Key words : Biliary complications, Bile duct stricture, Cholestasis, Donation after cardiac death, Transplant

Introduction

Donation after cardiac death (DCD) refers to organ donation after irreversible termination of cardio-pulmonary function.¹ Although DCD liver transplant has increased organ availability for patients awaiting liver transplant, there are additional risks associated with posttransplant complications com-pared with that shown in donation after brain death (DBD).^1-3

Donors of organs after cardiac death can have longer periods of hypotension, hypoxia, and poor blood circulation before organ procurement.^1,3 Consequently, biliary complications and graft failure can occur in DCD liver transplants compared with DBD liver transplants.^1-4,9-11 In a 2014 meta-analysis from O’Neill and colleagues, conducted to compare occurrences of biliary complications, graft survival, and recipient survival between DCD and DBD liver transplant,² biliary complications occurred significantly more in patients after a DCD liver transplant (26%) versus a DBD liver transplant (16%). Graft survival was shown to be significantly lower in DCD versus DBD liver transplant at 1 year and 3 years.² Although recipient survival at 1 year was not significantly different in DCD versus DBD liver transplant, by year 3, recipient survival was significantly decreased in the DCD liver transplants (82% vs 88%).² The increased risks of DCD liver transplant must be acknowledged, and advan-cements in treatment have been targeted to reduce these complications after liver transplant.

Endogenous hydrophobic bile acids are thought to be one of the factors associated with biliary complications after liver transplant.^5,11 Early after liver transplant, bile secretions have a higher concentration of cytotoxic hydrophobic bile acids, which can reduce the integrity of cell membranes, leading to cell death.^4,5,11 The retention of the toxic hydrophobic bile acids and sustained preservation injuries of the donor liver can prompt early hepatobiliary injury.^4,5,11 Prophylactic treatment modalities have been introduced to attempt to limit biliary complications after transplantation. Urso-deoxycholic acid (UDCA), otherwise known as ursodiol, is a natural hydrophilic bile acid that enriches the contents of the bile and neutralizes the hydrophobic bile acids, rendering it less cytotoxic.⁶

In a 2012 randomized, double-blind, placebo-controlled trial, Wang and colleagues investigated the efficacy of ursodiol (13-15 mg/kg/day) for the first 4 weeks after DCD liver transplant compared with patients who did not receive ursodiol.⁶ By day 7, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were both normalized and persistently decreased in both groups until the last assessment on day 28. At days 7, 21, and 28, AST and ALT were significantly decreased in the ursodiol group compared with the placebo group. There were no significant differences in total bilirubin (TB) and alkaline phosphatase (ALP) at any time point within the first 28 days. No difference was shown in levels of gamma-glutamyltransferase (GGT) between the 2 groups except for day 28, which showed significantly lower GGT in the ursodiol group versus placebo group (P = .002). Although no other significant biliary complications were found, biliary sludge and casts occurred significantly less frequently in the ursodiol group (3.6%) versus placebo group (14.3%) (P = .047). This study demonstrated that there may be a benefit in the use of ursodiol at 13 to 15 mg/kg/day to reduce biliary complication and to improve liver enzymes after a DCD liver transplant.⁶

In 2019, the Nebraska Medical Center implemen-ted a regimen that used ursodiol (13-15 mg/kg/day) for 1 month post-DCD liver transplant in addition to the previous regimen, which consisted of thymoglobulin 1.5 mg/kg for 3 doses and aspirin 81 mg daily for 30 days. The purpose of this study was to review the effects of the addition of ursodiol compared with treatment without ursodiol.

Materials and Methods

This study was a single-center, retrospective cohort that was approved by the Nebraska Medical Center’s ethics committee before start of research. The protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration. Because of the retrospective nature of this study, written informed consent was not obtained from patients or their guardians.

Patients were included if they were >19 years of age and received a DCD liver transplant between September 2012 to September 2021 at the Nebraska Medical Center. Patients were excluded if they received multiorgan transplant at the time of liver transplant or had history of multiorgan transplant. The cohort was divided into 2 groups: pre-UDCA group (n = 36), which were patients who were transplanted before the introduction of ursodiol into the posttransplant prophylaxis regimen, and post-UDCA group (n = 32), which included all patients who received ursodiol prophylaxis. Two patients in the pre-UDCA group died within 3 days after liver transplant and were not included in the primary analysis but were included for baseline characteristics.

For primary and secondary categorical data, we used the Fisher exact test; for continuous data, we used t tests. To give an unbiased estimate, t tests were either equal (null) or unequal variances based on a result from an F-test rejection. We assessed differences between the pre-UDCA and post-UDCA groups for statistical significance at an alpha level of 0.05.

Outcomes
The primary outcome was a composite of hepatobiliary complications (including cholestasis, bile duct stricture or leak, isolated anastomotic strictures, biliary casts or stones, biliary sludge, ischemic cholangiopathy, biloma, or abscess) within 30 days posttransplant. Secondary outcomes included change in biochemical serum liver tests (AST, ALT, GGT, ALP, and TB) and time to identification of hepatobiliary complications from posttransplant day 1 to days 7, 14, and 28. Other secondary outcomes at 1 and 6 months included acute graft loss, patient survival, and biopsy-proven acute rejection.

Results

(Table 1) and (Table 2) detail characteristics of the cohorts. Most patients were White males with the primary native liver disease of alcoholic cirrhosis and a mean (± SD) warm ischemia time of 51.4 ± 15.8 minutes. Patient characteristics at baseline were generally well balanced, with some notable exceptions. Transplant recipients were older in the pre-UDCA group (58.3 vs 47.9 years). There were more patients with primary sclerosis cholangitis in the post-UDCA group (18.8% vs 2.8%), and baseline GGT and ALP were higher at posttransplant day 1 in the post-UDCA versus the pre-UDCA group. Thymoglobulin was used more often in the post-UDCA group, thus requiring less use of a second bolus doses of intravenous methylprednisolone (1000 mg) posttransplant, compared with the pre-UDCA group.

Primary outcome
A primary composite of biliary outcomes occurred in 1 patient (2.9%) in the pre-UDCA group and 4 patients (12.5%) in the post-UDCA group, although this result was not significant (P = .19) (Table 3).

Secondary outcomes
Biochemical liver enzymes at days 7, 14, and 28 were not significantly different between the 2 groups ((Table 4), (Figure 1), (Figure 2) , (Figure 3) , (Figure 4), (Figure 5)). At each specified time point in both groups, AST, ALT, and TB decreased, but GGT and ALP were elevated and increased from baseline for both groups. The post-UDCA group started with significantly higher GGT and ALP, but results were numerically lower at nearly all prespecified time points versus that shown in the pre-UDCA group. No patient experienced acute graft loss within the first 6 months. Two patients died in the pre-UDCA group within 3 days posttransplant with a primary cause of death deemed to be cardiac arrest from hemodynamic instability posttransplant (Figure 6). One of the patients, who was unstable at baseline, had progressively worsening autoimmune hepatitis, whereas the other patient was brought back to the operating room due to refractory hypotension despite fluid resuscitation in the intensive care unit, resulting in intraoperative cardiac arrest. Biopsy-proven acute rejection at 6 months occurred in 11.76% of patients in the pre-UDCA group versus 15.63% in the post-UDCA group (Figure 7).

Discussion

In patients who received a liver transplant from a donor after cardiac death, we observed similar instances of biliary complications in patients who received ursodiol (13-15 mg/kg/day) versus patients who did not receive ursodiol.

As demonstrated in a previous study from Wang and colleagues, patients who received ursodiol (13-15 mg/kg/day) posttransplant had significant decreases in AST, ALT, and GGT at days 7, 21, and 28, but no difference was noted in biliary complications in 5-year follow-up.⁶ Our study showed similar decreases in AST and ALT at each time point, although differences were not significant between the 2 patient groups. Interestingly, GGT and ALP, which can signify biliary tract complications, were lower at each posttransplant evaluation in the post-UDCA group compared with the pre-UDCA group, although the difference was not significant.

Differences in findings from Wang and colleagues compared with our study could be because of multiple factors. The former study did not include any patients on ursodiol 1 month prior to transplant, which excluded a vulnerable patient population, including patients with primary biliary cholangitis. To achieve 80% power, our study would have needed 150 patients per group, which we were unable to accomplish.

There were several limitations to our study. Our study was a single-institution, retrospective review with a small sample size and was likely not sufficient to draw a definitive conclusion. Patient demog-raphics differed, which could have affected the outcomes. The pre-UDCA group included older patients (58 vs 48 years), with lower GGT and ALP levels on posttransplant day 1. The post-UDCA group had more patients with primary sclerosing cholangitis as the native liver disease than the pre-UDCA group (18.8% vs 2.8%) and used thymog-lobulin more for induction (90.6% vs 38.9%), which was a change in clinical practice during the study period. Elevated liver enzymes can mean a multitude of things, which made it difficult to differentiate original cause between graft rejection, reperfusion injury, or bile duct injury.^7,8

Ursodiol treatment could have resulted in less imaging, which was noted in the study from Wang and colleagues.6 This was not assessed in our study but would be a benefit of ursodiol use. Future studies are needed to assess the effects of ursodiol on total endoscopic therapies and need for diagnostic workup for biliary complications. This could have financial benefits for the institution and help define the role of ursodiol after DCD liver transplant.

The results of this study did not confirm that the use of ursodiol improved biliary outcomes in patients receiving a DCD liver transplant.

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