A bridge too far: We have not overstepped the line for extended deceased donors

In the early years of clinical liver transplantation, grafts were recovered, by and large, from relatively young and healthy donors who had suffered traumatic brain injury, typically in the context of a motor vehicle accident, and preserved in an adequate state of viability in a cold solution until the time of transplantation. Over the past 2 decades, however, organ donors have become progressively more elderly, more obese, and less healthy in general. Given an improved ability to care for patients with traumatic brain injury, fewer may be declared dead based on neurological criteria and instead have life support removed to provoke cardiac arrest.1 Livers that are older, steatotic, or recovered through donation after circulatory determination of death (DCD) suffer higher rates of early and late allograft dysfunction, leading to increased recipient morbidity and mortality as well as transplantation costs.2, 3 Given the fact that the need for liver transplantation continues to expand, however, simply avoiding the use of these livers is no longer an option. The most consistent and practical definition of extended-criteria or marginal livers includes those 1) arising from older donors (aged >50-65 years), 2) with severe macrosteatosis, 3) that have been split, 4) that have been recovered through the DCD process, or 5) with positive infectious serology for hepatitis B or C virus (HBV or HCV, respectively). Other factors (donor hypernatremia, prolonged hospital stay, elevated hepatic transaminases and/or bilirubin, race, height, and cause of brain death, for example) have also been variably associated with worse graft outcomes.4, 5 The liver ages with the person and develops a series of morphological, hemodynamic, histological, and synthetic functional changes influencing graft viability. Furthermore, as the age of the graft increases, so too does the prevalence of hepatic steatosis, and short-term graft survival has been shown to be significantly impaired when both factors (moderate-to-severe steatosis and advanced donor age) are present. Increased donor age is associated with a greater prevalence of comorbid conditions, including arterial disease, diabetes mellitus, and hypertension. The presence of arterial lesions, including atherosclerotic plaques in the hepatic artery, is a potential source of graft complications in the recipient.6 Donor hypertension and diabetes, however, have not been shown to have a negative impact on graft outcomes. Another fact to consider is that older donors more commonly harbor undetected neoplastic lesions (namely, prostatic and renal tumors), and it is crucial that the donor surgeon perform a meticulous intraoperative examination of the abdominal cavity and the graft under consideration. Ultrasound is a useful adjunct to detect the presence of intraparenchymal lesions that may not be palpable or observable at the liver surface. Initial controversy surrounding the upper age limit for liver donation appears to have been overcome with the publication of several series in which the results of liver transplantation were not negatively influenced by donor age.6 When the cold ischemia time (CIT) is kept below 8 hours, the results of liver grafts arising from donors older than age 50 years are equivalent to those achieved with grafts from younger donors. An analysis of the Spanish Liver Transplant Registry demonstrates that actuarial 1-year graft survival with livers from donors between 60 and 90 years of age is only slightly inferior to that achieved with livers from donors aged 15 to 60 years. At 5 years, these differences increase, although it is important to point out that the recipients of older liver grafts in this series suffered a higher prevalence of hepatocellular carcinoma, HCV infection, and recurrence of their underlying liver disease. The use of older liver grafts for transplantation appears to have a particularly deleterious effect in patients with cirrhosis resulting from HCV, with earlier and more severe viral recurrence.2 Currently, advanced donor age is not considered a contraindication for liver donation, and each liver should be evaluated on an individual basis, taking into account not only the physical status and age of the donor but also the functional status of the potential recipient as well as the presence of additional risk factors, namely, hepatic steatosis and prolonged CIT. As mentioned previously, the progressive increase in the number of potential donors with hepatic steatosis is associated with parallel increases in median donor age as well as steatosis-associated comorbid conditions (hypertension, diabetes mellitus, obesity, etc.). There are two different types of hepatic steatosis, macrovesicular and microvesicular. (In reality, however, both forms of steatosis are typically present simultaneously.) How steatosis affects graft survival depends on the type. Macrovesicular steatosis (macrosteatosis) most frequently arises in the context of obesity, diabetes mellitus, alcohol abuse, or hyperlipidemia. In macrosteatosis, one large fat vacuole disrupts the cellular architecture, both displacing the cell nucleus to the periphery and narrowing the extracellular sinusoidal space.7 Microvesicular steatosis (microsteatosis), on the other hand, is the result of toxin- or drug-induced impairment of mitochondrial β-oxidation. Numerous small fat vacuoles occupy the cytoplasm but have no effect on the localization of the nucleus or the diameter of the sinusoid. Outside the context of transplantation, severe microsteatosis is associated with fulminant hepatitis, multiorgan failure, coma, and death, whereas macrosteatosis is often a benign condition in the acute setting. However, in liver transplantation, grafts with microsteatosis have outcomes similar to those of nonfatty grafts, whereas graft survival in severely macrosteatotic livers is significantly impaired. Macrosteatotic livers are more susceptible to ischemic injury than lean livers. At baseline, the swollen hepatocytes impair microvascular flow through the hepatic sinusoid. During ischemia, the hepatocytes progressively lose the capacity to eliminate sodium into the extracellular space via the adenosine triphosphate-dependent sodium–potassium exchange pump and swell even further. On graft reperfusion, not only is the sinusoidal space notably narrowed but also blood cells and platelets marginate at the sinusoidal wall, thus providing yet another impediment to graft reperfusion. Quantitatively, hepatic steatosis is classified according to the percentage of hepatocytes affected by fat vacuoles: <30% mild, 30% to 60% moderate, and >60% severe steatosis. In general, microvesicular steatosis is not considered a contraindication for liver donation, but severe macrosteatosis is. Transplantation of severely macrosteatotic liver grafts is associated with a significantly increased risk of primary nonfunction (PNF), early and severe HCV recurrence, and worse posttransplant graft and patient survival.7 Although no doubt exists that grafts with obvious severe macrosteatosis should be discarded, it is unclear what should be done with grafts with a moderate degree of macrosteatosis. Although the use of liver grafts with moderate steatosis does not appear to lead to worse posttransplant patient survival, rates of PNF do appear to be higher with these grafts (13% versus 3% with mildly steatotic livers). When evaluating a moderately steatotic liver for transplantation, one must consider coexisting risk factors for a poor outcome, including, once again, prolonged CIT, advanced donor age, and the HCV status of the recipient. Anatomical study of the liver by Couinaud in 1957 led to the recognition of the segmental nature of the liver and the possibility of obtaining 2 separate liver grafts from a single donor. Given the functional reserve of a healthy liver, 30% to 40% of the standard liver volume is typically enough to support a patient's metabolic and synthetic needs. These 2 facts, together with the enormous regenerative capacity the liver possesses, have allowed split-liver transplantation to become a clinical reality. The key to splitting a donation after brain death (DBD) liver for 2 separate recipients is to transect the hepatic parenchyma while adequately preserving both vascular inflow and outflow and biliary structures to each hemiliver. Also, one has to ensure an appropriate size match between each partial liver graft and its potential recipient; each graft should represent at least 30% to 40% of the recipient's standard liver volume or at least 0.8% to 1% of the recipient's body weight.8 Two different techniques for liver splitting have been described: 1) ex situ during back-table surgery once the liver has been recovered from the donor cold perfused and 2) in situ during the organ recovery process with the donor heart still beating, albeit often with hemodynamic support. Each of the two techniques is associated with certain advantages and disadvantages. Nevertheless, the in situ splitting technique has been shown to be associated with a shorter CIT and lower incidences of biliary tract complications, postoperative hemorrhage, and ischemia of hepatic segment IV compared with the ex situ technique. In 1988, the first case of split-liver transplantation was reported, in which the right hemiliver was used for an adult and the left for a pediatric recipient. One year later, in 1989, Bismuth reported the first split-liver transplant for 2 adults. In 1990, Broelsch and colleagues9 reported the first series of split liver transplants, in which the results were significantly inferior to those with whole-liver transplantation: only 67% of children and 20% of adults in the series survived. Nevertheless, over the past 2 decades, refinement of the surgical technique and better patient selection have resulted in progressive improvements in patient and graft survival and the rates of postoperative complications to the point at which they are now in a range similar to those achieved with whole-liver grafts. Presently, split-liver transplantation is considered a safe and valid option for the transplantation of an adult and a pediatric recipient from a single graft.10 The primary factor limiting the greater expansion of split-liver transplantation for 2 adult recipients has to do with the difficulty of obtaining grafts of adequate size for each of the recipients. It is particularly difficult to find adult recipients for the left hemiliver who are small enough to undergo transplantation without risking the development of small-for-size syndrome (SFSS). SFSS is diagnosed clinically when cholestasis, coagulopathy, encephalopathy, ascites, gastrointestinal bleeding, and/or renal failure arise in a liver representing <0.8% of the recipient's body weight or <40% of the recipient's standard liver volume, with the exclusion of any other cause.8 The clinical presentation of SFSS is typically subacute; when it does occur, however, SFSS leads to graft failure within 2-3 months in up to 50% of recipients. Although strategies have successfully been employed in the experimental setting to avoid the development of SFSS after partial-liver transplantation (such as the placement of a calibrated portocaval shunt or recipient treatment with somatostatin), their utility and success in clinical split-liver transplantation remain to be determined. DCD donors suffer a period of cardiac arrest/warm ischemia prior to organ recovery. The traditional Maastricht classification describes 4 categories of DCD donors; for practical purposes, however, there are really only 2, those who suffer an unexpected cardiac arrest, typically outside the hospital (corresponding to Maastricht category II), and those with significant neurological injury in whom an expected cardiac arrest occurs after the intentional removal of ventilatory support (Maastricht category III).11 Fewer organs are transplanted from DCD donors, unexpected donors in particular, relative to DBD donors because of justifiable concerns over their viability resulting from the prerecovery period of cardiac arrest these donors suffer.12 Nevertheless, DCD continues to garner progressively greater interest as a much underused potential source of a considerable number of organs. Whereas primary nonfunction was once considered to be the most feared negative outcome of DCD liver transplantation, more experience and better patient-selection criteria have helped to reduce significantly the transplantation of nonviable DCD liver grafts. Presently, nonanastomotic biliary strictures and ischemic-type biliary lesions are now the so-called Achilles heel of this procedure. Ischemic injury to the biliary epithelium results in a subacute presentation of repeated bouts of cholestasis, cholangitis, and even hepatic abscesses, which may require repeated hospitalizations; interventional procedures; and, not infrequently, liver retransplantation.3 This unique pattern of injury in DCD livers is reflected by the fact that patient survival tends to be similar although graft survival is worse than in the recipients of DBD livers, and most centers adhere to strict limits for donor ischemic times in order to avoid irreversible cholangiocellular injury.11 To overcome the ischemic lesion in the donor, abdominal regional perfusion has been used to restore the flow of oxygenated blood to the kidneys, liver, and pancreas after death has been declared based on cardiorespiratory criteria. Abdomen regional perfusion involves isolation of the subdiaphragmatic vasculature from the systemic circulation and perfusion of the abdominal region with continuous flow. It relies on cardiopulmonary bypass/extracorporeal membrane oxygenation technology and uses an in-line pump to recover donor venous blood, mix it with substrates and solutions, deliver it to a membrane oxygenator, and then return the oxygenated blood to the donor subdiaphragmatic aorta. A period of normothermic regional perfusion (NRP) after warm ischemia, in particular, helps to restore cellular energy substrates, reduce levels of nucleotide degradation products, and improve the concentrations of endogenous antioxidants in DCD livers. In 2002, the Hospital Clinic in Barcelona initiated a protocol to transplant livers arising from human unexpected DCD donors—considered by some to be the most marginal donors in use today—treated with NRP.11, 12 Since then, over 40 such transplants have been performed. With a median follow-up of 45 months, 1-year graft and patient survival rates are 73% and 81%, respectively. Seven recipients have developed postoperative biliary complications (17%), including 3 patients who have been retransplanted for ischemic-type biliary strictures (7%). These rates of morbidity and mortality are at least comparable to, if not better than, those achieved with livers from expected/category III DCD. Experimental evidence offers hope that the quality of DCD livers may be further improved through the use of ex situ machine perfusion, in particular when combined with in situ NRP. A recent, large, animal liver transplant study demonstrates that continuous normothermic perfusion of DCD livers leads to excellent recovery from the ischemic injury and superior posttransplant outcomes versus static cold storage.13 Clinical trials on the use of normothermic machine perfusion in DCD liver transplantation are pending. Transplantation of livers recovered from HCV-positive donors is based on the facts that 1) HCV cirrhosis is a very common cause of end-stage liver disease and, therefore, an indication for liver transplantation and 2) recurrent HCV infection in the transplanted liver graft is universal (though novel antiviral treatments now in clinical trials may help to change these facts). The initial uncertainty regarding a possible deleterious effect of the existence of different HCV genotypes in the donor versus the recipient has been dispelled; it has been seen that recipients in whom the donor genotype has become the dominant genotype present milder HCV recurrence. When genotype 1 is present in either the donor or the recipient, however, it always becomes the dominant genotype.14 Although the majority of series include small numbers of patients, there do not appear to be any short-term differences in the postoperative evolutions of recipients of HCV-positive grafts versus HCV-negative grafts. Moreover, an analysis of the United Network for Organ Sharing database that includes 96 HCV-positive donors has shown that positive HCV serology in the donor does not affect the liver recipient at 5 years.14 Liver grafts from HCV-positive donors should be transplanted only into HCV-positive recipients. It is necessary to perform a pretransplant liver biopsy to rule out hepatitis or fibrosis. It is also advisable to perform serial protocol biopsies during posttransplant follow-up in order to monitor viral progression in the recipient of the HCV-positive graft. The major risk associated with the use of livers from donors with antibodies against hepatitis B core antigen (anti-HBc) is the development of de novo and potentially severe HBV infection, which may occur in up to 70% of HBV-naïve patients, although the risk is significantly lower (0%-15%) in recipients who are anti-HB core or surface antigen positive.15 Prophylactic administration of lamiduvine, however, with or without the addition of anti-HBV immunoglobulin, essentially eliminates the risk of HBV infection in patients who are HBV naïve. In general, livers from donors that are anti-HBc positive should be transplanted into recipients with antibodies against HBV, in particular patients infected with HBV (HBV surface antigen-positive), who will be treated with lamiduvine and anti-HBV immunoglobulin. However, if a liver from an anti-HBc-positive donor is transplanted into an HBV-naïve recipient, the recipient should receive treatment with prophylactic lamiduvine as soon as oral intake is initiated in the postoperative period and continued for a period no shorter than at least 1 year. Each potential liver donor should be evaluated on an individual basis as well as in the context of the potential liver recipient to determine excessive risk for graft failure after transplantation. Given the extreme shortage of viable donors, no single class of donors can be rejected outright. Although some liver donors, such as unexpected DCD, may present a particularly elevated risk for failure, clinical evidence has shown that, when additional risk factors and ischemic times are kept to a minimum, very good results can be achieved with even seemingly extremely marginal grafts. Additionally, advanced techniques of organ maintenance such as normothermic machine perfusion might play a role in the future in determining liver graft viability prior to transplantation and appear to offer better ex situ preservation than static cold storage. In considering the current panorama and future prospects for clinical liver transplantation, the bridge that extended-criteria donors represents is not a bridge too far but the only bridge remaining.