Kim M. Olthoff

Correlation between donor age and the pattern of liver graft recovery after transplantation

We have observed an increased rate of delayed non-function (DNF) of liver grafts procured from older donors. The aim of this study was to correlate donor age and the patterns of graft failure after transplantation. Pattern of liver injury, synthetic function, and graft survival in recipients receiving liver grafts from donor older than age 50 (group I, n=95) were compared with matched cohort of recipients transplanted with grafts from donors age 20–30 (group III, n=50). Primary nonfunction (PNF) of the graft was defined as non-recoverable hepatocellular function necessitating emergency retransplantation within 72 hr. DNF was defined as marginal graft function necessitating re-transplantation within one month. Recipient characteristics, including age and preoperative UNOS status, were similar between groups. Ischemic/reperfusion injury, reflected by SGOT and SGPT was more severe in older donors. PNF occurred at similar frequencies for all groups (7%). Normal liver function was regained in 76% of recipients in group I, and in 92% in group II. However, cholestatic pattern was observed in recipient of grafts from group I donors. Rapid rise in bilirubin, despite normalization of prothrombin time and liver transaminases, was the hallmark of DNF. DNF resulted in higher retransplantation rate in group I (24% vs. 8% in group II). Donor age did not affect patient survival. Liberalizing criteria for donor selection, and acceptance of older donors is a calculated risk. Over 75% of the recipients will regain normal liver function. However, a higher number of these grafts will exhibit slow recovery after transplantation, and a significant rate of DNF. Recognition of such

Adjuvant chemotherapy improves survival after liver transplantation for hepatocellular carcinoma

ObjectiveThe aim of this study was to evaluate the effect of postoperative adjuvant chemotherapy on the recurrence rate and survival of patients after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). Summary Background DataHistorically, liver transplantation for HCC has yielded poor long-term survival. Multimodality therapy has been initiated in an effort to improve survival statistics. MethodsTwenty-five patients were placed on 6 months of intravenous fluorouracil, doxorubicin, and cisplatin after OLT. Risk factors, recurrence rates, and survival rates were analyzed and compared with historic controls. ResultsOverall long-term survival in the protocol patients was 46% at 3 years, improved over our historic controls of 5.8% at 3 years (p = 0.0001). Overall recurrence rate was 20% (n = 4). Possible risk factors, such as tumor size, vascular invasion, multifocality, capsular invasion, and tumor differentiation, were not found to be significantly predictive of survival. Three patients with long-term, disease-free survival had tumors > 5 cm. Side effects from chemotherapy were common, but rarely severe. ConclusionsThis study suggests that adjuvant chemotherapy after transplantation for HCC can provide long-term cure and may improve survival, even in patients with stage III and IV disease.

The role of tumor necrosis factor in allograft rejection. III, Evidence that anti-TNF antibody therapy prolongs allograft survival in rats with acute rejection

We have previously demonstrated that TNF-alpha levels are elevated in liver transplant patients experiencing acute rejection. In addition, prophylactic administration of anti-TNF-alpha or anti-TNF-beta antibodies prolonged graft survival in a rat heterotopic cardiac transplant model. This experiment was designed to evaluate anti-TNF therapy in the treatment of acute allograft rejection. Heterotopic cardiac transplants were performed using Buffalo donors and Lewis recipients. Histologic sections of transplanted grafts from untreated animals revealed significant rejection at day 4 with terminal rejection occurring on day 10.8 +/- 0.4. Animals in the experimental groups received antirejection therapy from postoperative days 4-13. Treatment with cyclosporine at 2 mg/kg/day prolonged graft survival to 16.5 +/- 2.0 days (P = 0.01 versus controls). Administration of polyclonal anti-TNF-alpha in combination with polyclonal anti-TNF-beta increased graft survival to 14.6 +/- 0.4 days (P less than 0.001 versus controls). Use of a monoclonal anti-TNF-alpha antibody was even more effective, with graft survival of 17.4 +/- 0.7 days (P less than 0.001 versus controls). Combination immunotherapy with monoclonal anti-TNF-alpha in conjunction with CsA extended survival to greater than 30 days. In contrast, recombinant TNF-alpha (5 micrograms/day, i.p.) markedly accelerated the time to graft failure (7.4 +/- 0.2 days, P less than 0.001 versus controls). Examination of explanted graft tissue on postoperative day 9 from animals treated with anti-TNF showed decreased mononuclear cell infiltrate when compared to untreated animals. Treatment with TNF-alpha markedly increased the inflammatory process. These results suggest that TNF may play a role in the pathogenesis of acute rejection.

The role of tumor necrosis factor in allograft rejection. II. Evidence that antibody therapy against tumor necrosis factor-alpha and lymphotoxin enhances cardiac allograft survival in rats.

In the previous study we demonstrated that circulating levels of TNF-alpha are elevated during liver allograft rejection and may precede clinical manifestations. The current study was designed to investigate the efficacy of antibody therapy against tumor necrosis factor-alpha and lymphotoxin (LT) in a rat heterotropic cardiac transplant model utilizing Buffalo donors and Lewis recipients. Control animals received no immunotherapy and experienced rejection on postoperative day 11 +/- 0.4 (mean +/- SEM). Experimental animals received immunotherapy either intraperitoneal or intravenous from days 1 to 10. The i.p. administered anti-TNF-alpha prolonged graft survival to 16 +/- 2.7 days (P less than 0.05 vs. controls); the i.v. administration prolonged survival to 15 +/- 1.4 days (P less than 0.004). Animals treated with i.p. anti-LT survived 17 +/- 1.7 days (P less than 0.002 vs. controls). Combination immunotherapy of anti-TNF-alpha and anti-LT increased function to 21 +/- 2.2 days (P less than 0.001 vs controls). Conversely, administration of purified TNF-alpha or LT to graft recipients accelerated the time to rejection. Mean survival for both treatments was 7 days (P less than 0.001 vs. controls). Histologic examination of the transplanted cardiac tissue showed a typical pattern for acute rejection; there was no evidence of hemorrhagic or coagulative necrosis. In contrast, administration of purified TNF-alpha or LT to recipients of a syngeneic heart did not stimulate rejection. These data suggest that TNF-alpha and LT may play a role in the pathogenesis of acute allograft rejection. In addition, the mechanism appears to be distinct from that seen in TNF-alpha or LT-mediated cytotoxicity of tumor cells.

Rapid en bloc technique for pancreas-liver procurement : Improved early liver function

It is our experience that warm dissection in the porta hepatis as well as extensive organ mobilization during combined pancreas-liver procurements may cause posttransplant dysfunction of the liver. To avoid this, we recently utilized a rapid en bloc procurement technique with minimal warm dissection and division of the liver and pancreas ex vivo. Fifteen procurements were performed using this rapid en bloc technique; seventeen procurements involved extensive dissection followed by sequential in situ procurement of the liver and pancreas grafts. The control group consisted of 15 age-matched patients who received livers when no pancreas was harvested. Dissection time was 157 +/- 13 min (mean +/- SEM) in the in situ group, 78 +/- 3 min in the en bloc group (P<0.02), and 51 +/- 6 min in the liver only group (P<0.02). There was no difference in donor age, cold ischemia time, or recipient United Network for Organ Sharing status. Pancreata obtained using the en bloc technique all had immediate function and there were no episodes of acute pancreatitis. Early liver graft function, as assessed by lactate dehydrogenase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, and total bilirubin levels, was significantly lower in the en bloc and liver only group when compared with the in situ group. The total hospital stay was also significantly lower in these groups. We conclude that the rapid en bloc technique decreases operative time during the donor operation. Procurement-related injury to the liver graft is minimized without compromising pancreas graft function.

Comparison of UW solution and Euro-Collins solutions for cold preservation of human liver grafts.

University of Wisconsin solution, a new organ preservation medium, is reported to extend the period of cold storage. In order to evaluate the efficacy of UW solution in human liver preservation we compared 58 donor liver grafts preserved in Euro-Collins (EC) solution. All livers were harvested in a similar manner. Donor and recipient characteristics in the two groups were comparable. The mean preservation time of the UW solution was 11.5 +/- 4.2 hr (range 3-20 hr), significantly longer than the EC mean preservation time of 4.9 +/- 1.6 hr (2-9.6 hr) (P = 0.0001). Evaluation of mean postoperative liver function tests and coagulation factors on days 1-7 showed no statistical difference between the two groups. There was one primary graft nonfunction in the EC group and none with the UW organs. Hepatic artery thrombosis was similar in each group. The incidence of early retransplantation was similar. Three-month graft survival was 81% in the UW group vs. 73% in the EC group. Patient survival at three months was 87% with the UW organs and 84% with the EC organs. We conclude that cold storage of liver grafts in the UW solution has allowed for significantly longer preservation, permitting transplantation to be performed under semielective conditions and procurement of organs from much further distances. Grafts stored in UW solution perform as well as those stored in Euro-Collins, with no significant difference in liver function abnormalities postoperatively.

PGE1 reduces injury in hepatic allografts following preservation

Prostaglandins of the E series have been shown to decrease renal and hepatic ischemic injury as well as improve hepatic function in patients with primary nonfunction following transplantation. We wished to determine the effect of prostaglandin E1 (PGE1) on hepatic allograft reperfusion injury in the isolated perfused rat liver (IPRL) model. Livers were harvested from adult male Sprague-Dawley rats and the bile duct, portal vein, and suprahepatic vena cava were cannulated. Control livers were placed immediately on the IPRL apparatus and perfused for 2 hr with a blood-Krebs solution. Group A and B allografts were stored for 8 hr in heparinized lactated Ringers solution at 4 degrees C. Group A livers were then perfused with a PGE1 infusion at 0.1 micrograms/kg/min while B livers received a placebo infusion of NS at the same rate. Temperature, pH, and inflow pressures were kept constant. Oxygen consumption, portal flow, and resistance were calculated for each group and found not to be statistically different. LDH, SGOT, superoxide anion (SOA), and bile flow were measured at 30-min intervals. At the end of the 2-hr perfusion, the placebo Group B (N = 5) had LDH, SGOT, and SOA higher than those of either Group A (N = 5) or control (N = 4) livers. The difference between Group A and Group B was significant for SGOT and SOA (P less than 0.05). Bile flow was highest in the control group (24.2 +/- 1.8 microliters/g/30 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Living-donor liver transplantation at UCLA

BACKGROUNDnLiving-donor (LD) liver transplantation has been developed as an alternative to overcome the shortage of cadaver donor organs for pediatric recipients.nnnPATIENTS AND METHODSnWe reviewed our experience with 9 LD transplants performed between August 25, 1993 and August 3, 1994. The median recipient age and weight were 13 months and 10 kilograms. Left lateral segments from parental donors, with aortic inflow via saphenous vein grafts, were used in all cases.nnnRESULTSnAt a median follow-up of 160 days, all donors were alive and well. Recipient and graft survival were both 89%. Rates of hepatic artery thrombosis, portal vein thrombosis, biliary complications, and acute rejection were 22%, 11%, 11%, and 67%, respectively.nnnCONCLUSIONSnExcellent outcome can be achieved with LD liver transplantation in small children with minimal donor risk. This procedure has the potential to emerge as the preferred treatment for pediatric liver transplant candidates for whom it is an option.

Randomized controlled trial to evaluate flush and reperfusion techniques in liver transplantation

To determine the impact of different flush and reperfusion techniques on postreperfusion syndrome (PRS) and postoperative graft function, 100 transplants were randomly assigned into four groups as follows: group 1 (n=31), portal vein flush, no vena caval venting; group 2 (n=21), hepatic arterial flush, no vena caval venting; group 3 (n=29), portal vein flush with vena caval venting; and group 4 (n=19), hepatic artery flush with vena caval venting. Donor and recipient characteristics were similar. Extensive intraoperative and postoperative monitoring was performed and measurements were documented immediately before reperfusion and at 1, 5, 15, and 30 min after reperfusion. PRS was defined by three criteria: mean arterial pressure (MAP) <60 mmHg at 1 min after reperfusion, MAP <60 mmHg at 5 min after reperfusion, and a decrease of 30% or more for the MAP percent area under the curve during the initial 5 min after reperfusion (%AUC). Using these definitions, the overall incidence of PRS was 21%, 8%, and 43%, respectively. Group 1 was the most hemodynamically stable; the incidence of PRS in group 1 was 2/31 (7%) at 1 min and 8/31 (25%) using %AUC criteria compared with 7/21 (33%) at 1 min and 12/21 (57%) using %AUC criteria for group 2 (P<0.05). The patients in groups 3 and 4 (vena caval venting) demonstrated smaller percentage increases in serum potassium levels (as determined by %AUC; 4.3+/-6.8 and 0.3+/-5.4, vs. 15.1+/-8.1 for group 1 and 22.9+/-8.2 for group 2). The difference between group 4 and group 2 was statistically significant (P<0.05). The increases in serum potassium did not translate into increased cardiac or hemodynamic instability. Combining all data obtained over the first 30 min after reperfusion, there was no statistically significant difference in hemodynamic or biochemical changes noted among the four groups. Postoperative liver function was similar among the four groups. We conclude that portal vein flush without vena caval venting provided a lower incidence of PRS than any other technique. Vena caval venting decreased the release of potassium into the circulation. Postoperative graft function was not significantly affected by flush and reperfusion techniques.

Failure of duplex sonography to diagnose hepatic artery thrombosis in a high-risk group of pediatric liver transplant recipients

Excellent correlation between angiographic findings and duplex sonography has been previously reported in the diagnosis of hepatic artery thrombosis (HAT), the most common technical complication of pediatric orthotopic liver transplantation (OLT). We now report a significant incidence of false-negative sonograms, ie, hepatic artery reported as patent but thrombosed on subsequent angiography. HAT was diagnosed in 10 of 57 pediatric OLT recipients evaluated prospectively by duplex sonography. In 5 patients HAT was diagnosed only by angiography even though arterial wave forms were observed on duplex sonography. Selective angiography demonstrated extensive collateral vessel formation arising from the superior mesenteric artery, the celiac axis, or both. The 5 patients shared very similar clinical courses marked by relapsing bacteremias with multiple enteric organisms, associated with focal infarctions of the liver. Four of the grafts had difficult arterial reconstructions and 3 of 5 had segmental bile duct dilation. We conclude that duplex sonography has proven to be a valuable screening tool in evaluating hepatic artery patency but must be correlated with angiography studies in a high-risk group of pediatric transplant patients characterized clinically by relapsing bacteremia and radiographically by false-negative duplex examinations.