Impact of Volatile Anesthetic Agents on Early Clinical Outcomes in Liver Transplantation.

BACKGROUND: Few studies have assessed the ability of inhaled anesthetic agents to ameliorate ischemia-reperfusion injury (IRI) in liver transplantation (LT). This study compares inhaled anesthetics in early liver allograft IRI. LT recipient and organ donor data were extracted retrospectively for all LTs at a single center between 2001 and 2015. METHODS: LT recipient and organ donor data were extracted retrospectively for all LTs at a single center between 2001 and 2015. The choice of primary anesthetic agent was at the discretion of the anesthesiologist. Serum alanine aminotransferase (ALT) and total bilirubin (TB) levels were measured daily in the post-transplant period as measures of early graft injury and function. Survival and clinical outcomes are reported. RESULTS: There were 1291 primary LTs included in the analysis, with 3 primary inhaled agents: isoflurane (62%), desflurane (8%), and sevoflurane (30%). In the first 7 days post-transplant, the peak ALT level was lowest for desflurane (352), followed by sevoflurane (411) and isoflurane (481) (P = .09). All groups had similar ALT and TB by 7 days post-transplant. Graft survival for all 3 groups was statistically similar at 1, 7, and 30 days, with equivalent patient and graft survival at 1 year. CONCLUSIONS: All 3 agents had similar rates of early allograft dysfunction and renal dysfunction. Subgroup analysis of high-risk donor grafts showed no statistical difference. In conclusion, administration of desflurane or sevoflurane may provide some early hepatoprotection against IRI, but longer-term outcomes were equivalent for all agents.

Donation After Circulatory Arrest in Pancreas Transplantation: A Report of 10 Cases.

INTRODUCTION: Transplantation of pancreas allografts procured from donation after circulatory death (DCD) remains uncommon. This study reviews a series of pancreas transplants at a single center to assess the donor and recipient characteristics for DCD pancreas transplant and to compare clinical outcomes. METHODS: DCD procurement was performed with a 5-minute wait time from pronouncement of death to first incision. In 2 patients, tissue plasminogen activator was infused as a thrombolytic during the donor flush. All kidney grafts were placed on pulsatile perfusion. RESULTS: There were 606 deceased donor pancreas transplants, 596 standard donors and 10 DCD donors. Of the 10 DCD transplants, 6 were simultaneous pancreas-kidney and 4 were pancreas transplant alone. The average time from incision to aortic cannulation was less than 3 minutes. The median total ischemia time for the DCD grafts was 5.4 hours, compared with 8.0 hours for standard donors (P = .15). Median length of hospital stay was 7 days for both groups, and there were no episode of acute cellular rejection in the first year post-transplant for the DCD group (4.2 % for standard group, P = .65). There was no difference in early or late graft survival, with 100% graft survival in the DCD group up to 1 year post-transplant. Ten-year Kaplan-Meier analysis shows similar graft survival for the 2 groups (P = .92). CONCLUSIONS: These results support the routine use of carefully selected DCD pancreas donors. There were no differences in graft function, postoperative complications, and early and late graft survival.

Broadened Allocation of Pancreas Transplants Across Compatible ABO Blood Types.

BACKGROUND: Current Organ Procurement and Transplantation Network (OPTN) policy restricts certain blood type-compatible simultaneous pancreas and kidney (SPK) transplants. Using the Kidney Pancreas Simulated Allocation Model, we examined the effects of 5 alternative allocation sequences that allowed all clinically compatible ABO transplants. METHODS: The study cohort included kidney (KI), SPK, and pancreas alone (PA) candidates waiting for transplant for at least 1 day between January 1, 2010, and December 31, 2010 (full cohort), and kidneys and pancreata recovered for transplant during the same period. Additionally, because the waiting list has shrunk since 2010, the study population was reduced by random sampling to match the volume of the 2015 waiting list (reduced cohort). RESULTS: Compared with the current allocation sequence, R4 and R5 both showed an increase in SPK transplants, a nearly corresponding decrease in KI transplants, and virtually no change in PA transplants. Life-years from transplant and median years of benefit also increased. The distribution of transplants by blood type changed, with more ABO:A, B, and AB transplants performed, and fewer ABO:O across all transplant types (KI, SPK, PA), with the relative percent changes largest for SPK. DISCUSSION: Broadened ABO compatibility allowances primarily benefitted SPK ABO:A and AB candidates. ABO:O candidates saw potentially reduced access to transplant. The simulation results suggest that modifying the current allocation sequence to incorporate broadened ABO compatibility can result in an increase in annual SPK transplants.

Case Report: Primary De Novo Sarcoma In Transplant Pancreas Allograft.

BACKGROUND: The majority of malignancies after transplantation appear to be virally mediated and of recipient origin. Donor-derived neoplasms occur early, whereas recipient-origin tumors typically occur many years after transplantation. Sarcomas are a relatively rare form of cancer. The etiology of sarcomas remains largely unknown, although some are linked to viruses, familial cancer syndromes, or therapeutic radiation exposure. Primary sarcomas are extremely rare, accounting for <0.1% of all native pancreatic malignancies. The involvement of the allograft itself in the tumor is rare. CASE REPORT: A 53-year-old white woman (body mass index, 20.1 kg/m2) with a history of type 1 diabetes, chronic kidney disease, coronary artery disease, dyslipidemia, and pancreas-alone transplantation in 2007 was admitted with small bowel obstruction secondary to a mass in the head of the pancreas allograft, for which a laparotomy with allograft pancreatectomy was required. Histopathologic exam revealed a stage III high-grade unclassified spindle cell sarcoma positive for polyomavirus. After surgery, the patient was managed with close monitoring for disease recurrence. Her most recent scan was negative for recurrence at postoperative day 489. CONCLUSIONS: We report a previously unreported phenomenon of a soft tissue sarcoma arising in a pancreas allograft, likely of recipient origin and polyomavirus related. Standard treatment for sarcoma is wide excision of the tumor and close monitoring for recurrence. Systemic chemotherapy or radiotherapy is usually limited to advanced cases. Sarcomas may occur in a pancreas allograft. Allograft pancreatectomy and monitoring for recurrence is vital for a good outcome.

Pancreas Transplantation: An Alarming Crisis in Confidence.

In the past decade, the annual number of pancreas transplantations performed in the United States has steadily declined. From 2004 to 2011, the overall number of simultaneous pancreas-kidney (SPK) transplantations in the United States declined by 10%, whereas the decreases in pancreas after kidney (PAK) and pancreas transplant alone (PTA) procedures were 55% and 34%, respectively. Paradoxically, this has occurred in the setting of improvements in graft and patient survival outcomes and transplanting higher-risk patients. Only 11 centers in the United States currently perform ≥20 pancreas transplantations per year, and most centers perform <5 pancreas transplantations annually; many do not perform PAKs or PTAs. This national trend in decreasing numbers of pancreas transplantations is related to a number of factors including lack of a primary referral source, improvements in diabetes care and management, changing donor and recipient considerations, inadequate training opportunities, and increasing risk aversion because of regulatory scrutiny. A national initiative is needed to "reinvigorate" SPK and PAK procedures as preferred transplantation options for appropriately selected uremic patients taking insulin regardless of C-peptide levels or "type" of diabetes. Moreover, many patients may benefit from PTAs because all categories of pancreas transplantation are not only life enhancing but also life extending procedures.

Allograft Pancreatectomy: Indications and Outcomes.

This study evaluated the indications, surgical techniques, and outcomes of allograft pancreatectomy based on a single center experience. Between 2003 and 2013, 47 patients developed pancreas allograft failure, excluding mortality with a functioning pancreas allograft. Early graft loss (within 14 days) occurred in 16, and late graft loss in 31. All patients with early graft loss eventually required allograft pancreatectomy. Nineteen of 31 patients (61%) with late graft loss underwent allograft pancreatectomy. The main indication for early allograft pancreatectomy included vascular thrombosis with or without severe pancreatitis, whereas one recipient required urgent allograft pancreatectomy for gastrointestinal hemorrhage secondary to an arterioenteric fistula. In cases of late allograft pancreatectomy, graft failure with clinical symptoms such as abdominal discomfort, pain, and nausea were the main indications (13/19 [68%]), simultaneous retransplantation without clinical symptoms in 3 (16%), and vascular catastrophes including pseudoaneurysm and enteric arterial fistula in 3 (16%). Postoperative morbidity included one case each of pulmonary embolism leading to mortality, formation of pseudoaneurysm requiring placement of covered stent, and postoperative bleeding requiring relaparotomy eventually leading to femoro-femoral bypass surgery 2 years after allograftectomy. Allograft pancreatectomy can be performed safely, does not preclude subsequent retransplantation, and may be lifesaving in certain instances.

Conversion from tacrolimus to belatacept to prevent the progression of chronic kidney disease in pancreas transplantation: case report of two patients.

Belatacept is a novel immunosuppressive agent that may be used as an alternative to calcineurin inhibitors (CNI) in immunosuppression (IS) regimens. We report two cases of pancreas transplant that were switched from tacrolimus (TAC) to belatacept. Case 1: 38-year-old female with pancreas transplant alone maintained on TAC-based IS regimen whose serum creatinine (SCr) slowly deteriorated from 0.6 mg/dL at baseline to 2.2 mg/dL, 16 months posttransplant. A native kidney biopsy performed showed CNI toxicity. The patient was started on belatacept and TAC was eliminated. Case 2: 49-year-old female with simultaneous pancreas-kidney transplant, maintained on TAC-based regimen where the SCr worsened over an initial 3-month period from a baseline of 1.0 to 3.0 mg/dL. Belatacept was started and TAC was lowered. Due to persistent graft dysfunction and kidney transplant biopsy still showing changes consistent with CNI toxicity, the TAC was then discontinued. At >1 year postbelatacept and off TAC follow-up, kidney function as measured by SCr remains stable at 1.0±0.2 mg/dL in both recipients. Neither patient developed rejection following the switch, and pancreas allograft function remains stable in both recipients.

Aminocaproic Acid (amicar) as an alternative to aprotinin (trasylol) in liver transplantation.

INTRODUCTION: This study compared clinical outcomes for a large number of liver transplant patients receiving intraoperative epsilon-aminocaproic acid (EACA), aprotinin, or no antifibrinolytic agent over an 8-year period. PATIENTS AND METHODS: Records for deceased donor liver transplants were reviewed. Data included antifibrinolytic agent, blood loss, early graft function, and postoperative complications. Study groups included low-dose aprotinin, high-dose aprotinin, EACA (25 mg/kg, 1-hour infusion), or no antifibrinolytic agent. RESULTS: Data were included for 1170 consecutive transplants. Groups included low-dose aprotinin (n = 324 [28%]), high-dose aprotinin (n = 308 [26%]), EACA (n = 216 [18%]), or no antifibrinolytic (n = 322 [28%]). EACA had the lowest intraoperative blood loss and required the fewest transfusions of plasma. Patients receiving no agent required the most blood transfusions. Early graft loss was lowest in the EACA group, and 90-day and 1-year patient survival rates were significantly higher for the low-dose aprotinin and EACA groups according to Cox regression. Complications were similar, but there were more episodes of deep vein thrombosis in patients receiving EACA. CONCLUSIONS: These results suggest that transitioning from aprotinin to EACA did not result in worse outcomes. In addition to decreased intraoperative blood loss, a trend toward improved graft and patient survival was seen in patients receiving EACA.

Simultaneous liver-pancreas transplantation for cystic fibrosis-related liver disease: a multicenter experience.

BACKGROUND: Diabetes is associated with increased morbidity and mortality in patients with cystic fibrosis (CF). While liver transplantation is well established for CF-related liver disease (CFLD), the role of simultaneous liver-pancreas transplantation is less understood. METHODS: We polled 81 pediatric transplantation centers to identify and characterize subjects who had undergone simultaneous liver-pancreas transplantation and obtain opinions about this procedure in CFLD. RESULTS: Fifty (61.7%) polled transplant centers responded and 94% reported that they would consider simultaneous liver-pancreas transplantation for CFLD and diabetes. A total of 8 patients with simultaneous liver-pancreas transplantation were identified with median follow up of 38 months. All patients had pre-existing diabetes. Exocrine and endocrine pancreatic function was initially restored in all patients with later functional loss in one patient. Body mass index Z-score increased between one year pre-transplantation and one year post-transplantation (P=0.029). CONCLUSIONS: Patients with CFLD undergoing initial assessment for liver transplantation may benefit from consideration of simultaneous liver-pancreas transplantation.

Closure of the abdominal wall with acellular dermal allograft in intestinal transplantation.

Loss of abdominal domain is a common problem in intestinal transplantation. Several surgical options are available perioperatively for abdominal wall reconstruction. This study reports the management and complications for intestinal transplant patients with abdominal wall closure either primarily or with foreign material. This single center study reviews the records of intestinal transplant patients between 2004 and 2010. Study outcomes included reoperation for dehiscence, hernia or enterocutaneous fistula. There were 37 of 146 patients (25%) who required implantation of foreign material at transplant. Of these 37, 30 (81%) had implantation of acellular dermal allograft (ADA) and 7 (19%) implantation of another mesh. Perioperative dehiscence was rare with 2/109 (2%) for primary closure, 0/30 (0%) for ADA and 1/7 (14%) for other mesh. There were 12/146 (8%) patients who underwent ventral hernia repair: primary closure 7/109 (6%), ADA 3/30 (10%) and other mesh 2/7 (28%). There were 4/146 (3%) patients who required surgery for enterocutaneous fistulas: 2/109 (2%) primary closure, 1/30 (3%) ADA and 1/7 (14%) synthetic mesh. Abdominal wall reconstruction with ADA biologic mesh provides an expeditious means of performing a tension-free closure of the fascial layer after intestinal transplantation with complications similar to those seen for primary closure.

Simultaneous pancreas and kidney transplantation with concurrent allograft nephrectomy for recipients with prior renal transplants lost to BK virus nephropathy: two case reports.

Candidacy for retransplantation after allograft loss due to BK virus-associated nephropathy (BKVN) with or without allograft nephrectomy is controversial. This report describes 2 renal transplant recipients who lost their grafts to BKVN and subsequently underwent simultaneous kidney and pancreas transplantation with allograft nephrectomy.

Histidine-tryptophan-ketoglutarate for pancreas allograft preservation: the Indiana University experience.

Histidine-tryptophan-ketoglutarate solution (HTK) has been scrutinized for use in pancreas transplantation. A recent case series and a United Network for Organ Sharing data base review have suggested an increased incidence of allograft pancreatitis and graft loss with HTK compared to the University of Wisconsin solution (UW). Conversely, a recent randomized, controlled study failed to show any significant difference between HTK and UW for pancreas allograft preservation. This study was a retrospective review of all pancreas transplants performed at Indiana University between 2003 and 2009 comparing preservation with HTK or UW. Data included recipient and donor demographics, 7-day, 90-day and 1-year graft survival, peak 30-day serum amylase and lipase, HbA1c and C-peptide levels. Of the 308 pancreas transplants, 84% used HTK and 16% UW. There were more SPK compared to pancreas after kidney and pancreas transplant alone in the HTK group. Donor and recipient demographics were similar. There was no significant difference in 7-day, 90-day or 1-year graft survival, 30-day peak serum amylase and lipase, HbA1c or C-peptide. No clinically significant difference between HTK and UW for pancreas allograft preservation was identified. Specifically, in the context of low-to-moderate flush volume and short cold ischemia time (

Immediate retransplantation for pancreas allograft thrombosis.

Early pancreas allograft failure most commonly results from thrombosis and requires immediate allograft pancreatectomy. Optimal timing for retransplantation remains undefined. Immediate retransplantation facilitates reuse of the same anatomic site before extensive adhesions have formed. Some studies suggest that early retransplantation is associated with a higher incidence of graft loss. This study is a retrospective review of immediate pancreas retransplants performed at a single center. All cases of pancreas allograft loss within 2 weeks were examined. Of 228 pancreas transplants, 12 grafts were lost within 2 weeks of surgery. Eleven of these underwent allograft pancreatectomy for thrombosis. One suffered anoxic brain injury and was not a retransplantation candidate, one was retransplanted at 3.5 months and nine patients underwent retransplantation 1-16 days following the original transplant. Of the nine early retransplants, one pancreas was lost to heparin-induced thrombocytopenia, one recipient died with function at 2.9 years and the other grafts continue to function at 76-1137 days (mean 572 days). One-year graft survival for early retransplantation was 89% compared to 91% for all pancreas transplants at our center. Immediate retransplantation following pancreatic graft thrombosis restores durable allograft function with outcomes comparable to first-time pancreas transplantation.

Simultaneous bilateral lung and pancreas transplantation in recipient with cystic fibrosis.

INTRODUCTION: Cystic fibrosis (CF) is an inherited disorder that presents in childhood as a multisystem disease. Pulmonary failure and pancreatic insufficiency, including CF-related diabetes (CFRD) and exocrine insufficiency, are significant causes of morbidity and mortality in these patients. In this report we have reviewed our experience with a simultaneous lung and pancreas transplantation in a patient with CF. METHODS: The recipient was a 25-year-old man with CF complicated by bronchiectasis with recurrent episodes of pneumonia, pancreatic exocrine insufficiency, and CFRD. He had normal hepatic and renal function. SURGICAL TECHNIQUE: The lung and pancreas allografts were procured from a single cadaveric donor. The double lung transplantation was performed through separate thoracic incisions. The pancreas transplantation was performed through a midline incision with systemic venous drainage and proximal enteric exocrine drainage. RESULTS: The recipient recovered well from his transplantation with early extubation. The pancreas allograft functioned well with normal blood glucose independent of insulin. As a result of the enteric drainage of the pancreas allograft, the patient no longer required supplemental pancreatic enzymes. His postoperative course was complicated by distal intestinal obstruction, a complex wound infection, and reversible leukoencephalopathy. At 1-year posttransplantation he remains free of supplemental oxygen, insulin, and pancreatic enzyme replacement. CONCLUSION: Simultaneous lung and pancreas transplantation in a patient with CF was performed safely, providing the advantages of normalization of glucose and improved nutrition for a patient requiring lung transplantation.

Organ preservation with histidine-tryptophan ketogluatarate solution in clinical pancreas transplantation: an update of the indiana university experience.

In May 2003, University of Wisconsin (UW) solution was replaced with Histidine-Tryptophan Ketoglutarate (HTK) solution as the preservation fluid for abdominal organ procurements in our center. Herein we have reported our updated results with HTK in pancreas transplantation. Between May 2003 and October 2006, 152 pancreas transplantations were performed in which 146 used HTK. The procedures were as follows: simultaneous kidney pancreas transplantation (n = 85; 55%), pancreas after kidney transplantation (n = 41; 30%), and solitary pancreas transplantation (n = 20; 15%). Donor and recipient data were collected with primary outcomes as primary nonfunction (PNF), and 30-day and 1-year graft and patient survival. Patient demographics are as follows: age (36 +/- 12 years), gender (males, 89: females, 57), race (white, 135; African American, 11). Mean flush volume was 3.8 +/- 1 L. The mean cold ischemia time was 8 +/- 3 hours. Mean warm ischemia time was 48 +/- 23 minutes. There were no cases of PNF in this cohort. Thirty-day and 1-year patient survival rates were 99% and 95%, respectively. The 30-day and 1-year graft survivals rates were 95% and 93%, respectively. There were 10 grafts lost with 7 vascular complications (6 venous and 1 arterial thrombosis). There were 2 cases of chronic rejection and 1 graft lost to noncompliance. These statistics compare favorably with International Pancreas Transplant Registry reported 1-year survival for pancreas allografts. All other patients were insulin independent by discharge. Serum fasting blood glucose and serial amylase remained comparable at all intervals posttransplantation to those of a historical UW cohort. Within this range of cold ischemia times, HTK appears to provide effective pancreas preservation.

Predictors of blood product use in orthotopic liver transplantation using the piggyback hepatectomy technique.

UNLABELLED: Orthotopic liver transplantation (OLT) has historically been associated with massive blood loss and hemodynamic instability related to the coexistence of varices, coagulopathy, thrombocytopenia, and portal hypertension. Piggyback hepatectomy (PGB) is a technique increasingly utilized in OLT to avoid veno-venous bypass and vena cava clamping. This study evaluated the factors associated with blood loss and blood product requirement in PGB. METHODS: This study is a retrospective review of the anesthesia preoperative and operative notes and computerized lab values for all adult cadaveric liver transplants over a 42-month period. These data were combined with the liver transplant database for analysis. Approximately 98% of the transplants were performed using a standard piggyback approach with no use of veno-venous bypass. RESULTS: Data were included for all 526 transplants performed during this time period. Estimated blood loss (EBL) was 1000 cc. Median transfusion requirement was 3 units packed red blood cells, 7 units fresh frozen plasma, and 6 units platelets. Multivariate linear regression demonstrated that predictors of EBL were age, MELD score, preoperative hemoglobin, initial fibrinogen, initial central venous pressure, and total anesthesia time. Predictors of PRBC useage were age, MELD score, preoperative hemoglobin, initial fibrinogen, and anesthesia time. Postoperatively increased transfusion requirement was associated with increased length of hospital stay and lower 90-day and 1-year graft and patient survivals. CONCLUSION: These results demonstrate that PGB can be safely accomplished in nearly all liver transplant patients without venovenous bypass or vena cava clamping and with less warm ischemia, which may ultimately be associated with less perioperative morbidity and improved outcomes.

Survival after disseminated invasive aspergillosis in a multivisceral transplant recipient.

Disseminated invasive aspergillosis is a serious and potentially lethal infectious complication of immunosuppressed individuals, including transplant recipients. We report here a successfully treated case of disseminated Aspergillus fumigatus infection involving the lungs, brain, and endocardium in a multivisceral transplant recipient. In addition to supportive measures, the patient was aggressively treated with a combination of three antifungal agents, and all immunosuppression was significantly lowered with close observation for rejection. After 3 months of therapy, the patient cleared the fungal infection, made a full recovery of his cerebral function, and was discharged to a rehabilitation facility.

Follow-up experience using histidine-tryptophan ketoglutarate solution in clinical pancreas transplantation.

In May 2003, at Indiana University, the standard cold preservation solution University of Wisconsin (UW) solution was replaced by histidine-tryptophan ketogluatarate (HTK) solution. Earlier, we presented our initial experience with HTK in pancreas preservation with an analysis of the first 10 pancreas transplants. Here we report updated results with HTK in pancreas transplantation over the past 18 months. Between May 2003 and March 2005, a total of 87 pancreas transplants were performed with 78 of these organs utilizing HTK. Seventy five patients received 78 organ transplants. Surgical procedures performed were: simultaneous kidney pancreas transplantation (n = 50, 64%), pancreas after kidney transplantation (n = 19, 24%), solitary pancreas transplantation (n = 9, 12%). Donor and recipient data were collected with primary outcomes as primary nonfunction and 30-day graft and patient survivals, and compared to the UW cohort from our original report. Donor and recipient demographics were similar. Mean follow-up time is 12 +/- 6 months. The mean cold ischemia time was 9 +/- 3 hours. There were no cases of primary graft nonfunction. Thirty-day and 1-year patient survivals were 99% and 93%. The 30-day and 1-year graft survivals were 96% and 93%. There were five grafts lost, including three within the first month (two venous and one arterial thrombosis). There was one case of chronic rejection and one noncompliance. All other patients were insulin-independent by discharge. Serum fasting blood glucose and serial amylase remained comparable at all intervals posttransplantation. Within this range of cold ischemia time, HTK appears to provide effective pancreas preservation.

Simultaneous liver and pancreas transplantation in patients with cystic fibrosis.

BACKGROUND: Improved survival in patients with cystic fibrosis (CF) has led to an increased incidence of extrapulmonary complications of this disease. Of these, cirrhosis and pancreatic insufficiency, including CF-related diabetes (CFRD) and exocrine insufficiency, are significant causes of morbidity and mortality. Liver transplantation is the treatment of choice for cirrhosis in this setting, but the addition of an isolated simultaneous pancreas transplant in patients with CFRD has not been reported. METHODS: Two female patients with CF underwent simultaneous pancreas and liver transplantation. Both had pancreatic insufficiency, CFRD, cirrhosis, and preserved renal function. In each case, the liver and pancreas were procured from a single cadaveric donor. The liver transplant was performed first. A lower midline extension was added for improved exposure of the iliac vessels. The donor pancreas transplant was performed with systemic venous drainage and enteric exocrine drainage. Immunosuppression included rabbit anti-thymocyte globulin, tacrolimus, mycophenolate mofetil, and early steroid withdrawal. RESULTS: Both patients recovered well with normal liver function, resolution of portal hypertension, and normal blood glucoses independent of insulin. As a result of the enteric exocrine drainage of the pancreas, they are now independent of supplemental pancreatic enzymes. CONCLUSIONS: Simultaneous liver and pancreas transplantation in CF patients provides the advantages of normalization of glucose and improved nutrition for patients requiring liver transplantation and should be considered in CF patients with CFRD who require liver transplants.