Retransplantation of liver: Primary graft nonfunction and hepatitis C virus are associated with worse outcome

RAPID COMMUNICATION

Retransplantation of Liver: Primary Graft Nonfunction and Hepatitis C Virus Are Associated With Worse Outcome Hwan Y. Yoo, Anurag Maheshwari, and Paul J. Thuluvath It is not known whether the outcome of liver retransplantation (re-LT) is dependent on the indication for re-LT or cause of liver disease. In this study, our aim is to compare the outcome of re-LT in adults with that of primary liver transplantation (PLT) and determine whether the outcome of re-LT is dependent on its indication. United Network for Organ Sharing data from 1988 to 2001 were used for the study. Of 34,267 patients who met our inclusion criteria, 761 patients underwent re-LT for primary graft nonfunction (PGNF; group 1), 3,428 patients underwent re-LT for other reasons (group 2), and 30,078 patients underwent PLT (group 3). There was a greater incidence of PGNF (9.4% v 4.0%; P < .001) and regrafting (23.1% v 7.4%; P < .001) in the re-LT groups compared with the PLT group. Kaplan-Meier analysis and Cox regression analysis, after adjusting for confounding risk factors, showed significantly lower short- and longterm patient and graft survival in the re-LT groups compared with the PLT group. Kaplan-Meier survival showed lower patient and graft survival in group 1 compared with group 2. However, only graft, not patient, survival was lower in group 1 by Cox regression analysis when adjusted for other risk factors. Patients with hepatitis C virus (HCV) infection who underwent re-LT had lower patient and graft survival compared with those without HCV infection, and HCV was an independent predictor of mortality after re-LT. Re-LT was associated with a greater rate of complications and lower patient and graft survival compared with PLT. Re-LT for PGNF and HCV infection was associated with lower patient and graft survival compared with re-LT for other causes. (Liver Transpl 2003;9: 897-904.)

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here is considerable disparity between donor availability and the demand for liver transplantation. Hence, a significant number of patients die while waiting for liver transplantation.1 Approximately 15% of patients who receive a transplant will require liver retransplantation (re-LT) for a variety of reasons, including primary graft nonfunction (PGNF), chronic rejection, and disease recurrence.2,3 It has been shown that the outcome of re-LT is worse than that of primary liver transplantation (PLT; first transplantation).3,4 However, it is unclear whether the poor outcome is a reflection of the underlying cause of allograft failure requiring re-LT or caused by other confounding variables. Many factors, including age, race, cause of liver disease, United Network for Organ Sharing (UNOS)

status, creatinine level, diabetes, obesity, hypertension, and heart disease, influence posttransplantation survival.5-10 Patients who undergo re-LT are more likely to have these risk factors compared with those who undergo PLT. It is normal practice to perform re-LT for those who develop PGNF, but there is no convincing evidence to suggest that they have a better outcome than those who undergo late re-LT for other causes. In addition, it has been suggested that patients with hepatitis C virus (HCV) infection have a relatively poor outcome after re-LT compared with those with other liver diseases. Again, these observations are based on small sample sizes.11,12 The appropriateness of re-LT in these patients has been questioned on the basis of ethical and financial grounds, but to have a serious debate, it is important to understand the risk-adjusted outcome of re-LT in a large patient population and identify risk factors that determine poor outcome.3,13 The objective of our study is to analyze the UNOS database to determine outcome in patients who undergo re-LT after adjusting for other confounding variables and, more specifically, compare the outcome based on indication (PGNF versus others) and cause of liver disease (HCV versus others).

Patients and Methods We examined the UNOS database containing data for all patients who underwent liver transplantation in the United States from 1987 to 2001 (n ⫽ 48,887). Children (ⱕ18 years of age) and those with incomplete data or multiorgan transplants were excluded (n ⫽ 14,620). Of the remaining 34,267 patients, 761 patients underwent re-LT for PGNF (group 1),

From the Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD. Address reprint requests to Paul J. Thuluvath, MD, FRCP, The Johns Hopkins Hospital, Rm 429, 1830 E Monument St, Baltimore, MD 21205. Telephone: 410-614-5389; FAX: 410-614-9612; E-mail: [email protected] Copyright © 2003 by the American Association for the Study of Liver Diseases 1527-6465/03/0909-0002$30.00/0 doi:10.1053/jlts.2003.50176

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3,428 patients underwent re-LT for other reasons (group 2), and 30,078 patients underwent PLT (group 3). Fourteen percent of patients in group 2 had undergone a previous re-LT. We obtained the following information for transplant recipients: age; gender; race; height; weight; serum creatinine level; cause of liver disease; indication for re-LT; group A, group B, group O (ABO) blood type matching status; and UNOS listing status. We also recorded donor age, race, and cold ischemia time. We determined 1-month, 1-year, 2-year, 5-year, and 10-year patient and graft survival in all three groups. Body mass index (BMI) was calculated by dividing weight in kilograms by height in meters (both at the time of transplantation, in kilograms per meter squared). The definition of UNOS listing status underwent changes during the study period; therefore, the older system did not correspond to the listing system used in the later period except for status 1. However, for the purpose of analysis, UNOS listing status was divided into three categories: UNOS status 1, UNOS status 2A, and others. ABO matching was divided into three groups: matched, when donor and recipient were of same ABO blood type; compatible, when donor blood type was O and recipient blood type was other than O or recipient blood type was AB and donor blood type was either A or B; and mismatched, when donor blood type was A, B, or AB and recipient had another blood type. To exclude inaccurate data, BMI less than 15 or greater than 55 kg/m2 and a creatinine value of 0 mg/dL were considered missing data. We classified causes of liver disease into alcoholic liver disease, hepatitis C, hepatitis B, cryptogenic cirrhosis, primary biliary cirrhosis, primary sclerosing cholangitis, and others. Patients with a diagnosis of Non A Non B hepatitis were included as hepatitis C; combined hepatitis B and C, as hepatitis B; and combined alcoholic liver disease and postnecrotic cirrhosis (viral hepatitis), as alcoholic liver disease. Because information on HCV was available only after 1990, most data for HCV came after that year.

Statistical Analysis The demographics of patients in each group were compared by means of Chi-squared test and analysis of variance for categorical and continuous variables, respectively. One month, 1-year, 2-year, 5-year, and 10-year survival after liver transplantation were determined by means of Kaplan-Meier survival analysis. Log-rank test was used to compare differences in survival by Kaplan-Meier analysis. Cox regression analysis or logistic regression analysis was used to adjust the effect of other risk factors (confounding variables). Confounding variables used in Cox regression analysis were recipient age, gender, race, BMI, serum creatinine level, UNOS listing status, ABO matching, cause of liver disease, cold ischemia time, and donor age. Overall, 30,082 patients (group 1, 603 patients; group 2, 2,026 patients; group 3, 27,453 patients) were available for final Cox regression analysis after adjusting for the listed confounding variables. For all analyses, two-tailed P value of 0.05 or less is considered significant.

Statistical analyses were performed using SPSS software, version 10.0.6 (SPSS Inc, Chicago, IL)

Results Patient demographics are listed in Table 1. There were statistically significant differences in cause of liver disease, UNOS status, serum creatinine level, cold ischemia time, ABO matching status, and donor age among the three groups. Cold ischemia time was shorter and serum creatinine level was greater in group 1; 14.6% of patients in group 1 were on dialysis therapy at the time of re-LT compared with 5.5% in group 2 and 1.5% in group 3. A greater proportion of patients in group 1 underwent either ABO-compatible or ABO-mismatched transplantation. Hypertension was higher in group 2 (17.7%) compared with either group 1 (9.3%) or group 3 (10.3%). Prevalences of diabetes mellitus and coronary artery disease were similar in the three groups. Patients who underwent re-LT had greater rates of PGNF and re-LT (third transplantation for the re-LT group and second transplantation for the PLT group; Table 2). Whereas 10.6% in the re-LT groups received another (third graft) allograft, only 4% in group 3 received another allograft (second graft) within 6 months (P ⬍ .001; Table 2). Re-LT was an independent predictor for PGNF and subsequent re-LT on logistic regression analysis (Table 2). Other complications, such as recurrent diseases, acute or chronic rejection, vascular thrombosis, biliary complications, or infection after transplantation, could not be compared reliably because of inadequate data entry. Kaplan-Meier analysis showed significantly lower short- (1-month) and long-term (up to 10 years) patient (P ⬍ .001) and graft (P ⬍ .001) survival for the re-LT groups (groups 1 and 2) compared with the PLT group (Fig. 1). Cox regression analysis of patient and graft survival, after adjusting for age, gender, race, BMI, creatinine level, ABO matching, UNOS status, and cold ischemic time, showed lower survival (Fig. 2). Patient survival at 1 month (90.3% v 95.9%; hazard ratio [HR], 1.91; confidence interval [CI], 1.64 to 2.23; P ⬍ .0001), 5 years (60.3% v 75.2%; HR, 1.87; CI, 1.72 to 2.04; P ⬍ .0001), and 10 years (38.1% v 59.5%; HR, 1.91; CI, 1.76 to 2.07; P ⬍ .0001) were significantly lower in the re-LT group after adjusting for other risk factors (Cox regression, Fig. 2). Re-LT was an independent predictor of short- and long-term patient and graft survival after liver transplantation. Other independent predictors on Cox regression analysis were age, race, cause of liver disease, UNOS status, cold ischemia time, creatinine level, BMI, and donor age.

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Table 1. Patient Demographics

Age (yr) Gender (% female) Cause of liver failure (%) Hepatitis C Alcoholic Cholestatic Cryptogenic Race (%) White Black Asian Hispanic UNOS listing (%) 1 2A BMI (kg/m2) Creatinine (mg/dL) Cold ischemia time (hr) ABO matching (%) Compatible Mismatched Donor age (yr)

Group 1 (n ⫽ 761)

Group 2 (n ⫽ 3,428)

Group 3 (n ⫽ 30,078)

48.0 ⫾ 11.0 37.3

45.2 ⫾ 11.8 41.5

49.1 ⫾ 11.0 41.0

24.4 12.1 9.1 11.8

24.7 11.6 19.9 12.3

26.0 16.2 16.4 12.3

75.3 7.5 3.0 11.8

79.5 7.0 2.5 8.8

78.8 6.5 3.1 9.8

P .8 .09 ⬍.001

.05

⬍.001 21.9 12.5 27.0 ⫾ 5.5 2.27 ⫾ 1.66 7.4 ⫾ 5.4

33.9 31.0 25.6 ⫾ 5.3 1.87 ⫾ 1.42 9.5 ⫾ 6.0

12.3 22.7 26.9 ⫾ 5.5 1.27 ⫾ 1.09 8.9 ⫾ 5.6

23.1 4.2 38.5 ⫾ 17.5

13.6 3.3 33.2 ⫾ 15.7

7.3 1.3 34.6 ⫾ 16.7

.5 ⬍.001 .001 ⬍.001

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NOTE. Group 1 underwent re-LT for PGNF; Group 2 underwent re-LT for other causes; and Group 3 underwent PLT.

1 year, or 5 years. When patients who underwent a second transplantation were compared with those who underwent a third transplantation (14% of recipients), there was a significant survival difference between groups (Kaplan-Meier survival, log-rank test, P ⬍ .01). However, when the entire group was reanalyzed after excluding those who underwent more than two transplantations, results were similar to those reported in this study. Among patients who underwent re-LT, those who had HCV infection showed significantly lower patient and graft survival by Cox regression analysis compared with those who underwent re-LT for other reasons (Fig. 5). When re-LT data were analyzed after excluding PGNF (group 2 only), HCV infection was still an inde-

Kaplan-Meier analysis showed lower patient and graft survival in group 1 compared with group 2 (Fig. 3). Cox regression analysis, after adjusting for the described confounding variables, showed no difference in short- and long-term patient survival for patients who underwent re-LT for PGNF (group 1) compared with those who underwent re-LT for other causes (group 2; Fig. 4A). However, patients who underwent re-LT for PGNF had significantly lower graft survival (Fig. 4B) by Cox regression analysis. PGNF was an independent risk factor for poor graft survival at 1 month (HR, 1.02; CI, 1.009 to 1.02; P ⬍ .01), 1 year (HR, 1.2; CI, 1.02 to 1.4; P ⫽ .027), and 5 years (HR, 1.3; CI, 1.1 to 1.5; P ⫽ .001). PGNF was not an independent risk factor for patient survival at 1 month,

Table 2. PGNF and Re-LT Rates

PGNF (%) Re-LT (%) Early re-LT† (%)

Logistic Regression Analysis*

Group 1 ⫹ 2 (re-LT) (n ⫽ 4,189)

Group 3 (PLT) (n ⫽ 30,078)

P

HR (95% CI)

P

9.4 23.1 10.6

4.0 7.4 4.0

⬍.001 ⬍.001 ⬍.001

1.75 (1.48-2.08) 3.71 (3.30-4.17) 2.33 (1.97-2.77)

⬍.001 ⬍.001 ⬍.001

*PLT group was indicator (reference) variable. †Early re-LT indicates within 6 months.

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Figure 1. Kaplan-Meier survival of (A) patients and (B) grafts in patients who underwent PLT versus re-LT.

pendent risk factor for poor graft and patient survival from 1 to 5 years (1-year graft: HR, 1.2; CI, 1.04 to 1.4; P ⫽ 0.01; 1-year patient: HR, 1.6; CI, 1.3 to 1.9; P ⬍ .0001; 5-year graft: HR, 1.14; CI, 1.004 to 1.3; P ⫽ .04; 5-year patient: HR, 1.3; CI, 1.12 to 1.58; P ⫽ .001). Other risk factors for patient survival in this subgroup (group 2) were age, African-American race (HR, 1.7; CI, 1.3 to 2.2; P ⫽ .0003), UNOS status, creatinine level, and donor age.

Discussion Our study confirms that patient and graft survival were significantly lower after re-LT compared with PLT. More important, 23% of patients who underwent re-LT underwent repeated grafting (a third transplantation) during the follow-up period, and of these, approximately half were performed in the immediate

postoperative period (within 6 months). Although graft survival was lower, patient survival was similar in those who underwent re-LT for PGNF compared with other causes. Transplant recipients with HCV infection who underwent re-LT had significantly lower graft and patient survival compared with all other causes of liver disease. It has been suggested that outcomes after re-LT may depend on the cause of graft failure. In one study, patients who underwent re-LT within 30 days of PLT, presumably secondary to PGNF, had worse outcomes compared with those who underwent re-LT more than 30 days from their first transplantation.4 In another study, Azoulay et al2 found that re-LT for PGNF was associated with a better prognosis. Other studies have shown outcomes after re-LT for PGNF to be no different from those for re-LT for other reasons.14 These

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Figure 2. Cox multivariate regression survival analysis of (A) patients and (B) patient grafts for patients who underwent retransplantation (Re-LT; Group 1 and 2) and those who had primary liver transplantation (PLT; Group 3).

discrepant results could be explained easily on the basis of relatively small sample size and heterogeneity of patient population. Our analysis of UNOS data, using a very large sample size, showed that graft survival of patients who underwent re-LT for PGNF was significantly lower than that of patients who underwent re-LT for other reasons; those who underwent re-LT for PGNF were 20% more likely to lose their graft at 1 year compared with those who underwent re-LT for other reasons. This suggests that a greater proportion of patients who underwent re-LT for PGNF received a third graft. Moreover, Kaplan-Meier survival, unadjusted for other risk factors, indicates that those who underwent re-LT for PGNF had significantly lower patient survival. Renal failure was very common in group 1 (PGNF) compared with group 2 (14.6% v 5.5% on dialysis therapy), and this may explain in part the lower graft

and patient survival in patients who underwent re-LT for PGNF. We previously showed that elevated serum creatinine level is an independent predictor of poor patient and graft survival after liver transplantation, and the current study confirms that this also is true for those who undergo re-LT.8 Hepatitis C–induced cirrhosis is now the leading indication for liver transplantation.11,15 Recurrence of hepatitis C after transplantation is almost universal, but current data show the reason for allograft failure is unrelated to hepatitis C in a majority of these patients.15-17 However, it is likely that a substantial proportion of HCV-infected transplant recipients may develop cirrhosis in the allograft with longer follow-up.12 The decision to perform re-LT on patients with recurrent HCV remains controversial. Although some studies have shown poor survival in HCV-infected transplant recipients after re-LT, other studies have shown similar

Figure 3. Kaplan-Meier survival of (A) patients and (B) grafts in patients who underwent re-LT for PGNF (group 1) versus those who underwent re-LT for other reasons (group 2).

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Figure 4. Cox multivariate regression survival analysis of (A) patient survival and (B) graft survival after retransplantation. Group 1 underwent re-LT for PGNF, and group 2 underwent re-LT for other causes.

results.4,15,17,18 Examination of the UNOS database from 1990 to 1995 showed survival after re-LT in HCV-positive transplant recipients was worse than that of their HCV-negative counterparts, and moreover, the presence of HCV was an independent risk factor for mortality.11,12 In this study, we examined a much larger data set and our results were consistent with previous observations. Unlike the previous study, we analyzed data after including and excluding patients who underwent re-LT for PGNF, and results were similar. Analysis of group 2 (re-LT for reasons other than PGNF) showed that patients with HCV were 20% and 30% more likely to lose their graft at 1 and 3 years compared with non– HCV-infected patients, respectively. We believe that a large sample size is necessary to examine the indepen-

dent effect of cause of liver disease on re-LT, and the previously reported discrepancies could be explained easily on the basis of small sample size.4,15 Many studies showed lower survival rates in patients after re-LT compared with those who underwent PLT, and our data corroborate those observations.2-4 In addition, re-LT is associated with greater costs, longer hospital stays, and greater complexity of surgery.13,19 In this study, we show that patients who undergo re-LT are three times (23.1% v 7.4%) more likely to require a third graft. Survival of those who underwent a second re-LT was worse compared with those who underwent a first re-LT. In the context of limited organ supply, the decision to perform re-LT or re–re-LT inevitably denies organs to those awaiting their first transplant. Con-

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Figure 5. Cox multivariate regression survival analysis of (A) patients and (B) grafts based on HCV infection status among patients who underwent re-LT. HCV and non-HCV indicate patients with and without HCV infection among those who underwent re-LT, respectively. CI indicates confidence interval.

versely, patients who have survived one transplantation and face certain death without another may argue it is equally unfair to deny them another transplantation when they have a 60% chance for 5-year survival. This is a major dilemma for transplant physicians. One approach to this controversial problem is to identify those who are most likely to benefit from re-LT and selectively offer them re-LT. Most centers currently practice this philosophy without firm guidelines. In the absence of firm guidelines, this is likely to be interpreted as discriminatory by the lay public or outside observers. Many models and methods of risk assessment have been described to identify patients most likely to benefit from re-LT.13,19,20 These models have shown that patient preoperative ventilatory status, serum creatinine level, and bilirubin level are among the major determinants of postoperative survival. A model described by Rosen et al19 identified age, bilirubin level, creatinine level, UNOS status, and cause of graft failure as independent predictors of post–re-LT survival. Another model identified donor and recipient age, creatinine level, bilirubin level, and warm and cold ischemia times as independent variables affecting survival.20 Azoulay et

al2 found urgency of transplantation, age, and creatinine level to be independent variables affecting survival after re-LT. We perhaps could add HCV infection and transplantation for PGNF to the list of poor predictors of survival after re-LT. From a patient’s point of view, any chance of survival is better than no survival, but this should not be used as an argument to perform re-LT or re–re-LT because this denies many others the chance to undergo their first transplantation. Some data suggest that patients undergoing elective re-LT have survival rates approaching those of primary transplant recipients. However, the current UNOS policy of “sickest first” does not allow these patients to undergo re-LT until their clinical condition has deteriorated significantly. Under the current Model for End-Stage Liver Disease system, most of these patients will have renal failure at the time of re-LT; therefore, it is likely they will have a worse outcome than we have reported. To optimize re-LT and organ utilization, we need to develop better models and, until then, may have to adopt findings of large epidemiological studies to stratify patients based on risk-benefit ratio.

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Acknowledgment The authors thank UNOS for providing the data.

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in patients undergoing orthotopic liver transplantation in the United States. Hepatology 2002;35:105-109. Rosen HR, Martin P. Hepatitis C infection in patients undergoing liver retransplantation. Transplantation 1998;66:16121616. Rosen HR. Retransplantation for hepatitis C: Implications of different policies. Liver Transpl 2000;6(suppl):S41-S46. Biggins SW, Beldecos A, Rabkin JM, Rosen HR. Retransplantation for hepatic allograft failure: Prognostic modeling and ethical considerations. Liver Transpl 2002;8:313-322. Pokorny H, Gruenberger T, Soliman T, Rockenschaub S, Langle F, Steininger R. Organ survival after primary dysfunction of liver grafts in clinical orthotopic liver transplantation. Transpl Int 2000;13(suppl):S154-S157. Ghobrial RM. Retransplantation for hepatitis C. Liver Transpl 2002;8(suppl):S38-S43. Ghobrial RM, Farmer DG, Baquerizo S, Rosen HR, Yersiz H, Markmann JF, et al. Orthotopic liver transplantation for hepatitis C: Outcome, effect of immunosuppression, and causes of retransplantation during an 8 year single-center experience. Ann Surg 1999;229:824-833. Sheiner PA, Schluger LK, Sukru E, Thung SN, Lau JYN, Guy SR, et al. Retransplantation for recurrent hepatitis C. Liver Transpl Surg 1997;3:130-136. Rosen HR, O’Reilly PM, Shackleton CR, McDiarmid S, Holt C, Busuttil RW, Martin P. Graft loss following liver transplantation in patients with chronic hepatitis C. Transplantation 1996;66:1612-1616. Rosen HR, Madden JP, Martin P. A model to predict survival following liver retransplantation. Hepatology 1999;29:365-370. Ghobrial RM, Gornbein J, Steadman R, Danino N, Markmann JF, Holt C, et al. Pretransplant model to predict posttransplant survival in liver transplant patients. Ann Surg 2002;236:315323.