Retrospective Analysis of Risk Factors and Surgical Outcomes in Liver Transplant Recipients

Introduction

Liver transplantation is a widely accepted treatment option for patients with end-stage liver disease who no longer respond to conservative therapy [1–3]. Liver disease remains a significant global health issue and is a major healthcare challenge in Kazakhstan [4,5]. Despite significant improvements in liver transplant outcomes, liver transplantation surgery continues to carry a high risk of short-term mortality, primarily due to intraoperative technical complications and early postoperative infections [6,7].

Among postoperative infectious complications, sepsis remains one of the leading causes of early mortality in liver transplant recipients. It often arises from biliary, intra-abdominal, or pulmonary sources and is associated with a rapid deterioration in clinical status [8]. The immunosuppressed state of transplant recipients, coupled with complex surgical procedures and prolonged intensive care unit stays, further increases susceptibility to severe infections. Early recognition and aggressive management of sepsis are therefore critical for improving survival outcomes after liver transplantation [9].

Biliary complications, often referred to as the “Achilles’ heel” of liver transplantation, remain a significant challenge to both early postoperative recovery and long-term quality of life of liver recipients [10,11]. The incidence of biliary complications has markedly increased with the adoption of living donor liver transplantation (LDLT), which was introduced to address the growing gap between organ demand and availability [12]. In Asian countries, LDLT is more commonly performed than deceased donor liver transplantation (DDLT), and various bile duct anastomosis classifications and modifications have been developed to manage the complexity of partial liver transplantation [13,14]. A liver transplantation (LTx) program was established in Kazakhstan in 2012 [15]. According to a recent report, LTx from living donors is much more common than LTx from deceased donors. Between 2012 and 2024, a total of 474 liver transplantations were performed in Kazakhstan, among which 181 patients died and 183 patients survived. Kazakhstan currently leads Central Asia in liver transplantation activity [16].

In this retrospective study we analyzed the outcomes of DDLT and LDLT performed at the National Research Oncology Center between 2013 and 2025. The primary outcomes were the identification of risk factors for early postoperative mortality and the development of biliary complications. Secondary outcomes included long-term patient and graft survival and the evaluation of postoperative infectious complications, including sepsis.

Material and Methods

COMPLICATION CLASSIFICATION:

Complications were classified according to the Clavien-Dindo classification of surgical complications [17], as follows:

DEFINITION OF BILIARY COMPLICATIONS:

Biliary leakage (BL) was defined according to the International Study Group of Liver Surgery (ISGLS) as a bilirubin concentration in the abdominal drain > 3 times higher than the serum bilirubin level, or the need for radiologic/endoscopic intervention or relaparotomy to control bile leakage [18]. Biliary stricture was defined as a radiologically or endoscopically confirmed narrowing of the biliary anastomosis or intrahepatic bile ducts associated with hyperbilirubinemia and/or requiring endobiliary stenting or open surgery [19].

SEPSIS DEFINITION:

Sepsis was diagnosed using a combination of clinical conditions (hypotension, low urine output, fever), supported by elevated CRP and procalcitonin levels, and blood culture results when available. The onset of sepsis was documented from the day of transplantation, and only early postoperative episodes were included in analysis.

STATISTICAL ANALYSIS:

All statistical analyses were conducted using Stata 14 software (StataCorp. 2015, College Station, TX, USA). Continuous variables were assessed for normality using the Shapiro-Wilk test and visual inspection of histograms. Variables with normal distribution were analyzed using the t test or one-way ANOVA, and categorical variables were compared using the chi-square test. The significance level was set at α=0.05.

For survival analysis, Kaplan-Meier survival estimates were used to calculate survival probabilities at 1, 3, 5, and 7 years. The log-rank test was used to compare survival curves between groups. Cox proportional hazards regression was used to identify independent predictors of overall mortality. Although 30-day and 90-day mortality are the binary outcomes, time-to-event information with censoring was available in the dataset; therefore, Cox regression was used for these analyses. Cox regression was also used to explore factors associated with biliary complications.

Results

A total of 113 liver transplantations were performed at the National Research Oncology Center between 2013 and 2025. Our cohort included 1 pediatric case. There were 62 (54.9%) females and 51 males (45.1%), with a mean age 43.8 years. Indications for liver transplantation (LT) included viral hepatitis (54 patients), autoimmune hepatitis (8 patients), cholestatic hepatitis (20 patients), hepatocellular carcinoma (HCC) (10 patients), non-alcoholic steatohepatitis (NASH) (3 patients), and alcoholic hepatitis (4 patients). Rare indications included liver alveococcosis (2 patients), Chanarin-Dorfman syndrome (1 patients), Budd-Chiari syndrome (2 patients), idiopathic portal hypertension (9 patients). The mean pre-LTx MELD score in our cohort was 17.3 points and the Child-Pugh score was 9.3 points. Among 113 LTx, 88 (77.9%) were living donor liver transplants and 25 (22.1%) were from deceased donors (DDLT). Most liver grafts were retrieved from male donors (85 cases) and fewer from female donors (28 cases). Among living donors, most were siblings of recipients (39 cases), followed by offspring, cousins (11 cases), spouses (8 cases), and 1 parent. In 29 cases, donors were non-related, comprising all 25 deceased and 4 unrelated living donors. For living donor transplants, 6 were left-lobe LDLT, 1 was left lateral and 81 were right lobe LDLT. Clinical and demographic characteristics of recipients and donors are summarized in Table 1.

All surgeries were performed by qualified hepatopancreatobiliary and transplant surgeons. In the early years of the program, hepatic artery anastomoses were performed by cardiac surgeons. The mean duration of surgery was 544 minutes, ranging from 305 to 977 minutes. The mean total ischemic time (TIT) in both LDLT and DDLT cases was 217 minutes. Given the predominance of LDLT in our cohort, hepatic vein (HV) tributaries reconstruction was routinely performed. Specifically, reconstruction of segment V and segment VIII HV tributaries was performed in 45 cases, isolated SV in 7 cases, SVIII in in 4 cases, and inferior right hepatic vein (IRHV) in 2 cases. In 53 cases, including all 25 DDLTs, no HV tributary reconstruction was required. Regarding biliary reconstruction, most donors had a single bile duct (84 cases), including all DDLT cases. Two bile ducts were present in 26 cases and 3 ducts in 3 cases. Duct-to-duct anastomosis (DDA) was the preferred technique and was performed in 97 cases. Hepaticojejunostomy (HJ) was used in 14 cases, and in 2 cases a mixed approach was used (either DDA combined with HJ or DDA with an external cholangiostoma). External bile duct (EBD) stenting was used predominantly in the early years of the program and was used in a total of 34 cases. For analysis purposes, we categorized the bile duct anastomoses into 9 groups, based on the number of bile ducts and type of reconstruction (DDA or HJ). Surgical aspects are outlined in Table 2.

The most common complications following liver transplantation were bile leakage (26.5%) and anastomotic biliary strictures (20%), followed by sepsis (14%). Vascular complications included hepatic artery thrombosis in 16 patients (14.16%) and portal vein thrombosis (PVT) in 8 patients (7%). Acute rejection was diagnosed in 11 patients and small-for-size syndrome (SFSS) was observed in 18 (Table 3).

The overall 1-, 3-, 5-, 7-, and 10-year survival rates were 76.3%, 72.9%, 70%, 70%, and 70%, respectively. Survival outcomes were comparable between LDLT and DDLT groups and did not differ significantly (P=0.82). In the LDLT group, the 1-, 3-, 5-, and 7- year survival rates were 76.7%, 72.4%, 70.5%, and 70.5%, respectively, while survival rates at the same time points in the DDLT group were 74.7%, 74.7%, 68.9%, and 68.9% (Figure 1). Although LDLT showed slightly better early and late survival, the differences were small and not statistically significant. Confidence intervals were wider in DDLT group due to the smaller sample size.

We analyzed potential predictors of postoperative complications. In univariate logistic regression, several graft- and surgery-related variables were significantly associated with the development of BL. Graft steatosis increased the risk of BL occurrence 19% (OR=1.19, p=0.007). Hepaticojejunostomy was associated with 4.8-fold higher odds of developing BLs compared to duct-to-duct anastomosis (OR-4.80, P=0.06). Similarly, grafts with multiple bile ducts carried a 3.4-fold increased risk of developing BL compared to single-duct grafts (OR=3.43, P=0.006). Several variables showed a trend toward significance. Repeated surgery was associated with a 2.3-fold higher risk (OR=2.29, P=0.065), while pre- and post-portal vein thrombosis (PVT) increased the odds by approximately 2-fold (OR=2.10 and 2.39, respectively), but the difference was not statistically significant. EBD demonstrated reduction in risk of developing biliary complications (OR=0.49, P=0.143). Similarly, LDLT compared with DDLT showed a lower risk (OR=0.43, P=0.408), although not significant. In the multivariate analysis graft steatosis remained borderline, showing a 20% increased risk (adjusted OR=1.20, P=0.060). External biliary drainage continued to demonstrate a protective trend, reducing the odds by 69% (adjusted OR=0.31, P=0.062). (Table 4). In univariate analysis, most graft and perioperative variables were not significantly associated with biliary stricture. Higher bleeding volume showed a statistically significant but clinically small increase in risk of biliary strictures (OR= 1.0003, P=0.007). Lower GRWR demonstrated a strong trend toward increased risk of postoperative biliary strictures (OR=0.22, P=0.065), and the use of external biliary drainage (EBD) was associated with a 69% reduction in odds of stricture (OR=0.31, P=0.007). Other variables, including graft steatosis, donor and recipient age, MELD score, PVT, HAT, acute rejection, and biliary anatomy, were not statistically significant. In the multivariate analysis, no variable reached statistical significance. GRWR (OR=0.25, P=0.082) and EBD (OR=0.25, P=0.077) retained protective trends (Table 5). Regarding overall survival, HAT, sepsis, left-lobe transplantation, and the need for relaparotomy were associated with poorer outcome (Table 6). We also evaluated 30- and 90-day mortality, which were 10.6% and 15.9%, respectively. Multivariate analysis identified sepsis (OR=7.92, P=0.022), repeated surgery (OR=6.01, P=0.044) and male sex (OR=0.14, P=0.043) as significant predictors of 30-day mortality. For 90-day mortality, sepsis (OR=20.1, P<0.001) and HAT (OR=6.07, P=0.011) were significant predictors (Tables 7, 8).

Discussion

This retrospective study updates liver transplantation outcomes at the one of the 2 largest transplant centers in Kazakhstan between 2013 and 2025. Kazakhstan is a largest Central Asian country, where LDLT has become the predominant modality due to donor scarcity [20,21]. Our findings align with global trends, particularly in Asian countries, where LDLT is more common and is associated with greater technical complexity, especially regarding biliary reconstruction [22]. Biliary complications, including bile leakage and biliary strictures, remain a critical issue affecting short- and long-term outcomes after liver transplantation [23]. In our cohort study, BLs and BSs occurred in 26.5% and 20% of patients, respectively. These rates are consistent with the data from a recent LDLT series [24].

The wide range and high rate of biliary complications in LDLT is associated with increased complexity of biliary reconstruction in partial grafts, which often have multiple ducts and anatomical variations [25]. We did not analyze the occurrence of non-anastomotic stricture (NAS), due to the lack of radiological and histological confirmation. This limitation is primarily related to insufficient outpatient follow-up and absence of thorough differential diagnostics to distinguish NAS from other cholestatic conditions such as a recurrent primary sclerosing cholangitis.

Hepaticojejunostomy was initially the primary choice for biliary reconstruction due to the lack of microsurgical expertise within the surgical team. After adoption of the duct-to-duct (DDA) technique, external bile duct (EBD) stenting was applied to lower pressure on the DDA. EBD placement can significantly decrease the incidence of biliary strictures in LDLT [26,27]. Our analysis showed EBD was associated with lower rates of biliary leakage and biliary stricture, and although these associations did not reach statistical significance, they suggest that EBD may contribute to lowering the risk of postoperative biliary complications.

Various factors have been reported as predictors of biliary complications, including graft rejection and HAT. Despite improvements in surgical technique and a reduction in HAT incidence at our center, the overall rate of biliary complications has remained unchanged. Recent studies have highlighted the benefits of microsurgical biliary reconstruction technique (MBR) in reducing biliary complications. Lin et al proposed the classification of MBR based on the number of graft bile ducts, intraductal diameter, and duct size. Modification in MBR have been associated with a 10.2% rate of intervention-requiring biliary complications [28]. In our series, univariate analysis showed that patients who underwent hepaticojejunostomy (HJ) had a higher incidence of BLs compared to those with DDA. Multiple biliary reconstructions were also identified as a risk factor in univariate analysis, but these associations did not reach statistical significance in multivariate analysis. We believe that further refinement of biliary reconstruction techniques can substantially reduce the incidence of biliary complications, improve quality of life, and prolong survival of liver transplant recipients.

Vascular complications, in particular hepatic artery thrombosis (HAT), occurred in 14.1% of patients, which is higher than the generally reported rates of 3% to 9% [29]. This may reflect the learning curve of a developing transplant program or variations in perioperative management. HAT is the one of the most serious complications after liver transplantation, with 50% of patients with early HAT requiring retransplantation [30]. Although HAT is widely recognized as a predictor of BC, we did not observe a significant association, likely because most patients with HAT experienced early graft failure or death despite attempts at open or endovascular thrombectomy.

In our cohort, sepsis occurred most frequently within the first week after liver transplantation. Patients with end-stage liver disease (ESLD) are immunocompromised and often present with metabolic and coagulopathy [31,32]. The combination of cirrhosis complications, immunocompromised condition, and the need for immunosuppressive therapy after LTx places these patients at high risk for sepsis.

Sepsis, along with HAT, relaparotomy, and left-lobe grafts, was identified as a major predictor of poor overall survival.

The 10-year survival rate was 70% in our study, with no significant difference between LDLT and DDLT recipients in terms of long-term survival. The slightly longer survival in the LDLT group, although not statistically significant, reflects the global trend of comparable or even superior outcomes of LDLT.

We focused on 30- and 90-day mortality because most deaths occurred early in the postoperative period. Short-term mortality (30-day and 90-day) rates in our cohort were 10.6% and 15.9%, respectively. Sepsis emerged as a strong independent predictor of 30- and 90-day mortality, reinforcing the critical importance of infection control in immunosuppressed patients receiving solid organ transplantation. Relaparotomy and HAT were also significant contributors to early mortality, supporting the role of meticulous surgical technique and prompt recognition of HAT and PVT.

Interestingly, male sex appeared to be independent protective factor against 30-day mortality in our cohort study. While sex-associated better outcomes have not been widely reported, they may reflect better nutrition status and muscle condition in male recipients in comparison with female patients, but further investigation is needed.

The comprehensive bile duct reconstruction classification used in our study allowed for more detailed evaluation of surgical technique-related outcomes. This may serve as a useful framework for future studies aiming to correlate specific anastomotic configurations with biliary complication risk.

This study has several limitations. First, the retrospective design and single-center nature may limit the generalizability of our findings. Second, although our sample size is one of the largest in Central Asia, it is modest compared to global registries. Lastly, changes in surgical expertise and perioperative protocols over the 12-year period may have influenced outcomes, introducing potential temporal bias.

Despite these limitations, our study provides valuable insights into liver transplantation outcomes in a region with increasing transplantation activity. The findings highlight key areas for quality improvement, including minimizing biliary and vascular complications and reducing postoperative infections. Continuous refinement of surgical techniques, structured postoperative care, and the development of living donor selection protocols will be essential to improving outcomes further.

Conclusions

Sepsis, HAT, and repeated surgery are key predictors of early mortality after LT. Strategies for prevention and early detection of these complications may improve outcomes. Long-term survival remains high, supporting the efficacy of LT in appropriately selected patients.