A Novel Pre-Clinical Modeling of Massive Hemorrhagic Shock in Non-Human Primate: A Safe and Reproducible Method (Macaca fascicularis).

BACKGROUND: Although non-human primates are the closest animals to humans to simulate physiological and metabolic responses, there is a paucity of primate hemorrhagic shock models that are standardized and reproducible. Herein, we describe a model that is a clinical replica of extreme class IV hemorrhagic shock with a step-by-step description of the procedure in cynomolgus macaque monkeys. METHODS: The physiological changes that occurred during the process were evaluated using hemodynamic parameters, echocardiogram, and laboratory values. Five female monkeys were subjected to trauma laparotomy, followed by cannulation of the abdominal aorta to achieve graded hemorrhage. A central line was placed in the right internal jugular vein, which was subsequently used for laboratory sampling and volume resuscitation. The withdrawal of blood was ceased when a predefined cardiac endpoint with cardiac arrhythmia or bradycardia was reached. The animals were then immediately resuscitated with transfusion. The primary cardiac endpoint was consistently reached in all 5 animals during the fourth hemorrhage when more than 70% of the estimated total blood volume was lost. RESULTS: No mortality occurred during the process. The blood pressure, cardiac output measured from an echocardiogram, and hemoglobin correlated well with increasing loss of circulating volume, whereas the pulse pressure variation did not. The echocardiogram was also a useful predictor for urgent volume replacement. CONCLUSION: This model offers a safe and reproducible surgical hemorrhagic model in non-human primates and simulates clinical practice. This could provide a useful platform on which further studies can be carried out to address unanswered questions in trauma management.

Monitoring Porcine Cytomegalovirus in Both Donors and Recipients is Crucial for Recipient's Survival in Pig-to-Cynomolgus Xenotransplantation.

BACKGROUND: Xenotransplantation, particularly when involving pig donors, presents challenges related to the transmission of porcine cytomegalovirus (pCMV) and its potential impact on recipient outcomes. This study aimed to investigate the relationship between pCMV positivity in both donors and recipients and the survival time of cynomolgus monkey recipients after xenogeneic kidney transplantation. METHODS: We conducted 20 cynomolgus xenotransplants using 18 transgenic pigs. On the surgery day, donor pig blood was sampled, and DNA was extracted from serum and peripheral blood mononuclear cells. Recipient DNA extraction followed the same protocol from pre-transplantation to post-transplantation. Porcine cytomegalovirus detection used real-time polymerase chain reaction (real-time PCR) with the ViroReal kit, achieving a sensitivity of 50 copies/reaction. A Ct value of 37.0 was the pCMV positivity threshold. RESULTS: Of 20 cynomolgus recipients, when donors tested negative for pCMV, recipients also showed negative results in 9 cases. In 4 cases where donors were negative, recipients tested positive. All 5 cases with pCMV-positive donors resulted in positive assessments for recipients. Detection of donor pCMV correlated with shorter recipient survival. Continuous recipient positivity during observation correlated with shorter survival, whereas transient detection showed no significant change in survival rates. However, donor pig phenotypes and transplantation protocols did not significantly impact survival. CONCLUSION: The detection of pCMV in both donors and recipients plays a crucial role in xenotransplantation outcomes. These findings suggest the importance of monitoring and managing pCMV in xenotransplantation to enhance long-term outcomes.

Necessity of induction agent modification for old age kidney transplant recipients.

Background: Immunosenescence gradually deteriorates the function of the immune system, making elderly patients susceptible to infection, while reducing rejection of organ transplants. Therefore, age-adaptive immunosuppression is necessary in the elderly. We evaluated clinical outcomes such as rejection and infection rate when using basiliximab and rabbit anti-thymocyte globulin (r-ATG) as induction agents in elderly and young organ transplant recipients. Methods: We retrospectively reviewed patients who underwent kidney transplantation (KT) between June 2011 and April 2019. We enrolled 704 adult KT patients and classified the patients into groups according to patient age. We compared the outcomes of infection and biopsy-proven acute rejection (BPAR) according to the type of induction agent (basiliximab and r-ATG [4.5 mg/kg]). Results: The patient group included 520 recipients (74.6%) in the younger recipient group and 179 recipients (25.4%) in the older recipient group. When r-ATG was used as an induction agent, BPAR within 6 months occurred less (p = 0.03); however, infections within 6 months were higher in older recipients. Deaths due to infection were more common in older recipients (p = 0.003). Conclusion: It may be necessary to use less intensive induction therapy for older recipients, of which dose reduction of r-ATG is one option.

Upper thigh skeletal muscle index predicts outcomes in liver transplant recipients.

Purpose: The skeletal muscle index (SMI) at the L3 level is widely used to diagnose sarcopenia. The upper thigh (UT) also reflects changes in whole-body muscle mass, but no study has examined this using the UT to diagnose sarcopenia in liver transplantation (LT). This study aimed to determine an optimal cut-off value for UT-SMI and investigate how sarcopenia diagnosed by UT-SMI correlates with outcomes in LT recipients. Methods: In this retrospective study of 332 LT patients from 2018 to 2020, we investigated the association between sarcopenia diagnosed by UT-SMI and patient outcomes after LT. Results: The cut-off values for UT-SMI were 38.3 cm2/m2 for females (area under the curve [AUC], 0.927; P < 0.001) and 46.7 cm2/m2 for males (AUC, 0.898; P < 0.001). The prevalence of sarcopenia diagnosed by UT-SMI was 33.4% in our cohort. Patient and graft survival rates in the UT-SMI sarcopenia group were significantly poorer than those in the UT-SMI non-sarcopenia group (P < 0.001 and P < 0.001). UT-SMI was an independent prognostic factor for patient survival (hazard ratio [HR], 2.182; 95% confidence interval [CI], 1.183-4.025; P = 0.012) and graft survival (HR, 2.227; 95% CI, 1.054-4704; P = 0.036) in our multivariable Cox analysis. Conclusion: We confirmed that sarcopenia diagnosed by UT-SMI is associated with outcomes in LT recipients. In addition, UT-SMI was identified as an independent prognostic factor for patient survival and graft survival. Therefore, UT-SMI could be a good option for CT-based evaluations of sarcopenia in LT recipients.

Two-Week Protocol Biopsy in Renal Allograft: Feasibility, Safety, and Outcomes.

BACKGROUND: Protocol biopsy in renal allograft helps to early detect subclinical rejection (SCR) in patients who have no abnormal clinical and laboratory findings. Still, there are rare reports about the techniques and outcomes of two-week protocol biopsy. The aim of this study was to assess two-week protocol biopsy regarding the technical feasibility, procedure safety, and clinical outcomes. METHODS: A total of 894 protocol biopsies were performed in adult recipients between 2012 and 2019. Two-week and one-year protocol biopsies were guided with ultrasound in 842 and 399 patients by one of four radiologists with wide range of biopsy experience, respectively. These protocol biopsies were compared in terms of feasibility and safety. Standard references were clinico-laboratory findings and biopsy examinations. RESULTS: The median period of two-week and one-year protocol biopsies were 12 days (10-20 days) and 383 days (302-420 days), respectively. All protocol biopsies were technically successful and there was no difference between radiologists regarding technical success and complications (p = 0.453). Major complication (Clavien-Dindo grading II-IV) rates of two-week and one-year protocol biopsies were 0.3% (3/842) and 0.2% (1/399), respectively (p = 1.000). However, univariate analysis demonstrated that platelet count < 100 K/mL and blood urea nitrogen ≥ 40 mg/dL were associated with major complications in two-week protocol biopsy. The SCRs of these protocol biopsies were 15.4% (130/842) and 33.6% (134/399), respectively (p < 0.001). CONCLUSION: Two-week protocol biopsy is technically feasible and safe. It contributes to early detecting a substantial number of SCRs. Prior to the biopsy, platelet count and blood urea nitrogen should be carefully checked to predict major complications.

Laparoscopic versus open repeat liver resection for recurrent hepatocellular carcinoma in hepatectomy patients: inverse probability of treatment weighting.

Repeat liver resection (RLR) is a good treatment option for recurrent hepatocellular carcinoma (HCC). However, laparoscopic repeat liver resection (LRLR) is more technically demanding than open repeat liver resection (ORLR). The purpose of our study is to compare the surgical outcomes of ORLR and LRLR and to carefully present LRLR guidelines for HCC. We performed RLR at a single institution from January 2017 to November 2019. We divided the patients into an ORLR group and an LRLR group. Inverse probability of treatment weighting (IPTW) was applied in this study to compare the ORLR group and the LRLR group. There was no difference between the two groups in patient characteristics, preoperative blood tests and pathological characteristics. After stabilized IPTW, the LRLR group had a shorter hospital stay (5.52 vs. 9.27 days, p = 0.001) and superior disease-free survival (p = 0.020). LRLR yielded better short-term outcomes than ORLR. And if a regular radiologic examination is performed, most of the recurrent tumors could be detected less than 3 cm. In conclusion, LRLR might be feasible and useful for recurrent HCC located contralateral to the previous tumor at a size of less than 3 cm.

Hepatocellular Carcinoma Arising from Hepatocellular Adenoma in an Elderly Male Patient.

Hepatocellular adenoma is a benign tumor of the liver occurring predominantly in young women taking oral contraceptives. The malignant transformation of hepatocellular adenoma into hepatocellular carcinoma has rarely been reported. Herein, we report the case of an elderly male patient with hepatocellular carcinoma that developed from hepatocellular adenoma. The patient's high risk for surgery and conflicting biopsy and imaging results made it difficult to determine the treatment direction. Eventually, the mass was completely removed by laparoscopic left hemi-hepatectomy without complications.

Safety and effectiveness of kidney transplantation using a donation after brain death donor with acute kidney injury: a retrospective cohort study.

The use of kidneys from donation after brain death (DBD) donors with acute kidney injury (AKI) is a strategy to expand the donor pool. The aim of this study was to evaluate how kidney transplantation (KT) from a donor with AKI affects long-term graft survival in various situations. All patients who underwent KT from DBD donors between June 2003 and April 2016 were retrospectively reviewed. The KDIGO (Kidney Disease: Improving Global Outcomes) criteria were used to classify donor AKI. The cohort included 376 donors (no AKI group, n = 117 [31.1%]; AKI group n = 259 [68.9%]). Death-censored graft survival was similar according to the presence of AKI, AKI severity, and the AKI trend (p = 0.929, p = 0.077, and p = 0.658, respectively). Patients whose donors had AKI who received using low dose (1.5 mg/kg for three days) rabbit anti-thymocyte globulin (r-ATG) as the induction agent had significantly superior death-censored graft survival compared with patients in that group who received basiliximab (p = 0.039). AKI in DBD donors did not affect long-term death-censored graft survival. Low-dose r-ATG may be considered as an induction immunosuppression in recipients receiving kidneys with AKI because it showed better graft survival than basiliximab.

Comparison of clinical outcomes of deceased donor kidney transplantations, with a focus on three induction therapies.

Background: Graft survival rate of kidney transplantation recipients improves after induction therapy. However, there is no conclusive evidence on which regimen is superior for deceased donor kidney transplantation (DDKT). This study aims at discussing effective induction therapy in DDKT. Methods: Between 2003 and 2016, 395 DDKT recipients were divided into three groups following induction therapy. Recipients of the basiliximab group (n=184) received basiliximab (20 mg/kg) on days 0 and 4. Recipients of the low-dose rabbit anti-thymocyte globulin (rATG) group (n=113) received rATG (1.5 mg/kg) on days 0, 1, and 2, while those of the high-dose rATG group (n=98) received it for more than 4 days. We retrospectively reviewed and analyzed the clinical outcomes and adverse effects of induction therapy. Results: Compared to other groups, the low-dose rATG group donors were older (P<0.001); rATG group donors had higher serum creatinine levels (P<0.001), and the basiliximab group showed a lower delayed graft function rate (P=0.004). In graft failure, the low-dose rATG group did not differ significantly from the basiliximab group (P=0.080), but was significantly different from the high-dose rATG group (P=0.004). Conclusions: The low-dose rATG group had the best graft survival rate, although it had older donors and higher serum creatinine levels. Therefore, low-dose rATG may be considered an effective induction therapy in DDKT.