Abstract
Objective
To compare isolated liver transplantation (LT) for cystic fibrosis (CF) versus other indications and versus combined liver‐lung transplantation (CLLT) for CF in children and identify factors associated with survival.
Methods
We compared clinical and survival data after first isolated LT for CF versus other indications and versus CLLT for CF in children (<18 years) using United Network for Organ Sharing data (02/2002–12/2024).
Results
A total of 157 pediatric CF transplant recipients were included (LT: 145; CLLT: 12). Isolated CF LT recipients had higher total bilirubin (TB) than CLLT (median 1.6 vs. 0.7 mg/dL, p = 0.02). A higher proportion of CF transplant recipients with high TB levels (≥1.5 mg/dL) had ascites, encephalopathy, and required life support compared to those with low TB levels (<1.5 mg/dL). CF LT demonstrated superior patient survival versus CF CLLT (log‐rank test, p = 0.02; 5‐year: 89.1% vs. 72.2%), but inferior versus non‐CF LT (log‐rank test, p < 0.001; 5‐year: 91.5%). Multivariable Cox regression showed increased risk of patient mortality and liver graft loss in CF CLLT recipients compared to isolated CF LT recipients (hazard ratio [HR] = 2.92, 95% confidence interval [95% CI]: 1.20–7.07, p = 0.02 and HR = 2.56, 95% CI: 1.09–5.98, p = 0.03, respectively) and recipients with higher TB levels (HR = 1.05, 95% CI: 1.01–1.10, p = 0.008 and HR = 1.05, 95% CI: 1.01–1.09, p = 0.008, respectively), when adjusting for recipient age, albumin and international normalized ratio (INR) at time of LT, ICU status, and liver graft type. Multivariable Cox regression of isolated LT recipients showed increased risk of patient mortality (HR = 2.03, 95% CI: 1.41–2.93, p < 0.001) and liver graft loss (HR = 1.54, 95% CI: 1.13–2.11, p = 0.006) for CF compared to non‐CF etiologies, when adjusting for recipient age, albumin, INR, and TB at time of LT, ICU status, and liver graft type.
Conclusion
Isolated LT for CF was associated with superior survival compared to CLLT for CF, but inferior survival compared to LT for non‐CF indications. Higher TB in CF may be a marker of inferior outcomes post‐LT.
Keywords: bilirubin, cirrhosis, lung transplantation, pediatric liver transplantation, united network for organ sharing
What is Known
Cystic fibrosis (CF) is the most common autosomal recessive life‐limiting disease in the Caucasian population, often leading to multisystem complications, including advanced liver disease with portal hypertension.
Isolated liver transplantation and combined liver‐lung transplantation are treatment options for CF‐related advanced liver disease, but limited large‐scale pediatric data exist comparing outcomes of these approaches.
What is New
Isolated LT is associated with superior survival compared to CLLT for CF, but still inferior survival compared to other isolated LT indications.
High total bilirubin at the time of LT may be an indicator of high risk for inferior patient and liver graft survival in CF following LT.
1. INTRODUCTION
Cystic fibrosis (CF) is the most common life‐limiting autosomal recessive disease in the Caucasian population. 1 It is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which controls ion transport and water movement across epithelial barriers. 2 CFTR is present in epithelial cells of various organs, such as the lungs, sweat glands, liver, and pancreas, contributing to CF's multisystem nature. 1 , 2 Modern multidisciplinary care and highly effective modulator therapies (HEMT) have improved CF prognosis, showcasing the emergence of non‐pulmonary complications. 3 , 4 Among these, CF‐associated advanced liver disease with portal hypertension affects about 3%–10% of all persons with CF (pwCF) and thus is a leading cause of mortality. 3 , 4 , 5 , 6 , 7 , 8
Advanced liver disease typically develops within the first 20 years of life of pwCF, with variable progression. 9 While some degree of CF hepatobiliary involvement is common, clinically significant liver disease affects <10% with a median age at diagnosis of 10 years. 10 Management of CF‐related advanced liver disease focuses on addressing complications of both portal hypertension and nutritional deficiencies. 11 , 12 Isolated liver transplantation (LT) is the preferred treatment for patients with decompensated advanced liver disease. 13 , 14 , 15 However, careful assessment of pulmonary function is crucial during patient selection due to significant post‐transplant morbidity and mortality from pulmonary complications, primarily related to infections. 13 In cases of end‐stage liver disease with significant pulmonary complications, combined liver‐lung transplantation (CLLT) may be considered, though historical data indicate CLLT may carry a poorer prognosis compared with isolated LT. 15 In fact, each year, about 6‐8% of pwCF with advanced lung disease undergo lung transplantation. 16
Given the prevalence of single‐center studies with restricted patient cohorts and the lack of recent large cohort studies, we used US transplant registry data to evaluate patient and liver graft survival following either isolated LT or CLLT, and to identify risk factors associated with patient mortality and liver graft loss.
2. METHODS
2.1. Ethics statement
No Institutional Review Board approval was required as all data were de‐identified.
2.2. Data source, patient identification, data encoding
The United Network for Organ Sharing (UNOS) database administers the Organ Procurement and Transplantation Network under contract with the US Department of Health and Human Services. It contains data on all transplant candidates listed for solid organ transplantation in the USA since October 1987.
Patient transplant data were obtained from the UNOS Standard Transplant Analysis and Research data file (released on January 1, 2025). This retrospective cohort study included all pediatric (<18 years) pwCF who underwent their first isolated LT or CLLT (no previous LT or lung transplantation) between February 26, 2002, and December 31, 2024, in the USA. For a more accurate comparison between children receiving isolated LT for CF versus other indications, a non‐CF LT cohort was constructed consisting of all children (<18 years) who underwent their first isolated LT over the same time period.
2.3. Statistical analysis
Comparisons included pwCF who underwent LT versus CLLT, as well as children who underwent isolated LT for CF versus other indications. As we intended to explore total bilirubin (TB) as a marker of disease severity among pwCF, we performed a sub‐analysis within the pwCF cohort stratified by TB level with patient groups divided into high and low TB groups based on the median TB level at the time of LT. While TB is not a specific marker of cholestasis in CF, and its elevation may not reflect classical features of advanced CF‐related liver disease—particularly given the typically low bile acid levels and depleted bile acid pool in these patients—its use in this context was hypothesis‐driven. The rationale stems from recent observations that TB levels are increasingly elevated in pwCF, possibly partially due to the effects of HEMT. 17 Therefore, TB may serve as a composite surrogate of evolving hepatic and systemic disease processes in pwCF.
Categorical variables were reported using frequency and percentage, while continuous variables were reported using median and interquartile range (IQR). Differences between the comparison groups were assessed using the chi‐square test for categorical variables and the Mann–Whitney U test for continuous variables. Post‐transplant patient and liver graft survival were the primary outcomes of interest, with patient mortality and liver graft loss being the events of interest, respectively. Patients were censored at the last available follow‐up. The Kaplan–Meier method was used to determine the 1‐, 3‐, and 5‐year patient and liver graft survival rates. The log‐rank test was used to assess differences in post‐transplant patient and liver graft survival between the comparison groups (a. CF LT vs. CF CLLT vs. non‐CF LT, b. pwCF low vs. high TB levels).
Four multivariable Cox regression models were constructed (a. patient mortality in all pwCF, b. liver graft loss in all pwCF, c. patient mortality in all isolated LT, d. liver graft loss in all isolated LT) to assess factors that may influence patient and liver graft survival by transplant group (CF LT vs. CF CLLT) and by diagnosis (CF LT vs. non‐CF LT), while adjusting for confounding factors. The variables included in multivariable Cox regression were selected a priori based on biological importance and data availability to avoid the inferential limitations of selecting variables for multivariable models based on univariable comparisons or stepwise procedures. 18 These variables, captured at the time of LT, were recipient age, albumin, international normalized ratio (INR), TB, intensive care unit (ICU) status, and liver graft type. We also included transplant group in the two models comparing CF LT versus CF CLLT and diagnosis in the two models comparing CF LT versus non‐CF LT. Development and statistical analyses were conducted using Stata IC 16.0 (StataCorp LLC).
3. RESULTS
3.1. Demographic and clinical characteristics
A total of 157 children with CF were included, of whom 145 underwent isolated LT and 12 CLLT (approximately 6.3 LT/year and 0.5 CLLT/year), as well as 10,276 children who underwent isolated LT for non‐CF indications. Of the 145 children who underwent isolated LT for CF, two were simultaneously waitlisted for but did not undergo lung transplantation, four were subsequently waitlisted for but did not undergo lung transplantation, and 10 underwent sequential lung transplantation after LT (Figure 1). The median time between LT and listing for lung transplantation in the 16 patients who initially underwent isolated LT was 7.4 years (IQR: 3.8–10.1).
Figure 1.
Cohort flowchart.
In the pwCF cohort, the median recipient age was 13.0 years, and the median waitlist time was 122.0 days. Only 17 recipients were in the ICU at the time of transplant (10.8%), and most recipients underwent deceased donor whole graft (DDWG) LT (77.7%). A lower proportion of CF LT recipients was female compared to CF CLLT recipients (36.9% vs. 66.7%, p = 0.04). CF LT recipients had higher TB levels (median 1.6 [IQR: 0.9–3.2] vs. 0.7 [IQR: 0.2–2.0] mg/dL, p = 0.02) and higher INR levels (median 1.5 [IQR: 1.3–1.7] vs 1.4 [IQR: 1.1–1.4], p = 0.009) than CF CCLT recipients. No other statistically significant between‐group differences were identified in pwCF by transplant type regarding patient demographic and clinical characteristics as shown in Table 1.
Table 1.
Patient demographics and clinical characteristics by treatment group.
| Variablea | CF LT (n = 145) | CF CLLT (n = 12) | p‐value (CF LT vs. CF CLLT) | Non‐CF LT (n = 10,276) | p‐value (CF LT vs. non‐CF LT) |
|---|---|---|---|---|---|
| Age (years) | 13.0 (10.0–15.0) | 14.5 (12.5–16.5) | 0.19 | 2.0 (0.0–9.0) | <0.001 |
| Diagnosis (n = 10,245) | — | — | |||
| Biliary atresia | — | — | 3769 (36.8%) | ||
| Metabolic liver disease | — | — | 1513 (14.8%) | ||
| Other cholestatic liver disease | — | — | 1220 (11.9%) | ||
| Acute liver failure | — | — | 1145 (11.2%) | ||
| Tumor | — | — | 1044 (10.2%) | ||
| Other | — | — | 1554 (15.2%) | ||
| Waitlist time (days) | 115.0 (37.0–339.0) | 202.5 (102.5–377.0) | 0.32 | 51.0 (14.0–134.0) | <0.001 |
| Sex | 0.04 | <0.001 | |||
| Female | 52 (36.9%) | 8 (66.7%) | 5237 (51.0%) | ||
| Male | 93 (64.1%) | 4 (33.3%) | 5039 (49.0%) | ||
| Height (cm) | 147.5 (131.3–159.0) | 153.4 (139.5–159.6) | 0.47 | 84.0 (68.0–129.5) | <0.001 |
| Weight (kg) | 38.0 (28.3–48.6) | 40.4 (33.1–44.8) | 0.61 | 12.4 (8.0–28.6) | <0.001 |
| Laboratory Model for End‐stage Liver Disease/Pediatric End‐stage Liver Disease score | 11.0 (3.0–17.0) | 8.0 (0.5–11.5) | 0.13 | 14.0 (2.0–24.0) | 0.02 |
| Albumin (g/dL) | 3.3 (2.8–3.7) | 3.2 (3.0–3.4) | 0.48 | 3.2 (2.7–3.8) | 0.28 |
| Total bilirubin (mg/dL) | 1.6 (0.9–3.2) | 0.7 (0.2–2.0) | 0.02 | 6.1 (1.0–16.9) | <0.001 |
| International normalized ratio | 1.5 (1.3–1.7) | 1.4 (1.1–1.4) | 0.009 | 1.4 (1.1–2.0) | 0.001 |
| Serum creatinine (mg/dL) | 0.4 (0.4–0.6) | 0.4 (0.3–0.5) | 0.45 | 0.3 (0.2–0.4) | <0.001 |
| Serum sodium (mEq/L) (n = 131)b | 138.0 (136.0–140.0) | 138.0 (136.0–140.0) | 0.99 | 138.0 (136.0–140.0) | 0.84 |
| Ascites (n = 133)b | 62 (50.0%) | 3 (33.3%) | 0.33 | 3426 (46.1%) | 0.39 |
| Encephalopathy (n = 132)b | 27 (22.0%) | 1 (11.1%) | 0.44 | 2090 (28.3%) | 0.12 |
| Portal vein thrombosis (n = 154)b | 6 (4.2%) | 0 (0.0%) | 0.47 | 437 (4.4%) | 0.94 |
| Dialysis within prior week | 1 (0.7%) | 0 (0.0%) | 0.77 | 471 (4.7%) | 0.02 |
| Life support | 5 (3.4%) | 1 (8.3%) | 0.40 | 978 (9.6%) | 0.01 |
| Intensive care unit | 14 (9.7%) | 3 (25.0%) | 0.10 | 2161 (21.2%) | 0.001 |
| Cold ischemia time (hours) (n = 150)b | 6.0 (4.5–8.5) | 7.8 (7.0–8.4) | 0.07 | 6.2 (4.6–8.0) | 0.96 |
| Liver graft type | 0.40 | <0.001 | |||
| Deceased donor whole graft | 111 (76.6%) | 11 (91.7%) | 5935 (57.8%) | ||
| Deceased donor technical variant | 17 (11.7%) | 1 (8.3%) | 2871 (28.0%) | ||
| Living donor LT | 17 (11.7%) | 0 (0.0%) | 1467 (14.3%) |
Abbreviations: CF, cystic fibrosis; CLLT, combined liver‐lung transplantation; LT, liver transplantation.
All variables refer to values at the time of LT, unless otherwise specified. Presented as median (interquartile range) for continuous variables and frequency (percentage) for categorical variables.
Numbers in parentheses indicate number of persons with CF with available data.
In the isolated LT non‐CF cohort, the most common diagnosis was biliary atresia (36.8%) followed by metabolic liver disease (14.8%). CF LT recipients were older than non‐CF LT recipients (median 13 [IQR: 10.0–15.0] vs. 2.0 [0.0–9.0] years, p < 0.001) and consequently were taller (median 147.5 [IQR: 131.3–159.0] vs. 84.0 [IQR: 68.0–129.5] cm, p < 0.001) and weighed more (median 38.0 [IQR: 28.3–48.6] vs. 12.4 [IQR: 8.0–28.6] kg, p < 0.001). CF LT recipients had longer waitlist time than non‐CF LT recipients (median 115.0 [IQR: 37.0–339.0] vs. 51.0 [IQR: 14.0–134.0] days, p < 0.001). A higher proportion of CF LT recipients were male (64.1% vs. 49.0%, p < 0.001). CF LT recipients had lower laboratory Model for End‐stage Liver Disease (MELD)/Pediatric End‐stage Liver Disease (PELD) scores (median 11.0 [IQR: 3.0–17.0] vs. 14.0 [IQR: 2.0–24.0], p = 0.02) and TB levels (median 1.6 [IQR: 0.9–3.2] vs. 6.1 [IQR: 1.0–16.9] mg/dL, p < 0.001) but higher INR levels (median 1.5 [IQR: 1.3–1.7] vs. 1.4 [IQR: 1.1–2.0], p = 0.001) and serum creatinine levels (median 0.4 [IQR: 0.4–0.6] vs. 0.3 [IQR: 0.2–0.4] mg/dL, p < 0.001) than non‐CF LT recipients. A smaller proportion of CF LT recipients were on dialysis within the prior week (0.7% vs. 4.7%, p = 0.02), were on life support (3.4% vs. 9.6%, p = 0.01), and in the ICU (9.7% vs. 21.2%, p = 0.001) compared to non‐CF LT recipients. A higher proportion of CF LT recipients received DDWG compared to non‐CF LT recipients (76.6% vs. 57.8%, p < 0.001). No other statistically significant between‐group differences were identified in isolated LT recipients regarding patient demographic and clinical characteristics as shown in Table 1.
The pwCF cohort was divided into high and low TB groups based on the median TB level of 1.5 mg/dL. pwCF with high TB had higher laboratory MELD/PELD scores (median 16.0 [IQR: 11.0–21.0] vs. 4.5 [IQR: –1.0 to 10.0], p < 0.001), INR levels (median 1.6 [IQR: 1.4–1.9] vs. 1.4 [IQR: 1.3–1.6], p < 0.001), and serum creatinine levels (median 0.5 [IQR: 0.4–0.7] vs. 0.4 [IQR: 0.3–0.5] mg/dL, p < 0.001), but lower albumin levels than pwCF with low TB (median 3.2 [IQR: 2.7–3.6] vs. 3.5 [IQR: 3.0–3.8] mg/dL, p = 0.002). A higher proportion of pwCF with high TB had ascites (59.7% vs. 36.1%, p = 0.007), encephalopathy (29.6% vs. 11.5%, p = 0.01) and were on life support (7.2% vs. 0.0%, p = 0.02), and in the ICU (18.1% vs. 2.7%, p = 0.002) than pwCF with low TB. These findings suggest that pwCF with high TB levels were more likely to have decompensated advanced liver disease at the time of LT. No other statistically significant between‐group differences were identified in pwCF by TB group regarding patient demographic and clinical characteristics as shown in Table 2.
Table 2.
Patient demographics and clinical characteristics by TB group.
| Variablea | CF TB < 1.5 mg/dL (n = 74) | CF TB ≥ 1.5 mg/dL (n = 83) | CF total (n = 157) | p‐value |
|---|---|---|---|---|
| Age (years) | 12.0 (9.0–15.0) | 14.0 (11.0–16.0) | 13.0 (10.0–15.0) | 0.04 |
| Waitlist time (days) | 129.5 (52.0–341.0) | 117.0 (34.0–339.0) | 122.0 (38.0–339.0) | 0.83 |
| Sex | 0.81 | |||
| Female | 29 (39.2%) | 31 (37.4%) | 60 (38.2%) | |
| Male | 45 (60.8%) | 52 (62.6%) | 97 (61.8%) | |
| Height (cm) | 146.0 (130.3–155.0) | 150.3 (132.0–161.0) | 148.0 (132.0–159.0) | 0.22 |
| Weight (kg) | 36.0 (28.2–43.5) | 41.6 (30.2–51.8) | 38.4 (28.6–48.6) | 0.053 |
| Laboratory Model for End‐stage Liver Disease/Pediatric End‐stage Liver Disease score | 4.5 (–1.0 to 10.0) | 16.0 (11.0–21.0) | 11.0 (3.0–16.0) | <0.001 |
| Albumin (g/dL) | 3.5 (3.0–3.8) | 3.2 (2.7–3.6) | 3.3 (2.9–3.7) | 0.002 |
| International normalized ratio | 1.4 (1.3–1.6) | 1.6 (1.4–1.9) | 1.5 (0.7–3.1) | <0.001 |
| Serum creatinine (mg/dL) | 0.4 (0.3–0.5) | 0.5 (0.4–0.7) | 1.5 (1.3–1.7) | <0.001 |
| Serum sodium (mEq/L) (n = 131)b | 138.0 (136.0–140.0) | 138.0 (136.0–140.0) | 0.4 (0.3–0.6) | 0.92 |
| Ascites (n = 133)b | 22 (36.1%) | 43 (59.7%) | 65 (48.9%) | 0.007 |
| Encephalopathy (n = 132)b | 7 (11.5%) | 21 (29.6%) | 28 (21.2%) | 0.01 |
| Portal vein thrombosis (n = 154)b | 3 (4.1%) | 3 (3.7%) | 6 (3.9%) | 0.90 |
| Dialysis within prior week | 0 (0.0%) | 1 (1.2%) | 1 (0.6%) | 0.34 |
| Life support | 0 (0.0%) | 6 (7.2%) | 6 (3.8%) | 0.02 |
| Intensive care unit | 2 (2.7%) | 15 (18.1%) | 17 (10.8%) | 0.002 |
| Cold ischemia time (hours) (n = 150)b | 6.9 (5.0–8.5) | 6.0 (4.1–8.5) | 6.6 (4.9–8.5) | 0.68 |
| Liver graft type | 0.48 | |||
| Deceased donor whole graft | 58 (78.4%) | 64 (77.1%) | 122 (77.7%) | |
| Deceased donor technical variant | 10 (13.5%) | 8 (9.6%) | 18 (11.5%) | |
| Living donor liver transplantation | 6 (8.1%) | 11 (13.2%) | 17 (10.8%) | |
| Transplant type | 0.16 | |||
| Isolated liver transplantation | 66 (89.2%) | 79 (95.2%) | 145 (92.4%) | |
| Combined liver‐lung transplantation | 8 (10.8%) | 4 (4.8%) | 12 (7.6%) |
Abbreviations: CF, cystic fibrosis; TB, total bilirubin.
All variables refer to values at the time of liver transplantation unless otherwise specified. Presented as median (interquartile range) for continuous variables and frequency (percentage) for categorical variables.
Numbers in parentheses indicate number of persons with CF with available data.
3.2. Patient and liver graft survival
The 1‐, 3‐, and 5‐year patient survival rates for CF LT were superior to CF CLLT at 96.5%, 93.1%, and 89.1% for CF LT compared to 91.7%, 82.5%, and 72.2% for CLLT (log‐rank test, p = 0.02; Figure 2A). On the other hand, the CF LT group demonstrated inferior patient survival than the non‐CF LT group that had 1‐, 3‐, and 5‐year patient survival rates of 94.7%, 92.6%, and 91.5% (log‐rank test, p < 0.001; Figure 2A).
Figure 2.
Kaplan–Meier survival curves for patient (A) and liver graft (B) survival of CLLT for CF versus isolated LT for CF versus isolated LT for non‐CF indications. CF, cystic fibrosis; CLLT, combined liver‐lung transplantation; LT, liver transplantation.
The 1‐, 3‐, and 5‐year liver graft survival rates were 91.7%, 86.8%, and 83.1% for CF LT compared to 83.3%, 75.0%, and 75.0% for CF CLLT, respectively, without any statistically significant difference between the two groups (p = 0.09; Figure 2B). In contrast, the CF LT group demonstrated inferior liver graft survival than the non‐CF LT group that had 1‐, 3‐, and 5‐year liver graft survival rates of 90.4%, 86.9%, and 84.9% (log‐rank test, p < 0.001; Figure 2B).
Multivariable Cox regression in pwCF demonstrated increased risk of patient mortality in CF CLLT compared to CF LT (hazard ratio [HR] = 2.92, 95% confidence interval [95% CI]: 1.20–7.07, p = 0.02) and in those with higher TB level at the time of LT (HR = 1.05, 95% CI: 1.01–1.10, p = 0.008), when adjusting for recipient age, albumin and INR at the time of LT, ICU status, and liver graft type (Table 3). Additionally, there was increased risk of liver graft loss in CF CLLT compared to CF LT (HR = 2.56, 95% CI: 1.09–5.98, p = 0.03) and in those with higher TB level at the time of LT (HR = 1.05, 95% CI: 1.01–1.09, p = 0.008), when adjusting for recipient age, albumin, and INR at the time of LT, ICU status, and liver graft type (Table 3).
Table 3.
Multivariable cox regression models for risk factors of patient mortality and liver graft loss.
| All CF | All isolated LT | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Variablea | Patient mortality | Liver graft loss | Patient mortality | Liver graft loss | ||||||||
| Hazard ratio | 95% confidence interval | p‐value | Hazard ratio | 95% confidence interval | p‐value | Hazard ratio | 95% confidence interval | p‐value | Hazard ratio | 95% confidence interval | p‐value | |
| Group (reference: isolated LT) | — | — | — | — | — | — | — | — | — | — | — | — |
| Combined liver‐lung transplantation | 2.92 | 1.20–7.07 | 0.02 | 2.56 | 1.09–5.98 | 0.03 | — | — | — | — | — | — |
| Diagnosis (reference: non‐CF) | — | — | — | — | — | — | — | — | — | — | — | — |
| CF | — | — | — | — | — | — | 2.03 | 1.41–2.93 | <0.001 | 1.54 | 1.13–2.11 | 0.006 |
| Age (years) | 1.01 | 0.92–1.10 | 0.83 | 0.97 | 0.91–1.05 | 0.49 | 1.04 | 1.03–1.05 | <0.001 | 1.02 | 1.01–1.03 | <0.001 |
| Albumin (g/dL) | 1.30 | 0.71–2.38 | 0.40 | 1.16 | 0.67–1.98 | 0.60 | 0.97 | 0.90–1.06 | 0.53 | 0.96 | 0.90–1.02 | 0.16 |
| International normalized ratio | 0.90 | 0.55–1.47 | 0.68 | 0.83 | 0.48–1.43 | 0.50 | 1.02 | 0.99–1.04 | 0.19 | 1.01 | 0.99–1.03 | 0.45 |
| Total bilirubin (mg/dL) | 1.05 | 1.01–1.10 | 0.008 | 1.05 | 1.01–1.09 | 0.008 | 0.99 | 0.99–1.00 | 0.44 | 0.99 | 0.99–1.00 | 0.38 |
| Intensive care unit | 0.30 | 0.06–1.46 | 0.14 | 0.28 | 0.07–1.16 | 0.08 | 1.95 | 1.68–2.26 | <0.001 | 1.67 | 1.50–1.87 | <0.001 |
| Liver graft type (reference: Deceased donor whole graft) | — | — | — | — | — | — | — | — | — | — | — | — |
| Deceased donor technical variant | 0.31 | 0.07–1.34 | 0.12 | 0.36 | 0.11–1.22 | 0.10 | 1.27 | 1.09–1.47 | 0.002 | 1.19 | 1.07–1.32 | 0.002 |
| Living donor LT | 0.36 | 0.05–2.73 | 0.33 | 1.42 | 0.54–3.75 | 0.48 | 0.85 | 0.68–1.05 | 0.13 | 0.86 | 0.74–1.00 | 0.055 |
Abbreviations: CF, cystic fibrosis; LT, liver transplantation.
All variables refer to values at the time of LT unless otherwise‐specified.
Multivariable Cox regression in isolated LT demonstrated increased risk of patient mortality in CF LT compared to non‐CF LT (HR = 2.03, 95% CI: 1.41–2.93, p < 0.001), when adjusting for recipient age, albumin, INR and TB at the time of LT, ICU status, and liver graft type (Table 3). Additionally, CF LT recipients had an increased risk of liver graft loss compared to non‐CF LT recipients (HR = 1.54, 95% CI: 1.13–2.11, p = 0.006), when adjusting for recipient age, albumin, INR and TB at the time of LT, ICU status, and liver graft type (Table 3).
4. DISCUSSION
Advanced liver disease is a significant cause of mortality in pwCF, primarily affecting the pediatric population. 8 While LT is the primary treatment for advanced liver disease with cirrhosis, there are limited biomarkers to predict patient outcomes after LT and ongoing debate persists regarding the comparative outcomes of LT versus CLLT, especially in the pediatric population. This study is the first to use contemporary UNOS data to identify TB as a clinical predictor of disease severity and post‐transplant outcomes in pwCF and define patient and liver graft survival among children with CF undergoing either LT or CLLT in the contemporary era. Specifically, our findings highlight a superior patient and liver graft survival in the CF LT versus CF CLLT group, when adjusting for confounders. However, we showed that isolated LT for CF still is associated with inferior patient and liver graft survival compared to isolated LT for other indications.
The majority of data comparing LT versus CLLT for pwCF and advanced liver disease comes from small single‐center case series, with only a few national analyses attempted in the past, most of which were conducted over a decade ago. 13 , 19 , 20 , 21 , 22 , 23 , 24 , 25 Our study is distinct from prior publications 19 , 25 in that it focuses on the pediatric population—which is unique from the adult population in terms of associated comorbidities—and also because it clearly describes the characteristics and survival of this group by LT versus CLLT. Only 12 children underwent CLLT over the 23‐year study period, while another 16 children who underwent isolated LT were listed for subsequent lung transplantation, of whom 10 ultimately underwent lung transplantation. Previous reports from the UNOS database reported a post‐transplant 5‐year patient survival rate of 70.5%–85.8% for pediatric pwCF undergoing any type of LT. 19 , 20 , 25 Interestingly, the 5‐year patient survival rate in our cohort was 89.1%, which indicates an improvement in overall outcomes over the past decades with the widespread adoption of CFTR modulators, improved chronic airway clearance strategies, and targeted antimicrobial regimens that have dramatically changed CF care. 26 However, the impact of these therapies on hepatic disease progression and post‐transplant outcomes remains unclear, particularly in children with advanced liver disease.
Furthermore, our study demonstrates >10% improvement in 5‐year liver graft survival for CF LT at 83.1% when compared to 69.8% in an older UNOS report. 19 This finding is consistent with the overall improvements in pediatric LT outcomes due to advances in technique, organ allocation, and multidisciplinary care. 27 However, despite the improvements in CF LT patient and graft survival over time, CF LT survival remains inferior when compared to other indications similar to previous studies including adults and children. 25 , 28 It is noteworthy that our data showed an even higher risk of liver graft loss for CF CLLT when compared to CF LT. This finding highlights the ongoing unmet need to improve transplant outcomes in pwCF. Although prior studies have shown that approximately 40% of pediatric LT recipients with CF are female (similar to our study's 38.2%), 19 , 25 our study is the first to show that two‐thirds of the children undergoing CLLT are female in the recent era. This finding is in line with data suggesting that females with CF may have increased multisystem disease severity than males.
Consistent with prior evidence, 19 our findings highlight that higher TB at the time of LT is associated with an increased risk of post‐transplant patient mortality and liver graft loss, even after adjusting for confounding factors. Additionally, pediatric isolated CF LT recipients exhibited higher TB levels compared with CF CLLT recipients. Notably, children with TB level ≥1.5 mg/dL were more likely to have decompensated advanced liver disease at the time of LT as indicated by their higher laboratory MELD/PELD score, INR, and serum creatinine levels, lower albumin level, and the higher likelihood of having ascites and encephalopathy, being in the ICU, and requiring life support. While the TB levels in this cohort were relatively low compared to those observed in other, more common cholestatic indications for pediatric LT, 29 elevated TB levels are an indicator of disease severity in pwCF associated liver disease. 30 However, TB lacks sensitivity in assessing cholestasis and can be elevated due to HEMT and in disorders like Gilbert syndrome, which is relatively common in the general population. 17 , 31 Although high TB level alone cannot serve as an indicator for need for LT in CF, our data suggest that it can be used as a tool for identifying high‐risk patients with advanced liver disease that may be at risk for patient or graft loss post‐tra. Efforts to improve LT outcomes in pwCF may include improving access to living donor liver transplantation (LDLT), including the use of non‐directed LDLT. 32 In this cohort, only 11.7% of the isolated LTs were LDLTs, which is comparable to the 10.1%–13.2% reported in previous UNOS studies, 19 , 25 despite an overall increase in the number of LDLTs performed for pediatric LT in the USA over the past decades. 33
Although the UNOS database does not evaluate outcomes beyond survival, it is important to consider the effect of LT on the overall health of pwCF. An analysis from the United States Cystic Fibrosis Foundation Patient Registry reported that LT neither provided a benefit nor worsened pulmonary function in pwCF. 34 In contrast, a more recent retrospective study from North America showed that LT was associated with a slower decline in lung function and nutritional status, as well as a reduction in pulmonary exacerbations. 35 Additionally, a systematic review and meta‐analysis from 2024 reported improvements in the percent‐predicted forced expiratory volume in 1 s and a reduction in pulmonary exacerbations, 36 yet the impact of highly effective modulator therapy on these outcomes post‐transplant needs to be further investigated. Another study observed significant increases in bone mineral content, bone mineral density, fat‐free body mass, and serum vitamin A and E levels in the transplanted patients compared to the non‐transplanted controls. 4
The current study has limitations inherent to the use of retrospective UNOS registry data. Data acquisition from transplant centers primarily focuses on organ allocation, potentially affecting data accuracy and completeness. Moreover, there is a lack of granular data in the UNOS registry that is specific to CF, such as more specific laboratory markers of cholestasis (e.g., direct bilirubin, gamma‐glutamyl transferase, bile acids), life support measures, preoperative pulmonary function, CF‐specific indications for transplantation, post‐transplant outcomes, or complications (pulmonary, infectious, metabolic, etc.). Additionally, it is worth noting that because of the relatively small sample size in the CF CLLT group, the study may lack sufficient power to detect smaller effect sizes when comparing CLLT and isolated LT. Future research endeavors should aim to address these limitations by incorporating comprehensive data collection strategies, defining patients by CF‐liver disease subtypes, and adopting rigorous analytical approaches to enhance the robustness and reliability of the study outcomes.
5. CONCLUSIONS
In conclusion, this study indicates that pediatric pwCF undergoing LT have acceptable outcomes, but isolated LT is associated with inferior survival compared to non‐CF LT, while CLLT for CF carries even worse outcomes. Higher TB at the time of transplant for CF is independently associated with an increased risk of patient mortality and graft loss, suggesting this may be a marker of inferior outcomes post‐transplant. While TB alone should not determine transplant eligibility in pwCF, it may inform risk stratification and post‐transplant prognostication. Efforts to optimize outcomes in this population may include earlier referral, tailored transplant timing, and consideration of LDLT to expand access. Further studies incorporating CF‐specific clinical data and longitudinal outcomes are needed to better inform transplant decisions and improve care for this vulnerable pediatric population.
CONFLICT OF INTEREST STATEMENT
Dr. Sarah A. Taylor serves as a consultant for Ipsen and Mirum Pharma. Dr. Michael R. Narkewicz has received grant funding from Gilead and Cystic Fibrosis Foundation and serves as a consultant for Vertex, Cystic Fibrosis Foundation, and Scholar Rock.
Ziogas IA, Perim V, Yoeli D, et al. Contemporary outcomes of isolated liver and combined liver‐lung transplantation for cystic fibrosis in children. J Pediatr Gastroenterol Nutr. 2026;83:231‐240. 10.1002/jpn3.70392
See related article, pages 209–210.
Disclaimer: The data reported here have been supplied by the United Network for Organ Sharing 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 OPTN or the U.S. Government.
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