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Abstract

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

Studies have suggested that the use of hepatitis C virus (HCV)-positive (HCV+) donor allografts has no impact on survival. However, no studies have examined the effect that HCV+ donor histology has upon recipient and graft survival. We evaluated the clinical outcome and impact of histological features in HCV patients transplanted using HCV+ livers. We reviewed all patients transplanted for HCV at our institution from 1988 to 2004; 39 received HCV+ allografts and 580 received HCV-negative (HCV−) allografts. Survival curves compared graft and patient survival. Each HCV+ allograft was stringently matched to a control of HCV− graft recipients. No significant difference in survival was noted between recipients of HCV+ livers and controls. Patients receiving HCV+ allografts from older donors (age ≥50 yr) had higher rates of graft failure (hazard ratio, 2.74) and death rates (hazard ratio, 2.63) compared to HCV− allograft recipients receiving similarly-aged older donor livers. Matched case-control analysis revealed that recipients of HCV+ allografts had more severe fibrosis post-liver transplantation than recipients of HCV− livers (P = 0.008). More advanced fibrosis was observed in HCV+ grafts from older donors compared to HCV+ grafts from younger donors (P = 0.012). In conclusion, recipients of HCV+ grafts from older donors have higher rates of death and graft failure, and develop more extensive fibrosis than HCV− graft recipients from older donors. Recipients of HCV+ grafts, regardless of donor age, develop more advanced liver fibrosis than recipients of HCV− grafts. Liver Transpl 12:1496-1503, 2006. © 2006 AASLD.

Hepatitis C virus (HCV) is the most common cause of cirrhosis and thus, the most common indication for liver transplantation. Currently, there are 3.9 million people infected with HCV in the United States and 20% of the infected will likely develop cirrhosis requiring liver transplantation.1, 2 With only 5,000 livers donated annually over the last 10 yr, and over 17,000 patients currently on the United Network for Organ Sharing waiting list, it is clear that the demand for livers heavily outpaces the number of deceased organs available.3 Innovative ways of expanding the donor pool are the use of split and live donor liver transplantation as well as the use of liver allografts containing appreciable steatosis or with past exposure to hepatitis B.4–6 The use of HCV-positive (HCV+) allografts/grafts in HCV patients is another such strategy and has now become routine at most transplant centers.

Recent studies have suggested that the use of HCV infected grafts does not appear to impact clinical outcome or survival.7–13 Saab et al.14 recently reported no difference in patient survival, graft survival, or time to HCV recurrence in 59 recipients of HCV+ grafts compared to matched recipients of HCV-negative (HCV−) grafts. The authors did not comment on whether the donor age or allograft features impacted survival. This study confirmed an analysis by Vargas et al.15 that the clinical course of patients receiving a HCV+ graft does not differ significantly from those receiving HCV− grafts in the short term. None of these studies, however, have evaluated the impact of donor age or histological characteristics of the donor on recipient or graft survival. Historically, it has been shown that HCV+ patients have a lower 3- and 5-yr survival post-liver transplantation when compared to other indications for liver transplantation. More recently, donor age ≥50 yr has specifically been found to have a negative impact on both patient and graft survival as well as accelerating fibrosis progression and the progression to cirrhosis.16–18 There have been no studies to date examining the impact of donor age on liver transplantation using HCV+ donor livers.

In addition to donor age, the importance of histological characteristics of HCV+ donor organs has not yet been studied. While the use of histologically advanced fibrosis precludes the use of a potential graft, the impact of early to intermediate fibrosis is unknown. It has been shown that the rate of progression of fibrosis in chronic HCV in the general population is not linear and in fact the more advanced the fibrosis, the more quickly patients will progress to cirrhosis.19 Recent data regarding recurrence of HCV after liver transplantation when using an HCV− graft has demonstrated that early progression of fibrosis (from F0 to F1) takes longer than progression to late disease (from F1 to F3 or F4); and that a major risk factor for graft failure is having any baseline fibrosis.20 No study to date has evaluated the impact of baseline fibrosis of HCV-infected donor grafts on the histologic progression of fibrosis post-liver transplantation. We sought to assess the rate of fibrosis progression, and the effect of donor age and impact on patient and graft survival in HCV patients receiving HCV+ liver allografts.

MATERIALS AND METHODS

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

Using The Mount Sinai Liver Transplant database, patients transplanted for HCV from 1988 to 2003 were identified. Of 619 patients, 39 (6%) underwent liver transplantation using HCV+ donor organ and 580 (94%) were transplanted with were HCV− donor organs. For each HCV+ case, we retrieved information on baseline patient characteristics and liver transplantation data, including donor and recipient age and gender, date of transplant, United Network for Organ Sharing or Model for End-Stage Liver Disease scores, and warm and cold ischemia times. We did not have access to HCV genotype information for these individuals. To assess the patients' clinical course we reviewed patient charts for type of immunosuppression, episodes of cellular rejection, treatment of rejection, time to histological evidence of HCV recurrence, treatment of HCV posttransplantation, and evidence of clinical hepatic decompensation, i.e., ascites, jaundice, encephalopathy, or variceal bleeding. Finally, we recorded information on graft and patient survival, calculating time to either retransplantation and/or death.

Cohort Analysis

We first performed an initial cohort analysis to compare survival outcomes of HCV− donor transplants and HCV+ donor transplants. Our cohort group consisted of the 580 patients who received HCV− donor organs while our cases consisted of the 39 patients transplanted using HCV+ donor livers. Using Kaplan-Meier survival curves, we compared the cohort and index cases via 2 main endpoints: graft survival and patient survival. In addition, we assessed the effect of potential confounding variables on outcomes of liver transplantation for HCV by using proportional hazards regression analysis. The independent effect of the following variables were tested using a stepwise regression: donor HCV status, recipient age and gender, donor age and gender, warm and cold ischemia times.

Matched Analysis

Subsequently, we conducted a matched analysis in order to assess histologic fibrosis progression. Each of the 39 cases, i.e., recipients of HCV+ donor livers, was matched to 1 corresponding recipient of a HCV− donor liver, as a control. Through randomized, blinded fashion we matched each case with its corresponding control based on specific characteristics that previous studies have demonstrated to most likely influence clinical outcomes.18, 21 In order of importance, these variables included donor age (within 10 yr), year of transplantation (within 4 yr), United Network for Organ Sharing/Model for End-Stage Liver Disease score, and recipient age (within 20 yr). Donor age has shown to impact survival after liver transplantation in HCV and thus was chosen as a matching variable. The year of transplant was used to account for differences in treatment and liver biopsy practices between cases and their respective controls. We utilized the United Network for Organ Sharing/Model for End-Stage Liver Disease score to account for any clinical differences in severity of disease at the time of liver transplantation. All 39 recipients of HCV+ donor livers had acceptable matched controls based on the above criteria. Controls were used for more than 1 case if needed, given our limited number of controls available. A total of 3 controls were used as a match for more than 1 case. Finally, in order to adequately assess fibrosis progression, we required that each matched pair had equivalent length of survival post-liver transplantation. Of the 39 cases, 10 were excluded from the matched analysis of fibrosis progression due to a variety of factors. One patient was eliminated since he experienced primary graft nonfunction and underwent immediate retransplantation. One patient was excluded since he died shortly after liver transplantation due to hepatocellular carcinoma. Finally, the other 8 patients did not have adequate follow-up biopsy data after liver transplantation and were excluded from the analysis. The aim of our analysis was to determine if there was more significant fibrosis in recipients of HCV+ donor livers as compared to controls by calculating the difference in maximum fibrosis between each case and control over an equivalent length of time. The histologic variables of fibrosis, steatosis, and inflammation were tested 1 factor at a time.

Histopathology

For each matched case and control, all biopsy slides from time of liver transplantation to the present were identified and examined. Biopsies were routinely performed pre- and postperfusion in all cases and controls; subsequent biopsies were performed when clinically indicated; protocol biopsies are not performed at our institution. At our institution, only livers with preperfusion biopsy results revealing a fibrosis grade of 2 or less were utilized for transplantation. Biopsy slides were randomly pulled and an experienced liver pathologist reviewed all slides in a blinded fashion. Initial biopsies at time of transplantation, preperfusion, and postperfusion, as well as all subsequent biopsies until the present were evaluated. Scoring was performed according to the Knodell modified Histologic Activity Index.22 Each biopsy was given an Histologic Activity Index inflammatory grade (scale of 0-18), a fibrosis stage (scale of 0-6), and a total score (combining the previous 2 scores). In addition, a steatosis score was recorded as either none (0%), mild (1-30%), medium (31-60%), or severe (61-100%) based on the percentage of steatosis noted on biopsy. A total of 320 biopsies were reviewed, 162 among the cases and 158 among the controls. Within both the cases and controls, a median of 5 biopsies per patient were reviewed.

Statistical Analysis

The primary endpoints used in our statistical cohort analysis were patient survival and graft survival. Graft survival was recorded as number of days from liver transplantation to retransplantation, death, or to the present. Patient survival was recorded as length of time (in days) from liver transplantation until death or to the present, and age was treated as a categorical variable. The index cases were compared to our control cohort using Kaplan-Meier survival curves and proportional hazards regression analyses. Statistical analysis of fibrosis progression in the matched case-control design initially consisted of finding the difference in the maximum fibrosis between each case and its corresponding control for the equivalent length of survival. The median of this difference for all the pairs was determined and tested to see if it was significantly different from zero using the Wilcoxon Signed Rank test. For example, if case A had a maximum fibrosis of stage 2 post-liver transplantation and control A had a maximum fibrosis of stage 0, then the difference between them is 2 stages. The effect of donor age and recipient age on this fibrosis difference was tested separately using the Mann Whitney Exact test. Fibrosis progression rate of the 29 HCV+ allografts was compared between the groupings of donor age, recipient age, gender mismatch, and the initial biopsy characteristics of fibrosis, steatosis, and inflammation. The comparisons were made for 1 factor at a time using the Mann-Whitney Exact test. Donor/recipient age was grouped into 2 categories: ≥50 yr vs. <50 yr, preperfusion fibrosis was also grouped into 2 categories: 0 vs. >0, as were preperfusion steatosis: 0 vs. >0, and preperfusion Histologic Activity Index: ≤3 vs. > 3. A P-value of <0.05 in a 2-tailed test was considered statistically significant.

RESULTS

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

Comparing the 2, HCV+ and HCV−, groups in an unmatched, cohort design, we were able to assess overall survival outcomes, and through matched case-control analysis we determined the histological fibrosis progression. We reviewed baseline characteristics of both groups, and in comparing the cohort of 580 patients to the 39 cases (see Table 1), we found no statistically significant differences. As noted in Table 1, donor and recipient characteristics of age and gender were similar between the 2 groups. Both groups also had comparable severity of their liver disease prior to transplantation with no significant differences in United Network for Organ Sharing/Model for End-Stage Liver Disease scores. Additionally, there appeared to be equivalent warm and cold ischemia times during liver transplantation.

Table 1. Baseline Characteristics of Cohort and Index Groups
 HCV (−) Donor (n = 580)HCV (+) Donor (n = 39)P Values
  1. Abbreviations: NS, not significant; UNOS, United Network for Organ Sharing; MELD, Model for End-Stage Liver Disease.

  2. *Results are median values, with associated ranges in brackets.

Donor age46.0 [17-87]43.0 [17-66]NS
Recipient age52.0 [18-76]52.0 [32-68]NS
Donor gender (% male)334/580 (57.6%)27/39 (69.2%)NS
Recipient gender (% male)428/580 (73.8%)27/39 (69.2%)NS
UNOS status2.2 [1-4] (n = 33)2.2 [1-3] (n = 33)NS
MELD score29.0 [7-49] (n = 6)29.0 [27-29] (n = 6)NS
Warm ischemia time (hours)0.75 [0.2-12.7]0.78 [0.4-2.4]NS
Cold ischemia time (hours)9.3 [0.1-22.3]9.2 [4.4-11.2]NS

Clinical Outcomes

In comparing overall survival between the recipients of HCV− donor livers and recipients of HCV+ donor livers, no significant difference in overall patient or graft survival was found. Median length of follow-up for those individuals who had graft failure was 15.2 months and for those who did not have graft failure it was 54.1 months. Median length of follow up for those who died was 19.8 months and for those who remained alive it was 55.7 months. Figures 1 and 2 depict the comparable Kaplan-Meier survival curves of these 2 groups. The 10-yr graft survival in the HCV− and HCV+ donor liver groups was equivalent at (36%). While the 10-yr patient survival in the cohort receiving HCV+ donor livers was 47% vs. 39% in the cohort receiving HCV− donor livers, the Kaplan Meier curves for patient survival showed no difference overall.

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Figure 1. Overall graft survival in recipients of HCV+ and HCV− donor grafts. Kaplan-Meier curves depict the comparable survival curves between recipients of HCV− donor grafts and recipients of HCV+ donor grafts. No statistically significant difference was found in overall graft survival between the 2 groups.

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Figure 2. Overall patient survival in recipients of HCV+ and HCV− donor grafts. Kaplan-Meier curves depict the comparable survival curves between recipients of HCV− donor grafts and recipients of HCV+ donor grafts. No statistically significant difference was found in overall patient survival between the 2 groups.

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When analyzing the recipients of HCV− donor livers, we demonstrated that the group that received grafts from older donors (age ≥ 50 yr) had more frequent graft failure and patient deaths than the group that received grafts from younger HCV− donors, with a hazard ratio of 1.52 (95% CI, 1.2-1.92) for graft survival and 1.49 (95% CI, 1.16-1.92) for patient survival. Previous studies have also demonstrated these poor outcomes in recipients of HCV− transplants from older donors. Our results found this to be the case in the HCV+ donor cohort as well, in which recipients of HCV+ allografts from older donors (age ≥50 yr) had statistically significant worse graft and patient survival than recipients of HCV+ donor allografts from younger donors (hazard ratios [95% CIs], 5.93 [2.33-15.1] and 5.61 [2.08-15.1], respectively), to an even greater extent than recipients of HCV− donor grafts. For grafts from younger donors, graft survival of HCV+ and HCV− donor allografts was similar (hazard ratio, 0.70; 95% CI, 0.37-1.33) as was the survival of recipients of HCV+ and HCV− donor allografts (hazard ratio, 0.70; 95% CI, 0.36-1.38). However, in grafts from older donors there was a markedly decreased graft survival of HCV+ donor allografts, as compared to survival of HCV− donor allografts, with a hazard ratio of 2.74 (95% CI, 1.34-5.61). A similar effect was noted for the same comparison in patient survival among recipients of grafts from older donors, with a hazard ratio of 2.63 (95% CI, 1.23-5.64). As seen in Figures 3 and 4, patients who were transplanted with older HCV+ donor livers had worse outcomes compared to those patients transplanted with younger HCV+ donor livers, as well as those transplanted with livers from both younger and older HCV− donors. Recipient age and gender, donor gender, and warm and cold ischemia times were not found to be associated with either graft survival or death.

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Figure 3. Graft survival and donor age in patients receiving HCV+ and HCV− donor allografts. Kaplan-Meier curve revealing poorer graft survival in patients transplanted with older HCV+ donor allografts, compared to recipients of younger donor HCV+ allografts, as well as recipients of comparably-aged HCV− allografts.

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Figure 4. Patient survival and donor age in patients receiving HCV+ and HCV− donor allografts. Kaplan-Meier curve revealing poorer patient survival in patients transplanted with older HCV+ donor allografts, compared to recipients of younger donor HCV+ allografts, as well as recipients of comparably-aged HCV− allografts.

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The data was also divided into time periods, to account for any variations during different time intervals. There were a total of 104 transplants between 1988 and 1993, 323 during 1994-1999, and 192 during 2000-2003. In the first time period, there were 6 recipients of HCV+ donor livers (none of which were from donors aged ≥50 yr). In the second time period, there were 27 recipients of HCV+ donor livers (7 from donors aged ≥50 yr). Finally, in the third time interval, there were 6 recipients of HCV+ donor livers (2 from donor age ≥50 yr). There was no statistically significant difference when all the HCV+ donor livers were stratified by transplant interval.

Fibrosis Progression

In order to assess histological fibrosis progression, we utilized a matched case-control design. Of the 39 recipients of HCV+ donor livers, we needed to exclude 10 (25.6%) patients, leaving a total of 29 cases that were matched to 1 control from the HCV− donor cohort. Our median length of follow up for recipients of HCV+ donor livers was 58.4 months, with a range from 6.8 to 143.7 months.

Table 2 outlines the clinical characteristics of both the cases and controls with respect to HCV treatment, rejection episodes, need for retransplantation, clinical graft dysfunction, and immunosuppression. In both groups, the median number of biopsies post-liver transplantation analyzed was similar, at 5 biopsies per patient. Clinically, both groups had equal evidence of graft dysfunction at approximately 5 yr, with greater than 50% clinical decompensation over that time period. Although there were episodes of rejection seen in both cohorts, fewer patients had rejection episodes in the cases than the controls, 55% vs. 74%. However, rejection rates between cases and controls did not appear to be statistically different in our analysis (P < 0.48) and the total number of rejections between the cases and controls was not significantly different (P < 0.096). The most interesting finding was that none of the controls were retransplanted, while retransplantation was required in 5 of 29 (17%) cases.

Table 2. Clinical Characteristics of Matched Analysis Between Index Cases and Controls
 HCV (+) Cases (total # 29)HCV (−) Controls (total # 27)
  • Abbreviations: PEG, pegylated interferon; RIBA, ribavarin; INF, standard interferon.

  • *

    4 patients with missing data

  • 1 patient with missing data.

Median no. of biopsies per patient55
Re-OLT5/29 (17%)0 (0%)
No. of patients with rejection episodes16/29 (55%)20/27 (74%)
[Total no. of rejections in each group][21][36]
Clinical graft dysfunction13/25 (52%)*15/23 (65%)*
HCV Treatment
 Yes12/25 (48%)*9/26 (35%)
 No12/25 (48%)14/26 (54%)
 No recurrence1/25 (4%)3/26 (12%)
HCV Therapy
 PEG+RIBA4/12 (33%)4/9 (44%)
 PEG3/12 (25%)1/9 (11%)
 INF+RIBA3/12 (25%)0/9 (0%)
 INF2/12 (17%)0/9 (0%)
 2 Therapies0/12 (0%)4/9 (44%)
Immunosuppression
 Tacrolimus1916
 Cyclosporine1113
 Azathioprine85
 Mycophenolate96
 Prednisone2926
 Rapamycin02
 OKT323

Differences between the maximum fibrosis in each case and control were determined over an equivalent length of time, and the median of that difference was then compared. The overall rate of fibrosis progression rate in the HCV+ cases was 0.0035 stage/day (or 1.278 stage/yr). There was a statistically significant difference in fibrosis in the HCV+ cases and HCV− controls, with an overall median of difference in maximum fibrosis of 1 stage (P = 0.02), with a range between the 2 groups of −4 to 6. Figure 5 depicts the values for difference in maximum fibrosis between the case and control for each individual pair. In Figure 5 (left side) the controls have more fibrosis than cases, while the Figure 5 (right side) the index cases have more fibrosis than controls. Pairs with equal fibrosis have a zero difference. As seen in Figure 5, patients receiving HCV+ allografts had increased fibrosis over the same period of time as compared to their matched HCV− controls. When comparisons were made between the 2 donor age groupings, the median of difference in maximum fibrosis for cases with older donors was 2.5, compared to 0 in cases who received younger (age < 50 yr) donors (P = 0.021). There was no difference in maximum fibrosis difference between recipients of younger and older donor livers (P = not significant).

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Figure 5. Difference in maximum fibrosis between HCV+ and HCV− allograft recipients. Demonstrates the difference in maximum fibrosis between each matched pair (case-control). Bars to the right of center reveal more fibrosis in the index case, while bars to the left of center reveal more fibrosis in the control. As shown, in the majority of the pairs there was more advanced fibrosis in the case rather than its corresponding control.

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Fibrosis progression rate of the 29 HCV+ allografts was compared between the groupings of donor age, recipient age, gender mismatch, and the initial biopsy characteristics of fibrosis, steatosis, and inflammation (see Table 3). The amount of fibrosis on initial preperfusion liver biopsies was shown to have no effect on overall fibrosis progression. A fibrosis score of 0 had a median fibrosis rate of 0.005 stage/day as compared to 0.003 stage/day for a fibrosis score of >0 (P = 0.08). Similarly, a Histologic Activity Index grade <3 had a median of difference of 0.004, while a Histologic Activity Index grade >3 had a value of 0.002 stage/day (P = 0.05). Finally, an initial steatosis score of 0 demonstrated a median fibrosis rate of 0.004 stage/day as compared to 0.003 for a steatosis score of >0 (P = 0.56). Allografts from older donors had a more severe progression rate compared to those from younger donors (P = 0.02). We also evaluated the influence of the above factors on graft survival. Kaplan-Meier survival curves for recipients of HCV+ donor livers in the matched pairs revealed no association with allograft fibrosis, inflammation, or steatosis. When analyzed for influence of donor age, recipients of HCV+ grafts from older donors again had a statistically significant decrease in survival (P = 0.003). Complete information regarding genotype was not available and therefore could not be used for analysis.

Table 3. Comparison of Histological Fibrosis Progression Within Groupings of Histological Findings Noted in the Allograft and Clinical Factors
VariableFibrosis Rate: Median [Min, Max]Mann-Whitney Exact Test
  1. NOTE: Pre-Perfusion Biopsy = alograft.

Pre-Perfusion Fibrosis
 0 (n = 12).005 [0.002, 0.025]P = 0.08
 >0 (n = 17).003 [0, 0.02] 
Pre-Perfusion HAI
 ≤3 (n = 17).0042 [0.001, 0.025]P = 0.05
 >3 (n = 12).0026 [0, 0.017] 
Pre-Perfusion Steatosis
 0 (n = 17).0042 [0, 0.02]P = NS
 >0 (n = 12).0026 [0, 0.025] 
Donor Age
 <50 (n = 23).0028 [0, 0.022]P = 0.02
 ≥50 (n = 6).011 [0.003, 0.025] 
Recipient Age
 <50 (n = 11).0042 [0.001, 0.025]P = NS
 ≥50 (n = 18).0027 [0, 0.022]
Gender Mismatch
 No (n = 19).0042 [0, 0.025]P = NS
 Yes (n = 10).0031 [0, 0.017] 

DISCUSSION

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

The increasing organ donor shortage has necessitated the use of both older donor and HCV+ allografts. There have only been a small number of studies examining the use of HCV+ donor allografts and they have suggested equivalent patient and graft survival. Information from prior studies of grafts from HCV− donors has shown that HCV recurrence is almost universal when patients are transplanted for HCV and that certain characteristics such as donor age portend worse clinical outcomes.17, 23, 24 No study has evaluated the impact of specific clinical characteristics of the donor allograft on survival outcomes in recipients of HCV+ donor transplants, nor has a study previously evaluated fibrosis progression post-liver transplantation in this group of patients.

The current study demonstrates similar results to those of previous investigators in that overall patient and graft survival do not appear to be adversely affected with the use of HCV+ donor grafts. When adjusting for donor age in these patients, it was strongly evident that older donor age ≥50 yr had a severely reduced patient and graft survival. Moreover, within 5 yr, all grafts in the recipients of HCV+ grafts from older donors had failed. This was markedly worse than the outcomes noted in recipients of HCV+ grafts from younger donors. More significantly, mortality in recipients of HCV+ grafts from older donors was also much higher than in patients receiving grafts from older HCV− donors. Previous data in HCV− transplantation has demonstrated that patients receiving grafts from older donors have worse patient and graft survival after liver transplantation; however, this is the first data suggesting that HCV+ patients who receive older-donor grafts have even a worse outcome.

We used a matched study design to evaluate the impact of histological fibrosis progression in patients receiving HCV+ donor livers, as to remove confounding variables from influencing our data. Through reviewing serial biopsies of 29 pairs of patients having equal lengths of survival, we demonstrated that recipients of HCV+ donor livers had statistically more significant fibrosis over the same length of follow-up. Thus, their rate of fibrosis progression was higher than patients transplanted with HCV− livers. Interestingly, the worse histological outcome present in recipients of HCV+ donor grafts occurred despite the presence of fewer episodes of rejection in this group as compared to controls. The HCV+ cohort appeared to fare worse not only histologically, but also clinically; 17% of this group required retransplantation, while none of the HCV− group underwent retransplantation. Additionally, recipients of HCV+ grafts from older donors had an even higher retransplantation.

Previous studies have demonstrated equivalent incidence of recurrence in recipients of HCV+ donor grafts,7–12 and, most recently, equivalent time to biopsy-proven HCV recurrence.14 Our results suggest that patients receiving HCV+ donor organs develop more fibrosis over time than those receiving HCV− grafts. When making comparisons between the 2 donor age groups, we again found that patients developed more severe fibrosis if they received an older donor liver. Our study confirms prior results that overall clinical outcomes are similar in patients who receive HCV+ and HCV− donor livers. We do, however, demonstrate the negative impact of older donor age on survival and fibrosis progression in patients transplanted with HCV+ donor organs. It does not appear that preperfusion histology impacts on rate of fibrosis progression or survival.

One main limitation to our study was the lack of serial protocol biopsies in assessing histological progression. We included the year of transplantation as a key matching variable in order compensate for this shortcoming as well as stringently matching each index case with a control, in order to account for differences in liver biopsy practices and treatment regimens. We presumed that patients who were transplanted in the same period of time would have similar indications for biopsies to be performed. In our institution liver biopsies were performed pre- and postperfusion and then, when clinically indicated, posttransplantation. Second, we also made certain that each case and its respective control had follow-up over the same length of time, with a similar number if biopsies during that period of time. The only other matched case control study with HCV+ donors (Saab et al.13) did not perform protocol biopsies and gave no information regarding fibrosis scores, yet made a statement regarding HCV recurrence in this population. Given the lack of information available regarding HCV+ donors and transplantation, we aimed to provide as much insight as possible into histologic progression in this group, despite being limited by the lack of protocol biopsies. Another limiting factor was the limited number of matched pairs available for histological analysis. However, it is unlikely for a single liver transplantation center to have a much larger number of HCV+ donors, so a multicenter study would be necessary.

Despite these limitations, we clearly have demonstrated the negative impact of older donor age (≥50 yr) on survival and fibrosis progression when utilizing HCV+ donor liver allografts. Because of the critical shortage of donor livers and the burgeoning liver transplantation waiting list, the use of HCV+ liver allografts must remain a viable option for transplantation in HCV. However, the current study demonstrates that the use of older donor liver allografts from HCV+ individuals should be avoided. It does not appear that mild degrees of fibrosis, inflammation, or steatosis in HCV+ donor livers impacts rate of fibrosis progression. In conclusion, recipients of HCV+ liver allografts from donors aged ≥50 yr have even a higher rate of death and graft failure than recipients of HCV− grafts from older donors, probably related to more accelerated fibrosis progression. We suggest not utilizing HCV+ allografts from older donors. Although this recommendation may significantly restrict the number of usable HCV+ donor organs, the outcome of recipients of such allografts is so poor that we cannot advocate their use.

REFERENCES

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