Introduction

Liver transplantation (LT) is the definitive treatment for patients with acute-on-chronic liver failure (ACLF) [1]. The long-term survival of patients with ACLF undergoing LT is ≥ 80%, in contrast to ≤ 40% in those who do not undergo LT [2, 3]. Transplant-free mortality in patients with ACLF ranges between 6 and 18% for ACLF grade 1 compared to 45–90% in patients with ACLF grade 2 or 3 at day 28 [4, 5]. Several studies have reported comparable outcomes among patients with and without ACLF who undergo LT [1, 2, 5]. However, most of the data on LT are based on centers that are largely cadaveric LT programs. A few studies have reported excellent outcomes following living donor LT (LDLT) in patients with ACLF, which may have the advantages of timely and planned surgery [6,7,8]. In a large transplant center in India, Yadav et al. included 218 patients with ACLF identified using the European Association for Study of Liver-Chronic Liver Failure (EASL-CLIF) criteria [6]. Of these, > 70% of patients had ACLF grades 1 or 2, and 117 underwent LDLT [6]. The authors reported post-LT survival rates of 93, 85.4, and 75.6% for ACLF grades 1, 2, and 3, respectively [6]. In contrast, the 90-day mortality rates among those who could not undergo LDLT were 28.5, 78, and 93% in grades 1,2, and 3, respectively. Wang et al. included 112 patients with ACLF identified by Asian Pacific Association for Study of Liver (APASL) criteria (and graded according to EASL-CLIF criteria) who underwent LDLT [8]. The authors reported a survival rate of 95% at 3 years. Higher intraoperative blood loss and postoperative portal vein complications were observed in patients with ACLF [8]. These studies included patients with ACLF defined and/or graded by EASL criteria and did not address the key issues of performing LDLT for APASL-defined ACLF and APASL ACLF Research Consortium (AARC) risk score.

Recent studies have highlighted higher resource utilization post-LT in ACLF patients due to prolonged hospital stays, requirement for dialysis, recurrent infections, and surgical complications [9]. Approximately 30% of patients may be discharged to a rehabilitation center post-LT, and the expenditure post-LT proportionately increases with the grade of ACLF [9]. As such, clinical improvement prior to LT is well known to improve outcomes in patients with ACLF undergoing LT [7, 10, 11]. However, no studies to date have assessed the healthcare burden of bridging a patient with ACLF identified by APASL criteria to LDLT. Further, although it has been suggested early listing and transplantation within 30 days be pursued in ACLF, the feasibility of such early LDLT has been limited to very few centers [5, 12, 13]. Therefore, we aimed to evaluate the outcomes of patients with ACLF who underwent LDLT at our center and assess the healthcare burden and resource utilization by such patients.

Methods

This retrospective single-center study was conducted at Asian Institute of Gastroenterology Hospitals, Hyderabad, India. We included patients with ACLF who underwent LT between 1st April 2019 and 1st October 2021 and completed at least 1 year of follow-up. The primary outcome was to assess survival at one year. The secondary objective was to assess the major complications of LT, including biliary complications, vascular complications, rejection episodes, and renal injury requiring admission following LT. We also aimed to assess the time-to-LDLT, change in severity scores from diagnosis to LT, healthcare utilization by patients, and incidence and predictors of infection post-LT.

The following pre-LT data were extracted: age, sex, cause of acute precipitant, etiology of underlying chronic liver disease, comorbidities, number and duration of admission prior to LT, presence of acute kidney injury (AKI), hepatic encephalopathy, infection, requirement of vasopressor therapy, requirement of mechanical ventilation, and proportion of patients who underwent plasma exchange prior to LT. Biochemical variables extracted at admission were complete hemogram, liver function tests, kidney function tests, and blood gas analyses. Severity scores were assessed at the time of admission and at the time of LT. Biochemical variables on the day of or 24 h prior to LT were extracted to calculate the severity scores at the time of LT. The time from diagnosis of ACLF to LT was assessed.

The following LT data were extracted: duration of surgery, cold ischemia time, warm ischemia time, volume of packed red blood cells, fresh frozen plasma, and cryoprecipitate transfused were retrieved.

The following post-LT data were extracted: number and duration of admission post-LT, surgical complications including bile leaks, biliary strictures, vascular complications, surgical re-exploration, and proportion of patients developing infections within 3 months and more than 3 months were extracted.

Definitions

ACLF was defined according to the APASL criteria as patients with serum bilirubin ≥ 5 mg/dl and INR ≥ 1.5 complicated by ascites and/or hepatic encephalopathy within 28 days in a patient with known or unknown liver disease [14]. The grade of ACLF was classified according to the APASL ACLF Research Consortium (AARC) criteria [14]. Briefly, AARC scoring includes five criteria (serum bilirubin levels, INR, serum creatinine, blood lactate levels, and hepatic encephalopathy), with scores from 1 to 3 for each and a total score ranging from 5 to 15. The grading of ACLF was based on AARC scores as I (score 5–7), II (score 8–10), and III (score 11–15).

Inpatient care requiring > 24 h of hospitalization was considered as admission. The monetary amount spent prior to LT for stabilization, which included investigations and antibiotic therapy for infections, hospitalization, plasma exchanges, albumin infusions, and management of renal injury, was included in the pre-LT amount required for stabilization. The monetary amount spent prior to LT was retrieved from the finance department for each admission and the cumulative amount was added to assess the pre-transplant expenditure for the patients. Patients underwent LT when deemed stable enough to tolerate the surgery and had controlled infection or no active infection, without shock, or renal failure requiring renal replacement therapy.

AKI was defined as a rise in serum creatinine by 0.3 mg/dl within 48 h [15].

Statistical analysis

The extracted data were entered into Microsoft Excel and analyzed using SPSS ver.29 (IBM corp, NY, USA). Categorical data such as sex distribution, etiology of acute precipitant, and chronic liver disease, the proportion of patients with infection, AKI, hepatic encephalopathy, and grade of ACLF are expressed as n (%). Continuous data such as age, biochemical variables, severity scores, and intraoperative measures (ischemia time, duration of surgery, and volume of blood products transfused) were expressed as mean (standard deviation) or median (range), as applicable. Survival was assessed using Kaplan–Meier analysis method. The predictors of infections and post-transplant mortality were analyzed using stepwise logistic regression analysis, and values with p < 0.1 were included for multivariate analysis. Reciever operating characteristic curve (ROC) analysis was carried out as necessary to identify cut-off for predicting survival benefit with LT.

Results

In total, 73 patients were listed for LDLT and 18 (22%) patients died on the waitlist. The median AARC score of those who died on the waitlist was 11 (8–15). Thirty-three percent (n = 6) had ACLF grade II, and 66.7% (n = 12) had grade III. (Supplementary Table 1). The cause of mortality on the waitlist was sepsis in 66.7% (n = 12), variceal bleeding in 22.2% (n = 4), diffuse alveolar hemorrhage in 5.6% (n = 1), and last, one (5.6%) of the patients had sudden cardiac death.

A total of 55 patients underwent LDLT (Fig. 1: Consort chart). The most common cause of ACLF was alcohol-related disease. Most patients were diagnosed with AARC grade II (76.4%), while only 3.6% were diagnosed with ACLF grade I, and 20% were in grade III at the time of diagnosis. Prior to LT, 51%, 56%, and 40% had AKI, hepatic encephalopathy, and infection, respectively.

Fig. 1
figure 1

Consort chart. TTT time to transplantation, PLEX plasma exchange, LT liver transplantation, LDLT living donor liver transplantation

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The median time from diagnosis of ACLF to LT was 60 (10–120) days. At the time of LT, 87.3% were grade II, 7.3% were grade III, and 5.5% were grade I. None of the patients had received renal replacement therapy. Only one patient (Wilson disease) was on mechanical ventilation for hepatic encephalopathy and was taken to the operating room from the intensive care unit. The patient recovered gradually over 5 days and required prolonged ventilation. Four patients required vasopressor therapy prior to LT, but none were on vasopressor therapy at the time of LT. The MELD Na score decreased from 31 (26–40) at diagnosis to 28 (11–36) at the time of LT (delta change: − 3.27 ± 4.1; p < 0.001). The AARC score decreased from 11 (8–15) at the time of diagnosis to 9 (7–11) at the time of LT (delta change: − 0.56 ± 0.5; p < 0.001) (Table 1).

Table 1 Baseline characteristics of patients who underwent living donor liver transplantation
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Donor characteristics and details of LT (Table 2)

Table 2 Operative details
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The mean age of the voluntary healthy donors was 33.91 ± 9.48 years, and 69% of donors were females. The mean body mass index (BMI) of the donors was 24.62 ± 4.28 kg/m2, and graft-to-recipient weight ratio (GRWR) was 1.1 ± 0.62. Six recipients had GRWR < 0.7 and two of them died within 6 months (one with graft dysfunction and another with sepsis).

Outcomes

Twenty-two percent (12/55) of patients died in 6 months, and 27.3% of (15/55) patients died within 1 year of LT. All patients who died were in grade II of AARC class prior to LT. Survival at 1 year was 72.73% among the whole cohort. Thirteen patients died of sepsis, two of COVID-19, and one of graft failure. Survival remained at 72.73% even after a mean follow-up period of 925.21 days on Kaplan–Meier survival analysis (Fig. 2). Compared to patients who died on the waitlist, the mortality in those who underwent LT was 27.3% (p < 0.001). AARC score of ≥ 10.5, CLIF-C ACLF score of ≥ 44.5, and CLIF OF of ≥ 9.5 predicted survival benefits with LT with an excellent AUROC (Supplementary Fig. 1).

Fig. 2
figure 2

Kaplan–Meier Survival analysis

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Nine percent of patients developed vascular complications (hepatic artery thrombosis [HAT]-2 and neo-middle hepatic vein [MHV] thrombosis-2; hepatic vein obstruction-1). Two patients with HAT required re-exploration. One of the patients with right hepatic vein kinking required stenting because he developed hepatic venous outflow tract obstruction and ascites.

Ten percent (5/55) of patients developed biliary anastomotic strictures. All patients were managed using endoscopic retrograde cholangiopancreatography (ERCP) guided biliary dilatation and stent exchanges. One patient required prolonged cyclical antibiotics due to recurrent infections apart from stenting due to the involvement of the right posterior duct. Two patients developed biliary leaks and required percutaneous drainage and multiple ERCP-guided stent exchanges. One patient required re-exploration.

Rejection

Ten patients (18.2%) developed acute cellular rejection (7 were biopsy-proven and 3 suspected) within one year. All patients responded to pulse steroid therapy. Two patients developed graft dysfunctions. First patient (GRWR < 0.6) developed early graft dysfunction due to severe sepsis and multiorgan failure and died within 3 months. The second patient with autoimmune hepatitis-related ACLF developed graft failure after seven months. He had pleural tuberculosis, for which he was started on anti-tuberculous therapy, which led to drug-induced liver injury, followed by graft dysfunction.

Renal recovery

At the time of transplant, only one patient had a serum creatinine of 1.54, and the rest had serum creatinine < 1.5 mg/dl. Thirty-two percent (18/55) developed AKI (rise in serum creatinine by 0.3 mg/dL) within 3 months. However, only six patients (11%) with AKI required readmission. Of these, two patients (one with IgA nephropathy and the other with renal abscess) progressed to chronic kidney disease and were being managed conservatively without any need for renal replacement therapy to date.

Infection Risk Post-LT

Forty-five percent (25/55) of patients developed infections within 3 months. Multisite infections were noted in 20% (5/25) of the recipients. The sources of infection are listed in Table 3. Stepwise logistic regression analysis revealed hepatic encephalopathy and infection prior to LT as predictors of post-LT early infections (< 3 months) (Supplementary Table 2). Approximately 13% of the patients (7/55) developed late infections (> 3 months). Furthermore, early infections (< 3 months) post-transplant was the only significant predictor of mortality post-LT (Supplementary table 3).

Table 3 Source of infection after liver transplantation
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Other complications

Two patients required tracheostomy and prolonged ventilation. Four patients developed stress cardiomyopathy, proximal myopathy, or delirium. Last, two patients developed seizures when tacrolimus levels were within the therapeutic range. However, owing to concerns about recurrent seizures, cyclosporine was initiated. In total, 58.2% (32/55) developed complications (including vascular, biliary, graft rejections, AKI, neuromuscular, and cardiovascular complications) during the initial year post-LT and 27.3% (15/55) developed \(\ge\)2 complications (Table 4).

Table 4 Complications following LDLT and healthcare utilization by patients who underwent LT
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Immunosuppression

All patients received triple-drug immunosuppression with steroids, mycophenolate mofetil, and tacrolimus (except two patients who received cyclosporine). Basiliximab was administered with three patients with a history of AKI prior to LT.

Healthcare utilization

The median time from diagnosis of ACLF to LT was 60 (10–120) days. Thirty-one patients (56%) underwent a median of 2 (1–8) sessions of high-volume plasma exchange prior to LT. Prior to LT, each patient required a median of 2 (1–4) admissions for 17 (4–45) days. A median amount of Rs. 8,25,090 (INR 26,000–43,58,154) was utilized to stabilize the patient prior to LT. The mean [SD] amount spent for stabilization increased with grade of ACLF (Grade 1: Rs. 83,443 [47,295]; Grade 2: Rs. 12,19,818 [11,51,552] and Grade 3: Rs. 16,578,79 [11,89,259 INR]). The majority of these amounts was required for plasma exchange. Patients in the plasma exchange group had higher serum bilirubin and severity scores. Post-plasma exchange, the ACLF grade reduced from III to II in five patients. Time to transplant was significantly longer in the plasma exchange group (60 [10–120] days) than direct LT group (45 [15–60] days (p = 0.02). The proportion of patients developing complications post-LT was lower in the plasma exchange group but not significant (Supplementary Table 4). Each patient required Rs. 24,56,484 (18,00,599–49,30,440 INR) for surgery and managing post-LT complications for the initial three weeks. Twenty-nine percent (n = 16) of patients had insurance or a government medical grant supporting LT surgery. Thirty-four percent of patients required readmission (19/55) within 6 months, and each patient required a median of 2 (1–7) admissions following LT (Table 4).

Discussion

The salient features of the current study are as follows: (a) LDLT was associated with a survival rate of 73% for patients with ACLF; (b) 58.2% developed complications and 27.3% developed \(\ge\)2 complications; (c) 45% of patients developed infections within 3 months; (d) patients with ACLF utilized more healthcare resources pre-LT for stabilization.

LT is associated with higher morbidity in patients with ACLF. Artru et al. reported that 100% of patients with ACLF-3 develop complications following LT [2]. Common complications include vascular anastomosis dissection, thrombosis, biliary complications, and pulmonary, neurological, and cardiovascular complications [2]. Eighty-one percent of the patients developed bacterial infections, and 5% died of infection within one year. Approximately 15% had serum creatinine > 2 mg/dl, of which only two required renal replacement therapy. The authors also reported that 27% of patients underwent repeat laparotomy within 30 days. Similarly, Huebner et al. and Abgim et al. reported higher morbidity rates among patients with ACLF who underwent LT [10, 16]. Most patients in our study developed complications within the initial 6 months, and those surviving the initial period had excellent long-term survival. This has also been highlighted by previous studies [17, 18]. Compared to the study by Yadav et al., the survival was lower in our cohort, as we used APASL-defined ACLF who had dominant liver failure and were sicker [6]. MELD score and serum bilirubin levels were higher in our cohort than those reported previously [6, 8, 19]. Pre-transplant MELD score (and serum bilirubin levels) is known to predict survival and also complications post-LT [20,21,22,23]. A recent study that included the Japanese criteria for ACLF, which is similar to the APASL criteria, also reported a survival of 75% after LDLT [19]. Another large multicenter study from China also reported a survival of 77.2% in those undergoing LT compared to 27.6% at 1 year in those who could not undergo LT [24].

The average time to transplantation in our study was 60 days which is in contrast with the recommended early transplantation within 30 days and which is reported to be associated with improved survival [5, 12, 13, 25]. The reason for the delay is the poorer and ready acceptance of LT in Asian settings. A large multicenter study from Asia reported that only 7.2% (41/565) of the patients underwent LT for ACLF [13]. Further, the time required for the optimization of patients deemed too sick also delays LT [5, 12].

The mean age in our cohort was 38 years, highlighting the misuse of alcohol among the young population. A recent study reported that the misuse of alcohol begins in the second to third decade of life in India, and cirrhosis develops approximately 12–15 years later, which is in concurrence with the observation made in our study [26]. Thus, policies to curb alcohol use are essential to prevent alcohol-related deaths.

Recent studies have highlighted the major healthcare and cost burden utilized by patients with ACLF who undergo LT. Goussous et al. reported that the cost for patients with ACLF undergoing LT was $2,27,886 compared to $88,900 for those who could not undergo LT [27]. Similarly, Sundaram et al. reported that the expenditure proportionately increased (post-LT) with the ACLF grade from $102,698 for grade 1, to $244,406 for grade 3, compared to only $65,359 for patients without ACLF. In the current study, we noted that the cost of optimization increased proportionately with the ACLF grade, which has not been assessed or reported to date. Chen et al. reported that the healthcare utilization and cost burden of patients with ACLF is higher than those with decompensated cirrhosis [3]. However, the MELD score of the ACLF group was 27 compared to 14.5 in decompensated cirrhosis. It is difficult to match these two groups given the longer duration of disease in decompensated cirrhosis and expenditure related to recurrent admissions for infections, encephalopathy, and costs incurred for variceal ligation, drugs and ascitic tapping.

More than 60% of patients with ACLF are ineligible for LT because of sepsis, organ failure, or being too sick to transplant, contributing to high waitlist mortality [13]. Clinical improvement before LT has been associated with better survival post-LT [7, 10, 11]. It is well known that downgrading the ACLF grade before LT improves survival post-LT [11]. Plasma exchange has been suggested as a reasonable option to bridge patients with ACLF to LT [28, 29]. In our experience, time-to-transplantation was significantly longer in patients with ACLF who underwent plasma exchange. While plasma exchange may have helped patients with ACLF sustain and survive this long waiting time, plasma exchange did not have survival benefits as the grade of ACLF improved in only 13% and remained stable in others.

Limitations and future considerations

This was a retrospective single-center study that should be validated across other centers. The most common cause of mortality was infections in our study. Strategies for early identification of infections in patients undergoing LT are needed. Surveillance cultures can be performed for the early diagnosis and treatment of infections. In addition to universal precautions to prevent infections, lower-intensity immunosuppressive regimens may need to be considered to mitigate infection risk. The indication for plasma exchange was clinician-based and individualized. Further prospective randomized studies are required to assess the role of plasma exchange in effectively bridging patients with ACLF to LT, as noted by reduced complication rate and mortality, post-LT. We also did not evaluate the Chinese Group on the Study of Severe Hepatitis B (COSSH) scores as most of our patients had alcohol as a common precipitant, unlike the etiology of HBV as a cause of ACLF assessed by COSSH, and further, this scoring method is currently unavailable in India [24, 30]. Last, we included only patients who were listed for LT and did not have a priori defined futility and removal from LDLT considerations, which needs prospective studies.