Abstract
Background and objectives
Acute-on-chronic liver failure (ACLF) is associated with high short-term mortality without liver transplantation (LT). The selection criteria for LT in these patients are not well defined. The objective of this study was to determine factors associated with post-transplant survival in ACLF.
Methods
This was a single-center retrospective study of patients who underwent living donor liver transplantation (LDLT) for ACLF between 2012 and 2022. Out of 1093 transplants, 110 patients had underlying ACLF, based on the European Association for the Study of the Liver-Chronic Liver Failure Consortium (EASL-CLIF) criteria. We looked at factors associated with 1-year posttransplant survival.
Results
The median model for end-stage liver disease (MELD) score was 33.5 (31–38), and the 1-year posttransplant survival was 72%. Six risk factors were associated with posttransplant survival, namely, body mass index > 30 kg/m2 [HR, 4.4; 95% CI, 1.8–10.7], platelet count < 66,000/μl [HR, 2.91; CI,1.2–6.6], poor response to medical treatment [HR, 2.6; CI, 1.1–5.7], drug-resistant bacterial or fungal cultures [HR, 4.2; CI, 1.4–12.4], serum creatinine > 2.5 mg/dl [HR, 3.4; CI, 1.5–7.7], and graft-to-recipient weight ratio < 0.7 [HR, 4.8; CI, 1.4–16.3]. The 1-year post-transplant survival was 84% in patients with 0–2 risk factors (n = 89) and was 6% with 3 risk factors (n = 15) (P < 0.001). For 1-year posttransplant survival, the area under curve (AUC) for the current model was 0.8 (0.69–0.9). The AUC for CLIF-ACLF, Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA), and EASL-CLIF ACLF grades was < 0.5.
Conclusion
In LT for ACLF, acceptable survival can be achieved when less than three high-risk factors are present.
Keywords: European Association for the Study of the Liver-Chronic Liver Failure Consortium, graft to recipient weight ratio, living donor liver transplantation, mortality, multidrug resistant infection
Acute-on-chronic liver failure (ACLF) is associated with high short-term mortality without liver transplantation (LT).1 While LT remains the definitive treatment, it is not effective in a subset of patients.2, 3, 4 Therefore, patient selection is crucial to avoid futile surgery and unnecessary risk to a healthy living donor. In order to achieve acceptable outcomes with transplantation in ACLF, guidelines have been proposed by the International Liver Transplant Society (ILTS).5 These guidelines are predominantly based on deceased donor liver transplantation (DDLT) and should be judiciously applied to living donor liver transplantation (LDLT).
There is emerging data on the outcomes of LDLT for the European Association for the Study of Liver-Chronic Liver Failure (EASL-CLIF) ACLF. A clear survival benefit has been shown when compared with medical management, and posttransplant survival for various ACLF grades is comparable.6, 7, 8 The more established liver failure scores, such as the model for end-stage liver disease (MELD) score and the Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) scores, have limited ability to prognosticate posttransplant patients, and any cutoffs on these scores alone cannot be recommended to accept or deny LT in ACLF.5, 6, 7,9
In critically ill patients, LDLT might be associated with high rates of intra-operative complications, prolonged intensive care unit and hospital stay.6 Access to a comparatively young donor with favorable anatomy, minimal steatosis, and an acceptable graft-to-recipient weight ratio (GRWR) in an urgent clinical situation is not always easy. Donor risk must be balanced against the likely outcome in critically ill patients.10 Factors such as patient age, poor response to medical treatment, high MELD score, and need for mechanical ventilation have been associated with poor post-transplant outcomes in DDLT.2,3,10,11 It is not clear if any of these factors can be used alone to deny LT in the setting of ACLF. A multifactorial assessment of pretransplant factors is needed to select patients for LT. LDLT is frequently performed for high-MELD patients in Asia and occasionally in the West, where DDLT is the predominant mode of organ donation.6,12
The objective of the current study was to identify factors associated with 1-year post-transplant survival in patients undergoing LDLT for ACLF.
Methods
This study was performed in accordance with the Declaration of Helsinki and was approved by the ethics review committee and institutional review board (IRB #0202-23). The reporting of this single-center retrospective observational cohort study was in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (http://www.equator-network.org/reporting-guidelines/strobe/) reporting guidelines.
Patients
Between April 2012 and May 2022, 1093 patients underwent LDLT. Out of these, 110 patients fulfilled the EASL-CLIF consortium definition for ACLF at the time of last admission leading to transplant.1 After exclusion of six patients who underwent dual-graft LDLT, 104 patients were included in this study. All LDLTs were performed after obtaining approval from the hospital transplant committee and human organ transplant and tissue authority.
Donors are between 18 and 55 years of age, related (legally or by blood) to the patient, blood group-compatible, and enjoy good health. All patients with ACLF and age < 70 years, irrespective of etiology, are considered for LT. Since 2018, patients requiring intubation with mechanical ventilation for grade 3 or 4 encephalopathy have been offered LDLT. Patients with overt sepsis, such as those with high-grade fevers, who need triple inotropic support or high-dose single inotropic support are not considered good candidates for upfront LDLT. In awake patients, a subjective assessment with a hand grip test is performed for muscle strength. Patients with pan-drug-resistant cultures are not offered LDLT unless they demonstrate clinical stability over 3–5 days. Occasionally, patients with multidrug resistant (MDR) cultures are offered LDLT when overt sepsis is not present. Blood and urine cultures are sent as routine, while sputum and tracheal cultures are requested if clinically indicated. After transplant, patients are followed weekly for one month, twice weekly for two months, and three monthly subsequently. The standard immunosuppression consists of calcineurin inhibitors with or without mycophenolate mofetil.
Data Collection
For this study, we included patient demographics, body mass index (BMI), etiology of cirrhosis, organ failure at admission and transplant, MELD score at admission and transplant, time to transplant, white blood cell count at admission and transplant, albumin at admission and transplant, response to medical treatment, need for mechanical ventilation and inotropic support, grade 3–4 encephalopathy, and presence of MDR bacterial and fungal infection at admission and transplant. In addition, operative factors such as the GRWR, liver attenuation index (LAI), cold and warm ischemia time, blood loss, and operative time were also included. Response to medical treatment was defined as an improvement in the ACLF grade, as previously reported.11 For example, response to medical treatment for grade 3 ACLF at admission was defined as improvement to grade 0, 1, or 2 ACLF. If there was deterioration or no improvement in the ACLF grade, it was considered a poor response to medical treatment. Since a number of patients had multiple hospital admissions in the months preceding LT, the time to transplant was defined as the number of days between the last admission and LT. Postoperative complications were graded as per the Clavien–Dindo grading system.13
Statistical Analysis
The primary outcome of interest was 1-year posttransplant survival and factors associated with it. Categorical variables are presented as frequencies (%) and continuous variables as medians with interquartile ranges (IQR). For statistical significance, the chi square (χ2) test or Fischer's exact test were used. A P value < 0.05 was considered statistically significant. Cutoffs for continuous variables were determined using receiver operating curves (ROC), and Youden's index was used to generate dichotomous variables. Factors with an AUC > 0.6 were considered clinically relevant, as previously reported.14 Kaplan–Meier curves were used for analysis of 1-year post-LT survival, and the log-rank test was used to determine significance. A univariate analysis was performed, and significant factors (P < 0.1) were included in the multivariate analysis. Statistical analyses were performed using the IBM Statistical Package for Social Sciences (SPSS) version 22.
Results
Patient Characteristics and Outcomes
Out of 1093 patients who underwent LDLT, 104 patients [81.7% males; median age, 46 (38–54.5) years] with ACLF were included. The median MELD score in patients with grades 1, 2, and 3 ACLF was 31 (27–33), 37 (34–39) and 39 (33–40) (P < 0.001). Response to medical treatment was seen in 73/104 (70.2%) patients (Table 1). With a median time interval of 12 (8–25) days between admission and transplant, 32/45 (71.1%) patients with grade 1 ACLF, 27/40 (67.5%) patients with grade 2 ACLF, and 14/19 (73.6%) patients with grade 3 ACLF showed response to medical treatment. At the time of transplant, the median MELD score for grades 0, 1, 2, and 3 ACLF was 28 (24.7–31), 33 (25–33.5), 34.5 (33–39), and 32 (29–40). The 30-day mortality was 11/104 (10.5%). The 1-year posttransplant survival in patients with grades 1, 2, and 3 ACLF was 68.9%, 75%, and 73.7% (P = 0.838).
Table 1.
Patient Characteristics and Operative Details.
| Patient variables | Number (%) (n = 104) |
|---|---|
| Recipient age, median (IQR), years | 46 (38–54) |
| Body mass index, median (IQR), kg/m2 | 26.2 (23.1–29) |
| Body mass index ≥ 30 kg/m2, n (%) | 20 (19.2) |
| Sex, male, n (%) | 85 (81.7) |
| MELD score at admission, median (IQR) | 34 (31–38) |
| MELD score LT, median (IQR) | 30 (26–33) |
| Bilirubin at admission, median (IQR), mg/dl, | 18.1 (6.9–27.5) |
| Bilirubin at LT, median (IQR), mg/dl | 19.4 (7.6–29.1) |
| INR at admission, median (IQR) | 2.3 (1.79–3.2) |
| INR at LT, median (IQR) | 2.1 (1.68–2.54) |
| Serum creatinine at admission, median (IQR), mg/dl | 1.81 (0.8–2.6) |
| Serum creatinine at LT, median (IQR), mg/dl | 1 (0.73–1.6) |
| Platelets at admission, median (IQR),/μl | 67,000 (47,000–113,500) |
| Platelets at LT, median (IQR),/μl | 67,000 (38,750–106,250) |
| Serum albumin at admission, median (IQR), g/dl | 2.5 (2–2.9) |
| Serum albumin at LT, median (IQR), g/dl, | 2.9 (2.5–3.4) |
| WBC count at admission, median (IQR),/μl | 8400 (5550–12,650) |
| WBC count at transplant, median (IQR),/μl | 5865 (4322–9125) |
| Days to transplant, median (IQR) | 12 (8–25) |
| Etiology | |
| Hepatitis C virus related cirrhosis | 47 (45.1) |
| Hepatitis B virus related cirrhosis | 26 (25) |
| Non-B/Non-C cirrhosis | 12 (11.5) |
| Budd Chiari Syndrome | 3 (2.9) |
| Autoimmune hepatitis | 2 (1.9) |
| Others | 14 (13.4) |
| Organ failure | |
| Liver failure | 68 (65.3) |
| Renal failure | 52 (50) |
| Coagulation failure | 51 (49) |
| Cerebral failure | 8 (7.69) |
| Ventilator support | 3 (2.9) |
| Inotropic support | 4 (3.8) |
| Renal replacement therapy/dialysis | 12 (11.5) |
| Infection markers | |
| Leukocytosis (>11,000/μl) | 14 (13.4) |
| Positive cultures | 29 (27.9) |
| Fungal infections | 5 (4.8) |
| Drug resistant bacterial infections | 7 (6.7) |
| ACLF grade at admission | |
| Grade 1 | 45 (43.2) |
| Grade 2 | 40 (38.4) |
| Grade 3 | 19 (18.2) |
| Response to treatment | 73 (70.2) |
| Treatment response for ACLF grades | |
| Grade 1 | 32/45 (71.1) |
| Grade 2 | 27/40 (67.5) |
| Grade 3 | 14/19 (73.6) |
| Hepatocellular carcinoma | 15 (14.4) |
| Operative factors | |
| Graft to recipient weight ratio | 0.91 (0.81–1.1) |
| Liver attenuation index | 10 (7–15.7) |
| Graft weight, median (IQR), grams | 670 (606–782) |
| Operative time, median (IQR), minutes | 540 (480–660) |
| Blood loss, median (IQR), ml | 2000 (1300–2800) |
| Cold ischemia time, median (IQR), minutes | 41 (33–57) |
| Warm ischemia time, median (IQR), minutes | 39.5 (28–60) |
| 1-year mortality | 29 (27.9) |
| Sepsis | 15 (14.4) |
| Graft failure/dysfunction | 6 (5.7) |
| Cardiac | 2 (1.9) |
| Biliary | 4 (3.8) |
| Hepatic artery thrombosis | 1 (0.9) |
| Upper gastrointestinal bleed | 1 (0.9) |
ACLF, acute-on-chronic liver failure; BMI, body mass index; IQR, interquartile range; LT, liver transplantation; MELD, model for end-stage liver disease; WBC, white blood cell.
Predictors of 1-year Mortality
The one-year mortality was 29/104 (27.9%) and the reasons for death are shown in Table 1. Among continuous variables, BMI > 30 kg/m2, serum creatinine > 2.5 mg/dl, and platelet count < 66,000/μl were associated with one-year mortality (AUC > 0.6). In addition, response to medical treatment (P = 0.014), MDR cultures at transplant (P = 0.037), and GRWR < 0.7 (P = 0.008) were associated with 1-year survival, as shown in Table 2. These factors were included in the univariate analysis. On multivariate analysis, BMI > 30 kg/m2 [HR, 4.4; 95% CI,1.8–10.7], platelet count < 66,000/μl [HR, 2.91; CI,1.2–6.6], poor response to medical treatment [HR, 2.6; CI, 1.1–5.7], drug-resistant bacterial or fungal cultures [HR, 4.2; CI, 1.4–12.4], serum creatinine > 2.5 mg/dl [HR, 3.4; CI, 1.5–7.7], and graft-to-recipient weight ratio < 0.7 [HR, 4.8; CI, 1.4–16.3] were associated with survival (Table 3). The one-year posttransplant survival with 0, 1, 2, and 3 risk factors was 94.1%, 84.4%, 74.1%, and 6.7% (P < 0.001) (Figure 1a). The one-year posttransplant survival was 84% for patients with 0–2 risk factors and 6% for patients with 3 risk factors (Figure 1b) (P < 0.001).
Table 2.
Factors Associated With 1-year Survival After Living Donor Liver Transplantation for Acute-on-chronic Liver Failure.
| Variables | Number in each group(n = 104) | Dead within1 year(n = 29) | Alive at1 year(n = 75) | P value |
|---|---|---|---|---|
| Age, median (IQR), years | 45 (37–51) | 48 (38.5–58) | 0.421 | |
| BMI, median (IQR), kg/m2 | 25.5 (22.6–28.5) | 27.4 (24.8–31.3) | 0.029 | |
| MELD-Na at transplant, median (IQR) | 30 (25–33) | 31 (27.5–34) | 0.263 | |
| Gender | 0.193 | |||
| Male | 85 | 26 (30.5) | 59 (69.5) | |
| Female | 19 | 3 (15.7) | 16 (84.3) | |
| Etiology | 0.694 | |||
| Hepatitis C infection | 47 | 14 (29.7) | 33 (70.3) | |
| Others | 57 | 15 (26.3) | 42 (73.7) | |
| Etiology | 0.377 | |||
| Hepatitis B infection | 26 | 9 (34.6) | 17 (65.3) | |
| Others | 78 | 20 (25.6) | 58 (74.3) | |
| Time to transplant | 0.577 | |||
| <7 days | 21 | 5 (23.8) | 16 (76.1) | |
| >7 days | 80 | 24 (30) | 56 (70) | |
| Ventilator support | 0.282 | |||
| Yes | 3 | 0 (0) | 3 (100) | |
| No | 101 | 29 (28.7) | 72 (71.3) | |
| Inotropic support | 0.896 | |||
| Yes | 4 | 1 (25) | 3 (75) | |
| No | 100 | 28 (28) | 72 (72) | |
| Renal replacement therapy/Dialysis | 0.258 | |||
| Yes | 12 | 5 (41.7) | 7 (58.3) | |
| No | 92 | 24 (26.1) | 68 (73.9) | |
| Brain failure | 0.850 | |||
| Yes | 8 | 2 (25) | 6 (75) | |
| No | 96 | 27 (28.1) | 69 (71.9) | |
| Coagulation failure | 0.593 | |||
| Yes | 51 | 13 (25.5) | 38 (74.5) | |
| No | 53 | 16 (30.1) | 37 (69.9) | |
| Response to medical treatment | 0.014 | |||
| Yes | 66 | 13 (19.6) | 53 (80.4) | |
| No | 38 | 16 (42.1) | 22 (57.8) | |
| Liver failure | 0.173 | |||
| Yes | 68 | 16 (30.7) | 52 (69.3) | |
| No | 36 | 13 (36.1) | 23 (63.9) | |
| Renal failure | 0.274 | |||
| Yes | 52 | 17 (32.7) | 35 (67.3) | |
| No | 52 | 12 (23.1) | 40 (76.9) | |
| ACLF grade | 0.81 | |||
| 1 | 45 | 14 (31.1) | 31 (68.9) | |
| 2 | 40 | 10 (25) | 30 (75) | |
| 3 | 19 | 5 (26.3) | 14 (73.7) | |
| Positive drug resistant cultures | 0.037 | |||
| No | 93 | 23 (24.7) | 70 (75.3) | |
| Yes | 11 | 6 (54.5) | 5 (45.6) | |
| Graft to recipient weight ratio 0.8 | 0.087 | |||
| >0.8 | 83 | 20 (24.1) | 63 (75.9) | |
| <0.8 | 21 | 9 (42.9) | 12 (57.1) | |
| Graft to recipient weight ratio 0.7 | 0.008 | |||
| >0.7 | 99 | 25 (25.2) | 74 (74.7) | |
| <0.7 | 5 | 4 (80) | 1 (20) | |
| HCC | 0.462 | |||
| Yes | 15 | 3 (20) | 12 (80) | |
| No | 89 | 26 (29.2) | 63 (70.8) |
ACLF, acute-on-chronic liver failure; BMI, body mass index; IQR, interquartile range; MELD, model for end-stage liver disease.
Table 3.
Multivariate Analysis for Posttransplant 1-year Mortality.
| Univariate analysis |
Multivariate analysis |
|||
|---|---|---|---|---|
| Variables | Hazard ratio(confidenceinterval) | P Value | Hazard ratio (Confidence Interval) | P value |
| Body massindex | 0.036 | 0.001 | ||
| ≥30 | 2.2 (1.04–4.6) | 4.4 (1.8–10.7) | ||
| <30 | 1 | 1 | ||
| Plateletscount | 0.037 | 0.011 | ||
| <66,000 | 2.25 (1.04–4.8) | 2.91 (1.2–6.6) | ||
| ≥66,000 | 1 | 1 | ||
| Response tomedicaltreatment | 0.048 | 0.017 | ||
| No | 2 (1.005–2.34) | 2.6 (1.1–5.7) | ||
| Yes | 1 | 1 | ||
| MDR cultures | 0.020 | 0.009 | ||
| Positive | 2.91 (1.18–7.1) | 4.2 (1.4–12.4) | ||
| Negative | 1 | 1 | ||
| SerumCreatinine | 0.014 | 0.002 | ||
| ≥2.5 | 2.51 (1.2–5.2) | 3.4 (1.5–7.7) | ||
| <2.5 | 1 | 1 | ||
| GRWR | <0.001 | 0.011 | ||
| <0.7 | 7.26 (2.4–21.1) | 4.8 (1.4–16.3) | ||
| >0.7 | 1 | 1 | ||
GRWR, graft-to-recipient weight ratio; MDR, multidrug resistant.
Figure 1.
(a) one-year survival in patients who underwent living donor liver transplantation for acute-on-chronic liver failure with 0, 1, 2, and 3 risk factors; (b) one-year posttransplant survival in low-risk (0–2 risk factors) and high-risk groups (3 risk factors).
Comparison With Other Scores
For one-year posttransplant survival, the AUC for the current model was 0.8 (0.69–0.9). The AUC for CLIF-ACLF, CLIF-SOFA, and EASL-CLIF ACLF grades was < 0.5 (Figure 2).
Figure 2.
Receiver operator curves for the current risk score, ACLF grades at admission, CLIF-SOFA, and CLIF-ACLF scores. ACLF, acute-on-chronic liver failure; CLIF-SOFA, Chronic Liver Failure-Sequential Organ Failure Assessment.
Discussion
When considering LT in patients with ACLF, careful selection is needed to avoid futile transplantation. LT might be overutilized in these high-risk patients for presumed survival benefits. In fact posttransplant survival after LT in ACLF appears to be inferior to other standard indications for LT. Therefore, a judicious approach is warranted in this patient group with high MELD scores and multiple organ failures. In this study, we have identified pretransplant factors that, when present together, are associated with unacceptable posttransplant survival in ACLF.
There is limited evidence on the outcomes of LT in patients with ACLF. The one-year posttransplant survival is variable, depends on multiple factors, and ranges between 60 and 90%.2,6,7,10,15 Obviously, this is low compared with outcomes for other standard indications for LT. Therefore, it is logical to assume that a subgroup of patients in ACLF will not benefit from LT. In the current study, six pretransplant factors were associated with poor posttransplant outcomes. These include BMI > 30 kg/m2, lack of response to medical treatment, MDR infections, serum creatinine > 2.5 mg/dl, and platelet count < 66,000/μl. Lack of response to medical treatment is a well-known risk factor for poor posttransplant outcomes.11 ACLF is a dynamic syndrome, and an improvement in ACLF grade might improve survival both in the nontransplant and transplant settings.1,4,16 Failure to respond to medical treatment might represent an underlying terminal stage where organ recovery and functional improvement are unlikely despite LT.
Acute kidney injury with a creatinine > 2.5 mg/dl was associated with post-LT survival in the current study. The presence of acute kidney injury has been associated with 90-day mortality rates of 67.6% and 50% without transplant in patients with ACLF and decompensated cirrhosis, respectively.17 A creatinine > 2.5 mg/dl was considered to be grade 3 renal failure in the CANONIC study.1 In a recent multicenter study including 8 European LT centers, 234 patients underwent LT for ACLF. Pre-LT arterial lactate levels > 4 mmol/L (HR, 3.14), recent infection with MDR organisms (HR, 3.67), and renal replacement therapy (HR, 2.74) were independent predictors of post-LT mortality.18
There is general agreement that patients with ongoing sepsis and ACLF should not be offered LT.19 In fact, the presence of bacterial and fungal infections in patients with ACLF is associated with high grades of systemic inflammation, a worse clinical course, and a lower probability of survival at 90 days (49% vs. 72.5%, P < 0.001) than patients with ACLF without infection.20 Based on the recommendations of the expert consensus of the ILTS, pan-drug-resistant Enterobacteriaceae, persistent fever > 39 °C, and leucopenia lower than 0.5 g/L might be considered contraindications to LT.5 We adopted a similar policy for LDLT in patients with ACLF. Patients with ACLF and high-grade fever, leucopenia or leukocytosis, or pan-drug-resistant infection were treated with broad-spectrum antibiotics and considered for liver transplantation when clinical improvement was evident. A few selected patients with positive MDR bacterial or fungal cultures were considered for LT if active clinical infection was ruled out.20 Among the various risk factors in the current study, a positive culture with MDR bacterial or fungal cultures was the strongest predictor of poor post-LT survival [HR 4.2, P = 0.009].
An unexpected finding in the current study was the association of a platelet count < 66,000/μl with 1-year posttransplant survival. While a platelet count < 20,000/μl has been associated with poor outcomes in the pretransplant setting, the negative impact of a low pretransplant platelet count on post-LT mortality has not been reported.1,21 The association of low white blood cell (WBC) count with poor posttransplant outcomes in the Transplantation for Acute-on-chronic liver failure Model (TAM) score was presumed to be due to portal hypertension and underlying portosystemic shunts.10,22 The same mechanism might be responsible for pretransplant thrombocytopenia. Immediate postoperative thrombocytopenia is associated with graft dysfunction and mortality in patients undergoing LDLT.22, 23, 24, 25 More specifically, poor outcomes after LT have been reported with platelet counts < 68,000 on the first postoperative day.23 However, the prognostic impact of pretransplant thrombocytopenia in ACLF and its underlying mechanisms merit further exploration. We remain unsure about the prognostic impact of a platelet count < 66,000/μl, and this might just be a chance finding. This also reflects why multifactorial assessment of prognostic factors is crucial, and any single factor cannot be used to deny LT. The underlying portal hypertension in a high-risk patient might also explain poor outcomes in patients with a GRWR < 0.7, where 4/5 (80%) patients experienced one-year mortality. It has been suggested that in high-acuity situations with MELD > 20, the GRWR should be > 0.7.26
Grade 3 obesity has been linked to poor post-LT outcomes in patients with ACLF and might be considered a relative contraindication.27 In the current study, BMI > 30 kg/m2 was associated with poor outcomes after LT. These results should be interpreted with caution. With a high BMI, it is difficult to find suitable living donors with an acceptable graft weight. In fact, it has been shown that patients with grade 2 and 3 obesity are less likely to receive a graft due to presumed risks of graft dysfunction and small-for-size syndrome.28 This is likely to be worse in LDLT, where partial grafts are used. Moreover, the contribution of large-volume ascites and sarcopenic obesity to high BMI and poor outcomes remains largely unknown.28,29 The rationale of the current study was to exclude a small group of high-risk patients from LT. For this, we used cutoffs on continuous variables with high specificity. The specificity for BMI > 30 kg/m2 (n = 20) was 98.7% on ROC analysis, with an AUC > 0.6 (Supplementary table).
The role of LDLT in EASL-CLIF ACLF has only been investigated recently.7,8,15,30 There is a substantial survival benefit with LT when compared with medical treatment alone.7,8 The one-year post-LT mortality in ACLF is significantly high compared to non-ACLF patients (31–38% vs. 9.8%).15 However, it is difficult to draw comparisons between various studies due to variable lengths of posttransplant follow-ups, patient selection criteria, and a lack of assessment of response to medical treatment.7,8,15 For example, Yadav et al. excluded patients requiring mechanical ventilation or renal replacement therapy from LT.7 Wang et al. transplanted patients based on Asian Pacific Association for the study of the Liver ACLF criteria but reported outcomes based on EASL-CLIF grades, with a disproportionately low number of patients with renal failure.30
In summary, we have attempted to identify factors that lead to unacceptable post-transplant outcomes after LDLT in ACLF. The high-risk group included only 15/104 (14.4%) patients with a one-year posttransplant survival rate of 6%. This clearly shows transplant futility, while > 80% one-year survival in the low-risk group is satisfactory, given the critical condition and high short-term mortality without transplant in these patients. More importantly, all risk factors are dynamic and can be reversed with treatment.
The limitations of the current study include its retrospective design. While some prognostic factors such as response to medical treatment, drug-resistant infections, and renal impairment have been validated in other studies, the value of a low platelet count and a BMI > 30 kg/m2 should be viewed with caution. Nevertheless, these simple and easily applicable ACLF severity parameters can be assessed in any transplant setting. Another limitation was the small number of patients with respiratory and circulatory failure who underwent LDLT in the current study. Considering that previous studies have considered the need for mechanical ventilation and high inotropic support as contraindications to LDLT,7,8 we assume that this is a step forward, and LDLT can be considered for this patient group as well. Fifteen (14.4%) patients with ACLF had underlying HCC in our cohort. Overall, approximately 30% of our transplanted patients have underlying hepatocellular carcinoma (HCC), and we frequently perform LDLT for expanded-criteria HCC. This is substantially higher than the previous reports and probably reflects referral trends to our center.31 It remains debatable whether these patients should be included in the current analysis. Considering that the objective of the current study was to assess the impact of LT in patients at high risk of death within 30 days, the relatively small number of patients who undergo LDLT for EASL-CLIF ACLF, and the fact that there was no HCC recurrence-related death at one-year, we feel that background HCC should not impact the results of the current study.
In the setting of ACLF, careful patient selection might yield outcomes comparable with other standard indications. Therefore, patients in the low-risk group should be prioritized for LT, whereas those with higher scores need medical optimization with possible re-evaluation. It remains to be determined whether the results of this study are uniformly applicable to DDLT or to patients requiring mechanical ventilation or inotropic support. Further studies are needed, preferably in a multicenter setting with a larger patient cohort, to identify new factors or validate existing ones in the setting of LT for ACLF.
Credit authorship contribution statement
Study concept and design (ABH, SR), Acquisition of data (SFQ, ZZ), analysis and interpretation of data (ABH, MQ), critical revision of the manuscript (ABH, HHZ, NYK). All authors made significant contribution to the study have approved the final manuscript.
Conflicts of interest
The authors have none to declare.
Acknowledgements
None.
Funding
Not funding was received for this study.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jceh.2024.101403.
Appendix A. Supplementary data
The following is the Supplementary data to this article.
References
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