AST/ASTS workshop on increasing organ donation in the United States: creating an "arc of change" from removing disincentives to testing incentives.

The American Society of Transplantation (AST) and American Society of Transplant Surgeons (ASTS) convened a workshop on June 2-3, 2014, to explore increasing both living and deceased organ donation in the United States. Recent articles in the lay press on illegal organ sales and transplant tourism highlight the impact of the current black market in kidneys that accompanies the growing global organ shortage. We believe it important not to conflate the illegal market for organs, which we reject in the strongest possible terms, with the potential in the United States for concerted action to remove all remaining financial disincentives for donors and critically consider testing the impact and acceptability of incentives to increase organ availability in the United States. However, we do not support any trials of direct payments or valuable considerations to donors or families based on a process of market-assigned values of organs. This White Paper represents a summary by the authors of the deliberations of the Incentives Workshop Group and has been approved by both AST and ASTS Boards.

Parvovirus associated fulminant hepatic failure and aplastic anemia treated successfully with liver and bone marrow transplantation. A report of two cases.

Aplastic anemia (AA) has been observed in nearly a third of patients undergoing liver transplantation (LT) for non-A-E fulminant hepatic failure (FHF). Few of these patients have been successfully managed with sequential LT and bone marrow transplantation (BMT). No causative agent has been identified for the FHF or AA in these reported cases. At our center, two patients, aged 15 years and 7 years, respectively, underwent sequential living-related LT and living-unrelated BMT. These patients are 10/9 years and 5/4 years post-LT/BMT. Human parvovirus B19 (HPV-B19) was established as the causative agent for FHF in both these patients by polymerase chain reaction. This report presents the first two cases associating HPV-B19 with FHF and AA who underwent sequential LT and BMT with excellent outcomes.

Incidence, risk factors, and outcomes associated with cytomegalovirus disease in small bowel transplant recipients.

Despite improved prophylaxis, monitoring, and more efficient immunosuppression, CMV infection remains a common opportunistic infection in transplant recipients. We assessed the incidence of CMV disease in pediatric SBT recipients, the timing of CMV disease after transplantation, and its impact on patient outcome. The medical records of 98 SBT recipients were reviewed. We performed descriptive analysis, regression analysis, and Kaplan-Meier curves to determine the time-to-event after transplantation. Fifty-three percent patients were male and 47% female, with a mean age of 38.3 months. Thirty-five percent of patients received prophylactic VGC, 55% GCV, 10% a combination of GCV/VGC, and 99% CMV immunoglobulins. A total of 24.5% recipients were CMV D+/R- (CMV serostatus donor positive/recipient negative). Seven (c. 7%) patients developed CMV disease. CMV disease was associated with 2.5 times (0.52-12.1; p = 0.25) higher rate of CMV mismatch and 11.1 times (1.3-95.9; p = 0.03) higher risk of death. CMV prophylaxis increased time-to-death (p = 0.074). Time-to-CMV disease was shorter in patients with enteritis (p < 0.0001), and CMV disease was associated with shorter time-to-death after transplantation (p = 0.001). CMV disease in SBT recipients was associated with an 11-fold mortality increase and a fourfold faster time-to-death. Time-to-death was significantly shorter with CMV enteritis.

Staphylococcus aureus infections after liver transplantation.

BACKGROUND: More data on the risk factors and outcomes after Staphylococcus aureus infections in liver transplantation are needed. METHODS: Liver recipients with S. aureus infections (cases) were retrospectively identified and compared to gender-, age-, and transplant type-matched (1:2) non-S. aureus-infected controls. Risk factors associated with S. aureus infections were identified by conditional logistic regression analysis. RESULTS: We evaluated 51 patients (median age 52 years). First S. aureus infections developed at a median time of 29 days after transplantation, with 52.94% of them in the first month; 88.24% were nosocomial, 41.18% were polymicrobial, and 47.06% were caused by methicillin-resistant S. aureus (MRSA). Surgical site infections represented 58.82% and bacteremia 23.53%. By univariate analysis, patients with S. aureus infections were intubated more frequently (odds ratio [OR] 26.92, 95% confidence interval [CI] 3.23-3,504.15, p = 0.0006), had a central line (OR 11.69, 95% CI 1.42-95.9, p = 0.02), or recent surgery (OR 26.92, 95% CI 3.23-3,504.15, p = 0.0006) compared with controls. By multivariate analysis, subjects who underwent surgery within 2 weeks prior to infection had a 26.9 times higher risk of developing S. aureus infection (95% CI 3.23-3,504.15, p = 0.0006); these results were adjusted for matched criteria. S. aureus infections did not affect graft or patient survival, but the study was not powered for such outcomes. CONCLUSION: Only recent surgical procedure was found to be a significant independent risk factor for S. aureus infections after liver transplantation.

The Declaration of Istanbul: review and commentary by the American Society of Transplant Surgeons Ethics Committee and Executive Committee.

The American Society of Transplant Surgeons (ASTS) was asked to endorse the 'The Declaration of Istanbul on Organ Trafficking and Transplant Tourism.' The document has been reviewed by the ASTS Ethics Committee and their ensuing report was presented, discussed and approved by the ASTS Council. The ASTS vigorously supports the principles outlined in the Declaration and details specific current obstacles to implementation of some of its proposals in the United States.

Inflammatory bowel disease after liver transplantation: risk factors for recurrence and de novo disease.

Inflammatory bowel disease (IBD) is associated with primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) and can recur or develop de novo after orthotopic liver transplantation (OLT). The aim of this study was to investigate the incidence and severity of IBD after liver transplantation and to perform a multivariate analysis for possible risk factors. In this retrospective study, 91 patients transplanted for PSC or AIH, without prior colectomy, were included. Sixty patients were transplanted for PSC, 31 for AIH. IBD activity before and after OLT and other possible risk factors were analysed in a multivariate model. Forty-nine patients (54%) had IBD before OLT. Forty patients (44%) had active IBD after transplantation: recurrence in 32 and de novo in 8. Cumulative risk for IBD after OLT was 15, 39 and 54% after 1, 5 and 10 years, respectively. In 59% of patients with IBD prior to OLT the disease was more active after transplantation. Risk factors for recurrent disease were: symptoms at time of OLT, short interval of IBD before OLT and use of tacrolimus. 5-aminosalicylates were protective. A cytomegalovirus positive donor/negative recipient combination increased the risk for de novo IBD.

Functional liver recovery parallels autologous gut salvage in short bowel syndrome.

BACKGROUND/PURPOSE: Parenteral nutrition (PN) is life saving in short bowel syndrome. However, long-term parenteral nutrition is frequently complicated by a syndrome of progressive cholestatic liver disease that is considered to be irreversible beyond the early stages of cholestasis, particularly in the presence of any degree of fibrosis in the liver. The purpose of this study was to examine apparent improvement in PN-associated liver dysfunction in a cohort of children with short bowel syndrome. METHODS: A retrospective case-record review of all patients managed within a dedicated Intestinal Rehabilitation Program (IRP) identified 13 patients with short bowel who had PN-associated liver dysfunction, defined for this purpose as hyperbilirubinemia or an abnormal liver biopsy. RESULTS: At referral, 12 of the 13 patients were exclusively on PN, and one was on 50% PN. At current follow-up, 3 patients have achieved complete enteral autonomy from PN, and 7 patients have had smaller decrements in PN requirements. Specific operative procedures to improve intestinal function were undertaken in 11 patients; 4 patients also underwent cholecystectomies with biliary irrigation at the time of intestinal reconstruction. The median highest bilirubin level in these 13 patients was 10.7 mg% (range, 3.2 to 24.5 mg%). Liver biopsy results indicated that 5 patients were cirrhotic, 3 had bridging fibrosis, and 4 had severe cholestasis or lesser degrees of fibrosis. Of 10 survivors in this series, 9 patients currently have a serum bilirubin less than 1 mg% with a median bilirubin in the group of 0.6 mg% (range, 0.3 to 6.4 mg%). Twelve of the 13 patients in this series were initially referred for liver-small bowel transplantation. CONCLUSIONS: This preliminary experience suggests that PN-dependent patients with advanced liver dysfunction in the setting of the short bowel syndrome may, in some instances, experience functional and biochemical liver recovery. The latter appears to parallel autologous gut salvage in most cases. As a corollary, the authors believe that even advanced degrees of liver dysfunction should not preclude attempts at autologous gut salvage in very carefully selected patients. Such a policy of "aggressive conservatism" may help avoid the need for liver/intestinal transplantation in some patients who appear to be not responding to PN.

The interaction defect of accessory molecules is responsible for the poor ex vivo response to human antigens of mouse T helper cells.

Mouse T cells fail to respond to xenogeneic pig and human antigens using the direct antigen-presenting pathway. The poor response by mouse CD8 cells is because of multiple defects in the molecular interactions between mouse CD8 cells and xenogeneic antigen-presenting cells (APCs). Using human CD4/DR3+, mouse CD4-/major histocompatibility complex (MHC) class II - mice, we investigated the defects in molecular interaction responsible for the poor response to xenogeneic antigens by naïve mouse CD4+ cells. Mouse CD4 cells failed to respond to human leucocyte antigen (HLA)-DR3 expressed on mouse APCs but developed a strong response to alloantigens, indicating a defect in the interaction between mouse CD4 and HLA-DR3 molecules. Human CD4+/mouse CD4- mouse T cells respond poorly to human and pig APCs but not allogeneic APCs, indicating that accessory molecular interactions are deficient across highly separated species. Adding mouse interleukin-2 (IL-2) to the mixed lymphocyte reaction system did not improve the poor response to human or pig antigens by mouse or human CD4+/mouse CD4- mouse T cells. Therefore, multiple molecular interactions deficient between mouse CD4 cells and human or pig APCs may lead to the poor response to xenogeneic antigens by naïve mouse CD4 cells.

Late graft loss and long-term outcome after isolated intestinal transplantation in children.

BACKGROUND/PURPOSE: The aim of this study was to determine causes of late graft loss and long-term outcome after isolated intestinal transplantation in children at a single center. METHODS: All children who underwent primary isolated intestinal transplantation at our center with a minimum follow-up of 1 year were the subject of this retrospective study. RESULTS: Twenty-eight children underwent primary isolated intestinal transplantation. Median graft survival was 705 days (range, 0 to 2,630 days) and median patient survival was 1,006 days (range, 0 to 2,630 days). There were 6 deaths and 15 graft losses (including the 6 nonsurvivors). Seven of the losses occurred 6 or more months after transplant. Of these, 2 losses occurred because of death of the recipients of sepsis; both recipients had functioning grafts. The 5 remaining late graft losses occurred because of acute rejection in 2 patients, chronic rejection in 2 (1 with concomitant acute rejection) and a diffuse stricturing process without the histologic hallmarks of chronic rejection in the fifth. All late survivors with intact grafts are off total parenteral nutrition (TPN). CONCLUSIONS: Late graft loss remains a concern in a small percentage of patients after isolated intestinal transplantation. Nutritional autonomy from TPN is possible in the majority of these children after transplantation.

A new technique for combined liver/small intestinal transplantation.

The most common application of small bowel transplantation is for the patient with parenteral nutrition-induced liver failure. In this setting, the small intestine is transplanted simultaneously with the liver. We identified three technical problems that we believe contributed to complications in our first eight patients. First, pancreaticoduodenectomy was challenging in the infant donor. Second, the bowel graft was prone to volvulus around the skeletonized donor portal vein. Third, in the pediatric recipient, use of the donor bowel for Roux-en-Y biliary reconstruction was associated with biliary leaks in the early postoperative period. Our surgical technique of liver/small bowel (L/SB) transplantation has evolved since our early experience in 1990. Modifications in the L/SB operation, reported briefly in 1996 and 1997, have led to easier graft preparation and have reduced the incidence of technical complications.

Lack of utility of intestinal fatty acid binding protein levels in predicting intestinal allograft rejection.

INTRODUCTION: The enterocyte-specific protein, intestinal fatty acid binding protein (I-FABP), is detectable in serum only after intestinal injury. Previous studies in animals suggest that I-FABP might be a useful marker of intestinal allograft rejection. MATERIALS AND METHODS: I-FABP was repetitively measured in nine intestinal transplant recipients and correlated with findings of surveillance endoscopy. RESULTS: Average interval between I-FABP determination and biopsy was 3.4 days (SD=4.2 days). Average number of rejection episodes per patient totalled 1.6+/-1.2. General linear modeling demonstrated no tendency for increases in serum FABP to precede histologic graft rejection (P=0.263). Restriction of the analysis to I-FABP determinations 1 day before or on the day of biopsy failed to affect these results. Minor increases in I-FABP were often associated with histologically normal grafts, whereas rejection often occurred when I-FABP was not detectable. DISCUSSION: Serum I-FABP levels do not predict clinical intestinal allograft rejection.

Indications for pediatric intestinal transplantation: a position paper of the American Society of Transplantation.

Parenteral nutrition represents standard therapy for children with short bowel syndrome and other causes of intestinal failure. Most infants with short bowel syndrome eventually wean from parenteral nutrition, and most of those who do not wean tolerate parenteral nutrition for protracted periods. However, a subset of children with intestinal failure remaining dependent on parenteral nutrition will develop life-threatening complications arising from therapy. Intestinal transplantation (Tx) can now be recommended for this select group. Life-threatening complications warranting consideration of intestinal Tx include parenteral nutrition-associated liver disease, recurrent sepsis, and threatened loss of central venous access. Because a critical shortage of donor organs exists, waiting times for intestinal Tx are prolonged. Therefore, it is essential that children with life-threatening complications of intestinal failure and parenteral nutrition therapy be identified comparatively early, i.e. in time to receive suitable donor organs before they become critically ill. Children with liver dysfunction should be considered for isolated intestinal Tx before irreversible, advanced bridging fibrosis or cirrhosis supervenes, for which a combined liver and intestinal transplant is necessary. Irreversible liver disease is suggested by hyperbilirubinemia persisting beyond 3-4 months of age combined with features of portal hypertension such as splenomegaly, thrombocytopenia, or prominent superficial abdominal veins; esophageal varices, ascites, and impaired synthetic function are not always present. Death resulting from complications of liver failure is especially common during the wait for a combined liver and intestinal transplant, and survival following combined liver and intestinal Tx is probably lower than following an isolated intestinal transplant. The incidence of morbidity and mortality following intestinal Tx is greater than that following liver or kidney Tx, but long-term survival following intestinal Tx is now at least 50-60%. It is probable that outcomes shall improve in the future with continued refinements in operative technique and post-operative management, including immunosuppression.

Extracorporeal liver perfusion using human and pig livers for acute liver failure.

BACKGROUND: Patients with fulminant hepatic failure (FHF) often die awaiting liver transplantation. Extracorporeal liver perfusion (ECLP) has been proposed as a method of "bridging" such patients to transplantation. We report the largest experience to date of ECLP using human and porcine livers in patients with acute liver failure. METHODS: Patients with FHF unlikely to survive without liver transplantation were identified. ECLP was performed with human or porcine livers. Patients underwent continuous perfusion until liver transplantation or withdrawal of support. Two perfusion circuits were used: direct perfusion of patient blood through the extracorporeal liver and indirect perfusion with a plasma filter between the patient and the liver. FINDINGS: Fourteen patients were treated with 16 livers in 18 perfusion circuits. Nine patients were successfully "bridged" to transplantation. ECLP stabilized intracranial pressure (ICP) and cerebral perfusion pressure (CPP). Arterial ammonia levels fell from a median of 146 to 83 micromol/liter within 12 hr and this reduction was maintained at least 48 hr. Pig and human ECLP lowered ammonia levels equally. Serum bilirubin levels also fell from a median of 385 to 198 micromol/liter over the first 12 hr but the response was not sustained as well with porcine livers. There was no immunological benefit to using the the filtered perfusion circuit. INTERPRETATION: These data demonstrate that ECLP is safe and can provide metabolic support for comatose patients with fulminant hepatic failure for up to 5 days. While labor and resource intensive, this technology is available to centers caring for patients with acute liver failure and deserves wider evaluation and application.

Characterization of an outbreak due to extended-spectrum beta-lactamase-producing Klebsiella pneumoniae in a pediatric intensive care unit transplant population.

Limited information exists regarding Klebsiella pneumoniae's production of an extended-spectrum beta-lactamase (KP-ESBL) in pediatric patients, particularly solid-organ transplant recipients. This study characterized the microbiological, epidemiological, and clinical features of a KP-ESBL outbreak in children receiving a liver transplant, an intestinal transplant, or both. All children found to have microbiologically confirmed K. pneumoniae during a 21-month period were reviewed. ESBL production was defined by double-disk diffusion, and 6 distinct pulsed-field gel electrophoresis patterns were identified. Fifty-six percent of the transplant patients we studied developed KP-ESBL, representing 87% of all microbiologically confirmed cases at our institution. As compared with 16 control transplant patients who were negative for KP-ESBL, the 20 transplant patients who acquired KP-ESBL were younger (aged < or = 5 years; 80.0% vs. 43.8%, P = .038) and experienced placement of > or = 3 central venous catheters before recovery of the first K. pneumoniae isolate (73.7% vs. 18.8%, P = .002). This study suggests that children who receive liver or intestinal transplants are at high risk for KP-ESBL acquisition.