Mitsuhisa Takatsuki

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.

Perioperative synbiotic treatment to prevent infectious complications in patients after elective living donor liver transplantation: a prospective randomized study

BACKGROUND Although the effect of synbiotic therapy using prebiotics and probiotics has been reported in hepatobiliary surgery, there are no reports of the effect on elective living-donor liver transplantation (LDLT). METHODS Fifty adult patients undergoing LDLT between September 2005 and June 2009 were randomized into a group receiving 2 days of preoperative and 2 weeks of postoperative synbiotic therapy (Bifidobacterium breve, Lactobacillus casei, and galactooligosaccharides [the BLO group]) and a group without synbiotic therapy (the control group). Postoperative infectious complications were recorded as well as fecal microflora before and after LDLT in each group. RESULTS Only 1 systemic infection occurred in the BLO group (4%), whereas the control group showed 6 infectious complications (24%), with 3 cases of sepsis and 3 urinary tract infections with Enterococcus spp (P = .033 vs BLO group). No other type of complication showed any difference between the groups. CONCLUSIONS Infectious complications after elective LDLT significantly decreased with the perioperative administration of synbiotic therapy.

Differential effects of calcineurin inhibitors, tacrolimus and cyclosporin a, on interferon-induced antiviral protein in human hepatocyte cells†

The premise of our study is that selective inhibition of interferon (IFN) by calcineurin inhibitors contribute to the increased severity of hepatitis C virus (HCV) posttransplantation. Therefore, we examined the influence of calcineurin inhibitors in the human hepatocyte cell line on IFN‐α‐induced phosphorylation of Janus kinase (Jak) and signal transducers and activators of transcription (STAT), nuclear translocation of IFN‐stimulated gene factor 3 (ISGF‐3), IFN‐stimulated regulatory element (ISRE)‐contained promoter activity, and the expressions of antiviral proteins. Tacrolimus (Tac), but not cyclosporin A (CyA), had an inhibitory effect on IFN‐α‐induced double‐stranded ribonucleic acid (RNA)‐dependent protein kinase (PKR) in a dose‐dependent manner. STAT‐1 also acted in a similar fashion to PKR. IFN‐α combined with Tac attenuated the ISRE‐containing promoter gene activity as compared with IFN‐α alone. In contrast, its expression in pretreated CyA was slightly attenuated. In pretreated Tac, but not CyA, the levels of IFN‐α‐induced tyrosine phosphorylated STAT‐1 and ‐2 were clearly lower than those induced by IFN‐α alone. Tac and CyA did not decrease the IFN‐α‐induced JAK‐1 phosphorylation. The nuclear translocation rate of tyrosine phosphorylated STAT‐1 was inhibited by pretreatment of both Tac and CyA by western blotting and immunohistochemistry. In an HCV replicon system, pretreated Tac diminished the replication inhibitory effect of IFN‐α. In this study, we show that calcineurin inhibitors, especially Tac, are the negative regulators of IFN signaling in the hepatocyte; the greatest cause of such inhibition is the phosphorylation disturbance of STAT‐1, next to inhibition of the nuclear translocation of STAT‐1. In conclusion, disturbance of tyrosine phosphorylation of STAT‐1 resulted in diminished ISRE‐containing promoter activity and a decline in antiviral protein expression. Moreover, the replication of HCV was activated. This phenomenon is detrimental to IFN therapy after liver transplantation, and the selection of calcineurin inhibitors may warrant further discussion depending on the transplant situation. Liver Transpl 14:292–298, 2008.

Analysis of alloreactivity and intragraft cytokine profiles in living donor liver transplant recipients with graft acceptance

Although some previous studies have indicated the possibility of immunosuppression withdrawal in clinical liver transplantation, the mechanism of graft acceptance is not clear. The aim of this study is to elucidate the alloreactivity against the donor and intragraft cytokine profiles in living donor liver transplant (LDLT) recipients with graft acceptance. In October 1999, we had 23 patients who survived without immunosuppression after LDLT with a median drug-free period of 25 months (range: 3-69 months). They consisted of six patients who were electively weaned by an elective weaning protocol and 17 either forcibly or accidentally weaned patients due to various causes but mainly due to infection. We evaluated the alloreactivity against the donor in these patients by a mixed lymphocyte reaction and intragraft cytokine profiles by real-time reverse transcriptase-polymerase chain reaction. The development of donor-specific hyporeactivity was observed in the patients with graft acceptance. The cytokine pattern in the supernatant of the culture medium revealed a down regulation of T helper (Th) 1 cytokine INF gamma against the donor while no significant difference was seen in Th2 cytokine IL-10. Regarding the intragraft cytokine profiles, we could find no amplification of Thl cytokines (IL-2, INF y) and IL-4 while some of the patients revealed a gene expression of IL-10 with no significant difference from that of the normal, untransplanted liver specimen. In addition, no difference was observed in any other cytokines (IL-1beta, IL-8, IL-15, TNFalpha) compared with those of the normal controls. We propose that the down regulation of Th1 cytokine is one possible mechanism of graft acceptance in LDLT recipients.

Evolution of living donor liver transplantation over 10 years: experience of a single center.

PurposeTo evaluate the changes in living donor liver transplantations (LDLTs) over the last 10 years, we analyzed our experience of performing LDLT in a single center.MethodsWe performed 73 LDLTs over the 10 years between 1997 and 2007 in Nagasaki University Hospital, Japan.ResultsInitially, from 1997 to 2003, LDLT was performed for pediatric patients; then, between 2004 and 2007, adult-to-adult LDLT was introduced, primarily for hepatocellular carcinoma (HCC) in liver cirrhosis. We also began performing LDLTs for adults with ABO-incompatible blood type combination in the latter period. As the number of adult-to-adult LDLTs increased, left-sided grafts became fi rst choice for these patients. Survival rates were 88.3%, 77.2%, 70.2% at 1, 3, and 5 years, respectively. There was a relatively low incidence of arterial complications, and although the incidence of biliary complications was high initially, it decreased with experience. Likewise, the operative time, blood loss, and hospital stay after LDLT also improved remarkably.ConclusionOver the last 10 years the indications for, and operative techniques used in LDLT have changed dramatically, even in a single center in Japan.

Significance of hepatitis B virus core‐related antigen and covalently closed circular DNA levels as markers of hepatitis B virus re‐infection after liver transplantation

Currently, hepatitis B virus (HBV) re‐infection after liver transplantation (LT) can be almost completely suppressed by the administration of HBV reverse transcriptase inhibitors and hepatitis B immunoglobulins. However, after transplantation, there is no indicator of HBV replication because tests for the serum hepatitis B surface antigen and HBV‐DNA are both negative. Therefore, the criteria for reducing and discontinuing these precautions are unclear. In this study, we examined the serum HBV core‐related antigen (HBcrAg) and intrahepatic covalently closed circular DNA (cccDNA) in order to determine if these could be useful markers for HBV re‐infection.

Intraoperative portal venous pressure and long‐term outcome after curative resection for hepatocellular carcinoma

Outcomes of liver resection for hepatocellular carcinoma (HCC) have improved owing to better surgical techniques and patient selection. Portal hypertension may influence outcome but the preoperative definition and role of portal hypertension are far from clear. The aim of this study was to elucidate the influence of portal venous pressure (PVP) measured directly during surgery on outcomes of liver resection in patients with HCC.

Standardized less invasive living donor hemihepatectomy using the hybrid method through a short upper midline incision.

BACKGROUND Recently, applications of less invasive liver surgery in living donor hepatectomy (LDH) have been reported. The objective of this study was to evaluate the safety and efficacy of a hybrid method with a midline incision for LDH. METHODS Hemihepatectomy using the hybrid method was performed in the fifteen most recent among 150 living donors who underwent surgery between 1997 and August 2011. Six donors underwent right hemihepatectomy and 9 underwent left hemihepatectomy. An 8-cm subxiphoid midline incision was created for hand assistance during liver mobilization and graft extraction. After sufficient mobilization of the liver, the hand-assist/extraction incision was extended to 12 cm for the right hemihepatectomy and 10 cm for a left hemihepatectomy. Encircling the hepatic veins and hilar dissection were performed under direct vision. Parenchymal transection was performed with the liver hanging maneuver. Bile duct division was performed after visualizing the planned transection point by encircling the bile duct using a radiopaque marker filament under real-time C-arm cholangiography. RESULTS All procedures were completed without any extra subcostal incision. All grafts were safely extracted through the 10-12-cm upper midline incision without mechanical injury. No donors required an allogeneic transfusion; all of them have returned to their preoperative activity levels. CONCLUSION LDH by the hybrid method with a short upper midline incision is a safe procedure.

Elective living donor liver transplantation by hybrid hand-assisted laparoscopic surgery and short upper midline laparotomy

BACKGROUND Although the technique of liver transplantation is well developed, the invasiveness of the operation can be decreased with laparoscopic procedures. METHODS We performed elective living donor liver transplantation (LDLT) through a short midline incision combined with hand-assisted laparoscopic surgery (HALS). Nine selected patients with end stage liver disease underwent the procedure between July, 2010 and February, 2011 (median age 60, median Child-Pugh 9, median MELD score 14). Splenectomy was performed simultaneously in 7 cases. The liver (and spleen) were mobilized by a sealing device under a HALS procedure with an 8-cm upper midline incision, followed by explantation of the diseased liver (and spleen) through the upper midline incision which was extended to 12 to 15 cm. Partial liver grafts were implanted through the upper midline incision. RESULTS The median duration of the operation was 741 minutes, the median time needed for anastomosis was 48 minutes, the median blood loss was 3,940 g, and the median liver weight was 866 g. Eight recipients are alive and have good graft function. A difficult implantation for one patient required an additional right transverse incision. When compared with 13 recent liver recipients who underwent LDLT with a regular Mercedes-Benz-type incision, no clinically relevant drawbacks of the HALS hybrid procedure were observed. CONCLUSION We have shown the feasibility and safety of LDLT performed through a short midline incision without abdominal muscle disruption with the aid of HALS.

Two-surgeon technique using saline-linked electric cautery and ultrasonic surgical aspirator in living donor hepatectomy: its safety and efficacy

BACKGROUND Saline-linked electric cautery (SLC) is introduced as an effective device to reduce blood loss in liver surgery. The aim of the current study was to evaluate the safety and efficacy of a 2-surgeon technique using SLC and the Cavitron Ultrasonic Surgical Aspirator (CUSA; Valleylab, Boulder, CO) in living donor hepatectomy. METHODS Forty-three living donor right hepatectomy cases were enrolled in this study. The first 28 cases underwent liver transection with CUSA alone (CUSA group), while additional SLC was applied in the current 15 cases (2-surgeon technique, TS group). RESULTS Blood loss was significantly reduced by the 2-surgeon technique (1,115.2 +/- 652.9 g in CUSA group vs 732.3 +/- 363.6 g in TS group, P < .05). In the TS group, there was no bile leakage from the cut surface. The early graft function and postoperative recipient survival were not significantly different between the groups. CONCLUSIONS According to our single-center experience, blood loss and donor complications in living donor hepatectomies were significantly reduced using a 2-surgeon technique using CUSA and SLC, while maintaining the graft viability.