Intestinal and multivisceral transplantation

Intestinal and multivisceral transplantation is the surgical replacement of the small intestine, either alone or together with other abdominal organs, in people with irreversible intestinal failure who can no longer be safely maintained on long-term parenteral nutrition.[1][2] It is the least common form of solid organ transplantation in routine practice and is performed at a small number of specialized centers.[3][4] Because the transplanted bowel carries a large burden of immunologically active lymphoid tissue, these grafts are among the most immunologically challenging to manage, and they generally require more intensive immunosuppression than other abdominal organ transplants.[2][5] The procedure ranges from transplantation of the small intestine in isolation to "multivisceral" grafts that may include the stomach, duodenum, pancreas, liver, and small intestine as a single unit.[1][6]

Intestinal and multivisceral transplantation is a subspecialty within organ transplantation and is closely related to liver transplantation, since many recipients have concurrent liver disease. The immunology of these grafts is discussed more broadly in transplant immunology.

Graft types

There are four basic categories of intestinal-containing graft, selected according to which native organs are diseased or failing.[1][6]

| Graft type | Organs included | Typical use | |---|---|---| | Isolated intestine | Small intestine alone (sometimes with the pancreaticoduodenal complex) | Intestinal failure with preserved liver function; most common adult graft[1] | | Combined liver-intestine | Liver plus small intestine, often en bloc with duodenum and pancreas | Intestinal failure with irreversible parenteral-nutrition-associated liver disease[1][6] | | Multivisceral | Stomach, duodenum, pancreas, small intestine, and liver | Diffuse disease of the gastrointestinal tract or multiorgan failure[1][6] | | Modified multivisceral | Multivisceral graft excluding the liver | Diffuse foregut/midgut disease with preserved liver function[6] |

"Multivisceral transplantation" is used as an umbrella term for these variations, and grafts are customized to the individual patient.[1] In isolated intestinal transplantation, the donor small intestine is anastomosed to the recipient bowel, and a chimney (Bishop-Koop) ileostomy is created to allow endoscopic surveillance of the graft.[1] In combined liver-intestine and multivisceral grafts, the organs are increasingly procured and implanted en bloc as a single unit, a technique that reduced the high rate of biliary complications seen with earlier separate-organ approaches.[1] When the stomach is included, a pyloroplasty is commonly performed to improve gastric emptying, because the transplanted stomach is denervated.[1]

Indications

The fundamental indication is irreversible intestinal failure, most often from short bowel syndrome, in a patient who can no longer be safely maintained on total parenteral nutrition (TPN).[1][2] Short bowel syndrome is present in up to roughly 70% of recipients.[1] Long-term parenteral nutrition itself can sustain many patients indefinitely, so transplantation is generally reserved for those who develop life-threatening complications of that therapy.[2][7]

Widely cited indications for proceeding to transplantation, derived from the failure of parenteral nutrition, include:[1][2][7]

• Parenteral-nutrition-associated (intestinal-failure-associated) liver disease, ranging from cholestasis to cirrhosis, which is a principal trigger for adding a liver to the graft.[1][2]
• Loss of central venous access, defined by thrombosis or stenosis of central veins limiting the sites available for catheter-delivered nutrition.[1][2]
• Recurrent line sepsis, often defined as two or more episodes of catheter-associated bloodstream infection per year, or a single episode of line-related fungemia.[1][2]
• Frequent severe dehydration or fluid-electrolyte derangement despite parenteral nutrition.[1]

Additional adult indications include extensive mesenteric ischemia or thrombosis, certain intra-abdominal and desmoid tumors requiring evisceration, refractory inflammatory bowel disease, radiation enteritis, motility disorders such as chronic intestinal pseudo-obstruction, and trauma.[1][6] In children, common underlying causes include midgut volvulus, gastroschisis, necrotizing enterocolitis, intestinal atresia, and dysmotility syndromes.[1][8]

Recipient evaluation

Pre-transplant assessment is multidisciplinary and emphasizes both the suitability of the graft and the patient's reserve to tolerate intensive immunosuppression. Components reported in the literature include HLA typing and crossmatching; serologic testing for cytomegalovirus (CMV), Epstein-Barr virus (EBV), hepatitis A, B and C, and HIV; baseline laboratory studies including nutritional markers; cross-sectional imaging such as computed tomography enterography to assess remaining bowel; and venous and arterial duplex imaging to map vascular access and inflow/outflow for the graft.[1] Where parenteral-nutrition-associated liver disease is suspected, liver biopsy helps determine whether a liver-inclusive graft is required.[1] Dental and infectious-source evaluation and, when indicated, cardiac and pulmonary testing are also performed.[1]

Surgical considerations

The operation is technically demanding and varies with graft type. Arterial inflow and venous outflow must be reconstructed, intestinal continuity restored, and (for liver-inclusive and multivisceral grafts) biliary drainage and, where present, the stomach handled.[1] Early vascular thrombosis is the most feared complication; in one large single-center series of 500 transplants the arterial thrombosis rate was reported at 3.8%, and it typically mandates emergent reoperation.[1] Other early complications include anastomotic leaks and venous outflow problems.[1] A surveillance ileostomy is routinely created so the mucosa can be inspected and biopsied during the high-risk early period.[1] Some centers preserve or include a spleen to reduce the risk of overwhelming infection from encapsulated organisms, balanced against a possible increase in graft-versus-host disease risk.[1]

Immunosuppression

Intestinal and multivisceral grafts require more intensive immunosuppression than most other solid organ transplants. This reflects the unique immunology of the bowel: the graft carries a large mass of gut-associated lymphoid tissue (GALT), and intestinal epithelial cells can act as antigen-presenting cells, so the allograft both provokes a strong host response and is itself rich in donor lymphocytes.[5]

Induction therapy commonly uses lymphocyte-depleting or interleukin-2 receptor-blocking agents, including rabbit anti-thymocyte globulin, alemtuzumab, or an interleukin-2 receptor antagonist (for example basiliximab or, historically, daclizumab).[5] Alemtuzumab has been associated with higher infection-related morbidity and mortality in very young children.[5] Maintenance immunosuppression is typically tacrolimus-based, often combined with mycophenolate mofetil and corticosteroids, with relatively high tacrolimus trough targets in the early postoperative months (reported in some protocols as above 10 ng/mL for the first three months, then 8 to 12 ng/mL).[1][5] The introduction of tacrolimus in the early 1990s substantially improved outcomes compared with the earlier ciclosporin era.[1]

Rejection and graft-versus-host disease

Acute cellular rejection is frequent, particularly in the first months. In pediatric series, acute rejection has been reported in roughly 40% of children within the first three months.[5] Chronic rejection has been reported in approximately 20% of isolated intestinal grafts and about 5% of multivisceral grafts.[5] Diagnosis rests on endoscopic mucosal biopsy, which remains the gold standard; the ileum is sampled preferentially because of its dense Peyer patches.[1] Low serum citrulline and elevated fecal calprotectin are being studied as noninvasive markers of graft injury.[1] Liver-inclusive grafts appear to confer some protection, with reductions in acute and chronic rejection reported when the liver is co-transplanted.[1]

Because the graft carries donor immune cells, graft-versus-host disease (GVHD), in which donor lymphocytes attack recipient tissues, is a distinctive risk. Reported incidence is on the order of 4% to 10%, higher with multivisceral than isolated intestinal grafts.[1][5] Although uncommon, GVHD is dangerous: mortality as high as roughly 70% has been reported once it occurs.[1] Confirmation typically uses immunohistochemistry and chimerism testing by polymerase chain reaction.[1]

Infection risk

Infection is the dominant cause of morbidity, driven by the intensity of immunosuppression and the large microbial load of the gastrointestinal tract. In multivisceral recipients, post-transplant infection has been reported in up to 94% of patients.[1] CMV is of particular concern because of its tropism for gastrointestinal cells, and adenovirus and other viral infections are common; CMV infection has been reported in about 30% and adenovirus in about 20% of recipients in pediatric series.[1][5] EBV-driven post-transplant lymphoproliferative disorder (PTLD) is a recognized complication, with reported incidence on the order of 5% to 10% for intestinal recipients and higher for multivisceral recipients.[5]

Outcomes and survival

Outcomes have improved markedly since the early experience but remain lower than for most other abdominal organ transplants, reflecting the immunologic difficulty and the severity of underlying illness. Since the late 1980s the one-year survival rate has risen from roughly 40% to over 80%.[1] In a single-center review of 500 transplants, patient survival was reported at 85%, 61%, and 42% at 1, 5, and 10 years, and graft survival at 80%, 50%, and 33%, respectively; about 85% of survivors achieved normal functional status with freedom from parenteral nutrition.[1]

National United States registry data from the OPTN/SRTR 2023 Annual Data Report (cohorts transplanted 2016 to 2018) show the following graft and patient survival, with outcomes generally better in pediatric than adult recipients:[3]

| Group | 1-year graft survival | 5-year graft survival | 1-year patient survival | 5-year patient survival | |---|---|---|---|---| | Adult, intestine without liver | 78.3% | 46.5% | 89.8% | 62.5% | | Adult, intestine with liver | 57.8% | 45.6% | 62.2% | 50.0% | | Pediatric, intestine without liver | 76.1% | 52.2% | 91.3% | 78.3% | | Pediatric, intestine with liver | 81.1% | 60.0% | 82.1% | 65.3% |

These figures are point-in-time registry statistics and should be re-confirmed against the linked primary OPTN/SRTR pages.

United States volumes and trends

Intestinal transplantation is a low-volume procedure. According to the OPTN/SRTR 2023 Annual Data Report, 95 intestine transplants were performed in the United States in 2023, up from 82 in 2022, and the report characterized rates as stable over the preceding several years.[3] As of December 31, 2023, there were 167 candidates listed for intestine-without-liver and 182 for intestine-with-liver transplant.[3] The OPTN/SRTR 2024 Annual Data Report reported that the intestine transplant waiting list stood at 339 candidates in 2024, down slightly from 349 in 2023.[4] These counts are moving-target statistics as of the 2023 and 2024 reporting years and should be re-confirmed against current OPTN national data at publication.[4][9]

Pediatric considerations

Children make up a substantial share of intestinal transplant recipients, and their indications differ from adults', led by congenital and neonatal causes such as gastroschisis, midgut volvulus, necrotizing enterocolitis, and intestinal atresia.[1][8] Pediatric recipients tend to have better long-term graft and patient survival than adults for both liver-inclusive and liver-exclusive grafts.[3] At the same time, children carry distinct risks: acute rejection in the early months is common, and very young children appear especially vulnerable to infection-related complications of certain depleting induction agents.[5] Advances in intestinal rehabilitation and parenteral-nutrition management have allowed more children to avoid or defer transplantation.[2][7]

History

Experimental multivisceral transplantation was pioneered by Thomas E. Starzl, who described the multivisceral graft concept in canine experiments in 1960.[1] Clinical success in humans came only decades later, as immunosuppression improved. The first patient discharged from hospital after intestinal transplantation occurred in December 1989, with that recipient surviving about ten months free of parenteral nutrition.[1] The introduction of tacrolimus in the early 1990s was a turning point that markedly improved graft and patient survival, moving the field from an experimental procedure toward an accepted therapy for irreversible intestinal failure.[1][2]

See also

• Organ transplantation
• Liver transplantation
• Transplant immunology

References

• Grant J, et al. "Intestinal and Multivisceral Transplantation." StatPearls. NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK564370/
• "Intestinal transplantation." In: Surgical Treatment: Evidence-Based and Problem-Oriented. NCBI Bookshelf (NBK6902). https://www.ncbi.nlm.nih.gov/books/NBK6902/
• OPTN/SRTR 2023 Annual Data Report: Intestine. Scientific Registry of Transplant Recipients (SRTR), HRSA. https://srtr.hrsa.gov/adr/2023/Intestine
• OPTN/SRTR 2024 Annual Data Report: Overview of US Solid Organ Transplantation. SRTR, HRSA. https://srtr.hrsa.gov/adr/2024/Overview/
• "Intestinal/Multivisceral Transplantation." PMC (PubMed Central), article PMC7122145. https://pmc.ncbi.nlm.nih.gov/articles/PMC7122145/
• "Multivisceral Transplantation - an overview." ScienceDirect Topics. https://www.sciencedirect.com/topics/medicine-and-dentistry/multivisceral-transplantation
• "Indications for Multivisceral Transplantation." Gastroenterology Clinics of North America. https://www.gastro.theclinics.com/article/S0889-8553(24)00007-4/abstract
• "Multivisceral transplantation: expanding indications and improving outcomes." PubMed (PMID 23070622). https://pubmed.ncbi.nlm.nih.gov/23070622/
• Organ Procurement and Transplantation Network (OPTN), National Data. HRSA. https://www.hrsa.gov/optn