Transplantation of the liver in combination with other organs is an increasingly performed procedure. Over the years, continuous improvement in survival could be realized through careful patient selection and refined organ preservation techniques, in spite of the challenges posed by aging recipients and donors, as well as the increased use of steatotic liver grafts. Herein, we revisit the epidemiology, allocation policies in different transplant zones, indications, and outcomes with regard to simultaneous organ transplants involving the liver, that is combined heart-liver, liver-lung, liver-kidney, and multivisceral transplantation. We address challenges surrounding combined organ transplantation such as equity, utility, and logistics of dual organ implantation, but also advantages that come along with combined transplantation, thereby focusing on molecular mechanisms underlying immunoprotection provided by the liver to the other allografts. In addition, the current standing and knowledge of machine perfusion in combined organ transplantation, mostly based on center experience, will be reviewed. Notwithstanding all the technical advances, shortage of organs, and the lack of universal eligibility criteria for certain multi-organ combinations are hurdles that need to be tackled in the future.

To describe the worldwide experience with living donation (LD) in intestinal transplantation (ITx) and compare short-term and long-term outcomes to a propensity-matched cohort of deceased donors.

ITx is a rare life-saving procedure for patients with complicated intestinal failure (IF). Living donation (LD)-ITx has been performed with success, but no direct comparison with deceased donation (DD) has been performed. The Intestinal Transplant Registry (ITR) was created in 1985 by the Intestinal Transplant Association to capture the worldwide activity and promote center's collaborations.

Based on the ITR, 4156 ITx were performed between January 1987 and April 2019, of which 76 (1.8%) were LD, including 5 combined liver-ITx, 7 ITx-colon, and 64 isolated ITx. They were matched with 186 DD-ITx for recipient age/sex, weight, region, IF-cause, retransplant, pretransplant status, ABO compatibility, immunosuppression, and transplant date. Primary endpoints were acute rejection and 1-/5-year patient/graft survival.

Most LDs were performed in North America (61%), followed by Asia (29%). The mean recipient age was: 22 years; body mass index: 19kg/m²; and female/male ratio: 1/1.4. Volvulus (N=17) and ischemia (N=17) were the most frequent IF-causes. Fifty-two percent of patients were at home at the time of transplant. One-/5-year patient survival for LD and DD was 74.2/49.8% versus 80.3/48.1%, respectively ( P =0.826). One-/5-year graft survival was 60.3/40.6% versus 69.2/36.1%, respectively ( P =0.956). Acute rejection was diagnosed in 47% of LD versus 51% of DD ( P =0.723).

Worldwide, LD-ITx has been rarely performed. This retrospective matched ITR analysis revealed no difference in rejection and in patient/graft survival between LD and DD-ITx.

A safe, reproducible and standardized surgical technique for intestinal procurement and transplantation from a living donor (LD) was introduced in 1997 and has been used in the majority of cases since. The key principles are: 1. procurement of 180-200 cm of distal ileum in adults (about 60-150 cm in pediatric recipients depending on age and weight) on a vascular pedicle comprising the LD ileocolic vessels or terminal branches of the superior mesenteric vessels, 2. the terminal ileum (30-40 cm of the most distal ileum), the ileocecal valve and the cecum remain with the donor to not interfere with B12-absorption and bowel transit time, 3. systemic venous drainage with anastomoses between the LD ileocolic vessels and the recipient's infrarenal aorta and vena cava, and 4. restoration of recipient bowel continuity through proximal anastomosis and distal graft ileostomy for biopsy access and graft monitoring. Recipients of a successful LD intestinal transplant become total parenteral nutrition (TPN)-independent within a few weeks posttransplant. LD vs deceased donor (DD) intestinal transplants can be performed in a more timely fashion. Hence, LD (in contrast to DD) intestinal transplants are also pre-emptive procedures in patients with advanced, but still reversible, TPN-induced liver disease and help reduce the wait-list mortality for combined DD intestinal and liver transplants. Life-saving combined LD intestinal and liver transplants, albeit rare, have also been successfully performed either simultaneously or subsequently. There have been no reported deaths or major complications of living intestinal donors. A better metabolic profile has been reported in some donors post-donation. In total, 85 documented LD intestinal transplants have been performed worldwide at over 20 different transplant centers in 12 different countries. In about 70 transplants, the standardized technique was used. There has been no difference in outcome between LD vs DD intestinal transplants. Long-term studies have shown that > 10 year of graft function is not uncommon. Since the introduction of the standardized surgical technique, LD intestinal transplantation has evolved from an experimental to an established and standardized procedure.

Pediatric intestinal transplantation has moved from the theoretic to an actual therapy for children with irreversible intestinal failure who are suffering from complications of total parenteral nutrition. Owing to significant advancement in the management of intestinal failure and prevention of parenteral nutrition-related complications that have led to reduction in incidence of parenteral nutrition-associated liver disease and have improved intestinal adaptation, the indications for intestinal transplantation are evolving. Long-term outcomes have improved, but challenges in long-term graft function owing to chronic rejection and immunosuppressant-related complications remain the major opportunities for improvement.

Living donor intestinal transplantation (LDIT) has been improved leading to results comparable to those obtained with deceased donors. LDIT should be limited to specific indications and patient selection. The best indication is combined living donor intestinal/liver transplantation in pediatric recipients with intestinal and hepatic failure; the virtual elimination of waiting time may avoid the high mortality experienced by candidates on the deceased waiting list. Potentially, LDIT could be used in highly sensitized recipients to allow the application of de-sensitization protocols. In the case of available identical twins or HLA-identical sibling, LDIT has a significant immunologic advantage and should be offered.

Pre-emptive transplantation is a well-established practice for certain types of end-organ failure such as in the use of kidney transplantation. For irreversible intestinal failure, total parenteral nutrition (TPN) remains the gold standard, due to the suboptimal long-term results of intestinal transplantation. As such, the only role for pre-emptive transplantation, if at all, will be for patients identified to be at high risk of complications and mortality while on definitive long-term TPN. In these patients, the timing of early listing and transplantation could become life-saving, taking into account that mortality on the waiting list is still the highest for intestinal candidates. The development of simulation models or pre-transplant scoring systems could help in selecting patients based on potential outcome on TPN or with transplantation, and recent reports from high-volume centers identify few underlying pathologic conditions and some TPN complications as at higher risk of increased morbidity and mortality. A pre-emptive transplant could be used as a rehabilitative procedure in a well-selected case-by-case scenario, among TPN patients at risk of liver failure, repeated central line infections, mesenteric infarction, short bowel syndrome (SBS) <50 cm or with end stoma, congenital mucosal disease, desmoid tumors: These conditions must be carefully evaluated, not to underestimate the clinical stage nor to over-estimate the impact of a temporary situation. At the present time, diseases with a variable and unpredictable course, such as intestinal dysmotility disorders, or quality of life and financial issues are still far from being considered as indications for a pre-emptive transplant.

Pediatric patients with irreversible intestinal failure present a significant challenge to meet the nutritional needs that promote growth. From 2002 to 2013, 13 living-related small intestinal transplantations were performed in 10 children, with a median age of 18 months. Grafts included isolated living-related intestinal transplantation (n=7), and living-related liver and small intestine (n=6). The immunosuppression protocol consisted of induction with thymoglobulin and maintenance therapy with tacrolimus and steroids. Seven of 10 children are currently alive with a functioning graft and good quality of life. Six of the seven children who are alive have a follow-up longer than 10 years. The average time to initiation of oral diet was 32 days (range, 13-202 days). The median day for ileostomy takedown was 77 (range, 18-224 days). Seven children are on an oral diet, and one of them is on supplements at night through a g-tube. We observed an improvement in growth during the first 3 years post-transplant and progressive weight gain throughout the first year post-transplantation. Growth catch-up and weight gain plateaued after these time periods. We concluded that living donor intestinal transplantation potentially offers a feasible, alternative strategy for long-term treatment of irreversible intestinal failure in children.

Intestinal failure and associated parenteral nutrition-induced liver failure cause significant morbidity, mortality, and health care burden. Intestine transplantation is now considered to be the standard of care in patients with intestinal failure who fail intestinal rehabilitation. Intestinal failure-associated liver disease is an important sequela of intestinal failure, caused by parenteral lipids, requiring simultaneous liver-intestine transplant. Lipid minimization and, in recent years, the emergence of fish oil-based lipid emulsions have been shown to reverse parenteral nutrition-associated hyperbilirubinemia, but not fibrosis. Significant progress in surgical techniques and immunosuppression has led to improved outcomes after intestine transplantation. Intestine in varying combination with liver, stomach, and pancreas, also referred to as multivisceral transplantation, is performed for patients with intestinal failure along with liver disease, surgical abdominal catastrophes, neuroendocrine and slow-growing tumors, and complete portomesenteric thrombosis with cirrhosis of the liver. Although acute and chronic rejection are major problems, long-term survivors have excellent quality of life and remain free of parenteral nutrition.

A 59-year-old man with short-bowel syndrome received a small bowel transplantation. Because the recipient complained of severe abdominal pain 40 hours after the surgery and was highly suspected of having mesenteric vascular thrombosis, contrast-enhanced sonography (CEUS) was performed at his bedside. CEUS demonstrated that the superior mesenteric artery was patent, but the bowel graft showed hypoenhancement, indicating severely inadequate perfusion of the graft. Due to this complication, the patient underwent an exploratory laporatomy, and the bowel graft was removed. The pathologic findings support the diagnosis of acute vascular rejection after intestinal transplantation. This case suggests that CEUS can be used to assess perfusion and vascular complications after intestinal transplantation, as it is noninvasive and easily performed at bedside.

The increasing shortage of donors and the adverse effects of immunosuppression have restricted the impact of solid organ transplantation. Despite the initial promising developments in xenotransplantation, roadblocks still need to be overcome and this form of organ support remains a long way from clinical practice. While hepatocyte transplantation may be effectively correct metabolic defects, it is far less effective in restoring liver function than liver transplantation. Tissue engineering, using extracellular matrix scaffolds with an intact but decellularized vascular network that is repopulated with autologous or allogeneic stem cells and/or adult cells, holds great promise for the treatment of failure of organs within gastrointestinal tract, such as end-stage liver disease, pancreatic insufficiency, bowel failure and type 1 diabetes. Particularly in the liver field, where there is a significant mortality of patients awaiting transplant, human bioengineering may offer a source of readily available organs for transplantation. The use of autologous cells will mitigate the need for long term immunosuppression thus removing a major hurdle in transplantation.

An international symposium convened September 9-11, 2010, in Chicago to present the state of the art and science of the multidisciplinary care of intestinal failure in children. Medical and surgical management of the child with intestinal failure was presented with a focus on the importance of multidisciplinary intestinal failure management. Issues of timing of referral and benefit risk analysis for intestine "rehabilitation" and transplant were presented. Areas of opportunity such as increased donor recovery, improvement of long-term transplant outcomes, optimization of immune monitoring, and quality-of-life outcomes were reviewed.

Pediatric candidates for combined liver/bowel transplant (LBTx) experience a very high mortality on the cadaver waiting list. Our transplant center has successfully used adult living donors to treat pediatric candidates for LBTx. We report the long-term follow-up of this unique cohort of organ donors. The charts of six adult donors for LBTx performed between 2004 and 2007 were reviewed. All the pertinent clinical data were carefully reviewed and integrated with phone interviews of all donors. A total of six children (average age 13.5 months) received living donor LBTx. Average follow-up for the donors was 42 months (range 29-51). The donors' median age was 25 yr (19-32); five women and one man. The average median hospital stay was nine days. There were no peri-operative complications. At present all donors remain in good health. Three of the five mothers became pregnant after donation. Five of the six children are currently alive and well whereas one died with functioning grafts six months post-transplant due to plasmoblastic lymphoma. Living donor LBTx is an effective therapy for combined hepatic and intestinal failure in children less than five yr. The donor operation can be performed with minimal morbidity.

To analyze the current status of living donor intestinal transplantation (LDIT) as a treatment option for intestinal failure.

Long-term outcomes from LDIT and combined living donor intestinal/liver transplantation (CLDILT) are comparable with those from transplantation using deceased donors. In certain life-threatening situations, especially in pediatric patients, this strategy may offer potential advantages.

According United Network for Organ Sharing (UNOS) data children with intestinal failure affected by liver disease secondary to parenteral nutrition have the highest mortality on a waiting list compared with all candidates for solid organ transplantation. Elective nature of CLDILT offers multiple advantages for this patient population. LDIT also could be life-saving option for patients with intestinal failure who run out of venous access. Optimal timing, short ischemia time and good human leukocyte antigen (HLA) matching may contribute to lower postoperative complications. Current literature suggests that living intestinal donors experience very low morbidity and high level of satisfaction.

This review highlights current outcomes in intestinal transplantation and summarizes advances that have recently occurred in five interrelated areas: progress in intestinal rehabilitation, immunologic and technical modifications, awareness of opportunities for improved allograft monitoring, and better assessment of long-term complications and morbidities.

Improved long-term management of patients with intestinal failure as well as improved outcomes with intestine transplant are changing the previously established paradigms of timing for referral. For those requiring transplant, use of monoclonal and polyclonal antibody induction protocols have been associated with improved outcomes. Experience at centers of excellence demonstrates 1 and 5 year patient survival rates of 93 and 78%, respectively with ongoing investigations focusing on lowering long-term causes of graft loss such as chronic rejection or morbidities such as renal dysfunction. Descriptions of tissue, proteomic and genomic technologies to complement traditional methodologies to monitor graft function are emerging.

Optimal timing for referral of children with intestinal failure and improved medical and surgical therapies increase the opportunity for intestinal adaptation without the need for transplant. For those undergoing transplant, technical and immunologic modifications, developments in graft monitoring, and reduction of long-term morbidities are leading to improved outcomes.

Irreversible intestinal failure in children is predominantly caused by surgical conditions such as volvulus, necrotizing enterocolitis, and gastroschisis. Functional intestinal failure from motility disorders such as intestinal pseudo-obstruction or enterocyte dysfunction with microvillus inclusion disease also may require intestine replacement. Approved indications for intestinal transplantation include liver dysfunction, loss of major venous access, frequent central line-related sepsis, and recurrent episodes of severe dehydration despite intravenous fluid management. Surgical options include transplantation of the isolated intestine, combined liver-intestine transplantation, or multivisceral transplantation of the stomach, duodenum, pancreas, and small bowel (with or without the liver). Immunosuppression for intestinal transplantation is based on tacrolimus therapy, often with induction immunosuppression using antilymphocyte antibodies (eg, antithymocyte antibody and alemtuzumab). Experience at centers of excellence demonstrates 1- and 5-year patient survival rates of 95% and 77%, respectively, with ongoing investigations focusing on lowering long-term causes of graft loss such as chronic rejection.

This article reviews the most current indications, technical aspects and results of intestinal and multivisceral transplantation.

The introduction of induction therapy in the past 8 years, combined with advancements on surgical technique and clinical management, was vital for the improvement in patient and graft survival.

Intestinal transplantation is now a viable option for patients with intestinal failure who have failed parenteral nutrition. The improvement in the survival of intestinal and multivisceral transplant recipients has extended its use to selected patients with neoplastic disease, extensive splanchnic thrombosis and abdominal catastrophes.