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.

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.

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.

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.

The spectrum of Pneumocystis carinii infection after liver transplantation in children.

We report the experience with Pneumocystis carinii lung infections in the 109 children undergoing liver transplantation at our hospital between August, 1985 and May, 1989. PCP developed in 9 of the 86 patients (10%) surviving > or = 6 weeks after transplantation and not receiving P carinii chemoprophylaxis. Of the 59 patients undergoing BAL 2 or more weeks after transplantation there were 16 specimens from 14 patients (24%) positive for P carinii. These patients had a spectrum of illness ranging from asymptomatic to severe pneumonia requiring mechanical ventilation. The mean interval from first transplantation to bronchoalveolar lavage positive for P carinii was 24.9 weeks and the mean interval to first PCP was 28.0 weeks. The earliest and latest occurrences of PCP were 7 weeks and 73 weeks, respectively, after transplantation. There were no complications attributed to BAL.

Procurement and preparation of human isolated small intestinal grafts for transplantation.

We have developed a donor operation that incorporates en bloc removal of the liver and intestine with a limited surgical resection in vivo. Over the past 18 months, we have used the following technique for the retrieval and preparation of seven isolated small intestinal allografts. The donor operation and bench preparation can be divided into three phases. During the first phase, the small intestine is removed with the liver, pancreas, and an aortic segment. In the second phase performed ex vivo, the donor liver can be separated from the specimen. The third phase involves additional bench dissection to yield an isolated intestinal allograft. The principle advantage of this technique is that it reduces potential liver injury by minimizing the surgical dissection required in vivo. Also, dividing the liver from the intestine ex vivo allows the organs to be separated in a bloodless field under controlled conditions that may be especially important when two different surgical teams are involved.

The viability of microorganisms in preservation solutions.

In 1988 the University of Wisconsin solution was introduced into clinical transplantation. This solution is unique in that it contains no glucose but rather raffinose, lactobionate, and hydroxyethyl starch. In addition, it contains two antibiotics, penicillin and bactrim. Prior studies have shown that other preservation solutions allow the transmission of bacterial contamination from organ donor to recipient. However, there are no data on whether UW solution, with its unique composition and extended preservation times, allows bacterial transmission. We undertook the present study to establish if bacteria remain viable in UW solution at extended preservation times. Cultures of both aerobic (Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa) and anaerobic (Bacteroides fragilis) bacteria were suspended at 10(5), 10(4), 10(2), and 10(1) org./ml (calibrated from a .5 Macfarland turbidity standard) in both Eurocollins and UW preservation solutions. Samples were then stored in an ice bath to stimulate organ preservation. The organisms were removed and plated on blood and chocolate agar at 0, 6, 12, 18, 24, and 36 hr postsuspension. The samples were then incubated at 37 degrees C and read for growth at 24-48 hr after plating. Our results showed growth of all organisms except S epi in both preservation solutions, at all dilutions and preservation times. S epi grew in the Eurocollins solution at all dilutions and preservation times but did not grow in the UW solution. When the experiment was repeated omitting penicillin from the UW solution, S epi grew at all dilutions and preservation times. These results demonstrate that in spite of the inclusion of two different antibiotics, the majority of the common bacterial contaminants of the organ donor remain viable in UW solution with extended preservation times. It may be possible therefore to omit these antibiotics from the UW solution and obtain similar results. It is also important to note that routine culturing remains an expensive but necessary part of organ procurement and preservation.

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.

Frozen section evaluation of donor livers before transplantation.

Frozen section examination was performed on 385 donor livers before transplantation. Exclusion criteria were applied to the donor livers examined to exclude potentially dysfunctional livers. The exclusion criteria included the following: severe macrovesicular steatosis, ischemic necrosis, prominent chronic portal inflammation, prominent periductular fibrosis, granulomatous inflammation, bridging fibrosis, and malignancy. Twenty-seven of the 385 donor livers examined were excluded before transplantation. The following histologic features were present in the excluded livers: severe steatosis (22), ischemic necrosis (2), portal inflammation (1), and periductular fibrosis (2). Steatosis was present in 51 of the 385 (13.25%) organs examined, including 22 of the donor organs excluded before transplantation. Twenty-nine livers with mild to moderate steatosis were implanted into size and blood type-matched recipients. Indicators of allograft function (prothrombin time and bilirubin) and damage (aspartate aminotransferase and alanine aminotransferase) were measured daily for the first 10 days after transplant. There was no statistically significant difference between the group of nonfat livers and donor livers containing mild steatosis. Statistically significant higher posttransplant serum alanine aminotransferase and prothrombin time levels were present in the patients with livers implanted with mild versus moderate steatosis. The 1-year survival rate for patients receiving fatty versus nonfatty donor livers was not statistically different (Kaplan-Meier, P = 0.592). No significant differences were found in the clinical and laboratory characteristics of donors whose organs were implanted compared with the clinical and laboratory characteristics of donors whose organs were excluded. The primary nonfunction rate after applying the exclusion criteria was 1.4%, which is a significant decrease compared with our primary nonfunction rate of 8.5% before using frozen section examination. Frozen section examination is useful in excluding donor organs which may become dysfunctional after transplantation.

Hepatic allograft rescue following arterial thrombosis. Role of urgent revascularization.

Hepatic artery thrombosis is a continuing source of morbidity and mortality following orthotopic liver transplantation. The cornerstone of therapy has been urgent retransplantation that is limited by organ availability. For this reason we developed a policy of urgent revascularization for allograft rescue. Hepatic artery thrombosis developed following 15 transplants of which 11 underwent urgent rearterialization. The diagnosis was made a mean of 4.8 days (range 1-10) following transplantation. Duplex ultrasonography was diagnostic in all patients and confirmed by angiography in 4 (36%). Three patients with hepatic artery thrombosis were identified following screening ultrasonography and were clinically unsuspected. Upon reexploration, a specific technical reason for hepatic artery was found in 4 patients (36%). Twelve arterial revascularization procedures were performed in 11 patients including: thrombectomy alone (n = 4); revision of anastomosis with thrombectomy (n = 5); and thrombectomy with placement of vascular conduit (n = 3). Following revascularization, 8 patients maintained hepatic artery patency. Three patients eventually required retransplantation secondary to biliary sepsis. Biliary tract complications developed in 6 patients, at a mean of 23 days following revascularization and included: breakdown of the biliary anastomosis (n = 4); stricture (n = 1); and sludge formation (n = 1). The overall graft and patient survival are 74% and 82% respectively, with a mean follow-up of 6.8 months. Hepatic allograft rescue with the use of urgent revascularization following hepatic artery thrombosis appears to be an effective means of either avoiding retransplantation or providing a bridge until a suitable donor becomes available.

Transfusion-induced graft-versus-host disease after liver transplantation. Documentation using polymerase chain reaction with HLA-DR sequence-specific primers.

Graft-versus-host disease (GVHD) occurring after liver transplantation can pose a difficult diagnostic dilemma. Similar clinical and pathologic skin and gastrointestinal manifestations can result from other causes (i.e., drugs, infections). Treatment for each of these entities differs, and the high mortality associated with GVHD makes this distinction critical. GVHD has been assumed to result from the cotransplantation of donor lymphoid tissue along with the allograft. In most instances, the patient also receives blood products during the operation, and occasionally during the postoperative period, and the lymphoid cells in these products are also a potential source of concern. In this report, we describe a patient who developed GVHD after liver transplantation. Using molecular diagnostic techniques, we determined that the source for this GVHD was not the organ donor, but was most likely nonirradiated blood products received during the hospital course. Our results suggest that transplant recipients with concomitant hematopoietic dysfunction would benefit from irradiated blood products to reduce the likelihood of this complication.

Combined liver/small bowel transplantation using a blood group compatible but nonidentical donor.

A successful liver/small intestinal transplantation with a blood group O donor to a blood type A recipient is described. Mild graft versus host disease developed, manifested by hemolysis, but did not result in graft loss or patient mortality. This suggests that minor ABO incompatibility may be tolerated with intestinal transplantation, despite the transplantation of large amounts of lymphoid tissue.

The results of reduced-size liver transplantation, including split livers, in patients with end-stage liver disease.

We initiated a policy of using RSLT in critically ill patients in June of 1988. Since that time we have performed 30 RSLTs in 29 patients, including 28 children and 1 adult. The mean age of the children was 27 months (range 1 month to 10 years) with 14 (52%) being 1 year of age or less. The mean weight was 11.3 kg (range 2-50 kg) with 20 being 10 kg or less. A total of 22 patients were in the intensive care unit at the time of RSLT including 9 who were intubated. Of the 30 RSLTs, 23 were performed as a primary transplant while 7 were retransplants. Indications for primary transplantation included biliary atresia (n = 11), fulminant hepatic failure (n = 5), neonatal hepatitis (n = 4) and others (n = 3). The RSLT was used in retransplantation for primary nonfunction (n = 2), hepatic artery thrombosis (n = 2), chronic rejection (n = 2), and herpetic hepatitis (n = 1). The size reductions included 18 left lobes, 7 left lateral segments, and 5 right lobes. This group includes the use of the split-liver technique, which was applied to 10 patients (5 livers). The median donor/recipient weight ratio for left lobe transplants was 2:1; left lateral segments was 7.3:1; and right lobes 1.6:1. One year actuarial patient and graft survivals were 68 and 65%, respectively, with a mean follow-up of 10.6 months. The number of children dying awaiting transplantation has been significantly reduced following the introduction of RSLD (3 of 115, 2.6% vs. 12 of 95, 13%; P less than 0.02).

A pilot study of soluble adhesion molecules as surrogate markers for acute liver allograft rejection.

BACKGROUND: Tissue endothelial adhesion molecule expression is increased during acute liver allograft rejection. Soluble forms exist, but their correlation to rejection and their clinical value have not been determined. METHODS: We studied endothelial adhesion molecule tissue expression and soluble levels in blood and bile and correlated these to the clinical course of 11 adult patients followed for 30 consecutive days after liver transplantation. RESULTS: Three biopsies showing acute rejection demonstrated increased intercellular adhesion molecule (ICAM)-1 but not endothelial leukocyte adhesion molecule-1 expression on hepatic endothelial cells during rejection. Vascular cell adhesion molecule (VCAM)-1 staining was focally increased in two of three specimens. Levels of soluble ICAM-1 or soluble VCAM-1 by ELISA did not distinguish acute rejection from nonrejection conditions. CONCLUSION: We confirmed that endothelial ICAM-1 expression is more intense in rejecting allografts and is more sensitive than changes in VCAM-1 or endothelial leukocyte adhesion molecule-1. However, soluble adhesion molecule determination was not useful in the accurate detection of acute rejection.

Successful prophylaxis of cytomegalovirus disease after primary CMV exposure in liver transplant recipients.

UNLABELLED: During a 38-month period, we studied 320 liver transplants in 283 recipients (202 adults, 81 children). CMV disease was documented in 85 patients (30.0%) The major risk factor for CMV disease was primary CMV exposure (transplanting a seropositive allograft into a seronegative recipient). A total of 42 patients (14.8%) had primary CMV exposure. Twenty-one patients were historical controls, while the next 21 received prophylaxis for CMV infection in a nonrandomized trial of consecutive study groups. The regimen of prophylaxis consisted of intravenous immune globulin (IgG; 0.5 g/kg) at weekly intervals for 6 weeks and acyclovir for 3 months. CMV prophylaxis resulted in a dramatic reduction in the incidence of CMV disease (71.4% vs. 23.8%, (P less than 0.01). All cases of CMV were treated with intravenous ganciclovir (5 mg/kg b.i.d. for 14 days), with 5 patients in the control group developing recurrent CMV disease (33.3% relapse). In the 16 patients receiving prophylaxis who did not develop CMV disease, all developed positive CMV-IgG titers with the passive administration of IgG. However, none developed any evidence of CMV infection or viral shedding as assessed by IgM titers and surveillance viral cultures. Four deaths occurred (all control patients), but none were related to CMV disease. Overall patient and graft survivals after primary CMV exposure were 90.5% and 82.2%, respectively, after a mean follow-up of 14 months. CONCLUSION: Primary CMV exposure is a major risk factor for CMV disease in liver transplant recipients. Intravenous IgG plus acyclovir is safe and effective in preventing CMV infection and disease in this setting. Because of the scarcity of donor organs, we do not advocate protective matching to avoid primary CMV exposure but rather recommend prophylaxis to prevent CMV disease in this high-risk group.

The impact of extended preservation on clinical liver transplantation.

The introduction of UW solution into clinical transplantation has permitted extended cold storage preservation of the liver. Over a 46-month period, we have performed 308 orthotopic liver transplants (266 primary, 42 retransplants) in 266 recipients. Our experience is divided into cold-storage preservation in Eurocollins (163 transplants in 140 recipients) and UW (145 transplants in 131 recipients) solutions. Donor and recipient factors were comparable between the two groups. The use of UW solution has permitted an increase in the mean preservation time from 5.2 +/- 1.0 [EC] to 12.8 +/- 4.3 [UW] hr (P less than 0.001). The mean total operating time was reduced but intraoperative blood loss was unchanged with UW preservation. The number of transplants performed during the daytime hours has increased dramatically (21.5% [EC] vs. 71% [UW], P less than 0.001). The incidence of primary nonfunction, hepatic artery thrombosis, 1-month graft survival, and early retransplantation were similar in the 2 groups. Initial allograft function as determined by bile production, histology, and clinical assessment were likewise similar. Mean serum bilirubin, transaminase, and prothrombin levels were virtually identical by 5 days posttransplant. The enhanced margin of safety afforded by extended preservation has increased the capability for distant organ procurement and sharing, minimized organ wastage, and improved the efficiency of organ retrieval. With the relaxation of logistical constraints, our rate of liver import has nearly doubled (20.9% [EC] vs. 39.3% [UW], P less than 0.001). Extended preservation has permitted the development of reduced-size liver grafting (n = 12), resulting in a significant reduction in the number of deaths occurring while awaiting transplantation. Therefore, we advocate the use of UW solution with selective extension of preservation based not only on donor and recipient factors but also on manpower, resource, and logistical considerations.

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.

Recipient selection and evaluation for vascularized pancreas transplantation.

Vascularized pancreas transplantation (PT) is becoming an accepted therapy for selected type I diabetic patients. However, selection and evaluation criteria remain uncertain. In the last 3.5 years, we have interviewed 205 and evaluated 151 diabetic patients for PT. The degree of renal dysfunction (creatinine clearance below 45 ml/min) was used to select patients for combined pancreas-kidney transplantation (PKT) or solitary pancreas transplantation (PTA) (clearance above 70 ml/min). The cardiovascular evaluation (stress thallium study with liberal use of coronary angiography) was used to determine operative risk and provided the other major selection criterion. A total of 104 patients were selected as candidates for PT; 70 have undergone PKT with 98.6% patient survival (1 cardiovascular death), 97.1% kidney graft survival, and 94.2% pancreas graft survival. Thirty-three evaluated patients (24.1%) were not accepted as candidates for PT; 13 have undergone cadaveric kidney transplantation, 5 were placed on the kidney waiting list, and 9 have died. Criteria for PTA include 2 or more diabetic complications or hyperlabile diabetes. Patient (n = 12) and pancreas graft survival after PTA is 83.3 and 50%, respectively. Our conclusion is that a multidisciplinary approach was used for recipient selection for PT based on degree of nephropathy, cardiovascular risk, and presence of diabetic complications. Nearly 75% of diabetic patients evaluated were acceptable candidates for PT. Only 4 (3.8%) of these selected patients died while awaiting or undergoing PT, thus optimizing the use of scarce allograft resources and providing evidence for appropriate patient selection.

Effect of surrogate tolerogenesis on the vascular rejection of pig heart xenografts.

BACKGROUND: Organ xenografts are fulminantly rejected by antibody-mediated vascular rejection. Surrogate tolerogenesis (ST), the induction of tolerance within the donor, is effective with aorta xenografts. This preliminary study assesses the effect of ST on preformed antibodies and rejection of porcine heart xenografts. METHODS: Tolerance to the donor pig was induced by infusing recipient marrow into fetal pigs. Later, pig splenocytes were transfused and heterotopic pig hearts transplanted using chimeric or nonchimeric pigs. Anti-pig antibodies were assessed. RESULTS: With ST alone, xenografts developed cellular rejection at 4-6 days, whereas control grafts developed vascular rejection at 3-4 days (cellular vs. vascular, P<0.03). There was a reduction in preformed antibodies (P<0.03). ST combined with moderate cyclosporine prevented rejection at 9+ and 25 days in sensitized recipients compared with vascular rejection at 0.5-2 days for controls (P<0.07). CONCLUSIONS: ST seems to provide protection against vascular rejection. The cellular rejection seems sensitive to cyclosporine.