Intention-to-treat survival analysis of hepatitis C virus/human immunodeficiency virus coinfected liver transplant: Is it the waiting list?

In human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patients, the accelerated severity of liver disease, associated comorbidities, and mortality on the waiting list could change the possibility and results of liver transplantation (LT). Intention-to-treat survival analysis (ITTA) can accurately estimate the applicability and efficacy of LT. The primary objective of this study was to compare the survival of patients with HCV with and without HIV infection. We analyzed a cohort of 199 patients with HCV infection enrolled for LT between 1998 and 2015; 17 were also infected with HIV. The patients with HCV/HIV coinfection had higher mortality on the waiting list than those with HCV monoinfection (35.3% versus 4.6%; P < 0.001). ITTA at 1, 3, and 4 years was 75%, 64%, and 57% for HCV monoinfection and 52%, 47%, and 39% for HCV/HIV coinfection, respectively (Wilcoxon test P < 0.05). The ITTA at 1, 3, 6, and 12 months was 96%, 91%, 87%, and 75% for HCV monoinfection and 76%, 70%, 64%, and 52% for HCV/HIV coinfection, respectively (log-rank P < 0.05; Wilcoxon test P < 0.01). A Cox regression analysis was carried out including all variables with predictive value in the univariate analysis, showing that only donor age > 70 years (hazard ratio [HR] = 3.12; P < 0.05), United Network for Organ Sharing status 1 (HR = 10.1; P < 0.01), Model for End-Stage Liver Disease (HR = 1.13; P < 0.001), and HIV coinfection (HR = 2.65; P < 0.05) had independent negative predictive value for survival. In conclusion, our study indicates that HIV coinfection is a factor in mortality prior to transplantation and associated with higher mortality on the waiting list. Liver Transplantation 22 1186-1196 2016 AASLD.

Evaluation of Institut Georges Lopez-1 preservation solution in pig pancreas transplantation: a pilot study.

BACKGROUND: Institut Georges Lopez-1 preservation solution (IGL-1) is an emerging extracellular-type electrolyte solution, low in viscosity, containing polyethylene glycol 35 as a colloid. Although IGL-1 has shown beneficial outcomes in kidney and liver preservation, this pilot study is the first to evaluate the efficacy of IGL-1 in pancreas transplantation (PT) compared with the University of Wisconsin solution (UW). METHODS: Sixteen Landrace pigs underwent allogeneic PT with 16 hr of cold ischemia. Grafts were preserved with IGL-1 (n=8) or UW (n=8). No immunosuppression was administered. We analyzed graft function, the acute-phase response, and oxidative stress in the pancreatic graft monitoring membrane fluidity and lipid peroxidation. RESULTS: All eight grafts with IGL-1, but only six with UW, were functioning. Graft failures with UW resulted from graft thrombosis. There were no differences between the two solutions in the number of normoglycemic days (IGL-1: 11.5 ± 6.2 versus UW: 8.5 ± 4.4 days, P=0.1357), nor in lipid peroxidation during 16-hr cold ischemia (P=0.672), or reperfusion (P=0.185), but IGL-1 prevented changes in membrane fluidity after reperfusion when compared with UW (P=0.026). CONCLUSION: IGL-1 offered the same degree of safety and effectiveness as UW in our model of pig PT with 16 hr of cold ischemia.

Melatonin prolongs graft survival of pancreas allotransplants in pigs.

Oxidative stress is involved in ischemia-reperfusion injury and allograft rejection after transplantation. We studied two well-known antioxidants, melatonin and ascorbic acid (AA), in relation to the survival of a pancreas transplantation model without immunosuppression. Forty-eight Landrace pigs were divided into three groups (n = 16 each; eight donors and eight recipients) that received melatonin, AA, or no antioxidant therapy (controls). Melatonin and AA were administered (10 mg/kg body weight) intravenously to donors and recipients during surgery and on postoperative days 1-7. The molecules were also added (5 mm) to a University of Wisconsin preservation solution during organ cold storage. Melatonin significantly delayed acute rejection and prolonged allograft survival (25.1 ± 7.7 days) compared with the controls (8.1 ± 0.8 days, P = 0.013) and the AA group (9.4 ± 1.6 days, P = 0.049). Melatonin reduced indicators of oxidative stress, malondialdehyde, and 4-hydroxyalkenals, in pancreatic samples collected during procurement, cold ischemia, and reperfusion. Melatonin also reduced serum pig-major acute-phase protein/inter-α-trypsin inhibitor heavy chain 4 (pMAP/ITIH(4)) in the early post-transplantation period. AA only partially reduced oxidative damage 30 min postreperfusion and failed to prevent pMAP/ITIH(4) elevations. These findings suggested that melatonin may be a useful therapeutic tool for organ transplantation.

Celsior versus University of Wisconsin preserving solutions for liver transplantation: postreperfusion syndrome and outcome of a 5-year prospective randomized controlled study.

BACKGROUND: Celsior solution (CS) is a high-sodium, low-potassium, low-viscosity extracellular solution that has been used for liver graft preservation in recent years, although experience with it is still limited. We performed an open-label randomized active-controlled trial comparing CS with the University of Wisconsin solution (UW) for liver transplantation (LT), with a follow-up period of 5 years. METHODS: Adult transplant recipients (n=102) were prospectively randomized to receive either CS (n=51) or UW (n=51). The two groups were comparable with respect to donor and recipient characteristics. The primary outcome measure was the incidence of postreperfusion syndrome (PRS). Secondary outcome measures included primary nonfunction (PNF) or primary dysfunction (PDF), liver retransplantation, and graft and patient survival. Other secondary outcome measures were days in the intensive care unit (ICU) and the rates of acute rejection, chronic rejection, infectious complications, postoperative reoperations, and vascular and biliary complications. RESULTS: In all, 14 posttransplant variables revealed no significant differences between the groups. There were no cases of PNF or PDF. The incidence of PRS was 5.9% in the CS group and 21.6% in the UW group (P=0.041). After reperfusion, CS revealed greater control of serum potassium (P=0.015), magnesium levels (P=0.005), and plasma glucose (P=0.042) than UW. Respective patient survivals at 3, 12, and 60 months were 95.7, 87.2, and 82.0% for the CS group and 95.7, 83.3, and 66.6% for the UW group (P=0.123). CONCLUSIONS: While retaining the same degree of safety and effectiveness as UW for LT, CS may yield postliver graft reperfusion benefits, as shown in this study by a significant reduction in the incidence of PRS and greater metabolic control.

Melatonin protects steatotic and nonsteatotic liver grafts against cold ischemia and reperfusion injury.

Chronic organ-donor shortage has required the acceptance of steatotic livers for transplantation purposes despite the higher risk of graft dysfunction or nonfunction associated with the cold ischemia-reperfusion injury. This study evaluated the use of melatonin as an additive to Institute Georges Lopez (IGL-1) solution for protecting nonsteatotic and steatotic liver grafts against cold ischemia-reperfusion injury. In the current investigation, we used an ex vivo isolated perfused rat liver model. Steatotic and nonsteatotic livers were preserved for 24 hr (4°C) in University of Wisconsin or IGL-1 solutions with or without melatonin, as well as in University of Wisconsin solution alone. Thereafter, livers were subjected to 2-hr reperfusion (37°C). We assessed hepatic injury (transaminases) and function [bile production and sulfobromophthalein (BSP) clearance, vascular resistance], as well as other factors potentially implicated in the high vulnerability of steatotic livers against ischemia-reperfusion injury (oxidative stress and related inflammatory mediators including nitric oxide and cytokines). We also evaluated well-known cytoprotective factors as hemeoxygenase 1 (HO-1). Fatty livers preserved in IGL-1 solution enriched with melatonin showed lower transaminase levels and higher bile production and BSP clearance when compared to those obtained for livers maintained in IGL-1 solution alone. A significant diminution of vascular resistance was also observed when melatonin was added to the IGL-1 solution. The melatonin benefits correlated with the generation of nitric oxide (through constitutive e-NOS activation) and the prevention of oxidative stress and inflammatory cytokine release including tumor necrosis factor and adiponectin, respectively. The addition of melatonin to IGL-1 solution improved nonsteatotic and steatotic liver graft preservation, limiting their risk against cold ischemia-reperfusion injury.