Extended Criteria Donors: Opportunities and Advances

Abstract

In recent years, remarkable advancements have been achieved in the field of liver transplantation, offering renewed hope and better outcomes for individuals with end-stage liver disease or acute liver failure who rely on orthotopic liver transplantation (OLT) as their sole treatment option. Nevertheless, the scarcity of suitable donor organs continues to present a major hurdle for patients in need of liver transplants. Tragically, the demand for donor livers surpasses the limited supply, leaving numerous patients at risk of mortality while awaiting transplantation. In response to the persistent challenge of organ donation, scientists and medical experts are actively investigating the potential of extended criteria donors (ECDs) as a potential solution. ECDs encompass a wide range of potential donors, including older individuals and those with medical conditions or viral infections, who may not meet the conventional criteria for organ acceptance.

1. Introduction

In recent years, remarkable advancements have been achieved in the field of liver transplantation, offering renewed hope and better outcomes for individuals with end-stage liver disease or acute liver failure who rely on orthotopic liver transplantation (OLT) as their sole treatment option. Nevertheless, the scarcity of suitable donor organs continues to present a major hurdle for patients in need of liver transplants. Tragically, the demand for donor livers surpasses the limited supply, leaving numerous patients at risk of mortality while awaiting transplantation [1].

In response to the persistent challenge of organ donation, scientists and medical experts are actively investigating the potential of extended criteria donors (ECDs) as a potential solution. ECDs encompass a wide range of potential donors, including older individuals and those with medical conditions or viral infections, who may not meet the conventional criteria for organ acceptance. While a young brain-dead donor remains the preferred choice for liver transplants, exploring various other viable options for transplantation is crucial in addressing this issue (Table 1) [2].

Categories of extended criteria donors
Advanced donor age > 60 years
Steatosis (Macrovesicular steatosis > 30%)
Organ dysfunction at procurement; ICU stay > 7 days Hypernatremia > 165 Bilirubin > 3 Elevated aspartate aminotransferase/alanine aminotransferase Vasopressor use
Cause of death including anoxia or cerebrovascular accident
Extrahepatic malignancy
Disease transmission: HBsAg+, Hepatitis C, CDC high risk donors, HIV positive,
Long cold ischemia time (>12 h)
DCD

Table 1.

Characteristics of extended criteria donors.

A study conducted by Tector et al., has shown that the use of extended criteria donors (ECDs) has successfully addressed the shortage of suitable donor livers for transplantation, resulting in shorter wait times and improved survival. Evidence has showcased the favorable effect of utilizing extended criteria donor (ECD) livers on transplant outcomes, which are comparable to those achieved with standard donors. This highlights the potential of ECD livers as a valuable resource in addressing the critical shortage of organs, offering a promising solution to the ongoing organ shortage crisis [3].

Due to the heightened potential risks associated with different types of extended criteria donor (ECD) allografts, it is essential for medical professionals and patients to engage in a thorough discussion about the potential hazards and benefits before consenting to an organ transplant. By carefully selecting ECD liver donors and matching them with appropriate recipients, it is possible to achieve excellent survival rates and reduce wait-list mortality rates effectively. Efforts have been made to increase the availability of liver donors by using donations after circulatory death (DCD), donors who are HCV-positive and HBV-positive, HIV-positive donors and donors over the age of 60. However, livers from these donors are more susceptible to damage during transplantation, ischemia-reperfusion injury, and impaired allograft function due to prolonged cold ischemia time (CIT), which increases the risk of postoperative complications. Therefore, it is crucial to conduct thorough evaluations and carefully select ECDs to mitigate the risks associated with transplantation and maximize outcomes for those in needs [4].

2. Donation after circulatory death (DCD)

The donation after circulatory death (DCD) is a process that focuses on cardiopulmonary criteria rather than neurologic criteria. It involves recovering organs for transplantation after death has been confirmed using circulatory criteria. This method differs significantly from the conventional standard model for deceased donation, which relies on the confirmation of death using neurological criteria. There is also a variable period of warm ischemia that follows before the organs can be preserved for donation. This is why DCD is often considered an ECD.

Donation after circulatory death (DCD) donor livers are divided into five categories according to modified Maastricht’s classification. Categories I, II, and V pertain to the recovery of organs after an unforeseen and irreversible cardiac arrest (uncontrolled donation after circulatory death—DCD), while categories III and IV refer to the retrieval of organs after planned withdrawal of life-sustaining cardiorespiratory support (controlled DCD). Uncontrolled DCD can only take place in facilities equipped with organ perfusion and retrieval capabilities readily available, typically located near or within a transplantation center. On the other hand, controlled DCD can be supported in almost any intensive care unit (ICU) or emergency department (ED) [5].

According to the annual report from the US Organ Procurement and Transplantation Network, 10.6% of liver donations come from DCD donors unlike organs from donors who have experienced brain death [6].

A study conducted by Mihaylov et al., reviewed 135 consecutive DCD LTs and found that optimizing perioperative conditions by using a thrombolytic donor flush and minimizing ischemia times can improve outcomes for ECD DCD LT. They observed a significantly lower incidence of ischemic cholangiopathy (IC) (5% versus 17% in era 1; P = 0.03) and better 1-year graft survival (93% versus 75% in era 1; P = 0.07). This suggests that ECD DCD livers can be successfully transplanted optimizing perioperative conditions, expanding the donor pool for LT [7].

A recent study led by Duan et al. examined 1104 cases of deceased donor liver transplants, of which 807 patients received a liver from a donor after cardiac death (DCD). The researchers conducted a thorough evaluation of various donor characteristics, including age and fatty liver status. The analysis revealed that there were no significant differences in postoperative complications between the DCD and other groups, and the survival rates of both patients and grafts were similar at 90 days, 1 year, and 3 years. This study demonstrates that moderately steatotic livers from DCD donors can effectively broaden the pool of available livers for transplantation, offering valuable insights into the impact of these extended criteria on liver transplant outcomes [8].

Research shows that medical facilities with a high number of liver transplants tend to use donation after circulatory death (DCD) more frequently (over 5 times a year) than low-volume centers. This increased use of DCD is associated with better outcomes for patients, including graft survival, 1-year patient mortality, 1-year graft failure, and long-term patient survival [9]. Other study conducted by Pescarissi et al., concludes that there is potential to increase the supply and use of ECDs for transplantation and that the perioperative period of LT from selected DCD donors can be safe with careful management by experienced anesthesiologists and intensivists [10].

There is a lot of concern around post-transplantation outcomes when it comes to marginal organs. DCD livers in particular have a high rate of biliary strictures due to the period of warm ischemia between withdrawal of donor life support and organ preservation. This can lead to lower graft survival rates, increase re-transplantation, and higher hospital costs [11].

In liver transplantation, Donation after Circulatory Death (DCD) grafts are frequently utilized. These grafts, however, come with an elevated risk due to an additional ischemic event during the Donor Warm Ischemia Time (DWIT), leading to an increased chance of severe ischemia/reperfusion injury and postoperative complications like ischemic cholangiopathy. The duration of actual ischemia during DWIT varies widely among donors and depends on the course of vital parameters after life support withdrawal. This ischemic period, known as the functional DWIT, begins when either Spo2 (oxygen saturation) or blood pressure drops below a certain threshold and continues until the commencement of cold perfusion during organ retrieval. Numerous retrospective single and multicenter studies have examined the impact of DWIT on liver transplantation outcomes. However, there is still no standardized definition for DWIT, leading to the incorporation of different definitions and classifications by various authors to better understand its dynamics. Developing a unified definition for DWIT could aid clinicians in optimizing the utilization of DCD livers and reducing the risk of complications [12].

A liver transplantation (LT) using donation after circulatory death (DCD) has seen progress, but ischemic cholangiopathy (IC) remains a concern. IC is the primary cause of DCD graft loss and has prevented many transplant centers from accepting DCD grafts. Despite extensive research, the cause of IC is still unclear.

A study by Goussous et al. analyzed 112 patients who underwent liver transplantation from DCD between 2005 and 2017. In 2014, measures were taken to reduce donor hepatectomy time (DHT) and cold ischemic time (CIT) to improve DCD LT outcomes. The group that received transplants after the changes had shorter DHT and CIT, and fewer cases of IC than the historical group [13].

In a meta-analysis conducted by Jay et al., a comparison of biliary complications after liver transplantation was undertaken. The study examined 489 transplants from DCD donors and 4455 transplants from DBD donors. The findings indicated that DCD recipients had a higher overall rate of biliary complications (29%) compared to DBD recipients (17%). Specifically, DCD recipients had 2.4 times greater odds of experiencing biliary complications than those who received DBD transplants. Moreover, the study revealed that DCD recipients had a higher incidence of ischemic cholangiopathy (IC) (16%) compared to DBD recipients (3%), with DCD recipients having 10.8 times greater odds of developing IC [14].

In a recent study conducted by Mercado et al., the impact of portal vein thrombosis (PVT) during liver transplantation (LT) from donation after circulatory death (DCD) donors was investigated. The study revealed that PVT can add complexity to the surgical procedure. However, carefully selected recipients with grades I-II PVT showed successful outcomes when receiving DCD liver grafts. There were no significant differences in outcomes between patients with or without PVT with grades I-II, including rates of early allograft dysfunction, primary nonfunction, or ischemic cholangiopathy [15].

Also, according to Black et al. in 2022, living donor liver transplantation (LDLT) provides superior 5-year patient and graft survival rates compared to deceased donor liver transplantation (DCD-LT). LDLT also has comparable outcomes to deceased brain-dead donor liver transplantation (DBD-LT) in terms of survival rates, but it has a higher rate of readmissions. Despite this, LDLT has a higher rate of return to work and a lower rate of chronic kidney disease (CKD). When possible, LDLT should be the preferred method over DCD-LT. However, increasing the utilization of both LDLT and DCD-LT can help more patients gain access to life-saving liver transplants [16].

A recent study conducted by Haque et al. analyzed data from 33,429 deceased-donor liver transplants in the US from 2002 to 2008. The study followed up for 10 years after the implementation of MELD and compared transplantation outcomes between recipients of donation after circulatory death (DCD) and donation after brain death (DBD). The results showed that while DCD had lower 10-year graft survival compared to DBD, the rates of graft failure for both groups were the same after the first year post-transplant. Moreover, patient survival was similar between the two groups. The study suggests that the use of DCD livers could increase with the development of machine perfusion technology to address early biliary complications [17].

Donation after circulatory death (DCD) liver transplant recipients have experienced worse survival rates compared to DBD recipients due to the inevitable WIT during the declaration of death and organ retrieval process. To improve DCD liver transplant outcomes, multiple interventions have been suggested to recondition DCD liver grafts. Interventions, before and after death, may increase the likelihood of organs being suitable for transplant. Research has shown that pharmacologic protection and machine perfusion of the liver are promising strategies to protect against ischemia-reperfusion injury, especially for high-risk organs. These strategies aim to improve the viability and number of organs available for transplant and increase the likelihood of organs being suitable, ultimately expanding the donor pool. Also, liver transplants using cold preservation methods often lead to ischemia-reperfusion injury (IRI) in the donor’s liver. Donor livers that undergo normothermic machine perfusion (NMP) are also susceptible to IRI. NMP mimics the physiologic liver perfusion by utilizing a red blood cell-based solution at temperatures between 35.5 and 37.5°C, offering a range of potential benefits. The potential effects of normothermic perfusion include countering hyperfibrinolysis and inflammation after reperfusion, replenishing glycogen, and promoting the regeneration of adenosine triphosphate. Studies on normothermic machine perfusion are centered around developing biomarkers to predict allograft quality and susceptibility to ischemia-reperfusion injury. Additionally, normothermic perfusion of marginal allografts allows for the implementation of various therapeutic interventions to potentially enhance organ quality. Based on current clinical trials, normothermic perfusion not only increases the utilization of hepatic allografts but also appears to be associated with milder ischemia-reperfusion injury, leading to a reduced risk of early allograft dysfunction and fewer biliary complications, including ischemic cholangiopathy, compared to static cold storage [18].

Normothermic regional perfusion (NRP) is a method used to maintain allografts obtained from DCD by employing VA-ECMO to sustain thoracic and abdominal organ perfusion, allowing time for recovery from warm ischemic injury. Two forms of NRP are currently in use, depending on the organ being procured. Thoracoabdominal NRP (TA-NRP) for donors with planned heart and abdominal organ recovery, and abdominal NRP (A-NRP) for donors with only abdominal organ recovery. NRP offers several advantages, including continuous warm blood perfusion, which aids in restoring heart function, reducing myocardial injury, and maintaining organ homeostasis. It allows visual assessment of organs, promotes organ recovery by establishing perfusion, reduces warm ischemia time, and enables viability assessment in a non-ischemic state before retrieval, unlike direct cold storage. Limiting factors for broad application of NRP are related to implementation and acceptance by organ procurement organizations. The process of NRP is complex, requiring coordination among donor hospitals, procurement teams, perfusionists, and organ procurement organizations, with successful execution contingent upon agreement from all involved parties [19].

3. Donors of advanced age

The age range of liver donors for transplantation has changed significantly in recent years. The United Network for Organ Sharing (UNOS) reported that in 1989, only 2.4% of donors were above 50 years old. However, by 2013, this number had increased to 33%. In the past, donating a liver after 50 was not recommended as it was believed to be associated with poor outcomes. But recent studies have shown that older donors without additional risk factors can have results similar to younger donors [20].

The liver is more resistant to aging in healthy individuals compared to other organs because it has a large functional reserve, dual blood supply that exceeds its metabolic needs, and regenerative capacity. However, as livers from older donors are smaller in weight and volume and may have developed fibrous thickening of the capsule, it is unclear if these changes affect organ function after transplantation [21, 22].

The outcomes of liver transplants from donors over the age of 70 were examined in a study by Alamo et al. they found that while survival rates were similar, there was a greater incidence of ascites and primary dysfunction due to delayed graft function. Certain factors such as the recipient’s Model for End-Stage Liver Disease (MELD) score, cold ischemia time, diabetes, hypertension, and weight over 90 kg were associated with poor prognosis. The study concluded that liver transplants from elderly donors are safe, but careful selection of both donors and recipients is necessary [23].

Another study by Kim et al. analyzed liver transplant outcomes from donors aged 65 years and above and identified several factors that affected graft survival. They found that older donor livers should not be dismissed solely based on age and that they can result in good graft survival in selected cases [24].

Wang et al., divided 159 patients into two groups based on donor age and found no significant differences in graft or recipient survival rates at 1, 3, and 5 years. However, the older donor group required a larger volume of red blood cell transfusions during the surgical procedure. The authors concluded that Liver transplant with donors older than 50 years is safe and does not have significant adverse effects on graft function or long-term donor and patient survival [25].

Although the age of the liver donor is an important factor in liver transplantation outcomes, it is not the only factor to consider. Other factors such as surgical conditions, including ischemia time and hemodynamic instability during surgery, as well as recipient conditions, such as MELD score, also play a crucial role. Therefore, minimizing these Liver transplants with elderly donors can have similar outcomes to those with younger donors. Accepting an old liver donor (OLD) graft can improve survival for all waitlist candidates, especially those with high MELD scores. It’s important to note that both older and younger candidates benefit from accepting an OLD graft. Patients and providers should carefully consider the consequences of declining an OLD graft offer, as a quarter of candidates die after such a decline. These findings can help transplant providers make better decisions and improve patient counseling. Another consideration with aged donors is the risk of transmitting malignancy due to the higher incidence of unrecognized malignancies in the elderly [26].

4. Donors with viral infections

Viruses such as Hepatitis B and Hepatitis C are routinely screened in potential donors due to their potential impact. However, these infections can be managed effectively, especially in individuals with weakened immune systems. Therefore, a positive test result for these viruses does not necessarily disqualify someone from being a suitable donor.

4.1 Hepatitis B virus (HBV)

The prevalence of hepatitis B core antibody (HBcAb) positivity varies across different geographic locations. In liver donors within the United States, the prevalence is reported to be 4.8%. Considering the global prevalence of HBV “past” and present infections, with 2 billion and 350 million affected individuals respectively, the use of liver grafts from donors with past HBV infection (HBcAb-positive only) is a relatively common practice. This approach holds the potential to significantly alleviate the shortage of organs, especially in countries with high HBV endemicity. However, it is essential to note that donors who test positive for HBcAb may carry intrahepatic covalently closed circular DNA (cDNA) and may also have an occult infection with positive serum HBV DNA [27].

Donors who are hepatitis B surface antigen negative (HBsAg−) but hepatitis B core antigen positive (anti-HBc+) have transmitted HBV infection to liver recipients who are HBsAg−. Early studies of the use of hepatitis B core antibody-positive allografts to treat HBV+ recipients suggested that the risk of HBV transmission was extremely high and carried high mortality. However, in patients who are immune to HBV (previous vaccination), it is safe to use these organs [28]. Additionally, donors with positive hepatitis B surface antibodies (anti-HBs) do not appear to transmit HBV infection after liver transplantation.

The use of combined prophylaxis with hepatitis B immune globulin (HBIg) and lamivudine has proven effective against HBV recurrence and de-novo HBV infection or transmission in recipients of anti-HBcAb+ livers [29, 30].

Further data has shown that using an HBsAg-positive graft is feasible. HBsAg-positive recipients who received a graft from HBsAg-positive inactive carriers remained HBsAg positive, and HBIg was discontinued within the first-month post-LT. This experience demonstrates that LT using grafts from deceased HBsAg-positive donors is feasible and may expand the pool of organ donors with appropriate antiviral management and monitoring [31].

In a study by Saidi et al., the United Network for Organ Sharing (UNOS) database was used to review LT outcome data in the United States. The study found that both the graft and the patient had similar survival rates between the 92 recipients of HBsAg-positive grafts and recipients of HBsAg-negative grafts. The majority of the study population required LT for HBV-related disease (74%) [32].

The largest series describing the transplantation of HBV NAT+ kidney and liver allografts aimed to assess the 1-year safety and effectiveness of such transplants in seronegative kidney transplant (KT) and liver transplant (LT) recipients. Over a 1-year period, 89 recipients received HBV NAT+ organs, and no HBV-related complications were observed. Among 18 recipients who experienced viremic episodes, 16 of them achieved undetectable HBV DNA levels after approximately 80 days of entecavir therapy. Expanding the use of HBV NAT+ organs in nonviremic recipients may help alleviate the national organ shortage [33].

4.2 Hepatitis C virus (HCV)

In the past, there was much debate about using organs from donors with Hepatitis C virus (HCV+) for liver transplantation (LT). However, due to a shortage of organs for transplant, the use of HCV+ organs has become more common as a solution to increase the donor pool. Despite advances in treatment, many HCV+ liver allografts, several hundred per year, are still not being used. HCV infection affects an estimated 1–2% of the general US population, but the risk is higher (3–18%) among organ donors with more risk factors as defined by the Public Health Service [34].

A study by Alvaro et al. found that using HCV+ donors is a safe and effective source for liver donation. Out of 143 transplants performed in HCV+ recipients, 9.1% received an organ from an anti-HCV+ donor, with 72.7% showing a negative viral load. Although 80% of the patients experienced hepatitis during follow-up, there was no significant difference in patient or graft survival observed between the two groups [35].

A retrospective study by Ting et al. demonstrated that HCV seronegative patients who receive an HCV seropositive liver allograft can have good short-term outcomes with HCV cure following antiviral treatment [36].

Evaluating long-term outcomes in liver transplant recipients transplanted with HCV antibody-positive organs, A study conducted by Stepanova et al., in 2016 evaluated the long-term outcomes of liver transplant recipients who received organs from donors with HCV antibodies. The study compared the rates of mortality and graft loss between those who received organs from HCV antibody-positive (HCV+) donors and those who received organs from HCV antibody-negative donors. The study found that both mortality rates and graft loss rates were similar between HCV patients transplanted from HCV+ donors and those transplanted from HCV-negative donors. In fact, long-term outcomes were very similar in patients who received organs from HCV+ and HCV− donors [37].

A cross-sectional study by Da et al., found that HCV-positive donors were healthier and donated superior liver allografts compared with HCV-negative donors. The use of an HCV donor is a good option to increase the organ pool. Several studies suggest that LT from HCV+ donors are a safe procedure with the use of effective antiviral therapy [38].

4.3 Human immunodeficiency virus (HIV)

The worldwide occurrence of human immunodeficiency virus (HIV) has now affected 37 million people. Although antiretroviral treatment has been developed, HIV-unrelated reasons have become significant factors in determining survival rates. Liver disease is one of the main causes of death, accounting for 10%. This rise in prevalence is because of the high frequency of concomitant HBV and HCV infections with HIV. Consequently, it is crucial to encourage organ transplantation in this population, as HIV-infected recipients have similar survival rates to non-infected recipients, albeit with three times higher acute rejection rates [39]. Currently, organs from HIV-positive donors can only be transplanted to HIV-positive patients. In nations with a high prevalence of HIV, liver transplantation from HIV-positive donors has become a desirable choice. Furthermore, almost 66% of HIV-positive individuals are eager to donate their organs to other HIV-positive patients. They have distinct reasons, such as combating HIV-related prejudices and showing compassion toward other infected patients [40]. According to a recent publication by Rozera et al., it has been confirmed that HIV-positive individuals can safely receive transplants from HIV-positive donors without the risk of superinfection. The immunosuppressive treatment administered to prevent transplant rejection does not seem to have a significant impact on the progression of HIV disease or any other viral reactivations [41].

5. Conclusion

This chapter provides comprehensive insights into various aspects of liver transplantation, focusing on the utilization of extended criteria donors- including those from donation after circulatory death and donors with viral infections such as hepatitis B and hepatitis C. The findings emphasize the importance of expanding the donor pool to address the critical shortage of organs for transplantation. Despite the potential risks associated with ECDs, studies demonstrate promising outcomes with careful selection and optimization of perioperative conditions. Advancements in antiviral therapy and transplant management contribute to improved survival rates and outcomes for recipients of ECD livers, highlighting the significance of ongoing research and innovation in liver transplantation. Further studies are warranted to continue refining strategies for donor selection, perioperative management, and long-term outcomes, ultimately enhancing the effectiveness and accessibility of liver transplantation for patients in need.