Kenji Uryuhara

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.

Impact of recipient age on outcome of ABO-incompatible living-donor liver transplantation.

Background. Transplantation of hepatic grafts from ABO-incompatible donors is controversial because of the risk of hyperacute rejection mediated by preformed anti-ABO antibodies. The aim of the present study was to evaluate the outcome of liver transplants performed with ABO-incompatible living-donor livers and to detect risk factors for development of complications. Methods. From June 1990 to February 2000, 66 patients, 10 months to 55 years old (median, 2 years old), received 68 ABO-incompatible living-donor liver grafts. The antibody titer and clinical course were followed prospectively during a period ranging from 3 to 11 years. Results. The 5-year patient survival was 59%, 76%, and 80% for ABO-incompatible, ABO-compatible, and ABO-identical grafts, respectively (P <0.01). In patients <1 year old, ≥1 to <8, ≥8 to <16, and and ≥16 years old, 5-year survival was 76%, 68%, 53%, and 22%, respectively. The incidence of intrahepatic biliary complications and hepatic necrosis in ABO-incompatible living-related grafts (18% and 8%, respectively) was significantly (P <0.0001) greater than in ABO-compatible and ABO-identical grafts (both 0.6% and 0%, respectively). Predictive risk factors for increased mortality and morbidity were age greater than 1 year and elevated anti-ABO titers before transplantation. Conclusions. ABO-incompatible liver transplantation was carried out with relative safety in infants <1 year old but was not satisfactory in children >1 year in long-term follow-up. Patients aged >8 years remain at considerable risk of early fatal outcome because of hepatic necrosis, and new strategies to prevent antibody-mediated rejection are required.

Current role of liver transplantation for the treatment of urea cycle disorders: A review of the worldwide English literature and 13 cases at Kyoto University

To address the current role of liver transplantation (LT) for urea cycle disorders (UCDs), we reviewed the worldwide English literature on the outcomes of LT for UCD as well as 13 of our own cases of living donor liver transplantation (LDLT) for UCD. The total number of cases was 51, including our 13 cases. The overall cumulative patient survival rate is presumed to be more than 90% at 5 years. Most of the surviving patients under consideration are currently doing well with satisfactory quality of life. One advantage of LDLT over deceased donor liver transplantation (DDLT) is the opportunity to schedule surgery, which beneficially affects neurological consequences. Auxiliary partial orthotopic liver transplantation (APOLT) is no longer considered significant for the establishment of gene therapies or hepatocyte transplantation but plays a significant role in improving living liver donor safety; this is achieved by reducing the extent of the hepatectomy, which avoids right liver donation. Employing heterozygous carriers of the UCDs as donors in LDLT was generally acceptable. However, male hemizygotes with ornithine transcarbamylase deficiency (OTCD) must be excluded from donor candidacy because of the potential risk of sudden‐onset fatal hyperammonemia. Given this possibility as well as the necessity of identifying heterozygotes for other disorders, enzymatic and/or genetic assays of the liver tissues in cases of UCDs are essential to elucidate the impact of using heterozygous carrier donors on the risk or safety of LDLT donor‐recipient pairs. In conclusion, LT should be considered to be the definitive treatment for UCDs at this stage, although some issues remain unresolved. (Liver Transpl 2005;11:1332–1342.)

Selective hemi-portocaval shunt based on portal vein pressure for small-for-size graft in adult living donor liver transplantation

We developed an algorithm of graft selection in which left lobe donation is considered primarily if the graft‐to‐recipient weight ratio (GRWR) is estimated to be greater than 0.6% in preoperative volumetry with utilization of a hemi‐portocaval shunt (HPCS) based on portal vein pressure (PVP) more than 20 mmHg at the time of laparotomy. A total of 11 consecutive adult living donor liver transplantations with small‐for‐size graft according to our graft selection algorithm were performed between December 2005 and August 2007. Ten patients required HPCS using a vein graft all survived without small‐for‐size syndrome (SFSS) and shunt complications with a median follow‐up of 296 days. One patient without HPCS died of chronic vascular rejection. In all cases, PVP were regulated successfully under 20 mmHg by HPCS. Graft volume reached in mean 84.3% of standard liver volume in right lobe grafts and mean 95.4% in left lobe grafts at 3 months after liver transplantation. Actuarial rate of shunt patency at 1, 3, 6 months and 1 year were 80%, 55%, 26% and 20%, respectively. Selective HPCS based on PVP is an effective procedure and results in excellent patient and graft survival with avoidance of SFSS in grafts greater than 0.6% of GRWR.

Long-term outcomes of 600 living donor liver transplants for pediatric patients at a single center.

This report concerns the long‐term outcome of living donor liver transplantation (LDLT) for pediatric patients at a single center. Between June 1990 and December 2003, a total of 600 LDLTs, including 568 primary transplantations and 32 retransplantations, were performed for pediatric patients, who were immunosuppressed with FK506 and low‐dose corticosteroids. Patient survival at 1, 5, and 10 years were 84.6%, 82.4%, and 77.2%, respectively, and the corresponding findings for graft survivals were 84.1%, 80.9%, and 74.5%. Multivariate analysis demonstrated that fulminant hepatic failure (FHF), a graft vs. body weight (GBWR) ratio of <0.8, and ABO‐incompatible transplants were independently associated with both patient and graft survival. The retransplantation rate was 6%, and 55 patients (9.7%) have been completely weaned off immunosuppressants. Long‐term patient and graft survival after pediatric LDLT for a large cohort of children at our hospital were found to be as good as those for cadaveric liver transplantation, although this series includes 13% liver transplantations with ABO‐incompatible donors, which are obviously inferior in patient and graft survival. To obtain better outcomes for patients with FHF and for patients with ABO‐incompatible transplants, immunosuppressive therapy needs to be improved. Liver Transpl 12:1326‐1336, 2006.

Graft size assessment and analysis of donors for living donor liver transplantation using right lobe.

Background. Modality of living donor liver transplantation (LDLT) hasbeen expanded to adult cases. However, the safety of right lobectomy fromliving donors has not yet beenproven. Methods. A total of 62 cases of LDLT, using the right lobe, werereviewed. Study 1: Discrepancy between estimated graft volume and actual graftweight was evaluated. Study 2: Postoperative liver functions were analyzed inrelation to residual liver volume (RLV) or age. Residual liver volume ofdonors was defined using two indices, (RLV = estimated whole livervolume − estimated graft volume and %RLV = RLV/estimated wholeliver volume×100). Donors were divided into two groups on the basis ofeither %RLV (<40%; 40%≤) or age (<50 years old; 50 years old≤).Study 3: Right lobe donors were compared with left lobe donors (35 cases) interms of their postoperative liverfunctions. Results. Study 1: The relationship between estimated graft volumeand actual graft weight was linear (y=159.136+0.735x,R 2 =0.571, P <0.001). Study 2: %RLV ranged from23.5% to 55.8% (mean±SD: 43.2±6.0). Fifteen cases showed %RLVless than 40%. Postoperative bilirubin clearance was delayed in that group(%RLV<40%). Serum total bilirubin values on postoperative day 7 in theolder group (age ≥50) were significantly higher than those in the youngergroup (age<50). Study 3: Postoperative liver functions of right lobe donorswere significantly higher than those of left-lobe donors. Eleven donors(17.7%) had surgical complications, all of which were cured with propertreatment. Conclusions. Right lobectomy from living donors is a safe procedure withacceptable morbidity, but some care should be taken early after the operationfor donors with small residual liver and ageddonors.

Impact of Right Lobe with Middle Hepatic Vein Graft in Living-Donor Liver Transplantation

Technical improvements in adult‐to‐adult living‐donor liver transplantation (LDLT) have led to the use of right‐lobe grafts to overcome the problems encountered with ‘small‐for‐size grafts’. The major controversy remains that the venous drainage from anterior segment substantially depends on tributaries of the middle hepatic vein (MHV), and deprivation of such tributaries may critically influence the postoperative graft function. Right‐lobe grafts with MHV could resolve the potential problem of congestion in anterior segment. From December 2000 to January 2004, we performed 217 right‐lobe LDLTs for adult patients. Of these, 40 patients received a right lobe with MHV graft (18.4%). The overall cumulative 3‐year graft survival rate of a right lobe with (n = 40) and without MHV (n = 177) was 86.2% and 74.8% (p = NS). The proximal side of the MHV and the drainage vein of segment IV to the MHV (the left medial superior vein) were preserved in 24 patients. All of them needed venous interposition graft for anastomosis. All patients had a patent right hepatic vein (RHV) and MHV anastomosis during the follow‐up period. We adopted the right lobe with MHV graft in 40 LDLT cases. Vein graft is essential for safe MHV anastomosis in cases which preserve proximal side of the MHV.

Vascular reconstruction and complications in living donor liver transplantation in infants weighing less than 6 kilograms: The Kyoto experience

Smaller‐size infants undergoing living‐donor liver transplantation (LDLT) are at increased risks of vascular complications because of their smaller vascular structures in addition to vascular pedicles of insufficient length for reconstruction. Out of 585 child patients transplanted between June 1990 and March 2005, 64 (10%) weighing less than 6 kg underwent 65 LDLTs. Median age and weight were 6.9 months (range: 1‐16 months) and 5 kg (range: 2.8‐5.9 kg), respectively. Forty‐five lateral segment, 12 monosegment, and 8 reduced monosegment grafts were adopted, and median graft‐to‐recipient weight ratio was 4.4% (range: 2.3‐9.7). Outflow obstruction occurred in only 1 patient (1.5%). Portal vein complication occurred in 9 (14%) including 5 with portal vein thrombosis. Hepatic artery thrombosis (HAT) occurred in 5 (7.7%). Patient and graft survivals were 73% and 72% at 1 yr, and 69% and 68% at 5 yr after LDLT, respectively. Thirteen of 22 grafts (58%) lost during the follow‐up period occurred within the first 3 months posttransplantation. Overall graft survival in patients with and without portal vein complication was 67% and 65%, respectively (P = 0.54). Overall graft survival in patients with and without HAT was 40% and 67%, respectively. HAT significantly affected graft survival (P = 0.04). In conclusion, our surgical technique for smaller‐size recipients resulted in an acceptable rate of vascular complications. Overcoming early posttransplantation complications will further improve outcomes in infantile LDLT. Liver Transpl 12:1224–1232, 2006.

Living Donor Liver Transplantation for Noncirrhotic Inheritable Metabolic Liver Diseases: Impact of the Use of Heterozygous Donors

Background. In living donor liver transplantation (LDLT), the liver donor is almost always a blood relative; therefore, the donor is sometimes a heterozygous carrier of inheritable diseases. The use of such carriers as donors has not been validated. The aim of the present study was to evaluate the outcome of LDLT for noncirrhotic inheritable metabolic liver disease (NCIMLD) to clarify the effects of using a heterozygous carrier as a donor. Methods. Between June 1990 and December 2003, 21 patients with NCIMLD underwent LDLT at our institution. The indications for LDLT included type II citrullinemia (n = 7), ornithine transcarbamylase deficiency (n = 6), propionic acidemia (n = 3), Crigler-Najjar syndrome type I (n = 2), methylmalonic acidemia (n = 2), and familial amyloid polyneuropathy (n = 1). Of these 21 recipients, six underwent auxiliary partial orthotopic liver transplantation. Results. The cumulative survival rate of the recipients was 85.7% at both 1 and 5 years after operation. All surviving recipients are currently doing well without sequelae of the original diseases, including neurological impairments or physical growth retardation. Twelve of the 21 donors were considered to be heterozygous carriers based on the modes of inheritance of the recipients’ diseases and preoperative donor medical examinations. All donors were uneventfully discharged from the hospital and have been doing well since discharge. No mortality or morbidity related to the use of heterozygous donors was observed in donors or recipients. Conclusions. Our results suggest that the use of heterozygous donors in LDLT for NCIMLD has no negative impact on either donors or recipients, although some issues remain unsolved and should be evaluated in further studies.

Clinical implications of flow cytometry crossmatch with T or B cells in living donor liver transplantation

Background: Acute allograft rejection (AR) in solid organ transplantation is generally regarded to develop through cell‐mediated immune response following activation of helper T cells. Since production of antibodies is also mediated by helper T cells, humoral immunity may play some roles in AR. Although flow cytometry crossmatch (FCXM) is reported as a useful method for the detection of antibodies against donor antigen, specific role of T‐ or B‐cell FCXM and its sensitivity for AR is controversial. 
Methods: T‐ and B‐cell FCXM using fresh donor peripheral lymphocytes were performed before and after blood‐type compatible living donor liver transplantation in 47 patients. IgM and IgG anti‐donor antibodies were analyzed in relation to clinical AR. 
Results: Positive pre‐transplant T‐cell FCXM was associated with a high incidence of positive post‐transplant T‐cell FCXM (p=0.017). Four of five cases (80%) with positive pre‐transplant T‐cell FCXM experienced earlier AR (day 8.0±4.4, mean±SD) than 16 of 42 cases (31%) with negative pre‐transplant T‐cell FCXM (17.3±6.8; p=0.016). In addition, higher dose of steroids was given to treat AR episodes in cases with positive pre‐transplant T‐cell FCXM (79.9±10.3 mg/kg/month) than in those with negative pre‐transplant T‐cell FCXM (47.1±26.6; p=0.039). In the first month after transplantation, 13 episodes of positive post‐transplant T‐cell FCXM were all concomitant with or preceded clinical AR compared with seven ARs in T‐cell FCXM‐negative cases (p<0.0001). T‐cell FCXM between positive sera and third parties revealed some crossreactions. In contrast, detection of antibodies by B‐cell FCXM in pre‐ and post‐transplant phases was scarcely associated with AR, and no correlation was found between T‐ and B‐cell FCXM before and after transplantation. 
Conclusions: Positive T‐cell FCXM is closely related with AR and that before transplantation is a predictor of early and refractory AR as well as post‐transplant FCXM. In contrast, not a few detections of antibodies irrelevant to AR are observed in B‐cell FCXM, suggesting its low specificity.