Liver bioengineering:Current status and future perspectives

The present review aims to illustrate the strategies that are being implemented to regenerate or bioengineer livers for clinical purposes.There are two general pathways to liver bioengineering and regeneration.The first consists of creating a supporting scaffold,either synthetically or by decellularization of human or animal organs,and seeding cells on the scaffold,where they will mature either in bioreactors or in vivo.This strategy seems to offer the quickest route to clinical translation,as demonstrated by the development of liver organoids from rodent livers which were repopulated with organ specific cells of animal and/or human origin.Liver bioengineering has potential for transplantation and for toxicity testing during preclinical drug development.The second possibility is to induce liver regeneration of dead or resected tissue by manipulating cell pathways.In fact,it is well known that the liver has peculiar regenerative potential which allows hepatocyte hyperplasia after amputation of liver volume.Infusion of autologous bone marrow cells,which aids in liver regeneration,into patients was shown to be safe and to improve their clinical condition,but the specific cells responsible for liver regeneration have not yet been determined and the underlying mechanisms remain largely unknown.A complete understanding of the cell pathways and dynamics and of the functioning of liver stem cell niche is necessary for the clinical translation of regenerative medicine strategies.As well,it will be crucial to elucidate the mechanisms through which cells interact with the extracellular matrix,and how this latter supports and drives cell fate.

Single vs dual(en bloc) kidney transplants from donors ≤ 5 years of age: A single center experience

AIM: To compare outcomes between single and dual en bloc(EB) kidney transplants(KT) from small pediatric donors. METHODS: Monocentric nonprospective review of KTs from pediatric donors ≤ 5 years of age. Dual EB KT was defined as keeping both donor kidneys attached tothe inferior vena cava and aorta, which were then used as venous and arterial conduits for the subsequent transplant into a single recipient. Donor age was less useful than either donor weight or kidney size in decision-making for kidney utilization as kidneys from donors < 8 kg or kidneys < 6 cm in length were not transplanted. Post-transplant management strategies were standardized in all patients.RESULTS: From 2002-2015, 59 KTs were performed including 34 dual EB and 25 single KTs. Mean age of donors(17 mo vs 38 mo, P < 0.001), mean weight(11.0 kg vs 17.4 kg, P = 0.046) and male donors(50% vs 84%, P = 0.01) were lower in the dual EB compared to the single KT group, respectively. Mean cold ischemia time(21 h), kidney donor profile index(KDPI; 73% vs 62%) and levels of serum creatinine(SCr, 0.37 mg/d L vs 0.49 mg/d L, all P = NS) were comparable in the dual EB and single KT groups, respectively. Actuarial graft and patient survival rates at 5-years follow-up were comparable. There was one case of thrombosis resulting in graft loss in each group. Delayed graft function incidence(12% dual EB vs 20% single KT, P = NS) was slightly lower in dual EB KT recipients. Initial duration of hospital stay(mean 5.4 d vs 5.6 d) and the one-year incidences of acute rejection(6% vs 16%), operative complications(3% vs 4%), and major infection were comparable in the dual EB and single KT groups, respectively(all P = NS). Mean 12 mo SCr and abbreviated MDRD levels were 1.17 mg/d L vs 1.35 mg/d L and 72.5 m L/min per 1.73 m^2 vs 60.5 m L/min per 1.73 m^2(both P = NS) in the dual EB and single KT groups, respectively. CONCLUSION: By transplanting kidneys from young pediatric donors into adult recipients, one can effectively expand the limited donor pool and achieve excellent medium-term outcomes.

Pancreas transplantation: The Wake Forest experience in the new millennium

AIM: To investigate the Wake Forest experience with pancreas transplantation in the new millennium with attention to surgical techniques and immunosuppression. METHODS: A monocentric, retrospective review of outcomes in simultaneous kidney-pancreas transplant(SKPT) and solitary pancreas transplant(SPT) recipients was performed. All patients underwent pancreas transplantation as intent-to-treat with portal venous and enteric exocrine drainage and received depleting antibody induction; maintenance therapy included tapered steroids or early steroid elimination with my-cophenolate and tacrolimus. Recipient selection was based on clinical judgment whether or not the patient exhibited measureable levels of C-peptide. RESULTS: Over an 11.25 year period, 202 pancreas transplants were performed in 192 patients including 162 SKPTs and 40 SPTs. A total of 186(92%) were primary and 16(8%) pancreas retransplants; portalenteric drainage was performed in 179 cases. A total of 39 pancreas transplants were performed in African American(AA) patients; of the 162 SKPTs, 30 were performed in patients with pretransplant C-peptide levels > 2.0 ng/m L. In addition, from 2005-2008, 46 SKPT patients were enrolled in a prospective study of single dose alemtuzumab vs 3-5 doses of rabbit antithymocyte globulin induction therapy. With a mean follow-up of 5.7 in SKPT vs 7.7 years in SPT recipients, overall patient(86% SKPT vs 87% SPT) and kidney(74% SKPT vs 80% SPT) graft survival rates as well as insulin-free rates(both 65%) were similar(P = NS). Although mortality rates were nearly identical in SKPT compared to SPT recipients, patterns and timing of death were different as no early mortality occurred in SPT recipients whereas the rates of mortality following SKPT were 4%, 9% and 12%, at 1-, 3- and 5-years follow-up, respectively(P < 0.05). The primary cause of graft loss in SKPT recipients was death with a functioning graft whereas the major cause of graft loss following SPT was acute and chronic rejection. The overall incidence of acute rejection was 29% in SKPT and 27.5% in SPT recipients(P = NS). Lower rates of acute rejection and major infection were evidenced in SKPT patients receiving alemtuzumab induction therapy. Comparable kidney and pancreas graft survival rates were observed in AA and non-AA recipients despite a higher prevalence of a "type 2 diabetes" phenotype in AA. Results comparable to those achieved in insulinopenic diabetics were found in the transplantation of type 2 diabetics with detectable C-peptide levels.CONCLUSION: In the new millennium, acceptablemedium-term outcomes can be achieved in SKPT and SPTs as nearly 2/3rds of patients are insulin independent following pancreas transplantation.

Exocrine drainage in vascularized pancreas transplantation in the new millennium

The history of vascularized pancreas transplantation largely parallels developments in immunosuppression and technical refinements in transplant surgery. From the late-1980 s to 1995, most pancreas transplants were whole organ pancreatic grafts with insulin delivery to the iliac vein and diversion of the pancreatic ductal secretions to the urinary bladder(systemic-bladder technique). The advent of bladder drainage revolutionized the safety and improved the success of pancreas transplantation. However, starting in 1995, a seismic change occurred from bladder to bowel exocrine drainage coincident with improvements in immunosuppression, preservation techniques, diagnostic monitoring, general medical care, and the success and frequency of enteric conversion. In the new millennium, pancreas transplants are performed predominantly as pancreatico-duodenal grafts with enteric diversion of the pancreatic ductal secretions coupled with iliac vein provision of insulin(systemic-enteric technique) although the systemic-bladder technique endures as a preferred alternative in selected cases. In the early 1990 s, a novel technique of venous drainage into the superior mesenteric vein combined with bowel exocrine diversion(portal-enteric technique) was designed and subsequently refined over the next ≥ 20 years to recreate the natural physiology of the pancreas with firstpass hepatic processing of insulin. Enteric drainage usually refers to jejunal or ileal diversion of the exocrine secretions either with a primary enteric anastomosis or with an additional Roux limb. The portal-enteric technique has spawned a number of newer and revisited techniques of enteric exocrine drainage including duodenal or gastric diversion. Reports in the literature suggest no differences in pancreas transplant outcomes irrespective of type of either venous or exocrine diversion. The purpose of this review is to examine theliterature on exocrine drainage in the new millennium(the purported "enteric drainage" era) with special attention to technical variations and nuances in vascularized pancreas transplantation that have been proposed and studied in this time period.