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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Hepatitis C recurs universally after liver transplantation (LT). Whether its progression differs after live donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT) is still debated. We retrospectively analyzed 201 consecutive LTs performed at our institution for hepatitis C–related end-stage liver disease between April 2000 and December 2005 (46 LDLTs and 155 DDLTs). Patients were followed with protocol biopsies for medians of 29 (LDLT) and 39 months (DDLT; P = 0.7). Although overall graft and patient survival did not differ, the mean fibrosis stage (Metavir) was significantly higher at 12 to 48 months post-LT (all P < 0.05), and the rate of fibrosis progression tended to be faster after DDLT than LDLT (0.19 versus 0.11 stage/year, P = 0.05). In univariate analysis, donor age, cold ischemic time, and DDLT were significantly associated with a fibrosis stage ≥ 1 at 1 year and a fibrosis stage of 3 or 4 at 2 years post-LT. In multivariate analysis, however, donor age was the sole variable independently associated with both surrogate outcomes. Thus, donor age > 45 years carried a relative risk of 8.17 (confidence interval = 2.6–25.5, P = 0.001) for reaching fibrosis stage 3 or 4 at 2 years post-LT. In conclusion, donor age, rather than the transplant approach, determines the progression of recurrent hepatitis C after LT. LDLT, allowing for the selection of younger donors, may particularly benefit hepatitis C patients. Liver Transpl 14:1778–1786, 2008. © 2008 AASLD.

End-stage liver disease secondary to chronic hepatitis C virus (HCV) infection is the most common indication for liver transplantation (LT) worldwide.1, 2 Unfortunately, HCV reinfection of the graft occurs universally, is associated with an aggressive course in a proportion of patients, and leads to graft cirrhosis in 10% to 30% of recipients within 3 to 5 years.3, 4 Therefore, the 5-year survival of HCV-positive LT recipients is overall significantly lower than that of HCV-negative patients.5

Donor age is the most consistently reported factor associated with accelerated fibrosis progression and/or impaired graft/patient survival in recurrent hepatitis C after LT.6–10 Other factors include the use of intravenous steroid bolus doses or its surrogate, acute cellular rejection,9, 11 pretransplant HCV viral load,12 and hepatitis B virus or human immunodeficiency virus coinfection.13

It has been hypothesized that, compared to deceased donor liver transplantation (DDLT), live donor liver transplantation (LDLT) may accelerate HCV recurrence post-transplant because of increased hepatocellular proliferation and, in the case of a biological relation, fewer immunological differences between the donor and recipient.14 Whether the donor type indeed affects the outcome of HCV recipients post-LT remains, however, controversial. Some authors reported that HCV recurrence occurred earlier and was more severe after LDLT than after DDLT,15, 16 whereas others did not observe these differences.17–20

Several of these studies are limited by the lack of protocol biopsy data and a relatively short follow-up. Protocol biopsies are, however, mandatory for using histologic progression (fibrosis stage) as a surrogate for survival outcome. The 3 studies with protocol biopsies are contradictory: 2 of them show no difference,19, 20 and the other reports accelerated progression of disease in LDLT versus DDLT.15 All 3 studies are limited by the small number of LDLT patients analyzed (around 20).

The present study, therefore, is aimed at assessing posttransplant fibrosis progression with protocol biopsies in a sizable number of consecutive LDLT and DDLT recipients with HCV infection. We found that fibrosis progression is more rapid in DDLT than LDLT, but this is attributable to older donor age in DDLT, rather than the transplant approach.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Population

We retrospectively analyzed data from all 220 patients (48 LDLTs and 172 DDLTs) transplanted at our institution for HCV-related end-stage liver disease between April 2000 (when our LDLT program started) and December 31, 2005. The latter time point was chosen to allow for a ≥1-year posttransplant follow-up in all patients. Patients with transplantation of an additional organ (eg, a kidney; n = 5), with concomitant liver disease etiologies such as hepatitis B virus coinfection (n = 4), with spontaneous or treatment-induced HCV clearance, that is, serum HCV RNA below the detection limit by polymerase chain reaction (<50 IU/mL; Amplicor, Roche, Basel Switzerland), prior to transplant (n = 4), or surviving fewer than 6 months post-transplant (n = 6; 2 LDLTs and 4 DDLTs) were excluded. This left 46 right lobe LDLT and 155 DDLT recipients for analysis. None of these patients suffered from HCV recurrence in the form of fibrosing cholestatic hepatitis.

Immunosuppression

All patients were managed according to our institution's internal guidelines. Accordingly, immunosuppression regimens differed between LDLT and DDLT by the routine use of anti-thymocyte globulin (ATG) induction in the former (Thymoglobulin, Genzyme, Cambridge, MA; 1.5 mg/kg of body weight intravenously and daily for 5 days). In DDLT, ATG (the aforementioned dose schedule) was used only in case of postoperative renal failure (serum creatinine ≥ 200 μmol/L) in order to allow a delayed start of calcineurin inhibitors. Steroids were given preoperatively (methylprednisolone, 500 mg intravenously), with a rapid taper to prednisone (20 mg daily by mouth) after 4 days and a slower further taper over the ensuing 3 to 6 months. At 6 months post-transplant, all patients were on a steroid-free regimen. All LDLT recipients received tacrolimus (Prograf, Astellas Pharma, Inc., Japan) per our institutional protocol. In DDLT, the use of cyclosporin A (Neoral, Novartis, Basel, Switzerland) or tacrolimus was at the discretion of the attending transplant hepatologist and surgeon, who were together responsible for the recipient during the immediate postoperative period (our group consists of 4 transplant hepatologists and 4 surgeons who attend to the inpatient service in a weekly rotation). Calcineurin inhibitors were dosed according to predefined target trough (tacrolimus) and 2-hour postingestion (C2) whole blood levels (cyclosporin A), as previously described.21 Mycophenolate mofetil (CellCept, Roche, Basel, Switzerland; highest tolerated dose, maximum of 1000 mg by mouth twice daily) was used in patients requiring dose reduction (ie, reduction of the target blood level), or discontinuation of the calcineurin inhibitor, for side effects.

Liver biopsy documentation of any suspected acute cellular rejection episode was required before antirejection therapy was initiated in both LDLT and DDLT. In both groups, histologically documented mild acute cellular allograft rejections (rejection activity index ≤ 4) were treated solely by an increase in the dosage of the calcineurin inhibitor in order to maintain a higher target blood level. Moderate and severe acute cellular rejection episodes (rejection activity index > 4) were treated identically in LDLT and DDLT recipients with methylprednisolone (Solumedrol, Pfizer, Inc., New York, NY; 500 mg intravenously daily on 3 consecutive days) followed by a gradual taper to prednisone (10 mg/day), which was then maintained for a prolonged period of time. In the case of histologically documented inadequate response, that is, steroid-resistant rejection (n = 3; 0 LDLTs and 3 DDLTs), ATG (1.5 mg/kg of body weight daily and intravenously) was given for 7 days.

Protocol Biochemical and Histological Monitoring

In all LDLT and DDLT recipients, the complete blood count, serum liver chemistries, renal function (blood urea nitrogen and serum creatinine), and whole blood levels of calcineurin inhibitors were monitored daily during the postoperative in-hospital stay and, after discharge, weekly to biweekly for the first 3 postoperative months. The frequency of monitoring was then reduced to once monthly for the remainder of the follow-up. Additional blood work was scheduled according to clinical needs, if necessary.

All LDLT and DDLT recipients underwent protocol liver biopsies at 3, 6, and 12 months post-LT and yearly thereafter. Additional biopsies were performed if clinically indicated. All liver biopsies were read by 1 of 2 experienced liver pathologists (M.G. and O.A.). The diagnosis of HCV recurrence was based on typical histopathological characteristics with a mononuclear portal infiltrate, with or without lobular necroinflammatory activity and with or without fibrosis. Necroinflammatory activity and fibrosis stage were scored according to Metavir.22

Variables Potentially Associated with HCV Recurrence

In order to further explore factors potentially associated with the progression of graft fibrosis, the following prospectively collected parameters were extracted from our transplant database (Organ Transplant Tracking Record, Kenyon Hicks, Omaha, NE): recipient age, gender, ethnicity, pretransplant Model for End-Stage Liver Disease (MELD) score, donor age, cold ischemia time, blood transfusion requirement, HCV genotype, presence/number of acute cellular rejection episodes, number of corticosteroid bolus doses, type of calcineurin inhibitor used, ATG use, cytomegalovirus disease, and alanine aminotransferase levels at days 1 and 7 and at 1, 2, and 3 months post-transplant. Ontario's universal health program (Ontario Health Insurance Plan) does not cover costs for the determination of HCV viral loads outside of antiviral therapy. Viral loads before and after LT were therefore not available in our patients and could not be entered into our analysis. All patients were followed and data were collected for analysis up to the end of October 2007, retransplantation, or death.

Data Analysis and Statistics

Results of descriptive statistics are reported as mean and standard error or median and range, as appropriate. The Student t test, Fisher's exact test, or 2-way analysis of variance followed by the Bonferroni test for post hoc analysis was used for group comparisons. Rates of patient and graft survival were calculated with the Kaplan-Meier method and compared between groups with the log-rank test. Factors potentially associated with fibrosis progression were analyzed by univariate logistic regression analysis followed by multivariate analysis with a forward selection procedure. Patients who died from complications of or underwent retransplantation for end-stage liver disease related to HCV recurrence were carried forward to subsequent time points as stage 4 fibrosis. Factors with a P value > 0.05 were removed from the multivariate model. Results are given as the relative risk (RR) and 95% confidence interval (CI). A P value ≤ 0.05 was considered significant. All statistics were performed with the SPSS program (version 15.0 for Windows, SPSS, Inc., Chicago, IL).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Demographics and Baseline Characteristics

The demographics and baseline characteristics of the DDLT and LDLT recipients are summarized in Table 1. Both groups had similar age and gender distributions and ethnic backgrounds. Although a history of alcohol misuse and the prevalence of hepatocellular carcinoma tended to be somewhat higher in DDLT recipients than in LDLT recipients, this did not reach statistical significance. The severity of the underlying liver disease at the time of transplantation was also similar between groups, as assessed by the MELD score (determined on admission for LT surgery) and each of its individual variables (international normalized ratio, serum bilirubin, and serum creatinine). Two-thirds of the patients in both groups had HCV genotype 1 infection. The median follow-up from the time of transplant, though numerically somewhat lower, was not statistically different in LDLT (29 months, range = 7–64) versus DDLT (39 months, range = 6–72).

Table 1. Demographics and Baseline Characteristics of Recipients Undergoing Liver Transplantation According to the Approach of Transplantation
 LDLT RecipientsDDLT RecipientsP*
  • Abbreviations: DDLT, deceased donor liver transplantation; HCC, hepatocellular carcinoma; INR, international normalized ratio; LDLT, live donor liver transplantation.

  • *

    Student t test or Fisher's exact test.

  • Median (range).

Number of patients46155 
Age (years)52 (32–68)53 (36–71)0.7
Male (%)71770.9
Caucasian (%)93930.3
Alcohol associated [n (%)]4 (9%)22 (14%)0.6
HCC [n (%)]8 (17%)48 (30%)0.2
Bilirubin (μmol/L)42 (4–229)72 (3–750)0.6
INR1.6 (1.0–3.7)1.7 (0.9–4.6)0.8
Serum creatinine (μmol/L)87 (20–377)101 (25–564)0.3
MELD14 (7–39)17 (6–40)0.3
Genotype [n (%)]  0.9
 123 (50%)87 (56%) 
 29 (19%)26 (16%) 
 311 (23%)33 (21%) 
 Other3 (6%)9 (5%) 
Follow-up (months)29 (7–64)39 (6–72)0.7

Donor and Intraoperative Characteristics

Table 2 summarizes donor and intraoperative data for the LDLT and DDLT groups. Live liver donors were younger by a median of 8 years (median = 38 years, range = 19–59) than deceased liver donors (46 years, 11–79; P = 0.001). Furthermore, 37% of the deceased donors were older than 55 years versus only 4% of the live donors. Although gender and ethnicity were similar, the cold ischemia time was significantly shorter in LDLT than DDLT (median = 89 minutes, range = 29–295 versus 449 minutes, 68–988; P = 0.003). There was no difference between the 2 groups in the number of blood transfusions required. No difference was also observed for the opening levels of the liver enzymes alanine aminotransferase and aspartate aminotransferase in live donor and deceased donor liver recipients.

Table 2. Baseline Donor and Intraoperative Characteristics According to the Approach of Transplantation
 LDLT DonorsDDLT DonorsP*
  • Abbreviations: ALT, alanine aminotransferase; DDLT, deceased donor liver transplantation; GRWR, graft-to-recipient weight ratio; LDLT, live donor liver transplantation; RBC, red blood cells.

  • *

    Student t test or Fisher's exact test

  • Median (range)

  • Not available

Donor age (years)38 (19–59)46 (11–79)<0.001
Donor gender (% male)61560.8
Donor ethnicity (% Caucasian)87810.9
Graft volume (mL)955 (526–1731) 
GRWR (%)1.38 
Cold ischemia time (minutes)89 (29–295)449 (69–988)0.003
Warm ischemic time (minutes)43 (25–68)50 (25–75)0.9
Transfusion requirement (units of RBC)5 (2–26)4 (0–22)0.8
ALT on postoperative day 1 (IU/L)43 (6–791)53 (9–8260)0.7

Immunosuppression

The posttransplant immunosuppression in LDLT and DDLT is summarized in Table 3. Per our protocol, the use of tacrolimus and ATG induction was significantly more frequent in LDLT recipients than in DDLT recipients, and none of our LDLT recipients received cyclosporine. In DDLT patients receiving tacrolimus, trough levels at various time points post-transplant were similar to those of LDLT recipients. Likely because of the more frequent use of ATG induction, the incidence of acute cellular rejection episodes and the need for antirejection therapy with bolus steroids was significantly lower in LDLT recipients compared to DDLT recipients. Steroid-resistant rejection episodes requiring ATG therapy occurred in none of the LDLT patients and in 3 (2%) of the DDLT patients; all resolved with ATG therapy. The incidence of cytomegalovirus disease did not significantly differ in LDLT (61/155, 36%) and DDLT recipients (26/46, 56%; P = not significant).

Table 3. Posttransplant Immunosuppression Characteristics of the Recipients According to the Approach of Transplantation
 LDLT RecipientsDDLT RecipientsP*
  • Abbreviations: ATG, anti–thymocyte globulin; CMV, cytomegalovirus; DDLT, deceased donor liver transplantation; LDLT, live donor liver transplantation; NS, not significant.

  • *

    Student t test or Fisher's exact test

  • Median (range) for whole blood trough level (ng/mL).

  • Requiring intravenous gancyclovir therapy.

Tacrolimus [n (%)]46 (100%)89 (57%)0.0001
 Week 111.5 (3.2–20.8)8.6 (3.0–18.1)NS
 Month 113.1 (7.7–18.2)11. 8 (6.6–16.7)NS
 Month 310.7 (5.5–16.5)10.3 (4.3–19.1)NS
 Month 127.5 (6.1–12.2)8.2 (5.0–10.8)NS
ATG induction [n (%)]43 (93%)32 (21%)0.0001
Acute cellular rejection [n (%)]4 (9%)49 (32%)0.001
Steroid boluses [n (%)]3 (7%)36 (23%)0.05
CMV disease [n (%)]26 (56%)61 (39%)NS

Clinical Outcome

Graft function (serum bilirubin, albumin, and international normalized ratio) during the entire follow-up did not significantly differ after LDLT and DDLT (data not shown).

Overall patient and graft survival is depicted in Fig. 1 and did not significantly differ after LDLT and DDLT. Thus, 1- and 5-year overall graft and patient survival was on average after LDLT 91% and 76% and 93% and 84%, respectively, versus 86% and 74% and 90% and 78%, respectively, after DDLT (all P for LDLT versus DDLT = not significant). However, only 1 of 46 (2%) patients in the LDLT group had died from recurrent hepatitis C at 5 years post-transplant versus 11 of 155 (7%) patients in the DDLT group (P = 0.01).

thumbnail image

Figure 1. Kaplan-Meier cumulative (A) patient and (B) graft survival for (- - -) LDLT and (—) DDLT. There was no significant difference in overall graft or patient survival between the 2 groups (log-rank test). Abbreviations: DDLT, deceased donor liver transplantation; LDLT, live donor liver transplantation.

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Histologic Evolution

All 436 protocol liver biopsies performed (99 from LDLT patients and 337 from DDLT patients) were analyzed for this study. As depicted in Fig. 2A, necroinflammatory activity was higher at all time points in DDLT recipients compared to LDLT recipients. This difference was statistically significant up to 24 months post-transplant, but not at later time points. Fibrosis stage was higher at all time points in DDLT compared to LDLT. This difference remained statistically significant up to 48 months post-transplant (Fig. 2B). Moreover, fibrosis seemed to progress more rapidly over time in DDLT than LDLT, the fibrosis progression rate averaging 0.19 stage/year in DDLT versus 0.11 stage/year in LDLT (P = 0.05).

thumbnail image

Figure 2. Average scores (Metavir) for (A) the necroinflammatory activity and (B) the fibrosis stage on protocol liver biopsies performed at various time intervals after DDLT (dark gray bars) and LDLT (light gray bars). Error bars denote the standard error. The asterisks denote a P value < 0.05 between groups (2-way analysis of variance followed by the Bonferroni test). At all time points, the average necroinflammatory activity and fibrosis stage were higher after DDLT than after LDLT. Abbreviations: DDLT, deceased donor liver transplantation; LDLT, live donor liver transplantation.

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Antiviral Therapy

Sixty-eight recipients (44%) in the DDLT group and 15 (32%) in the LDLT group were treated for >3 months with interferon/pegylated interferon and ribavirin during the follow-up period (P = not significant). The indication for antiviral therapy was identical in both groups, that is, histological evidence of HCV recurrence with fibrosis stage > 1. The rate of sustained virologic response was almost identical in DDLT (31/68, 45%) and LDLT recipients (7/15, 46%; P = not significant).

Factors Associated with Fibrosis Progression

Although portal fibrosis (Metavir stage 1) does not seem to be clinically relevant, the development of portal fibrosis within a relatively short period of time (eg, within a year post-transplant) may be taken as an indicator of accelerated disease progression. Metavir fibrosis stages 3 and 4 clearly indicate the presence of advanced fibrosis or cirrhosis, that is, advanced recurrent disease. For this reason, and because the median follow-up in our patients was around 2 years, we have chosen to use (1) a Metavir stage ≥ 1 at 1 year post-transplant and (2) a Metavir stage of 3 or 4 at 2 years post-transplant as endpoints for further analysis of risk factors associated with disease progression. A potential effect of the following parameters on these endpoints was then analyzed by univariate logistic regression analysis followed by multivariate analysis: LDLT versus DDLT, recipient age (≥60 versus <60 years), gender (male versus female), ethnicity (Caucasian versus non-Caucasian), pretransplant MELD score (≥15 versus <15), donor age (≥45 versus <45 years and as a continuous variable), cold ischemia time (≥100 versus <100 minutes as well as ≥400 versus <400, warm ischemic time of (≥45 versus <45 minutes). HCV genotype (1/4 versus 2/3), acute cellular rejection episodes (presence versus absence), administration of corticosteroid bolus doses (yes versus no), type of calcineurin inhibitor (cyclosporin A versus tacrolimus), use of ATG (yes versus no), and alanine aminotransferase levels (as a continuous variable) at day 7 and at 1, 2, and 3 months post-transplant.

Univariate analysis revealed donor age > 45 years (RR = 2.5, 95% CI = 1.68-3.92, P = 0.02), cold ischemia time > 400 minutes (RR = 1.56, 95% CI = 1.05–6.34, P = 0.01), and DDLT (RR = 1.87, 95% CI = 1.05–10.54, P = 0.04) as being significantly associated with the presence of a Metavir stage ≥ 1 at 1 year post-transplant. All other tested parameters failed to be significantly associated with a Metavir stage ≥ 1 at 1 year post-transplant (all P values > 0.1). With a Metavir stage of 3 or 4 at 2 years post-transplant as the endpoint in the univariate analysis, donor age > 45 years (RR = 6.6, 95% CI = 1.5–10.42, P = 0.001), cold ischemia time > 400 minutes (RR = 3.2, 95% CI = 1.34–7.81, P = 0.003), and DDLT (RR = 4.11, 95% CI = 1.9–8.31, P = 0.002) were again found to be risk factors for disease progression. In addition, the nonuse of tacrolimus (RR = 1.5, 95% CI = 1.02–3.55, P = 0.040) and ATG (RR = 2.1, 95% CI = 1.91–4.96, P = 0.037), but none of the other parameters tested (all P > 0.1), were significantly associated with this outcome. The association of both outcome measures with donor age remained highly significant when donor age was treated as a continuous variable (RR per year = 1.2, 95% CI = 1.12–5.11, P = 0.005, and RR per year = 1.8, 95% CI = 1.05–6.4, P = 0.001, respectively).

All parameters showing a P value of ≤0.05 by univariate analysis were then entered into a multivariate model (Table 4). Only donor age > 45 years remained significantly associated with disease progression whether assessed as a Metavir stage ≥ 1 at 1 year (RR = 1.94, CI = 1.01–3.7, P = 0.046) or as a Metavir stage of 3 or 4 at 2 years post-transplant (RR = 8.17, CI = 2.61–25.5, P = 0.001). This also held true when donor age was treated as a continuous variable (RR per year = 1.1, 95% CI = 1.09–5.41, P = 0.04, and RR per year = 1.74, 95% CI = 1.05–6.74, P = 0.02, respectively). All other parameters, including the type of transplant (DDLT versus LDLT), were not independently associated with the histologic outcomes and therefore were removed from the model.

Table 4. Multivariate Analysis for Factors Associated with Metavir Stages ≥ 1 at 1 Year Post–Transplant and for Factors Associated with Metavir Stages 3 or 4 at 2 Years Post-Transplant
 Relative Risk95% Confidence IntervalP
  1. Abbreviations: ATG, anti-thymocyte globulin; DDLT deceased donor liver transplantation.

Metavir stage ≥ 1 at 1 year   
 Donor age > 451.91.01–3.070.046
 Cold ischemic time > 4001.20.41–4.620.13
 DDLT1.30.31–8.610.10
Metavir stage 3 or 4 at 2 years   
 Donor age > 45 years8.12.61–25.570.001
 Cold ischemic time > 400 minutes1.00.30–3.110.95
 DDLT1.10.71–4.610.21
 Nonuse of ATG1.60.22–8.190.70
 Nonuse of tacrolimus2.10.41–16.710.49

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

This is the largest study reported to date on fibrosis progression of recurrent HCV in LDLT compared to DDLT. All transplants were performed for HCV-related end-stage liver disease within the same time interval in a single institution. All patients were followed with protocol biopsies for an extended period of time. Baseline characteristics of LDLT and DDLT recipients were comparable. Our multivariate analysis shows that the transplant approach chosen is not an independent variable associated with the severity of HCV recurrence post-LT. Instead, donor age was the sole independent predictor of fibrosis progression in our series. Live donors were on average 8 years younger than the deceased donors. This entirely explains the slower fibrosis progression observed in LDLT compared to DDLT.

Differences in donor age may, at least in part, explain the discrepant findings reported by others in the past for fibrosis progression in recurrent hepatitis C after LDLT compared to DDLT.15, 19, 20 A potential effect of donor age on disease progression was not analyzed in any detail in these studies.

Donor age has been previously found to be associated with the progression of HCV recurrence after LT.6–10, 23, 24 Thus, increased rates of fibrosis progression have been reported for recurrent hepatitis C in grafts from deceased donors older than 49,7 55,8 and 60 years.24 In addition, donor age greater than 45 to 50 years has been reported to carry an RR for developing severe fibrosis of around 3.5.10, 25 Our observation that donor age above 45 years carries an 8-fold increased risk for developing advanced fibrosis/cirrhosis (Metavir stage 3 or 4) by 2 years post-transplant is consistent with these previous reports.

The observation that increasing donor age accelerates disease progression in recurrent hepatitis C after LT also fits well with findings in nontransplant cohorts demonstrating that the natural history of hepatitis C is accelerated with older age at infection7, 25, 26 Collectively, these observations seem to suggest that HCV infection is more aggressive in older livers, regardless of whether they are native livers of older nontransplanted subjects or liver grafts from older donors. Although the mechanisms underlying this observation remain entirely speculative to date, they warrant further investigation.

Overall patient and graft survival was similar in LDLT and DDLT. However, posttransplant mortality from complications related to recurrent hepatitis C was more than 3-fold higher in DDLT (11/155, 7%) than in LDLT (1/46, 2%). Despite the small number of events, this difference was highly statistically significant (P = 0.01). The observed difference in liver-related mortality is entirely compatible with donor age affecting not only histologic disease progression, that is, a surrogate marker for outcome, but also the survival outcome itself. This raises the question of whether (and with which age cutoff) it remains justified to use older donors when HCV-positive recipients are transplanted. In contrast to DDLT, LDLT allows one to control for donor characteristics such as age, at least to some extent. Our data would therefore seem to argue that LDLT may have significant advantages over DDLT in HCV-related end-stage liver disease. The selection of live donors for LDLT for any indication in our institution is based on a rigorous evaluation process that includes a detailed health history questionnaire, blood work, imaging studies, and medical and psychiatric assessment. The overall mean age of live donors in our program is 38 years (Adcock, 2008). Recipients with HCV-related end-stage liver disease may particularly benefit from such a selection of young donors, that is, LDLT.

Although a history of acute cellular rejection showed in univariate analysis a trend of being associated with a Metavir fibrosis stage ≥ 1 at 1 year post-transplant, it was not an independent predictor, as shown by multivariate testing. No significant association was found between acute cellular rejection and advanced fibrosis/cirrhosis (Metavir stage 3 or 4) at 2 years post-transplant. Moreover, the use of bolus steroids was not significantly associated with either of the 2 histologic outcomes in both univariate and multivariate logistic regression analyses. This is at variance with a number of previous studies reporting an association of bolus steroid use (or its surrogate, acute cellular rejection) and a more aggressive course of recurrent hepatitis C after LT.11, 27–29 As detailed in the Patients and Methods section, ATG induction was routinely used after LDLT in our series, and the incidence of acute cellular rejection was very low, with rejection occurring in only 3 LDLT recipients (<10%). The event rate of acute cellular rejection (and consequently of bolus steroid use) may therefore have simply been too low to allow detection as an independent predictor of disease progression. This observation is also compatible with the recent study from Horton et al.30 reporting a lower incidence of acute cellular rejection in a cohort of 76 HCV patients receiving ATG as induction therapy following a cadaveric LT. ATG induction did not increase the risk of HCV-related graft loss or patient death in the latter study. These observations together encourage the use of ATG induction therapy in HCV-positive recipients.

In a recent multivariate analysis by Cameron et al.,31 a MELD score > 27 increased the RR of HCV recurrence post-LT.31 In our series, the mean MELD score of LDLT and DDLT recipients at the time of transplant was only 14 and 17, respectively, and only a few patients had a MELD score > 27. A high MELD score at the time of transplantation may therefore have escaped detection as a predictor of disease progression in our series.

Ontario's universal health program (Ontario Health Insurance Plan) does not cover costs for the determination of HCV viral loads outside of antiviral therapy. Viral loads pre-LT and post-LT were therefore not available in our patients and could not be entered into our analysis. Thus, our data do not allow us to comment on the potential association of pretransplant and/or posttransplant HCV viral loads and progression of recurrent hepatitis C after LT, which has previously been reported by others.32–34

The proportions of patients receiving antiviral therapy were similar in DDLT and LDLT recipients, and the rates of sustained virological response were virtually identical in the two groups. Analyzing DDLT and LDLT recipients separately according to their therapy response is beyond the scope of this article but would unlikely affect the overall results, given the highly similar proportions of patients treated/clearing virus.

Finally, our analysis failed to detect a specific calcineurin inhibitor and/or the use of ATG induction therapy as independent variables for the progression of recurrent HCV after LT. During the study period, all our live donor recipients were on a tacrolimus-based protocol versus only 57% of DDLT recipients. Furthermore, 93% of LDLT recipients underwent induction therapy with ATG versus only 21% of the DDLT recipients. This strong association by design of tacrolimus and ATG use with LDLT may have obscured the detection of their use as an independent risk factor for disease progression.

In conclusion, our large single-center study shows that donor age, rather than the transplant approach, independently affects the progression rate of recurrent hepatitis C after LT. LDLT, allowing for the selection of donors younger than 45 years, may therefore particularly benefit recipients with HCV-related end-stage liver disease.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
    United Network for Organ Sharing. Available at: http://www.unos.org. Accessed May 2008.
  • 2
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  • 3
    Berenguer M, Ferrell L, Watson J, Prieto M, Kim M, Rayon M, et al. HCV-related fibrosis progression following liver transplantation: increase in recent years. J Hepatol 2000; 32: 673684.
  • 4
    Berenguer M. What determines the natural history of recurrent hepatitis C after liver transplantation? J Hepatol 2005; 42: 448456.
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    Forman LM, Lewis JD, Berlin JA, Feldman HI, Lucey MR. The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 2002; 122: 889896.
  • 6
    Berenguer M, Prieto M, San Juan F, Rayon JM, Martinez F, Carrasco D, et al. Contribution of donor age to the recent decrease in patient survival among HCV-infected liver transplant recipients. Hepatology 2002; 36: 202210.
  • 7
    Wali M, Harrison RF, Gow PJ, Mutimer D. Advancing donor liver age and rapid fibrosis progression following transplantation for hepatitis C. Gut 2002; 51: 248252.
  • 8
    Firpi RJ, Abdelmalek MF, Soldevila-Pico C, Cabrera R, Shuster JJ, Theriaque D, et al. One-year protocol liver biopsy can stratify fibrosis progression in liver transplant recipients with recurrent hepatitis C infection. Liver Transpl 2004; 10: 12401247.
  • 9
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