Jean C. Emond

Application of reduced-size liver transplants as split grafts, auxiliary orthotopic grafts, and living related segmental transplants.

The University of Chicago program in pediatric liver transplantation continues actively to seek innovative surgical solutions to problems related to the management of children with end-stage liver disease. Among the most important problems facing these children is a shortage of donor organs, which results from three factors in addition to the actual supply of pediatric donors: the concentration of pediatric liver disease in the population younger than 2 years; the necessity for a graft that is small enough; and the epidemiology of accidents and other events that lead to organ donation. Transplantation using a liver lobe as a graft overcomes size disparity and shifts the available supply of organs from older donors to younger recipients. This work describes the technical aspects of recent innovations in the use of liver lobes in pediatric transplantation, simple reduced-size liver transplantation (RLT), split-liver transplantation (SLT), orthotopic auxiliary liver grafting (ALT), and transplantation using a living related donor (LRLT), and compares their results. Since November 1986 a total of 61 procedures have been performed in which a liver lobe was used as a graft: 26 RLT; 30 SLT, 25 in children and 5 in adults; 5 LRLT; and 1 ALT. Overall 62% of transplants performed in children have involved using a liver lobe as a graft. The rates of complications are somewhat higher than with whole-liver transplantation, but this may not be entirely the result of the complex procedures. Split liver transplantation is associated with the highest mortality and complication rates. Living related liver transplantation has been associated with complications in donors and recipients, but to date survival is 100%. Orthotopic auxiliary liver transplantation effectively corrected the metabolic defect in one patient with ornithine transcarbamylase deficiency. Overall the various modalities of using graft reduction have resulted in postoperative results similar to those achieved with full-size grafts, while pretransplantation mortality has been limited to less than 2%. Thus the use of grafts as liver lobes accomplishes the goal of reducing global mortality among children with end-stage liver disease, but at the cost of increased surgical complexity and more postoperative complications.

The risk of transmission of hepatitis B from HBsAg(-), HBcAb(+), HBIgM(-) organ donors.

Liver allografts from HBcAb(+), IgM(-), HBsAg(-) donors can transmit HBV to uninfected recipients. We currently no longer accept these livers for transplantation while continuing to accept the kidneys. The purpose of this study is to determine the risk of donor-transmitted HBV infections from HBcAb(+), HBIgM(-), HBsAg(-) organ donors and determine if the risk of donor-transmitted HBV infections and their severity is dependent on the organ being transplanted. This study consists of a retrospective review of the posttransplant course of recipients of HBcAb(+), HBIgM(-), HBsAg(-) donors accepted at UCSF from 6/85 to 12/93. Transmitted HBV infection was defined as one in which the recipient changed from HBsAg(-) prior to transplantation to HBsAg(+) posttransplant, with no other source. There were 25 of 1190 donors who were HBcAb(+), HBIgM(-), HBsAg(-); 1/42 kidney, 3/6 liver, and 0/7 heart HBsAg(-) transplant recipients of organs from these donors became HBsAg(+) after transplantation. This difference in infection rate (liver vs. kidney and heart) is statistically significant. The clinical course of the liver recipients was also more severe. All of the patients who became infected were HBsAb(-) and HBcAb(-) prior to transplant. We conclude that (1) HBV can be transmitted from HBcAb(+), HBIgM(-), HBsAg(-) organ donors, (2) the rate of transmission is highest and severity of infection is worst in the liver recipients; and (3) we will continue to transplant kidneys from these donors, preferably into immunized recipients.

Functional analysis of grafts from living donors. Implications for the treatment of older recipients.

OBJECTIVE Living-related liver transplantation (LRLT) has established efficacy in children. In a larger recipient, LRLT requires the use of a small graft because of limits on the donor hepatectomy. SUMMARY BACKGROUND DATA The minimum graft weight required for successful transplantation has not been well established, although a characteristic pattern of graft dysfunction has been observed in our patients who receive small grafts. The authors present a clinicopathologic study of small liver grafts obtained from living donors. METHODS Clinical and histologic data were reviewed for 25 patients receiving LRLT. In five older recipients (small group), the graft represented 50% or less of expected liver weight, whereas in 20 others (large group), the graft represented at least 60% of expected liver weight. A retrospective analysis of graft function was conducted by analyzing clinical parameters and histology. RESULTS In the small group, 2 of 5 grafts (40%) were lost due to poor function, leading to one patient death (20% mortality), whereas in the large group, 2 of 20 grafts (10%) were lost due to arterial thrombosis without patient mortality. Early ischemic damage related to transplant was comparable with aspartate aminotransferase 203 +/- 23 (small group) and 290 +/- 120 (large group) at 24 hours (p = not significant). Early function was significantly decreased in the small group, with prothrombin time 18.2 +/- 2.2 seconds versus 14.8 +/- 1.6 seconds (large group) on day 3 (p = 0.034). All small group patients developed cholestasis with significantly increased total bilirubin levels at day 7 (16 +/- 5.2 mg% vs. 3.7 +/- 2.7 mg%; p = 0.021) and day 14 (12.0 +/- 7.4 vs. 1.8 +/- 0.7; p = 0.021) compared with the large group. Protocol biopsies in the small group revealed a diffuse ischemic pattern with cellular ballooning on day 7, which progressed to cholestasis in subsequent biopsies. Large group biopsies showed minimal ischemic changes. Three small group patients recovered with normal liver function by 12 weeks. CONCLUSIONS Clinical recovery after a small-for-size transplant is characterized by significant functional impairment associated with paradoxical histologic changes typical of ischemia. These changes apparently are due to graft injury, which can only be the result of small graft size. These findings have significant implications for the extension of LRLT to adults.

Donor Morbidity After Living Donation for Liver Transplantation

BACKGROUND & AIMS Reports of complications among adult right hepatic lobe donors have been limited to single centers. The rate and severity of complications in living donors were investigated in the 9-center Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL). METHODS A retrospective observational study design was used. Participants included all potential living donors evaluated between 1998 and 2003. Complication severity was graded using the Clavien scoring system. RESULTS Of 405 donors accepted for donation, 393 underwent donation, and 12 procedures were aborted. There were 245 donors (62%) who did not experience complications; 82 (21%) had 1 complication, and 66 (17%) had 2 or more. Complications were scored as grade 1 (minor; n = 106, 27%), grade 2 (potentially life threatening; n = 103, 26%), grade 3 (life threatening; n = 8, 2%), and grade 4 (leading to death; n = 3, 0.8%). Common complications included biliary leaks beyond postoperative day 7 (n = 36, 9%), bacterial infections (n = 49, 12%), incisional hernia (n = 22, 6%), pleural effusion requiring intervention (n = 21, 5%), neuropraxia (n = 16, 4%), reexploration (n = 12, 3%), wound infections (n = 12, 3%), and intraabdominal abscess (n = 9, 2%). Two donors developed portal vein thrombosis, and 1 had inferior vena caval thrombosis. Fifty-one (13%) donors required hospital readmission, and 14 (4%) required 2 to 5 readmissions. CONCLUSIONS Adult living liver donation was associated with significant donor complications. Although most complications were of low-grade severity, a significant proportion were severe or life threatening. Quantification of complication risk may improve the informed consent process, perioperative planning, and donor care.

Hypothermic Machine Preservation in Human Liver Transplantation: The First Clinical Series

Hypothermic machine perfusion (HMP) is widely used to preserve kidneys for transplantation with improved results over cold storage (CS). To date, successful transplantation of livers preserved with HMP has been reported only in animal models. In this, the first prospective liver HMP study, 20 adults received HMP‐preserved livers and were compared to a matched group transplanted with CS livers. HMP was performed for 3–7 h using centrifugal perfusion with Vasosol® solution at 4–6°C. There were no cases of primary nonfunction in either group. Early allograft dysfunction rates were 5% in the HMP group versus 25% in controls (p = 0.08). At 12 months, there were two deaths in each group, all unrelated to preservation or graft function. There were no vascular complications in HMP livers. Two biliary complications were observed in HMP livers compared with four in the CS group. Serum injury markers were significantly lower in the HMP group. Mean hospital stay was shorter in the HMP group (10.9 ± 4.7 days vs. 15.3 ± 4.9 days in the CS group, p = 0.006). HMP of donor livers provided safe and reliable preservation in this pilot case‐controlled series. Further multicenter HMP trials are now warranted.

Report of the Crystal City Meeting to Maximize the Use of Organs Recovered from the Cadaver Donor

A consensus meeting to develop guidelines that would improve the recovery and transplantation of organs from the cadaver donor was held on 28–29 March 2001, in Crystal City, Virginia, sponsored by the American Society of Transplant Surgeons and the American Society of Transplantation. The crisis in organ supply persists and the continuing shortage presents a compelling responsibility for the transplant community to maximize the use of organs procured from cadaver donors.

Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors

Translational studies in liver transplantation often require an endpoint of graft function or dysfunction beyond graft loss. Prior definitions of early allograft dysfunction (EAD) vary, and none have been validated in a large multicenter population in the Model for End‐Stage Liver Disease (MELD) era. We examined an updated definition of EAD to validate previously used criteria, and correlated this definition with graft and patient outcome. We performed a cohort study of 300 deceased donor liver transplants at 3 U.S. programs. 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 ≥10mg/dL on day 7, international normalized ratio ≥1.6 on day 7, and alanine or aspartate aminotransferases >2000 IU/L within the first 7 days. To assess predictive validity, the EAD definition was tested for association with graft and patient survival. Risk factors for EAD were assessed using multivariable logistic regression. Overall incidence of EAD was 23.2%. Most grafts met the definition with increased bilirubin at day 7 or high levels of aminotransferases. Of recipients meeting the EAD definition, 18.8% died, as opposed to 1.8% of recipients without EAD (relative risk = 10.7 [95% confidence interval: 3.6, 31.9] P < 0.0001). More recipients with EAD lost their grafts (26.1%) than recipients with no EAD (3.5%) (relative risk = 7.4 [95% confidence interval: 3.4, 16.3] P < 0.0001). Donor age and MELD score were significant EAD risk factors in a multivariate model. In summary a simple definition of EAD using objective posttransplant criteria identified a 23% incidence, and was highly associated with graft loss and patient mortality, validating previously published criteria. This definition can be used as an endpoint in translational studies aiming to identify mechanistic pathways leading to a subgroup of liver grafts with clinical expression of suboptimal function. Liver Transpl 16:943‐949, 2010.

OUTCOMES OF 385 ADULT-TO-ADULT LIVING DONOR LIVER TRANSPLANT RECIPIENTS: A REPORT FROM THE A2ALL CONSORTIUM

Objective:The objective of this study was to characterize the patient population with respect to patient selection, assess surgical morbidity and graft failures, and analyze the contribution of perioperative clinical factors to recipient outcome in adult living donor liver transplantation (ALDLT). Summary Background Data:Previous reports have been center-specific or from large databases lacking detailed variables. The Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) represents the first detailed North American multicenter report of recipient risk and outcome aiming to characterize variables predictive of graft failure. Methods:Three hundred eighty-five ALDLT recipients transplanted at 9 centers were studied with analysis of over 35 donor, recipient, intraoperative, and postoperative variables. Cox regression models were used to examine the relationship of variables to the risk of graft failure. Results:Ninety-day and 1-year graft survival were 87% and 81%, respectively. Fifty-one (13.2%) grafts failed in the first 90 days. The most common causes of graft failure were vascular thrombosis, primary nonfunction, and sepsis. Biliary complications were common (30% early, 11% late). Older recipient age and length of cold ischemia were significant predictors of graft failure. Center experience greater than 20 ALDLT was associated with a significantly lower risk of graft failure. Recipient Model for End-stage Liver Disease score and graft size were not significant predictors. Conclusions:This multicenter A2ALL experience provides evidence that ALDLT is a viable option for liver replacement. Older recipient age and prolonged cold ischemia time increase the risk of graft failure. Outcomes improve with increasing center experience.

Transplantation of two patients with one liver. Analysis of a preliminary experience with 'split-liver' grafting.

Surgical reduction of donor livers to treat small children has been performed successfully in several centers. While this procedure improves the allocation of livers, it does not increase the organ supply. We have extended reduced-size orthotopic liver transplantation (OLT) to treat 18 patients with 9 livers, accounting for 26% of our transplants during a 10-month period and have evaluated the results. In 18 split liver OLTs, patient survival was 67% and graft survival was 50%. In comparison, for 34 patients treated with full-size OLT during the same period, patient survival was 84% (p = 0.298) and graft survival was 76% (p = 0.126). Biliary complications were significantly more frequent in split grafts, occurring in 27%, as compared to 4% in full-sized grafts (p = 0.017). Primary nonfunction (4% versus 5.5%) and arterial thrombosis (6% versus 9%) occurred with similar frequency in split and full-size OLT (p = not significant). These results demonstrated that split-liver OLT is feasible and could have a substantial impact in transplant practice. We believe that biliary complications can be prevented by technical improvements and that split-liver OLT will improve transplant therapy by making more livers available.

Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers.

BACKGROUND & AIMS Excellent single-center outcomes of neoadjuvant chemoradiation and liver transplantation for unresectable perihilar cholangiocarcinoma caused the United Network of Organ Sharing to offer a standardized model of end-stage liver disease (MELD) exception for this disease. We analyzed data from multiple centers to determine the effectiveness of this treatment and the appropriateness of the MELD exception. METHODS We collected and analyzed data from 12 large-volume transplant centers in the United States. These centers met the inclusion criteria of treating 3 or more patients with perihilar cholangiocarcinoma using neoadjuvant therapy, followed by liver transplantation, from 1993 to 2010 (n = 287 total patients). Center-specific protocols and medical charts were reviewed on-site. RESULTS The patients completed external radiation (99%), brachytherapy (75%), radiosensitizing therapy (98%), and/or maintenance chemotherapy (65%). Seventy-one patients dropped out before liver transplantation (rate, 11.5% in 3 months). Intent-to-treat survival rates were 68% and 53%, 2 and 5 years after therapy, respectively; post-transplant, recurrence-free survival rates were 78% and 65%, respectively. Patients outside the United Network of Organ Sharing criteria (those with tumor mass >3 cm, transperitoneal tumor biopsy, or metastatic disease) or with a prior malignancy had significantly shorter survival times (P < .001). There were no differences in outcomes among patients based on differences in surgical staging or brachytherapy. Although most patients came from 1 center (n = 193), the other 11 centers had similar survival times after therapy. CONCLUSIONS Patients with perihilar cholangiocarcinoma who were treated with neoadjuvant therapy followed up by liver transplantation at 12 US centers had a 65% rate of recurrence-free survival after 5 years, showing this therapy to be highly effective. An 11.5% drop-out rate after 3.5 months of therapy indicates the appropriateness of the MELD exception. Rigorous selection is important for the continued success of this treatment.