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Volume: 19 Issue: 6 June 2021

FULL TEXT

ARTICLE
Predicting the Safe Use of Deceased After Circulatory Death Liver Allografts in Primary Sclerosing Cholangitis

Abstract

Objectives: The use of deceased after circulatory death liver allografts in patients with primary sclerosing cholangitis is controversial, given the increased risk of graft complications in patients with primary sclerosing cholangitis. We hypothesized that transplant of deceased after circulatory death livers into recipients with primary sclerosing cholangitis when appropriately selected using the UK deceased after circulatory death scoring system is not associated with increased graft failure and mortality. Materials and Methods: We analyzed 99?229 transplants (between January 2001 and December 2018) from the Organ Procurement and Transplantation Network database. Deceased after circulatory death transplants were stratified by the UK scoring system as low risk or high risk. We identified 3958 patients with primary sclerosing cholangitis who received deceased after brain death transplant and 95 patients with primary sclerosing cholangitis who received deceased after circulatory death transplant. Results: As expected, 5-year graft survival was lower in the circulatory death recipient group (69.0% vs 78.4%; P = .02). However, 5-year graft survival was significantly lower in the high-risk versus low-risk UK scoring system group (60.0% vs 75.4%; P = .02), with rate in the low-risk group similar to the brain death recipient group (78.4% vs 75.4%; P = .52). On multivariate analysis, the high-risk group had significantly increased risk of graft loss (hazard ratio of 1.92; P = .01). However, the low-risk group had equivalent graft survival to the brain death recipient group (hazard ratio of 1.23; P = .31). Conclusions: Graft failure was higher in patients with primary sclerosing cholangitis who received livers from deceased after circulatory death donors; however, the risk of graft loss was abrogated using appropriately matched donor and recipient combinations.


Key words : Autoimmune liver disease, Deceased after circulatory death transplantation, Liver allocation, Model for End-Stage Liver Disease, Retransplantation

Introduction

Primary sclerosing cholangitis (PSC) is a cholestatic liver disease characterized by strictures of the intra- and extrahepatic biliary ducts. Primary sclerosing cholangitis is the fifth leading indication for liver transplant, and patients with PSC comprise 3.6% of all liver transplants in the Model for End-Stage
Liver Disease (MELD) era.1 Unlike other common indications for liver transplantation, PSC does not always cause cirrhosis, and 25% to 50% of patients on wait lists for liver transplant have neither radiologic nor histologic evidence of cirrhosis nor portal hypertension.2 This absence of cirrhotic morphology is thought to disadvantage patients with PSC under the current MELD allocation system, as this group presents with elevated bilirubin but tends to retain normal values for creatinine and international normalized ratio.3 Although these patients have not been observed to have higher wait list mortality,2 there is a 4-fold higher utilization of living donors in the PSC population,4 indicating that PSC patients frequently seek options outside the deceased donor pool to have equitable access to transplant.

Donation after circulatory death (DCD) livers have been routinely used to expand the donor pool since 1993.5 Although they carry higher risks of primary nonfunction and ischemic-type biliary strictures than deceased after brain death (DBD) grafts, DCD livers can confer a significant survival benefit over waiting for a DBD liver when adjusted for recipient characteristics.6 However, DCD utilization is almost 30% lower in patients with PSC.4 The decreased utilization may be attributable to the conflicting data on whether DCD allografts are safe in recipients with PSC,7,8 considering the combined risks of PSC recurrence and the potential for ischemic-type biliary lesions (ITBLs).

Recent studies have shown that the risks involved with DCD liver transplantation can be abrogated by careful donor and recipient selection. The UK DCD scoring system (UKSS)9 has demonstrated that DCD outcomes can be improved by using donor and recipient variables to stratify individual combinations into low-risk, high-risk, and “futile” categories(Table 1). Individualizing care in this way may benefit patients considered to be high-risk recipients of DCD livers, such as the PSC population.

The purpose of our study was to determine whether the suggested negative effects of DCD liver transplantation in PSC patients were abrogated when appropriate donor-recipient matching was performed using the UKSS tool.

Materials and Methods

Data source and cohort identification

We performed a review of the national Organ Procurement and Transplantation Network (OPTN) database, selecting patients by their unique registration identifiers. The population was drawn from patients transplanted after February 1, 2001 and before March 31, 2015, when data on warm ischemic time ceased to be collected. Data from the OPTN database were obtained via a Standard Transplant Analysis and Research file request with permission.

Inclusion criteria were adults (>18 years of age) with PSC as a primary or secondary diagnosis who received a liver transplant. Within patients who had received a DCD liver transplant, only patients who had complete documentation of the UKSS components (95 complete/115 total recipients) were included.

Patient and donor characteristics

We collected information on multiple sociodemo-graphic characteristics, including recipient and donor age, ethnicity, body mass index, sex, and MELD score. We further examined whether the patient had previously received a liver transplant, had undergone a transjugular intrahepatic portosystemic shunt pro­cedure (TIPS), had a portal venous thrombus (PVT), were dialysis dependent, or were ventilator dependent at the time of transplant. Graft data were collected to include graft type (split vs whole), share type (local vs regional), and cold and warm ischemic times. The warm ischemic time variable was coded within
the Scientific Registry of Transplant Recipient database as a single variable fillable by the individual center.

Risk groups

The entire population of PSC patients who received a DCD liver transplant were analyzed as a single cohort and also analyzed as stratified by their UKSS risk group10 to form low-risk (UKSS score <5) and high-risk (UKSS score 6-10) groups. The futile group (UKSS score >11) was analyzed and consisted of only 6 patients. Therefore, the futile group was excluded from further analysis as it was felt to be insufficiently powered to draw any meaningful conclusions. All groups were compared with the DBD group, which consisted of patients with PSC who received a DBD graft.

Outcome measures

Our primary endpoints were graft failure and mortality. We were unable to assess the individual causes of graft failure and mortality due to high degrees of missing results in the database (89% and 69% missing, respectively).

Statistical analyses

Continuous variables were compared between groups using t tests, and categorical variables were compared between groups with Fisher exact or chi-square tests. Survival rates were estimated utilizing the methods of Kaplan and Meier and compared between groups with log-rank tests. Cox proportional hazards models were used to further evaluate impacts on survival after adjusting for other factors. P < .05 was considered significant. All analyses were performed using SAS statistical software version 9.4 (SAS Institute, Inc).

Results

Use of donation after circulatory death grafts among patients with primary sclerosing cholangitis

We identified 3618 recipients transplanted for PSC, of which 3050 (84.3%) had DBD donors and 115 (3.2%) had DCD donors. Data were complete on 95 DCD recipients (3.1% of total recipients). Living donors provided grafts for 453 recipients (12.5%) (Figure 1). In contrast, livers transplants for patients with non-PSC liver disease included 92.1% DBDs, 4.5% DCDs, and 3.4% living donors.

Univariate outcomes of donation after circulatory death graft use in patients with primary sclerosing cholangitis

Donor demographics were compared between DBD and DCD donors for patients transplanted for PSC (Table 2). Donor demographics differed on age and ethnicity, with DBD donors more commonly older (40.7 vs 33.1 y; P < .001) and more commonly African American (16.0% vs 5.2%; P = .006) than DCD donors. In addition, cold ischemic time was on average 1 hour longer in DBD organs (7.2 vs 6.3 hours; P = .005).

Age, body mass index, sex, and MELD score were similar between PSC recipients who received a DBD or DCD liver. However, there was a higher rate of prior liver transplant in DBD recipients (11.9% vs 3.5%; P = .003). Rates of portal vein abnormalities, specifically TIPS and PVT, were similar between groups. None (0.0%) of the PSC patients who received a DCD liver had a prior transplant compared with 13.4% of PSC patients who received a DBD liver.

Graft survival in patients with PSC transplanted with a DCD liver was worse than in patients who received a DBD liver (Figure 2, left; P = .018). The majority of the survival drop-off for patients with PSC transplanted with a DCD liver was noted in the first 2 years. After early graft failures, survival followed the same slope as for the DBD group. However, patient survival was similar between DBD and DCD groups (Figure 2, right; P = .85).

Risk-stratified univariate outcomes of donation after circulatory death use in primary sclerosing cholangitis

The PSC-DCD group was then risk stratified according to the UKSS index (Table 3). Donor demographics and cold ischemic times were similar between groups. However, functional warm ischemic time increased on average between groups (results in low-risk and high-risk groups of 14.4 vs 18.8 min). In addition, patients in the low-risk group tended to be younger (45.8 vs 57.0 y; P < .001) and had significantly lower MELD scores (18.7 vs. 23.4; P = .01). Results of other markers of more complex surgery (prior liver transplant, TIPS, PVT) and results for patients with more complex need (dialysis and ventilator dependence) were equal between groups.

When stratified by low- and high-risk UKSS, graft survival was significantly different between groups (Figure 3, left; P = .019). Graft survival in the low-risk group was similar to the DBD group (P = .52). However, the high-risk group had significantly worse graft survival than the DBD group (Figure 2, right; P = .01).

Although patient survival in the DBD and DCD groups were comparable, the patient survival curves diverged significantly when stratified by UKSS risk group (Figure 3, right; P = .003). The low-risk group displayed similar survival to the DBD group (P = .18), whereas the high-risk group displayed a trend toward inferior patient survival compared with the DBD group (P = .08). However, patient survival in the low-risk group was significantly better than in the high-risk group (P = .02).

Multivariate analysis

To analyze the effects of non-UKSS components on outcomes, a multivariate analysis was performed, which included donor and recipient sex and ethnicity, recipient body mass index, graft type, share type, presence of TIPS, presence of PVT, ventilator dependence at time of transplant, and dialysis need at time of transplant.

On multivariate analysis, a non-risk-stratified DCD transplant for a patient with PSC was an independent risk factor for graft failure (hazard ratio of 1.70; P < .001) compared with a patient who received a DBD transplant.

When DCD transplants were stratified by risk group, belonging to the low-risk group conferred similar graft survival compared with that shown in the DBD group (hazard ratio of 1.23; P = .31). However, belonging to the high-risk group was an independent risk factor for graft loss (hazard ratio of 1.92; P = .01). Recipient sex and ventilator dependence were similarly independent risk factors for graft loss (Table 4).

With regard to patient survival, receiving a DCD transplant did not increase the risk of mortality in the PSC population (P = .66). Similarly, the low-risk and high-risk groups did not differ in patient survival rates (P = .42). However, use of a split graft, national share type, male sex, previous upper abdominal surgery, ventilator dependence, and dialysis dependence at time of transplant were independent risk factors for mortality.

Discussion

In our analysis, we found that the overall use of DCD allografts in patients with PSC was associated with inferior graft survival compared with use of DBD allografts in PSC. However, we also found that appropriate donor and recipient matching with the use of the UKSS could ameliorate these inferior outcomes. Only 2 prior studies have addressed the use of DCD allografts in patients with PSC. Our results concur with the first, a United Network for Organ Sharing (UNOS) database study in 2015, which showed DCD to be an independent risk factor on multivariate analysis for graft failure. Furthermore, the study showed an interaction between PSC and DCD potentiating the odds of graft failure.7 However, as this study predated the UKSS, it did not attempt to stratify donors by quality or otherwise match donor and recipient factors to examine the safety of DCD livers in patients with PSC. The second study, in 2017, was a single-center trial that examined biliary stricture, graft loss, and mortality with PSC-DCD versus PSC-DBD and found no difference in any of these endpoints.8 The lack of difference may have been due to location and volume effects; this study was performed in the United Kingdom, where DCD donors represent up to 40% of the donor pool and where normothermic regional perfusion and other techniques have been used to improve short-term outcomes.10

Allografts from DCDs are used less commonly for patients with PSC than for those without, with non-PSC patients 30% more likely to receive a DCD allograft than patients with PSC in our analysis. This relative reluctance to allocate a DCD graft to a PSC patient has not been formally studied but may stem from 2 concerns: the first being the additive risk of ITBLs with the strictures of recurrent PSC and the second being the risk of poor donor quality causing PSC recurrence.7

Liver allografts from DCDs develop ITBLs in approximately 15% of cases11; up to 65% of those cases progress to graft failure.11 Although the ITBL risk is high, data in the general population have shown a significant survival benefit with the use of DCD livers, from 65% decreased mortality in all patients undergoing DCD liver transplant to 81% decreased mortality in those with the most advanced liver disease.6 Primary sclerosing cholangitis is an independent risk factor for development of intra- and extrahepatic biliary strictures.12 Transplant surgeons may be concerned about adding the risk of PSC-associated strictures to the already-increased risk of ITBL, thereby increasing the risk of biliary graft loss. As a result of the limitations of a nongranular database, our study was unable to specifically address biliary stricture or biliary graft loss; however, we did find that the use of livers with low-risk UKSS abrogated the graft loss seen in the PSC-DCD recipients, suggesting that use of selected DCD grafts in PSC does not add to the risk of biliary graft loss. Further study is needed to examine whether the observed decline in graft failure when allocating by the risk score is due to decreased biliary complications.

The concern for the use of marginal donors in PSC derives from studies that demonstrated extended donor criteria as a risk factor for PSC recurrence,13,14 which develops in 15% to 25% of liver transplant recipients.14 Studies have demonstrated a 17% increased risk of recurrence for every 5 additional years of donor age14 and a hazard ratio for recurrence of >5 in patients who receive an extended donor criteria graft.13 Grafts from DCDs are considered extended criteria; however, the factors known to contribute to greater injury, increased warm15 and cold ischemic time11 as well as increased donor age, are accounted for in the UKSS. Therefore, the risks of PSC recurrence using DCD donors can be reduced by appropriately matching donor and recipient characteristics.

Our findings have shown that patients with PSC who receive a DCD allograft had worse overall graft survival, but similar patient survival, when compared with DBD allografts. Most graft losses sustained were in the first 2 years, with similar losses per year between the low- and high-risk UKSS groups thereafter. The concordance in DBD and DCD patient survival curves shows an appropriate rescue mechanism for failed DCDs, likely through timely and successful retransplantation. However, we showed that DCD graft survival can be equivalent to DBD graft survival when using the low-risk UKSS group. Patient survival did not seem to be affected by DCD use, again likely due to appropriate use of retransplantation.

Our data are concordant with those elaborated in the original UK DCD study9 but provide the additional benefit of examining a high-risk population in greater detail. Although the original data presented by Schlegel and associates9 demonstrated that a higher-quality allograft-recipient combination provi­ded a graft survival benefit over a lower-quality allograft-recipient combination, it did not address the question of whether individual disease processes provided an additional risk of graft failure not captured by the score. In our study, we addressed a population (PSC patients) who receive fewer DCD transplants, possibly in part because of concerns about interactions between PSC and DCD that could lead to an additive risk of graft failure.7 We were able to show that, on deeper analysis, PSC alone does not confer additional risk of graft failure. Further analysis may show the survival benefit of accepting a DCD liver over waiting for a DBD or living donor.

It is important to note that our main endpoint was graft failure, but ITBL development itself is an important endpoint. Even without graft failure, ITBL significantly impacts recipient quality of life in ways not quantifiable through large databases. Development of ITBL is worse for patients with a Roux-en-Y reconstruction, who cannot be easily instrumented for biliary clearance and stenting, than for duct-to-duct recipients. Historically, Roux-en-Y reconstruction has been recommended in PSC for more complete duct excision, abrogating the risk of cholangiocarcinoma in residual ductal tissue.16 Duct-to-duct and Roux-en-Y reconstruction have been compared in 2 recent meta-analyses,17,18 which demonstrated no differences in nonanastomotic or anastomotic strictures, 1-year graft or patient survival, biliary leaks, or development of cholangiocarcinoma, but did show increased rates of ascending cholangitis with Roux-en-Y reconstruction. When choosing a DCD recipient for a PSC patient, the clinician should first consider whether the donor-recipient combination is advantageous, as detailed in our study, but may further consider whether the patient is a good candidate for duct-to-duct reconstruction to minimize consequences of ischemic cholangiopathy beyond graft failure.

There are limitations to our study. The most important is the use of a retrospective database, allowing us to make general distinctions in outcomes but disallowing us sufficient granularity to parse out the individual causes of graft losses or the landscape of PSC recurrence in this population. Although the benefit of such a database is a large number of events from which to draw conclusions, the power of our study was limited in the experimental group (PSC patients who received DCD grafts) by the small number of these patients with complete data (n = 95). Of the patients in either group who had graft loss or mortality, causes for either were insufficiently recorded in order to draw conclusions (89% missing and 69% missing, respectively). Finally, our results depended on a score that was new, retrospective, and, although validated with the use of large-scale UK and UNOS registry data, lacked center-level prospective study. We acknowledge that, as our field evolves with the use of even more marginal donors and more advanced graft preservation techniques, our results may change.

Conclusions

The use of DCD liver allografts in patients with PSC is safe when using appropriately matched donor and recipient low-risk pairs using the UKSS. Given the high wait list mortality rates for patients with PSC, DCD donors should be considered a viable organ source for these patients.


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Volume : 19
Issue : 6
Pages : 563 - 569
DOI : 10.6002/ect.2020.0387


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From the 1Division of Transplant Surgery, Department of General Surgery, School of Medicine and Public Health, University of Wisconsin; the 2Department of General Surgery, School of Medicine and Public Health, University of Wisconsin; and the 3Department of Biostatistics, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts interest.
Corresponding author: David Al-Adra, University of Wisconsin School of Medicine and Public Health, H4/750 CSC, 600 Highland Avenue, Madison, WI 53792-7375, USA
Phone: +608 265 6471
E-mail: aladra@wisc.edu