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Patient and graft survival in hepatitis C recipients after adult living donor liver transplantation in the United States
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Mark W. Russo *, Joseph Galanko, Kimberly Beavers, Michael W. Fried, Roshan ShresthaDepartment of Medicine, University of North Carolina, Chapel Hill, NC
Liver Transplantation
Volume 10, Issue 3, March 2004
See Editorial following this article.
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.
ARTICLE EXCERPTS
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. 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. 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.
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.
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.
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. 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. 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. 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. The activity of the internal ribosomal entry site is greatest in actively growing cells, especially during mitotic phases. 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. 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. 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. 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.
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. 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., 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.
EDITORIAL
Living donor liver transplantation and hepatitis C
Lisa M. Forman 1, James F. Trotter 1 *, Jean Emond 21Division of Gastroenterology/Hepatology, University of Colorado Health Sciences Center, Denver, CO 2Department of Surgery, New York Presbyterian Hospital, Columbia University, New York, NY
Outcomes for living donor liver transplantation (LDLT) recipients infected with hepatitis C (HCV) are some of the most important and controversial issues in liver transplantation: important because HCV is the most common indication for liver transplantation, and controversial because the current data is insufficient to determine whether LDLT recipients have the same outcome or a worse outcome than deceased-donor (DD) transplant recipients. Some reports have indicated that LDLT recipients have earlier and more severe recurrence of HCV following transplantation; other data have failed to show a difference. The important study by Russo et al. in this issue of Liver Transplantation helps provide another piece of the picture. These investigators reviewed the data in the Scientific Registry of Transplantation Recipients to compare the patient and graft survival in LDLT versus DD patients infected with HCV. Their findings are particularly important because the data set is the largest reported to date for posttransplantation outcomes for HCV-infected LDLT recipients; the data set includes most or all LDLT cases performed in the United States since 1999. Furthermore, the investigators have performed a careful analysis that provides important insights into the topic. In their paper, Russo et al. demonstrate that HCV patients who have undergone transplantation with a live donor have similar patient and graft survival rates compared to HCV patients receiving a DD graft. For patients and physicians, this information could provide assurance that LDLT is as efficacious as transplantation with a DD.
However, these data should be interpreted with caution because of the important clinical distinction between LDLT and DD recipients. At the time of transplantation, LDLT recipients are far less sick than their DD counterparts. LDLT recipients are younger, thinner, less likely to be hospitalized in the intensive care unit, and they have a lower Model for End-Stage Liver Disease (MELD) score. These factors are important to consider regarding posttransplantation outcomes for two reasons. First, the sicker the patient at the time of transplantation, the worse the posttransplantation outcome. That is, without assessing the illness severity at the time of transplantation, direct comparisons of posttransplantation outcomes between LDLT and DD recipients are problematic. Although patient and graft survival for LDLT and DD patients may be similar, the relative outcome for LDLT recipients is actually worse because they are significantly less sick at transplantation than DD patients. This was demonstrated in a recent presentation by Shaked, who reported that the relative risk of patient and graft survival for LDLT recipients was 88% and 123% higher, respectively, compared to DD recipients (P .001). These data take into the account the severity of illness at the time of transplantation. In fact, a closer look at Russo's data supports the same conclusion. Although univariate analysis suggests that LDLT and DD have similar survival rates, after adjusting for illness severity (age, bilirubin, creatinine, diabetes, and presence of life support), Russo et al. in fact demonstrate that LDLT is associated with a 44% increased risk of graft failure compared to DD[5] Second, compared to DD patients, LDLT recipients do not receive as great a benefit from transplantation since the urgency of transplantation may be less than for DD patients. According toRusso et al., the technical success of the LDLT operation is similar to DD: approximately 88% survival 1 year after surgery. For the typical DD patient with a MELD score of 24, 88% survival is a favorable outcome. Without transplantation, such a patient would die within a few months. However, for the LDLT recipient, who is typically less ill and has an average MELD of 14, the benefit of transplantation may be less clear. An 88% 1-year survival for this patient could be lower than the expected 1-year survival without transplantation. Therefore, survival statistics must be interpreted relative to the expected outcome without transplantation. For LDLT patients, the benefit is less than for DD patients who are far sicker at time of transplantation.
What does all of this mean in terms of comparison of outcomes for LDLT and DD recipients? If DD recipients are significantly sicker at the time of transplantation, can we ever perform meaningful outcome comparisons with LDLT patients? The answer is yes, but we need to change our point of reference. As noted above, using the time of surgery as the point of reference for measuring the efficacy of LDLT is inadequate. The outcomes relative to LDLT must be measured while the patient is listed for transplantation. In doing this, we recognize that selection of LDLT as a treatment option fundamentally changes the risk-benefit equation for a given patient. The potential benefit of expedited transplantation with a live donor eliminates one of the greatest risks of DD transplantation: death on the waiting list. On the other hand, expedited transplantation with a live donor places the patient at immediate risk of posttransplantation problems, which are fatal in approximately 12% of patients within 1 year. For the DD patient, waiting time before transplantation is longer compared to the LDLT recipient. During this time, the patient may develop problems related to end-stage liver disease, which can lead to death on the waiting list. In addition, the DD recipient is usually sicker at the time of surgery; this can jeopardize the success of the procedure. To determine whether LDLT is better or worse for a given patient than DD, we must measure outcomes following the selection of LDLT as a treatment option while the patient is still listed for transplantation. Thereafter, the rate of complications and mortality for LDLT recipients compared to DD patients will determine whether the choice of LDLT is better or worse than DD transplantation. Currently, there is no data to determine which alternative will lead to the best outcome for a particular patient. To answer this question will clearly require a long-term prospective trial. The most likely source of this information is the National Institutes of Health LDLT Cohort Study, which will begin enrollment in 2004. However, meaningful data regarding patient and graft survival will not be available for several more years.
In the meantime, how should we select appropriate candidates for LDLT, and how should the results by Russo et al. impact the selection of HCV-infected patients for LDLT? One could interpret the data to support LDLT as a treatment option for any patient with HCV, since patient and graft survival are the same as DD transplantation. However, as discussed above, we believe that the illness severity must be carefully considered in each patient. The patients who stand the most to gain from an expedited transplantation with a live donor are those at risk for dying while on the transplant list. From a practical standpoint, the MELD score provides some help in identifying these patients. In general, the 90-day mortality begins to increase precipitously for patients with a MELD score greater than or equal to 18. In almost all cases, these patients should be considered sick enough to potentially benefit from LDLT. However, since the MELD score is a statistical formula that may not accurately predict mortality risk for all patients, there may be selected patients with a MELD score less than 18 who may benefit from live donation. In fact, a substantial number of appropriate LDLT recipients may be patients who are at risk for dying despite a low MELD score. These patients have virtually no chance for cadaveric transplantation, and live donation may be their only viable treatment option under the current MELD allocation scheme. In short, the MELD score along with clinical judgment should be used to select patients at risk for dying on the transplant list. These patients should be offered live donation as a treatment option to prevent one of the most important risks of DD transplantation: death on the waiting list.
In summary, the current data are inadequate to determine whether outcomes for HCV-infected patients are better or worse following LDLT compared to DD. The study by Russo et al. demonstrates that, after LDLT, patient and graft survival are similar compared to DD transplantation. However, multivariate analysis suggests that LDLT may be associated with worse survival compared to DD liver transplantation. A full measure of the impact of LDLT will require a prospective analysis that evaluates outcomes at the time that LDLT is selected as a treatment option for a given patient.
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