Postoperative outcomes in living donor liver transplant vs. deceased donor liver transplant in patients with metabolic dysfunction-associated steatohepatitis: a UNOS database analysis

Introduction

There is a clear need to increase access to transplantation for patients with metabolic dysfunction-associated steatohepatitis (MASH). Despite being the second most common indication for liver transplant in the Unites States, accounting for 19.6% of adults liver transplants, mortality in the waiting list for these patients is higher when compared to other diagnoses, and almost as high as those with acute liver failure (1). With rates of metabolic dysfunction-associated steatotic liver disease (MASLD) surpassing 40% in North America (2), strategies to optimize access to transplantation and improve postoperative outcomes for recipients under this metabolic umbrella—particularly MASH patients—is imperative.

However, the ongoing organ shortage, along with the innate complexity of MASH patients and the conflicting evidence regarding impaired postoperative outcomes, makes liver transplantation (LT) for these patients a very challenging clinical scenario. Associated postoperative risks include developing recurrent or de novo MASLD, metabolic syndrome, and increase risk of cardiovascular events (3-5). Nonetheless, emerging evidence favors careful selection of donors and recipients in order to optimize postoperative outcomes. Some groups have even found similar survival rates and post-transplant outcomes for MASH patients under specific recipient and donor circumstances (6-8).

Moreover, as medical comorbidity increases the rate of waitlist dropout in patients with MASH cirrhosis (9), and with past MELD score calculations and liver allocation policies not accurately correlating to severity of disease (10), transplanting this population in a timely fashion after medical optimization is ideal. Therefore, living donor liver transplant (LDLT) appears as a promising option for these patients. A survival advantage for LDLT compared with deceased donor liver transplant (DDLT) has been demonstrated when analyzed from the time of listing, possibly because LDLT allows transplantation of patients at an earlier stage of disease (11) and has been shown to provide survival benefit when compared to remaining on the waitlist, even at low MELD scores (12). However, there is limited literature on the comparison of outcomes between LDLT and DDLT for MASH. The aim of this study is to evaluate the role of LDLT for MASH patients and compare outcomes between LDLT and DDLT for this population using data from the United Network for Organ Sharing (UNOS) database. We present this article in accordance with the STROBE reporting checklist (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-319/rc).

Methods

Study design

We performed a retrospective review of the UNOS Standard Transplant Analysis and Research (STAR) file from 2002 until June 2022. Cases included in the main analysis were adult patients with diagnosis of MASH who underwent LT. We compared outcomes in this population based on graft type: LDLT and DDLT. Identification of LT recipients with MASH diagnosis revealed that the first case was reported in 2002. Therefore, LT cases performed before 2002 were excluded from the analysis. In addition, recipients <18 years, previous LTs, multi-organ transplants, those undergoing domino liver transplant, LT with donation after circulatory death (DCD) grafts, and all recipients with a diagnosis other than MASH (also MASH and another diagnosis) were excluded from the analysis. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Data analysis

Donor demographic variables such as age, gender, weight (kg), height (cm), body mass index (BMI), and ethnicity were analyzed. Graft type and cold ischemia time were also included in the analysis.

Recipient demographic and anthropometric characteristics were included and compared between groups. In addition, associated comorbidities and variables deemed important for estimation of recipients disease severity such as history of diabetes, spontaneous peritonitis, dialysis requirement a week prior to transplant, portal vein thrombosis (PVT) history, transjugular intrahepatic portosystemic shunt (TIPS) history, and model for end-stage liver disease (MELD) at the time of transplant, were also included and compared between groups. Key recipient pre-transplant laboratory values and total time on waitlist were analyzed.

Post-operative outcomes including length of stay and 1-, 3-, and 5-year patient and graft survival were compared between groups. Granular data on postoperative complications is not available in the UNOS/STAR file. Therefore, we were unable to evaluate such data. Nevertheless, reported causes of graft failure were evaluated and compared between groups, including vascular thrombosis rates leading to graft failure, primary non-function, infection, rejection, recurrent disease, cholangiopathy, and recurrent disease.

Statistical analysis

All analyses were performed using IBM SPSS Statistics Version 26 (IBM Corp., Armonk, NY, USA). Data were presented as median (interquartile range) for continuous variables and count (percentages) for categorical data. Continuous variables were calculated using the independent two-sample t-test or Mann-Whitney U test according to the normality of the data distribution. For categorical data, Pearson Chi-squared test or Fisher’s exact test were used as appropriate. For all analysis, two-tailed P values ≤0.05 were considered statistically significant. The Kaplan-Meier method was used to analyze survival between study groups and the groups were compared using log-rank test. Outcome for graft and patient survival were calculated by using the variables “pstatus” and “gstatus”—Boolean most recent patient status (based on composite death date)—respectively. Cox proportional hazards regression was performed to examine the effect of donor type on recipient survival. All comparisons made were adjusted for recipient age, BMI, MELD score, prior history of PVT, dialysis within the week prior to transplant, and history of upper abdominal surgery. Due to the retrospective nature of the study and abstraction of de-identified data from the national registry, the present study was deemed exempt by the Institutional Review Board.

Results

A total of 13,107 records of LT recipients with diagnosis of MASH were identified from the UNOS/STAR database from 2002 until June 2022. After exclusion criteria, 10,344 cases were included in the analysis. Of those, 655 underwent LDLT and 9,689 DDLT. Within the LDLT cohort, 603 were right lobe grafts, 47 were left lobe grafts, and in 5 cases the type of graft was not indicated.

Donor characteristics

Donor characteristics are shown in Table 1. LDLT donors were significantly younger than DDLT donors {37 [29–45] vs. 45 [30–58] years; P<0.001}. In the LDLT group, the proportion of females was significantly higher than in the DDLT group (54.8% vs. 45.2%; P<0.001). The BMI differed statistically between groups, however the difference was not clinically significant {LDLT 27.0 [24.6–29.5] vs. DDLT 27.5 [23.8–32.1] kg/m²; P=0.001}. As expected, cold ischemia time for LDLT was significantly shorter than for DDLT {1.7 [1.0–2.2] vs. 5.9 [4.7–7.3] hours; P<0.001}.

Recipient characteristics

Recipient characteristics are shown in Table 2. The age at transplant was statistically different, although, clinically comparable between groups {LDLT 61 [56–66] years vs. DDLT 60 [54–65] years; P<0.001}. The majority of LDLT recipients were female (55.7% vs. 44.3%; P<0.001). LDLT recipients had a significantly lower BMI compared to DDLT recipients {29.8 [26.5–33.7] vs. 31.7 [27.8–36.1] kg/m²; P<0.001}. The proportion of previous upper abdominal surgery was significantly lower in LDLT recipients than in DDLT recipients (48.9% vs. 54%; P=0.01). The proportion of LDLT recipients on dialysis was lower than the proportion of DDLT recipients (1.2% vs. 12.9%; P<0.001), and the creatinine levels were lower in the LDLT group {1.0 [0.7–1.3] vs. 1.2 [0.9–1.8] mg/dL; P<0.001}. The mean calculated MELD score was significantly lower in the LDLT group {16 [12–21] vs. 24 [17–31]; P<0.001}. LDLT recipients were on the waiting list longer {130 [67–266] vs. 69 [14–229] days; P<0.001}.

Postoperative recipient outcomes

Postoperative recipient outcomes are shown in Table 3. Overall mortality was significantly lower in the LDLT group (14.2% vs. 23.2%; P<0.001). The proportion of re-transplants was higher in the LDLT group compared to the DDLT group (5.3% vs. 2.2%; P<0.001). There were no differences in patients treated for rejection within 6 months and 1 year in either group (6.1% vs. 5.8%, P=0.83; 6.6% vs. 6.4%, P=0.59). Causes of graft failure due to hepatic artery thrombosis occurred more frequently in the LDLT group (1.4% vs. 0.3%; P<0.001). Actuarial 1-/3-/5-year patient survival was significantly higher in the LDLT group (94%/89%/82% vs. 91%/85%/79%, P=0.01; median follow up time 12.4 years for DDLT, 15.6 years for LDLT) (Figure 1). The 1-/3-/5-year graft survival was similar in both groups (89%/83%/77% vs. 90%/83%/78%, P=0.65; median follow up 12.7 years for DDLT, 15.3 years for LDLT). In multivariable Cox-regression model, DDLT maintained a significant association with mortality [hazard ratio (HR) =1.25, 95% confidence interval (CI): 1.026–1.523, P=0.03] (see Table 4).

Figure 1 Graft and recipient survival after liver transplantation. (A) Graft survival following liver transplantation in adult recipients with MASH according to donor type [P=0.65, log rank (Mantel-Cox)]. (B) Patient survival following liver transplantation in adult recipients with MASH according to donor type [P=0.01, log rank (Mantel-Cox)]. DDLT, deceased donor liver transplant; LDLT, living donor liver transplantation; MASH, metabolic dysfunction-associated steatohepatitis.

Sub-analyses on waitlist time

A series of sub-analyses were performed in an attempt to better characterize the reason for a longer time on waitlist amongst the patients in the LDLT group vs. the DDLT group. The analysis of waitlist time in LDLT and DDLT recipients with similar MELD score is shown in Table 5. LDLT recipients with MELD <25 {134 [69–278] vs. 115 [35–302] days; P<0.001} and MELD ≥25 {100 [55–191] vs. 26 [6–135] days; P<0.001} were on the waitlist significantly longer. LDLT recipients with MELD ≤18 were on the waitlist shorter, but without statistical significance {134 [62–278] vs. 151 [54–356] days, P=0.44}. LDLT recipients had a significantly lower MELD score in all of the three subgroups MELD <25 {15 [11–19] vs. 18 [14–21]; P<0.001}, MELD ≥25 {27 [26–31] vs. 32 [28–37]; P<0.001}, and MELD <18 {13 [10–16] vs. 15 [12–17]; P<0.001}.

The analysis of waitlist time among LDLT recipients based on donor relationship is shown in Table 6. Biologically related LDLT recipients were on the waitlist significantly shorter than non-biologically related LDLT recipients {115 [59–237] vs. 158 [77–316] days; P=0.002} and showed similar MELD score {16 [12–21] vs. 17 [13–23]; P=0.65}.

The analysis of waitlist time between biologically related LDLT and DDLT is shown in Table 7. Biologically related LDLT were on the waitlist significantly longer than DDLT {115 [59–237] vs. 69 [14–229] days, P<0.001}. The mean calculated MELD score was significantly lower in biologically related LDLT {16 [12–21] vs. 24 [17–31], P<0.001}.

Discussion

The increasing prevalence of MASLD and MASH due to the obesity epidemic is a major public health concern. MASH is now one of the leading indications for LT in the United States and the number of MASH patients on the LT waitlist has increased substantially over the last years (13-16). Our study suggests that there is a potential patient survival benefit for patients with MASH who undergo LDLT.

In view of the impending shortage of organs, LDLT has been shown to be a safe and effective alternative to DDLT (11). Overall, 10-year outcomes for LT in the setting of MASH are inferior when compared to LT for other indications (17). However, data on LDLT in MASH patients are lacking. For example, large retrospective studies such as the A2ALL study have not specifically analyzed these two groups (18). Barbas et al., in a study from the University of Toronto, reported their experience with 48 LDLTs from a total 176 total LT performed for MASH and found that LDLT had similar perioperative outcomes and graft and patient survival compared with DDLT. In addition, they found that LDLT allows transplantation at an earlier stage and in a less decompensated state in MASH patients (11). Cho et al. demonstrated equivalent outcomes in obese and non-obese recipients who underwent LDLT, although the majority of their patients underwent LT for hepatitis B virus, and medical comorbidity reported in the study was equivalent between the obese and non-obese cohorts (19). In a similar study, Tanaka et al. reported their experience at a single Japanese center where they compared outcomes of LDLT for patient with and without MASH. They found no difference in recipient or graft survival, but the study was limited in that only 7 patients in their LDLT cohort of 425 patients underwent LT for MASH cirrhosis (20).

Our study shows that LDLT in MASH patients has higher patient survival rates at 1, 3, and 5 years, respectively, compared with DDLT. The 1-, 3-, and 5-year graft survival for LDLT was similar to that for DDLT. These results highlight that LDLT is a safe and effective alternative to DDLT in MASH patients. In addition, this study shows that LDLT has lower overall mortality despite higher rates of re-transplantation. The significantly lower mean MELD score and dialysis rates in the week before transplantation in LDLT suggest that MASH patients may undergo transplant in a less decompensated stage of disease than in DDLT. This is likely to be an important reason why survival rates were higher in LDLT patients. The decreased cold ischemia time in LDLT likely also has a positive influence on the outcome, as LDLT allow these patients access to a high-quality graft in a more controlled setting.

Overall, LDLT recipients had a longer time on waitlist. Given that LDLT recipients had a lower mean MELD score, we performed several sub-analyses for waitlist time, including a comparison between similar MELD scores in LDLT and DDLT. Nonetheless, despite this stratification, LDLT recipients continued to have longer time on waitlist, with the exception of recipients with MELD <18, in which LDLT recipients had shorter time on waitlist, but without statistical significance. However, even after being divided into groups with similar MELD scores, LDLT recipients continued to have lower average MELD scores within each MELD subset group. Interestingly though, biologically related LDLT recipients had a significantly shorter time on waitlist than non-biologically related LDLT recipients. This may be due to earlier identification, workup, and acceptance of related donors in the recipient’s known acquaintances, whereas if no acceptable donor is found among relatives, the workup is then expanded to non-related donors. Possible explanations for the longer waitlist time in the LDLT cohort may be related to the lower MELD and not attracting adequate organ offers during earlier stages of disease and the living donor work up period, and delaying pursuance of LT in patients who are potentially “too well” for transplant during the workup of potential donors. It may also be that it is difficult to find an acceptable living donor able to meet the metabolic and anatomic needs of MASH cirrhotic recipients. There may also be other individual center LDLT practices (developing programs, protocols, and surgical comfort level in this patient population) which are not accounted for in this national database.

This study has some limitations, mainly associated with the nature of retrospective analysis. There is potential for selection bias without randomization of the two treatment groups. Also, we are limited by the nature of a large de-identified dataset, in that we are unable to account for patient- and center-specific factors that may impact outcomes. Moreover, we are unable to analyze specific causes of graft loss, nor are we able to analyze short- and long-term complications. Despite these limitations, this is a large national dataset representing multiple centers, which affords the opportunity to assess for statistically significant differences in the two groups.

Conclusions

In conclusion, LDLT offers access to LT for MASH patients at an earlier stage of disease, with lower MELD and lower incidence of pre-operative renal failure. This study shows that LDLT for MASH has equivalent graft survival outcomes and increased patient survival.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-319/rc

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-319/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-319/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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