Risk Factors in Liver Retransplantation: A Single-Center Experience

Risk Factors in Liver Retransplantation: A Single-Center Experience C. Crivellin, E. De Martin, G. Germani, M. Gambato, M. Senzolo, F.P. Russo, A. Vitale, G. Zanus, U. Cillo, and P. Burra ABSTRACT Liver retransplantation (Re-OLT) is one of the most debated issues in medicine over the past decade. Re-OLT, currently is accepted for patients with irreversible failure of a hepatic graft caused by primary nonfunction (PNF), hyperacute/chronic rejection, or hepatic artery thrombosis (HAT); whereas it is still controversial for patients with recurrent viral disease, in particular hepatitis C virus (HCV) cirrhosis. Patient and graft survival rates are lower than those observed after primary liver transplantation (OLT). The aim of the present study was to analyze the risk factors that adversely affect survival after Re-OLT in a single center. Medical data were collected for 23 patients who underwent Re-OLT from November 2002 to December 2008 including six men and seven women of mean age of 51.3 years. The most frequent indications for Re-OLT were: PNF (69.5%; 16/23), HCV recurrence (8.6%; 2/23), or HAT (8.6%; 2/23). Mean Model for End-Stage Liver Disease (MELD) at Re-OLT was 27.7 (range ⫽ 9 – 40). After a mean follow-up of 37.4 ⫾ 30 (standard deviation) months, 43% (10/23) of patients had died, including 70% within the first 2 months after Re-OLT. Sepsis represented the commonest cause of death (40%). Re-OLT was performed for PNF among 90% of succumbing patients. As regards dead patients, 4/10 were HCV⫹ whose causes of death were sepsis (n ⫽ 2), alcoholic cirrhosis (n ⫽ 2), and undetermined (n ⫽ 1). Comparing patients who died after liver Re-OLT versus alive patients, we did not find any significant difference in terms of mean MELD (28.6 vs 27; P ⫽ NS), MELD ⬎ 25 (60% vs 61.5%, P ⫽ NS), donor age ⬎ 60 years (30% vs 15.3%, P ⫽ NS), HCV⫹ (40% vs 62%, P ⫽ NS), or time interval from OLT to Re-OLT (12.2 vs 777.7 days, P ⫽ NS). Patient survivals after Re-OLT were 67% at 3 years and 50% at 5 years, which were lower than those of first transplantations, as reported by other European and International Centers. Forty percent of deaths after Re-OLT occurred among HCV⫹ recipients, but for reasons unrelated to HCV infection. IVER RETRANSPLANTATION (Re-OLT) is the only form of treatment for patients with irreversible hepatic graft failure.1 The reported rate of retransplantation varies from 7% to 23% at various transplant centers.2,3 The commonest accepted indications for Re-OLT are primary nonfunction (PNF), hyperacute/chronic rejection, and hepatic artery thrombosis (HAT), while Re-OLT for hepatitis C virus (HCV) recurrence is still debated. Patient and graft survival rates are lower in Re-OLT patients compared with those after a first liver transplantation (OLT). This result must be considered in the context of the increasing number of patients listed for OLT and the growing shortage of donor organs. A considerable number of scores have been proposed to predict patient outcomes after Re-OLT; however none has entered routine clinical practice,4 so the

L

inferior results in the outcome of Re-OLT continue to be a major challenge. The aims of this study were to identify the indications for and outcomes of retransplantation and to analyze the risk factors that can adversely affect survival after Re-OLT in a single transplant center.

From the Multivisceral Transplant Unit (C.C., E.D.M., G.G., M.G., M.S., F.P.R., P.B.) and Hepatobiliary Surgery and Liver Transplantation Unit (A.V., G.Z., U.C.), Department of Surgical and Gastroenterological Sciences, University Hospital of Padua, Padua, Italy. Address reprint requests to Patrizia Burra, Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, Padova University Hospital, 6th floor, via Giustiniani 2, 35121, Padua, Italy. E-mail: [email protected]

0041-1345/11/$–see front matter doi:10.1016/j.transproceed.2011.01.141

© 2011 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

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Transplantation Proceedings, 43, 1110 –1113 (2011)

RISK FACTORS IN LIVER RETRANSPLANTATION

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METHODS We evaluated the patients who underwent Re-OLT between November 2002 and December 2008. Twenty-six of 393 (6.6%) OLT patients underwent Re-OLT. Clinical data to calculate Model for End-Stage Liver Disease (MELD) scores were not available in three patients, who were excluded. Only one patient underwent a third liver transplantation. We retrospectively analyzed the medical records of the 23 patients considering the following parameters: primary diagnosis, indication for retransplantation, time interval to retransplantation, patient survival, MELD score (⬎25 or ⬍25), donor age (⬎60 or ⬍60) and recipient HCV infection. Twenty-two patients received organs from cadaveric donors; one, from a living donor. The statistical analysis compared categorical variables using the chi-square test, while the Mann-Whitney test was used for the evaluation of continuous variables. Kaplan-Meier curves were used to calculate patient survival rates.

RESULTS

Three hundred ninety-three adult patients underwent primary OLT between November 2002 and December 2008. Among these, 23 patients underwent retransplantation in the same period (16 men and 7 women). Their mean age ⫾ standard deviation was 50.4 ⫾ 11.9 (range ⫽ 21– 67) at the moment of primary OLT and 51.3 ⫾ 10.9 (range ⫽ 21– 67) for the second transplantation. The mean interval between the first LT and retransplantation was 14.8 months (range ⫽ 2– 4322 days). At first OLT, 52.2% (12/23) patients were HCV⫹; 47.8% (11/23) were HCV⫺. The prevalent indications for OLT were HCV cirrhosis (26%; 6/23), cryptogenic cirrhosis (21%; 5/23), HCV - alcholic cirrhosis cirrhosis (13%; 3/23) and hepatitis B virus (HBV)/hepatitis D virus (HDV)/ETOH (8.6%; 2/23). Other causes were: HCV/ hepatocellular carcinoma (HCC) (4.3%; 1/23), HCV/HCC/ ETOH (4.3%; 1/23), HCV/cryptogenic (4.3%; 1/23), Caroli syndrome (4.3%; 1/23), ETOH/HCC (4.3%; 1/23), autoimmune liver disease (4.3%; 1/23), and HBV/HCC (4.3%; 1/23). The most frequent indications for Re-OLT were PNF (69.5%; 16/23), HCV recurrence (8.6%; 2/23), and HAT (8.6%; 2/23). Other causes were prolonged warm ischemia (4.3%; 1/23), de novo autoimmune liver disease (4.3%; 1/23), and esophageal cancer in the donor (4.3%; 1/23). The mean MELD ⫾ DS at Re-OLT was 27.7 ⫾ 8.9 (range ⫽ 9 – 40), with a median of 29. Regarding donor characteristics at Re-OLT, 11 were men and 12 women of mean age 43 years (range ⫽ 15–77); 21% (5/23) donors were over 60 years of age. After a mean follow-up of 37.4 ⫾ 30 months, 43% (10/23) patients died; among these, 70% succumbed within the first 2 months after Re-OLT. The most frequent cause of death was sepsis (40%; 4/10), followed by bleeding (10%; 1/10) and relapse of alcohol intake (10%; 1/10). The other events remained undetermined. In 90% of deaths Re-OLT had been performed for PNF. As regards dead patients, 40% (4/10) were HCV-infected with causes of death being sepsis (n ⫽ 2), recurrent alcohol intake (n ⫽ 1), and undeter-

Fig 1. Patient survival at 5 years after retransplantation in a single center.

mined (n ⫽ 1). Patient survival after Re-OLT was 67% at 3 years and 50% at 5 years, as shown in Fig 1. Comparing patients who died after liver Re-OLT versus living patients, we did not find any significant difference in terms of mean MELD (28.6 vs 27; P ⫽ NS); MELD ⬎ 25 (60% vs 61.5%, P ⫽ NS); donor age over 60 years (30% vs 15.3%, P ⫽ NS); HCV⫹ (40% vs 62%, P ⫽ NS), time interval OLT-Re-OLT (12.2 vs 777.7 days, P ⫽ NS), as shown in Table 1. DISCUSSION

Re-OLT is the only therapeutic option for patients with irreversible failure of hepatic graft. The association of a second transplantation with increased mortality is well documented.5,6 Both patient and graft survivals are lower than after first liver transplantation, which must be considTable 1. Factors Affecting Survival After Re-OLT

⫹

HCV HCV⫺ MELD MELD Donor Donor

⬎ 25 ⬍ 25 age ⬎ 60 age ⬍ 60

Dead (%)

Alive (%)

40 60 60 40 30 70

62 38 61.5 38.5 15.3 84.7

Re-OLT, liver retransplantation; HCV, hepatitis C virus; MELD, Model for End-stage Liver Disease.

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ered in the context of the constant increase in the number of patient listed for OLT and the growing shortage of donor organs. Furthermore, Re-OLT has higher costs and longer hospitalizations in comparison with a first liver transplantation.7 Such considerations have cast doubt on the appropriateness of hepatic Re-OLT both on economic and ethical grounds.8 The organ shortage has led some centers to accept marginal donors for Re-OLT, which causes a higher incidence of severe ischemic/preservation injury, as reflected by the development of PNF.4 The best way to reconcile the need for Re-OLT in some patients with the best use of the few available organs may be a careful selection of the cases that could obtain the maximal benefits from liver Re-OLT. A considerable number of scores have been proposed to predict patient outcomes before performing a second surgical procedure; however, to date, none has entered the routine clinical practice.4 The MELD score does not consider liver allograft characteristics; thus, the use of this score to predict the survival of candidates for Re-OLT is not reliable. The overall outcome after Re-OLT (as after OLT) depends on a combination of donor, recipient, and surgical factors. In our experience, the most frequent indication for Re-OLT was PNF, as reported also by Carriòn et al.9 In contrast, the main cause of liver graft failure was HAT in the two studies of the University Hospital La Fe (Valencia) and the Birmingham University Hospital by TorresQuevedo10 and by Marudanayagam et al.1 Meneu Diaz et al reported that the most common indication for Re-OLT in their center was rejection.11 Survival of retransplanted patients at 5 years varies from 47 to 67% in different studies.10,12,13 In our center, the survival rates of retransplanted patients were 67% and 50% at 3 and 5 years, respectively. We did not observe any significant difference between dead and living patients in terms of MELD score, donor age, time interval from OLT to Re-OLT or HCV⫹. Watt et al reported worse survival for patients who underwent Re-OLT with MELD scores greater than 25,14 while Onaca et al noted similar MELD scores among 2-year survivors versus nonsurvivors after late Re-OLT.15 In our study, grafts explanted from donors older than 60 years showed a 15% greater rate of deaths than living patients, but the difference was not significant probably due to the small sample size. However, Re-OLT appears to be more successful in healthier patients, with lower MELD scores, and higher allograft quality.16 Re-OLT in older and severely ill recipients, with advanced renal insufficiency, on mechanical ventilation, or using older donors is associated with a worse prognosis and should be restrained.16 Another parameter is the time interval between the first and the second OLT: in our center, it was shorter among dead than living patients, but the difference did not reach significance, probably because of the small number of patients in the sample. Ninety percent of dead patients underwent ReOLT for PNF, and 70% of them were deceased within the first 2 months after Re-OLT. Early Re-OLT due to initial graft failure appeared to be associated with a greater risk of

CRIVELLIN, DE MARTIN, GERMANI ET AL

death than late Re-OLT performed for disease recurrence. As Doyle et al reported, the increased probability of graft failure after Re-OLT reaches a maximum of 0.8 at day 38, followed by a slow decline thereafter.17 In the setting of early graft failure after primary OLT, Re-OLT should be undertaken within the first 7 days and discouraged during 8 to 30 days, because Re-OLT is associated with the worst results within this intermediate time frame.13 Still, late Re-OLT can be associated with a number of complications, especially when it is performed for recurrence of viral disease. In particular, 40% of Re-OLT in United States are performed in HCV⫹ patients.16 When recipients have detectable HCV RNA at the time of transplantation, HCV infection always recurs after OLT,18 with the development of cirrhosis in 30% of patients after 5 years.19 Pelletier et al reported a 30% increase in mortality for HCV-infected Re-OLT recipients.20 Mc Cashland et al did not note any difference in survival between HCV⫹ and non-HCV-infected patients undergoing Re-OLT after a careful recipient selection.16 Forty percent of dead patients retransplanted at our hospital were HCV⫹, but none died due to HCV-related causes. However, the best approach to HCVpositive patients is to prevent severe hepatitis by supplying antiviral therapy after OLT, reserving Re-OLT for nonresponders or for patients who develop graft cirrhosis. Our study confirmed the greater incidence of death due to sepsis in the Re-OLT group, as previously reported by Shaw et al and by Anthuber et al,21,22 as 40% of succumbing patients after retransplantation were septic. In conclusion, the most common cause for retransplantation was primary graft nonfunction. The survival rates of retransplanted patients were 67% and 50% at 3 and 5 years, respectively, which were lower than the results of first transplantations, as reported by other European and International centers. MELD, HCV status, and donor age did not show an impact on patient survival after Re-OLT. Early Re-OLT due to PNF appeared to be associated with a greater risk of death. Sepsis represented the commonest cause of death after Re-OLT with 40% of them occurring in HCV⫹ recipients, but for reasons apparently unrelated to HCV infection.

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RISK FACTORS IN LIVER RETRANSPLANTATION 6. Rosen HR, Martin P: Hepatitis C infection in patients undergoing liver retransplantation. Transplantation 66:1612, 1998 7. D’Alessandro AM, Ploeg RJ, Knechtle SJ, et al: Retransplantation of the liver- a seven year experience. Transplantation 55:1083, 1993 8. Evans R, Manninen D, Dong F, et al: Is retransplantation cost effective? Transplant Proc 25:1694, 1993 9. Carrión JA, Navasa M, Forns X: Retransplantation in patients with hepatitis C recurrence after liver transplantation J Hepatol 53:962, 2010 10. Torres Quevedo R, Moya-Herraiz A, San Juan F, et al: Indications for and results of liver retransplantation. Transplant Proc 41:1016, 2009 11. Meneu Diaz JC, Moreno Gonzales E, Vicente E, et al: Early mortality in liver retransplantation: a multivariate analysis of risk factor. Transplant Proc 34:301, 2002 12. Markmann JF, Markowitz JS, Yersiz H. et al: Long term survival after retransplantation of the liver. Ann Surg 226:408, 1997 13. Zimmerman MA, Ghobrial RM: When Shouldn’t we Retransplant? Liver Transpl 11(Suppl 2):S14, 2005 14. Watt KDS, Lyden ER, Mc Cashland TM: Poor survival after liver retransplantation: is hepatitis C to blame? Liver Transpl 9:1025, 2003

1113 15. Onaca N, Levy MF, Ueno T, et al: An outcome comparison between primary liver transplantation and retransplantation based on the pretransplant MELD score. Transpl Int 19:282, 2006 16. McCashland TM: Retransplantation for recurrent hepatitis C: Positive aspects. Liver Transpl 9(Suppl):S67, 2003 17. Doyle HR, Morelli F, McMichael J, et al: Hepatic retransplantation—an analysis of risk factors associated with outcome. Transplantation 61:1499, 1996 18. Garcia-Retortillo M, Forns X, Feliu A, et al: Hepatitis C virus kinetics during and immediately after liver transplantation. Hepatology 35:680, 2002 19. Berenguer M, Prieto M, Rajon JM, et al: Natural history of clinically compensated hepatitis C virus-related graft cirrhosis after liver transplantation. Hepatology 32:852, 2000 20. Pelletier SJ, Schaubel DE, Punch JD, et al: Hepatitis C is a risk factor for death after liver retransplantation. Liver Transpl 11:434, 2005 21. Shaw B, Gordon R, Iwatsuki S, et al: Hepatic retransplantation. Transplant Proc 17:264, 1985 22. Anthuber M, Pratschke E, Jauch K, et al: Liver retransplantation: indications, frequency, results. Transplant Proc 24:1965, 1992