Patient and graft survival in hepatitis C recipients after adult living donor liver transplantation in the United States

Authors


Abstract

End stage liver disease from chronic hepatitis C is the leading indication for liver transplantation in the United States. Small studies suggest that recurrent hepatitis C may be more common and occur earlier after living donor liver transplantation compared to deceased donor liver transplantation. The objective of our study was to analyze the United Network for Organ Sharing liver transplant database to compare patient and graft survival in recipients transplanted for chronic hepatitis C who received a living donor organ and deceased donor organ between 1999 and 2002. We identified 279 living donor recipients and 3,955 deceased donor recipients. Living donor recipients were less ill at the time of transplant, more likely to be female, and received grafts from younger donors. In the living donor group and deceased donor group, 1-year graft survival was 77% and 82%, respectively, and 2-year graft survival was 72% and 75%, respectively, P = .11. One-year patient survival was 87% in both groups and 2-year patient survival was 83% and 81% in the living donor group and deceased donor group, respectively, P = .68. Short-term patient and graft survival are similar between living donor and deceased donor liver transplant recipients with hepatitis C suggesting that recurrent hepatitis C does not seem to affect short-term outcomes. (Liver Transpl 2004;10:340–346.)

Adult living donor liver transplantation (LDLT) evolved, in part, as a response to the deceased donor organ shortage and mortality associated with waiting for liver transplantation. LDLT offers patients the opportunity to undergo transplantation and avoid continued complications associated with cirrhosis and portal hypertension.

Although LDLT offers patients transplantation sooner compared to patients awaiting deceased liver transplantation there may be complications associated with receiving a partial graft. Complications due to reduced graft size and bile duct strictures have been reported.1–7 In patients undergoing LDLT for hepatitis C, small preliminary studies suggest that recurrent hepatitis C may be more common and occur earlier after transplant compared to a deceased donor control group.8, 9, 10 The concern is that if hepatic regeneration promotes viral recurrence then graft failure may be more common leading to lower patient and graft survival. These series have been criticized because they have not performed protocol liver biopsies. One study that performed protocol biopsies did not demonstrate a difference in recurrent hepatitis C and graft survival in LDLT recipients compared to a deceased donor control group.11

The purpose of our study was to compare patient and graft survival in patients with end stage liver disease from chronic hepatitis C infection undergoing LDLT and deceased donor liver transplantation in the United States. Thus far, studies of outcomes in living donor liver transplant recipients with chronic hepatitis C have been limited to small, single-center studies. The United Network for Organ Sharing liver transplant database provides the opportunity to analyze patient and graft survival in a large number of living donor and deceased donor liver transplant recipients.

Abbreviations

LDLT, adult living donor liver transplantation; MELD, model for end stage liver disease; INR, international normalized ratio.

Patients and Methods

A detailed analysis of the United Network for Organ Sharing liver transplant database was performed between January 1, 1999 and December 31, 2002. We chose to initiate the analysis in 1999 because before this very few adult-to-adult living donor liver transplants were performed (a total of 22 LDLTs before 1999). Patients with hepatitis C were identified if their primary diagnosis was recorded as hepatitis C. We included adult recipients (> 18 years old) transplanted for end stage liver disease from chronic hepatitis C in the deceased donor group and adult recipients (> 18 years old) with end stage liver disease from chronic hepatitis C of organs from living donors. Subjects were excluded if they were hepatitis B surface antigen positive, recipients of a prior organ transplant, or a concurrent organ transplant.

To control for severity of illness we adjusted for the following variables: age, gender, donor age, total bilirubin, serum creatinine, cold ischemia time, diabetes, hypertension, and recipient on life support at the time of transplant. We did not control for model for end stage liver disease (MELD) score at the time of transplant because international normalized ratio (INR) was missing on 48% of transplant candidates, however, total bilirubin and serum creatinine were analyzed in the final model.

Because diagnosis code may not accurately identify patients with chronic hepatitis C, a separate analysis was conducted including only transplant candidates who were positive for anti-HCV antibody. Graft and patient survival were analyzed by year of transplantation to determine the effect of experience and “learning curve” on LDLT outcomes. In addition, an analysis was conducted excluding recipients transplanted in 1999 and including recipients transplanted in 2000 and 2001 to remove the effect of the “early experience” with LDLT.

Statistical Analysis

The differences in characteristics between the living donor group and deceased donor group were compared using a chi-squared test and Student's t test for categorical and continuous variables, respectively. Survival statistics were calculated at 1 and 2 years (with December 31, 2002 as the last date of follow-up). Kaplan-Meier curves were generated and the log-rank test was used for comparing the survival between the groups. For all analyses, a 2-tailed P value of .05 or less was considered significant. For multivariate analyses, Cox proportional hazard modeling was used to test the association between survival and living donor liver transplantation in the presence of other variables. The association between each variable and survival was tested in the presence of LDLT and variables with a p less than .1 were kept in the final model.

Results

Over the 3-year period, 4,234 liver transplants were performed in adults with 279 (6.6%) living donor liver transplants and 3,955 (93.4%) deceased donor liver transplants. Of the 279 living donor recipients with hepatitis C as their primary diagnosis, 230 (82%) were positive for anti-HCV and 3,217 (81%) of deceased recipients were anti-HCV antibody positive. The characteristics of each group are shown in Table 1. Living donor recipients were more likely to be female, receive a graft from a younger donor, and have less severe disease, as measured by total bilirubin and serum creatinine compared to deceased recipients. Not surprisingly, cold ischemia time was shorter in LDLT recipients.

Table 1. Characteristics of the Study Population
Variable*Deceased Group (n = 3,955)Living donor Group (n = 279)
  • *

    More than 10% of missing values for prothrombin time (48% LDLT, 49% Deceased group), cold ischemia time (39% LDLT, 17% Deceased group).

  • P < 0.001; SD, standard deviation.

Age (mean) years5151
Male (%)7159
Total bilirubin (mean) mg/dl4.83.1
Prothrombin time (mean) seconds17.115.5
Creatinine (mean) mg/dl1.20.9
Cold ischemia time (hours)8.12.6
Donor age (yr)4037
Waiting time (mean + SD) days330 + 353326 + 397
Hypertension (%)453 (11)32 (11)
Diabetes (%)587 (15)36 (13)
Number of transplants by year (%)  
 1999966 (24)34 (12)
 20001,096 (28)80 (29)
 20011,114 (28)113 (40)
 2002779 (20)52 (19)

In the living donor group and deceased donor group 1-year graft survival was 77% and 82%, respectively, and 2-year graft survival was 72% and 75%, respectively, P = .11 (Fig. 1). One-year patient survival was 87% in both groups, and 2-year patient survival was 83% and 81% in the living donor group and deceased donor group, respectively, P = .68 (Fig. 2).

Figure 1.

Graft survival in liver transplant recipients diagnosed with hepatitis C, by type of transplant, P = .11 by the log-rank test.

Figure 2.

Patient survival in liver transplant recipients diagnosed with hepatitis C, by type of transplant P = .68 by the log-rank test.

Because methods for organ allocation changed in the United States on February 27, 2002 due to the MELD, we conducted the survival analyses for the pre-MELD era including patients transplanted from January 1, 1999 to February 28, 2002. During the pre-MELD era, 240 patients underwent LDLT and 3,321 patients underwent deceased transplant. The 1-year graft survival for the LDLT and deceased group was 78% and 83%, respectively, P = .10.

During the study period in the deceased group and living donor group 750 (19%) and 59 (21%) number of grafts failed, respectively. In grafts that failed, recurrent hepatitis C as a cause of graft failure was reported in 111 (14.8%) and 10 (16.9%) in the deceased donor group and living donor group, respectively (P = .70). In LDLT recipients, 8 (80%) grafts that were lost to hepatitis C occurred within the first post-transplant year compared to 57 (63%) in the deceased group, P = .49.

Biliary tract complications as a cause of graft failure were reported in 4% of LDLT recipients and 2% of deceased recipients. Primary graft nonfunction was reported in 21% and 15% of LDLT recipients and deceased recipients, respectively, and vascular thrombosis was reported in 15% and 9% of LDLT recipients and deceased recipients, respectively. None of these differences were statistically significant, and data on cause of graft failure were missing on 23% of LDLT recipients and 46% of deceased recipients.

Results of multivariate analysis for graft survival are shown in Table 2. LDLT was weakly associated with graft survival after controlling for clinical factors. The age of the donor was the variable most strongly associated with graft survival. For each year, increase in donor age graft survival decreased by 1%. LDLT was not associated with patient survival (Table 3). Total bilirubin was the variable most strongly associated with patient survival. For each 1 mg/dl increase in total bilirubin, patient survival decreased by 2%.

Table 2. Multivariate Analysis of Graft Survival
VariableHazard Ratio (95% CI)
Living donor liver transplant1.44 (0.99, 2.08), P = 0.054
Male0.79 (0.67, 0.94), P = 0.007
Donor age (years)1.01 (0.99, 1.01), P < 0.0001
Total bilirubin (recipient) mg/dl1.01 (1.00, 1.02), P = 0.01
Serum creatinine (recipient) mg/dl1.12 (1.04, 1.22), P = 0.005
Cold ischemia time (hours)1.02 (1.01, 1.04), P = 0.005
Diabetes1.32 (1.07, 1.62), P = 0.009
Recipient on life support1.68 (1.01, 2.80), P = 0.045
Table 3. Multivariate Analysis of Patient Survival
VariableHazard Ratio (95%, CI)
Age (years)1.02 (1.01, 1.04), P = 0.0001
Donor age (years)1.01 (1.00, 1.01), P = 0.03
Total bilirubin (recipient) mg/dl1.02 (1.01, 1.03), P < 0.0001
Serum creatinine (recipient) mg/dl1.18 (1.08, 1.29), P = 0.0002
Cold ischemia time (hours)1.02 (1.00, 1.04), P = 0.04
Diabetes1.33 (1.04, 1.70), P = 0.02

Subgroup Analysis

Hepatitis C antibody positive group

We analyzed the subgroup of patients in the LDLT group (n = 230) and deceased group (n = 3,217) who were hepatitis C antibody positive. In the LDLT group, 14% of data were missing for hepatitis C antibody and 2% of patients were antibody negative. In the deceased group, 15% of data were missing for hepatitis C antibody and 1% of patients were antibody negative.

Characteristics of patients who were hepatitis C antibody positive were similar to those presented in Table 1 for the entire cohort of patients with a diagnosis of hepatitis C. One-year graft survival in the living donor group and deceased group was 75% and 83%, respectively, P = .04 and 2-year graft survival in the living donor group and deceased group was 69% and 75%, respectively, P = .21 (Fig. 3). One-year graft survival was significantly different between the living donor group and deceased donor group because of low graft survival in living donor recipients transplanted in 1999. If patients transplanted in 1999 were excluded from the analysis (living donor group n = 34), there is not a significant difference in graft survival between the living donor group and deceased donor group.

Figure 3.

Graft survival after living donor liver transplantation and deceased donor liver transplantation in patients who were hepatitis C antibody positive, P = .01 by the log-rank test.

One-year patient survival in the living donor group and deceased group was 84% and 87%, respectively, P = .64 and 2-year patient survival in the living donor group and deceased group was 81% and 82%, respectively, P = .73.

Multivariate analysis was conducted in the subgroup of patients who were hepatitis C antibody positive, and results were similar to the results reported in the entire cohort of recipients presented in Tables 2 and 3.

Year of transplantation

We compared patient and graft survival in the living donor group by year of transplantation in the entire cohort diagnosed with hepatitis C to determine the affect of experience and “learning curve” on outcomes after LDLT (Table 4). From 1999 to 2000, in LDLT recipients, 1-year patient survival in the living donor group increased from 69% to 90%, P = .04 (Fig. 4), and 1-year graft survival increased from 63% to 79%, P = .16. One-year survival rates in the LDLT group were similar between 2000 and 2001. In the deceased group, 1-year patient and graft survival did not substantially change from 1999 to 2001.

Table 4. One-Year Patient Survival in the Living Donor and Deceased Donor Groups, by Year of Transplantation
Year of TransplantEntire Group Diagnosed with Hepatitis CHepatitis C Antibody Positive Group
Deceased Group (%)Living Donor Group (%)Deceased Group (%)Living Donor Group (%)
  • *

    P = 0.04 for the difference in patient survival between 1999, 2000, and 2001.

199986698658*
200089908988
200186908790
Figure 4.

Patient survival in living donor liver transplant recipients diagnosed with chronic hepatitis C, by year of transplantation, P = .04 by the log-rank test.

From 1999 to 2000, in recipients who were hepatitis C, antibody positive 1-year patient survival increased from 58% to 88%, P = .18, and 1-year graft survival increased from 51% to 77%, P = .56. Graft or patient survival did not substantially change in the hepatitis C antibody positive group from 2000 to 2001 (data not shown).

Discussion

The number of adult-to-adult living donor liver transplants has increased over the past 5 years as has the number of centers performing LDLT. In 1997, 1 LDLT was performed, and the number of LDLTs increased to 266 in 2000.12 Furthermore, the number of centers performing LDLT has increased from 7 in 1998 to 38 in 2000, and 76% of surveyed programs not performing LDLT plan on initiating a program.12 End stage liver disease from chronic hepatitis C is the leading indication for liver transplantation, and many LDLT candidates will be transplanted with chronic hepatitis C.

LDLT is associated with complications that are either more common or distinct from those seen with deceased donor liver transplantation. Biliary tract complications are reported in 10–30% of patients, and small for size syndrome, a condition unique to LDLT because of reduced graft size, has been reported in a minority of recipients.2–7 In our analysis causes of graft failure that were more common in the LDLT group compared to the deceased group included recurrent hepatitis C, primary graft nonfunction, and vascular thrombosis, but none of these differences were statistically significant. Although LDLT offers patients organ transplantation before they become too ill for transplant or die, technical complications and complications due to reduced graft size may offset some of these advantages.

A potential disadvantage of LDLT is that hepatic regeneration may promote viral replication and accelerate recurrent hepatitis C. There are data supporting increased viral replication in the setting of hepatic regeneration. Hepatitis C viral replication is dependent upon translation of a large polyprotein mediated by the internal ribosomal entry site.13 The activity of the internal ribosomal entry site is greatest in actively growing cells, especially during mitotic phases.13 Therefore, there is a biological basis for the concern of accelerating hepatitis C infection in a regenerating graft compared to a graft from a deceased donor.

In transplant recipients, small single center studies have reported greater rates of recurrence of hepatitis C in LDLT recipients compared to deceased recipients, but other reports have demonstrated no difference in recurrent hepatitis C between these groups.8, 9, 10, 11, 14 In a study of 11 LDLT recipients with chronic hepatitis C and 510 hepatitis C infected deceased recipients, 86% of LDLT recipients and 30% of deceased donor recipients developed histologic recurrence of hepatitis C.10 In a separate series of 24 LDLT recipients with HCV who were compared to 41 deceased donor recipients with HCV, the authors reported that histologic evidence of recurrent hepatitis C evolved more rapidly in the LDLT group, 90 days and 168 days, respectively.14 Furthermore, LDLT recipients with smaller graft volumes had the most rapid HCV recurrence suggesting that hepatic regeneration accelerates hepatitis C. However, these studies have been criticized for not performing protocol liver biopsies, and therefore, not capturing the true rate of histologic HCV recurrence. In a study that performed protocol liver biopsies, no significant difference in histological recurrent hepatitis C was demonstrated between LDLT recipients and deceased donor recipients.11

We found that the proportion of cases of graft failure due to recurrent hepatitis C that occurred within 1 year of liver transplantation was higher in the LDLT group than the deceased group, although the difference was not statistically significant. Furthermore, a substantial proportion of cases were missing data on causes of graft failure, limiting our ability to draw conclusions. In our analysis, we were unable to determine rates of histologic recurrence of hepatitis C or the rate of hepatitis C cirrhosis. The association between LDLT and hepatitis C related cirrhosis and hepatitis C related death should be studied. In addition, we were unable to control for medications and immunosuppressive therapies that have been associated with recurrent hepatitis C, although other studies have not demonstrated an association between immunosuppression and recurrent hepatitis C.15–24 Future studies will need to control for immunosuppression, viral load, and technical experience when comparing recurrent hepatitis C in living donor recipients and deceased donor recipients, as is planned with the large NIH multicenter study of living donor liver transplantation.

In multivariate analysis, LDLT was associated with graft survival. This is not surprising, and perhaps misleading, because for any given severity of illness outcomes should be superior in recipients of whole grafts. A better comparison group may be patients at a similar MELD score who are not transplanted. There is, however, a balance between morbidity and mortality awaiting liver transplantation versus morbidity and mortality associated with LDLT. LDLT recipients will have lower MELD scores compared to deceased recipients to achieve similar post-transplant graft survival. The optimal MELD score at time of transplantation in which recipients of grafts from living donors achieve similar outcomes to recipients of whole grafts has not been established. We were unable to calculate the MELD score at the time of transplant because data were missing on INR in half of the candidates. Although we were unable to control for MELD score, we were able to control for serum creatinine and total bilirubin, in addition to other comorbid illnesses. Obtaining INR and MELD score has become a requirement, and future studies on the association between MELD score on post-transplant outcomes in LDLT recipients will be of interest.

By analyzing 1-year graft survival in the LDLT group by year of transplantation, we demonstrated that there may have been a “learning curve” in 1999. One-year graft survival increased by 16% from 1999 to 2000 in the group with a diagnosis of hepatitis C, and graft survival increased by 26% in the subgroup that was hepatitis C antibody positive. One-year graft survival in the LDLT group did not substantially change from 2000 to 2001, nor did 1-year graft survival substantially change in the deceased group from 1999 to 2001. Improvements in patient selection, technical advances, and center experience may account for the increase in graft survival in the LDLT group seen after 1999.

The strength of our analysis is the large sample size that was analyzed for patient and graft survival. Given the number of subjects included in the United Network for Organ Sharing database it is unlikely we were underpowered to detect meaningful differences in survival. Limitations of our analysis include those inherent to most large databases, such as accuracy of data, missing data, and unavailable data. Similar to findings by Forman et al.,25 we found a discrepancy between the number of patients diagnosed with hepatitis C and the proportion reported to be positive for hepatitis C antibody. Unlike their study which included patients transplanted since 1992, our analysis included patients transplanted recently, which may explain why more patients in our analysis had a positive hepatitis C antibody. It seems unlikely that patients transplanted since 1999 were misdiagnosed with hepatitis C. Transplant centers usually have coordinators complete data on patient diagnoses, and these personnel are experienced clinicians familiar with the transplant candidate's case. Nevertheless, we performed analyses in hepatitis C antibody positive recipients and demonstrated small differences in graft survival between this subgroup and the entire group of patients diagnosed with hepatitis C. In addition to missing data on hepatitis C antibody, data on causes of graft loss were less than optimal and missing on a substantial number of patients. Complete data on causes of graft loss would prove useful for future studies of LDLT. Finally, data on long-term outcomes is not yet available, and longer follow-up is needed to compare long-term survival rates of LDLT recipients with deceased recipients.

In conclusion, our study of liver transplantation in the United States for end stage liver disease from chronic hepatitis C did not demonstrate a significant difference in short-term graft or patient survival between recipients of live donor organs and deceased donor organs. A significant improvement in survival after living donor liver transplantation was seen after 1999. Continued follow-up will determine if there is a significant difference in long-term patient and graft survival in living donor liver transplant recipients and deceased donor liver transplant recipients.

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