The concept of using organs from controlled donors following donation after cardiac death (DCD) as alternative to expand the donor pool was conceived in the early 1990s, relying on successes reported by renal transplant programs (1–3). Initial results of liver transplantation (LT) with DCD grafts were promising, and the transplant community embraced this to supplement the existing donor pool. In the United Kingdom, there has been a steady increase in activity of DCD donation, contributing to one third of solid organ transplant activity (4). Apart from specific complications such as ischemic-type biliary strictures (ITBS), recent experience suggests that early outcomes from controlled DCD are comparable to other forms of organ donation (5–8).
Use of livers from DCD was introduced into the LT program at Queen Elizabeth Hospital, Birmingham, in 2004; since then, the use of these grafts has increased steadily in parallel with UK donor activity. The early phase of this DCD program used fairly conservative donor selection criteria. Once satisfactory initial outcomes were achieved, these criteria were relaxed to further increase the DCD donor pool. The criteria included length of donor warm ischemia, advanced age, prolonged cold ischemia, and donor obesity. The aim of this study was to report our experience, comparing the outcomes of DCD liver grafts from the “Extended” criteria DCD donors.
A total of 127 potential DCD donors were made available to our institution during the study period; 21 donors (16%) were unsuitable for organ donation on medical grounds, and 28 (22%) offers were accepted but these did not proceed with donation because of time criteria for DCD donation. Further 15 (12%) grafts were discarded at the time of retrieval or subsequently, for different other reasons (e.g., liver not well perfused, cirrhotic liver, or severe steatosis of the graft). A total of 63 (50%) grafts were used in adult patients undergoing LT as a whole DCD graft. During the same study period, 581 grafts were used from donation after brain death (DBD) donors and 4 domino LTs. The DCD grafts comprised 10% of all adult LTs over the study period.
On the basis of definition outlined under Materials and Methods, 52% (n=33) of patients received a “Standard” DCD liver, whereas the remainder (48%, n=30) received an Extended graft (21 with one additional factor, 8 with two, and 1 with three additional factors). Donor characteristics comparing the two groups are shown in Table 1. According to the selection criteria, there was an obvious tendency in the Extended group toward a greater age, body mass index (BMI), and donor warm ischemia time (dWIT). These factors contributed to a higher donor risk index in the Extended group, reaching significant difference (P=0.044; t test).
A Menghini core postreperfusion liver biopsy was performed in most cases (n=48, 76%) before closure; seven biopsies were missing in the Standard and eight in the Extended group. Liver steatosis was reported as mild, moderate, or severe if, less than 30%, 30% to 60%, and more than 60% macrovesicular steatosis was seen, respectively (9). Only one recipient in the Standard group received a graft with severe macrosteatosis, whereas five DCD grafts with moderate macrosteatosis were in both groups; remaining patients received a graft with no or mild steatosis. Recipient characteristics are listed in Table 2. As expected, cold ischemia time (CIT) was also longer in the Extended group, and there was also a higher preponderance of patients transplanted with hepatocellular carcinoma (HCC) as major indication in this group.
There was no significant difference in the duration of hospital stay (median hospital stay, Standard group vs. Extended group 10.5 vs. 13 days, P=0.46). Peak laboratory values at day 1, 7, and at 1-month post-LT were also compared as shown in Table 3. The hepatic and renal function biochemistry was not significantly different in the two groups. Mycophenolate was started in patients presenting with impaired renal function post-LT, and this comprised 70% (n=23) and 53% (n=16) of recipients in the Standard and Extended group, respectively. This was introduced at a median time of 1 (range 1–30) and 3 (range 1–24) days. There was also no difference in renal replacement therapy requirement for perioperative renal dysfunction, despite there was a greater frequency of continuous veno-venous hemofiltration use in the Standard group (33%, n=11 vs. 27%, n=8 in the Extended group; P=0.595).
Primary Nonfunction and Early Retransplantation
One episode of primary nonfunction (PNF) occurred in both groups, leading to retransplantation. The patient in the Standard group is still alive after having received a new graft 2 days after LT. The recipient in the comparison group underwent retransplantation at 1 week followed by death because of multiorgan failure after retransplantation. Overall early retransplantation rate (within 30 days) was 5% and included the above two patients, in addition to another recipient diagnosed with early hepatic artery thrombosis (HAT) in the Standard group. All retransplants were carried out using DBD full liver grafts.
A total of 18% (n=6) recipients of Standard DCD grafts vs. 7% (n=2) in the Extended group developed biliary complications; this was not statistically significant (P=0.261). Details of biliary complications are shown in Table 4. Of the ITBS, one patient in the Extended group presented 4 months post-LT with prominent intrahepatic ducts on ultrasound imaging. Magnetic resonance cholangiography (MRC) revealed a dominant main duct stricture and a typical intrahepatic pattern of ITBS of the biliary tree; this patient subsequently underwent biliary reconstruction 11 months post-LT. However, liver biochemistry remains persistently deranged; hence, this patient is under evaluation for retransplantation. The other ITBS occurred in the Standard group was proven by endoscopic retrograde cholangiopancreatography (ERCP) 12 months since LT. This patient was listed for retransplantation; however, the patient died from multiorgan failure secondary to biliary sepsis at 17 months while on the wait list.
All biliary anastomotic strictures (n=4) in both groups were managed by percutaneous transhepatic cholangiogram and balloon dilatation with biliary drainage, alone or in combination with ERCP. Only one of three patients in the Standard group required a biliary reconstruction at 22 months post-LT, having confirmed the persistent stricture by MRC. The other biliary anastomotic strictures in this group became clinically evident at 1 week and 4 months post-LT. The only biliary stricture in the Extended criteria group presented at 2 weeks. All these patients were managed with successful internal biliary drainage in the short term.
Of the anastomotic bile leaks, both occurring in the Standard group, one patient required a refashioning of hepaticojejunostomy 1 month after LT. This bile leak probably was related to the ischemia of donor bile duct. The other bile leak occurred 22 days post-LT and was treated conservatively with a percutaneous drain of the bile collection.
Characteristics of the DCD donors were analyzed to determine which factors are contributory in the development of biliary complications. However, univariate or multivariate Cox regression analysis was not able to identify any donor factor associated with biliary complication, and limited number of cases may have been contributory (Table 5).
In the Extended group, one recipient developed left hepatic artery stenosis (HAS) demonstrated on contrast- enhanced computed tomography performed, and this was managed conservatively. In the Standard group, four (12%) presented with vascular complications (three HATs and one HAS). One HAT required retransplantation with a DBD liver on day 7. One more case of HAT occurred 1 month from LT after relaparotomy for bile leak described earlier; this patient was listed for retransplantation but later suspended because of improved liver function possibly from collateralization of the arterial supply. Late HAT occurred in a recipient almost 3 years post-LT presenting with liver bilomas and abscesses, and this patient is now on active waiting list for retransplantation. The only patient with HAS in this group was identified during investigations performed to examine the biliary system 6 months post-LT but did not require any intervention. The vascular complications are also summarized in Table 4. Overall, there was no difference of vascular complications between the two groups (P=0.199).
Overall 1-year mortality was 11% (n=7) after LT equally distributed in the two groups. Of the deaths in the Standard group, infective complications contributed to two (invasive fungal infection from Aspergillus at day 25 post-LT and viral disease from Varicella Zoster virus at day 38 post-LT). Other causes of mortality included a massive cerebrovascular accident at day 5 and an ischemic cardiac complication at day 6. Causes of death in the Extended group were due to significant hemorrhage compounded by coagulopathy on day 1 in one patient. One further patient although recovered well from LT subsequently developed abdominal distension, acidosis, and symptoms of intestinal obstruction. Mechanical obstruction was ruled out, however, this patient died on day 15 from nondiarrheal Clostridium difficile infection. PNF contributed to the death of the last patient in this group.
There were two late deaths in the Extended group, both for HCC recurrence, one at 14 months post-LT and one after 21 months. Both were found to be outside Milan criteria on the histology of the native liver, having been within UK listing criteria at time of transplantation (10, 11). Attempted analysis of the different risk factors for graft failure and early mortality did not identify common risk factors.
Follow-Up and Survival
Median follow-up period at the time of the study was 25 months (range: 5 days to 77 months) in the Standard group and 18.5 months (range: 1 day to 49 months) in the Extended group. One-year patient and graft survival were 88% and 82% in the Standard group and 90% and 90% in the Extended group, respectively (Fig. 1). These were not significantly different between the two groups.
The renewed interest in DCD donation has resulted in some centers exploring the maximum potential of DCD donor organs to help to address the disparity between organ supply and demand. This study evaluated the feasibility of LT from DCD donors with Extended criteria. Organ donation rates have remained static over the past decade, coupled with the fact that the age of the average donor is rising. World over, more than 60% of donors are older than 40 years. Feng et al. (12) have shown donor age more than 60 years as an important predictor of graft failure. Many authors have reported inferior outcomes when using older donors (13–16). In contrast to these reports, other analyses have failed to demonstrate significant differences in short/medium-term graft and patient survival using donors older than 60, 70, and even 80 years (17–19) although these are likely to be highly selected donor livers. These reports and others have demonstrated excellent outcomes using older donors, especially in the absence of other donor risk factors and in carefully selected recipients (20, 21). However, there is much less information available on outcomes after transplantation with older DCD livers. For these reasons, it is appropriate to selectively use these older DCD liver grafts only when other risk factors are well controlled such as absence of significant steatosis, short CIT, and dWIT to mitigate this unfavorable donor characteristic.
There are still other unresolved questions about the potential risks involved with the use of Extended DCD livers, in particular related to a prolonged dWIT and CIT that can be responsible for a higher rate of PNF and late occurring ITBS. American Society of Transplant Surgeons (22) recommends that dWIT and CIT should be kept below 30 min and 8 hr, respectively, to avoid an increased rate of complications using DCD grafts. Selection criteria for a DCD donor liver are usually more restrictive because of a higher potential risk of PNF and biliary complications. When using livers from extended DCDs, it is logical to argue against compounding multiple risk factors (i.e., long dWIT, CIT, advanced age, obesity, moderate or severe macrosteatosis, etc.), which may contribute to the increased susceptibility of these grafts to PNF. Strasberg et al. (23) reported that the major donor related risk factors for DBD livers are moderate macrosteatosis, CIT longer than 12 hr, and donor age more than 50 years.
Moderate or severe hepatic macrosteatosis, which is frequently associated with donor obesity, is considered an important risk factor for preservation injury with higher incidence of postoperative graft dysfunction. Severely fatty livers are more susceptible to preservation and ischemia-reperfusion injury that could lead to initial poor function and PNF (24). In our series, only one patient has received a graft with moderate to severe steatosis, the indication for transplant was seronegative sub-acute hepatitis, and this recipient is still alive after 44 months post-LT without having developed any complication. Donors with high BMI also have associated comorbidity including cardiovascular disease, dyslipidemia, metabolic syndrome, type II diabetes, and systemic hypertension, thus increasing the degree of risk associated with these donors. Moreover, a high BMI is likely to lengthen the time from skin incision to cannulation and aortic perfusion resulting in a longer dWIT. Hepatocyte ATP depletion occurs during dWIT, and longer dWIT acts synergistically with cold preservation, culminating in even greater energy depletion. Therefore, grafts with prolonged dWIT will be less tolerant to longer cold preservation, supporting the case to keep the CIT short (25, 26) in this situation. It is widely accepted that CIT alone acts as an independent predictor with influence on graft function. CIT and sharing of liver grafts outside the local donor service area are associated with an increased risk of poor graft outcome (12). Therefore, we have minimized CIT by making efforts to reduce organ transfer time, early start to the recipient's operation, and selection of technically uncomplicated recipients to reduce the time of the hepatectomy. In the United Kingdom, we are able to allocate this organ locally, which is usually the retrieving center to minimize CIT and promote greater use of these organs. This was not always achievable in those circumstances when the liver was recovered outside our allocation zone as seen on nine Extended grafts that were retrieved by other centers against only four in the Standard group.
A challenge that arises with the use of Extended donor organs is to decide which recipients should be chosen to have maximum benefit from this additional organ resource. Ideally, these DCD livers should be used in recipients capable of withstanding a period of initial dysfunction. Two distinct schools of thought have emerged regarding the use of higher risk organs. The first is to transplant these livers into patients with low MELD scores in the hope that their relative good health will allow them to withstand poor allograft function and still survive. The alternative approach is to use these organs in sicker patients with higher MELD scores because they are more likely to die without a LT. The policy of our center was to select relatively stable recipients for Extended DCD livers, although there were no statistical differences in MELD and UKELD status between the two groups. Recipients usually included those with less advanced parenchymal liver disease, and this explains the higher proportion of patients with HCC as the main indication for LT.
In this study, 13% patients developed biliary complications; several studies have shown similar or even higher incidence of biliary complications (13.7%–33%) after LT with DCD grafts (27–29). It has been reported that average time duration to develop ITBS is within 90 to 120 days. Despite a mediocre follow-up in the Extended group (median follow-up: 18.5 months), the biliary complications in this series may reflect a reliable incidence. The pathophysiology of biliary stricturing after LT is varied; it is accepted that the initial injury to the bile duct is more likely of ischemic nature. This series failed to identify a common variable associated with biliary complications that could be explained by the relatively small number of patients in our series. Injury to biliary epithelial cells is central to the eventual formation of strictures, and this injury may occur before or after organ retrieval (30). Biliary epithelial injury is augmented by hydrophobic bile salts and cast formation (31). Biliary flushing during organ retrieval helps minimize this insult. Depletion of energy stores has also been implicated (32). Other etiological factors implicated are the ischemic injury to microvascular endothelium and microvascular thrombosis, condition more frequent to DCD grafts from postmortem clot formation (31, 33).
Our LT results are acceptable in early patient and graft survival when considering grafts from Extended donors. These results have also proved to be compatible with LT from donors after brain death performed in the same period of time (n=518, all primary grafts) with 30-day mortality of 4% (vs. 9.5% in the DCD group) and a similar median hospital stay of 12 days (range: 0–142). The requirement for renal replacement was 25% in this group. In a recent study, reported 30-day mortality was 3% to 17% in three different centers (8). Our results are well within these reported data. Our long-term outcomes are also consistent with other series reporting 1-year patient and graft survival of 89% and 74%, respectively (34). Several other series have also reported lower patient and graft survival after DCD LT (28, 35).
In summary, we believe that livers from Extended criteria DCDs can be used safely. Advanced age, higher BMI, longer dWIT, and CIT alone should not be an absolute contraindication to LT with DCD grafts. Best clinical judgment should be advocated in using Extended criteria DCD grafts, given the overall circumstances of the donor offer. Our results indicate that surgeons may be able to incorporate at least up to two Extended criteria in their donor selection with acceptable results. These results also support performing LT with extended DCDs with safe outcomes provided the recipients are selected carefully to avoid other risk factors. LT with extended DCDs could therefore have an impact on organ shortage.
MATERIALS AND METHODS
All adult LT performed with grafts from controlled DCDs between November 2004 and January 2010 were analyzed. The retrieval procedure was protocol based in all cases. Treatment withdrawal was carried out in the intensive care unit or in the anesthetic room in some cases. Cardiac death was determined by sustained asystole. Five minutes of obligatory stand-off time was observed as recommended by the Institute of Medicine. The operation was performed with a modification of the super rapid technique previously described and included cannulation of aorta for perfusion, venting from inferior vena cava, aortic cross clamp, and topical cooling (3). Portal cannulation was carried out immediately after starting aortic perfusion. Aortic perfusion was with pressurized University of Wisconsin solution when pancreas graft was also recovered. In other cases, 4 L of Marshall's solution was used to flush the aorta at pressure and 1 L of University of Wisconsin for portal vein perfusion. Heparin (20,000 U) was added to the first 2 L of aortic perfusion and the 1 L of portal venous perfusion. The dWIT was defined as the interval between the drop in mean arterial pressure below 50 mm Hg or oxygen saturation less than 80% (whichever occurred first) and initiation of aortic perfusion (7). We did not consider using a DCD liver unless organ donation did not proceed within an hour after treatment withdrawal.
As a general rule, recipients expected to have a difficult explant procedure were excluded from receiving a DCD liver graft and include the following: previous history of upper abdominal surgery, preoperative portal vein thrombosis, and retransplantation. The chosen recipients therefore were expected to have a straightforward procedure by undergoing a less complicated hepatectomy.
The study population was divided based on donor characteristics: dWIT less than or equal to 30 min, age 60 years or younger, BMI less than 30 kg/m2, and CIT less than or equal to 8 hr. Patients receiving a liver from donors fulfilling the above criteria were defined as Standard, whereas those receiving a liver with at least one characteristic beyond these criteria were defined as Extended DCDs. Donor risk index (12) was calculated for all grafts. Extended DCD grafts were carefully selected, and in most cases, to include only one donor characteristic not meeting our Standard DCD criteria. This was the case especially when the donor also had abnormal liver chemistry, an adverse medical history, or other comorbidity. This deliberate approach to cautiously expand acceptance criteria was adopted so that recipients were not exposed to additional risk. All recipients received a protocol-based triple immunosuppression, with tacrolimus, prednisolone, and azathioprine. Patients presenting post-LT renal impairment were switched to a renal sparing protocol with low dose of tacrolimus and mycophenolate.
All patients have been followed up regularly with liver biochemistry tests, with liver ultrasonography performed for deranged chemistry. Patients with biliary dilatation were further investigated with MRC or ERCP. The criteria for the diagnosis of ITBS were diffuse intrahepatic stricturing seen on cholangiographic studies in the presence of patent vasculature.
The following variables were analyzed: donor and recipient demographics, peak laboratory values at day 1, day 7, and 1 month post-LT; incidence of PNF (36), postoperative outcomes, and survival of the two groups were compared. Descriptive statistics were calculated for all variables. Continuous variables were assessed by the Mann-Whitney U test or t test where appropriate; comparisons between categorical variables were determined by χ2 and Fisher's exact test. Survival was estimated by the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards model was used to find donor covariates predicting the development of biliary complications. The level of statistical significance was assigned to P less than 0.05 at 95% confidence interval. Statistical Program for Social Statistics software package (version 15.0; SPSS Inc., Chicago, IL) was used for statistical analysis.
1. Cho YW, Terasaki PI, Cecka JM, et al. Transplantation of kidneys from donors whose hearts have stopped beating. N Engl J Med
1998; 338: 221.
2. D'Alessandro AM, Hoffmann RM, Knechtle SJ, et al. Successful extrarenal transplantation from non-heart-beating donors. Transplantation
1995; 59: 977.
3. Casavilla A, Ramirez C, Shapiro R, et al. Experience with liver and kidney allografts from non-heart-beating donors. Transplantation
1995; 59: 197.
5. Foley DP, Fernandez LA, Leverson G, et al. Donation after cardiac death
: The University of Wisconsin experience with liver transplantation
. Ann Surg
6. Manzarbeitia CY, Ortiz JA, Jeon H, et al. Long-term outcome of controlled, non-heart-beating donor liver transplantation
2004; 78: 211.
7. Muiesan P, Girlanda R, Jassem W, et al. Single-center experience with liver transplantation
from controlled non-heartbeating donors: A viable source of grafts. Ann Surg
2005; 242: 732.
8. Dubbeld J, Hoekstra H, Farid W, et al. Similar liver transplantation
survival with selected cardiac death donors and brain death donors. Br J Surg
2010; 97: 744.
9. McCormack L, Clavien PA. Understanding the meaning of fat in the liver. Liver Transpl
2005; 11: 137.
10. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation
for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med
1996; 334: 693.
12. Feng S, Goodrich NP, Bragg-Gresham JL, et al. Characteristics associated with liver graft failure: The concept of a donor risk index. Am J Transplant
2006; 6: 783.
13. Hoofnagle JH, Lombardero M, Zetterman RK, et al. Donor age and outcome of liver transplantation
1996; 24: 89.
14. Greig PD, Forster J, Superina RA, et al. Donor-specific factors predict graft function following liver transplantation
. Transplant Proc
1990; 22: 2072.
15. Deschênes M, Forbes C, Tchervenkov J, et al. Use of older donor livers is associated with more extensive ischemic damage on intraoperative biopsies during liver transplantation
. Liver Transpl Surg
1999; 5: 357.
16. Busuttil RW, Farmer DG, Yersiz H, et al. Analysis of long-term outcomes of 3200 liver transplantations over two decades: A single-center experience. Ann Surg
2005; 241: 905.
17. Grande L, Matus D, Rimola A, et al. Expanded liver donor age over 60 years for hepatic transplantation. Clin Transpl
18. Zhao Y, Lo CM, Liu CL, et al. Use of elderly donors (>60 years) for liver transplantation
. Asian J Surg
2004; 27: 114.
19. Segev DL, Maley WR, Simpkins CE, et al. Minimizing risk associated with elderly liver donors by matching to preferred recipients. Hepatology
2007; 46: 1907.
20. Cameron AM, Ghobrial RM, Yersiz H, et al. Optimal utilization of donor grafts with extended criteria
: A single-center experience in over 1000 liver transplants. Ann Surg
2006; 243: 748.
21. Gruttadauria S, Vizzini G, Biondo D, et al. Critical use of extended criteria
donor liver grafts in adult-to-adult whole liver transplantation
: A single-center experience. Liver Transpl
2008; 14: 220.
22. Reich DJ, Mulligan DC, Abt PL, et al; ASTS Standards on Organ Transplantation Committee. ASTS recommended practice guidelines for controlled donation after cardiac death
organ procurement and transplantation. Am J Transplant
2009; 9: 2004.
23. Strasberg SM, Howard TK, Molmenti EP, Hertl M. Selecting the donor liver: Risk factors for poor function after orthotopic liver transplantation
1994; 20: 829.
24. Yang SQ, Lin HZ, Lane MD, et al. Obesity increases sensitivity to endotoxin liver injury: Implications for the pathogenesis of steatohepatitis. Proc Natl Acad Sci USA
1997; 94: 2557.
25. Qing DK. Prolonging warm ischemia reduces the cold preservation limits of liver grafts in swine. Hepatobiliary Pancreat Dis Int
2006; 5: 515.
26. Ikeda T, Yanaga K, Kishikawa K, et al. Ischemic injury in liver transplantation
: Difference in injury sites between warm and cold ischemia in rats. Hepatology
1992; 16: 454.
27. Chan EY, Olson LC, Kisthard JA, et al. Ischemic cholangiopathy following liver transplantation
from donation after cardiac death
donors. Liver Transpl
2008; 14: 604.
28. de Vera ME, Lopez-Solis R, Dvorchik I, et al. Liver transplantation
using donation after cardiac death
donors: Long-term follow-up from a single center. Am J Transplant
2009; 9: 773.
29. Abt P, Crawford M, Desai N, et al. Liver transplantation
from controlled non-heart-beating donors: An increased incidence of biliary complications. Transplantation
2003; 75: 1659.
30. Pirenne J, Van Gelder F, Coosemans W, et al. Type of donor aortic preservation solution and not cold ischemia time is a major determinant of biliary strictures after liver transplantation
. Liver Transpl
2001; 7: 540.
31. Kukan M, Haddad PS. Role of hepatocytes and bile duct cells in preservation-reperfusion injury of liver grafts. Liver Transpl
2001; 7: 381.
32. Topp SA, Upadhya GA, Strasberg SM. Cold preservation of isolated sinusoidal endothelial cells in MMP 9 knockout mice: Effect on morphology and platelet adhesion. Liver Transpl
2004; 10: 1041.
33. Teoh NC, Farrell GC. Hepatic ischemia reperfusion injury: Pathogenic mechanisms and basis for hepatoprotection. J Gastroenterol Hepatol
2003; 18: 891.
34. Nguyen JH, Bonatti H, Dickson RC, et al. Long-term outcomes of donation after cardiac death
liver allografts from a single center. Clin Transplant
2009; 23: 168.
35. Skaro AI, Jay CL, Baker TB, et al. The impact of ischemic cholangiopathy in liver transplantation
using donors after cardiac death: The untold story. Surgery
2009; 146: 543.
36. Ploeg RJ, D'Alessandro AM, Knechtle SJ, et al. Risk factors for primary dysfunction after liver transplantation
—A multivariate analysis. Transplantation
1993; 55: 807.