Christopher B. Hughes

Liver Transplantation Using Controlled Donation After Cardiac Death Donors: An Analysis of a Large Single-Center Experience

The use of donation after cardiac death (DCD) donors may provide a valuable source of organs for liver transplantation. Concerns regarding primary nonfunction (PNF) and intrahepatic biliary stricture (IHBSs) have limited the enthusiasm for their use. A retrospective analysis of 1436 consecutive deceased donor liver transplants performed between December 1998 and October 2006 was conducted. These included 108 DCD liver transplants, which were compared to 1328 transplants performed with organs from donors meeting the criteria for donation after brain death (DBD). The median follow‐up was 48 months. The 1‐, 3‐, and 5‐year patient survival and graft survival for DCD donors were 91.5%, 88.1%, and 88.1% and 79.3%, 74.5%, and 71.0%, respectively. The 1‐, 3‐, and 5‐year patient survival and graft survival for DBD donors were 87.3%, 81.1%, and 77.2% and 81.6%, 74.7%, and 69.1%, respectively. Patient survival and graft survival were not significantly different between DCD donors less than 60 years old, DCD donors greater than 60 years old, and DBD donors. Causes of graft loss included IHBSs (n = 9), PNF (n = 4), recurrent hepatitis C virus (n = 4), hepatic artery thrombosis (n = 1), rejection (n = 2), and patient death (n = 13). Contrary to previously published data, excellent long‐term patient survival and graft survival can be obtained with DCD allografts, and in our experience, they are equivalent to those obtained from DBD allografts. Liver Transpl 15: 1028–1035, 2009.

A randomized, prospective, double-blinded evaluation of selective bowel decontamination in liver transplantation.

Background. Bacterial infection is a frequent, morbid, and mortal complication of liver transplantation. Selective bowel decontamination (SBD) has been reported to reduce the rate of bacterial infection after liver transplantation in uncontrolled trials, but benefits of this intervention have been less clear in controlled studies. Methods. Eighty candidates for liver transplantation were randomly assigned in a double-blinded fashion to an SBD regimen consisting of gentamicin 80 mg+polymyxin E 100 mg+nystatin 2 million units (37 patients) or to nystatin alone (43 patients). Both treatments were administered orally in 10 ml (increasing to 20 ml, according to predefined criteria), four times daily, through day 21 after transplantation. Anal fecal swab cultures were performed on days 0, 4, 7, and 21. Rates of infection, death, and charges for medical care were assessed from day 0 through day 60. Results. More than 85% of patients in both treatment groups began study treatment more than 3 days before transplantation. Rates of infection (32.4 vs. 27.9%), death (5.4 vs. 4.7%), or charges for medical care (median

Early and late onset Clostridium difficile-associated colitis following liver transplantation.

194,000 vs.

Serum fibrosis markers can predict rapid fibrosis progression after liver transplantation for hepatitis C

163,000) were not reduced in patients assigned to SBD. On days 0, 4, 7, and 21, growth of aerobic gram-negative flora in fecal cultures of patients assigned to SBD was significantly less than that of patients taking nystatin alone; growth of aerobic gram-positive flora, anaerobes, and yeast was not significantly different. Conclusion. Routine use of SBD in patients undergoing liver transplantation is not associated with significant benefit.

Risk stratification and targeted antifungal prophylaxis for prevention of aspergillosis and other invasive mold infections after liver transplantation

Clostridium difficile colitis (CDC) remains a serious and common complication after liver transplantation (LT). Four hundred and sixty‐seven consecutive LTs in 402 individuals were performed between 1998 and 2001 at our center. Standard immunosuppression consisted of tacrolimus, mycophenolate, and steroids. CD toxins A and B were detected by using a rapid immunoassay or enzyme immunoassay. CDC was diagnosed in 32 patients (5–1999 days post‐LT), with 93.8% (30/32) of patients developing CDC during the first year post‐LT; three individuals had CDC more than 3 years post‐LT, one of which also had early CDC. All patients presented with abdominal pain and watery diarrhea. Patients who developed CDC within 1‐year post‐LT were significantly more likely to have a hemorrhagic, biliary, or infectious complication. Patients who developed CDC within 28 days post‐LT had a significantly higher model end‐stage liver disease score. Treatment consisted of fluid and electrolyte replacement and metronidazole and no patients developed toxic megacolon, required colonic resection, or died from CDC. CDC represents a potentially severe complication following LT. Most cases occur early post‐LT. Development of a hemorrhagic, biliary, or infectious complication is associated with the development of CDC.

Long-term outcomes of donation after cardiac death liver allografts from a single center.

Although recurrent hepatitis C virus (HCV) after liver transplantation (LT) is universal, a minority of patients will develop cirrhosis within 5 years of surgery, which places them at risk for allograft failure. This retrospective study investigated whether 2 serum fibrosis markers, serum hyaluronic acid (HA) and YKL‐40, could be used to predict rapid fibrosis progression (RFP) post‐LT. These markers were compared with conventional laboratory tests, histological assessment, and hepatic stellate cell activity (HSCA), a key step in fibrogenesis, as assessed by immunohistochemical staining for alpha‐smooth muscle actin. Serum and protocol liver biopsy samples were obtained from 46 LT recipients at means of 5 ± 2 (biopsy 1) and 39 ± 6 (biopsy 2) months post‐LT, respectively. RFP was defined as an increase in the fibrosis score ≥ 2 from biopsy 1 to biopsy 2 (a mean interval of 33 ± 6 months). The ability of parameters at biopsy 1 to predict RFP was compared with the areas under receiver operating characteristic curves (AUROCs). Of the 46 subjects, 15 developed RFP. Serum HA and YKL‐40 performed significantly better than conventional parameters and HSCA in predicting RFP post‐LT for HCV at biopsy 1, with AUROCs of 0.89 and 0.92, respectively. The accuracy of serum HA ≥ 90 μg/L and YKL‐40 ≥ 200 μg/L in predicting RFP at biopsy 1 was 80% and 96%, respectively. In conclusion, we found that elevated levels of serum HA and YKL‐40 within the first 6 months after LT accurately predicted RFP. Larger studies evaluating the role of serum HA and YKL‐40 in post‐LT management are warranted. Liver Transpl 14:1294–1302, 2008.

Induction of acute pancreatitis in germ-free rats: evidence of a primary role for tumor necrosis factor-alpha.

Antifungal prophylaxis has been proposed for liver transplant recipients at increased risk for invasive mold infection. Risk factors for invasive mold infection after liver transplantation were selected to divide recipients into 3 groups: (1) high risk—transplantation on hemodialysis or delay of hospital discharge beyond day 7 after transplantation because of allograft or renal insufficiency; (2) intermediate risk—retransplantation or transplantation for fulminant hepatic failure; (3) low risk—absence of conditions in groups 1 and 2. During an intervention period (February 1999–April 2001), prophylactic administration of a lipid complex of amphotericin (Abelcet) at 5 mg/kg intravenously every 24 to 48 hours was recommended for high‐risk recipients. The frequency of mold infection was compared to that of a preintervention period (February 1998–January 1999) when antifungal prophylaxis was not provided. During the intervention period, invasive mold infection developed in 2 (6%) of 35 high‐risk recipients, 0 of 28 intermediate‐risk recipients, and 1 (0.5%) of 187 low‐risk recipients. Overall, of 58 liver transplant recipients, 3 (5%) developed an invasive mold infection during the preintervention period, compared with 3 (1%) of 250 during the intervention period (P = 0.08). The only death from invasive mold infection occurred during the preintervention period. Rates of pulse corticosteroid treatment of rejection and cytomegalovirus infection were lower during the intervention period. In conclusion, readily identifiable patient characteristics can be used to stratify liver transplant recipients for risk of invasive mold infection. Antifungal prophylaxis given to high‐risk recipients may provide cost‐effective prevention of these infections. (Liver Transpl 2005;11:656–662.)

Excellent Renal Allograft Survival in Donor-Specific Antibody Positive Transplant Patients—Role of Intravenous Immunoglobulin and Rabbit Antithymocyte Globulin

Abstract:  Organ shortage continues to be a major challenge in transplantation. Recent experience with controlled non‐heart‐beating or donation after cardiac death (DCD) are encouraging. However, long‐term outcomes of DCD liver allografts are limited. In this study, we present outcomes of 19 DCD liver allografts with follow‐up >4.5 years. During 1998–2001, 19 (4.1%) liver transplants (LT) with DCD allografts were performed at our center. Conventional heart‐beating donors included 234 standard criteria donors (SCD) and 214 extended criteria donors (ECD). We found that DCD allografts had equivalent rates of primary non‐function and biliary complications as compared with SCD and ECD. The overall one‐, two‐, and five‐yr DCD graft and patient survival was 73.7%, 68.4%, and 63.2%, and 89.5%, 89.5%, and 89.5%, respectively. DCD graft survival was similar to graft survival of SCD and ECD in non hepatitis C virus (HCV) recipients (p > 0.370). In contrast, DCD graft survival was significantly reduced in HCV recipients (p = 0.007). In conclusion, DCD liver allografts are durable and have acceptable long‐term outcomes. Further research is required to assess the impact of HCV on DCD allograft survival.

Gallbladder carcinosarcoma: A case report and literature review

BACKGROUND Tumor necrosis factor-alpha (TNF-alpha) has been implicated as a mediator of the systemic manifestations associated with acute pancreatitis. The purpose of this study was to show that TNF-alpha expression in pancreatitis is a primary response and is not the result of endotoxemia. METHODS Severe acute pancreatitis was induced in germ-free rats, which have no source of endogenous endotoxin, by ductal infusion of artificial bile. Control animals underwent sham operation and ductal infusion of saline solution. TNF-alpha levels were measured by the WEHI bioassay. Endotoxin was measured by the Limulus assay. RESULTS TNF-alpha levels remained low in the sham group (mean, 24.6 +/- 8.0 pg/ml) but were significantly elevated in normal rats with pancreatitis (181 +/- 26.8 pg/ml; p < 0.001 versus sham group) and in germ-free rats with pancreatitis (213 +/- 90 pg/ml; p < 0.002 versus sham group). No endotoxin was detected in any of the experimental rats. CONCLUSIONS Our results indicate that TNF-alpha levels are elevated in acute pancreatitis despite the absence of endotoxin, indicating a primary role of TNF-alpha in this disease.

Surgical site infection after liver transplantation: risk factors and association with graft loss or death.

Background. Timely transplantation of sensitized kidney recipients remains a challenge. Patients with a complement-dependent cytotoxicity negative and flow cytometry (FC) positive crossmatch carry increased risk of antibody-mediated rejection and thus graft loss. Solid phase assays are available to confirm donor specificity for antibody identified by FC crossmatch. Treatment using induction therapy with rabbit antithymocyte globulin (RATG) and intravenous immunoglobulin (IVIG) may allow successful transplant of these high-risk patients. Methods. A retrospective study of 264 consecutive patients after exclusions yielded 94 complement-dependent cytotoxicity anti-human globulin crossmatch-negative patients, including group 1: 58 primary transplants with panel-reactive antibody (PRA) less than 20%, group 2: 16 retransplants and PRA more than 20% who were FC crossmatch-negative, and group 3: 20 retransplants and PRA more than 20% who were FC crossmatch-positive. All were treated with RATG induction and maintenance therapy with tacrolimus, mycophenolate mofetil, and corticosteroids. Only group 3 received IVIG at 500 mg/kg daily in three doses. Results. Eighteen of 20 patients in group 3 had donor-specific antibody identified by solid phase assay. Cellular- and antibody-mediated rejections were statistically higher in group 3. Two-year serum creatinine and glomerular filtration rate along with 3-year patient and graft survival were comparable between the groups. Conclusions. Sensitized patients with positive FC crossmatch and donor-specific antibody identified by solid phase assays can be successfully transplanted using standard RATG induction, IVIG, and maintenance immunosuppression with equal renal function and graft survival to immunologically lower risk recipients. Given these results, this patient group should not be excluded from transplantation based on antibody specificities determined by virtual crossmatch techniques.