transplantation with livers from deceased donors older than 75 years

OriginalClinicalScience

Transplantation With Livers from DeceasedDonors Older Than 75 YearsTrygve Thorsen,1 Einar Martin Aandahl,1,2,3 William Bennet,4 Michael Olausson,4 Bo-Göran Ericzon,5

Greg Nowak,5 Frans Duraj,6 Helena Isoniemi,7 Allan Rasmussen,8 Tom H. Karlsen,9,10 and Aksel Foss1,10

Background. The availability of donor organs limits the number of patients in need who are offered liver transplantation. Mea-sures to expand the donor pool are crucial to prevent on-list mortality. The aim of this study was to evaluate the use of livers fromdeceased donors who were older than 75 years. Methods. Fifty-four patients who received a first liver transplant (D75 group)from 2001 to 2011 were included. Donor and recipient data were collected from the Nordic Liver Transplant Registry and medicalrecords. The outcome was compared with a control group of 54 patients who received a liver graft from donors aged 20 to49 years (D20-49 group). Median donor agewas 77 years (range, 75-86 years) in the D75 group and 41 years (range, 20-49 years)in the D20-49 group. Median recipient age was 59 years (range, 31-73 years) in the D75 group and 58 years (range, 31-74 years)in the D20-49 group.Results.The 1-, 3-, and 5-year patient/graft survival values were 87/87%, 81/81%, and 71/67% for theD75 group and 88/87%, 75/73%, and 75/73% for the D20-49 group, respectively. Patient (P = 0.89) and graft (P = 0.79) sur-vival did not differ between groups. The frequency of biliary complications was higher in the D75 group (29.6/13%, P = 0.03).Conclusions. Selected livers from donors over age 75 years should not be excluded based on age, which does not com-promise patient or graft survival despite a higher frequency of biliary complications.

(Transplantation 2015;00: 00–00)

L iver transplantation (Lt) is the only curative treatmentfor end-stage liver disease.1–3 The availability of donor

organs limits the number of procedures and motivates effortsto use liver grafts that would not have been accepted previ-ously. Currently, more than 10,000 patients are listed forLt in Europe, and the discrepancy between this need andthe number of transplantations performed is approximately7000 per year4; 1350 patients died on the waiting list in2011.5,6 At the end of 2011, a total of 17,000 patients werelisted for Lt in the United States, and almost 2500 patientsdied on the waiting list that year.7 Optimal use and allocationof deceased donor livers is therefore crucial to provide lifesav-ing treatment to patients in need.

Several strategies have been explored to improve or-gan availability. Complications and fatal incidents have unfor-tunately prohibited expansion of living donor Lt programs in

Received 24 July 2014. Revision requested 17 January 2015.

Accepted 20 January 2015.1 Department of TransplantationMedicine, Section for Transplant Surgery, Oslo Uni-versity Hospital, Oslo, Norway.2 Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway.3 Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University ofOslo, Oslo, Norway.4 Department of Transplantation, Institute of Clinical Sciences, Sahlgrenska Acad-emy, Sahlgrenska University Hospital, Gothenburg, Sweden.5 Division of Transplantation Surgery, Karolinska University Hospital Huddinge,Solna, Sweden.6 Department of Surgical Sciences, Upper Abdominal Surgery, Uppsala AcademicHospital, Uppsala, Sweden.7 Transplantation and Liver Surgery Clinic, Helsinki University Hospital, Helsinki,Finland.8 Department of Surgical Gastroenterology and Transplantation, University of Co-penhagen, Rigshospitalet, Copenhagen, Denmark.

Transplantation ■ Month 2015 ■ Volume 00 ■ Number 00

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most western countries.4,7–10 The use of split liver grafts forLt is also declining because of a higher frequency of complica-tions compared to whole Lt.11–15 High-risk donor livers, fromwhat are termedmarginal donors or extended-criteria donors,may represent an option to providemore organs for transplan-tation but at the cost of potentially inferior results. The defini-tion of high-risk liver donors is not yet precise, but donor riskindices and donor-recipient risk factors can be determined aspredictors for long-term outcome and graft function.14 Donorrisk factors together with the quality of the organ, retrievalprocedure, warm and cold ischemia and logistics, transplanta-tion procedure, status of the recipient, and posttransplanttreatment ultimately determine graft survival (GS) and patientsurvival (PS). Proper handling of all of these aspects is essentialfor optimal clinical outcome, and careful management of therisk factors may allow the use of nonideal donors for trans-plantation in selected cases.

9 Division of Cancer medicine, Surgery and Transplantation, Department of Trans-plantation Medicine, Norwegian PSC Research Centre, Oslo University Hospital,Rikshospitalet, Oslo, Norway.10 Institute for Clinical Medicine, University of Oslo, Oslo, Norway.

The Scandiatransplant Research Grant for 2011 supported the study.

The authors declare no conflicts of interest.

T.T., W.B., M.O., B-G.E., G.N., F.D., H.I., A.R., and A.F. designed the study,analyzed data, and wrote the paper. E.M. and T.H.K. analyzed data and wrote thepaper. T.T., W.B., M.O., B-G.E., G.N., F.D., H.I., and A.R. collected data.

Correspondence: Trygve Thorsen, MD, Section for Transplant Surgery, Departmentof Transplantation Medicine, Oslo University Hospital, Postboks 4950 Nydalen,0424 Oslo, Norway. ([email protected]).

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ISSN: 0041-1337/15/0000-00

DOI: 10.1097/TP.0000000000000728

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Although donor age is an independent risk factor for clin-ical outcome of Lt,14 the use of liver grafts from donors overage 65 years is increasing within the Eurotransplant area.11

In contrast, older donors are less used in the United States.7

Organs from elderly donors may partly relieve the shortageof livers for transplantation, and the impact of donor ageon outcome is crucial to determine. The liver is a complex or-gan16 with a large functional capacity and regenerative po-tential, and results from previous studies of the use ofelderly donors in Lt have been divergent16–37 (Table 1).

Scandiatransplant is an organ procurement and alloca-tion organization in which the Nordic countries participate.The primary allocation policy is center based, and exchangeamong the countries is based only on high urgency. Withinthe countries, the allocation policies vary, although old-to-old allocation is predominant when using livers fromolder donors. A similar allocation policy is used in theEurotransplant area. At the end of 2011, a total of102 patients were on the waiting list for a liver graft inthe Nordic countries, and 11 patients died on the waiting listthat year.

In this study, we aimed to determine the PS and GS of pa-tients receiving liver transplants from donors older than75 years.We performed a thorough analysis of the clinical re-sults and donor and recipient characteristics and comparedthese to a similar group of patients transplanted with liversfrom donors younger than 50 years.

MATERIALS AND METHODS

From 2001 to 2011, a total of 3087 Lt procedures wereperformed at six transplant centers in the Scandiatransplant

TABLE 1.

Studies on older liver donors

Author, year No. patients Donor age, y

Ghinolfi et al, 2014 16 85 >85Jimenez-Romero et al, 201317 50 70-81Darius et al, 2012 18 58 70-89Lai et al, 201119 28 70-89Álamo et al, 201120 72 72-82Faber et al, 201121 49 70-91Cascales Campos et al, 201122 29 >75Rauchfuss et al, 201023 17 >75Singhal et al, 201024 197 >80Petridis et al, 200825 10 80–93Fouzas et al, 200826 17 70–83Anderson et al, 200827 25 >70Segev et al, 200728 1043 70-92Gastaca et al, 2005 29 55 >70Borchert et al, 200530 41 70-80Zapletal et al, 200531 5 80-83Nardo et al, 200432 30 80-93Cescon et al, 200333 12 80-87Cuende et al, 200234 19 80-89Grazi et al, 200135 36 70-87Jimenez-Romero et al, 199936 4 82-89Emre et al, 199637 36 70-84

Copyright © 2015 Wolters Kluwer Health, Inc. Unau

region (Sweden, n = 1447; Norway, n = 657; Finland,n = 528; and Denmark, n = 455). In 2011 alone, a combinedtotal of 352 Lt procedures were performed in the Nordic coun-tries. Between March 2001 and October 2011, 54 patientsunderwent Lt with grafts from deceased brain-dead donorsover age 75 years (D75 group). Complete medical files ofall donors and corresponding recipients were extracted fromthe Scandiatransplant database, the Nordic Liver TransplantRegistry (NLTR), and center-specific medical records. Donordata consisted of age, sex, medical history, cause of death,time in intensive care unit, cardiovascular status, use of ino-tropic agents, liver function tests, blood group, and virus se-rology. Recipient data included age, gender, diagnosis, modelof end-stage liver disease (MELD) score, waiting time for Lt,blood group, perioperative data, complications, and long-term outcome.

Most patients received triple immunosuppression with ta-crolimus in combination with steroids and mycophenolatemofetil. A total of 22 patients (40.7%) in the D75 groupand 15 (27.8%) in the D20-49 group received anti–interleu-kin-2 induction therapy (basiliximab or daclizumab) becauseof kidney insufficiency at the time of transplantation. Patientsdiagnosed with cancer were in most cases treated witha mechanistic target of rapamycin inhibitor (sirolimus/everolimus), either as primary immunosuppression or as de-layed treatment 4 weeks after transplantation.

Primary endpoints of the studywere PS andGS at 1, 3, and5 years after transplantation. The data were compared tothose for a control group of patients transplanted with liversfrom donors who were 20 to 49 years old. For further analy-sis, the GS for patients in the D75 group with a benign diag-nosis was compared to the GS of all liver transplants in the

Patient survival, % Graft survival, %

1 y 3 y 5 y 1 y 3 y 5 y

86 78 78 85 77 7776 70 63 71 65 5888 80 86 78

67 47 60 4161 5890 86

78 6194 8881 69 75.5 6180 40 70 2070 58 4684 75 80 70

81 7593 91 93 8991 83 77 86 81 75100 100

75 7275 75

72 5177 73100 6691 85

thorized reproduction of this article is prohibited.

© 2015 Wolters Kluwer Thorsen et al 3

NLTR during the 2001 to 2011 period using grafts from do-nors aged 20 to 49 years in adult patients with benign diag-nosis (NLTR group, n = 802).

Characteristics of the D75 Group

Only first liver transplant recipients were included in thestudy (n = 54). The severity of the liver failure was catego-rized according to the mathematical MELD score, and addi-tional points for patients with hepatocellular carcinoma(HCC) were not used. Twenty-six patients (48%) were diag-nosed with malignant disease, and the majority of these weresuffering from HCC (n = 19). Other cancers were cholangio-carcinoma in 3 patients and secondary liver carcinomas in4 patients. Nineteen patients had known hepatitis C infectionbefore transplantation, of whom 14 also had HCC.

The general criteria for accepting a donor older than75 years included the presence of normal or slightly increasedliver enzymes before procurement and absence of macro-scopic steatosis or other liver disease, as judged by the sur-geon performing the donor operation. Zero biopsies wereobtained from 32 of 54 donors (59.3%), but zero biopsieswere not performed routinely. Patient and donor characteris-tics are given in Tables 2 and 3.

The use of old livers increased during the study periodalong with increased experience and the observed satisfac-tory results (Figure 1). The number of patients on waitinglists also increased during the study, and old donors weremore frequently used to limit death of those on the waitinglists. The total number of donors older than 75 years in the2001 to 2011 period was 121, whereas the number usedfor transplantation was 54 (44.6%). The fraction of trans-plants involving donors older than 75 years relative to the

TABLE 2.

Patient characteristics

D75 group

No. patients 54Age, y 58.5 (31.1-73.3)Sex (F/M) 22/32 (41/59%)Body mass index 25.4 (17.9-42.2)MELD score 12 (6-40)Waiting time, d 34 (1-342)Blood type A 27 (50%)

O 22 (40.7%)B 3 (5.6%)AB 2 (3.7%)

Ethiology HCC 19 (35.2%) (14 HCV+)SECA 4 (7.4%)

Cholangiocarcinoma 3 (5.6%)HCV (alone) 5 (9.3%)

PSC 4 (7.4%)PBC 3 (5.6%)AIH 3 (5.6%)

Alcoholic 2 (3.7%)Polycystic 2 (3.7%)Other 9 (16.7%)

Numbers are given in median and range.a Mann-Whitney test.b χ2 test.SECA indicates secondary liver cancer (colorectal); HCV, hepatitis C virus; PSC, primary sclerosing cholan


total number of transplantations during the study periodwas 54/3087 (1.75%). In addition to the general criteria usedto decline livers irrespective of age, potential donors olderthan 75 years were also refused when comorbidities and gen-eral health considerations were deemed unacceptable by thesurgeons on duty.

The main criterion used for selecting recipients of old do-nor livers was low MELD score or malignant liver disease(n = 26, 48%). However, old donor livers were also usedfor younger recipients in cases deemed highly urgent whenno other organs were available. Furthermore, the selectionwas performed on a case-by-case basis, determined by donorand recipient characteristics and the current number of pa-tients on the waiting lists.However, it is important to appre-ciate that the allocation policies evolved during the studyperiod in parallel with the general policies for recipient anddonor matching in the younger cohorts. In addition, the offerof organs from extended-criteria donors by the Organ Pro-curement Organisation has steadily increased, which also im-plies that the donor pool has changed during these years. It istherefore difficult to draw any definitive conclusion regard-ing inclusion and exclusion criteria that have consistentlybeen used throughout the study.

Characteristics of the D20-49 Group

The control group (D20-49-group) was extracted from theNLTR and consisted of adult first liver transplant recipientsolder than 18 years receiving grafts from donors aged 20 to49 years in the same period (2001-2011). The D20-49 groupwas matched to the D75 group by patient age and diagnosis,and the proportion of cancer patients in the D20-49 (48%)group was similar to the proportion of cancer patients in

D20-49 group P RR 95% CI

5457.9 (30-73.9) 0.92a

17/37 (31.5/68.5%) 0.32b 1.22 0.84–1.7724.4 (19-39.2) 0.36a

12 (3-39) 0.98a

47 (0-1102) 0.55a

30 (55.6%) 0.56b 0.89 0.61–1.3117 (31.5%) 0.32b 1.22 0.84–1.776 (11.1%) 0.30b 0.65 0.25–1.661 (1.9%) 0.56b 1.35 0.59–3.1022 (40.7%) (12 HCV+) 0.55b 0.89 0.59–1.332 (3.7%) 0.40b 1.36 0.75–2.482 (3.7%) 0.65b 1.21 0.58–2.555 (9.3%) >0.99b

4 (7.4%) >0.99b

3 (5.6%) >0.99b

4 (7.4%) 0.70b 0.85 0.35–2.043 (5.6%) 0.65b 0.79 0.27–2.36

0 0.15b 2.04 1.68–2.489 (16.7%) >0.99b

gitis; PBC, primary biliary cirrhosis; AIH, autoimmune hepatitis.


TABLE 3.

Donor characteristics

D75 group D20-49 group P RR 95% CI

Age, y 77 (75-86) 40.5 (20-49) <0.001a

Sex (F/M) 25/29 (46.3/53.7%) 20/34 [37/63%] 0.33b 1.21 0.83-1.75Body mass index 24.4 (19.5-30.2) 24.8 (18.4-34.8) 0.28c 0-2.03Preservation fluid UW 41 (75.9%) 42/50d(84%) 0.31b 0.80 0.53-1.19

Custodiol 13 (24.1%) 8/50d (16%) 0.31b 1.25 0.84-1.87ICU stay, d 1.5 (1-6) 2 (1-30) 0.005a

Blood type A 27 (50%) 22 (40.7%) 0.33b 1.20 0.83-1.75O 25 (46.3%) 21 (38.9%) 0.44b 1.16 0.80-1.69B 2 (3.7%) 10 (18.5%) 0.01b 0.31 0.09-1.10AB 0 1 (1.9%) 0.32b

Primary reason for death Cerebral hemorrhage 45 (83.3 %) 27 (50%) 0.001b 2.50 1.32-4.53Cerebral thrombosis 1 (1.9 %) 3 (5.6%) 0.31b 0.49 0.09-2.71

Trauma 3 (5.6 %) 8 (14.8%) 0.11b 0.52 0.19-1.39Suicide 1 (1.9 %) 4 (7.4%) 0.17b 0.39 0.07-2.27

Cardiac arrest 0 3 (5.6%) 0.08b

Other 4 (7.4%) 9 (16.7%) 0.14b 0.58 0.25-1.35Cardiac arreste 2 (3.7%) 7 (13%) 0.08b 0.42 0.12-1.46Pressor Yes 50/51f (98 %) 47/52g (90.4%) 0.10b 3.10 0.51-18.71

Not registered 3 (5.5 %) 2 (3.7%) 0.65b 1.21 0.58-2.55Methylprednisoloneh Yes 41 (76 %) 31/44i (70.5%) 0.54b 1.14 0.74-1.76

Not registered 0 10 (18.5%) 0.001b

Blood tests ALAT, U/L 26 (10-293) 38 (10–889) 0.02a

ASAT, U/L 45 (18-361) 40 (10–841) 0.05a

Bilirubine, mmol/L 12 (4-48) 9 (2–51) 0.02a

INR 1.2 (0.9-4.8) na na

Numbers are given in median and range. Data presented in italics are statistically significant.a Mann-Whitney test.b χ2 test.c Student’s t-test.d Registered in 50 of 54 donors.e Cardiac arrest before admission to hospital or in ICU.f Registered in 51 of 54 donors.g Registered in 52 of 54 donors.h 1 g given preprocurement.i Registered in 44 of 54 donors.na indicates not available; UW, University of Wisconsin; ICU, intensive care unit; ALAT, alanine aminotransferase; ASAT, aspartate aminotransferase; INR, international normalized ratio.


the D75 group (48%). Data on their corresponding donorswere extracted from the Scandiatransplant database. Furtherdetails are given in Tables 2 and 3.

Statistical Analysis

The primary endpoints were calculated from the day ofLt until February 1, 2012, or to patient death or graft loss.Kaplan-Meier survival analysis was performed usingGraphPad Prism version 5 (GraphPad Software, Inc., LaJolla, CA). Survival data of the D75- and D20-49 groupswere compared using the log-rank test. P values less than0.05 were considered as statistically significant. The Studentt test and the Mann-Whitney U test were used to comparecontinuous variables groups. Categorical variables werecompared using the χ2 test.

RESULTS

Median follow-up time was 30.5 months (range, 0.5-86 months) in the D75 group and 41.5 months (range, 0.1-124 months) in the control group (P = 0.001). No patientwas lost to follow-up, and there were no incidents of primary


nonfunction in any of the 2 groups. Only whole liver graftswere used in the D75 group, whereas there were 2 splitgrafts in the control group. Neither of these two patients ex-perienced short- or long-term complications. As shown inTable 4, median cold ischemia time (CIT) was 469 minutesin the D75 group and 510 minutes in the control group(P = 0.55). In the D75 group, 43 patients (79.6%) had CITless than 10 hours versus 38 hours (70.4%) in the D20-49group. The main results of the 2 groups are summarizedin Table 4.

Zero biopsies were obtained from 32 liver grafts. In theD75 group, 29 liver grafts (90.6%) showed no or mildsteatosis (0-30%), and 9 liver grafts (9.4%) showed moder-ate steatosis (30-60%). Ten biopsies (31.3%) had signs ofmild fibrosis. Fourteen biopsies (43.8%) showed signs ofmild preservation injury. Five specimens (15.6%) were con-sidered to havemoderate preservation injury, whereas 3 spec-imens (9.4%) had signs of severe preservation damage.

Patient and Graft Survival

In the D75 group, 1-, 3-, and 5-year PS values were 87.4%,81.1%, and 71.4%, respectively (Figure 2A), which did not


FIGURE 1. Bar graph illustrating the proportion of donors over age75 years whose livers are used each year.


differ significantly from the corresponding results in theD20-49 group of 88.3%, 75.1%, and 75.1%, respectively(P = 0.89). The 1-, 3-, and 5-year GS values in the D75 groupwere 87.4%, 81.1%, and 67.0%, respectively, compared with86.5%, 73.1%, and 73.1%, in the D20-49 group (Figure 2B),which also did not differ significantly (P = 0.79; Table 4).

Restricting the analysis to patients with nonmalignantindications (n = 28 in the D75 group and n = 28 in theD20-49 group), the 1-, 3-, and 5-year PS/GS were 84.6/80.8%, 80.2/76.3%, and 80.2/76.3%, respectively, in theD75 group. The corresponding results for the D20-49 groupwere 88.9/88.9%, 88.9/88.9%, and 88.9/88.9%, respec-tively (Figure 2C). The differences were not statistically sig-nificant (P = 0.45/0.27).

TABLE 4.

Results

D75 group

Follow-up, mo 30.5 (0.5-86)CIT, min 469 (227-900)Transfusion peroperatively Units of SAG 9.5 (0-82)ICU stay, d 1 (1-52)Acute rejectionc Steroid-sensitive 24 (44.4%)

Steroid-resistant 4 (7.4%)Need for retransplantation 2 (3.7%)Patient survival (KM) 1 y 87.4%

3 y 81.1%5 y 71.4%

Graft survival (KM) 1 y 87.4%3 y 81.1%5 y 67.0%

Complications Vascular 4 (7.4%)Biliary 16 (29.6%)

Numbers are given in median and rangea Mann-Whitney test.b Student t test.c Biopsy proven and/or clinical signs of rejection.d χ2 test.e Log-rank test.SAG indicates saline/adenine/glucose solution; KM, Kaplan-Meier; HR, hazard ratio.


For patients with malignant transplant indications, the 1-,3-, and 5-year PS/GS values were 92/92%, 83/83%, and60.1/50%, respectively, in the D75 group compared to83.8/79.8%, 59.5/55.1%, and 59.5/55.1%, respectively, inthe D20-49 group (Figure 2D) (P = 0.73/0.44).

The GS values for patients with benign diagnoses in theD75 group (n = 28) were compared to all liver transplantsin NLTR during the 2001 to 2011 period using grafts fromdonors aged 20 to 49 years in adult patients diagnosedwith nonmalignant disease (n = 802). The 1-, 3-, and 5-yearGS values in the NLTR group were 89.0%, 84.5%, and80.6%, which did not differ statistically from the correspond-ing results in the D75 group (P = 0.36) (Figure 3).

Nineteen patients in the D75 group were diagnosed withhepatitis C before Lt, of whom 14 also had HCC. In these19 patients, the 1-, 3-, and 5-year GS values were 89.2%,81.7%, and 81.7%, which did not differ significantly fromthe corresponding results for the D20-49 patients who hadbeen diagnosed with hepatitis C (P = 0.12; hazard ratio,0.12-1.30).

Retransplantations

Retransplantations were performed in 2 patients (3.7%) inthe D75 group and 1 patient (1.9%) in the control group. Inthe D75 group, 1 patient with primary sclerosing cholangitisand cholangiocarcinoma had repeat Lt because of chroniccholangitis at 41 months, while 1 patient with autoimmunehepatitis was retransplanted after 67 months because of mul-tiple rejection episodes and development of cholestatic cir-rhosis. One patient in the control group was retransplantedafter 1 month because of a fungal infection in the liver graftand sepsis.

Vascular Complications

Four patients (7.4%) in the D75 group and 5 patients(9.3%) in the control group were diagnosed with vascular

D20-49 group P RR/HR 95% CI

41.6 (0.1-124) 0.001a

510 (183-960) 0.55b 0–43.46 (0-40) 0.72a

1 (1-15) 0.59a

16 (29.6%) 0.11d 1.50 0.90–2.493 (5.6%) 0.70d 1.33 0.31–5.681 (1.9%) 0.56d 2.00 0.19–21.488.3%75.1% 0.89e 0.94a 0.41–2.1575.1%86.5%73.1% 0.79e 1.11a 0.51–2.4573.1%5 (9.3%) 0.73d 0.80 0.23–2.827 (13%) 0.03d 2.29 1.02–5.11


FIGURE 2. Kaplan-Meier plots of (A) patient survival in the D75 group versus the D20-49 group, (B) graft survival in the D75 group versusD20-49 group, (C) graft survival in the D75 versus D20-49 group for patients with nonmalignant indications for Lt, and (D) graft survival inthe D75 versus D20-49 group for patients with malignant indications for Lt. Curves were compared using the log-rank test.

FIGURE 3. Kaplan-Meier plot comparing graft survival in the D75group versus all other adult patients in the Nordic Liver TransplantRegistry during the 2001 to 2011 period using grafts from donorsaged 20 to 49 years. Only patients with nonmalignant diagnosesare included in each group. Curves were compared using the log-rank test.


complications during the follow-up period (relative risk[RR], 0.80; 95% confidence interval [95% CI], 0.23-2.82;P = 0.73). In the D75 group, one of these incidents occurredwithin 30 days from the Lt. Two patients had hepatic arterythrombosis (HAT) or stenosis. One patient was reoperatedon day 14, whereas the other patient was diagnosed with he-patic artery stenosis after 19 months and was successfullytreated by percutaneous transluminal angioplasty with dila-tation of the stenosis. One patient developed a mycoticpseudoaneurysm on the hepatic artery and was reoperatedon day 105. Additionally, 1 patient was diagnosed withthrombosis of the portal vein on day 414. She was moribundbecause of liver failure and sepsis at the time of diagnosis andpassed away at day 418.

In the control group, 3 of the 5 vascular incidents occurredin the first 30 days after Lt. Two patients had HAT or steno-sis. One patient was reoperated on day 1 because of HAT,whereas 1 patient was diagnosed with a relative hepatic ar-tery stenosis on day 365. The second patient needed no activetreatment for HAT. Two patients developed portal veinthrombus after Lt, one on day 23 and the other on day 119.Both patients were treated with intensive anticoagulation. Inaddition, 1 patient in the control group was reoperated onday 5 for rupture of the hepatic artery. None of the patientsin the D75 group or D20-49 group who suffered vascularcomplications were retransplanted.

Biliary Complications

A total of 16 patients (29.6%) in the D75 group and7 patients (13%) in the D20-49 group presented with biliarycomplications after the Lt (RR, 2.29; 95% CI, 1.02-5.11;P = 0.03). In the D75 group, 8 of these patients were


diagnosed within 30 days after the transplantation. In 15 of16 patients, the complications derived from the common bileduct. Eight patientswere diagnosedwith a leakage, and 6 suf-fered from strictures. In addition, 2 patients were treatedfor stones/sludge in the biliary tree. Of these 16 patients,6 patients had to be reoperated, 9 patients were successfullytreated by endoscopic retrograde cholangioscopy with stent,and 1 patient did not need any active treatment.



Seven patients (13%) in the D20-49 group were diagnosedwith biliary complications, 4 patients of which occurredwithin the first 30 days after Lt. Two patients had leakage,and 3 patients had strictures. Two more patients were diag-nosed with cholangitis. Of these7 patients, none had to bereoperated. Three patients were successfully treated by endo-scopic retrograde cholangioscopy with stent and 1 patientwith percutaneous transhepatic cholangiography, and3 patients were treated conservatively with antibiotics.

Statistical analyses were performed to evaluate differencesin the frequency of biliary complications in relation to CIT.We observed no statistical differences in CIT between thosewho developed biliary complications compared to thosewho did not in either the D75 group (P = 0.32) or theD20-49 group (P = 0.26).

Rejections

Twenty-four patients (44.4%) in the D75 group and16 patients (29.6%) in the D20-49 group were treated foracute cellular rejections (ACRs) occurring within the first4 weeks postoperatively (RR, 1.50; 95% CI, 0.90-2.49;P = 0.11). This value accounts for both biopsy-proven acuterejection (BPAR) cases (83.3% in D75 and 56.3% inD20-49) and rejections based only on clinical suspicion.A Banff rejection activity index score of 3 or more was de-fined as positive for rejection. In the D75 group, 4 patientshad steroid-resistant rejection and were treated witheither antithymocyte globulin or OKT3 or both. In theD20-49 group, 3 patients had steroid-resistant rejectionand were treated with antithymocyte globulin, OKT3, orimmunoglobulins.

DISCUSSION

In the present study, we demonstrate that patients receiv-ing liver grafts from donors aged 75 years or older appearto experience equivalent outcomes with respect to PS andGS compared to patients in the D20-49 group at 1, 3, and5 years after transplantation. Previous studies have not beenconclusive regarding whether liver grafts from older donorsshould be used in selected patients. However, our findingsare in line with a recent report by Ghinolfi et al16 showingthat GS at 1 and 5 years was similar in recipients of liversfrom donors under age 60 years compared with donors olderthan 80 years. Only one other study has investigated 5-yearGS using donors older than age 75 years, reporting a GS of51% in 19 patients receiving livers from donors aged 80 to89 years,34 and recently a 5-year GS of 58% in 50 patientswas reported in recipients of grafts from donors older than70 years.17 Darius et al18 identified a 5-year GS of 78% in58 patients with donors aged 70 to 89 years, and Borchertet al30 reported 75% 5-year GS in 41 patients with donorsaged 70 to 80 years. In a large analysis of the UnitedNetworkfor Organ Sharing database, Segev et al28 found a 3-year GSof 75% in selected patients receiving livers from donors olderthan 70 years. In contrast, a 3-year GS as low as 20% in pa-tients with donors aged 80 to 93 years has been reported,25

and Lai et al19 published a 5-year GS of only 41% in a studyof 28 patients with donors from 70 to 89 years of age.Taken together, the implication of these findings is thatprimary nonfunction of livers from older donors rarelyoccurs.18,27,32,33


The rate of biliary complications of almost 30% in theD75 group compared to 13% in the D20-49 group(RR, 2.29; P = 0.03) was disappointing. The frequency ofbiliary complications in Lt is reported to be from 10% to33%.38–43 In our study, all biliary incidents reported duringfollow-up were registered, including incidental stenosis ofthe bile tree without hyperbilirubinemia. The difference inbiliary complications between the study groups indicates thatold livers are more vulnerable than donor livers from youn-ger individuals, which may be related to both donor andrecipient factors. Livers from older donors have less func-tional reserves and regenerative potential and are likely tobe more susceptible to ischemic injury resulting from inade-quate blood supply to the distal bile ducts.44–47

The rate of vascular complications in the study groupwas comparable to that of the D20-49 group (7.4% in theD75 group versus 9.3% in the control group; P = 0.73).The rates were within the normal range after Lt.

A total of 20% to 65% of Lt recipients develop ACR afterLt,48–53 and 20% to 40%of the recipients experience at least1 episode of ACR that requires additional immunosuppres-sive treatment.53 The incidence of ACR in our study was44% (37% BPAR) in the D75 group and 30% (17% BPAR)in the control group (P = 0.11). These results are in corre-spondence with previous observations that high donor agedoes not affect the risk for rejection.18,21,32

Old livers aremore prone to preservation injury than liversfrom younger donors. Median CIT in the D75 group was ap-proximately 8.2 hours compared to 8.5 hours in the D20-49group. The recipients in our D75 group were patients withlowMELD scores or malignant liver diseases. A median stayin the intensive care unit of only 1 day after Lt indicates thatthe patients were in good health and nutritional status atthe time of transplantation. However, old donor livers werealso used for younger recipients in highly urgent cases andon a case-by-case basis as determined by donor and recipientcharacteristics and the current number of patients on thewaiting lists.

The risk of hepatitis C relapse is markedly increased inolder livers.54 In our study, the observed 1-, 3-, and 5-yearGS in the D75 group with hepatitis C was not inferior tothe GS in the D20-D49 group.

Our results should be evaluated carefully because the epi-demiology and disease landscape in the study represent theScandinavian population. The majority of donors come froma population with generally good health and low body massindex, and the current life expectancy in Scandinavian coun-tries is between 82 and 84 years for women and 78 and80 years for men.55 With respect to the recipient characteris-tics, the prevalence of hepatitis C in Scandinavia is lower thanin many southern European countries and in particularcompared to the prevalence in southeast Asia. The preva-lence of nonalcoholic fatty liver disease and nonalcoholicsteatohepatitis is also substantially lower in Scandinavia thanin the United States.

In addition, because our study is retrospective andreports data from 2001 to 2011, the results should beinterpreted with caution. Clinical practice changed duringthe study period and the inclusion criteria have been ex-panded both in terms of patient selection and the accep-tance of donor livers, along with improvements in thesurgical procedures.



With these cautions inmind, we conclude that our findingsdemonstrate that selected livers from donors over age75 years can be used and should not be considered high-risk donor livers or marginal per se. Short- and long-term(5 years) PS and GS were satisfactory and not significantlydifferent from the outcome using livers from donors aged20 to 49 years. The risk for biliary complications was in-creased in the D75 group, but these complications weremanageable by early reoperation or endoscopic treatment.Although high donor age may be associated with inferior5-year GS, growing waiting lists and on-list mortalitysupport the use of a higher number of available grafts fortransplantation.

ACKNOWLEDGMENTSThe authors appreciate the invaluable assistance from systemadministrator Frank Pedersen at the Scandiatransplant officein providing respective donor data for all patients.

REFERENCES1. Sagmeister M, Mullhaupt B, Kadry Z, et al. Cost-effectiveness of

cadaveric and living-donor liver transplantation. Transplantation.2002;73:616–622.

2. Longworth L, Young T, BuxtonMJ, et al. Midterm cost-effectiveness of theliver transplantation program of England and Wales for three diseasegroups. Liver Transpl. 2003;9:1295–1307.

3. Aberg F, Maklin S, Rasanen P, et al. Cost of a quality-adjusted lifeyear in liver transplantation: the influence of the indication andthe model for end-stage liver disease score. Liver Transpl. 2011;17:1333–1343.

4. http://ec.europa.eu/health/blood_tissues_organs/docs/ev_20121009_facts_figures.pdf. Internet, 2012.

5. Newsletter Transplant, International Figures on Donation andTransplantation 2011. 2012.

6. Eurotransplant Annual Report 2011 2012.7. Kim WR, Stock PG, Smith JM, et al. OPTN/SRTR 2011 Annual Data

Report: liver. Am J Transplantat. 2013;13(Suppl 1):73–102.8. Wertheim JA, Petrowsky H, Saab S, et al. Major challenges limiting liver

transplantation in the United States. Am J Transplant. 2011;11: 1773–1784.9. Ghobrial RM, Freise CE, Trotter JF, et al. Donor morbidity after living

donation for liver transplantation. Gastroenterology. 2008;135:468–476.10. Marsh JW, Gray E, Ness R, et al. Complications of right lobe living donor

liver transplantation. J Hepatol. 2009;51:715–724.11. http://www.eurotransplant.org/cms/mediaobject.php?file=ar_2011.pdf.

Internet, 2012.12. Zambelli M, Andorno E, De Carlis L, et al. Full-right-full-left split liver

transplantation: the retrospective analysis of an early multicenter experienceincluding graft sharing. Am J Transplant. 2012;12:2198–2210.

13. Burroughs AK, Sabin CA, Rolles K, et al. 3-month and 12-month mortalityafter first liver transplant in adults in Europe: predictive models foroutcome. Lancet. 2006;367:225–232.

14. Feng S, Goodrich NP, Bragg-Gresham JL, et al. Characteristicsassociated with liver graft failure: the concept of a donor risk index. AmJ Transplant. 2006;6:783–790.

15. Aseni P, De Feo TM, DeCarlis L, et al. A prospective policy development toincrease split-liver transplantation for 2 adult recipients: results of a12-year multicenter collaborative study. Ann Surg. 2014;259:157–165.

16. Ghinolfi D, Marti J, De Simone P, et al. Use of octogenarian donors for livertransplantation: a survival analysis. Am J Transplant. 2014;14:2062–2071.

17. Jimenez-Romero C, Clemares-LamaM, Manrique-Municio A, et al. Long-term results using old liver grafts for transplantation: sexagenerian versusliver donors older than 70 years. World J Surg. 2013;37:2211–2221.

18. Darius T,Monbaliu D, Jochmans I, et al. Septuagenarian and octogenariandonors provide excellent liver grafts for transplantation. Transplant Proc.2012;44:2861–2867.

19. Lai Q, Melandro F, Levi Sandri GB, et al. Use of elderly donors for livertransplantation: has the limit been reached? J Gastrointestin Liver Dis.2011;20:383–387.


20. Álamo JM, Barrera L, Marin LM, et al. Results of liver transplantation withdonors older than 70 years: a case-control study. Transplant Proc.2011;43:2227–2229.

21. Faber W, Seehofer D, Puhl G, et al. Donor age does not influence12-month outcome after orthotopic liver transplantation. TransplantProc. 2011;43:3789–3795.

22. Cascales Campos PA, Romero PR, Gonzalez R, et al. Improving thewaiting list by using 75-year-old donors for recipients with hepatocellularcarcinoma. Transplant Proc. 2010;42:627–630.

23. Rauchfuss F, Voigt R, Dittmar Y, et al. Liver transplantation utilizing olddonor organs: a German single-center experience. Transplant Proc.2010;42:175–177.

24. Singhal A, Sezginsoy B, Ghuloom AE, et al. Orthotopic liver transplantusing allografts from geriatric population in the United States: is thereany age limit? Exp Clin Transplant. 2010;8:196–201.

25. Petridis I, Gruttadauria S, Nadalin S, et al. Liver transplantation usingdonors older than 80 years: a single-center experience. Transplant Proc.2008;40:1976–1978.

26. Fouzas I, Sgourakis G, Nowak KM, et al. Liver transplantation with graftsfrom septuagenarians. Transplant Proc. 2008;40:3198–3200.

27. Anderson CD, Vachharajani N, Doyle M, et al. Advanced donor agealone does not affect patient or graft survival after liver transplantation.J Am Coll Surg. 2008;207:847–852.

28. Segev DL, Maley WR, Simpkins CE, et al. Minimizing risk associated withelderly liver donors by matching to preferred recipients. Hepatology.2007;46:1907–1918.

29. Gastaca M, Valdivieso A, Pijoan J, et al. Donors older than 70 years in livertransplantation. Transplant Proc. 2005;37:3851–3854.

30. Borchert DH, Glanemann M, Mogl M, et al. Adult liver transplantationusing liver grafts from donors over 70 years of age. Transplant Proc.2005;37:1186–1187.

31. Zapletal C, Faust D, Wullstein C, et al. Does the liver ever age? Results ofliver transplantation with donors above 80 years of age. Transplant Proc.2005;37:1182–1185.

32. Nardo B, Masetti M, Urbani L, et al. Liver transplantation from donorsaged 80 years and over: pushing the limit. Am J Transplant. 2004;4:1139–1147.

33. Cescon M, Grazi GL, Ercolani G, et al. Long-term survival of recipients ofliver grafts from donors older than 80 years: is it achievable? Liver Transpl.2003;9:1174–1180.

34. Cuende N, Grande L, Sanjuan F, et al. Liver transplant with organs fromelderly donors: Spanish experience with more than 300 liver donors over70 years of age. Transplantation. 2002;73:1360.

35. Grazi GL, Cescon M, Ravaioli M, et al. A revised consideration on theuse of very aged donors for liver transplantation. Am J Transplant. 2001;1:61–68.

36. Jimenez Romero C, Moreno Gonzalez E, Colina Ruiz F, et al. Use ofoctogenarian livers safely expands the donor pool. Transplantation.1999;68:572–575.

37. Emre S, Schwartz ME, Altaca G, et al. Safe use of hepatic allografts fromdonors older than 70 years. Transplantation. 1996;62:62–65.

38. Greif F, Bronsther OL, Van Thiel DH, et al. The incidence, timing,and management of biliary tract complications after orthotopic livertransplantation. Ann Surg. 1994;219:40–45.

39. Lerut J, Gordon RD, Iwatsuki S, et al. Biliary tract complicationsin human orthotopic liver transplantation. Transplantation. 1987;43:47–51.

40. Foley DP, Fernandez LA, Leverson G, et al. Biliary complications after livertransplantation from donation after cardiac death donors: an analysis ofrisk factors and long-term outcomes from a single center. Ann Surg.2011;253:817–825.

41. Welling TH, Heidt DG, Englesbe MJ, et al. Biliary complicationsfollowing liver transplantation in the model for end-stage liver diseaseera: effect of donor, recipient, and technical factors. Liver Transpl.2008;14:73–80.

42. Qian YB, Liu CL, Lo CM, et al. Risk factors for biliary complications afterliver transplantation . Arch Surg. 2004;139:1101–1105.

43. Rerknimitr R, Sherman S, Fogel EL, et al. Biliary tract complicationsafter orthotopic liver transplantation with choledochocholedochostomyanastomosis: endoscopic findings and results of therapy. GastrointestEndosc. 2002;55:224–231.

44. Schmucker DL. Age-related changes in liver structure and function:implications for disease ? Exp Gerontol. 2005;40:650–659.

45. Gordon Burroughs S, Busuttil RW. Optimal utilization of extended hepaticgrafts. Surg Today. 2009;39:746–751.


http://ec.europa.eu/health/blood_tissues_organs/docs/ev_20121009_facts_figures.pdf

http://ec.europa.eu/health/blood_tissues_organs/docs/ev_20121009_facts_figures.pdf

http://www.eurotransplant.org/cms/mediaobject.php?file=ar_2011.pdf


46. Busuttil RW, Tanaka K. The utility of marginal donors in liver transplantation.Liver Transpl. 2003;9:651–663.

47. Seehofer D, Eurich D, Veltzke-Schlieker W, et al. Biliary complications afterliver transplantation: old problems and new challenges. Am J Transplant.2013;13:253–265.

48. Neumann U, Samuel D, Trunecka P, et al. A randomized multicenterstudy comparing a tacrolimus-based protocol with and withoutsteroids in HCV-positive liver allograft recipients. J transplant.2012;2012:894215.

49. Guo H, Chen ZH, Chen ZS, et al. Histopathological study of 268 hepaticallograft biopsies. Zhonghua Yi Xue Za Zhi. 2011;91:3401–3404.

50. Klintmalm GB, Davis GL, Teperman L, et al. A randomized, multicenterstudy comparing steroid-free immunosuppression and standard


immunosuppression for liver transplant recipients with chronichepatitis C. Liver Transpl. 2011;17:1394–1403.

51. Demetris AJ, Ruppert K, Dvorchik I, et al. Real-time monitoring ofacute liver-allograft rejection using the Banff schema. Transplantation. 2002;74:1290–1296.

52. Fosby B, Karlsen TH, Melum E. Recurrence and rejection in livertransplantation for primary sclerosing cholangitis. World J Gastroenterol.2012;18:1–15.

53. Neil DA, Hubscher SG. Current views on rejection pathology in livertransplantation. Transpl Int. 2010;23:971–983.

54. Rubin A, Aguilera V, Berenguer M. Liver transplantation and hepatitis C.Clin Res Hepatol Gastroenterol. 2011;35:805–812.

55. http://www.who.int/gho/countries/en/.


http://www.who.int/gho/countries/en/

transplantation with livers from deceased donors older than 75 years

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