Hepatic Hilar Lymph Node Reactivity at Kasai Portoenterostomy for Biliary Atresia: Correlations With Age, Outcome, and Histology of Proximal Biliary Remnant.

We hypothesized that if infection is the proximate cause of congenital biliary atresia, an appropriate response to antigen would occur in lymph nodes contiguous with the biliary remnant. We compared the number of follicular germinal centers (GC) in 79 surgically excised hilar lymph nodes (LN) and 27 incidentally discovered cystic duct LNs in 84 subjects at the time of hepatic portoenterostomy (HPE) for biliary atresia (BA) to autopsy controls from the pancreaticobiliary region of non-septic infants >3 months old at death. All 27 control LN lacked GC, a sign in infants of a primary response to antigenic stimulation. GC were found in 53% of 106 LN in 56 of 84 subjects. Visible surgically excised LN contiguous with the most proximal biliary remnants had 1 or more well-formed reactive GC in only 26/51 subjects. Presence of GC and number of GC/LN was unrelated to age at onset of jaundice or to active fibroplasia in the biliary remnant but was related to older age at HPE. Absent GC in visible and incidentally removed cystic duct LNs predicted survival with the native liver at 2 and 3 years after HPE, P = .03, but significance was lost at longer intervals. The uncommon inflammatory lesions occasionally found in remnants could be secondary either to bile-induced injury or secondary infection established as obstruction evolves. The absence of consistent evidence of antigenic stimulation in LN contiguous with the biliary remnant supports existence of at least 1 major alternative to infection in the etiology of biliary atresia.

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.

Loss of pediatric kidney grafts during the "high-risk age window": insights from pediatric liver and simultaneous liver-kidney recipients.

Pediatric kidney transplant recipients experience a high-risk age window of increased graft loss during late adolescence and early adulthood that has been attributed primarily to sociobehavioral mechanisms such as nonadherence. An examination of how this age window affects recipients of other organs may inform the extent to which sociobehavioral mechanisms are to blame or whether kidney-specific biologic mechanisms may also exist. Graft loss risk across current recipient age was compared between pediatric kidney (n = 17,446), liver (n = 12,161) and simultaneous liver-kidney (n = 224) transplants using piecewise-constant hazard rate models. Kidney graft loss during late adolescence and early adulthood (ages 17-24 years) was significantly greater than during ages <17 (aHR = 1.79, 95%CI = 1.69-1.90, p < 0.001) and ages >24 (aHR = 1.11, 95%CI = 1.03-1.20, p = 0.005). In contrast, liver graft loss during ages 17-24 was no different than during ages <17 (aHR = 1.03, 95%CI = 0.92-1.16, p = 0.6) or ages >24 (aHR = 1.18, 95%CI = 0.98-1.42, p = 0.1). In simultaneous liver-kidney recipients, a trend towards increased kidney compared to liver graft loss was observed during ages 17-24 years. Late adolescence and early adulthood are less detrimental to pediatric liver grafts compared to kidney grafts, suggesting that sociobehavioral mechanisms alone may be insufficient to create the high-risk age window and that additional biologic mechanisms may also be required.

Reducing pediatric liver transplant complications: a potential roadmap for transplant quality improvement initiatives within North America.

Though robust clinical data are available within transplantation, these data are not used for broad-based, multicentered quality improvement initiates. This article describes a targeted quality improvement initiative within the Studies of Pediatric Liver Transplantation (SPLIT) Registry. Using standard statistical techniques and clinical expertise to adjust for data and statistical reliability, we identified the pediatric liver transplant centers in North America with the lowest hepatic artery thrombosis rate and biliary complication rates. A survey was completed to establish current practices within the entire SPLIT group. Surgeons from the highest performing centers presented a detailed, technically oriented overview of their current practices. The presentations and discussion that followed were recorded and form the basis of the best practices described herein. We frame this work as a unique six-step approach roadmap that may serve as an efficient and cost effective model for novel broad-based quality improvement initiatives within transplantation.

Transplant surgery fellow perceptions about training and the ensuing job market-are the right number of surgeons being trained?

The American Society of Transplant Surgeons (ASTS) sought whether the right number of abdominal organ transplant surgeons are being trained in the United States. Data regarding fellowship training and the ensuing job market were obtained by surveying program directors and fellowship graduates from 2003 to 2005. Sixty-four ASTS-approved programs were surveyed, representing 139 fellowship positions in kidney, pancreas and/or liver transplantation. One-quarter of programs did not fill their positions. Forty-five fellows graduated annually. Most were male (86%), aged 31-35 years (57%), married (75%) and parents (62%). Upon graduation, 12% did not find transplant jobs (including 8% of Americans/Canadians), 14% did not get jobs for transplanting their preferred organ(s), 11% wished they focused more on transplantation and 27% changed jobs early. Half fellows were international medical graduates; 45% found US/Canadian transplant jobs, particularly 73% with US/Canadian residency training. Fellows reported adequate exposure to training volume, candidate selection, pre/postoperative care and organ procurement, but not to donor management/selection, outpatient care and core didactics. One-sixth noted insufficient 'mentoring/preparation for a transplantation career'. Currently, there seem to be enough trainees to fill entry-level positions. One-third program directors believe that there are too many trainees, given the current and foreseeable job market. ASTS is assessing the total workforce of transplant surgeons and evolving manpower needs.

Intestine transplantation in the United States, 1999-2008.

Improving short-term results with intestine transplantation have allowed more patients to benefit with nearly 700 patients alive in the United States with a functioning allograft at the end of 2007. This success has led to an increase in demand. Time to transplant and waiting list mortality have significantly improved over the decade, but mortality remains high, especially for infants and adults with concomitant liver failure. The approximately 200 intestines recovered annually from deceased donors represent less than 3% of donors who have at least one organ recovered. Consent practice varies widely by OPTN region. Opportunities for improving intestine recovery and utilization include improving consent rates and standardizing donor selection criteria. One-year patient and intestine graft survival is 89% and 79% for intestine-only recipients and 72% and 69% for liver-intestine recipients, respectively. By 10 years, patient and intestine survival falls to 46% and 29% for intestine-only recipients, and 42% and 39% for liver-intestine, respectively. Immunosuppression practice employs peri-operative antibody induction therapy in 60% of cases; acute rejection is reported in 30%-40% of recipients at one year. Data on long-term nutritional outcomes and morbidities are limited, while the cause and therapy for late graft loss from chronic rejection are areas of ongoing investigation.

Liver and intestine transplantation in the United States 1998-2007.

Liver transplantation numbers in the United States remained constant from 2004 to 2007, while the number of waiting list candidates has trended down. In 2007, the waiting list was at its smallest since 1999, with adults > or =50 years representing the majority of candidates. Noncholestatic cirrhosis was most commonly diagnosed. Most age groups had decreased waiting list death rates; however, children <1 year had the highest death rate. Use of liver allografts from donation after cardiac death (DCD) donors increased in 2007. Model for end-stage liver disease (MELD)/pediatric model for end-stage liver disease (PELD) scores have changed very little since 2002, with MELD/PELD <15 accounting for 75% of the waiting list. Over the same period, the number of transplants for MELD/PELD <15 decreased from 16.4% to 9.8%. Hepatocellular carcinoma exceptions increased slightly. The intestine transplantation waiting list decreased from 2006, with the majority of candidates being children <5 years old. Death rates improved, but remain unacceptably high. Policy changes have been implemented to improve allocation and recovery of intestine grafts to positively impact mortality. In addition to evaluating trends in liver and intestine transplantation, we review in depth, issues related to organ acceptance rates, DCD, living donor transplantation and MELD/PELD exceptions.

Improving long-term outcomes after liver transplantation in children.

The objective was to review the current state of knowledge and recommend future research directions related to long-term outcomes for pediatric liver transplant recipients. A 1-day Clinical Research Workshop on Improving Long-Term Outcomes for Pediatric Liver Transplant Recipients was held on February 12, 2007, in Washington, DC. The speaker topics were germane to research priorities delineated in the chapters on Pediatric Liver Diseases and on Liver Transplantation in the Trans-NIH Action Plan for Liver Disease Research. Issues that compromise long-term well-being and survival but are amenable to existing and new research efforts were presented and discussed. Areas of research that further enhanced the research priorities in the Action Plan for Liver Disease Research included collection of longitudinal data to define emerging trends of clinical challenges; identification of risk factors associated with long-term immunosuppression complications; development of tolerance-inducing regimens; definition of biomarkers that reflect the level of clinical immunosuppression; development of instruments for the measurement of health wellness; identification of risk factors that impede growth and intellectual development before and after liver transplantation and identification of barriers and facilitators that impact nonadherence and transition of care for adolescents.

Should pediatric patients wait for HLA-DR-matched renal transplants?

Graft survival rates from deceased donors aged 35 years or less among all primary pediatric kidney transplant recipients in the United States between 1996 and 2004 were retrospectively examined to determine the effect of HLA-DR mismatches on graft survival. Zero HLA-DR-mismatched kidneys had statistically comparable 5-year graft survival (71%), to 1-DR-mismatched kidneys (69%) and 2-DR-mismatched kidneys (71%). When compared to donors less than 35 years of age, the relative rate of allograft failure was 1.32 (p = 0.0326) for donor age greater than or equal to age 35. There was no statistical increase in the odds of developing a panel-reactive antibody (PRA) greater than 30% at the time of second waitlisting, based upon the degree of HLA-A, -B or -DR mismatch of the first transplant, nor was there a 'dose effect' when more HLA antigens were mismatched between the donor and recipient. Therefore, pediatric transplant programs should utilize the recently implemented Organ Procurement and Transplantation Network's (OPTN)allocation policy, which prioritizes pediatric recipients to receive kidneys from deceased donors less than 35 years of age, and should not turn down such kidney offers to wait for a better HLA-DR-matched kidney.

Altered synaptic and non-synaptic properties of CA1 pyramidal neurons in Kv4.2 knockout mice.

Back-propagating action potentials (bAPs) travelling from the soma to the dendrites of neurons are involved in various aspects of synaptic plasticity. The distance-dependent increase in Kv4.2-mediated A-type K(+) current along the apical dendrites of CA1 pyramidal cells (CA1 PCs) is responsible for the attenuation of bAP amplitude with distance from the soma. Genetic deletion of Kv4.2 reduced dendritic A-type K(+) current and increased the bAP amplitude in distal dendrites. Our previous studies revealed that the amplitude of unitary Schaffer collateral inputs increases with distance from the soma along the apical dendrites of CA1 PCs. We tested the hypothesis that the weight of distal synapses is dependent on dendritic Kv4.2 channels. We compared the amplitude and kinetics of mEPSCs at different locations on the main apical trunk of CA1 PCs from wild-type (WT) and Kv4.2 knockout (KO) mice. While wild-type mice showed normal distance-dependent scaling, it was missing in the Kv4.2 KO mice. We also tested whether there was an increase in inhibition in the Kv4.2 knockout, induced in an attempt to compensate for a non-specific increase in neuronal excitability (after-polarization duration and burst firing probability were increased in KO). Indeed, we found that the magnitude of the tonic GABA current increased in Kv4.2 KO mice by 53% and the amplitude of mIPSCs increased by 25%, as recorded at the soma. Our results suggest important roles for the dendritic K(+) channels in distance-dependent adjustment of synaptic strength as well as a primary role for tonic inhibition in the regulation of global synaptic strength and membrane excitability.

Pediatric transplantation in the United States, 1997-2006.

This article represents the sixth annual review of the current state of pediatric transplantation in the United States from the Scientific Registry of Transplant Recipients (SRTR). It presents updated trends, discussion of analyses presented during the year by the SRTR to the committees of the Organ Procurement and Transplantation Network (OPTN) and discussion of important issues currently facing pediatric organ transplantation. Unless otherwise stated, the statistics in this article are drawn from the reference tables of the 2007 OPTN/SRTR Annual Report. In this article, pediatric patients are defined as candidates, recipients or donors aged 17 years or less. Data for both graft and patient survival are reported as unadjusted survival, unless otherwise stated (adjusted patient and graft survival are available in the reference tables). Short-term survival (3 month and 1 year) reflects outcomes for transplants performed in 2004 and 2005; 3-year survival reflects transplants from 2002 to 2005; and 5-year survival reports on transplants performed from 2000 to 2005. Details on the methods of analysis employed may be found in the reference tables themselves or in the technical notes of the 2007 OTPN/SRTR Annual Report, both available online at http://www.ustransplant.org.

Psychological functioning, nonadherence and health outcomes after pediatric liver transplantation.

The present study empirically assessed the relationships between adherence behaviors and HRQOL, parent and child psychological functioning and family functioning, and investigated the relationship between adherence behaviors and health outcomes in children who were within 5 years of their liver transplantation. Participants included 38 children (mean = 8.5 years, range 28 months to 16 years) and their parent/guardian(s). HRQOL and psychological functioning were examined using well-validated assessment measures. Measures of adherence included the rate of clinic attendance and standard deviations (SDs) of consecutive tacrolimus blood levels, which were collected and evaluated retrospectively. Measures of child health status included the frequency of hospital admissions, liver biopsies, episodes of rejection and graft function for the year prior to study participation. Results indicated that nonadherence was related to lower physical HRQOL, more limitations in social and school activities related to emotional and behavioral problems, parental emotional distress and decreased family cohesion. Nonadherence was also related to frequency and duration of hospitalizations, liver biopsies and rejection episodes. These results suggest that empirically based assessment of HRQOL, parenting stress and family functioning may help identify patients at risk for nonadherence, and may allow for the need-based delivery of appropriate clinical interventions.

Financial implications of pancreas transplant complications: a business case for quality improvement.

We quantified the financial implications of surgical complications following pancreas transplantation. We reviewed medical and financial records of 49 pancreas transplant recipients at the University of Michigan Health System (UMHS) between 1/6/2002 and 11/22/2004. The association of donor, transplant recipient and financial variables was assessed. The median costs to UMHS of procedures and follow-up were $92,917 for recipients without surgical complications versus $108,431 when a surgical complication occurred, a difference of $15,514 (p = 0.03). Median reimbursement by the payer was $17,363 higher in patients with a surgical complication (p = 0.001). Similar trends (higher insurer costs) were noted when stratifying by payer (public and private) and specific procedure (SPK and PAK). All parties (patient, physician, payer and medical center) should benefit from quality improvement, with payers having a financial interest in pancreas transplant surgical quality initiatives.

Pediatric transplantation in the United States, 1996-2005.

Solid organ transplantation is accepted as a standard lifesaving therapy for end-stage organ failure in children. This article reviews trends in pediatric transplantation from 1996 to 2005 using OPTN data analyzed by the Scientific Registry of Transplant Recipients. Over this period, children have contributed significantly to the donor pool, and although the number of pediatric donors has fallen from 1062 to 900, this still accounts for 12% of all deceased donors. In 2005, 2% of 89,884 candidates listed for transplantation were less than 18 years old; in 2005, 1955 children, or 7% of 28,105 recipients, received a transplant. Improvement in waiting list mortality is documented for most organs, but pretransplant mortality, especially among the youngest children, remains a concern. Posttransplant survival for both patients and allografts similarly has shown improvement throughout the period; in most cases, survival is as good as or better than that seen in adults. Examination of immunosuppressive practices shows an increasing tendency across organs toward tacrolimus-based regimens. In addition, use of induction immunotherapy in the form of anti-lymphocyte antibody preparations, especially the interleukin-2 receptor antagonists, has increased steadily. Despite documented advances in care and outcomes for children undergoing transplantation, several considerations remain that require attention as we attempt to optimize transplant management.

Repeat organ transplantation in the United States, 1996-2005.

The prospect of graft loss is a problem faced by all transplant recipients, and retransplantation is often an option when loss occurs. To assess current trends in retransplantation, we analyzed data for retransplant candidates and recipients over the last 10 years, as well as current outcomes. During 2005, retransplant candidates represented 13.5%, 7.9%, 4.1% and 5.5% of all newly registered kidney, liver, heart and lung candidates, respectively. At the end of 2005, candidates for retransplantation accounted for 15.3% of kidney transplant candidates, and lower proportions of liver (5.1%), heart (5.3%) and lung (3.3%) candidates. Retransplants represented 12.4% of kidney, 9.0% of liver, 4.7% of heart and 5.3% of lung transplants performed in 2005. The absolute number of retransplants has grown most notably in kidney transplantation, increasing 40% over the last 10 years; the relative growth of retransplantation was most marked in heart and lung transplantation, increasing 66% and 217%, respectively. The growth of liver retransplantation was only 11%. Unadjusted graft survival remains significantly lower after retransplantation in the most recent cohorts analyzed. Even with careful case mix adjustments, the risk of graft failure following retransplantation is significantly higher than that observed for primary transplants.

Risk factors for urinary complications after renal transplantation.

Urinary complications are common following renal transplantation. The aim of this study is to evaluate the risk factors associated with renal transplant urinary complications. We collected data on 1698 consecutive renal transplants patients. The association of donor, transplant and recipient characteristics with urinary complications was assessed by univariable and multivariable Cox proportional hazards models, fitted to analyze time-to-event outcomes of urinary complications and graft failure. Urinary complications were observed in 105 (6.2%) recipients, with a 2.8% ureteral stricture rate, a 1.7% rate of leak and stricture, and a 1.6% rate of urine leaks. Seventy percent of these complications were definitively managed with a percutaneous intervention. Independent risk factors for a urinary complication included: male recipient, African American recipient, and the "U"-stitch technique. Ureteral stricture was an independent risk factor for graft loss, while urinary leak was not. Laparoscopic donor technique (compared to open living donor nephrectomy) was not associated with more urinary complications. Our data suggest that several patient characteristics are associated with an increased risk of a urinary complication. The U-stitch technique should not be used for the ureteral anastomosis.

Recovery and utilization of deceased donor kidneys from small pediatric donors.

The optimal use of kidneys from small pediatric deceased donors remains undetermined. Using data from the Scientific Registry of Transplant Recipients, 2886 small (< 21 kg) pediatric donors between 1993 and 2002 were identified. Donor factors predictive of kidney recovery and transplantation (1343 en bloc; 1600 single) were identified by logistic regression. Multivariable Cox regression was used to assess the risk of graft loss. The rate of kidney recovery from small pediatric donors was significantly higher with increasing age, weight and height. The odds of transplant of recovered small donor kidneys were significantly higher with increasing age, weight, height and en bloc recovery (adjusted odds ratio = 65.8 vs. single; p < 0.0001), and significantly lower with increasing creatinine. Compared to en bloc, solitary transplants had a 78% higher risk of graft loss (p < 0.0001). En bloc transplants had a similar graft survival to ideal donors (p = 0.45) while solitary transplants had an increased risk of graft loss (p < 0.0001). En bloc recovery of kidneys from small pediatric donors may result in the highest probability of transplantation. Although limited by the retrospective nature of the study, kidneys transplanted en bloc had a similar graft survival to ideal donors but may not maximize the number of successfully transplanted recipients.

Pediatric transplantation in the United States, 1995-2004.

This article reviews trends in pediatric solid organ transplantation over the last decade, as reflected in OPTN/SRTR data. In 2004, children younger than 18 years made up nearly 3% of the 86,378 candidates for organ transplantation and nearly 7% of the 27,031 organ transplant recipients. Children accounted for nearly 14% of the 7152 deceased organ donors. The transplant community recognizes important differences between pediatric and adult organ transplant recipients, including different etiologies of organ failure, surgical procedures that are more complex or technically challenging, effects of development on the pharmacokinetic properties of common immunosuppressants, unique immunological aspects of transplant in the developing immune system and increased susceptibility to posttransplant complications, particularly infectious diseases. For these reasons, and because of the impact of end-stage organ failure on growth and development, the transplant community has generally provided pediatric candidates with special consideration in the allocation of deceased donor organs. Outcomes following kidney, liver and heart transplantation in children often rank among the best. This article emphasizes that the prospects for solid organ transplantation in children, especially those aged 1-10 years are excellent. It also identifies themes warranting further consideration, including organ availability, adolescent survival and challenges facing pediatric transplant clinical research.

The Art and Science of Immunosuppression: the Fifth Annual American Society of Transplant Surgeon's State-of-the-Art Winter Symposium.

The 2005 American Society of Transplant Surgeons (ASTS) Winter Symposium entitled 'The Art and Science of Immunosuppression' explored ways to maximize existing immunosuppressive protocols and to develop new strategies incorporating novel agents and emerging diagnostic technologies to customize immunosuppression and reduce side effects. Several presentations evaluated steroid withdrawal or avoidance protocols reflecting the significant difficulties of bone loss, glucose control and growth retardation in children associated with long-term steroid use. Calcineurin-inhibitor related renal dysfunction of both native and transplanted kidneys was identified as significant, but no consensus was reached concerning effective prevention. Similarly, recurrence of Hepatitis C following liver transplantation was identified as problematic without identifying a preferred immunosuppressive regimen in this setting. Control of T-cell mediated rejection was found to be excellent, but recognition and treatment of non-T cell causes of allograft damage (i.e. B- or NK-cell mediated) was identified as an area of current interest. Immunosuppressive agents under development, such as those blocking co-stimulation or cytokine signals, and JAK-3 inhibitors were discussed. Finally, the available technologies for molecular and genetic diagnostics and the clinical correlation in the post-transplant setting were discussed.