials (RCTs) aimed to examine the efficacy and safety of extracorporeal liver support (ECLS) in liver failure.
The MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials databases were searched from inception through March 13, 2019. Randomized control trials (RCTs) comparing ECLS to usual care in acute liver failure (ALF) or acute chronic liver failure (ACLF) were included. Included studies met the following criteria: (1) the study design was a randomized controlled trial (RCT); (2) the population were adults with ALF or ACLF; (3) the interventions were any form of artificial or bio-artificial ECLS; (4) the control group received supportive care not including ECLS; (5) the outcomes were all-cause mortality or liver-related mortality, bridging to liver transplant, improvement of HE and adverse events such as hypotension, bleeding, thrombocytopenia, line infection, and citrate toxicity.
A total of 25 randomized controlled trials, comprising 1796 patients were identified and used in this study.
The main outcomes explored were mortality, hepatic encephalopathy and adverse effects.
Up to 6 months
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
This is a systematic review and meta-anlaysis of 25 RCTs including a total of 1796 patients randomised to extra-corporeal liver support (ECLS) for acute liver failure or acute on chronic liver failure. Overall the review was conducted with several signs of good quality, by following the PRISMA statement and registering a protocol in advance. Multiple databases were searched and only RCTs were included. Report screening, data extraction and bias assessment were all completed in duplicate by 2 reviewers, another good indicator. Publication bias was assessed by funnel plot with Egger’s test. Among artificial systems, MARS (Teraklin AG, Germany, was the
most commonly used (8 studies) followed by Biologic-DT (HemoCleanse, Inc., USA, 5 studies), FPSA (Prometheus, Fresenius Medical Care, Germany, 2 studies), plasma exchange with hemoperfusion, whole blood exchange, and charcoal hemoperfusion (1 study each). Bio-artifcial modalities included extracorporeal liver assist device (ELAD, Vital Terapies Inc., USA, 3 studies) and HepatAssist (Circe Biomedical Inc., USA, 1 study). Twenty four studies reported mortality and in meta-analysis extra-corporeal liver support was associated with improved mortality, albeit potentially a very small effect (RR=0.84, 95%CI= 0.74-0.96), with low-moderate heterogeneity. The use of ECLS was associated with improved hepatic encephalopathy compared to usual care (RR=0.71; 95% CI= 0.60- 0.84), with low heterogeneity between studies, however some evidence of publication bias was suspected following funnel plot and Egger’s test (P=0.041). There was no significant differences in the risk of bleeding, hypotension or thrombocytopenia. The authors include a number of sensitivity analyses as well to explore the effect of type of liver failure, type of ECLS and study risk of bias, not finding any significant interaction. This is a thorough study overall and if the level of certainty in the conclusions is low, it is not the fault of the authors here. The results suggest that ECLS may reduce mortality and hepatic encephalopathy in acute and acute on chronic liver failure but the degree of benefit for each of the different types of system is not clear. Each of the included studies was small and RCTs using new technology in specific groups of patients are required.
PURPOSE Acute liver failure (ALF) and acute on chronic liver failure (ACLF) are associated with significant mortality and morbidity. Extracorporeal liver support (ECLS) devices have been used as a bridge to liver transplant; however, the efficacy and safety of ECLS are unclear. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to examine the efficacy and safety of ECLS in liver failure. METHODS We searched MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials from inception through March 13, 2019. RCTs comparing ECLS to usual care in ALF or ACLF were included. We used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the certainty of the evidence. RESULTS We identified 25 RCTs (1796 patients). ECLS use was associated with reduction in mortality (RR 0.84; 95% CI 0.74, 0.96, moderate certainty) and improvement in hepatic encephalopathy (HE) (RR 0.71; 95% CI 0.60, 0.84, low certainty) in patients with ALF or ACLF. The effect of ECLS on hypotension (RR 1.46; 95% CI 0.98, 2.2, low certainty), bleeding (RR 1.21; 95% CI 0.88, 1.66, moderate certainty), thrombocytopenia (RR 1.62; 95% CI 1.0, 2.64, very low certainty) and line infection (RR 1.92; 95% CI 0.11, 33.44, low certainty) was uncertain. CONCLUSIONS ECLS may reduce mortality and improve HE in patients with ALF and ACLF. The effect on other outcomes is uncertain. However, the evidence is limited by risk of bias and imprecision, and larger trials are needed to better determine the effect of ECLS on patient-important outcomes.
A randomized, phase 1b study of the pharmacokinetics, pharmacodynamics, safety, and tolerability of bleselumab, a fully human, anti-CD40 monoclonal antibody, in kidney transplantation
American Journal of Transplantation. 2020;20(1):172-180
This study aimed to evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of four dose levels of bleselumab administered with standard immunosuppressants to de novo kidney transplant recipients.
Kidney transplant recipients were randomized to receive bleselumab, 50mg, 100mg, 200mg, or 500mg, or placebo with standard immunosuppression.
50 Adult (18‐65 years of age) de novo kidney transplant recipients who received their kidney from either a living or deceased donors.
The primary pharmacokinetic endpoints were AUCinf, Cmax, and AUClast. The primary pharmacodynamic endpoint was B cell CD40 receptor occupancy over time.
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
This phase Ib study investigates the safety and pharmacokinetics of a novel anti-CD40 monoclonal antibody in renal transplant recipients. Participants received standard baseline immunosuppression, and were randomised to either placebo or a single infusion of the monoclonal antibody at one of 4 doses. The drug appeared well tolerated at all doses, and pharmacokinetic data including AUCs and receptor occupancy over time are presented. These results are encouraging, and the drug has now moved on to phase II investigation. It is not yet clear how this will sit within our current immunosuppressive armoury, but it may ultimately provide an alternative
agent to facilitate CNI minimisation.
This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of various doses of the anti-CD40 monoclonal antibody bleselumab (ASKP1240) in de novo kidney transplant recipients receiving concomitant standard immunosuppression over 90 days post-transplant. Transplant recipients were randomized (1:1:1:1:1) to bleselumab 50 mg, 100 mg, 200 mg, or 500 mg, or placebo, in addition to standard maintenance immunosuppression. The primary pharmacokinetic endpoints were AUCinf , Cmax , and AUClast . The primary pharmacodynamic endpoint was B-cell CD40 receptor occupancy over time. Overall, 50 kidney transplant recipients were randomized; 45 received their randomized treatment (bleselumab [n = 37] or placebo [n = 8]). AUCinf and AUClast demonstrated a more than dose-proportional increase in the range of 50-500 mg, and Cmax increased linearly with increasing dose. Maximal receptor occupancy for B-cell CD40 was reached at all dose levels and was prolonged as dose increased. No kidney transplant recipients experienced cytokine release syndrome or a thromboembolic event. Treatment-emergent anti-bleselumab antibodies were found in one kidney transplant recipient in the bleselumab 50 mg group; these were only detected at Day 7. Overall, bleselumab demonstrated non-linear pharmacokinetics and dose-dependent prolonged B-cell CD40 receptor occupancy, and was well tolerated at all doses. This article is protected by copyright. All rights reserved.
Large-for-Size Orthotopic Liver Transplantation: a Systematic Review of Definitions, Outcomes, and Solutions
Journal of Gastrointestinal Surgery. 2020;[record in progress]:09
BACKGROUND We systematically reviewed the literature on definitions and outcomes of large-for-size (LFS) syndrome in orthotopic liver transplantation (LT). METHODS This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The Cochrane Library, PubMed, and Embase were searched (January 1990-January 2019) for studies reporting LFS in LT. Primary outcomes were definitions and mortality of LFS LT. RESULTS Eleven studies reporting patients with LFS LT were identified. Four different formulas (graft-to-recipient weight ratio (GRWR), body surface area index (BSAi), donor standardized total liver volume (sTLV)-to-recipient sTLV ratio, and graft weight/right anteroposterior distance (RAP) ratio) with their critical thresholds were found. There were 81 patients (54% women) with a median weight and height of 62.5 kg (range, 40-105 kg) and 165 cm (range, 145-180 cm). The median graft weight was 1772 g (range, 1290-2400 g), and the median GWRW was 2.77% (range, 2.1-4.00%). Graft venous outflow obstruction was described in seven patients (8.6%). At the time of LT, fascial closure was not achieved in 24 patients (29.6%) and the graft size was reduced by a liver resection in three patients (3.7%). Thirteen deaths (16%) were reported in the first 90 postoperative days with two patients undergoing re-transplant. CONCLUSIONS LFS LT remains heterogeneously defined but characterized by high mortality rates despite the use of tailored surgical solutions (graft reduction and open abdomen). A composite definition is proposed in order to better describe LFS clinical syndrome.
Utilization of deceased donors during a pandemic: An argument against using SARS-CoV-2 positive donors
American Journal of Transplantation. 2020;[record in progress]
SARS-CoV-2 has rapidly become an unprecedented pandemic that has impacted society, disrupted hospital functions, strained healthcare resources and impacted the lives of transplant professionals. Despite this, organ failure and the need for transplantation continues throughout the United States. Considering the perpetual scarcity of deceased donor organs, Kates et al present a viewpoint that advocates for the utilization of COVID-19 positive donors in selected cases. We present a review of the current literature that details the potential negative consequences of COVID-19 positive donors. The factors we consider include: 1) the risk of blood transmission SARS-CoV-2, 2) involvement of donor organs, 3) lack of effective therapies, 4) exposure of healthcare and recovery teams, 5) disease transmission and propagation, and 6) hospital resource utilization. While we acknowledge that transplantation fulfills the mission of saving lives, it is imperative to consider the consequences not only to our recipients, but also to the community and to healthcare workers, particularly in the absence of effective preventative or curative therapies. For these reasons, we believe the evidence and risks show that COVID-19 infection should continue to remain a contraindication for donation, as has been the initial response of donation and transplantation societies.
Policies to promote timely referral for kidney transplantation
Seminars in Dialysis. 2020;33(1):58-67
There are numerous patient, provider, and health system barriers to accessing kidney transplantation. Patient barriers such as sociocultural and clinical characteristics and provider factors such as provider knowledge and awareness of transplantation play important roles in facilitating transplant. Health system factors like misaligned incentives and quality metrics for dialysis facilities and transplant centers also influence transplant access. While numerous studies have documented the impact of these barriers on wait-listing and transplant, few studies have examined referral from a dialysis facility to a transplant center and start of the transplant evaluation process. While the Centers for Medicare and Medicaid Services (CMS) require that dialysis facilities educate patients about transplant, there are no guidelines for the content and objectives for this education. In addition, policies to require timely referral for transplantation have been considered by CMS but are difficult to implement without national data on referral. Federal policies should be amended to mandate transplant center submission of referral data-while decreasing the unfunded mandate to collect other unusable data currently collected as part of regulatory monitoring of transplant centers-to promote timely access to transplant, increased transplant rates, and to better understand the multilevel barriers and facilitators to transplant referral.
Solid Organ Transplantation Programs Facing Lack of Empiric Evidence in the COVID-19 Pandemic: A By-proxy Society Recommendation Consensus Approach
American Journal of Transplantation. 2020;[record in progress]
The ongoing SARS-CoV-2 pandemic has a drastic impact on national healthcare systems. Given the overwhelming demand of facility capacity, the impact on all healthcare sectors has to be addressed. Solid organ transplantation represents a field with a high demand on staff, intensive care units and follow-up facilities. The great therapeutic value of organ transplantation has to be weighed against mandatory constraints of healthcare capacities. In addition, the management of immunosuppressed recipients has to be reassessed during the ongoing COVID-19 pandemic. In addressing these crucial questions, transplant physicians are facing a total lack of scientific evidence. Therefore, the aim of this study was to offer an approach of consensus-based guidance, derived from individual information of 22 transplant societies. Key recommendations were extracted and the degree of consensus among different organizations was calculated. A high degree of consensus was found for temporarily suspending non-urgent transplant procedures and living donation programs. Systematic PCR-based testing of donors and recipients was broadly recommended. Additionally, more specific aspects (e.g., screening of surgical explant teams and restricted use of marginal donor organs) were included in our analysis. This study offers a novel approach on informed guidance for healthcare management when a priori no scientific evidence is available.
Kidney transplantation with pre-symptomatic COVID-19 positive surgeon
American Journal of Transplantation. 2020;[record in progress]
In Italy the Coronavirus Disease 2019 (COVID-19) outbreak caused by SARS-CoV-2 is testing the national health system and the intensive care unit are at the limits of their capacity. Severe travel limitation and containment at home were applied, such as in the Chinese experience and isolation of the diseased patients to control the exponential trend of the infection spread.
Meta-analysis and Meta-regression of Survival After Liver Transplantation for Unresectable Perihilar Cholangiocarcinoma
Annals of Surgery. 2020;24:24
The systematic review aimed to summarise the reported survival and recurrence rate after neoadjuvant chemoradiation and orthotopic liver transplantation (NCR-OLT) for unresectable perihilar cholangiocarcinoma (pCC).
Neoadjuvant chemoradiation and orthotopic liver transplantation
Patients with unresectable pCC undergoing NCR-OLT
The primary outcome was overall survival at 1, 3 and 5 years and the secondary outcome was the recurrence rate at 3 years.
Dr Liset Pengel, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
The systematic review evaluated survival after liver transplantation for unresectable perihilar cholangiocarcinoma (pCC). A senior information specialist assisted to develop a comprehensive literature search from 2000-2019. Study selection was done by two independent reviewers, quality assessment using the Newcastle-Ottawa scale was conducted by three independent reviewers and data extraction was done by a single reviewer. The study included 20 observational studies of which 16 were assessed as being of poor methodological quality. The authors provided a detailed description of surgical techniques and adjunctive procedures that varied between studies. Survival for all patients after liver transplantation for pCC was 76.9% at
1 year (18 studies), 55.3% at 3 years (13 studies) and 44.9% at 5 years (10 studies). However, survival increased after undergoing a neoadjuvant protocol to 82.8%, 65.5% and 65.1 at 1, 3 and 5 year, respectively. To explore potential sources of heterogeneity meta-regression analysis investigated whether there was a correlation between the proportion of patients with PSC and survival. There was no significant correlation for the 3-year survival data but there was a positive, significant correlation for 5-year survival data. Disease recurrence was analysed for studies that followed patients for at least 3 years. The analysis showed an overall recurrence rate of 29.4% (8 studies), with a recurrence rate of 24.1% for patients who had neoadjuvant therapy (6 studies) and 51.7% for patients who did not have neoadjuvant therapy (2 studies).
OBJECTIVE To systematically review studies reporting survival data following neoadjuvant chemoradiation and orthotopic liver transplantation (NCR-OLT) for unresectable perihilar cholangiocarcinoma (pCC). BACKGROUND Despite survival improvements for other cancers, the prognosis of pCC remains dismal. Since publication of the Mayo protocol in 2000, increasing numbers of series globally are reporting outcomes after NCR-OLT. METHODS MEDLINE, EMBASE, Scopus, and Web of Science databases were searched from January 2000 to February 2019. A meta-analysis of proportions was conducted, pooling 1, 3-, and 5-year overall survival and recurrence rates following NCR-OLT across centers. Per protocol and intention to treat data were interrogated. Meta-regression was used to evaluate PSC as a confounder affecting survival. RESULTS Twenty studies comprising 428 patients were eligible for analysis. No RCTs were retrieved; the majority of studies were noncomparative cohort studies. The pooled 1, 3-, and 5-year overall survival rates following OLT without neoadjuvant therapy were 71.2% (95% CI 62.2%-79.4%), 48.0% (95% CI 35.0%-60.9%), and 31.6% (95% CI 23.1%-40.7%). These improved to 82.8% (95% CI 73.0%-90.8%), 65.5% (95% CI 48.7%-80.5%), and 65.1% (95% CI 55.1%-74.5%) if neoadjuvant chemoradiation was completed. Pooled recurrence after 3 years was 24.1% (95% CI 17.9%-30.9%) with neoadjuvant chemoradiation, 51.7% (95% CI 33.8%-69.4%) without. CONCLUSIONS In unresectable pCC, NCR-OLT confers long-term survival in highly selected patients able to complete neoadjuvant chemoradiation followed by transplantation. PSC patients appear to have the most favorable outcomes. A high recurrence rate is of concern when considering extending national graft selection policy to pCC.