Tetsuya Kiuchi

Impact of graft size mismatching on graft prognosis in liver transplantation from living donors

BACKGROUND Although living donor liver transplantation for small pediatric patients is increasingly accepted, its expansion to older/larger patients is still in question because of the lack of sufficient information on the impact of graft size mismatching. METHODS A total of 276 cases of living donor liver transplantation, excluding ABO-incompatible, auxiliary, or secondary transplants, were reviewed from graft size matching. Forty-three cases were highly urgent cases receiving intensive care preoperatively. Cases were categorized into five groups by graft-to-recipient weight ratio (GRWR): extra-small-for-size (XS; GRWR<0.8%, 17 elective and 4 urgent cases), small (S; 0.8< or =GRWR< 1.0%, 21 and 7), medium (M; 1.0< or =GRWR<3.0%, 119 and 19), large (L; 3.0< or =GRWR<5.0%, 67 and 10), and extra-large (XL; GRWR> or =5.0%, 9 and 3). RESULTS Smaller-for-size grafts were associated not only with larger and older recipients, but also with rather older donors. Posttransplant bilirubin clearance was delayed and aspartate aminotransferase corrected by relative graft size was higher in XS and S. Posttransplant hemorrhage and intestinal perforation were more frequent in XS and S, and vascular complications and acute rejection were more frequent in larger-for-size grafts. Consequently, graft survival in XS (cumulative 58% and actuarial 42% at 1 year) and S (76% and 74%) was significantly lower compared with that in M (93% and 92%) in elective cases. Graft survival in L (83% and 82%) and XL (75% and 71%) did not reach statistical significance. CONCLUSIONS The use of small-for-size grafts (less than 1% of recipient body weight) leads to lower graft survival, probably through enhanced parenchymal cell injury and reduced metabolic and synthetic capacity. Although large-for-size grafts are associated with some anatomical and immunological disadvantages, the negative impact is less pronounced.

Right lobe graft in living donor liver transplantation.

BACKGROUND For the sake of donor safety in living donor liver transplantation (LDLT), the left lobe is currently being used most often for the graft. However, size mismatch has been a major obstacle for an expansion of the indication for LDLT to larger-size recipients, because a left lobe graft is not safe enough for them. METHODS In 1998, LDLT using a right lobe graft was introduced and performed on 26 recipients to overcome the small-for-size problem. The right lobe, which does not include the middle hepatic vein of the donor, was used. Initially, indication for right lobe LDLT was basically defined as an estimated left lobe graft volume/recipient body weight ratio (GRWR) of <0.8%, which was later raised to <1.0%. RESULTS All the donors recovered from the operation without persistent complications. Two donors with transient bile leakage were successfully treated with a conservative approach. A right lobectomy resulted in more blood loss (337+/-175 ml), and a longer operative time (6.67+/-0.85 hr) than a lateral segmentectomy, but not a left lobectomy. Grafts with a GRWR >0.8% were implanted in all recipients, except for two, who received relatively smaller right lobes (GRWR of 0.68% and 0.66%). In one of these two, the right lobe from the donor was used as the orthotopic auxiliary graft. Postoperative transitory increases in total bilirubin and aspartate transaminoferase for right lobe donors were higher than those for the left lateral segmentectomy. Nineteen recipients (73.1%) were successfully treated with this procedure. The causes of death were not specific for right lobe LDLT, except for one patient with a graft that had multiple hepatic venous orifices. These multiple and separate anastomoses of the hepatic veins caused an outflow block as a result of a positional shift of the graft, which finally led to graft loss. CONCLUSION Our experience suggests that right lobe grafting is a safe and effective procedure, resulting in the expansion of the indication for LDLT to large-size recipients. How to deal with the possible variation in the anatomy of the right lobe graft should be given attention throughout the procedure.

WEANING OF IMMUNOSUPPRESSION IN LIVING DONOR LIVER TRANSPLANT RECIPIENTS

Background. Some reported studies have indicated the possibility of immunosuppression withdrawal in cadaveric liver transplantation. The aim of this study was to evaluate the possibility and feasibility of weaning living donor liver transplant recipients from immunosuppression. Methods. From June of 1990 to October of 1999, 63 patients were considered to be weaned from immunosuppression. They consisted of 26 electively weaned patients and 37 either forcibly or incidentally weaned patients (nonelective weaning) due to various causes but mainly due to infection. Regarding elective weaning, we gradually reduced the frequency of tacrolimus administration for patients who survived more than 2 years after transplantation, maintained a good graft function, and had no rejection episodes in the preceding 12 months. The frequency of administration was reduced from the conventional b.i.d. until the start of weaning to q.d., 4 times a week, 3 times a week, twice a week, once a week, twice a month, once a month, and finally, the patients were completely weaned off with each weaning period lasting from 3 to 6 months. The reduction method of nonelective weaning depended on the clinical course of each individual case. When the patients were clinically diagnosed to develop rejection during weaning, then such patients were treated by a reintroduction of tacrolimus or an additional steroid bolus when indicated. Results. Twenty-four patients (38.1%) achieved a complete withdrawal of tacrolimus with a median drug-free period of 23.5 months (range, 3–69 months). Twenty-three patients (36.5%) are still being weaned at various stages. Sixteen patients (25.4%) encountered rejection while weaning at median period of 9.5 months (range, 1–63 months) from the start of weaning. All 16 were easily treated with the reintroduction of tacrolimus or additional steroid bolus therapy. Conclusions. We were able to achieve a complete withdrawal of immunosuppression in some selected patients. Although the mechanism of graft acceptance in these patients has yet to be elucidated, we believe that a majority of long-term patients undergoing living donor liver transplantation may, thus, be potential candidates to be successfully weaned from immunosuppression.

Transmission of hepatitis B virus from hepatitis B core antibody- positive donors in living related liver transplants

BACKGROUND In order to clarify the risk of hepatitis B virus (HBV) transmission from hepatitis B core antibody-positive (HBcAb(+)) donors and to evolve a new strategy to counter such a risk, we undertook a retrospective (1990-1995) and prospective (1995-1996) analysis of our experience with living related liver transplantation involving HBcAb(+) donors. METHODS Between June 15, 1990, and June 30, 1995, HBcAb(+) individuals were not excluded as donor candidates at our institutions. For 171 liver transplants, 16 donors were HBcAb(+). Between July 1, 1995, and June 30, 1996, HBcAb(+) individuals were generally excluded as donor candidates; however, three recipients were given liver grafts from HBcAb(+) donors because other donor candidates presented even higher risks. In the latter period, recipients with transplants from HBcAb(+) donors underwent prophylactic passive immunization with hyperimmune hepatitis B immunoglobulin (HBIG). The serum of 10 HBcAb(+) donors was examined by nested polymerase chain reaction for the presence of HBV-DNA, but it was not detected in any of them. However, the same examination of the liver tissue of five such donors yielded positive results in all cases. RESULTS In the first 5-year period, out of 16 recipients with HBcAb(+) donors, 15 became hepatitis B surface antigen-positive after transplant. The three recipients with HBcAb(+) donors during the second 1-year period, who were treated by prophylactic passive immunization with HBIG, remained hepatitis B surface antigen-negative and negative for serum HBV-DNA after transplant. CONCLUSIONS HBV exists in the liver of healthy HBcAb(+) individuals, but not in the blood. Therefore, HBV is thought to be transmitted to recipients by liver grafts from the HBcAb(+) donors at a significantly high rate. The prevention of viral activation and clinical disease development by means of passive immunization with HBIG seems promising, although the follow-up period in our study may be too short for any definitive conclusions.

Changes in portal venous pressure in the early phase after living donor liver transplantation: pathogenesis and clinical implications.

Background. Although living-donor liver transplantation (LDLT) has been accepted for adult populations, the occurrence and pathogenesis of small-for-size syndrome remain highly controversial. Methods. Portal venous pressure (PVP) was measured in 79 cases of LDLT from anhepatic phase to day 14. PVP was monitored through a catheter inserted via the inferior mesenteric vein. In a separate series of seven cases of adult LDLT, the splenic artery was ligated following arterial reperfusion. Results. For days 2 to 4 and 9 to 11, recipients of small-for-size graft (<0.8% of body weight) displayed significantly higher PVP than recipients of larger grafts. The 13 patients with elevated mean PVP (≥20 mm Hg) early in the first week (days 0–4) demonstrated significantly worse survival (84.5% vs. 38.5% at 6 months;P < 0.01), but this was not applicable to elevated mean PVP late in the first week (days 5–7). Elevated PVP early in the first week was also associated with higher incidence of bacteremia, cholestasis, prolonged prothrombin time, and ascites. Splenic artery ligation (SAL) immediately reduced PVP from 10 to 20 mm Hg (median, 16 mm Hg) to 9 to 13 mm Hg (median, 11 mm Hg;P = 0.02). Posttransplant PVP was significantly lower in SAL patients than in non-SAL patients from days 2 to 7 despite small graft size. Early PVP in SAL patients was consistently below 20 mm Hg, and survival was significantly better than in non-SAL patients with high early PVP (P < 0.01). Conclusion. Elevated PVP in the early phase is strongly associated with poor patient survival attributable, at least in part, to small-for-size graft. Further elucidation of the pathogenesis behind this phenomenon and efforts to modify PVP will be key to improving results.

Anatomical variations and surgical strategies in right lobe living donor liver transplantation: lessons from 120 cases.

Background. Anatomical variations in right liver lobe are common. However, clinical implications and surgical management of these variations in living donor liver transplantation have not been analyzed systematically. Methods. Surgical anatomy of vascular and biliary structures in 120 right lobe grafts were reevaluated by reviewing the results of preoperative (computerized tomography and Doppler ultrasonography) and intraoperative (cholangiography) imaging as well as surgical findings. The data were analyzed in relation to surgical management of anatomical variations. Results. The incidence of variants leading to multiple portal vein anastomoses was 7.5%. The incidence of dual right hepatic veins was 0.8%; 30% of the grafts had significant accessory hepatic veins (>5 mm) and 13.9% of these were multiple. All of them were successfully reconstructed with technical modifications including venoplasty and venous grafts, except for two cases with multiple intraparenchymal portal vein branches to the anterior segment. The incidence of dual hepatic arteries was 1.7%, but only one of them was reconstructed without negative sequelae. The incidence of variants potentially leading to multiple bile duct anastomoses was 35.0%, and eventually 39.2% of the grafts had multiple orifices. With a variety of techniques including ductoplasty, hepaticohepaticostomy, and biliary stent, total incidence of leakage and stenosis was 10.8% and 9.2%, respectively. Although ductoplasty, internal stent or no stenting, seemed to be associated with increased risk of complications, anatomical variants, multiple bile ducts, and duct-to-duct reconstruction did not bear a significant risk. Conclusions. Anatomical variations of vascular and biliary structures in right lobe grafts are common. However, most can be managed safely with technical modifications. Only cases with intraparenchymal origin of the anterior portal vein(s) may form a relative contraindication, especially when combined with similar biliary variants. Otherwise, intraoperative assessment of biliary anatomy was enough for successful management. Detailed and precise assessment of vascular and biliary anatomy is vital for appropriate surgical management.

C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3A4 rather than Pgp in recipients of living-donor liver transplantation.

The bioavailability of structurally unrelated drugs is limited by active secretion via the multidrug resistance gene (MDR1) product P-glycoprotein (Pgp) from enterocyte into lumen as well as intestinal metabolism by cytochrome P450 IIIA4 (CYP3A4). In the present study, we analyzed whether genetic polymorphism of the MDR1 had some influence on the intestinal expression levels of Pgp and CYP3A4 and the tacrolimus concentration/dose ratio over the first postoperative days in recipients of living-donor liver transplantation (LDLT). Genotyping assays were performed for the major 10 polymorphisms in the MDR1 gene by the polymerase chain reaction-restriction enzyme length polymorphism method. The allele frequencies of variations at five positions were almost comparable with those in the former studies in Caucasians and Japanese, but there was no variation at the other five positions. Although no polymorphism correlated with the intestinal expression of MDR1 mRNA or the tacrolimus concentration/dose ratio in the LDLT recipients, the C3435T polymorphism significantly affected the intestinal expression level of CYP3A4 mRNA as follows; 3435C/C>3435C/T (P < 0.05 vs. 3435C/C)>3435T/T (P < 0.01 vs. 3435C/C). Therefore, the identified polymorphisms including C3435T in the MDR1 gene were indicated to have no influence on the intestinal expression level of Pgp or the tacrolimus concentration/dose ratio in the recipients of LDLT. On the other hand, the C3435T polymorphism of MDR1 was suggested to correlate with the enterocyte expression of CYP3A4 rather than Pgp linking unknown genetic variation in CYP3A4 gene.

Biliary Anastomotic Complications in 400 Living Related Liver Transplantations

Abstract. The purpose of this study was to evaluate the cause and outcome of biliary anastomotic complications occurring after living related liver transplantation (LRLT). A database of 391 patients undergoing 400 LRLT from June 1990 to August 1998 was reviewed. The overall incidence of biliary anastomotic complications was 18.2% (71 patients). There were 45 bile leaks, 35 anastomotic strictures, and the bile duct was ligated inadvertently in 3 cases. Univariative analysis revealed that the manner of stent usage, intrapulmonary shunting, and gender of recipients were significant risk factors for leakage. Anastomotic leaks, cytomegalovirus infection, hepatic artery complications, and gender of recipients were significant risk factors for stricture. In pediatric patients older than 2 years old, ABO blood type compatibility was another risk factor for leakage and stricture. Choice of stent usage and earlier transplantation for patients with intrapulmonary shunting should reduce the rate of biliary leaks, and prophylaxis of leaks for patients with intrapulmonary shunting, and minimizing hepatic artery complications should reduce the rate of biliary stricture after LRLT. Avoidance of ABO-incompatible donors or innovative immunosuppression in ABO-incompatible transplantation should be considered in children.

Biliary reconstruction in right lobe living-donor liver transplantation : Comparison of different techniques in 321 recipients

Objective:To assess the incidence of biliary complications after right lobe living-donor liver transplantation (LDLT) in patients undergoing duct-to-duct choledochocholedochostomy or Roux-en-Y choledochojejunostomy reconstruction. Summary Background Data:Biliary tract complications remain one of the most serious morbidities following liver transplantation. No large series has yet been carried out to compare the 2 techniques in LDLT. This study undertook a retrospective assessment of the relation between the method of biliary reconstruction used and the complications reported. Methods:Between February 1998 and June 2004, 321 patients received right lobe LDLT. Biliary reconstruction was achieved with Roux-en-Y choledochojejunostomy in 121 patients, duct-to-duct choledochocholedochostomy in 192 patients, and combined Roux-en-Y and duct-to-duct choledochocholedochostomy in 8 patients. The number of graft bile duct and anastomosis, mode of anastomosis, use of stent tube, and management of biliary complications were analyzed. Results:The overall incidence of biliary complications was 24.0%. Univariate analysis revealed that hepatic artery complications, cytomegalovirus infections, and blood type incompatibility were significant risk factors for biliary complications. The respective incidence of biliary leakage and stricture were 12.4% and 8.3% for Roux-en-Y, and 4.7% and 26.6% for duct-to-duct reconstruction. Duct-to-duct choledochocholedochostomy showed a significantly lower incidence of leakage and a higher incidence of stricture; however, 74.5% of the stricture was managed with endoscopic treatment. Conclusions:The authors found an increase in the biliary stricture rate in the duct-to-duct choledochocholedochostomy group. Because of greater physiologic bilioenteric continuity, less incidence of leakage, and easy endoscopic access, duct-to-duct reconstruction represents a feasible technique in right lobe LDLT.

Living-donor liver transplantation for hepatocellular carcinoma.

In cadaveric liver transplantation, the Milan criteria have been accepted as the selection criteria for hepatocellular carcinoma (HCC) patients in considering organ allocation. However, the situation is different in living-donor liver transplantation (LDLT), in which the donor has a strong preference for altruism. The authors describe herein their experience with LDLT for HCC patients using their patient selection criteria. From February 1999 to March 2002, right lobe LDLT was performed in 56 patients with HCC. The authors’ exclusion criteria included only those with extrahepatic metastasis or vascular invasion detected during preoperative evaluation. Thirty patients (54%) were in tumor, node, metastases stage IVa and 25 patients (45%) did not meet the Milan criteria at the time of LDLT. The follow-up period was 1 to 39 months (median, 11 months). The overall survival rates at 1 and 3 years were 73% and 55%, respectively, and the latter was significantly lower than that of adult right lobe LDLT without HCC (71% at 3 years). Fourteen patients died because of postoperative complications without tumor recurrence. Thirty-six patients survived without recurrence and six patients had recurrence. Among the six patients with recurrence, four had survived for 11 to 36 months after LDLT. In the analysis of patients who survived longer than 3 months after transplantation, 19 of 20 within the Milan criteria survived without recurrence. However, 15 of 20 patients beyond the criteria also survived without recurrence for 3 to 33 months (median, 12 months) and three of five patients with recurrence were alive for 11 to 36 months (median, 20 months). Histopathologic grading and microscopic portal venous invasion had significant negative impact on tumor recurrence. LDLT was an effective treatment for uncontrollable hepatocellular carcinoma. Because many patients who did not meet the Milan criteria survived without tumor recurrence after transplantation, different patient selection criteria are necessary in LDLT to save those with advanced HCC.