Critical Use of Extended Criteria Donor Liver Grafts in Adult-to-Adult Whole Liver Transplantation: A Single-Center Experience

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1 LIVER TRANSPLANTATION 14: , 2008 ORIGINAL ARTICLE Critical Use of Extended Criteria Donor Liver Grafts in Adult-to-Adult Whole Liver Transplantation: A Single-Center Experience Salvatore Gruttadauria, Giovanni Vizzini, Domenico Biondo, Lucio Mandalà, Riccardo Volpes, Ugo Palazzo, and Bruno Gridelli Mediterranean Institute for Transplantation and Specialized Therapies University of Pittsburgh Medical Center in Italy, Palermo, Italy This study presents our experience with the use of extended criteria donor (ECD) liver grafts. One hundred fifteen liver transplants were divided into 2 groups: standard (S) and nonstandard (NS). Fifty-eight patients in group S received a liver procured from an ideal donor, whereas 57 patients in group NS received an organ from an ECD. On the basis of the number of risk factors, patients were divided into 3 subgroups: the S group with 58 receiving a standard graft, the NS1 group with 44 receiving a graft with 1 or 2 risk factors, and the NS2 group with 13 receiving a graft with 3 to 4 risk factors. Patient survival was not different at 6, 12, and 24 months (P 0.05), whereas graft survival was different (P ). Both patient survival and graft survival were influenced by the cumulative number of risk factors. The univariate analysis of the donor risk factors detected hemodynamic factors as predictive of graft failure (P 0.024) and death (P 0.018). In the multivariate analysis, which was adjusted for recipient age and donor and recipient gender, hemodynamic risk factors and Model for End-Stage Liver. Disease score in the recipient were the only variables independently associated with graft failure (P 0.006, P 0.012, negatively). Finally, we observed a reduction of dropout from the list to 9% from 14.1% (P 0.04) and of mortality on the list to 32.55% from 41.01% (P 0.11). Critical use of ECD liver grafts allowed recipients in the waiting list to have a greater chance of being transplanted. Liver Transpl 14: , AASLD. Received June 11, 2007; accepted August 21, Transplantation of the liver has for many years been the treatment of choice for both chronic and acute endstage liver disease. However, despite advances in patient selection, surgical technique, immunosuppression, and perioperative management, the need for liver replacement exceeds organ availability. 1 In Italy, for example, although the number of liver transplants performed every year has increased, from 202 in 1992 to 1089 in 2006, the number of patients waiting for liver transplantation continues to increase, with 1729 patients on the waiting list in The mean waiting time for a liver transplant in 2006 was 20.4 months, with a wait-list death rate of 5.59%. Moreover, in Italy, where the overall rate of cadaver donation is 21 donors per million per year, there are areas of the country, such as Sicily, where the rate of cadaver donation was 9.3 donors per million per year in 2006 and was only 6.6 effective donors per million per year in In fact, the ongoing shortage of organs has led surgeons to develop innovative techniques in an attempt to expand the donor pool, namely, living donor liver transplantation, which represents the natural evolution of the procedure based on the segmental anatomy of the liver, and reduced-size cadaver and split liver transplants. 2,3 Nonetheless, in order to expand the pool, clinicians are continually modifying criteria to accept organs, particularly the previously defined expanded or marginal donor organs, which are now defined as extended criteria donor (ECD). 4 Despite the lack of general consensus within the transplant com- Abbreviations: ACR, acute cellular rejection; ECD, extended criteria donor; FHF, fulminant hepatic failure; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HDV, hepatitis D virus; MELD, Model for End-Stage Liver Disease; NS, nonstandard; Oltx, orthotopic liver transplantation; PNF, primary nonfunction; S, standard; SD, standard deviation. Address reprint requests to Salvatore Gruttadauria, M.D., Mediterranean Institute for Transplantation and Specialized Therapies, Via E. Tricomi 1, Palermo, Italy. Telephone: ; FAX: ; sgruttadauria@ismett.edu DOI /lt Published online in Wiley InterScience ( American Association for the Study of Liver Diseases.

2 USE OF EXTENDED CRITERIA DONOR LIVER GRAFTS 221 TABLE 1. ECD Factors, Patient and Graft Failure in Recipients of ECD Livers, and Univariate and Multivariate Analysis Including Donor and Recipient Factors Number of Donors P Value for Graft P Value for Patient Presenting Risk Factor Graft Failure Univariate Analysis Multivariate Analysis Deaths Univariate Analysis Multivariate Analysis Age Macrosteatosis 30% Intensive care unit length of stay 7 days Hemodynamic factors Cold ischemic time (12 hours) Peak serum Na 160 meq/l Total number MELD score in the recipients Recipient s age Recipient s sex Donor s sex Abbreviations: ECD, extended criteria donor; MELD, Model for End-Stage Liver Disease. munity on the definition of an ECD, we consider one as having certain characteristics (either real or perceived) that impact short-term and long-term risks to the recipient. The concept and definition of an ECD continue to evolve, and the impact of its use is the result of a combination of donor and recipient factors. Most clinicians accept the definition of ECD for an organ that might carry a potential risk for the recipient in terms of impaired allograft function or donor-transmitted disease. These 2 potential complications can affect the recipient immediately or in the long term. The aim of the present study was to present our experience in changing, over time, donor selection through the critical use of ECD liver grafts, which have allowed us to increase consistently every year the number of liver transplants at our center. ECD liver grafts were defined according to guidelines formulated by the Italian National Transplant Center. PATIENTS AND METHODS Between July 1999 and April 2007, we performed 401 liver transplants in 364 patients, of whom 311 are still alive. Of these liver transplants, 67 were adult-to-adult living-related liver transplants, and 93 were split liver transplants; consequently, they were not included in the present series. In this study, a retrospective analysis of full-size cadaver adult allografts used for adult recipients from June 2003 to June 2006 was done. One hundred fifteen liver transplants were divided into 2 main groups: standard (S) liver transplants and nonstandard (NS) liver transplants. Fifty-eight patients in group S received a liver procured from a donor considered ideal, whereas 57 patients in group NS received an ECD organ. Because of the short follow-up (12 months) achieved for the transplants performed in June 2006, we focused our attention in this study on those risk factors that potentially affect short-term and medium-term outcome. An ECD was defined as follows (Table 1): (1) age 60 years; (2) macrovesicular steatosis 30%; (3) prolonged intensive care unit stay ( 7 days); (4) hemodynamic risk factors, including prolonged hypotension (systolic blood pressure 60 mm Hg for more than 2 hours), use of dopamine 10 g/kg/minute for more than 6 hours to sustain blood pressure, and need for 2 inotropic drugs to sustain donor blood pressure for more than 6 hours; (5) cold ischemic time 12 hours; and (6) hypernatremia (Na peak 160 meq/l) before aortic cross clamp. On the basis of the cumulative number of risk factors, patients were then divided into 3 subgroups (Table 2): the S group with 58 patients receiving a standard graft, the NS1 group with 44 patients receiving a graft with 1 or 2 risk factors, and the NS2 group with 13 patients receiving a graft with 3 to 4 risk factors. In Tables 3 and 4, we report the demographic and clinical data of the 2 groups of patients in terms of age, sex, primary diagnosis for liver transplantation, waiting time on the list before liver transplant, Model for End- Stage Liver Disease (MELD) score, and clinical MELD for the patients with hepatocellular carcinoma (HCC). In Table 5, we report the same demographic and clinical data related to the 3 subgroups. Statistical Analysis Survival analysis was performed with the Kaplan-Meier method; the log rank test was used to test for statistically significant observed differences. Data are expressed as means standard deviation for continuous variables and as percentages for categorical variables. Other variables are expressed as medians. Data were compared with the 2-tailed chi-square test or Fisher s exact test for categorical variables and with the Student t test; analysis of variance and the

3 222 GRUTTADAURIA ET AL. TABLE 2. Recipient Subgroups According to the Cumulative Risk Factors NS1 Group NS2 Group Total 21 patients 23 patients 8 patients 5 patients 57 patients 36.84% 40.35% 14.04% 8.77% % Abbreviations: NS1, nonstandard 1; NS2, nonstandard 2. TABLE 3. Demographic and Clinical Data of the Two Groups of Patients S Group (58) NS Group (57) Characteristics n Mean SD or % n Mean SD or % P Value Age Range 20, 68 19, 65 Age (years) % % % % % % % % Sex Male % % Female % % Time on waiting list Mean Median Range (0, 1506) (1, 1672) Clinical MELD score % % % % % % % % MELD score % % % % % % % % Abbreviations: MELD, Model for End-Stage Liver Disease; NS, nonstandard; S, standard; SD, standard deviation. median test were used for continuous variables. P values less than 0.05 were considered significant. Multivariate analysis was used to assess the impact on recipient survival of variables currently listed to define an ECD. All statistical analyses 5 were performed with SPSS (SPSS, Inc., Chicago, IL). RESULTS Age, MELD, and clinical MELD in patients with HCC were not statistically different in all the groups and subgroups (Tables 3-5), although the gender balance varied significantly among the 3 subgroups S, NS1, and NS2 (P 0.006; Table 5). The difference in gender composition was statistically significant between the S and NS1 groups (P 0.006), whereas there was no statistically significant difference between the NS1 and NS2 groups or between the S and NS2 groups (P 0.05). Patient survival was 94.83% at 6 months, 94.83% at 12 months, and 91.95% at 24 months in group S but 85.96% at 6 months, 83.87% at 12 months, and 81.16% at 24 months in group NS (P ). Graft survival was 93.22% at 6 months, 93.22% at 12 months, and 90.40% at 24 months in S but 78.95% at 6 months, 75.44% at 12 months, and 71.37% at 24 months in NS (P ; Figs. 1 and 2). The different incidences of acute cellular rejection, hepatitis C virus viral recurrence, HCC recurrence, vascular complication, biliary complication, primary graft nonfunction, and graft malfunction in the 2 groups were not significant (Table 6). Acute cellular rejection was diagnosed by histology; primary graft nonfunction was diagnosed if it occurred within 14 days after transplant and, in the absence of vascular thrombosis and biliary obstruction, if a constant increase in liver enzymes and parallel drop in the coagulative indices were present. Graft malfunction

4 USE OF EXTENDED CRITERIA DONOR LIVER GRAFTS 223 TABLE 4. Primary Diagnosis S Group (58) NS Group (57) n % n % Alcohol CBP Cryptogenic FHF HBV HBV alcohol HBV HDV HCC alcohol HCC HBV HCC HBV HDV HCC HCV HCV HCV alcohol HCV HBV HCV multiorgan failure Metastasis from carcinoid Redo Oltx: delayed graft function Redo Oltx: artery graft bleeding Redo Oltx: hepatic artery thrombosis Wilson s disease PNF Abbreviations: HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HDV, hepatitis D virus; FHF, fulminant hepatic failure; NS, nonstandard; Oltx, orthotopic liver transplantation; PBC, primary biliary cirrhosis; PNF, primary nonfunction; S, standard. TABLE 5. Demographic and Clinical Data of the Three Subgroups of Patients S Group (58) NS1 Group (44) NS2 Group(13) Characteristics n Mean SD or % n Mean SD or % n Mean SD or % P Value Age Range 20,68 19, 64 38, 62 Sex Male % % % Female % % % Time on waiting list Mean Median Range 0, , , 1672 Clinical MELD score MELD score Abbreviations: MELD, Model for End-Stage Liver Disease; NS1, nonstandard 1; NS2, nonstandard 2; S, standard; SD, standard deviation. was diagnosed if it occurred within 90 days after transplant and, in the absence of vascular thrombosis and biliary obstruction, if a constant increase in liver enzymes and parallel drop in the coagulative indices were present. Hepatitis C virus recurrence was diagnosed by histology. No differences in the incidence of medical and surgical complications were noted in the 3 subgroups (Table 7). In a comparison of the 3 subgroups S, NS1, and NS2, there was no difference in patient survival (P ), although there was a difference in graft survival (P ; Figs. 3 and 4). In detail, if we compare patient survival between the S and NS1 groups, we find that there was a difference (P 0.050), whereas we find no difference if we compare the NS1 and NS2 groups (P 0.642) and the S and NS2 groups (P 0.424). Likewise, looking at graft survival, if we compare the NS1 and NS2 groups, we find that there was no difference (P 0.142), whereas if we compare the S and NS1

5 224 GRUTTADAURIA ET AL. Figure 1. Survival analysis (Kaplan-Meier): standard (S) group versus nonstandard (NS) group. Figure 2. Survival analysis (Kaplan-Meier): standard (S) group versus nonstandard (NS) group. groups or S and NS2 groups, we find that the difference was significant (P 0.041, P 0.001). Both patient survival and graft survival were influenced by the cumulative number of risk factors. Finally, the univariate analysis of the donor risk factors detected hemodynamic factors as predictive of graft failure (P 0.024) and death (P 0.018; Table 1). In the multivariate analysis, adjusted for recipient age and donor and recipient gender, hemodynamic factors and MELD score in the recipient were the only variables independently associated with graft failure (P 0.006, P 0.012) and death (P 0.018, P 0.042; Table 1). The probability of receiving a liver transplant for recipients on our waiting list increased every year after the change in donor selection through the use of ECDs despite the lack of growth in the number of cadaver donors per million people per year (Fig. 5). DISCUSSION The use of ECDs may be the simplest way to increase the donor supply. 6 However, initial graft nonfunction is associated with high postoperative morbidity and mortality, although severe damage to the graft may be overcome within 3 or 4 weeks. 7 Ideally, good liver grafts should be used for transplantation, but because of the organ shortage we are prompted to use ECDs. The lesson that we have learned is that the worst thing that can happen to a potential liver transplant recipient is not to be transplanted. 8 More and more liver transplant centers are adopting the practice of using ECD liver grafts. In fact, 24% of all

6 USE OF EXTENDED CRITERIA DONOR LIVER GRAFTS 225 TABLE 6. Medical and Surgical Complications in the Two Main Groups Complications S Group (n 58) NS Group (n 57) P Value ACR 2 (3.44%) 5 (8.77%) HCV viral recurrence 12 (20.70%) 15 (26.31%) HCC recurrence 1 (1.72%) 2 (3.51%) Vascular complication 3 (5.17%) 2 (3.51%) Biliary complication 17 (29.31) 17 (29.82%) Primary graft nonfunction 0 3 (5.26%) Graft malfunction 2 (3.44%) 4 (7.02%) Abbreviations: ACR, acute cellular rejection; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; NS, nonstandard; S, standard. TABLE 7. Medical and Surgical Complications in the Three Subgroups S Group (n 58) NS1 Group (n 44) NS2 Group (n 23) P Value Acute cellular rejection 2 (3.44%) 4 (9.09%) 2 (8.70%) 0.29 HCV viral recurrence 12 (20.70%) 10 (22.72%) 7 (30.43%) 0.64 HCC recurrence 1 (1.72%) 2 (4.54%) Vascular complication 3 (5.17%) 1 (2.27%) 1 (4.35) 0.76 Biliary complication 17 (29.31) 14 (31.81%) 5 (21.74) 0.68 Primary graft nonfunction 0 1 (2.27%) 2 (8.70) 0.07 Graft malfunction 2 (3.44%) 2 (4.54%) 2 (8.69) 0.61 Abbreviations: HCC, hepatocellular carcinoma; HCV, hepatitis C virus; MELD, Model for End-Stage Liver Disease; NS1, nonstandard 1; NS2, nonstandard 2; S, standard. Figure 3. Survival analysis (Kaplan-Meier): standard (S), nonstandard 1 (NS1), and nonstandard 2 (NS2) groups. liver transplants in the United States are now performed with ECD liver grafts. 9 In the MELD score era, 8 the immediate expansion of the donor pool determines an increased risk of graft failure following liver transplantation. On the other hand, recipients with a high MELD are those more likely to die while on the waiting list if not transplanted. 10,11 However, it has recently been shown 12 that the increased risk of liver failure in recipients with a high MELD score ( 27) when ECD liver grafts are used is no greater than that seen in patients with a lower MELD. For this purpose, several recent studies have tried to

7 226 GRUTTADAURIA ET AL. Figure 4. Survival analysis (Kaplan-Meier): standard (S), nonstandard 1 (NS1), and nonstandard 2 (NS2) groups. Figure 5. Trends in liver transplantation at our center. propose ideal donor-recipient scores in order to predict the best donor-recipient match Use of ECD liver grafts has been debated and advocated for decades, 16 and several reports have failed to unify criteria for ECD liver grafts that are universally accepted 6 ; the most important message from this body of literature is the acceptance of the increased risk of failure determined by the use of ECD liver grafts, although, on the other hand, their use immediately expands the donor pool. Critical in this regard is the adoption of a policy of detailed informed consent that addresses both the risks generated by the use of that specific ECD graft and the risk generated by not using that graft for the specific clinical condition of the recipient. In this study, we report our experience with a dynamic process based on the use of ECD liver grafts rather than offering a strict definition of what constitutes an ECD liver graft. At our center in Sicily, with a waiting list for orthotopic liver transplantation of more than 200 potential recipients, we offset the organ shortage with the use of ECD 7 and the development of a partial liver transplant program. 17,18 This has allowed our center to perform more than 400 liver transplants since In our center, we experienced a dramatic increase in the number of liver transplantations performed since the acceptance of ECDs, reducing the dropout from the list to 9% from 14.1% (P 0.04). In our experience, criteria for the use of ECD livers for orthotopic liver transplantation were the following: optimal donor care; an expert donor team, preferably from the same institution; minimized cold ischemic time; and routine use of liver biopsy. On the basis of our data, it would seem evident that

8 USE OF EXTENDED CRITERIA DONOR LIVER GRAFTS 227 the outcome in this study is influenced by cumulative risk factors in the ECD pool. In fact, both patient survival and graft survival decrease with an increase in the number of risk factors, especially in comparison with the outcome of recipients transplanted with grafts procured from ideal donors. The risk factors in the donors that seem to play a role in the failure of the transplant are those indicating severe hemodynamic instability. Despite this fact, our experience suggests that a change in donor selection criteria, namely, a more aggressive acceptance of ECDs, did not negatively influence the overall outcome. It is critical to realize that there are no golden rules for identifying the best donor-recipient match, although there seems to be an overall benefit in accepting ECD liver grafts. This policy could be seen as the result of a natural evolution, over time, of a transplant program toward changing the approach to donor selection without sacrificing posttransplant survival. ACKNOWLEDGMENT The authors thank Warren Blumberg and Antonella Vassallo for their help in editing this article. REFERENCES 1. Tector AJ, Mangus RS, Chestovich P, Vienna R, Fridell JA, Milgrom ML, et al. Use of extended criteria livers decreases wait time for liver transplantation without adversely impacting post transplant survival. Ann Surg 2006;244: Heffron TG, Gruttadauria S, Campi O, Cavanna JM, Pillen T. Surgical innovations in pediatric liver transplantation: reduced-size, split, and living-related transplantation. Prob Gen Surg 1998;15: Gridelli B, Remuzzi G. Strategies for making more organs available for transplantation. N Engl J Med 2000;343: Cameron AM, Ghobrial RM, Yersiz H, Farmer DG, Lipshutz GS, Gordon SA, et al. Optimal utilization of donor grafts with extended criteria: a single-center experience in over 1000 liver transplants. Ann Surg 2006;243: Bailar JC III, Mosteller F. Guidelines for statistical reporting in articles for medical journals. Ann Intern Med 1998; 108: Renz JF, Kin C, Kinhabwala M, Jan D, Varadarajan R, Goldstein M, et al. Utilization of extended donor criteria liver allografts maximizes donor use and patient access to liver transplantation. Ann Surg 2005;242: Gruttadauria S, Wallis Marsh J, Cintorino D, Biondo D, Luca A, Arcadipane A, et al. Adult to adult living-related liver transplant: report on an initial experience in Italy. Dig Liver Dis 2007;39: Merion RM, Schaubel DE, Dykstra DM, Freeman RB, Port FK, Wolfe RA. The survival benefit of liver transplantation. Am J Transplant 2005;5: Organ Procurement and Transplantation Network. Available at: Accessed July 1, Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg CL, et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001; 33: Freeman RB, Wiesner RH, Edwards E, Harper A, Merion R, Wolfe R, for the United Network for Organ Sharing Organ Procurement and Transplantation Network Liver and Transplantation Committee. Results of the first year of the new liver allocation plan. Liver Transpl 2004;10: Maluf DG, Edwards EB, Kauffman HM. Utilization of extended donor criteria liver allograft: is the elevated risk of failure independent of the model for end-stage liver disease score of the recipient? Transplantation 2006;82: Feng S, Goodrich NP, Brann-Gresham JL, Dykstra DM, Punch JD, DebRoy MA, et al. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant 2006;6: Briceno J, Solorzano G, Pera C. A proposal for scoring marginal liver grafts. Transpl Int 2000;13(suppl): Tekin K, Imber CJ, Atli M, Gunson BK, Bramball SR, Mayer D, et al. A simple scoring system to evaluate the effects of cold ischemia on marginal liver donors. Transplantation 2004: Alexander JW, Vaughn WK. The use of marginal donors for organ transplantation. Transplantation 1991;51: Gruttadauria S, Cintorino D, Mandalà L, Musumeci A, Volpes R, Vizzini GB, et al. Acceptance of marginal liver donors increases the volume of liver transplant: early results of a single-center experience. Transplant Proc 2005; 37: Cescon M, Spada M, Colledan M, Torre G, Andorno E, Valente U, et al. Feasibility and limits of split liver transplantation from pediatric donors: an Italian multicenter experience. Ann Surg 2006;244: