In patients without any previous history of liver disease, acute liver failure (ALF) is a potentially fatal consequence of acute liver injury that can cause coagulopathy, altered mental status, and frequent multiorgan dysfunction [1]. It can impact almost every organ system and has a wide range of clinical manifestations and etiologies. Patients with chronic liver illness can have abrupt worsening in the form of acute-on-chronic liver failure (ACLF), which has a significant short-term death rate ranging from 14.6% to 78.6% [2]. For children with ACLF or ALF who do not respond to medical treatment, liver transplantation (LT) is the last choice [3]. Because the rapid worsening of liver function in patients with ALF or ACLF can be deadly, LT must be administered as soon as feasible [4,5].

For children with ALF or ACLF, emergency living donor liver transplantation (LDLT) could be considered even critically ill individuals have a high chance of receiving rapid DDLT in places with high rates of deceased organ donation. However, LDLT could be the only treatment option available to save infants who are dying of ALF or ACLF in places like Korea where there is a dearth of organ donors. In Korea, living liver donors (LLDs) are only allowed to be close relatives. Due to the high risk of antibody-mediated rejection (AMR), ABO-incompatible (ABOi)-LDLT was once thought to be contraindicated for pediatric patients. However, due to reports that its outcomes are comparable to those from ABO-compatible LDLT (ABOc-LDLT), its usefulness has recently been reopened [6]. When an ABOc LLD is unavailable, an ABOi LLD ought to be taken into consideration.

Pre-transplant desensitization is typically required for most potential recipients of ABOi-LDLT who are older than one year in order to lower the risk of hyperacute rejection and AMR. This process typically takes two to three weeks [7]. Time constraints, however, may make it impractical to implement those methods in emergency LDLT conditions for ALF or ACLF. Prior studies on emergency ABOi-LT have not demonstrated positive results or provided agreement on the best desensitization approach. Nevertheless, no prior research has conducted a comparison between emergency pediatric ABOc-LDLT and emergency pediatric ABOi-LDLT.

Therefore, the purpose of our study is to compare the outcomes between emergent pediatric ABOi-LDLT and emergent pediatric ABOc-LDLT.

Study Design

Retrospective Korean Network for Organ Sharing (KONOS) data for consecutive pediatric emergency patients who received LDLT from 2017 to 2021 was investigated. The KONOS provided the patient list, demographics, and dates of death or LT, which were combined with the necessary lab data from every center. Fifty-three emergency pediatric LDLTs were conducted between 2017 and 2021. The Samsung Medical Center Institutional Review Board gave its approval to this study (SMC-2022-11-057-002). Informed consent was not required because this was a retrospective investigation into de-identified data.

Data Collection

Every patient’s sex, age, body mass index, pediatric end-stage liver disease scores, graft-to-recipient weight ratio, postoperative complications, graft failure, and mortality were recorded for every patient in KONOS and every institution. Pre-transplant ventilator support, pre-transplant intensive care unit (ICU) admission, hepatorenal syndrome, and grade of hepatic encephalopathy were the categorical variables that we evaluated in order to characterize the severity of the patient. ABOi between the recipient and donor blood types and re-transplantation were also evaluated. The time gap between the day KONOS received the emergency LDLT application and the day of transplantation was also assessed.

Administrative LDLT Approval Process in the Korea

KONOS approval is required prior to doing an LDLT. Documents pertaining to the donor and recipient status, such as an identification, consultation report, and statement of purpose, must be submitted by the transplantation center (Supplementary Fig. 1). Following receipt and examination of those records, KONOS normally issues a decision either permission or disapproval within 14 days.

It can be difficult to explain a practical judgment on an emergency application of LDLT based only on laboratory data or medical records. Each patient must have a note from their physician and receive clearance from a government agency under Korea’s current LT application process.

Statistical Analysis

For continuous data, the patient features are shown as the median and range; for categorical variables, they are shown as the frequency and percentage. The chi-square test or Fisher’s exact test was used to compare categorical data, while the Mann–Whitney U-test was used to analyze continuous data. A Cox regression analysis was conducted in order to determine the risk factors for mortality and graft failure after emergency LDLT. Odds ratios and 95% confidence intervals were computed. All clinically meaningful potential risk variables were included in the multivariate analysis, and the final decision was made using backward variable selection to determine statistical significance. Two-sided p-values less than 0.05 indicated statistical significance in the results. SAS analytic software version 9.4 (SAS Institute, Cary, NC, USA) and R software version 4.2.2 (R Foundation for Statistical Computing, Vienna, Austria) were used for all statistical analyses.

Ethics Statement

The study was approved by the Samsung Medical Center Institutional Review Board (SMC-2023-11-038) and complied with the Declaration of Helsinki. The Institutional Review Board waived the need for patient consent because of the retrospective nature of this observational study and its use of data from patient medical records.

Baseline Characteristics of the Recipients

The incidence of ABOc-LDLT and ABOi-LDLT was 83% (n=44) and 17% (n=9), respectively. The primary cause of both ABOc-LDLT and ABOi-LDLT was ALF. ICU care was required for over 70% of patients as they awaited LDLT. Furthermore, approximately 30% of patients in both groups underwent continuous renal replacement therapy (CRRT) due to renal failure, and approximately 40% of patients in both groups required mechanical breathing for support. In both groups, the average wait time for emergency LDLT was one day (range, 0–7 days). There was no discernible difference in any of the recipient characteristics between the two groups (Table 1).

Table 1 . Comparison of pediatric recipients of emergency ABOc or ABOi LDLT.

Total (n=53)	ABOc LDLT (n=44)	ABOi LDLT (n=9)	p-value
Sex (male)	16 (36.4)	6 (66.7)	0.140
Liver disease progression			0.722
Acute liver failure	32 (72.7)	7 (77.8)
Acute on chronic liver failure	9 (20.5)	2 (22.2)
Critical cirrhosis	3 (6.8)	0 (0)
Age (yr)	1.0 (0.3–18)	1 (0.2–12)	0.765
BMI	17.6 (14.2–26.0)	17.9 (14.6–19.8)	0.950
Re-transplantation	6 (13.6)	0 (0)	0.574
Hepatic encephalopathy			0.535
None	24 (54.5)	6 (66.7)
Grade I or II	13 (29.5)	2 (22.2)
Grade III or IV	7 (15.9)	1 (11.1)
Hepatorenal syndrome	4 (9.1)	0 (0)	0.347
Pre-transplant ICU care	32 (72.7)	6 (66.7)	0.701
Pre-transplant ICU stay (day)	3 (1–14)	3 (1–5)	0.656
Pre-transplant ventilator support	18 (40.9)	4 (44.4)	0.845
Pre-transplant CRRT	12 (27.3)	3 (33.3)	0.713
Ascites	21 (47.7)	1 (11.1)	0.037
PELD score	25 (10–40)	33 (22–40)	0.463
PELD score >30	19 (43.2)	4 (44.4)	0.989
Wait time (day)	1 (0–7)	1 (0–7)	0.732
GRWR	2.09 (0.86–4.99)	1.75 (0.87–3.18)	0.462

Values are presented as number (%) or median (range)..

ABOc, ABO-compatible; ABOi, ABO-incompatible; LDLT, living donor liver transplantation; BMI, body mass index; ICU, intensive care unit; CRRT, continuous renal replacement therapy; PELD, pediatric end-stage liver disease; GRWR, graft-to-recipient weight ratio..

Characteristics of Living Liver Donors

Ninety-nine LLDs (92.5%) were the parents of the children in need of transplantation. In the ABOc-LDLT group, their median age ranged from 28 to 50 years, while in the ABOi-LDLT group, it was 35 years, with a range of 25 to 46 years. Compared to ABOc-LDLT, a larger percentage of robotic donor hepatectomy was performed in ABOi-LDLT. Following donor hepatectomy, the median hospital stays and follow-up periods for both groups were 8 days and about 1 year, respectively. There was no difference in any LLD characteristic between the two groups (Table 2).

Table 2 . Comparison of living liver donors for emergency pediatric ABOc and ABOi LDLT.

Total (n=53)	ABOc LDLT (n=44)	ABOi LDLT (n=9)	p-value
Sex (male)	15 (34.1)	1 (11.1)	0.248
Age (yr)	37 (28–50)	35 (25–46)	0.765
BMI	22.1 (17.5–29.4)	22.8 (21.3–32.4)	0.427
HTN	1 (2.3)	0 (0)	0.648
Donor and recipient relationship			0.572
Parents	40 (90.9)	9 (100)
Relatives	4 (9.1)	0 (0)
Donor operation			0.018
Open	21 (47.7)	1 (11.1)
Laparoscopic	10 (22.7)	1 (11.1)
Robotic	12 (27.3)	7 (77.8)
Postoperative complications	4 (9.1)	1 (11.1)	0.780
Hospitalization	8 (4–17)	8 (4–13)	0.958
Follow-up duration (day)	365 (13–1,265)	368 (43–382)	0.999

Values are presented as number (%) or median (range)..

ABOc, ABO-compatible; ABOi, ABO-incompatible; LDLT, living donor liver transplantation; BMI, body mass index; HTN, hypertension..

Recipient Outcomes

Complications following LDLT were common in individuals. In the ABOc-LDLT group, the incidence of infectious complications was 52.3%, while in the ABOi-LDLT group, it was 66.7%. It’s interesting to note that the ABOi-LDLT group had the viral infection at a higher rate than the ABOc-LDLT group. The two groups’ median hospitalization periods were identical. During follow-up, two patients in the ABOc-LDLT group were dead.

For the ABOc-LDLT group, the median follow-up period was 26.9 months (range, 0–67.1 months), while for the ABOi-LDLT group, it was 22.3 months (range, 0.9–66.9 months). In the ABOc-LDLT group, diagnoses of acute cellular rejection (ACR) (n=6) and AMR (n=1) were made. During follow-up, graft failure emerged in seven patients and mortality occurred in eight patients, respectively. There was no discernible difference in recipient outcomes between the two groups (Table 3). Although the ABOi-LDLT group outperformed the ABOc-LDLT group in terms of graft survival and overall survival, the difference was not statistically significant (Fig. 1).

Figure 1. (A) Graft survival and (B) overall survival. ABOc, ABO-compatible; LDLT, living donor liver transplantation; ABOi, ABO-incompatible.

Table 3 . Recipient outcomes from emergency pediatric ABOc and ABOi LDLT.

Total (n=53)	ABOc LDLT (n=44)	ABOi LDLT (n=9)	p-value
Post-transplant ICU stay (day)	8 (3–119)	6 (2–18)	0.159
Post-operative complications	34 (77.3)	8 (88.9)	0.665
Post-transplant infectious complications	23 (52.3)	6 (66.7)	0.487
Viral infection	12 (27.3)	5 (55.6)	0.126
Bacterial infection	15 (34.1)	4 (44.4)	0.706
Fungal infection	7 (15.9)	0 (0)	0.334
Hospitalization (day)	25 (1–78)	24 (2–42)	0.950
In hospital mortality	2 (4.5)	0 (0)	0.514
Rejection			0.438
None	37 (84.1)	9 (100)
ACR	6 (13.6)	0 (0)
AMR	1 (2.3)	0 (0)
Graft failure	6 (13.6)	1 (11.1)	0.838
Death	7 (15.9)	1 (11.1)	0.714
Cause of death			0.330
Postoperative complications	1 (2.3)	0 (0)
Graft failure	1 (2.3)	0 (0)
Infection	4 (9.1)	0 (0)
Others	1 (2.3)	1 (11.1)
Follow-up duration	26.9 (0–67.1)	22.3 (0.9–66.9)	0.700

Values are presented as median (range) or number (%)..

ABOc, ABO-compatible; ABOi, ABO-incompatible; LDLT, living donor liver transplantation; ICU, intensive care unit; ACR, acute cellular rejection; AMR, antibody-mediated rejection..

Risk Factors for Death and Graft Failure

The univariate analysis revealed a strong correlation between pre-transplant CRRT and hepatorenal syndrome and death. Moreover, in the univariate analysis, extended stays in the ICU following transplantation were linked to graft failure (Table 4). In the multivariate analysis, no factors were found to be significant. Neither graft failure nor death was associated with ABOi-LDLT.

Table 4 . Risk factors of pediatric patients receiving emergency LDLT.

Univariate	Patient mortality (n=53, events=8)			Graft failure (n=53, events=7)
	HR (95% CI)	p-value		HR (95% CI)	p-value
Male sex	1.38 (0.35–5.52)	0.649		1.96 (0.44–8.77)	0.378
Age	1.03 (0.92–1.16)	0.598		1.06 (0.94–1.19)	0.355
BMI	1.03 (0.80–1.31)	0.841		1.06 (0.83–1.37)	0.623
Ascites	0.07 (0.00–1.44)	0.085		0.20 (0.02–1.68)	0.138
Reason for emergent LDLT
Acute liver failure	Reference	1		Reference	1
Acute-on-chronic liver failure	0.75 (0.11–5.04)	0.764		0.24 (0.01–5.61)	0.373
Pre-transplant ICU care	2.52 (0.31–20.45)	0.389		2.05 (0.25–17.02)	0.508
Pre-transplant ventilator care	2.76 (0.66–11.55)	0.166		1.24 (0.28–5.55)	0.779
Pre-transplant CRRT	4.90 (1.17–20.52)	0.030		2.27 (0.51–10.16)	0.283
Hepatorenal syndrome	6.61 (1.32–33.03)	0.021		1.33 (0.06–28.53)	0.857
Hepatic encephalopathy
Grade I or II	2.13 (0.43–10.56)	0.355		2.14 (0.43–10.60)	0.352
Grade III or IV	3.03 (0.51–18.18)	0.226		1.46 (0.15–14.05)	0.744
MELD score	1.01 (0.94–1.09)	0.763		1.07 (0.98–1.17)	0.117
ABO-incompatibility	1.09 (0.11–1.04)	0.943		1.55 (0.14–17.11)	0.719
Re-transplantation	1.18 (0.14–9.57)	0.879		0.53 (0.03–11.44)	0.687
Post-transplant ICU stay	1.02 (1.00–1.04)	0.067		1.03 (1.00–1.05)	0.041
GRWR	0.38 (0.12–1.16)	0.089		0.44 (0.16–1.23)	0.118

LDLT, living donor liver transplantation; HR, hazard ratio; CI, confidence interval; BMI, body mass index; ICU, intensive care unit; CRRT, continuous renal replacement therapy; MELD, model for end-stage liver disease; GRWR, graft-versus-weight ratio..

LT is the only effective treatment for pediatric ALF patients; without it, they would not survive. Many centers have expanded their donor selection to include LDLT due to high waitlist mortality [8,9]. Early Western experience with high-urgency transplantation demonstrating inferior outcomes and ethical concerns about the emotional pressure that a high-urgency situation can impose on the LLD, potentially influencing their decision-making, are the main causes of the reluctance to do LDLT for ALF [10].

Fifty-three pediatric patients underwent emergency LDLT in Korea during the research period, according to KONOS data. All ABOi-LDLT patients (n=9) lived for five years without developing AMR and ACR. Due to the limitation of available DDLT choices, LDLT is frequently utilized for the therapy of ALF in Korea. Excellent recipient survival and reported LLD safety have been documented [11,12]. In an emergency, ABOi LLDs will be the only option if ABOc LLDs are unavailable. By decreasing anti-blood type isoagglutinin and depleting B-cells, ABOi-LDLT can currently be carried out effectively and produce results comparable to ABOc-LDLT [13,14].

For patients with ALF or those admitted to the ICU, several centers expressly refrain from using ABOi-LDLT [15]. Several factors make planning an ABOi-LDLT to treat ALF more difficult. There is not much time between deciding to transplant and doing the LT surgery. In both ABOc- and ABOi-LDLTs in our study, the median duration between the decision to transplant and the emergency LDLT was one day. In order to sufficiently reduce the B lymphocyte cohort for ABOi-LDLT desensitization, preoperative rituximab must be administered two to three weeks before the transplant. But waiting that long for LT is risky for an ALF patient because of rapid deterioration. Overcoming the ABO barrier in the limited time permitted for ABOi-LDLT for ALF is difficult. Because patients with multiple organ failure have a narrow period of urgency for transplantation, increasing donor availability and decreasing wait times are essential to improve patient outcomes.

Extracorporeal therapy and organ support are necessary for children with ALF, which raises their risk of infection complications. Thus, it is especially difficult to balance desensitization and infection in these patients. There is no information regarding desensitization therapy in our data. On the other hand, we presume that very little desensitization treatment was used given that the median wait duration was one day.

Emergency ABOi-LDLT is typically reserved for extreme cases and is not a routine operation. Early research on emergency ABOi-LT in the LDLT circumstances revealed a significant rate of complications from infections, graft loss by immunologic injury, and other vascular issues [16]. Mendes et al. [16] reported that five out of ten patients who underwent emergency ABOi-LT were still living at the time of publication and four of them had received original grafts. Nine months following the initial transplant, one patient had a second transplant. Infections (n=3), AMR (n=3), ACR (n=1), and biliary problems were the main consequences. Approximately 60% of emergency ABOi-LDLT patients had a bacterial or viral illness after transplantation. The median length of hospital stay was 24 days in our study; thus any additional issues were easily managed despite the infectious complications. Even though AMR-related graft loss is a significant factor in ABOi-LT, our investigation did not produce any AMR or ACR.

There are various restrictions on our investigation. First, selection bias was introduced when we used KONOS data to retrospectively assess emergency LDLT cases. We lacked extensive details regarding isoagglutinin titers and desensitization procedures. Second, there were only nine emergency pediatric ABO-LDLTs, which reduced our statistical power. Third, the circumstances around the transplantation center and the donor’s or family’s willingness can have an impact on whether or not emergency LDLT is received. These factors are hard to measure. Fourth, the etiology was not carefully assessed or examined within each subgroup, particularly with regard to whether the patient had ALF or ACLF.

This study concludes that emergency pediatric ABOi-LDLT is safe and feasible for use in ALF patients as well as other urgent instances.

Supplementary data related to this article can be found online at https://doi.org/10.52604/alt.24.0009.

The Korean National Health Insurance (NHIS) helped with data collection for this study, but the Korean NHIS and Korean NRF did not influence study design, data analysis, data interpretation, or drafting of the manuscript.

This study was funded or supported by the KONOS of the Ministry of Health and Welfare (NHIS-2022110058F-00).

This research was supported by the Basic Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2023R1A2C2005946).

Jongman Kim is a chief editor of the journal but was not involved in the review process of this manuscript. Any other authors have no conflict of interest.

Conceptualization: JK. Data curation: SA, JK, SJK, SYK, JBP. Formal analysis: SA, JK. Investigation: JK. Methodology: SA, JK, YH, DHJ. Project administration: JK, DHJ. Resources: JK, YH. Software: JK. Supervision: JK. Validation: JK, SYK, JBP, YH, DHJ. Visualization: JK. Writing – original draft: SA, JK. Writing – review & editing: JK.