Intestinal and Multivisceral Transplantation

Indications

Operative indications vary from children to adults, but intestinal transplant is considered when intestinal failure has led to multi-organ dysfunction. Gastrointestinal failure is met when the body can no longer maintain the delicate balance of proteins, fats, carbohydrates, electrolytes, fluids, and micronutrients.[3] The most common cause of failure is short bowel syndrome, which can be present in up to 70% of transplant recipients.[4]  While not every short bowel syndrome diagnosis ultimately requires MVT, additional variables factor into whether MVT would be indicated.

• Multiple infections in the parenteral central line (2+ episodes yearly or a single episode of fungemia)
• Organ dysfunction secondary to parenteral nutrition – most commonly liver
• Peripheral and central venous thrombosis/stenosis limiting central venous access to parenteral nutrition
• Frequent dehydration in the setting of concurrent parenteral nutrition and intravenous fluids

Other common indications for MVT for adults include short bowel syndrome, mesenteric ischemia (arterial or venous), abdominal neoplasms, inflammatory bowel disease (typically leading to short bowel syndrome), radiation enteritis, and trauma. Common indications for MVT for children include volvulus (most common indication), gastroschisis, necrotizing enterocolitis, intestinal dysmotility diseases (ex aganglionosis, Hirschsprung's disease), intestinal atresias, and short bowel syndrome.[5][6]

Contraindications

Similar to other guidelines laid out for solid organ transplants, the contraindications for MVT can include:[5][7]

• The metastatic disease is not treatable with transplantation
• Unmanaged/untreatable systemic or local infections
• Cardiopulmonary disease limiting positive outcomes
• Lack of adequate family or social support
• Active drug or alcohol addiction

Personnel

As with most transplant surgeries, an interdisciplinary team is critical for patient outcomes. Depending on the planned en bloc transplantation, medicine and surgical evaluation are required in the pre-and post-transplant phases. Medical teams include hepatologists, dietitians, case managers, social workers, transplant nurse coordinators, transplant surgeons, and physical and occupational therapists. Each member plays a vital role in long-term recovery. In some cases, psychiatric evaluation is required in the setting of alcohol/drug use; however, a significant number of transplants are those of children and may not require formal evaluation.

Preparation

The following workup should be performed:

• HLA typing and blood crossmatching
• Laboratory: CBC, CMP, prealbumin, coagulation panel
• Serologic: cytomegalovirus, Epstein-Barr virus, hepatitis A, B, and C, HIV
• Evaluation of bowel length and function utilizing computed tomography enterography

Venous and arterial duplex of the intraabdominal vascular system. Splenoportography and mesentericography are only required for select patients utilizing the Miami classification. Depending on the class, recipients may also be required to undergo vein or arterial angioplasty preoperatively.[8] Donor liver biopsy. Liver biopsy in recipients in the setting of parenteral nutrition-induced liver dysfunction. Dental and possibly ENT consults to limit infectious sources. Sometimes, it requires dental extraction. Systemic disease evaluation and peri-operative risk modification tailored to the patient. It could include coronary angiography, pulmonary function tests, and nutritional status.

Technique or Treatment

Isolated Intestinal Transplantation (IITx)

IITx is performed more in adults than in children (14), with the ability also to operate with a living donor. The IITx can also be modified to include the pancreaticoduodenal complex. In a deceased donor, the mesenteric arterial supply and venous drainage are identified and dissected clearly. The aorta is cross-clamped and flushed with the University of Wisconsin solution. The SMA is freed, including a segment of the aorta, and the splenic vein is ligated at the junction of the SMV. Depending on the patient – a segment of the ascending colon, along with the right and middle colic arteries, can also be freed. The donor small intestine is inserted in a side-to-side anastomosis and placed on the proximal host duodenum/jejunum. The distal end is created with either the native colon or a segment of the ileocecal complex. Critical to the transplantation of an end chimney, or Bishop-Koop, the ileostomy allows frequent transtomal endoscopic access for routine postoperative graft surveillance. The arterial system is then restored with anastomosis to the intrarenal aorta and the venous system to the portal vein or infrarenal vena cava.[9][10]

The operation is modified in a living donor to allow both individuals adequate bowel for vitamin and bile absorption. Typically, about 150 cm of an ileal segment of the donor is isolated, along with its vascular pedicle, and removed. The remaining donor ileum is reconnected in an ileo-ileal anastomosis. The donor vascular pedicle is attached from the end to the side onto the recipient's ileocolic artery and vein. Depending on the recipient’s anatomy and intra-operative findings, vascular anastomosis may also be created using the infrarenal aorta and inferior vena cava. The distal ileocecal intestinal complex on the donor remains to allow for adequate B12 absorption.

Combined Liver-Intestine

Patients with compromised liver function, typically secondary to prolonged parenteral nutrition – more commonly seen in children, undergo combined liver-intestine transplants. In the 1990s, the liver and bowel were transplanted in a separate fashion, and then a Roux-en-Y choledochojejunostomy reconstruction was performed, restoring the biliary system. This led to a high rate of biliary-related complications, leading to en bloc transplantation.[10] The organs are harvested as one unit, and the critical structures are identified and cleaned on the back table. The host hepatectomy is performed. Arterial and venous end to side anastomosis is then attached to the host aorta and IVC, respectively. The host duodenum and pancreas are left in place. The donor pancreaticoduodenal complex is placed over the respective anatomical location, and the host distal duodenum is then anastomosed in the end-to-side fashion to the donor jejunum. As a result, the patient has two duodena and two pancreata.[11]

Multivisceral

There is no true consensus on what multi-visceral transplant organs are standard, and the concept of a multi-visceral transplant can be considered an umbrella term for all variations. The allograft is tailored to the individual patient’s need with the exclusion or inclusion of multiple organs (eg, kidney and spleen). The main difference between the combined liver intestine is the addition of the stomach into the graft, but this can be modified to exclude the liver. Due to the denervation of the stomach graft, a pyloroplasty is performed, which allows for improved gastric emptying. The proximal host esophagus, or sometimes a segment of the host stomach, is anastomosed to the donor's stomach, and the vascular conduits are restored similarly as the other types of intestinal transplantation.[12]

Complications

Rejection

Considered to be the largest lymphoid organ, the small bowel creates a substantial lifelong challenge for managing both acute and chronic allograft rejection. The introduction of novel immunosuppression agents in the 1990s catapulted MVT into a viable armamentarium for patients. Graft survival did not significantly change after the introduction of cyclosporin A compared to the improvements seen in other solid organ transplants. It was not until the introduction of tacrolimus in the 1990s that patient outcomes and rejection rates improved.[13] Typical maintenance therapy includes tacrolimus, mycophenolate mofetil, and prednisone. Due to the vague clinical manifestation of rejection symptoms (increased stoma output, abdominal discomfort distension, and weight loss), routine surveillance of rejection is performed at planned intervals on an institutional basis. 

Histologic confirmation of rejection is considered the gold standard for diagnosis. The tissue is obtained through endoscopic transitional biopsies taken from multiple areas of the graft, with increased suspicion of rejection in ileal segments due to the increased amount of Peyer patches. Depending on the surgical approach, biopsies of the transplanted abdominal wall flap can provide a less invasive approach to the diagnosis of rejection. The development of laboratory screening has also played a role in the early recognition of rejection. Low serum citrulline levels and high fecal calprotectin are emerging as reliable, noninvasive measures of allograft rejection.[14][15] There also has been some data to suggest that combined liver-intestinal transplants, compared to intestinal transplantation alone, offer a benefit regarding the reduction of acute and chronic rejection.[16][17]

Graft versus Host Disease (GVHD)

Graft versus host disease occurs when donor cells recognize the host cells as foreign antigens and begin to mount a donor-mediated immune response against the recipient tissue. Along with the significant concerns of rejection in intestinal transplants, the amount of lymphoid tissue also creates concerns about the allograft assaulting the recipient. Thankfully, the incidence is relatively low (approximately 6%), but GVHD carries significant mortality, as high as 70%.[18]  Diagnosis is through polymerase chain reaction and immunohistologic staining. Treatment includes increasing immunomodulating drugs and even stem cell therapy.[19] Risk factors for GVHD include younger age and spleen in the en bloc transplantation. Although a single center reporting 100 MVTs did not see a statistically significant increase in GVHD when transplanting the spleen. Other solid organ transplantations have expressed a theoretical increase in GVHD when combined with a splenic transplant.[20]

PTLD

PTLD is a well-documented complication for many solid organ transplantations and should be briefly mentioned in this review of complications. While not classified as a single disease, it is more of a syndromic presentation that involves potentially neoplastic lymphocytic proliferation that can create a difficult and deadly presentation for post-transplant care. The growths are common in B lymphocyte origin, which is typically related to Epstein-Barr virus. Treatment includes reduction of immunosuppression and antiviral therapy, but this comes with the risk of graft failure secondary to rejection. The median time for development for one institution was 25.3 months, and all patients could recover clinically. There has been some data to suggest that the transplantation of the spleen could increase the incidence of PTLD.[21]

Infections

Opportunistic infections, from bacterial to viral, are well-established as a necessary risk in all solid organ transplantations. Subjecting the body to immunosuppression medication opens the body up to life-threatening otherwise unremarkable infections in immunocompetent individuals. Some institutions make every effort to preserve the native spleen to prevent acquired asplenic opportunistic infections (from encapsulated bacteria) and attempt to reduce the incidence of asplenic sepsis. In the setting of MVT, cytomegalovirus is a clinically significant pathogen due tocytomegalovirus's higher tropism in gastrointestinal cells and the increased amount of potential cellular hosts (due to the increased lymphoid cells in the small bowel). In one study, up to 94% of MVT patients developed infections post-transplant.[22][23]

Surgical Complications

Post-surgical complications vary depending on the organs transplanted but tend to occur in the early post-transplant period. These can include anastomotic leaks, arterial and venous graft thrombosis, and bleeding. Some are managed non-operatively, but the most feared complication is arterial thrombus, creating an emergent relaparotomy. Unfortunately, the graft can often not be salvaged in this setting, and retransplantation may be required. Signs of arterial graft thrombosis are like that of acute mesenteric ischemia. In a single institution of 500 transplants, the arterial thrombosis incidence was 3.8%[24]

Clinical Significance

Intestinal and Multivisceral transplants have progressed from a highly morbid surgery in the late 1980s to a life-altering intervention. A review of 500 transplants shows patient survival rates at 1, 5, and 10 years to be 85%, 61%, and 42%, respectively. Graft survival rates were lower than patient survival rates at 80%, 50%, and 33%, respectively.[25] Studies comparing parenteral nutrition to MVT show a statistically significant increase in functional status, decreased anxiety, and quality of life.[26] Approximately 85% of patients reported having normal functional status.[27]

Enhancing Healthcare Team Outcomes

Multivisceral transplant combines the anatomy and physiology of multiple systems, requiring a robust and active multidisciplinary team. Each provider, from dietitian to therapist, plays a critical role in the profound improvement in the quality of life that MVT provides. Leading institutions have been more aggressive at transplanting earlier due to the life-changing improvements. Over the past three decades, patient outcomes have improved over two-fold – largely due to establishing a dedicated interdisciplinary team. The team must be proactive in following up with pre and post-transplant patients. Patients from lower socioeconomic environments and pediatric populations benefit from close surveillance; this improves compliance and early recognition of potential complications.[28]