Intestinal Transplantation Treatment & Management

Updated: Mar 16, 2021
  • Author: Oya M Andacoglu, MD; Chief Editor: Mary C Mancini, MD, PhD, MMM  more...
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Treatment

Surgical Therapy

Procurement

The basic steps of the procurement of an isolated small bowel graft are as follows:

  • Decontamination of the donor bowel via a nasogastric tube (program specific; not universal)

  • Administration of antithymocyte globulin, muromonab, basiliximab, and/or corticosteroids to the donor (program specific; not universal); this needs to be discussed with other procuring teams (eg, cardiac team) to make sure they agree with administration of these medication to the donor. 

  • Midline or cruciate incision for abdomen

  • Aortic control obtained

  • Exposure of the superior mesenteric artery (SMA) and superior mesenteric vein (SMV) at the root of the mesentery is the key step in intestine procurement. In multi-organ procurement, the surgeons procuring the liver, pancreas, and intestine usually need to operate together to agree on where to divide these vessels, or which branches of the vein to take. Variations in anatomy may be present. This dissection must be performed meticulously and with strict hemostasis in order to prevent hematomas in the pancreas head or other organs. 

  • Small bowel mesentery and mesocolon are protected during mobilization (Cattell-Braasch).  

  • Division points of GI tract are identified (usually proximal jejunum and distal colon). 

  • After cross clamping, the SMA and SMV are divided at the level of the mesentery root. Intestine, liver, and pancreas are removed sequentially. 

  • Iliac arteries, veins, carotid arteries, and jugular and/or innominate veins are procured for vascular conduits, since donor vessels are shared between liver, pancreas, and intestine teams.

  • Note: for living donors, a technique has been described for laparoscopic removal of the allograft. [22]

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Intraoperative Details

The recipient operation proceeds as follows:

  • Once the graft is harvested, the SMA may be lengthened with a vascular conduit from the same donor (eg, carotid artery to SMA) in the recipient operation.

  • Colon graft can be stapled off at terminal ileum if recipient has sufficient functional colon.  

  • Recipient operation starts with exploratory laparotomy and lysis of adhesions, which is usually challenging due to multiple previous surgeries.

  • Remaining intestine is stapled off and removed.  

  • The SMA, infrarenal aorta, and infrarenal vena cava are exposed.

  • If vascular conduit is used, these are sewn first: venous graft to recipient cava and arterial conduit to infrarenal aorta. SMA-to-SMA and SMV-to-SMV approach can be used as well. 

  • After reperfusion, hemostasis is obtained.

  • The proximal and distal ends of the intestinal graft are anastomosed to the proximal and distal ends of the remnant digestive track. Gastrostomy tube is placed for tube feeding. 

  • A loop ileostomy is created for postoperative endoscopic surveillance. 

  • The completed procedure is illustrated in the image below.

  • Isolated intestinal transplant. A gastrostomy tube Isolated intestinal transplant. A gastrostomy tube, jejunostomy tube, and loop ileostomy are in place.
  • Tension-free closure is necessary to prevent graft malperfusion. Mesh closure or staged closure approach are commonly utilized. 

  • Transplantation of the abdominal wall is also described. [30, 31]

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Postoperative Care and Immunosupression

Induction therapy is initiated intraoperatively. The most commonly used agents are T-cell–depleting agents (thymoglobulin), interleukin 2 (IL-2) receptor antagonists (basiliximab), anti-CD52 (alemtuzumab). [32, 33] High-dose intravenous corticosteroid is also given in the operating room. Maintenance immunosuppressive regimens are combinations of tacrolimus, steroids, and mycophenolate.

Patients require intensive care unit (ICU) monitoring and frequent lab studies for close postoperative monitoring. 

Endoscopic surveillance and surveillance biopsies start in the first postoperative week and can be done as often as twice weekly. Tube feeding with low-fat formula is initiated if there is no immediate graft concern (usually after first endoscopy). Oral intake usually follows succesful initiation of tube feeds and is advanced gradually. 

The transplanted intestine initiates peristalsis immediately after reperfusion but in a less orderly fashion, because the graft does not have extrinsic innervation. Therefore, ultimate motility and functionality of the graft can be variable. 

The carbohydrate- and amino acid–absorptive capacity of the transplanted intestine normalize within the first several months. Fat absorption is impaired for several months following intestinal transplantation. Absorption of dietary lipids, which are primarily composed of long-chain triglycerides, depends on lymphatic drainage. Medium-chain triglycerides can be directly absorbed into the portal circulation. Consequently, supplemention of enteral feeds with medium-chain triglycerides is necessary for several months following transplantation. Intermittently supplementing the diet with intravenous fats and fat-soluble vitamins (vitamin D, E, A, and K) may be necessary until the intestinal lymphatics are reestablished.

Once patient reaches goal caloric intake via enteral route, total parenteral nutrition (TPN) is discontinued.

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Follow-up

Once patients are discharged from hospital, the primary issues are as follows:

  • Nutritional status
  • Oral intake
  • Tolerance of tube feeds
  • Weaning from TPN
  • Keeping up with ileostomy losses
  • Hydration
  • Drain care
  • Surveillance endoscopies
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Complications

Infectious Complications 

Patients undergoing intestinal transplant have higher incidence of infectious complications compared with other solid organ recipients due greater immunosuppression levels. [34, 35] Infectious complications and sepsis are the leading cause of death in intestinal transplantation patients, account for 48% of all deaths within 5 years of transplant  [36] . An autopsy series found that even in cases in which sepsis was not the immediate cause of death, 94% of patients had a coexisting infection.

Posttransplant lymphoproliferative disease (PTLD) and graft rejection can lead to breakdown of the mucosal barrier, resulting in bacteremia or fungemia. [37]

The most common infectious organisms include Escherichia coli, Klebsiella, Enterobacter, staphylococci, and Enterococcus. A single-center study found the most common pathogens isolated were Pseudomonas (19%), Enterococcus (15%), and E coli (13%). [18]

Primeggia et al reported a 30-day postoperative infection rate of 57.5% and mean time to first infection of 10.78 ± 8.99 days. [18] The most common sites of infection were the abdomen, followed by the lungs, surgical site, and urinary tract.

Cytomegalovirus (CMV) infection reportedly occurs in 15-30% of patients receiving intestinal grafts and often involves the intestine allograft. [38] CMV disease is one of the most serious infections that can occur after a transplant because it can lead to graft loss and even death. The incidence of CMV disease is highest in CMV-negative recipients who receive CMV-positive grafts. For that reason, transplantation of isolated intestines from CMV-positive donors to CMV-negative recipients is often avoided.

Patients can be only viremic or may have tissue/organ disease. Patients with CMV enteritis usually present with fever, increased stoma output, and GI symptoms. Besides routine blood CMV tests, CMV inclusions are investigated in tissue samples (ie, surveillance biopsies from intestine). Endoscopy usually reveals ulcers and friable mucosa and histopathology confirms CMV inclusion bodies.

If CMV is diagnosed, the patient should be treated with therapeutic doses of ganciclovir. Foscarnet or CMV immunoglobulin (CytoGam) should be considered in case of ganciclovir resistance. Immunosuppression should be reduced until the CMV infection is controlled.

Epstein-Barr virus (EBV) is also a concern. The risk is higher in EBV-negative recipients who receive an EBV-positive graft. An acute EBV virus infection is typically associated with severe malaise and fever, flulike symptoms, increase of liver enzyme levels, splenomegaly, and lymphadenopathy. Relapse rates have been measured as high as 20%. [39]

Vascular Complications

Many patients with intestinal failure have prothrombotic state and prior episodes of thromboembolic events, and so are at high risk of having these complications. Early recognition is the key to save the graft. 

Post-transplant Lymphoproliferative Disorder

The incidence of PTLD is higher in intestinal transplant recipients than other solid organ transplant recipients. It occurs 2-4 times more often in children than in adults, [40] and the incidence is higher after multivisceral transplantation than isolated intestinal transplantation. Although PTLD tends to manifest in the first year after transplantation, it can occur any time.

Surveillance for PTLD should begin immediately following the transplant using in situ hybridization staining for EBV, and early RNA and EBV polymerase chain reaction (PCR) surveillance.

Two basic approaches exist to prevent PTLD: One is long-term prophylaxis with ganciclovir, valganciclovir, or intravenous immunoglobulin for 3-12 months. The other involves shorter period of prophylaxis (2–6 wk) followed by monthly surveillance and pre-emptive therapy should surveillance identify increased EBV replication.

In a study examining PTLD in pediatric intestinal transplants, Ramos et al found the highest incidence at 4 months post-transplant. [41] These authors found no correlation between immunosuppressant regimen used and PTLD rates, but did find an increased association between EBV- negative recipients receiving an EBV-positive graft. [41] In their cohort, fever was the most common manifestation of PTLD. [41]

Positron emission tomography (PET) scan can be helpful to identify the active lymph nodes, but confirmatory diagnosis and subtyping of lymphoma require biopsy. If the suspected organ is the intestine graft itself, differentiating PTLD from rejection or CMV infection can be difficult. Evaluating the serum for a typical monoclonal or polyclonal immunoglobulin band, which can sometimes be present, is also useful.

Gene studies are often helpful to identify abnormal karyotypes (eg, C-myc, N-ras, p53), which can aid in diagnosis and prognosis as well as to determine whether the abnormal lymphocytes sites are primarily B cells or T cells. Real-time PCR can also be used to detect changes in viral DNA levels. T-cell lymphomas are less common than B-cell lymphomas in PTLDs.

If the diagnosis of PTLD is made, immunosuppression should be reduced. Some cases may require additional therapies, including chemotherapy using R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and/or immunotherapy, depending on the subtype of the lymphoma. Radiotherapy may also be considered. [40]

Rejection

Rejection can occur at any time but is most common in the first year, particularly the first 6 months. Early diagnosis of allograft rejection, a major contributor to both the high morbidity and the high mortality associated with small-intestine transplantation, is essential. Intestinal graft rejection can manifest clinically as fever, abdominal pain, increased output from the ostomy, abdominal distention, acidosis, and malabsorption. It can also be asymptomatic.

To detect rejection, surveillance via endoscopy and intestinal biopsy through the ileostomy are used. A rise in the plasma citrulline level may also be indicative of rejection, although this is not commonly used at present. [42] Diagnosis can be difficult because of the patchy nature of rejection and the presence of bleeding.

In order to identify rejection in a timely manner, surveillance endoscopy of the entire graft is perfomed and random multiple biopsies are obtained.

Histologic evidence of allograft rejection includes mucosal necrosis and loss of villous architecture with transmural cellular infiltrate. Histopathology reveals crypt cell apoptosis, cryptitis or crypt loss, necrosis, and endotheliitis.

Treatment of rejection ranges from pulse corticosteroid administration to more aggressive immunosuppressive regimens, including repeat doses of antithymocyte globulin. 

If the rejection is refractory to treatment and donor-specific anti-HLA antibodies are detected, plasmapharesis and IVIG followed by rituximab and/or bortezomib can be used. [43]

Due to the immunologic properties of the liver itself, combined liver-intestine transplantation provides a greater protective benefit against rejection (ie, lower incidence and severity of acute rejection) than isolated intestinal transplantation does. 

Graft versus host disease

Graft versus host disease (GVHD) is a progressive, potentially fatal complication of intestine transplantation. It occurs in 7-9% of intestinal transplants, [44] more commonly in multivisceral transplants and pediatric patients. GVHD may be difficult to diagnose. Patients with acute GVHD usually present 1-8 weeks after transplantation with fever, leukopenia, diarrhea, or rash; therefore, full skin exam is extremely important. Maculopapular rash in the palms and soles is highly suspicious. Other symptoms may include malaise, anorexia, arthralgia, abdominal pain, or organ-specific issues (eg, liver enzyme elevation if the liver is involved).

Diagnosis should be confirmed by biopsy of the skin or suspected native tissue involved. A study by Crowell et al supported the practice of performing a sigmoidoscopy to examine and biopsy the native sigmoid to rule out GVHD.43

Once the diagnosis is confirmed, or if suspicion is high, treatment is promptly initiated with high-dose steroids and/or antithrombocyte globulin.

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Outcome and Prognosis

Intestinal transplantation has much more complex immunologic alterations and requires higher immunosuppressive levels compared with other solid organ transplants. As a result, life-threatening opportunistic infections and other rare immunologic complications (eg, graft versus host disease [GVHD]) are more commonly seen in this population. With broader understanding of immonology, advances in immunosuppression, and advances in the management of all complications, patient and graft survival rates are much improved. 

Graft failure has declined since the late 1990s, but plateaued over the past decade, and early graft loss has increased in the past 2 years, notably in recipients of a combined liver and intestine allograft. In 2012‐2014, the 1‐ and 5‐year graft survival for intestine transplants with or without a liver was 81.1% and 60.8%, respectively, for recipients aged younger than 18 years and 68.9% and 44.7% for recipients aged 18 years or older. In 2012--2014, 1- and 5-year graft survival was 75.6% and 45.6%, respectively, for intestine recipients, and 72.4% and 57.5%, respectively, for intestine‐liver recipients. [1]

The incidence of first acute rejection in the first posttransplant year varies by age group and transplant procedure. Among recipients in 2017‐2018, the incidence of acute rejection was highest in pediatric intestine recipients (62.5%) and lowest in adult intestine‐liver recipients (25.9%) Among recipients in 2007‐2017, posttransplant lymphoproliferative disorder developed within 5 years posttransplant in 9.1% of intestine recipients and 7.7% of intestine‐liver recipients.  Patient survival for transplants in 2012‐2014 was similar by transplant type: 1‐ and 5‐year survival was 82.0% and 57.3% for intestine recipients and 77.6% and 63.2% for intestine‐liver recipients. [1]

Chronic rejection can occur up to 40% of cases. Refractory cases may require graft enterectomy. 

Rehospitalization is common. 

Although children may report improved quality of life after intestinal transplantation, such improvement is not guaranteed. In addition, intestinal transplantation does not necessarily lead to a quality of life comparable to that of other transplant recipients (eg, liver) or the general population. [45, 46, 47]

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Future and Controversies

Major issues regarding intestinal transplant are:

  • High mortality in patients on the waiting list
  • Organ shortage
  • Very difficult balance between immunosuppression and immunosuppression-related complications (very high infection rates)
  • Other immune alteration–related complications (ie, GVHD, PTLD)

Cutting-edge research is being performed on topics such as regulatory T-cells, mesenchymal stem cells, [48] glucagon-like peptide 2 analogue for the treatment of short bowel syndrome, [49] intestinal adaptation after massive small bowel resection, [50] post-transplantation microchimerism, and tolerance. These studies offer the promise of changing the future of transplantation of the small bowel and other solid organs, minimizing complications and further improving outcomes.

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