Assessment and optimization of liver volume before major hepatic resection: Current guidelines and a narrative review.

Post hepatectomy liver failure (PHLF) remains a significant cause of morbidity and mortality after major liver resection. Although the etiology of PHLF is multifactorial, an inadequate functional liver remnant (FLR) is felt to be the most important modifiable predictor of PHLF. Pre-operative evaluation of FLR function and volume is of paramount importance before proceeding with any major liver resection. Patients with inadequate or borderline FLR volume must be considered for volume optimization strategies such as portal vein embolization (PVE), two stage hepatectomy with portal vein ligation (PVL), Yttrium-90 radioembolization, and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). This paper provides an overview of assessing FLR volume and function, and discusses indications and outcomes of commonly used volume optimization strategies.

Hepatic venous outflow obstruction in pediatric liver transplantation: technical considerations in prevention, diagnosis, and management.

HVOO creates significant diagnostic and management dilemmas in pediatric liver transplant recipients, particularly with TVGs (split or reduced-size grafts). Numerous technical variations for the hepatic vein to IVC anastomosis have been described to minimize the incidence of this complication, but no consensus for an optimal anastomotic technique exists. One hundred and thirty-four liver transplants (70 TVGs) were performed in 124 patients between 1994 and 2011. These were divided into two cohorts. Group 1 (95 transplants, 41 TVGs) utilized a continuous running anastomosis. Group 2 (39 transplants, 29 TVGs) implemented a triangulated (three-stitch) anastomosis. All were reviewed for demographics, diagnostics, interventions, and outcome. The overall HVOO incidence was seven of 134 transplants (5.2%) and six of 70 transplants utilizing TVGs (8.6%). Group 1 incidence was five of 41 (12.2%) compared with one of 29 (3.4%; p = 0.20, OR 3.89) in Group 2. Liver Doppler was employed in all patients, and only three suggested HVOO. All patients with HVOO underwent venogram, at a median of 81 days post-transplant. All underwent percutaneous venoplasty and required 1-6 treatments, all resulting in HVOO resolution. Incidence of HVOO has improved since adopting the triangulated anastomosis, although not to a level of statistical significance. US is not adequately sensitive to exclude HVOO. Venogram is recommended in patients with prolonged ascites, and venoplasty has been highly successful in HVOO treatment.

A novel organ donor facility: a decade of experience with liver donors.

Transplant surgeons have historically traveled to donor hospitals, performing complex, time-sensitive procedures with unfamiliar personnel. This often involves air travel, significant delays, and frequently occurs overnight.In 2001, we established the nation's first organ recovery center. The goal was to increase efficiency,reduce costs and reduce surgeon travel. Liver donors and recipients, donor costs, surgeon hours and travel time, from April 1,2001 through December 31,2011 were analyzed. Nine hundred and fifteen liver transplants performed at our center were analyzed based on procurement location (living donors and donation after cardiac death donors were excluded). In year 1, 36% (9/25) of donor procurements occurred at the organ procurement organization (OPO) facility, rising to 93%(56/60) in the last year of analysis. Travel time was reduced from 8 to 2.7 h (p<0.0001), with a reduction of surgeon fly outs by 93% (14/15) in 2011. Liver organ donor charges generated by the donor were reduced by37% overall for donors recovered at the OPO facility versus acute care hospital. Organs recovered in this novel facility resulted in significantly reduced surgeon hours, air travel and cost. This practice has major implications for cost containment and OPO national policy and could become the standard of care.

Effect of donor body mass index on the outcome of donation after cardiac death kidneys: how big is too big?

INTRODUCTION: Morbid obesity (MO) has become an epidemic in the United Sates and is associated with adverse effects on health. The purpose of this study was to examine the effects of MO on the short-term outcomes of kidneys transplanted from donation after cardiac death (DCD) donors. PATIENTS AND METHODS: Using a prospectively collected database, we reviewed 467 kidney transplantations performed at a single center between January 2008 and June 2011 to identify 67 recipients who received transplants from 40 DCD donors. The outcomes of 14 MO DCD donor kidneys were compared with 53 non-MO DCD grafts. MO was defined as a body mass index ≥ 35. Mean patient follow-up was 16 months. RESULTS: The MO and non-MO DCD donor groups were similar with respect to donor and recipient age, gender, race, cause of death and renal disease, time from withdrawal of life support to organ perfusion, mean human leukocyte antigen (HLA) mismatch, and overall recipient survival. Organs from MO DCD donors also had comparable rates of delayed graft function (21.4% vs 20.0%; P = not significant [NS]). At 1 year post-transplantation, a small but statistically insignificant difference was observed in the graft survival rates of MO and non-MO donors (87% vs. 96%; P = NS). One MO kidney had primary nonfunction. CONCLUSIONS: These data demonstrate that kidneys procured from MO DCD donors have equivalent short-term outcomes compared with non-MO grafts and should continue to be used. Further investigation is needed to examine the effect of MO on long-term renal allograft survival.

Immune responses to collagen-IV and fibronectin in renal transplant recipients with transplant glomerulopathy.

Antibodies (Abs) to donor HLA (donor-specific antibodies [DSA]) have been associated with transplant glomerulopathy (TG) following kidney transplantation (KTx). Immune responses to tissue-restricted self-antigens (self-Ags) have been proposed to play a role in chronic rejection. We determined whether KTx with TG have immune responses to self-Ags, Collagen-IV (Col-IV) and fibronectin (FN). DSA were determined by solid phase assay, Abs against Col-IV and FN by enzyme-linked immunosorbent assay and CD4+ T cells secreting interferon gamma (IFN-γ), IL-17 or IL-10 by ELISPOT. Development of Abs to self-Ags following KTx increased the risk for TG with an odds ratio of 22 (p-value = 0.001). Abs to self-Ags were IgG and IgM isotypes. Pretransplant Abs to self-Ags increased the risk of TG (22% vs. 10%, p < 0.05). Abs to self-Ags were identified frequently in KTx with DSA. TG patients demonstrated increased Col-IV and FN specific CD4+ T cells secreting IFN-γ and IL-17 with reduction in IL-10. We conclude that development of Abs to self-Ags is a risk factor and having both DSA and Abs to self-Ags increases the risk for TG. The increased frequency of self-Ag-specific IFN-γ and IL-17 cells with reduction in IL-10 demonstrate tolerance breakdown to self-Ags which we propose play a role in the pathogenesis of TG.

Renal function at two years in liver transplant patients receiving everolimus: results of a randomized, multicenter study.

In a 24-month prospective, randomized, multicenter, open-label study, de novo liver transplant patients were randomized at 30 days to everolimus (EVR) + Reduced tacrolimus (TAC; n = 245), TAC Control (n = 243) or TAC Elimination (n = 231). Randomization to TAC Elimination was stopped prematurely due to a significantly higher rate of treated biopsy-proven acute rejection (tBPAR). The incidence of the primary efficacy endpoint, composite efficacy failure rate of tBPAR, graft loss or death postrandomization was similar with EVR + Reduced TAC (10.3%) or TAC Control (12.5%) at month 24 (difference -2.2%, 97.5% confidence interval [CI] -8.8%, 4.4%). BPAR was less frequent in the EVR + Reduced TAC group (6.1% vs. 13.3% in TAC Control, p = 0.010). Adjusted change in estimated glomerular filtration rate (eGFR) from randomization to month 24 was superior with EVR + Reduced TAC versus TAC Control: difference 6.7 mL/min/1.73 m(2) (97.5% CI 1.9, 11.4 mL/min/1.73 m(2), p = 0.002). Among patients who remained on treatment, mean (SD) eGFR at month 24 was 77.6 (26.5) mL/min/1.73 m(2) in the EVR + Reduced TAC group and 66.1 (19.3) mL/min/1.73 m(2) in the TAC Control group (p < 0.001). Study medication was discontinued due to adverse events in 28.6% of EVR + Reduced TAC and 18.2% of TAC Control patients. Early introduction of everolimus with reduced-exposure tacrolimus at 1 month after liver transplantation provided a significant and clinically relevant benefit for renal function at 2 years posttransplant.

Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial.

In a prospective, multicenter, open-label study, de novo liver transplant patients were randomized at day 30±5 to (i) everolimus initiation with tacrolimus elimination (TAC Elimination) (ii) everolimus initiation with reduced-exposure tacrolimus (EVR+Reduced TAC) or (iii) standard-exposure tacrolimus (TAC Control). Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy-proven acute rejection (tBPAR). EVR+Reduced TAC was noninferior to TAC Control for the primary efficacy endpoint (tBPAR, graft loss or death at 12 months posttransplantation): 6.7% versus 9.7% (-3.0%; 95% CI -8.7, 2.6%; p<0.001 for noninferiority [12% margin]). tBPAR occurred in 2.9% of EVR+Reduced TAC patients versus 7.0% of TAC Controls (p = 0.035). The change in adjusted estimated GFR from randomization to month 12 was superior with EVR+Reduced TAC versus TAC Control (difference 8.50 mL/min/1.73 m(2) , 97.5% CI 3.74, 13.27 mL/min/1.73 m(2) , p<0.001 for superiority). Drug discontinuation for adverse events occurred in 25.7% of EVR+Reduced TAC and 14.1% of TAC Controls (relative risk 1.82, 95% CI 1.25, 2.66). Relative risk of serious infections between the EVR+Reduced TAC group versus TAC Controls was 1.76 (95% CI 1.03, 3.00). Everolimus facilitates early tacrolimus minimization with comparable efficacy and superior renal function, compared to a standard tacrolimus exposure regimen 12 months after liver transplantation.

ABO-incompatible organ transplantation.

Increases in the patients on the organ transplant wait list have far out paced the number of available organs. This has lead to longer time awaiting transplantation and thus increased morbidity and mortality associated with it. Making more organs available for transplantation remains critical, and hence, extended criteria donors and ABO-incompatible organs are being utilized. Recent reports on the use of conventional immunosuppressive regimens for ABO-incompatible grafts suggest outcomes can be obtained similar to those of ABO-compatible transplants. The delay in the development of natural antibodies to ABO antigens in infants provides an 'immunological window' that allows for successful ABO-incompatible transplants in this age group. This also allows for a unique mechanism long-term tolerance to the graft in infants. ABO incompatibility may no longer be a contraindication in case of kidney transplantation and paediatric heart transplantation. Increased utilization of ABO-incompatible grafts can alleviate the shortage for organs and decrease waitlist times and associated morbidity. In this review, we will discuss the current status of ABO-incompatible transplantation in adult and paediatric solid organ transplantation with attention on recent developments on understanding the mechanisms of graft acceptance in these ABO-incompatible organs.

Characterization of HCV-specific CD4+Th17 immunity in recurrent hepatitis C-induced liver allograft fibrosis.

Hepatitis C virus (HCV) recurrence with accelerated fibrosis following orthotopic liver transplantation (OLT) is a universal phenomenon. To evaluate mechanisms contributing to HCV induced allograft fibrosis/cirrhosis, we investigated HCV-specific CD4+Th17 cells and their induction in OLT recipients with recurrence utilizing 51 HCV+ OLT recipients, 15 healthy controls and 9 HCV- OLT recipients. Frequency of HCV specific CD4+ Tcells secreting IFN-γ, IL-17 and IL-10 was analyzed by ELISpot. Serum cytokines and chemokines were analyzed by LUMINEX. Recipients with recurrent HCV induced allograft inflammation and fibrosis/cirrhosis demonstrated a significant increase in frequency of HCV specific CD4+Th17 cells. Increased pro-inflammatory mediators (IL-17, IL-1ß, IL-6, IL-8 and MCP-1), decreased IFN-γ, and increased IL-4, IL-5 and IL-10 levels were identified. OLT recipients with allograft inflammation and fibrosis/cirrhosis demonstrated increased frequency of Foxp3+ regulatory T cells (Tregs) that inhibited HCV specific CD4+Th1 but not Th17 cells. This suggests that recurrent HCV infection in OLT recipients induces an inflammatory milieu characterized by increased IL-6, IL-1ß and decreased IFN-γ which facilitates induction of HCV specific CD4+Th17 cells. These cells are resistant to suppression by Tregs and may mediate an inflammatory cascade leading to cirrhosis in OLT recipients following HCV recurrence.

The role of liver transplantation for hepatic adenomatosis in the pediatric population: case report and review of the literature.

Hepatic adenomas are benign lesions often found in young women during childbearing age. These tumors are often solitary but can also be multiple in which case this is referred to as hepatic adenomatosis (HA). HA is defined as having greater than or equal to ten adenomas within an otherwise normal liver. We present a case of a teenager with HA who underwent an orthotopic liver transplant for complications of her HA. To date there are only four reports of teenagers, without an underlying glycogen storage disease, who have undergone a liver transplant for HA. Liver transplantation within the pediatric population is an acceptable treatment for HA that are deemed unresectable.

Improved islet yields from pancreas preserved in perflurocarbon is via inhibition of apoptosis mediated by mitochondrial pathway.

Islet transplantation is a treatment option for type I diabetic patients. Preservation of human pancreata prior to islet isolation using two-layer method with perfluorocarbon (PFC) and University of Wisconsin solution (UW) results in twofold increase in islet yields. The objective of this study was to determine the mechanism by which islets undergo apoptosis and determine PFC's effects on this process. Gene array analysis was used to analyze the expression of pro- and anti-apoptotic genes in islets isolated from pancreata preserved under varying conditions. A 12-fold increase in the expression of inhibitor of apoptosis (IAP) and survivin was observed in islets isolated from pancreata preserved in PFC. This was accompanied by decreased expression of BAD (3.7-fold), BAX (2.7-fold) and caspases (5.2-fold). Levels of activated caspase-9 (77.98%), caspase-2 (61.5%), caspase-3 (68.3%) and caspase-8 (37.2%) were also reduced. 'Rescue' of pancreata after storage (12 h) in UW by preservation using PFC also resulted in a down-regulation of pro-apoptotic genes and inhibition of caspase activation. Apoptosis observed in islets from all groups was mainly mitochondria-dependent, mediated by change in redox potential initiated by hypoxia. We demonstrate that reduction in hypoxia of pancreata preserved using PFC leads to significant up-regulation of anti-apoptotic and inhibition of pro-apoptotic genes.

Liver transplantation in a patient with undiagnosed bipolar disorder.

We present the case of a 55-year-old woman with no previous diagnosis of bipolar disorder, who underwent orthotopic liver transplantation for hepatitis C and alcohol-related liver disease. Two weeks posttransplant, she exhibited manic symptoms including hyperactivity, racing thoughts, and pressured speech. Although drug and alcohol abuse had been in remission for a 10-year period, a long history consistent with bipolar disorder was only identified after surgery. This article discusses the role of psychiatric evaluation prior to undergoing liver transplantation, and provides the transplant team with suggestions for comprehensively assessing psychiatric disorders in addition to alcohol and drug use.

Radical resection improves survival for patients with pT2 gallbladder carcinoma.

Radical resection (wedge resection of the gallbladder bed and dissection of the hepatoduodenal ligament, portal, and celiac lymph nodes) has been reported to improve survival from pathologic T2 gallbladder carcinoma (pT2 GBCa; invasion through the muscularis without perforation of the serosa). We report our experience and the outcome of patients with pT2 GBCa. Between 1989 and 2000 at Vanderbilt University Medical Center ten patients were found to have pT2 disease after cholecystectomy. The patients had an average age of 64+/-13 years and underwent either radical resection (n = 5) or no further surgical therapy (n = 5). Of the patients who underwent cholecystectomy only, one (20%) is still alive at 27 months and four (80%) died of recurrent GBCa between 6.5 and 21 months. For the patients who underwent radical resection all five are alive at 15 to 83 months with no recurrence. The proportion of patients surviving pT2 GBCa after radical resection was significantly greater than with cholecystectomy alone (P < 0.05). The difference in length of survival between the two groups was also significant (P < 0.05). Morbidity after radical resection was low (pancreatic leak in one patient), and there were no operative mortalities. Radical resection significantly improved survival over cholecystectomy alone for patients with pT2 GBCa. The procedure has low morbidity and mortality rates. Therefore a radical resection operation is indicated for patients with pT2 GBCa.

Bile duct injury following laparoscopic cholecystectomy: a cause for continued concern.

Previous reports suggest that bile duct injuries sustained during laparoscopic cholecystectomy (lap chole) are frequently severe and related to cautery and high clip ligation. We performed a review of patients who sustained bile duct injury from lap chole since 1990 and assessed time to injury recognition, time to referral, Bismuth classification, initial and subsequent repairs, rate of recurrence, and length of follow-up. Seventy-four patients [median age 44 years, 58 of 74 female (78%)] were referred with a bile duct injury after lap chole. The level of injury was evenly divided between the bile duct bifurcation and the common hepatic duct: Bismuth III, IV, and V (40 of 74, 54%) versus Bismuth I and II (34 of 74, 46%). Concomitant hepatic arterial injury was identified in nine (12%) patients. Patients referred early after bile duct injury and requiring operative intervention underwent hepaticojejunostomy at a median of 2 days after referral. After surgical reconstruction at our center there has been an overall success rate of 89 per cent with no need for reintervention. Six (10%) of these patients have required one additional balloon dilatation at a mean follow-up of >24 months. One (2%) patient underwent biliary-enteric revision in follow-up. In patients with bile duct injury, stricture repair without delay was successful in the majority of patients treated in this series. Only one of 64 patients reconstructed at our center has required reoperation; six others have required a single balloon dilatation with subsequent good or excellent results. The majority of patients treated with operative repair at an experienced center can expect good long-term results with rare need for reintervention.

Control of bone bleeding at the sternum and iliac crest donor sites using a collagen-based composite combined with autologous plasma: results of a randomized controlled trial.

In a randomized controlled trial, hemostatic effectiveness of a collagen-based composite (experimental group) was compared with standard hemostatic methods (ie, electrocautery and collagen sponge) (control group) at two bone sites. Hemostatic success, time to "controlled bleeding," and time to "complete hemostasis" were determined at the sternal edge following median sternotomy (n=64) and at the iliac crest following bone graft harvest (n=19). Almost twice the percentage of sternal edge patients (83% versus 44%, P=.002) and nearly three times the percentage of iliac crest patients (83% versus 29%, P<.05) achieved complete hemostasis in the experimental group compared to controls. Time to controlled bleeding and complete hemostasis for all bone sites also favored the experimental group over the control group at highly significant levels (P<.0001 for most comparisons). There were no adverse events related to experimental treatment use. The results support the use of this investigational hemostatic agent to control cancellous bone bleeding.