J. R. Thistlethwaite

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.

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.

A Randomized Clinical Trial Of Induction Therapy With Okt3 In Kidney Transplantation

A randomized, prospective multicenter trial was conducted to compare the safety and efficacy of OKT3 as an induction therapy with that of conventional immunosuppressive therapy administered to cadaveric renal allograft recipients. Two hundred fifteen patients were treated either with OKT3 plus azathioprine and steroids for 14 days with the delayed addition of cyclosporine on day 11, or with conventional immunosuppression (steroids, azathioprine, and cyclosporine). OKT3 patients had significantly fewer rejection episodes (51% vs. 66%, P=0.032), a longer time to initial rejection (46 days vs. 8 days, P=0.001), and fewer rejection episodes per patient (0.82 vs. 1.14, P=0.014) than conventionally treated patients. Kaplan-Meier estimates of two-year graft and patient survival rates were 84% and 95%, respectively, for the OKT3-treated group, and 75% and 94%, respectively, for the conventionally treated group. Following a subsequent first rejection episode, OKT3 reversed 93% of the rejections in patients receiving OKT3 induction therapy and 94% in patients receiving conventional therapy. Adverse experiences reported during OKT3 induction therapy were similar to those seen when the drug was used for rejection. Following initial exposure, 40.3% of the patients tested were positive for anti-OKT3 antibody, only 6.7% of which were of high titer (1:1000). In the presence of low titer (1:100 or less) antibody, OKT3 was successful in reversing rejection in five of six retreated patients tested. In conclusion, treatment with OKT3 (in combination with azathioprine, steroids, and the delayed addition of cyclosporine) is an effective approach for renal allograft maintenance.

Biliary complications in pediatric liver transplantation: A comparison of reduced-size and whole grafts

One of the major changes in liver transplantation has been the application of reduced-size liver transplants(RLT). RLT has the great advantage of expanding the donor pool up to ten times the weight of the recipient, thereby decreasing pretransplant mortality in the pediatric age group. It has been suggested that RLT is a risk factor for biliary complications. To analyze the role of RLT and biliary complications, the results of 213 consecutive liver transplants in 164 pediatric patients over a 6-year period will were reviewed. These included 113 whole-liver transplants and 100 reduced-size liver transplants (49 reduced cadaveric liver transplants (RCLT), 38 split-liver transplants (SLT) and 13 living-related liver transplants (LRLT). The average weight and age were significantly higher in recipients receiving whole-size grafts (average weight 18.4 mg, average age 4.9 years) than in those receiving reduced size grafts (average age 2.3 years, average weight 11.1 kg). Biliary reconstruction consisted of Roux-en-Y, cholangiojejunostomy (n = 203) or choledochocholedochostomy (n = 10). There were 29 total biliary complications, (13.6%) with no significant difference in the complication rate between the whole (n = 13, 11.5%) or reduced livers (n = 16, 16%). Biliary leakage was the most common complication (n = 20), and it occurred at the biliary enteric anastomoses (n = 10), the roux limb (n = 7), or at the cut edge (n = 3). Of the leaks occurring at the biliary enteric anastomoses, 50% were caused by hepatic artery thrombosis. Biliary obstruction accounted for their remaining complications (n = 9) or 4.2%. Actuarial survival from 6 years to a minimum of two months of follow-up was 73% in the whole-size and 70% in reduced-size liver transplants. This series demonstrates that the incidence of biliary complications is similar in reduced-size and full-size grafts. No grafts were lost to biliary complications in the absence of hepatic artery thrombosis.

Orthotopic auxiliary liver transplantation for Crigler-Najjar syndrome type 1

Some diseases that result from inborn errors of critical metabolic or synthetic processes mainly involving the liver do not cause structural liver damage. These disorders can be treated by the addition of liver tissue (auxiliary liver transplantation) rather than liver replacement. We report correction of the metabolic error in a 13-year-old girl with Crigler-Najjar syndrome type 1 by auxiliary (left lateral segment) transplantation. The first graft failed and was replaced successfully. The second graft shows features of chronic rejection, but at 2 years postoperatively bilirubin conjugating ability has not been impaired. Another graft may become necessary in due course.

Incidence and outcome of infection by vancomycin-resistant Enterococcus following orthotopic liver transplantation

Vancomycin-resistant Enterococcus (VRE) has become a significant nosocomial pathogen. For this study, the records of 325 patients who underwent orthotopic liver transplantation (OLT) were reviewed. Thirty-four patients were infected by VRE (incidence of 10.5%, 14% in adults vs. 5% in children, P < 0.01). Common features of patients who developed infections with VRE included previous antibiotic use (25 patients, 15 of whom received vancomycin), co-infection by other pathogens (28 patients), and relaparotomy following OLT (20 patients). Pulmonary and/or renal failure preceded infection by VRE in 11 and 4 adult patients, respectively. Biliary complications were exceedingly common in patients infected by VRE (28 patients) and significantly increased the risk of infection by VRE (21.5% vs. 3.1% for patients without biliary complications, P < 0.0001). Mortality associated with VRE infections was high (56% vs. 19% for patients not infected by VRE, P < 0.0005). The most frequent cause of death was sepsis (16 of 19 patient deaths), often polymicrobial. The high incidence of infection by VRE following OLT, the lack of effective antibiotics for the treatment of VRE, and the association of VRE with patient mortality emphasizes the need to define the risk factors associated with VRE infection. We suggest early surgical intervention to treat complications that may predispose patients to infection by VRE.

OKT3 treatment of steroid-resistant renal allograft rejection.

The monoclonal antibody, Orthoclone OKT3 (OKT3), has been used with great efficacy in a prospective multicenter trial as therapy for first rejection episodes in cadaveric donor (CD) renal allograft recipients treated with azathioprine (AZA) and prednisone (P). However, although almost all rejection episodes were reversed, recurrent rejection occurred in approximately two-thirds of OKT3-treated patients in this earlier trial; infections also occurred in about two-thirds of patients, often related to the additional immunosuppression necessary to reverse the rerejection episodes. In the current series of patients, OKT3 was used to treat rejection in CD renal graft recipients in a protocol differing from the multicenter trial in two respects: (1) baseline immunosuppression was cyclosporine (CsA) and P or CsA, AZA, and P (probably more potent immunosuppressive combinations than the AZA and P in the multicenter trial); and (2) OKT3 treatment was reserved for rejection episodes resistant to 3 bolus infusions of methyl-prednisolone (MP), 5–10 mg/kg, rather than as primary therapy for first rejection episodes. Using this protocol, 46 of 74 rejection episodes (62%) diagnosed between 3/85 and 3/86 in CD renal allograft recipients were treated successfully with MP. Of the remaining 28 steroid-resistant rejection episodes, 27 (96%) were reversed with a 7–14-day course of OKT3, 5 mg/day. Only 5 recurrent rejection episodes (19%) have been observed in the 2–14-month follow-up period after OKT3 treatment; infections have occurred in 10 patients (36%), and three grafts (11%) have been lost in OKT3 treated patients. These results suggest that recurrent rejection and subsequent infection after OKT3 is used to treat rejection may be reduced in a protocol where CD renal allograft recipients are treated with baseline immunosuppression regimens including CsA and where OKT3 is reserved for steroid-resistant rejection. This approach appears to be both more cost-effective than, and as effective therapeutically as, treating all first rejection episodes with the monoclonal antibody.

Complete lymphoid chimerism and chronic graft-versus-host disease in an infant recipient of a hepatic allograft from an HLA-homozygous parental living donor

Living-related donor liver transplantation (LDLT) is an accepted approach to pediatric liver transplantation. Parental donation imposes a significant risk of chimerism with graft-versus-host disease (GVHD) because donors homozygous at all HLA loci (1.6% of the population) present no mismatched HLA antigens to be recognized by their offsprings immune system. The case of a 9-month-old who underwent LDLT with her 23-year-old HLA-homozygous mother as a donor demonstrates the consequences of this occurrence. The patient developed GVHD with aplastic anemia; the patients nucleated peripheral blood elements were shown to be entirely derived from the donor. Later, after some marrow recovery, the patients circulating lymphocytes had a donor origin, while the marrow-derived neutrophils had a recipient origin. The patient suffers from chronic GVHD and debilitating skin disease several years posttransplant. Our current protocol calls for HLA typing to eliminate parents who are homozygous at all HLA loci as donors of hepatic allografts to their children.

An analysis of hepatic retransplantation in children

BACKGROUND The limited supply of organ donors has led some groups to reconsider the role of retransplantation. Historically, except for children with malignancies, extrahepatic sources of sepsis, or severe irreversible neurologic injuries, our institution has offered all children with failing liver grafts the option of retransplantation regardless of their current severity of illness. The purpose of this study was to examine the outcome of hepatic retransplantation in children in an attempt to identify factors predictive of outcome and to assess the results of our approach to retransplantation. METHODS Between October 1984 and December 1995, 314 children less than 15 years of age underwent a total of 441 liver transplants. Data were obtained retrospectively by review of hospital records. RESULTS With a mean follow-up period of 5.3+/-2.7 years, the overall patient survival rates at 1 and 5 years were 77.1% and 67.1%, respectively. Primary allograft survival rates were 65.6% and 56.5%, respectively. Of the 137 patients who developed failure of their primary allograft, 92 underwent retransplantation (29.3% of all primary transplants). Both patient and allograft survival rates were significantly decreased after retransplantation (P<0.0001 versus primary transplants). Univariate and multivariate analysis of retransplanted patients revealed only two factors that were statistically related to patient and graft survival: age at the time of retransplantation (P<0.02 univariate and P<0.05 multivariate) and retransplantation with a reduced-size allograft (P<0.005 univariate and P<0.05 multivariate). In this series, the effect on patient survival of differences in medical condition as reflected by United Network for Organ Sharing (UNOS) status approached, but did not achieve, significance (P=0.08 for UNOS 1 versus UNOS 2 and 3). UNOS status did not affect graft survival. Neither the cause of primary allograft loss or the timing of retransplantation relative to the first transplant were related to outcome. CONCLUSIONS These data demonstrate that the failure of primary hepatic allografts remains a major problem in pediatric liver transplantation and that the overall results of retransplantation were significantly worse than those associated with primary transplants. We have identified a group of children who experienced a significantly worse outcome after retransplantation. This group consisted of children less than 3 years of age retransplanted using reduced-size grafts. Based on this finding, we now attempt to avoid retransplanting young children with reduced-size grafts. By using this approach, we hope to be able to offer children the option of retransplantation with improved results and simultaneously minimize the negative impact on patients awaiting primary transplants.

Attitudes of minority patients with end-stage renal disease regarding ABO-incompatible list-paired exchanges.

A few transplant centers in the United States have implemented list‐paired exchange programs that include both ABO‐compatible and ABO‐incompatible living‐donor recipients. ABO‐incompatible list‐paired exchanges raise ethical concerns because they increase the total number of organs available but increase the waiting time for wait‐list candidates of blood type O. In this manuscript, we explore attitudes of a convenience sample of minority patients with end‐stage renal disease (ESRD) regarding living paired exchanges, ABO‐compatible and ABO‐incompatible list‐paired exchanges and ABO‐incompatible direct transplants. Data from 87 minority respondents were analyzed. Eighty‐seven (100%) supported living paired exchanges and ABO‐compatible list‐paired exchanges. In contrast, only 50 of 85 (59%) respondents supported ABO‐incompatible list‐paired exchanges (p < 0.001), including half (12 of 24) of those with blood type O. Subjects were asked how much additional time it would be fair to ask wait‐list candidates of blood type O to wait to implement ABO‐incompatible list‐paired exchanges. Forty percent (35 of 87) responded ‘no additional time’ and another 10% (9 of 87) responded ‘one month or shorter’. Minority dialysis patients hold mixed opinions about the fairness of ABO‐incompatible list‐paired exchanges. If our findings are confirmed in a more diverse randomly selected sample, then the UNOS variances that permit these exchanges should be reconsidered.