Objectives: We investigated the impact of liver transplant from donors after circulatory death on incidence and severity of recurrent hepatitis C virus infection, graft and patient survival and aimed to identify predictors of outcomes.
Materials and Methods: We retrospectively reviewed all liver transplants performed at a single center (July 2007-February 2014). Patients with hepatitis C who underwent liver transplant from donors after circulatory death (group 1) were compared with hepatitis C patients who received grafts from donors after brain death (group 2) and patients without hepatitis C who received grafts from donors after circulatory death (group 3). We used the Kaplan-Meier method for survival analysis and performed a multivariable analysis for predictors of outcomes using Cox regression. Competing risk was used to analyze hepatitis C recurrence.
Results: Of 196 patients, 107 were included: 25 in group 1, 46 in group 2, and 36 in group 3. All 3 groups were comparable, except for longer cold ischemia time (P < .01) in group 1, lower Model for End-Stage Liver Disease score at transplant in groups 1 and 3 (P < .01), and greater proportion of recipients with hepatocellular carcinoma in groups 1 and 2 (P = .02). Hepatitis C recurrence and severe recurrence at 1 and 3 years were higher in group 1 (but not statistically significant). Severe recurrence was noted in 17% versus 8% at 1 year (P = .12) and 30% versus 14% at 3 years (P = .08). Graft and patient survival rates at 1, 3, and 5 years were comparable in all 3 study groups.
Conclusions: Recurrent hepatitis C, including severe recurrence, was greater following donation after circulatory death compared with donation after brain death liver transplant. However, graft survival and patient survival were comparable, including in recipients of donation after circulatory death grafts without hepatitis C.
Key words : Donation after circulatory death, Hepatitis C, Outcomes
Organ availability remains a challenge in liver transplantation (LT), prompting consideration of extended criteria donors, including grafts from donors after circulatory death (DCDs). This has resulted in increased utilization of DCD allografts in the United States, primarily driven by high-volume LT centers, with DCD organs currently accounting for about 6% of all LTs performed in the United States. 1,2
Outcomes after DCD LT have been reported to be inferior to outcomes after donation after brain death (DBD) LT, which has been primarily attributed to an increased incidence of biliary complications.3-5 Although large database analyses suggested that DCD LT had inferior outcomes compared with DBD LT, several single-center analyses have shown comparable outcomes.6,7
The presence of hepatitis C virus (HCV) has been shown to be an independent predictor of outcome after LT, primarily due to recurrence of HCV posttransplant.8 Moreover, in recipients with HCV, the quality of the liver graft has also been shown to impact outcomes.9 The use of grafts from DCDs has been reported to be associated with an increased risk of HCV recurrence, thereby impacting graft and patient survival. However, available data on outcomes in this cohort are limited and have shown conflicting results. Moreover, much of the published literature on DCD LT, including DCD HCV, have been from high-volume LT centers or from registry analyses, limiting its applicability to low-volume centers.10 Our aim was to determine the impact of DCD allografts on recurrent HCV and graft and patient survival following LT at a single low-volume center and to determine predictors of outcome.
Materials and Methods
The study protocol was approved by our institu-tional review board and conformed to the ethical guidelines of the 1975 Declaration of Helsinki.
We conducted a retrospective review of all primary LTs performed at Aurora St. Luke’s Medical Center in Milwaukee, Wisconsin, USA, from July 2007 through February 2014. Outcomes of HCV recipients of DCD allografts (group 1; DCD-HCV) were compared to HCV recipients of DBD allografts (group 2; DBD-HCV) and recipients without HCV who received DCD allografts (group 3; DCD-non-HCV).
Variables and outcomes analyzed
The following recipient variables were obtained: age, sex, etiology of liver disease, Model for End-Stage Liver Disease (MELD) score at transplant, presence of hepatocellular carcinoma (HCC), HCV status, death, cause of graft loss, and last follow-up date. Donor and organ procurement parameters analyzed included donor age, sex, cause of death, and warm and cold ischemia times.
Primary outcome measures evaluated were incidence and severity of HCV recurrence, graft survival, and patient survival. Graft survival was estimated from transplant until graft loss, defined as date of retransplant or death or date of last follow-up. Patient survival was estimated from transplant until death or date of last follow-up. Graft survival analysis was limited to primary LTs, and patient survival analysis was limited to primary solitary LTs only. Recurrence of HCV was defined as biochemical graft dysfunction with detectable HCV RNA by polymerase chain reaction assay, which was then confirmed histologically as recurrent HCV.
Surgical techniques and immunosuppression
All donor and recipient surgical procedures were performed by 1 of 3 transplant surgeons from our center. University of Wisconsin solution was used for preservation of all liver allografts. After declaration of death, a 5-minute period of observation was followed before organ retrieval. Donor warm ischemia time was defined as the interval from withdrawal of ventilatory and circulatory support to aortic cross clamping and perfusion with cold preservation solution; and cold ischemia time was defined as the interval from initiation of donor in vivo cold organ preservation to removal of the graft from 4 °C cold storage; recipient warm ischemia time was defined as the interval between removal from cold storage to establishment of reperfusion of the liver graft. Thrombolytic agents were not used during procurement over the study period.
All recipient surgical procedures were performed using the standard piggyback technique without venovenous bypass. Duct-to-duct biliary reconstruction with transcystic biliary tube (5-Fr ureteral stent, Bard polyurethane ureteral catheter; C. R. Bard, Inc) was used except when deemed not feasible by the recipient’s surgeon. In recipients with an in-dwelling biliary tube, cholangiogram was performed on posttransplant days 7 and 21 and as clinically indicated. Standard immunosuppression protocol was followed in all recipients (steroid induction followed by tacrolimus, the dosage of which was adjusted based on trough levels). Rejection episodes were treated with increasing tacrolimus levels and steroid boluses, if necessary.
Liver biopsies were performed as clinically indicated if there was biochemical evidence of hepatic inflammation in the setting of positive HCV RNA level. All liver biopsies were evaluated by experienced transplant hepato-pathologists. Recurrent HCV was diagnosed in the setting of a compatible liver biopsy in a transplant recipient with biochemical evidence of allograft dysfunction and positive HCV RNA. Severe HCV recurrence was defined as presence of ≥stage 2 fibrosis within 1 year of LT or development of cirrhosis secondary to recurrent HCV with or without graft failure or death. Antiviral therapy consisted of a 48-week course of pegylated interferon, ribavirin (and telaprevir for patients treated after July 2011) for 48 weeks, with sustained virologic response defined by negative HCV RNA 24 weeks after cessation of treatment.
We compared recipient and donor factors among the groups using chi-square tests for categorical variables and used Wilcoxon rank sum test to compare conti-nuous variables between the 3 groups and t tests to compare continuous variables between 2 groups. Data are presented as frequency and percent or as mean ± SD; MELD at the time of transplant was presented as median and interquartile ranges. Competing risk analysis was used to examine incidence of HCV recurrence, treating graft loss as the competing event. We used the Kaplan-Meier method for comparisons of patient and graft survival, the Cox proportional hazards model for univariate models to predict graft loss and death, and forward stepwise selection for development of final multivariable models. We used SAS version 9.4 for statistical analyses.
Of 196 LTs performed during the study period from July 2007 through February 2014, 61 (31%) were performed using DCD grafts. The average annual LT volume at our center over the study period was 27, with the percentage of DCD LT performed annually ranging from 14% to 78% (Figure 1).
Of 196 LTs, 71 (36%) had HCV listed as the indication for LT. Among those with HCV, 25 (35%) belonged to group 1 (DCD-HCV) and 46 (65%) belonged to group 2 (DBD-HCV). In addition, 36 patients without HCV also underwent DCD LT over the study period (belonging to group 3) (Figure 2). The median time period of follow-up posttransplant was 39.6 months.
Donor and recipient variables
Recipient, transplant, and donor characteristics for the 3 study groups are listed in Table 1. All 3 groups were similar with respect to age, sex, and other demographic variables. Among all HCV recipients, 88% were noted to have genotype 1 infection (81% for group 1, 92% for group 2). Presence of HCC in the 2 HCV groups were comparable, with 12 recipients (48%) in group 1 and 22 recipients (48%) in group 2 (P = .99), but significantly higher than the non-HCV group (group 3) (P = .02). Median MELD score at LT was significantly higher in group 2 recipients (DBD-HCV) compared with group 1 and group 3 (P < .01).
Although no difference was observed in mean recipient warm ischemia time among the 3 groups, group 1 (DCD-HCV) had longer cold ischemia time than group 2 (DBD-HCV) and group 3 (DCD-non-HCV) (10.0 ± 3.1 vs 7.2 ± 2.6 vs 8.6 ± 2.3 hours; P < 0.01). Age, sex, and proportion of donors >50 years of age were not statistically different among all 3 groups. Although group 1 recipients had lower rates of donors over age 50 years, this did not reach statistical significance.
Hepatitis C virus recurrence and episodes of rejection
At 1 and 3 years, HCV recurrence was noted in 39% and 58% of those in group 1 and 25% and 47% of those in group 2 (P = .12). Severe HCV recurrence was noted at 1 and 3 years in 17% and 30% of patients in group 1 and 7.5% and 14% of patients in group 2 (P = .08) (Table 2). In group 1, 8 of 17 patients with information (47%) received pegylated interferon-based antiviral therapy. In group 2, 11 of 21 patient with information (52%) received pegylated interferon-based antiviral therapy. In these patients, sustained virologic response was observed in 1 patient (12%) and 9 patients (82%) from groups 1 and 2, respectively (P = .01). Recurrence of HCV was not significantly associated with graft survival in HCV recipients (hazard ratio [HR] 0.92; 95% confidence interval [95% CI], 0.28-2.97; P = .89).
The number of episodes of acute cellular rejection within the first year of transplant among groups 1, 2, and 3 were 4, 5, and 2, respectively (P = .53 comparing all groups; P = .54 for group 1 vs group 2). Rates of acute rejection at 3, 6, and 12 months were 13.0%, 17.7%, and 17.7% for group 1; 11.9%, 11.9%, and 11.9% for group 2; and 7.1%, 7.1%, and 7.1% for group 3, respectively.
Patient and graft survival
In total, 7, 12, and 7 grafts in groups 1, 2, and 3, respectively, were lost over the study period. After a median follow-up of 39.6 months, patient and graft survival rates were not statistically different between group 1 (DCD-HCV) and group 2 (DBD-HCV) (P = .77 and P = .86, respectively) (Figure 3 and Figure 4). Respective group 1 and group 2 graft and patient survival rates were 81.8% versus 84.4% and 82.6% versus 84.4% at 1 year, 81.8% versus 69.5% and 82.6% versus 69.5% at 3 years, and 47.7% versus 59.6% and 52.5% versus 69.5% at 5 years.
Predictors of graft failure and death
On univariable analysis, in HCV recipients (groups 1 and 2), donor age >50 years was predictive of graft survival (HR 4.07; 95% CI, 1.53-10.85; P < .01) and patient survival (HR 4.18; 95% CI, 1.52-11.46; P < .01). Although the study population and number of events were both small, continuous donor age (HR 2.56; 95% CI, 1.12-5.87; P = .03) and donor age >50 years (HR 13.59; 95% CI, 1.44-128.17; P = 0.02) were significantly associated with graft loss among group 1 solitary recipients (Table 3).
Forward stepwise selection was performed to develop a final multivariable model to predict graft and patient survival by evaluating all donor, procurement, transplant, and recipient variables. When we examined all 3 groups, multivariable analysis only identified HCV recipients receiving organs from donors>50 years as a significant predictor of graft survival (HR 4.46; 95% CI, 1.49-13.30; P < .01) and patient survival (HR 4.33; 95% CI, 1.45-12.91; P < .01).
Strategies to increase the available donor pool for LT include optimal utilization of extended criteria donors, including DCDs. Utilization of DCD allografts in LT, however, has been limited by concerns regarding decreased allograft survival, primarily due to an increased incidence of biliary complications.3,11,12 However, this has to be weighed against the survival benefit conferred by these extended criteria grafts, especially in recipients with more advanced liver disease.13 Several factors have been identified as predictors of outcome following DCD LT, including donor age, body mass index, warm and cold ischemia time, recipient sex, African American race/ethnicity, and MELD score.5,11 In a single-center report evaluating long-term outcomes (median follow-up >4.5 y) following DCD LT, Nguyen and colleagues observed inferior outcomes among recipients with HCV.14 Although recipient HCV infection has been reported to be associated with inferior outcomes in DCD LT, other studies have shown comparable outcomes.15-17
In the absence of antiviral therapy, recurrence of HCV infection after LT is nearly universal and often progressive, resulting in higher risk of graft loss.8 Virus-, donor-, recipient-, and transplant-related variables have been associated with likelihood and progression of recurrent HCV after LT, including HCV RNA at LT, use of older donors, choice of induction therapy, and cytomegalovirus (CMV) infection.18-21 However, limited data are available on the impact of DCD grafts on incidence and progression of recurrent HCV post-LT, with its consequent impact on graft and patient survival.
High-volume LT centers have been observed to use high-risk grafts, including DCDs, more often and with improved outcomes.22 We have previously demonstrated the applicability of DCD LT to low-volume centers.23 Despite the increased utilization of DCD grafts, available data on the impact of DCD grafts on outcomes after LT for HCV mostly are confined to high-volume LT centers or to registry analyses and have produced conflicting results.15-17,24,25 The advent of newer direct-acting antiviral agents has significantly improved outcomes after LT for HCV, even enabling transplant of organs from donors infected with HCV into HCV-naive recipients.26,27 However, the increased use of DCD donors and HCV-positive donors in LT necessitates a better understanding of outcomes and variables affecting outcomes, since variable access to therapy and compliance could result in potential delay in initiation of antiviral therapy with clinical consequences.28-30
Only 7 prior studies have specifically addressed the effects of DCD LT in HCV recipients (Table 4).15-17,24,25,31,32 In an analyses of the United Network for Organ Sharing database, Uemura and colleagues reported inferior graft survival but comparable patient survival in DCD-HCV patients compared with DBD-HCV patients.24 Although Yagci and colleagues32 also demonstrated inferior graft and patient survival in DCD-HCV patients, the remaining 5 single-center studies reported comparable outcomes, although sample sizes were small.15-17,25,31,33
Studies that evaluated the effects of DCD on recurrence of HCV and fibrosis progression have also produced conflicting results. Both Tao and colleagues17 and Taner and colleagues15 reported comparable rates of HCV recurrence and fibrosis progression after DCD and DBT LT in patients with HCV; however, 3 other single-center studies noted significantly higher risk of HCV recurrence and fibrosis progression after DCD LT.16,25,31 However, many of these studies were limited by sample size, thereby limiting the generalizability of their observations.
In this, to our knowledge, first single-center study from a low-volume center evaluating outcomes following DCD LT in HCV recipients, we demonst-rated comparable graft and patient survival rates to DBD-HCV and DCD-non-HCV recipients. Although we observed a trend toward greater likelihood of recurrent HCV among DCD-HCV recipients, this did not reach statistical significance, and perhaps, more importantly, graft and patient survival rates were not affected. Despite episodes of acute cellular rejection and its treatment being associated with greater likelihood of HCV recurrence,17 rates of acute cellular rejection were comparable in HCV recipients of DCD and DBD grafts in our study, thereby excluding this as a potential confounding variable. Most DCD-HCV LT procedures in our study cohort were performed before the advent of highly effective direct-acting antiviral therapy; arguably, our outcomes in DCD-HCV would have been even better in the context of widespread availability of these agents.
Information on prognostic variables in the DCD-HCV subset remains limited.5 In DCD recipients with HCV, Uemura and colleagues identified recipient male sex, donor age, female sex, non-White race/ethnicity, and cold ischemia time as factors impacting outcomes.24 In line with this observation and our prior overall experience in DCD LT,23 the only determinant of outcome in our analysis was donor age. Although Tao and colleagues identified rejection and CMV infection as independent factors for severe HCV recurrence, Taner and colleagues observed that recipient MELD at LT and CMV infection in the first year posttransplant were significant predictors of graft loss.15,17
Our study is limited by its retrospective design and the fact that most patients analyzed were in the era before the availability of direct-acting antivirals. Registry analyses and reports from high-volume LT centers have provided valuable information; however, these results may not be applicable to lower-volume LT centers.29 In addition, unlike database or multicenter studies, our experience eliminates the effects of variations in practice patterns among transplant centers. Despite our lower annual mean LT volume, the proportion of DCD LTs in our cohort was higher than other single-center and registry analyses, underscoring our experience with this subset of liver transplant recipients.23 Despite the advent of highly effective direct-acting antivirals, the increasing utilization of organs from DCDs and organs from HCV-positive donors mandates a better understan-ding of the impact of HCV in this subset of DCD LT.
Outcomes after DCD LT in HCV recipients were comparable to HCV recipients of DBD grafts and DCD recipients without HCV. The use of DCDs in LT offers the potential to safely expand the donor pool for recipients with HCV without compromising graft and patient survival. Our experience also confirmed the feasibility of DCD LT in HCV in low-volume centers in the context of continued scarcity of deceased donor organs and increasing consideration of DCDs and HCV-positive donors.
Volume : 20
Issue : 11
Pages : 984 - 991
DOI : 10.6002/ect.2022.0320
From the 1Transplant Center, Advocate Aurora Health, Milwaukee, Wisconsin, USA; and the 2Department of Gastroenterology and Hepatology, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
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 of interest.
Corresponding author: Shiva Kumar, Department of Gastroenterology & Hepatology, Digestive Disease Institute, Cleveland Clinic Abu Dhabi, Al Maryah Island, Abu Dhabi United Arab Emirates
Phone: +971 2 501 9000
Figure 1. Liver Transplants Performed in Our Center Over the Study Period
Figure 2. Number of Patients in the 3 Study Groups Per Year Over the Study Period
Table 1. Recipient and Donor Characteristics of the 3 Study Groups
Table 2. Recurrence Rate of Hepatitis C Virus in Group 1 and Group 2
Figure 3. Graft Survival in Hepatitis C Recipients of Donation After Brain Death and Donation After Circulatory Death Liver Transplants
Figure 4. Patient Survival in Hepatitis C Recipients of Donation After Brain Death and Donation After Circulatory Death Liver Transplants
Table 3. Univariate Model With Predictors of Graft and Patient Survival
Table 4. Summary ofAll Reported Studies to Date Evaluating OutcomesAfter Liver Transplant with DonationsAfter Circulatory Death in Recipients with Hepatitis C Virus