Endovascular Intervention of Portal Vein Stenosis in Pediatric Patients After Liver Transplantation: A Single-Center Experience

Introduction

Pediatric liver transplantation (pLT) is the only effective treatment for severe liver diseases and end-stage liver failure in children [1]. With the continuous advancement of surgical techniques and improvements in postoperative care, survival rates and quality of life have significantly improved. However, despite these overall improvements in postoperative outcomes, challenges remain, including complications such as portal vein stenosis (PVS), biliary strictures, and immunological rejection [2]. PVS is a complication resulting from various factors that obstruct portal vein (PV) blood flow in recipients after transplantation. Reported incidence rates of PVS range from 2% to 14% [3]. PVS can lead to portal hypertension, resulting in ascites, splenomegaly, gastrointestinal bleeding, and even severe liver dysfunction or liver failure [4]. Consequently, PVS is a critical factor affecting graft survival and patient longevity, making its management critically important [5]. Surgical PV reconstruction has traditionally been used to address PVS following pLT. However, this approach is associated with significant challenges, including high complexity, substantial risk, extended recovery periods, and the potential for persistent PVS, even after reanastomosis [4]. With advances in medical technology, endovascular intervention has emerged as an effective alternative for managing PVS [6]. Endovascular techniques allow for precise localization and treatment of stenotic regions, effectively restoring blood flow and improving hepatic perfusion and function. Compared with traditional surgical methods, endovascular intervention offers lower procedural risk, shorter hospital stays, and faster recovery [7]. These advantages make endovascular treatment a valuable option for managing PVS in pLT.

However, the application of endovascular interventions in pediatric patients remains challenging. PV balloon angioplasty and PV stent placement are the primary endovascular techniques for managing PVS [8]. Nonetheless, there is no standardized protocol for selecting the appropriate interventional method in clinical practice, and effective predictive tools to identify which patients will benefit most from these interventions are lacking. Therefore, in-depth research on these issues is crucial for optimizing treatment strategies, enhancing therapeutic outcomes, and ultimately improving survival rates and quality of life for pLT recipients.

In this study, we retrospectively analyzed pLT recipients (age ≤12 years) who developed PVS following LT at the First Affiliated Hospital of Zhejiang University School of Medicine. We aimed to assess the efficacy of interventional treatments for these PVS patients, providing clinical insights into the selection of interventional methods and the evaluation of patient prognosis in the management of PVS.

Material and Methods

PORTAL VEIN ANASTOMOSIS:

At our institution, LT surgeries were conducted by surgeons who adhere to established policies and technical standards. During these procedures, PV anastomosis was typically performed using either end-to-end anastomosis or by using fresh or cryopreserved vascular conduits for bridging. A 6–0 Prolene polypropylene suture (Ethicon, LLC, USA) was used with a continuous suturing technique. Specifically, if intraoperative findings revealed a PV diameter less than 3 mm or significant PV inflammation or sclerosis, we may have selected allograft vessels for donor-recipient portal vein bridging (PVB). For interposition graft vascular anastomosis, interrupted sutures were applied on the recipient side, while a continuous technique was used on the donor side to accommodate differential vessel compliance. In other cases, end-to-end anastomosis was routinely used for PV connection.

DIAGNOSIS AND INCLUSION CRITERIA FOR PVS:

The cut-off diameter for the diagnosis of PVS varied from an absolute value of less than 3 mm [9,10], to a reduction up to 50% of the diameter of the PV anastomosis, as compared with the extrahepatic PV on the mesenteric side, with flow acceleration at the stenotic segment up to 3 times that of the pre-stenotic PV [11]. Ultrasound was performed every day for the first week after surgery, once a week for the next 3 months, and once a month thereafter. If ultrasound indicated PVS, a computed tomography (CT) scan was performed to confirm the diagnosis. Normally, the CT was performed at 1 month, 3 months, 6 months, and 1 year after surgery.

INTERVENTIONAL TREATMENT TECHNIQUES:

Endovascular intervention decisions were made by a multidisciplinary team at our center. The procedures were performed by experienced specialists following regulatory standards. The process was as follows. Under general anesthesia, the procedure was conducted using the GE Innova 4100 DSA system. Based on preoperative imaging (CT, ultrasound), a 22G needle was used to access the PV, either via the right axillary midline or subxiphoid puncture. A 0.018-inch guidewire (Cook, USA) was advanced into the main PV, and a 5F vascular sheath (Cook, USA) was inserted. A 0.035-inch guidewire (Cook, USA) and a 5F catheter were then advanced through the stenotic segment. Fluoroscopy was used to measure the stenosis diameter and the pressure gradient across the stenosis. PVS was diagnosed if the stenosis exceeded 50% or if the pressure gradient was over 5 mm Hg. Treatment involved balloon angioplasty or stent placement, with balloon diameters typically 6 to 8 mm and lengths of 20 to 40 mm. Balloon angioplasty was performed at 10 atmospheres for 60 s per inflation, repeated 3 to 6 times. For persistent stenosis, a balloon-expandable stent (10 mm diameter, 25 mm length) was implanted. After the procedure, the puncture site was sealed with a gelatin sponge. Anticoagulation was managed with low-molecular-weight heparin and warfarin sodium, with regular monitoring to maintain an international normalized ratio between 1.5 and 2.0.

EFFECTIVENESS AND SAFETY EVALUATION:

Technical success was defined by successful guidewire and catheter passage, adequate balloon or stent angioplasty, a pressure gradient less than 5 mm Hg, and residual stenosis less than 30% [12]. Clinical success was indicated by significant improvement in symptoms, signs, and imaging, compared with pre-treatment values [13]. Safety was assessed based on patient quality of life and absence of PVS-related complications. Poor prognosis was indicated by recurrent symptoms, need for repeat liver transplantation, or death related to PVS stenosis [12,13].

STATISTICAL ANALYSIS:

The data in this study were analyzed using the Kolmogorov-Smirnov test and were found to follow a normal distribution. Continuous variables are presented as means±standard deviations (x±s) if normally distributed. Intergroup comparisons were conducted using t tests or analysis of variance for normally distributed data. Categorical variables were analyzed using chi-square tests or Fisher exact tests. Logistic regression was used for univariate and multivariate analysis to construct a logistic regression model. Survival rates for patients and grafts were estimated using Kaplan-Meier curves. A P value of <0.05 is considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics version 29.0.

Results

PATIENTS AND PLT CHARACTERISTICS:

Among 884 pLT recipients at our center from March 2020 to July 2024, a total of 67 patients developed PVS. The mean time to onset of stenosis was 119.3±126.3 days after transplantation. Table 1 summarizes the baseline characteristics and transplant-related information of these patients. The average age of the recipients at the time of PVS diagnosis was 10.7±16.2 months (range: 3–114 months), with a male-to-female ratio of 1: 1.68. The mean weight was 7.5±3.8 kg (range: 4.6–30.5 kg), and the mean height was 67.0±13.1 cm (range: 54–140 cm). The average pediatric end-stage liver disease (PELD) score was 17.1±14.9 (range: −9 to 52). Primary diseases included biliary atresia in 65 patients, metabolic disease in 1 patient, and congenital hepatic venous obstruction in 1 patient. Of the 65 patients with biliary atresia, 40 (61.5%) underwent Kasai portoenterostomy. Of the 67 patients, 44 (65.7%) received blood-type-compatible grafts. Donor characteristics were as follows: average age 25±15 years (range: 0–60 years), male-to-female ratio of 1: 1.09, average weight 49.4±23.3 kg (range: 4–85 kg), average height 143.5±36.4 cm (range: 50–180 cm), and mean graft-to-recipient weight ratio 4.1±1.6% (range: 1.3–9.0%). The mean PV diameter was 0.41±0.15 cm (range: 0.1–0.9 cm) in recipients and 0.69±0.23 cm (range: 0.19–1.27 cm) in donors, with a mean PVDr of 88.5±112.21% (range: 1–792%). The average time to PVS was 119.3±126.3 days (range: 8–786 days). Surgical techniques for PV anastomosis included end-to-end anastomosis in 54 cases, cryopreserved allograft bridging in 11 cases, and fresh allograft bridging in 2 cases. Graft types were categorized as follows: 14 whole livers, 42 left lateral segment livers, 9 extended left lateral segment livers, 1 right trisegmental liver, and 1 extended right lobe liver. Of these, 48 grafts were from living donors, and the remaining were from donation after circulatory death donors. Surgical metrics included warm ischemia time of 2.8±3.7 min (range: 0–20 min), cold ischemia time of 3.6±3.7 h (range: 0.7–13.8 h), operative time of 6.6±1.4 h (range: 3.4–10.4 h), and intraoperative blood loss of 612.0±532.2 mL (range: 50–3500 mL).

BALLOON ANGIOPLASTY AND STENT PLACEMENT:

Figure 1 illustrates the procedural flow and outcomes for the 67 patients with PVS who underwent interventional treatment. The success rate of the interventional techniques was 95.5%. In 3 patients, severe PVS with cavernous transformation was identified during the procedure, preventing guidewire passage into the main PV and thus precluding balloon angioplasty or stent placement. Of these, 1 patient underwent re-transplantation, and the other 2 were placed on the transplant waiting list. Among the remaining 64 patients, balloon angioplasty effectively relieved PVS. After angioplasty, the PV flow velocity decreased from 52.8±28.7 cm/s to 31.1±12.1 cm/s, and the PV diameter increased from 0.21±0.06 cm to 0.51±0.15 cm, with both changes showing significant differences (P<0.001). During follow-up, 52 patients (81.25%) demonstrated significant improvement, with no recurrence of stenosis. Recurrent stenosis occurred in 12 patients, with a mean time to recurrence of 162.8±153.4 days (range: 58–626 days). Among these, 1 patient experienced failed re-intervention and subsequently underwent a second LT. Four patients received stent placement with favorable outcomes. The remaining 7 patients underwent a second balloon angioplasty, with 4 of these patients showing no further stenosis. However, 3 patients developed recurrent PVS and were treated with stent placement. Of these, 2 patients achieved good results, with unobstructed PV flow, while 1 patient developed in-stent thrombosis. This patient subsequently underwent a second LT and died due to acute graft failure.

FACTORS ASSOCIATED WITH RECURRENT STENOSIS FOLLOWING BALLOON ANGIOPLASTY FOR PVS:

A comparative analysis was conducted between patients with PVS who experienced successful single-balloon angioplasty and those requiring multiple interventional treatments. We identified significant differences between these 2 groups concerning 2 factors: the history of PVB during LT and the PVDr (P<0.05; Table 2). Other factors, including primary disease, ABO blood type, PELD score, graft-to-recipient weight ratio, history of Kasai procedure, donor and recipient sex, age, height, weight, preoperative PV diameter, time of initial stenosis occurrence, graft type, transplant type, warm ischemia time, cold ischemia time, operative time, and intraoperative blood loss, did not show significant differences between the 2 groups. Among the pLT patients with PVB, whether the bridging vessel was cryopreserved or fresh did not significantly affect the incidence of recurrent stenosis following balloon angioplasty (Table 3).

PREDICTION MODEL FOR RECURRENT PVS FOLLOWING BALLOON ANGIOPLASTY IN PLT RECIPIENTS BASED ON LOGISTIC REGRESSION:

Univariate analysis identified a history of PVB and PVDr as significant indicators with notable differences. Further multivariate logistic regression analysis of these 2 indicators resulted in a prediction model for recurrent PVS following initial balloon angioplasty. The expression formula is as follows:

The odds ratios (OR) for PVDr and PVB were 5.7 and 2.3, respectively. The sensitivity of the combined prediction model was 66.7%, specificity was 92.3%, and the Youden index was 0.59. The accuracy was 89.1%, with a cutoff value of 0.275 (Table 4). The receiver operating characteristic curve (Figure 2) demonstrates an area under the curve (AUC) of 0.778 [95% CI (0.596, 0.96)], P=0.003.

PATIENT AND GRAFT SURVIVAL OUTCOMES:

Among the 67 pLT recipients with post-transplant PVS, no graft losses or patient deaths related to the interventional procedures were observed during the treatment process. One patient experienced graft failure due to thrombosis after stent placement and subsequently died from acute graft dysfunction following a second LT. Another patient developed PV occlusion after initial balloon angioplasty, which precluded further intervention, leading to the necessity of a second LT. Additionally, 2 patients were unable to undergo balloon angioplasty or stent placement during the interventional evaluation and were placed on the transplant waiting list. For the remaining patients, PV patency was maintained throughout the follow-up period after intervention. Survival analysis (Figure 3) indicated a 1-year survival rate of 100% and a 3-year survival rate of 95% for children with PVS following LT. The 1-year graft survival rate was 100%, with a 3-year graft survival rate of 91%.

Discussion

PVS is a prevalent complication following pLT. Research indicates that several factors, including living donor liver transplantation, split liver transplantation, use of low-age donors, and PVB, are associated with an increased risk of PVS [5,14]. PVS is a significant factor impacting the success of pLT, making its effective management critical in improving post-transplant outcomes. The safety and efficacy of endovascular intervention for PVS have been widely recognized. Interventional therapy also plays a significant role in special types of liver transplantation. For instance, according to a report by Yilihaer et al, it is highly recommended for managing postoperative portal vein stenosis in patients undergoing ex vivo liver resection and autotransplantation for hepatic alveolar echinococcosis combined with cavernous transformation of the portal vein [15]. Kyaw et al demonstrated that balloon angioplasty and stent placement under intervention are both effective and safe. They recommend initially opting for balloon angioplasty, with stent placement serving as a remedial measure in cases in which balloon angioplasty fails [8]. Kim et al propose that stent insertion can be considered when fibrotic changes are expected due to repeated inflammation and when the balloon size to be used is small [16]. In this study, we found that the overall efficacy of endovascular intervention for PVS in pLT reached 96.9%, with 81.25% of patients achieving resolution of PVS with a single balloon angioplasty procedure. Figure 4 illustrates the endovascular intervention process for balloon angioplasty and PV stent placement at our center, with angiographic confirmation of PVS resolution. This underscores the safety and efficacy of endovascular techniques in managing PVS following pLT. Our comparison between patients who achieved successful single balloon angioplasty and those requiring multiple interventions for PVS indicates that individuals undergoing PV reconstruction with allografts or those with poor donor-recipient PV matching are more susceptible to recurrent stenosis following initial balloon angioplasty. These patients frequently require additional intervention, such as repeat balloon angioplasty or portal vein stent placement. Our preliminary research has confirmed that intraoperative PV reconstruction and a donor age under 12 years are significant risk factors for postoperative PVS [17]. This study further identifies PV reconstruction as a critical factor contributing to recurrent stenosis after the initial intervention. Structural and functional alterations of bridge vessels during procurement and preservation can lead to endothelial damage, decreased elasticity, or increased wall thickness. These changes can predispose the vessels to thrombosis and restenosis [18]. Although Yin et al suggested that the use of cryopreserved vein graft in transplantation is a significant factor contributing to PVS [19], we found no statistically significant difference in the likelihood of restenosis after initial intervention between patients who received fresh vein grafts and cryopreserved vein grafts. Significant discrepancies between donor and recipient PV diameters represent another critical factor influencing the efficacy of balloon angioplasty. We hypothesize that such discrepancies result in uneven suture tension at the PV anastomosis, which, when subjected to balloon angioplasty, generates substantial resistance and adversely affects the balloon angioplasty outcome. Previous reports have indicated that mismatched donor and recipient PV diameters can lead to perivascular inflammation and the development of PV cavernous transformation [20], further diminishing the effectiveness of balloon angioplasty. Our study underscores that poor donor-recipient PV matching adversely affects the outcome of the initial balloon angioplasty, suggesting that stent implantation during the first intervention offers more significant therapeutic value for patients with PVS. Gao et al suggest that stent implantation is advisable in cases involving PV torsion, vascular intimal tears, or long-segment PV occlusion [7]. Our study suggests that for patients with pLT with postoperative PVS, especially those with PVB history or poor donor-recipient PV matching, direct stent implantation should be considered during the initial intervention.

In this study, we developed a predictive mathematical model using logistic regression to estimate the likelihood of PVS recurrence after balloon angioplasty in pediatric patients, incorporating key risk factors. The model showed a sensitivity of 66.7%, specificity of 92.3%, and AUC of 0.778, reflecting strong predictive value. This model aids in evaluating the probability of successful initial balloon angioplasty for patients with PVS, potentially reducing the need for repeated interventions, minimizing complications associated with the intervention, and alleviating patient trauma and economic burden. Overall, interventional procedures demonstrate a high success rate and safety profile; however, there remains a certain rate of failure and complication incidence. Among the 67 patients with PVS, 3 experienced procedural failure, in which the guidewire could not traverse the PVS. This was associated with severe PVS, thrombus formation, or PV occlusion. Common complications of stent placement include stent dislocation, in-stent thrombosis, bleeding, and infection [21,22]. Notably,1 patient developed in-stent thrombosis despite anticoagulation with rivaroxaban, ultimately requiring a second LT. Another patient required laparotomy for hemostasis, due to bleeding at the liver puncture site.

Our study has several limitations. First, all data were sourced from a single center, lacking external validation from other institutions. Second, as a retrospective analysis, the predictive model requires further validation. Our future research will involve designing a prospective study with multi-center data to explore optimized treatment strategies for pLT recipients with PVS.

Conclusions

PATIENT PERMISSION/CONSENT DECLARATIONS:

Written informed consent was obtained from all participants (their legal guardians for pediatric patients) for publication of this study. The study was approved by the Clinical Research Ethics Committee of the first affiliated hospital, Zhejiang University School of Medicine.