Simultaneous liver and kidney transplantation (SLKT) is an appropriate option for those suffering from end-stage liver disease and critical renal insufficiency. Following the introduction of the Model for End-Stage Liver Disease (MELD) scoring system in 2002, the number of SLKT has increased because serum creatinine substantially impacts MELD score prioritization [1]. Due to concern about the potentially disproportionate use of renal allografts in SLKT, standardized medical criteria were established in 2017 to promote equitable allocation between kidney and liver transplant candidates [2, 3]. We previously reported that following the 2017 policy change, the number of SLKT declined despite increased registrations, while LT (liver transplantation) alone increased and were associated with worse 1-year graft survival (GS), highlighting the need for ongoing evaluation of transplant policy [4].

As the MELD score does not incorporate the etiology of liver disease, the current allocation system does not account for liver etiology. We previously evaluated disease-specific differences in waitlist outcomes among LT alone candidates with different underlying etiologies, including alcohol-related liver disease (ALD), nonalcoholic steatohepatitis (NASH), hepatitis C virus infection (HCV), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis [5]. Patients with NASH had a significantly higher risk of 1-year waitlist mortality than those with ALD at comparable MELD scores [5]. The recent retrospective studies also showed that patients with metabolic dysfunction-associated steatohepatitis (MASH) had higher LT waitlist mortality [6, 7]. An Italian registry study showed that patients with MASH were associated with higher LT waitlist mortality, while these candidates demonstrated the greatest 5-year LT survival benefit at the same MELD score [6]. However, few studies have evaluated potential differences in disparities in waitlist outcomes among major liver disease etiologies in the context of SLKT.

This study aims to assess differences in waitlist outcomes among major liver disease groups, including ALD, HCV, MASH and biliary diseases by using Organ Procurement and Transplantation Network (OPTN) dataset in the contemporary SLKT policy era established in 2017. On February 4, 2020, the liver allocation system in the United States underwent a major revision, replacing donation service areas with acuity circles as the geographic basis for organ distribution, and shifting from a predominantly local allocation approach to a broader sharing model [8]. Therefore, we also examined whether disease-specific waitlist outcomes changed before and after the allocation system change in 2020.

In this study, we evaluated waitlist outcome variations across major liver disease etiologies, including ALD, HCV, MASH, and biliary diseases in SLKT. Waitlist outcomes varied significantly depending on the liver etiology in SLKT candidates. The Fine-Gray model revealed that patients with MASH had worse 1-year mortality compared to patients with ALD, after adjustment for patient characteristics at listing, whereas the 1-year SLKT probability was comparable between patients with MASH and patients with ALD. When patients were categorized by MELD score at listing (6–20, 21–29, and ≥30), in the middle MELD score group, patients with MASH had a significantly higher 1-year mortality compared to those with ALD. In addition, prior to the allocation policy change in 2020, patients with MASH experienced significantly higher 1-year waitlist mortality compared to those with ALD; however, this disparity was not observed following the policy change. During the post-transplantation period, recipients with MASH had worse 1-year and 3-year patient survival compared to those with ALD.

Prior studies have reported higher LT waitlist mortality in patients with MASH [6, 7, 18], which are consistent with our findings. MASH, previously known as non-alcoholic fatty liver disease, affects an estimated 30% of the global population, although prevalence varies considerably based on individual risk profiles [19]. MASH carries a risk of progression to advanced fibrosis and cirrhosis, and is associated with increased likelihood of HCC, LT, and liver-related mortality [20]. The impact of MASH extends beyond hepatic involvement, such as CVD, CKD, and type 2 diabetes mellitus [21]. Indeed, MASH has been related to an increased risk of CKD, with a recent meta-analysis indicating nearly a twofold higher risk of CKD among patients with MASH [22]. In addition, the majority of deaths among patients with MASH are attributable to CVD [21]. Thus, MASH is a clinically significant condition with systemic involvement, contributing to multi-organ dysfunction and increased mortality. In our study, post-SLKT mortality was higher in recipients with MASH compared with those with ALD. In cause-specific analyses, patients with MASH were associated with a higher risk of CVD-related death than those with ALD, suggesting that CVD risk may have contributed to the increased mortality in this group.

In contrast, several previous reports have suggested that MASH was not independently associated with increased mortality among LT waitlist candidates. Thuluvath et al reported that adjusted cumulative incidence of death on LT waitlist was comparable between MASH and autoimmune hepatitis cirrhosis [23]. However, dialysis and serum creatinine were identified as negative predictors of receiving LT. Thus, the renal dysfunction may play a vital role, particularly among candidates for SLKT. Wong et al analyzed waitlist outcomes among LT alone by disease etiology among patients registered in the United States between 2004 and 2013 [18]. In their report, patients with HCV were associated with higher 1-year waitlist mortality, compared to those with MASH. It should be noted that their study period ended in 2013, prior to the widespread availability of direct-acting antivirals (DAA) for HCV [24]. With the introduction of DAAs as a curative therapy, LT in patients with HCV now shows improved GS compared to the pre-DAA era [25]. This reflects a key difference in the historical context between that study and our current analysis, as our analysis was conducted during the DAA era.

In our study, ALD patients demonstrated the highest 90-day and 1-year LT alone (without receiving KT) probability. When adjusted for clinical factors at listing, this difference was no longer significant among liver etiologies. The reasons for not receiving KT were not clearly identifiable, whether due to renal recovery or the decision of dialysis. Thus, it was difficult to determine which etiology was more likely to be associated with kidney recovery and avoidance of SLKT. However, patients with ALD may have a higher potential for renal recovery than those with other etiologies. Meanwhile, according to the report by Singal et al, OPTN database analysis confirms the rising use of SLKT, particularly among patients with MASH cirrhosis [26]. Notably, the study highlights that SLKT has increased most rapidly in this group and that patients with MASH have worse renal outcomes compared to those with cholestatic or ALD. Future research is warranted to clarify whether the course of renal function differs by etiology among SLKT candidates.

Then, how should our findings be applied to optimize clinical management of SLKT candidates? When evaluating outcomes according to MELD score categories at listing, among SLKT candidates in the middle MELD subgroup, patients with MASH had higher 1-year waitlist mortality than those with ALD, while SLKT probability was comparable. Earlier referral for SLKT and more intensive management during the waiting period may be beneficial for patients with MASH in the middle MELD group. Although incorporation of liver etiology into the MELD score is challenging because overlap exists among etiologies, risk stratification cannot be fully achieved using the MELD score alone. MELD score-based assessment for urgency may be complemented by individual additional risk evaluation, careful follow-up while on the waitlist, including comorbidities, disease trajectory, and the likelihood of renal recovery. A strategy incorporating delayed KT and the safety-net may also be considered for patients with potential for renal recovery.

Since the adoption of the MELD score for organ allocation in 2002, the system of liver allocation and distribution has been changing dynamically with the goal of decreasing waitlist mortality and minimizing geographic variability in median MELD score at the time of transplantation, without compromising graft or patient survival [27]. We previously evaluated the impact of the MELD score, introduced in January 2016 for LT allocation, on waitlist and post-transplantation outcomes, using OPTN data [28]. The introduction of the MELD score improved LT waitlist outcomes by reducing mortality and increasing transplantation rates. In July 2023, MELD 3.0 was implemented to address sex-based disparities by incorporating additional variables such as serum albumin and female sex. ¹ According to retrospective analysis of MELD 3.0 reclassification using OPTN data, female SLKT candidates were more likely to have higher MELD 3.0 scores than their listing MELD/MELD-Na score, suggesting potential benefits for female candidates [29]. Other than the introduction of MELD score, changes to the system of liver allocation and distribution, including Regional Share 15, Regional Share for Status 1, Regional Share 35/National Share 15, and, most recently, the Acuity Circles Distribution Model, have been made [30–32]. On February 4, 2020, the United States implemented a new liver allocation policy, replacing Donation Service Areas (DSAs) with acuity circles as the primary geographic unit for organ distribution, shifting from a primarily local to a broader sharing system [33]. After this allocation policy change, transplantation volume increased nationwide and increased for both high MELD and low MELD centers [8]. Regarding the effect of the acuity circle policy on SLKT, Okumura et al demonstrated that, following the policy change, SLKT candidates had higher MELD scores and were more likely to receive SLKT, with no increase in 90-day waitlist mortality [34]. Additionally, post-transplantation outcomes including one-year patient, liver, and kidney graft survival were comparable between the pre- and post-AC periods, suggesting that the AC policy improved access to SLKT without compromising outcomes [34]. In our analysis, the differences in both 90-day and 1-year waitlist mortality by etiology were no longer observed after the 2020 allocation policy change. This finding suggests a temporal association between the 2020 allocation policy revision and mortality differences by etiology. This observation may also be influenced by the increasing use of marginal livers, including older donors or DCD (donation after circulatory death) [35], as well as growing use of DCD donors and machine perfusion in SLKT [36].

There are several limitations in our study using OPTN database. First, the etiology in this study was based solely on classifications within OPTN database, and cases with overlapping liver diseases could not be fully identified. In OPTN dataset, only 101 cases were identified as having both ALD and HCV during the study period. Given the limited sample size, this group was excluded in this analysis. Second, due to the retrospective cohort, a direct causal relationship with the acuity circle policy could not be determined. Of note, this study focused on patients without exception scores. The number of donors has been increasing consistently since 2010, reaching 14,905 in 2022, which represents a 7.5% increase compared with the previous year [37]. The increase in donor numbers may also have contributed to reducing disparities in mortality across different liver etiologies. Third, given the lack of comprehensive longitudinal data on serum creatinine and GFR prior to listing and throughout the waitlist period, precise classification of renal phenotypes (CKD or sustained AKI) was not available and thus could not be included in the analysis. Dialysis duration was also not included in the analysis due to a substantial amount of missing data. Fourth, there may be potential confounding by era effects such as the COVID-19 period, donor supply shifts and the MELD 3.0 implementation. However, it is difficult to precisely define discrete time periods for factors such as the COVID-19 era and shifts in donor supply. MELD 3.0 was implemented on July 13, 2023 and this study period was from January 2018 to March 2024. As the post-implementation period was relatively short (approximately 8 months), it was also difficult to evaluate its impact adequately. Finally, OPTN database lacks certain detailed clinical information, and unmeasured confounders may have influenced waitlist outcomes.

In conclusion, waitlist outcomes varied significantly depending on the etiology in SLKT. One-year waitlist mortality was higher in patients with MASH compared to those with ALD, despite similar SLKT probabilities. When stratified by MELD score at listing, patients with MASH in the middle score group had significantly higher mortality compared to those with ALD. The revised 2020 allocation policy may be temporally associated with changes in mortality disparities across different liver etiologies; however, further approaches to risk assessment tailored to the etiology of liver disease in SLKT are needed to ensure greater equity.