Extended Criteria Donors Research Articles

Human umbilical cord mesenchymal stem cells alleviate fatty liver ischemia-reperfusion injury by activating autophagy through upregulation of IFNγ.

Liver ischemia-reperfusion injury (IRI) is an important factor affecting the prognosis of liver transplantation, and extended criteria donors (e.g., steatosis donor livers) are considered to be more sensitive to ischemia-reperfusion injury in liver transplantation. Currently, the application of human umbilical cord mesenchymal stem cells (hMSCs) has great promise in the treatment of various injuries in the liver. This study aimed to investigate the therapeutic role and mechanism of hMSCs in fatty liver IRI. After more than 8 weeks of high-fat chow feeding, we constructed a fatty liver mouse model and established ischemic injury of about 70% of the liver. Six hours after IRI, liver injury was significantly alleviated in hMSCs-treated mice, and the expression levels of liver enzyme, inflammatory factor TNF-α, and apoptotic proteins were significantly lower than those of the control group, which were also significant in pathological sections. Transcriptomics analysis showed that IFNγ was significantly upregulated in the hMSCs group. Mechanistically, IFNγ, which activates the MAPK pathway, is a potent agonist that promotes the occurrence of autophagy in hepatocytes to exert a protective function, which was confirmed by in vitro experiments. In summary, hMSCs treatment could slow down IRI in fatty liver by activating autophagy through upregulation of IFNγ, and this effect was partly direct.

Viability assessment of the liver during ex-situ machine perfusion prior to transplantation.

In an attempt to reduce waiting list mortality in liver transplantation, less-than-ideal quality donor livers from extended criteria donors are increasingly accepted. Predicting the outcome of these organs remains a challenge. Machine perfusion provides the unique possibility to assess donor liver viability pretransplantation and predict postreperfusion organ function. Assessing liver viability during hypothermic machine perfusion remains challenging, as the liver is not metabolically active. Nevertheless, the levels of flavin mononucleotide, transaminases, lactate dehydrogenase, glucose and pH in the perfusate have proven to be predictors of liver viability. During normothermic machine perfusion, the liver is metabolically active and in addition to the perfusate levels of pH, transaminases, glucose and lactate, the production of bile is a crucial criterion for hepatocyte viability. Cholangiocyte viability can be determined by analyzing bile composition. The differences between perfusate and bile levels of pH, bicarbonate and glucose are good predictors of freedom from ischemic cholangiopathy. Although consensus is lacking regarding precise cut-off values during machine perfusion, there is general consensus on the importance of evaluating both hepatocyte and cholangiocyte compartments. The challenge is to reach consensus for increased organ utilization, while at the same time pushing the boundaries by expanding the possibilities for viability testing.

Graft repair during machine perfusion: a current overview of strategies.

With changing donor characteristics (advanced age, obesity), an increase in the use of extended criteria donor (ECD) livers in liver transplantation is seen. Machine perfusion allows graft viability assessment, but still many donor livers are considered nontransplantable. Besides being used as graft viability assessment tool, ex situ machine perfusion offers a platform for therapeutic strategies to ameliorate grafts prior to transplantation. This review describes the current landscape of graft repair during machine perfusion. Explored anti-inflammatory therapies, including inflammasome inhibitors, hemoabsorption, and cellular therapies mitigate the inflammatory response and improve hepatic function. Cholangiocyte organoids show promise in repairing the damaged biliary tree. Defatting during normothermic machine perfusion shows a reduction of steatosis and improved hepatobiliary function compared to nontreated livers. Uptake of RNA interference therapies during machine perfusion paves the way for an additional treatment modality. The possibility to repair injured donor livers during ex situ machine perfusion might increase the utilization of ECD-livers. Application of defatting agents is currently explored in clinical trials, whereas other therapeutics require further research or optimization before entering clinical research.

A tale of two kidneys, and the case for machine perfusion in South Africa.

Extended-criteria donors (ECDs) are seen as a means of addressing the shortfall in solid-organ availability for transplant. However, the use of ECD kidneys is associated with a greater risk of primary non-function compared with standard-criteria donor kidneys, and a higher discard rate has been described internationally. There seems to be a lack of consensus in the consideration of ECD kidneys for transplant, with reliance often placed on the subjective assessment of individual clinicians. The following case examines the difference in the institutional decision-making process applied to two kidneys from a single donor, and provides an argument for the use of hypothermic machine perfusion in low- to middle-income countries as an efficacious and objective means of assessing ECD kidney suitability.

Steatotic Donor Transplant Livers: Preservation Strategies to Mitigate against Ischaemia-Reperfusion Injury.

Liver transplantation (LT) is the only definitive treatment for end-stage liver disease, yet the UK has seen a 400% increase in liver disease-related deaths since 1970, constrained further by a critical shortage of donor organs. This shortfall has necessitated the use of extended criteria donor organs, including those with evidence of steatosis. The impact of hepatic steatosis (HS) on graft viability remains a concern, particularly for donor livers with moderate to severe steatosis which are highly sensitive to the process of ischaemia-reperfusion injury (IRI) and static cold storage (SCS) leading to poor post-transplantation outcomes. This review explores the pathophysiological predisposition of steatotic livers to IRI, the limitations of SCS, and alternative preservation strategies, including novel organ preservation solutions (OPS) and normothermic machine perfusion (NMP), to mitigate IRI and improve outcomes for steatotic donor livers. By addressing these challenges, the liver transplant community can enhance the utilisation of steatotic donor livers which is crucial in the context of the global obesity crisis and the growing need to expand the donor pool.

Kidney transplant utilising donors after circulatory death: The first report from the African continent.

At Groote Schuur Hospital in Cape Town, South Africa, the number of deceased organ donors has declined over the past 2 decades, necessitating a more liberal approach to donor selection. In 2007, measures to expand the deceased kidney donor pool were implemented, including an HIV positive-to-positive transplant programme and the utilisation of extended-criteria donors as well as donors after circulatory death (DCDs). To report on our institutional experience with DCD kidney transplants and to encourage this approach among other African centres to improve access to transplantation. An observational cohort study of consecutive DCD kidney transplants at Groote Schuur Hospital over a 17-year period was performed. Primary endpoints were 1-, 2- and 5-year graft and patient survival. Secondary endpoints included the incidence of delayed graft function (DGF), 30-day morbidity, length of stay, and donor and recipient clinical characteristics. Fifteen DCD procurements were performed, with no kidneys discarded. Thirty kidney transplants were performed, with a median (interquartile range) cold ischaemic time of 11.5 (8 - 14) hours. The incidence of DGF was 60.0%, and 30-day morbidity (other than DGF) was 20.0%. Graft survival at 1, 2 and 5 years was 100%, 96.0% and 73.7%, respectively. Patient survival at 1, 2 and 5 years was 93.3%, 93.3% and 88.4%, respectively. Long-term graft and patient survival was comparable with the international literature. DCD may present a unique opportunity to expand deceased donation throughout Africa, particularly in areas affected by a lack of brain death legislation and religious or cultural objections to donation after brain death.

A novel modified Steen solution limits inflammatory processes during ex vivo lung perfusion and improves graft function post-transplantation

BackgroundEx vivo lung perfusion allows donor lung preservation, assessment and reconditioning prior to transplantation, but is associated with increased inflammatory injury over time. Addition of anti-oxidative and anti-inflammatory agents to perfusate formulations could limit iatrogenic injury during perfusion. The effectiveness of a modified Steen solution containing acetyl salicylic acid, retinoic acid and methylprednisolone, was examined using a porcine extended criteria donor ex vivo lung perfusion and transplantation model. MethodsPorcine donor lungs underwent 24 hours cold storage and were then randomised to 4 hours normothermic ex vivo lung perfusion with modified Steen or original Steen, followed by single lung transplantation into a recipient pig. RNA-sequencing was used to assess tissue inflammatory changes during perfusion. Organ function was examined during perfusion and following transplantation and compared between groups. ResultsLungs perfused with modified Steen showed reduced pulmonary vascular resistance (p=0.0391) and stable pulmonary artery pressure despite achieving higher flows (p=0.0001) compared to Steen. Lung tissue showed negative enrichment of the TNF-α signalling via NF-κB pathway (p=0.0040) in modified Steen compared to Steen. Recipients of lungs perfused with modified Steen also showed improved post-transplantation oxygenation (p=0.0462). ConclusionsThis study highlights the superiority of modified Steen compared with original Steen. The modifications to Steen solution appear to limit inflammatory injury via the NF-κB signalling pathway during perfusion, leading to improved post-transplant function. Modified Steen provides the potential to improve post-transplant outcomes following EVLP of extended criteria lungs and could also facilitate extended assessment and preservation, as well as administration of advanced therapies.

Ex vivo lung perfusion and the Organ Care System: a review.

With the increasing prevalence of heart failure and end-stage lung disease, there is a sustained interest in expanding the donor pool to alleviate the thoracic organ shortage crisis. Efforts to extend the standard donor criteria and to include donation after circulatory death have been made to increase the availability of suitable organs. Studies have demonstrated that outcomes with extended-criteria donors are comparable to those with standard-criteria donors. Another promising approach to augment the donor pool is the improvement of organ preservation techniques. Both ex vivo lung perfusion (EVLP) for the lungs and the Organ Care System (OCS, TransMedics) for the heart have shown encouraging results in preserving organs and extending ischemia time through the application of normothermic regional perfusion. EVLP has been effective in improving marginal or borderline lungs by preserving and reconditioning them. The use of OCS is associated with excellent short-term outcomes for cardiac allografts and has improved utilization rates of hearts from extended-criteria donors. While both EVLP and OCS have successfully transitioned from research to clinical practice, the costs associated with commercially available systems and consumables must be considered. The ex vivo perfusion platform, which includes both EVLP and OCS, holds the potential for diverse and innovative therapies, thereby transforming the landscape of thoracic organ transplantation.

Wasted Potential: Decoding the Trifecta of Donor Kidney Shortage, Underutilization, and Rising Discard Rates

Kidney transplantation is a life-saving intervention for end-stage renal disease; yet, the persistent gap between organ demand and supply remains a significant challenge. This paper explores the escalating discard rates of deceased donor kidneys in the United States to assess trends, discard reasons, demographical differences, and preservation techniques. Data from the Scientific Registry of Transplant Recipients from 2010 to 2021 was analyzed using chi-squared tests for trend significance and logistic regression to estimate odds ratios for kidney discard. Over the last decade, discard rates have risen to 25% in 2021. Most discarded kidneys came from extended criteria donor (ECD) donors and elevated kidney donor profile index (KDPI) scores. Kidney biopsy status was a significant factor and predictor of discard. Discard rates varied greatly between Organ Procurement and Transplantation Network regions. Of reasons for discard, “no recipient located” reached a high of 60%. Additionally, there has been a twofold increase in hypothermic machine perfusion (HMP) since 2010, with transportation difficulties being the main reason for the discard of perfused kidneys. Our findings suggest a need to recalibrate organ utilization strategies, optimize the use of lower-quality kidneys through advanced preservation methods, and address the evolving landscape of organ allocation policies to reduce kidney discard rates.

Real-time monitoring of mitochondrial oxygenation during machine perfusion using resonance Raman spectroscopy predicts organ function

Organ transplantation is a life-saving procedure affecting over 100,000 people on the transplant waitlist. Ischemia reperfusion injury (IRI) is a major challenge in the field as it can cause post-transplantation complications and limit the use of organs from extended criteria donors. Machine perfusion technology has the potential to mitigate IRI; however, it currently fails to achieve its full potential due to a lack of highly sensitive and specific assays to assess organ quality during perfusion. We developed a real-time and non-invasive method of assessing organs during perfusion based on mitochondrial function and injury using resonance Raman spectroscopy. It uses a 441 nm laser and a high-resolution spectrometer to quantify the oxidation state of mitochondrial cytochromes during perfusion. This index of mitochondrial oxidation, or 3RMR, was used to understand differences in mitochondrial recovery of cold ischemic rodent livers during machine perfusion at normothermic temperatures with an acellular versus cellular perfusate. Measurement of the mitochondrial oxidation revealed that there was no difference in 3RMR of fresh livers as a function of normothermic perfusion when comparing acellular versus cellular-based perfusates. However, following 24 h of static cold storage, 3RMR returned to baseline faster with a cellular-based perfusate, yet 3RMR progressively increased during perfusion, indicating injury may develop over time. Thus, this study emphasizes the need for further refinement of a reoxygenation strategy during normothermic machine perfusion that considers cold ischemia durations, gradual recovery/rewarming, and risk of hemolysis.

Liver machine perfusion technology: Expanding the donor pool to improve access to liver transplantation

The imbalance between organ supply and demand continues to limit the broader benefits of organ transplantation. Machine perfusion (MP) may increase the supply of donor livers by expanding the use of extended-criteria donors. Using the United Network for Organ Sharing/Organ Procurement and Transplantation Network and the Standard Transplant Analysis and Research dataset, we reviewed the effect of MP implementation on the behavior of transplant centers. We identified 15 high-utilizing MP centers that were matched to suitable controls based on volume and geographical proximity. We conducted a differences-in-differences analysis using linear regression to estimate the impact of MP adoption on the transplant centers’ donor utilization. We found a significant increase in cold ischemia time and organs with donor warm ischemia time over 30 minutes (P < .05). After removing one outlier center, the analysis showed that these centers through MP accepted overall more donation after circulatory death donors, donation after circulatory death donors over 50 years old, donors with macrovesicular steatosis greater than 30% on liver biopsy, and donor warm ischemia time over 30 minutes (P < .05). MP has allowed centers to expand their use of extended-criteria donors beyond traditional cutoffs and to increase patient access to liver transplantation.

Ex vivo lung perfusion in donation after circulatory death: A post hoc analysis of the Normothermic Ex Vivo Lung Perfusion as an Assessment of Extended/Marginal Donors Lungs trial

ObjectiveDonation after circulatory death (DCD) donors offer the ability to expand the lung donor pool and ex vivo lung perfusion (EVLP) further contributes to this ability by allowing for additional evaluation and resuscitation of these extended criteria donors. We sought to determine the outcomes of recipients receiving organs from DCD EVLP donors in a multicenter setting. MethodsThis was an unplanned post hoc analysis of a multicenter, prospective, nonrandomized trial that took place during 2011 to 2017 with 3 years of follow-up. Patients were placed into 3 groups based off procurement strategy: brain-dead donor (control), brain-dead donor evaluated by EVLP, and DCD donors evaluated by EVLP. The primary outcomes were severe primary graft dysfunction at 72 hours and survival. Secondary outcomes included select perioperative outcomes, and 1-year and 3-years allograft function and quality of life measures. ResultsThe DCD EVLP group had significantly higher incidence of severe primary graft dysfunction at 72 hours (P = .03), longer days on mechanical ventilation (P < .001) and in-hospital length of stay (P = .045). Survival at 3 years was 76.5% (95% CI, 69.2%-84.7%) for the control group, 68.3% (95% CI, 58.9%-79.1%) for the brain-dead donor group, and 60.7% (95% CI, 45.1%-81.8%) for the DCD group (P = .36). At 3-year follow-up, presence observed bronchiolitis obliterans syndrome or quality of life metrics did not differ among the groups. ConclusionsAlthough DCD EVLP allografts might not be appropriate to transplant in every candidate recipient, the expansion of their use might afford recipients stagnant on the waitlist a viable therapy.

Mitochondrial DNA levels in perfusate and bile during ex vivo normothermic machine correspond with donor liver quality

Ex vivo normothermic machine perfusion (NMP) preserves donor organs and permits real-time assessment of allograft health, but the most effective indicators of graft viability are uncertain. Mitochondrial DNA (mtDNA), released consequent to traumatic cell injury and death, including the ischemia-reperfusion injury inherent in transplantation, may meet the need for a biomarker in this context. We describe a real time PCR-based approach to assess cell-free mtDNA during NMP as a universal biomarker of allograft quality. Measured in the perfusate fluid of 29 livers, the quantity of mtDNA correlated with metrics of donor liver health including International Normalized Ratio (INR), lactate, and warm ischemia time, and inversely correlated with inferior vena cava (IVC) flow during perfusion. Our findings endorse mtDNA as a simple and rapidly measured feature that can inform donor liver health, opening the possibility to better assess livers acquired from extended criteria donors to improve organ supply.

Liver transplantation from extended criteria donors, a considerable source for donor pool expansion

Liver transplantation from extended criteria donors, a considerable source for donor pool expansion

Improved outcomes after liver transplantation from extended criteria donors

Improved outcomes after liver transplantation from extended criteria donors

End-ischemic hypothermic oxygenated perfusion in extended criteria donation liver transplantation from donation after brain death - results from a French multicenter randomized controlled trial (HOPExt)

End-ischemic hypothermic oxygenated perfusion in extended criteria donation liver transplantation from donation after brain death - results from a French multicenter randomized controlled trial (HOPExt)

Recipient Outcomes With Extended Criteria Donors Using Advanced Heart Preservation: An Analysis of the GUARDIAN-Heart Registry

PurposeThe prevalence of end stage heart failure and patients that could benefit from heart transplantation requires an expansion of the donor pool, relying on the transplant community to continually re-evaluate and expand the use of extended criteria donor organs. Introduction of new technologies such as the Paragonix SherpaPak Cardiac Transport System aids in this shift. We seek to analyze the impact of the SherpaPak system on recipient outcomes who receive extended criteria organs in the GUARDIAN Heart Registry. MethodsBetween October 2015-December 2022, 1,113 adults from 15 US centers receiving donor hearts utilizing either SherpaPak (N=560) or conventional ice storage (Ice, N=453) were analyzed from the GUARDIAN-Heart registry using summary statistics. A previously published set of criteria was used to identify extended criteria donors, which included 193 SherpaPak and 137 ice. ResultsThere were a few baseline differences among recipients in the 2 cohorts, most notably IMPACT Scores, distance traveled and total ischemic time were significantly greater in SherpaPak, and significantly more donor hearts in the SherpaPak cohort had >4 hours total ischemia time. Post-transplant MCS utilization (SherpaPak 22.3% vs. ice 35.0%, p=0.012) and new ECMO/VAD (SherpaPak 7.8% vs. ice 15.3%, p=0.033) was significantly reduced, and the rate of severe PGD (SherpaPak 6.2% vs. ice 13.9%, p=0.022) was significantly reduced by over 50% in hearts preserved using SherpaPak. One-year survival between cohorts was similar (SherpaPak 92.9% vs. ice 89.6%, p=0.27). ConclusionThis subgroup analysis demonstrates that SherpaPak can be safely used to utilize extended criteria donors, with low severe PGD rates.

Beating Heart Transplants—Overview and Implications for Anesthesiologists

As the demand of heart allografts for transplantation continues to rise, ex-vivo organ perfusion strategies are playing an increasingly important role in preservation of organs from donation after circulatory death (DCD) and extended-criteria donors. One such method utilizes the Organ Care System™ (TransMedics, Andover, MA). Traditionally, this technique of preservation requires two periods of warm ischemia and subsequent cardioplegic arrest. In a novel surgical technique pioneered at our institution, heart allograft implantation no longer requires a second cardioplegic arrest. This article discusses the surgical approach for this procedure, advantages and disadvantages to this approach, and analogues to current clinical practice to theorize what impact this may have on cardiac transplantation volumes in the future.

National utilization, trends, and lung transplant outcomes of static versus portable ex vivo lung perfusion platforms

BackgroundThis study compared utilization and outcomes of the 2 widely utilized ex vivo lung perfusion (EVLP) platforms in the United States: a static platform and a portable platform. MethodsAdult (age 18 years or older) bilateral lung-only transplants utilizing EVLP between February 28, 2018, and December 31, 2022, in the United Network for Organ Sharing database were included. Predischarge acute rejection, intubation at 72 hours posttransplant, extracorporeal membrane oxygenation at 72 hours posttransplant, primary graft dysfunction grade 3 at 72 hours posttransplant, 30-day mortality, and 1-year mortality were evaluated using multivariable regressions. ResultsOverall, 607 (6.3%) lung transplants during the study period used EVLP (51.2% static, 48.8% portable). Static EVLP was primarily utilized in the eastern United States, whereas portable EVLP was primarily utilized in the western United States. Static EVLP donors were more likely to be donation after circulatory death (33.4% vs 26.0%; P = .005), have a >20 pack-year smoking history (13.5% vs 6.5%; P = .005), and be extended criteria donors (92.3% vs 85.0%; P = .013), whereas portable EVLP donors were more likely to be older than age 55 years (14.2% vs 8.0%; P = .02). Transplants utilizing the static and portable platforms had similar risk of acute rejection, intubation at 72 hours, extracorporeal membrane oxygenation at 72 hours, primary graft dysfunction grade 3 at 72 hours, and posttransplant mortality at 30 days and 1 year (all P values > .05). ConclusionsThe static and portable platforms had significant differences in donor characteristics and geographic distributions of utilization. Despite this, posttransplant survival was similar between the 2 EVLP platforms.

The Role of Normothermic Machine Perfusion in Extended Criteria Donor Grafts: A New Direction in Liver Graft Assessment and Preservation

Despite improvements in short-term and long-term outcomes of liver transplant patients, the discrepancy between the number of available livers and transplant candidates continues to increase. The use of expanded criteria donors is one strategy that can be used to address donor shortages. In recent years, preservation strategies such as normothermic machine perfusion (NMP) have been explored to improve the preservation of organs and test their viability before transplantation. We reviewed the recent literature and trials assessing the use of NMP in the setting of liver transplantation. Multiple feasibility trials have demonstrated the clinical prospect of NMP and proved its numerous advantages compared to conventional static cold storage. These advantages include preservation and viability assessment of high-risk donor allografts and grafts that would have otherwise been discarded. This review aims to address the topic of liver NMP in the setting of current and future applications in the setting of extended criteria donor grafts.