Abstract
Background
Combined lung+liver transplant (CLLT) is a rare procedure for patients with end-stage lung and liver failure, but has recently gained traction, with many academic centers performing CLLT for the first time. This study describes the state of CLLT in the United States and assesses outcomes.
Methods
The United Network for Organ Sharing Database was queried for all CLLT between October 1994 and March 2024. Transplant sequence was determined by utilizing individual organ ischemic times. Cumulative risk was assessed to determine primary causes of graft failure or death after CLLT, and risk stratification was defined based on patient survival status, lung-graft status, or liver-graft status. Posttransplant survival was further assessed utilizing Kaplan-Meier survival analysis.
Results
A total of 193 CLLTs were analyzed across 39 centers. The number of CLLTs has increased over the last decade. Most of the transplants were lung(s) followed by liver (157 of 179, 87.7%). Most were male (121 of 179, 67.6%), and the median age at transplant was 47 years (interquartile range, 25-59 years). Kaplan-Meier survival at 1 month, 6 months, 1 year, 3 years, 5 years, and 10 years was: 96.3% (95% CI, 92.6%-99.0%), 85.1% (95% CI, 80.1%-90.5%), 81.5% (95% CI, 76.0%-87.4%), 70.4% (95% CI, 63.7%-77.9%), 63.2% (95% CI, 55.7%-71.6%), and 53.3% (95% CI, 44.1%-64.3%). No difference was evident in survival between lung-first or liver-first sequences. Most deaths were due to non–graft-related causes.
Conclusions
CLLT is growing in popularity and serves as a viable option for patients with combined end-stage lung disease and end-stage liver disease. CLLT shows excellent longitudinal survival. No difference exists in survival between a lung-first approach and a liver-first approach. Most deaths after CLLT are unrelated to liver-graft or lung-graft failure.
Visual Abstract
In Short.
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The United Network for Organ Sharing Database was queried for all combined lung+liver transplant (CLLT) between October 1994 and March 2024: 193 CLLTs across 39 centers, lung-first (157/193, 81.3%); liver-first (22/193, 11.4%); transplant sequence unknown (14/193, 7.3%).
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Overall Kaplan-Meier survival at 1 month, 6 months, 1 year, 3 years, 5 years, and 10 years was: 96.3% (95% CI, 92.6%-99.0%), 85.1% (95% CI, 80.1%-90.5%), 81.5% (95% CI, 76.0%-87.4%), 70.4% (95% CI, 63.7%-77.9%), 63.2% (95% CI, 55.7%-71.6%), and 53.3% (95% CI, 44.1%-64.3%).
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No statistical difference exists in survival by sequence, and most deaths after CLLT are due to non–graft-related causes.
Simultaneous end-stage lung and liver failure represents a challenging clinical scenario. Isolated organ transplantation remains an ineffective procedure to restore long-term quality of life and improved survival for patients who present with pathologies that concurrently and irreversibly impact both the lungs and the liver, such as cystic fibrosis, alpha-1 antitrypsin deficiency, idiopathic pulmonary fibrosis, and portopulmonary hypertension with vascular remodeling.1, 2, 3, 4 This limitation arises from the pathophysiologic interplay between these 2 organs, wherein severe dysfunction in one organ often exacerbates the risk of graft dysfunction and failure in the other organ after isolated transplantation, ultimately precluding the restoration of systemic homeostasis.5 Combined lung+liver transplant (CLLT) offers a definitive recourse for this unique population, addressing dual-organ failure while providing an opportunity for durable, long-term outcomes. One unique advantage of a dual-organ transplant that includes a liver is the ability of the liver to modulate the recipient's immune system and induce immunotolerance.6, 7, 8 The first CLLT was undertaken in 1994.5 Since 1988, CLLTs constitute <0.01% of all multiorgan transplants performed in the United States.5
Prior studies on CLLT have been primarily limited to single-center experiences, small case series, or reviews focused on indications and procedural nuances. Our study builds upon the foundational 2005 multiinstitutional analysis of Barshes and colleagues1 by leveraging nearly 2 decades of additional data. This expanded data set allows for a deeper analysis of a significantly larger cohort. We hypothesized that (1) CLLT in the United States is growing in utilization; (2) outcomes after lung-first CLLT and liver-first CLLT are similar; and (3) analysis of an updated cohort of multiinstitutional national data about CLLT will provide valuable insight related to the risk factors associated with primary graft failure or death after CLLT. Therefore, the purpose of this study is (1) to describe the current state of CLLT in the United States and its evolution over time, providing an in-depth analysis of patient demographics, perioperative risk factors, and outcomes, and (2) to identify risk factors for primary graft failure or death that could be addressed to improve outcomes and optimize care delivery for this complex population.
Material and Methods
Study Design and Population
The United Network for Organ Sharing (UNOS) database thoracic data set was queried for all thoracic transplantations between October 1994, the conception of the UNOS database, and March 2024, when the data file was requested. All 220,009 thoracic transplants were filtered for individuals who underwent CLLT. Patients were excluded if they underwent multiorgan transplantation that included other organs in addition to lung+liver or if they underwent previous organ transplantation, as shown in Figure 1. Recipient data were then combined with donor data using an encrypted donor identification, producing a final cohort of 193 patients.
Figure 1.
CONSORT (Consolidated Standards of Reporting Trials) diagram of the cohort. (CLLT, combined lung+liver transplant.)
Transplant sequence was determined using individual organ ischemic times. Transplant order could not be determined for patients with missing lung or liver ischemic time (14 of 193, 7.3%). Therefore, these 14 patients were excluded from Supplemental Tables 1 and 2. Two cohorts were generated based on lung-first (157 of 193, 81.3%) or liver-first (22 of 193,11.4%) CLLT.
This study was determined to be exempt by the University of Florida institutional review board (NH00045110). The data reported here have been supplied by UNOS as the contractor for the Organ Procurement and Transplantation Network. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy of or interpretation by the Organ Procurement and Transplantation Network or the US Government.
Statistical Analysis
Mann-Whitney U tests and Fisher’s exact tests were performed to compare continuous and categorical variables, respectively. All descriptive and comparative statistical analyses were performed in JMP Pro 18 (SAS Institute Inc). A P value less than .05 was considered statistically significant.
Longitudinal survival for the overall cohort and liver-first vs lung-first cohorts was assessed utilizing the Kaplan-Meier method. Survival was assessed with “time-zero” being the date of CLLT. Specific post-CLLT survival estimates were generated at 1 month, 6 months, 1 year, 3 years, 5 years, and 10 years. Post-CLLT survival was compared at each time point utilizing a log-rank test with right censoring.
Competing risks analysis was performed to assess the cumulative incidence of developing graft failure at follow-up. The competing risk outcomes included: (1) alive with no graft failure, (2) primary lung-graft failure, (3) primary liver-graft failure, and (4) death from non-graft causes. Risk estimates were generated out to 10 years post-CLLT. All survival and competing risk examinations were conducted using R software (r-project.org).
Results
Study Population and Demographics
After data filtering, the cohort consisted of 193 patients across 39 centers. In the overall cohort, the median age of recipients was 47 (interquartile range [IQR], 25-59) years. Most recipients were adults (≥18 years) (180 of 193, 93.3%), while 13 of 193 (6.7%) were 12-18 years and none were <12 years. Most were male (131 of 193, 67.9%). Median body mass index was 22.4 (IQR, 19-26.95) kg/m2 and median distance to donor was 84 (IQR, 10.5-207) miles.
Supplemental Table 1 provides demographics and operative data for patients undergoing liver-first transplantation or lung-first transplantation. Supplemental Table 2 provides postoperative and outcome data for patients undergoing liver-first transplantation or lung-first transplantation. Median age of the donor was 26 (IQR, 20-38) years, while the median age of the recipient was 47 (IQR, 25-59) years. The majority of donors were male (118 of 179, 65.92%), and the majority of recipients were male (121 of 179, 67.60%). The most common cause of donor death was stroke (49 of 179, 27.37%), while the most common indication for transplant was cystic fibrosis (lung diagnosis: 79 of 179, 44.13%; liver diagnosis: 71 of 179, 39.66%). When comparing the demographics between the 2 cohorts, there were no statistically significant differences in liver-first CLLT or lung-first CLLT.
Preoperative and Intraoperative Characteristics
Preoperatively, there was a statistically significant difference in donor blood type between lung-first and liver-first transplants (P = .028). Additionally, there was a significant difference in recipient blood type between transplant sequences (P = .044). ABO matching between donor and recipient was also significantly different between the 2 groups (P = .044). Liver-first recipients were more likely to have a history of prostacyclin use vs lung-first recipients (P = .015). Finally, lung-first recipients were more likely to have spent a longer time on the transplant waitlist. No other differences were identified in preoperative labs, hemodynamics, or medical conditions between the 2 cohorts.
Median liver ischemic time for liver-first recipients was 4.58 (IQR, 3.00-5.53) hours, while median lung ischemic time was 8.30 (IQR, 6.50-10.25) hours. Median lung ischemic time for lung-first recipients was 4.80 (IQR, 3.80-5.80) hours, while median liver ischemic time was 8.40 (IQR, 7.27-10.12) hours. No other differences were identified in intraoperative characteristics between the 2 cohorts.
Postoperatively, the most common complication overall was the need for dialysis (32 of 179, 17.88%). No statistical difference in postoperative complications was identified between the 2 cohorts.
Lung+Liver Transplant in the United States
The proportions of combined lung+liver procurements and transplants are displayed on a map of the United States demarcated by UNOS Region, as seen in Figure 2, with the heatmap representing the proportion of transplants occurring within that region. A time series of the overall number of CLLTs by year is displayed at the bottom of Figure 2. Over the last decade, there has been an increase in the number of CLLTs in the United States.
Figure 2.
US map depicting the number and percentage of combined lung+liver procurements and transplants by United Network for Organ Sharing regions. The heatmap is determined by the number of combined lung+liver transplants in each region. The total number of combined lung+liver transplants is seen by year in the time series.
Survival Analysis
Of 193 CLLTs, 188 contained survival data and were used when calculating Kaplan-Meier survival. Figure 3 documents the estimated 10-year survival of the entire cohort. Kaplan-Meier survival at 1 month, 6 months, 1 year, 3 years, 5 years, and 10 years was: 96.3% (95% CI, 92.6%-99.0%), 85.1% (95% CI, 80.1%-90.5%), 81.5% (95% CI, 76.0%-87.4%), 70.4% (95% CI, 63.7%-77.9%), 63.2% (95% CI, 55.7%-71.6%), and 53.3% (95% CI, 44.1%-64.3%).
Figure 3.
Kaplan-Meier survival analysis of overall survival of combined lung+liver transplants over 10 years with a 95% CI.
Kaplan-Meier survival stratified by transplant sequence was also estimated for all 179 patients with ischemic time data, as seen in Figure 4A. Enlarged survival graphs for up to 1 year post-CLLT can be seen in Figure 4B. Survival data was available for 22 patients who underwent liver-first CLLT and 157 patients who underwent lung-first CLLT. No difference was identified in survival between lung-first and liver-first transplants.
Figure 4.
Kaplan-Meier survival analysis of combined lung+liver transplants stratified by transplant sequence. (A) Kaplan-Meier survival analysis of combined lung+liver transplants stratified by transplant sequence for up to 10 years after combined lung+liver transplantation. (B) Enlarged Kaplan-Meier survival analysis of combined lung+liver transplants stratified by transplant sequence for up to 1 year after combined lung+liver transplantation.
Competing Risk Analysis
Supplemental Figure 1 documents cumulative risk, with risk stratification defined by patient status, lung-graft status, or liver-graft status. Most deaths were not associated with graft failure.
The cumulative incidence after CLLT of lung-graft failure was 3.44% (95% CI, 1.41%-6.96%) at 1 year, 7.78% (95% CI, 4.21%-12.8%) at 3 years, 11.6% (95% CI, 6.83%-17.9%) at 5 years, and 16.9% (95% CI, 10.4%-24.7%) at 10 years. The cumulative incidence after CLLT of liver-graft failure was 3.31% (95% CI, 1.36%-6.69%) at 1 year, 4.59% (95% CI, 2.14%-8.46%) at 3 years, 5.48% (95% CI, 2.65%-9.81%) at 5 years, and 6.72% (95% CI, 3.28%-11.8%) at 10 years. The cumulative incidence of death after CLLT from non-graft related causes was 12.2% (95% CI, 7.94%-17.5%) at 1 year, 19.8% (95% CI, 14.1%-26.3%) at 3 years, 23.4% (95% CI, 17.0%-30.5%) at 5 years, and 30.7% (95% CI, 21.8%-40.0%) at 10 years.
Comment
This analysis describes the contemporary state of CLLT in the United States and the associated outcomes. Among the 193 CLLTs examined: (1) most underwent lung-first transplantation, (2) no difference was identified in survival between lung-first and liver-first transplants, and (3) most deaths were not associated with graft failure.
Previous studies regarding CLLT are sparse and generally focused on single-center experiences.2,3,9 Multiinstitutional studies of CLLT lack contemporary data.1,4 Given the rise in popularity of CLLT, it was justified to reanalyze this unique approach to managing multiorgan failure.
Overall survival after CLLT in our current multiinstitutional cohort at 1 year and 5 years was 81.5% and 63.2%, respectively. Interestingly, a multiinstitutional analysis of UNOS published in 2005 analyzed 11 patients who underwent CLLT in the United States and reported “The 1- and 5-year patient survival rates are of 79% and 63%, respectively, and no patient has required retransplantation.”1
An additional analysis of interest is the comparison of overall survival after CLLT vs overall survival after isolated lung transplantation or isolated liver transplantation. Purvis and colleagues4 compared survival after CLLT vs survival after isolated liver transplantation, reporting 82.5% and 62.2% survival after CLLT at 1 year and 5 years, respectively, similar to the survival after CLLT at 1 year and 5 years of 81.5% and 63.2%, respectively, reported in our current analysis. As such, their comparisons to historical survival after isolated liver transplantation apply to our analysis and demonstrate superior 1-year and 5-year survival after isolated liver transplantation of 92.2% and 80.9%, respectively. Even with propensity matching, Purvis and colleagues demonstrated a 105% increased risk of death after CLLT compared with isolated liver transplantation.4 Given this disparity, Purvis and associates concluded: “CLLT has significantly worse survival than liver-alone transplant. With an increasing organ shortage, medical necessity criteria such as those developed for simultaneous liver-kidney transplantation should be developed for simultaneous lung-liver transplants to assure liver allografts are only allocated when truly needed.”
Similar to Purvis and colleagues, Freischlag and colleagues10 compared CLLT to matched survival after isolated lung transplantation. They reported comparable 1-year survival of 89.5% after CLLT and 86.7% after isolated lung transplantation, as well as 5-year survival of 67.0% after CLLT and 64.6% after isolated lung transplantation.10 Freischlag and colleagues reported that no statistical difference was demonstrated in the comparison of overall survival after CLLT vs after isolated lung transplantation(P = .20).10 Of note, the survival after CLLT reported by Freischlag and colleagues is similar to the survival reported after CLLT in our current analysis.
Limitations
This study must be interpreted in the context of several limitations. First, a retrospective analysis of a publicly available data set is susceptible to errors. Second, due to the period of time during which these data were analyzed, new granular data variables being collected by UNOS could not be adequately compared because of a lack of completeness in more temporally remote CLLTs. Third, incomplete data for some patients may reduce the representativeness of the samples and introduce bias (188 of 193 [97.4%] had survival data, and 179 of 193 [92.7%] had survival data and transplant sequence data). Fourth, the data set consists of transplants being performed at only 39 centers, which may make it challenging to apply the results to all centers (although these 39 centers are the only centers to have performed CLLT in the United States). Fourth, the UNOS data set used in this analysis supplies data only on patients who were successfully transplanted; data are not included about the population of patients who were listed for transplantation and either were withdrawn from the waiting list, died on the waiting list, or remain on the waiting list at the time of the analysis.
Future Direction
Future analyses should (1) examine factors that may contribute to survival differences in matched outcomes between CLLT and isolated organ recipients, (2) characterize the impact of the MELD (Model for End-Stage Liver Disease) score and lung allocation scores on outcomes after CLLT, (3) develop more robust forms of risk adjustment specifically for patients undergoing CLLT, (4) examine the impact of the era of CLLT on outcomes after CLLT, and (5) evaluate the impact of pretransplant mechanical circulatory support on outcomes after CLLT.
Conclusions
Combined lung+liver transplantation in the United States has shown an increase in popularity over the past decade when compared with the previous decades. Analysis shows CLLT mostly occurs in a lung-first approach across the United States; however, no statistical difference exists in survival by sequence. Most deaths after CLLT are due to non–graft-related causes.
Acknowledgments
The Supplemental Material can be viewed in the online version of this article [https://doi.org/10.1016/j.atssr.2025.12.011] on https://www.annalsthoracicsurgeryshortrep.org.
Funding Sources
This research was funded in part through National Institutes of Health National Heart, Lung, and Blood Institute grant 2T35HL007489-41.
Disclosures
The authors have no conflicts of interest to disclose.
Footnotes
Presented at the Sixty-first Annual Meeting of The Society of Thoracic Surgeons, Los Angeles, CA, Jan 24-26, 2025.
Supplementary Data
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