With the rising disparity between the number of

Transcription

1 Original Article / Transplantation Hepatobiliary & Pancreatic Diseases International 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 ( ) years in the older donor group and 25.0 ( ) in the younger donor group. There was no significant 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 significant adverse effect on graft function and long-term patients' survival. (Hepatobiliary Pancreat Dis Int 2015;14:50-55) Author Affiliations: Department of Transplant Surgery, Tianjin First Center Hospital, Key Laboratory of Organ Transplantation of Tianjin, Tianjin , China (Wang K, Jiang WT, Deng YL, Pan C and Shen ZY) Corresponding Author: Zhong-Yang Shen, MD, PhD, Department of Transplant Surgery, Tianjin First Center Hospital, Key Laboratory of Organ Transplantation of Tianjin, Tianjin , China (Tel: ; Fax: ; zhongyangshen666@hotmail.com) 2015, Hepatobiliary Pancreat Dis Int. All rights reserved. doi: /S (15) Published online January 29, KEY WORDS: 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 data 50 Hepatobiliary Pancreat Dis Int,Vol 14,No 1 February 15,2015

2 Donor age on graft function in LDLT from all LDLTs performed in our hospital from March 2007 to December 2011, and patient follow-up was ended in July 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 first 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, 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: ). 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 defined as steatosis donor when more than 10% hepatocytes were steatotic in pathology. 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 the Declaration 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's t test and non-parametric data were analyzed by the Mann-Whitney U test. 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-Meier method. All analyses were performed with SPSS version 13.0 (SPSS Inc., Chicago, IL, USA). Data were considered to be significant when a P value was less than 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 significant 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 significant difference in intra-opera- Table 1. Characteristics of donor livers and recipients pre-operation Characteristics Older donor group (n=10) Younger donor group (n=149) P value Donor age (yr) 58.5 ( ) 25.0 ( ) Donor gender (M/F) 7/3 121/ * Donor steatosis 4 (40.0%) 31 (20.8%) * CIT (min) 90.0 ( ) ( ) GRWR (%) 1.17± ± # Recipients age (yr) 37.4± ± # Recipients gender (M/F) 6/4 125/ * Recipients BMI (kg/m 2 ) 22.66± ± # Recipients MELD score 19.5 ( ) 15.0 ( ) Recipients diagnosis Cirrhosis related HBV * Cirrhosis related HCV * Autoimmune cirrhosis * Alcoholic cirrhosis * Cryptogenic cirrhosis * Wilson's disease * Fulminant hepatic failure * Combined tumor * *: Chi-square test; #: t test; : Mann-Whitney U test. GRWR: graft/recipient weight ratio; CIT: cold ischemic time; BMI: body mass index; MELD: model for end-stage liver disease. Hepatobiliary Pancreat Dis Int,Vol 14,No 1 February 15,

3 Hepatobiliary & Pancreatic Diseases International tion 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 first 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 significant 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 first year post-ldlt Graft function recovered slowly in the first week post-ldlt. Laboratory examination revealed that liver function was significantly 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 μmol/l on the 7th day post-ldlt, then declined to μmol/l on the 14th day, and finally returned to normal level at the end of the first month after LDLT. Long-term survival of grafts and recipients The average follow-up time was 60.8±5.1 months (range ) and 66.0±1.7 months (range ) 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 tu- mor, 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 Characteristics Table 3. Characteristics of intra- and post-hepatectomy status of donors Characteristics Table 4. Graft function of the older donor group in the first year post-ldlt Variables 1 Older donor group (n=10) 3 Older donor group (n=10) Younger donor group (n=149) P value Operation time (h) 10.05± ± # Hospital stay (day) 20.0 ( ) 18.0 ( ) Complications (n, %) Biliary leakage 1 (10) 0 Bleeding 0 1 (0.67) Peripheral nerve compression 0 1 (0.67) Delayed wound healing 0 6 (4.03) #: t test; : Mann-Whitney U test. Younger donor group (n=149) P value Anhepatic time (min) 62.5 ( ) 60.0 ( ) Operative duration (h) 12.3 ( ) 12.0 ( ) Volume of RBC (ml) 1900 ( ) 1200 ( ) Combinations Rejection * HAT * Portal thrombosis * Bleeding * Biliary leakage * Immunosuppressant Tacrolimus * Cyclosporine * Rapamycin * *: Chi-square test; : Mann-Whitney U test. HAT: hepatic artery thrombosis. 360 ALT (IU/L) AST (IU/L) GGT (IU/L) ALP (IU/L) TBIL (µmol/l) DBIL (µmol/l) ALB (g/l) All data were expressed as median. ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: γ-glutamyl transpeptidase; ALP: alkaline phosphatase; TBIL: total bilirubin; DBIL: direct bilirubin; ALB: albumin. 52 Hepatobiliary Pancreat Dis Int,Vol 14,No 1 February 15,2015

4 Donor age on graft function in LDLT Graft survival rate was 80.0% (8/10) and 87.2% (130/149) in the older and younger donor groups, respectively, and no significant difference was observed between the two groups (χ 2 =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 significant difference between the two groups (χ 2 =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 significant 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 significant difference between the two groups (P=0.811). To determine whether donor age is a factor influencing 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 significant difference in recipient survival among the older (90.0%, 9/10), middle-age (93.8%, 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. 30/32), and preferred donor group (86.3%, 101/117) (χ 2 =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 significant difference among these three groups (χ 2 =1.833, P=0.400) (Fig. 2). 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 [9, 10] and safety of donors. Elderly donor livers are usually smaller in size and more prone to become fibrotic 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. Nardo Hepatobiliary Pancreat Dis Int,Vol 14,No 1 February 15,

5 Hepatobiliary & Pancreatic Diseases International et 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 satisfied with the 5-year survival rate more than 80%, which was mostly benefited from strict control on recipients' condition pre-ldlt and CIT in operations. One study showed that, [19] after specific 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 significantly lower than in those who received young ones (P<0.001). Significant 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 significant correlation between donor age and the progression of HCV related liver fibrosis 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 significant 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 find 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 definitely had beneficial 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 significant 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 first 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 benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. References 1 Cescon M, Grazi GL, Cucchetti A, Ravaioli M, Ercolani G, Vivarelli M, et al. Improving the outcome of liver transplantation with very old donors with updated selection and management criteria. Liver Transpl 2008;14: Anderson CD, Vachharajani N, Doyle M, Lowell JA, Wellen JR, Shenoy S, et al. Advanced donor age alone does not affect patient or graft survival after liver transplantation. J Am Coll Surg 2008;207: Cascales Campos PA, Romero PR, Gonzalez R, Zambudio AR, Martinez Frutos IM, de la Peña J, et al. Improving the waiting list by using 75-year-old donors for recipients with hepatocellular carcinoma. Transplant Proc 2010;42: Serrano MT, Garcia-Gil A, Arenas J, Ber Y, Cortes L, Valiente C, et al. Outcome of liver transplantation using donors older than 60 years of age. Clin Transplant 2010;24: Hepatobiliary Pancreat Dis Int,Vol 14,No 1 February 15,2015

6 Donor age on graft function in LDLT 5 Feng S, Goodrich NP, Bragg-Gresham JL, Dykstra DM, Punch JD, DebRoy MA, et al. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant 2006;6: Selzner M, Kashfi A, Selzner N, McCluskey S, Greig PD, Cattral MS, et al. Recipient age affects long-term outcome and hepatitis C recurrence in old donor livers following transplantation. Liver Transpl 2009;15: Valadao RM, Terrault NA. Older donors: mounting risks for the hepatitis C-infected liver transplant recipient? Liver Transpl 2009;15: Halldorson J, Roberts JP. Decadal analysis of deceased organ donation in Spain and the United States linking an increased donation rate and the utilization of older donors. Liver Transpl 2013;19: Kiuchi T, Tanaka K, Ito T, Oike F, Ogura Y, Fujimoto Y, et al. Small-for-size graft in living donor liver transplantation: how far should we go? Liver Transpl 2003;9:S Lee DS, Gil WH, Lee HH, Lee KW, Lee SK, Kim SJ, et al. Factors affecting graft survival after living donor liver transplantation. Transplant Proc 2004;36: Wakabayashi H, Nishiyama Y, Ushiyama T, Maeba T, Maeta H. Evaluation of the effect of age on functioning hepatocyte mass and liver blood flow using liver scintigraphy in preoperative estimations for surgical patients: comparison with CT volumetry. J Surg Res 2002;106: Briceño J, Marchal T, Padillo J, Solórzano G, Pera C. Influence of marginal donors on liver preservation injury. Transplantation 2002;74: Zeeh J, Platt D. The aging liver: structural and functional changes and their consequences for drug treatment in old age. Gerontology 2002;48: Tanemura A, Mizuno S, Wada H, Yamada T, Nobori T, Isaji S. Donor age affects liver regeneration during early period in the graft liver and late period in the remnant liver after living donor liver transplantation. World J Surg 2012;36: Borchert DH, Glanemann M, Mogl M, Langrehr J, Neuhaus P. Adult liver transplantation using liver grafts from donors over 70 years of age. Transplant Proc 2005;37: Nardo B, Masetti M, Urbani L, Caraceni P, Montalti R, Filipponi F, et al. Liver transplantation from donors aged 80 years and over: pushing the limit. Am J Transplant 2004;4: Ono Y, Kawachi S, Hayashida T, Wakui M, Tanabe M, Itano O, et al. The influence of donor age on liver regeneration and hepatic progenitor cell populations. Surgery 2011;150: Segev DL, Maley WR, Simpkins CE, Locke JE, Nguyen GC, Montgomery RA, et al. Minimizing risk associated with elderly liver donors by matching to preferred recipients. Hepatology 2007;46: Modanlou KA, Oliver DA, Grossman BJ. Liver donor's age and recipient's serum creatinine predict blood component use during liver transplantation. Transfusion 2009;49: Selzner N, Girgrah N, Lilly L, Guindi M, Selzner M, Therapondos G, et al. The difference in the fibrosis progression of recurrent hepatitis C after live donor liver transplantation versus deceased donor liver transplantation is attributable to the difference in donor age. Liver Transpl 2008;14: Jiménez-Romero C, Clemares-Lama M, Manrique-Municio A, García-Sesma A, Calvo-Pulido J, Moreno-González E. Long-term results using old liver grafts for transplantation: sexagenerian versus liver donors older than 70 years. World J Surg 2013;37: Sersté T, Bourgeois N. Ageing and the liver. Acta Gastroenterol Belg 2006;69: Received June 9, 2014 Accepted after revision December 12, 2014 Hepatobiliary Pancreat Dis Int,Vol 14,No 1 February 15,