Strategies for Widening Liver Donor Pool

Strategies for Widening Liver Donor Pool

Review Article Strategies for Widening Liver Donor Pool Ho Yu Chung, See Ching Chan, Chung Mau Lo and Sheung Tat Fan, Department of Surgery, The Univ...

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Review Article

Strategies for Widening Liver Donor Pool Ho Yu Chung, See Ching Chan, Chung Mau Lo and Sheung Tat Fan, Department of Surgery, The University of Hong Kong, Hong Kong SAR, China.

Liver transplantation is a life-saving treatment modality, but is hindered by the scarcity of deceased-donor liver grafts. To acquire more liver grafts and thus save more lives, various techniques have been devised and policies adopted, including living-donor, split-graft and sequential liver transplantation; extended donor criteria; and donation after cardiac death. However, with these techniques and policies come a range of entailed medical concerns and concomitant ethical dilemmas, mainly bearing on the welfare of donors and potential donors. In this article, we provide an overview of how the transplant community works towards the end of extending the liver donor pool, with the aim of ensuring that more liver transplant candidates receive their transplant as early as possible. The current strategies in Hong Kong in this regard are also reviewed. [Asian J Surg 2010;33(2):63–9] Key Words: deceased donor, dual graft, liver transplantation, living donor, split graft

Introduction Liver transplantation (LT) is an effective treatment for endstage liver disease of various etiologies, small unresectable hepatocellular carcinoma, and inborn errors of metabolism of liver origin. Unfortunately, this life-saving treatment is limited by the availability of deceased-donor liver grafts. Urged on by the shortage of grafts, the transplant community has devised techniques and adjusted policies to save more lives. Here, we give a synopsis of how more liver transplants are carried out by various means. The local practice in Hong Kong in such an endeavour is also reported.

Living-donor liver transplantation (LDLT) The idea of LDLT was first promulgated in 1969 by Smith,1 only 2 years after the first success in deceaseddonor liver transplantation (DDLT) by Starzl et al2 in 1967. The initial intention was to obtain transplant organs of good quality when reliable organ preservation was not

available in the 1960s. However, despite a serious graft shortage, it took two decades for LDLT to come into clinical practice in 1989,3 underpinned by advances in surgical techniques and therapeutics. In DDLT, the shortage of paediatric liver grafts was particularly severe. To overcome size disparity between adult liver grafts and paediatric recipients, reduced-graft LT was devised by Bismuth and Houssin in 1984.4 Through extension of this concept, split-graft LT was developed by Pichlmayr et al in 1988.5 Experience gained from in situ donor hepatectomy in split-graft LT was subsequently applied to LDLT. However, graft harvesting from a living donor required much more technical ingenuity. The first success was achieved by Strong et al in July 1989.3 Later, a group led by Broelsch et al6 developed the first adult-tochild LDLT programme. Small series of adult-to-child LDLT were then reported in the United States7 and Europe.8 In Japan where deceased-donor graft donation was nonexistent and liver surgery was well-developed, LDLT flourished. For adult-to-adult LDLT, the left liver lobe

Address correspondence and reprint requests to Professor Chung Mau Lo, Queen Mary Hospital, 102 Pok Fu Lam Road, Hong Kong SAR, China. E-mail: [email protected] ● Date of acceptance: 4 August 2010 © 2010 Elsevier. All rights reserved.

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was used initially by the Hashikura group.9 However, adult-to-adult left-liver LDLT was often handicapped by inadequate graft size. In 1993, Kyoto reported their improvisation on the operating table of using the right liver lobe in a case of LDLT for a 9-year-old recipient.10 The intention was to avoid precarious arterial anatomy of the left lobe. The first case of adult-to-adult right-liver LDLT was performed at Queen Mary Hospital, Hong Kong, on 9 May 1996. The first series was reported shortly afterwards.11 A priori, the right liver graft design includes the middle hepatic vein. This design ensures excellent venous outflow capacity and thus addresses the problem of smallfor-size syndrome.12 Through continued development and innovation, graft and recipient survival of adult-toadult LDLT now compare favourably with those of DDLT. Recipients without hepatocellular carcinoma even have an excellent 5-year survival rate of 93.4%.13 From 1991 to 2008, a total of 414 cases of LDLT were carried out at Queen Mary Hospital (Figure 1).

donor death is too many for the transplant community, and there have been at least 19 known donor deaths.17 The changes in donors’ quality of life in comparison with their pre-donation state are less tangible.18 The long-term biological consequences of donor hepatectomy are yet to be completely established.19 Quantification of such is mandatory in defining the field strength of LDLT. Efforts to improve care of donors, while not depriving them of the chance of saving or improving the life of their beloved recipients, are worthy of investigation the transplant community. Liver donation from altruistic living donors (2 cases, 2008) demands even more caution in potential-donor assessment and preparation. The first paired donorinterchange LDLT in Hong Kong was performed at Queen Mary Hospital on 13 January 2009, in which two simultaneous transplants were achieved by interchange of donors to match the ABO blood group of the two respective recipients; one with acute liver failure and the other with Child–Pugh class C cirrhosis. The two donor and recipient operations were performed simultaneously.

Donor safety and well-being As the application of LDLT extended from children to adults, and from using the left lobe to using the right lobe, the dilemma between recipient success and donor risk came under the spotlight. The recipient needs a liver graft with at least 35% of his/her estimated liver volume to meet his/her metabolic requirements.14 However, the donor also needs to have a remnant liver > 30% of his/her original liver volume.15 The reported overall complication rate for LDLT donors is around 20% but was as high as 67% in one review.16 One

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Split-graft liver transplantation The initial idea of splitting a deceased-donor liver aimed at surgical reduction of the graft for transplantation to a paediatric or small-sized patient. However, in such a case, the remaining major portion of the liver graft was wasted. This reduction technique was later modified to create a left lateral segment (LLS) graft for a paediatric recipient and a right trisection (RTS) graft for an adult recipient at the

Deceased donor liver transplantation Sequential liver transplantation Living donor liver transplantation

60 50 40 30 20 10 0 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 Year

Figure 1. Liver transplantation at Queen Mary Hospital (1991–2008).

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same time. Pichlmayr et al5 and Bismuth et al20 were the first groups to report their experience in creating two grafts from one deceased-donor liver. Since then, many other studies have supported the use of this method to expand the donor pool.

The criteria for being a split-graft donor are more restricted. A deceased donor must be younger than 55 years old and haemodynamically stable. Other parameters for consideration of graft splitting include body weight, past medical history, results of liver function tests, and electrolyte balance.21 In general, 15–20% of donors are eligible for splitgraft LT.22 The requirements of organ quality are more demanding if full right and left split grafts are wanted.

inferior to the commonly quoted 80% graft and 90% recipient survival rates at 1 year for DDLT. Split-graft LT using LLS grafts and split-graft LT using RTS grafts have similar complications. With respect to biliary and vascular complications, LLS-graft split-graft LT, LLS-graft LDLT and paediatric whole-graft LT show similar outcomes. Yet, LLS grafts of split-graft LT have a higher incidence of primary non-function. For RTS grafts of splitgraft LT, the outcomes are more controversial. Encouraging results have come from a recent study by Corno et al published in 2006.25 The 5-year graft and patient survival rates for split-graft LT using RTS grafts were both 94%. In that series, RTS grafts were also transplanted to 10 paediatric recipients by split-graft LT. An excellent outcome with 100% 5-year graft and patient survival rates was achieved.

Liver transection

Adult–adult recipients

The splitting procedure can be broadly divided into in situ and ex situ splitting of the liver. The former has the advantage of shorter cold ischaemic time but a longer duration of the donor procedure. By convention, the ultimate outcome is production of an LLS graft that includes Couinaud segments 2 and 3 for a paediatric recipient, and an RTS graft that includes Couinaud segments 1 and 4–8 for an adult recipient. The line of splitting is to the right of the falciform ligament. With increasing concern to expand the donor pool for the adult population, some studies have tried to produce two grafts from one liver for two adult recipients, with a right graft including Couinaud segments 5–8 and a left graft with Couinaud segments 1–4. In such cases, the line of splitting is Cantlie’s line.23 Yersiz et al24 published their experience of 100 cases of in situ split-graft LT in 2003. In that series, 190 allografts were obtained from 100 livers from September 1991 to February 2003. The liver was divided in the conventional manner into LLS and RTS grafts. A total of 165 grafts (LLS: 94, RTS: 71) were transplanted into 105 children and 60 adults. For split-graft LT using LLS graft for paediatric patients, the 3-year graft survival rate was 64%, which was slightly inferior to the reported 73% in whole-graft LT and 71% in LDLT using LLS grafts (p = 0.12). The 3-year recipient survival rate for split-graft LT using LLS graft was 75%, whereas the whole-graft LT group had 81% survival and the LDLT group using LLS graft had 84% (p = 0.01). As to split-graft LT using RTS graft for adult recipients, the overall 1-year graft survival rate was 69%, whereas the 1-year recipient survival rate was 78%. The results were slightly

With initially successful experience in split-graft LT for adult–child recipients, split-graft LT has been extended to adult–adult recipients in order to alleviate the grave graft shortage for adult recipients, which accounts for > 95% of waiting-list deaths. In a study on split-graft LT for two adult recipients by Azoulay et al,26 there was no difference in graft survival between whole and right split grafts. The survival of left split grafts, however, was significantly lower at 2 years (43%) compared with whole grafts (85%; p = 0.003). For patient survival, there was no significant difference between patients who received whole grafts, right split grafts, or left split grafts at 2 years (85%, 74% and 64%, respectively), with the result of re-transplantation for failing left split grafts taken into account. At Queen Mary Hospital, a total of 260 cases of DDLT have been carried out in the past 17 years, among which, 229 were whole-graft LT, 21 were split-graft LT, and 10 were reduced-graft LT (Figure 2).

Criteria

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Extended donor criteria (EDCs) Traditional donor selection is based on the strict criteria laid down by the transplant registry. However, to meet the ever-increasing demand for liver donors, some centres have advocated relaxation of customary restrictions on donation for donor-pool expansion. Contrary to general belief, there are only a few absolute contraindications to liver donation. These include transmissible diseases and highgrade extracranial primary malignancies or metastases.

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Deceased donor reduced size liver transplantation n = 10 (1.5%)

Deceased donor split liver transplantation n = 21 (3.1%)

Deceased donor whole graft liver transplantation n = 229 (34%)

Living donor liver transplantation n = 410 (60.8%)

Sequential liver transplantation n = 4 (0.6%) Figure 2. Liver transplantation by different techniques at Queen Mary Hospital (1991–2008).

On the other hand, the suitability of a liver to be a graft is only limited by its gross functional or structural deficiency.

Donor characteristics At present, there is still no standard definition for EDCs. In general, EDCs signify donor characteristics that are associated with higher risks of graft failure or disease transmission, including age > 65 years, macrovesicular steatosis > 40%, serum sodium > 155 mmol/L, positive serological data, carcinoma outside the liver, donation after cardiac death, and split-graft LT.

Clinical trials A retrospective analysis of 116 standard-criteria recipients and 99 EDC recipients was conducted at the Center for Liver Disease and Transplantation in New York.27 The 3-year patient survival rate was 80% for standard-criteria recipients and 78% for EDC recipients (not significant). The EDC recipients demonstrated a higher incidence of graft failure that resulted in re-transplantation or death, but the difference did not reach statistical significance. The 3-year graft survival rates for both groups were exactly the same as the respective 3-year patient survival rates. Donor age > 40 years, donation after cardiac death and partial graft are factors that adversely affect graft survival. Grafts harvested under these criteria can well be utilised in recipients who have moderately severe illness and without hepatitis C.28

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Sequential LT In sequential LT, the first transplant is from a deceased or living donor to a recipient who has familial amyloidosis. This recipient is also a donor, called a domino donor, because his/her own liver is subsequently transplanted to another recipient, called the domino recipient, who has end-stage liver disease. The feasibility of such practice is based on the pathogenesis of familial amyloidosis. It is a disease caused by the mutated transthyretin gene, inducing adverse effects to blood vessels, nerve tissues and organs including the liver. However, the related symptoms usually take 20–30 years to develop. The technique of sequential LT was first developed by Furtado et al29 in 1995. In Queen Mary Hospital, until 2008, four cases of sequential LT had been carried out (Figure 2).

Technical challenges Most sequential LTs have living donors as first donors because deceased donors are very scarce. A major concern in domino LDLT is to ensure the safety of the living and the domino donors. The graft from a living donor is usually smaller than a deceased-donor graft. Furthermore, the vascular cuffs of a living-donor graft are shorter for anastomosis. As a result, it is necessary to leave the hepatic vessels as long as possible when removing the liver from the domino donor, which renders very short the vessels that are attached to the domino graft, thus causing technical

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difficulties in transplantation. Careful decision making during division of vessels, in addition to experience gained from LDLT can help to tackle this problem.

Results A review of sequential LT was published by Nunes et al in 2004.30 The series consisted of 41 cases among 207 transplants from April 1999 to December 2002. It confirmed the importance of sequential LT in increasing the number of available grafts for transplantation. The percentage of transplants was increased significantly from 12.5% in 1999 to 24.5% in 2002. Nevertheless, amyloidosis could be manifest in recipients as early as 2 years after transplantation, as reported by Goto et al.31 A study by Delahaye et al32 also has indicated that domino donors might not have their symptoms relieved, and those with prior cardiac sympathetic denervation might have further deterioration in the first 2 years.

Dual-graft LT Graft size is one of the major determining factors for a successful transplantation outcome, therefore it is essential that the recipient obtains a graft of appropriate size. In LDLT, the use of the right liver usually allows this criterion to be met, but the remaining left liver might be insufficient for the donor. If this happens, the donor should not be allowed to donate his/her liver. To tackle the problem of inadequate graft size, one innovative approach is to transplant the recipient with two left-lobe grafts from two donors. With this approach, dual-graft LT, the donors and the recipient can all have an appropriately sized liver after transplantation. In selected cases, the left lateral lobe can be used and donor morbidity is further reduced; successful cases have been reported.33

Donation after cardiac death A deceased donor is either heart-beating or non-heartbeating (cardiac-dead). Heart-beating death is determined by irreversible cessation of all brain functions, whereas cardiac death is characterized by simultaneous and irreversible unresponsiveness, apnoea, and absence of circulation. Organs harvested from cardiac-dead donors are subjected to longer warm ischaemia over the period from circulatory dysfunction and arrest to perfusion and cooling. A liver graft can only tolerate warm ischaemia of up to 30 minutes,34 therefore, the organ procurement procedure has to

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be performed swiftly to avoid extending the already longer warm ischaemic time. The Pittsburgh super-rapid technique features cannulation of the aorta and flushing with 5 L of cold University of Wisconsin solution. Premortem cannulation of femoral vessels allows infusion of preservation solution right after declaration of death.35

Maastricht categories In the early 1990s, investigators from the Netherlands described four categories of cardiac death, which are known as the Maastricht categories: (I) death on arrival; (II) unsuccessful resuscitation; (III) awaiting cardiac arrest; and (IV) cardiac arrest while brain dead.36 The fourth category includes unsuccessful resuscitation after unexpected cardiac arrest in intensive care. The first, second and fourth categories are categorized as the uncontrolled group in which cardiac death is unexpected. Warm ischaemic time for organs harvested from this group is variable but often long. Conversely, the third group is termed the controlled group because the organ retrieval team can be mobilized prior to withdrawal of life support to the donor, and warm ischaemia is not prolonged. Lately, most cardiac deaths in reported series of post-cardiac-death organ donation have belonged to the controlled group.

Results The Pittsburgh programme was among the first to report the results of cardiac-death LT. In 1995, a series of six controlled-cardiac-death-liver recipients had a graft survival rate of 50%.35 In a study in 2000, the Madison programme compared 19 cases of controlled-cardiac-death LT with 364 cases of heart-beating-donor LT.37 The 3-year patient survival rate of the cardiac-death group was similar to that of the heart-beating-donor group (72.6% vs. 84.8%, p = 0.36). The 3-year graft survival rate, however, was lower in the cardiac-death group (53.8% vs. 80.9%, p = 0.007). It is worth noting that half of the graft losses were due to patient death with normal liver graft function. Subsequent reports from 2000 to 2004 showed that the graft and patient survival rates after cardiac-death LT ranged from 53.8% to 100% and 72.6% to 100%, respectively.38 A recent series from Philadelphia39 has compared 16 cases of controlled-cardiac-death LT with 221 of heartbeating-donor LT. The patient and graft survival rates after 3 years were similar between the two groups. The graft survival rates were 71.8% and 73.9% (p = 0.68), respectively, and the patient survival rates were 79.0% and 77.0% (p = 0.8).

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Common complications Three types of graft-related complications after cardiacdeath LT have been reported: complications of vascular origin, primary nonfunction, and biliary strictures. Vascular complications are mainly hepatic artery thrombosis. According to various studies, the occurrence of hepatic artery thrombosis after cardiac-death LT can be as high as 5.3%.37 Cardiac-death liver grafts have a higher primary non-function rate. Studies have reported a 6.7–10.5% primary nonfunction rate in a cardiac-death group, whereas it was 1.3–3.6% in the corresponding heart-beating-donor group.37,39,40 This outcome was likely to have been a result of prolonged warm ischaemia in the cardiac-death group. In a study by Abt et al,39 the rate of major biliary complications in the cardiac-death group was 33.3% (5/25 patients) and that in the heart-beatingdonor group was 9.5% (21/221 patients; p < 0.01). The heart-beating-donor group had a higher rate of anastomotic stricture (46.2% vs. 16.7%), whereas the cardiacdeath group had a higher rate of ischaemic-type stricture (66.6% vs. 19.2%). Intrahepatic ischaemic stricture is related to warm ischaemic time, therefore, it is not surprising that patients in the cardiac-death group suffered more ischaemic-type biliary stricture.

system can extend the waiting time for several days, it cannot replace transplantation. In paediatric patients, the commonest cause for LT is biliary atresia, for which the Kasai operation might not be curative in the long term, but an initial successful operation can delay the need for LT for a few years by making the patient’s condition less critical. To ease the heavy demand for liver grafts, reducing the need for LT should be the primary strategy. To reduce the need for LT, we should strive to minimize the chances of cirrhosis, hepatocellular carcinoma, and liver failure. This can be achieved by effective screening of patients with hepatitis B or C and give them proper therapies.

Conclusion In the near future, liver donation will be mainly from brain-dead donors in the west and living donors in the east. Through education and motivation, the supply of deceased-donor livers might increase and therefore promote DDLT. As to LDLT, the use of marginal, split, sequential and cardiac-death grafts boosts its use markedly. The cost-effectiveness of LDLT will improve with better survival of recipients and lower risks for donors. These can be attained through continuing audit and research on LDLT.

Ethical issues Controversy remains in defining controlled cardiac death as to whether loss of cardiac electrical activity or absence of heart sounds, pulse and blood pressure is sufficient. The waiting time after cardiac arrest is also variably determined. The Maastricht workshop has maintained that 10 minutes are required,36 whereas the group from King’s College Hospital (London, UK) waits for only 5 minutes,41 and the Pittsburgh group for 2 minutes.42 The 5-minute and 10-minute periods have the benefit of rendering cardiac death de facto brain-dead. The results of cardiac-death LT are constantly improving. Further refinements in donor selection, graft procurement and ethical guidelines should strengthen cardiac-death LT as a valuable clinical endeavour.

Artificial organ support and others The molecular adsorbents recirculating system works as a bridge to LT by keeping a potential recipient’s condition suitable for transplantation during the waiting time that might be extended for various reasons.43 Although this

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26. Azoulay D, Castaing D, Adam R, et al. Split-liver transplantation for two adult recipients: feasibility and long-term outcomes. Ann Surg 2001;233:565–74. 27. Renz JF, Kin C, Kinkhabwala M, et al. Utilization of extended donor criteria liver allografts maximizes donor use and patient access to liver transplantation. Ann Surg 2005;242:556–63. 28. Feng S, Goodrich NP, Bragg-Gresham JL, et al. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant 2006;6:783–90. 29. Furtado L, Oliveira F, Furtado E, et al. Maximum sharing of cadaver liver grafts composite split and domino liver transplants. Liver Transpl Surg 1999;5:157–8. 30. Nunes F, Valente M, Pereira R, et al. Domino liver transplant: influence on the number of donors and transplant coordination. Transplant Proc 2004;36:916–7. 31. Goto T, Yamashita T, Ueda M, et al. Iatrogenic amyloid neuropathy in a Japanese patient after sequential liver transplantation. Am J Transplant 2006;6:2512–5. 32. Delahaye N, Rouzet F, Sarda L, et al. Impact of liver transplantation on cardiac autonomic denervation in familial amyloid polyneuropathy. Medicine (Baltimore) 2006;85:229–38. 33. Lee SG, Hwang S, Park KM, et al. An adult-to-adult living donor liver transplant using dual left lobe grafts. Surgery 2001;129:647–53. 34. Monbaliu D, Crabbe T, Roskams T, et al. Livers from non-heartbeating donors tolerate short periods of warm ischemia. Transplantation 2005;79:1226–30. 35. Casavilla A, Ramirez C, Shapiro R, et al. Experience with liver and kidney allografts from non-heart-beating donors. Transplant Proc 1995;27:2898. 36. Kootstra G, Daemen JH, Oomen AP. Categories of non-heartbeating donors. Transplant Proc 1995;27:2893–4. 37. D’Alessandro AM, Hoffmann RM, Knechtle SJ, et al. Liver transplantation from controlled non-heart-beating donors. Surgery 2000;128:579–88. 38. Reddy S, Zilvetti M, Brockmann J, et al. Liver transplantation from non-heart-beating donors: current status and future prospects. Liver Transpl 2004;10:1223–32. 39. Abt P, Crawford M, Desai N, et al. Liver transplantation from controlled non-heart-beating donors: an increased incidence of biliary complications. Transplantation 2003;75:1659–63. 40. Fukumori T, Kato T, Levi D, et al. Use of older controlled nonheart-beating donors for liver transplantation. Transplantation 2003;75:1171–4. 41. Muiesan P, Girlanda R, Jassem W, et al. Single-center experience with liver transplantation from controlled non-heartbeating donors: a viable source of grafts. Ann Surg 2005;242:732–8. 42. Bell MD. Non-heart beating organ donation: old procurement strategy—new ethical problems. J Med Ethics 2003;29:176–81. 43. Chiu A, Tsoi NS, Fan ST. Use of the molecular adsorbents recirculating system as a treatment for acute decompensated Wilson disease. Liver Transpl 2008;14:1512–6.

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