Bowel Transplantation for Inflammatory Bowel Disease

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Introduction

Bowel transplantation has become a valuable option for patients with intestinal failure or short-bowel syndrome who do not tolerate total parenteral nutrition or have no vascular access for TPN. Up until March 31, 2005, a total of 1292 intestinal transplants (in altogether 1210 patients) have been reported to the international registry. Of these 1292 transplants, 570 of them were isolated small-bowel transplants, 490 combined small-bowel/liver transplants, and 232 were multivisceral transplants. Additionally, 772 transplants were performed in 721 pediatric recipients and 520 transplants in 489 adult patients [1].

It goes without saying that no bowel transplantation was done for inflammatory bowel diseases in the pediatric group, but 68 transplants were performed in adults for this indication. In total, we have experience with 16 isolated small-bowel transplants and ten multivisceral transplants, and four of the isolated intestinal transplants in three patients were performed for Crohn’s disease.

Presently, appropriate indications, the timing of referral and the outcome of bowel transplantation are not well recognized among physicians caring for patients who may be candidates for this therapeutic option. Definitions of terms such as “intestinal failure” and “failure of parenteral nutrition” are not standardized and there is no accepted algorithm that integrates parenteral nutrition, intestinal rehabilitation and transplantation for patients with intestinal failure.

Herein, with special emphasis on inflammatory bowel diseases, we review the various aspects of bowel transplantation such as the indications for it, the current state of medical practice in intestinal transplantation, and its outcome.

History

Intestinal transplantation techniques were developed in animal models in 1959 and first attempted in

humans in 1964 [2]. In those days, immunosuppression consisted of steroids and azathioprine after induction with an antilymphocyteglobulin. Under this type of rejection prophylaxis, altogether eight isolated intestinal transplants were performed. The first two transplants performed in Boston in 1964, however, have never been officially reported as files remain untraceable. The first well-documented case was reported from Minneapolis in 1967 [3]. Under unconventional immunosuppression, all but one graft failed within a few days. The last graft in this series was from a HLA identical sister and survived for 79 days. The recipient was able to be fed orally from day 23 until day 60 [4].

The first bowel transplant in the Cyclosporine era was performed in 1985 in Toronto [5]. Patient No. 8 in this series received 60 cm of jejunoileum from her sister in 1988 and became the first long-term sur- vivor. It has to be said, however, that oral food intake was never sufficient and had to be supplemented by parenteral infusions. The patient experienced several episodes of rejection, developed end-stage renal disease and died a few years later [6].

On March 19, 1989, a 5-month old girl received 80 cm of jejunoileum from a neonate. This patient transplanted in Paris is still alive and well with a nor- mally functioning graft [7]. Already in 1960, Starzl reported on a series of multivisceral transplants in dogs [8]. The same author performed the first human multivisceral transplant in 1983 in a 6-year-old girl in Pittsburgh. The girl, however, died only a few hours after surgery from exsanguination. The same hap- pened to a 1-year-old male who underwent transplantation in 1986 in Chicago. In 1987, Starzl performed another transplantation in a 3.5-year-old girl and Williams in Chicago did the same in the following year in a 0.7-year-old neonate. Both children died 192 and 109 days, respectively, after transplantation from lymphoma. The type of IS consisted of OKT3 induction followed by cyclosporin and steroids. Both children were never discharged from the hospital [9, 10].

On December 26, 1989, a multivisceral transplant was carried out for the first time in an adult recipient

Bowel Transplantation for Inflammatory Bowel Disease

Raimund Margreiter

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48 years of age in Innsbruck. This patient lived on oral food intake for 9 months when he died from tumor recurrence [11].

On November 13, 1988, Grant performed the first combined small-bowel/liver transplantation in Lon- don/Ontario in a 41-year-old woman with short-gut syndrome with a hypercoagulable state associated with low antithrombin III levels. The patient survived for several years [12].

Indications

It is now generally accepted that small-bowel transplantation is indicated in patients suffering from irreversible small-intestinal failure coexisting with failure of parenteral nutrition. The main causes of parenteral nutrition failure are recurrent line related sepsis, loss of venous access due to thrombosis and PN-related liver disease. Medicare and Medicaid Ser- vices in the US have established indications that include impending or overt liver failure due to TPN- induced liver injury, thrombosis of two or more central veins, the development of two or more episodes of systemic sepsis secondary to line infection per year that require hospitalization, a single episode of line- related fungemia, septic shock and/or acute respiratory distress, and frequent episodes of severe dehydration despite intravenous fluid supplementation in addition to TPN [13].

These criteria should help to avoid late referrals. A timely referral for pretransplant assessment is essential for allowing the optimization of physical and psy- chological factors and should be at a stage when the central venous access is adequate for surgery and management of postoperative complications which may include renal replacement therapy. Unfortu- nately, it is our experience, that most patients are not referred, but rather come on their own initiative.

Diseases Causing Intestinal Failure

Diseases leading to intestinal failure include loss of bowel length, loss of bowel function, or convention- ally unresectable tumors involving the bowel or its feeding vessels. Short-bowel syndrome, the loss of intestinal length and absorptive surface areas due to surgical resection, are the most common cause of intestinal failure leading to bowel transplantation.

The loss of mucosal absorptive surface area is associated with malabsorption and rapid transit through the jejunoileum leading to malnutrition, recurrent dehydration, and electrolyte abnormalities. Short- bowel syndrome can be caused by a variety of condi- tions and diseases in adults such as thrombosis or

embolism to the superior mesenteric vessels, inflammatory bowel disease, volvulus, radiation enteritis, trauma or other causes of infarction.

In pediatric patients, most frequent causes of short-bowel syndrome are malrotation, volvulus, necrotizing enterocolitis, jejunoileal artresias, gas- troschisis, and omphalocele among other congenital disorders. Transplant candidacy has to be considered in the context of alternatives to transplantation including the potential for rehabilitation or successful lifelong parenteral nutrition. In a large series, about 20% of adult patients with less than 100 cm of residual intestine could be weaned from TPN. In children, less than 30 cm of jejunoileum, lack of entero- colonic continuity, and lack of feeding tolerance early after birth correlate to failure of weaning from parenteral nutrition [14].

Functional Disorders

Functional disorders of the small bowel that may lead to intestinal failure include disorders of motility and disorders of enterocyte function. The most common motility disorders are chronic pseudo-obstruction, visceral myopathy, visceral neuropathy, total intestinal aganglionosis, and some forms of mitochondri- al respiratory chain disorders that affect gastrointestinal motor function.

Epithelial disorders causing intractable secretory diarrhea or failure of absorption are more common in children and include microvillus inclusion disease, tufting enteropathy and autoimmune enteritis.

Tumors

Tumors involving the root of the mesentery are often benign but locally invasive and therefore lethal. The most common of these lesions are desmoid tumors in patients with familial adenomatous polyposis. Only complete resection of the tumor and sacrifice of the intestines can provide a cure. The most common of these lesions are desmoid tumors in patients with Gardeners’ syndrome. This tumor often involves the mesenteric vessels and requires exenteration of the small bowel for complete resection. Since these tumors may involve other foregut organs such as the pancreas, stomach, duodenum or spleen, a multivisceral transplant is required in these patients. Patients with Gardeners’ syndrome usually do not have intestinal failure and are therefore not dependent on parenteral nutrition prior to transplantation.

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Types of Transplants

Intestinal transplantation may be performed as an isolated bowel transplant together with the liver as a combined small-bowel–intestinal transplant or as a multivisceral transplant procedure. The common element of these procedures is transplantation of the jejunoileum, with or without other organs. Soon after transplantation, most surgeons create an ileostomy to allow easy endoscopic surveillance of the graft for abnormalities. We prefer a technique where the dis- tal end of the graft is brought out as a stoma wherev- er it is best situated; the ileum, however, is anastomosed with the remaining colon some 10–20 cm before its entrance into the abdominal wall. Gas- trointestinal continuity is restored simply by stapling and transecting this chimney just distally to the anastomosis, which can then be used as a sentinel grafted tissue. We call this the “Innsbruck stoma.”

Isolated Bowel Transplantation

Isolated intestinal transplantation may be performed with portal or systemic drainage. If the venous out- flow is drained into the portal system via the superi- or mesenteric vein or directly into the portal vein, the transplant is called orthotopic. If, for technical rea- sons, portal drainage cannot be achieved, the superi- or mesenteric vein of the graft is anastomosed to the inferior vena cava; therefore, this type of transplant called heterotopic.

The graft artery is virtually in all cases anastomosed to the infrarenal aorta. In case of a segmental jejunoileum graft from a live donor, recipient iliac vessels are preferentially used for revascularization.

The proximal end of the gut is attached to the first loop of native jejunum or to the third portion of duodenum. Isolated bowel transplant is carried out in patients with intestinal failure but no damage to the liver or other organs.

Combined Liver–Bowel Transplantation

Presently, most centers would transplant a liver and bowel that has an intact mesenteric–portal circulato- ry system en bloc. Therefore, the entire duodenum with a rim of pancreas is left with the graft. Because all the other upper abdominal organs such as the stomach, pancreas, spleen and duodenum are left in place, a portocaval shunt has to be created in order to provide venous drainage for these organs. This technique makes reconstruction of the biliary system unnecessary. Both grafts, however, can be transplant-

ed simultaneously but not as a composite graft.

Combined liver-intestinal transplantation is performed in patients with intestinal failure together with liver damage (considered irreversible), usually due to parenteral nutrition. Severe fibrosis on histol- ogy with bilirubin of more than 10 mg/dl may indi- cate a point of no recovery for liver function.

Multivisceral Transplantation

Multivisceral transplantation refers to en-bloc transplantation of the liver, stomach, pancreaticoduode- nal complex as well as the small bowel, sometimes also including a kidney. Some authors, however, call it a multivisceral transplant if the stomach, pancreas and intestine are transplanted together without the liver. Exenteration of all native viscera which must precede the multivisceral transplants can be techni- cally demanding in patients with portal hypertension due to diffuse splanchnic thrombosis or with severe adhesions after multiple laparotomies. Multivisceral transplantation is performed in patients with either diffuse thrombosis of all splanchnic veins usually associated with coagulation abnormalities, desmoid tumors involving the vascular supply of the liver, pancreas and intestines, or severe motility disorders.

Postoperative Management

Immunosuppression

The enormous amount of lymphatic tissue transplanted together with the bowel, be it in the form of mesenteric lymph nodes or mucosa-associated lymphatic tissue, is responsible for the heightened immunogenicity of an intestinal graft over other solid organs. This is the reason why recipients of a bowel transplant require more immunosuppression as compared to recipients of a kidney or heart transplant.

Following induction with lymphocyte depleting antibodies such as antithymocite globulin, Campath 1H (Genzyme, MA, USA), OKT3 (Ortho Biotech, NJ, USA) or with monoclonal anti-interleukin 2 (IL-2) receptor antibodies. Maintenance immunosuppression is usually based on the calcineurin inhibitor tacrolimus together with other anti-proliferative agents such as mycophenolate mofetil and steroids.

There is a trend to minimize the use of the latter. The combination of tacrolimus and sirolimus seems not to have additional benefit over tacrolimus alone.

Antibody preconditioning seems to allow less potent subsequent maintenance immunosuppression. Anti- bodies, however, are occasionally associated with

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severe adverse reactions caused by cytokine release [14, 15].

Infection Prophylaxis

Decontamination of bacterial and fungal organisms of the intestinal allograft is attempted before pro- curement by administering enteric antibiotics to the donor. Mechanical cleansing has turned out to be impractical in deceased donors. Since the graft is cer- tainly not sterile, broad-spectrum antibiotics together with antifungal agents are given to the recipient during transplantation. Because of the powerful immunosuppression, patients are particularly at high risk for developing viral infections. The matching of allografts for cytomegalovirus is difficult to put into routine practice. Patients are given an antiviral agent (usually ganciclovir) prophylactically. Some centers add to this therapy CMV specific hyperimmunoglob- ulin in recipients of CMV positive grafts. Early diagnosis of CMV infection by a variety of means permits pre-emptive treatment of asymptomatic viremia [14].

Lymphoproliferative disorders related to Epstein- Barr virus mediated B-cell proliferation still repre- sent a major problem after intestinal transplantation.

In recent years, it occurs less frequently after a general reduction of immunosuppression, but it still occurs more often than after most solid organ transplantations. This complication is more common in the pediatric population with de novo EBV infection.

Quantification of the viral load using quantitative polymerase chain reaction allow for the early imple- mentation of therapeutic strategies including changes in the immunosuppression and medication of antiviral therapy. The use of rituximab, a human- ized monoclonal antibody, directed against the CD20 molecule expressed on most B-cell lines and most PTLD clones, has led to a significant improvement in outcome [14].

Graft Monitoring

The enormous antigen load makes an intestinal transplant more prone to rejection than other solid organs. In addition, rejection may impair the absorptive capacity of the graft leading to further under- immunosuppression and aggravation of the rejection process. Therefore, timely diagnosis of any patholo- gy of the graft is essential. For graft monitoring, routine endoscopies and biopsies are performed frequently in the early phase after transplantation.

Starting at three times a week immediately following surgery, the frequency is continuously reduced over

the following weeks. After restoration of the gastrointestinal continuity, biopsies can be obtained from above with the help of an endoscope and from below via a colonoscopic approach. It has to be emphasized, however, that these patients require lifelong monitoring and attention. Therefore, a close relationship between the physician following the patient, the patient himself and the transplant center is essential. Although most rejection episodes are observed during the first year, they may occur any time after transplantation. Rejection is clinically recognized by the development of diarrhea, but other gastrointestinal symptoms such as ileus, emesis, or general malaise may also occur. These symptoms should always prompt endoscopic evaluation of the graft which usually looks grossly normal unless rejection is severe. Therefore, multiple random biopsies should be taken and evaluated by a pathologist experienced with intestinal transplants. It should be recognized that no serum marker accurately diagnoses bowel rejection at present. Even concomitantly transplanted organs such as the liver or a pancreas are not reliable indicators for rejection of the intestinal component of the graft.

Results

Up until March 31, 2005, a total of 1292 intestinal transplants in 1210 patients have been reported at 65 centers to the International Intestinal Registry: 570 were isolated small-bowel transplants, 490 combined liver–small-bowel transplants and 232 were multivisceral transplants. Of the 1292, 772 intestinal transplants were performed in 721 pediatric recipients.

For transplants carried out between 2003 and 2005, graft survival at 1 year was calculated to be around 80% with a patient survival percentage that was somewhat higher. Center experience, patient status prior to transplantation and induction therapy and the type of calcineurin inhibitor had a significant impact on outcome. Sepsis was the leading cause of death. Most survivors have full graft function with no requirement for parenteral nutrition (Figs. 1–4;

Table 1) [1].

We have performed altogether 4 small bowel transplants in three patients suffering from end stage Crohn’s disease. Patient characteristics are summa- rized in Table 1.

Patient #1 was a 35-year-old male who had a com- pletely uneventful postoperative course and is alive and well with good graft function 64 months after transplantation.

Patient #2 was a 37-year-old female who lost the first graft 2 years after transplantation for chronic rejection and underwent re-transplantation in June

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2002. 42 months later she has a well function bowel allograft, but requires intermittent hemodialysis for chronic renal failure.

Patient #3 was a 60-year-old female suffering from endstage intestinal and renal failure due to chronic pyelonephritis und underwent combined small bowel-kidney transplantation on July 7, 2003. She developed early after transplantation a T-cell lymphoma of the intestinal graft requiring resection of the graft. 29 months later she is alive with good renal allograft function.

Recurrence of Crohn’s Disease

Crohn’s disease is considered to be an autoimmune disorder. Therefore, the possibility of recurrence within the graft is an important issue. So far, only two well-documented cases of recurrent disease have been reported. The first case was a 33-year-old female, who underwent small-bowel transplantation in December 1994. After induction with donor bone marrow infusion and with OKT3, immunosuppression consisted of tacrolimus and methylpred- nisolone. Only 7 months post-transplant did the Fig. 1.2003–2005 patient survival according to transplant

type. MVT, multivisceral transplantation; SB/Liver com- bined small bowel-liver transplantation; SBT, small bowel transplantation alone

Fig. 3.Graft survival according to pretransplantation status of the recipients. Home, patients awaiting transplantations at home; hospitalized, patients awaiting transplantation at the hospital

Fig. 4.Graft survival according to centre size: >100, number of transplants more than hundred; 11–100, number of transplants between 11 and 100; 1–10, transplants per cen- tre

Fig. 2.2003–2005 graft survival according to D-transplant type. MVT, multivisceral transplantation; SB/Liver, com- bined small bowel-liver transplantation; SBT, small bowel transplantation alone

p=0.531 p=0.544

p=0.000

p=0.014

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patient develop epithelial granulomas, which is char- acteristic of Crohn’s disease. Resection of a bowel segment became necessary and the graft was eventu- ally removed 17 months after transplantation. Histol- ogy revealed recurrent Crohn’s disease and no signs of chronic or acute rejection [16].

The second case was a 19-year-old male who had an isolated small-bowel transplant in 1994. Mainte- nance immunosuppression included tacrolimus, azathioprine, and prednisolone. At 8 years post-transplantation, recurrent Crohn’s disease was diagnosed that responded to prednisolone [17].

At another center, two patients transplanted for Crohn’s disease were reported to have a significant incidence of granulomas in the graft. Both patients remained asymptomatic for as long as 40 months after transplantation [14]. Even if there are only few reports on disease recurrence, it has to be recognized that Crohn’s disease can recur despite high-level immunosuppression.

Summary

Improved survival after intestinal transplantation mainly due to both patient condition at the time of transplantation and greater center experience, made small-bowel transplantation an attractive prospect for patients with complications on TPN and eventu- ally became an alternative to conservative treatment

of intestinal failure. Patient selection and lifelong surveillance are crucial to the long-term results.

References

1. The International Intestinal Transplant Registry (2005) www.intestinaltransplant.org

2. Lillehei RC, Goot B, Miller FA (1959) The physiologi- cal response of the small bowel of the dog to ischemia including prolonged in vitro preservation of the bowel with successful replacement and survival. Ann Surg 150:543–560

3. Lillehei RC, Idezuki Y, Feemster JA et al (1967) Trans- plantation of stomach, intestine and pancreas: experi- mental and clinical observation. Surgery 62:721–741 4. Fortner JG, Sichuk G, Litwin SD et al (1972) Immuno-

logical responses to an intestinal allograft with HLA identical donor-recipient. Transplantation 14:531–535 5. Cohen Z, Silverman RE, Wassef R et al (1986) Small intestinal transplantation using cyclosporine: report of a case. Transplantation 42:613–621

6. Deltz E, Schroeder P, Gebhardt H et al (1989) Success- ful clinical small bowel transplantation: report of a case. Clin Transplantation 3:89–91

7. Goulet O, Revillon Y, Canioni D et al (1992) Two and one-half-year follow-up after isolated cadaveric small bowel transplantation in an infant. Transplant Proc 24:1224–1225

8. Starzl TE, Kaupp HA Jr (1960) Mass homotransplanta- tions of abdominal organs in dogs. Surg Forum 11:28–29

9. Starzl TE, Rowe MI, Todo S et al (1989) Transplanta- Table 1.Intestinal transplants for Crohn’s disease (Innsbruck experience)

No. Initials Age Gender Underlying disease Date Immuno- Complication Outcome

suppression

1 T.M. 35 M Crohn’s disease, 14.08.98 ATG 0 Well

short-bowel syndrome TAC 64 months

(after two resections) Aza Good intestinal

P graft function

2 H.S. 37 F Crohn’s disease, 10.04.00 Zenapax Bleeding from Graft loss

short-bowel syndrome, TAC anastomosis (22.04.04)

impaired renal function Aza rejection

P

3 H.S. 37 F Loss of 1st intestinal graft 05.06.02 ATG Recurrent Well

TAC line sepsis Good intestinal Aza two acute graft function

P rejections 42 months

on dialysis

4 S.H. 6 F Crohn’s disease, 07.07.03 ATG T-cell Intestinal graft

short-bowel + kidney^a TAC lymphoma removed

syndrome, renal failure Aza intestinal graft 29 months

(pyelonephritis) P Good kidney

function

aThe kidney was transplanted separate from the small bowel

ATG, anti-thymocyte globulin; TAC, tacrolimus; Aza, azathioprine; P, prednisone

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tion of Multiple Abdominal Viscera. JAMA 261(10):1449–1457

10. Williams JW, Sankary HN, Foster PF et al (1989) Splanchnic Transplantation. JAMA 261(10):1458–1462 11. Margreiter R, Königsrainer A, Schmid TH et al (1992) Successful multivisceral transplantation. Transplant Proc 24:1226–1227

12. Grant D, Wall W, Mimeault R et al (1990) Successful small-bowel liver transplantation. Lancet 335:181–184 13. Buchman AL, Scolapio J, Fryer J AGA (2003) Technical review on short bowel syndrome and intestinal transplantation. Gastroenterology 124:1111–1134

14. Fishbein TM, Gondolesi GE, Kaufman SS (2003) Intestinal transplantation for gut failure. Gastroen- terology 124:1615–1628

15. Middleton SJ, Jamieson NV (2005) The current status of small bowel transplantation in the UK and interna- tionally. Gut 54:1650–1657

16. Sustento-Reodica N, Ruiz P, Rogers A et al (1997) Recurrent Crohn’s disease in transplanted bowel.

Lancet 349:688–691

17. Kaila B, Grant D, Pettigrew N et al (2003) Crohn’s disease recurrence in a small bowel transplant. Am J Gas- troenterol 99(1):158–162