Effect of donor age on graft function and longterm survival of recipients undergoing living donor liver transplantation

Tianjin, China

Effect of donor age on graft function and longterm survival of recipients undergoing living donor liver transplantation

Kai Wang, Wen-Tao Jiang, Yong-Lin Deng, Cheng Pan and Zhong-Yang Shen

Tianjin, China

BACKGROUND:Donor shortage is the biggest obstacle in organ transplantation. Living donor liver transplantation (LDLT) has been considered as a valuable approach to shortening waiting time. The objectives of this study were to investigate the feasibility of utilizing donors older than 50 years in LDLT and to evaluate the graft function and recipient survival.

METHODS:All LDLT cases (n=159) were divided into the older (donor age ≥50 years,n=10) and younger (donor age <50 years,n=149) donor groups. Donor graft and recipient condition pre-, intra- and post-operation were compared between the two groups. In particular, graft functions and recipient survivals were analyzed.

RESULTS:The median donor age was 58.5 (52.5-60.0) years in the older donor group and 25.0 (23.0-32.0) in the younger donor group. There was no signifcant difference in cold ischemic time, anhepatic phase and operation time between the older and younger donor groups (P>0.05). However, the volume of red blood cell transfused in operation was greater in the older donor group than in the younger donor group (1900 vs 1200 mL,P=0.023). The 1-, 3- and 5-year graft survival rates were 90%, 80% and 80% for the older donor group, and 92%, 87% and 87% for the younger donor group, respectively (P=0.459). The 1-, 3- and 5-year survival rates were 100%, 90% and 90% for recipients with older grafts, and 93%, 87% and 87% for those with younger grafts, respectively (P=0.811).

CONCLUSION:It is safe for a LDLT recipient to receive liver from donors older than 50 years, and there is no signifcant adverse effect on graft function and long-term patients' survival.

(

Hepatobiliary Pancreat Dis Int 2015;14：50-55)

living donor liver transplantation;donor age; graft; liver function; long-term survival

Introduction

With the rising disparity between the number of transplants needed and the number of organ donors available, many transplant centers have adopted a variety of approaches to expand the donor pool, including living donor liver transplantation (LDLT), split liver transplantation and the utilization of marginal donor livers. Compared with the high proportion of grafts from donors younger than 50 years, the organ discarding rate of donors older than 50 years was around 40%.[1]In recent years, the upper age limit of donors has been elevated from 50 to 65 years in many transplant centers, some of which began to try to use derived grafts from 70-year-old or even 75-year-old donor and obtained excellent results.[2,3]On the contrary, some researchers reported that patients who received older livers had a higher rate of primary non-function, prolonged graft function recovery, increased graft loss and mortality.[4-7]

Compared with cadaveric donor derived whole liver grafts, grafts from living donor in LDLT are partial and were supposed to regenerate to meet the recipient's functional requirement. Therefore, because of the possible effect of age on liver regeneration, donor age might have an impact on graft function and long-term survival of recipients.

The present study was undertaken to evaluate the effect of donor age on the function grafts and long-term survival of the recipients in LDLT.

Methods

Patients

A retrospective study was conducted by analyzing datafrom all LDLTs performed in our hospital from March 2007 to December 2011, and patient follow-up was ended in July 2013. Among 159 recipients included, 131 were males and 28 females with mean age of 44.9±9.2 years (range 14-65). Patients who were diagnosed as having hepatocellular carcinoma generally met the Milan standard pre-LDLT.

Graft livers were generally implanted in piggy-back fashion, and patients were treated with nucleoside analogues plus hepatitis B immunoglobulin to prevent hepatitis B recurrence post-LDLT. The immunosuppressants were rapamycin+mycophenolate mofetil (MMF)+ methylprednisolone or calcineurin inhibitor (CNI) in the frst 3-6 months post-LDLT and CNI (or rapamycin)+MMF in the following 6-12 months. In a long-term maintenance, mono-therapy of CNI or rapamycin was applied. The concentrations of these immunosuppressants were 6-8, 150-200 and 5-10 ng/mL for tacrolimus, cyclosporine and rapamycin, respectively.

Among 159 partial liver donors, 128 were males and 31 females, with a median age of 26.0 years (interquartile range: 23.0-36.0). Donor candidates were limited to family relatives of recipients and all of them were healthy and suitable to donate part of their livers without any danger, and blood types of donors and recipients were compatible. Graft/recipient weight ratio was 0.62%-2.02% and the percentage of remnant liver volume to donor liver was generally greater than 30%. Grafts were preserved with histidine-tryptophan-ketoglutarate solution and specimens were routinely preserved for pathology. Donor was defned as steatosis donor when more than 10% hepatocytes were steatotic in pathology. method. All analyses were performed with SPSS version 13.0 (SPSS Inc., Chicago, IL, USA). Data were considered to be signifcant when aPvalue was less than 0.05.

Results

Donor livers and recipients pre-LDLT

The older donor group comprised 10 donors including 7 males and 3 females; and the younger donor group consisted of 149 donors including 121 males and 28 females (Table 1). In all donors, 35 including 4 from the older donor group and 31 from the younger donor group had mild or moderate steatosis; however, there was no signifcant difference in percentage of steatosis between the two groups (P>0.05). In addition, median cold ischemic time (CIT) in the older and younger donor groups was not statistically different (P>0.05).

There was no difference in gender, body mass index and model for end-stage liver disease score between the older and younger donor recipients (P>0.05). The average age of recipients in the older donor group was lower than that in the younger donor group (P<0.01). Etiological results showed that 77% of the recipients in this cohort had hepatitis B related cirrhosis.

Intra- and post-operation status of recipients and donors

There was no signifcant difference in intra-opera-

Table 1.Characteristics of donor livers and recipients pre-operation

Grouping criteria

Based on donor age, recipients were divided into the older (≥50 years) and younger donor groups (<50 years). The younger donor group was further divided into the middle-age donor group (≥35 and <50 years) and preferred donor group (<35 years). All subjects signed the informed consent form. All treatments and operations were authorized by the Ethics Committee of Tianjin First Center Hospital. The study was conducted in accordance with the principles delineated in theDeclaration of Helsinki.

Statistical analysis

The results of measured variables were expressed as mean±standard deviation or median and interquartile range. The data were analyzed by Student'sttest and non-parametric data were analyzed by the Mann-WhitneyUtest. Sample ratios between the two groups were compared by the Chi-square test. Long-term survival of grafts and recipients were analyzed by the Kaplan-Meiertion variables between the two recipient groups (P>0.05), except for the volume of red blood cell (RBC) transfused during the operation (P<0.05). Small-for-size syndrome was not found in any patient. Eight recipients in the younger donor group were detected with hepatic artery thrombosis post-LDLT, and 2 of them were treated with surgery, 3 with interventional therapy in the transcatheter artery, and 3 with conservative therapy. All of the symptoms were observed in the frst month post-LDLT, and 7 recipients recovered to normal graft function after treatment and one died from the second transplantation due to biliary complications. No recipient in the older donor group suffered from bleeding or biliary leakage (Table 2).

There was no signifcant difference in operation time and hospital stay between the two groups (P>0.05). No donor died in peri-operation. One older donor was detected with biliary leakage in the second week postoperation, and then received re-operation to place drainage tube along with nutrition support therapy. The donor eventually recovered and was discharged in 122 days. Eight younger donors had post-hepatectomy complications. Donor complicated with bleeding was re-operated. Peripheral nerve compression in the left leg in 1 case was treated with conservative therapy. Delayed wound healing was another complication and treated with conservative therapy (Table 3).

Graft function of patients in the older donor group in the frst year post-LDLT

Graft function recovered slowly in the frst week post-LDLT. Laboratory examination revealed that liver function was signifcantly improved in 14 days, and almost returned to normal one month post-LDLT. In the period of 1 month to 12 months after LDLT, liver function was kept normal (Table 4). In the 10 recipients, the one who was diagnosed with Wilson's disease pre-LDLT had a high bilirubin level pre-operation, and the graft function recovered slowly with a total bilirubin of 540.50 μmol/L on the 7th day post-LDLT, then declined to 301.82 μmol/L on the 14th day, and fnally returned to normal level at the end of the frst month after LDLT.

Long-term survival of grafts and recipients

The average follow-up time was 60.8±5.1 months (range 12.6-66.2) and 66.0±1.7 months (range 0.9-73.6) in the older and younger donor groups, respectively. There were 19 deaths and 21 graft losses, of which, 2 occurred in the older donor group. One recipient died from neurological complications and another was rescued by re-transplantation. In 18 deaths in the younger donor group, 8 died from graft failure, 8 from recurrence of tumor, 1 from neurological complication, and 1 from other causes. Only one recipient received re-transplantation because of biliary complication, but died in two weeks after the operation.

Table 2.Characteristics of intra- and post-operation status of recipients

Table 3.Characteristics of intra- and post-hepatectomy status of donors

Table 4.Graft function of the older donor group in the first year post-LDLT

Graft survival rate was 80.0% (8/10) and 87.2% (130/149) in the older and younger donor groups, respectively, and no signifcant difference was observed between the two groups (χ2=0.459,P=0.498) (Fig. 1). The survival rate was 90.0% (9/10) in the older donor group and 87.9% (131/149) in the younger donor group, respectively, and also there was no signifcant difference between the two groups (χ2=0.057,P=0.812). The 1-, 3-and 5-year graft survival rates were 90%, 80% and 80% in the older donor group, and 92%, 87% and 87% in the younger donor group, respectively; there was no signifcant difference between the two groups (P=0.459). In addition, the 1-, 3- and 5-year survival rates were 100%, 90% and 90% in the older donor group and 93%, 87%, and 87% in the younger donor group, respectively; there was no signifcant difference between the two groups (P=0.811).

To determine whether donor age is a factor infuencing graft and recipient survival, we further divided the younger donors into the preffered donor group (<35 years) and middle-age donor group (≥35 and <50 years). The donor age for the older, middle-age and preferred donor groups was 56.5 ±4.1, 41.2±4.3 and 24.3±3.1 years, respectively. There was no signifcant difference in recipient survival among the older (90.0%, 9/10), middle-age (93.8%, 30/32), and preferred donor group (86.3%, 101/117) (χ2=1.276,P=0.528). The graft survival rates were 80.0% (8/10), 93.8% (30/32) and 85.5% (100/117) for the older, middle-age and preferred donor groups, respectively; there was also no signifcant difference among these three groups (χ2=1.833,P=0.400) (Fig. 2).

Fig. 1.Comparison of long-term graft survival rate between the older and younger donor groups.

Fig. 2.Long-term graft survival among different age donor groups.

Discussion

The disparity between the demand for organ transplant and the shortage of donors is the most serious problem in transplantation communities. Use of livers from aged donors is an effective way to alleviate donor shortage and shorten waiting time. In Spain, the number of old donors in transplantation increased from 3.8/million in 1999 to 8.8/million in 2009 (increased by 132%), which accounted for 25.4% in the total number of organ donations in that country.[8]Although it is generally accepted that donor age should be limited to below 50 years in adult to adult LDLT, whether the prognosis of LDLT is affected by donor age, particularly older age, is still obsecure in consideration of satisfactory graft liver function and safety of donors.[9,10]

Elderly donor livers are usually smaller in size and more prone to become fbrotic than those from younger donors. Such difference has been shown not as a morphological discrepancy of livers, but a decreased volume of hepatocytes.[11]A previous study showed that exchange of oxygen and other nutrients can be limited by the ultrastructural changes of hepatocytes in aged livers.[12]In addition, the content of cytochrome P450 in the liver was found to decline by 16% from 40 to 69 years old, and even further declined by 32% at 70 years old.[13]Furthermore, elderly livers are more prone to present steatosis.[14]In whole liver transplantation from cadaveric donor, grafts and recipients survivals with elderly donor livers were as high as those with younger donors. No difference in the rate of re-transplantation and frequency of rejection was shown in a study for patients who received older grafts (donor age >70 years) compared with those accepted younger grafts (donor age <70 years).[15]Compared with whole liver grafts, partial grafts in LDLT are subjected to post-operative synthesis and graft regeneration, which would directly affect recovery of graft function in early stage and long-term prognosis post-LDLT. In our study, the graft function in the older donor group mostly recovered to normal in early post-LDLT, indicating that the function of synthesis and the ability of regeneration in LDLT from the older donor liver can be comparable with the younger donor liver. In addition, neither steatosis nor aggravation of existing steatosis was detected in new grafts at least one year post-LDLT. Nardoet al[16]reported that endothelial cells in elderly livers were more prone to be injured by cold ischemia, which may in turn result in steatosis. Some studies suggested that the effect of age on liver regeneration may be correlated with liver stem cells or progenitor cells in LDLT.[14,17]

Our study demonstrated that volume of RBC transfusion in the older donor group was higher than that of the younger donor group. This was due to the weaker grafts function in older donor livers after reperfusion in operation, particularly the ability to produce coagulative factors. Similarly, another study[18]showed that the volume of RBC transfusion in liver transplantation from donors aged more than 50 years was nearly three times more than that from younger donors.

Careful selection of donors and recipients may be helpful in improving long-term survival of grafts and recipients with older donor liver transplantation. We found that both graft survival and recipient survival in the older donor group were satisfed with the 5-year survival rate more than 80%, which was mostly benefted from strict control on recipients' condition pre-LDLT and CIT in operations. One study showed that,[19]after specifc recipients selection, the 3-year graft survival rate was 74.9% in recipients with donors more than 70 years old, which was similar to the group less than 70 years (75%,P=0.6) and the ideal age group with mean donor age less than 40 years (77.3%,P=0.2). For recipients without selection, however, the graft and recipient survival rates in recipients who received elderly donor livers were signifcantly lower than in those who received young ones (P<0.001).

Signifcant attention should be paid to hepatitis C virus (HCV) positive recipients undergoing LDLT with elderly donor livers. A retrospective study[20]showed that there was signifcant correlation between donor age and the progression of HCV related liver fbrosis after liver transplantation, and the relative risk in donor age over 45 years was 8.17 (P=0.001). However, Jiménez-Romero and colleagues[21]reported that there was no signifcant difference either in patient survival rate (P=0.074) or in graft survival rate (P=0.29) between the older liver (>60 years) and younger liver groups (≤60 years). There were few cases of HCV related end-stage liver disease in our study, and we did not fnd the same case discussed above.

Our results suggested that it is safe and feasible to use livers from donors older than 50 years in LDLT. In our study, the median CIT was 90.0 minutes and the median anhepatic phase was 62.5 minutes in LDLT with donors older than 50 years, which defnitely had benefcial effect on the recovery of graft function in early stage post-LDLT. The graft from donors older than 50 years exhibited no impaired hepatic synthetic function which may be due to the powerful reserve capacity, dual blood supply and strong regenerative capacity of the liver, such that metabolic requirements can be easily met.[22]However, we have to point out that the recipients' age in the older donor group was younger than that in the younger donor group. It is speculated that younger recipients may have better overall physical conditions and stronger recovering ability than the older recipients. Thus, we consider the above factors may partially contribute to the similar results between the livers from donors older than 50 years and those younger than 50 years in LDLT.

In conclusion, a wider range of donor age selection can be adopted to expand the donor pool, especially in the present situation of signifcant shortage of donor livers. Such selection is safe, but should be cautious. A large number and longer follow-up time trial is indispensable before elderly donor livers can be widely used in LDLT.

Acknowledgements:The authors thank China Liver Transplant Registry (CLTR) for providing the information about the patients intended for LDLT and the support of the follow-up team who effectively conducted data collection of pre-, intra- and postoperation patients into CLTR.

Contributors:SZY proposed the study. WK performed the research, analyzed the data and wrote the frst draft. JWT, DYL and PC helped to collect the data. All authors contributed to the design and interpretation of the study and to further drafts. SZY is the guarantor.

Funding:This study is supported by a grant from the 863 National High-Tech Research and Development Program of China: Establishing Integrated Organ Preserving and Recovering System In Vitro as well as Evaluating and Screening Criteria of DCD donors (2012AA021001).

Ethical approval:The study was approved by the Ethics Committee of Tianjin First Center Hospital.

Competing interest:No benefts in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received June 9, 2014

Accepted after revision December 12, 2014

AuthorAffliations:Department of Transplant Surgery, Tianjin First Center Hospital, Key Laboratory of Organ Transplantation of Tianjin, Tianjin 300192, China (Wang K, Jiang WT, Deng YL, Pan C and Shen ZY)

Zhong-Yang Shen, MD, PhD, Department of Transplant Surgery, Tianjin First Center Hospital, Key Laboratory of Organ Transplantation of Tianjin, Tianjin 300192, China (Tel: +86-22-23626611; Fax: +86-22-23626612; Email: zhongyangshen666@hotmail.com)

© 2015, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(15)60334-4

Published online January 29, 2015.