Operative Outcomes of Adult Living Donor Liver Transplantation and Deceased Donor Liver Transplantation: A Systematic Review and Meta-Analysis

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1 LIVER TRANSPLANTATION 20: , 2014 ORIGINAL ARTICLE Operative Outcomes of Adult Living Donor Liver Transplantation and Deceased Donor Liver Transplantation: A Systematic Review and Meta-Analysis Ping Wan, 1 * Xin Yu, 2 * and Qiang Xia 1 1 Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; and 2 Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, China Living donor liver transplantation (LDLT) has emerged as an alternative to deceased donor liver transplantation (DDLT) because of the increasing number of patients waiting for liver transplantation (LT). However, whether it can achieve operative outcomes similar to those achieved with DDLT for adult patients remains controversial. We conducted this metaanalysis to compare the operative outcomes of LDLT and DDLT recipients. A literature search was performed to identify clinical controlled studies comparing LDLT and DDLT that were published before October Four perioperative outcomes [duration of the recipient operation (DRO), red blood cell (RBC) transfusion requirement, length of the hospital stay, and cold ischemia time (CIT)] and 5 postoperative complication outcomes (biliary complications, vascular complications, intraabdominal bleeding, perioperative death, and retransplantation) were the main outcomes assessed. Nineteen studies with a total of 5450 patients were included in the meta-analysis. In comparison with DDLT, LDLT was associated with a significantly longer DRO and a shorter CIT. We found that biliary complications [odds ratio (OR) , 95% confidence interval (CI) , P < 0.001], vascular complications (OR , 95% CI , P ), and retransplantation (OR , 95% CI , P ) occurred more frequently for LDLT recipients, and the subgroup analysis indicated that the biliary complication rate decreased dramatically with greater LDLT experience. No significant difference was observed in RBC transfusion requirements, the lengths of hospital stays, intra-abdominal bleeding rates, or perioperative mortality between LDLT and DDLT recipients. In conclusion, LDLT is associated with a higher rate of surgical complications after transplantation. A reduction of postoperative complication rates can be achieved as centers gain greater experience with LDLT. However, LDLT is still an excellent alternative to DDLT because it facilitates access to LT. Liver Transpl 20: , VC 2014 AASLD. Received November 18, 2013; accepted January 5, Abbreviations: A2ALL, Adult-to-Adult Living Donor Liver Transplantation Cohort Study; CI, confidence interval; CIT, cold ischemia time; DDLT, deceased donor liver transplantation; DRO, duration of the recipient operation; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LDLT, living donor liver transplantation; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; NA, not available; OR, odds ratio; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta- Analyses; RBC, red blood cell; SD, standard deviation; SRTR, Scientific Registry of Transplant Recipients; UNOS, United Network for Organ Sharing; WMD, weighted mean difference. There are no conflicts of interest to report. This study was supported by the Training Program for Superb Academic Leaders in the Shanghai Health System (XBR ) and the Special Fund for the Building of Leading Talent Teams in Shanghai. *These authors contributed equally to this work. Address reprint requests to Qiang Xia, M.D., Ph.D., Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai , China. Telephone: ; FAX: ; xiaqiang@medmail.com.cn DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases VC 2014 American Association for the Study of Liver Diseases.

2 426 WAN, YU, AND XIA LIVER TRANSPLANTATION, April 2014 Liver transplantation (LT) is performed for irremediable end-stage liver disease. A shortage of donor organs continues to be the main obstacle to the treatment of this group of patients, even though the surgical techniques have progressed immensely. Living donor liver transplantation (LDLT) has emerged as an alternative to deceased donor liver transplantation (DDLT) because of the increasing number of patients waiting for LT. To those with end-stage liver disease, it offers the potential advantages of a shortened waiting time, an optimal donor graft, and the ability to optimize the recipient s health. 1,2 In the United States, the adoption of the Model for End-Stage Liver Disease (MELD) by the United Network for Organ Sharing (UNOS), on February 27, 2002, dramatically altered the allocation system for cadaveric organs. 3,4 Results from the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) further demonstrated that compelling survival benefits were associated with the receipt of LDLT in comparison with waiting for a deceased donor in the MELD liver allocation era. 5 It is generally accepted by most researchers that LDLT can lead to long-term survival rates for adult patients comparable to those associated with DDLT, and this has been shown in many comparative cohorts. 6,7 However, LDLT is criticized for its underlying higher rate of biliary complications in comparison with DDLT, 8 and it remains characterized by its technical complexity and ethical controversies. Although the outcomes of perioperative results and postoperative complications have been investigated in several controlled trials, whether a distinct disparity exists between the 2 techniques in terms of these issues remains controversial. We, therefore, sought to compare the perioperative outcomes and postoperative surgical complication rates associated with LDLT and DDLT in adult patients through a meta-analysis of the published data. MATERIALS AND METHODS Literature Search and Study Selection We identified publications by searching major medical databases such as MEDLINE, Embase, and the Cochrane Library for relevant articles published before October To supplement the primary search, we performed an additional search with Google Scholar. The search strategy consisted of a combination of the following terms: living donor liver transplantation, deceased donor liver transplantation, LDLT, DDLT, living donor, cadaveric donor, andliver transplantation. Relevant articles were also identified from the reference lists of previous articles. The study protocol was approved by the Science and Research Office of Ren Ji Hospital (Shanghai). Two authors (P.W. and X.Y.) carried out searches independently. There were no search restrictions with respect to language or publication type. Inclusion and Exclusion Criteria The inclusion criteria were as follows: (1) published clinical studies comparing LDLT to DDLT in adult patients and (2) studies with at least 1 of the aforementioned outcomes of interest. The exclusion criteria were the following: (1) reviews, case reports, letters, and editorials; (2) studies without a control group of DDLT recipients; (3) studies without available data; (4) studies investigating only patients with hepatocellular carcinoma (HCC); (5) studies investigating emergency LT or patients with acute liver failure; (6) studies focusing on deceased donor split LT; and (7) studies based on data from UNOS or Scientific Registry of Transplant Recipients (SRTR) databases. Moreover, several studies based on overlapping cohorts from the same institutions reported different outcome data because of their respective research aims. Those studies might have been included in the metaanalysis simultaneously, but only 1 study with available data and of better quality was used in each synthetic analysis for a single outcome. Outcomes of Interest Perioperative outcomes and postoperative surgical complications were evaluated in the meta-analysis. The duration of the recipient operation (DRO), the allogeneic red blood cell (RBC) transfusion requirement, the length of the hospital stay, and the cold ischemia time (CIT) were the main perioperative outcomes to be assessed. Specific postoperative complications, including biliary complications, vascular complications, intra-abdominal bleeding, perioperative death, and retransplantation, were recorded and compared between LDLT and DDLT recipients. Data Extraction and Quality Assessment Three observers (P.W., X.Y., and Q.X.) independently extracted data from each study with standardized forms and entered the data into a database. The extracted information included study characteristics (first author, region, year of publication, source journal, study design, and study period), population characteristics (sample size and ages, sexes, and diagnoses of patients), and 9 outcome parameters (DRO, RBC transfusion requirement, length of the hospital stay, CIT, biliary complications, vascular complications, intra-abdominal bleeding, perioperative death, and retransplantation). The Newcastle- Ottawa quality assessment scale 9 was used for the quality assessment of each study, and this was also carried out independently by the 3 observers. Statistical Analysis The meta-analysis was performed with RevMan according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. 10 Weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated for continuous variables, whereas odds ratios (ORs) with 95% CIs were calculated for dichotomous variables. Data for continuous variables in the form of means and

3 LIVER TRANSPLANTATION, Vol. 20, No. 4, 2014 WAN, YU, AND XIA 427 Figure 1. PRISMA 2009 flowchart providing information about the different phases of the systematic review. standard deviations (SDs) were required for the statistical analysis. However, some of the published clinical trials did not report the means and SDs of parameters but rather reported the size of the trial and the medians and ranges. From these available statistics, estimates of the means and SDs were obtained with formulas proposed by Hozo et al. 11 P values < 0.05 were considered to indicate statistical significance in the meta-analysis. Heterogeneity among studies was assessed with the Q statistic (P < 0.10 was considered to represent statistically significant heterogeneity) and the I 2 statistic (I 2 > 50% was considered to represent significant heterogeneity). 12 If there was no significant heterogeneity, a fixed-effect model was used. Otherwise, a random-effect model was used, and a subgroup analysis was performed to explore and explain the differences in the results of different studies. Potential publication bias was assessed with funnel plots. We also conducted a sensitivity analysis in which each trial was excluded in turn to evaluate the influence of a single trial on the pooled estimate. RESULTS Study Characteristics As shown in Fig. 1, the systematic literature search identified 196 relevant references. After screening titles and abstracts, we excluded 147 ineligible or irrelevant articles according to the exclusion criteria. The full text of the 49 remaining articles was retrieved for a formal review. After independent reviews, 30 full-text articles were excluded for the following reasons: (1) 11 studies were based on overlapping cohorts from the same institution, (2) 4 studies were based on UNOS or SRTR databases, and (3) 15 studies lacked available data. Finally, 19 published clinical cohort studies (4 prospective cohorts and 15 retrospective cohorts) were included in the meta-analysis. 6,7,13-29 The characteristics of the 19 included studies are presented in Table 1. All the studies were well designed to compare the 2 arms: LDLT and DDLT. Ten of them investigated patient populations with

4 428 WAN, YU, AND XIA LIVER TRANSPLANTATION, April 2014 TABLE 1. Characteristics of the Included Studies Sample Size (n) Recipient Age (Years)* Patient Reference Year Region Study Design LDLT DDLT LDLT DDLT Diagnosis Garcia-Retortillo et al Spain Prospective cohort (24-68) 59 (38-66) HCV-related Van Vlierberghe et al Belgium Retrospective cohort HCV-related Schiano et al United States Prospective cohort (50-66) 53 (44-65) HCV-related Liu et al Hong Kong Prospective cohort (18-68) 48 (27-66) Mixed Shah et al Canada Retrospective cohort NA Mixed Al-Sebayel et al Saudi Arabia Retrospective cohort (2-63) 44 (11-63) Mixed Schmeding et al Germany Retrospective cohort HCV-related Selzner et al Canada Retrospective cohort (32-68) 53 (36-71) HCV-related Freise et al United States (A2ALL) Retrospective cohort Mixed Gomez et al Argentina Retrospective cohort NA NA Mixed Gallegos-Orozco et al United States Retrospective cohort HCV-related Fisher et al United States Prospective cohort Mixed Lai et al United States Retrospective cohort Mixed Shin et al Korea Retrospective cohort (47-57) 52 (43-60) Mixed Merion et al United States (A2ALL) Retrospective cohort Mixed Li et al Mainland China Retrospective cohort Benign Jain et al United States Retrospective cohort HCV-related Reichman et al Canada Retrospective cohort Mixed Jiang et al Mainland China Retrospective cohort Benign (HBV-related) NOTE: References with the same marker (,, or ) were based on overlapping cohorts. *The data are presented as means and SDs or as medians and ranges.

5 LIVER TRANSPLANTATION, Vol. 20, No. 4, 2014 WAN, YU, AND XIA 429 TABLE 2. Newcastle-Ottawa Scoring System for Cohort Studies Reference Selection Stars Comparability Stars Outcome Stars Total Stars Garcia-Retortillo et al Van Vlierberghe et al Schiano et al Liu et al Shah et al Al-Sebayel et al Schmeding et al Selzner et al Freise et al Gomez et al Gallegos-Orozco et al Fisher et al Lai et al Shin et al Merion et al Li et al Jain et al Reichman et al Jiang et al Figure 2. Meta-analysis of controlled trials comparing DROs for LDLT and DDLT recipients on the basis of a random-effect model. There was significant heterogeneity in the results of the 5 studies. The pooled results showed a significant difference between LDLT and DDLT in terms of DRO, and DRO for LDLT was longer than that for DDLT. various primary diagnoses, whereas 7 studies and 2 studies focused on patients with hepatitis C virus (HCV) related diseases and patients with benign liver diseases, respectively. Three of the studies from Canada (conducted by Shah et al., 17 Selzner et al., 20 and Reichman et al. 6 ) and 2 from mainland China (conducted by Li et al. 27 and Jiang et al. 29 ) were based on overlapping cohorts. Moreover, the data of 2 multicenter studies from the United States (conducted by Freise et al. 21 and Merion et al. 26 ) were derived from the A2ALL database, which included 9 US transplant centers with LDLT experience. Two other US singlecenter studies conducted by Fisher et al. 7 and Lai et al. 24 were based on 2 different cohorts, but their study populations may have overlapped with patients in the A2ALL study. We extracted different outcome data from the overlapping cohorts, and thus no overlapping data were involved in the synthesis for a single outcome. The quality assessment of the included studies is shown in Table 2, and all studies got 6 or more stars. Perioperative Outcomes DRO Five studies reported DRO, and all of them showed that it was significantly longer for LDLT versus DDLT. The heterogeneity test indicated that there was significant heterogeneity in the results of the 5 studies (P , I %), a random-effect model showed a significant difference between LDLT and DDLT in terms of DRO, and DRO was longer for LDLT versus DDLT (WMD , 95% CI , P < 0.001; Fig. 2). Allogeneic RBC Transfusion Five studies provided data on the requirement for allogeneic RBC transfusions, with all of them showing no significant difference between LDLT and DDLT. Significant heterogeneity among the 5 studies was found for RBC transfusion requirements (P , I %); therefore, a random-effect model was used to combine the data. Pooled results revealed that LDLT and DDLT

6 430 WAN, YU, AND XIA LIVER TRANSPLANTATION, April 2014 Figure 3. Meta-analysis of controlled trials comparing allogeneic RBC transfusion requirements for LDLT and DDLT recipients on the basis of a random-effect model. There was significant heterogeneity in the results of the 5 studies. The pooled results showed no significant difference between LDLT and DDLT in terms of allogeneic RBC transfusion requirements. Figure 4. Meta-analysis of controlled trials comparing lengths of hospital stay for LDLT and DDLT recipients on the basis of a fixedeffect model. There was no significant heterogeneity in the results of the 4 studies. The pooled results showed no significant difference between LDLT and DDLT in terms of lengths of hospital stay. groups were comparable in terms of RBC transfusion requirements (WMD , 95% CI to 1.66, P ; Fig. 3). Length of the Hospital Stay The length of the hospital stay was reported in 4 studies, and all of them suggested that no significant difference existed between LDLT and DDLT recipients. There was no significant heterogeneity observed in the length of the hospital stay among the 4 studies (P , I %). Pooled results of a fixed-effect model were found to be equivalent between LDLT and DDLT for the length of the hospital stay (WMD , 95% CI to 1.64, P ; Fig. 4). CIT Seven studies reported CITs, and all of them showed that CIT was significantly longer for DDLT versus LDLT. A random-effect model was used to combine the data because of evident heterogeneity among the studies (P < 0.001, I %). According to the pooled data, CIT for the DDLT group was significantly longer than that for the LDLT group (WMD , 95% CI to , P < 0.001; Fig. 5). Postoperative Complications Biliary Complications Biliary complication rates were reported in 8 of the included studies. In 7 studies, LDLT was associated with significantly higher rates of biliary complications in comparison with DDLT; and only 1 study showed comparable results between the 2 groups. Significant heterogeneity was shown in the 8 studies in terms of biliary complication rates (P , I %). Therefore, pooled results of a random-effect model revealed that a larger percentage of patients suffered from biliary complications in the LDLT group versus the DDLT group (OR , 95% CI , P < 0.001; Fig. 6). Vascular Complications Four studies compared the vascular complication rates of LDLT and DDLT groups. Two reported that LDLT was associated with a significantly higher vascular complication rate than DDLT, whereas no significant difference was observed between the 2 groups in the remaining studies. The results of the 4 studies showed no heterogeneity (P , I 2 5 0%), and pooled results of a fixed-effect model revealed that vascular complications tended to be more common in the LDLT group versus the DDLT group (OR , 95% CI , P ; Fig. 7). Intra-Abdominal Bleeding Three studies reported intra-abdominal bleeding rates after LT. The results of 2 studies showed no significant difference between LDLT and DDLT recipients, whereas the other study suggested a significantly higher intra-abdominal bleeding rate associated with

7 LIVER TRANSPLANTATION, Vol. 20, No. 4, 2014 WAN, YU, AND XIA 431 Figure 5. Meta-analysis of controlled trials comparing CITs for LDLT and DDLT recipients on the basis of a random-effect model. There was significant heterogeneity in the results of the 7 studies. The pooled results showed a significant difference between LDLT and DDLT in terms of CIT, and CIT for LDLT was shorter than that for DDLT. Figure 6. Meta-analysis of controlled trials comparing the biliary complication rates after LDLT and DDLT on the basis of a randomeffect model. There was significant heterogeneity in the results of the 8 studies. The pooled results showed a significant difference between LDLT and DDLT in terms of biliary complication rates, and biliary complications occurred more frequently in LDLT recipients versus DDLT recipients. Figure 7. Meta-analysis of controlled trials comparing the vascular complication rates after LDLT and DDLT on the basis of a fixedeffect model. There was no significant heterogeneity in the results of the 4 studies. The pooled results showed a significant difference between LDLT and DDLT in terms of vascular complication rates, and vascular complications occurred more frequently in LDLT recipients versus DDLT recipients. DDLT recipients. There was no significant heterogeneity in the intra-abdominal bleeding rates of the 3 studies (P , I %), and a fixed-effect model showed that the intra-abdominal bleeding rate for the LDLT group was similar to the rate for the DDLT group (OR , 95% CI , P ; Fig. 8). Perioperative Death Four studies provided data for perioperative mortality after LT, and all of them showed that there was no significant difference between LDLT and DDLT recipients. The heterogeneity test showed no significant heterogeneity in the perioperative mortality rates of the 4

8 432 WAN, YU, AND XIA LIVER TRANSPLANTATION, April 2014 Figure 8. Meta-analysis of controlled trials comparing intra-abdominal bleeding rates after LDLT and DDLT on the basis of a fixedeffect model. There was no significant heterogeneity in the results of the 3 studies. The pooled results showed no significant difference between LDLT and DDLT in terms of intra-abdominal bleeding rates. Figure 9. Meta-analysis of controlled trials comparing perioperative mortality rates after LDLT and DDLT on the basis of a fixed-effect model. There was no significant heterogeneity in the results of the 4 studies. The pooled results showed no significant difference between LDLT and DDLT in terms of perioperative mortality. Figure 10. Meta-analysis of controlled trials comparing retransplantation rates after LDLT and DDLT on the basis of a fixed-effect model. There was no significant heterogeneity in the results of the 7 studies. The pooled results showed a significant difference between LDLT and DDLT in terms of retransplantation rates, and retransplantation occurred more frequently for LDLT recipients versus DDLT recipients. studies (P , I %). The pooled results of a fixed-effect model were found to be comparable for LDLT and DDLT recipients (OR , 95% CI , P ; Fig. 9). Retransplantation Data for retransplantation rates were provided by 7 studies. Five of these studies showed no significant difference between LDLT and DDLT groups with respect to retransplantation rates, whereas 2 studies suggested that retransplantation occurred more frequently in LDLT recipients. No significant heterogeneity was found in the results of the 7 studies (P , I %), and a fixed-effect model was used to combine the data. According to the pooled data, LDLT was associated with a significantly higher retransplantation rate than DDLT (OR , 95% CI , P ; Fig. 10).

9 LIVER TRANSPLANTATION, Vol. 20, No. 4, 2014 WAN, YU, AND XIA 433 TABLE 3. Subgroup Analysis Studies Outcome Subgroup (n) Effect Estimate (95% CI) P Value Heterogeneity DRO Prospective cohort ( ) <0.001 P > 0.99, I 2 5 0% Retrospective cohort ( ) <0.001 P , I % Overall ( ) <0.001 P , I % Allogeneic RBC transfusion requirement Prospective cohort ( to 4.67) 0.40 P , I % Retrospective cohort (20.21 to 1.83) 0.12 P , I 2 5 0% Overall (23.37 to 1.66) 0.51 P , I % CIT Western ( to ) <0.001 P < 0.001, I % Eastern ( to ) <0.001 P , I 2 5 0% Overall ( to ) <0.001 P < 0.001, I % Biliary complication rate <50 LDLT procedures ( ) <0.001 P , I 2 5 0% 50 LDLT procedures ( ) <0.001 P , I 2 5 8% Overall ( ) <0.001 P , I % Subgroup Analysis In order to investigate the source of heterogeneity among the studies, we carried out a subgroup analysis for those syntheses with significant heterogeneity (DRO, allogeneic RBC transfusion requirement, CIT, and biliary complication rate). We stratified the syntheses according to 3 important factors that might be related to the heterogeneity among the studies: study design (prospective or retrospective cohort), transplant area (Western or Eastern country), and number of LDLT patients (<50 or 50 procedures). In the subgroup analysis, we found that heterogeneity among the studies decreased largely when we stratified the DRO and RBC transfusion requirement syntheses by the study design, the CIT synthesis by the transplant area, and the biliary complication rate synthesis by the number of LDLT patients (Table 3). It is worth highlighting here that the biliary complication rate was higher after LDLT versus DDLT, and it might decline dramatically with a center s LDLT experience. The OR of the biliary complication rates for LDLT and DDLT was significantly greater in those studies with a smaller sample size for the LDLT group (<50 LDLT procedures: OR , 95% CI , P < 0.001; 50 LDLT procedures: OR , 95% CI , P < 0.001). Publication Bias Assessment and Sensitivity Analysis In funnel plots (not shown), no points fell outside the 95% CI limits for the length of the hospital stay, vascular complications, intra-abdominal bleeding, perioperative death, and retransplantation, and this suggests an absence of publication bias for these outcomes. For biliary complications and CITs, funnel plots indicated an asymmetry suggesting that negative studies might be less reported. According to a sensitivity analysis, results for subgroups were all in line with the main results, and the exclusion of a single study from the analysis did not significantly alter the overall findings. DISCUSSION Currently, approximately 70% of LDLT recipients are from Asian regions such as Japan, Korea, Hong Kong, and Taiwan. Although the shortage of deceased donors is a universal problem, the situation is particularly serious in Asia for various social, cultural, and historical reasons. Many patients with end-stage liver disease die of disease progression on the waiting list; however, the waiting period has been greatly shortened and survival has been hugely improved with the advent of LDLT. Living donors provide a large pool of organs, and LDLT seems to be the only immediately available alternative to DDLT Furthermore, for emergency patients with fulminant hepatic failure, LDLT has often proved to be an optimal selection and can provide timely grafts to save their lives. 33 It has been demonstrated by many cohort studies that LDLT does not show a weakness in terms of long-term overall survival in comparison with DDLT. 6,7 Even for patients with HCC, the overall survival rates of the 2 groups after listing (intention to treat) and after LT (only for those patients with HCC confirmed in the explanted liver) are quite comparable. 34 In the United States, cadaveric liver allocation was based on the Child-Turcotte-Pugh score before the implementation of the MELD allocation policy. 4 Since 2002, the MELD-based system has extremely altered the allocation of deceased donor livers; it uses 3 objective variables (creatinine, bilirubin, and international normalized ratio) to predict the survival of patients waiting for LT. Berg et al. 5 investigated the benefits of pursuing LDLT versus waiting for DDLT for adult patients in the MELD allocation era. In that study, A2ALL data were used to assess patients outcomes from the time of the first living donor

10 434 WAN, YU, AND XIA LIVER TRANSPLANTATION, April 2014 evaluation on the basis of the transplant candidate MELD score (<15 or 15) and the presence or absence of HCC. The data revealed that among candidates without HCC, a mortality benefit was seen with both a MELD score < 15 and a MELD score 15, whereas a benefit from LDLT was observed only with a MELD score 15 for patients with HCC. Patients with HCC have been prioritized with the assignment of 24 points for T1 lesions and 29 points for T2 lesions in the MELD-based system. 4,35 As a result, the waiting time for a cadaveric graft for HCC patients with a low MELD score is similar to the waiting time for a living donor. In this setting, the lack of a survival advantage associated with LDLT for HCC transplant candidates with a low MELD score is not surprising. Nonetheless, a huge number of patients have derived a significant survival benefit from undergoing LDLT rather than waiting for DDLT in the MELD liver allocation era. The primary aim of our meta-analysis was to compare the operative outcomes of LDLT and DDLT for adult patients; long-term survival outcomes were not included in the comparison. Therefore, we did not set a strict limit on the etiologies of liver diseases. However, we had no doubt that if a study focusing on HCC patients had involved too many patients with advanced HCC or salvage LT, the operative outcomes and perioperative morality rates would have been quite different from those of other studies, so those studies investigating only HCC patients were excluded from our meta-analysis. Mixed diagnoses among studies might have led to some degree of increased heterogeneity in the meta-analysis; thus, we evaluated only surgery-related complications rather than medical complications (eg, acute cellular rejection, infections, and renal dysfunction) after LT in order to minimize the heterogeneity from the mixed etiologies of the studies. We have to acknowledge several limitations inevitably appearing in a meta-analysis investigating postoperative complications: (1) most studies were retrospective observational trials, no randomized controlled trials were identified in the meta-analysis, and the retrospective extraction of data from medical records could not cover the complete results of the complications; (2) surgeons technical experience and medical management during the perioperative period differed greatly in different regions; and (3) the definitions and classification of postoperative complications were not uniform across the different studies. Such characteristics might have caused increased heterogeneity and thus were a weak point of the study. Another limitation of this meta-analysis was the presence of heterogeneity detected within several outcomes (eg, DRO, allogeneic RBC transfusion requirement, CIT, and biliary complications). Although some degree of heterogeneity was inevitable in a medical meta-analysis because of the reality of clinical practice, the heterogeneity of the studies might have undermined the quality of the results obtained. Therefore, we performed a subgroup analysis of the syntheses with significant heterogeneity, and this showed better homogeneity in the subgroups and results similar to the primary findings. On the other hand, a visual assessment with funnel plots was not an ideal method for assessing publication bias, and an inadequate number of studies might have weakened the legitimacy of the results; however, funnel plots remain the accepted method for the assessment of publication bias. Despite such limitations, both heterogeneity tests and funnel plots showed acceptable results for the outcomes of postoperative complications in the present study (the heterogeneity in biliary complications decreased dramatically in the subgroup analysis), and the sensitivity analysis indicated that the results of our meta-analysis could be regarded with a high degree of certainty. In a word, our results provided a systematic and comprehensive evaluation of operative outcomes after LDLT versus DDLT despite the existence of some limitations to the study. A living donor is a patient s private resource, and the implementation of LDLT does not depend on the public organ allocation system, so it has many irreplaceable advantages as a surgical intervention for end-stage liver disease. However, the results of the present study suggest that LDLT could lead to unfavorable results in terms of perioperative outcomes and postoperative surgical complications in comparison with DDLT. Above all, biliary complications occurred at a higher rate in LDLT recipients and represented a significant cause of morbidity in the meta-analysis. When we detected significant heterogeneity in the synthesis of biliary complication rates, we performed a subgroup analysis to determine the source of the heterogeneity. Interestingly, heterogeneity among the studies lost significance when we stratified the studies by different sample sizes in the LDLT group (<50 or 50). The subgroup of studies with less LDLT experience showed an even higher OR for biliary complications, and this means that transplant centers LDLT experience might greatly influence the incidence of biliary complications. Furthermore, several cohort studies have also shown that as centers gain greater LDLT experience, the LDLT benefit is magnified with respect to hospital mortality, postoperative hospitalization rates, and intermediate-term survival. 26,32,36 However, biliary complications might not be lethal events in most situations because they usually can be successfully controlled with radiological interventions. 37 We also found significantly higher rates of vascular complications and retransplantation for LDLT recipients. The technical complexity is much greater with LDLT versus DDLT, and this could be reflected in the significant difference between the 2 groups DROs. Therefore, a reduction of adverse events could be achieved with an accumulation of experience; in other words, LDLT should be conducted at large, experienced transplant centers to enable patients to maximize the benefit gained from the surgery. Moreover, the ethical controversy is another important criticism of LDLT. With the recent surge in the number of LDLT procedures for adult recipients, there

11 LIVER TRANSPLANTATION, Vol. 20, No. 4, 2014 WAN, YU, AND XIA 435 is greater concern about the safety of donors. The transplantation of part of a liver from a living donor was first performed as a response to the needs of children. 38 Their parents could be left with an adequate amount of liver tissue after they had donated segments of the left hepatic lobe. Subsequently, right lobe LDLT was widely performed in adult patients because of the ultimate need for organs. However, a right lobe liver donor had to face a high risk of complications after surgery. In the early stage of LDLT implementation, a report from the United States claimed that 7 donors died after liver donation, and 2 others underwent LT because of an insufficient liver volume left after surgery. 39 Therefore, specialized technical training and accurate assessments of donors before surgery are particularly important for LDLT. In conclusion, biliary complications, vascular complications, and retransplantation occur more frequently in LDLT recipients because of its technical complexity, but the biliary complication rate appears to decrease dramatically as a center gains greater LDLT experience. However, LDLT offers an excellent alternative to DDLT because it facilitates access to LT without compromising long-term recipient outcomes. A significant long-term survival benefit has been shown for potential recipients when they choose to pursue LDLT instead of remaining on the waiting list for DDLT in the MELD era. REFERENCES 1. Thuluvath PJ, Yoo HY. Graft and patient survival after adult live donor liver transplantation compared to a matched cohort who received a deceased donor transplantation. Liver Transpl 2004;10: Abt PL, Mange KC, Olthoff KM, Markmann JF, Reddy KR, Shaked A. Allograft survival following adult-to-adult living donor liver transplantation. 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