Outcomes after liver transplantation in Korea: Incidence and risk factors from Korean transplantation registry

Article information

Clin Mol Hepatol. 2021;27(3):451-462

Publication date (electronic) : 2021 February 2

doi : https://doi.org/10.3350/cmh.2020.0292

Jong Man Kim^1,*, Deok Gie Kim^2,*, Jihyun Kim³, Keunsung Lee³, Kwang-Woong Lee⁴, Je Ho Ryu⁵, Bong-Wan Kim⁶, Dong Lak Choi⁷, Young Kyoung You⁸, Dong-Sik Kim⁹, Yang Won Nah¹⁰, Koo Jeong Kang¹¹, Jai Young Cho¹², Geun Hong¹³, Hee Chul Yu¹⁴, Ju Ik Moon¹⁵, Dongho Choi¹⁶, Shin Hwang^,17, Myoung Soo Kim^,18

¹Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

²Department of Surgery, Yonsei University Wonju College of Medicine, Wonju, Korea

³Novartis Korea Ltd., Seoul, Korea

⁴Department of Surgery, Seoul National University College of Medicine, Seoul, Korea

⁵Division of Hepato-Biliary-Pancreatic Surgery and liver Transplantation, Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea

⁶Department of Liver Transplantation and Hepatobiliary Surgery, Ajou University School of Medicine, Suwon, Korea

⁷Department of Surgery, Catholic University of Daegu College of Medicine, Daegu, Korea

⁸Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea

⁹Division of HBP Surgery & Liver Transplantation, Department of Surgery, Korea University College of Medicine, Seoul, Korea

¹⁰Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea

¹¹Department of Surgery, Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Korea

¹²Department of Surgery, Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Korea

¹³Department of Surgery, Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Korea

¹⁴Department of Surgery, Jeonbuk National University Medical School, Jeonju, Korea

¹⁵Department of Surgery, Konyang University Hospital, Konyang University College of Medicine, Daejeon, Korea

¹⁶Department of Surgery, Hanyang University College of Medicine, Seoul, Korea

¹⁷Department of Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea

¹⁸Department of Surgery, Yonsei University College of Medicine, Seoul, Korea

Corresponding author : Myoung Soo Kim Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea Tel: +82-2-2228-2123, Fax: +82-2-313-8289 E-mail: ysms91@yuhs.ac

Shin Hwang Department of Surgery, Asan Medical Center, College of Medicine, University of Ulsan, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 0505, Korea Tel: +82-2-3010-3930, Fax: +82-2-3010-6701 E-mail: shwang@amc.seoul.kr

*Jong Man Kim and Deok Gie Kim equally contributed to manuscript as co-first author.

Editor: Moon Young Kim, Yonsei University Wonju College of Medicine, Korea

Received 2020 October 26; Revised 2021 January 11; Accepted 2021 January 29.

Abstract

INTRODUCTION

Liver diseases are a public health problem worldwide and are highly prevalent in Asian countries [1]. In Korea, liver diseases have a high prevalence along with diabetes mellitus (DM), respiratory diseases, and hypertension. According to the Korea Statistics Office, liver diseases accounted for 13.3 deaths per 100,000 population in Korea, and ranked the seventh leading cause of death in 2017 [2].

Liver transplantation (LT) is the gold standard treatment for patients with end-stage liver disease. Since the first LT in Korea in 1988, the number of LT has increased dramatically over time [3]. To meet such an increased demand, living donor LT (LDLT) has become an inevitable option as it shortens the waiting time and lowers the dropout rate in comparison to deceased donor LT (DDLT) [4,5].

According to the Korean Network for Organ Sharing (KONOS), the number of LT performed annually in Korea increased more than seven-fold between 2000 (n=205) and 2019 (n=1,579). Of the total LT procedures in 2019, LDLT accounted for 1,188 cases (75.24%) [6]. The most common indication for LT was alcoholic liver disease (21.85%), followed by hepatitis B virus (HBV; 18.43%), malignant neoplasms (17.10%) and acute liver failure (4.05%) [6]. The survival rate reported in 2019 for LDLT was 94.63% at 3 months, 90.41% at 1 year and 81.01% at 5 years post-transplant. DDLT showed a relatively lower survival rate of 82.24%, 77.31% and 68.46%, respectively [6].

Despite advancement in LT surgery techniques and post-LT management, complications after LT are still frequent. Graft loss, rejection, renal dysfunction, and new onset diabetes mellitus (NODM) are well-known post-LT complications [7]. Recipient and donor age, gender, and blood group type matching have been identified as representative risk factors along with the need for appropriate management after LT to improve outcomes [8-12].

Study on LT outcomes and associated risk factors in Korean population are still scarce. Identification of this data gap utilizing locally generated database will be worthy of understanding the current status of LT prognosis in Korea. The Korean Organ Transplantation Registry (KOTRY), which was established in 2014, is the first integrated national transplant registry in Korea that includes post-transplantation data from five solid organ transplantation cohorts, comprising of lung, kidney, heart, liver, and pancreas transplants [13].

The objective of the present study was to investigate the incidence and risk factors of post-LT outcomes among LT recipients in Korea by leveraging the KOTRY registry database.

MATERIALS AND METHODS

RESULTS

Baseline characteristics

Two thousand five hundred sixty-three adult recipients were included in the analysis, with a mean follow-up duration of 14.7±10.6 months based on the data collected until June 2018. One thousand nine hundred fifty-six (76.3%) recipients had LDLT and 607 (23.7%) had DDLT. The mean±SD age of LDLT and DDLT recipients were 54.3±8.4 and 52.6±10.3 years, respectively. Recipient demographics and clinical characteristics according to donor type are summarized in Table 1.

Table 1.

Demographics and clinical characteristics of liver transplant recipients overall and by donor types

Hepatitis B and alcoholic liver disease were the two most common underlying liver diseases among LDLT (60.5% and 20.5%) and DDLT (41.0% and 36.4%) recipients. Nearly half (49.2%) of all recipients had liver cancer, and HCC was accountable for majority (97.4%) of the neoplasms. Among recipients with HCC, about two-thirds (64.2% in LDLT and 65.7% in DDLT) had pretransplant HCC within Milan criteria.

A higher proportion of DDLT than LDLT recipients had MELD score ≥35 (31.0% vs. 3.0%), whereas more recipients of LDLT than DDLT had KONOS status score of 5 (81.4% vs. 30.3%). Left liver graft was most frequently used for LDLT (95.7%), while the whole liver graft was commonly used in DDLT (95.1%) (Table 1).

Outcomes after LT

Incidence of death was 4.0% in LDLT group and 14.7% in DDLT group (Fig. 1). Graft loss was observed in 5.0% and 16.1% of LDLT and DDLT recipients, respectively. The leading causes of graft loss were death of patient with functioning graft (69.7%), primary non-function of the graft (10.3%) and recurrence of HCC (5.6%) (Fig. 2).

Figure 1.

The incidence of post-transplantation outcomes among the recipients of liver transplantation by type of donors. N is the total number of recipients in each group; n is the number of recipients with a particular outcome. In DDLT group, N=568 (for rejection) and N=254 (for HCC recurrence). In LDLT group, N=1,942 for rejection and N=1,245 for HCC recurrence. DDLT, deceased donor liver transplantation; LDLT, living donor liver transplantation; NODM, new onset of diabetes mellitus; HCC, hepatocellular carcinoma.

Figure 2.

Causes of graft loss in adult patients with liver transplantation (N=195). N is the total number of recipients with graft loss; n is the number of recipients with a particular reason. HCC, hepatocellular carcinoma; IVC, inferior vena cava.

Seven percent of LDLT and 12.0% of DDLT recipients experienced rejection. In both LDLT and DDLT recipients, the most common (>20%) post-LT complications were renal dysfunction (33.6% and 51.4%), infection (26.7% and 48.4%), and surgical complication (22.5% and 23.9%). Incidence of renal failure (2.7% and 13.8%). NODM (12.5% and 15.4%) and HCC recurrence (both 6.7%) were generally low in both LDLT and DDLT groups. Except for NODM and HCC recurrence, the incidence rate of post-LT outcomes was higher in recipients of DDLT than LDLT (Fig. 1).

Kaplan-Meier survival curves for each outcome are presented in Figure 3. Survival rate of LDLT recipients were significantly higher than DDLT recipients during the first 3 years post LT (3-year, 90.4% vs. 80.4%; P<0.001). Similar differences were observed for graft survival (3-year, 89.1% vs. 79.2%; P<0.001) and rejection free survival (3-year, 90.2% vs. 83.3%; P<0.001) between the two groups. Event-free survival rates for renal failure (3-year, 95.6% vs. 78.3%; P<0.001), renal dysfunction (3-year, 50.5% vs. 31.1%; P<0.001) and infection (3-year, 64.1% vs. 44.2%; P<0.001) were also significantly higher in LDLT recipients than DDLT. The survival distribution of patients not developing NODM were significantly different among LDLT and DDLT (3-year, 83.3% vs. 84.0%, P=0.039) and LDLT was higher than DDLT. No significant difference between LDLT and DDLT was observed for HCC recurrence free survival (P=0.527) and surgical complication (P=0.538).

Figure 3.

Kaplan-Meier survival curve of post-transplantation outcomes in adult patients with liver transplantation. LDLT, living donor liver transplantation; DDLT, deceased donor liver transplantation; HCC, hepatocellular carcinoma; NODM, new onset of diabetes mellitus.

DISCUSSION

This study showed the outcomes and their risk factor in patients who underwent LT. Renal dysfunction is the most common posttransplantation outcome in LDLT and DDLT, followed by infections, and surgical complications, while NODM, graft rejection, graft loss, HCC recurrence, and renal failure were other outcomes. With the exception of NODM, the incidence rate of these outcomes was greater among DDLT recipients compared with LDLT recipients. The age of recipient, MELD score, LDLT, underlying liver disease, Milan criteria were representative risk factors for the outcomes.

In the present study, incidence of death during follow-up duration was 6.5% for all recipients (4.0% in LDLT and 14.7% in DDLT) and the survival rates at 1, 2, and 3 years after transplantation were notably higher in LDLT recipients than DDLT. The survival rates at 3-year observed in our study were consistent with recent studies showing superior survival in LDLT recipients than DDLT [15,16]. In alignment with literature, our study also supports that recipient age is a risk factor for survival in LT recipients [15-17]. We observed that LDLT was associated with lower risk of death compared to DDLT. Several studies have shown better survival outcomes among recipients with LDLT than DDLT [15,16,18], indicating this as a preferable option for LT. Evidence suggests that problem of organ shortage for transplantation in Asia has been successfully addressed by increasing the number of LDLT. However, in Western countries, the number of LDLTs have remained stagnant for over a decade, and the demand for DDLT continues to increase [19]. In Asian countries, high incidence of HCC and low organ donation rate from the deceased has evolved LDLT as a new emerging treatment modality for HCC [20].

We observed graft loss in 7.6% of our study population (5.0% in LDLT and 16.1% in DDLT). The death of the LT recipient was the most common cause of graft loss, which is consistent with findings from literature [21]. A study by Olthoff et al. [22] showed recipient age, hepatitis C virus and HCC as the risk factors for graft loss. The study by Azzam demonstrated ABO-incompatible, the age and sex of the donor, hepatitis B and C virus, HCC as the independent risk factors for graft loss [17]. Our study revealed that increased age of the recipient, DDLT, HCC, acute hepatitis, use of steroids, and use of anti-metabolites were risk factors for graft loss, which are in alignment with several studies published previously [22-24]. Thus, it also becomes important that recipients’ characteristics, including the underlying liver disease should be considered during management.

In this study, the recurrence of HCC was observed in 6.7% each of LDLT and DDLT recipients. A study by Sandhu et al. [25] reported the low and similar rates of HCC recurrence at 3-year among recipients of LDLT and DDLT (10.7% and 14.8%). Previous research by Park et al. [26] reported the low occurrence of de novo malignancies in 2.3% of Korean patients after a mean post-LT period of 41 months. Another study by Hong et al. [27] reported the recurrence of HCC in 24.5% of the recipients at 5 years. Based on the Milan criteria, Lee et al. [28] reported that the recurrence of HCC was 3.3% in patients within Milan and 29.4% in patients beyond Milan. Our study also supports this observation, as the multivariate analysis revealed that the risk of HCC recurrence was higher among patients with HCC beyond the Milan criteria compared to those within the criteria. In addition to the Milan criteria, other factors such as male gender, tumor size of more than 5 cm, positive positron emission tomography scan, high serum alpha-fetoprotein level (>1,000 ng/mL), and poor histologic grade (Edmonson-Steiner grade III and IV) have also been suggested to be associated with higher recurrence of HCC in Korean studies [26-28].

Despite the progress made in preoperative evaluation, surgical procedures, postoperative care, and immunosuppressant therapy, chronic renal disease remains a common complication post LT [29,30]. Approximately 37.8% of all LT recipients (33.6% in LDLT and 51.4% in DDLT) in the present study were observed to have some degree of renal dysfunction post-transplantation, which is consistent with finding from earlier studies in Korea [31,32]. A study by Lee et al. [32] evaluating the early postoperative renal dysfunction in LDLT showed that 34.9% of recipients had renal dysfunction (defined as the creatinine level ≥1.5 mg/dL) at 1-year post LT. In another study by Kim et al. [31], 43.5% of the overall LT recipients were reported to have moderate renal dysfunction (defined as the 30≤ eGFR <60 mL/min/1.73 m²). The rate of renal dysfunction post-LT varies considerably among recipients in other countries, with 8.0% in Egypt [33], 48.0% in Spain [34], and 46.7% in Brazil [35]. This disparity in post-LT renal dysfunction rates between these studies might arise from differences in pre-LT renal function status, source of graft (LDLT or DDLT), presence of diabetes/hypertension, post-LT care, timing of kidney function monitoring, or definitions used for renal dysfunction. Thus, there is a need to standardize these definitions to enable better appraisal of studies worldwide.

The MELD scoring system has been reported as a validated tool that predicts the renal failure post LT [36]. In consistency with previous research [32,36], the pre-transplant MELD score ≥35 was found to be a strong predictor of both renal failure and renal dysfunction in our study. Other significant risk factors such as increased recipient age and comorbid hypertension as predictor of renal dysfunction post LT were also in line with literature [29]. The occurrence of renal dysfunction post LT leads to poor prognosis. We observed an increasing trend of renal dysfunction rates with longer followups (44.2%, 50.2%, and 54.8% at 1, 2, and 3 years, respectively). Since renal dysfunction can increase the need for renal replacement therapy and also increase the risk of cardiovascular diseases, preventive measures are warranted for better prognosis [37,38].

The rate of NODM in the current study was observed to be approximately 14.8%. In a meta-analysis based on 56 studies, NODM was reported in 13.4% of patients following transplantation [39]. We found that pre-transplant obesity (BMI ≥25 kg/m²), use of steroids, and anti-metabolites were associated with a higher risk of NODM post LT. These results are in alignment with recent results published by KOTRY on NODM in the same population [40].

In order to improve the outcomes after LT, appropriate surgical technique, donor-recipient matching and optimization of immunosuppressants is essential. Also, there is a need for further research on innovative management strategies such as machine perfusion, liver support device and tissue bioengineering [41].

Our study has several limitations. First, this study was a retrospective study. We analyzed registry database and cautious interpretation is required since the severity of each patient in database is different and interventional adjustment was not possible. Second, the KOTRY is a relatively new registry with short follow-up period, so long-term outcomes, including median survival time, could not be assessed. Third, it was difficult to compare the effects of medications because the patient population using these medications was heterogeneous. The use of immunosuppressants as the risk factor for the occurrence of post LT outcomes could not be ascertained because patients’ status were different for choosing an immunosuppressant agent which may lead to different outcomes. Lastly, in case of HCC recurrence, the use of mTOR inhibitors has the advantage of lowering the post-transplant malignancy compared with other immunosuppressants; however, the study showed that the use of an mTOR inhibitor at 6 months of transplantation poses a higher risk. Given that the order of the incidents could not be confirmed, the use of immunosuppressant was not considered as one of the risk factors.

Despite of these limitations, this study is a good indicator of the outcomes after transplantation in Korean LT recipients. Following LT, recipients of deceased donor reported higher rates of graft loss, rejection and death and the most frequent complications were renal dysfunction, infection, and surgical complications. Risk factors associated with poor outcomes warrant special attention to improve patient prognosis.

SUPPLEMENTAL MATERIAL

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Notes