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Evaluation of graft and recipient risk factors in liver transplantation
Digestive and Liver Disease Supplements 3 (2009) 108–111
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Evaluation of graft and recipient risk factors in liver transplantation P. Burra *, E. De Martin, M. Senzolo Gastroenterology, Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences University Hospital, Padova, Italy
Abstract Donor–recipient matching is an important factor influencing the outcome of liver transplantation (LT), especially when, due to organ shortage, extended criteria donors (ECD) are used. Among donor risk factors, donor age has been associated with severe HCV recurrence after LT, and severe steatosis increases the risk of NAFLD after LT and impairs liver regeneration when partial liver is used. Grafts from HCV positive donors can be used (in absence of fibrosis) in HCV positive recipients; however, attention should be paid when donor age is over 50. Anti-HB core positive grafts are used in patients with HBsAg or anti-HBc patients with long term prophylaxis to prevent recurrence. The use of partial (living or cadaveric) livers is marginal in western countries but seems not to worsen prognosis. Decision whether to allocate ECD to sickest or healthiest recipients is still a matter of debate in terms of outcome and utility, therefore dedicated studies are needed. © 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Donor age; HBV; HCV; Liver transplantation; Split liver; Steatosis
1. Introduction The policy for allocating organs to candidates for liver transplantation (LT) is based on principles of utility, equity, containment of waiting list mortality, and benefit deriving from the transplant, in a constant effort to obtain a balance between individual justice and the common good. The shortage of organs, in part with the increasing demand for LT, has prompted the use not only of optimal donors, but also of extended criteria donors (ECD, i.e. donors with risk factors). A donor risk index (DRI) has been developed as expression of the factors associated with graft failure after LT, indicating that donor age over 40 years (and particularly over 60 years), donation after cardiac death and split/partial grafts are factors strongly associated with worse outcome after LT [1]. To take advantage of the organs available, donor–recipient matching (i.e. combining donor and recipient profiles) seems to be crucial [2]. * Correspondence to: Patrizia Burra, MD, PhD, Gastroenterology, Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences University Hospital, Via Giustiniani 2, 35128 Padova, Italy. Tel.: +39-049-8212892, fax: +39-049-8760820. E-mail address: [email protected] (P. Burra).
Donor and graft factors which influence transplant outcome, and thus should be considered for the purposes of donor–recipient matching, are: the donor’s age, steatosis in the graft, infections (HCV and HBV) in the donor, and any use of partial LT (living-related liver transplants and the split-liver technique).
2. Donor age The donor’s age is not a limiting factor per se. A donor–recipient liver matching study conducted in Italy, coordinated by the Italian Association for the Study of the Liver (AISF) and the National Transplant Center (CNT), reported that 41% of organs come from donors over 60 years of age and 21% of donors are over 70 years of age [3]. However, the use of older donors may influence the liver’s ability to regenerate and the use of grafts from donors over 60 years of age has been associated with poor outcome regardless the cause of primary liver disease [1]. Several studies have confirmed the negative impact of advanced donor age (>70 years) on time of HCV recurrence after LT [4], while others reported inferior graft and patient survival when donors older than 50 years are used [5].
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P. Burra et al. / Digestive and Liver Disease Supplements 3 (2009) 108–111
Moreover, the matching of older donor and advanced recipient age is a positive predictor of graft failure after LT in HCV positive recipients [6]. Although we should consider all potential donors, accurate matching with the proper recipient is suggested.
3. Donor steatosis In the experience of the Padova Liver Transplant Center, nearly 50% of donor grafts have steatosis (39.6% mild, 9.5% moderate/severe). Steatosis seems to be a good parameter for defining marginal organs, but in our experience survival was not lower in patients who received organs with steatosis, although we did observe a worse trend (albeit lacking in statistical significance) in terms of 3-year patient survival in HCV+ recipients of grafts with moderate/severe steatosis and donor age ≥50 versus <50 years [7]. The use of grafts with severe steatosis in urgent cases of retransplantation has been associated with primary non-function in 100% of cases [8]. Therefore, judging from previous experience, a significantly worse prognosis is to be expected in the event of multiple risk factors being associated. In fact, graft and patient survival have been lower when >15% of macrovesicular steatosis was associated with a total ischemia time >10 hours, donor age >65 years and HCV-positive recipient [9]. Evaluation of macrosteatosis is crucial for patients who undergo partial LT (as in living-donor or split-liver transplants), especially because severe steatosis can increase hepatocellular damage and impair liver regeneration in animal models of partial hepatectomy [10]. A still controversial issue concerns the reduction of steatosis in the graft after transplantation. A recent study reported that the amount of steatosis found at follow-up liver biopsies decreased significantly, from 90% to 15% [11]. As for the problem of liver steatosis, it is well known that obesity, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are common complications after LT. It has been calculated that NAFLD and NASH may develop in 25% and 16%, respectively, of patients transplanted for cryptogenic cirrhosis [12]. A recent study reported the correlation between a more than 10% increase in body mass index (BMI) after LT and the onset of NAFLD [13]. The increase in body weight after LT is due to numerous factors, such as insulin resistance, diabetes mellitus, and the metabolic effects of immunosuppressive therapy (corticosteroids, calcineurin inhibitors). In such cases, it is hard to say whether the presence of fatty liver following transplantation represents the recurrence of primary liver disease or the onset of a de novo NALFD/NASH, or the consequences of donor graft steatosis.
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4. HCV and HBV positive donor Anti-HCV positive donors can be used for anti-HCV positive recipients with no more negative fallout on the outcome than if the graft were an anti-HCV negative graft, although they show more severe fibrosis progression in the same length of follow-up, as reported in a case-control study. Moreover, more severe fibrosis progression, and a higher rate of retransplantation and death was reported in 29 HCV positive recipients of HCV positive donors with age >50 years, compared to younger donors [14]. Anti-HB core positive donors are used for recipients who have already come into contact with hepatitis B virus and are hepatitis B surface antigen (HBsAg) positive, or anti-HB core positive or anti-HB core and anti-HBs positive. When an anti-HB core positive donor is used in an HBsAg negative recipient, HBV reactivation is avoided by prophylaxis therapy with only nucleos(t)ide analogues or only hepatitis B immunoglobulin (HBIG), though many different strategies are adopted around the world. A recent study compared the prophylactic strategies adopted to prevent HBV infection at different liver transplant centers in the US and Europe. By interviewing 78 specialists it was found that all specialists reported using nucleoside analogue therapy; 65% of them preferred lamivudine (58% US vs 81% non-US, p = 0.05); 81% used nucleoside analogue therapy for an indefinite period; 61% used HBIG (38% always, 23% sometimes) in association with the nucleoside analogue. HBIG is used more frequently in the US than in other parts of the world (69% vs 46%, p = 0.03), and the duration of HBIG treatment varies widely. In anti-HBs+ or anti-HBs+ and anti-HBc+ recipients some centers omit nucleoside analogue or HBIG therapy [15]. An HBsAg positive donor can be allocated to an HBsAg positive recipient without HDV infection. Prophylactic strategy to prevent HBV recurrence is not different from the common clinical practice in patients transplanted for HBV liver cirrhosis.
5. Split-liver graft Partial LT is not considered a standard transplant procedure but it is commonly used to increase organ availability. In previous studies, living-donor liver transplants (LDLT) in HCV-positive recipients have been associated with more severe HCV recurrences than in recipients transplanted with deceased-donor livers (DDLT) [16]. This was supposed to be due to the influence of liver regeneration on HCV replication. More recently, however, no differences were found in terms of fibrosis progression in HCV-positive recipients when LDLT was compared with DDLT [17], nor in graft survival [18]. Similar results were reported by the North Italian Transplant program (NITp) in Italy, describing a similar
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3-year patient survival in HCV positive patients who underwent LDLT or DDLT [19]. Moreover, no difference in patient survival was seen in HCV positive recipients who underwent split-liver transplantation compared with whole liver transplantation in another study [20]. In a study conducted at UCLA, long-term outcomes of 55 left-lateral segment and right-trisegment grafts were compared with 600 whole graft transplants: 3-year patient survival did not differ significantly, but at multivariate analysis 3-year survival was 90% for non-urgent split-graft recipients and 65% for urgent split-graft recipients [21]. In the NITp experience in Italy, 3-year graft and patient survival was assessed in 300 split-liver recipients with a median follow-up of 22 months and was found to be much the same in the recipients of a left-lateral segment as in whole graft recipients. At multivariate analysis, the independent predictors of survival were advanced donor age (>60 years old), urgent transplantation, prolonged cold ischemia time (>7 hours), retransplantation and low transplant center volume (<50 transplants per year) [22], similarly to already known risk factors for mortality in whole liver transplantation.
6. Donor–recipient matching Different scores have been proposed with a view to establishing objective criteria for prioritizing patients on the waiting list for liver transplantation. The Model for End-Stage Liver Disease (MELD) scoring system was introduced in 2002 based on its correlation with 3-month mortality on the waiting list. More recently, donor status has been assessed by means of the donor risk index (DRI), and liver transplant outcome evaluation is based, in many LT centers, on matching the MELD and the DRI. A recipient with a low MELD score who receives an organ from a donor with a high DRI has no survival benefit, whereas a recipient with a high MELD score would gain from the transplant by comparison with the alternative of remaining on the waiting list whatever the donor’s DRI [23]. However, concerns about the possibility that the sickest patient could have worse outcome with a suboptimal donor should be considered. The AISF/CNT Italian study found a median DRI of 1.6 in donors used for LT with no differences between the indexes recorded at 3 organ allocation agencies in Italy. No correlation between DRI-recipients’ MELD scores at the time of the transplant could be demonstrated. When recipients were grouped according to their MELD score at the time of the transplant (<17 vs ≥17), the distribution of grafts was similar in terms of all donor variables except for split liver (7.3% to MELD <17 and 3.8% to MELD ≥17 recipients) [3]. Two attitudes on ECD use in different liver recipients have been put forward during a recent consensus meeting by the International Liver Transplant Society (ILTS): (1)
should ECD be used for the healthiest recipients, who can tolerate a more difficult postoperative course, even though they can also wait for a better graft? or (2) should ECD be used for the sickest recipients, who will soon die without an organ donation (the choice is acceptable because no synergistically adverse interactions between DRI and MELD were identified) but who are unlikely to endure a difficult postoperative course? [24]. The allocation of ECD organs to the sickest patients thus remains a matter of debate. In fact, assigning steatotic livers by means of the MELD score suggests that grafts with >30% fatty infiltration can be used safely in low-risk recipients, but these organs should be rejected for use in recipients with MELD scores >30 [25,26]. A recent study based on a mathematical model was published regarding recipients with low MELD scores. The authors generated a simulation model that censored patients with MELD scores ≤14 from the waiting list for transplantation. This “Rule 14” policy led to a 3% improvement in patient survival at 1, 2, 3, and 4 years, and predicted a 13% reduction in the time on the waiting list for patients with MELD scores between 15 and 40. The greatest benefit of the a “Rule 14” policy was seen in patients with MELD scores between 6 and 10, for whom a 17% survival advantage was predicted for waiting on the list versus undergoing LT [27]. A new score for matching donors and recipients has consequently been proposed, called the D-MELD, which is the product of the donor’s age and the recipient’s preoperative MELD score. This DMELD score effectively stratified post-transplant survival. Using a cut-off of 1600, the authors identified a subgroup of donor–recipient matches with significantly worse short and long-term outcomes, as measured by survival and length of hospital stay, particularly for HCV positive recipients, indicating that the match at highest risk is a donor over 60 years old and a recipient with a MELD score greater than 30 [28]. The need for equity in organ allocation has led the Organ Procurement and Transplantation Network (OPTN) to oversee liver organ donation and transplantation in the US. The proliferation of regulations certainly leads to rising costs for the healthcare system, but it remains to be seen whether there is any consequent improvement in quality of care and patient outcomes. Future efforts will concentrate on more in-depth analyses of donor-related risks and outcomes, and more focused recommendations based on data that are being collected [29]. Matas gave some thought to the word allocation used in the transplant setting, which means a process of distributing something, and he proposed replacing it with the word rationing, which means a “controlled distribution of resources and scarce goods and services”, and thus implies a shortage that cannot be ignored, meaning that some transplant candidates will receive an organ and some will not [30]. Donation is a concept which seems stuck on past paradigms, and effective organizations in recent years have
P. Burra et al. / Digestive and Liver Disease Supplements 3 (2009) 108–111
become bureaucratic. What the transplant community needs is more people and resources to take care of donors and recipients, and a constant research effort to seek further advances [31]. Further investments are also needed to awaken public opinion concerning donation. Finally, international guidelines on how to define ECD organs and decide on their allocation should be agreed among expert transplant physicians and surgeons.
[15]
[16]
[17]
Conflict of interest The authors have no actual or potential conflict of interest relevant to this paper.
[18]
[19]
References [1] Feng S, Goodrich NP, Bragg-Gresham JL, et al. Characteristics associated with liver graft failure: the concept of a donor risk index. Am. J. Transpl 2006;6:783–790. [2] Burra P, Porte R, Should donors and recipients be matched in liver transplantation? J Hepatol 2006;45:488–94. [3] Angelico M, Marianelli T, Ricci A. A national survey on the quality of deceased liver donors and their allocation in relation to recipients disease severity in Italy J. Hepatol 2009;50:S167. [4] Ercolani G, Grazi GL, Ravaioli M, et al. Histological recurrent hepatitis C after liver transplantation: outcome and role of retransplantation. Liver Transpl 2006;12:1104–11. [5] Mutimer DJ, Gunson B, Chen J, et al. Impact of donor age and year of transplantation on graft and patient survival following liver transplantation for hepatitis C virus. Transplantation 2006;81:7–14. [6] Condron SL, Heneghan MA, Patel K, et al. Effect of donor age on survival of liver transplant recipients with hepatitis C virus infection. Transplantation 2005;80:145–8. [7] Burra P, Loreno M, Russo FP, et al. Donor livers with steatosis are safe to use in HCV-positive recipients. Liver Transpl 2009;15:619– 28. [8] Yoong KF, Gunson BK, Neil DA, et al. Impact of donor liver microvesicular steatosis on the outcome of liver retransplantation. Transplant Proc 1999;31:550–1. [9] Salizzoni M, Franchello A, Zamboni F, et al. Marginal grafts: finding the correct treatment for fatty livers. Transpl Int 2003;16:486–93. [10] Veteläinen R, van Vliet AK, van Gulik TM. Severe steatosis increases hepatocellular injury and impairs liver regeneration in a rat model of partial hepatectomy. Ann Surg 2007;245:44–50. [11] McCormack L, Petrowsky H, Jochum W, et al. Use of severely steatotic grafts in liver transplantation: a matched case-control study. Ann Surg 2007;246:940–6. [12] Ong J, Younossi ZM, Reddy V, et al. Cryptogenic cirrhosis and posttransplantation nonalcoholic fatty liver disease. Liver Transpl 2001;7:797–801. [13] Seo S, Maganti K, Khehra M, et al. De novo nonalcoholic fatty liver disease after liver transplantation. Liver Transpl 2007;13:844–7. [14] Khapra AP, Agarwal K, Fiel MI, et al. Impact of donor age on
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survival and fibrosis progression in patients with hepatitis C undergoing liver transplantation using HCV+ allografts. Liver Transpl 2006;12:1496–503. Perrillo R. Hepatitis B virus prevention strategies for antibody to hepatitis B core antigen-positive liver donation: a survey of North American, European, and Asian–Pacific transplant programs. Liver Transpl 2009;15:223–32. Garcia-Retortillo M, Forns X, Llovet JM, et al. Hepatitis C recurrence is more severe after living donor compared to cadaveric liver transplantation. Hepatology 2004;40:699–707. Schmeding M, Neumann UP, Puhl G, et al. Hepatitis C recurrence and fibrosis progression are not increased after living donor liver transplantation: a single-center study of 289 patients. Liver Transpl 2007;13:687–92. Terrault NA, Shiffman ML, Lok AS, et al. Outcomes in hepatitis C virus-infected recipients of living donor vs. deceased donor liver transplantation. Liver Transpl 2007;13:122–9. De Feo TM, De Fazio N, Brolese A, et al. Cadaveric and living donor split transplantation from cadaver and living donor in HCV plus recipients: a multicenter experience of an Italian transplant agency. Transpl Int 2008;21:6-6 Suppl. Lawal A, Ghobrial R, Te H, et al. Comparison of hepatitis C histological recurrence rates and patient survival between split and deceased donor liver transplantation. Transplant Proc 2007;39(10):3261–5. Ghobrial RM, Farmer DG, Amersi F, Busuttil RW. Advances in pediatric liver and intestinal transplantation. Am J Surg 2000;180(5):328–34. Cardillo M, De Fazio N, Pedotti P, et al. Split and whole liver transplantation outcomes: a comparative cohort study. NITp Transplantation Working Group. Liver Transpl 2006;12:402–10. Pomfret EA, Sung RS, Allan J, et al. Solving the organ shortage crisis: the 7th annual American Society of Transplant Surgeons’ State-of-the-Art Winter Symposium. Am J Transplant 2008;8:745– 52. Durand F, Renz JF, Alkofer B, et al. Report of the Paris consensus meeting on expanded criteria donors in liver transplantation. Liver Transpl 2008;14:1694–707. Briceño J, Padillo J, Rufián S, et al. Assignment of steatotic livers by the Mayo model for end-stage liver disease. Transpl Int 2005;18:577–83. Nocito A, El-Badry AM, Clavien PA. When is steatosis too much for transplantation? J Hepatol 2006;45:494–9. Perkins JD, Halldorson JB, Bakthavatsalam R, et al. Should liver transplantation in patients with model for end-stage liver disease scores < or = 14 be avoided? A decision analysis approach. Liver Transpl 2009;15:242–54. Halldorson JB, Bakthavatsalam R, Fix O, et al. D-MELD, a simple predictor of post liver transplant mortality for optimization of donor/recipient matching. Am J Transplant 2009;9:318–26. Klintmalm GB, Abecassis MM. Transplantation oversight-finding the right balance between the layperson, the transplant professional and the regulator. Am J Transplant 2009;9:5–6. Matas AJ. Allocation or rationing-word choice is crucial. Am J Transplant 2009;9:9–10. Bromberg JS, Halloran PF. Nine things you might not say or hear in transplantation. Am J Transplant 2009;9:11–3.
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Evaluation of graft and recipient risk factors in liver transplantation P. Burra *, E. De Martin, M. Senzolo Gastroenterology, Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences University Hospital, Padova, Italy
Abstract Donor–recipient matching is an important factor influencing the outcome of liver transplantation (LT), especially when, due to organ shortage, extended criteria donors (ECD) are used. Among donor risk factors, donor age has been associated with severe HCV recurrence after LT, and severe steatosis increases the risk of NAFLD after LT and impairs liver regeneration when partial liver is used. Grafts from HCV positive donors can be used (in absence of fibrosis) in HCV positive recipients; however, attention should be paid when donor age is over 50. Anti-HB core positive grafts are used in patients with HBsAg or anti-HBc patients with long term prophylaxis to prevent recurrence. The use of partial (living or cadaveric) livers is marginal in western countries but seems not to worsen prognosis. Decision whether to allocate ECD to sickest or healthiest recipients is still a matter of debate in terms of outcome and utility, therefore dedicated studies are needed. © 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Donor age; HBV; HCV; Liver transplantation; Split liver; Steatosis
1. Introduction The policy for allocating organs to candidates for liver transplantation (LT) is based on principles of utility, equity, containment of waiting list mortality, and benefit deriving from the transplant, in a constant effort to obtain a balance between individual justice and the common good. The shortage of organs, in part with the increasing demand for LT, has prompted the use not only of optimal donors, but also of extended criteria donors (ECD, i.e. donors with risk factors). A donor risk index (DRI) has been developed as expression of the factors associated with graft failure after LT, indicating that donor age over 40 years (and particularly over 60 years), donation after cardiac death and split/partial grafts are factors strongly associated with worse outcome after LT [1]. To take advantage of the organs available, donor–recipient matching (i.e. combining donor and recipient profiles) seems to be crucial [2]. * Correspondence to: Patrizia Burra, MD, PhD, Gastroenterology, Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences University Hospital, Via Giustiniani 2, 35128 Padova, Italy. Tel.: +39-049-8212892, fax: +39-049-8760820. E-mail address: [email protected] (P. Burra).
Donor and graft factors which influence transplant outcome, and thus should be considered for the purposes of donor–recipient matching, are: the donor’s age, steatosis in the graft, infections (HCV and HBV) in the donor, and any use of partial LT (living-related liver transplants and the split-liver technique).
2. Donor age The donor’s age is not a limiting factor per se. A donor–recipient liver matching study conducted in Italy, coordinated by the Italian Association for the Study of the Liver (AISF) and the National Transplant Center (CNT), reported that 41% of organs come from donors over 60 years of age and 21% of donors are over 70 years of age [3]. However, the use of older donors may influence the liver’s ability to regenerate and the use of grafts from donors over 60 years of age has been associated with poor outcome regardless the cause of primary liver disease [1]. Several studies have confirmed the negative impact of advanced donor age (>70 years) on time of HCV recurrence after LT [4], while others reported inferior graft and patient survival when donors older than 50 years are used [5].
© 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
P. Burra et al. / Digestive and Liver Disease Supplements 3 (2009) 108–111
Moreover, the matching of older donor and advanced recipient age is a positive predictor of graft failure after LT in HCV positive recipients [6]. Although we should consider all potential donors, accurate matching with the proper recipient is suggested.
3. Donor steatosis In the experience of the Padova Liver Transplant Center, nearly 50% of donor grafts have steatosis (39.6% mild, 9.5% moderate/severe). Steatosis seems to be a good parameter for defining marginal organs, but in our experience survival was not lower in patients who received organs with steatosis, although we did observe a worse trend (albeit lacking in statistical significance) in terms of 3-year patient survival in HCV+ recipients of grafts with moderate/severe steatosis and donor age ≥50 versus <50 years [7]. The use of grafts with severe steatosis in urgent cases of retransplantation has been associated with primary non-function in 100% of cases [8]. Therefore, judging from previous experience, a significantly worse prognosis is to be expected in the event of multiple risk factors being associated. In fact, graft and patient survival have been lower when >15% of macrovesicular steatosis was associated with a total ischemia time >10 hours, donor age >65 years and HCV-positive recipient [9]. Evaluation of macrosteatosis is crucial for patients who undergo partial LT (as in living-donor or split-liver transplants), especially because severe steatosis can increase hepatocellular damage and impair liver regeneration in animal models of partial hepatectomy [10]. A still controversial issue concerns the reduction of steatosis in the graft after transplantation. A recent study reported that the amount of steatosis found at follow-up liver biopsies decreased significantly, from 90% to 15% [11]. As for the problem of liver steatosis, it is well known that obesity, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are common complications after LT. It has been calculated that NAFLD and NASH may develop in 25% and 16%, respectively, of patients transplanted for cryptogenic cirrhosis [12]. A recent study reported the correlation between a more than 10% increase in body mass index (BMI) after LT and the onset of NAFLD [13]. The increase in body weight after LT is due to numerous factors, such as insulin resistance, diabetes mellitus, and the metabolic effects of immunosuppressive therapy (corticosteroids, calcineurin inhibitors). In such cases, it is hard to say whether the presence of fatty liver following transplantation represents the recurrence of primary liver disease or the onset of a de novo NALFD/NASH, or the consequences of donor graft steatosis.
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4. HCV and HBV positive donor Anti-HCV positive donors can be used for anti-HCV positive recipients with no more negative fallout on the outcome than if the graft were an anti-HCV negative graft, although they show more severe fibrosis progression in the same length of follow-up, as reported in a case-control study. Moreover, more severe fibrosis progression, and a higher rate of retransplantation and death was reported in 29 HCV positive recipients of HCV positive donors with age >50 years, compared to younger donors [14]. Anti-HB core positive donors are used for recipients who have already come into contact with hepatitis B virus and are hepatitis B surface antigen (HBsAg) positive, or anti-HB core positive or anti-HB core and anti-HBs positive. When an anti-HB core positive donor is used in an HBsAg negative recipient, HBV reactivation is avoided by prophylaxis therapy with only nucleos(t)ide analogues or only hepatitis B immunoglobulin (HBIG), though many different strategies are adopted around the world. A recent study compared the prophylactic strategies adopted to prevent HBV infection at different liver transplant centers in the US and Europe. By interviewing 78 specialists it was found that all specialists reported using nucleoside analogue therapy; 65% of them preferred lamivudine (58% US vs 81% non-US, p = 0.05); 81% used nucleoside analogue therapy for an indefinite period; 61% used HBIG (38% always, 23% sometimes) in association with the nucleoside analogue. HBIG is used more frequently in the US than in other parts of the world (69% vs 46%, p = 0.03), and the duration of HBIG treatment varies widely. In anti-HBs+ or anti-HBs+ and anti-HBc+ recipients some centers omit nucleoside analogue or HBIG therapy [15]. An HBsAg positive donor can be allocated to an HBsAg positive recipient without HDV infection. Prophylactic strategy to prevent HBV recurrence is not different from the common clinical practice in patients transplanted for HBV liver cirrhosis.
5. Split-liver graft Partial LT is not considered a standard transplant procedure but it is commonly used to increase organ availability. In previous studies, living-donor liver transplants (LDLT) in HCV-positive recipients have been associated with more severe HCV recurrences than in recipients transplanted with deceased-donor livers (DDLT) [16]. This was supposed to be due to the influence of liver regeneration on HCV replication. More recently, however, no differences were found in terms of fibrosis progression in HCV-positive recipients when LDLT was compared with DDLT [17], nor in graft survival [18]. Similar results were reported by the North Italian Transplant program (NITp) in Italy, describing a similar
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3-year patient survival in HCV positive patients who underwent LDLT or DDLT [19]. Moreover, no difference in patient survival was seen in HCV positive recipients who underwent split-liver transplantation compared with whole liver transplantation in another study [20]. In a study conducted at UCLA, long-term outcomes of 55 left-lateral segment and right-trisegment grafts were compared with 600 whole graft transplants: 3-year patient survival did not differ significantly, but at multivariate analysis 3-year survival was 90% for non-urgent split-graft recipients and 65% for urgent split-graft recipients [21]. In the NITp experience in Italy, 3-year graft and patient survival was assessed in 300 split-liver recipients with a median follow-up of 22 months and was found to be much the same in the recipients of a left-lateral segment as in whole graft recipients. At multivariate analysis, the independent predictors of survival were advanced donor age (>60 years old), urgent transplantation, prolonged cold ischemia time (>7 hours), retransplantation and low transplant center volume (<50 transplants per year) [22], similarly to already known risk factors for mortality in whole liver transplantation.
6. Donor–recipient matching Different scores have been proposed with a view to establishing objective criteria for prioritizing patients on the waiting list for liver transplantation. The Model for End-Stage Liver Disease (MELD) scoring system was introduced in 2002 based on its correlation with 3-month mortality on the waiting list. More recently, donor status has been assessed by means of the donor risk index (DRI), and liver transplant outcome evaluation is based, in many LT centers, on matching the MELD and the DRI. A recipient with a low MELD score who receives an organ from a donor with a high DRI has no survival benefit, whereas a recipient with a high MELD score would gain from the transplant by comparison with the alternative of remaining on the waiting list whatever the donor’s DRI [23]. However, concerns about the possibility that the sickest patient could have worse outcome with a suboptimal donor should be considered. The AISF/CNT Italian study found a median DRI of 1.6 in donors used for LT with no differences between the indexes recorded at 3 organ allocation agencies in Italy. No correlation between DRI-recipients’ MELD scores at the time of the transplant could be demonstrated. When recipients were grouped according to their MELD score at the time of the transplant (<17 vs ≥17), the distribution of grafts was similar in terms of all donor variables except for split liver (7.3% to MELD <17 and 3.8% to MELD ≥17 recipients) [3]. Two attitudes on ECD use in different liver recipients have been put forward during a recent consensus meeting by the International Liver Transplant Society (ILTS): (1)
should ECD be used for the healthiest recipients, who can tolerate a more difficult postoperative course, even though they can also wait for a better graft? or (2) should ECD be used for the sickest recipients, who will soon die without an organ donation (the choice is acceptable because no synergistically adverse interactions between DRI and MELD were identified) but who are unlikely to endure a difficult postoperative course? [24]. The allocation of ECD organs to the sickest patients thus remains a matter of debate. In fact, assigning steatotic livers by means of the MELD score suggests that grafts with >30% fatty infiltration can be used safely in low-risk recipients, but these organs should be rejected for use in recipients with MELD scores >30 [25,26]. A recent study based on a mathematical model was published regarding recipients with low MELD scores. The authors generated a simulation model that censored patients with MELD scores ≤14 from the waiting list for transplantation. This “Rule 14” policy led to a 3% improvement in patient survival at 1, 2, 3, and 4 years, and predicted a 13% reduction in the time on the waiting list for patients with MELD scores between 15 and 40. The greatest benefit of the a “Rule 14” policy was seen in patients with MELD scores between 6 and 10, for whom a 17% survival advantage was predicted for waiting on the list versus undergoing LT [27]. A new score for matching donors and recipients has consequently been proposed, called the D-MELD, which is the product of the donor’s age and the recipient’s preoperative MELD score. This DMELD score effectively stratified post-transplant survival. Using a cut-off of 1600, the authors identified a subgroup of donor–recipient matches with significantly worse short and long-term outcomes, as measured by survival and length of hospital stay, particularly for HCV positive recipients, indicating that the match at highest risk is a donor over 60 years old and a recipient with a MELD score greater than 30 [28]. The need for equity in organ allocation has led the Organ Procurement and Transplantation Network (OPTN) to oversee liver organ donation and transplantation in the US. The proliferation of regulations certainly leads to rising costs for the healthcare system, but it remains to be seen whether there is any consequent improvement in quality of care and patient outcomes. Future efforts will concentrate on more in-depth analyses of donor-related risks and outcomes, and more focused recommendations based on data that are being collected [29]. Matas gave some thought to the word allocation used in the transplant setting, which means a process of distributing something, and he proposed replacing it with the word rationing, which means a “controlled distribution of resources and scarce goods and services”, and thus implies a shortage that cannot be ignored, meaning that some transplant candidates will receive an organ and some will not [30]. Donation is a concept which seems stuck on past paradigms, and effective organizations in recent years have
P. Burra et al. / Digestive and Liver Disease Supplements 3 (2009) 108–111
become bureaucratic. What the transplant community needs is more people and resources to take care of donors and recipients, and a constant research effort to seek further advances [31]. Further investments are also needed to awaken public opinion concerning donation. Finally, international guidelines on how to define ECD organs and decide on their allocation should be agreed among expert transplant physicians and surgeons.
[15]
[16]
[17]
Conflict of interest The authors have no actual or potential conflict of interest relevant to this paper.
[18]
[19]
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