Extended Criteria Donors Research Articles

Analysis of criteria for definition of extended criteria donors in liver transplantation: a systematic review and meta-analysis

Analysis of criteria for definition of extended criteria donors in liver transplantation: a systematic review and meta-analysis

Hypothermic oxygenated perfusion - initial experience

Purpose: In liver transplantation, the need for extended criteria donors may reduce graft and patient survival related to early and late complications.The last decade saw a renewed interest in organ preservation with perfusion strategies. Hypothermic Oxygenated Perfusion (HOPE) has been thoroughly investigated showing promising results regarding lower early complication rate, improvement of overall transplantation results and suggesting better survival for HCC patients. This work reports preliminary results with HOPE experience in our Unit, the first and only Portuguese Liver Transplant Centre to use machine perfusion. Method: There was a broad indication for HOPE use, for procedure training.Over a 5-month period, HOPE was used efficiently in 8 cases. We analyzed donor, receptor, graft, as well perioperative period data. Results: Donors: median age was 67 years, average BMI of 26,2 kg/m2, high risk scores (average DRI 1,693 and half the patients with D-MELD above 1600).Patients: average MELD-Na was 23; risk factors: 3 cases of ACLF, 4 cases of portal vein thrombosis, 1 re-transplant; 5 patients with urgent liver request. There was no post-reperfusion syndrome nor PNF cases; there was a death duo to graft loss (vascular complications) and sepsis (excluded). Average peak ALT/AST were 623/783 U/L; average bilirubin and INR on the 7 th day were 2,9 mg/dL and 1,28.There was a CIT increase (60-70’); however, 120’ of CIT was attributable to “oxygenated ischemia”. There is yet no time span for delayed complications evaluation. Conclusion: From the initial experience we highlight ease of technique implementation and good immediate graft function on severely ill patients.We await series enlargement as well as future studies that allow confirmation of the multiple advantages described in the literature.

Early Allograft Dysfunction Increases Hospital Associated Costs After Liver Transplantation-A Propensity Score-Matched Analysis.

Concepts to ameliorate the continued mismatch between demand for liver allografts and supply include the acceptance of allografts that meet extended donor criteria (ECD). ECD grafts are generally associated with an increased rate of complications such as early allograft dysfunction (EAD). The costs of liver transplantation for the health care system with respect to specific risk factors remain unclear and are subject to change. We analyzed 317 liver transplant recipients from 2013 to 2018 for outcome after liver transplantation and hospital costs in a German transplant center. In our study period, 1‐year survival after transplantation was 80.1% (95% confidence interval: 75.8%‐84.6%) and median hospital stay was 33 days (interquartile rage: 24), with mean hospital costs of €115,924 (SD €113,347). There was a positive correlation between costs and laboratory Model for End‐Stage Liver Disease score (rs = 0.48, P < 0.001), and the development of EAD increased hospital costs by €26,229. ECD grafts were not associated with a higher risk of EAD in our cohort. When adjusting for recipient‐associated risk factors such as laboratory Model for End‐Stage Liver Disease score, recipient age, and split liver transplantation with propensity score matching, only EAD and cold ischemia increased total costs. Conclusion: Our data show that EAD leads to significantly higher hospital costs for liver transplantation, which are primarily attributed to recipient health status. Strategies to reduce the incidence of EAD are needed to control costs in liver transplantation.

Ex vivo machine perfusion: current applications and future directions in liver transplantation

BackgroundLiver transplantation is the only curative treatment option for end-stage liver disease; however, its use remains limited due to a shortage of suitable organs. In recent years, ex vivo liver machine perfusion has been introduced to liver transplantation, as a means to expand the donor organ pool.PurposeTo present a systematic review of prospective clinical studies on ex vivo liver machine perfusion, in order to assess current applications and highlight future directions.MethodsA systematic literature search of both PubMed and ISI web of science databases as well as the ClinicalTrials.gov registry was performed.ResultsTwenty-one articles on prospective clinical trials on ex vivo liver machine perfusion were identified. Out of these, eight reported on hypothermic, eleven on normothermic, and two on sequential perfusion. These trials have demonstrated the safety and feasibility of ex vivo liver machine perfusion in both standard and expanded criteria donors. Currently, there are twelve studies enrolled in the clinicaltrials.gov registry, and these focus on use of ex vivo perfusion in extended criteria donors and declined organs.ConclusionEx vivo liver machine perfusion seems to be a suitable strategy to expand the donor pool for liver transplantation and holds promise as a platform for reconditioning diseased organs.

Liver graft harbouring hydatid disease: how far can we extend our donor pool?

As the current demand for liver transplantation exceeds our donor pool, the donor search is shifted towards the extended donor criteria. The livers harbouring hydatid disease are a controversial source of grafts. We report the use of a liver graft harbouring hydatid disease in urgent liver transplantation in a patient with autoimmune hepatitis. Corroborated with previous experiences, we show that the liver grafts harbouring hydatid cysts provide a rare but valuable source of organs.

The Actual Operative Costs of Liver Transplantation and Normothermic Machine Perfusion in a Canadian Setting.

BackgroundLiver transplantation is an effective treatment for end-stage liver disease. However, waiting lists continue to lengthen as demand exceeds supply. Use of extended criteria donors has helped but is associated with increased rates of complications. The application of normothermic machine perfusion (NMP) has been shown to be protective, especially in more marginal grafts. Despite this benefit, no cost-effectiveness studies have been published.ObjectiveThis study serves as a prelude to a cost-effectiveness analysis of the costs of liver procurement, transplantation, and machine perfusion in a Canadian setting.MethodsThe total costs were calculated for 106 in-province procurements, the set cost for 237 out-of-province procurements, and 343 liver transplantations. These costs include overheads, supplies, anaesthesia technologist and nursing salaries, and physician billings. Base and modified costs for all procedures were calculated, with consideration of physician billing modifiers. The total cost per run of NMP was calculated, with a range based on variations in the exchange rates for Great British pounds (₤) to Canadian dollars ($Can), year 2019 values.ResultsCosts were $Can30,770.22 for in-province and $Can44,636.73 for out-of-province liver procurement and transplantation. These increased to $Can35,659.22 and 48,076.18 when considering modifiers. The minimum cost per NMP run was $Can18,593.02.ConclusionsAlthough the cost per run is substantial, NMP could potentially lead to cost savings by decreasing night-time salary premiums, complications, and patient length of stay. A formal cost-effectiveness study of NMP in liver transplantation is underway to help clarify the financial benefit or burden of this new technology.Electronic supplementary materialThe online version of this article (10.1007/s41669-020-00241-8) contains supplementary material, which is available to authorized users.

Clinical transplantation using negative pressure ventilation ex situ lung perfusion with extended criteria donor lungs

Lung transplantation remains the best treatment option for end-stage lung disease; however, is limited by a shortage of donor grafts. Ex situ lung perfusion, also known as ex vivo lung perfusion, has been shown to allow for the safe evaluation and reconditioning of extended criteria donor lungs, increasing donor utilization. Negative pressure ventilation ex situ lung perfusion has been shown, preclinically, to result in less ventilator-induced lung injury than positive pressure ventilation. Here we demonstrate that, in a single-arm interventional study (ClinicalTrials.gov number NCT03293043) of 12 extended criteria donor human lungs, negative pressure ventilation ex situ lung perfusion allows for preservation and evaluation of donor lungs with all grafts and patients surviving to 30 days and recovered to discharge from hospital. This trial also demonstrates that ex situ lung perfusion is safe and feasible with no patients demonstrating primary graft dysfunction scores grade 3 at 72 h or requiring post-operative extracorporeal membrane oxygenation.

Histological Evaluation of Extended Criteria Donors: Donor’s Kidney Biopsy and Graft Outcome after 5 Years of Transplantation

Pre-transplant kidney biopsy is routinely used to decide whether kidneys from marginal donors should be transplanted as single or double trans-plantation. This is a 5-year extension of the follow-up of a previous study. In that study, graft outcomes were compared retrospectively between a group of 44 recipients of a single kidney graft from an extended criteria donor and a Karpinski histological score of 3 or less, and another group of 56 recipients of a single transplant with a Karpinski histological score of 4 or 5. After 5 years of transplantation, there was no difference between the two groups in terms of recipient’s serum creatinine levels (1.8 ± 0.5 vs 1.9 ± 0.6 mg/dL, P = 0.5), creatinine clearance (53 ± 23 vs 49 ± 27.0 mL/min, P = 0.6), or the rates of graft loss (41% vs 49%,P = 0.5). Therefore, the choice between single and double transplant should not be made only on the basis of histological score but should be done together with the evaluation of donor’s clinical parameters, especially the renal function.

In Vitro/Ex Vivo Models for the Study of Ischemia Reperfusion Injury during Kidney Perfusion.

Oxidative stress is a key element of ischemia–reperfusion injury, occurring during kidney preservation and transplantation. Current options for kidney graft preservation prior to transplantation are static cold storage (CS) and hypothermic machine perfusion (HMP), the latter demonstrating clear improvement of preservation quality, particularly for marginal donors, such as extended criteria donors (ECDs) and donation after circulatory death (DCDs). Nevertheless, complications still exist, fostering the need to improve kidney preservation. This review highlights the most promising avenues of in kidney perfusion improvement on two critical aspects: ex vivo and in vitro evaluation.

Decrease of renal resistance during hypothermic oxygenated machine perfusion is associated with early allograft function in extended criteria donation kidney transplantation

Hypothermic oxygenated machine perfusion (HOPE) was recently tested in preclinical trials in kidney transplantation (KT). Here we investigate the effects of HOPE on extended-criteria-donation (ECD) kidney allografts (KA). Fifteen ECD-KA were submitted to 152 ± 92 min of end-ischemic HOPE and were compared to a matched group undergoing conventional-cold-storage (CCS) KT (n = 30). Primary (delayed graft function-DGF) and secondary (e.g. postoperative complications, perfusion parameters) endpoints were analyzed within 6-months follow-up. There was no difference in the development of DGF between the HOPE and CCS groups (53% vs. 33%, respectively; p = 0.197). Serum urea was lower following HOPE compared to CCS (p = 0.003), whereas the CCS group displayed lower serum creatinine and higher eGFR rates on postoperative days (POD) 7 and 14. The relative decrease of renal vascular resistance (RR) following HOPE showed a significant inverse association with serum creatinine on POD1 (r = − 0.682; p = 0.006) as well as with serum urea and eGFR. Besides, the relative RR decrease was more prominent in KA with primary function when compared to KA with DGF (p = 0.013). Here we provide clinical evidence on HOPE in ECD-KT after brain death donation. Relative RR may be a useful predictive marker for KA function. Further validation in randomized controlled trials is warranted.Trial registration: clinicaltrials.gov (NCT03378817, Date of first registration: 20/12/2017).

Treatment of transplant kidneys during machine perfusion.

The increasing use of donation after circulatory death (DCD) and extended criteria donor (ECD) organs has raised awareness of the need to improve the quality of kidneys for transplantation. Treating kidneys during the preservation interval could improve early and long-term graft function and survival. Dynamic modes of preservation including hypothermic machine perfusion (HMP) and normothermic machine perfusion (NMP) may provide the functional platforms to treat these kidneys. Therapies in the field of regenerative medicine including cellular therapies and genetic modification and the application of biological agents targeting ischaemia reperfusion injury (IRI) and acute rejection are a growing area of research. This review reports on the application of cellular and gene manipulating therapies, nanoparticles, anti-inflammatory agents, anti-thrombolytic agents and monoclonal antibodies administered during HMP and NMP in experimental models. The review also reports on the clinical effectiveness of several biological agents administered during HMP. All of the experimental studies provide proof of principle that therapies can be successfully delivered during HMP and NMP. However, few have examined the effects after transplantation. Evidence for clinical application during HMP is sparse and only one study has demonstrated a beneficial effect on graft function. More investigation is needed to develop perfusion strategies and investigate the different experimental approaches.

Ex Vivo Lung Perfusion: Current Achievements and Future Directions.

There is a severe shortage in the availability of donor organs for lung transplantation. Novel strategies are needed to optimize usage of available organs to address the growing global needs. Ex vivo lung perfusion has emerged as a powerful tool for the assessment, rehabilitation, and optimization of donor lungs before transplantation. In this review, we discuss the history of ex vivo lung perfusion, current evidence on its use for standard and extended criteria donors, and consider the exciting future opportunities that this technology provides for lung transplantation.

Bacterial Pneumonia in Brain-Dead Patients: Clinical Features and Impact on Lung Suitability for Donation.

To appraise the epidemiological features of bacterial pneumonia and its impact on lung suitability for donation in brain-dead patients managed with protective ventilatory settings. Retrospective observational study. Six ICUs from two university-affiliated hospitals. Brain-dead adult patients managed in the participating ICUs over a 4-year period. None. Among the 231 included patients, 145 (62.8%) were classified as ideal or extended-criteria potential lung donors at ICU admission and the remaining 86 patients having baseline contraindication for donation. Culture-proven aspiration pneumonia and early-onset ventilator-associated pneumonia occurred in 54 patients (23.4%) and 15 patients (6.5%), respectively (overall pneumonia incidence, 29.9%). Staphylococcus aureus and Enterobacterales were the most common pathogens. Using mixed-effects Cox proportional hazard models, age (adjusted hazard ratio, 0.98; 95% CI [0.96-0.99]), anoxic brain injury (3.55 [1.2-10.5]), aspiration (2.29 [1.22-4.29]), and not receiving antimicrobial agents at day 1 (3.56 [1.94-6.53]) were identified as independent predictors of pneumonia occurrence in the whole study population. Analyses restricted to potential lung donors yielded similar results. Pneumonia was associated with a postadmission decrease in the PaO2/FIO2 ratio and lower values at brain death, in the whole study population (estimated marginal mean, 294 [264-323] vs 365 [346-385] mm Hg in uninfected patients; p = 0.0005) as in potential lung donors (299 [248-350] vs 379 [350-408] mm Hg; p = 0.04; linear mixed models). Lungs were eventually retrieved in 31 patients (34.4%) among the 90 potential lung donors with at least one other organ harvested (pneumonia prevalence in lung donors (9.7%) vs nondonors (49.2%); p = 0.0002). Pneumonia occurs in one-third of brain-dead patients and appears as the main reason for lung nonharvesting in those presenting as potential lung donors. The initiation of antimicrobial prophylaxis upon the first day of the ICU stay in comatose patients with severe brain injury could enlarge the pool of actual lung donors.

Impact of extended-criteria donor lungs according to preoperative recipient status and age in lung transplantation.

BackgroundOrgan donor shortage remains as one of the limiting factors for lung transplantation. Given the increase in waiting time, preoperative condition has worsened and affects surgical outcomes. This study aimed to evaluate the immediate postoperative and long-term outcomes of lung transplantation in extended-criteria donor (ECD) lungs compared with standard-criteria donor (SCD) lungs.MethodsA total of 246 patients who had undergone double-lung transplantation during the study period were enrolled. SCD was defined based on the following characteristics age <55 years, <20 pack-years smoking history, and PaO2/fraction of O2 ratio >300 mmHg. Organ donors who do not fulfill these criteria were classified as ECD. Pre- and postoperative data for outcomes and survival data were analyzed.ResultsECD showed significant association with extracorporeal membrane oxygenation weaning in the operating room (hazard ratio [HR], 0.531; 95% confidence interval [CI], 0.291–0.970; P=0.039) considering recipient’s age and status at operation. The ECD group showed comparable survival rate with the SCD group (HR, 1.413; 95% CI, 0.885–2.255; P=0.148), with adjustment of other factors. However, when the recipient had Korean Network for Organ Sharing (KONOS) status 0 at the time of transplantation (HR, 1.662; 95% CI, 1.025–2.568; P=0.039), G3 primary graft dysfunction at 72 hours after surgery (HR, 2.508; 95% CI, 1.416–4.440; P=0.002) was a risk factor that decreased survival.ConclusionsThe outcome of ECD is not inferior to that of SCD. Therefore, ECD lung should be considered a potential donor organ following active donor management rather than a contraindication of transplantation in highly selected recipients.

Pro-IL-1β Is an Early Prognostic Indicator of Severe Donor Lung Injury During Ex Vivo Lung Perfusion.

Ex vivo lung perfusion (EVLP) is used to evaluate and recondition extended criteria donor lungs for transplantation. Interleukin-1β (IL-1β) has been identified as a prognostic indicator of nonrecovery during EVLP. This may be an effect of inflammasome activation or cellular necrosis following donation and graft preservation. Delineating the mechanism of IL-1β release is required. The inactive intracellular precursor molecule, pro-IL-1β, was characterized along with the pro-IL-1β processing enzyme, caspase-1, in the perfusate of n = 20 human lungs that had undergone EVLP (n = 10 lungs that failed to recover and were discarded versus n = 10 lungs that reconditioned and were transplanted). In an experimental porcine model, n = 8 lungs underwent EVLP and were randomized to receive either a specific NLRP3 inflammasome inhibitor or control. Significant increases in pro-IL-1β and caspase-1 were observed in the perfusate from human lungs that did not recondition during EVLP compared with those that successfully reconditioned and were used for transplantation. Within the porcine EVLP, NLRP3 inflammasome inhibition reduced IL-1β within the perfusate compared with controls, but this had no impact on lung function, hemodynamics, or inflammation. Our data suggest that pro-IL-1β is passively released following cellular necrosis of the donor lung.

Differential Impact of Extended Criteria Donors After Brain Death or Circulatory Death in Adult Liver Transplantation.

Using grafts from extended criteria donors (ECDs) and donation after circulatory death (DCD) donors is a strategy to address organ shortage in liver transplantation (LT). We studied the characteristics and outcomes of ECD and DCD grafts. We retrospectively studied consecutive adults who underwent deceased donor LT between 2006 and 2019. ECD was defined using modified Eurotransplant criteria. Our primary outcomes were graft and patient survival. A total of 798 grafts were used for LT, of which 93.1% were donation after brain death (DBD; 59.9% were also ECD) and 6.9% were DCD grafts (49.1% were also ECD). Among DBD graft recipients, donors having >33% liver steatosis or 3 ECD criteria resulted in poorer graft survival. Otherwise ECD graft recipients had similar graft and patient survival compared with non-ECD graft recipients. DCD graft recipients also had similar patient survival compared with DBD recipients. However, DCD grafts from an ECD appeared to have worse outcomes. DCD graft recipients experienced higher rates of early allograft dysfunction (50.9% versus 24.7%; P<0.001) and ischemic biliopathy (16.4% versus 1.5%; P<0.001) compared with DBD graft recipients. Use of DBD grafts from ECDs did not impact outcomes unless there was significant donor steatosis or 3 Eurotransplant criteria were met. DCD graft recipients have similar patient survival compared with DBD graft recipients as long as the donor was not an ECD. We recommend that DBD donors with 3 or more ECD features or >33% steatosis and DCD donors with any ECD features be used with caution in adult LT.

SC153 - Perioperative and functional outcomes after kidney transplantation from uncontrolled donors after circulatory death (UDCD) vs extended criteria donors after brain death (eDBD): A single-centre experience

SC153 - Perioperative and functional outcomes after kidney transplantation from uncontrolled donors after circulatory death (UDCD) vs extended criteria donors after brain death (eDBD): A single-centre experience

The Role of Metabolomics in Current Concepts of Organ Preservation.

In solid organ transplantation (Tx), both survival rates and quality of life have improved dramatically over the last few decades. Each year, the number of people on the wait list continues to increase, widening the gap between organ supply and demand. Therefore, the use of extended criteria donor grafts is growing, despite higher susceptibility to ischemia-reperfusion injury (IRI) and consecutive inferior Tx outcomes. Thus, tools to characterize organ quality prior to Tx are crucial components for Tx success. Innovative techniques of metabolic profiling revealed key pathways and mechanisms involved in IRI occurring during organ preservation. Although large-scale trials are needed, metabolomics appears to be a promising tool to characterize potential biomarkers, for the assessment of graft quality before Tx and evaluate graft-related outcomes. In this comprehensive review, we summarize the currently available literature on the use of metabolomics in solid organ Tx, with a special focus on metabolic profiling during graft preservation to assess organ quality prior to Tx.

Living donor liver transplantation for colorectal liver metastasis: a narrative review

: Colorectal cancer (CRC) is a spread disease worldwide. Most of the patients with CRC will develop liver metastases along the time and more than 75% of them are unresectable (uCRLM). In this case, despite the actual modern chemotherapy, the 5-year overall survival (OS) is lower than 10%. In the recent ten years liver transplantation (LT) for uCRLM experienced a “comeback” with excellent results in terms of OS at 5 years ranging from 60% to 100% according to different selection criteria, notwithstanding high recurrence rates (mainly extrahepatic). These promising results are based on a global population of almost 50 patients who underwent a DDLT. In times of organ paucity and still critical indication, standard DDLT will not find any place outside of studies. Additionally, the use of extended criteria donors (ECD) showed recently poor results in this context. Therefore, one way out of this dilemma may be represented by the use of Living-Donor liver transplantation (LDLT). In this review, we report about LDLT for uCRLM. In addition to a report of initial experience (i.e., global amount of 25 cases), we mainly focused on ethical, technical and oncological aspects of the procedure and proposed future applications as well. In summary, in times of scarcity of organs, LDLT for uCRLM may represent a valid alternative to DDLT with minimal donor risk and maximal recipient benefit in selected cases.

Strategies in Organ Preservation-A New Golden Age.

Strategies in Organ Preservation-A New Golden Age.