Original Article
Use of Elderly Donors (> 60 Years) for Liver Transplantation Yi Zhao, Chung Mau Lo, Chi Leung Liu and Sheung Tat Fan, Centre for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Hong Kong SAR, China.
BACKGROUND: As the demand for liver transplantation has become greater than the availability of donor livers, the criteria for donor selection or rejection are more important than ever before. In view of an increasing number of patients on the waiting list, some centres are expanding their donor pool by relaxing the criteria, such as by using organs from elderly (> 60 years) brainstem-dead donors. In this study, we reviewed our experience of using elderly brain-dead donor livers, investigating the potential prognostic factors of the donor, and analysing the influence of donor age on early graft function and graft survival. METHODS: We retrospectively evaluated 106 cadaveric donor liver transplantations in 98 patients. Seven patients (6.6%, 7 vs 106) received livers from donors older than 60 years. Pre-transplantation characteristics of donors and the outcome of recipients were evaluated. Donor prognostic factors were analysed using Cox univariate analysis and confirmed by a multivariate forward stepwise Cox model. Early graft function was compared between recipients of grafts from donors older and younger than 60 years. RESULTS: There were no primary non-functions or re-transplants in the group receiving elderly grafts. Early graft function was similar in patients with grafts from elderly and younger donors. Univariate analysis demonstrated that prognostic factors had no relationship with long-term recipient survival. The 3-month and 1-year cumulative graft survival rates were 100% and 82% in the elderly graft group and 84% and 83% in the younger graft group, respectively. Kaplan-Meier curves and the log-rank test indicated that there was no difference in graft and patient survival rates between the two groups. CONCLUSIONS: Old age is not a contraindication for liver donation. Liver grafts from donors older than 60 years can be used safely. [Asian J Surg 2004;27(2):114–9]
Introduction With the improvement in surgical techniques, immunosuppression regimens,1 recipient preparation and organ preservation, liver transplantation has become the accepted treatment for end-stage liver disease. The 1-year patient survival rate increased to about 85% in the 1990s. 2 As a result, the demand for transplantation has become greater than the availability of donor livers. Faced with the growing discrepancy between the demand for and supply of donor organs,
many centres are trying to broaden their donor pool, for example, by the use of non-heart-beating donors 3 and the initiation of living related liver transplantation.4 The use of elderly donors is a possible means of expanding the donor pool, but the impact of donor age on liver transplantation outcome has yet to be clarified. Livers from donors older than 60 years are considered to be inadequate for transplantation by many centres because older livers are more susceptible to various hepatocyte insults.3,5,6 Recently, several reports have pointed out that donors older than 60 years can be safely
Address correspondence and reprint requests to Professor Sheung Tat Fan, Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong SAR, China. E-mail:
[email protected] • Date of acceptance: 15th May, 2003 © 2004 Elsevier. All rights reserved.
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used.7–10 Kampmann et al indicated that, because of its great functional reserve and regenerative capacity, the liver does not usually suffer from functional deterioration with ageing.11 Therefore, utilization of liver grafts from elderly donors has been advocated.5,6 From 1988 to 1993, the percentage of elderly donors between the ages of 50 and 65 in the United Network for Organ Sharing increased from 2.5% to 15.9%. Based on these developments, some centres now routinely use elderly donors to tackle the imbalance between the increasing demand for liver transplantation and the inadequate supply of donor organs. The aim of this study was to review our experience with transplantation of liver grafts from cadaveric donors over the age of 60 years, to investigate the potential donor risk factors for graft survival, and to compare early graft function between patients receiving livers from donors over 60 years old and those receiving livers from donors aged 60 years or less.
Patients and methods We retrospectively evaluated 106 cadaveric liver transplantations in 98 patients at Queen Mary Hospital, Hong Kong, between October 1991 and June 2002. Seven patients (6.6%, 7 vs 106) received livers from donors older than 60 years. These included one patient who received a second re-transplant and one patient who received a fourth re-transplant. During the study period, three grafts from donors older than 60 years were not used because, at the harvesting operation, the grafts were found to be cirrhotic (n = 2) or had severe (60–70%) steatosis. All grafts were procured and preserved using University of Wisconsin (UW) solution by the standard technique for multiple organ harvesting, and all recipients had similar perioperative intensive care. All elderly donors were ABO identical or compatible with the recipient. Two of 99 donors in the younger group were ABO incompatible. All patients who received livers from elderly donors received FK506-based double immunosuppression therapy,1 whereas others received cyclosporine-based triple or FK506-based double therapy. Donors were examined intraoperatively. In the case of suspected fatty infiltration, routine liver biopsy was performed. The liver would not be used if it had apparent fibrosis, cirrhosis or steatosis (> 30%). Liver transplantations were performed using the standardized method. In all cases, the cold ischaemia time was kept as short as possible by preparing the recipient for transplantation upon acceptance of the liver allograft by the harvesting team.
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The 106 cadaveric liver transplantations were categorized into two groups. Group I included patients receiving grafts from elderly donors (> 60 years), and Group II included patients receiving grafts from younger donors (≤ 60 years). We recorded donor age, gender, body mass index (BMI), cause of death, length of intensive care unit (ICU) stay, liver enzymes, minimum systolic pressure and duration, and quantity of inotrope used; these are the risk factors identified by Jimenez Romero et al.12 For all recipients, we recorded pre-transplant data (age, gender, liver enzymes), perioperative data including platelet count, prothrombin time and cold ischaemia time, postoperative liver enzymes, peak bilirubin, peak alanine aminotransferase and aspartate aminotransferase on days 1 to 7, occurrence of primary non-function, and complications. The pre-transplant status of recipients was compared between the two groups, as were the postoperative variables and graft outcomes. Comparisons were made using the MannWhitney U test and Fisher’s exact test. Data are expressed as median (range). A difference was considered significant if p was less than 0.05. A Cox univariate analysis was constructed to identify the donor risk factors on long-term graft survival. Afterwards, a multivariate forward stepwise Cox model was constructed with donor variables. Actuarial graft and recipient survival analyses were performed using the Kaplan-Meier method and compared using the log-rank test.
Results The median follow-up was 22 months (range, 3–63.9 months) in Group I and 28 months (range, 0.03–116 months) in Group II. Table 1 summarizes donor and recipient characteristics in Group I. In Group I, median donor age was 63 years (range, 61– 76 years). The cause of death was cerebrovascular accident in five donors, carotid artery thrombosis in one donor, and traumatic subdural haemorrhage in one donor. Median donor BMI was 22.68 (range, 19–26.22; BMI > 27 considered overweight12). Three recipients had major complications. The patient who received the second re-transplant had venous outflow obstruction and biliary leakage 18 days after transplantation. We performed caval-caval anastomosis twice and hepaticojejunostomy. Another recipient had minimal bile leakage. Neither had hepatic artery thrombosis and both recovered after re-operation. One patient who is still alive but in a vegetative state because of central pontine myelinolysis had acute kinking of the hepatic artery without thrombosis. The other three patients had no major complications, including
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Table 1. Characteristics of donors and recipients of elderly grafts Donor age (yr)
No. of donor risk factors
CIT (mins)
Recipient age (yr)
Gender
Diagnosis
Child-Pugh score
Patient outcome
61 61 61 68 63 76 66
3 3 3 1 2 3 3
443 702 402 560 429 334 364
44 39 47 40 61 52 25
M M M F M M M
Hep B Hep B + drinker Hep B Wilson’s disease Hep B + HCC Hep B Wilson’s disease
13 9 6 9 6 11 9
Alive Alive Dead Alive Alive Alive Alive
Cause of graft loss
HA thrombosis
CIT = cold ischaemia time; M = male; Hep B = hepatitis B; HA = hepatic artery; F = female; HCC = hepatocellular carcinoma.
the one who received the fourth re-transplant. Normalization of aminotransferase levels and prothrombin times were noted within 5 days after transplantation in four of the seven recipients of elderly donor grafts. There were two total rejection episodes among these seven patients. Four months after transplantation, one patient died of hepatic artery thrombosis before re-transplantation, despite normal postoperative liver enzymes and prothrombin time. We retrospectively found that this patient had severe atherosclerosis in the graft common hepatic artery. Median recipient age was 44 years (range, 25–61 years) in Group I and 44 years (range, 0.6–66 years) in Group II. The preoperative status of recipients based on laboratory tests was not significantly different between the two groups (Table 2). The early intraoperative and early postoperative parameters and graft outcomes in the two groups are summarized in Table 3 and Figures 1–4. Peak serum alanine aminotransferase and aspartate aminotransferase levels within 1 week postoperatively were not significantly different between the two groups. Peak serum total bilirubin levels, postoperative aminotransferase levels, prothrombin times and platelet counts on postoperative days 1 to 7 did not differ between the two groups (p > 0.05). There was no significant difference in cold ischaemia time, primary non-function, retransplantation, occurrence of biliary complications, and hepatic artery thrombosis. There were six re-transplants and one primary non-function in Group II but no primary nonfunction or re-transplantation in Group I. The number of rejection episodes was two in Group I and 66 in Group II. No donor risk factors had a significant effect on long-term graft survival according to the Cox univariate analysis and multivariate stepwise Cox model (Table 4). The 3-month cumulative graft and patient survival rates were both 100% in Group I and 84.3% and 87.8% in Group II, respectively. The 1-
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Table 2. Comparison of recipients’ pre-transplantation status Group I (> 60 yr) n=7 Age (yr) Total bilirubin (µmol/L) ALP (U/L) Creatinine (µmol/L) BUN (mmol/L) PT (mins)
44 74 134 100 5 17.1
(25–61) (29–957) (74–290) (49–457) (4.1–24.1) (15–34)
Group II (≤ 60 yr) n = 99 44 70 148 91.5 5.2 17.4
(0.6–66) (4–1,240) (42–1,560) (19–999) (1.2–34.3) (12–110)
Values expressed as median (range). ALP = alkaline phosphatase; BUN = blood urea nitrogen; PT = prothrombin time.
year cumulative graft and recipient survival rates were 81.8% and 77.8% in Group I and 82.9% and 85.1% in Group II, respectively. There was no significant difference in survival between the two groups.
Discussion Traditionally, the use of liver allografts from donors older than 60 years has been considered a major risk factor for immediate and post-transplant poor graft function.13 The results of our study suggest that it is unreasonable to reject elderly donors just because of age. Early graft function and graft and patient survival rates were not significantly different between the two groups, and there were no instances of primary non-function and re-transplant in recipients of grafts from elderly donors. In fact, this outcome is comparable with that from Wall et al.14 Some reports show that many donor factors might have an adverse impact on graft outcome.12,15 Jimenez Romero et al identified risk factors to predict the prognosis for liver transplantation that included age, gender, BMI, cold ischaemia
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Table 3. Comparison of perioperative parameters and recipient outcome
Recipient age (yr) CIT Peak AST (U/L) Peak ALT (U/L) Peak bilirubin (µmol/L) Primary non-function Re-transplant Biliary complication Hepatic artery thrombosis Mean follow-up (mo) Graft survival (%) 3-month 1-year Recipient survival (%) 3-month 1-year
Group I (> 60 yr)
Group II (≤ 60 yr)
44 (25–61) 429 (334–702) 687 (184–1,390) 412 (216–871) 132 (82–542) 0 0 3 1 22 (3–63.9)
44 (0.6–66) 444 (242–884) 913 (146–10,000) 609.5 (63–6,860) 135.5 (28–999) 1 6 11 2 28 (0.03–116)
100 81.8
84.3 82.9
100 77.8
87.8 85.1
Values expressed as median (range). CIT = cold ischaemia time; AST = aspartate aminotransferase; ALT = alanine aminotransferase.
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25 –
Minutes
20 – 15 – 10 – 5– 0– 0
1
2
3
4
5
6
7
Postoperative day Figure 1. Postoperative prothrombin time. ▲ = Group 1; ■ = Group 2.
100 –
Platelet count x 109/L
time, ICU stay, abnormal liver enzyme levels and high inotrope dosage.12 In this study, even though we had carefully selected donors, we retrospectively found that there were 18 risk factors among the seven elderly donors, and five of these donors had three risk factors (Table 1). Therefore, it seemed that this group was not comprised of optimal potential donors. However, univariate and multivariate analyses could not identify any impact of these risk factors on long-term graft survival. The same results were observed in the studies of Busquets et al16, Wall et al14 and Emre et al.5 Based on these results, the value of traditional prognostic factors is questionable. The success in our study can be attributed to many factors. First, we did not allocate elderly donor grafts to critically ill patients. A better result could be achieved by allocating such grafts to recipients waiting at home.14 Second, the cold ischaemia time in our study was relatively short. One major risk factor in aged liver is the susceptibility of the graft to ischaemia/reperfusion injury. It has been reported that livers from elderly donors with cold ischaemia times of more than 12 hours have a deleterious impact on graft and recipient outcomes.5,6 Therefore, it is our policy to avoid prolonged cold ischaemia times. The mean cold ischaemia time in our study was less than 8 hours. Third, in our study, all donor assessments were made by senior surgeons who had considerable experience with donor operations. According to one study, the harvesting surgeon’s assessment of elderly donor livers had a better correlation with graft survival than other more objec-
80 – 60 – 40 – 20 – 0– 0
1
2
3
4
5
6
7
Postoperative day Figure 2. Postoperative platelet count. ▲ = Group 1; ■ = Group 2.
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Serum total bilirubin (µmol/L)
140 – 120 – 100 – 80 – 60 – 40 – 20 – 0– 0
1
2
3
4
5
6
7
Postoperative day Figure 3. Postoperative serum total bilirubin level. ▲ = Group 1; ■ = Group 2.
450 – 400 – 350 –
Serum ALT (U/L)
tive measures of the graft such as donor bilirubin, albumin, creatinine and donor days in the hospital.17 All transplants were performed by three experienced surgeons. Although it cannot be demonstrated by data, we believe the judgement of surgeons and the technique played an important role in the function and survival of the graft. Fourth, all seven liver transplantations from elderly donors were performed after 1997, when the more effective FK506-based immunosuppression regimen was used.1 This could have had an impact on survival. Though there was no statistical significance, the total number of rejection episodes in Group II (n = 66, 66.7%) was higher than that in Group I (n = 2, 28.6%). Finally, we had a low threshold for re-operation. Re-operation would be performed immediately if a patient developed any signs of complications that required emergency surgery. After re-operation, many patients recovered very well. Hepatic artery thrombosis remains the most common technical complication that causes graft failure following orthotopic liver transplantation. Therefore, hepatic artery anastomosis should be performed using a meticulous technique and adequate magnification. There were three hepatic artery thromboses (2.8%) in the entire study, and only one in Group I (the patient’s hepatic artery had severe atherosclerosis). This rate was a little higher than the 1.3% in the study of Rela et al,18 who adopted the microvascular technique in 150 adult liver transplants. In our study, we did not use the microvascular technique for hepatic artery anastomosis except for a child. The microvascular technique should probably be used for elderly grafts to minimize the incidence of hepatic artery thrombosis. In conclusion, based on this study, we believe that livers from elderly donors over 60 years of age can be safely used un-
300 – 250 – 200 – 150 – 100 – 50 – 0– 0
1
2
3
4
5
6
7
Postoperative day Figure 4. Postoperative serum alanine aminotransferase (ALT). ▲ = Group 1; ■ = Group 2.
der optimal protocols. Age alone is not an independent risk factor for recipient survival. Exclusion of elderly donors has no scientific foundation. The reliability of parameters that can
Table 4. Possible donor prognostic risk factors for long-term graft survival Univariate cRR (95% CI) Age > 60 yr Gender (female) BMI > 25 CIT > 720 mins ICU stay > 3 days AST > 36 U/L ALT > 53 U/L Total bilirubin > 34 µmol/L High dose of inotrope
1.688 0.821 1.159 0.905 1.013 1.156 2.178 0.709 1.207
(0.228–12.491) (0.372–1.812) (0.192–3.874) (0.148–8.218) (0.438–2.223) (0.300–2.499) (0.519–3.827) (0.107–1.975) (0.505–2.887)
p
Multivariate aRR
p
0.608 0.625 0.847 0.923 0.975 0.789 0.296 0.500 0.672
– – – – – – – – –
0.369 0.784 0.186 0.592 0.637 0.721 0.262 0.722 0.068
cRR = crude Relative Risk; CI = confidence interval; aRR = adjusted Relative Risk; – = variables not in the equation; BMI = body mass index; CIT = cold ischaemia time; ICU = intensive care unit; AST = aspartate aminotransferase; ALT = alanine aminotransferase.
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predict graft function is still questionable. In Asia, the major factor that limits the application of liver transplantation is the shortage of donor grafts. Hence, relaxation of the selection criteria for donors would be beneficial to potential recipients who are suitable candidates for transplantation.
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