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.

Tailored eculizumab therapy in the management of complement factor H-mediated atypical hemolytic uremic syndrome in an adult kidney transplant recipient: a case report.

Atypical hemolytic uremic syndrome (aHUS) is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury (AKI) which frequently progresses to end-stage renal disease (ESRD). In 50% of affected patients, mutations in complement regulatory proteins cause inappropriate complement activation with endothelial injury. Complement factor H (CFH) mutations cause 25% of aHUS cases; these patients have an 80% recurrence risk after kidney transplantation. Eculizumab, an anti-C5 antibody, is effective in limiting hemolysis episodes in patients with aHUS, but less is known about preventing recurrence after kidney transplantation. Herein we report the use of prophylactic eculizumab in an adult with aHUS who underwent kidney transplantation. A 31-year-old female presented with aHUS and progressive AKI associated with low complement 3 level leading to ESRD despite plasmapheresis and corticosteroids. She had a heterozygous nonsense mutation in CFH and reduced plasma CFH levels. She was given preoperative plasmapheresis and eculizumab and underwent living unrelated renal transplantation. Postoperatively, eculizumab was dosed to achieve low functional complement 5 levels and low soluble membrane attack complex levels and she has maintained excellent graft function without aHUS recurrence. We propose that eculizumab with titrated dosing should be used in CFH-mediated aHUS patients who are at a high risk of recurrence.

Case report: Eculizumab rescue of severe accelerated antibody-mediated rejection after ABO-incompatible kidney transplant.

ABO-incompatible (ABOI) living donor kidney transplantation has become a well-accepted practice with standard protocols using perioperative antibody-depleting therapies to lower blood group titers to an acceptable threshold for transplantation. However, a subset of patients will experience accelerated antibody-mediated rejection (AMR) after ABOI kidney transplantation and require aggressive intervention to prevent allograft loss. Here in we report the successful use of terminal complement inhibition with eculizumab to rescue an ABOI kidney allograft with accelerated AMR refractory to salvage splenectomy and daily plasmapheresis. This case emphasizes the fact that, despite close postoperative surveillance and aggressive intervention, graft loss from accelerated AMR after ABOI kidney transplantation remains a very real risk. Eculizumab may offer a graft-saving therapeutic option for isolated cases of severe AMR after ABOI kidney transplantation refractory to standard treatment.

Report of a consensus conference on transplant program quality and surveillance.

Public reports of organ transplant program outcomes by the US Scientific Registry of Transplant Recipients have been both groundbreaking and controversial. The reports are used by regulatory agencies, private insurance providers, transplant centers and patients. Failure to adequately adjust outcomes for risk may cause programs to avoid performing transplants involving suitable but high-risk candidates and donors. At a consensus conference of stakeholders held February 13-15, 2012, the participants recommended that program-specific reports be better designed to address the needs of all users. Additional comorbidity variables should be collected, but innovation should also be protected by excluding patients who are in approved protocols from statistical models that identify underperforming centers. The potential benefits of hierarchical and mixed-effects statistical methods should be studied. Transplant centers should be provided with tools to facilitate quality assessment and performance improvement. Additional statistical methods to assess outcomes at small-volume transplant programs should be developed. More data on waiting list risk and outcomes should be provided. Monitoring and reporting of short-term living donor outcomes should be enhanced. Overall, there was broad consensus that substantial improvement in reporting outcomes of transplant programs in the United States could and should be made in a cost-effective manner.

Case report: successful treatment of recurrent focal segmental glomerulosclerosis with a novel rituximab regimen.

Focal segmental glomerulosclerosis (FSGS) is the cause of renal failure in more than 10% of pediatric patients undergoing renal transplantation. Recurrent FSGS is a major cause of pediatric allograft failure, with the risk increasing for patients undergoing retransplantation. Standard therapy for recurrent posttransplantation FSGS includes the use of intensive plasmapheresis (PP) in conjunction with cyclophosphamide or high-dose cyclosporine. However, many patients exhibit refractory disease, with rapid progression to allograft loss despite these interventions. Prior studies have reported conflicting data on the efficacy of adding rituximab therapy to the standard treatment regimen for recurrent posttransplantation FSGS. Here we present a successful therapeutic protocol with rapid elimination of PP after initiation of rituximab therapy for an adolescent patient with recurrent FSGS in the immediate postoperative period. The patient has maintained excellent allograft function through 12 months posttransplantation.

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.

Stimulus for organ donation: a survey of the American Society of Transplant Surgeons membership.

Federal legislation has been proposed to modify the National Organ Transplant Act in a way that would permit government-regulated strategies, including financial incentives, to be implemented and evaluated. The Council and Ethics Committee of the American Society of Transplant Surgeons conducted a brief web-based survey of its members' (n = 449, 41.6% response rate) views on acceptable or unacceptable strategies to increase organ donation. The majority of the membership supports reimbursement for funeral expenses, an income tax credit on the final return of a deceased donor and an income tax credit for registering as an organ donor as strategies for increasing deceased donation. Payment for lost wages, guaranteed health insurance and an income tax credit are strategies most strongly supported by the membership to increase living donation. For both deceased and living donation, the membership is mostly opposed to cash payments to donors, their estates or to next-of-kin. There is strong support for a government-regulated trial to evaluate the potential benefits and harms of financial incentives for both deceased and living donation. Overall, there is strong support within the ASTS membership for changes to NOTA that would permit the implementation and careful evaluation of indirect, government-regulated strategies to increase organ donation.

A "weight-listing" paradox for candidates of renal transplantation?

Research suggests that end-stage renal disease patients with elevated body mass index (BMI) have superior outcomes on dialysis. In contrast, low and high BMI patients represent the highest risk cohorts for kidney transplant recipients. The important question remains concerning how to manage transplant candidates given the potentially incommensurate impact of BMI by treatment modality. We conducted a retrospective analysis of waitlisted and transplanted patients in the United States from 1990 to 2003. We constructed Cox models to evaluate the effect of BMI on mortality of waitlisted candidates and identified risk factors for rapid weight change. We then assessed the impact of weight change during waitlisting on transplant outcomes. Decline in BMI on the waiting list was not protective for posttransplant mortality or graft loss across BMI strata. Substantial weight loss pretransplantation was associated with rapid gain posttransplantation. The highest risk for death was among listed patients with low BMI (13-20 kg/m(2), adjusted hazard ratio = 1.47, p < 0.01). Approximately one-third of candidates had a change in BMI category prior to transplantation. While observed declines in BMI may be volitional or markers of disease processes, there is no evidence that candidates have improved transplant outcomes attributable to weight loss. Prospective trials are needed to evaluate the efficacy of weight loss protocols for candidates of kidney transplantation.

Clinical and financial impact of obesity on the outcome of liver transplantation.

The purpose of this study was to determine whether body mass index (BMI) influences the clinical outcomes and overall cost of transplantation in adult liver transplantation (OLT) using records of 700 adult OLT recipients. Patients were divided into BMI range groups over the range of 15 to 42 (mean = 26.7), namely: <25, n = 288 (41%); 25 to 30, n = 245 (35%); > or =30, n = 167 (24%). Only a small subset of this last group was morbidly obese (BMI > or = 35, n = 37, 5% of total). We did not detect an effect of BMI on patient or graft survival, the incidence of acute graft rejection, or major surgical complications. BMI was not related to length of hospital stay. There were no statistical differences between the three groups with respect to the ratio of overall hospital cost in a general linear model, corrected for age, gender, calculated Model for End-Stage Liver Disease score, retransplant status, or return to the operating room. In conclusion, obesity did not influence either the costs or the clinical outcomes following OLT. Further analysis of the morbidly obese population with respect to cost and outcome is warranted.

Effect of early recurrence of hepatitis C on late biliary anastomotic stricture after liver transplantation.

The aim of the current study was to clarify whether recurrence of hepatitis C (HCV) infection affects biliary complications after liver transplantation (OLT), with special reference to late biliary anastomotic strictures (LBAS). We reviewed 665 consecutive adult OLT recipients with a choledochocholedochostomy without T-tube placement between 1990 and 2005. Biliary anastomotic stricture was confirmed by ERCP. The LBAS was defined as stricture that occurred 30 days or more after OLT. Recurrence of HCV was diagnosed by histological examination using liver biopsy specimen and confirmed by the presence of HCV-RNA. Early HCV recurrence was defined as recurrence that occurred within 6 months after OLT; LBAS occurred in 54 patients (8% of total). Mean duration from OLT to occurrence of LBAS was 6.9 months (1-44 months). Patients with HCV infection had higher occurrence of LBAS than did non-HCV patients (11% vs 5%, P = .0093). Among HCV patients, those with early HCV recurrence had exclusively high rate of LBAS (16%). In multivariate analyses, early recurrence of HCV (P < .001, relative risk [RR] 6.4), as well as occurrence of HAT (P = .0018, RR 8.0), and prolonged CIT (P = .034, RR 3.3) were independent risk factors affecting LBAS. In conclusion, patients with HCV infection have increased occurrence of LBAS after OLT. Additionally, early recurrence of HCV contributes to a higher rate of LBAS.

Liver transplantation for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the commonest malignancies worldwide, and accounts for more than 1 million deaths annually. Identification of tumors early in the course of disease appears to be important for treatment, yet remains difficult to accomplish. Without treatment the prognosis is dismal with a median survival of 6-9 months. Partial hepatic resection is generally accepted as the treatment of choice for HCC with reported survival rates of up to 50% at 5 years. Unfortunately poor underlying liver function as well as tumor number or location preclude traditional hepatic resection in many cases. Total hepatectomy with transplantation (LT) has been advocated such cases, but the results have been variable. LT offers the advantage of radical tumor removal even in patients with multifocal disease or severe cirrhosis. Additionally, LT removes the possibility of metachronous lesions developing in the liver remnant and restores normal liver function. The critical limitation to advocating LT as primary oncotherapy in patients with HCC is the severe shortage of donor livers. Until organ availability improves, transplantation for HCC can only be offered to patients whose survival is predicted to be similar to that in patients transplanted for benign disease. This report reviews the current role and indications for liver transplantation as therapy for hepatocellular carcinoma.

Resection of the inferior vena cava for hepatic malignancy.

Involvement of the inferior vena cava (IVC) by hepatic tumors, although uncommon, is considered to be unresectable by standard surgical techniques. Recent advances in hepatic surgery have made combined hepatic and vena caval resection possible. The purpose of this study is to describe the surgical techniques and early results of combined resection of the liver and IVC. From 1997 to 2000, 11 patients underwent resection of the IVC along with four to seven liver segments. Resections were carried out for hepatocellular carcinoma (four); colorectal metastases (four); and hepatoblastoma, gastrointestinal stromal tumor metastases, and squamous cell carcinoma in one patient each. Ex vivo procedures were performed twice, and total vascular isolation was used in the nine other cases. The IVC was reconstructed with ringed Gore-Tex tube graft (five), primarily (five), or with Gore-Tex patches (one). There were two early deaths: one from liver failure at 3 weeks and one from sepsis secondary to a perforated segment of small bowel 4 months postresection. One patient with a gastrointestinal stromal tumor died at 32 months of recurrent tumor and one patient with hepatocellular carcinoma is alive with recurrent tumor at 16 months. The remaining patients are alive and disease free with follow-up ranging from 3 to 40 months without evidence of IVC occlusion. Combined resection of the liver and IVC is a formidable undertaking with substantial surgical risk. However, this aggressive surgical approach offers a chance for cure in patients with tumors involving the IVC that would otherwise have a dismal prognosis.

Graft survival in pediatric liver transplantation.

BACKGROUND/PURPOSE: Liver transplantation is standard therapy for children with a variety of liver diseases. The current shortage of organ donors has led to aggressive use of reduced or split grafts and living-related donors to provide timely liver transplants to these children. The purpose of this study is to examine the impact of these techniques on graft survival in children currently treated with liver transplantation. METHODS: Data were obtained on all patients less than 21 years of age treated with isolated liver transplants performed after January 1, 1996 in an integrated statewide pediatric liver transplant program, which encompasses 2 high-volume centers. Nonparametric tests of association and life table analysis were used to analyze these data (SAS v 6.12). RESULTS: One hundred twenty-three children received 147 grafts (62 at the University of Florida, 85 at the University of Miami). Fifty-two (36%) children were less than 1 year of age at time of transplant, and 80 (55%) were less than 2 years of age. Patient survival rate was identical in the 2 centers (1-year actuarial survival rate, 88.4% and 87.1%). Twenty-five (17%) grafts were reduced, 28 (19%) were split, 6 were from living donors (4%), and 88 (60%) were whole organs. One-year graft survival rate was 80% for whole grafts, 71.6% for reduced grafts, and 64.3% for split grafts (P =.06). Children who received whole organs (mean age, 6.1 years) were older than those who received segmental grafts (mean age, 2.5 years; P <.01). Multifactorial analysis suggested that patient age, gender, and use of the graft for retransplant did not influence graft survival, nor did the type of graft used influence patient survival. CONCLUSIONS: The survival rate of children after liver transplantation is excellent independent of graft type. Use of current techniques to split grafts between 2 recipients is associated with an increased graft loss and need for retransplantation. Improvement in graft survival of these organs could reduce the morbidity and cost of liver transplantation significantly in children.

What happens to renal transplant recipients who lose their grafts?

Little attention has been given to the fate of patients who lose their grafts. We reviewed outcomes of 438 recipients of first renal allografts who underwent transplantation at our institution between January 1, 1988, and December 31, 1997, and lost their grafts or died with a functioning transplant. Of the 438 patients, 168 patients died with a functioning transplant. The most common causes of death were cardiac disease, infection, and cancer. Patients who died with a functioning graft were older (>49 years, 64.3%) than patients who died after returning to dialysis therapy or who are still alive (>49 years, 25.9%). Eighty-six patients (39%) who returned to dialysis therapy were again placed on a cadaveric waiting list. Only 44 patients received a second transplant, of which 30 transplants (68.2%) are still functioning. Our study shows that relatively few patients who lose kidney transplants are returned to the cadaveric waiting list and even fewer undergo retransplantation.

Outcome of kidney transplants in patients known to be flow cytometry crossmatch positive.

BACKGROUND: The clinical significance of the flow cytometry crossmatch has been addressed in several retrospective studies, but the results have been controversial. There are no prospective studies in which patients known to be antibody positive underwent transplantation. METHODS: The flow cytometry crossmatch was performed prospectively in 1130 renal transplant recipients. A decision to perform transplantation was based on whether the positive results were on T or B cells, in the current or peak specimen, and taking into account the presence or absence of other immunological risk factors. One hundred antibody-positive patients received a transplant. Graft survival and rejection episodes were analyzed in this group and compared with 100 crossmatch-negative patients matched for age, sex, race, and time of transplantation. RESULTS: The incidence of rejection at 1 month was higher in antibody-positive patients (26%) than in antibody-negative patients (12%, P<0.01). Early rejection seemed to be more frequent in antibody-positive patients regardless of whether the antibodies were current or historic, or against T or B cells. There were more steroid-resistant rejections in antibody-positive than in antibody-negative patients. However, biopsy specimens showed that vascular lesions that can be associated with humoral rejection were not more frequent in the antibody-positive patients than in the controls. There were no differences in graft survival between the two groups. CONCLUSIONS: Low-level preformed alloantibodies detected by flow cytometry represent a risk of rejection even for patients purposely selected for having no additional immunological risk factors. The risk seems to be due to donor-specific memory rather than to a direct effect of the antibodies. The results indicate that flow cytometry provides useful information to assess donor-recipient compatibility.

Liver transplantation for hepatocellular carcinoma.

OBJECTIVE: To analyze patient and tumor characteristics that influence patient survival to select patients who would most benefit from liver transplantation. SUMMARY BACKGROUND DATA: The selection of patients with hepatocellular carcinoma (HCC) for liver transplantation remains controversial. METHODS: One hundred twelve patients with nonfibrolamellar HCC who underwent a liver transplant from 1985 to 2000 were reviewed. Survival was calculated using the Kaplan-Meier method, with differences in outcome assessed using the log-rank procedure. Multivariate analysis was then performed using a Cox regression model. RESULTS: Overall patient survival rates were 78%, 63%, and 57% at 1, 3, and 5 years, respectively. Patients infected with the hepatitis B virus had a worse 5-year survival than those who were not (43% vs. 64%), with most deaths being attributed to recurrent hepatitis B. However, patients with hepatitis B virus who underwent more recent transplants using antiviral therapy fared as well as those who were negative for the virus, showing a 5-year survival rate of 77%. Patients with vascular invasion by tumor had a worse 5-year survival than patients without vascular invasion (33% vs. 68%). Vascular invasion, tumor size greater than 5 cm, and poorly differentiated tumor grade were predictors of tumor recurrence by univariate analysis; however, only vascular invasion remained significant on multivariate analysis: the rate of tumor recurrence at 5 years was 65% in patients with vascular invasion and only 4% for patients without vascular invasion. CONCLUSIONS: For well-selected patients with HCC, liver transplantation in the current era can achieve equivalent results to transplantation for nonmalignant indications. Vascular invasion is an indicator of high risk of tumor recurrence but is difficult to detect before transplantation.

Susceptibility of liver allografts to high or low concentrations of preformed antibodies as measured by flow cytometry.

Liver grafts are more resistant to damage by HLA antibodies than other organ allografts, but it is not clear if the antibodies are associated with graft rejection or graft loss, or if different antibody concentrations have different effects. To explore potential associations between antibody concentrations and outcome, preformed IgG antibodies against donor cells were quantified by flow cytometry in 465 consecutive liver transplant recipients. Antibody-positive patients were classified according to whether they had high or low antibody concentrations and analyzed for possible correlation with graft rejection or graft loss. The results showed that the incidence of rejection was not significantly different between antibody-positive and negative patients. However, patients with high antibody concentrations had a higher incidence of steroid-resistant rejections (31% at 1 year) than patients with low antibody (4%) or no antibody (8%, p < 0.0004). These effects were mainly due to T-cell (HLA class 1) antibodies. The overall incidence of rejection at 1 year was 69% for high antibody patients, 51% for patients with low antibodies and 53% for patients with no antibodies (p not significant). In an apparent paradox, antibody-positive patients underwent fewer early graft losses. Thus, the associations of preformed antibodies and outcome depend, on the one hand, on antibody concentrations, and on the other hand on whether the outcome measured is steroid-sensitive rejection, steroid-resistant rejection or graft survival. These complex interactions may explain the controversial results observed in previous studies.