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Keywords:

  • Alcohal;
  • cholestatic;
  • organ

Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Studies suggest donor age and year of transplantation are associated with low graft survival in liver transplant recipients with hepatitis C. We sought to determine if advanced donor age and recent year of transplantation are associated with graft survival in hepatitis C recipients and to determine if the effect of donor age on graft survival is specific to hepatitis C. We analyzed the United Network for Organ Sharing liver transplant database from 1994 to 2002. Six thousand four hundred and four subjects transplanted for end-stage liver disease from chronic hepatitis C met our criteria. One-year graft survival in hepatitis C recipients with organs from donors <40 years old and ≥60 years old was 84% and 73%, p = 0.003, respectively. These rates in recipients with cholestatic liver disease and alcoholic liver disease were 85% and 82%, respectively, p = 0.11 and 82% and 78%, respectively, p = 0.14. Three-year graft survival in hepatitis C recipients transplanted from 1994 to 1995 and 1996 to 1999 was 67% and 69%, respectively, p = 0.10. Graft survival in hepatitis C recipients has not declined in recent years. Older donor age is associated with lower short-term graft survival in recipients with hepatitis C, but not in recipients with cholestatic or alcoholic liver disease.

As the discrepancy between the number of patients waiting for liver transplantation and the number of deceased donor organs increases alternative strategies are sought to expand the organ pool. The use of marginal organs is increasing in frequency as physicians try to cope with the deceased donor organ shortage. Strategies to expand the donor pool have included split liver transplantation, living donor liver transplantation, and increasing the upper limit of the age for an acceptable donor organ (1).

Studies in liver transplant recipients demonstrate that advanced donor age is associated with lower graft survival after liver transplantation (2,3). Results from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) database show that 2-year post-transplant graft survival was lower in recipients of grafts from deceased donors 50 years of age or older (2). An analysis of 32 514 liver transplants over an 8-year period from the United Network for Organ Sharing (UNOS) database reported a 90% increase in the likelihood of graft failure in recipients with organs from donors 70 years of age or older compared with organs from younger donors (3). These studies analyzed the impact of donor age in recipients transplanted for any cause of end-stage liver disease and did not conduct subgroup analyses in hepatitis C recipients.

Hepatitis C is the leading indication for liver transplantation in the United States (4,5). Identifying factors associated with graft survival in recipients with hepatitis C may have important implications. Prior studies on factors associated with recurrent hepatitis C with cirrhosis have demonstrated that older donor age and recent year of transplantation are associated with rapid progression to cirrhosis in hepatitis C recipients (6–12). These studies typically have been small, single or limited multicenter studies that fail to capture a substantial number of recipients who receive organs from donors 60 years of age or older in order to detect differences in graft survival. Furthermore, these studies have not compared the effect of donor age on graft survival in recipients with other types of liver diseases.

In an era of critical organ shortage, expansion of the donor pool has led to the use of organs from increasingly older donors. The effect of donor age on graft survival in patients with hepatitis C infection is a clinically relevant issue. The purpose of our study was to use the strengths of the UNOS database to test the association between donor age, year of transplantation and graft survival in patients transplanted for end-stage liver disease from chronic hepatitis C infection. We also sought to determine if donor age had a greater effect on graft survival in patients transplanted for hepatitis C compared with patients transplanted for other indications.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

We analyzed the UNOS liver transplant database from January 1, 1994 through to October 31, 2002. The database consists of 9540 adult liver transplant recipients whose primary diagnosis was chronic hepatitis C. Because a prior study demonstrated that diagnosis code may not accurately identify patients with chronic hepatitis C, patients were identified if their primary diagnosis was chronic hepatitis C and they were positive for anti-HCV antibody (n = 7041) (4). Our analysis was initiated in 1994 because before 1994 testing for antibody to the hepatitis C virus was not widely available and only nine transplant recipients with a primary diagnosis of hepatitis C had a documented hepatitis C antibody (anti-HCV). The UNOS database consists of information from the transplant candidate registration and transplant recipient registration forms, which collect demographic, clinical and laboratory data. We only used data from patients that had at least one follow-up record after transplant. Separate analyses were conducted in subjects with a primary diagnosis of hepatocellular carcinoma and cirrhosis who were anti-HCV positive to determine the effect of donor age on graft survival in the presence of hepatocellular carcinoma.

Recipients were excluded for the following reasons: missing donor age (n = 10), missing graft survival time (n = 9), less than 18 year old (n = 30), hepatitis B surface antigen positive (n = 124), or simultaneous or prior organ transplant (n = 464), leaving 6404 recipients for the final analysis.

We analyzed the impact of donor age <40, 40–49, 50–59, ≥60 years old on graft survival. To determine if the effect of donor age on graft survival was specific to hepatitis C recipients, the association between donor age and graft survival was determined in recipients transplanted for cholestatic liver disease (primary sclerosing cholangitis and primary biliary cirrhosis) and alcoholic liver disease. We also analyzed the association between graft survival by year of transplantation based upon a study suggesting greater hepatitis C recurrence and graft loss since 1996 (12). Time to graft failure was determined as the time from transplantation to the first recorded graft failure date.

We conducted a subgroup analysis to determine the effect of donor age in older and younger recipients. We hypothesized a priori that older recipients with grafts from older donors (recipient age ≥60 years old, donor age ≥60 years old) would have significantly lower graft survival compared with younger recipients with grafts from older donors (recipient's age <40 years old, donor age ≥60 years old).

Means were compared using Student's t-test or Wilcoxon's rank sum test where appropriate and proportions were compared with the chi-squared test. Kaplan–Meier survival curves were compared with the log-rank test. Proportional hazards modeling was used to examine the effect of donor age on graft survival while controlling for recipient age, prothrombin time, total bilirubin, creatinine, gender, race (white vs. nonwhite), and status at the time of transplant (status 1 vs. other), cold ischemic time, life support, and year of transplantation. Comorbidities controlled for included diabetes, dialysis, coronary artery disease/angina, hypertension, symptomatic cerebrovascular disease, and symptomatic peripheral vascular disease. Interaction terms between diagnosis and donor age were created to determine if donor age had a greater effect on graft survival in hepatitis C recipients compared with recipients transplanted for other indications. Patients with functioning grafts were censored at last follow-up. A p < 0.05 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Over the study period, 6404 recipients with chronic hepatitis C underwent liver transplantation who met our inclusion and exclusion criteria. Most recipients with hepatitis C received an organ from donors less than 40 years old (Table 1). Patient characteristics were similar across donor age groups. The proportion of organs used from donors 60 years of age or older has increased from 8.0% in 1994 to as high as 14.8% in 2000 (Figure 1).

Table 1.  Characteristics of the study population
 <40 n = 342140–49 n = 125050–59 n = 956>60 n = 777
Recipient age (mean years)50505152
Male (%)66706767
Prothrombin time (mean s)16.516.316.716.6
Creatinine (mean mg/dL)1.21.21.21.2
Total bilirubin (mean mg/dL)5.14.95.34.9
Cold ischemic time (mean hours)8.38.58.78.6
Life support (%)2.52.22.83.4
Diabetes (%)17.214.717.019.2
Hypertension (%)11.711.310.611.1
Coronary artery disease (%)2.72.13.03.2
Peripheral vascular disease (%)0.70.80.90.4
Cerebrovascular disease (%)0.50.80.60.3
Mean follow-up (days)859727651614
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Figure 1. Proportion of deceased donors 60 years of age and older in patients transplanted for end-stage liver disease from chronic hepatitis C, by year of liver transplantation.

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Effect of donor age on graft survival

There was a decrease in graft survival with increasing donor age (Figure 2). In hepatitis C recipients who received deceased donor organs from donors <40 years old and ≥60 years old 1-year graft survival was 84% and 73%, respectively, p = 0.003. Graft survival decreased with increasing donor age (Figure 2). However, graft survival was not significantly different between recipients who received grafts from donors 50–59 years old and ≥60 years old.

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Figure 2. Graft survival in recipients with chronic hepatitis C, by donor age group, p < 0.0001 by the log rank test.

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One-year graft survival was not significantly different in older and younger donor age groups in recipients with cholestatic liver disease and alcoholic liver disease. One-year graft survival for recipients with cholestatic liver disease (n = 4179) who received an organ from donors <40 years old and ≥60 years old was 85% and 82%, respectively (p = 0.11) and for recipients with alcoholic liver disease (n = 4254) these rates were 82% and 78%, respectively (p = 0.14) (Figure 3).

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Figure 3. One-year graft survival, by donor age group and diagnosis. The difference in graft survival by donor age group was only significant in recipients with hepatitis C.

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Five-year graft survival, by donor age group, was determined in recipients with hepatitis C, cholestatic liver disease, and alcoholic liver disease transplanted from 1994 to 1997. In the hepatitis C group, 5-year graft survival was 67% in recipients who received organs from donors less than 40 years old (n = 1254) and 45% in the group who received organs from donors 60 years of age and older (n = 222), p < 0.001. In the group with cholestatic liver diseases, 5-year graft survival in recipients with organs from donors less than 40 years old (n = 1343) and recipients with organs from donors 60 years of age or older (n = 217) were 77% and 58%, respectively, p < 0.001. For alcoholic liver disease, 5-year graft survival in the younger (n = 1105) and older (n = 203) donor age groups were 69% and 49%, respectively, p < 0.001.

Effect of donor age on graft survival in younger and older recipients

We analyzed the effect of recipient age on graft survival in the group of recipients who received organs from donors 60 years of age and older, with the hypothesis that older recipients that received livers from older donors would have lower graft survival than younger recipients who received organs from older donors. One- and 2-year graft survival in recipients younger than 40 years old who received organs from donors 60 years of age or older (n = 64) were 62% and 49%, respectively. In comparison, 1- and 2-year graft survival in recipients 60 years of age or older with organs from donors 60 years of age or older (n = 236) were 66% and 57%, respectively (p = 0.31). In the group with recipient age <40 years old and donor age ≥60 years old, the total bilirubin, prothrombin time and creatinine were 6.3 mg/dL, 16.0 s, 1.0 mg/dL, respectively, and in the group with recipient age ≥60 years old and donor age ≥60 years old these values were 4.0 mg/dL, 16.2 s, 1.3 mg/dL, respectively. None of these differences were statistically significant

Causes of graft failure

Over the study period, 1754 grafts failed and cause of graft failure was available for 796 (45%) recipients. Primary graft nonfunction, infection, and recurrent hepatitis C were the most common causes of graft failure across all donor age groups. There were no significant differences in causes of graft failure among the donor age groups.

Eight hundred and sixty-nine (49.5%) grafts failed 6 months or longer after liver transplantation. In the recipients who lost their graft and a cause was listed (n = 796), 375 (43%) lost their graft 6 months or longer after their transplant. In comparison, of the 958 recipients who lost their graft and a cause was not listed, 494 (57%) lost their graft 6 months or longer after their transplant (p = 0.06). The mean time to graft failure in recipients with and without a listed cause of graft failure was 372 + 509 d and 460 + 590 d, respectively, p = 0.0009.

Year of transplantation and graft survival

One-year graft survival of recipients transplanted from 1994 to 1995 (n = 953) was 77% and it was 79% for patients transplanted 1996–2001 (n = 4739) (Figure 4). Three-year graft survival for patients transplanted from 1994 to 1995 and from 1996 to 1999 (n = 2745) was 67% and 69%, respectively, p = 0.10. In multivariate analysis, recent time period (1996–2001) was not associated with graft failure.

image

Figure 4. Graft survival in recipients with chronic hepatitis C transplanted from 1994 to 1995 and 1996 to 1999, p = 0.22 by the log rank test.

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In recipients with available data on graft loss, cause of graft failure was not significantly different from 1994 to 2000. Primary graft nonfunction was the most common cause of graft failure implicated in 23% to 30% of failed grafts. Infection was implicated in 11% to 19% of failed grafts and recurrent hepatitis in 4% to 11% of failed grafts. There were no significant differences in causes of graft failure by year of transplantation.

Multivariate analysis

After controlling for multiple factors (see Methods) the risk of developing graft failure increased with donor age (Table 2). Recipients with hepatitis C who received organs from donors 60 years of age or older were 1.9 times more likely to lose their graft compared with recipients who received a liver from donors less than 40 years old. Each year increase in donor age was associated with a 1% increase in graft failure, hazard ratio (HR) = 1.01 [95% confidence interval (CI) 1.01–1.02], p < 0.0001. In both unadjusted and adjusted models, none of the interaction terms between primary diagnosis and donor age were statistically significant indicating that the effect of donor age on hepatitis C was not different from the effect of donor age on recipients for cholestatic liver disease or alcoholic liver disease. Graft survival was not significantly different in recipients with hepatocellular carcinoma with hepatitis C (n = 364) who received an organ from a donor <40 years old (n = 169) or ≥60 years old (n = 66), 76% and 64%, p = 0.38, HR = 1.5 [95% CI 0.9, 2.4].

Table 2.  Multivariate analysis of variables associated with graft failure
Donor age (years)Multivariate hazard ratio (95% confidence interval) p-value
<40 (Reference)1.0 
40–491.3 (1.1, 1.6) 0.002
50–591.8 (1.5, 2.2)<0.0001
>601.9 (1.6, 2.4)<0.0001
Creatinine1.1 (1.0, 1.14) 0.04
On life support1.7 (1.2, 2.3) 0.002
Diabetes1.2 (1.0, 1.5) 0.03
UNOS status 11.6 (1.3, 2.0)<0.0001

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Our study demonstrates that age of the donor graft is one of the strongest factors associated with graft survival in recipients transplanted with hepatitis C. Prior studies suggest the effect of donor age may be specific to hepatitis C and have not reported the effect of donor age on graft survival by etiology of liver disease (6–11). We demonstrated that short-term graft survival is decreased only in hepatitis C recipients with organs from older donors and long-term graft survival is decreased in recipients with organs from older donors with hepatitis C as well as cholestatic and alcoholic liver disease. In addition, we found that graft survival is not lower in recent years compared with earlier time periods. Investigators speculate that changes in immunosuppression to more potent agents have resulted in a higher recurrence of hepatitis C with graft loss (12). Our results do not support this theory and suggest that a shift to the use of organs from older donors is an alternative explanation for lower graft survival rates in recent years that has been reported in other studies (8).

The negative effect of donor age on graft survival seems to be accelerated in recipients with hepatitis C compared with recipients transplanted for cholestatic liver disease or alcoholic liver disease. A possible biological mechanism to explain this finding is that livers from older donors are associated with hepatocyte telomere shortening which reduces the life span of hepatocytes. This process is accelerated during viral hepatitis (13,14). In our analysis, the effect of donor age on 5-year graft survival is similar in recipients with hepatitis C, cholestatic liver disease, or alcoholic liver disease suggesting that the negative effect of donor age on graft survival is eventually seen irrespective of the underlying liver disease. The effect of viral hepatitis and donor age on telomere shortening may not continue to be seen at 5 years because recipients susceptible to this effect may lose their grafts early, which would preferentially select hepatitis C recipients 'resistant' to this effect for long-term survival analyses.

Primary graft nonfunction, infection, and recurrent hepatitis C were the most common causes of graft failure in recipients with hepatitis C with an identified cause of graft loss. We did not demonstrate a difference in cause of graft loss by donor age. However, a substantial proportion of recipients with graft failure were missing data on cause of graft loss. Recipients whose cause of graft loss was missing were more likely to lose their graft later compared with recipients who lost their graft in the early post-transplant period suggesting that data on cause of graft loss are less likely to be collected in patients who lose their graft more than 6 months after transplantation. Improvement in the collection of data from recipients who lose their grafts could provide insight into factors associated with graft failure. For example, if studies demonstrate higher rates of graft loss within the first post-transplant year in hepatitis C recipients who receive organs from older donors are due to higher rates of recurrent hepatitis C then these recipients may be targeted for early antiviral therapy post-transplantation.

Data from older donors are critically important because as the boundaries of the donor pool continue to expand graft survival rates in recipients of organs from older donors are needed. In hepatitis C recipients graft survival decreases with increasing donor age. However, graft survival was similar in recipients who received organs from donors 50–59 years old and 60 years of age and older suggesting that most changes that occur in the liver with aging that effect graft survival occur by the age of 50 years old. Prior studies have not reported graft survival in hepatitis C-infected recipients who received organs from donors 60 years of age or older either because donor age was not reported, follow-up was too short, or there were too few donors 60 years of age or older to detect significant differences in graft survival (9,10,15) The European Collaborative Study did not include donor age in their analysis of factors associated with survival (15). An analysis of 166 HCV-infected patients from the NIDDK Liver Transplant database did not report an association between donor age and graft survival; however, the mean donor age was relatively young, 35 years old (9). A study that included 554 liver transplant recipients with chronic hepatitis C from four centers (three US centers, one European center) reported that donor age was associated with advanced fibrosis, but only 105 recipients received organs from donors 50 years of age or older (10). Differences in graft survival were not demonstrated probably because their analysis lacked power to detect significant differences in graft survival.

The strength of our analysis was that there were 777 hepatitis C recipients who received a liver from a donor 60 years of age or older. With this large number of liver transplant recipients with livers from older donors, we demonstrated significant differences in graft survival between older and younger donor age groups. A limitation of our analysis was that we were unable to evaluate histologic recurrence of hepatitis C. Studies demonstrate that fibrosis is more rapid and cirrhosis is more common in recipients with hepatitis C who receive organs from older donors (7,8,10). Other limitations of our analysis included the inability to control for other factors that have been reported to be associated with recurrent hepatitis C and graft loss including genotype 1, high pre-transplant or post-transplant viral load, rejection episodes, immunosuppression regimen, and cytomegalovirus (CMV) infection (16–26).

We did not find an association between graft survival and donor age in recipients transplanted with hepatocellular carcinoma and hepatitis C, but our sample size was small and many of these recipients were transplanted before the Milan criteria were adopted (27). Survival has improved in patients with hepatocellular carcinoma after the Milan criteria were adopted. Because the number of patients with hepatocellular carcinoma who were hepatitis C antibody positive was small we had too few patients to conduct meaningful analyses after the Milan criteria were widely implemented.

In addition to analyzing the effect of donor age on graft survival, we also stratified our analysis on recipient age hypothesizing that older recipients with livers from older donors would have worse survival compared with younger recipients with organs from older donors. To our knowledge, our study is the first to analyze the association between donor age and graft survival stratified by recipient age. This information may be important in the allocation of organs from older donors based upon recipient age. Because graft survival was similar in young recipients who received organs from older donors compared with older recipients who received organs from older donors, allocation of organs from older donors should not be stratified by recipient age.

Berenguer et al. reported that hepatitis C fibrosis progression has been more rapid in 'recent' years (12). Their two-center study of 284 liver transplant recipients infected with chronic hepatitis C reported that 2% of recipients transplanted from 1990 to 1993 developed cirrhosis 3 years after liver transplantation compared with 26% of recipient transplanted from 1994 to 1995. In a follow-up study, patients transplanted from 1995 to 1997 were more likely to develop severe recurrent hepatitis C compared with recipients transplanted before 1993 (8). In multivariate analysis, year of transplantation was not reported to be associated with severe recurrent hepatitis C, but donor age (>50 years old) was strongly associated with recurrent hepatitis C. Our results demonstrate that graft survival is similar in recipients transplanted in recent years compared with earlier years. In recent years, the proportion of organs used for liver transplantation from older donors has increased. Thus, one might speculate that in other studies it is not the year of transplantation that is adversely affecting graft survival in transplant recipients with hepatitis C, but rather the age of the donor liver.

In conclusion, findings from our analysis of data reported by liver transplant centers throughout the United States demonstrate decreasing graft survival with increasing donor age in recipients transplanted for hepatitis C. The effect of donor age on graft survival seems to be accelerated in recipients with hepatitis C compared with recipients with cholestatic liver disease and alcoholic liver disease. Studies are needed to determine if recipients with hepatitis C who receive grafts from older donors are more likely to lose their graft to recurrent hepatitis C in the early post-transplant period. If this is demonstrated then hepatitis C-infected recipients who receive grafts from older donors may benefit from early antiviral therapy.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

We would like to thank UNOS for providing the data. Dr. Russo is partly supported by the American Gastroenterological Association Merck Clinical Research Career Development Award.

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
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