Zhassulan Baimakhanov

Extended-criteria donors in liver transplantation Part II: reviewing the impact of extended-criteria donors on the complications and outcomes of liver transplantation

ABSTRACT Extended-criteria donors (ECDs) have an impact on early allograft dysfunction (EAD), biliary complications, relapse of hepatitis C virus (HCV), and survivals. Early allograft dysfunction was frequently seen in grafts with moderate and severe steatosis. Donors after cardiac death (DCD) have been associated with higher rates of graft failure and biliary complications compared to donors after brain death. Extended warm ischemia, reperfusion injury and endothelial activation trigger a cascade, leading to microvascular thrombosis, resulting in biliary necrosis, cholangitis, and graft failure. The risk of HCV recurrence increased by donor age, and associated with using moderately and severely steatotic grafts. With the administration of protease inhibitors sustained virological response was achieved in majority of the patients. Donor risk index and EC donor scores (DS) are reported to be useful, to assess the outcome. The 1-year survival rates were 87% and 40% respectively, for donors with a DS of 0 and 3. Graft survival was excellent up to a DS of 2, however a DS >2 should be avoided in higher-risk recipients. The 1, 3 and 5-year survival of DCD recipients was comparable to optimal donors. However ECDs had minor survival means of 85%, 78.6%, and 72.3%. The graft survival of split liver transplantation (SLT) was comparable to that of whole liver orthotopic liver transplantation. SLT was not regarded as an ECD factor in the MELD era any more. Full-right-full-left split liver transplantation has a significant advantage to extend the high quality donor pool. Hypothermic oxygenated machine perfusion can be applied clinically in DCD liver grafts. Feasibility and safety were confirmed. Reperfusion injury was also rare in machine perfused DCD livers.

Extended criteria donors in liver transplantation Part I: reviewing the impact of determining factors

ABSTRACT The definition and factors of extended criteria donors have already been set; however, details of the various opinions still differ in many respects. In this review, we summarize the impact of these factors and their clinical relevance. Elderly livers must not be allocated for hepatitis C virus (HCV) positives, or patients with acute liver failure. In cases of markedly increased serum transaminases, donor hemodynamics is an essential consideration. A prolonged hypotension of the donor does not always lead to an increase in post-transplantation graft loss if post-OLT care is proper. Hypernatremia of less than 160 mEq/L is not an absolute contraindication to accept a liver graft per se. The presence of steatosis is an independent and determinant risk factor for the outcome. The gold standard of the diagnosis is the biopsy. This is recommended in all doubtful cases. The use of HCV+ grafts for HCV+ recipients is comparable in outcome. The leading risk factor for HCV recurrence is the actual RNA positivity of the donor. The presence of a proper anti-HBs level seems to protect from de novo HBV infection. A favourable outcome can be expected if a donation after cardiac death liver is transplanted in a favourable condition, meaning, a warm ischemia time < 30 minutes, cold ischemia time < 8–10 hours, and donor age 50–60 years. The pathway of organ quality assessment is to obtain the most relevant information (e.g. biopsy), consider the co-existing donor risk factors and the reserve capacity of the recipient, and avoid further technical issues.

Efficacy of Multilayered Hepatocyte Sheet Transplantation for Radiation-Induced Liver Damage and Partial Hepatectomy in a Rat Model

Although cell sheet technology has recently been developed for use in both animal experiments and in the clinical setting, it remains unclear whether transplanted hepatocyte sheets improve the liver function in vivo. Radiation-induced liver damage (RILD) combined with partial hepatectomy (PH) has been reported to suppress the proliferation of host hepatocytes and induce critical liver failure. The aim of this study was to improve the liver function in the above-mentioned diseased rat model (RILD + PH) using multilayered hepatocyte sheet transplantation. In this study, we used Fischer rats as a donor for primary hepatocytes and dermal fibroblast isolation. Cocultured multilayered hepatocyte sheets were generated by disseminating hepatocytes onto fibroblasts cultured beforehand on temperature-responsive culture dishes. Four cell sheets were transplanted into the recipient rats subcutaneously. Prior to transplantation, RILD (50 Gy) with 2/3PH was induced in the recipients. The same model was applied in the control group without transplantation. The serum was collected each week. The rats in both groups were sacrificed at 2 months after transplantation for the histological analysis. Consequently, the serum albumin concentrations were significantly higher in the transplant group than in the control group (54.3 ± 9.6 vs. 32.7 ± 5.7 mg/ml; p < 0.01) after 2 months and comparable to the serum albumin levels in the normal rats (58.1 ± 6.4 mg/ml). In addition, treatment with the transplanted sheets significantly improved the survival rate (57% vs. 22%, p < 0.05), and the hepatocyte sheets showed the storage of albumin, glycogen, and bile canaliculus structures. Some hepatocytes and fibroblasts were positive for Ki-67, and vascularization was observed around the cell sheets. Transplanted multilayered hepatocyte sheets can survive with additional proliferative activity, thereby maintaining the liver function in vivo for at least 2 months, providing metabolic support for rats with RILD.

Hybrid procedure in living donor liver transplantation.

BACKGROUND We have previously reported a hybrid procedure that uses a combination of laparoscopic mobilization of the liver and subsequent hepatectomy under direct vision in living donor liver transplantation (LDLT). We present the details of this hybrid procedure and the outcomes of the procedure. METHODS Between January 1997 and August 2014, 204 LDLTs were performed at Nagasaki University Hospital. Among them, 67 recent donors underwent hybrid donor hepatectomy. Forty-one donors underwent left hemihepatectomy, 25 underwent right hemihepatectomy, and 1 underwent posterior sectionectomy. First, an 8-cm subxiphoid midline incision was made; laparoscopic mobilization of the liver was then achieved with a hand-assist through the midline incision under the pneumoperitoneum. Thereafter, the incision was extended up to 12 cm for the right lobe and posterior sector graft and 10 cm left lobe graft procurement. Under direct vision, parenchymal transection was performed by means of the liver-hanging maneuver. The hybrid procedure for LDLT recipients was indicated only for selected cases with atrophic liver cirrhosis without a history of upper abdominal surgery, significant retroperitoneal collateral vessels, or hypertrophic change of the liver (n = 29). For total hepatectomy and splenectomy, the midline incision was sufficiently extended. RESULTS All of the hybrid donor hepatectomies were completed without an extra subcostal incision. No significant differences were observed in the blood loss or length of the operation compared with conventional open procedures. All of the donors have returned to their preoperative activity level, with fewer wound-related complaints compared with those treated with the use of the conventional open procedure. In recipients treated with the hybrid procedure, no clinically relevant drawbacks were observed compared with the recipients treated with a regular Mercedes-Benz-type incision. CONCLUSIONS Our hybrid procedure was safely conducted with the same quality as the conventional open procedure in both LDLT donors and recipients.

Preoperative simulation with a 3-dimensional printed solid model for one-step reconstruction of multiple hepatic veins during living donor liver transplantation

Meticulous preoperative volumetry of the partial liver graft is essential for both assessing the postoperative graft function and to ensure the donor safety in the field of living donor liver transplantation (LDLT). We herein report the case of a 53-year-old patient who underwent LDLT for hepatitis C virusinfected liver cirrhosis complicated with hepatocellular carcinoma. Preoperative 3D images were obtained using a 3D image analysis system to evaluate the graft volume and possible congested volume after implantation in LDLT, which revealed that a large middle hepatic vein drained a vast area in the right lobe. The extended left graft was considered to be small for size of the recipient, with an estimated congested area of 407 ml, which was equivalent to 39% of the donor’s liver volume in the remnant right lobe. We decided to use a right lobe graft with the middle hepatic vein, because the volume was considered to be sufficient. A preoperative contrast-enhanced CT scan revealed a distance of 2 cm between the donor’s right hepatic vein and middle hepatic vein at the estimated Cantlie line. Because of the location, we planned to use autologous portal vein Y-graft interposition for the hepatic venous anastomosis. Three-dimensional printed solid models of the donor’s right lobe graft and the Y-graft from the recipient’s portal vein were also made for preoperative simulation using the Vincent program. Based on the estimation, we were able to evaluate whether to reconstruct the middle hepatic vein tributaries or anomalous hepatic veins in LDLT. The 3D solid model was effective for preoperative simulation and planning, which made it easy to imagine the reconstructed shape of the anastomosis with appropriate spatial perception.

Analysis of early relaparotomy following living donor liver transplantation

We retrospectively analyzed the causes, risk factors, and impact of early relaparotomy after adult‐to‐adult living donor liver transplantation (LDLT) on the posttransplant outcome. Adult recipients who underwent initial LDLT at our institution between August 1997 and August 2015 (n = 196) were included. Any patients who required early retransplantation were excluded. Early relaparotomy was defined as surgical treatment within 30 days after LDLT. Relaparotomy was performed 66 times in 52 recipients (a maximum of 4 times in 1 patient). The reasons for relaparotomy comprised postoperative bleeding (39.4%), vascular complications (27.3%), suspicion of abdominal sepsis or bile leakage (25.8%), and others (7.6%). A multivariate analysis revealed that previous upper abdominal surgery and prolonged operative time were independent risk factors for early relaparotomy. The overall survival rate in the relaparotomy group was worse than that in the nonrelaparotomy group (6 months, 67.3% versus 90.1%, P < 0.001; 1 year, 67.3% versus 88.6%, P < 0.001; and 5 years, 62.6% versus 70.6%, P = 0.06). The outcome of patients who underwent 2 or more relaparotomies was worse compared with patients who underwent only 1 relaparotomy. In a subgroup analysis according to the cause of initial relaparotomy, the survival rate of the postoperative bleeding group was comparable with the nonrelaparotomy group (P = 0.96). On the other hand, the survival rate of the vascular complication group was significantly worse than that of the nonrelaparotomy group (P = 0.001). Previous upper abdominal surgery is a risk factor for early relaparotomy after LDLT. A favorable longterm outcome is expected in patients who undergo early relaparotomy due to postoperative bleeding. Liver Transplantation 22 1519–1525 2016 AASLD.

A Donor Age-based and Graft Volume–based Analysis for Living Donor Liver Transplantation in Elderly Recipients

Background Given the expected increase in the number of elderly recipients, details regarding how clinical factors influence the outcome in living donor liver transplantation (LDLT) for the elderly remain unclear. We examined the survival outcomes according to the results of donor age-based and graft volume–based analyses and assessed the impact of prognostic factors on the survival after LDLT for elderly recipients. Methods The 198 adult recipients were classified into 2 groups: an elderly group (n = 70, E group; ≥ 60 years of age) and a younger group (n = 128, Y group; <60 years of age). We analyzed the prognostic factors for the survival in the E group and the survival rate for both groups at several follow-up points and conducted subgroup analyses in the E group by combining the donor age (≥50 vs <50 years) and graft weight (GW)/standard liver volume (SLV) (≥40% vs <40%). Results Donor age (hazard ratio [HR], 2.17; P = 0.062) and GW/SLV (HR, 1.80; P = 0.23) tended to have a high HR in the E group. The overall patient survival rates at 1, 3, and 5 years were 78.3%, 73.0%, and 61.0% in the E group, and 82.0%, 75.1%, and 69.2% in the Y group, respectively (P = 0.459). However, the outcomes tended to be worse in recipients of grafts from donors ≥50 years of age than in those with grafts from younger donors with GW/SLV < 40% (P = 0.048). Conclusions A worse outcome might be associated with aging of the donor, which leads to impairment of the graft function and liver regeneration. Both the graft volume and donor age should be considered when choosing grafts for LDLT in elderly patients.

Up-regulated extracellular matrix components and inflammatory chemokines may impair the regeneration of cholestatic liver.

Although the healthy liver is known to have high regenerative potential, poor liver regeneration under pathological conditions remains a substantial problem. We investigated the key molecules that impair the regeneration of cholestatic liver. C57BL/6 mice were randomly subjected to partial hepatectomy and bile duct ligation (PH+BDL group, n = 16), partial hepatectomy only (PH group, n = 16), or sham operation (Sham group, n = 16). The liver sizes and histological findings were similar in the PH and sham groups 14 days after operation. However, compared with those in the sham group, the livers in mice in the PH+BDL group had a smaller size, a lower cell proliferative activity, and more fibrotic tissue 14 days after the operation, suggesting the insufficient regeneration of the cholestatic liver. Pathway-focused array analysis showed that many genes were up- or down-regulated over 1.5-fold in both PH+BDL and PH groups at 1, 3, 7, and 14 days after treatment. Interestingly, more genes that were functionally related to the extracellular matrix and inflammatory chemokines were found in the PH+BDL group than in the PH group at 7 and 14 days after treatment. Our data suggest that up-regulated extracellular matrix components and inflammatory chemokines may impair the regeneration of cholestatic liver.

In vivo construction of liver tissue by implantation of a hepatic non‐parenchymal/adipose‐derived stem cell sheet

Subcutaneous hepatocyte sheet implantation is an attractive therapeutic option for various liver diseases. However, this technique is limited by the availability of hepatocytes. Thus, the use of hepatic non‐parenchymal cells (NPCs) containing small hepatocytes, which have the ability to proliferate more rapidly than mature hepatocytes, for transplantation has been suggested. The aim of our study was to construct liver tissue subcutaneously in rats by implanting NPC sheets co‐cultivated with adipose‐derived stem cells (ADSCs), which produce certain angiogenic factors. We crafted NPC‐ADSC sheets on temperature‐responsive culture dishes. NPCs formed functioning bile canaliculi and stored glycogen. In addition, their ability to produce albumin was not inferior to that of hepatocytes. Albumin production increased over time when co‐cultivated with ADSCs. We then implanted the co‐cultivated cell sheets subcutaneously. The co‐cultivated sheets retained glycogen, formed bile canaliculi, showed signs of vascularization and survived subcutaneously without pre‐vascularization. These results suggest that NPCs can be a viable option in cell therapy for liver diseases. This technique using co‐cultivated cell sheets may be useful in the field of regenerative medicine. Copyright

Aspartate transaminase–platelet ratio and Fibrosis-4 indices as effective markers for monitoring esophageal varices in HIV/hepatitis C virus co-infected patients due to contaminated blood products for hemophilia

We examined the feasibility of the aspartate transaminase (AST)–platelet ratio index (APRI) and Fibrosis‐4 (FIB4) score, which are well‐established markers for liver fibrosis, as indicators for monitoring esophageal varices in patients who were co‐infected with HIV and hepatitis C virus (HCV) due to contaminated blood products for hemophilia in Japan.