Evaluation of the updated definition of early allograft dysfunction in donation after brain death and donation after cardiac death liver allografts

Kris P Croome, William Wall, Douglas Quan, Sai Vangala, Vivian McAlister, Paul Marotta and Roberto Hernandez-Alejandro

London, Canada

Original Article / Transplantation

Evaluation of the updated definition of early allograft dysfunction in donation after brain death and donation after cardiac death liver allografts

Kris P Croome, William Wall, Douglas Quan, Sai Vangala, Vivian McAlister, Paul Marotta and Roberto Hernandez-Alejandro

London, Canada

BACKGROUND:An updated definition of early allograft dysfunction (EAD) was recently validated in a multicenter study of 300 deceased donor liver transplant recipients. This analysis did not differentiate between donation after brain death (DBD) and donation after cardiac death (DCD) allograft recipients.

METHODS:We reviewed our prospectively entered database for all DBD (n=377) and DCD (n=38) liver transplantations between January 1, 2006 and October 30, 2011. The incidence of EAD as well as its ability to predict graft failure and survival was compared between DBD and DCD groups.

RESULTS:EAD was a valid predictor of both graft and patient survival at six months in DBD allograft recipients, but in DCD allograft recipients there was no significant difference in the rate of graft failure in those with EAD (11.5%) compared with those without EAD (16.7%) (P=0.664) or in the rate of death in recipients with EAD (3.8%) compared with those without EAD (8.3%) (P=0.565). The graft failure rate in the first 6 months in those with international normalized ratio≥1.6 on day 7 who received a DCD allograft was 37.5% compared with 6.7% for those with international normalized ratio <1.6 on day 7 (P=0.022).

CONCLUSIONS:The recently validated definition of EAD is a valid predictor of patient and graft survival in recipients of DBD allografts. On initial assessment, it does not appear to be a useful predictor of patient and graft survival in recipients of DCD allografts, however a study with a larger sample size ofDCD allografts is needed to confirm these findings. The high ALT/AST levels in most recipients of DCD livers as well as the predisposition to biliary complications and early cholestasis make these parameters as poor predictors of graft failure. An alternative definition of EAD that gives greater weight to the INR on day 7 may be more relevant in this population.

(Hepatobiliary Pancreat Dis Int 2012;11:372-376)

donor risk index; model for end-stage liver disease; early allograft dysfunction; donation after brain death

Introduction

As the transplant community continues to pursue extended criteria organs, it is important to evaluate the impact on patient and graft survival using clinical and translational studies. Multiple previous definitions of early allograft dysfunction (EAD) were suggested in the pre-MELD era.[1-5]Several more recent definitions of EAD were reported from single centers; however these were not validated in large multicenter populations.[6-8]An updated definition of EAD was validated with graft and patient outcome at 6 months in patients receiving deceased donor liver allografts in a multicenter population.[9]EAD can be used as a clinical end-point in future studies acting as a proxy or surrogate for graft and patient survival. The population studied by Olthoff et al[9]consisted of both donation after brain death (DBD) (90%) and donation after cardiac death (DCD) (10%) allograft recipients. The analysis did not specifically address the validity of the aforementioned definition in specific donor types. There is a need to determine the validity of the definition of EAD by source of donor allografts.

DCD liver allografts have a unique subset of post-operative complications because of the ischemicreperfusion injury inherent to warm ischemia. Despite this, with careful organ selection acceptable long-term results of DCD liver allografts have been shown.[10-12]Increased ALT and AST levels in most recipients of DCD livers as well as the cholestasis associated with biliary ischemia may make certain parameters less accurate as predictors of graft failure.[13]We hypothesized that the updated version of EAD would prove to be a better predictor of graft and patient survival at 6 months in DBD recipients compared with DCD recipients because of the unique factors inherent to the latter category of patients.

Methods

After approval from our Institutional Review Board, we reviewed our prospectively entered database for all DBD and DCD liver transplantation recipients at our transplant program between January 1, 2006 and October 30, 2011.

Model of end-stage liver disease (MELD) scores and donor risk index (DRI) were calculated using previously described techniques.[14,15]MELD scores were calculated based on lab values and do not represent adjusted MELDs based on exception points. EAD was defined as the presence of one or more of the following previously defined postoperative laboratory analyses reflective of liver injury and function: bilirubin ≥10 mg/dL (171 μmol/L) on day 7, international normalized ratio (INR)≥1.6 on day 7, and alanine or aspartate aminotransferases >2000 IU/L within the first 7 days after liver transplantation.[9]The validity of the updated definition of EAD at our institution in predicting death or need for retransplantation within the 6-month period following transplantation was examined in DBD and DCD liver transplants. The incidence of EAD as well as its ability to predict graft failure and survival was compared between the DBD and DCD groups.

Currently in Canada, organs are allocated by region on a 4-point scale reflecting the severity of illness.[16]All DCD allografts were procured from controlled DCD donors using techniques previously described by our institution.[17,18]Withdrawal was performed in the intensive care unit in 36 (95%) patients and in the operating room in 3 (7.9%). Warm ischemia time (WIT) was defined as the time elapsed from withdrawal of life support until aortic cold perfusion was initiated. Mean arterial pressure (MAP) was recorded in all patients from the time of withdrawal of life support until declaration of death. At present, we generally use a maximal WIT of 30 minutes and a maximal donor age of 55 as a cutoff when deciding to use livers; however, each case is assessed individually. During the initial development of our DCD program, several organs with longer WITs were used. Re-warming ischemia time during anastomosis in the recipient ranged from 45 to 70 minutes. Graft failure was defined as death or need for retransplantation within the 6-month period after transplantation.

Statistical analyses were performed using STATA version 10.0 software (STATA Corp., College Station, TX). Univariate logistic regression was performed. All statistical tests were considered significant whenP<0.05.

Results

Between January 1, 2006 and October 30, 2011, 415 adult patients receiving DBD and DCD liver allografts were identified. Of these, 377 underwent liver transplantation with DBD allografts. In DBD recipients, the mean donor age was 45.9±10.0 years. The mean cold ischemia time was 7.2±2.5 hours. The average DRI score was 1.51±0.39. The average recipient age was 54.9±10.0 years. The mean MELD score was 18.98±9.77. Males represented 74% of the recipients (Table 1).

A total of 38 patients underwent DCD liver transplantation during the time period. In DCD recipients, the mean donor age was 41.8±13.2 years. The median WIT was 27 minutes (range 18-124). The mean cold ischemia time was 5.6±1.1 hours. The average DRI score was 2.03±0.35. The mean recipient age was 53.6±8.0 years. The mean MELD score was 17.50±8.30. Eighteen patients were diagnosed with hepatitis C virus, 9 with alcoholic cirrhosis, 2 with autoimmune hepatitis, 3 with nonalcoholic steatohepatitis, 2 with primary sclerosing cholangitis, and 4 with "other". Males represented 84% of the recipients (Table 1).

Table 1. Patient demographics in the DBD and DCD groups

Table 2. Rate of graft failure and death in patients with and without EAD

In recipients of DBD allografts, the overall incidence of EAD was 23.6%. The death rate in those with EAD was 21% compared with 2.8% in those without [relative risk (RR)=7.69; 95% CI: 3.48, 16.95] (P<0.001). The graft failure rate in those with EAD was 28% compared with 5.6% for those without (RR=5.06; 95% CI: 2.83, 9.04) (P<0.001) (Table 2). The sensitivity and specificity for predicting graft failure in those who met the definition of EAD were 61% and 81%, while for predicting death were 70% and 80%, respectively.

The overall incidence of EAD was 68.4% in DCD recipients. There was no significant difference in the rate of graft failure between those with EAD (11.5%) and without (16.7%) (RR=0.69; 95% CI: 0.13, 3.62) (P=0.664). There was no significant difference in the rate of death between those with EAD (3.8%) and those without (8.3%) (RR=0.46; 95% CI: 0.03, 6.77) (P=0.565) (Table 2). The sensitivity and specificity for predicting graft failure in those who met the definition of EAD were 60% and 30%, while for predicting death were 50% and 31%, respectively.

In contrast, in logistic regression in those who received DCD allografts, bilirubin on day 7 (P=0.474), and alanine or aspartate aminotransferases within the first 7 days (P=0.289) were not associated with the odds of graft failure. However, INR on day 7 was associated with the odds of graft failure (P=0.040).

The rate of EAD was higher in the DCD (68.4%) group than in the DBD group (23.6%) (P<0.001). The distribution of variables in the patients who qualified as having EAD in the DBD and DCD groups are shown inTable 3. The most common criterion by which recipients of DBD allografts met the definition of EAD was elevated bilirubin on postoperative day 7. The most common criterion by which recipients of DCD allografts met the definition of EAD was elevated alanine or aspartate aminotransferases >2000 IU/L within the first 7 days. Elevated level of aminotransferases was the criterion by which 92% of DCD recipients met the definition of EAD (Fig). Graft failure rate in the first 6 months in those with INR≥1.6 on day 7 was 37.5% compared with 6.7% for those with INR<1.6 on day 7 (P=0.022).

Table 3. Individual components of EAD in patients who met the criteria of EAD

Fig. Mean ALT/AST in DBD and DCD groups over the first 7 days post-operatively.

Discussion

The new definition of EAD was recently validated as a predictor of both graft and patient survival at 6 monthsin a multicenter study of 300 deceased donor liver transplant recipients.[9]The recipients were a combined population of both DBD (90%) and DCD (10%). In the current study, we investigated the validity of this definition of EAD depending on recipient graft type (DBD or DCD).

In the present study the incidence of EAD in recipients of DBD allografts was 23.6%, which is comparable to that reported by previous authors (23.2%).[9]In addition, EAD proved to be a valid predictor of death and graft failure in recipients of DBD livers when compared with patients who did not meet the criteria of EAD; relative risk 7.69 and 5.06, respectively. However, the incidence of EAD was significantly higher in recipients of DCD allografts (68.4%) than in recipients of DBD allografts (23.6%). Meeting the definition of EAD in DCD allograft recipients was not a valid predictor of death and graft failure at 6 months. In DCD allograft recipients there was no significant difference in the rate of graft failure or death in those with EAD compared with those without EAD. While these results are very interesting, one must be cautious in their interpretation given the relatively small number of DCD cases and the low graft failure and mortality rates in the present study. Indeed, the present study is the first to suggest that the new definition of EAD cannot be applied to all populations of patients receiving deceased donor liver transplants. Despite the small number of DCD cases in our study there is a biological plausibility that a definition of EAD based on ALT/AST levels in the first week might be inappropriate for DCD recipients. DCD allografts are, by their very nature, subjected to WIT, resulting in elevated ALT/AST levels in most recipients. This was clearly demonstrated in the present study where over half the DCD recipients had elevated ALT/AST (>2000 IU/L) and has also been shown by our group in animal models.[19]

A study[20]showed that in pediatric recipients of DCD allografts, serum AST was significantly higher on days 1, 2 and 3, and thereafter was not different from DBD recipients. In this group of DCD recipients there was a patient and graft survival of 100% at a median follow-up of 41.8 months. This correlates with the findings of the present study that showed near normal ALT/AST values by day 7. The initial rise in ALT/AST clearly highlights the acute liver injury that occurs as a result of warm ischemia. In many cases, however, this acute injury is reversible, as demonstrated by the normalization of the liver function tests by day 7. The INR on day 7, on the other hand, is an indicator for synthetic function of the new allograft. This index is therefore more predictive of how the graft will ultimately function, and is a more robust predictor than the almost ubiquitous elevation of liver function tests.

In addition, cholestasis and elevated bilirubin are also commonly seen in DCD allografts. In addition in logistic regression, bilirubin on day 7, alanine or aspartate aminotransferases within the first 7 days, and INR on day 7 were all significantly associated with the odds of graft failure in DBD allograft recipients, while only INR on day 7 was associated with graft failure in DCD allograft recipients.

Interestingly, graft failure rate in the first 6 months in those with INR≥1.6 on day 7 was 37.5% compared with 6.7% for those with INR<1.6 on day 7. The incidence of DCD allograft recipients meeting the definition of EAD by INR alone was 21%. This is similar to the incidence of EAD using all three parameters in DBD allograft recipients in both our study (23.6%) and that by Olthoff et al (23.2%). These findings suggest that INR on day 7 is a good predictor of both graft and patient survival.

In DCD allograft recipients, not meeting the updated definition of EAD still retained some sensitivity as a predictor of good graft and patient survival at 6 months (sensitivity 60%); meeting the definition of EAD was not a good predictor (specificity 30%) because most recipients of DCD liver allografts have elevated ALT/AST.

Limitations of the current study are the relatively small number of DCD recipients as well as its singlecenter nature. A larger multicenter study to define a postoperative surrogate predictor of graft and patient survival at 6 months, placing more weight on INR at day 7, is needed.

In conclusion, our study lends additional support to the updated definition of EAD as a valid predictor of death and graft failure in recipients of DBD livers. This definition of EAD does not appear to be a useful predictor of patient and graft survival in recipients of DCD allografts. The high ALT/AST levels in most recipients of DCD livers and the predisposition to biliary complications make these parameters as poor predictors of graft failure. An alternative definition of EAD is likely needed for this population. A definition of EAD in DCD recipients using an INR≥1.6 on day 7 may provide a better predictor of EAD than the new definition of EAD for DBD recipients.

Contributors:HR proposed the study. CKP, WW, MP and HR, wrote the first draft. CKP, VS and MV analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. HR is the guarantor.

Funding:None.

Ethical approval:This study was approved by the Institutional Review Board.

Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

1 Ardite E, Ramos C, Rimola A, Grande L, Fernández-Checa JC. Hepatocellular oxidative stress and initial graft injury in human liver transplantation. J Hepatol 1999;31:921-927.

2 González FX, Rimola A, Grande L, Antolin M, Garcia-Valdecasas JC, Fuster J, et al. Predictive factors of early postoperative graft function in human liver transplantation. Hepatology 1994;20:565-573.

3 Mor E, Tillery W, Solomon H, Netto G, Watemberg I, Klintmalm GB. The predictive value of hepatocyte glycogen content on liver allograft biopsy. Correlation with early graft function. Transplantation 1995;59:141-143.

4 Ploeg RJ, D'Alessandro AM, Knechtle SJ, Stegall MD, Pirsch JD, Hoffmann RM, et al. Risk factors for primary dysfunction after liver transplantation--a multivariate analysis. Transplantation 1993;55:807-813.

5 Strasberg SM, Howard TK, Molmenti EP, Hertl M. Selecting the donor liver: risk factors for poor function after orthotopic liver transplantation. Hepatology 1994;20:829-838.

6 Ben-Ari Z, Weiss-Schmilovitz H, Sulkes J, Brown M, Bar-Nathan N, Shaharabani E, et al. Serum cholestasis markers as predictors of early outcome after liver transplantation. Clin Transplant 2004;18:130-136.

7 Nanashima A, Pillay P, Verran DJ, Painter D, Nakasuji M, Crawford M, et al. Analysis of initial poor graft function after orthotopic liver transplantation: experience of an australian single liver transplantation center. Transplant Proc 2002;34:1231-1235.

8 Tekin K, Imber CJ, Atli M, Gunson BK, Bramhall SR, Mayer D, et al. A simple scoring system to evaluate the effects of cold ischemia on marginal liver donors. Transplantation 2004;77:411-416.

9 Olthoff KM, Kulik L, Samstein B, Kaminski M, Abecassis M, Emond J, et al. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl 2010;16:943-949.

10 Bellingham JM, Santhanakrishnan C, Neidlinger N, Wai P, Kim J, Niederhaus S, et al. Donation after cardiac death: a 29-year experience. Surgery 2011;150:692-702.

11 Hong JC, Yersiz H, Kositamongkol P, Xia VW, Kaldas FM, Petrowsky H, et al. Liver transplantation using organ donation after cardiac death: a clinical predictive index for graft failure-free survival. Arch Surg 2011;146:1017-1023.

12 Foley DP, Fernandez LA, Leverson G, Anderson M, Mezrich J, Sollinger HW, et al. Biliary complications after liver transplantation from donation after cardiac death donors: an analysis of risk factors and long-term outcomes from a single center. Ann Surg 2011;253:817-825.

13 Detry O, Donckier V, Lucidi V, Ysebaert D, Chapelle T, Lerut J, et al. Liver transplantation from donation after cardiac death donors: initial Belgian experience 2003-2007. Transpl Int 2010;23:611-618.

14 Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 2000;31:864-871.

15 Feng S, Goodrich NP, Bragg-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;6:783-790.

16 Bazarah SM, Peltekian KM, McAlister VC, Bitter-Suermann H, MacDonald AS. Utility of MELD and Child-Turcotte-Pugh scores and the Canadian waitlisting algorithm in predicting short-term survival after liver transplant. Clin Invest Med 2004;27:162-167.

17 Hernandez-Alejandro R, Croome KP, Quan D, Mawardi M, Chandok N, Dale C, et al. Increased risk of severe recurrence of hepatitis C virus in liver transplant recipients of donation after cardiac death allografts. Transplantation 2011;92:686-689.

18 Hernandez-Alejandro R, Caumartin Y, Chent C, Levstik MA, Quan D, Muirhead N, et al. Kidney and liver transplants from donors after cardiac death: initial experience at the London Health Sciences Centre. Can J Surg 2010;53:93-102.

19 Hernandez-Alejandro R, Zhang X, Croome KP, Zheng X, Parfitt J, Chen D, et al. Reduction of Liver Ischemia Reperfusion Injury by Silencing of TNF-α Gene with shRNA. J Surg Res 2011 Nov 1.

20 Bartlett A, Vara R, Muiesan P, Mariott P, Dhawan A, Mieli-Vergani G, et al. A single center experience of donation after cardiac death liver transplantation in pediatric recipients. Pediatr Transplant 2010;14:388-392.

Received December 28, 2011

Accepted after revision March 13, 2012

ic regression in those who

DBD allografts, bilirubin on day 7, alanine or aspartate aminotransferases within the first 7 days, and INR on day 7 were associated with the odds of graft failure (P=0.029, 0.041, and 0.030, respectively).

Author Affiliations: Multi-Organ Transplant Program, London Health Sciences Centre (Croome KP, Wall W, Quan D, Vangala S, McAlister V, Marotta P and Hernandez-Alejandro R) and Department of Surgery, Division of General Surgery (Croome KP, Wall W, Quan D, McAlister V and Hernandez-Alejandro R) and Division of Gastroenterology (Marotta P), The University of Western Ontario, London, Canada

Kris P Croome, MD, MS, London Health Sciences Centre-University Hospital, 339 Windermere Rd. London, ON, N6A 5A5, Canada (Tel: 519-494-9945; Email: kris.croome@hotmail.com)

? 2012, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(12)60194-5