Ex vivo kidney machine perfusion: meta-analysis of randomized clinical trials.

BACKGROUND: Machine perfusion is an organ preservation strategy used to improve function over simple storage in a cold environment. This article presents an updated systematic review and meta-analysis of machine perfusion in deceased donor kidneys. METHODS: RCTs from November 2018 to July 2023 comparing machine perfusion versus static cold storage in kidney transplantation were evaluated for systematic review. The primary outcome in meta-analysis was delayed graft function. RESULTS: A total 19 studies were included, and 16 comparing hypothermic machine perfusion with static cold storage were analysed. The risk of delayed graft function was lower with hypothermic machine perfusion (risk ratio (RR) 0.77, 95% c.i. 0.69 to 0.86), even in kidneys after circulatory death (RR 0.78, 0.68 to 0.90) or brain death (RR 0.73, 0.63 to 0.84). Full hypothermic machine perfusion decreased the risk of delayed graft function (RR 0.69, 0.60 to 0.79), whereas partial hypothermic machine perfusion did not (RR 0.92, 0.69 to 1.22). Normothermic machine perfusion or short-term oxygenated hypothermic machine perfusion preservation after static cold storage was equivalent to static cold storage in terms of delayed graft function and 1-year graft survival. CONCLUSION: Hypothermic machine perfusion reduces delayed graft function risks and normothermic approaches show promise.

Comparison between laparoscopic liver resection and open liver resection in patients with hepatocellular carcinoma with portal vein tumor thrombosis.

BACKGROUND: Recently, the outcomes of surgical treatment for advanced hepatocellular carcinoma (HCC) have improved. However, despite the technical advancements in laparoscopic liver resection (LLR), it is still not recommended as the standard treatment for HCC with portal vein tumor thrombosis (PVTT) because of the poor oncological outcomes. This study aims to compare the clinical outcomes of open liver resection (OLR) and LLR in patients with HCC with PVTT. METHODS: A total of 86 patients with PVTT confirmed in the pathological report between January 2014 and December 2018, were enrolled. Short-term, postoperative, and long-term outcomes, including recurrence-free survival and overall survival rates, were evaluated. RESULTS: No difference between the two groups, except for age, was detected. The median age in the laparoscopic group was significantly higher than that in the open group. Regarding the pathological features, the maximal tumor size was significantly larger in the OLR; other pathological factors did not differ. There was no significant difference between overall survival (OS) and recurrence-free survival (RFS). Vp3 PVTT (hazards ratio [HR] 6.1, 95% confidence interval [CI] 1.9-18.5), Edmondson grade IV (HR 4.7, 95% CI 1.7-12.9, p = 0.003), and intrahepatic metastasis (HR 3.9, 95% CI 2.1-7.2, p < 0.001) remained the unique independent predictors of recurrence-free survival according to a multivariate Cox proportional hazard regression analysis. CONCLUSIONS: Laparoscopic liver resection for the management of HCC with PVTT provides the same short- and long-term results as those of the open approach.

A systematic review and meta-analysis of blood transfusion rates during liver resection by country.

Purpose: This study aimed to determine the blood transfusion rates during liver resection by country to prepare a basis for patient blood management policy. Methods: Relevant articles from January 2020 to December 2022 were identified through an electronic database search. Meta-analyses were performed using fixed- or random-effects models. Study heterogeneity was assessed using the Q-test and I2 test. Publication bias was evaluated using funnel plots and Egger's and Begg's tests. Results: Of 104 studies (103,778 participants), the mean transfusion rate was 16.20%. Korea's rate (9.72%) was lower than Western (14.97%) and other Eastern nations (18.61%). Although open surgery rates were alike (approximately 25%) globally, Korea's minimally invasive surgery rate was lower (6.28% vs. ≥10%). Odds ratios (ORs) indicated a higher transfusion risk in open surgeries than minimally invasive surgery, especially in Korea (8.82; 95% confidence interval [CI], 5.55-14.02) compared to other Eastern (OR, 2.57) and Western countries (OR, 2.20). For liver resections due to hepatocellular carcinoma and benign diseases, Korea's rates (10.86% and 15.62%) were less than in Eastern (18.90% and 29.81%) and Western countries (20.15% and 25.22%). Conclusion: Korea showed a lower transfusion rate during liver resection than other countries. In addition to the patient's characteristics, including diagnosis and surgical methods, differences in the medical environment affect blood transfusion rates during liver resection.

Enhancing generation efficiency of liver organoids in a collagen scaffold using human chemically derived hepatic progenitors.

Backgrounds/Aims: Liver organoids have emerged as a powerful tool for studying liver biology and disease and for developing new therapies and regenerative medicine approaches. For organoid culture, Matrigel, a type of extracellular matrix, is the most commonly used material. However, Matrigel cannot be used for clinical applications due to the presence of unknown proteins that can cause immune rejection, batch-to-batch variability, and angiogenesis. Methods: To obtain human primary hepatocytes (hPHs), we performed 2 steps collagenase liver perfusion protocol. We treated three small molecules cocktails (A83-01, CHIR99021, and HGF) for reprogramming the hPHs into human chemically derived hepatic progenitors (hCdHs) and used hCdHs to generate liver organoids. Results: In this study, we report the generation of liver organoids in a collagen scaffold using hCdHs. In comparison with adult liver (or primary hepatocyte)-derived organoids with collagen scaffold (hALO_C), hCdH-derived organoids in a collagen scaffold (hCdHO_C) showed a 10-fold increase in organoid generation efficiency with higher expression of liver- or liver progenitor-specific markers. Moreover, we demonstrated that hCdHO_C could differentiate into hepatic organoids (hCdHO_C_DM), indicating the potential of these organoids as a platform for drug screening. Conclusions: Overall, our study highlights the potential of hCdHO_C as a tool for liver research and presents a new approach for generating liver organoids using hCdHs with a collagen scaffold.

Comparison of pure laparoscopic donor right posterior sectionectomy versus right hemihepatectomy for living donor liver transplantation.

The right posterior section (RPS) graft for living donor liver transplantation is an alternative graft in a live liver donor with insufficient remnant left lobe volume and portal vein anomaly. Although there have been some reports regarding pure laparoscopic donor right posterior sectionectomy (PLDRPS), no study has compared PLDRPS versus pure laparoscopic donor right hemihepatectomy (PLDRH). The aim of our study was to compare the surgical outcomes of PLDRPS versus PLDRH at centers achieving a complete transition from open to laparoscopic approach in liver donor surgery. From March 2019 to March 2022, a total of 351 living donor liver transplantations, including 16 and 335 donors who underwent PLDRPS and PLDRH, respectively, were included in the study. In the donor cohort, there were no significant differences in major complication (≥grade III) rate and comprehensive complication index between the PLDRPS versus PLDRH group (6.3% vs. 4.8%; p = 0.556 and 2.7 ± 8.6 vs.1.7 ± 6.4; p = 0.553). In the recipient cohort, there was a significant difference in major complication (≥grade III) rate (62.5% vs. 35.2%; p = 0.034) but no significant difference in comprehensive complication index (18.3 ± 14.9 vs. 15.2 ± 24.9; p = 0.623) between the PLDRPS and PLDRH groups. PLDRPS in live liver donors with portal vein anomaly and insufficient left lobe was technically feasible and safe with experienced surgeons. The PLDRPS group might be comparable with the PLDRH group based on the surgical outcomes of donors and recipients. However, in terms of recipient outcomes, more careful selection of donors of the RPS graft and further research in a large number of cases are necessary to evaluate the usefulness of PLDRPS.

Therapeutic applications of gene editing in chronic liver diseases: an update.

Innovative genome editing techniques developed in recent decades have revolutionized the biomedical research field. Liver is the most favored target organ for genome editing owing to its ability to regenerate. The regenerative capacity of the liver enables ex vivo gene editing in which the mutated gene in hepatocytes isolated from the animal model of genetic disease is repaired. The edited hepatocytes are injected back into the animal to mitigate the disease. Furthermore, the liver is considered as the easiest target organ for gene editing as it absorbs almost all foreign molecules. The mRNA vaccines, which have been developed to manage the COVID-19 pandemic, have provided a novel gene editing strategy using Cas mRNA. A single injection of gene editing components with Cas mRNA is reported to be efficient in the treatment of patients with genetic liver diseases. In this review, we first discuss previously reported gene editing tools and cases managed using them, as well as liver diseases caused by genetic mutations. Next, we summarize the recent successes of ex vivo and in vivo gene editing approaches in ameliorating liver diseases in animals and humans. [BMB Reports 2022; 55(6): 251-258].

Elimination of Reprogramming Transgenes Facilitates the Differentiation of Induced Pluripotent Stem Cells into Hepatocyte-like Cells and Hepatic Organoids.

Hepatocytes and hepatic organoids (HOs) derived from human induced pluripotent stem cells (hiPSCs) are promising cell-based therapies for liver diseases. The removal of reprogramming transgenes can affect hiPSC differentiation potential into the three germ layers but not into hepatocytes and hepatic organoids in the late developmental stage. Herein, we generated hiPSCs from normal human fibroblasts using an excisable polycistronic lentiviral vector based on the Cre recombinase-mediated removal of the loxP-flanked reprogramming cassette. Comparing the properties of transgene-carrying and transgene-free hiPSCs with the same genetic background, the pluripotent states of all hiPSCs were quite similar, as indicated by the expression of pluripotent markers, embryonic body formation, and tri-lineage differentiation in vitro. However, after in vitro differentiation into hepatocytes, transgene-free hiPSCs were superior to the transgene-residual hiPSCs. Interestingly, the generation and hepatic differentiation of human hepatic organoids (hHOs) were significantly enhanced by transgene elimination from hiPSCs, as observed by the upregulated fetal liver (CK19, SOX9, and ITGA6) and functional hepatocyte (albumin, ASGR1, HNF4α, CYP1A2, CYP3A4, and AAT) markers upon culture in differentiation media. Thus, the elimination of reprogramming transgenes facilitates hiPSC differentiation into hepatocyte-like cells and hepatic organoids with properties of liver progenitor cells. Our findings thus provide significant insights into the characteristics of iPSC-derived hepatic organoids.

Long-term Outcome of the Rendezvous Technique in Patients With Severe Biliary Anastomotic Stricture That Cannot Cannulate After Liver Transplant.

BACKGROUND: Nearly all publications related to endoscopic treatment of biliary anastomotic stricture after liver transplant have reported cases that can be cannulated. However, very few publications discuss endoscopic treatment of biliary anastomotic stricture (BAS) in which the guide wire does not pass through the stricture site. The purpose of this article is to analyze the long-term outcome of the Rendezvous technique in severe strictures through which guide wires cannot cannulate. METHODS: Between 2010 and 2017, a total of 29 patients who underwent Rendezvous technique because of severe BAS after liver transplant were included in the study. RESULTS: Twenty-nine patients who underwent the Rendezvous technique showed a 100% technical success rate. Ten patients (34.4%) required stent removal; the mean stenting period was 14.9 (SD, 5.6) months (range, 6.65-24.14 months). A total of 19 patients were maintained without stent removal; the stent-maintaining period was 13.1 (SD, 8.4) months (range, 3.48-38.61 months). Two patients receiving left lobe grafts maintained the stents for 27.1 (SD, 16.2) months. In left lobe graft, the duct anastomosis position moves to the right posteroinferior side of the patient. CONCLUSIONS: Our results suggest that the stenting period of the Rendezvous technique was longer in severe BAS than in cannulated endoscopic retrograde cholangiopancreatography cases. Especially in the left liver, the position of the duct anastomosis changed to the right posteroinferior of the patient. Thus, the donor duct and the recipient duct are angulated, kinking worsens, and the stenting period becomes longer.

Risk of osteoporosis and fracture in long-term breast cancer survivors.

Purpose: High incidence of osteoporosis has been reported in breast cancer patients due to early menopause triggered by adjuvant treatment and temporary ovarian function suppression. In this study, we sought to determine whether long-term breast cancer survivors had an elevated risk of low bone density compared to the general population. Methods: Long-term breast cancer survivors who had been treated for more than 5 years were selected for this study. Data were obtained from medical records and using a questionnaire from the Korea National Health and Nutrition Examination Survey (KNHANES). An age-matched non-cancer control group was selected from the KNHANES records. Incidence of fracture and bone mineral density (BMD) were compared between the two groups. Results: In total, 74 long-term breast cancer survivors and 296 non-cancer controls were evaluated. The incidence of fracture did not differ between the two groups (P=0.130). No differences were detected in lumbar BMD (P=0.051) following adjustment for body mass index, while hip BMD was significantly lower in breast cancer survivors (P=0.028). Chemotherapy and endocrine treatment were not related to low BMD in breast cancer survivors. In more than half of the survivors, the 10-year risk of osteoporotic fracture was less than 1%. Conclusion: Long-term breast cancer survivors had low bone density but a comparable risk of fracture compared to non-cancer age-matched controls. Further studies on the factors related to low bone density in long-term breast cancer survivors are required.

Inducing Transient Mixed Chimerism for Allograft Survival Without Maintenance Immunosuppression With Combined Kidney and Bone Marrow Transplantation: Protocol Optimization.

BACKGROUND: Tolerance induction is an important goal in the field of organ transplantation. We have sequentially modified our conditioning regimen for induction of donor-specific tolerance in recipients of major histocompatibility complex-mismatched combined kidney and bone marrow transplantation (CKBMT). METHODS: From December 2011 to May 2017, 8 major histocompatibility complex-mismatched patients received CKBMT. The initial conditioning regimen (protocol 1) consisted of cyclophosphamide (CP), rituximab, rabbit antithymocyte globulin, and thymic irradiation. Tacrolimus and steroids were used for the maintenance of immunosuppression (IS). RESULTS: This regimen was complicated by transient acute kidney injury, which has been the major clinical feature of engraftment syndrome and side effects of CP, although one of 2 subjects successfully discontinued his IS for 14 months. The conditioning regimen was modified by reducing the CP dose and adding fludarabine (protocol 2). The final modification was reducing the fludarabine and rabbit antithymocyte globulin doses (protocol 3). Mixed chimerism, detected by the short tandem repeat method, was achieved transiently in all subjects for 3-20 weeks. Among the 3 subjects treated with protocol 2, IS was successfully discontinued for >35 months in one subject, but the other 2 subjects suffered from severe BK virus-associated nephritis. All 3 subjects treated with protocol 3 tolerated the protocol well and have successfully discontinued IS for >4-41 months. Interestingly, de novo donor-specific antibody was not detected in any subject during all the follow-up periods. CONCLUSIONS: Our clinical trial has shown that long-term renal allograft survival without maintenance IS can be achieved by induction of mixed chimerism following CKBMT.

Safety and Risk Factors of Pure Laparoscopic Living Donor Right Hepatectomy: Comparison to Open Technique in Propensity Score-matched Analysis.

BACKGROUND: The innovative pure laparoscopic living donor right hepatectomy (LLDRH) procedure for liver transplantation has never been fully compared to open living donor right hepatectomy (OLDRH). We aimed to compare the donor safety and graft results of pure LLDRH to those of OLDRH. METHODS: From May 2013 to July 2017, 288 consecutive donors underwent either OLDRH (n = 197) or pure LLDRH (n = 91). After propensity score matching, 72 donors were included in each group. The primary outcome was postoperative complications during a 90-day follow-up period. Comprehensive complication index, duration of hospital stay, need for additional pain control, readmission, and donor outcomes were also compared. RESULTS: The incidence of major complication during the 90-day follow-up was higher in the LLDRH group than the OLDRH group (6.6% vs 15.4%, P = 0.017) but was not statistically significant in propensity-matched analysis (11.1% vs 13.9%, odds ratio [OR], 1.29; 95% confidence interval [CI], 0.47-3.51; P = 0.62). A right hepatic duct <1 cm was independently associated with complication in the pure LLDRH group (odds ratio, 4.01; 95% confidence interval, 1.08-14.99; P = 0.04). CONCLUSIONS: In the initial 91 pure LLDRH cases, incidence of major complication was higher than in the OLDRH group, but the difference was not significant in propensity-matched analysis. A right hepatic duct verified as <1 cm may be related to increased frequency of complications in pure LLDRH donors. Further analysis is needed.

One-Year Recipient Morbidity of Liver Transplantation Using Pure Laparoscopic Versus Open Living Donor Right Hepatectomy: Propensity Score Analysis.

Donor safety and graft results of pure laparoscopic living donor right hepatectomy (LLDRH) have previously been compared with those of open living donor right hepatectomy (OLDRH). However, the clinical outcomes of recipients at 1-year follow-up have never been accurately compared. We aimed to compare 1-year outcomes of recipients of living donor right liver transplantation (LRLT) using pure LLDRH and OLDRH. From May 2013 to May 2017, 197 consecutive recipients underwent LRLT. Donor hepatectomies were performed either by OLDRH (n = 127) or pure LLDRH (n = 70). After propensity score matching, 53 recipients were included in each group for analysis. The clinical outcomes at 1-year follow-up were compared between the 2 groups. The primary outcome was recipient death or graft failure during the 1-year follow-up period. In the propensity-matched analysis, the incidence of death or graft failure during the 1-year follow-up period was not different between the 2 groups (3.8% versus 5.7%; odds ratio [OR], 1.45; 95% confidence interval [CI], 0.24-8.95; P = 0.69). However, the composite of Clavien-Dindo 3b-5 complications was more frequent in the pure LLDRH group (OR, 2.62; 95% CI, 1.15-5.96; P = 0.02). In conclusion, although pure LLDRH affords a comparable incidence of fatal complications in recipients, operative complications may increase at the beginning of the program. The safety of the recipients should be confirmed to accept pure LLDRH as a feasible option.

Tablet or capsule form of generic mycophenolate mofetil (My-Rept®) after liver transplantation: a prospective randomized trial.

BACKGROUND: Tablet and capsule forms have advantages and disadvantages in the market. Generally, the tablet form (500 mg) of mycophenolate mofetil (MMF) is more convenient for drug ingestion and more cost-effective than the capsule form (250 mg). We examined the efficacy and safety of MMF in its different forms combined with tacrolimus in liver transplant recipients. METHODS: A randomized controlled trial was performed to compare the efficacy and safety between the tablet form of MMF (tablet group) and the capsule form of MMF (capsule group) in liver transplant patients. One hundred sixteen patients were enrolled in the present study from 2014 to 2017. Fifty-six patients in the full-analysis set (FAS) population were in the capsule group and 60 were in the tablet group. The primary endpoint was incidence of biopsy-proven acute rejection (BPAR) by 24 weeks after liver transplantation (LT). Secondary endpoints were patient survival, serum creatinine level, and adverse events (AEs). RESULTS: In the per-protocol population, 45 patients were in the tablet group and 49 were in the capsule group. There were no statistically significant differences in MMF dose, mycophenolic acid trough level, and tacrolimus trough level between the two groups. The incidence of BPAR at 24 weeks after randomization was 6.7% in the tablet group and 6.1% in the capsule group (P=0.627). All patients with BPAR responded well to steroid pulse therapy and increased tacrolimus. Serum creatine level and eGFR were not different between the two groups. The incidence of serious AEs was 7.2% in the tablet group and 7.6% in the capsule group, and none were related to formulation. There was no significant difference in incidence of discontinuations or serious AEs between the two groups. CONCLUSION: The present study suggests that the new tablet formulation can be a useful treatment option to maintain a consistent systemic exposure level of MMF, which may help reduce graft failure in liver transplant patients.

Stent insertion and balloon angioplasty for portal vein stenosis after liver transplantation: long-term follow-up results.

PURPOSE: It is not easy to determine whether balloon angioplasty or stenting should be performed in patients with portal vein stenosis after liver transplantation. We aimed to propose appropriate indication by evaluating long-term outcomes of balloon angioplasty and stent insertion in adult liver transplant patients. METHODS: We retrospectively reviewed 31 patients with portal vein stenosis among 1369 patients who underwent adult liver transplantation from January 2001 to December 2015. When stenosis was confirmed by venography, angioplasty was performed first. When there was no flow improvement or pressure gradient was not decreased after angioplasty, stent insertion was performed. We also performed primary stent insertion without angioplasty for diffuse stenosis, kinking, external compression, and near occlusion of portal vein in venography. We assessed patency in patients who underwent percutaneous transluminal angioplasty and stent insertion through regular outpatient follow-up and evaluated technical and clinical success and long-term results. RESULTS: Technical success was 85% and 100% in balloon angioplasty and stent insertion, respectively. Clinical success was achieved in 78% of balloon angioplasties and in 100% of stent insertions. At 1, 5, and 10 years after balloon angioplasty, patency rates were 87%, 82%, and 68% respectively, and the rates of stent patency were all 100%. Portal vein size measured during the operation of patients with and without recurrence were 19±4.2 mm and 19±3.0 mm (P = 0.956), respectively. The balloon size of patients with and without recurrence were 11±1.95 mm and 14±1.66 mm, respectively (P = 0.013), when balloon angioplasty was performed after stenosis diagnosis. CONCLUSION: Stent insertion can be considered when fibrotic changes are expected due to repeated inflammation and when the balloon size to be used is small. Balloon angioplasty seems less risky for anastomotic ruptures in portal vein stenosis in the early post liver transplantation period.

Impact of Induction Immunosuppression on the Recurrence of Primary IgA Nephropathy.

OBJECTIVE: The objective of this study was to analyze the impact of induction immunosuppression on the incidence of recurrent IgA nephropathy (IgAN). METHODS: We conducted recurrence-free survival analysis of recipients of a first kidney transplant for IgAN who received a graft between 1995 and 2015. Kaplan-Meier and Cox regression analyses were used to sort the significant risk factors for recurrence. A total of 226 recipients with biopsy-proven IgAN received a kidney transplant, and 218 recipients were enrolled. RESULTS: Among the recipients, 29 cases of IgAN recurrence were observed. The recipients were categorized into 3 groups according to induction immunosuppression: no induction (group 1, n = 72), anti-CD25 (group 2, n = 86), and antithymocyte globulin (ATG, group 3, n = 60). The 5- and 10-year cumulative IgAN recurrence rates were 9.7% and 21.0%, respectively. Recipients receiving ATG (group 3) exhibited significantly higher 4- and 5-year recurrence-free graft survival rates (both 96.4%) than recipients who received anti-CD25 (group 2, both 85.1%, P = .03). However, the induction therapy used (ATG or basiliximab) was not the risk factor for IgAN recurrence. CONCLUSIONS: Therefore, we concluded that ATG induction seems to postpone IgAN recurrence. These findings should be evaluated with well-designed prospective studies.

Coagulation biomarkers in healthy male Cynomolgus macaque monkeys (Macaca fascicularis).

We designed this study to define reference values of the cynomolgus monkey coagulation system, as the normal range of values has not been established. Measurement of coagulation function was determined by testing plasma samples from 30 healthy male cynomolgus monkeys. Prothrombin time (PT), PT activity, PT international normalized ratio (INR), activated prothrombin time (aPTT), antithrombin III activity, factor II, V, VII, VIII, IX, X, XI, and XII, protein C activity, protein S activity, and d-dimer were measured using standardized techniques. Mean age and body weight were 69.5 ± 11.8 months and 5.3 ± 0.8 kg, respectively. The mean PT, PT activity, PT INR, aPTT, and antithrombin III activities were 11.72 seconds (95% CI = 10.55-12.88), 143.4% (95% CI = 102.0-184.9), 0.85 (95% CI = 0.74-0.96), 28.2 seconds (95% CI = 23.24-33.09), and 99.7% (95% CI = 79.2-120.3), respectively. The mean activities of factors II, V, VII, VIII, IX, X, XI, and XII were 110.2% (95% CI = 88.8-131.5), 134.1% (95% CI = 73.0-195.2), 318.9% (95% CI = 185.0-452.9) 160.2% (95% CI = 96.9-261.3), 38.0% (95% CI = 20.9-55.1), 85.7% (95% CI = 61.4-110.0), 155.0% (95% CI = 81.4-228.6), and 353.7% (95% CI = 246.7-460.6), respectively. The mean activities of protein C and protein S were 195.7% (95% CI = 133.4-258.0) and 122.7% (95% CI = 83.2-162.3), respectively. The mean level of d-dimer was 1.80 µg/mL (95% CI = 0.27-3.33). Factors V (P = 0.008), IX (P = 0.002), and XI (P = 0.002), and protein S activity (P = 0.025) were positively correlated with age. Our study presented the baseline values of coagulation biomarkers of cynomolgus monkeys. Despite the similarity to previous published studies, more data are required to elucidate the age effect on coagulation biomarkers.

Reduced variability in tacrolimus pharmacokinetics following intramuscular injection compared to oral administration in cynomolgus monkeys: Investigating optimal dosing regimens.

Tacrolimus is one of the most commonly used immunosuppressive agents in animal models of transplantation. However, in these models, oral administration is often problematic due to the lowered compliance associated with highly invasive surgery and due to malabsorption in the intestinal tract. Therefore, we carried out a study to determine the pharmacokinetics of tacrolimus after intramuscular (IM) injection and to determine the optimal IM dosing regimens in primate models. Six male cynomolgus monkeys (Macaca fascicularis) were used in the study. Doses of 0.1 mg/kg and 5 mg were administered via IM injection and oral administration, respectively, once to determine single-dose pharmacokinetics and once daily for 5 days to determine multiple-dose pharmacokinetics. According to pharmacokinetic model estimates, the inter- and intra-individual variabilities in bioavailability following IM injection were remarkably reduced compared with those following oral administration. Monte Carlo simulations revealed that Cpeak, Ctrough and AUC would also have less variability following IM injection compared with oral administration. In this study, we found that the pharmacokinetic characteristics of tacrolimus were more constant following IM injection compared with oral administration. These results suggest that IM injection can be an alternative route of administration fin non-human primate model studies.

Long-term outcomes after stent insertion in patients with early and late hepatic vein outflow obstruction after living donor liver transplantation.

PURPOSE: The purpose of this study was to describe the long-term effects of stenting in patients with hepatic venous outflow obstruction (HVOO), who underwent living donor liver transplantation (LDLT). METHODS: Between January 2000 and December 2009, 622 adult patients underwent LDLT at our hospital, and of these patients, 21 (3.3%) were diagnosed with HVOO; among these patients, 17 underwent stenting. The patients were divided into early or late groups according to the time of their HVOO diagnoses (cutoff: 60 days after liver transplantation). RESULTS: The median follow-up period was 54.2 months (range, 0.5-192.4 months). Stent insertion was successful in 8 of 10 patients in the early group and 6 of 7 in the late group. The 5-year primary patency rates were 46% and 20%, respectively. In both groups, patients with recurrent HVOO at the beginning showed kinking confirmed by venography. Patients who carried their stents for more than 3 years maintained long-term patency. There was no significant difference in spleen size between groups; however, when the groups were compared according to whether they maintained patency, spleens tended to be smaller in the patency-maintained group. CONCLUSION: Unlike stenosis, if kinking is confirmed on venography, stenting is not feasible in the long term for patients with LDLT.

Renal Ischemia-Reperfusion Injury in a Diabetic Monkey Model and Therapeutic Testing of Human Bone Marrow-Derived Mesenchymal Stem Cells.

Clinically, acute kidney injury (AKI) episodes in diabetes mellitus (DM) patients are associated with a cumulative risk of developing end-stage renal disease. In this study, we asked whether the severity of AKI induced by renal ischemia-reperfusion injury (IRI) is more prominent in DM than in non-DM control using a cynomolgus monkey (Macaca fascicularis) model. We also investigated whether human bone marrow-derived mesenchymal stem cells (hBM-MSCs) infused via the renal artery could ameliorate renal IRI in DM monkeys. The experimental data, including mortality rate, histologic findings, and urinary albumin secretion indicate that the severity of AKI was greater in DM monkeys than in control animals. Moreover, histological findings and qRT-PCR analysis of Ngal mRNA in renal biopsy tissue showed that hBM-MSC promoted the recovery of tubular damage caused by AKI. Serum analysis also revealed that the level of albumin and ALT was increased 24 and 48 hours after AKI, respectively, suggesting that AKI induced acute liver injury. We suggest that this nonhuman primate model could provide essential information about the renal and nonrenal impairment related to DM and help determine the clinical usefulness of MSCs in AKI.