Ischemic cholangiopathy following liver transplantation from donation after cardiac death donors

Authors


Abstract

The use of donation after cardiac death (DCD) donor hepatic allografts is becoming more widespread; however, there have been published reports of increased graft failure from specific complications associated with this type of allograft. The complication of ischemic cholangiopathy (IC) has been reported to occur more frequently after the use of DCD hepatic allografts. We report the results of 52 liver transplants from DCD donors and the factors that influenced the development of IC. We conducted a retrospective review of all DCD and donation after brain death (DBD) donor liver recipients from September 2003 through December 2006 at a single institution. Survival and complication rates were compared between the 2 groups. The Cox proportional hazards model was then used to identify recipient and donor factors that predict the development of IC in the DCD group. There was no difference in 1-year patient or graft survival rates between the 2 groups. There was no incidence of primary nonfunction from the DCD allografts. Hepatic artery complications and anastomotic bile duct complications were comparable in the 2 groups. There was, however, an increased risk for the development of IC in the DCD group (13.7% versus 1%, P = 0.001). Donor weight >100 kg and total ischemia times ≥9 hours, in donors older than 50 years of age, predicted the development of IC in the DCD group. In conclusion, there is a higher incidence of IC in recipients receiving DCD donor livers; however, patient and graft outcomes with DCD donors remain comparable to those with DBD donors. Careful donor selection may improve utilization of these grafts. Liver Transpl 14:604–610, 2008. © 2008 AASLD.

Since 2000, the number of transplant centers that have begun using donation after cardiac death (DCD) donor livers has more than tripled.1 There have been conflicting reports on whether DCD donor livers result in lower patient and graft survival and whether DCD donor livers lead to an increased incidence of biliary complications in the allografts, especially ischemic cholangiopathy (IC).2–5 Diffuse ischemic nonanastomotic lesions of the biliary tree are most often associated with hepatic artery thrombosis (HAT).6 Such strictures in the presence of a patent hepatic artery have been described by Sanchez-Urdazpal et al.7 at the Mayo Clinic and Li et al.8 at the University of Nebraska and are generally referred to as ischemic biliary lesions or IC. More recently, this pathology has become associated with the use of DCD donor livers.3

To assess the outcomes of patients receiving DCD liver allografts, we studied our program experience beginning in September 2003, comparing the outcomes of liver transplants from donation after brain death (DBD) donors from the same time period. Recipient and donor factors from the DCD liver transplants were then reviewed to elucidate causes of IC in these DCD liver transplants. Through our study, we have been able to clarify specific risk factors for the development of IC. This will enable optimal utilization of livers from high-risk donors, helping to increase the supply of transplantable organs.

Abbreviations

BMI, body mass index; CI, confidence interval; DBD, donation after brain death; DCD, donation after cardiac death; HAT, hepatic artery thrombosis; HTK, histidine-tryptophan-ketoglutarate; IC, ischemic cholangiopathy; MAP, mean arterial pressure; MELD, Model for End-Stage Liver Disease; NS, not significant; PNF, primary nonfunction; S70, saturation <70%; T35, time from which the mean arterial pressure dropped below 35 mg Hg; T50, time from which the mean arterial pressure dropped below 50 mm Hg; TIT, total ischemia time; UNOS, United Network for Organ Sharing; UW, University of Wisconsin; WIT, warm ischemia time.

PATIENTS AND METHODS

After Institutional Review Board approval, a retrospective review of all liver transplantations in our program from September 2003 to December 2006 was performed. All DCD and DBD liver transplant recipient records were reviewed. Patients who had received a primary liver transplant before the study period and required retransplantation during the study period were excluded from this study.

All of the procurement operations were performed in the operating room. For the DCD donor livers, withdrawal of ventilatory support occurred in the intensive care unit for all but 2 donors, for whom this occurred in the operating room. Once there was cessation of all cardiac activity, death was declared by the intensive care unit physician. A 2-minute wait period was observed to ensure no return of cardiac activity. After declaration of death, the patient was immediately transferred to the operating room. The time from withdrawal of ventilatory support until cold perfusion was recorded minute by minute on a datasheet by the organ procurement organization. Additionally, upon withdrawal of ventilatory support, the systolic, diastolic, and mean blood pressure, pulse, and oxygen saturations were recorded each minute until cessation of cardiac activity. Heparin was administered after extubation when the patient developed a mean arterial pressure (MAP) less than 50 mm Hg but prior to cardiac arrest if permitted by individual hospital policy. With the exception of 4 donors, all of the donors received heparin. The surgical technique used for both the DCD and DBD hepatic allografts was the rapid flush procedure for donor hepatectomies as described by Starzl et al.9

First, we compared the recipients of DBD donor livers and DCD donor livers. The factors reviewed included recipient age, recipient gender, Model for End-Stage Liver Disease (MELD) score, status 1 designation, donor age, donor gender, total ischemia time (defined by the time from donor aortic cross clamp at procurement until reperfusion in the recipient), and anastomosis time (defined by removal of the organ from ice in the recipient operation until reperfusion).10 Additional factors reviewed were patient survival, graft survival, primary nonfunction (PNF), HAT, and bile duct complications. Bile duct complications were separated into anastomotic strictures and IC. The criteria for the diagnosis of IC were diffuse intrahepatic stricturing seen on cholangiographic studies within 120 days of liver transplantation in patients with patent vasculature; all cases of IC at our institution occurred within this time frame.

Second, only recipients of DCD donor livers were then reviewed to determine any donor, recipient, or transplant factors that could predict the development of IC. Recipient factors reviewed included age, gender, etiology of liver disease, history of cardiovascular disease (evidence of atherosclerotic disease by coronary angiogram), renal disease (based on creatinine clearance), diabetes mellitus (requiring insulin or antihypoglycemics), systemic hypertension (defined by the use of antihypertensive medications), body mass index (BMI), previous major abdominal surgery (diagnosed by any surgery to the upper abdomen including an open incision on the liver, stomach, small intestines, etc.), history of smoking (within 6 months prior to transplantation), MELD score, ascites (documented via ultrasound or computed tomography), muscle wasting (as determined by the midarm muscle circumference), and history of prior transjugular intrahepatic portosystemic shunt placement. Donor factors included age, gender, height, weight, BMI, presence of steatosis by biopsy (assessed either in a prior liver biopsy of the donor liver or in a liver biopsy in the recipient immediately after reperfusion; this variable was used as a dichotomous variable for steatosis >10%), peak serum sodium prior to procurement, peak serum glucose prior to procurement, type of preservation solution used [histidine-tryptophan-ketoglutarate (HTK) versus University of Wisconsin (UW)], heparin given, cold ischemia time (defined by the time from donor aortic cross clamp at procurement until reperfusion in the recipient), and warm ischemia time (WIT; defined as the time from withdrawal of ventilatory support of the donor to the initiation of cold perfusion).10 The WIT was then further divided into 3 variables to determine if different degrees of hypoperfusion affected these livers; these variables included the time from which the MAP dropped below 50 mm Hg (T50) until cold perfusion, the time from which the MAP dropped below 35 mm Hg (T35) until cold perfusion, a saturation <70% (S70) until cold perfusion. Transplant factors reviewed included anastomosis time, hepatic artery flow after reperfusion (mL/minute), portal vein flow after reperfusion (mL/minute), cardiac index of the recipient at reperfusion, and estimated blood loss during transplantation and nonconventional arterial anatomy (diagnosed by the absence of a common hepatic artery and replacement of aberrant arteries including the superior mesenteric artery and the dominant left gastric artery). Finally, we evaluated the different combinations of gender, cytomegalovirus designation, and blood grouping between donor and recipient to determine if these led to the development of IC.

Statistical Analysis

Fisher's exact test to compare proportions, the Mann-Whitney test to compare variables, and Kaplan-Meier recipient log-rank survival curves were performed with GraphPad Instat version 3.0b for MacIntosh and Prism 4 for MacIntosh (GraphPad Software, San Diego, CA). The Cox proportional hazards model was used to find covariates predicting the development of IC in the DCD recipients, utilizing S-Plus 7.06 for Windows (Insightful, Seattle, WA). Results were considered significant with a P value of <0.05.

RESULTS

Fifty-two livers from DCD donors and 349 livers from DBD donors were procured in this time period. Of these DBD donor livers, 15 went to patients requiring a retransplant who had received their primary liver prior to our study period and were excluded from our analysis. One DCD graft went to retransplant a recipient originally transplanted with a DBD graft, who was excluded from the DCD analysis. There was no statistical difference in the 1-year actuarial patient and graft survival rates between the recipients of the DBD and DCD donor livers (Fig. 1A,B). There was also no statistical difference with respect to recipient age, recipient gender, MELD score, status 1 designation, donor age, donor gender, total ischemia time, and anastomosis time between these groups. There was no increased risk for PNF, vascular complications, or anastomotic bile duct complications (Table 1). The only significant difference (P = 0.0001) was the development of IC in the DCD liver recipients (13.7%) versus the DBD liver recipients (1%).

Figure 1.

(A) Kaplan-Meier survival curve: Comparison of patient survival between recipients of DCD and DBD donor livers. (B) Kaplan-Meier survival curve: Comparison of graft survival between recipients of DCD and DBD donor livers. Although the survival at 1 year appears to be different, there was no statistically significant difference between the 2 groups at the 1-year period. Abbreviations: DBD, donation after brain death; DCD, donation after cardiac death.

Table 1. Comparison of DCD Versus DBD Liver Transplants
 DCDDBDP
  1. Abbreviations: DBD, donation after brain death; DCD, donation after cardiac death; F, female; M, male; MELD, Model for End-Stage Liver Disease; NS, not significant.

Number51334 
Recipient age (years)54.8 ± 6.853.3 ± 9.4NS
Recipient genderM38/F13M236/F98NS
MELD19.6 ± 6.918.8 ± 8.2NS
Status 106NS
Donor age (years)37.7 ± 14.540 ± 16.4NS
Donor genderM37/F14M206/F128NS
Total ischemia time (minutes)473 ± 130463 ± 160NS
Anastomosis time (minutes)36.1 ± 1134.8 ± 8.1NS
Primary nonfunction011NS
Hepatic artery thrombosis016NS
Biliary anastomotic strictures526NS
Ischemic cholangiopathy740.0001

Characteristics of the DCD donors, recipients, and transplant procedure were then analyzed to determine what factors led to the development of IC. There were no recipient, transplant, or donor/recipient combination factors that were predictive of the development of IC. Only 5 univariate donor factors were predictive of IC by Cox regression analysis. These were donor weight and, when controlled for donor age, total ischemia time, WIT, and T50 and T35 (Table 2). With the use of these 5 univariate donor risk factors in a multivariate Cox regression analysis for predicting the development of IC, only donor weight ≥100 kg and, in donors older than 50 years, a total ischemia time ≥9 hours were significant (risk ratio = 2.7, 95% confidence interval = 2.6-2.8, P = 0.013).

Table 2. Univariate Analysis of Donor Factors That Predict the Occurrence of Ischemic Cholangiopathy
Donor FactorRisk Ratio95% CIPRisk Ratio (Control Age >50)95% CIP
  • Abbreviations: BMI, body mass index; CI, confidence interval; HTK, histidine-tryptophan-ketoglutarate; S70, saturation <70%; T35, time from which the mean arterial pressure dropped below 35 mg Hg; T50, time from which the mean arterial pressure dropped below 50 mm Hg; UW, University of Wisconsin; WIT, warm ischemia time.

  • *

    Significant.

Cold ischemia time1.040.974–1.10.120.950.89–1.010.1
Total ischemia time1.0040.999–1.010.121.0051.0003–1.010.01*
Age1.040.984–1.110.17   
Height1.030.979–1.090.230.960.80–1.020.17
Weight1.031.01–1.050.01*1.0010.99–1.090.08
BMI1.060.965–1.140.181.040.976–1.120.12
Gender1.020.971–1.130.181.030.981–1.110.19
Aberrant artery1.050.981–1.120.190.980.91–1.010.43
Steatosis of liver >10%20.9–4.20.091.230.3–3.20.7
UW versus HTK0.90.33–2.050.821.010.996–1.080.55
Heparin not given1.30.3–3.20.61.20.3–2.80.8
WIT1.080.983–1.160.11.061–1.110.04*
 T501.050.93–1.160.41.081–1.180.05*
 T351.090.94–1.240.241.121.01–1.250.04*
 S701.070.97–1.170.150.960.87–1.010.67
Highest glucose level0.990.97–1.0010.111.0020.995–1.070.53
Highest Na+ level0.940.84–1.020.180.990.92–1.070.74

A trellis graph comparing donor weight, total ischemia time, and donor age associated with IC shows 7 patients who developed IC (Fig. 2). Three of 4 recipients who received livers from donors >100 kg developed IC. Three of 4 recipients who received livers from donors >50 years old, with a total ischemia time ≥9 hours, developed IC.

Figure 2.

Trellis graph for donor weight, TIT, and donor age associated with IC. Black, solid dots represent patients who developed IC. Three of 4 recipients who received livers from donors weighing >100 kg developed IC. Three of 4 recipients who received livers from donors >50 years old, with a TIT ≥9 hours (540 minutes), developed IC. If all donors were excluded with weights >100 kg and age >50, with ≥9 hours of TIT, 6 of 7 cases of IC would have been avoided. With these criteria, only 2 donors would have been turned down that did not lead to IC in the recipients. Abbreviations: IC, ischemic cholangiopathy; TIT, total ischemia time.

Of the 7 patients who developed IC among the DCD liver recipients, 3 have required retransplantation for recurrent episodes of cholangitis. All 3 patients are doing well post-retransplantation and have normal liver function. One patient presented also with ischemic bowel 5 months post-transplantation and died. One patient is doing well without retransplantation, returning for yearly follow-up with no episodes of cholangitis. Two patients have had recurrent episodes of cholangitis requiring percutaneous biliary drainage and are candidates for retransplantation.

There were 8 deaths in the DCD group that occurred in the absence of IC. Two of the 8 deaths occurred perioperatively. These 2 patients developed significant pulmonary hypertension and right-sided heart failure, which was unresponsive to vasopressors and inotropes. The other 6 deaths occurred within the first 6 months post-transplantation. One of these deaths was a patient retransplanted with a DCD donor liver because of PNF of the original DBD donor liver. (This death was assigned to the DBD group.) This patient subsequently died of a ruptured hepatic artery pseudoaneurysm 2 months post-transplantation. The causes of death in the other 5 patients included pneumonia and gram-negative sepsis after treatment for moderate cellular rejection, primary pulmonary hypertension and right heart failure, acute respiratory distress syndrome, aspergillus pneumonia, and severe mucormycosis of the renal allograft and native urinary system in a patient who received a liver/kidney transplant. With the exception of the patient who died after treatment for rejection, all of the other patients had normal graft function at the time of death.

DISCUSSION

We began using DCD donor livers in September 2003 to decrease the wait times for liver transplantation in the region. Although there was initial concern for patient and graft survival, our results have not demonstrated a statistically significant difference in 1-year and 2-year actuarial patient and graft survival rates between the DCD and DBD liver recipients, similar to other published case series.3, 11 In contrast, Foley et al.5 reviewed the DCD experience at the University of Wisconsin and found a decreased 1-year and 3-year patient and graft survival rate compared to the DBD donor recipients. Also in contrast to our results, Abt et al.12 retrospectively reviewed the United Network for Organ Sharing (UNOS) database from 1993 to 2001 to compare the outcomes of recipients who received DCD versus DBD donor livers and found significantly shorter graft survival in the DCD recipients. Likewise, Mateo et al.13 analyzed the UNOS data from 1996 to 2003 on DCD donor livers with a similar conclusion of inferior graft survival in recipients of the DCD donor livers versus recipients of the DBD donor livers. These studies, however, were early reviews of either center experience or UNOS database information in the initial use of DCD liver transplantation and were not reflective of later developments. As with all innovation in transplantation, there is a learning curve for the optimal utilization of DCD organs. Consequently, center-specific experience will reflect superior survivals, as has been seen and reported with split liver transplantation.14 In our review of our experience, we did note a learning curve in the use of these liver allografts. The incidence of IC decreased each year of our experience; however, our patient and graft survival was the same throughout our experience.

In our series, the rate of IC in the DCD population compared to the DBD group was significantly higher (13.7% versus 1%) with 3-year follow-up. All of our patients who developed IC did so in 120 days. Forty-two of these patients have had at least 1 year of follow-up within this study, and all of the patients have had >120 days of follow-up. Although the development of IC did not increase the risk for death, it did significantly increase the morbidity associated with multiple invasive procedures and hospitalizations from recurrent cholangitis. Foley et al.5 noted a higher incidence in the development of IC among recipients of DCD liver allografts. Similarly, a retrospective case series by Abt et al.3 revealed that 4 out of the 15 patients receiving a DCD liver transplant developed ischemic-type strictures. All patients within their series had developed symptoms within 90 days of transplantation, and although the risk of death was not increased, they also noted an increased need for invasive therapeutic procedures.3 Avoiding donors that lead to IC would be a tremendous benefit not only to the patient but also to the center.

Two factors—donor weight and age >50 years with total ischemia times ≥9 hours—appear to be predictive for the development of IC in our series. Regarding donor weight, to our knowledge this has not previously been reported as a contributing factor to IC. We had 3 of 4 donors with weights >100 kg who developed IC. Two of these livers had a biopsy showing the presence of steatosis, and 2 livers showed no steatosis on biopsy. Although the exact cause of IC is unknown, we hypothesize that the larger donor weight may lead to an inadequate flush of the preservation solution of the smaller arterioles that feed the biliary tree. Some authors have hypothesized that the high viscosity of UW solution leads to inadequate perfusion of the biliary tree, but there has been no difference shown in rates of biliary complications between UW and HTK solutions.15 Two of the 3 livers that developed IC in this series were flushed with UW solution, and the other liver was flushed with HTK. Unfortunately, we do not yet have enough patients to detect a difference between the 2 solutions in this study. Another possibility is that there is inadequate pressure perfusion of the preservative solution. Moench et al.16 hypothesized that insufficient arterial perfusion led to an increase in ischemic-type biliary lesions. These investigators randomized 131 brain dead donors to a standard arterial flush with in situ portal perfusion and 59 brain dead donors to an additional arterial back-table perfusion flush. The patients with the additional arterial back-table flush had a significantly lower rate of ischemic biliary lesions. For most standard procurements, the preservation solution is flushed through gravity. In donors with a larger weight, the amount of pressure generated by gravity may not be enough to adequately flush the smaller arterioles, and this may lead to inadequate preservation with subsequent biliary strictures. Potentially, donors >100 kg may still be utilized with the development of protocols for cold pump perfusion as seen with DCD kidneys or pressurized back-table perfusion with hypoviscous preservation solutions.

The second factor found to be predictive for developing IC in this series was donor age >50 with total ischemia times ≥9 hours. Of the 51 patients who received DCD liver grafts, 10 of those patients received livers from donors older than 50. Four of these patients had total ischemia times ≥9 hours, and 3 out of the 4 developed IC. These 2 factors, age and total ischemia time, are consistent with the characteristics recently published by Feng et al.17 that led to the concept of the donor risk index. Donor age and cold ischemia times were also found to be significantly associated with graft loss in DCD livers in an analysis of the UNOS database by Mateo et al.13 These authors noted increased risk of graft loss from donors older than 35 years of age, cold ischemia times >10 hours, anastomosis times >30 minutes, and stroke as a cause of death. The relative risk of graft loss increased as the age of the donor increased. In our review, not all patients who received DCD livers from older donors developed IC; however, the addition of another risk factor such as increased total ischemia times does appear to lead to a cumulative risk. Optimal utilization of these donors in the future may include limiting the number of additive risk factors per donor. Older donors may best be used loco-regionally, or the development of better preservation methods may also play a role.

To our surprise, the WIT did not influence the development of IC in this series. WIT definitions vary among centers that recover DCD organs. It was recently recommended by the National Conference on Donation After Cardiac Death that the WIT be defined as 2 phases: a withdrawal phase and an acirculatory phase.10 The withdrawal phase defines the period from withdrawal of ventilatory support to cardiopulmonary cessation, and the acirculatory phase defines the time from cardiac arrest until cold perfusion. We further divided this phase into 3 other variables, which included the time from a MAP of ≤50 mm Hg (T50) to perfusion, the time from a MAP ≤35 mm Hg (T35) to perfusion, and an oxygen saturation of <70% (S70) to perfusion. It is unknown at what MAP or oxygen saturation the liver parenchyma and biliary system undergo irrecoverable injury. However, we did not find any difference in the different times as predictive of the development of IC in a multivariate analysis.

As the experience with the use of DCD liver allografts increases in transplant centers, there is a need to develop a standard protocol for the procurement of these organs to decrease the factors that may influence outcomes. For instance, although the Society of Critical Care Medicine has declared a 2-minute observation after asystole to be adequate for the declaration of death, there are some centers that use a mandatory 5 minutes and others that use 4 minutes.10 The use of heparin is also not standard in all organ procurement organizations, and some centers will use other pharmacological agents such as phentolamine or mannitol.10 There is also no standard preservation solution for these allografts, with many centers using UW and other centers using HTK. Unifying these different variables may allow for large multicenter trials to further evaluate the potential causes of biliary ischemia and create new therapies that may bridge the gap between DBD and DCD organs.

In summary, the use of DCD liver allografts is a life-saving solution for patients with end-stage liver disease. Although there is an increased incidence of IC with the use of these livers, the data from our study have shown that patient and graft outcomes with DCD donors are comparable to those with DBD donor livers. In our series, 7 patients developed IC. If we had excluded donors that weighed >100 kg or those older than 50 years of age with ≥9 hours of total ischemia time, 6 out of 7 livers that did develop IC could have been avoided. Therefore, careful selection of donors by limiting the number of risk factors associated with graft failure may improve utilization of these livers.

Ancillary