INTRODUCTION
Kidney and liver transplantation have essentially become a “victim of their own success”. Specifically, after overcoming the initial technical and immunological challenges, both kidney and liver transplantation have become the main therapy for patients with end-stage renal and end-stage hepatic disease respectively. This has led to a significant increase in the number of patients on the waiting list for a renal or a liver transplant, without a corresponding increase in the number of deceased donors (DD), thus leading to increasing mortality rates on the liver transplant waiting list [1]. In an attempt to respond to this organ shortage, the US Department of Health and Human Services initiated in 2003 the Organ Donation Breakthrough Collaborative seeking to identify best practices, as well as viable solutions for the organ shortage [2].
Strategies that were followed included the increased use of grafts from donors after cardiac death (DCD), the increased use of grafts from living donors and the increased use of partial grafts, such as the case with split liver transplantation. The need to push the envelope has led to the concept of the Extended or Expanded Criteria Donors (ECD). The main idea is to identify those high-risk grafts, which when used appropriately can offer the recipient a survival benefit. As enticing as this sentence sounds, it has the makings of an election-year political platform, in that it lacks specifics; and that is exactly where the problem (and the opportunity) are with Extended Criteria Donors.
This short editorial will present certain critical issues having to do with the use of ECD. Specifically, a) what is an extended criteria donor, b) how can we improve an ECD graft, and c) what would be the best allocation for an ECD graft. We will focus mainly on renal and hepatic transplantation, although some of the concepts and arguments easily apply to the transplantation of other organs.
DEFINITION OF AN EXTENDED CRITERIA DONOR
The first obstacle is that, despite numerous attempts, there is no universally-accepted definition for what constitutes an ECD donor, especially in the case of hepatic grafts. The general concept refers to donor factors that lead to a hepatic graft at a higher risk for primary non-function or delayed graft function or increased long-term risk that could affect the recipient survival. However, the core of the problem lies in the heterogeneity of the factors constituting the “high-risk” identity of the graft, as can be seen in the Table. In the ECD cases where the “high-risk” may be the result of the social or medical history of the donor, the quality of the hepatic graft itself may be excellent, thus increasing the importance of proper allocation.
Characteristics of Extended Criteria Donors |
|
High Risk Based on Organ Quality |
|
|
Age |
|
Steatosis |
|
Donor ICU (Vasopressors, length of stay etc) |
|
BMI |
|
Donor cause of death |
|
Serum Sodium |
|
Liver function tests |
|
Graft type (split or partial liver from a living donor) |
|
Donation after cardiac death |
|
Allocation |
|
Technical issues (anatomical variances, vascular or biliary or hepatic injury during procurement) |
High Risk based on the Social History of the Donor |
|
|
History of incarceration |
|
History of intravenous drug use |
High Risk based on the Medical History of the Donor |
|
|
History of extrahepatic malignancy |
|
History of infections (pneumonia, meningitis), presence of sepsis |
|
Positive serology for hepatitis |
|
Donor-specific disease transmission |
There have been several attempts to define and categorize these criteria, culminating with the Paris consensus meeting [3-8]. During the latter and with the participation of experts from around the world, the discussion shifted from a “good” or “bad” graft to one where there is a continuous variable of “risk” with a range from “low” to “high” based on the specific characteristics of the extended criteria donor and their interactions (for example an older donor with HBV or a donor with macrosteatosis >40% and HCV). There is common agreement that, given the organ shortage, use of grafts from ECD is necessary, even if it may lead to increased morbidity and mortality [8].
Even though a universally-accepted definition may not exist, in an effort to provide some sort of objective assessment of the donor, Sandy Feng et al. proposed the use of the Donor Risk Index (DRI) after evaluating the data of over 20, 000 donors from the Organ Procurement and Transplantation Network (OPTN) in 2006 [9]. The variables used included age, cause of death, race, donation after cardiac death, type of graft (partial/split liver), height, location (local vs. regional vs. national) and cold ischemia time. An attempt to expand this and validate the DRI using the Eurotransplant data set was made by Blok et al., who created the Eurotransplant- Donor Risk Index (ET-DRI) [10]. Most of the American DRI covariates were used with the exception of race and height, and the addition of serum gamma glutamyl transpeptidase (γGT), as well as a change in the location variable for the donor. Although both of these indices are an important step towards having a “common language” when assessing a donor, there are still several steps in the process (as we will see later in the editorial) given that these metrics need to be externally validated on different population sets.
In the case of renal transplantation, things are a little bit easier given the fact that there a definition for ECD renal grafts does exist. Specifically, in 2002 ECD were defined for renal transplantation based on a higher donor age, presence of hypertension and death from cerebrovascular accident [11]. As useful as this definition has been, it lacks detail and it may fail to take into account the finer details in the evaluation of the donor. Several efforts to improve on this definition followed with the most promising being the Kidney Donor Risk Index (KDRI) by Rao et al. in 2009 [12]. The KDRI is based on the association between graft survival and ten donor characteristics, which include age, height, weight, ethnicity, cause of death, serum creatinine, HCV positive serology, history of diabetes or hypertension and donation after cardiac death. The factors are all thought to be indirect measures of the quality of the donor and the renal function. An evolution of the KDRI has been the Kidney Donor Profile Index (KDPI), which provides a comparison to a reference population of donors within the previous year. Despite this improvement, in that it is more detailed, there are still several important factors, such as cold ischemia time or HLA mismatching, which are not included. More importantly, the question of what really constitutes an ECD is cautiously being expanded to the area of living donor renal transplantation, where issues such as using living donors with hypertension or significant obesity are being considered. Although the KDRI and the KDPI are not by themselves an adequate tool to make a decision to accept or discard a kidney, they provide useful information in the effort to combat the organ shortage.
EFFORTS TO IMPROVE THE GRAFT EXTENDED CRITERIA DONOR
Although there is no universally accepted definition for an ECD, there is consensus regarding the fact that the grafts from ECD are higher risk and thus any efforts to improve them would be welcome. Specifically, there are three areas where the efforts to improve the grafts from ECD have been focusing on: a) the retrieval process, including the management of the cold ischemia time (CIT), b) the preservation of the organ till the transplant with methods such as machine perfusion and essentially finding ways to address the major threat of ischemia/reperfusion (I/R) injury, which is even more pronounced in the case of ECD and, finally, c) the transplantation surgery itself.
Regarding the retrieval process and possible interventions aimed at improving the quality of the ECD graft, there have been several approaches including rapid en bloc procurement with minimal manipulation in the case of DCD, different preservation solutions, perfusion with fibrinolytic drugs such as plasminogen activators among others [13-15]. As far as the CIT is concerned, there is general agreement that keeping it under 8 hours, especially in the case of steatotic livers or those from older donors, can be a key factor of success. An important part of the retrieval process, which can give valuable information and help with the decision to accept the graft or not, is the pre-transplant biopsy performed at the beginning of the procurement. It should be stated however that there are no guidelines regarding its routine use and that there are several issues, such as the need for an experienced liver pathologist available at the procurement site and excellent communication between the pathologist and the procurement team, the OPTN and the transplant team.
Minimizing the effects of the I/R injury has been a major goal of transplantation, and even more so in the case of ECD, given their increasingly susceptible nature. Several methods and strategies have been suggested including medications, ischemic preconditioning, and pharmacologic preconditioning all in an effort to decrease the inflammatory process and improve the hepatic microcirculation [16-18]. Machine perfusion represents a significant effort to overcome the I/R associated with limited available preservation options [19-20]. It is interesting that very frequently this is exacerbated by a process where a series of denials for an ECD graft (not an unusual scenario in the donation process) will only increase the I/R injury by increasing the CIT and the preservation time. Having said that, machine perfusion also has several variables that need to be controlled, not least among them the timing and duration of the preservation, the environment and the temperature, the use of single or dual (arterial and portal) oxygenated perfusion, the type and composition of the perfusion fluid, and the pre- and post-perfusion flushing of the organ [21-23]. Despite the significant and multiple intricacies of the machine perfusion process of the ECD graft, the overall experience appears to be a positive one and definitely worthy of further research.
As far as the transplantation process of the ECD organ is concerned, the available options to ameliorate the prospects of an ECD graft are basically the need for technical excellence (given the potentially limited functional reserves of the organ and the patient) and, in the case of hepatic grafts, the debate about the use of sequential or simultaneous reperfusion [24-25]. In the first case there is a shorter CIT, whereas in the case of simultaneous perfusion there is increased oxygenation of the graft at the time of reperfusion.
CHALLENGES IN THE ALLOCATION OF ECD GRAFTS
Before trying to devise the best strategy for allocating an ECD graft, we have to decide on what the proper question that we are trying to answer is. Specifically, are we trying to identify which is the ideal graft overall or which is the best graft for a specific patient or which is a “good enough” graft for a specific patient? Essentially, given the existing organ shortage and the alternative to transplantation (which in the case of liver failure is essentially non-existent), we have to balance the risk(s) posed by the ECD graft with the needs of the specific donor and match them appropriately. That still leaves the question of how to proceed with the best allocation process.
One suggestion is using indices, such as the KDRI and the KDPI in the case of ECD kidneys and the DRI in the case of hepatic grafts. However, as helpful as they may be there are still limitations. In the case of ECD kidneys a decline in the use of ECD kidneys with KDPI>85% was seen after 2008 owing partly to the increase seen in the cost and resources associated with their use compared to SCD grafts, as well as the “labeling” effect [26]. Specifically, the CMS introduction of the Conditions of Participation for organ transplant centers meant that centers had to be more conservative regarding their outcomes from fear of endangering public funding [27]. Over time this strategy was shown to be unjustified, as associating donor and recipient risk (such as selecting older recipients) could maintain patient access to transplantation without affecting outcomes from the use of higher risk grafts [28]. Although there is certainly a benefit to the pre-implantation biopsy, there is an active debate regarding the technical aspects (needle vs. wedge) and the expertise required (renal vs. general pathologist) [29-30]. Similarly, in the case of the DRI, it has not always been possible to achieve external validation with neither the DRI, nor the Eurotransplant ET-DRI, as seen in the study of a sample of the French population [31]. The difficulty was in the fact that the assumptions required for the models to be effective were not met, as there are differences between the construction datasets and the validation database, in addition to differences in the variables studied or their particular weight between the populations studied (such as the importance of geographical allocation distance and the need for additional factors such as organ perfusion solution) [31].
CONCLUSION
It is quite possible that at the end of this editorial the reader is left with more questions than answers. This is exactly the challenge when discussing ECD grafts. We have to remember that the concept of ECD was the product of the need to respond to the organ shortage in a constructive and productive manner. The result was moving away from absolute definitions of what constitutes an “ideal” donor and understanding the there is essentially a continuum in the risks associated with the use of ECD grafts. Additionally, we have realized that the donor is only one part of the equation and that the quest is to identify “the right graft for the right recipient”. This has also meant changing (or at least trying to) our expectations, in the sense that outcomes with ECD grafts may frequently be inferior to those seen with standard criteria donors; however, they are still superior to prolonged periods on the waiting list.
The success of ECD grafts in combating organ shortage has also allowed us to push the envelope even further, with examples such as considering the use of higher risk living donors (those with hypertension or elevated BMI in the case of living donor renal transplantation). The challenge remains in identifying the proper place for ECD grafts and a critical part of answering this challenge is the use of national/international registries for the proper follow-up of the recipients.
REFERENCES
Dr Georgios Tsoulfas received his medical degree from Brown University School of Medicine and completed his general surgery residency at the University of Iowa Hospitals and Clinics, as well as a transplant research fellowship at the Starzl Transplant Institute at the University of Pittsburgh. He then completed a two-year transplantation surgery fellowship at the Massachusetts General Hospital, Harvard Medical School and then joined the Division of Solid Organ Transplantation and Hepatobiliary Surgery at the University of Rochester Medical Center as an Associate Professor of Surgery. He has currently moved back to Greece, where he is an Assistant Professor of Surgery at the Aristoteleion University of Thessaloniki. He has published over 70 papers in peer-reviewed Journals and in PubMed, as well as 17 book chapters. He is a reviewer for 15 International Journal and on the Editorial Board of several others.
The recipient of awards such as the Edward E. Mason award for excellence in patient care and education, he is a Fellow of the American College of Surgeons and a member of a number of professional organizations including the TTS, the American Society of Transplant Surgeons, Association for Academic Surgery, International College of Surgeons, American College of Surgeons, International Liver Transplantation Society, Society for Laparoscopic Surgeons and International HepaticoPancreaticoBilliary Association. Dr Tsoulfas is the recipient of the American College of Surgeons International Guest Scholarship. He is a member of multiple committees, including the International Relations Committee of the American College of Surgeons and the International Relations Committee of the American HepaticoPancreaticoBiliary Association (AHPBA). Dr Tsoulfas is currently the president of the Greek Chapter of the International College of Surgeons, as well as President-Elect of the International College of Surgeons and Chairman of the Education, Quality and Communications Subcommittee of the IRC of the American College of Surgeons.
Deceased Organ Donors and PHS Risk Identification: Impact Upon Organ Usage and Outcomes. [published online March 1, 2017].
Pruett TL, Clark MA, Taranto S.
Transplantation. doi: 10.1097/TP.0000000000001716
The Public Health Services (PHS) increased risk designation is intended to identify potential donors that put the associated recipients at increased risk of acquiring HIV, HBV, and HCV. In 2013, the United States adopted this classification. Pruett et al found that over 20% of all deceased donors in the United States fit this classification. Many are otherwise good candidates for donation, but fewer organs were used if classified as high risk (3.9 vs. 4.2 organs per donor). Importantly, there was no difference in the rate of transmission regardless of PHS donor status. Considering this data is of interest in the United States, where the opiate epidemic has led to an increase in the number of potentially suitable donors who may be considered high risk.
Strategies for an Expanded Use of Kidneys From Elderly Donors.
Pérez-Sáez MJ, Montero N, Redondo-Pachón D, Crespo M, Pascual J.
Transplantation. 2017 ;101(4):727-745.
The issue of demand far outstripping organ supply is certainly not new; as such, there are ongoing efforts toward expanding the available donor pool. In a systematic review, Pérez-Sáez et al analyze the risks and benefits of an expanded use of older kidney donors. While outcomes are generally worse with kidneys from older donors, there is definite benefit for patients who do not require a high-quality kidney. The use of older donors varies significantly across countries, and the authors propose solutions to decrease the discard of these kidneys.
Anti-viral therapy enables transplantation of HCV+kidneys
May 15th, 2017 - Kidneys for transplantation are in very short supply; yet, hundreds of kidneys from deceased patients with hepatitis C virus (HCV) infection are discarded every year. In a new open label, single group, pilot trial [doctors found that] direct anti-viral treatment led to excellent allograft function with limited and transient liver inflammation. *Rest of article is only accessible with subscription.
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